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J Thorac Cardiovasc Surg 1999;118:975-977
© 1999 Mosby, Inc.
LETTERS TO THE EDITOR |
Department of Cardiothoracic Surgery
UCLA Medical Center
Room62-258
Box 951741
Los Angeles, CA 90095-1741
To the Editor:
The two criteria for cardiac surgical success are a technically adequateprocedure and safe myocardial protection. Experienced surgeons can readilyintroduce satisfactory technical changes that visibly work. For example, acoronary anastomosis can be made with interrupted or running sutures, by passinga needle either from the outside to inside, or inside to outside, and eitherone surgeon doing all, or two surgeons, each doing half, to maintain an ongoingforehand direct suturing method. The barometer is that the anastomosis ishemostatic, is patent, and remains open at follow-up examination. This endpoint is clear and documentable.
These specific limitations with cardioplegia may not be clear in theoperating room without this knowledge. For example, an untested solution mayproduce a minor decrease in protection, resulting in raised left ventricularend-diastolic pressure (or left atrial pressure increases from 8 mm Hg to16 mm Hg) with normal cardiac output in normal hearts. This depression ofthe Starling function curve is not clear from baseline resting measurements.However, cardiac output may not increase sufficiently during anemia or fever.Of course, these changes can occur also with tested solutions with any formof myocardial protection, especially in damaged hearts. Recognition of changesby a solution alone allows more proper selection of crystalloid or blood cardioplegicconstituents.
The surgeon is not qualified to make arbitrary changes in solutionsto meet a whim. Suspicion of a useful change is only a reason for pharmacologictesting. This was stated clearly by Claude Bernard: "Clinical anecdotesshould be the seeds of subsequent investigative studies, and not the basisof future decision making."
The calcium concentration (Ca++) is lowered in the cardioplegicsolution and reperfusate, because intracellular Ca++ accumulationfollows ischemic and reperfusion injury. However, Ca++ is not loweredtoo severely (<50 µm) to avoid sarcolemmal damage that is caused bythe calcium paradox.
This deleterious change was seen at the outset of clinical cardioplegiawith the Melrose solution in 1955. Careful experimental testing (as describedabove) was not done. We now know that Ca++ was lowered severelywhen citrate-phosphatedextrose (CPD) solution (which chelates calcium) wasadded in high concentrations. Cardioplegia was initially abandoned and thensubsequently restored when Bretschneider in 1964 and Gay and Ebert in 1971implemented experimental studies and showed clear benefits. Today, our currentblood cardioplegic solution uses safer potassium and citrate components thanwere used in the original Melrose solution. The quantity of blood/cardioplegiamixture is recorded, and Ca++ is lowered to 0.5 to 0.6 µmol/Lwith a 4:1 mixture and more severely, to 0.2 to 0.3 µmol/L, in solutionsfor energy-depleted hearts or those with acute myocardial infarction.
Similar testing with crystalloid Bretschneider solution or St Thomas’Hospital solution exposed the potential advantages and disadvantages of theseapproaches. Consequently, the literature contains comparisons that allow surgeonsto make more knowledgeable selections of a desired blood or crystalloid solution.
I will relate specific issues with blood cardioplegia to show that inaccuratechoices can be problematic. Several years ago, in children, we saw immediatelyafter aortic unclamping, transient atrioventricular dissociation or ventricularfibrillation. Normal rhythm was readily restored by pacing or defibrillation.The spontaneous beating empty state seen in adults was not routine. We foundthat our hemodilution primes diluted Ca++ to 0.6 to 0.8 µm inthe blood component of our cardioplegic solution. This iatrogenic hypocalcemiadeveloped after extracorporeal circulation was begun and before the cardioplegicmixture was made. Clearly a further lowering of Ca++ occurred withany cardioplegic solution containing a fixed CPD concentration.
The lowering depended on the pump prime, with its known content of Ringer’slactate or electrolyte solution (Plasma-Lyte). A supplemental plasma componentwill lower Ca++ further. We worked out the formulation of the amountof calcium to be added to the crystalloid or crystalloid/plasma pump primeto restore Ca++ to normal limits. These transient arrhythmias wereavoided by restoring normal Ca++ in the pump prime.
1
A more serious problem occurred at another institution. The surgeondid not dilute our 4:1 cardioplegic solution, but administered the entirecardioplegic component (containing high potassium and CPD) directly into theheart. A problem similar to that with the Melrose solution occurred, and apatient died. I 2 reportedthis hazard in a letter partially titled, "Cardioplegic Solutions AreNot Equal."
St Thomas’ Hospital solution (ie, a crystalloid solution) wasdescribed in that report to show that this solution can be delivered directlyinto the heart without blood. Our blood cardioplegic components were alsopresented to show that the crystalloid components of blood cardioplegia woulddiffer depending on the ratio of 8:1, 4:1, 1:1, or other values. Clearly,a reverse problem occurs by mixing crystalloid St Thomas’ Hospital solutionwith blood, unless the electrolyte concentrations are increased.
St Thomas’ Hospital solution contains magnesium, 16 mEq/L, andnormal calcium at 1.2 µL/L. As with blood cardioplegia, hypocalcemia inSt Thomas’ Hospital solutions was reported by Baker, Olinger, and Baker 3 to be an important cardioplegicelement in hypoxic immature hearts. To produce hypocalcemia with St Thomas’Hospital solution, there was consideration of adding CPD, since CPD is usedroutinely in blood cardioplegic solutions. The crystalloid component of StThomas’ Hospital solution is different from the blood cardioplegic crystalloidaliquot sample, so that new testing was needed.
