Sedation And Paralysis In The MICU

James Allen, MD

 

 

Co-author: Mary Beth Shirk, Pharm.D.; Department of Pharmacy

 

I. Introduction:

A. Appropriate use of sedatives and analgesics can greatly facilitate the care of patients in the ICU by improving rest and relieving suffering.

B. Appropriate use of paralytics can greatly facilitate mechanical ventilation in these many of these patients.

C. Over-dosing of these agents or selection of an inappropriate agent can result in a prolongation of mechanical ventilation and or the ICU stay which in turn can result in thousands of dollars of extra costs to the patient.

D. Accurate knowledge of the onset of action, duration of action, side effects, monitoring, and dosing of these agents is vital to the appropriate use of them.

II. Sedatives (Society of Critical Care Medicine: "Practice Parameters For Systemic Intravenous Analgesia And Sedation For Adult Patients In The Intensive Care Unit"; September, 1995)

A. General principles:

1. use non-pharmacologic measures whenever possible:

a) establish regular sleep-wake cycles

b) minimize stimulation during sleep

c) reassure patient and provide general comfort

d) use opiates as needed for pain; sedatives are a poor substitute for analgesics when pain is the primary problem facing the patient

2. identify withdrawl symptoms which can contribute to agitation

a) narcotics

b) benzodiazapines

c) caffeine

d) nicotine

(1) nicotine patches are underutilized in the ICU

3. there are no sedation scales which have been validated for use in adults making objective assessment of the level of sedation difficult

a) bispectral EEG may be useful in the future to titrate sedation

b) the concurrent use of narcotics can enhance the effectiveness of these agents and often allow for reductions in the dose of both classes of drugs

B. Specific agents:

1. benzodiazapines:

a) general properties:

(1) provides sedation

(2) induces antegrade amnesia

(3) no analgesic properties

(4) can be reversed with flumazenil (0.3 - 0.5 mg IV)

b) specific agents:

(1) lorazepam (Ativan)

(a) general properties:

i) slow onset of action (10-20 minutes)

ii) intermediate half life (6 hours)

iii) less lipophilic than diazapam and therefore does not accumulate in tissues as much as diazepam and is less likely to exhibit prolonged sedation

iv) no active metabolites

v) elimination not affected by renal or hepatic failure

vi) price recently fell dramatically after the patent ran out and generic lorazapam became available

(b) side effects:

i) respiratory depression

(c) use:

i) good for intermittent bolus administration; can also be used as a drip - especially if prolonged sedation is anticipated

ii) usual starting dose = 2-4 mg Q 2-4 hours (can go up to 10 mg/hr)

(2) midazolam (Versed)

(a) general properties:

i) rapid onset of action (usually 2-5 minutes)

ii) relatively short half life ( < 2 hours), however, in critically ill patients, it can accumulate and result in sedation for many hours or even days after discontinuation

(b) side effects:

i) respiratory depression

ii) there is no difference between lorazepam and midazolam in terms of time to awakening after prolonged continuous IV infusion because midazolam accumulates in fat (Crit Care Med 1994; 22:1241-7)

(c) use:

i) can be used as a continuous drip but it is costly

ii) usual dose = 2 mg IV, increase dose by 2 mg every 3-5 minutes until desired level of sedation achieved

(3) diazepam (Valium)

(a) general properties:

i) peak effect seen in Å 3-5 minutes

ii) duration of action extended because of active metabolites

(b) side effects:

i) respiratory depression

ii) effects of an initial dose abate rapidly because of redistribution to peripheral tissues; sustained effect seen with repeated administration

iii) active metabolites have half lives of up to 200 hours

(c) use:

i) rarely used because of:

(1) long half life

(2) difficulty maintaining in solution for prolonged drip administration

ii) best reserved for intermittent administration when patient is anticipated to require very prolonged sedation

iii) dose = 2-5 mg Q 5-10 minutes until desired level of sedation achieved

2. propofol (Diprovan - Chest 1995;108:539-48):

a) general properties:

(1) no analgesic properties

(2) very rapid onset of action (1-2 minutes)

(3) very short half life (10-15 minutes)

b) side effects:

(1) very lipophilic; requires a dedicated central IV line

(2) respiratory depression

(3) bradycardia

(4) pain at infusion site (central lines preferred)

(5) in high doses, it can result in clinically significant hypertriglyceridemia due to the emulsifying lipids

(a) care must be taken to avoid accidental contamination of the lipid by unusual infectious organisms (NEJM 1995; 333:147-54)

i) change bottles and tubing Q 12 hours

(6) may cause a 20-30% fall in systolic blood pressure in some patients

(7) use cautiously in patients with increased intracranial pressure

c) use:

