Ketamine VS Midazolam in Head Injury Sedation

Medicine

Traumatic brain injury is the leading cause of death among young adults worldwide. Adequate sedation can reduce secondary brain injury and improve outcomes.

Traumatic brain injury (TBI) is a heterogeneous disease that has been a leading cause of morbidity and mortality in young adults. TBI is a brain function impairment caused by an external force that results in anatomic injury or functional impairment of the skull, meninges, the brain, or its vessels.

TBI is typically classified as primary and secondary injury:

The multifactorial etiology of secondary brain injury includes hypoxemia, hypotension, increased intracranial pressure (ICP), and decreased cerebral blood flow (CBF). Studies show that spreading depolarization is another important contributor to the progression of brain injuries.

A sufficient level of sedation and analgesia plays a significant role in the management of TBI. The main purpose of sedation is the prevention of secondary brain injury by the manipulation of ventilation and optimization of cerebral metabolic rate (CMRO2), CBF, and ICP.

Despite the growing evidence, it is currently unclear which drug is the most effective in achieving these goals.

They also must keep the CBF/ CMRO2 combination, maintain cerebral autoregulation, allow cerebrovascular depression, brain tissue recovery, and prevent secondary neuronal damage.

Benzodiazepines, such as midazolam, have been often used for TBI sedation.

Benzodiazepines are nonselective central nervous system depressants and anticonvulsants that augment the action of γ-Aminobutyric acid (GABA) at GABAA receptors, causing increased conductance of chloride ions. Benzodiazepines have no analgesic effects.

They are associated with significant respiratory depression and inhibition of the cough reflex.

Midazolam is the most widely used benzodiazepine due to its favorable pharmacokinetics and pharmacodynamics. Midazolam is also commonly used by pre-hospital care providers to sedate TBI patients as it has a rapid onset of action and a shorter half-life.

Ketamine is an NMDA receptor antagonist. It is a potent sedative, amnestic, analgesic, and anesthetic agent.

Since its invention in the 1960s, then its FDA approval as an anesthetic in 1970, ketamine has been used for several purposes.

Unlike benzodiazepines, ketamine does not have a vasodilator effect, therefore it may be a safer alternative for hemodynamically unstable patients.

Due to the increasing data suggesting that ketamine is safe for sedation in TBI patients, it has been introduced to practice in the NHS ambulance services across the UK and in other countries too, such as Canada.

Experts have been aware of the importance of adequate ICP and CPP management: previous studies reported worse outcomes in TBI patients with ICP persistently over 20 mmHg.

Regardless of the dosage, ketamine infusion was found to have no effect on ICP. One study found that boluses, however, can cause non-sustained small decreases in ICP.

One study found that midazolam infusion can decrease ICP and may reduce the need for neuromuscular blockers (NMBs).

NMBs are commonly considered in patients with TBI and increase of ICP, however, the use of NMBs in critically ill TBI patients is based on theoretical considerations with currently poor evidence.

Randomized prospective trials found no evidence that midazolam changes ICP values. One prospective study found that midazolam boluses lower ICP and CPP.

The effects of ketamine and midazolam on ICP and CPP were influenced by co-administered sedatives, such as propofol. In all of the studies, patients received concomitant drugs, often not the same drug.

Ketamine has a positive inotropic effect on the myocardium resulting in increased cardiac output.

Only one study found that midazolam boluses cause a significant decrease in MAP which was related to the increase in ICP. The decrease was only significant when the control ICP was less than 18 mmHg.

Spreading depolarizations are a common mechanism of secondary injury.

Spreading depolarizations are a sustained wave of mass depolarization in the brain tissue, characterized by dramatic changes in ion distribution reflected by a large but transient negative shift of the extracellular direct current potential.

It occurs during the first two weeks after TBI and is associated with delayed ischemic neurological deficit and worsened outcome.

The review found that ketamine suppresses bursts and may increase the number of beta frequencies, inhibiting the occurrence of spreading depolarization. This supports the theory of an inhibitory effect on neuronal activity of ketamine.

To date, there is no evidence that midazolam has any effect on spreading depolarization.

Current evidence suggests that ketamine doesn’t increase ICP in severe TBI patients, and ketamine boluses may temporarily lower ICP.

Ketamine administration has better hemodynamic properties than midazolam, which may make sedation safer for polytraumatized, or hemodynamically unstable patients.

While not conclusive, these results indicate that ketamine is a viable alternative to midazolam in TBI patients, in particular those with suspected cortical spreading depolarization.

Spreading depolarization is a potentially modifiable secondary brain injury mechanism, and the likely positive effect of ketamine makes a strong case for a focused high-quality RCT.

If ketamine reduces spreading depolarizations, routine TBI sedation regimes should include ketamine for TBI management.

The relative poor quality and heterogeneity of the studies speak to the need for further investigation.

This article is based on my recent systematic review on this subject.

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