Effect of Sevoflurane on Serum CK-MB Levels After Percutaneous Coronary Stent Placement: A Prospective Randomized Clinical Trial

Objectives. Markers of myocardial injury, such as creatine kinase-myocardial band (CK-MB) mass, are elevated in up to 30% of patients undergoing percutaneous coronary intervention (PCI) with stent deployment. This elevation represents myocardial injury that can impact the patient in the long term, including the risk of death. Sevoflurane, an inhaled anesthetic, may have cardioprotective properties that benefit patients undergoing PCI. The primary objective was to compare serum CK-MB mass raise in patients who received sevoflurane to those who received a placebo prior to PCI.

Methods. We enrolled patients with coronary artery disease who were eligible for PCI in a randomized (1:1), double-blind, placebo-controlled trial; patients having experienced acute myocardial infarction within 72 hours and those with saphenous vein graft stenting were excluded. Patients (n = 1254) were randomized to receive sevoflurane (2% inspired fraction) or placebo (oxygen alone) for 30 minutes prior to PCI. Additionally, we compared substantial elevations in CK-MB mass (defined as >5x the upper limit of normal), length of stay in the intensive care unit and in-hospital, and 1-year mortality.

Results.  Sevoflurane was unable to promote cardioprotection, as determined by CK-MB mass levels (sevoflurane group: 2.52 ± 9.64; control group: 1.84 ± 8.58; P=.32). No effect was noticed on the reduction among patients who (AQ: with?) increase (AQ: increased?) marker levels (prevalence of increase in CK-MB mass greater than the upper limit of normality was 30.8% in the sevoflurane group and 28.9% in the control group; P=.33; 4.6% vs 3.1%, respectively, for increases 5x above the upper limit of normality [P=.21]).

Conclusions. Sevoflurane failed to reduce myocardial injury after PCI. Therefore, its usage should not be routinely recommended.

The combination of instrumental development and technique refinement has increased percutaneous coronary intervention (PCI) indications, which has become the most prevalent revascularization modality with approximately 1 million procedures per year in just the United States.¹

Elevation in biomarkers of myocardial injury (creatine phosphokinase [CPK], creatine kinase-myocardial band [CK-MB], troponin, etc.) may occur in up to 30% of all PCI and is of multifactorial etiology, being related to patient profile, procedure, and plaque characteristics. Observational studies and metanalyses have suggested that as biomarker elevation increases, clinical outcomes worsen.^2,3

In the preclinical scenario, the use of volatile (inhaled) anesthesia before, during, or after periods of organ ischemia was associated with a cell-protective effect through a pharmacologic preconditioning related to different pathways, including modulation of G-protein-coupled receptors, gene expression, and mitochondrial function.^4,5,6

The use of these anesthetic agents for prevention/reduction of myocardial damage after coronary revascularization (coronary artery bypass graft [CABG] or PCI) is still controversial. Although a few small trials and metanalyses have suggested a benefit in reduction of myocardial damage with their use,^7-11 a recent, well-designed, large (n = 5400 patients) randomized trial failed to demonstrate differences with respect to death of any cause and myocardial infarction (MI) in patients undergoing CABG with intravenous vs volatile anesthesia.¹² 

There is a paucity of data on inhaled anesthesia for this purpose following PCI. A pilot study published by Landoni et al in 2008 failed to show benefit in reduction of troponin I release after coronary stenting and raised questions about the safety of these inhaled drugs during PCI.¹³ However, the trial enrolled only 30 patients, which precluded defined conclusions.

In the present study, we sought to investigate the role of sevoflurane in reduction of CK-MB mass release after PCI with drug-eluting stents (DES).

Study design and population. This is a randomized (1:1), double-blind, placebo-controlled trial conducted at a single center, public, tertiary hospital to assess the superiority of volatile anesthesia (sevoflurane) over the use of placebo in the reduction of CK-MB mass elevation following PCI with DES.

Between January 2017 and August 2019, we enrolled consecutive patients with indication for PCI. Exclusion criteria included the following:

1. Patients with altered cardiac biomarkers (troponin I and/or CK-MB) less than 72 hours before enrollment;
2. Complications during the procedure (cardiac arrest, pulmonary edema, cardiogenic shock, and stroke);
3. PCI in venous or arterial grafts and/or in angiographic-detected thrombus-containing lesions;
4. Pregnancy;
5. Renal failure requiring dialysis;
6. Current use of medications that might inhibit pharmacologic preconditioning, such as allopurinol, theophylline, and sulfonylurea; and
7. Previous allergy or unusual response to any of the used anesthetic.