The role of a careful investigator, making an experimental evaluationbefore changing the clinical solution, became clear. A laboratory study wasdone by Frank Rosenfeldt of Melbourne, Australia (personal communication,1999). Adding CPD to St Thomas’ Hospital solution (containing 16 µL/Lcalcium) caused marked depression (ie, >50%) in left ventricular functionin normal ventricles. Conversely, lowering calcium to 0.25 µmol/L, as seenin the blood cardioplegic study, was useful. This dilemma of adding CPD toSt Thomas’ Hospital solution was clear, and Dr Rosenfeldt and colleaguesavoided making this change clinically. Conversely, failure to do this evaluationmay provide an intraoperative counterpart of decreased function (as we describedearlier). Consequently, in more damaged hearts, severe complications suchas arrhythmia or mortality might occur because of the lack of proper experimentalevaluation before clinical introduction.
Several years ago, I asked a commercial pharmaceutical company to produceour cardioplegic solution because of a clinical problem encountered in a westernstate. Before that, our group made glutamate/aspartate solution in the hospitalat the University of California at Los Angeles (UCLA) in a pharmacy that hadgood manufacturing practices. Many groups wanted to change to add amino acids,so we published and distributed the method of UCLA formulation to any hospitalthat made such requests.
A western hospital that used our formulations found them successfulin more than 1000 cases. Evidently, the hospital pharmacy changed, and a newpharmacist observed Escherichia coli in 2of 30 bottles that were made. Several bottles on either side of the contaminatedones were discarded. Random testing of 2 other bottles showed that no othercontamination occurred. However, the pharmacist did not check or discard allbottles because of "isolated" contamination. Unfortunately, 2patients died and 6 others had severe infections. Cardiac function was normal.These morbidity and mortality changes relate to the manufacturing practicein a specific pharmacy. This deleterious consequence led the Food and DrugAdministration to shut down hospital pharmacies making amino acid solutionswhere good manufacturing practices were not present.
Hospital pharmacies had to prove to the Food and Drug Administrationthat they were capable of making solutions with proper environments. For thisreason, we went to a pharmaceutical company, McGaw, with a subsidiary CAPS(Central Admixture Pharmacy Services) to ensure that our solution was madesafely, with reliable preparation, and that others could obtain this in apredictable way.
We 4 recently reportedthe benefit of L-arginine as an additive toour cardioplegic solution. This additive was selected because of our interestin cardioplegia to protect the endothelium as well as the myocardium. Ourexperiment reports show that myocardial function was excellent with both solutions,but L-arginine provided endothelial protection.A surgical colleague, reading this, began to add L-arginineto his cardioplegic solution. His source was a company that provided solutionsfor experimental laboratories. These are sterile solutions, but this laboratorydoes not make solutions for patients.
The use of an untested solution, although producing no acute cardiovasculareffects, caused renal failure in 6 patients. Subsequent analysis showed thatthe L-arginine solution contained arsenicand other nephrotoxic agents. The kidney, not the heart, was affected adversely.This, of course, was not seen with our clinical protocol, where 20 patientsreceived the L-arginine cardioplegic solutionwithout effect. We asked the pharmaceutical company making our glutamate/aspartateclinical solution to add the L-arginine additive.
The same surgical colleague avoided these renal changes by administeringthe L-arginine solution additive from thissame pharmaceutical source. The composite glutamate/aspartate L-arginine solution has now been administered in more than 500cases, without renal damage.
Similar problems with either improper additives or bacterial contaminationcan occur when perfusionists, with no pharmacologic or electrolyte physiologicbackground, must construct a cardioplegic solution. This may be especiallyproblematic if done under emergency circumstances.
These vignettes are recorded to call attention to the adverse effectsfrom changing cardioplegic solutions for well-intentioned surgical considerations,but without clinical testing. All cardioplegic solutions can be supplementedto augment their benefit, but careful testing is needed before their clinicalapplication. Surgeons making changes on a conceptual basis alone can producedilemmas they did not desire. This pharmacologic limitation differs from theadvantages of solid surgical judgment to make decisions, as in the coronaryanastomosis described previously.
Fortunately, many tested crystalloid or blood cardioplegic solutionsare made and used worldwide. Clearly, pharmaceutical firms, and some hospitalswith good manufacturing practices, can safely produce these solutions. Thismay avoid complications related directly to a cardioplegic solution used formyocardial protection.
I was surprised to learn from CAPS that although there is wide use ofthe glutamate/aspartate supplementation to blood cardioplegic solutions, severalinstitutions made changes from the originally described concentrations. Ofcourse, these changes may be safe, but only testing will prove that the compositionof an otherwise untested solution did not cause a clinical problem. Detrimentalcardiac or other organ changes may be difficult to defend if no backgrounddata are available regarding how the solution was evaluated before its clinicaluse. The analogy of a comparison between "unproven herbal approach versustested scientific study" must be considered.
12/8/101735
References
This article has been cited by other articles:
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  G. D. Buckberg Substrate enriched warm blood cardioplegia reperfusion: an alternate view Ann. Thorac. Surg., February 1, 2000; 69(2): 334 - 335. [Full Text] [PDF]
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