Nociception assessment with videopupillometry in deeply sedated intensive care patients: Discriminative and criterion validations.

BACKGROUND: Nociceptive assessment in deeply sedated patients is challenging. Validated instruments are lacking for this unresponsive population. Videopupillometry is a promising tool but has not been established in intensive care settings. AIM/OBJECTIVE: To test the discriminate validity of pupillary dilation reflex (PDR) between non-noxious and noxious procedures for assessing nociception in non-neurological intensive care unit (ICU) patients and to test the criterion validity of pupil dilation using recommended PDR cut-off points to determine nociception. METHODS: A single-centre prospective observational study was conducted in medical-surgical ICU patients. Two independent investigators performed videopupillometer measurements during a non-noxious and a noxious procedure, once a day (up to 7 days), when the patient remained deeply sedated (Richmond Agitation-Sedation Scale score: -5 or -4). The non-noxious procedures consisted of a gentle touch on each shoulder and the noxious procedures were endotracheal suctioning or turning onto the side. Bivariable and multivariable general linear mixed models were used to account for multiple measurements in same patients. Sensitivity and specificity, and areas under the curve of the receiver operating characteristic curve were calculated. RESULTS: Sixty patients were included, and 305 sets of 3 measurements (before, during, and after), were performed. PDR was higher during noxious procedures than before (mean difference between noxious and non-noxious procedures = 31.66%). After testing all variables of patient and stimulation characteristics in bivariable models, age and noxious procedures were kept in the multivariable model. Adjusting for age, noxious procedures (coefficient = -15.14 (95% confidence interval = -20.17 to -15.52, p < 0.001) remained the only predictive factor for higher pupil change. Testing recommended cut-offs, a PDR of >12% showed a sensitivity of 65%, and a specificity of 94% for nociception prediction, with an area under the receiver operating curve of 0.828 (95% confidence interval = 0.779-0.877). CONCLUSIONS: In conclusion, PDR is a potentially appropriate measure to assess nociception in deeply sedated ICU patients, and we suggest considering its utility in daily practices. REGISTRATION: This study was not preregistered in a clinical registry. TWEETABLE ABSTRACT: Pupillometry may help clinicians to assess nociception in deeply sedated ICU patients.

Early processed electroencephalography for the monitoring of deeply sedated mechanically ventilated critically ill patients.

BACKGROUND: Deep sedation may be indicated in the intensive care unit (ICU) for the management of acute organ failure, but leads to sedative-induced delirium. Whether processed electroencephalography (p-EEG) is useful in this setting is unclear. METHODS: We conducted a single-centre observational study of non-neurological ICU patients sedated according to a standardized guideline of deep sedation (Richmond Agitation Sedation Scale [RASS] between -5 and -4) during the acute phase of respiratory and/or cardio-circulatory failure. The SedLine (Masimo Incorporated, Irvine, California) was used to monitor the Patient State Index (PSI) (ranging from 0 to 100, <25 = very deep sedation and >50 = light sedation to full awareness) during the first 72 h of care. Delirium was assessed with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). RESULTS: The median duration of PSI monitoring was 43 h. Patients spent 49% in median of the total PSI monitoring duration with a PSI <25. Patients with delirium (n = 41/97, 42%) spent a higher percentage of total monitored time with PSI <25 (median 67% [19-91] vs. 47% [12.2-78.9]) in non-delirious patients (p .047). After adjusting for the cumulative dose of analgesia and sedation, increased time spent with PSI <25 was associated with higher delirium (odds ratio 1.014; 95% CI 1.001-1.027, p = .036). CONCLUSIONS: A clinical protocol of deep sedation targeted to RASS at the acute ICU phase may be associated with prolonged EEG suppression and increased delirium. Whether PSI-targeted sedation may help reducing sedative dose and delirium deserves further clinical investigation. RELEVANCE TO CLINICAL PRACTICE: Patients requiring deep sedation are at high risk of being over-sedated and developing delirium despite the application of an evidence-based sedation guideline. Development of early objective measures are essential to improve sedation management in these critically ill patients.

