Controlled initial hyperkalemic reperfusion after cardiac transplantation: Coronary vascular resistance and blood flow

Controlled Initial Hyperkalemic Reperfusion After Cardiac Transplantation: Coronary Vascular Resistance and Blood Flow James K. Kirklin, MD, Jose Neves, MD, David C. Naftel, PhD, Stanley B. Digerness, PhD, John W. Kirklin, MD, and Eugene H. Blackstone, MD Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama

The coronary vascular response to controlled initial hyperkalemic reperfusion after global ischemia during cardiac transplantation was studied in 11 patients. The mean global ischemic time was 206 minutes (range, 143 to 245 minutes). All donor hearts received initial hyperkalemic crystalloid cardioplegia and subsequent oxygenated crystalloid cardioplegia during implantation. Coronary blood flow was highest during the first one to two minutes of controlled reperfusion but remained normal throughout the first ten minutes of reperfusion. Coronary

vascular resistance was less than normal throughout the first ten minutes of controlled reperfusion, but there was a gradual increase throughout this period. Systemic vascular resistance remained within normal limits. The time to effective contraction was highly variable, but a greater potassium load during initial reperfusion was generally associated with a longer time to effective contraction.

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tributed to more reproducibly good cardiac function immediately after transplantation. The present study was undertaken to examine coronary vascular resistance and flow during the initial phase of controlled aortic root reperfusion after prolonged ischemia in cardiac transplantation and to provide a comparison with similar observations of the coronary vascular response to controlled reperfusion after coronary bypass grafting [12]. Such comparisons may provide insights into potential mechanisms of coronary reactivity after global myocardial ischemia.

s reported by the International Registry of Cardiac Transplantation, the current mortality during the first month after cardiac transplantation is approximately 10% [l],and the major cause for this mortality is acute cardiac failure after transplantation. Although many factors, such as donor management [2, 31 and alterations in recipient pulmonary vascular resistance [4], contribute to cardiac function immediately after transplantation, the major determinant of acute cardiac performance is likely the effectiveness of myocardial preservation during the three to five hours of global ischemia required for transport and reimplantation. Emery and colleagues [5] demonstrated a progressive decrease in intermediate-term survival as the ischemic time (approximated by procurement distance) increased. Profound myocardial hypothermia and cold cardioplegia have been the main components of myocardial protection during cardiac transplantation. With these techniques, ischemic periods up to approximately five hours are generally considered safe. Experimentally and in clinical cardiac surgical studies, an initial period of reperfusion with hyperkalemicinduced asystole has been shown to provide a further increment of myocardial protection, allowing repletion of adenosine triphosphate [6-111. The routine use of controlled hyperkalemic reperfusion in cardiac operations has been employed at our institution since 1986. These techniques were then applied to patients undergoing cardiac transplantation, and we believe this technique has conAccepted for publication Nov 7, 1989 Address reprint requests to Lh James K. Kirklin, Department of Surgery, University of Alabama at Birmingham, UAB Station, Birmingham, AL 35294. 0 1990 by The Society of Thoracic Surgeons

(Ann Thorac Surg 1990;49:625-31)

Material and Methods Donor Hearts and Implantation Eleven consecutive patients undergoing primary orthotopic cardiac transplantation were formally studied. During procurement, all donor hearts received 1 L of cold (4°C) crystalloid cardioplegic solution (20 mmol KCK) and were immersed in cold saline solution in a plastiebag surrounded by ice slush. This maintained the myocardial septa1 temperature at 5" to 10°C during transport. At the time of implantation, the distal aorta was stapled shut, and a cardioplegic needle was inserted. Cold (4"C), oxygenated, crystalloid cardioplegic solution (30 mmol KCK) was infused initially; the infusion was repeated after 30 minutes during cardiopulmonary bypass at a systemic perfusate temperature of 25°C. Topical cooling with cold saline solution was also employed. The period of global myocardial ischemia ranged from 143 to 245 minutes (mean, 206 minutes). Controlled aortic root reperfusion was initiated with warm blood (37°C) from the oxygenator, and the initial 0003-4975/90/$3.50

