The Impact of Sedativeson Sleep in the ICU

Kyle A. Amelung, Pharm.D. Candidate

Barnes-Jewish Hospital, SICU

Preceptor: Lee P. Skrupky, Pharm.D., BCPS

November 9, 2011

Patient CaseCC: Acute chest pain and back pain

HPI: LZ is a 78yo WM with a history of a type A ascending aortic dissection s/p repair in 2006 with a chronic residual 5cm aortic dissection which was being followed by his physician. LZ presented on 10/21/11 from an OSH with sudden, severe, non-radiating chest and back pain. A chest X-ray and MRI revealed no evidence of rupture. While in the MRI scanner, LZ suddenly experienced a dramatic increase in pain and hypertension, followed by vomiting and hypotension. An emergent CT scan with contrast showed evidence of a type B aneurysm rupture with a left hemothorax and LZ subsequently underwent an emergent TEVAR with complication and was then transferred to the SICU.

Surgical: Type A ascending aortic

dissection s/p repair (2006) L nephrectomy (2006) Cholecystectomy

Past History

Medical: Ischemic Stroke (10/3/11) Polycythemia/Thrombocytosis Diastolic Heart Failure CKD Hypertension Hyperlipidemia Hypokalemia Depression Glaucoma Skin Cancer Bladder Cancer Renal Cell Carcinoma

Social : [-] Tobacco (60 PY history) [-] EtOH [-] Illicit Drugs Retired Banker Lives with wife

Allergies: NKDA

Lisinopril 10mg PO daily for HTN/CKD Doxazosin 4mg PO HS for HTN Metoprolol tartrate (IR) 25mg BID for HTN Furosemide 80mg PO qAM + 40mg qPM for HTN Atorvastatin 20mg PO daily for HLD Escitalopram 10mg PO daily for mood Brimonidine 0.1% 1 gtt OU daily for glaucoma Latanoprost 0.005% 1 gtt OU HS for glaucoma Aspirin 81mg PO daily for CV prophylaxis Vitamin D 50000 IU PO weekly for supplement KCl 20mEq PO BID for supplement Docusate 100mg PO daily PRN for constipation

Home Medications

Course of ICU Stay

10/21Tx to SICU on NE 36, fentanyl, 11 midazolam, and sodium bicarbonate 20.8 198Perioperative cefazolin 33.3SCVO2 74.5%Lactate 8.6Vasopressin 0.04, Phenylephrine 15

10/22Chest tube placed, ~1500ml of bloody fluid drainedMoving all extremities, not following commandsNE at 12Lactate 5.6Troponin 0.27MV with volume control at 18 / 580 / 60% / 5; Failed BESTLipid Panel: Cholesterol 62, TG 108, LDL 22, HDL 18,

Course of ICU Stay

10/23~300ml out of chest tubeLactate 1.4Midazolam to 0, then back on later in the eveningPhenylephrine 5MV at 18 / 580 / 40% / 7.5WBC 14, Tmax 38.3oC; Blood [-] x2Home glaucoma medications added

10/24~110ml out of chest tubeMidazolam 0.5, fentanyl 50CAM-ICU [+]Vasopressors weaned to 0; home antihypertensives addedMV at 18 / 580 / 40% / 5; Failed BESTHgbA1c 6.1%WBC 12.2, Tmax 38.4oC; Urine, Tracheal Aspirate [-]; UA WNLTTE - Inferior-posterior hypokinesis; LVEF 40-45%

Course of ICU Stay

10/25 Extubated 6L NC K at 3.1, repleted Chest tube to water seal Tube feeds at goal Midazolam and fentanyl discontinued Brief AFib noted Periods of delirium and agitation at night WBC 10, Tmax 38oC

10/26 Eszopiclone 2mg HS ordered for sleep hygiene WBC 11.5, Tmax 37.4oC

CK 1347 ECG - QTc 461 PT 15.8, INR 1.21

Course of ICU Stay

10/27 Eszopiclone increased to 3mg CAM-ICU [+] Cardiology medications titrated 3L NC WBC 12.9, Tmax 37.2oC

10/28 Mag (2.3) and Ca (8.2) supplementation for ~3 beats of PVCs Chest X-ray – mild, but increasing atelectasis CAM-ICU [+] 2L NC

