November 2011

1. The Impact of Sedatives
on Sleep in the ICU
Kyle A. Amelung, Pharm.D. Candidate
Barnes-Jewish Hospital, SICU
Preceptor: Lee P. Skrupky, Pharm.D., BCPS
November 9, 2011

2. Patient Case
CC: 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.

3. Past History
Medical: Surgical:
 Ischemic Stroke (10/3/11)  Type A ascending aortic
 Polycythemia/Thrombocytosis dissection s/p repair (2006)
 Diastolic Heart Failure  L nephrectomy (2006)
 CKD  Cholecystectomy
 Hypertension
 Hyperlipidemia Social :
 Hypokalemia  [-] Tobacco (60 PY history)
 Depression  [-] EtOH
 Glaucoma  [-] Illicit Drugs
 Skin Cancer  Retired Banker
 Bladder Cancer  Lives with wife
 Renal Cell Carcinoma
Allergies: NKDA

4. Home Medications
 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

5. Course of ICU Stay
10/21
 Tx to SICU on NE 36, fentanyl, 11
midazolam, and sodium bicarbonate 20.8 198
 Perioperative cefazolin 33.3
 SCVO2 74.5%
 Lactate 8.6
 Vasopressin 0.04, Phenylephrine 15
10/22
 Chest tube placed, ~1500ml of bloody fluid drained
 Moving all extremities, not following commands
 NE at 12
 Lactate 5.6
 Troponin 0.27
 MV with volume control at 18 / 580 / 60% / 5; Failed BEST
 Lipid Panel: Cholesterol 62, TG 108, LDL 22, HDL 18,

6. Course of ICU Stay
10/23
 ~300ml out of chest tube
 Lactate 1.4
 Midazolam to 0, then back on later in the evening
 Phenylephrine 5
 MV at 18 / 580 / 40% / 7.5
 WBC 14, Tmax 38.3oC; Blood [-] x2
 Home glaucoma medications added
10/24
 ~110ml out of chest tube
 Midazolam 0.5, fentanyl 50
 CAM-ICU [+]
 Vasopressors weaned to 0; home antihypertensives added
 MV at 18 / 580 / 40% / 5; Failed BEST
 HgbA1c 6.1%
 WBC 12.2, Tmax 38.4oC; Urine, Tracheal Aspirate [-]; UA WNL
 TTE - Inferior-posterior hypokinesis; LVEF 40-45%

7. 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

8. 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

9. 10/28 Physical Exam
 Tmax: 37.2oC  Ht: 67”
 HR: 69-96 bpm  Wt: 70 kg (IBW: 66.1 kg)
 MAP: 76-102
 RR: 25-30 bpm  Net Fluid Balance: -1900 ml
 O2sat: 96-100% on 2L NC  24-hour UO: 2500 ml
Neuro: RASS 0, CAM-ICU [+], AAO x2
Cardiac: RRR
Pulmonary: CTAB; Chest tube placed
Abdomen: Soft, non-tender without masses;
Sutured RLQ and LLQ incisions
Other: Decreased vision

10. 10/28 Laboratory Values
151 111 38
146
3.3 28 2.14
9.5
13.6 238
23.8
Ca: 8.2
Mg: 2.3
Phos: 3.4

11. 10/28 Inpatient Medications
Scheduled: PRN:
*Aspirin 325mg PO daily for CV prophylaxis Insulin lispro SS
*Lisinopril 10mg PO BID for HTN/CKD Glucose/glucagon IV/IM/PO
Hydralazine 25mg PO QID for HTN Magnesium, Potassium IV
*Docusate 100mg PO BID
Amlodipine 10mg PO daily for HTN
*Metoprolol tartrate 25mg PO QID for HTN Relevant Past Meds:
*Furosemide 60mg IV BID for edema Fentanyl 10/21-25
*Atorvastatin 20mg PO daily for HLD Midazolam 10/21-25
*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

12. ICU Problem List
1. 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).

13. 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.

14. ICU Problem List
5. 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.

15. 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.

16. The Impact of Sedatives
on Sleep in the ICU
Kyle A. Amelung, Pharm.D. Candidate
Barnes-Jewish Hospital, SICU
Preceptor: Lee P. Skrupky, Pharm.D., BCPS
November 9, 2011

17. Objectives
 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

18. Sleep Cycle
Sleep
Description %
Stage
Defined: A periodic, reversible
Stage 1
Light sleep 2-5% state of cognitive and sensory
(N1)
disengagement from the external
Stage 2
Light sleep 45-55% environment
(N2)
Deep sleep;
restoration;
SWS
anabolic; 15-20%
(N3)
promoted
by GABA
Greatest
cardiac and
REM respiratory 20-25%
variability;
catabolic
Kamdar et al. Sleep Deprivation in Critical Illness: Its Role in Physical Hardin KA. Sleep in the ICU: potential mechanisms
and Psychological Recovery. J Intensive Care Med. 2011 Feb 7. Web. and clinical implications. Chest. 2009 Jul;136(1):284-94.

19. Differences in ICU Patients
Parameter Changes
SWS Decreased
Decreased  Adaptive/Protective
REM
mechanism?
May be equivalent, but distributed
Total Hours
across the 24h day
REM Rebound May affect critically ill patients more
Patients with acute illness require
Need
more total sleep time for recovery
Kamdar et al. Sleep Deprivation in Critical Illness: Its Role in Physical Hardin KA. Sleep in the ICU: potential mechanisms
and Psychological Recovery. J Intensive Care Med. 2011 Feb 7. Web. and clinical implications. Chest. 2009 Jul;136(1):284-94.

