REVIEW ARTICLE
The Impact of Sedative Choice on Intracranial
and Systemic Physiology in Moderate to Severe
Downloaded from http://journals.lww.com/jnsa by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
Traumatic Brain Injury: A Scoping Review
Toby Jeffcote, MBChB, FCICM, PhD,*† Timothy Weir, MBBS,* James Anstey, FCICM,‡
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 07/28/2023
Robert Mcnamara, FCICM,§ Rinaldo Bellomo, FRACP, FCICM, PhD,†‡∥¶
and Andrew Udy, MBChB, FCICM, PhD*†
infusions were not associated with increased ICP and may reduce the
Abstract: Although sedative use is near-ubiquitous in the acute incidence of cortical spreading depolarization events. In conclusion,
management of moderate to severe traumatic brain injury (m-sTBI), there is a paucity of high-quality evidence to inform the optimal use
the evidence base for these agents is undefined. This review sum- of analgosedative agents in the management of m-sTBI, inferring
marizes the evidence for analgosedative agent use in the intensive significant scope for further research.
care unit management of m-sTBI. Clinical studies of sedative and
analgosedative agents currently utilized in adult m-sTBI management Key Words: traumatic brain injury, sedation, intracranial pres-
(propofol, ketamine, benzodiazepines, opioids, and alpha-2 agonists) sure, neurocritical care
were identified and assessed for relevance and methodological qual- (J Neurosurg Anesthesiol 2023;35:265–273)
ity. The primary outcome was the effect of the analgosedative agent
on intracranial pressure (ICP). Secondary outcomes included intra-
cranial hemodynamic and metabolic parameters, systemic hemody-
namic parameters, measures of therapeutic intensity, and clinical T raumatic brain injury (TBI) is a major health and soci-
oeconomic problem. It is a complex and potentially
devastating condition with high rates of acute and chronic
outcomes. Of 594 articles identified, 61 met methodological review
criteria, and 40 were included in the qualitative summary; of these, 33 morbidity and mortality. Moderate to severe traumatic brain
were prospective studies, 18 were randomized controlled trials, and 8 injury (m-sTBI) accounts for 10% to 15% of the total TBI
were blinded. There was consistent evidence for the efficacy of sed- burden and frequently requires admission to an intensive
ative agents in the management of m-sTBI and raised ICP, but the care unit (ICU)1 where management is focused on main-
overall quality of the evidence was poor, consisting of small studies tenance of optimal organ support as injuries and patho-
(median sample size, 23.5) of variable methodological quality. Pro- physiological processes evolve. Central to these supportive
pofol and midazolam achieve the goals of sedation without notable strategies is avoidance of secondary brain injury which can
differences in efficacy or safety, although high-dose propofol may be precipitated by systemic compromise (eg, hypoxia, hy-
disrupt cerebral autoregulation. Dexmedetomidine and propofol/ potension, metabolic derangement),2 or intracranial physio-
dexmedetomidine combination may cause clinically significant hy- logical dysfunction, such as raised intracranial pressure
potension. Dexmedetomidine was effective to achieve a target seda- (ICP), autoregulatory dysfunction, or compromised cerebral
tion score. De novo opioid boluses were associated with increased blood flow (CBF) and cerebral metabolism.3
ICP and reduced cerebral perfusion pressure. Ketamine bolus and The importance of sedative infusions in the manage-
ment of m-sTBI has been recognized in multiple widely
adopted guidelines.4 Sedation allows for airway in-
Received for publication October 4, 2021; accepted January 6, 2022. strumentation, mechanical ventilation, and supportive care
From the *Department of Intensive Care Medicine, The Alfred Hospital; to be provided safely and effectively. Sedative agents are
∥Department of Intensive Care Medicine, The Austin Hospital; characterized by their ability to cross the blood-brain barrier
‡Department of Intensive Care, Royal Melbourne Hospital, Mel-
bourne; ¶Department of Critical Care, University of Melbourne,
and their influence on cerebral function, blood flow, and
Parkville; †Australian and New Zealand Intensive Care Research metabolism.5 These properties have led to their widespread
Centre, School of Public Health and Preventive Medicine, Monash adoption as a means of optimizing intracranial hemody-
University, Prahran, Vic.; and §Department of Intensive Care, Royal namics, including ICP and cerebral perfusion pressure
Perth Hospital, Perth, WA, Australia.
