Sevoflurane in acute myocardial infarction: A pilot randomized study Shahar Lavi, MD, a,b Daniel Bainbridge, MD, a,b Sabrina D'Alfonso, MSc, b Pantelis Diamantouros, MD, a,b Jaffer Syed, MD, a,b George Jablonsky, MD, a,b and Ronit Lavi, MD a,b Ontario, Canada
Background Experimental evidence suggests that the inhalational anesthetic sevoflurane has a cardioprotective effect. Our objective was to determine if sedation with sevoflurane will reduce infarct size in patients with acute myocardial infarction (MI) who are treated with primary percutaneous coronary intervention (PCI). Methods We randomized 50 patients presenting with a first acute ST-elevation MI treated by primary PCI within 6 hours from symptom onset to sedation with sevoflurane inhalation or standard sedation (control). Coronary flow at the end of PCI was assessed by corrected Thrombolysis In Myocardial Infarction frame count. Myocardial reperfusion was assessed by ST-segment resolution 60 minutes post-PCI. Infarct size was assessed by release of creatinine kinase (CK) and troponin T. Results
There was no difference in the primary end point: troponin T or CK release adjusted to the area at risk, between groups. However, among patients with anterior MI, there was a trend toward lower CK (P = .05) and nonsignificant decrease in troponin (P = .11) levels in the sevoflurane group. Corrected Thrombolysis In Myocardial Infarction frame count was 12.3 ± 1.5 in the sevoflurane group and 15.6 ± 9.1 in the control group (P = .16). There was more ST resolution in patients treated by sevoflurane 80.7% ± 25.8% versus 56.6% ± 35.7% (P = .01). Sevoflurane had no significant adverse effect during administration. Conclusions Sevoflurane administration during primary PCI did not reduce infarct size. There was a trend toward a reduction in infarct size among patients with anterior MI. Sevoflurane administration was associated with improvement in ST-segment resolution. (Am Heart J 2014;168:776-83.)
ST-elevation myocardial infarction (STEMI) is an important source of morbidity and mortality. Restoration of flow to the occluded coronary artery by primary percutaneous coronary intervention (pPCI) is associated with improved outcome and is considered the preferred reperfusion approach if performed in a timely manner. 1,2 However, restoration of flow is often associated with reperfusion injury that may account for up to 50% of the infarct size. 3 Therefore, identifying interventions or medications that can reduce reperfusion injury could have a major impact on the outcome of patients with STEMI. A possible mechanism to reduce ischemic-reperfusion injury involves ischemic conditioning. 4 Ischemic From the aWestern University, London, Ontario, Canada, and bLondon Health Sciences Centre, London, Ontario, Canada. RCT No. NCT00971607. Meeting presentation: Presented in part at the European Society of Cardiology meeting in Amsterdam, 2013, and published as an abstract, Eur Heart J 2013:34(suppl 1). Submitted January 15, 2014; accepted July 16, 2014. Reprint requests: Shahar Lavi, MD, Division of Cardiology, The University of Western Ontario, 339 Windermere Road, PO Box 5339, London, ON, Canada N6A 5A5. E-mail: [email protected] 0002-8703 © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.07.009
conditioning by way of transient occlusion of a coronary artery during pPCI has been associated with short- and long-term benefits. 5,6 This intervention cannot be applied to patients with STEMI who present to hospitals without PCI facilities and receive reperfusion with thrombolytic therapy 7 and is not used routinely during pPCI, possibly due to concern about causing injury to the coronary arteries. 8 Pharmacologic agents that mimic ischemic conditioning may be suitable for all patients with STEMI who receive reperfusion therapy, including fibrinolysis and pPCI. These agents can be initiated early prior to reperfusion and, therefore, may be more effective. A potential pharmacologic agent that mimics ischemic conditioning is the volatile anesthetic sevoflurane. 9 If proven to be effective, anesthetics may be the preferred myocardial protective drugs for patients with myocardial infarction (MI) because effective sedation is often required for these patients. Sevoflurane administration during cardiac surgery was found to reduce the incidence of MI, intensive care unit and hospital stay, time on mechanical ventilation, in-hospital mortality, and long-term cardiac events. 10–13 A recent meta-analysis demonstrated that volatile agents and, in particular, sevoflurane and desflurane reduce mortality after cardiac surgery compared
American Heart Journal Volume 168, Number 5
with intravenous anesthesia. 14 There are few data regarding the effect of sevoflurane during PCI. In a small study, low-dose sevoflurane before elective PCI had no effect on myocardial damage. 12 A potential protective effect is likely to be more robust in patients with STEMI, but this has not been studied thus far. In this proof-of-concept study, we investigated the cardioprotective effect of sevoflurane during pPCI.
Methods This was a single-center, randomized, double-blind, controlled trial. The design of the trial, data collection and analysis, and the writing of the manuscript were undertaken solely by the authors. The manufacturers of the anesthetic products had no role in the study. The Research Ethics Board of Western University approved the study. All patients provided written informed consent prior to enrollment. The study is registered at www.clinicaltrials. gov; identifier NCT00971607.
Study population Male and female patients aged 18 to 75 years who presented within 6 hours of onset of chest pain with a first STEMI and referred for pPCI were eligible for enrollment. Patients had to have symptoms lasting N30 minutes and electrocardiogram (ECG) demonstrating ST-segment elevation N0.1 mV in 2 or more contiguous leads. Exclusion criteria included the following: cardiac arrest, cardiogenic shock, previous MI, previous coronary artery bypass surgery, preinfarction angina, heart failure (New York Heart Association class III/IV), chronic inflammatory disease (eg, lupus and rheumatoid arthritis), known severe renal impairment (creatinine N 2× upper limit of normal), hepatic dysfunction, use of glybenclamide (an ATP potassium channel blocker that blocks the ischemic conditioning effect) 15, history of familial malignant hyperthermia, and hypersensitivity to halogenated agents. Percutaneous coronary intervention procedures All procedures were performed according to standard clinical practice and using approved devices including use of aspiration thrombectomy catheters and direct stenting if deemed appropriate. Patients received dual antiplatelet therapy, including aspirin and a loading dose of clopidogrel. Anticoagulation and administration of GPIIbIIIa inhibitors were given according to the operator's discretion. Randomization Computer-generated randomization sequence was set in random blocks of 8, 12, and 16 using sealed opaque envelopes. Because randomization envelopes were opened by the anesthesiologist administering the sedation, the anesthesia team was not blinded to the study drug. The anesthesia team assisted in the administration
Lavi et al 777
of intravenous medications including midazolam and fentanyl, as deemed needed, and therefore, the blindness of other team members to the randomization, including the interventional cardiologist and the cardiac catheterization laboratory and coronary care unit nurses, was maintained. Data were collected and analyzed in a blinded fashion.
