Diltiazem cardioplegia

Volume 91,

Number 5

May 1986

THORACIC AND CARDIOVASCULAR SURGERY The Journal

J

THORAC CARDIOVASC SURG

of

91:647-661, 1986

Original Communications

Diltiazem cardioplegia A balance of risk and benefit Calcium channel blockers may prevent myocardial injury during cardioplegia and reperfusion. A prospective, randomized trial was instituted to evaluate the hemodynamic and myocardial metabolic recovery in 40 patients undergoing elective aorta-coronary bypass with either diltiazem in crystalloid potassium cardioplegia (n = 20) or crystalloid potassium cardioplegia (n = 20). In a preliminary trial, doses between 150 and 250 #gjkg reducedthe periodof heart block after cross-clampremoval (90 ± 110 minutes) from that found with higher doses and improved myocardialmetabolism. In the randomizedtrial, diltiazem cardioplegia (150 #gjkg) produced coronary vasodilatation during cardioplegia and produced less reactive hyperemia during reperfusion. Myocardial oxygen extraction was lower and myocardial lactateproduction was less after diltiazem cardioplegiaduring reperfusion. Tissue adenosinetriphosphate and creatine phosphate concentrations were preserved better after diltiazem cardioplegia. The postoperative creatine kinase MB levels were less (p < 0.05) after diltiazem cardioplegia, which indicated less myocardial injury. Postoperativevolume loadingdemonstrated that systolicfunction(the relation between systolic blood pressure and end-systolic volume index) was depressed after diltiazem cardioplegia compared to crystalloid cardioplegia, but cardiac index was higher because afterload (mean arterial pressure) was lowerand preload(end-diastolic volume index)was higher.Diltiazem cardioplegiapreserved high-energy phosphates, improved postoperative myocardial metabolism, and reduced ischemic injury afterelective coronary bypass.However, diltiazemwas a potent negative inotropeand producedprolonged periods of electromechanical arrest. Diltiazem cardioplegia may be of value in patients with severe ischemia but should be used with caution in patients with ventricular dysfunction, and a dose-response relation must be established at each institution before clinical use.

George T. Christakis, M.D., Stephen E. Fremes, M.D., Richard D. Weisel, M.D., Jacques G. Tittley, M.D., Donald A. G. Mickle, M.D., Joan Ivanov, R.N., M. Mindy Madonik, B.Sc., Arnold M. Benak, C.C.P., Peter R. McLaughlin, M.D., and Ronald J. Baird, M.D., Toronto, Ontario, Canada

From the Divisionsof Cardiovascular Surgery, Clinical Biochemistry, and Cardiology, the Toronto General Hospital and the University of Toronto, Toronto, Ontario, Canada.

Read at the Eleventh Annual Meeting of The Western Thoracic Surgical Association, Incline Village, Nev., June, 16-20, 1985, and awarded the Samson Resident Prize.

Supported by the Heart and Stroke Foundation of Ontario, the Canadian Heart Foundation and the Medical Research Council of Canada.

Address for reprints: Richard D. Weisel, M.D., Cardiovascular Surgery, Toronto General Hospital, 200 Elizabeth St., Eaton North 13-224, Toronto, Ontario, Canada M5G 2C4.

647

6 4 8 Christakis et al.

Cold potassium cardioplegia provides excellent protection for elective coronary bypass operations, but recent studies have identified evidence of perioperative ischemic injury.!" Inadequate myocardial protection has been suggested because of postoperative reactive hyperemia,':? depressed oxygen utilization, 1·3 anaerobic metabolism in response to stress, I, 2 and transient biventricular dysfunction.F" Although blood cardioplegia provides better protection than crystalloid cardioplegia, anaerobic metabolism and depletion of high-energy phosphates have been demonstrated after blood as well as crystalloid cardioplegia.' In addition, blood cardioplegic solutions deliver catecholamines and activated leukocytes and platelets to the ischemic myocardium. The addition of drugs or substrates to crystalloid cardioplegic solutions may offer a simpler method to protect the heart during cardiac procedures. Calcium antagonist cardioplegia may reduce perioperative ischemic injury.':" In experimental studies, calcium antagonists have been shown to preserve myocardial function and metabolism after normothermic ischemia, 12·I5 crystalloid cardioplegia, 7-10 or blood cardioplegia. I I These agents prevent calcium influx 16 and adenosine triphosphate hydrolysis'? during cardioplegic arrest. Calcium antagonists may improve cardioplegic delivery by coronary vasodilatation" 18 and may improve cardioplegic efficiency by eliminating microfibrillary activity occasionally seen during potassium arrest. Calcium antagonists may also improve myocardial metabolic recovery during reperfusion by maintaining electromechanical arrest and inhibiting calcium influx. These agents may also reduce the incidence of postoperative hypertension, arrhythmias,'? and coronary spasm." 21 The potential benefits of calcium antagonist cardioplegia must be balanced by the potential risks. All calcium antagonists depress cardiac function and can induce heart block.22, 23 Diltiazem,":" verapamil.F''!" and nifedipinev" are the most widely used calcium antagonists for myocardial preservation. Diltiazem has distinct hemodynamic and pharmacokinetic advantages as a cardioplegic additive. It has the least negative inotropic effect," the greatest antidromotropic effect," and it preferentially dilates coronary over systemic arteries." Diltiazem prolongs the A-H interval* more than nifedipine but less than verapamil." Conduction defects may be more readily reversed during reperfusion with diltiazem than verapamil or nifedipine." The cardioprotective effects of calcium antagonists are dose dependent but not linear." Inappropriate doses *The A-H interval is the time from atrial activation in the region of the atrioventricular node to His bundle activation.

The Journal of Thoracic and Cardiovascular Surgery

may provide inadequate protection," and different types, volumes, and modes of cardioplegic delivery may alter the dose-response relation of calcium antagonists in cardioplegic solutions." The optimal dose of a calcium antagonist should produce electromechanical arrest limited to the immediate reperfusion period. Prolonged periods of complete heart block after discontinuation of cardiopulmonary bypass may be dangerous because of the risks of pacemaker failure. Therefore, a preliminary dose-response study was performed to assess pacemaker dependency and postoperative myocardial metabolism with increasing doses of diltiazem. Then, a prospective, randomized trials was performed to evaluate the hemodynamic and myocardial metabolic recovery after elective aorta-coronary bypass grafting performed with cold crystalloid potassium cardioplegia with and without diltiazem.

