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International Journal of Critical Illness and Injury Science logoLink to International Journal of Critical Illness and Injury Science
. 2024 Sep 20;14(3):160–175. doi: 10.4103/ijciis.ijciis_36_24

Clinical outcomes of ketamine in patients with traumatic brain injury: A systematic review

Mohammad Sameer 1,✉, Duaa Al Abbas 1
PMCID: PMC11540192  PMID: 39512554

ABSTRACT

The current literature provides contradictory results concerning the impact of ketamine-induced anesthesia on traumatic brain injury (TBI) outcomes. This study aimed to investigate the potential of ketamine boluses to influence the brain pathophysiology in TBI patients. Twenty-one studies (n = 886) were extracted from PubMed, Web of Science, Scopus, CINAHL, and Cochrane Library. The primary endpoints included intracranial pressure (ICP) and cerebral perfusion pressure (CPP). The secondary endpoints were mean arterial pressure (MAP), heart rate (HR), electroencephalography (EEG), mean cerebral blood flow velocity, jugular oxygen saturation, ventilation, neurological outcomes, mortality, and overall efficacy and side-effects of ketamine-induced anesthesia. Four studies indicated a statistically significant decline in ICP in TBI patients, with ketamine sedation. Contrastingly, two studies revealed statistically significant ICP elevations, after ketamine-induced anesthesia, in TBI patients. Five studies negated any correlation between ketamine dosages and ICP changes. Three studies indicated a statistically significant increase in CPP after ketamine-induced anesthesia in TBI patients. One study revealed CPP decline after the administration of ketamine-midazolam treatment to TBI patients. Five studies revealed no noticeable influence of ketamine bolus on CPP in TBI patients. Similarly, inconsistent variations were observed in most of the secondary endpoints, including electroencephalography, neurologic outcomes, and ketamine-related side effects (all P <0.05). This systematic review emphasizes the role of ketamine-induced anesthesia in inconsistently improving or deteriorating clinical outcomes in patients with TBI. Future studies should evaluate the predominant causes (i.e., factors and attributes) of ketamine-related clinical outcomes in the TBI setting.

Keywords: Anesthesia, ketamine, sedatives, traumatic brain injury, ventilation

INTRODUCTION

Traumatic brain injury (TBI) is a widely recognized cause of serious/fatal clinical complications worldwide.[1] TBI could trigger exon degeneration, glial cell death, oxidative stress, excitotoxicity, and mitochondrial dysfunction.[2] The N-methyl-D-aspartate (NMDA) receptor (ketamine) is presently considered a viable sedation option for TBI management.[3] Contrastingly, the variable influence of ketamine on the neurophysiology of TBI patients is still being researched in scientific studies.

Intracranial pressure (ICP) elevation, after ketamine boluses, in TBI patients is emphasized by several contemporary studies.[4,5] Contrastingly, several other studies negate any possible impact of ketamine on ICP, whereas some studies advocate a decrease in ICP following ketamine sedation in traumatized patients.[6,7,8,9] Similarly, preclinical studies provide contrasting evidence regarding the role of ketamine-induced anesthesia in elevating or lowering/stabilizing metabolic activity and cerebral perfusion pressure (CPP).[10,11]

Ketamine-induced sedation is a preferred option to anesthetize TBI patients with a known history of hypotension.[12] This is because this NMDA antagonist is not known to have any chronotropic effect, due to which it does not cause blood pressure changes. Research evidence demonstrates noticeable changes in the electrical activity of the traumatized brain, leading to spreading depolarization (SD).[13] The occurrence of SD in the electroencephalography (EEG) of TBI patients is indicative of neuronal transmembrane disruption/inactivity.[14] TBI also impacts ventilation, jugular oxygen saturation, mean cerebral blood flow velocity, heart rate (HR), and mean arterial pressure (MAP).[15] In addition, ketamine-induced anesthesia could further interfere with these parameters and improve or aggravate them in TBI patients.[8] This is why it is important to examine the clinical relationship of ketamine boluses with these pathophysiological parameters. Accordingly, this study aimed to examine the impact of sedation with ketamine boluses on the clinical outcomes among all age-grouped subjects with TBI.

