Discordance among assays for monitoring? Anticoagulation during extracorporeal life support.

OBJECTIVES: The optimal method for monitoring of anticoagulation in patients on extracorporeal life support (ECLS) is unknown. The objective of this study was to assess the relationship between anti-factor Xa level (anti-Xa; IU/mL) and activated partial thromboplastin time (aPTT; seconds) for monitoring intravenous unfractionated heparin anticoagulation in adult ECLS patients. METHODS: Charts of all adult patients cannulated for ECLS from 2015 through 2017 were reviewed and laboratory and heparin infusion data were extracted for analysis. Time matched pairs of anti-Xa and aPTT were considered concordant if both laboratory values were within the same clinically utilized range. A hierarchical logistic regression model was used to determine factors associated with discordance while accounting for patient level effects. RESULTS: A total of 1016 paired anti-Xa and aPTT values from 65 patients were evaluated. 500 (49.2%) paired samples were discordant with a degree of variability on linear regression (r2 = 0.315). The aPTT fell into a higher therapeutic range compared to the anti-Xa in 31.6% and lower in 17.3%. Logistic regression demonstrated that discordance was independently associated with time from initiation of ECLS (OR 1.17 per day, p < 0.001), average heparin infusion rate (OR 1.25 per U/kg/hr, p < 0.001), and INR (OR 3.22, p < 0.001). CONCLUSIONS: Nearly half of all aPTT and anti-Xa values were in discordant ranges and discordance is more likely as the time on ECLS and the INR level increase. The use of either assay in isolation to guide heparin anticoagulation may lead to misestimation of the degree of anticoagulation in complex ECLS patients.

Gastric Aspiration and Ventilator-Induced Model of Acute Respiratory Distress Syndrome in Swine.

INTRODUCTION: Mainstays of current treatment for acute respiratory distress syndrome (ARDS) focus on supportive care and rely on intrinsic organ recovery. Animal models of ARDS are often limited by systemic injury. We hypothesize that superimposing gastric aspiration and ventilator-induced injury will induce a lung-specific injury model of severe ARDS. MATERIALS AND METHODS: Adult swine (n = 8) were subject to a 12 h injury development period followed by 24 h of post-injury monitoring. Lung injury was induced with gastric secretions (3 cc/kg body weight/lung, pH 1-2) instilled to bilateral mainstem bronchi under direct bronchoscopic vision. Ventilator settings within the injury period contradicted baseline settings using high tidal volumes and low positive end-expiratory pressure. Baseline settings were restored following the injury period. Arterial oxygenation and lung compliance were monitored. RESULTS: At 12 h, PaO2/FiO2 ratio and static and dynamic compliance were significantly reduced from baseline (P < 0.05). During the postinjury period, animals showed no signs of recovery in PaO2/FiO2 ratio and lung compliance. Lung edema (wet/dry weight ratio) of injured lungs was significantly elevated versus noninjured lungs (8.5 ± 1.7 versus 5.6 ± 0.3, P = 0.009). Expression of proinflammatory cytokines IL-6 and IL-8 were significantly elevated in injured lungs (P < 0.05). CONCLUSIONS: Twelve hours of high tidal volume and low positive end-expiratory pressure in conjunction with low-pH gastric content instillation produces significant acute lung injury in swine. This large animal model may be useful for testing severe ARDS treatment strategies.

Commentary: Predictors of postoperative adverse events after cone reconstruction for Ebstein's anomaly.

Prediction scores and metrics are being increasingly utilized throughout the fields of cardiothoracic and congenital cardiac surgery to identify areas for perioperative optimization or guide therapeutic intent. Here, we review a novel submission by Yang and colleagues to the Journal of Cardiac Surgery identifying preoperative factors that predict adverse postoperative outcomes from cone reconstruction for Ebstein's anomaly.

Commentary: When will the robots come marching in?