Cerebral Metabolic Dysfunction at the Acute Phase of Traumatic Brain Injury Correlates with Long-Term Tissue Loss.

Following traumatic brain injury (TBI), cerebral metabolic dysfunction, characterized by an elevated cerebral microdialysis (CMD) lactate/pyruvate (LP) ratio, is associated with poor outcome. However, the exact pathophysiological mechanisms underlying this association are not entirely established. In this pre-planned analysis of the BIOmarkers of AXonal injury after Traumatic Brain Injury (BIO-AX-TBI) prospective study, we investigated any associations of LP ratio with brain structure volume change rates at 1 year. Fourteen subjects underwent acute-phase (0-96 h post-TBI) CMD monitoring and had longitudinal magnetic resonance imaging (MRI) quantification of brain volume loss between the subacute phase (14 days to 6 weeks) and 1 year after TBI, recalculated as an annual rate. On average, CMD showed an elevated (>25) LP ratio (31 [interquartile range (IQR) 24-34]), indicating acute cerebral metabolic dysfunction. Annualized whole brain and total gray matter (GM) volume change rates were abnormally reduced (-3.2% [-9.3 to -2.2] and -1.9% [-4.4 to 1.7], respectively). Reduced annualized total GM volume correlated significantly with elevated CMD LP ratio (Spearman's ρ = -0.68, p-value = 0.01) and low CMD glucose (ρ = 0.66, p-value = 0.01). After adjusting for age, admission Glasgow Coma Scale (GCS) score and CT Marshall score, CMD LP ratio remained strongly associated with 1-year total GM volume change rate (p < 0.001; multi-variable analysis). No relationship was found between WM volume changes and CMD metabolites. We demonstrate a strong association between acute post-traumatic cerebral metabolic dysfunction and 1-year gray matter atrophy, reinforcing the role of CMD LP ratio as an early biomarker of poor long-term recovery after TBI.

Neurological Pupil Index for the Early Prediction of Outcome in Severe Acute Brain Injury Patients.

In this study, we examined the early value of automated quantitative pupillary examination, using the Neurological Pupil index (NPi), to predict the long-term outcome of acute brain injured (ABI) patients. We performed a single-centre retrospective study (October 2016−March 2019) in ABI patients who underwent NPi measurement during the first 3 days following brain insult. We examined the performance of NPi­alone or in combination with other baseline demographic (age) and radiologic (CT midline shift) predictors­to prognosticate unfavourable 6-month outcome (Glasgow Outcome Scale 1−3). A total of 145 severely brain-injured subjects (65 traumatic brain injury, TBI; 80 non-TBI) were studied. At each time point tested, NPi <3 was highly predictive of unfavourable outcome, with highest specificity (100% (90−100)) at day 3 (sensitivity 24% (15−35), negative predictive value 36% (34−39)). The addition of NPi, from day 1 following ABI to age and cerebral CT scan, provided the best prognostic performance (AUROC curve 0.85 vs. 0.78 without NPi, p = 0.008; DeLong test) for 6-month neurological outcome prediction. NPi, assessed at the early post-injury phase, has a superior ability to predict unfavourable long-term neurological outcomes in severely brain-injured patients. The added prognostic value of NPi was most significant when complemented with baseline demographic and radiologic information.

Factors Associated With Brain Tissue Oxygenation Changes After RBC Transfusion in Acute Brain Injury Patients.

