Recent developments and emerging concepts in cardiopulmonary cerebral resuscitation

This discussion reviews new andemerging concepts in resuscitation thatmight be unfamiliar to pediatricemergency medicine clinicians.Specifically discussed are: (1) newmethods of cardiopulmonaryresuscitation, (2) automated externaldefibrillators for children, (3) the drugsvasopressin and amiodarone, (4) oxygenas a potential toxin, (5) postresuscitationtemperature control, (6) inherited causesof sudden death, and (7) suspendedanimation.Clin Ped Emerg Med 5:217-223.© 2004 Elsevier Inc. All rights reserved.

Supported in part by the NationalInstitutes of Health, National Institute ofChild Health and Human DevelopmentGrant No. KO8-HD40848, and theCompetitive Medical Research Fund ofthe University of Pittsburgh MedicalCenter Health System.

Recent Developments andEmerging Concepts in

Cardiopulmonary CerebralResuscitation

By Robert W. HickeyPITTSBURGH, PENNSYLVANIA

THE LAST SEVERAL YEARS have seen a number of impor-tant advances made in resuscitation science. One has onlyto walk through an airport to witness the impact of auto-mated external defibrillators (AEDs) on public awareness

and treatment of sudden death. Similarly, a search of the NewEngland Journal of Medicine since 2000 yields 11 clinical trials,6 editorials, and 3 review articles related to cardiac arrest. Com-plementing the public awareness and academic research, therehas been a growth of federal funding opportunities in resuscita-tion science. Thus, this is an opportune time to review recentdevelopments in cardiopulmonary cerebral resuscitation. Thisarticle will focus on new and emerging concepts in resuscitationthat might be unfamiliar to pediatric emergency medicine clini-cians.

Cardiopulmonary Resuscitation

The lifesaving capability of cardiopulmonary resuscitation(CPR) is well-documented. However, two-thirds of cardiac arrestvictims do not receive bystander CPR, most often because ofconfusion or fear on the part of the bystander. Those who receiveCPR often receive suboptimal CPR. Thus, there is a need tosimplify and/or improve the technique of CPR.

The most recent modification to CPR training was to drop thepulse check from lay-rescuer CPR. This decision was reached

From the Division of PediatricEmergency Medicine, University ofPittsburgh, Children’s Hospital ofPittsburgh, Pittsburgh, PA.

Address reprint requests to Robert W.Hickey, MD, Division of PediatricEmergency Medicine, University ofPittsburgh, Children’s Hospital ofPittsburgh, 3705 Fifth Avenue,Pittsburgh, PA 15213.

1522-8401/$—see front matter© 2004 Elsevier Inc. All rights

reserved.doi:10.1016/j.cpem.2004.08.005

DEVELOPMENT S IN CARD IOPULMONARY CEREBRAL RE SU S C I T A T ION / ROBERT W . H I C KE Y 217

after an elegant study showed that lay persons wereinaccurate at detecting a carotid pulse in adultsduring cardiac surgery.1 The study design took ad-vantage of the fact that patients have palpable ca-rotid pulses prior to and following bypass but notduring the stage of the operation that blood flow isrouted through the bypass machine (blood flowduring bypass is not pulsatile). The lay personstested in the study were unable to reliably detect apulse (or the absence of one) under either circum-stance. Although this study was limited to adultpatients, it is generally recognized that detectingpulses in young children is more difficult than de-tecting pulses in adults.

Several devices to improve myocardial or cere-bral blood flow during CPR have been invented. Theactive compression/decompression (ACD) deviceand the impedance threshold valve augment thechanges in intrathoracic pressure that drive bloodflow during CPR (Figure 1). Specifically, these de-vices enhance the negative intrathoracic pressurecreated during the relaxation phase of the chestcompression cycle. The greater negative intratho-racic pressure facilitates blood return to the chestand thus primes the heart with more blood that isthen available for the next compression. The ACDdevice was inspired by a family that used a toiletbowl plunger to successfully resuscitate a familymember wedged between a bathtub and a toiletbowl in the bathroom. Months later the victim col-lapsed in the living room, and the family ran to getthe plunger from the bathroom—again, using itwith success.2 The alternating current-direct cur-rent design is more refined than a toilet plunger butthe principle remains the same (Figure 2). Theimpedance threshold valve is attached to an endo-tracheal tube and limits the amount of air that canbe entrained through the endotracheal tube duringthe decompression phase of CPR, thus augmentingthe negative intrathoracic pressure during decom-pression and improving blood flow.3

