Ebook Cardiac arrest - The science and practice of resuscitation medicine (2nd edition): Part 2

(BQ) Part 2 book Cardiac arrest - The science and practice of resuscitation medicine presents the following contents: Postresuscitation disease and its care, special resuscitation circumstances, special resuscitation circumstances, special issues in resuscitation.

Postresuscitation disease and its care

The postresuscitation syndrome (PRS) has been defined

as a condition of an organism resuscitated following

prolonged cardiac arrest, caused by a combination of

whole body ischemia and reperfusion, and characterized

by multiple organ dysfunction, including neurologic

impairment.1

Background

Following resuscitation from cardiac arrest, patients either

recover consciousness or remain unconscious, depending

on the duration of cardiac arrest and the effectiveness of

any CPR, but also on prearrest conditions such as age and

comorbidities.2

Shortening no-flow times by timely interventions that can

maintain some perfusion and promote the restoration of

spontaneous circulation (e.g., bystander CPR, early

defibril-lation, and other means) improves the possibility of a

suc-cessful outcome with the patient recovering consciousness.3

The wider availability of resuscitation techniques to

reverse clinical death, however, has led to increasingly

fre-quent observations of a pathological condition occurring

in patients who remain unconscious, involving multiple

organ injury or failure following reperfusion after

pro-longed cardiac arrest

The concept of postresuscitation disease as a unique

and new nosological entity was introduced by Negovsky

in 1972;4,5 the most interesting aspect of this

innov-ative concept was the recognition that the etiologydepended on a combination of severe circulatory hypoxiawith the unintended sequelae of measures used forresuscitation

On the basis of the wide variety of ischemic/hypoxicmechanisms that can trigger its development, the diseasewas redefined by Safar as a syndrome in which patho-genetic processes triggered by cardiac arrest were exacer-bated by reperfusion, causing damage to the brain andother organs, the complex interactions of which combine

to determine overall outcome (see early experimental ings summary).6,7

find-The evidence of features common to the citation syndrome and multiple organ dysfunction syn-drome led to the hypothesis that a systemic inflammatoryresponse of the entire organism was triggered by ischemiaand reperfusion, adding to the damage directly induced byischemia during cardiac arrest.8

postresus-Two landmark studies, showing that mild therapeutichypothermia started after reperfusion can improve recov-ery after cardiac arrest, confirm that outcome is deter-mined not only by events occurring during arrest andCPR but also by pathogenetic processes continuing afterreperfusion.9,10

Recent reports confirm the occurrence of a “sepsis-likesyndrome” after resuscitation from cardiac arrest,11,12although the mechanistic relationship to the directdamage induced by ischemia during cardiac arrest has yet

to be clarified

817

Cardiac Arrest: The Science and Practice of Resuscitation Medicine 2nd edn., ed Norman Paradis, Henry Halperin, Karl Kern, Volker Wenzel, Douglas

Chamberlain Published by Cambridge University Press © Cambridge University Press, 2007.

Postresuscitation syndrome

Erga L CerchiariDepartment of Anaesthesia and Critical Care, Ospedale Maggiore, and Area of Anaesthesia and Critical Care, Surgical Department, Provincial Health Care Structure, Bologna, Italy

Early Experimental Findings

Negovsky 4,5 and his group of Russian investigators pioneered the concept of postresuscitation disease as a unique

noso-logical entity, caused by the combination of severe hypoxia and resuscitation, on the basis of hundreds of experimentalobservations that fall into three groups:

1 Phasic Pattern of Postresuscitation Recovery

Independent of the type of insult, alterations in cerebral and extracerebral organs occur starting with reperfusion anddeveloping over time

From insult to 6 to 9 hours postinsult: rapid changes in cerebral and systemic hemodynamics, metabolism, and

rheol-ogy (clotting disturbances, increased viscosity), increase levels of biologically active substances and prostaglandin atives; alterations of the immune system (increased bactericidal activity, depressed reticuloendothelial system, andhyperreactivity of B- and T-lymphocytes), and toxic factors in the blood (peptide fraction 800 to 2000 Daltons and endo-toxin secondary to gram-negative bacteremia)

deriv-From 10 to 24 hours postinsult: normalization of cardiovascular variables and progression of metabolic derangements

ensue During this time, 50% of deaths occur as a result of recurrent cardiac arrest

From 1 to 3 days postinsult: stable cardiovascular variables and improvement in cerebral function associated with

increased intestinal permeability leading to bacteremia

The stabilization phase (more than 3 days postinsult): characterized by the prevalence of localized or generalized

infection that represents the major cause of delayed deaths The degree of cerebral and extracerebral organ ments is reported to be more severe and prolonged the longer the duration of the hypoxic–ischemic insult

derange-2 Interactions between Cerebral and Extracerebral Postischemic Damage on Outcome

The severity of systemic and hemodynamic derangements after 20 minutes of isolated brain ischemia is comparable tothat recorded after only 12–15 minutes of total circulatory arrest with ventricular fibrillation, suggesting that cerebralpostischemic damage plays a role in development of extracerebral dysfunction, probably by inducing changes in neu-rohumoral regulation

Cerebral function recovers better after bloodless global brain ischemia than after the same duration of circulatoryarrest from ventricular fibrillation, leading to the conclusion that extracerebral factors account for about half of thepathological findings in the brain induced by cardiac arrest

3 Benefical Effect of Trials with Detoxification Techniques

A series of trials aimed at removing toxins and normalizing homeostasis by various detoxification techniques showedthat all the techniques can improve neurological recovery and survival compared with concurrent controls; cross-cir-culation was the most effective, in which circulation in the body of the resuscitated dog was maintained for 30 minutespost-ROSC by the heart of a healthy donor dog, aided by an extracorporeal circulation system

Safar and his group in Pittsburgh, in parallel with – but subsequent to – the Russian experimental work, confirmed

that extracerebral organ dysfunction may hamper cerebral recovery following resuscitation from cardiac arrest, based

on the observations that (a) cerebral function after isolated global brain ischemia recovers better than after ble durations of total body ischemia13,14and (b) the use of cardiopulmonary bypass for resuscitation and for short-termpostresuscitation assistance improves myocardial performance after weaning, and significantly increases neurologicaloutcome and survival.15Extracerebral organ dysfunction following resuscitation from cardiac arrest of increasing dura-tions was studied in animal experimental models:1,6,7,14–19

compara-• cardiac output and arterial oxygen transport, after a transient increase, showed a prolonged and profound decreaseassociated with increased peripheral resistance; this starts sooner and is more severe and prolonged after longerdurations of VF, resolving by 12 to 24 hours postresuscitation

• pulmonary gas exchange, with assisted ventilation for 6 to 24 hours postresuscitation, is well maintained even afterextubation (normoxia, normocarbia, and rapid pH normalization)

• coagulation disturbances with hypocoagulability start during resuscitation, with prolonged clotting times anddecreased platelets and fibrinogen, and normalize at 24 hours after resuscitation; elevated fibrin-degradation prod-ucts and decreased platelet counts were observed to 72 hours postresuscitation

Incidence and prevalence

The incidence of out-of-hospital cardiac arrest is estimated

to be 49.5–66 per 100 000 cases per year:2in these, return of

spontaneous circulation can be achieved in 17% to 33%,

depending on the efficiency of the emergency response

system.20

The incidence of in-hospital cardiac arrest has been

esti-mated as 1.4/100 admissions/year:21in these cases,

restora-tion of spontaneous circularestora-tion occurs in 40%–44%.22

Of the patients resuscitated from cardiac arrest, a

small proportion (variable as a function of timeliness and

effectiveness of response) achieve early recovery, with

restoration of spontaneous respiration and consciousness

Identification and treatment of the cause of arrest is the

main or only therapeutic challenge for this group of subjects

But most survivors of cardiac arrest (80%) are comatose

postresuscitation, and are admitted to the ICU where they

represent the population of patients with

postresuscita-tion syndrome (PRS), amounting to about 15%–20% of allcardiac arrest victims (Fig 47.2)

Among the PRS patients, mortality has been reported to

be very high, reaching 80% by 6 months tion:23–25approximately one-third of the deaths are due tocardiac causes (early deaths usually24 hours), one-third

postresuscita-to malfunction of extracerebral organs, and one-third postresuscita-toneurologic causes (late deaths)

The prevalence of the postresuscitation syndrome canonly be inferred, because of the bias of data resulting fromdecisions to limit treatment, including instructions for “donot attempt resuscitation,” in cases of recurrent cardiacarrest.22–26

Etiology

Following resuscitation from cardiac arrest of less than 5minutes, recovery is rapid and complete After prolongedarrest, ROSC is impossible or only transient

• erythrocyte count decreases significantly

• renal function (blood urea nitrogen, serum creatinine, osmolarity, sodium, potassium, and calcium) remain normal

after a transient reduction in urine output with positive fluid balance, normalizing at 3 to 6 hours

• hepatic function is altered transiently; plasma ammonia and branched chain and aromatic amino acids increase,

with higher levels in the animals with poor outcome, suggesting an alteration of liver-detoxifying function

• bacteremia is a constant feature after cardiac arrest, with transient leukocytosis but without hyperthermia (90% were

constituents of the intestinal flora, suggesting postischemic bacterial translocation)

In summary, following resuscitation from cardiac arrest, multiorgan dysfunction occurs, but the abnormalities have

different time patterns (Fig 47.1)

NeurologicClotting/FibrinolysisCardiovascular

Fig 47.1 Time pattern of organ dysfunction after resuscitation from cardiac arrest from the early experimental work.1,4–7

Therefore, the postresuscitation syndrome only

devel-ops following resuscitation given during an intermediate

duration of ischemia (the limits of which are affected

by prearrest conditions) and depending on the

cir-cumstances of resuscitation, leading to the “reperfusion

paradox.”

The insult induced by cardiac arrest and CPR is

multi-faceted, encompassing several contributing factors

occur-ring duoccur-ring cardiac arrest, duoccur-ring CPR, and following

restoration of spontaneous circulation:1,6,7

• ischemia – anoxia occurring during the cardiac arrest

with no-flow

• hypoperfusion – hypoxia during the low-flow of external

cardiac compressions (inducing at best a cardiac output

of 25% baseline)

• reperfusion, which, although potentially permitting

sur-vival, adds to the ischemic-hypoxic–hypoperfusion

insult, inducing a variety of mechanisms that continue

to evolve subsequently, including reperfusion failure

and injury, altered coagulation, and activation of a

sys-temic inflammatory response

Pathogenesis

Two major pathways have been identified

1 a direct insult to the brain, which is particularly

sensi-tive to ischemia; and to the heart, which may suffer

postresuscitation myocardial stunning leading in turn

to a secondary insult from postreperfusion impairment

of cardiac output and hypoperfusion

2 postreperfusion activation of the systemic tory response syndrome, with hypoperfusion and/oraltered perfusion as one pathological mechanism;12inthis pathway, the PRS shares many features with severesepsis, including elevation of plasma cytokines withdysregulated cytokine production, endothelial injury,complement activation, coagulation and fibrinolysisabnormalities, endotoxemia, disturbed modulation ofthe immune response, and adrenal dysfunction

inflamma-Organ function postresuscitation

The postresuscitation syndrome occurs in patients citated after cardiac arrest of more than 5 minutes’duration and is characterized by different components:neurologic functional impairment, cardiovascular func-tional impairment – both well characterized – andthe extracerebral extracardiac functional impairmentcomprising a complex picture of determinants andinteractions

resus-The three major components variously contribute tothe complex clinical picture of the patient resuscitatedfrom cardiac arrest and admitted to ICU Rapidly occur-ring early post-resuscitation changes create an acutephase of instability during which specific and aggressivetreatments may favorably affect outcome After the first

Optimalrecovery

DeathcausesROSC

PRS

No ROSC

No resuscitation attempt

Fig 47.2 Estimated fate for cardiac arrest patients.

24 hours the clinical picture stabilizes and treatment

becomes less specific, and is not different from that of a

comatose ICU patient

For purposes of clarity, the three components are

described separately, with analysis of the relative

contri-bution of the two pathogenetic pathways, functional

derangement interactions, and contributions to outcome

and specific early treatments

Neurologic function postresuscitation

The best defined component of the postresuscitation

syn-drome is neurologic functional impairment

With the increased application of resuscitation

interven-tions, postcardiac arrest unconsciousness has become the

third most common cause of coma Almost 80% of patients

who initially survive cardiac arrest remain comatose for

variable lengths of time, approximately 40% enter a

persis-tent vegetative state, while 10% to 30% of survivors achieve

a meaningful recovery.27

Cardiac arrest causes a global ischemic insult to the

brain The extent of cerebral damage is a function of the

duration of interrrupted blood flow Accordingly,

minimiz-ing both the arrest (no-flow) time and the

cardiopul-monary resuscitation (low-flow) time, is critical

Even in selected patients with a witnessed cardiac arrest

after ventricular fibrillation and an estimated arrest to ALS

intervention interval no longer than 15 minutes, mortality

at 6 months was 55% and of the survivors, 61% had an

unfavorable neurological outcome.9 With reperfusion,

extracerebral factors may hamper neurological recovery,

requiring interventions aimed at mitigating secondary

postischemic anoxic encephalopathy.7

Pathophysiology

The mechanisms of cerebral damage following ischemia

and reperfusion have been studied in detail (for detailed

reviews see refs 7,27)

Changes induced by ischemia set the stage for

reoxy-genation-induced, free radical-triggered injury cascades,

exacerbated by reduced cardiac output and local

circu-latory impairment that starts during cardiac arrest with

altered blood–brain barrier permeability and systemic

changes such as activation of complement, coagulation,

platelet aggregation, and adhesion of white blood cells.28

The pattern of prolonged global and multifocal cerebral

hypoperfusion is associated with variations of regional

cere-bral blood flow both in the cortex and in the basal ganglia29

with regional anoxic cerebral anaerobic metabolism

Posthypoxic encephalopathy has been shown to be

asso-ciated with a marked decrease of cerebral metabolic activity

and of glucose uptake, even 24 hours after resuscitation.30

A significant activation of inflammatory mediators(Interleukin 8, soluble elastin, and polymorphonuclearelastase) immediately postinsult and lasting about 12hours has recently been reported following both cardiacarrest and isolated brain trauma, suggesting an inflamma-tory response as a common pathogenetic pathway acti-vated by cerebral damage.31

Clinical features and prognostic evaluation

A variety of methods have been proposed to monitor theevolution of the depth of coma and its prognosis, includingneurological examination, electrophysiologic techniques,and biochemical tests

A recent meta-analysis, including nearly 2000 patients,assessed the reliability of neurological examination, includ-ing Glasgow Coma Scale (GCS) and brainstem reflexes,reviewed at different time intervals after resuscitation; itconcluded that patients who lack pupillary and cornealreflexes at 24 hours and have no motor response to pain at

72 hours have an extremely small chance of meaningfulrecovery

The most reliable signs of prognosis occur at 24 hoursafter cardiac arrest: earlier assessment should not be based

on clinical evidence alone.32

A systematic review of 18 studies analyzed the predictiveability of somatosensory evoked potentials (SSEP) acquiredearly after the onset of coma (1–3 days) in 1136 adultpatients with hypoxic-ischemic encephalopathy: the resultsshowed that patients with absent cortical SSEP responseshave a less than 1% chance of regaining consciousness.33

A recent study tested the value of serial measurement ofserum neuron-specific enolase (NSE) at admission anddaily postinsult, in combination with GCS and SSEP meas-urements, to predict neurological prognosis in uncon-scious patients admitted to the ICU after resuscitation fromcardiac arrest High serum NSE levels at 24 and 48 hoursafter resuscitation predict a poor neurological outcome

Addition of NSE to GCS and SSEP increases predictability.34

By 48–72 hours postresuscitation, predictability of vorable long-term neurologic outcome may guide deci-sions to curtail treatment, because only patients withlighter levels of coma or who have regained consciousness

unfa-by this time have any realistic prospect of long-termsurvival.32

Treatment

Research into cardiopulmonary cerebral resuscitationhas attempted to mitigate the postischemic–anoxicencephalopathy but, until recently, experimental resultshad never been replicated in patients.7

Mild therapeutic hypothermia induced following

reper-fusion in patients who have been successfully resuscitated

from ventricular fibrillation cardiac arrest is the only

postre-suscitation intervention that has proved effective in

increas-ing the rate of favorable neurologic outcome in two different

randomized studies conducted in Europe and Australia9,10

and in reducing mortality in one of them.9 Clinical and

experimental results show a multifactorial neuroprotective

effect of hypothermia during and after ischemic situations

by influencing several damaging pathways.27

Thrombolytics, administered during arrest or early after

reperfusion, have been shown in animal experiments to

improve the microcirculation in the brain and may, by this

mechanism, contribute to the favorable neurological

outcome of patients as described in many case reports and

small case series with predominantly positive results.35The

first properly designed, large, randomized, double-blind

multicenter study of thrombolytics was stopped before

completion of recruitment because the data safety

moni-toring board judged it unlikely that, in the population in

study, tenecteplase would demonstrate superiority over

placebo These results, presented at a 2006 conference,

should be considered preliminary until a detailed analysis

is performed and published.36

Cardiovascular function postresuscitation

Following successful resuscitation from prolonged cardiac

arrest, a typical component of the postresuscitation

syn-drome is prolonged myocardial contractile failure,

associ-ated with life-threatening ventricular arrhythmias and

hemodynamic instability.37,38

Cardiac complications are stated to occur in 50% of

resuscitated patients, ranging from transient – but

some-times severe – impairment of myocardial function

(occur-ring early and normalizing several days later) to

permanent malfunction and fatal rearrest The severe

impairment of myocardial function in the early hours

fol-lowing resuscitation accounts for 25% to 45% of early

postresuscitation deaths.23–25

The global nature of ischemic myocardial dysfunction38

and also its occurrence following resuscitation from

respi-ratory arrest39 or electroconvulsive treatment40 strongly

support its role during cardiac arrest and cardiopulmonary

resuscitation as the primary etiological determinant, as

opposed to the role of the primary cause of arrest which is

cardiac in 55%–65% of cases.41

The severity and duration of postresuscitation

myocar-dial impairment is a function of both duration of cardiac

arrest and subsequent resuscitation efforts,16–42 with a

contribution from adrenaline (epinephrine) used during

CPR,43,44and the energy and waveform required for rillation.45,46In humans, the dose of adrenaline used duringCPR has been reported to be the only variable indepen-dently associated with postresuscitation myocardialdysfunction.44

defib-Pathophysiology

The mechanisms responsible for myocardial stunning afterglobal myocardial ischemia remain unclear, but severalhypothesis have been proposed Among these are thepostreperfusion long-lasting depletion of the total adeninenucleotide pool, the generation of oxygen-derived free rad-icals, calcium overload, and uncoupling of excitation-con-traction due to sarcoplasmic reticulum dysfunction.37,38Recently, a correlation has been established betweenlevels of proinflammatory cytokines, synthesized andreleased in response to the stress of global ischemia, andthe depression of myocardial function in the early postre-suscitation period.47

Clinical features

In animal studies, postresuscitation myocardial tion is characterized by increased filling pressures,impaired contractile function, decreased cardiac index,decrease in both systolic and diastolic right ventricularfunction,16,38starting at 2–6 hours and returning to normal

dysfunc-at 24 hours postresuscitdysfunc-ation

These findings were confirmed initially by anedoctalobservations of prolonged reversible myocardial dysfunc-tion in human cardiac arrest survivors50,51and, later, werebetter defined in systematic studies in patients.44,52The global nature of postresuscitation dysfunction hasbeen demonstrated with echocardiography and ventricu-lography, which show a decrease in ejection fraction and infractional shortening

Myocardial dysfunction in patients may improve at 24–48hours postresuscitation with return to normal values; per-sistently low cardiac index at 24 hours postresuscitation isassociated with early death by multiple organ failure.44In thesame study, despite the significant improvement of cardiacindex at 24 hours, persisting vasodilatation was described,delaying the discontinuation of vasoactive drugs

