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Cardioprotective Effects of Acute Normovolemic Hemodilution in Patients Undergoing Coronary Artery Bypass Surgery* Marc Licker, MD; Christoph Ellenberger, MD; Jorge Sierra, MD; Afksendiyos Kalangos, MD; John Diaper, RN; and Denis Morel, MD Study objectives: We hypothesized that lowering blood viscosity with acute normovolemic hemodilution (ANH) would confer additional cardioprotection in patients undergoing coronary artery bypass surgery (CABG) with aortic cross-clamping. Design: In a prospective, randomized controlled trial, we studied the efficacy of ANH in anesthetized patients prior to cardiopulmonary bypass for the prevention of myocardial injuries. Setting: Cardiac surgical center in a university hospital. Patients and methods: Patients scheduled to undergo elective CABG entered the study protocol and were randomly allocated to one of two groups: ANH (n ⴝ 43 patients) or standard care management (n ⴝ 41 patients). In the ANH group, the whole-blood/colloid exchange was aimed to achieve a hematocrit value of 28%. All patients were managed with standard myocardial preservation techniques including cold-blood cardioplegia and anesthetic preconditioning. The outcome measures included the release of myocardial enzymes (plasma troponin I and creatinine phosphokinase), perioperative hemodynamic changes, need for pharmacologic cardiovascular support, and cardiac complications. Results: In the hemodilution group, the postoperative release of troponin I (mean peak plasma concentration, 1.4 ng/mL; 95% confidence interval, 1.0 to 1.8) and myocardial fraction of creatine kinase (mean, 29 U/L; 95% confidence interval, 23 to 35) were significantly lower than in the control group (mean, 3.8 ng/mL; 95% confidence interval, 3.2 to 4.5; and 71 U/L; 95% confidence interval, 53 to 89). Requirement for inotropic support was significantly lower in the protocol patients (7 of 41 patients vs 15 of 39 patients), and fewer patients presented with either atrial fibrillation, atrioventricular conduction blockade, or combined disorders (12 of 41 patients vs 26 of 39 patients, p < 0.05). Conclusions: In addition to conventional myocardial preservation techniques, preoperative ANH achieved further cardiac protection in patients undergoing on-pump myocardial revascularization. (CHEST 2005; 128:838 – 847) Key words: cardiac surgery; cardiopulmonary bypass; coronary artery disease; hemodilution; troponin; myocardial ischemia Abbreviations: ANH ⫽ acute normovolemic hemodilution; CABG ⫽ coronary artery bypass surgery; CPB ⫽ cardiopulmonary bypass n the Western world, coronary artery bypass I surgery (CABG) is one of the most frequently performed major operations and is highly effective in improving life expectancy and quality of life in patients with coronary artery disease.1 Although the number of surgical procedures will continue to decline along with the advances in interventional cardiology, the proportion of higher-risk patients requiring complex surgical procedures will likely continue to increase in the near future.2 Moreover, in spite of improvements in surgical, anesthetic, and perfusion techniques, a wide spectrum of perioper- *From the Department of Anesthesiology, Pharmacology and Surgical Intensive Care (Drs. Licker, Ellenberger, and Morel, and Mr. Diaper) and the Clinic of Cardiovascular Surgery (Drs. Dierra and Kalangos), University Hospital of Geneva, Geneva, Switzerland. The study was supported by institutional department funds. Manuscript received October 25, 2004; revision accepted February 14, 2005. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Marc Licker, MD, Department of Anesthesiology, Pharmacology, and Surgical Intensive Care, Hopital Universitaire, rue Micheli-Ducrest, CH-1211 Genève 14, Switzerland; e-mail: [email protected] 838 Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/22028/ on 05/03/2017 Clinical Investigations ative ischemic myocardial injuries still result in significant cardiac morbidity complications including contractile dysfunction, myocardial infarction, and low output syndrome requiring prolonged intensive care.3,4 Over the last 2 decades, the potential benefits of avoiding homologous blood transfusion and optimizing oxygen delivery in vital organs have led to a renewed interest for acute normovolemic hemodilution (ANH) in major surgery.5 With this technique, the adequacy of tissue oxygenation and organ function is maintained by compensatory increases in cardiac output, improved blood