10/28 Physical Exam

Tmax: 37.2oC

HR: 69-96 bpm MAP: 76-102 RR: 25-30 bpm O2sat: 96-100% on 2L NC

 Neuro:Cardiac:Pulmonary:Abdomen:

Other:

Ht: 67” Wt: 70 kg (IBW: 66.1 kg)

Net Fluid Balance: -1900 ml 24-hour UO: 2500 ml

RASS 0, CAM-ICU [+], AAO x2RRRCTAB; Chest tube placedSoft, non-tender without masses;Sutured RLQ and LLQ incisionsDecreased vision

10/28 Laboratory Values

151 111 38

3.3 28 2.14

13.6 238 9.5 23.8

Ca: 8.2Mg: 2.3Phos: 3.4

146

10/28 Inpatient Medications

Scheduled:

*Aspirin 325mg PO daily for CV prophylaxis

*Lisinopril 10mg PO BID for HTN/CKD

Hydralazine 25mg PO QID for HTN

Amlodipine 10mg PO daily for HTN

*Metoprolol tartrate 25mg PO QID for HTN

*Furosemide 60mg IV BID for edema

*Atorvastatin 20mg PO daily for HLD

*Escitalopram 10mg PO daily for mood

*Brimonidine 0.1% 1 gtt OU daily for glaucoma

*Latanoprost 0.005% 1 gtt OU HS for glaucoma

*KCl 40mEq PO daily for replacement

Heparin 5000 units SQ TID for DVT prophylaxis

Eszopiclone 3mg PO HS for sleep hygiene *Home Medication

PRN:Insulin lispro SSGlucose/glucagon IV/IM/POMagnesium, Potassium IV*Docusate 100mg PO BID

Relevant Past Meds:Fentanyl 10/21-25Midazolam 10/21-25

ICU Problem List1. Type B Aortic Aneurysm Rupture

S/p repair and currently controlled. Heparin for anticoagulant therapy which is appropriate for this vascular surgery patient.

Monitor CBC daily for decreasing platelets (HIT), decreasing H/H, and other signs/symptoms of bleeding. PTT should also be measured intermittently to monitor proper anticoagulation.

2. Hemodynamic Instability/Vasodilatory Shock Patient was on vasopressor therapy which was needed for hypotension control

s/p surgery. No evidence of infection rules out sepsis. Vasopressin 0.04 was appropriately added to decrease ectopy of high dose NE. Currently, he is being followed by his home cardiologist who has placed him on an ACE-I, DHP-CCB, BB, and vasodilator which are appropriate for his chronic hypertensive condition.

Diastolic HF plays a role in this problem and is being monitored, previous EF 40-45%. Fluid administration being monitored.

Monitoring of his BP and HR are essential while s/p vascular surgery. BMP should be monitored to watch for hyperkalemia, increases in BUN (ACE-I) and peripheral edema (CCB).

ICU Problem List

3. Delirium/Sleep Hygiene Patient is experiencing abnormalities in sleep hygiene and

reports not being able to sleep at night. CAM-ICU [+]. Signs of delirium such as not following through on thoughts or knowing where he is. Etiology includes past BZD use, critical illness, and ICU conditions.

Eszopiclone added for sleep hygiene (and dose increased) which is appropriate to maintain a healthy sleep cycle and promote recovery.

Monitor sleep habits and CAM-ICU twice a day.

4. Respiratory Failure Patient intubated for 4 days s/p surgery. Recent ABGs not

drawn, but patient is now extubated and is saturating adequately on 2L NC.

Monitor oxygen saturation, RR, and dyspnea.

ICU Problem List5. Electrolyte Disturbances

Patient has chronic hypokalemia for which he takes a KCl supplement, which is appropriate. This medication is being continued for his low inpatient K levels. LZ also currently has hypernatremia which is seen as a free water deficit of about 3.3 liters. Crystalloids and FW flushes should be continued. BMP should be monitored daily.

6. Acute Kidney Injury + CKD Patient has underlying Stage 3/4 CKD, baseline SCr of 1.8-2.0. Treated,

in part, with an ACE-I, which is appropriate. Current AKI possibly due to hypoperfusion 2/2 vasodilator shock and/or imaging contrast. Bicarb drip started appropriately and fluids/vasopressors administered as above. Monitor SCr, BUN, urine output daily.

