Cardiopulmonary cerebral resuscitation – present and future perspectives

Acta Anaesthesiol Scand 1999; 43: 526–535 Copyright C Acta Anaesthesiol Scand 1999Printed in Denmark. All rights reserved

ACTA ANAESTHESIOLOGICA SCANDINAVICA

ISSN 0001-5172

Review

Cardiopulmonary cerebral resuscitation –present and future perspectives

S. RUBERTSSON

Department of Anesthesiology and Intensive Care, Uppsala University Hospital, Uppsala, Sweden

INTENSE research over the past 40 years within thefield of cardiopulmonary resuscitation (CPR) has

only resulted in minor improvement in final outcome.A recent review of in-hospital cardiac arrests found awide variation in the reported survival to dischargeranging from 0% to 28.9% with a mean of 14% (1).This is largely explained by underlying diseases. Inout-of-hospital cardiac arrests the survival to dis-charge is similar (2, 3). Unfortunately, not all of thepatients who survive to hospital discharge are able toreturn to productive lives. For many, cardiac arrest isa natural ending to a long and productive life. A sub-stantial number, however, are struck by this event tooearly in life when their ‘‘hearts and brains are toogood to die’’ (C. Beck, P. Safar), with tragic conse-quences, including financial problems for both familyand society.

There are many factors involved which have an in-fluence on the outcome of cardiac arrest victims, in-cluding the rapidity and efficacy with which resusci-tation interventions are delivered. In several studies,early initiation and effective performance of CPR bybystanders has been proven beneficial to the survivaland final outcome of cardiac arrest victims (3, 4). By-stander CPR is an important link in ‘‘the chain of sur-vival’’ before more advanced interventions can beavailable at the scene (4). Therefore, CPR training pro-grams for lay people have been organized in manycountries with millions of people trained in basicCPR. It is important to continue this education of laypeople since at the moment early bystander CPR, be-sides defibrillation, is probably the single most im-

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Received 11 June, accepted for publication 24 December 1998

Key words: Cardiopulmonary resuscitation; advanced cardiaclife support; epinephrine; alkaline buffers; brain resuscitation.

c Acta Anaesthesiologica Scandinavica 43 (1999)

portant intervention. Some countries have done agreat deal in this field, but many others need to domuch more. Sudden prehospital cardiac deathstreated with early activation of the emergency medi-cal system, early basic life support (BLS), includingprecordial compression and artificial ventilation, earlydefibrillation, and early advanced cardiac life support(ACLS) could achieve 25–40% survival rates (3). Theseconcepts for emergency cardiac care have been rec-ommended by the American Heart Association (5) aswell as the European Resuscitation Council (6).

Advanced cardiac life support protocols combinepharmacological and mechanical interventions forrestoration of spontaneous circulation (ROSC) by im-proving perfusion pressures and blood flow to vitalorgans and treating arrhythmias. The present ad-vanced cardiac life support protocol is based on fourcomponents: early defibrillation, administration ofdrugs, ventilation (oxygenation), and circulatory sup-port.

Defibrillation

Early defibrillation is without doubt the most import-ant intervention in improving ROSC and thus, hope-fully, outcome (3). It is estimated that at least 50% ofpatients in cardiac arrest are in ventricular fibrillation(VF) when the first ECG recording is done (3). Theamplitude of VF decreases over time to a flat line, re-flecting worsening of the ischemic condition of theheart. A minimal delay to defibrillation shouldimprove the chance of survival. Ideally, the

CPCR – present and future perspectives

countershocks should be delivered by the first re-sponder within 2 min of untreated VF. In patientswith very fine/poor VF, it might be advantageous todo some myocardial reoxygenation with ventilationand sternal compressions before defibrillating (7, 8).Portable defibrillators that read ECG, recognize VF,and discharge automatically or semi-automaticallyneed to be more readily available for use by the emer-gency service team and trained lay persons. Further-more, selected patients at particularly high risk of de-veloping VF should be equipped with implantedautomatic defibrillators.

