Updates in Therapeutics® 2015: Critical Care Pharmacy Preparatory Review Course
Shock SyndromesIshaq Lat, Pharm,D., FCCP, FCCM, BCPSRush University Medical CenterChicago, Illinois
Seth Bauer, Pharm.D., FCCM, BCPSCleveland ClinicCleveland, Ohio
Conflict of Interest Disclosures
Ishaq Lat I have no conflicts of interest to disclose
Seth Bauer Consultant for Johnson, Graffe, Keay, Moniz &
Wick Law (case regarding vasopressin)
Learning Objectives1. Distinguish between various shock syndromes
according to a patient’s clinical and hemodynamic parameters
2. Identify critical determinants affecting oxygen delivery
3. Construct a hemodynamic monitoring plan that incorporates data from monitoring devices and markers of perfusion
4. Devise a treatment strategy for the management of a patient with shock
Agenda What is “shock”? Pathophysiology of shock syndromes Monitoring techniques and markers of perfusion Differentiating between shock syndromes Resuscitation end points Treatment of shock
Hypovolemic Obstructive Distributive/Vasodilatory
Septic shock will be covered in a separate lecture Cardiogenic (will be covered in a separate lecture)
What is Shock?
Acute circulatory failure best characterized as “oxygen debt”
Hypotension may not always be the defining characteristic
Clinical exam: “windows” of perfusion Mentation Integumentary system Kidney function
Workbook Page 1-141
The Physiology of the Circulatory System MAP HR CO SVR CVP PCWP
Workbook Pages 1-141, 1-142
The Mechanisms of Oxygen Delivery VO2 = DO2
DO2 = 10 x CO x CaO2
CaO2 = (1.34 x Hgb x SaO2) + (0.003 x PaO2) VO2 = 10 x CO x (CaO2 – CvO2) DO2 is prioritized for the vital organs of the heart
and brain
Workbook Pages 1-142, 1-143
Hemodynamic Monitoring Devices
Workbook Pages 1-143, 1-144
Device Major Advantages LimitationsCentral venous catheter (CVC)
• Easier and safer to insert than a PAC
• Continuous ScvO2 available
• CVP not accurate predictorof fluid responsiveness
• ScvO2 ≠ SvO2
Pulmonary artery catheter (PAC)
• Directly measure CO and SvO2• Assess pulmonary artery pressures
• No superiority data• Arrhythmias• VO2 estimate typically used in Fick CO calculation
Arterial pulse pressure waveform analysis (FloTrac™/ Vigileo™, PiCCO™, LiDCO™)
• Continuous CO measurement• Assessment of stroke volume variation (SVV) and pulse pressure variation (PPV)
• Minimally invasive
• Accuracy issues• Arterial catheter waveform• Mitral or aortic valve dysfunction
• Arrhythmias (SVV and PPV more of a concern than CO or CI)
• SVV and PPV rely on positive pressure ventilation
ScvO2 = central venous oxygen saturation
Markers of Perfusion - Lactate Lactate usually produced under
anaerobic conditions Concentrations >2 mmol/L should be evaluated Elevated when production exceeds clearance
Causes of elevated lactate concentrations Tissue hypoxia (O2 demand > DO2) Impaired clearance (hepatic dysfunction) Aerobic glycolysis (epinephrine) Impaired oxidative phosphorylation (propofol)
Workbook Page 1-146 Kraut JA, Madias NE. N Engl J Med 2014;371:2309-19
Markers of Perfusion - SvO2, ScvO2
SvO2 and ScvO2 reflect tissue oxygen extractionHeart
TissuesArteriesVeinsCvO2
(SvO2 ~75%)DO2(SaO2 ~100%)
ERO2(~25%) SvO2 ≈ 1 - ERO2
ScvO2 ≠ SvO2, but correlate Femoral CVC cannot be used for ScvO2
Must be interpreted in context of other markers
Inadequate DO2 ↑ERO2 ↓SvO2
Workbook Page 1-146
Patient Case # 1
77-year-old male with light-headedness and fatigue
History: hypertension, asthma, and GERD Increasing melena over past 24 hours BP 88/54 mm Hg, HR 124 beats/min,
RR 18 breaths/min, temperature 39°C WBC: 10.2, Hgb: 6.6 g/dL, platelets 180,000 Which value most contributes to reduced DO2?
