Michael A. Gropper

Transfusion related acute lung injury: incidence and risk factors

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality. To determine TRALI incidence by prospective, active surveillance and to identify risk factors by a case-control study, 2 academic medical centers enrolled 89 cases and 164 transfused controls. Recipient risk factors identified by multivariate analysis were higher IL-8 levels, liver surgery, chronic alcohol abuse, shock, higher peak airway pressure while being mechanically ventilated, current smoking, and positive fluid balance. Transfusion risk factors were receipt of plasma or whole blood from female donors (odds ratio = 4.5, 95% confidence interval [CI], 1.85-11.2, P = .001), volume of HLA class II antibody with normalized background ratio more than 27.5 (OR = 1.92/100 mL, 95% CI, 1.08-3.4, P = .03), and volume of anti-human neutrophil antigen positive by granulocyte immunofluoresence test (OR = 1.71/100 mL, 95% CI, 1.18-2.5, P = .004). Little or no risk was associated with older red blood cell units, noncognate or weak cognate class II antibody, or class I antibody. Reduced transfusion of plasma from female donors was concurrent with reduced TRALI incidence: 2.57 (95% CI, 1.72-3.86) in 2006 versus 0.81 (95% CI, 0.44-1.49) in 2009 per 10 000 transfused units (P = .002). The identified risk factors provide potential targets for reducing residual TRALI.

Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia.

The pathogenesis of septic shock occurring after Pseudomonas aeruginosa pneumonia was studied in a rabbit model. The airspace instillation of the cytotoxic P. aeruginosa strain PA103 into the rabbit caused a consistent alveolar epithelial injury, progressive bacteremia, and septic shock. The lung instillation of a noncytotoxic, isogenic mutant strain (PA103DeltaUT), which is defective for production of type III secreted toxins, did not cause either systemic inflammatory response or septic shock, despite a potent inflammatory response in the lung. The intravenous injection of PA103 did not cause shock or an increase in TNF-alpha, despite the fact that the animals were bacteremic. The systemic administration of either anti-TNF-alpha serum or recombinant human IL-10 improved both septic shock and bacteremia in the animals that were instilled with PA103. Radiolabeled TNF-alpha instilled in the lung significantly leaked into the circulation only in the presence of alveolar epithelial injury. We conclude that injury to the alveolar epithelium allows the release of proinflammatory mediators into the circulation that are primarily responsible for septic shock. Our results demonstrate the importance of compartmentalization of inflammatory mediators in the lung, and the crucial role of bacterial cytotoxins in causing alveolar epithelial damage in the pathogenesis of acute septic shock in P. aeruginosa pneumonia.

ACTIVE AND PASSIVE IMMUNIZATION WITH THE PSEUDOMONAS V ANTIGEN PROTECTS AGAINST TYPE III INTOXICATION AND LUNG INJURY

Pseudomonas aeruginosa is an opportunistic bacterial pathogen that can cause fatal acute lung infections in critically ill individuals. Damage to the lung epithelium is associated with the expression of toxins that are directly injected into eukaryotic cells through a type III-mediated secretion and translocation mechanism. Here we show that the P. aeruginosa homolog of the Yersinia V antigen, PcrV, is involved in the translocation of type III toxins. Vaccination against PcrV ensured the survival of challenged mice and decreased lung inflammation and injury. Antibodies to PcrV inhibited the translocation of type III toxins.

Perioperative glycemic control: an evidence-based review.

Hyperglycemia in perioperative patients has been identified as a risk factor for morbidity and mortality. Intensive insulin therapy (IIT) has been shown to reduce morbidity and mortality among the critically ill, decrease infection rates and improve survival after cardiac surgery, and improve outcomes in acute neurologic injury and acute myocardial infarction. However, recent evidence of severe hypoglycemia and adverse events associated with IIT brings its safety and efficacy into question. In this article, we summarize the mechanisms and rationale of hyperglycemia and IIT, review the evidence behind the use of IIT in the perioperative period, and discuss the implications of including glycemic control in national quality benchmarks. We conclude that while avoidance of hyperglycemia is clearly beneficial, the appropriate glucose target and specific subpopulations who might benefit from IIT have yet to be identified. Given the potential for harm, inclusion of glucose targets in national quality benchmarks is premature.