The authors have no funding or conflicts of interest to disclose.
(CPP).6 However, the evidence on which sedation practices
Address correspondence to: Andrew Udy, MBChB, FCICM, PhD. are based appears to be incomplete and of variable quality.7,8
E-mail: . Systematic reviews of the literature emphasize the lack of
Supplemental Digital Content is available for this article. Direct URL high-quality randomized controlled studies in this area.9,10
citations appear in the printed text and are provided in the HTML This lack of robust evidence is particularly striking given the
and PDF versions of this article on the journal’s website, www.jnsa.
com. emerging benefits associated with early sedative weaning and
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. minimizing sedative medication usage in the general ICU
DOI: 10.1097/ANA.0000000000000836 population.11
J Neurosurg Anesthesiol Volume 35, Number 3, July 2023 www.jnsa.com | 265
Copyright r 2022 Wolters Kluwer Health, Inc. All rights reserved.
, Jeffcote et al J Neurosurg Anesthesiol Volume 35, Number 3, July 2023
As such, the purpose of this scoping review was to arterial pressure [MAP], heart rate [HR]), measures of
provide an overview of currently available evidence for therapeutic intensity, and patient-centered outcomes
sedative and analgesic use in the acute ICU management of (eg, frequency of a favorable neurological outcome,
m-sTBI. Given that much of the evidence lacks the statistical mortality, and incidence of delirium) were reported.
power to identify differences in patient-centered outcomes, We defined commonly used sedative drugs as pro-
Downloaded from http://journals.lww.com/jnsa by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
such as mortality and neurological outcomes, the current pofol, ketamine, and any agent from the opioid, benzo-
review focused on more granular physiological outcome diazepine, or alpha-2 agonist classes. We excluded studies
measures, including intracranial and systemic hemodynamic investigating barbiturates as they were the subject of a
parameters and measures of therapeutic intensity. The re- previous systematic review17 and are not currently used for
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 07/28/2023
view covers the most commonly used sedatives and an- routine sedation management in m-sTBI. Studies inves-
algesics, including propofol, midazolam, and opioids, and tigating inhalational anesthetic agents were not included
also emerging alternatives such as ketamine12,13 and as they are not widely used in the ICU.
dexmedetomidine.14 Our goal was to summarize the known
physiological effects of sedatives/analgesics in m-sTBI, and Search Strategy
potentially to identify safe and effective candidate agents that The full search strategy is described in the Supple-
could be investigated in future large-scale patient-centered mentary Material (Supplemental Digital Content 1: Seach
randomized controlled trials. strategies, http://links.lww.com/JNA/A491). We first searched
Our objectives were to perform a scoping review of the Ovid MEDLINE, Ovid EMBASE, PubMed, and Co-
the analgosedative agents available for the acute man- chrane database of systematic reviews to identify relevant
agement of m-sTBI to answer 3 key questions: systematic reviews and guidelines for each major sedative class.
(1) Is there efficacy and safety evidence for specific The reference sections of these reviews were used to generate a
analgosedative agents in the management of m-sTBI? gold-standard reference list to act as an internal validation of
(2) What is the strength and methodological quality of the search strategy.
this evidence? Database searches were then performed in Pubmed,
(3) Do emerging alternatives to the most commonly used Ovid MEDLINE, and Ovid EMBASE databases using
agents offer potential advantages in terms of efficacy and keyword searches and exploded term searches for all rel-
safety? evant subjects (Supplemental Digital Content 1: Search
strategies, http://links.lww.com/JNA/A491). Initial search
METHODS results were cross-referenced against the reference lists
Methods for inclusion and analysis of studies in this from the previously identified systematic reviews to iden-
review were prespecified in a protocol developed in accord- tify unsuccessful search strategies and to adapt search
ance with the most recent Preferred Reporting Items for strategies until the maximum number of relevant articles
Systematic Reviews and Meta-analyses (PRISMA)15 and the were identified. Each search was limited to human and
Cochrane collaboration guidelines.16 The protocol was pro- English language studies before combination with the
spectively registered with the Open Science Framework on Boolean operator “OR” to combine all results from
July 19, 2021. searches based on pathology-related search terms and
treatment-related search terms. The results of these com-
Screening Criteria bined searches were then combined with the Boolean op-
Each study had to meet the following criteria for erator “AND”; the results of this combined search were
methodological review: then limited to clinical studies with adult participants. No
(1) Language: English language studies. date limit was imposed on searches to illustrate the evo-
(2) Design: Clinical investigations with 5 or more human lution of practice over time and the methodological
participants. Study design was not restricted to quality of the evidence on which current practice is based.
