Brainstem Dysfunction is Associated With Mortality in Deeply Sedated Critically Ill Patients

Brainstem Dysfunction is Associated With Mortality in Deeply Sedated Critically Ill Patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Brainstem Dysfunction is Associated With Mortality in Deeply Sedated Critically Ill Patients Eleonore Bouchereau, Estelle Pruvost-Robieux, Shidasp SIAMI, Cendrine Chaffaut, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5654002/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Jun, 2025 Read the published version in Intensive Care Medicine → Version 1 posted 5 You are reading this latest preprint version Abstract Background and objectives – Absent cough reflex is associated with mortality intensive care unit (ICU) patients requiring deep sedation, suggesting that lower brainstem dysfunction contributed to adverse outcomes. We conducted a multicenter observational cohort study to confirm this hypothesis by assessing the peak latency (PL) of the lower brainstem-generated P14 evoked potential (EP), which is slightly increased by sedatives. We aimed to demonstrate that a P14-PL> 16 ms is independently associated with day-28 mortality. Patients and methods - Mechanically ventilated adult patients, comatose or deeply sedated, brain-injured or not, were included. At day 3, EPs were performed in patients remaining unconscious. The Simplified Acute Physiological Score (SAPSII), initial Glasgow Coma Scale (GCS), sedation depth and brainstem reflexes were collected. The primary outcome was 28-day mortality. The secondary outcomes were delayed awakening and delirium after sedation discontinuation. Results - Between 2015 and 2019, 322 patients were included. EPs were performed in 264 (82%) patients, including 140 (53%) brain-injured and 251 (95%) deeply sedated patients. The median age, SAPSII and initial GCS were 62 years [50; 71], 49 [40; 62] and 11 [6; 15], respectively. A P14-PL > 16ms was found in 76 (29%) patients and was associated with day-28 mortality (adjusted hazard ratio, 3.0; 95% confidence interval, [1.7-5.2]). Absent cough and pupillary light reflexes were associated with death. Only absent oculocephalogyre reflex was associated with delayed awakening (adjusted odds ratio, 2.1, 95%CI, [1.1 - 3.7]). Interpretation – Impaired neurological and neurophysiological lower brainstem responses are associated with mortality in deeply sedated patients. Funded by the French Ministry of Health; PRORETRO; n° P120915; ClinicalTrials.gov registry: NCT02395861; date: 24 March 2015 Figures Figure 1 Figure 2 Take Home Messages Brainstem dysfunction, whether detected clinically (absence of cough reflex or PLR) or through neurophysiological measures (P14 latency > 16ms or P14-N20-IPL > 5.4ms), is an independent predictor of day-28 mortality. These results will help ICU physicians in more accurately assessing the prognosis of the most severe critically ill patients, particularly those requiring prolonged deep sedation Introduction Critically illness is often complicated by a brain dysfunction, which is mainly characterized by a disorders of consciousness and is associated with ICU-mortality and long-term psycho-cognitive disorders. 1 There are various arguments supporting a brainstem involvement in these outcomes. The brainstem controls the sleep-wake cycle and vital functions via the reticular formation and the medullary autonomic nuclei. 2 Therefore, a brainstem dysfunction can contribute to impairment of arousal but also to mortality. Indeed, a cough reflex abolition 3 , 4 or a decreased sympathetic control of the heart rate variability 5 – which both may reflect a dysfunction of the medulla autonomic centers in the lower brainstem– are associated with critical illness severity and mortality. Similarly, the prognosis value of pupillary light reflex (PLR) is well-established 6 , 7 and an altered mental status is more frequent in case of absent oculocephalic reflex (OCR). In addition to clinical examination, some brainstem neurophysiological responses have a prognostic value. An increased intracranial conduction time (ICCT) of somatosensory evoked potentials (SSEP) is associated with mortality, 8 while an increased intrapontine conduction time (IPCT) of brainstem auditory EP (BAEP) tended to be associated with an altered mental status (delayed awakening or delirium). 8 Lastly, the brainstem nuclei are liable to neuro-inflammatory insult. 9 Most of these clinical and neurophysiological findings have been reported in deeply sedated critically ill patients, either primary brain-injured or not (including severe COVID-19 patients). 10 – 12 In patients with primary brain injury, the brainstem can be injured by direct lesions, transtentorial herniation, or tonsillar herniation. However, most of the brain-injured patients included in our previous study 8 had no evidence of direct brainstem damage. This suggests that brainstem dysfunction may be related to secondary insult to which both non-(primary)-brain-injured patients and primary-brain injured patients are exposed. Deep sedation may play a role in revealing or exacerbating this underlying brainstem dysfunction, perhaps explaining the relationship between deep sedation and increased mortality or delayed awakening. 13 – 15 Altogether, these findings suggest that clinical and neurophysiological brainstem dysfunctions could be integrated in the neuromonitoring of the deeply sedated patients, who are at the highest risk of poor outcomes. Because it is generated by the lower brainstem 5 , specifically at the level of the caudal median lemniscus and the cuneate nucleus 16 , 17 (which transmit tactile and proprioceptive information) and because its latency is only slightly affected by sedation 18 , we hypothesized that P14 SSEP is the closest neurophysiological correlate of the cough reflex and an increase in its latency is a surrogate marker of regional insult. We conducted the ProReTro (i.e., Prognosis of Brainstem Responses) multicenter observational prospective cohort study to determine whether a delayed P14 response (i.e., peak latency (PL) > 16ms) 8,17,19 is independently associated with mortality at day-28 in critically ill patients, comatose or deeply sedated, with or without brain injury. The secondary objectives were first to confirm that absent cough reflex and increased ICCT were associated with day-28 mortality, second to assess whether the absent OCR and increased IPCT are associated with delayed awakening or delirium. METHODS Study design and setting ProReTro study is a multicenter observational prospective cohort study, conducted in six French ICUs. It aimed to assess the prognostic value of the brainstem clinical and neurophysiological responses in critically ill patients with impaired consciousness, related or not to primary brain injury and related or not to deep sedation. The written informed consent was obtained by the investigator of the participating center from the patient's next of kin. If the latter was not present, the patient could still be included because the deferred consent has been approved by the ethics committee, according to French law (Art L1122-1-2 of the Public Health Code). Ethics approval was granted by the French regulatory board ( Comité de Protection des Personnes Ile de France XI , CPP number 2014/49) on 05/04/2014. The study was prospectively registered in the ClinicalTrials.gov registry (NCT02395861) on March 24, 2015. The overall study duration for each participant was their ICU stay. The participants were recruited from July 2015 to May 2019. Data collection was prospectively performed. Eligibility criteria Medical-surgical or brain-injured adult patients admitted in ICU were eligible if: 1– they required invasive mechanical ventilation (MV) for a foreseeable duration greater than 48 hours; 2– they had an impairment of consciousness that evolved from 24 (± 12) hours and defined by a coma with Glasgow Coma Scale (GCS) ≤ 8 in non-sedated patients 20 or by a Richmond Assessment Sedation Scale (RASS) < − 3 in sedated patients (deep sedation) 21 . Main exclusion criteria were post-anoxic or toxic coma, brain death, ongoing pregnancy, acute peripheral neurological disorders or chronic disorders impairing the brainstem reflexes or peripheral nerve conduction time, cervical spinal cord injury and absence of health insurance coverage and guardianship. Assessments The baseline characteristics, sedation level, and neurological features were measured at inclusion (day 1) and at the time of neurophysiological tests. Due to organizational constraints, neurophysiological tests were planned at day 3, in patients who remained comatose or required deep sedation. The time points of the evaluations are detailed in Appendix 1 . Baseline characteristics – We collected the demographic characteristics, body weight, comorbidities, main cause of critical illness, coma and brain injury, dates of ICU admission, coma, MV initiation and deep sedation onset. The Simplified Acute Physiological Score-II (SAPSII) 22 and the initial GCS before sedation were collected. The Sequential Organ Failure Assessment (SOFA) 23 was assessed at day 1 and at time of neurophysiological tests. Sedation characteristics - Depth of sedation and analgesia were assessed on day 1 and at the time of neurophysiological tests, using the RASS and Behavioral Pain Scale (BPS) 24 . Concomitantly, we assessed the type and cumulative dose of sedatives and analgesics but also the administration of neuromuscular blocking agents (NMBA). The reason for maintaining deep sedation at time of neurophysiological tests was collected. The highest RASS and lowest BPS were collected daily in sedated patients up to day-28 unless ICU discharge. Neurological examination –We assessed at day-1 and at time of neurophysiological tests: 1) arousal and consciousness using the GCS and the Full Outline of Unresponsiveness (FOUR) 25 ; 2) in patients without NMBA: the pupils size and brainstem reflexes, including PLR (tested with regular flashlight), corneal reflex, grimace in response to a bilateral and strong pressure to the retro-mandibular region, OCR to lateral passive head rotation, and cough reflex in response to tracheal suctioning. The brainstem dysfunction was scored using the Brainstem Response Assessment Sedation Scale (BRASS, Appendix 2 ). 4 , 26 The GCS, FOUR and CAM-ICU were collected daily up to day-28 unless ICU discharge. Neurophysiological tests - Neurophysiological assessment included SSEPs and BAEPs. All recordings were interpreted by neurophysiologists (MG, EPR, EA, JZ and EB), blinded to patient outcomes (see Appendix 3 ), according to international/national guidelines. 