Workbook Page 1-148
Patient Case #1
A. History of hypertension
B. Hemoglobin
C. Tachycardia
D. Leukocytosis
Workbook Page 1-148
Differentiation of Shock StatesShock State CVP PCWP CO* SVR
Hypovolemic ↓ ↓ ↓ ↑Cardiogenic ↑ ↑ ↓ ↑Obstructive
Impaired diastolic filling ↑ ↑ ↓ ↑Impaired systolic contraction ↑ ↓ ↓ ↑
Vasodilatory/Distributive
Pre-resuscitation ↓ ↓ ↓ ↓Post-resuscitation ↑ ↑ ↑ ↓
*ScvO2 or LV function on echocardiography often used as a surrogate for CO
Workbook Page 1-149
Patient Case # 2 77 y/o man with cirrhosis p/w hematemesis Hgb 9.2 7.3 g/dL and BP 82/36 mm Hg Given 2L LR and 2 units blood Hgb 9.1 g/dL PAC placed: CVP 8 mm Hg, PCWP 14 mm Hg,
CO 7 L/min, MAP 58 mm Hg With which shock type are the patient’s
hemodynamic parameters most consistent?A. HypovolemicB. ObstructiveC. VasodilatoryD. Cardiogenic
Workbook Page 1-151
Blood pressure Generally MAP >65 mm Hg or SBP >90 mm Hg
Adequate end-organ perfusion Examples
Resolution of altered mental status Urine output >0.5 ml/kg/hr
May be challenging to assess Lack of fluid responsiveness Adequate DO2
Resuscitation End Points
Workbook Page 1-149
End Points - Fluid Responsiveness Fluid given to increase stroke volume and CO Giving unnecessary fluids may be detrimental Best predicted by dynamic markers CVP <8 or PCWP <12 mm Hg: ~50% prediction Stroke volume variation (SVV) or pulse pressure
variation (PPV): ~85-95% prediction SVV and PPV not accurate with arrhythmias
and require mechanical ventilation Passive leg raise (PLR) test another option
Osman D, et al. Crit Care Med 2007;35:64-8Marik PE, et al. Crit Care Med 2009;37:2642-47
Workbook Pages 1-150, 1-151
End Points - Adequate DO2
CO, SvO2, and ScvO2
Shouldn’t target pre-defined “supra-normal” levels Best interpreted as “adequate” or “inadequate”
Adequacy determined with concomitant assessments If inadequate, target interventions to increase DO2
Fluids (if fluid responsive), blood (Hgb<7), or inotropes
Likely more important to optimize DO2 in early vs. later resuscitation
Gattinoni L, et al. N Engl J Med 1995;333:1025-32Teboul J-L, et al. Crit Care 2011;15:1005
Workbook Page 1-152
Adequate DO2, continued Lactate clearance and normalization Decline in lactate concentration suggests improved
global tissue perfusion Improving DO2 may decrease lactate Does not require invasive monitoring Most frequently utilized in patients with septic shock
Workbook Pages 1-153, 1-154
Patient Case # 3 Previous patient developed hypoxemia requiring
intubation and mechanical ventilation FIO2 90% sedated and given atracurium Remained hypotensive with low urine output Which value best predicts fluid responsiveness?
