9 Acute Care Cardiology_ Critical Care & Fluids

Acute Care Cardiology

© 2008 American College of Clinical Pharmacy

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Acute Care CardiologyJo E. Rodgers, Pharm.D., BCPS (AQ Cardiology)

University of North Carolina School of PharmacyChapel Hill, North Carolina



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Learning Objectives:

1. Formulate treatment strategies for patients with acute decompensated heart failure (ADHF) and formulate an appropriate pharmacotherapeutical regimen for a given case scenario (e.g., warm and wet, cold and dry, other).

2. Create an evidence-based medication regimen for a patient with acute coronary syndrome given a variety of clinical scenarios (e.g., invasive/conservative strategy, upstream antiplatelet therapy).

3. Describe an appropriate treatment strategy for ventricular arrhythmias using evidence-based medicine.

4. Prepare a treatment strategy for a newly diagnosed patient with idiopathic pulmonary arterial hypertension (PAH).

5. Develop an appropriate pharmacological and monitoring plan for antihypertensive drug therapy for managing hypertensive emergencies.

Self-Assessment Questions:Answers to these questions may be found at the end of this chapter.

1. A.A. is a 25-year-old woman with a new diagnosis of idiopathic PAH. Her home drugs include warfarin 5 mg/day, furosemide 60 mg 2 times/day, and bosentan 62.5 mg 2 times/day. Which one of the following is the best contraceptive strategy for this patient?A. Estrogen-progesterone oral contraceptive.B. Injectable hormonal contraceptive.C. Any hormonal contraceptive and barrier

methods.D. Barrier method only.

2. F.F. is a 64-year-old man with New York Heart

Association (NYHA) class III heart failure (HF) admitted for increased shortness of breath, dyspnea on exertion, and decreased exercise tolerance. He admits to dietary noncompliance and has indulged in bacon and eggs, popcorn, and french fries in the past 72 hours. His extremities appear well perfused, but he does have 3+ pitting edema in all four extremities. F.F.’s blood pressure (BP) is 115/75 mm Hg. Which one of the following is the most appropriate intravenous

(IV) vasoactive drug to treat this patient if the IV diuretic therapy fails?A. Dobutamine.B. Milrinone.C. Nesiritide.D. IV nitroglycerin.

3. H.E. is a 53-year-old woman admitted to the

hospital after the worst headache she has ever experienced. Her medical history includes exertional asthma, poorly controlled hypertension, and hyperlipidemia. She is drug noncompliant and has not taken her BP drugs, including clonidine, in 4 days. Vital signs include BP 220/100 mm Hg and heart rate (HR) 65 beats/minute. She receives a diagnosis of a cerebrovascular accident and hypertensive emergency. Which one of the following choices is the best management option for this patient’s hypertensive emergency?A. Fenoldopam 0.1 mcg/kg/minute.B. Nicardipine 5 mg/hour.C. Labetalol 0.5 mg/minute.D. Enalaprilat 0.625 mg IV every 6 hours.

4. W.M. is a 69-year-old man who presents to the

hospital with a 3-mm ST-elevation myocardial infarction (MI) within 2 hours of chest pain onset. He is given clopidogrel 300 mg once daily and instructed to chew aspirin 81 mg 4 times/day. Abciximab and unfractionated heparin are initiated as he is being wheeled to the cardiac catheterization laboratory for primary percutaneous coronary intervention (PCI). Four hours after returning to the intensive care unit, a complete blood cell count shows a platelet count of 15 × 103 cells/mm3. Which one of the following choices is the most likely culprit of this patient’s thrombocytopenia?A. Clopidogrel.B. Aspirin.C. Unfractionated heparin.D. Abciximab.

5. The Sudden Cardiac Death in Heart Failure trial evaluated the effi cacy of amiodarone or internal cardioverter-defi brillator (ICD) versus placebo in preventing all-cause mortality in ischemic and non-ischemic NYHA class II and III patients with HF. There was a 7.2% absolute risk reduction and a 23% relative risk reduction in all-cause mortality at 60 months with an ICD versus placebo. What is the number of patients needed to treat with an ICD to prevent one death versus placebo? A. 1.3 patients.B. 4.3 patients.



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C. 13.8 patients.D. 43.4 patients.

6. A.D. is a 52-year-old woman with a history of witnessed cardiac arrest in a shopping mall; she was resuscitated with an automatic external defi brillator device. On electrophysiology study, she is found to have inducible ventricular tachycardia. Which one of the following has signifi cantly decreased the incidence of sudden cardiac death over other therapies in a patient population such as this (secondary prevention)?A. Propafenone.B. Amiodarone.C. ICD.D. Metoprolol.

7. S.V. is a 75-year-old woman with a history of

NYHA class III HF (LV ejection fraction [LVEF] 25%) and multiple non–ST-elevation MIs. She had an episode of sustained ventricular tachycardia during hospitalization for pneumonia. Her QTc interval was 380 milliseconds on the telemetry monitor. Given her comorbidities, what is the most appropriate treatment option for S.V.?A. Procainamide.B. Metoprolol.C. IV magnesium.D. Amiodarone.

8. You are working on a review article on newer

treatment strategies for antiplatelet and anticoagulant therapy during PCI. You want to ensure that you retrieve all relevant clinical trials and related articles on your subject. You have searched MEDLINE and found 42 articles, but a few that you have seen before were not pulled up in a search by Medical Subject Headings. Which one of the following comprehensive databases should be searched next to ensure that you did not miss any key articles?A. International Pharmaceutical Abstracts.B. Iowa Drug Information Service.C. Clin-Alert.D. Excerpta Medica.

9. A physician on your team wants you to “do the

paperwork” regarding an adverse drug reaction (ADR) that a patient on your team experienced caused by nesiritide. The patient had severe hypotension after the initial bolus dose of nesiritide for treatment of decompensated HF, even though his BP was safely in the “normal” range before therapy initiation. The hypotension led to decreased renal perfusion, resulting in

oliguric acute renal failure and subsequent hemodialysis initiation. The patient had no known renal insuffi ciency before developing this complication. Which one of the following statements is correct regarding Joint Commission on Accreditation of Healthcare Organizations requirements for institutional ADR reporting?A. A MedWatch form explaining the scenario

in which the ADR occurred must be completed.

B. I n s t i t u t ions must c rea t e t he i r ow n defi nition of ADR and make sure that practitioners are familiar with it.

C. Hospital practitioners/staff must use the Naranjo Algorithm for assessing the severity

of the ADR.D. Only severe or life-threatening ADRs need

to be reported. 10. Your Pharmacy and Therapeutics Committee

wants you to perform a pharmacoeconomic analysis on a new drug available to treat decompensated HF. This drug works through a specifi c mechanism of action. Unlike other available inotropics (dobutamine and milrinone), which can increase mortality over time, this drug appears to reduce mortality in the long-term setting. However, the price is 10 times higher per day than other available drugs. Your fi ndings will be presented at the next P and T committee meeting to make a formulary decision about which medications to stock in your hospital pharmacy. What type of pharmacoeconomic analysis should be used to determine whether this new drug would be a better formulary choice than currently available products?A. Cost-minimization analysis.B. Cost-effectiveness analysis.C. Cost-benefi t analysis.D. Cost-utility analysis.



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ACUTE DECOMPENSATED HEART FAILUREI.

ADHF may occur because of one of the following: 1. An acute worsening of chronic HF, 2. A new cardiac event (e.g., MI, atrial fi brillation), or 3. An acute massive MI whose initial presentation is severe HF.

Hemodynamic MonitoringA.

Table 1. Hemodynamic Values in Patients with ADHF and Sepsisa

Parameter NormalValue

Typical ADHFValue

Typical SepsisValue

Mean arterial pressure (MAP)(mm Hg)

80–100 60–80 60–80

Heart rate(beats/minute)

60–80 70–90 90–100

Cardiac output (CO)(L/minute)

4–7 2–4 5–8

Cardiac index (CI)(L/minute/m2)

2.8–3.6 1.3–2 3.5–4

Pulmonary capillary wedge pressure (PCWP)(mm Hg)

8–12b 18–30 5–8

Systemic vascular resistance (SVR) (dynes/second/cm−5)

800–1200 1500–3000 300–800

Central venous pressure (CVP) (mm Hg)

2–6 6–15 2–6

aMAP = DBP + 1/3(SBP − DBP) (SBP = systolic blood pressure; DBP = diastolic blood pressure), CI = CO/BSA (BSA = body surface area), SVR = (MAP – CVP)(80)/CO.b15–18 mm Hg often desired/optimal in patients with HF to ensure optimal fi lling pressures.

Hemodynamic equations 1. BP = cardiac output (CO) × systemic vascular resistancea. CO = stroke volume (SV) × HRb.

Parameters infl uencing CO2. Heart ratea.

Also known as chronotropyi. Controlled by autonomic nervous systemii.

Stroke volumeb. Amount of blood ejected by the heart during systolei. Controlled by four factors:ii.

Inotropy—ventricular contractility or “squeezing” force.(a) Afterload—resistance or pressure the left ventricular (LV) pumps against to eject (b) blood into the aorta; estimated by the systemic vascular resistance.Preload—amount of tension applied to the LV before contraction; equivalent to (c) LF end diastolic volume; estimated by the pulmonary capillary wedge pressure.Lusitropy—diastolic relaxation of the ventricle.(d)



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Forrester hemodynamic classifi cation3.

Figure 1. Forrester Hemodynamic Classifi cationReprinted with permission from the American Medical Association. Nohria A, Lewis E, Warner Stevenson L. Medical management of advanced heart failure. JAMA 2002;287:628–40.

Clinical Presentation of ADHFB.

Table 2. Signs and Symptoms of ADHF

Congestion (Elevated Pulmonary Capillary Wedge Pressure)

Hypoperfusion (Reduced CO)

Dyspnea on exertion or at restOrthopnea, paroxysmal nocturnal dyspnea

Peripheral edemaRales

Early satiety, nausea/vomitingAscites

Hepatomegaly, splenomegalyJugular venous distention

Hepatojugular refl ux

FatigueAltered mental status or sleepiness

Cold extremitiesWorsening renal function

Narrow pulse pressureHypotension

Hyponatremia

Guideline Recommendations for ADHFC.

Table 3. Level of Evidence and Class of Effect for ADHF Guidelines

Level of EvidenceLevel A Randomized, controlled clinical trialsLevel B Case-control or cohort studies (post hoc, subgroup analysis, meta-analysis)Level C Expert opinion or observational studiesClass of effect“Recommended” for routine clinical practice in all patients“Should be considered” for the majority of patients“May be considered” for individual patients“Is not recommended” for any patient

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2

Category I: Normal Warm and dry

Category II: Pulmonary congestion Warm and wet

Category III: Hypoperfusion Cold and dry

Category IV: Pulmonary congestion and hypoperfusion Cold and wet

Cardiac index (L/minute)

PCWP

10 15 18 20 25

2.2

3

4

mm Hg



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Drug Therapy RecommendationsD.

Table 4. Overview of ADHF Guideline Recommendations

Diuretic Therapy1. Recommended as an IV loop diuretic for patients admitted with fl uid overload (LOE = B).2. When response to diuretics is minimal, the following options should be considered:

a. Fluid and sodium restriction, b. Initiation of increased doses or continuous infusion of loop diuretic, c. Addition of a second type of diuretic (metolazone or chlorothiazide), ord. Ultrafi ltration.

(LOE = C).Inotropic Therapy

1. May be considered to relieve symptoms and improve end-organ function in patients with diminished peripheral perfusion or end-organ dysfunction (low output syndrome), particularly if:

a. marginal systolic blood pressure (less than 90 mm Hg), b. symptomatic hypotension despite adequate fi lling pressure, or c. unresponsive to, or intolerant of, IV vasodilators (LOE = C)

2. May be considered in similar patients with evidence of fl uid overload if they respond poorly to IV diuretics or manifest diminished or worsening renal function (LOE = C).

Vasodilator Therapy1. May be considered in addition to IV loop diuretics to rapidly improve symptoms in patients

without symptomatic hypotension (LOE = B).2. May be considered in patients with persistent symptoms despite maximal loop diuretics and

oral drug therapy (LOE = C).3. When adjunctive therapy is required in addition to loop diuretics, IV vasodilators should be

considered over inotropic drugs (LOE = B).Invasive Hemodynamic Monitoring

1. Routine use of hemodynamic monitoring with invasive IV lines (e.g., Swan-Ganz pulmonary artery catheters) is not recommended (LOE = A).

Diuretic MedicationsE. Loop diuretics (ascending limb of loop of Henle)1.

Most widely used and most potent, effective at low glomerular fi ltration rate (less than 30 a. mL/minute)Furosemide (Lasix) most commonly usedb.

Thiazides (distal tubule)2. Relatively weak diuretics when used alone, not effective at low glomerular fi ltration ratea. Reserved for add-on therapy in patients refractory to loop diureticsb.

Therapy for patients with diuretic resistance3. Increase dose rather than frequency of loop diuretic. a.

(Note: Ceiling effect at approximately 160–200 mg IV furosemide.)Add a second diuretic with a different mechanism of action.b.

Hydrochlorothiazide 12.5–25 mg PO daily, metolazone 2.5–5 mg PO dailyi. Chlorothiazide 250–500 mg IV daily; consider if gastrointestinal edema (poor PO ii. absorption)

Continuous infusion of loop diuretic c. Furosemide 0.1 mg/kg/hour IV doubled every 4–8 hours to a maximum of 0.4 mg/kg/i. hour

Adverse effects: electrolyte depletion (potassium and magnesium), worsening renal function4.



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Inotropic MedicationsF.

Table 5. Inotropic Therapy for ADHF

Dobutamine (Dobutrex) Milrinone (Primacor)

Mechanismof action

β1-agonist: stimulates AC to convert ATP to cAMP to ↑ CO; slight peripheral vasodilation.

PDE inhibitor: inhibits cAMP breakdown in heart to ↑ CO and in vascular smooth muscle to ↓ SVR.

Clinical effects Positive inotropic, chronotropic, and lusitropic effects

Positive inotropic and lusitropic effects, no chronotropic effects

Indication ADHF short-term management—effective in “cold and wet” exacerbations with hypoperfusion and congestion

Dosing Start at 2.5–5 mcg/kg/minute; may titrate up to maximum 20 mcg/kg/minute

50 mcg/kg IV bolus for 10 minutes, then 0.375–0.75 mcg/kg/minute

Typical dose 5 mcg/kg/minute fi xed infusion No bolus, 0.1–0.5 mcg/kg/minute fi xed infusionHalf-life 2 minutes 1 hour, prolonged to 2–3 hours if CrCl < 50 mL/

minElimination Hepatically metabolized (inactive) and renally

eliminated90% renal

Adverse effects Proarrhythmia, tachycardia, hypokalemia, myocardial ischemia, and tachyphylaxis (> 72 hours), possible increased mortality with long-term use

Proarrhythmia, hypotension (avoid bolus), tachycardia, < 1% thrombocytopenia, possible increased mortality with long-term use

Other comments Recommended if hypotensive. Recommended if receiving a β-blocker.

AC = adenylate cyclase; ADHF = acute decompensated heart failure; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; CO = cardiac output; CrCl = creatinine clearance; PDE = phosphodiesterase; SVR = systemic vascular resistance.



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Vasodilator TherapyG.

Table 6. Vasodilator Therapy for ADHF

Sodium Nitroprusside (Nipride)

Nesiritide (Natrecor)

IV Nitroglycerin

Mechanism of action

Nitric oxide–induced stimulation of GC to convert GTP to cGMP.

Recombinant B-type natriuretic peptide binds to natriuretic peptide receptor A to stimulate guanylate cyclase and production of cGMP. Natriuretic mechanism unknown.

Combines with sulfhydryl groups in vascular endothelium to create s-nitrosothiol compounds, which mimic nitric oxide’s stimulation of guanylate cyclase and production of cGMP.

Clinical effects Balanced arterial and venous vasodilator

Hemodynamic effects: ↓ PCWP and SVR, minimal changes in HR or CINeurohormonal effects: ↓ NE, ET-1, and aldosteroneNatriuretic effects: ↑ urine output and sodium excretion

Preferential venous vasodilator > arterial vasodilator, arterial vasodilation at high doses

Indication “Warm and wet” ADHF, hypertensive crises

“Warm and wet” ADHF, alternative to inotropes in “cold and wet” ADHF

“Warm and wet” ADHF, ACS, or hypertensive crises

Dosing 0.3–0.5 mcg/kg/minute, ↑ by 0.5 mcg/kg/minute up to 3 mcg/kg/minute

2 mcg/kg bolus, 0.01 mcg/kg/minute, ↑ by 0.005 mcg/kg/minute up to 0.03 mcg/kg/minute

5 mcg/minute, ↑ by 5 mcg/minute up to 200 mcg/minute

Typical dose 0.5–1 mcg/kg/minute 0.01 mcg/kg/minute fi xed infusionMay omit bolus if low SBP

25–75 mcg/minute, titrated to response

Half-life < 10 minutes 20 minutes 1–4 minutesElimination Cyanide hepatically

metabolized, thiocyanate renally excreted

Natriuretic peptide receptor C (no renal/hepatic adjustment)

Inactive metabolites in urine

Adverse effects Hypotension, cyanide or thiocyanate toxicity

Primarily hypotension (up to 1 hour), tachycardia (less than inotropes)

Hypotension, refl ex tachycardia, headache, tachyphylaxis

ACS = acute coronary syndrome; ADHF = acute decompensated heart failure; CI = cardiac index; cGMP = cyclic guanine monophosphate; ET = endothelin; GC = guanylate cyclase; guanosine triphosphate = GTP; HR = heart rate; NE = norepinephrine; PAC = pulmonary artery catheter; PCWP = pulmonary capillary wedge pressure; SBP = systolic blood pressure; SVR = systemic vascular resistance.



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Patient Cases1. D.D. is a 72-year-old man admitted to the ward team for HF decompensation. D.D. notes progressively

increased dyspnea on exertion (now 10 feet, previously 30 feet) and orthopnea (now four pillows, previously two pillows), increasing bilateral lower extremity swelling (3+), a 13.6-kg weight gain in the past 3 weeks, and dietary noncompliance. He has a history of idiopathic dilated cardiomyopathy (LVEF 25%, NYHA class III), paroxysmal atrial fi brillation, and hyperlipidemia. Pertinent laboratory fi ndings: B-type natriuretic peptide 2300 pg/mL (0–50 pg/mL), potassium+ 4.9 mEq/L, blood urea nitrogen (BUN) 22 mg/dL, serum creatinine (SCr) 1 mg/dL, aspartate aminotransferase 40 IU/L, alanine aminotransferase 42 IU/L, international normalized ratio 1.3, partial thromboplastin time 42 seconds, BP 108/62 mm Hg, and HR 82 beats/minute. Home drugs include carvedilol 12.5 mg 2 times/day, lisinopril 40 mg/day, furosemide 80 mg 2 times/day, spironolactone 25 mg/day, and digoxin 0.125 mg/day. Which one of the following is the best option for treating his ADHF?A. Carvedilol 25 mg 2 times/day. B. Nesiritide 2 mcg/kg bolus, then 0.01 mcg/kg/minute. C. Furosemide 120 mg IV 2 times/day. D. Milrinone 0.5 mcg/kg/minute.

2. After being started on IV loop diuretics and metolazone 2.5 mg with only minimal urine output and rising creatinine (CrCl now 30 mL/minute), he is transferred to the coronary care unit for further management of diuretic-refractory decompensated HF. His carvedilol dose is now 6.25 mg 2 times/day, and lisinopril and spironolactone are being withheld. His BP is 110/75 mm Hg, and his HR is 75 beats/minute. How else should his decompensated HF be treated? A. Nesiritide 2 mcg/kg bolus, then 0.01 mcg/kg/minute. B. Sodium nitroprusside 0.3 mg/kg/minute. C. Dobutamine 5 mcg/kg/minute. D. Milrinone 0.5 mcg/kg/minute.

3. D.D. initially responds with 2 L of urine output overnight and weight decreased by 1 kg the next day. However, by day 5, his urine output has diminished again, and his SCr has risen to 4.3 mg/dL. He was drowsy and confused this morning during rounds. His extremities are cool and cyanotic, BP is 102/58 mm Hg, and HR is 98 beats/minute. It is believed that he is no longer responding to his current regimen. A Swan-Ganz catheter is placed to determine further management. Hemodynamic values are cardiac index 1.5 L/minute/m2, systemic vascular resistance 2650 dynes/cm−5, and pulmonary capillary wedge pressure 30 mm Hg. Which of the following is the most appropriate medication based on his current symptoms? A. Milrinone 0.2 mcg/kg/minute. B. Dobutamine 5 mcg/kg/minute. C. Nitroglycerin 20 mcg/minute. D. Phenylephrine 20 mcg/kg/minute.

ARRHYTHMIASII.

Guideline Recommendations for ArrhythmiasA.

Table 7. Level of Evidence and Classifi cation for Arrhythmia Guidelines

Level of EvidenceLevel A Multiple (3–5) clinical trials or registries or meta-analyses.Level B Limited (2–3) clinical trials or registries; generally, a single randomized clinical trial or several

non-randomized trials.Level C Few (1–2) clinical trials/registries; may be only expert opinion, case series, or standard care.



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Table 7. Level of Evidence and Classifi cation for Dysrhythmia Guidelines (continued)

Class of EffectClass I Agreement that benefi t strongly outweighs the risk of the procedure or treatment, and it should be

performed because of its effi cacy.Class IIa May be confl icting evidence or diverging opinions, but the benefi t is greater than the risk; it is

reasonable to consider the procedure or treatment because of its effi cacy.Class IIb May be confl icting evidence or diverging opinions, but benefi t outweighs the risk; procedure or

treatment may be considered, but additional data are needed.Class III Agreement that the risk outweighs the benefi t; procedure or treatment is not effective and should

not be performed and may be harmful.Indeterminate An area of ongoing research but no defi nitive recommendations for or against.

TerminologyA. Table 8. Common Arrhythmia Terms and Defi nitions

Term Defi nitionQT interval Time from beginning of ventricular depolarization to end of ventricular repolarizationQTc interval QT interval corrected for heart rate (HR)Supraventricular arrhythmias

Typically narrow QRS complex arrhythmias—atrial fi brillation, atrial fl utter, multifocal atrial tachycardia (MAT), paroxysmal supraventricular tachycardia, including atrial-ventricular nodal reentrant tachycardia (AVNRT) and AV reentrant tachycardia (AVRT)

Ventricular arrhythmias

Typically wide QRS complex arrhythmias—ventricular tachycardia (VT)

Ventricular tachycardia

At least three consecutive premature ventricular contractions at a rate > 100 beats/minute - monomorphic ventricular tachycardia and polymorphic ventricular tachycardia (e.g., torsade de pointes)

Nonsustained ventricular tachycardia

Spontaneously terminates in less than 30 seconds

Sustained ventricular tachycardia

Lasts > 30 seconds or requires cardioversion because of hemodynamic instability

Torsade de pointes Induced primarily when QTc interval > 500 millisecondsSudden cardiac death Rapid death caused by pulseless VT or ventricular fi brillation (VF), pulseless electrical

activity, or asystoleProarrhythmic events New type of arrhythmia or worsening of existing arrhythmia after initiation of an

antiarrhythmic medication (drug-induced), most commonly torsade de pointesStructural heart disease

HF, status post-acute myocardial infarction, valvular heart disease, left valvular (LV) hypertrophyNote: Class IA and IC medications are contraindicated because of increased proarrhythmia risk.

Defi brillation threshold

Energy requirement (joules) necessary for defi brillation of an arrhythmia into sinus rhythm



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Table 9. Antiarrhythmic Drug Effects

Na+ channel blockersClass IAClass IBClass IC

Quinidine, procainamide, disopyramideLidocaine, mexiletinePropafenone, fl ecainide, moricizine

ECG Effect↑ QRS, QT ↑ QRS, ↑ QT↑↑ QRS

Primary EffectSlows depolarizationSlows depolarizationSlows depolarization

β-blockersClass II Metoprolol, esmolol, atenolol ↑ PR

Slows AV nodal conduction

K+ channel blockersClass III

Amiodarone, sotalol, dofetilide, ibutilide ↑ QT Slows repolarization

Ca2+ channel blockersClass IV

Diltiazem, verapamil ↑ PR Slows AV nodal conduction

AV = atrioventricular; ECG = electrocardiography; K+ = potassium plus.

Table 10. Antiarrhythmic Drug Properties

Drug Mechanism of Action, Pharmacokinetics Adverse Effects, and Drug Interactions

Dosing by Indication

Quinidine MOA: strong vagolytic and anticholinergic properties, Na+ channel blockadeAEs: Nausea, vomiting, diarrhea 30%,use-dependent proarrhythmia fi rst 72 hours (torsade de pointes), “cinchonism” (CNS symptoms, tinnitus), and HF (causes exacerbation)DI: warfarin, digoxin

Avoid use for atrial fi brillation cardioversion caused by GI AEsAfi b maintenance: sulfate: 200–400 mg every 6 hoursGluconate: 324 mg every 8–12 hours

Procainamide MOA: Na+ channel blockade AEs: decrease dose in renal and liver dysfunction (active metabolite NAPA accumulates),lupus-like syndrome in 30% of patients if > 6 months treatment, hypotension (IV): 5%, and HF (causes exacerbation)

Afi b conversion (IV): 1 g for 30 minutes, followed by 2 mg/minute over one hour (effi cacy 51% at 1 hour)Afi b maintenance: Not recommendedVT (preserved LVEF > 40%): 20 mg/minute loading infusion until 17 mg/kg, arrhythmia ceases, or QRS widens > 50%VT maintenance: 2–4 mg/minute

Disopyramide MOA: potent Na+ and M2 blockade; strong negative inotropic effectAEs: anticholinergic side effects (urinary retention, constipation, tachycardia, dry eyes), heart block and HF (causes exacerbation)CI: glaucomaDI: 3A4 inhibitors

Afi b conversion: 200 mg PO q4h (maximum 800 mg)Maintenance: 400–600 mg/day in divided doses

Lidocaine MOA: inactive Na+ channel blockerDose adjust in HF, liver failure, elderly patients, renal dysfunctionAEs: CNS symptoms, perioral numbness, seizures, confusion, blurry vision, tinnitus CI: third-degree AV heart block

VT/VF conversion:pulseless VT/VF or stable VT withLVEF > 40%: 1–1.5 mg/kg IVP × 1; repeat 0.5–0.75 mg/kg every 3–5 minutes (maximum 3 mg/kg)LVEF < 40%: 0.5–0.75 mg/kg IVP; repeat 0.5–0.75 mg/kg every 3–5 minutes (maximum 3 mg/kg)VT maintenance: 1–2 mg/minute

Mexiletine MOA: inactive Na+ channel blocker CI: third-degree AV heart block

VT maintenance: 200–300 mg every 8 hours



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Propafenone MOA: Na+ and Ca2+ channel blocker, ß-blockerAEs: metallic taste, dizzinessCI: HF (causes exacerbation), liver disease DI: digoxin ↑ by 70%; warfarin ↑ by 50%

Afi b conversion: 600 mg PO × 1 (effi cacy 45% at 3 hours)Afi b maintenance: 150–300 mg every 8–12 hours

Flecainide MOA: strong Na+ channel blockade; vagolytic, anticholinergic, and negative inotropic effectsAEs: dizziness, tremorCI: HF (causes exacerbation), CADDI: digoxin ↑ by 25%

Afi b conversion: 300 mg PO × 1 (effi cacy 50% at 3 hours)Afi b maintenance: 50–150 mg every 12 hours

Amiodarone MOA: sodium, K+, calcium channel blocker, β-blockerAEs: pulmonary fi brosis 3%–17%, hyperthyroidism 3%; hypothyroidism 30%–50%; neurologic toxicity 20%–40%; blue-gray skin 15%; torsade < 1%; AV block 14%; hypotension, phlebitis (IV)CI: iodine hypersensitivity, hyperthyroidism, heart blockDI: warfarin, digoxin, HMG-CoA-reductase inhibitors, phenytoin ↑ ≥ 50% (among others)

Inhibits cytochrome P450 (CYP) metabolism: • CYP2C9, CYP2D6, and CYP3A4

Inhibits P-glycoprotein in GI tract to increase • digoxin bioavailability

• Maximum simvastatin dosage 20 mg/day*Does not increase mortality in patients with HF.

Afi b conversion: IV: 5–7 mg/kg over 30–60 minutes then 1.2–1.8 g/day continuous IV or in divided oral dose until 10 g PO/5gIVPO: 400 mg 3 times/day for 5–7 days (until 10 g)Afi b maintenance:200–400 mg/dayPulseless VT/VF conversion:300 mg IVP × 1 in 20 mL D5W; repeat 150 mg IVP every 3–5 minutes (ARREST trial)Or 5 mg/kg IVP in 30 mL D5W; repeat 2.5 mg/kg (ALIVE trial)Stable VT: 150 mg IVP × 1 over 10 minutesVT/VF maintenance: 1 mg/minute × 6 hours, followed by 0.5 mg/minute(maximum 2.2 g/day)

Sotalol MOA: K+ channel blocker, also β1- and β2-receptor blocking propertiesAEs: HF exacerbation, bradycardia, wheezing; 3%–8% torsade within 3 days of initiation; bronchospasmCI: baseline QTc > 440 milliseconds or CrCl < 40 mL/minute in atrial arrhythmias

*Double dose every 3 days; NTE QTc > 500 milliseconds; hospitalization mandatory for initiation

Not effective for conversionAfi b maintenance: CrCl80 mg 2 times/day > 60 mL/minute80 mg/day 40–60 mL/minuteContraindicated < 40 mL/minute

VT maintenance: CrCl80 mg 2 times/day > 60 mL/minute80 mg/day 30–60 mL/minute80 mg every 36–48 hours 10–30 mL/minute80 mg > every 48 hours < 10 mL/minute

Dofetilide MOA: Pure K+ channel blocker onlyAEs: torsade (0.8%; 4% if no renal adjust), dizziness, diarrheaDI: 3A4 inhibitors or drugs secreted by kidney: cimetidine, ketoconazole, verapamil, trimethoprim, prochlorperazine, megestrol and hydrochlorothiazideCI: baseline QTc > 440 milliseconds or CrCl < 20 mL/minute*Does not increase mortality in patients with HF.

Afi b conversion: CrCl 500 mcg PO 2 times/day > 60 mL/minute250 mcg PO 2 times/day 40–60 mL/minute125 mcg PO 2 times/day 20–40 mL/minute(effi cacy 12% at 1 month)

Afi b maintenance:Titrate upward based on QTc NTE 500 milliseconds or > 15% ↑ in QTc after initial 5 doses (hospitalization mandatory!)



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Ibutilide MOA: K+ channel blocker; also Na+ and β-blocking propertiesAEs: 8% torsade risk; requires ECG monitoring during and 4 hours after cardioversionDI: 3A4 inhibitors or QT prolonging drugsCI: receiving concomitant antiarrhythmics or QTc > 440 milliseconds before initiation

Afi b conversion: 1 mg × 1 IV (≥ 60 kg) or 0.01 mg/kg (< 60 kg), repeat in 10 minutes if ineffective(effi cacy 47% at 90 minutes)

Slightly more effective for converting atrial fl utter than atrial fi brillation

AE = adverse effect; Afi b = atrial fi brillation; ALIVE = amiodarone versus lidocaine in prehospital refractory ventricular fi brillation evaluation; ARREST = amiodarone out of hospital resuscitation of refractory sustained ventricular tachycardia; CAD = coronary artery disease; CI = contraindications; CrCl = creatinine clearance; CNS = central nervous system; ECG = electrocardiogram; DI = drug interactions; GI = gastrointestinal; HF = heart failure; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; IV = intravenous; IVP = intravenous push; K+ = potassium plus; MOA = mechanism of action; NTE = not to exceed; VF = ventricular fi brillation; VT = ventricular tachycardia.

Acute TachyarrhythmiasC. Tachycardia with a pulse1.

Give oxygen; assess airway, breathing, and circulation and treat reversible causes.a. If b. unstable, administer immediate direct current cardioversion (DCC).If c. stable, determine whether QRS complex is narrow or wide.

Narrow complex tachycardia (usually i. atrial arrhythmias).Regular rhythm(a)

Supraventricular tachycardia (SVT) or sinus tachycardia likely(1) Vagal maneuvers (class I, level of evidence [LOE B](a) ) and/or adenosine 6 mg IVP, followed by 12 mg IVP (may repeat 1 time) (class I, LOE A)

Use adenosine cautiously in severe coronary artery disease (CAD) (i) because it may produce atrial fi brillation and induce myocaridal ischemia.

Table 11. Management of Supraventricular Tachycardia

Scenario ManagementIf converts, likely AT, AVNRT, AVRT, or WPWIf AVNRT Any of the following depending on clinical presentation:

Catheter ablation-OR-Verapamil, diltiazem, β-blockers, sotalol, amiodarone-OR-Flecainide, propafenonea

-OR-If infrequent, no therapy or pill-in-the-pocket(LOE varies depending on clinical presentation)

If WPW Same as above; however, AVOID verapamil, diltiazem, and digoxinIf persistent with AV block, likely atrial fl utter or ATIV ibutilide,b procainamide, or fl ecainide plus AV nodal blocking agents or overdrive pacing/DCC

aRelatively contraindicated for patients with coronary artery disease, LV dysfunction, or other signifi cant heart disease., bIbutilide is especially effective if atrial fl utter but should not be used if LVEF < 30% because of risk of polymorphic ventricular tachycardia., AT = atrial tachycardia; AV = atrioventricular; AVNRT = atrioventricular nodal reciprocating/reentrant tachycardia; AVRT = atrioventricular reciprocating/reentrant tachycardia; DCC = direct current cardioversion; SVT = supraventricular tachycardia; WPW = Wolff-Parkinson-White [syndrome].



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Irregular rhythm(b) Atrial fi brillation or atrial fl utter likely(1)

Rate control versus rhythm control(a) Rate control recommended for patients with persistent or permanent (i) atrial fi brillation (class I, LOE B).If hemodynamically unstable, DCC recommended (class I, LOE C).(ii)

Table 12. Management of Atrial Fibrillation

Type ManagementNewly Discovered AF

Paroxysmal No therapy needed unless symptoms, AC as neededPersistent If accepted as permanent, AC and RC as needed; otherwise, consider AAD with DCC

Recurrent AFParoxysmal If minimal or no symptoms, AC and RC as neededPersistent If disabling symptoms, use anticoagulation and rate control as needed with AAD (ablation if AAD fails)

Permanent AFAC and RC as needed

AAD = antiarrhythmic drug; AC = anticoagulation; AF = atrial fi brillation; DCC = direct current cardioversion; RC = rate control.

Table 13. Rate Control and Rhythm ControlRate Control

General presentation β-blockers or nondihydropyridine calcium channel blockers (diltiazem, verapamil) (class I, LOE B)

If HF and no accessory pathway present Digoxina (class I, LOE B) or amiodarone (class IIa, LOE C)If accessory pathway present Amiodarone (class IIa, LOE C)

Rhythm ControlUnstable and known duration < 48 hours Before DCC, IV UFH immediately beforehand

DCC (class I, LOE C)Unstable and duration unknown or > 48 hours

Before DCC, TEE to rule out thrombus + IV UFH before DCC if possibleDCC (class I, LOE C)

Stable and duration unknown or > 48 hours

Before DCC, RC + warfarin (international normalized ratio 2–3) 3–4 weeks before and 4 weeks after (class I, LOE C)If AF for up to 7 days, either elective DCC or chemical cardioversionb

Flecainide, dofetilide, propafenone, ibutilide (class I, LOE A) or - amiodarone (class IIa, LOE A) Digoxin and sotalol may be harmful when used for - pharmacological cardioversion of AF and are not recommended (class II, LOE A).

If AF more than 7 days, either elective DCC or chemical cardioversion Dofetilide (class I, LOE A), amiodarone, ibutilide (class IIa, LOE A)- b

aIf paroxysmal AF, avoid digoxin (class III, LOE B), bQuinidine, procainamide, disopyramide, and dofetilide should NOT be started out of hospital for conversion of AF to sinus rhythm (class III, LOE B).AF = atrial fi brillation; DCC = direct current cardioversion; IV = intravenous; LOE = level of evidence; RC = rate control; TEE = transesophageal echocardiograph; UFH = unfractionated heparin.

ii. Wide complex tachycardia (usually ventricular arrhythmias)Ventricular tachycardia or unknown mechanism(a)



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IV procainamide, amiodarone (class I, LOE B), or lidocaine (class IIb, B)(1) Amiodarone preferred if LV dysfunction or signs of HF (class I, LOE B)(2) Prepare for synchronized DCC if drug therapy fails.(3)

Defi nite supraventricular tachycardia (see narrow complex tachycardia)(b) If supraventricular tachycardia and bundle branch block (BBB), treat as (1) supraventricular tachycardia (see above).If pre-excited supraventricular tachycardia, IV, ibutilide or procainamide (2) (class I, LOE B) or DCC (class I, LOE C)

Premature ventricular contractions2. Avoid fl ecainide, encainide, and moricizine (class IC) post MI due to increased mortality.a. ββ. -blockers are useful for controlling symptomatic premature ventricular contractions.

Ventricular tachycardia3. Nonsustained ventricular tachycardiaa.

If i. asymptomatic, no therapy required.If ii. symptomatic, β-blockers.

If unresponsive, use amiodarone or sotalol.(a) Sustained ventricular tachycardia (QTc not prolonged)b.

Table 14. Management of Sustained Ventricular Tachycardia

Presentation ManagementStable Sustained Monomorphic VT

General presentation Procainamide IV (class IIa, LOE = B)Associated with AMI Lidocaine IV (class IIb, LOE = C)Associated with CAD and idiopathic VT (Repetitive)

Amiodarone IV, β-blockers, procainamide IV (class IIa, LOE C) (Note: avoid procainamide if LV disfunction)

Unstable Sustained Monomorphic VTGeneral presentation DCC (class I, LOE = C)Refractory to DCC Amiodarone 150 mg IV for 10 minutes (class IIa, LOE = C)Recurrent with procainamide Amiodarone 150 mg IV for 10 minutes (class IIa, LOE = C)AMI = acute myocardial infarction; CAD = coronary artery disease; DCC = direct current cardioversion; IV = intravenous; LOE = level of evidence; VT = ventricular tachycardia.

Polymorphic ventricular tachycardia (prolonged QTc)c. Torsade de pointesi.

Induced primarily when QTc interval more than 500 milliseconds(a) Withdrawal of any offending medications that may induce torsade de pointes and (b) correction of electrolyte abnormalities (low Mg2+ or potassium+) is recommended (class I, LOE = A).

Class I and class III antiarrhythmic drugs(1) Drug interactions via cytochrome P450 3A4 metabolized drugs: azole (2) antifungals, erythromycin, clarithromycin, or QT prolonging drugs: pentamidine, haloperidol, ziprasidone, droperidol, sulfamethoxazole/trimethoprim, promethazine.



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Table 15. Management of Torsade de Pointes

Presentation ManagementUnstable DCC with sedation (class I, LOE = B)Few episodes of TdP with prolonged QT IV Mg2+ 1–2 g IVP (maximum 16 g/24 hoursa) (class IIa, LOE = B)Heart block and symptomatic bradycardia Pacemaker placement (class I, LOE A)Recurrent β-blockers (especially if ischemia suspected) (class I, LOE = B)If associated with AMI Lidocaine 1–1.5 mg/kg IVP (class IIb, LOE = C)

aIf normal renal function. AMI = acute myocardial infarction; DCC = direct current cardioversion; IVP = intravenous push; LOE = level of evidence; TdP = torsade de pointes.

Pulseless ventricular tachycardia or fi brillation algorithmd. Defi brillate and perform cardiopulmonary resuscitation.i. Epinephrine 1 mg IV/IO (intravenously/intraosseous)ii. every 3–5 minutes during cardiopulmonary resuscitation (evidence = IIb) or vasopressin 40 U IV/IO × 1 dose to replace fi rst or second epinephrine dose during cardiopulmonary resuscitation (evidence = indeterminant).Amiodarone 300 mg IV/IO × 1 (LOE = IIb), additional 150 mg IV/IO × 1 can be iii. administered.

Consider if pulseless ventricular tachycardia/ventricular fi brillation persists after (a) two or three shocks, cardiopulmonary resuscitation, and vasopressor therapy.Give during cardiopulmonary resuscitation to facilitate circulation of drug before (b) or after shock.

Lidocaine 1–1.5 mg/kg intravenous push (IVP) second line to amiodarone (class iv. indeterminant); may repeat with 0.5–0.75 mg/kg IV/IO every 5–10 minutes (maximum 3 mg/kg) and continue with 1–4 mg/minute infusion if return of spontaneous circulation with lidocaine boluses.

Pulseless electrical activity or asystole algorithm4. Cardiopulmonary resuscitation (no defi brillation).a. Epinephrine 1 mg IV/IO every 3–5 minutes or vasopressin 40 U IV/IO (1 dose to replace b. the fi rst or second epinephrine doses) (class IIb).Atropine 1 mg every 3–5 minutes × 3 (total 0.04 mg/kg) if HR < 60 beats/minute for c. asystole or slow pulseless electrical activity (class indeterminant).

Primary Prevention of Sudden Cardiac DeathD. ICD therapy is recommended to reduce total mortality due to sudden cardiac death in patients 1. with LV dysfunction caused by prior MI (more than 40 days post-MI), have LVEF 30%–40% or less, are NYHA class II or III, are receiving optimal chronic medications, and have reasonable survival expectation (class I, LOE = A).