flow distribution, and higher oxygen extraction ratios.5–7 In the myocardium, hemodilution-induced lowering of blood viscosity is thought to facilitate blood flow through stenotic and collateral vessels, thereby counteracting the reduced blood oxygen-carrying capacity.8 To date, although ischemic cardiac dysfunction has not been detected during moderate normovolemic hemodilution (reduction of hemoglobin concentrations to 90 g/L or hematocrit levels of 28%) even in anesthetized patients with coronary artery disease,9,10 clinical outcome benefits (or adverse events) have not been thoroughly investigated in high-risk patients for myocardial ischemia. In this study, we hypothesized that ANH afforded cardioprotective effects in patients undergoing CABG. Indeed, improved rheologic blood flow conditions might restore an optimal balance between flow and metabolic demand within the myocardium before the obligatory period of ischemia associated with aortic cross-clamping. Therefore, we designed a randomized controlled trial in patients undergoing elective on-pump coronary revascularization procedures and evaluated the protective potential of moderate hemodilution vs standard management. Myocardial injuries were assessed postoperatively by determination of the release of myocardial enzymes (troponin I and creatine kinase), ECG changes, and the need for pharmacologic interventions. Materials and Methods Selection of Patients and Sample Size After approval by the local Ethics Committee, written informed consent was obtained from all patients scheduled for elective CABG and thought to meet the eligibility criteria. Inclusion criteria were as follows: a screening hemoglobin concentration ⬎ 120 g/L in men or 110 g/L in women; stable angina (classes I and II of the Canadian Cardiology Society); left ventricular ejection fraction ⬎ 30%; and absence of significant coexistent diseases, namely, valvular disease, recent myocardial infarct (⬍ 6 weeks), significant carotid stenosis (⬎ 70%) or recent stroke (⬍ 3 weeks), renal insufficiency (estimated creatinine clearance ⬍ 20 mL/min), chronic respiratory disease (arterial www.chestjournal.org oxygen pressure ⬎ 7 kPa on room air), liver insufficiency (aspartate transaminase or alanine transaminase two or more times the upper range), and uncontrolled hypertension or diabetes mellitus. Samples sizes were calculated for a two-sided significance level of ␣ ⫽ 0.05 and a power of 1⫺ ⫽ 0.8 to detect a difference of 0.5 g/L in troponin I concentrations between the two groups. In a preliminary assessment including cardiac surgical patients, the SD of postoperative troponin I measurements was 0.8; thus, the number of subjects required was 38 per group. Randomization and Masking Eligible patients were randomized to one of the two groups: the ANH group and the standard care group. The allocations were generated from random-number tables by an independent observer and concealed in sealed envelopes. Although intraoperative masking was not possible in the ICU, the attending physicians and nurses were blinded to the treatment group. Trial Protocol Anesthesia and Surgical Procedure: On the morning of surgery, the patients were premedicated (morphine, 0.1 mg/kg; midazolam, 7.5 mg) and received their usual cardiac drug regimen, except aspirin, diuretics, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers, which were withdrawn at least 24 h before surgery. In the operating theater, cannulae were inserted in a peripheral vein, a radial artery, and the right jugular vein. Standard monitoring included pulse oximetry, leads II and V5 of the ECG for heart rate and automated ST-segment trend analysis, continuous measurements of mean arterial and central venous pressures, nasopharyngeal temperature, end-tidal capnography, bispectral analysis of the EEG (BIS A-2000 XP; Aspect Medical Systems; De Meern, the Netherlands), as well as transesophageal echocardiography (Philips Sonos 5500; Philips Medical Systems; Andover, MA). A balanced anesthetic technique included sufentanyl (bolus of 0.5 to 0.9 g/kg followed by 0.4 to 0.8 g/kg/h), midazolam (bolus of 0.05 to 0.1 mg/kg followed by 0.1 mg/kg/h), pancuronium (0.1 mg/kg) and inhaled isoflurane (0.5 to 1% in the prebypass period), which was administered to enhance cardiac protection before aortic clamping (anesthetic preconditioning). In the two groups, a similar depth of anesthesia was obtained by targeting bispectral EEG values between 40 and 60 arbitrary units. ANH: In the ANH group, after anesthesia induction, blood