Drugs

EpinephrineDuring cardiopulmonary resuscitation there are onlya few drugs that have proved useful. Epinephrine hasbeen accepted as the drug of choice in the ACLS pro-tocol (5, 6). This is essentially based on the fact thatseveral experimental studies have shown that epine-phrine increases myocardial and cerebral blood flowduring CPR (9, 10). Epinephrine also helps to restorespontaneous normotension in cardiac arrest of morethan about 1–2 min duration, irrespective of the ECGdiagnosis (5). These effects have mainly been accred-ited to: 1) peripheral alpha-receptor stimulation re-sulting in greater perfusion pressure through heartand brain; and 2) possible beta-receptor effect on thecoronary arteries and brain vessels resulting in in-creased blood flow to both of these organs. Althoughepinephrine can produce VF, it can also help convertfine VF into coarse VF, which is more susceptible totermination by electric countershock (11). The currentrecommended dose of epinephrine is 1 mg/70 kgbody weight as an IV bolus, repeated every 3–5 minuntil ROSC (5). There is no current agreement, how-ever, on the optimal dose of epinephrine. Therefore,extensive experimental efforts have been made to de-termine whether a larger dose would result in ahigher survival rate.

Several experimental studies have supported theuse of ‘‘high-dose’’ epinephrine to improve myocar-dial and brain blood flow and enhance ROSC (12, 13).These promising results initiated clinical trials with 5–10 times the recommended dose of epinephrine (14–19). Some of these studies showed enhanced ROSCrates (14, 17, 18) but no overall difference in good cer-ebral outcome rates. One explanation for this mightbe that high doses of epinephrine restart more heartspartly because of better organ blood flow. If, however,the hearts and brains of these patients have alreadybeen subjected to poor circulation, this is of no benefit.

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Another possible explanation for the failure of ‘‘high-dose’’ epinephrine to improve cerebral outcome inclinical trials has been suggested in a recent study byour group where cortical blood flow tended to belower and the blood flow increase of shorter durationin the group treated with a high dose as compared toa standard dose of epinephrine (20). This indicates theinduction of vasoconstriction and reduced blood flowin superficial cerebral cortex in response to ‘‘high-dose’’ epinephrine.

VasopressinOne negative effect of epinephrine is the intensetachycardia often observed immediately after ROSC,which can lead to recurrent ventricular fibrillationand myocardial ischemia. Therefore, several otherdrugs with primarily peripheral vasoconstrictor ef-fects have been studied as a substitute for epinephrineduring CPR. One promising drug is vasopressin,which during CPR appears to increase systemic vas-cular resistance (21). Circulating endogenous vaso-pressin concentrations are very high in patients in car-diac arrest during CPR, and the levels of vasopressinhave been shown to be significantly higher in resusci-tated than in nonresuscitated patients (22). Vaso-pressin may increase peripheral vasoconstriction di-rectly via the V1 receptor and/or by potentiating thevasoconstrictor effect of endogenous catecholamines(23, 24). Vasopressin administered during cardiac ar-rest to pigs receiving either open or closed-chest CPRhas resulted in higher blood flow through heart andbrain when compared with epinephrine (25, 26). Inthese studies, however, cerebral blood flow was meas-ured with microspheres during CPR at only two arbi-trarily chosen time points after the administration ofvasopressin. Furthermore, no measurements of cer-ebral blood flow were done in the immediate post-resuscitation period. A preliminary study comparingepinephrine and vasopressin in 40 patients with out-of-hospital ventricular fibrillation has recently beenpresented (27). In that study, a significantly greaternumber of patients treated with vasopressin com-pared to those treated with epinephrine were resusci-tated successfully and survived for 24 h. There was nodifference, however, in neurologic outcome at hospitaldischarge. Before larger multicenter studies of vaso-pressin are undertaken in the treatment of cardiac ar-rest, continuous cerebral blood flow measurementsneed to be made during CPR as well as in the immedi-ate post-resuscitation period after vasopressin admin-istration. Clinical trials are not to be recommendedbefore neurological outcome studies in animals havebeen completed.