Secondary Prevention of Sudden Cardiac DeathE. ICD implantation is a reasonable treatment of recurrent sustained ventricular tachycardia in 1. post-MI patients with normal or near-normal LVEF who are on optimal medications and have a reasonable survival expectation of more than 1 year (class IIa, LOE = C).Contraindications: evolving acute MI with ventricular tachycardia, acute ventricular tachycardia 2. after coronary artery bypass graft, ventricular fi brillation caused by atrial fi brillation, terminal illness, psychiatric disorder, severe NYHA class IV (nontransplantable) HF



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Table 16. Alteration of Defi brillation Threshold

Threshold Alteration Medications CommentsIncrease threshold Amiodarone, lidocaine, and mexiletine Reprogram ICD, increased energy (joules) requiredDecrease threshold Sotalol May decrease energy needed for DCCNo change β-blockers, class IA —DCC = direct current cardioversion; ICD = internal cardioverter-defi brillator.

Special Patient PopulationsF. Heart failure1.

Dofetilide—neutral effect on mortalitya. Acute MI2.

Encainide, fl ecainide, moricizine—increases mortality when used for a. premature ventricular contraction control post-MIClass IA medications—increase mortality in post-MI survivorsb. Dofetilide—neutral effect on mortality in LV dysfunction post-MIc.

ACUTE CORONARY SYNDROMESIII.

See “Levels of Evidence and Classes of Recommendations from the Arrhythmias” section.A.

Unstable Angina and Non–ST-Elevation MIB.

Patient Cases4. C.D. is a 68-year-old man admitted after an episode of syncope with a presyncopal syndrome of seeing black

spots and dizziness before passing out. Telemetry monitor shows sustained ventricular tachycardia, however this patient still has a pulse and his BP is 100/64. His medical history includes HF NYHA class III, LVEF 30%, MI × 2, hypertension × 20 years, left-ventricular hypertrophy, diabetes mellitus, and diabetic nephropathy. His current drugs include lisinopril 5 mg/day, furosemide 20 mg 2 times/day, metoprolol 25 mg 2 times/day, digoxin 0.125 mg/day, glyburide 5 mg/day, and aspirin 325 mg/day. BP 120/75 mm Hg, HR 80 beats/minute, BUN 30 mg/dL, SCr 2.2 mg/dL, 70 kg. Which one of the following is the best therapy to initiate for conversion of his sustained ventricular tachycardia? A. Amiodarone 150 mg IV for 10 minutes, followed by 1 mg/minute × 6 hours and then 0.5 mg/minute.B. Sotalol 80 mg 2 times/day, titrated to QTc about 450 milliseconds. C. Dofetilide 500 mcg 2 times/day, titrated to QTc about 450 milliseconds. D. Procainamide 20 mg/minute, maximum 17 mg/kg.

5. C.D. presents to the emergency department 3 months after amiodarone maintenance initiation (he refused ICD placement) after a syncopal episode in which he lost consciousness for 30 seconds, according to witnesses. He also complains of rapid HR episodes where he feels dizzy and lightheaded. He feels very warm all the time (he wears shorts even though it is winter), is unable to sleep, and has experienced a 3-kg weight loss. He received a diagnosis of hyperthyroidism due to amiodarone therapy. On telemetry, he shows runs of nonsustained ventricular tachycardia. With an amiodarone half-life of 50 days, how long do you expect the effects of amiodarone to be provoking hyperthyroidism in this patient? A. Never. B. 1 month. C. 6 months. D. 1 year.



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Table 17. Unstable Angina and Non–ST-Elevation MI Defi nitions

UA Acute angina at rest, typically prolonged > 20 minutes, ST-segment depression, T-wave inversion, or no ECG changes may occur, but no biomarkers for cardiac necrosis present

NSTEMI Same as above, only with positive cardiac enzyme biomarkers of necrosis (troponin I or T elevation, CKMB fraction > 5%–10% of total CK)

CKMB = creatine kinase myocardial band; ECG = electrocardiogram; NSTEMI = non–ST-elevation MI; UA = unstable angina.

Unstable angina/non–ST-elevation MI (UA/NSTEMI) goals1. Prevent total occlusion of the infarct-related artery.a.

Glycoprotein IIb/IIIa inhibitors plus unfractionated heparin or enoxaparin (preferred).i. PCI can be either or both:ii.

PCI = either percutaneous transluminal coronary angiography, (i.e., “balloon”);(a) Stent implantation.(b)

Thrombolytics have shown no benefi t in NSTEMI or unstable angina and (1) ↑ bleeding.

Control chest pain and associated symptoms.b. Initial Management 2.

“MONA”a.

Table 18. “MONA” Algorithm

M = Morphine Morphine 1–5 mg IV is reasonable for patients whose symptoms are not relieved despite NTG or if they recur (class IIa, LOE N/A).

O = Oxygen Oxygen if O2 saturation < 90% or high-risk features for hypoxemia (class I, LOE B).N = Nitroglycerin Nitroglycerin spray or SL tablet 0.4 mg × 3 doses to relieve acute chest pain (if pain

unrelieved after 1 dose, call 911) (class I, LOE C).Nitroglycerin IV 5 mcg/minute, titrate to chest pain relief or 200 mcg/minute if pain is unrelieved by morphine and sublingual NTG (class I, LOE C). Dose may be limited by hypotension.

Used during fi rst 48 hours for treatment of persistent chest pain, HF, and HTN- A = Aspirin Aspirin chew and swallow nonenteric-coated 162–325 mg × 1 dose (class I, LOE A).HF = heart failure; HTN = hypertension; IV = intravenous; LOE = level of evidence; N/A = not available; NTG = nitroglycerin; SL = sublingual.

Diagnosisb. History of chest pain syndrome, ECG changes, serum biomarkers.i.

Early Hospital Anti-ischemic and Analgesic Therapy3. IV nitroglycerina.

Indicated in fi rst 48 hours for persistent ischemia, HF, or hypertension (class I, LOE i. C)Use should not preclude other mortality-reducing therapies (ii. β-blocker or angiotensin-converting enzyme inhibitor [ACEI]) due to no mortality benefi t.Dose: 10 mcg/minute, titrate to pain relief or maximum 200 mcg/minute.iii. Adverse effects: headache, hypotension, and tolerance.iv. Contraindications: sildenafi l or vardenafi l use within 24 hours or tadalafi l use within v.



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48 hours; systolic BP less than 100 mm Hg or more than 30 mm Hg below baseline, HR less than 50 beats/minute, HR less than 100 beats/minute in the absence of symptomatic HF or right ventricular infarction

b. β-Blockersi. Indicated within fi rst 24 hours if no contraindications (class I-PO/class IIa–IV, LOE B)ii. First-line therapy for reducing chest pain, infarction size, and LV wall stress.iii. Oral (PO) route preferred.iv. Metoprolol 5 mg IV every 5 minutes × 3 doses, then 25–50 mg PO 2 times/day

uptitrated as tolerated.v. Contraindication: signs of HF or low-output state, other risk factors for cardiogenic

shock, or other relative contraindications (PR > 0.24 seconds or third-degree heart block, active asthma, or reactive airway disease)

c. Angiotensin-Converting Enzyme Inhibitorsi. Indicated PO within fi rst 24 hours if pulmonary congestion or LVEF 40% or less in

absence of hypotension (class I, LOE A).ii. Contraindication (IV therapy): increased risk of hypotension with exception of

patients with refractory hypertension.iii. Angiotensin receptor blocker indicated if contraindication to ACEI.

d. Nondihydropyridine calcium channel blockers—verapamil, diltiazemi. Recommended if continuing or frequently recurring ischemia and contraindication to

β-blocker therapy (LOE I, class B) or recurrent ischemia after β-blockers and nitrates fully used (LOE IIa, class C).

No real benefi t or detriment on mortality; primarily symptom relief effects.(a) ii. Contraindication: clinically signifi cant LV dysfunction, immediate release

dihydropyridine calcium channel blockers should not be administered in the absence of a β-blocker.

Early Hospital Antiplatelet Therapy4. Aspirina.

Indicated immediately after hospital presentation and continue indefi nitely (class I, i. LOE A).

Clopidogrelb. Indicated if aspirin allergy or major gastrointestinal intolerance (class I, LOE A).i. Loading dose (LD) 300 mg PO followed by daily oral maintenance dose 75 mg.ii. Higher oral LD of 600 or 900 mg more rapidly inhibits platelet aggregation with iii. higher absolute level of inhibition, but additive clinical effi cacy and safety has not been established.



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Table 19. Antiplatelet and Anticoagulant Therapy

Initial Invasive Strategy Initial Conservative StrategyAntiplatelet Therapy

ASA + CLO or IV GP IIb/IIIa inhibitor (upstream)(class I, LOE A)

-OR- ASA + CLO plus IV GP IIb/IIIa inhibitor (upstream)

(class IIa, LOE B)a

-OR- ASA + CLO > 300 mg given > 6 hours before cath if bivalirudin used as anticoagulant (i.e., omit IV GP IIb/

IIIa inhibitor)(class IIa, LOE B)

ASA + CLO × 1 month(class I, LOE A)

-OR- ASA + CLO ideally up to 1 year(class I, LOE B)

-OR- ASA + CLO + eptifi batide or tirofi ban (class IIb, LOE B)

Anticoagulant TherapyEnoxaparin or UFH (class I, LOE A)b,c

-OR- Bivalirudin or fondaparinux (class I, LOE B)Enoxaparin or UFH (class I, LOE A)d

-OR- Fondaparinux (class I, LOE B)-OR- other LMWH such as dalteparin

(limited evidence)aFactors favoring administration of both clopidorel and GP IIb/IIIa inhibitor: delay to angiography, high risk features, early recurrent ischemic discomfort.bLMWH is reasonable alternative to UFH in patients with UA/NSTEMI (class IIa, LOE B) or STEMI (class IIb, LOE B) in patient undergoing PCI.cIf HIT, bivalrudin or argatroban preferred (Class I, LOE B).dEnoxaparin or fondaparinux are preferable to UFH, unless CABG is planned within 24 hours (Class IIa, LOE B).ASA = aspirin; cath = catheterization; CLO = clopidogrel; GP = glycoprotein; IV = intravenous; LOE = level of evidence.

Table 20. Managing Anti-platelet and Anticoagulant Therapies Based on Various Scenarios

If, after stress testing, patient classifi ed as low risk

- ASA (Class I, LOE A)- CLO for 1 month (class I, LOE A), ideally up to 1 year (class I, LOE B)- D/C IV GP IIb/IIIa inhibitor (class I, LOE A)- UFH for 48 hours -OR- enoxaparin or fondaparinux for hospital duration, up to 8 days (class I, LOE B)

CABG post-catheter - ASA (Class I, LOE A) - D/C CLO 5–7 days before elective CABG (class I, LOE B)- D/C IV GP IIb/IIIa inhibitor 4 hours before CABG (class I, LOE C)- Continue UFH (class I, LOE B) -OR- discontinue enoxaparin 12–24 hours, fondaparinux 24 hours, or bivalirudin 3 hours before CABG and initiate UFH (class I, LOE B)

PCI post-cathetera - ASA (Class I, LOE A)- CLO LD if not started before diagnostic angiography (class I, LOE A)- IV GP IIb/IIIa inhibitor if not started before diagnostic angiography (class I, LOE A)- Discontinue anticoagulant after PCI if uncomplicated case (class I, LOE B)

Medical therapy postcatheter

If no signifi cant CAD on cath- Antiplatelet and anticoagulant therapy at clinician discretion (class I, LOE C)

If CAD on cath - ASA (Class I, LOE A)

- CLO LD if not started before diagnostic angiography (class I, LOE A)- Discontinue IV GP IIb/IIIa inhibitor (class I, LOE B)- If given before angiography, continue UFH for 48 hours or until discharge -OR- enoxaparin or fondaparinux for hospital duration, for up to 8 days (class I, LOE B)- If given before angiography, either discontinue bivalirudin or continue at 0.25 mg/kg/hour for up to 72 hours at clinician’s discretion (class I, LOE B)



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aMay omit IV GP IIb/IIIa inhibitor upstream if bivalirudin used as anticoagulant and > 300 mg CLO > 6 hours before catheterization (class IIa, LOE B) or if troponin (−) and without high-risk features.ASA = aspirin; CABG = coronary artery bypass grafting; cath = catheterization; CLO = clopidogrel; D/C = discontinue; GP = glycoprotein; LD = loading dose; LOE = level of evidence; PCI = percutaneous coronary intervention; UFH = unfractionated heparin.

Table 21. Aspirin and Clopidogrel

Aspirina,b Clopidogrelc (Plavix)Dosing Initial therapy

- ASA 162–325 mg nonenteric PO or chewed × 1(class I, LOE C)Pre-PCI- If taking long-term ASA, ASA 75-325 mg before PCI (class I, LOE A)- If not taking long-term ASA, ASA 300-325 mg at least 2 hours before PCI, preferably 24 hours (class I, LOE C)No stent- ASA 75–162 mg/day indefi nitely (class I, LOE A)Post-stent- ASA 162–325 mg/day for: at least 1 month (bare-metal stent), at least 3 months (sirolimus-eluting stent), at least 6 months (paclitaxel-eluting stent)(class I, LOE B); then, 75–162 mg/day indefi nitely (class I, LOE A)

Initial therapy- CLO 300 mg LD × 1 (class I, LOE A)Pre-PCI- CLO 300 mg LD at least 6 hours before PCI (class I, LOE A)No stent- CLO 75 mg/day for at least 1 month (class I, LOE A) and ideally for up to 1 year (class I, LOE B)Post-stent- If bare-metal stent, CLO 75 mg/day for at least 1 month and ideally for up to 1 year (class I, LOE B)- If drug-eluting stent, CLO 75 mg/day for at least 1 year (class I, LOE B)

Contraindications Anaphylaxis, bronchospasm after therapy, serious bleeding

Withhold for up to 5–7 days before elective CABG

aIf ASA contraindicated, CLO 75 mg/day long-term or 300 mg LD at least 6 hours prior to PCI +/- Glycoprotein IIb/IIIa inhibitor (class I, LOE A).bIf bleeding risk, reduce ASA dosage post-stent PCI 75–162 mg/day (class IIa, LOE C).cHigher oral LD of 600 or 900 mg more rapidly inhibits platelet aggregation with higher absolute level of inhibition, but additive clinical effi cacy and safety have not been established.ASA = aspirin; CABG = coronary artery bypass graft; CLO = clopidogrel; LOE = level of evidence; PO = orally.

Table 22. Glycoprotein IIb/IIIa Inhibitors

FDA-approved Indications

UA/NSTEMI Dose PCI Dose Renal Adjustment

Abciximab (ReoPro)

GP receptor irreversible inhibitor

PCI only Same as PCI dose if cardiac catheterization planned soon

0.25 mg/kg IV bolus, then 0.125 mcg/kg/minute (maximum 10 mcg/kg) for 12 hours

Not necessary; reticuloendothelial system clearance

Eptifi batide (Integrelin)

GP receptor competitive antagonist

UA/NSTEMI, elective PCI

180 mcg/kg IV bolus, followed by 2 mcg/kg/minute

180 mcg/kg IV bolus × 2 (10 minutes apart), then 2 mcg/kg/minute for 18–24 hours post-PCI

If CrCl < 50 mL/minute, reduce infusion 50%; IP dialysis, contraindicated

Tirofi ban (Aggrastat)

GP receptor competitive antagonist

UA/NSTEMI only

0.4 mcg/kg/minute for 30 minutes (LD infusion), followed by 0.1 mcg/kg/minute

Same as UA/NSTEMI dose, continue for 18–24 hours post-PCI

If CrCl < 30 mL/minute,reduce infusion 50%

Abciximab is preferred upstream agent if no appreciable delay to angiography and PCI is likely to be performed; otherwise, eptifi batide or tirofi ban preferred.



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CrCl = creatinine clearance; GP = glycoprotein; LD = loading dose; NSTEMI = non–ST-elevation myocardial infarction; PCI = percutaneous coronary intervention; SCr = serum creatinine; UA = unstable angina.

Table 23. Anticoagulants

Unfractionated Heparin Enoxaparin(Lovenox)

Dalteparin(Fragmin)

Fondaparinux(Arixtra)

Bivalirudin(Angiomax)

Classifi cation — LMWH LMWH Factor Xa inhibitor

DTI

Dosing 60 U/kg IV bolus, 12 U/kg/hour infusion

1 mg/kg subcutaneously twice daily

120 IU/kg bcutaneously twice daily × 5–8 days

2.5 mg subcutaneously once daily

UA/NSTEMI:0.1 mg/kg IV bolus, then 0.25 mg/kg/hourPCI: 0.5–0.75 mg/kg IV bolus, then 1.75 mg/kg/hour for 4 hours post-PCI

Comments Maximum 4000 U bolus and 1000 U/hour infusion; titrate to goal activated partial thromboplastin time 1.5–2.5× control

1 mg/kg subcutaneouslyonce dailyif CrCl < 30 mL/minute

Maximum dose 10,000 IU twice daily

Not FDA approved for HIT

Useful in setting of HIT

Contraindications Previous HIT, serious active bleeding

Weight > 175 kg or SCr > 2.5 not well studied

Signifi cant renal or hepatic dysfunction

Contraindicated if CrCl < 30 mL/minute

Adjust infusion dose in severe renal dysfunction (bolus dose same)

CrCl = creatinine clearance; DTI = direct thrombin inhibitor; FDA = U.S. Food and Drug Administration; HIT = heparin-induced thrombocytopenia; LMWH = low-molecular-weight heparin; PCI = percutaneous coronary intervention; NSTEMI = non–ST-elevation MI; SCr = serum creatinine; UA = unstable angina.

Additional Long-term Medical Therapy5. a. β-Blockers

Indicated for all patients unless contraindicated (class I, LOE B).i. Initiate within a few days of even, if not acutely, and continue indefi nitely.ii. If moderate or severe LV failure, initiate with gradual titration.iii.

b. ACE Inhibitorsi. Indicated for all patients with HF, LVEF less than 40%, hypertension, or diabetes

mellitus (class I, LOE A).ii. Also reasonable if no LV dysfunction, hypertension, or diabetes mellitus

(class I, LOE A).iii. Angiotensin receptor blocker if ACEI intolerant and signs of HF and LVEF less than

40% (class I, LOE A).May consider combination ACEI and angiotensin receptor blocker if iv. persistent symptomatic HF and LVEF less than 40% despite standard therapy (class IIb, LOE B).

c. Aldosterone Receptor Blockersi. Indicated if LVEF less than 40% and symptomatic HF or diabetes mellitus and

receiving therapeutic doses of ACEI.Contraindicated if CrCl less than 30 mL/minute or potassium more (a) than 5 mEq/L



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d. Lipid Managementi. Statins indicated with low-density lipoprotein goal less than 100 mg/dL (class I, LOE

A) with a goal less than 70 mg/dL reasonable (class IIa, LOE A).ii. See “Chronic Cardiology” section for additional detail.

ST-elevation MIC.

Defi nition1. Complete occlusion of epicardial coronary artery (red blood cells plus platelets, fi brin).a. Clinical chest pain syndrome lasting more than 20 minutes with good angina history, plus b. ST-elevation of more than 1 mm above baseline on ECG, plus positive cardiac enzyme biomarkers of necrosis (troponin I or T, creatine kinase, myocardial bound fraction more than 5%–10% of total creatine kinase).

STEMI Goals2. Restore patency of the infarct-related artery and minimize infarct size.a.

Thrombolytic medications or “Door-to-Needle” within 30 minutes.i. PCI or “Door-to-Balloon” within 90 minutes.ii.

Either percutaneous transluminal coronary angioplasty i.e., “balloon,”(a) Stent implantation, or both.(b)

Patient Cases6. J.D. is a 66-year-old, 70-kg woman with history of MI, hypertension, hyperlipidemia, and diabetes who

presents with sudden-onset diaphoresis, nausea, vomiting, and dyspnea, followed by a bandlike upper chest pain (8/10) radiating to her left arm. She had felt well until 1 month ago, when she noticed her typical angina was occurring with less exertion. The ECG showed ST-depressions in leads II , III, and AVF, and hyperdynamic T waves. Cardiac enzymes are positive, and she receives a diagnosis of NSTEMI. Home medications: aspirin 81 mg/day, simvastatin 40 mg every night, metoprolol 50 mg 2 times/day, and metformin 1 g 2 times/day. Which one of the following is the best antiplatelet/anticoagulant strategy for this patient? A. Eptifi batide 180 mcg/kg bolus × 1, then 2 mcg/kg/minute plus unfractionated heparin titrated to 50–70

seconds, aspirin 325 mg, and clopidogrel 300 mg × 1 and then 75 mg/day plus cardiac catheterization for possible PCI.

B. Aspirin 325 mg and enoxaparin 80 mg subcutaneously 2 times/day plus cardiac catheterization for possible PCI.

C. Medical management with abciximab 0.25 mg/kg bolus, then 0.125 mg/kg/minute for 12 hours plus enoxaparin 80 mg subcutaneously 2 times/day, aspirin 325 mg/day, and clopidogrel 300 mg × 1, then 75 mg/day.

D. Medical management with aspirin 325 mg and clopidogrel 300 mg × 1; then 75 mg/day plus unfractionated heparin 70 U/kg bolus, followed by 15 U/kg/hour.

7. J.D. received a percutaneous transluminal coronary angioplasty and paclitaxel-eluting stent in her right coronary artery. What is the optimal length of time clopidogrel therapy be continued? A. 1 month. B. 6 months. C. 12 months. D. Lifelong.

8. Which one of the following is the optimal lifelong aspirin dose once dual therapy with clopidogrel after PCI with stent implantation is completed? A. 25 mg. B. 81 mg. C. 325 mg. D. 650 mg.



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Prevent complications such as arrhythmias or death.b. Control chest pain and associated symptoms.c.

Acute Symptom Relief3. “MONA” plus a. β-blocker.

Table 24. “MONA” Plus β-Blocker for AMI

M = Morphine Morphine 1–5 mg IV is reasonable for patients whose symptoms are not relieved despite NTG or if they recur (class I, LOE C)

O = Oxygen Oxygen 4 L/minute by nasal cannula if O2 saturation < 90%N = Nitroglycerin Nitroglycerin spray or SL tablet 0.4 mg × 3 doses to relieve acute chest pain (if pain

unrelieved after one dose, call 911) (class I, LOE C)Nitroglycerin IV 5 mcg/minute, titrate to chest pain relief or 200 mcg/minute if pain unrelieved by morphine and sublingual NTG (class I, LOE C)

No mortality benefi ts but high placebo crossover rate.- Used in fi rst 48 hours for treatment of persistent chest pain, HF, and hypertension.-

A = Aspirin Aspirin chew and swallow nonenteric-coated 162–325 mg × 1 dose (class I, LOE A/C)β-blocker Oral or IV β-blocker (class I, LOE A—oral, class IIa, LOE B—IV)

Mortality benefi t in early phases of acute MI (metoprolol 5.7% vs. placebo 8.9%).- AMI = acute myocardial infarction; HF = heart failure; IV = intravenous; LOE = level of evidence; MI = myocardial infarction; NTG = nitroglycerin.

Reperfusion4. If presenting to a facility without the capability for expert, prompt intervention with a. primary PCI within 90 minutes of fi rst medical contact, patient should undergo fi brinolysis unless contraindicated (class I, LOE A).Facilitated PCI might be performed as a reperfusion strategy in high-risk patients when b. PCI is not immediately available and bleeding risk is low (class IIb, LOE B).

Facilitated PCI refers to a strategy of planned immediate PCI after an initial i. pharmacological regimen such as full-dose fi brinolysis, half-dose fi brinolysis, a glycoprotein IIb/IIIa inhibitor, or a combination of reduced-dose fi brinolytic therapy and a platelet glycoprotein IIb/IIIa inhibitor.

c. Rescue PCI or PCI following failed thrombolysis is indicated in select patients if the following develops: shock, severe HF and/or pulmonary edema, hemodynamic or electrical instability, evidence of persistent ischemia.

Table 25. Thrombolytic Therapy

DosingAlteplase (TPA) 15 mg IVP and then 0.75 mg/kg for 30 minutes (maximum 50 mg), followed by 0.5

mg/kg (maximum 35 mg) for 60 minutesReteplase (r-PA) 10 U IVP, repeat 10 U IVP in 30 minutesTenecteplase (TNKase) < 60 kg to 30 mg, 60–69 kg to 35 mg, 70–79 kg to 40 mg, 80–89 kg to 45 mg, > 90

kg to 50 mg *about 0.5 mg/kgStreptokinase (Streptase) 1.5 MU IV for 60 minutes

Thrombolytic therapy is preferred within six hours of the onset of chest pain. UFH should be given to patients undergoing reperfusion with thrombolytic therapy. (Class I, B/C)



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Table 26. Contraindications to Thrombolytic Therapy

Relative Contraindications Absolute ContraindicationsBP > 180/110 mm Hg on presentation• History of TIA or CVA > 3 months prior• History of chronic poorly controlled HTN• INR 2–3 on warfarin• Recent trauma, major surgery, CPR, internal bleeding • in 2–4 weeksStreptokinase exposure • > 5 days prior or prior allergic reaction (if given streptokinase again)Active peptic ulcer• Age > 75 years• Pregnancy• Known intracranial pathology (dementia)•

ANY prior hemorrhagic stroke• Ischemic stroke within 3 months (except in past 3 • hours)Intracranial neoplasm or arteriovenous • malformationActive internal bleeding• Aortic dissection• Signifi cant facial trauma or closed-head trauma in • past 3 months

CPR = cardiopulmonary resuscitation; CVA = cerebrovascular accident; HTN = hypertension; INR = international normalized ratio; TIA = transient ischemic attack.

Patient Cases9. R.V. is a 52-year-old man with a history of hypertension and hypertriglyceridemia who presents to a major

university teaching hospital with a cardiac catheterization laboratory. He has 3 hours of crushing 10/10 substernal chest pain radiating to both arms that began while he sat eating his lunch, accompanied by nausea, diaphoresis, and shortness of breath. He has never experienced chest pain of this character or intensity before. He usually can walk several miles without diffi culty and is a 1.5 pack/day smoker. Home medications: lisinopril 2.5 mg/day, gemfi brozil 600 mg 2 times/day. Current vital signs: HR 68 beats/minute and BP 178/94 mm Hg; weight 100 kg. An ECG shows 3-mm ST-elevation in leads V2–V4, I, and AVL. Serum chemistry values are within normal limits. First set of cardiac enzymes showed positive myoglobin levels, creatine kinase 175 U/L, myokinase 17.4 U/L, and troponin T 0.8 mcg/L (less than 0.1 mcg/L). Which one of the following should be done to treat this patient’s STEMI? A. Cardiac catheterization with primary PCI (stent) of occluded artery together with abciximab, clopidogrel,

aspirin, and unfractionated heparin. B. Reteplase 10 U bolus twice, 30 minutes apart, plus unfractionated heparin 60 U/kg bolus and 12 U/kg/

hour infusion. C. Abciximab 0.25 mg/kg IVP and 0.125 mg/kg/minute for 12 hours plus enoxaparin 100 mg subcutaneously

2 times/day plus tenecteplase 25 mg IVP 1 time. D. Tirofi ban 0.04 mcg/kg/minute × 30 minutes, followed by 0.01 mcg/kg/minute plus unfractionated heparin

60 U/kg bolus and 12 U/kg/hour infusion.

10. W.F. is a 70-year-old male smoker with a history of hypertension, benign prostatic hypertrophy, and lower back pain. Three weeks ago, he started experiencing substernal chest pain with exertion (together with dyspnea), which radiated to both arms and was associated with nausea and diaphoresis. Episodes have increased in frequency to 4–5 times/day and are relieved with rest. He has never had an ECG. Today, he awoke with 7/10 chest pain and went to the emergency department of a rural community hospital 2 hours later. He was acutely dyspneic and had continuing pain. Home medications: aspirin 81 mg/day for 2 months, doxazosin 2 mg/day, ibuprofen 800 mg 3 times/day. Vital signs include HR 42 beats/minute (bradycardic with complete heart block); BP 104/48 mm Hg; weight 61 kg. Laboratory results include BUN 45 mg/dL, SCr 1.7 mg/dL, creatine kinase 277 U/L, creatine kinase, myocardial bound 35.2 U/L, troponin T 1.5 mcg/L (less than 0.1 mcg/L). ECG showed a 3-mm ST-elevation. Aspirin, clopidogrel, and sublingual nitroglycerin were given in the emergency department. Which one of the following best describes how he should be managed? A. Alteplase plus enoxaparin. B. Unfractionated heparin. C. Tenecteplase plus unfractionated heparin. D. Diagnostic cardiac catheterization for possible primary PCI.



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Mortality-reducing Medications5. Aspirina.

See dosing under “UA/NSTEMI” (class I, LOE A).i. b. β-Blockers

Shown to reduce mortality in both early and late phases of STEMI.ii. See dosing under “UA/NSTEMI.”iii. Oral iv. β-blocker therapy should be administered promptly to those patients without a contraindication, irrespective of concomitant fi brinolytic therapy or performance of primary PCI (class I, LOE A).IV v. β-blockers are reasonable for patients without contraindications, especially if a tachyarrhythmia or hypertension is present (class IIa, LOE B).

vi. β-blockers should be used cautiously or not at all in patients with symptoms of heart failure.

c. Thrombolyticsi. Mechanism of action: Plasminogen is a proenzyme and is converted to the active

enzyme plasmin by plasminogen activators (endogenous or exogenous alteplase [TPA] derivatives); plasmin digests fi brin to soluble degradation products.

ii. Administer within 12 hours of symptom onset (preferably within 6 hours, and ideally within 30 minutes of arrival to hospital).

iii. Primary PCI preferred over thrombolytics in hospitals with cardiac catheterization laboratories.

iv. Alteplase, reteplase, and tenecteplase require concomitant unfractionated heparin administration of 60 U/kg bolus (maximum 4000 U) and 12 U/kg/hour (maximum 1000 U/hour), adjusted for activated partial thromboplastin time of about 50–70 seconds (class I, LOE C).

Low-molecular-weight heparins can be used in combination with (a) thrombolytics if the patient is younger than 75 years without signifi cant renal dysfunction; SCr less than 2.5 mg/dL in men and less than 2 mg/dL in women (class IIb, LOE B).

Enoxaparin 30-mg IV bolus, followed by 1 mg/kg subcutaneously every (1) 12 hours until discharge.

In patients with known heparin-induced thrombocytopenia, it is reasonable to (b) consider bivalirudin a useful alternative to heparin to be used in conjunction with streptokinase (class IIa, LOE B).

v. No added mortality benefi t at 30 days or 1 year when thrombolytics administered in half-dose, together with full-dose unfractionated heparin or enoxaparin and full-dose glycoprotein IIb/IIIa inhibitor.

Increased risk of major bleeding events by 3 times (i.e., intracranial (a) hemorrhage), particularly in patients older than 75 years.Can be used to prevent reinfarction if anterior MI in patients younger than 75 years (b) with no risk of bleeding.

d. ACE Inhibitorsi. Give oral ACEIs in low doses to all patients during fi rst 24 hours of anterior STEMI,

HF signs (pulmonary congestion), or LVEF less than 40%, provided no hypotension exists (systolic BP less than 100 mm Hg) or other contraindication, to reduce mortality and remodeling (class I, LOE A).

ii. Consider oral ACEIs even if the above indications are not present (class IIa, LOE B)—benefi t less (fi ve lives saved per 1000 treated) than if LV dysfunction is present.



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iii. Angiotensin receptor blocker if ACEI intolerant (class I, LOE C).iv. Administer after β-blockers and sublingual nitroglycerin to avoid excess hypotension,

but in fi rst 24 hours.v. Avoid IV ACEIs as it may cause hypotension (class III, LOE B).

e. Statin Therapyi. Lipid panel should be drawn within the fi rst 24 hours of admission to prevent

checking during acute-phase reaction (low-density lipoprotein falsely low for up to 2 months post-MI).

ii. All patients should be discharged on statin therapy unless a contraindication exists.f. Insulin

i. During the fi rst 24–48 hours after STEMI, control hyperglycemia with insulin infusion (class I, LOE B).

After 48 hours, manage patients with diabetes with individualized regimens.(c)

Post-MI Medical Care and Secondary PreventionD. Antiplatelet medications1.

Aspirin 75–162 mg/day (class I, LOE A).a. Clopidogrel 75 mg/day if PCI or medical management (see dosing under “UA/b. NSTEMI”).

BP control2. See Joint National Committee VII recommendations in outpatient section for goals.a.

b. β-Blocker therapy (class I/class IIa if low risk, LOE A)Begin within a few days of the event, if not initiated acutely.i. If moderate or severe LV failure, use gradual titration scheme.ii.

c. ACEI therapy (class I, LOE A) or angiotensin receptor blocker if ACEI intolerant (class I, LOE B) i. Should be initiated at discharge if not already prescribed.

d. Aldosterone antagonist (class I, LOE A)i. Recommended after STEMI in patients with normal renal function (SCr 2.5 mg/dL or

lower in men and 2 mg/dL or lower in women) if:Already receiving therapeutic dose of ACEI.(a) LVEF 40% or less.(b) Symptomatic HF or diabetes.(c)

Lipid-lowering therapy: statins3. Goal low-density lipoprotein less than 100 mg/dL (class I, LOE A), consider low-density a. lipoprotein less than 70 mg/dL in high-risk patients.Goal non–high-density lipoprotein-cholesterol* less than 130 mg/dL (class I, LOE B).b.

After low-density lipoprotein-cholesterol–lowering therapy, consider adding fi brate i. or niacin (class IIa, LOE B).

Diabetes management4. Goal glycosylated hemoglobin less than 7%.a.

Smoking cessation in all patients5. Weight management6.

Goal body mass index 18.5–24.9 kg/ma. 2; begin diet program if above goal weight.Exercise7.

Minimum goal 3–4 times/week.a.



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PULMONARY ARTERIAL HYPERTENSIONIV.

A. Defi nition and Treatment GoalsPulmonary arterial hypertension1.

Idiopathic PAHa. Change in nomenclature during 2003 World Conference on Pulmonary Hypertension; i. used to be known as primary pulmonary hypertension.Familial PAH.ii.

Pulmonary artery hypertensionb. Secondary causesi.

Scleroderma (most common), chronic thromboembolic disease, human (a) immunodefi ciency virus disease, liver disease, connective tissue diseases, medications, toxins, and others.

Symptoms2. Dyspnea with exertion (60% of patients), fatigue, chest pain, syncope, and weakness i. (40%).

Caused by impaired oxygen delivery to tissues and diminished CO.(a) Orthopnea, peripheral edema, liver congestion, abdominal bloating, and other signs ii. of right ventricular hypertrophy and failure occur when disease progresses to the heart.

Diagnosis3.

Table 27. Diagnostic Findings of PAH

Hemodynamic alterations MPAP > 25 mm Hg with a PCWP < 15 mm Hg on PA catheterization with failed vasodilator challenge

Electrocardiography Signs of RV hypertrophy, right-axis deviation, and anterior ST- and T-wave abnormalities consistent with RV strain pattern

Echocardiography Estimated RV systolic pressure elevation, enlarged RV, RV dysfunctionChest radiography Enlarged pulmonary arteries and diminished peripheral pulmonary vascular

markings, RV enlargementPhysical examination Cool and/or cyanotic extremities, jugular venous distension, pulsatile

hepatomegaly, peripheral edema, ascitesMPAP = mean pulmonary artery pressure; PA = pulmonary artery; PCWP = pulmonary capillary wedge pressure; RV = right ventricle.

World Health Organization functional assessment classifi cation 4.

Table 28. World Health Organization Classifi cation for PAH

Class Defi nitionClass I No symptoms (dyspnea, fatigue, syncope, chest pain) with normal daily activities Class II Symptoms with strenuous normal daily activities that slightly limit functional status and activity levelClass III Symptoms of dyspnea, fatigue, syncope, and chest pain with normal daily activities that severely limit

functional status and activity levelClass IV Symptoms at rest; cannot conduct normal daily activities without symptoms



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Guideline Recommendations for PAH5.

Table 29. Levels of Evidence and Grades of Recommendations for PAH Guidelines

Levels of EvidenceGood Well-designed randomized controlled clinical trials or meta-analysesFair Other controlled trials or randomized controlled trials with minor fl awsLow Non-randomized trials, case-control studies, or observational studiesExpert opinion Consensus opinion of a panel of experts in the topic fi eld; no clinical trials

meet the criteria for inclusionGrades of RecommendationGrade A Strong recommendationGrade B Moderate recommendationGrade C Weak recommendationGrade D Negative recommendationGrade I No recommendation possible (inconclusive)Grade E/A Strong recommendation based on expert opinionGrade E/B Moderate recommendation based on expert opinionGrade E/C Weak recommendation based on expert opinion

Treatment goals6. Relieve acute dyspnea symptoms.a. Improve exercise capacity/quality of life and prevent death.b.

Acute vasodilator response testing (evidence: fair, grade A for idiopathic PAH; i. evidence: expert opinion, grade E/C for other PAH causes).

Use IV epoprostenol, inhaled nitric oxide, or IV adenosine.(a) Positive response: reduction in mean pulmonary artery pressure by 10–40 mm (b) Hg.

Positive response predicts mortality reduction with long-term calcium (1) channel blocker or vasodilator use.

Treatment of PAHA. Supportive care1.

Supplemental oxygen to maintain Oa. 2 saturation more than 90% at all times (evidence: expert opinion, grade E/A).Loop diuretics if symptoms of peripheral edema or ascites.b. Warfarin anticoagulation: goal international normalized ratio 1.5–2.5 in patients with idiopathic c. PAH (evidence: fair, grade B for idiopathic PAH; evidence: expert opinion, grade E/C for other PAH).

Prevents catheter thrombosis in patients on epoprostenol, clot formation caused by i. venous stasis, or right ventricular failure.

Immunizations for infl uenza and pneumococcus.d. Calcium channel blockers2.

First-line drug for all patients with PAH with positive acute vasodilator response (evidence: low, a. grade B for idiopathic PAH; evidence: expert opinion, grade E/B for other PAH causes).

If cannot use or calcium channel blocker therapy fails, consider use of other i. vasodilatory medications as second-line alternative.

Should not be used empirically without acute vasodilatory response testing or without a b. positive response to testing (evidence: expert opinion, grade E/A).

Diltiazem, amlodipine, and nifedipine are most commonly used.i.



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Choose on the basis of HR at baseline.(a) If relatively bradycardic, choose amlodipine or nifedipine.(1) If relatively tachycardic, choose diltiazem.(2)

Functional class II patients who are not candidates or for whom calcium channel blocker c. treatment failed may benefi t from other therapies, but no specifi c drugs are recommended because of a lack of evidence (evidence: expert opinion, grade: E/B).

Bosentan3. Mechanism of action: endothelin-1 types A (ET-A) and B (ET-B) receptor antagonista.

ET-A produces vasoconstriction and increases vascular smooth muscle.i. ET-B clears endothelin-1 from vasculature in kidneys and lungs; produces ii. vasodilation.

Treatment effect: improves cardiac index, reduces mean pulmonary artery pressure and b. pulmonary capillary wedge pressure as well as mean right atrial pressure, and improves functional class.Place in therapy:c.

First-line therapy for patients with PAH in functional class III who cannot take i. calcium channel blockers (evidence: good; grade A).Alternative option in patients in functional class IV who cannot take calcium channel ii. blockers or IV epoprostenol (evidence: fair, grade B).

Epoprostenol4. Mechanism of action: prostacyclin analogue a.

Potent vasodilator of pulmonary and systemic vessels.i. Treatment effect: improved survival by 3–5 years, increased 6-minute walk time and b. distance, increased quality of life and cardiac index, and symptomatic improvement.Place in therapy:c.

First-line therapy for patients with PAH in functional class IV who experience failure i. with or cannot take calcium channel blockers (evidence: good, grade A).Second-line therapy for patients with PAH in functional class III who experience ii. failure with or cannot take calcium channel blockers or fi rst-line vasodilators (bosentan) (evidence: good, grade A).

Contraindications: inability to keep drug refrigerated before and during infusion; requires d. ice packs to keep stable; unable to reconstitute drug in sterile environment.Other considerations: costs $100,000/year or more; if infusion is abruptly discontinued, e. because of the short half-life (t1/2 less than 6 minutes); acute symptomatic decompensation and possibly death may occur if medical attention is not sought immediately.

Subcutaneous treprostinil5. Mechanism of action: prostacyclin analogue: potent vasodilator of pulmonary and a. systemic vessels.Treatment effect: dose-related symptomatic improvement and effect on exercise b. tolerance; more effective in functional class III and IV patients but is an alternative therapy (minimal/no effect in functional class II patients or patients with congenital heart disease) (evidence: fair, grade B).Other considerations: If subcutaneous infusion is abruptly discontinued because of the c. longer half-life (t1/2 = 3 hours), patients have more time to seek medical attention than with epoprostenol.

Premixed, prefi lled syringe is easier to administer than epoprostenol.i. Inhaled iloprost6.

Mechanism of action: potent pulmonary vasodilator.a.



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Treatment effect: symptomatic improvement of functional class, quality of life for b. functional classes III or IV but is an alternative therapy.

Functional class III patients (evidence: fair, grade B).i. Functional class IV patients (evidence: low, grade C).ii.

Other considerations: must be used with Prodose AAD nebulization system.c. Sildenafi l7.

Mechanism of action: sildenafi l selectively inhibits phosphodiesterase-5 in the lungs to a. increase and prolong pulmonary vasodilation in response to nitric oxide.Treatment effect: reduces pulmonary artery wedge pressure, increases cardiac index, b. decreases pulmonary vascular resistance, and improves NYHA functional class, symptoms, and distance walked on 6-minute walk test.

Alternative option in any patient with PAH who is not a candidate for any other drug i. therapy (evidence: low, grade C)

Treatment OptionsB.

