Eric J. Charles

Hypocaloric compared with eucaloric nutritional support and its effect on infection rates in a surgical intensive care unit: a randomized controlled trial

BACKGROUND Proper caloric intake goals in critically ill surgical patients are unclear. It is possible that overnutrition can lead to hyperglycemia and an increased risk of infection. OBJECTIVE This study was conducted to determine whether surgical infection outcomes in the intensive care unit (ICU) could be improved with the use of hypocaloric nutritional support. DESIGN Eighty-three critically ill patients were randomly allocated to receive either the standard calculated daily caloric requirement of 25-30 kcal · kg(-1) · d(-1) (eucaloric) or 50% of that value (hypocaloric) via enteral tube feeds or parenteral nutrition, with an equal protein allocation in each group (1.5 g · kg(-1) · d(-1)). RESULTS There were 82 infections in the hypocaloric group and 66 in the eucaloric group, with no significant difference in the mean (± SE) number of infections per patient (2.0 ± 0.6 and 1.6 ± 0.2, respectively; P = 0.50), percentage of patients acquiring infection [70.7% (29 of 41) and 76.2% (32 of 42), respectively; P = 0.57], mean ICU length of stay (16.7 ± 2.7 and 13.5 ± 1.1 d, respectively; P = 0.28), mean hospital length of stay (35.2 ± 4.9 and 31.0 ± 2.5 d, respectively; P = 0.45), mean 0600 glucose concentration (132 ± 2.9 and 135 ± 3.1 mg/dL, respectively; P = 0.63), or number of mortalities [3 (7.3%) and 4 (9.5%), respectively; P = 0.72]. Further analyses revealed no differences when analyzed by sex, admission diagnosis, site of infection, or causative organism. CONCLUSIONS Among critically ill surgical patients, caloric provision across a wide acceptable range does not appear to be associated with major outcomes, including infectious complications. The optimum target for caloric provision remains elusive.

Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury

Outcomes for lung transplantation are the worst of any solid organ, and ischemia-reperfusion injury (IRI) limits both short- and long-term outcomes. Presently no therapeutic agents are available to prevent IRI. Sphingosine 1-phosphate (S1P) modulates immune function through binding to a set of G protein-coupled receptors (S1PR1-5). Although S1P has been shown to attenuate lung IRI, the S1P receptors responsible for protection have not been defined. The present study tests the hypothesis that protection from lung IRI is primarily mediated through S1PR1 activation. Mice were treated with either vehicle, FTY720 (a nonselective S1P receptor agonist), or VPC01091 (a selective S1PR1 agonist and S1PR3 antagonist) before left lung IR. Function, vascular permeability, cytokine expression, neutrophil infiltration, and myeloperoxidase levels were measured in lungs. After IR, both FTY720 and VPC01091 significantly improved lung function (reduced pulmonary artery pressure and increased pulmonary compliance) vs. vehicle control. In addition, FTY720 and VPC01091 significantly reduced vascular permeability, expression of proinflammatory cytokines (IL-6, IL-17, IL-12/IL-23 p40, CC chemokine ligand-2, and TNF-α), myeloperoxidase levels, and neutrophil infiltration compared with control. No significant differences were observed between VPC01091 and FTY720 treatment groups. VPC01091 did not significantly affect elevated invariant natural killer T cell infiltration after IR, and administration of an S1PR1 antagonist reversed VPC01091-mediated protection after IR. In conclusion, VPC01091 and FTY720 provide comparable protection from lung injury and dysfunction after IR. These findings suggest that S1P-mediated protection from IRI is mediated by S1PR1 activation, independent of S1PR3, and that selective S1PR1 agonists may provide a novel therapeutic strategy to prevent lung IRI.

Ex vivo lung perfusion with adenosine A2A receptor agonist allows prolonged cold preservation of lungs donated after cardiac death

