Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation.

Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac output in heart failure patients and diminishes ischemia-reperfusion injury, presumably by improving mitochondrial metabolism. We investigated effects of 3-OHB on cardiac and mitochondrial function in transplanted hearts and in cardiac organoids. Donor pigs (n = 14) underwent circulatory death followed by NRP. Following static cold storage, hearts were transplanted into recipient pigs. 3-OHB or Ringer's acetate infusions were initiated during NRP and after transplantation. We evaluated hemodynamics and mitochondrial function. 3-OHB mediated effects on contractility, relaxation, calcium, and conduction were tested in cardiac organoids from human pluripotent stem cells. Following NRP, 3-OHB increased cardiac output (P < 0.0001) by increasing stroke volume (P = 0.006), dP/dt (P = 0.02) and reducing arterial elastance (P = 0.02). Following transplantation, infusion of 3-OHB maintained mitochondrial respiration (P = 0.009) but caused inotropy-resistant vasoplegia that prevented weaning. In cardiac organoids, 3-OHB increased contraction amplitude (P = 0.002) and shortened contraction duration (P = 0.013) without affecting calcium handling or conduction velocity. 3-OHB had beneficial cardiac effects and may have a potential to secure cardiac function during heart transplantation. Further studies are needed to optimize administration practice in donors and recipients and to validate the effect on mitochondrial function.

Ex-situ oxygenated hypothermic machine perfusion in donation after circulatory death heart transplantation following either direct procurement or in-situ normothermic regional perfusion.

BACKGROUND: Heart transplantation in donation after circulatory death (DCD) relies on warm perfusion using either in situ normothermic regional perfusion (NRP) or ex situ normothermic machine perfusion. In this study, we explore an alternative: oxygenated hypothermic machine perfusion (HMP) using a novel clinically applicable perfusion system, which is compared to NRP with static cold storage (SCS). METHODS: In a porcine model, a DCD setting was simulated, followed by either (1) NRP and SCS (2) NRP and HMP with the XVIVO Heart preservation system or (3) direct procurement (DPP) and HMP. After preservation, heart transplantation (HTX) was performed. After weaning from cardiopulmonary bypass (CPB), biventricular function was assessed by admittance and Swan-Ganz catheters. RESULTS: Only transplanted hearts in the HMP groups showed significantly increased biventricular contractility (end-systole elastance) 2 hour post-CPB (left ventricle absolute change: NRP HMP: +1.8 ± 0.56, p = 0.047, DPP HMP: +1.5 ± 0.43, p = 0.045 and NRP SCS: +0.97 ± 0.47 mmHg/ml, p = 0.21; right ventricle absolute change: NRP HMP: +0.50 ± 0.12, p = 0.025, DPP HMP: +0.82 ± 0.23, p = 0.039 and NRP SCS: +0.28 ± 0.26, p = 0.52) while receiving significantly less dobutamine to maintain a cardiac output >4l/min compared to SCS. Diastolic function was preserved in all groups. Post-HTX, both HMP groups showed significantly less increments in plasma troponin T compared to SCS. CONCLUSION: In DCD HTX, increased biventricular contractility post-HTX was only observed in hearts preserved with HMP. In addition, the need for inotropic support and signs of myocardial damage were lower in the HMP groups. DCD HTX can be successfully performed using DPP followed by preservation with HMP in a preclinical setting.

Clamping of the Aortic Arch Vessels During Normothermic Regional Perfusion Does Not Negatively Affect Donor Cardiac Function in Donation After Circulatory Death.

BACKGROUND: The hemodynamic effects of aortic arch vessel (AAV) clamping during normothermic regional perfusion (NRP) in donation after circulatory death is unknown. We investigated effects of AAV clamping during NRP compared with no clamping in a porcine model. METHODS: In 16 pigs, hemodynamic parameters were recorded including biventricular pressure-volume measurements and invasive blood pressure. Additionally, blood gas parameters and inflammatory cytokines were used to assess the effect of AAV clamping. The animals were centrally cannulated for NRP, and baseline measurements were obtained before hypoxic circulatory arrest was induced by halting mechanical ventilation. During an 8-min asystole period, the animals were randomized to clamp (n = 8) or no-clamp (n = 8) of the AAV before commencement of NRP. During NRP, circulation was supported with norepinephrine (NE) and dobutamine. After 30 min of NRP, animals were weaned and observed for 180 min post-NRP. RESULTS: All hearts were successfully reanimated and weaned from NRP. The nonclamp groups received significantly more NE to maintain a mean arterial pressure >60 mm Hg during and after NRP compared with the clamp group. There were no between group differences in blood pressure or cardiac output. Pressure-volume measurements demonstrated preserved cardiac function' including ejection fraction and diastolic and systolic function. No between group differences in inflammatory markers were observed. CONCLUSIONS: AAV clamping did not negatively affect donor cardiac function or inflammation after circulatory death and NRP. Significantly less NE was used to support in the clamp group than in the nonclamp group.