OBJECTIVES: Anemia is common after acute brain injury and can be associated with brain tissue hypoxia. RBC transfusion (RBCT) can improve brain oxygenation; however, predictors of such improvement remain unknown. We aimed to identify the factors associated with PbtO2 increase (greater than 20% from baseline value) after RBCT, using a generalized mixed model. DESIGN: This is a multicentric retrospective cohort study (2012-2020). SETTING: This study was conducted in three European ICUs of University Hospitals located in Belgium, Switzerland, and Austria. PATIENTS: All patients with acute brain injury who were monitored with brain tissue oxygenation (PbtO2) catheters and received at least one RBCT. INTERVENTION: Patients received at least one RBCT. PbtO2 was recorded before, 1 hour, and 2 hours after RBCT. MEASUREMENTS AND MAIN RESULTS: We included 69 patients receiving a total of 109 RBCTs after a median of 9 days (5-13 d) after injury. Baseline hemoglobin (Hb) and PbtO2 were 7.9 g/dL [7.3-8.7 g/dL] and 21 mm Hg (16-26 mm Hg), respectively; 2 hours after RBCT, the median absolute Hb and PbtO2 increases from baseline were 1.2 g/dL [0.8-1.8 g/dL] (p = 0.001) and 3 mm Hg (0-6 mm Hg) (p = 0.001). A 20% increase in PbtO2 after RBCT was observed in 45 transfusions (41%). High heart rate (HR) and low PbtO2 at baseline were independently associated with a 20% increase in PbtO2 after RBCT. Baseline PbtO2 had an area under receiver operator characteristic of 0.73 (95% CI, 0.64-0.83) to predict PbtO2 increase; a PbtO2 of 20 mm Hg had a sensitivity of 58% and a specificity of 73% to predict PbtO2 increase after RBCT. CONCLUSIONS: Lower PbtO2 values and high HR at baseline could predict a significant increase in brain oxygenation after RBCT.

Hypertonic lactate for the treatment of intracranial hypertension in patients with acute brain injury.

Hypertonic lactate (HL) is emerging as alternative treatment of intracranial hypertension following acute brain injury (ABI), but comparative studies are limited. Here, we examined the effectiveness of HL on main cerebral and systemic physiologic variables, and further compared it to that of standard hypertonic saline (HS). Retrospective cohort analysis of ABI subjects who received sequential osmotherapy with 7.5% HS followed by HL-given at equi-osmolar (2400 mOsmol/L) and isovolumic (1.5 mL/kg) bolus doses-to reduce sustained elevations of ICP (> 20 mmHg). The effect of HL on brain (intracranial pressure [ICP], brain tissue PO2 [PbtO2], cerebral microdialysis [CMD] glucose and lactate/pyruvate ratio [LPR]) and blood (chloride, pH) variables was examined at different time-points (30, 60, 90, 120 min vs. baseline), and compared to that of HS. A total of 34 treatments among 17 consecutive subjects (13 traumatic brain injury [TBI], 4 non-TBI) were studied. Both agents significantly reduced ICP (p < 0.001, at all time-points tested): when comparing treatment effectiveness, absolute ICP decrease in mmHg and the duration of treatment effect (median time with ICP < 20 mmHg following osmotherapy 183 [108-257] vs. 150 [111-419] min) did not differ significantly between HL and HS (all p > 0.2). None of the treatment had statistically significant effects on PbtO2 and CMD biomarkers. Treatment with HL did not cause hyperchloremia and resulted in a more favourable systemic chloride balance than HS (Δ blood chloride - 1 ± 2.5 vs. + 4 ± 3 mmol/L; p < 0.001). This is the first clinical study showing that HL has comparative effectiveness than HS for the treatment of intracranial hypertension, while at the same time avoiding hyperchloremic acidosis. Both agents had no significant effect on cerebral oxygenation and metabolism.

Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury.

Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication.

Sensitivity of Rapid Antigen Testing and RT-PCR Performed on Nasopharyngeal Swabs versus Saliva Samples in COVID-19 Hospitalized Patients: Results of a Prospective Comparative Trial (RESTART).