OBJECTIVE Ex vivo lung perfusion has been successful in the assessment of marginal donor lungs, including donation after cardiac death (DCD) donor lungs. Ex vivo lung perfusion also represents a unique platform for targeted drug delivery. We sought to determine whether ischemia-reperfusion injury would be decreased after transplantation of DCD donor lungs subjected to prolonged cold preservation and treated with an adenosine A2A receptor agonist during ex vivo lung perfusion. METHODS Porcine DCD donor lungs were preserved at 4°C for 12 hours and underwent ex vivo lung perfusion for 4 hours. Left lungs were then transplanted and reperfused for 4 hours. Three groups (n = 4/group) were randomized according to treatment with the adenosine A2A receptor agonist ATL-1223 or the dimethyl sulfoxide vehicle: Infusion of dimethyl sulfoxide during ex vivo lung perfusion and reperfusion (DMSO), infusion of ATL-1223 during ex vivo lung perfusion and dimethyl sulfoxide during reperfusion (ATL-E), and infusion of ATL-1223 during ex vivo lung perfusion and reperfusion (ATL-E/R). Final Pao2/Fio2 ratios (arterial oxygen partial pressure/fraction of inspired oxygen) were determined from samples obtained from the left superior and inferior pulmonary veins. RESULTS Final Pao2/Fio2 ratios in the ATL-E/R group (430.1 ± 26.4 mm Hg) were similar to final Pao2/Fio2 ratios in the ATL-E group (413.6 ± 18.8 mm Hg), but both treated groups had significantly higher final Pao2/Fio2 ratios compared with the dimethyl sulfoxide group (84.8 ± 17.7 mm Hg). Low oxygenation gradients during ex vivo lung perfusion did not preclude superior oxygenation capacity during reperfusion. CONCLUSIONS After prolonged cold preservation, treatment of DCD donor lungs with an adenosine A2A receptor agonist during ex vivo lung perfusion enabled Pao2/Fio2 ratios greater than 400 mm Hg after transplantation in a preclinical porcine model. Pulmonary function during ex vivo lung perfusion was not predictive of outcomes after transplantation.

Lungs donated after circulatory death and prolonged warm ischemia are transplanted successfully after enhanced ex vivo lung perfusion using adenosine A2B receptor antagonism

Objective: The current supply of acceptable donor lungs is not sufficient for the number of patients awaiting transplantation. We hypothesized that ex vivo lung perfusion (EVLP) with targeted drug therapy would allow successful rehabilitation and transplantation of donation after circulatory death lungs exposed to 2 hours of warm ischemia. Methods: Donor porcine lungs were procured after 2 hours of warm ischemia postcardiac arrest and subjected to 4 hours of cold preservation or EVLP. ATL802, an adenosine A2B receptor antagonist, was administered to select groups. Four groups (n = 4/group) were randomized: cold preservation (Cold), cold preservation with ATL802 during reperfusion (Cold + ATL802), EVLP (EVLP), and EVLP with ATL802 during ex vivo perfusion (EVLP + ATL802). Lungs subsequently were transplanted, reperfused, and assessed by measuring dynamic lung compliance and oxygenation capacity. Results: EVLP + ATL802 significantly improved dynamic lung compliance compared with EVLP (25.0 ± 1.8 vs 17.0 ± 2.4 mL/cmH2O, P = .04), and compared with cold preservation (Cold: 12.2 ± 1.3, P = .004; Cold + ATL802: 10.6 ± 2.0 mL/cmH2O, P = .002). Oxygenation capacity was highest in EVLP (440.4 ± 37.0 vs Cold: 174.0 ± 61.3 mm Hg, P = .037). No differences in oxygenation or pulmonary edema were observed between EVLP and EVLP + ATL802. A significant decrease in interleukin‐12 expression in tissue and bronchoalveolar lavage was identified between groups EVLP and EVLP + ATL802, along with less neutrophil infiltration. Conclusions: Severely injured donation after circulatory death lungs subjected to 2 hours of warm ischemia are transplanted successfully after enhanced EVLP with targeted drug therapy. Increased use of lungs after uncontrolled donor cardiac death and prolonged warm ischemia may be possible and may improve transplant wait list times and mortality.

Airway pressure release ventilation during ex vivo lung perfusion attenuates injury

Objective: Critical organ shortages have resulted in ex vivo lung perfusion gaining clinical acceptance for lung evaluation and rehabilitation to expand the use of donation after circulatory death organs for lung transplantation. We hypothesized that an innovative use of airway pressure release ventilation during ex vivo lung perfusion improves lung function after transplantation. Methods: Two groups (n = 4 animals/group) of porcine donation after circulatory death donor lungs were procured after hypoxic cardiac arrest and a 2‐hour period of warm ischemia, followed by a 4‐hour period of ex vivo lung perfusion rehabilitation with standard conventional volume‐based ventilation or pressure‐based airway pressure release ventilation. Left lungs were subsequently transplanted into recipient animals and reperfused for 4 hours. Blood gases for partial pressure of oxygen/inspired oxygen fraction ratios, airway pressures for calculation of compliance, and percent wet weight gain during ex vivo lung perfusion and reperfusion were measured. Results: Airway pressure release ventilation during ex vivo lung perfusion significantly improved left lung oxygenation at 2 hours (561.5 ± 83.9 mm Hg vs 341.1 ± 136.1 mm Hg) and 4 hours (569.1 ± 18.3 mm Hg vs 463.5 ± 78.4 mm Hg). Likewise, compliance was significantly higher at 2 hours (26.0 ± 5.2 mL/cm H2O vs 15.0 ± 4.6 mL/cm H2O) and 4 hours (30.6 ± 1.3 mL/cm H2O vs 17.7 ± 5.9 mL/cm H2O) after transplantation. Finally, airway pressure release ventilation significantly reduced lung edema development on ex vivo lung perfusion on the basis of percentage of weight gain (36.9% ± 14.6% vs 73.9% ± 4.9%). There was no difference in additional edema accumulation 4 hours after reperfusion. Conclusions: Pressure‐directed airway pressure release ventilation strategy during ex vivo lung perfusion improves the rehabilitation of severely injured donation after circulatory death lungs. After transplant, these lungs demonstrate superior lung‐specific oxygenation and dynamic compliance compared with lungs ventilated with standard conventional ventilation. This strategy, if implemented into clinical ex vivo lung perfusion protocols, could advance the field of donation after circulatory death lung rehabilitation to expand the lung donor pool.