27 SSEPs were recorded after both right and left stimulations of the median nerve at the wrist using a bipolar surface electrode. Peak latencies (PL) of N9 (brachial plexus), N13 (cervical spinal cord), P14 (lower brainstem), N20 and P25 (cortical) responses were measured. The distal and proximal peripheral nerve conduction (PNC) were assessed with measuring the arm length/N9-PL ratio and N9-N13 interpeak latency (IPL), respectively. The central conduction was assessed with measuring P14-N20 and N20-P25-IPL, with the P14–N20-IPL representing the ICCT. 8 For the distal and proximal PNC, we presented the shortest N9-PL/arm length ratio between right and left responses. For the central parameters, we presented: 1) the shortest PL and IPL between right and left responses; 2) the percentage of asymmetry (i.e. a difference in latencies at least of 10%) between right and left responses; 3) the percentage of unilateral and bilateral abolished responses. BAEPs were recorded following auditory stimulation of each ear, alternatively. The I–III, III–V, and I–V-IPL were calculated, with the III-V-IPL representing the IPCT. For each wave, the percentage of abolished response was reported. The SSEPs and BAEPs IPL were expressed in milliseconds (ms). The SSEPs and BAEPs components were considered absent (abolished) if their amplitude was less than 0.2 µV and/or indistinguishable from background noise. IPL were considered not accessible when the first response was absent and delayed when the last response was abolished. SSEPs and BAEPs normal and delayed values are presented in Appendix 4 . Delayed P14 was defined as a PL > 16ms, a lengthened ICCT by an IPL > 5.4ms and a lengthened IPCT by III-V-IPL > 2.5ms. 8 Method for confounding factors assessment Confounding factors which may influence the neurological examination, neurophysiological tests, mortality, and the occurrence of delayed awakening or delirium were assessed. They include severity of critical illness according to the SAPSII, its type (i.e., primary brain injury or not) and the pre-sedation GCS. ICU physicians were not informed of the neurophysiological results and neurophysiologists were blinded to the patient's clinical status and outcomes, limiting the risk of self-fulfilling prophecy. Follow-up The patients were followed up to ICU discharge. The dates of sedation discontinuation, awakening, extubation, death, ICU and hospital discharges, neuroimaging data when available and the occurrence of intracranial hypertension were collected. The cause of ICU death was also collected, including decisions of withdrawal of care. The in-hospital mortality was assessed. Variable of interest The variable of interest was a bilaterally delayed P14 response (i.e., > 16ms). Because P14 is a positive potential that appears 14ms after median nerve stimulation, we hypothesized that a 2ms increase could be considered as abnormally delayed 8 , 17 , 19 . Only one patient had an abolished P14, considered as delayed in the analysis. Outcomes The primary outcome was mortality at day-28. The secondary outcomes were delayed awakening and delirium after discontinuation of sedation. Delayed awakening was arbitrarily and a priori defined by the absence of eye contact to voice (i.e., RASS ≤ − 1) at least 3 days after discontinuation of sedation. Delirium was assessed using the Confusion Assessment Method-ICU (CAM-ICU), when RASS was ≥ -3. Statistical analyses Assuming that the day-28 mortality would be 35% and that 25% of patients would have a P14 PL > 16ms, it was necessary to include 260 patients to demonstrate an adjusted OR of 2.5 by controlling for the risks of type I and II errors at 5% and 10%, respectively. 8 We anticipated that one third of patients will die or leave the ICU between day 1 and 3. Therefore, we planned to include about 400 patients to obtain 260 having underwent neurophysiological test at day-3. The analysis was performed by a multivariate logistic regression model adjusted for the type of admission (primary brain-injury or not), the SAPSII score, and the pre-sedation GCS ( Appendix 5 ). In addition, as sensitivity analyses, models were also adjusted on RASS. Summary statistics are reported, namely numbers (percentage), mean (standard deviation), or median (inter-quartile range, IQR). Day-28 mortality was analyzed using the Kaplan-Meier method, with Cox multivariable regression models used to estimate the hazard ratio (HR) as a measure of the association between variable of interest and outcome. We also used a Cox model with splines to assess the impact of the P14-PL value on the hazard of death. Interaction of the effect of P14 with brain injury was tested using the Gail and Simon statistics. 28 Probability of delayed awakening or delirium after sedation discontinuation was computed ignoring the time scale, with association of absent OCR and P14-N20-IPL; effect of P14-PL > 16ms on mortality was measured on odds ratio estimated from multivariable logistic regression models. All regression models were adjusted for brain injury, SAPSII (calculated by removing GCS) and pre-sedation GCS. All analyses were performed using R version 4·4·0 (The R Foundation for Statistical Computing, Vienna, Austria). P-values < 0.05 were considered statistically significant. RESULTS Study population Between July 2015 and April 2019, 342 mechanically ventilated patients admitted in the participating ICU were eligible. Eleven did not met the eligibility criteria, 2 refused to participate, and 7 were duplicates ( Figure 1 ). Among the 322 patients enrolled at day-1, 264 (82 %) underwent neurophysiological tests, including 140 (92 %) of the 152 primary brain-injured patients and 124 (73 %) of the 170 non-brain-injured patients, whose main primary diagnoses are listed in Appendix 6 . The main reason for not performing the neurophysiological tests was a RASS > -3 in 21patients, unavailability of the neurophysiological team in 30 patients and death in 7 patients. Thus, further results only deal with the 264 tested patients. The median age, SAPSII and pre-sedation GCS were 62 years (IQR 50-71), 49 (IQR 40-62) and 11 (IQR 6-15), respectively ( Table 1 ). At the time of neurophysiological tests, performed at day-3 in median (IQR 2-5), 251 (95 %) patients were deeply sedated and 56 (22 %) were receiving NMBA. Primary outcome Out of the 264 patients analyzed, 53 (20%) died within 28 days of inclusion, including 52 in ICU and 1 in hospital after ICU discharge. Additionally, 25 (9%) patients died after day-28, (48 in ICU and 7 in hospital after ICU discharge). Survivors at day-28 were younger and less frequently brain injured ( Table 1 ). Of the 53 early deaths, 20 (38%) died following multiple organ failure, 23 (43%) after withdrawal of care and 5 (10%) of brain death (including 4 primary brain-injured patients). A P14-PL>16ms was observed in 76 (29 %) patients, including in 39 (28%) in the 140 non-brain-injured and 37 (30%) in the 124 brain-injured patients. Delayed P14 was significantly associated with mortality, as exemplified by a day-28 cumulative incidence of death of 35.5 % (95%CI, 24.9-46.3) and of 13.8 % (95%CI, 9.3-19.2) in patient with and those without P14-PL>16ms, respectively ( Figure 2 ). The association with day-28 mortality persisted after adjustment on brain injury, SAPS-II and GCS prior to sedation (adjusted HR=3.0 [95% CI, 1.7-5.2], p<0.0001) but also after additional adjustment on RASS ( Table 2 ). Moreover, the effect of the P14 response showed no interaction with the presence of brain injury (HR=2.5 [95%CI, 1.2-5.0] in case of brain injury versus 4.5 [95%CI, 1.9-10.8] in the absence of brain injury, p=0.29). A forest plot showing the effect in each brain injury subset, with interaction tests is available on Appendix 9 . Of note, the effect of the P14 latency on the day-28 mortality linearly increased over the scale ( Figure 2 ). The day-28 mortality was also associated with absent cough reflex at inclusion (HR 2.8 [95%CI,1.4-5.7]), with absent cough reflex and absent PLR at day 3 (HR=2.8 [95%CI, 1.5-5.5] and HR=3.9 [95%CI, 1.8-8.5], respectively) and with P14-N20-IPL > 5.4ms (HR=2.4 [95%CI, 1.2-4.6]). When P14>16ms, absent cough reflex, and absent PLR at day 3 were simultaneously included in a multivariable model, they all added prognostic information to each other ( Table 2 ). Secondary outcomes After discontinuation of sedation, 131 (50 %) and 103 (39 %) patients developed a delayed awakening or a delirium, respectively. No patient died before awakening while 43 patients died without delirium. The main characteristics of patients with and without delayed awakening or delirium are presented in the Appendix 10 and 11 respectively . Absent OCR was associated with delayed awakening, either assessed at inclusion or at day 3 (adjusted HR = 2.8 [95%CI, 1.2-6.1] and adjusted HR=2.2 [95%CI, 1.1-4.1]) ( Table 3 ). Brainstem reflex abolition and EPs responses were not associated with the occurrence of delirium, regardless of imputation of missing data due to competing deaths ( Appendix 12 ). DISCUSSION This multicenter prospective observational study confirms our main hypothesis that day-28 mortality is associated with a P14-PL > 16ms in deeply sedated critical ill patients, even after adjustment on the pre-sedation state of consciousness (i.e., GCS), as well as the severity and type of critical illness (i.e., SAPSII and brain injury versus non-brain-injury). The study also corroborates our previous findings that day-28 mortality is associated with absent cough reflex, BRASS score or increased P14-N20-IPL; while delayed awakening with absent OCR. 4,8 Conversely, no brainstem neurophysiological responses were associated with delayed awakening or delirium following sedation discontinuation. The prognostic value of increased P14-PL and absent cough reflex supports our hypothesis that lower brainstem dysfunction may contribute to mortality. Our main mechanistic explanation for the association between lower brainstem dysfunction and mortality is a secondary neuroinflammatory insult to the brainstem that is triggered by a systemic inflammatory response that occurrs in both non-primary brain-injured and primary brain-injured patients. Several arguments support the role of the area postrema (AP) in mediating this secondary neuroinflammatory insult. The AP is a unique circumventricular structure that permits circulating cytokines to reach the medulla and is closely linked to the cardiovascular and respiratory autonomic nuclei. This AP-autonomic nuclei complex is a central component of the body’s adaptive response to systemic inflammation. Interestingly, the P14 generators are anatomically adjacent to this complex. Moreover, P14 responses have been shown to be more sensitive than MRI in detecting brainstem dysfunction in patients with inflammatory lesions, highlighting their ability to detect subclinical inflammation. 