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Abstract
Objective This study was conducted to determine whether the administration of intralipid just before aortic cross-unclamping would reduce myocardial injury in patients undergoing valve replacement surgery.
Methods Seventy-three adult patients, scheduled for elective aortic or mitral valve surgery without significant coronary stenosis (>70%), were randomly assigned to the intralipid postconditioning (ILPC) group (n=37) or control group (n=36): the ILPC group received an intravenous infusion of 20% intralipid (2 mL/kg) just 10 min before aortic cross-unclamping, and the control group received an equivalent volume of normal saline. Serum cardiac troponin T (cTnT) and creatine kinase-MB (CK-MB) was measured before surgery and at 4, 12, 24, 48 and 72 hours after surgery. The primary end points were the 72-hour area under the curve (AUC) for cTnT and CK-MB.
Results No significant difference between the ILPC and control arm was observed, including the age, sex or number of aortic versus mitral valves or left ventricular ejection fraction at baseline. The total 72-hour AUC of cTnT and CK-MB in patients assigned to ILPC were significantly reduced by 32.3% (p=0.004) and 26.4% (p=0.0185) compared with control, respectively. None of the treated patients had abnormal blood lipid metabolism, abnormal renal or hepatic function or significant related complications.
Conclusion The protective effect of postischaemic administration of intralipid prior to aortic cross-unclamping on reperfusion injury was found when determined by biomarkers of myocardial injury but not by cardiac function or other clinical outcomes in patients undergoing valve replacement surgery. Hence, clinical benefits of this protection need larger clinical trials to confirm.
Trial registration number ClinicalTrials.gov ID: ChiCTR-IOR-14005318.
- Valve disease surgery
- Cardiac surgery
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Introduction
Cardiopulmonary bypass (CPB) is one of the most commonly used techniques during cardiac surgery, and it leads to the postoperative myocardial injury (PMI), which results in increased morbidity and mortality, especially in patients with much higher risk.1 2 Myocardial damage during CPB is partly a consequence of the ischaemic/reperfusion (I/R) injury, possibly through the opening of the mitochondrial permeability transition pore (mPTP).2 In recent years, intralipid, as an inhibitor of mPTP opening, is being studied for its potential effect on cardiac protection.3–5 Animal studies have shown that ischaemic postconditioning with intralipid administration protects the heart against reperfusion injury in vivo and ex vivo rat model by inhibiting the mPTP.3–5 However, these studies regarding the cardioprotective effects of intralipid are in experimental models, and whether it is effective in clinical situation remains unknown.6 7
Thus, we hypothesised that intralipid postconditioning (ILPC) administered just before reperfusion (aortic cross-unclamping) could attenuate the degree of myocardial injury. We focused on the amount of cardiac troponin T (cTnT) and creatine kinase-MB (CK-MB) release after cardiac surgery, which are biomarkers of PMI and associated with worse clinical outcomes in patients undergoing valve replacement surgery using CPB.8 9
Methods
Study design
A prospective, randomised, single-blinded, placebo-controlled trial with two parallel arms was undertaken in West China Hospital of Sichuan University, China. The trial was performed in accordance with the Declaration of Helsinki (revised version, 1996). The ethics committee of our institution approved the study protocol. Written informed consent was obtained from all patients before inclusion. The trial was prospectively registered at ClinicalTrials.gov (ID ChiCTR-IOR-14005318).
Inclusion and exclusion criteria
Patients were eligible for participation if they met the following criteria: elective aortic valve or mitral valve surgery and age older than 18 years, less than 70 years. Exclusion criteria were as follows: redo cardiac surgery, combined cardiac valves surgery, combined valve and coronary surgery, ventricular fibrillation, significant coronary stenosis (>70%), left ventricular ejection fraction (LVEF) less than 30%, positive baseline serum cTnT or CK-MB, experienced cardiogenic shock or cardiac arrest, hyperlipidaemia, significant hepatic (international normalised ratio >2.0), pulmonary (forced expiratory volume-1<40% predicted) or renal disease (serum creatine level ≥150 μmol/L), uncontrolled hypertension, current infections, any disorder associated with immunological dysfunction (eg, malignancy or positive serological test for the HIV) in the last 6 months, preoperative treatment with intralipid in the last 1 month, preoperative treatment with nicorandil (an ATP-sensitive potassium channel opener), sulfonylurea (an ATP-sensitive potassium channel blocker). Patients who are participating in other interventional studies are also ineligible.
Experimental protocol
Patients who met the enrollment criteria were randomised 1:1 to either control or ILPC group. Randomisation was performed with the use of a computer-generated randomisation sequence. Allocation concealment was maintained until the time of anaesthesia induction by using opaque, numbered and sealed envelopes, prepared by a person independent of the study.
