Brainstem responses can predict death and delirium in sedated patients in intensive care unit.

OBJECTIVES: In critically ill patients, the assessment of neurologic function can be difficult because of the use of sedative agents. It is not known whether neurologic signs observed under sedation can predict short-term outcomes. The objective of this study was to assess whether abnormal brainstem responses within the first 24 hrs of sedation are associated with mortality and altered mental status postsedation. DESIGN: Observational prospective study including an initial single-center and a subsequent multicenter study to develop and then validate the prognostic models. SETTING: Three mixed and two medical intensive care units. PATIENTS: Mechanically ventilated intensive care unit patients sedated with midazolam (± sufentanyl). INTERVENTIONS: Neurologic examination including the Glasgow Coma Scale, the Assessment to Intensive Care Environment score, cranial nerve examination, response to noxious stimuli, and the cough reflex was performed. MEASUREMENTS AND MAIN RESULTS: Seventy-two patients were included in the initial group and 72 in a subsequent validation study. Neurologic responses were independent of sedative dose. Twenty-two patients in the development cohort and 21 (29%) in the validation group died within 28 days of inclusion. Adjusted for Simplified Acute Physiology Score II score, absent cough reflex was independently associated with 28-day mortality in the development (adjusted odds ratio [OR], 7.80; 95% confidence interval [CI], 2.00-30.4; p = .003) and validation groups (adjusted OR, 5.44; 95% CI, 1.35-22.0; p = .017). Absent oculocephalic response, adjusted for Simplified Acute Physiology Score II score, was independently associated with altered mental status after the withdrawal of sedation in the development (adjusted OR, 4.54; 95% CI, 1.34-15.4; p = .015) and validation groups (adjusted OR, 6.10; 95% CI, 1.18-25.5; p = .012). CONCLUSIONS: Assessment of brainstem responses is feasible in sedated critically ill patients and loss of selected responses is predictive of mortality and altered mental status.

Early abolition of cough reflex predicts mortality in deeply sedated brain-injured patients.

BACKGROUND: Deep sedation may hamper the detection of neurological deterioration in brain-injured patients. Impaired brainstem reflexes within the first 24 h of deep sedation are associated with increased mortality in non-brain-injured patients. Our objective was to confirm this association in brain-injured patients. METHODS: This was an observational prospective multicenter cohort study involving four neuro-intensive care units. We included acute brain-injured patients requiring deep sedation, defined by a Richmond Assessment Sedation Scale (RASS) < -3. Neurological assessment was performed at day 1 and included pupillary diameter, pupillary light, corneal and cough reflexes, and grimace and motor response to noxious stimuli. Pre-sedation Glasgow Coma Scale (GCS) and Simplified Acute Physiology Score (SAPS-II) were collected, as well as the cause of death in the Intensive Care Unit (ICU). RESULTS: A total of 137 brain-injured patients were recruited, including 70 (51%) traumatic brain-injured patients, 40 (29%) vascular (subarachnoid hemorrhage or intracerebral hemorrhage). Thirty patients (22%) died in the ICU. At day 1, the corneal (OR 2.69, p = 0.034) and cough reflexes (OR 5.12, p = 0.0003) were more frequently abolished in patients that died in the ICU. In a multivariate analysis, abolished cough reflex was associated with ICU mortality after adjustment to pre-sedation GCS, SAPS-II, RASS (OR: 5.19, 95% CI [1.92-14.1], p = 0.001) or dose of sedatives (OR: 8.89, 95% CI [2.64-30.0], p = 0.0004). CONCLUSION: Early (day 1) cough reflex abolition is an independent predictor of mortality in deeply sedated brain-injured patients. Abolished cough reflex likely reflects a brainstem dysfunction that might result from the combination of primary and secondary neuro-inflammatory cerebral insults revealed and/or worsened by sedation.

Early impairment of intracranial conduction time predicts mortality in deeply sedated critically ill patients: a prospective observational pilot study.

BACKGROUND: Somatosensory (SSEP) and brainstem auditory (BAEP) evoked potentials are neurophysiological tools which, respectively, explore the intracranial conduction time (ICCT) and the intrapontine conduction time (IPCT). The prognostic values of prolonged cerebral conduction times in deeply sedated patients have never been assessed. Sedated patients are at risk of developing new neurological complications, undetected. In this prospective observational bi-center pilot study, we investigated whether early impairment of SSEP's ICCT and/or BAEP's IPCT could predict in-ICU mortality or altered mental status (AMS), in deeply sedated critically ill patients. METHODS: SSEP by stimulation of the median nerve and BAEP were assessed in critically ill patients receiving deep sedation on day 3 following ICU admission. Deep sedation was defined by a Richmond Assessment sedation Scale (RASS) <-3. Mean left- and right-side ICCT and IPCT were measured for each patient. Primary and secondary outcomes were, respectively, in-ICU mortality and AMS defined as the occurrence of delirium and/or delayed awakening after discontinuation of sedation. RESULTS: Eighty-six patients were studied of which 49 (57%) were non-brain-injured and 37 (43%) were brain-injured. Impaired ICCT was a predictor of in-ICU mortality after adjustment on the global Sequential Organ Failure Assessment score (SOFA) [OR (95% CI) = 2.69 (1.05-6.85); p = 0.039] and on the non-neurological SOFA components [2.67 (1.05-6.81); p = 0.040]. IPCT was more frequently delayed in the subgroup of patients who developed post-sedation AMS (24%) compared those without AMS (0%). However, this difference did not reach statistical significance (p = 0.053). Impairment rates of ICCT and IPCT were not found to be significantly different between non-brain- and brain-injured subgroups of patients. CONCLUSION: In critically ill patients receiving deep sedation, early ICCT impairment was associated with mortality. Somatosensory and brainstem auditory evoked potentials may be useful early warning indicators of brain dysfunction as well as prognostic markers in deeply sedated critically ill patients.

