697

High-Dose Epinephrine Therapy andOther Advances in Treating Cardiac Arrest

DiscussantMICHAEL L. CALLAHAM, MD

These discussions are selected from the weekly staff conferences in the Department of Medicine, University ofCalifornia, San Francisco. Taken from transcriptions, they are prepared by Homer A. Boushey, MD, Professor ofMedicine, and Nathan M. Bass, MD, PhD, Associate Professor of Medicine, under the direction of Lloyd H. Smith, Jr,MD, Professor of Medicine and Associate Dean in the School of Medicine. Requests for reprints should be sent to theDepartment of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA 94143.

RICHARD K. RooT, MD*: Dr Michael Callaham, chiefofour division of Emergency Medicine since 1982 and

also a Professor ofMedicine, will discuss a subject pertinentto anyone who works in emergency services: advances in themanagement of cardiac arrest.

MICHAEL L. CALLAHAM, MDt: The topic of the managementof cardiac arrest is very broad, so in this review I will focuson a few areas in which there have been the most controversyand change.

Are the Advanced Cardiac Life SupportGuidelines a Standard of Care?

A word of warning. Many of my conclusions are not inagreement with what is taught in the American Heart Associ-ation's Advanced Cardiac Life Support (ACLS) course. If aphysician is involved in treating a cardiac arrest perhaps once

a year or less often, then the best choice would be to take theACLS course, memorize the algorithms, and think no moreabout it. If, on the other hand, a physician is involved inresuscitation more frequently, he or she has an obligation toread the literature, to be informed, and to deviate intelli-gently from standard protocols. Everybody worries that thisis illegal or that they are violating a standard of care and thatthey could be sued, for example, for giving larger doses ofepinephrine than are recommended. To alleviate these fears,I would remind them of a crucial disclaimer in the article onthe Standards and Guidelines for Advanced Cardiac LifeSupport published in the Journal of the American MedicalAssociation.' It states that the ACLS standards and guide-lines are not intended to imply that justifiable deviations byqualified physicians represent a breech of the medical stand-ards of care or that new knowledge, new techniques, orclinical experience are not valid reasons for alternative ap-proaches. It is written there in black and white that physiciansare justified in deviating from the guidelines if they do so onthe basis of knowledge or expertise.

*Professor and Chair, Department of Medicine, University of California, San Fran-cisco (UCSF), School of Medicine.

tChief of Division of Emergency Medicine, Professor of Medicine, UCSF Schoolof Medicine.

Although I am going to discuss the use of catecholaminesand bicarbonate, these drugs are not the most important pri-orities in resuscitation, and they never will be. Only a smallminority ofpatients will ever be saved by them. The only typeof cardiac arrest treated effectively is ventricular fibrillation,and the treatment of ventricular fibrillation is prompt defi-brillation, not medication use.

Catecholamine Use in Cardiac ArrestEpinephrine has been in standard use for resuscitating

patients with cardiac arrest for 30 to 40 years. Let me reviewhow adrenergic drugs work in cardiac arrest. What physi-cians try to achieve with chest compression and drug admin-istration is an adequate coronary artery perfusion pressure.Coronary artery perfusion pressure, which equals the aorticdiastolic pressure minus the right atrial diastolic pressure,determines blood flow through the heart. Studies in animalsshow that a minimal coronary artery perfusion pressure ofabout 20 mm of mercury is needed to resuscitate the heart.2

Typical early experiments done in 1965 by Joseph Red-ding, one of the pioneers of cardiac arrest research, showedthat if dogs in cardiac arrest received basic cardiopulmonaryresuscitation (CPR) only, about 30% of them were resusci-tated.3 These animals had an aortic diastolic pressure of lessthan 20 mm of mercury, so obviously the coronary arteryperfusion pressure could not have been good. When givenepinephrine, the diastolic pressure rose to over 30 mm ofmercury, and 100% of animals were resuscitated. Whengiven isoproterenol, primarily a f3-adrenergic agent, the dia-stolic pressure fell, and the resuscitation rates were lowerthan when no drugs were given at all. When methoxamine, apure a-adrenergic agent, was given, the diastolic pressurerose even further, and 100% were resuscitated. These andother studies showed that essentially all the benefits of adren-ergic drugs in cardiac arrest are derived from the a-

adrenergic effects.4 The 3-adrenergic effects are not crucialto resuscitation insofar as is known and have no effect ondefibrillation. a-Adrenergic receptor stimulation causesvasoconstriction throughout the vascular bed, raises the per-fusion pressure, and shunts blood to the heart and brain,allowing resuscitation.

