Transmural myocardial flow distribution during hypothermia

J

THORAC CARDIOVASC SURG

86:61-69, 1983

Transmural myocardial flow distribution during hypothermia Effects of coronary inflow restriction Hypothermic coronary perfusion and blood cardioplegia have been used clinically to minimize intraoperative myocardial damage. However, pressure-flow characteristics in regions supplied by inflow-limiting collateral coronary arteries have not been investigated during hypothermic conditions. In this study tracer microspheres determined transmural myocardial blood flow distribution during cardiopulmonary bypass in normothermic empty, beating dog hearts (EBH), during hypothermic sanguineous perfusion at 15 C (HP), and after hemodilution of cooled (15 C) hearts to a hematocrit value of 20 vol% (HDL). Animals in Group I (N = 8) had normal hearts. Group II dogs (N = 9) had one region supplied predominantly by narrow collateral vessels (CR) and another nourished by normal coronary arteries (NR). Retrograde circumflex pressures were measured continuously for Group II as an additional index of CR perfusion. Flow characteristics in Group I hearts were always similar to the NR of Group II dogs. With HP, endocardial blood flow in the NR decreased from approximately 0.80 to 0.50 mlfminfgm. Subsequently,following HDL this flow increased to approximately 1.70 mlfminfgm. or over twice control levels. In comparison, flow to CR endocardium decreased even more during HP (0.12 mlfminfgm]. Even though control flow levels were reestablished in CR endocardium by adding HDL, an unfavorable endocardial/epicardial ratio persisted. With both HP and HDL, retrograde circumflex pressure never changed from EBH values. These data suggest that a significant endocardial flow defect exists during periods of hypothermic sanguineous perfusion and may become more prevalent in regions subserved by inflow-limiting coronary vessels. Similar flow maldistributions may occur in patients if blood-eontaining cardioplegic solutions are used and during systemic hypothermia. Significant hemodilution helps minimize these imbalances and permits salutary effects of hypothermia to be delivered more evenly across the ventricular wall. 0

0

W. Randolph Chitwood, Jr., M.D., Ronald C. Hill, M.D., Leonard H. Kleinman, M.D., and Andrew S. Wechsler, M.D., Durham, N. C.

DesPite a variety of sophisticated protective techniques, intraoperative myocardial damage still develops in many patients. Systemic cooling, topical cardiac hypothermia, pharmacologic Cardioplegia, and hypothermic coronary perfusion all have been employed to improve surgical results by reducing cellular metabolic

From the Department of Surgery, Duke University Medical Center, and the Veterans Administration Hospital, Durham, N. C. Supported in part by National Institutes of Health Grant No. 1-ROI-H I20226-01 and the Medical Research Service of the Veterans Administration. Received for publication June 2, 1982. Accepted for publication Oct. 8, 1982. Address for reprints: W. Randolph Chitwood, Jr., M.D., Box 31214, Department of Surgery, Duke University Medical Center, Durham, N. C. 27710.

demands."? Although pharmacologic arrest decreases metabolic activity by 65% to 80%, adequate ventricular cooling becomes necessary to reduce energy utilization sufficiently for optimal clinical recovery.8,9 Therefore, homogeneous myocardial flow is important to ensure uniform tissue hypothermia. This is especially true in compromised myocardial regions where energy reserves may be attenuated.'? Previous studies from this laboratory have described pressure-flow characteristics in myocardium supplied by inflow restricting collateral coronary vessels under various cardiopulmonary bypass techniques. In those experiments, dependent myocardium was highly susceptible to perfusion imbalances induced by many routine clinical interventions. 11·14 As similar occurrences may develop during hypothermia, this study was designed to evaluate transmural pressure-flow characteristics in nor-

61

The Journal of Thoracic and Cardiovascular Surgery

6 2 Chitwood et al.

