Introduction
Traumatic brain injury (TBI) poses a substantial global health challenge, impacting millions of people annually.1 It leads to severe health complications, increased mortality rates, and imposes significant economic burdens. Unlike chronic illness patients, trauma patients often face acute physiological disturbances, necessitating comprehensive analgesic management.2,3 Through extensive research, healthcare professionals and institutions have developed clinical protocols to enhance TBI treatment and improve patient outcomes.4,5
TBI is a clinical diagnosis traditionally classified using the Glasgow Coma Scale (GCS). GCS scores 13–15 are mild brain injuries, 9–12 are moderate, and 3–8 are severe. In addition to structural damage, a broad spectrum of physiological changes secondary to TBI occur in the brain including increase intracranial pressure, brain swelling, and decrease blood supply among other changes. The challenges in TBI management are the wide spectrum of different presentations of other traumatic injuries and complications. While mild head injuries (GCS 13–15) typically have excellent outcomes and often do not require specific sedative interventions, a widely accepted approach involves using sedatives and analgesics to modulate intracranial pressure, decrease cerebral oxygen consumption, prevent seizures, and aid in mechanical ventilation.6–10 Dexmedetomidine is highlighted as a promising sedative for TBI patients due to its ability to induce sedation without causing respiratory depression. It offers the advantages of lacking active metabolites, providing combined analgesic and sympatholytic effects, and not disrupting neurological assessments or the process of ventilator weaning.11 Existing TBI guidelines from the Trauma Brain Foundation presently furnish only Level IIB endorsement for the infusion of propofol and barbiturates, underscoring the insufficiency and inadequacy of current studies.12 Various reviews and a meta-analysis have thoroughly examined the systemic and intracranial hemodynamic effects of dexmedetomidine.13–15 Recently, anticipation surrounded the A2B trial, designed to explore the effects of alpha-2 agonists within the general intensive care unit (ICU) population.16
The widespread preference for dexmedetomidine is attributed to its selective function as an alpha-2-adrenergic receptor agonist.17 This specificity allows dexmedetomidine to target the locus coeruleus in the brainstem and the spinal cord to provide sedative and analgesic effects.17 This property is especially beneficial for trauma patients, who endure more severe pain compared to general ICU patients and therefore have an elevated risk of developing opioid use disorders and other complications after discharge.13,18 In summary, dexmedetomidine is indicated for sedation in TBI patients due to its ability to reduce intracranial pressure, modulate sympathetic hyperactivity, and provide analgesia without respiratory depression, offering advantages over traditional sedatives like propofol or midazolam.
This systematic review sought to comprehensively evaluate the impact of administering dexmedetomidine to patients with TBI on both hospital and ICU length of stay based on disease severity.
Methods
Search Strategy
A comprehensive literature search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify relevant studies across multiple databases, including PubMed, ScienceDirect, Scopus, and Web of Science, up to March 2024. The search strategy was meticulously formulated to include Medical Subject Headings terms and pertinent keywords related to traumatic brain injury and dexmedetomidine (ie, “traumatic brain injury”, “TBI”, “head injury”, “brain trauma”, “dexmedetomidine”, “Precedex”, “Dex”, “alpha-2 agonist”, etc) in English only. The authors decided not to perform a meta-analysis due to the heterogeneity and discrepancies among the selected studies.
Study Selection
Two authors screened the titles and abstracts of the retrieved articles to identify the relevant studies. These articles were then thoroughly assessed for eligibility based on predefined criteria that included a confirmed adult TBI diagnosis and interventions involving dexmedetomidine as well as reporting the length of hospital and/or ICU stay. Additionally, a stated assessment of TBI severity based on the GCS and/or Abbreviated Injury Scale (AIS) scores was required for inclusion. Because of the heterogeneous nature of trauma in medicine, the studies included patients with isolated TBI as well as those with multiple injuries. The exclusion criteria were administration of dexmedetomidine before hospitalization or in battlefield settings and animal studies, review articles, case reports, studies unrelated to TBI, and studies that did not report relevant outcomes. Any disagreements between the reviewers were resolved through constructive discussions and consensus.