A. CVP 7 mm Hg
B. PCWP 11 mm Hg
C. SVV 16%
D. MAP 62 mm Hg
Workbook Page 1-152
Agents to Treat Shock - Fluids Crystalloids usually initial resuscitation choice Similar outcomes with 0.9% NaCl and 4% albumin
Increasing interest in crystalloids with lower chloride content Chloride can cause afferent renal arteriole
vasoconstriction and lower the strong ion difference Chloride-poor fluids (e.g. LR) associated with less
AKI than chloride-rich fluids (e.g. 0.9% NaCl) Hydroxyethyl starches should be avoided
SAFE Study Investigators. N Engl J Med 2004;350:2247-56Yunos NM, et al. JAMA 2012;308:1566-72
Zarychanski R, et al. JAMA 2013;309:678-88Workbook Pages 1-154, 1-155
Agents to Treat Shock - Vasoactives Indicated when hypotension persists after fluid
resuscitation or severe hypoperfusion while fluids infusing
Workbook Page 1-156
53%
26% 24%
49%
20% 12%0%
25%
50%
75%
28-Day Mortality Open-label NE Arrhythmias
DopamineNorepinephrine (NE)
n=1679p=0.10
p<0.001 p<0.001
De Backer D, et al. N Engl J Med 2010;362:779-89
Selection of a specific agent based on shock state, pathophysiology, and therapeutic goal
Patient Case # 5 28 y/o male presented to SICU with shock after
appendectomy c/b perforation in the OR Given 2L LR, 1L 5% albumin, and 2L 6% HES MAP 64, lactate 5.2, NE 14 mcg/min, ScvO2 61% Echo: large ventricles with poor contractility Which action is best?
A. Start phenylephrine
B. Start vasopressin
C. Increase norepinephrine
D. Start epinephrineWorkbook Page 1-157
Hypovolemic Shock
Commonly attributed to trauma, hypovolemic shock can also occur due to: Gastrointestinal bleeding Surgical bleeding Obstetrical bleeding Pharmacologic toxicity
Estimated 2 million deaths per year due to hemorrhage following trauma
Workbook Page 1-157
Classification of Trauma Hemorrhage
Class I Class II Class III Class IV
Blood loss (mL)/% <750< 15%
750-100015-30%
1500-200030-40%
>2000>40%
HR (beats/minute) <100 >100 >120 >140
RR (breaths/minute) 14-20 20-30 30-40 >35
UOP (mL/hour) >30 20-30 5-15<5
CNS symptoms Normal Anxious Confused Lethargic
ATLS manual. American College of Surgeons, 1997:103-112Workbook Page 1-157
41-year-old male s/p motorcycle accident Rib, pelvis, and bilateral femur fractures BP: 82/4 mm Hg HR: 125 beats/minute RR 34 breaths/minute 35°C Which is the appropriate class of hypovolemic
shock according to the ATLS?
Workbook Page 1-139
SAQ #7
A. Class I
B. Class II
C. Class III
D. Class IV
Workbook Page 1-139, Answer: 1-176
SAQ #7
Physiologic Response to Hemorrhage Sympathetic response
Low-pressure and high-pressure receptors activated HR, myocardial contractility, arteriolar tone
Parasympathetic response vagal tone, HR
Intrinsic response Redistribution of interstitial fluid into vascular compartment
Humoral response RAAS activation
Workbook Page 1-158
Resuscitation of Hypovolemic Shock Due to Bleeding1. Identify and treat reversible bleeding cause2. Fluids
Indication: diminished mental status, SBP < 90 mm Hg LR and NS preferred (crystalloids)
3. Transfusion strategies Indication: > 30% total blood volume loss Maintain Hgb > 10 g/dL (trauma), > 7 g/dL (GIB)
4. Vasopressors Temporizing measure
Workbook Page 1-158
Burn Resuscitation
Third-spacing of intravascular fluid common following burn injury
Fluid resuscitation is needed to maintain intravascular volume
Therapeutic goals: UOP > 0.5 mL/kg/hr (adults), > 1 mL/kg/hr (children)
Parkland Formula: 4 mL/kg/% TBSA (LR)
2 mL/kg/% over first 8 hours 2 mL/kg/% over remaining 16 hours
Workbook Pages 1-158, 1-159
Patient Case #6
29-year-old man (85 kg, 72 inches) 40% TBSA burn to lower extremity and buttocks Which is the best option for resuscitations?