MICROSPHERE INJECTION

L.V. VENT

=-+ TO SYSTEMIC

PERFUSION

LY PRESSURE

Fig. 1. Diagrammatic illustration of the experimental cardiopulmonary bypass technique used. A heatexchanging coil delivered hypothermic coronary perfusion, independent of the systemic circulation. The left ventricle (LV) was decompressed to 0 mm Hg by an apical vent. Retrograde pressures in the collateral bed were determined from the Ameroid-occluded circumflex coronary artery.

mal myocardium and in areas supplied by narrowed collateral channels at temperatures employed clinically. Methods Seventeen adult mongrel dogs (18.2 to 26.0 kg) were divided into two groups for experimental studies. In Group I (N = 8) the entire myocardium was supplied by normal coronary arteries. Group II (N = 9) dogs had a region dependent mainly on collateral vessels (CR) and one perfused by normal coronary arteries (NR). Normal coronary arteries (Group I). Animals were anesthetized with pentobarbital (30 mg/kg), intubated, and ventilated with a Harvard mechanical respirator F102 1.00). A median sternotomy was performed, and polyvinyl chloride (16 gauge) catheters were inserted to monitor aortic arch, left ventricular, and femoral arterial pressures on sychronously calibrated Model 1280 Hewlett-Packard pressure transducers. Microsphere reference samples were collected from a left subclavian artery catheter. Anterior wall endocardial and epicardial microthermistors (Yellow Springs Instrument Company, Yellow Springs, Ohio; Model 534) measured trans-

mural ventricular temperatures continuously (± 0.1 C). All physiological data were collected with an Electronics for Medicine eight-channel writing oscillograph and Hewlett-Packard (Model 8805 C) pressure amplifiers. A Harvey bubble oxygenator (HlOOO) was primed with fresh heparinized whole blood, and cardiopulmonary bypass was instituted with a Sarns Model 1900 roller pump. A silicone rubber vent (7 mm outer diameter) was placed through a relatively avascular area in the ventricular apex for decompression. Subsequently, normothermic (37 C) perfusion was stabilized at 80 mm Hg by adjusting systemic flow rates to between 75 and 150 nil/min/kg. Within the first 15 minutes of bypass, the left carotid artery was cannulated separately. Then the aorta was clamped distal to the left subclavian artery, and independent hypothermic arch perfusion was established with a separate flowmetered Cole-Parmer roller pump with an interposed cooling coil (Fig. 1). A plastic systemic carotid shunt maintained cerebral perfusion (60 to 80 mm Hg) throughout each study. During the bypass interval, which ranged from 90 to 120 minutes, perfusate pH was maintained between 0

0

Volume 86 Number 1 July. 1983

Myocardial perfusion during hypothermia

PRE' BYPASS

EMPTY

BEATING HEART

HYPOTHERMIC PERFUSION

HEMOOIWTKfl • HYPQTHERMIC PERFUSMJl

63

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(.... Hg )

RETROGRAO£

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I

(.... Hg)

lEfT VENTRIClJlAR PRESSURE

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(mmHg)

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Fig. 2. Representative intraoperative recording showing aortic, left ventricular, and retrograde circumflex pressure from a Group II dog. Panels from left to right depict data before bypass, during normothermic empty beating conditions (37 ° C, hematocrit 40 vol%), during hypothermic perfusion (15 ° C, hematocrit 40 vol%), after hemodilution (15° C, hematocrit 20 vol%), and after rewarming of this hemodiluted heart to 37° C. Note the significant drop in circumflex pressure between hypothermic and normothermic hemodilution.