Minimally invasive techniques for coronary artery bypass grafting (CABG), specifically robotic-assisted CABG has increased in popularity despite conflicting evidence. Here, we review a report by Yokoyama and colleagues to the Journal of Cardiac Surgery investigating outcomes of robotic versus nonrobotic CABG utilizing the National Inpatient Sample (NIS).

Mixed type TAPVR-Measure twice, cut once.

Total anomalous pulmonary venous return (TAVR) can have varying drainage configurations. Here, we review a report by Nagulakonda et al. to the Journal of Cardiac Surgery detailing how additional computed tomography imaging revealed a mixed type presentation of TAPVR not identified on echocardiography.

Commentary: Cardiothoracic surgery training made SIMPL.

BACKGROUND: Effective cardiothoracic surgical training requires an emphasis on education through timely feedback and constructive criticism. AIMS: Review of the implementation of the System for Improving and Measuring Procedural Learning application within a cardiothoracic surgical training program. MATERIALS & METHODS: Here, we review a report by Bergquist et al. to the Journal of Cardiac Surgery detailing their implementation of the System for Improving and Measuring Procedural Learning application. CONCLUSION: It is feasible for the SIMPL application to be implemented with acceptable use in a cardiothoracic training program.

Role of the purinergic signaling network in lung ischemia-reperfusion injury.

PURPOSE OF REVIEW: Primary graft dysfunction (PGD) is the leading cause of early mortality following lung transplantation and is typically caused by lung ischemia-reperfusion injury (IRI). Current management of PGD is largely supportive and there are no approved therapies to prevent lung IRI after transplantation. The purinergic signaling network plays an important role in this sterile inflammatory process, and pharmacologic manipulation of said network is a promising therapeutic strategy. This review will summarize recent findings in this area. RECENT FINDINGS: In the past 18 months, our understanding of lung IRI has improved, and it is becoming clear that the purinergic signaling network plays a vital role. Recent works have identified critical components of the purinergic signaling network (Pannexin-1 channels, ectonucleotidases, purinergic P1 and P2 receptors) involved in inflammation in a number of pathologic states including lung IRI. In addition, a functionally-related calcium channel, the transient receptor potential vanilloid type 4 (TRPV4) channel, has recently been linked to purinergic signaling and has also been shown to mediate lung IRI. SUMMARY: Agents targeting components of the purinergic signaling network are promising potential therapeutics to limit inflammation associated with lung IRI and thus decrease the risk of developing PGD.

Five-Year Sustained Impact of a Thoracic Enhanced Recovery After Surgery Program.

BACKGROUND: Our thoracic enhanced recovery program (ERP) decreased the use of postoperative morphine equivalents and hospital costs 1 year after implementation at our tertiary center. The sustainability and potential increasing benefit of this program were evaluated. METHODS: From 2015 to 2021, we prospectively analyzed the outcomes of patients who underwent elective pleural, pulmonary, or mediastinal operations at our institution. Patients were separated on the basis of the incision (video-assisted thoracoscopic surgery [VATS] or thoracotomy). The ERP protocol was initiated on May 1, 2016, and includes preoperative education, carbohydrate loading, opioid-sparing analgesia, conservative fluid management, protective ventilation, and early ambulation. Outcomes of patients before (2015, pre-VATS and pre-thoracotomy) and after (May 1, 2016, to December 31, 2021, ERP-VATS and ERP-thoracotomy) ERP implementation were compared. RESULTS: The cohort included 1079 patients (pre-ERP era, n = 224 [21%]; ERP era, n = 855 [79%]). There was a median reduction of 1.5 hospital days per patient for ERP-thoracotomy and 1 hospital day per patient for ERP-VATS. Median postoperative morphine equivalents decreased in both groups (125 vs 45 mg, in ERP-thoracotomy; 84 vs 23 mg, ERP-VATS; P < .001), as did total admission cost ($32,118 vs $23,775, ERP-thoracotomy; $17,367 vs $11,560, ERP-VATS; P < .001). Median total fluid balance during the hospital stay decreased significantly. Rates of postoperative atrial fibrillation and urinary retention decreased across both subgroups. CONCLUSIONS: ERP for thoracic surgery is sustainable and has been demonstrated to improve patient outcomes, to decrease opioid use, and to lower hospital costs. Therefore, it has the potential to become the standard of care.