Methods Patient population. The preliminary study was conducted in 15 patients to identify a safe and effectivedose of diltiazem added to a cold potassium crystalloid cardioplegic solution. After the preliminary study, 40 patients scheduled for elective coronary bypass agreed to participate in a prospective, randomized trial comparing diltiazem (DILT group, n = 20) and crystalloid cardioplegia (CCP group, n = 20). All 55 patients signed a consent form approved by the University Human Experimentation Committee. Patients were included in the study if they had double- or triple-vessel coronary artery disease, stable exertional angina, and normal preoperative ventricular function (left ventricular ejection fraction >30% at preoperative ventriculography). Patients in the preliminary study were randomized to receive a total diltiazem dose in the crystalloid cardioplegic solution of 5 mg (50 to 100 ~gjkg, n = 5), 15 mg (150 to 250 ~gjkg, n = 5), or 25 mg (>300 ~gjkg, n = 5). The 20 patients randomized to receive diltiazem were given 150 ~gjkg in the crystalloid cardioplegic solution. Cardioplegic technique. The anesthetic management, conduct of cardiopulmonary bypass, and cardioplegic technique have been recently described. I. 2, 30 The crystalloid cardioplegic solution contained the following: K+ 20 mmoljL, Na' 27 mmoljL, Ct : 47 mmoljL, MgS0 4 3 mmoljL, tromethamine 4 mmoljL, and glucose 280 mmoljL. The cardioplegic techniques were identical in the two groups. After application of the cross-clamp, 1 L of the cardioplegic solution was delivered into the aortic root at a temperature of 50 ± 10 C and an aortic root pressure of 70 mm Hg (measured directly by a separate port of the cardioplegic

Volume 91

Diltiazem cardioplegia 6 4 9

Number 5 May, 1986

cannula*). Myocardial temperatures were measured and the first distal anastomosis was constructed to the coronary artery with the most significant stenosis and the warmest myocardial temperature. After each distal anastomosis, 100 ml of the cardioplegic solution was given into the vein graft. A proximal anastomosis was then performed and 400 m1 was given into the aortic root at a pressure of 60 mm Hg. Systemic rewarming (from 25° to 34° C) was commenced during construction of the final distal anastomosis. After completion of all anastomoses and immediately before aortic unclamping, 250 ml of room temperature cardioplegic solution was infused into the aortic root. Reperfusion on cardiopulmonary bypass was continued for 30 minutes after cross-clamp removal. One gram of calcium chloride was given before discontinuation of bypass, and atrial or atrioventricular sequential pacing was instituted when bradycardia «50 beats/min) or asystole was present. For patients randomized to diltiazem cardioplegia, the calculated dose of diltiazem was divided; half was given with the first infusion and half in the final infusion before aortic unclamping. The diltiazem hydrochloride powder] was dissolved in 20 ml of 5% dextrose in water and injected slowly into the cardioplegic tubing during the infusion of the potassium crystalloid cardioplegic solution to ensure that the entire dose was delivered into the aortic root and that none was left in the tubing. Measurements. The following catheters were inserted intraoperatively: radial arterial, left atrial, and pulmonary arterial. Hemodynamic measurements included pulse, left and right atrial pressures, systolic and mean arterial pressures, mean pulmonary arterial pressure, and cardiac output (by thermodilution). Measurements of cardiac index, stroke index, and left and right ventricular stroke work indices were derived by standard formulas. 30, 31 A 5F infant feeding tube and a double thermistor cathetert were inserted into the coronary sinus for blood sampling and measurement of coronary sinus blood flow (by the continuous thermodilution technique)." Arterial and coronary sinus blood samples were assayed for oxygen tension and saturation,§ lactate.] and glycerol.~ Oxygen content was derived by a standard formula." *DLP lnc., Grand Rapids, Mich. tDiltiazem was supplied by Nordic Laboratories, Quebec, PQ, Canada. [Webster Labs, Inc., Altadena, Calif.

The extraction of oxygen, lactate, and glycerol was calculated as the difference between the arterial (or aortic root) and coronary sinus content of oxygen, lactate, and glycerol, respectively. Myocardial oxygen consumption, lactate flux, and glycerol flux were calculated as the product of coronary sinus blood flow and the respective coronary sinus content difference. Myocardial temperatures were measured with needle thermistor probes* in regions supplied by the left anterior descending, circumflex, and posterior interventricular coronary arteries, the anterior surface of the right ventricle (3 em lateral to the septum), and the right atrium (4 em inferior to the sinoatrial node) after each cardioplegic infusion. The regions supplied by the left anterior descending, circumflex, and posterior interventricular coronary arteries were graded as most ischemic, intermediate ischemic, or least ischemic based on the degree of stenosis found on the preoperative angiogram and the myocardial temperatures after the first cardioplegic infusion. Transumuralleft ventricular tissue was obtained from the most ischemic region with a biopsy needle.t Biopsy specimens were immediately submerged in liquid nitrogen and subsequently freeze-dried. The tissue metabolities of adenosine triphosphate, creatine phosphate, glycogen, and lactate were analyzed spectrofluorometrically.t The time required for cardioplegic delivery, the aortic root pressure (AP), and the right atrial pressure (RAP) were recorded during each cardioplegic infusion to calculate coronary flow (CBF = volume infused + time of infusion) and coronary vascular resistance (CVR = [AP - RAP] X 79.9 + CBF). The length of time that atrial or atrioventricular sequential pacing was required after cross-clamp removal was noted for each patient. In patients who required pacing after discontinuation of cardiopulmonary bypass, pacemaker dependency was assessed every 30 minutes. The pacemaker rate was slowly decreased to 50 beats/ min, and patients were deemed pacemaker dependent if their underlying rate was less than 50 beats/min. Equilibrium gated nuclear ventriculograrns were performed in the intensive care unit between 3 and 6 hours postoperatively, as previously described. I, 2, 30 Left ventricular end-diastolic volume index (LVEDVI) was calculated from the nuclear-derived ejection fraction *Shiley Inc., Irvine, Calif.

§Co-Oximeter, Instrumentation Laboratory, Inc., Lexington, Mass.

tTru-Cut biopsy needle, Travenol Laboratories, Inc" Deerfield, III.

IlRapid Lactate Stat Pack Kit, Calbiochem-Behring, La Jolla, Calif.

:j:Greiner Selective Analyzer II, Greiner Electronics, Langenthal, Switzerland. Perkin-Elmer 650-105 Fluorescence Spectrophotometer, Perkin-Elmer Corp., Norwalk, Conn.

~Enzymatic

da,

Triglyceride, Boehringer-Mannheirn, Dorval, PQ, Cana-

The Journal of Thoracic and Cardiovascular Surgery

6 5 0 Christakis et al.

300


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Fig. 1. The relation between pacemaker dependency (in minutes after cross-clamp removal) and the total dose of diltiazem added to the potassium crystalloid cardioplegic solution in the preliminary study is depicted. A significant linear relation was found over the range of doses employed (r = 0.94, p < 0.001).

