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CARDIOVASCULAR ANESTHESIA

Strict Thermoregulation Attenuates Myocardial Injury During Coronary Artery Bypass Graft Surgery as Reflected by Reduced Levels of Cardiac-Specific Troponin I

Nahum Nesher, MD^*, Eli Zisman, MD, Tamir Wolf, PhD^*, Ram Sharony, MD^*, Gil Bolotin, MD^*, Miriam David, DSc, Gideon Uretzky, MD^*, and Reuven Pizov, MD

*Department of Cardiothoracic Surgery, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and Department of Anesthesiology and General Hospital Laboratories, Lady Davis Carmel Medical Center, Israel Technion, Haifa, Israel

Address correspondence and reprint requests to Nahum Nesher, MD, The Department of Cardiothoracic Surgery, Tel Aviv Sourasky Medical Center, 6 Weitzman St., Tel Aviv 64269, Israel. Address e-mail to nnesher{at}netvision.net.il

	Abstract

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We assessed the cardioprotective effects of perioperative maintenance of normothermia by determining the perioperative profile of troponin I, a highly cardiac-specific protein important in risk stratification of patients with acute ischemic events. Candidates for their primary coronary artery bypass grafting (CABG) were randomized into a new thermoregulation system group, Allon^TM thermoregulation (AT; n = 30), and a routine thermal care (RTC; n = 30) group. Anesthetic and operative techniques were similar in both groups. Intraoperative warming was applied before and after cardiopulmonary bypass (CPB) and up to 4 h after surgery. Perioperative temperature and hemodynamic data were recorded. Blood samples for creatine kinase (CK) and its isoform, MB (CK-MB), and for cardiac-specific troponin I (cTnI) were obtained at predetermined intervals throughout the entire operation. Core and skin temperatures were higher in the AT group at all time points. The systemic vascular resistance was lower and the cardiac index higher in the AT group at all intra- and postoperative time points. Increases in CK, CK-MB, and cTnI levels indicated intraoperative ischemic insult in all patients. The respective CK levels for the AT and RTC groups were 53.3 ± 22.7 IU/L and 47.9 ± 17.86 IU/L at the time of anesthesia and 64.7 ± 45.6 IU/L and 47.8 ± 19.4 IU/L 30 min after the onset of surgery, demonstrating thereafter a steep increase before the discontinuation of CPB. CK-MB mass concentrations in both groups behaved almost identically. Pre-CPB cTnI levels at anesthesia induction were 0.3 ± 0 ng/mL in both groups, followed by a distinctive profile observed after separation from CPB: 28.1 ± 11.4 ng/mL, 26.05 ± 9.20 ng/mL, and 22.3 ± 8.9 ng/mL at discontinuation from CPB, chest closure, and 2 h after surgery, respectively, in the RTC group, versus 0.6 ± 4.6 ng/mL, 6.6 ± 5.5 ng/mL, and 7.9 ± 4.76 ng/mL at these three time points, respectively, in the AT group (P < 0.01 between groups at the specified time points). Contrary to conventional thinking about the benefits of hypothermia, maintenance of normothermia throughout the non-CPB phases during CABG was demonstrated to be important in attenuating myocardial ischemic injury. Insofar as troponin I was more sensitive than other tested markers, it may provide important data on possible protection from myocardial insult and on other cardioprotective measures.

IMPLICATIONS: Maintenance of normothermia throughout the nonbypass phases of coronary artery bypass graft surgery is important in the attenuation of myocardial ischemic injury as assessed by intraoperative cardiac-specific troponin I measurements. It may also provide a method of assessing the efficacy of current cardioprotective strategies, as well as of future pharmacological and mechanical approaches.

	Introduction

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Patients with coronary artery disease who undergo surgery are more at risk for perioperative cardiovascular morbidity and mortality than patients without coronary artery disease, because their reserves to withstand the stress of the induction of anesthesia and surgery are reduced (1–5). For patients undergoing coronary artery bypass grafting surgery (CABG) with cardiopulmonary bypass (CPB), the latter, in and of itself, has deleterious effects as well, such as the systemic inflammatory response syndrome that predisposes to ischemic injury in both cardiac and cerebral tissue (6–8). Importantly, current cardioplegic techniques are limited by their inability to sustain coronary perfusion and oxygen supply to the myocardium such as that achieved via the native coronary circulation, especially in high-risk patients (9). In addition, hypothermia is further intensified during open-heart surgery, especially during the time when CPB is being implemented (6).