Search approach and data collection

The databases, such as PubMed, Scopus, Web of Science, Cochrane Library, and CINAHL were explored to screen the articles of interest. This search was undertaken on March 2024 through the following MESH terms: (1) brain injury, (2) traumatic, (3) ketamine, (4) N-Methyl-D-Aspartate Receptor Antagonists, (5) NMDA, (6) acute, (7) neuroprotective agents, (8) analgesics, (9) anesthesia, and (10) sedation [Supplementary Table 1]. Data were collected by two independent authors on an Excel sheet. Double data entry checks by the authors ascertained the exclusion of data entry errors. A librarian was involved in formulating the search strategy. Of note, the search was limited by the English language and the date range of 1982–2023 based on the availability of research papers.

Supplementary Table 1.

Search strategy

Searches Search terms
Search string - 1 Traumatic AND Brain Injury
Search string - 2 Bran injury AND Acute
Search string - 3 NMDA OR Ketamine
Search string - 4 N-Methyl-D-Aspartate Receptor
 Antagonists OR Ketamine
Search string - 5 Sedation OR Anesthesia OR Analgesics
 OR Neuroprotective Agents
Search string - 6 Sedation AND Acute AND NMDA AND
 Traumatic AND Brain Injury
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Inclusion and exclusion parameters

This study analyzed data from all age groups, including pediatric and elderly patients. The diagnosis of TBI, sedation with ketamine (versus sedation with a comparator), and clinical outcomes following anesthesia were the necessary parameters to be considered in the included studies. Furthermore, this systematic review included retrospective, prospective, cross-sectional observational, explorative, and randomized controlled studies. The authors did not include meta-analyses, systematic reviews, preprints, review papers, editorials/correspondences, narrative reviews, opinion papers, scoping reviews, and other secondary studies for analyzing the primary and secondary endpoints. In addition, gray literature was not eligible for inclusion. Clinical trial registries were not searched for unpublished studies.

Primary and secondary endpoints

ICP and CPP were the primary endpoints for this study. The secondary endpoints included MAP, HR, EEG, mean cerebral blood flow velocity, jugular oxygen saturation, ventilation, neurological outcomes, mortality, and overall efficacy and side-effects of ketamine-induced anesthesia.

Risk of bias

The risk of bias (ROB) assessment of the randomized controlled/prospective studies was undertaken through the Cochrane ROB-2 algorithm.[16] However, Cochrane ROBINS-I was used to identify the ROB in nonrandomized (observational) studies.[17]

RESULTS

Extraction of studies

Three hundred and forty-one studies were extracted from PubMed, Web of Science, and Scopus databases [Figure 1]. In addition, 47 articles were explored across CINAHL and Cochrane Library. Subsequently, 294 studies were screened after excluding 243 articles based on unrelated data. Fifty-one studies were assessed for eligibility; of them, 30 articles were eliminated due to inappropriate comparisons, quality issues, language bias, flaws in the study design, and incorrect population parameters. Finally, 21 studies (including 7 randomized controlled/prospective and 14 observational studies) qualified for this systematic review (n = 886).

Figure 1.

Figure 1

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Study flow chart

Systematic review

Table 1a and b elaborate on the author details, publication year, sample size, study type, aims/interventions, primary/secondary endpoints, and overall outcomes/inferences from the included studies.

Table 1.