S. Rubertsson

Alkaline buffersAcidosis during cardiac arrest is mainly a result ofperfusion failure with inadequate tissue oxygenation,resulting in anaerobic metabolism with decrease inadenosine triphosphate (ATP) production and lacticacid and carbon dioxide accumulation. There is also arespiratory component due to failure of ventilation,resulting in further accumulation of carbon dioxidethat exceeds normal buffering capacity (28). Duringthe past 20 years, the role of alkaline buffering duringCPR has been discussed by several authors. It hasbeen demonstrated that the administration of sodiumbicarbonate in this situation may cause hyperosmolar-ity (29) and increase PCO2 of mixed venous and coro-nary sinus blood as well as cerebrospinal fluid (30–32). Reduced coronary perfusion pressure (33) and noimprovement of survival (34–36) after the administra-tion of sodium bicarbonate during CPR have alsobeen reported. These results have induced the Ameri-can Heart Association to recommend cautious use ofbuffering in the treatment of cardiac arrest (5). On theother hand, it is well known that metabolic and respir-atory acidemia (pH∞7.2) decreases myocardial con-tractility and inhibits the cardiovascular response tocatecholamines (37–39). Furthermore, recent experi-mental data demonstrating improved outcome withthe administration of sodium bicarbonate during CPRin dogs (40) support the use of buffers. Another studydemonstrated that sodium bicarbonate or tris buffermixture during CPR increased intracellular adenosineconcentration, which is potentially beneficial asadenosine has positive metabolic effects and anti-arrhythmic and cardioprotective properties (41).These latter results supporting the use of alkaline buf-fers may lead to a less restrictive attitude regardingits use in future ACLS protocols.

Ventilation

Since the 1950s, CPR has included airway control andmouth-to-mouth ventilation followed by intubationand mechanical ventilation with oxygen (42). Arti-ficial ventilation with 100% oxygen during basic andadvanced CPR has been recommended by the Ameri-can Heart Association (5). The optimal FIO2 duringCPR attempts and after possible ROSC remains to bedetermined. The reason for this is the existing evi-dence of reperfusion injury by partially reduced oxy-gen species causing microvascular and neuronal in-jury of the brain (43–45). When comparing ventilationwith pure oxygen to air during experimental CPR, ithas been demonstrated that the arterial-mixed venousoxygen content difference was approximately 25%

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greater with pure oxygen than with air. However,there was no difference in systemic oxygen uptake(46). In paralyzed humans, with normal circulation,normal blood gases can be achieved with ambient airor expired air (47–49).

Lately, there has been discussion whether or not toventilate at all during basic CPR (50, 51). The debateis based on conflicting reports on the importance andeffectiveness of initial ventilation during CPR (52–54).These reports, however, concern animals which havestraight airways and do not obstruct, even in the ab-sence of a tracheal tube when unconscious. Inhumans, the airways are kinked and therefore alwaysobstruct in the absence of backward tilt of the headwhen in coma (49, 57). In the intubated human withcardiac arrest, forceful sternal compressions alonehave been shown essentially not to move ventilation(57). The same debate has also focused on the trainingobstacles to performing effective CPR by the lay res-cuer and the reluctance to perform mouth-to-mouthventilation because of fear of disease transmission (50,51). Mouth-to-mouth ventilation is safe and there isno documented case of transmission of the HIV virusby this route. The current recommendation is thatventilation should start promptly. For the lay rescuer,this means putting the individual in a backward tiltof the head position and giving mouth-to-mouth ven-tilation. This should be followed by intubation andventilation with pure oxygen as soon as available,since flow of oxygenated blood is the limiting factorduring CPR.

