Anaesthesia

General

Used for

Prophylaxis or control of intracranial hypertension and seizures.
When patient is agitated
To blunt the elevation of ICP that occurs with certain maneuvers such as moving the patient to CT table.

Caution: with heavy sedation or paralysis, the ability to follow the neurologic exam is lost (follow ICPs)

For heavy sedation (intubation recommended to avoid respiratory depression → elevation of PaCO2 →↑ ICP): e.g. one of the following:

Paralysis (intubation mandatory): e.g. vecuronium 8–10mg IV q 2–3 hrs

Neuromuscular blocking agents do not reduce ICP,
Although they may prevent increases during endotracheal suctioning and other interventions.
They should not be used routinely because of the increased risk of extracranial complications including pneumonia and ICU- acquired weakness.

Choice of agents

A number of agents have been studied; however, there are inadequate data to recommend one drug over another.

Barbiturates

Examples

Phenobarbital
Pentobarbital

Indications

The use of barbiturates should be reserved for situations where the ICP cannot be controlled by the previously outlined measures

Eisenberg et al., 1988: ICP is more likely to be controlled in treatment arm. Patients who responded to treatment with lower ICP had higher likelihood of survival (92% vs. 17% for non-responders.) In patients with hypotension prior to randomization, barbiturates provided no benefit.

Theoretical benefits of barbiturates in head injury:

Vasoconstriction in normal areas → shunt blood to ischemic brain tissue
Decreased metabolic demand for O2 (CMRO2) with accompanying reduction of CBF
Free radical scavenging
Reduced intracellular calcium
Lysosomal stabilization
Barbiturates lower ICP, even when other treatments have failed,

Outcome

A subgroup of patients with preserved vasoreactivity may benefit from the use of barbiturates;
When reserved for use in patients who failed to respond sufficiently to other measures, barbiturates have been shown to lower ICP.
Patients that do respond have a lower mortality (33%) than those in whom ICP control could not be accomplished (75%).

The limiting factor for therapy

Hypotension:

Barbiturate-induced reduction of sympathetic tone →

Peripheral vasodilatation
Direct mild myocardial depression

Hypotension occurs in ≈ 50% of patients in spite of adequate blood volume and use of dopamine.
NB: the ability to follow the neurologic exam is lost with high-dose barbiturates, and one must follow ICP.

“Barbiturate coma” vs. high-dose therapy:

Barbiturate coma

Barbiturates are given until there is burst suppression on EEG → Near maximal reductions in CMRO2 and CBF.

High does therapy

Most regimens should technically be called “high dose intravenous therapy” since they simply try to establish target serum barbiturate levels (e.g. 3–4mg% for pentobarbital), even though there is poor correlation between serum level, therapeutic benefit, and systemic complications.
High-dose barbiturate administration is recommended to control elevated ICP refractory to maximum standard medical and surgical treatment. Hemodynamic stability is essential before and during barbiturate therapy
Adjunctive measures to administration of high-dose barbiturates:

Consider a Swan-Ganz (PA) catheter placed during the first hour of loading dose
High-dose barbiturates often causes paralytic ileus:

Therefore NG tube to suction & IV hyperalimentation are usually needed

Continuous EEG monitor:

A double “banana” EEG montage is often used to cover a wide area
Drug is titrated to 2–5 bursts per minute

Has a fast onset (full effects within ≈ 15 minutes), short duration of action (3–4 hrs), and a half–life of 15–48 hrs.

Downside

The neuro exam cannot be assessed on pentobarbital.
A myocardial suppressant, therefore watch for hypotension.
GI motility is reduced or absent, some use trickle tube feeds during pentobarbital therapy.