prospective randomized controlled trials. Retrospec- Identified studies were tabulated, and an initial
tive and observational studies were also eligible for screening review was performed to identify duplicate re-
inclusion, but systematic reviews, case reports, edito- sults, inappropriate article types (eg, systematic reviews,
rials, and conference proceedings were not eligible. case reports, editorials, or conference proceedings), and
(3) Population: Adult (aged 18 y or older) ICU patient clearly inappropriate research areas according to the ar-
cohorts including a significant proportion ( > 20%) of ticle title. After the initial screening review, articles were
patients with m-sTBI (defined as Glasgow Coma Scale identified for abstract review and organized according to
score <13). category (opioids, propofol, benzodiazepines, dexmede-
(4) Intervention: Evaluation of the use of 1 or more of the tomidine, and ketamine). Studies from the systematic re-
sedative or analgesic drugs commonly used in the view reference lists that were not identified by the fully
acute management of m-sTBI. expanded search criteria were then added manually.
(5) Outcomes: Reporting of the effect of the intervention
on ICP as the primary outcome. Secondary outcomes Study Selection and Analysis
included effects on CPP, cerebral autoregulation, A full list of articles identified by the database searches
markers of cerebral metabolism, biomarkers of cere- was collated into a data chart organized into 3 data col-
bral injury, measures of systemic physiology (mean lection forms: (1) basic eligibility according to the selection
266 | www.jnsa.com Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2022 Wolters Kluwer Health, Inc. All rights reserved.
The Impact of Sedative Choice on Intracranial
and Systemic Physiology in Moderate to Severe
Downloaded from http://journals.lww.com/jnsa by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
Traumatic Brain Injury: A Scoping Review
Toby Jeffcote, MBChB, FCICM, PhD,*† Timothy Weir, MBBS,* James Anstey, FCICM,‡
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 07/28/2023
Robert Mcnamara, FCICM,§ Rinaldo Bellomo, FRACP, FCICM, PhD,†‡∥¶
and Andrew Udy, MBChB, FCICM, PhD*†
infusions were not associated with increased ICP and may reduce the
Abstract: Although sedative use is near-ubiquitous in the acute incidence of cortical spreading depolarization events. In conclusion,
management of moderate to severe traumatic brain injury (m-sTBI), there is a paucity of high-quality evidence to inform the optimal use
the evidence base for these agents is undefined. This review sum- of analgosedative agents in the management of m-sTBI, inferring
marizes the evidence for analgosedative agent use in the intensive significant scope for further research.