Table 30. Overview of PAH Treatment Options

Drug Dose Indications Adverse Effects ConsiderationsEpoprostenol(Flolan)

1–40 ng/kg/minute First line: chronic therapy in PAH functional class IV; alternative in functional class III

Jaw pain, nausea, vomiting, fl ushing, headache, muscle aches and pain, catheter-related thrombosis, IV line infections; rebound worsening of symptoms if abruptly discontinued

Continuous IV infusion by a pumpUnstable at room temperature and acidic pHDrug requires reconstitutionMedical emergency if infusion interrupted (spare drug cassette and infusion pump should be available)

Treprostinil(Remodulin)

1.25–40 ng/kg/minute subcutaneous infusion

Alternative in functional class III patients whose calcium channel blocker treatment failed and ET-1 antagonists or class IV failing epoprostenol

Severe erythema and induration (83%) and injection site pain (85%) limit use; also headache, nausea, diarrhea, rash

Local treatments (hot and cold packs or topical analgesics) can be used to minimize infusion site discomfortMoving infusion site every 3 days minimizes irritation

Inhaled iloprost(Ventavis)

2.5 × 1, followed by 5 mcg/inhalation through a nebulizer 6–9 times/day while awake

Alternative in functional class III in patients whose calcium channel blocker treatment failed and endothelin-1 antagonists or class IV failing epoprostenol

Mild, transient cough, fl ushing, headache,syncope

Requires 6–9 inhalations daily (15 minutes each with jet nebulizer)Inhalation form has fewer systemic adverse reactions than other prostacyclin analoguesUse no more often than every 2 hours



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Drug Dose Indications Adverse Effects ConsiderationsBosentan(Tracleer)

62.5–125 mg PO 2 times/day

First-line therapy for functional class III in patients whose calcium channel blocker treatment failed; alternative in class IV patients whose epoprostenol therapy failed

Hypotension, dose-related increased liver enzymes (up to 14%), possible male infertility, syncope, fl ushing

Effi cacy decreased with CYP2C8/9 and 3A4 inducers and toxicity increased with 3A4 and CYP2C8/9 inhibitors

Severe drug interactions with glyburide (increased LFTs) and cyclosporine (decreased effi cacy of both cyclosporine and bosentan)Monitor LFTs monthly because of risk of hepatotoxicityAnemia risk requires Hgb/Hct monitoring periodicallyPotential teratogen; if child-bearing age, use two contraceptive methods (reduced effi cacy of hormonal contraceptives); monthly pregnancy test required

Sildenafi l(Revatio)

20 mg PO 3 times/day fi xed dose

Indicated in WHO functional class I patients to improve exercise ability or for PAH patients for whom all other therapies have failed

Headache, epistaxis, facial fl ushing, bluish or blurry vision, light sensitivity, dyspepsia, insomnia

May augment effects of other vasodilators when used in combination (especially prostacyclin)Contraindicated in patients receiving nitrates

CYP = cytochrome P450; ET-1 antagonists = endothelin-1 antagonists; Hct = hematocrit; Hgb = hemoglobin; IV = intravenous; LFTs = liver function tests; PAH = pulmonary arterial hypertension; PO = orally; WHO = World Health Organization.

Patient Case11. R.W. is a 38-year-old obese woman who presents with increasing symptoms of fatigue and shortness of

breath. She could walk only 10–20 feet at baseline and is now short of breath at rest. Her arterial blood gas is pH 7.31/pCO2 65/pO2 53/85% O2 saturation. She has three-pillow orthopnea and 3+ pitting edema in her lower extremities. Medical history is signifi cant only for atrial fi brillation. On computed tomographic angiography, the pulmonary artery trunk was signifi cantly enlarged and had a mean pressure of 56 mm Hg. ECHO: right atrial and ventricular hypertrophy. Chest radiograph showed prominent interstitial markings. Pertinent laboratory fi ndings: BUN 21 mg/dL, SCr 1.2 mg/dL, aspartate aminotransferase 145 IU/L, alanine aminotransferase 90 IU/L, international normalized ratio 2.1, partial thromboplastin time 52 seconds. Vital signs: BP 108/62 mm Hg, HR 62 beats/minute. Home medications: warfarin 2.5 mg/day, ipratropium 2 puffs every 6 hours, salmeterol 2 puffs 2 times/day, diltiazem controlled delivery 480 mg/day. Her diagnosis is idiopathic PAH. Given the options below, which one is the best evidence-based management strategy? A. Increase diltiazem to 600 mg/day. B. Start sildenafi l 20 mg 3 times/day. C. Start epoprostenol 2 ng/kg/minute. D. Start bosentan 62.5 mg 2 times/day.



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HYPERTENSIVE CRISES (URGENCY AND EMERGENCY)V.

Defi nitionsA. Hypertensive urgency1.

Acutely elevated BP, particularly diastolic pressure more than 120–130 mm Hg without a. evidence of target organ damage.

Hypertensive emergency2. Hypertension with evidence of target organ damage.a.

Target organ damage: brain, heart, kidneys, and eyes.i. Hypertensive encephalopathy, intracranial hemorrhage, or other acute neurologic (a) defi cit, UA or acute MI, acute HF, pulmonary edema (shortness of breath), aortic dissection, retinopathy or papilledema, decreased urine output or acute renal failure, eclampsia.

GoalsB. Urgency1.

Lower mean arterial pressure to goal or near goal within 24 hours; oral medications can a. be used.

Emergency2. Lower mean arterial pressure by 25% or diastolic pressure to 100–110 mm Hg within 30–60 a. minutes.

Treatment OptionsC.

Table 31. Recommended Antihypertensive Agents for Hypertensive Crises

Conditions Preferred Antihypertensive AgentsAcute pulmonary edema/systolic dysfunction Nicardipine, fenoldopam, or NTP + NTG and a loop diureticAcute pulmonary edema/diastolic dysfunction Esmolol, metoprolol, labetalol, or verapamil + low-dose NTG

and a loop diureticAcute myocardial ischemia Labetalol or esmolol + NTGHypertensive encephalopathy Nicardipine, labetalol, or fenoldopamAcute aortic dissection Labetalol, nicardipine + esmolol, NTP + esmolol or IV

metoprololPre-eclampsia, eclampsia Labetalol or nicardipineAcute renal failure/microangiopathic anemia Nicardipine or fenoldopamSympathetic crisis/cocaine overdose Veramapmil, diltiazem, or nicardipine + a benzodiazepineAcute postoperative hypertension Esmolol, nicardipine, or labetalolAcute ischemic stroke/intracerebral bleed Nicardipine, labetalol, or fenoldopamIV = intravenous; NTG = nitroglycerin; NTP = nitroprusside.Reprinted with permission from Marik PE, Varon J. Hypertensive crises: challenges and management. Chest 2007;131:1949–62.



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Table 32. Dosage and Adverse Effects of Commonly Used Parenteral Antihypertensive Drugs

Drug Dosage Adverse EffectsSodium nitroprusside(Nipride)

0.25–0.5 mcg/kg/minute, maximum 3 mcg/kg/minute

Cyanide/thiocyanate toxicity, nauseaCI: renal, hepatic failure

Esmolol(Brevibloc)

500 mcg/kg LD for 1 minute, followed by 25–50 mcg/kg/minute; maximum of 300 mcg/kg/minute

Bronchospasm, especially in patients with asthma, HF exacerbation, bradycardia/heart block

Labetalol(Normodyne, Trandate)

20–80 mg IV every 15 minutes OR 0.5–2 mg/minute with maximum 24-hour dose of 300 mg

Bronchospasm, especially in patients with asthma, HF exacerbation, bradycardia/heart block

Nicardipine(Cardene)

5–15 mg/hour, maximum 15 mg/hour

Refl ex tachycardia, nausea, vomiting

Nitroglycerin 5–10 mcg/minute, maximum 100 mcg/minute

Headache, nausea, tachyphylaxis

Hydralazine(Apresoline)

5–10 mg IV every4–6 hours (not to exceed 20 mg/dose)

Refl ex tachycardia, headache, variable duration of action

Enalaprilat(Vasotec)

0.625–1.25 mg IV every 4–6 hours, maximum 5 mg every 6 hours

Renal insuffi ciency/failure, variable response based on renin state

Fenoldopam(Corlopam)

1 mcg/kg/minute, maximum 1.6 mcg/kg/minute

Hypotension; cerebral ischemia, headache

CI = contraindications; HF = heart failure; IV = intravenously; LD = loading dose.

Patient Case12. A.W. is a 68-year-old man with a history of end-stage renal disease on hemodialysis, hypertension, coronary

artery disease status post-MI, moderately depressed LVEF, and gastroesophageal refl ex disease who presents with acute-onset shortness of breath and chest pain. After his recent dialysis, he had a large barbecue meal with salt and smoked some marijuana laced with cocaine. He was medication noncompliant for 2 days and noticed he had gained 2 kg during 24 hours. His baseline orthopnea worsened to sleeping while sitting up in a chair for the two nights before admission. He developed acute-onset chest tightness with diaphoresis and nausea, pain 7/10. He went to the emergency department, where a BP of 250/120 mm Hg was noted. He had crackles halfway up his lungs on examination, and a chest radiograph showed bilateral fl uffy infi ltrates with prominent vessel cephalization. An electrocardiogram showed sinus tachycardia, HR 122 beats/minute, ST-depressions in leads II and III, and AVF. He was admitted for hypertensive emergency. Laboratory results: BUN 48 mg/dL, SCr 11.4 mg/dL, B-type natriuretic peptide 2350 pg/mL, troponin T 1.5 mcg/L (less than 0.1 mcg/L), creatinine kinase 227 U/L, and myokinase 22 U/L. Which one of the following is the best medication to manage A.W.’s hypertensive emergency? A. IV nitroglycerin 5 mcg/minute, titrated to 25% reduction in mean arterial pressure. B. Labetalol 2 mcg/minute, titrated to 50% reduction in mean arterial pressure. C. Sodium nitroprusside 0.25 mcg/kg/minute, titrated to 25% reduction in mean arterial pressure. D. Clonidine 0.1 mg PO every 2 hours as needed, 50% reduction in mean arterial pressure.



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Decompensated HF and Cardiogenic Shock1. Adams KF, Lindenfeld J, Arnold JMO, et al.

Executive summary: HFSA 2006 comprehensive heart failure practice guideline. J Card Fail 2006;12:10–38.

2. Nohria A, Lewis E, Warner Stevenson LW. Medical management of advanced heart failure. JAMA 2002; 87:628–40.

Acute Dysrhythmias1. Fuster V, Ryden LE, Cannom DS, et al. ACC/

AHA/ESC 2006 guidelines for the management of patients with atrial fi brillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). Circulation 2006;114:700–52.

2. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death—executive summary: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). Circulation 2006;114:1088–132.

3. Blomström-Lundqvist C, Scheinman MM, Aliot EM, et al. ACC/AHA/ESC 2003 Guidelines for the management of patients with supraventricular arrhythmias—executive summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients with Supraventricular Arrhythmias). JACC 2003;42:1493–531.

4. Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee on Pacemaker Implantation). 2002.

5. American Heart Association. 2005 guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2005;112:1–211.

Acute Coronary Syndromes1. Antman EM, Anbe DT, Armstrong PW, et al.

ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation 2004;110:588–636.

3. Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines (Committee to Update the 1999 Guidelines on Coronary Artery Bypass Graft Surgery). Circulation 2004;110:1168–76.

4. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Circulation 2007;50:e1–157.

6. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2006;47:e1–121.

Pulmonary Arterial Hypertension1. Badesch DB, Abman SH, Ahearn S, et al. Medical

therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:35S–62S.

2. Badesch DB, Abman SH, Simonneau G, et al. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest 2007;131:1917–28.

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3. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006;114:1417–31.

4. McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:14S–34S.

Hypertensive Emergency1. Haas AR, Marik PE. Current diagnosis and

management of hypertensive emergency. Semin Dial 2006;19:502–12.

2. Marik PE, Varon J. Hypertensive crises: challenges and management. Chest 2007;131:1949–62.



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1. Answer: C This patient has ADHF and is receiving a β-blocker. Although long-term β-blockers can improve HF symptoms and reduce mortality, in the short term, β-blockers can worsen symptoms. It is recommended to maintain the maintenance β-blocker therapy at the same or slightly reduced dose compared with outpatient therapy in patients with ADHF, and increasing the dose may acutely worsen symptoms and CO. In patients who are admitted with volume overload without signifi cant signs of decreased CO, it is reasonable to fi rst try IV loop diuretics. As gastrointestinal edema increases, oral loop diuretics (notably furosemide) become less effective because of decreased absorption. Nesiritide is a vasodilatory medication that can be initiated if IV loop diuretic therapy fails, but because of its adverse effects and signifi cant cost, it is not recommended before a trial of IV diuretics. Milrinone is an inotropic medication. Due to their adverse effects Inotropes are recommended in cold/wet exacerbations after vasodilatory medications have failed.

2. Answer: A Intravenous vasoldilators are reasonable options if IV diuretics fail and the patient needs further diuresis and afterload reduction. Although nesiritide is linked with the potential for worsening SCr in a meta-analysis, its use is not contraindicated in patients with pre-existing renal insuffi ciency. This patient is demonstrating signs of a “warm and wet” exacerbation and has experienced failure with IV loop diuretics and the addition of the thiazide diuretic metolazone, so the addition of a vasodilatory medication such as nesiritide is the most appropriate option in this patient at this time. Sodium nitroprusside can lead to thiocyanate toxicity in patients with severe renal insuffi ciency, so it is contraindicated in this case. Dobutamine is typically used in states of low CO decompensation and is counteracted by concomitant β-blocker therapy, making it a poor choice in patients receiving β-blockers. Although milrinone is a more acceptable inotropic medication in a patient receiving β-blockers, the dosing strategy in this case is not appropriate for the degree of renal insuffi ciency this patient exhibits. Because of its renal clearance, milrinone must be dose adjusted if creatinine clearance is less than 50 mL/minute.

3. Answer: A Signs of a decreased CO state in HF, such as increased SCr, decreased mental status, and cool extremities, indicate that a “cold and wet” state exists and that adjunctive therapy is needed. Positive inotropic agents, such as milrinone, will increase cardiac output to

maintain perfusion to vital organs. Milrinone will also vasodilate the peripheral vessels to unload the heart (↓ systemic vascular resistance). The milrinone dose has been adjusted to accommodate the patient’s degree of renal insuffi ciency. Again, although dobutamine would be a potential choice in this patient, it is not recommended in patients receiving β-blockers. Low-dose nitroglycerin will cause venous dilation; however, this patient would benefi t from arterial dilation as well. Only higher doses of nitroglycerin will cause arterial dilation. Phenylephrine has no positive β effects, so it will not augment contractility. In addition, it will cause vasoconstriction through α-stimulation, which will further increase systemic vascular resistance and likely worsen CO. Vasoconstrictors are reserved for patients in cardiogenic shock. Although this patient does exhibit signs of signifi cant hypoperfusion, the BP remains preserved.

4. Answer: A Treatment options for sustained ventricular tachycardia are dependent on concomitant disease states. In a patient with left-ventricular dysfunction, class I agents such as procainamide are contraindicated. In a patient with creatinine clearance less than 60 mL/minute, sotalol requires signifi cant dosage reduction to avoid excess torsade de pointes. Sotalol is not an effective cardioversion medication and is more useful for preventing future episodes of arrhythmias (maintaining sinus rhythm) once sinus rhythm is achieved. Dofetilide is indicated only for atrial fi brillation, not for ventricular arrhythmias, and similarly, cardioversion rates with dofetilide are low. Amiodarone is fi rst-line therapy for sustained ventricular tachycardia in patients with severe renal insuffi ciency, HF, and structural heart disease.

5. Answer: C With the prolonged half-life of amiodarone and extensive fat tissue volume of distribution, it would be expected for hyperthyroid adverse effects to last for at least 3–5 half-lives of the drug, which is anywhere from 5 to 8 months. Although therapeutic levels may fall off substantially by then, 1 month is too soon to expect the effects to subside. Even though some iodine and amiodarone molecules will remain absorbed in fat stores likely for years, if not for life, therapeutic levels should not exist longer than what is predicted by half-life.

6. Answer: A In this patient, the presence of ST-depressions on ECG, positive biomarkers for myocardial necrosis, at least three risk factors for coronary artery disease,

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and a prior history of coronary artery disease suggests high risk. (prior MI) In high-risk patients, cardiac catheterization is used to determine whether occluded or partially occluded epicardial arteries exist, which can be intervened on, and to make an intervention (stent or percutaneous transluminal coronary angiography). Glycoprotein IIb/IIIa inhibitors in combination with heparin (either unfractionated heparin or enoxaparin), aspirin, and clopidogrel have the best outcomes in the early invasive strategy. Low-molecular-weight heparins are now preferred over unfractionated heparin for managing non–ST-elevation acute coronary syndromes, but medical management alone is not optimal in such a high-risk patient. Abciximab was benefi cial only in clinical trials of primary PCI or PCI during the abciximab infusion (early invasive strategy). Abciximab was not superior to placebo when used in a conservative medical management strategy without PCI. Unfractionated heparin alone with clopidogrel has been studied in medically managed patients not pursuing catheterization (CURE trial) but was studied in a low-risk patient population. Metformin should be withheld for 24 hours prior to PCI (esprcially in those with renal dysfunction) to prevent lactic acidosis.

7. Answer: C Clopidogrel has been studied most commonly for a 30-day post-stenting procedure to prevent acute re-occlusion of coronary vessels. Because the stent is not endothelialized for a longer time after drug-eluting stent placement compared with traditional stents, a clopidogrel duration of at least 3 months is desired to prevent acute stent thrombosis (sirolimus-eluting stent). However, clopidogrel is recommended for use in combination with aspirin for at least 6 months after paclitaxel drug-eluting stent placement to prevent risk of acute stent thrombosis, and current guidelines recommend therapy for at least one year. Trials using 9–12 months of clopidogrel primarily used a medical management strategy (conservative) with unfractionated heparin, clopidogrel, and aspirin and enrolled mostly unstable angina patients, or they were elective PCI trials with low glycoprotein IIb/IIIa inhibitor use. Lifelong therapy is not warranted by any published trial to date.

8. Answer: B Doses of aspirin lower than 75 mg/day (e.g., 25 mg) have not been proven to be as effi cacious as higher doses of aspirin after combination therapy with clopidogrel after a PCI procedure. Aspirin 325 mg should be given to all patients after a PCI procedure with stent implantation throughout the recommended duration of clopidogrel therapy (1 month for bare metal stents, 3 months for sirolimus-eluting stents, and 6 months for paclitaxel-eluting stents). Once the

recommended duration of dual therapy is completed, patients should receive a reduced dose of 75–162 mg/day to prevent gastrointestinal and bleeding complications, and 81 mg is within this range of doses (class I, LOE B). There is no evidence that a higher dose of aspirin (650 mg) has any benefi t over lower doses of aspirin, and it has a higher risk of adverse effects, so it is not recommended.

9. Answer: A Although this patient presented within 3 hours of chest pain onset and is a thrombolytic candidate (within less than 6 hours of onset is preferred), up to 95% of patients can achieve normal, brisk TIMI-3 fl ow rates with primary PCI, versus only 50%–60% of patients achieving normal TIMI-3 coronary fl ow with thrombolytic therapy. Because he is in a hospital that can perform a primary PCI with stent implantation, this is the therapy of choice. Although glycoprotein IIb/IIIa inhibitors have been studied in combination with thrombolytics and anticoagulants for STEMI, the slight increase in TIMI-3 blood fl ow rates was accompanied by a signifi cantly increased risk of bleeding; thus, they are not recommended. Tirofi ban and unfractionated heparin alone are not indicated for treatment of ST-elevation MI (recommended for medical management of non–ST-elevation acute coronary syndrome only).

10. Answer: C Unlike the patient in case 9, this patient presented with an ST-elevation MI to a rural community hospital. He presents within the window for thrombolytic therapy consideration (less than 6 hours after chest pain onset). He is experiencing complete heart block and bradycardia, which could indicate an occlusion above the area perfusing his SA and/or AV nodes. Because he is still having ischemic chest pain and ST-segment elevation, he should benefi t from reperfusion therapy. Enoxaparin is a treatment option for medical management, but the patient is at higher risk of bleeding from impaired enoxaparin clearance and will require dosage adjustment. Simply managing this patient conservatively with unfractionated heparin alone in the setting of ongoing chest pain, shortness of breath, and pulmonary edema is not an optimal choice. Diagnostic catheterization and possible PCI to determine whether an artery can be reperfused is not desirable because of the patient’s elevated SCr (creatinine clearance 35 mL/minute). Because of the shorter half-life and ease of administration of tenecteplase, it is preferable to alteplase. Clearance of unfractionated heparin is not as altered as enoxaparin and would be a more appropriate therapy than enoxaparin in combination with a thrombolytic.



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11. Answer: C This patient is already receiving calcium channel blocker therapy to control her HR caused by atrial fi brillation. She is on a signifi cant dose of diltiazem, and her HR likely would not tolerate further increases in therapy. Sildenafi l is indicated for functional class I patients or patients who have failed all other therapies. Although bosentan is an attractive oral option to manage her PAH, her liver enzymes are elevated more than 3 times the upper limit of normal. In this setting, administering bosentan is not recommended. If liver transaminases are elevated transiently because of hepatic congestion, bosentan may be reconsidered later. Because this patient is currently in functional class IV with symptoms at rest, epoprostenol is indicated for a survival benefi t.

12. Answer: A Hypertensive emergency should be immediately treated by a 25% reduction in mean arterial pressure, followed by slow reduction to goal for 5–7 days. This patient’s comorbidities guide which therapy is optimal. His dialysis and SCr of 11.4 mg/dL are a contraindication to sodium nitroprusside because of possible cyanide toxicity. Labetalol (β-blockers in general) therapy is controversial for patients who have taken cocaine, but its nonselective nature makes it an option; however, a reduction of 50% initially is too rapid a decrease in BP for safety. Clonidine is not an appropriate medication for hypertensive emergency, because its unpredictable oral nature is diffi cult to titrate and can lead to precipitous drops in BP beyond the goal 25% reduction and possible stroke or worsening MI. Nitroglycerin is an optimal choice, considering the patient’s lack of contraindications to this therapy and his evolving MI.



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1. Answer: CBosentan is an inducer of cytochrome P450 3A4 and 2C9 isoenzymes. Bosentan has been shown to decrease the plasma concentrations of all hormonal contraceptive medications, including both estrogen- and progesterone-containing formulations, because of its effects on cytochrome P450 metabolism. No hormonal contraceptive, including oral, injectable, topical (patch), and implantable formulations, should be used as the only means of contraception because these may not be effective in preventing pregnancy in patients on bosentan. Use of a double-barrier method with a condom and diaphragm plus spermicide is indicated in patients receiving bosentan and hormonal contraceptives. Because bosentan is also a known teratogen, a barrier method alone may not be a suffi cient form of contraception.

2. Answer: CPatients with dietary and/or drug noncompliance most commonly present with “warm and wet” exacerbation of their HF. Although they are well perfused and CO has not signifi cantly changed (i.e., disease has not progressed), their habits have caused them to retain excess fl uid. Dobutamine and milrinone primarily act to increase CO, which is not a signifi cant problem in warm and wet exacerbations. In addition, the adverse effects of these agents (increased mortality and proarrhythmias) limit their use. Nesiritide is a balanced arterial and venous dilator that decreases afterload and preload, respectively, and is the best choice for this patient without an invasive hemodynamic monitoring catheter in place. Although IV nitroglycerin is effective in warm and wet exacerbations, its use requires dosage titration by a Swan-Ganz catheter or central venous catheter, which is not in place in this patient at this time.

3. Answer: BThis patient is exhibiting target organ damage from poorly controlled hypertension in the form of a cerebrovascular accident. Nicardipine is an appropriate choice in this patient, because its calcium channel blocking effects will reduce BP and potentially decrease vasospasm in the cerebral arteries, which may lead to further ischemia or seizure activity. Although fenoldopam is indicated for treating hypertensive emergency, its use is cautioned in patients with stroke symptoms, because its dopamine agonist activity can cause cerebral vasodilation and potentially reduced blood fl ow to the ischemic areas of the brain. Although labetalol is an effective option for treating H.E.’s hypertensive emergency, she has a history of asthma and a low HR, making this drug a

less-than-ideal option for treating her symptoms. The antihypertensive effects of enalaprilat are dependent on a given patient’s renin activity, which is not known in this patient. Therefore, the BP-reducing effects may be more diffi cult to control than a drug with a more consistent effect in individuals. In addition, the bolus nature of the drug is not ideal for tightly controlling BP with a 25% reduction in mean arterial pressure. Continuous infusion drugs are preferable for easier titration to effect in hypertensive emergency.

4. Answer: DAlthough several drug classes for treating acute MI are linked with thrombocytopenia, the timeframe in which the thrombocytopenia occurs is key in distinguishing which agent is causative. Although unfractionated heparin can produce a rapid drop in platelets on reexposure, the nadir in platelet count is typically around 50 × 103/mm3. Adenosine diphosphate inhibitors, particularly ticlopidine, are linked with rare, isolated thrombocytopenia. Clopidogrel is known to rarely cause thrombotic thrombocytopenic purpura, which causes thrombocytopenia and a constellation of other symptoms (mental status changes, acute renal failure, etc.) usually lasting for a longer treatment duration of weeks to months after therapy initiation. Abciximab can cause acute profound thrombocytopenia in approximately 1.5% of patients treated. The timeframe is nearly immediate (usually within 2–24 hours of administration initiation) and causes a nadir of about 20 × 103/mm3 platelets.

5. Answer: CThe number needed to treat can be calculated by 1/absolute risk reduction. Because the absolute risk reduction in mortality at 60 months was 7.2% with ICD versus placebo, 1/0.072 would be used to calculate the number of patients needed to treat to prevent one death during this time. Approximately 13.8 patients would need to be treated with ICD to prevent one death in 60 months versus placebo. Other calculations in this fashion, including relative risk reduction, do not provides useful information for interpreting the trial results.

6. Answer: CThe Cardiac Arrest Study Hamburg trial compared ICD implantation with antiarrhythmic therapy in cardiac arrest survivors for secondary prevention of sudden cardiac death. The propafenone study arm was discontinued early because it had a signifi cantly (61%) higher mortality rate than ICDs. Although this trial had a small sample size that prevented a statistically signifi cant difference in total mortality from being

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shown in ICD-treated patients versus patients treated with either amiodarone or metoprolol, the incidence of sudden death was signifi cantly reduced in patients with an ICD implanted (33% versus 13%, p=0.005). The AVID trial also evaluated ICD implantation versus antiarrhythmic drug therapy (primarily amiodarone) in survivors of sudden cardiac death. Patients implanted with ICDs had a signifi cantly greater rate of survival than those treated with drug therapy (89% versus 82%, p<0.02).

7. Answer: DS.V. has a depressed LVEF less than 40%, so her drug therapy options are limited to prevent development of worsening HF, which could occur if she were administered procainamide for treatment of her arrhythmia. Procainamide is indicated only in secondary prevention of sustained ventricular tachycardia (SVT) in patients with a normal LVEF more than 40%. Metoprolol is indicated only for treatment of patients with symptomatic nonsustained ventricular tachycardia and SVT associated with CAD. S.V. had a symptomatic episode of SVT. Her QTc interval is not prolonged at 380 milliseconds, so she does not require IV magnesium therapy. She qualifi es for treatment with either amiodarone or lidocaine. Amiodarone is fi rst line for patients without contraindications because of its effi cacy.

8. Answer: DInternational Pharmaceutical Abstracts is a database of primarily pharmaceutical abstracts in more than 750 journals, including foreign pharmacy journals and state pharmacy journals, in addition to key U.S. medical and pharmacy journals. Many of the citations are not included on MEDLINE, so a broader search can be performed; however, subject descriptors are not consistently defi ned in a uniform way, and multiword terms are often cited backward. Iowa Drug Information Service is a database that offers full-text articles from 1966 in approximately 200 medical and pharmacy journals (primarily U.S.-based journals). It is updated monthly, so newly available articles may take longer to be accessed from this service. ClinAlert is a database of more than 100 medical and pharmacy journals focused on adverse events, drug interactions, and medical-legal issues. It is used primarily to look up adverse events (especially recent reports) associated with medications. EMBASE is a comprehensive database of more than 4000 journals from 74 countries dating from 1974 to the present. Recently published articles appear in the system within 10 days of article publication, and this database often contains data not found in a typical MEDLINE search.

9. Answer: BMedWatch is a post–U.S. Food and Drug Administration approval program established by the U.S. Food and Drug Administration for health care professionals to report adverse events to the U.S. Food and Drug Administration that occur after a drug is approved. Although it is commonly used only for reporting serious reactions to the U.S. Food and Drug Administration, it can be used to report any adverse event. Information recorded on these forms is reported to the manufacturer and is used to determine whether black box warnings are necessary or whether new adverse effects are seen with a drug. The Joint Commission on Accreditation of Healthcare Organizations requires that all institutions have a defi nition of an ADR for the institution that all health care professionals can understand and remember. In addition, the Joint Commission on Accreditation of Healthcare Organizations requires that each dose of drug administered be monitored for adverse effects, that each institution have a system for reporting ADRs in place, and that the institution ensure that the reporting mechanism is identifying all key ADRs.

10. Answer: BBecause the Pharmacy and Therapeutics committee wants to discover whether the new drug is worth the extra cost for the added mortality benefi ts it can provide for patients with decompensated HF over currently available therapies, a cost-effectiveness analysis is the best pharmacoeconomic analysis to perform. Cost-minimization analysis is used to determine whether a therapeutically equivalent drug within a class that provides the same therapeutic outcome as others available can be used for less cost. Cost-utility analysis is used to determine whether a drug can improve the quality of a patient’s life more than other available therapies. Cost-benefi t analysis is used to evaluate new programs or services to determine whether they provide enough benefi t to be worth the cost to run the program.



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NOTES

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Critical CareTudy Hodgman, Pharm.D., BCPS, FCCM

Midwestern UniversityNorthwest Community Hospital

Arlington Heights, Illinois

Gretchen M. Brophy, Pharm.D., FCCP, BCPSVirginia Commonwealth University

Richmond, Virginia

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Learning Objectives:

1. Identify and distinguish between the four primary acid-base disturbances and the expected compensatory responses when provided clinical presentation and laboratory data, including arterial blood gases.

2. Select appropriate management (drug and nondrug) for the four primary acid-base disturbances.

3. List the indications for mechanical ventilation.

4. Describe the indications for sedation, neuromuscular-blocking drugs, and antidelirium drugs in mechanically ventilated patients.

5. Select appropriate agents for the sedation, neuromuscular blockade, and control of delirium in mechanically ventilated patients.

6. Distinguish between the different types of shock.

7. Select appropriate pharmacotherapeutic management for severe sepsis and shock.

8. Describe the pharmacotherapy of cardiac arrest.

9. List the risk factors and select appropriate pharmacotherapy for the prevention of stress-related mucosal damage.


1. A 58-year-old woman remains intubated in the intensive care unit (ICU) after a recent abdominal surgery. In the operating room, she received more than 10 L of fl uid and blood products but has been aggressively diuresed since that time. In the past 3 days, she has generated 7.5 L of urine output, and her blood urea nitrogen (BUN) and serum creatinine (SCr) have steadily increased to 40 and 1.5 mg/dL, respectively. Her urine chloride concentration was 9 mEq/L (24 hours after her last dose of furosemide). This morning, her arterial blood gas reveals pH 7.50, partial pressure of carbon dioxide in arterial blood (PaCO2) 46 mm Hg, and bicarbonate (HCO3

-) 34 mEq/L. Which one of the following actions is best to improve her acid-base status?

A. Sodium chloride infusion. B. Hydrochloric acid infusion. C. HCO3

- 100 mEq for 30 minutes. D. Increased tidal volume on the mechanical

ventilator. 2. A 21-year-old man post-gunshot wound to the

abdomen is receiving mechanical ventilation and is thrashing around in bed and pulling at his breathing tube. He is considered very agitated. He is receiving morphine 4 mg/hour intravenously for control of pain, which is currently 3/10. Vital signs include blood pressure (BP) 110/70 mm Hg and HR 110 beats/minute. What is the most appropriate intervention to control this patient’s agitation? A. Initiate propofol 50 mcg/kg/minute

intravenously. B. Give lorazepam 3 mg intravenous load

followed by lorazepam 3 mg/hour intravenously.

C. Give haloperidol 10 mg intravenously 1 time.

D. Give lorazepam 3 mg intravenous load followed by lorazepam 3 mg/hour intravenously, and give haloperidol 10 mg intravenously 1 time.

3. A patient is admitted to the ICU for a traumatic

brain injury and multiple abdominal injuries. He is started on a high dose of propofol, morphine, and vecuronium for sedation, analgesia, and paralysis to help control his intracranial pressure. On day 3 of hospitalization, the patient develops pancreatitis and requires total parenteral nutrition. He is started on a 2-in-1 total parenteral nutrition and given lipids 20% 250 mL/day. His electrolytes on day 5 are within normal limits, with the exception of an elevated magnesium concentration. His train-of-four is 0/4. His current medications include piperacillin/tazobactam 4.5 g intravenously every 8 hours and tobramycin 350 mg/day intravenously for a possible pancreatic abscess. Which one of the following pharmacotherapeutic issues is a concern in this patient? A. Vecuronium and propofol are having an

additive effect on sedation. B. High magnesium concentrations and

tobramycin can inhibit the effects of vecuronium.

C. Propofol needs to be considered in his daily nutritional assessment.

D. Morphine is antagonized by propofol and may require a dosage increase.

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4. A 43-year-old man in the medical ICU has been receiving mechanical ventilation for 3 days for management of a severe asthma exacerbation. He is sedated and comfortable and responds to commands. The patient reports no pain, and no wheezes are heard on examination. During patient care rounds in the morning, the medical team decides to start weaning the patient from the ventilator. The current sedation regimen is lorazepam 3 mg/hour intravenously continuously and morphine 2 mg/hour intravenously continuously. Which one of the following interventions will most likely hasten the weaning process and his discharge from the ICU? A. Continue the current sedation regimen. B. Continue lorazepam, discontinue morphine,

and initiate fentanyl at 50 mcg/hour intravenously continuously.

C. Stop all sedation and wait for the patient to fully awaken.

D. Continue lorazepam and discontinue morphine.

5. A 62-year-old woman is admitted to your ICU

for respiratory dysfunction requiring mechanical ventilation. Her medical history is nonsignifi cant, and she is currently on no medications at home. Her chest radiograph shows bilateral lower lobe infi ltrates, her white blood cell (WBC) count is 21,000, temperature is 39.6°C, BP 82/45 mm Hg (normal for her is 115/70 mm Hg), and HR is 110 beats/minute. She is diagnosed with community-acquired pneumonia and is empirically started on ceftriaxone 1 g intravenously daily and levofl oxacin 500 mg/day intravenously. Thirty-six hours later, the patient’s temperature is 38.6°C, WBC count is 16,000, and PaO2/fractional concentration of oxygen in inspired gas (FiO2) ratio is 200. She remains hypotensive even after fl uid resuscitation, and her SCr has increased from 0.5 on admission to 3.2 mg/dL. She is started on a dopamine drip for BP support. Her APACHE II score is 26. Which one of the following drug therapies should you recommend for this patient at this time? A. Continue current antibiotics and monitor the

patient for clinical improvement. B. Initiate a 96-hour infusion of drotrecogin-α

and titrate to a partial prothrombin time of 60–80; continue current antibiotics.

C. Initiate a 96-hour infusion of drotrecogin-α and monitor for bleeding; reevaluate current antibiotics based on culture and sensitivities.

D. Continue current antibiotic therapy and evaluate for drotrecogin-α in 24 hours.

6. A 92-year-old woman is admitted to the ICU with urosepsis and septic shock. She is living in a nursing home and has a medical history signifi cant for myocardial infarction, hypertension, and congestive heart failure. Her BP is 72/44 mm Hg, HR 120 beats/minute, O2 saturation of 99%, and laboratory tests normal, except for a BUN of 74 mg/dL and a Cr of 2.7 mg/dL. Empiric antibiotics were started. Which one of the following therapies should be initiated next? A. Dobutamine. B. Epinephrine. C. Normal saline. D. Vasopressin.

7. A trauma patient is admitted to the ICU and found to be in hypovolemic shock after massive blood loss. She is given multiple blood transfusions and 6 L of intravenous fl uids. Her medical history is signifi cant for a myocardial infarction 2 years ago. The patient’s HR is 105 beats/minute, and BP is 89/45 mm Hg; the team starts dopamine at 5 mcg/kg/minute. The BP does not increase, but the HR increases to 138 beats/minute. Which one of the following is the best vasopressor recommendation for this patient? A. Increase the dose of dopamine to 8 mcg/kg/

minute. B. Add a vasopressin continuous infusion at

0.06 units/minute. C. Initiate phenylephrine continuous infusion

at 100 mcg/minute. D. Initiate epinephrine 1 mg intravenous push

every 3–5 minutes.

8. A 46-year-old man had a witnessed cardiac arrest in an airport terminal. When emergency medical services arrived and defi brillator pads were applied, pulseless ventricular tachycardia was observed. He was defi brillated with 200, 300, and 360 J without return of spontaneous circulation. Epinephrine 1 mg intravenous push was given, and chest compressions and artifi cial respirations were initiated. Within 1 minute, the patient was reassessed. The cardiac monitor still shows ventricular tachycardia, and he remains pulseless; therefore, another shock of 360 J is given. Which one of the following drugs should be administered within the next minute of cardiopulmonary resuscitation? A. Atropine 1 mg intravenously. B. Epinephrine 3 mg intravenously. C. Vasopressin 10 units intravenously. D. Amiodarone 300 mg intravenously.

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9. A study comparing seven different drug regimens for the treatment of actively bleeding peptic ulcer disease is being conducted in your ICU (n=75 patients per group). The primary outcome is the time (measured in minutes) to cessation of clinically evident bleeding. Which one of the following statistical tests is most appropriate for the comparison of the means between treatment groups? A. Paired t-test. B. t-test for independent samples. C. Analysis of covariance. D. Analysis of variance.

10. C.J. is a 22-year-old man admitted to the trauma ICU after a motor vehicle accident. He has multiple rib fractures, a ruptured spleen, and a small brain contusion. He is taken to the operating room for a splenectomy, and the trauma team places a postpyloric nasojejunal (NJ) feeding tube before returning him to the ICU. The patient is unresponsive and mechanically ventilated. Which one of the following is the best recommendation for stress ulcer prophylaxis (SUP)? A. Pantoprazole intravenously. B. Famotidine suspension by NJ tube. C. Sucralfate slurry by NJ tube. D. The patient needs no SUP.

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I. ACID-BASE DISORDERS

Primary Acid-Base DisturbancesA. 1. Respiratory acidosis

a. EtiologiesPulmonary/cardiovascular (massive pulmonary embolus)/cardiopulmonary arresti. Central nervous system depression (anesthesia, trauma, stroke, medications)ii. Impaired chest bellows (severe pulmonary edema, severe pneumonia, acuteiii. respiratory distress syndrome, end-stage chronic obstructive pulmonary disease)Spinal cord or peripheral nerve injuryiv.

Compensation: renalb. HCO3

- increases by 1 mEq/L above normal (24 mEq/L) for every 10mm Hg increase in partial pressure of carbon dioxide (pCO2) above normal (40 mm Hg) ACUTELY or 4 mEq/L for CHRONIC

c. TreatmentOxygeni. Treat causesii.

2. Respiratory alkalosisa. Etiologies

Central nervous system–mediated respiratory stimulation (anxiety, pain, injury, i. central nervous system tumor, stroke, head trauma)Hypoxia-induced respiratory stimulation (high altitude, hypotension, pulseless ii. electrical activity, congestive heart failure, pneumonia, medications [salicylates, nicotine, thyroid hormones, catecholamines, theophylline])

b. Compensation: renal HCO3- decreases by 2–3 mEq/L below normal (24 mEq/L) for

every 10mm Hg decrease in pCO2 below normal (40 mm Hg) ACUTELY or 5 mEq/L for CHRONIC

c. TreatmentHypoventilationi. Sedationii.

3. Metabolic acidosisa. Anion gap = [Na+] − ([Cl-] + [HCO3

-]) Normal anion gap = (140) − (104 + 24) = 12 ± 2 mEq/L = 10–14 mEq/L

b. EtiologiesElevated anion gap: i. Methanol

Uremia Diabetic ketoacidosis Poisoning/propylene glycol ingestion Intoxication/infection Lactic acidosis/lactate Ethylene glycol Salicylates/sepsis

Normal anion gap (nongap-hyperchloremic)-bicarbonate loss is accompanied by ii. increased renal reabsorption of Cl-): diarrhea, lower GI losses, ileostomy, acid ingestion, carbonic anhydrase inhibitors, renal tubular acidosis

iii. Compensation: respiratory pCO2 decreased by 1–1.5 mm Hg below normal (40 mm Hg) for each 1-mEq/L decrease in HCO3

- below normal (24 mEq/L)d. Treatment

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pH 7.20–7.35: correct causesi. pH less than 7.20: ii. consider direct administration of base

HCO(a) 3- Calculate bicarbonate defi cit (in mEq) = (body wt)(0.4 L/kg)(24 − serum

HCO3-)

Give 50 mEq intravenous bolus and then infusion (150 mEq of NaHCO in 1 L of dextrose 5% in water [D5W]). May replace up to half of bicarbonate defi cit during 4 hours. Tromethamine(b) Bicarbonate equivalents: for mild and/or chronic disease(c) (1) Citrate (oral)(2) Acetate (parenteral)(3) Lactate (parenteral)

4. Metabolic alkalosisa. Etiologies

Net loss of hydrogen ioni. Net gain of bicarbonateii.