(LVEF) and the thermodilution stroke index (SI) by the formula: LVEDI = (SI + LVEF). Left ventricular endsystolic volume index was calculated as the difference between end-diastolic volume index and the stroke index. Right ventricular end-diastolic and end-systolic volume indices were similarly calculated from the right ventricular ejection fraction and stroke index. Left ventricular volumes independent of the thermodilution cardiac output measurements were calculated directly from the scintigraphic counts as described by Bums and

colleagues." 35

Protocol for measurements. In the operating room, measurements were recorded on cardiopulmonary bypass before aortic occlusion, during the three cardioplegic infusions, at the time of cross-clamp removal, at 10 minute intervals during the first hour, in the intensive care unit at hourly intervals between 3 and 6 hours, and again 24 hours after cross-clamp removal. The metabolic response (myocardial extraction or production of metabolites) to atrial or atrioventricular sequential pacing at 110 beats/min for 5 minutes! was assessed on bypass after 30 minutes of reperfusion and off bypass 1 hour after cross-clamp removal. Left ventricular biopsy specimens were obtained at baseline during cardiopulmonary bypass before aortic clamping, immediately

after cross-clamp removal, and 30 minutes after crossclamp removal. Patients were transferred to the intensive care unit between 60 and 90 minutes after cross-clamp removal. During the first hour in the intensive care unit, patients were rewarmed, volume repleted, and sedated with intravenous diazepam (5 mg) and morphine (4 mg). Volume loading was performed in the intensive care unit 2 to 3 hours after cross-clamp removal in 33 patients (DILT group, n = 15; CCP group, n = 18), as previously described.': 2, 36 Hemodynamic, nuclear ventriculographic, and metabolic measurements were made before and after volume loading. Patients who had postoperative hypertension (mean arterial pressure >95 mm Hg) and did not respond to sedation were treated with sodium nitroprusside to maintain mean arterial pressure between 80 and 90 mm Hg.37 All measurements made during hypertension or its treatment were excluded from analysis. The incidence of hypertension in the first 24 hours after operation was recorded. The myocardial isoenzyme of creatine kinase (CKMB) was measured 2, 4, 8, 16,24, and 48 hours after cross-clamp removal as an index of myocardial injury. Statistical analysis. Statistical analysis was performed by the Statistical Analysis System programs. * The serial measurements were divided into the following time periods: on cardiopulmonary bypass before aortic occlusion; during cardioplegic administration; during the first hour after cross-clamp removal; and in the intensive care unit. Separate, two-way, repeated measures analyses of variance were performed by the general linear models procedure" for each time period. Unpaired t tests or least square means t tests" were employed to specify differences between means when the p value associated with the F ratio was significant at the 0.05 level. The response to volume loading and atrial pacing was analyzed by an analysis of variance. Diastolic compliance, systolic function, and myocardial performance were determined from the volume-loading data. Analyses of variance and covariance" were used to evaluate diastolic compliance (the relation between left or right atrial pressure and the left or right ventricular end-diastolic volume index),39,40 systolic function (the relation between systolic arterial or pulmonary arterial pressure and the left or right ventricular end-systolic volume index),40,4! and myocardial performance (the relation between cardiac index or left or right ventricular stroke work index and the left or right ventricular end-diastolic volume index).': 40 Clinical data were com*SAS Institute, Inc., Box 8000, Cary, N. C.

Volume 91 Number 5 May, 1986

Diltiazem cardioplegia

651

Table I. Myocardial lactate extraction (mmol/L) in response to pacing: Preliminary dose-response study On bypass

Diltiazem dose (Jlgjkg)

Baseline

50-100 150-250 >300

0.07 ± 0.07 0.05 ± 0.07 0.15 ± 0.10

I

Ojfbypass Pacing

Baseline

-0.10 ± 0.05' 0.12 ± 0.05 0.18 ± 0.10

0.55 ± 0.40 0.40 ± 0.38 0.40 ± 0.32

I

Pacing

0.28 ± 0.19t 0.38 ± 0.21 0.10 ± O.07t

'Different by ANOVA, P < 0.05. tDifferent from baseline, p < 0.05.

pared by unpaired t tests, chi square tests, or Fisher's exact test where appropriate. Categorical data were summarized as the absolute frequency or percent frequency. Continuous variables were summarized as the mean and standard deviation in the text and tables and as the mean and standard error in the figures. Statistical significance was assumed for p values less than 0.05. Results Preliminary dose-response study. Fig. 1 depicts the relation between the time (minutes after cross-clamp removal) of pacemaker dependency and the total dose (micrograms per kilogram) of diltiazem added to the cardioplegic solution. A significant linear relation was found (r = 0.94, P < 0.001). Patients who received 50 to 100 JLg/kg required 10 ± 15 minutes of pacing postoperatively, those who received 150 to 250 JLg/kg were paced for 90 ± 110 minutes, and those who received more than 300 JLg/kg required 140 ± 120 minutes of pacing. Only one patient who received less than 100 JLg/kg required pacing to come off bypass, and in that patient pacing was discontinued within 5 minutes after bypass. All patients who received more than 300 JLg/kg required pacing to come off bypass, and three of the five patients who received 150 to 250 JLg/kg required pacing to come off bypass. No pacemaker-related morbidity or arrhythmias developed postoperatively. Table I presents the myocardial lactate extraction before (baseline) and after pacing and at 30 minutes (on bypass) and 60 minutes (off bypass) after cross-clamp removal for the three diltiazem dosage groups. Pacing during cardiopulmonary bypass resulted in cardiac lactate production in those who received 50 to 100 JLg/kg, whereas those who received more than 150 JLg/kg had increased myocardial lactate extraction with pacing. Thirty minutes after discontinuation of cardiopulmonary bypass, pacing resulted in decreased myocardial lactate extraction in those who received a high (> 300 JLg/kg) or a low « 100 JLg/kg) dose of diltiazem, but not in those who received 150 to 250 JLg/kg. To

Table II. Clinical information: Randomized study CCP Patients Age (yr) NYHA (J/Il/III/IV) Diseased vessels (2/3) Bypasses (3/4/5 or more) Ejection fraction (%) Calcium antagonists preop. Beta blockers preop. CPB time (min) Cross-clamp time (min) Mortality Myocardial infarction Low output syndrome Highest CK-MB (U/L) Highest AST (U/L)

20 55.7 ± 8.8 2/4/14/0 5/15 4/11/5 59 ± 7 II (55%) 16 (80%) 121 ± 25 65 ± 21

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3 44.9 ± 21.0 111.6 ± 63.0

32.1 ± 19.0' 83.6 ± 64.2

Legend: CCP, Crystalloid cardioplegia. DILT, Diltiazem cardioplegia. NYHA, New York Heart Association. CPB, Cardiopulmonary bypass. CK-MB, Cardiac isoenzyme of creatine kinase. AST. Aspartate aminotransferase.