7. Hyperlipidemia Currently treated with an HMG-CoA reductase inhibitor (statin) which is

appropriate. Dose should be decreased from 20mg to 10mg, as recent lipid panel should low HDL and LDL much lower than goal of <70. Monitor FLP in 3 months, then every 6 months.

ICU Problem List

8. Depression Diagnosed as an outpatient. Correctly treated with an SSRI.

Monitor mood.

9. Glaucoma Treated as an outpatient with topical medications to decrease

pressure, which are appropriate. Current decrease in vision could be due to recent vasopressor administration. Monitor for worsening vision. If needed, consider an ophthalmology consult.

10. Health Maintenance/Prophylaxis Aspirin for stoke/CV prophylaxis is appropriate s/p stroke. Administer influenza vaccine at discharge.

The Impact of Sedativeson Sleep in the ICU

Kyle A. Amelung, Pharm.D. Candidate

Barnes-Jewish Hospital, SICU

Preceptor: Lee P. Skrupky, Pharm.D., BCPS

November 9, 2011

Explain the normal sleep cycle and changes in critical illness

Describe the barriers to healthy sleep regimens for patients in an ICU, focusing on sedative use

Understand clinical outcomes after sleep deprivation

Discuss the effects of sedatives on the natural sleep pattern

Objectives

Sleep CycleSleep Stage

Description %

Stage 1 (N1)

Light sleep 2-5%

Stage 2 (N2)

Light sleep 45-55%

SWS (N3)

Deep sleep; restoration; anabolic; promoted by GABA

15-20%

REM

Greatest cardiac and respiratory variability; catabolic

20-25%

Hardin KA. Sleep in the ICU: potential mechanismsand clinical implications. Chest. 2009 Jul;136(1):284-94.

Kamdar et al. Sleep Deprivation in Critical Illness: Its Role in Physical and Psychological Recovery. J Intensive Care Med. 2011 Feb 7. Web.

Defined: A periodic, reversible state of cognitive and sensory disengagement from the external environment

Differences in ICU Patients

Hardin KA. Sleep in the ICU: potential mechanismsand clinical implications. Chest. 2009 Jul;136(1):284-94.

Parameter Changes

SWS Decreased

REMDecreased Adaptive/Protective mechanism?

Total HoursMay be equivalent, but distributed across the 24h day

REM Rebound May affect critically ill patients more

NeedPatients with acute illness require more total sleep time for recovery

Kamdar et al. Sleep Deprivation in Critical Illness: Its Role in Physical and Psychological Recovery. J Intensive Care Med. 2011 Feb 7. Web.

All possibly elevated during times of critical illness.

Clinical Effects of Sleep Deprivation

Salas RE and CE Gamaldo. Adverse effects of sleep deprivationin the ICU. Crit Care Clin. 2008 Jul;24(3):461-76, v-vi.

• Increased blood pressure

• Mood changes

• Elevated metabolic rate

• Immune system disruption

• Hyperalgesia

• Decreased mentation

Relation with Delirium

Weinhouse et al. Bench-to-bedside review: delirium in ICU patients -importance of sleep deprivation. Crit Care. 2009;13(6):234.

Barriers to Sleep in the ICU

Salas RE and CE Gamaldo. Adverse effects of sleep deprivationin the ICU. Crit Care Clin. 2008 Jul;24(3):461-76, v-vi.

60% of ICU patients Poor sleep or sleep deprivationStaff estimations of sleep quality/quantity are inaccurate ~25% of the time

•Baseline sleep insufficiency/disorder

•Medical Illness

•Pain

•Environmental factors

•Staff-patient interactions

•Mechanical ventilation

•Medications

•Medication withdrawal

The sedative-sleep relationship is complex The functions of sleep are unknown Sleep and sedation have some similarities, but

many differences.

Overall, sedatives may have both [+] and [-] effects on patients’ sleep and ICU quality of life.

Sedatives

First line recommendation in sedation guidelines, but only a limited number of studies on their effects on sleep.

Benzodiazepines – Midazolam, Lorazepam

[+] Decrease in sleep latency and awakenings, increase sleep time efficiency

[-] Increase Stage II NREM, decreased SWS and REM

GABAA Agonists

Weinhouse GL and PL Watson. Sedation and sleep disturbancesin the ICU. Crit Care Clin. 2009 Jul;25(3):539-49, ix.

