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J Thorac Cardiovasc Surg 1998;115:1196-1202
© 1998 Mosby, Inc.

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

Prevention of cell swelling with low chloride St. Thomas'Hospital solution improves postischemic myocardial recovery

Supported by National Institutes of Health grants HL-51032 (R.J.D.),HL-09310 (A.M.J., R.J.D.), and HL-46764 (C.M.B.).

Received for publication April 25, 1997 Revisions requested Sept. 15, 1997. Revisions received Dec. 10, 1997 Accepted for publication Dec. 22, 1997. Address for reprints: Ralph J. Damiano, Jr., MD, Chief, Division ofCardiothoracic Surgery, The Milton S. Hershey Medical Center, Penn StateGeisinger Health System, P.O. Box 850, Hershey, PA 17033.

	Abstract

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Objective: In isolated myocytescardioplegia-induced cell swelling can be prevented by lowering the KCl productby replacing Cl^- with an impermeant ion. This study tested thehypothesis that Cl^- substitution in St. Thomas' Hospitalcardioplegic solution would result in superior myocardial protection in theintact, blood-perfused heart.
Methods:Using a parabiotic, isolated rabbit heart Langendorff model, hearts were exposedto 1 hour of hypothermic (10° to 12° C), global ischemia followed by 30minutes of reperfusion. Isosmotic cardioplegia was administered as a single 50ml bolus of either standard St. Thomas' Hospital solution ([K⁺]_ox [Cl^-]_o = 2566.4 (mmol/L)²) orlow Cl^- St. Thomas' Hospital solution ([K⁺]_ox [Cl^-]_o = 700 (mmol/L)²).Chloride was replaced by a large, impermeant ion, methanesulfonate.Postreperfusion systolic function and atrioventricular conduction times weremeasured before ischemia and after reperfusion.
Results:Hearts receiving low Cl St. Thomas' Hospital cardioplegia demonstratedsignificantly better postischemic functional recovery (74% ± 3%)compared with those treated with standard high Cl St. Thomas' Hospital solution(55% ± 4%, p = 0.003).In addition, atrioventricular conduction times remained normal in the low Clgroup but were significantly prolonged in the St. Thomas' Hospital group.
Conclusions: Lowering the KCl product of St. Thomas'Hospital solution makes it isotonic with plasma and prevents cellular edema.This ameliorates the detrimental functional and electrophysiologic sequelae ofhypothermic, hyperkalemic cardioplegia. (J Thorac Cardiovasc Surg1998;115:1196-202)

	Introduction

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Previous attempts to prevent myocardial edema have focused on theosmolarity of the cardioplegic solutions and the use of membrane stabilizingagents. ^1-4 However, a solution may beisosmotic with plasma and still induce cell swelling if it is hypotonic.Although osmolarity is an intrinsic property of the solution, tonicity dependson the properties of both the solution and the cell membrane, and membraneproperties are highly sensitive to temperature. ⁵Recent studies on isolated rabbitand human myocytes suggest that edema may be a direct consequence of thetonicity of isosmotic cardioplegic solutions. ^6,7Loweringthe KCl product by partially replacing [Cl^-]_o witha large, impermeant ion made St. Thomas' Hospital solution isotonic andprevented cell swelling during the period of exposure. ⁶ However, extrapolation of data fromsingle myocytes to the intact heart must be done cautiously. The single cellmodel fails to incorporate the myriad interactions between myocytes and neural,vascular, and interstitial elements, and the complex geometry of the intactheart. ^6,7 Therefore this study was designedto test the hypothesis that the prevention of cellular swelling by changing thetonicity of the cardioplegic solution would ameliorate the detrimentalcontractile and electrophysiologic sequelae of hypothermic, hyperkalemiccardioplegia in the more clinically relevant intact heart.

	Methods

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Adult New Zealand White rabbits of either sex, weighing 2.8 to 3.1 kg,were used in this study. All animals received humane care in AmericanAssociation for the Accreditation of Laboratory Animal Care–approved,United States Department of Agriculture–registered facilities incompliance with the "Principles of Laboratory Animal Care"formulated by the National Society for Medical Research and the "Guide forthe Care and Use of Laboratory Animals" prepared by the Institute ofLaboratory Animal Resources and published by the National Institutes of Health(NIH Publication No. 86-23, revised 1985.) Experiments were designed to comparethe effect of standard and low Cl^- St. Thomas' Hospitalcardioplegic solution on postischemic function of hearts mounted and perfused ona parabiotic Langendorff apparatus.