High Oxygenation During Normothermic Regional Perfusion After Circulatory Death Is Beneficial on Donor Cardiac Function in a Porcine Model.

BACKGROUND: Thoracoabdominal normothermic regional perfusion (NRP) is a new method for in situ reperfusion and reanimation of potential donor organs in donation after circulatory death by reperfusion of the thoracic and abdominal organs with oxygenated blood. We investigated effects of high oxygenation (HOX) versus low oxygenation (LOX) during NRP on donor heart function in a porcine model. METHODS: Pigs (80 kg) underwent a 15-min anoxic cardiac arrest followed by cardiac reanimation on NRP using a heart-lung bypass machine with subsequent assessment 180 min post-NRP. The animals were randomized to HOX (FiO2 1.0) or LOX (FiO2 0.21 increased to 0.40 during NRP). Hemodynamic data were obtained by invasive blood pressure and biventricular pressure-volume measurements. Blood gases, biomarkers of inflammation, and oxidative stress were measured. RESULTS: Eight of 9 animals in the HOX group and 7 of 10 in the LOX group were successfully weaned from NRP. Right ventricular end-systole elastance was significantly improved in the HOX group compared with the LOX group, whereas left ventricular end-systole elastance was preserved at baseline levels. Post-NRP cardiac output, mean arterial, central venous, and pulmonary capillary wedge pressure were all comparable to baseline. Creatinine kinase-MB increased more in the LOX group than the HOX group, whereas proinflammatory cytokines increased more in the HOX group than the LOX group. No difference was found in oxidative stress between groups. CONCLUSIONS: All hearts weaned from NRP showed acceptable hemodynamic function for transplantation. Hearts exposed to LOX showed more myocardial damage and showed poorer contractile performance than hearts reperfused with high oxygen.

Clamping of the Aortic Arch Vessels During Normothermic Regional Perfusion After Circulatory Death Prevents the Return of Brain Activity in a Porcine Model.

BACKGROUND: The cerebral effect of clamping following normothermic regional perfusion (NRP) in donation after circulatory death (DCD) remains unknown. We investigated the effect of cerebral reperfusion during NRP and the preventive effect of clamping on brain function in a porcine model. METHODS: In 16 pigs, intracranial physiological parameters were recorded, including pressure, cerebral blood perfusion (CBF), temperature, and oxygen. Additionally, electroencephalography (EEG) and somatosensory evoked potentials (SSEPs) were used to assess brain function. The animals were cannulated for the heart-lung machine, and baseline measurements were performed before withdrawal from life support. After 8 min of mechanical asystole, the animals were randomly allocated to clamp (n = 8) or nonclamp (n = 8) of the aortic arch vessels. After 30 min of NRP, the animals were monitored for 3 h after weaning (AW). RESULTS: Intracranial measurements of CBF, oxygen, and temperature indicated successful occlusion of the arch vessels following NRP and AW in the clamp group versus the nonclamp group. In the clamp group, EEG was isoelectric and SSEPs were absent AW in all pigs. In the nonclamp group, EEG activity was observed in all 8 pigs, whereas SSEPs were observed in 6 of 8 pigs. Additionally, agonal respiratory movements in the form of gasping were observed in 6 of 8 pigs in the nonclamp group. CONCLUSIONS: Reperfusion of the brain during NRP led to a return of brain activity. Conversely, clamping of the arch vessels halted cerebral circulation, ensuring the permanent cessation of brain function and maintaining the determination of death in DCD.

Fast-track cardiac anaesthesia protocols: Is quality pushed to the edge?

