Overdose reperfusion of blood cardioplegic solution

J

THORAC CARDIOVASC SURG

1991;101:275-83

Overdose reperfusion of blood cardioplegic solution A preventable cause ofpostischemic myocardial depression Reperfusion of warm blood cardioplegic solution is useful in minimizing reperfusion damage after ischemia. This study tests the hypothesis that overzealous administration of blood cardioplegic solution at reperfusion counteracts these benefits and can lead to a prevalence of depressed ventricular performance and mortality similar to that seen after normal blood reperfusion. Thirty-one dogs underwent 45 minutes of 37° C global ischemia on vented bypass. Six received normal blood reperfusion and 25 were reperfused with a warm aspartate/glutamate-enriched blood cardioplegic solution; of these, eight received high-dose (3600 ± 600 00) and 17 received limited-dose (1180 ± 120 00) blood cardioplegic reperfusion over 10 to 20 minutes. High-dose blood cardioplegic perfusion (5100 ± 200 00) without prior ischemia was tested in an additional five dogs. High-dose blood cardioplegia without preceding ischemia did not alter ventricular function (peak stroke work index 96 % of control). After ischemia, normal blood reperfusion (no cardioplegia) resulted in marked left ventricular dysfunction (peak stroke work index 36% of control, p < 0.05 versus control) and a 33% mortality rate (2/6 died), High-dose cardioplegic reperfusion yielded marginal recovery of stroke work index (40% of control, p < 0.05 versus control) and a 25% mortality rate (2/8 died), In contrast, limited-dose reperfusion of blood cardioplegic solution allowed 100% survival (17/17) and restored stroke work index to 90% of control (1.3 versus 1.45 gra-m/kg), We conclude that reperfusion damage can be avoided by initial reoxygenation with limited doses of substrate-enriched blood cardioplegic solution. Conversely, high-dose reperfusion of blood cardioplegic solution offsets this benefit, reduces recovery substantially, and may be lethaL

Edward R. Kofsky, MD, Pierre L. Julia, MD, and Gerald D. Buckberg, MD Los Angeles. Calif.

Reperfusion of warm blood cardioplegic solution has been used experimentally and clinically to limit reperfusion damage after global and regional ischemia."> The objectives of controlling reperfusion conditions and composition are to reduce myocardial energy demands by keeping the heart arrested and decompressed and to channel energy production during initial reoxygenation to reparative processes while optimizing the rate of repair by normothermia. We have previously limited the dose, duration, and pressure of controlled reperfusion and found this treatment to be especially useful in energy-depleted hearts in which myocardial protection was inadeFrom the University of California at Los Angeles School of Medicine, Division of Cardiothoracic Surgery, Los Angeles, Calif. Received for publication Aug. 8, 1989. Accepted for publication March 2, 1990. Address for reprints: Gerald D. Buckberg, MD, UCLA Medical Center, Department of Surgery, Los Angeles, CA 90024.

12/1/21223

quate or absent during preceding ischemia. 1,6 We did not consider the possibility that large volumes of this helpful adjunct might be harmful, because large doses of cardioplegic solution to prevent ischemic damage are reported to be safe in normal hearts subjected to aortic

clamping" 8 The current report will confirm the safety of high-dose blood cardioplegia in hearts that are not subjected to ischemic injury, and it will contrast the effects of normal blood reperfusion against limited-dose and high-dose reperfusion of blood cardioplegic solution in hearts subjected to 45 minutes of normothermic aortic clamping without preceding myocardial protection. The results will (l) document the profound myocardial depression and high mortality that follows normal blood reperfusion, (2) show that limited-dose reperfusion of warm blood cardioplegic solution avoids this damage and restores near normal postischemic function, and (3) demonstrate that delivery oflarge volumes of the same cardioplegic solution counteracts its beneficial actions and results in the same 275

of

276

The Journal Thoracic and Cardiovascular Surgery

Kofsky, Julia, Buckberg

prevalence of myocardial depression and mortality that follows normal blood reperfusion.

