John D. Lang

Early packed red blood cell transfusion and acute respiratory distress syndrome after trauma

Background:Transfusion of packed red blood cells (PRBCs) is a risk factor for acute respiratory distress syndrome (ARDS) in trauma patients. Yet, there is a paucity of information regarding the risk of ARDS with incremental PRBCs exposure. Methods:For this retrospective analysis, eligible patients from National Study on Costs and Outcomes of Trauma were included. Our main exposure was defined as units of PRBCs transfused during the first 24 h after admission. The main outcome was ARDS. Results:A total of 521 (4.6%) of 14070 patients developed ARDS, and 331 patients (63.5%) who developed ARDS received PRBCs transfusion. Injury severity, thoracic injury, polytrauma, and pneumonia receiving more than 5 units of fresh frozen plasma and 6–10 units of PRBCs were independent predictors of ARDS. Patients receiving more than 5 units of PRBCs had higher risk of developing ARDS (patients who received 6–10 units: adjusted odds ratio 2.5, 95% CI 1.12–5.3; patients who received more than 10 units: odds ratio 2.6, 95% CI 1.1–6.4). Each additional unit of PRBCs transfused conferred a 6% higher risk of ARDS (adjusted odds ratio 1.06; 95% CI 1.03–1.10). Conclusions:Early transfusion of PRBCs is an independent predictor of ARDS in adult trauma patients. Conservative transfusion strategies that decrease PRBC exposure by even 1 unit may be warranted to reduce the risk of ARDS in injured patients.

Inhaled nitric oxide attenuates reperfusion inflammatory responses in humans.

Background:Reduced bioavailability of endothelium-derived nitric oxide associated with reperfusion could potentially exacerbate the inflammatory response during reperfusion. Evidence suggests the pharmacologic effects of inhaled nitric oxide may extend beyond the pulmonary vasculature, and this is attributed to nitric oxide–derived complexes in blood that ultimately orchestrate antiinflammatory effects. In this study, the authors evaluated the potential for inhaled nitric oxide (80 ppm) to attenuate inflammation instigated by ischemia–reperfusion in a human model using patients undergoing knee surgery where a tourniquet was used to produce a bloodless surgical field. Methods:Inhaled nitric oxide (80 ppm) was administered before tourniquet application and continued throughout reperfusion until the completion of surgery. Venous blood samples were collected before and after reperfusion, for the measurements of nitrate and nitrite, CD11b/CD18, soluble P-selectin, and lipid hydroperoxide. Muscle biopsies were obtained from the quadriceps muscle before skin closure and analyzed for myeloperoxide, conjugated dienes, and nuclear factor-&kgr;B translocation. Results:Administration of inhaled nitric oxide (80 ppm) significantly attenuated the inflammatory response characterized by reduced expression of CD11b/CD18, P-selectin, and nuclear factor &kgr;B compared with the control group. This was accompanied by increased plasma levels of nitrate and nitrite and reduced oxidative stress. Conclusions:Administration of inhaled nitric oxide at 80 ppm significantly reduces inflammation in lower extremity ischemia–reperfusion in humans. This observation supports the concept that during diseases characterized by dysfunction in nitric oxide metabolism, inhaled nitric oxide may be an effective therapy to replenish systemic nitric oxide, thus retarding inflammatory-mediated injury.

Medical Gases: A Novel Strategy for Attenuating Ischemia—Reperfusion Injury in Organ Transplantation?

Ischemia reperfusion injury (IRI) is an inevitable clinical consequence in organ transplantation. It can lead to early graft nonfunction and contribute to acute and chronic graft rejection. Advanced molecular biology has revealed the highly complex nature of this phenomenon and few definitive therapies exist. This paper reviews factors involved in the pathophysiology of IRI and potential ways to attenuate it. In recent years, inhaled nitric oxide, carbon monoxide, and hydrogen sulfide have been increasingly explored as plausible novel medical gases that can attenuate IRI via multiple mechanisms, including microvascular vasorelaxation, reduced inflammation, and mitochondrial modulation. Here, we review recent advances in research utilizing inhaled nitric oxide, carbon monoxide, and hydrogen sulfide in animal and human studies of IRI and postulate on its future applications specific to solid organ transplantation.

