R. Scott Stephens

Lung Injury and Acute Respiratory Distress Syndrome After Cardiac Surgery

As many as 20% of patients undergoing cardiac surgery will have acute respiratory distress syndrome during the perioperative period, with a mortality as high as 80%. If patients at risk can be identified, preventative measures can be taken and may improve outcomes. Care for patients with acute respiratory distress syndrome is supportive, with low tidal volume ventilation being the mainstay of therapy. Careful fluid management, minimization of blood product transfusion, appropriate nutrition, and early physical rehabilitation may improve outcomes. In cases of refractory hypoxemia, rescue therapies such as recruitment maneuvers, high-frequency oscillatory ventilation, and extracorporeal membrane oxygenation may preserve life.

Physical Rehabilitation of Patients in the Intensive Care Unit Requiring Extracorporeal Membrane Oxygenation: A Small Case Series

Background and Purpose Neuromuscular weakness and impaired physical function are common and long-lasting complications experienced by intensive care unit (ICU) survivors. There is growing evidence that implementing rehabilitation therapy shortly after ICU admission improves physical function and reduces health care utilization. Recently, there is increasing interest and utilization of extracorporeal membrane oxygenation (ECMO) to support patients with severe respiratory failure. Patients receiving ECMO are at great risk for significant physical impairments and pose unique challenges for delivering rehabilitation therapy. Consequently, there is a need for innovative examples of safely and feasibly delivering active rehabilitation to these patients. Case Description This case report describes 3 patients with respiratory failure requiring ECMO who received physical rehabilitation to illustrate and discuss relevant feasibility and safety issues. Outcomes In case 1, sedation and femoral cannulation limited rehabilitation therapy while on ECMO. In the 2 subsequent cases, minimizing sedation and utilizing a single bicaval dual lumen ECMO cannula placed in the internal jugular vein allowed patients to be alert and participate in active physical therapy while on ECMO, illustrating feasible rehabilitation techniques for these patients. Discussion Although greater experience is needed to more fully evaluate the safety of rehabilitation on ECMO, these initial cases are encouraging. We recommend systematically and prospectively tracking safety events and patient outcomes during rehabilitation on ECMO to provide greater evidence in this area.

Postoperative critical care of the adult cardiac surgical patient. Part I: Routine postoperative care

Objectives:Cardiac surgery, including coronary artery bypass, cardiac valve, and aortic procedures, is among the most common surgical procedures performed in the United States. Successful outcomes after cardiac surgery depend on optimum postoperative critical care. The cardiac intensivist must have a comprehensive understanding of cardiopulmonary physiology and the sequelae of cardiopulmonary bypass. In this concise review, targeted at intensivists and surgeons, we discuss the routine management of the postoperative cardiac surgical patient. Data Source and Synthesis:Narrative review of relevant English-language peer-reviewed medical literature. Conclusions:Critical care of the cardiac surgical patient is a complex and dynamic endeavor. Adequate fluid resuscitation, appropriate inotropic support, attention to rewarming, and ventilator management are key components. Patient safety is enhanced by experienced personnel, a structured handover between the operating room and ICU teams, and appropriate transfusion strategies.

Xanthine oxidoreductase is a critical mediator of cigarette smoke-induced endothelial cell DNA damage and apoptosis

Cigarette smoke (CS) exposure is unquestionably the most frequent cause of emphysema in the United States. Accelerated pulmonary endothelial cell (EC) apoptosis is an early determinant of lung destruction in emphysema. One of the pathogenic causes of emphysema is an alveolar oxidant and antioxidant imbalance. The enzyme xanthine oxidoreductase (XOR) has been shown to be a source of reactive oxygen species (ROS) in a multitude of diseases (S. Sakao et al., FASEB J.21, 3640-3652; 2007). The contribution of XOR to CS-induced apoptosis is not well defined. Here we demonstrate that C57/bl6 mice exposed to CS have increased pulmonary XOR activity and protein levels compared to filtered-air-exposed controls. In addition, we demonstrate that primary pulmonary human lung microvascular endothelial cells exposed to cigarette smoke extract undergo increased rates of caspase-dependent apoptosis that are reliant on XOR activity, ROS production, and p53 function/expression. We also demonstrate that exogenous XOR is sufficient to increase p53 expression and induce apoptosis, suggesting that XOR is an upstream mediator of p53 in CS-induced EC apoptosis. Furthermore, we show that XOR activation results in DNA double-strand breaks that activate the enzyme ataxia telangiectasia mutated, which phosphorylates histone H2AX and upregulates p53. In conclusion, CS increases XOR expression, and the enzyme is both sufficient and necessary for p53 induction and CS-induced EC apoptosis.