'Different from CCP, p < 0.05.

mmumze postoperative pacemaker dependency but improve postoperative metabolic recovery, a dose of 150 JLg/kg was selected for the prospective randomized trial. Randomized clinical trial of diltiazem and crystalloid potassium cardioplegia. The preoperative, perioperative, and postoperative clinical information for the 40 randomized patients is presented in Table II. Randomization was adequate, because the two groups were similar with respect to sex (all men), age, New York Heart Association functional class, extent of coronary disease and number of bypass grafts, preoperative ejection fraction, cardiopulmonary bypass time, and cross-clamp time. Similar numbers of patients were receiving preoperative beta blockers and calcium antagonists in the two groups. One patient died of complications of a stroke 2 weeks after receiving diltiazem cardioplegia. One patient had a perioperative myocardial infarction (the appearance of a

The Journal of Thoracic and Cardiovascular Surgery

6 5 2 Christakis et al.

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new Q wave) after receiving crystalloid cardioplegia. Three patients had postoperative low-output syndrome (hypotension [systolic blood pressure < 90 mm Hg] necessitating inotropic support, intra-aortic balloon pump assistance, or both) after crystalloid cardioplegia. Eight patients in the crystalloid group (40%) and none in the diltiazem group (p < 0.05) had postoperative hypertension (mean arterial pressure >95 mm Hg). Both the highest CK-MB (Table II) and the entire enzyme concentration-time curve (Fig. 2) were significantly lower after diltiazem cardioplegia. Pacemaker dependency. After cross-clamp removal, 18 of 20 patients who received diltiazem had complete heart block and were asystolic, and two patients had spontaneous ventricular fibrillation that reverted to asystole upon defibrillation. All patients remained asystolic during the 30 minutes of reperfusion on bypass and required atrioventricular sequential pacing to discontinue cardiopulmonary bypass. The patients receiving diltiazem remained pacemaker dependent for 82 ± 45 minutes after cross-clamp removal. Two of the 20 patients who received diltiazem required pacing in the intensive care unit, but none required pacing more than 2 hours postoperatively. Eight of the 20 patients who received crystalloid cardioplegia were in sinus rhythm after cross-clamp removal, seven patients required defibrillation and returned to sinus rhythm, and fivepatients

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Fig. 2. The amount of CK-MB released postoperatively was significantly (p < 0.01) less in patients who received diltiazem cardioplegia (by analysis of variance), which suggested less myocardial injury. Differences were significant by least squared means t tests 4 and 8 hours after cross-clamp (XCL) removal.

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had complete heart block that persisted for 15 ± 5 minutes. All patients were in sinus rhythm and none required pacing to discontinue cardiopulmonary bypass. Cardioplegia. Fig. 3 illustrates the aortic root pressures and flows during cardioplegic delivery. The aortic root pressure was 70 mm Hg during the first cardioplegic infusion in both groups but was significantly lower with diltiazem during the second infusion. The rate of cardioplegic administration (coronary flow) was signifi-

Volume 91 Number 5

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Diltiazem cardioplegia

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Fig. 5. Cardiac lactate extraction (LEx). oxygen extraction (O}Ex). and coronary sinus blood flow (CSBF) are depicted at baseline (B) and in response to pacing (P. 110 beats/min) on bypass (ON CPB) 30 minutes after cross-clamp removal, and off bypass (OFF CPB) 60 minutes after cross-clamp removal. On bypass, lactate extraction increased significantly in response to pacing after diltiazem but not crystalloid cardioplegia. Off bypass, lactate extraction tended to decrease with pacing in both groups. Myocardial oxygen extraction was lower at baseline following diltiazem cardioplegia because the hearts were arrested, but oxygen extraction increased in response to pacing on and off bypass in both groups. Coronary sinus blood flow did not change significantly with pacing in either group.

cantly higher with diltiazem cardioplegia during the first and second infusions but increased with crystalloid cardioplegia during the third infusion. The coronary vascular resistance decreased in both groups with each successive cardioplegic infusion, but was significantly lower with diltiazem during the first and third infusions.

The Journal of

6 5 4 Christakis et al.

Thoracic and Cardiovascular Surgery

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Fig. 6. The results from the left ventricular biopsies are depicted at baseline (B) before cardioplegia, at cross-clamp removal (XCL ojj), and after 30 minutes of reperfusion (R) for diltiazem and crystalloid cardioplegia. Tissue concentrations of adenosine triphosphate (ATP) decreased in both groups but were significantly higher after diltiazem cardioplegia (by analysis of variance). Creatine phosphate (CP) levels decreased significantly during the cross-clamp period after crystalloid but not diltiazem cardioplegia. Myocardial lactate concentrations increased significantly (p < 0.05) at cross-clamp release in both groups. Myocardial glycogen levels fell significantly (p < 0.05) at cross-clamp release after crystalloid but not diltiazem cardioplegia.

Myocardial temperatures in the most ischemic regions were similar after diltiazem or crystalloid cardioplegia (Fig. 3). However, myocardial temperatures were significantly warmer in the intermediate ischemic regions after the first and second infusions of the diltiazem cardioplegic solution. Temperatures were also warmer in the least ischemic regions after the first diltiazem infusion. The severity of coronary stenosis was similar in the two groups in all three regions, and more severe coronary stenoses did not explain the warmer temperatures after diltiazem cardioplegia. The mean temperatures after cardioplegia were similar in the right atrium (DILT: 12.80 ± 3.5 0 C; CCP: 12.80 ± 3.2 0 C) and right ventricle (DILT: 15.40 ± 3.9 0 C; CCP: 14.50 ± 4.0 0 C). Myocardial oxygen extraction was significantly greater (p < 0.05) during the first and second infusions of the crystalloid cardioplegic solution as compared to the diltiazem cardioplegic solution. Oxygen consumption during cardioplegia was similar in the two groups because coronary blood flow was higher during diltiazem cardioplegic infusions. Both lactate (L) and glycerol (Gly) were released from the heart (negative extraction, -Ex) during cardioplegia in both grops (DILT: LEx -0.65 ± 0.50 mmol/L, GlyEx -14.9 ± 10.3

mmol/L; CCP: LEx -0.62 ± 0.48 mmol/L, GlyEx -17.5 ± 11.3 mmol/L; difference not significant). Reperfusion. Fig. 4 illustrates the coronary sinus blood flow measurements and the cardiac extractions of oxygen, lactate, and glycerol before and during the first 60 minutes after aortic unclamping. The groups were similar before aortic cross-clamping. Coronary sinus blood flow was elevated 10 minutes after cross-clamp removal following crystalloid but not diltiazem cardioplegia, a reaction suggesting reactive hyperemia. There were no other differences in coronary sinus blood flow. Myocardial oxygen extraction and oxygen consumption were higher after crystalloid cardioplegia on bypass, but not after cardiopulmonary bypass. Myocardial lactate production (negative lactate extraction) was significantly less after diltiazem cardioplegia, and lactate extraction resumed sooner after diltiazem (10 ± 5 minutes) than crystalloid cardioplegia (40 ± 8 minutes, p < 0.05). After cross-clamp release, more glycerol was released from the heart following crystalloid than diltiazem cardioplegia, which suggested that diltiazem reduced myocardial lipolysis. Fig. 5 presents the myocardial extraction of oxygen and lactate and the coronary sinus flow measurements before and during pacing. Coronary sinus blood flow

Volume 91

Diltiazem cardioplegia

Number 5

May, 1986

Table

655

m. Postoperative metabolism Hours pOS10p.