Background: The quest for methods expediting rapid postoperative patient turnover has triggered implementation of various fast-track cardiac anaesthesia protocols. Using three different fast-track protocols in randomized controlled studies (RCT) conducted 2010-2016 we found minimal achievements in ventilation time together with actual and eligible length of stay in cardiac recovery unit. The comparable control group patients were evaluated in this retrospective post hoc analysis, for an association between above mentioned parameters and quality parameters, to assess whether the marginal gains have been at the expense of quality of recovery and patient comfort. Method: 90 control patients from three RCT with comparable demographic parameters and receiving standard department treatment were evaluated using time parameters and an objective/semi-objective Intensive Care Unit (ICU) score system (IDS score). Results: Ventilation time was statistical significant lower in latest study (C) than the early (A) and intermedium (B) studies (A=293, B=261, C=205 minutes; P=0.04). The IDS was lower at extubation and all time points in the early study compared to other studies (P < 0.001;). The average IDS in latest study were the double of previous studies at the end of observations, and marginally above the acceptable score for discharge. The postoperative morphine requirement A=15.0, B=10.0 and C=26.5 mg; P=0.002) was statistical significant higher in the latest study compared to previous studies. Conclusion: The implementation of strict fast-track protocols resulting in shorter ventilation time did not convert to earlier eligibility to discharge from the ICU. However, the quality of recovery appears challenged.

Lower Dose of Sufentanil Does Not Enhance Fast Track Significantly-A Randomized Study.

OBJECTIVE: Adjustment in the doses of opioids has been a focus of interest for achieving better fast-track conditions in cardiac anesthesia, but relatively sparse information exists on the potential effect of psychologic and behavioral factors, such as stress, anxiety, and type of personality, on anesthesia requirements and patient turnover in the cardiac recovery unit (CRU); to the authors' knowledge, this particular focus has not been systematically investigated. In this randomized study, the authors tested the hypothesis that low-dose sufentanil, compared with a standard dose, can improve fast-track parameters and the overall quality of recovery. Opioid requirements related to personality type, pain sensitivity, and preoperative stress and anxiety also were assessed. DESIGN: A randomized, prospective study. PARTICIPANTS: The study comprised 60 patients scheduled for elective coronary artery bypass grafting with or without aortic valve replacement. SETTING: A university hospital. INTERVENTIONS: Patients were randomly assigned to receive either a standard dose (bolus 0.5 µg/kg) or low dose (bolus 0.25 µg/kg) of sufentanil combined with propofol. MEASUREMENTS AND MAIN RESULTS: The primary outcome variables were ventilation time and eligible time to discharge from the CRU. The secondary objective was to evaluate the relationship between opioid requirements and personality type, pain sensitivity, and preoperative stress and anxiety. The groups were comparable in selected demographics and perioperative parameters. There was no difference between groups in ventilation time (low dose: 191 [163-257] v standard dose: 205 [139-279] min; p = 0.405); eligible CRU discharge time (10.3 ± 5.0 v 10.3 ± 4.2 h; p = 0.978); or administration of postoperative morphine (25 [11-34) v 27 [10-39] g; p = 0.790). There was no difference between groups in total sufentanil administration and various preoperative psychologic and behavioral test levels nor in the time to reach bispectral index <50 during induction, except that personality type A demonstrated a longer induction time of 10 (8-12) minutes versus 6 (4-8) minutes in low-score patients. CONCLUSION: A lower dose of sufentanil, compared with a standard dose, does not enhance fast-track conditions significantly.

Colloids in Cardiac Surgery-Friend or Foe?

OBJECTIVE: The right choice of fluid replacement still is a matter of debate. Recently, two large-scale studies on the use of hydroxyethyl starches (HES) in the intensive care setting have been published, which have caused a huge shift in the daily practice of volume therapy. These results have been applied to patients outside intensive care. The aim of this study was to evaluate the impact this change has had on the outcomes in a large population of cardiac surgery patients, with a focus on the type of colloid infusion. DESIGN: A prospective, registered, observational study, using propensity score matching. SETTING: Cohort study from 3 university hospitals using a common registry. PARTICIPANTS: The study comprised 17,742 patients who were referred for cardiac surgery from 2007 to 2014. INTERVENTIONS: Patients were divided in groups according to perioperative fluid replacement with either crystalloids or colloids. The colloid group was further divided into HES or human albumin (HA). Analyses were based on the following 3 subsections: HES versus crystalloids, HA versus crystalloids, and HES versus HA, with use of propensity score matching or direct matching of cases. Primary outcome parameters were 30-day and 6-month mortality, new postoperative renal replacement therapy, and new cardiac ischemic events. MEASUREMENTS AND MAIN RESULTS: The groups were fully comparable in individual analyses. The use of HES had no impact on new dialysis and 30-day mortality. A Cox proportional regression analysis showed that HES had no impact on 6-month mortality and new postoperative ischemic events. When comparing HA with crystalloid use, a significantly increased risk in crude analysis was demonstrated on all outcome parameters; and when comparing HA with HES, a significantly higher risk was observed in HA patients in mortality parameters and new postoperative, but after adjustment, only the risk of new postoperative dialysis persisted. CONCLUSION: This study underlined the difficulties in establishing hardcore outcome data, even in large cohort studies. The findings seemed to diminish the magnitude of risk when using HES in cardiac surgery patients and seriously questioned the choice of HA when a plasma expander is needed.