Saliva sampling could serve as an alternative non-invasive sample for SARS-CoV-2 diagnosis while rapid antigen tests (RATs) might help to mitigate the shortage of reagents sporadically encountered with RT-PCR. Thus, in the RESTART study we compared antigen and RT-PCR testing methods on nasopharyngeal (NP) swabs and salivary samples. We conducted a prospective observational study among COVID-19 hospitalized patients between 10 December 2020 and 1 February 2021. Paired saliva and NP samples were investigated by RT-PCR (Cobas 6800, Roche-Switzerland, Basel, Switzerland) and by two rapid antigen tests: One Step Immunoassay Exdia® COVID-19 Ag (Precision Biosensor, Daejeon, Korea) and Standard Q® COVID-19 Rapid Antigen Test (Roche-Switzerland). A total of 58 paired NP-saliva specimens were collected. A total of 32 of 58 (55%) patients were hospitalized in the intensive care unit, and the median duration of symptoms was 11 days (IQR 5-19). NP and salivary RT-PCR exhibited sensitivity of 98% and 69% respectively, whereas the specificity of these RT-PCRs assays was 100%. The NP RATs exhibited much lower diagnostic performance, with sensitivities of 35% and 41% for the Standard Q® and Exdia® assays, respectively, when a wet-swab approach was used (i.e., when the swab was diluted in the viral transport medium (VTM) before testing). The sensitivity of the dry-swab approach was slightly better (47%). These antigen tests exhibited very low sensitivity (4% and 8%) when applied to salivary swabs. Nasopharyngeal RT-PCR is the most accurate test for COVID-19 diagnosis in hospitalized patients. RT-PCR on salivary samples may be used when nasopharyngeal swabs are contraindicated. RATs are not appropriate for hospitalized patients.

Neuromonitoring of delirium with quantitative pupillometry in sedated mechanically ventilated critically ill patients.

BACKGROUND: Intensive care unit (ICU) delirium is a frequent secondary neurological complication in critically ill patients undergoing prolonged mechanical ventilation. Quantitative pupillometry is an emerging modality for the neuromonitoring of primary acute brain injury, but its potential utility in patients at risk of ICU delirium is unknown. METHODS: This was an observational cohort study of medical-surgical ICU patients, without acute or known primary brain injury, who underwent sedation and mechanical ventilation for at least 48 h. Starting at day 3, automated infrared pupillometry-blinded to ICU caregivers-was used for repeated measurement of the pupillary function, including quantitative pupillary light reflex (q-PLR, expressed as % pupil constriction to a standardized light stimulus) and constriction velocity (CV, mm/s). The relationship between delirium, using the CAM-ICU score, and quantitative pupillary variables was examined. RESULTS: A total of 59/100 patients had ICU delirium, diagnosed at a median 8 (5-13) days from admission. Compared to non-delirious patients, subjects with ICU delirium had lower values of q-PLR (25 [19-31] vs. 20 [15-28] %) and CV (2.5 [1.7-2.8] vs. 1.7 [1.4-2.4] mm/s) at day 3, and at all additional time-points tested (p < 0.05). After adjusting for the SOFA score and the cumulative dose of analgesia and sedation, lower q-PLR was associated with an increased risk of ICU delirium (OR 1.057 [1.007-1.113] at day 3; p = 0.03). CONCLUSIONS: Sustained abnormalities of quantitative pupillary variables at the early ICU phase correlate with delirium and precede clinical diagnosis by a median 5 days. These findings suggest a potential utility of quantitative pupillometry in sedated mechanically ventilated ICU patients at high risk of delirium.

Modulation of cerebral ketone metabolism following traumatic brain injury in humans.

Adaptive metabolic response to injury includes the utilization of alternative energy substrates - such as ketone bodies (KB) - to protect the brain against further damage. Here, we examined cerebral ketone metabolism in patients with traumatic brain injury (TBI; n = 34 subjects) monitored with cerebral microdialysis to measure total brain interstitial tissue KB levels (acetoacetate and ß-hydroxybutyrate). Nutrition - from fasting vs. stable nutrition state - was associated with a significant decrease of brain KB (34.7 [10th-90th percentiles 10.7-189] µmol/L vs. 13.1 [6.5-64.3] µmol/L, p < 0.001) and blood KB (668 [168.4-3824.9] vs. 129.4 [82.6-1033.8] µmol/L, p < 0.01). Blood KB correlated with brain KB (Spearman's rho 0.56, p = 0.0013). Continuous feeding with medium-chain triglycerides-enriched enteral nutrition did not increase blood KB, and provided a modest increase in blood and brain free medium chain fatty acids. Higher brain KB at the acute TBI phase correlated with age and brain lactate, pyruvate and glutamate, but not brain glucose. These novel findings suggest that nutritional ketosis was the main determinant of cerebral KB metabolism following TBI. Age and cerebral metabolic distress contributed to brain KB supporting the hypothesis that ketones might act as alternative energy substrates to glucose. Further studies testing KB supplementation after TBI are warranted.