was withdrawn (60 to 80 mL/min) from a central vein by gravity into citrate-phosphate-dextrose collection bags that were placed on a rocking platform of a precision scale. In parallel, poly(0 –2hydroxy-ethyl)amidon (hydroxyethyl starch; HAES-Steril; KabiFresenius; Stans, Switzerland) [mean molecular weight, 200,000; 50% substitution degree; C2/C6 ratio ⫽ 5] was infused through a 16-gauge peripheral catheter on the opposite arm, to a ratio of 1.15:1 to the donated blood.11 The blood volume to be removed was calculated according to a standard formula to reach a hematocrit of 28%.12 The whole-blood/colloid exchange procedure lasted 20 min (range, 15 to 25 min), and it could be interrupted if there were signs of myocardial ischemia and/or unresponsive hypotension. The autologous blood was labeled and reinfused intraoperatively when the transfusion criteria were met. Perioperative Standardized Interventions: In the two groups, additional blood saving methods were used: aprotinin (2 million kallikrein inhibitory units before surgical incision, 2 million units in the bypass circuit with a continuous infusion of 200,000 UI/h) and a cell saver device to retrieve blood shed from the surgical field and from the bypass circuit at the end of surgery. Using CHEST / 128 / 2 / AUGUST, 2005 Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/22028/ on 05/03/2017 839 transesophageal echocardiography, systematic evaluation of cardiac function, chamber size, and valves were repeatedly performed before and after cardiopulmonary bypass (CPB) according to the guidelines of the American Society of Echocardiography and the Society of Cardiovascular Anesthesiologists.13 Strategies for CPB and myocardial preservation were uniform among the three participating surgeons. After full heparinization (300 IU/kg), CPB including a membrane oxygenator and a circuit primed with a 2-L normal saline solution was instituted using nonpulsatile flow (2.2 to 2.5 L/min/m2) and mild hypothermia (32° to 34°C). An ␣-stat control for acid-base management was applied, and mean arterial pressure was targeted between 50 and 70 mm Hg with pharmacologic manipulation as necessary. Myocardial protection was achieved with anterograde hyperkalemic blood cardioplegia (4°C, 20 mEq potassium) repeated every 30 min and single aortic clamping for all distal anastomosis. Before aortic unclamping, warm-blood cardioplegia was administered and IV nitroglycerine was started (2 mg/h). Hemofiltration was not performed during CPB. After achieving a rectal temperature ⱖ 35.5°C, weaning from CPB was guided by echocardiographic assessment and standard hemodynamic measurements. The pump flow was gradually reduced while the heart was progressively filled in order to optimize the preload-recruitable stroke volume and to reach a mean arterial pressure ⱖ 65 mm Hg (Table 1). Optimal cardiac filling was judged by achieving a maximal left ventricular diameter in the short-axis view of 2.5 to 2.8 cm/m2. The heart was electrically paced if it failed to maintain a heart rate ⱖ 70 beats/min because of atrioventricular conduction blockade or bradyarrhythmia. Phenylephrine (50 to 100 g, repeated boli) was administered to maintain mean arterial pressure ⱖ 65 mm Hg after optimizing cardiac preload and contractility parameters. Inotropes were not routinely administered during weaning from CPB. Dobutamine was initiated (starting at 3 g/kg/min) in the presence of mean arterial pressure ⬍ 65 mm Hg and persistent, new, or worsening cardiac systolic dysfunction (left ventricular fractional area ⬍ 30%); norepinephrine infusion was added to this regimen if mean arterial pressure remained ⬍ 65 mm Hg despite satisfactory cardiac filling parameter (vasoplegia syndrome). At the end of CPB, protamine was administered to neutralize circulating heparin; the residual bypass circuit volume and shed blood processed by the cell salvage machine were retransfused to the patient. The threshold for blood transfusion was a hematocrit value ⬍ 18% during CPB and ⬍ 25% after CPB, or higher values (26 to 30%) when accompanied by hemodynamic instability and/or ECG signs of myocardial ischemia. In the ANH group, the whole autologous blood volume was retransfused during CPB or shortly after weaning from CPB. Clinical, Hemodynamic, and Biochemical Measurements: Myocardial tissue ischemic injury—the main study end point—was quantified by the release of cardiac biomarkers. Venous blood samples were sequentially collected (before surgery [baseline], at 1 to 3 h, 18 to 24 h, 40 to 48 