(1) only useful as a continuous infusion

(2) usual dose:

(a) 0.5 mg/kg/hr

(b) increase by 0.3-0.6 mg/kg/hr every 5 or 10 minutes

(c) usual maintenance dose = 0.5 - 3 mg/kg/hr

3. barbiturates:

a) general properties:

(1) anticonvulsants

(2) may reduce intracranial pressure in some patients

(3) cause sedation

(4) lack analgesic properties and lack amnestic properties

b) side effects:

(1) cause histamine release & depression of central vasomotor centers

(a) tachycardia

(b) hypotension

(c) myocardial suppression

(2) stimulate hepatic enzymes to degrade other drugs

(3) causes respiratory depression

(4) patients can develop tolerance to effects

c) use:

(1) rarely used for sedation purposes because of hemodynamic effects

4. etomidate:

a) general properties:

(1) analgesic and hypnotic properties

(2) minimal cardiovascular and respiratory depression

b) side effects

(1) causes adrenal suppression in as little as 1 or 2 doses

c) use:

(1) mainly for short procedures, such as intubation

(2) adrenal suppression severely limits its use in the ICU

5. ketamine:

a) general properties

(1) analgesic properties

(2) little respiratory depression

(3) intrinsic bronchodilator properties

b) side effects:

(1) associated with bad dreams ("disassociative state")

(2) increases intracranial pressure

(3) increases blood pressure

(4) excess secretions (can be blocked with pre-medication using atropine)

c) use:

(1) primarily used in conjunction with a benzodiazapine in patients with status asthmaticus in whom the bronchodilator properties can be useful

(2) also useful for temporary analgesia & sedation during brief, painful procedures such as dressing changes

(3) dose:

(a) load with 0.75 mg/kg

(b) maintenance = 0.15 mg/kg/hr

6. haloperidol:

a) general properties:

(1) lessens agitation, anxiety, aggression

(2) has no sedative effects

(3) does not depress respiratory centers

(4) onset of action usually 30-60 minutes

(5) half-life = 10-25 hours

(a) prolonged in hepatic [but not renal] failure

b) side effects:

(1) extrapyramidal symptoms (less if benzodiazapine is concurrently used)

(2) prolongation of QT interval

c) use:

(1) not FDA approved for IV use although it is usually used this way in the ICU

(2) 2-10 mg every 30 minutes until delirium controlled or maximum dose of 50-60 mg is reached

(3) use about 50-75% of loading dose every 24 hours to control delirium

7. sedative costs per day (average wholesale costs)

a) diazepam $11-44

b) lorazepam $45-69

c) midazolam $90-180

d) propofol $54-325

e) haloperidol $6-72

III. Analgesics

A. Opiods:

1. general properties:

a) provides sedation

b) no amnestic properties

c) good analgesic properties

(1) tolerance often develops after Å 3-4 days

d) can be reversed with naloxone

e) side effects:

(1) hypotension can be a problem

(a) causes:

i) vagal-induced bradycardia

ii) increased venous capacitance

iii) increased histamine release

(b) worse if the patient is hypovolemic

(2) gastric slowing can be a problem

(3) respiratory depression

(a) in non-intubated patients in the ICU, consideration should be given to continuous pulse oximetry monitoring

(4) central vagal stimulation often results in bradycardia

(5) withdrawl symptoms can occur if the drugs are used for more than 7 days; this can be avoided by tapering the drug by 25% of the original dose every 12-24 hours

2. specific agents:

a) morphine

(1) general properties:

(a) relatively slow onset of action (Å 30 minutes)

(b) half-life = 1/5 - 2 hours

i) may be prolonged in renal or hepatic failure

ii) active metabolite (morphine-6-glucuronide) can accumulate in renal failure

(2) side effects:

(a) histamine release

(b) respiratory depression

(c) active metabolites accumulate in renal failure

(3) use:

(a) this is the preferred analgesic agent in the ICU

(b) initial dose = 2-5 mg IV

(c) subsequent dose = 2-10 mg/hr

b) hydromorphone

(1) general properties:

(a) more potent than morphine

(b) more sedating than morphine

(c) safer to use in renal failure than morphine

(2) side effects:

(3) use:

(a) 1-2 mg Q 1-2 hours

c) fentanyl

(1) general properties:

(a) more potent (100 times) than morphine

(b) more rapid onset of action and longer duration of action than morphine

(c) half-life = 30-60 minutes

i) with prolonged administration, half-life can increase to 9-16 hours

ii) accumulates in patients with hepatic dysfunction

(d) less histamine release than morphine (and thus fewer cardiovascular side effects)