Division, Oxnard, Calif.). Global cardiac function was expressed as stroke work index (SWI) by using the formula: SWI

Methods Thirty-six mongrel dogs weighing 20 to 27 kg were anesthetized with a 1:1 mixture of sodium pentobarbital (Nembutal) and sodium thiamylal (30 mg/kg) intravenously, supplemented by sodium pentobarbital (50 to 100 mg) to keep the corneal reflex abolished. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and with the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication No. 80-23, revised 1978). Experimental preparation. After endotracheal intubation and positive-pressure ventilation with 100% oxygen, a median sternotomy was performed and the azygos vein was ligated. After systemic heparinization (3 mg/kg intravenously), polyethylene catheters were placed into the aortic arch via the right internal mammary artery, left atrium, distal aorta, and inferior vena cava (via left femoral veins) for monitoring pressure and delivering infusions. The pericardium was incised and cradled, the superior and inferior venae cavae were isolated and cannulated (28F), and a femoral artery cannula (l6F) was inserted. These cannulas were connected to a pump oxygneator circuit (SI00 model, Shiley, Inc., Irvine, Calif.) primed with 1500 ml of whole blood and 300 of hetastarch (Hespan). A pediatric thermodilution catheter (SF) was directed into the pulmonary artery for monitoring temperature and for measuring cardiac output. An aortic cardioplegia cannula with a pressure monitoring port was placed into the proximal aorta, and a lOF catheter was inserted into the right ventricle for subsequent volume loading and to collect coronary venous effluent samples for metabolic studies. . Experimental protocol. Baseline measurements of left ventricular performance were made by inscribing Starling curves just before starting extracorporeal circulation; blood from the oxygenator was infused into the right ventricle at a rate of 3 to 4 ml/kg/min for 10 minutes, and heart rate, left atrial pressure, systemic blood pressure, and cardiac output were recorded each 2 minutes. Total vented bypass was then initiated and the left ventricle was decompressed by inserting a vent through an apical stab wound and placing it on low suction to keep left ventricular pressure at 0 mm Hg. Systemic temperature was kept as 37° C and systemic flowrate at 100 ml/kg. Measurements. Samples of arterial or venous blood, or both, were analyzed for oxygen, carbon dioxide, pH, potassium, and ionized calcium every 15 to 20 minutes throughout the experiment by a Nova STAT II analyzer (Nova Biomedical Corporation, Waltham, Mass.) or a Ciba Corning 288 blood gas system (Ciba Corning Diagnostics Corp., Medfield, Mass.), or both. The pH was kept at 7.4 ± 0.05 and oxygen tension was kept at more than 100 torr by adjusting the respirator or adding sodium bicarbonate as necessary. All hemodynamic data were recorded on a Honeywell 1508B Visicorder oscillograph (PPG Biomedical Systems, Medical Electronics Division, Pleasantville, N.Y.). Pressure measurements were made by connecting saline-filled catheters to Statham P23db transducers, (Spectramed Inc., Critical Care

(MAP - LAP) X CO Dog weight X HR X 0.0136

where MAP is mean arterial pressure, LAP is left atrial pressure, CO is cardiac output, and HR is heart rate. Cardiac output was determined by injecting 5 ml of iced saline into the proximal port of the Swan-Ganz catheter (Baxter Edwards Division, Irvine, Calif.). Oxygen utilization was expressed as MV02 in milliliters per 100 gm per minute from the formula: MV0 2

CBF X (02 content A-02content V) Heart weight (gm)

where arterial blood (A) was sampled from the blood cardioplegic solution, venous blood (V) was sampled from the right ventricle (coronary sinus), and coronary blood flow (CBF) was determined from the flow delivered into the aorta by a calibrated pump. Oxygen content was calculated as:

O 2 content

1.36 ml 02/gm HgbX Hct . 3 X O 2 saturation + (0.003 X Po 2)

where Hgb is hemoglobin, Het is hematocrit, and P02 is oxygen tension. Transmural samples were obtained with a high-speed drill and were separated into endocardial and epicardial halves and dried at 85° C for 24 hours to achieve constant weight. Water content was determined as: H20content(%)

