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Cipolloni, L. Ketamine in Acute Brain Injury. Encyclopedia. Available online: https://encyclopedia.pub/entry/20791 (accessed on 16 November 2024).
Cipolloni L. Ketamine in Acute Brain Injury. Encyclopedia. Available at: https://encyclopedia.pub/entry/20791. Accessed November 16, 2024.
Cipolloni, Luigi. "Ketamine in Acute Brain Injury" Encyclopedia, https://encyclopedia.pub/entry/20791 (accessed November 16, 2024).
Cipolloni, L. (2022, March 21). Ketamine in Acute Brain Injury. In Encyclopedia. https://encyclopedia.pub/entry/20791
Cipolloni, Luigi. "Ketamine in Acute Brain Injury." Encyclopedia. Web. 21 March, 2022.
Ketamine in Acute Brain Injury
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This entry is adapted from the peer-reviewed paper 10.3390/healthcare10030566

Ketamine is a non-competitive antagonist of the NDMA receptor. The use of ketamine in patients with traumatic brain injury (TBI) has often been argued due to its possible deleterious effects on cerebral circulation and perfusion. Early studies suggested that ketamine could increase intracranial pressure, decreasing cerebral perfusion pressure and thereby reducing oxygen supply to the damaged cerebral cortex. Some recent studies have refuted these conclusions relating to the role of ketamine, especially in patients with TBI, showing that ketamine should be the first-choice drug in this type of patient at induction. 

ketamine intracranial pressure cerebral circulation

1. Introduction

Ketamine is a non-competitive antagonist of the NDMA receptor, discovered in 1956 with promising general anesthetic properties [1]. After nine years and still today, ketamine got in the operative room as a general anesthetic in humans. Chemically, ketamine is called 2-(2-chlorfelin)-2-(methylamino) cyclohexanone with two isomeric forms: (S)-(+) and (R)-(−). Currently, S-ketamine, the more potent of the two stereoisomers, is the most available or racemic mixture, containing both the (S+) and (R+) forms.
In addition to being NMDA antagonist, ketamine also shows synergism with other receptors such as opioid, monoaminergic, cholinergic, nicotinergic, and muscarinic, conferring a broad neuro-pharmacological pleiotropism [2].
After binding with the NMDA receptor, the main clinical effect is dissociative without vascular bed dilatation, so that no hypotension or heart rate variation is induced. This clinical combination makes ketamine potentially attractive when hypotension and cardiogenic shock occur, or high perfusion pressure is a priority, such as in patients with traumatic brain injury (TBI) [2][3].
This last clinical condition had been debated for many years; indeed, in the 1990s, ketamine was abandoned, on the assumption that the drug negatively influenced intracranial pressure [4].
Even more, its use must be carefully evaluated in cases of TBI. In these cases, various modifications occur in the damaged brain tissue [5][6][7][8], down to the subcellular level [9][10][11][12]. However, the greatest caution concerning the use of ketamine in patients with TBI should be linked to the potential increase in intracranial pressure through sympathetic stimulation, worsening the outcomes. Nevertheless, it has been observed that if combined with γ-aminobutyric acid (GABA), ketamine does not raise intracranial pressure [13].
Moreover, spreading depolarization (SD), an anomalous propagation of electrical activity described by electroencephalogram (EEG) or by internal measurement by adequate electrodes, is associated with worsening outcomes in patients with TBI [14][15][16]. It is a near-complete disruption of the transmembrane ion gradient, which takes origin from areas of local acute ischemia, as an expression of tissue suffering from lack of energy [17].
Recently, some trials have shown that a curative effect of ketamine may occur after TBI, probably related to the suppression of SD onset after brain damage [18].

2. Human Cerebral Circulation: Intracranial Pressure, Cerebral Perfusion Pressure, Mean Arterial Pressure, Heart Rate

Ketamine is a medicine with multiple effects that are applied in neurological/neurosurgical diseases. The principal mechanism of ketamine is NMDA receptor antagonism which then leads to the inhibition of glutamate activation. This inhibition leads to the suppression of the activity of the sensory cortex, limbic system, and thalamus, thus promoting the effect of dissociative anesthesia. At the peripheral level, ketamine acts on NMDA receptors, supporting the pain relief mechanism [19].
Seven studies analyzed the impact on intracranial pressure (ICP) in adults [20][21][22][23][24][25][26] and one in the pediatric population [22] with TBI, subarachnoid hemorrhage, or other intra-cranial traumatic diseases who had been admitted to intensive care in mechanical ventilation.