Brainstem response patterns in deeply-sedated critically-ill patients predict 28-day mortality.

BACKGROUND AND PURPOSE: Deep sedation is associated with acute brain dysfunction and increased mortality. We had previously shown that early-assessed brainstem reflexes may predict outcome in deeply sedated patients. The primary objective was to determine whether patterns of brainstem reflexes might predict mortality in deeply sedated patients. The secondary objective was to generate a score predicting mortality in these patients. METHODS: Observational prospective multicenter cohort study of 148 non-brain injured deeply sedated patients, defined by a Richmond Assessment sedation Scale (RASS) <-3. Brainstem reflexes and Glasgow Coma Scale were assessed within 24 hours of sedation and categorized using latent class analysis. The Full Outline Of Unresponsiveness score (FOUR) was also assessed. Primary outcome measure was 28-day mortality. A "Brainstem Responses Assessment Sedation Score" (BRASS) was generated. RESULTS: Two distinct sub-phenotypes referred as homogeneous and heterogeneous brainstem reactivity were identified (accounting for respectively 54.6% and 45.4% of patients). Homogeneous brainstem reactivity was characterized by preserved reactivity to nociceptive stimuli and a partial and topographically homogenous depression of brainstem reflexes. Heterogeneous brainstem reactivity was characterized by a loss of reactivity to nociceptive stimuli associated with heterogeneous brainstem reflexes depression. Heterogeneous sub-phenotype was a predictor of increased risk of 28-day mortality after adjustment to Simplified Acute Physiology Score-II (SAPS-II) and RASS (Odds Ratio [95% confidence interval] = 6.44 [2.63-15.8]; p<0.0001) or Sequential Organ Failure Assessment (SOFA) and RASS (OR [95%CI] = 5.02 [2.01-12.5]; p = 0.0005). The BRASS (and marginally the FOUR) predicted 28-day mortality (c-index [95%CI] = 0.69 [0.54-0.84] and 0.65 [0.49-0.80] respectively). CONCLUSION: In this prospective cohort study, around half of all deeply sedated critically ill patients displayed an early particular neurological sub-phenotype predicting 28-day mortality, which may reflect a dysfunction of the brainstem.

Hydrocortisone and fludrocortisone for prevention of hospital-acquired pneumonia in patients with severe traumatic brain injury (Corti-TC): a double-blind, multicentre phase 3, randomised placebo-controlled trial.

BACKGROUND: Hospital-acquired pneumonia is common after traumatic brain injury, and might be partly a result of traumatic brain injury-induced adrenal insufficiency. We tested the efficacy of low-dose hydrocortisone with fludrocortisone for the prevention of hospital-acquired pneumonia. METHODS: We did this double-blind, phase 3, placebo-controlled trial in 19 intensive care units in France. We enrolled patients aged 15-65 years in the first 24 h after severe traumatic brain injury (Glasgow coma scale score ≤8 and trauma-associated lesion on brain CT scan). Patients were randomly assigned (1:1; fixed blocks of 12, stratified by centre and mechanism, Glasgow coma scale, age, and arterial pressure [MGAP] score) to receive either hydrocortisone (200 mg per day tapered) and fludrocortisone (50 µg tablet once per day) or matching placebo for 10 days. Before receiving study drug, adrenal function was assessed with a short corticotropin test. Treatment was stopped if patients had no adrenal insufficiency. The primary outcome was the occurrence of hospital-acquired pneumonia within 28 days after randomisation. We did an intention-to-treat analysis and a modified intention-to-treat analysis including only patients with adrenal insufficiency (adjusted for etomidate use). This study is registered with ClinicalTrials.gov, number NCT01093261. FINDINGS: From Sept 1, 2010, to Nov 29, 2012, we enrolled 336 patients (168 assigned to each group). Eight patients withdrew consent. At day 28, 74 of 165 patients (45%) in the steroid group and 87 of 163 (53%) in the placebo group had developed one or more episodes of hospital-acquired pneumonia (hazard ratio [HR] 0.75; 95% CI 0.55-1.03, p=0.07). In intention-to-treat analysis, we recorded 86 episodes of hospital-acquired pneumonia in the steroid group versus 110 in the placebo group (median 0, IQR 0-1 vs median 1, IQR 0-1 cases per patient, p=0.07). In modified intention-to-treat analyses, the HR for hospital-acquired pneumonia with steroids versus placebo was 0.80 (95% CI 0.56-1.14, p=0.22) in patients with adrenal insufficiency, and, in an exploratory preplanned analysis, 0·48 (0·23-1·01; p=0·05) in patients with normal adrenal function. We recorded no adverse events related to treatment. INTERPRETATION: Low-dose hydrocortisone with fludrocortisone did not improve the outcome of patients with traumatic brain injury. However, the study was underpowered because the proportion of patients with hospital-acquired pneumonia in the placebo group was lower than expected. The results were close to statistical significance for efficacy, meaning that further studies are therefore needed. FUNDING: Société Française d'Anesthésie Réanimation.