Sedation protocol An anesthesia gas machine with a standard anesthesia circuit, a gas-scavenging system, and monitoring was available for all procedures. All patients were connected to standard monitoring, and sevoflurane was administered with a mixture of oxygen and air through a tightfitted mask by the anesthesiologist. The mask was applied immediately after the beginning of standard monitoring according to the American Society of Anesthesiologist and The Canadian Anesthesiologists' Society guidelines, and prior to PCI. The sevoflurane group received 50% oxygen and sevoflurane. Sevoflurane was given for 30 minutes or until completion of PCI, whichever occurred first. Sevoflurane levels were monitored continuously with sevoflurane mean alveolar concentration (MAC) levels. All patients in the control group received 50% oxygen by a similar mask connected to the anesthesia machine and sedation by intravenous midazolam. Patients in the sevoflurane group could receive standard sedatives, including midazolam, in addition to sevoflurane. Patients in both groups could receive fentanyl if needed. The depth of anesthesia was monitored continuously using bispectral index (BIS) in both groups, with a target BIS value of 80. An anesthesiologist provided sedation and analgesia, titrating both approaches to achieve an appropriate BIS, and was present throughout the procedure as well as in the postprocedure recovery area until patients were fully alert. The feasibility, effectiveness, efficacy, and safety of both sedation routes were also assessed. Study end points The primary end point was infarct size as assessed by the area under the curve of creatinine kinase (CK) and troponin, adjusted to area at risk. Secondary end points included the following: final Thrombolysis In Myocardial Infarction (TIMI) flow, STsegment elevation resolution, peak plasma troponin T and CK, inflammatory markers, and renal function. The infarct-related area at risk was estimated according to the modified Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) score. 16 Images were processed independently by 2 cardiologists who were blinded to the treatment arms. Blood samples for CK and troponin T were measured every 4 hours during the first 24 ours, and then every 8 hours for the next 2 days. The area under the curve (arbitrary units) was used to assess infarct size. 17 Creatinine
American Heart Journal November 2014
778 Lavi et al
Figure 1
SIAMI Study Flow Diagram Assessed for eligibility (n = 71)
Excluded (n = 21) ♦ Not meeting inclusion criteria (n = 14) ♦ Declined to participate (n = 5) ♦ Other reasons (n = 2)
Randomized (n = 50)
Allocated to Control (n = 25) ♦ Received allocated intervention (n = 25)
Allocated to Sevoflurane (n = 25) ♦ Received allocated intervention (n = 25)
Analysed (n = 22) ♦ Excluded from analysis (not an MI) (n = 3)
Analysed (n = 25)
Study flow diagram.
was measured in the first 2 days. High-sensitivity C-reactive protein was measured the day after the infarct. Myocardial perfusion at the end of PCI was assessed by angiography and by ECG. Coronary blood flow was calculated by a technician blinded to the randomization, according to the corrected TIMI frame count (CTFC) method. 18 The left anterior descending frame count was divided by 1.7 to correct for length. 18 ST-segment elevation resolution of ≤50% compared with baseline was considered as ECG index of the absence of myocardial reperfusion. 19 Baseline ECG was performed within 30 minutes prior to cardiac catheterization. STsegment resolution was assessed 60 minutes after the completion of PCI. Electrocardiogram interpretation was performed by a cardiologist blinded to the randomization. A questioner was given to the patients shortly after completion of PCI when the patients were transferred to the recovery area. The questioner was given by an interviewer who answered any questions and explained the scales used. Below each question, there was a scale consisting of a line and a scale of 0 to 10, with 10 being most satisfied. The patient had to circle the most appropriate number.
Statistical analysis Continuous baseline variables are summarized by mean and SD or median and interquartile range (if not normally distributed) and counts/percentages (categorical variables).
Comparisons between continuous variables were performed using Student t test or Wilcoxon rank sum test, where appropriate. Categorical variables were compared with the Pearson χ 2 test. P values are 2 tailed, and statistical significance was defined as P b .05. Data were analyzed according to the intention-to-treat principle. Regarding sample size, we hypothesized that the effect of pharmacologic postconditioning with sevoflurane would be similar to that of mechanical postconditioning. 5 Assuming a 35% reduction in infarct size, a type I error of 0.05 using a 2-sided test and statistical power of 80%, we required a total of 50 patients. This study was supported by The Academic Medical Organization of Southwestern Ontario; The Program of Experimental Medicine in the Department of Medicine, Western University; and The Canadian Anesthesiologists' Society. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Results Fifty patients were enrolled. Three patients were found to have acute pericarditis and not MI and therefore were excluded. 20 The flow diagram of the study is depicted in Figure 1. Baseline characteristics are presented in Table I. Twenty-three percent were women, and 17% had a history of diabetes. Patients were brought directly to the
American Heart Journal Volume 168, Number 5
Lavi et al 779
Table I. Baseline characteristics
Table II. PCI and anesthesia procedure characteristics
Sevoflurane (n = 25) Age (y) Female sex, no. (%) Current smokers, no. (%) Hypertension, no. (%) History of dyslipidemia, no. (%) Diabetes mellitus, no. (%) Family history of IHD, no. (%) Body mass index (kg/m 2) Systolic blood pressure (mm Hg) Heart rate (beats/min) Symptom onset to first device (min) First contact to first device (min) Creatinine baseline (μmol/L)
62 ± 12 6 (24) 7/25 (28) 15/25 (60) 12/24 (50) 3/25 (12) 11/25 (44) 27.2 ± 4 144 ± 26 79 ± 13 164 ± 96 77 ± 23 79 ± 22
Control (n = 22) 62 ± 11 5 (23) 11/20 (55) 15/22 (68) 8/22 (36) 5/22 (23) 6/22 (27) 29.0 ± 5 150 ± 32 76 ± 18 194 ± 111 79 ± 22 81 ± 22
P
.83 .92 .07 .56 .35 .33 .23 .17 .51 .56 .34 .81 .76
Abbreviation: IHD, Ischemic artery disease.
catheterization laboratory as soon as the diagnosis of MI was made, from the emergency department, ambulance, or nearby hospital. First contact-to-balloon time was similar in the 2 groups (~78 minutes). Procedural characteristics are presented in Table II. In the sevoflurane arm, there were more patients with anterior MI (64% vs 36%, P = .06). Anesthesia was provided for a similar duration (~60 minutes) to both groups. Midazolam and fentanyl were used more often in the control group (Table II). A sevoflurane MAC of 0.32% ± 0.12% provided adequate sedation for the procedure. The use of sevoflurane was not associated with any hemodynamic or airway adverse affects and was continued as per protocol. Both groups archived similar degree of depth of anesthesia, monitored with continuous BIS. Use of aspiration catheters and administration of IIbIIIa inhibitors were similar in both groups. Percutaneous coronary intervention was performed in 94% of patients. Two patients, one from each group, underwent urgent coronary artery bypass grafting (CABG). One patient in the sevoflurane group was treated after angiography with medications only without further revascularization because the lesion was relatively distal. All patients received aspirin, statins, angiotensin-converting enzyme inhibitors, and β-blockers upon discharge. Clopidogrel was given to all patients initially, but discontinued for the 2 patients who were referred for CABG.
End points The primary end point, infarct size, corrected to area at risk, was not different between groups (Figure 2), but the regression lines for sevoflurane had smaller slopes compared with control. The area at risk, estimated by the modified APPROACH criteria, was larger in the sevoflurane group, 32.3% ± 11.7%, compared with the control group, 24.8% ± 11.3% (P = .03).