Wet weight - Dry weight 00 W ' ht Xl et weig

These biopsy specimens were obtained at the end of the experiment. At experiment's end, hearts were excised, cut into 5 mm circular slices, incubated in a 1% solution of triphenyltetrasolium chloride (ITC), and bathed in 8 mmol/L dibasic and 2 mmol/ L monobasic buffer (pH 8.4) for 15 minutes at 37° C to allow for assessment of histochemical damage.S 10 Statistical analyses. Statistical analyses were performed with the Statistical Analysis Systems (SAS Institutes, Cary, N.C.) program package provided by the University of California, Los Angeles Computing Facility and in consultation with Edward C. DeLand, PhD, a biomathernatician. All values are expressed as mean ± standard error of the mean. Experimental groups were compared with themselves by analysis of variance, and the Student's t test was used to compare data in individual dogs. Differences were considered significant if they reached the p < 0.05 level. Experimental groups. Dogs were placed into experimental groups on the basis of the presence or absence of ischemia and the method of reperfusion. High-dose cardioplegia without ischemia. Fivedogs received high-dose cardioplegia without ischemia. The cardioplegic solution (Table I) was delivered at a rate of 200 ml/rnin over 20 to 30 minutes (average 5100 ± 700 ml) and aortic pressure ranged from 30 to 60 mm Hg. The aortic clamp was removed immediately after the caridoplegic infusion was completed, and hearts were kept in the beating empty state for 30 minutes before extracorporeal circulation was discontinued.

Volume 101 Number 2 February 1991

Blood cardioplegia 2 7 7

Table I. Blood cardioplegia formulation Principle

Constituent

Deliver oxygen Maintain arrest

Blood KCI

Buffer acidosis Avoid edema

THAM Glucose (osmolarity) Glutamate Aspartate Glucose CPD

Restore substrate

Limit calcium influx

THAM, Tris(hydroxymethyl)aminomethane:

5000

Final concentration Hematocrit 20%-24% 18-20 mliq/L for warm reperfusion pH 7.6-7.7 >400mOsm 13 mmol 13 mmol >400 mg% (Ca++) 0.2-0.3 rnmol/L

Volume

(ml)

3000 2000

1000

CPO, citrate-phosphate-dextrose.

o

Normothermic ischemia (45 minutes). Thirty-one dogs underwent 45 minutes of normothermis (37° C) ischemia to

produce global damage and were subjected to the following methods of reperfusion: NORMAL BLOOD REPERFUSION. Six dogs were reperfused with normal blood by removing the aortic clamp and keeping reperfusion pressure at 50 mm Hg until electromechanical activity resumed. Systemic pressure was then raised to 70 mm Hg. REPERFUSION OFBLOOD CARDIOPLEGIC SOLUTION LIMITED DOSE. Seventeen dogs received controlled reperfusion with 37° C blood cardioplegic solution at a rate of approximately '100 ml/rnin for 10 to 15 minutes (12 dogs had controlled reperfusion for 10 minutes and five dogs for 15 minutes), and proximal aortic pressure ranged from 25 to 50 mm Hg. The total volume of cardioplegic solution averaged 1180 ± 120 ml (Fig. 1). Thirty additional minutes of total vented bypass was allowed before extracorporeal circulation was discontinued. HIGH DOSE. Eight dogs were reperfused with 37° C blood cardioplegic solution for 15 to 20 minutes at 50 mm Hg pressure. Flow rates ranged from 300 to 650 ml/rnin at the initiation of 50 mm Hg blood cardioplegic reperfusion and tapered to approximately 100 ml/min, The total volume of cardioplegic solution averaged 3600 ± 600 ml (Fig. 1). Each dog underwent an additional 30 minutes of total vented bypass before extracorporeal circulation was discontinued. Aortic (systemic) pressure was lowered to 50 mm Hg just before aortic unclamping and kept at this level until electromechanical activity returned. Defibrillation, when necessary, was accomplished. by electric countershock (5 to 15 Wsec) and reperfusion pressure was increased to 70 mm Hg until bypass was discontinued. In all studies, arterial pH was restored to 7.4 before bypass was discontinued. If extracorporeal circulation could not be discontinued readily after the heart had been in the beating empty state for 30 minutes, bypass was extended an additional 5 to 10 minutes and a bolus injection of calcium chloride (10 mg/kg) was delivered into the extracorporeal circuit. All dogs were then observed for an additional 60 minutes in the beating working state and Starling curves were inscribed again before the experiment was ended. No inotropic drugs (i.e., dopamine, dobutamine) were given after bypass was discontinued. Volume infusion was added (from the coronary port of the oxygenator) to try to keep mean arterial pressure at more than 60 mm Hg during the I-hour postobservation interval.