3

4

5

6

24

156 ± 92 148 ± 84

178 ± 88 127 ± 60

216 ± 100 196 ± 110

202 ± 74 220 ± 102

193 ± 76 177 ± 100

7.9 ± 2.9 7.5 ± 1.6

8.1 ± 2.8 8.0 ± 2.0

8.5 ± 1.7 8.5 ± 1.5

7.9 ± 1.3 8.6 ± 1.2

6.8 ± 1.7 7.6±1.4

0.44 ± 0.32 0.50 ± 0.45

0.44 ± 0.26 0.49 ± 0.50

0.44 ± 0.37 0.56 ± 0.32

0.39 ± 0.60 0.40 ± 0.16

0.001 ± 0.26 0.24 ± 0.33*

15.6 ± 8.0* -1.7 ± 18.3

5.0 ± 5.0 9.6 ± 6.4

17.8 ± 23.8 4.6 ± 31.7

11.4 ± 22.1 19.6 ± 22.8

-9.9 ± 22.1 5.8 ± 9.6

CSBF (mljmin)

CCP OILT O,Ex (mljdL)

CCP OILT LEx (mmoljL)

CCP OILT GlyEx (mmoljL) CCP

OILT

Legend: CSBF, Coronary sinus blood flow. Ex, Myocardial extraction. 0" Oxygen. L, Lactate. Gly, Glycerol. "Different from CCP, p < 0.05

was similar in the two groups and did not change significantly in response to pacing, Myocardial oxygen extraction and consumption were significantly lower on bypass after diltiazem cardioplegia because the hearts were asystolic. During pacing (at 110 beats/min) myocardial oxygen extraction and consumption were similar, but myocardial lactate extraction increased after diltiazem but not crystalloid cardioplegia. After bypass, myocardial lactate extraction tended to be higher after diltiazem cardioplegia and tended to decrease with pacing in both groups. The results of the left ventricular biopsies are presented in Fig. 6. Adenosine triphosphate decreased significantly at cross-clamp (X) removal and again after 30 minutes of reperfusion (R) in both groups. Adenosine triphosphate levels were significantly higher after diltiazem cardioplegia. In addition, the percent decrease from baseline was greater after crystalloid cardioplegia (X:DILT = -25%, CCP = -37%; R:DILT = -30%, CCP = -41%, P < 0.05). Creatine phosphate levels decreased significantly after crystalloid but not diltiazem cardioplegia at crossclamp removal. Creatine phosphate levels increased significantly after 30 minutes of reperfusion in the crystalloid group to levels higher than baseline. Myocardial lactate concentrations increased significantly (p < 0.05) during aortic occlusion and decreased significantly (p < 0.05) during reperfusion in both groups. Myocardial glycogen levels decreased significantly (p < 0.05) during aortic occlusion and increased after reperfusion following crystalloid but not diltiazem cardioplegia. Postoperative myocardial metabolism. Table III presents the coronary sinus blood flow measurements

and the cardiac extractions of oxygen, lactate, and glycerol between 3 and 24 hours after cross-clamp removal. Coronary sinus blood flow measurements were similar in the two groups. Myocardial oxygen extraction and consumption were significantly higher postoperatively (Table III) than during the first hour after cross-clamp removal (Fig. 3) in both groups. Myocardiallactate extraction tended to be higher after diltiazem cardioplegia, but the difference was statistically significant only at 24 hours. Myocardial glycerol extraction was higher after crystalloid cardioplegia between 3 and 5 hours postoperatively. Postoperative ventricular function. Hemodynamic measurements obtained in the intensive care unit between 3 and 24 hours postoperatively are illustrated in Fig. 7. Cardiac index and left ventricular stroke work index were significantly higher and pulse and mean arterial pressure were significantly lower after diltiazem cardioplegia (p < 0.05, by analysis of variance). Left atrial pressures were not different between the groups. Mean pulmonary arterial pressures tended to be lower and right ventricular stroke work indices tended to be higher after diltiazem cardioplegia, but the differences did not attain statistical significance. Right atrial pressures were similar in the two groups postoperatively. Nuclear ventriculographic data between 3 and 6 hours postoperatively are depicted in Fig. 8. Left ventricular ejection fractions were similar between 4 and 6 hours postoperatively, but tended to be higher (p = 0.1) after diltiazem cardioplegia at 3 hours when mean arterial pressures were significantly lower (Fig. 7). Left ventricular end-diastolic volume indices were higher after diltiazem cardioplegia. Left ventricular endsystolic volume indices also tended to be higher after

656

The Journalof Thoracic and Cardiovascular Surgery

Christakis et al.

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Fig. 8. Nuclear ventriculographic variables are depicted between 3 and 6 hours after cross-clamp removal (Post XCL). Right (RVEF) and left (LVEF) ventricular ejection fractions tended to be higher 3 hours after cross-clamp removal when the pulmonary and systemic pressures were lower. Right (RVEDVI) and left (LVEDVI) ventricular end-diastolic volume indices tended to be larger following diltiazem cardioplegia, and LVEDVI was significant by an analysis of variance (ANOVA). Right (RVESVI) and left (LVESVI) ventricular end-systolic volume indices were similar in the two groups.

diltiazem cardioplegia, but the difference did not achieve statistical significance. Right ventricular ejection fractions were greater after diltiazem cardioplegia 3 hours postoperatively when mean pulmonary arterial pressures tended to be lower. Right ventricular end-

diastolic and end-systolic volume indices also tended to be higher in diltiazem-treated patients, but the differences were not statistically significant. Fig. 9 illustrates the response to volume loading. Left ventricular end-diastolic volume indices were greater at

