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

Part V
Postresuscitation disease and its care



47
Postresuscitation syndrome
Erga L. Cerchiari
Department of Anaesthesia and Critical Care,
Ospedale Maggiore, and Area of Anaesthesia and Critical Care,
Surgical Department, Provincial Health Care Structure, Bologna, Italy

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 defibrillation, and other means) improves the possibility of a successful outcome with the patient recovering consciousness.3
The wider availability of resuscitation techniques to
reverse clinical death, however, has led to increasingly frequent observations of a pathological condition occurring
in patients who remain unconscious, involving multiple

organ injury or failure following reperfusion after prolonged 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 etiology
depended on a combination of severe circulatory hypoxia
with the unintended sequelae of measures used for
resuscitation.
On the basis of the wide variety of ischemic/hypoxic
mechanisms that can trigger its development, the disease
was redefined by Safar as a syndrome in which pathogenetic processes triggered by cardiac arrest were exacerbated by reperfusion, causing damage to the brain and
other organs, the complex interactions of which combine
to determine overall outcome (see early experimental findings summary).6,7
The evidence of features common to the postresuscitation syndrome and multiple organ dysfunction syndrome led to the hypothesis that a systemic inflammatory
response of the entire organism was triggered by ischemia
and reperfusion, adding to the damage directly induced by
ischemia during cardiac arrest.8
Two landmark studies, showing that mild therapeutic
hypothermia started after reperfusion can improve recovery after cardiac arrest, confirm that outcome is determined not only by events occurring during arrest and
CPR but also by pathogenetic processes continuing after
reperfusion.9,10
Recent reports confirm the occurrence of a “sepsis-like
syndrome” after resuscitation from cardiac arrest,11,12
although the mechanistic relationship to the direct
damage induced by ischemia during cardiac arrest has yet
to be clarified.

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.

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Early Experimental Findings
Negovsky4,5 and his group of Russian investigators pioneered the concept of postresuscitation disease as a unique nosological entity, caused by the combination of severe hypoxia and resuscitation, on the basis of hundreds of experimental
observations 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 and
developing over time.
From insult to 6 to 9 hours postinsult: rapid changes in cerebral and systemic hemodynamics, metabolism, and rheology (clotting disturbances, increased viscosity), increase levels of biologically active substances and prostaglandin derivatives; alterations of the immune system (increased bactericidal activity, depressed reticuloendothelial system, and
hyperreactivity of B- and T-lymphocytes), and toxic factors in the blood (peptide fraction 800 to 2000 Daltons and endotoxin secondary to gram-negative bacteremia).
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 derangements is reported to be more severe and prolonged the longer the duration of the hypoxic–ischemic insult.
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 to
that recorded after only 12–15 minutes of total circulatory arrest with ventricular fibrillation, suggesting that cerebral
postischemic damage plays a role in development of extracerebral dysfunction, probably by inducing changes in neurohumoral regulation.
Cerebral function recovers better after bloodless global brain ischemia than after the same duration of circulatory
arrest from ventricular fibrillation, leading to the conclusion that extracerebral factors account for about half of the
pathological 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 showed
that all the techniques can improve neurological recovery and survival compared with concurrent controls; cross-circulation was the most effective, in which circulation in the body of the resuscitated dog was maintained for 30 minutes
post-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 comparable durations of total body ischemia13,14 and (b) the use of cardiopulmonary bypass for resuscitation and for short-term
postresuscitation assistance improves myocardial performance after weaning, and significantly increases neurological
outcome and survival.15 Extracerebral organ dysfunction following resuscitation from cardiac arrest of increasing durations was studied in animal experimental models:1,6,7,14–19
• cardiac output and arterial oxygen transport, after a transient increase, showed a prolonged and profound decrease
associated with increased peripheral resistance; this starts sooner and is more severe and prolonged after longer
durations 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 after
extubation (normoxia, normocarbia, and rapid pH normalization)
• coagulation disturbances with hypocoagulability start during resuscitation, with prolonged clotting times and
decreased platelets and fibrinogen, and normalize at 24 hours after resuscitation; elevated fibrin-degradation products and decreased platelet counts were observed to 72 hours postresuscitation.


Postresuscitation syndrome

• 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).

ine

tok

Cy

100

in

tox

o
nd

E

80

ry

to
ma

lam nse
po
res

Inf
60

Cardiovascular

40

Clotting/Fibrinolysis

20

Neurologic
Clotting/Fibrinolysis

72 h

60 h

48 h

36 h

Neurologic
24 h

12 h

ROSC

0

Cardiovascular

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

Incidence and prevalence
The incidence of out-of-hospital cardiac arrest is estimated
to be 49.5–66 per 100 000 cases per year:2 in 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 estimated as 1.4/100 admissions/year:21 in these cases, restoration of spontaneous circulation 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 all
cardiac arrest victims (Fig. 47.2).
Among the PRS patients, mortality has been reported to
be very high, reaching 80% by 6 months postresuscitation:23–25 approximately one-third of the deaths are due to
cardiac causes (early deaths usually Ͻ 24 hours), one-third
to malfunction of extracerebral organs, and one-third to
neurologic causes (late deaths).
The prevalence of the postresuscitation syndrome can
only be inferred, because of the bias of data resulting from
decisions to limit treatment, including instructions for “do
not attempt resuscitation,” in cases of recurrent cardiac

arrest.22–26

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

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Cardiac arrest

Postresuscitation syndrome

Optimal
recovery
No ROSC

Cardiac

P
ROSC

Neurological

Death

causes

R
S

Other

No resuscitation attempt
Alive

Fig. 47.2. Estimated fate for cardiac arrest patients.

Therefore, the postresuscitation syndrome only develops following resuscitation given during an intermediate
duration of ischemia (the limits of which are affected
by prearrest conditions) and depending on the circumstances of resuscitation, leading to the “reperfusion
paradox.”
The insult induced by cardiac arrest and CPR is multifaceted, encompassing several contributing factors occurring during cardiac arrest, during 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 survival, 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 systemic inflammatory response.

Pathogenesis
Two major pathways have been identified

1. a direct insult to the brain, which is particularly sensitive 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 inflammatory response syndrome, with hypoperfusion and/or
altered perfusion as one pathological mechanism;12 in
this pathway, the PRS shares many features with severe
sepsis, including elevation of plasma cytokines with
dysregulated cytokine production, endothelial injury,
complement activation, coagulation and fibrinolysis
abnormalities, endotoxemia, disturbed modulation of
the immune response, and adrenal dysfunction.