Red blood cell transfusion triggers in acute leukemia: a randomized pilot study.

Red blood cell (RBC) transfusion thresholds have yet to be examined in large randomized trials in hematologic malignancies. This pilot study in acute leukemia uses a restrictive compared to a liberal transfusion strategy.

Protein kinase G increases antioxidant function in lung microvascular endothelial cells by inhibiting the c-Abl tyrosine kinase

Oxidant injury contributes to acute lung injury (ALI). We previously reported that activation of protein kinase GI (PKGI) posttranscriptionally increased the key antioxidant enzymes catalase and glutathione peroxidase 1 (Gpx-1) and attenuated oxidant-induced cytotoxicity in mouse lung microvascular endothelial cells (MLMVEC). The present studies tested the hypothesis that the antioxidant effect of PKGI is mediated via inhibition of the c-Abl tyrosine kinase. We found that activation of PKGI with the cGMP analog 8pCPT-cGMP inhibited c-Abl activity and decreased c-Abl expression in wild-type but not PKGI(-/-) MLMVEC. Treatment of wild-type MLMVEC with atrial natriuretic peptide also inhibited c-Abl activation. Moreover, treatment of MLMVEC with the c-Abl inhibitor imatinib increased catalase and GPx-1 protein in a posttranscriptional fashion. In imatinib-treated MLMVEC, there was no additional effect of 8pCPT-cGMP on catalase or GPx-1. The imatinib-induced increase in antioxidant proteins was associated with an increase in extracellular H2O2 scavenging by MLMVEC, attenuation of oxidant-induced endothelial barrier dysfunction, and prevention of oxidant-induced endothelial cell death. Finally, in the isolated perfused lung, imatinib prevented oxidant-induced endothelial toxicity. We conclude that cGMP, through activation of PKGI, inhibits c-Abl, leading to increased key antioxidant enzymes and resistance to lung endothelial oxidant injury. Inhibition of c-Abl by active PKGI may be the downstream mechanism underlying PKGI-mediated antioxidant signaling. Tyrosine kinase inhibitors may represent a novel therapeutic approach in oxidant-induced ALI.

CD36 and Fyn Kinase Mediate Malaria-Induced Lung Endothelial Barrier Dysfunction in Mice Infected with Plasmodium berghei

Severe malaria can trigger acute lung injury characterized by pulmonary edema resulting from increased endothelial permeability. However, the mechanism through which lung fluid conductance is altered during malaria remains unclear. To define the role that the scavenger receptor CD36 may play in mediating this response, C57BL/6J (WT) and CD36−/− mice were infected with P. berghei ANKA and monitored for changes in pulmonary endothelial barrier function employing an isolated perfused lung system. WT lungs demonstrated a >10-fold increase in two measures of paracellular fluid conductance and a decrease in the albumin reflection coefficient (σalb) compared to control lungs indicating a loss of barrier function. In contrast, malaria-infected CD36−/− mice had near normal fluid conductance but a similar reduction in σalb. In WT mice, lung sequestered iRBCs demonstrated production of reactive oxygen species (ROS). To determine whether knockout of CD36 could protect against ROS-induced endothelial barrier dysfunction, mouse lung microvascular endothelial monolayers (MLMVEC) from WT and CD36−/− mice were exposed to H2O2. Unlike WT monolayers, which showed dose-dependent decreases in transendothelial electrical resistance (TER) from H2O2 indicating loss of barrier function, CD36−/− MLMVEC demonstrated dose-dependent increases in TER. The differences between responses in WT and CD36−/− endothelial cells correlated with important differences in the intracellular compartmentalization of the CD36-associated Fyn kinase. Malaria infection increased total lung Fyn levels in CD36−/− lungs compared to WT, but this increase was due to elevated production of the inactive form of Fyn further suggesting a dysregulation of Fyn-mediated signaling. The importance of Fyn in CD36-dependent endothelial signaling was confirmed using in vitro Fyn knockdown as well as Fyn−/− mice, which were also protected from H2O2- and malaria-induced lung endothelial leak, respectively. Our results demonstrate that CD36 and Fyn kinase are critical mediators of the increased lung endothelial fluid conductance caused by malaria infection.