Pulmonary edema after transfusion: How to differentiate transfusion-associated circulatory overload from transfusion-related acute lung injury

Objective:Pulmonary edema is an underrecognized and potentially serious complication of blood transfusion. Distinct mechanisms include adverse immune reactions and circulatory overload. The former is associated with increased pulmonary vascular permeability and is commonly referred to as transfusion-related acute lung injury (TRALI). The latter causes hydrostatic pulmonary edema and is commonly referred to as transfusion-associated circulatory overload (TACO). In this review article we searched the National Library of Medicine PubMed database as well as references of retrieved articles and summarized the methods for differentiating between hydrostatic and permeability pulmonary edema. Results:The clinical and radiologic manifestations of TACO and TRALI are similar. Although echocardiography and B-type natriuretic peptide measurements may aid in the differential diagnosis between hydrostatic and permeability pulmonary edema, invasive techniques such as right heart catheterization and the sampling of alveolar fluid protein are sometimes necessary. The diagnostic differentiation is especially difficult in critically ill patients will multiple comorbidities so that the cause of edema may only be determined post hoc based on the clinical course and response to therapy. Guided by available evidence, we present an algorithm for establishing the pretest probability of TRALI as opposed to TACO. The decision to test donor and recipient blood for immunocompatibility may be made on this basis. Conclusions:The distinction between hydrostatic (TACO) and permeability (TRALI) pulmonary edema after transfusion is difficult, in part because the two conditions may coexist. Knowledge of strengths and limitations of different diagnostic techniques is necessary before initiation of complex TRALI workup.

Injury and repair in lung and airways.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common causes of morbidity and mortality in the intensive care unit. ALI/ARDS occurs as a result of systemic inflammation, usually triggered by a microorganism. Activation of leukocytes and release of proinflammatory mediators from multiple cellular sources result in both local and distant tissue injury. Tumor necrosis factor-alpha and interleukin-1 beta are the best characterized of the proinflammatory cytokines contributing to ALI/ARDS and subsequent fibrosis. The ultimate clinical course of ALI/ARDS often is determined by the ability of the injured lung to repopulate the alveolar epithelium with functional cells. Death may occur when fibrosis predominates the healing response, as it results in worsening lung compliance and oxygenation. The rodent bleomycin model of lung fibrosis allows the use of molecular tools to dissect the cellular and subcellular processes leading to fibrosis. The elements of this response may provide therapeutic targets for the prevention of this devastating complication of ALI/ARDS.

Relationship of pleural effusions to increased permeability pulmonary edema in anesthetized sheep.

Abstract We studied anesthetized sheep to determine the relationship between increased permeability pulmonary edema and the development and mechanism of pleural effusion formation. In 12 sheep with intact, closed thoraces, we studied the time course of pleural liquid formation after 0.12 ml/kg i.v. oleic acid. After 1 h, there were no pleural effusions, even though extravascular lung water increased 50% to 6.0 +/- 0.7 g/g dry lung. By 3 h pleural effusions had formed, they reached a maximum at 5 h (48.5 +/- 16.9 ml/thorax), and at 8 h there was no additional accumulation of pleural liquid (45.5 +/- 16.9 ml). Morphologic studies by light and electron microscopy demonstrated subpleural edema but no detectable injury to the visceral pleura, suggesting that the pleural liquid originated from the lung and not the pleura. In nine sheep, we quantified the rate of formation of pleural liquid by enclosing one lung in a plastic bag. By comparing in the same sheep the volume of pleural liquid collected from the enclosed lung to the volume found in the opposite intact chest, we estimated the rate of liquid absorption from the intact chest to be 0.32 ml/(kg.h); we had previously reported a liquid absorption rate of 0.28 ml/(kg.h) in normal sheep. These studies also supported the conclusion that the majority of the pleural liquid originated from the lung because we could account for all of the pleural liquid that was formed and cleared. The volume of pleural liquid collected from the enclosed lungs was equal to 21% of the excess lung liquid that formed after oleic acid-induced lung injury. Thus, the pleural space and parietal pleural lymphatic pathways are important pathways for the clearance of pulmonary edema liquid after experimentally induced increased permeability pulmonary edema.