Organ function postresuscitation
The postresuscitation syndrome occurs in patients resuscitated after cardiac arrest of more than 5 minutes’
duration and is characterized by different components:
neurologic functional impairment, cardiovascular functional impairment – both well characterized – and
the extracerebral extracardiac functional impairment
comprising a complex picture of determinants and
interactions.
The three major components variously contribute to
the complex clinical picture of the patient resuscitated
from cardiac arrest and admitted to ICU. Rapidly occurring early post-resuscitation changes create an acute
phase of instability during which specific and aggressive
treatments may favorably affect outcome. After the first


Postresuscitation syndrome

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 contribution 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 syndrome is neurologic functional impairment.
With the increased application of resuscitation interventions, 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 persistent 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, minimizing both the arrest (no-flow) time and the cardiopulmonary 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 reoxygenation-induced, free radical-triggered injury cascades,
exacerbated by reduced cardiac output and local circulatory 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 cerebral blood flow both in the cortex and in the basal ganglia29
with regional anoxic cerebral anaerobic metabolism.
Posthypoxic encephalopathy has been shown to be associated 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 polymorphonuclear
elastase) immediately postinsult and lasting about 12
hours has recently been reported following both cardiac
arrest and isolated brain trauma, suggesting an inflammatory response as a common pathogenetic pathway activated by cerebral damage.31
Clinical features and prognostic evaluation
A variety of methods have been proposed to monitor the
evolution of the depth of coma and its prognosis, including
neurological examination, electrophysiologic techniques,
and biochemical tests.
A recent meta-analysis, including nearly 2000 patients,
assessed the reliability of neurological examination, including Glasgow Coma Scale (GCS) and brainstem reflexes,
reviewed at different time intervals after resuscitation; it
concluded that patients who lack pupillary and corneal
reflexes at 24 hours and have no motor response to pain at
72 hours have an extremely small chance of meaningful
recovery.
The most reliable signs of prognosis occur at 24 hours
after cardiac arrest: earlier assessment should not be based

on clinical evidence alone.32
A systematic review of 18 studies analyzed the predictive
ability of somatosensory evoked potentials (SSEP) acquired
early after the onset of coma (1–3 days) in 1136 adult
patients with hypoxic-ischemic encephalopathy: the results
showed that patients with absent cortical SSEP responses
have a less than 1% chance of regaining consciousness.33
A recent study tested the value of serial measurement of
serum neuron-specific enolase (NSE) at admission and
daily postinsult, in combination with GCS and SSEP measurements, to predict neurological prognosis in unconscious patients admitted to the ICU after resuscitation from
cardiac arrest. High serum NSE levels at 24 and 48 hours
after resuscitation predict a poor neurological outcome.
Addition of NSE to GCS and SSEP increases predictability.34
By 48–72 hours postresuscitation, predictability of unfavorable long-term neurologic outcome may guide decisions to curtail treatment, because only patients with
lighter levels of coma or who have regained consciousness
by this time have any realistic prospect of long-term
survival.32
Treatment
Research into cardiopulmonary cerebral resuscitation
has attempted to mitigate the postischemic–anoxic
encephalopathy but, until recently, experimental results
had never been replicated in patients.7

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Mild therapeutic hypothermia induced following reperfusion in patients who have been successfully resuscitated
from ventricular fibrillation cardiac arrest is the only postresuscitation intervention that has proved effective in increasing 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.35 The
first properly designed, large, randomized, double-blind
multicenter study of thrombolytics was stopped before
completion of recruitment because the data safety monitoring 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 syndrome is prolonged myocardial contractile failure, associated 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 sometimes severe – impairment of myocardial function (occurring early and normalizing several days later) to
permanent malfunction and fatal rearrest. The severe
impairment of myocardial function in the early hours following 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 respiratory 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 myocardial 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,43,44 and the energy and waveform required for defibrillation.45,46 In humans, the dose of adrenaline used during
CPR has been reported to be the only variable independently associated with postresuscitation myocardial
dysfunction.44
Pathophysiology
The mechanisms responsible for myocardial stunning after
global myocardial ischemia remain unclear, but several
hypothesis have been proposed. Among these are the
postreperfusion long-lasting depletion of the total adenine
nucleotide pool, the generation of oxygen-derived free radicals, calcium overload, and uncoupling of excitation-contraction due to sarcoplasmic reticulum dysfunction.37,38
Recently, a correlation has been established between
levels of proinflammatory cytokines, synthesized and
released in response to the stress of global ischemia, and
the depression of myocardial function in the early postresuscitation period.47
Clinical features
In animal studies, postresuscitation myocardial dysfunction is characterized by increased filling pressures,
impaired contractile function, decreased cardiac index,
decrease in both systolic and diastolic right ventricular
function,16,38 starting at 2–6 hours and returning to normal
at 24 hours postresuscitation.
These findings were confirmed initially by anedoctal

observations of prolonged reversible myocardial dysfunction in human cardiac arrest survivors50,51 and, later, were
better defined in systematic studies in patients.44,52
The global nature of postresuscitation dysfunction has
been demonstrated with echocardiography and ventriculography, which show a decrease in ejection fraction and in
fractional shortening.
Myocardial dysfunction in patients may improve at 24–48
hours postresuscitation with return to normal values; persistently low cardiac index at 24 hours postresuscitation is
associated with early death by multiple organ failure.44 In the
same study, despite the significant improvement of cardiac
index at 24 hours, persisting vasodilatation was described,
delaying the discontinuation of vasoactive drugs.
In parallel with the failure of the heart to sustain normal
circulation, a condition of altered peripheral oxygen utilization has been described.44 These two mechanisms
together account for the persistent anaerobic metabolism
characteristic of the early postresuscitation phase.
Relationship to neurological recovery and outcome
The cardiovascular impairment in the early postresuscitation hours has been reported to correlate with impaired