Workbook Page 1-161
Patient Case #6
A. 15 L of LR over 24 hours: 1000 mL/hour x 12 hours, followed by 250 mL/hour, titrating to UOPof 1 mL/kg/hour
B. 13 L of LR over 24 hours: initiate 813 mL/hour x 8 hours, followed by 406 mL/hour, titrating to UOP of 0.5 mL/kg/hour
C. 12 L of LR over 12 hours: initiate 1 L/hour, titrating to UOP of 0.5 mL/kg/hour
D. 24 L of LR over 24 hours: initiate 1 L/hour, titrating to UOP of 0.5 mL/kg/hour
Workbook Page 1-161
Management of Coagulopathy
Correction of hypothermia (core > 34°C, acidemia (pH < 7.20), and hypocalcemia(ionized calcium > 4.4 mg/dL)
PRBCs: plasma: cryoprecipitate: platelets 1:1:1:1
Workbook Page 1-159
Treatment Options for Bleeding
rFVIIa PCCs Tranexamic acid Alpha-aminocaproic acid
Workbook Page 1-159
Recombinant factor VIIa
Activates TF, factor X, and factor IX RCT data lacking data to support survival
benefit Increased arterial and venous
thromboembolic events
Yank V, et al. Ann Intern Med 2011;154:529-40Workbook Page 1-159
Prothrombin Complex Concentrates (PCCs)
Factor II(units/vial)
Factor VII(units/vial)
Factor IX(units/vial)
Factor X(units/vial)
Bebulin VH 120 13 100 139
FEIBA* 650 1200 700 550
Kcentra† 380-800 200-500 400-620 500-1020
Profilnine SD 148 11 100 64
* Contains mainly non-activated factors II, IX, and X; factor VII is mainly in the activated form. Values expressed are for the FEIBA 500 units vial, which also contains Protein C 550 units.
† Values expressed are for the Kcentra 500 units vial, which also contains Protein C 420-820 units and Protein S 240-680 units.
Workbook Pages 1-159, 1-160
Tranexamic Acid in Trauma Patients Competitive inhibition of plasminogen Prevents dissolution of fibrin clot
CRASH-2 study. 40 countries, n=20,211 adult trauma patients TXA (n=10,096) vs. placebo (n=10,115) 1 g over 10 minutes, 1 g infusion over 8 hours
All-cause mortality: 1463 (14.5%) vs. 1613 (16.0%) RR (0.91; 95% CI, 0.85-0.97, p=0.0035)
Death due to bleeding: 489 (4.9%) vs. 574 (5.7%) RR (0.85; 95% CI, 0.76-0.96, p=0.007)
Lancet 2010;376:23-32Workbook Pages 1-159, 1-160
Overview of Target-SpecificOral Anticoagulants
Warfarin Dabigatran Apixaban Rivaroxaban
Action Vitamin K antagonist
Factor II inhibitor
Factor X inhibitor
Factor X inhibitor
Peak action 4-5 days ~ 2 hours ~ 2 hours ~ 2 hours
Half-life ~ 2 days 24 hours 12 hours 12 hours
Renal elimination
-- +++(CI with CrCl< 30 mL/min)
+(CI with CrCl< 15 mL/min)
++(CI with CrCl< 30 mL/min)
Workbook Pages 1-160, 1-161
Kcentra prescribing information. CSL Behring LLC, April 2013
Reversal of Warfarin Indications: Hgb decrease > 2 g/dL within 24 hours Bleeding in critical site
Warfarin: KcentraINR 2-4 INR 4-6 INR > 6
Kcentra dose(Factor IX units/kg)
25 35 50
Maximum dose(Factor IX units/kg)
2500 3500 5000
Workbook Pages 1-160, 1-161
Treatment of Bleeding Due to Target-Specific Oral Anticoagulants Reversal of TSOACs is challenging Activated charcoal: ingestion < 2 hours Dabigatran: hemodialysis Proposed reversal with rFVIIa and PCCs is
variable in small studies Reversal agents in development
Rivaroxaban: r-Antidote (PRT064445), binds Xa site Dabigatran: aDabi-Fab, monoclonal antibody TSOACs: PER977, binds Xa and IIa
Workbook Page 1-160
Patient Case #7
67-year-old male shot in buttocks deer hunting 500-mL LR in transfer BP: 92/48 mm Hg HR: 118 beats/minute RR: 25 breaths/minute Temperature: 35°C Drowsy and incoherent following morphine 2 mg Which is the best resuscitative strategy?