(Callaham ML: High-dose epinephrine therapy and other advances in treating cardiac arrest [Medical Staff Conference]. West J Med 1990 Jun; 152:697-703)

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698CARDIAC

Studies in animals have proved that epinephrine is effec-tive-there have been no studies in humans-but what is theproper dose? The American Heart Association has alwaysrecommended giving 0.5 to 1.0 mg of epinephrine every fiveminutes. Based on weight, that is equivalent to 7.5 to 17 itgper kg every five minutes. On what basis did they choose thisdose? In the first studies conducted by Crile and Dolley in1906, they used 1 to 2 mg intravenously in a 20-kg dog,which averages 200 /tg per kg.' Redding, who did much ofthe research on which the original ACLS guidelines were

based, used doses of 75 to 150 /ig per kg. Particularly inter-esting is a paper he published in 1965 in which he picked a

dose that he was sure would be ineffective, which he refers torepeatedly as "suboptimal."6 That dose was 10 to 20 itg per

kg, essentially the dose that the ACLS guidelines recom-

mend be used in humans. This dose had no effect at all.Nonetheless, the standard low ACLS-recommended dose

has been unchanged up until the present time, although it hasnever been shown to be effective in any species. In recentyears more sophisticated studies of the effects of epinephrineon regional blood flow through various portions of the heartmeasured by radioactive microspheres found that administer-ing 20 tg per kg of epinephrine did not provide sufficientblood flow for resuscitation (Figure 1).7 In a series of elegantstudies, Brown and co-workers showed that a dose of 200 /,tgper kg is needed to provide significant blood flow (Figure2). 8 Similar results have been shown for cerebral artery bloodflow.

In the past few years, these results in animals have begunto be substantiated in humans. Humans in whom standardACLS therapy failed were given graded doses of epineph-rine. The diastolic pressure rose only slightly when 1 mg ofepinephrine was administered but rose more sharply withdoses as high as 5 mg given intravenously.9 This is a rela-tively small dose in humans; 15 mg of epinephrine would beneeded for a dose of 200 Atg per kg. A similar study in whichpatients were given 200 ,tg per kg of epinephrine showed an

average increase of 12 mm of mercury in coronary arteryperfusion pressure. Some persons increased their diastolicpressure by 45 mm of mercury.'0 Recently a case was re-

ported of a patient who had been in refractory ventricularfibrillation for 22 minutes, was given 5 mg of epinephrine,was resuscitated, and eventually was sent home neurologi-cally intact-not the usual outcome for such a long cardiacarrest."I A second report described a patient with asystole for36 minutes; the patient received 6 mg of epinephrine and wasresuscitated to a sinus tachycardia and brief normotension.Seven children in arrest were treated with 200 Itg per kg afterstandard therapy failed; six had a prompt return of spontane-ous circulation, and four were long-term survivors.'2

We have had extensive experience with these large dosesover the past few years. For example, in 49 adults we treatedwith epinephrine in cardiac arrest, 29 (59%) of those givenhigh doses had a return of circulation compared with 7 (14 %)of those given standard ACLS doses.'3 High-dose epineph-rine was given to these patients late in arrest in a nonran-

domized fashion, however, and did not enhance ultimate sur-vival.

Could epinephrine use be doing harm in this situation?Certainly 15-mg doses bring this concern to mind. Similarly,large doses injected into somebody with a perfusing rhythmcould well be lethal. High levels of ,B-adrenergic stimulationcan cause direct myofibrillar destruction and also might in-crease the heart rate and blood pressure after resuscitation,increasing the risk of ischemia. High doses of epinephrinecan cause arrhythmias, acidosis-the drug itself is acidotic-and pulmonary edema. These adverse effects, however, havebeen reported chiefly in cases of overdose not involving car-diac arrest.