3. Ketamine, Spreading Depolarization and Burst Suppression

It has been observed that ketamine doses influence the electroencephalogram (EEG) tracing in a dose-dependent manner. Akeiju et al. [27] and Vlisides et al. [28], in their research, demonstrated that at the standard ketamine dosage required to induce unconsciousness, TBI EEGs showed a “gamma burst” pattern consisting of alterations in slow delta waves and gamma waves, associated with an increase in theta waves and a decrease in alpha and beta waves. In addition, in one study a quantitative EEG was used to determine deep sedation induced by ketamine, which may subsequently worsen the outcome of TBI [29].
Four studies [18][20][22][26] evaluated SD and burst suppression (EEG activity) during ketamine administration in brain-damaged patients. One of two studies, performed by the same team, concluded that ketamine significantly reduces SD, with a dose-dependent mechanism [17][18].

4. Ketamine Dosage

Fatal effects or life-threatening side effects were not reported and, in all papers, analyzing the ketamine bolus was not used uniformly and the dosage was 1–5 mg/kg [21][22][26]. In the outstanding research instead, the dosage of continuous intravenous administration was 0.3–200 mg/kg/h [18][20][30][31][23][24][25][26][32][27][28][29][33].
Four studies [20][24][25][26] indicated precise ketamine dosage titlated to the desired sedation level according to Ramsey Score or the Riker sedation-agitation scale. It is strongly recommended to keep the RASS score between -3 and -4 initially, which is then modified according to the therapeutic objectives [16].
The dosage of ketamine varies widely between studies and in many, there were concomitant medications (propofol, fentanyl, sufentanyl, midazolam, morphine, and etomidate) which can mask the real effects. The most anesthetic drug used in the operating room and ICU is propofol which among the anesthetics is the one that reduces the ICP quickly more than the others, in patients with TBI [34]. Moreover, the ketamine appears to have different effects if carried out before, during, and after an experimentally induced head injury as analyzed [35].

5. Controlled Ventilation and Arterial CO2

Related to its pharmacokinetics, pharmacodynamics, and central nervous system effect, ketamine is a potential alternative to be considered in TBI patients who require mechanical ventilation or in combination with other sedatives. In addition, one of the effects of ketamine is vasodilation and bronchodilatation [13][36]. Thus, ketamine is strongly recommended in patients with severe TBI who have asthma and/or chronic obstructive pulmonary disease (COPD) or situations at risk for severe bronchospasm [29][36]. This makes ketamine a useful drug to be used in TBI situations where it is necessary to maintain hemodynamic stability and avoid respiratory depression.
Furthermore, some authors reported that ketamine should be considered one of the best agents to facilitate airway management in patients with traumatic brain injury [37]. Even though ventilation management has a pivotal role in patients with severe head injuries [38], none of the 11 studies reported the monitoring of arterial CO2. On the other hand, in all studies, patients received mechanical ventilation, with no patient in spontaneous breath, which, in animal models, was related to increases in ICP during ketamine sedation [39][40].

6. Ketamine Toxicity

Regardless of the various possible and useful therapeutic applications of ketamine, its psychotropic properties on the CNS, well known in the forensic toxicological field, limit its widespread clinical use [41].
According to Krystal et al., indeed, even at 0.1 mg/kg doses, subjects may experience “endogenous psychosis-like” symptoms, behaviors, and cognitive deficits [42]. It should be remembered that ketamine use induces a state, known as “dissociative anesthesia”, in which the individual, albeit cardio-pulmonary functioning, is unable to respond to sensory stimuli [1]. These patterned effects, characterized by dissociation with visual, auditory, and somatosensory hallucinations and space–time distortion, have made ketamine a popular recreational drug. On the other hand, at higher doses, these effects will be amplified inducing a schizophrenia-like clinical condition [42][43]. Although these effects are transient and reversible, long-term use can cause cognitive impairment with severe cerebral atrophy [44]. To this, particular attention must be paid given the analogous long-term effects of TBI, such as recurrent depressive symptoms, dementia, and cognitive impairment, which could mutually influence each other negatively, worsening the overall clinic of the affected subjects [45][46][47].

7. Conclusions

As a result of its pharmacokinetic and pharmacodynamic characteristics, including neuromodulation properties, ketamine appears to be a safe drug and could be used alone or in combination with other sedatives in patients with moderate-to-severe TBI requiring mechanical ventilation.
After more than 50 years of research, ketamine use in patients with acute brain trauma still appears to be underused. Various prospective and retrospective trials have been completed, but all of these show a weakness that does not allow for solid recommendations to be formulated. However, no studies have shown any dangers of using ketamine in head trauma. This allows, therefore, to imagine the possibility of including this therapy in well-established clinical practice procedures for the treatment of brain injury. To this end, the next desirable move would be to carry out a double-blind, randomized, controlled multicenter study, identifying the multiple confounding factors by a multidisciplinary team that involves at least an anesthetist, a neurologist-neurophysiopathologist, a toxicologist, and a medico-legal expert.

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