Saline-resistant (urine Cl(a) - more than 20 mmol/L) Hyperaldosteronism Mineralocorticoid excess (Cushing or Bartter’s syndrome) Severe K+ depletionSaline-responsive urine (Cl(b) - less than 10 mmol/L); chloride loss is the culprit (loss of Cl-rich, bicarbonate-poor fl uid)—GI disorders, diuretics, cystic fi brosis, chronic respiratory acidosis

b. Compensation: respiratory: pCO2 increases by 0.6–0.7 mm Hg above normal (40 mm Hg) for every 1mEq/L increase in HCO3

- above normal (24 mEq/L)

c. TreatmentSaline-resistant treatment: correct the causes (renal or adrenal disease)i. Saline-responsive treatment pH less than 7.55: intravenous normal saline pH more ii. than 7.55: HCl intravenously Calculate chloride defi cit (in milliequivalents) = (body wt)(0.2 L/kg)(103 − serum Cl-) Administer half of chloride defi cit over at least 12 hours through a central line (0.1 N HCl contains 100 mEq of chloride)

Alternatives: Ammonium chloride, Acetazolamide (Diamox)(a)

B. Detection of Acid-Base DisturbancesSerum bicarbonate: if no arterial blood gas is available (as is usually is the case), then an 1. isolated decrease (serum bicarbonate less than 20 mEq/L) or increase (serum bicarbonate more than 28 mEq/L) indicates a metabolic acidosis and alkalosis, respectively.

2. Arterial blood gas interpretation is reported as pH/pCO2/pO2/HCO3-/oxygen saturation (SaO2)

Normal values pH = 7.40 (range = 7.35–7.45) pCO2 = 40 mm Hg (range = 35–45 mm Hg) pO2 = 80–100 mm Hg HCO3

- = 24 mEq/L (range = 22–26 mEq/L) SaO2 = 95%–100% (percent hemoglobin fully saturated with O2)

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Step 1: Diagnose the acid-base disturbance a. Look at pH. Less than 7.35: acidosis More than 7.45: alkalosis b. Look at pCO2. An increased pCO2 with a low pH is a respiratory acidosis. A decreased pCO2 with a high pH is a respiratory alkalosis. c. Look at bicarbonate to verify your suspected diagnosis. An increased bicarbonate with a high pH is a metabolic alkalosis. A decreased bicarbonate with a low pH is a metabolic acidosis.

Step 2: Check for compensationa. Compensatory value is near normal or normal: little or no compensation (i.e., pCO2

should increase or decrease in response to a metabolic disturbance).b. If the compensatory value has signifi cantly changed in the appropriate direction,

then it is a compensated disturbance

Step 3: Isolate the cause(s) of the acid-base disturbance (e.g., anion gap).

Useful hints to remember for compensation:Acutea. respiratory acidosis: an acute 10-mm Hg increase in pCO2 will be buffered by an increase in HCO3

- of about 1 mEq/L.Chronicb. respiratory acidosis: a chronic 10-mm Hg increase in pCO2 will be buffered by an increase in HCO3

- of about 4 mEq/L.Acutec. respiratory alkalosis: an acute 10-mm Hg decrease in pCO2 will be buffered by a decrease in HCO3 of about 2–3 mEq/L.Chronicd. respiratory alkalosis: a chronic 10-mm Hg decrease in pCO2 will be buffered by a decrease in HCO3

- of about 5 mEq/L.Metabolic acidosis: use Winter’s formula to predict full compensation: e. expected pCO2 = 1.5 (HCO3

-) + 8 ± 2.Metabolic alkalosis: each 10-mEq/L increase in HCOf. 3

- will be buffered by an increase in pCO2 of about 6–7 mm Hg.

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Patient Cases1. A 62-year-old woman has been hospitalized in the ICU for several weeks. Her hospital course was complicated

by aspiration pneumonia and sepsis, requiring prolonged courses of antibiotics. During the past few days, she has begun spiking fevers again, and her stool output has increased dramatically. Her most recent stool samples have tested positive for Clostridium diffi cile toxin, and her laboratory tests show serum Na 138 mEq/L; K 3.5 mEq/L; Cl 115 mEq/L; albumin 4.4 g/dL; pH 7.32; PaCO2 30 mm Hg; and HCO3

- 15 mEq/L. Which one of the following acid-base disturbances is consistent with this patient’s arterial blood gas? A. Anion gap metabolic acidosis. B. Normal anion gap metabolic acidosis. C. Saline-responsive metabolic alkalosis. D. Acute respiratory acidosis.

2. An 18-year-old man with no medical history is brought to the emergency department in a semicomatose state. His parents report that he was complaining of a vague abdominal pain earlier in the morning, and then began vomiting and urinating frequently in the hours before admission. His toxicology screen proved negative for drugs of abuse, but his urine tested positive for ketones. Laboratory tests show serum Na 142 mEq/L; K 4.5 mEq/L; Cl 100 mEq/L; glucose 795 mg/dL; lactate 1.0 mmol/L; pH 7.26; PaCO2 23 mm Hg; and HCO3

- 10 mEq/L. Which one of the following acid-base disturbances is consistent with this patient’s arterial blood gas? A. Anion gap metabolic acidosis. B. Normal anion gap metabolic acidosis. C. Saline-responsive metabolic alkalosis. D. Acute respiratory acidosis.

3. A 27-year-old man with no medical history is admitted to the hospital after being “found down” at a party, where he reportedly ingested a fi fth of whiskey during a 20-minute period. On arrival to the emergency department, he was neurologically unresponsive and had the following arterial blood gas values: pH 7.23, PaCO2 58 mm Hg, PaO2 111 mm Hg, HCO3

- 24 mEq/L, and SaO2 100% on 2 L/minute of oxygen by nasal cannula. Which one of the following actions is best?A. Albuterol 4 puffs every 20 minutes for 4 hours; then, 2–4 puffs every 2–4 hours as needed.B. 100% oxygen by face mask.C. HCO3

- 100 mEq over 30 minutes.D. Intubate and transfer to the ICU.

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II. RESPIRATORY FAILURE AND MECHANICAL VENTILATION

Table 1. Indications for Intubation/Mechanical Ventilation

Indication Examples Diagnostic Test Ventilation Indicated

Hypoventilation(hypercapnic respiratory failure)

Hypoxemia (hypoxic respiratory failure)

Airway protection

Drug overdoseNeuromuscular diseaseCardiopulmonary resuscitationCentral nervous system injury or disease

Pulmonary injury or diseasePneumoniaPulmonary edemaAdult respiratory distress syndrome

Loss of airway patency (mechanical obstruction, tracheal/chest wall injury)

Loss of gag/cough refl ex with large volume aspiration risk (central nervous system injury, central nervous system depression, CVA, seizures, cardiac arrest, etc.)

PaCO2

PaO2SaO2

CXR, RR, airfl ow assessment

Gag/cough refl ex

> 50–55 mm Hg

< 60 mm Hg< 88%–92%

Lack of airway, RR persistently < 6

Loss of consciousness, negative gag refl ex

CVA = cerebrovascular accident; CXR = chest x-ray; RR = respiratory rate.

Acute Respiratory Distress SyndromeA. 1. Defi nition: clinical syndrome including respiratory distress, severe hypoxemia, diffuse chest

radiography infi ltrates, decreased lung compliance, and an association with an underlying medical or surgical conditionEtiologies: sepsis, trauma, pneumonia, pancreatitis, burns, noxious inhalation, emboli 2. (amniotic, fat, air), massive blood transfusions, eclampsia, radiation, poisonings, others

3. PathophysiologyInfl ammatory phase – exudative phasea.

Mediators of injuryi. Apoptosisii. Endothelial injuryiii. Epithelial injuryiv. Cytokine cascadev. Pulmonary vascular dysregulationvi.

b. Fibroproliferative phase – chronic phaseRepair phase of acute respiratory distress syndromei. Fibrosisii. Angiogenesisiii.

c. Recovery phase4. Diagnostic criteria (American-European Consensus Conference on Acute Respiratory Distress Syndrome, 1994)

a. PaO2/FiO2 ratio less than 200 (acute lung injury requires PaO2/FiO2 ratio 200–300)b. Chest radiograph with bilateral pulmonary infi ltrates consistent with pulmonary edema

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c. No clinical or pulmonary artery catheterization evidence of heart failure (pulmonary artery occlusion pressure less than 18 mm Hg)

5. Clinical featuresa. Rapid (within 12–48 hours of insult) development of dyspnea at rest and hypoxemia

(PaO2 less than 60 mm Hg, SaO2 less than 90%)b. Decreased lung compliancec. Tachypnea (respiratory rate more than 20)d. Small VT (less than 5 mL/kg)

6. Nonpharmacologic managementa. Mechanical ventilation (may require deeper sedation)

Pressure-cycled (pressure-targeted) ventilationi. Limit V1. T to 4–6 mL/kg.Limit plateau pressure to less than 30 cm H2. 2O.

Permissive hypercapnia: allow pCOii. 2 to rise to meet the above objectives; keep pH more than 7.25.Titrate positive end-respiratory pressure to keep PaOiii. 2/FiO2 ratio more than 200 without cardiac compromiseTitrate FiOiv. 2 down as quickly as possible (less than 55%)

Fluid restrictionb. 7. Pharmacologic management

a. Fluid managementb. Lung-specifi c pharmacotherapy

Correction of physiologic abnormalitiesi. Inhaled nitric oxide(a) Surfactant(b) Perfl uorocarbons(c)

Suppression of lung infl ammationii. Corticosteroids: after 7 days but before 28 days of acute respiratory distress (a) syndrome; methylprednisolone 1 mg/kg intravenously every 12 hours (or 2 mg/kg/day) for 14 days, 1 mg/kg/day for 7 days, 0.5 mg/kg/day for 7 days, 0.25 mg/kg/day for 2 days, 0.125 mg/kg/day for 2 days, and then stopOther anti-infl ammatory agents were not effective.

Patient Cases4. A 55-year-old woman with a history of severe chronic obstructive pulmonary disease is admitted after several

days of worsening shortness of breath. Recently, she was discharged from the hospital after a similar episode and was doing fi ne until 3 days before admission, when she developed a productive cough. This cough required an increase in her home O2 and more frequent use of her metered-dose inhalers. On admission to the medical ICU, she was anxious and markedly distressed with rapid, shallow breaths. She was hypertensive (160/80 mm Hg), tachycardic (140 beats/minute), and tachypneic (28). Her arterial blood gas showed pH 7.30, PaCO2 59 mm Hg, PaO2 50 mm Hg, HCO3

- 28 mEq/L, and SaO2 83% on 6 L/minute of oxygen by face mask, and she was immediately intubated. Which one of the following acid-base disturbances is consistent with this patient’s presentation and laboratory data? A. Metabolic acidosis. B. Metabolic alkalosis. C. Respiratory acidosis. D. Respiratory alkalosis.

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III. SEDATION IN MECHANICALLY VENTILATED PATIENTS

A. Goals of ICU Sedation (set a goal, evaluate response, and communicate)1. Improve oxygenation/ventilator interaction.2. Decrease anxiety/stress response.

Initiate a. after achieving adequate analgesia, and treat reversible causes.Assess pain response to therapy regularly with a scale/tool appropriate for patient (e.g., b. visual analog scale, critical care pain observation tool).

3. Avoid self-injury.4. Allow completion of invasive patient care.5. Promote normal sleep cycles.

B. Complications of ICU Sedation1. Prolonged ICU stay2. Prolonged mechanical ventilation3. Physiologic dependence (withdrawal reactions)4. Respiratory depression5. Delirium

5. Her initial ventilator settings included assist control mode at a rate of 20 breaths/minute (although she is still breathing 36 times/minute) with a tidal volume of 700 mL and an FiO2 of 100%. A subsequent arterial blood gas showed pH 7.54, PaCO2 34 mm Hg, PaO2 49 mm Hg, HCO3

- 28 mEq/L, and SaO2 82%. Which one of the following acid-base disturbances is consistent with this arterial blood gas? A. Mixed metabolic acidosis with a respiratory alkalosis. B. Mixed metabolic acidosis with a respiratory acidosis. C. Mixed metabolic alkalosis with a respiratory acidosis. D. Mixed metabolic and respiratory alkalosis.

Patient Cases6. Overnight, the patient in case 4 continued to breathe rapidly, appeared very agitated, and eventually began

pulling at her endotracheal tube. Her last arterial blood gas showed PaO2 55 mm Hg and SaO2 89%, despite 100% FiO2. The medical team decides to sedate her to help coordinate her breathing with the ventilator and reduce oxygen consumption. Which one of the following statements about sedatives is true? A. Lorazepam has a quicker onset of action than midazolam. B. Fentanyl causes more hypotension and histamine release than morphine. C. Haloperidol has been associated with ventricular arrhythmias. D. Propofol may accumulate in renal dysfunction.

7. An ICU patient is agitated and having diffi culty breathing. The physician decides to intubate the patient and

wants you to recommend drug therapy for sedation. Which one of the following is the best recommendation for this patient? A. Start propofol at 5 mcg/kg/minute and titrate until the patient is sedated; then, intubate the patient.B. Start lorazepam intravenous continuous infusion before intubating the patient. C. Give vecuronium intravenous bolus and start a continuous infusion; then, intubate the patient. D. Give midazolam 2.5 mg intravenously now and rebolus until the patient is sedated; then, intubate the

patient.

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C. Sedative Agents1. Benzodiazepines

Diazepam Lorazepam MidazolamTrade name Valium Ativan VersedPharmacokinetics Onset (minutes) 2–4 20–40 2–4 Duration of effect (hours) 2–4 4–6 1–2 Prolonged in renal failure Yes No Yes Prolonged in hepatic failure Yes Yes Yes Elimination half-life (hours) 24–48 10–20 1–4 Active metabolites Yes No YesAdverse effects Hypotension Yes No No Thrombophlebitis Yes Maybe No

2. Opioid analgesicsMorphine Fentanyl Hydromorphone

Trade name Various Sublimaze DilaudidPharmacokinetics Onset (minutes) 2–4 1–2 2–4 Duration of effect (hours) 2–4 1–2 2–6 Prolonged in renal failure Yes No Yes Prolonged in hepatic failure Yes Yes Yes Elimination half-life (hours) 1–3 2–5 2–3 Active metabolites Yes No NoAdverse effects Hypotension Yes No Yes Flushing Yes No Yes Bronchospasm Yes No No Constipation Yes Yes Yes

3. Miscellaneous sedative agentsa. Propofol (Diprivan)

i. Rapid onset (1–2 minutes) and short duration (3–5 minutes)ii. Starting dosage is 5 mcg/kg/minute, titrating by 5 mcg/kg/minute every 5 minutes to

achieve desired effect; no loading dose should be given because of the increased risk of hypotension.

iii. Monitor BP and triglycerides; adjust lipid content in total parenteral nutrition (if applicable).

iv. Propofol can induce apnea but is being used for conscious sedation; use caution in nonintubated patients.

v. Propofol infusion syndrome (rare and often fatal): rapid-onset metabolic acidosis with cardiac failure, rhabdomyolysis, and renal failure

b. Dexmedetomidine (Precedex)i. A selective α2-agonist with analgesic and sedative propertiesii. Short distribution (5 minutes) and elimination half-lives (2–5 hours)iii. A loading dose of 1 mcg/kg given for 20 minutes is suggested for operating

room patients; however, loading doses are NOT recommended for ICU patients (bradycardia risk).

iv. The maintenance dose is 0.2–0.7 mcg/kg/hour. The dose should be decreased in patients with hepatic insuffi ciency; maximum duration of 24 hours per U.S. Food and Drug Administration (FDA) labeling

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D. Managing ICU Sedation1. Nonpharmacologic therapy: frequent reorientation, maintain comfort and analgesia, optimize environment (e.g., lighting, noise), use relaxation techniques, back massage, music therapy2. Correct any correctable causes of agitation (endotracheal tube placement, vent settings, pain,

etc.) before pharmacologic intervention.3. Address pain management before initiating a sedative agent.4. Achieve desired level of sedation with boluses BEFORE initiating a maintenance infusion or

bolus dose regimen (“Bolus Before”).5. Regain desired level of sedation with boluses BEFORE increasing the maintenance infusion

or bolus dose regimen (“Bolus Before”).6. Evaluate adequacy of sedation using an objective sedation scale, and titrate infusion to

minimum effective dose; set goal at least daily. Goal should be comfortable, arousable sedation. No evidence for one tool over another.

Ramsey scale: intended for use in the operating room (general anesthesia)a. Sedation-agitation scale, Richmond Agitation-Sedation Scale, Motor Activity Assessment b. Scale: all validated in the ICUBispectral analysis: correlate clinical signs with electroencephalogram, potential role for c. monitoring sedation in a patient who is paralyzed

E. Clinical Considerations for Highest Quality Care:1. Optimize combination therapy

a. Additive sedation effectsb. Minimize adverse events from high-dose, single-agent therapy.

2. Daily sedation interruption: reassess needs daily. What is your goal today?3. Daily sedation tapering4. Use of a sedation protocol/guideline with a sedation-assessment scale is strongly

recommended.5. When used for more than a few days, especially at high doses, taper over time to avoid

withdrawal (10%–20% decrease per day).6. Remember adjunctive therapies: Lacri-Lube for eyes as needed, deep vein thrombosis

prophylaxis, and physical therapy.

IV. ICU DELIRIUM

A. Clinical Features1. Defi nition: acute-onset ∆ mental status, with fl uctuating course, and the ability to focus,

sustain, or shift attention is impaired2. Common themes

a. Sensory alterationsb. Reversed sleep-wake patternc. Alternating lethargy/agitation (hypoactive/hyperactive)d. Fluctuations in orientation and memory

3. Risk factorsa. Age: older than 60 yearsb. Substance abuse history (including tobacco)c. Psychiatric history (especially dementia)/central nervous system eventd. Infection

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e. Untreated painf. Electrolyte/metabolic derangementsg. Use of benzodiazepines before ICU admission

4. Tool for assessmentConfusion assessment method for the ICU: validated in the ICU, requires patient a. participationIntensive Care Delirium Screening Checklistb.

B. Nonpharmacologic Interventions1. Baseline mental status2. Obtain psychiatric history if possible.3. Maintain patient communication.4. Maximize uninterrupted sleep (limit noise/talking).5. Maximize natural lighting.6. Remove unnecessary equipment from room.7. Encourage patient autonomy.

C. Pharmacologic Interventions1. Butyrophenone neuroleptics

a. Haloperidol (Haldol): drug of choice for ICU deliriumi. “Neuroleptization” dosing:

Mild delirium: 2 mg intravenously(a) Moderate delirium: 5 mg intravenously(b) Severe delirium: 10 mg intravenously(c)

ii. Rapid dose escalation:Double the previous dose every 20 minutes. If no response, increase to maximum (a) 80-mg bolus.After the fi rst two doses, start giving 1 mg of lorazepam with each haloperidol (b) dose.When patient is calm, add total milligrams administered and give intravenously (c) for the next 3–5 days, divided into doses every 6 hours.

iii. Taper over 5–7 days.iv. Adverse effects

Cardiovascular: hypotension(a) , torsades de pointesExtrapyramidal effects: after prolonged duration (more than 7 days)(b) Lowering of seizure threshold(c)

b. Droperidol (Inapsine): not effective for delirium2. Atypical antipsychotics (possible alternative therapy for patients intolerant to haloperidol)

a. Olanzapine (Zyprexa) 2.5–5 mg orally/nasogastric tube/orogastric tube/intramuscularly once daily (5–20mg total daily dose)

b. Risperidone (Risperdal) 2–10mg oral total daily dosec. Quetiapine (Seroquel) 75–750mg oral total daily dosed. Ziprasidone (Geodon) 40–160mg orally or 10- to 40-mg intramuscular total daily dose

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V. THERAPEUTIC PARALYSIS

A. Indications for Neuromuscular Blockade 1. Poor oxygenation or patient-ventilator interaction that persists despite adequate sedation 2. Potentially dangerous movements in an instrumented patient that persists despite sedation 3. Assist in the control of elevated intracranial pressure 4. Assist in the control of muscle spasm (tetanus, neuroleptic malignant syndrome)

B. Nondepolarizing Neuromuscular-blocking Agents for Prolonged Use (not just intubation, e.g., rapid-sequence intubation)

Pancuronium Vecuronium Atracurium CisatracuriumTrade nameDuration of effect (hours)Prolonged in renal failureProlonged in hepatic failure

Loading doseMaintenance

Adverse effectsTachycardiaHypotension

Daily drug cost per 70 kg

Pavulon0.75–1.5YesYes

0.08 mg/kg0.02–0.04 mg/kg as needed

YesNo

$5–$15

Norcuron0.5–0.75YesYes

0.1 mg/kg0.02–0.04 mg/kg/hour

NoNo

$100–$200

Tracrium0.25–0.5NoNo

0.4 mg/kg0.4 mg/kg/hour

NoDose dependent

$100–$200

Nimbex0.5–1NoNo

0.1 mg/kg2–10 mcg/kg/minute

NoNo

$200–$400

C. Monitoring Therapeutic Paralysis1. Adequate sedation and analgesia MUST be achieved before starting paralytic agent; sedation

should be ordered around the clock as a continuous infusion (never as needed).2. Dosage should be monitored with a peripheral nerve stimulator.

a. A baseline train-of-four should be documented before initiating paralysis.b. Doses should be titrated to maintain one or two twitches on train-of-four and desired

clinical effect.c. Depth of paralysis (i.e., train-of-four) should be assessed several times per day.

3. Paralysis should be allowed to dissipate at least once daily (“drug holiday”) to ensure adequate sedation and assess the need for continued paralysis. Once this assessment is made, patients may be reparalyzed, if necessary.

Patient Case8. A 42-year-old woman with a signifi cant history of alcohol and tobacco abuse and acute respiratory distress

syndrome is transferred to the medical ICU from an outside hospital. She presented to the outside hospital after 1 week of productive cough, fevers, chills, and increasing shortness of breath. On admission to the medical ICU, she is hypotensive (80/60 mm Hg), tachycardic (130 beats/minute), and febrile (39.0). Her arterial blood gas shows pH 7.1, PaCO2 56 mm Hg, PaO2 49 mm Hg, HCO3- 16 mEq/L, and SaO2 76% on 100% FiO2. The only other signifi cant laboratory results were an SCr of 1.5 mg/dL and WBC 16,000. She appears to be adequately sedated with 3 mg/hour of lorazepam and 200 mcg/hour of fentanyl. In an attempt to improve her oxygenation, she is paralyzed and placed on inverse ratio ventilation. Which one of the following statements about therapeutic paralysis is true?A. Sedatives should be discontinued after paralysis is initiated.B. Once paralysis is initiated, it should not be stopped until after the patient is extubated.C. Depth of paralysis should be monitored with a peripheral nerve stimulator.D. The goal of monitoring paralysis is to continuously observe four of four twitches on train-of-four.

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E. Common Factors That May Affect Neuromuscular BlockadePotentiate Block Antagonize Block

Drugs CorticosteroidsAminoglycosidesClindamycinTetracyclinesColistinCalcium channel blockersType Ia antiarrhythmicsFurosemideLithium

AminophyllineTheophyllineCarbamazepinePhenytoin (chronic)

Electrolyte disorders HypermagnesemiaHypocalcemiaHypokalemia

HypercalcemiaHyperkalemia

Patient Cases9. The patient in case 8 was paralyzed as instructed and appeared to being doing well until about 1 hour after

her third dose of pancuronium, when she began to move around violently in her bed. At this time, she was tachycardic (120 beats/minute) and appeared very agitated; her SaO2 fell to 80%, and the nurse reported that the patient had regained all four twitches on train-of-four. Which one of the following actions is best? A. Administer a pancuronium bolus. B. Administer a fentanyl bolus. C. Increase the lorazepam drip rate. D. Change pancuronium to vecuronium.

10. After that event, the patient did poorly throughout the rest of the night. A Swan-Ganz catheter was placed,

confi rming the diagnosis of sepsis (i.e., high cardiac output and low systemic vascular resistance). The patient was started on a dopamine infusion at 20 mcg/kg/minute to maintain an adequate BP. Other medications included clindamycin, cefepime, and gentamicin. By morning, her SCr has increased to 2.8 mg/dL, and the night shift nurse reports that the patient had zero of four twitches on train-of-four for the past 8 hours. Which one of the following may potentiate the effects of pancuronium?A. Clindamycin.B. Gentamicin.C. Renal failure.D. All of the above.

11. Which one of the following agents has been associated with prolonged paralysis when used with the

nondepolarizing neuromuscular-blocking agents?A. Penicillin.B. Prednisone.C. Theophylline.D. Digoxin.

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VI. SHOCK AND SEPSIS

A. Differential Diagnosis of Shock Based on Hemodynamic ParametersHemodynamic Subset

Cardiac Index(2.5–4.0 L/minute/m2)

PCWP(8–12 mm Hg)

SVR(800–1400)

Treatment

Septic High Low Low FluidsVasopressorsAntibiotics

Hypovolemic Low Low High Normal salineColloidsBlood products

Cardiogenic Low High High InotropesAfterload reducersDiuretics

PCWP = pulmonary capillary wedge pressure; SVR = systemic vascular resistance.

B. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 (Dellinger RP, Levy MM, Carlet JM, et al. Intensive Care Med 2007: DOI 10.1007/s00134-007-0934-2). *Only drug- or fl uid-related recommendations are included in this chart.*

Sepsis = systemic response to infection (confi rmed or suspected infection PLUS more than two systemic infl ammatory response syndrome criteria)

Severe sepsis = sepsis associated with organ dysfunction or tissue hypoperfusion or hypotension (systolic BP [SBP] less than 90 or mean arterial pressure less than 70 or drop of SBP more than 40 mm Hg)

Hypoperfusion abnormalities include (but are not limited to):

Altered metal status Edema or increased fl uid balanceHyperglycemia in the absence of diabetes Decreased venous oxygen saturationCardiac index less than 3.5 L/minute/m2 Arterial hypoxemia PaO2/FiO2 less than 300Acute oliguria (more than 2 hours) Coagulopathy (international normalized ratio more than

1.5 with no anticoagulant)Increased SCr (more than 0.5 mg/dL over baseline) Ileus (absent bowel sounds)Thrombocytopenia: platelets less than 100,000/cm3 Hyperbilirubinemia (more than 40 mg/dL)Hyperlactatemia (more than 4 mmol/L) Decreased capillary refi ll or mottling

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Recommendation Treatment Rationale/Clinical PearlsEarly goal-directed therapy: (fi rst 6 hours of resuscitation)CVP 8–12 mm Hg (12–15 if ventilated)MAP ≥ 65 mm HgUrine output: ≥ 0.5 mL/kg/hourCentral venous (ScVO2) > 70% or mixed SvO2 ≥ 65%

FluidsRed blood cell transfusions (hematocrit > 30%)Dobutamine (maximum 20 mcg/kg/minute)

Improved survival in patients presenting with septic shock in emergency department

AbxEmpiric therapy of one or two drugs that cover likely pathogens; broad spectrumPenetrate presumed source of sepsis

Start within the fi rst hour of recognition of severe sepsis, after appropriate cultures are obtainedReassess dailyCombination therapy for 3–5 days, with deescalation therapy when sensitivities availableD/C after 7–10 days, unless slow response, undrainable foci, or immunosuppressionD/C Abx if noninfectious cause is determined

Change to narrow-spectrum Abx when possible to prevent resistance, reduce toxicity, and reduce cost. Be aware that blood cultures will be negative in most cases of sepsis; therefore, use clinical judgment and other cultures as a basis to change therapy

Fluid resuscitationCrystalloid (normal saline, lactated ringers)Colloid (albumin, hetastarch)

Most patients require aggressive resuscitation during the fi rst 24 hours of managementFluid challenges: 1000 mL of crystalloids or 300–500 mL of colloids over 30 minutes; repeat based on responseDecrease rate of fl uid challenge if cardiac fi lling pressures (CVP or PAOP) increase without concurrent hemodynamic improvement

No clinical outcome differences between treatments; crystalloids require more fl uid to achieve the same end points and result in more edema

Vasopressors (central line)After appropriate fl uid challenge fails to restore BP and organ perfusionUse arterial catheter for BP Vasopressin may be considered in refractory shock (0.03 units/minute, no titration)Do NOT use DA for renal protection

NE (more potent) or DA (good for systolic dysfunction but more tachycardia and arrhythmias and HPA and immunosuppressive effects)Epinephrine should be the alternative if NE or DA fail

Advantages of these agents over epinephrine (potential tachycardia, dec splanchnic perfusion, and hyperlactemia) and phenylephrine (decreased stroke volume)Vasopressin may decrease cardiac output

Inotropic therapyFor low cardiac output after adequate fl uid resuscitationCombine with vasopressor in patients with low BP

Dobutamine (2–20 mcg/kg/minute)

First-line inotropic therapyGoal: achieve adequate levels of oxygen delivery or avoid fl ow-dependent tissue hypoxia

Table 2. 2008 Surviving Sepsis Campaign International Guidelines for Management of Severe Sepsis and Septic Shock

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Recommendation Treatment Rationale/Clinical PearlsSteroidsIntravenous corticosteroidsFor SHOCK refractory to vasopressors No contraindication to continuing maintenance steroid therapy or using stress dose steroids in patients with sepsis on maintenance steroid therapy or with endocrine disorders

Hydrocortisone 200–300 mg/day for 7 days, divided TID or QIDSome experts would add fl udrocortisone 50 mcg/day PO if hydrocortisone is not available

Signifi cant shock reversal and decrease in mortality ONLY in patients who are nonresponsive to fl uids and pressors Do NOT use doses of corticosteroids > 300 mg hydrocortisoneDecrease dosage or taper off steroids when vasopressors are no longer requiredUncertain if tapering or abrupt discontinuation is best

Recombinant human activated protein CFor patients at high risk of death (APACHE II > 25) or sepsis induced (> 2) multiple organ failure and with no contraindicationsEndogenous anticoagulant with anti-infl ammatory properties

24 mcg/kg/hour for 96 hours, based on actual body weightNo change in PK parameters was observed in patients weighing up to 227 kg (Levy H, Small D, Heiselman DE, et al. Obesity does not alter the pharmacokinetics of drotrecogin alfa (activated) in severe sepsis. Ann Pharmacother 2005;39:262–7)

Improves survival in patients with sepsis-induced organ failure (PROWESS)Once patient has been identifi ed as high risk, start treatment immediatelyDo not use in APACHE II < 20 or one organ failure

Blood product administrationOnly when hemoglobin decreases to < 7 g/dL to target a hemoglobin of 7–9 g/dLDo not use fresh frozen plasma for clotting abnormalities in the absence of bleeding or planned invasive proceduresEPO is NOT recommended as a specifi c treatment of anemia but may be used in patients with renal failure and compromised RBC productionPlatelets should be given when < 5000/mm3 regardless of apparent bleeding, 5000–30,000/mm3 and signifi cant risk of bleeding. Maintain platelets > 50,000/mm3 for surgery or invasive procedures

A transfusion threshold of 7 g/dL was NOT associated with increased mortalityRBC transfusion in patients with sepsis increases O2 delivery but not consumptionThis contrasts with the hematocrit target of 30% in the fi rst 6 hours of resuscitation of septic shockEPO use in critical care clinical trials shows some decrease in transfusions but no effect on clinical outcome

Sedation, analgesia, and neuromuscular blockadeUse protocols and sedation scales (to a predefi ned end point) to manage sedation of mechanically ventilated patientsIntermittent bolus or continuous infusion sedationNeuromuscular blockers should be avoided if possible because of the risk of prolonged blockade after discontinuation in patients with sepsis.Train-of-four monitoring should be conducted to determine depth of block

Daily interruptions/lightening of continuous sedation with awakening and retitration if necessary can decrease duration of MV and ICU stay (improved neurologic assessment and decreased cost)Sedation protocols have been shown to decrease the duration of MV, LOS, and tracheostomy ratesProlonged skeletal muscle weakness has been reported after neuromuscular blockade in critically ill patientsKeep inspiratory plateau pressures < 30 cm H20

Table 2. 2008 Surviving Sepsis Campaign International Guidelines for Management of Severe Sepsis and Septic Shock

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Recommendation Treatment Rationale/Clinical PearlsGlucose controlMaintain blood glucose < 150 mg/dL with an insulin protocolMonitor glucose every 1–2 hours until stable and then on a regular basis (every 4 hours)A nutritional protocol with preference of the enteral route should be included in the treatment of patients with severe sepsis requiring glycemic control

Continuous infusion of insulin and glucoseProtocol should be developed for patient safetyMinimize hypoglycemia by continuous glucose supplementation (5% or 10% dextrose infusion followed by continuous enteral feeds)Use of POC testing should be interpreted with caution, because of the potential for overestimation of glucose values

Improvement in survival of surgical patients when insulin was used to maintain glucose between 80 and 110 mg/dLBest results were obtained when glucose was 80–110, but < 150 mg/dL also improved outcome when compared with higher concentrationsControl of blood glucose appears to be more important than the amount of insulin givenUse arterial or central catheters for blood sampling because of frequency

Bicarbonate therapyNot recommended for the treatment of hypoperfusion/lactic acidemia with pH > 7.15

No evidence to support its use for the purpose of improving hemodynamics or reducing vasopressor requirements at lower pH or clinical outcome at any pH

DVT prophylaxisShould be considered for all patients with severe sepsisConsider combination therapy (pharmacologic and mechanical) in very high-risk patients (e.g., severe sepsis, history of DVT)

Low-dose unfractionated heparin or low-molecular-weight heparinIf contraindications (thrombocytopenia, severe coagulopathy, active bleeding, or recent intracerebral hemorrhage): use mechanical devices

Benefi t of DVT prophylaxis has been confi rmed in trials of general ICU populations, including patients with sepsisPatients at very high risk should receive a low-molecular-weight heparin because they are superior in this population

SUPShould be given to all patients with severe sepsisBenefi t must be weighed against the potential for increased risk of ventilator-associated pneumonia

H2-receptor antagonist (preferred agents)Proton pump inhibitors

Patients with severe sepsis and septic shock present with conditions that have been shown to benefi t from SUP: coagulopathy, MV, hypotension

Abx = intravenous antibiotics; APACHE II = Acute Physiology and Chronic Health Evaluation II; BP = blood pressure; CVP = central venous pressure; DA = dopamine; D/C = discontinue; DVT = deep vein thrombosis; EPO = erythropoietin; HPA = hypothalamus-pituitary-adrenal; ICU = intensive care unit; LOS = length of stay; MAP = mean arterial pressure; MV = mechanical ventilation; NE = norepinephrine; PAOP = pulmonary artery occlusion pressure; PK = pharmacokinetics; PO = orally; POC = point-of-care; PROWESS = Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis [PROWESS] Trial; QID = 4 times/day; RBC = red blood cell; SUP = stress ulcer prophylaxis; SvO2 = mixed venous oxygen saturation; TID = 3 times/day.

Table 2. 2008 Surviving Sepsis Campaign International Guidelines for Management of Severe Sepsis and Septic Shock.

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C. Vasopressors and Inotropic AgentsDrug Dose α1 β1 β2

Dopa Cautions/Clinical EffectsDopamine 1–3 mcg/kg/

minuteNOT recommended

+/- ++ +/- ++++ Renal, coronary, mesenteric, and cerebral arterial vasodilation and natriuretic response

3–10 mcg/kg/minute

++ +++ + ++ A choice in sepsis can ↑ BP by ↑ contractility and SVRCan induce tachyarrhythmias

10–20 mcg/kg/minute

++++ +++ 0 + Immediate precursor of norepinephrineProlonged infusions can deplete endogenous norepinephrine stores resulting in a loss of vasopressor responseEffects on renal blood fl ow may be lost at higher doses because of predominant α1 effects

Norepinephrine 0.01–1 mcg/kg/minute for septic shock

Dose should be tapered slowly

++++ +++ 0 0 ↓ Renal perfusion↑ SVR, ↑ BP0 – ↓ cardiac outputCan induce tachyarrhythmias and myocardial ischemiaExtravasation produces ischemic necrosis and sloughing (treatment: phentolamine 5–10 mg IV diluted)

Epinephrine 0.04–1 mcg/kg/minute for refractory hypotension

+++ +++ ++ 0 Positive inotropic and chronotropic effects can induce myocardial ischemia↑ SVR, ↑ BPLow doses = β-adrenergic; α-adrenergic = with escalating dosesExtravasation produces ischemic necrosis and sloughing (treatment: phentolamine 5–10 mg diluted)

Phenylephrine 0.5–8 mcg/kg/minute for septic shock

Dose should be tapered slowly

++++ 0 0 0 ↓ Renal perfusionPure α-adrenergic agonist with minimal cardiac activityRapid ↑ SBP and DBP can cause a refl ex bradycardiaExtravasation produces ischemic necrosis and sloughing (treatment: phentolamine 5–10 mg diluted)

Vasopressin 0.03 units/minute(physiologic replacement dose)

0 0 0 0 Direct stimulation of smooth muscle V1 receptors; peripheral vasoconstriction, no adrenergic activityDoses > 0.04 units/minute associated with coronary vasoconstriction and peripheral necrosis

Dobutamine 2–20 mcg/kg/minute

+ +++ + 0 Positive inotrope↑ cardiac output can lead to ↓ SVRHigher doses can cause tachyarrhythmias and changes in BP, which can lead to myocardial ischemia

Milrinone (Primacor)

50 mcg/kg load for 10 minutes, followed by 0.375–0.75 mcg/kg/minute

0 0 0 0 Noncatecholamine, phosphodiesterase inhibitorPositive inotropeVasodilation, arrhythmias possibleUse lower doses in renal failure

α = α-adrenergic effect; β = β-adrenergic effect; BP = blood pressure; DBP = diastolic blood pressure; Dopa = dopaminergic effect; SBP = systolic blood pressure; SVR = systemic vascular resistance; ++++ = maximal effect ranging to 0 = no effect; ↑ increase; ↓ decrease.

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D. Recombinant Human Activated Protein C (Drotrecogin-α [Xigris])1. Criteria for use (per the Recombinant Human Activated Protein C Worldwide Evaluation in

Severe Sepsis [PROWESS] Trial): patients must meet ALL three criteria.a. Known or suspected infectionb. At least THREE of the following systemic infl ammatory response syndrome criteria:

i. Temperature 36°C or less OR 38°C or moreii. HR 90 beats/minute or moreiii. Respiratory rate 20 or more OR PaCO2 32 mm Hg or less or need for intubation and

mechanical ventilationiv. WBC of 4000 or less OR 12,000 or more OR 10% or more immature neutrophils

c. At least ONE of the following sepsis-induced organ or system dysfunctions within the past 48 hoursi. Mean arterial pressure less than 70 or SBP less than 90 or need for vasopressor

support after adequate fl uid challengeii. UOP less than 0.5 mL/kg/hour for 1 hour after adequate fl uid challengeiii. PaO2/FiO2 ratio less than 250iv. Platelets less than 80,000 or 50% decrease from baseline within 72 hoursv. Unexplained metabolic acidosis pH 7.3 or less or base excess −5 or more with lactate

more than 1.5 times normal2. Contraindications: active internal bleeding; recent (within 3 months) hemorrhagic stroke;

recent (within 2 months) intracranial or intraspinal surgery or severe head trauma; trauma with an increased risk of life-threatening bleeding; presence of an epidural catheter; intracranial neoplasm or mass lesion; or evidence of cerebral herniation

3. Monitoring signs and symptoms of bleeding: the study showed a trend toward increased risk for serious bleeding events in the drotrecogin-α group (p=0.06); patients were excluded from the study for platelet count less than 30,000, conditions that increased the risk of bleeding; the activated partial prothrombin time may be elevated during therapy, but should not be used to determine adjustments in treatment.

4. Cost of therapy: $7000–$8000 (70kg patient × 96 hour infusion)

VII. ADVANCED CARDIAC LIFE SUPPORT (ACLS)/CARDIOPULMONARY RESUSCITATION

Patient Case12. A 65-year-old woman was admitted to the coronary care unit after suffering a myocardial infarction. On

the fourth day of hospitalization, she is hypotensive (BP 80/50 mm Hg), tachycardic (HR 125 beats/minute), tachypneic (respiratory rate 30), hypoxemic (PaO2 55 mm Hg), febrile (102°F), and confused. The patient is given two 500-mL boluses of normal saline, intubated, and started on piperacillin/tazobactam 4.5 g intravenously every 8 hours and ciprofl oxacin 400 mg intravenously every 12 hours for possible nosocomial pneumonia. After further fl uid boluses fail to improve her clinical status, a pulmonary artery catheter is placed, which reveals a pulmonary capillary wedge pressure of 14 mm Hg, cardiac index of 3.8 L/minute/m2, and systemic vascular resistance of 515 dynes/second/cm-5. Her chest radiograph shows diffuse interstitial infi ltrates, and she is still requiring 100% FiO2. Which one of the following actions is best? A. Add clindamycin 600 mg intravenously every 8 hours for possible aspiration pneumonia. B. Add drotrecogin-α 24 mcg/kg/hour immediately for severe sepsis. C. Dobutamine infusion titrated to achieve an SBP of 100 mm Hg. D. Norepinephrine infusion titrated to achieve an SBP of 100 mm Hg.

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A. Early Cardiopulmonary Resuscitation (Chain of Survival):1. Check for responsiveness2. Activate emergency response systems3. Call for defi brillator4. “ABCDs”

Airway: Open the airway.Breathing: Provide positive pressure ventilations.Circulation: Chest compressionsDefi brillation: Assess and shock ventricular fi brillation/pulseless ventricular tachycardia, up to 3 times (200 J, 200–300 J, and 360 J) if necessary.