Sevoflurane (n = 25) Infarct-related artery - Left anterior descending - Right coronary - Circumflex artery - Intermediate artery Baseline TIMI flow -0 -1 -2 -3 Final TIMI flow -0 -1 -2 -3 CTFC No. of vessels with significant disease -1 -2 -3 Use of aspiration catheter Anesthesia - BIS - Anesthesia time (min) - Midazolam use - Fentanyl use - MAC Drugs given during PCI - Unfractionated heparin - Bivalirudin - IIbIIIa inhibitors
Control (n = 22)
16/25 (64%) 6 (24%) 4 (16%) 0
8/22 (36%) 10 (45%) 3 (14%) 1 (5%)
16 (64%) 0 4 (16%) 5 (20%)
12 (57%) 2 (10%) 2 (10%) 5 (24%)
1 (4%) 0 0 24 (96%) 12.3 ± 1.5
0 1 (4.5%) 0 21 (95%) 15.6 ± 9.1
14 (56%) 3 (12%) 8 (32%) 14 (56%)
7 (32%) 7 (32%) 8 (36%) 12 (55%)
83.3 ± 6.3 60 ± 24 7 (28%) 11 (44%) 0.32% ± 0.12%
84.9 ± 2.7 61 ± 23 21 (95%) 18 (82%) 0
24 (96%) 0 23/25 (92%)
18 (81%) 3 (14%) 17/20 (85%)
P
.06 .12 .82 .40
.36
.16 .15
.92 .27 .86 b.001 .008
.11 .06 .46
In patients presenting with anterior MI, there was a trend toward lower CK and troponin T levels in the sevoflurane group (Figure 3). Ninety-six percent of patients had final TIMI 3 flow. The final CTFC was not different between groups (Table II). When excluding the patients who had baseline TIMI flow N1, the final CTFC was 15.6 ± 10.9 in the control group and 12 ± 5.6 in the sevoflurane group (P = .29). Electrocardiogram findings are described in Table III. There was more resolution of ST-segment elevation in the sevoflurane group. However, the proportion of patients achieving more than 50% resolution was not different between groups. Laboratory results are presented in Table III. There was no difference between groups in the levels of inflammatory markers or creatinine values the day after admission. The patients who underwent CABG had patent infarctrelated artery. Their infarct size was smaller compared with the average. Excluding these patients had no effect on outcome. The results of the patients' satisfaction and pain survey are presented in Table IV. Sedation with sevoflurane was more effective in pain management and provided more
780 Lavi et al
American Heart Journal November 2014
Figure 2
Primary end point: infarct size according to area at risk. The area at risk was estimated according to the modified APPROACH score. A, Peak troponin T. B, Area under the curve of troponin T for 24 hours. C, Peak CK. D, Area under the curve of CK for 24 hours.
relaxing effect compared with standard therapy. Patients in both groups were satisfied with the sedation and indicated their preference to have the anesthesia team involved in future cardiac procedures. This perception was significantly stronger among patients who received sedation with sevoflurane.
Discussion The present study demonstrates that sedation with lowdose sevoflurane during pPCI is safe and effective in reducing pain and anxiety compared with standard sedation. Treatment with sevoflurane was associated with improvement in ST-segment elevation resolution, without affecting final infarct size. In the higher-risk patient cohort who presented with anterior MI, administration of sevoflurane was associated with a statistically nonsignificant reduction in infarct size. The outcome of patients with STEMI has improved substantially in the last decade. This improvement is related to rapid administration of reperfusion therapy, use of effective antiplatelet and anticoagulant agents, and
improvement in myocardial remodeling post MI. At the same time, despite evaluation of different pharmacologic agents, there is no myocardial protective agent that is used routinely for patients with STEMI. The rationale to evaluate the effect of sevoflurane as a myocardial protective agent in the setting of STEMI is based on experimental and clinical evidence. Peri-ischemic administration of low sedative concentrations (b1 vol%) of sevoflurane attenuated ischemia-reperfusion injury of the endothelium, as assessed by hyperemic blood flow response and inhibited leukocyte adhesion. 21 The same low concentration inhibits agonist-induced granulocyte-platelet interactions up to 24 hours after administration and thus counteracts the thromboinflammatory processes. 22 Sevoflurane was found to be cardioprotective in patients undergoing cardiac surgery. 10–13 In the current study, we did not find a difference in the degree of myocardial injury between the sevoflurane and the control groups. Patients in both groups received pPCI relatively quickly, along with contemporary medical therapy that included, in most patients, administration of IIbIIIa inhibitors and frequent use of aspiration thrombectomy. Patients in both groups had a relatively
American Heart Journal Volume 168, Number 5
Figure 3
Lavi et al 781
Table III. Laboratory results and ECG findings Sevoflurane (n = 25) LDL HDL hsCRP WBC Creatinine 24 h (μmol/L) No. of leads with ST elevation Total ST elevation (mm) No. of leads with ST depression Total ST depression ST resolution (%) at 60 min (lead with maximum ST elevation) Residual total ST elevation at 60 min No. of patients with ST resolution N50%
Control (n = 22)
P
2.69 (1.89-3.12) 0.98 (0.83-1.25) 9.26 (3.53-14) 10.6 ± 3.1 77 ± 21 5 ± 1.7 11.6 ± 10.7 3.3 ± 2.1
2.29 (1.76-3.03) 1.09 (0.83-1.21) 6.45 (3.21-12.92) 10.4 ± 3.5 78 ± 12 4.6 ± 1.6 8.4 ± 6.2 2.2 ± 1.1
.47 .96 .64 .78 .91 .47 .22 .04
4.7 ± 3.8 80.7 ± 25.8
4±5 56.6 ± 35.7
.58 .01
2.2 ± 2.64
4.18 ± 4.63
.07
19/24 (79%)
12/22 (55%)
.07
Abbreviations: LDL, Low-density lipoprotein; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; WBC, white blood cells.
Assessment of infarct size in patients with anterior MI.
favorable outcome. Therefore, our pilot study may have been underpowered to detect a clinical effect in the overall study population. As a pilot study that tested for the first time administration of sevoflurane to patients with STEMI, we chose a sample size that was similar to previous studies of ischemic conditioning. 6,17 Our study population was broad and included patients with inferior infarcts as well as patients who had normal flow on coronary angiography. In contrast, most previous studies that showed a beneficial effect of ischemic conditioning in the setting of acute MI restricted inclusion to patients with anterior or other large infarcts who had complete occlusion of the coronary artery. 6,17,23,24 Any intervention or medication that is used to prevent ischemic-reperfusion injury is more likely to be effective if begun prior to restoration of flow in the occluded artery. 25 Experimental evidence suggests that this is true for sevoflurane. 26 Therefore, in the current study, patients were randomized and sedation was initiated, immediately on arrival to the catheterization laboratory, prior to diagnostic coronary angiography. In addition to the potential for higher protective effect, patients benefited from effective sedation provided by the
anesthesia team. Our approach also reduced selection bias related to findings on coronary angiography. On the other hand, our approach resulted in inclusion of patients at low risk or with patent coronary arteries. Although we did not find a significant effect of sevoflurane on infarct size in the overall study population, our study suggests a beneficial effect with a larger area at risk and anterior infarcts. This finding in a subgroup should be interpreted with caution because several recent studies did not find a beneficial effect of ischemic postconditioning, and some even suggested a potential harmful effect. 23,24,27,28 However, consistent with our results, it was previously proposed that a beneficial effect of ischemic conditioning is seen only in patients with large infarcts. 29 We allowed elderly patients to be included in the study. Analysis of previous studies suggests that ischemic conditioning is more effective in younger patients. 30 Our sample size is too small for further subgroup analysis according to age and baseline coronary flow. One of the important findings in our study is the safety of sedation with sevoflurane in the catheterization laboratory with favorable impact on patients' satisfaction. The low sevoflurane MAC needed for adequate sedation is promising, as this inhalational drug can be easily stopped at any time when the patient is sedated yet cooperative. Sevoflurane is thought to have some analgesic properties, and indeed, in the sevoflurane group, the use of fentanyl was significantly decreased. With the increasing number of complex procedures being performed in the catheterization laboratory, it is possible that the anesthesia team will become an integral
American Heart Journal November 2014
782 Lavi et al
Table IV. Patient satisfaction
Disclosures
Sevoflurane (n = 25) Pain on arrival Pain during the procedure Relaxed during the procedure Pain at end of procedure Relaxed at end of procedure Nausea Preference for anesthesia team involvement in future cardiac procedures
7 0 10 0 10 0 10
(6-10) (0-3) (10-10) (0-2.3) (8.75-10) (0-0) (10-10)
Control (n = 22) 6.3 (3-8) 3 (1.8-5.3) 8 (7-9.25) 1 (0-2.1) 9.75 (8.75-10) 0 (0-0) 10 (6-10)
P
.07 .006 .0003 .40 .28 .57 .004
Scale of 0 to 10. Median and Q1-Q3.