*

4000

o

Limited Dose

High Dose

Blood Cardioplegia

* p
Fig. 1. Volume of blood cardioplegic solution delivered during limited-dose and high-dose reperfusion after 45 minutes of normothermic ischemia. Note: more than threefold reperfusate volume in high-dose group. 100

75

VF (%) 50

25

o REPERFUSATE:

Normal Blood (6/6)

Blood Cardioplegia (1/25)

Fig. 2. Prevalence of ventricular fibrillation (VF) after controlled reperfusion. Note: Ventricular fibrillation occurred in all dogs receiving normal blood reperfusion.

Results Results are summarized in Tables II and III and Figs. 2 to 5. Reperfusion arrhythmias. Regular sinus rhythm resumed spontaneously in all five hearts undergoing high-dose blood cardioplegia without ischemia. In contrast, reperfusion ventricular fibrillation occurred in each of the fivehearts (Fig. 2) receiving normal blood reperfusion, and an average of 3 ± I (range 2 to 6) counter-

The Journal of Thoracic and Cardiovascular Surgery

2 7 8 Kofsky, Julia, Buckberg

Table II Normothermic ischemia (45 min) High-dose BCP (no ischemia) Ca++ Control Reperfusion* K+ Control Reperfusion* Endocardial water content (%)

BCP reperjusion

Normal blood reperjusion

Limited dose

High dose

1.19 ± 0.87 ± 0.04*

om

1.23 ± 0.04 0.99t ± 0.05

1.2 ± 0.04 0.77 ± 0.03

1.2 ± 0.Q2 1.22 ± 0.04

3.6 ± 0.2 3.9 ± 0.4 78.6 ± 0.2:1:

3.6 ± 0.13 3.55 ± 0.2 79.8 ± 0.2

3.5 ± 0.2 3.7 ± 0.2 79.3 ± 0.3

3.7 ± 0.3 3.6 ± 0.2 81.9 ± 0.3

Bep, Blood cardioplegia 'Values measured 15 minutes into beating, empty recovery period. tp < 0.05 versus control, :j:p < 0.05 versus other groups.

shocks were needed to restore normal regularly conducted rhythm. Conversely, a conducted rhythm resumed spontaneously within 1 to 3 minutes of aortic unclamping in 24 of 25 hearts reperfusedwith blood cardioplegic solution (including all eight dogs receiving high-dose reperfusion). One heart had reperfusion ventricular fibrillation that could be cardioverted with a single countershock. One other heart with bradycardia required ventricular pacing for 10 minutes before a conducted rhythm returned. Serum electrolytes. Control levelsof serum potassium and ionized calcium averaged 3.7 ± 0.13 mEqjL and 1.12 ± 0.03 mmoljL, respectively (p < 0.05). Serum potassium measured 15 minutes after delivery of cardioplegic solution remained at control levels despite delivery of 30 to 50 mEq of potassium to control and ischemic hearts receiving high-dose cardioplegia. Conversely, serum calcium was lowered to 0.99 ± 0.05 and 0.79 ± 0.03 mmoljL respectively, after the limited-dose and high-dose reperfusions of blood cardioplegic solution were completed (Table II). Injections of calcium chloride were given to dogs in the high-dose group to restore serum ionized calcium to normal before cardiopulmonary bypass was discontinued. Oxygen utilization. Cardiac oxygen uptake averaged 3.2 mljlOO gmjmin in beating empty hearts when measurements were made before ischemia. Myocardial oxygen consumption fell to 1.04 ± 0.02 mljloo gmjmin when hearts were arrested by blood cardioplegic solution without ischemia (control studies). Reperfusion oxygen utilization was not measured in hearts reperfused with normal blood after 45 minutes of normothermic ischemia. All hearts reperfused with an initial blood cardioplegic reperfusate showed a similar pattern of augmented oxygen uptake during the first 2 minutes (averaging approx-

