Amy W. Wozniak

One year outcomes in patients with acute lung injury randomised to initial trophic or full enteral feeding: prospective follow-up of EDEN randomised trial

Objective To evaluate the effect of initial low energy permissive underfeeding (“trophic feeding”) versus full energy enteral feeding (“full feeding”) on physical function and secondary outcomes in patients with acute lung injury. Design Prospective longitudinal follow-up evaluation of the NHLBI ARDS Clinical Trials Network’s EDEN trial Setting 41hospitals in the United States. Participants 525 patients with acute lung injury. Interventions Randomised assignment to trophic or full feeding for up to six days; thereafter, all patients still receiving mechanical ventilation received full feeding. Measurements Blinded assessment of the age and sex adjusted physical function domain of the SF-36 instrument at 12 months after acute lung injury. Secondary outcome measures included survival; physical, psychological, and cognitive functioning; quality of life; and employment status at six and 12 months. Results After acute lung injury, patients had substantial physical, psychological, and cognitive impairments, reduced quality of life, and impaired return to work. Initial trophic versus full feeding did not affect mean SF-36 physical function at 12 months (55 (SD 33) v 55 (31), P=0.54), survival to 12 months (65% v 63%, P=0.63), or nearly all of the secondary outcomes. Conclusion In survivors of acute lung injury, there was no difference in physical function, survival, or multiple secondary outcomes at 6 and 12 month follow-up after initial trophic or full enteral feeding. Trial Registration NCT No 00719446

VOR gain by head impulse video-oculography differentiates acute vestibular neuritis from stroke

Objective Vestibular neuritis is often mimicked by stroke (pseudoneuritis). Vestibular eye movements help discriminate the two conditions. We report vestibulo-ocular reflex (VOR) gain measures in neuritis and stroke presenting acute vestibular syndrome (AVS). Methods Prospective cross-sectional study of AVS (acute continuous vertigo/dizziness lasting >24 h) at two academic centers. We measured horizontal head impulse test (HIT) VOR gains in 26 AVS patients using a video HIT device (ICS Impulse). All patients were assessed within 1 week of symptom onset. Diagnoses were confirmed by clinical examinations, brain magnetic resonance imaging with diffusion-weighted images, and follow-up. Brainstem and cerebellar strokes were classified by vascular territory—posterior inferior cerebellar artery (PICA) or anterior inferior cerebellar artery (AICA). Results Diagnoses were vestibular neuritis (n = 16) and posterior fossa stroke (PICA, n = 7; AICA, n = 3). Mean HIT VOR gains (ipsilesional [standard error of the mean], contralesional [standard error of the mean]) were as follows: vestibular neuritis (0.52 [0.04], 0.87 [0.04]); PICA stroke (0.94 [0.04], 0.93 [0.04]); AICA stroke (0.84 [0.10], 0.74 [0.10]). VOR gains were asymmetric in neuritis (unilateral vestibulopathy) and symmetric in PICA stroke (bilaterally normal VOR), whereas gains in AICA stroke were heterogeneous (asymmetric, bilaterally low, or normal). In vestibular neuritis, borderline gains ranged from 0.62 to 0.73. Twenty patients (12 neuritis, six PICA strokes, two AICA strokes) had at least five interpretable HIT trials (for both ears), allowing an appropriate classification based on mean VOR gains per ear. Classifying AVS patients with bilateral VOR mean gains of 0.70 or more as suspected strokes yielded a total diagnostic accuracy of 90%, with stroke sensitivity of 88% and specificity of 92%. Conclusion Video HIT VOR gains differ between peripheral and central causes of AVS. PICA strokes were readily separated from neuritis using gain measures, but AICA strokes were at risk of being misclassified based on VOR gain alone.

Rosuvastatin versus placebo for delirium in intensive care and subsequent cognitive impairment in patients with sepsis-associated acute respiratory distress syndrome: an ancillary study to a randomised controlled trial

