Sedation: Choosing the Right Drug for the Right Patient

Sedation:

Choosing the Right Drug

for the Right Patient

Kimberly Varney Gill, Pharm.D., BCPS VCU Health System

VCU School of Pharmacy

Objectives

1. Discuss a general sedation strategy

2. Review commonly used sedatives

3. Present individual uses for specific sedative

medications

Sedation Strategy

Sedation Strategy

New Goal:

Awake, but Comfortable

I. Medication Reconciliation and Patient History

1. Restart home psych / pain medications if not contraindicated, to prevent drug withdrawal

2. Identify specific disease states which direct toward a particular class of sedatives. (pain indication? EtOH abuse? Opiate / bzd abuse?)

Sedation Strategy

New Goal:

Awake, but Comfortable

I. Medication Reconciliation and Patient History

1. Restart home psych / pain medications if not contraindicated, to prevent drug withdrawal

2. Identify specific disease states which direct toward a particular class of sedatives. (pain indication? EtOH abuse? Underlying psych disorder?)

II. Drug or Delivery Method

1. Analgesia 1st_{: “A1” method} 1,2

2. “PRN only” method 4

3. Patient Controlled Sedation (PCS) / PCA method 3

4. Shorter acting infusion agents: propofol, dexmedetomidine 5. Anti-psychotics over benzos for hyperactive delirium

1 Breen D, Wilmer A, Bodenham A, et al. Crit Care 2004;8:R21-30. 2 SCCM Sedation and Analgesia Guidelines 2002. 3 Chian LL et al. Chest. 2010 Nov;138(5):1045-53 4 Strom T et al. Lancet 2010. Feb 6;375(9713):475-80

Sedation Strategy

III. Monitoring and Mobilization

1. RASS to lighter goal: -1 to -2 may be more appropriate. REASSESS daily1

2. Daily interruption in appropriate pts 3. Delirium assessment

4. Daily mobilization protocol2

1 _{Patel SB, Kress JP. Sedation and Analgesia in the mechanically ventilated patient. Am J Resp and}

Crit Care Med Oct 20, 2011.

2 _{Schweickert WD et al. . Early physical and occupational therapy in critically ill patients. Lancet}

Sedation Strategy

III. Monitoring and Mobilization

1. RASS to lighter goal: -1 to -2 may be more appropriate. REASSESS daily

2. Daily interruption in appropriate pts 3. Delirium assessment

4. Daily mobilization protocol

IV. Weaning to Extubate

1. Pairing daily interruption with spontaneous breathing trial (ABC Trial)1

2. Observe for withdrawal from pre-hosp exposure, or ICU exposure to continuous sedative meds of >/= 3 days

3. If withdrawal: transition to longer acting agents (oral route).

PLAN FOR TAPERING OFF POST-ICU should be well documented to avoid inadvertent long-term / post hospital exposure to

anxiolytics/antipsychotics/opiates. 1 _{Girard T et al. ABC Trial. Lancet 2008;371:126-34.}

Analgesia Before Sedation

Patients experience pain in the ICU

– Endotracheal tube suctioning

– Repositioning

– Insertion of lines and tubes

– Desired outcomes have not been achieved; report of pain

(50-65%) same now as data from 17 yrs ago

Analgesia First

Characteristic Remifentanil

(n = 57) (n = 48) Control P

Number (%) of pts extubated 29 (51%) 16 (33%) Hours from start of study drugs to weaning

- (Difference)

83.0 (- 15.0)

98.0 0.523

Hours from start of study drugs to extubation - (Difference)

94.0

(- 53.5) 147.5 0.033 Hours from weaning time until extubation

- (Difference)

0.9

(- 26.6) 27.5 <0.001

Hours from start of study drugs until ICU discharge

- (Difference)

187.3 (- 22.5)

209.8 0.326

1 Des Breen et al. Decreased duration of mechanical ventilation when comparing analgesia-based sedation with standard hypnotic-based sedation. Critical Care Dec 2005 9:R200 -210

Remifentanyl-based vs Standard hypnotic-based sedation in

Benzodiazepine

a

Infusions

Appropriate Use

Use Caution or Avoid Use

Status Epilepticus

Older population (>65 yrs)

Alcohol Withdrawal

Treatment of delirium

Patients < 65 yrs

Hepatic failure, cirrhosis

Chronic outpt benzo use

End-stage renal failure

No hepatic failure

No end stage renal failure

A _{midazolam and lorazepam} b _{avoid infusion or prn use}

Propofol

Mechanism of Action

- sedative and hypnotic properties; no analgesic properties - GABA_A receptor agonist; NMDA receptor blockade

- Highly lipophilic with high Vd

Short acting agent

– Adult Dose: 5-100 mcg/kg/min

– Onset ~ 30 seconds; Duration ~ 3-10 minutes (may be prolonged in obese, elderly)

– Titration fast, ~ every 5-10 minutes

Monitoring

–  BP,  HR,  RR

– Triglycerides > 500 mg/dL (~ 10 %)

– 10% Lipid emulsion: 1.1 kcal/ml; the calories count – PRIS

Propofol

Use has steadily increased over last 10 years.