Workbook Page 1-162
A. LR 1000 mL/hour to target UOP > 30 mL/hour and SBP > 100 mm Hg
B. Transfuse 2 units PRBCs, 1L LR bolus to target UOP > 1 mL/kg/hour
C. Transfuse 2 units PRBCs, 2 units FFP, and 1L bolus of LR to target normal mentation
D. LR 1L/hour to maintain UOP > 30 mL/hour, SBP > 90 mm Hg, and normal mentation
Patient Case #7
Workbook Page 1-162
Obstructive Shock Extra-cardiac obstruction to flow (↓CO) Impaired diastolic filling Examples include cardiac tamponade, tension
pneumothorax, and constrictive pericarditis Inhibition of venous return ↓RV preload Treatment
1. Mechanical (e.g., pericardiocentesis)2. Fluids (recommended, but may be ineffective)3. Vasopressors to maintain perfusion pressure Inotropes likely ineffective (not recommended)
Workbook Pages 1-162, 1-163
Impaired Systolic Contraction Examples include
pulmonary embolism (PE) and acute on chronic pulmonary hypertension (PH)
Ventricular afterload acutely increased
Right ventricular (RV) pressure overload
Reduced cardiac output
Systemic hypotension
Reduced RV tissue perfusion
RV free wall ischemia
Reduced RV free wall contractility
Greyson CR. Crit Care Med 2008;36[Suppl.]:S57-S65Workbook Page 1-162
Fluids PH: Most require diuresis, not fluid administration PE: Recommended, but avoid RV volume overload
Vasopressors recommended (typically NE) Inotropes likely more effective in PH than PE Disease-specific therapies PH: Aerosolized pulmonary vasodilators (iNO, aEPO) PE: Thrombolytics or embolectomy
Impaired Systolic Contraction -Treatment
Workbook Pages 1-162, 1-163
Thrombolytics for PE No mortality benefit in unselected patients Recommended for massive PE (hypotension) Controversial for submassive PE (RV
dysfunction or myocardial necrosis [or both])
Workbook Page 1-163, 1-164 Jaff MR, et al. Circulation 2011;123:1788-1830Meyer G, et al. N Engl J Med 2014;370:1402-11
2.6%
6.3%
2.4%
5.6%1.2% 0.2%0%
4%
8%
7-Day Death orDecompensation
Major ExtracranialBleeding
Stroke
TenecteplasePlacebo
n=1005p=0.02 p<0.001
p=0.003
Risk/benefit determined on case-by-case basis
Patient Case # 8
48 y/o female (weight 75 kg) with subsegmental PE Echo: No RV dilation or dysfunction HR 118, BP 98/62, TnT 0.06 ng/mL, BNP 60 pg/mL In addition to parenteral anticoagulation, which is
best for the patient?A. Tenecteplase 40mg bolus
B. Alteplase 100mg infusion over 2 hours
C. Alteplase 50mg bolus
D. No thrombolytic therapy
Workbook Page 1-166
Vasodilatory and Distributive Shock Hypoperfusion due to decreased SVR Most common shock type Septic shock most frequent cause Neurogenic shock and immune-mediated
(“anaphylactic”) shock are other causes Failure of vascular smooth muscle constriction Neurogenic shock: decrease in sympathetic outflow
from the CNS Immune-mediated shock: IgE-mediated mast cell or
basophil degranulation Vasodilation leads to decreased preload
Workbook Page 1-166 Landry DW, Oliver JA. N Engl J Med 2001;345:588-95
Address underlying cause Fluids Crystalloids initial fluid choice
Vasopressors Neurogenic: commonly norepinephrine first-line
Higher MAP target (85 mm Hg) in acute SCI Immune-mediated: epinephrine conventionally
Adjunctive agents (e.g., steroids) controversial
Vasodilatory and Distributive Shock, Treatment
Workbook Pages 1-167, 1-168 J Spinal Cord Med 2008;31:403-79Sampson HA, et al. J Allergy Clin Immunol 2005;115:584-91