The Evolution of Ketamine in Severe Pediatric Traumatic Brain Injury, From Contraband to Promising Neuroprotectant?

Abstract

The first report of the use of ketamine (CI-581) in humans in 1965 described it as a promising dissociative analgesic and anesthetic phencyclidine derivative with less psychotomimetic effects (1). Ketamine rapidly gained increasing use in anesthesia, given its favorable systemic hemodynamic profile. However, beginning in the early 1970s, concerning effects on intracranial pressure (ICP) were reported in both healthy adults undergoing herniorrhaphy and orthopedic surgical procedures, and infants and children anesthetized for ventriculoperitoneal shunt placement, among other studies (2,3). This raised concerns over its use in patients where there might be raised ICP, and thus its utility in patients with acute brain injury. Increases in cerebral blood flow (CBF), possibly mediated in part by increases in Paco2 during anesthesia, were suggested to mediate the increases in ICP (4). In the 1990s, several studies questioned the concerns regarding the utility of ketamine in patients with severe traumatic brain injury (TBI). Kolenda et al (5), and Albanèse et al (6), reported that continuous infusion or bolus administration of racemic ketamine was associated with improved cerebral perfusion pressure (CPP) and decreased ICP, respectively, in critically ill adults with TBI. The patients in those studies were also sedated with midazolam or propofol infusions and managed with controlled normoventilation. Both studies and others prompted reviews suggesting that it might be time to revise the dogma against ketamine in the management of TBI and other neurocritical care disorders (7). However, ketamine use as an analgesic or sedative gained little traction in the field of TBI, although sporadic reports continued to suggest potential utility. In pediatric neurocritical care, Bar-Joseph et al (8), reported that bolus administration of ketamine (1–1.5 mg/kg IV) to 30 children with ICP greater than 18 mm Hg, resistant to first-tier therapies, decreased ICP by 30% and increased CPP by 7%. Those patients included critically ill infants and children with a variety of acute neurologic diseases, although 24 had TBI. Unfortunately, the inability to define the effects on ICP and CPP in the TBI cohort, and the lack of provision of Glasgow Coma Scale scores in the TBI group, made that study inadmissible evidence in the 2012 or 2019 Pediatric TBI Guidelines (9,10), although it was mentioned in the 2019 Guidelines (10) but not in the accompanying treatment algorithm (11). The report by Laws et al (12) in this issue of Critical Care Medicine is a welcome addition to the pediatric severe TBI literature and one that could impact future guidelines and/or spur additional investigation. In a retrospective observational study in 33 critically ill pediatric patients with severe TBI managed within a guidelines-based approach, 22 received 127 doses of ketamine (0.5–2.0 mg/kg, IV) for either sedation or for ICP crises. Notably, 11 of those patients received a total of 18 boluses of ketamine for ICP crises (ICP > 20 mm Hg for ≥ 5 min). When used as part of an analgesia-sedative regimen with a remifentanil, fentanyl, hydromorphone, or morphine infusion, after bolus ketamine administration, ICP and CPP did not differ from baseline. When used to treat ICP crises, ICP was significantly reduced versus baseline at 0–5 minutes and for all temporal epochs between 21 and 120 minutes after ketamine administration. In addition, when used to treat ICP crises, CPP significantly improved versus baseline between 81 and 120 minutes after administration. This report continues to provide evidence dispelling the long-standing belief that ketamine raises ICP as a sedative in patients with severe TBI and provides evidence in a limited sample that it may be useful during ICP crises. Many of the 33 patients received various second-tier therapies such as pentobarbital infusions and/or decompressive craniectomy, however, of the 11 that received a ketamine bolus for an ICP crises, only 5 (28%) were receiving a continuous infusion of 3% saline and only one was receiving a continuous infusion of pentobarbital. This suggests that for some patients, ketamine may have been part of early first-tier therapy, after cerebrospinal fluid drainage, for ICP crises, as outlined in the treatment Algorithm at Vanderbilt Children’s Hospital (see Suppl. Figure 1 [12] in the original report). Given the evidence that more strongly supports the use of bolus hyperosmolar therapy to reduce ICP and improve CPP in crises settings recently published by the multicenter Approaches and Decisions in Acute Pediatric Traumatic Brain Injury comparative effectiveness trial (13), once adequate analgesia and sedation are ensured, ketamine use should not supplant the use of bolus 3% saline or mannitol in the treatment algorithm. However, based on the prior work of Bar-Joseph et al (8) and this report, ketamine is gaining