•

IV infusion sedation almost doubled 2001-2007: 39% to 68%

•

Attributed to increased use of propofol 2001-2007: 31% to 55%

Meta-analysis of Propofol from 1966-2007

•

16 controlled studies, 1386 patients on mechanical ventilation

1 Wunsch, H ET all. Project IMPACT data. Crit Care Med Dec 2009;3031-39.

2 Ho KM, Ng, KY. Propofol Meta-Analysis. Int Care Med Nov 2008;34(11):1969-79.

Endpoint

Propofol vs Control

Mortality

No difference

Length of ICU stay (med-long term

sedation

Decreased LOS vs sedatives;

No diff LOS compared to midazolam

Duration of mech ventilation (4 studies)

Shorter duration vs control

PRIS

36 yo female adm to MICU for severe sepsis/resp failure

requiring intubation, secondary to strep pneumoniae. PMH

included substance abuse, HIV, and hep C, schizoaffective,

and DM. Abx, fluids, and pressors were started. Sedation

included propofol 30 mcg/kg/min, and midazolam infusion.

Renal and hepatic lab values WNL.

Day 7

• Morbilliform rash on neck, shoulders, chest

• AST 115 ALT 536 Amylase 294 Lipase 608

CK 36,327 TGs 1005

Sinus tach

• Abd CT showed hepatomegaly w/ fatty infiltration of liver

PRIS

Total dose of propofol over 8 days 35,200 mg

(avg 49 mcg/kg/min).

Propofol stopped and phenobarb was added.

Laboratory test values normalized, and rash and

tachycardia resoved within 72 hrs of propofol

discontinuation.

PRIS

– High mortality, must stop infusion

– Lipemic serum may be an indicator

– Rhabdomyolysis, heart failure, renal failure, liver failure, high

triglycerides, metabolic acidosis, lactic acidosis, arrhythmias

– Dose and time related (> 50 mcg/kg/min), for ≥ 48hrs…

Labs: lactate, TGs, CK, SCr, LFTs, pancreatic enzymes, ECG,

echocardiogram

Propofol Place in Therapy

•

Along with an opiate, patients on mechanical ventilation (out to

7-10 days..)

•

Effective to prevent alcohol withdrawal

•

Preferred over midazolam in patients with renal failure, hepatic

failure

•

If on a longer acting infusion, can consider switching to propofol

as pt gets closer to extubation (shorter acting)

•

Monitor for hypertriglyceridemia, PRIS

Dexmedetomidine (Precedex

®

)

Central alpha

agonist



Sedation / Analgesia (



opiate requirements

~ 25-30%)





HR and



BP



NO effect on respiratory drive



Mimics non-REM sleep

Ann Pharmacother. 2009;43:1707-13., Acta Anaesthesiol Scand. 2008;52:289-94.

Dosing and Monitoring



Starting dose: 0.2 mcg/kg/hr – 1.4 mcg/kg/hr (optional bolus)



Titration up: every 30 mins



Titration down: every 2-4 hrs; maybe longer if on for several

days



Peak effect (steady state): ~2-4 hours if no bolus given



Monitor for bradycardia, hypotension

Dexmedetomidine for Pain

Dexmedetomidine produces antinociception via



-2

agonist

activity in the locus ceruleus, and dorsal horn in the spinal

cord.

•

decreased opiate and anesthesia requirements peri- and

post-operatively, and in the intensive care unit

N Ohtani et al. Peri-operative effects of dexmedetomidine. J Anesth Sept 2011 Tian-Zhi Guo et al. Anesthesiology 1996;84(4):873-881.

Dexmedetomidine for Pain

Palliative care:

intractable pain control and decreased

delirium at end of life

Opioid-induced hyperalgesia (OIH):

opiates in high dose and

with prolonged exposure can have pronociceptive

/antinociceptive properties

–

Unable to achieve pain control despite escalating opioid

doses

–

Dexmedetomidine provides pain control via a different

mechanism which acts synergistically with opioids.

Coyne PJ et al. Dexmedetomidine: its role for intractable pain and dosing guideline. J of Pain and Pall Care Pharmacother Dec 2010;24(4):384-386.

E Prommer. Dexmedetomidine: role in palliative care medicine. Am J Hosp P Med 2011;28(4):276-283. Belgrade M, Hall S. Dexmedetomidine for OIH. Pain Med Dec 2010;11(12):1819-1826.