7.35 and 7.48. Oxygenator P02 varied between 180 and 325 mm Hg . Vasopressors were never used to alter arterial pressure or pump flow. Collateral coronary arteries (Group II). Four weeks prior to cardiopulmonary bypass studies, healthy dogs were anesthetized and ventilated as described. Under sterile conditions, a small left thoracotomy was performed, and a 2.5 to 2.77 mm (inner diameter) Ameroid constrictor (Three Points Products, Montreal, Quebec, Canada) was placed on the left circumflex coronary artery immediately distal to the left main coronary bifurcation. The chest was closed and each dog recovered fully. Bypass preparations were made exactly as in Group I, except that an 18 gauge catheter was inserted into the circumflex coronary vessel just distal to the occluding Ameroid constrictor. From this cannula retrograde circumflex pressures were determined before and during each bypass intervention. II . 13. i4 A separate thermistor continuously measured epicardial temperatures in the CR . Fig. 2 is a representative tracing from an experiment showing simultaneous coronary perfusion, left ventricular, and retrograde circumflex pressures. At the termination of each experiment, hearts were extirpated, and contrast medium (Renografin) was injected into the circumflex coronary artery at pressures of 150 to 200 mm Hg to confirm Ameroid closure and collateral development. Animals having incomplete Ameroid occlusion or histologic evidence of myocardial infarction were excluded from the study. Myocardial blood flow determinations. Myocardial

blood flow was measured using 8 Il microspheres (3M Company, Minneapolis, Minn.) labeled with 141Ce, 85S r, 46SC, 51C r, or 1251. flow determinations were made by previously described microsphere analysis and injection techniques. II . 13 After being fixed in formalin for 5 days, a central myocardial ring was divided into anterior and posterior papillary sections . In Group II dogs these sections were representative of the NR and CR, respectively. Tissue samples were separated into endocardial, endomyocardial, epimyocardial, and epicardial layers. Subsequently, quantitative myocardial blood flow was determined by using a Beckman Biogamma counter and an IBM 1130 computer program. All data were compared by Student's t test for paired and unpaired data and are expressed as mean ± standard error of the mean (SEM). Data collection. In all 17 dogs, transmural myocardial blood flow was determined for three separate interventions during the cardiopulmonary bypass interval. After 15 minutes of normothermic perfusion (37 0 C and hematocrit 40 vol%), the first or control flow determination was made by injecting 3.5 X 106 suspended microspheres into empty, beating, nonworking hearts (EBH). Thereafter, hypothermic coronary inflow (12 ° to 15° C) lowered the subendocardium to 15° C over approximately 20 minutes, and a second microsphere injection (HP) was made. Subsequently, the perfusate was diluted from 40 to 20 ± I vol% by adding cold electrolyte solution (Normosol-R, pH 7.4) to the oxygenator. After 15 minutes of hemodiluted 15° C perfusion (HDL), the last microsphere injection was

64

The Journal of Thoracic and Cardiovascular Surgery

Chitwood et al.

3.50 .. ---.. Anterior Papi Ilory Region 0----0

300

2 = Epimyocardium 3 =Endomyocardium 4 =Endocardium

E

co

~

Posterior Papillary Region

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~

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~

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(Ep;)l 2 3 4 {Endo) I 2 3 4 EMPTY BEATING HEART-3T'C He! 40 HYPOTHERMIC PERFUSION-15'C He! 40

I

2 3 4 HYPOTHERMIC PERFUSION • HEMOOILUTION-15'C Hct 20

Fig. 3. Normal dogs (Group I): Comparisons of myocardial blood flow to each left ventricular layer are shown during the following bypass interventions (panels left to right): empty beating heart (37° C, hematocrit 40 vol%), hypothermic perfusion (I5° C, hematocrit 40 vol%), and hypothermic perfusion following hemodilution (I5° C, hematocrit 20 vol%). Myocardial layers are represented from epicardium (l) to endocardium (4). In this group both anterior and posterior papillary regions were supplied by normal coronary arteries.

made. For each injection the coronary perfusion pressure was maintained at 80 mm Hg. In all dogs, sufficient time was allowed for NR endocardial and CR epicardial temperature equilibration at 15.0° ± 0.3 ° C before HP and HDL injections were made. NR endocardial cooling to IS° always lagged behind the epicardium by 1 to 3 minutes. Moreover, after NR epicardial temperature had reached 15° C, epicardial temperatures in the CR were 3° to 4° higher. Temperature equilibration eventually occurred.

