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Intravenous Lipid Emulsion During Heart Transplantation

2021; Elsevier BV; Volume: 35; Issue: 10 Linguagem: Inglês

10.1053/j.jvca.2021.02.042

1532-8422

Frederick C. Cobey, Masashi Kawabori, Roman Schumann, Gregory Couper, Iwona Bonney, Michael R. Fettiplace, Guy Weinberg,

Cardiac Ischemia and Reperfusion

WE REPORT our experience using intravenous lipid emulsion (ILE) in adult heart transplantation to treat primary graft dysfunction from ischemia reperfusion injury (IRI). A 60-year-old man (167 cm, 60 kg, body surface area 1.7) with a failed coronary artery bypass graft presented in cardiogenic shock, received an intra-aortic balloon pump (IABP), and was transferred to our institution with a United Network for Organ Sharing status of 2. He was transplanted with a 30-year-old donor (184 cm, 72 kg, body surface area 1.9) heart with normal biventricular function (on echocardiography) and normal coronary arteries. The cause of death was drug overdose. Coronary angiogram was performed because of cocaine use history. The donor heart procurement procedure was successful. The heart immediately arrested after starting 2 L of cold antegrade University of Wisconsin solution. The heart temperature was maintained at International Society for Heart & Lung Transplantation consensus-recommended temperature 5.1°-to 6.6°C in the SherpaPak (Paragonix Technologies, Cambridge, MA) system. Surgery was technically uneventful. Donor and warm ischemic times were 203 and 47 minutes, respectively, with a cardiopulmonary bypass (CPB) time of 212 minutes and temperature nadir at 30.6°C. The IABP was continued throughout CPB. We initiated vasopressin at 0.02 units/min at rewarming and then started dobutamine 79 minutes after cross-clamp removal, with an escalation to 10 µg/kg/min. The commencement of ventilation, epoprostenol 50 ng/kg/min, and a single bolus of milrinone, 3 mg via ultrasonic nebulizer, were administered as per routine. Epicardial pacing accelerated an initial junctional rhythm from 40-to-90 beats/min. Despite adding epinephrine at 0.05 µg/kg/min to the 1:1 IABP and dobutamine, the aortic valve did not open given the absence of innate cardiac contraction, as CPB flows were decreased and the heart was filled. Although we considered extracorporeal membrane oxygenation, ILE (Intralipid 20%, Baxter Health Care Corporation, Deerfield IL) was started as a 50-mL rapid bolus followed by 200 mL over one hour. Soon after the ILE bolus, aortic valve opening ensued, with concomitant increase in arterial pulse pressure. Separation from bypass was possible nine minutes after the ILE bolus, 115 minutes after cross-clamp removal. The initial cardiac output was 4 L/min, with a mixed venous oxygen saturation of 64.9% and the intraoperative echocardiogram demonstrated a left ventricular ejection fraction (LVEF) of 30%-to-35% (Fig 1). On postoperative day (POD) two the LVEF was 45%-to-50%, with mildly reduced right ventricular function while on IABP, the latter being discontinued on POD three. The patient was discharged home on POD 16 and no ILE-related complications were noted. Beyond ILE's primary use as parenteral nutrition, practitioners use it off-label to treat local anesthetic systemic toxicity and evidence supports its use as a postconditioning agent.1Fettiplace M.R. Weinberg G. The mechanisms underlying lipid resuscitation therapy.Reg Anesth Pain Med. 2018; 43: 138-149Crossref PubMed Scopus (47) Google Scholar Van de Velde et al. originally identified the postconditioning benefit of ILE in canine2Van de Velde M. Wouters P.F. Rolf N. et al.Long-chain triglycerides improve recovery from myocardial stunning in conscious dogs.Cardiovasc Res. 1996; 32: 1008-1015Crossref PubMed Scopus (71) Google Scholar and rabbit models.3Van de Velde M. DeWolff M. Leather H.A. et al.Effects of lipids on the functional and metabolic recovery from global myocardial stunning in isolated rabbit hearts.Cardiovasc Res. 2000; 48: 129-137Crossref PubMed Scopus (42) Google Scholar Others confirmed the effect in murine and cellular models, and identified that ILE activates the reperfusion injury salvage kinase (RISK) pathway and delays opening of the mitochondrial permeability transition pore.4Rahman S. Li J. Bopassa J.C. et al.Phosphorylation of GSK-3β mediates intralipid-induced cardioprotection against ischemia/reperfusion injury.Anesthesiology. 