Nandor Marczin

Early outcomes of bilateral sequential single lung transplantation after ex-vivo lung evaluation and reconditioning

BACKGROUND Ex vivo lung perfusion (EVLP) is a novel approach for extended evaluation and/or reconditioning of donor lungs not meeting standard International Society for Heart and Lung Transplantation criteria for transplantation. METHODS We retrospectively evaluated 13 consecutive EVLP runs between January 2009 and December 2010. Lungs rejected for routine transplantation were implanted to the EVLP circuit and reperfused using acellular supplemented Steen Solution (Vitrolife, Göteborg, Sweden) up to a target flow rate of 40% of the donors calculated flow at a cardiac index of 3.0 liters/min/m(2); target left atrial pressure < 5 mm Hg; and pulmonary artery pressure < 15 mm Hg. Mechanical ventilation was introduced after rewarming to 32°C: tidal volume, 6 to 8 ml/kg; respiratory rate, 7 to 8 breaths/min; duration of inspiration/expiration (I/E) ratio, 1:2; and positive end-expiratory pressure, 5 to 10 cm H(2)O. Hemodynamic and respiratory data monitoring with hourly clinical assessment were performed. Donor data, conversion rate to transplantation, and recipient outcome were analyzed. RESULTS Donor data (n = 13) were: age, 44.23 ± 8.33 years; female/male, 8:5; cause of death: intracranial hemorrhage, 11 (85%), stroke, 1 (7.5%), hypoxic brain injury, 1 (7.5%); smoking history, 9 (69%), 17.44 ± 8.92 pack-years; mechanical ventilation, 102.6 ± 91.92 hours; chest x-ray imaging: abnormal, 12 (92.5%); normal, 1 (7.5%). EVLP: mean 141 ± 28.83 minutes. Arterial partial pressure of oxygen/fraction of inspired oxygen 100% before termination of the circuit vs pre-retrieval value: 57.32 ± 9.1 vs 42.36 ± 14.13 kPa (p < 0.05). Six (46%) pairs of donor lungs were transplanted. Median follow-up was 297.5 days (range, 100-390 days), with 100% survival at 3 months. CONCLUSIONS EVLP may facilitate assessment and/or reconditioning of borderline lungs, with a conversion rate of 46 % and good short-term survival.

Inhaled nitric oxide therapy in adults: European expert recommendations.

BackgroundInhaled nitric oxide (iNO) has been used for treatment of acute respiratory failure and pulmonary hypertension since 1991 in adult patients in the perioperative setting and in critical care.MethodsThis contribution assesses evidence for the use of iNO in this population as presented to a expert group jointly organised by the European Society of Intensive Care Medicine and the European Association of Cardiothoracic Anaesthesiologists.ConclusionsExpert recommendations on the use of iNO in adults were agreed on following presentation of the evidence at the expert meeting held in June 2004.

Inhaled nitric oxide after left ventricular assist device implantation: A prospective, randomized, double-blind, multicenter, placebo-controlled trial

BACKGROUND Used frequently for right ventricular dysfunction (RVD), the clinical benefit of inhaled nitric oxide (iNO) is still unclear. We conducted a randomized, double-blind, controlled trial to determine the effect of iNO on post-operative outcomes in the setting of left ventricular assist device (LVAD) placement. METHODS Included were 150 patients undergoing LVAD placement with pulmonary vascular resistance ≥ 200 dyne/sec/cm(-5). Patients received iNO (40 ppm) or placebo (an equivalent concentration of nitrogen) until 48 hours after separation from cardiopulmonary bypass, extubation, or upon meeting study-defined RVD. For ethical reasons, crossover to open-label iNO was allowed during the 48-hour treatment period if RVD criteria were met. RESULTS RVD criteria were met by 7 of 73 patients (9.6%; 95% confidence interval, 2.8-16.3) in the iNO group compared with 12 of 77 (15.6%; 95% confidence interval, 7.5-23.7) who received placebo (p = 0.330). Time on mechanical ventilation decreased in the iNO group (median days, 2.0 vs 3.0; p = 0.077), and fewer patients in the iNO group required an RVAD (5.6% vs 10%; p = 0.468); however, these trends did not meet statistical boundaries of significance. Hospital stay, intensive care unit stay, and 28-day mortality rates were similar between groups, as were adverse events. Thirty-five patients crossed over to open-label iNO (iNO, n = 15; placebo, n = 20). Eighteen patients (iNO, n = 9; placebo, n = 9) crossed over before RVD criteria were met. CONCLUSIONS Use of iNO at 40 ppm in the perioperative phase of LVAD implantation did not achieve significance for the primary end point of reduction in RVD. Similarly, secondary end points of time on mechanical ventilation, hospital or intensive care unit stay, and the need for RVAD support after LVAD placement were not significantly improved.