Results Normal coronary arteries: Group I (N = 8). Sys-

temic blood pressures were 116 ± 2/80 ± 3 mm Hg (mean 92 ± 3) in prebypass anesthetized dogs. Fig. 3 shows collective regional blood flow data for the normal group during each bypass intervention. Throughout normothermic bypass perfusion, EBH hearts maintained a normal endocardial/epicardial flow ratio in both anterior and posterior papillary regions. Also, no statistical difference existed between comparable myocardiallayers in each region. With perfusion cooling to IS° C, epicardial flow increased (0.80 ± 0.15 to 1.44 ± 0.13 ml/rnin/gm) with endocardial perfusion diminish-

ing concomitantly (1.02 ± 0.18 to 0.58 ± 0.15 mI/ min/gm), Thus, even though mean transmural levels were unchanged, endocardial/epicardial flow ratios fell significantly (1.3 ± 0.1 to 0.39 ± 0.08). Fig. 3 shows this flow gradient that developed across the left ventricular wall with profound cooling. When these hypothermic normal hearts were hemodiluted, flow increased markedly to each layer of all myocardial regions. Nearly a twofold epicardial increase and a 4.5-fold endocardial augmentation developed by hemodilution to a level of 20 vol%. At the same time, mean flow was augmented to 3.5 times control levels. Although ventricular endocardial/epicardial ratios approximated control levels during cold HDL, some transmural imbalance persisted.

Collateral coronary vessels: Group II (N

= 9). Ani-

mals excluded from this group included those having histologically proven infarction (N = 3), incomplete Ameroid closure (N = 1), or intraoperative technical problems (N = 2). Before bypass, anesthetized animals had systemic blood pressures of 120 ± 4/83 ± 4 mm Hg (mean 96 ± 4). Regional myocardial blood flow values for dogs having a collateral zone are illustrated in Fig. 4. In EBH

Volume 86

Myocardial perfusion during hypothermia

Number 1 July, 1983

65

350

300

...---. NORMAL REGION o----
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Fig. 4. Dogs with collateral flow (Group II): Comparisons of myocardial blood flow to each left ventricular layer are shown during the following bypass interventions (panels leftto right): empty beating heart (37° C, hematocrit 40 vol%), hypothermic perfusion (15° C, hematocrit 40 vol%), and hypothermic perfusion following hemodilution (15° C, hematocrit 20 vol%). Myocardial layers are represented from epicardium (1) to endocardium (4). In this group the anterior papillary region was nourished by normal coronary vessels and posterior papillary myocardium was supplied by collateral coronary arteries.

preparations, flow distribution to NR of Group II dogs was statistically equal to that of Group I hearts. At the same time, no significant difference existed between individual NR and CR laminae. In comparison, CR epicardial flow levels were not changed by hypothermia, whereas endocardial flow fell much more than in either Group I hearts or NR of Group II dogs. In CR myocardium, flow levels became as low as 0.12 ± 0.03 ml/rnin/gm. This resulted in a significantly lower CR endocardial/epicardial ratio than NR (0.15 ± 0.04 CR and 0.30 ± 0.08 NR), even though mean flow was unaltered (Figs. 5 and 6). As found in normal myocardium, a progressive transmural flow decrement evolved in CRs (Fig. 4). • Hemodiluting the 15° C perfusate augmented flow in all layers of both the NR and CR. However, endocardial and epicardial flow increases were significantly less for CR than NR. Even after HDL, endocardial/epicardial ratios and mean flow values continued to be much lower for CRs (p < 0.02). Fig. 7 shows simultaneous retrograde circumflex pressures measured during each cardiopulmonary bypass intervention. In anesthetized dogs, retrograde

