Outcomes and physiologic responses associated with ketamine administration after traumatic brain injury in the United States and Canada: a retrospective analysis

The authors contextualise ketamine as a dissociative anaesthetic historically avoided in traumatic brain injury (TBI) because early reports suggested it could raise intracranial pressure (ICP), cerebral blood flow and metabolic rate. More recent clinical practice has increasingly used ketamine in trauma because of its haemodynamic stability, analgesic properties and respiratory-sparing effects. Small-scale prospective studies in TBI have reported either no increase or a reduction in ICP after ketamine, and preclinical mechanisms (e.g. reduction of glutamate toxicity and inhibition of cortical spreading depression) have suggested possible neuroprotective effects. However, earlier work did not examine patient-centred outcomes such as survival or disability, leaving uncertainty about the overall safety and outcome implications of ketamine use after TBI. Using the dataset from the multicentre Prehospital Tranexamic Acid Use for Traumatic Brain Injury (TXA for TBI) trial, the researchers set out to examine whether prehospital ketamine administration is associated with mortality, disability and physiologic responses in subjects with moderate-to-severe TBI. They also investigated ketamine's association with longitudinal trajectories of circulating TBI protein biomarkers (GFAP, MAP2, UCHL1) and performed a predefined subgroup analysis in patients with intracranial haemorrhage (ICH). The a priori hypothesis was that ketamine exposure would not be associated with worse survival or disability and would not produce different physiologic or biomarker responses compared with no ketamine exposure.

This study is a retrospective analysis of prospectively collected data from the TXA for TBI trial, a multicentre, North American randomised controlled trial that enrolled subjects from May 2015 to November 2017. The original trial randomised subjects with moderate-to-severe TBI to different tranexamic acid (TXA) regimens; the present analysis used that trial's dataset to compare subjects with and without recorded prehospital ketamine administration. Ketamine exposure was defined as documentation of ketamine given by emergency medical services in the prehospital setting; exact dosing and timing were not available. Subjects without ketamine exposure data were excluded, leaving 841 subjects for analysis (131 ketamine-exposed, 710 unexposed). Demographic and clinical variables extracted included age, sex, BMI, weight, initial Glasgow Coma Scale (GCS), Injury Severity Score (ISS), history of seizure, intubation status, presence of radiographic ICH and TXA study arm. The primary outcome was death within 6 months of injury. Secondary outcomes comprised Glasgow Outcome Scale Extended (GOSE) and Disability Rating Scale (DRS) at discharge and 6 months, incidence of seizure activity, cardiac events (cardiac arrest or heart failure), and surgical interventions. Physiologic measures recorded during the first 24 hours after hospital presentation included systolic blood pressure (SBP), heart rate, temperature, arterial oxygen pressure (PaO2), and ICP. ICP elevation was defined as ICP > 20 cmH2O. Definitions for bradycardia, tachycardia, hypoxia, hypotension, hypertension, hypothermia and hyperthermia were prespecified. Longitudinal serum measurements of GFAP, MAP2 and UCHL1 were available at admission and at 6, 12, 24 and 48 hours; biomarker analyses used change from admission and absolute concentrations. Statistical analysis used multivariate mixed-effects logistic regression to evaluate associations between ketamine exposure and outcomes, with covariates including age, sex, race, BMI, seizure history, intubation status and TXA study assignment. Because cardiac events and seizures were rare, simplified models with reduced covariates were specified for those outcomes (details of which covariates were removed are reported). Biomarker concentrations were log-transformed and analysed with mixed-effects models using the same covariates; p-values for biomarker models were adjusted for multiple comparisons using Bonferroni correction. Stratifications and score cut-offs (e.g. GCS, ISS, GOSE, DRS) are reported, and analyses were performed using Stata v17.0. The ICH subgroup (radiographically confirmed intracranial haemorrhage) was analysed separately given prior findings in the parent trial.