Neurological Pupil index for Early Prognostication After Venoarterial Extracorporeal Membrane Oxygenation.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation therapy (VA-ECMO) after refractory cardiogenic shock or cardiac arrest has significant morbidity and mortality. Early outcome prediction is crucial in this setting, but data on neuroprognostication are limited. We examined the prognostic value of clinical neurologic examination, using an automated device for the quantitative measurement of pupillary light reactivity. METHODS: An observational cohort of sedated, mechanically ventilated VA-ECMO patients was analyzed during the early phase after ECMO insertion (first 72 h). Using the NPi-200 automated infrared pupillometer, pupillary light reactivity was assessed repeatedly (every 12 h) by calculating the Neurological Pupil index (NPi). Trends of NPi over time were correlated to 90-day mortality, and the prognostic performance of the NPi, alone and in combination with the 12-h PREDICT VA-ECMO score, was evaluated. RESULTS: One hundred consecutive patients were studied (51 with refractory cardiogenic shock and 49 with refractory cardiac arrest; 12-h PREDICT VA-ECMO, 40%; observed 90-day survival, 43%). Nonsurvivors (n = 57) had significantly lower NPi than did survivors at all time points (all P < .01). Abnormal NPi (< 3, at any time from 24 to 72 h) was 100% specific for 90-day mortality, with 0% false positives. Adding the 12-h PREDICT VA-ECMO score to the NPi provided the best prognostic performance (specificity, 100% [95% CI, 92%-100%]; sensitivity, 60% [95% CI, 46%-72%]; area under the receiver operating characteristic curve, 0.82). CONCLUSIONS: Quantitative NPi alone had excellent ability to predict a poor outcome from day 1 after VA-ECMO insertion, with no false positives. Combining NPi and 12-h PREDICT-VA ECMO score increased the sensitivity of outcome prediction, while maintaining 100% specificity.

Discovery and validation of temporal patterns involved in human brain ketometabolism in cerebral microdialysis fluids of traumatic brain injury patients.

BACKGROUND: Traumatic brain injury (TBI) is recognized as a metabolic disease, characterized by acute cerebral glucose hypo-metabolism. Adaptive metabolic responses to TBI involve the utilization of alternative energy substrates, such as ketone bodies. Cerebral microdialysis (CMD) has evolved as an accurate technique allowing continuous sampling of brain extracellular fluid and assessment of regional cerebral metabolism. We present the successful application of a combined hypothesis- and data-driven metabolomics approach using repeated CMD sampling obtained routinely at patient bedside. Investigating two patient cohorts (n = 26 and n = 12), we identified clinically relevant metabolic patterns at the acute post-TBI critical care phase. METHODS: Clinical and CMD metabolomics data were integrated and analysed using in silico and data modelling approaches. We used both unsupervised and supervised multivariate analysis techniques to investigate structures within the time series and associations with patient outcome. FINDINGS: The multivariate metabolite time series exhibited two characteristic brain metabolic states that were attributed to changes in key metabolites: valine, 4-methyl-2-oxovaleric acid (4-MOV), isobeta-hydroxybutyrate (iso-bHB), tyrosyine, and 2-ketoisovaleric acid (2-KIV). These identified cerebral metabolic states differed significantly with respect to standard clinical values. We validated our findings in a second cohort using a classification model trained on the cerebral metabolic states. We demonstrated that short-term (therapeutic intensity level (TIL)) and mid-term patient outcome (6-month Glasgow Outcome Score (GOS)) can be predicted from the time series characteristics. INTERPRETATION: We identified two specific cerebral metabolic patterns that are closely linked to ketometabolism and were associated with both TIL and GOS. Our findings support the view that advanced metabolomics approaches combined with CMD may be applied in real-time to predict short-term treatment intensity and long-term patient outcome.

Protocolized Brain Oxygen Optimization in Subarachnoid Hemorrhage.