circumflex pressures prior to bypass were 86 ± 6/ 47 ± 4 mm Hg with a simultaneous diastolic gradient across the collateral system of 37 ± 3 mm Hg. During EBH conditions, retrograde circumflex pressures were 64 ± 4/42 ± 3 mm Hg. With both HP (45 ± 3 mm Hg) and HDL (43 ± 4 mm Hg), mean retrograde circumflex pressures remained unchanged from control diastolic values. To test maintenance of coronary vasomotor capabilities after cooling, six hemodiluted Group II hearts were rewarmed to 37° C (Figs. 2 and 7). With normothermic hemodilution, diastolic retrograde circumflex pressures fell to 24 ± 3 mm Hg (p < 0.001), this fall suggesting that larger coronaries, supplied by collaterals, could still autoregulate." Discussion In general, myocardial protective techniques are designed to deter substrate consumption while providing a more physiological cellular milieu during periods of requisite ischemia." Selective coronary perfusion, intermittent ischemic arrest, and topical hypothermia each provide varying degrees of protection, however; cold pharmacologic cardioplegia has been shown clearly to

The Journal of Thoracic and Cardiovascular Surgery

6 6 Chitwood et al.

1.25

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Fig. 5. Endocardial/epicardial flow ratios (EndofBpii are shown for collateral-dependent myocardial regions during the following interventions (left to right): EBH, empty beating heart (37° C, hematocrit 40 vol%); HP, hypothermic perfusion (15° C, hematocrit 40 vol%); and HDL, hypothermic perfusion following hemodilution (15° C, hematocrit 20vol%). The asterisk (*) denotes statistical significance, p < 0.05. Data are mean ± standard error of mean.

Fig. 6. Mean myocardial blood flow values for normal and collateral regions are shown during each bypass intervention (left to right): EBH. empty beating heart (37° C, hematocrit 40 vol%); HP, hypothermic perfusion (15° C, hematocrit 40 vol%); and HDL, hypothermic perfusion following hemodilution (15° C, hematocrit 20 vol%). The asterisk (*) denotes statistical significance, p < 0.05. Data are mean ± standard error of mean.

promote optimal clinical preservation. 3-6.16.17 Recently, Jones and associates'? demonstrated diminished subendocardial adenosine triphosphate and creatine phosphate levels in patients prior to bypass grafting. As these inner ventricular layers are more susceptible to flow imbalances during many cardiopulmonary bypass interventions, this apparent jeopardy is amplified." 18 Therefore, homogeneous myocardial protection remains paramount for ideal recovery of patients following periods of induced global ischemia. Most surgeons have abandoned selective coronary perfusion during coronary grafting and valvular replacement, owing to operative complications and inferior myocardial protection. 19 However, cold sanguineous perfusates are still used commonly during these procedures.2.5.7.2o Hypothermic systemic perfusion (20 0 to 320 C) initiates cardiac cooling before aortic clamping and minimizes warming by noncoronary collateral flow and adjacent tissues during the arrest period. In the last few years, blood-containing cardioplegic solutions have been advocated as offering superior cardiac protection intraoperatively.v" Hypothermia provides a major protective influence during these conditions. Thus delivery

of uniform flow to all myocardial regions remains optimal. Previous studies suggest that significant coronary lesions result in detrimental temperature gradients following cold pharmacologic arrest.>" Presently, little data exist describing transmural flow patterns in compromised regions when hypothermic blood-containing perfusates are used. Even though coronary collaterals in dogs are developmentally superior to those in human beings, Ameroid preparations provide an excellent model of regional inflow restriction." Physiological responses in dependent myocardium appear similar to clinical situations where flow in vasoactive distal vessels may be governed by stenotic coronary arteries.v" Earlier studies show maintenance of balanced transmural ventricular perfusion during resting conditions. However, with elevated energy demands, as part of the postischemic response, or during oxygen deprivation, subservient vesselsdilate and inflow may become insufficient to maintain the distal perfusion pressure, I I. 13, 14,31 This usually results in an unfavorable endocardial/epicardial flow ratio with subsequent deterioration of regional function. In our laboratory these collateral preparations have provided a

