Ketamine for critically ill patients with severe acute brain injury: Protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials.

INTRODUCTION: Intensive care for patients with severe acute brain injury aims both to treat the immediate consequences of the injury and to prevent and treat secondary brain injury to ensure a good functional outcome. Sedation may be used to facilitate mechanical ventilation, for treating agitation, and for controlling intracranial pressure. Ketamine is an N-methyl-D-aspartate receptor antagonist with sedative, analgesic, and potentially neuroprotective properties. We describe a protocol for a systematic review of randomised clinical trials assessing the beneficial and harmful effects of ketamine for patients with severe acute brain injury. METHODS AND ANALYSIS: We will systematically search international databases for randomised clinical trials, including CENTRAL, MEDLINE, Embase, and trial registries. Two authors will independently review and select trials for inclusion, and extract data. We will compare ketamine by any regimen versus placebo, no intervention, or other sedatives or analgesics for patients with severe acute brain injury. The primary outcomes will be functional outcome at maximal follow up, quality of life, and serious adverse events. We will also assess secondary and exploratory outcomes. The extracted data will be analysed using Review Manager and Trials Sequential Analysis. Evidence certainty will be graded using GRADE. ETHICS AND DISSEMINATION: The results of the systematic review will be disseminated through peer-reviewed publication. With the review, we hope to inform future randomised clinical trials and improve clinical practice. PROSPERO NO: CRD42021210447.

Introduction

Intensive care for patients with severe acute brain injury often includes administration of sedative and analgesic medications. The use of ketamine, which has both sedative and analgesic properties, reportedly lowers the incidence of cortical spreading depolarisation, a pathophysiological phemomenon that may cause secondary brain injury [1-6]. Existing guidelines do not specify sedative and analgesic agents of choice in patients with severe acute brain injury. Propofol and midazolam are currently the most frequently used drugs in this setting [6-10]. Ketamine is not commonly used [8]. Here we describe a protocol for a systematic review, which explores potential benefits and harms of ketamine for treating critically ill patients with severe acute brain injury.

Description of the patient population

Encompassing traumatic brain injury, subarachnoid haemorrhage, intracerebral haemorrhage, acute ischaemic stroke, hypoxic brain injury after cardiac arrest [11-20], as well as complications from neurosurgery [21], severe acute brain injury is a common cause of critical illness requiring admission to intensive or neurointensive care units [11, 22–24].

Severe acute brain injury is associated with prolonged intensive care unit and hospital stay, permanent disability, low quality of life, and death [17]. These outcomes depend on both the primary brain injury, which is immediate and irreversible, and the ensuing secondary brain injury, which is potentially reversible [18, 25–27] and induced by triggers such as hypoxia, hypotension, and inflammation [12, 13, 18, 28, 29].

Aneurysmal subarachnoid haemorrhage, which occurs in approximately 9 persons per 100,000 population-years at risk globally, has a fatality of around 25% with 20% of all patients remaining functionally dependent on help for activities of daily living [20, 30]. Early-phase complications such as rebleeding and delayed cerebral ischaemia are important predictors of long-term outcome [12, 31]. Early aneurysm closure may prevent rebleeding, but the mechanisms leading to delayed cerebral ischaemia are poorly understood and there is currently no known effective treatment [27]. Traumatic brain injury warranting admission to hospital (though not necessarily to the intensive care unit) occurs in 287 per 100,000 population-years at risk in Europe and is the cause of death in 37% of all trauma-related deaths [32]. Traumatic brain injury leads to a wide range of long-term disabilities that affects functional outcomes in survivors. Hypotension or hypoxia early after the injury are notorious risk factors for a poor outcome [33, 34]. Spontaneous intracerebral haemorrhage occurs in 25 per 100,000 population-years at risk globally and has a one-year mortality of 60%. Only 12% to 39% of afflicted patients will achieve functional independence [35]. Haematoma growth during the early phase is widely accepted as the most important risk factor for death and a poor outcome [35, 36].

Treatment of severe acute brain injury focuses on limiting the consequences of the primary injury and preventing secondary injury [37]. Administration of nimodipine, for example, may reduce the risk of delayed cerebral ischaemia and a poor functional outcome in patients with aneurysmal subarachnoid haemorrhage [38]. Moreover, multiple parameters such as intracranial pressure (ICP), cerebral metabolism (through microdialysis), cerebral electrical activity (measured using electroencephalography or electrocorticography), and brain-tissue oxygenation (PbtO2) [11, 28, 39] may be monitored to support the clinical neurological examination for early identification of known complications to brain injury [28].

Description of the intervention

Ketamine is a phenylcyclidine derivate with two optical enantiomers [40]. It is commercially available either as a racemic mixture, or as the (S)-enantiomer alone, which features approximately twice the potency of the racemic mixture [41], with potentially fewer psychomimetic adverse effects [42]. The main mechanism of action of ketamine has been attributed to NMDA-receptor (N-methyl-D-aspartate-receptor) antagonism [43]. The NMDA receptor is an ionotropic glutamate receptor. Activation of the receptor requires two distinct stimuli with temporal proximity–glutamate binding and membrane depolarisation [44]. Even though ketamine has a direct negative inotropic and chronotropic effect on the heart, ketamine has an overall sympathomimetic effect resulting in increased heart rate, cardiac output, and mean arterial blood pressure [45]. It is often stated that the cardiovascular stability of ketamine makes it a favourable choice in haemodynamically compromised patients, although there have been voices of dissent [46].

Featuring sedative, amnestic, and analgesic properties, ketamine has the potential to be the sole agent for induction and maintenance of anaesthesia [40]. Furthermore, protective airway reflexes, such as pharyngeal and laryngeal reflexes, are generally preserved and only negligible respiratory depression is reported [40]. Due to its sympathomimetic and bronchodilating effects, ketamine has found favour internationally as a sedative hypnotic agent in patients with haemodynamic instability and in those with reactive airway disease. In the prehospital setting, ketamine is used for rapid sequence induction prior to intubation as well as for pain management, in particular in patients with hypovolaemic shock as well as in war and combat zones [47]. In developing countries, ketamine is used as a simple and inexpensive alternative to a combinatorial drug approach that typically involves a concoction of more costly sedatives and analgesics [48]. Other notable clinical uses of ketamine include sedation of children and burn victims [47].

