Sedation

Stanford PICU Sedation Protocol v1.0


Intermittent Sedation Protocol v1.0


General Approach

  • Most patients admitted to the PICU with needs for general sedation on mechanical ventilation:
    • Step 1: Fentanyl (1 mcg/kg/hr) and Dexmedetomidine (0.3 mcg/kg/hr titrated up to max of about 1.5 mcg/kr/hr) to start with q1hr PRNs of fentanyl
    • Step 2: Add midazolam(20 mcg/kg/hr titrated up to max of about 300 mcg/kg/hr)  if additional sedation needed
    • Step 3: Consider transition to morphine or hydromorphone if on fentanyl >5 days as tachyphylaxis can develop to fentanyl and morphine is naturally more sedating. Morphine may not be ideal in a patient with an asthma exacerbation or extremely tenuous hemodynamics due to histamine release.
    • Step 4: Consider transition from midazolam to lorazepam
    • Step 5: Consider additional adjuvant agents (i.e. chloral hydrate, PRN ketamine, benadryl, some might use gabapentin for neuropathic pain)
    • Step 6: Consider adding neuromuscular blocking agent as an adjuvant (titrated to weaken a patient generally well sedated but occasional movements threaten tubes/devices/therapeutics)
    • Step 7: Consider brief propofol wash out (12 hours) to "reset" body's receptors and decrease doses needed
    • Step 8: Consider pentobarbital infusion with PRN's recognizing long half life, potential for hemodynamic compromise
  • Special circumstances:
    • Status asthmaticus: Ketamine (for sedation + bronchodilation)
    • Need for quick on/off (i.e. for neuro exam): Propofol or trial of using PRN's of fentanyl/midazolam only
    • Brief, painful procedure while maintaining spontaneous respirations: local anesthetic +:  ketamine PRN's vs. dexmedetomidine infusion + fentanyl PRN vs. low dose propofol infusion + propofol boluses
    • Take the edge off while maintaining spontaneous respirations (i.e. younger patient who is anxious about noninvasive positive pressure ventilation): dexmedetomidine
  • Propofol Washout:
    • Using propofol as a single agent, one can turn off the rest of the infusions (recognizing propofol does not have analgesic properties), allowing the other drugs (benzodiazepenes and narcotics typically) to "wash out." This allows you to shut off the propofol and the patient should wake fairly readily, rather than waiting for a much longer and indeterminate amount of time for the child to wake up as the drug levels slowly decrease
    • In addition, propofol wash outs can be used as a bridge to decrease narcotic/benzodiazepene dosage requirements by theoretically desaturating the receptors and and thus increasing their overall efficacy.
    • In children, we are limited to 12 hours due to the risk of propofol infusion syndrome which is dose and duration dependent and more commonly occurs in children. This is due to mitochondrial toxicity which results in lactic acidosis and can result in profound cardiovascular collapse and death. Green urine can also be seen due to a metabolite of propofol although this does not necessarily increase the risk of propofol infusion syndrome
  • Methadone and Valium
    • These are used as medications to prevent withdrawal. The approximate risk of withdrawal is ~50% after 5 days worth of sedative infusions but is again, dose and duration dependent. 
    • Often these are started at 0.1 mg/kg IV q6 each a few days before extubation to allow for the drugs to reach steady state. They can also be started as an additional sedative agent if one is already utilizing high dose narcotic or benzodiazepene infusions.
    • Methadone IV:PO conversion is generally about 1:1.4-2 (ie PO is about half as potent) while diazpeam IV:PO is 1:1. 
    • Weans generally occur over about 10 days (or roughly 1-1.5 x the duration of the infusions in days) with 10% weans of the total dose of one medication each day alternating. This is adjusted based on withdrawal assessment tool (WAT) scoring with scores >4 suggesting some withdrawal (higher scores indicate more withdrawal)
  • Neuromuscular Blockade
    • Generally use vecuronium or ciastracurium infusions to chemically paralyze ("muscle relax") patients.
    • Can serve to reduce metabolic demand in cases where oxygen delivery is impaired, reduce shivering, improve ventilator patient synchrony (ie with HFOV), or as an adjuvant agent in a patient who is generally well sedated but an intermittent threat to vital lines and tubes
    • Cisatracurium is often used as the infusion of choice given its elimination occurs via Hoffman degradation (pH and temperature dependent) rather than being dependent upon renal (ie rocuronium) or hepatic function (ie vecuronium)
    • Train of four monitoring is essential for patients who are not moving to ensure that they are not being overly blocked, which can lead to polyneuropathy and iatrogenic muscle weakness/atrophy. We generally aim for 2 twitches out of four.

Sedation, Analgesia, and Neuromuscular Blockade (courtesy of Kato Han, M.D.)