In parallel with the failure of the heart to sustain normalcirculation, a condition of altered peripheral oxygen uti-lization has been described.44 These two mechanismstogether account for the persistent anaerobic metabolismcharacteristic of the early postresuscitation phase

Relationship to neurological recovery and outcome

The cardiovascular impairment in the early tion hours has been reported to correlate with impaired

postresuscita-cerebral recovery from the ischemic insult of cardiac

arrest.16

Indirect evidence of the role of impaired perfusion

on cerebral recovery comes from the beneficial effect of

cardiopulmonary bypass in augmenting flow after cardiac

arrest.15

In cardiac arrest survivors, good functional neurological

recovery has been independently and positively associated

with arterial blood pressure during the first 2 hours

post-resuscitation, whereas hypotensive episodes correlate

with poor cerebral outcome.52The latter finding could be

explained by the loss or impairment of cerebral

autoregu-lation in comatose patients resuscitated from cardiac

arrest, causing a reduction in cerebral blood flow if blood

pressure is low.54,55

The finding of a correlation between low cardiac index

and neurologic outcome, however, has not been confirmed

in a recent study in humans.44

Treatment

Successful treatment of myocardial dysfunction could

reduce or prevent the cardiac causes of death that are the

major determinants of early postresuscitation deaths

Treatment with dobutamine has proved effective in

sup-porting output and pressure during the postresuscitation

phase prior to return to baseline function.56A dobutamine

dose of 5 mcg/kg min has been shown to be better than a

dose of 2 or 7.5 mcg/kg min, and better than placebo or

aortic counterpulsation in sustaining cardiovascular

per-formance for 6 hours postresuscitation.56–58

The similarities in cardiovascular status between septic

and postresuscitation patients have suggested that in

addi-tion to the inotropic support with dobutamine the ‘early

goal-directed therapy’ that has proved effective in severe

sepsis should be included59 – namely normalization of

intravascular volume, of blood pressure by vasoactive

drugs, and of oxygen transport by red cell transfusion

during the first 6 hours postresuscitation.11,12Data on its

effectiveness in cardiac arrest patients are not yet available

Extracerebral extracardiac function postresuscitation

The extracerebral extracardiac function derangements,

accounting for one-third of deaths,23–25represent the less

specific component of the postresuscitation syndrome.11,12

In patients surviving the early postresuscitation phase,

cardiovascular function improves, neurologic function

may show gradual improvement or remain severely

com-promised, but conditions facilitating the development

of sepsis are created, leading ultimately to multiorgan

dysfunction

Systemic findings and pathogenesis

The direct effect of cardiac arrest, besides its role in ronal injury and myocardial dysfunction, is also involved

neu-in the genesis of coagulation disturbances,60endothelialinjury,60,61and in triggering the cascades of inflammatoryresponses.7,63

A variety of changes and findings, which still need to beclearly classified and systematized, have been describedfollowing resuscitation from cardiac arrest:

• a considerable increase in various acute phase responseproteins64

• a sharp rise in plasma cytokines and soluble receptorswithin the blood compartment as early as 3 hourspostarrest31,46,65–69

• endothelial injury and release of intracellular adhesionmolecules

• marked activation of complement, polymorphonuclear(PMN) leukocytes, and an increased PMN-endothelialinteraction61–64

• marked activation of blood coagulation and fibrinolysis60

• leukocyte dysregulation11,12

• evidence of the presence of endotoxin in plasmaThe complex interaction of endothelial injury, inflammatoryand procoagulant host responses, intravascular fibrinformation, and microvascular thrombosis contribute

to reperfusion defects,7,60,64which augment systemic erfusion induced by cardiovascular dysfunction to trigger

hypop-a secondhypop-ary insult of persisting hypop-anerobic methypop-abolism

The altered systemic oxygen utilization, together withcirculating endotoxin and immune hyporeactivity, mayfacilitate development of infection.11,12

Extracerebral and extracardiac organs, however, can erate periods of ischemia much longer than those gener-ally occurring in cardiac arrest and resuscitation: thus, theimpairment of function in these organs appears to be thecombined result of the mechanisms triggered by ischemiabut compounded by reperfusion

tol-Derangements of organ function

Clotting and fibrinolytic function

Starting during cardiopulmonary resuscitation, markedactivation of coagulation has been demonstrated, withoutadequate concomitant activation of endogenous fibrino-lysis,60,70 suggesting that intravascular fibrin formationand microvascular thrombosis after cardiac arrestmay contribute to organ dysfunction, including neurolo-gical impairment With restoration of spontaneouscirculation and reperfusion, coagulation activity (throm-bin-antithrombin complex) increases, anticoagulation(antithrombin, protein C, and protein S) decreases, and

fibrinolysis (plasmin–antiplasmin complex) is activated or

in some cases inhibited (increased plasminogen activator

inhibitor-1 with a peak on day 1) These abnormalities are

more severe in patients dying within 2 days and most

severe in patients dying from early refractory shock

Protein C and S levels are low compared with those in

healthy volunteers and discriminated OHCA survivors

from non-survivors.66

Marked activation of complement, polymorphonuclear

leukocytes, and an increased PMN-endothelieal

interac-tion have been clearly demonstrated during

cardiopul-monary resuscitation and early reperfusion after cardiac

arrest in humans.62

Adrenal function

Serum cortisol levels have been reported consistently to be

high in all patients resuscitated from cardiac arrest for up

to 36 hours postresuscitation,74–76with lower levels in

non-survivors,74particularly in those who died of early

refrac-tory shock.76

Relative adrenal insufficiency as assessed by

corti-cotropin tests was observed in 42% of patients but showed

no association with arrest duration variables or with

outcome.76

Renal function

Renal dysfunction,77was recently confirmed in patients

presenting with hemodynamic instability and was

charac-terized by significant increases in plasma creatinine and by

a decrease in the International Normalized Ratio.44

Intestinal function

Following cardiac arrest and reperfusion, severe intestinal

ischemia occurs, showing a pattern of metabolic

extracel-lular changes similar to those recorded in the brain.78It is

associated with early intestinal dysfunction and/or

endo-scopic lesions identified in 60% of patients.79

A role for ischemia-reperfusion-mediated increase in

intestinal permeability has been proposed as predisposing

the patient to the sepsis syndrome

Endotoxin and infection

The finding of plasma endotoxin detected in 46% of

patients 1–2 days after resuscitation (although with no

relation to outcome), and of endotoxin-dependent

hyporeactivity of patients’ leukocytes, with high levels

of circulating cytokines and dysregulated production

of plasma cytokines, delineates an immunological pattern

similar to the profile characterizing patients with sepsis

Half of endotoxin-positive patients have been found

to develop secondarily acquired bacterial infection

3–4 days postresuscitation (mostly pulmonary, ally bacteremia).11,12

occasion-The finding of bacteremia, generally associated withpathogens of intestinal origin, occurring in 39% of patientswithin the first 24 hours of admission postresuscitationassociated with increased mortality,80was not confirmed

in a subsequent study in which bacteremia was tered only sporadically.12

encoun-The incidence of pneumonia in patients admitted to theICU following cardiac arrest has been reported to vary from24% to 45% of patients.9,81

In a systematic study,82newly acquired infection oped in 46% of patients resuscitated from cardiac arrestand admitted to the ICU, the most common being pneu-monia (65% of infections) Compared with cardiac arrestsurvivors without infection, patients with infection hadlonger mechanical ventilation and ICU length of stay, butmortality was similar

devel-A possible role for procalcitonin has been proposed forthe early identification of post-resuscitation patients with

an acute phase response and bacterial complications: itwas the only marker higher in patients with ventilator-acquired pneumonia.83

Hyperthermia not associated with positive blood tures has been reported frequently during the first 24 hoursfollowing CPR, suggesting that mechanisms other thaninfection may contribute to the development of fever incardiac arrest survivors.82,84

cul-Correlation with outcome

The peak level and the time of occurrence of many of theabove-mentioned mediators of the inflammatory res-ponse have been reported to correlate with outcome (dif-ferently defined as: early death, early death from cardiaccauses, death at 1 month, and others) in different caseseries from single centers and without precise standard-ization of resuscitation procedures and postresuscitationtreatments.61–72

The data now available suggest the opportunity for areassessment and systematic analysis of the interactionsinvolving various cascades and of their role in determiningoutcome in a well-designed multicenter study adopting astandardized treatment and evaluation protocol

The better characterization of PRS in its early phase isconfirmed by the high predictive value of cerebral impair-ment, the severity of which can be quantified, allowing areliable prognostication of outcome.47,52

In the later phase of PRS, when secondary multipleorgan derangement syndrome (MODS) becomes appar-ent, the existing limitations of prognostic evaluation based

on severity scoring systems85inherent to MODS are further

complicated by the persisting postischemic impairment of

cerebral function

Treatment

Similar to the treatment of patients with impaired

cardio-vascular function, in PRS patients showing extracerebral

and extracadiac impairment, the standard treatment

encompasses mild hypothermia induced after reperfusion

from cardiac arrest to improve neurological outcome9,10

and dobutamine to sustain transient myocardial

dysfunc-tion.56–58 Mild hypothermia has been hypothesized to

interfere with the inflammatory cascades of cardiac arrest

in its effect on survival

One interesting trial studied the effect of isovolumic

high-volume hemofiltration (HF) (200 ml/kg/h over 8

hours) with and without hypothermia, in an attempt to

remove circulating molecules believed to be responsible

for ischemia-reperfusion injury.86Compared with controls,

the high-volume hemofiltration with and without

hypo-thermia decreased the relative risk of death from

intractable shock and improved survival Nonetheless,

def-inite conclusions must await larger randomized clinical

trials testing the combination of HF with hypothermia in a

larger cohort of cardiac arrest survivors

The relevance of the quality of in-hospital treatment and

its impact on overall outcome after resuscitation from

cardiac arrest has been confirmed in two studies showing

that factors associated with better outcome encompassed:

the condition of patients prearrest (age under median 71

years old and better overall performance category

prear-rest); prehospital care (shorter time from emergency call to

CPR initiation and no use of adrenaline); and in-hospital

care (no seizure activity, temperature under 37.8C

(median), S-glucose under 10.6 mmol/l 24 hours after

admission (median), and BE over3.5 mmol/l 12 hours

(median) after admission).87,88

Summary

Widespread implementation of adequate system

respon-ses and application of resuscitation techniques to reverse

clinical death increase both the rate of optimal recovery

and, by raising the number of patients with restored

spon-taneous circulation, the occurrence of PRS

Reduction of the duration of ischemia is the most

obvious intervention to prevent development of PRS;

nev-ertheless, strengthening the “chain of survival,” may also

restore spontaneous circulation in patients who otherwise

would not have been revived and are at high risk for the

development of this complex condition

During the first 24 hours postresuscitation, the PRS iswell characterized and requires aggressive treatment,aimed at reducing the progression of cerebral injury andthe effects of the secondary insult determined byimpaired cardiovascular performance Besides standardintensive care support of impaired function, the goldstandard includes mild hypothermia maintained for atleast 12 hours and optimization of perfusion and oxygendelivery

After the first 24 hours postresuscitation, the clinicalpicture is not different from that of a comatose intensivecare patient The role of the quality of treatment adminis-tered in this phase has been shown and includes brain-oriented care (prevention of hyperthermia and seizures,optimization of perfusion, glucose and metabolic control),and standard intensive care oriented to prevention ofinfection and support of impaired organ function

It is of paramount importance to optimize tation treatment in the first 2–3 days after the arrest, untilreliable prognostic instruments permit the prediction of

postresusci-an unfavorable neurologic outcome, in order to excludeself-fulfilling prophecies and provide sound information

to families, but also to plan the continuation of ate treatment strategies

appropri-Promising prognostic markers of the acute phaseresponse and treatment strategies, aimed at improving dis-turbances in microcirculation and reducing the impact ofthe specific inflammatory response, deserve further evalu-ation in systematic, well-controlled studies

R E F E R E N C E S

1 Safar, P Effects of the postresuscitation syndrome on cerebral

recovery from cardiac arrest Crit Care Med 1985; 13:

932–935

2 Pell, J.P., Sirel, J.M., Marsden, A.K., Ford, I., Walker, N.L &

Cobbe, S.M Presentation, management, and outcome of out

of hospital cardiopulmonary arrest: comparison by underlying

Association Circulation 1991; 83: 1832–1847.

4 Negovsky, V.A The second step in resuscitation: the treatment

of the post-resuscitation disease Resuscitation 1972; 1: 1–7.

5 Negovsky, V.A., Gurvitch, A.M & Zolo-tokrylina, E.S

Post-resuscitation Disease Amsterdam: Elsevier, 1983.

6 Safar, P Resuscitation from clinical death Crit Care Med 1988;

16: 923–941.

7 Safar, P., Behringer, W., Böttiger, B.W et al Cerebral

resuscita-tion potentials for cardiac arrest Crit Care Med 2002,

30(Suppl): 140–144.

8 Cerchiari, E.L & Ferrante, M Postresuscitation syndrome In

Paradis, N.A., Halperin, H.R & Novak, R.M Cardiac Arrest The

Science and Practice of Resuscitation Medicine Baltimore:

Williams and Wilkins, 1996; 837–949

9 The Hypothermia After Cardiac Arrest study group: Mild

ther-apeutic hypothermia to improve the neurologic outcome after

cardiac arrest N Engl J Med 2002, 346: 549–556.

10 Bernard, S.A., Gray, T.W., Buist, M.D et al Treatment of

comatose survivors of out-of-hospital cardiac arrest with

induced hypothermia N Engl J Med 2002, 346: 557–563.

11 Adrie, C., Adib-Conquy, M., Laurent, I et al Successful

car-diopulmonary resuscitation after cardiac arrest as a

“sepsis-like” syndrome Circulation 2002; 106: 562–568.

12 Adrie, C., Laurent, I., Monchi, M et al Postresuscitation

disease after cardiac arrest: a sepsis-like syndrome? Curr Opin.

Crit Care 2004; 10: 208–212.

13 Pulsinelli, W.A., Brierley, J.B & Plum, F Temporal profile of

neuronal damage in a model of transient forebrain ischemia

Ann Neurol 1982; 11: 491–498.

14 Vaagenes, P., Cantadore, R., Safar, P et al Amelioration of brain

damage by lidoflazine after prolonged ventricular fibrillation

cardiac arrest in dogs Crit Care Med 1984; 12: 846–855.

15 Safar, P., Abramson, N.S., Angelos, M et al Emergency

car-diopulmonary bypass for resuscitation from prolonged

cardiac arrest Am J Emerg Med 1990; 8: 55–67.

16 Cerchiari, E.L., Safar, P., Klein, E., Cantadore, R & Pinsky, M

Cardiovascular function and neurologic outcome after cardiac

arrest in dogs: the cardiovascular post-resuscitation

syn-drome Resuscitation 1993; 25: 9–33.

17 Cerchiari, E.L., Safar, P., Klein, E & Diven, W Visceral

post-resuscitation syndrome and neurologic outcome

Resuscitation 1993; 25: 119–136.

18 Hossmann, K.A & Hossmann, V Coagulopathy following

experimental cerebral ischemia Stroke 1977; 8: 249–253.

19 Sterz, F., Safar, P., Diven, W., Leonov, Y., Radovsky, A & Oku, K

Detoxification with hemabsorption after cardiac arrest does not

improve neurologic recovery Resuscitation 1993; 25: 137–160.

20 Rea, T.D., Eisenberg, M.S., Sinibaldi, G & White, R.D Incidence

of EMS-treated out-of-hospital cardiac arrest in the United

States Resuscitation 2004; 63: 17–24.

21 Parish, D.C., Dane, F.C., Montgomery, M et al Resuscitation in

the hospital: differential relationships between age and

sur-vival across rhythms Crit Care Med 1999; 27: 2137–2141.

22 Peberdy, M.A., Kaye, W., Ornato, J.P et al Cardiopulmonary

resuscitation of adults in the hospital: a report of 14,720

cardiac arrests from the National Registry of Cardiopulmonary

Resuscitation Resuscitation 2003; 58: 297–308.

23 Brain Resuscitation Clinical Trial I Study Group Randomized

clinical study of thiopental loading in comatose survivors of

cardiac arrest N Engl J Med 1986; 314: 397–403.

24 Brain Resuscitation Clinical Trial 2 Study Group A randomized

clinical study of calcium-entry blocker in the treatment of

comatose survivors of cardiac arrest N Engl J Med 1991; 324:

1125–1131

25 Becker, L.B., Ostrander, M.P., Barrett, J et al Outcome of

car-diopulmonary resuscitation in a large metropolitan area:

where are the survivors? Ann Emerg Med 1991; 20: 355–361.

26 Niemann, J.T & Stratton, S.J The Utstein template and theeffect of in-hospital decisions: the impact of do-not-attemptresuscitation status on survival to discharge statistics

Resuscitation 2001; 51: 233–237.

27 Madl, C Holzer, M Brain function after resuscitation from

cardiac arrest Curr Opin Crit Care 2004; 10: 213–217.

28 Bottiger, B.W., Motsch, J., Bohrer, H et al Activation of blood

coagulation following cardiac arrest is not balanced

ade-quately by activation of endogenous fibrinolysis Circulation

1995; 92: 2572–2578.

29 Krep, H., Bottiger, B.W., Bock, C et al Time course of

circula-tory and metabolic recovery of cat brain after cardiac arrestassessed by perfusion- and diffusion weighted imaging and

MR-spectroscopy Resuscitation 2003; 58: 337–348.

30 Schaafsma, A., de Jong, B.M., Bams, J.L et al Cerebral

perfu-sion and metabolism in resuscitated patients with severe

post-hypoxic encephalopathy J Neurol Sci 2003; 210: 23–30.

31 Mussack, T & Peter Biberthaler, P.A., Cornelia

Gippner-Steppert, C et al Early cellular brain damage and systemic

inflammatory response after cardiopulmonary resuscitation

or isolated severe head trauma: a comparative pilot study on

common pathomechanisms Resuscitation 2001; 49: 193–199.

32 Booth, C.M., Boone, R.H., Tomlinson, G & Detsky, A.S Is thispatient dead, vegetative, or severely neurologically impaired?

Assessing outcome for comatose survivors of cardiac arrest J.

Am Med Assoc 2004; 291: 870–879.

33 Robinson, L.R., Micklesen, P.J., Tirschwell, D.L et al Predictive

value of somatosensory evoked potentials for awakening from

coma Crit Care Med 2003, 31: 960–967.

34 Meynaar, I.A., Oudemans-van Straaten, H.W., Wetering, J et al.

Serum neuron-specific enolase predicts outcome in

post-anoxic coma: a prospective cohort study Intens Care Med.

2003; 29: 189–195.

35 Böttiger, B.W., Bode, C., Kern, S et al Efficacy and safety of

thrombolytic therapy after initially unsuccessful

cardiopul-monary resuscitation: a prospective clinical trial Lancet 2001;

357: 1583–1585.

36 Spohr, H.R., Bluhmki, E et al International multicentre trail

protocol to assess the efficacy and safety of tneecteplaseduring cardiopulmonay resiscitation in patients with out-of-hospital cardiac arrest: the Thrombolysis in Cardiac Arrest

(TROICA) Study Eur J Clin Invest 2005; 35: 315–323.

37 Elmenyar, A.A Postresuscitation myocardial stunning and its

outcome Crit Pathways Cardiol 2004; 3: 209–215.

38 Kern, K.B Postresuscitation myocardial dysfunction Cardiol.

Clin 2002; 20: 89–101.

39 Bashir, R., Padder, F.A & Khan, F.A Myocardial stunning

fol-lowing respiratory arrest Chest 1995; 108: 1459–1460.