Intravenous nitrate vasodilators and exhaled nitric oxide

Isoenzymes that generate nitric oxide (NO) are present in the respiratory tract and NO is believed to play a part in controlling lung function in both health and disease. Endogenous NO can be detected in exhaled air. Measuring exhaled NO concentrations is becoming a useful diagnostic test. The biological effect of nitrate vasodilators, such as nitroglycerin (GTN) and sodium nitroprusside (SNP), is thought to be mediated by NO and subsequent activation of vascular smooth muscle soluble guanylate cyclase. The release of NO from these drugs is thought to be through non-enzymic release for SNP and thiol-dependent cellular biotransformation for GTN. Studies have shown that in rabbits and lambs intravenous GTN and SNP cause increased concentrations of exhaled NO. The effect of nitrate vasodilators on exhaled NO in human beings remains unknown. Measurements were made in patients undergoing openheart surgery for coronary-artery-bypass grafting or aorticvalve replacement by a real-time, computer-controlled, integrated system (Logan Research Ltd 2000 series). Exhaled NO and carbon dioxide (CO 2 ) was sampled through a Teflon tube positioned at the distal end of the endotracheal tube with ventilation standardised for inspired gas (100% O 2 ), tidal volume (5 mL/kg), and respiratory rate (10 per min). Seven patients were investigated, NO was detectable in the exhaled air with a characteristic oscillating signal which appeared to increase with expiration (as judged by the CO 2 signal) reaching peak NO concentrations of 3–13 ppb. No NO signal was detected when the patient was replaced with a reservoir bag, suggesting that the NO signal was derived from the patient’s lungs. In all patients, intravenous bolus administration of GTN resulted in a rapid, marked, and transient increase in exhaled concentrations of NO which coincided with reduction of arterial blood pressure. The figure shows representative results in a patient before and after bolus injection of 250 mcg GTN. This patient exhibited baseline peak exhaled NO concentrations of 5·5 ppb, which increased to 16·8 ppb 11 s after the injection into a central vein. There were dosedependent effects of GTN boluses on exhaled NO: increases of 3·1, 6·0, and 8·1 ppb from baseline in peak exhaled NO concentrations after injecting 125, 250, and 500 mcg GTN. In one patient, a high rate of GTN infusion was clinically indicated to control blood pressure after replacement of the stenotic aortic valve. At baseline, peak exhaled NO concentrations of 12·6 (0·2) were observed. After infusing 45 mg/h GTN for 5 min, peak exhaled NO concentrations increased significantly to 14·1 (0·1) ppb. 5 min after stopping the GTN infusion, NO concentrations returned to baseline: 12·6 (0·2) ppb.To investigate whether the proposed different mechanisms of NO release from the nitrate vasodilators affects exhaled NO concentrations, we tested clinically equipotent doses of SNP and GTN. Injection of 150 mcg SNP caused only a small increase (0·8 ppb) in exhaled NO concentrations, whereas injection of 125 mcg GTN produced a substantial increase (4·2 ppb) in exhaled NO in the same patient. To investigate if release of NO could be observed from bolus injections of small amounts of GTN after prolonged intravenous administration of GTN—relevant to understanding nitrate tolerance—250 mcg GTN boluses were injected before and after intravenous administration of 20 and 40 mg GTN in the postoperative period. Large amounts of NO were released from 250 mcg GTN boluses into exhaled air even after administering large quantities of GTN (40 mg) over 6 h. We have shown that there is endogenously produced NO in exhaled breath or artificially-ventilated, anaesthetised patients undergoing open-heart surgery, and that there is a transient, proportionate, and dose-dependent increase in NO in exhaled air after administration of GTN and to a lesser extent SNP. Our findings may provide a new way to monitor metabolic function of the pulmonary endothelium, as well as investigating nitrate pharmacology and tolerance.