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the aortic root was generated by cardiac systole, coronary blood flow exceeded the aortic root flow by an unknown amount. The roller pump used to generate the controlled aortic root reperfusion flow was adjusted to be just occlusive. It was calibrated volumetrically after each operation, and a regression equation was created to convert revolutions per minute (read from a pump tachometer at closely spaced intervals during reperfusion) to flow rate in milliliters per minute. Calibrations on different days were in close agreement. Approximately 15 minutes before the beginning of controlled reperfusion, the desired volume of blood was removed from the oxygenator reservoir to a cardioplegia reservoir (CPS-2000; Gish Biomedical Inc, Santa Ana, CA) and warmed to 37°C with a heating coil. The potassium concentration in this blood was approximately 4 mmoVL. Fifteen mmoYL of potassium chloride was added, and the blood was recirculated. Coronary vascular resistance was calculated by dividing the aortic root pressure by the controlled aortic root reperfusion flow rate, expressed in millimeters of mercury per milliliter per minute. The coronary sinus and right atrial pressures were zero, using separate caval cannulation with loosened tourniquets to ensure a collapsed right atrium. The coronary vascular resistance and coronary blood flow were also normalized to estimated heart weight. As all of the implanted hearts were normal in size, the heart weight was estimated to be 310 grams. As a reference for normal coronary blood flow and resistance, the values for the beating heart of resting humans were used [13, 141. Systemic blood flow was identical to arterial pumpoxygenator output during the period of controlled aortic root reperfusion. Arterial blood pressure was measured through a catheter placed in the radial artery and connected to a strain-gauge manometer. Systemic vascular resistance was calculated in the same manner as coronary vascular resistance.

Table 1 . Potassium Load of lnitial Hyperkalemic Reperfusate Volume ImL)

1,000 500 250

Ann Thorac Surg 1990;49:62531

KIRKLIN ET AL CONTROLLED REPERFUSION AFTER CARDIAC TRANSPLANTATION

Potassium Concentration

Potassium Load

(mmoYL)

(mmol)

Patients

19 19 19

19 9.5

6 4 1

No. of

4.75

phase was hyperkalemic (one to four minutes). The hyperkalemic solution was generated by drawing up blood from the oxygenator (containing approximately 4 mmoYL) and adding 15 mmoVL of potassium chloride. The total volume of hyperkalemic solution infused ranged from 250 to 1,000 mL (Table 1).This was followed by normokalemic blood (without interruption) from the pump oxygenator infused through the cardioplegic needle into the isolated aortic root with the cross-clamp still in place. The rate of flow of the controlled aortic root reperfusion was regulated so that the aortic root pressure (continuously measured) was maintained at about 60 mm Hg (Fig 1).The aortic cross-clamp was left in place until the heart was beating vigorously with ejection into the aortic root. The distal, aortic cross-clamp was gradually removed when the systolic aortic root pressure exceeded about 100 mm Hg. The left ventricle either remained collapsed (left atrial pressure less than 6 mm Hg) or was vented with a large-bore needle (13 gauge) across the interventricular septum.

Measurements and Calculations The coronary blood flow rate was equal to the controlled aortic root reperfusion flow rate as long as the heart was asystolic, because the aorta remained cross-clamped beyond the aortic root catheter and the aortic valve was competent in each of these patients. Hemodynamic data are presented only in the interval before cardiac contraction occurred, because when a systolic pressure pulse in

Fig 1 . Mean arterial pressure in aortic root during controlled reperfusion. The circles represent the median values at each minute; the upper broken line, the 75th percentile, and the lower broken line, the 25th percentile. Time zero on the horizontal axis represents the start of controlled aortic root reperfusion.

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KIRKLIN ET AL CONTROLLED REPERFUSION AFTER CARDIAC TRANSPLANTATION

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Fig 2. (A) Coronary blood pow during controlled initially hyperkalemic repetfusion (the depiction is as in Figure 1) and ( B ) coronary blood flow normalized to estimated heart weight. The term normal values indicates those for the beating heart in resting humans 113, 141.

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Results

Coronary Blood Flow There was a gradual decrease in coronary blood flow during the first ten minutes of reperfusion (Fig 2A), but these differences were likely due to chance (Table 2). When coronary flow was normalized to heart size, the values during initial controlled reperfusion were very similar to the normal values in the beating heart of resting humans (Fig 2B).

Coronary Vascular Resis tame Coronary vascular resistance increased slightly during the first ten minutes of reperfusion (Fig 3A), but the difference in resistance at one and ten minutes was likely due to chance (Table 2). Coronary vascular resistance remained at or below normal levels for the beating heart during the period of controlled asystolic reperfusion (Fig 3B).