2011; 115: 242-253Crossref PubMed Scopus (105) Google Scholar, 5Li J. Fettiplace M. Chen S.J. et al.Lipid emulsion rapidly restores contractility in stunned mouse cardiomyocytes: A comparison with therapeutic hypothermia.Crit Care Med. 2014; 42: e734-e740Crossref PubMed Scopus (12) Google Scholar, 6Li J. Iorga A. Sharma S. et al.Intralipid, a clinically safe compound, protects the heart against ischemia-reperfusion injury more efficiently than cyclosporine-A.Anesthesiology. 2012; 117: 836-846Crossref PubMed Scopus (61) Google Scholar In 2014, Lou et al. found that RISK activation originates from reactive oxygen species leakage out of an uncoupled complex IV due to accumulation of palmitoylcarnitine derived from Intralipid.7Lou P.H. Lucchinetti E. Zhang L. et al.The mechanism of Intralipid®-mediated cardioprotection complex IV inhibition by the active metabolite, palmitoylcarnitine, generates reactive oxygen species and activates reperfusion injury salvage kinases.PLoS One. 2014; 9: e87205Crossref PubMed Scopus (40) Google Scholar Lipid emulsion also exerts an inotropic and lusitropic benefit in animal models, with another Intralipid-derived fatty acid—oleic acid—implicated as improving contractility in animal models of heart failure.8Fettiplace M.R. Ripper R. Lis K. et al.Rapid cardiotonic effects of lipid emulsion infusion*.Crit Care Med. 2013; 41: e156-e162Crossref PubMed Scopus (85) Google Scholar,9Lahey R. Wang X. Carley A.N. et al.Dietary fat supply to failing hearts determines dynamic lipid signaling for nuclear receptor activation and oxidation of stored triglyceride.Circulation. 2014; 130: 1790-1799Crossref PubMed Scopus (68) Google Scholar Although the complete mechanism of improved contractility is unclear, ILE modulates multiple targets that control contractility (Fig 2). Given the mechanistic benefits, it is unsurprising that ILE improves contractility and reduces cell damage compared with cardioplegia in porcine models of transplant.10Lucchinetti E. Lou P.H. Hatami S. et al.Enhanced myocardial protection in cardiac donation after circulatory death using Intralipid® postconditioning in a porcine model.Can J Anaesth. 2019; 66: 672-685Crossref PubMed Scopus (8) Google Scholar We believe the improvement in our patient's cardiac function reflected attenuation of IRI by ILE, which averted bridging with extracorporeal membrane oxygenation. A previous humantrial of 80 patients demonstrated an improvement in biomarkers with the addition of ILE during valvesurgery,11Zhou R.H. Yu H. Yin X.R. et al.Effect of intralipid postconditioning on myocardial injury in patients undergoing valve replacement surgery: A randomised controlled trial.Heart. 2017; 103: 1122-1127Crossref PubMed Scopus (8) Google Scholar and a double-blind randomized controlled trial of 1,000 patients is ongoing.12Yuan Y. Xiong H. Zhang Y. et al.Intralipid postconditioning in patients of cardiac surgery undergoing cardiopulmonary bypass (iCPB): Study protocol for a randomized controlled trial.Trials. 2020; 21: 953Crossref PubMed Scopus (3) Google Scholar However, the prior trials excluded heart transplants, redo cardiac surgeries, and patients with low ejection fractions, and, thus, would have excluded our patient. Given the high morbidity of graft dysfunction and relative safety of ILE as parenteral nutrition, the role for ILE in postischemic injury after cardiac transplantation deserves attention and formal human studies. Dr. Weinberg is a shareholder of ResQ Pharma, Inc and has a patent application related to use of lipid emulsion for potential indications including cardiac transplantation pending.