A number of national guidelines on intensive care recommend only light sedation during mechanical ventilation [7-9], though deep sedation is indicated for a series of specific clinical conditions, including increased intracranial pressure [6, 7, 9]. The choice of sedative is guided by indications and sedation goals, though propofol and midazolam are the standard sedatives used, and none of the guidelines suggests the use of ketamine specifically [7-10].

How the intervention might work

Subarachnoid haemorrhage, traumatic brain injury, acute ischaemic stroke with massive hemispheric infarction, and spontaneous intracerebral haemorrhage with postoperative perihaematomal oedema progression have all been associated with the presence of cortical spreading depolarisation [49-52]. These are slowly migrating depolarisation waves in the cerebral cortex, which may be monitored in patients using electrocorticography [53] or, potentially, electroencephalography [54, 55]. Repolarisation after such depolarisations dramatically increases brain metabolism [56]. The haemodynamic response to cortical spreading depolarisation often involves prolonged hypoperfusion [57], which may result in ischaemia and hypoxia in vulnerable brain tissue [57]. Cortical spreading depolarisations are associated with an increased risk of an unfavourable outcome after severe acute brain injury [58] and may thus represent a potential target for intervention. Ketamine appears to inhibit cortical spreading depolarisations in both animal and human studies [1–3, 5], has been suggested to attenuate excitotoxicity, and has anti-inflammatory and anti-apoptotic effects [59]. Ketamine administration could therefore be advantageous in critically ill patients with severe acute brain injury.

Why it is important to do this systematic review

Despite its multiple potential benefits, concerns of increased ICP has limited the use of ketamine in patients with severe acute brain injury [8, 60]. Yet recent analyses suggest that ICP-related reservations about ketamine may be unfounded [61, 62]. Today, the use of ketamine in the ICU is an emerging area of interest [6]. Thus, in vitro studies [2, 63], patient series [1, 3, 4, 53], and a cross-over study [5] indicate that ketamine compared to other types of sedatives reduces the incidence of cortical spreading depolarisation in patients with acute brain injury (primarily traumatic brain injury and subarachnoid haemorrhage). A previous systematic review of sedatives and analgesics in critically ill patients with traumatic brain injury found no randomised clinical trials that addressed the effect of ketamine compared with other sedatives or analgesics on clinical outcomes [64]. Two randomised trials [65, 66] investigated the effect of ketamine versus the drug sufentanil on intracranial pressure and cerebral perfusion pressure, reporting no differences in these variables.

One systematic review examined the use of ketamine for patients with traumatic brain injury, focusing mainly on ICP, and concluded that the overall evidence of using ketamine for this patient population is low [67].

In conclusion, ketamine may potentially improve outcome after acute brain injury, but the existing literature on its benefits and harms has not been sufficiently examined previously.

Objectives

The objective of this systematic review is to assess benefits and harms of ketamine for critically ill patients with severe acute brain injury.

Methods and analysis

In this systematic review, we will use standard methodological procedures following the recommendations by the Cochrane Handbook for Systematic Reviews of Interventions [68]. We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for grading evidence of the outcomes of interest [69], and the eight-step approach proposed by Jakobsen and colleagues to assess the intervention effect [70]. This protocol will adhere to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA-P) checklist [71]. Likewise, the upcoming systematic review will be reported according to the PRISMA 2020 guidelines [72]. Inclusion and exclusion of trials will be visualised in a 2020 PRISMA flow diagram [72].

The protocol is registered in the PROSPERO database with registration no. CRD42021210447.

Ethics and dissemination

There are no ethical or safety considerations related to this systematic review. The results from the upcoming systematic review will be disseminated through publication in a peer-reviewed journal.

Criteria for considering studies for inclusion

Types of studies

We will search for and include randomised clinical trials and cross-over randomised clinical trials as well as cluster-randomised trials for the assessments of benefits and harms, irrespective of reported outcomes, publication date, publication language, publication type, and publication status.

For the assessment of harms, we will also include quasi-randomised studies and observational studies, that are identified during our searches for trials. Such studies will be reported narratively and separately.

Participants

Studies of patients of all ages with severe acute brain injury treated in the ICU are included. Severe acute brain injury is defined as aneurysmal subarachnoid haemorrhage, traumatic brain injury, acute ischaemic stroke, intracerebral haemorrhage, or hypoxic brain injury.

Interventions

We will include trials in which ketamine administration is compared with either placebo, ‘no intervention’, or drugs that are used as standard of care in the ICU (e.g. propofol, benzodiazepines, opioids, alpha-2-agonists, and antipsychotics). No limitations to dose, formulation, or treatment duration will be made. Racemic mixtures of ketamine as well as S-ketamine will be included. Trials investigating ketamine administration for procedural sedation only will be excluded.

Types of outcomes

The ideal assessment time depends on the different outcomes. We will specify the time points below.

Primary outcomes.

Proportion of participants with unfavourable functional outcome at maximal follow up. We will evaluate functional outcome by the dichotomised Glasgow Outcome Scale (GOS), Glasgow Outcome Scale—Extended (GOSE), or modified Rankin Scale (mRS) and through them categorise a patient to unfavourable or favourable functional outcome. Unfavourable outcome is defined by the trial authors or by a GOS score of 1–3, GOSE score of 1–5, or mRS score of 3–6.

Quality of life at maximal follow up as measured using any validated scale.

Proportion of participants with one or more serious adverse events at maximal follow up. These are defined according to the International Conference on Harmonization (ICH) Guidelines (ICH‐GCP 1997) [73], that is, any event that leads to death; is life‐threatening; requires in‐patient hospitalisation or prolongs an existing hospital stay; or results in persistent or significant disability, congenital birth, or anomaly; and any important medical event that may have jeopardised the patient or required intervention to prevent it. All other adverse events are classified as non‐serious.

Secondary outcomes.

All-cause mortality at maximal follow-up.

The proportion of participants with neurological complications (rebleeding, seizures, worsening of neurological deficits, etc.) at maximal follow up.

Reported agitation during the ICU stay, as measured by validated sedation scales such as the Richmond Agitation Sedation Scale (RASS) or the Ramsay Sedation Scale, during administration of experimental and control interventions.

Proportion of participants with one or more adverse event (dichotomous data) during the hospital stay that is not considered serious.

Exploratory outcomes.