care unit management of m-sTBI. Clinical studies of sedative and
analgosedative agents currently utilized in adult m-sTBI management Key Words: traumatic brain injury, sedation, intracranial pres-
(propofol, ketamine, benzodiazepines, opioids, and alpha-2 agonists) sure, neurocritical care
were identified and assessed for relevance and methodological qual- (J Neurosurg Anesthesiol 2023;35:265–273)
ity. The primary outcome was the effect of the analgosedative agent
on intracranial pressure (ICP). Secondary outcomes included intra-
cranial hemodynamic and metabolic parameters, systemic hemody-
namic parameters, measures of therapeutic intensity, and clinical T raumatic brain injury (TBI) is a major health and soci-
oeconomic problem. It is a complex and potentially
devastating condition with high rates of acute and chronic
outcomes. Of 594 articles identified, 61 met methodological review
criteria, and 40 were included in the qualitative summary; of these, 33 morbidity and mortality. Moderate to severe traumatic brain
were prospective studies, 18 were randomized controlled trials, and 8 injury (m-sTBI) accounts for 10% to 15% of the total TBI
were blinded. There was consistent evidence for the efficacy of sed- burden and frequently requires admission to an intensive
ative agents in the management of m-sTBI and raised ICP, but the care unit (ICU)1 where management is focused on main-
overall quality of the evidence was poor, consisting of small studies tenance of optimal organ support as injuries and patho-
(median sample size, 23.5) of variable methodological quality. Pro- physiological processes evolve. Central to these supportive
pofol and midazolam achieve the goals of sedation without notable strategies is avoidance of secondary brain injury which can
differences in efficacy or safety, although high-dose propofol may be precipitated by systemic compromise (eg, hypoxia, hy-
disrupt cerebral autoregulation. Dexmedetomidine and propofol/ potension, metabolic derangement),2 or intracranial physio-
dexmedetomidine combination may cause clinically significant hy- logical dysfunction, such as raised intracranial pressure
potension. Dexmedetomidine was effective to achieve a target seda- (ICP), autoregulatory dysfunction, or compromised cerebral
tion score. De novo opioid boluses were associated with increased blood flow (CBF) and cerebral metabolism.3
ICP and reduced cerebral perfusion pressure. Ketamine bolus and The importance of sedative infusions in the manage-
ment of m-sTBI has been recognized in multiple widely
adopted guidelines.4 Sedation allows for airway in-
Received for publication October 4, 2021; accepted January 6, 2022. strumentation, mechanical ventilation, and supportive care
From the *Department of Intensive Care Medicine, The Alfred Hospital; to be provided safely and effectively. Sedative agents are
∥Department of Intensive Care Medicine, The Austin Hospital; characterized by their ability to cross the blood-brain barrier
‡Department of Intensive Care, Royal Melbourne Hospital, Mel-
bourne; ¶Department of Critical Care, University of Melbourne,
and their influence on cerebral function, blood flow, and
Parkville; †Australian and New Zealand Intensive Care Research metabolism.5 These properties have led to their widespread
Centre, School of Public Health and Preventive Medicine, Monash adoption as a means of optimizing intracranial hemody-
University, Prahran, Vic.; and §Department of Intensive Care, Royal namics, including ICP and cerebral perfusion pressure
Perth Hospital, Perth, WA, Australia.
The authors have no funding or conflicts of interest to disclose.
(CPP).6 However, the evidence on which sedation practices
Address correspondence to: Andrew Udy, MBChB, FCICM, PhD. are based appears to be incomplete and of variable quality.7,8
E-mail: . Systematic reviews of the literature emphasize the lack of
Supplemental Digital Content is available for this article. Direct URL high-quality randomized controlled studies in this area.9,10
citations appear in the printed text and are provided in the HTML This lack of robust evidence is particularly striking given the
and PDF versions of this article on the journal’s website, www.jnsa.
com. emerging benefits associated with early sedative weaning and
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. minimizing sedative medication usage in the general ICU
DOI: 10.1097/ANA.0000000000000836 population.11
J Neurosurg Anesthesiol Volume 35, Number 3, July 2023 www.jnsa.com | 265
Copyright r 2022 Wolters Kluwer Health, Inc. All rights reserved.
, Jeffcote et al J Neurosurg Anesthesiol Volume 35, Number 3, July 2023
As such, the purpose of this scoping review was to arterial pressure [MAP], heart rate [HR]), measures of
provide an overview of currently available evidence for therapeutic intensity, and patient-centered outcomes
sedative and analgesic use in the acute ICU management of (eg, frequency of a favorable neurological outcome,
m-sTBI. Given that much of the evidence lacks the statistical mortality, and incidence of delirium) were reported.
power to identify differences in patient-centered outcomes, We defined commonly used sedative drugs as pro-
Downloaded from http://journals.lww.com/jnsa by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
such as mortality and neurological outcomes, the current pofol, ketamine, and any agent from the opioid, benzo-
review focused on more granular physiological outcome diazepine, or alpha-2 agonist classes. We excluded studies
measures, including intracranial and systemic hemodynamic investigating barbiturates as they were the subject of a
parameters and measures of therapeutic intensity. The re- previous systematic review17 and are not currently used for
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 07/28/2023
view covers the most commonly used sedatives and an- routine sedation management in m-sTBI. Studies inves-
algesics, including propofol, midazolam, and opioids, and tigating inhalational anesthetic agents were not included
also emerging alternatives such as ketamine12,13 and as they are not widely used in the ICU.
