Matthias J. Merkel

Soluble epoxide hydrolase inhibition and gene deletion are protective against myocardial ischemia-reperfusion injury in vivo

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids. EETs are formed from arachidonic acid during myocardial ischemia and play a protective role against ischemic cell death. Deletion of sEH has been shown to be protective against myocardial ischemia in the isolated heart preparation. We tested the hypothesis that sEH inactivation by targeted gene deletion or pharmacological inhibition reduces infarct size (I) after regional myocardial ischemia-reperfusion injury in vivo. Male C57BL\6J wild-type or sEH knockout mice were subjected to 40 min of left coronary artery (LCA) occlusion and 2 h of reperfusion. Wild-type mice were injected intraperitoneally with 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE), a sEH inhibitor, 30 min before LCA occlusion or during ischemia 10 min before reperfusion. 14,15-EET, the main substrate for sEH, was administered intravenously 15 min before LCA occlusion or during ischemia 5 min before reperfusion. The EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (EEZE) was given intravenously 15 min before reperfusion. Area at risk (AAR) and I were assessed using fluorescent microspheres and triphenyltetrazolium chloride, and I was expressed as I/AAR. I was significantly reduced in animals treated with AUDA-BE or 14,15-EET, independent of the time of administration. The cardioprotective effect of AUDA-BE was abolished by the EET antagonist 14,15-EEZE. Immunohistochemistry revealed abundant sEH protein expression in left ventricular tissue. Strategies to increase 14,15-EET, including sEH inactivation, may represent a novel therapeutic approach for cardioprotection against myocardial ischemia-reperfusion injury.

Inhaled nitric oxide (NO) for the treatment of early allograft failure after lung transplantation

Objective: Inhalation of high concentrations of nitric oxide (NO) has been shown to improve gas exchange and to reduce pulmonary vascular resistance in individuals with ischemia-reperfusion injury following orthotopic lung transplantation. We assessed the cardiopulmonary effects of low doses of NO in early allograft dysfunction following lung transplantion. Design: Prospective clinical dose- response study. Setting: Anesthesiological intensive care unit of a university hospital. Patients and participants: 8 patients following a single or double lung transplantation who had a mean pulmonary arterial pressure (PAP) in excess of 4.7 kPa (35 mmHg) or an arterial oxygen tension/fractional inspired oxygen ratio (PaO2/FIO2) of less than 13.3 kPa (100 mmHg). Interventions: Gaseous NO was inhaled in increasing concentrations (1, 4 and 8 parts per million, each for 15 min) via a Siemens Servo 300 ventilator. Measurements and results: Cardiorespiratory parameters were assessed at baseline, after each concentration of NO, and 15 min after withdrawal of the agent [statistics: median (25th/75th percentiles: Q1/Q3), rANOVA, Dunnetts test, p < 0.05]. Inhaled NO resulted in a significant, reversible, dose-dependent, selective reduction in PAP from 5.5(5.2/6.0) kPa at control to 5.1(4.7/5.6) kPa at 1 ppm, 4.9(4.3/5.3) kPa at 4 ppm, and to 4.7(4.1/5.1) kPa at 8 ppm. PaO2 increased from 12.7(10.4/17.1) to 19.2(12.4/26.0) kPa at 1 ppm NO, to 23.9(4.67/26.7) kPa at 4 ppm NO and to 24.5(11.9/28.7) kPa at 8 ppm NO. All patients responded to NO inhalation (either with PAP or PaO2), all were subject to long-term inhalation (1–19 days). All were successfully weaned from NO and were discharged from the intensive care unit. Conclusion: The present study demonstrates that low-dose inhaled NO may be an effective drug for symptomatic treatment of hypoxemia and/or pulmonary hypertension due to allograft dysfunction subsequent to lung transplantation.

The Role of Echocardiography in Hemodynamic Assessment of Septic Shock

Echocardiography is a rapid, noninvasive, comprehensive cardiac assessment option for patients presenting with hemodynamic instability. In patients with septic shock, echocardiography can be used to guide fluid therapy by measuring collapsibility of the inferior vena cava. Sepsis-induced myocardial dysfunction can be diagnosed, and responses to therapy can be monitored with echo. Patients with persistent shock should be evaluated for right heart failure, dynamic left ventricular obstruction, or tamponade if they do not respond to resuscitation and norepinephrine. Unexpected or rare findings that affect management may be revealed using focused echocardiography. This article presents national and international competency statements regarding critical care echocardiography and training resources for intensivists.

Critical Care Basic Ultrasound Learning Goals for American Anesthesiology Critical Care Trainees: Recommendations from an Expert Group.