Data Extraction
A comprehensive data extraction process was performed using a standardized form to obtain key data from the eligible studies. Essential information such as author name, publication year, country of study, study design, sample size, patient characteristics (age, sex), intervention specifics (dosage, duration), injury mechanism, TBI severity, and inclusion and exclusion criteria were carefully noted. Moreover, outcome data, including length of hospital and ICU stay, mechanical ventilation duration, initial GCS scores, and GCS score at discharge, were documented.
Risk of Bias Assessment
The risk of bias within the included studies was evaluated using tools tailored to the study designs. For randomized control trials (RCTs), the Cochrane risk of bias tool was employed, which assesses various domains, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, completeness of outcome data, selective reporting, and other biases. Each domain was evaluated as having low, high, or unclear risk of bias.19 For observational studies, the Newcastle–Ottawa scale was utilized.20 This scale evaluates the quality of nonrandomized studies based on three domains: selection of study groups, comparability of groups, and ascertainment of outcomes. Each domain was assessed using specific criteria and the studies were awarded stars based on their adherence to these criteria. A higher number of stars indicates a lower risk of bias. Two independent reviewers assessed the risk of bias for each included study. Discrepancies were resolved through discussion and consensus among authors.
Results
Study Selection
An initial comprehensive search across the included databases identified 1650 articles. After eliminating duplicates, 1240 articles remained for further evaluation. The screening of titles and abstracts resulted in the identification of 69 articles deemed potentially relevant for inclusion. Subsequently, these articles underwent a full-text review, resulting in the final selection of three randomized trials21–23 and five observational studies24–28 that met the predetermined inclusion and exclusion criteria (Figure 1). No study was excluded from the final selection.
|
Table 1 Baseline Characteristics of Included Studies
|
 |
Table 2 Assessment of Risk of Bias in Included Studies Using the Cochrane Risk of Bias Tool for Randomized Controlled Trials
|
 |
Table 3 Risk of Bias Assessment of Observational Studies Using the Newcastle-Ottawa Assessment Scale
|
 |
Figure 1 Flowchart illustrating the study selection process, including identification, screening, eligibility, and inclusion of studies, according to the PRISMA guidelines.
Notes: PRISMA figure adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1-e34. Creative Commons. doi: 10.1016/j.jclinepi.2009.06.006.29
|
Baseline Characteristics
The baseline characteristics of the included studies are shown in Table 1. All studies were conducted in ICU settings, with those by Huang et al including patients after neurosurgical interventions.23 The follow-up durations varied, ranging from short-term assessments during ICU stay to longer-term evaluations extending for up to 6 months after injury, as observed by Liu et al.27 The sex distributions varied, with some studies reporting a predominance of men, reflecting the demographic diversity in TBI populations. Geographical diversity was evident, with studies conducted in the USA, Canada, China, Iran, and Egypt highlighting the global burden of TBI and allowing the exploration of regional variations in management practices. The sample sizes varied from 41 to 352 individuals across studies and exhibited disparities between observational studies and RCTs. The age ranged from 24 to 65 years. The risk of bias for the included RCTs and observational studies is shown in Tables 2 and 3, respectively.
Hospital Length of Stay
Hospital length of stay varied significantly across the studies, with mean lengths ranging from 19.8 to 48 days. It was observed that the administration of dexmedetomidine may be linked to shorter hospital stays when compared to the control groups or the administration of other sedatives such as propofol and midazolam, as indicated by reports from Liu et al and Tang et al22,23 However, contrasting results were found by Khallaf et al and Huang et al, who revealed minimal to no reduction in the length of hospital stay with dexmedetomidine administration.22,23 Additionally, some studies such as those by Pajoumand et al, Bilodeau et al, and Humble et al, did not include comparative groups for length of hospital stay, yet still reported median lengths ranging from 15 to 27 days.24–26
Studies Reporting on Mild to Moderate Traumatic Brain Injury
Studies conducted by Khallaf et al and Bilodeau et al focused on patients with GCS scores indicative of mild to moderate TBI.22,24 Khallaf et al found that patients sedated with dexmedetomidine had a slightly longer hospital stay than those sedated with propofol alone or in combination with dexmedetomidine. However, Bilodeau et al did not note direct comparisons with other interventions regarding the length of hospital stay, but did observe a median stay of 27 days in all patients sedated using either dexmedetomidine, propofol, or benzodiazepines. The longest hospital stay reported in the study by Bilodeau et al was 38 days, which is notably shorter than the mean of 48 days observed by Khallaf et al, despite including patients with lower initial GCS scores of 6 to 8.