Transient receptor potential vanilloid 4 channel inhibition attenuates lung ischemia-reperfusion injury in a porcine lung transplant model.

OBJECTIVE: Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel important in many physiological and pathophysiological processes, including pulmonary disease. Using a murine model, we previously demonstrated that TRPV4 mediates lung ischemia-reperfusion injury, the major cause of primary graft dysfunction after transplant. The current study tests the hypothesis that treatment with a TRPV4 inhibitor will attenuate lung ischemia-reperfusion injury in a clinically relevant porcine lung transplant model. METHODS: A porcine left-lung transplant model was used. Animals were randomized to 2 treatment groups (n = 5/group): vehicle or GSK2193874 (selective TRPV4 inhibitor). Donor lungs underwent 30 minutes of warm ischemia and 24 hours of cold preservation before left lung allotransplantation and 4 hours of reperfusion. Vehicle or GSK2193874 (1 mg/kg) was administered to the recipient as a systemic infusion after recipient lung explant. Lung function, injury, and inflammatory biomarkers were compared. RESULTS: After transplant, left lung oxygenation was significantly improved in the TRPV4 inhibitor group after 3 and 4 hours of reperfusion. Lung histology scores and edema were significantly improved, and neutrophil infiltration was significantly reduced in the TRPV4 inhibitor group. TRPV4 inhibitor-treated recipients had significantly reduced expression of interleukin-8, high mobility group box 1, P-selectin, and tight junction proteins (occludin, claudin-5, and zonula occludens-1) in bronchoalveolar lavage fluid as well as reduced angiopoietin-2 in plasma, all indicative of preservation of endothelial barrier function. CONCLUSIONS: Treatment of lung transplant recipients with TRPV4 inhibitor significantly improves lung function and attenuates ischemia-reperfusion injury. Thus, selective TRPV4 inhibition may be a promising therapeutic strategy to prevent primary graft dysfunction after transplant.

Implementation of a non-intensive-care unit medical emergency team improves failure to rescue rates in cardiac surgery patients.

OBJECTIVE: Failure to rescue (FTR) is an emerging measure in cardiac surgery, defined as mortality after a postoperative complication. We hypothesized that establishing a medical emergency team (MET) reduced rates of FTR in adults undergoing cardiac surgery. METHODS: All patients (N = 11,218) undergoing a The Society of Thoracic Surgeons index operation at our center (1994-2018) were stratified by pre-MET or MET era based on the 2009 institutional implementation of a MET to respond to clinical decompensation in non-intensive-care patients. Patients missing The Society of Thoracic Surgeons predicted risk of mortality were excluded from all cohorts. Risk adjusted multivariable regression analyzed the association of postoperative complications, operative mortality, and FTR by era. Nearest neighbor propensity score matching utilizing patients' The Society of Thoracic Surgeons predicted risk of mortality was performed to create balanced control and exposure groups for secondary subgroup analysis. RESULTS: In the risk-adjusted multivariable analysis, surgery during the MET era was associated with decreased mortality (odds ratio [OR], 0.51; 95% CI, 0.45-0.77; P < .001), postoperative renal failure (OR, 0.57; 95% CI, 0.46-0.70; P < .001), reoperation (OR, 0.75; 95% CI, 0.59-0.95; P = .017), and deep sternal wound infection (OR, 0.16; 95% CI, 0.04-0.45; P = .002). Surgery performed during the MET era was associated with a decreased rate of FTR in the risk-adjusted analysis (OR, 0.46; 95% CI, 0.34-0.70; P < .001). CONCLUSIONS: The development of an institutional MET program was associated with a decrease in major complications and FTR. These findings support the development of MET programs to improve FTR after cardiac surgery.

Changes in Controllable Coronary Artery Bypass Grafting Practice for White and Black Americans.