Generation of blood flow

Several investigations during the most recent decadeshave focused on two major theories for the generationof blood flow during closed-chest CPR. The first ofthose, the ‘‘cardiac pump’’ theory, describes the heartfunction as a multichamber pump with competentvalves. The heart is squeezed between the sternumand the spine during compression of the chest, caus-ing forward ejection of blood. This was first suggestedby Kouwenhoven et al. (58), and has been further sup-ported by many authors (59, 60). The second is the‘‘thoracic pump’’ theory, a consequence of the fact thatall contents of the chest are subjected to the samepressure variations. Thoracic compression producesglobal elevation of intrathoracic pressure and a result-ant pressure gradient across the thoracic inlet, squeez-ing blood from the pulmonary vascular bed throughthe heart and into the peripheral vessels. The heartacts like a passive conduit without significant valvefunction. During compression, the great systemic


veins are more easily collapsed than the aorta and thesystemic arteries. Venous valves at the thoracic inletfavour blood flow into the arterial circulation (61–66).However, Babbs et al. (59) and later Paradis et al. (67)have indicated that one or the other mechanism maypredominate in different situations or in individualvictims of cardiopulmonary arrest. It is most likelythat the ‘‘cardiac pump’’ is the predominating mech-anism initially when the heart valves may remain atleast partially competent (68). In children, who aremore inherently broad chested, ‘‘cardiac pump’’ willprobably predominate as the mechanism to generateblood flow during CPR. With increasing ischemictime, the ‘‘thoracic pump’’ mechanism may becomemore important in generating blood flow during tra-ditional closed-chest CPR (68).

Circulatory support

Open-chest CPROne of the main reasons for standard external CPR tofail and not result in successful ROSC might be thevery low blood flow generated by sternal com-pressions. Cardiac output values have been reportedat 20–40% of normal during experimental closed-chestCPR (69, 70). Newer data in pigs with a more reliableflow measurement technique, such as the transit-timeultrasound flowmetry, indicate that cardiac output isonly 10% of normal during experimental closed-chestCPR (71, 72) and 20% during open-chest CPR (71–73).The open-chest technique was replaced by sternalcompressions (closed-chest CPR) in the beginning ofthe 1960s (58). Kouwenhoven et al. (58) published re-sults demonstrating a 70% survival rate after in-hospi-tal cardiac arrest treated immediately with closed-chest CPR. Subsequent clinical studies have not beenable to demonstrate such high survival rates but, dueto its simplicity, closed-chest CPR became the stan-dard procedure. Without doubt, open-chest CPR isphysiologically superior, producing higher perfusionpressures and blood flows than closed-chest CPR inhumans (74) and better outcome in dogs (75). Theopen-chest technique has unfortunately been largelyforgotten and currently is recommended only in cer-tain situations. The total switch from open-chest CPRto the non-invasive closed-chest technique in the be-ginning of the 1960s may have been a mistake. Newerclosed-chest techniques have been tried but with noimprovement in survival. If we had kept up the open-chest technique as a first line intervention instead ofthe present standard, closed-chest CPR, more livesmay have been saved. Early thoracotomy and switchfrom closed-chest CPR to open-chest CPR within 5

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min from hospital arrival resulted in higher ROSCand hospital discharge in a small study of non-trau-matic cardiac arrest victims (76). Furthermore, in a re-cent study of out-of-hospital cardiac arrests, switch toopen-chest CPR, after initial failure of prolongedclosed-chest CPR to restart heart beat, resulted inROSC (77). Open-chest CPR needs to be taught again,upgraded within the new ACLS protocol and not onlyused as a last resort. Several other techniques to im-prove perfusion pressures and blood flow to the vitalorgans have been tested (Table 1).

Emergency cardiopulmonary bypassEmergency cardiopulmonary bypass (CPB) is the ulti-mate form of artificial circulatory support but also themost invasive method, even when veno-arterialpumping via oxygenator is performed without thora-cotomy (78). The technique is even more efficaciousthan open-chest CPR to generate blood flow. WithCPB it will be possible to control reperfusion pressurepatterns, oxygenation, temperature, and blood com-position (78). Cannulation of the femoral artery aswell as placement of a catheter draining the venaecava are technically problematic and time-consuming.In dog studies using CPB, it has been possible to re-verse normothermic cardiac arrest of up to 15 minwithout blood flow (78) and achieve survival withoutneurologic deficit after 11 min of no blood flow (79).Between 1984 and 1991, 125 patients in 17 hospitalswithin the USA in whom conventional CPR had failedshowed a 20% ROSC rate after use of CPB and 14%were alive after 30 days (80). It is questionable howfeasible this technique could become out-of-hospital.At least for now it is limited to in-hospital use sinceno realistic portable CPB unit for the out-of-hospitalscenario has yet become available.

