# Impact of inhaled sedation on delirium incidence and neurological outcome after cardiac arrest – A propensity-matched control study (Isocare)

Christelle Teiten, Pierre Bailly, Jean-Marie Tonnelier, Laetitia Bodenes, Kahaia de Longeaux, Erwan L'her

► To cite this version:

Christelle Teiten, Pierre Bailly, Jean-Marie Tonnelier, Laetitia Bodenes, Kahaia de Longeaux, et al. Impact of inhaled sedation on delirium incidence and neurological outcome after cardiac arrest – A propensity-matched control study (Isocare). Resuscitation, 2024, 203, pp.110358. 10.1016/j.resuscitation.2024.110358. hal-05288191

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Clinical paper

# Impact of inhaled sedation on delirium incidence and neurological outcome after cardiac arrest – A propensity-matched control study (Isocare)

<figure><img src="image_4.png" /></figure>

Christelle Teitenª, Pierre Baillyª,*, Jean-Marie TONNELIERª, Laetitia Bodenesª, Kahaia de Longeauxª, Erwan L'Herª,ᵇ,⁺

**Abstract**

**Rationale:** Poor neurological outcome is common following a cardiac arrest. The use of volatile anesthetic agents has been proposed during post-resuscitation to improve outcome.

**Objectives:** To determine the effects of inhaled isoflurane on neurological outcome, delirium incidence, ICU length-of-stay, ventilation duration, mortality during post-resuscitation care of ICU patients.

**Patients:** 510 patients were admitted within our medical ICU following a cardiac arrest during the study period, 401 of them being sedated using intravenous sedation prior to 2017 and 109 of them using inhaled isoflurane according to a standardized protocol following 2017.

**Results:** Matched-pair analysis depicted a delirium incidence decrease, without improved neurologic outcome on ICU discharge (CPC ≤ 2) for isoflurane patients (16.1% vs 32.2%, p 0.03 and 29% vs 23%, p 0.47, respectively). Ventilation duration and ICU length of stay were shorter for isoflurane patients (78 vs 167 h, p 0.01 and 7.9 vs 8.5 days, p 0.01 respectively). Isoflurane had no impact on mortality.

**Conclusion:** In this propensity-matched control study, isoflurane sedation during the post-resuscitation care of ICU patients was associated with a lower incidence of delirium, a shorter duration of mechanical ventilation and a reduced ICU length of stay. Prospective data are needed before its widespread use.

**Keywords:** Cardiac arrest, Volatile anesthetics, Delirium, Post-anoxic encephalopathy

**Introduction**

Targeted temperature management (TTM) following a cardiac arrest (CA) is recommended to improve outcome.¹ It often requires deep sedation (Richmond Agitation-Sedation Scale (RASS) of minus 4 to 5).²,³ Following a CA, as compared to intravenous (IV) sedation, inhaled sedation using halogeneous agents may promote a more rapid awakening, and thus a more rapid endotracheal extubation and decreased ventilation duration with shorter intensive care unit (ICU) length of stay, whatever the comparative intravenous hypnotic agent.⁴,⁵ These benefits have been recently confirmed in a meta-analysis.⁶ Beside these benefits for CA patients, volatile sedation

may also enable a decreased opiates consumption, or a P/F ratio improvement in ARDS patients.⁷,⁸

However the effects of volatile sedation on delirium and neurolog- ical outcomes after CA remains unclear.⁶

Isoflurane sedation has been introduced in routine for more than 20 years within our ICU as a substitute to hypnotics for several pathologies and clinical situations (patients requiring deep sedation, difficult to sedate patients, toxicomania, status asthmaticus, status epilepticus...). In 2017, a change for the sedation medium of our pro- tocolized post-resuscitation protocol was proposed, in an attempt to promote early neurological assessment after patients’ stabilization.