29 Thus, an excessive systemic inflammation can induce brainstem neuroinflammation, potentially disrupting the AP-autonomic nuclei complex, leading to delayed P14 responses and extending to upper brainstem structures, accounting then for the relationship between the absence of OCR and delayed awakening. This mechanism is supported by experimental studies 30 and further suggested by our findings: the prognostic significance of absent PLR and increased ICCT. The hypothesis of an AP-mediated secondary neuroinflammatory insult may also explain why brainstem dysfunction did not follow a typical rostro-caudal pattern of deterioration, particularly in patients with primary brain injury, and why brainstem EPs did not differ between patients with and without brain injury. Although we cannot completely rule out the occurrence of structural brainstem injury after neurophysiological testing, confirmation of this would have required neuroimaging of all patients prior to ICU discharge. Several arguments suggest that sedation is unlikely to be a confounding factor in this study. The indications and the depth of sedation were comparable between survivors and non-survivors, as were the cumulative doses of propofol and sufentanil. Only the cumulative dose of midazolam was significantly higher in non-survivors, but it did not differ between patients with and without elevated P14-PL. Furthermore, sedative dose cannot account for the increase in P14-PL above 16ms and the increased risk of death with P14-PL (Figure 2). Finally, P14-PL>16ms remained associated with day-28 mortality after adjustment for RASS, the most commonly used marker of sedation. Nevertheless, we cannot completely exclude a possible contribution of sedation to brainstem dysfunction. Taken together, our results suggest that, at equivalent levels of deep sedation, patients who lack a cough reflex or PLR, or who have increased P14-PL or increased P14-N20-IPL, are at higher risk of mortality than those with preserved brainstem reflexes and neurophysiological responses. Our study has several limitations. First, it primarily focused on deeply sedated ICU patients. It would be valuable to investigate whether a delayed P14 also allows to predict mortality in non-sedated critically ill patients. While the day-28 mortality rate in our cohort was slightly below the commonly reported 30 %-rate, the cohort appears representative of deeply sedated ICU patients in terms of severity score, causes of admission, and the indications, types and durations of sedation. 13 Second, the inclusion of both brain-injured and non-brain-injured patients may have complicated the interpretation of study findings by conflating primary and secondary brain insults. To address this, we adjusted the analysis on the presence of brain injury and collected brain imaging data. We demonstrated that delayed P14 remained a predictor of day-28 mortality within each subgroup. However, repeating neurophysiological testing over time would have provided further clarity on the relationships between delayed P14, critical illness, sedation, and mortality. The prognostic value of an absent PLR aligns with previous studies using automated pupillometry, 6 supporting the reliability of our brainstem reflexes clinical assessments. The evaluation of brainstem dysfunction could be more comprehensive, with including additional clinical, autonomic and neurophysiological responses. Although the definition of delayed awakening is arbitrary, it allows us to identify a subpopulation at risk, which is rather elderly, presents a more severe brain insult and required deeper sedation. Finally, we found that neither brainstem reflexes nor brainstem EPs were associated with delirium, challenging our initial hypothesis, probably because delirium is a complex, multifactorial disorder involving supratentorial networks and structures. Despite its limitation, the present study offers new pathophysiological – and potentially therapeutic – insights into the complex interplay between critical illness, brain function and patient outcomes. Its main clinical implication is that clinical and neurophysiological testing of brainstem function improves the prognostic assessment in critically ill patients requiring deep sedation. Our findings are generalizable, as brainstem reflexes are routinely assessed in comatose patients. We recommend their systematic assessment in deeply sedated patients, whether brain-damaged or not, in addition to the RASS score. Furthermore, technological advances will likely simplify the measurement of P14-PL. Future studies could aim to refine the P14-PL threshold values, as we observed an increased risk of death with the latter. In conclusion, our study demonstrates that brainstem dysfunction, whether detected clinically (absence of cough reflex or PLR) or through neurophysiological measures (P14 latency > 16ms or P14-N20-IPL > 5.4ms), is an independent predictor of day-28 mortality These results will help ICU-physicians in more accurately assessing the prognosis of the most severe critically ill patients, particularly those requiring prolonged deep sedation. Declarations Availability of data and materials Data available: Yes Data types: Deidentified participant data How to access data: De-identified patient data to reproduce results presented in the article When available: With publication Document types: None Who can access the data: Researchers whose proposed use of the data has been approved. Types of analyses: Research projects with the same scientific purpose as the original study (post-intensive care follow-up), such as meta-analysis, for instance. Mechanisms of data availability: Data will be made available upon approval of a proposal, and after a signed data access agreement with the trial sponsor. Any additional restrictions: none Competing interests All authors declare no conflicts of interest. Funding The funders ( i.e. the French Ministry of Health ) of the study had no role in study design, data collection, analysis, and interpretation, nor in the writing of the report, or in the decision to submit the article for publication. Authors’ contributions Stanislas Kandelman, Eric Azabou and Tarek Sharshar:Conception of the work (PI), funding application, enrolment of participating centers, Eleonore Bouchereau and Tarek Sharshar: Supervision of the data collection, participation in data analysis, verification of the data and interpretation, writing of the manuscript, critical revision of the manuscript. Cendrine Chaffaut and Sylvie Chevret: Methodology, data management, statistical analysis, verification of the data and interpretation, critical revision of the manuscript. Estelle Pruvost, Sarah Benghanem, Martine Gavaret, Eric Azabou and Bertrand Hermann: Data collection, interpretation of the results, critical revision of the manuscript. Other authors: patients’ recruitment and data collection. Acknowledgements We are grateful to the investigators of all participating centres: Djillali Annane (Réanimation Médico-Chirurgicale, Hôpital Raymond Poincaré, 104 Boulevard Raymond Poincaré, 92380 Garches, France), Eric Azabou (Service d’Explorations Fonctionnelles Hôpital Raymond Poincaré, 104 Boulevard Raymond Poincaré, 92380 Garches, France), Sarah Benghanem (Service de Réanimation Médicale, Hôpital Cochin, 27 rue du Faubourg Saint-Honoré, 75014 Paris, France), Eléonore Bouchereau (Neuroréanimation, GHU-Paris, Site Sainte-Anne, 1 rue Cabanis, 75014 Paris, France), Adrien Bouglé (Département d’Anesthésie et de Réanimation, Institut de Cardiologie, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), Vincent Degos (Département d’Anesthésie et de Réanimation, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), Sophie Demeret (Réanimation Neurologique, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), Chung-Hi Do (Département d’Anesthésie et de Réanimation, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), Martine Gavaret (Service de Neurophysiologie clinique, GHU-Paris, Site Sainte-Anne, 1 rue Cabanis, 75014 Paris, France), Nicholas Heming (Réanimation Médico-Chirurgicale, Hôpital Raymond Poincaré, 104 Boulevard Raymond Poincaré, 92380 Garches, France), Bertrand Hermann (Neuroréanimation, GHU-Paris, Site Sainte-Anne, 1 rue Cabanis, 75014 Paris, France), Tarik Hissem (Réanimation Polyvalente, Centre Hospitalier Sud-Essonne, 26 avenue du Général de Gaulle, Etampes, 91150 France), Stanislas Kandelmann (Département d’Anesthésie et Réanimation chirurgicale, Hôpital Baujon, 100 Boulverad du Général Leclerc, 92110 Clichy, France), Lionel Naccache (Service de Neurophysiologie Clinique, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), Estelle Pruvost (Service de Neurophysiologie clinique, GHU-Paris, Site Sainte-Anne, 1 rue Cabanis, 75014 Paris, France), Benjamin Rohaut (Réanimation Neurologique, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), Shidasp Siami (Réanimation Polyvalente, Centre Hospitalier Sud-Essonne, 26 avenue du Général de Gaulle, Etampes, 91150 France), Tarek Sharshar (Neuroréanimation, GHU-Paris, Site Sainte-Anne, 1 rue Cabanis, 75014 Paris, France), Sivanthiny Sivanandamoorthy (Réanimation Polyvalente, Centre Hospitalier Sud-Essonne, 26 avenue du Général de Gaulle, Etampes, 91150 France), Nicolas Weiss (Réanimation Neurologique, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), Julie Zyss (Service de Neurophysiologie Clinique, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), We thank the members of the data and safety monitoring board, the neurophysiology technicians (Vera Benamenyo, Laurence Nogret, Audrey Pons, Anne-Marie Pointrenaud, Emma Léon at GHU Paris Sainte Anne), Professor Raphael Porcher (Clinical Epidemiology, Hôtel Dieu, Paris) for his commitment in the writing of the ProReTro project and the study participants. This manuscript is dedicated to the memory of Professor Jean Mantz. References Palakshappa JA, Batt JAE, Bodine SC, et al. Tackling Brain and Muscle Dysfunction in Acute Respiratory Distress Syndrome Survivors: National Heart, Lung, and Blood Institute Workshop Report. Am J Respir Crit Care Med 2024; published online March 13. DOI:10.1164/rccm.202311-2130WS. Benghanem S, Mazeraud A, Azabou E, et al. Brainstem dysfunction in critically ill patients. Crit Care 2020; 24 : 5. Sharshar T, Porcher R, Siami S, et al. Brainstem responses can predict death and delirium in sedated patients in intensive care unit. Crit Care Med 2011; 39 : 1960–7. Rohaut B, Porcher R, Hissem T, et al. Brainstem response patterns in deeply-sedated critically-ill patients predict 28-day mortality. PLoS ONE 2017; 12 : e0176012. Annane D, Trabold F, Sharshar T, et al. Inappropriate sympathetic activation at onset of septic shock: a spectral analysis approach. Am J Respir Crit Care Med 1999; 160 : 458–65. 