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Does Barbiturate Coma Help to Improve Outcome from Head Injury?

Manuela Cormio and Claudia S. Robertson

BRIEF ANSWER

Background

Despite aggressive management to control elevated ICP, 10 to 25% of patients with severe traumatic brain injury develop intractable intracranial hypertension. The mortality rate is very high (84 to 100%) in this group of patients (class III data).^1–4 Barbiturate coma has been recommended as a last-ditch treatment after routine therapy fails to control elevated ICP.

The use of barbiturates for controlling refractory intracranial hypertension is based on the following two assumptions:

1. Barbiturates improve long-term ICP control when other treatments have failed.
   
2. ICP control improves ultimate outcome.

Cerebral Effects of Barbiturates

The mechanism of ICP reduction by barbiturates is not entirely clear but is almost certainly multifactorial. Because of the immediacy of the ICP-lowering effect, the mechanism is commonly thought to be hemodynamic. This immediacy of effect may be due to direct cerebral vasoconstriction (increased cerebral vascular resistance) since the reduction in ICP has been associated with reductions in cerebral blood flow (CBF) and cerebral blood volume (CBV) in laboratory studies.⁵

The immediacy of effect of barbiturates could also be explained by a metabolically coupled reduction in CBF. Barbiturates cause a reversible depression of neurologic function and reduce cerebral metabolic rate of oxygen (CMRO₂) by 50% in normal adults and by 58% in experimental studies.⁶ This reduction in CMRO₂ is caused by inhibition of energy-dependent synaptic transmission. Therefore, reduction in CMRO₂ by pentobarbital is closely related to the pretreatment CMRO₂. Only those patients with a CMRO₂ ≥1.6 mL/100 g/min demonstrate a consistent reduction in CMRO₂ with barbiturates and a resulting reduction in ICP (class III data).⁷ Patients with an extremely low CMRO₂ from overwhelming cerebral injury are not likely to benefit from barbiturate coma.

Other mechanisms by which barbiturates may exert cerebral protective effects in the injured brain have also been described: stabilization of lysosomal membranes, reduction of intracellular calcium concentrations, modification of release of amino acids and neurotransmitters, scavenging of free radicals, alteration of fatty acid metabolism, inhibition of phospholipase activation, reduction in cerebrospinal fluid (CSF) secretion, lowering of temperature, and suppression of seizures.8–10 Using cerebral microdialysis, Goodman et al¹¹ described a 37% reduction of lactate, 59% reduction of glutamate, and 66% reduction in aspartate in the extracellular space of the brain when severely elevated ICP was managed with barbiturate coma (class III data). Stover et al¹² indicated that despite successful suppression of neuronal activity in patients with refractory intracranial hypertension, the use of barbiturate coma does not unequivocally preserve energetic stability (class III data). They reported that elevated levels of glutamate, presumably associated with ongoing anaerobic metabolism, may still be detected in some cases.

Indications

Indications for initiating barbiturate coma have not been consistently defined. It is used most commonly in selected patients in the setting of uncontrollable intracranial hypertension refractory to all other conventional treatments.^2,7,13 It should be instituted before irreversible brain injury has occurred. If barbiturates are started too late in the course of treatment, ICP may be controlled, but the patient is more likely to remain neurologically devastated.

Reasonable indications to begin high-dose barbiturates include 30 minutes of ICP over 30 mmHg with cerebral perfusion pressure (CPP) less than 60 mmHg, or ICP over 40 mmHg despite a CPP of 60 mmHg. Patients with overwhelmingly severe injuries are not likely to benefit from barbiturate coma, partly because their CMRO₂ is already markedly reduced by the injury and partly because their outcome is already predetermined by the injury. Patients with systemic hypotension are not likely to have a good response because hypotension limits the amount of barbiturates that can be given.

Ethical issues may arise over how aggressively therapy for intracranial hypertension should be pursued and for how long. An ever-present concern is that prolonged barbiturate coma may prevent death, but with unacceptably severe disability.

Dose

A commonly used dosing regimen for pentobarbital is 10 mg/kg loading dose over 30 minutes, followed by 5 mg/kg/h over the next 3 hours. If systolic blood pressure decreases, the rate of loading dose infusion should be slowed. Maintenance infusion is usually begun at 1 to 3 mg/kg/h.^7,14

The lowest dose that effectively controls ICP should be utilized. When ICP control has been achieved for 24 hours, tapering of the barbiturate dose may be started. Such weaning should be performed slowly; decreasing the hourly infusion rate by 50% each day is a useful approach. Long-term administration may result in significant accumulation of barbiturates and may cause barbiturate levels in CSF and serum to remain elevated for days after administration is stopped. Clinical evaluation is impossible until these stores are eliminated. Thus, quantitative analysis of barbiturates in serum may be valuable in predicting the length of drug-induced neurologic impairment and in avoiding misinterpretation of the patient’s neurologic status.

Complications and Adverse Effects

High-dose barbiturate therapy has a significant potential for serious complications that limit its utility. Continuous infusions are difficult to control because of accumulation of the drug over time. Systemic arterial hypotension is commonly observed in patients receiving barbiturates,^7,13,14 and this complication has the potential to offset beneficial effects of the drug on ICP. In fact, the one absolute contraindication to the initiation of barbiturate coma is the presence of cardiovascular compromise, including episodes of hypotension, before the administration of barbiturates.¹⁴ Potential mechanisms of hemodynamic instability include a myocardial depressant effect, reduced ventricular filling pressure, reduced peripheral vascular resistance, reduced tone in venous capacitance vessels, redistribution of blood volume, impaired venous return, and inhibition of sympathetic activity.

Another complication of barbiturate coma that may offset the beneficial effects on ICP is immunosuppression, leading to an increased risk of infection. A high incidence of infections (55%) and respiratory complications (76%) has been described in patients treated with barbiturate coma. Inhibition of lymphocytes, depression of lung mucociliary clearance, prolonged intubation, mechanical ventilation, immobilization, and/or loss of cough reflexes may be involved.13 Hepatic (87%) and renal dysfunction (47%) are also very common.¹³ Physiologic changes associated with the primary cerebral injury, combined with the pharmacodynamic influences of barbiturate therapy, contribute to the difficulties of initiating aggressive nutritional support.¹⁵

Management of Patients in Barbiturate Coma

The successful use of high-dose barbiturate therapy mandates vigilant and aggressive monitoring and management on the part of the physician and nurse. Hypotension and other potential complications associated with this form of therapy mandate that its use be limited to the intensive care unit (ICU) and that aggressive systemic hemodynamic support and monitoring be undertaken to avoid or treat any hemodynamic instability. A Swan-Ganz catheter is highly recommended, and cardiac filling pressure, systemic vascular resistance, and cardiac output should be optimized before initiation of barbiturate therapy. Throughout the time of barbiturate administration, blood pressure must be aggressively maintained with fluid and pressors.

The increased incidence of severe infection is a serious consequence of barbiturate coma. Patients are anergic, and, in conjunction with the poikilothermic effect of barbiturates, early signs of infection such as leukocytosis, fever, and tachycardia may be suppressed. A high degree of vigilance must be maintained, including clinical, laboratory, and radiologic monitoring to detect both common and uncommon sources of infection.