Alcohol Withdrawal

1_{Muzyk AJ et al. Annals of Pharm May 2011, Vol 45:649-57.} 2_{Davis KM et al. J Biomed Sci 2000;8:7-19.} 3_{Patkar AA et al. Alcohol Alcohol 2003;38:224-31.}

Neurotransmitter Long term EtOH Removal of EtOH Targeted Drug Therapy

GABA(a)

(inh)1  GABA receptors

 inhibitory fxn leading to anxiety and seizures

Benzos, Barbs Carbamazepine Propofol Glutamate (excit)2  glutamate via NMDA receptors  excitatory function from elevated receptor

levels

Propofol

Calcium channel blockers

Norepinephrine (excit)3

 brain adrenergic output

 noradren levels to above pre-EtOH levels

(early in w/dr)

Clonidine Dexmedetomidine

Alcohol Withdrawal

1_{Muzyk AJ et al. Annals of Pharm May 2011, Vol 45:649-57.} 2_{Davis KM et al. J Biomed Sci 2000;8:7-19.} 3_{Patkar AA et al. Alcohol Alcohol 2003;38:224-31.}

Neurotransmitter Long term EtOH Removal of EtOH Targeted Drug Therapy

GABA(a)

(inh)1  GABA receptors

 inhibitory fxn leading to anxiety and seizures

Benzos, Barbs Carbamazepine Propofol Glutamate (excit)2  glutamate via NMDA receptors  excitatory function from elevated receptor

levels

Propofol

Calcium channel blockers

Norepinephrine (excit)3

 brain adrenergic output

 noradren levels to

above pre-EtOH levels

(early in w/dr)

Clonidine Dexmedetomidine

Dexmedetomidine in Alcohol

Withdrawal

30 year old male hx of chronic alcohol abuse admitted for AMS

and agitation. Last EtOH intake was 24 hrs previous. Pt

went into withdrawal on hosp d 2.

– Lorazepam IM bolus, midazolam gtt titrated to 12 mg/hr

Pt remained altered with episodes of severe agitation,

tremors.

– Dexmed initiated at 0.2 mcg/kg/hr titrated to 0.7 mcg/kg/hr. Total of 39 hrs of dexmed.

– Midazolam titrated down after 3 hrs of dexmed; mental status, tremors/agitation improved. Midaz stopped after 14 hrs of overlap with dexmed.

– Patient on oxazepam by day 3; discharged home day 5.

Dexmed

mcg/kg/hr

Patient had been on high dose dexmed for roughly 7 days. Dexmed was titrated off over 4 ½ hrs.

Lorazepam also decreased slightly (from q4h to q6). Next morning 10 am, pt having rigors, tachy 130s, hypertsn 160s, extreme anxiety. Gave 2 mg midazolam, HR decreased to 110s; gave dexmed full bolus, HR to 70s and SBP to 105/65. Patient calm and sedated.

Total dexmed infusion time was 32 days; pt eventually started on PO phenobarb and clonidine to wean off infusion medications. Dexmed was not successfully weaned off until clonidine was initiated.

Dexmedetomidine

Place in Therapy



Short-medium term sedation and analgesia



Pain requiring increased opiate dosing with concerns for

respiratory depression; intractable pain, palliative care



Substance abuse withdrawal w/ benzo, barb



Decrease benzodiazepine use*



Cost: ~60 $ per bag (~ 350 - 750 $ / day)

Concerns

 Still FDA approved for only 24 hours

 Case reports of severe withdrawal when weaned too

quickly from long term use (>7 days)

 Titration down can be tricky when on drug for several days.

? Consider PO clonidine if withdrawal occurs.

Delirium in the ICU

Cause(s)

of delirium is usually multifactorial, therefore

needing a multicomponent approach to targeting

treatment of delirium.

Expected

based on disease state(s)? Correctable

disease-related cause? Drug disease-related?

– Attempt to correct underlying pathophysiology and/or removing medications that may be causing delirium

DRUGS

causing delirium and/or altered mental status

– Benzodiazepines, opiates, propofol, dexmedetomidine, antipsychotics

Delirium

* Non-pharmacologic therapy

• “Normalizing” ICU atmosphere: sleep, light, alarms, family

visitation

• Discontinue medications contributing to delirium

Antipsychotics

• May be beneficial for hyperactive delirium

• Haloperidol, quetiapine, olanzapine, ziprasidone have been

published with some efficacy

• Adverse effects: sedation, QTc prolongation, EPS

Medication reconciliation

• If treatment drugs are started, need to plan for taper or

discontinue before ICU or hospital discharge**

Summary

• Think through sedation strategy on a case

by case basis.

• Use individual drug characteristics to base

decision.

PRN method study, Lancet 2010

Outcome data No sedation (n=55) Sedation (n=58) p value

Days w/o MV 13·8 (11·0) 9·6 (10·0) 0·0191*†

Length of stay (days)

Intensive care unit 13·1 (5·7) 22·8 (11·7)

0·0316*§

Hospital 34 (17–65) 58 (33–85) 0·0039*§¶

Mortality

Intensive care unit 12 (22%) 22 (38%) 0·06

Hospital 20 (36%) 27 (47%) 0·27

Drug doses (mg/kg)‖

Propofol (per h of infusion)** _{0 (0–0·515) 0·773 (0·154–1·648) 0·0001}

Midazolam (per h of infusion) 0 (0–0) 0·0034 (0–0·0240) <0·0001

Morphine (per h of MV) 0·0048 (0·0014–0·0111) 0·0045 (0·0020–0·0064) 0·39

Haloperidol (per day of MV) 0 (0–0·0145) 0 (0–0) 0·0140

Tracheostomy 16 (29%) 17 (29%) 0·98