Intra-aortic balloon occlusionIntra-aortic balloon occlusion of the descending aortais a new and promising technique in CPR. It re-sembles the aortic cross-clamping previously used in

Table 1

Techniques to generate blood flow to the vital organs during cardio-pulmonary-cerebral resuscitation.

O Open-chest CPRO Emergency cardiopulmonary bypassO Intra-aortic balloon occlusionO Interposed abdominal compression CPRO Pneumatic vest CPRO Active compression-decompression CPR

Phased chest and abdominal compression-decompression CPRO Minimally invasive direct cardiac massage

S. Rubertsson

combination with the open-chest CPR technique. Sev-eral recent studies using intra-aortic balloon occlusionduring CPR have demonstrated improved coronaryperfusion pressure (81, 82), increased carotid andcoronary artery blood flow (83), greater survival (81,82) and better neurologic outcome (82). Placement ofan aortic balloon catheter provides unique access tothe coronary and cerebral vascular beds during CPR.This aortic access opens a whole new field of possibleresuscitative interventions during and after CPR.Combined with intra-aortic infusion of hypertonic sa-line and dextran, it has been shown to improve cer-ebral blood flow and brain oxygen supply duringopen-chest CPR (84). Furthermore, intra-aortic bal-loon occlusion in combination with selective aorticarch perfusion with oxygenated ultrapurified poly-merized bovine hemoglobin or oxygenated perflub-ron emulsion improved the rate of ROSC (85, 86). In-tra-aortic balloon occlusion is clinically feasible, espe-cially in the hospital’s emergency department andintensive care units, where a percutaneous approachmay be quickly employed for positioning of the bal-loon catheter without fluoroscopy. In assistance foridentification of the femoral artery, portable ultra-sound equipment might be useful. However, furtherstudies, in both animals and humans, will be neededto determine the potential advantages of this tech-nique.

Interposed abdominal compression CPRWith interposed abdominal compression CPR, ab-dominal counterpulsations aim to increase intrathor-acic and aortic pressure, provide retrograde aorticflow and thereby improve blood flow to the heartand brain, and increase venous return. The abdomi-nal compression technique was first described byHarris et al. (87) and Redding (88) and was furtherdeveloped by Ohomoto and associates (89), whocombined the interposed abdominal compressionsalong with standard closed-chest CPR. Animalstudies have shown increased coronary perfusionpressure, cardiac output and common carotid bloodflow using interposed abdominal compression CPR(90–92) compared with standard closed-chest CPR.In humans, improved resuscitation rate and survivalto hospital discharge has been reported with in-hos-pital cardiac arrests (93). In out-of-hospital cardiacarrests treated with interposed abdominal com-pression CPR, compared to standard CPR, no differ-ence in survival has been found (94). However, im-proved neurologic outcome in patients at dischargefrom the hospital could not be demonstrated in anystudy.

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Pneumatic vest CPRThe pneumatic vest CPR increases intrathoracic press-ure fluctuations by circumferential changes in the di-mensions of the thorax and thereby improves venousreturn and forward aortic flow. In dogs, Halperin andco-workers demonstrated improved coronary bloodflow and survival when using cyclical inflations of apneumatic vest during CPR (95). In a small humanstudy, pneumatic vest CPR compared to standardCPR resulted in greater coronary perfusion pressure,but there was no difference in survival between thetwo techniques (96). In this study, however, there wasan initial period of 11∫4 min before the patients wererandomized to receive either vest CPR or continue tobe treated with standard closed-chest CPR. Currently,an international multicenter study in Europe and theUnited States is comparing the pneumatic circumfer-ential vest with standard CPR but the results are stillpending. A pneumatic vest is under development foruse by ambulance personnel.