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Brainstem clinical and neurophysiological involvement in COVID-19. J Neurol 2021; 268 : 3598–600. Benghanem S, Cariou A, Diehl J-L, et al. Early Clinical and Electrophysiological Brain Dysfunction Is Associated With ICU Outcomes in COVID-19 Critically Ill Patients With Acute Respiratory Distress Syndrome: A Prospective Bicentric Observational Study. Critical Care Medicine 2022; published online Feb 15. DOI:10.1097/CCM.0000000000005491. Rua C, Raman B, Rodgers CT, et al. Quantitative susceptibility mapping at 7 T in COVID-19: brainstem effects and outcome associations. Brain 2024; : awae215. Shehabi Y, Howe BD, Bellomo R, et al. Early Sedation with Dexmedetomidine in Critically Ill Patients. N Engl J Med 2019; 380 : 2506–17. Oddo M, Crippa IA, Mehta S, et al. Optimizing sedation in patients with acute brain injury. Crit Care 2016; 20 : 128. Bouchereau E, Sharshar T, Legouy C. Delayed awakening in neurocritical care. Revue Neurologique 2021; published online Aug 13. DOI:10.1016/j.neurol.2021.06.001. Morioka T, Tobimatsu S, Fujii K, Fukui M, Kato M, Matsubara T. Origin and distribution of brain-stem somatosensory evoked potentials in humans. Electroencephalogr Clin Neurophysiol 1991; 80 : 221–7. Cruccu G, Aminoff MJ, Curio G, et al. Recommendations for the clinical use of somatosensory-evoked potentials. Clin Neurophysiol 2008; 119 : 1705–19. García-Larrea L, Fischer C, Artru F. [Effect of anesthetics on sensory evoked potentials]. Neurophysiol Clin 1993; 23 : 141–62. Mauguière F, Allison T, Babiloni C, et al. Somatosensory evoked potentials. The International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl 1999; 52 : 79–90. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974; 2 : 81–4. Ely EW, Truman B, Shintani A, et al. Monitoring Sedation Status Over Time in ICU PatientsReliability and Validity of the Richmond Agitation-Sedation Scale (RASS). JAMA 2003; 289 : 2983–91. Le Gall J-R, Lemeshow S, Saulnier F. A New Simplified Acute Physiology Score (SAPS II) Based on a European/North American Multicenter Study. JAMA 1993; 270 : 2957–63. Vincent J-L, de Mendonca A, Cantraine F, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: Results of a multicenter, prospective study. Critical Care Medicine 1998; 26 : 1793. Payen JF, Bru O, Bosson JL, et al. Assessing pain in critically ill sedated patients by using a behavioral pain scale. Crit Care Med 2001; 29 : 2258–63. Wijdicks EFM, Bamlet WR, Maramattom BV, Manno EM, McClelland RL. Validation of a new coma scale: The FOUR score. Ann Neurol 2005; 58 : 585–93. Legros V, Mourvillier B, Floch T, et al. Use of BRASS in sedated critically-ill patients as a predictable mortality factor: BRASS-ICU. Neurol Res 2021; 43 : 283–90. André-Obadia N, Zyss J, Gavaret M, et al. Recommendations for the use of electroencephalography and evoked potentials in comatose patients. Neurophysiol Clin 2018; 48 : 143–69. Gail M, Simon R. Testing for Qualitative Interactions between Treatment Effects and Patient Subsets. Biometrics 1985; 41 : 361–72. Magnano I, Pes GM, Pilurzi G, et al. Exploring brainstem function in multiple sclerosis by combining brainstem reflexes, evoked potentials, clinical and MRI investigations. Clinical Neurophysiology 2014; 125 : 2286–96. Kola G, Clifford CW, Campanaro CK, et al. Peritoneal sepsis caused by Escherichia coli triggers brainstem inflammation and alters the function of sympatho-respiratory control circuits. Journal of Neuroinflammation 2024; 21 : 45. Tables Tables 1 to 3 are available in the Supplementary Files section Supplementary Files ProretrosupplementarymaterialsR217042025.docx Appendix STROBEchecklistcohort.pdf ProretroICMtablesR217042025.docx Cite Share Download PDF Status: Published Journal Publication published 13 Jun, 2025 Read the published version in Intensive Care Medicine → Version 1 posted Reviewers agreed at journal 26 Apr, 2025 Reviewers invited by journal 26 Apr, 2025 Editor assigned by journal 25 Apr, 2025 First submitted to journal 25 Apr, 2025 Editorial decision: Major revisions 10 Feb, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5654002","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":448247521,"identity":"b4edddd3-1512-4fb0-a1f3-dd832b93b37f","order_by":0,"name":"Eleonore 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Universitaire Pitie Salpetriere","correspondingAuthor":false,"prefix":"","firstName":"Lionel","middleName":"","lastName":"NACCACHE","suffix":""},{"id":448247535,"identity":"d476ed4e-2380-43d2-96d2-289bc4c44e3a","order_by":14,"name":"Benjamin ROHAUT","email":"","orcid":"","institution":"Hospital Pitie-Salpetriere: Hopital Universitaire Pitie Salpetriere","correspondingAuthor":false,"prefix":"","firstName":"Benjamin","middleName":"","lastName":"ROHAUT","suffix":""},{"id":448247536,"identity":"abe1e6fd-ac4a-4f68-8344-384abd4a6686","order_by":15,"name":"Bertrand HERMANN","email":"","orcid":"","institution":"Hôpital Europeen Georges-Pompidou: Hopital Europeen Georges Pompidou","correspondingAuthor":false,"prefix":"","firstName":"Bertrand","middleName":"","lastName":"HERMANN","suffix":""},{"id":448247537,"identity":"0441289e-c6da-44c9-9fce-89f824967adf","order_by":16,"name":"Eric AZABOU","email":"","orcid":"","institution":"Hôpital Raymond-Poincare: Hopital Raymond-Poincare","correspondingAuthor":false,"prefix":"","firstName":"Eric","middleName":"","lastName":"AZABOU","suffix":""},{"id":448247538,"identity":"9bae5d2b-2081-418b-98d2-953272f582ef","order_by":17,"name":"Sylvie CHEVRET","email":"","orcid":"","institution":"Hopital Saint Louis","correspondingAuthor":false,"prefix":"","firstName":"Sylvie","middleName":"","lastName":"CHEVRET","suffix":""},{"id":448247539,"identity":"77bc46b5-a889-4693-96fc-6f91b434212c","order_by":18,"name":"Tarek SHARSHAR","email":"","orcid":"","institution":"GHU Paris: Groupe Hospitalier Universitaire Paris psychiatrie \u0026 neurosciences","correspondingAuthor":false,"prefix":"","firstName":"Tarek","middleName":"","lastName":"SHARSHAR","suffix":""}],"badges":[],"createdAt":"2024-12-16 12:57:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5654002/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5654002/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00134-025-07945-7","type":"published","date":"2025-06-13T15:57:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82348266,"identity":"74f346bf-69d0-4eaa-9d10-093319e5a33c","added_by":"auto","created_at":"2025-05-09 10:40:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":127816,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5654002/v1/c960d8b4167373c2a1fb2b90.png"},{"id":82349785,"identity":"8ab18c07-b369-41e8-a22f-5c290a338064","added_by":"auto","created_at":"2025-05-09 10:48:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":109386,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5654002/v1/96f540fc6009a7e884aa7f83.png"},{"id":84726515,"identity":"d10a0e28-0bb5-4fef-b9b9-482fb127cc31","added_by":"auto","created_at":"2025-06-16 16:06:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1021993,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5654002/v1/5af9193c-1551-4806-a916-ab3bed939381.pdf"},{"id":82349787,"identity":"3d0488fa-3235-403d-b759-65acefccf190","added_by":"auto","created_at":"2025-05-09 10:48:37","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":293635,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAppendix\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"ProretrosupplementarymaterialsR217042025.docx","url":"https://assets-eu.researchsquare.com/files/rs-5654002/v1/c2c8ff78ded794f71bd4f70e.docx"},{"id":82348268,"identity":"710fe189-b602-4901-a350-6b8bfb6e1304","added_by":"auto","created_at":"2025-05-09 10:40:36","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":117933,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEchecklistcohort.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5654002/v1/6abee4e2bc98ed3a3679e0cc.pdf"},{"id":82349786,"identity":"4c0f37c3-476e-4398-b8a1-7b461dcea87f","added_by":"auto","created_at":"2025-05-09 10:48:36","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":46052,"visible":true,"origin":"","legend":"","description":"","filename":"ProretroICMtablesR217042025.docx","url":"https://assets-eu.researchsquare.com/files/rs-5654002/v1/674eb646ed1294e259be3133.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eBrainstem Dysfunction is Associated With Mortality in Deeply Sedated Critically Ill Patients\u003c/p\u003e","fulltext":[{"header":"Take Home Messages ","content":"\u003cp\u003eBrainstem dysfunction, whether detected clinically (absence of cough reflex or PLR) or through neurophysiological measures (P14 latency\u0026nbsp;\u0026gt;\u0026nbsp;16ms or P14-N20-IPL\u0026nbsp;\u0026gt;\u0026nbsp;5.4ms), is an independent predictor of day-28 mortality. These results will help ICU physicians in more accurately assessing the prognosis of the most severe critically ill patients, particularly those requiring prolonged deep sedation\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eCritically illness is often complicated by a brain dysfunction, which is mainly characterized by a disorders of consciousness and is associated with ICU-mortality and long-term psycho-cognitive disorders.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e There are various arguments supporting a brainstem involvement in these outcomes. The brainstem controls the sleep-wake cycle and vital functions via the reticular formation and the medullary autonomic nuclei.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Therefore, a brainstem dysfunction can contribute to impairment of arousal but also to mortality. Indeed, a cough reflex abolition\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e or a decreased sympathetic control of the heart rate variability\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e \u0026ndash; which both may reflect a dysfunction of the medulla autonomic centers in the lower brainstem\u0026ndash; are associated with critical illness severity and mortality. Similarly, the prognosis value of pupillary light reflex (PLR) is well-established\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e and an altered mental status is more frequent in case of absent oculocephalic reflex (OCR). In addition to clinical examination, some brainstem neurophysiological responses have a prognostic value. An increased intracranial conduction time (ICCT) of somatosensory evoked potentials (SSEP) is associated with mortality,\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e while an increased intrapontine conduction time (IPCT) of brainstem auditory EP (BAEP) tended to be associated with an altered mental status (delayed awakening or delirium).