Functional clinical outcome defined by authors or evaluated with a valid neurological outcome scale, e.g. GOS, GOSE, or mRS at maximal follow-up.

Reported pain during the ICU stay during administration of experimental and control interventions (number of patients and frequency).

ICU length of stay (in days).

Duration of mechanical ventilation (in days).

Proportion of participants with individual serious adverse events at maximal follow up.

Proportion of participants with individual adverse events not considered serious during the hospital stay.

Multimodal neuromonitoring parameters during the ICU stay, such as (but not restricted to) ICP, PbtO2, and electrocorticographic spreading depolarisations, as defined by the trial authors.

Search methods for identification of studies

Databases

The following databases will be searched for published studies: MEDLINE, Embase, CENTRAL, CINAHL, LILACS, and Web of Science. For unpublished studies, we will search: ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP), and EU Clinical Trials Register. The full search strategy can be found in S1 File.

Other sources

Reference lists of relevant papers will be screened for further studies or randomised clinical trials not found in the database searches.

Data collection and analysis

Selection of studies

Two authors (FM and THA) will independently select studies, perform data extraction, and assess risks of bias. Any disagreement will be resolved by consensus, with a third author (KM) as the final arbiter. Titles and abstracts of all reports identified by the searches are screened. Potentially relevant reports are obtained in full text and are assessed for inclusion.

Data extraction and management

Two authors (FM and THA) will independently extract predefined data of included reports using a data collection form designed by the review team. Corresponding authors will be contacted for further information if there are issues related to data reporting or missing data.

Assessment of risk of bias in included randomised clinical trials

Two authors (FM and THA) will independently assess the included trials for risks of bias using the revised Cochrane risk of bias tool for randomised trials (RoB 2) [74]. The following five domains are evaluated: 1) bias arising during the randomisation process, 2) bias due to deviations from intended interventions, 3) bias due to missing outcome data, 4) bias in measurement of the outcome, and 5) bias in selection of the reported result.

Measures of treatment effect

The primary outcome of the present protocol is functional clinical outcome, and this is usually assessed using a multi-step (ordinal) scale with perfect neurological outcome at one end and death at the other end. For practical purposes, in clinical trials this multi-step assessment is frequently converted into a dichotomous outcome (‘favourable outcome’ and ‘unfavourable outcome’, or similar terminology). However, the original ordinal scales contain more information and have been reported to correspond better to long-term functional outcomes, at least for ischaemic stroke [75].

We will use an intention‐to‐treat analysis to make comparisons, where possible. For proportions (dichotomous outcomes), we will use relative risks (RRs) with 95% confidence intervals (CI) and Trial Sequential Analysis-adjusted CI. To analyse ordinal scale scores, we will use several analytic methods to test the robustness of our data. First, we will analyse the scales as dichotomised scales (functional outcomes: GOS 1–3 compared to 4–5, GOSE 1–5 compared to 6–8, mRS 0–2 compared to 3–6). Second, we will analyse the scales as continuous data with mean differences with 95% CIs and Trial Sequential Analysis-adjusted CI. Third, we will consider using the proportional odds model, if possible [68]. We will consider the results of all three analyses in the interpretation of effects and directions of effects. Finally, we will calculate the number needed to treat (NNT) and number needed to harm (NNH) with 95% CI where appropriate.

Unit of analysis issues

In case of multi-group trials comparing different drugs, including ketamine, as interventions, we will not combine the other drugs into one intervention group and compare this group to the ketamine group. The analyses will be conducted independently so that conclusions may be drawn.

Cluster-randomised trials, if detected, are included for analysis provided that they can be reduced to their effective sample sizes (with regard to the intracluster correlation).

For cross-over trials, we will include only outcomes from the end of the first period of the trial where cross-over trials resemble usual randomised clinical trials, to avoid bias arising from carry-over effects.

We will analyse additional domains of bias in cluster-randomised trials and cross-over trials in accordance with the recommendations presented in the Cochrane Handbook for Systematic Reviews of Interventions [68].

Missing data

We will contact investigators to retrieve important missing data. This applies to missing data for our primary, secondary, and exploratory outcomes, as well as methodological information for the risk of bias assessment. Additionally, we will seek information on the relevant subgroup(s) in case of trials with a mixed population. In case of no reply, we will make a second and third attempt to get in contact with the authors in question. If the missing data is irretrievable, we will take the percentage of missing data into account when interpreting the results (see below). Standard deviations (SD), if not reported by authors, will be calculated using data from the trial if possible.

Assessment of heterogeneity

We will assess heterogeneity by visual inspection of the forest plots, by performing chi-squared test with a P < 0.10 as statistical level of significance, and by measuring I2. According to the Cochrane Handbook for Systematic Reviews of Interventions (Version 6, 2019), heterogeneity is described as considerable if I2 is between 75% to 100%, substantial between 50% to 90%, moderate between 30% to 60%, and nonexistent or low between 0% to 40%.

Assessment of reporting bias

We will visually examine funnel plots for signs of asymmetry if ten or more trials are included in an analysis [70].

Data synthesis

Meta-analysis

We will conduct meta-analysis based on recommendations in the Cochrane Handbook for Systematic Reviews of Interventions [68] if effect measures from two or more trials are comparable and the clinical heterogeneity is not too extensive. If the results are not suitable for quantitative analysis, they will be reported narratively.

We will report results from both fixed-effect and random-effects meta-analyses. If they show differing results, we will choose the one with the most conservative result (highest P-value and widest confidence interval) as the main result. For these analyses, we will make use of Review Manager, a statistical software program offered by The Cochrane Collaboration.

Assessment of significance

We will follow the eight-step approach proposed by Jakobsen et al. [70] for evaluating statistical and clinical significance of the meta-analysis. This includes fixed-effect meta-analysis, random-effects meta-analysis, subgroup analysis, sensitivity analysis, adjustments of the thresholds for significance, calculations of realistic diversity-adjusted required information size, Trial Sequential Analysis, calculations of Bayes factor, assessment of the impact of bias, assessment of publication bias, and assessment of clinical significance [70].

To control problems with multiplicity, we will adjust the significance thresholds by a modified Bonferroni adjustment, dividing the threshold by the value halfway between 1 (no adjustment) and the number of primary or secondary outcomes, respectively [70]. Consequently, the threshold of statistical significance will be 0.025 for our three primary outcomes and 0.02 for our four secondary outcomes. For exploratory outcomes, we will use P < 0.05, as we only consider these analyses as hypothesis generating.