Studies Reporting on Moderate to Severe Traumatic Brain Injury
Four observational studies25–28 and one RCT23 investigated a cohort of 839 patients with a GCS score <13. Tang et al and Huang et al investigated a cohort exclusively comprising patients with severe TBI and found that those in the dexmedetomidine group had shorter mean hospital lengths of stay than those sedated with propofol or midazolam.23,28 Specifically, Tang et al reported a reduction in the mean hospital length of stay of 5 days, while Huang et al reported a reduction of 1.8 days. Humble et al exclusively examined individuals with severe TBI who received dexmedetomidine infusion, and found that the median length of hospital stay was 15 days.25 Similarly, Liu et al have observed a 4-day reduction in mean hospital length of stay in patients with moderate to severe TBI with early exposure to dexmedetomidine—within the first 5 days of ICU admission—compared with those with late exposure to dexmedetomidine.27 The study by Pajoumand et al included 198 patients with all severities of TBI, with only 37 having mild TBI, and reported a median length of hospital stay of 17 days.26
ICU Length of Stay
In the double-arm studies, the mean ICU length of stay ranged from 9.5 to 24.1 days in the dexmedetomidine groups and 11.8 to 23.5 days in the control groups. Conversely, the median ICU length of stay in single-arm studies varied from 9 to 14 days. Several reports have demonstrated a decrease in ICU length of stay when dexmedetomidine was administered compared to when alternative interventions were used.22,23,28 A study by Liu et al revealed that early administration of dexmedetomidine resulted in a shorter ICU stay than late administration.27 Conversely, Soltani et al found that patients in the haloperidol group had a shorter ICU length of stay than those in the dexmedetomidine group.21 Unfortunately, the timing of dexmedetomidine administration varies significantly, and has been poorly documented in some studies.
Studies Reporting on Mild to Moderate Traumatic Brain Injury
Two RCTs21,22 and one observational study24 included cohorts with mild to moderate TBI. In their study, Khallaf et al observed a marginal increase in the ICU length of stay in patients administered propofol alone, whereas the administration of a combination of dexmedetomidine and propofol resulted in a mean reduction in ICU stay of 1.2 days when compared with the administration of dexmedetomidine alone. In contrast, a study by Soltani et al showed that administration of haloperidol was more effective in reducing ICU length of stay than administration of dexmedetomidine. Additionally, Bilodeau et al conducted a single-arm study revealing that the administration of a combination of dexmedetomidine and other sedatives, namely, propofol and benzodiazepines, resulted in a median ICU stay of 11 days.
Studies Reporting on Moderate to Severe Traumatic Brain Injury
Three studies focused only on patients with severe TBI, namely, those by Tang et al, Huang et al, and Humble et al, and have found an overall reduced ICU length of stay.23,25,28 The studies conducted by Tang et al and Huang et al compared a dexmedetomidine group with a propofol or midazolam group and have demonstrated a reduction in the mean ICU length of stay by 4.95 and 2.4 days, respectively. Additionally, a single-arm study by Humble et al revealed a median ICU stay of 9 days for patients administered dexmedetomidine in conjunction with propofol or midazolam. Furthermore, a cohort study conducted by Liu et al showed that those who were administered dexmedetomidine within the first 5 days of admission had a mean reduction in ICU length of stay of 2.9 days when compared with unexposed patients. Moreover, the single-arm study by Pajoumand et al, which included patients with a wide range of TBI severities, with a minimal proportion of patients with mild TBI, found a median ICU stay of 14 days.26
Discussion
Managing patients with TBI in a clinical setting requires a multifaceted approach aimed at optimizing outcomes and minimizing complications.30,31 Dexmedetomidine holds promise in this regard. This systematic review aimed to thoroughly evaluate the effect of dexmedetomidine on the length of hospital and ICU stay in adult patients with TBI.