67

Myocardial perfusion during hypothermia

~

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NORMAL REGION

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01 ASTOLIC

HP+HDL EBH+HDL 15 20

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Fig. 7. Dogs with collateral flow (Group II): Retrograde circumflex pressures in the collateral region are shown before bypass and for empty beating hearts (EBH), hypothermic perfusion (HP), hypothermic perfusion plus hemodilution (HP + HDL), and normothermic perfusion plus hemodilution (EBH+HDL).

more stable model of fixed coronary supply during cardiopulmonary bypass than have partially occluding snares and clamps. Figs. 3 and 4 illustrate transmural flow patterns that were prevalent in collateral and normal myocardium upon cooling nonhemodiluted blood to 15° C. Temperatures approximating this level of hypothermia have been shown to be maximally protective of high-energy phosphate stores and are used often clinically." Although electrical fibrillation was evident at 15 ° C (Fig. 2), no mechanical activity was obvious. We have shown previously that flow imbalances seen during ventricular fibrillation in CRs at 37° C appear to be normalized by cooling to 32°C. II. 13 In this study, both hypothermic interventions were done during similar contractile conditions, establishing independently the influence of inflow restriction and rheologic properties on myocardial flow distribution. In normal epicardial layers of both groups, flow became augmented with progressive cooling. Previous studies suggest that impaired autoregulation develops in larger coronary arteries under hypothermic conditions, with significant flowaugmentation occurring despite decreased metabol-

EBH

HP

HDL

EBH

HP

HDL

Fig. 8. Mean flow resistance is shown for epicardial and endocardial layers of both normal and collateral regions in Group II dogs. Resistance was calculated from pressuremicrosphere flow data under these conditions: empty beating normothermic hearts (EBH), hypothermic perfusion at 15° C (HP), and after hemodilution at 15° C (HDL). Asterisk (*) denotes statistical significance, p < om.

ic demands.''-" Conversely, in these dogs a simultaneous 40% to 50% endocardial flow decrement developed. Underperfusion of deeper layers may have resulted from epicardial coronary dilation at 15 ° C resulting in a lower endocardial coronary driving pressure. Moreover, blood viscosity increases significantly on cooling to these levels.P" Thus the effective transmural perfusion pressure may decrease even more with development of these unphysiological rheologic properties." 37 Cooling failed to enhance epicardial flow distal to narrow collaterals, in contrast to normal myocardium. In this restricted region a much greater endocardial defect developed at these temperatures, with flow levels decreasing to approximately 0.12 mljminjgm. Thus, at 15° C, blood flow was merely 20% of control levels without hemodilution. Abnormal perfusion characteristics, already present at these myocardial depths, may be potentiated by the added length of collateral vessels and decreased regional coronary pressure (i.e., 45 ± 3 mm Hg). Viscosity effects of hypothermia have been shown to be more pronounced at lower perfusion pressures." It is probable that a combination of these factors is responsible for the exaggerated flow deficit present in collateral endocardium during hypothermia. Hemodilution brought about a notable flow increase

The Journal of Thoracic and Cardiovascular Surgery

6 8 Chitwood et al.