Modulatory effects of hypercapnia on in vitro and in vivo pulmonary endothelial-neutrophil adhesive responses during inflammation.

Reducing tidal volume as a part of a protective ventilation strategy may result in hypercapnia. In this study, we focused on the influence of hypercapnia on endothelial-neutrophil responses in models of inflammatory-stimulated human pulmonary microvascular endothelial cells (HMVEC) and in an animal model of lipopolysaccharide (LPS)-induced acute lung injury. Neutrophil adhesion and adhesion molecules expression and nuclear factor-kappaB (NF-kappaB) were analyzed in TNF-alpha and LPS-treated HMVEC exposed to either eucapnia or hypercapnia. In the in vivo limb, bronchoalveolar lavage fluid cell counts and differentials, adhesion molecule and chemokine expression were assessed in LPS-treated rabbits ventilated with either low tidal volume ventilation and eucapnia or hypercapnia. In both the in vitro and in vivo models, hypercapnia significantly increased neutrophil adhesion and adhesion molecule expression compared to eucapnia. Activity of NF-kappaB was significantly enhanced by hypercapnia in the in vitro experiments. IL-8 expression was greatest both in vitro and in vivo under conditions of hypercapnia and concomitant inflammation. CD11a expression was greatest in isolated human neutrophils exposed to hypercapnia+LPS. Our results demonstrate that endothelial-neutrophil responses per measurement of fundamental molecules of adhesion are significantly increased during hypercapnia and that hypercapnia mimics conditions of eucapnia+inflammation.

A Randomized Clinical Trial Testing the Anti-Inflammatory Effects of Preemptive Inhaled Nitric Oxide in Human Liver Transplantation

Decreases in endothelial nitric oxide synthase derived nitric oxide (NO) production during liver transplantation promotes injury. We hypothesized that preemptive inhaled NO (iNO) would improve allograft function (primary) and reduce complications post-transplantation (secondary). Patients at two university centers (Center A and B) were randomized to receive placebo (n = 20/center) or iNO (80 ppm, n = 20/center) during the operative phase of liver transplantation. Data were analyzed at set intervals for up to 9-months post-transplantation and compared between groups. Patient characteristics and outcomes were examined with the Mann-Whitney U test, Student t-test, logistic regression, repeated measures ANOVA, and Cox proportional hazards models. Combined and site stratified analyses were performed. MELD scores were significantly higher at Center B (22.5 vs. 19.5, p<0.0001), surgical times were greater at Center B (7.7 vs. 4.5 hrs, p<0.001) and warm ischemia times were greater at Center B (95.4 vs. 69.7 min, p<0.0001). No adverse metabolic or hematologic effects from iNO occurred. iNO enhanced allograft function indexed by liver function tests (Center B, p<0.05; and p<0.03 for ALT with center data combined) and reduced complications at 9-months (Center A and B, p = 0.0062, OR = 0.15, 95% CI (0.04, 0.59)). ICU (p = 0.47) and hospital length of stay (p = 0.49) were not decreased. iNO increased concentrations of nitrate (p<0.001), nitrite (p<0.001) and nitrosylhemoglobin (p<0.001), with nitrite being postulated as a protective mechanism. Mean costs of iNO were

Intraoperative adherence to a low tidal volume ventilation strategy in critically ill patients with preexisting acute lung injury.

1,020 per transplant. iNO was safe and improved allograft function at one center and trended toward improving allograft function at the other. ClinicalTrials.gov with registry number 00582010 and the following URL:http://clinicaltrials.gov/show/NCT00582010.

Redox therapeutics in hepatic ischemia reperfusion injury

PURPOSE Low tidal volume (LTV) ventilation reduces mortality in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). This study investigates adherence of intraoperative LTV and whether patient outcomes were different with or without continued intraoperative LTV ventilation in patients with previously established ALI or ARDS. MATERIALS AND METHODS A retrospective analysis was performed of adults with ALI/ARDS over a 2-year period who underwent surgery between 24 hours and 14 days after the diagnosis of ALI/ARDS. The main outcome was intraoperative LTV use. Secondary outcomes included perioperative respiratory and clinical outcomes. RESULTS Of the 249 patients who underwent surgery between 24 hours and 14 days after ALI/ARDS diagnosis, 101 (41%) received preoperative LTV ventilation. Fifty-four (53%) received intraoperative LTV ventilation, whereas 47 (47%) did not. Use of preoperative LTV ventilation was associated with use of intraoperative LTV ventilation (P < .01). No differences in respiratory or clinical outcomes between patients with or without intraoperative LTV ventilation were observed. CONCLUSIONS Adherence to intraoperative LTV in surgical patients was low. Adherence of LTV intraoperatively was not associated with improved oxygenation, reductions in hospital length of stay, or in-hospital mortality. The importance of adhering to an intraoperative LTV strategy remains unclear.