imately 5 mljlOO gmjmin); postischemic oxygen utilization then declined similarly toward baseline levelsduring the next 7 to 9 minutes; the longer period of blood cardioplegic reperfusion did not raise oxygen uptake above demands in either high- or low-dosegroups (Fig. 3). The total oxygen uptake in excess of requirements was comparable in limited-dose and high-dose cardioplegic reperfusion groups (averaging 12 ± 3 and 10 ± 3 mlj 100 gm, respectively. Ventricular performance Nonischemic studies. Several hearts appeared somewhat dilated and sluggish immediately after unclamping after high-dose (5100 ± 700 ml) blood cardioplegia without preceding ischemia, but they regained vigorous contractility during the subsequent 3D-minute recovery period on bypass. Postbypass ventricular performance returned to normal levels;stroke work index recovered to 96% ± 7% of control at left atrial pressures ranging from 6 to 9 mm Hg. All other hemodynamic parameters were comparable with control values (Table III, Figs. 4 and 5). Postischemic studies. All hearts receiving normal blood reperfusion after ischemia contracted sluggishly during the 3D-minute interval of extended bypass. Extracorporeal circulation could not be discontinued in one dog and another could not sustain satisfactory hemodynamics during the l-hour observation period (33% mortality rate). Severe cardiac depression persisted in the four survivors, and peak stroke work index reached only 36% of control with a left atrial pressure ranging from 18 to 25 mm Hg (p < 0.05 versus control). Cardiac output and mean arterial pressure were also severely depressed (Table III). In contrast, all hearts reperfused with limited-dose warm blood cardioplegic solution resumed vigorous contractility on bypass. Two hearts (both in the IS-minute

Volume 101 Number 2 February 1991

Blood cardioplegia 2 7 9

Table III Normothermic ischemia* (45 min) Control Peak SWI (gm . m/kg)

CO§ (ml/rnin)

MAP§ (mm Hg) LAP (range in mm Hg) HR (beats/min)

1.45 ± 3429 ± 116 ± 6-8 149 ±

0.2 225 4 5

High dose BCP (no ischemia)

BCP reperfusion Limited dose

High dosei

106 ± 6

1.3 ± 0.3 3460 ± 173 95 ± 3

6-9 150 ± 5

146 ± 6

1.58* ± 0.4 2465* ± 340 70* ± 5 12-14 141 ± 5

1.39 ± 0.2 3391 ± 240

7-10

Normal blood reperfusionf 0.53* 2150* ± 205 65* ± 6 18-25 155 ± 5

BCP. Blood cardioplegia; SWI, stroke work index; MAP, mean arterial pressure; LAP, left atrial pressure; HR, heart rate. 'Values were determined I hour after bypass was discontinued. tHemodynamic results do not include two dogs in each group that died. +P < 0.05 versus other groups. §Value at peak stroke work index.

limited-dose reperfusion group) required a single 10 mg/kg injection of calcium chloride during the early recovery period, and all recovered excellent ventricular function when final measurements were made 1 hour later; stroke work index returned to 90% ± 5% of control (1.3 versus 1.45 m/kg), left atrial pressure ranged from 8 to 12 mm Hg, and results were similar after 10 and 15 minutes-of limited-dose reperfusion. None of these dogs died (0% mortality rate). Conversely, hearts receiving high-dose reperfusion of warm blood cardioplegic solution appeared sluggish during the 3D-minute recovery period. All hearts required bolus injections of calcium chloride as bypass support was withdrawn, and two of eight could not be separated from extracorporeal circulation despite multiple calcium chloride bolus injections (25% mortality rate). Recovery of left ventricular performance in the six others averaged only 40% of control at left atrial pressures ranging from 13 to 18 mm Hg. The extent of recovery was variable in these survivors; one recovered 80% of stroke work index, whereas stroke work index could be increased to 70% of control in three others by repeated calcium chloride injections. These pharmacologically supported functional results were achieved at left atrial pressures averaging 15 mm Hg (p < 0.05 versus limited-dose cardioplegia). Tissue analyses. Large doses of blood cardioplegic solution without prior ischemia did not produce edema (endocardial water content 78.6% ± 0.2%, comparable with control). In contrast, hearts reperfused with normal blood after 45 minutes of normothermic global ischemia demonstrated marked water accumulation (endocardial water content 81.9% ± 0.3%, P < 0.05 versus control). The extent of postischemic edema was more limited and comparable after both limited-dose and high-dose blood cardioplegia (endocardial tissue water content 79.8% ± 0.2% and 79.3% ± 0.3% [p < 0.05] versus normal