BACKGROUND: Racial disparities in outcomes after cardiac surgery are well reported. We sought to determine whether variation by race exists in controllable practices during coronary artery bypass graft surgery (CABG). We hypothesized that racial disparities exist in CABG quality metrics, but have improved over time. METHODS: All patients undergoing isolated CABG (2000 to 2019) in a multiple state database were stratified into three eras by race. Analysis included propensity matched White Americans and Black Americans. Primary outcomes included left internal mammary artery use, multiple arterial grafting, revascularization completeness, and guideline-directed medication prescription. RESULTS: Of 72 248 patients undergoing CABG, Black American patients (n = 10 270, 15%) had higher rates of diabetes mellitus, hypertension, prior stroke, and myocardial infarction. After matching, 19 806 patients (n = 9903 per group) were well balanced. Left internal mammary artery use was significantly different early (era 1, Black Americans 84.7% vs White Americans 86.6%; P = .03), but equalized over time. Importantly, multiarterial grafting differed between Black Americans and White Americans over the entire study (9.1% vs 11.5%, P < .001) and within each era. Black Americans had more incomplete revascularization during the study period (14% vs 12.8%, P = .02) driven by a large disparity in era 1 (9.5% vs 7.2%, P < .001). Despite similar rates of preoperative use, Black Americans were more often discharged on a regimen of ß-blockers (91.8% vs 89.6%, P < .001). CONCLUSIONS: Coronary artery bypass graft surgery metrics of left internal mammary artery use and optimal medical therapy have improved over time and are similar despite patient race. Black Americans undergo less frequent multiarterial grafting and greater discharge ß-blocker prescription. Identifying changes in controllable CABG quality practices across races supports a continued focus on standardizing such efforts.

Off-Hours Intensive Care Unit Transfer Is Associated With Increased Mortality and Failure to Rescue.

BACKGROUND: Cardiac postoperative intensive care unit (ICU) beds are a limited resource, and when a patient no longer requires this level of care they are quickly transferred out. We hypothesized that complications and ICU readmission increased when transfer occurred during off-hours compared with regular work hours. METHODS: From 2010 to 2021, patients who underwent a Society of Thoracic Surgeons index operation at a single center were assigned a group based on their ICU transfer time, defined as when they physically arrived on the acute care floor. Patients were stratified into off-hours vs regular hours by their transfer time. Off-hours was defined as 9 pm to 5 am. Risk-adjusted multivariable logistic regression analyzed the association of ICU readmission, postoperative complications, operative mortality, and failure to rescue by group. RESULTS: The cohort included 5951 patients (off-hours n = 292 [4.9%], regular-hours n = 5659 [95.1%]). Patients in the off-hours group had significantly greater odds of risk-adjusted ICU readmission (odds ratio 1.99, 95% CI 1.25-3.04, P < .002) and mortality (odds ratio 3.88, 95% CI 2.27-6.33, P < .001). In the major complications subgroup (Off-hours n = 55, Regular-hours n = 603), Off-hours transfer was associated with increased mortality (failure to rescue) (odds ratio 3.05, 95% CI 1.58-5.69, P = .001). CONCLUSIONS: Off-hours ICU to floor transfer was associated with increased postoperative complications, ICU readmission, and mortality, suggesting that the timing of ICU transfer may impact outcomes. This elucidates targets for quality and process improvement for our center and others facing the same resource constraints.

Effect of Cardiopulmonary Bypass on SARS-CoV-2 Vaccination Antibody Levels.