Volume 91 Number 5

Diltiazem cardioplegia

May, 1986

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Fig. 9. Right and left ventricular performance as well as the systolic and diastolic pressure-volume relations are depicted 3 hours after diltiazem or crystalloid cardioplegia before (baseline, B) and after volume loading (V) with 250 ml of plasma. Right and left ventricular performance (the relation between right [RVSWI) or left [LVSWI} ventricularstroke work index and right [RVEDVI} ventricular or left [LVEDVI} ventricular end-diastolicvolume index) weresimilar in the two groups. Left ventricular systolic function (the relation betweensystolic bloodpressure [SBP) and left ventricular end-systolic volume index [LVESVlj) was depressed after diltiazem cardioplegia (by analysis of variance, ANOVA). Right ventricular systolic function (the relation between systolic pulmonary artery pressure [SPA) and right ventricular end-systolic volume index [RVESVI}) were similar in the two groups. Left ventricular end-diastolic volume indices were significantly higher at similar left atrial pressures (LAP) after diltiazem cardioplegia, which suggested better preservation of diastoliccompliance. Right ventricular end-diastolic volume indices tended to be higher at similar right atrial pressuresafter diltiazem cardioplegia, but the differences were not statistically significant.

similar left atrial pressures after diltiazem cardioplegia (Fig. 9, right panel), which suggested increased diastolic compliance. Right ventricular volumes tended to be greater at similar right atrial pressures after diltiazem cardioplegia, but the differences were not statistically significant. Systolic blood pressures were significantly lower after diltiazem cardioplegia at similar left ventricular end-systolic volume indices (Fig. 9, middle panel), which suggested depressed systolic function. Right ventricular systolic function (the relation between systolic pulmonary arterial pressure and right ventricular endsystolic volume index) was similar in the two groups. Both left and right ventricular stroke work indices and

left and right ventricular end-diastolic volumes (Fig. 9,

left panel) were higher after diltiazem cardioplegia. Discussion Addition of the calcium antagonist diltiazem to a cold crystalloid potassium cardioplegic solution provided better myocardial protection for elective coronary bypass grafting in this prospective, randomized trial. Ischemic injury (by CK-MB determinations) was reduced and high-energy phosphates were better preserved with diltiazem cardioplegia. The metabolic response to pacing during thge early reperfusion period was improved. Postoperatively, systolic function was

6 5 8 Christakis et al.

depressed after diltiazem cardioplegia, but cardiac index and stroke work index were maintained because of lower blood pressures and higher diastolic ventricular volumes. Cardioplegia. The dose of diltiazem used in crystalloid cardioplegia (I50 ~g/kg) was both safe and effective. Our preliminary dose-response assessment found that lower doses did not improve myocardial metabolic recovery (myocardial lactate production in response to pacing on bypass, Table I). Higher doses produced unacceptably prolonged periods of atrioventricular block (Fig. 1), and atrioventricular pacing was associated with inadequate myocardial metabolic reserve (decreased myocardial lactate extraction with pacing after bypass, Table I). A dose-response relation must be established for each cardiac surgical unit because the dose may vary with the type, volume, and mode of cardioplegic delivery." The optimal dose should provide profound cardioplegic arrest, improve metabolic recovery, produce a short period of electromechanical arrest during reperfusion, and prevent postoperative hypertension and tachycardia without severely depressing ventricular function. We elected to administer diltiazem with the first cardioplegic infusion during cooling (to produce profound cardioplegic arrest and increase the tolerance to ischemia) and with the last cardioplegic infusion during rewarming (to improve reperfusion). Diltiazem was not administered with the second or third cardioplegic infusions when the heart was coldest. Hypothermia produces phase transitions in the myocardial membrane lipoproteins, reduces calcium antagonist binding, and eliminates the beneficial effects of calcium antagonist cardioplegia." Diltiazem induced coronary vasodilation during cardioplegic administration but did not enhance myocardial cooling in patients with coronary artery disease.": 18 Myocardial metabolism. Diltiazem reduced anaerobic glycolysis and lipolysis and preserved adenosine triphosphate and creatine phosphate concentrations during cardioplegic arrest. Diltiazem may have reduced the microfibrillary electrical and resultant mechanical activity seen with potassium cardioplegic arrest." The cardioplegic effect of calcium antagonists may augment the arrest achieved by potassium.t" Diltiazem may have reduced intracellular calcium accumulation during ischemia and reduced adenosine triphosphate hydrolysis by calcium dependent phosphatase enzymes. After aortic unclamping, less lactate and glycerol were washed from the heart in the diltiazem group, and postischemic reactive hyperemia was reduced (Fig. 4). The electromechanical arrest induced by diltiazem dur-

The Journal of Thoracic and Cardiovascular Surgery

ing reperfusion may have facilitated myocardial metabolic recovery, because myocardial oxygen consumption relative to the work performed was significantly greater after diltiazem cardioplegia. In addition, experimental studies have suggested that calcium antagonists limit calcium-mediated uncoupling of mitochondrial oxidative phosphorylation during reperfusion after ischemia. 16,43 Myocardial metabolism in response to pacing was improved on bypass after diltiazem cardioplegia, but not after bypass (Fig. 5), perhaps because the atrioventricular pacing required after diltiazem cardioplegia may have induced anaerobic metabolism." Calcium antagonist cardioplegia preserved high-energy phosphates in some experimental studies 10, 45, 46 but not in others." Differences in experimental design, drug doses, and drug infusion techniques could explain the different results. Ventricular function. The hemodynamic effects of diltiazem cardioplegia persisted for 6 hours postoperatively. Both mean arterial pressure and pulse were lower after diltiazem cardioplegia. After diltiazem cardioplegia, left ventricular enddiastolic volume indices were higher but left atrial pressures were similar, which suggested increased distensibility or enhanced ventricular relaxation. Calcium antagonist cardioplegia has been shown to prevent the fall in diastolic compliance seen after incomplete potassium cardioplegia." Left ventricular ejection fractions were similar in the two groups. After diltiazem cardioplegia, left ventricular afterload was lower and a similar ejection fraction suggested a negative inotropic effect of diltiazem. Systolic blood pressure was lower at similar end-systolic volume indices after diltiazem cardioplegia, which suggested depressed systolic function. Sagawa" suggested that the slope of the systolic pressure-volume relation provided the best estimate of left ventricular inotropic state. We found a decrease in position but not a decrease in slope of this relation, but we were able to assess only a small portion of the systolic pressure-volume curve. If the volume at zero pressure was similar in the two groups, then the difference we found represented a difference in slope. If the volume at zero pressure was greater after diltiazem cardioplegia, then the shift may also represent depressed contractility. Experimental studies have suggested that calcium antagonist cardioplegia depressed ventricular function and prevented the deterioration in ventricular function in response to ischemiay,48 Although diltiazem cardioplegia depressed systolic function, cardiac index and stroke work index were maintained by the lower afterload (mean arterial pres-