Postresuscitation syndrome

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 postresuscitation, whereas hypotensive episodes correlate

with poor cerebral outcome.52 The latter finding could be
explained by the loss or impairment of cerebral autoregulation 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 supporting output and pressure during the postresuscitation
phase prior to return to baseline function.56 A 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 performance for 6 hours postresuscitation.56–58
The similarities in cardiovascular status between septic
and postresuscitation patients have suggested that in addition 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.11,12 Data 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,23–25 represent 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 compromised, 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 neuronal injury and myocardial dysfunction, is also involved
in the genesis of coagulation disturbances,60 endothelial
injury,60,61 and in triggering the cascades of inflammatory
responses.7,63
A variety of changes and findings, which still need to be
clearly classified and systematized, have been described
following resuscitation from cardiac arrest:
• a considerable increase in various acute phase response
proteins64
• a sharp rise in plasma cytokines and soluble receptors
within the blood compartment as early as 3 hours
postarrest31,46,65–69
• endothelial injury and release of intracellular adhesion
molecules
• marked activation of complement, polymorphonuclear
(PMN) leukocytes, and an increased PMN-endothelial
interaction61–64
• marked activation of blood coagulation and fibrinolysis60
• leukocyte dysregulation11,12
• evidence of the presence of endotoxin in plasma
The complex interaction of endothelial injury, inflammatory
and procoagulant host responses, intravascular fibrin
formation, and microvascular thrombosis contribute
to reperfusion defects,7,60,64 which augment systemic hypoperfusion induced by cardiovascular dysfunction to trigger

a secondary insult of persisting anerobic metabolism.
The altered systemic oxygen utilization, together with
circulating endotoxin and immune hyporeactivity, may
facilitate development of infection.11,12
Extracerebral and extracardiac organs, however, can tolerate periods of ischemia much longer than those generally occurring in cardiac arrest and resuscitation: thus, the
impairment of function in these organs appears to be the
combined result of the mechanisms triggered by ischemia
but compounded by reperfusion.

Derangements of organ function
Clotting and fibrinolytic function
Starting during cardiopulmonary resuscitation, marked
activation of coagulation has been demonstrated, without
adequate concomitant activation of endogenous fibrinolysis,60,70 suggesting that intravascular fibrin formation
and microvascular thrombosis after cardiac arrest
may contribute to organ dysfunction, including neurological impairment. With restoration of spontaneous
circulation and reperfusion, coagulation activity (thrombin-antithrombin complex) increases, anticoagulation
(antithrombin, protein C, and protein S) decreases, and

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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 interaction have been clearly demonstrated during cardiopulmonary 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,74–76 with lower levels in nonsurvivors,74 particularly in those who died of early refractory shock.76
Relative adrenal insufficiency as assessed by corticotropin tests was observed in 42% of patients but showed
no association with arrest duration variables or with
outcome.76
Renal function
Renal dysfunction,77 was recently confirmed in patients
presenting with hemodynamic instability and was characterized 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 extracellular changes similar to those recorded in the brain.78 It is
associated with early intestinal dysfunction and/or endoscopic 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, occasionally bacteremia).11,12
The finding of bacteremia, generally associated with
pathogens of intestinal origin, occurring in 39% of patients
within the first 24 hours of admission postresuscitation
associated with increased mortality,80 was not confirmed
in a subsequent study in which bacteremia was encountered only sporadically.12
The incidence of pneumonia in patients admitted to the
ICU following cardiac arrest has been reported to vary from
24% to 45% of patients.9,81
In a systematic study,82 newly acquired infection developed in 46% of patients resuscitated from cardiac arrest
and admitted to the ICU, the most common being pneumonia (65% of infections). Compared with cardiac arrest
survivors without infection, patients with infection had
longer mechanical ventilation and ICU length of stay, but
mortality was similar.
A possible role for procalcitonin has been proposed for
the early identification of post-resuscitation patients with
an acute phase response and bacterial complications: it
was the only marker higher in patients with ventilatoracquired pneumonia.83
Hyperthermia not associated with positive blood cultures has been reported frequently during the first 24 hours
following CPR, suggesting that mechanisms other than
infection may contribute to the development of fever in
cardiac arrest survivors.82,84
Correlation with outcome
The peak level and the time of occurrence of many of the

above-mentioned mediators of the inflammatory response have been reported to correlate with outcome (differently defined as: early death, early death from cardiac
causes, death at 1 month, and others) in different case
series from single centers and without precise standardization of resuscitation procedures and postresuscitation
treatments.61–72
The data now available suggest the opportunity for a
reassessment and systematic analysis of the interactions
involving various cascades and of their role in determining
outcome in a well-designed multicenter study adopting a
standardized treatment and evaluation protocol.
The better characterization of PRS in its early phase is
confirmed by the high predictive value of cerebral impairment, the severity of which can be quantified, allowing a
reliable prognostication of outcome.47,52
In the later phase of PRS, when secondary multiple
organ derangement syndrome (MODS) becomes apparent, the existing limitations of prognostic evaluation based
on severity scoring systems85 inherent to MODS are further


Postresuscitation syndrome

complicated by the persisting postischemic impairment of
cerebral function.

Treatment
Similar to the treatment of patients with impaired cardiovascular 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 dysfunction.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.86 Compared with controls,
the high-volume hemofiltration with and without hypothermia decreased the relative risk of death from
intractable shock and improved survival. Nonetheless, definite 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 prearrest); prehospital care (shorter time from emergency call to
CPR initiation and no use of adrenaline); and in-hospital
care (no seizure activity, temperature under 37.8 ЊC
(median), S-glucose under 10.6 mmol/l 24 hours after
admission (median), and BE over Ͼ 3.5 mmol/l 12 hours
(median) after admission).87,88

Summary
Widespread implementation of adequate system responses 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 spontaneous circulation, the occurrence of PRS.
Reduction of the duration of ischemia is the most
obvious intervention to prevent development of PRS; nevertheless, 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 is
well characterized and requires aggressive treatment,
aimed at reducing the progression of cerebral injury and
the effects of the secondary insult determined by
impaired cardiovascular performance. Besides standard
intensive care support of impaired function, the gold
standard includes mild hypothermia maintained for at
least 12 hours and optimization of perfusion and oxygen
delivery.
After the first 24 hours postresuscitation, the clinical
picture is not different from that of a comatose intensive
care patient. The role of the quality of treatment administered in this phase has been shown and includes brainoriented care (prevention of hyperthermia and seizures,
optimization of perfusion, glucose and metabolic control),
and standard intensive care oriented to prevention of
infection and support of impaired organ function.
It is of paramount importance to optimize postresuscitation treatment in the first 2–3 days after the arrest, until
reliable prognostic instruments permit the prediction of
an unfavorable neurologic outcome, in order to exclude
self-fulfilling prophecies and provide sound information
to families, but also to plan the continuation of appropriate treatment strategies.
Promising prognostic markers of the acute phase
response and treatment strategies, aimed at improving disturbances in microcirculation and reducing the impact of
the specific inflammatory response, deserve further evaluation in systematic, well-controlled studies.