Experimental preparation
Preparation of the support animal.
The support animal was anesthetized by intramuscular administration ofacepromazine maleate (INN: acepromazine) (1 mg/kg) and xylazine (17.5 mg/kg)followed by ketamine (62.5 mg/kg). A tracheostomy was performed, and mechanicalventilation was initiated (model 683, Harvard Apparatus, Dover, Mass.).Ventilator settings were adjusted to maintain arterial pH between 7.35 and 7.5,carbon dioxide tension (PCO₂)between 35 and 45 mm Hg, and oxygen tension (PO₂)more than 200 mm Hg.

Heparin (2500 U) was given through an ear vein. The right femoral arterywas cannulated, the cannula connected to a pressure transducer (model P231D,Gould Inc., Cleveland, Ohio), and blood pressure was continuously displayed.Systolic blood pressure was maintained greater than 80 mm Hg by transfusion ofeither blood collected from the donor animal or electrolyte solution(Plasma-Lyte, Baxter Healthcare Corp., Deerfield, Ill.), and serial hematocritswere measured.

The left internal jugular vein and carotid artery were cannulated toprovide extracorporeal circulation, and arterial blood was delivered to perfusea modified Langendorff apparatus as described previously. ⁸ Column effluent was returned to thesupport animal.

Preparation of the donor animal and isolated heart.
The donor animal was also prepared as described above. A rapidcardiectomy was accomplished through a median sternotomy, and blood fortransfusion was collected from the thoracic cavity. The aorta was rapidlycannulated, the heart suspended from a modified Langendorff apparatus, and bloodperfusion begun.

To monitor contractile function, a fluid-filled latex balloon was placedinto the left ventricle and secured with a purse-string suture in the mitralvalve anulus. The balloon was connected by way of polyethylene tubing to apressure transducer (model P231D, Gould, Cleveland, Ohio). The zero pressurereference was set at the level of the aortic valve.

Two needle electrodes were secured in the right atrial appendage andconnected to a pacemaker (model 5320, Medtronic, Inc., Minneapolis, Minn.). Theheart was paced at a constant rate throughout the study. Two additionalelectrodes were placed on the left ventricular epicardium to monitor a bipolarelectrogram. The electrodes were connected to a preamplifier and amplifier(model 11-G5407-58 and 13-4615-58, Gould Inc.) and band pass filtered between0.05 and 1000 Hz. The pressure and electrogram waveforms were displayedcontinuously and digitized at 1000 Hz with a WINDAQ/200 system (DATAQInstruments, Akron, Ohio). Coronary flow was measured by an in-line flow probeand continuously monitored with a flowmeter (model T206, Transonic Systems,Inc., Ithaca, N.Y.).

The heart was enclosed in a water-jacketed beaker, and myocardialtemperature was monitored with a probe placed in the right ventricle (model BAT8, Bailey Instruments, Saddle Brook, N.J.). Hearts were warmed and cooled byswitching flow between a 37° C water bath (model D1, Haake Co., Berlin,Germany) and a 10° C water bath (model 9010, Fisher Scientific, Pittsburgh,Pa.) connected in parallel to the water-jacketed beaker. Blood perfusate wasmaintained at 37° C by a separate water bath (model D1, Haake Co., Berlin,Germany). At hourly intervals, heparin (500 U) was administered to the supportanimal.

Experimental protocol
After instrumentation, hearts were given 30 minutes to equilibrate, andbaseline data were acquired. Hearts that did not generate a systolic pressureexceeding 80 mm Hg at an end-diastolic pressure (EDP) of 10 mm Hg were excludedfrom the study. Intracavitary left ventricular pressure waveforms and leftventricular bipolar electrograms were recorded at seven fixed left-ventricularend-diastolic pressures (LVEDP) (0, 2.5, 5, 10, 15, 20, and 25 mm Hg) attainedby adjusting balloon volume. Then balloon volume was reduced to produce a 5 mmHg LVEDP.