Of 966 subjects in the original trial, 910 had ketamine data and 841 had complete ketamine exposure data for this analysis; 131 subjects (15.6%) received prehospital ketamine and 710 (84.4%) did not. Ketamine-exposed subjects were younger (mean age 37.3 ± 16.9 years vs. 42.0 ± 18.6 years; P = 0.037), had a worse initial GCS (mean 7 ± 3 vs. 8 ± 4; P = 0.003) and were more frequently intubated (88.5% vs. 44.2%; P < 0.001). ISS and ICH prevalence were similar between groups. Primary outcome: death within 6 months occurred in 12.2% of ketamine-exposed subjects versus 15.5% of unexposed subjects (P = 0.391), indicating no statistically significant difference in mortality. Secondary outcomes: there were no significant differences in disability measures (GOSE at discharge or at 6 months; DRS) or in the need for surgical interventions (6.9% ketamine-exposed vs. 11.1% unexposed; P = 0.113). Using simplified models due to low event counts, seizure activity was more frequent in ketamine-exposed subjects (3.1% vs. 1.0%; P = 0.010). Cardiac events were rare and not associated with ketamine exposure in the whole cohort (1.5% vs. 0.8%; P = 0.961). Physiologic responses in the first 24 hours: instances of elevated ICP (ICP > 20 cmH2O) were less frequent in the ketamine-exposed group (56.3% vs. 82.3%; P = 0.048). Other extremes (hypoxia, heart rate, SBP, temperature) showed no significant differences between groups. Biomarkers: ketamine exposure was associated with smaller increases from admission in GFAP at 12, 24 and 48 hours, and in MAP2 at 12 and 24 hours. Changes in UCHL1 from baseline did not differ significantly between groups. Absolute biomarker concentrations were not different between groups after correction for multiple comparisons, except that in the ICH subgroup GFAP concentration at 48 hours was lower in ketamine-exposed subjects (2,261 ± 4,727 pg/mL vs. 4,497 ± 10,508 pg/mL; P = 0.003). ICH subgroup (n = 502 with radiographic ICH; 86 ketamine-exposed): demographic patterns mirrored the full cohort (ketamine-exposed younger and more often intubated). Mortality was higher overall in the ICH subgroup but did not differ by ketamine exposure (18.6% vs. 23.3%; P = 0.177). Ketamine exposure remained associated with increased seizure activity in the ICH subgroup (3.5% vs. 1.0%; P = 0.009) and, in this subgroup, cardiac events were more frequent with ketamine (2.3% vs. 0.2%; P = 0.025). The difference in ICP elevation observed in the full cohort did not reach statistical significance in the ICH subgroup (56.3% vs. 82.0%; P = 0.055). Biomarker trajectories in the ICH subgroup paralleled the overall findings (smaller rises in GFAP and MAP2 with ketamine, no difference in UCHL1).

The authors interpret these retrospective findings as indicating that prehospital ketamine administration was relatively common (15.5%) in the TXA for TBI trial and, despite being administered to subjects with a worse initial neurologic profile (lower GCS, higher intubation rates), ketamine exposure was not associated with increased mortality or disability. They note that the ketamine-exposed group was on average younger, which could favour outcomes, but emphasise that no prior studies have examined ketamine's association with morbidity and mortality after TBI and consider these results reassuring given ketamine's frequent use. The authors also highlight safety signals: seizure activity was significantly more common among ketamine-exposed subjects in both the full cohort and the ICH subgroup, and cardiac events were associated with ketamine in the ICH subgroup. They caution that these events were rare and that it is unclear whether the associations reflect ketamine effects or residual confounding related to the worse injury profile of the ketamine group. The authors remind readers that ketamine has been associated with cardiovascular collapse in other populations and recommend continued caution regarding cardiovascular and neurological side effects when administering ketamine. Contrary to historical concerns that ketamine raises ICP, the authors found fewer instances of elevated ICP in ketamine-exposed subjects. They situate this result with prior small clinical studies in TBI that showed no increase or reductions in ICP with ketamine, and they note limitations of the early studies (e.g. healthy volunteers, uncontrolled respiratory rate) that may have contributed to earlier findings. The authors acknowledge that their analysis captured instances of ICP extremes rather than duration or magnitude of ICP elevation. Regarding biomarkers, the authors report that ketamine exposure was associated with smaller rises in GFAP and MAP2 over time, and a significantly lower GFAP concentration at 48 hours in the ICH subgroup. They suggest this could indicate a suppressive effect of ketamine on these circulating TBI biomarkers and propose that longitudinal biomarker trajectories might be useful to monitor pharmacologic effects and therapeutic responses to ketamine. The authors conclude by noting that these associations are hypothesis-generating and warrant further investigation. Limitations acknowledged by the authors include the retrospective nature of the analysis (precluding causal inference), ICP measurements being available in fewer than 20% of subjects (limiting power to draw conclusions about ICP), absence of detailed ketamine dosing and timing data, and physiologic analyses being limited to instances of extremes rather than continuous measures of severity or duration.