(a) Systematic review

graphic file with name IJCIIS-14-160-g002.jpg

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Primary endpoints

Intracranial pressure

Eleven studies evaluated the impact of ketamine anesthesia on the ICPs of patients with TBI. Of them, four studies indicated a statistically significant decline in ICP in TBI patients, who were sedated with ketamine. The retrospective analysis by Dengler et al.[18] revealed that ketamine bolus anesthesia for patients with TBI resulted in −3.5 mmHg ICP decline (P < 0.001). The assessment by Albanèse et al.[19] affirmed that irrespective of ketamine dosages, the ketamine bolus resulted in a statistically significant (2–5 mmHg) decline in the ICP (P < 0.05). The prospective-controlled study by Bar-Joseph et al.[6] confirmed a 30% (25.8–18 mmHg) decline in ICP after ketamine bolus administration (P < 0.001) in the TBI patients. Findings from the retrospective study by Laws et al.[20] revealed that during the ICP crisis, a decline in ICP was observed in TBI patients who were anesthetized with ketamine bolus, following the sedation guidelines.

Alternatively, two studies revealed statistically significant ICP elevations, after ketamine-induced anesthesia, in TBI patients. The findings from the prospective study by Kolenda et al.[21] indicated > 25 mmHg ICP elevation in patients receiving ketamine sedation, in comparison to the control group. Another prospective cohort study by Belopavlovic and Buchthal[22] affirmed that ketamine dosage significantly increased ICP (>6 mmHg) versus the comparator.

Five studies negated any correlation between ketamine dosages and ICP changes in patients who were intubated or surgically intervened for TBI. A randomized double-blinded prospective trial conducted by Bourgoin et al.[23] found no statistically significant variations in intracranial pressure (ICP) between mechanically ventilated traumatic brain injury (TBI) patients who were sedated with ketamine and those who received the current anesthetic midazolam. Another randomized study by Bourgoin et al.[24] revealed that an increase in ketamine plasma concentration had no significant impact on ICP in TBI patients. A prospective observational study by Caricato et al.[25] defied any change in ICP in TBI patients, after ketamine administration. A randomized, controlled, prospective study by Schmittner et al.[26] affirmed no ICP elevation, following ketamine sedation in TBI patients. A retrospective observational analysis by Mazandi et al.[27] affirmed that ketamine did not exacerbate ICP in pediatric patients with TBI.

Cerebral perfusion pressure

Nine studies investigated the correlation of ketamine sedation with CPP in the TBI setting. Three studies indicated a statistically significant increase in CPP after ketamine-induced anesthesia in TBI patients. The assessment by Dengler et al.[18] revealed a 2 mm increase in CPP, from baseline, after ketamine boluses (P < 0.001). The study by Bar-Joseph et al.[6] indicated a statistically significant elevation (54.4–58.3 mmHg) in CPP after ketamine administration (P < 0.005). Laws et al.[20] reported a noticeable increase in CPP in TBI patients after their conscious sedation with ketamine boluses.

Alternatively, the study by Belopavlovic and Buchthal revealed CPP decline after the administration of ketamine–midazolam treatment to TBI patients.[22]

Findings from five studies revealed no noticeable influence of ketamine bolus on CPP of the TBI patients. The study by Albanèse et al.[19] emphasized that ketamine bolus did not significantly influence CPP from baseline. Results from the study by Bourgoin et al.[23] indicated no statistically significant difference in CPP between TBI patients with midazolam-sufentanil infusion and those with midazolam–ketamine infusion. The subsequent analysis by Bourgoin et al.[24] revealed that an increase in ketamine plasma concentration had no significant impact on CPP in TBI patients. Similarly, the analysis of Caricato et al.[25] revealed no change in CPP after ketamine-induced anesthesia. A randomized, controlled, prospective study by Schmittner et al.[26] indicated no significant difference in CPP between TBI patients with ketamine-induced anesthesia and those with fentanyl-induced sedation.

Secondary endpoints

Mean arterial pressure

Four studies were analyzed for the impact of ketamine anesthesia on MAP in TBI patients. The analysis of Bourgoin et al.[23] revealed no significant difference in the MAP between TBI patients administered with midazolam-sufentanil infusion and those with midazolam–ketamine infusion (P < 0.05). The observational (prospective) study by Caricato et al.[25] affirmed no change in MAP after ketamine-based anesthesia in TBI patients who underwent endotracheal suctioning. Contrastingly, a prospective study by Kolenda et al.[21] revealed that ketamine-induced sedation was associated with >10 mmHg MAP elevation, in comparison to contemporary sedation, in TBI patients. Similarly, the analysis by Maheswari et al.[28] revealed that patients (n = 10, 40%), who were sedated with ketofol had > 20% reduction in MAP.

