Journal Logo

Neurologic Critical Care

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*

Benghanem, Sarah MD, MSc1–3; Cariou, Alain MD, PhD1,2,4; Diehl, Jean-Luc MD, PhD2,5–7; Marchi, Angela MD2,8; Charpentier, Julien MD1; Augy, Jean-Loup MD, MSc2,5; Hauw-Berlemont, Caroline MD, MSc2,5; Gavaret, Martine MD, PhD2,3,8; Pène, Frédéric MD, PhD1,2; Mira, Jean-Paul MD, PhD1,2; Sharshar, Tarek MD, PhD2,3,9; Hermann, Bertrand MD, PhD2,5,10

Author Information
doi: 10.1097/CCM.0000000000005491

Abstract

COVID-19 disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic since November 2019. Although SARS-CoV-2 primarily targets the respiratory tract with the most severe condition being the acute respiratory distress syndrome (ARDS) (1), other organs are also affected. In particular, neurologic symptoms have been commonly reported, from peripheral (including neurosensory disorders such as anosmia) to CNS involvement (stroke, seizure, and encephalitis) (2–7). In critically ill patients, the prevalence of delirium and abnormal neurologic examination seems especially high (8). Yet, why SARS-CoV-2 infection leads to neurologic symptoms, and whether the virus gains access to the CNS is still pending. Recent neuropathological studies reported vascular and inflammatory lesions most pronounced in the brainstem (9–11).

As brain injury is often a major determinant of functional outcomes in critically ill patients (12), objective tools are necessary to precisely assess its mechanisms and depth. Electroencephalography (EEG) is one of the simplest and most used technique to monitor real-time brain activity at the bedside allowing to assess encephalopathy and epileptogenicity, and to detect focal abnormalities in critically ill patients (13,14). EEG could also be used as a tool for neuroprognostication, for instance, in cardiac arrest survivors (15) and non-COVID-19 septic patients (16–19). EEG analysis has been reported in COVID-19 patients, but few data are available in critically ill patients, and association between EEG abnormalities and outcomes remains poorly known (20). We aimed to describe the prevalence of cerebral dysfunction evaluated by a clinical and a neurophysiologic approach in critically ill, COVID-19 patients and to assess the relationship between early EEG abnormalities and outcomes.

MATERIALS AND METHODS

Population

We conducted a prospective bicentric observational study between April and December 2020. We included patients admitted in medical ICU of two university hospitals for a severe SARS-CoV-2 infection leading to ARDS (as defined by the Berlin criteria [21]) and requiring invasive mechanical ventilation (IMV) with initial deep sedation (defined as a Richmond Agitation-Sedation Scale (RASS) less than –3 during at least 12 hr). All patients had a positive SARS-CoV-2 polymerase chain reaction (nasopharyngeal swab and/or endotracheal pulmonary specimen). Patients with history of central neurologic disorders were excluded. This study was approved by the “Comité de Protection des Personnes ‘Ile de France II’” (n°ID RCB: 2020-01559-30) ethic committee and was registered on clinicaltrials.gouv: NCT04527198. A written informed consent was obtained from each patient or relative.

ICU and Sedation Management

Patients were managed following current COVID-19 (22) and ARDS guidelines (23). Specific treatments used for SARS-CoV-2 infection are reported. Management of sedation, analgesia, and neuromuscular blockers (NMBs) were protocolized based on the RASS, behavioral pain scale (BPS), and train of four according to guidelines (24). Sedatives and opioids were administered following a nurse-protocolized targeted sedation based on BPS and RASS levels, assessed at least every 4 hours and followed in both participating centers (Supplementary Fig. 1, https://links.lww.com/CCM/H26).

Standardized Neurologic Assessment

We assessed acute cerebral dysfunction using a standardized clinical and neurophysiologic approach at two predefined time points. First assessment (T1) was performed in sedated patients, 12–72 hours following the first NMB cessation if patients received paralyzing agents, to rule out any potential lasting effect of NMB and ensure an interpretable clinical examination. Second assessment (T2) was performed 4–7 days after definitive sedative cessation.

Clinical Examination

Standardized clinical neurologic examination was performed by two senior neurointensivists using validated scales: assessment of arousal, awareness and responsiveness using the Full Outline of UnResponsiveness (FOUR) (25) and RASS scores, and assessment of brainstem responses through brainstem reflexes and cranial nerves (pupillary light reflex, corneal reflex, oculocephalic reflex [OCR] to lateral passive head rotation and cough reflex in response to five tracheal suctioning and grimacing to pain through bilateral, persistent, and strong pressure to the retromandibular region). Each one of the above was scored as present or abolished, and brainstem dysfunction was defined as a Brainstem Responses Assessment Sedation Score (BRASS) (26) greater than or equal to 1 (Supplementary Table 1, https://links.lww.com/CCM/H26).

Electroencephalogram Assessment

Standard 20-minute EEG recordings with 11 scalp electrodes (Fp1, Fp2, Fz, C3, C4, Cz, T3, Pz, T4, O1, and O2 in the 10–20 international reference system) were interpreted by certified electrophysiologists blinded from patient’s neurologic examination and outcomes. The following EEG patterns were prospectively described: predominant background frequency (Delta 1–4 Hz, Theta 4–8 Hz, and Alpha 8–12 Hz), background continuity, symmetry and reactivity to standardized nociceptive and auditory stimuli, paroxysmal activity, and seizures.