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52. Mullner, M., Domanovits, H., Sterz, F. et al. Measurement of
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53. Mullner, M., Sterz, F., Binder, M. et al. Arterial blood pressure
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58. Meyer, R.J., Kern, K.B., Berg, R.A., Hilwig, R.W. & Ewy, G.A.
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61. Gando, S., Nanzaki, S., Morimoto, Y. et al. Out-of-hospital
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48
Prevention and therapy of postresuscitation
myocardial dysfunction
Raúl J. Gazmuri1, Max Harry Weil2, Karl B. Kern3, Wanchun Tang4,
Iyad M. Ayoub5, Julieta Kolarova6, Jeejabai Radhakrishnan7
1

North Chicago VA Medical Center, IL, USA, 2 Rancho Springs, CA, 3 Tucson, AZ, 4 Palm Springs, CA, 5 North Chicago, IL, 6 North Chicago, IL, 7 North Chicago, IL

Introduction
It is estimated that between 400 000 and 460 000 individuals suffer an episode of sudden cardiac arrest every year in
the United States.1 Yet, the percentage of individuals who
are successfully resuscitated and leave the hospital alive
with intact neurological function averages less than 10%
nationwide.2–4 Efforts to restore life successfully are formidably challenging. They require not only that cardiac activity
be initially restored but that injury to vital organs be prevented 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.5–7 Yet,
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 initially resuscitated victims leaves the hospital alive.
Although the causes of postresuscitation deaths have

not been systematically investigated, the available information suggests that postresuscitation myocardial dysfunction, 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 variable duration that organs suffer after cessation of blood
flow and the subsequent reperfusion injury that accompanies the resuscitation effort. In addition, the precipitating
event of cardiac arrest may also play a role in the postresuscitation 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) the
functional myocardial abnormalities that occur during and
after resuscitation from cardiac arrest; (2) the underlying
cellular mechanisms of such injury; (3) factors that may
contribute to myocardial injury; (4) therapies that have
been shown in the laboratory to prevent or ameliorate
myocardial injury; and (5) the management of postresuscitation myocardial dysfunction. As the chapter develops the
reader will learn that postresuscitation myocardial dysfunction is largely a reversible phenomenon such that
support of the failing heart during the critical postresuscitation interval is fully justified.

Functional myocardial manifestations
The working heart is a highly metabolically active organ
that consumes close to 10% of the total body oxygen consumption and extracts nearly 70% of the oxygen supplied
by the coronary circuit. Nevertheless, it has minimal capability for extracting additional oxygen such that increased
metabolic demands are met through coronary vasodilatation with augmentation of blood flow and oxygen delivery.11,12 Consequently, a severe energy imbalance develops
immediately after cardiac arrest supervenes and coronary
blood flow ceases. The severity of the energy deficit is contingent on the metabolic requirements and is particularly
high in the setting of ventricular fibrillation (VF) when the
oxygen requirements are comparable to or exceed that of
the normally beating heart.13,14 A lesser energy deficit is

anticipated when cardiac arrest occurs in a quiescent or
minimally active heart (i.e., asystole or pulseless electrical

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.

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activity as a result of asphyxia or exsanguination).15
Because most experimental studies have examined the
myocardial manifestations of cardiac arrest and resuscitation in animal models of VF, caution 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 availability, 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.16–18 Hence, 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.19 Coincident with the energy deficit, accumulation of CO2 and Hϩ account 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 compounded by specific interventions, such as electrical
shocks and adrenergic vasopressor agents, that can also
contribute to myocardial injury. As a result, various functional myocardial abnormalities develop that may themselves 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 consequent to myocardial ischemia. Ischemic contracture
was first reported in the early 1970s during open heart
surgery when operations were conducted under normothermic conditions and in the fibrillating heart to
render a bloodless surgical field.22,23 The onset of ischemic

contracture in this setting was associated with reductions
in myocardial ATP levels to Ͻ 10% of normal.24 An extreme
manifestation of ischemic contracture is the so-called
“stony heart” and typically heralds irreversible ischemic

injury.
More recent studies in animal models of VF and closed
chest resuscitation have demonstrated a phenomenon
akin to ischemic contracture, but of earlier onset and associated with less ATP depletion.25,26 This form of ischemic
contracture is likely to represent a manifestation of reperfusion injury27 such that withholding chest compression
(and hence coronary blood flow) markedly delays the
onset of contracture.28,29 The resulting left ventricular
thickening with reductions in cavity size compromises
ventricular preload and the amount of blood that can be
ejected by chest compression.14,27,30 Thus, ischemic contracture may partly explain the characteristic timedependent reductions in the hemodynamic efficacy of
chest compression.31 Moreover, recent studies in a porcine
model of VF demonstrate that the severity of ischemic contracture is proportional to the preceding interval of
untreated VF.26 In humans, ischemic contracture has been
described as myocardial “firmness” during open-chest
resuscitation after failure of closed-chest attempts and
found also to compromise resuscitability.32 Studies in the
research laboratory have shown that ischemic contracture
can be attenuated by pharmacologic interventions targeting reperfusion injury, resulting in hemodynamically more
stable closed-chest resuscitation.27,33 The possibility that
ischemic contracture might increase coronary vascular
resistance by extrinsic compression of the coronary
circuit14,34 has not been substantiated.33,35

Resistance to defibrillation
Electrical shocks delivered immediately after onset of VF
are consistently effective in re-establishing cardiac activity. Even short delays (i.e., up to 3 minutes) may not be
substantially detrimental and result in more than 50%
likelihood of successful resuscitation.36 Longer intervals of
untreated VF Ϫ as usually occurs in out-of-hospital settings Ϫ predict decreased effectiveness of defibrillation
attempts, however, in which electrical shocks may fail to

reverse VF or may precipitate asystole or pulseless electrical activity.37 Under these conditions, additional resuscitation interventions are required to restore myocardial
conditions favorable for successful defibrillation. New
approaches are being developed to optimize the effectiveness of electrical defibrillation by identifying the proper
timing for shock delivery and by using safer and more
effective defibrillation waveforms.38,39