The local institutional medical ethics committee approved the study protocol. All patients provided written informed consent before procedures. The study was registered at https://www.clinicaltrials.gov (NCT02671084).

Randomization. After providing written informed consent, patients were randomized in a 1:1 ratio to inhaled sevoflurane or a placebo according to the protocol. The Figure shows the study flow chart.

To guarantee concealment of the allocation list, randomization was implemented in blocks of 10 patients, using a randomization scheme generated by an online software (www.randomization.com). There was no prespecified stratification. Study medication and placebo were prepared identically by an independent researcher who did not participate in the procedure or in post-procedure evaluations.

Objectives. The primary objective of this trial was to assess the superiority of volatile anesthesia with sevoflurane over the use of placebo at decreasing perioperative myocardial damage, as defined by CK-MB release (>1 the normal limit), anytime between PCI and hospital discharge. Secondarily, we compared the incidence of periprocedural MI (CK-MB mass release >5x the normal limit), duration of stay in hospital, and the occurrence of death/MI) at 1 year. We also collected data on several prespecified anesthesia-related adverse events, including allergic reaction, malignant hyperthermia, hemodynamic instability, mental confusion, and seizure.

Anesthetic procedure. All patients were kept NPO for at least 8 hours, had a peripheral venous access positioned, and were monitored for noninvasive blood pressure, 2 electrocardiogram leads, and pulse oximetry by the Infinity Delta system (Dräger).

Midazolam was administered at a dose of 2 mg intravenously in both groups. After 5 minutes, patients were asked to spontaneously breathe in a tight-fitting occlusive mask; patients in the control group received 50% oxygen and air (fresh gas flow = 10L) delivered through the breathing circuit of a Dräger anesthesia machine, and patients in the active cohort received a mixture of 50% oxygen and sevoflurane with a 2% inspired fraction at a flowrate of 10 L/minute. This procedure lasted 30 minutes.

Ten minutes after the end of exposure, patients were ready to get into the catheterization laboratory (awake and maintaining oxygen saturation >92%, without supplemental oxygen) and did not receive any other intravenous or inhaled anesthetic agents until the end of the PCI.

All pre-PCI anesthetics procedures were performed by the same 2 senior anesthesiologists. The entire interventional team (cardiologists, nurses, and technicians) was blinded to the randomization. Procedure data was collected by a research team who was also blinded to patients’ allocations. 

To minimize potential bias, the anesthesiologists who gave the medication (or control) did not take part in the PCI procedure at the catheterization laboratory, which was monitored by different anesthesiologists who were blinded to the treatment allocation.

Data and laboratory collection. A team of research coordinators, blinded to protocol allocation, collected data on baseline patient and procedure characteristics, intra- and postoperative care, length of stay in the intensive care unit (ICU) and in-hospital, and the occurrence of adverse events. At 30-day and 1-year follow-up, they also assessed the vital statuses and procedure-related characteristics of other patients via phone call, following a specifically designed questionnaire.

CK-MB mass was collected up to 48 hours before enrollment and repeated in the first 24 hours after. In case of being altered, the collection was repeated until deemed normal and the highest value was the one used for the primary endpoint calculation. CK-MB mass was determined from plasma levels measured using the amplified chemiluminescence method (VITROS 5600 equipment; Johnson & Johnson). The reference values ranged from 0 to 3.38 ug/L.

Statistical analysis. The study followed the intention-to-treat principle. The null hypothesis was that the sevoflurane group would have an increase in CK-MB mass equal to or greater than the control group. The alternative hypothesis was that the sevoflurane group would have less release of CK-MB mass than the control arm. The rejection of the null hypothesis would mean that the sevoflurane group is superior to the control group with regards to the primary outcome.

Sample size estimation was exploratory, due to the lack of studies in the literature with similar populations and outcomes. Based on previous studies with volatile anesthetics for myocardial preconditioning in patients undergoing CABG, we expected a 9% reduction in the primary endpoint (CK-MB mass release >1x the reference value) in the cohort receiving sevoflurane. Assuming a 10% loss of the sample, a total of 690 patients in each arm would assure a 90% power to detect the difference, at a 5% significance level.

An interim analysis to assess excessive benefit, harm, or futility was planned to take place after at least 50% of the population was enrolled. The interim analysis was performed using De Met’s criteria, with a 95% confidence interval based on the Wilson score. The futility analysis was performed with the PASS program (NCSS, LLC), using the Conditional Power Calculator (http://resourcetepee.com/free-statistical-calculators/conditional-power-calculator; Resource Tepee, LLC).   