Hypothermia has also been shown to initiate profound increases in serum norepinephrine concentrations, thus increasing systemic vascular resistance (SVR) (i.e., cardiac afterload) (10). This eventually puts a greater burden on an already ischemic myocardium to provide perfusion to body tissues, thus further contributing to the undesirable effects of CPB.

Circulating levels of cardiac protein markers have been measured for assessing the presence and extent of myocardial injury after CABG surgery (11). Of the various markers used—e.g., creatine kinase (CK); MB, the isoform of CK (CK-MB); myosin heavy-chain kinase; myoglobin; cardiac troponin T; and cardiac-specific troponin I (cTnI)—cTnI proved to be the most specific, even though it is thought not to be suitable for intraoperative assessment because of its slow release (12).

Most studies assessed only postoperative ischemic injury with the cTnI assay. Our investigation was designed to compare perioperative hemodynamics and cTnI levels as indices of ischemic insult in two patient populations undergoing CABG surgery. One group was subjected to traditional warming technologies, while a novel thermowrapping thermoregulatory system, the Allon^TM system, was used in the second group. Thereafter, assessment of the cardioprotective effect of maintaining perioperative normothermia during CABG was performed by using these hemodynamic factors and the aforementioned specific cardiac proteins.

	Methods

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This study was performed after approval of the Institutional Ethical Review Board and after obtaining the patients’ informed consent. Sixty patients scheduled for elective CABG surgery were preoperatively randomized into two groups according to the type of strategy to be undertaken for the maintenance of normothermia: either Allon^TM thermoregulation (AT; n = 30) or routine thermal care (RTC; n = 30).

Inclusion criteria were age 40–80 yr; a left ventricular ejection fraction >25% as assessed by echocardiography, multigated angiogram scan, or angiographic contrast left ventriculography; and preoperative core body (rectal) temperatures of 36°C–37.5°C. Exclusion criteria were known concomitant life-threatening and/or debilitating disease of noncardiac origin; severe peripheral vascular disease, as defined by a history of intermittent claudication within a walking distance of <100 m; uncontrolled insulin-dependent diabetes mellitus (preoperative fasting glucose levels >250 mg%); a history of fever or infection within the week before surgery; and clinically significant laboratory abnormalities (i.e., creatinine 2.0 mg%, total bilirubin 1.5 mg%, hemoglobin 10.0 g%, platelet count 100,000/mL, or a white blood cell count of either <3,000 or >14,000/mL).

The Allon^TM technology used in the AT study group consists of a microprocessor-controlled heating/cooling unit, body temperature sensors (core [i.e., rectal]) and skin thermistors, and a specially designed garment that wraps around the patient (Fig. 1). Continuous monitoring of the patient’s rectal and skin temperature is performed via the thermistors. All skin temperature measurements are recorded with two skin sensors placed on the patient’s upper thorax, taking care to avoid any contact between them and the garment. A feedback-controlled microprocessor unit receives the data from the rectal thermistor, which serves as the afferent arm. Water is then circulated by a pump and is controlled and maintained at a set point ranging from 30°C to 39.5°C in a closed loop between the garment and the unit. Water temperature is continuously adjusting through the feedback loop to achieve a preset temperature determined by the anesthesiologist/surgeon.

View larger version (34K): [in this window] [in a new window]   Figure 1. Perioperative levels of cardiac enzymes. A, Creatine kinase (CK) MB isoform (ng/mL). B, CK-MB mass fraction (IU). C, Specific cardiac troponin I (ng/mL). All three indices demonstrated myocardial damage, but only the cTnI levels could delineate the difference between the study groups. Allon = AllonTM thermoregulation group; Routine = routine thermal care group; CPB = cardiopulmonary bypass.