Ultrashort acting remifentanil is not superior to long-acting sufentanil in preserving cognitive function-a randomized study.

STUDY OBJECTIVE: Postoperative cognitive dysfunction (POCD) is a well-known complication after cardiac surgery and may cause permanent disabilities with severe consequences for quality of life. The objectives of this study were, first, to estimate the frequency of POCD after on-pump cardiac surgery in patients randomized to remifentanil- or sufentanil-based anesthesia and, second, to evaluate the association between POCD and quality of recovery and perioperative hemodynamics, respectively. DESIGN: Randomized study. SETTING: Postoperative cardiac recovery unit, University Hospital. PATIENTS: Sixty patients with ischemic heart disease scheduled for elective coronary artery bypass grafting ± aortic valve replacement. INTERVENTIONS AND HANDLING: Randomized to either remifentanil or sufentanil anesthesia as basis opioid. Postoperative pain management consisted of morphine in both groups. MEASUREMENTS: Cognitive functioning evaluated preoperatively and on the 1st, 4th, and 30th postoperative day using the cognitive test from the Palo Alto Veterans Affairs Hospital. Perioperative invasive hemodynamics and the quality of recovery was evaluated by means of invasive measurements and an intensive care unit discharge score. MAIN RESULTS: No difference between opioids in POCD at any time. A negative correlation was found between preoperative cognitive function and POCD on the first postoperative day (r=-0.47; P=.0002). The fraction of patients with POCD on the first postoperative day was statistically greater in patients with more than 15minutes of Svo2 <60 (P=.037; χ(2) test). Among patients with postoperative ventilation time exceeding 300minutes, more patients had POCD on postoperative day 4 (P=.002). CONCLUSIONS: We could not demonstrate differences in POCD between remifentanil and sufentanil based anaesthesia, but in general, the fraction of patients with POCD seemed smaller than previously reported. We found an association between POCD and both perioperative low Svo2 and postoperative ventilation time, underlining the importance of perioperative stable hemodynamics and possible fast-track protocols with short ventilation times to attenuate POCD.

Remifentanil Compared With Sufentanil Does Not Enhance Fast-Track Possibilities in Cardiac Surgery-A Randomized Study.

OBJECTIVE: Progressive cost containment has resulted in a growing interest for fast-track cardiac surgery. Ventilation time and length of stay (LOS) in the intensive care unit (ICU) are important factors in patient turnover, a more efficient use of resources, and early patient mobilization. However, LOS in ICU is not an objective measure because, in addition to medical factors, patient discharge may be guided by logistics and policy, and thus more objective measures are warranted. The authors hypothesized that remifentanil compared with sufentanil would reduce ventilation time and LOS in the ICU and that remifentanil would have beneficial effects on the overall quality of recovery. DESIGN: A randomized, prospective study. PARTICIPANTS: Sixty patients scheduled for elective coronary artery bypass grafting with or without aortic valve replacement. SETTING: A university hospital. INTERVENTIONS: Patients were assigned randomly to receive either remifentanil or sufentanil combined with propofol. MEASUREMENTS AND MAIN RESULTS: Patients with ejection fraction<0.3, myocardial infarction within the last 4 weeks, diabetes, and severe pulmonary or arterial hypertension were excluded. The primary outcome variables were ventilation time and time to eligibility of discharge from the cardiac recovery unit. Secondary outcomes were actual LOS in the cardiac recovery unit and quality of recovery. The groups were comparable in selected demographics and perioperative parameters. There were no differences in ventilation time or eligible ICU discharge time between the groups. Remifentanil patients received more morphine than did the sufentanil patients during recovery (20 mg v 10 mg; p = 0.040). No difference was found in pharmacologic support or use of a pacemaker. CONCLUSION: In a fast-track protocol, remifentanil did not seem to be superior to a standard moderate- to high-dose sufentanil regimen.

High thoracic epidural analgesia in cardiac surgery. Part 2--high thoracic epidural analgesia does not reduce time in or improve quality of recovery in the intensive care unit.