Active compression-decompression CPRActive compression-decompression (ACD) CPRworks by the same principle as vest CPR with in-creased intrathoracic pressure fluctuations with en-hanced cardiac compression and forward aortic flow.Venous return to the chest is improved during decom-pression. The concept for this technique arose from ananecdotal report where a lay rescuer had used a toiletplunger to perform chest compressions and decom-pressions on a cardiac arrest victim and the personsurvived (97). The currently available ACD deviceconsists of a corrugated silicon rubber suction header,steel central piston, and reinforced glass fiber handle.The ACD device is placed over the midsternum andprovides active manual compression of the chest aswell as active chest decompression. Animal studieshave shown increased cardiac output and coronaryperfusion pressure (98) and also greater cerebral andmyocardial blood flow compared to standard closed-chest CPR (99). In a preliminary study, increasedROSC and 24-h survival, but not improved hospitaldischarge rate, was reported from in-hospital cardiacarrest victims treated with ACD-CPR (100). This wasfollowed by three studies in patients with out-of-hos-pital cardiac arrest that reported no difference inROSC or survival to hospital discharge when com-paring this technique to standard CPR (101–103). Oneof these studies also reported no improvement in sur-vival or neurologic outcome in 773 patients with in-hospital cardiac arrest compared to standard closed-chest CPR (103). Recently, a randomized multicenterstudy of ACD-CPR, reported improved short-term


survival and neurologic outcome at hospital dischargein out-of-hospital cardiac arrest victims comparedwith standard closed-chest CPR (104). There was,however, no difference in 1-month survival or neuro-logic outcome. In Europe, several additional studiesusing this technique have been performed but a de-finitive clinical advantage has not yet been demon-strated (105).

Phased chest and abdominal compression-decompression CPRPhased chest and abdominal compression-decom-pression CPR is a combination of active compression-decompression CPR and interposed abdominal com-pression. There is a device that resembles a see-sawwith piston suction cups positioned both on the chestand the abdomen. Chest compression is coincidentwith abdominal decompression, followed by chest de-compression plus abdominal compression. In an ex-perimental study on pigs, improved coronary per-fusion pressure, ROSC, survival and neurologic out-come was found compared to standard CPR (106).This was a small, preliminary study but the techniquelooks promising. Clinical trials are being performedbut no results have been presented so far.

Minimally invasive direct cardiac massageMinimally invasive direct cardiac massage utilizes aplunger-like device inserted through a small intercos-tal incision over the apex of the heart. Without open-ing the pericardium the device is placed directly onthe ventricles of the heart, producing an artificial cir-culation by cyclic cardiac compression and relaxation.In two studies on pigs this technique has been re-ported to result in cardiac output, systemic bloodpressure, and coronary and cerebral perfusion similarto that produced by conventional open-chest, biman-ual cardiac massage (107, 108). This technique, how-ever, has only been tested in a few patients and needsfurther clinical investigation.

Brain oriented resuscitation

Over the past 28 years, brain oriented research hastried to find interventions that minimize the ischemicinsult of the brain and augment the effectiveness ofCPR. Several mechanisms during the ischemic insultand after ROSC have been suggested. After ROSC andhypertensive reperfusion, there is transient hyperemiafollowed by delayed protracted cerebral hypoperfu-sion (109). The no-reflow phenomenon seen withhypotensive reperfusion seems to be prevented withnormotensive or hypertensive reperfusion (109). Is-