Our results highlight the potential benefits of incorporating dexmedetomidine into treatment regimens for TBI of varying severity, particularly in conjunction with other sedatives, to optimize patient outcomes and resource utilization. The existing literature supports the notion that dexmedetomidine exhibits enhanced efficacy in reducing hospital stay when combined with other sedatives, particularly propofol and midazolam. However, despite the importance of considering the severity of TBI to fully comprehend the impact of dexmedetomidine, the current body of evidence does not provide conclusive recommendations in this regard mainly due to the quality of the studies. Therefore, further research is required in this field.
Sedation and analgesia are critical components in the management of patients with TBI. These interventions are used to control agitation, facilitate mechanical ventilation, and reduce the risk of secondary brain damage.32–34 Dexmedetomidine, an alpha-2 adrenergic agonist, has emerged as a noteworthy sedative due to its unique properties: it induces sedation, provides analgesic effects, and reduces sympathetic nervous system activity, all while exerting minimal impact on respiratory function.35–37 Recent studies underscore its efficacy when administered intravenously, either as a primary sedative in ICU patients requiring mechanical ventilation or during surgical procedures not involving endotracheal intubation.38–41
Notably, precaution is advised when using dexmedetomidine in patients with hypotension or bradycardia, as it may worsen these conditions and lead to complications such as heart block or severe ventricular dysfunction.42,43 Furthermore, a contemporary study has identified a potential link between the use of dexmedetomidine and elevated mortality rates in individuals under 65 years of age, when compared to traditional sedatives like propofol or midazolam.44
A scoping review conducted by Hatfield et al provides a detailed elaboration of the cerebral physiology and systemic hemodynamics in patients with TBI who have been sedated using dexmedetomidine.45 The review highlights the similarities observed when dexmedetomidine is used independently and in combination with standard sedation options, particularly in terms of hemodynamic stability. Our study findings are in line with the results presented by Hatfield et al, suggesting that the reduced or sustained length of hospital stay in patients with TBI could be attributed to the comparable or even superior safety and efficacy of dexmedetomidine compared to that of other sedatives. This indicates that dexmedetomidine may offer promising efficacy in sedating patients with TBI in terms of both safety and reducing the length of hospital stay.
Individuals with severe TBI exhibit a higher susceptibility to complications arising from autonomic dysfunction.46,47 In their comprehensive review, Tang et al28 conducted the sole study examining dexmedetomidine capacity to mitigate post-traumatic sympathetic hyperactivity (PSH). PSH, which correlates with TBI severity, is associated with adverse hospital outcomes, including prolonged ICU stays, extended mechanical ventilation periods, and increased infection rates. Recent case reports have also demonstrated dexmedetomidine’s efficacy in alleviating PSH symptoms.48,49 Dexmedetomidine’s sympatholytic properties may potentially inhibit norepinephrine release, offering a viable approach for managing autonomic dysregulation, either as a monotherapy or in combination with medications such as beta blockers.50 Current research has not identified any significant differences in intracranial pressure changes, and there is limited data regarding the efficacy of additional sedatives, hyperosmolar therapy, mannitol administration, and external ventricular drain insertion for managing intracranial pressure.51–53 While dexmedetomidine has been demonstrated to have no effect on brain oxygenation and to reduce the requirement for narcotics and additional sedatives in TBI patients, it is hypothesized that its protective effects are mediated through anti-inflammatory mechanisms.54 These mechanisms involve the inhibition of NF-κB and NLRP3 inflammasome activation by attenuating endoplasmic reticulum stress-induced apoptosis.55,56 Karakaya et al57 have also demonstrated that various dexmedetomidine doses can effectively mitigate neuroinflammation. Despite divergent opinions on dexmedetomidine’s side effects, particularly its potential to induce hypotension and bradycardia, researchers concur that further studies are necessary to evaluate its impact on TBI patients. The observed reduction in ICU length of stay associated with dexmedetomidine administration has significant implications for healthcare resource utilization by alleviating the burden on healthcare facilities and diminishing the risk of complications such as hospital-acquired infections and delirium, ultimately contributing to improved patient outcomes.