Trial Sequential Analysis

If meta-analysis is appropriate, we will conduct Trial Sequential Analysis (TSA) to control the risk of random errors due to sparse data and repetitive testing [76]. Both primary and secondary outcomes will be analysed. TSA of the meta-analysis will be performed by using the TSA software provided by The Copenhagen Trial Unit [77] and will yield the required information size to obtain definite evidence on the effect of an intervention, an adjusted confidence interval, and an adjusted level of statistical significance [76].

For dichotomous outcomes, we will estimate the required information size based on the observed proportion of patients with an outcome in the control group of the meta-analysis (the cumulative proportion of patients with an event in the control groups relative to all patients in the control groups), a relative risk reduction or increase of 20%, an alpha of 2.5% for all primary outcomes, a beta of 10%, and the observed diversity as suggested by the trials in the meta-analysis. For continuous outcomes, we will use the observed SD, a mean difference of the observed SD/2, an alpha of 2.5% for all primary outcomes, a beta of 10%, and the observed diversity as suggested by the trials in the meta-analysis. For the secondary outcomes we will use an alpha of 2% plus similar parameters as to the primary outcomes.

Subgroup analysis and investigation of heterogeneity

In order to assess whether a given effect is present in only a subgroup of trials, patients, or dosage regimens, or whether the effect is influenced by the type of comparator, we will conduct the following comparisons between estimated intervention effects, if possible:

Trials at overall ‘low’ compared to trials at ‘high’ risk of bias

Different patient diagnoses (aneurysmal subarachnoid haemorrhage, traumatic brain injury, acute ischaemic stroke, intracerebral haemorrhage, and hypoxic brain injury)

Different age groups (infants, children, adolescents, and adults)

Doses of ketamine at or higher compared to lower than the median dose

Treatment duration at or longer compared to shorter than the median duration

Different comparators (‘no intervention’, placebo, other sedatives, or analgesics)

Sensitivity analysis

In line with the eight step approach [70], we will conduct sensitivity analyses to assess the potential impact of missing outcome data. Thus, dichotomous outcomes will undergo two sensitivity analyses on both the primary and secondary outcomes, i.e. ‘best-worst-case’ and ‘worst-best-case’ scenarios [70]. Continuous outcomes in the best group, e.g. quality of life, will be imputed as the group mean plus two standard deviations (SDs) of the group mean. Worst groups are imputed as the group mean minus two SDs of the group mean. We will present results of all scenarios in our review. Other post-hoc sensitivity analyses might be warranted if unexpected clinical or statistical heterogeneity is identified during the analysis of the review results.

Summary of findings

We will assess the quality of primary and secondary outcomes and the certainty of evidence with GRADE [69]. We will construct summary of findings tables in the GRADEpro GDT software [78] including the following outcomes:

The proportion of participants with unfavourable functional clinical outcome at maximal follow

Quality of life at maximal follow

The proportion of participants with one or more serious adverse events

All-cause mortality at maximal follow-up.

The proportion of participants with neurological complications (rebleeding, seizures, worsening of neurological deficits, etc.)

Reported agitation during the ICU stay, as measured by validated sedation scales such as the Richmond Agitation Sedation Scale (RASS) or the Ramsay Sedation Scale, during administration of experimental and control interventions.

Proportion of participants with at least one adverse event (dichotomous data) during the hospital stay that is not considered serious

Discussion

We aim to explore the benefits and harms of ketamine for critically ill patients with severe acute brain injury based on conducted randomised clinical trials. Because these patients have a high risk of poor outcomes such as death and permanent disability [17], there is a need to improve the current standard of care. According to recent studies, ketamine may prevent secondary brain injury due to cortical spreading depolarisation [1–3, 5], one of several potentially deleterious mechanisms [59].

Concerning strengths, this protocol is made in accordance with PRISMA-P [71] and the Cochrane Handbook for Systematic Reviews of Interventions [68]. To further strengthen our review, we will use Trial Sequential Analysis [76, 77], the GRADE methodology [69], and the eight-step assessment suggested by Jakobsen et al. [70].

Concerning weaknesses, first, we have decided only to search for randomised clinical trials, cross-over trials and cluster-randomised trials, and not for quasi-randomised studies and observational studies. Quasi-randomised studies and observational studies that are identified during our searches, e.g. as important references cited in manuscripts of randomised, cross-over and cluster-randomised trials, will however be included for a crude assessments of harms. This means that we may overlook late or rare adverse effects, which may necessitate further review of quasi-randomised studies and observational studies in the future [79]. Second, we intend to dichotomise ordinal outcomes, at the risk of losing statistical power. Any results on unfavourable functional clinical outcome at maximal follow up should be interpreted with caution for a number of reasons [80]: 1) the assessments of unfavourable functional clinical outcome is based on single scores and it is questionable whether single scores are indications of unfavourable functional clinical outcome to the intervention; 2) information is lost when continuous data are transformed to dichotomous data and the analysis results can be greatly influenced by the distribution of data and the choice of an arbitrary cut-point; 3) even though a larger proportion of participants cross the arbitrary cut-point in the experimental group compared with the control group, the effect measured might still be limited; 4) by only focusing on how many patients cross a certain line for poor outcome, investigators ignore how many patients are improving at the same time. The clinical significance of our results on functional outcome may therefore be questioned. According to Kirsch and Moncrieff, “response rates based on continuous data do not add information, and they can create an illusion of clinical effectiveness” [81].

We hope that this systematic review may elucidate possible beneficial and harmful effects of ketamine in critically ill patients with severe acute brain injury. This may lead the way for future good-quality randomised clinical trials and evidence-based clinical practise.

PRISMA-P 2015 checklist.

(DOCX)

Click here for additional data file.

Search strategy.

(DOC)

Click here for additional data file.

31 Aug 2021

PONE-D-21-17647

Ketamine for critically ill patients with severe acute brain injury: protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials

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2- Please report more details on missing outcome data. What does “important missing data” mean? You will contact corresponding authors only for primary outcome data? What about, for example, secondary outcomes or methodological information for risk of bias? Probably you should define a priori some important missing data to be asked to corresponding authors. How many time will you contact corresponding authors in case of no reply?