support to be considered as an additional second-tier option for refractory-raised ICP. Ketamine merits further testing in larger studies both in the setting of raised ICP refractory to tier 1 therapy and/or as part of the baseline sedative-analgesia regimen in pediatric severe TBI. This is also true given the limited efficacy of fentanyl and/or midazolam to reduce ICP and improve CPP in prior reports (14,15), the known associations between benzodiazepine use and delirium in pediatric critical care (16), and recent reports suggesting possibly less delirium with ketamine use as an adjunct for analgesia and sedation in the PICU (17,18). Future prospective studies should seek to examine the effect of ketamine within the multimodal treatment of severe TBI patients. Laws et al (12) were unable to incorporate ventilator changes, vasoactive medication use, or electroencephalogram findings that may affect ICP in their report. The impact of ketamine on ICP at later timepoints (> 20 min after administration) in the study may reflect nonsedative changes in the management of these patients with intracranial hypertension. Nonetheless, the potential utility of ketamine to treat refractory raised ICP in severe TBI is further supported by the recent report of Dengler et al (19), who assessed the effect of a ketamine bolus (average dose 150 mg) in 30 adults with severe TBI and refractory ICP (> 20 mm Hg) deemed to be adequately sedated, at target serum sodium level, and with Paco2 controlled between 35 and 40 mm Hg. In that retrospective study, an ICP reduction of 3.5 mm Hg and CPP increase of 2 mm Hg were observed. One of the remaining questions is why did the early reports note raised ICP in patients (both children and adults) receiving ketamine? Although increases in Paco2 have been suggested to explain this finding, along with lack of monitoring in early studies in spontaneously breathing patients (12), Takeshita et al (4) observed a nearly doubling of CBF in adults after a 3 mg/kg dose of ketamine, despite only a 3.7 mm Hg increase in Paco2. In that study, and many of the other early reports (2,3), ketamine was the sole anesthetic, and it may be that unlike the early reports, use in severe TBI, where it is accompanied by narcotics and other sedatives, potential direct effects of ketamine on CBF are blunted. A direct increase of CBF in humans by ketamine independent of Paco2 or blood pressure that could be prevented by midazolam has been reported (20). Thus, to treat refractory ICP in severe pediatric TBI, caution may still be in order, and ketamine should not be used as the sole sedative. However, it should be recognized that in the report of Takeshita et al (4), the Kety-Schmidt technique was used, which fails to take into account the failure to use delivered oxygen and might produce erroneous conclusions on the CBF increase. Ketamine could also have neuroprotective effects in TBI independent of its effects on ICP. Recent studies suggest a role for spreading depolarizations in mediating secondary injury after severe TBI and other neurocritical care conditions such as stroke and subarachnoid hemorrhage. Ketamine is one of only a few drugs that inhibits spreading depolarizations. Carlson et al (21), in a study in 10 adults with severe TBI reported that ketamine, at doses greater than 1.15 mg/kg, was associated with a markedly reduced risk of spreading depolarization (odds ratio 13.8). Hartings et al (22) also reported a case where bolus administration of ketamine (1.5 mg/kg) eliminated spreading depolarizations in a severe TBI patient. Spreading depolarizations also could be more common after pediatric versus adult acute brain injury based on preclinical studies (23). Similarly, ketamine has anticonvulsant properties and a recent report by Jacobwitz et al (24) revealed that ketamine infusion to treat refractory status epilepticus in 69 pediatric patients terminated status in 32, reduced seizures in 19, and was associated with few adverse effects. Thus, additional secondary injury mechanisms related to excitation might also be targeted by ketamine use in severe pediatric TBI. Finally, beneficial effects could also result from anti-excitotoxic effects, given its N-methyl-D-aspartate receptor antagonism. Sustained glutamate elevations have long been reported in both adult and pediatric TBI (25,26). The work of Laws et al (12), in this issue of Critical Care Medicine, is a welcome addition to the pediatric TBI literature and adds ketamine to the list of therapies available to treat refractory raised ICP in severe pediatric TBI. Ketamine may also have efficacy beyond that role, namely as part of background sedation and analgesia, and via exciting multifaceted potential effects on spreading depolarization and seizures. Laws et al (12), and the other reports discussed here support the need for clinical trials of ketamine in pediatric severe TBI, assessing not only effects on ICP and other facets of acute neuromonitoring but also evaluating effects on long-term outcomes.