MOA – activate GABAA at the hypothalamus, enhancing the CNS inhibitory system psychomotor depression

Propofol

No definite effect on REM [+] The normal homeostatic control of sleep may occur

during use; Decrease in sleep latency and increase in total sleep time

[-] SWS suppression

Positive animal data

GABAA Agonists

Weinhouse GL and PL Watson. Sedation and sleep disturbancesin the ICU. Crit Care Clin. 2009 Jul;25(3):539-49, ix.

MOA – also binds to GABAA but at a different site, and allosterically enhances receptor activity+/- Endocannabinoid receptors?

Kamdar et al. Sleep Deprivation in Critical Illness: Its Role in Physical and Psychological Recovery. J Intensive Care Med. 2011 Feb 7. Web.

Treggiari-Venzi et al., 1996

Overnight sedation with midazolam or propofol in the ICU: effects on sleep quality, anxiety and depression

Treggiari-Venzi M, Borgeat A, Fuchs-Buder T, Gachoud JP, Suter PM. Intensive Care Med. 1996 Nov;22(11):1186-90.

Design Open, comparative prospective, randomized study in one SICU

Inclusions Exclusions

Trauma or elective orthopedic, thoracic or abdominal surgery

Long term sedative or psychotropic medication use

Expected ICU stay 5+ days Alcohol abuse

Non-intubated Neurologic disorder, head trauma

Treggiari-Venzi et al., 1996

Methods: Bolus + continuous gtt from 2200 to 0600 for 5 consecutive nights, Infusion adjusted to sedation level of Ramsay 3 Morphine to all patients No patients received other BZDs or psychotropic medications Hospital Anxiety and Depression (HAD) Scale used 6h post-infusion

Patient Demographics:

Midazolam (n=13) Propofol (n=19)

Age (years) 41 +/- 16 48 +/- 17

Weight (kg) 70.1 +/- 8.4 71.4 +/- 8.2

APACHE II 14.5 +/- 4.1 13.5 +/- 4.5

Treggiari-Venzi et al., 1996

Conclusions:(1) Sleep quality tended to improve during the study in the two groups,

but the change didn’t reach statistical significance. (2) The beneficial effects of sedation on sleep quality were

comparable for the two medications.

Limitations: Small study sample Limited length of follow up results 2/2 decrease in post-op pain? Patients were not intubated Relatively low APACHE II scores Only studied the sedatives in overnight sedation

Quality of Sleep (10 = best)

Midazolam Propofol

Day 1 6.3 +/- 3.4 6.5 +/- 3.3

Day 3 6.3 +/- 3.2 6.6 +/- 2.9

Day 5 7.2 +/- 2.9 7.2 +/- 2.3

Dexmedetomidine

[+] Increase in SWS; Decreased sleep latency; clinically, more closely resemble natural sleep than with GABAA agonists

[-] Increase in Stage II, Decrease in REM

Its role in improving sleep in the ICU is still undefined.

a2 Agonist

Weinhouse GL and PL Watson. Sedation and sleep disturbancesin the ICU. Crit Care Clin. 2009 Jul;25(3):539-49, ix.

MOA – acts centrally at the locus coeruleus to agonize a2 receptors G-proteins and second messengers inhibition of AC and decrease in cAMP hyperpolarization suppression of neuronal firing and decreased NE release

Kamdar et al. Sleep Deprivation in Critical Illness: Its Role in Physical and Psychological Recovery. J Intensive Care Med. 2011 Feb 7. Web.

Corbett et al., 2005

Dexmedetomidine does not improve patient satisfaction when compared with propofol during mechanical ventilation.

Corbett SM, Rebuck JA, Greene CM, Callas PW, Neale BW, Healey MA, Leavitt BJ. Crit Care Med. 2005 May;33(5):940-5.