Less than 10 min before aortic cross-unclamping, patients in the ILPC group received an intravenous infusion of 2 mL/kg of 20% intralipid (medium-chain and long-chain fat emulsion injection C6~C24, SINO SWED Pharmaceutical). Intralipid should be infused over 10 min in constant speed. Patients in the control group received an equivalent volume of normal saline. The dose of intralipid was chosen on the basis of the bolus dose when it is used in the treatment of severe cardiotoxicity from intravenous overdose of bupivacaine.10 11
Standard procedures
On arrival in the operating room, standard monitoring consisted of 5-lead ECG, pulse oximetry. A peripheral venous cannula was inserted, and patients were sedated with midazolam intravenously. A radial arterial cannula was inserted before anaesthesia. Intravenous anaesthesia was induced with midazolam (0.1–0.2 mg/kg), sufentanil (0.5–1 µg/kg) and rocuronium (0.6 mg/kg). The trachea was intubated, and mechanical ventilation started to achieve an end-tidal carbon dioxide tension of 35–45 mm Hg. After the induction, anaesthesia was maintained with continuous infusion of propofol 80–100 µg/kg/min until the end of surgery. Midazolam, sufentanil and rocuronium were given as needed. Because of their potential myocardial effects, halogenated volatile anaesthetics were not used in this study.12 13 Arterial blood pressure, central venous pressure and nasopharyngeal temperature were recorded continuously.
Cardiac surgeons were blinded to the treatment allocation. After systemic heparinisation (3 mg/kg, activated clotting time >480 s), the ascending aorta, superior vena cava and inferior vena cava or right atrium were cannulated. A standard CPB with a disposable hollow-fibre membrane oxygenator (Affinity NT 541; Medtronic, USA) and a roller pump (Stockert-5, Sorin Group, Germany) was started with a target output of 2.4 L/min m2 of body surface area. Surgery was performed under mild hypothermia (33°C). After aortic cross-clamping, cardioprotection was provided by cold-blood cardioplegia (1:4) at the dose of 20 mL/kg. The cardioplegia was repeated half dose every 25 min during surgery. After the valve replacement procedure, the heart was defibrillated after aortic unclamping if sinus rhythm did not resume spontaneously. CPB was discontinued, and protamine was used to reverse the effect of heparin. Patients were transferred to the intensive care unit (ICU) after surgery and were extubated at the earliest clinically appropriate time when their ventilatory, haemodynamic and neurological states were deemed to be stable by the attending physician.
Outcomes
Primary end points
The primary end points were the total 72-hour area under the curve (AUC) for cTnT and CK-MB release. Blood samples were taken before surgery and 4, 12, 24, 48 and 72 hours after surgery.
Secondary end points
These included the followings:
The serum levels of blood lipids are as follows: triglyceride, total cholesterol, high-density lipoprotein and low-density lipoprotein. The blood samples were taken before surgery, 4 hour after surgery and at hospital discharge.
The examination of hepatic and renal function before surgery, 24 hours after surgery and at hospital discharge, measured by blood urea nitrogen, serum creatine, total bilirubin, direct bilirubin and indirect bilirubin.
Echocardiography analysis: Transthoracic echocardiography was performed in all patients before surgery and at hospital discharge. LVEF quantification with echocardiography was done with Simpsons and reevaluated after 1 week. The average values were calculated and analysed to eliminate intraobserver variability.
The extubation time, length of stay in the ICU and length of stay in the hospital were collected.
All complications occurring during hospitalisation and 3 months after surgery include the following: all-cause death, arrhythmias, myocardial infarction, stroke, infection, respiratory failure, hepatic or renal failure and any complications related to operation.
Statistical analysis
We hypothesised that ILPC would cause a 25% reduction of cTnT-AUC release compared with that in the control group. At 90% power and significance at the two-sided 5% level, this required a sample size of 60 subjects (30 per group), which we increased by 33% to accommodate withdrawal or missing data points. All analyses were performed by an independent expert unaware of the allocated treatment group.
Data are expressed as mean ± SD. The 72-hour AUC for plasma cTnT and CK-MB concentrations were analysed using integration by software originpro 8.0. Comparisons between both independent groups were performed using unequal-variance Student's t-test for continuous variables that followed a normal distribution. Chi-square or Fisher's exact tests were used as appropriate for categorical variable comparisons between groups. A two-way analysis of variance with repeated measures was used to analyse the comparison of the plasma cTnT and CK-MB concentrations, hepatic and renal function between groups. When appropriate, post hoc analysis was performed with the Tukey test to identify time and within and between treatment differences. Results were considered statistically significant at a p value less than 0.05. Statistical analyses were done using statistical software SPSS 17.0.