part of the catheterization lab staff and, thereby, provides more effective sedation to patients with STEMI. 31
Limitations Our study has several important limitations. First, this was a small pilot study. As such, it was underpowered to demonstrate moderate differences between groups. There were nonsignificant differences in baseline characteristics, such as onset of symptoms to device time duration, which may affect the results. There was a higher proportion of anterior MI in the sevoflurane group. We compared the subgroup of patients with anterior MI, but the results from such a small subgroup may be further affected by chance findings. Therefore, our results should be interpreted with caution. With the challenges of performing such a complex study, we thought that this would be a reasonable sample size, and the results are sufficient to help design a future study. We suggest that such a study will focus on patients with anterior MI and documentation of an occluded infarct-related artery. In summary, in this small pilot study, we found that use of low-dose sevoflurane during pPCI is safe and provides effective sedation. Administration of sevoflurane was associated with improved ST-segment elevation resolution but failed to reduce infarct size. Further larger clinical trials are required.
Acknowledgment We would like to thank the nurses and the technicians in the cardiac catheterization laboratory and the nurses and clerks in the coronary care unit. We thank Dr Hesham Youssef, Dr Sunisa Prapaitrakool, and the respiratory therapists and anesthesia assistants at University Hospital, London, Ontario, for their assistance. We thank Andrew McLellan and Dr Anthony Camuglia for assistance with imaging processing, and Jeffrey M. Landreville and Shemer Ratner for assistance with data collection. The BIS monitor was provided in kind by Caster Medical Systems.
No conflicts to disclose.
References 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361(9351): 13-20. 2. Stone GW. Angioplasty strategies in ST-segment-elevation myocardial infarction: part II: intervention after fibrinolytic therapy, integrated treatment recommendations, and future directions. Circulation 2008;118(5):552-66. 3. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357(11):1121-35. 4. Lavi R, Lavi S. Remote ischaemic conditioning before exercise: are we there yet? Heart 2011;97(16):1284-5. 5. Thibault H, Piot C, Staat P, et al. Long-term benefit of postconditioning. Circulation 2008;117(8):1037-44. 6. Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation 2005;112(14):2143-8. 7. Cantor WJ, Fitchett D, Borgundvaag B, et al. Rationale and design of the Trial of Routine ANgioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI). Am Heart J 2008;155(1):19-25. 8. Lavi S, Lavi R. Conditioning of the heart: from pharmacological interventions to local and remote protection: possible implications for clinical practice. Int J Cardiol 2011;146(3):311-8. 9. Zhao J, Wang F, Zhang Y, et al. Sevoflurane preconditioning attenuates myocardial ischemia/reperfusion injury via caveolin-3–dependent cyclooxygenase-2 inhibition. Circulation 2013;128(11 Suppl 1):S121-9. 10. Symons JA, Myles PS. Myocardial protection with volatile anaesthetic agents during coronary artery bypass surgery: a meta-analysis. Br J Anaesth 2006;97(2):127-36. 11. Jakobsen C-J, Berg H, Hindsholm KB, et al. The influence of propofol versus sevoflurane anesthesia on outcome in 10,535 cardiac surgical procedures. J Cardiothorac Vasc Anesth 2007;21(5):664-71. 12. Landoni G, Zangrillo A, Fochi O, et al. Cardiac protection with volatile anesthetics in stenting procedures. J Cardiothorac Vasc Anesth 2008;22(4):543-7. 13. Hemmerling T, Olivier JF, Le N, et al. Myocardial protection by isoflurane vs. sevoflurane in ultra-fast-track anaesthesia for off-pump aortocoronary bypass grafting. Eur J Anaesthesiol 2008;25(3):230-6. 14. Landoni G, Greco T, Biondi-Zoccai G, et al. Anaesthetic drugs and survival: a Bayesian network meta-analysis of randomized trials in cardiac surgery. Br J Anaesth 2013;111(6):886-96. 15. Loukogeorgakis SP, Williams R, Panagiotidou AT, et al. Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a KATP channel dependent mechanism. Circulation 2007;116(12):1386-95. 16. Ortiz-Perez JT, Meyers SN, Lee DC, et al. Angiographic estimates of myocardium at risk during acute myocardial infarction: validation study using cardiac magnetic resonance imaging. Eur Heart J 2007;28(14):1750-8. 17. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359(5): 473-81. 18. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996;93(5):879-88.
American Heart Journal Volume 168, Number 5
19. Niccoli G, Giubilato S, Russo E, et al. Plasma levels of thromboxane A2 on admission are associated with no-reflow after primary percutaneous coronary intervention. Eur Heart J 2008;29(15):1843-50. 20. Fergusson D, Aaron SD, Guyatt G, et al. Post-randomisation exclusions: the intention to treat principle and excluding patients from analysis. BMJ 2002;325(7365):652-4. 21. Lucchinetti E, Ambrosio S, Aguirre J, et al. Sevoflurane inhalation at sedative concentrations provides endothelial protection against ischemiareperfusion injury in humans. Anesthesiology 2007;106(2):262-8. 22. Wacker J, Lucchinetti E, Jamnicki M, et al. Delayed inhibition of agonist-induced granulocyte-platelet aggregation after low-dose sevoflurane inhalation in humans; 2008. p. 1749-58. 23. Tarantini G, Favaretto E, Marra MP, et al. Postconditioning during coronary angioplasty in acute myocardial infarction: the POST-AMI trial. Int J Cardiol 2012;162(1):33-8. 24. Freixa X, Bellera N, Ortiz-Perez JT, et al. Ischaemic postconditioning revisited: lack of effects on infarct size following primary percutaneous coronary intervention. Eur Heart J 2012;33(1):103-12. 25. Kloner RA, Rezkalla SH. Preconditioning, postconditioning and their application to clinical cardiology. Cardiovasc Res 2006;70(2):297-307. 26. Zitta K, Meybohm P, Bein B, et al. Cytoprotective effects of the volatile anesthetic sevoflurane are highly dependent on timing and duration
Lavi et al 783
27.
28.
29.
30.
31.
of sevoflurane conditioning: findings from a human, in-vitro hypoxia model. Eur J Pharmacol 2010;645(1–3):39-46. Sorensson P, Saleh N, Bouvier F, et al. Effect of postconditioning on infarct size in patients with ST elevation myocardial infarction. Heart 2010;96(21):1710-5. Lavi S, D'Alfonso S, Diamantouros P, et al. Remote ischemic postconditioning during percutaneous coronary interventions: remote ischemic postconditioning–percutaneous coronary intervention randomized trial. Circ Cardiovasc Intervent 2014;7(2): 225-32. Sorensson P, Ryden L, Saleh N, et al. Long-term impact of postconditioning on infarct size and left ventricular ejection fraction in patients with ST-elevation myocardial infarction. BMC Cardiovasc Disord 2013;13:22. http://www.biomedcentral.com/1471-2261/ 13/22. Zhou C, Yao Y, Zheng Z, et al. Stenting technique, gender, and age are associated with cardioprotection by ischaemic postconditioning in primary coronary intervention: a systematic review of 10 randomized trials. Eur Heart J 2012;33(24):3070-7. Lavi S, Jolly SS, Bainbridge D, et al. Sedation, analgesia, and anaesthesia variability in laboratory-based cardiac procedures: an international survey. Can J Cardiol 2014;30(6):627-33.