We have closely examined 63 of our patients who sur-vived longer than six hours after resuscitation from cardiacarrest. 1' Half received standard doses and half received high

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Septum LV-meso LV-endo Total CPPFigure 1.-The effects of standard epinephrine doses are shown onregional blood flow. Regional blood flow achieved by standard ad-vanced cardiac life support doses of epinephrine (20 ,ug/kg) is insuffi-cient to achieve the 25 ml per minute per 100 grams needed forresuscitation (from Brown et a17). CPP = coronary [artery] perfusionpressure, CPR = cardiopulmonary resuscitation only, CPR plus Epi20 Mg/kg = CPR plus epinephrine at that dose, LV-endo = left ventric-ular endocardium, LV-meso = left ventricular mesocardium

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Figure 2.-The effects of graded doses of epinephrine on regionalblood flow are shown. Doses of epinephrine of 200 ug/kg are neededto achieve the blood flow threshold of 25 ml/minute/100 gramsneeded to resuscitate the heart; the standard advanced cardiac lifesupport doses of 20 ,ug/kg are inadequate. Doses of 2,000 jAg/kg donot further improve blood flow (from Brown et al8). CPR=car-diopulmonary resuscitation, Epi = epinephrine

ABBREVIATIONS USED IN TEXTACLS = Advanced Cardiac Life SupportATP = adenosine triphosphateCPR = cardiopulmonary resuscitationUCSF = University of California, San Francisco

698 CARDIAC ARREST

699

doses; our record dose (in a neurologically intact survivor) sofar is 105 mg. We looked carefully for every conceivablecomplication of epinephrine use-electrolyte abnormalities,arrhythmias, postresuscitation hypertension, evidence ofmyocardial infarction, pulmonary insufficiency, elevatedcreatine kinase levels and MB isoenzyme fractions, and thelike. We found no significant differences in the frequency orseverity of any of these complications in the high-dose andlow-dose groups, so we feel comfortable that even high dosesof epinephrine can be given safely. Adverse effects wouldhave to be great indeed to be worse than the certain death thatthese patients otherwise face, but our experience shows thatadverse effects are almost nonexistent.

We use a 30-mg vial of a 1:1,000 solution of epinephrine(Bristojects are impractical for these doses), and we give 200/g per kg (15 mg for a 70-kg person) by intravenous pushevery five minutes. We do not worry about the total dose aslong as the patient remains in cardiac arrest. We do not useintravenous drips because they are too slow and unpredict-able in the amount they deliver. As soon as there is a return ofthe circulation, the epinephrine is switched to dopamine if,as is often the case, the patient is hypotensive.

Could other adrenergic drugs be better than epinephrine

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in cardiac arrest? I have already mentioned the successful useof methoxamine, an oa-adrenergic agonist. ,B-Adrenergicdrugs buffer intracellular pH changes, but everything elsethey do during cardiac arrest is undesirable. They cause vaso-dilation and a lower perfusion pressure and increase the vigorof fibrillation, increasing the cardiac energy consumptionand decreasing coronary artery perfusion. Early studies in196i showed that administering isoproterenol hydrochloridelowered the diastolic pressure and decreased the likelihood ofresuscitation. Like other important findings, this was ig-nored in the ACLS recommendations. Subsequent studiesshowed that isoproterenol causes diffuse vasodilation, in-creasing cardiac output at the expense of the heart and thebrain. Coronary artery flow is worse after isoproterenol ad-ministration than it is after no treatment at all (Figure 3),15but it was not deleted from the ACLS protocols until the 1985revision.

There is little literature on the use of dopamine. In dogs,both epinephrine and dopamine use produced a 95 % returnof the circulation, but the dose of dopamine used was 2,000itg per kg.16 Two more recent studies also suggest that inlarge doses dopamine may have a role in treating cardiacarrest. In one, dopamine at only 15 /g per kg eliminated thebenefits (in terms of increased diastolic pressure) seen withincremental doses of epinephrine."7 The implication is thatthat dose of dopamine caused maximal vasoconstriction. Ifind this difficult to believe, and the observation has not beenconfirmed to date. A study in pigs compared the use of45 /gper kg ofdopamine with that of45 Ag per kg ofepinephrine.18The resuscitation results were the same, but dopamine pro-duced its effects faster- 174 seconds versus 667 seconds toresuscitation-and the animals resuscitated with dopaminewere reported to have less hypertension and tachycardia.These are preliminary data, however, and I would not recom-mend using dopamine in place of epinephrine at this time.