Background Adults undergoing heart surgery are particularly vulnerable to respiratory complications, including COVID-19. Immunization can significantly reduce this risk; however, the effect of cardiopulmonary bypass (CPB) on immunization status is unknown. We sought to evaluate the effect of CPB on COVID-19 vaccination antibody concentration after cardiac surgery. Methods and Results This prospective observational clinical trial evaluated adult participants undergoing cardiac surgery requiring CPB at a single institution. All participants received a full primary COVID-19 vaccination series before CPB. SARS-CoV-2 spike protein-specific antibody concentrations were measured before CPB (pre-CPB measurement), 24 hours following CPB (postoperative day 1 measurement), and approximately 1 month following their procedure. Relationships between demographic or surgical variables and change in antibody concentration were assessed via linear regression. A total of 77 participants were enrolled in the study and underwent surgery. Among all participants, mean antibody concentration was significantly decreased on postoperative day 1, relative to pre-CPB levels (-2091 AU/mL, P<0.001). Antibody concentration increased between postoperative day 1and 1 month post CPB measurement (2465 AU/mL, P=0.015). Importantly, no significant difference was observed between pre-CPB and 1 month post CPB concentrations (P=0.983). Two participants (2.63%) developed symptomatic COVID-19 pneumonia postoperatively; 1 case of postoperative COVID-19 pneumonia resulted in mortality (1.3%). Conclusions COVID-19 vaccine antibody concentrations were significantly reduced in the short-term following CPB but returned to pre-CPB levels within 1 month. One case of postoperative COVID 19 pneumonia-specific mortality was observed. These findings suggest the need for heightened precautions in the perioperative period for cardiac surgery patients.

Center case volume is associated with Society of Thoracic Surgeons-defined failure to rescue in cardiac surgery.

OBJECTIVE: Our understanding of the impact of a center's case volume on failure to rescue (FTR) after cardiac surgery is incomplete. We hypothesized that increasing center case volume would be associated with lower FTR. METHODS: Patients undergoing a Society of Thoracic Surgeons index operation in a regional collaborative (2011-2021) were included. After we excluded patients with missing Society of Thoracic Surgeons Predicted Risk of Mortality scores, patients were stratified by mean annual center case volume. The lowest quartile of case volume was compared with all other patients. Logistic regression analyzed the association between center case volume and FTR, adjusting for patient demographics, race, insurance, comorbidities, procedure type, and year. RESULTS: A total of 43,641 patients were included across 17 centers during the study period. Of these, 5315 (12.2%) developed an FTR complication, and 735 (13.8% of those who developed an FTR complication) experienced FTR. Median annual case volume was 226, with 25th and 75th percentile cutoffs of 136 and 284 cases, respectively. Increasing center-level case volume was associated with significantly greater center-level major complication rates but lower mortality and FTR rates (all P values < .01). Observed-to-expected FTR was significantly associated with case volume (P = .040). Increasing case volume was independently associated with decreasing FTR rate in the final multivariable model (odds ratio, 0.87 per quartile; confidence interval, 0.799-0.946, P = .001). CONCLUSIONS: Increasing center case volume is significantly associated with improved FTR rates. Assessment of low-volume centers' FTR performance represents an opportunity for quality improvement.

Minimally Invasive Approaches Are Safe for Concomitant Mitral and Tricuspid Valve Surgery.

OBJECTIVE: The need for concomitant tricuspid surgery during mitral valve surgery is associated with higher operative risk. We hypothesized that concomitant tricuspid surgery through a minimally invasive thoracotomy (MICS) is associated with noninferior risk compared with a sternotomy. METHODS: All patients undergoing mitral valve surgery at a single institution (2010 to 2020) were evaluated. After excluding endocarditis, emergent operations, and concomitant aortic valve or coronary artery bypass grafting procedures, patients were stratified by MICS versus sternotomy. Multivariable logistic regression assessed the risk-adjusted association between concomitant tricuspid valve procedure and Society of Thoracic Surgeons major morbidity or mortality. An interaction term evaluated the impact of approach on concomitant tricuspid surgery. RESULTS: A total of 772 patients underwent mitral valve surgery, including 138 (17.9%) with concomitant tricuspid valve operation. Of the total cohort, 243 patients (31.5%) underwent the MICS approach. Concomitant tricuspid operation was performed in 104 sternotomy patients (19.7%) compared with 34 MICS patients (14.0%, P = 0.056). After risk adjustment, patients who underwent concomitant tricuspid valve surgery via sternotomy had nearly 2 times greater odds of morbidity and mortality relative to those undergoing isolated mitral surgery via sternotomy (adjOR = 1.86, P = 0.049), while patients who underwent concomitant tricuspid surgery via the MICS approach had no increased risk of the composite outcome (adjOR = 0.66, P = 0.543), relative to isolated mitral surgery via MICS approach. CONCLUSIONS: Concomitant tricuspid surgery at the time of mitral valve surgery carries additional risk in a broad patient population. A minimally invasive approach appears to be safe for selected patients requiring concomitant tricuspid valve surgery.