The primary aim of this propensity-matched control study was to evaluate the potential benefits of volatile sedation strategy in terms of

* Corresponding authors at: Médecine Intensive et Réanimation CHU de Brest – La Cavale Blanche, Bvd Tanguy-Prigent, 29609 Brest Cedex.
E-mail address: pierre.bailly@chu-brest.fr (P. Bailly).
https://doi.org/10.1016/j.resuscitation.2024.110358
Received 10 June 2024; Received in Revised form 6 August 2024; Accepted 7 August 2024
neurological outcome, in comparison to conventional intravenous sedation. Secondary aims were to evaluate the impact of such sedation strategy on ventilation duration, ventilatory-free days, ICU length-of-stay, and survival.

## Material and methods

### Patients and setting

We retrospectively studied all consecutive adult patients admitted to our ICU for CA between November 2013 and November 2021 and included within a previously established local database. Exclusion criteria were Glasgow Coma Scale $>$ 8 on admission to the ICU, an age $\le$ 18 years, and those considered as moribund.

### Ethical concerns

The local ethics committee of the Brest University Hospital approved the study and waived the need for informed consent (n° B2021CE.07, 29BRC21.0043, approved on 06/04/2021).

### Cardiac arrest therapeutic protocol (see Appendix 1)

All patients remaining comatose (score $\le$ 8 on the Glasgow Coma Scale) after return of spontaneous circulation underwent TTM irrespective of initial rhythm according to local standard procedures that were implemented prior to 2010 and following international guidelines.¹ Targeted temperature was between 32 and 34 °C and maintained for 24 h. Temperature was measured centrally using an esophageal probe. Patients' core temperature was maintained at the target for 24 h, followed by slow rewarming at 0.25 °C/h using an automated feedback cooling device (Meditherm II). Automated cooling device was maintained for at least 24-h following return to baseline temperature. All patients were mechanically ventilated in controlled assisted ventilation with a target inspired tidal volume 6–8 mL/kg of predicted bodyweight and a respiratory rate adjusted to maintain normocapnia ($PaCO_2$ = 35–45 mm Hg). $FiO_2$ had to be adjusted to maintain $SpO_2$ between 92 and 98%. Patients received IV sedation with a combination of a benzodiazepine (midazolam, 6 mg/h) and an opioid (sufentanyl, 30 µg/h), according to a nurse-driven sedation protocol based on a clinical sedation scale (Ramsay = 6 for all patients during the first 24-h of care).⁹

After 2016 modification of our sedation protocol, midazolam was no longer used and volatile sedation using isoflurane was administered using the European Commission approved anesthetic-conserving device AnaConDa (ACD, Sedana Medical, Danderyd, Sweden). Isoflurane can know be used in routine within ICUs, while using the Anaconda according to french regulation (CEDACONDA avis CT-19512). Isoflurane is placed in a standard syringe pump. The AnaConDa is installed in the breathing circuit between the Y-piece and the ET-tube. Liquid isoflurane is delivered from the syringe through the dedicated line into the AnaConDa where it is vaporised within the device. According to a written nurse driven protocol, isoflurane was titrated during the first 24-h to achieve a Ramsay score = 6 for all patients with an isoflurane gas end-tidal concentration between 0.5 and 1. Following isoflurane discontinuation, intravenous sedation could be used based on the attending physician's discretion if shivering occurred, strictly adhering to the nurse-driven sedation protocol.

Paralytic agents for both arms were systematic during cooling and rewarming procedures.

### Neurological evaluation

For patients remaining comatose after sedation stop, prognostic evaluation was performed according to the standards at the time of the study, including clinical examination, electroencephalogram registration, somatosensory-evoked potentials (SSEP) testing, neuron specific enolase (NSE) dosage and radiologic imaging.