Methoxamine and phenylephrine are theoretically attrac-tive because they are pure a-adrenergic agents. The chiefproblem with using methoxamine hydrochloride is that itseffects last for several hours, and a recent prospective trial inhumans showed methoxamine resuscitation and dischargerates 50% lower than those for epinephrine.19

Phenylephrine hydrochloride has been shown effectiveonly at very high doses, and it has no proven advantages overepinephrine. Norepinephrine is theoretically attractive be-cause of its strong a-adrenergic and its j3-adrenergic activity.In animals the resuscitation rate with norepinephrine was asgood as with epinephrine, and resuscitation from ventricularfibrillation arrest was much quicker.20 This certainly war-rants more study, but, as with other catecholamines, there isnot yet enough evidence to warrant using it in place of epi-nephrine in humans.

In summary, epinephrine is effective in high doses, whichshould be given as early as possible, and it remains the stan-dard catecholamine drug to use in cardiac arrest. The dosesrecommended in ACLS guidelines have never been shown tohave any benefit in any species and probably should beabandoned.

The use of isoproterenol, dobutamine, or low-normaldoses of dopamine is contraindicated because their f-adre-nergic effects cause vasodilation, decrease the coronary ar-tery perfusion pressure, and worsen the outcome. Methox-amine and phenylephrine, pure ae-adrenergic agents, havenot lived up to their initial promise.

THE WESTERN JOURNAL OF MEDICINE - JUNE 1990 o 152 699

Training the Public in CPRLet us leave pharmacology for a minute. How many phy-

sicians caring for high-risk cardiac patients specifically rec-ommend CPR training to family members? Very few, and thisreflects one of the failures of the medical community. Lay-person bystander CPR is known to work, and yet physiciansso often fail to prescribe it. Cardiac arrest most often occursat home, and the person most likely to witness it is a familymember, but these are typically the people least likely to havebeen trained in CPR. Physicians should always recommendCPR training for the family of high-risk cardiac patients. Itcan make all the difference; with it, a victim of out-of-hospital ventricular fibrillation has as much as a 50% chanceof full functional recovery. Too many physicians have be-come accustomed to seeing and managing a case of nearlyhopeless asystolic arrest and have forgotten that patients canbe awake and talking half an hour after an arrest.

Automatic DefibrillatorsOne of the biggest advances in the past few years is the

automatic defibrillator. It is a self-contained, electronic de-vice that a minimally trained layperson can attach to a pa-tient. The machine analyzes the cardiac rhythm with sophis-ticated electronic algorithms; if it detects ventricularfibrillation, it administers a shock to the patient. These defi-brillators are very accurate. They have great potential be-cause they can be placed in the hands of people who haveminimal medical skills but who are often the first to reach thescene of a prehospital cardiac arrest. In San Francisco, wehelped train the entire fire department to use these. In ourcity, the firefighters routinely arrive at a scene of cardiacarrest six to ten minutes sooner than the paramedics. For thefirst time we are seeing a reversal of San Francisco's lowcardiac-arrest save rate, attributed at least partially to ourlong ambulance response times. We are now seeing a notablenumber of patients resuscitated in the field and conscious onarrival in the emergency department because of early defi-brillation by firefighters.

These machines have several advantages besides the easeand speed with which almost anybody can be trained to usethem. First of all, they are the fastest way to defibrillate. Withthis defibrillator highly trained people will deliver a shockabout a minute sooner than with standard equipment. Thisgain in time, which is very important in ventricular fibrilla-tion, is achieved partly because the semiautomatic devicedelivers the shock through pads, which are faster than pad-dles.21 The device also senses and shocks ventricular fibrilla-tion faster than can be done manually.