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chemia sets the stage for a cascade of reactions affect-ing cerebral neurons during and after reperfusion(109). Calcium loading, glutamate release, release ofoxygen radicals and other cascades leads to lipid per-oxidation and apoptosis or necrosis of selectively vul-nerable neurons (110, 111). These resulting disturb-ances most likely lead to the ultimate neuronal celldeath. The efficacy of thiopental loading on survivaland neurologic recovery was tested in the brain re-suscitation clinical trial I (BRCT I) (112). Even thoughsupported by promising animal data (113), this bar-biturate treatment did not increase overall the pro-portion of patients with good cerebral outcome (112).The calcium entry blockers, lidoflazine (114) and nim-odipine (115), have demonstrated beneficial effect inanimal models of global brain ischemia. In the BRCTII study, comatose survivors after cardiac arrest wererandomized into treatment with either lidoflazine orstandard treatment (116). There was no difference inoverall neurologic outcome between the patients inthe study. Similarly, two separate clinical studies withnimodipine administered after cardiac arrest did notshow any overall improvement in neurologic outcome(117, 118). As commonly found in research, there wasa discrepancy between experimental and clinical re-sults. When BRCT II data were retrospectively ana-lyzed with those patients excluded who had inad-equate blood pressure support or re-arrest afterROSC, the lidoflazine group had significantly moresurvivors with good cerebral outcome than the con-trol group (119). Safar has concluded that randomizedclinical outcome studies of cerebral resuscitation areplagued by many uncontrollable and unknown fac-tors, which make the proof of ‘‘no benefit’’ difficult(109, 119). The ideal drug or intervention for brain re-suscitation must have a positive effect on outcomeafter administration during CPR or after successfulROSC. After better understanding of the mechanismsinvolved, more effective pharmacologic approacheswill hopefully appear. One interesting approach thatneeds further evaluation is the results presented byFolbergrova and co-workers (120). They showed inanimals that nitrones administered after induced focalischemia act as free radical spin traps reducing infarctsize.

Mild resuscitative hypothermia to 34æC during CPRor immediately after ROSC has been shown to reverseinsult and support recovery with improved neuro-logic outcome in dogs (79, 121, 122). Several syner-gistic mechanisms in mild resuscitative hypothermiaare suggested both during and after ischemia (121).These include preservation of ATP, reduced lactac-idosis, reduced free fatty acid production, and im-

S. Rubertsson

proved glucose utilization; mitigation of abnormal ionfluxes; decreasing oxygen demand, excitotoxicity, freeradical reactions, and deleterious enzyme reactions;and tightening of membranes. Clinical studies in out-of-hospital as well as in-hospital cardiac arrests areongoing. In dogs, after 11 min of normothermic VF,no flow was reversed to complete recovery withoutneurologic deficit using a combination of mild hypo-thermia from ROSC to 12 h, plus promotion of cer-ebral blood flow with control of arterial pressure,hematocrit, and PaCO2 (79). Safar suggests (79, 109)that attempts at optimizing cerebral O2 delivery couldbe guided by normalizing mixed cerebral venous (su-perior jugular bulb) blood oxygen values. Most likelymild hypothermia and cerebral blood flow promotionwill be included in future recommendations.

Future

Future CPR research needs to focus on findingmethods that are feasible not only in the hospitals butalso in the field for ambulance services to improveblood flow to vital organs and to restore spontaneouscirculation with beneficial neurologic outcome. Thereare a few promising methods and interventions thatin the future might be used not only in the labora-tories but also in the clinical situation. These newmethods or interventions are more invasive but hope-fully will improve patient outcome. Until these newmethods are proven beneficial to patient outcome,open-chest CPR needs to be taught and wheneverpossible reinstituted as a first line intervention, replac-ing the now standard, closed-chest CPR. We also needto intensify brain oriented research to better under-stand how neurons die. This will help us to find anintervention and/or a drug that can reduce such celldeath and improve neurologic function and quality oflife of the survivors. The studies on drugs with pri-marily peripheral vasoconstrictor effects as a substi-tute for epinephrine during CPR have to continue. Allthis needs to be supported with studies in animal out-come models to evaluate neurologic outcome beforeclinical studies are initiated. Finally, the education oflay people in basic CPR has to continue. Hopefully,all this will reduce the still dismal outcome of cardiacarrest victims. Even minor improvements may have agreat impact on the numbers of survivors and theirquality of life.

Acknowledgement

The author wishes to express his gratitude to Jan Eklund, ÅkeGrenvik, Peter Safar and Lars Wiklund for reviewing the paper.

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Address:Sten Rubertsson MD, PhD, EDICMDepartment of Anesthesiology and Intensive CareUppsala University HospitalS-751 85 UppsalaSweden

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Cardiopulmonary cerebral resuscitation – present and future perspectives