Reducing noninfectious risks of blood transfusion.

As screening for transfusion-associated infections has improved, noninfectious complications of transfusion now cause the majority of morbidity and mortality associated with transfusion in the United States. For example, transfusion-related acute lung injury, transfusion-associated circulatory overload, and hemolytic transfusion-reactions are the first, second, and third leading causes of death from transfusion, respectively. These complications and others are reviewed, and several controversial methods for prevention of noninfectious complications of transfusion are discussed, including universal leukoreduction of erythrocyte units, use of male-only plasma, and restriction of erythrocyte storage age.

Looking Forward, Looking Back: Assessing Variations in Hospital Resource Use and Outcomes for Elderly Patients With Heart Failure

Background—Recent studies have found substantial variation in hospital resource use by expired Medicare beneficiaries with chronic illnesses. By analyzing only expired patients, these studies cannot identify differences across hospitals in health outcomes like mortality. This study examines the association between mortality and resource use at the hospital level, when all Medicare beneficiaries hospitalized for heart failure are examined. Methods and Results—A total of 3999 individuals hospitalized with a principal diagnosis of heart failure at 6 California teaching hospitals between January 1, 2001, and June 30, 2005, were analyzed with multivariate risk-adjustment models for total hospital days, total hospital direct costs, and mortality within 180-days after initial admission (“Looking Forward”). A subset of 1639 individuals who died during the study period were analyzed with multivariate risk-adjustment models for total hospital days and total hospital direct costs within 180-days before death (“Looking Back”). “Looking Forward” risk-adjusted hospital means ranged from 17.0% to 26.0% for mortality, 7.8 to 14.9 days for total hospital days, and 0.66 to 1.30 times the mean value for indexed total direct costs. Spearman rank correlation coefficients were −0.68 between mortality and hospital days, and −0.93 between mortality and indexed total direct costs. “Looking Back” risk-adjusted hospital means ranged from 9.1 to 21.7 days for total hospital days and 0.91 to 1.79 times the mean value for indexed total direct costs. Variation in resource use site ranks between expired and all individuals were attributable to insignificant differences. Conclusions—California teaching hospitals that used more resources caring for patients hospitalized for heart failure had lower mortality rates. Focusing only on expired individuals may overlook mortality variation as well as associations between greater resource use and lower mortality. Reporting values without identifying significant differences may result in incorrect assumption of true differences.

ICU Early Mobilization: From Recommendation to Implementation at Three Medical Centers

Objective:To compare and contrast the process used to implement an early mobility program in ICUs at three different medical centers and to assess their impact on clinical outcomes in critically ill patients. Design:Three ICU early mobilization quality improvement projects are summarized utilizing the Institute for Healthcare Improvement framework of Plan-Do-Study-Act. Intervention:Each of the three ICU early mobilization programs required an interprofessional team-based approach to plan, educate, and implement the ICU early mobility program. Champions from each profession—nursing, physical therapy, physician, and respiratory care—were identified to facilitate changes in ICU culture and clinical practice and to identify and address barriers to early mobility program implementation at each institution. Setting:The medical ICU at Wake Forest University, the medical ICU at Johns Hopkins Hospital, and the mixed medical-surgical ICU at the University of California San Francisco Medical Center. Results:Establishing an ICU early mobilization quality improvement program resulted in a reduced ICU and hospital length of stay at all three institutions and decreased rates of delirium and the need for sedation for the patients enrolled in the Johns Hopkins ICU early mobility program. Conclusion:Instituting a planned, structured ICU early mobility quality improvement project can result in improved outcomes and reduced costs for ICU patients across healthcare systems.