Before the induction of anesthesia and until the time of initiation of CPB, the Allon^TM system is set to a rectal temperature of 37°C (the pre-CPB period). This regulatory feature is discontinued during the CPB period and reintroduced at the time of rewarming via the CPB system (the post-CPB period; target temperature, 37°C). After surgery, rewarming is performed for up to 4 h in the cardiac intensive care unit (ICU; target temperature, 37°C).

All patients in the RTC group were warmed by using a combination of water blankets (Thermostat T1000; JMW Medical Systems Ltd., Midlothian, UK) and IV fluid warmers (Model BW5; Fenwal, Deerfield, IL) from the induction of anesthesia throughout the entire perioperative period. After the termination of surgery, these patients were covered with convective air warmers (Bair Hugger cardiac blanket; Augustine Medical Inc., Eden Prairie, MN) and warm blankets until the end of the postoperative phase of the analysis.

Anesthesia was induced with 10–15 µg/kg of fen-tanyl, 0.07 mg/kg of midazolam, 1.5 mg/kg of lidocaine, and up to 1 mg/kg of propofol. Muscle paralysis was achieved with 0.1 mg/kg of pancuronium bromide. Anesthesia was maintained with isoflurane in oxygen and the addition of fentanyl as required. During CPB, an additional dose of midazolam and pancuronium at half the induction dose was added, and isoflurane was administered directly through the blood membrane oxygenator as required. The alpha-stat acid-base management approach was used.

CPB was established with a single two-stage right atrial cannula and was conducted with a Univox membrane oxygenator (Jostra Corp., Irvine, CA) and a Sarns 9000 CPB machine (Terumo Cardiovascular, Ann Arbor, MI). The extracorporeal circuit was primed with 1500 mL of Plasmalyte and 10 mEq of sodium bicarbonate. Active cooling was not done. Cardioplegia was established through antegrade priming followed by intermittent, tepid-blood, retrograde intervals. Rectal temperature was allowed to decline during bypass to 33°C–34°C. Nonpulsatile perfusion was used throughout the procedure, with a flow maintained between 2.0 and 2.5 L · m^-2 · min^-1. Phenylephrine was used as needed to maintain systemic perfusion pressures at 50–60 mm Hg. During bypass, hematocrit levels were maintained between 20% and 25%. Intraoperative autotransfusion and postoperative reinfusion of shed blood were not used. Distal anastomoses were constructed during a single period of aortic cross-clamping, and proximal anastomoses were performed without global ischemia. Rewarming of patients in both study groups commenced during the construction of the last distal anastomoses. Warming was initiated before the induction of anesthesia, halted at the commencement of CPB, and then continued on separation from CPB until the end of surgery and up to the next 4 h in the cardiac ICU.

Temperature, both rectal and skin, was continuously assessed throughout the perioperative period. Electrocardiography was routinely performed on the patient’s arrival to the ICU and 6 and 12 h later for the inspection of ischemic changes. Hemodynamic variables, including blood pressure, heart rate, pulmonary artery and pulmonary artery wedge pressure, cardiac index (CI), and SVR, were assessed at predetermined time points.

Assessment of myocardial ischemic injury was performed on all patients by determining serum levels of total CK, CK-MB, and cTnI. Blood samples were collected at the induction of anesthesia, 30 min after the commencement of surgery, at separation from CPB, after chest closure, and 2 h after the termination of surgery. Blood was kept on ice until serum separation. CK and CK-MB mass were determined within 2–6 h from the time of sample collection.

Serum CK levels (physiological range, 24–195 IU/L) were measured spectrophotometrically (Cobas Integra; Roche). Serum cTnI mass (physiological range, <0.5 ng/mL) and CK-MB mass (physiological range, <30 IU/L) were determined by an immunoassay by using the Abbott Axsym system (Abbott Park, IL).

