Brainstem Dysfunction in COVID-19 Critically Ill Patients: a Prospective Observational Study (BRAINSTEM-COV)

Brainstem Dysfunction in Ventilated and Deeply Sedated COVID-19 Critically Ill Patients: a Prospective Observational Study

The purpose of this study is to determine the prevalence of brainstem dysfunction in critically ill ventilated and deeply sedated patients hospitalized in the Intensive Care Unit (ICU) for a SARS-CoV-s2 infection.

The recent development of the pandemic due to the SARS-CoV-2 virus has showed that a substantial proportion of patients developed a severe condition requiring critical care, notably because of acute respiratory distress syndrome requiring mechanical ventilation and deep sedation. Outside of this coronavirus infection, this situation is classically associated with a high prevalence of brainstem dysfunction, even in the absence of brain injury. This dysfunction, either structural or functional, can be detected using appropriate clinical tools such as the BRASS score and/or using the quantitative analysis of EKG and EEG. Crucially, brainstem dysfunction is associated not only with ICU complications such as delirium, but also with a poorer survival. Moreover, some reports of encephalitis cases and the presence of anosmia/agueusia raised the question of whether the virus could directly invade the central nervous system. For these two reasons, it is reasonable to assume that brainstem dysfunction is particularly prevalent in critically ill patients infected with SARS-CoV-2 and that this dysfunction could be one of the major determinant of patients outcome.

Brainstem dysfunction, Delirium, Awareness, Arousal, Dysautonomia, Autonomic system, SARS-COV-2, COVID-19, sedation, mechanical ventilation, EEG, EKG

Major patients, admitted in intensive care for a SARS-CoV-2 infection and requiring mechanical ventilation and deep sedation (with or without neuromuscular blockade)

It consists of a standardized evaluation of brainstem reflexes with a score of 1 attributed for absence of pupillary light reflex, cough reflex and the combined absence of grimace and oculocephalic reflex, a score of 2 for absent corneal reflex and a score of 3 for absent grimace in the presence of oculocephalic The resulting sum ranges from 0 to 7. It will be performed at two times points: a first time under sedation and a second time 3 to 5 days after sedation weaning.

A 20 minutes clinical (12 electrodes) EEG with an EKG lead will be performed a first time under sedation and a second time 3 to 5 days after sedation weaning. These EEG recordings will allow to measure the sympathic-parasympathetic ratio using spectral analysis of the EKG and also to measure quantitative markers of brain EEG activity (spectral power and connectivity in delta, theta, alpha, beta and gamma band; complexity).

Clinical cranial nerves anomalies using validated scale (BRASS score- ranges from 0 to 7 - ) in deeply sedated patient (RASS <-3)

At inclusion or in patients with neuromuscular blockade 12h-72h following neuromuscular blocking agent cessation

Analysis of the sympathico-parasympathetic ratio (using spectral analysis of the EKG signal) according to the presence or absence of brainstem dysfunction and its severity

At inclusion or in patients with neuromuscular blockade 12h-72h following neuromuscular blocking agent cessationn

Analysis of the sympathico-parasympathetic ratio (using spectral analysis of the EKG signal) according to the presence or absence of brainstem dysfunction and its severity

EEG power in delta, theta, alpha, beta and gamma frequency bands according to the presence or absence of brainstem dysfunction and its severity

At inclusion or in patients with neuromuscular blockade 12h-72h following neuromuscular blocking agent cessation

EEG power in delta, theta, alpha, beta and gamma frequency bands according to the presence or absence of brainstem dysfunction and its severity

EEG functional connectivity using weighted Symbolic Mutual Information and weighted Phase Lag Index according to the presence or absence of brainstem dysfunction and its severity

At inclusion or in patients with neuromuscular blockade 12h-72h following neuromuscular blocking agent cessation

Characterization of brainstem dysfunction in COVID-19 patients: EEG functional connectivity, after sedation weaning

EEG functional connectivity using weighted Symbolic Mutual Information and weighted Phase Lag Index according to the presence or absence of brainstem dysfunction and its severity

EEG complexity using Kolmogorov complexity and permutation entropy according to the presence or absence of brainstem dysfunction and its severity

At inclusion or in patients with neuromuscular blockade 12h-72h following neuromuscular blocking agent cessation

Characterization of brainstem dysfunction in COVID-19 patients: EEG complexity after sedation weaning

EEG complexity using Kolmogorov complexity and permutation entropy according to the presence or absence of brainstem dysfunction and its severity

Multivariate classification of the presence or absence of brainstem dysfunction using support vector machine and extra-trees algorithm based on the EEG derived quantitative features presented above

At inclusion or in patients with neuromuscular blockade 12h-72h following neuromuscular blocking agent cessation

Characterization of brainstem dysfunction in COVID-19 patients: multivariate classification after sedation weaning

Multivariate classification of the presence or absence of brainstem dysfunction using support vector machine and extra-trees algorithm based on the EEG derived quantitative features presented above

Using validated functional scale modified Rankin (mRankin) for independence assessment (mRankin ranges from 0 to 6 with higher scores indicating more severe disability)

Using validated functional scale Glasgow Outcome Scale Extended (GOSE) for independence assessment (GOSE ranges from 1 to 8 with higher scores indicating less severe disability outcome)

Inclusion Criteria: ICU hospitalization Invasive mechanical ventilation Deep sedation (RASS<-3) >12 hours Positive SARS-COV-2 PCR Exclusion Criteria: History of neurologic disease (stroke, degenerative disease) Pregnant women Moribund patients Minor patient Major patient under guardianship or curatorship Prior inclusion in the study Patient not affiliated to a social security scheme Limitations and cessation of active therapies

Rohaut B, Porcher R, Hissem T, Heming N, Chillet P, Djedaini K, Moneger G, Kandelman S, Allary J, Cariou A, Sonneville R, Polito A, Antona M, Azabou E, Annane D, Siami S, Chretien F, Mantz J, Sharshar T; Groupe d'Exploration Neurologique en Reanimation (GENER). Brainstem response patterns in deeply-sedated critically-ill patients predict 28-day mortality. PLoS One. 2017 Apr 25;12(4):e0176012. doi: 10.1371/journal.pone.0176012. eCollection 2017.

Benghanem S, Cariou A, Diehl JL, Marchi A, Charpentier J, Augy JL, Hauw-Berlemont C, Gavaret M, Pene F, Mira JP, Sharshar T, Hermann B. 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. Crit Care Med. 2022 Jul 1;50(7):1103-1115. doi: 10.1097/CCM.0000000000005491. Epub 2022 Feb 9.