In Seattle, 30% of patients whose ventricular fibrillationwas treated by firefighters with this defibrillator were dis-charged from the hospital alive. This compares with a sur-vival of about 17% if firefighters just did traditional basicCPR and waited for paramedics to arrive and defibrillate apatient.

Early defibrillation will save far more lives than any phar-macologic intervention. California law now allows lay peo-ple to be trained to use this device. I think we are going to seethese machines spreading into large corporate headquartersand public places because most members of corporate boardsof directors are usually male, of prime age, and have otherrisk factors for a myocardial infarction. Automatic defibrilla-tors probably also have a place on hospital "crash" carts,where they could cut precious minutes from the duration of

arrest by allowing virtually any hospital personnel to dodefibrillation.

Metabolic and Respiratory Acidosis inCardiac Arrest

Whether metabolic acidosis in cardiac arrest should betreated is worth discussing. Is metabolic acidosis in this situ-ation bad? Physicians were all taught so in medical school.All physicians can recite the theoretic reasons acidosis couldbe harmful: it could make defibrillation more difficult; itcould prevent catecholamines from working; it could worsencardiac contractility and conduction; and it could make over-all resuscitation less likely. Let us examine the literature andsee if any of these beliefs are true.

In experiments in animals, there really is no significantmetabolic acidosis for the first 15 minutes of resuscitation,and outcome is largely determined in the first 20 minutes. Ina sense, what happens later does not much matter. Similarly,most humans are not acidotic before cardiac arrest, eventhose in an intensive care unit, and they, too, take about 15minutes for significant metabolic acidosis to develop. On theother hand, respiratory acidosis in cardiac arrest is common,severe, and develops quickly.

What about the effects of acidosis on the defibrillationthreshold? Metabolic acidosis does lower the threshold atwhich the heart fibrillates, but it does not at all affect theamount of energy required to defibrillate the heart.22 Whatabout catecholamines? The studies on the effects of acidosison catecholamines are mostly old, mostly primitive, andnone ofthem focused on events during cardiac arrest. Typicalresults are that acidosis decreases the pressor response toepinephrine by a third to a half, but the blood pressure stillincreases significantly. So these studies in animals suggestthat the effect is blunted but by no means abolished. Prelimi-nary unpublished studies of human victims of cardiac arrestfound no relationship between the venous or arterial pH andthe response of the coronary artery perfusion pressure tolarge doses of epinephrine.23

In some ways metabolic acidosis might even be beneficialin cardiac arrest. Acidosis increases oxygen unloading fromhemoglobin and substantially increases oxygen delivery totissues. Some studies of cardioplegic solutions have shownthat acidotic solutions preserve the adenosine triphosphate(ATP) energy stores of an arrested heart better than alkaloticsolutions do. Redding studied the arterial pH of dogs afterfive minutes of cardiac arrest. The animals that could not beresuscitated had pHs near normal, whereas those that wereresuscitated had pHs of 7.2 or 7. 1.6 Certainly metabolicacidosis did not worsen, and perhaps improved, the outcomein these animals. Similar results are seen in humans. The twofactors that do predict increased mortality in humans are apH greater than 7.55 and plasma osmolality greater than330 mOsm per liter.24 Both of these thresholds are easilyand routinely exceeded with the administration of sodiumbicarbonate.

There is thus no proof that metabolic acidosis needs ur-gent treatment early in arrest. It does not affect defibrillationenergy, and although it may blunt the catechol response,there is nothing to suggest that this cannot be overcome byusing large doses of catechols. Acidosis may even protect anischemic heart against further damage during cardiac arrestand may improve the chance of resuscitation.