h, and 72 h after surgery) for measurements of troponin I (Access Immunoassay System; Beckman Instruments; Fullerton, CA), creatinine kinase and myocardial fraction of creatinine kinase (optical standard technique). Sensitivity for troponin I determination was 0.09 ng/mL. Hemodynamic measurements and calculation of the ratepressure-product were obtained at the following times: (1) 5 min after anesthesia induction (baseline), (2) 5 min after the end of ANH or 30 min after anesthesia induction, (3) 5 min after sternotomy, (4) after weaning from CPB, and (5) during skin closure. All patients underwent a 12-lead ECG before surgery, at arrival in ICU, and then daily after surgery; transmural myocardial infarction was defined by the presence of new Q-waves (at least 0.04 ms and a reduction in R-waves of ⬎ 25% in at least two leads). Data regarding perioperative fluid management, homologous transfusion, and pharmacologic intervention were recorded intraoperatively and for the first 24 h after surgery. All patients were followed up until hospital discharge to detect adverse events. In-hospital mortality rate, hemodynamic changes, need for pharmacologic cardiac support, and the incidence of cardiovascular complications (new Q wave on ECG, atrial fibrillation, conduction blockade requiring electrical stimulation, stroke) were considered as secondary study end points. Statistical Analysis All data were analyzed using statistical software (version 9.0 for Windows; SPPS; Chicago, IL). Values were expressed as mean (⫾ SD or 95% confidence interval), median (interquartile range, 25 to 75%), or percentage as appropriate. Dichotomous variables were compared by the x2 statistic or Fisher Exact Test, and quantitative variables were compared with unpaired Student t test. Cardiac markers and hemodynamic data were compared with repeated-measures analysis of variance, having the group (ANH vs control) as a between-factor and time as a within-factor. Statistical significance was attributed to p ]ltequ] 0.05. Results Four patients who consented to take part were excluded because myocardial revascularization was performed without CPB (Fig 1). Data were obtained in 80 patients (39 in the ANH group and 41 in the control group). Baseline Characteristics and Operative Data The preoperative characteristics of the two groups were similar with regards to age, gender, body mass Table 1—Hemodynamic Management and End Points During Weaning From CPB* Hemodynamics End Points Heart rate ⬍ 70 beats/min EDD ⬍ 2.5–2.8 cm/m2 and MAP ⬍ 65 mm Hg EDD ⱖ 2.5–2.8 cm/m2 and MAP ⬍ 65 mm Hg EDD ⱖ 2.5–2.8 cm/m2, MAP ⬍ 65 mm Hg and systolic LV dysfunction Electrical cardiac pacing (A, V, or AV) Fluid challenge (100-mL increments) Phenylephrine (50–100 g repeated boli, up to 50 g) 1, dobutamine infusion (starting at 3 g/kg/min); 2, norepinephrine infusion (if dobutamine ⬎ 8 g/kg/min) *A ⫽ atrial; V ⫽ ventricular; AV ⫽ atrioventricular; EDD ⫽ end-diastolic diameter; LV ⫽ left ventricle; MAP ⫽ mean arterial pressure. 840 Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/22028/ on 05/03/2017 Clinical Investigations Figure 1. Flow of the participants through the trial. index, concomitant morbidity, left ventricular ejection fraction, and use of medications (Table 2). Also, the number of grafted coronary arteries as well as the durations of aortic cross-clamping, CPB, and surgery were comparable (Table 2). Hemodynamics, Fluid Balance, and Hemoglobin Results Following blood withdrawal and isovolemic compensation with colloids, hematocrit decreased from Table 2—Preoperative Characteristics and Operative Data of Patients Undergoing Myocardial Revascularization With CPB* Characteristics ANH (n ⫽ 41) Control (n ⫽ 39) p Value Age, yr BSA, m2 Male/female gender, No. Medical history Diabetes mellitus Hypercholesterolemia Hypertension Prior myocardial infarction Left ventricular ejection fraction, % Medications -Blockers Nitrates Angiotensin-converting enzyme inhibitors/angiotensin II blockers Calcium blockers Diuretics Statins Aspirine taken ⱕ 72 h preoperatively Cross-clamp time, min CPB time, min Surgical time, min Grafted coronary arteries, No. (range) 67 (63–70) 27 (26–28) 33/8 65 (62–68) 28 (24–30) 33/6 0.7 0.6 0.9 12 (29) 31 (76) 33 (80) 17 (41) 54 (51–57) 9 (23) 32 (82) 30 (77) 15 (38) 55 (51–59) 0.7 0.7 0.9 0.9 0.8 38 (93) 18 (41) 21 (51) 10 (24) 7 (17) 22 (54) 8 (20) 78 (63–93) 114 (101–127) 269 (251–287) 3 (1–5) 37 (95) 17 (44) 16 (41) 7 (18) 5 (13) 20 (51) 8 (21) 87 (70–104) 122 (111–133) 281 (263–300) 3 (1–4) 0.9 