Data Collection

We also collected demographic characteristics, body weight, medical history and SARS-CoV-2 symptoms, Simplified Acute Physiologic Score II at admission, Sequential Organ Failure Assessment (SOFA) at admission and at T1 and T2, sedative/opioid exposure (duration, cumulative doses, and infusion rates), length of stay, duration of mechanical ventilation, duration of ICU stay, and mortality. Laboratory findings performed at T1 and T2 and results of brain CT/MRI and cerebrospinal fluid analyses, performed at the treating physician discretion, were also collected.

Neurologic Follow-Up

Besides the T1 and T2 assessments, level of consciousness and command following were assessed every 4 hours using FOUR and RASS scales. In patients with an RASS of –3 to +4, delirium (27,28) was assessed using the Confusion Assessment Method-ICU (CAM-ICU) at least twice a day (29). Medical Research Council (MRC) score motor testing was performed at ICU discharge with a score less than 48/60 defining ICU-acquired weakness.

Coma was defined by RASS scores between –4 and –5 and awakening by two successive RASS scores greater than or equal to –2. Delayed awakening was defined by the absence of awakening 3 days after sedation discontinuation. Delirium was defined as a positive CAM-ICU assessment and classified as hypoactive, hyperactive, or mixed depending on the associated RASS. Each day was recorded as spent in coma, delirium, or neither of both (all assessments in a 24-h period needed to be negative for a patient to be delirium-free and coma-free, and in the case of both coma and delirium, the day was recorded as “with delirium”). Patients were followed from T1 for 28 days or up to ICU discharge, whichever came first.

Outcomes

Primary end points were the prevalences of acute neurologic failure (coma, delayed awakening, and hypoactive/hyperactive/mixed delirium). Secondary outcomes were first the prevalence at T1 and T2 of brainstem dysfunction and EEG abnormalities and second the association between both at T1 and day-28 outcomes.

Statistical Analyses

Continuous variables were summarized using medians and interquartile ranges and compared with Wilcoxon rank-sum test, and categorical variables were reported as proportions and compared with Pearson chi-square or Fisher exact test as appropriate. Univariate associations between brainstem dysfunction, EEG patterns, or sedatives/opioids exposure and outcomes were explored through logistic regression for binary outcome with area under the receiver operating characteristic curve (AUC), and its 2,000 replicates bootstrap 95% CI, and with linear regression for quantitative outcomes, with the R2, which represents the proportion of variance of the dependent variable explained by the independent variable. We also explored these associations through time-to-event analyses of the cumulative incidence of ICU survival, weaning from IMV, coma recovery for at least 48 hours, and delirium recovery for at least 48 hours (expressed as days free of coma and delirium for at least 48 hr) from T1 to day 14 and day 28 or up to ICU discharge, whichever came first. Kaplan-Meier survival curves were used for visual presentation of the results. Crude hazard ratio (HR) and adjusted HR (aHR) on sedatives/opioids exposure and/or nonneurologic SOFA at T1 were computed using Cox proportional hazards models. All tests were two-sided with p values of less than 0.05 considered as significant. Statistical analyses were performed using R Software, Version 3.6.3 (2020-02-29; https://cran.r-project.org/).

RESULTS

Patients From April to December 2020, among the 146 mechanically ventilated patients with COVID-19 ARDS who were admitted in participating centers, 52 patients were included in the study. Compared with eligible patients who could not be included within the 12–72 hours following first NMB cessation time-window, included patients had less comorbid conditions, were less severe at ICU admission, and had higher ICU survival (Supplementary Fig. 2 and Supplementary Table 2, https://links.lww.com/CCM/H26). Patients were mostly male (81%), with a median age of 68 years (56–74 yr). All patients presented respiratory symptoms at admission, and 12% presented neurologic symptoms of mild encephalopathy with a median Glasgow Coma Scale at ICU admission of 15 (15–15) without any focal sign (Table 1). Patients were mainly sedated with midazolam (98%) and/or with propofol (12%), and analgesia was maintained with sufentanil in all patients. Median lowest Pao2/Fio2 ratio within the 24 hours of IMV was 104 (83–118), and almost all patients (98%) received NMB (atracurium), started within 1 hour (0.5–2 hr) of sedation infusion (Table 2).

TABLE 1. - Population Characteristics
Demographic Characteristics n = 52
Age (yr) 68 (56–74)
Male sex 42 (81)
BMI (kg/m2)/obesity (BMI > 30 kg/m2) 27.8 (25.5–29.8)/15 (29%)
Knaus score A—no limitation B—moderate limitation C—severe limitation 23 (44)24 (46)5 (9.6)
MacCabe score
 1—no chronic disease 2—chronic disease with at least 5 yr of expected survival 42 (81)10 (19)
Comorbidities Diabetes Hypertension Cardiac history Cancer history Respiratory history Renal history Immunodepression 34 (65)15 (29)13 (25)7 (13)10 (19)4 (7.7)5 (9.6)9 (17)
Characteristics at ICU Admission
COVID-19 symptoms
 Respiratory 52 (100)
 Neurologic 6 (12)
Positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction 52 (100)
First symptoms to ICU delay (d) 10 (7–13)
Glasgow Coma Scale at hospital admission 15 (15–15)
Simplified Acute Physiology Score II at ICU admission 48 (35–69)
Sequential Organ Failure Assessment-total at ICU admission 5 (4–8)
Lowest Pao 2/Fio 2 within 24 hr of IMV 104 (83–118)
Treatments Received
High-flow nasal canula oxygenotherapy before IMV 35 (67)
Prone positioning during IMV 47 (90)
Neuromuscular blocking agent 50 (96)
Renal replacement therapy 21 (40)
Extracorporeal membrane oxygenation 3 (5.8)
Dexamethasone 46 (88)
Anticoagulant: reinforced prophylactic / therapeutic 29 (56)/23 (44)
Anti-interleukin-6/remdesivir/other 6 (12)/3 (5)/2 (4)
BMI = body mass index, IMV = invasive mechanical ventilation.