Increasing circulating sphingosine-1-phosphate attenuates lung injury during ex vivo lung perfusion

Background Sphingosine‐1‐phosphate regulates endothelial barrier integrity and promotes cell survival and proliferation. We hypothesized that upregulation of sphingosine‐1‐phosphate during ex vivo lung perfusion would attenuate acute lung injury and improve graft function. Methods C57BL/6 mice (n = 4‐8/group) were euthanized, followed by 1 hour of warm ischemia and 1 hour of cold preservation in a model of donation after cardiac death. Subsequently, mice underwent 1 hour of ex vivo lung perfusion with 1 of 4 different perfusion solutions: Steen solution (Steen, control arm), Steen with added sphingosine‐1‐phosphate (Steen + sphingosine‐1‐phosphate), Steen plus a selective sphingosine kinase 2 inhibitor (Steen + sphingosine kinase inhibitor), or Steen plus both additives (Steen + sphingosine‐1‐phosphate + sphingosine kinase inhibitor). During ex vivo lung perfusion, lung compliance and pulmonary artery pressure were continuously measured. Pulmonary vascular permeability was assessed with injection of Evans Blue dye. Results The combination of 1 hour of warm ischemia, followed by 1 hour of cold ischemia created significant lung injury compared with lungs that were immediately harvested after circulatory death and put on ex vivo lung perfusion. Addition of sphingosine‐1‐phosphate or sphingosine kinase inhibitor alone did not significantly improve lung function during ex vivo lung perfusion compared with Steen without additives. However, group Steen + sphingosine‐1‐phosphate + sphingosine kinase inhibitor resulted in significantly increased compliance (110% ± 13.9% vs 57.7% ± 6.6%, P < .0001) and decreased pulmonary vascular permeability (33.1 ± 11.9 &mgr;g/g vs 75.8 ± 11.4 &mgr;g/g tissue, P = .04) compared with Steen alone. Conclusions Targeted drug therapy with a combination of sphingosine‐1‐phosphate + sphingosine kinase inhibitor during ex vivo lung perfusion improves lung function in a murine donation after cardiac death model. Elevation of circulating sphingosine‐1‐phosphate via specific pharmacologic modalities during ex vivo lung perfusion may provide endothelial protection in marginal donor lungs leading to successful lung rehabilitation for transplantation.

Cost of individual complications following coronary artery bypass grafting

Objective: The financial implications of postoperative complications in cardiac surgery remain poorly understood. The purpose of this study was to define the cost of surgery without complications and demonstrate the incremental cost of each complication. Methods: All patients undergoing isolated coronary artery bypass grafting (CABG) were evaluated (2006‐2015) from a statewide Society of Thoracic Surgeons database collaborative (N = 36,588). Patients were stratified by presence of postoperative complications, including major morbidities as defined by the Society of Thoracic Surgeons (ie, prolonged ventilation, renal failure, reoperation, stroke, and deep sternal wound infection). Hierarchical modeling was used to identify the independent inflation‐adjusted cost of each complication while controlling for hospital variation and time. Results: The median age was 64 years, 74.3% were men, and average predicted risk of mortality was 1.9%. A total of 24,738 (67.7%) patients experienced no complications at an average cost of

Enteral Access is not Required for Esophageal Cancer Patients Undergoing Neoadjuvant Therapy

36,580. Each complication independently increases the cost of care and resulted in an exponential increase in cost. After accounting for incidence and incremental costs, institutions in our collaborative have spent an estimated

In vivo lung perfusion rehabilitates sepsis-induced lung injury

59.1 million on prolonged ventilation,

Revisiting successful transplantation with marginal lungs: Fourteen years later, a new era of extended criteria

8.3 million on renal failure,