dexmedetomidine.14 Our goal was to summarize the known
physiological effects of sedatives/analgesics in m-sTBI, and Search Strategy
potentially to identify safe and effective candidate agents that The full search strategy is described in the Supple-
could be investigated in future large-scale patient-centered mentary Material (Supplemental Digital Content 1: Seach
randomized controlled trials. strategies, http://links.lww.com/JNA/A491). We first searched
Our objectives were to perform a scoping review of the Ovid MEDLINE, Ovid EMBASE, PubMed, and Co-
the analgosedative agents available for the acute man- chrane database of systematic reviews to identify relevant
agement of m-sTBI to answer 3 key questions: systematic reviews and guidelines for each major sedative class.
(1) Is there efficacy and safety evidence for specific The reference sections of these reviews were used to generate a
analgosedative agents in the management of m-sTBI? gold-standard reference list to act as an internal validation of
(2) What is the strength and methodological quality of the search strategy.
this evidence? Database searches were then performed in Pubmed,
(3) Do emerging alternatives to the most commonly used Ovid MEDLINE, and Ovid EMBASE databases using
agents offer potential advantages in terms of efficacy and keyword searches and exploded term searches for all rel-
safety? evant subjects (Supplemental Digital Content 1: Search
strategies, http://links.lww.com/JNA/A491). Initial search
METHODS results were cross-referenced against the reference lists
Methods for inclusion and analysis of studies in this from the previously identified systematic reviews to iden-
review were prespecified in a protocol developed in accord- tify unsuccessful search strategies and to adapt search
ance with the most recent Preferred Reporting Items for strategies until the maximum number of relevant articles
Systematic Reviews and Meta-analyses (PRISMA)15 and the were identified. Each search was limited to human and
Cochrane collaboration guidelines.16 The protocol was pro- English language studies before combination with the
spectively registered with the Open Science Framework on Boolean operator “OR” to combine all results from
July 19, 2021. searches based on pathology-related search terms and
treatment-related search terms. The results of these com-
Screening Criteria bined searches were then combined with the Boolean op-
Each study had to meet the following criteria for erator “AND”; the results of this combined search were
methodological review: then limited to clinical studies with adult participants. No
(1) Language: English language studies. date limit was imposed on searches to illustrate the evo-
(2) Design: Clinical investigations with 5 or more human lution of practice over time and the methodological
participants. Study design was not restricted to quality of the evidence on which current practice is based.
prospective randomized controlled trials. Retrospec- Identified studies were tabulated, and an initial
tive and observational studies were also eligible for screening review was performed to identify duplicate re-
inclusion, but systematic reviews, case reports, edito- sults, inappropriate article types (eg, systematic reviews,
rials, and conference proceedings were not eligible. case reports, editorials, or conference proceedings), and
(3) Population: Adult (aged 18 y or older) ICU patient clearly inappropriate research areas according to the ar-
cohorts including a significant proportion ( > 20%) of ticle title. After the initial screening review, articles were
patients with m-sTBI (defined as Glasgow Coma Scale identified for abstract review and organized according to
score <13). category (opioids, propofol, benzodiazepines, dexmede-
(4) Intervention: Evaluation of the use of 1 or more of the tomidine, and ketamine). Studies from the systematic re-
sedative or analgesic drugs commonly used in the view reference lists that were not identified by the fully
acute management of m-sTBI. expanded search criteria were then added manually.
(5) Outcomes: Reporting of the effect of the intervention
on ICP as the primary outcome. Secondary outcomes Study Selection and Analysis
included effects on CPP, cerebral autoregulation, A full list of articles identified by the database searches
markers of cerebral metabolism, biomarkers of cere- was collated into a data chart organized into 3 data col-
bral injury, measures of systemic physiology (mean lection forms: (1) basic eligibility according to the selection
266 | www.jnsa.com Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2022 Wolters Kluwer Health, Inc. All rights reserved.