TABLE 2. - Standardized Neurologic Assessments
Assessment T1, n = 52 T2, n = 42
Assessment Conditions
Delays
 ICU admission to assessment (d) 4 (3–7) 17 (10–25)
 Neuromuscular blockade offset to assessment (hr) 26 (22–44) NA
EEG to clinical assessment (hr) 1 (0–2) 1 (0–3)
Nonneurologic Sequential Organ Failure Assessment 6 (4–9) 3 (2–6)
Sedatives/opioids drugs
 Midazolam 51 (98) 0 (0)
 Propofol 6 (12) 0 (0)
 Sufentanil 52 (100) 2 (5)
Sedatives/opioids infusion rate (mg/kg/hr)
 Midazolam 0.11 (0.07–0.19) NA
 Propofol 2.0 (1.5–2.7) NA
 Midazolam and propofol (midazolam equivalent) 0.11 (0.07–0.23) NA
 Sufentanil 0.17 (0.09–0.23) 0.07 (0.07–0.07)
Sedatives/opioids cumulative dose (mg/kg)
 Midazolam 12 (8–18) 29 (15–42)
 Propofol 23 (2–40) 40 (13–95)
 Midazolam and propofol (midazolam equivalent) 13 (8–20) 32 (20–48)
 Sufentanil 17 (10–26) 42 (30–73)
Sedatives/opioids duration (d) 4 (3–7) 9 (6–17)
Clinical Assessment
Richmond Agitation-Sedation Scale score –4 (–5 to –4) 0 (–3 to 0)
Full Outlined of Unresponsiveness score 5 (5–7) 13 (9–16)
Brainstem Response Assessment Sedation Scale score 0 (0–1) 0 (0–0)
Brainstem reflexes
 Absent oculocephalic reflex 32 (62) 7 (17)
 Absent corneal reflex 4 (8) 0 (0)
 Absent pupillary reflex 0 (0) 0 (0)
 Absent cough reflex 12 (23) 2 (5)
 No grimacing to pain 22 (42) 4 (10)
Electrophysiology Assessment
EEG dominant frequency
 Alpha 4 (7) 20 (51)
 Theta 30 (58) 17 (44)
 Delta 18 (35) 2 (5)
EEG symmetry 50 (96) 38 (97)
EEG unreactive 17 (33) 6 (15)
EEG discontinuous and/or suppressed background 25 (48) 1 (3)
Bifrontal slow waves 17 (33) 12 (31)
Seizure 1 (2) 0 (0)
EEG = electroencephalography, NA = not applicable.
T1 assessment was performed in sedated patients, 12–72 hr after neuromuscular blockade weaning for patients receiving paralyzing agents, whereas T2 assessment was performed 4–7 d after definite sedation cessation. Statistics presented: median (interquartile range); n (%). Midazolam equivalent dose is computed assuming that 10 mg of propofol would be equal to l mg of midazolam (30, 31).

Standardized Neurologic Assessments

T1 assessment (12–72 hr after the NMB weaning) was performed in all patients after a median delay of 4 days (3–7 d) from intubation and 26 hours (22–44 hr) after NMB cessation. T2 assessment (4–7 d after definitive sedation cessation) was performed in all the 42 patients alive, after a median delay of 17 d (10–24 d) from intubation and median delay from sedatives definitive cessation of 83 hours (73–117 hr). Median sedation duration was 9 days (6–17 d), with a total cumulative dose of 32 mg/kg of midazolam equivalent and 42 µg/kg of sufentanil.

Clinical Assessment

At T1, RASS was –4 (–4 to –5), and FOUR was 5 (5–7). To note, nine patients were RASS-3 (median time of 4 hr [2–6 hr] spent in RASS-3). OCR was abolished in 32 of patients (62%), grimacing to pain in 22 (42%), cough reflex in 12 (23%), and corneal reflex in 4 (7.7%), leading to a prevalence of brainstem dysfunction (defined as a BRASS greater than or equal to 1, Supplementary Table 1, https://links.lww.com/CCM/H26) of 50%, with a median BRASS of 1 (1–2) (Table 2; Supplementary Figs. 3 and 4, https://links.lww.com/CCM/H26). At T2, RASS was 0 (–3 to 0) and FOUR 13 (9–16). Brainstem dysfunction was present in 4/42 patients (10%) with absent grimacing to pain in 4 (10%), cough reflex in 2 (5%), and OCR in 7 (17%) (Table 2; Supplementary Fig. 3, https://links.lww.com/CCM/H26).