A more direct approach to CPR is taken by thecuriously named minimally invasive cardiac mas-sage device (MIDCM; Figure 3). This device re-quires a small incision and subsequent placementof a trocar fitted with an umbrella that expands toallow direct intrathoracic compression of the heart.The device has also been engineered to deliver adefibrillating current directly to the heart.4

Interposed abdominal compression CPR (IAC-CPR) received the highest recommendation in theAmerican Heart Association (AHA) 2000 Guide-lines relevant to alternative methods of CPR.5 It isalso the least technical. IAC-CPR entails compres-sion of the abdomen during the relaxation phase of

the chest compression. This maneuver increasesthe resistance in the descending aorta and thusincreases coronary perfusion pressure. Coronaryperfusion pressure (CPP) is the pressure gradientfrom the root of the aorta (where the coronaryarteries originate) to the right atrium (where thecoronary veins return). CPP is correlated with abil-ity to restart the arrested heart. Favorable resultswith IAC-CPR have been documented in animalstudies and in clinical trials with adults. It has notyet been studied in children.

Recently, there has been interest in altering theratio of chest compressions to ventilations deliv-ered during CPR. A variety of ratios have beenproposed including 30:2, 50:2, or even continuouschest compressions without any ventilation. Therationale for delivering a longer sequence of chestcompressions is based upon the observation thatthe initial compressions in a compression-ventila-

Figure 1. One mechanism for blood flow during cardiopul-monary resuscitation is the intrathoracic pump. During com-pression, there is a general rise in intrathoracic pressure and acollapse of venous structures at the thoracic inlet (preventingretrograde venous flow at C). The increased intrathoracicpressure forces blood out of the heart and lungs. Duringrelaxation, intrathoracic pressure falls and blood is drawn backinto the chest. Reprinted with permission from Paradis NA,Halperin HR, Nowak RM: Cardiac Arrest: The Science andPractice of Resuscitation Medicine. Baltimore, MD, Williams &Wilkins, 1996.

218 DEVELOPMENT S IN CARD IOPULMONARY CEREBRAL RE SU S C I T A T ION / ROBERT W . H I C KE Y

tion cycle are spent “priming the pump” to buildCPP (Figure 4). When compressions are interruptedfor ventilation, CPP falls and the pump must beprimed again. Thus, there is a price to pay forinterrupting chest compressions. Ratios with moreuninterrupted chest compressions are targeted to-wards increasing CPP and augmenting the resuscit-ability of the arrested heart. In contrast, ratios that favor more frequent ventilations might be of benefit

in patients with respiratory causes of arrest (themost common cause of arrest in pediatrics). The“best” ratio with respect to patient outcome andease of teaching is an area of continued debate.

Automated External Defibrillators

The widespread availability and deployment ofautomated external defibrillators (AEDs) has revo-lutionized the approach to prehospital cardiopul-monary arrest. Studies in casinos and airlinesdocumenting survival from ventricular fibrillation(VF) in 60% and 40% of patients, respectively,treated with AEDs demonstrate the potential life-saving impact of these devices.6,7 AEDs have alsofacilitated a public discourse on the importance ofCPR in first-aid training and have become the “Tro-jan horse” for development of Medical EmergencyResponse Plans (MERPS) in school and workplacesettings.8 Recently, AED engineers developed pedi-atric adaptor units consisting of a resistor andsmaller pads that drop the dosage to 50 joules. Inresponse, the AHA now supports the use of AEDs inyoung children (1-8 years).9

Figure 2. Device for active compression-decompression car-diopulmonary resuscitation. Reprinted with permission fromTucker KJ, Galli F, Savitt MA, et al: Active compression-de-compression resuscitation: Effect on resuscitation success afterin-hospital cardiac arrest. J Am Coll Cardiol 24:201-209, 1994.