Limitations and Future Perspectives
The present research provides valuable insights into dexmedetomidine’s potential benefits for reducing hospital and intensive care unit stays in critically ill patients with traumatic brain injury; however, it has several limitations. Additional research, particularly randomized controlled trials (RCTs) that address confounding factors, is essential to strengthen the evidence and elucidate dexmedetomidine’s true impact on this patient population. The implementation of a standardized protocol would minimize inconsistencies and enhance study comparability, thereby enabling more definitive conclusions regarding dexmedetomidine’s efficacy for patients with traumatic brain injury. Subsequent studies should examine intensive care unit length of stay while considering specific comorbidities and complications associated with early versus late dexmedetomidine administration. Trauma to other regions of the body should be interpretated with TBI population especially for effects of sedatives, length of stay, and mortality. Mixing different anesthetics is practice of sedating patients, hence, studying a combined regimen of sedatives in trauma population would match the common practice.
Conclusion
This comprehensive review elucidates the efficacy of dexmedetomidine in reducing ICU and hospital stays for TBI patients. An analysis of eight selected studies demonstrates dexmedetomidine’s potential to decrease ICU duration across various TBI severity levels, particularly in severe cases, although evidence regarding hospital stay reduction remains inconclusive. The investigators acknowledge the methodological challenges inherent in designing a well-controlled study for sedation use in trauma cases. Future research should focus on optimizing dosing and timing protocols, identifying TBI patient subgroups that may derive maximal benefit from dexmedetomidine, and investigating its long-term impact on functional outcomes and quality of life among TBI survivors. Addressing these research gaps will enable researchers to enhance dexmedetomidine’s therapeutic value and improve overall care and outcomes for TBI patients.
Abbreviations
ICU, Intensive Care Unit; TBI, Traumatic Brain Injury; GCS, Glasgow Coma Scale; AIS, Abbreviated Injury Scale; RCT, Randomized Control Trials; PSH, Post-traumatic Sympathetic Hyperactivity.
Data Sharing Statement
All data supporting the findings of this study are available within the paper. Raw data can be provided upon request.
Ethics Approval and Consent to Participate
This article does not include any interventions that require consent to participate. Confidential data were used in the preparation of this manuscript.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
References
1. Dewan MC, Rattani A, Gupta S, et al. Estimating the global incidence of traumatic brain injury. J Neurosurg. 2019;130(4):1080–1097. doi:10.3171/2017.10.JNS17352
2. Chen Q, Bharadwaj V, Irvine K-A, Clark JD. Mechanisms and treatments of chronic pain after traumatic brain injury. Neurochem Int. 2023;171:105630. doi:10.1016/j.neuint.2023.105630
3. Sander AM, Christensen K, Loyo K, et al. Coping with chronic pain after traumatic brain injury: role of race/ethnicity and effect on participation outcomes in a TBI model systems sample. Arch Phys Med Rehabil. 2023;104(7):1099–1106. doi:10.1016/j.apmr.2023.03.003
4. Ashina H, Eigenbrodt AK, Seifert T, et al. Post-traumatic headache attributed to traumatic brain injury: classification, clinical characteristics, and treatment. Lancet Neurol. 2021;20(6):460–469. doi:10.1016/S1474-4422(21)00094-6
5. Ponsford J, Velikonja D, Janzen S, et al. INCOG 2.0 guidelines for cognitive rehabilitation following traumatic brain injury, part II: attention and information processing speed. J Head Trauma Rehabil. 2023;38(1):38–51. doi:10.1097/HTR.0000000000000839
6. Bernard F. Neurotrauma and intracranial pressure management. Critic Care Clin. 2023;39(1):103–121. doi:10.1016/j.ccc.2022.08.002
7. Rezoagli E, Petrosino M, Rebora P, et al. High arterial oxygen levels and supplemental oxygen administration in traumatic brain injury: insights from CENTER-TBI and OzENTER-TBI. Intensive Care Med. 2022;48(12):1709–1725. doi:10.1007/s00134-022-06884-x
8. Bernard F, Barsan W, Diaz-Arrastia R, Merck LH, Yeatts S, Shutter LA. Brain oxygen optimization in severe traumatic brain injury (BOOST-3): a multicentre, randomised, blinded-endpoint, comparative effectiveness study of brain tissue oxygen and intracranial pressure monitoring versus intracranial pressure alone. BMJ Open. 2022;12(3):e060188. doi:10.1136/bmjopen-2021-060188