Neurophysiologic Assessment

EEG was performed in all patients at T1 within 1 hour (0–2 hr) of clinical assessment and in 39 (92%) of the 42 patients alive at T2 within 1 hour (0–3 hr) of clinical assessment. At T1, EEG was mostly symmetric (96%) with a dominant theta (58%) and delta (35%) background rhythm. Background activity was discontinuous and/or suppressed in 25 (patients 48%) and nonreactive in 17 patients (33%). Paroxysmal activity with bifrontal slow waves was observed in 17 patients (33%), and only one patient (1.9%) presented a seizure. At T2, background rhythm was still slowed in 19 patients (49%). Bifrontal slow waves were observed in 12 patients (31%), EEG was nonreactive in 6 patients (15%), and background was discontinuous in 1 (2.6%) (Table 2; Supplementary Fig. 4, https://links.lww.com/CCM/H26). Biological and brain-imaging results are presented in Supplementary Material 2c and Supplementary Table 3 (https://links.lww.com/CCM/H26).

Neurologic and ICU Outcomes

ICU mortality rate was 23% with a median length of stay of 20 days (12–36 d) and a median length of IMV of 18 days (10–34 d). No death was due to withdrawal of life-sustaining therapy decisions. Nine patients (17%) died without awakening from coma. In patients who awoke, median duration of coma was 13 days (8–26 d), and delayed awakening was present in 29 (67%), with a median awakening delay of 4 days (1–13 d). Delirium was present in 32 patients (62%) overall, that is 74% (32/43) of patients who awoke from coma, with a predominance of mixed delirium (62%) and median duration of 5 days (3–8 d). Prevalence of ICU-acquired weakness at ICU discharge was 64% (median MRC of 40 [30–54]).

Association of Brainstem Dysfunction and EEG Patterns With ICU Outcomes

Twenty-five patients (96%) without brainstem dysfunction awoke from coma versus 18 patients (69%) with brainstem dysfunction (p = 0.024). Median delay of awakening was 2 (0–8) versus 9 (2–19) days (p = 0.019), respectively (Supplementary Table 4, https://links.lww.com/CCM/H26). Brainstem dysfunction was associated with lower ventilator-free days (VFDs) (0 d [0–12 d] vs 18 d [0–24 d]; p = 0.004), coma-free days (CFDs) (6 d [0–16 d] vs 23 d [6–25 d]; p = 0.021), and delirium-free days (DFDs) (5 d [0–14 d] vs 18 d [2–25 d]; p = 0.015) at day-28 from T1, whereas mortality (31% vs 12%; p = 0.09) did not differ between the groups.

EEG patterns at T1 were also significantly associated with outcomes. Discontinuous background was associated with lower VFD (0 [0–14] vs 17 [0–22]; p = 0.010), CFD (1 [0–14] vs 22 [12–26]; p < 0.001), DFD (0 [0–9] vs 17 [12–25]; p = 0.001), and higher mortality (40% vs 4%; p = 0.001) at day 28 from T1 (Table 2), whereas bifrontal slow waves were associated with higher CFD (25 [10–26] vs 8 [0–22]; p = 0.009) and DFD (19 [10–26] vs 6 [0–17]; p = 0.006). Nonreactive EEG was associated with lower VFD (0 [0–14] vs 16 [0–22]; p = 0.025), CFD (6 [0–13] vs 22 [2–26]; p = 0.006), DFD (0 [0–9] vs 17 [0–25]; p = 0.006), and higher mortality (41% vs 11%; p = 0.027). Similar results were observed in time-to-event analyses for both brain stem dysfunction and EEG patterns (Supplementary Table 5, https://links.lww.com/CCM/H26).

Investigation of the Role of Sedation

In order to assess the potential confounding effect of sedation, we first investigated bivariate associations at T1 between brainstem dysfunction or EEG patterns and sedatives/opioids exposure, and between each outcome and sedatives/opioids exposure. Among these, only opioids infusion rate was significantly higher in patients with brainstem dysfunction (0.21 μg/kg/hr [0.14–0.26 μg/kg/hr] vs 0.11 μg/kg/hr [0.07–0.18 μg/kg/hr]; p = 0.004; Supplementary Table 3, https://links.lww.com/CCM/H26). Yet, neither sedation infusion rate, cumulative dose, nor duration was significantly associated with outcomes. Conversely, clinical features and electrophysiology patterns of brain dysfunction significantly outperformed sedatives/opioids exposure for explaining the variance of day-28 CFD and DFD (R2 between 11% and 22%; p < 0.05 vs R2 ≤ 1%; p > 0.05), as well as in predicting mortality (AUC ≥ 0.7; p < 0.05 for discontinuous or nonreactive EEG vs AUC < 0.7; p > 0.05 for sedatives/opioids exposure) (Table 4).