Figure 3. Device for minimally invasive direct cardiac mas-sage: A trocar is inserted through a small incision and anumbrella-like plunger unfolds for direct compression of theheart. Reprinted with permission from Tisherman SA, Vande-velde K, Safar P, et al: Future directions for resuscitationresearch. V. Ultra-advanced life support. Resuscitation 34:281-293, 1997.

Figure 4. Changes in cerebral perfusion pressure (CPP) dur-ing cardiopulmonary resuscitation: CPP is the pressure gradi-ent from the aorta (A0) to the right atrium (RA) that drivesblood flow to the myocardium via the coronary arteries. CPPbuilds during the first few compressions of a cycle but rapidlyfalls during interruption for ventilation as demonstrated in thistracing with a 15:2 compression:ventilation ratio. Reprintedwith permission from Berg RA, Sanders AB, Kern KB, et al:Adverse hemodynamic effects of interrupting chest compres-sions for rescue breathing during cardiopulmonary resuscita-tion for ventricular fibrillation cardiac arrest. Circulation 104:2465-2470, 2001.


Animal models of VF have demonstrated thatdefibrillation has a high rate of success when ad-ministered early during fibrillation. However, defi-brillation after 5 to 10 minutes of fibrillation is lesslikely to be successful and can result in additionalmyocardial injury or conversion to asystole. Inter-estingly, the likelihood of successful defibrillationafter prolonged fibrillation can be improved by de-laying defibrillation to provide a short period ofCPR to “prime the heart” before defibrillation. Thissame observation has now been made in humanswith cardiac arrest, and some EMS systems havedeveloped protocols to deliver CPR before defibril-lation in victims with “prolonged” cardiac arrest.10

The obvious difficulty is determining duration ofarrest and then extrapolating that into a risk-ben-efit analysis for immediate versus delayed defibril-lation. One potential solution would be toincorporate a waveform analysis of the fibrillationsignal. VF often progresses from a coarse, polymor-phic waveform to a smaller amplitude waveform(fine VF) and eventually asystole. Several groups ofinvestigators have applied mathematical tech-niques to analyze these temporal changes and todevelop predictive rules for duration of fibrillationand likelihood of successful defibrillation.11,12 Thegoal of this work is to develop “smart defibrillators”that will enable the rescuer to determine whether ashock should be applied immediately or whetherthere should be a preceding interval of CPR (ordrugs) until a more favorable waveform can beachieved.

Drugs

In addition to changes in the techniques anddevices used in CPR, new studies regarding high-dose epinephrine therapy in children and newpharmaceutical agents have become available. Per-ondi and colleagues13 performed a prospective, ran-domized, double-blind trial to compare high-doseepinephrine (0.1 mg/kg) with standard-dose epi-nephrine (0.01 mg/kg) as rescue therapy for in-hospital cardiac arrest in children after failure of aninitial, standard dose of epinephrine. The primaryoutcome measure was survival 24 hours after thearrest. High-dose epinephrine was not found to beof benefit after failure of initial standard-dose epi-nephrine. In addition, the data from the study sug-gested that high-dose therapy appeared to beharmful among children with asphyxia-precipitatedcardiac arrest.

Two drugs, amiodarone and vasopressin, wereadded to the advanced cardiovascular life support

algorithms in the AHA 2000 guidelines.14 Vasopres-sin was listed as an alternative to epinephrine inselected adult-based algorithms. This decision wasbased upon animal data and small clinical trials.More recently, however, prospective trials that ex-amined in-hospital and out-of-hospital cardiac ar-rest did not show vasopressin to be superior toepinephrine.15,16 There is very little data in chil-dren.