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Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This proposed study protocol has sound methodology. This study proposal is certainly a question worth asking, with important clinical implications that could change the way we manage this vulnerable subset of patients.

Some small changes to the language used may make it easier to follow. I've included some examples below:

Suggestions for the Introduction:

Have faith in your audience. Most would agree that severe acute brain injury generally has two initial pathways, admission to ICU or death. It doesn't add much to say they may be admitted to ICU. Instead your intro may be more effective if the first line read: "Intensive care for patients with severe acute brain injury often includes administration of sedative and analgesic medications."

The sentence beginning with "Existing guidelines" probably shouldn't read "do not recommend," as this may also be interpreted as "recommend against," which is not your intent. Instead you may consider: "Existing guidelines do not specify sedative and analgesic agents of choice in patients with severe acute brain injury. Propofol and midazolam are currently the most frequently used drugs in this setting."

Suggestions for "Description of the Patient Population"

Consider consolidating the first 2 sentences in this section: "Encompassing traumatic brain injury, subarachnoid haemorrhage, intracerebral haemorrhage, acute ischaemic stroke, hypoxic brain injury after cardiac arrest, as well as complications from neurosurgery, Severe acute brain injury is a common cause of critical illness requiring admission to intensive or neurointensive care units."

paragraph 2: substitute "prolonged" for "long durations of"

paragraph 3: You already described the range of specific diseases that severe acute brain injury encompasses. Consider removing the intro sentence beginning "the specific diseases." and delete the words "as examples." Instead begin the paragraph with "Aneurysmal subarachnoid hemorrhage, which occurs...."

after "long-term outcome", "Early aneurysm closure..." should be it's own new sentence (not a semicolon)

After "60%" consider ending the sentence and starting a new sentence. Consider "Only 12% to 39% of afflicted patients will achieve functional independence."

Paragraph 4 (Treatment):

2nd sentence reads awkwardly. Consider instead, "Administration of nimodipine, for example, may reduce the risk of delayed cerebral ischemia..."

Suggestions for "Description of the intervention"

Paragraph 1: I would spend a little more time expanding here. (some physicians may also be less familiar with S-ketamine so there is an opportunity to educate. As written, it starts out a bit unclear when describing the different enantiomers of ketamine. Consider instead: "Ketamine is phenylcyclidine derivative with two optical enantiomers. It is commercially available either as a racemic mixture, or as the (S) enantiomer alone, which features approximately twice the potency of the racemic mixture with potentially fewer psychomimetic side effects." (i found some case reports on this, including "Paul R, Schaaff N, Padberg F, Möller HJ, Frodl T. Comparison of racemic ketamine and S-ketamine in treatment-resistant major depression: report of two cases. World J Biol Psychiatry. 2009;10(3):241-4. doi: 10.1080/15622970701714370. PMID: 19224412."). While you are describing the chemical characteristics of the drug, before getting into its use, this would be an ideal place to merge in the mechanism of action/ NMDA receptor antagonism, which was previously paragraph 3. From there you can more smoothly transition into the effects and benefits of the drug:

"Featuring sedative, amnestic, and analgesic properties, Ketamine has the potential to be a sole agent for induction and maintenance of anaesthesia."

Paragraph 4:

Much of the material at the beginning of this paragraph would serve you better in paragraph 1 or 2, where you already started to describe ketamine's multiple uses and favorable traits. I would consolidate. After the line ending in "maintenance of anaesthesia." in paragraph 1, you can expand a little with its multiple roles in current medical practice.. Instead of "the clinical use of ketamine is primarily for..." consider "Due to its sympathomimetic and bronchodilating effects, Ketamine has found favor internationally as a sedative hypnotic agent in patients with hemodynamic instability and those with reactive airway disease." You can add in the use in developing countries there as well as you close out the second paragraph. I would make a break/new paragraph that begins with your line "A number of national guidelines..." because this is where you bring the reader back to your purpose, an exploration of the merits of this multifaceted sedative and analgesic medicine in the context of brain injury patients.

Suggestions for "Why it is important"

This is where your article does a very nice job of drawing the reader in. I think you could enhance up the argument by starting this paragraph slightly stronger. Instead of "Ketamine has been used scarcely..." consider:

"Despite its multiple potential benefits, concerns of increased ICP has limited ketamine's use in patients with severe acute brain injury. Yet recent analyses suggest that ICP-related reservations about ketamine may be unfounded."

The rest of the paper read very well for me.

Overall this strikes me as a very thoughtful proposal and I'm eager to read your findings when the meta analysis is complete.

Reviewer #2: The authors propose a protocol for a systematic review focusing on use of ketamine in acute neurological injury. For all the many reasons the authors discuss, this is becoming a topic of high interest.

-The authors acknowledge that the literature on this topic will be highly heterogeneous in terms of patient population, study design, and outcomes assessed. They also acknowledge that they may analyze the results differently depending on the findings. Combining these heterogenous studies, which all used ketamine in a different way with different doses in different patient populations focusing on different outcomes seems like attempting to combine these results into a meaningful meta-analysis is of questionable validity. Knowing this literature moderately well at least, I do not think the authors will find any well done RCTs that would fit into the analysis approach they suggest. With strict rigorous criteria, do the authors think that there are additional published studies that will add to the systematic review from 2011 (Roberts) which identified no comparative studies?

-Given that there may need to be multiple different approaches depending on what the authors find and the bottom line is that this SR will most likely be focused on low quality data, what is the justification for publishing a protocol?

Reviewer #3: In this manuscript, dr. Andreasen and colleagues present the study protocol for a systematic review and meta-analysis of RCTs investigating the effect of ketamine in patients with traumatic brain injury.

The protocol deals with a very interesting topic, as in my experience use of ketamine for "neuro" patients is still considered contraindicated by many colleagues despite potential advantages.

The protocol is well written, and the study well planned. I only have few minor comments:

- I assume that PRISMA-P will be followed for this protocol and PRISMA 2020 for the full report (see p. 8, first Methods paragraph)

- I suggest to plan a subgroup/sensitivity analysis excluding crossover studies

**********

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Reviewer #1: Yes: Christopher Conley, MD

Reviewer #2: No

Reviewer #3: No

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4 Oct 2021

Title of the Manuscript: Ketamine for critically ill patients with severe acute brain injury: protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised

clinical trials

Manuscript number: PONE-D-21-17647

Response to reviewers and Editor

We thank you for the opportunity to reply to the reviewers’ and Editor’s comments regarding our submission entitled “Ketamine for critically ill patients with severe acute brain injury: protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials” (PONE-D-21-17647).