Heart rate

Three studies examined the correlation between ketamine sedation with the HR of patients with TBI. The prospective controlled study by Bar-Joseph et al.[6] revealed no significant change from baseline, following ketamine bolus, in TBI patients. The assessment in the randomized double-blinded prospective study by Bourgoin et al.[23] indicated that day 3 and day 4 of ketamine administration to the TBI patients resulted in a statistically significant increase in HR values (P < 0.05). The real-world analysis by Kolenda et al.[21] revealed >20 bpm mean pulse rate elevation in TBI patients who were administered midazolam–ketamine, compared to those who were treated with midazolam-fentanyl.

Electroencephalography

Four studies investigated EEG activity in TBI patients, treated with ketamine bolus. A retrospective study by Albanèse et al.[19] revealed a burst suppression in the EEG activity after ketamine administration in TBI patients. A retrospective study by Akeju et al.[29] recorded a gamma burst in TBI patients who were sedated with ketamine. A multiple crossover, randomized, prospective study by Carlson et al.[30] indicated that ketamine dosage (1.15 mg/kg/h) resulted in a significant decline in SD Alternatively, reduced ketamine dosages minimally impacted SD in patients with TBI. An explorative retrospective study by Hertle et al.[31] affirmed the association of SD with relative beta frequency. The authors further confirmed that ketamine minimized SDs and elevated the relative beta frequency in TBI patients. In addition, beta frequency reduction independently correlated with SD count elevation. This study also correlated low SD counts with ketamine-induced/nonketamine-induced beta frequency suppression.

Mean cerebral blood flow velocity

A retrospective study by Albanèse et al.[19] and an observational prospective study by Caricato et al.[25] affirmed no impact of ketamine bolus on the mean cerebral blood flow velocity in patients with TBI (P > 0.05).

Jugular oxygen saturation

The analyses by Albanèse et al.[19] and Caricato et al.[25] negated any change in the jugular oxygen saturation in TBI patients, following their ketamine-induced anesthesia.

Ventilation

While three studies[6,22,23] confirmed the provision of controlled/assisted mechanical ventilation for TBI patients, the assessment by Kolenda et al.[21] reported bronchodilation following the administration of ketamine bolus for anesthesia.

Neurologic outcomes

The retrospective study by Grathwohl et al.[32] indicated that 75% of patients with ketamine-induced total intravenous anesthesia had better neurological outcomes versus 54% of patients who were sedated with volatile gas anesthesia. Furthermore, the retrospective observational analysis by Mazandi et al.[27] revealed no differences between the study groups (ketamine versus other sedatives, such as propofol, midazolam, or fentanyl) in the requirements for hypertonic saline, tracheal intubation-related operating room emergency visit, CT scan, as well as neurologic episodes (P = 0.42). A retrospective cohort assessment by Loi et al.[33] revealed that in neurotrauma intubations, ketamine administration was not associated with elevated side effects, hemodynamic instability, and peri-intubation hypoxemia (adjusted odds ratio [OR]: 1.34, 95% confidence interval [CI] 0.99–1.81; P = 0.057).

Mortality

The retrospective analysis by Grathwohl et al.[32] revealed a reduced mortality rate in patients with ketamine-based total intravenous anesthesia versus volatile gas anesthesia patients (5% vs. 16%; P < 0.05). Furthermore, the study by Mazandi et al.[27] confirmed the absence of 24-h mortality, following ketamine administration in pediatric patients with TBI.