40 Wei, X Myocardial stunning electroconvulsive therapy Ann.

Intern Med 1995; 117: 914–915.

41 Engdahl, J., Holmberg, M., Karlson, B.W., Luepker, R & Herlitz,

J The epidemiology of out-of-hospital ‘sudden’ cardiac arrest

Resuscitation 2002; 52(3): 235–245.

42 Kern, K.B., Hilwig, R.W., Rhee, K.H & Berg, R.A Myocardial

dysfunction after resuscitation from cardiac arrest: an

example of global myocardial stunning J Am Coll Cardiol.

1996; 28: 232–240.

43 Tang, W., Weil, M.H., Sun, S et al Epinephrine increases

the severity of postresuscitation myocardial dysfunction

Circulation 1995; 92: 3089–3093.

44 Laurent et al Myocardial dysfunction after cardiac arrest J.

Am Coll Cardiol 2000; 40(12): 2110–2116.

45 Xie, J., Weil, M.H., Sun, S.J et al High-energy defibrillation

increases the severity of postresuscitation myocardial

dys-function Circulation 1997; 96: 683–688.

46 Tang, W., Weil, M.H., Sun, S et al The effects of biphasic

wave-form design on post-resuscitation myocardial function J Am.

Coll Cardiol 2004; 43: 1228–1235.

47 Jennings, R.B., Murry, C.E & Steenbergen, C Jr Development

of cell injury in sustained acute ischemia Circulation 1990;

82(Suppl 3): 2–12.

48 Bolli, R & Marban, E Molecular and cellular mechanisms of

myocardial stunning Physiol Rev 1999; 79: 609–634.

49 Niemann, J.T., Garner, D & Lewis, R.J Tumor necrosis factor is

associated with early postresuscitation myocardial

dysfunc-tion Crit Care Med 2004; 32: 1753–1758.

50 De Antonio, A.J., Kaul, S & Lerman, B.B Reversible myocardial

depression in survivors of cardiac arrest PACE 1990; 13:

982–986

51 Rivers, E.P., Rady, M.Y., Martin, G.B., Smithline, H.A.,

Alexander, M.E & Nowak, R.M Venous hyperoxia after cardiac

arrest: characterization of a defect in systemic oxygen

utiliza-tion Chest 1992; 102: 1787–1793.

52 Mullner, M., Domanovits, H., Sterz, F et al Measurement of

myocardial contractility following successful resuscitation:

quantitated left ventricular systolic function utilising

non-invasive wall stress analysis Resuscitation 1998; 39: 51–59.

53 Mullner, M., Sterz, F., Binder, M et al Arterial blood pressure

after human cardiac arrest and neurological recovery Stroke

1996; 27: 59–62.

54 Nishizawa, H & Kudoh, I Cerebral autoregulation is impaired

in patients resuscitated after cardiac arrest Acta Anaesthesiol.

Scand 1996; 40: 1149–1153.

55 Sundgreen, C., Larsen, F.S., Herzog, T.M., Knudsen, G.M.,

Boesgaard, S & Aldershvile, J Autoregulation of cerebral blood

flow in patients resuscitated from cardiac arrest Stroke 2001;

32: 128–132.

56 Tennyson, H., Kern, K.B., Hilwig, R.W., Berg, R.A & Ewy, G.A

Treatment of post resuscitation myocardial dysfunction: aortic

counterpulsation versus dobutamine Resuscitation 2002; 54:

69–75

57 Vasquez, A., Kern, K.B., Hilwig, R.W., Heidenreich, J., Berg, R.A

& Ewy, G.A Optimal dosing of dobutamine for treating

post-resuscitation left ventricular dysfunction Resuscitation 2004;

61: 199–207.

58 Meyer, R.J., Kern, K.B., Berg, R.A., Hilwig, R.W & Ewy, G.A

Postresuscitation right ventricular dysfunction: delineation and

treatment with dobutamine Resuscitation 2002; 55: 187–191.

59 Rivers, E., Nguyen, B., Havstad, S et al Early goal-directed therapy in the treatment of severe sepsis and septic shock N.

Engl J Med 2001; 345: 1368–1377.

60 Böttiger, B.W., Motsch, J., Böhrer, H et al Activation of blood

coagulation after cardiac arrest is not balanced adequately by

activation of endogenous fibrinolysis Circulation 1995; 92:

2572–2578

61 Gando, S., Nanzaki, S., Morimoto, Y et al Out-of-hospital

cardiac arrest increases soluble vascular endothelial adhesionmolecules and neutrophil elastase associated with endothelial

injury Intens Care Med 2000; 26: 38–44.

62 Böttiger, B.W., Motsch, J., Braun, V et al Marked activation of

complement and leukocytes and an increase in the centrations of soluble endothelial adhesion moleculesduring cardiopulmonary resuscitation and early reperfusion

con-after cardiac arrest in humans Crit Care Med 2002; 30:

2473–2480

63 Geppert, A., Zorn, G., Karth, G.D et al Soluble selectins

and the systemic inflammatory response syndrome after

successful cardiopulmonary resuscitation Crit Care Med.

2000; 28: 2360–2365.

64 Geppert, A., Zorn, G., Delle-Karth, G et al Plasma

concen-trations of von Willebrand factor and intracellular adhesionmolecule-1 for prediction of outcome after successful car-

diopulmonary resuscitation Crit Care Med 2003; 31:

805–811

65 Oppert, M., Gleiter, C.H., Müller, C et al Kinetics and

charac-teristics of an acute phase response following cardiac arrest

Intens Care Med 1999; 25: 1386–1394.

66 Adrie, C., Monchi, M., Laurent, I et al Coagulopathy after

suc-cessful cardiopulmonary resuscitation following cardiac arrest

– implication of the protein C anticoagulant pathway J Am.

Coll Cardiol 2005; 46: 21–28.

67 Gando, S., Nanzaki, S., Morimoto, Y., Kobayashi, S &

Kemmotsu, O Tissue factor and tissue factor pathwayinhibitor levels during and after cardiopulmonary resuscita-

tion Thromb Res 1999; 96: 107–113.

68 Kempski, O & Behmanesh, S Endothelial cell swelling and

brain perfusion J Trauma 1997; 42: S38–S40.

69 Ito, T., Saitoh, D., Fukuzuka, K et al Significance of elevated

serum interleukin-8 in patients resuscitated after

cardiopul-monary arrest Resuscitation 2001; 51: 47–53.

70 Shyu, K., Chang, H., Likn, C et al Concentrations of serum

interleukin-8 after successful cardiopulmonary resuscitation

in patients with cardiopulmonary arrest Am Heart J 1997;

73 Gando, S., Kameue, T., Nanzaki, S et al Massive fibrin

forma-tion with consecutive impairment of fibrinolysis in patients

with out-of-hospital cardiac arrest Thromb Haemost 1997;

77: 278–282.

74 Schultz, C.H., Rivers, E.P., Feldkamp, C.S et al A

characteriza-tion of hypothalamic-pituitaryadrenal axis funccharacteriza-tion during

and after human cardiac arrest Crit Care Med 1993; 21:

1339–1347

75 Ito, T., Saitoh, D., Takasu, A et al Serum cortisol as a

predictive marker of the outcome in patients resuscitated

after cardiopulmonary arrest arrest Resuscitation 2004; 62:

55–60

76 Hékimian, G., Baugnon, T., Thuong, M et al Cortisol levels and

adrenal reserve after successful cardiac arrest resuscitation

SHOCK, 2004; 22 (2): 116–119.

77 Mattana, J & Singhal, P.C Prevalence and determinants of

acute renal failure following cardiopulmonary resuscitation

Arch Intern Med 1993; 153: 235–239.

78 Korth, U., Krieter, H., Denz, C et al Intestinal ischaemia

during cardiac arrest and resuscitation: comparative analysis

of extracellular metabolites by microdialysis, Resuscitation

2003; 58: 209–217.

79 L’Her, E., Cassaz, C., Le Gal, G et al Gut dysfunction and

endo-scopic lesions after out-of-hospital cardiac arrest Resuscitation

2005; 66: 331–334.

80 Gaussorgues, P., Gueugniaud, P.Y., Vedrinne, J.M et al.

Bacteraemia following cardiac arrest and cardiopulmonary

resuscitation Intens Care Med 1998; 14: 575–577.

81 Rello, J., Valles, J., Jubert, P et al Lower respiratory tract

infec-tions following cardiac arrest and cardiopulmonary

resuscita-tion Clin Infect Dis 1995; 21: 310–314.

82 Gajic, O., Emir Festic, E & Afessa, B Infectious complications

in survivors of cardiac arrest admitted to the medical intensive

care unit, Resuscitation 2004; 60: 65–69.

83 Oppert, M., Albrecht Reinicke, A., Christian Muller, C et al.

Elevations in procalcitonin but not C-reactive protein areassociated with pneumonia after cardiopulmonary resuscita-

tion Resuscitation 2002; 53: 167–170.

84 Takino, M & Okada, Y Hyperthermia following

cardiopul-monary resuscitation Intens Care Med 1991; 17: 419–420.

85 Bone, R.C., Balk, R.A., Cerra, F.B et al (The ACCP/SCCM

Consensus Conference Committee) Definitions for sepsis andorgan failure and guidelines for the use of innovative therapies

in sepsis Chest 1992; 101: 1644–1655.

86 Laurent, I., Adrie, C., Vinsonneau, C et al High-volume

hemofiltration to improve prognosis after cardiac arrest – a

randomised study J Am Coll Cardiol 2005; 46: 432–437.

87 Langhelle, A., Tyvold, S.S., Lexow, K et al In-hospital factors

associated with improved outcome after out-of-hospitalcardiac arrest A comparison between four regions in Norway

Resuscitation 2003; 56: 247–263.

88 Skrifvars, M.B., Rosenberg, P.H., Finne, P et al Evaluation of

the in-hospital Utstein template in cardiopulmonary

resusci-tation in secondary hospitals Resusciresusci-tation 2003; 56: 275–282.

It is estimated that between 400 000 and 460 000

individu-als suffer an episode of sudden cardiac arrest every year in

the United States.1Yet, the percentage of individuals who

are successfully resuscitated and leave the hospital alive

with intact neurological function averages less than 10%

nationwide.2–4Efforts to restore life successfully are

formid-ably challenging They require not only that cardiac activity

be initially restored but that injury to vital organs be

pre-vented or minimized A closer examination of resuscitation

statistics reveals that efficient Emergency Medical Services

systems are able to re-establish cardiac activity in 30% to

40% of sudden cardiac arrest victims at the scene.5–7Yet,

close to 40% die before admission to a hospital presumably

from recurrent cardiac arrest or complications during

transport.8 Of those admitted to the hospital nearly 60%

succumb before discharge, such that only one in four

ini-tially resuscitated victims leaves the hospital alive

Although the causes of postresuscitation deaths have

not been systematically investigated, the available

infor-mation suggests that postresuscitation myocardial

dys-function, hypoxic brain damage, systemic inflammatory

responses, intercurrent illnesses, or a combination thereof

are the main culprits.8–10 The core pathogenic process

driving such poor outcome is the intense ischemia of

vari-able duration that organs suffer after cessation of blood

flow and the subsequent reperfusion injury that

accompa-nies the resuscitation effort In addition, the precipitating

event of cardiac arrest may also play a role in the

post-resuscitation phase

This chapter focuses on the effects of cardiac arrest and

resuscitation on the myocardium, mindful that many other

organs are concomitantly affected by similar mechanisms

of cell injury The chapter is organized to describe: (1) thefunctional myocardial abnormalities that occur during andafter resuscitation from cardiac arrest; (2) the underlyingcellular mechanisms of such injury; (3) factors that maycontribute to myocardial injury; (4) therapies that havebeen shown in the laboratory to prevent or amelioratemyocardial injury; and (5) the management of postresusci-tation myocardial dysfunction As the chapter develops thereader will learn that postresuscitation myocardial dys-function is largely a reversible phenomenon such thatsupport of the failing heart during the critical postresusci-tation interval is fully justified

Functional myocardial manifestations

The working heart is a highly metabolically active organthat consumes close to 10% of the total body oxygen con-sumption and extracts nearly 70% of the oxygen supplied

by the coronary circuit Nevertheless, it has minimal bility for extracting additional oxygen such that increasedmetabolic demands are met through coronary vasodilata-tion with augmentation of blood flow and oxygen deliv-ery.11,12Consequently, a severe energy imbalance developsimmediately after cardiac arrest supervenes and coronaryblood flow ceases The severity of the energy deficit is con-tingent on the metabolic requirements and is particularlyhigh in the setting of ventricular fibrillation (VF) when theoxygen requirements are comparable to or exceed that ofthe normally beating heart.13,14A lesser energy deficit isanticipated when cardiac arrest occurs in a quiescent orminimally active heart (i.e., asystole or pulseless electrical

capa-829

Cardiac Arrest: The Science and Practice of Resuscitation Medicine 2nd edn., ed Norman Paradis, Henry Halperin, Karl Kern, Volker Wenzel, Douglas

Chamberlain Published by Cambridge University Press © Cambridge University Press, 2007.

Prevention and therapy of postresuscitation

activity as a result of asphyxia or exsanguination).15

Because most experimental studies have examined the

myocardial manifestations of cardiac arrest and

resuscita-tion in animal models of VF, cauresuscita-tion should be exercised

when extrapolating these findings to cardiac arrest settings

precipitated by mechanisms other than VF

With cessation of coronary blood flow and oxygen

avail-ability, the mitochondrial capability for regenerating ATP

through oxidative phosphorylation stops, prompting

anaerobic regeneration of limited amounts of ATP at the

substrate level from breakdown of creatine phosphate and

oxidation of pyruvate to lactate.16–18Hence, there is rapid

depletion of creatine phosphate, marked elevation in

lactate, and a relatively slow depletion of ATP.17 In one

recent study in a rat model of VF, 10 minutes of untreated VF

were accompanied by decreases in myocardial creatine

phosphate and ATP to levels 7% and 19% of baseline,

respectively, whereas the lactate content increased by more

than 50-fold.19Coincident with the energy deficit,

accu-mulation of CO2and Haccount for profound myocardial

acidosis.18,20

When conventional closed-chest resuscitation is used,

the coronary blood flow generated rarely exceeds 20% of

the normal flow,21 thus failing to reverse myocardial

ischemia In addition, reperfusion of ischemic myocardium

activates multiple pathogenic mechanisms, leading to what

is known as reperfusion injury Accordingly, resuscitation

typically proceeds during and in spite of severe myocardial

ischemia and in the midst of reperfusion injury

com-pounded by specific interventions, such as electrical

shocks and adrenergic vasopressor agents, that can also

contribute to myocardial injury As a result, various

func-tional myocardial abnormalities develop that may

them-selves compromise resuscitability and survival These

myocardial abnormalities represent a continuum along the

injury process that can be grouped into those that manifest

during the resuscitation effort and those that manifest after

the return of spontaneous circulation The former include

ischemic contracture and increased resistance to electrical

defibrillation; the latter include reperfusion arrhythmias

and myocardial dysfunction

Ischemic contracture

Ischemic contracture refers to progressive left ventricular

wall thickening with parallel reductions in cavity size

con-sequent to myocardial ischemia Ischemic contracture

was first reported in the early 1970s during open heart

surgery when operations were conducted under

nor-mothermic conditions and in the fibrillating heart to

render a bloodless surgical field.22,23The onset of ischemic

contracture in this setting was associated with reductions

in myocardial ATP levels to10% of normal.24An extrememanifestation of ischemic contracture is the so-called

“stony heart” and typically heralds irreversible ischemicinjury

More recent studies in animal models of VF and closedchest resuscitation have demonstrated a phenomenonakin to ischemic contracture, but of earlier onset and asso-ciated with less ATP depletion.25,26This form of ischemiccontracture is likely to represent a manifestation of reper-fusion injury27such that withholding chest compression(and hence coronary blood flow) markedly delays theonset of contracture.28,29 The resulting left ventricularthickening with reductions in cavity size compromisesventricular preload and the amount of blood that can beejected by chest compression.14,27,30Thus, ischemic con-tracture may partly explain the characteristic time-dependent reductions in the hemodynamic efficacy ofchest compression.31Moreover, recent studies in a porcinemodel of VF demonstrate that the severity of ischemic con-tracture is proportional to the preceding interval ofuntreated VF.26In humans, ischemic contracture has beendescribed as myocardial “firmness” during open-chestresuscitation after failure of closed-chest attempts andfound also to compromise resuscitability.32Studies in theresearch laboratory have shown that ischemic contracturecan be attenuated by pharmacologic interventions target-ing reperfusion injury, resulting in hemodynamically morestable closed-chest resuscitation.27,33The possibility thatischemic contracture might increase coronary vascularresistance by extrinsic compression of the coronarycircuit14,34has not been substantiated.33,35

Resistance to defibrillation

Electrical shocks delivered immediately after onset of VFare consistently effective in re-establishing cardiac activ-ity Even short delays (i.e., up to 3 minutes) may not besubstantially detrimental and result in more than 50%likelihood of successful resuscitation.36Longer intervals ofuntreated VFas usually occurs in out-of-hospital set-tingspredict decreased effectiveness of defibrillationattempts, however, in which electrical shocks may fail toreverse VF or may precipitate asystole or pulseless electri-cal activity.37Under these conditions, additional resuscita-tion interventions are required to restore myocardialconditions favorable for successful defibrillation Newapproaches are being developed to optimize the effective-ness of electrical defibrillation by identifying the propertiming for shock delivery and by using safer and moreeffective defibrillation waveforms.38,39

Reperfusion arrhythmias

Electrical instability manifested by premature ventricular

complexes and episodes of ventricular tachycardia and VF

commonly occurs during the early minutes after return of

cardiac activity Episodes of VF have been reported to occur

in up to 79% of patients, with the number of episodes

inversely correlated with ultimate survival.40The

mech-anism responsible for postresuscitation arrhythmias is

complex and probably involves prominent cytosolic Ca2

overload with afterdepolarizations triggering ventricular

ectopic activity.41 In addition, there are repolarization

abnormalities that include shortening of the action

poten-tial (AP) duration, decreased AP amplitude, and

develop-ment of AP duration alternans creating conditions for

re-entry.42Experimentally, these repolarization

abnormal-ities are short-lived (5 to 10 minutes) and coincide with the

interval of increased propensity for ventricular

arrhyth-mias and recurrent VF.27They are in part related to opening

of sarcolemmal KATPchannels;43however, recent evidence

suggests that activation of the sarcolemmal Na-H

exchanger isoform-1 (NHE-1) may also play a role.44

Postresuscitation myocardial dysfunction

Variable degrees of left ventricular systolic and diastolic

dysfunction develop after resuscitation from cardiac

arrest, despite full restoration of coronary blood flow Left

ventricular dysfunction is largely reversible, conforming to

the definition of myocardial stunning.45–48

Systolic dysfunction has been documented by using

load-independent indices of contractility, which

demon-strates decreases in the slope of the end-systolic

pressure-volume relationship (elastance) and increases in the

volume intercept at a left ventricular pressure of 100 mm

Hg (V100).46Impaired contractility leads to reductions in

indices of global ventricular performance, such as cardiac

index, ejection fraction, and left ventricular stroke

work,8,47,49and renders the heart susceptible to afterload

increases during the postresuscitation phase In a pig

model of VF and closed chest resuscitation, the

adminis-tration of vasopressin during cardiac resuscitation was

associated with decreased left ventricular performance,

with reversal by administration of a specific antagonist of

the V1receptor.50

Diastolic dysfunction is characterized by left ventricular

wall thickening with reductions in end-diastolic volume

and impaired relaxation,27 and appears to be maximal

immediately after restoration of spontaneous circulation

The magnitude of diastolic dysfunction correlates closely

with the magnitude of ischemic contracture,51suggesting a

common pathogenic thread with diastolic dysfunctionbeing a manifestation of resolving ischemic contracture