0.8 0.9 0.7 0.8 0.9 0.9 0.44 0.35 0.41 1 *Data are presented as mean (95% confidence interval) or No. (%) of patients unless otherwise indicated. www.chestjournal.org CHEST / 128 / 2 / AUGUST, 2005 Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/22028/ on 05/03/2017 841 41 ⫾ 2 to 28 ⫾ 1% (p ⬍ 0.001) and was accompanied by a significant increase in central venous pressure and a decrease in heart rate and ratepressure product compared with baseline values (Table 3). No patients exhibited signs of myocardial ischemia as judged by the analysis of automated ST-segment and left ventricular wall motion monitoring. Before CPB, hematocrit levels, heart rate, and rate-pressure-product remained significantly lower in the ANH group compared with the control group (Table 3). After weaning from CPB and at the end of surgery, hemodynamic data and hematocrit levels did not differ between the two groups. Intraoperatively, the total volume of colloids was slightly but significantly higher in the ANH group compared with the control group. However, cumulative fluid balance and allogenic blood transfusion requirements were comparable in the two groups over the 24-h perioperative period (Table 4). In the ANH group, the autologous blood was reinfused during CPB in all the patients as the transfusion trigger was reached. Primary Outcomes In the two groups, troponin I concentrations were below the detection limit before CPB and increased significantly after arrival in the ICU. At 18 to 24 h, 40 to 48 h, and 72 h after aortic unclamping, myocardial release of troponin was significantly lower in the ANH group than in the control group (Table 5). Values for creatine kinase and myocardial fraction of creatine kinase were also comparable at the beginning of surgery and increased significantly after arrival in ICU in both groups. Compared with the control group, the release of the myocardial fraction of creatine kinase in the ANH group was significantly lower at arrival in ICU and 18 to 24 h after aortic unclamping (Table 5). Secondary Outcomes All patients survived, and one patient in each group met the ECG criteria for perioperative myocardial infarct. The groups were similar with respect to length of stay in the ICU and in the hospital, as well as the occurrence of noncardiac complications (Table 6). However, of 41 patients in the ANH group, 7 patients were administered dobutamine, compared with 15 patients in the control group (odds ratio, 0.35; confidence interval, 0.12 to 0.98; p ⫽ 0.04), and the total amount of dobutamine was significantly lower in the ANH group than in the control group. The combined incidence of arrhythmia and conduction disorders requiring transient cardiac pacing was also significantly lower in the ANH group, compared with the control group. Plasma troponin I concentrations (18 to 24 h after the end of CPB) were significantly higher in subgroups of patients receiving dobutamine infusion compared with those not requiring inotropic support (4.5 ⫾ 3.1 ng/mL vs 2.2 ⫾ 1.9 ng/mL in the control group, and 3.1 ⫾ 2.3 ng/mL vs 0.7 ⫾ 0.4 ng/mL in the ANH group, respectively). Table 3—Intraoperative Time Course of Hemoglobin and Hemodynamic Variables* Variables Hematocrit, % Control group ANH group Baseline 1 After Hemodilution or Baseline 2 Sternotomy 10 min After Starting CPB After Weaning From CPB End of Surgery 27 (24–29)‡ 20 (18–22)†‡ 25 (23–27)‡ 24 (22–26)‡ 27 (25–29)‡ 27 (24–30)‡ 81 (77–85)‡ 78 (74–82)‡ 81 (78–84)‡ 79 (75–83)‡ 73 (70–76) 74 (71–77) 78 (74–82) 79 (75–84) 40 (38–42) 41 (39–43) 39 (37–43) 28 (27–29)†‡ 39 (37–43) 27 (26–9.3)†‡ Heart rate, beats/min Control group 67 (64–70) ANH group 65 (61–69) 64 (61–77) 54 (51–57)†‡ 65 (61–69) 55 (52–58)†‡ Mean arterial pressure, mm Hg Control group 80 (76–84) ANH group 77 (74–80) 78 (74–82) 74 (71–77) 87 (84–90) 85 (81–89) Rate-pressure product, mm Hg/beats/min Control group 6,849 (6,102–7,496) 6,304 (5,960–6,640) ANH group 6,502 (6,140–6,904) 5,522 (5,290–5,755)†‡ Central venous pressure, mm Hg Control group 11.4 (10.3–12.5) ANH group 11.8 (10.9–12.7) 11.6 (10.7–12.5) 13.9 (13.1–14.7)†‡ 7,373 (6,895–7,851) 6,353 (5,812–6,894)† 12.0 (11.1–12.9) 13.1 (12.1–14.1) 65 (52–68)‡ 64 (61–67)‡ 8,263 (7,475–9,055) 7,746 (7,311–8,181) 8,204 (7,667–8,741) 8,160 (7,427–8,893) 14.4 (13.4–15.4)‡ 14.6 (13.4–15.8)‡ 14.6 (13.6–15.6)‡ 14.9 (13.7–15.1)‡ *Data are presented as mean (95% confidence interval). †p ⬍ 0.05 between groups. ‡p ⬍ 0.05 compared with baseline 1. 