Hearts were randomized to undergo a single 50 ml infusion of one of twocold cardioplegic solutions (10° C) at the onset of 60 minutes of globalischemia (10° to 12° C). Either standard St. Thomas' Hospital solution([KC^-]_o x [Cl^-]_o= 2566.4 [mmol/L]², Plegisol, Abbott Laboratories, North Chicago,Ill.), or a modified, low Cl^- St. Thomas' Hospital solutionwas administered. ⁶

Low Cl^- St. Thomas' Hospital solution ([Cl^-]_o= 43.75 mmol/L) was made by substituting an equimolar amount ofNa-methanesulfonate for all NaCl and K-methanesulfonate for part of the KCl inSt. Thomas' Hospital solution so that the product [K⁺]_ox [Cl^-]_o was 700 (mmol/L)². Thislow Cl^- cardioplegic solution is isotonic and did not affectthe volume of isolated myocytes. ⁶Methanesulfonate was chosen as the substitute for Cl^- becauseit is a large impermeant anion that does not chelate Ca²⁺.Furthermore, its pK_a of approximately 1.2 is sufficiently low thatnegligible amounts of the permeant protonated species are present at physiologicpH. ⁶ The osmolarities of thestandard and low Cl^- solutions were not significantlydifferent (243 ± 5 and 237 ± 6 mOsm, respectively).

To examine whether methanesulfonate itself had a cardioprotective effect,another large impermeant anion, aspartate, was used to lower the [K⁺][Cl^-]product. Aspartate also has a low pKa. In this group (n =6), equimolar amounts of Na-aspartate was substituted for all the NaCl andK-aspartate for some of the KCl in St. Thomas' Hospital solution. This alsolowered the [K⁺][Cl^-] product to 700 (mmol/L)².

After 1 hour of global ischemia, hearts were rewarmed and reperfused for30 minutes. Intracavitary left ventricular pressure waveforms and electrogramswere recorded every 5 minutes during the reperfusion period at a fixed balloonvolume corresponding to a preischemic LVEDP of 5 mm Hg. After 30 minutes ofreperfusion, data were acquired over the identical range of balloon volumesexamined before ischemia. At the conclusion of the study, a sample of the leftventricle was excised, blotted, weighed, and then dried until a constant dryweight was reached. The extent of myocardial edema was determined by calculatingpercent tissue (%H₂O):%H₂O = (Wetweight – Dry weight)/Wet weight.

Data analysis
Digitized pressure waveforms were analyzed, as described previously,using software developed in our laboratory. ⁹

End-systolic pressure.
End-systolic pressure (ESP) was calculated for each of the sevenpreischemic and seven postreperfusion balloon volumes. The ESP-volumerelationship (ESPVR) was fitted with a least-squares linear regression:
ESP = E_max x V + k
where E_max was the slope of theESPVR, V was the balloon volume, andk was the y-axis intercept of the ESPVR.

EDP
EDP was calculated for each balloon volume and the EDPVR was fitted witha least-squares linear regression:
EDP = m(V –Vo)
wherem was the slope of the EDPVR andVowas the balloon volume at which EDP is zero or the x-axis intercept. A linearrepresentation of the EDPVR has been shown to be appropriate over the limitedrange of volumes examined in this model. ¹⁰The mean linear repression coefficients for the EDPVR were 0.98 ±0.01, and 0.99 ± 0.00 for the standard and low Cl St. Thomas'Hospital solution groups, respectively. The slope of the relationship was usedas an estimate of diastolic compliance.

Developed pressure
Developed pressure in the left ventricle (DP) was defined as thedifference between ESP and EDP, and 10 consecutive beats were averaged for eachballoon volume. The pressure-volume relationship was fitted using the followinglinear regression:
DP = ESP – EDP = (Emax x V + k)– m(V – Vo)

Recovery of DP
The recovery of DP, expressed as a percentage, was calculated as theratio of the postreperfusion DP to the preischemic DP at the same balloonvolume. The average percent recovery of DP (%DP) was determined from thefollowing definite integral, approximated using the trapezoidal rule: ⁸

Statistical analysis
Results are expressed as the mean ± standard error of themean. A one-way repeated measures analysis of variance was used for comparisonsthat involved sequential, time-based measurements. When appropriate, theKruskal-Wallis analysis of variance on ranks was used as a nonparametricalternative. Individual comparisons between groups were made using a Tukey posttest. A t test, or paired ttest when appropriate, was used for comparisons between two sets. A ²analysis of contingency tables was used to compare mutually exclusive, categoricdata where appropriate.