Even if acidosis should be treated, is bicarbonate a safe

700 CARDIAC ARREST

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and effective agent for it? The Henderson-Hasselbalch equa-tion predicts that when sodium bicarbonate is given, the onlyway hydrogen ion concentration can be reduced is by gettingrid of the carbon dioxide that is generated in the process. Ifcarbon dioxide cannot be eliminated, acidosis will not bereversed. Bicarbonate administration always increases thePco2 6 to 10 mm of mercury, even in normal healthy humans.In a patient with poor perfusion, such as during cardiac ar-

rest, little blood is perfusing the lung and little carbon diox-ide can be blown off. In fact, carbon dioxide exhalation incardiac arrest is virtually nil, and the mixed venous Pco2 isoften over 100 mm of mercury.25 In this setting, bicarbonateis an ineffective buffer and only increases the already severe

respiratory acidosis. Studies in animals have shown that bi-carbonate has no buffering effect whatever on myocardialtissue in CPR.26

No study of cardiac arrest has been completed thatshowed any benefit from giving bicarbonate. Like ACLS-recommended doses of epinephrine, bicarbonate is a com-

pletely unproved therapy in cardiac arrest. On the otherhand, the use of bicarbonate has many harmful effects, andthe worst of these is the generation of carbon dioxide (Table1). Now, the pH that matters in cardiac arrest is not the pHthat is measured in the arterial blood; it is the intracellular pHthat determines whether the heart can resume function. Bi-carbonate does not pass through the cell membranes rapidly,and it takes this ion three to five hours to change the intracel-lular pH.2" Intracellular pH is well buffered, and it does notdrop dramatically in the first 15 or 20 minutes almost regard-less of the degree of metabolic acidosis. But the situation isentirely different with carbon dioxide, which crosses the cellmembrane quickly and easily. It immediately causes intracel-lular acidosis because there is virtually a linear relationshipbetween the intracellular Pco2 and the intracellular pH.

A high intramyocardial Pco2 is closely associated withmyocardial dysfunction, and the intramyocardial Pco2 risessteadily after cardiac arrest to phenomenal levels. The intra-myocardial Pco2 is 240 mm of mercury at 5 minutes andexceeds 400 mm of mercury at 15 minutes.27 This correlateswell with histologic injury, a decreased myocardial oxygen

concentration and pH, and decreased ATP. Isolated hearttissue shows the different effects on functions of an identical

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Figure 4.-The effect of metabolic versus respiratory acidosis (pH6.8) is shown on the developed tension of an isolated, perfused,spontaneously beating adult rabbit heart in vitro. Similar results areobtained for effects on cardiac conduction (from Nakanishi et a128).Developed tension in metabolic acidosis stabilized after 10 minutesand declined no further for up to an hour. In respiratory acidosis, itstabilized in 5 minutes and persisted at those levels throughout theexperiment.

pH achieved by metabolic versus respiratory acidosis (Figure4).28

Recent studies of lactic acidosis in animals show an in-verse correlation between mixed venous carbon dioxide andcardiac output; administering sodium bicarbonate increasedthe mixed venous carbon dioxide levels and directly de-pressed cardiac function.29 An elegant study done recently atthis medical center showed that even small amounts ofbicar-bonate given to stable normotensive patients with congestiveheart disease lowered Po2 levels, lessened cardiac contractil-ity, worsened myocardial oxygen extraction, increased an-

aerobic metabolism and myocardial lactate production, andeven induced angina and transient pump failure in severalpatients.30 Administering a saline solution in equimolarquantities had no such effects.

In conclusion, bicarbonate has many proven harmful ef-fects and no proven beneficial effects in cardiac arrest. TheACLS guidelines have reduced the recommended doses ofbicarbonate in every revision. They currently state that bicar-bonate should be given on the basis ofblood gas values and atthe discretion of the team leader, placing the dilemmasquarely in the clinician's lap. I personally have not usedbicarbonate in cases of cardiac arrest for years. The questionthat physicians usually ask at this point is, "What if you getthe blood gases back and the pH is 6.7; don't you give bicar-bonate then?" My answer is still no. Improving ventilationand blowing offcarbon dioxide is the answer at this point, forthe real problem is severe respiratory acidosis. Unfortu-nately, acidosis cannot be assessed where it really mattersinside the cell. Typical blood gas values during a well-doneresuscitation show an arterial pH of 7.41 and a Pco2 of 19mm of mercury, and it is tempting to think that the patient isin great shape. But the patient's mixed venous pH is likely6.5 with a Pco2 of 90 mm of mercury. The moral is thatarterial blood gas measurements in patients in cardiac arrestare not useful for much other than determining oxygenation.