B. Goals1. Cerebral resuscitation2. Return of spontaneous circulation

a. Cessation of arrhythmiab. Adequate vascular tone

3. American Heart Association Treatment algorithms can be found on the following web sites (accessed March 1, 2008): http://circ.ahajournals.org/cgi/reprint/112/24_supp/IV-78 http://circ.ahajournals.org/cgi/reprint/112/24_supp/IV-58 http://circ.ahajournals.org/cgi/reprint/112/24_supp/IV-67

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C. ACLS Medication ManagementDrug Indication Dose Adverse Effects Compatibility/PearlsEpinephrine (Epi)

Shock refractory ventricular fi brillation (VF)/pulseless ventricular tachycardia (VT)Pulseless electrical activity (PEA)AsystoleBradycardia w/serious signs or symptoms

1 mg intravenous push (IVP)/intra-osseous (IO) every 3–5 minutesHigh-dose Epi is not recommendedContinuous infusion (for bradycardia) 2–10 mcg/minute

Tachyarrhythmias, myocardial infarction (MI), tissue necrosis from extravasation

Not compatible with sodium bicarbonate (HCO3

-) (inactivates catecholamines)

Vasopressin Equivalent to Epi as fi rst line for shock refractory VF/pulseless VTPEAAsystoleHypovolemic shock

40 units IVP/IO one time only (two vials of 20 units/mL) to replace either fi rst or second dose of Epi—if no response after 10–20 minutes, start Epi at 1 mg IVP every 3–5 minutesEndotracheal tube dose same as IV (but endotracheal route not recommended)0.04–0.1 units/minute IV infusion

Hypertension, bradycardia, MI, decreased cardiac output, possible necrosis if infi ltrates into the tissue

Compatible with normal saline (NS) and D5WOnset 1–2 minutes, half-life: 10–20 minutes (can last up to 60 minutes)

Amiodarone Shock refractory VF/pulseless VT

Atrial fi brillation/fl utter

300 mg IVP/IO diluted in 20 mL of D5WCan repeat at a dose of 150 mg IV pushMaintenance continuous infusion 1 mg/minute for 6 hours, then decrease to 0.5 mg/minute thereafter150 mg IV over 10 minutes for breakthrough VFMax cumulative dose of 2.2 g IV/24 hours

Hypotension (decrease infusion rate, give fl uid bolus), bradycardia (decrease or discontinue infusion, pacemaker)

Dilute with D5WUndiluted may cause more hypotensionMaintenance infusion should be prepared in a non–polyvinyl chloride (PVC) containerNot compatible with HCO3

-

Hepatically metabolized with multiple drug interactionsLong half-life and large volume of distribution

Lidocaine Shock refractory VF/pulseless VT

1–1.5 mg/kg IVP/IORepeat in 3–5 minutesMaximum dose 3 mg/kgContinuous infusion 1–4 mg/minute

Bradycardia, sinus arrest, seizures

Reduce maintenance infusion by 50% in hepatic dysfunction, congestive heart failure, elderly (> 70 years)Contraindicated in patients with hypersensitivity to amide local anesthetics

Procainamide Intermittent/recurrent VF/VTAtrial fi brillation/fl utter

Loading dose up to 17 mg/kg until rhythm suppressed, widening of QRS or QT intervals by 50% of baseline, or hypotensionMaximum rate of infusion 20 mg/minuteMaintenance infusion 1–4 mg/minute

Hypotension, QRS/QT prolongations, depressed myocardial contractility, proarrhythmic effects

Infusion rates > 30 mg/minute exacerbate adverse effectsCommon cause of torsades de pointes

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Drug Indication Dose Adverse Effects Compatibility/PearlsAtropine Symptomatic sinus

bradycardiaAtrioventricular (AV) block at the nodal levelAsystole or PEA with relative or absolute bradycardia

0.5 mg IVP/IO as needed for bradycardia or AV block1 mg IVP/IO every 3–5 minutes (3 mg max) for asystole or PEA

Tachycardia, mydriasis

Paradoxical bradycardia at dose < 0.5 mg in adults

Adenosine Narrow complex paroxysmal supraventricular tachycardia (PSVT)

Rapid 6 mg IV bolus for 1–3 secondsMay repeat twice at a dose of 12 mg IV bolus for 1–3 seconds after 1–2 minutesFollow each bolus with 20 mL of normal saline fl ush

Flushing, dyspnea, chest pain, transient bradycardia

Brief period of asystole may follow rapid injectionHalf-life < 10 secondsMethylxanthines (e.g., caffeine, theophylline) are competitive antagonists and can be used to reverse adenosine-induced hypotension and/or bradycardiaLower dose (3 mg) with carbamazepine, dipyridamole, or cardiac transplantHigher doses with large caffeine users and theophylline

Calcium chloride

HyperkalemiaHypocalcemiaCalcium channel blocker toxicity

1–2 g IVP 10% solution over 10-minute intervals

Hypotension, syncope, bradycardia, skin necrosis

Not compatible with HCO3-

(forms precipitate)

Magnesium sulfate

Drug of choice for torsades de pointesPotential benefi t in refractory VF/VTHypomagnesemia

1–2 g in 10 mL of D5W IVP over 1–2 minutes Give IV push in VFMay be followed by a continuous infusion of 0.5–1 g/hour

Hypotension, asystole, fl ushing

Do not exceed a rate of 150 mg/minute because of risk of severe hypotension or asystole

HCO3- Hyperkalemia

Documented or preexisting bicarbonate responsive acidosis or tricyclic overdose or to alkalinize the urine in aspirin or other drug overdosesHypoxic lactic acidosis

1 mEq/kg IVPRepeat doses of ≤ 0.5 mEq/kg every 10 minutes during continued cardiac arrest

Hyperosmolarity, hypernatremia, intracellular and cerebral acidosis, mixed venous hypercarbia, tissue necrosis possible if infi ltration occurs

Dosing guided by arterial blood gas (ABG)FLUSH IV lines before and after use due to compatibility issues

D. Antiarrhythmics in ACLS1. Consider underlying cardiac function before choosing agent (all are negative inotropes except

for amiodarone).2. It is better not to combine multiple antiarrhythmics secondary to No. 1.

E. Intravenous Drug Administration1. Central venous administration preferred2. Peripheral administration should be followed by a 10–20 mL fl ush of 0.9% NaCl (normal

saline), and elevate the limb.3. Continuous infusions should be administered by a central line.

Monitor for extravasation.4. Do NOT stop cardiopulmonary resuscitation for drug administration.5.

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F. Intra-osseous Administration Preferred Over Endotracheal if Intravenous Administration Not Possible

G. Endotracheal Drug Administration1. Dose = 2–2.5 times the standard intravenous dose2. Dilute the dose in 5–10 mL of sterile water.3. Stop cardiopulmonary resuscitation.4. Inject deep into endotracheal tube; give fi ve quick insuffl ations.5. Resume cardiopulmonary resuscitation.6. Drugs that can be given by endotracheal tube

LidocaineAtropineNaloxoneEpinephrineVasopressin (same as intravenous dose, no adjustment)

H. Hypothermia (32–34°C) × 24 hours postarrest1. Improve neurologic recovery and mortality2. Ice packs to armpits, neck, torso, and groin3. Cooling blankets4. Iced fl uid infusions5. Cooling pads6. Adjunctive sedation, analgesia, neuromuscular blockade

VIII. STRESS ULCER PROPHYLAXIS (SUP)

A. Pathogenesis of Stress-related Mucosal Damage (SRMD)1. Physiologic stress→mucosal ischemia→inability to maintain homeostasis in the gastric

mucosa→failure of mucosal defense mechanisms→SRMD→bleeding2. Disruption of mucosal defense mechanisms

Decreased mucosal blood fl owa. Decreased secretion of mucus and bicarbonateb. Decreased protective prostaglandin productionc. Decreased cell regenerationd. Decreased gastrointestinal (GI) motilitye.

Patient Cases13. Which one of the following statements about epinephrine is true?

A. The recommended dose of epinephrine is 1 mg intravenously every 10 minutes. B. Benefi cial effects of epinephrine in cardiac arrest are caused by its α-agonist effects. C. Epinephrine is the drug of choice for bradycardia. D. High-dose epinephrine is more effective than the 1 mg dose.

14. A 70 kg patient is to receive a continuous infusion of dopamine for BP support. The nurse has a 250 mL bag of

D5W containing 400 mg of dopamine. At what rate should the dopamine drip be given to provide the patient with a dose of 5 mcg/kg/minute? A. 13 mL/hour. B. 13 mL/minute. C. 22 mL/hour. D. 22 mL/minute.

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B. Overt Stress-related Mucosal Bleeding1. Hematemesis2. Gross blood in nasogastric aspirates: “coffee grounds”3. Hematochezia4. Melena

C. Clinically Signifi cant Stress-related Mucosal BleedingOvert bleeding complicated by any one of the following:1. Decreased SBP of 20 mm Hg or moreIncreased HR more than 20 beats/minuteDecreased SBP more than 10 mm Hg orthostatic changeDecreased hemoglobin by 2 g/dL or more without recovery after transfusion

D. Risk Factors for Clinically Important Stress-related Mucosal Bleeding 1. Mechanical ventilation more than 48 hours (independent risk factor) 2. Coagulopathy more than 24 hours (platelet less than 50,000/mm3 or international normalized

ratio more than 1.5 or partial prothrombin time more than 2 times “control”) (independent risk factor) or any two or more of the following:

3. Neurologic trauma (head injury/spinal cord injury)4. Hypoperfusion (sepsis, shock)5. Severe burns (more than 35% of body surface area)6. Multiple organ failure three or more organs7. Medical history of GI ulcers/bleeding within 1 year8. High-dose steroids (more than 200 mg of hydrocortisone equivalents)9. Multiple traumas10. Liver failure with associated coagulopathy

Postoperative transplant11. Acute renal insuffi ciency12.

13. Major surgery

E. Goals of Therapy for SUPGastric pH Physiologic Effects≥3.5 Decreased incidence of stress-related mucosal bleeding≥ 4.5 Pepsin inactivation5 Acid neutralization≥ 7 Clotting and platelet aggregation≥ 8 Pepsin destruction

F. Therapeutic Options for SUP1. Antacids

Action Dose-dependent Neutralization of AcidAdverse effects Electrolyte imbalances

Diarrhea/constipationDisadvantages Require multiple daily doses and frequent administration

Available only for PO or NG administrationNumerous drug interactionsRisk of nosocomial pneumonia caused by high gastric volumes

NG = nasogastric; PO = orally.

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2. Sucralfate (Carafate)Action Forms a complex by binding with positively charged proteins in exudates,

forming a protective coating that protects the lining. It may also stimulate prostaglandin release, causing an increase in bicarbonate and mucus production.

Available agents/dosage

1 g tablet PO/NG QID

Adverse effects ConstipationPossible aluminum accumulation in renal dysfunction

Disadvantages Inferior to H2RA for the prevention of clinically signifi cant bleeding More frequent dosing than H2RA and PPIsDrug interactionsOnly available for PO or NG administration

H2RA = H2-receptor antagonist; NG = nasogastrically; PO = orally; PPI = proton pump inhibitor; QID = 4 times/day.

H3. 2-Receptor Antagonists (H2RAs)Action Competitive blocker of H2-receptors on parietal cellsAvailable agents/dosage(dosage based on clinical data, not FDA approved for SUP)

Ranitidine 150 mg PO every 12 hours or 50 mg IV every 8 hoursFamotidine 20 mg IV/PO every 12 hoursNizatidine 150 mg PO every 12 hoursCimetidine 300 mg PO/IV every 6 hours or continuous infusion 37.5–50 mg/hour (only FDA-approved agent for SUP)

Adverse effects Mental status changes, thrombocytopeniaAdvantages Ease of administration

CostDisadvantages Drug interactions (cimetidine)

Potential for reduced effi cacy over time (tolerance)Adjustment in dose for renal dysfunctionRisk for nosocomial pneumonia

FDA = U.S. Food and Drug Administration; IV = intravenously; PO = orally; SUP = stress ulcer prophylaxis.

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Proton Pump Inhibitors (PPIs)4. Action Prodrugs that are activated in the acidic environment of the parietal cell and then bind to and inhibit

active proton pumps. Oral formulations are designed to dissolve at a pH > 5.6 to protect from degradation and premature activation in the stomach.

Available agents/dose (dose based on clinical data, not FDA approved for SUP)

POOmeprazole (Prilosec)

Capsules 20 mg/day PO• Capsules 20 mg/day by tube•

Open capsule and suspend granules in a syringe with 40 mL of apple juice and give o by NGT/OGT, fl ush with 20 mL apple juice (DO NOT CRUSH GRANULES)Simplifi ed omeprazole suspension (SOS): by NGT/OGT dissolve granules in 10 mL o of 8.4% HCO3

- and fl ush with 10 mL of HCO3- or water

Powder for oral suspension (Zegerid) 20 mg/day PO• Esomeprazole (Nexium)

Capsules 40 mg/day PO• Capsules 40 mg by tube•

Suspend granules in a syringe with 50 mL of water and give by NGT/OGT, fl ush o with 10 mL of water so all granules are delivered (DO NOT CRUSH GRANULES)

Lansoprazole (Prevacid)Capsules 30 mg/day PO• Capsules 30 mg by tube•

Open capsule and suspend granules in a syringe with 40 mL of apple juice and give by o NGT/OGT, fl ush with 20 mL of apple juice (DO NOT CRUSH GRANULES)Simplifi ed lansoprazole suspension (SLS): dissolve granules in o 10 mL of 8.4% HCO3

- and fl ush with 10 mL of HCO3- or water

Delayed-release orally disintegrating table (Prevacid SoluTab) 30 mg, dissolve in 10 mL of • water and give PO/NGT/OGT; fl ush NGT/OGT with 5 mL of water (NGT/OGT > 8 French)Delayed-release suspension: DO NOT USE by NGT/OGT, xantham gum in formulation that • will likely clog the NGT/OGT

Pantoprazole (Protonix)Enteric-coated tablet 40 mg/day PO• Enteric-coated tablet 40 mg by tube•

Crush and dissolve tablet in 10 mL of 4.2% HCOo 3-, add an additional 10 mL for a total

volume of 20 mL, and fl ush with 10 mL of HCO3- or water

Rabeprazole (AcipHex): 20 mg/day enteric-coated tablet PO

IV (ONLY for patients who can NOT tolerate PO/NG administration):Lansoprazole 30 mg/day IV

In-line fi lter required, administer for 30 minutes, little incompatibility information• Pantoprazole 40 mg/day IV

No fi lter required (fl ush before and after administration); administer for 2–5 minutes• Esomeprazole 20–40 mg/day IV; administer over 3 minutes; little compatibility information

Adverse effects Headache, diarrhea, constipation, abdominal pain, nauseaAdvantages No adjustment needed for renal or liver dysfunction• Disadvantages Drug interactions: omeprazole and esomeprazole (2C19 inhibitors: diazepam, phenytoin, warfarin), •

lansoprazole (1A2 inducer: theophylline)Cost• Administration issues• Risk of nosocomial pneumonia• Risk of • Clostridium diffi cile infection (nosocomial or community acquired)

FDA = U.S. Food and Drug Administration; HCO3- = sodium bicarbonate; IV = intravenous; NG = nasogastric; NGT =

nasogastric tube; OGT = orogastric tube; PO = orally; SUP = stress ulcer prophylaxis.

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G. Recommendations for Therapy1. Identify patients at high risk for SRMD.2. Evaluate route of administration.

a. Nasogastric/oral access→H2RAb. No nasogastric/oral access→intravenous H2RA

i. H2RA-associated thrombocytopenia→intravenous PPI3. Discontinue therapy when risk factors are no longer present. If the risk factor is gone, the SUP should be gone.

Patient Cases15. A 73-year-old woman is admitted to the ICU after an episode of cardiac arrest with successful resuscitation.

She was intubated during the code. Now, she is being mechanically ventilated. Twenty-four hours after resuscitation, she develops acute renal failure. Her BP is currently 104/65 mm Hg, her HR is 88 beats/minute, her O2 saturations are 98% on 40% FiO2 and PEEP 5, and her Glasgow Coma Scale score is 11. She has a nasogastric tube in place, is being fed enterally, and has no gastric residuals. Her current medications include amiodarone 400 mg 2 times/day, simvastatin 20 mg every night, heparin 5000 units subcutaneously every 8 hours, and 0.9% NaCl intravenously at 75 mL/hour. The physicians would like to start SUP. Which one of the following is the best recommendation for this patient? A. Famotidine 20 mg intravenously every 12 hours. B. Simplifi ed lansoprazole suspension 30 mg/day by NG tube. C. Pantoprazole 80 mg intravenous bolus and then 8 mg/hour as a continuous infusion. D. Cimetidine 50 mg/hour as a continuous infusion.

16. One week later, the patient from question 15 has improved substantially. She is extubated, and her acute renal

failure has resolved. Her Glasgow Coma Scale score is 15, her BP is 112/70 mm Hg, and her HR is 75 beats/minute; she is eating a general diet. Which one of the following statements is true regarding SUP for this patient? A. SUP should continue for 6 weeks. B. SUP should be discontinued because she no longer has risk factors for SRMD. C. A PPI is more effective than an H2RA for SUP. D. Either an H2RA or PPI is appropriate prophylaxis at this time.

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Acid/Base1. Gehlbach BK, Schmidt GA. Bench-to-bedside

review: treating acid-base abnormalities in the intensive care unit—the role of buffers. Crit Care 2004;8:259–65.

2. Adrogue HJ, Madias NE. Management of life-threatening acid-base disorders. Part I. N Engl J Med 1998;338:26–34.

3. Adrogue HJ, Madias NE. Management of life-threatening acid-base disorders. Part II. N Engl J Med 1998;338:107–11.

Respiratory Failure and Mechanical Ventilation1. Bulger EM, Jurkovich GJ, Gentilello LM, Maier

RV. Current clinical options for the treatment and management of acute respiratory distress syndrome. J Trauma 2000;48:562–71.

2. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334–49.

3. Adhikari N, Burns KEA, Meade MO. Pharmacologic therapies for adults with acute lung injury and acute respiratory distress syndrome. The Cochrane Database of Systematic Reviews 2004, Issue 4. Article No.: CD004477.pub2. DOI: 10.1002/14651858.CD004477.pub2.

Sedation1. Jacobi J, Fraser GL, Coursin DB, et al. Clinical

practice guidelines for the use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002;30:119–41.

2. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000;342:1471–7.

3. Pun B, Dunn J. The sedation of critically ill adults. Part 1. Assessment. Am J Nurs 2007;107:40–8.

Delirium1. Ely EW, Shintani A, Truman B, et al. Delirium

as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004;291:1753–62.

2. Milbrandt EB, Kersten A, Kong L, et al. Haloperidol use is associated with lower hospital mortality in mechanically ventilated patients. Crit Care Med 2005;33:226–9.

3. ICU Delirium and Cognitive Impairment Study Group: brain dysfunction in critically ill patients. Vanderbilt Medical Center. Available at http://www.icudelirium.org/delirium. Accessed February 27, 2006.

Therapeutic Paralysis1. Murray MJ, Cowen J, DeBlock H, et al. Clinical

practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med 2002;30:142–56.

Shock and Sepsis1. Surviving Sepsis Campaign: international

guidelines for management of severe sepsis and septic shock: 2008 (Dellinger RP, Levy MM, Carlet JM, et al. Intensive Care Med 2007: DOI 10.1007/s00134-007-0934-2).

2. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858–73.

3. Dellinger RP, Masur H, Carlet JM, Gerlach H, eds. The Surviving Sepsis Campaign guidelines for the management of severe sepsis and septic shock: background, recommendations, and discussion from an evidence-based review. Crit Care Med 2004;32:S445–597.

4. Hollenberg SM, Ahrens TS, Annane D, et al. Practice parameters for the hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med 2004;32:1928–48.

5. Kumar A, Mann HJ. Appraisal of four novel approaches to the prevention and treatment of sepsis. Am J Health-Syst Pharm 2004;61:765–76.

6. Mutlu GM, Factor P. Role of vasopressin in the management of septic shock. Intensive Care Med 2004;30:1276–91.

7. Russell JA. Management of sepsis. N Engl J Med 2006;355:1699–713.

Advanced Cardiac Life Support/Cardiopulmonary Resuscitation1. American Heart Association. Advanced

Cardiovascular Life Support Provider Manual. Dallas, TX: American Heart Association, 2006.

2. Wenzel V, Krismer AC, Arntz HR, Sitter H, Stadbauer KH, Linder KH. A comparison of vasopressin and epinephrine for out-of-hospital

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cardiopulmonary resuscitation. N Engl J Med 2004;350:105–13.

3. American Heart Association. ACLS algorithms. Available at http://www.ace.cc/new%20acls%20guidelines.htm OR http://w w w.amer icanhear t .org /downloadable /heart/1053714937281ACLSPROV_ App3.pdf. Accessed February 27, 2006.

4. Emergency Cardiovascular Care Committee, Subcommittees and Task Forces of the American Heart Association. 2005 American Heart Associate guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2005;112(suppl 24):1–203.

Stress Ulcer Prophylaxis1. ASHP Commission on Therapeutics. ASHP

therapeutic guidelines on stress ulcer prophylaxis. Am J Health-Syst Pharm 1999;56:347–79.

2. Allen ME, Kopp BJ, Erstad BL. Stress ulcer prophylaxis in the postoperative period. Am J Health-Syst Pharm 2004;61:588–96.

3. Cook D, Guyatt G, Marshall J, et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. N Engl J Med 1998;338:791–7.

4. Cadle RM, Mansouri MD, Logan N, et al. Association of proton-pump inhibitors with outcomes in Clostridum diffi cile colitis. Am J Health-Syst-Pharm 2007;64:2359–63.

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1. Answer: B This arterial blood gas is consistent with a metabolic acidosis. The pH is less than 7.40 (indicating it is an acidosis), and the HCO3

- and PaCO2 are both decreased from normal. In a metabolic acidosis, the decrease in HCO3

- is the primary disorder. When a metabolic acidosis is present, the anion gap should be calculated to provide additional insight regarding the potential cause of the disorder. The anion gap is calculated by subtracting the sum of measured anions (Cl- and HCO3

-) from cations (Na+). This patient’s anion gap (8 mEq/L) is within the normal range of 6–12 mEq/L; thus, it is referred to as a “normal anion gap metabolic acidosis” or “nonanion gap metabolic acidosis.” C. diffi cile–induced diarrhea is the most likely cause of this patient’s acid-base disorder.

2. Answer: A This patient has an elevated anion gap metabolic acidosis (anion gap = 32 mEq/L). The causes of an anion gap metabolic acidosis may be remembered using the pneumonic “MUDPILES” (see III.C). This patient’s presentation is most consistent with diabetic ketoacidosis (complaints of vague abdominal pain, vomiting, polyuria, elevated glucose, and positive urine ketones). As illustrated by this case, ketoacidosis may be the initial presenting manifestation of type 1 diabetes mellitus.

3. Answer: D Given this patient’s neurologic status and his elevated PaCO2, he should be intubated and transferred to the ICU. In patients without chronic obstructive pulmonary disease, a PaCO2 above 50 mm Hg is usually an indication for mechanical ventilation regardless of oxygenation status (this patient was oxygenating well; PaO2 111 mm Hg, SaO2 100%). Albuterol or oxygen therapy alone is unlikely to correct this patient’s cause of respiratory failure (i.e., hypoventilation). Likewise, his acid-base disturbance is consistent with pure acute respiratory acidosis (elevated PaCO2 and normal HCO3) and is therefore unlikely to respond to HCO3

which is usually reserved for severe metabolic acidosis.

4. Answer: C This arterial blood gas is consistent with a respiratory acidosis. The pH is below 7.40 (indicating it is an acidosis), and the PaCO2 (an acid) is higher than normal (about 40 mm Hg). In chronic respiratory acidosis, the kidneys will conserve bicarbonate (a base) in an attempt to maintain a normal pH. This compensatory response is obvious in this patient, because her serum HCO3

- is 28 mEq/L (about 4

mEq/L higher than normal). The elevated HCO3-

concentration in this patient confi rms the diagnosis of respiratory acidosis (because one would expect the HCO3

- to be less than 24 mEq/L if the acidemia were due to a metabolic cause).

5. Answer: D Now, the patient has a mixed metabolic and respiratory alkalosis. The pH is greater than 7.40 (indicating that it is an alkalosis), and now, the PaCO2 (an acid) is below normal, leading one to suspect that this is simply a respiratory alkalosis. However, this patient’s HCO3

- (a base) is still elevated at 28 mEq/L (due to long-standing compensation for an elevated PaCO2). If this were a pure respiratory alkalosis, the serum HCO3

- would be 24 mEq/L, because the primary and compensatory changes always occur in the same direction in simple acid-base disorders. Because the HCO3

- is above normal and the PaCO2 is below normal, this is a “mixed” disorder. In this case, the pH indicates it is an alkalosis; the PaCO2 is below normal, which is consistent with a respiratory alkalosis, and the HCO3

- is above normal, which is consistent with a metabolic alkalosis (therefore, it is a mixed metabolic and respiratory alkalosis). This occurred because of rapid “hyperventilation” (36 breaths/minute on assisted-control ventilation) in a patient with a chronically elevated HCO3

- concentration, which is a normal compensatory response in chronic CO2 retention. Serum HCO3

- concentrations require more time to correct than PaCO2 concentrations. Ideally, the ventilator mode/rate would be adjusted to maintain a PaCO2 that is “normal” for the patient (in this case, probably around 50 mm Hg).

6. Answer: C One of the primary disadvantages of injectable haloperidol for ICU sedation is the risk for QTc prolongation, torsades de pointes, and ventricular fi brillation. This risk is probably greatest in patients with a baseline QTc more than 480 milliseconds, those with hypokalemia, those with hypomagnesemia, or those with concomitant medications known to prolong QT intervals. The other answers are wrong for obvious reasons.

7. Answer: D The patient should be given midazolam 2.5 mg intravenously now and then be rebolused until the patient is sedated; then, the patient should be intubated. Midazolam is a short-acting sedative used frequently for rapid sedation. The drug should be dosed to desired effect. Propofol can induce apnea and is only recommended for use in intubated

ANSWERS AND EXPLANATIONS TO PATIENT CASES

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patients. All sedatives should be given as bolus doses to achieve rapid sedation goals before starting a continuous infusion; therefore, answer B is not correct. Vecuronium is a paralytic; it should never be used in a patient who is not intubated and sedated.

8. Answer: C Although it is not universally accepted, there is a consensus among experts that peripheral nerve stimulation should be used to guide therapeutic paralysis in the ICU. This is most often accomplished with the train-of-four sequence. It is imperative for clinicians to recognize that neuromuscular-blocking agents do not cross the blood-brain barrier and are not useful as either sedatives or analgesics. Adequate sedation and analgesia must be achieved before starting a paralytic agent and should continue throughout the paralysis. In addition, the paralytic should be allowed to dissipate at least once daily to assess the adequacy of sedation/analgesia. The goal response on train-of-four is typically one or two twitches. Four of four twitches would indicate inadequate paralysis (or possibly misplacement of electrodes directly over a muscle group).

9. Answer: B Although the patient is no longer paralyzed (moving around in bed, four of four twitches on train-of-four), it would be inappropriate to reparalyze an obviously agitated patient. That she is so agitated and tachycardic could be the result of being paralyzed without adequate sedation or analgesia. Before reinstituting pancuronium, the patient should be given a rapid-acting sedative, such as fentanyl (midazolam or diazepam may also be appropriate). In paralyzed patients, it is generally better to err on the side of oversedation rather than undersedation, so an increase in the sedative drip rates would also be appropriate in this patient. However, lorazepam has such a long half-life (and slow onset) that simply increasing the drip rate without fi rst giving a bolus of a rapid-acting agent would not result in timely sedation. Switching paralytics is unwarranted because her tachycardia can be explained by factors other than the pancuronium.

10.Answer: D Clindamycin and gentamicin have pharmacodynamic effects (i.e., they inhibit the release of acetylcholine at the nicotinic receptor), which may potentiate the action of nondepolarizing neuromuscular-blocking agents. About 60%–80% of a pancuronium dose is excreted unchanged in the urine; therefore, renal insuffi ciency may also result in signifi cantly prolonged effects.

11.Answer: B Prolonged treatment with either a neuromuscular-blocking agent or a corticosteroid can result in acute

myopathy. However, the combined treatment appears to be associated with a signifi cantly higher risk. Numerous reports have described profound muscle weakness (lasting days to weeks) in otherwise healthy asthmatic patients who received methylprednisolone, hydrocortisone, dexamethasone, or prednisone during therapeutic paralysis. Because most of these patients had no other risk factors for prolonged paralysis (e.g., organ dysfunction, aminoglycosides), it would be prudent to avoid this combination when possible.

12. Answer: D This patient’s hemodynamic profi le is most consistent with sepsis (i.e., high cardiac index and low systemic vascular resistance). Her pulmonary capillary wedge pressure is also relatively low considering the degree of fl uid challenge she has received. Because she remains hypotensive despite receiving an adequate fl uid load, an α-adrenergic agent such as dopamine or norepinephrine should be started. Norepinephrine is a more potent vasoconstrictor than phenylephrine and provides less β-stimulation than dopamine. If she became more tachycardic on norepinephrine, phenylephrine could be tried. Dobutamine is an inotropic agent that increases the cardiac index and lowers pulmonary capillary wedge pressure. Dobutamine is usually avoided when the SBP is less than 100 mm Hg. The goals of treatment are to improve BP (typically, mean arterial pressure) and restore adequate organ perfusion. Piperacillin/tazobactam and ciprofl oxacin will provide adequate gram-positive, gram-negative, and anaerobic coverage for nosocomial pneumonia, eliminating the need for clindamycin. The patient appears to meet the criteria for the use of drotrecogin-α; however, her symptoms started less than 24 hours ago, and there has not been an adequate amount of time for evaluation of the current antibiotic treatment. There is no urgency to start drotrecogin-α, because therapy appears to be benefi cial when initiated within 48 hours of meeting criteria.

13. Answer: B When using epinephrine in the patient with cardiac arrest, the primary goal of therapy is return of spontaneous circulation. Therefore, the benefi cial effects of epinephrine are caused by its α-agonist effects. The recommended dose of epinephrine is a 1 mg intravenous push every 3–5 minutes during resuscitation. High-dose epinephrine and escalating doses of epinephrine are no longer recommended. Epinephrine is used as fi rst-line therapy for ventricular tachycardia/pulseless ventricular fi brillation, pulseless electrical activity, and asystole. It can be used for bradycardia with serious symptoms, but the fi rst-line agent for bradycardia is atropine.

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14. Answer: A Calculating an infusion rate is a very important role for the pharmacist in code situations. The infusion pump is set to run in milliliters per hour, so your answer should always be in these units. To determine the rate (milliliter per hour) to achieve a 5 mcg/kg/minute dose, use the following calculation:concentration of dopamine drip: 400 mg/250 mL = 1.6 mg/mL or 1600 mcg/mL70 kg × 5 mcg/kg/minute × 60 minutes/1 hour × 1 mL/1600 mcg = 13 mL/hour

15. Answer: B Although this patient had hypotensive episodes during her resuscitation period, she currently has a functioning GI system, as evidenced by her tolerance of tube feeds. Therefore, SUP should be given through her nasogastric tube if possible, making the best choice for this patient the simplifi ed lansoprazole suspension. The remaining answers were not appropriate because they were intravenous. In addition, the famotidine and cimetidine dose choices were not appropriate for renal dysfunction, and the pantoprazole dose listed was for a GI bleed, not SUP. Cimetidine is the only FDA-approved agent for SUP; however, it is rarely used because of its high rate of drug interactions. The H2RAs are also associated with mental status changes in the elderly, which should be considered in this patient with neurologic defi cits.

16. Answer: B This patient’s risk factors for SUP (mechanical ventilation, acute renal failure, and hypoperfusion) are no longer present, so SUP should be discontinued. There is no evidence to prove that a PPI is more effi cacious than an H2RA for SUP. Several studies have shown that PPIs can maintain a gastric pH of more than 4 for a longer time than H2RAs, but no data showing superior effi cacy have been published. If cost is not an issue and there are no contraindications to a PPI or H2RA, agents in either class can be used for SUP when indicated.

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1. Answer: AThis patient’s arterial blood gas and urine chloride are consistent with a saline-responsive metabolic alkalosis. In critically ill patients, the most common cause of metabolic alkalosis is volume contraction. In this case, the volume contraction is most likely caused by overly aggressive diuresis. In patients receiving diuretics, the urine chloride should be measured at least 12–24 hours after the last dose. This patient should receive a normal saline infusion. Hydrochloric acid infusions are typically reserved for more severe alkalosis (pH more than 7.55) that is not responding to conventional therapy. Using HCO3

- or increasing the patient’s tidal volume would be inappropriate, because these actions would likely worsen the alkalosis.

2. Answer: DThis patient has severe acute delirium. This medical emergency must be treated with haloperidol and lorazepam because both are additive. Lorazepam provides anxiolysis, and haloperidol provides antidelirium effects. Propofol alone (Answer a) is incorrect, because it will simply mask the patient’s agitation but will not treat the underlying causes (anxiety and delirium). Answers b and c are incorrect because either agent alone is inferior to the combination of both agents in Answer d.

3. Answer: CPropofol is formulated in a 10% lipid emulsion, which will contribute to the total calories the patient is receiving. In addition, triglycerides should be monitored, especially in a patient with pancreatitis and in patients receiving high doses or prolonged infusions of propofol. Vecuronium is a paralytic and has no sedative properties. Tobramycin and magnesium may prolong paralysis and should be avoided in this patient, if possible. Morphine and propofol can have additive central nervous system effects when used in combination, so routine neurologic assessments need to be conducted, and doses should be titrated accordingly.

4. Answer: CA stable, comfortable, and responsive patient who is currently receiving mechanical ventilation and sedation is a candidate for daily sedation interruption (Answer C). This intervention has been shown to hasten the time to extubation by 2 days compared with conventional sedation in a randomized controlled trial (Kress JP, Pohlman AS, O’Connor MF, Hall JB, N Engl J Med 2000;342:1471–7). No rationale exists to change opioid narcotics (Answer b). Answers a and d represent conventional sedation, which resulted

in prolonged duration of mechanical ventilation and length of ICU stay.

5. Answer: CThis patient meets the criteria for severe sepsis as defi ned by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Guidelines and the PROWESS Trial. This patient would be a good candidate for drotrecogin-α therapy. The criteria that qualify her for drotrecogin-α include a suspected infection; meeting systemic infl ammatory response syndrome criteria (temperature more than 38°C, SBP less than 90 mm Hg, HR more than 90 beats/minute, and WBC more than 12,000), and having one or more organ system failures (e.g., respiratory, renal, cardiovascular). She is on the appropriate empiric antibiotics; however, this regimen should be reevaluated when culture and sensitivity results are available. Hemodynamic instability is still a problem despite fl uid resuscitation. The patient’s APACHE score is more than 25, which is associated with a high mortality rate, but a better response to drotrecogin-α treatment. Drotrecogin-α therapy has shown benefi t for up to 48 hours after symptom onset; therefore, treatment should be started immediately in this patient.

6. Answer: CThe Surviving Sepsis Campaign guidelines recommend adequate fl uid resuscitation before the addition of vasopressor agents in patients with severe sepsis. This patient’s BP, HR, and BUN/Cr ratio indicate that she is severely dehydrated and needs to “fi ll up her tank” immediately. Therefore, intravenous fl uids should be the next therapy added to this patient’s regimen.

7. Answer: CDopamine has both β-adrenergic and α-adrenergic properties, with the best β-adrenergic effects achieved at doses of 5–10 mcg/kg/minute. This can cause an increased oxygen demand on the heart, which would not be benefi cial in a patient with a past myocardial infarction. Tachycardia is also a side effect of dopamine administration and appears to be causing this patient’s increase in HR, so increasing the dose will likely cause more tachycardia. The epinephrine dose listed is for cardiopulmonary resuscitation cases only and is therefore incorrect. Vasopressin continuous infusions should be added at doses less than 0.04 units/minute after other vasopressor agents have failed. Higher doses of vasopressin can cause myocardial ischemia and are not recommended. Phenylephrine is a potent

ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS

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α-receptor agonist and is the best choice for the patient at this time.

8. Answer: DThe patient has refractory pulseless ventricular tachycardia; therefore, amiodarone should be the next agent given. Atropine is used for bradycardia and pulseless electrical activity, not ventricular tachycardia. It has been only 1 minute since the last dose of epinephrine, so another dose (or a dose of vasopressin) is not recommended for another 2 minutes. The ACLS guidelines recommend a dose of 40 units of intravenous push vasopressin.

9. Answer: DMultiple t-tests are not the answer (Answers a or b), because as the number of groups exceeds two, the number of needed pairwise comparisons also grows. For this study, there are 21 possible pairwise comparisons that could be done; it would be likely to detect a signifi cant difference (which would happen less than 5% of the time) if we compared 21 pairs of means rather than 1 pair of means. In other words, for 21 pairwise comparisons, a p=0.05 for 1 pair cannot be considered signifi cant. One would have to adjust the p-value threshold for signifi cance downward accordingly to account for this, thereby making it much more diffi cult to achieve statistical signifi cance. Analysis of variance (Answer d) puts all the data into one number (F) and provides a single p-value for the null hypothesis. Analysis of covariance (Answer c) is used when factors are identifi ed that may explain a statistical difference between groups. These may include a prior history of GI bleeding or nonsteroidal anti-infl ammatory drug use.

10. Answer: BMechanical ventilation and coagulopathy are independent risk factors for SRMD. This patient is critically ill and may be intubated for an extended period; therefore, he is at risk for SRMD and requires SUP. The patient currently has an NJ feeding tube, which means that enteral nutrition and medication administered by the tube will go directly into the jejunum. Sucralfate has been shown to be inferior to H2-antagonists for the prevention of clinically signifi cant bleeding from SRMD in a large randomized controlled trial (Cook DJ, et al, N Engl J Med 1998;338:791–7) and is generally not recommended for SUP. PPIs, such as intravenous pantoprazole, are reserved as second-line alternatives for patients who are intolerant to H2-antagonists. Thus, famotidine is the best agent for SUP in this patient.

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NOTES

Fluids, Electrolytes, and Nutrition


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Fluids, Electrolytes, and NutritionGordon S. Sacks, Pharm.D., BCNSP

The University of Wisconsin–Madison.Madison, Wisconsin



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Learning Objectives

1. Understand the importance of the route of nutrient administration on host defense mechanisms in the metabolic response.

2. Understand the potential mechanisms for differences in outcome related to enteral versus parenteral nutrient delivery.

3. Discuss the physiologic processes involved in acid-base disorders.

4. Identify primary and secondary acid-base disorders based on arterial blood gases (ABGs).

5. Determine and use the anion gap for diagnostic purposes.

6. Outline a stepwise approach for interpretation and treatment of acid-base disorders.

7. Understand the importance of the route of nutrient administration on host defense mechanisms in the metabolic response.

8. Understand the potential mechanisms for differences in outcome related to enteral versus parenteral nutrient delivery.

9. Identify the multiple enteral access routes and administration devices that are available.

10. List the complications associated with enteral access devices and administration of EN.

11. Describe the uses of PN in specifi c diseases and conditions.

12. Compare and contrast central PN and peripheral PN in terms of techniques, advantages, and disadvantages.

13. Describe the adverse effects of excessive carbohydrate administration.

14. Recall the available intravenous protein substrates and state the marketed use for each one.

15. Describe the current recommendations for intravenous fat administration and discuss recent advances in intravenous fat products.

16. Discuss the advantages and disadvantages associated with total nutrient admixtures (TNAs).

17. Identify stability issues associated with calcium and phosphorus compatibility.

18. Be familiar with the complications associated with PN therapy.

19. Describe the homeostatic mechanisms responsible for sodium and water balance.

20. Discuss the most common etiologies and list the signs and symptoms of hypo/hypernatremia, hypo/hypermagnesemia, and hypo/hyperphosphatemia.

21. Develop a treatment plan for the management of common electrolyte disorders in patients receiving nutritional support.


1. A 2-year-old, 13-kg boy with a history of Hirschsprung’s disease is postoperative day 2 s/p a small bowel resection. His nasogastric tube is connected to low intermittent suction and is draining copious amounts of green fl uid. Urine output has decreased to 0.3 mL/kg/hour despite receiving maintenance intravenous fl uids of dextrose 5%/0.2% normal saline. Laboratory values and ABGs on room air are as follows: sodium, 144 mEq/L; potassium, 3.2 mEq/L; chloride, 94 mEq/L; pH 7.52; PO2, 90 mm Hg; PCO2, 48; and HCO3, 39. What acid-base disorder is present?A. Compensated metabolic alkalemia.B. Uncompensated metabolic alkalemia.C. Respiratory alkalemia.D. Respiratory alkalemia with compensated

metabolic acidemia.

2. A 9-year-old girl with a history of Crohn’s disease is admitted to the hospital with a perforated bowel and peritonitis. After undergoing surgery for a colectomy and peritoneal irrigation, she is transferred to the intensive care unit. Postoperatively, she becomes septic with a temperature of 103°F. ABGs and laboratory values on arrival to the intensive care unit are as follows: pH, 7.12; PCO2, 19 mm Hg; HCO3, 5 mEq/L; sodium, 140 mEq/L; potassium, 4.8 mEq/L; and chloride, 105 mEq/L. What is acid-base disorder is present?A. Metabolic acidemia.B. Compensated respiratory acidemia.C. Combined respiratory and metabolic

acidemia.D. Metabolic acidemia with respiratory

alkalemia.

3. A 5-year old, 25-kg boy sustained severe head injuries, a grade IV splenic laceration, a tibia-fi bula fracture, and a pulmonary contusion after being hit by a car while riding his bicycle. He is stabilized and transferred to the intensive care unit with the following laboratory values and ABGs on admission: sodium, 135 mEq/L; potassium, 3.1 mEq/L; chloride, 103 mEq/L; pH, 7.51; PCO2, 25 mm Hg; and HCO3, 22 mEq/L. What acid-base disorder is present?A. Compensated respiratory alkalemia.B. Uncompensated respiratory alkalemia.



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C. Metabolic alkalemia with compensated respiratory acidemia.

D. Combined metabolic and respiratory alkalemia.

4. Which one of the following is the best treatment strategy for correcting hyponatremia in a patient with syndrome of inappropriate section of antidiuretic hormone (SIADH)?A. Intravenous D5W.B. Intravenous D51/4NS.C. Vasopressin administration.D. Free water restriction.