Neurological status was assessed at ICU discharge using the cerebral performance categories scale (CPC).¹⁰

While this was a retrospective study, the patient was diagnosed with delirium if confusion assessment method for the intensive care unit (CAMICU) was positive, or if agitation or confusion prompted the prescription of symptomatic medication.¹¹

## Statistical analysis

In the absence of an a priori hypothesis, no number of subjects was calculated and all available data were used for analysis. Descriptive statistical analysis of the global population was performed using mean $\pm$ standard deviations (SD) or number (percentage). The influence of additional variables was mitigated through pairwise next neighbor matching using the propensity score method.¹² The propensity score is the probability that an individual would have been treated based on that individual's observed pretreatment variables. The estimated propensity score was obtained from the fit of a logistic regression model for which we considered the following pretreatment variables: age, time to return of spontaneous circulation, gender, simplified acute physiology score (SAPS II), and first cardiac rhythm. We matched participants who did not receive isoflurane treatment to those treated with isoflurane based on a range of $\pm$ 0.05 of the propensity score for time and SAPS II, and exact value for other dichotomous variables. We chose the matching range of $\pm$ 0.05 because it is commonly used, provides reasonable balance of the included covariates, and does not lose many treated individuals as unmatchable. Comparison in between matched groups was performed using Student t-test or Wilcoxon test, according to distribution normality. The probability of delirium or CPC $\le$ 2 incidence was analyzed using a Kaplan-Meier curve, after censoring patients for death. All analyses were performed using R++ (Rplusplus, Toulouse, France). All p values are two sided and a p value of less than 0.05 was considered significant.

## Results

Between 2013 and 2021, 510 CA patients with return of spontaneous circulation (ROSC) were admitted to our ICU. All of them were treated with TTM, 401 of them being sedated using intravenous sedation (prior to 2017) and 109 of them using inhaled isoflurane (after 2017).

For the propensity score-matched analysis, 87 patients from the IV group were paired with 87 patients from the isoflurane group, ensuring matching for age, time to return of spontaneous circulation, gender, SAPS II and first rhythm (Fig. 1).

Overall analysis and baseline parameters used for matched pair analysis and outcome findings are summarized in Table 1.
<figure><img src="image_5.png" /></figure>

WLST: withdrawal of life-sustaining therapies; MF: multiorgan failure; BD: brain death

<caption>Fig. 1 - Patients' flow chart according to propensity matching.</caption>