Operating Room Versus Intensive Care Unit Extubation Within 6 Hours After On-Pump Cardiac Surgery: Early Results and Hospital Costs.

Time-directed extubation (fast-track) protocols may decrease length of stay and cost but data on operating room (OR) extubation is limited. The objective of this study was to compare the outcomes of extubation in the OR versus fast-track extubation within 6 hours of leaving the operating room. Patients undergoing nonemergent STS index cases (2011-2021) who were extubated within 6 hours were identified from a regional STS quality collaborative. Patients were stratified by extubation in the OR versus fast track. Propensity score matching (1:n) was performed to balance baseline differences. Of the 24,962 patients, 498 were extubated in the OR. After matching, 487 OR extubation cases and 899 fast track cases were well balanced. The rate of reintubation was higher for patients extubated in the OR [21/487 (4.3%) vs 16/899 (1.8%), P = 0.008] as was the incidence of reoperation for bleeding [12/487 (2.5%) vs 8/899 (0.9%), P = 0.03]. There was no significant difference in the rate of any reoperation [16/487 (3.3%) vs 15/899 (1.6%), P = 0.06] or operative mortality [4/487 (0.8%) vs 6/899 (0.6%), P = 0.7]. OR extubation was associated with shorter hospital length of stay (5.6 vs 6.2 days, P < 0.001) and lower total cost of admission ($29,602 vs $31,565 P < 0.001). OR extubation is associated with a higher postoperative risk of reintubation and reoperation due to bleeding, but lower resource utilization.Future research exploring predictors of extubation readiness may be required prior to widespread adoption of this practice.

Perioperative acetaminophen is associated with reduced acute kidney injury after cardiac surgery.

BACKGROUND: Cardiac surgery-associated acute kidney injury (AKI) is associated with increased postoperative morbidity and mortality. Evidence suggests an association between perioperative acetaminophen administration and decreased incidence of postoperative AKI in pediatric cardiac surgery patients; however, an effect in adults is unknown. METHODS: All patients (n = 6192) undergoing coronary and/or valve surgery with a recorded Society of Thoracic Surgeons (STS) risk score at our institution between 2010 and 2018 were stratified by acetaminophen exposure on the day of surgery using institutional pharmacy records. AKI was determined using the Kidney Disease: Improving Global Outcomes (KDIGO) staging criteria. Logistic regression was used to analyze the association between perioperative acetaminophen and postoperative kidney injury or STS major morbidity. A sensitivity analysis using propensity score matching on the STS predicted risk of renal failure and cardiopulmonary bypass time was performed to account for time bias. RESULTS: Perioperative acetaminophen exposure was associated with lower odds of stage 1 to 3 acute kidney injury (odds ratio [OR], 0.68; 95% CI, 0.56-0.83; P < .001) and decreased prolonged postoperative ventilation (OR, 0.53; 95% CI, 0.37-0.76; P < .001). A sensitivity analysis provided well-balanced (standard mean difference <0.10) groups of 401 pairs, in which acetaminophen was associated with a decreased incidence of postoperative AKI (OR, 0.7; 95% CI, 0.52-0.94; P = .016). CONCLUSIONS: Exposure to acetaminophen on the day of surgery was associated with a decreased incidence of AKI in our patients undergoing cardiac surgery. These data serve as a measure of effect size to further explore the therapeutic potential of acetaminophen to reduce postoperative AKI after cardiac surgery and to elucidate the mechanisms involved.

Prediction of Prolonged Intensive Care Unit Length of Stay Following Cardiac Surgery.