Cirrhosis-Associated Cardiomyopathy

Ischemia-reperfusion plays a major role in the injury experienced by the liver during transplantation. Much work has been done recently investigating the role of redox species in hepatic ischemia-reperfusion. As animal models are better characterized and developed, and more insights are gained into the pathophysiology of hepatic ischemia reperfusion injury in humans the questions into exactly how oxidants participate in this injury are becoming more refined. These questions include effects of cellular location, timing of injury, and ability of therapeutics to access this site are increasing our appreciation of the complexity of ischemia reperfusion and improving attempts to ameliorate its effects. In this review, we aim to discuss the various methods to alter redox chemistry during ischemia reperfusion injury and future prospects for preventing organ injury during hepatic ischemia reperfusion.

Role of nitric oxide in liver transplantation: Should it be routinely used?

Liver cirrhosis is the 12 th leading cause of death in the US. The heart is one of the most adversely affected organs in liver cirrhosis. Cirrhosis-induced cardiomyopathy describes the cardiac dysfunction in patients with cirrhosis characterized by impaired contractile response to stress and/or altered diastolic relaxation with electrophysiologic abnormalities in the absence of other known cardiac disease. The current definition of cirrhosis-induced cardiomyopathy does not take into account recent evidence of resting contractile and relaxation dysfunction that can be appreciated by advanced imaging tools such as Doppler tissue imaging and cardiac magnetic resonance imaging. Cirrhosis-induced cardiomyopathy is caused by cellular as well as physiological mechanisms including but not limited to: beta adrenergic receptor dysfunction, calcium channelopathy, elevated levels of catecholamines, elevated levels of nitric oxide, carbon monoxide and hydrogen sulphide and stimulation of endogenous cannabinoid pathways capable of producing negative inotropic, relaxation, and electrophysiological defects. Currently there is no specific therapy for cirrhosis-induced cardiomyopathy. There is some evidence that short courses of beta blockers may restore prolonged QT interval to normal values. Also, there is an emerging evidence for a role of aldosterone antagonists in reducing myocardial hypertrophy. Liver transplantation may revert cardiac dysfunction, but surgery and shunt insertion may also aggravate the condition. More standardized tools are needed to screen for and treat cirrhosis-induced cardiomyopathy.

Towards a better characterization of cirrhosis-associated cardiomyopathy?

Ischemia-reperfusion injury (IRI) continues to be a major contributor to graft dysfunction, thus supporting the need for therapeutic strategies focused on minimizing organ damage especially with growing numbers of extended criteria grafts being utilized which are more vulnerable to cold and warm ischemia. Nitric oxide (NO·) is highly reactive gaseous molecule found in air and regarded as a pollutant. Not surprising, it is extremely bioactive, and has been demonstrated to play major roles in vascular homeostasis, neurotransmission, and host defense inflammatory reactions. Under conditions of ischemia, NO· has consistently been demonstrated to enhance microcirculatory vasorelaxation and mitigate pro-inflammatory responses, making it an excellent strategy for patients undergoing organ transplantation. Clinical studies designed to test this hypothesis have yielded very promising results that includes reduced hepatocellular injury and enhanced graft recovery without any identifiable complications. By what means NO· facilitates extra-pulmonary actions is up for debate and speculation. The general premise is that they are NO· containing intermediates in the circulation, that ultimately mediate either direct or indirect effects. A plethora of data exists explaining how NO·-containing intermediate molecules form in the plasma as S-nitrosothiols (e.g., S-nitrosoalbumin), whereas other compelling data suggest nitrite to be a protective mediator. In this article, we discuss the use of inhaled NO· as a way to protect the donor liver graft against IRI in patients undergoing liver transplantation.