Jeremy R. Beitler

Personalized medicine for ARDS: the 2035 research agenda

In the last 20 years, survival among patients with acute respiratory distress syndrome (ARDS) has increased substantially with advances in lung-protective ventilation and resuscitation. Building on this success, personalizing mechanical ventilation to patient-specific physiology for enhanced lung protection will be a top research priority for the years ahead. However, the ARDS research agenda must be broader in scope. Further understanding of the heterogeneous biology, from molecular to mechanical, underlying early ARDS pathogenesis is essential to inform therapeutic discovery and tailor treatment and prevention strategies to the individual patient. The ARDSne(x)t research agenda for the next 20 years calls for bringing personalized medicine to ARDS, asking simultaneously both whether a treatment affords clinically meaningful benefit and for whom. This expanded scope necessitates standard acquisition of highly granular biological, physiological, and clinical data across studies to identify biologically distinct subgroups that may respond differently to a given intervention. Clinical trials will need to consider enrichment strategies and incorporate long-term functional outcomes. Tremendous investment in research infrastructure and global collaboration will be vital to fulfilling this agenda.

Preventing ARDS: Progress, Promise, and Pitfalls

Advances in critical care practice have led to a substantial decline in the incidence of ARDS over the past several years. Low tidal volume ventilation, timely resuscitation and antimicrobial administration, restrictive transfusion practices, and primary prevention of aspiration and nosocomial pneumonia have likely contributed to this reduction. Despite decades of research, there is no proven pharmacologic treatment of ARDS, and mortality from ARDS remains high. Consequently, recent initiatives have broadened the scope of lung injury research to include targeted prevention of ARDS. Prediction scores have been developed to identify patients at risk for ARDS, and clinical trials testing aspirin and inhaled budesonide/formoterol for ARDS prevention are ongoing. Future trials aimed at preventing ARDS face several key challenges. ARDS has not been validated as an end point for pivotal clinical trials, and caution is needed when testing toxic therapies that may prevent ARDS yet potentially increase mortality.

Obstructive sleep apnea is associated with impaired exercise capacity: A cross-sectional study

OBJECTIVE Obstructive sleep apnea (OSA) is associated with increased risk of adverse cardiovascular events. Because cardiopulmonary exercise testing (CPET) aids in prognostic assessment of heart disease, there is rising interest in its utility for cardiovascular risk stratification of patients with OSA. However, the relationship between OSA and exercise capacity is unclear. This study was conducted to test the hypothesis that OSA is associated with impaired exercise capacity. METHODS Fifteen subjects with moderate-to-severe OSA (apnea-hypopnea index [AHI] ≥15 events/h) and 19 controls with mild or no OSA (AHI <15 events/h) were enrolled. Subjects underwent standard polysomnography to determine AHI and exclude other sleep disorders. Resting metabolic rate was measured via indirect calorimetry, followed by maximum, symptom-limited CPET. Subjects completed a sleep diary and physical activity questionnaire characterizing behaviors in the week prior to testing. RESULTS Percent predicted peak oxygen uptake (V˙O2) was significantly lower in OSA subjects than controls (70.1%±17.5% vs 83.8%±13.9%; p = 0.02). Each 1-unit increase in log-transformed AHI was associated with a decrease in percent predicted peak V˙O2 of 3.20 (95% CI 0.53-5.88; p = 0.02). After adjusting for baseline differences, this association remained significant (p < 0.01). AHI alone explained 16.1% of the variability observed in percent predicted peak V˙O2 (p = 0.02). CONCLUSIONS OSA is associated with impaired exercise capacity. Further study is needed to evaluate the utility of CPET for prognostic assessment of patients with OSA.

Treatment of ARDS With Prone Positioning

Prone positioning was first proposed in the 1970s as a method to improve gas exchange in ARDS. Subsequent observations of dramatic improvement in oxygenation with simple patient rotation motivated the next several decades of research. This work elucidated the physiological mechanisms underlying changes in gas exchange and respiratory mechanics with prone ventilation. However, translating physiological improvements into a clinical benefit has proved challenging; several contemporary trials showed no major clinical benefits with prone positioning. By optimizing patient selection and treatment protocols, the recent Proning Severe ARDS Patients (PROSEVA) trial demonstrated a significant mortality benefit with prone ventilation. This trial, and subsequent meta-analyses, support the role of prone positioning as an effective therapy to reduce mortality in severe ARDS, particularly when applied early with other lung-protective strategies. This review discusses the physiological principles, clinical evidence, and practical application of prone ventilation in ARDS.

Expanding the horizons of histoplasmosis: disseminated histoplasmosis in a renal transplant patient after a trip to Bangladesh.