BACKGROUND Delirium is common in mechanically ventilated patients and is associated with cognitive impairment lasting at least 1 year after hospital discharge. Preclinical and observational studies suggest that the use of statins might reduce delirium in intensive care. We assessed whether the pleiotropic effects of statins can reduce delirium in intensive care and decrease subsequent cognitive impairment in a randomised controlled trial. METHODS We did this ancillary study within the SAILS trial, a randomised controlled trial assessing mortality and ventilator-free days for rosuvastatin versus placebo for patients with sepsis-associated acute respiratory distress syndrome. This study was done at 35 hospitals in the USA. Patients were randomly assigned in permuted blocks of eight and stratified by hospital to receive either rosuvastatin (40 mg loading dose and then 20 mg daily until the earliest of 3 days after discharge from intensive care, study day 28, or death) or placebo. Patients and investigators were masked to treatment assignment. Delirium was assessed with the validated Confusion Assessment Method for intensive care. Cognitive function was assessed with tests for executive function, language, verbal reasoning and concept formation, and working, immediate, and delayed memory. We defined cognitive impairment as having one of these domains at least two SDs below population norms or at least two domains at least 1·5 SDs below norms. The primary endpoint was daily delirium status in intensive care up to 28 days in the intention-to-treat population and secondary endpoints were cognitive function at 6 months and 12 months. This trial is registered with ClinicalTrials.gov (NCT00979121 and NCT00719446). FINDINGS 272 patients were assessed for delirium daily in intensive care. The mean proportion of days with delirium was 34% (SD 30%) in the rosuvastatin group versus 31% (29%) in the placebo group; hazard ratio 1·14, 95% CI 0·92-1·41, p=0·22. At 6 months, 19 (36%) of 53 patients in the rosuvastatin group versus 29 (38%) of 77 in the placebo group had cognitive impairment, with no significant difference between groups (treatment effect 0·93, 95% CI 0·39-2·22; p=0·87). At 12 months, 20 (30%) of 67 patients versus 23 (28%) of 81 patients had cognitive impairment, with no significant difference between groups (treatment effect 1·1, 95% CI 0·5-2·6; p=0·82). INTERPRETATION Most patients had delirium, with around a third of survivors having cognitive impairment over 1 year of follow-up. Despite encouraging preclinical and observational studies, this trial shows no benefit of rosuvastatin in reducing delirium in intensive care or cognitive impairment during 12 months of follow-up although the study was not powered for superiority. Thus, there is continued need to evaluate interventions aimed at attenuating intensive care and post-intensive-care cognitive impairments commonly observed in this population. FUNDING National Heart, Lung and Blood Institute; Johns Hopkins Institute for Clinical and Translational Research; the SAILS trial was also supported by AstraZeneca.

One-year outcomes of rosuvastatin versus placebo in sepsis-associated acute respiratory distress syndrome: prospective follow-up of SAILS randomised trial

Background Prior randomised trials have evaluated statins in patients with sepsis and acute respiratory distress syndrome (ARDS), but there has been no comprehensive evaluation of long-term effects, despite potential neuromuscular and mental health adverse effects of these drugs. Aim To evaluate the effect of rosuvastatin versus placebo on survival, physical function and performance, and mental health outcomes in patients with sepsis-associated ARDS. Methods Prospective follow-up evaluation of the ARDS Clinical Trials Network Statins for Acutely Injured Lungs from Sepsis trial of rosuvastatin versus placebo in 568 mechanically ventilated patients with sepsis-associated ARDS, with blinded 6-month outcome assessment performed in the 272 eligible survivors for age-adjusted and sex-adjusted 36-Item Short Form Health Survey (SF-36) physical function and mental health domains, and in 84 eligible survivors for the 6 min walk test, along with secondary outcomes evaluations of survival, and additional patient-reported and performance-based measures at 6-month and 12-month follow-up. Results Over 1-year follow-up, there was no significant difference in cumulative survival in the rosuvastatin versus placebo groups (58% vs 61%; p=0.377), with survivors demonstrating substantial impairments in physical function and mental health. Rosuvastatin versus placebo had no effect (mean treatment effect (95% CI)) on SF-36 physical function (0 (−7 to 8), p=0.939) or mental health (−6 (−12 to 1) p=0.085) domains, 6 min walk distance (per cent predicted: 2 (−9 to 14), p=0.679) or the vast majority of secondary outcomes. Conclusions Over 1-year follow-up, patients with sepsis-associated ARDS had high cumulative mortality, with survivors commonly experiencing impairments in physical functioning and performance, and mental health. Randomisation to rosuvastatin had no effect on these outcomes. Trial registration number NCT00979121 and NCT00719446.

General anxiety symptoms after acute lung injury: Predictors and correlates

OBJECTIVE Acute lung injury (ALI) is common in the intensive care unit (ICU), typically requiring life support ventilation. Survivors often experience anxiety after hospital discharge. We evaluated general anxiety symptoms 3 months after ALI for: (1) associations with patient characteristics and ICU variables, and (2) cross-sectional associations with physical function and quality of life (QOL). METHODS General anxiety was assessed as part of a prospective cohort study recruiting patients from 13 ICUs at four hospitals in Baltimore, MD using the Hospital Anxiety and Depression Scale--Anxiety Subscale (HAD-A), with associations evaluated using multivariable linear and logistic regression models. RESULTS Of 152 patients, 38% had a positive screening test for general anxiety (HAD-A≥8). Pre-ICU body mass index and psychiatric comorbidity were associated with general anxiety (OR, 95% confidence interval (CI): 1.06 (1.00, 1.13) and 3.59 (1.25, 10.30), respectively). No ICU-related variables were associated with general anxiety. General anxiety was associated with the number of instrumental ADL dependencies (Spearmans rho=0.22; p=0.004) and worse overall QOL as measured by EQ-5D visual analog scale (VAS) (rho=-0.34; p<0.001) and utility score (rho=-0.30; p<0.001), and by the SF-36 mental health domain (rho=-0.70; p<0.001) and Mental Component Summary score (rho=-0.73; p<0.001). CONCLUSION Many patients have substantial general anxiety symptoms 3 months after ALI. General anxiety was associated with patient characteristics and impaired physical function and quality of life. Early identification and treatment of general anxiety may enhance physical and emotional function in patients surviving critical illnesses.