Overall efficacy and side-effects of ketamine-induced anesthesia

Four of the included studies provided information about ketamine-related side effects in TBI patients. The analysis by Kolenda et al.[21] revealed that one patient in the ketamine group had cardiovascular arrest and was eventually withdrawn during the study. A retrospective study by Kane et al.[34] affirmed ketamine-induced side effects in 24.4% of patients with brain trauma, compared to 18.8% of those without brain trauma. A single-blind randomized-controlled study by Jabre et al.[35] revealed no statistically significant difference in the sequential organ failure assessment score between TBI patients with ketamine-induced sedation and those with etomidate-based sedation (P > 0.05). Furthermore, etomidate group patients had higher occurrences of adrenal insufficiency versus those who were sedated with ketamine (OR: 6.7, 95% CI 3.5–12.7; P < 0.05). A double-blinded, randomized controlled, prospective study by Maheswari et al.[28] negated statistically significant differences in the Glasgow Outcome Scale and brain relaxation scores (intraoperative) between ketofol and propofol TBI groups. A cross-sectional, observational, multicenter study by Groth et al.[36] evidenced the association of postrapid sequence intubation hypotension with ketamine use in TBI patients (relative risk: 1.78, 95% CI 1.36–2.35). A placebo-controlled, double-blinded, randomized study by Smischney et al.[37] revealed an enhancement of hemodynamic stability after ketofol administration until 10 min of anesthesia administration in TBI patients. However, a 20% decline in SBP was observed in patients who received general anesthesia through propofol. A single-blind randomized controlled study by Jabre et al.[35] recognized ketamine-assisted endotracheal intubation as a viable replacement of etomidate sedation in patients with TBI.

Risk of bias

Seven randomized controlled/prospective studies were evaluated through the Cochrane ROB2 tool to evaluate their biases [Figure 2a]. The study by Bourgoin et al.[23] had some concerns regarding the randomization process. However, the analyses by Bourgoin et al.[24] and Schmittner et al.[26] had some concerns regarding a possible bias due to noncompliance with the study procedures. In addition, some concerns regarding missing study data bias were underscored in the study by Jabre et al.[35] Low biases were observed in the randomization procedures, intervention deviations, missing information, outcome assessment, and the data selection process in the study by Smischney et al.[37] However, the study by Carlson et al.[30] had some concerns regarding the procedural deviations and outcomes measurement. Similarly, the analysis by Maheswari et al.[28] had some concerns regarding the outcome assessment bias. Overall, low bias was reported in all randomized studies despite some concerns in 10%–15% of the analyzed data [Figure 2b].

Figure 2.

Figure 2

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(a) Risk of bias (ROB) 2 traffic light plot, (b) ROB2 summary plot, (c) ROBINS-I traffic light plot, (d) ROBINS-I summary plot

Fourteen observational studies were evaluated for biases through the ROBINS-I tool [Figure 2c]. Moderate confounding-related bias was observed in the studies by Dengler et al.,[18] Laws et al.,[20] and Loi et al.[33] Serious and critical confounding-related biases were observed in studies by Grathwohl et al.[32] and Groth et al.,[36] respectively. Of note, low ROBs in patient selection and procedure classification were tracked in all observational studies. Moderate biases concerning intervention nonadherence were observed in studies by Dengler et al.[18] and Mazandi et al.[27] Furthermore, missing data-related moderate biases were observed in studies by Grathwohl et al.,[32] Mazandi et al.,[27] Loi et al.,[33] and Groth et al.[36] Notably, the result measurement-related moderate biases were observed in studies by Dengler et al.,[18] Albanèse et al.,[19] Bar-Joseph et al.,[6] Caricato et al.,[25] Kolenda et al.,[21] and Laws et al.[20] Moderate bias regarding result categorization was further observed in the study by Loi et al.[33] Overall, moderate and low biases were observed in 4 and 10 studies, respectively. The summary plot revealed critical, serious, moderate, and low ROBs in 5%, 5%, 5%–25%, and 65%–85% of the observational studies, respectively [Figure 2d].