9. Coelho LMG, Blacker D, Hsu J, et al. Association of early seizure prophylaxis with posttraumatic seizures and mortality: a meta-analysis with evidence quality assessment. Neurol Clin Pract. 2023;13(3):e200145. doi:10.1212/CPJ.0000000000200145
10. Taran S, Cho S-M, Stevens RD. Mechanical ventilation in patients with traumatic brain injury: is it so different? Neurocrit Care. 2023;38(1):178–191. doi:10.1007/s12028-022-01593-1
11. Hu Y, Zhou H, Zhang H, et al. The neuroprotective effect of dexmedetomidine and its mechanism. Front Pharmacol. 2022;13:965661. doi:10.3389/fphar.2022.965661
12. Carney N, Totten AM, O’Reilly C, et al. Guidelines for the management of severe traumatic brain injury. Neurosurgery. 2017;80(1):6. doi:10.1227/NEU.0000000000001432
13. Jeffcote T, Weir T, Anstey J, Mcnamara R, Bellomo R, Udy A. The impact of sedative choice on intracranial and systemic physiology in moderate to severe traumatic brain injury: a scoping review. J Neurosurg Anesthesiol. 2023;35(3):265–273. doi:10.1097/ANA.0000000000000836
14. Tran A, Blinder H, Hutton B, English SW. A systematic review of alpha-2 agonists for sedation in mechanically ventilated neurocritical care patients. Neurocrit Care. 2018;28(1):12–25. doi:10.1007/s12028-017-0388-5
15. Tsaousi GG, Lamperti M, Bilotta F. Role of dexmedetomidine for sedation in neurocritical care patients: a qualitative systematic review and meta-analysis of current evidence. Clin Neuropharmacol. 2016;39(3):144–151. doi:10.1097/WNF.0000000000000151
16. Aitken LM, Emerson LM, Kydonaki K, et al. Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B trial): protocol for a mixed-methods process evaluation of a randomised controlled trial. BMJ Open. 2024;14(4):e081637. doi:10.1136/bmjopen-2023-081637
17. Yang T, Feng X, Zhao Y, et al. Dexmedetomidine enhances autophagy via α2-AR/AMPK/mTOR pathway to inhibit the activation of NLRP3 inflammasome and subsequently alleviates lipopolysaccharide-induced acute kidney injury. Front Pharmacol. 2020;11:790. doi:10.3389/fphar.2020.00790
18. Huang YQ, Weiss S, Gros P, et al. Prevention and treatment of traumatic brain injury-related delirium: a systematic review. J Neurol. 2023;270(12):5966–5987. doi:10.1007/s00415-023-11889-7
19. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019:l4898. doi:10.1136/bmj.l4898.
20. Wells G, Shea B, O’connell D, et al. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed: August 9, 2024.
21. Soltani F, Tabatabaei S, Jannatmakan F, et al. Comparison of the effects of haloperidol and dexmedetomidine on delirium and agitation in patients with a traumatic brain injury admitted to the intensive care unit. Anesth Pain Med. 2021;11(3):e113802. doi:10.5812/aapm.113802
22. Khallaf M, Thabet AM, Ali M, Sharkawy E, Abdel-rehim S. The effect of dexmedetomidine versus propofol in traumatic brain injury: evaluation of some hemodynamic and intracranial pressure changes. Egypt J Neurosurg. 2019;34(1):17. doi:10.1186/s41984-019-0041-z
23. Huang Y, Deng Y, Zhang R, Meng M, Chen D. Comparing the effect of dexmedetomidine and midazolam in patients with brain injury. Brain Sci. 2022;12(6):752. doi:10.3390/brainsci12060752
24. Bilodeau V, Saavedra-Mitjans M, Frenette AJ, et al. Safety of dexmedetomidine for the control of agitation in critically ill traumatic brain injury patients: a descriptive study. J Clin Pharm Ther. 2021;46(4):1020–1026. doi:10.1111/jcpt.13389
25. Humble SS, Wilson LD, Leath TC, et al. ICU sedation with dexmedetomidine after severe traumatic brain injury. Brain Inj. 2016;30(10):1266–1270. doi:10.1080/02699052.2016.1187289
26. Pajoumand M, Kufera JA, Bonds BW, et al. Dexmedetomidine as an adjunct for sedation in patients with traumatic brain injury. J Trauma Acute Care Surg. 2016;81(2):345–351. doi:10.1097/TA.0000000000001069
27. Liu SY, Kelly-Hedrick M, Temkin N, et al. Association of early dexmedetomidine utilization with clinical and functional outcomes following moderate-severe traumatic brain injury: a transforming clinical research and knowledge in traumatic brain injury study. Crit Care Med. 2024;52(4):607–617. doi:10.1097/CCM.0000000000006106
28. Tang Q, Wu X, Weng W, et al. The preventive effect of dexmedetomidine on paroxysmal sympathetic hyperactivity in severe traumatic brain injury patients who have undergone surgery: a retrospective study. PeerJ. 2017;5:e2986. doi:10.7717/peerj.2986
29. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1-e34. doi:10.1016/j.jclinepi.2009.06.006), e1–e34.