Amiodarone was listed as an alternative antiar-rhythmic to lidocaine for selected algorithms inboth pediatrics and adults. Data in children is ex-tremely limited, but data in adults show that ami-odarone is more likely than lidocaine to result insuccessful defibrillation and admission to the hos-pital.17

Oxygen, which can be considered a “drug,” hasrecently come under scrutiny.18,19 Although toolittle oxygen is often a precipitant of arrest (espe-cially in children), too much oxygen during or fol-lowing resuscitation may also be harmful. Excessoxygen can be converted to reactive oxygen speciesthat damage cell membranes, proteins, and DNA.Conversion of oxygen to reactive species is morelikely to occur under ischemic conditions whenthere is depletion of cellular antioxidants and im-paired mitochondrial electron transport. Animalstudies that compared the use of 100% oxygen toroom air for resuscitation revealed either no out-come advantage or worse outcome in those animalsresuscitated with 100% oxygen. Clinical studiescomparing the use of room air to 100% oxygen forresuscitation have been performed in newbornswith birth asphyxia.20-23 The original impetus forthese studies was not a concern about oxygen tox-icity but rather the need for obtaining oxygen indeveloping countries with limited resources. Re-gardless, the studies demonstrate no advantage to100% oxygen and show circumstantial evidence ofpotential harm. Specifically, newborns resuscitatedwith 100% oxygen have a delayed onset of sponta-neous respiration and have evidence of prolongedoxidative stress measured at 1 month. Thus, thereappears to be a “Goldilocks phenomenon,” with toolittle or too much oxygen causing harm. A compli-cating factor is that following resuscitation, there isa prolonged period of heterogeneous cerebral bloodflow (CBF) with some areas receiving adequate flowand others with continued low flow. Consequently,some neurons suffer from an accumulating oxygendebt that might be best treated with oxygen,whereas other neurons have adequate oxygenationand any “excess” oxygen increases the potential foroxidative injury. Indicators of global oxygenation,such as pulse oximetry, do not reflect conditions at


the tissue level. There is emerging noninvasivetechnology, such as sublingual capnometry andnear-infrared spectroscopy, that can more accu-rately assess tissue perfusion, but additional studiesare needed before these devices become clinicallyuseful.24,25 In the interim, it is best to avoid pro-longed delivery of unnecessarily high concentra-tions of oxygen.

Temperature Control

Body temperature is an important modulator ofbrain injury.26,27 In general, hypothermia is neuro-protective, whereas hyperthermia exacerbatesbrain injury. This phenomenon has been demon-strated both in vitro and in vivo. It has been shownin a diversity of species including mice, gerbils,rats, squirrels, dogs, cats, pigs, and primates as wellas with a range of injuries including traumatic braininjury, focal ischemia (stroke), global ischemia(cardiac arrest), and neonatal hypoxic ischemia.Thus, temperature sensitivity of the injured brain isrobustly expressed across a variety of species andinjuries. This has clinical relevance because chil-dren often develop hypothermia followed by feverafter resuscitation from cardiac arrest.28 Accord-ingly, clinical management of these children shouldinclude vigorous temperature surveillance, antipy-retic treatment, and avoidance of injudicious use ofwarming lamps.

Recently, the benefit of inducing hypothermia(therapeutic hypothermia) following cardiac arrestwas demonstrated in prospective, randomized, trialsof adults resuscitated from ventricular fibrillation.29,30

In these trials, adults randomized to therapeutic hy-pothermia were maintained at a body temperature of32°C to 34°C for 12 to 24 hours. Cooled patients hadimproved survival and improved neurologic outcomeversus normothermic controls. The number neededto treat in these trials was 6 to 7—in other words, only6 or 7 patients needed to be cooled to prevent oneunfavorable neurologic outcome or to prevent onedeath. This is a remarkably strong treatment effect.However, there is an increased risk of sepsis, pneu-monia, and coagulopathy in cooled patients. Accord-ingly, extrapolation to a pediatric patient withprimary lung disease or bleeding requires careful clin-ical judgment. Prospective, randomized, clinical trialsof asphyxiated neonates treated with cooling capshave been completed but are not yet published.

Future directions of research in therapeutic hy-pothermia will include assessment of utility innon-VF arrest and determination of the optimaldepth and duration of hypothermia. Emerging tech-

nologies in this field include cooling caps (for neo-nates), cooling rods that can be placed in largeblood vessels, and engineered isotonic “slurries”(similar to frozen drinks) with maximal heat trans-fer for IV administration.31,32

Molecular Medicine

Clinicians and scientists interested in trauma,stroke, and global ischemia have made importantadvances in understanding the cellular mecha-nisms of brain injury and repair. Similarly, clini-cians and scientists interested in myocardialischemia and failure have made advances in under-standing the mechanisms of myocardial injury andrepair. Detailed discussion of these mechanisms isbeyond the scope of this article. However, it isimportant to note that many of these disease pro-cesses share common mechanisms, and advancesin one field can result in progress (including poten-tial therapy) for others.