DISCUSSION

This systematic review underscores significant variations in the impact of ketamine boluses on the primary and secondary endpoints. Various investigations have shown considerable differences in the CPP and ICP following anesthesia caused by ketamine. For example, four studies affirmed a significant reduction in ICP,[6,18,19,20] whereas two studies emphasized elevated ICP following ketamine-based anesthesia.[21,22] Contrastingly, evidence from five studies revealed that ICP changes did not correlate with ketamine dosages.[23,24,25,26,27] A similar pattern was observed concerning the influence of ketamine boluses on CPP in TBI patients. While three studies provided evidence regarding CPP elevation following ketamine-induced sedation,[6,18,20] five contemporary studies negated any association between CPP and ketamine boluses.[19,23,24,25,26] Furthermore, one study emphasized the role of the ketamine–midazolam combination in reducing CPP.[22] These differences in outcomes are possibly the results of significant variations in ketamine administration timing/duration, dosages, patient attributes, and study design.

The secondary endpoints also demonstrated variations across studies that aimed to evaluate the clinical outcomes of ketamine boluses in TBI patients. While two studies indicated no significant correlation between ketamine boluses and MAP,[23,25] the other two studies revealed > 10 mmHg MAP elevation21 versus > 20% MAP reduction,[28] after ketamine-induced anesthesia, in TBI patients. Two studies revealed statistically significant HR elevation in TBI patients, after ketamine boluses.[21,23] However, one study negated these results by defying any HR alteration in the ketamine bolus group.[6] The included studies provided contrasting results about SD in TBI patients, following ketamine-induced anesthesia. For example, two studies emphasized SD decline/relative beta frequency elevation after ketamine boluses.[30,31] However, one study indicated a gamma burst and another study revealed a burst suppression in EEG, in TBI patients with ketamine boluses.[19,29]

In addition, findings from this systematic review revealed no change in mean cerebral blood flow velocity and jugular oxygen saturation in TBI patients, after ketamine-induced sedation.[19,25] They also affirmed ketamine bolus-induced bronchodilation in the TBI setting.[21] While one study affirmed the neuroprotective effects of ketamine bolus,[32] two other studies negated ketamine-induced neurological complications in TBI patients.[27,33] In addition, the findings from this systematic review revealed the role of ketamine bolus in minimizing mortality rates in patients with TBI.[27,32] Overall, the results indicated improved hemodynamic stability and low side effects in patients with ketamine-induced anesthesia versus contemporary sedation procedures.

Importantly, noticeable variations in the primary and secondary outcomes among TBI patients with ketamine-induced sedation trigger the requirement for a personalized assessment of patient demographics, medical history, ongoing treatments, and TBI, to determine the scope of using ketamine treatment. Furthermore, prospective studies should reevaluate the neuroprotective effects of ketamine boluses while following the standardized treatment algorithms, with large sample sizes.

Limitations

The observational nature of most studies in this systematic review increased the risk of selection bias. In addition, moderate/critical biases and heterogeneity in the outcomes from observational studies could reduce the reliability of the overall findings. Low sample size further impacts the generalizability of results in TBI patients of various age groups. In addition, due to a lack of absolute data, we could not perform age-based subgroup analyses for comparing ICP, CPP, and direction of the delta between pediatric, adult, and elderly subjects.

CONCLUSION

This systematic review underscores the impact of ketamine boluses on the clinical outcomes of TBI patients. Findings emphasize the need for a thorough assessment of patient factors, including demographics, clinical history, treatment history, and the traumatic brain’s neuropathology to determine the requirement of ketamine-induced anesthesia for TBI management. Future studies should investigate the potential risk factors impacting the clinical outcomes in TBI patients, following their sedation with ketamine boluses.

Research quality and ethics statement

This project did not require approval by the Institutional Review Board/Ethics Committee. The authors followed the applicable EQUATOR Network (http://www.equator-network.org/) guidelines, specifically the PRISMA 2020 Statement, during the conduct of this research project, and this project was registered retroactively with PROSPERO.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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