\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Lastly, the brainstem nuclei are liable to neuro-inflammatory insult.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMost of these clinical and neurophysiological findings have been reported in deeply sedated critically ill patients, either primary brain-injured or not (including severe COVID-19 patients).\u003csup\u003e\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e In patients with primary brain injury, the brainstem can be injured by direct lesions, transtentorial herniation, or tonsillar herniation. However, most of the brain-injured patients included in our previous study\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e had no evidence of direct brainstem damage. This suggests that brainstem dysfunction may be related to secondary insult to which both non-(primary)-brain-injured patients and primary-brain injured patients are exposed. Deep sedation may play a role in revealing or exacerbating this underlying brainstem dysfunction, perhaps explaining the relationship between deep sedation and increased mortality or delayed awakening.\u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Altogether, these findings suggest that clinical and neurophysiological brainstem dysfunctions could be integrated in the neuromonitoring of the deeply sedated patients, who are at the highest risk of poor outcomes.\u003c/p\u003e \u003cp\u003eBecause it is generated by the lower brainstem\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, specifically at the level of the caudal median lemniscus and the cuneate nucleus\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e (which transmit tactile and proprioceptive information) and because its latency is only slightly affected by sedation\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, we hypothesized that P14 SSEP is the closest neurophysiological correlate of the cough reflex and an increase in its latency is a surrogate marker of regional insult.\u003c/p\u003e \u003cp\u003eWe conducted the ProReTro (i.e., Prognosis of Brainstem Responses) multicenter observational prospective cohort study to determine whether a delayed P14 response (i.e., peak latency (PL)\u0026thinsp;\u0026gt;\u0026thinsp;16ms)\u003csup\u003e8,17,19\u003c/sup\u003e is independently associated with mortality at day-28 in critically ill patients, comatose or deeply sedated, with or without brain injury. The secondary objectives were first to confirm that absent cough reflex and increased ICCT were associated with day-28 mortality, second to assess whether the absent OCR and increased IPCT are associated with delayed awakening or delirium.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and setting\u003c/h2\u003e \u003cp\u003eProReTro study is a multicenter observational prospective cohort study, conducted in six French ICUs. It aimed to assess the prognostic value of the brainstem clinical and neurophysiological responses in critically ill patients with impaired consciousness, related or not to primary brain injury and related or not to deep sedation. The written informed consent was obtained by the investigator of the participating center from the patient's next of kin. If the latter was not present, the patient could still be included because the deferred consent has been approved by the ethics committee, according to French law (Art L1122-1-2 of the Public Health Code). Ethics approval was granted by the French regulatory board (\u003cem\u003eComit\u0026eacute; de Protection des Personnes Ile de France XI\u003c/em\u003e, CPP number 2014/49) on 05/04/2014. The study was prospectively registered in the ClinicalTrials.gov registry (NCT02395861) on March 24, 2015. The overall study duration for each participant was their ICU stay. The participants were recruited from July 2015 to May 2019. Data collection was prospectively performed.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEligibility criteria\u003c/h3\u003e\n\u003cp\u003eMedical-surgical or brain-injured adult patients admitted in ICU were eligible if: 1\u0026ndash; they required invasive mechanical ventilation (MV) for a foreseeable duration greater than 48 hours; 2\u0026ndash; they had an impairment of consciousness that evolved from 24 (\u0026plusmn;\u0026thinsp;12) hours and defined by a coma with Glasgow Coma Scale (GCS)\u0026thinsp;\u0026le;\u0026thinsp;8 in non-sedated patients\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e or by a Richmond Assessment Sedation Scale (RASS)\u0026thinsp;\u0026lt;\u0026thinsp;\u0026minus;\u0026thinsp;3 in sedated patients (deep sedation)\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMain exclusion criteria were post-anoxic or toxic coma, brain death, ongoing pregnancy, acute peripheral neurological disorders or chronic disorders impairing the brainstem reflexes or peripheral nerve conduction time, cervical spinal cord injury and absence of health insurance coverage and guardianship.\u003c/p\u003e\n\u003ch3\u003eAssessments\u003c/h3\u003e\n\u003cp\u003eThe baseline characteristics, sedation level, and neurological features were measured at inclusion (day 1) and at the time of neurophysiological tests. Due to organizational constraints, neurophysiological tests were planned at day 3, in patients who remained comatose or required deep sedation. The time points of the evaluations are detailed in \u003cb\u003eAppendix 1\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eBaseline characteristics\u003c/b\u003e \u0026ndash; We collected the demographic characteristics, body weight, comorbidities, main cause of critical illness, coma and brain injury, dates of ICU admission, coma, MV initiation and deep sedation onset. The Simplified Acute Physiological Score-II (SAPSII)\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e and the initial GCS before sedation were collected. The Sequential Organ Failure Assessment (SOFA)\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e was assessed at day 1 and at time of neurophysiological tests.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSedation characteristics\u003c/b\u003e - Depth of sedation and analgesia were assessed on day 1 and at the time of neurophysiological tests, using the RASS and Behavioral Pain Scale (BPS)\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Concomitantly, we assessed the type and cumulative dose of sedatives and analgesics but also the administration of neuromuscular blocking agents (NMBA). The reason for maintaining deep sedation at time of neurophysiological tests was collected. The highest RASS and lowest BPS were collected daily in sedated patients up to day-28 unless ICU discharge.\u003c/p\u003e \u003cp\u003e \u003cb\u003eNeurological examination\u003c/b\u003e \u0026ndash;We assessed at day-1 and at time of neurophysiological tests: 1) arousal and consciousness using the GCS and the Full Outline of Unresponsiveness (FOUR)\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e; 2) in patients without NMBA: the pupils size and brainstem reflexes, including PLR (tested with regular flashlight), corneal reflex, grimace in response to a bilateral and strong pressure to the retro-mandibular region, OCR to lateral passive head rotation, and cough reflex in response to tracheal suctioning. The brainstem dysfunction was scored using the Brainstem Response Assessment Sedation Scale (BRASS, \u003cb\u003eAppendix 2\u003c/b\u003e).\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e The GCS, FOUR and CAM-ICU were collected daily up to day-28 unless ICU discharge.\u003c/p\u003e \u003cp\u003e\u003cb\u003eNeurophysiological tests\u003c/b\u003e - Neurophysiological assessment included SSEPs and BAEPs. All recordings were interpreted by neurophysiologists (MG, EPR, EA, JZ and EB), blinded to patient outcomes (see \u003cb\u003eAppendix 3\u003c/b\u003e), according to international/national guidelines.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSSEPs were recorded after both right and left stimulations of the median nerve at the wrist using a bipolar surface electrode. Peak latencies (PL) of N9 (brachial plexus), N13 (cervical spinal cord), P14 (lower brainstem), N20 and P25 (cortical) responses were measured. The distal and proximal peripheral nerve conduction (PNC) were assessed with measuring the arm length/N9-PL ratio and N9-N13 interpeak latency (IPL), respectively. The central conduction was assessed with measuring P14-N20 and N20-P25-IPL, with the P14\u0026ndash;N20-IPL representing the ICCT.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e For the distal and proximal PNC, we presented the shortest N9-PL/arm length ratio between right and left responses. For the central parameters, we presented: 1) the shortest PL and IPL between right and left responses; 2) the percentage of asymmetry (i.e. a difference in latencies at least of 10%) between right and left responses; 3) the percentage of unilateral and bilateral abolished responses. BAEPs were recorded following auditory stimulation of each ear, alternatively. The I\u0026ndash;III, III\u0026ndash;V, and I\u0026ndash;V-IPL were calculated, with the III-V-IPL representing the IPCT. For each wave, the percentage of abolished response was reported.\u003c/p\u003e \u003cp\u003eThe SSEPs and BAEPs IPL were expressed in milliseconds (ms). The SSEPs and BAEPs components were considered absent (abolished) if their amplitude was less than 0.2 \u0026micro;V and/or indistinguishable from background noise. IPL were considered not accessible when the first response was absent and delayed when the last response was abolished. SSEPs and BAEPs normal and delayed values are presented in \u003cb\u003eAppendix 4\u003c/b\u003e. Delayed P14 was defined as a PL\u0026thinsp;\u0026gt;\u0026thinsp;16ms, a lengthened ICCT by an IPL\u0026thinsp;\u0026gt;\u0026thinsp;5.4ms and a lengthened IPCT by III-V-IPL\u0026thinsp;\u0026gt;\u0026thinsp;2.5ms.