Design Prospective, randomized study with questionnaire administration

Inclusions Exclusions

Non-emergent CABG patients requiring post-op MV

Systolic BP <90 or HR <40 before administration

Expected MV length <24 hours CrCl <30 ml/min, AST >183, or ALT >287

Need for neuromuscular blockade or epidural

Obesity

Alcohol or drug abuse or neurologic impairment

Corbett et al., 2005

Similar in all reported characteristics (P >0.05):

Sex Baseline SCr Alice at Discharge

Age Morphine and midazolam requirements

Weight SBP, MAP, HR, and CVP

Length of anesthesia, surgery, MV, and ICU stay

Methods: All patients underwent induction with propofol Post-bypass, patients were randomized to dexmedetomidine

bolus+gtt or propofol bolus+gtt and titrated to Ramsay 5 for two hours, then Ramsay 3-4 (obtained q2 hours)

Questionnaire: Administered 24+ hours after extubation. Modified Hewitt (1-10 scale), validated pre-study by interviewing 10

random CABG patients after extubation Consistent, understood Same investigator participated in all questionnaire administrations

Corbett et al., 2005

Dexmedetomidine (n=43)

Propofol (n=46)

How easy was it to sleep? 3.8 (1.0 – 5.3) 3.0 (1.0 – 5.3) P = 0.430

How much did difficulty resting or sleeping upset you?

5.0 (1.0 - 7.8) 2.0 (1.0 - 5.0) P = 0.051

Median (intraquartile range)

Conclusions: Authors Propofol resulted in a more comfortable patient

experience during MV with fewer sleep difficulties.

Personal Many unaccounted for factors probably played a role; short MV possibly makes external validity diminish

1=best; 10=worst

Typicals (1st Gen.) – Haloperidol

[+] Increased total sleep time and possibly SWS [-] Increased sleep latency; Increased Stage II; ADRs

Atypicals (2nd Gen.) – Olanzapine, Quetiapine

Similar to haloperidol, but with less ADRs [-] At best, 30% sedation rate

Very limited data

DA-5HT2 Antagonists

MOA – 5HT2A >> DA antagonist;sedative effects due to H1 antagonism

MOA – 5HT2A, 5HT2C, DA antagonist; however, sedative effects due to H1 antagonism

Kamdar et al. Sleep Deprivation in Critical Illness: Its Role in Physical and Psychological Recovery. J Intensive Care Med. 2011 Feb 7. Web.

“Z-drugs” – Eszopiclone, Zolpidem

[+] Decreased latency [-] Decreased REM, ADRs

GABAA Agonists

Weinhouse GL and PL Watson. Sedation and sleep disturbancesin the ICU. Crit Care Clin. 2009 Jul;25(3):539-49, ix.

MOA – Unknown completely, but thought to involve GABAA-receptor complexes at binding domains located close to the BZD binding site (a1). While BZDs, non-selectively bind to and activate all BZD subtypes, these medications are thought to activate a smaller number of specific subtypes.

Winsky-Sommerer R. Role of GABAA receptors in the physiology and pharmacology of sleep. Eur J Neurosci. 2009 May;29(9):1779-94.

Patient Case Revisited

10/27: Eszopiclone increased to 3mg

10/26: Eszopiclone 2mg given for sleep

10/25: Midazolam discontinued and patient extubated; Periods of delirium and agitation at night; CAM-ICU [+]

10/21: Midazolam began for sedation

• Sedative use in the ICU is both a cause and potential treatment for sleep disruption.

• Sleep in the ICU should first be allowed to occur naturally by controlling pain and environmental factors.

• There has never been a sedation algorithm studied specifically for its effects on sleep.

• Guideline Recommendations: “Sleep promotion should include optimization of the environment and nonpharmacologic methods to promote relaxation with adjunctive use of hypnotics.” (B)

Summary

Weinhouse GL and PL Watson. Sedation and sleep disturbancesin the ICU. Crit Care Clin. 2009 Jul;25(3):539-49, ix.

Jacobi et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002 Jan;30(1):119-41.

Proposed Algorithm forOptimal Sleep in the ICU

Z-Drug

Does patient have an underlying sleep disorder?

Home medication?

Has patient been napping during the day?

Have barriers to sleep been minimized?

Pain Environmental Staff Interactions

Mechanical Ventilation Medications

The Impact of Sedativeson Sleep in the ICU

Kyle A. Amelung, Pharm.D. Candidate

Barnes-Jewish Hospital, SICU

Preceptor: Lee P. Skrupky, Pharm.D., BCPS

November 9, 2011