Volume 91 Number 5 May, 1986

sure) and greater preload (left ventricular end-diastolic volume index). Calcium antagonist cardioplegia. Diltiazem cardiplegia reduced perioperative ischemic injury, improved myocardial metabolic recovery, produced greater diastolic distensibility, and prevented postoperative tachycardia and hypertension. However, diltiazem depressed systolicfunction and induced atrioventricular block for a variable period after cross-clamp removal. Diltiazem cardioplegia, therefore, offers benefits and risks. Nifedipine cardioplegia produced excellent clinical results, but the effects on myocardial function and metabolism were not assessed.29, 49, 50 Grondin and colleagues" found that diltiazem cardioplegia reduced perioperative CK-MB release and resulted in fewer pyrophosphate defects postoperatively. Diltiazem cardioplegia may be beneficial for patients with normal ventricular function who are at risk of postoperative hypertension, tachycardia, coronary spasm, or ischemia. Diltiazem cardioplegia may not be beneficial for patients with poor ventricular function, and a dose-response relation must be established at each institution because of differences in cardioplegic techniques. We extend our appreciation to Penelope J. Maton, B.Sc., and Yasmin Jivraj, R.T.(N.M.), for nuclear data acquisition and analysis, to Barbara Brown, B.Sc., for biochemical measurements, to Jose Chang and David Levitt for assistance with hemodynamic and clinical data acquisition, and to Ms. Catherine Andrews for preparation of the manuscript. We wish to thank the perfusionists: Ian Ross, c.c.P., Katherine Benedict, c.c.P., Jennifer McDonough, c.c.P., Mark Henderson, c.c.P., and Talara Hill, c.c.P.. We also wish to extend our appreciation to the nurses and physicians of the cardiovascular operating rooms and intensive care unit at the Toronto General Hospital for their assistance and patience with this trial. REFERENCES Fremes SE, Weisel RD, Mickle DAG, Ivanov J, Madonik M, Seawright SJ, Houle S, McLaughlin PR, Baird RJ: Myocardial metabolism and ventricular function following cold potassium cardioplegia. J THORAC CARDIOVASC SURG 89:531-546,1985 2 Fremes SE, Christakis GT, Weisel RD, Mickle DAG, Madonik MM, Ivanov J, Harding R, Seawright SJ, Houle S, McLaughlin PR, Baird RJ: A clinical trial of blood and crystalloid cardioplegia. J THORAC CARDIOVASC SURG 88:726-741, 1984 3 Bomfim Y, Kaijser L, Bendz R, Sylven C, Olin C: Myocardial protection during aortic valve replacement. Comparison between sanguineous and asanguineous cardioplegic solutions. Scand J Thorac Cardiovasc Surg 15:135-139, 1981

Diltiazem cardioplegia 6 5 9

4 Engelman RM, Rousou JH, Lemeshow S: High-volume crystalloid cardioplegia. An improved method of myocardial preservation. J THORAC CARDIOVASC SURG 86:87-96, 1983 5 Phillips HR, Carter JE, Okada RD, Levine FH, Boucher CA, Osbakken M, Lappas D, Buckley M, Pohost GM: Serial changes in left ventricular ejection fraction in the early hours after aortocoronary bypass grafting. Chest 83:28-34, 1983 6 Reduto LA, Lawrie RM, Reid JW, Whissenand HH, Noon GP, Kanon D, DeBakey ME, Miller RR: Sequential postoperative assessment of left ventricular performance with gated cardiac blood pool imaging following aortocoronary bypass surgery. Am Heart J 101:59-66, 1981 7 Lowe JE, Kleinman LH, Reimer KA, Wechsler AR: Effects of cardioplegia produced by calcium flux inhibition. Surg Forum 28:279-280, 1977 8 Magovern GJ, Dixon CM, Burkholder JA: Improved myocardial protection with nifedipine and potassiumbased cardioplegia. J THORAC CARDIOVASC SURG 82:239244, 1981 9 Pinsky WW, Lewis RM, McMillin-Wood JB, Hara H, Hartley CJ, Gillette PC, Entman ML: Myocardial protection from ischemic arrest. Potassium and verapamil cardioplegia. Am J Physiol 9:H326-H335, 1981 10 Lupinetti FM, Hammon JW, Huddleston CB, Boucek RJ, Bender HW: Global ischemia in the immature canine ventricle. Enhanced protective effect of verapamil and potassium. J THORAC CARDIOVASC SURG 87:213-219, 1984 11 Standeven JW, Jellinek M, Menz LJ, Kolata RJ, Barner HB: Cold blood potassium diltiazem cardioplegia. J THORAC CARDIOVASC SURG 87:201-212, 1984 12 Smith SJ, Singh BN, Nisbet HD, Norris RM: Effects of verapamil on infarct size following experimental coronary occlusion. Cardiovasc Res 9:569-571, 1975 13 Henry PO, Shuchleib R, Weiss ES, Hoffman E, Roberts P, Sobel B: Protection of the ischemic myocardium in conscious dogs with nifedipine. Am J Cardiol 37:142-148, 1976 14 Henry PO, Shuchleib R, Clark RE, Perez JE: Effect of nifedipine on myocardial ischemia. Analysis of collateral flow, pulsatile heart, and regional muscle shortening. Am J Cardiol 44:817-825, 1979 15 Nagao T, Matlib MA, Franklin 0, Millard RW, Schwartz A: Effects of diltiazem, a calcium antagonist, on regional myocardial function and mitochondria after brief coronary occlusion. J Mol Cell Cardiol 12:29-43, 1980 16 Boe SL, Dixon CM, Tamara A, Sakert MS, Magovern GJ: The control of myocardial Ca" sequestration with nifedipine cardioplegia. J THORAC CARDIOVASC SURG 84:678-684, 1982 17 Vouhe PR, Helias J, Robert P, Grondin CM: Myocardial protection through cold cardioplegia with potassium or diltiazem. Experimental evidence that diltiazem provides better protection even when coronary flow is impaired by critical stenosis. Circulation 65:1078-1085, 1982