Twenty-four hour quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice

Mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (Mecp2) cause most cases of Rett syndrome (RTT). Currently there is no cure for RTT. Abnormal EEGs are found in 100% of RTT cases and are associated with severe sleep dysfunction, the cause of which is not well understood. Mice deficient in MeCP2 protein have been studied and characterized for their neuropathological and behavioral deficits to better understand RTT. With the goal to study the non-ictal EEG correlates in symptomatic Mecp2 KO mice (Mecp2tm1.1Bird/y), and determine novel EEG biomarkers of their reported progressive neurodegeneration, we used 24 h video-EEG/EMG with synchronous in-vivo cortical glutamate biosensor in the frontal cortex. We scored the EEG for activity states and spectral analysis was performed to evaluate correlations to the synchronous extracellular glutamate fluctuations underlying Mecp2 inactivation as compared to WT. Significant alterations in sleep structure due to dark cycle-specific long wake states and poor quality of slow-wave sleep were associated with a significant increase in glutamate loads per activity cycle. The dynamics of the activity-state-dependent physiological rise and fall of glutamate indicative of glutamate homeostasis were significantly altered in the KO mice. Colorimetric quantitation of absolute glutamate levels in frontal cortex also indicated the presence of significantly higher levels in KO. This study for the first time found evidence of uncompensated sleep deprivation-like EEG biomarkers that were associated with glutamate homeostatic dysfunction in the Mecp2 KO mice.

Authors' response to commentaries on rosuvastatin for delirium and cognitive impairment in sepsis-associated acute respiratory distress syndrome

We are encouraged by the interest (1,2) in our publication that evaluated the effect of rosuvastatin vs. placebo on delirium in the intensive care unit (ICU) and subsequent cognitive impairment (3). We appreciate the critique of our publication by Pourafkari et al. (2) commented about our study being underpowered for secondary analyses of cognitive impairment at 6- and 12-month follow-up. We reported a 2% absolute reduction in the proportion of patients with cognitive impairment for rosuvastatin vs. placebo at 6-month follow-up (36% vs. 38%). This 2% reduction was not statistically significant (treatment effect 0.93; 95% confidence interval: 0.39–2.22; P=0.87), which may be due to the study being underpowered (i.e., too few patients to detect such a small effect). However, the subsequent comparison of cognitive impairment at 12-months (30% vs. 28% for rosuvastatin vs. placebo, respectively) and the vast majority of the individual standardized tests used to evaluate cognitive impairment favored placebo relative to rosuvastatin. Hence, to be convinced that the lack of statistical significance at 6 months was attributable to the trial’s sample size, we would have expected non-significant results consistently favoring rosuvastatin, which was not the case.

Corticosteroids and transition to delirium in acute lung injury: multinomial logistic regression analysis accounting for multiple States.

In Devlin et. al.’s editorial (1) on our publication evaluating the association of corticosteroids with transitioning from a “normal” (i.e. non-comatose and non-delirious) state to a delirious state,(2) they noted our exclusion of the competing transitions to coma, intensive care unit (ICU) discharge and death, raising the question of “overestimation of the risk for delirium associated with corticosteroid administration.”(1) To address this question, we used a first order Markov model(3) to estimate the probability of transitioning from a normal, delirious or comatose state on a given day to one of the following 5 states on the next day: normal, delirious, comatose, ICU discharge or death. This model included all consecutive days with delirium or coma assessments, and was fit using a multinomial logistic regression model with robust variance estimates that included the 12 exposure variables in our original multivariable analysis.(2) We allowed the association of corticosteroids (and other exposure variables) with transition to a delirious state to vary based on the subject’s prior state (normal vs. comatose) using statistical interaction terms. In our original analysis,(2) estimating the probability of transitioning from a normal state to a delirious state (reported as 14% (2)) was not the primary goal, instead our focus was on the association of corticosteroids with this transition. When analyzing the data to consider all possible states, as suggested by Devlin et al.,(1) this probability was modestly lower at 11% (see bolded value in Table 1). The complete set of transition probabilities (Table 1), also demonstrates the high probability of delirium when transitioning out of a comatose state. Of 2397 days in which a patient was comatose on the prior day, in 1865 (78%) days patients remained comatose and in 106 (4%) they transitioned to death. In the remaining 426 days where survivors transitioned out of coma, 389 (91%) transitioned to delirium, with only 30 (7%) transitioning to a normal state and 7 (2%) being discharged from ICU. Table 1 Transition probabilities for all possible states from an initial day (day T) to the next day (day T+1) In Table 2, we report our original results(2) versus results from the expanded statistical analysis as previously described. The primary exposure variable, systematic corticosteroids administered on the prior day, was significantly associated with transition to delirium with an odds ratio (95% confidence interval [CI]) of 1.46 (1.02, 2.11, p=0.04) that was very similar to the originally reported value of 1.52 (1.05, 2.21, p=0.03) (2). Therefore, the similar estimate produced by the expanded model, accounting for all states, suggests that the original results did not overestimate the association of corticosteroids with the transition from a normal to a delirious state. Table 2 Patient and ICU variables associated with transition to delirium from a prior normal state