blood). Histochemical damage was negligible in all postischemic hearts, and TIC nonstaining never exceeded 10% in any heart. Discussion These data indicate that the severe functional depression that followsnormal blood reperfusion can be avoided by a limited dose of warm blood cardioplegia under controlled conditions. We describe the phenomenon of "overdose blood cardioplegic reperfusion" whereby these beneficial effects can be blunted or offset completely by delivering excessive amounts of cardioplegic solution. The model selected for study (i.e., 45 minutes of normothermic ischemia) produces such profound cardiac energy depletion and temporary functional depression that the perioperative mortality rate is prohibitive (100%) without mechanical support and the survival rate only 70% after biventricular support for 24 hours. 1I Magovern and associates!' showed the potentially reversible nature of this injury by reporting (1) minimal (i.e., <10%) histochemical damage despite profound hemodynamic depression and (2) excellent subsequent recovery, so that this model may be the global equivalent of the "stunned" myocardium described after regional ischemia.P: 13 We l4 demonstrated previously the immediate reversibility of this global ischemic injury in hearts subjected to 2 added hours of aortic clamping when they were "resuscitated" with warm cardioplegic induction and reperfusion and given a cold multidose blood cardioplegic solution to "prevent" further damage. These earlier global studies 1, 6,14-16 led subsequently to development of a strategy for prolonged regional reperfusion (i.e., 20 minutes at 50 mm Hg) that permitted immediate functional recovery after acute coronary occlusion for up to 6 hours.' Incomplete immediate contractile recovery was tolerated well in regional ischemic studies inasmuch as remote and

The Journal of Thoracic and Cardiovascular

2 8 0 Kolsky, Julia, Buckberg

Surgery

"limited Dose"

"High Dose"

6

MVoz cc/l00 gm/ min

4 2 45'

o

5' 10' 15' 20'

Fig. 3. Myocardial oxygen uptake (MVO z) during limited-dose and high-dose blood cardioplegic reperfusion. Note: (1) baseline oxygen requirements are only I ml/IOO gm/rnin in the arrested state, (2) similar patterns and total quantities of oxygen used above baseline needs in both groups, and (3) return to baseline oxygen uptake after the seventh to ninth minute in both groups.

2

2

I Control

1.5

1.5

SWI (g·m/kg)

J'

0.5

i

I

I

I

/r /t

/

. . . .1

SWI

J'

(g·mlkg)

High Dose Blood Cardioplegia

0.5

r

}J/umited

T,/

:' 1/1'

r/t-1 T/.-rrtII /

If

/1/

1/

OOS8

~ Reperfusion

-> Cardioplegia

HighDose

1 • -'- -'- -'rl~

T

Normal Blood

O ' - - - ' - - _ - ' -_ _'-_......J.._ _-"-

O'--_---1_ _---l._ _-L._ _...J.... _ _

5

10

15

20

5

10

15

20

25

~

25

LAP(mm Hg)

Fig. 4. Left ventricular performance after high-dose blood cardioplegic perfusion without prior ischemia. Note: Normal function curves at all filling pressures. SWI, Stroke work index; LAP, left atrial pressure.

Fig. 5. Left ventricular performance after 45 minutes at 37° C global ischemia. Note: (1) profound depression after normal blood reperfusion, (2) excellent recovery after limited-dose blood cardioplegic reperfusion, and (3) severe depression after either high-dose blood cardioplegic reperfusion or normal blood reperfusion. SWI, Stroke work index; LAP, left atrial pressure.

adjacent myocardium developed compensatory hypercontractility to support the circulation.'? Global ischemia is a lesssevereinsult then regional ischemia.P: 19 but persistent global depression is more problematic because remote or adjacent myocardium cannot be recruited for compensatory support.f 15 This study confirms the detrimental effectsof normal blood reperfusion after ischemia,2,6, 11,20-24 as reperfusion ventricular fibrillation always occurred and postischemic performance was depressed severely in survivors, Controlled blood cardioplegic reperfusion did not avoidthesedeleteriouseffectswhenweusedthe technique that was effective in regional studies, becausedelivery of the controlled reperfusate for 20 minutes at 50 mm Hg

resulted in a cardioplegic doseof 3600 ± 500 ml and the same decreased function and mortality as with normal blood reperfusion, These hearts defibrillated simultaneously but appeared flaccid and contracted sluggishly after unclamping ofthe aorta. Conversely, limitation of the total dose to approximately 1000 ml over 10 to 15 minutes resulted in return of prompt vigorous contractility,near completerecovery ofcontractility,and 100% survival. Large volumes of blood cardioplegicsolution (i.e, up to 6 L) did not producedysfunction in normalhearts (Fig. 4) whereit isintendedto "prevent" ischemicdamage,The possibility of excessive cardioplegia as a cause of the depression of postischemic hearts wasconsideredbecause