Protocols for pentobarbital therapy in adults

Simple protocol

Loading dose:

10mg/kg IV over 30 minutes
Then 5mg/kg q 1 hr × 3 doses

Maintenance: 1mg/kg/hr

A more elaborate protocol:

Loading dose:

10mg/kg/hr IV over 4 hrs as follows:

FIRST HOUR: 2.5 mg/kg slow IVP q 15min× 4 doses (total: 10mg/kg in first hr), follow BP closely
Next 3 hours: 10 mg/kg/hr continuous infusion (put 2500mg in 250ml of appropriate IVF, run at K ml/hr × 3 hrs (K = patient’s weight in kg))

Maintenance: 1.5mg/kg/hr infusion (put 250mg in 250ml IVF and run at 1.5 ×K ml/hr)
Check serum pentobarbital level 1 hr after loading dose completed; usually 3.5–5.0mg%
Check serum pentobarbital level q day thereafter
If level ever > 5mg% and ICP acceptable, reduce dose
Baseline brainstem auditory evoked response (BAER) early in treatment. May be omitted on clinical grounds. Repeat BAER if pentobarbital level ever > 6mg%. Reduce dose if BAER deteriorates (NB: hemotympanum may interfere with BAER)
Goal: ICP < 24mm Hg and pentobarbital level 3–5mg%. Consider discontinuing pentobarbital due to ineffectiveness if ICP still > 24 with adequate drug levels × 24 hrs
If ICP < 20mm Hg, continue treatment× 48 hrs, then taper dose. Backtrack if ICP rises

Sample orders if continuous EEG monitoring is available:

Pentobarb concentration: 3000/mg/600ml NS
Loading dose: 5–15mg/kg over 1 hour
Maintenance dose:

0.4–4mg/kg/hour
Titrate up or down by 0.5–1mg/kg/hour steps to maintain 2–5 bursts/minute (some use 4–12 bursts/minute)
Absolute maximum dose: 10 mg/kg/hr

Neuro function takes ≈ 2 days off pentobarbital to return

If it is desired to perform a brain death exam, the pentobarbital level needs to be ≈≤10 mcg/ml before the exam is valid.

Thiopental

May be useful when a rapidly acting barbiturate is needed (e.g. intra-op) or when large doses of pentobarbital are not available.

Protocol of using

Note: thiopental has not been as well studied for this indication, but is theoretically similar to pentobarbital:
Loading dose:

Thiopental 5mg/kg (range: 3–5) IV over 10 minutes → transient burst suppression (< 10 minutes) and blood thiopental levels of 10–30 mcg/ml.
Higher doses (≈ 35 mg/kg) have been used in the absence of hypothermia to produce longer duration burst suppression for cardiopulmonary bypass

Continuous infusion

5 mg/kg/hr (range: 3–5) for 24 hours

May need to rebolus with 2.5 mg/kg as needed for ICP control
After 24 hours, fat stores become saturated, reduce infusion to 2.5 mg/kg/hr
Titrate to control ICP or use EEG to monitor for electrocerebral silence
“Therapeutic” serum level: 6–8.5 mg/dl

Propofol

Advantage

Hypnotic anesthetic agent
Rapid onset
Short duration of action.
Depress cerebral metabolism
Depress oxygen consumption

Disadvantage

❌ Caution: high-dose propofol (total dose > 100mg/kg for > 48 hrs) can cause significant morbidity

Propofol infusion syndrome

Found in children> Adults
Hyperkalemia
Hepatomegaly
Lipemia
Metabolic
Acidosis
Myocardial failure
Rhabdomyolysis
Renal failure
Death

Kelly et al., 1999:

Propofol may control ICP after several hours of dosing,
Propofol does not improve mortality or 6 month outcome.
High dose ((total dose of >100 mg/kg for >48 hours) propofol had better outcomes than low dose

℞:

0.5 mg/kg test dose, then 20–75 mcg/kg/min infusion.
Increase by 5–10 mcg/kg/min q 5–10 minutes
PRN ICP control (do not exceed 83 mcg/kg/min= 5mg/kg/hr).
❌ avoid high dose Propofol (do not exceed 83 mcg/kg/min)

Side effects:

Include Propofol infusion syndrome
Use with caution at doses > 5mg/kg/hr or at any dose for > 48 hrs.