<table><caption>Table 1 - Physiological characteristics according to the sedation group.</caption><thead><tr><th></th><th>IV sedation<br>409 (80.2%)</th><th>Isoflurane sedation<br>101 (19.8%)</th><th>Overall<br>510 (100%)</th></tr></thead><tbody><tr><td>Age (year)</td><td>62.4 ± 14.0</td><td>60.0 ± 13.6</td><td>61.9 ± 13.9</td></tr><tr><td>Gender</td><td></td><td></td><td></td></tr><tr><td>Male n(%)</td><td>278 (68.0%)</td><td>80.0 (79.2%)</td><td>361 (70.1%)</td></tr><tr><td>SAPS 2</td><td>72.4 ± 16.4</td><td>70.4 ± 16.1</td><td>72.0 ± 16.2</td></tr><tr><td>Survival n(%)</td><td>132 (32.4%)</td><td>39.0 (38.6%)</td><td>171 (33.3%)</td></tr><tr><td>Survival Day 28 n(%)</td><td>139 (34.0%)</td><td>36.0 (35.6%)</td><td>175 (34.0%)</td></tr><tr><td>ICU LOS (days)</td><td>7.4 ± 9.9</td><td>7.23 ± 6.3</td><td>7.3 ± 9.3</td></tr><tr><td>Hospital LOS (days)</td><td>12.5 ± 16.5</td><td>14.2 ± 17.7</td><td>12.7 ± 16.7</td></tr><tr><td>Asystole n(%)</td><td>232 (56.9%)</td><td>50.0 (49.5%)</td><td>283 (55.4%)</td></tr><tr><td>Shockable rythm n(%)</td><td>180 (44.1%)</td><td>51.0 (50.5%)</td><td>232 (45.4%)</td></tr><tr><td>CPR Duration (min)</td><td>24.8 ± 20.1</td><td>23.4 ± 14.1</td><td>24.6 ± 19.2</td></tr><tr><td>No-flow Duration (min)</td><td>3.9 ± 6.5</td><td>3.7 ± 5.8</td><td>3.9 ± 6.5</td></tr><tr><td>Coronarography</td><td>130 (31.9%)</td><td>30.0 (29.7%)</td><td>160 (31.4%)</td></tr><tr><td>Sufentanil cumulated dose (µg)</td><td>1742.5 ± 3665.5</td><td>1066.1 ± 1303.4</td><td>1581.8 ± 3273.9</td></tr><tr><td>Midazolam cumulated dose (mg)</td><td>366.1 ± 690.9</td><td>248.3 ± 334.3</td><td>353.2 ± 661.9</td></tr><tr><td>Time to spontaneous breathing (h)</td><td>146.5 ± 195.4</td><td>102.9 ± 111.4</td><td>137.1 ± 181.3</td></tr><tr><td>Ventilation duration (h)</td><td>144.4 ± 202.8</td><td>130.9 ± 121.6</td><td>141.2 ± 188.4</td></tr><tr><td>VAP n(%)</td><td>118 (33.2%)</td><td>29 (29.9%)</td><td>147 (32.5%)</td></tr><tr><td>CPC ≤ 2 n(%)</td><td></td><td></td><td></td></tr><tr><td>No</td><td>183 (62.0%)</td><td>46 (55.4%)</td><td>229 (60.5%)</td></tr><tr><td>Yes</td><td>112 (38.0%)</td><td>37 (44.6%)</td><td>149 (39.4%)</td></tr><tr><td>Renal replacement therapy n(%)</td><td>98.0 (26.3%)</td><td>21 (22.1%)</td><td>119 (25.37%)</td></tr></tbody></table>

IV: intravenous; SAPS 2: simplified acute physiology score; ICU: intensive care unit; LOS: length of stay; CPR: cardio-pulmonary resuscitation; VAP: ventilator-associated pneumonia according to the Infectious Diseases Society of America and the American Thoracic Society definition³⁴; CPC: cerebral performance categories scale.

Table 2 displays the baseline characteristics, encompassing matching variables and outcome variables, of the 174 matched pair patients.

Delirium incidence was lower in the isoflurane group than in the IV group (16.1% vs 32.2%, *p* = 0.03). No neurological outcome difference (defined with CPC ≤ 2) was found between the two groups