LAP(mm Hg)

Volume 101 Number 2 February 1991

of their flaccid, sluggishappearance after unclamping of the aorta and the occasional sustained hemodynamic improvement that followed calcium chloride injection. In these hearts, warm bloodcardioplegicsolutionwas given to "avoid" reperfusion damage by keeping oxygen demandsof the decompressed heart lowduring the initial phase of reoxygenation, while optimizing the metabolic rate of repair with normothermia.P Ionic calcium is lowered by citrate-phosphate-dextrose to limit postischemic calcium accumulation-" and improve postischemic performance.F Amino acids replenish those lost during ischemia28, 29 and buffers are administered for ischemic acidosis to create a favorable metabolic environmentfor cellular repair. Hyperglycemia provides the metabolic fuel preferentially used during reperfusion.P:31 and hyperosmolarity reducescellularedema to improvereperfusate distribution.P:33 Postischemic hearts reperfused with warm blood cardioplegic solutionusually take up oxygenin excess of the basal demands (1 rnI/lOO gm/min),34 despite impaired oxygen utilization capacity." We presume this extra oxygen produces the energy needed to restore ionic gradients, repair damaged cellular processes, and avoid reperfusion injury. Myocardial oxygen delivery was increasedalmost fourfold, but net excessoxygen uptake wascomparableto that of the limited-dose group (Fig. 3) and returned to baseline levels between 7 and 9 minutes of reperfusion, so that longer periods of reperfusion only increased the cardioplegicdose. The initial 50 mm Hg reperfusion pressure was an unlikely cause of reduced recovery, becausepressurerose to that level in the low-dose group when coronary autoregulatory capacity recovered, and postischemic edema was minimal in both cardioplegic groups compared with the group receiving normal blood reperfusion. These observations suggest that incompletefunctional recovery with high-dose blood cardioplegia was caused by excessive administration of a solution whose components, either together or separately, altered postischemic myocytefunction. The high-dose groupreceived30 to 50 mEq of potassium and in vitro studies suggest that excess potassium causes residual functional depression." Ischemic impairment of the sodium/potassium adenosinetriphosphatase pump'? may have allowed potassium accumulationduring initialreoxygenation and caused the flaccid appearance of the heart despite normal serum potassium levels. Some of the extra potassium may also have entered peripheral smooth muscle cells and caused vasodilatation.l" becausepostischemic bloodpressurewas lower (70 mm Hg versus 95 rnrn Hg, p < 0.05) in dogs receiving high-dose cardioplegia. Cardiac output should have been higher and left atrial pressure lower if the

Blood cardioplegia 2 8 1

depressed stroke work indices were caused by systemic vascular changes (Table III). The peripheral effects of amino acid solutions are variable.'?"! but vasomotor impairment by high-doseamino acid infusionis unlikely. Pisarenko, Lepelin, and Ivanov" reported that rapid infusions of glutamate 60 mmol/L improvehemodynamics after ischemia. Any residual cardioplegiceffects were probably compounded by hypocalcemiacaused by the large quantities of citrate-phosphate-dextrose, because systemic hypocalcemia is a negativeinotropicinfluencei- 43; ionizedcalcium levels fellmore after high-dosethan after limited-dose cardioplegic reperfusion (0.70 versus 0.99 mliq/L, p < 0.05). Boluscalcium chlorideinjectionsrestored normal calcium levels but did not improve function reliably (seeResults). The occasionalsustainedimprovementthat followed calcium bolus injections suggests that either residual intracellular hyperkalemia or hypocalcemia was counteracted, because premature inotropic stimulation worsens ischemic/reperfusiondamage." These data that show that large volumes of an otherwise useful solution can offsetits salutary effectsand may be fatal imply that more ofgood treatment is not necessarily better. The influenceof the experimentalmodelon finalresults is emphasized by the finding that high-dose blood cardioplegia did not alter function of normal hearts yet caused profound myocardial depression in damaged hearts. We have encountered this influencepreviously in studies showingthat (1) spontaneousfibrillation is tolerated well in normal hearts45 but is deleterious in hearts wtih hypertrophy" or coronary stenosis"? and (2) cold blood cardioplegia allows Complete functional recovery after 4 hours of aortic clamping in normal hearts 16 but is lessprotectiveafter only 1 hour of aortic clamping if there is poor distributionf- " or if used in energy-depleted hearts without warm induction and warm reperfusion.P The clinicalcorrelatesof theseexperimentalmodelsoccur when problems with distribution of cardioplegicsolution are encountered or when there is preexisting ischemia. The tendency to give excessive cardioplegic solution to increase its benefit in these patients must be weighed against the possibility of causing myocardial depression. We conclude that limited-dose reperfusion of warm blood cardioplegic solution provides the surgeon with a valuableadjunct to avoidreperfusiondamage. These data define a syndrome of "overdose cardioplegia" that is a preventable cause of postischemic myocardial dysfunction,whichcan be lethal. These observations may provide an explanation for the anecdotal reports of flaccidpostischemic hearts that have been subjected to large volumes of cardioplegic solution. We hopethese results willlead to more prudent cardioplegicstrategies.