Morphine (MSO4): ℞ 2–4 mg/hr IV drip
Fentanyl: ℞ 1–2ml IV q 1 hr (or 2–5 mcg/kg/hr IV drip)
Sufentanil: ℞ 10–30 mcg test dose, then 0.05 -2 mcg/kg/hr IV drip
Midazolam (Versed®): ℞ 2mg test dose, then 2–4mg/hr IV drip
"Low dose” pentobarbital (adult: 100mg IV q 4 hrs; peds: 2–5mg/kg IV q 4 hrs)

Dexmedetomidine

Mech alpha- 2 agonist

Used in awake craniotomies

Has shown some promise for sedation after brain injury but there are no RCTs in patients with TBI

Early use of paralytics and sedation (prior to ICP monitoring)

Sedation and neuromuscular blockade (NMB)

Advantage

Helpful for transporting the head-injured patient
Sedatives and paralytics in neurotrauma patients may lead to a higher incidence of

Pneumonia
Longer ICU stays
Possibly sepsis.

Disadvantage

Interfere with the neuro exam

NMB should be used when sedation alone is inadequate
Indicated for

Patient with intracranial hypertension
Intubation, or where use is necessary for transport or to permit evaluation of the patient (e.g. to get a combative patient to hold still for a CT scan).

Trial Eisenberg et al 1988

First RCT assessing efficacy of pentobarbital to treat raised ICP in severe TBI
1982-87, USA
Two previous trials did not show benefit (Shwartz et al 1984; Ward et al., 1985)
Placebo controlled RCT, Class I evidence, n = 73, 5 centres
6 month follow up
1ary endpoint= response to treatment. Other endpoints: survival, GOS
Stratification: medical complications, time to randomisation, initial GCS
Inclusion criteria: GCS 4-7 post resuscitation, age 15-50, serum osmo >= 315, mannitol w/in 1hr prior to randomisation
Exclusion: GCS 3, fixed pupils, pregnancy
Conventional therapy standardised across the 5 centres
Findings:

Intracranial mass lesions, haematoma and accessible contusions resected
Patients with uncontrolled ICP despite best conventional therapy (BCT) received pentobarbital (titrated to serum concentration) + continued BCT
ICP randomisation criteria based on ICP levels and length of time ICP raised
Treatment response successful if ICP < 20 mmHg for 48h (closed injury)
Unsuccessful = failed reduction in ICP or severe clinical deterioration (e.g. fixed pupil, death)
Patients whose ICP remained uncontrolled in BCT arm allowed to cross over to pentobarbital

Results:

ㅤ	BCT	BCT + pentobarbital	Benefit ratio of pentobarbital + BCT:BCT
Control of ICP in all patients (% of patients)	16.7%	32.4%	2:1
Control of ICP in patients with cardiovascular complications prior to randomization (% of patients)	9%	40%	4:1

Multiple logistic model statistical analysis revealed a significant positive treatment effect of pentobarbital (p = 0.04).
Significant effects of timing of randomization were also found: twice as many.
Uncontrolled ICP was robustly associated with death in both treatment arms (>90% of patients with controlled ICP survived).
Conclusion – high dose barbiturates are appropriate adjunct in the control of raised ICP in severely head injured patients

Criticisms:

Only 12% considered for randomisation criteria and total number in trial quite low
Nonetheless a multicentre trial with standardised treatment regimens
Control of ICP not survival as primary outcome
This avoids ethical dilemma of not giving barbiturates when ICP reaches potentially lethal levels
Possible that raised ICP and outcome both pre-determined by pathology of severe head injury
However ICP >/= 20mmHg consistently associated with poor outcome in previous studies
This trial provided first evidence that barbiturates may be effective in controlling ICP in several head injured patients
Debate regarding relationship between ICP and outcome continues – Roberts 2000 Cochrane review concluded that barbiturates control ICP but no evidence of beneficial effect on outcome