OBJECTIVE: To evaluate the postoperative effect of high thoracic epidural analgesia on the time in the intensive care unit (ICU) and the quality of cardiac recovery in patients undergoing cardiac surgery. DESIGN: A randomized prospective study. PARTICIPANTS: Sixty low-risk patients 65 to 80 years of age scheduled for elective coronary artery bypass graft surgery with or without aortic valve replacement. SETTING: A university hospital. INTERVENTIONS: Patients randomized to receive high thoracic epidural analgesia (HTEA) as a supplement to general anesthesia. MEASUREMENTS AND MAIN RESULTS: The eligible time to discharge from the ICU and the quality of recovery were evaluated by an objective ICU scoring system. The time to eligible discharge from the ICU, the ventilation time, and the actual time in the ICU were not shorter in the HTEA group compared with patients receiving conventional general anesthesia. Patients receiving HTEA in addition to general anesthesia received less morphine postoperatively but with no consequent beneficial effect on respiration, nausea, sedation, or motor function. CONCLUSIONS: HTEA does not reduce the time in the ICU or improve the quality of recovery in the ICU.

High thoracic epidural analgesia in cardiac surgery. Part 1--high thoracic epidural analgesia improves cardiac performance in cardiac surgery patients.

OBJECTIVE: The purpose of this study was to evaluate the perioperative cardioprotective effect of high thoracic epidural analgesia (HTEA), primarily expressed as an effect on cardiac performance and hemodynamics in patients undergoing cardiac surgery. DESIGN: A randomized, prospective study. PARTICIPANTS: Sixty low-to-moderate risk patients between the ages of 65 and 80 years scheduled for elective coronary artery bypass graft surgery with or without aortic valve replacement. SETTING: A university hospital. INTERVENTION: Patients randomized to receive HTEA as a supplement to general anesthesia. MEASUREMENTS AND MAIN RESULTS: Perioperative hemodynamic measurements, perioperative fluid balance, and postoperative release of cardiac enzymes were collected. The end-diastolic volume index (EDVI), the stroke volume index (overall 38 v 32 mL), the cardiac index (overall 2.35 v. 2.18 L/minute/m(2)), the central venous pressure, and central venous oxygenation were higher in the HTEA group. The mean arterial blood pressure was marginally lower in the HTEA group, whereas no difference was noted in the heart rate or peripheral saturation between the groups. No differences were found in the postoperative levels of troponin T and CK-MB between groups. NT-proBNP changed over time (p < 0.001) and was lower in the HTEA group (p = 0.013), with maximal values of 291 ± 265 versus 326 ± 274. CONCLUSIONS: The findings of a higher stroke volume index and central venous oxygenation without an increase in heart rate or mean arterial pressure suggest that HTEA improves cardiac performance in elderly cardiac surgery patients.

Transfusion of blood during cardiac surgery is associated with higher long-term mortality in low-risk patients.

OBJECTIVE: Numerous reports have emphasized the need for reduction in transfusions of allogeneic red blood cells (RBC) due to increased morbidity and mortality. Nevertheless, transfusion rates are still high in several cardiac surgery institutions. Reports on long-term survival after cardiac surgery and RBC transfusion are few. METHODS: Data from the Western Denmark Heart Registry (WDHR) were used to identify all (25,117) adult cardiac surgery performed in four centres during 1999-2010. Patients with multiple entries (1049), re-do cardiac surgery (985), special/complex procedures (2329), dying within 30 days (668) and not eligible for follow-up (85) were excluded leaving a cohort of 20,001. Registration in the WDHR is mandatory. WDHR and the unique Danish Civil Registration System with continuous sequential updates of the Danish population ensure that all patients and outcomes are accounted for. RESULTS: Kaplan-Meier survival plot for low-risk patients (EuroSCORE 0-4), undergoing simple cardiac surgery showed a significantly lower estimated survival after >4500 days (0.637 vs. 0.745) when receiving perioperative RBC transfusion (P<0.0001). The difference was less evident in patients with EuroSCORE 5-9 (0.373 vs. 0.4436, P<0.0001), while high-risk patients showed no difference. Adjusted risk ratio, after RBC transfusion, containing among others age, sex, EuroSCORE and diabetes, was 1.83 (95% CI (confidence interval) 1.67-2.01). The survival rate was independent of up till six units of RBC. CONCLUSION: Long-term follow-up of low-risk patients undergoing simple cardiac surgery demonstrates a more than 10% higher mortality when receiving perioperative RBC transfusion. Even transfusion of 1-2 units seems to carry a risk of that magnitude.