Questions and AnswersPHYSICIAN IN THE AUDIENCE: Should a patient's age be a

factor in whether or not to resuscitate?DR CALLAHAM: Resuscitation in the elderly has been fairlywell studied, and age alone does not preclude a good out-come. Underlying disease is far more important. Very el-derly patients can be successfully resuscitated, and age is nota reason to withhold resuscitation.

PHYSICIAN IN THE AUDIENCE: Exactly what as a team leadershould I tell the pharmacist and the nurse? Should I say,

TABLE 1.-Harmful Effects of Administering Sodium Bicarbonate

Hyperosmolality (solution has osmolality of 2,000 mOsm/liter)HypematremiaBohr effect decreases Po2 and oxygen release to tissuesAlkalemia causes coronary vasoconstrictionDecreases coronary artery perfusion pressure in animals about 50%6Elevates Pco2 and causes rapid intracellular acidosis

Myocardial Pco2 is highly correlated with ST changes, histologic in-jury, and decreased ATP and high-energy phosphate levels

Depression of cardiac contractility and conductionIncreased cardiac oxygen debt and anaerobic metabolismATP=adenosine triphosphate

701THE WESTERN JOURNAL OF MEDICINE - JUNE 1990 * 152 - 6

"Open a 30-mg ampule of epinephrine, put it in 250 ml ofD5W, and run it in asfast as you can ? "Howprecisely do yougive a dose of200 ,tg per kg?

DR CALLAHAM: I do not use epinephrine drips anymore, andthe reason is that we want to achieve as high a level of epi-nephrine as possible as fast as possible for maximal vasocon-

striction. Therefore, I use an intravenous push. The otherreason I abandoned drips is that "wide open" is a totallyunpredictable rate. If you actually measure how much runs

in, it may be only 25 to 35 ml over 15 to 20 minutes; it isseldom that the full 250 ml goes in. So we draw up 15 mgfrom a 30-ml vial of 1:1,000 epinephrine. We usually try todilute the epinephrine with 10 ml of a saline solution, but thatis not based on any studies or hard science. Then we just giveit as an intravenous push, assuring high levels very rapidlyand making life much simpler for us during the resuscitation.

PHYSICIAN IN THE AUDIENCE: Is there any reason to use

intracardiac epinephrine anymore?DR CALLAHAM: No. I wish I had brought along a slide of oneof my favorite references from about 20 years ago. I alwaysthought the purpose of the technique was to administer epi-

nephrine directly into the heart and deliver it to the arterialcirculation, where it does its work. However, this articlestated that the stimulation provided by multiple punctures ofthe heart with a needle might be sufficient to get it goingagain. Nobody recommends the intracardiac administrationofepinephrine anymore, and postmortem studies have shownthat it was seldom accurately delivered to the heart anyhow.The underlying question of whether we might do better if wedelivered the epinephrine to the arterial side ofthe circulationis unstudied and unanswered.

PHYSICIAN IN THE AUDIENCE: What is the role of calcium?DR CALLAHAM: Calcium poses some interesting questions,but I do not have the answers. I thought the use ofcalcium didnot make much sense in the old ACLS protocols. Then a

couple of retrospective and somewhat debatable studies wereconducted showing that calcium provided no benefit in resus-

citation, and it was removed from all of the protocols. Isuspect that part of the reason it was removed was the some-times'simplistic logic of physicians. Calcium channel block-ers had become available during that period and are regardedas effective, "good" medications. Therefore, the substancethey block must be "bad," and we should not administer it. Inany event, we do not understand what calcium really does incardiac arrest. One of the adverse effects of intracellularacidosis is that the hydrogen ion competes with calcium foruptake; calcium administration helps reverse this effect ofacidosis.

PHYSICIAN IN THE AUDIENCE: Has anybody looked at usinghigh-dose epinephrine along with esmolol, a short-acting 13-

blocker?DR CALLAHAM: No, not with a short-acting $-blocker. Theonly study that examined the two drug types together was

done with propranolol, in animals, and ,B-blockade did notdiminish the effectiveness of epinephrine at all. The role ofthe adrenergic nervous system in cardiac arrest is poorlyunderstood, and there may be some important effect of epi-

nephrine's ,B-adrenergic properties, but until more studiesare done, nobody is going to know.