 

 

General Considerations:

1)       What is the overall goal? (i.e. pain control?, amnesia to procedure?, etc.)

2)       What is the medical condition of the patient? (i.e. co-morbidities?)

3)       How quickly do you want the desired effect? [most relevant when considering intubation]

4)       What is the duration of the desired effect?

5)       What are the potential side effects, and are they unacceptable in that particular setting?

6)       How is the medication metabolized/cleared, and is this important?

7)       Is the route of delivery important?

8)       Are there cost considerations?

 

 

Neuromuscular Blockers:

Class

Name

(Trade Name)

Onset (sec)

Duration  (min)

Metabolism/ Clearance

Dose

Cost (U of M)

Comments

Depolarizing

succinylcholine

(Anectine)

30-60

5-7

Plasma cholinesterases

1-2 mg/kg

$1.53/200 mg

Quickest onset of all NMB’s. Contraindicated in muscular dystrophies, multiple sclerosis, spinal cord injuries, encephalitis, glaucoma, malignant hyperthermia, burns, and crush injuries. Pseudocholinesterase deficiency results in prolonged NMB. Will raise serum K+ levels.  Has been associated with bradyarrhythmia/cardiac arrest. May be given IM: 3-5 mg/kg (max 150 mg).

Nondepolarizing

pancuronium

(Pavulon)

120-180

45-60

1 Renal

Hepatic

0.1 mg/kg

Infusion: 1-2 mcg/kg/min

$1.02/10 mg

Causes tachycardia from sympathomimetic effect.

 

vecuronium

(Norcuron)

120-180

30-40

1 Hepatic

Renal

0.1 mg/kg

Infusion: 1-3 mcg/kg/min

$3.84/10 mg

Minimal CV effects. Can use 0.3 mg/kg dose for more rapid onset (60-90 sec).

1/3 of a dose is metabolized to 3-, 17-, and 3,17-descetylvecuronium. (Relative potency is 1:2:20:60, respectively).

 

rocuronium

(Zemuron)

60-90

30-40

1 Hepatic

Renal

0.6-1.2 mg/kg

Infusion: 10-12 mcg/kg/min (generally not done in PICU).

$3.85/50 mg

Quickest onset of nondepolarizing NMB’s. Minimal CV effects. Should be stored under refrigeration. 17-desacetyl rocuronium metabolite has 1/20th the activity of the parent drug.

 

cis-atracurium

(Nimbex)

180-300

35-45

Hoffman degradation

Renal

0.1-0.2 mg/kg

Infusion: 1-3 mcg/kg/min

$22.5/20 mg

“Cis” isomer of atracurium. More potent than atracurium, so less used and less laudanosine accumulation. Histamine release.

 

 

Neuromuscular Blockers not on Formulary:

Class

Name

(Trade Name)

Onset (sec)

Duration  (min)

Metabolism

Dose

Comments

Nondepolarizing

atracurium

(Tracrium)

180-300

35-45

Hoffman degradation

Renal

0.3-0.5 mg/kg

Infusion: 10-15 mcg/kg/min

 

Histamine release. Laudanosine metabolite can cause seizures. Some vials contain benzyl alcohol (avoid in infants).

 

doxacurium

(Nuromax)

240-360

90-100

Not metabolized

0.05 mg/kg

Contains benzyl alcohol (avoid in infants).

 

tubocurarine

(Tubarine)

120-180

30-60

1 Renal

0.25-0.5 mg/kg

Histamine release. (Can be used to diagnose myasthenia gravis: 0.004-0.033 mg/kg; administer neostigmine 1.5-2 mg  min after tubocurarine to terminate test).

 

 

Analgesics:

Class

Name

(Trade Name)

Duration of Action (hr)

Relative Potency

Dose

Cost (U of M)

Comments

Opioids

morphine (Duramorph)

2-4

1

0.1-0.2 mg/kg

Infusion: 25-200 mcg/kg/hr

$0.85/10 mg

Histamine release. Onset of action is not as quick as fentanyl (Peak iv effect ~5 min vs 2 min for fentanyl).

 

fentanyl (Sublimaze)

1-2

100

1-2 mcg/kg

Infusion: 1-5 mcg/kg/hr

$0.89/250 mcg

No histamine release. Minimal CV effects. Developed for less sedating effects.

Intubating doses are 5-10 mcg/kg, if used as sole agent. “Anesthestic” doses are 25-150 mcg/kg. Rapid, high doses are associated with “rigid chest syndrome”. Generally avoided on ECMO due to membrane binding concerns.

 

hydromorphone

(Dilaudid)

4-5

7.5

0.015 mg/kg

Infusion: 0.002-0.004 mg/kg/hr

$6.60/6 mg (PCA)

Histamine release. Often used as PCA.