(33.3 vs 26.4, *p* = 0.47) (Fig. 2). There was no difference in ICU or 28 days mortality between the two groups (65.5% vs 65.5%, *p* = 1; 64.4% vs 66%, *p* = 0.88 respectively). ICU length of stay (LOS) was significantly lower in the isoflurane group (7.9 vs 8.5 days, *p* = 0.01) although this did not affect the total hospital LOS (11.4 days vs 13.9 days, *p* = 0.2). Time to spontaneous breathing (defined as
<table><caption>Table 2 - Physiological characteristics according to the sedation group, after propensity matching.</caption><thead><tr><th></th><th></th><th>IV sedation<br>(n = 87)</th><th>Isoflurane sedation<br>(n = 87)</th><th>p</th></tr></thead><tbody><tr><td>Age (year)</td><td>Mean (SD)</td><td>61.1 ± 12.3</td><td>61.1 ± 12.0</td><td>NA</td></tr><tr><td>Gender n(%)</td><td>Male</td><td>68 (78%)</td><td>68 (78%)</td><td>NA</td></tr><tr><td>CPR Duration (min)</td><td>Mean ± SD</td><td>21.7 ± 11.6</td><td>22.2 ± 12.0</td><td>NA</td></tr><tr><td>Asystole n(%)</td><td>N (%)</td><td>43 (49.4%)</td><td>43 (49.4%)</td><td>NA</td></tr><tr><td>Switch from Iso. to IV n(%)</td><td>N (%)</td><td>/</td><td>12 (13.8%)</td><td>NA</td></tr><tr><td>SAPS 2</td><td>Mean ± SD</td><td>72.1 ± 14.6</td><td>71.0 ± 16.0</td><td>0.6</td></tr><tr><td>Death n(%)</td><td>N (%)</td><td>57 (65.5%)</td><td>57 (65.5%)</td><td>1.0</td></tr><tr><td>Death Day-28 n(%)</td><td>N (%)</td><td>59 (66.0%)</td><td>60 (64.4%)</td><td>0.88</td></tr><tr><td>ICU LOS (days)</td><td>Mean ± SD</td><td>8.5 ± 9.4</td><td>7.9 ± 6.4</td><td><strong>0.01</strong></td></tr><tr><td>Hospital LOS (days)</td><td>Mean ± SD</td><td>13.9 ± 14.0</td><td>11.4 ± 13.1</td><td>0.2</td></tr><tr><td>Sufentanil (µg)</td><td>Mean ± SD</td><td>1433 ± 1148</td><td>956 ± 1418</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Midazolam (mg)</td><td>Mean ± SD</td><td>218 ± 98</td><td>117 ± 104</td><td><strong>&lt;0.01</strong></td></tr><tr><td>Propofol (mg)</td><td>Mean ± SD</td><td>8942 ± 5190</td><td>5038 ± 4452</td><td>0.10</td></tr><tr><td>Time to SB (h)</td><td>Mean ± SD</td><td>155 ± 137</td><td>109 ± 123</td><td><strong>0.01</strong></td></tr><tr><td>Ventilation duration (h)</td><td>Mean ± SD</td><td>167 ± 155</td><td>78 ± 99</td><td><strong>0.01</strong></td></tr><tr><td>VAP n(%)</td><td>N (%)</td><td>25 (28.7%)</td><td>26 (29.9%)</td><td>0.9</td></tr><tr><td>Delirium n(%)</td><td>N (%)</td><td>28 (32.2%)</td><td>14 (16.1%)</td><td><strong>0.03</strong></td></tr><tr><td>CPC ≤ 2 n(%)</td><td>N (%)</td><td>23 (26.4%)</td><td>29 (33.3%)</td><td>0.47</td></tr><tr><td>Renal Replacement n(%)</td><td>N (%)</td><td>33 (37.9%)</td><td>12 (13.7%)</td><td><strong>0.03</strong></td></tr><tr><td>Norepinephrine (mg/h)</td><td>Mean ± SD</td><td>3.7 ± 4.1</td><td>3.8 ± 3.5</td><td>0.29</td></tr></tbody></table>

SD: standard deviations; Iso: isoflurane; IV sedation: intra-venous sedation; SAPS 2: simplified acute physiology score; ICU: intensive care unit; LOS: length of stay; CPR: cardio-pulmonary resuscitation; SB: spontaneous breathing; VAP: ventilator-associated pneumonia; CPC: cerebral performance categories scale; Norepinephrine: maximal dose during the 24-h of post-resuscitation care; NA: not applicable.

<figure><img src="image_6.png" /><figcaption>Fig. 2 - Kaplan-Meier estimate of delirium incidence (left) and good neurological outcome (cerebral performance categories scale ≤ 2) incidence in both groups. Events are defined as the first incidence of either. Numbers in green (T = 1) depict the remaining patients without event incidence in the intravenous group; numbers in red (T = 0) depict the remaining patients in the isoflurane group. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)</figcaption></figure>

the success of the spontaneous breathing trial leading to extubation) was shorter in the isoflurane group (109 h vs 155, *p* = 0.01) and lead to shorter ventilation duration (78 h vs 167 h, *p* = 0.01). Sufentanil dose was significantly lower when treated with isoflurane (956 vs 1433 µg, *p* < 0.001). There was a lower use of renal replacement therapy in the isoflurane group compared to the IV group (13.7% vs. 37.9%, *p* = 0.03).