TABLE 3. - ICU Outcomes According to EEG Continuity and Reactivity at T1
Populations Overalln = 52 EEG Continuity EEG Reactivity
Absent (n = 25) Present (n = 27) p Absent (n = 17) Present (n = 35) p
Outcomes at ICU discharge
 ICU mortality 12 (23) 11 (44) 1 (4) < 0.001 7 (41) 5 (14) 0.042
 ICU length of stay (d) 20 (12–36) 23 (11–36) 20 (14–36) 0.707 19 (14–33) 20 (12–37) 0.740
 Invasive mechanical ventilation duration (d) 18 (10–34) 17 (10–33) 18 (10–35) 0.728 17 (13–33) 18 (10–35) 0.922
 Coma
  Awakening
   Number of patients 43 (83) 16 (64) 27 (100) < 0.001 12 (71) 31 (89) 0.133
   Delayed, n = 43 29 (67) 12 (75) 17 (63) 0.416 10 (83) 19 (61) 0.279
   Delay (d), n = 43 4 (1–13) 6 (1–17) 2 (0–10) 0.579 9 (4–12) 2 (0–13) 0.392
  Duration (d)
   All patients 13 (8–26) 14 (10–24) 13 (6–28) 0.667 13 (11–24) 13 (6–28) 0.661
   Awakened patients only, n = 43 13 (8–26) 17 (11–25) 13 (6–28) 0.546 17 (12–24) 12 (6–28) 0.343
 Delirium, n = 43
  Delirium 32 (74) 12 (75) 20 (74) 0.946 11 (92) 21 (68) 0.139
  Type of delirium
   Hyperactive 4 (12) 0 (0) 4 (20) 0.110 0 (0) 4 (19) 0.091
   Hypoactive 8 (25) 5 (42) 3 (15) 5 (45) 3 (14)
   Mixed 20 (62) 7 (58) 13 (65) 6 (55) 14 (67)
  Duration (d), n = 32 5 (3–8) 8 (5–8) 3 (2–6) 0.026 6 (4–8) 4 (3–8) 0.484
Outcomes at day 28 from assessment
 Mortality 11 (21) 10 (40) 1 (4) 0.001 7 (41) 4 (11) 0.027
 Ventilator-free days (d) 6 (0–20) 0 (0–14) 17 (0–22) 0.010 0 (0–14) 16 (0–22) 0.025
 Coma-free days (d) 14 (0–25) 1 (0–13) 22 (12–26) < 0.001 6 (0–13) 22 (2–26) 0.006
 Delirium-free days (d) 12 (0–22) 0 (0–9) 17 (12–25) 0.001 0 (0–9) 17 (0–25) 0.006
EEG = electroencephalography.
Statistics presented: median (interquartile range); n (%). Statistical tests performed: Mann-Whitney U test; Fisher exact test; and χ2 of independence.

TABLE 4. - Univariate Associations Between Day-28 Outcomes and Brainstem Dysfunction, EEG Patterns, and Sedatives/Opioids Exposure
Dependent VariableIndependent Variable Mortality Coma-Free Days Delirium-Free Days
Area Under the Receiver Operating Characteristic Curve (95% CI) p R 2 p R 2 p
Brainstem dysfunction 0.64 (0.49–0.8) 0.101 0.11 0.015 0.13 0.008
Discontinuous EEG 0.77 (0.66–0.89) 0.009 0.22 0.001 0.22 < 0.001
Nonreactive EEG 0.7 (0.53–0.86) 0.02 0.13 0.008 0.16 0.004
Bifrontal slow waves 0.65 (0.53–0.77) 0.09 0.1 0.021 0.14 0.007
Sedatives infusion rate 0.67 (0.52–0.83) 0.204 0.01 0.421 0.01 0.584
Opioid infusion rate 0.62 (0.44–0.81) 0.398 0.01 0.414 0 0.637
Sedative cumulative dose 0.49 (0.29–0.68) 0.651 0 0.723 0 0.994
Opioid cumulative dose 0.5 (0.3–0.7) 0.829 0.01 0.623 0 0.828
Sedative and opioid duration 0.54 (0.36–0.72) 0.839 0 0.79 0 0.911
EEG = electroencephalography.
Area under the receiver operating characteristic curve with 95% CI and p from logistic regressions between day-28 mortality (dependent variable) and each independent variable (brainstem dysfunction, EEG patterns, and sedative/opioid exposure variables). R2 (measure of explained variance) and corresponding p values from liner regressions between coma-free days and delirium-free days and each independent variable.

Second, we adjusted time-to-event analyses on sedatives/opioids exposure. Whether adjusted on infusions rates, cumulative doses or duration alone (Supplementary Table 6, https://links.lww.com/CCM/H26), or all at the same time (Supplementary Table 7, https://links.lww.com/CCM/H26), discontinuous and nonreactive EEG backgrounds remained independently associated with lower cumulative incidences of survival at day 28 (aHR, 14.95 [1.37–163.16]; p = 0.027 and 3.74 [1.06–13.17]; p = 0.04, respectively). Brain stem dysfunction and discontinuous EEG background were also significantly associated with a lower cumulative incidence of delirium recovery (aHR, 0.37 [0.15–0.89]; p = 0.026 and 0.32 [0.14–0.71]; p = 0.005, respectively) within 28 days of T1 assessment (Fig. 1; Supplementary Fig. 5 and Supplementary Table 5, https://links.lww.com/CCM/H26), whereas bifrontal slow waves were associated with a higher cumulative incidence of delirium recovery (aHR, 2.84 [1.35–5.96]; p = 0.006) at day 28.

Finally, after adjusting for nonneurologic SOFA at T1 in addition to sedatives/opioids exposure, brainstem dysfunction remained independently associated with day-14 coma and delirium recovery, nonreactive EEG with day-28 survival and discontinuous EEG with day-28 survival, coma, and delirium recovery, suggesting that clinical features and electrophysiology patterns of brain dysfunction association with outcomes were independent of organ dysfunction (Supplementary Table 8, https://links.lww.com/CCM/H26).

DISCUSSION

The main findings of this prospective observational study are the high frequency of acute brain dysfunction and EEG abnormalities in COVID-19 critically ill patients with ARDS. More importantly, early discontinuous and/or nonreactive EEG backgrounds were associated with both mortality and neurologic outcomes. Finally, patients frequently exhibited a brain stem dysfunction that was also associated with short-term neurologic outcomes.