 

methadone (Dolophine)

6-8

1

0.1-0.2 mg/kg

$0.33/1 mg (IV)

$0.06/1 mg (PO)

Histamine release. Very sedating. Oral form has ~50% bioavailability. Duration of action increases to 24-48 hrs with repeated doses. Typically used to control narcotic withdrawal.

 

meperidine (Demerol)

2-4

0.1

1 mg/kg

$0.65/25 mg

Histamine release. Do not use with MAO inhibitors. Normeperidine metabolite can cause seizures, hallucinations, and agitation. Less association with biliary tract spasm. Has been used for fevers caused by excessive shivering.

 

sufentanil (Sufenta)

1

500

10-25 mcg/kg

$10.84/250 mcg

Fentanyl derivative. Typically used during cardiac surgery.

 

alfentanil (Alfenta)

15-45 min

10

10-50 mcg/kg

$3.44/1000 mcg

Fentanyl derivative. Should be given as a continuous infusion.

 

remifentanil (Ultiva)

3-10 min

200

0.25 mcg/kg/min

$8.05/1000 mcg

Fentanyl derivative. Metabolized by blood and non-specific tissue esterases. Should be given as a continuous infusion.

 

codeine

(Tylenol w/ codeine)

4-6

0.08

1 mg/kg (PO)

$0.39/12 mg (5 mL elixir)

Minor route of metabolism forms morphine. IV formulation does exists but is not on formulary.

 

oxycodone (Oxycontin)

(Percocet [Tylenol], Percodan [aspirin])

4-6

0.5

0.1 mg/kg (PO)

$1.87/5 mg (5 mL solution)

$0.33/5 mg (tablet)

Must be given enterally.

 

hydrocodone

(Vicodin [Tylenol])

4-6

 

0.135 mg/kg (PO)

$2.36/7.5 mg (15 mL elixir)

$0.31/5 mg (tablet)

Must be given enterally.

As a class, all opioids can cause respiratory depression, slow gut motility, sedation, and dysphoria. Most cause histamine release.

Remember: Naloxone (Narcan) can be used in case of opioid overdose (Use 5-10 mcg/kg/dose [max 200 mcg/dose]).

 

Analgesics (cont.):

Class

Name

(Trade Name)

Comments

Non-opioids

 

 

NSAID

ibuprofen

(Motrin)

Must be given enterally. Can cause renal insufficiency in setting of marginal renal blood flow. Avoid in patients with calcineurin inhibitor immunosuppressants (tacrolimus, cyclosporine).

 

ketorolac

(Toradol)

IV formulation. Associated with increased post-operative bleeding.

Dose: 0.5-1 mg/kg; Cost: $1.76/60 mg.

Non-NSAID

acetaminophen

(Tylenol)

Must be given enterally.

 

 

 

 

 

 

Sedatives/Hypnotics/Anesthetics:

Class

Name

(Trade Name)

Duration of Action

Dose

Cost (U of M)

Comments

Benzodiazepines

diazepam (Valium)

Long

0.1-0.3 mg/kg

$2.29/10 mg

$1.58/5 mg (5 mL solution PO)

Has active metabolite. Excellent enteral bioavailability.

May be given IM. May be given rectally for seizures.

 

lorazepam (Ativan)

Moderate

0.1 mg/kg

Infusion: 10-100 mcg/kg/hr

$6.38/20 mg

No active metabolite. Infusion can cause metabolic acidosis due to propylene glycol carrier, especially with renal insufficiency. Although not commonly done here, it can be given enterally. May be given IM.

 

midazolam (Versed)

Short

0.1 mg/kg

Infusion: 25-300 mcg/kg/hr

$1.09/5 mg

Has active metabolite. IV form does not need alcohol carrier. Powerful amnestic. Associated with ataxic movements. May be given IM or intranasally. Poor enteral bioavailability due to extensive liver 1st pass metabolism.

As a class, all benzodiazepines produce anxiolysis, amnesia, and muscle relaxation; they can all depress respiration and cause hypotension.

Remember: Flumazenil (Romazicon) can be used in case of benzodiazepine overdose (Use 5-10 mcg/kg/dose [max 200 mcg/dose]).

Barbiturates

thiopental

(Pentothal) *supplies disappearing in USA

Very short

5 mg/kg

Infuse: 2-10 mg/kg/hr

$1.58/50 mg

Onset of action in 30-60 secs. Lowers ICP. Causes myocardial/circulatory depression. Use continuous EEG if on infusion. Pentobarbital is a metabolite.

 

pentobarbital

(Nembutal)

Short to Moderate

1-3 mg/kg

Infusion: 1-4 mg/kg/hr

$6.61/50 mg

Causes myocardial/circulatory depression. Lowers ICP. Can impair immune function. May be given IM: 2-6 mg/kg (max 100 mg). Use continuous EEG if on infusion. Has propylene glycol carrier that can cause metabolic acidosis.