From a functional perspective, diastolic dysfunction maylimit the compensatory ventricular dilatation required toovercome decreased contractility according to the Frank-Starling mechanism

Postresuscitation myocardial dysfunction was first mented in humans by Deantonio and colleagues.45Theyreported on three female patients who were successfullyresuscitated following transthoracic defibrillation afterapproximately 3, 10, and 30 minutes of cardiac arrest andwho developed prominent left ventricular dilatation withreduction in fractional shortening within 3 days postresus-citation None of these patients had coronary artery diseaseand ventricular function normalized within 2 weeks

docu-Likewise, Ruiz-Bailen and coworkers reported severe suscitation myocardial dysfunction with reductions in leftventricular ejection fraction to 0.42 in 29 patients within theinitial 24 hours postresuscitation.52In a subset of 20 patientswho had left ventricular dysfunction, the ejection fraction

postre-decreased to 0.28 (P0.05) Patients who died had a

signifi-cantly lower ejection fraction Patients who survived ally normalized their ejection fraction within an interval ofapproximately 4 weeks postresuscitation (Fig 48.1)

gradu-Laurent and colleagues stratified 165 patients fully resuscitated from out-of-hospital cardiac arrest based

success-on whether hemodynamic instability was present withinthe initial 72 hours postresuscitation.8 Hemodynamicinstability was defined as hypotension requiring vasoac-tive drugs after fluid resuscitation It occurred in 55% of thepatients and was associated with longer resuscitationtimes, greater number of electrical shocks, larger amounts

of adrenaline, and worse left ventricular function (Table48.1) The incidence and severity of coronary artery diseasewas comparable between groups; however, a trend wasnoted towards a higher incidence of recent coronary occlu-sion in patients with hemodynamic instability Myocardialdysfunction was initially accompanied by a low cardiacindex (2.05 l/min per m2) with elevated systemic vascularresistance (2908 dynes s/cm5per m2) However, a hyperdy-namic state developed during the ensuing 72 hours, char-acterized by increased cardiac index, decreased systemicvascular resistance, and the need for large amounts offluids to maintain adequate filling pressures (Fig 48.2)

The late hyperdynamic state reported by Laurent andcoworkers is consistent with the development of a systemicinflammatory response akin to that observed during sepsisbutprecipitatedbycardiacarrestandresuscitation.53–55Adrieand colleagues measured circulating cytokines in 61 victims

of out-of-hospital cardiac arrest who were successfully citated.55Measurements obtained at approximately 3 hours

resus-postresuscitation demonstrated prominent increases in

plasma levels of tumor necrosis factor (TNF)-, interleukin

(IL)-6, IL-8, IL-10, soluble TNF receptor type II (sTNFII), IL-1

receptor antagonist (IL-1ra), and regulated on activation,

normal T-cell expressed and secreted (RANTES) In a subset

of 35 patients, increased endotoxin levels were detected in

46% within the initial 48 hours postresuscitation

Underlying cell mechanisms: role of mitochondria

The underlying mechanism of cell injury is complex andprobably time-sensitive There are processes that developshortly after onset ischemia and during reperfusion thatlead to abnormalities in energy metabolism, acid basestatus, and intracellular ion homeostasis Other processes

1st week

2nd–3rd week

1st month

3rd–6th month

Fig 48.1 Serial measurements of left ventricular ejection fraction by echocardiography in 29 patients

successfully resuscitated from cardiac arrest (CA) without known cardiovascular diseaseexcept for

hypertensionand who survived a minimum of 72 hours Patients had a median age of 65 years and

41% were females Prearrest echocardiograms were available in 16 patients demonstrating a mean left

ventricular ejection fraction of 0.60 Squares represent the entire cohort of 29 patients; circles represent

a subset of 20 patients who had myocardial dysfunction (Adapted from ref 52.)

Table 48.1 Factors associated with postresuscitation hemodynamic instability

Hemodynamic stability Hemodynamic

(n75) instability (n73) P

Resuscitation data

Collapse to ROSC, min 15 (7–30) 25 (14–28)  0.01

Countershocks, n 2 (1–3) 3 (1–6)  0.01Total epinephrine, mg 2 (0–10) 10 (3–15)  0.01

Angiography/ventriculography data

Heart rate, beats/min 85 (48–118) 105 (75–143)  0.05LVEF 0.43 (0.35–0.50) 0.32 (0.25–0.40)  0.01LVEDP, mmHg 12 (5–25) 19 (10–32)  0.01Recent coronary occlusion, % 37 51 0.06ROSCReturn of spontaneous circulation; LVEFLeft ventricular ejection fraction; LVEDPLeft ventricular end diastolic pressure.Median (interquartile range) (Adapted from ref 8.)

develop at a slower pace and encompass signaling

mecha-nisms, leading to sustained disruption of energy production

and contractile function with activation of apoptotic

path-ways Discussion on the various cell mechanisms

responsi-ble for cell injury is beyond the scope of this chapter

Nonetheless, pertinent to our discussion is the growing

evi-dence placing the mitochondria at the center of myocardial

preservation, reperfusion injury, and postischemic

dysfunc-tion Better understanding of mitochondrial injury may also

serve to identify novel therapeutic strategies.56–66

Energy production

The mitochondria are organelles present in all eukaryotic

cells that play an essential role in aerobic metabolism and

generation of ATP Mitochondria have an inner membrane

that is highly impermeable and folds inwardly into the

mitochondrial matrix, forming multiple cristae where

pro-teins responsible for oxidative phosphorylation reside The

outer mitochondrial membrane is more porous and

sur-rounds the inner mitochondrial membrane Generation of

energy in the form of ATP results from oxidation of NADH

in the electron transport chain This chain is composed of

protein complexes assembled along the inner

mitochon-drial membrane where electrons are transferred down

their redox potential while Hare pumped into the

inter-membrane space The accumulation of Hestablishes an

electromotive force, which is used by FoF1ATP synthase to

form ATP from ADP and inorganic phosphate ATP is then

exported into the cytosol in exchange for ADP by the

adenine nucleotide translocase (Fig 48.3)

Disruption of the inner membrane permeability leads to

reduction of the Hgradient, compromising the

electro-motive force required for ATP synthesis Factors that may

contribute to such injury during ischemia and reperfusion

include mitochondrial Ca2 overload and generation of

reactive oxygen species (ROS) explaining decreased

mito-chondrial capability for regeneration of ATP

Apoptotic signaling

In addition to the key role on energy production,

mitochon-dria can also signal cell death by activation of the intrinsic

apoptotic pathway through release of cytochrome c.

Cytochrome c is a 14-kDa hemoprotein normally present in

the intermembrane mitochondrial space that plays a key role

by transferring electrons from complex III to complex IV (Fig

48.3) Cytochrome c can be released to the cytosol,

prompt-ing the formation of an oligomeric complex with dATP and

the apoptotic protease activating factor-1 (Apaf-1).57This

complex recruits procaspase-9, forming the so-called

apop-tosome In the apoptosome, procaspase-9 is activated andthen released as caspase-9, which in turn, activates the exe-cutioner caspases 3, 6, and 7.67,68Active executioner caspasescleave several cytoplasmic proteins, including-spectrinand actin, and nuclear proteins including poly (ADP-ribose)polymerase (PARP), lamin A, and the inhibitor of caspase-activated DNase (ICAD) Cleavage of ICAD leads to activation

of caspase activated DNase (CAD), which in turn cleaveschromatin into 180 to 200 bp fragments Other substratesactivated during apoptosis include components of DNArepair machinery and a number of protein kinases,67ulti-mately culminating in cell death

Various mechanisms have been proposed to explain

cytochrome c release One mechanism involves opening of

a high-conductance mega channel formed by apposition

of transmembrane proteins from the inner and the outermitochondrial membrane known as the mitochondrialpermeability transition pore (MPTP).59 Opening of thepore allows molecules up to 1.5 kDa to enter the mito-chondrial matrix along with water and solutes, leading tomitochondrial swelling with stretching and disruption ofthe outer mitochondrial membrane, ultimately causing

Postresuscitation (hours)

8.0 (7.0–9.0)

12.0 (11.0–13.5)

24.0 (23.0–25.7)

67.0 (52.0–72.0)0

1000200030004000

SVRI (dynes s/cm5 m2)

†

0.51.52.53.54.5

Cardiac index (l/min per m2)

*

Fig 48.2 Serial measurements of cardiac index and systemic

vascular resistance index (SVRI) in a subset of 73 patients whohad hemodynamic instability after resuscitation from out-of-hospital cardiac arrest A cumulative amount of 8,000 ml wasrequired to maintain a pulmonary artery occlusive pressure

12 mmHg The mortality was 19 % Median (interquartile range)

*P 0.05; † P0.001 (Adapted from ref 8.)

release of cytochrome c.59Pathophysiological conditions

responsible for opening of the MPTP include Ca2

over-load, production of reactive oxygen species (ROS),

deple-tion of ATP and ADP, increases in inorganic phosphate, and

acidosis.59 Cytochrome c can also be released without

MPTP opening through formation of pores in the outer

mitochondrial membrane This is best explained by

perm-eabilization of the outer membrane by apoptotic

pro-teins such as Bcl-2–associated X protein (Bax), Bcl-2

homologous antagonist killer (Bak), or truncated BH3

interacting domain death agonist (Bid).69Anti-apoptotic

proteins such as Bcl-2, Bcl-x, and Bcl-w, however, may play

important roles by counterbalancing the aforementioned

pro-apoptotic effects.70

Mitochondrial Ca 2

Mitochondrial Ca2 overload plays a critical role during

ischemia and reperfusion Ca2normally enters the

mito-chondria through a Ca2uniporter and leaves through a

Na-Ca2exchanger located in the inner mitochondrialmembrane This transport mechanism enables changes incytosolic Ca2to be relayed to the mitochondrial matrixand thus regulate the activity of various enzymes of the tri-carboxylic acid cycle Increases in cytosolic Ca2 duringischemia prompt mitochondrial Ca2increases leading toproduction of reactive oxygen species (ROS) ROS causeperoxidation of cardiolipin, which is the principal lipidconstituent of the inner mitochondrial membrane and to

which a fraction of cytochrome c is bound Peroxidation

decreases the binding affinity of cardiolipin for

cyto-chrome c,71facilitating its release out of the mitochondria.Modest increases in extramitochondrial Ca2(i.e., 2 M)

cause cytochrome c release without MPTP opening At

higher Ca2 levels (i.e., 20 M), ROS and Ca2 actingtogether prompt MPTP opening, presumably throughoxidative injury of the adenine nucleotide translocase

Both mechanisms of cytochrome c release can be

pre-vented by blocking the mitochondrial Ca2uniporter withruthenium red.72

Fig 48.3 Scheme depicting the structural organization of the electron transport chain, the

mitochondrial permeability transition pore (MPTP), and the FoF1ATP synthase in relation to the inner

and outer mitochondrial membranes PBRperipheral benzodiazepine receptor; VDACvoltage

dependent anion channel; HKhexokinase; CKcreatine kinase; ANTadenine nucleotide

translocase; CypDcyclophilin-D; I, II, III, and IVrespiratory complexes; Qcoenzyme Q; C

cytochrome c; OMMouter mitochondrial membrane; IMSintermembrane space; IMMinner

Link to myocardial dysfunction

Mounting evidence suggests that acute modifications of

regulatory proteins of the contractile apparatus occur

through cleavage of specific components73,74 following

intracellular Ca2 increase and activation of proteases

such as calpain-1 and caspase-3.75–78 Communal and

col-leagues reported that activated caspase-3 cleaves -actin

and -actinin but not myosin heavy chain, myosin light

chain 1/2, and tropomyosin.77Incubation of recombinant

troponin (Tn) complex with caspase-3 selectively cleaved

cardiac TnT, resulting in 25-kDa fragments Functionally,

activated caspase-3 decreases maximal Ca2-activated

force and myofibrillar ATPase activity, suggesting that

activation of apoptotic pathways may lead to contractile

dysfunction Radhakrishnan and coworkers recently

demonstrated activation of caspase-3 in left ventricular

homogenates of rat hearts harvested at 4 hours

postresus-citation coincident with left ventricular dysfunction.79In

models of VF and coronary occlusion, Ca2overload was

associated with decreases in the Ca2-force relationship

presumably following modifications in the interaction

between proteins of the troponin complex.80,81Zaugg and

coworkers specifically demonstrated, in a model of

pro-longed untreated VF, prominent cytosolic Ca2increases

leading to reduced Ca2sensitivity of troponin, TnC and

impaired contractility.82 Similarly, Barta and coworkers

demonstrated cleavage of TnI and TnT following activation

of calpain-1.78In addition, these proteases have also been

shown to cleave structural proteins such as titin, -actinin,

-fodrin, and desmin.83–85

Various novel pharmacological interventions that have

been investigated in the setting of cardiac arrest (and are

discussed below) seem to protect the myocardium by

limiting mitochondrial Ca2 overload Postresuscitation

myocardial dysfunction, as pointed out earlier, is largely a

reversible phenomenon It is less clear, however, whether

dysfunction and cell death represent part of a continuum

manifesting varying degrees of severity Much work

remains before we can fully elucidate the process of

ischemic injury and postischemic dysfunction Meanwhile,

understanding the mechanisms that affect mitochondrial

function and its signaling of apoptosis may provide an

opportunity for developing new resuscitation therapies

Factors contributing to myocardial injury

Factors that contribute to myocardial injury during cardiac

resuscitation include the duration of cardiac arrest, the

delivery of electrical shocks, and the use of adrenergic

vasopressor agents Efforts to shorten the duration of thecardiac arrest by prompt recognition and rapid interven-tion are thus important to minimize injury Likewise, deliv-ery of quality cardiopulmonary resuscitation (CPR) mayhelp reduce the duration of tissue ischemia by promptingearlier return of spontaneous circulation Quality CPR may

be attained by paying close attention to the rate, depth,and site of compression, minimizing the interruptionsrequired to secure the airway, verify rhythm, and delivershocks In addition, adequate venous return is essential forhemodynamically effective chest compression, which can

be secured by allowing full re-expansion of the chest cavity,avoiding hyperventilation, and creating an intrathoracicvacuum between compressions by using impedancethreshold devices.86 The following sections address thepotential detrimental effects of electrical shocks andadrenergic vasopressor agents along with options to mini-mize such injury

Electrical defibrillation

Delivery of electrical shocks during the resuscitation effortmay contribute to myocardial injury and worsen postre-suscitation electrical and mechanical dysfunction.87–89Manifestations of such injury include increased postresus-citation ectopic activity, atrioventricular block, and wors-ened postresuscitation myocardial dysfunction.90 Keyfactors that determine injury include the energy level,number of shocks, and defibrillation waveforms

Energy level

The presence and severity of myocardial injury is enced by the amount of energy delivered to themyocardium In an isolated perfused rabbit heart, Koningand coworkers reported minimal injury after epicardialshocks of 0.6 joule/cm2 Nevertheless, as the energy wasincreased to up to 4.2 joule/cm2 additional and moresevere injury developed, including impaired systolic func-tion, myocardial stiffness, release of creatine kinase, andcell necrosis.91 Similarly, Doherty and coworkers foundthat significant myocardial injury, as evidenced by creatinekinase release, increased technetium-99m pyrophosphateuptake, and decreased thallium-201 and indium-113muptake, developed only when the energy of shocks deliv-ered directly to beating canine hearts (15- to 26-kg dogs)exceeded 20 joules.92 The injury was characterized bydehiscence of intercalated disks between damagedmyocytes Kerber and coworkers, also in dogs, reportedcontractile abnormalities only when the energy of epicar-dial shocks was 40 Joules or more in 17- to 45-kg dogs.93Inthe cardiac arrest setting, Xie and coworkers using an intact

influ-rat model of VF reported that postresuscitation myocardial

dysfunction worsened in close relationship to stepwise

increases in the energy used for external defibrillation

from 2, to 10, and to 20 Joules.89It is important to realize,

however, that the energy required to reverse VF is typically

below the threshold at which significant myocardial cell

injury occurs.94

The mechanisms of cell injury following electrical

shocks relate in part to increased cytosolic Ca2 In

single-isolated, cultured chick-embryo heart cells, exposure to

defibrillator-type electrical shocks causes reversible

depo-larization followed by intensity-independent Ca2 entry,

attributed to opening of normal excitation channels,

and intensity-dependent Ca2 entry attributed to cell

damage.95 Further evidence that Ca2 may play a role

stems from observations in dogs in which prior

adminis-tration of the Ca2channel blocker verapamilbut not the

beta-blocker propranololattenuates the myocardial

injury caused by transthoracic countershocks.96

Number of shocks

Multiple shocks are often required to terminate VF Yet,

repetitive electrical shocks may cause myocardial injury

beyond that which is caused by individual shocks.88,90,92,97

Injury may manifest by worsened diastolic dysfunction

postresuscitation, despite no adverse effects on

postresus-citation systolic function.98 Thus, efforts to limit the

number of electrical shocks are warranted Until recently,

delivery of electrical shocks immediately upon recognition

of VF was regarded as an essential component of the chain

of survival Observations in a dog model of VF by Niemann

and coworkers99and studies in victims of out-of-hospital

sudden cardiac arrest by Cobb and coworkers100and by Wik

and coworkers,101 however, have challenged such an

approach, suggesting that a period of chest compression

before attempting defibrillation under conditions of

pro-longed untreated VF may improve the myocardial

respon-siveness to electrical shocks The 2005 guidelines for

cardiopulmonary resuscitation recommend that CPR be

given for approximately 2 minutes before attempting

elec-trical defibrillation when the ambulance response time is

prolonged (i.e.,4 minutes) Moreover, the same

recom-mendation states that only a single shock be given and that

CPR be resumed without a pulse check These

recommen-dations recognize that untimely delivery of electrical

shocks may be detrimental to the resuscitation efforts, in

part because of interruption in chest compression and

because the ischemic myocardium seems to tolerate poorly

the repetitive delivery of electrical shocks

A more optimal approach would be to guide the timing

of defibrillation based on real-time analysis of the VF

waveform Previous studies have recognized the value ofmeasuring the amplitude and frequency characteristics of

VF waveforms to estimate the duration of untreated VF,102assess myocardial energy metabolism,103and predict theresponse to defibrillation attempts.104,105Waveform analy-sis that incorporates amplitude and frequency in a singleindex has been demonstrated experimentally to havebetter positive and negative predictor power than VFamplitude and frequency alone.106Use of these indices inreal-time could allow better targeting of individual shocks,thus avoiding the delivery of shocks when the probability

of success is low

Defibrillation waveforms

Until recently, delivery of electrical shocks by external(transthoracic) defibrillators used monophasic exponen-tial waveforms, but the advent of implantable car-dioverter-defibrillators introduced into clinical practicethe use of biphasic truncated exponential waveforms.Biphasic waveforms have proven to be more effective forterminating VF and less damaging to the myocardiumthan monophasic waveforms In a study of 40- to 45-kgpigs subjected to 10 minutes of VF, Tang and coworkers107reported comparable defibrillation efficacy by biphasic(fixed 150-joule) and monophasic (escalating 200-, 300-,and 360-joule) shocks Biphasic waveform defibrillationwas associated with significantly less postresuscitationmyocardial dysfunction, as evidenced by lesser postresus-citation reductions in stroke volume, cardiac output, andejection fraction In contrast, Niemann and coworkers37using 26- to 36-kg pigs subjected to 5 minutes of untreated

VF reported comparable defibrillation success usingbiphasic (fixed 150-joule) and monophasic (escalating200-, 300-, and 360-joule) shocks without differences inpostresuscitation myocardial or hemodynamic function

It is possible that the competitive advantage of biphasicwaveform defibrillation occurs at lower energy levels thanthose that were used in this experimental setting