On completion of the operation, the patients were transferred to the ICU, where they were allowed to wake up when they were hemodynamically stable and blood loss from their chest drains was minimal and stable. If subsequent aggressive behavior was encountered, those patients were tranquilized by short-acting sedative drugs, i.e., midazolam, and allowed to subsequently reawaken. A single extubation protocol was used for all patients. Tracheal extubation occurred when patients had been adequately rewarmed and oxygenated (arterial oxygen tension >80 mm Hg on an inspired oxygen fraction of 50%). Reexploration for the cause of bleeding was performed if blood loss continued at a rate of >200 mL/h for several hours or if it was rapid and uncontrolled, thereby compromising hemodynamic status.

Temperature, CI, SVR, and cardiac protein level differences between groups were assessed with ANOVA. Chi-square analysis and Fisher’s exact test were used for categorical data. The statistical difference for troponin I between the two groups was assessed with the nonparametric Wilcoxon’s ranked sum test. The test consists of combining the two groups into one, ordering the results, and assigning ranks to the ordered values, i.e., first, second, third, etc. The mean rank was used when there was a tie. The sum of the ranks of each group is then calculated. If the two groups, i.e., AT and RTC, have the same distribution, then the sums of the ranks should be similar. A P value was then generated for the null hypothesis that the troponin I levels in the two groups are the same.

All values are given as mean ± SD. For all statistical comparisons, a P value <0.05 was considered significant.

	Results

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The patients’ demographic and preoperative clinical data are shown in Table 1. There were no significant differences between the groups.

The relevant temperature and hemodynamic data, corresponding to the specific time points of CK, CK-MB, and cTnI measurements, are shown in Table 2: the patients’ core and skin temperatures were higher in the AT group at all time points. Patients were allowed to cool passively during CPB to 32°C–34°C. Then, during suturing of the last anastomosis, they were warmed by the CPB machine and by the different modalities of this study until normothermia was reached, at which point they were weaned from CPB. Notably, the AT patients were warmer by approximately 1°C at the lowest point of measurement and were warmed more quickly than the RTC patients. The SVR was lower and the CI higher in the AT group at all intra- and postoperative time points.

Two patients from the AT group and one from the RTC group were excluded from the evaluation of cardiac proteins, although they were not removed from the study. One patient from each group underwent surgery during an acute myocardial infarction (MI) that was eventually followed by an unrelated increase of cardiac enzymes during the study period. The third patient had a perioperative MI because of acute occlusion of the anastomosis to the posterior descending artery that was visualized on urgent angiography. That patient also had an unrelated increase of cardiac enzymes. The exclusion of data occurred under the supervision of an international monitoring company (C.A.T.O., Tel Aviv, Israel) according to the good clinical practice guidelines (13). None of the remaining patients showed other observable symptoms indicating myocardial damage as detected by echocardiography, ST changes in a new electrocardiogram, or unexplained signs of hemodynamic instability.

The profiles of serum levels of CK, CK-MB mass, and cTnI are shown in Figure 1. The serum CK levels were comparable in the AT and RTC groups at the time of anesthesia induction (53.3 ± 22.7 IU/L and 47.9 ± 17.86 IU/L, respectively) and at 30 min after the onset of surgery (64.7 ± 45.6 IU/L and 47.8 ± 19.4 IU/L, respectively), demonstrating thereafter a steep increase before the discontinuation of CPB. Similarly, CK-MB mass concentrations in both groups behaved almost identically, with increased values observed before weaning from CPB and thereafter.

Prebypass cTnI levels were similar in the AT and RTC groups (0.3 ± 0 ng/mL in both groups at anesthesia induction, followed by levels of 0.3 ± 0.69 ng/mL and 1.31 ± 0.14 ng/mL, respectively, at the onset of surgery; P = 0.68). A distinctive profile was then observed for cTnI levels in each group, with the levels higher in the RTC group at certain time points. Specifically, cTnI levels in the RTC group were 28.1 ± 11.4 ng/mL, 26.05 ± 9.20 ng/mL, and 22.3 ± 8.9 ng/mL at discontinuation from CPB, chest closure, and 2 h after surgery, respectively, versus 0.6 ± 4.6 ng/mL, 6.6 ± 5.5 ng/mL, and 7.9 ± 4.76 ng/mL at these three time points, respectively, in the AT group (P < 0.01 between groups at the specified time points). The lowest troponin level observed in the RTC group at the off-CPB point was 14.3 ng/mL (the normal value is 0.3 ng/mL), and the maximal value at the same point was 98.8 ng/mL. For the AT group, the minimal value was 1.2 ng/mL and the maximal value was 24.8 ng/mL. Packed red blood cell administration was significantly decreased in the AT group compared with the RTC group both during and up to 8 h after surgery: 1.7 versus 3.5 units (P < 0.01).