Our results are coherent with the literature reporting a particularly high rate of protracted coma and delirium (8,30), predominantly of hyperactive or mixed motoric subtype (31), in contrast with non-COVID-19 patients (32), also we potentially underestimated the prevalence of acute encephalopathy as nonincluded eligible patients had more comorbid conditions and were more severe than the included patients. Nevertheless, our results raise the question of the long-term impact of COVID-19–related delirium, as both ARDS and delirium are detrimental to long-term cognition (33–35) and reports of lasting cognitive symptoms in postacute COVID-19 are accumulating (36).

Predicting subsequent delirium to set up preventive and therapeutic strategies is thus of prime interest, and our findings indicate that an early standard EEG, widely available and noninvasive, could be helpful to do so. EEG abnormalities have been described in up to 96.1% of COVID-19 patients (37), ranging from seizure to focal or diffuse periodic/rhythmic discharges or slowing (38), the most frequent being frontal slowing or discharge, associated with severe cases (39). Although we found a similar rate of patients with bifrontal slowing (one-third), these were associated with a better outcome than other pathologic patterns in our study, in accordance with a recent study in which intermittent slow waves were associated with survival (40). Interestingly, these anterior slow waves were observed regardless of the EEG timing, in contrast with the other pathologic patterns, which dwindled during the stay. Most of the previous studies were retrospective (20), included heterogeneous populations in terms of COVID-19 severity and features (40), whereas we prospectively focused on an homogenous cohort of critically ill patients. Interestingly, a study in a similar population reported a high prevalence of low voltage, rapid rhythm, and bifrontal slow EEG activity but did not assess the relationship of EEG patterns with outcome (8). A recent retrospective study of 33 critically ill COVID-19 patients found that nonreactive EEG was associated with unfavorable neurologic outcome (20). Our study confirms prospectively that EEG helps predicting mortality and neurologic outcomes. Although our conclusions are limited to COVID-19 patients due to the lack of control population, these results are reminiscent of the EEG abnormalities previously reported in septic-sedated critically ill patients, with a roughly similar prognostic value (16–19), as it is also the case for the brainstem dysfunction (26,41). As EEG rhythms arise from complex corticosubcortical interactions through thalamocortical loops receiving inputs from the brainstem, these results together with brain-imaging (42,43) and neuropathological studies (9–11,44,45) suggest common pathophysiological pathways involving subcortical structures shared by COVID-19 and non-COVID-19 septic patients (46). Rather than stemming from a direct tropism of SARS-CoV-2, COVID-19–related acute brain injury would result from multifactorial unspecific mechanisms associating neuroinflammatory processes triggered by systemic inflammatory response (47) such as cytokine release syndrome (48) and endothelial activation (49) with other well-recognized risk factors of delirium such as metabolic disorders, organ dysfunction, and sedation (50). Regarding the latter, we found that acute brainstem dysfunction and EEG patterns remained associated with subsequent occurrence of delirium and ICU mortality, after adjustment on either sedatives/opioids infusion rates, cumulative doses, or duration. Although we tried to minimize sedation exposure with a goal-directed nurse-protocolized sedation protocol as recommended (24), these findings do not rule out any contribution of sedation, as it is well-established that deep sedation is a risk factor of delirium and death (51–54). These multivariate analyses indicate, however, that EEG and clinical assessment of brainstem responses have a prognosis value per se, mainly because they enable to detect brain-insulting processes despite deep sedation. Another limitation of our study is the use of benzodiazepine, which is recognized as an independent factor of delirium and delayed awakening, as a first-line sedative agent. This is, however, in agreement with recent studies showing that midazolam was used in two-third of patients with severe COVID-19 (31) with the need of higher dose and longer infusion than in non-COVID-19 ARDS (55). The risk of propofol infusion syndrome in patients with severe ARDS could account for the reluctance to use propofol as a first-line sedative agent, which has also been associated with delirium occurrence. Some patients also received interleukin-6 inhibitors, but we could not determine if this treatment had a neuroprotective effect due to the limited number of patients. Finally, almost all patients were treated with NMB due to the severity of ARDS, potentially limiting the generalizability of our results to the most severe patients. Yet, we believe that they are clinically relevant as critically ill adults with COVID frequently have moderate-to-severe ARDS requiring prolonged deep sedation and NMB (56).

CONCLUSIONS

Clinical and neurophysiological brain dysfunctions are frequent in critically ill COVID-19 patients with ARDS. Early nonreactive and/or discontinuous EEG backgrounds are associated with delayed awakening, delirium, and day-28 mortality. An early multimodal neurological assessment could help identifying patients at risk of delirium, who could then be elective to preventive strategies.

F1
Figure 1.:
Time-to-event analyses at day 28 from neurologic assessment according to electroencephalography (EEG) background discontinuity survival probability (A) and cumulative incidences of mechanical ventilation weaning (B), of coma (C), and of delirium (D) recovery according to EEG background discontinuity. Kaplan-Meier curves were used for visual presentation, and Cox proportional hazards models were used to compute the crude and adjusted hazard ratio (HR) and corresponding 95% CIs on sedatives and opioids infusion rates, cumulative doses, and duration at the time of neurologic assessment. Patients were followed for 28 d from the neurologic assessment or up to ICU discharge, whichever came first.