Intravenous Anesthetics

ketamine (Ketalar)

Short to Moderate

0.5-1 mg/kg

$0.80/10 mg

$4.76/500 mg

PCP derivative. Generally does not blunt respiratory drive. Contraindicated for increased ICP. Causes release of endogenous norepinephrine. Causes bronchodilation. May cause bronchorrhea, excessive salivation, and larynospasm. Associated with “emergence reactions”. May be given IM.

 

propofol (Diprivan)

(chemical name: 2,6-diisopropylphenol)

 

Very short

2-4 mg/kg

Infusion: 20-200 mcg/kg/min

$4.00/200 mg

$10.00/500 mg

Should be given as a continuous infusion. Does not have analgesic properties. Prolonged use is associated with fatal metabolic acidosis. Mixed in oil/lipid mixture with egg derived substances; susceptible to microbial contamination. Can cause brief period of apnea during induction and hypotension/bradycardia with higher infusion rates.

 

etomidate (Amidate)

Very short

0.3 mg/kg

$4.73/20 mg

Very quick onset of action. Believed to lower ICP but with no cardiovascular depression. Associated with suppression of hypothalamic-adrenal axis. Associated with myoclonus.

Hypnotics

dexmedetomidine

(Precedex)

Very short

0.2-0.7 mcg/kg/hr

$63.90/200 mcg

Selective a2-adrenegic receptor agonist. Related to clonidine. Can cause hypotension and bradycardia. Paradoxical hypertension reported with high doses.

 

chloral hydrate

(Nortec)

Moderate

25-50 mg/kg

$0.50/500 mg (5 mL syrup PO)

Must be given enterally. Active metabolite is trichloroethanol. Chronic use may be associated with cardiac dysfunction. Usually does not blunt respiratory drive. Seems to work well in patients with Trisomy 21.

Antihistamines

diphenhydramine

(Benadryl)

Moderate

0.5-1 mg/kg

$0.82/50 mg (IV)

Has anticholinergic properties (e.g. dry mouth, dry eyes, etc.)

Antipsychotics

haloperidol

(Haldol)

Moderate

0.05 mg/kg/dose or 1-5 mg/dose

$0.85/5 mg

Has anticholinergic properties. May cause extrapyramidal effects (acute dystonic reaction and pseudoparkinsonian symptoms) and rarely, malignant hyperthermia. IV administration may cause hypotension.

 

droperidol (Inapsin)

Moderate

0.03-0.1 mg/kg/dose (max 2.5 mg/dose)

$0.08/0.25 mg

Similar to haloperidol. Less risk for extrapyramidal effects.

Has black box warning for prolonged QT/torsades de point risk.

 

Cases:

1) 9 month old infant with jaundice and liver failure requiring percutaneous liver biopsy.

2) Same patient 2 hours later, tachycardic, appearing pale and mottled.

3) Same patient 24 hours later, on HFOV for ARDS, requiring epinephrine infusion, no urine for past 8 hours.

4) 10 year old s/p MVA, initially following commands but now becoming unresponsive after arrival into the trauma room.

5) 6 year old initially admitted for septic shock/ARDS/MODS, continuing to require moderate amounts of support and increasing sedative doses for “agitation”; seems somewhat “wild” at times.




Evidence

  • RESTORE by Curley et al demonstrated no difference in length of mechanical ventilation when utilizing a protocol for sedation vs. usual care in pediatric patients with acute respiratory failure


Withdrawal

  • Generally consider WAT-1 score >4 consistent with withdrawal
  • Risk of withdrawal related to cumulative dose and duration of opioid and benzodiazepene exposure
  • Often start methadone/valium if patient has been on moderate/high dose benzodiazepenes and narcotics for 5+ days
  • Initial description of the WAT-1 score


References

1) Curley MA, Wypij D, Watson RS, Grant MJ, Asaro LA, Cheifetz IM, Dodson BL,Franck LS, Gedeit RG, Angus DC, Matthay MA; RESTORE Study Investigators and the
Pediatric Acute Lung Injury and Sepsis Investigators Network. Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute
respiratory failure: a randomized clinical trial. JAMA. 2015 Jan 27;313(4):379-89. doi: 10.1001/jama.2014.18399. PubMed PMID: 25602358.

2) Franck LS, Harris SK, Soetenga DJ, Amling JK, Curley MA. The Withdrawal Assessment Tool-1 (WAT-1): an assessment instrument for monitoring opioid andbenzodiazepine withdrawal symptoms in pediatric patients. Pediatr Crit Care Med. 2008 Nov;9(6):573-80.