in all myocardial regions studied. However, in collateral zones this increase was significantly less than in normal tissues, and a lower endocardialjepicardial flow ratio persisted, even at a hematocrit value of 20 vol%. Fig. 8 illustrates calculated resistance values for epicardial and endocardial layers during each intervention. With hemodilution, flow did increase in collateral myocardium; however, endocardial resistance remained significantly higher at 15° C. Therefore, even though during cooling hemodilution affords improved flow characteristics in all regions, unfavorable impedence to flow may persist, eventuating in detrimental transmural and regional cooling gradients shown in this study. During clinical situations, these changes may become manifest when hypothermic systemic perfusion and blood cardioplegia are used. Most surgeons using bloodcontaining cardioplegic solutions have maintained hematocrit levels between 15 and 30 vol%. However, temperatures as low as 6° C are being used intraoperatively under these conditions. O'Neill and associates" recently showed that hemodiluted blood-containing infusion solutions exhibits significantly higher flow resistances when compared with crystalloid cardioplegic solutions. It is very difficult to assess pressure-flow characteristics in similar human situations. However, those data suggest that if perfusion pressures are not sufficient to ensure adequate distribution of sanguineous coolants across stenotic lesions,poor myocardial protection may result. Detailed attention is necessary to minimize unphysiological transmural temperature gradients that may be even greater in compromised myocardium. No doubt multiple thermistors measuring endocardial temperatures distal to coronary stenoses would be advantageous; however, such measurements become difficult to obtain in the operating room. In summary, these studies suggest that abnormal transmural flow imbalances may develop during hypothermia when blood perfusates are used. These abnormalities are exaggerated in regions supplied by inflowrestricting vessels with development of a marked subendocardial perfusion defect. Such gradients are only partially obliterated with significant hemodilution. It is likely that these flow imbalances evolve from unfavorable rheologic properties compounded with a decreased regional perfusion pressure, present during inflow compromise. Ineffective cooling of deeper myocardial layers may result from these changes. This is important clinically, as similar flow maldistributions may occur during systemic hypothermia and with blood cardioplegia. Significant hemodilution, meticulous myocardial temperature monitoring, and an adequate infusion pressure may minimize these effects and help provide

optimal protection during coronary grafting and valvular replacement procedures. We wish to express our appreciation to the following persons: Mrs. Margaret Garrison and Mrs. Ruby Griffin for secretarial assistance; Mr. Ed Ristanio, Mr. Gary PelIom, Mr. James E. Toney, and Mr. Ernest Hill for their technical support; Mr. Donald G. Powell and Medical Media Productions (Durham Veterans Administration Hospital) for their creative illustrations. REFERENCES

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Kirklin JW, Conti VR, Blackstone EH: Prevention of myocardial damage during cardiac operation. N Engl J Med 301:135-141,1979 Landymore RW, Tice 0, Trehan N, Spencer F: Importance of topical hypothermia to ensure uniform myocardial cooling during coronary artery bypass. J THORAC CARDIOVASC SURG 82:832-836,' 1981 Stiles QR, Hughes RK, Lindesmith GG: The effectiveness of topical cardiac hypothermia. J THORAC CARDIOVASC SURG 73: 176-180, 1977 Macmanus Q, Grunkemeier G, Lambert L, Dietl C, Starr A: Aortic valve replacement and aorta-coronary bypass surgery. Results with perfusion of proximal and distal coronary arteries. J THORAC CARDIOVASC SURG 75:865869, 1978 Conti VR, Bertranou EG, Blackstone EH, Kirklin JW, Digerness SB: Cold cardioplegia versus hypothermia for myocardial protection. Randomized clinical study. J THORAC CARDIOVASC SURG 76:577-589, 1978 Adappa MG, Jacobson LB, Hetzer R, Hill JD, Kamm B, Kerth W J: Cold hyperkalemic cardiac arrest versus intermittent aortic cross-clamping and topical hypothermia for coronary bypass surgery. J THORAC CARDIOVASC SURG 75:171-178, 1978 Craver JM, Sams AB, Hatcher CR: Potassium-induced cardioplegia. Additive protection against ischemic myocardial injury during coronary revascularization. J THORAC CARDIOVASC SURG 76:24-27, 1978 Chitwood WR, Sink JD, Hill RC, Wechsler AS, Sabiston DC: The effects of hypothermia on myocardial oxygen consumption and transmural coronary blood flow in the potassium-arrested heart. Ann Surg 190: 106-116, 1979 Buckberg GO, Brazier JR, Nelson RL, Goldstein SM, McConnell DH, Cooper N: Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. I. The adequately perfused beating, fibrillating, and arrested heart. J THORAC CARDIOVASC SURG 73:87-94, 1977 Jones RN, Peyton RB, Sabina RL, Swain JL, Holmes EW, Spray TL, Van Trigt PV, Wechsler AS: Transmural gradient in high-energy phosphate content in patients with coronary artery disease. Ann Thorac Surg 32:546-553, 1981 Kleinman LH, Wechsler AS: Pressure-flow characteristics of coronary collateral circulation during cardiopulmonary