Results
Characteristics of the study population
From September 2014 to May 2015, 410 patients who underwent aortic valve or mitral valve surgery were recruited. Among them, 80 were included and randomly assigned to the ILPC group (n=40) or control group (n=40). After randomisation, seven patients were excluded, and 37 patients (ILPL) versus 36 patients (control) were included for final analysis (figure 1). No significant difference was found between the two groups regarding baseline characteristics or clinical data (table 1 and online supplementary figure 1). Intraoperative data listed in table 2 were comparable.
Supplementary file
Study profile. ILPC, intralipid postconditioning.
Baseline patient characteristics
Intraoperative patient data and outcome data
Primary end points
The 72-hour AUC for cTnT release after surgery was significantly lower in the ILPC group (26 096.0±12 218.4 arbitrary units) compared with that in the control group (38542.3±16 318.1 arbitrary units), with a reduction of 32.3% (mean difference 12 446.3; 95% CI 5731.0 to 19 161.6, p=0.004). Similarly, the 72-hour AUC for CK-MB release of these two groups was significantly different (865.2±431.5 arbitrary units vs 1176.7±653.0 arbitrary units, mean difference 311.5; 95% CI 53.8 to 569.1, p=0.0185) with a reduction of 26.4% (figure 2).
![[Figure1S_EF.jpg]](https://heart.bmj.com/content/heartjnl/103/14/1122/DC1/embed/inline-supplementary-material-1.jpg?download=true){kind=link}
The 72-hour AUC for cTnT (A) and CK-MB (B) values after surgery. ILPC resulted in a 32.3% reduction of cTnT release (p=0.004) and a 26.4% reduction of CK-MB release (p=0.0185), respectively. T bars denote SD. *When compared with the control group, p<0.05. AUC, area under the curve; CK-MB, creatine kinase-MB; cTnT, cardiac troponin T; ILPC, intralipid postconditioning.
Secondary end points
The blood lipids tests, including triglyceride, total cholesterol, high-density lipoprotein and low-density lipoprotein, in the two study groups at baseline, 4 hours after surgery and at discharge were comparable (table 3). Biological measurements of hepatic and renal function at baseline, 24 hours after surgery or at discharge did not significantly differ between the two groups (table 3).
Tests for blood lipids and biological measurements of hepatic and kidney function
The clinical outcomes were displayed in table 2. The rate of inotrope requirement over 48 hours, LVEF at discharge (Supplementary figure 1), extubation time, length of stay in the ICU and length of stay in the hospital did not differ between the two groups. Complications occurred similarly in the two groups during hospitalisation. There was no major complication such as wound infection, infective endocarditis, stroke, myocardial infarction, hepatic or renal function failure or death at 3 months after discharge.
Discussion
The aortic cross-clamping during CPB induces a global myocardial I/R injury in cardiac surgery.1 Although it is attenuated by usual cardioprotective strategies such as cardioplegia and myocardial hypothermia, perioperative myocardial injury remains a challenging problem that results in postoperative cardiac morbidity and mortality.1 2 In this proof-of-concept randomised controlled clinical trial, it was observed that (1) postischaemic administration with intralipid induced a significant reduction of postoperative cTnT and CK-MB release, the biomarkers of PMI in patients undergoing valve replacement surgery and (2) a single intravenous bolus (2 mL/kg) of intralipid did not bring abnormal blood lipid metabolism and was found to be safe, with no difference in perioperative hepatic or renal function or any other significant related complications.
The current result from this clinical trial is concordant with experimental research that ischaemic postconditioning with intralipid can protect the heart against myocardial reperfusion injury in both the in vivo and ex vivo rat models.3 This has also been confirmed by another animal study that administration of intralipid at the onset of reperfusion resulted in approximately 70% reduction in infarct size in the in vivo rat model and significantly improved functional recovery of isolated Langendorff-perfused mouse hearts.5 The subsequent mechanistic study defined that intralipid attenuated I/R injury through inhibiting mPTP opening.5 The mPTP, located in the inner mitochondrial membrane, opens at the time of reperfusion as a consequence of mitochondrial calcium overload and overproduction of reactive oxygen species.14 The opening of mPTP results in cellular apoptosis and necrosis through an increase in mitochondrial membrane permeability, thus being a critical determinant of cardiomyocyte death in acute I/R injury.14 15 Hence, intralipid, an mPTP opening inhibitor, has been considered to be a promising target for cardiac protection.