Regional pulmonary perfusion using model-free analysis of contrast-enhanced MRI in meconium-aspirated piglets.

PURPOSE: To investigate if dynamic contrast-enhanced MRI in lungs could add new information to pulmonary hypertension in a newborn piglet model. MATERIALS AND METHODS: Six newborn piglets were subjected to instillation of meconium following treatment with sildenafil. Before and after both of these events, dynamic contrast-enhanced MRI was performed to determine pulmonary blood flow (PBF) using a model-free deconvolution of the dynamic signal-time curve, together with invasive measurements of mean airway pressure (PAW), cardiac output (CO), and oxygenation index (OI). RESULTS: Meconium instillation caused a significant increase in PAW (P < 0.05) accompanied by a marked increase in OI, the average PBF in the four lung regions (apical-anterior, apical-posterior, distal-anterior, and distal-posterior) decreased significantly by 33% (P < 0.001), but it did not significantly affect CO. On the other hand, infusion of sildenafil caused a significant increase in CO (P < 0.01), and administration resulted mainly in an increased PBF in the distal parts of the lungs. CONCLUSION: By using dynamic contrast-enhanced MRI, we demonstrated a marked decrease in PBF following instillation of meconium, which was not followed by an equivalent decrease in CO, suggesting that measurements of CO inadequately reflect the intrapulmonary changes in the blood circulation.

Effect of intravenous sildenafil on pulmonary hemodynamics and gas exchange in the presence and absence of acute lung injury in piglets.

Sildenafil is becoming increasingly popular for the treatment of pulmonary hypertension. However, there are potential concerns regarding its effects on oxygenation and systemic hemodynamics that could theoretically reduce its utility in the neonatal population. We performed a prospective cumulative dose-response study of increasing doses of i.v. sildenafil (0.4, 1, and 3 mg/kg) on hemodynamics and oxygenation in 32 anesthetized piglets, of which 17 had meconium-induced pulmonary hypertension and lung injury, and 15 did not. Sildenafil caused a reduction in mean pulmonary artery pressure and pulmonary vascular resistance (PVR) at all doses, in non-lung-injured animals. There was no difference in pulmonary hemodynamics between doses. Oxygenation index [OI = mean airway pressure (cm H2O) * FiO2 * 100/PaO2 (mm Hg)] did not reach critical levels at any dose. In lung-injured animals, sildenafil also reduced mean pulmonary artery pressure and PVR by 30%. Again, this effect was achieved at the lowest dose, without subsequent changes at higher doses. However, in lung-injured animals, sildenafil produced a dose-related increase in oxygenation index. Sildenafil reduced the systemic vascular resistance (SVR) at the lowest dose in lung-injured animals, but this occurred only at higher doses in non-lung-injured animals. In conclusion, sildenafil is a potent pulmonary vasodilator. However, it should be administered with caution in the presence of lung injury because of a dose-related increase in oxygenation index and concomitant systemic vasodilatation.

Endothelin-A receptor blockade and inhaled nitric oxide in a porcine model of meconium aspiration syndrome.

Acute neonatal pulmonary hypertension is associated with increased activation of the endogenous endothelin pathway. We investigated the role of selective endothelin-A receptor blockade using i.v. BQ-123 in a piglet model of meconium aspiration syndrome. Meconium aspiration was induced in 18 anesthetized piglets. Six controls received no further intervention. Six piglets received 1 mg/kg BQ-123 at 120 min, with the addition of 20 ppm inhaled nitric oxide at 240 min. Six commenced nitric oxide therapy at 120 min, and were given i.v. BQ-123 at 240 min. The total study duration was 360 min. Meconium aspiration resulted in acute pulmonary hypertension and elevated endothelin-1 levels in all animals. There were no changes in pulmonary hemodynamics or endothelin-1 levels beyond 120 min in controls. In the group receiving BQ-123 first, this agent alone reduced the pulmonary artery pressure and pulmonary vascular resistance, and the subsequent addition of inhaled nitric oxide further reduced pulmonary artery pressure. In the group first receiving nitric oxide alone, this reduced the pulmonary artery pressure, and the addition of BQ-123 resulted in a fall in pulmonary vascular resistance. Endothelin-1 levels increased with both agents. BQ-123 was found to be a highly effective pulmonary vasodilator and augmented the effects of nitric oxide in this model of acute pulmonary hypertension.