(e) dose usually does not require alteration in renal or hepatic failure

(2) side effects:

(a) chest wall rigidity unresponsive to mechanical ventilation but reversible with naloxone when administered by rapid IV push - avoidable when administered over 30 seconds

(3) use:

(a) preferred over morphine for analgesia when the patient is hemodynamically unstable or having bronchospasm

(b) load with 25-100 ug then 25-100 ug/hr

d) meperidine (Demerol)

(1) general properties:

(a) less respiratory depression than morphine

(2) side effects:

(a) histamine release

(b) it's metabolite (normeperidine) can accumulate with repeated dosing causing CNS excitation (apprehension, tremors, seizures)

i) accumulates more in renal failure

(3) use:

(a) no advantage over morphine for ICU sedation for most patients and excessive side effects when used long term substantially limit the usefulness of Demerol in the ICU

3. narcotic costs per day (average wholesale costs)

a) morphine $6-9

b) hydromorphone $4-15

c) fentanyl $23-69

B. Tricyclic antidepressants:

1. mainly used for neuropathic pain (eg, Guillian-Barré syndrome)

C. Non-steriodal anti-inflammatory agents

1. general properties:

a) analgesic

2. side effects:

a) anti-platelets effects

b) gastrointestinal ulceration

c) renal insufficiency

d) cover up fever

3. use:

a) rarely used in the ICU for analgesia because of undesirable side effects

b) may be occasionally useful in select patients

IV. Neuromuscular blocking agents (Society of Critical Care Medicine: "Practice Parameters For Systemic Intravenous Analgesia And Sedation For Adult Patients In The Intensive Care Unit"; September, 1995)

A. The neuromuscular junction:

1. acetylcholine is produced in nerve terminals by acetylation of choline by choline acetylase

2. nerve impulses cause release of acetylcholine

3. acetylcholine binds to nicotinic cholinergic receptors on muscle

4. depolarizing agents bind to receptor and prevent normal closure of receptor with loss of intracellular potassium

a) these agents cause fasiculations as the drug initially takes effect

5. non-depolarizing agents block acetylcholine from interacting with the receptor

a) these agents do not cause fasiculations

6. extrajunctional receptors proliferate during inactivity (trauma, immobilization, stroke, spinal cord injury, burns) and can result in massive potassium shifts out of muscle cells when channels are opened with depolarizing blockers

a) avoid succinylcholine in these settings

B. Uses:

1. facilitating intubation

2. facilitating ventilation

3. minimizing increases in intracranial pressure by coughing, suctioning, etc.

4. treating neuroleptic malignant syndrome & tetanus

C. Caution: patients are awake and not sedated by these agents

1. ALL patients receiving these drugs need concurrent use of sedatives

2. lack of sedation may be manifest as unexplained hypertension, tachycardia, or diaphoresis

3. use of a daily neuromuscular blocker holiday facilitates assessment of the adequacy of concurrent sedation

D. Types (Chest 1992; 102:1258-66):

1. depolarizing (succinylcholine):

a) general properties:

(1) onset of action = 1 minute

(2) duration of action = 5-10 minutes

b) side effects:

(1) hyperkalemia, especially in patients with:

(a) burns

(b) flaccid paralysis

(c) patients with malignant hyperthermia

(2) bradycardia

(3) increased secretions

(4) histamine release

c) use:

(1) dose: 1 mg/kg bolus

(a) should NOT be used for continuous paralysis

2. non-depolarizing (NEJM 1995; 332:1691-99):

a) advantages:

(1) hyperkalemia not a problem

b) disadvantages:

(1) usually have a slower onset of action than succinylcholine

(2) some patients can suffer from a prolonged paralysis syndrome which appears to be more common with vecuronium and more common in patients with either concurrent renal failure or concurrent corticosteroid use (Crit Care Med 1994; 22:884-93)

(a) this may be heralded by a rise in the CK and for this reason, the CK should be measured daily in patients receiving prolonged administration

(3) extra caution should be taken to insure that ventilator alarms are always on since the patient is unable to ventilate on their own and can rapidly die if there is an unrecognized ventilator malfunction

(4) patients require specialized nursing care:

(a) eye lubricant & taping lids shut to prevent corneal ulcers

(b) frequent repositioning to avoid decubitus ulcers and compression neuropathy

(c) liberal use of DVT prophylaxis

(d) frequent range of motion activities to prevent contractures

(5) peripheral nerve stimulation is recommended for all patients receiving prolonged paralysis