	Results

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There were no significant differences in pH, PO₂,PCO₂, serum sodium, potassium,calcium, or hematocrit in the support animal between baseline data acquisitionand after 30 minutes of reperfusion. The mean hematocrit was 31 ± 1at baseline versus 30 ± 2 after reperfusion (p =0.53). There were no significant differences in times to electrical andmechanical arrest between low Cl St. Thomas' Hospital (28.2 ± 2.8seconds and 27.6 ± 2.9 seconds, respectively) and standard St.Thomas' Hospital solutions (31.4 ± 3.2 seconds and 27.1 ±1.2 seconds, respectively).

Postischemic diastolic compliance
Postreperfusion changes in diastolic compliance were quantified bydetermining the slope of the LVEDP-V (

I). Both groups demonstrated significantly decreased compliance afterreperfusion compared with before ischemia. However, there was no differencebetween standard and low Cl solutions.

View larger version (25K): [in this window] [in a new window]   Fig. 1. Developed pressure (DP) under preischemic conditions (time = 0 minutes)and effect of standard and low Cl– St. Thomas' Hospitalsolution on DP during the reperfusion period (time = 60 to 90 minutes).Values are expressed as mean ± standard error of the mean.*Significant difference versus St. Thomas' Hospital solution, withp values shown in parentheses.

View larger version (21K): [in this window] [in a new window]   Fig. 2. Coronary blood flow (CBF) under preischemic conditions (time = 0 minutes)and effect of standard and low Cl– St. Thomas' Hospitalsolution on CBF during the reperfusion period (time = 60 to 90 minutes).Values are expressed as mean ± standard error of the mean. *p < 0.05 versus respective preischemic level.

Atrioventricular conduction times.
The P-R interval was significantly prolonged throughout the reperfusionperiod compared with baseline in the standard St. Thomas' Hospital group (Fig.3). In contrast, no conduction delay wasobserved in the low Cl^– St. Thomas' Hospital group.

View larger version (17K): [in this window] [in a new window]   Fig. 3. Effect of standard andlow Cl– St. Thomas' Hospital solution on atrioventricularconduction times after reperfusion. Values are expressed as mean ±standard error of the mean. LOW Cl–,Low Cl– St. Thomas' Hospitalsolution;STANDARD, Standard St. Thomas' Hospitalsolution. *p < 0.05 versus preischemicP-R interval.

	Discussion

Top Abstract Introduction Methods Results Discussion Conclusion References

 
Under hypothermic conditions, the activity of the transporters and pumpsthat normally regulate cell volume are markedly depressed, which leaves onlypassive fluxes of ions to modulate cell volume. ^6,7,11 Because of the high membranepermeabilities to Kand Cl^-, the KCl product inside the cellmust equal the KCl product outside the cell under these conditions. ⁵ This would predict that cellswelling would occur with exposure to St. Thomas' Hospital solution because St.Thomas' Hospital solution has a much greater KCl product (2566.4 [mmol/L]²)than either blood plasma (350 to 550 [mmol/L]²) or physiologiccrystalloid (e.g., Tyrode's solution, 700 [mmol/L]²). By loweringthe KCl product of cardioplegic solution while maintaining osmolarity constantby partially replacing [Cl^-]_o with a large,impermeant ion, cell swelling was prevented in isolated myocytes. ⁶ This study was designed to examinewhether lowering the KCl product would improve myocardial protection in anintact, blood-perfused heart.