In a recent clinical trial, fixed 150-joule compensating, biphasic truncated exponential defibrilla-tion waveforms were compared with monophasic(truncated exponential or damped sine) defibrillationwaveforms in 115 victims of out-of-hospital VF.108Biphasicwaveform defibrillation was associated with significantly

impedance-higher rates of successful defibrillation (100% vs 84%, P

0.003) and return of spontaneous circulation (76% vs 54%,

P0.01), but not hospital admission (61% vs 51%, NS) or survival (28% vs 31%, NS) Although a larger sample size

would be required to assess effects on survival outcomes,hospital survivors who had received biphasic waveformdefibrillation were noted to have better neurological out-

comes This observation was attributed to possible earlier

restoration of spontaneous circulation with biphasic

waveform defibrillation Larger clinical trials are awaited

to assess impact on hospital survival

Vasopressor agents

Although a prominent neuroendocrine vasoconstrictive

response occurs during cardiac arrest that reduces

distal aortic runoff, enabling preferential perfusion of

the coronary and cerebral circuits, this response is limited,

and exogenous vasopressor agents are typically required

to secure increases in the coronary perfusion pressures

above critical resuscitability thresholds For this purpose,

the American Heart Association recommends the use

of either adrenaline or vasopressin Studies have shown,

however, that adrenaline under these low-flow

condit-ions may not only fail to improve the myocardial energy

deficit despite increases in coronary blood flow,109 but

may actually intensify ischemic injury and worsen

postre-suscitation myocardial dysfunction and survival.110,111

These adverse effects of epinephrine are attributed to

stimulation of -receptors whereby the myocardial

oxygen requirements are disproportionately increased

during cardiac arrest109and can be minimized

experimen-tally by using -blocking agents.112 In a rat model

of VF and closed-chest resuscitation,111 use of the 1

-blocking agent esmolol in conjunction with epinephrine

ameliorated the severity of postresuscitation myocardial

dysfunction Similar effects have been documented

in larger animal models of cardiac arrest.112,113 Even

administration of the selective 1-blocker esmolol

alone during chest compression has been shown to

ameliorate postresuscitation myocardial dysfunction (Fig

48.4).114

Notwithstanding the adverse effect of adrenergic agents

under the low blood flow conditions of standard CPR,

provocative studies by Angelos and coworkers suggest that

epinephrine may be effective and devoid of its adverse

effects when used in association with hemodynamically

more effective resuscitation techniques.115

An alternative approach is the use of non-adrenergic

vasopressor agents such as vasopressin This agent

appears to be more potent than epinephrine and to lack

adverse effects on myocardial energy metabolism.116

Nonetheless, vasopressin has a longer half-life and the

vasopressor effects persist during the postresuscitation

interval, leading to adverse effects on blood flow to

various regional tissue beds The vasopressor effect may

also compromise myocardial performance by increasing

afterload.50

More recently, activation of 2- receptors has emerged as

a promising new experimental approach These receptorsare expressed in pre- and postsynaptic junctions of vascu-lar smooth cells Activation of presynaptic 2-receptorsinhibits the release of norepinephrine Activation of post-synaptic 2-receptors promotes peripheral vasoconstric-tion Studies in rat and pig models of VF and closed-chestresuscitation have shown that administration of the 2-receptor agonist -methyl-norepinephrine during chestcompression is associated with less postresuscitationmyocardial dysfunction when compared to epineph-rine.117,118Activation of these receptors in Purkinje cells hasbeen shown to reduce reperfusion arrhythmias in rats afterleft anterior descending coronary artery occlusion andreperfusion.119These effects have been linked to signalingvia G-protein, causing attenuation in intracellular cyclicadenosine monophosphate levels

Novel experimental therapies

The realization that ischemia and reperfusion activates amyriad of pathogenic pathways has persuaded researchers

to investigate whether targeting such pathways mayprotect the myocardium and minimize postresuscitationmyocardial dysfunction Some of these studies aredescribed below exposing the specific mechanisms ofinjury targeted

Sarcolemmal Na–Hexchange

Increased sarcolemmal Nainflux with subsequent cellular Na overload due to the inability of the Na–Kpump to extrude Na during myocardial ischemia hasbeen recognized as an important pathogenic mechanism

intra-of cell injury during ischemia and reperfusion.120–122Nabecomes a “substrate” for reperfusion injury123and inten-sifies processes detrimental to cell function primarily bypromoting sarcolemmal Ca2entry through the Na–Ca2

exchanger (NCX) acting in its reverse mode.124The conditions that develop during cardiac arrest areuniquely poised to trigger maximal and sustained NHE-1activity The intense intracellular acidosis that developsduring ischemia is the initial trigger for NHE-1 activation

The subsequent resuscitation attempt, with closed-chesttechniques, promotes reperfusion with coronary flows thatrarely exceed 20% of normal These low blood flow levels arenot sufficient to reverse ischemia,125but are sufficient tosupply the coronary circuit with normo-acidic blood,hence washing out the excess of extracellular protons favor-ing a trans-sarcolemmal proton gradient that maintains

NHE-1 activity throughout the resuscitation effort and

probably the initial postresuscitation phase

Administration of selective NHE-1 inhibitors, such as

cariporide, has been shown consistently to ameliorate

myocardial injury during cardiac resuscitation.25,27,33,126–129

In an intact pig model, cariporide reduced ischemic

con-tracture during chest compression such that there was less

ventricular wall thickening and better preservation of

cavity size This effect enabled chest compression to

gener-ate and maintain a coronary perfusion pressure above the

threshold for resuscitability and to augment the

hemody-namic efficacy of vasopressor agents.27,128,129 Cariporide

also ameliorated postresuscitation ventricular ectopic

activity, prevented episodes of recurrent VF, and minimized

postresuscitation myocardial dysfunction (Fig 48.5).25,27Although cariporide inhibits sarcolemmal NHE-1 andameliorates cytosolic Na and Ca2overload, recent evi-dence suggests that protection may also involve directeffects on the mitochondria by preserving the inner mem-brane Hgradient and delaying ATP depletion.130

The potential clinical applicability of NHE-1 inhibitorshas been halted for the moment A recent clinical trial inpatients undergoing coronary artery bypass graft surgerydemonstrated increased incidence of cerebrovascularocclusive events and higher overall mortality despite asignificant reduction in non-fatal postoperative myocar-dial infarction.131 Although information on the mecha-nism of this adverse effect of cariporide is not currently

3456789

Cardiac Index (ml/kg per min)

Fig 48.4 Myocardial effects of 1-adrenergic blockade during closed-chest resuscitation in a rat model of VF Esmolol (300 g/kg, n9)

or NaCl 0.9% (n9) was given into the right atrium at the second minute of precordial compression (PC) after a 6-minute interval of

untreated VF All esmolol-treated rats but only 5 controls were successfully resuscitated Closed symbols represent esmolol (n9); open symbols represent control (n 5) BLBaseline; LVDPLeft ventricular diastolic pressure dP/dt40= rate of left ventricular pressure rise

at left ventricular pressure of 40 mmHg; – dP/dt = rate of left ventricular pressure decline Mean

NaCl (Adapted from Cammarata G et al Crit Care Med 2004;32:S440.)

available, it appears to be unrelated to the mode of action.

Development of newer compounds is anticipated

K

ATP channel activation

Interventions aimed at activating known mechanisms of

preconditioning during cardiac resuscitation may have

favorable effects on postresuscitation myocardial

dysfunc-tion One important mechanism of ischemic

precondi-tioning that can be emulated pharmacologically involves

opening of mitochondrial K

ATPchannels.132–135Opening of

K

ATPchannels leads to increased Kconductivity of the

inner mitochondrial membrane, an effect that is

bioener-getically beneficial136and limits mitochondrial Ca2 

over-load.137In a rat model of VF and closed chest resuscitation,

administration of the K

ATPchannel opener cromakalimreduced postresuscitation myocardial function despite a

significant reduction in coronary perfusion pressure

during chest compression.138 The favorable effect on

postresuscitation myocardial function was comparable to

that of preconditioning and manifested by a higher suscitation dP/dt40, -dP/dtmax, cardiac index, and longerpostresuscitation survival

postre--Opioid receptor activation

Activation of -opioid receptors has been shown to play

an important role in hibernation, leading to reductions inmyocardial oxygen consumption Activation of -opioidreceptors, and more specifically 1- and 2- receptors,has been shown to ameliorate postischemic myocardialdysfunction and to preserve ultrastructural integrity inchick cardiomyocytes and isolated perfused rabbithearts.139,140 Sun and coworkers investigated, in a ratmodel of VF and closed-chest resuscitation, the effect ofadministering the -opioid receptor agonist penta-zocine.141Administration of pentazocine was associatedwith significantly lower postresuscitation arterial lactateand less postresuscitation myocardial dysfunction, evi-denced by a higher dP/dt , -dP/dt , and cardiac

60

80

100

120

Mean aortic pressure (mmHg)

Cardiac index (l/min per m2)

Left ventricular stroke work index (gm m/m2)

Fig 48.5 Postresuscitation hemodynamic and left ventricular function in pigs randomized to receive

cariporide (3 mg/kg, open bars, n 4) or NaCl 0.9% (closed bars, n4) immediately before starting

chest compression after a 6-minute interval of untreated VF Each animal was successfully defibrillated

after 8 minutes of closed-chest resuscitation and observed for 60 minutes postresuscitation Mean

SEM *P0.05 vs baseline (BL) by repeated measures ANOVA; †P0.05 vs cariporide by one-way

ANOVA (Adapted from ref 27.)

index These effects were abrogated by pretreatment with

naloxone

Lazaroids

Lazaroids are 21-aminosteroid molecules that inhibit lipid

peroxidation and scavenge oxygen free radicals.142–144

Studies in a canine model of cardiac transplantation have

shown that the lazaroid compound U-74389G given before

reperfusion improves post-transplantation myocardial

function.145 Studies in a rat model of VF and closed

chest resuscitation demonstrated that administration of

U-74389G before chest compression ameliorates

postresus-citation myocardial dysfunction as evidenced by a higher

cardiac index and higher dP/dt40and a lower left

ventric-ular end diastolic pressure with increased postresuscitation

survival time.146 Administration of the lazaroid was also

associated with significantly fewer premature ventricular

complexes These studies suggest that antioxidants may

play a role during cardiac resuscitation, further supporting

the pivotal role of mitochondria for cardiac resuscitation.72

Erythropoietin

Erythropoietin is a 30.4-kDa glycoprotein best known for

its action on erythroid progenitor cells and regulation of

circulating red cell mass.147 Within the past few years,

however, investigators have reported that erythropoietin

also signals survival responses during ischemia and

reper-fusion in a broad range of tissues including the heart.148–157

Some of these protective actions are induced immediately

upon administration and result in attenuating of ischemia

and reperfusion injury even when given after the onset of

ischemia and at the time of reperfusion,154,156,158,159

sug-gesting that erythropoietin could be beneficial for cardiac

resuscitation Administration of human recombinant

ery-thropoietin in a rat model of prolonged VF (5000 U/kg) at

the start of closed-chest resuscitation enabled

hemody-namically more effective chest compression and improved

postresuscitation hemodynamic function.160

Management of postresuscitation myocardial

dysfunction

The current approach to cardiac resuscitation emphasizes

the prompt reversal of the precipitating cause of cardiac

arrest (i.e., terminating VF or correcting hypoxemia) and

the generation, by external means, of blood flow across the

coronary circuit This paradigm, however, does not include

specific interventions aimed at myocardial protection and

prevention of postresuscitation myocardial dysfunction.Yet, as pointed out earlier, opportunities exist to minimizemyocardial injury by reducing the time interval for initiat-ing CPR, and by providing quality CPR that can promotehigher coronary blood flows In addition, strategies aimed

at more precise timing of shock delivery could minimizeinjury by avoiding repetitive defibrillation attempts.Regarding vasopressor agents, it is to be hoped that qualityCPR might enable more judicious use of vasopressoragents by avoiding excessive dosing, and development ofmore effective and less toxic vasopressor agents is eagerlyawaited Of increasing interest is the possibility that -adrenoceptor blocking agents administered during cardiacresuscitation may prevent injury stemming from endoge-nous and exogenous adrenergic stimulation; clinicalstudies are awaited to support this concept The experi-mental agents shown above to be effective in variousanimal models of cardiac arrest support the concept thattargeting pathways to ischemic injury may be effective Yet,again, clinical data are awaited

Recognition and assessment of myocardial dysfunction

Although critical care and emergency medicine icians are well-trained to recognize and treat acute heartfailure, it is not clear that myocardial dysfunction is com-monly deemed a diagnostic possibility after an episode ofcardiac arrest Thus, it is important to consider postresus-citation myocardial dysfunction in every patient success-fully resuscitated from cardiac arrest Equally important

phys-is to recognize that such dysfunction phys-is potentiallyreversible, thus justifying efforts to support the failingmyocardium until competent pump function resumes.Assessment of postresuscitation myocardial dysfunctionfollows conventional practice and includes recognition ofthe classical symptoms and signs of pulmonary vascularcongestion and reduced forward blood flow Accordingly,the assessment should include, at the very least, a focusedhistory and physical examination, a 12-lead electro-cardiogram, a chest x-ray, and routine blood tests.Postresuscitation myocardial dysfunction should be sus-pected in the presence of increased heart rate, decreasedarterial blood pressure and cardiac output, and arrhyth-mias, especially those of ventricular origin Evaluation ofcardiac function and morphology by echocardiographymay be critical to establish the presence of and to quantifythe severity of myocardial dysfunction In addition,echocardiography may serve to identify associated condi-tions such as cardiac tamponade, myocardial infarction,papillary muscle rupture, pulmonary embolism, rupturedaorta, and aortic dissection.161,162

Further diagnostic work is dictated by the clinical course

and may include the use of a pulmonary artery catheter to

assess filling pressures and cardiac output more precisely

As previously discussed, a pattern of myocardial

dysfunc-tion found early after successful resuscitadysfunc-tion may evolve

into a hyperdynamic state as systemic inflammation

unfolds (Fig 48.2) Recognition of this transition is

impor-tant, because the management is substantially different

and large amounts of fluids may be required to ensure

hemodynamic stability

Inotropic interventions

The stunned myocardium is responsive to inotropic

stim-ulation and therefore pump function may be improved by

administration of traditional inotropic agents such as

-agonists (i.e., dobutamine) and phosphodiesterase

inhibitors (i.e., milrinone) Dobutamine acts primarily on

1-,2-, and-receptors Its hemodynamic effects include

increases in stroke volume and cardiac output, with

decreases in systemic and pulmonary vascular

resis-tance Studies in animal models of cardiac arrest have

demonstrated substantial reversal of postresuscitation

systolic and diastolic dysfunction by using doses rangingbetween 5 and 10 g/kg per minute (Fig 48.6).163–165

A dose of 5 g/kg/minute was found in domestic pigs (24resuscitation systolic and diastolic function withoutadverse effects on myocardial oxygen consumption.164Phosphodiesterase inhibitors such as milrinone also exertinotropic and vasodilator effects and have been shownexperimentally to improve postresuscitation myocardialdysfunction.166Nevertheless, the effectiveness of conven-tional inotropic agents may be limited by effects on heartrate and the possibility of worsening ischemic injury

in settings of critically reduced coronary artery bloodflow

Conventional inotropic agents act by increasing cAMPafter stimulation of -adrenergic receptors or after inhibi-tion of phosphodiesterases Increased cAMP levels, inturn, signal phosphorylation of several Ca2 regulatoryproteins (i.e., L-type Ca2channels, phospholamban, theryanodine receptor, TnI, and the myosin binding protein)leading to increased cytosolic Ca2cycling Of note, Ca2

cycling consumes energy and may predispose to lar arrhythmias An alternative approach, therefore, is toLeft ventricular ejection fraction

Fig 48.6 Reversal of postresuscitation myocardial dysfunction by administration of dobutamine in a

pig model of VF VF was untreated for 15 minutes before attempting resuscitation by cardiopulmonary

resuscitation including advanced life support and administration of epinephrine Dobutamine was

started at 15 minutes postresuscitation Mean

mediate inotropic responses by augmenting the

sensitiv-ity of the contractile apparatus to Ca2acting on TnC and

downstream regulatory proteins,167so as to exert positive

inotropic actions without increasing cAMP or cytosolic

Ca2

Agents that promote inotropy through these

mecha-nisms are known as Ca2sensitizers They are

energeti-cally more favorable168 and are potentially devoid of

Ca2-mediated arrythmogenic effects.169One compound,

levosimendan, acts by binding to the N-terminal domain

of TnC in a Ca2-dependent manner Levosimedan was

shown by Huang and colleagues in a pig model of VF and

closed-chest resuscitation to improve postresuscitation

myocardial function, resulting in greater increases in

ejection fraction and greater reductions in pulmonary

artery occlusive pressure when compared to

dobuta-mine.170 Further work, however, is required to define

dose-response relationships, interactions with

underly-ing coronary and myocardial disease, and the conditions

under which inotropic stimulation may help manage

postresuscitation myocardial dysfunction and improve

outcome

R E F E R E N C E S

1 Zheng, Z.J., Croft, J.B., Giles, W.H & Mensah, G.A Sudden

cardiac death in the United States, 1989 to 1998 Circulation

2001; 104: 2158–2163.

2 Nichol, G., Stiell, I.G., Laupacis, A et al A cumulative

meta-analysis of the effectiveness of defibrillator-capable

emer-gency medical services for victims of out-of-hospital cardiac

arrest Ann Emerg Med 1999; 34: 517–525.

3 Fredriksson, M., Herlitz, J & Nichol, G Variation in outcome

in studies of out-of-hospital cardiac arrest: a review of studies

conforming to the Utstein guidelines Am J Emerg Med.

2003; 21: 276–281.

4 Rea, T.D., Eisenberg, M.S., Sinibaldi, G & White, R.D

Incidence of EMS-treated out-of-hospital cardiac arrest in

the United States Resuscitation 2004; 63: 17–24.

5 Brown, C.G., Martin, D.R., Pepe, P.E et al and the

Multicenter High-Dose Epinephrine Study Group A

com-parison of standard-dose and high-dose epinephrine in

cardiac arrest outside the hospital N Engl J Med 1992; 327:

1051–1055

6 Kellermann, A.L., Hackman, B.B & Somes, G Predicting the

outcome of unsuccessful prehospital advanced cardiac life

support J Am Med Assoc 1993; 270: 1433–1436.

7 Lombardi, G., Gallagher, J & Gennis, P Outcome of

out-of-hospital cardiac arrest in New York City The pre-out-of-hospital

arrest survival evaluation (PHASE) study J Am Med Assoc.

1994; 271: 678–683.

8 Laurent, I., Monchi, M., Chiche, J.D et al Reversible

myocar-dial dysfunction in survivors of out-of-hospital cardiac arrest

J Am Coll Cardiol 2002; 40: 2110–2116.

9 Schoenenberger, R.A., von Planta, M & von Planta, I Survivalafter failed out-of-hospital resuscitation Are further thera-

peutic efforts in the emergency department futile? Arch.

Intern Med 1994; 154: 2433–2437.

10 Laver, S., Farrow, C., Turner, D & Nolan, J Mode of death afteradmission to an intensive care unit following cardiac arrest

Intens Care Med 2004; 30: 2126–2128.

11 Klocke, F.J & Ellis, A.K Control of coronary blood flow Annu.

Rev Med 1980; 31: 489–508.

12 Hoffman, J.I.E Maximal coronary flow and the concept of

coronary vascular reserve Circulation 1984; 70: 153–159.

13 Yaku, H., Goto, Y., Ohgoshi, Y et al Determinant of

myocar-dial oxygen consumption in fibrillating dog hearts:Comparison between normothermia and hypothermia

J Thorac Cardiovasc Surg 1993; 105: 679–688.

14 Gazmuri, R.J., Berkowitz, M & Cajigas, H Myocardial effects

of ventricular fibrillation in the isolated rat heart Crit Care

Med 1999; 27: 1542–1550.