	Discussion

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In this study, we demonstrated that the maintenance of normothermia throughout cardiac surgery could attenuate ischemic injury to the myocardium, as demonstrated by improved hemodynamic variables and reduced levels of serum cTnI, a sensitive marker of intraoperative myocardial ischemic insult. cTnI and CK-MB mass are specific markers of myocardial injury and have been used to detect myocardial damage in the postoperative period after CABG surgery (11). Troponin I is part of the troponin-tropomyosin complex in striated muscle. Its isoform, cTnI, is specific to cardiac tissue and is, therefore, considered to be a more useful marker than conventional CK and CK-MB that are also found in regenerating skeletal muscles (12,14).

The current approaches for attenuation of global myocardial ischemia during cardiac surgery include a variety of cardioprotective techniques, such as mild-to-moderate hypothermia and various cardioplegic methodologies. Notably, postoperative augmentation of cTnI levels has been reported in all patients undergoing CABG surgery (11). This increase is attributed to myocardial ischemia during the initial phases of the operation and throughout the CPB period in which the myocardium has not yet been vascularized. Additional mechanisms that can contribute to the further augmentation of myocardial damage in CABG include manipulation of the myocardium, dissection of the myocardium for intramyocardial artery exposure, reperfusion injury, and placement of sutures for cannulation (11). The degree to which cTnI increases during cardiac surgery has been ascribed to the type and extent of surgery, the method of myocardial protection, the preoperative cardiac status of the patient, the anesthetic protocol applied (15), and the extent of reperfusion injury.

We observed significant differences between the two groups of patients who underwent the same CABG surgery, had the same anesthetic protocol, were similar in their preoperative cardiac status, and had similar surgical time, cross-clamping time, and amount of anastomoses, but who apparently differed only by the method used for intraoperative thermoregulation. We contend that the discrepancy of the cTnI profiles and cardiac indices observed in the two groups stems from the difference in the patients’ body temperature during the various phases of the operative period. Although we must consider that troponin clearance may be delayed during hypothermia because of a slower metabolic rate, this same reduced metabolism may attenuate its production. We therefore had expected the troponin levels to be lower in the RTC group. Another important consideration is that the presence of renal dysfunction may reduce troponin clearance, but, unfortunately, creatinine clearance was not measured in our study. Our results failed to reveal any difference between the groups in patients with pre- or postoperative renal failure as expressed by their creatinine levels. Patients with creatinine levels >2 mg% had been excluded from the study.

It is currently believed that mild-to-moderate hypothermia plays a protective role in preventing myocardial damage by reducing oxygen consumption (16). Our results demonstrate that maintaining normothermia at specific critical intraoperative levels results in less myocardial damage.

Although most previously published studies have reported increases in cTnI levels during the postoperative period, we found only two reports on the continuing changes in the serum cTnI profile that occurred throughout the operation (17,18). This study confirms these findings but further contributes to our knowledge by documenting the effect of normothermia versus hypothermia on the attenuation of intraoperative myocardial ischemic damage as expressed by this cardiac-specific protein.

The dramatic augmentation in cTnI levels reflecting myocardial injury after discontinuation of CPB is intriguing. Patients undergoing a CABG procedure are more at risk for myocardial damage than any other group that undergoes any other major surgery: this is due to a decreased tolerance of the hypoperfused heart to stress and an increased afterload. In addition, CPB induces a variety of deleterious effects related to systemic and local myocardial neutrophil activation, interleukin production, and free-radical generation (7,19).

Both of our study groups did experience myocardial injury, as reflected by increase of the CK level, but although CK levels were essentially the same for both groups, cTnI seemed to be more sensitive for demonstrating a difference. The difference in the cTnI values that had been observed between the two groups after disconnection from CPB most probably reflects damage that had already been sustained by the myocardium before CPB establishment (i.e., occurring while the chest was opened, while the heart was prepared for bypass engagement, and while the conduits were harvested).