Systemic Arterial Pressure and Resistance With a mean systemic flow rate of 2.0 L/min/m2(Table 2), the mean systemic arterial pressure was approximately 60

mm Hg throughout most of the period of reperfusion (Fig 4). Systemic vascular resistance remained close to normal values during controlled aortic root reperfusion (Fig 5).

lnterval Until Beating There was considerable variability in the time of first electrical activity, with the period of asystole ranging from 2.5 to 26 minutes. The time of first beating and the time of first effective cardiac contraction (with ejection into the aortic root) were also variable; the longest interval until effective cardiac contraction was 45.5 minutes (Table 3). The time until effective contraction was directly related to the total potassium dose during controlled reperfusion, a greater potassium load resulting in longer delay until effective contraction (Table 4).

Comment

Controlled Reperfusion Numerous experimental studies [Sll,15171 support the benefits of a period of initial controlled hyperkalemic asystolic reperfusion after global ischemia. Although no

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KIRKLIN ET AL CONTROLLED REPERFUSION AFTER CARDIAC TRANSPLANTATION

Ann Thorac Surg 1990;49625-31

Table 2. Hemodynamic Variables During Reperfusion Time After Starting Reperfusion (min) 1.0

5.0

Variable

n

Mean

Coronary flow (mL * min-l) Coronary flow (mL min-' 100 g-') Coronary resistance (mm Hg * mL-' * min * 100 g) Aortic root pressure (mm Hg) Systemic flow (L min-' m-') Systemic resistance (mm Hg * L-' * min * m2)

11 11

-

-

a

n

Mean

f SE

310 -+ 25 101 f 7.9

10 10

290 95

12.5

8

0.59 2 0.099

10

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57 f 4.5 1.97 f 0.046

10 10

9

34

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f

SE

10.0

3.6

P

n

Mean

10 10

260 f 55 86 -+ 17.6

0.4 0.4

0.77 f 0.076

10

1.1 2 0.24

0.15

66 f 3.6 2.00 -+ 0.056

10 10

63 2.07

10

30

10

30

f 39 f

f

3.0

f SE

Value"

f 4.8 ?

0.099

0.4 0.25

f

3.5

0.4

p value comparing 1.0 and 10.0 minute values (paired t test)

SE = standard error.

Fig 3. (A) Coronary vascular resistance during controlled aortic root reperfusion and ( B ) Coron a y vascular resistance normalized to estimated heart weight. The depiction and definition of norma1 values is as in Figure 2.

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KIFXLIN ET AL CONTROLLED REPERFUSION AFTER CARDIAC TRANSPLANTATION

Ann Thorac Surg 1990;4962531

Fig 4 . Systemic arterial pressure during controlled aortic root reperfusion. The depiction is as in Figure

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specific studies have addressed this issue in cardiac transplantation, the obligatory long ischemic periods that are often necessary underscore the potential importance of any methodology that would minimize ischemic and reperfusion injury. It is noteworthy that the average 30-day mortality after cardiac transplantation (as reported by the International Cardiac Transplant Registry) is approximately 10% [l],and the majority of these deaths are related to acute cardiac failure. In our own institution, the small but important incidence of immediate posttransplantation acute cardiac dysfunction (often isolated left ventricular failure) during the first 4 years of our experience led to the evolution of our current methodology for myocardial protection during transplantation (which includes initial cardioplegic arrest during procurement, hypothermic storage for transport at 5" to 8"C, reinfusion of two additional doses of oxygenated crystalloid or blood cardioplegia during implantation, topical cooling with cold saline solution or ice slush, and controlled aortic root reperfusion).

Coronary Blood Flow and Resistance The low coronary vascular resistance (compared with the normal beating heart) during controlled reperfusion and the higher coronary blood flow early during reperfusion suggest an initial reactive hyperemic response after extended global ischemia [181. The dynamics of coronary blood flow and resistance during initial reperfusion in this study differed considerably from the findings of our previous study of controlled reperfusion after coronary operations [12], in which coronary vascular resistance progressively increased (Fig 6) and coronary blood flow progressively fell during the first ten minutes of controlled reperfusion. Although the exact reasons for these differences between the transplanted normal heart and the heart with extensive atherosclerosis undergoing coronary revascularization are unknown, several possibilities exist. The endothelium of severely atherosclerotic coronary arteries is very abnormal and frequently absent, and the response to endothelial-