BACKGROUND: Brain tissue hypoxia (PbtO2 < 20 mmHg) is common after subarachnoid hemorrhage (SAH) and associated with poor outcome. Recent data suggest that brain oxygen optimization is feasible and reduces the time spent with PbtO2 < 20 mmHg from 45 to 16% in patients with severe traumatic brain injury. Here, we intended to quantify the brain tissue hypoxia burden despite implementation of a protocolized treatment approach in poor-grade SAH patients and to identify the simultaneous occurrence of pathologic values potentially amenable to treatment. METHODS: We present a bi-centric observational cohort study including 100 poor-grade SAH patients admitted to two tertiary care centers who underwent multimodal brain monitoring and were managed with a PbtO2-targeted protocolized approach. PbtO2 optimization (≥ 20 mmHg) included a stepwise neuro-intensive care approach, aiming to prevent low cerebral perfusion pressure (CPP), and blood hemoglobin, and to keep normocapnia, normoxemia, and normothermia. Based on routine blood gas analysis, hemoglobin, PaCO2, and PaO2 data were matched to 2-h averaged data of continuous CPP, PbtO2, core temperature, and to hourly cerebral microdialysis (CMD) samples over the first 11 days. RESULTS: Patients had a Glasgow Coma Scale of 3 (IQR 3-4) and were 58 years old (IQR 48-66). Overall incidence of brain tissue hypoxia was 25%, which was not different between both sites despite differences in the treatment approach. During brain tissue hypoxia, episodes of CPP < 70 mmHg (27%), PaCO2 < 35 mmHg (19%), PaO2 < 80 mmHg (14%), Hb < 9 g/dL (11%), metabolic crisis (CMD-lactate/pyruvate ratio > 40, and CMD-glucose < 0.7 mmol/L; 7%), and temperature > 38.3 °C (4%) were common. CONCLUSIONS: Our results demonstrate that brain tissue hypoxia remains common despite implementation of a PbtO2-targeted therapy in poor-grade SAH patients, suggesting room for further optimization.

Quantitative pupillometry for the monitoring of intracranial hypertension in patients with severe traumatic brain injury.

BACKGROUND: Elevated intracranial pressure (ICP) is frequent after traumatic brain injury (TBI) and may cause abnormal pupillary reactivity, which in turn is associated with a worse prognosis. Using automated infrared pupillometry, we examined the relationship between the Neurological Pupil index (NPi) and invasive ICP in patients with severe TBI. METHODS: This was an observational cohort of consecutive subjects with severe TBI (Glasgow Coma Scale [GCS] < 9 with abnormal lesions on head CT) who underwent parenchymal ICP monitoring and repeated NPi assessment with the NPi-200® pupillometer. We examined NPi trends over time (four consecutive measurements over intervals of 6 h) prior to sustained elevated ICP > 20 mmHg. We further analyzed the relationship of cumulative abnormal NPi burden (%NPi values < 3 during total ICP monitoring time) with intracranial hypertension (ICHT)-categorized as refractory (ICHT-r; requiring surgical decompression) vs. non-refractory (ICHT-nr; responsive to medical therapy)-and with the 6-month Glasgow Outcome Score (GOS). RESULTS: A total of 54 patients were studied (mean age 54 ± 21 years, 74% with focal injuries on CT), of whom 32 (59%) had ICHT. Among subjects with ICHT, episodes of sustained elevated ICP (n = 43, 172 matched ICP-NPi samples; baseline ICP [T- 6 h] 14 ± 5 mmHg vs. ICPmax [T0 h] 30 ± 9 mmHg) were associated with a concomitant decrease of the NPi (baseline 4.2 ± 0.5 vs. 2.8 ± 1.6, p < 0.0001 ANOVA for repeated measures). Abnormal NPi values were more frequent in patients with ICHT-r (n = 17; 38 [3-96]% of monitored time vs. 1 [0-9]% in patients with ICHT-nr [n = 15] and 0.5 [0-10]% in those without ICHT [n = 22]; p = 0.007) and were associated with an unfavorable 6-month outcome (15 [1-80]% in GOS 1-3 vs. 0 [0-7]% in GOS 4-5 patients; p = 0.002). CONCLUSIONS: In a selected cohort of severe TBI patients with abnormal head CT lesions and predominantly focal cerebral injury, elevated ICP episodes correlated with a concomitant decrease of NPi. Sustained abnormal NPi was in turn associated with a more complicated ICP course and worse outcome.