842 Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/22028/ on 05/03/2017 Clinical Investigations Table 4 —Intraoperative and Postoperative Fluid Balance and Allogenic Blood Transfusion* ANH (n ⫽ 41) Variables Intraoperative fluid balance, mL Cristalloids Colloids Urine output Postoperative fluid balance (first 24 h), mL Cristalloids plus colloids Urine output Chest tube drainage, mL/24 h Patients receiving RBC concentrates (intra- and postoperatively) No. of patients Mean (SD) of units per patient Patients receiving fresh frozen plasma (intra- and postoperatively) No. of patients Mean (SD) of units per patient Control (n ⫽ 39) p Value 3,753 (3,427–4,079) 1,370 (1,270–1,470) 942 (735–1,149) 3,580 (3,116–4,044) 974 (850–1,098) 739 (554–924) 0.5 0.04 0.14 2,864 (2,448–3,280) 2,074 (1,808–2,340) 623 (515–731) 3,444 (2,991–3,847) 1,732 (1,452–2,006) 567 (430–704) 0.07 0.08 0.5 17 0.9 (1.3) 14 1.0 (1.4) 0.8 0.7 3 0.3 (1.1) 4 0.3 (1.3) 0.9 0.9 *Data are presented as mean (95% confidence interval) unless otherwise indicated. Discussion The results of this investigation demonstrate that moderate ANH prior to on-pump CABG confers additional myocardial protection beyond that provided by blood cardioplegia and anesthetic preconditioning, as expressed by lower release of biomarkers of myocardial injury, lesser requirements for inotropic support, as well as fewer patients presenting with arrhythmia’s or conduction disorders after weaning from CPB. Perioperative Myocardial Injury After CABG, the variable incidence of myocardial infarcts (from 1 to 29%) has been attributed to nonuniform definitions and different baseline patient characteristics.1,14 In addition, postoperative sternal pain makes clinical symptoms unreliable, and ECG-derived diagnosis of myocardial infarct cannot be satisfied in the presence of transient conduction block, arrhythmias, and ventricular hypertrophy.15–17 To detect myocardial injury, we adopted measurements of troponin I and restrictive ECG criteria, ie, the occurrence of new Q waves. As shown by radionuclide techniques using single-photon emission CT imaging, plasma release of cardiac biomarkers parallels the extent of myocardial damage in the transmural or subendocardial areas regardless of its mechanisms.18 Importantly, most episodes of perioperative myocardial necrosis are clinically silent, unaccompanied by Q-wave evolution and result in plasma release of troponin, which carries both shortterm and long-term prognostic significance for inhospital mortality and later complications.19 –21 The Table 5—Perioperative Biological Markers of Cellular Injury* After Weaning From CPB, h Variables Troponin I, ng/mL Control group ANH group 1–3 Before Surgery 0.04 (0.04–0.06) 0.04 (0.03–0.05) Creatinine phosphokinase, U/L Control group 82 (76–88) ANH group 85 (77–93) 1.64 (1.25–2.03)‡ 0.63 (0.51–0.75)†‡ 740 (514–966)‡ 469 (350–588)‡ 18–24 3.87 (3.15–4.59)‡ 1.43 (1.02–1.84)†‡ 40–48 3.16 (2.30–4.02)‡ 1.13 (0.84–1.42)†‡ 1,284 (928–1,640)‡ 603 (497–705)†‡ 1,120 (775–1,465)‡ 490 (449–541)†‡ Myocardial fraction of creatinine phosphokinase, U/L Control group 13 (10–16) 35 (28–42) ANH group 10 (7–13) 28 (24–32) 71 (53–89)‡ 29 (23–35)†‡ 62 (40–84)‡ 21 (16–26)† C-reactive protein, ng/dL Control group ANH group 72 (48–96)† 66 (46–86)† ⬍5 ⬍5 72 2.31 (1.63–2.97)‡ 0.81 (0.58–1.02)†‡ 787 (592–982)‡ 380 (272–428)†‡ 38 (25–51)‡ 15 (12–18) 78 (52–94)‡ 71 (56–86)‡ *Data are presented as mean (95% confidence interval). †p ⬍ 0.05 between groups. ‡p ⬍ 0.05 compared with baseline (before surgery). www.chestjournal.org CHEST / 128 / 2 / AUGUST, 2005 Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/22028/ on 05/03/2017 843 Table 6 —Pharmacologic Cardiac Support and Perioperative Complications Variables Cardiac drugs Dobutamine No. of patients Median dose (interquartile range), mg Norepinephrine No. of patients Median dose (interquartile range), mg Cardiac complications, No. of patients New Q wave on ECG Conduction block Atrial fibrillation Noncardiac complication, No. of patients Postoperative ventilation ⬎ 24 h Reoperation for bleeding Stroke or transient cerebral ischemia Renal dysfunction (creatinine ⬎ 120% of baseline) ICU stay, median d (range) Hospital stay, median d (range) ANH (n ⫽ 41) 7 71 (20–255)* Control (n ⫽ 39) 15 112 (34–425) 4 0.8 (0.4–2.1) 12* 1 8 10 4 0.7 (0.3–2.1) 26 1 12 17 1 1 2 3 2 (1–5) 12 (10–15) 2 1 2 3 2 (1–7) 13 (10–16) p Value 0.04 ⬍ 0.01 0.9 0.28 ⬍ 0.01 0.9 0.36 0.11 0.9 0.9 0.6 0.7 1.0 1.0 *p ⬍ 0.05 between groups. most recent consensus guidelines22 from the American Heart Association/American College of Cardiology