Background Experimental evidence suggests that the inhalational anesthetic sevoflurane has a cardioprotective effect. Our objective was to determine if sedation with sevoflurane will reduce infarct size in patients with acute myocardial infarction (MI) who are treated with primary percutaneous coronary intervention (PCI). Methods We randomized 50 patients presenting with a first acute ST-elevation MI treated by primary PCI within 6 hours from symptom onset to sedation with sevoflurane inhalation or standard sedation (control). Coronary flow at the end of PCI was assessed by corrected Thrombolysis In Myocardial Infarction frame count. Myocardial reperfusion was assessed by ST-segment resolution 60 minutes post-PCI. Infarct size was assessed by release of creatinine kinase (CK) and troponin T. Results
There was no difference in the primary end point: troponin T or CK release adjusted to the area at risk, between groups. However, among patients with anterior MI, there was a trend toward lower CK (P = .05) and nonsignificant decrease in troponin (P = .11) levels in the sevoflurane group. Corrected Thrombolysis In Myocardial Infarction frame count was 12.3 ± 1.5 in the sevoflurane group and 15.6 ± 9.1 in the control group (P = .16). There was more ST resolution in patients treated by sevoflurane 80.7% ± 25.8% versus 56.6% ± 35.7% (P = .01). Sevoflurane had no significant adverse effect during administration. Conclusions Sevoflurane administration during primary PCI did not reduce infarct size. There was a trend toward a reduction in infarct size among patients with anterior MI. Sevoflurane administration was associated with improvement in ST-segment resolution. (Am Heart J 2014;168:776-83.)
ST-elevation myocardial infarction (STEMI) is an important source of morbidity and mortality. Restoration of flow to the occluded coronary artery by primary percutaneous coronary intervention (pPCI) is associated with improved outcome and is considered the preferred reperfusion approach if performed in a timely manner. 1,2 However, restoration of flow is often associated with reperfusion injury that may account for up to 50% of the infarct size. 3 Therefore, identifying interventions or medications that can reduce reperfusion injury could have a major impact on the outcome of patients with STEMI. A possible mechanism to reduce ischemic-reperfusion injury involves ischemic conditioning. 4 Ischemic From the aWestern University, London, Ontario, Canada, and bLondon Health Sciences Centre, London, Ontario, Canada. RCT No. NCT00971607. Meeting presentation: Presented in part at the European Society of Cardiology meeting in Amsterdam, 2013, and published as an abstract, Eur Heart J 2013:34(suppl 1). Submitted January 15, 2014; accepted July 16, 2014. Reprint requests: Shahar Lavi, MD, Division of Cardiology, The University of Western Ontario, 339 Windermere Road, PO Box 5339, London, ON, Canada N6A 5A5. E-mail: [email protected] 0002-8703 © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.07.009
conditioning by way of transient occlusion of a coronary artery during pPCI has been associated with short- and long-term benefits. 5,6 This intervention cannot be applied to patients with STEMI who present to hospitals without PCI facilities and receive reperfusion with thrombolytic therapy 7 and is not used routinely during pPCI, possibly due to concern about causing injury to the coronary arteries. 8 Pharmacologic agents that mimic ischemic conditioning may be suitable for all patients with STEMI who receive reperfusion therapy, including fibrinolysis and pPCI. These agents can be initiated early prior to reperfusion and, therefore, may be more effective. A potential pharmacologic agent that mimics ischemic conditioning is the volatile anesthetic sevoflurane. 9 If proven to be effective, anesthetics may be the preferred myocardial protective drugs for patients with myocardial infarction (MI) because effective sedation is often required for these patients. Sevoflurane administration during cardiac surgery was found to reduce the incidence of MI, intensive care unit and hospital stay, time on mechanical ventilation, in-hospital mortality, and long-term cardiac events. 10–13 A recent meta-analysis demonstrated that volatile agents and, in particular, sevoflurane and desflurane reduce mortality after cardiac surgery compared
American Heart Journal Volume 168, Number 5
with intravenous anesthesia. 14 There are few data regarding the effect of sevoflurane during PCI. In a small study, low-dose sevoflurane before elective PCI had no effect on myocardial damage. 12 A potential protective effect is likely to be more robust in patients with STEMI, but this has not been studied thus far. In this proof-of-concept study, we investigated the cardioprotective effect of sevoflurane during pPCI.
Methods This was a single-center, randomized, double-blind, controlled trial. The design of the trial, data collection and analysis, and the writing of the manuscript were undertaken solely by the authors. The manufacturers of the anesthetic products had no role in the study. The Research Ethics Board of Western University approved the study. All patients provided written informed consent prior to enrollment. The study is registered at www.clinicaltrials. gov; identifier NCT00971607.
Study population Male and female patients aged 18 to 75 years who presented within 6 hours of onset of chest pain with a first STEMI and referred for pPCI were eligible for enrollment. Patients had to have symptoms lasting N30 minutes and electrocardiogram (ECG) demonstrating ST-segment elevation N0.1 mV in 2 or more contiguous leads. Exclusion criteria included the following: cardiac arrest, cardiogenic shock, previous MI, previous coronary artery bypass surgery, preinfarction angina, heart failure (New York Heart Association class III/IV), chronic inflammatory disease (eg, lupus and rheumatoid arthritis), known severe renal impairment (creatinine N 2× upper limit of normal), hepatic dysfunction, use of glybenclamide (an ATP potassium channel blocker that blocks the ischemic conditioning effect) 15, history of familial malignant hyperthermia, and hypersensitivity to halogenated agents. Percutaneous coronary intervention procedures All procedures were performed according to standard clinical practice and using approved devices including use of aspiration thrombectomy catheters and direct stenting if deemed appropriate. Patients received dual antiplatelet therapy, including aspirin and a loading dose of clopidogrel. Anticoagulation and administration of GPIIbIIIa inhibitors were given according to the operator's discretion. Randomization Computer-generated randomization sequence was set in random blocks of 8, 12, and 16 using sealed opaque envelopes. Because randomization envelopes were opened by the anesthesiologist administering the sedation, the anesthesia team was not blinded to the study drug. The anesthesia team assisted in the administration
Lavi et al 777
of intravenous medications including midazolam and fentanyl, as deemed needed, and therefore, the blindness of other team members to the randomization, including the interventional cardiologist and the cardiac catheterization laboratory and coronary care unit nurses, was maintained. Data were collected and analyzed in a blinded fashion.