15 Kamohara, T., Weil, M.H., Tang, W et al A comparison of

myocardial function after primary cardiac and primary

asphyxial cardiac arrest Am J Respir Crit Care Med 2001;

164: 1221–1224.

16 Neumar, R.W., Brown, C.G., Van Ligten, P., Hoekstra, J.,Altschuld, R.A & Baker, P Estimation of myocardial ischemicinjury during ventricular fibrillation with total circulatoryarrest using high-energy phosphates and lactate as metabolic

markers Ann Emerg Med 1991; 20: 222–229.

17 Kern, K.B., Garewal, H.S., Sanders, A.B et al Depletion of

myocardial adenosine triphosphate during prolongeduntreated ventricular fibrillation: effect on defibrillation

sis during cardiac arrest J Appl Physiol 1995; 78: 1579–1584.

21 Duggal, C., Weil, M.H., Gazmuri, R.J et al Regional blood flow during closed-chest cardiac resuscitation in rats J Appl.

Physiol 1993; 74: 147–152.

22 Cooley, D.A., Reul, G.J & Wukasch, D.C Ischemic contracture

of the heart: “Stone Heart” Am J Cardiol 1972; 29: 575–577.

23 Katz, A.M & Tada, M The “Stone Heart”: A challenge to the

biochemist Am J Cardiol 1972; 29: 578–580.

24 Koretsune, Y & Marban, E Mechanism of ischemic ture in ferret hearts: relative roles of [Ca2]ielevation and ATP

contrac-depletion Am J Physiol 1990; 258: H9–H16.

25 Gazmuri, R.J., Ayoub, I.M., Hoffner, E & Kolarova, J.D.

Successful ventricular defibrillation by the selective

sodium-hydrogen exchanger isoform-1 inhibitor cariporide

Circula-tion 2001; 104: 234–239.

26 Klouche, K., Weil, M.H., Sun, S et al Evolution of the stone

heart after prolonged cardiac arrest Chest 2002; 122:

1006–1011

27 Ayoub, I.M., Kolarova, J.D., Yi, Z et al Sodium-hydrogen

exchange inhibition during ventricular fibrillation: beneficial

effects on ischemic contracture, action potential duration,

reperfusion arrhythmias, myocardial function, and

resus-citability Circulation 2003; 107: 1804–1809.

28 Berg, R.A., Sorrell, V.L., Kern, K.B et al Magnetic resonance

imaging during untreated ventricular fibrillation reveals

prompt right ventricular overdistention without left

ventric-ular volume loss Circulation 2005; 111: 1136–1140.

29 Sorrell, V.L., Altbach, M.I., Kern, K.B et al Images in

cardio-vascular medicine Continuous cardiac magnetic resonance

imaging during untreated ventricular fibrillation Circulation

2005; 111: e294.

30 Klouche, K.,Weil, M.H., Sun, S., Tang,W., Povoas, H & Bisera, J

Stroke volumes generated by precordial compression

during cardiac resuscitation Crit Care Med 2002; 30:

2626–2631

31 Sharff, J.A., Pantley, G & Noel, E Effect of time on regional

organ perfusion during two methods of cardiopulmonary

resuscitation Ann Emerg Med 1984; 13: 649–656.

32 Takino, M & Okada, Y Firm myocardium in cardiopulmonary

resuscitation Resuscitation 1996; 33: 101–106.

33 Kolarova, J.D., Ayoub, I.M & Gazmuri, R.J Cariporide enables

hemodynamically more effective chest compression by

left-ward shift of its flow-depth relationship Am J Physiol Heart

Circ Physiol 2005; 288: H2904–H2911.

34 Downey, J.M Chagrasulis, R.W & Hemphill, V Quantitative

study of intramyocardial compression in the fibrillating

heart Am J Physiol 1979; 237: H191–H196.

35 Ayoub, I.M., Kolarova, J.D., Radhakrishnan, J., Wang, S &

Gazmuri, R.J Zoniporide ameliorates post-resuscitation

myocardial dysfunction by flow independent mechanisms

Crit Care Med 2004; 32: A57 (abstract).

36 Valenzuela, T.D., Roe, D.J., Nichol, G., Clark, L.L., Spaite, D.W

& Hardman, R.G Outcomes of rapid defibrillation by security

officers after cardiac arrest in casinos N Engl J Med 2000;

343: 1206–1209.

37 Niemann, J.T., Burian, D., Garner, D & Lewis, R.J

Monophasic versus biphasic transthoracic countershock

after prolonged ventricular fibrillation in a swine model

J Am Coll Cardiol 2000; 36: 932–938.

38 Kolarova, J., Ayoub, I.M., Yi, Z & Gazmuri, R.J Optimal

timing for electrical defibrillation after prolonged

untreated ventricular fibrillation Crit Care Med 2003; 31:

2022–2028

39 Tang, W., Weil, M.H., Sun, S et al The effects of biphasic

wave-form design on post-resuscitation myocardial function

J Am Coll Cardiol 2004; 43: 1228–1235.

40 van Alem, A.P., Post, J & Koster, R.W VF recurrence: teristics and patient outcome in out-of-hospital cardiac

pretations In Franz, M.R., ed Monophasic Action Potentials.

Bridging Cell and Bedside Armonk, New York: Futura

Publishing Company, Inc., 2000: 19–45

43 Wirth, K.J., Uhde, J., Rosenstein, B et al K(ATP) channel

blocker HMR 1883 reduces monophasic action potentialshortening during coronary ischemia in anesthetised pigs

Naunyn Schmiedebergs Arch Pharmacol 2000; 361: 155–160.

44 Wirth, K.J., Maier, T & Busch, A.E NHE1-inhibitor cariporideprevents the transient reperfusion-induced shortening of themonophasic action potential after coronary ischemia in pigs

Basic Res Cardiol 2001; 96: 192–197.

45 Deantonio, H.J., Kaul, S & Lerman, B.B Reversible

myocar-dial depression in survivors of cardiac arrest PACE 1990; 13:

982–985

46 Gazmuri, R.J., Weil, M.H., Bisera, J., Tang, W., Fukui, M &

McKee, D Myocardial dysfunction after successful

resusci-tation from cardiac arrest Crit Care Med 1996; 24:

49 Mullner, M., Domanovits, H., Sterz, F et al Measurement of

myocardial contractility following successful resuscitation:

quantitated left ventricular systolic function utilising

non-invasive wall stress analysis Resuscitation 1998; 39: 51–59.

50 Kern, K.B., Heidenreich, J.H., Higdon, T.A et al Effect of

vaso-pressin on postresuscitation ventricular function: unknownconsequences of the recent Guidelines 2000 for Cardio-pulmonary Resuscitation and Emergency Cardiovascular

Care Crit Care Med 2004; 32: S393–S397.

51 Gazmuri, R.J Effects of repetitive electrical shocks on

postre-suscitation myocardial function Crit Care Med 2000; 28:

N228–N232

52 Ruiz-Bailen, M., Aguayo, d.H., Ruiz-Navarro, S et al.

Reversible myocardial dysfunction after cardiopulmonary

resuscitation Resuscitation 2005; 66: 175–181.

53 Shyu, K.G., Chang, H., Lin, C.C., Huang, F.Y & Hung, C.R

Concentrations of serum interleukin-8 after successful diopulmonary resuscitation in patients with cardiopul-

car-monary arrest Am Heart J 1997; 134: 551–556.

54 Ito, T., Saitoh, D., Fukuzuka, K et al Significance of elevated

serum interleukin-8 in patients resuscitated after

cardiopul-monary arrest Resuscitation 2001; 51: 47–53.

55 Adrie, C., Adib-Conquy, M., Laurent, I et al Successful

car-diopulmonary resuscitation after cardiac arrest as a

“sepsis-like” syndrome Circulation 2002; 106: 562–568.

56 Kluck, R.M., Bossy-Wetzel, E., Green, D.R & Newmeyer, D.D

The release of cytochrome c from mitochondria: a primary

site for Bcl-2 regulation of apoptosis Science 1997; 275:

1132–1136

57 Li, P., Nijhawan, D., Budihardjo, I et al Cytochrome c and

dATP-dependent formation of Apaf-1/caspase-9 complex

ini-tiates an apoptotic protease cascade Cell 1997; 91: 479–489.

58 Green, D.R & Reed, J.C Mitochondria and apoptosis Science

1998; 281: 1309–1312.

59 Crompton, M The mitochondrial permeability transition

pore and its role in cell death Biochem J 1999; 341: 233–249.

60 Weiss, J.N., Korge, P., Honda, H.M & Ping, P Role of the

mito-chondrial permeability transition in myocardial disease Circ.

Res 2003; 93: 292–301.

61 Halestrap, A.P., Clarke, S.J & Javadov, S.A Mitochondrial

per-meability transition pore opening during myocardial

reper-fusion – a target for cardioprotection Cardiovasc Res 2004;

61: 372–385.

62 Juhaszova, M., Zorov, D.B., Kim, S.H et al Glycogen synthase

kinase-3beta mediates convergence of protection signaling

to inhibit the mitochondrial permeability transition pore

J Clin Invest 2004; 113: 1535–1549.

63 Murphy, E Primary and secondary signaling pathways in

early preconditioning that converge on the mitochondria to

produce cardioprotection Circ Res 2004; 94: 7–16.

64 Pan, G., Humke, E.W & Dixit, V.M Activation of caspases

trig-gered by cytochrome c in vitro FEBS Lett 1998; 426: 151–154.

65 Iwai, T., Tanonaka, K., Inoue, R., Kasahara, S., Kamo, N &

Takeo, S Mitochondrial damage during ischemia determines

post-ischemic contractile dysfunction in perfused rat heart

J Mol Cell Cardiol 2002; 34: 725–738.

66 Vanden Hoek, T.L., Qin, Y., Wojcik, K et al Reperfusion, not

simulated ischemia, initiates intrinsic apoptosis injury in

chick cardiomyocytes Am J Physiol Heart Circ Physiol.

2003; 284: H141–H150.

67 Earnshaw, W.C., Martins, L.M & Kaufmann, S.H Mammalian

caspases: structure, activation, substrates, and functions

during apoptosis Annu Rev Biochem 1999; 68: 383–424.

68 Zou, H., Li, Y., Liu, X & Wang, X An APAF-1.cytochrome c

multimeric complex is a functional apoptosome that

acti-vates procaspase-9 J Biol Chem 1999; 274: 11549–11556.

69 Schlesinger, P.H., Gross, A., Yin, X.M et al Comparison of the

ion channel characteristics of proapoptotic BAX and

anti-apoptotic BCL-2 Proc Natl Acad Sci USA 1997; 94:

11357–11362

70 Niquet, J & Wasterlain, C.G Bim, Bad, and Bax: a deadly

com-bination in epileptic seizures J Clin Invest 2004; 113:

960–962

71 Ott, M., Robertson, J.D., Gogvadze, V., Zhivotovsky, B &

Orrenius, S Cytochrome c release from mitochondria

proceeds by a two-step process Proc Natl Acad Sci USA

2002; 99: 1259–1263.

72 Petrosillo, G., Ruggiero, F.M., Pistolese, M & Paradies, G

Ca2-induced reactive oxygen species production promotescytochrome c release from rat liver mitochondria via mito-chondrial permeability transition (MPT)-dependent and

MPT-independent mechanisms: role of cardiolipin J Biol.

Chem 2004; 279: 53103–53108.

73 Van Eyk, J.E., Powers, F., Law, W., Larue, C., Hodges, R.S &Solaro, R.J Breakdown and release of myofilament proteinsduring ischemia and ischemia/reperfusion in rat hearts:identification of degradation products and effects on the

pCa-force relation Circ Res 1998; 82: 261–271.

74 Bolli, R & Marban, E Molecular and cellular mechanisms of

myocardial stunning Physiol Rev 1999; 79: 609–634.

75 Marban, E., Kitakaze, M., Koretsune, Y., Yue, D.T., Chacko, V.P

& Pike, M.M Quantification of [Ca2]iin perfused hearts.Critical evaluation of the 5F-BAPTA and nuclear magneticresonance method as applied to the study of ischemia and

reperfusion Circ Res 1990; 66: 1255–1267.

76 Carrozza, J.P., Jr., Bentivegna, L.A., Williams, C.P., Kuntz, R.E.,Grossman, W & Morgan, J.P Decreased myofilament respon-siveness in myocardial stunning follows transient calcium

overload during ischemia and reperfusion Circ Res 1992; 71:

80 Miller, W.P., McDonald, K.S & Moss, R.L Onset of reduced

Ca2 sensitivity of tension during stunning in porcine

myocardium J Mol Cell Cardiol 1996; 28: 689–697.

81 Burkart, E.M., Sumandea, M.P., Kobayashi, T et al.

Phosphorylation or glutamic acid substitution at proteinkinase C sites on cardiac troponin I differentially depress

myofilament tension and shortening velocity J Biol Chem.

2003; 278: 11265–11272.

82 Zaugg, C.E., Ziegler, A., Lee, R.J., Barbosa, V & Buser, P.T.Postresuscitation stunning: postfibrillatory myocardialdysfunction caused by reduced myofilament Ca2responsive-ness after ventricular fibrillation-induced myocyte Ca2over-

load J Cardiovasc Electrophysiol 2002; 13: 1017–1024.

83 Matsumura, Y., Kusuoka, H., Inoue, M., Hori, M & Kamada, T.Protective effect of the protease inhibitor leupeptin against

myocardial stunning J Cardiovasc Pharmacol 1993; 22:

135–142

84 Matsumura, Y., Saeki, E., Inoue, M., Hori, M., Kamada, T

& Kusuoka, H Inhomogeneous disappearance ofmyofilament-related cytoskeletal proteins in stunned

myocardium of guinea pig Circ Res 1996; 79: 447–454.

85 Rudzinski, T., Mussur, M., Gwiazda, Z & Mussur, M Protease

inhibitor leupeptin attenuates myocardial stunning in rat

heart Med Sci Monit 2004; 10: BR4–BR10.

86 Aufderheide, T.P., Pirrallo, R.G., Provo, T.A & Lurie, K.G

Clinical evaluation of an inspiratory impedance threshold

device during standard cardiopulmonary resuscitation in

patients with out-of-hospital cardiac arrest Crit Care Med.

2005; 33: 734–740.

87 Warner, E.D., Dahl, C & Ewy, G.A Myocardial injury from

transthoracic defibrillator countershock Arch Pathol 1975;

99: 55–59.

88 Mehta, J., Runge, W., Cohn, J.N & Carlyle, P Myocardial

damage after repetitive direct current shock in the dog:

cor-relation between left ventricular end-diastolic pressure and

extent of myocardial necrosis J Lab Clin Med 1978; 91:

272–289

89 Xie, J., Weil, M.H., Sun, S et al High-energy defibrillation

increases the severity of postresuscitation myocardial

dys-function Circulation 1997; 96: 683–688.

90 Ehsani, A., Ewy, G.A & Sobel, B.E Effects of electrical

coun-tershock on serum creatine phosphokinase (CPK) isoenzyme

activity Am J Cardiol 1976; 37: 12–18.

91 Koning, G., Veefkind, A.H & Schneider, H Cardiac damage

caused by direct application of defibrillator shocks to isolated

Langendorff-perfused rabbit heart Am Heart J 1980; 100:

473–482

92 Doherty, P.W., McLaughlin, P.R., Billingham, M., Kernoff, R.,

Goris, M.L & Harrison, D.C Cardiac damage produced by

direct current countershock applied to the heart Am J.

Cardiol 1979; 43: 225–232.

93 Kerber, R.E., Martins, J.B., Gascho, J.A., Marcus, M.L &

Grayzel, J Effect of direct-current countershocks on regional

myocardial contractility and perfusion Experimental

studies Circulation 1981; 63: 323–332.

94 Geddes, L.A., Tacker, W.A., Rosborough, J et al The electrical

dose for ventricular defibrillation with electrodes applied

directly to the heart J Thorac Cardiovasc Surg 1974; 68:

593–602

95 Krauthamer, V & Jones, J.L Calcium dynamics in cultured

heart cells exposed to defibrillator-type electric shocks Life

Sci 1997; 60: 1977–1985.

96 Patton, J.N., Allen, J.D & Pantridge, J.F The effects of shock

energy, propranolol, and verapamil on cardiac damage caused

by transthoracic countershock Circulation 1984; 69: 357–368.

97 Gazmuri, R.J., Deshmukh, S & Shah, P.R Myocardial effects

of repeated electrical defibrillations in the isolated fibrillating

rat heart Crit Care Med 2000; 28: 2690–2696.

98 Runsio, M., Bergfeldt, L., Brodin, L.A., et al Left ventricular

function after repeated episodes of ventricular fibrillation

and defibrillation assessed by transoesophageal

echocar-diography Eur Heart J 1997; 18: 124–131.

99 Niemann, J.T., Cairns, C.B., Sharma, J & Lewis, R.J Treatment

of prolonged ventricular fibrillation Immediate

counter-shock versus high-dose epinephrine and CPR preceding

countershock Circulation 1992; 85: 281–287.

100 Cobb, L.A., Fahrenbruch, C.E., Walsh, T.R et al Influence of

cardiopulmonary resuscitation prior to defibrillation in

patients with out-of-hospital ventricular fibrillation J Am.

Med Assoc 1999; 281: 1182–1188.

101 Wik, L., Hansen, T.B., Fylling, F et al Delaying defibrillation to

give basic cardiopulmonary resuscitation to patients without-of-hospital ventricular fibrillation: a randomized trial

J Am Med Assoc 2003; 289: 1389–1395.

102 Brown, C.G., Dzwonczyk, R & Martin, D.R Physiologic surement of the ventricular fibrillation ECG signal: estimat-

mea-ing the duration of ventricular fibrillation Ann Emerg Med.

1993; 22: 70–74.

103 Noc, M., Weil, M.H., Gazmuri, R.J., Sun, S., Biscera, J &

Tang, W Ventricular fibrillation voltage as a monitor of the

effectiveness of cardiopulmonary resuscitation J Lab Clin.

Med 1994; 124: 421–426.

104 Brown, C.G., Griffith, R.F., Van Ligten, P et al Median

fre-quency – a new parameter for predicting defibrillation

success rate Ann Emerg Med 1991; 20: 787–789.

105 Strohmenger, H.U., Lindner, K.H & Brown, C.G Analysis ofthe ventricular fibrillation ECG signal amplitude and fre-quency parameters as predictors of countershock success in

humans Chest 1997; 111: 584–589.

106 Povoas, H.P., Weil, M.H., Tang, W., Bisera, J., Klouche, K

& Barbatsis, A Predicting the success of defibrillation

by electrocardiographic analysis Resuscitation 2002; 53:

77–82

107 Tang, W., Weil, M.H., Sun, S et al A comparison of biphasic

and monophasic waveform defibrillation after prolonged

ventricular fibrillation Chest 2001; 120: 948–954.

108 Schneider, T., Martens, P.R., Paschen, H et al Multicenter,

randomized, controlled trial of 150-J biphasic shocks pared with 200- to 360-J monophasic shocks in the resuscita-tion of out-of-hospital cardiac arrest victims Optimized

com-Response to Cardiac Arrest (ORCA) Investigators Circulation

2000; 102: 1780–1787.

109 Ditchey, R.V & Lindenfeld, J Failure of epinephrine toimprove the balance between myocardial oxygen supplyand demand during closed-chest resuscitation in dogs

Circulation 1988; 78: 382–389.

110 Berg, R.A., Otto, C.W., Kern, K.B et al High-dose epinephrine

results in greater early mortality after resuscitation from longed cardiac arrest in pigs: a prospective, randomized

pro-study Crit Care Med 1994; 22: 282–290.

111 Tang, W., Weil, M.H., Sun, S., Noc, M., Yang, L & Gazmuri, R.J

Epinephrine increases the severity of postresuscitation

myocardial dysfunction Circulation 1995; 92: 3089–3093.