630

Ann Thorac Surg 1990;49:625-31

IURKLINETAL CONTROLLED REPERFUSION ARER CARDIAC TRANSPLANTATION

Table 4 . Potassium Load of lnitial Hyperkalemic Reperfusate

Table 3 . Onset of Cardiac Activity During Reperfusion Time From Beginning of Reperfusion (min) Event

n Mean

Time of transfer hyper K+ to norm0 K+ Time of first electrical activity Time of first beating (pacing) Time of first effective Contraction" Time of first cross-clamp removalb

11 2.5

f 0.43

1.0

6.0

11

f 2.6

2.5

26.0

9

?

SE Minimum Maximum

10

16

f 2.8

5.0

27.5

11

26 -+ 4.3

5.5

45.5

11

28

10.5

49.5

?

3.7

(mmo1)a

n

Mean? SE

Minimum

Maximum

4.75 9.5 19

1 4 6

13.5 24 f 9.1 30 f 5.2

13.5 5.5 12.0

13.5 45.5 45.5

a Total amount of additional potassium added to normokalemic oxygenator blood plus an assumed concentration in oxygenator blood of 4 mmol/L to produce the hyperkalemic reperfusate.

SE = standard error.

an increased level of coronary resistance during early reperfusion as compared with the nonhypertrophied transplanted heart.

In 3 patients, the Effective contraction = contraction with ejection. cross-damp was removed before there was effective beating.

a

SE = standard error.

Interval Until Beating Considerable experimental evidence suggests that a period of electrical-mechanical quiescence during initial reperfusion is advantageous to myocardial recovery after a period of global ischemia [6, 8, 91. Rapid replenishment of adenosine triphosphate for membrane stabilization and recovery of reversibly injured myocytes is likely aided by three to five minutes of asystolic reperfusion, but prolonged periods of quiescence during reperfusion only prolong the duration of cardiopulmonary bypass without apparent additional benefit. In this study, the time until first electrical activity ranged from 2.5 to 26 minutes with time to first effective contraction as long as 45 minutes, which is clearly excessive. This was associated with a mean cardiopulmonary bypass time of 143 minutes in these 11 study patients compared with 91 minutes for 63 consecutive patients undergoing primary or secondary cardiac transplantation between 1981 and July 1985. The direct relationship between the period of quiescence and the total potassium load during initial reperfusion suggests that a smaller total potassium load during reperfusion would provide a more

dependent relaxation factors such as acetylcholine differs markedly from normal. Werns and colleagues [19] have demonstrated a vasoconstrictive response to acetylcholine in atherosclerotic human coronary arteries, whereas normal human coronary arteries exhibit vasodilation with acetylcholine. In normal canine coronary arteries with intact endothelium (presumably the case immediately after cardiac transplantation), the administration of endothelial-dependent relaxation factors such as acetylcholine and platelet-derived adenosine diphosphate and serotonine induces vasodilation and a decrease in coronary vascular resistance [20]. Thus, the diffusely abnormal endothelium in atherosclerotic coronary arteries may contribute to the increased coronary vascular resistance during early reperfusion. The denervated transplanted heart, with its loss of sympathetic innervation, may also have less vasoconstrictive tendency than the normal innervated heart. Finally, the variable degree of hypertrophy in the atherosclerotic heart undergoing revascularization [121 may contribute to Fig 6 . Comparison of coronary vascular resistance during controlled aortic root reperfusion in patients undergoing coronary artery bypass grafting (previous published data 1121) and cardiac transplantation (p = 0.001). The depiction and definition of normal values are as in Figure 2 .

Time Until Effective Beating (min)

Potassium Load

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Ann Thorac Surg 1990;4962531

KIRKLIN ET AL CONTROLLED REPERFUSION AFTER CARDIAC TRANSPLANTATION

desirable period of quiescence (perhaps two to six minutes) and reduce the duration of cardiopulmonary bypass.

Clinical Implications The early (30-day) mortality reported in the International Registry of Heart Transplantation [l] as well as in our own institution between 1981 and 1985 was approximately 10%; it was largely related to acute cardiac failure immediately or early after transplantation. A major part of this mortality likely relates to inadequate preservation of the transplanted heart. Since January 1987, we have experienced only one instance (1.7%) of acute donor failure resulting in death or early retransplantation owing to acute donor dysfunction, related at least in part to the added protocols of multidose cardioplegia during implantation and to controlled reperfusion. Our current protocol employs 250 mL of blood reperfusion containing 19 mmoYL of KCL with a total potassium load of 4.75 mmol. Despite this reduced potassium load, the duration of quiescence is more variable than that in routine coronary bypass operations.