OBJECTIVE:In this review, we define learning goals and recommend competencies concerning focused basic critical care ultrasound (CCUS) for critical care specialists in training. DESIGN:The narrative review is, and the recommendations contained herein are, sponsored by the Society of Critical Care Anesthesiologists. Our recommendations are based on a structured literature review by an expert panel of anesthesiology intensivists and cardiologists with formal training in ultrasound. Published descriptions of learning and training routines from anesthesia–critical care and other specialties were identified and considered. Sections were written by groups with special expertise, with dissent included in the text. RESULTS:Learning goals and objectives were identified for achieving competence in the use of CCUS at a specialist level (critical care fellowship training) for diagnosis and monitoring of vital organ dysfunction in the critical care environment. The ultrasound examination was divided into vascular, abdominal, thoracic, and cardiac components. For each component, learning goals and specific skills were presented. Suggestions for teaching and training methods were described. DISCUSSION:Immediate bedside availability of ultrasound resources can dramatically improve the ability of critical care physicians to care for critically ill patients. Anesthesia--critical care medicine training should have definitive expectations and performance standards for basic CCUS interpretation by anesthesiology--critical care specialists. The learning goals in this review reflect current trends in the multispecialty critical care environment where ultrasound-based diagnostic strategies are already frequently applied. These competencies should be formally taught as part of an established anesthesiology-critical care medicine graduate medical education programs.

Inhibition of soluble epoxide hydrolase preserves cardiomyocytes: role of STAT3 signaling

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs), primarily 14,15-EET. EETs are derived from arachidonic acid via P-450 epoxygenases and are cardioprotective. We tested the hypothesis that sEH deficiency and pharmacological inhibition elicit tolerance to ischemia via EET-mediated STAT3 signaling in vitro and in vivo. In addition, the relevance of single nucleotide polymorphisms (SNPs) of EPHX2 (the gene encoding sEH) on tolerance to oxygen and glucose deprivation and reoxygenation and glucose repletion (OGD/RGR) was assessed in male C57BL\6J (WT) or sEH knockout (sEHKO) cardiomyocytes by using transactivator of transcription (TAT)-mediated transduction with sEH mutant proteins. Cell death and hydrolase activity was lower in Arg287Gln EPHX2 mutants vs. nontransduced controls. Excess 14,15-EET and SEH inhibition did not improve cell survival in Arg287Gln mutants. In WT cells, the putative EET receptor antagonist, 14,15-EEZE, abolished the effect of 14,15-EET and sEH inhibition. Cotreatment with 14,15-EET and SEH inhibition did not provide increased protection. In vitro, STAT3 inhibition blocked 14,15-EET cytoprotection, but not the effect of SEH inhibition. However, STAT3 small interfering RNA (siRNA) abolished cytoprotection by 14,15-EET and sEH inhibition, but cells pretreated with JAK2 siRNA remained protected. In vivo, STAT3 inhibition abolished 14,15-EET-mediated infarct size reduction. In summary, the Arg287Gln mutation is associated with improved tolerance against ischemia in vitro, and inhibition of sEH preserves cardiomyocyte viability following OGD/RGR via an EET-dependent mechanism. In vivo and in vitro, 14,15-EET-mediated protection is mediated in part by STAT3.

The effect of inhaled nitric oxide and inhaled iloprost on hypoxaemia in a patient with pulmonary hypertension after pulmonary thrombarterectomy

Acute pulmonary hypertension with life‐threatening right heart failure may complicate the postoperative course following cardiothoracic surgery. Both inhaled nitric oxide and inhaled iloprost, a stable analogue of prostacyclin, have been used frequently for this purpose in acute pulmonary hypertension of various origins. We present a case of a patient with acute pulmonary hypertension and severely impaired gas exchange following pulmonary thrombo‐endarterectomy. Therapy with one inhaled vasodilator alone did not satisfactorily abort a postoperative pulmonary hypertensive crisis and low‐output syndrome due to right heart failure. Combined inhaled nitric oxide and inhaled iloprost, however, showed additive effects. Hence, the combination of both drugs may be reasonable in cases where the standard therapy fails. The effect has been demonstrated by means of continuous blood gas monitoring.

Postcardiac arrest temperature management: infectious risks.

Purpose of reviewTherapeutic hypothermia following out-of-hospital cardiac arrest improves neurological recovery. Coupled with neurological benefit, multiple complications including infection have been associated with therapeutic hypothermia following out-of-hospital cardiac arrest. In this review, we will discuss therapeutic hypothermia, and more broadly, temperature management, as a risk for ICU infection. Recent findingsThe application of therapeutic hypothermia following out-of-hospital cardiac arrest has been associated with infectious complications. Studies of hypothermic animal models have provided useful insights into mechanisms by which therapeutic hypothermia confers neuroprotection. Ironically, the same mechanisms through which therapeutic hypothermia provides neuroprotection have been implicated in the risk of infection associated with therapeutic hypothermia. Studies have demonstrated types of infections, pathogens, and the impact of infections on mortality and neurological recovery. SummaryStudies demonstrate increased rate of pneumonia and bacteremia but decreased rate of other infections, suggesting redistribution but no overall increased risk of infection per se. The diagnosis of infection during therapeutic hypothermia does not impact mortality or neurological recovery.