REFERENCES

1. Zou L, Ruan F, Huang M, et al.: SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med. 2020; 382:1177–1179
2. Mao L, Wang M, Chen S, et al.: Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: A retrospective case series study. JAMA Neurol. 2020; 77:683–690
3. Oxley TJ, Mocco J, Majidi S, et al.: Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. 2020; 382:e60
4. Poyiadji N, Shahin G, Noujaim D, et al.: COVID-19–associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology. 2020; 296:E119-E120
5. Kandemirli SG, Dogan L, Sarikaya ZT, et al.: Brain MRI findings in patients in the intensive care unit with COVID-19 infection. Radiology. 2020; 297:E232–E235
6. Nalleballe K, Reddy Onteddu S, Sharma R, et al.: Spectrum of neuropsychiatric manifestations in COVID-19. Brain Behav Immun. 2020; 88:71–74
7. Huang YH, Jiang D, Huang JT: SARS-CoV-2 detected in cerebrospinal fluid by PCR in a case of COVID-19 encephalitis. Brain Behav Immun. 2020; 87:149
8. Helms J, Kremer S, Merdji H, et al.: Delirium and encephalopathy in severe COVID-19: A cohort analysis of ICU patients. Crit Care. 2020; 24:491
9. Matschke J, Lütgehetmann M, Hagel C, et al.: Neuropathology of patients with COVID-19 in Germany: A post-mortem case series. Lancet Neurol. 2020; 19:919–929
10. Wichmann D: Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med. 2020; 173:1030
11. Thakur KT, Miller EH, Glendinning MD, et al.: COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital. Brain. 2021; 144:2696–2708
12. Tasker RC, Menon DK: Critical care and the brain. JAMA. 2016; 315:749–750
13. André-Obadia N, Zyss J, Gavaret M, et al.: Recommendations for the use of electroencephalography and evoked potentials in comatose patients. Neurophysiol Clin. 2018; 48:143–169
14. Claassen J, Taccone FS, Horn P, et al.; Neurointensive Care Section of the European Society of Intensive Care Medicine: Recommendations on the use of EEG monitoring in critically ill patients: Consensus statement from the neurointensive care section of the ESICM. Intensive Care Med. 2013; 39:1337–1351
15. Bongiovanni F, Romagnosi F, Barbella G, et al.: Standardized EEG analysis to reduce the uncertainty of outcome prognostication after cardiac arrest. Intensive Care Med. 2020; 46:963–972
16. Nielsen RM, Urdanibia-Centelles O, Vedel-Larsen E, et al.: Continuous EEG monitoring in a consecutive patient cohort with sepsis and delirium. Neurocrit Care. 2020; 32:121–130
17. Azabou E, Magalhaes E, Braconnier A, et al.; Groupe d’Explorations Neurologiques en Réanimation (GENER): Early standard electroencephalogram abnormalities predict mortality in septic intensive care unit patients. PLoS One. 2015; 10:e0139969
18. Azabou E, Navarro V, Kubis N, et al.: Value and mechanisms of EEG reactivity in the prognosis of patients with impaired consciousness: A systematic review. Crit Care. 2018; 22:184
19. Gilmore EJ, Gaspard N, Choi HA, et al.: Acute brain failure in severe sepsis: A prospective study in the medical intensive care unit utilizing continuous EEG monitoring. Intensive Care Med. 2015; 41:686–694
20. Niguet JP, Tortuyaux R, Garcia B, et al.; Lille Intensive Care and Neurophysiology COVID-19 study group: Neurophysiological findings and their prognostic value in critical COVID-19 patients: An observational study. Clin Neurophysiol. 2021; 132:1009–1017
21. Ranieri VM, Rubenfeld GD, Thompson BT, et al.; ARDS Definition Task Force: Acute respiratory distress syndrome: The Berlin Definition. JAMA. 2012; 307:2526–2533
22. Alhazzani W, Møller MH, Arabi YM, et al.: Surviving Sepsis Campaign: Guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Intensive Care Med. 2020; 46:854–887
23. Papazian L, Aubron C, Brochard L, et al.: Formal guidelines: Management of acute respiratory distress syndrome. Ann Intensive Care. 2019; 9:69
24. Devlin JW, Skrobik Y, Gélinas C, et al.: Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46:e825–e873
25. Wijdicks EF, Bamlet WR, Maramattom BV, et al.: Validation of a new coma scale: The FOUR score. Ann Neurol. 2005; 58:585–593
26. Rohaut B, Porcher R, Hissem T, et al.; Groupe d’Exploration Neurologique en Réanimation (GENER): Brainstem response patterns in deeply-sedated critically-ill patients predict 28-day mortality. PLoS One. 2017; 12:e0176012
27. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. Washington, DC, American Psychiatric Association, 2013
28. Wilson JE, Mart MF, Cunningham C, et al.: Delirium. Nat Rev Dis Primers. 2020; 6:90
29. Ely EW, Inouye SK, Bernard GR, et al.: Delirium in mechanically ventilated patients: Validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001; 286:2703–2710
30. Helms J, Kremer S, Merdji H, et al.: Neurologic features in severe SARS-CoV-2 infection. N Engl J Med. 2020; 382:2268–2270
31. Pun BT, Badenes R, Calle GHL, et al.: Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): A multicentre cohort study. Lancet Respir Med. 2021; 9:239–250