and European Society of Cardiology have incorporated troponin (I or T) as the myocardial biomarkers of choice, not only in medical patients with suspected acute coronary syndrome but also following cardiac surgery. A large range of troponin I cut-off levels (3 to 9 ng/mL, depending on the immunoassay) has been reported for diagnosing early graft failure and transmural myocardial infarct.22,23 In the two groups, postoperative elevation of troponin and myocardial fraction of creatine kinase was the biological expression of myocardial cellular damage consequent to prolonged aortic clamping time with ischemia-reperfusion phenomenon, possible coronary microembolization, and direct myocardial trauma by surgical manipulations.24 Neither patient required reoperation nor mechanical assistance for ventricular failure, the incidence of Q-wave myocardial infarct was low (2.5%), and plasma troponin I levels were in the low-to-intermediate range, excluding early vascular graft failure or coronary occlusion. Such a favorable cardiac outcome reflected the low preoperative risk profile of our surgical population (eg, stable coronary disease, preserved left ventricular function, without associated valve disease) and the successful application of myocardial preservation techniques including blood cardioplegia and anesthetic preconditioning with isoflurane.25 The postoperative release of cardiac biochemical markers has been shown to correlate with the amount of infarcted myocardium as determined by contrast-enhanced MRI; accordingly, peak troponin I levels in the low-to-intermediate range (1 to 9 ng/mL) would correspond to myonecrosis involving 0.5 to 17 g of left ventricle mass (or 1.2 to 10% of ventricular volume).26 Patients requiring temporary inotropic support to maintain hemodynamic stability after weaning from CPB also presented the highest blood levels of troponin I, regardless of the treatment group. In clinical and experimental studies, correlations have been demonstrated between the duration of global myocardial ischemia, the extent of necrosis/apoptosis, and the severity of ventricular dysfunction following reperfusion.27,28 Likewise, higher 30-day mortality rate after cardiac surgery has been associated with the use of inotropic agents, a surrogate of unstable hemodynamics and impaired ventricular function.29 Taken together, these results suggest that both global myocardial stunning (reversible) and necrosis (irreversible) are responsible for the transient decline in cardiac contractility that has been shown to correlate with the duration of cardioplegic arrest. ANH In addition to the use of antifibrinolytics and intraoperative cell saving, preoperative hemodilution failed to provide any blood-sparing effects. Consistent with these data, a recent meta-analysis30 including 42 trials demonstrated that the risk of allogenic transfusion was similar among hemodiluted patients, those managed with another conservation method, and those receiving standard care. The safety of the hemodilution procedure was 844 Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/22028/ on 05/03/2017 Clinical Investigations ascertained by maintaining circulatory normovolemia and by close monitoring of cardiovascular parameters with ECG and echocardiography. Presumably, general anesthesia and chronic -blockade decreased the metabolic needs (approximately 20 to 30%) and prevented the sympathetic-mediated inotropic and chronotropic response in our patients.31 Occasional reports of myocardial ischemia have been attributed to extremely low hemoglobin levels, concomitant hypovolemia, reflex tachycardia in awake volunteers, and/or increased postoperative metabolic needs.32–34 In preliminary studies, we demonstrated that lowering blood viscosity at similar levels of hemodilution induced a predominant preload-dependent increase in stroke volume (⫹ 28%) owing to enhanced venous return and mobilization of a fraction of the unstressed splanchnic volume, whereas left ventricular contractility and afterload were unaffected.35 As a result, the decreased blood oxygen carrying capacity was partially offset by the increased cardiac output with systemic oxygen delivery remaining above the critical anaerobic threshold. In this study, the improved intraoperative myocardial preservation in the hemodiluted patients was clearly demonstrated by the lower postoperative release of myocardial biomarkers, the reduced need for inotropic support, and the lower incidence of combined arrhythmia and conduction disorders, compared