Therapeutic Hypothermia After Perioperative Cardiac Arrest in Cardiac Surgical Patients

BACKGROUND: Therapeutic hypothermia (TH) has been established as an effective treatment for preserving neurological function after out of hospital cardiac arrest (CA). Use of TH has been limited in cardiac surgery patients in particular because of concern about adverse effects such as hemorrhage and dysrhythmia. Little published data describe efficacy or safety of TH in cardiac surgical patients who suffer unintentional CA. However, the benefits of TH are such as may suggest clinical equipoise, even in this high risk patient population. OBJECTIVE: To report a series of three patients in our institutions cardiac surgery intensive care unit who suffered unintentional CA within 48 hours of cardiac surgery and were treated with TH. METHODS: After institutional review board approval, study patients were identified by diagnosis of undesired intraoperative CA or arrest on ICU days 1-2, as well as having documented TH. The institutions electronic medical record and the Society of Thoracic Surgeons database were retrospectively reviewed for demographic information, comorbid diagnoses, surgical procedure, and outcomes including hemorrhage, re-warming dysrhythmias, infection, in-hospital mortality, and neurologic outcome were assessed. TH was initiated and monitored using active cooling pads according to written institutional protocol. RESULTS: Four patients received TH after perioperative arrest. One patient was inadequately cooled and had massive surgical bleeding, and was therefore excluded from this review. The remaining three patients had a predicted mortality of 14.6% (±13.3) based on Euroscore calculation, and were cooled for 17.6±4.0 hours after CA. Coagulopathy, hypovolemia, severe electrolyte abnormalities, and re-warming dysrhythmias were not identified in any patient. 2 patients were discharged home and 1 was discharged to a long-term care facility. CONCLUSION: Herein we report the safe and successful use of TH after unintentional perioperative CA in 3 cardiac surgery patients. These data suggest that further investigation of this therapy may be warranted given the potential benefit and apparent safety in a small series.

A Structured Transfer of Care Process Reduces Perioperative Complications in Cardiac Surgery Patients

INTRODUCTION: Serious complications are common during the intensive care of postoperative cardiac surgery patients. Some of these complications may be influenced by communication during the process of handover of care from the operating room to the intensive care unit (ICU) team. A structured transfer of care process may reduce the rate of communication errors and perioperative complications. METHODS: We hypothesized that a collaborative, comprehensive, structured handover of care from the intraoperative team to the ICU team would reduce a specific set of postoperative complications. We tested this hypothesis by developing and introducing a comprehensive multidisciplinary transfer of care process. We measured patient outcomes before and after the intervention using a linkage between 2 care databases: an Anesthesia Information Management System and a critical care complication registry database. RESULTS: There were 1127 total postoperative cardiac surgery admissions during the study period, 550 before and 577 after the intervention. There was no statistical difference between overall complications before and after the intervention (P = .154). However, there was a statistically significant reduction in preventable complications after the intervention (P = .023). DISCUSSION: The main finding of this investigation is that the introduction of a collaborative, comprehensive transfer of care process from the operating room to the ICU was associated with patients suffering fewer preventable complications.

Process Improvement Initiative for the Perioperative Management of Patients With a Cardiovascular Implantable Electronic Device

BACKGROUND: Economic, personnel, and procedural challenges often complicate and interfere with efficient and safe perioperative care of patients with cardiovascular implantable electronic devices (CIEDs). In the context of a process improvement initiative, we created and implemented a comprehensive anesthesiologist-run perioperative CIED service to respond to all routine requests for perioperative CIED consultations at a large academic medical center. This study was designed to determine whether this new care model was associated with improved operating room efficiency, reduced institutional cost, and adequate patient safety. METHODS: We included patients with a CIED and a concurrent cohort of patients with the same eligibility criteria but without a CIED who underwent first-case-of-the-day surgery during the periods between February 1, 2008, and August 17, 2010 (preintervention) and between March 4, 2012, and August 1, 2014 (postintervention). The primary end point was delay in first-case-of-the day start time. We used multiple linear regression to compare delays in start times during the preintervention and postintervention periods and to adjust for potential confounders. A patient safety database was queried for CIED-related complications. Cost analysis was based on labor minutes saved and was calculated using nationally published administrative estimates. RESULTS: A total of 18,148 first-case surgical procedures were performed in 15,100 patients (preintervention period—7293 patients and postintervention period—7807 patients). Of those, 151 (2.1%) patients had a CIED in the preintervention period, and 146 (1.9%) had a CIED in the postintervention period. After adjustment for imbalances in baseline characteristics (age, American Society of Anesthesiologists physical status, and surgical specialty), the difference in mean first-case start delay between the postintervention and preintervention periods in the cohort of patients with a CIED was −16.7 minutes (95% confidence interval [CI], −26.1 to −7.2). The difference in mean delay between the postintervention and preintervention periods in the cohort without a CIED was −4.7 minutes (95% CI, −5.4 to −3.9). There were 3 CIED-related adverse events during the preintervention period and none during the postintervention period. Based on reduction in first-case start delay, the intervention was associated with cost savings (estimated institutional savings