30. Orr TJ, Lesha E, Kramer AH, et al. Traumatic brain injury: a comprehensive review of biomechanics and molecular pathophysiology. World Neurosurg. 2024;185:74–88. doi:10.1016/j.wneu.2024.01.084
31. Hussain R, Nedergaard M. Managing noradrenaline after traumatic brain injury. Clin Translational Med. 2024;14(1):e1562. doi:10.1002/ctm2.1562
32. Andrews PJ, Sinclair HL, Rodríguez A, et al. Therapeutic hypothermia to reduce intracranial pressure after traumatic brain injury: the eurotherm3235 RCT. Health Technol Assess. 2018;22(45):1–134. doi:10.3310/hta22450
33. Knapp J, Doppmann P, Huber M, et al. Pre-hospital endotracheal intubation in severe traumatic brain injury: ventilation targets and mortality—a retrospective analysis of 308 patients. Scand J Trauma Resusc Emerg Med. 2023;31(1):46. doi:10.1186/s13049-023-01115-8
34. Kim H. Anesthetic management of the traumatic brain injury patients undergoing non-neurosurgery. Anesth Pain Med. 2023;18(2):104–113. doi:10.17085/apm.23017
35. Møller MH, Alhazzani W, Lewis K, et al. Use of dexmedetomidine for sedation in mechanically ventilated adult ICU patients: a rapid practice guideline. Intensive Care Med. 2022;48:801–810. doi:10.1007/s00134-022-06660-x
36. Chima AM, Mahmoud MA, Narayanasamy S. What is the role of dexmedetomidine in modern anesthesia and critical care? Advances in Anesthesia. 2022;40(1):111–130. doi:10.1016/j.aan.2022.06.003
37. Yavuz A, Küçük A, Ergörün A, et al. Evaluation of the efficacy of silymarin and dexmedetomidine on kidney and lung tissue in the treatment of sepsis in rats with cecal perforation. Exp Ther Med. 2024;27(6):242. doi:10.3892/etm.2024.12530
38. Abedzadeh E, Modir H, Pazooki S, Barsari F, Almasi-Hashiani A. Comparison of adding magnesium sulfate, dexmedetomidine and ondansetron to lidocaine for gargling before laryngoscopy and endotracheal intubation to prevent sore throat: a randomized clinical trial. Med Gas Res. 2024;14(2):54–60. doi:10.4103/2045-9912.372664
39. Long Y, Xu Q, Zhao W, et al. Dexmedetomidine infusion versus placebo during light or deep anesthesia on postoperative delirium in older patients undergoing major noncardiac surgery: a pilot randomized factorial trial. Anesthesia Analgesia. 2023;2023:1. doi:10.1213/ANE.0000000000006686
40. Shehabi Y, Serpa Neto A, Bellomo R, et al. Dexmedetomidine and propofol sedation in critically ill patients and dose-associated 90-day mortality: a secondary cohort analysis of a randomized controlled trial (SPICE III). Am J Respir Crit Care Med. 2023;207(7):876–886. doi:10.1164/rccm.202206-1208OC
41. Chitnis S, Mullane D, Brohan J, et al. Dexmedetomidine use in intensive care unit sedation and postoperative recovery in elderly patients post-cardiac surgery (DIRECT). J Cardiothoracic Vascular Anesthesia. 2022;36(3):880–892. doi:10.1053/j.jvca.2021.09.024
42. Lewis K, Piticaru J, Chaudhuri D, et al. Safety and efficacy of dexmedetomidine in acutely ill adults requiring noninvasive ventilation. Chest. 2021;159(6):2274–2288. doi:10.1016/j.chest.2020.12.052
43. Wen J, Ding X, Liu C, Jiang W, Xu Y, Wei X. A comparation of dexmedetomidine and midazolam for sedation in patients with mechanical ventilation in ICU: a systematic review and meta-analysis. PLoS One. 2023;18(11):e0294292. doi:10.1371/journal.pone.0294292