In this response, we have written the reviewer comment, followed by our response, and the text parts from the revised manuscript. The page references are to the Manuscript file without track changes.

Responses to the Editor’s comments

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https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: Changes have been made to the title page so that the formatting guidelines for title, authors, and affiliations are met. Likewise, changes in font size of headings have been made throughout the manuscript, as well as a few minor corrections to the wording, and the section Supporting information has been moved to after the reference list.

2. Thank you for stating the following financial disclosure:

At this time, please address the following queries:

a) Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.

b) State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

c) If any authors received a salary from any of your funders, please state which authors and which funders.

d) If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

Response: We have updated our information on funding. The authors received financial support from the Department of Neurosurgery Research Pool (Neurokirurgisk forskningspulje) at Rigshospitalet, Master Carpenter Sophus Jacobsen and wife Astrid Jacobsen’s Foundation (Snedkermester Sophus Jacobsen og hustru Astrid Jacobsen’s Fond), Rigshospitalet’s 3-year PhD scholarship, and the Danish Victims Foundation (20-610-00103) in the form of salary for author TA. Funding was also received from: The A.P. Møller Foundation (20-L-0041), Knud og Edith Eriksen’s Memorial Fund (Knud og Edith Eriksens Mindefond, 62786-2021), and The Novo Nordisk Foundation (NNF20OC0065750). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

This information was also added to the cover letter.

3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript.

Response: The ethics statement has been moved to the Methods section on page 8.

4. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response: The reference list has been reviewed and no changes have been made. We assert that it stands complete and correct.

5. Thank you for submitting the above manuscript to PLOS ONE. During our internal evaluation of the manuscript, we found significant text overlap between your submission and the following previously published works, some of which you are an author.

https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/s13643-019-0957-0

https://link.springer.com/chapter/10.1007%2F978-981-13-7272-8_1

We would like to make you aware that copying extracts from previous publications, especially outside the methods section, word-for-word is unacceptable. In addition, the reproduction of text from published reports has implications for the copyright that may apply to the publications.

Please revise the manuscript to rephrase the duplicated text, cite your sources, and provide details as to how the current manuscript advances on previous work. Please note that further consideration is dependent on the submission of a manuscript that addresses these concerns about the overlap in text with published work.

We will carefully review your manuscript upon resubmission, so please ensure that your revision is thorough.

Response: Thank you for making us aware of this text overlap. We have not intentionally copied text from other publications and agree that duplicating text is not acceptable. We have now read the two listed publications carefully to identify the text overlap.

For the first publication, we found text overlap for Primary outcomes (page 9-10), in the Selection of studies and Data extraction and management sections (page 11-129, as well as the section Trial Sequential Analysis (page 16), and how continuous outcomes is managed under Sensitivity analysis (page 17). As mentioned, one of the authors of our protocol (CG) was also the co-author of the protocol entitled “Ivabradine for coronary artery disease and/or heart failure—a protocol for a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis”. The resemblance in text must therefore be considered text recycling. We as authors of the present protocol find that the resemblance in text is limited to certain phrases of the Methods section. Accuracy and precision in the description of the methods applied is key for comprehension and reproducibility. Therefore, text recycling is not uncommon in the mentioned sections, especially not for the same author, who may have evolved a precise wording of methodological definitions and practice.

As an example, we share two of the same primary outcomes (quality of life and proportion of participants with one or more serious adverse events); both these outcomes are highly relevant, especially when dealing with patients suffering from acute severe brain injury. In our description of a serious adverse event, we have included the definition from the ICH (International Conference on Harmonization) since international consensus has been achieved around these criteria. This gives rise to overlap in text because the authors of the Ivabradine protocol also used this definition.

In the description of the parameters we will use in the Trial Sequential Analysis (TSA), there is also some overlap in text. Nevertheless, this paragraph is a short and precise account of the methods chosen for the TSA.

For the second publication, the chapter called “Sedation and Analgesia for Patients with Acute Brain Injury” from the book “Neurocritical Care”, we the authors of the present protocol were unaware of this publication before you directed our attention to it. Also, we cannot find any overlap in text. Please advise on any misunderstanding on our part.

Minor comments from Editor:

1. I suggest including a PRISMA 2020 checklist and a PRISMA 2020 flow-chart in your systematic review.

Response: We have now clarified in the manuscript that a PRISMA 2020 checklist and a PRISMA 2020 flow-chart will be used in our systematic review.

"We have added the following on page 8: This protocol will adhere to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA-P) checklist [71]. Likewise, the upcoming systematic review will be reported according to the PRISMA 2020 guidelines [72]. Inclusion and exclusion of trials will be visualised in a 2020 PRISMA flow diagram [72]."

2. Please report more details on missing outcome data. What does “important missing data” mean? You will contact corresponding authors only for primary outcome data? What about, for example, secondary outcomes or methodological information for risk of bias? Probably you should define a priori some important missing data to be asked to corresponding authors. How many times will you contact corresponding authors in case of no reply?

Response: We have extended the “Missing data” section with the following paragraph, page 14:

"We will contact investigators to retrieve missing data. This applies to missing data for our primary, secondary, and exploratory outcomes, as well as methodological information for the risk of bias assessment. Additionally, we will seek information on the relevant subgroup in case of trials with a mixed population. In case of no reply, we will make a second and third attempt to get in contact with the authors in question. If the missing data is irretrievable, we will take the percentage of missing data into account when interpreting the results (see below). Standard deviations (SD), if not reported by authors, will be calculated using data from the trial if possible."

Responces to the reviewers’ comments

Reviewer #1

This proposed study protocol has sound methodology. This study proposal is certainly a question worth asking, with important clinical implications that could change the way we manage this vulnerable subset of patients. Some small changes to the language used may make it easier to follow. I've included some examples below:

Responses: We thank the reviewer for the kind words. We would also like to thank the reviewer for their time and work on this protocol.