Sedation protocol An anesthesia gas machine with a standard anesthesia circuit, a gas-scavenging system, and monitoring was available for all procedures. All patients were connected to standard monitoring, and sevoflurane was administered with a mixture of oxygen and air through a tightfitted mask by the anesthesiologist. The mask was applied immediately after the beginning of standard monitoring according to the American Society of Anesthesiologist and The Canadian Anesthesiologists' Society guidelines, and prior to PCI. The sevoflurane group received 50% oxygen and sevoflurane. Sevoflurane was given for 30 minutes or until completion of PCI, whichever occurred first. Sevoflurane levels were monitored continuously with sevoflurane mean alveolar concentration (MAC) levels. All patients in the control group received 50% oxygen by a similar mask connected to the anesthesia machine and sedation by intravenous midazolam. Patients in the sevoflurane group could receive standard sedatives, including midazolam, in addition to sevoflurane. Patients in both groups could receive fentanyl if needed. The depth of anesthesia was monitored continuously using bispectral index (BIS) in both groups, with a target BIS value of 80. An anesthesiologist provided sedation and analgesia, titrating both approaches to achieve an appropriate BIS, and was present throughout the procedure as well as in the postprocedure recovery area until patients were fully alert. The feasibility, effectiveness, efficacy, and safety of both sedation routes were also assessed. Study end points The primary end point was infarct size as assessed by the area under the curve of creatinine kinase (CK) and troponin, adjusted to area at risk. Secondary end points included the following: final Thrombolysis In Myocardial Infarction (TIMI) flow, STsegment elevation resolution, peak plasma troponin T and CK, inflammatory markers, and renal function. The infarct-related area at risk was estimated according to the modified Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) score. 16 Images were processed independently by 2 cardiologists who were blinded to the treatment arms. Blood samples for CK and troponin T were measured every 4 hours during the first 24 ours, and then every 8 hours for the next 2 days. The area under the curve (arbitrary units) was used to assess infarct size. 17 Creatinine
American Heart Journal November 2014
778 Lavi et al
Figure 1
SIAMI Study Flow Diagram Assessed for eligibility (n = 71)
Excluded (n = 21) ♦ Not meeting inclusion criteria (n = 14) ♦ Declined to participate (n = 5) ♦ Other reasons (n = 2)
Randomized (n = 50)
Allocated to Control (n = 25) ♦ Received allocated intervention (n = 25)
Allocated to Sevoflurane (n = 25) ♦ Received allocated intervention (n = 25)
Analysed (n = 22) ♦ Excluded from analysis (not an MI) (n = 3)
Analysed (n = 25)
Study flow diagram.
was measured in the first 2 days. High-sensitivity C-reactive protein was measured the day after the infarct. Myocardial perfusion at the end of PCI was assessed by angiography and by ECG. Coronary blood flow was calculated by a technician blinded to the randomization, according to the corrected TIMI frame count (CTFC) method. 18 The left anterior descending frame count was divided by 1.7 to correct for length. 18 ST-segment elevation resolution of ≤50% compared with baseline was considered as ECG index of the absence of myocardial reperfusion. 19 Baseline ECG was performed within 30 minutes prior to cardiac catheterization. STsegment resolution was assessed 60 minutes after the completion of PCI. Electrocardiogram interpretation was performed by a cardiologist blinded to the randomization. A questioner was given to the patients shortly after completion of PCI when the patients were transferred to the recovery area. The questioner was given by an interviewer who answered any questions and explained the scales used. Below each question, there was a scale consisting of a line and a scale of 0 to 10, with 10 being most satisfied. The patient had to circle the most appropriate number.
Statistical analysis Continuous baseline variables are summarized by mean and SD or median and interquartile range (if not normally distributed) and counts/percentages (categorical variables).
Comparisons between continuous variables were performed using Student t test or Wilcoxon rank sum test, where appropriate. Categorical variables were compared with the Pearson χ 2 test. P values are 2 tailed, and statistical significance was defined as P b .05. Data were analyzed according to the intention-to-treat principle. Regarding sample size, we hypothesized that the effect of pharmacologic postconditioning with sevoflurane would be similar to that of mechanical postconditioning. 5 Assuming a 35% reduction in infarct size, a type I error of 0.05 using a 2-sided test and statistical power of 80%, we required a total of 50 patients. This study was supported by The Academic Medical Organization of Southwestern Ontario; The Program of Experimental Medicine in the Department of Medicine, Western University; and The Canadian Anesthesiologists' Society. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Results Fifty patients were enrolled. Three patients were found to have acute pericarditis and not MI and therefore were excluded. 20 The flow diagram of the study is depicted in Figure 1. Baseline characteristics are presented in Table I. Twenty-three percent were women, and 17% had a history of diabetes. Patients were brought directly to the
American Heart Journal Volume 168, Number 5
Lavi et al 779
Table I. Baseline characteristics
Table II. PCI and anesthesia procedure characteristics
Sevoflurane (n = 25) Age (y) Female sex, no. (%) Current smokers, no. (%) Hypertension, no. (%) History of dyslipidemia, no. (%) Diabetes mellitus, no. (%) Family history of IHD, no. (%) Body mass index (kg/m 2) Systolic blood pressure (mm Hg) Heart rate (beats/min) Symptom onset to first device (min) First contact to first device (min) Creatinine baseline (μmol/L)
62 ± 12 6 (24) 7/25 (28) 15/25 (60) 12/24 (50) 3/25 (12) 11/25 (44) 27.2 ± 4 144 ± 26 79 ± 13 164 ± 96 77 ± 23 79 ± 22
Control (n = 22) 62 ± 11 5 (23) 11/20 (55) 15/22 (68) 8/22 (36) 5/22 (23) 6/22 (27) 29.0 ± 5 150 ± 32 76 ± 18 194 ± 111 79 ± 22 81 ± 22
P
.83 .92 .07 .56 .35 .33 .23 .17 .51 .56 .34 .81 .76
Abbreviation: IHD, Ischemic artery disease.
catheterization laboratory as soon as the diagnosis of MI was made, from the emergency department, ambulance, or nearby hospital. First contact-to-balloon time was similar in the 2 groups (~78 minutes). Procedural characteristics are presented in Table II. In the sevoflurane arm, there were more patients with anterior MI (64% vs 36%, P = .06). Anesthesia was provided for a similar duration (~60 minutes) to both groups. Midazolam and fentanyl were used more often in the control group (Table II). A sevoflurane MAC of 0.32% ± 0.12% provided adequate sedation for the procedure. The use of sevoflurane was not associated with any hemodynamic or airway adverse affects and was continued as per protocol. Both groups archived similar degree of depth of anesthesia, monitored with continuous BIS. Use of aspiration catheters and administration of IIbIIIa inhibitors were similar in both groups. Percutaneous coronary intervention was performed in 94% of patients. Two patients, one from each group, underwent urgent coronary artery bypass grafting (CABG). One patient in the sevoflurane group was treated after angiography with medications only without further revascularization because the lesion was relatively distal. All patients received aspirin, statins, angiotensin-converting enzyme inhibitors, and β-blockers upon discharge. Clopidogrel was given to all patients initially, but discontinued for the 2 patients who were referred for CABG.
End points The primary end point, infarct size, corrected to area at risk, was not different between groups (Figure 2), but the regression lines for sevoflurane had smaller slopes compared with control. The area at risk, estimated by the modified APPROACH criteria, was larger in the sevoflurane group, 32.3% ± 11.7%, compared with the control group, 24.8% ± 11.3% (P = .03).
