Faculty Bibliography

BACKGROUND:Fluid and vasopressor management in septic shock remains controversial. In this randomized controlled trial, we evaluated the efficacy of dynamic measures (stroke volume change during passive leg raise) to guide resuscitation and improve patient outcome. RESEARCH QUESTION/OBJECTIVE:Will resuscitation guided by dynamic assessments of fluid responsiveness in patients with septic shock improve patient outcomes? STUDY DESIGN/METHODS:and Methods: Prospective, multicenter, randomized clinical trial at 13 hospitals in the United States and United Kingdom. Patients presented to Emergency Rooms with sepsis associated hypotension and anticipated Intensive Care Unit (ICU) admission. Intervention arm patients were assessed for fluid responsiveness before clinically driven fluid bolus or increase in vasopressors. The protocol included reassessment and therapy as indicated by the PLR result. The control arm received Usual Care. Primary clinical outcome was positive fluid balance at 72 hours or ICU discharge, whichever occurred first. RESULTS:In modified-ITT (mITT) analysis including 83 Intervention and 41 Usual Care eligible patients, fluid balance at 72 hours or ICU discharge was significantly lower (-1.37L favoring Intervention arm, 0.65 ± 2.85L Intervention arm vs. 2.02 ± 3.44L Usual Care arm, p=0.021. Fewer patients required renal replacement therapy (5.1% vs 17.5%, p=0.04) or mechanical ventilation (17.7% vs 34.1%, p=0.04) in the Intervention arm compared to Usual Care. In the all-randomized Intent to Treat (ITT) population (102 Intervention, 48 Usual Care) there were no significant differences in safety signals. INTERPRETATION/CONCLUSIONS:Physiologically informed fluid and vasopressor resuscitation using passive leg raise-induced stroke volume change to guide management of septic shock is safe and demonstrated lower net fluid balance and reductions in the risk of renal and respiratory failure. Dynamic assessments to guide fluid administration may improve outcomes for septic shock patients compared with Usual Care.

The severe acute respiratory syndrome coronavirus-2 emerged as a serious human pathogen in late 2019, causing the disease coronavirus disease 2019 (COVID-19). The most common clinical presentation of severe COVID-19 is acute respiratory failure consistent with the acute respiratory distress syndrome. Airway, lung parenchymal, pulmonary vascular, and respiratory neuromuscular disorders all feature in COVID-19. This article reviews what is known about the effects of severe acute respiratory syndrome coronavirus-2 infection on different parts of the respiratory system, clues to understanding the underlying biology of respiratory disease, and highlights current and future translation and clinical research questions.

Background/UNASSIGNED:Optimal fluid therapy in the perioperative and critical care settings depends on understanding the underlying cardiovascular physiology and individualizing assessment of the dynamic patient state. Methods/UNASSIGNED:The Perioperative Quality Initiative (POQI-5) consensus conference brought together an international team of multidisciplinary experts to survey and evaluate the literature on the physiology of volume responsiveness and perioperative fluid management. The group used a modified Delphi method to develop consensus statements applicable to the physiologically based management of intravenous fluid therapy in the perioperative setting. Discussion/UNASSIGNED:We discussed the clinical and physiological evidence underlying fluid responsiveness and venous capacitance as relevant factors in fluid management and developed consensus statements with clinical implications for a broad group of clinicians involved in intravenous fluid therapy. Two key concepts emerged as follows: (1) The ultimate goal of fluid therapy and hemodynamic management is to support the conditions that enable normal cellular metabolic function in order to produce optimal patient outcomes, and (2) optimal fluid and hemodynamic management is dependent on an understanding of the relationship between pressure, volume, and flow in a dynamic system which is distensible with variable elastance and capacitance properties.