2 8 2 Kojsky, Julia, Buckberg

We wish to acknowledge the technical assistance of Ms. Nanci Stellino, Mr. Garland Hodges,and Mr. Edward Dolendo and the organizational assistanceof Ms. ludith Becker. REFERENCES 1. Follette DM, Fey K, Mulder DG, Maloney lV lr, Buckberg GD. Prolonged safe aortic clamping by combining membrane stabilization, multidose cardioplegia, and appropriate pH reperfusion. 1 THORAC CARDIOVASC SURG 1977;74:682-94. 2. Haas GS, DeBoer LWV, O'Keefe DD, et al. Reductionof postischemic myocardialdysfunction bysubstrate repletion during reperfusion. Circulation 1984;70(Pt 2):165-74. 3. Allen BS, Okamoto F, BuckbergGD, et al. Studies of controlled reperfusion after ischemia. XV. Immediate functional recoveryafter 6 hours of regionalischemia by careful control of conditionsof reperfusion and composition of reperfusate. 1 THORAC CARDIOVASC SURG 1986;92:62135. 4. Allen BS, Buckberg GD, Schwaiger M, et al. Studies of controlledreperfusion after ischemia. XVI. Consistentearly recovery of regional wall motion following surgical revascularization after eight hoursof acute coronaryocclusion. 1 THORAC CARDIOVASC SURG 1986;92:636-48. 5. Teoh KH, Christakis GT, Weisel RD, et al. Accelerated myocardial metabolic recovery with terminal warm blood cardioplegia.1 THORAC CARDIOVASC SURG 1986;91:88895. 6. Rosenkranz ER, Okamoto F, Buckberg GD, Robertson 1M, Vinten-Johansen1, BugyiH. Safety of prolonged aortic clampingwith bloodcardioplegia. III. Aspartate enrichment of glutamate-blood cardioplegia in energy-depleted hearts after ischemic and reperfusion injury. 1 THORAC CARDIOVASC SURG 1986;91:428-35. 7. Engelman RM, Rousou lH, Lemeshow S. High-volume crystalloid cardioplegia. 1 THORAC CARDIOVASC SURG 1983;86:87-96. 8. Saydjari R, Asimakis G, Conti VR. Effect of increasing volume of cardioplegic solution on postischemic myocardial recovery. 1 THORAC CARDIOVASC SURG 1987;94: 234-40. 9. FishbeinMC, Meerbaum S, Rit 1, et al. Early phase acute myocardial infarct size quantification: validation of the triphenyltetrazoliumchloride tissue enzyme staining technique. Am Heart 11981;101:593-606. 10. Lie IT, Pairolero PC, Holley KE, Titus lL. Macroscopic enzyme-mapping verification of large, homogeneous, experimental myocardial infarcts of predictable size and location in dogs. 1 THORAC CARDIOVASC SURG 1975; 69:599-604. 11. MagovernG1, ChrisliebIY, Kao RL, et al. Recovery of the failing canine heart with biventricular support in a previously fatal experimental model. 1 THORAC CARDIOVASC SURG 1987;94:656-63. 12. Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 1982;66:1146-50.

The Journal of Thoracic and Cardiovascular Surgery

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