Suggestions for the Introduction:

Have faith in your audience. Most would agree that severe acute brain injury generally has two initial pathways, admission to ICU or death. It doesn't add much to say they may be admitted to ICU. Instead your intro may be more effective if the first line read: "Intensive care for patients with severe acute brain injury often includes administration of sedative and analgesic medications."

Responses: We thank the reviewer for the suggestion. We have changed the text in the Introduction on page 3 as suggested.

The sentence beginning with "Existing guidelines" probably shouldn't read "do not recommend," as this may also be interpreted as "recommend against," which is not your intent. Instead you may consider: "Existing guidelines do not specify sedative and analgesic agents of choice in patients with severe acute brain injury. Propofol and midazolam are currently the most frequently used drugs in this setting."

Response: We have changed the text in the Introduction on page 3 accordingly.

Suggestions for "Description of the Patient Population"

Consider consolidating the first 2 sentences in this section: "Encompassing traumatic brain injury, subarachnoid haemorrhage, intracerebral haemorrhage, acute ischaemic stroke, hypoxic brain injury after cardiac arrest, as well as complications from neurosurgery, Severe acute brain injury is a common cause of critical illness requiring admission to intensive or neurointensive care units."

Response: We thank the reviewer. We have changed the text in the Introduction under “Description of the patient population” on page 3.

Paragraph 2: substitute "prolonged" for "long durations of"

Response: We have changed the text in the Introduction under “Description of the patient population” on page 3 as suggested.

Paragraph 3: You already described the range of specific diseases that severe acute brain injury encompasses. Consider removing the intro sentence beginning "the specific diseases." and delete the words "as examples." Instead begin the paragraph with "Aneurysmal subarachnoid hemorrhage, which occurs...."

Response: We have changed the text in the Introduction under “Description of the patient population” on page 3 as suggested.

After "long-term outcome", "Early aneurysm closure..." should be it's own new sentence (not a semicolon)

Response: We have changed the text in the Introduction under “Description of the patient population” on page 3 as suggested.

After "60%" consider ending the sentence and starting a new sentence. Consider "Only 12% to 39% of afflicted patients will achieve functional independence."

Response: We agree and have changed the text in the Introduction under “Description of the patient population” on page 4 as suggested.

Paragraph 4 (Treatment):

2nd sentence reads awkwardly. Consider instead, "Administration of nimodipine, for example, may reduce the risk of delayed cerebral ischemia..."

Response: We have changed the text in the Introduction under “Description of the patient population” on page 4 as suggested.

Suggestions for "Description of the intervention"

Paragraph 1: I would spend a little more time expanding here. (some physicians may also be less familiar with S-ketamine so there is an opportunity to educate. As written, it starts out a bit unclear when describing the different enantiomers of ketamine. Consider instead: "Ketamine is phenylcyclidine derivative with two optical enantiomers. It is commercially available either as a racemic mixture, or as the (S) enantiomer alone, which features approximately twice the potency of the racemic mixture with potentially fewer psychomimetic side effects." (i found some case reports on this, including "Paul R, Schaaff N, Padberg F, Möller HJ, Frodl T. Comparison of racemic ketamine and S-ketamine in treatment-resistant major depression: report of two cases. World J Biol Psychiatry. 2009;10(3):241-4. doi: 10.1080/15622970701714370. PMID: 19224412."). While you are describing the chemical characteristics of the drug, before getting into its use, this would be an ideal place to merge in the mechanism of action/ NMDA receptor antagonism, which was previously paragraph 3. From there you can more smoothly transition into the effects and benefits of the drug: "Featuring sedative, amnestic, and analgesic properties, Ketamine has the potential to be a sole agent for induction and maintenance of anaesthesia."

Response: We thank the reviewer for their thoughtful comments and suggestions. We have changed the text accordingly on page 5:

"Ketamine is a phenylcyclidine derivate with two optical enantiomers [40]. It is commercially available either as a racemic mixture, or as the (S)-enantiomer alone, which features approximately twice the potency of the racemic mixture [41], with potentially fewer psychomimetic adverse effects [42]."

Reference 42 is the reference Paul et al. 2009 as proposed by the reviewer.

The text is followed by these two paragraphs, which were moved from page 5:

"The main mechanism of action of ketamine has been attributed to NMDA-receptor (N-methyl-D-aspartate-receptor) antagonism [43]. The NMDA receptor is an ionotropic glutamate receptor. Activation of the receptor requires two distinct stimuli with temporal proximity – glutamate binding and membrane depolarisation [44].

Even though ketamine has a direct negative inotropic and chronotropic effect on the heart, ketamine has an overall sympathomimetic effect resulting in increased heart rate, cardiac output, and mean arterial blood pressure [45]. It is often stated that the cardiovascular stability of ketamine makes it a favourable choice in haemodynamically compromised patients, although there have been voices of dissent [46]."

Followed by the suggested change on page 5:

"Featuring sedative, amnestic, and analgesic properties, ketamine has the potential to be the sole agent for induction and maintenance of anaesthesia [40]."

Paragraph 4:

Much of the material at the beginning of this paragraph would serve you better in paragraph 1 or 2, where you already started to describe ketamine's multiple uses and favorable traits. I would consolidate. After the line ending in "maintenance of anaesthesia." in paragraph 1, you can expand a little with its multiple roles in current medical practice. Instead of "the clinical use of ketamine is primarily for..." consider "Due to its sympathomimetic and bronchodilating effects, Ketamine has found favor internationally as a sedative hypnotic agent in patients with hemodynamic instability and those with reactive airway disease." You can add in the use in developing countries there as well as you close out the second paragraph. I would make a break/new paragraph that begins with your line "A number of national guidelines..." because this is where you bring the reader back to your purpose, an exploration of the merits of this multifaceted sedative and analgesic medicine in the context of brain injury patients.

Response: We agree with the proposed changes and have rephrased the text as suggested by adding the following on page 5:

"Due to its sympathomimetic and bronchodilating effects, ketamine has found favour internationally as a sedative hypnotic agent in patients with hemodynamic instability and in those with reactive airway disease."

We have also deleted the suggested sentence “The clinical use of ketamine is primarily for patients with haemodynamic instability and reactive airway disease.” and made a new paragraph before “A number of national guidelines...” on page 5-6.