5. Which one of the following situations could be responsible for a persistent hypokalemia refractory to potassium supplementation?A. Hyponatremia.B. Hypophosphatemia.C. Hypomagnesemia.D. Hypoaldosteronism.

6. Which one of the following has been associated with hypomagnesemia?A. Amphotericin B.B. Severe thermal injury.C. Alcoholism.D. GI fl uid loss.

7. Too aggressive phosphate repletion therapy may result in:A. Hypophosphatemia rebound.B. Hypocalcemia.C. Metastatic calcifi cation.D. B and C.

8. Which one of the following best describes the concept of bacterial translocation?A. Infection caused by touch contamination.B. Bacterial uptake of iron from the

circulation.C. Peristaltic movement of microorganisms

along the intestinal tract.D. Passage of microorganisms from the

intestinal tract across the mucosa into the systemic circulation.

9. When compared with patients receiving PN, early enteral feeding after major trauma is associated with:A. Greater caloric intake.B. Decreased mortality.C. Decreased days of antibiotics.D. Fewer postoperative infections.

10. What is the most effective method of alimentation for decreasing gut mucosal atrophy?A. Central PN.B. PPN enriched with branch chain amino

acids.C. EN.D. Pharmacological doses of zinc.

11. Aggressive nutrition support is most effective in reducing lean tissue breakdown in which one of the following disease states?A. Sepsis.B. Starvation.C. Multiple trauma.D. Head injury.

12. Which one of the following immunoglobulins found in intestinal secretions prevents luminal pathogens from attaching to and invading intestinal epithelial cells?A. IgA.B. IgE.C. IgG.D. IgM.



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I. ABCs OF ACID-BASE BALANCE

A. The Basics1. Defi nitions

a. Acid: a substance that can donate hydrogen ions (H+)

H2CO3 H+ + HCO3-

(acid)

b. Base: a substance that can accept H+

HCO3- + H+ H2CO3

(base)

c. Acidemia refers to an acid condition of the blood, pH less than 7.35, whereas acidosis is the process in the patient that causes acidemia.

d. Likewise, alkalosis refers to the process in the patient that causes the alkalemia, pH more than 7.45.

e. Primary disorder: a pathologic change in the respiratory component or the metabolic component, resulting in an acidosis or an alkalosis

f. Correction: normalization of the component involved in a primary disorderg. Compensation: change in pH toward normal by the component not involved in the

primary disorder. For every addition of acid the body receives, the body attempts to bring the pH back toward normal by an addition of a base. For example, a respiratory alkalosis can compensate for a primary metabolic acidosis.

h. Buffers: agents that decrease the ability of acids and bases added to a solution to alter pH

2. Table 1. Normal Blood Gas ValuesArterial Blood Venous Blood

pH 7.40 (7.35–7.45) 7.36 (7.33–7.43)PO2 80–100 mm Hg 35–40 mm HgPCO2 35–45 mm Hg 41–51 mm HgHCO3- 22–26 mEq/L 24–28 mEq/LO2 saturation ≥ 95% 70%–75%Base excess −2 to +2 0 to +4

a. Blood gases are obtained for two major reasons:i. To determine the oxygenation of a patientii. To determine the acid-base status of a patient

b. Types of blood gases:i. Arterial (ABGs): mixture of blood from various parts of the body; characterizes how

well lungs are oxygenating the bloodii. Venous: represents tissue oxygenation; identifi es possible heart and circulation failure

c. Components of ABGsi. pH = identifi es the presence of acidemia or alkalemiaii. PO2 = pressure exerted by oxygen dissolved in the plasmaiii. PCO2 = pressure of dissolved CO2 gas in the bloodiv. O2 saturation = percentage of oxygen that hemoglobin is carrying related to the total

amount the hemoglobin could carryv. Base excess = primarily refl ects the concentration of bicarbonate and is affected only

by metabolic processes; positive values refl ect metabolic alkalosis, and negative values refl ect metabolic acidosis



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3. Buffer Systema. Optimal function of the human body depends on the maintenance of the H+ concentration

within a relatively narrow range: pH range of 7.10–7.60.b. The body counters excessive shifts in pH by three mechanisms:

i. Chemical buffering: bicarbonate (HCO3-), hemoglobin, proteins, phosphates

ii. Respiratory compensation: PCO2iii. Renal compensation: HCO3

-

c. PCO2 (respiratory component)i. Infl uenced ONLY BY THE LUNGSii. Considered an ACIDIC substanceiii. Breathing is regulated to match CO2 production (about 18,000 mmol/day) and to

maintain a constant PCO2.(a) Increased PCO2 = “hypoventilation” or ventilation too low for CO2 production

rate(b) Decreased PCO2 = “hyperventilation” or ventilation too high for CO2 production

rateiv. Ventilation rate can change PCO2 and pH of the blood, and this can happen very

quickly (i.e., with a few breaths) in a matter of minutes. Maximal compensation is achieved within 12–24 hours.

d. HCO3- (metabolic component)

i. Infl uenced ONLY BY METABOLIC PROCESSES, i.e., the kidneysii. Considered a BASIC substanceiii. Kidneys can affect blood pH by reabsorbing HCO3

-, by allowing excess HCO3- to be

excreted in the urine, and by generating new HCO3- by acid secretion.

iv. Kidneys also excrete nonvolatile (“titratable”) acids that are metabolic end products.v. Thus, kidneys contribute to acid-base homeostasis by excreting nonvolatile acids and

by controlling HCO3- concentration in the extracellular fl uid (ECF) compartment.

*Note: “CO2” is reported on serum electrolytes in milliequivalents per liter and represents total CO2, which is a combination of HCO3

- and dissolved CO2/H2CO3 in

the blood; because CO2 and H2CO3 are only a small fraction of total CO2 in a serum sample, total CO2 is considered equal to HCO3. Do not confuse PCO2 (expressed in mm Hg) in the ABG report with CO2 (expressed in millimeters of mercury) in the serum electrolytes report.

vi. Metabolic compensation through the kidneys is slow, requiring several hours to change ECF HCO3

- and 5–7 days to achieve maximal compensation.

B. Stepwise Approach to Acid-Base Disorders1. Use the ABG to determine the presence of acidemia or alkalemia.

a. pH less than 7.35 = acidemiab. pH more than 7.45 = alkalemia

2. Determine whether the primary process is respiratory or metabolic.a. Abnormal PCO2 (less than 35 mm Hg or more than 45 mm Hg): respiratoryb. Abnormal HCO3

- (less than 22 mEq/L or more than 26 mEq/L): metabolic

3. Calculate the “gaps”: a. Law of electrical neutrality: number of cations in serum must equal the number of anions.

i. Cl- plus HCO3- plus unmeasured anions = Na+ plus unmeasured cations

ii. Unmeasured anions = phosphates, sulfates, organic anions, proteinsiii. Unmeasured cations = Ca+2, K+, Mg+2



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b. Anion gap = Na+ minus (HCO3- plus Cl-)

i. Normal anion gap = 10 plus or minus 4 mEq/Lii. Increased anion gap (more than 14 mEq/L) can indicate metabolic acidosis.iii. Increased anion gap (more than 25 mEq/L) always indicates metabolic acidosis.

4. Check for the degree of compensation.a. Compensation in metabolic acidemia

i. “Eyeball” method: decrease in PCO2 = last two digits of the pHii. Formula method: decrease in PCO2 = 1.2 × decrease in HCO3

-

b. Compensation in metabolic alkalemiai. Formula method: increase in PCO2 = 0.6 × increase in HCO3

-

c. Compensation for respiratory acidemia i. Acute: change in PCO2 = 0.1 × change in HCO3

-

ii. Chronic: change in PCO2 = 0.4 × change in HCO3-

d. Compensation for respiratory alkalemiai. Acute: change in PCO2 = 0.2 × change in HCO3

-

ii. Chronic: change in PCO2 = 0.5 × change in HCO3-

5. Determine whether there is a 1:1 relationship between anions in the blood.a. Increased anion gap metabolic acidosis: every one-point increase in anion gap should be

accompanied by a 1-mEq/L decrease in HCO3-

i. Decline in HCO3- of less than the increase in the anion gap suggests an underlying

metabolic alkalemia (i.e., complex acid-base disorder)

b. Normal anion gap metabolic acidosis: every 1-mEq/L increase in chloride should be accompanied by a 1-mEq/L decrease in HCO3

-

i. Decline in HCO3- of less than the increase in Cl-: an additional primary metabolic

alkalemia is present

C. Etiologies and Management of Acid-Base Disorders1. Metabolic Acidosis

a. Gain of strong acid or loss of base from ECF, resulting in decreased HCO3-and decreased

BE less than 2.5 mEq/Lb. Respiratory compensation: onset is rapid, and maximal compensation averages about 1.2

mm Hg PCO2 for every 1-mEq/L decrease in HCO3-

c. Correction mechanisms:i. Increased renal acid secretion (decreased urine pH)ii. Metabolism of organic acids

(a) Lactic acid is buffered by HCO3- and therefore decreasing HCO3

-

(b) Lactic acid is metabolized to pyruvic acid and then acetyl coenzyme A and then to CO2 and H2O by the tricarboxylic acid cycle.

(c) For each lactic acid metabolized, an HCO3- is recovered as the buffer equation

shifts:

Lact- plus H2CO3 HCO3- plus HLact

CO2 plus H2O

This is why salts of metabolizable organic acids can be used therapeutically as “bicarbonate precursors.”



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d. Clinical causes of metabolic acidosis with normal anion gapi. GI losses of HCO3

-: diarrhea, enteric or pancreatic fi stulaeii. Ileal or colonic conduit (urinary diversions): these segments secrete Na+ and HCO3

-

while reabsorbing NH3, NH4+, H+, and Cl- when exposed to urine

iii. Renal tubular acidosisiv. Drugs: acetazolamide, amphotericin B, cholestyraminev. Urinary anion gap may be helpful diagnostically.

(a) Urine anion gap = Na+ plus K+ minus Cl-

(b) Normal urine anion gap = −20 to 0 mEq/L(c) NH4

+ is the predominant unmeasured cation, and its excretion is usually accompanied by Cl-. Under normal circumstances, 20–40 mEq/L of NH4

+

is excreted each day, and the urine anion gap has a negative value (−20 to 0 mEq/L). The normal response to an acid load is an increase in renal generation of ammonia, with an increase in urine NH4

+ excretion.(d) In metabolic acidosis, NH4

+ excretion should increase dramatically if acidifi cation is intact, resulting in a large negative urine anion gap (−20 to −50 mEq/L).

(e) If a defect in renal acidifi cation is present (e.g., renal tubular acidosis), NH4+

excretion is impaired, and the urine anion gap is positive.e. Clinical causes of metabolic acidosis with an increased anion gap. Think of the

mnemonic A MUDPIEi. Aspirinii. Methanoliii. Uremic renal failure (kidney disease)iv. Diabetic ketoacidosis and other forms of ketoacidosisv. Paraldehydevi. Ischemic or idiopathic lactic acidosisvii. Ethylene glycol

f. Management of patients with metabolic acidosisi. Identify and treat cause of acidosis

Examples:(a) GI losses: treat diarrhea or fi stula(b) Ketoacidosis: initiate insulin drip if diabetic ketoacidosis(c) Lactic acidosis: treat underlying cause (e.g., shock)

ii. Circumstances that require acute management of acidemia(a) Cardiovascular depression, hyperkalemia(b) Sustained pH less than 6.9 incompatible with life; pH less than 7.2 with

hypotension is usually treated with alkalinizing agentsg. Medications used to treat metabolic acidosis

i. NaHCO3: problems associated with its use as a treatment of acidemia include:(a) CO2 generation(b) Overshoot alkalosis(c) Overcompensation(d) Na+ load

ii. Dosing guidelines for NaHCO3(a) If the base excess is decreased but the anion gap is normal, it usually represents a

true HCO3- loss.

(b) To estimate the HCO3- defi cit, multiply the base excess (expressed as

milliequivalents per liter) × the apparent volume of distribution (0.3–0.5 L/kg).(c) If there is an increased anion gap, it usually means that the low HCO3

- is due to

buffering rather than depletion, and the buffer may be recovered if the acid is



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metabolizable; thus, NaHCO3 therapy is not indicated because there is a greater risk of complications associated with alkali therapy.

iii. If the patient is receiving total PN (TPN), use acetate salts (e.g., NaAc, KAc).iv. Choices for oral bicarbonate supplements:

(a) NaHCO3 tablets: 1 g is about 12 mEq; some patients dislike taste; baking soda is an alternative to tablets

(b) Shohl’s solution: sodium citrate plus citric acid, equivalent to 1 mEq of NaHCO3/mL of solution; preferred to NaHCO3 tablets by some patients; citrate may increase gastrointestinal (GI) absorption of Al+3, which can be a problem for patients with renal failure

(c) Potassium bicarbonate, acetate, and citrate: good choices for patients that require supplements of K as well as bicarbonate but must be avoided in patients with renal failure

2. Metabolic Alkalosisa. An increase in ECF HCO3

-, with a BE greater than +2.5; caused by a gain of base or a loss of H+ from ECF

b. Compensation mechanism is hypoventilation (increased PCO2)i. Respiratory compensation is rapid.ii. Maximal compensation is extremely variable among patients and is limited by

the necessity of maintaining adequate ventilation for gas exchange; the average compensation is about a 0.5-mm Hg increase in PCO2 for each milliliter per liter rise in HCO3. The maximum PCO2 will rarely exceed 50–55 mm Hg unless lung disease or another cause of ventilatory depression is present.

c. Correction mechanismi. Excess bicarbonate can be excreted by the kidneys under normal conditions.ii. The ability of kidneys to excrete excess bicarbonate is compromised by decreased

renal perfusion, inadequate availability of Cl- or K+, and mineralocorticoid activity.d. Clinical causes of metabolic alkalosis

i. Usually a combination of an initiating acid loss/base gain together with a condition that compromises the kidneys’ ability to excrete the excess bicarbonate

ii. If the kidneys are normal, it is usually possible to anticipate and prevent the development of metabolic alkalosis by providing intravenous fl uid maintenance that ensures good renal perfusion and adequate availability of K+ and Cl-.

iii. ECF/Cl- depletion: loss of gastric juice, diuretic therapy, posthypercapneaiv. Mineralocorticoid excess: hyperaldosteronism, Cushing’s diseasev. Hypokalemia: increases renal tubular bicarbonate generation and the maximal

reabsorptive capacity for bicarbonate; note that potassium depletion commonly is present in metabolic alkalosis.

e. Situations that require acute management of alkalemia:i. A pH of more than 7.55 is of concern, and a pH of more than 7.6 would require

urgent treatment.ii. May cause tetany, muscle weakness, ileus, arrhythmias because of decreased ionized

calcium, and intracellular shifts of K+, Mg+2, and PO4-3

f. Management of metabolic alkalosis. Think of the mnemonic CRAP.i. If adequate renal function, maximize the patient’s ability to excrete excess

bicarbonate by correcting ECF volume depletion with NaCl and fl uid to improve Renal perfusion and minimize Aldosterone production, and supplement Potassium chloride.

ii. If alkalemia is caused by gastric losses, the patient is usually ECF volume depleted,



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chloride depleted, and K+ depleted; H2-antagonists or proton pump inhibitors are useful to decrease gastric acid losses

iii. If alkalemia is diuretic induced, K+ and ECF volumes are often depleted; K+-sparing diuretic and NaCl may be helpful; also, temporarily stop diuresis and/or reduce dose

iv. If alkalemia is due to mineralocorticoid excess and patient is on high-dose steroid, change to steroid with lower mineralocorticoid activity (i.e., dexamethasone, methylprednisolone).

v. Acetazolamide: 250- to 500-mg single dose will promote bicarbonate diuresis if adequate renal perfusion/renal function, adequate K+ and Cl-

vi. Acid therapy for severe alkalosis (i.e., HCl)(a) HCl is not commercially available and must be extemporaneously compounded

by a pharmacist(b) Mix concentrated HCl with intravenous fl uids to make 0.1 N HCl in 5% dextrose

as the fi nal solution and administer through the central vein only.vii. If the patient is receiving TPN, use chloride salts (e.g., NaCl, KCl), and add H2-

antagonist to the TPN.

3. Respiratory Acidosisa. Increased PCO2 due to inadequate ventilation relative to CO2 production (hypoventilation)b. Compensation mechanisms:

i. Small immediate increase in HCO3-from plasma buffers (slight decrease or no change

in BE)ii. Increased renal reabsorption of HCO3

- (increased BE)

(a) Slow onset of 6–18 hours, maximal in 5–7 days(b) pH restored to close to normal range if hypoventilation continues for several days

c. Clinical causes for respiratory acidosis:i. Decreased central nervous system

(a) Central nervous system disease (e.g., injury, neoplasm, infection)(b) Drugs/Poison (e.g., opiates, alcohols, anesthetics)(c) Metabolic (e.g., anoxia)

ii. Mechanical(a) Airway obstruction (e.g., severe asthma, foreign body, tumor)(b) Pneumothoraces

iii. Neuromuscular(a) Spinal injury(b) Paralyzing drugs(c) Muscular dystrophy(d) Guillain-Barre, acute lateral sclerosis, multiple sclerosis

iv. Loss of gas exchange area(a) Severe pneumonia(b) Severe pulmonary edema(c) Emphysema(d) Massive pulmonary embolus

d. Situations that require acute management of acidosisi. pH values less than 7.2 may affect cardiovascular function.ii. Decreased O2 because of hypoventilation

e. Management of respiratory acidosisi. Treat underlying cause; in chronic obstructive pulmonary disease, keep PO2 more



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than 60 mm Hg with cautious oxygen supplementation because it may exacerbate hypoventilation further in a patient who is chronically hypoxic and hypercapneic.

ii. Drugs to improve ventilation(a) Naloxone: effective for opiate-induced respiratory depression(b) Cholinesterase inhibitors (e.g., neostigmine): effective for partial reversal of

paralyzing drugs or myasthenia gravis(c) Flumazenil: effective for benzodiazepine-induced respiratory depression(d) Mechanical ventilation: necessary if underlying cause is not reversed quickly and

patient is unable to maintain PO2**NOTE: Bicarbonate therapy is not indicated and may depress ventilation further.

4. Respiratory Alkalosisa. Decreased PCO2 due to ventilation in excess of CO2 production (hyperventilation)b. Compensation mechanisms

i. Small decrease in HCO3- immediately (with no change in BE) due to plasma buffers

ii. Small increase in serum lactic acidiii. Increased renal excretion of HCO3

-

(a) Slow onset of 6–18 hours with maximal effect in 5–7 days(b) Compensation very effective in chronic hyperventilation, but most cases are not

chronicc. Clinical causes for respiratory alkalosis:

i. Psychogenic hyperventilation: anxietyii. Hypoxia: severe asthma, pneumonia, pulmonary embolusiii. Chronic heart failure/pulmonary edemaiv. Feverv. Gram (−) sepsisvi. Increased intracranial pressure: head trauma, stroke/hemorrhage, tumorvii. Salicylate toxicityviii. Liver diseaseix. Excessive mechanical ventilation

d. Situations that require acute management of alkalosis:i. Symptoms of paresthesia, muscle spasms, seizures due to intracellular shifts of Ca+2,

K+, PO4-3, Mg+2

ii. Hyperventilation can be caused by serious underlying conditions that are more urgent than hyperventilation itself.

e. Management of respiratory alkalosisi. Treat underlying cause.ii. Psychogenic hyperventilation: training to control breathing or paper bag breathing

(rebreathing exhaled CO2 prevents large decreases in blood PCO2)iii. Mechanically ventilated patients: may be necessary to suppress patient-triggered

breaths, using opiates/sedatives; paralyzing drugs in some cases

II. ADVANTAGES OF EN

A. Specialized Nutrition Support (JPEN 1995;19:1–2)

“Provision of specially formulated and/or delivered parenteral or enteral nutrients to maintain or restore optimal nutrition status”



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B. Nutritionally at Risk (JPEN 1995;19:1–2)1. Involuntary weight loss or gain of 10% or more of usual body weight (BW) within 6 months

or 5% or more of usual BW in 1 month or 20% or more of ideal BW (IBW)2. Inadequate nutrition intake, including not receiving food or nutrition products (impaired

ability to ingest or absorb food adequately) for more than 7 days

C. General Practice Guidelines for ENCandidates for EN are patients at risk for malnutrition in whom oral feedings are inadequate 1. to maintain their nutritional status.Enteral access should be obtained in critically ill patients whenever possible, either at the 2. time of surgery with direct enteral access or with nasoenteric feeding tubes.Parenteral feedings should be administered 3. ONLY when enteral access cannot be obtained or when feeding into the GI tract is contraindicated.

D. EN Administration Routes and Techniques1. Route

a. Orogastric tubes—preferred with nasal/facial trauma, sinusitisi. Advantages: lower incidence of sinusitis compared with nasoenteric tubesii. Disadvantages: not tolerated for prolonged time in alert patientsiii. Complications: esophageal perforation, pneumothorax, gastrointestinal (GI) bleeding,

otitis media, pulmonary aspirationb. Nasally placed tube—for short-term feeding (less than 3 weeks)

i. Nasogastric—most common tube used; may perform multiple functions in addition to feeding such as decompression of stomach, administration of medications, measurement of gastric pH(a) Advantages: available in a variety of sizes and tube materials, easily placed,

permit bolus feeding and medication administration(b) Disadvantages: contraindicated in patients with nasal/facial trauma, intrinsic

problems of the esophagus (e.g., masses, strictures), increased risk of complications such as GI bleeding, perforation, otitis media, sinusitis, nasal mucosal ulceration

ii. Nasoduodenal—if the tip is past the pyloric sphincter, the risk of EN-associated aspiration is reduced (a) Advantages: effective for patients with gastroparesis; usually, tubes are of smaller

diameter and thus cause less patient discomfort(b) Disadvantages: small diameter may preclude administration of some medications,

usually requires infusion pump for administration, precludes bolus feedings(c) Complications similar to that of nasogastric tube except decreased risk of

aspirationiii. Nasojejunal—defi ned as tip of tube in fourth portion of the duodenum or past the

ligament of Treitz(a) Advantages: associated with the lowest risk of pulmonary aspiration, allows early

postoperative feeding(b) Disadvantages: increased risk of tube occlusion, precludes early postoperative

feeding in hemodynamically unstable patientsc. Tube enterostomy

i. Gastrostomy(a) Stamm gastrostomy—for patients requiring feeding for more than 4 weeks;

surgically placed tube under general anesthesia, easily cared for and allows bolus as well as continuous feeds. Disadvantages are that these tubes are more



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invasive than the nasal route, with possible complications of dislodgment, wound infection, pneumoperitoneum, and stomal leakage.

(b) Percutaneous endoscopic gastrostomy—for patients requiring feeding for more than 4 weeks; can be placed under conscious sedation, is easily cared for, and is replaceable. Disadvantages similar to Stamm gastrostomy

ii. Jejunostomy(a) Needle catheter jejunostomy—small-caliber tubes that are placed during a

laparotomy for only 6–8 weeks. These tubes have a low risk of enteric leakage if inadvertently dislodged but are prone to occlusion if not fl ushed often after medication administration

(b) Percutaneous endoscopic jejunostomy—similar to needle catheter jejunostomy except that tubes are placed endoscopically into the small intestine. Associated with decreased risk of pulmonary aspiration but are diffi cult to replace compared with percutaneous endoscopic gastrostomy

(c) Permanent jejunostomy—similar to needle catheter jejunostomy except that the tubes are of larger diameter and used for prolonged duration. Complications similar to Stamm gastrostomy and percutaneous endoscopic gastrostomy

2. Delivery methodsa. Gravity control—refers to delivery with tubing that is fi tted with a roller clamp to allow

infusion for several minutes to hours based on patient tolerancei. Used for gastric feedingsii. Indicated only for neurologically intact patients because of risk of aspirationiii. Most common use in home care or long-term care environments

b. Pump-assisted continuous infusion is indicated in the presence of volume sensitivity, small bowel feedings, and delayed gastric motility.i. Assists with decreased GI complications associated with rapid infusion such as

nausea, cramping, and diarrheaii. Usually delivered by a stationary or ambulatory pump without interruption

c. Intermittent feeding is a delivery method in which predetermined volumes are administered for a specifi ed period several times daily (e.g., 100–300 mL for 30–60 minutes every 4–6 hours). This method is considered more “physiologic” than the continuous infusion method but may be more appropriate for patients with fl uid balance or tolerance issues.

d. Bolus feedings refer to the delivery of a predetermined volume of feeding at specifi ed intervals by gravity or syringe for a short time.i. This delivery method is simple, inexpensive, and the most “physiologic,” and it

provides the patient with freedom or “breaks” from feeding. ii. Does not require an infusion pump because but is administered by gravity or a

syringeiii. Disadvantages include an increased risk of aspiration, volume intolerance, emesis,

diarrhea, and delayed gastric emptying

E. Selection of Route of Delivery1. Enteral Nutrition (EN) Versus Parenteral Nutrition (PN) Support: Clinical Studies

a. Alexander et al. Ann Surg 1980;192:505–17.i. Eighteen pediatric thermal injury patients (around 60% total body surface area)

(a) Control group: 16.5% of total kilocalories from protein(b) High-protein group: 23% of total kilocalories from protein

ii. Results: control group displayed a signifi cantly lower opsonic index, lower levels of C3, lower levels of transferrin, more bacteremic days, and worse survival



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iii. Control group received 2 times as much of their nutrients by PN.b. Moore EE et al. J Trauma 1986;26:874–81.

i. Seventy-fi ve trauma patients abdominal trauma index (ATI) more than 15)(a) Control group: 5% dextrose in distilled water (D5W) for fi rst 5 days and then PN(b) EN: Vivonex TEN by needle catheter jejunostomy within 18 hours

ii. Results: septic complications were 29% in control versus 9% in EN groupiii. Criticism: comparing fed versus non-fed rather than EN versus PN

c. Moore FA et al. J Trauma 1989;29:916–23.i. Seventy-fi ve trauma patients (ATI more than 15 and less than 40)

(a) TPN group: within 12 hours of injury by central line(b) EN group: within 12 hours of injury by needle catheter jejunostomy

ii. Results: EN group exhibited a signifi cantly lower incidence of major infections (e.g., abdominal abscesses, pneumonia) compared with PN group (3% vs. 20%, p<0.05).

d. Kudsk et al. Ann Surg 1992;215:503–13.i. 98 trauma with ATI at least 15, even if reop within 72 hours, ATI more than 40, pelvic

fracture with more than 6 units of blood loss, or blood loss of more than 25 units within the fi rst 24 hours(a) EN: within 24 hours by needle catheter jejunostomy(b) TPN: within 24 hours by central line

ii. Results—septic morbidity (a) There were no differences in infection rates in patients with injury severity scores

less than 20 or ATI 24 or less.(b) Signifi cantly fewer infections in EN patients with an injury severity score more

than 20 (p<0.002) and an ATI more than 24 (p<0.005) versus PN patients(c) EN patients developed signifi cantly fewer pneumonias (11.8% vs. 31%, p<0.02),

abscesses (1.9% vs. 13.3%, p<0.04), and episodes of line sepsis (1.9% vs. 13.3%, p<0.05) than PN patients.

(d) Evaluating outcome by organs injured, signifi cantly fewer infection rates were noted in EN patients with pancreas or liver injuries than in PN patients.

2. Potential mechanisms for host defense related to nutritiona. Mucosal thickness and permeability

i. Mucosal atrophy with absence of ENii. ↑ Bacterial translocation

b. Gut-associated lymphoid tissuei. Peyer’s patches and mesenteric lymphoid cells → secretory immunoglobulin A

(sIgA)ii. ↓ sIgA with PN; ↑ sIgA with EN

c. Metabolic effectsi. Delayed EN → ↑ resting energy expenditure, ↑ counterregulatory hormones, ↑

catecholamines3. Early EN—how early is early?

a. It appears that initiation of EN in hemodynamically stable patients within 24–48 hours of injury is desirable.

b. Seventy-two hours may or may not be too late to see an appreciable effect.4. Early EN effects on intestinal permeability

a. Increased intestinal permeability with EN started 24 hours after admissionb. More severe form of multiple organ dysfunction syndrome if started on EN 24 hours after

admission5. Summary of Advantages of EN over PN

a. Ease and safety of administration



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b. More economicalc. More physiologic

i. Maintenance of GI integrityii. Bacterial translocation (?)iii. ↓ Septic complications

6. (Relative) Contraindications to EN supporta. Intestinal obstructionb. GI fi stulasc. Severe diarrhead. Intractable vomitinge. Hemodynamic instability

F. Composition and Characteristics of Enteral Formulations1. Carbohydrate

a. Common carbohydrate sources include maltodextrin, modifi ed cornstarch, and corn syrup.

b. Maltodextrin is the most complex carbohydrate source; it is easily digested and has a low osmotic contribution to the formulation.

c. Modifi ed cornstarch is generally used to reduce the osmolality of high osmolar enteral formulations.

d. Carbohydrate content of enteral formulations may vary from 30% to 90% depending on the condition for which the product is intended.

2. Fata. Common sources of fat include vegetable oils (corn, canola, soybean, sunfl ower, and

saffl ower).b. Long-chain triglycerides contributed by vegetable oils are the source of essential fatty

acids such as linoleic acid and α-linolenic acid.c. Medium-chain triglycerides, 6–12 carbons in length, have advantages over long-chain

triglycerides because bile salts or pancreatic lipase is not required for absorption.d. Fat content of enteral formulations may vary from 1% to 55% based on the formulation’s

intended use.e. Adult formulations developed for pulmonary disease or glucose intolerance have high-fat

contents, whereas products designed for malabsorption disorders are low in total fat and long-chain triglycerides.

3. Proteina. Commonly used intact protein or polymeric protein sources include cow milk protein,

whey protein isolates, caseinates, soy protein isolates, milk protein concentrate, and beef. b. Protein sources that have undergone enzymatic hydrolysis may be referred to as

oligomeric, semielemental, or peptide formulations. Examples of these protein sources include hydrolyzed casein, whey, lactalbumin, wheat, soy, and meat protein.

c. Free amino acids are often used in enteral formulations intended for specifi c populations to avoid allergens. Monomeric or elemental formulations usually contain free amino acids.

d. Specialty amino acids, such as branched-chain amino acids, glutamine, and arginine, may be added to enteral formulations. Branched-chain amino acids have been promoted for use in liver disorders, whereas glutamine and arginine have been denoted as having immunomodulating properties in critically ill patients.

4. Fibera. Categories include insoluble and soluble fi bers.b. Insoluble fi ber is the most prevalent type of fi ber and includes soy polysaccharide. Uses

include constipation prevention, increased stool volume, and decreased GI transit time.



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c. Soluble fi ber includes gum arabic, guar gum, and pectin. Uses include improvement of glucose tolerance, reduction of serum cholesterol, and maintenance of colonic mucosal surfaces.

d. Fructooligosaccharides are naturally occurring nondigestible sugars that are used by bifi dobacteria in the GI tract.

e. In the fl uid-restricted patient, fi ber-containing formulations may be associated with abdominal distention, gas, cramping, or even impaction.

5. Water contenta. Enteral formulations that have a concentration of 1 kcal/mL are about 75%–85% water.b. Enteral formulations that have a concentration of 2 kcal/mL are about 70% water.

G. Categories of EN Products1. Polymeric, nutritionally complete tube feeding

a. Use: patients with normal digestive processes and normal organ functionb. Caloric density: 1 kcal/mLc. Examples: Osmolite, Isocal

2. Polymeric, nutritionally complete concentrated tube feedinga. Use: patients with normal digestive processes who need fl uid restrictionb. Caloric density: 2 kcal/mLc. Examples: Magnacal, TwoCal HN, Deliver 2.0

3. Polymeric, nutritionally complete oral supplementa. Use: to supplement a patient’s oral dietb. Caloric density: 1–1.5 kcal/mLc. Examples: Boost, Boost Plus, Ensure

4. Chemically defi ned, nutritionally complete tube feeding (elemental)a. Use: patients with malabsorption (short bowel, pancreatic insuffi ciency)b. Caloric density: 1 kcal/mLc. Examples: Subdue, Peptamen, Vital HN, Vivonex TEN

5. Fiber-containing, nutritionally complete tube feedinga. Use: patients with either constipation or diarrhea/long-term tube feedingb. Caloric density: 1–1.5 kcal/mLc. Examples: Boost w/fi ber, Ultracal, Fibersource, Jevity, Promote w/fi ber, Protain XL

6. Peptide-based, nutritionally complete tube feedinga. Use: patients with malabsorptionb. Caloric density: 1–1.2 kcal/mLc. Examples: Reabilan HN, Sandosource Peptide, Peptamen

7. Disease-specifi c formulas (several are nutritionally incomplete)a. Renal failure

i. Use: acute renal failure without dialysis (low protein, low electrolytes) Caloric density: 2 kcal/mL Examples: Suplena, Renalcal Dietii. Use: acute renal failure with dialysis (more protein, moderate electrolytes) Caloric density: 2 kcal/mL Examples: Magnacal Renal, Nepro, NovaSource Renal

b. Hepatic failure (increased branched-chain amino acids, decreased aromatic amino acids)i. Use: liver failure with hepatic encephalopathyii. Caloric density: 1.1–1.5 kcal/mLiii. Examples: NutriHep

c. Pulmonary failure (increased fat, decreased carbohydrate)i. Use: patients with chronic carbon dioxide retentionii. Caloric density: 1.5 kcal/mLiii. Examples: Respalor, NovaSource Pulmonary, NutriVent, Pulmocare



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Oxepa (for patients with acute respiratory distress syndrome)d. Diabetes mellitus (increased fat, decreased carbohydrate, added fi ber)

i. Use: glucose-intolerant patientsii. Caloric density: 1–1.06 kcal/mLiii. Examples: Choice DM, DiabetiSource, Glucerna, Glytrol, Resource Diabetic

e. Immunocompromised states (enhanced with arginine, glutamine, omega-3 fatty acids, nucleotides, beta carotene)i. Use: stressed, trauma, burn patientsii. Caloric density: 1.3 kcal/mLiii. Examples: Impact, Impact w/glutamine, ImmunAid, Perative, Crucial

f. Stress states (enhanced branched-chain amino acids, increased protein, or both)i. Use: stressed patients (burn, trauma, infection)ii. Caloric density: 1–1.2 kcal/mLiii Examples: TraumaCal, Protain XL, IsoSource VHN, Promote w/fi ber, Replete w/fi ber

H. Complications of EN Support1. Mechanical

a. Displaced feeding tubesb. Clogged feeding tubes—most effi cacious strategy to restore tube patency is to use a

combination of pancreatic enzymes plus sodium bicarbonate 2. Pulmonary

a. Aspiration of enteral feeding formula can result in signifi cant morbidity such as pneumonia and prolonged mechanical ventilation.

b. Raising the head of the bed (around 30 degrees) is still the current practice for prevention of this problem.

3. GastrointestinalElevated gastric residualsa. Diarrheab.

Hypoalbuminemia—minor causeiii. Hyperosmolar formulas—minor causeiv. Pharmacotherapy—major cause (primarily sorbitol-containing elixirs)v.

4. Metabolica. Dehydrationb. Electrolyte disorders—virtually all of them can occur

I. Monitoring Guidelines for EN Support1. Use a small-bore feeding tube for nasoenteric feedings and verify placement with an

abdominal radiograph or physical examination.2. Initially order every 6-hour AccuChecks with sliding scale insulin.3. Chemstrip urine for glucose for AccuChecks more than 200 mg/dL4. Have the head of patient’s bed elevated 30 degrees at all times during feedings.5. Check gastric residuals every 6 hours; if more than 200 mL, replace feeding and hold for 4

hours and then recheck. If still more than 200 mL, hold feedings. If less than 200 mL, resume feedings (not necessary for jejunostomy feedings).

6. Order appropriate laboratory tests (check Chem-7, Chem-15, prealbumin at least weekly).

J. Developing an EN Regimen1. Determine energy and protein requirements.

a. Usually 25–30 kcal/kg/day and 1.0–1.5 g/kg/day of proteinb. Calculation: (70 kg)(25 kcal/kg/day) = 1750 kcal/day



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(70 kg)(1.2 g/kg/day) = 84 g/dayc. Decide which formula to use and identify its concentration (i.e., 1.06 kcal/mL vs.

1.5 kcal/mL vs. 2 kcal/mL)d. Divide total kcal per day by formula concentration: 1750 kcal/day ÷ 1.06 kcal/mL = 1650 mL/daye. Divide total milliliters by 24 hours to get the number of milliliters per hour: 1650 mL/day ÷ 24 hours/day ≅ 70 mL/hour

2. Checking your calculationsa. Multiply enteral formula rate × formula concentration × 24 hours to get total kcal/day:

(70 mL/hour)(1.06 kcal/mL)(24 hours/day) = 1781 kcal/day or 25 kcal/kg/day

b. Multiply enteral formula rate × grams of protein per liter or grams of protein/1000 kcal × 24 hours to get total grams per day:

(70 mL/hour) (44.4 g/L) (24 hours/day) = 74.6 g/day or 1.1 g, (1000 mL/L)

III. PN INITIATION AND MANAGEMENT

A. Indications1. PN is defi ned as the delivery of nutrients by vein in patients whose GI tract is nonfunctioning

or inaccessible. 2. Appropriate conditions for which PN may be indicated include:

a. Severely undernourished patients unable to take oral nutrition for more than 1 week or unable to be fed through the GI tract

b. Severe pancreatitis precluding use of the GI tractc. Severe infl ammatory bowel disease (Crohn’s disease and ulcerative colitis) exacerbated

by oral food/EN extensive bowel surgery (i.e., short bowel syndrome) causing malabsorption/maldigestion

d. Small or large bowel obstructione. Pregnancy (in cases of severe nausea and vomiting)f. Head-injury patients with no enteral access or GI dysfunction

B. Basic Components of PN Formulations1. Energy Substrates

a. Dextrose monohydrate is the major source of carbohydrate calories.i. Each gram of dextrose monohydrate provides 3.4 kcal.ii. Dextrose monohydrate is commercially available in concentrations ranging from 5%

to 70%.iii. Final concentrations of dextrose greater than 10% are usually delivered only through

central veins because of the risk of thrombophlebitis associated with peripheral vein delivery.

b. Glycerol, an alternative carbohydrate source, is a sugar alcohol that is contained in some premixed PN formulations.i. Glycerol provides 4.3 kcal/g.ii. In combination with amino acids, glycerol administration produces a protein-sparing

effect.c. Intravenous fat emulsions (IVFEs) provide essential fatty acids and may serve as an

additional source of calories.i. Components of IVFEs available in the United States include soybean oil or a mixture



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of soybean and saffl ower oils as the source of fatty acids; egg yolk phospholipids, which act as an emulsifi er; glycerin to adjust the osmolarity; and sodium hydroxide to maintain the fi nal pH (between 6 and 9).

ii. See “Special Considerations” for alternative IVFEs available outside the United States.

iii. IVFEs are commercially available in concentrations of 10% (1.1 kcal/mL), 20% (2 kcal/mL), and 30% (3 kcal/mL).

iv. The 30% product is approved only for use as a component of a TNA and not for administration as a separate infusion.

v. Whereas each gram of an IVFE provides 9 kcal, the glycerol component contributes additional calories such that an IVFE 10% is equivalent to 11 kcal and IVFEs 20% and 30% are equivalent to 10 kcal.

2. Amino acids are provided as a source for protein synthesis, which is required for body functions such as tissue growth, tissue repair, and immune function. a. Each gram of crystalline amino acids yields 4 kcal on oxidation.b. Amino acids preparations may be categorized as standard or specialized.

i. Standard or balanced amino acid preparations contain a physiologic mixture of essential and nonessential amino acids.

ii. Specialized or modifi ed amino acid products are formulated to contain mixtures of amino acids to meet certain disease-state or age-specifi c requirements.

c. Amino acid preparations are commercially available in concentrations ranging from 3% to 20%, although 8.5% and 10% are the most common concentrations used in compounding PN formulations.

3. Electrolytes are added to PN formulations to maintain physiologic serum concentrations. Commercially available electrolyte salts added to PN include:a. Sodium—chloride and acetateb. Potassium—chloride and acetatec. Phosphorus—sodium and potassiumd. Calcium—gluconate (preferred salt) and gluceptatee. Magnesium—sulfate (preferred salt) and chloride

4. Parenteral multivitamins are added to the PN formulation based on the recommendations of the American Medical Association and the Food and Drug Administration (FDA).a. Commercially available multivitamin products consist of both water-soluble and fat-

soluble vitamins.b. Parenteral multivitamin products for use in adults include retinol (vitamin A),

ergocalciferol (vitamin D), DL-α-tocopheryl acetate (vitamin E), phylloquinone (vitamin K), ascorbic acid (vitamin C), thiamin (vitamin B1), ribofl avin, pyridoxine (vitamin B6), niacinamide, dexpanthenol, biotin, folic acid, and cyanocobalamin (vitamin B12).

5. Sterile water is often added to PN formulations to adjust the fi nal volume and meet a patient’s daily fl uid requirements.

6. Histamine H2-receptor antagonists are often included in PN formulations to prevent and treat upper GI, stress-related ulceration.

7. Regular insulin may be added to PN formulations to control blood glucose concentrations for patients who are at risk or exhibit signs of hyperglycemia.

C. PN Initiation1. Quick nutritional assessment to determine nutritional status and requirements

a. IBW:Female: 45.5 kg/5 ft + 2.3 (1 inch over 5 ft)i. Male: 50 kg/5 ft + 2.3 (1 inch over 5 ft)ii.