Late Awakening in Survivors of Postanoxic Coma: Early Neurophysiologic Predictors and Association With ICU and Long-Term Neurologic Recovery.

OBJECTIVES: To examine neurophysiologic predictors and outcomes of patients with late awakening following cardiac arrest. DESIGN: Observational cohort study. SETTING: Academic ICU. PATIENTS: Adult comatose cardiac arrest patients treated with targeted temperature management and sedation. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Time to awakening was calculated starting from initial sedation stop following targeted temperature management and rewarming (median 34 hr from ICU admission). Two-hundred twenty-eight of 402 patients (57%) awoke: late awakening (> 48 hr from sedation stop; median time to awakening 5 days [range, 3-23 d]) was observed in 78 subjects (34%). When considering single neurophysiologic tests, late awakening was associated with a higher proportion of discontinuous electroencephalography (21% vs 6% of early awakeners), absent motor and brainstem responses (38% vs 11%; 23 vs 4%, respectively), and serum neuron specific enolase greater than 33 ng/mL (23% vs 8%; all p < 0.01): no patient had greater than 2 unfavorable tests. By multivariable analysis-adjusting for cardiac arrest duration, Sequential Organ Failure Assessment score, and type of sedation-discontinuous electroencephalography and absent neurologic responses were independently associated with late awakening. Late awakening was more frequent with midazolam (58% vs 45%) and was associated with higher rates of delirium (62% vs 39%) and unfavorable 3-months outcome (27% vs 12%; all p = 0.005). CONCLUSIONS: Late awakening is frequent after cardiac arrest, despite early unfavorable neurophysiologic signs and is associated with greater neurologic complications. Limiting benzodiazepines during targeted temperature management may accelerate awakening. Postcardiac arrest patients with late awakening had a high rate of favorable outcome, thereby supporting prognostication strategies relying on multiple rather than single tests and that allow sufficient time for outcome prediction.

Quantitative versus standard pupillary light reflex for early prognostication in comatose cardiac arrest patients: an international prospective multicenter double-blinded study.

PURPOSE: To assess the ability of quantitative pupillometry [using the Neurological Pupil index (NPi)] to predict an unfavorable neurological outcome after cardiac arrest (CA). METHODS: We performed a prospective international multicenter study (10 centers) in adult comatose CA patients. Quantitative NPi and standard manual pupillary light reflex (sPLR)-blinded to clinicians and outcome assessors-were recorded in parallel from day 1 to 3 after CA. Primary study endpoint was to compare the value of NPi versus sPLR to predict 3-month Cerebral Performance Category (CPC), dichotomized as favorable (CPC 1-2: full recovery or moderate disability) versus unfavorable outcome (CPC 3-5: severe disability, vegetative state, or death). RESULTS: At any time between day 1 and 3, an NPi ≤ 2 (n = 456 patients) had a 51% (95% CI 49-53) negative predictive value and a 100% positive predictive value [PPV; 0% (0-2) false-positive rate], with a 100% (98-100) specificity and 32% (27-38) sensitivity for the prediction of unfavorable outcome. Compared with NPi, sPLR had significantly lower PPV and significantly lower specificity (p  < 0.001 at day 1 and 2; p  = 0.06 at day 3). The combination of NPi ≤ 2 with bilaterally absent somatosensory evoked potentials (SSEP; n = 188 patients) provided higher sensitivity [58% (49-67) vs. 48% (39-57) for SSEP alone], with comparable specificity [100% (94-100)]. CONCLUSIONS: Quantitative NPi had excellent ability to predict an unfavorable outcome from day 1 after CA, with no false positives, and significantly higher specificity than standard manual pupillary examination. The addition of NPi to SSEP increased sensitivity of outcome prediction, while maintaining 100% specificity.