Discussion

This propensity-matched control study comparing the use of inhaled isoflurane with IV sedation in patients admitted with ROSC following CA and undergoing TTM suggests that isoflurane sedation was associated with less delirium, without improvement of neurological outcome at ICU discharge, a shorter ventilation duration and ICU LOS.
While a reduction of the delirium incidence had already been advocated in a previous study,⁵ the main mechanisms of such benefits remain unclear. It might be explained by a specific neuroprotective effect of inhaled sedation (class effect), as indicated in animal research (through pre- and post-conditioning),¹³,¹⁴ even though its efficacy in human studies remains inconclusive.¹⁵,¹⁶ The mechanisms may include a decrease in hypoxia-induced release of amino acid neurotransmitters, suppression of apoptosis via anti-apoptotic pathways, stimulation of ATP-regulated potassium channels, modulation of various genes linked to cell survival, and a reduction in the increase of mitochondrial membrane permeability induced by ischemia/reperfusion.¹³ A prospective multicenter randomized controlled study focused on the incidence of delirium as a primary end-point is currently ongoing.¹⁷

Another explanation for such benefit might be a significant decrease in the overall sedation duration, which has been recognized as a major factor contributing to delirium,¹⁸ or the opioids sparing effect of isoflurane.¹⁹,²⁰ The shorter ICU LOS observed while using isoflurane may also contribute to a limitation of patients’ exposure to the usual risk factors for delirium. In our study, before 2016, sedation was provided by midazolam. The potential benefit of isoflurane on delirium warrants a comparison with propofol, the most commonly used agent.

Despite such reduction in delirium incidence for isoflurane patients, no significant improvement of the neurological outcome was observed at ICU discharge (CPC ≤ 2), despite trends. However, it is widely accepted that delirium occurrence within ICU patients is associated with subsequent long-term cognitive impairment, and that the very early assessment of outcome within our study may have prevented the identification of such long-term cognitive differences, as well as the impact on outcome of post-intensive care syndrome (PICS). Moreover CPC scoring may also be considered as too gross, or imprecise, for such evaluation which is the reason why it is no longer recommended for assessing functional outcomes in effectiveness trials conducted in CA patients.²¹

ICU-free days (IFD) and ventilator-free days (VFD) were more frequent in the isoflurane group. Within our study, the IV sedation was mainly induced by midazolam. One may consider that such difference would not have occurred with a very short-acting sedation strategy using propofol. However, in a previous study comparing isoflurane or propofol sedation in patients with TTM after CA no difference was observed.²² Post-hoc analysis of a prospective randomized controlled trial comparing isoflurane or propofol as a primary sedative found more IFD and VFD in the isoflurane group.²³ Within our study, the sedation strategy during the post-resuscitation care did not modify the overall ICU mortality. To the best of our knowledge, a single study already depicted a survival increase after long-term isoflurane sedation as opposed to intravenous sedation in critically ill surgical patients.²⁴ The potential impact of sedation choice on mortality after CA might be mitigated by the overall effectiveness of the entire treatment regimen, making it difficult to isolate its specific influence on mortality outcomes.

The internal volume of the reflection system dictates the volumetric dead space: ACD use results in a dead space effect that exceeds its internal volume because of CO₂ reflection.²⁵ One could argue that hypercapnia was associated with better cerebral oxygenation and decrease of biomarker of brain injury however a prospective study

on 1700 post-resuscitation patient compared normocapnia to mild hypercapnia and found no outcome difference.²⁶⁻²⁸

Medico-economics evaluation of any impact in terms of delirium incidence modification in response to a therapeutic strategy is important in order to better explore the overall impact of our intervention and its feasibility within healthcare systems. Such cost analysis would provide valuable insights for decision-making and resource allocation. Environmental concerns associated with the use of inhaled sedation in ICU may also be considered, which could potentially be offset by a reduction of the overall ICU LOS.²⁹ Both of these concerns will be investigated in the ongoing INASED study.¹⁶