The modern era of molecular medicine has al-ready yielded dividends with respect to identifica-tion of patients at high risk for brain or cardiacinjury. For example, patients inheriting the apoli-poprotein E epsilon4 gene are at increased risk forearly development of Alzheimer’s disease and are atincreased risk for dementia following traumaticbrain injury.33,34 Non-CNS examples of importantgenetic factors include polymorphisms of the P450system effecting drug metabolism and polymor-phisms associated with immune function and riskfor sepsis.35-37 In the future, it is likely that indi-vidual patient genotypes will be screened for riskfactors of disease, and therapy will be targeted to-wards the results of genotypic screening. Further-more, identification of pre-existing, inherited riskfactors is important for stratification of patientsenrolled in research trials.

A recent case report38 of a 19-year-old womanfound drowned in a health club pool demonstratesthe potential promise of contemporary molecularmedicine. The woman was briefly resuscitated butlater died, and a sample of her myocardium wasobtained at autopsy. DNA from the tissue was thenscreened for mutations associated with prolongedQT syndrome. After failing to find any of the knownmutations, the investigators sequenced the pa-tient’s DNA and discovered a novel mutation in anion-channel gene associated with QT duration. Thesame mutation was then confirmed in the patient’s18-year-old sister, 49-year-old mother, and 81-year-old grandfather. These investigators have alsoreported a mutation causing prolonged QT in an


infant with sudden infant death syndrome (SIDS).39

The proportion of infants with SIDS caused by in-herited nonstructural cardiac disease is not known.However, a recent study investigating adults withsudden arrhythmic death syndrome reported in-heritable familial cardiac disease in 7 of 32 families(22%).40 Most of these families had members withprolonged QT syndrome. Thus, family members ofchildren with sudden unexpected death (includingSIDS and drowning in patients capable of swim-ming) should undergo a very careful cardiovascularassessment. In the future, we may be able to screenfor these inherited conditions and decrease the as-sociated mortality.

Suspended Animation

The boundaries of resuscitation have recentlybeen pushed by investigators in the Safar Center forResuscitation Research. This group has used pro-found hypothermia with a combination of brain-oriented treatments to place dogs in a state ofsuspended animation during hemorrhagic cardiacarrest.41 The experiments mimic a civilian or sol-dier with exsanguinating hemorrhagic shock, andthe goal of therapy is to preserve the viability of thebrain and organism until transport to an operatingroom where the injuries are repaired and the victimis resuscitated. In these experiments, dogs are bleduntil they reach impending cardiovascular collapse.At this point, clinical death (and preservation) isinduced by aortic flush with an ice-cold saline so-lution containing antioxidants. Dogs can be main-tained in this state with no blood flow for up to 2hours and then resuscitated using cardiac bypass.Many of the dogs treated with suspended animationhave a full recovery. In contrast, dogs resuscitatedafter just 10 to 15 minutes of normothermic arrestare typically moribund and suffer severe, perma-nent brain injury.

Summary

There have been many recent, encouraging ad-vances in resuscitation science. CPR continues tobe an important part of resuscitation, and modifi-cations of CPR techniques and adjuncts are ex-pected. AEDs have revolutionized treatment forprehospital cardiac arrest and “smart” AEDs areunder development. The application of 100% oxy-gen and external warmers, previously consideredroutine care for sick patients, is being re-examinedin the context of ischemic brain injury. Emergingtechnologies will permit better measurement of tis-

sue oxygenation and more precise control of bodytemperature. The power of modern molecular tech-niques to detect inheritable cardiac disease (suchas long QT syndrome) forecasts the tremendousadvances that are expected from the human ge-nome project. Work in suspended animation sug-gests that the duration of tolerable ischemiaextends far beyond the 10 to 15 minutes found incurrent clinical experience.

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Recent developments and emerging concepts in cardiopulmonary cerebral resuscitation