Hypertonic Lactate to Improve Cerebral Perfusion and Glucose Availability After Acute Brain Injury.

OBJECTIVES: Lactate promotes cerebral blood flow and is an efficient substrate for the brain, particularly at times of glucose shortage. Hypertonic lactate is neuroprotective after experimental brain injury; however, human data are limited. DESIGN: Prospective study (clinicaltrials.gov NCT01573507). SETTING: Academic ICU. PATIENTS: Twenty-three brain-injured subjects (13 traumatic brain injury/10 subarachnoid hemorrhage; median age, 59 yr [41-65 yr]; median Glasgow Coma Scale, 6 [3-7]). INTERVENTIONS: Three-hour IV infusion of hypertonic lactate (sodium lactate, 1,000 mmol/L; concentration, 30 µmol/kg/min) administered 39 hours (26-49 hr) from injury. MEASUREMENTS AND MAIN RESULTS: We examined the effect of hypertonic lactate on cerebral perfusion (using transcranial Doppler) and brain energy metabolism (using cerebral microdialysis). The majority of subjects (13/23 = 57%) had reduced brain glucose availability (baseline pretreatment cerebral microdialysis glucose, < 1 mmol/L) despite normal baseline intracranial pressure (10 [7-15] mm Hg). Hypertonic lactate was associated with increased cerebral microdialysis lactate (+55% [31-80%]) that was paralleled by an increase in middle cerebral artery mean cerebral blood flow velocities (+36% [21-66%]) and a decrease in pulsatility index (-21% [13-26%]; all p < 0.001). Cerebral microdialysis glucose increased above normal range during hypertonic lactate (+42% [30-78%]; p < 0.05); reduced brain glucose availability correlated with a greater improvement of cerebral microdialysis glucose (Spearman r = -0.53; p = 0.009). No significant changes in cerebral perfusion pressure, mean arterial pressure, systemic carbon dioxide, and blood glucose were observed during hypertonic lactate (all p > 0.1). CONCLUSIONS: This is the first clinical demonstration that hypertonic lactate resuscitation improves both cerebral perfusion and brain glucose availability after brain injury. These cerebral vascular and metabolic effects appeared related to brain lactate supplementation rather than to systemic effects.

Early prediction of coma recovery after cardiac arrest with blinded pupillometry.

OBJECTIVE: Prognostication studies on comatose cardiac arrest (CA) patients are limited by lack of blinding, potentially causing overestimation of outcome predictors and self-fulfilling prophecy. Using a blinded approach, we analyzed the value of quantitative automated pupillometry to predict neurological recovery after CA. METHODS: We examined a prospective cohort of 103 comatose adult patients who were unconscious 48 hours after CA and underwent repeated measurements of quantitative pupillary light reflex (PLR) using the Neurolight-Algiscan device. Clinical examination, electroencephalography (EEG), somatosensory evoked potentials (SSEP), and serum neuron-specific enolase were performed in parallel, as part of standard multimodal assessment. Automated pupillometry results were blinded to clinicians involved in patient care. Cerebral Performance Categories (CPC) at 1 year was the outcome endpoint. RESULTS: Survivors (n = 50 patients; 32 CPC 1, 16 CPC 2, 2 CPC 3) had higher quantitative PLR (median = 20 [range = 13-41] vs 11 [0-55] %, p < 0.0001) and constriction velocity (1.46 [0.85-4.63] vs 0.94 [0.16-4.97] mm/s, p < 0.0001) than nonsurvivors. At 48 hours, a quantitative PLR < 13% had 100% specificity and positive predictive value to predict poor recovery (0% false-positive rate), and provided equal performance to that of EEG and SSEP. Reduced quantitative PLR correlated with higher serum neuron-specific enolase (Spearman r = -0.52, p < 0.0001). INTERPRETATION: Reduced quantitative PLR correlates with postanoxic brain injury and, when compared to standard multimodal assessment, is highly accurate in predicting long-term prognosis after CA. This is the first prognostication study to show the value of automated pupillometry using a blinded approach to minimize self-fulfilling prophecy. Ann Neurol 2017;81:804-810.