Variables with normal distribution were expressed as mean and standard deviation, and those without symmetrical distribution were expressed as median and interquartile range (25th-75th percentile). The Kolmogorov-Smirnov test was used to determine the normality of the quantitative variables. The Student’s t-test was used for the comparison of the groups when normality was demonstrated, and the Mann-Whitney test was used when normality was not found. Categorical variables were expressed as absolute (n) and relative (%) frequency, and Fisher’s exact test was used to determine possible associations between these variables.

For the multivariate Cox model, we selected variables with known clinical significance in the literature and/or those with a P-value of less than .1 in the univariate analysis. The stepwise method was used to obtain the final reduced model. The data were analyzed with the aid of IBM SPSS version 20.0.

Clinical, demographic, and procedure characteristics. Between February 2017 and September 2019, 807 consecutive patients were screened for eligibility. A total of 701 patients signed the informed consent and were enrolled (352 in the sevoflurane group and 349 in the placebo cohort).  After randomization, 53 patients (7.5%) were excluded from the final analysis (30 in the active cohort and 23 in the control group). The Figure displays the study flowchart. Demographic and clinical characteristics were comparable between the cohorts, except for the body mass index, which was slightly higher in the placebo group (28.94 ± 4.79 vs 27.90 ± 4.33) (Table 1).

Most of the procedures were performed by radial access, and the number of implanted stents was similar in both cohorts (1.76 ± 0.3 in the control vs 1.79 ± 0.3 in the sevoflurane group, P=.21).

Thirty-nine patients had adverse events in the volatile anesthetic group:  there were 24 cases of hypotension (mostly controlled with fluid infusion), 9 cases of mental confusion, 2 cases of nausea, 2 cases of laryngospasms, 1 case of hypoxia, and 1 case of involuntary muscle contraction. All these events were classified as mild and ceased with the interruption of the sevoflurane. No adverse effect was observed in the placebo cohort.

At the time of the first interim analysis (56% of the total expected population) and upon consideration of the real event rates, the data and safety monitoring committee recommended that the investigators halt the study due to futility, since it was highly implausible that a statistically significant result would be obtained, even after the inclusion of the total sample (probability: 0.01%). 

CK-MB mass increase and clinical events. Pre-PCI CK-MB mass was mostly normal and comparable between groups (2.20 ± 7.76 in the placebo vs 1.72 ± 2.21 in the active group, P=.17).

The frequency of myocardial injury attributed to the increase in serum levels of CK-MB mass in the sample was 29.78% for increases above the upper limit of normality and 3.42% for increases that exceeded 5 times the upper limit of normality. In the comparative analysis, the frequency of elevation above the upper limit of normality was 30.8% among the patients in the sevoflurane group and 28.9% among the patients in the control group (P=.33). These figures were 4.6% and 3.1%, respectively, in the comparative analysis of the frequency 5 times above the upper limit of normality (P=.21).

After hospital discharge and up to 1 year post procedure, there were 6 spontaneous MIs (5 in the control and 1 in the sevoflurane cohort, P=.12). No stroke was documented along the trial. Thirteen deaths occurred during the total follow-up period (7 in the placebo group and 6 in the sevoflurane cohort, P=.67).

In-hospital stay was very short and did not significantly differ between populations (1.3 days in the placebo group vs 1.23 in the volatile anesthetic cohort, P=.39).

Table 2 details the in-hospital and 1-year main outcomes of the enrolled population.

To the best of our knowledge, this is the largest trial to assess the role of inhaled anesthetic to prevent myocardial damage after PCI. In our main findings, sevoflurane was not shown to prevent CK-MB release and reduce periprocedural MI. Furthermore, a few anesthetic-related side effects of mild severity were observed in the active group.

In this study, we evaluated the hypothesis of pharmacologically induced myocardial preconditioning as well as the capacity of volatile anesthetics to modify myocardial supply-and-demand relation. Promising results in the field of cardioprotection promoted by pharmacological and remote ischemic preconditioning in animals led to testing its applicability in humans.

In 2006, Guarracino et al published their experience comparing the use of desflurane (analogous of sevoflurane and volatile anesthetic) to pure venous anesthesia during CABG and were able to demonstrate a protective myocardial effect of the inhaled anesthesia in terms of reducing troponin T in the postoperative period (1.2 [0.9-1.9] ng/dL vs 2.7 [2.1-4.0] ng/dL, P<.001).¹⁴ In 2009, De Hert et al published the results of a multicenter trial with 404 patients undergoing CABG who were randomized for volatile agents (sevoflurane and desflurane) vs pure venous anesthesia. Although inhaled anesthetics failed to reduce troponin T elevation, their use was associated with shorter in-hospital stay and late mortality rate.¹⁵