Postresuscitation myocardial dysfunction

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.40 The mechanism responsible for postresuscitation arrhythmias is
complex and probably involves prominent cytosolic Ca2ϩ
overload with afterdepolarizations triggering ventricular
ectopic activity.41 In addition, there are repolarization
abnormalities that include shortening of the action potential (AP) duration, decreased AP amplitude, and development of AP duration alternans creating conditions for
re-entry.42 Experimentally, these repolarization abnormalities are short-lived (5 to 10 minutes) and coincide with the
interval of increased propensity for ventricular arrhythmias and recurrent VF.27 They are in part related to opening
of sarcolemmal Kϩ ATP channels;43 however, recent evidence
suggests that activation of the sarcolemmal Naϩ -Hϩ
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 demonstrates decreases in the slope of the end-systolic pressurevolume relationship (elastance) and increases in the
volume intercept at a left ventricular pressure of 100 mm
Hg (V100).46 Impaired contractility leads to reductions in
indices of global ventricular performance, such as cardiac
index, ejection fraction, and left ventricular stroke
work,8,47,49 and renders the heart susceptible to afterload
increases during the postresuscitation phase. In a pig
model of VF and closed chest resuscitation, the administration of vasopressin during cardiac resuscitation was
associated with decreased left ventricular performance,
with reversal by administration of a specific antagonist of
the V1 receptor.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,51 suggesting a

common pathogenic thread with diastolic dysfunction
being a manifestation of resolving ischemic contracture.
From a functional perspective, diastolic dysfunction may
limit the compensatory ventricular dilatation required to
overcome decreased contractility according to the FrankStarling mechanism.
Postresuscitation myocardial dysfunction was first documented in humans by Deantonio and colleagues.45 They
reported on three female patients who were successfully
resuscitated following transthoracic defibrillation after
approximately 3, 10, and 30 minutes of cardiac arrest and

who developed prominent left ventricular dilatation with
reduction in fractional shortening within 3 days postresuscitation. None of these patients had coronary artery disease
and ventricular function normalized within 2 weeks.
Likewise, Ruiz-Bailen and coworkers reported severe postresuscitation myocardial dysfunction with reductions in left
ventricular ejection fraction to 0.42 in 29 patients within the
initial 24 hours postresuscitation.52 In a subset of 20 patients
who had left ventricular dysfunction, the ejection fraction
decreased to 0.28 (P Ͻ 0.05). Patients who died had a significantly lower ejection fraction. Patients who survived gradually normalized their ejection fraction within an interval of
approximately 4 weeks postresuscitation (Fig. 48.1).
Laurent and colleagues stratified 165 patients successfully resuscitated from out-of-hospital cardiac arrest based
on whether hemodynamic instability was present within
the initial 72 hours postresuscitation.8 Hemodynamic
instability was defined as hypotension requiring vasoactive drugs after fluid resuscitation. It occurred in 55% of the
patients and was associated with longer resuscitation
times, greater number of electrical shocks, larger amounts
of adrenaline, and worse left ventricular function (Table
48.1). The incidence and severity of coronary artery disease
was comparable between groups; however, a trend was
noted towards a higher incidence of recent coronary occlusion in patients with hemodynamic instability. Myocardial
dysfunction was initially accompanied by a low cardiac
index (2.05 l/min per m2) with elevated systemic vascular
resistance (2908 dynes s/cm5 per m2). However, a hyperdynamic state developed during the ensuing 72 hours, characterized by increased cardiac index, decreased systemic
vascular resistance, and the need for large amounts of
fluids to maintain adequate filling pressures (Fig. 48.2).
The late hyperdynamic state reported by Laurent and
coworkers is consistent with the development of a systemic
inflammatory response akin to that observed during sepsis
butprecipitatedbycardiacarrestandresuscitation.53–55 Adrie
and colleagues measured circulating cytokines in 61 victims
of out-of-hospital cardiac arrest who were successfully resuscitated.55 Measurements obtained at approximately 3 hours

831


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R.J. Gazmuri et al.

Table 48.1. Factors associated with postresuscitation hemodynamic instability

Resuscitation data
Collapse to ROSC, min
Countershocks, n
Total epinephrine, mg
Angiography/ventriculography data
Heart rate, beats/min
LVEF
LVEDP, mmHg
Recent coronary occlusion, %

Hemodynamic stability
(n ϭ 75)

Hemodynamic
instability (n ϭ 73)

P

15 (7–30)
2 (1–3)

2 (0–10)

25 (14–28)
3 (1–6)
10 (3–15)

Ͻ 0.01
Ͻ 0.01
Ͻ 0.01

85 (48–118)
0.43 (0.35–0.50)
12 (5–25)
37

105 (75–143)
0.32 (0.25–0.40)
19 (10–32)
51

Ͻ 0.05
Ͻ 0.01
Ͻ 0.01
0.06

ROSC ϭ Return of spontaneous circulation; LVEF ϭ Left ventricular ejection fraction; LVEDP ϭ Left ventricular end diastolic pressure.
Median (interquartile range). (Adapted from ref. 8.)

0.80

0.60

0.40

0.20
Before
CA

24
hours

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 disease Ϫ except for
hypertension Ϫ and 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.)

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 and
probably time-sensitive. There are processes that develop
shortly after onset ischemia and during reperfusion that
lead to abnormalities in energy metabolism, acid base
status, and intracellular ion homeostasis. Other processes


Postresuscitation myocardial dysfunction

develop at a slower pace and encompass signaling mechanisms, leading to sustained disruption of energy production
and contractile function with activation of apoptotic pathways. Discussion on the various cell mechanisms responsible for cell injury is beyond the scope of this chapter.
Nonetheless, pertinent to our discussion is the growing evidence placing the mitochondria at the center of myocardial
preservation, reperfusion injury, and postischemic dysfunction. Better understanding of mitochondrial injury may also
serve to identify novel therapeutic strategies.56–66

833

Cardiac index (l/min per m2)

*

4.5
3.5
2.5
1.5
0.5
SVRI (dynes s/cm5 m2)
4000

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 proteins responsible for oxidative phosphorylation reside. The
outer mitochondrial membrane is more porous and surrounds 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 mitochondrial membrane where electrons are transferred down
their redox potential while Hϩ are pumped into the intermembrane space. The accumulation of Hϩ establishes an
electromotive force, which is used by FoF1 ATP 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 Hϩ gradient, compromising the electromotive force required for ATP synthesis. Factors that may
contribute to such injury during ischemia and reperfusion
include mitochondrial Ca2ϩ overload and generation of
reactive oxygen species (ROS) explaining decreased mitochondrial capability for regeneration of ATP.

