The correlation between ketamine and posttraumatic stress disorder in burned service members

Early reports from Operation Iraqi Freedom and Operation Enduring Freedom (OIF/OEF) describe substantial rates of posttraumatic stress disorder (PTSD) among returning service members, and untreated pain and physical injury have been proposed as contributors to PTSD risk. Ketamine, an anaesthetic with analgesic properties that also produces dissociative and psychotomimetic effects, is used at low doses as part of multimodal perioperative pain management in military burn care. Because of ketamine's psychoactive effects there has been concern that its perioperative use might increase the likelihood of later PTSD. Mcghee and colleagues set out to examine the prevalence of PTSD among OIF/OEF service members treated for thermal injuries at the United States Army Institute of Surgical Research (USAISR) Burn Centre between 2002 and 2007, and to explore whether receiving ketamine during operative procedures was associated with PTSD screening results. The study used the military version of the PTSD Checklist (PCL-M) as the screening instrument and compared patients who did and did not receive intraoperative ketamine, while also investigating the relationship between burn size and PTSD prevalence.

This was a retrospective chart review of US military personnel with thermal injuries treated at the USAISR Burn Centre from 2002 to 2007. Inclusion required completion of the PTSD Checklist–Military (PCL-M), a 17-item screening tool scored 17–85; the investigators used a threshold score of 44 or greater to indicate a positive PTSD screen. After institutional review board approval, hospital records were reviewed for percent total body surface area burned (%TBSA), injury severity score (ISS), number of surgeries performed at USAISR, details of the anaesthetic regimen including whether ketamine was given and amounts, and length of intensive care unit (ICU) stay. Opioid analgesics recorded in the charts were converted to intravenous morphine equivalents using standard conversion factors. To explore whether burn size predicted PTSD, the cohort of 241 patients who completed the PCL-M was dichotomised at 20% TBSA (less than 20% versus 20% or greater), a clinical threshold the authors describe as a point of maximal inflammatory response. Statistical analysis comprised nonparametric comparisons using the Mann–Whitney test, Spearman rank correlation to assess associations between PTSD and clinical variables, and receiver operating characteristic (ROC) analysis where indicated. The investigators report using SPSS software for correlation calculations.

From an estimated 25,000 OIF/OEF casualties, 603 burn patients were treated at USAISR; 241 of these completed the PCL-M and 147 underwent at least one operation at the centre. Among the 147 operatively managed patients, 119 received ketamine intraoperatively and 28 did not. The group who received ketamine had markers of greater acute morbidity: mean %TBSA 21.43 versus 10.22, mean ISS 16.94 versus 8.5, mean ICU stay 21.14 versus 11.67 days, and mean number of operations 2.55 versus 1.07. The authors state that these differences (TBSA, ISS, ICU days, number of operations, and total morphine equivalent units during surgery) were statistically significant by Mann–Whitney testing; age and morphine per surgical procedure did not differ between groups. The primary outcome—prevalence of a positive PTSD screen—was lower in the ketamine group: 26.9% (32 of 119) versus 46.4% (13 of 28) in patients not receiving ketamine (p = 0.044, Mann–Whitney). Using Spearman correlation, ketamine use was negatively associated with PTSD (correlation coefficient −0.166), indicating a weak inverse relationship. By contrast, PTSD did not correlate with total morphine equivalents during operations, burn size, ISS, days in ICU, or number of operations. Looking at the larger set of 241 screened patients, prevalence of PTSD was similar across burn-size strata: 49 of 180 (27%) for <20% TBSA and 17 of 61 (27.8%) for ≥20% TBSA. Plotting %TBSA against PTSD diagnosis and PCL-M score showed no identifiable threshold or slope change predictive of PTSD development.

The investigators interpret their findings as confirming that burn size is not a reliable predictor of PTSD in this cohort of combat-injured soldiers and report an unexpected association: patients who received perioperative ketamine screened positive for PTSD less often than those who did not, despite having larger burns and higher injury severity. Mcghee and colleagues emphasise that ketamine is commonly used as part of multimodal anaesthesia and is an NMDA receptor antagonist with analgesic and anaesthetic effects; it also reduces opioid requirements. Given ketamine's psychoactive profile, the initial expectation was that it might increase PTSD risk, but the observed lower prevalence suggests otherwise. The authors propose several possible explanations for their observation: improved pain control in patients receiving ketamine, neuroprotective effects of ketamine, and pharmacological antagonism of NMDA-mediated pathways involved in memory or stress-related neurobiology. They note that total morphine equivalents did not correlate with PTSD, which argues against opioid exposure during operations explaining the PTSD differences. Mcghee and colleagues acknowledge the retrospective design and that the mechanism remains unclear; they also raise the possibility that interactions with other anaesthetic agents might contribute and call for prospective research to clarify causation and mechanisms. The extracted text includes an invited commentary by Dr Carl Andrew Castro, who speculated that NMDA antagonism might disrupt memory consolidation or retrieval and thereby reduce PTSD, and who highlighted ethical issues around any deliberate pharmacological ‘‘erasure’’ of traumatic memories. Mcghee responded in the discussion, reiterating the retrospective limits of the data, agreeing that mechanisms need investigation, and suggesting future studies to test whether ketamine itself is protective or whether its use reveals deleterious effects of other agents.

The authors conclude that perioperative low-dose ketamine use in burned service members undergoing surgery was associated with a lower prevalence of positive PTSD screens in this retrospective cohort. They reiterate that the mechanism is uncertain—possible explanations include better analgesia, neuronal protection, or NMDA receptor antagonism—and recommend further studies to determine mechanisms and identify factors that might predict PTSD outcomes in patients who receive ketamine.