\u003csup\u003e8\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eMethod for confounding factors assessment\u003c/h3\u003e\n\u003cp\u003eConfounding factors which may influence the neurological examination, neurophysiological tests, mortality, and the occurrence of delayed awakening or delirium were assessed. They include severity of critical illness according to the SAPSII, its type (i.e., primary brain injury or not) and the pre-sedation GCS. ICU physicians were not informed of the neurophysiological results and neurophysiologists were blinded to the patient's clinical status and outcomes, limiting the risk of self-fulfilling prophecy.\u003c/p\u003e\n\u003ch3\u003eFollow-up\u003c/h3\u003e\n\u003cp\u003eThe patients were followed up to ICU discharge. The dates of sedation discontinuation, awakening, extubation, death, ICU and hospital discharges, neuroimaging data when available and the occurrence of intracranial hypertension were collected. The cause of ICU death was also collected, including decisions of withdrawal of care. The in-hospital mortality was assessed.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eVariable of interest\u003c/h2\u003e \u003cp\u003eThe variable of interest was a bilaterally delayed P14 response (i.e., \u0026gt; 16ms). Because P14 is a positive potential that appears 14ms after median nerve stimulation, we hypothesized that a 2ms increase could be considered as abnormally delayed\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Only one patient had an abolished P14, considered as delayed in the analysis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was mortality at day-28. The secondary outcomes were delayed awakening and delirium after discontinuation of sedation. Delayed awakening was arbitrarily and \u003cem\u003ea priori\u003c/em\u003e defined by the absence of eye contact to voice (i.e., RASS\u0026thinsp;\u0026le;\u0026thinsp;\u0026minus;\u0026thinsp;1) at least 3 days after discontinuation of sedation. Delirium was assessed using the Confusion Assessment Method-ICU (CAM-ICU), when RASS was \u0026ge; -3.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eAssuming that the day-28 mortality would be 35% and that 25% of patients would have a P14 PL\u0026thinsp;\u0026gt;\u0026thinsp;16ms, it was necessary to include 260 patients to demonstrate an adjusted OR of 2.5 by controlling for the risks of type I and II errors at 5% and 10%, respectively.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e We anticipated that one third of patients will die or leave the ICU between day 1 and 3. Therefore, we planned to include about 400 patients to obtain 260 having underwent neurophysiological test at day-3. The analysis was performed by a multivariate logistic regression model adjusted for the type of admission (primary brain-injury or not), the SAPSII score, and the pre-sedation GCS (\u003cb\u003eAppendix 5\u003c/b\u003e). In addition, as sensitivity analyses, models were also adjusted on RASS.\u003c/p\u003e \u003cp\u003eSummary statistics are reported, namely numbers (percentage), mean (standard deviation), or median (inter-quartile range, IQR).\u003c/p\u003e \u003cp\u003eDay-28 mortality was analyzed using the Kaplan-Meier method, with Cox multivariable regression models used to estimate the hazard ratio (HR) as a measure of the association between variable of interest and outcome. We also used a Cox model with splines to assess the impact of the P14-PL value on the hazard of death. Interaction of the effect of P14 with brain injury was tested using the Gail and Simon statistics.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eProbability of delayed awakening or delirium after sedation discontinuation was computed ignoring the time scale, with association of absent OCR and P14-N20-IPL; effect of P14-PL\u0026thinsp;\u0026gt;\u0026thinsp;16ms on mortality was measured on odds ratio estimated from multivariable logistic regression models.\u003c/p\u003e \u003cp\u003eAll regression models were adjusted for brain injury, SAPSII (calculated by removing GCS) and pre-sedation GCS.\u003c/p\u003e \u003cp\u003eAll analyses were performed using R version 4\u0026middot;4\u0026middot;0 (The R Foundation for Statistical Computing, Vienna, Austria). P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween July 2015 and April 2019,\u0026nbsp;342\u0026nbsp;mechanically ventilated patients admitted in the participating ICU were eligible. Eleven did not met the eligibility criteria, 2 refused to participate, and 7 were duplicates (\u003cstrong\u003eFigure\u0026nbsp;1\u003c/strong\u003e). Among the 322 patients enrolled at day-1, 264 (82 %) underwent neurophysiological tests, including 140 (92 %) of the 152 primary brain-injured patients and 124 (73 %) of the 170 non-brain-injured patients, whose main primary diagnoses are listed in \u003cstrong\u003eAppendix\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e6\u003c/strong\u003e. The main reason for not performing the neurophysiological tests was a RASS \u0026gt; -3 in 21patients, unavailability of the neurophysiological team in 30 patients and death in 7 patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThus, further results only deal with the 264 tested patients. The median age, SAPSII and pre-sedation GCS were 62\u0026nbsp;years (IQR\u0026nbsp;50-71), 49 (IQR\u0026nbsp;40-62) and 11 (IQR\u0026nbsp;6-15), respectively (\u003cstrong\u003eTable\u0026nbsp;1\u003c/strong\u003e). At the time of neurophysiological tests, performed at day-3 in median (IQR 2-5), 251 (95 %) patients were deeply sedated and 56 (22 %) were receiving NMBA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOut of the 264\u0026nbsp;patients analyzed, 53 (20%) died within 28 days of inclusion, including 52 in ICU and 1 in hospital after ICU discharge. Additionally, 25 (9%) patients died after day-28, (48 in ICU and 7 in hospital after ICU discharge). Survivors at day-28 were younger and less frequently brain injured (\u003cstrong\u003eTable 1\u003c/strong\u003e). Of the 53 early deaths, 20 (38%) died following multiple organ failure, 23 (43%) after withdrawal of care and 5 (10%) of brain death (including 4 primary brain-injured patients).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA P14-PL\u0026gt;16ms\u0026nbsp;was observed in 76 (29 %) patients, including in 39 (28%) in the 140 non-brain-injured and 37 (30%) in the 124 brain-injured patients. Delayed P14 was significantly associated with mortality,\u0026nbsp;as exemplified by a day-28 cumulative incidence of death of 35.5 % (95%CI, 24.9-46.3) and of 13.8 % (95%CI, 9.3-19.2) in patient with and those without P14-PL\u0026gt;16ms, respectively\u0026nbsp;(\u003cstrong\u003eFigure\u0026nbsp;2\u003c/strong\u003e). The association with day-28 mortality persisted after adjustment on brain injury, SAPS-II and GCS prior to sedation (adjusted HR=3.0 [95% CI, 1.7-5.2], p\u0026lt;0.0001) but also after additional adjustment on RASS\u0026nbsp;(\u003cstrong\u003eTable\u0026nbsp;2\u003c/strong\u003e).\u0026nbsp;Moreover, the effect of the P14 response showed no interaction with the presence of brain injury (HR=2.5 [95%CI, 1.2-5.0] in case of brain injury \u003cem\u003eversus\u003c/em\u003e 4.5 [95%CI, 1.9-10.8] in the absence of brain injury, p=0.29). A forest plot showing the effect in each brain injury subset, with interaction\u0026nbsp;tests is available on\u0026nbsp;\u003cstrong\u003eAppendix 9\u003c/strong\u003e.\u0026nbsp;Of note, the effect of the P14 latency on the day-28 mortality linearly increased over the scale (\u003cstrong\u003eFigure 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eThe day-28 mortality was also associated with absent cough reflex at inclusion (HR 2.8 [95%CI,1.4-5.7]), with absent cough reflex and absent PLR at\u0026nbsp;day 3\u0026nbsp;(HR=2.8 [95%CI, 1.5-5.5] and HR=3.9 [95%CI, 1.8-8.5], respectively) and with P14-N20-IPL \u0026gt; 5.4ms (HR=2.4 [95%CI, 1.2-4.6]). When P14\u0026gt;16ms, absent cough reflex, and absent PLR at day 3 were simultaneously included in a multivariable model, they all added prognostic information to each other (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter discontinuation of sedation, 131 (50 %) and 103 (39 %) patients developed a delayed awakening or a delirium, respectively. No patient died before awakening while 43 patients died without delirium. The main characteristics of patients with and without delayed awakening or delirium are presented in the \u003cstrong\u003eAppendix\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e10 and 11\u003c/strong\u003e respectively\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003eAbsent OCR was associated with delayed awakening, either assessed at inclusion or\u0026nbsp;at day 3\u0026nbsp;(adjusted HR\u003cstrong\u003e=\u003c/strong\u003e2.8 [95%CI, 1.2-6.1] and adjusted HR=2.2 [95%CI, 1.1-4.1]) (\u003cstrong\u003eTable\u0026nbsp;3\u003c/strong\u003e). Brainstem reflex abolition and EPs responses were not associated with the occurrence of delirium, regardless of imputation of missing data due to competing deaths (\u003cstrong\u003eAppendix\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e12\u003c/strong\u003e).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis multicenter prospective observational study confirms our main hypothesis that day-28 mortality is associated with a\u0026nbsp;P14-PL \u0026gt; 16ms\u0026nbsp;in deeply sedated critical ill patients, even after adjustment on the pre-sedation state of consciousness (i.e., GCS), as well as the severity and type of critical illness (i.e., SAPSII and brain injury \u003cem\u003eversus\u003c/em\u003e non-brain-injury). The study also corroborates our previous findings that day-28 mortality is associated with absent cough reflex, BRASS score or increased P14-N20-IPL; while delayed awakening with absent OCR.\u003csup\u003e4,8\u003c/sup\u003e Conversely, no brainstem neurophysiological responses were associated with delayed awakening or delirium following sedation discontinuation.\u003c/p\u003e\n\u003cp\u003eThe prognostic value of increased P14-PL and absent cough reflex supports our hypothesis that lower brainstem dysfunction may contribute to mortality. Our main mechanistic explanation for the association between lower brainstem dysfunction and mortality is a secondary neuroinflammatory insult to the brainstem that is triggered by a systemic inflammatory response that occurrs in both non-primary brain-injured and primary brain-injured patients. Several arguments support the role of the area postrema (AP) in mediating this secondary neuroinflammatory insult.\u0026nbsp;The AP is a unique circumventricular structure that permits circulating cytokines to reach the medulla and\u0026nbsp;is closely linked to the cardiovascular and respiratory autonomic nuclei.