U. Rappo, J.R. Beitler, J.R. Faulhaber, B. Firoz, J.S. Henning, K.M. Thomas, M. Maslow, D.S. Goldfarb, H.W. Horowitz. Expanding the horizons of histoplasmosis: disseminated histoplasmosis in a renal transplant patient after a trip to Bangladesh.
Transpl Infect Dis 2010: 12: 155–160. All rights reserved

Favorable Neurocognitive Outcome with Low Tidal Volume Ventilation after Cardiac Arrest

Rationale: Neurocognitive outcome after out‐of‐hospital cardiac arrest (OHCA) is often poor, even when initial resuscitation succeeds. Lower tidal volumes (Vts) attenuate extrapulmonary organ injury in other disease states and are neuroprotective in preclinical models of critical illness. Objective: To evaluate the association between Vt and neurocognitive outcome after OHCA. Methods: We performed a propensity‐adjusted analysis of a two‐center retrospective cohort of patients experiencing OHCA who received mechanical ventilation for at least the first 48 hours of hospitalization. Vt was calculated as the time‐weighted average over the first 48 hours, in milliliters per kilogram of predicted body weight (PBW). The primary endpoint was favorable neurocognitive outcome (cerebral performance category of 1 or 2) at discharge. Measurements and Main Results: Of 256 included patients, 38% received time‐weighted average Vt greater than 8 ml/kg PBW during the first 48 hours. Lower Vt was independently associated with favorable neurocognitive outcome in propensity‐adjusted analysis (odds ratio, 1.61; 95% confidence interval [CI], 1.13‐2.28 per 1‐ml/kg PBW decrease in Vt; P = 0.008). This finding was robust to several sensitivity analyses. Lower Vt also was associated with more ventilator‐free days (&bgr; = 1.78; 95% CI, 0.39‐3.16 per 1‐ml/kg PBW decrease; P = 0.012) and shock‐free days (&bgr; = 1.31; 95% CI, 0.10‐2.51; P = 0.034). Vt was not associated with hypercapnia (P = 1.00). Although the propensity score incorporated several biologically relevant covariates, only height, weight, and admitting hospital were independent predictors of Vt less than or equal to 8 ml/kg PBW. Conclusions: Lower Vt after OHCA is independently associated with favorable neurocognitive outcome, more ventilator‐free days, and more shock‐free days. These findings suggest a role for low‐Vt ventilation after cardiac arrest.

Ventilator-induced Lung Injury

Prevention of ventilator-induced lung injury (VILI) can attenuate multiorgan failure and improve survival in at-risk patients. Clinically significant VILI occurs from volutrauma, barotrauma, atelectrauma, biotrauma, and shear strain. Differences in regional mechanics are important in VILI pathogenesis. Several interventions are available to protect against VILI. However, most patients at risk of lung injury do not develop VILI. VILI occurs most readily in patients with concomitant physiologic insults. VILI prevention strategies must balance risk of lung injury with untoward side effects from the preventive effort, and may be most effective when targeted to subsets of patients at increased risk.

CrossTalk opposing view: There is not added benefit to providing permissive hypercapnia in the treatment of ARDS

Current ventilator strategies for acute respiratory distress syndrome (ARDS) aim to impact lung function and clinical outcomes in several ways: low tidal volumes to minimize overdistension, titrated positive end-expiratory pressure (PEEP) to prevent alveolar derecruitment, and recruitment manoeuvres to promote parenchymal homogeneity. Among these interventions, only low tidal volume has been shown definitively to improve mortality from ARDS (Malhotra, 2007). During low tidal volume ventilation, practice varies substantially on whether to allow some degree of alveolar hypoventilation with incidental hypercapnic acidosis (Amato et al. 1998), or to increase respiratory rate to maintain alveolar ventilation, often requiring respiratory rates >30 breaths min−1 (Brower et al. 2000). As the independent effect of hypercapnia has

Personalizing mechanical ventilation for acute respiratory distress syndrome

Lung-protective ventilation with low tidal volumes remains the cornerstone for treating patient with acute respiratory distress syndrome (ARDS). Personalizing such an approach to each patients unique physiology may improve outcomes further. Many factors should be considered when mechanically ventilating a critically ill patient with ARDS. Estimations of transpulmonary pressures as well as individuals hemodynamics and respiratory mechanics should influence PEEP decisions as well as response to therapy (recruitability). This summary will emphasize the potential role of personalized therapy in mechanical ventilation.

Ventilator-induced lung injury increases expression of endothelial inflammatory mediators in the kidney

In critical illness, such as sepsis or the acute respiratory distress syndrome, acute kidney injury (AKI) is common and associated with increased morbidity and mortality. Mechanical ventilation in critical illnesses is also a risk factor for AKI, but it is potentially modifiable. Injurious ventilation strategies may lead to the systemic release of inflammatory mediators from the lung due to ventilator induced lung injury (VILI). The systemic consequences of VILI are difficult to differentiate clinically from other systemic inflammatory syndromes, such as sepsis. The purpose of this study was to identify unique changes in the expression of inflammatory mediators in kidney tissue in response to VILI compared with systemic sepsis to gain insight into direct effects of VILI on the kidney. Four groups of mice were compared-mice with sepsis from cecal ligation and puncture (CLP), mice subjected to injurious mechanical ventilation with high tidal volumes (VILI), mice exposed to CLP followed by VILI (CLP+VILI), and sham controls. Protein expression of common inflammatory mediators in kidneys was analyzed using a proteome array and confirmed by Western blot analysis or ELISA. VEGF and VCAM-1 were found to be significantly elevated in kidneys from VILI mice compared with sham and CLP. Angiopoietin-2 was significantly increased in CLP+VILI compared with CLP alone and was also correlated with higher levels of AKI biomarker, neutrophil gelatinase-associated lipocalin. These results suggest that VILI alters the renal expression of VEGF, VCAM-1, and angiopoietin-2, and these proteins warrant further investigation as potential biomarkers and therapeutic targets.