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18 Guyton RA, Dorsey LM, Colgan TK, Hatcher CR: Calcium-channel blockade as an adjunct to heterogenous delivery of cardioplegia. Ann Thorac Surg 35:626-632, 1983 19 Sheehan FH, Epstein SE: Effects of calcium channel blocking agents on reperfusion arrhythmias. Am Heart J 103:973-977, 1982 20 Kopf GS, Riba A, Zito R: Intraoperative use of nifedipine for hemodynamic collapse due to coronary artery spasm following myocardial revascularization. Ann Thorac Surg 34:457-460, 1982 21 Hicks GL, Salley RK, DeWeese JA: Calcium channel blockers. An intraoperative and postoperative trial in women. Ann Thorac Surg 37:319-323, 1984 22 Millard R, Lathrop DA, Grupp G, Ashraf M, Grupp IL, Schwartz A: Differential cardiovascular effects of calcium channel blocking agents. Potential mechanisms. Am J Cardiol 49:499-506, 1981 23 Lathrop DA, Valle-Aguilera JR, Millard RW, Gaum WE, Hannon DW, Francis PD, Nakaya H, Schwartz A: Comparative e1ectrophysiologic and coronary hemodynamic effects of diltiazem, nisoldipine and verapamil on myocardial tissue. Am J Cardiol 49:613-620, 1982 24 Antman EM, Stone PH, Muller JE, Braunwald E: Calcium channel block agents in the treatment of cardiovascular disorders. Part I. Basic and clinical electrophysiologic effects. Ann Intern Med 93:875-885, 1980 25 Low RI, Takeda P, Mason DT, DeMaria AN: The effects of calcium channel blocking agents on cardiovascular function. Am J Cardiol 49:547-553, 1982 26 Sugimoto T, Ishikawa T, Kaseno K, Nakase S: Electrophysiologic effects of diltiazem, a calcium antagonist, in patients with impaired sinus or atrio-ventricular node function. Angiology 31:700-709, 1980 27 Yamamoto F, Manning AS, Braimbridge MV, Hearse DJ: Cardioplegia and slow calcium-channel blockers. Studies with verapamil. J THoRAc CARDIOVASC SURG 86:252-261, 1983 28 Baker JE, Hearse DJ: A comparison of the ability of slow calcium blockers to reduce tissue damage during calcium paradox. J Mol Cell Cardiol 13:Suppl 1:6-11, 1981 29 Clark RE, Christlieb IY, Ferguson TB, Weldon CS, Marbarger JP, Sobel BE, Roberts R, Henry PD, Ludbrook PA, Biello D, Clark BK: Laboratory and initial clinical studies of nifedipine, a calcium antagonist, for improved myocardial preservation. Ann Surg 193:719732,1981 30 Weisel RD, Hoy FBY, Baird RJ, Ivanov J, Hilton JD, Burns RJ, Mickle DAG, Mickleborough LL, Scully HE, Goldman BS, McLaughlin PR: A comparison of alternative cardioplegic techniques. J THORAC CARDIOVASC SURG 86:97-107, 1983 31 Weisel RD, Lipton IH, Lyall RN, Baird RJ: Cardiac metabolism and performance following cold potassium cardioplegia. Circulation 58:Suppl 1:217-226, 1978 32 Ganz W, Tamura K, Marcus HS, Donoso R, Toshida S, Swan HJC: Measurement of coronary sinus blood flow by

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34

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continuous thermodilution in man. Circulation 44:181195,1971 Weisel RD: Techniques of measuring pulmonary function in the critically ill, Acute Respiratory Failure. Etiology and Treatment, HB Hechtman ed., Boca Raton, 1979, CRC Press Inc. Burns RJ, Druck MN, Woodward S, Houle S, McLaughlin PR: Repeatability of estimates of left ventricular volume from blood-pool counts. J Nucl Med 24:775-781, 1983 Burns RJ, Nitkin RS, Weisel RD, Houle S, Prieur TG, McLaughlin PR, Druck MN: Optimized count-based scintigraphic left ventricular volume measurement. Can J Cardiol 1:42-46, 1985 Fremes SE, Weisel RD, Baird RJ, Mickleborough LL, Burns RJ, Teasdale SJ, Ivanov J, Seawright SJ, Madonik MM, Mickle DAG, Scully HE, Goldman BS, Mcl.aughlin PR: The effects of postoperative hypertension and its treatment. J THoRAc CARDIOVASC SURG 86:47-56, 1983 Weisel RD, Burns RJ, Baird RJ, Hilton JD, Ivanov J, Mickle DAG, Teoh KH, Christakis GT, Evans PJ, Scully HE, Goldman BS, McLaughlin PR: Optimal postoperative volume loading. J THORAC CARDIOVASC SURG 86:4756, 1983 Goodnight JH, Sail JP, Sarle WS: The GLM procedure, SAS User's Guide. Statistics, AA Ray, JP Sail, J, Saffer, eds., Cary, N. C., 1982, SAS Institute Inc., pp 139-199 Mirsky I: Myocardial mechanics, Handbook of Physiology, Cardiovascular System, Vol 1, Sec 2, RM Berne, N Sperelakis, SR Geiger, eds., Bethesda, 1979, American Physiological Society, pp 497-531 Christakis GT, Fremes SE, Weisel RD, Ivanov J, Madonik MM, Seawright SJ, McLaughlin PR: Right ventricular dysfunction following cold potassium cardioplegia. J THO· RAC CARDIOVASC SURG 90:243-250, 1985 Sagawa K: The end-systolic pressure-volume relation of the ventricle. definitions, modifications and clinical use. Circulation 63: 1223-1227, 1981 Ferguson TB, Smith PK, Buhrman WC, Lofland CK, Cox JL: Monitoring of the electrical status of the ventricle during cardioplegic arrest. Circulation 66:Suppl 2:152154, 1982 Weishaar R, Ashikawa K, Bing RJ: Effect of diltiazem,a calcium antagonist, on myocardial ischemia. Am J Cardiol 43:1137-1143,1979 Hilton JD, Weisel RD, Baird RJ, Jablonsky G, Pym J, Goldman BS, Scully HE, Ivanov J, Mickle DAG, Feiglin DH, Morch JE, McLaughlin PR: The hemodynamic and metabolic response to pacing following aorto-coronary bypass. Circulation 64:Suppl 2:48-53, 1981 Barner HB, Jellinek M, Standeven JW, Menz LJ, Hahn JW: Cold blood-diltiazem cardioplegia. Ann Thorac Surg 33:55-63, 1982 Balderman SC, Chan AK, Gage AA: Verapamil cardioplegia. Improved myocardial preservation during global ischemia. J THoRAc CARDIOVASC SURG 88:57-66, 1984 Johnson RG, Jacocks MA, Aretz TH, Griffin GA,

Volume 91 Number 5 May, 1986

O'Keefe DO, Deboer LWV, Guyton RA, Fallon JT, Daggett WM: Comparison of myocardial preservation with hypothermic potassium and nifedipine arrest. Circulation 66:Suppl 1:73-80, 1982 48 BollingSF, Schirmer WJ, Gott VL, F1aherty JT, Bulkley BH, Gardner TJ: Enhanced myocardial protection with verapamil prior to postischemic reflow, Surgery 94:283290, 1983 49 Clark RE, Christlieb IY, Ferguson TB, Weldon CS, Marbarger JP, Biello DR, Roberts R, Ludbrook PA,

Diltiazem cardioplegia 6 6 1

Sobel BE: The first American clinical trial of nifedipine in cardioplegia. A report of the first 12 month experience. J THoRAc CARDIOVASC SURG 82:848-859, 1981 50 Clark RE, Magovern GJ, Christlieb IY, Boe S: Nifedipine cardioplegia experience. Results of a 3-year cooperative clinical study. Ann Thorac Surg 36:654-663, 1983 51 Grondin CM, Pomar JL, Vouhe PR, Hebert Y: Cold cardioplegia with diltiazem, a calcium channel blocker, during coronary revascularization [abstr]. J Cardiovasc Surg 24:291, 1983

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