A retrospective study of ketamine administration and the development of acute or post-traumatic stress disorder in 274 war-wounded soldiers

Ketamine is widely used for pre-hospital anaesthesia in combat settings, but its effects on subsequent psychological sequelae of trauma are unclear. Acute stress disorder (ASD) and post‑traumatic stress disorder (PTSD) have distinct diagnostic windows and symptom clusters under DSM‑5: ASD occurs within days to a month after trauma and is a risk factor for PTSD, which is typically diagnosed 3–6 months later. Previous clinical reports have been conflicting: some observational work suggested peri-operative ketamine might reduce PTSD in burned soldiers, other analyses found no effect, and a randomised trial has reported ketamine can treat chronic PTSD symptoms. Mechanistically, ketamine has both psychomimetic and rapid antidepressant effects, and preclinical studies propose multiple neurobiological pathways by which it could either protect against or exacerbate stress‑related disorders. Mion and colleagues set out to examine whether ketamine administration to combat‑injured soldiers was associated with the subsequent development of ASD or PTSD. The primary objective was to assess the association between ketamine given to the war wounded and later PTSD; the secondary objective was to evaluate the relationship between ketamine and the incidence of ASD.

This was a retrospective, observational cohort study using a database compiled from French Military Health Service (FMHS) sources covering injuries sustained between 1 January 2010 and 31 December 2012 during the French military intervention in Afghanistan. The sampling frame comprised all soldiers who survived injuries from firearms, explosives or military transport accidents. A 780‑item database created by one of the authors from cross‑checked FMHS records supplied the data used for analysis. Diagnoses of PTSD followed FMHS procedures: soldiers completed a PTSD checklist (PCL‑S) 3–6 months after returning from mission, underwent a medical interview, and a psychiatrist made the final diagnosis. The investigators selected a prespecified set of covariables from the database to explore factors associated with ASD and PTSD. These included ASD presence, blast injury, associated fatality among the unit, injury severity score (ISS), head injury (ranging from scalp lesion to brain trauma), initial Glasgow Coma Scale (GCS), traumatic amputation, administered drugs (ketamine pre‑hospital or at field hospital with doses where available; morphine and midazolam at battlefield and field hospital), number of surgical procedures from field hospital to metropolitan hospital, physical/neurosensory/aesthetic sequelae, and chronic pain. Patients were classified into PTSD and no‑PTSD groups based on psychiatrist diagnosis; ASD status was also recorded. Bivariate comparisons used Student’s t‑test or Mann–Whitney test for quantitative variables, Chi‑square for categorical variables, and Kruskal–Wallis for groupings by ISS. Tests were two‑tailed with p < 0.05 considered significant; Bonferroni correction was not applied because multivariable analysis was planned. Covariates with p ≤ 0.10 on univariate comparison were entered into a multivariable logistic regression to identify independent associations with PTSD. Two regression approaches were used: a full model including all covariates and a backward stepwise model removing non‑significant variables. To reduce collinearity, ketamine and morphine were considered as global administrations (battlefield plus field hospital) in the multivariate models. Statistical analyses were performed with StatEL software.

The initial database contained 450 patients; 51 died, leaving 399 survivors, of whom 274 were analysed (two women, 0.7%). Age was available for 257 patients with mean ages of 30 years in the PTSD group and 29 years in the no‑PTSD group. Overall, 89 patients (32%) received ketamine, 98 (36%) were diagnosed with PTSD, and 49 (18%) had ASD. Patients who received ketamine had higher injury severity: median ISS was 5 (IQR 3–13) in the 89 who received ketamine versus 3 (IQR 2–4) in the 185 who did not (p < 0.001). ISS correlated positively with the number of surgical procedures (p < 0.001). In bivariate comparisons, PTSD cases were more severely injured, had higher rates of head injury and amputation, more chronic pain and physical/neurosensory/aesthetic sequelae, and underwent a substantially greater number of surgical procedures (the number was described as nearly six‑times higher than in the no‑PTSD group). Medication exposure differed by group: soldiers in the PTSD group received roughly twice as much morphine, three times as much ketamine and six times as much midazolam as those without PTSD. Ketamine exposure was more common among PTSD cases: 54 of 98 patients with PTSD (55%) received ketamine versus 35 of 176 without PTSD (20%); this difference was statistically significant (p < 0.001). The pattern held for ketamine given on the battlefield (27/98 [28%] vs 14/176 [8%]; p < 0.001) and at the field hospital (44/98 [45%] vs 26/176 [15%]; p < 0.001); some patients received ketamine at both time points. Among those who received ketamine, 54 of 89 (61%) developed PTSD compared with 24% of the 185 patients who did not receive ketamine (p < 0.001). Ketamine doses were incompletely recorded: battlefield doses were available for 193 patients, field hospital doses for 63, and both for 50. For the subset with dose data, mean ketamine dose did not differ between PTSD and no‑PTSD patients (173 (SD 144) mg vs 209 (SD 152) mg; p = 0.42). In multivariable logistic regression including covariates with p ≤ 0.10, ketamine administration was not an independent predictor of PTSD. The two variables that remained independently associated with PTSD were presence of ASD and total number of surgical procedures. In the stepwise model ASD had an odds ratio (OR) 16.5 (95% CI 6.5–41.8; p < 0.001) and number of surgical procedures had OR 1.4 per procedure (95% CI 1.2–1.6; p < 0.001). ASD itself predicted subsequent PTSD with 42% sensitivity and 95% specificity. There was no independent association between ketamine and ASD development; among 50 patients with simultaneous battlefield and field hospital dose data there was no significant difference in mean ketamine dose between those who developed ASD and those who did not (226 (SD 171) mg vs 175 (SD 139) mg; p = 0.34).

Mion and colleagues interpret their findings to indicate that, in this retrospective cohort of 274 war‑wounded soldiers with 36% PTSD prevalence, ketamine administration was not independently associated with either ASD or subsequent PTSD after adjustment for injury‑related covariates. The authors note that unadjusted comparisons showed higher ketamine exposure among PTSD cases, but attribute this to confounding by injury severity: more severely injured soldiers received more ketamine, and injury severity and number of surgical procedures were linked to PTSD risk. The discussion places these results in the context of prior, conflicting literature. Some retrospective studies had suggested ketamine might elicit or be associated with stress symptoms, while other work—including a randomised trial—has found ketamine can reduce PTSD symptoms. The authors review plausible mechanisms by which ketamine could either exacerbate or protect against stress disorders, including NMDA‑receptor antagonism, AMPA receptor effects, modulation of brain‑derived neurotrophic factor, activation of mTOR pathways, and subsequent synaptogenesis and network reconfiguration in prefrontal and cingulate regions. Strengths highlighted include the relatively long post‑event observation period and psychiatrist‑based PTSD diagnosis rather than relying solely on screening checklists. The investigators acknowledge several limitations: the retrospective design, incomplete dose data for many patients, and possible insufficient power for the primary endpoint despite a cohort size comparable with prior studies. They also state a randomised, controlled trial in the war setting would be impractical. The authors conclude that while debate continues, their data suggest ketamine use in traumatic military care does not have a detrimental effect on the later development of acute or chronic stress disorders.