with patients receiving standard care. Except for prebypass and intrabypass hematocrit levels, the two groups were comparable in terms of baseline characteristics as well as perioperative hemodynamics and medical management. Such hemodilution-induced cardioprotection might be related to optimization of the myocardial balance in oxygen demand/delivery before aortic cross-clamping. Indeed, an approximate 12% reduction in myocardial oxygen consumption was expected according to the decline of the rate-pressure product, a sensitive index of cardiac metabolic requirements. The increased cardiac filling pressure following hemodilution was associated with a baroreflex-mediated lowering of heart rate that would also contribute to facilitate coronary blood flow and enhance ventricular relaxation due to prolonged diastolic time. Owing to the reduced blood viscosity, oxygen delivery within underperfused myocardial areas might be improved before aortic cross-clamping and global cardiac ischemia. Physical concepts and experimental data lend support for increased tissue blood flow distribution following moderate hemodilution as a result of increased collateral blood flow, higher density of functional capillaries, increased Fahraeus effects, and shear-dependent vasodilatation.7,36,37 www.chestjournal.org Limitations First, monitoring of ECG changes was not continued postoperatively to detect transient myocardial ischemia or ischemia-reperfusion phenomenon. Although Holter monitors have a high specificity (88 to 92%) to detect ischemia, sensitivity is low (37 to 50%).38 Moreover, changes in acid-base balance and electrolytes, surgical wound and draping, hypothermia, as well as arrhythmia and left ventricular hypertrophy may all interfere with interpretation of ECG changes and explain the high variability in the reported incidence of perioperative myocardial ischemia. Second, an increase in central venous pressure following hemodilution could be related to excess fluid administration or to enhanced venous blood return from the peripheral “slow flow/low shear rate” compartment. However, hypervolemic hemodilution was unlikely since the amount of blood withdrawn was precisely measured and compensated by infusing colloid in a 1/1.15 ratio, which took into account the extravasation of fluids into the interstitial space.11 Third, our trial involved low-risk patients undergoing elective CABG, and the study was not sufficiently powered to detect overall differences in mortality, major cardiac complications, and ICU or hospital resources. In previous reports, a nonsignificant trend toward fewer serious adverse events has been observed in patients undergoing ANH (death or myocardial infarct: 2.6% vs 4.0% in ANH vs non-ANH groups, respectively).30 Accordingly, a large number of patients would be required (⬎ 600 patients in each group) to detect significant reduction in major clinical events; in contrast, smaller studies using surrogate biological end points such as cardiac troponin are suitable to detect clinically “silent” myocardial injuries, which carries long-term prognostic values. Finally, although intraoperative masking was not possible, the ICU staffs were blinded to allocation to group, perioperative medical care was standardized, and similar clinical and physiologic end points were achieved in the two groups. Preoperative cardiac condition and intraoperative surgical treatment were also comparable, although nonsignificant shorter duration of aortic cross-clamping (⬍ 10%) was noted in the ANH group. As no protocol violations occurred, we can assume that the reduction in postoperative myocardial release of troponin was related to preoperative ANH. Conclusions Preventing myocardial damage during cardiac surgery contributes to better postoperative recovery. CHEST / 128 / 2 / AUGUST, 2005 Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/22028/ on 05/03/2017 845 Along with standard blood cardioplegia and anesthetic preconditioning, acute preoperative hemodilution attenuates the deleterious effects of aortic cross-clamping and improves myocardial recovery in patients undergoing CABG. The optimal value of hematocrit levels before CPB remains unknown. Further studies are warranted to confirm these preliminary results, to investigate the mechanisms of hemodilution-related cardioprotection, and to test the efficacy of this simple procedure in higher-risk patients with poor ventricular function and those requiring complex cardiac surgery. 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