Apoptotic signaling

In addition to the key role on energy production, mitochondria 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, prompting the formation of an oligomeric complex with dATP and
the apoptotic protease activating factor-1 (Apaf-1).57 This
complex recruits procaspase-9, forming the so-called apop-

3000

†

†

†

2000
1000
0
8.0
(7.0–9.0)

12.0
(11.0–13.5)

24.0
(23.0–25.7)

67.0

(52.0–72.0)

Postresuscitation (hours)
Fig. 48.2. Serial measurements of cardiac index and systemic
vascular resistance index (SVRI) in a subset of 73 patients who
had hemodynamic instability after resuscitation from out-ofhospital cardiac arrest. A cumulative amount of 8,000 ml was
required to maintain a pulmonary artery occlusive pressure Ͼ
12 mmHg. The mortality was 19 %. Median (interquartile range)
*P Ͻ 0.05; † P Ͻ 0.001. (Adapted from ref. 8.)

tosome. In the apoptosome, procaspase-9 is activated and
then released as caspase-9, which in turn, activates the executioner caspases 3, 6, and 7.67,68 Active executioner caspases
cleave several cytoplasmic proteins, including ␣-spectrin
and actin, and nuclear proteins including poly (ADP-ribose)
polymerase (PARP), lamin A, and the inhibitor of caspaseactivated DNase (ICAD). Cleavage of ICAD leads to activation
of caspase activated DNase (CAD), which in turn cleaves
chromatin into 180 to 200 bp fragments. Other substrates
activated during apoptosis include components of DNA
repair machinery and a number of protein kinases,67 ultimately 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 outer
mitochondrial membrane known as the mitochondrial
permeability transition pore (MPTP).59 Opening of the
pore allows molecules up to 1.5 kDa to enter the mitochondrial matrix along with water and solutes, leading to
mitochondrial swelling with stretching and disruption of
the outer mitochondrial membrane, ultimately causing

834

R.J. Gazmuri et al.

CYTOSOL
HK

PBR

OMM

VDAC
CK

IMS

H+

H+

H+

H+
ANT

·

H+
⌬pH
H+

CypD

C
I

Q III

MPTP

FOF1 ATP
synthase

+++
⌬⌿

IMM

IV

II
e-

O2

␣

2H2O

␤

␣

- - -

Respiratory complexes
MATRIX

ATP

ADP+Pi
H+

Fig. 48.3. Scheme depicting the structural organization of the electron transport chain, the
mitochondrial permeability transition pore (MPTP), and the FoF1 ATP synthase in relation to the inner
and outer mitochondrial membranes. PBR ϭ peripheral benzodiazepine receptor; VDAC ϭ voltage
dependent anion channel; HK ϭ hexokinase; CK ϭ creatine kinase; ANT ϭ adenine nucleotide
translocase; CypD ϭ cyclophilin-D; I, II, III, and IV ϭ respiratory complexes; Q ϭ coenzyme Q; C ϭ
cytochrome c; OMM ϭ outer mitochondrial membrane; IMS ϭ intermembrane space; IMM ϭ inner
mitochondrial membrane; ⌬pH ϭ pH gradient; ⌿⌬ ϭ mitochondrial membrane potential. (Adapted
from Gross A et al. Genes Dev 1999;13:1899 and Kim JS et al. Biochem Biophys Res Commun
2003;304:463.)

release of cytochrome c.59 Pathophysiological conditions
responsible for opening of the MPTP include Ca2ϩ overload, production of reactive oxygen species (ROS), depletion 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 permeabilization of the outer membrane by pro-apoptotic proteins such as Bcl-2–associated X protein (Bax), Bcl-2
homologous antagonist killer (Bak), or truncated BH3
interacting domain death agonist (Bid).69 Anti-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 Ca2ϩ
Mitochondrial Ca2ϩ overload plays a critical role during
ischemia and reperfusion. Ca2ϩ normally enters the mitochondria through a Ca2ϩ uniporter and leaves through a

Naϩ -Ca2ϩ exchanger located in the inner mitochondrial
membrane. This transport mechanism enables changes in
cytosolic Ca2ϩ to be relayed to the mitochondrial matrix
and thus regulate the activity of various enzymes of the tricarboxylic acid cycle. Increases in cytosolic Ca2ϩ during
ischemia prompt mitochondrial Ca2ϩ increases leading to
production of reactive oxygen species (ROS). ROS cause
peroxidation of cardiolipin, which is the principal lipid
constituent of the inner mitochondrial membrane and to
which a fraction of cytochrome c is bound. Peroxidation
decreases the binding affinity of cardiolipin for cytochrome c,71 facilitating its release out of the mitochondria.
Modest increases in extramitochondrial Ca2ϩ (i.e., 2 ␮M)
cause cytochrome c release without MPTP opening. At
higher Ca2ϩ levels (i.e., 20 ␮M), ROS and Ca2ϩ acting
together prompt MPTP opening, presumably through
oxidative injury of the adenine nucleotide translocase.
Both mechanisms of cytochrome c release can be prevented by blocking the mitochondrial Ca2ϩ uniporter with
ruthenium red.72