More recently, a randomized study by Likhvantsev et al including 900 patients demonstrated that the use of sevoflurane reduced the length of hospital stay (10 [9-11] days vs 14 [10-16] days, P<.001), the levels of post-PCI troponin I (0.18 ng/ml vs 0.57 at 24h, P<.001), and NT-proBNP (633 pg/mL vs 878 at 24h, P<.001; 482 vs 1036 at 48h, P<.001), and was even capable of impacting the 1-year mortality rate (17.8% vs 24.8%, P=.03) when compared with intravenous anesthetic in cardiac surgeries.¹⁶ Of note, a 2016 metanalysis failed to show impact of inhaled anesthetic in mortality in noncardiac surgeries (odds ratio = 1.31; 95% CI: 0.83 -2.05; P=.242).¹⁷

Despite the above-mentioned benefits obtained from data derived from small studies, the recent MYRIAD trial with 5400 patients randomized to volatile vs intravenous anesthesia failed to show difference in mortality (risk ratio [RR] = 1.11; 95% CI: 0.70-1.76) or other endpoints including MI, time in the ICU, and hospital stay. In accordance with our findings, no late benefit (1 year) was observed in the MYRIAD trial (incidence of mortality: 2.8% and 3.0%, respectively [RR = 0.94; 95% CI: 0.69-1.29; P= .71]).¹²

In contrast to these studies, we used CK-MB mass as the surrogate of myocardial damage instead of troponins. Although CK-MB is less sensitive than the troponins for the diagnosis, CK-MB raise has its prognostic value better defined after PCI than troponins.^18,19 Many previous studies have correlated CK-MB raise with myocardial damage and whenever the raise is 5x upper (AQ: above?) the cutoff value, this finding correlates with worse clinical outcomes, including higher death rates in the mid- to long-term follow-up.^20,21,22 While troponin elevation also correlates strongly with myocardial damage, the best cutoff values to predict adverse clinical outcomes are still unclear. Furthermore, at the time of trial design, CK-MB was the recommended cardiac biomarker to be collected after PCI and was the routine biomarker dosed in our center.

Additionally, we evaluated the role of these drugs after PCI, where the cardiac injury is much inferior to that usually observed with open heart surgical procedures. Even in cardiac surgeries, where the damage extension is expected to be higher, the role of inhaled anesthesia is controversial.

Finally, it is worth noting that volatile anesthetics such as sevoflurane have been implicated in both postoperative cognitive dysfunction and neurotoxicity,²³ and have been observed to impact metabolism, especially blood glucose level,²⁴which might further mitigate any possible cardioprotective effect.

Limitations. This study has some important limitations. First, this is a single-center trial that enrolled low- to moderate-risk patients submitted to PCI. Lack of angiographic core laboratory analysis precluded evaluation of the cause for marker raise (eg, embolization, side branch occlusion, etc). Although similar doses of sevoflurane and shorter times of administration have been shown to reduce the release of cardiac biomarkers after CABG, it is possible that higher doses and/or a prolonged exposure time to this volatile anesthetic might have achieved different effects regarding cardiac preconditioning. Also, the study was stopped prior to completion, which increases type 2 error despite the lack of any trend demonstrating the benefit of sevoflurane. Finally, if troponin had been chosen as the marker for myocardial damage, the raise would probably have been higher since it is a more sensitive marker. However, for post-PCI prognosis, CK-MB is a better-established marker.

The use of inhaled sevoflurane neither reduced CK-MB mass elevation nor prevented the occurrence of myocardial damage and perioperative MI after PCI and, therefore, should not be considered in this scenario. In addition, the present research abolishes the concept of myocardial protection induced by sevoflurane during percutaneous coronary interventions (PCI) with stents, either in elective as well as in acute coronary syndrome patients (except for STEMI patients, who were not included in this trial). Furthermore, the use of these inhale drugs results in increased costs and might be associated with higher untoward events.

From the ¹Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil; ²Hospital Israelita Albert Einstein, São Paulo, Brazil; ³Hospital Sâo Domingos, Rede DASA, São Luis, Brazil.

Disclosures: The authors report no financial relationships or conflicts of interest regarding the content herein.

Acknowledgments: The authors would like to acknowledge the nurse team, in particular Edna Maria (RN) and Maria Helena (RN), who helped to make possible the development of an anesthetic station in their interventional catheterization laboratory facility.

Address for correspondence: J Ribamar Costa Jr, MD, PhD, Instituto Dante Pazzanese de Cardiologia, Avenida Dr. Dante Pazzanese, 500. São Paulo/SP, CEP 04012-909, Brazil. Email: rmvcosta@uol.com.br