Suggestions for "Why it is important"

This is where your article does a very nice job of drawing the reader in. I think you could enhance up the argument by starting this paragraph slightly stronger. Instead of "Ketamine has been used scarcely..." consider:

"Despite its multiple potential benefits, concerns of increased ICP has limited ketamine's use in patients with severe acute brain injury. Yet recent analyses suggest that ICP-related reservations about ketamine may be unfounded."

Response: We have changed the text accordingly by adding on page 7:

"Despite its multiple potential benefits, concerns of increased ICP has limited the use of ketamine in patients with severe acute brain injury [8,60]. Yet recent analyses suggest that ICP-related reservations about ketamine may be unfounded [61,62]."

We have deleted “Ketamine has been used scarcely in the ICU for patients with severe acute brain injury [8], as it was reported to increase ICP [59]. However, this was not confirmed by recent analyses.”

The rest of the paper read very well for me.

Overall this strikes me as a very thoughtful proposal and I'm eager to read your findings when the meta-analysis is complete.

Response: We thank the reviewer for their thoughtful and valuable comments.

Reviewer #2

The authors propose a protocol for a systematic review focusing on use of ketamine in acute neurological injury. For all the many reasons the authors discuss, this is becoming a topic of high interest.

- The authors acknowledge that the literature on this topic will be highly heterogeneous in terms of patient population, study design, and outcomes assessed. They also acknowledge that they may analyse the results differently depending on the findings. Combining these heterogenous studies, which all used ketamine in a different way with different doses in different patient populations focusing on different outcomes seems like attempting to combine these results into a meaningful meta-analysis is of questionable validity. Knowing this literature moderately well at least, I do not think the authors will find any well done RCTs that would fit into the analysis approach they suggest. With strict rigorous criteria, do the authors think that there are additional published studies that will add to the systematic review from 2011 (Roberts) which identified no comparative studies?

Response: We thank the reviewer for the thorough work and thoughtful comments to our protocol. We agree that the literature on this topic is highly heterogeneous. We believe that it is meaningful to explore the use of ketamine in patients with severe acute brain injury since these patients are in high risk of a poor outcome, and there is a need to improve the current standard of care. Ketamine is scarcely used in neurointensive care, although recent findings suggest that ketamine inhibits cortical spreading depolarisations, which may be causally related to lesion expansion in patients with acute severe brain injury. The review by Roberts et al. from 2011 on sedation for critically ill adults focuses mainly on traumatic brain injury patients. The present protocol focuses on trials with patients suffering from the full range of diseases known to be associated with cotical spreading depolarisation. This includes subarachnoid haemorrhage, traumatic brain injury, acute ischaemic stroke with massive hemispheric infarction, and spontaneous intracerebral haemorrhage with postoperative perihaematomal oedema progression. Since ketamine appears to inhibit these pathological electrophysical changes, it is exactly this patient population that may be worth examining. Additionally, the review by Roberts et al. was published 10 years ago, and new trials and studies trials could have emerged in the meantime, especially given the emerging interest in cortical spreading depolarisations. We think that it is important to approach this question in a systematic manner. This entails undertaking a systematic review. By nature, this includes conducting a systematic search and subsequently analysing and interpreting the pooled results through sound and robust methodology. That is why we have proposed this systematic review following the recommendations from the Cochrane Handbook for Systematic Reviews of Interventions and the eight-step assessment suggested by Jakobsen et al. Only by doing this, we can obtain definite evidence, or lack thereof, on the effect of ketamine in this vulnerable subset of patients.

- Given that there may need to be multiple different approaches depending on what the authors find and the bottom line is that this SR will most likely be focused on low quality data, what is the justification for publishing a protocol?

Response: We chose to be transparent in our methodology and therefore seek to publish the protocol. By publishing the protocol, and making our planned methodology public, we intend to decrease the risk of bias for the systematic review and meta-analysis as we have thus committed ourselves to the specified methods before performing the review.

Reviewer #3

In this manuscript, dr. Andreasen and colleagues present the study protocol for a systematic review and meta-analysis of RCTs investigating the effect of ketamine in patients with traumatic brain injury. The protocol deals with a very interesting topic, as in my experience use of ketamine for "neuro" patients is still considered contraindicated by many colleagues despite potential advantages. The protocol is well written, and the study well planned. I only have few minor comments:

- I assume that PRISMA-P will be followed for this protocol and PRISMA 2020 for the full report (see p. 8, first Methods paragraph)

Response: We thank the reviewer for the kind words as well as the time and work spent on this protocol. PRISMA-P will be followed for this protocol and PRISMA 2020 for the systematic review. It is now clarified in the revised manuscript on page 8:

"This protocol will adhere to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA-P) checklist [71]. Likewise, the upcoming systematic review will be reported according to the PRISMA 2020 guidelines [72]. Inclusion and exclusion of trials will be visualised in a 2020 PRISMA flow diagram [72]."

- I suggest planning a subgroup/sensitivity analysis excluding crossover studies

Response: We thank the reviewer for this suggestion, but as we only intend to use data of the first period of the cross over trials (during which they resemble all other randomised trials) we are not sure that this sensitivity may be meaningful. We have now clarified that we only use data from the first period of such trials on page 13:

"For cross-over trials, we will include only outcomes from the end of the first period of the trial where cross-over trials resemble usual randomised clinical trials, to avoid bias arising from carry-over effects."

We would like to thank both the reviewers and the Editor for consideration and thorough reading of our manuscript, and for the constructive comments and suggestions, which have helped us improve the manuscript. This is hereby resubmitted to PLOS ONE.

On behalf of all authors,

Yours sincerely

Trine Hjorslev Andreasen, MD

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

29 Oct 2021

Ketamine for critically ill patients with severe acute brain injury: protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials

PONE-D-21-17647R1

Dear Dr. Andreasen,

Thank you for your further work on this manuscript which now makes a fine contribution to consideration of this important topic.

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #3: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #3: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #3: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript reads better now. Thank you for incorporating my feedback. Hopefully this article will catalyze further study of ketamine's potential in this vulnerable patient population.

Reviewer #3: In this manuscript, dr. Andreasen and colleagues now present a revised version of their work.

I believe that all of my comments have been adequately addressed and the manuscript is in my opinion now suitable for publication.

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Reviewer #1: No

Reviewer #3: No

4 Nov 2021

PONE-D-21-17647R1

Ketamine for critically ill patients with severe acute brain injury: protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials

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