112 Ditchey, R.V., Rubio-Perez, A., Slinker, B.K Beta-adrenergicblockade reduces myocardial injury during experimental

cardiopulmonary resuscitation J Am Coll Cardiol 1994; 24:

804–812

113 Killingsworth, C.R., Wei, C.C., Dell’Italia, L.J et al Short-acting

beta-adrenergic antagonist esmolol given at reperfusionimproves survival after prolonged ventricular fibrillation

Circulation 2004; 109: 2469–2474.

114 Cammarata, G., Weil, M.H., Sun, S., Tang, W., Wang, J &

Huang, L Beta1-adrenergic blockade during

cardiopul-monary resuscitation improves survival Crit Care Med 2004;

32: S440–S443.

115 Angelos, M.G., Torres, C.A.A., Waite, D.W et al Left

ventricu-lar myocardial ATP changes during reperfusion of ventricuventricu-lar

fibrillation: The influence of flow and epinephrine Crit Care

Med 2000; 28: 1503–1508.

116 Wenzel, V & Lindner, K.H Arginine vasopressin during

car-diopulmonary resuscitation: laboratory evidence, clinical

experience and recommendations, and a view to the future

Crit Care Med 2002; 30: S157–S161.

117 Sun, S., Weil, M.H., Tang, W., Kamohara, T & Klouche, K

alpha-Methylnorepinephrine, a selective alpha2-adrenergic

agonist for cardiac resuscitation J Am Coll Cardiol 2001; 37:

951–956

118 Klouche, K., Weil, M.H., Tang, W., Povoas, H., Kamohara, T &

Bisera, J A selective alpha(2)-adrenergic agonist for cardiac

resuscitation J Lab Clin Med 2002; 140: 27–34.

119 Cai, J.J., Morgan, D.A., Haynes, W.G., Martins, J.B & Lee, H.C

Alpha 2-Adrenergic stimulation is protective against

ischemia-reperfusion-induced ventricular arrhythmias in vivo Am J.

Physiol Heart Circ Physiol 2002; 283: H2606–H2611.

120 Karmazyn, M Amiloride enhances postischemic ventricular

recovery: possible role of Na/Hexchange Am J Physiol.

1988; 255: H608–H615.

121 Lazdunski, M., Frelin, C & Vigne, P The sodium/hydrogen

exchange system in cardiac cells: its biochemical and

phar-macological properties and its role in regulating internal

con-centrations of sodium and internal pH J Mol Cell Cardiol.

1985; 17: 1029–1042.

122 Avkiran, M Rational basis for use of sodium–hydrogen

exchange inhibitors in myocardial ischemia Am J Cardiol.

1999; 83: 10G–17G.

123 Imahashi, K., Kusuoka, H., Hashimoto, K., Yoshioka, J.,

Yamaguchi, H & Nishimura, T Intracellular sodium

accumu-lation during ischemia as the substrate for reperfusion injury

Circ Res 1999; 84: 1401–1406.

124 Mosca, S.M & Cingolani, H.E [The Na/Ca2exchanger as

responsible for myocardial stunning] Medicina (B Aires)

2001; 61: 167–173.

125 Ditchey, R.V & Horwitz, L.D Metabolic evidence of

inade-quate coronary blood flow during closed-chest resuscitation

in dogs Cardiovasc Res 1985; 19: 419–425.

126 Gazmuri, R.J., Hoffner, E., Kalcheim, J et al Myocardial

pro-tection during ventricular fibrillation by reduction of

proton-driven sarcolemmal sodium influx J Lab Clin Med 2001;

137: 43–55.

127 Wann, S.R., Weil, M.H., Sun, S., Tang, W & Yu, T Cariporide for

pharmacologic defibrillation after prolonged cardiac arrest J.

Cardiovasc Pharmacol Ther 2002; 7: 161–169.

128 Kolarova, J., Yi, Z., Ayoub, I.M & Gazmuri, R.J Cariporide

potentiates the effects of epinephrine and vasopressin by

nonvascular mechanisms during closed-chest resuscitation

Chest 2005; 127: 1327–1334.

129 Ayoub, I.M., Kolarova, J., Kantola, R.L., Sanders, R & Gazmuri,R.J Cariporide minimizes adverse myocardial effects of epi-nephrine during resuscitation from ventricular fibrillation

Crit Care Med 2005; 33: 2599–2605.

130 Ruiz-Meana, M., Garcia-Dorado, D., Pina, P., Inserte, J.,Agullo, L & Soler-Soler, J Cariporide preserves mitochondr-ial proton gradient and delays ATP depletion in cardiomy-

ocytes during ischemic conditions Am J Physiol Heart Circ.

Physiol 2003; 285: H999–H1006.

131 Mentzer, R.J Effects of Na/Hexchange inhibition by poride on death and nonfatal myocardial infarction inpatients undergoing coronary artery bypass graft surgery:

cari-The EXPEDITION study Circulation 2003; 108: 3M

(abstract)

132 Liu, Y & O’Rourke, B Opening of mitochondrial K(ATP) nels triggers cardioprotection Are reactive oxygen species

chan-involved? Circ Res 2001; 88: 750–752.

133 Kevelaitis, E., Oubenaissa, A., Mouas, C., Peynet, J &Menasche, P Ischemic preconditioning with opening ofmitochondrial adenosine triphosphate-sensitive potassiumchannels or Na/H exchange inhibition: which is the best pro-

tective strategy for heart transplants? J Thorac Cardiovasc.

135 O’Rourke, B Evidence for mitochondrial K channels

and their role in cardioprotection Circ Res 2004; 94:

140 McPherson, B.C & Yao, Z Signal transduction of

opioid-induced cardioprotection in ischemia-reperfusion

143 Perna, A.M., Liguori, P., Bonacchi, M et al Protection of rat

heart from ischaemia-reperfusion injury by the

21-aminos-teroid U-74389G Pharmacol Res 1996; 34: 25–31.

144 Tseng, M.T., Chan, S.A., Reid, K & Lyer, V Post-ischemic

treat-ment with a lazaroid (U74389G) prevents transient global

ischemic damage in rat hippocampus Neurol Res 1997; 19:

431–434

145 Takahashi, T., Takeyoshi, I., Hasegawa, Y et al

Cardio-protective effects of Lazaroid U-74389G on

ischemia-reper-fusion injury in canine hearts J Heart Lung Transpl 1999; 18:

285–291

146 Wang, J., Weil, M.H., Kamohara, T et al A lazaroid mitigates

postresuscitation myocardial dysfunction Crit Care Med.

2004; 32: 553–558.

147 Fisher, J.W Erythropoietin: physiology and pharmacology

update Exp Biol Med (Maywood) 2003; 228: 1–14.

148 Cai, Z., Manalo, D.J., Wei, G et al Hearts from rodents

exposed to intermittent hypoxia or erythropoietin are

pro-tected against ischemia-reperfusion injury Circulation 2003;

108: 79–85.

149 Calvillo, L., Latini, R., Kajstura, J et al Recombinant human

erythropoietin protects the myocardium from

ischemia-reperfusion injury and promotes beneficial remodeling Proc.

Natl Acad Sci USA 2003; 100: 4802–4806.

150 Moon, C., Krawczyk, M., Ahn, D et al Erythropoietin reduces

myocardial infarction and left ventricular functional decline

after coronary artery ligation in rats Proc Natl Acad Sci USA

2003; 100: 11612–11617.

151 Parsa, C.J., Matsumoto, A., Kim, J et al A novel protective

effect of erythropoietin in the infarcted heart J Clin Invest.

2003; 112: 999–1007.

152 Tramontano, A.F., Muniyappa, R., Black, A.D et al.

Erythropoietin protects cardiac myocytes from

hypoxia-induced apoptosis through an Akt-dependent pathway

Biochem Biophys Res Commun 2003; 308: 990–994.

153 Cai, Z & Semenza, G.L Phosphatidylinositol-3-kinase

signaling is required for erythropoietin-mediated acute

pro-tection against myocardial ischemia/reperfusion injury

Circulation 2004; 109: 2050–2053.

154 Lipsic, E., van der, M.P., Henning, R.H et al Timing of

erythropoietin treatment for cardioprotection in ischemia

/reperfusion J Cardiovasc Pharmacol 2004; 44: 473–479.

155 Parsa, C.J., Kim, J., Riel, R.U et al Cardioprotective effects of

erythropoietin in the reperfused ischemic heart: a potential

role for cardiac fibroblasts J Biol Chem 2004; 279:

20655–20662

156 Wright, G.L., Hanlon, P., Amin, K., Steenbergen, C., Murphy, E

& Arcasoy, M.O Erythropoietin receptor expression in

adult rat cardiomyocytes is associated with an acute

cardioprotective effect for recombinant erythropoietin

during ischemia-reperfusion injury FASEB J 2004; 18:

1031–1033

157 Namiuchi, S., Kagaya, Y., Ohta, J et al High serum

ery-thropoietin level is associated with smaller infarct size in

patients with acute myocardial infarction who undergo

suc-cessful primary percutaneous coronary intervention J Am.

Coll Cardiol 2005; 45: 1406–1412.

158 Hirata, A., Minamino, T., Asanuma, H et al Erythropoietin just

before reperfusion reduces both lethal arrhythmias and infarctsize via the phosphatidylinositol-3 kinase-dependent pathway

in canine hearts Cardiovasc Drugs Ther 2005; 19: 33–40.

159 Hanlon, P.R., Fu, P., Wright, G.L., Steenbergen, C., Arcasoy,M.O & Murphy, E Mechanisms of erythropoietin-mediatedcardioprotection during ischemia-reperfusion injury: role ofprotein kinase C and phosphatidylinositol 3-kinase signaling

of transesophageal echocardiography during

cardiopul-monary resuscitation J Am Coll Cardiol 1997; 30: 780–783.

162 Varriale, P & Maldonado, J.M Echocardiographic

observa-tions during in hospital cardiopulmonary resuscitation Crit.

Care Med 1997; 25: 1717–1720.

163 Kern, K.B., Hilwig, R.W., Berg, R.A et al Postresuscitation left

ventricular systolic and diastolic dysfunction Treatment with

165 Studer, W., Wu, X., Siegemund, M., Marsch, S., Seeberger, M

& Filipovic, M Influence of dobutamine on the variables ofsystemic haemodynamics, metabolism, and intestinal per-fusion after cardiopulmonary resuscitation in the rat

167 Endoh, M Mechanism of action of Ca2sensitizers – update

2001 Cardiovasc Drugs Ther 2001; 15: 397–403.

168 Kaheinen, P., Pollesello, P., Levijoki, J & Haikala, H Effects oflevosimendan and milrinone on oxygen consumption in iso-

lated guinea-pig heart J Cardiovasc Pharmacol 2004; 43:

555–561

169 Lilleberg, J., Ylonen, V., Lehtonen, L & Toivonen, L Thecalcium sensitizer levosimendan and cardiac arrhythmias:

an analysis of the safety database of heart failure treatment

studies Scand Cardiovasc J 2004; 38: 80–84.

170 Huang, L., Weil, M.H., Tang, W., Sun, S & Wang, J Comparisonbetween dobutamine and levosimendan for management of

postresuscitation myocardial dysfunction Crit Care Med.

2005; 33: 487–491.

This book chapter is dedicated to Peter Safar, the father of modern

resuscitation, and world leading pioneer in the field of therapeutic

hypothermia

Introduction

The history of induced hypothermia began in the 1950s

with elective moderate hypothermia of the brain,

intro-duced under anesthesia, for the protection–preservation

during brain ischemia needed for surgery on heart or

brain.1,2In the early 1960s, Peter Safar recommended the

use of therapeutic resuscitative hypothermia for humans

after cardiac arrest in his cardiopulmonary–cerebral

resus-citation algorithm.3At this time, it was thought that

moder-ate hypothermia (28–32C) was required for brain

protection Resuscitative hypothermia research was then

given up for 25 years, as experimental and clinical trials had

been complicated by the injurious systemic effects of total

body cooling, such as shivering, vasospasm, increased

plasma viscosity, increased hematocrit, hypocoagulation,

arrhythmias, and ventricular fibrillation, when

tempera-tures dropped below 30C, and lowered resistance to

infec-tion during prolonged moderate hypothermia.4–7Moderate

hypothermia was too difficult to induce and to maintain

Peter Safar deserves most of the credit that mild

thera-peutic hypothermia was re-discovered in the mid 1980s

When he considered the reasons for various outcomes with

the same durations of cardiac arrest in his dog experiments,

he observed that relatively small differences in brain

tem-perature in the range of mild hypothermia (33–36C) at the

start of the experiments had a major influence on

neuro-logic outcome He and his research group then confirmedthese observations in systematic studies of mild hypother-mia before, during, and after cardiac arrest in dogs.8–12Fritz Sterz, who was research fellow in Safar’s laboratory

at this time, initiated after his return to Vienna theHypothermia After Cardiac Arrest (HACA) European multi-center trial in the mid 1990s.13This landmark study, togetherwith the Australian study by Bernard,14led to the recom-mendation to use mild hypothermia in patients resusci-tated from cardiac arrest by the European ResuscitationCouncil15and the American Heart Association16in 2005,more than 40 years after the first recommendation by PeterSafar

This chapter reviews the current status of therapeuticmild hypothermia in cardiac arrest Laboratory and clini-cal studies are described, potential mechanisms and sideeffects of hypothermia, and cooling methods to inducemild hypothermia The influence of mild hypothermia onthe prediction of neurologic outcome after cardiac arrest

is presented In the conclusion, recommendations for thecurrent use of hypothermia and recommendations forfuture laboratory and clinical research are given

Therapeutic mild hypothermia

Animal outcome studies (Behringer)

This section documents the background of therapeutichypothermia with regard to animal models with cardiacarrest or vessel occlusion that led to the recent trials of ther-apeutic hypothermia after cardiac arrest in humans.13,14,17–21

848

Prevention of postresuscitation neurologic dysfunction and

injury by the use of therapeutic mild hypothermia

Wilhelm Behringer1, Stephen Bernard2, Michael Holzer3, Kees Polderman4, Marjaana Tiainen5and Risto O Roine6

1 University AKH, Vienna, Austria, 2 Department of Epidemiology and Preventive Medicine, Monash University, Australia,

3 University Klinik fur Notfallmedizin, Vienna, Austria, 4 Department of Intensive Care, VU University Medical Center, Amsterdam, The Netherlands,

5 Department of Neurology, Helsinki University Hospital, Finland, 6 Department of Neurology, Turku University Hospital, Finland

Cardiac Arrest: The Science and Practice of Resuscitation Medicine 2nd edn., ed Norman Paradis, Henry Halperin, Karl Kern, Volker Wenzel, Douglas

Chamberlain Published by Cambridge University Press © Cambridge University Press, 2007.

Protective hypothermia, induced before cardiac arrest, is

differentiated from preservative hypothermia, induced

during cardiac arrest, and from resuscitative hypothermia,

induced after resuscitation from cardiac arrest The first

animal studies of resuscitative hypothermia after cardiac

arrest were reported in the 1950s.22,23

Protective-preservative hypothermia

Therapeutic hypothermia was rediscovered in the

mid-1980s, when Hossmann reported the beneficial effect of

mild hypothermia, unintentionally induced before the

experiment, on EEG recovery in cats subjected to 1 hour of

global brain ischemia, followed by blood recirculation for 3

hours or longer.24At the same time, Safar analysed the

outcome data of several cardiac arrest dog studies, and

found that dogs that were mildly hypothermic at the

begin-ning of the experiment showed better neurologic outcome

than dogs that were normothermic at the beginning of the

experiment.25These observations were followed by

con-trolled randomized animal studies in various laboratories

In dogs, ventricular fibrillation cardiac arrest of

12.5-minute no-flow was accompanied by head immersion in

ice water (which reduced brain temperature by only 1C)

and followed by reperfusion cooling with brief

cardiopul-monary bypass to 34C for 1 hour; functional and

mor-phologic brain outcome variables were significantly

improved in the hypothermic groups 4 days after the

insult.8Busto and colleagues found in a 20-minute

four-vessel occlusion rat model that small increments of

intra-ischemic brain temperature (33, 34, 36, or 39 C)

markedly accentuated histopathological changes

follow-ing 3-day survival, despite severe depletion of brain energy

metabolites during ischemia at all temperatures.26Siesjö

and colleagues confirmed the beneficial effects of

intra-ischemic hypothermia in a two-vessel occlusion rat model

with various durations of ischemia by showing that

inten-tional lowering of brain temperature from 37 to 35 C

markedly reduced and to 33C virtually prevented

neu-ronal necrosis.27

Importantly, the benefit of intra-ischemic mild to

mod-erate hypothermia on neuronal death is regarded as

long-lasting Green and colleagues found in a 12.5-minute

four-vessel occlusion rat model that intra-ischemic

hypothermia to 30C protected from behavioral deficits

and neuronal injury for up to 2 months.28This longlasting

effect of intra-ischemic hypothermia was confirmed by

the same group in a 10-minute two-vessel occlusion rat

model,29and by Corbett and colleagues in a 5-minute

global ischemia gerbil model with brain temperature to

32C.30

Resuscitative hypothermia

The rediscovery of protective-preservative mild to ate hypothermia in brain ischemia led to widespread

moder-research of resuscitative mild to moderate hypothermia in

several animal models in the 1990s Safar and colleaguesconducted a systematic series of outcome studies in dogs ofprolonged normothermic cardiac arrest followed by mildresuscitative cerebral hypothermia (34C), induced imme-diately after reperfusion and maintained for 2–3 hours9,10,12

or 12 hours.11Controlled ventilation was maintained for 24hours, and intensive care was provided for 3 to 4 days, withfinal evaluation of neurologic outcome and histologicdamage in various brain regions In one study,9ventricularfibrillation cardiac arrest after 10-minute no-flow wasreversed by standard external cardiopulmonary resuscita-tion; cooling to 34C for 2 hours with a combination ofhead-neck-trunk surface cooling, plus cold fluid loadsadministered intravenously, intragastrically, and nasopha-ryngeally, was induced in one group at the beginning ofresuscitation, and in another group after restoration ofspontaneous circulation In both groups, neurologic recov-ery in terms of histologic damage and functional outcomewas improved compared to that in control animals Next,10ventricular fibrillation cardiac arrest of 12.5-minutes no-flow was reversed by brief cardiopulmonary bypass; imme-diate mild (34C) or moderate (30 C) hypothermia,induced with bypass, for 1 hour improved functional andmorphologic brain outcome, but deep postarrest hypother-mia (15C) did not improve function and worsened brainhistology In the next study,12ventricular fibrillation cardiacarrest of 12.5-minute no-flow was reversed by brief car-diopulmonary bypass; delaying cooling (to 34C for 1 hour)until 15 minutes after normothermic reperfusion did notimprove functional outcome but histologic damage

Finally,11ventricular fibrillation cardiac arrest of 11-minuteno-flow was reversed by brief cardiopulmonary bypass; acombination treatment of mild hypothermia by head-neck-surface cooling plus peritoneal instillation of coldRinger’s solution to keep brain temperature at 34C fromreperfusion for 12 hours, plus cerebral blood flow promo-tion by induced moderate hypertension for 4 hours, pluscolloid-induced hemodilution for 12 hours, led to the bestoutcome yet encountered in dogs, with lowest histologicdamage ever achieved Mild cooling in all dog studiescaused no cardiovascular or other side effects