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b. Percent IBW = actual BW/IBW × 100obesity: more than 130% i. moderate malnutrition: 70%–79%ii. severe malnutrition: less than 70%iii.

c. Actual BW (ABW) is most commonly used for calculation of fl uid and nutritional requirements. When the actual weight of a patient exceeds a body mass index (BMI) more than 30 kg/m2, an adjusted BW can be calculated and used to determine nutritional requirements. The following equation may be used to calculate adjusted BW:i. Adjusted BW: (ABW – IBW)0.25 + IBWii. Alternatively, a high-protein, low-calorie prescription may be implemented for a

grade II obese patient using the IBW. In this case, a goal of 22 total kcal/kg of IBW/day and 2 g of protein/kg IBW/day is targeted to avoid overfeeding while maintaining lean tissue mass

d. Body mass index (BMI): weight (kg)/height (m2) may be used to assess patients for obesity.i. Normal: 20–24.9ii. Grade I obesity (overweight): 25–29.9iii. Grade II obesity (moderate): 30–40iv. Grade III obesity (severe or morbid): more than 40

2. Fluid Requirementsa. General:

i. For the average adult with normal renal function, daily fl uid requirements may range from 2500 to 3500 mL.

ii. For the average adult with renal insuffi ciency, daily fl uid requirements may be reduced to a range of 500–1500 mL (depending on the severity of the disease) to prevent fl uid overload.

b. Fluid reuirements may be calculated using either of the two methods below: i. 1500 mL/fi rst 20 kg and then 20 mL/for each kilogram of IBW above the fi rst 20 kg Ex. For a 70-kg adult = 1500 mL + (20 mL/kg × 50 kg) = 2500 mL ii. 30–35 mL/kg of ABW Ex. For a 70-kg adult = (30–35 mL/kg)(70 kg) = 2100–2450 mL

3. Protein (Amino Acid) Requirements—amino acid products are generally manufactured in 10%, 15%, or 20% concentrationsa. In an adult, protein requirements range from 0.8 to 2.0 g of protein (amino acids) per

kilogram of actual BW. Ex. For a 70-kg adult: (1.5 g/kg)(70 kg) = 70–105 g amino acidsb. The amount of amino acids given will depend on the stress level and/or the extent and

level of body injury, with 1.2 g of protein per kg given for mild stress and up to 2 g/kg for severe stress.

c. The following items are general guidelines for protein requirements based on stress or changes in organ function:Maintenance 1 g/kg/day actual BWStress or repletion 1.3–2 g/kg/day actual BWRenal failure/predialysis 0.8–1 g/kg/day dry BWRenal failure/hemodialysis 1.2–1.5 g/kg/day dry BWRenal failure/peritonealOR continuous veno-venous hemodialysis

1.5–2 g/kg/day dry BW

Hepatic failure 0.6–1.2 g/kg/day dry BWLiver transplant 1–1.5 g/kg/day dry BWBone marrow transplant 1.5–2 g/kg/day dry BW



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d. The choice of stock solution used (10% vs. 15% or 20%) will depend on the patient’s fl uid status. A 15% amino acid stock solution is the more concentrated amino acid product that is used in cases of fl uid restriction.

4. Dextrose—product used for compounding of PN is 70% dextrose in watera. Dextrose is the major source of nonprotein kilocalories, but intravenous fat is also used.b. General requirements

i. Because the maximum oxidation rate for glucose is 7 mg/kg/minute, most clinicians use a target range of 3–5 mg/kg/minute for glucose administration.(a) Ex. For a 70-kg adult: 3–5 mg/kg/minute × 70 kg × 1 g/1000 mg × 1440 minutes/

day =302–504 g of dextrose each 24 hours.(b) On the fi rst day of PN, start with 2 mg/kg/minute of dextrose; do not

add intravenous fat to the TNA formulation because lipid is unstable in a TNA formulation with low concentrations of dextrose (less than 10% fi nal concentration) and low amino acid concentrations (less than 4% fi nal concentration).

(c) For a TNA to be stable, the fi nal dextrose concentration must be more than 10%, the fi nal amino acid concentration more than 4%, and the fi nal fat concentration more than 2%.

c. Control of hyperglycemia: Only regular human insulin may be added to the PN.i. The initial dose of insulin to start with in a PN is generally 0.1 unit/g of dextrose. For

example, for a PN with 250 g of dextrose per day, 25 units of regular human insulin would be added to the bag.

ii. After the fi rst day, add the total amount of sliding scale insulin used during the previous 24 hours to the next bag.

iii. Caution must be used when adding insulin to the PN bag for patients with impaired renal function because insulin is renally eliminated and may be cleared more slowly in this patient population.

iv. If a patient is on an insulin drip, clinical judgment is used to determine when insulin is added to the PN. Often, it is safe to add insulin to the PN when the rate of the insulin drip is stable and the patient is becoming more clinically stable (e.g., off vasopressor agents, off steroids) To calculate the amount of insulin to add to the PN bag, add the total amount of insulin used in the previous 24 hours, take two-thirds of that amount and add it to the next PN bag.

For example: insulin drip rate = 2 units/hour 2 units/hour × 24 hours = 48 units 2/3 of 48 units = 32 units to add to the PN

5. Intravenous Fat Emulsiona. IVFE is given on a daily basis to nearly all patients.b. Intravenous fat should consist of 1%–4% of the total calories delivered to prevent

essential fatty acid defi ciency.c. The dextrose, amino acids, electrolytes, and fat emulsion are often incorporated into one

container. This is referred to as “All-in-One,” “3-in-1” solutions, or TNAs, and these preparations are infused through a central vein.

d. The package insert for IVFEs warns against the provision to patients with egg allergies because the emulsion is stabilized with egg phospholipids.

e. Intravenous preparations containing fat emulsion should be given with an in-line intravenous fi lter, and a fi lter size of 1.2 μm is recommended.

f. IVFEs may be given as a separate peripheral intravenous infusion. When administered as a separate infusion in addition to dextrose/amino acids, the duration of infusion



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should not exceed 12 hours in order to prevent the growth of microorganisms within the manufacturer’s original container.

g. The product should always be examined visually before administration, per the standards in the USP monograph for IVFE. It should not be used if there is any evidence of creaming, aggregation, coalescence, or any other form of phase separation.

h. Propofol, a sedative used in intensive care unit patients, is manufactured in a lipid vehicle, which provides 1.1 kcal/mL. Thus, the amount of lipid in the PN formula should be adjusted to account for the caloric contribution from propofol.

6. Electrolytes: when adding electrolytes to PN, it is best to add only one salt of each electrolyte to reduce the potential for errors (e.g., do NOT add K Phos AND Na Phos, do NOT add KCl AND KAc).a. Sodium—parenteral recommended daily intake (RDI) is determined by clinical need

i. Sodium is principally an extracellular cation with no established RDI. Its inclusion in the PN is based on clinical need.

ii. Usually, try to make about ½ normal saline; therefore, add 80 mEq/L.iii. Patients with end-stage liver disease, congestive heart failure, or iatrogenic fl uid

overload may require severe sodium restriction. iv. In general, if serum sodium is more than 150 mEq/L, no more than 40 mEq/day of

sodium should be in the PN.v. Review the patient’s medication list for sources of sodium, such as albumin,

medications in normal saline, and sodium-containing antibiotics such as Timentin. Other medications can cause dehydration that is manifested as hypernatremia, such as with lactulose.

vi. Certain disease states can cause fl uid overload which is manifested as hyponatremia, such as worsening edema with chronic heart failure, cirrhosis, or nephrotic syndrome. In this case, sodium content of the PN should still be restricted.

vii. Conversely, patients with large nasogastric fl uid losses, high ileostomy or pancreatic fi stula outputs, or large small bowel losses often require substantial quantities of sodium per day.

viii. Sodium content in PN should not exceed 154 mEq/L. (It should contain no more sodium than normal saline.)

b. Potassium—parenteral RDI is determined by clinical need.i. Potassium is principally an intracellular cation with no established RDI; thus, its

inclusion in PN is dictated by clinical need.ii. To estimate potassium requirements, see if the patient is already receiving potassium

in the intravenous fl uid, and add this amount to the PN; if there is no potassium in the intravenous fl uid and the patient has normal renal function, then around 40 mEq/L is usually suffi cient.

iii. Potassium requirements can be greatly infl uenced by acid-base status. (a) During metabolic acidosis (pH less than 7.2), an excess of hydrogen ions are

present in the circulation, and potassium exchanges its intracellular position for hydrogen ions in an attempt to abate the transfer, thus causing hyperkalemia.

(b) Conversely, hypokalemia results during metabolic alkalosis.iv. Renal insuffi ciency (creatinine clearance less than 30 mL/minute) is also associated

with impaired potassium clearance and hyperkalemia.v. Many medications are associated with alterations in serum potassium concentrations:

(a) Hyperkalemia: K-sparing drugs, including angiotensin-converting enzyme inhibitors, spironolactone, triamterene, amiloride, heparin, trimethoprim (i.e., Bactrim)

(b) Hypokalemia: K-wasting drugs, including amphotericin B, aminoglycosides,



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antipseudomonal penicillins (Ticarcillin), loop/thiazide diuretics, glucocorticoids, insulin, inhaled β-agonists (e.g., albuterol)

vi. In general, if serum potassium is more than 5.1 mEq/L, no more than 20 mEq/day of potassium should be in the PN.

c. Calcium—parenteral RDI is about 10 mEq or 200 mg/dayi. Up to 98% of total body calcium is in bone and can be readily mobilized in times of

need under the infl uence of parathyroid hormone.ii. Certain patients, such as those with severe short bowel syndrome or those requiring

massive blood transfusions, may require substantially greater quantities of calcium, and such increases in the PN admixture should be accomplished gradually.

iii. Dosage increases of 5 mEq daily for acute care are reasonable, and simultaneous monitoring of serum phosphorus is recommended during such times.

iv. Remember that calcium is highly protein bound (especially to albumin). The following formula may be used to adjust serum calcium concentrations for low albumin concentrations, although it is still inaccurate:

corrected calcium = [(4-albumin) × 0.8] + measured calcium The most sensitive measure of calcium is ionized calcium.v. Low amounts of calcium may be required for patients with hyperphosphatemia,

metastatic cancer, or hyperparathyroidism.vi. Usually, 10 mEq/day is a suffi cient amount to add to the PN.

d. Magnesium—parenteral RDI is around 10 mEq or 120 mg/dayi. Magnesium is closely linked to calcium metabolism where it is necessary for

parathyroid hormone secretion.ii. Patients with short bowel syndrome, alcoholics, etc., often require larger doses to

achieve magnesium homeostasis and can be advanced incrementally by 50% of the parenteral RDI as with calcium.

iii. Medications associated with magnesium wasting include amphotericin B, aminoglycosides, cyclosporin A, cisplatin, loop and thiazide diuretics, and piperacillin.

iv. The amount of magnesium plus calcium should NOT exceed 20 mEq/L for a 3-in-1 formulation; otherwise, the emulsion may become unstable.

v. In general, 12 mEq/L is appropriate to add to the PN; if the patient has renal dysfunction, then add 4 mEq/L.

e. Phosphorus—parenteral RDI is about 30 mmol or 1000 mg/dayi. The role of phosphorus in physiologic processes is diverse, and it infl uences

respiration, myocardial function, platelets, and red and white blood cell function.ii. If omitted from PN formulations in the presence of normal renal function, it can

induce a potentially life-threatening hypophosphatemia within a week of PN therapy.iii. Disease states associated with low serum phosphorus concentrations include alcohol

abuse, thermal injury, trauma, and refeeding syndrome.iv. Medications associated with hypophosphatemia include antacids, sucralfate,

diuretics, theophylline, and insulin.v. Medications associated with increased serum phosphorus concentrations include

intravenous lipid emulsions and Fleet’s enemas in the presence of renal dysfunction.vi. In general, 30 mmol/day should be added to the PN; if the patient has renal

dysfunction, then add 3–5 mmol/L.f. Chloride and acetate

i. The use of chloride and acetate salts in the PN admixture should be based on the acid-base status of the patient.

ii. For example, in cases of metabolic alkalosis, only chloride salts of either sodium or



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potassium should be used.iii. Conversely, in cases of acidemia, the emphasis should be placed on acetate salts of

either sodium or potassium.iv. Under no circumstances should salts such as calcium chloride or sodium bicarbonate

be used in a PN formula, because these can result in the formation of insoluble precipitates, which could fatal.

7. Trace elements—most institutions use combination products containing four or fi ve individual trace elementsa. Trace elements are added to the PN solution once each day.b. Standard trace element solutions: fi ve trace elements, such as Se, Cr, Cu, Mn, and Zn. Commercially available combination products typically provide 12 mcg of chromium, 1.2

mg of copper, 0.3 mg of manganese, 60 mcg of selenium, and 3 mg of zinc per 3 mL.c. Patients who have sustained small bowel or large bowel fl uid losses should receive

supplemental zinc (5–10 mg/day) added separately in addition to the amount in the trace element cocktail (3–5 mg/day).

d. Patients who have hepatic cholestasis should have copper and manganese withheld from the PN solution because these trace elements are excreted in the bile. Neurologic damage from deposition of manganese in the basal ganglia has been reported in PN patients with chronic liver disease or cholestasis.

e. Under certain conditions, such as for long-term home PN, additional selenium may be necessary.

8. Vitamins—MVI—Adult (Hospira, Chicago, IL) and Infuvite Adult (Baxter Healthcare, Deerfi eld, IL) are the only two products available in the United Statesa. See Table 1 for the individual vitamin content of multivitamin for infusion. The

multivitamin solutions are mixed together just before use and added to the PN. The limited stability of the combined multiple vitamins should be considered when assigning an expiration date to a PN solution that contains multiple vitamins.

b. Every PN should contain multivitamins daily.c. Although prescribers may ask to add intravenous iron to a TNA formulation, iron is

generally not stable.

D. Infusion of the formulation1. Line access

a. PN should be given through a central line, unless the solutions are specifi cally formulated to be given peripherally (peripheral PN, or PPN).

b. Central lines include PICC, Hickman, and Port-a-Cath or any lines inserted in which the tip of the catheter is positioned in the superior vena cava.

c. If a peripheral vein is used for the administration of PN, the solution given must be less hypertonic. PPN solutions have osmolarities of around 700–900 mOsm/L.

d. To avoid exceeding normal daily fl uid requirements, the nutrients are usually administered as highly concentrated hypertonic solutions. To get some perspective, approximate osmolarities of plasma (in milliosmoles per liter) and typical large volume parenterals are as follows:Plasma 3000.9% NaCl 300D5W 250PN (central) 1800

e. Vein damage that would be caused by giving these highly hypertonic solutions (more than 900 mOsm/L) is minimized by administering the PN solution through a large-diameter central vein where blood fl ow is rapid. This enables the PN solution to be diluted rapidly as it fl ows into the body.



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f. If a peripheral vein is used for the administration of PN, the solution given must be less hypertonic. PPN solutions have osmolarities of about 700–900 mOsm/L.

g. Calculating the osmolarity of a PPN formulai. (grams of dextrose per liter of PN) × 5 = milliosmole per literii. (grams of protein per liter of PN) × 10 = milliosmole per literiii. Convert total milliosmoles supplied by electrolytes in PN to milliosmoles per liter

(see table below).iv. Total milliosmoles per liter of PPN should be less than 900 (see below).

Electrolyte mEq/mL mOsm/mLNaCl 2.5 5Sodium acetate 4 8KCl 2 4K acetate 2 4Na Phos – 7Na 4 –Phos 3 mmol –K Phos – 7.4K 4 –Phos 3 mmol –Ca 0.465 0.68Mg 4 4.06

h. In essence, the electrolyte and intravenous fat contents are similar to central PN, but the amino acid content is cut by about half, and the dextrose is greatly reduced. i. Uses of PPN - PPN may be used to support patients who are only able to ingest a

portion of their caloric and protein requirements orally or enterally and when central vein PN is not feasible.

ii. PPN is traditionally a short-term therapy (less than 10 days) because it does not provide total caloric/protein requirements and is not tolerated well by peripheral veins for extended periods.

iii. Limitations of PPN include lower concentrations (osmolarity) of nutrients to avoid thrombophlebitis and fl uid overload. Thus, PPN is not recommended for patients with severe undernutrition, increased electrolyte needs (especially potassium), fl uid restriction, or need for prolonged intravenous nutrition support.

i. Heparin (3000 units/day) and hydrocortisone (5 mg/L) are often added to PPN formulations to decrease the risk of thrombophlebitis.

2. Cycling the PN:a. Sometimes, cycling the PN overnight for 12 hours is desired to allow the patient freedom

for physical activity during the day or avoid hepatic fat accumulation.b. The PN infusion should be gradually decreased for 3–4 days to prevent hyperglycemia

while tapering the infusion rate up and rebound hypoglycemia when tapering the infusion rate downward. For example, the PN infusion should be decreased from 24 hours to 18 hours to 14 hours to 12 hours.

c. The following formula should be used to calculate the cyclic rates for PN:i. Divide the total volume of the PN by the [desired cycle infusion time minus 1 hour]

to identify the maximum infusion rate during the cycle.ii. Multiply the maximum infusion rate by the [desired cycle infusion time minus 2

hours].iii. Subtract the total volume from [maximum infusion rate – 2 hours] to obtain the

volume left for tapering up and down the PN.iv. Divide the volume left by 2 and this will be the rate for the fi rst and last hour of the

PN cycle.



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v. For example, suppose a 2-L PN is to be infused for 18 hours:2000 mL ÷ (18 hours – 1) = 117 mL/hour (round up to 120 mL/hour)(a) 120 mL/hour × (18 hours – 2) = 1920 mL(b) 2000 mL – 1920 mL = 80 mL (volume left for tapering up/down)(c) 80 mL ÷ 2 = 40 mL/hour(d)

vi. Thus, the cycle regimen would be 40 mL/hour × 1 hour, followed by an increase to 120 mL/hour × 16 hours and then a decrease to 40 mL/hour × 1 hour.

vii. Fingerstick glucose tests should be checked 3 hours after the PN is started (to monitor for hyperglycemia) and 30 minutes after the PN is stopped (to monitor for rebound hypoglycemia).

3. Discontinuation of the PN Formulationa. Abruptly stopping the PN formulation may result in rebound hypoglycemia.b. If a patient is not receiving continuous enteral feedings, the PN rate should be reduced by

50% every 2 hours until the rate is less than 25 mL/hour.c. Once the PN rate is less than 25 mL/hour, the PN may be stopped.d. It is usually recommended to check a fi ngerstick glucose test 30 minutes after the PN is

stopped to make sure the patient is not hypoglycemic.

E. Special Considerations with PN Formulations 1. Special Amino Acid Solutions

a. Formulas and descriptions of various specialty amino acid solutions can be found in Drug Facts and Comparisons. There are special formulations for patients under stress, those with hepatic failure, and those with renal disease.

b. The use of these specialty products is somewhat controversial. They are usually more expensive than standard formulas, and some practitioners think they offer little signifi cant advantage. Additional information on this subject can be found in the journal article, “Value of specialty intravenous amino acid solutions,” beginning on page 671 of the March 15, 1996, issue of American Journal of Health-System Pharmacy.

c. Amino Acid Solutions for Patients with Hepatic Failurei. These solutions contain higher concentrations of branched-chain amino acids, such

as isoleucine, leucine, and valine, and lower concentrations of aromatic amino acids (tryptophan and phenylalanine) and of methionine. An example product is HepatAmine 7.

ii. This formula modifi cation resulted from an analysis of the plasma content of patients with encephalopathy, a clinical complication found in patients with liver failure. It was noted that in the plasma of these patients, there was an elevation of the ratio of aromatic amino acids to branched-chain amino acids. It was thought that the increased concentrations of aromatic amino acids were contributing to the development of encephalopathy.

iii. Current recommendations support the use of branched-chain amino acid formulations only in chronic encephalopathy that is unresponsive to standard amino acid products and pharmacotherapy (i.e., lactulose).

3. PN Stability and Compatibilitya. A distinction should be made between the terms stability and compatibility in reference to

PN formulations.b. Stability of PN formulations denotes the degradation of components, which causes

alterations from their original characteristics.i. The Maillard reaction, which occurs between amino acids such as lysine and

intravenous dextrose causing a brownish discoloration, is an example of an instability issue with PN formulations.



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ii. Stability issues may also pertain to changes in chemical integrity or pharmacological action, such as the photodegradation associated with some vitamins due to light exposure.

c. Compatibility issues, on the other hand, refer to precipitate formation, either solid or liquid.i. Liquid precipitates in PN formulations occur when there is phase separation of the

IVFEs into oil and water.ii. An example of a solid precipitation problem with PN formulations is the formation of

calcium phosphate precipitates.4. Factors Affecting the Precipitation of Calcium Phosphate in PN Solutions Calcium and phosphate, two nutritional requirements for PN solutions, are conditionally

compatible. Precipitation depends on several factors, as described below. The chemical equation given here should aid in understanding these factors.

HPO4-2 + Ca+2 ↔ H2PO4

-1 + Ca+2

CaHPO4 Ca(H2PO4)2very insoluble relatively soluble

a. The pH of the solution The pH dependence of the phosphate-calcium precipitation is illustrated in the equation

above. Dibasic calcium phosphate (CaHPO4) is very insoluble, whereas monobasic calcium phosphate (Ca(H2PO4)2) is relatively soluble. At low pH, the soluble monobasic form (H2PO4) is predominant, but as the pH increases, more dibasic phosphate (HPO4

2) becomes available to bind with calcium and precipitate. Therefore, the lower the pH of the parenteral solution, the higher the amount of calcium and phosphate that can be solubilized.

b. The concentration of the calcium Because it is the free calcium that can form insoluble precipitates, enhanced precipitate

formation is expected as the concentration of calcium is increased.c. The salt form of the calcium Although calcium gluconate is much more soluble than calcium chloride, calcium

chloride has a much higher percent dissociation. The higher the dissociation, the more free calcium available. The concentration of calcium available for precipitation when added as the gluconate salt is less than that available when an equimolar amount of calcium is added as the chloride salt. Calcium gluceptate has no real advantage over the gluconate salt form.

d. The concentration of the phosphate As in the previous equations, it is the dibasic calcium phosphate salt that is insoluble.

The concentration of dibasic phosphate in solution depends on both the total phosphate concentration and the pH of the solution. Potassium phosphate Injection has a high pH (6.2–6.8) relative to that of dextrose or amino acid solutions. Addition of potassium phosphate injection to a PN solution not only increases the concentration of the phosphate but also may increase the pH of the solution, which favors precipitation.

e. The concentration of amino acids Amino acids form soluble complexes with calcium and phosphate, reducing the amount

of the free calcium and phosphate available for precipitation. Amino acids also appear to provide an intrinsic buffering system to a PN solution. Amino acid formulations have pH values in the range of 4.5–6.5. Those containing higher concentrations of amino acids show less of an increase in pH when phosphate is added and, consequently, an increased



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tolerance for calcium addition.f. The composition of amino acid solutions Amino acid solutions formulated with electrolytes contain calcium and phosphate, and

these must be considered in any projection of compatibility. Some amino acids contain cysteine hydrochloride, which may affect the solubility of calcium and phosphate. Cysteine hydrochloride lowers the pH of the solution, enabling the more soluble monobasic form of phosphate to exist. Therefore, adding cysteine hydrochloride can increase the solubility of calcium and phosphate in a PN solution.

g. The concentration of dextrose in the solution Dextrose forms a soluble complex with calcium and phosphate. In addition, it can act as

a weak buffer. The pH of dextrose solutions is relatively low (4–5) because of the free sugar acids (e.g., gluconic acid) present and formed from the oxidation of the aldehyde moiety on dextrose during sterilization and storage of dextrose solutions. Studies have shown that higher concentrations of dextrose reduce the free calcium and phosphate that can form insoluble precipitates.

h. The temperature of the solution Temperature of solution also plays a key role. As temperature is increased, the calcium

salts (chloride or gluconate) are dissociated more completely, and more calcium ions become available for precipitation. Therefore, an increase in temperature increases the amount or possibility of precipitation. Care must be exercised when transferring these solutions to warmer environments.

i. The presence of other additives The addition of other drugs to a PN solution may alter the pH of the solution. Additives

may also introduce the possibility of precipitation of other products or incompatibilities with other ions.

j. The order of mixing The FDA recommends that phosphate be the fi rst additive added to an admixture and that

calcium be the last additive.4. Monitoring

a. For an excellent review article on PN monitoring, see “Parenteral Nutrition Monitoring in Hospitalized Patients” (2).

b. Monitoring parameters i. Temperature—daily to detect infection or sepsisii. Weight—daily to monitor fl uid imbalance and maintenance and improvement of

clinical condition. In general, patients should gain only 1–2 pounds per week. Larger weight gains are usually retained fl uid or fat from too many calories; a sudden weight gain usually refl ects fl uid retention.

iii. Nitrogen balance (NB)—this monitors nitrogen use to determine if the patient’s metabolic status is anabolic (buildup) or catabolic (breakdown). It is defi ned as the difference between the nitrogen intake and nitrogen excretion.

NB = NI NO

NI is the nitrogen put into the body by PN and other nutritional sources. NO is the nitrogen excreted by all routes.

˜



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You may see two different, but equivalent, forms of this basic equation in the literature:

NB = NI(g/24h) ˜(UUN(g/24h) + 4 g)orNB = (protein(g/24h) ÷ 6.25)(UUN(g/24h) + 4 g)

NI is obtained by calculating the number of grams of protein infused in the form of amino acids and multiplying that by 16% (the approximate amount of nitrogen in amino acids). Note that you get the same number by dividing the number of grams of protein or amino acids given by 6.25. This value also can be determined from the specifi cations for the particular amino acid solutions being used. This information can be found in the product package insert or from Drug Facts and Comparisons.

UUN is urine urea nitrogen. Urea is the breakdown product of protein. 4 g is the estimated loss by other routes such as through the skin or in the feces.

E X A M P L E:

(a) J.S. is a patient receiving a PN solution that contains 100 g of amino acids (AA). The 24-hour urine urea nitrogen reported by the laboratory is 9.5 g/24 hours. What is his NI(g/24h)?

(100 g AA ÷ 6.25) = 16 g N/24 hours

(b) Calculate the Nitrogen balance (NB) for this patient:

NB = 16˜ (9.5 + 4) = 2.5 g

What is an acceptable value for NB? Although this depends on the clinical situation, a positive 4–6 g/day in unstressed patients is considered acceptable. If the NB is too low or is negative, the PN formula can be changed to increase the amino acid content.

iv. Plasma proteins—concentrations of serum plasma proteins can be used as a measure of nutritional status because an increase in these proteins refl ects an anabolic response.

(a) Serum albumin is the most commonly determined plasma protein, but its usefulness in monitoring nutritional status is limited because of its long half-life, because the body pool of albumin is large and because its concentration in the serum is affected by so many other factors (2).

(b) Two other plasma proteins, transferrin and prealbumin, have been found to be useful indicators (2).

(c) Assessment of C-reactive protein will help quantify if the fall in short-term serum proteins (i.e., prealbumin) are associated with an acute-phase response or nutritional defi ciency. C-reactive protein is recognized as a positive acute-phase protein, defi ned as one whose plasma concentration increases by at least 25% during infl ammatory disorders.

(d) If C-reactive protein is elevated and prealbumin has fallen, this is more indicative



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of the systemic response to infl ammation. However, a falling prealbumin with a concurrent low C-reactive protein concentration may represent an inadequate intake of energy or protein.

(e) Use of these basic principles can assist the clinician in determining the appropriate time to alter a patient’s nutritional regimen.

v. Laboratory Tests(a) Refer to the appendix for a typical frequency of laboratory test determinations.

The tests done, the frequency, and the normal values vary with the hospital and the clinical condition of the patient. Note that there are hematologic tests, electrolyte and glucose concentrations, fat-cholesterol monitoring tests, and liver and renal function tests. For more detailed information on laboratory tests, see the article on monitoring PN therapy (2).

(b) It is important to realize that acceptable concentrations for some laboratory tests may be different for patients on PN than for normal healthy individuals.

(c) Monitoring of laboratory values with adjustments of PN formulas and therapy is becoming a focal point of pharmacist input and participation on the health care team.

vi. Clinical Status—how is the patient doing. This is a very important monitoring parameter. A desired clinical outcome of therapy should be determined, and all efforts in PN therapy should be geared toward this end.

Example:

PN Order:

G.D. is a 52-year-old, 176-lb man who is 6′1″ tall. He is admitted to the trauma unit after an automobile accident. He is not expected to eat or take tube feedings for more than 7 days because of multiple injuries to his small bowel. His physician, Dr. Solier, has written the following PN order:

The prescribed PN contains:Amino acids 120 gDextrose 346 gFat 55 gSodium chloride 150 mEq/dayPotassium acetate 80 mEq/daySodium phosphate 30 mmol/dayMagnesium sulfate 24 mEq/dayCalcium gluconate 10 mEq/dayRanitidine 150 mg/dayMultivitamins 10 mL/dayMultiple trace elements 10 mL/day

The fl ow rate for this PN is 100 mL/hour.

1. Calculate G.D.’s IBW. Then, using a PN fl ow rate of 100 mL/hour, determine if all the nutrients, electrolytes, and fl uid volumes are within the normal range for G.D. You may ignore the electrolyte contributions in the intravenous fat. Sample calculations are given below.

2. Calculate the number of milliliters of each component for this PN solution. The crystalline amino acid solution is Travasol 10%; the dextrose solution is dextrose 70% in water. Sample calculations are given below.



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Sample Calculations for 24-hour Requirements:

For G.D.:

A. BW 1. Weight in pounds (given): 176 lb 2. Actual weight in kilograms:176 lb ÷ 2.2 lb/kg = 80 kg 3. IBW in kilograms: IBW = 50 kg + 2.3 (13″) = 79.9 kg G.D.’s current weight is appropriate for his height.

B. Fluid1. Volume ordered per day: (100 mL/hour)(24 hours/day) = 2400 mL2. Fluid requirements: 30–35 mL/kg/day (30–35 mL/kg/day)(80 kg) = 2400–2800 mL/day

C. Protein (Amino Acids)1. Grams of protein ordered per day: 120 g AA ÷ 80 kg actual BW = 1.5 g AA/kg actual BW2. Kilocalories per day from protein: (120 g AA)(4 kcal/1 g AA) = 480 kcal/day3. General requirement: 1–1.5 g AA/kg of actual BW

D. Nonprotein Kilocalories (dextrose and fat)1. Kilocalories per day from ordered dextrose: (346 g dextrose) (3.4 kcal/1 g dextrose) = 1176 kcal/day2. Milligrams per kilogram per minute from ordered dextrose: (346 g dextrose/80 kg)(1000 mg/1 g dextrose)(1 day/1440 minutes) = 3 mg/kg/minute3. General dextrose requirements: 3–5 mg/kg/minute4. Kilocalories per day from ordered fat (do not add fat until second day): (55 g fat)(9 kcal/1 g fat) = 495 kcal/day5. Total ordered kcal per day = 480 + 1176 + 495 = 2151 kcal/day6. Total ordered kilocalories per kilogram of actual BW per day: (2151 kcal/80 kg actual BW)= 26.9 kcal/kg/day actual BW7. General requirements for total kilocalories per day: 25–35 kcal/kg actual BW8. % total kilocalories as intravenous fat: (495 kcal/2151 kcal) = 23% total kcal as intravenous fat9. General requirements for intravenous fat: 30% or less of total kilocalories/day

E. Electrolytes1. Sodium—in general, most patients require 1–2 mEq/kg/day in the PN2. Potassium—in general, most patients require 1–2 mEq/kg/day in the PN3. Calcium—the parenteral RDI of about 10 mEq/day is suffi cient for most PN patients4. Magnesium—4–20 mEq/day are typically added to PN formulations5. Phosphorus—the parenteral RDI of about 30 mmol is suffi cient for most PN patients



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WATER HOMEOSTASISV.

Fluid distributionA. In humans, total body water accounts for about 55% of total BW.1. Body water is distributed throughout three compartments:2.

Intracellular fl uid has a volume that approximates 35% of total body water.a. ECF has a volume that accounts for 20% of total body water.b. i. Interstitial fl uid (16%)ii. Intravascular fl uid (7%)

B. Volume regulation and sodium metabolism1. Serum sodium concentration refl ects the osmolality of all body fl uids.2. *Serum osmolality = (2 × Na+) + (glucose) + (blood urea nitrogen) 18 2.8

*The number of osmoles acting to hold fl uid within the ECF; therefore, serum osmolality becomes important in the distribution of total body water between intravascular, interstitial, and intracellular fl uid compartments

3. The two most important hormones that infl uence water and sodium physiology in the body:a. Antidiuretic hormone (ADH)b. Aldosterone

4. ADHa. Synthesized in the hypothalamus and released from the posterior aspect of the pituitary

glandb. An increase in osmolality stimulates the secretion of ADH.c. A decrease in blood volume stimulates ADH secretion.

Aldosterone5. Mineralocorticoid synthesized in the adrenal glanda. Causes Nab. + to be reabsorbed and K+ and H+ to be secretedThe major stimulus for release of aldosterone is angiotensin II, a substance activated by c. renin, which is released in response to a depletion of ECF volume.

VI. WATER AND NA+ DISORDERS

Hyponatremia (less than 135 mEq/L)A. Etiologies1. a. ↓Total Body Na+ more than ↓ Total Body Water

i. Extrarenalii. Renal

b. Normal Total Body Na+ and ↑ Total Body Wateri. Glucocorticoid insuffi ciencyii. Hypothyroidismiii. Psychogenic polydipsiaiv. SIADH

c. ↑ Total Body Na+ less than ↑ Total Body Wateri. Chronic heart failureii. Cirrhosisiii. Nephrotic syndrome



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2. Table 2. Signs and Symptoms of Hyponatremia↓ Total Body Na+ > ↓ Total Body Water

↔ Total Body Na+

↑ Total Body Water↑ Total Body Na+ < ↑ Total Body Water

Symptoms

Signs

DizzyLightheaded

Poor skin turgor↓ Blood pressureTachycardiaFlat neck veins

Normal blood pressure

Shortness of breathSwollen ankles

Weight gainDistended neck veinsPeripheral edemaAscites

Laboratory values Urine Na+ ↑ Urine Na+ ↓ Urine Na+

3. Table 3. Treatment of HyponatremiaTotal Body Na+ > ↓ Total Body Water

↔ Total Body Na+

↑ Total Body Water↑ Total Body Na+ < ↑ Total Body Water

Intravenous normal salinea Free water restriction FurosemideDiscontinue diuretics Normal saline Free water restrictionTreat diarrhea/vomiting Furosemide Give intravenous

medications in normal saline

aHypertonic saline.

4. *Guidelines for Use of Hypertonic Salinea. Rapid infusion: 3% saline at 1–2 mL/kg/hour × 2–3 hours

i. Indications:(a) Seizures and coma(b) Symptoms of acute water intoxication

b. Slow infusion: 3% saline at 15 mL/houri. Indications:

c. Slow response to water restrictioni. Inability to take oral saltii. Cautions

(a) Avoid correction by more than 12 mEq/L/day(b) Use with furosemide in patients at risk for chronic heart failure.

A. Hypernatremia (more than 145 mEq/L)1. Etiologies

a. ↓ Total Body Na+ less than ↓ Total Body Wateri. Replacement with hypertonic fl uidsii. Drugs

b. ↔ Total Body Na+ and ↓ Total Body Wateri. Nonrenal lossesii. Diabetes insipidusiii. Drugs

c. ↑ Total Body Na+ more than ↑ Total Body Wateri. Iatrogenic administration of Na+

ii. Drugs



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d. Table 4. Laboratory Values↓ Total Body Na+ < ↓ Total Body Water

↔ Total Body Na+

↓ Total Body Water↑ Total Body Na+ > ↑ Total Body Water

Urine Na+ > 20 mEq/L UOP > 3 L Urine Na+ > 20 mEq/LUrine osmolality < 300 mOsm

UOP = urinary output.e. Physical symptoms

i. Thirstii. Restlessnessiii. Irritabilityiv. Hyperactive refl exesv. Muscle rigidityvi. Seizures

2. Table 5. Treatment of Hypernatremia↓ Total Body Na+ < ↓ Total Body Water

↔ Total Body Na+

↓ Total Body Water↑ Total Body Na+ > ↑ Total Body Water

IV NS IV D5W or ½ NS IV D5WIV D5W or ½ NS Vasopressin DiureticsD5W = 5% dextrose in distilled water; IV = intravenous; NS = normal saline.

VI. POTASSIUM HOMEOSTASIS

A. Total body stores about 50–55 mmol/kg in an adult; more than 95% intracellular; serum K 3.5–4.8 mmol/L; unit conversions: 1 mmol of K = 39.1 mg; 1 g of K= 25.6 mmol

B. Median daily turnover in the United States: 85 mmol for men and 55 mmol for women; Institute of Medicine recommendation is 120 mmol/day for adults with good renal function and no interfering medications; 90% of excretion is renal, and the remainder is secreted into the gut

C. Balance between intracellular and ECF affected by: 1. Insulin: increases glucose and potassium uptake by liver and skeletal muscle 2. Catecholamines (β2-receptors increase vs. α-receptors decrease uptake into cells); β2 effect

dominates when both receptors are stimulated, e.g., with endogenous epinephrine3. pH—decreased pH shifts K+ out of cells, increased pH shifts K+ into cells; however, this

effect is highly variable clinically

D. Adaptations to high K intake: renal tubular secretion (aldosterone-modulated and direct tubular effect of K+) and secretion into gut; adaptations in renal failure prevent problems of K retention until glomerular fi ltration rate is less than 10 mL/minute

E. Causes of hyperkalemia1. Decreased urinary excretion: renal failure, decreased renal blood fl ow, hypoaldosteronism,

renal tubular defects2. Shift from intracellular to extracellular compartment: acidosis, insulin defi ciency, cell lysis/

catabolism, severe exercise, hyperkalemic periodic paralysis; pseudohyperkalemia—red blood cell lysis in blood sample

3. Increased K intake combined with compromised ability to excrete—diet, salt substitutes, oral supplements, iatrogenic intravenous potassium supplementation, potassium-rich herbal supplements



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4. Drugs that may contribute to or cause hyperkalemia:a. Intracellular to extracellular shift: succinylcholine, digitalis poisoning, β-blockers,

α-agonistsb. Potassium salts: dietary salt substitutes, penicillin G or V (less than 2 mmol of K per

million units), phosphate supplement (i.e., K Phos)c. Decreased excretion: K-sparing diuretics, angiotensin-converting enzyme inhibitors,

trimethoprim, heparin, cyclosporine, nonsteroidal anti-infl ammatory drugs5. Increasing frequency of drug-induced hyperkalemias in elderly people with congestive heart

failure, due to reduced renal function and treatment with angiotensin-converting enzyme inhibitors plus spironolactone.

F. Manifestations of hyperkalemia1. Skeletal muscle weakness—unusual at serum K less than 8 mmol/L2. Cardiac conduction disturbances: increased T waves (K more than 6), widening QRS (K more

than 7–8), decreased P wave (K more than 8), progressing to sin wave pattern, V fi brillation, and asystole

G. Treatment of hyperkalemia1. Determine urgency: immediate aggressive Rx indicated for serum K more than 8, severe

muscle weakness, or marked electrocardiographic (ECG) changes; for asymptomatic K 6.5–8.0, can start Rx with K removal (e.g., Kayexalate or dialysis); conservative management for mild asymptomatic hyperkalemia.

