This is a single-center, retrospective, observational study of prospectively collected data. The study was carried out during the COVID-19 pandemic, from February 28 through June 30, 2020, at the ICU of the San Martino Policlinico Hospital (SMPH) IRCCS for Oncology and Neurosciences, Genoa, Italy. The SMPH is the main hospital serving both the metropolitan area of Genoa (approximate population 840,000) and the wider Liguria Region (approximate population 1,543,000). The usual ICU capacity is 52 adult beds, increased to 74 during the peak of the SARS-CoV-2 outbreak in Italy. The study protocol followed Good Clinical Practice principles in compliance with the Declaration of Helsinki. Approval was obtained from the Ethics Committee of Liguria, Italy (registry number 163/2020), which waived informed consent for participation because of the retrospective nature of the study.
Patients aged ≥18 years, confirmed positive for SARS-CoV-2 infection by reverse transcriptase-polymerase chain reaction (RT-PCR) of nasopharyngeal swab specimens at the moment of ICU admission, and who were critically ill requiring invasive mechanical ventilation were eligible for inclusion. Patients who were not neurologically evaluable due to life-threatening respiratory failure resulting in use of sedatives were excluded, as were those who died before sedation could be weaned.
The following data were collected from patients’ electronical records at the time of ICU admission: age in years; gender; body mass index (BMI) in kg/m2; sequential organ failure assessment (SOFA) score (24); a series of comorbidities, namely hypertension, diabetes mellitus, respiratory disease (defined as asthma or chronic obstructive pulmonary disease), end-stage renal disease (defined as estimated glomerular filtration rate <15 mL/min/1.73 m2), moderate/severe liver disease (defined as compensated/decompensated liver cirrhosis) (25), and cancer, The highest C-reactive protein (normal range 0-5 mg/L) and D-dimer (normal range 0-500 mcg/L), as well as the lowest partial pressure of oxygen (PaO2) (normal range 72-104 mmHg), were collected from daily test results throughout each patient’s ICU stay. At the time of ICU and hospital discharge, data on ICU length of stay (ICU-LOS) (days), overall hospital LOS (days), duration of mechanical ventilation (days), neurological complications (type and number), and mortality were collected.
The following data were collected from patients who underwent noninvasive neuromonitoring during the day of assessment and throughout their ICU stay: ventilatory parameters [type of ventilation, positive end-expiratory pressure (PEEP) in cmH2O, pressure control or pressure support in cmH2O, respiratory rate in breaths per minute, tidal volume in mL, and fraction of inspired oxygen (FiO2)]; arterial blood gas values [PaO2 in mmHg, partial pressure of carbon dioxide (PaCO2) in mmHg, pH]; vital signs [mean arterial pressure (MAP) in mmHg, heart rate in beats per minute]; sedation (including type of sedative); analgesia (including analgesic agent); and neuromuscular blockade. Neurological complications and scales used for outcome measures are defined in the Electronic Supplemental Material (ESM - Table 1-4).
Noninvasive neuromonitoring systems
Ultrasound measurements were performed by two experienced operators (defined as having received more than 5 years of training and performing more than 70 examinations/year) (DB, CR) and three mentored trainees in Anesthesia and Intensive Care (KC, FI, MB). MAP, heart rate, mean cerebral artery (MCA) flow velocities (diastolic, mean, and systolic), and ONSD were recorded during ICU stay, according to the clinical context and need (availability of personal protective equipment and clinical rationale).
Transcranial doppler (TCD)
A low-frequency (2 MHz) microconvex transducer (Philips SparQ®) was used to investigate intracranial vessels. The temporal window was preferred for passage of the Doppler signal for MCA assessment. Systolic (sFV), diastolic (dFV), and mean flow velocity (mFV) in the MCA were collected. MAP was also measured. The pulsatility index (PI) was calculated as the mean value between the right and left MCA flow velocities using the following formula :
Noninvasive ICP (nICPTCD) was calculated according to the formula:
where cerebral perfusion pressure (CPPe) was calculated as follows (27):
Intracranial pressure (ICP) values > 20 mmHg were considered indicative of intracranial hypertension (27).
Optic nerve sheath diameter (ONSD)
A linear probe (Philips SparQ®) was used for ONSD evaluation. The probe was placed on the closed upper eyelid, and ONSD was evaluated 3 mm behind the retinal papilla. Two measurements were obtained from each optic nerve, the first in the transverse plane and the second in the sagittal plane (28). Noninvasive intracranial pressure measured by ONSD (nICPONSD) was derived from a mathematic formula described elsewhere in the literature (29,30). Again, ICP values > 20 mmHg were considered indicative of intracranial hypertension (27).
Pupillary light reactivity was measured by a handheld quantitative automated pupillometer (Neurolight Algiscan®, ID-MED, Marseille, France) in both eyes. This device measures quantitative variation in pupillary light reactivity by using an infrared camera to record video footage of changes in the pupillary surface. Pupillary light reactivity was assessed by a calibrated light stimulation (320 lux for 1 second) with a precision limit of 0.05 mm. Quantitative reactivity was expressed as the percentage of pupillary light response, and baseline pupil size was expressed in mm. The pupillary constriction velocity (mm/sec) was also reported (31–33). Abnormal pupillary reactivity was defined as an abnormal pupillary light reflex as reported by the pupillometer (e.g., a weaker than normal or “sluggish” pupil response) (34).
The results are expressed as mean ± standard deviation, median, 1st quartile (Q1), 3rd quartile (Q3), interquartile range (IQR), and absolute and relative frequencies. No sample size calculation was performed due to the retrospective design of this study. The Shapiro–Wilk test was used to assess the normality of distribution of continuous variables. The Mann–Whitney U-test was used to compare continuous variables, while categorical variables were compared with Fisher’s exact test. Patient survival was estimated by the Kaplan–Meier method; the log-rank test was used to compare survival curves. Continuous and categorical variables were entered into univariate Cox proportional hazard regression models, which returned regression coefficients and hazard ratios (HRs) with 95% confidence intervals (CIs) as the main outputs. The Efron approximation was used for each Cox model. The proportional hazards assumption for each significant Cox regression model was evaluated using correlation coefficients between transformed survival times and scaled Schoenfeld residuals. Variables significant on univariate Cox regression which satisfied the proportional-hazards assumption were carried forward to the multivariate model. A forest plot and a rank-hazard plot were provided for multivariate regression. The rank-hazard plot is able to visualize the relationship between the relative hazard of variables entered in a multivariate Cox regression model . Logistic regression was performed to assess the risk factors associated with neurological complications. The Hosmer–Lemeshow omnibus test was used for goodness-of-fit evaluation of each significant logistic regression model. Variables significant on univariate logistic regression were entered in the multivariate model, with regression coefficients and odds ratios (ORs) with 95%CIs as the main outputs. A receiver operating characteristic (ROC) curve was calculated for the multivariate logistic regression model, as well as sensitivity and specificity. Statistical significance was accepted at a two-tailed P-value <0.05 for all tests. Statistical analyses were conducted in the R software environment (version 3.6.3; R Foundation for Statistical Computing, Vienna, Austria).