Our study has several limitations. First, our study sample size following the propensity score-matching may be considered as limited, and larger prospective study are required to validate such beneficial effects. Second, while considering its retrospective design, there might be a lack of objective cognitive function evaluation, or extended follow-up assessments. Third, our retrospective definition of delirium might be questionable, thus being a potential source of delirium underreporting, especially for patients experiencing hypoactive delirium or other conditions associated with decreased consciousness. As this selection bias was present in both groups, it may probably not have influenced the difference that was observed concerning the endpoint. Fourth, while we scrupulously followed international guidelines, one could question the choice of a 33 °C target which can lead to deeper and more prolonged sedation¹,³⁰ even though our initial shockable rhythm rate was relatively low comparing to TTM2 trial.³ Last, one could also question about the fact that sedation might not always be mandatory following a CA. Such issue is currently investigated within the STEPCARE trial (NCT 05564754). However, the last three major studies on sedation in intensive care demonstrated that deep sedation was necessary in nearly 50% of patients during the first 48 h.³¹⁻³³

## Conclusions

The use of isoflurane during post-resuscitation care could have led to a reduced delirium incidence but did not modify neurological outcomes upon ICU discharge. It may be associated with shorter durations of mechanical ventilation and ICU stays. Prospective data are required before considering the widespread use of volatile sedation in such indication.

## Funding

This study did not receive any funding.

## CRediT authorship contribution statement

**Christelle Teiten:** Writing – review & editing, Visualization, Validation, Methodology, Formal analysis, Data curation, Conceptualization. **Pierre Bailly:** Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Conceptualization. **Jean-Marie Tonnelier:** Writing – review & editing. **Laetitia Bodesnes:** Writing – review & editing. **Kahaia de Longeaux:** Writing –
review & editing. Erwan L'Her: Writing – review & editing, Writing – original draft, Formal analysis, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing inter- ests: [CT, JMT, LB, KL declare that they have no conflicts of interest. PB is investigator coordinator of a study fully funded by Sedana med- ical. ELH is co-founder and shareholder of Oxynov Inc., Canada and Consultant for GE Healthcare and Sedana Medical.].

Appendix 1. Targeted temperature manag-
ment protocol

Induction phase

Achieve a body temperature of 32–34 °C as quickly as possible
Head >30°

Esophageal, nasogastric and urinary thermal probes

Standard breathing circuit (no filter in the inhaled sedation group, humidifier filter in the intravenous group)

2 cooling blankets with 33 °C target

Body temperature monitoring/30 min up to a temperature of 34 °C
Midazolam 6 mg/h and Sufentanyl 30 µg/h according to the nurse
driven sedation protocol (Ramsay 6 goal) in the intravenous
group

Isoflurane sedation (Ramsay 6 goal and Fe between 0.5 and 1)
and Sufentanyl 30 µg/h according to the nurse driven sedation
protocol in the inhaled sedation group

Paralytics agents between 36 °C and 34 °C

Maintenance phase

Maintain body temperature between 32–34 °C for 24 h after
effective hypothermia

2 cooling blankets with 33 °C target

Hourly body temperature monitoring

Kalemia/4 h

Warm-up phase

Increase target temperature by 0.5 °C/h to 37 °C

Paralytics agents between 34 °C and 36 °C

Hourly body temperature monitoring

Kalemia/4 h

Stop sedation when body temperature at 37 °C

Maintain blanket with a target of 37 °C for at least 24 h after heat-
ing has been completed

Author details

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<footnote>ªMédecine Intensive Réanimation, CHU de la Cavale Blanche, Bvd Tanguy-Prigent, 29609 Brest Cedex, France bLaboratoire de Traite-
ment de l'Information Médicale INSERM Mixte de Recherche Unité
1101, Université de Bretagne Occidentale, France</footnote>
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