44. Shehabi Y, Howe BD, Bellomo R, et al. Early sedation with dexmedetomidine in critically ill patients. N Engl J Med. 2019;380(26):2506–2517. doi:10.1056/NEJMoa1904710
45. Hatfield J, Soto AL, Kelly-Hedrick M, et al. Safety, efficacy, and clinical outcomes of dexmedetomidine for sedation in traumatic brain injury: a scoping review. J Neurosurg Anesthesiol. 2024;36(2):101–108. doi:10.1097/ANA.0000000000000907
46. Sykora M, Czosnyka M, Liu X, et al. Autonomic impairment in severe traumatic brain injury: a multimodal neuromonitoring study. Crit Care Med. 2016;44(6):1173–1181. doi:10.1097/CCM.0000000000001624
47. Hendricks HT, Heeren AH, Vos PE. Dysautonomia after severe traumatic brain injury. Eur J Neurology. 2010;17(9):1172–1177. doi:10.1111/j.1468-1331.2010.02989.x
48. Kern J, Bodek D, Niazi OT, Maher J. Refractory case of paroxysmal autonomic instability with dystonia syndrome secondary to hypoxia. Chest. 2016;149(2):e39–40. doi:10.1016/j.chest.2015.08.003
49. Goddeau RP, Silverman SB, Sims JR. Dexmedetomidine for the treatment of paroxysmal autonomic instability with dystonia. Neurocrit Care. 2007;7(3):217–220. doi:10.1007/s12028-007-0066-0
50. Godoy DA, Piñero GR, Masotti L. Paroxysmal sympathetic hyperactivity, traumatic brain injury, and β-blockers. J Trauma Acute Care Surg. 2014;77(2):387. doi:10.1097/TA.0000000000000298
51. Orešković D, Maraković J, Varda R, Radoš M, Jurjević I, Klarica M. New insight into the mechanism of mannitol effects on cerebrospinal fluid pressure decrease and craniospinal fluid redistribution. Neuroscience. 2018;392:164–171. doi:10.1016/j.neuroscience.2018.09.029
52. Iqbal U, Kumar A, Arsal SA, et al. Efficacy of hypertonic saline and mannitol in patients with traumatic brain injury and cerebral edema: a systematic review and meta-analysis. Egypt J Neurosurg. 2023;38(1):54. doi:10.1186/s41984-023-00233-w
53. Kochanek PM, Tasker RC, Bell MJ, et al. Management of pediatric severe traumatic brain injury: 2019 consensus and guidelines-based algorithm for first and second tier therapies. Pediatr Crit Care Med. 2019;20(3):269–279. doi:10.1097/PCC.0000000000001737
54. Mei B, Li J, Zuo Z. Dexmedetomidine attenuates sepsis-associated inflammation and encephalopathy via central α2A adrenoceptor. Brain Behav Immun. 2021;91:296–314. doi:10.1016/j.bbi.2020.10.008
55. Li N, Ma Y, Li C, Sun M, Qi F. Dexmedetomidine alleviates sevoflurane-induced neuroinflammation and neurocognitive disorders by suppressing the P2X4R/NLRP3 pathway in aged mice. Int J Neurosci. 2024;134(5):511–521. doi:10.1080/00207454.2022.2121921
56. Wang L, Liu X, Zhou X, Gao F, Li X, Wang X. Dexmedetomidine inhibits parthanatos in cardiomyocytes and in aortic banded mice by the ROS-mediated NLRP3 inflammasome activation. J Cardiovasc Trans Res. 2023;16(3):624–635. doi:10.1007/s12265-022-10340-y
57. Karakaya D, Cakir-Aktas C, Uzun S, Soylemezoglu F, Mut M. Tailored therapeutic doses of dexmedetomidine in evolving neuroinflammation after traumatic brain injury. Neurocrit Care. 2022;36(3):802–814. doi:10.1007/s12028-021-01381-3