2. Urgent Rxa. Intravenous calcium ion to antagonize electrophysiologic effects of hyperkalemia; e.g.,

calcium gluconate 1–2 g (4.8–9.6 mEq) for 3–5 minutes; onset immediate, duration less than 30 minutes. Note that calcium is a physiologic antagonist and does not affect K+ concentrations in body fl uids.

b. Intracellular shift of K into cells:i. Insulin and dextrose; e.g., 5–10 units of regular insulin plus 25 g of 50% dextrose

intravenous bolus, followed by 10% dextrose at 50 mL/hour; onset less than 15 minutes, duration hours.

ii. β2-agonist; for example, nebulized albuterol 20 mg, inhaled for 10 minutes after insulin and dextrose administration; note inhaled albuterol dose is several-fold higher than that used for asthma to achieve systemic effect; subcutaneous epinephrine also works, but avoid in patient on β-blockers—may get increase in serum K due to dominant α effect; onset less than 30 minutes, duration several hours

iii. Sodium bicarbonate 45 mmol intravenously for several minutes; effi cacy variable, unlikely to work unless patient is acidotic; onset 30 minutes to 4 hours

3. Removal of potassium from the body: note that serum [K] will decrease with relatively small amounts of K removed when in hyperkalemic range

4. Sodium polystyrene sulfonate (Kayexalate)—cation exchange resin that exchanges Na for K in the gut (nonabsorbable); administer orally (more effective) or by retention enema (more rapid onset), 15–30 g; onset 1–2 hours; each gram of resin exchanges 0.5–1 mmol of K; resin usually suspended in 33%–70% sorbitol solution to prevent constipation/impaction problems

5. Dialysis: hemodialysis (most rapid removal) or peritoneal dialysis

H. Causes of hypokalemia1. Inadequate intake—poor dietary intake; inadequate intravenous supplements in NPO (nothing

by mouth) patients; clay ingestion (geophagia or pica)2. Extracellular/Intracellular shift—increased pH; insulin; β-adrenergic (exogenous agonists;



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endogenous sympathoadrenal discharge—thyrotoxicosis, delirium tremens, coronary ischemia); familial periodic paralysis; hypothermia; drug toxicity—xanthines, verapamil, chloroquine; pseudohypokalemia (intracellular shift after blood sample drawn)

3. GI or sweat losses—laxative or enema abuse may be cause of occult K+ losses 4. Urinary losses—diuretic Rx; mineralocorticoid excess (renin/angiotensin/aldosterone system,

adrenal tumor or hyperplasia, steroids, licorice); salt-wasting nephropathies; large dose penicillin; amphotericin B; hypomagnesemia; renal tubular acidosis; osmotic diuresis

I. Clinical manifestations of hypokalemia1. Muscle weakness/paralysis-associated with serum K+ less than 2.5, together with other factors

(Ca++, pH, type, and rapidity of change); due to alterations in cell membrane potentials; lower extremities most sensitive; may also cause muscle cramps, tetany, paresthesias, tenderness; impaired muscle blood fl ow—ischemia, rhabdomyolysis/myoglobinuria; smooth muscle involvement—constipation or ileus

2. Cardiovascular effects—ECG changes (see above)—T-wave fl attening, appearance of U wave; digitalis toxicity; arrhythmias (unusual in healthy hearts); chronic low-grade K+ depletion may contribute to hypertension

3. Renal effects—impaired concentrating ability; increased renal NH3 production and bicarbonate reabsorption resulting in metabolic alkalosis

4. Glucose intolerance—impaired insulin secretion

J. Treatment of hypokalemia—note that large amounts of K may be necessary to raise serum [K] from the hypokalemic range1. Urgency 3.0 less than K+ less than 3.5: usually asymptomatic; if patient on digitalis, should give oral

supplement to correct; otherwise, dietary sources of K+ usually adequate to correct 2.5 less than K+ less than 3.0: treat with oral supplements 2.0 less than K+ less than 2.5: some clinical manifestations likely; treat promptly with oral

supplements; use intravenous supplement if oral route is questionable K+ less than 2.0: severe hypokalemia with probable total body defi cit more than 600 mmol of

K+; intravenous supplement should start immediately2. Choice of potassium salts and preparations

a. Dietary sources—Much of dietary K is present as phosphate rather than chloride salt and may not restore K defi ciency effectively if patient is also chloride defi cient

b. KCl is preferred salt in most cases of hypokalemia due to concomitant chloride losses; options for oral Rx include solutions (bad taste/poor compliance), KCl wax matrix tablets (8, 10 mEq), KCl microencapsulated capsule (8, 10 mEq), KCl sustained-release microcrystalloids (10, 20 mEq)

c. Other salts—K Phosphate (preferred if patient also needs P replacement); bicarbonate or “bicarbonate precursors” (citrate, acetate, lactate, gluconate)—preferred if patient also has bicarbonate losses (e.g., lower GI tract losses, renal tubular acidosis).

d. Cautions: potassium supplements may cause a precipitous rise in K+ in patients having compromised ability to excrete a potassium load—renal dysfunction, potassium-sparing diuretics; angiotensin-converting enzyme inhibitors, angiotensin II antagonists, heparin, and trimethoprim may have some effect, also. Patients on β-blockers have a slower penetration of K into their intracellular compartment.

e. Parenteral potassium: general guidelinesi. Concentration in intravenous fl uid should not exceed 40 mEq/L for peripheral vein,

120 mEq/L for central vein; a pump or controller should be used if concentration more than 80 mEq/L.



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ii Infusion rate should not exceed 40 mEq/hour (0.5 mEq/kg/hour for pediatrics); when infusing 20 mEq/hour or more (0.2 mEq/kg/hour or more in pediatrics), should monitor for ECG changes during infusion. Some experts reco mmend a maximum infusion rate of 20 mEq/hour.

VII. DISORDERS OF MAGNESIUM HOMEOSTASIS

A. Biological functions and physiologic processesCofactor in oxidative-phosphorylation reactions in mitochondria1. Catalyzes enzymatic processes and activates phosphatases concerning transfer, storage, and 2. use of adenosine triphosphate (ATP)Involved in second messenger generation of adenyl cyclase3. DNA/protein/fat synthesis, glucose use4. Maintenance of sodium-potassium ATPase pump and cell membrane electrolyte composition/5. action potentialStructural component of bone6. Parathyroid hormone secretion/synthesis (?)7. Neuromuscular transmission8. Cardiovascular excitability9. Vasomotor tone10. Muscle contraction11. Pharmacokinetics (absorption, distribution, elimination)12. a. Total body distribution

i. Second most common intracellular cationii. 1 mEq = 12 mg = 0.5 mmoliii. Stores: 25 mEq/kg (1750–2000 mEq) in normal adultiv. 53% located in bone

(a) 30% is exchangeable from surface-limited pool and source for endogenous supply

(b) Crystal mineral lattice pool is not readily exchangeable.v. 27% located in skeletal muscle, 19% in soft tissues (liver, brain, heart, and kidney)vi. Less than 1% in extracellular (0.3% serum) and red blood cell count (0.5%

erythrocyte)b. Serum

i. 0.3% of total body stores, 25% bound to albumin and 8% bound to globulins (33% bound to proteins)

ii. 55% of serum Mg is in ionized (free) form, and 12% is complexed to phosphate, citrate, and other compounds

iii. Normal range is 1.5–2.0 mEq/L (1.6–2.3 mg/dL)c. Absorption

i. RDI for adult is 0.4 mEq/kg/day (5 mg/kg/day)ii. 30%–50% is absorbed (8–15 mEq/day)

(a) Primarily in jejunum and ileum(b) Begins about 1 hour after ingestion and continues at uniform rate for 2–8 hours(c) Absorptive capacity may be as low as 25% on a high Mg diet and as high as 75%

on a low Mg diet.d. Elimination

i. Primarily eliminated through the kidney (a) 8–10 mEq/day in the urine



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(b) 35%–45% of daily oral intake renally excreted in normal adult (c) circadian rhythm of Mg renal excretion occurs maximally at night (d) Only 1%–2% of endogenous Mg is eliminated in the feces

B. Hypomagnesemia (less than 1.5 mEq/L)Laboratory diagnosis is often diffi cult.1. a. Diffi cult to predict cellular effects of low serum Mg based on serum concentrationb. Urinary Mg less than 1–2 mEq (12–24 mg)/24 hours is more refl ective of Mg defi ciency

i. May develop within 7 days after decreased Mg intakeii. May develop decreased urinary Mg before decreased serum Mg in patients with

normal renal functionc. 24-hour urinary excretion after Mg load of 64 mEq of Mg sulfate

i. Mg-defi cient patients excrete less than 50% of load. ii. NormoMg patients excrete more than 60% of load.

2. Mechanisms and etiologiesa. Gastrointestinal

i. Reduced intake: protein-calorie malnutrition, prolonged intravenous fl uid without Mg, TPN without Mg, alcoholism, anorexia

ii. Reduced absorption: malabsorption syndromes (celiac disease, Whipple’s disease, radiation enteritis, tropical sprue), short bowel syndrome, intestinal bypass surgery for obesity, acute pancreatitis

iii. Increased losses: diarrhea (ulcerative colitis, colonic neoplasms, Crohn’s disease), laxative abuse, bulimia or excessive vomiting, gastric suctioning, intestinal and biliary fi stulas

b. Renal i. Drug induced: diuretics (especially loop), aminoglycosides, amphotericin B,

cyclosporine A, cisplatin, alcohol, ticarcillin, piperacillin, carbenicillin, digoxin ii. Other: renal tubular acidosis, hypercalcemic states including malignancies,

postobstructive diuresis, diuretic phase of acute tubular necrosis, hereditary renal magnesium wasting, hyperaldosteronism, and renal transplantation

c. Intracellular redistribution i. Diabetic ketoacidosis, hyperthyroidism

d. Miscellaneous: thermal injury patients, pregnancy, lactation, exchange transfusion3. Clinical manifestations of hypomagnesemia

a. Central nervous system: nystagmus, seizures, depression, agitation, psychosisb. Muscular: muscle fasciculations, tremors, hyperrefl exia, paresthesias, positive Chvostek’s

and Trousseau’s signs, choreoathetosis, tetanyc. Cardiovascular: premature ventricular beats, ventricular fi brillation and tachycardia,

Torsades de pointes, predisposition to digoxin-mediated arrhythmias, PR prolongation and QT prolongation

4. Treatmenta. Table 6. IV Dosage Guidelines for Hypomagnesemia

Serum Mg(mg/dL)

Dose(mEq/kg)

Infusion Rate(hours)

1.5–1.8 0.5 121.1–1.4 1 24< 1.0 1.5 24

b. Oral dosage guidelines for hypomagnesemia



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i. Table 7. Oral Replacement PreparationsMg Salt Elemental Mg Content

per Salt Form (mg/g)Diarrhea

Sulfate 100 ++Oxide 600 ++Hydroxide 410 ++Gluconate 54 ±

C. Hypermagnesemia (more than 2.4 mEq/L)Etiologies1. a. Decreased renal eliminationb. Excessive intakec. Drugs

2. Table 8. Signs and Symptoms of HypermagnesemiaMagnesium Serum

Concentration (mEq/L)Sign/Symptom

> 4 ↓ Deep tendon refl exes4–7 Hypotension, bradycardia,

somnolence7–10 EKG changes, fl accid paralysis> 10 Voluntary muscle paralysis, apnea> 15 Respiratory paralysis, complete heart

block EKG = electrocardiographic.3. Treatment of hypermagnesemia

a. Discontinue supplemental magnesiumb. Calcium administrationc. Diuresis

VIII. DISORDERS OF PHOSPHORUS HOMEOSTASIS

A. Phosphorus1. Biological functions and physiologic processes

a. Important role in cell structure as a constituent of nucleotides (DNA), nucleoproteins, and membrane phospholipids

b. Critical role in cell function because inorganic phosphorus (Pi) is required for:i. Normal glycolytic pathway functioning in red blood cells and other tissuesii. Production of phosphorylated intermediates including 2,3-diphosphoglycerate and

ATP for maintenance of normal oxygen-hemoglobin dissociation and subsequent oxygen delivery to tissues

c. Physiologic processes that have phosphorus-dependent metabolic pathways include, but are not limited to:i. Leukocyte phagocytic activityii. Neurologic functioniii. Skeletal, respiratory, and cardiac muscle function

d. Phosphate is an important urinary buffer system that facilitates excretion of fi xed acids.2. Pharmacokinetics (absorption, distribution, elimination)

a. Absorption: normal adult dietary intake is about 1 g/day, of which 70%–90% is absorbed.b. Adult body stores:

i. Under normal conditions, there are about 500–800 g, of which around 80% is stored in bones/teeth and around 9% is located in skeletal muscle/viscera.



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ii. Storage is in the organic form of phospholipids, phosphosugars, and phosphoproteins.iii. Most of the phosphorus located in skeletal muscle and viscera is intracellular.

(a) Phosphorus is the major intracellular anion.(b) Serum phosphorus is not a reliable indicator of total body phosphate stores

because phosphate is mainly an intracellular ion.iv. Only a small portion of the phosphorus pool is Pi and subsequently available for

synthesis of intracellular energy compounds (i.e., ATP).c. Serum phosphorus is tightly regulated and maintained within a narrow range.

i. Diurnal variationii. Variation with meal ingestion (mean decrease of 0.25 mg/dL below fasting level

common after carbohydrate and fat meals)iii. Serum concentrations drawn before breakfast are the most reliable.

d. Hormonal controlsi. 1,25-dihydroxyvitamin D3 (calcitriol)

(a) Stimulates bone phosphate resorption(b) Increases GI phosphate absorption

ii. Parathyroid hormone(a) Increases phosphate excretion and calcium in renal proximal tubule(b) Stimulates 1-α-hydroxylation of vitamin D to calcitriol

e. Excretion of absorbed phosphate is around 90% in urine and around 10% in feces.

B. Hypophosphatemia (less than 2.5 mg/dL)1. Mechanisms and etiologies

a. Nutritionali. Decreased intake through dietary defi ciency (rarely occurs) does not cause signifi cant

hypophosphatemia by itself, but when a stress is imposed on the patient, acute severe hypophosphatemia can result.

ii. Starvation is associated with catabolic release of intracellular phosphate, which is subsequently lost in the urine (maintaining normal serum phosphorus).

iii. Ineffective GI absorption caused by medications (i.e., chronic antacid therapy or sucralfate) binding phosphorus in the GI tract and inhibiting absorption of ingested and secreted phosphorus

iv. GI disorders (Crohn’s disease) causing malabsorption, maldigestion (pancreatic insuffi ciency), or steatorrhea (postgastrectomy), all of which decrease calcium and vitamin D absorption, inducing secondary hyperparathyroidism and increased phosphaturia

b. Increased lossi. Renal

(a) Intrinsic (renal tubular abnormality): Fanconi’s syndrome and vitamin D–resistant rickets

(b) Extrinsic (inhibition of phosphate reabsorption): hyperparathyroidism, acute expansion of ECF volume with saline or sodium bicarbonate, theophylline, glycosuria, hypokalemia, and hypomagnesemia

ii. Nonrenal(a) GI losses: prolonged nasogastric suctioning, vomiting, and chronic diarrhea(b) Hemodialysis against a phosphate-poor dialysis solution(c) Renal losses do not account for the hypophosphatemia seen in patients with

refeeding syndrome (urinary phosphorus concentrations decline to zero, and tubular reabsorption of phosphorus increases in this setting).

c. Transcellular shifts



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i. Acute shift of phosphate from the extracellular to the intracellular compartmentii. The primary mechanism causing severe hypophosphatemia, especially in patients

who are already phosphorus depletediii. Intracellular Pi is used to form phosphorylated intermediates during glycolysis,

glycogenolysis, oxidative phosphorylation, and the synthesis of protein and glycogen, which causes a depletion of intracellular Pi.

iv. Extracellular Pi shifts inside the cell, leading to hypophosphatemia.v. Anabolism (synthesis of protoplasm) requires deposition of nitrogen in parallel with

phosphorus (ratio of 0.07 g of phosphorus/1 g of nitrogen) as well as sodium and potassium.

vi. Anabolism and glycolysis, precipitating cellular uptake of phosphorus, are stimulated by the administration of carbohydrates and amino acids.

vii. Severe respiratory alkalosis is also thought to work by this mechanism of increased formation of phosphorylated organic compounds with subsequent intracellular shifting of Pi.

viii. Metabolic alkalosis does not cause as profound a hypophosphatemia.ix. Medications such as insulin and β2-inhaled agonists can cause an intracellular shift.

2. Clinical manifestations of hypophosphatemiaCentral nervous system: acute arefl exic paralysis, paresthesias, dysarthria, weakness, a. numbness, seizures, confusion, coma, altered mental status, myalgias, Guillain-Barre–like syndrome, lethargy, rhabdomyolysis, and hyporefl exiaPulmonary: respiratory muscle fatigue, decreased diaphragmatic contractility, ventilator b. dependenceGI: anorexia, emesis, nauseac. Hematologic: decreased diphosphoglycerate, causing increased oxygen affi nity for d. hemoglobin and increased red blood cell count rigidity, thrombocytopenia, and white blood cell count dysfunctionCardiovascular: arrhythmias, congestive heart failure, decreased cardiac output, and e. sudden death

3. Treatment

a. Table 9. Intravenous Dosage Guidelines for HypophosphatemiaPhosphorus (mg/dL) Dose (mmol/kg) Infusion Time (hours)2.3–3 0.32 4–61.6–2.2 0.64 4–6≤ 1.5 1 8–12

b. Oral dosing guidelines for hypophosphatemiai. Table 10. Oral Replacement Preparations

Product(mmol)

Potassium(mmol)

Sodium(mmol)

Phosphorus(mmol)

Neutra Phos caplets 7.13 7.13 8Neutra Phos K caplets 14.25 0 8Neutra Phos powder 7.13 7.13 8Neutra Phos K powder 14.25 0 8Fleet’s Phosphosoda (per mL) 0 4.8 4.1

ii. Must provide 20–40 mmol per day because of poor oral absorptioniii. Best option: 5–10 mL of Fleet’s Phosphosoda



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C. Hyperphosphatemia (more than 4.5 mg/dL)1. Etiologies

a. Renal dysfunction: primary glomerular or tubulointerstitial disease, primary hypoparathyroidism

b. Intracellular to extracellular shift: hemolysis, rhabdomyolysis, tumor lysis syndromec. Drugs: antacids, enemas, or laxatives

1. Signs and symptoms of hyperphosphatemiaa. Attributable to hypocalcemia: neuromuscular (paresthesias, tetany, seizures), cardiac

(arrhythmia, hypotension)b. Serum Ca (mg/dL) × P (mg/dL) product more than 60: increased risk of ectopic

calcifi cation in the heart, kidney, GI tract, and skin2. Treatment of hyperphosphatemia

a. Oral phosphate binders: Al(OH), calcium carbonate, calcium acetateb. Sucralfatec. Extracellular volume expansion (to achieve urinary output of more than 3 L/day)d. Hemodialysis

IX. DISORDERS OF CALCIUM HOMEOSTASIS

A. Biological functions and physiologic processes1. Bone metabolism2. Blood coagulation3. Platelet adhesion4. Neuromuscular activity5. Electrophysiology of the heart and smooth muscles

B. Pharmacokinetics (absorption, distribution, elimination)1. About 99% of Ca++ is in the bones, with less than 1% residing in the serum.2. Ca++ in the blood is 45% bound to plasma proteins, primarily albumin.3. Free, ionized calcium accounts for 45% of total plasma calcium; it is the free, unbound,

ionized form that is physiologically active.4. The remaining 10% of total plasma calcium is complexed to various anions, including

bicarbonate, citrate, and phosphate.5. Because Ca++ is highly bound to albumin, hypoalbuminemia can cause a decrease in total

serum Ca++.a. For each 1-g/dL decrease in serum albumin concentration below 4 g/dL, total serum

Ca++ decreases by about 0.8 mg/dL.b. Corrected serum Ca++ formula:

i. Measured Ca++ (mg/dL) + [0.8 × (4 − measured albumin (g/dL))]6. Ionized serum Ca++ is affected by acid-base status.

a. Metabolic alkalosis increases Ca++ binding to plasma proteins, thus reducing the ionized serum Ca++.

b. Metabolic acidosis decreases Ca++ binding to plasma proteins, thus increasing the ionized serum Ca++.

C. Hypocalcemia (less than 8.6 mg/dL)1. Mechanisms and etiologies

a. Increased sequestration



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i. Hyperphosphatemia: Ca × P product more than 60, soft tissue deposition of Ca-P complexes

ii. Chelation: citrate (from transfusion or hemodialysis)iii. Soft tissue deposition: in acute pancreatitis and rhabdomyolysisiv Bone deposition: osteoblastic metastases

b. Decreased parathyroid actioni. Destruction of parathyroid glands: surgery, radiation, cancerii. Inhibition of parathyroid release: hypomagnesemia

c. Resistance to parathyroid actioni. Vitamin D defi ciency: nutritional, malabsorptionii. Pseudohypoparathyroidism

d. Medicationsi. Plicamycin (mithramycin), loop diuretics, pentamidine, phenytoin, foscarnet,

intravenous amino acids2. Clinical manifestations of hypocalcemia

a. Central nervous system: lethargy, depression, psychoses seizuresb. Neuromuscular: Chvostek’s sign, Trousseau’s sign, paresthesias, muscle cramps, tetanyc. Cardiovascular: arrhythmias (heart block, ventricular fi brillation), prolonged QT interval

3. Treatmenta. Intravenous dosing guidelines for symptomatic hypocalcemia

i. 1–2 g of calcium gluconate for 30–60 minutes and then 10–15 mg/kg for 4–6 hoursii. Avoid calcium chloride because of thrombophlebitis and risk of acidosis

b. Oral dosing guidelines for asymptomatic hypocalcemiai. Table 11. Comparison of Selected Calcium Products

Calcium Salt Elemental Calcium Route

Ca chloride 13.6 mEq = 272 mg = 1 g IntravenousCa gluconate 4.5 mEq = 90 mg = 1 g Intravenous

90 mg/g salt OralCa citrate 210 mg/g salt OralCa carbonate 400 mg/g salt OralCa acetate 250 mg/g salt Oral

ii. Oral calcium supplements should be supplemented as 1–2 g/day elemental calcium.iii. Foods high in calcium: milk, ice cream, cheese, canned salmon, fresh oysters

D. Hypercalcemia (more than 10.5 mg/dL)1. Mechanisms and etiologies

a. Increased calcium absorption due to increased vitamin D: tuberculosis, histoplasmosis, milk-alkali syndrome

b. Malignancy: breast cancer, lung cancer, multiple myeloma, non-Hodgkin’s lymphomac. Parathyroid excess: parathyroid hyperplasia, adenomad. Enhanced bone calcium mobilization (non–parathyroid mediated): hyperthyroidism,

adrenal insuffi ciency, pheochromocytomae. Miscellaneous: prolonged immobilization, vitamin A toxicity

2. Manifestations of hypercalcemiaa. Central nervous system: depression, confusion, psychosis, comab. Neuromuscular: muscle weakness, decreased deep tendon refl exesc. Cardiovascular: arrhythmias, hypertension, shortened QT intervald. GI: nausea, vomiting, pancreatitise. Renal: nephrolithiasis, nephrocalcinosis, type II distal renal tubular acidosis



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3. Treatment of acute, symptomatic hypercalcemiaa. Extracellular volume expansion: fi rst line of therapy

i. Normal saline: initially, 1–2 L for 1 hour, followed by 300–500 mL/hour to maintain diuresis

ii. Hydration can increase urinary calcium excretion.iii. Can add loop diuretic (furosemide 20–40 every 2–3 hours) to increase calciuric effect

of volume expansioniv. Monitor K+ and Mg++ due to losses from forced diuresis.

b. Biphosphonates (etidronate, pamidronate, alendronate, zoledronate): inhibitors of bone resorption through action on osteoblast and osteoclast precursorsi. Often used for hypercalcemia of malignancyii. Dosing:

(a) Pamidronate: 60–90 mg intravenously for 2–24 hours × 1 dose(b) Zoledronate: 4–8 mg intravenously for 15 minutes × 1 dose(c) Etidronate: 7.5 mg/kg/day for 2 hours × 3–7 days

c. Calcitonini. Moderate effi cacy for hypercalcemia of carcinoma, multiple myeloma, and primary

hyperparathyroidismii. Dose: 4 IU/kg subcutaneously or intramuscularly every 12 hours

d. Glucocorticoidsi. Useful in decreasing excessive vitamin D production or calcium absorption; not

helpful in hyperparathyroid statesii. Dose: prednisone 10–30 mg/day orally; takes several days to 2 weeks for onset

e. Plicamycini. Useful in hypercalcemia of malignancyii. Blocks bone resorption by inhibiting RNA synthesis in bone cellsiii. Dose: 25 mcg/kg intravenously for 2–3 hoursiv. Risk of increased toxicity (renal, hepatic, hematopoietic) with repeated doses

f. Hemodialysisg. Avoid intravenous phosphates because of risk of soft tissue calcifi cation.



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Table 12. Drugs Tested for Compatibility with 2-in-1 Parenteral Nutrition SolutionsAcyclovir 7 mg/mL D5W Hydromorphone 0.5 mg/mL D5WAmikacin 5 mg/mL D5W Hydroxyzine 2 mg/mL D5WAminophylline 2.5 mg/mL D5W Imipenem/Cilastatin 10 mg/mL 0.9% NaCl Amphotericin B 0.6 mg/mL D5W Insulin 1 unit/mL D5WAmpicillin 20 mg/mL 0.9% NaCl Ifosfamide 25 mg/mL D5WAmpicillin/Sulbactam 20/10 mg/mL 0.9% NaCl Leucovorin 2 mg/mL D5WAztreonam 40 mg/mL D5W Levorphanol 0.5 mg/mL D5WBumetanide 0.04 mg/mL D5W Lorazepam 0.1 mg/mL D5WBuprenorphine 0.04 mg/mL D5W Magnesium sulfate 100 mg (0.81 mEq)/mL D5WButorphanol 0.04 mg/mL D5W Mannitol 15% undiluted solution (150 mg/mL)Calcium gluconate 40 mg (0.19 mEq)/mL D5W Meperidine 4 mg/mL D5WCarboplatin 5 mg/mL D5W Mesna 10 mg/mL D5WCefazolin 20 mg/mL D5W Methylprednisolone 5 mg/mL D5WCefonicid 20 mg/mL D5W Methotrexate 15 mg/mL D5WCefoperazone 40 mg/mL D5W Metoclopramide 5 mg/mL D5WCefotaxime 20 mg/mL D5W Metronidazole 5 mg/mL undilutedCefotetan 20 mg/mL D5W Mezlocillin 40 mg/mL D5WCefoxitin 20 mg/mL D5W Miconazole 3.5 mg/mL D5WCeftazidime 40 mg/mL D5W Midazolam 2 mg/mL D5WCeftizoxime 20 mg/mL D5W Minocycline 0.2 mg/mL D5WCeftriaxone 20 mg/mL D5W Mitoxantrone 0.5 mg/mL D5WCefuroxime 30 mg/mL D5W Morphine 1 mg/mL D5WChlorpromazine 2 mg/mL D5W Nafcillin 20 mg/mL D5WCimetidine 12 mg/mL D5W Nalbuphine 10 mg/mL undilutedCiprofl oxacin 1 mg/mL D5W Netilmicin 5 mg/mL D5WCisplatin 1 mg/mL undiluted Nitroglycerin 400 mcg/mL D5WClindamycin 10 mg/mL D5W Nitroprusside 400 mcg/mL D5WCyclophosphamide 10 mg/mL D5W Norepinephrine 16 mcg/mL D5WCyclosporine 5 mg/mL D5W Octreotide 10 mcg/mL D5WCytarabine 50 mg/mL undiluted Ofl oxacin 4 mg/mL D5WDexamethasone 1 mg/mL D5W Ondansetron 1 mg/mL D5WDigoxin 0.25 mg/mL undiluted Paclitaxel 1.2 mg/mL D5WDiphenhydramine 2 mg/mL D5W and 50 mg/mL undiluted Pentobarbital 5 mg/mL D5WDobutamine 4 mg/mL D5W Phenobarbital 5 mg/mL D5WDopamine 3200 mcg/mL D5W Piperacillin 40 mg/mL D5WDoxorubicin 2 mg/mL undiluted Piperacillin/Tazobactam 40/5 mg/mL D5WDoxycycline 1 mg/mL D5W Potassium chloride 0.1 mEq/mL D5WDroperidol 0.4 mg/mL D5W Potassium phosphates 3 mmol/mL undilutedEnalaprilat 0.1 mg/mL D5W Prochlorperazine 0.5 mg/mL D5WFamotidine 2 mg/mL D5W Promethazine 2 mg/mL D5WFentanyl 12.5 mcg/mL D5W and 50 mcg/mL undiluted Ranitidine 2 mg/mL D5WFluconazole 2 mg/mL undiluted Sodium bicarbonate 1 mEq/mL undilutedFluorouracil 16 mg/mL D5W Sodium phosphates 3 mmol/mL undilutedFurosemide 3 mg/mL D5W Tacrolimus 1 mg/mL D5WGanciclovir 20 mg/mL D5W Ticarcillin 30 mg/mL D5WGentamicin 5 mg/mL D5W Ticarcillin/Clavulanate 30/0.1 mg/mL D5WGranisetron 50 mcg/mL D5W Tobramycin 5 mg/mL D5WHaloperidol 0.2 mg/mL D5W Trimethoprim/Sulfamethoxazole 0.8/4 mg/mL D5WHeparin 100 units/mL undiluted Vancomycin 10 mg/mL D5WHydrocortisone 1 mg/mL D5W Zidovudine 4 mg/mL D5WDrugs listed in bold and italicized are incompatible: Trissel LA, Gilbert DL, Martinez JF, et al. Compatibility of parenteral nutrient solutions with selected drugs during simulated Y-site administration. Am J Health-Syst Pharm 1997;54:1295–300.



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Table 13. Drugs Tested for Compatibility with 3-in-1 Parenteral Nutrition SolutionsAcyclovir 7 mg/mL D5W Hydroxyzine 2 mg/mL D5WAmikacin 5 mg/mL D5W Imipenem/Cilastatin 10 mg/mL 0.9% NaCl Aminophylline 2.5 mg/mL D5W Insulin 1 unit/mL D5WAmphotericin B 0.6 mg/mL D5W Ifosfamide 25 mg/mL D5WAmpicillin 20 mg/mL 0.9% NaCl Leucovorin 2 mg/mL D5WAmpicillin/Sulbactam 20/10 mg/mL 0.9% NaCl Levorphanol 0.5 mg/mL D5WAztreonam 40 mg/mL D5W Lorazepam 0.1 mg/mL D5WBumetanide 0.04 mg/mL D5W Magnesium Sulfate 100 mg (0.81 mEq)/mL D5WBuprenorphine 0.04 mg/mL D5W Mannitol 15% undiluted solution (150 mg/mL)Butorphanol 0.04 mg/mL D5W Meperidine 4 mg/mL D5WCalcium gluconate 40 mg (0.19 mEq)/mL D5W Meropenem 20 mg/mL D5WCarboplatin 5 mg/mL D5W Mesna 10 mg/mL D5WCefazolin 20 mg/mL D5W Methylprednisolone 5 mg/mL D5WCefonicid 20 mg/mL D5W Methotrexate 15 mg/mL D5WCefoperazone 40 mg/mL D5W Metoclopramide 5 mg/mL D5WCefotaxime 20 mg/mL D5W Metronidazole 5 mg/mL undilutedCefotetan 20 mg/mL D5W Mezlocillin 40 mg/mL D5WCefoxitin 20 mg/mL D5W Miconazole 3.5 mg/mL D5WCeftazidime 40 mg/mL D5W Midazolam 2 mg/mL D5WCeftizoxime 20 mg/mL D5W Minocycline 0.2 mg/mL D5WCeftriaxone 20 mg/mL D5W Mitoxantrone 0.5 mg/mL D5WCefuroxime 30 mg/mL D5W Morphine 1 mg/mL D5W and 15 mg/mL undilutedChlorpromazine 2 mg/mL D5W Nafcillin 20 mg/mL D5WCimetidine 12 mg/mL D5W Nalbuphine 10 mg/mL undilutedCiprofl oxacin 1 mg/mL D5W Netilmicin 5 mg/mL D5WCisplatin 1 mg/mL undiluted Nitroglycerin 400 mcg/mL D5WClindamycin 10 mg/mL D5W Nitroprusside 400 mcg/mL D5WCyclophosphamide 10 mg/mL D5W Norepinephrine 16 mcg/mL D5WCyclosporine 5 mg/mL D5W Octreotide 10 mcg/mL D5WCytarabine 50 mg/mL undiluted Ofl oxacin 4 mg/mL D5WDexamethasone 1 mg/mL D5W Ondansetron 1 mg/mL D5WDigoxin 0.25 mg/mL undiluted Paclitaxel 1.2 mg/mL D5WDiphenhydramine 2 mg/mL D5W and 50 mg/mL undiluted Pentobarbital 5 mg/mL D5WDobutamine 4 mg/mL D5W Phenobarbital 5 mg/mL D5WDopamine 3200 mcg/mL D5W Piperacillin 40 mg/mL D5WDoxorubicin 2 mg/mL undiluted Piperacillin/Tazobactam 40/5 mg/mL D5WDoxycycline 1 mg/mL D5W Potassium chloride 0.1 mEq/mL D5WDroperidol 0.4 mg/mL D5W Potassium phosphates 3 mmol/mL undilutedEnalaprilat 0.1 mg/mL D5W Prochlorperazine 0.5 mg/mL D5WFamotidine 2 mg/mL D5W Promethazine 2 mg/mL D5WFentanyl 12.5 mcg/mL D5W and 50 mcg/mL undiluted Ranitidine 2 mg/mL D5WFluconazole 2 mg/mL undiluted Sodium Bicarbonate 1 mEq/mL undilutedFluorouracil 16 mg/mL D5W Sodium phosphates 3 mmol/mL undilutedFurosemide 3 mg/mL D5W Tacrolimus 1 mg/mL D5WGanciclovir 20 mg/mL D5W Ticarcillin 30 mg/mL D5WGentamicin 5 mg/mL D5W Ticarcillin/Clavulanate 30/0.1 mg/mL D5WGranisetron 50 mcg/mL D5W Tobramycin 5 mg/mL D5WHaloperidol 0.2 mg/mL D5W Trimethoprim/Sulfamethoxazole 0.8/4 mg/mL D5WHeparin 100 units/mL undiluted Vancomycin 10 mg/mL D5WHydrocortisone 1 mg/mL D5W Zidovudine 4 mg/mL D5WHydromorphone 0.5 mg/mL D5WDrugs listed in bold and italicized are incompatible: Trissel LA, Gilbert DL, Martinez JF, et al. Compatibility of medications with 3-in-1 parenteral nutrition admixtures. JPEN 1999;23:67–74.



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Table 14. Monitoring Guidelines for Patients Receiving Parenteral NutritionParameter Baseline Monitoring

Chem-7a X Every 3 days; then, 3 or 4 times/week PRNCa, Phos, Mg X 2 or 3 times for 1 week; then, once or twice weeklyFingerstick glucose X PRN; in an unstable patient every 4–6 hoursLiver function tests X WeeklyPrealbumin and CRP X WeeklyCBC w/differential X WeeklyTriglyceride X WeeklyPT/PTT X Weekly24-hour urine for UUN X PRN; for persistently low prealbumin and CRPWeight X DailyVital signs, fl uid intake/output X Daily

aChem-7 includes serum Na, K, Cl, CO2, BUN, creatinine, and glucose. A critically ill patient most likely would require a Chem-7 daily.BUN = blood urea nitrogen; CBC = complete blood cell count; CRP = C-reactive protein; PRN = as needed; PT = prothrombin time; PTT = partial thromboplastin time; UUN = urine urea nitrogen.



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Enteral Nutrition1. A.S.P.E.N. Board of Directors. Guidelines for the

use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enter Nutr JPEN 2002;26(suppl):1SA–138SA

2. Edes TE, Walk BE, Austin JL. Diarrhea in tube-fed patients: feeding formula not necessarily the cause. Am J Med 1990;88:91–3.

3. Kirby DF, Delegge MH, Fleming CR. American Gastroenterological Association technical review on tube feeding for enteral nutrition. Gastroenterology 1995;108:1282–301.

4. Klein S, Kinney J, Jeejeebhoy K, et al. Nutrition support in clinical practice: review of published data and recommendations for future research directions. J Parenter Enter Nutr JPEN 1997;21:133–56.

5. Kompan L, Kremzar B, Gadzijev E, et al. Effects of early enteral nutrition on intestinal permeability and the development of multiple organ failure after multiple injury. Intensive Care Med 1999;25:157–61.

6. Kudsk KA, Croce MA, Fabian TC, et al. Enteral vs parenteral feeding: effects on septic morbidity following blunt and penetrating trauma. Ann Surg 1992;215:503–13.

7. McMahon MM, Farnell MB, Murray MJ. Nutritional support of critically ill patients. Mayo Clin Proc 1993;68:911–20.

8. Minard G, Kudsk KA. Nutritional support and infection: does the route matter? World J Surg 1998;22:213–9.

9. Vanek V. Ins and outs of enteral access. I. Short-term enteral access. Nutr Clin Pract 2002;17:275–83.

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11. Vanek V. Ins and outs of enteral access. III. Long-term enteral access—jejunostomy. Nutr Clin Pract 2003;18:201–20.

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nutrition: a review of its current status in hospitalized patients and the need for patient-specifi c feeding. Drugs 1990;40:346–63.

2. Eggert LD, Rusho WJ, MacKay MW, et al. Calcium and phosphorus compatibility in

parenteral nutrition solutions for neonates. Am J Hosp Pharm 1982;39:49–53.

3. Fitzgerald KA, MacKay MW. Calcium and phosphate solubility in neonatal parenteral nutrition solutions containing Aminosyn PF. Am J Hosp Pharm 1987;44:1396–400.

4. Henry RS, Jurgens RW, Sturgeon R, et al. Compatibility of calcium chloride and calcium gluconate with sodium phosphate in a mixed PN solution. Am J Hosp Pharm 1980;37:673–4.

5. Klein S, Kinney J, Jeejeebhoy K, et al. Nutrition support in clinical practice: review of published data and recommendations for future research directions. J Parenter Enter Nutr JPEN 1997;21:133–56.

6. Lenz GT, Mikrut BA. Calcium and phosphate solubility in neonatal parenteral nutrient solutions containing Aminosyn-PF or TrophAmine. Am J Hosp Pharm 1988;45:2367–71.

7. Manzo CB, Dickerson RN. Parenteral nutrition monitoring in hospitalized patients. Hosp Pharm 1993;28:561–8.

8. McMahon MM, Farnell MB, Murray MJ. Nutritional support of critically ill patients. Mayo Clin Proc 1993;68:911–20.

9. Mikrut BA. Calcium and phosphate solubility in neonatal parenteral nutrient solutions containing Aminosyn PF or TrophAmine. Am J Hosp Pharm 1987:44:2702–4.

10. Schuetz DH, King JC. Compatibility and stability of electrolytes, vitamins and antibiotics in combination with 8% amino acids solution. Am J Hosp Pharm 1978;35:33–44.

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Fluid & Electrolyte RequirementsGeneral1. Arieff AL, DeFronzo RA. Fluid, Electrolyte and

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1. Answer: AStep 1: Elevated pH indicates the presence of alkalemia.Step 2: The primary process is metabolic because the HCO3 is elevated and the PCO2 is not decreased.Step 3: Calculate the gaps.anion gap (AG) = 144 − (39 + 94) = 11 mEq/L; a normal AG = 10 ± 4 mEq/L; thus, the AG is normal.Step 4: Check for the degree of compensation. The increase in PCO2 is 8.4 (0.6 × 14); thus, 40 + 8.4 = 48.4. The calculated increase in PCO2 of 48.4 mm Hg is equal to the measured PCO2 of 48 mm Hg; thus, the metabolic alkalemia is fully compensated.Step 5: Determine the 1:1 relationship. This calculation is not necessary.

2. Answer: C Step 1: Acidemia is present because the pH is less

than 7.35.Step 2: The primary process is metabolic because

the bicarbonate is decreased and the PCO2 is not increased.

Step 3: The anion gap is dramatically elevated: 140 − (105 + 5) = 30. (normal AG = 10 ± 4)

Step 4: Compensation for metabolic acidosis is calculated by the following formula: ΔPCO2 = 1.3 × decrease in HCO3. The decrease in bicarbonate is by 20 (25 − 5 = 20), so the PCO2 should decrease to 14 mm Hg (ΔPCO2 = 1.3 × 20 = 26; 40 − 26 = 14). The compensation for the metabolic acidemia is not complete because the PCO2 of 19 mm Hg is slightly high for normal compensation. Thus, the PCO2 is consistent with a mild superimposed respiratory acidosis. A second disorder, respiratory acidosis, is present.

Step 5: 1:1 Relationship—The bicarbonate decrease of 20 (25 − 5 = 20) is close enough to the AG of 18 (30 − 12 = 18) to exclude an underlying metabolic alkalosis.

3. Answer: AStep 1: Alkalemia is present because the pH is more

than 7.45.Step 2: The primary process is respiratory because

the PCO2 is less than 40 mm Hg and the HCO3 is not increased.

Step 3: The AG is normal [135 − (103 + 22) = 10].Step 4: Compensation for respiratory alkalemia is

calculated by the following formula: the HCO3 decreases by 2 mEq/L for every 10-mm Hg decrease in PCO2 (for acute respiratory alkalosis).

Because the decrease in PCO2 is 15 (40 − 25 = 15 mm Hg), the calculated decrease is 3. In this case, the calculated decrease is identical to the actual decrease (25 − 22 = 3), so only acute respiratory alkalemia is present with normal compensation. If the situation is chronic (more than 3 days), the degree of compensation varies: for every PCO2 decrease of 10 mm Hg, the HCO3 decreases by 4 mEq/L. If the calculation of the degree of metabolic compensation is not close to the actual value for the HCO3 (± 2 mEq/L), an additional primary metabolic disorder is present.

Step 5: 1:1 Relationship—Because the AG is normal, the bicarbonate decrease of 3 (25 − 22 = 3) is the same as the chloride increase of 3 (103 − 100 = 3). Thus, no underlying metabolic alkalosis exists.

4. Answer: DFree water restriction is the best treatment as patients with SIADH have impaired free-water excretion, with normal excretion of sodium. Continued intake of water or hypotonic fl uids will worsen the hyponatremia.

5. Answer: CHypomagnesemia can result in refractory hypokalemia due to accelerated renal potassium loss or impairment of the sodium-potassium ATPase pump.

6. Answer: ECauses of hypomagnesemia include excessive GI fl uid losses rich in magnesium, excessive renal losses from medications (i.e., amphotericin B) or underlying conditions (i.e., thermal injury, alcoholism), and inadequate intake (alcoholism).

7. Answer: DThe aggressive treatment of hypophosphatemia can lead to transiently high serum phosphorus concentrations that may result in precipitation of calcium phosphate salts and soft tissue (metastatic) calcifi cation with symptomatic hypocalcemia.

8. Answer: DBacterial translocation represents migration from the intestinal lumen to gut lymphatic or the portal venous. Studies suggest that early enteral feeding may protect the mucosal barrier.

9. Answer: DProspective randomized clinical trials in trauma patients have shown that enteral nutrition compared with PN can decrease postoperative infections

ANSWERS TO SELF-ASSESSMENT QUESTIONS



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including pneumonia, intraabdominal abscesses, and catheter-related line infections

10. Answer: CEnteral nutrition prevents the structural and functional alterations associated with bowel rest and the lack of luminal nutrients

11. Answer: BDue to the metabolic response to injury that occurs in sepsis, trauma and head injury, there is an increase release in pro-infl ammatory cytokines (glucagon, cortisol, catecholamines) which are catabolic and promote lean tissue breakdown. The delivery of aggressive nutrition support does not overcome this hormonal release, thus lean tissue breakdown persists even with the delivery of nutrition support. However, this hormonal environment does not exist in starvation, thus the provision of nutrition support does reduce lean tissue breakdown during starvation.

12. Answer: AThe presence of luminal nutrients in the intestinal stimulates the secretion of immunoglobulin A (IgA), an immunoglobulin that can prevent bacterial adherence and translocation from the intestine across the mucosal and into the circulation.

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