RATIONALE/BACKGROUND:No previous studies have examined the role of pre-hospital vulnerability in acute respiratory distress syndrome (ARDS) development and mortality in an acutely ill adult population. OBJECTIVES/OBJECTIVE:To describe the association between pre-hospital vulnerability and 1) the development of ARDS; 2) 28-day mortality and 3) 1-year mortality. METHODS:This was a longitudinal prospective cohort study nested within the multi-center Lung Injury Prevention Study-Aspirin (LIPS-A) trial. We analyzed 301 participants who completed Vulnerable Elders Survey (VES) at baseline. Multivariable logistic regression and cox regression analyses were used to describe the association between vulnerability and short-term outcomes (ARDS and 28-day mortality) and long-term outcomes (1-year mortality) respectively. RESULTS:The VES score ranged from 0-10, median (interquartile range (IQR) 2.0 (0-6); 143 (47.5%) fit criteria for pre-hospital vulnerability (VES≥3). Vulnerability was not significantly associated with ARDS development (10 (7.0%) vulnerable patients developed ARDS as per LIPS-A study criteria versus 20 (12.7%) without vulnerability, p=0.10, adjusted Odds Ratio (aOR) (95% Confidence Interval (CI) 0.54 (0.24-1.24), p=0.15). Nor was vulnerability associated with 28-day mortality (15 (10.5%) vulnerable patients were dead by day-28 versus 11 (7.0%) non-vulnerable patients, p=0.28; aOR (95% CI) 0.95 (0.39-2.26) p=0.90). Vulnerability was significantly associated with 1-year mortality in hospital survivors (35 (26.9%) versus 13 (9.3%), adjusted Hazard Ratio (95% CI) 2.20 (1.10-4.37) p=0.02). CONCLUSIONS:In a population of adults recruited for their high risk of ARDS, pre-hospital vulnerability, measured by VES, was highly prevalent and strongly associated with 1-year mortality.

Important recent insights have emerged regarding the cellular and molecular role of carbon dioxide (CO2) and the effects of hypercapnia. The latter may have beneficial effects in patients with acute lung injury, affording reductions in pulmonary inflammation, lessened oxidative alveolar damage, and the regulation of innate immunity and host defenses by inhibiting the expression of inflammatory cytokines. However, other studies suggest that CO2can have deleterious effects upon the lung, reducing alveolar wound repair in lung injury, decreasing the rate of reabsorption of alveolar fluid, and inhibiting alveolar cell proliferation. Clearly, hypercapnia has both beneficial and harmful consequences, and it is important to determine the net effect under specific conditions. The purpose of this review is to describe the immunological and physiological effects of carbon dioxide, considering their potential consequences in patients with acute respiratory failure.

Introduction: Cardiac function is known to be negatively impacted by sepsis. Stroke volume (SV) change in response to Passive Leg Raise (PLR) is an effective method to predict fluid responsiveness (FR) or cardiac response to preload expansion. We have previously shown that fluid responsiveness is a dynamic state, changing frequently over a 72 hour monitoring period.
Method(s): FRESH is a currently enrolling prospective randomized controlled study, evaluating the incidence of FR and patient centered outcomes in critically ill patients with sepsis or septic shock (NCT02837731). Patients randomized to PLR guided resuscitation were evaluated every 6-12 hours over the first 72 hours of care and classified as FR if the SV increased > 10% when measured with non-invasive bioreactance (Starling SV, Cheetah Medical). The time of first FR was noted.
Result(s): A total of 608 PLR assessments were performed in 86 patients over a 72 hour monitoring period. 56 % were female, and the average age was 61 years. PLRs were evaluated over time, with time 0 representing initial fluid resuscitation (Figure 1). When individual subjects were evaluated over time, 100% of subjects who became FR only after 24 hours showed evidence of LV/RV dysfunction (Figure 2).
Conclusion(s): Fluid responsiveness or preload dependence frequently changes for septic shock patients over the first 72 hours of care. Evidence suggests it is beneficial to periodically perform an assessment of preload responsiveness to guide fluid administration, as preload dependence is a dynamic and changing state. Preload dependence provides additional information beyond fluid responsiveness. Those patients who remain primarily fluid non-responsive (preload independent) are more likely to demonstrate ECHO confirmed LV/RV dysfunction, as the delay in return to cardiac function may be related to underlying cardiac deficits. Further evaluation may be indicated in preload independent patients. (Figure Presented)

PURPOSE OF REVIEW/OBJECTIVE:In this review, we will discuss efforts and challenges in understanding and developing meaningful outcomes of critical care research, quality improvement and policy, which are patient-centered and goal concordant, rather than mortality alone. We shall discuss different aspects of what could constitute outcomes of critical illness as meaningful to the patients and other stakeholders, including families and providers. RECENT FINDINGS/RESULTS:Different outcome pathways after critical illness impact the patients, families and providers in multiple ways. For patients who die, it is important to consider the experience of dying. For the increasing number of survivors of critical illness, challenges of survival have surfaced. The physical, mental and social debility that survivors experience has evolved into the entity called post-ICU syndrome. The importance of prehospital health state trajectory and the need for the outcome of critical care to be aligned with the patients' goals and preferences have been increasingly recognized. SUMMARY/CONCLUSIONS:A theoretical framework is outlined to help understand the impact of critical care interventions on outcomes that are meaningful to patients, families and healthcare providers.

BACKGROUND:Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia. METHODS:We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS:Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, non-invasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy. CONCLUSIONS:Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.