20. Clinical Effects of Sleep Deprivation
• Increased blood pressure
• Mood changes
• Elevated metabolic rate
All possibly
elevated during
• Immune system disruption times of critical
illness.
• Hyperalgesia
• Decreased mentation
Salas RE and CE Gamaldo. Adverse effects of sleep deprivation
in the ICU. Crit Care Clin. 2008 Jul;24(3):461-76, v-vi.

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

22. Barriers to Sleep in the ICU
60% of ICU patients  Poor sleep or sleep deprivation
Staff 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
Salas RE and CE Gamaldo. Adverse effects of sleep deprivation
in the ICU. Crit Care Clin. 2008 Jul;24(3):461-76, v-vi.

23. Sedatives
 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.

24. GABAA Agonists
 First line recommendation in sedation guidelines, but only a
limited number of studies on their effects on sleep.
Benzodiazepines – Midazolam, Lorazepam
MOA – activate GABAA at the hypothalamus, enhancing
the CNS inhibitory system  psychomotor depression
 [+]  Decrease in sleep latency and awakenings,
increase sleep time efficiency
 [-]  Increase Stage II NREM, decreased SWS and REM
Weinhouse GL and PL Watson. Sedation and sleep disturbances
in the ICU. Crit Care Clin. 2009 Jul;25(3):539-49, ix.

25. GABAA Agonists
Propofol
MOA – also binds to GABAA but at a different site,
and allosterically enhances receptor activity
+/- Endocannabinoid receptors?
 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
Kamdar et al. Sleep Deprivation in Critical Illness: Its Role in Physical Weinhouse GL and PL Watson. Sedation and sleep disturbances
and Psychological Recovery. J Intensive Care Med. 2011 Feb 7. Web. in the ICU. Crit Care Clin. 2009 Jul;25(3):539-49, ix.

26. 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, Long term sedative or
thoracic or abdominal surgery psychotropic medication use
Expected ICU stay 5+ days Alcohol abuse
Non-intubated Neurologic disorder, head trauma

27. 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

28. Treggiari-Venzi et al., 1996
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
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

29. 2 Agonist
Dexmedetomidine
MOA – acts centrally at the locus coeruleus to agonize 2 receptors 
G-proteins and second messengers  inhibition of AC and decrease in
cAMP  hyperpolarization  suppression of neuronal firing and
decreased NE release
 [+]  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.
Kamdar et al. Sleep Deprivation in Critical Illness: Its Role in Physical Weinhouse GL and PL Watson. Sedation and sleep disturbances
and Psychological Recovery. J Intensive Care Med. 2011 Feb 7. Web. in the ICU. Crit Care Clin. 2009 Jul;25(3):539-49, ix.

30. 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 Systolic BP <90 or HR <40 before
requiring post-op MV 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

31. Corbett et al., 2005
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
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

32. Corbett et al., 2005
Dexmedetomidine Propofol
(n=43) (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 5.0 (1.0 - 7.8) 2.0 (1.0 - 5.0) P = 0.051
you?
1=best; 10=worst 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

33. DA-5HT2 Antagonists
Typicals (1st Gen.) – Haloperidol
MOA – 5HT2A, 5HT2C, DA antagonist;
however, sedative effects due to H1 antagonism
 [+]  Increased total sleep time and possibly SWS
 [-]  Increased sleep latency; Increased Stage II; ADRs
Atypicals (2nd Gen.) – Olanzapine, Quetiapine
MOA – 5HT2A >> DA antagonist;
sedative effects due to H1 antagonism
 Similar to haloperidol, but with less ADRs
 [-]  At best, 30% sedation rate
 Very limited data
Kamdar et al. Sleep Deprivation in Critical Illness: Its Role in Physical
and Psychological Recovery. J Intensive Care Med. 2011 Feb 7. Web.

34. GABAA Agonists
“Z-drugs” – Eszopiclone, Zolpidem
MOA – Unknown completely, but thought to involve GABAA-receptor
complexes at binding domains located close to the BZD binding site ( 1).
While BZDs, non-selectively bind to and activate all BZD subtypes, these
medications are thought to activate a smaller number of specific subtypes.
 [+]  Decreased latency
 [-]  Decreased REM, ADRs
Winsky-Sommerer R. Role of GABAA receptors in the physiology and Weinhouse GL and PL Watson. Sedation and sleep disturbances
pharmacology of sleep. Eur J Neurosci. 2009 May;29(9):1779-94. in the ICU. Crit Care Clin. 2009 Jul;25(3):539-49, ix.

35. Patient Case Revisited
10/21: Midazolam began for sedation
10/25: Midazolam discontinued and patient extubated;
Periods of delirium and agitation at night; CAM-ICU [+]
10/26: Eszopiclone 2mg given for sleep
10/27: Eszopiclone increased to 3mg

36. Summary
• 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)
Weinhouse GL and PL Watson. Sedation and sleep disturbances Jacobi et al. Clinical practice guidelines for the sustained use of sedatives and
in the ICU. Crit Care Clin. 2009 Jul;25(3):539-49, ix. analgesics in the critically ill adult. Crit Care Med. 2002 Jan;30(1):119-41.

37. Proposed Algorithm for
Optimal Sleep in the ICU
Have barriers to sleep been minimized?
Staff Mechanical
Pain Environmental Medications
Interactions Ventilation
Has patient been napping during the day?
Does patient have an underlying sleep disorder?
Home medication?
Z-Drug

38. The Impact of Sedatives
on Sleep in the ICU
Kyle A. Amelung, Pharm.D. Candidate
Barnes-Jewish Hospital, SICU
Preceptor: Lee P. Skrupky, Pharm.D., BCPS
November 9, 2011