Intralipid is the first safe fat emulsion for human use and is widely used as a vehicle for different drugs such as propofol and etomidate.5 In recent years, intralipid has subsequently been used off label in the treatment of severe cardiotoxicity from intravenous overdose of local anaesthetic drugs such as bupivacaine.16 17 In the current study, a single dose of 2 mL/kg of 20% intralipid administered was found to be safe, with no related adverse effects. When compared with the control group, none of the treated patients had abnormal blood lipid metabolism or exhibited detectable signs of hepatic or renal toxicity or any related complications. In addition, there are no clinical data showing that intralipid administered during cardiac surgery has a negative effect on the myocardium. It must be emphasised, however, that the duration of intralipid intravenous infusion should be over almost 10 min, as the fast intravenous injection of massive intralipid would increase the risk of fat embolism.
Because of potential myocardial effects of halogenated volatile anaesthetics, propofol, despite using the lipid emulsion as a vehicle, could not be avoided in the current study during anaesthesia.18 19 One implication that needed to be addressed was the potential interaction between propofol anaesthesia and intralipid as study drug intervention, as the propofol decreases oxidative stress and counteracts oxygen-free radicals production following I/R injury during CPB.20–23 Meanwhile, both animal studies and clinical trials have shown that the protective effect of propofol on myocardial function was dose dependent.21 23–25 Xia and colleagues found that administration of a large dose of propofol (120 µg/kg/min) during CPB attenuates postoperative myocardial cellular damage compared with a small dose of propofol anaesthesia (60 µg/kg/min).24 Another experimental study found that the propofol’s cardioprotection after myocardial ischemia and reperfusion was effective at concentrations of 5 µg/mL or more and not effective at concentrations of 2 µg/mL or less.25 For the current study, the doses of propofol used were 80–100 µg/kg/min and comparable between two groups. In addition, the current results cannot extend to cardioprotection of intralipid during volatile anaesthesia. The results would be strengthened if there was a volatile anaesthetics arm.
One important limitation of this clinical study was the unblinding of the ILPC protocol in the operating room. Because of intralipid being white emulsion, it was difficult to achieve in an optimal manner of double blinding. However, the investigator collecting and analysing the data, patients, cardiac surgeons and staff on the ICU and cardiac wards were all blinded to treatment allocation. In addition, the current study is a single-center, single-blinded trial with the isolated observation of reduced serum cardiac enzymes (the cTnT and CK-MB) of myocardial injury, which are reported to be important indicators to assess the myocardial injury and be clearly independent risk factors for worse clinical outcomes after cardiac surgery,.8 9 26–28 Our study found no significant difference in left ventricular function at discharge between the two groups. LVEF had normalised (LVEF >50%) in two (22%) of nine patients in the control group and two (40%) of five patients in the ILPC group with a low preoperative ejection fraction. The small number of patients might have influenced the statistical power of this change. Moreover, ejection fraction after valve replacement was reported to improve during the first year after surgery, which was related to late remodeling.29 30 Therefore, the LV function might improve markedly during a relative long term after surgery, and the hypothesis regarding the benefit of intralipid on long-term cardiac function requires further validation.
In conclusion, the protective effect of postischaemic administration of intralipid prior to aortic cross-unclamping on reperfusion injury was found when determined by biomarkers of myocardial injury but not by cardiac function or other clinical outcomes in patients undergoing valve replacement surgery. Hence, clinical benefits of this protection need larger clinical trials to confirm.
Key messages
What is already known on this subject?
Myocardial damage during cardiopulmonary bypass (CPB) is partly a consequence of the ischaemic/reperfusion (I/R) injury, and animal studies have shown that ischaemic postconditioning with intralipid administration protects the heart against reperfusion injury in in vivo and ex vivo rat models by inhibiting the mitochondrial permeability transition pore.
What might this study add?
Studies regarding the cardioprotective effects of intralipid are in experimental models, and whether it is effective in clinical situation remains unknown. This study has shown that postischaemic administration of intralipid prior to aortic cross-unclamping protects against reperfusion injury determined by biomarkers of myocardial injury and brings no adverse effects in patients undergoing valve replacement surgery.
How might this impact on clinical practice?
The myocardial injury as a consequence of the I/R injury during CPB results in increased morbidity and mortality. Our findings provide a potential alternative to attenuate the degree of myocardial injury in clinical practice.
Acknowledgments
We thank the perfusion team and the cardiovascular anaesthesiology team in West China Hospital for their continued support and the patients and staff at the Department of Cardiovascular Surgery for their assistance throughout this study.
References
Footnotes
Funding This work was supported by Science & TechnologyAgency of Sichuan Province, China. The approval number is 2012FZ0123.