Functional consequences of low Cl hyperkalemic cardioplegia
Lowering the KCl product significantly improved postischemic recovery ofDP, ameliorating myocardial stunning. This is consistent with the fact thatintracellular edema has been shown to result in ultrastructural disturbancessuch as mitochondrial swelling and vacuolization of the sarcoplasm. ¹² Moreover, derangements inintracellular volume may adversely influence the regulation of cellularmetabolism, hormone, and transmitter release. ^12-14Further studies will be needed to address the specific mechanisms involved inthis injury.

An alternate explanation for our results is that the Cl^-ion possesses some inherent toxicity. However, this ubiquitous ion has not beenshown in any previous study to be toxic within its physiologic range ofconcentrations. Another explanation for our findings would be thatmethanesulfonate itself possessed inherent cardioprotective effects. However, weobtained identical results with an alternate impermeant anion, aspartate. Thesedata strongly suggest that it is the correction of the hypotonicity of thecardioplegic solution that is critical, not the specific impermeant anion usedto achieve this result.

Low Cl^- St. Thomas' Hospital solution did not offerbetter preservation of LV diastolic compliance (Table I).This is not surprising. In isolated myocyte preparations, cell swelling returnedto baseline within 20 minutes of reperfusion. ⁶ In this study, percent tissue waterin the standard St. Thomas' Hospital group was not significantly different fromthat of the low Cl St. Thomas' Hospital group after 30 minutes of reperfusion.Thus one would not have expected a change in ventricular compliance at thatpoint.

Coronary blood flow
Myocardial edema has been associated with decreased coronary perfusion. ^15,16In the standard St. Thomas' Hospital group an initial reperfusion hyperemiadropped to preischemic values almost immediately. In the low Cl^-cardioplegia group reperfusion flow remained elevated for 5 minutes (Fig. 2). One explanation for this is that myocardial, or perhapsvascular, edema early in the reperfusion period blunted the hyperemic responsein the standard St. Thomas' Hospital group compared with the low Cl group. Asedema resolved over the reperfusion period, coronary flow returned to normallevels. Alternatively, whole-cell patch-clamp studies of isolated rabbitcoronary artery smooth muscle cells have characterized a chloride current thatcontributes to coronary vasoconstriction. ¹⁷It is possible that coronary smooth muscle activation was transiently affectedby the low Cl milieu.

Atrioventricular conduction
Our laboratory and others have shown that cell swelling and edema areassociated with slowed ventricular conduction. ^9,18In this study, the conduction delay observed after standard cardioplegia (Fig. 3) was not seen in the low Cl^- cardioplegiagroup. In previous work, we have hypothesized that the conduction delaysassociated with hyperkalemic solutions were due to an increase in cell volume,which decreased the extracellular space, resulting in a higher resistance tocurrent flow. ^18,19 This hypothesis is supportedby our observations in isolated myocytes ⁶and by this study. Because slowed conduction velocity plays a central role inarrhythmogenesis, ^20,21 the postoperative arrhythmiascommon after cardiac procedures may be prevented by reformulating standardcardioplegic solutions.

Advantages and disadvantages of the blood-perfused isolated heartLangendorff model
The advantages and drawbacks of this model have been previouslydescribed. ⁸ The morephysiologic nature of this model is a distinct advantage over nonparabiotic andcrystalloid-perfused models. However, although this model offers a closerapproximation to the clinical scenario, care should be taken in extrapolatingresults from in vitro studies to the clinical setting.

	Conclusion

Top Abstract Introduction Methods Results Discussion Conclusion References

 
These results demonstrate a clear correlation between the prevention ofcell swelling and the amelioration of the detrimental contractile andelectrophysiologic sequelae of hypothermic, hyperkalemic cardioplegia.Blood-perfused isolated hearts treated with low Cl^-, St.Thomas' Hospital cardioplegic solution displayed significantly improvedpostischemic functional recovery and shorter atrioventricular conduction timeswhen compared with standard high Cl^- St. Thomas' Hospitalsolution. New strategies aimed at correcting the hypotonicity of cardioplegicsolutions and preventing cell swelling may improve myocardial protection withhyperkalemic cardioplegia.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Ralph J. Damiano, Jr. Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jayawant, A. M. Articles by Damiano, R. J. Search for Related Content PubMed PubMed Citation Articles by Jayawant, A. M. Articles by Damiano, R. J., Jr.