Cardiac surgery-associated acute kidney injury

Acute kidney injury develops in up to 30% of patients who undergo cardiac surgery, with up to 3% of patients requiring dialysis. The requirement for dialysis after cardiac surgery is associated with an increased risk of infection, prolonged stay in critical care units and long-term need for dialysis. The development of acute kidney injury is independently associated with substantial short- and long-term morbidity and mortality. Its pathogenesis involves multiple pathways. Haemodynamic, inflammatory, metabolic and nephrotoxic factors are involved and overlap each other leading to kidney injury. Clinical studies have identified predictors for cardiac surgery-associated acute kidney injury that can be used effectively to determine the risk for acute kidney injury in patients undergoing cardiac surgery. High-risk patients can be targeted for renal protective strategies. Nonetheless, there is little compelling evidence from randomized trials supporting specific interventions to protect or prevent acute kidney injury in cardiac surgery patients. Several strategies have shown some promise, including less invasive procedures in those at greatest risk, natriuretic peptide, fenoldopam, preoperative hydration, preoperative optimization of anaemia and postoperative early use of renal replacement therapy. The efficacy of larger-scale trials remains to be confirmed.

Repeatability of the measurement of exhaled volatile metabolites using selected ion flow tube mass spectrometry.

Selected ion flow tube mass spectrometry, SIFT-MS, has been used to determine the repeatability of the analysis of volatile metabolites within the breath of healthy volunteers, with emphasis on the influence of sampling methodology. Baseline instrument specific coefficients of variability for examined metabolites were as follows: acetone (1%), ammonia (1%), isoprene (2%), propanol (6%), ethanol (7%), acetic acid (7%), and hydrogen cyanide (19%). Metabolite concentration and related product ion count rate were identified as strong determinants of measurement variation. With the exception of ammonia, an orally released metabolite, variability in repeated on-line breath analysis tended to be lower for metabolites of systemic origin. Standardization of sampling technique improved the repeatability of the analysis of selected metabolites. Off-line (bag) alveolar breath sampling, as opposed to mixed (whole) breath sampling, likewise improved the repeatability of the analysis of all metabolites investigated, with the exception of acetic acid. We conclude that SIFT-MS analysis of common volatile metabolites within the breath of healthy volunteers is both reliable and repeatable. For selected metabolites, the finding that repeatability is improved through modification of sampling methodology may have implications in terms of future recommended practices.

CentriMag® short-term ventricular assist as a bridge to solution in patients with advanced heart failure: use beyond 30 days

OBJECTIVES Left ventricular assist devices (LVADs) offer very valuable therapeutic options for patients with advanced heart failure. CentriMag (Thoratec, Pleasanton, CA, USA) is an extracorporeal short-term circulatory assist device Conformité Européenne-marked in Europe for use up to 30 days. METHODS Retrospective analysis of 41 patients with advanced heart failure who, from 2003 to 2011, were supported with CentriMag for >30 days as a bridge to recovery, long-term VAD or transplantation. RESULTS Forty-one adult patients were supported with 46 CentriMag devices for a total of 2695 days with a mean support time of 59 (range: 31-167) days. Indications were post-cardiotomy cardiogenic shock (PC = 4), primary graft failure (PGF = 7) and refractory heart failure (RHF = 35). Six devices were used to support the left ventricle, 19 to support the right ventricle and 21 to support both the ventricles (biventricular support considered as single device unit). In the PC cohort, 3 (75%) patients were weaned from support, while 4 (57%) were weaned from support in the PGF cohort. In the RHF cohort, 8 patients were bridged to long-term VAD and 5 were bridged to transplantation; heart function recovered and device explanted in 14, while 8 patients died on support. There were no device failures. Overall, 34 (74%) patients were recovered or bridged, with a 1-year survival of 54%. CONCLUSIONS CentriMag proved to be a versatile, safe and effective short-term circulatory support for patients with advanced heart failure as a bridge to solution. Its use over 30 days is associated with acceptable survival and does not increase device-related complications.

Carbon monoxide: Endogenous mediator, potential diagnostic and therapeutic target

Abstract The primary objectives of this article are to review the potential role of carbon monoxide (CO) as an endogenous mediator, diagnostic marker for pulmonary disorders, and therapeutic target in critical illness. The review will start by focusing on the importance of the heme oxygenase (HO)-CO axis as an endogenous system as it relates to the cardiovascular and pulmonary systems. It will elucidate the influence of HO gene expression on critical events like shock, sepsis, ischemia-reperfusion and others. Our focus will then shift and look at the potential diagnostic role of exhaled CO in major inflammatory states of the lung, and finally we will highlight the activities on inhaled CO being considered as a possible therapeutic tool and the controversies surrounding it.