(a) this is performed by respiratory therapy using the "train of four" protocol

i) ulnar nerve (use lateral face if hand is edematous)

ii) patients rarely require paralysis associated with less than 2-3 twitches on nerve stimulation

iii) if there are 0 twitches, the patient is overparalyzed

(b) this is only recommended as an adjunct to clinical assessment

i) in general - use the lowest amount of an agent that provides the desired end-point (ie, facilitating ventilation); this may be associated with a full 4 twitches on train of four assessment but the true end point is the clinical assessment

(1) titrate to weakness NOT paralysis

(c) patients should be given a "neuromuscular blockade holiday" and the dose held once per day while receiving non-depolarizing blockers to insure that they are not over paralyzed

(6) these agents provide NO sedation and unless patients are concurrently given a sedative (preferably a benzodiazapine with amnestic properties) then they will be paralyzed but completely awake

(a) unexplained tachycardia in the paralyzed patient should be considered as evidence of inadequate sedation

(b) appropriate use of sedatives will generally reduce the amount of a neuromuscular blocker required for clinical effect by relieving anxiety and causing hypnosis

(7) prolonged use of non-depolarizing agents will result in proliferation of acetylcholine receptors on the myocyte (similar to neuromuscular disease or stroke) - this can result in massive potassium release if succinylcholine is subsequently used; therefore, if a patient has been receiving non-depolarizing agents, they should NOT subsequently receive succinylcholine

c) specific agents:

(1) pancuronium

(a) general properties:

i) onset of action = 1.5 - 2 minutes

ii) duration of action = 60 minutes

iii) clearance = renal (80%) hepatic (20%)

iv) inexpensive

v) unless there are contraindication: this is the drug of choice for prolonged paralysis

(b) side effects:

i) histamine release can be a problem in patients with asthma, left ventricular failure, or arrhythmias

ii) tachycardia, hypotension or hypertension limits use in hemodynamically unstable patients

iii) prolonged paralysis can be seen

(c) use:

i) best used as an intermittent bolus agent

ii) dose:

(1) loading = 100 ug/kg

(2) maintenance =

(a) 10 ug/kg Q 1-2 hours intermittent bolus

(b) not recommended for continuous infusion

(2) vecuronium

(a) general properties:

i) onset of action = 1.5 minutes

ii) duration of action = 30 minutes

iii) very little histamine release

iv) clearance = hepatic (80%), renal (20%)

(b) side effects:

i) prolonged paralysis can be seen

ii) occasional hypotension and bradycardia

(c) use:

i) give as either intermittent bolus or continuous infusion

ii) dose:

(1) loading = 100 ug/kg

(2) maintenance =

(a) 10 ug/kg Q 20-30 minutes intermittent bolus

(b) 0.8 - 1.2 ug/kg/min continuous infusion

(3) cisatracurium

(a) general properties:

i) onset of action = 3-5 minutes

ii) duration of action = 60-80 minutes

iii) very little histamine release

iv) no dosage adjustments in renal or hepatic failure

v) if pancuronium is contraindicated, this is the drug of choice for most patients requiring prolonged neuromuscular blockade

(b) side effects:

i) very rare

(c) use:

i) dose:

(1) loading = 150-200 ug/kg

(2) maintenance =

(a) 30 ug/kg Q 1 hour intermittent bolus

(b) 1-5 ug/kg/minute continuous infusion

(4) doxacurium

(a) general principles:

i) onset of action = 6 minutes

ii) duration of action = 90 minutes

iii) clearance = predominately renal

iv) little or no histamine release

v) little or no cardiac side effects

(b) side effects:

i) hypotension

(c) use:

i) dose:

(1) load = 50-80 ug/kg

(2) maintenance =

(a) 5-10 ug/kg Q 30-45 minutes intermittent bolus

(b) not usually used for continuous infusion

d) approximate daily cost comparisons (based on OSU cost)

(1) pancuronium = $4-6

(2) vecuronium = $130-200

(3) atracurium = $200-365

(4) cisatracurium = $70-350

(5) doxacurium = $50-150

V. Summary - Drugs of Choice:

A. Analgesia:

1. morphine

2. fentanyl if the patient is hemodynamically unstable or at risk of histamine release

B. Sedation:

1. propofol or midazolam - short term sedation (< 24 hours):

2. lorazepam - long term sedation (> 24 hours):

C. Delerium:

1. haloperidol

D. Neuromuscular blockade:

1. pancuronium

2. cisatracurium if the patient is hemodynamically unstable, has cardiac disease, or at risk of histamine release

 

updated 11/10/96

 

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