Postresuscitation myocardial dysfunction

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 Ca2ϩ increase and activation of proteases
such as calpain-1 and caspase-3.75–78 Communal and colleagues reported that activated caspase-3 cleaves ␣-actin
and ␣-actinin but not myosin heavy chain, myosin light
chain 1/2, and tropomyosin.77 Incubation of recombinant
troponin (Tn) complex with caspase-3 selectively cleaved
cardiac TnT, resulting in 25-kDa fragments. Functionally,
activated caspase-3 decreases maximal Ca2ϩ -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 postresuscitation coincident with left ventricular dysfunction.79 In
models of VF and coronary occlusion, Ca2ϩ overload was
associated with decreases in the Ca2ϩ -force relationship
presumably following modifications in the interaction
between proteins of the troponin complex.80,81 Zaugg and
coworkers specifically demonstrated, in a model of prolonged untreated VF, prominent cytosolic Ca2ϩ increases
leading to reduced Ca2ϩ sensitivity of troponin, TnC and
impaired contractility.82 Similarly, Barta and coworkers
demonstrated cleavage of TnI and TnT following activation
of calpain-1.78 In 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 Ca2ϩ 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 the
cardiac arrest by prompt recognition and rapid intervention are thus important to minimize injury. Likewise, delivery of quality cardiopulmonary resuscitation (CPR) may
help reduce the duration of tissue ischemia by prompting
earlier return of spontaneous circulation. Quality CPR may
be attained by paying close attention to the rate, depth,
and site of compression, minimizing the interruptions
required to secure the airway, verify rhythm, and deliver
shocks. In addition, adequate venous return is essential for
hemodynamically effective chest compression, which can
be secured by allowing full re-expansion of the chest cavity,
avoiding hyperventilation, and creating an intrathoracic
vacuum between compressions by using impedance
threshold devices.86 The following sections address the
potential detrimental effects of electrical shocks and
adrenergic vasopressor agents along with options to minimize such injury.

Electrical defibrillation
Delivery of electrical shocks during the resuscitation effort
may contribute to myocardial injury and worsen postresuscitation electrical and mechanical dysfunction.87–89
Manifestations of such injury include increased postresuscitation ectopic activity, atrioventricular block, and worsened postresuscitation myocardial dysfunction.90 Key
factors that determine injury include the energy level,
number of shocks, and defibrillation waveforms.
Energy level
The presence and severity of myocardial injury is influenced by the amount of energy delivered to the
myocardium. In an isolated perfused rabbit heart, Koning
and coworkers reported minimal injury after epicardial
shocks of 0.6 joule/cm2. Nevertheless, as the energy was
increased to up to 4.2 joule/cm2 additional and more
severe injury developed, including impaired systolic function, myocardial stiffness, release of creatine kinase, and
cell necrosis.91 Similarly, Doherty and coworkers found
that significant myocardial injury, as evidenced by creatine
kinase release, increased technetium-99m pyrophosphate
uptake, and decreased thallium-201 and indium-113m
uptake, developed only when the energy of shocks delivered directly to beating canine hearts (15- to 26-kg dogs)
exceeded 20 joules.92 The injury was characterized by
dehiscence of intercalated disks between damaged
myocytes. Kerber and coworkers, also in dogs, reported
contractile abnormalities only when the energy of epicardial shocks was 40 Joules or more in 17- to 45-kg dogs.93 In
the cardiac arrest setting, Xie and coworkers using an intact

835


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R.J. Gazmuri et al.

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.89 It 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 Ca2ϩ . In singleisolated, cultured chick-embryo heart cells, exposure to
defibrillator-type electrical shocks causes reversible depolarization followed by intensity-independent Ca2ϩ entry,
attributed to opening of normal excitation channels,
and intensity-dependent Ca2ϩ entry attributed to cell
damage.95 Further evidence that Ca2ϩ may play a role
stems from observations in dogs in which prior administration of the Ca2ϩ channel blocker verapamil Ϫ but not the
beta-blocker propranolol Ϫ attenuates 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 postresuscitation 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 coworkers99 and studies in victims of out-of-hospital
sudden cardiac arrest by Cobb and coworkers100 and by Wik

and coworkers,101 however, have challenged such an
approach, suggesting that a period of chest compression
before attempting defibrillation under conditions of prolonged untreated VF may improve the myocardial responsiveness to electrical shocks. The 2005 guidelines for
cardiopulmonary resuscitation recommend that CPR be
given for approximately 2 minutes before attempting electrical defibrillation when the ambulance response time is
prolonged (i.e., Ͼ 4 minutes). Moreover, the same recommendation states that only a single shock be given and that
CPR be resumed without a pulse check. These recommendations 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 of
measuring the amplitude and frequency characteristics of
VF waveforms to estimate the duration of untreated VF,102
assess myocardial energy metabolism,103 and predict the
response to defibrillation attempts.104,105 Waveform analysis that incorporates amplitude and frequency in a single
index has been demonstrated experimentally to have
better positive and negative predictor power than VF
amplitude and frequency alone.106 Use of these indices in
real-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 exponential waveforms, but the advent of implantable cardioverter-defibrillators introduced into clinical practice
the use of biphasic truncated exponential waveforms.
Biphasic waveforms have proven to be more effective for

terminating VF and less damaging to the myocardium
than monophasic waveforms. In a study of 40- to 45-kg
pigs subjected to 10 minutes of VF, Tang and coworkers107
reported comparable defibrillation efficacy by biphasic
(fixed 150-joule) and monophasic (escalating 200-, 300-,
and 360-joule) shocks. Biphasic waveform defibrillation
was associated with significantly less postresuscitation
myocardial dysfunction, as evidenced by lesser postresuscitation reductions in stroke volume, cardiac output, and
ejection fraction. In contrast, Niemann and coworkers37
using 26- to 36-kg pigs subjected to 5 minutes of untreated
VF reported comparable defibrillation success using
biphasic (fixed 150-joule) and monophasic (escalating
200-, 300-, and 360-joule) shocks without differences in
postresuscitation myocardial or hemodynamic function.
It is possible that the competitive advantage of biphasic
waveform defibrillation occurs at lower energy levels than
those that were used in this experimental setting.
In a recent clinical trial, fixed 150-joule impedancecompensating, biphasic truncated exponential defibrillation waveforms were compared with monophasic
(truncated exponential or damped sine) defibrillation
waveforms in 115 victims of out-of-hospital VF.108 Biphasic
waveform defibrillation was associated with significantly
higher rates of successful defibrillation (100% vs. 84%, P ϭ
0.003) and return of spontaneous circulation (76% vs. 54%,
P ϭ 0.01), 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 waveform
defibrillation were noted to have better neurological out-

Postresuscitation myocardial dysfunction

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 conditions 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 postresuscitation 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 arrest109 and can be minimized experimentally by using ␤-blocking agents.112 In a rat model
of VF and closed-chest resuscitation,111 use of the ␤1blocking 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 receptors
are expressed in pre- and postsynaptic junctions of vascular smooth cells. Activation of presynaptic ␣2-receptors
inhibits the release of norepinephrine. Activation of postsynaptic ␣2-receptors promotes peripheral vasoconstriction. Studies in rat and pig models of VF and closed-chest
resuscitation have shown that administration of the ␣2receptor agonist ␣-methyl-norepinephrine during chest
compression is associated with less postresuscitation
myocardial dysfunction when compared to epinephrine.117,118 Activation of these receptors in Purkinje cells has
been shown to reduce reperfusion arrhythmias in rats after
left anterior descending coronary artery occlusion and
reperfusion.119 These effects have been linked to signaling
via G-protein, causing attenuation in intracellular cyclic

adenosine monophosphate levels.