Sevoflurane (n = 25) Infarct-related artery - Left anterior descending - Right coronary - Circumflex artery - Intermediate artery Baseline TIMI flow -0 -1 -2 -3 Final TIMI flow -0 -1 -2 -3 CTFC No. of vessels with significant disease -1 -2 -3 Use of aspiration catheter Anesthesia - BIS - Anesthesia time (min) - Midazolam use - Fentanyl use - MAC Drugs given during PCI - Unfractionated heparin - Bivalirudin - IIbIIIa inhibitors
Control (n = 22)
16/25 (64%) 6 (24%) 4 (16%) 0
8/22 (36%) 10 (45%) 3 (14%) 1 (5%)
16 (64%) 0 4 (16%) 5 (20%)
12 (57%) 2 (10%) 2 (10%) 5 (24%)
1 (4%) 0 0 24 (96%) 12.3 ± 1.5
0 1 (4.5%) 0 21 (95%) 15.6 ± 9.1
14 (56%) 3 (12%) 8 (32%) 14 (56%)
7 (32%) 7 (32%) 8 (36%) 12 (55%)
83.3 ± 6.3 60 ± 24 7 (28%) 11 (44%) 0.32% ± 0.12%
84.9 ± 2.7 61 ± 23 21 (95%) 18 (82%) 0
24 (96%) 0 23/25 (92%)
18 (81%) 3 (14%) 17/20 (85%)
P
.06 .12 .82 .40
.36
.16 .15
.92 .27 .86 b.001 .008
.11 .06 .46
In patients presenting with anterior MI, there was a trend toward lower CK and troponin T levels in the sevoflurane group (Figure 3). Ninety-six percent of patients had final TIMI 3 flow. The final CTFC was not different between groups (Table II). When excluding the patients who had baseline TIMI flow N1, the final CTFC was 15.6 ± 10.9 in the control group and 12 ± 5.6 in the sevoflurane group (P = .29). Electrocardiogram findings are described in Table III. There was more resolution of ST-segment elevation in the sevoflurane group. However, the proportion of patients achieving more than 50% resolution was not different between groups. Laboratory results are presented in Table III. There was no difference between groups in the levels of inflammatory markers or creatinine values the day after admission. The patients who underwent CABG had patent infarctrelated artery. Their infarct size was smaller compared with the average. Excluding these patients had no effect on outcome. The results of the patients' satisfaction and pain survey are presented in Table IV. Sedation with sevoflurane was more effective in pain management and provided more
780 Lavi et al
American Heart Journal November 2014
Figure 2
Primary end point: infarct size according to area at risk. The area at risk was estimated according to the modified APPROACH score. A, Peak troponin T. B, Area under the curve of troponin T for 24 hours. C, Peak CK. D, Area under the curve of CK for 24 hours.
relaxing effect compared with standard therapy. Patients in both groups were satisfied with the sedation and indicated their preference to have the anesthesia team involved in future cardiac procedures. This perception was significantly stronger among patients who received sedation with sevoflurane.
Discussion The present study demonstrates that sedation with lowdose sevoflurane during pPCI is safe and effective in reducing pain and anxiety compared with standard sedation. Treatment with sevoflurane was associated with improvement in ST-segment elevation resolution, without affecting final infarct size. In the higher-risk patient cohort who presented with anterior MI, administration of sevoflurane was associated with a statistically nonsignificant reduction in infarct size. The outcome of patients with STEMI has improved substantially in the last decade. This improvement is related to rapid administration of reperfusion therapy, use of effective antiplatelet and anticoagulant agents, and
improvement in myocardial remodeling post MI. At the same time, despite evaluation of different pharmacologic agents, there is no myocardial protective agent that is used routinely for patients with STEMI. The rationale to evaluate the effect of sevoflurane as a myocardial protective agent in the setting of STEMI is based on experimental and clinical evidence. Peri-ischemic administration of low sedative concentrations (b1 vol%) of sevoflurane attenuated ischemia-reperfusion injury of the endothelium, as assessed by hyperemic blood flow response and inhibited leukocyte adhesion. 21 The same low concentration inhibits agonist-induced granulocyte-platelet interactions up to 24 hours after administration and thus counteracts the thromboinflammatory processes. 22 Sevoflurane was found to be cardioprotective in patients undergoing cardiac surgery. 10–13 In the current study, we did not find a difference in the degree of myocardial injury between the sevoflurane and the control groups. Patients in both groups received pPCI relatively quickly, along with contemporary medical therapy that included, in most patients, administration of IIbIIIa inhibitors and frequent use of aspiration thrombectomy. Patients in both groups had a relatively
American Heart Journal Volume 168, Number 5
Figure 3
Lavi et al 781
Table III. Laboratory results and ECG findings Sevoflurane (n = 25) LDL HDL hsCRP WBC Creatinine 24 h (μmol/L) No. of leads with ST elevation Total ST elevation (mm) No. of leads with ST depression Total ST depression ST resolution (%) at 60 min (lead with maximum ST elevation) Residual total ST elevation at 60 min No. of patients with ST resolution N50%
Control (n = 22)
P
2.69 (1.89-3.12) 0.98 (0.83-1.25) 9.26 (3.53-14) 10.6 ± 3.1 77 ± 21 5 ± 1.7 11.6 ± 10.7 3.3 ± 2.1
2.29 (1.76-3.03) 1.09 (0.83-1.21) 6.45 (3.21-12.92) 10.4 ± 3.5 78 ± 12 4.6 ± 1.6 8.4 ± 6.2 2.2 ± 1.1
.47 .96 .64 .78 .91 .47 .22 .04
4.7 ± 3.8 80.7 ± 25.8
4±5 56.6 ± 35.7
.58 .01
2.2 ± 2.64
4.18 ± 4.63
.07
19/24 (79%)
12/22 (55%)
.07
Abbreviations: LDL, Low-density lipoprotein; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; WBC, white blood cells.
Assessment of infarct size in patients with anterior MI.
favorable outcome. Therefore, our pilot study may have been underpowered to detect a clinical effect in the overall study population. As a pilot study that tested for the first time administration of sevoflurane to patients with STEMI, we chose a sample size that was similar to previous studies of ischemic conditioning. 6,17 Our study population was broad and included patients with inferior infarcts as well as patients who had normal flow on coronary angiography. In contrast, most previous studies that showed a beneficial effect of ischemic conditioning in the setting of acute MI restricted inclusion to patients with anterior or other large infarcts who had complete occlusion of the coronary artery. 6,17,23,24 Any intervention or medication that is used to prevent ischemic-reperfusion injury is more likely to be effective if begun prior to restoration of flow in the occluded artery. 25 Experimental evidence suggests that this is true for sevoflurane. 26 Therefore, in the current study, patients were randomized and sedation was initiated, immediately on arrival to the catheterization laboratory, prior to diagnostic coronary angiography. In addition to the potential for higher protective effect, patients benefited from effective sedation provided by the
anesthesia team. Our approach also reduced selection bias related to findings on coronary angiography. On the other hand, our approach resulted in inclusion of patients at low risk or with patent coronary arteries. Although we did not find a significant effect of sevoflurane on infarct size in the overall study population, our study suggests a beneficial effect with a larger area at risk and anterior infarcts. This finding in a subgroup should be interpreted with caution because several recent studies did not find a beneficial effect of ischemic postconditioning, and some even suggested a potential harmful effect. 23,24,27,28 However, consistent with our results, it was previously proposed that a beneficial effect of ischemic conditioning is seen only in patients with large infarcts. 29 We allowed elderly patients to be included in the study. Analysis of previous studies suggests that ischemic conditioning is more effective in younger patients. 30 Our sample size is too small for further subgroup analysis according to age and baseline coronary flow. One of the important findings in our study is the safety of sedation with sevoflurane in the catheterization laboratory with favorable impact on patients' satisfaction. The low sevoflurane MAC needed for adequate sedation is promising, as this inhalational drug can be easily stopped at any time when the patient is sedated yet cooperative. Sevoflurane is thought to have some analgesic properties, and indeed, in the sevoflurane group, the use of fentanyl was significantly decreased. With the increasing number of complex procedures being performed in the catheterization laboratory, it is possible that the anesthesia team will become an integral
American Heart Journal November 2014
782 Lavi et al
Table IV. Patient satisfaction
Disclosures
Sevoflurane (n = 25) Pain on arrival Pain during the procedure Relaxed during the procedure Pain at end of procedure Relaxed at end of procedure Nausea Preference for anesthesia team involvement in future cardiac procedures
7 0 10 0 10 0 10
(6-10) (0-3) (10-10) (0-2.3) (8.75-10) (0-0) (10-10)
Control (n = 22) 6.3 (3-8) 3 (1.8-5.3) 8 (7-9.25) 1 (0-2.1) 9.75 (8.75-10) 0 (0-0) 10 (6-10)
P
.07 .006 .0003 .40 .28 .57 .004
Scale of 0 to 10. Median and Q1-Q3.