References 1. Fragomeni LS, Kaye MI'. The Registry of the International Society for Heart Transplantation: Fifth Official Report1988. J Heart Transplant 1988;7249-53. 2. Wheeldon DR, Wallwork J, Bethune DW, English TAH. Storage and transport of heart and heart-lung donor organs with inflatable cushions and eutectoid cooling. J Heart Transplant 1988;7265-8. 3. Novitzky D, Human PA, Cooper DKC. Effect of triiodothyronine (T3) on myocardial high energy phosphates and lactate after ischemia and cardiopulmonary bypass. J Thorac Cardiovasc Surg 1988;96:600-7. 4. Kirklin JK, Naftel DC, Kirklin JW, Blackstone EH, WhiteWilliams C, Bourge RC. Pulmonary vascular resistance and the risk of heart transplantation. J Heart Transplant 1988; 7331-6. 5. Emery RW, Cork RC, Levinson MM, et al. The cardiac donor: a six-year experience. Ann Thorac Surg 1986;41:356-62. 6. Danforth WH, Naegle S, Bing RJ. Effect of ischemia and reoxygenation on glycotic reactions and adenosine triphosphate in heart muscle. Circ Res 1960;8:965. 7. Digemess SB, Tracy WG, Andrews NF, et al. Reversal of myocardial ischemic contracture and the relationship to func-

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tional recovery and tissue calcium. Circulation 1983;68(SuppI 2):34. 8. Follette DM, Steed DL, Foglia RP, et al. Reduction of postischemic myocardial damage by maintaining arrest during initial reperfusion. Surg Forum 1977;28:2813. 9. Follette DM, Fey KH, Steed DL, et al. Reducing reperfusion injury with hypocalcemic, hyperkalemic, akalotic blood during reoxygenation. Surg Forum 1978;29:2844. 10. Lazar HL, Buckberg GD, Manganaro A, et al. Reversal of ischemic damage with secondary blood cardioplegia. J Thorac Cardiovasc Surg 1979;78:688-97. 11. Teoh KH, Christakis GT, Weisel RD, et al. Accelerated myocardial metabolic recovery with terminal warm blood cardioplegia. J Thorac Cardiovasc Surg 1986;91:888-95. 12. Digerness SB, Kirklin JW, Naftel DC, Blackstone EH, Kirklin JK, Samuelson PN. Coronary and systemic vascular resistance during reperfusion after global myocardial ischemia. Ann Thorac Surg 1988;46:447-54. 13. Bard P. Medical physiology. 11th ed. St. Louis: Mosby, 1961:240. 14. Beme RM, Rubio R. Coronary circulation. In: Handbook of physiology: section 2, the cardiovascular system. Vol. 1: The Heart. Bethesda, MD; American Physiological Society, 1979; 873-952. 15. Follette DM, Fey K, Mulder DG, et al. Prolonged safe aortic clamping by combining membrane stabilization, multidose cardioplegia, and appropriate pH reperfusion. J Thorac Cardiovasc Surg 1977;84:682-94. 16. Kirklin JK, Shimazaki Y, Digerness SB, Kirklin JW. Emergent surgical revascularization following acute myocardial infarction: experimental and clinical considerations. In: Walter PJ, ed. Advances in cardiology: treatment of end-stage coronary artery disease. Basel: Karger, 1988;36:202-12. 17. Todd EP, Koster JK, Utley JR, et al. The effect of coronary perfusion pressure on recovery of myocardial function following normothermic ischemia. J Surg Res 1977;22667-70. 18. Engleman RM, Chandra R, Baumann FG, Goldman RA. Myocardial reperfusion: a cause of ischemic injury during cardiopulmonary bypass. Surgery 1976;80:266-76. 19. Werns SW, Walton JA, Hsia HH, Nabel EG, Sanz ML, Pitt B. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation 1989;79:287-91. 20. Houston DS, Shepherd JT, Vanhoutte PM. Aggregating human platelets cause direct contraction and endotheliumdependent relaxation of isolated canine coronary arteries. J Clin Invest 1986;78:539-44.