At the same time, resuscitative hypothermia was alsostudied in rodent ischemia models First, Busto and col-leagues reduced hippocampal CA1 injury with 3 hours ofimmediate, but not 30-minute delayed postischemichypothermia to 30C in a two-vessel occlusion rat model

with 10 minutes of ischemia and survival to 3 days.26

Buchan and colleagues reduced hippocampal CA1 injury

with 8 hours of immediate hypothermia to 34.5C in gerbils

with 5 minutes of ischemia and survival to 5 days.31

Coimbra and colleagues reduced hippocampal CA1 injury

with 5 hours of immediate hypothermia to 29C in gerbils

with 5 minutes of ischemia and survival to 7 days.32Chopp

and colleagues reduced hippocampal CA1 injury with 2

hours of immediate hypothermia to 34C in a two-vessel

occlusion rat model with 8 but not 12 minutes of ischemia,

and survival to 7 days.33Carroll and colleagues

progres-sively reduced hippocampal CA1 injury with immediate

hypothermia to 28–32C for 1/2, 1, 2, 4, and 6 hours in

gerbils after 5 minutes of ischemia, and survival to 4 days; 6

hours of hypothermia delayed for 1 hour after reperfusion

also resulted in protection, but 6 hours of hypothermia

delayed for 3 hours after reperfusion was not effective In

another study by Coimbra and colleagues hippocampal

CA1 injury was reduced with 5 hours of hypothermia to

33C, delayed for 2 hours after reperfusion, in a two-vessel

occlusion rat model with 10-minutes of ischemia, and

sur-vival to 7 days.34The same group reduced hippocampal CA1

injury with 5 hours of hypothermia to 33C, delayed for 2,

6, and 12 hours, but not for 24 and 36 hours, after

reperfu-sion in a two-vessel occlureperfu-sion rat model with 10-minutes of

ischemia, and survival to 7 days; 3.5 hours of hypothermia

delayed for 2 hours after reperfusion was less effective, and

30 minutes of hypothermia delayed for 2 hours after

reper-fusion was ineffective in the same model.35

Although the benefit of intra-ischemic hypothermia on

neuronal death is regarded as longlasting,28,30results on

longlasting effects of postischemic hypothermia are more

controversial Dietrich and colleagues found hippocampal

CA1 protection in a two-vessel occlusion rat model

with 10-minutes of ischemia and postarrest immediate

hypothermia to 30C for 4 hours, when histologic

evalua-tion was at 3 days after the insult; this protecevalua-tion

signifi-cantly declined by 7 days, and was completely absent by 60

days after the insult.29

Colbourne and colleagues systematically explored

factors affecting neuroprotection of hypothermia in

gerbils.36–38In the first study,36Experiment 1 found that 12

hours of hypothermia (3C) delayed for 1 hour after

reper-fusion attenuated the early (10-day) ischemia-induced

open-field habituation impairments, and substantially

reduced CA1 necrosis against 3 minutes of ischemia when

assessed at 10 and 30 days, but was only partially effective

against a 5-minute occlusion; in Experiment 2, prolonged

hypothermia (32C) for 24 hours delayed for 1 hour after

reperfusion resulted in near total preservation of CA1

neurons at 30 days even after 5 minutes of ischemia In the

second study with ischemia of 5 minutes.37The tion period was extended to 6 months; hypothermia (32C)for 24 hours delayed for 1 hour after reperfusion providedsubstantial CA1 protection at 6 months, but there was lessprotection than at 1 month Delaying hypothermia (32C,

observa-24 hours) to 4 hours after reperfusion also provided icant protection at 6 months survival, but significantly lessthan delaying hypothermia for only 1 hour In the thirdstudy with ischemia of 5 minutes,38increasing the duration

signif-of hypothermia to 48 hours resulted in longlasting tion of neurons at 1 month, even when hypothermia wasdelayed to 6 hours after reperfusion

protec-The longlasting effect of delayed (6 hours), prolonged(48 hours) hypothermia (32 °–34 ºC) on functional and his-tologic outcome at 1 month was confirmed in rats with 10minutes of severe four-vessel occlusion ischemia.39The studies described above suggest that minimal delayand longer durations of hypothermia are of critical impor-tance to extend the therapeutic window and to providepermanent protection of resuscitative hypothermia

Clinical outcome studies (Holzer)

Historic use of therapeutic hypothermia after cardiac arrest

The first experiences of hypothermia after cardiac arrest

were obtained in the 1950s by Benson et al.40who sented four cases of hypothermic therapy after cardiacarrest (temperature 30 to 34 C) and Williams andSpencer41 who compared treatment with hypothermia(31–32 C) in 12 patients with 7 normothermic controls Inthis controlled pioneer case study, patients treated withhypothermia had a favorable neurological recovery in 50%compared to 14% in the control group Nonetheless,because of hemodynamic and respiratory problems inthese early hypothermia protocols, hypothermia was notused clinically for this indication until the late 1990s

pre-Clinical pilot trials of hypothermia

In 1997 Bernard et al.17 found improved neurologicoutcome in survivors of out-of-hospital cardiac arrestwith postarrest mild hypothermia (33C) by surfacecooling with ice packs over 12 hours compared to a his-toric normothermic control group (11 of 22 vs 3 of 22patients)

Yanagawa et al.19used water-filled cooling blankets incombination with alcohol to cool cardiac arrest survivors

to a core temperature between 33C and 34 C over 48hours Three of 13 patients in the hypothermia group sur-vived without disabilities as compared to 1 of 15 patients inthe historical control group The long duration of cooling

in this study led to a higher rate of pneumonia, but it was

stated that in none of these cases the pulmonary infection

was a direct cause of death

In a different approach, Nagao et al.,42 resuscitated

patients in cardiac arrest on arrival at the emergency

department with emergency cardiopulmonary bypass

and intra-aortic balloon pumping After successful

resus-citation, hypothermia was attained by direct blood

cooling to 34C via a dialysis coil for a minimum of 48 (71

with good neurologic recovery and no major side effects

were reported

The pilot study for the HACA trial20 included 27

comatose patients after ventricular fibrillation cardiac

arrest Cooling blankets (Blanketrol II Hypothermia

System, Cincinnati Sub-Zero Products, Inc) were placed

within a special mattress consisting of air cushions

(TheraKair, Kinetic Concepts, Inc), which allowed cold

air to flow around the patient; head and body were

cooled with a cooling blanket with constant cold air

flow (Polar Bair, Augustin Medical, Inc) Patients were

cooled to a target temperature of 33

maintained for 24 hours, after which period the patients

were passively rewarmed After 6 months, good

neurologi-cal recovery was achieved by 14 (52%) patients, 2 (7%) had

poor neurological recovery and 11 (41%) died before

dis-charge Compared to historic controls this was a twofold

improvement of outcome and no major complications

were directly related to treatment with mild hypothermia

For a safety and feasibility trial of therapeutic

hypother-mia after cardiac arrest, Felberg et al.43 used external

cooling blankets in nine patients with persistent coma

and lack of acute myocardial infarction or unstable

dysrhythmia Hypothermia to 33C was maintained for 24hours followed by passive rewarming Three of the ninepatients (33%) recovered completely, and one patientdeveloped unstable cardiac dysrhythmia Figure 49.1 sum-marizes outcome data of the pilot trials

Randomized trials and meta-analysis of therapeutic hypothermia after cardiac arrest

The first randomized trial took place in one of the centersalso participating in the European multicenter study.18Incontrast to the multicenter trial the author included onlypatients with asystole and pulseless electrical activity andtherefore no patient was included in more than one trial Ahelmet device (Frigicap®) containing a solution of aqueousglycerol placed around the head and neck induced mildhypothermia in 30 patients Once a bladder temperature of

34C was reached, or if cooling took longer than 4 hours,the patient was allowed to rewarm spontaneously overthe next 8 hours Two of 16 patients in the hypothermiagroup and none of 14 patients in the normothermia group

had a favorable neurologic recovery (P0.49) Three

patients in the hypothermia group survived vs 1 patient in

the normothermia group (P0.60) Oliguria occurred in

4 hypothermic and in five normothermic patients Therewere no further complications reported

In 2002 two randomized studies on hypothermia aftercardiac arrest were published In the Australian trial, 77patients with return of spontaneous circulation aftercardiac arrest of cardiac origin (ventricular fibrillation orpulseless ventricular tachycardia) were randomly treatedwith therapeutic hypothermia (33C, core temperatureover 12 hours, cooled with ice packs) or normothermia.14

Fig 49.1 Favorable neurologic recovery in clinical pilot trials of therapeutic hypothermia after cardiac

arrest Therapeutic hypothermia, shaded columns; historic control group, white columns

The primary outcome measure was survival to hospital

dis-charge, with neurologic function appropriate for discharge

to home or a rehabilitation facility Twenty-one of the 43

patients treated with hypothermia (49%) survived with a

good neurologic function at hospital discharge as

com-pared with 9 of the 34 treated with normothermia (26%, P

0.046) After multivariate adjustment for baseline

differ-ences, the odds ratio for a good outcome with hypothermia

therapy as compared with standard treatment was 5.25

(95% CI, 1.47 to 18.76; P0.011) There was no difference in

the frequency of adverse events, but hypothermia was

asso-ciated with a lower cardiac index, higher systemic vascular

resistance, and hyperglycemia

In the European multicenter trial13patients resuscitated

after ventricular fibrillation or pulseless ventricular

tachy-cardia tachy-cardiac arrest were randomly treated with

therapeu-tic hypothermia (32 °–34C bladder temperature, cooled

with cold air) over 24 hours or with normothermia All

patients received standard intensive care according to a

detailed protocol including the use of sedation

(midazo-lam, initially 0.125 mg/kg per hour), analgesia (fentanyl,

initially 0.002 mg/kg per hour), and relaxation

(pancuro-nium, initially 1 mg/kg every 2 hours, then as needed to

prevent shivering) Mechanical ventilation was mandatory

for at least 32 hours The primary end point was a favorable

neurologic recovery within 6 months after cardiac arrest;

secondary end points were mortality within 6 months and

the rate of complications within 7 days Seventy-five of the

136 patients in the hypothermia group (55%) had a

favor-able neurologic recovery (defined as cerebral performance

category 1 or 2) In the normothermia group 54 of 137(39%) had favorable neurologic recovery (risk ratio, 1.40;95% CI 1.08 to 1.81) Mortality at 6 months was 41% in thehypothermia group (56 of 137 patients died), as comparedwith 55% in the normothermia group (76 of 138 patients;risk ratio, 0.74; 95% CI 0.58 to 0.95) The proportion ofpatients with any complication was not significantly dif-ferent between the two groups (93 of 132 patients in thenormothermia group (70%) and 98 of 135 in the hypother-

mia group (73%), P0.70) Sepsis was more likely to occur

in the hypothermia group, however, this difference was notstatistically significant As inclusion and exclusion criteriawere very strict only 8% of patients assessed for eligibilitywere included in this trial

In all randomized trials only outcome assessment wasblinded and therefore it was possible that some aspects ofcare differed between the groups Figure 49.2 shows asummary of the neurologic outcome of the randomizedtrials

In a meta-analysis,44which included individual patientdata of all three randomized trials of therapeutic hypother-mia after cardiac arrest it was shown that more patients inthe hypothermia group were discharged with favorableneurologic recovery (risk ratio, 1.68; 95% CI 1.29–2.07).Furthermore, the 95% CI of the number-needed-to-treat toallow one additional patient to leave the hospital withfavorable neurologic recovery was 4–13 Additionally,patients were more likely to be alive at 6 months with favor-able functional neurologic recovery if they were treatedwith hypothermia (risk ratio, 1.44; 95% CI 1.11–1.76)

Fig 49.2 Favorable neurologic recovery in randomized clinical trials of therapeutic hypothermia after

cardiac arrest Therapeutic hypothermia, shaded columns; normothermic control group, white

columns

Neurologic outcome in recent clinical studies of

different cooling methods

In a study of rapid infusion of large volume (30 ml/kg),

ice-cold (4C) intravenous lactated Ringer’s solution, Bernard

resuscitation from out-of-hospital cardiac arrest Eight of

these patients had primary rhythms other than ventricular

fibrillation The rapid cold infusion resulted in a significant

decrease in median core temperature from 35.5 to 33.8 C

and improvement of the hemodynamic situation Of the

22 patients 10 (45%) survived to hospital discharge (2 of 8

patients with non-ventricular fibrillation rhythm)

A case series of three patients described the effect of

therapeutic hypothermia after cardiac arrest from

non-cardiac causes:46one patient had cardiac arrest from

electro-cution (rhythm ventricular fibrillation), one from drowning

(rhythm asystole) and one from pulmonary embolism

(rhythm pulseless electrical activity) All patients were

treated with hypothermia (33C) over 24 hours and

survived to hospital discharge with favorable neurologic

recovery

In a study evaluating the safety and feasibility of

endovas-cular cooling in comatose patients who had been

success-fully resuscitated after cardiac arrest, Al-Senani et al.47

cooled 13 patients to a target bladder temperature of 33C

for 24 hours, followed by slow controlled rewarming over

18.3

neurologic recovery No unanticipated or procedure-related

adverse events occurred

A pilot study was performed by Friberg et al.48using cold

intravenous fluids and surface cooling with a cold helmet

and a cold-water blanket (Thermowrap® and Allon®

control unit, MTRE, Or Akiva, Israel) in five unconscious

patients after cardiac arrest; three survived with good

recovery to 6-month follow-up (60%) No adverse events

were reported during treatment

Virkkunen et al.49cooled 13 adult patients in the

prehos-pital setting with ice-cold Ringer’s solution after successful

resuscitation from non-traumatic cardiac arrest After

hemodynamic stabilization, 30 ml/kg of Ringer’s solution

was infused at a rate of 100 ml/min into the antecubital

vein Four of these 13 patients (31%) survived to hospital

discharge with favorable neurologic recovery

Summary

Sufficient clinical evidence supports the use of therapeutic

hypothermia after cardiac arrest in unconscious survivors

of cardiac arrest, particularly if the primary rhythm was

ventricular fibrillation and the arrest occurred outside the

hospital; such hypothermia may also be beneficial in

patients with other rhythms and in-hospital cardiac arrest

Initial patient evaluation

The optimal timing and technique for induction ofhypothermia after cardiac arrest are uncertain, and this isnow the major focus of current research The induction ofhypothermia after cardiac arrest should be an integralcomponent of the initial evaluation and stabilization of thepatient The steps are described below

Airway/breathing

All patients who have been resuscitated from prolongedcardiac arrest remain comatose and will require endotra-cheal intubation for airway protection, oxygenation andcontrol of ventilation Mechanical ventilation with supple-mental oxygen at a tidal volume of 10 ml/kg and a rate of8–10 breaths per minute should ensure adequate oxygena-tion and normocapnea Notably, production of CO2 isdecreased by 30% when core temperature is 33C, andtherefore the minute ventilatory volume will need to bedecreased to avoid hypocapnea, as guided by end-carbondioxide readings and/or arterial blood gas analysis

To facilitate both mechanical ventilation and assist inthe rapid induction of hypothermia, a large dose of a non-depolarizing muscle relaxant should be administeredimmediately after initial neurological assessment, as well

as an infusion of a sedative agent such as midazolam; thesemedications will abolish shivering

Circulation

Evidence from laboratory studies indicates that sion after cardiac arrest is associated with improved neu-rological outcome.11One treatment that both induces mildhypothermia and improves blood pressure is rapid infu-sion of large volume (40 ml/kg), ice-cold (4 ºC) intravenousfluid (see later) If hypotension (MAP90 mmHg) persistsdespite this fluid therapy, then an inotropic drug may beinfused In our studies of induced hypothermia (IH),45adrenaline was the vasoactive drug of first choice as it has

hyperten-a low incidence of hyperten-adverse chyperten-ardihyperten-ac effect But if it doescause adverse side effects, noradrenaline would be a rea-sonable alternative

If the patient is initially hypertensive, additional tion may be administered (such as propofol) and consider-ation given to vasodilator therapy with glyceryl trinitrateconsidered

seda-Initial procedures

After initial “ABC” resuscitation measures described above,the following procedures and investigations should beundertaken An orogastric tube should be inserted, sincebystander expired air ventilation commonly results in airinflation of the stomach Insertion of an intra-arterial line

facilitates continuous blood pressure monitoring and

blood drawing for laboratory tests A 12-lead

electrocardio-gram is required to diagnose acute coronary syndromes A

chest X-ray should be obtained during initial evaluation to

exclude right main bronchus intubation and to evaluate

any pulmonary complications of cardiac arrest such as

aspiration pneumonitis and/ or pulmonary edema

Central venous access may be required for central

venous pressure monitoring and/or vasoactive drug

infu-sion A femoral venous line may be safer in this setting

compared with subclavian or internal jugular puncture if

thrombolysis is planned.50

Core temperature measurement

Core temperature must be monitored continuously and

accurately when induction of hypothermia is planned

There is minimal temperature gradient among brain,

bladder and rectal temperature51,52and it is usually most

convenient to monitor bladder temperature after arrival at

hospital Tympanic temperature monitoring may be used

pre-hospital, but is less accurate, particularly when the

head is surrounded by ice-packs during surface cooling

(see below)

Induction of hypothermia

Rapid lowering of core temperature in an adult patient

after cardiac arrest requires that shivering be suppressed

by administration of sedation and/or muscle relaxants,

while heat is concurrently lowered A range of techniques

for rapid cooling may be applicable in this setting,

depend-ing on availability of resources and physician expertise (see

Table 49.1)

Surface cooling

The simplest technique for cooling after cardiac arrest is

extensive application of ice packs to the head, neck, and

torso of the patient In preliminary hypothermia studies,45

this technique was effective but provided relatively slow

core cooling (approximately 0.9C per hour) It was also

very time-consuming and inconvenient for attending

medical and nursing staff

The European (HACA) study of hypothermia after

cardiac arrest used surface cooling with a refrigerated air

blanket to induce hypothermia.13This was also found to be

very slow, however, with a decrease in core temperature of

only 0.3 ºC/hour

Increased conductive heat loss may be achieved using

water blankets rather than cold-air blankets These were

compared by Theard et al in surgical patients.53Both of

these techniques (water and cold-air blankets) were

rela-tively slow and there was no significant difference between

the groups in the time taken for core temperature to dropfrom 35C to less than 34 C (mean 178 minutes vs 142minutes) Nevertheless, cooling blankets are a feasible andsafe for induction of mild hypothermia.43

More recently, developments in cooling technology havemade surface cooling much more efficient The mostpromising commercially available system uses largeadhesive pads that are cooled by water at a controlledtemperature applied around the trunk and limbs (ArcticSun, Medivance, Colarado, USA) The water is circulatedwith a feedback control system, allowing very accuratecontrol of patient core temperature Although publisheddata on patients after cardiac arrest are limited, this systemhas provided improved temperature control comparedwith traditional surface cooling blankets in febrile patients

in a neurological intensive care unit.54 Moreover, thissystem is non-invasive and can be readily applied bynursing staff

Surface heat loss can also be attained with evaporativetechniques by using fans and alcohol baths, but these aretime consuming and impractical in most emergency andcritical care units

The fastest rate of surface cooling has been achievedwith complete patient immersion in an ice-water bath.55This results in a rapid decrease in core temperature of9.7C/hour, but is impractical for critically ill patients.Since the skin of the torso and limbs may be poorly per-fused in the early post-cardiac arrest period, while brainblood flow is preserved, it was proposed that coolinghelmets may be more efficient than cooling blankets, and

two studies have investigated this issue First Wang et al.

assigned 14 patients with neurological injury to either acooling helmet or no cooling.56 Brain temperature wasmeasured directly (just below the surface of the brain) andcompared with the patients’ core temperatures Brainsurface temperature was reduced by 1.8C (range0.9–2.4C) within 1 hour of helmet application, but a mean

of 3.4 hours was required to achieve a brain temperature

Table 49.1 Techniques for induction of hypothermia after

cardiac arrest

• Surface cooling

• Large volume ice cold intravenous fluid

• Intravascular catheter cooling

• Extracorporeal cooling

• Partial liquid ventilation with cold fluorocarbons

• Pharmacological approaches

• Isolated brain cooling

• Body cavity lavage