Novel experimental therapies
The realization that ischemia and reperfusion activates a
myriad of pathogenic pathways has persuaded researchers
to investigate whether targeting such pathways may
protect the myocardium and minimize postresuscitation
myocardial dysfunction. Some of these studies are
described below exposing the specific mechanisms of
injury targeted.

Sarcolemmal Na؉ –H؉ exchange
Increased sarcolemmal Naϩ influx with subsequent intracellular Naϩ overload due to the inability of the Naϩ –Kϩ
pump to extrude Naϩ during myocardial ischemia has
been recognized as an important pathogenic mechanism
of cell injury during ischemia and reperfusion.120–122 Naϩ
becomes a “substrate” for reperfusion injury123 and intensifies processes detrimental to cell function primarily by
promoting sarcolemmal Ca2ϩ entry through the Naϩ –Ca2ϩ
exchanger (NCX) acting in its reverse mode.124
The conditions that develop during cardiac arrest are
uniquely poised to trigger maximal and sustained NHE-1
activity. The intense intracellular acidosis that develops
during ischemia is the initial trigger for NHE-1 activation.
The subsequent resuscitation attempt, with closed-chest
techniques, promotes reperfusion with coronary flows that
rarely exceed 20% of normal. These low blood flow levels are
not sufficient to reverse ischemia,125 but are sufficient to
supply the coronary circuit with normo-acidic blood,
hence washing out the excess of extracellular protons favoring a trans-sarcolemmal proton gradient that maintains

837


838

R.J. Gazmuri et al.

dP/dt40 (mmHg sec–1)103

Cardiac Index (ml/kg per min)
BL

VF PC

Postresuscitation

BL

VF PC

Postresuscitation

9

300
DF
250

Esmolol

******

*

DF

8

***

7

***** *** *** ***

6

200

5
150
4
NaCl
3

100
30

–15

60

120

180

LVDP (mmHg)
BL

VF PC

30

–15

240

60

120

180

240

–dP/dt (mmHg s–1)103

Postresuscitation

BL

12

VF PC

Postresuscitation

9

10

8
DF

DF

8

7

6

6

4

5

2

****** ***

0
–15

30

60
120
Minutes

*** ***

** *

**

*** ***

4
3

180

240

–15

30

60

120
Minutes

180

240

Fig. 48.4. Myocardial effects of ␤1-adrenergic blockade during closed-chest resuscitation in a rat model of VF. Esmolol (300 ␮g/kg, n ϭ 9)
or NaCl 0.9% (n ϭ 9) 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 (n ϭ 9); open
symbols represent control (n ϭ 5). BL ϭ Baseline; LVDP ϭ Left 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 Ϯ SD. *P Ͻ 0.05; **P Յ 0.03; *** P Ͻ 0.01 vs.
NaCl. (Adapted from Cammarata G et al. Crit Care Med 2004;32:S440.)

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 contracture during chest compression such that there was less
ventricular wall thickening and better preservation of
cavity size. This effect enabled chest compression to generate and maintain a coronary perfusion pressure above the
threshold for resuscitability and to augment the hemodynamic 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).25,27
Although cariporide inhibits sarcolemmal NHE-1 and
ameliorates cytosolic Naϩ and Ca2ϩ overload, recent evidence suggests that protection may also involve direct
effects on the mitochondria by preserving the inner membrane Hϩ gradient and delaying ATP depletion.130

The potential clinical applicability of NHE-1 inhibitors
has been halted for the moment. A recent clinical trial in
patients undergoing coronary artery bypass graft surgery
demonstrated increased incidence of cerebrovascular
occlusive events and higher overall mortality despite a
significant reduction in non-fatal postoperative myocardial infarction.131 Although information on the mechanism of this adverse effect of cariporide is not currently


Postresuscitation myocardial dysfunction

Mean aortic pressure (mmHg)
120
100
80
60
Cardiac index (l/min per m2)

8

*

6

*†

4

*

*†

2
Left ventricular stroke work index (gm m/m2)
80

*

40

*

*

*

0
BL

PR 5 min

PR 15 min

PR 30 min

PR 60 min

Fig. 48.5. Postresuscitation hemodynamic and left ventricular function in pigs randomized to receive
cariporide (3 mg/kg, open bars, n ϭ 4) or NaCl 0.9% (closed bars, n ϭ 4) 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 Ϯ

SEM. *P Ͻ 0.05 vs. baseline (BL) by repeated measures ANOVA; †P Ͻ 0.05 vs. cariporide by one-way
ANOVA. (Adapted from ref. 27.)

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 dysfunction. One important mechanism of ischemic preconditioning that can be emulated pharmacologically involves
opening of mitochondrial Kϩ ATP channels.132–135 Opening of
Kϩ ATP channels leads to increased Kϩ conductivity of the
inner mitochondrial membrane, an effect that is bioenergetically beneficial136 and limits mitochondrial Ca2ϩ overload.137 In a rat model of VF and closed chest resuscitation,
administration of the Kϩ ATP channel opener cromakalim
reduced 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 postresuscitation ϩdP/dt40, -dP/dtmax, cardiac index, and longer
postresuscitation survival.

␦-Opioid receptor activation
Activation of ␦-opioid receptors has been shown to play
an important role in hibernation, leading to reductions in
myocardial oxygen consumption. Activation of ␦-opioid
receptors, and more specifically ␦1- and ␦2- receptors,
has been shown to ameliorate postischemic myocardial
dysfunction and to preserve ultrastructural integrity in
chick cardiomyocytes and isolated perfused rabbit

hearts.139,140 Sun and coworkers investigated, in a rat
model of VF and closed-chest resuscitation, the effect of
administering the ␦-opioid receptor agonist pentazocine.141 Administration of pentazocine was associated
with significantly lower postresuscitation arterial lactate
and less postresuscitation myocardial dysfunction, evidenced by a higher ϩ dP/dt40, -dP/dtmax, and cardiac

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