Transplant atherosclerosis: Role of phenotypic modulation of vascular smooth muscle by nitric oxide

Occlusive accelerated atherosclerosis of coronary grafts is the predominant factor that limits longevity of heart transplant recipients. This form of vascular disease affects both the large epicardial and the smaller intramyocardial vessels, leading to characteristic clinical presentation that necessitates the use of sophisticated techniques for their accurate detection. Accelerated atherosclerosis after transplantation is a multifactorial disease with many events contributing to its progression. The initial vascular injury associated with ischemia-reperfusion appears to aggravate preexisting conditions in the donor vasculature in addition to activation of new immunological and nonimmunological mechanisms. Throughout these events, the endothelium remains a primary target of cell- and humoral-mediated injury. Changes in the vascular intima leads to alterations in vascular smooth muscle cell (VSMC) physiology, resulting in VSMC phenotypic modulation with the orchestration of a broad spectrum of growth and inflammatory reactions, which might be a healing response to vascular injury. Endogenous nitric oxide (NO) pathways regulate a multiplicity of cellular mechanisms that play a major role in determining the structure and function of the vessel wall during normal conditions and during remodeling associated with accelerated atherosclerosis. Recently identified signaling pathways, including mitogen-activated protein kinase, cGMP-dependent protein kinase, phosphatidylinositol 3-kinase, and transcriptional events in which nuclear factor kappa B and activator protein 1 take part, can be associated with NO modulation of cell cycle perturbations and phenotypic alteration of VSMC during accelerated atherosclerosis. This article reviews recent progress covering the aforementioned matters. We start by summarizing the clincal aspects and pathogenesis of accelerated atherosclerosis associated with transplantation, including clinical presentation and detection. This summary is followed by a discussion of the multiple factors of the disease process, including immunological and nonimmunolgical contributions. The next section focuses on cellular responses of the VSMCs relevant to lesion formation, with special emphasis on classical and recent paradigms of phenotypic modulation of these cells. To examine the influence of NO on VSMC phenotypic modulation and consequent lesion development, we briefly overview characteristics of NO production in the normal coronary vascular bed and the changes in endogenous NO release and activity during atherosclerosis. This overview is followed by a section covering molecular mechanisms whereby NO regulates a range of signaling pathways, transcriptional events underlying cell cycle perturbation, and phenotypic alteration of VSMC in accelerated atherosclerosis.

A redox-based mechanism for nitric oxide-induced inhibition of DNA synthesis in human vascular smooth muscle cells

The current study explored potential redox mechanisms of nitric oxide (NO)‐induced inhibition of DNA synthesis in cultured human and rat aortic smooth muscle cells. Exposure to S‐nitrosothiols, DETA‐NONOate and NO itself inhibited ongoing DNA synthesis and S phase progression in a concentration‐dependent manner, as measured by thymidine incorporation and flow cytometry. Inhibition by NO donors occurred by release of NO, as detected by chemiluminescence and judged by the effects of NO scavengers, haemoglobin and cPTIO. Co‐incubation with redox compounds, N‐acetyl‐L‐cysteine, glutathione and L‐ascorbic acid prevented NO inhibition of DNA synthesis. These observations suggest that redox agents may alternatively attenuate NO bioactivity extracellularly, interfere with intracellular actions of NO on the DNA synthesis machinery or restore DNA synthesis after established inhibition by NO. Recovery of DNA synthesis after inhibition by NO was similar with and without redox agents suggesting that augmented restoration of DNA synthesis is an unlikely mechanism to explain redox regulation. Study of extracellular interactions revealed that all redox agents potentiated S‐nitrosothiol decomposition and NO release. Examination of intracellular NO bioactivity showed that as opposed to attenuation of NO inhibition of DNA synthesis by redox agents, there was no inhibition (potentiation in the presence of ascorbic acid) of soluble guanylate cyclase (sGC) activation judged by cyclic GMP accumulation in rat cells. These data provide evidence that NO‐induced inhibition of ongoing DNA synthesis is sensitive to redox environment. Redox processes might protect the DNA synthesis machinery from inhibition by NO, in the setting of augmented liberation of biologically active NO from NO donors.