PHYSICIAN IN THE AUDIENCE: Are there any data on the useof carbicarb for severe acidosis?DR CALLAHAM: Carbicarb is a buffer that consumes ratherthan generates carbon dioxide, and it has been nicely studiedby Dr Bersin of UCSF in an animal model of lactic acidosis,showing that it corrected the pH to nearly normal withoutelevating the Pco2, without causing intracellular acidosis,and without depressing the heart. That is very attractive, butanother study showed it did not buffer the intramyocardialpH in animals during cardiac arrest. The proper questionmay not be whether we can correct pH in cardiac arrest, otherthan by eliminating respiratory acidosis, but whether weneed to.

PHYSICIAN IN THE AUDIENCE: What is the availability ofcarbicarb ?DR CALLAHAM: It was not available the last I heard. I know itis supposed to come on the market.

PHYSICIAN IN THE AUDIENCE: Can you tell us whether yourwork and that ofothers is beginning to have an effect on thepublished guidelines regarding the use ofbicarbonate? Is itstill recommended officially?DR CALLAHAM: The recommendations have not changed, butthen, of course, the last revision was done in 1985, and thenext one is due out in 1990. I suspect, judging by the historyof the ACLS Committee, that the next set of recommenda-tions will probably either discard the use of bicarbonate alto-gether or further decrease its use. Probably they will movepart of the way towards a higher dose of epinephrine. Re-member that these guidelines are all written by a committeeand revisions are only made every five years, so the pace ofchange is inherently slow and the recommendations are al-most by definition out of date. But change does occur.

PHYSICIAN IN THE AUDIENCE: Would you agree also thatthe data you showed in this situation would apply to themisuse ofbicarbonate in a situation like mesenteric vascularischemia, where bicarbonate is given as soon as the patientbegins to show acidosis by pH measurement alone, disre-garding everything else?DR CALLAHAM: I am not an authority on the treatment ofmetabolic acidosis in noncardiac arrest situations, but frommy reading of the literature, I do not think there is any situa-tion in which bicarbonate is the buffer of choice for acidosis.We certainly know it does only harm in patients with lacticacidosis. It does not improve the outcome in diabetic ketoaci-dosis, nor in cardiac arrest, and in fact may well worsen theoutcome. Bersin, Chatterjee, and Arieff have shown in ele-gant studies that even in stable cardiac patients, giving bicar-bonate increases the oxygen debt and myocardial anaerobicmetabolism, even inducing angina and failure.30 My guesswould be that in five years we will not be using it for thispurpose at all.

PHYSICIAN IN THE AUDIENCE: Considering what you saidabout the PCo2, it seems that blood gas determinations wouldbe useful tojudge the efficacy ofventilation, and maybe thatwould put the focus on whether you are actually achievingadequate ventilation.DR CALLAHAM: No, they are not useful. There are two rea-sons. One is that there is only poor correlation between arte-rial and venous blood gas values (or mixed venous blood gas)

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in arrest. The other reason is that blood gas values are ameasure ofboth ventilation and perfusion in arrest. The usualsituation is that you are ventilating the patient nicely, but youare not perfusing the lungs. Chris Barton and I have beenstudying end-tidal capnometry here in our emergency depart-ment at Moffitt Hospital to measure how much perfusion isactually achieved during CPR. The blood flow through thelungs in most patients is absolutely minimal. This blood flowcorrelates highly with their end-tidal Pco2 and their coronaryartery perfusion pressure, and in turn that value predicts thelikelihood of successful resuscitation with a positive predic-tive value of 91% .31,32 In most patients in cardiac arrest, themixed venous carbon dioxide level is high-over 100 mm ofmercury-but pulmonary blood flow (and alveolar Pco2) islow. These same patients will often, however, have nearlynormal arterial blood gas values, which reflects the trickle ofoxygenated blood getting through the pulmonary circuit andnot the vast stagnant pool of acidotic, hypercarbic, hypoxicblood in most tissues.

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