\u0026nbsp;This AP-autonomic nuclei complex is a central component of the body\u0026rsquo;s adaptive response to systemic inflammation. Interestingly, the P14 generators are anatomically adjacent to this complex. Moreover, P14 responses have been shown to be more sensitive than MRI in detecting brainstem dysfunction in patients with inflammatory lesions, highlighting their ability to detect subclinical inflammation.\u003csup\u003e29\u003c/sup\u003e Thus, an excessive systemic inflammation can induce brainstem neuroinflammation, potentially disrupting the AP-autonomic nuclei complex, leading to delayed P14 responses and extending to upper brainstem structures, accounting then for the relationship between the absence of OCR and delayed awakening. This mechanism is supported by experimental studies\u003csup\u003e30\u003c/sup\u003e and further suggested by our findings: the prognostic significance of absent PLR and increased ICCT.\u0026nbsp;The hypothesis of an AP-mediated secondary neuroinflammatory insult may also explain why brainstem dysfunction did not follow a typical rostro-caudal pattern of deterioration, particularly in patients with primary brain injury, and why brainstem EPs did not differ between patients with and without brain injury. Although we cannot completely rule out the occurrence of structural brainstem injury after neurophysiological testing, confirmation of this would have required neuroimaging of all patients prior to ICU discharge.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSeveral arguments suggest that sedation is unlikely to be a confounding factor in this study. The indications and the depth of sedation were comparable between survivors and non-survivors, as were the cumulative doses of propofol and sufentanil. Only the cumulative dose of midazolam was significantly higher in non-survivors, but it did not differ between patients with and without elevated P14-PL. Furthermore, sedative dose cannot account for the increase in P14-PL above 16ms and the increased risk of death with P14-PL (Figure 2). Finally, P14-PL\u0026gt;16ms remained associated with day-28 mortality after adjustment for RASS, the most commonly used marker of sedation. Nevertheless, we cannot completely exclude a possible contribution of sedation to brainstem dysfunction. Taken together, our results suggest that, at equivalent levels of deep sedation, patients who lack a cough reflex or PLR, or who have increased P14-PL or increased P14-N20-IPL, are at higher risk of mortality than those with preserved brainstem reflexes and neurophysiological responses.\u003c/p\u003e\n\u003cp\u003eOur study has several limitations. First, it primarily focused on deeply sedated ICU patients. It would be valuable to investigate whether a delayed P14 also allows to predict mortality in non-sedated critically ill patients. While the day-28 mortality rate in our cohort was slightly below the commonly reported 30\u0026nbsp;%-rate, the cohort appears representative of deeply sedated ICU patients in terms of severity score, causes of admission, and the indications, types and durations of sedation.\u003csup\u003e13\u003c/sup\u003eSecond, the inclusion of both brain-injured and non-brain-injured patients may have complicated the interpretation of study findings by conflating primary and secondary brain insults. To address this, we adjusted the analysis on the presence of brain injury and collected brain imaging data. We demonstrated that delayed P14 remained a predictor of day-28 mortality within each subgroup. However, repeating neurophysiological testing over time would have provided further clarity on the relationships between delayed P14, critical illness, sedation, and mortality.\u0026nbsp;The\u0026nbsp;prognostic value of an absent PLR aligns with previous studies using automated pupillometry,\u003csup\u003e6\u003c/sup\u003e supporting the reliability of our brainstem reflexes clinical assessments. The evaluation\u0026nbsp;of brainstem dysfunction could be more\u0026nbsp;comprehensive, with including additional clinical, autonomic and neurophysiological responses.\u0026nbsp;Although the definition of delayed awakening is arbitrary, it allows us to identify a subpopulation at risk, which is rather elderly, presents a more severe brain insult and required deeper sedation.\u0026nbsp;Finally, we found that neither brainstem reflexes nor brainstem EPs were associated with delirium, challenging our initial hypothesis, probably because delirium is a complex, multifactorial disorder involving supratentorial networks and structures.\u003c/p\u003e\n\u003cp\u003eDespite its limitation, the present study offers new pathophysiological \u0026ndash; and potentially therapeutic \u0026ndash; insights into the complex interplay between critical illness, brain function and patient outcomes. Its main clinical implication is that clinical and neurophysiological testing of brainstem function improves the prognostic assessment in critically ill patients requiring deep sedation. Our findings are generalizable, as brainstem reflexes are routinely assessed in comatose patients. We recommend their systematic assessment in deeply sedated patients, whether brain-damaged or not, in addition to the RASS score. Furthermore, technological advances will likely simplify the measurement of P14-PL. Future studies could aim to refine the P14-PL threshold values, as we observed an increased risk of death with the latter.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion, our study demonstrates that brainstem dysfunction, whether detected clinically (absence of cough reflex or PLR) or through neurophysiological measures (P14 latency \u0026gt; 16ms or P14-N20-IPL \u0026gt; 5.4ms), is an independent predictor of day-28 mortality These results will help ICU-physicians in more accurately assessing the prognosis of the most severe critically ill patients, particularly those requiring prolonged deep sedation.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData available: Yes\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData types: Deidentified participant data\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHow to access data: De-identified patient data to reproduce results presented in the article\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhen available: With publication\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDocument types: None\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWho can access the data: Researchers whose proposed use of the data has been approved.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTypes of analyses: Research projects with the same scientific purpose as the original study (post-intensive care follow-up), such as meta-analysis, for instance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMechanisms of data availability: Data will be made available upon approval of a proposal, and after a signed data access agreement with the trial sponsor.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAny additional restrictions: none\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe funders (\u003cstrong\u003ei.e. the French Ministry of Health\u003c/strong\u003e) of the study had no role in study design, data collection, analysis, and interpretation, nor in the writing of the report, or in the decision to submit the article for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStanislas Kandelman, Eric Azabou and Tarek Sharshar:Conception of the work (PI), funding application, enrolment of participating centers,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEleonore Bouchereau and Tarek Sharshar: Supervision of the data collection, participation in data analysis, verification of the data and interpretation, writing of the manuscript, critical revision of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCendrine Chaffaut and Sylvie Chevret: Methodology, data management, statistical analysis, verification of the data and interpretation, critical revision of the manuscript.\u003c/p\u003e\n\u003cp\u003eEstelle Pruvost, Sarah Benghanem, Martine Gavaret, Eric Azabou and Bertrand Hermann: Data collection, interpretation of the results, critical revision of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOther authors: patients’ recruitment and data collection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to the investigators of all participating centres: Djillali Annane (Réanimation Médico-Chirurgicale, Hôpital Raymond Poincaré, 104 Boulevard Raymond Poincaré, 92380 Garches, France), Eric Azabou (Service d’Explorations Fonctionnelles Hôpital Raymond Poincaré, 104 Boulevard Raymond Poincaré, 92380 Garches, France), Sarah Benghanem (Service de Réanimation Médicale, Hôpital Cochin, 27 rue du Faubourg Saint-Honoré, 75014 Paris, France), Eléonore Bouchereau (Neuroréanimation, GHU-Paris, Site Sainte-Anne, 1 rue Cabanis, 75014 Paris, France), Adrien Bouglé (Département d’Anesthésie et de Réanimation, Institut de Cardiologie, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), Vincent Degos (Département d’Anesthésie et de Réanimation, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), Sophie Demeret (Réanimation Neurologique, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), Chung-Hi Do (Département d’Anesthésie et de Réanimation, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), \u0026nbsp;Martine Gavaret \u0026nbsp;(Service de Neurophysiologie clinique, GHU-Paris, Site Sainte-Anne, 1 rue Cabanis, 75014 Paris, France), Nicholas Heming (Réanimation Médico-Chirurgicale, Hôpital Raymond Poincaré, 104 Boulevard Raymond Poincaré, 92380 Garches, France), Bertrand Hermann (Neuroréanimation, GHU-Paris, Site Sainte-Anne, 1 rue Cabanis, 75014 Paris, France), Tarik Hissem (Réanimation Polyvalente, Centre Hospitalier Sud-Essonne, 26 avenue du Général de Gaulle, Etampes, 91150 France), Stanislas Kandelmann (Département d’Anesthésie et Réanimation chirurgicale, Hôpital Baujon, 100 Boulverad du Général Leclerc, 92110 Clichy, France), Lionel Naccache (Service de Neurophysiologie Clinique, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), Estelle Pruvost \u0026nbsp;(Service de Neurophysiologie clinique, GHU-Paris, Site Sainte-Anne, 1 rue Cabanis, 75014 Paris, France), Benjamin Rohaut (Réanimation Neurologique, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), Shidasp Siami (Réanimation Polyvalente, Centre Hospitalier Sud-Essonne, 26 avenue du Général de Gaulle, Etampes, 91150 France), Tarek Sharshar (Neuroréanimation, GHU-Paris, Site Sainte-Anne, 1 rue Cabanis, 75014 Paris, France), Sivanthiny Sivanandamoorthy (Réanimation Polyvalente, Centre Hospitalier Sud-Essonne, 26 avenue du Général de Gaulle, Etampes, 91150 France), Nicolas Weiss (Réanimation Neurologique, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France), \u0026nbsp;Julie Zyss (Service de Neurophysiologie Clinique, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France),\u003c/p\u003e\n\u003cp\u003eWe thank the members of the data and safety monitoring board, the neurophysiology technicians (Vera Benamenyo, Laurence Nogret, Audrey Pons, Anne-Marie Pointrenaud, Emma Léon at GHU Paris Sainte Anne), Professor Raphael Porcher (Clinical Epidemiology, Hôtel Dieu, Paris) for his commitment in the writing of the ProReTro project and the study participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis manuscript is dedicated to the memory of Professor Jean Mantz.