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bypass. Effects of ventricular fibrillation. Circulation 58:233-239, 1978 12 Sink JD, Hill RC, Chitwood WR, Abriss R, Wechsler AS: Effects of phenylephrine on transmural distribution of myocardial blood flow in regions supplied by normal and collateral arteries during cardiopulmonary bypass. J THORAC CARDIOVASC SURG 78:236-243, 1979 13 Chitwood WR, Hill RC, Kleinman LH, Wechsler AS: The effects of intermittent ischemic arrest on the perfusion of myocardium supplied by collateral arteries. Ann Thorac Surg 26:535-547, 1978 14 Kleinman LH, Yarbrough JW, Symmonds JB, Wechsler AS: Pressure-flow characteristics of the coronary collateral circulation during cardiopulmonary bypass. Effects of hemodilution. J THORAC CARDJOVASC SURG 75:17-27, 1978 15 Hearse OJ, Braimbridge MV, Jynge P: Protection of the ischemic myocardium, Cardioplegia, New York, 1981, Raven Press, pp 151-163 16 Chitwood WR Jr, Hill RC, Sink JD, Wechsler AS: Diastolic ventricular properties in patients during coronary revascularization. Intermittent ischemic arrest versus cardioplegia. J THORAC CARDJOVASC SURG 85:595-605, 1983 17 Phillips SJ, Zeff RH, Kongtahwom C, Iannone LA, Brown TM, Gordon OF: Anoxic hypothermic cardioplegia compared to intermittent anoxic fibrillatory cardiac arrest. Ann Surg 190:80-83, 1979 18 Braimbridge MV, Chayen J, Bitensky L, Hearse OJ, Jynge P, Cankovic-Darracott S: Cold cardioplegia or continuous coronary perfusion? J THORAC CARDIOVASC SURG 74:900-906, 1977 19 Cunningham IN Jr, Adams PX, Knopp EA, Baumann FG, Snively SL, Gross RI, Nathan 1M, Spencer FC: Preservation of ATP, ultrastructure, and ventricular function after aortic cross-clamping and reperfusion. Clinical use of blood potassium cardioplegia. J THORAC CARDlOVASC SURG 78:708-720, 1979 20 Follette OM, Mulder DG, Maloney JV, Buckberg GO: Advantages of blood cardioplegia over continuous coronary perfusion or intermittent ischemia. Experimental and clinical study. J THORAC CARDJOVASC SURG 76:604-619, 1978 21 Barner HB, Kaiser GC, Codd JE, Tyras DH, Pennington DG, Laks H, Willman VL: Clinical experience with cold blood as the vehicle for hypothermic potassium cardioplegia. Ann Thorac Surg 29:224-227, 1980 22 Shapira N, Kirsh M, Jochim K, Behrendt OM: Compar• ison of the effect of blood cardioplegia to crystalloid cardioplegia on myocardial contractility in man. J THORAC CARDIOVASC SURG 80:647-655, 1980 23 Engelman RM, Rousou JH, Lemeshow S, Dobbs WA: The metabolic consequences of blood and crystalloid cardioplegia. Circulation 64:Suppl 2:67-74, 1981

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