Postoperative Critical Care of the Adult Cardiac Surgical Patient: Part II: Procedure-Specific Considerations, Management of Complications, and Quality Improvement.

Objectives:The armamentarium of cardiac surgery continues to expand, and the cardiac intensivist must be familiar with a broad spectrum of procedures and their specific management concerns. In the conclusion of this two-part review, we will review procedure-specific concerns after cardiac surgery and the management of common complications. We also discuss performance improvement and outcome assurance. Data Source and Synthesis:Narrative review of relative English language peer-reviewed medical literature. Conclusions:Knowledge of procedure-specific sequelae informs anticipation and prevention of many complications after cardiac surgery. Most complications after cardiac surgery fall into a limited number of categories. Familiarity with common complications combined with a structured approach to management facilitates response to even the most complicated postoperative situations. Standardized care and constant self-examination are essential for programmatic improvement and consistent high-quality care.

The tyrosine kinase inhibitor imatinib prevents lung injury and death after intravenous LPS in mice

Severe sepsis and septic shock are frequent causes of the acute respiratory distress syndrome, and important sources of human mortality. Lipopolysaccharide (LPS), a component of Gram‐negative bacterial cell walls, plays a major role in the pathogenesis of severe sepsis and septic shock. LPS exposure induces the production of harmful reactive oxygen species, and the resultant oxidant injury has been implicated in the pathogenesis of both severe sepsis and ARDS. We previously showed that the tyrosine kinase inhibitor imatinib increases lung endothelial antioxidant enzymes and protects against pulmonary endothelial antioxidant injury. In the present study, we tested the hypothesis that imatinib would protect against lung injury and systemic inflammation caused by intravenous LPS in an intact mouse model of endotoxemia mimicking early sepsis. We found that intravenous LPS induced a significant increase in the activity of lung xanthine oxidoreductase (XOR), an enzyme which is a major source of reactive oxygen species and implicated in the pathogenesis of acute lung injury. Imatinib had no effect of LPS‐induced XOR activity. However, pretreatment of mice with imatinib increased lung catalase activity and decreased intravenous LPS‐induced lung oxidant injury as measured by γ‐H2AX, a marker of oxidant‐induced DNA damage, lung apoptosis, and pulmonary edema. Imatinib also attenuated systemic cytokine expression after intravenous LPS exposure. Finally, imatinib completely prevented mortality in an in vivo, intravenous LPS mouse model of endotoxemia and lung injury. These results support the testing of imatinib as a novel pharmacologic agent in the treatment of Gram‐negative sepsis and sepsis‐induced ARDS.

Choosing wisely - when to mend a broken heart with ECMO?

Refractory cardiac shock in the cardiac surgical intensive care unit confers significant morbidity and mortality. Extracorporeal membrane oxygenation (ECMO) has become a common intervention for refractory cardiogenic shock when other therapies have failed. However, it is difficult to predict who will benefit from this costly, resource-intensive, but potentially life-saving technology. Here, we discuss the utility of a novel biomarker, serum butylcholinesterase, in determining survival in patients supported with ECMO following cardiac surgery.