32. Girard TD, Exline MC, Carson SS, et al.: Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018; 379:2506–2516
33. Girard TD, Thompson JL, Pandharipande PP, et al.: Clinical phenotypes of delirium during critical illness and severity of subsequent long-term cognitive impairment: A prospective cohort study. Lancet Respir Med. 2018; 6:213–222
34. Hayhurst CJ, Marra A, Han JH, et al.: Association of hypoactive and hyperactive delirium with cognitive function after critical illness. Crit Care Med. 2020; 48:e480–e488
35. Herridge MS, Chu LM, Matte A, et al.; RECOVER Program Investigators (Phase 1: towards RECOVER); Canadian Critical Care Trials Group: The RECOVER program: Disability risk groups and 1-year outcome after 7 or more days of mechanical ventilation. Am J Respir Crit Care Med. 2016; 194:831–844
36. Rousseau AF, Minguet P, Colson C, et al.: Post-intensive care syndrome after a critical COVID-19: Cohort study from a Belgian follow-up clinic. Ann Intensive Care. 2021; 11:118
37. Kubota T, Gajera PK, Kuroda N: Meta-analysis of EEG findings in patients with COVID-19. Epilepsy Behav. 2021; 115:107682
38. Vellieux G, Sonneville R, Vledouts S, et al.: COVID-19-associated neurological manifestations: An emerging electroencephalographic literature. Front Physiol. 2021; 11:622466
39. Antony AR, Haneef Z: Systematic review of EEG findings in 617 patients diagnosed with COVID-19. Seizure. 2020; 83:234–241
40. Skorin I, Carrillo R, Perez CP, et al.: EEG findings and clinical prognostic factors associated with mortality in a prospective cohort of inpatients with COVID-19. Seizure. 2020; 83:1–4
41. Sharshar T, Porcher R, Siami S, et al.; Paris-Ouest Study Group on Neurological Effect of Sedation (POSGNES): Brainstem responses can predict death and delirium in sedated patients in intensive care unit. Crit Care Med. 2011; 39:1960–1967
42. Azabou E, Rohaut B, Heming N, et al.: Early impairment of intracranial conduction time predicts mortality in deeply sedated critically ill patients: A prospective observational pilot study. Ann Intensive Care. 2017; 7:63
43. Newcombe VFJ, Spindler LRB, Das T, et al.; Cambridge NeuroCovid Imaging Collaborators: Neuroanatomical substrates of generalized brain dysfunction in COVID-19. Intensive Care Med. 2021; 47:116–118
44. von Weyhern CH, Kaufmann I, Neff F, et al.: Early evidence of pronounced brain involvement in fatal COVID-19 outcomes. Lancet. 2020; 395:e109
45. Sharshar T, Gray F, Poron F, et al.: Multifocal necrotizing leukoencephalopathy in septic shock. Crit Care Med. 2002; 30:2371–2375
46. Mazeraud A, Righy C, Bouchereau E, et al.: Septic-associated encephalopathy: A comprehensive review. Neurotherapeutics. 2020; 17:392–403
47. Kox M, Waalders NJB, Kooistra EJ, et al.: Cytokine levels in critically ill patients with COVID-19 and other conditions. JAMA. 2020; 324:1565
48. Perrin P, Collongues N, Baloglu S, et al.: Cytokine release syndrome-associated encephalopathy in patients with COVID-19. Eur J Neurol. 2021; 28:248–258
49. Libby P, Lüscher T: COVID-19 is, in the end, an endothelial disease. Eur Heart J. 2020; 41:3038–3044
50. Sonneville R, de Montmollin E, Poujade J, et al.: Potentially modifiable factors contributing to sepsis-associated encephalopathy. Intensive Care Med. 2017; 43:1075–1084
51. Jaber S, Chanques G, Altairac C, et al.: A prospective study of agitation in a medical-surgical ICU: Incidence, risk factors, and outcomes. Chest. 2005; 128:2749–2757
52. Patel SB, Poston JT, Pohlman A, et al.: Rapidly reversible, sedation-related delirium versus persistent delirium in the intensive care unit. Am J Respir Crit Care Med. 2014; 189:658–665
53. Shehabi Y, Chan L, Kadiman S, et al.; Sedation Practice in Intensive Care Evaluation (SPICE) Study Group investigators: Sedation depth and long-term mortality in mechanically ventilated critically ill adults: A prospective longitudinal multicentre cohort study. Intensive Care Med. 2013; 39:910–918
54. Stephens RJ, Dettmer MR, Roberts BW, et al.: Practice patterns and outcomes associated with early sedation depth in mechanically ventilated patients: A systematic review and meta-analysis. Crit Care Med. 2018; 46:471–479
55. Wongtangman K, Santer P, Wachtendorf LJ, et al.; SICU Optimal Mobilization Team (SOMT) Group: Association of sedation, coma, and in-hospital mortality in mechanically ventilated patients with coronavirus disease 2019-related acute respiratory distress syndrome: A retrospective Cohort study. Crit Care Med. 2021; 49:1524–1534
56. COVID-ICU Group on behalf of the REVA Network and the COVID-ICU Investigators: Clinical characteristics and day-90 outcomes of 4244 critically ill adults with COVID-19: A prospective cohort study. Intensive Care Med. 2021; 47:60–73
Keywords:

acute brain dysfunction; acute respiratory distress syndrome; brainstem; COVID-19; delirium; EEG

Supplemental Digital Content

Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.