part of the catheterization lab staff and, thereby, provides more effective sedation to patients with STEMI. 31
Limitations Our study has several important limitations. First, this was a small pilot study. As such, it was underpowered to demonstrate moderate differences between groups. There were nonsignificant differences in baseline characteristics, such as onset of symptoms to device time duration, which may affect the results. There was a higher proportion of anterior MI in the sevoflurane group. We compared the subgroup of patients with anterior MI, but the results from such a small subgroup may be further affected by chance findings. Therefore, our results should be interpreted with caution. With the challenges of performing such a complex study, we thought that this would be a reasonable sample size, and the results are sufficient to help design a future study. We suggest that such a study will focus on patients with anterior MI and documentation of an occluded infarct-related artery. In summary, in this small pilot study, we found that use of low-dose sevoflurane during pPCI is safe and provides effective sedation. Administration of sevoflurane was associated with improved ST-segment elevation resolution but failed to reduce infarct size. Further larger clinical trials are required.
Acknowledgment We would like to thank the nurses and the technicians in the cardiac catheterization laboratory and the nurses and clerks in the coronary care unit. We thank Dr Hesham Youssef, Dr Sunisa Prapaitrakool, and the respiratory therapists and anesthesia assistants at University Hospital, London, Ontario, for their assistance. We thank Andrew McLellan and Dr Anthony Camuglia for assistance with imaging processing, and Jeffrey M. Landreville and Shemer Ratner for assistance with data collection. The BIS monitor was provided in kind by Caster Medical Systems.
No conflicts to disclose.
References 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361(9351): 13-20. 2. Stone GW. Angioplasty strategies in ST-segment-elevation myocardial infarction: part II: intervention after fibrinolytic therapy, integrated treatment recommendations, and future directions. Circulation 2008;118(5):552-66. 3. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357(11):1121-35. 4. Lavi R, Lavi S. Remote ischaemic conditioning before exercise: are we there yet? Heart 2011;97(16):1284-5. 5. Thibault H, Piot C, Staat P, et al. Long-term benefit of postconditioning. Circulation 2008;117(8):1037-44. 6. Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation 2005;112(14):2143-8. 7. Cantor WJ, Fitchett D, Borgundvaag B, et al. Rationale and design of the Trial of Routine ANgioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI). Am Heart J 2008;155(1):19-25. 8. Lavi S, Lavi R. Conditioning of the heart: from pharmacological interventions to local and remote protection: possible implications for clinical practice. Int J Cardiol 2011;146(3):311-8. 9. Zhao J, Wang F, Zhang Y, et al. Sevoflurane preconditioning attenuates myocardial ischemia/reperfusion injury via caveolin-3–dependent cyclooxygenase-2 inhibition. Circulation 2013;128(11 Suppl 1):S121-9. 10. Symons JA, Myles PS. Myocardial protection with volatile anaesthetic agents during coronary artery bypass surgery: a meta-analysis. Br J Anaesth 2006;97(2):127-36. 11. Jakobsen C-J, Berg H, Hindsholm KB, et al. The influence of propofol versus sevoflurane anesthesia on outcome in 10,535 cardiac surgical procedures. J Cardiothorac Vasc Anesth 2007;21(5):664-71. 12. Landoni G, Zangrillo A, Fochi O, et al. Cardiac protection with volatile anesthetics in stenting procedures. J Cardiothorac Vasc Anesth 2008;22(4):543-7. 13. Hemmerling T, Olivier JF, Le N, et al. Myocardial protection by isoflurane vs. sevoflurane in ultra-fast-track anaesthesia for off-pump aortocoronary bypass grafting. Eur J Anaesthesiol 2008;25(3):230-6. 14. Landoni G, Greco T, Biondi-Zoccai G, et al. Anaesthetic drugs and survival: a Bayesian network meta-analysis of randomized trials in cardiac surgery. Br J Anaesth 2013;111(6):886-96. 15. Loukogeorgakis SP, Williams R, Panagiotidou AT, et al. Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a KATP channel dependent mechanism. Circulation 2007;116(12):1386-95. 16. Ortiz-Perez JT, Meyers SN, Lee DC, et al. Angiographic estimates of myocardium at risk during acute myocardial infarction: validation study using cardiac magnetic resonance imaging. Eur Heart J 2007;28(14):1750-8. 17. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359(5): 473-81. 18. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996;93(5):879-88.
American Heart Journal Volume 168, Number 5
19. Niccoli G, Giubilato S, Russo E, et al. Plasma levels of thromboxane A2 on admission are associated with no-reflow after primary percutaneous coronary intervention. Eur Heart J 2008;29(15):1843-50. 20. Fergusson D, Aaron SD, Guyatt G, et al. Post-randomisation exclusions: the intention to treat principle and excluding patients from analysis. BMJ 2002;325(7365):652-4. 21. Lucchinetti E, Ambrosio S, Aguirre J, et al. Sevoflurane inhalation at sedative concentrations provides endothelial protection against ischemiareperfusion injury in humans. Anesthesiology 2007;106(2):262-8. 22. Wacker J, Lucchinetti E, Jamnicki M, et al. Delayed inhibition of agonist-induced granulocyte-platelet aggregation after low-dose sevoflurane inhalation in humans; 2008. p. 1749-58. 23. Tarantini G, Favaretto E, Marra MP, et al. Postconditioning during coronary angioplasty in acute myocardial infarction: the POST-AMI trial. Int J Cardiol 2012;162(1):33-8. 24. Freixa X, Bellera N, Ortiz-Perez JT, et al. Ischaemic postconditioning revisited: lack of effects on infarct size following primary percutaneous coronary intervention. Eur Heart J 2012;33(1):103-12. 25. Kloner RA, Rezkalla SH. Preconditioning, postconditioning and their application to clinical cardiology. Cardiovasc Res 2006;70(2):297-307. 26. Zitta K, Meybohm P, Bein B, et al. Cytoprotective effects of the volatile anesthetic sevoflurane are highly dependent on timing and duration
Lavi et al 783
27.
28.
29.
30.
31.
of sevoflurane conditioning: findings from a human, in-vitro hypoxia model. Eur J Pharmacol 2010;645(1–3):39-46. Sorensson P, Saleh N, Bouvier F, et al. Effect of postconditioning on infarct size in patients with ST elevation myocardial infarction. Heart 2010;96(21):1710-5. Lavi S, D'Alfonso S, Diamantouros P, et al. Remote ischemic postconditioning during percutaneous coronary interventions: remote ischemic postconditioning–percutaneous coronary intervention randomized trial. Circ Cardiovasc Intervent 2014;7(2): 225-32. Sorensson P, Ryden L, Saleh N, et al. Long-term impact of postconditioning on infarct size and left ventricular ejection fraction in patients with ST-elevation myocardial infarction. BMC Cardiovasc Disord 2013;13:22. http://www.biomedcentral.com/1471-2261/ 13/22. Zhou C, Yao Y, Zheng Z, et al. Stenting technique, gender, and age are associated with cardioprotection by ischaemic postconditioning in primary coronary intervention: a systematic review of 10 randomized trials. Eur Heart J 2012;33(24):3070-7. Lavi S, Jolly SS, Bainbridge D, et al. Sedation, analgesia, and anaesthesia variability in laboratory-based cardiac procedures: an international survey. Can J Cardiol 2014;30(6):627-33.