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003ePalakshappa JA, Batt JAE, Bodine SC, \u003cem\u003eet al.\u003c/em\u003e Tackling Brain and Muscle 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DOI:10.1097/CCM.0000000000005491.\u003c/li\u003e\n \u003cli\u003eRua C, Raman B, Rodgers CT, \u003cem\u003eet al.\u003c/em\u003e Quantitative susceptibility mapping at 7 T in COVID-19: brainstem effects and outcome associations. \u003cem\u003eBrain\u003c/em\u003e 2024; : awae215.\u003c/li\u003e\n \u003cli\u003eShehabi Y, Howe BD, Bellomo R, \u003cem\u003eet al.\u003c/em\u003e Early Sedation with Dexmedetomidine in Critically Ill Patients. \u003cem\u003eN Engl J Med\u003c/em\u003e 2019; \u003cstrong\u003e380\u003c/strong\u003e: 2506\u0026ndash;17.\u003c/li\u003e\n \u003cli\u003eOddo M, Crippa IA, Mehta S, \u003cem\u003eet al.\u003c/em\u003e Optimizing sedation in patients with acute brain injury. \u003cem\u003eCrit Care\u003c/em\u003e 2016; \u003cstrong\u003e20\u003c/strong\u003e: 128.\u003c/li\u003e\n \u003cli\u003eBouchereau E, Sharshar T, Legouy C. Delayed awakening in neurocritical care. \u003cem\u003eRevue Neurologique\u003c/em\u003e 2021; published online Aug 13. DOI:10.1016/j.neurol.2021.06.001.\u003c/li\u003e\n \u003cli\u003eMorioka T, Tobimatsu S, Fujii K, Fukui M, Kato M, Matsubara T. Origin and distribution of brain-stem somatosensory evoked potentials in humans. \u003cem\u003eElectroencephalogr Clin Neurophysiol\u003c/em\u003e 1991; \u003cstrong\u003e80\u003c/strong\u003e: 221\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003eCruccu G, Aminoff MJ, Curio G, \u003cem\u003eet al.\u003c/em\u003e Recommendations for the clinical use of somatosensory-evoked potentials. \u003cem\u003eClin Neurophysiol\u003c/em\u003e 2008; \u003cstrong\u003e119\u003c/strong\u003e: 1705\u0026ndash;19.\u003c/li\u003e\n \u003cli\u003eGarc\u0026iacute;a-Larrea L, Fischer C, Artru F. [Effect of anesthetics on sensory evoked potentials]. \u003cem\u003eNeurophysiol Clin\u003c/em\u003e 1993; \u003cstrong\u003e23\u003c/strong\u003e: 141\u0026ndash;62.\u003c/li\u003e\n \u003cli\u003eMaugui\u0026egrave;re F, Allison T, Babiloni C, \u003cem\u003eet al.\u003c/em\u003e Somatosensory evoked potentials. The International Federation of Clinical Neurophysiology. \u003cem\u003eElectroencephalogr Clin Neurophysiol Suppl\u003c/em\u003e 1999; \u003cstrong\u003e52\u003c/strong\u003e: 79\u0026ndash;90.\u003c/li\u003e\n \u003cli\u003eTeasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. \u003cem\u003eLancet\u003c/em\u003e 1974; \u003cstrong\u003e2\u003c/strong\u003e: 81\u0026ndash;4.\u003c/li\u003e\n \u003cli\u003eEly EW, Truman B, Shintani A, \u003cem\u003eet al.\u003c/em\u003e Monitoring Sedation Status Over Time in ICU PatientsReliability and Validity of the Richmond Agitation-Sedation Scale (RASS). \u003cem\u003eJAMA\u003c/em\u003e 2003; \u003cstrong\u003e289\u003c/strong\u003e: 2983\u0026ndash;91.\u003c/li\u003e\n \u003cli\u003eLe Gall J-R, Lemeshow S, Saulnier F. A New Simplified Acute Physiology Score (SAPS II) Based on a European/North American Multicenter Study. \u003cem\u003eJAMA\u003c/em\u003e 1993; \u003cstrong\u003e270\u003c/strong\u003e: 2957\u0026ndash;63.\u003c/li\u003e\n \u003cli\u003eVincent J-L, de Mendonca A, Cantraine F, \u003cem\u003eet al.\u003c/em\u003e Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: Results of a multicenter, prospective study. \u003cem\u003eCritical Care Medicine\u003c/em\u003e 1998; \u003cstrong\u003e26\u003c/strong\u003e: 1793.\u003c/li\u003e\n \u003cli\u003ePayen JF, Bru O, Bosson JL, \u003cem\u003eet al.\u003c/em\u003e Assessing pain in critically ill sedated patients by using a behavioral pain scale. \u003cem\u003eCrit Care Med\u003c/em\u003e 2001; \u003cstrong\u003e29\u003c/strong\u003e: 2258\u0026ndash;63.\u003c/li\u003e\n \u003cli\u003eWijdicks EFM, Bamlet WR, Maramattom BV, Manno EM, McClelland RL. Validation of a new coma scale: The FOUR score. \u003cem\u003eAnn Neurol\u003c/em\u003e 2005; \u003cstrong\u003e58\u003c/strong\u003e: 585\u0026ndash;93.\u003c/li\u003e\n \u003cli\u003eLegros V, Mourvillier B, Floch T, \u003cem\u003eet al.\u003c/em\u003e Use of BRASS in sedated critically-ill patients as a predictable mortality factor: BRASS-ICU. \u003cem\u003eNeurol Res\u003c/em\u003e 2021; \u003cstrong\u003e43\u003c/strong\u003e: 283\u0026ndash;90.\u003c/li\u003e\n \u003cli\u003eAndr\u0026eacute;-Obadia N, Zyss J, Gavaret M, \u003cem\u003eet al.\u003c/em\u003e Recommendations for the use of electroencephalography and evoked potentials in comatose patients. \u003cem\u003eNeurophysiol Clin\u003c/em\u003e 2018; \u003cstrong\u003e48\u003c/strong\u003e: 143\u0026ndash;69.\u003c/li\u003e\n \u003cli\u003eGail M, Simon R. Testing for Qualitative Interactions between Treatment Effects and Patient Subsets. \u003cem\u003eBiometrics\u003c/em\u003e 1985; \u003cstrong\u003e41\u003c/strong\u003e: 361\u0026ndash;72.\u003c/li\u003e\n \u003cli\u003eMagnano I, Pes GM, Pilurzi G, \u003cem\u003eet al.\u003c/em\u003e Exploring brainstem function in multiple sclerosis by combining brainstem reflexes, evoked potentials, clinical and MRI investigations. \u003cem\u003eClinical Neurophysiology\u003c/em\u003e 2014; \u003cstrong\u003e125\u003c/strong\u003e: 2286\u0026ndash;96.\u003c/li\u003e\n \u003cli\u003eKola G, Clifford CW, Campanaro CK, \u003cem\u003eet al.\u003c/em\u003e Peritoneal sepsis caused by Escherichia coli triggers brainstem inflammation and alters the function of sympatho-respiratory control circuits. \u003cem\u003eJournal of Neuroinflammation\u003c/em\u003e 2024; \u003cstrong\u003e21\u003c/strong\u003e: 45.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"intensive-care-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"icme","sideBox":"Learn more about [Intensive Care Medicine](http://link.springer.com/journal/134)","snPcode":"134","submissionUrl":"https://www.editorialmanager.com/icme/default2.aspx","title":"Intensive Care Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5654002/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5654002/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and objectives – \u003c/strong\u003eAbsent cough reflex is associated with mortality intensive care unit (ICU) patients requiring deep sedation, suggesting that lower brainstem dysfunction contributed to adverse outcomes. We conducted a multicenter observational cohort study to confirm this hypothesis by assessing the peak latency (PL) of the lower brainstem-generated P14 evoked potential (EP), which is slightly increased by sedatives. We aimed to demonstrate that a P14-PL\u0026gt; 16 ms is independently associated with day-28 mortality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and methods\u003c/strong\u003e - Mechanically ventilated adult patients, comatose or deeply sedated, brain-injured or not, were included. At day 3, EPs were performed in patients remaining unconscious. The Simplified Acute Physiological Score (SAPSII), initial Glasgow Coma Scale (GCS), sedation depth and brainstem reflexes were collected. The primary outcome was 28-day mortality. The secondary outcomes were delayed awakening and delirium after sedation discontinuation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e - Between 2015 and 2019, 322 patients were included. EPs were performed in 264 (82%) patients, including 140 (53%) brain-injured and 251 (95%) deeply sedated patients. The median age, SAPSII and initial GCS were 62 years [50; 71], 49 [40; 62] and 11 [6; 15], respectively. A P14-PL \u0026gt; 16ms was found in 76 (29%) patients and was associated with day-28 mortality (adjusted hazard ratio, 3.0; 95% confidence interval, [1.7-5.2]). Absent cough and pupillary light reflexes were associated with death. Only absent oculocephalogyre reflex was associated with delayed awakening (adjusted odds ratio, 2.1, 95%CI, [1.1 - 3.7]).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterpretation\u003c/strong\u003e – Impaired neurological and neurophysiological lower brainstem responses are associated with mortality in deeply sedated patients.\u003c/p\u003e\n\u003cp\u003eFunded by the French Ministry of Health; PRORETRO; n° P120915; ClinicalTrials.gov registry: NCT02395861; date: 24 March 2015\u003c/p\u003e","manuscriptTitle":"Brainstem Dysfunction is Associated With Mortality in Deeply Sedated Critically Ill Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 10:40:32","doi":"10.21203/rs.3.rs-5654002/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-04-26T07:34:23+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-26T04:05:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-25T13:27:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Intensive Care Medicine","date":"2025-04-25T09:27:16+00:00","index":"","fulltext":""},{"type":"decision","content":"Major revisions","date":"2025-02-10T06:53:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"intensive-care-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"icme","sideBox":"Learn more about [Intensive Care Medicine](http://link.springer.com/journal/134)","snPcode":"134","submissionUrl":"https://www.editorialmanager.com/icme/default2.aspx","title":"Intensive Care Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"94795cd5-2747-4ff9-81fc-8618e0d8dbcc","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-16T16:01:05+00:00","versionOfRecord":{"articleIdentity":"rs-5654002","link":"https://doi.org/10.1007/s00134-025-07945-7","journal":{"identity":"intensive-care-medicine","isVorOnly":false,"title":"Intensive Care Medicine"},"publishedOn":"2025-06-13 15:57:34","publishedOnDateReadable":"June 13th, 2025"},"versionCreatedAt":"2025-05-09 10:40:32","video":"","vorDoi":"10.1007/s00134-025-07945-7","vorDoiUrl":"https://doi.org/10.1007/s00134-025-07945-7","workflowStages":[]},"version":"v1","identity":"rs-5654002","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5654002","identity":"rs-5654002","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}