Intensive care unit (ICU) costs comprise a significant proportion of the total inpatient charges for cardiac surgery. No reliable method for predicting intensive care unit length of stay following cardiac surgery exists, making appropriate staffing and resource allocation challenging. We sought to develop a predictive model to anticipate prolonged ICU length of stay (LOS). All patients undergoing coronary artery bypass grafting (CABG) and/or valve surgery with a Society of Thoracic Surgeons (STS) predicted risk score were evaluated from an institutional STS database. Models were developed using 2014-2017 data; validation used 2018-2019 data. Prolonged ICU LOS was defined as requiring ICU care for at least three days postoperatively. Predictive models were created using lasso regression and relative utility compared. A total of 3283 patients were included with 1669 (50.8%) undergoing isolated CABG. Overall, 32% of patients had prolonged ICU LOS. Patients with comorbid conditions including severe COPD (53% vs 29%, P < 0.001), recent pneumonia (46% vs 31%, P < 0.001), dialysis-dependent renal failure (57% vs 31%, P < 0.001) or reoperative status (41% vs 31%, P < 0.001) were more likely to experience prolonged ICU stays. A prediction model utilizing preoperative and intraoperative variables correctly predicted prolonged ICU stay 76% of the time. A preoperative variable-only model exhibited 74% prediction accuracy. Excellent prediction of prolonged ICU stay can be achieved using STS data. Moreover, there is limited loss of predictive ability when restricting models to preoperative variables. This novel model can be applied to aid patient counseling, resource allocation, and staff utilization.

Endothelial Transient Receptor Potential Vanilloid 4 Channels Mediate Lung Ischemia-Reperfusion Injury.

BACKGROUND: Lung ischemia-reperfusion injury (IRI), involving severe inflammation and edema, is a major cause of primary graft dysfunction after transplant. Activation of transient receptor potential vanilloid 4 (TRPV4) channels modulates vascular permeability. Thus, this study tests the hypothesis that endothelial TRPV4 channels mediate lung IRI. METHODS: A left lung hilar-ligation model was used to induce lung IR in C57BL/6 wild-type (WT), Trpv4-/-, tamoxifen-inducible endothelial Trpv4 knockout (Trpv4EC-/-), and tamoxifen-treated control (Trpv4fl/fl) (n ≥ 6 mice/group). WT mice were also treated with GSK2193874 (WT+GSK219), a TRPV4-specific inhibitor (1 mg/kg). Partial pressure of arterial oxygen, edema (wet-to-dry weight ratio), compliance, neutrophil infiltration, and cytokine concentrations in bronchoalveolar lavage fluid were assessed. Pulmonary microvascular endothelial cells were characterized in vitro after exposure to hypoxia-reoxygenation. RESULTS: Compared with WT, partial pressure of arterial oxygen after IR was significantly improved in Trpv4-/- mice (133.1 ± 43.9 vs 427.8 ± 83.1 mm Hg, P < .001) and WT+GSK219 mice (133.1 ± 43.9 vs 447.0 ± 67.6 mm Hg, P < .001). Pulmonary edema and neutrophil infiltration were also significantly reduced after IR in Trpv4-/- and WT+GSK219 mice vs WT. Trpv4EC-/- mice after IR demonstrated significantly improved oxygenation vs control (109.2 ± 21.6 vs 405.3 ± 41.4 mm Hg, P < .001) as well as significantly improved compliance and significantly less edema, neutrophil infiltration, and proinflammatory cytokine production (tumor necrosis factor-a, chemokine [C-X-C motif] ligand 1, interleukin 17, interferon-γ). Hypoxia-reoxygenation-induced permeability and chemokine (C-X-C motif) ligand 1 expression by pulmonary microvascular endothelial cells were significantly attenuated by TRPV4 inhibitors. CONCLUSIONS: Endothelial TRPV4 plays a key role in vascular permeability and lung inflammation after IR. TRPV4 channels may be a promising therapeutic target to mitigate lung IRI and decrease the incidence of primary graft dysfunction after transplant.