In terms of hemodynamic effects, the AT patients maintained a better status throughout the various phases of the perioperative period. There were no intergroup differences in the amounts of either vasodilatory or vasoactive drugs administered. Therefore, the higher CI and the lower SVR levels in the AT group can be attributed to temperature regulation; i.e., skin warming minimized the adrenergic response and reduced the afterload, whereupon an increased cardiac output was maintained.

Numerous studies have shown that restoration of the blood supply to ischemic tissue is not without complications. Although some degree of reperfusion injury, as reflected by the release of cardiac proteins, was observed in both of our groups, the revascularized hearts of patients in the normothermic group were associated with a "friendlier" environment, i.e., reduced SVR. As a result, myocardial injury at the phase of return to autonomic cardiac function after discontinuation of CPB was less pronounced in normothermic patients, as assessed by cTnI. Therefore, the difference between the groups in the post-CPB and recovery stages could most probably be attributed to the differences in temperatures that were present during the first hypothermic phase of the operation.

Intraoperative assessment of myocardial damage is important in any type of surgery, but it is especially vital during procedures involving the heart and CPB. Postoperative evaluation is not sufficient, because it may underestimate the amount of tissue damage (18).

This study once again confirmed the lack of specificity of intraoperatively measured CK and CK-MB compared with that of cTnI. Although all three measures did indicate that there was some myocardial insult, cTnI was the only marker that enabled delineation between the two study groups. This finding is supported by the fact that CK and CK-MB are expressed in injured striated muscle as well and are thus not specific to the myocardium (14,20,21).

Serum cTnI cutoff values have been suggested as a marker of postoperative MI. Previously, cTnI levels of more than 11.6 ng/mL at 24 hours after unclamping of the aorta were determined as being highly sensitive and specific in the diagnosis of MI (22). More recently, Carrier et al. (23) proposed that serum cTnI levels >39 ng/mL at 24 hours after the operation should be accepted as an indicator of postoperative MI. In this investigation, none of the patients in either study group demonstrated a perioperative MI as assessed by the conventionally accepted criteria, i.e., newly appearing Q waves in the electrocardiogram and CK-MB mass levels >50 IU/L or unexplained hemodynamic instability as evidenced by newly recognized reduction of wall motion demonstrated by echocardiography. However, this does not necessarily mean that no injury had been sustained by the myocardium, especially in light of the observed increases in serum concentrations of cardiac proteins. Specifically, cTnI levels were increased beyond the aforementioned cutoff values for MI (a cTnI level of 0.495 ng/L calculated by the Youden index) at more than one intraoperative time point, which, as had been suggested by Eigel et al. (18), may play a role in late prognosis.

On the basis of these findings, we propose intraoperative cTnI measurements as a method of ascertaining a more precise assessment of perioperative myocardial injury, in addition to other conventional methods (transesophageal echocardiography, pulmonary artery catheter, and so on). They may also provide a method of assessing the efficacy of current cardioprotective strategies as well as of future pharmacological and mechanical approaches. Our findings clearly indicated the beneficial myocardial effects of maintaining normothermia throughout the nonbypass phases of CABG surgery.

	Acknowledgments

 
Supported by a grant from Medical ThermoRegulation Equipment Advanced Technologies, Or-Akiva, Israel.

The authors thank Esther Eshkol, MA (institutional medical copyeditor, Tel Aviv Sourasky Medical Center), for editorial assistance.

	References

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				N. Nesher, G. Uretzky, S. Insler, P. Nataf, I. Frolkis, E. Pineau, E. Cantoni, G. Bolotin, M. Vardi, D. Pevni, et al. Thermo-wrap technology preserves normothermia better than routine thermal care in patients undergoing off-pump coronary artery bypass and is associated with lower immune response and lesser myocardial damage J. Thorac. Cardiovasc. Surg., June 1, 2005; 129(6): 1371 - 1378. [Abstract] [Full Text] [PDF]

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