Journal of Critical Care 40 (2017) 128–135

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Journal of Critical Care

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Sepsis-associated in-hospital cardiac arrest: Epidemiology,

pathophysiology, and potential therapies
Ryan W. Morgan ⁎, Julie C. Fitzgerald, Scott L. Weiss, Vinay M. Nadkarni, Robert M. Sutton, Robert A. Berg
The Children's Hospital of Philadelphia, Department of Anesthesiology and Critical Care Medicine, 34th Street & Civic Center Boulevard, Suite 8566, Philadelphia 19104, PA, USA

a r t i c l e i n f o a b s t r a c t

Keywords: Sepsis-associated cardiac arrest is a relatively common occurrence with especially poor outcomes. Of the greater
Cardiac arrest than 200,000 in-hospital cardiac arrests that occur in the United States annually, between 30,000 and 60,000
Cardiopulmonary resuscitation occur in patients with underlying sepsis. These patients are less likely to survive than cardiac arrest victims with-
Sepsis out sepsis. In this review, we discuss the epidemiology of sepsis-associated in-hospital cardiac arrest in adults and
Septic shock
children, the relevant physiology responsible for its pathogenesis and poor outcomes, and potential therapeutic
interventions based on this pathophysiology. We postulate that persistence of sepsis pathophysiology during and
after cardiac arrest is responsible for these poor outcomes. This includes derangements of vascular tone and in-
travascular volume status; myocardial dysfunction; hypoxemia, acidemia, and other metabolic derangements;
and pulmonary hypertension. Potential interventions that specifically target this pathophysiology before, during,
and after cardiac arrest may augment standard cardiopulmonary resuscitation and post-resuscitation care for pa-
tients with sepsis and septic shock.
© 2017 Elsevier Inc. All rights reserved.

Contents

1. Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
2. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
2.1. Prevalence of sepsis-associated IHCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
2.2. Outcome of sepsis-associated IHCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
2.3. Limitations of sepsis-associated IHCA epidemiological data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
3. Pathophysiology of sepsis-associated cardiac arrest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
3.1. Derangements of vascular tone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
3.2. Derangements of volume status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
3.3. Myocardial dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
3.4. Hypoxemia/acidosis/metabolic derangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
3.5. Pulmonary hypertension and right ventricular failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
4. Prevention of sepsis-associated IHCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
5. Cardiopulmonary resuscitation in sepsis-associated IHCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
5.1. Derangements of vascular tone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
5.2. Derangements of volume status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
5.3. Myocardial dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
5.4. Hypoxemia/acidosis/metabolic derangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
5.5. Pulmonary hypertension and right ventricular failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
6. Post-cardiac arrest care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

Abbreviations: IHCA, in-hospital cardiac arrest; CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation; NRCPR, National Registry of Cardiopulmonary
Resuscitation; GWTG, Get with the Guidelines; NOS, nitric oxide synthase; ACLS, advanced cardiac life support.
⁎ Corresponding author.
E-mail addresses: morganR1@email.chop.edu (R.W. Morgan), fitzgeraldJ@email.chop.edu (J.C. Fitzgerald), weisss@email.chop.edu (S.L. Weiss), nadkarni@email.chop.edu
(V.M. Nadkarni), suttonr@email.chop.edu (R.M. Sutton), bergra@email.chop.edu (R.A. Berg).

http://dx.doi.org/10.1016/j.jcrc.2017.03.023
0883-9441/© 2017 Elsevier Inc. All rights reserved.
 R.W. Morgan et al. / Journal of Critical Care 40 (2017) 128–135 129

7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Financial disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

1. Background 2.2. Outcome of sepsis-associated IHCA

Over 200,000 patients suffer an in-hospital cardiac arrest (IHCA) Early reports of adult sepsis-associated IHCA demonstrated nearly
each year in the United States, with only one-fourth surviving to hospi- universal mortality with just one of 199 adults with sepsis-associated
tal discharge [1-4]. Although septic shock is a leading cause of IHCA in IHCA surviving to hospital discharge across four studies published be-
both adults and children, the cardinal pathophysiologic features of sep- tween 1983 and 1992 [21-24]. More recent registry data suggest that
sis – hypovolemia, vasodilation, and myocardial dysfunction – limit the survival from sepsis-associated IHCA has improved over the last
effectiveness of cardiopulmonary resuscitation (CPR). Consequently, two decades; however, patients with sepsis continue to have worse
patients with sepsis are less likely to achieve return of spontaneous cir- outcomes than patients without sepsis. For example, in the nearly
culation (ROSC) or survive to hospital discharge following IHCA [5-7]. 50,000 adult patients with IHCA captured in the Get With The
To date, few studies have specifically evaluated risk factors for and the Guidelines (GWTG)-Resuscitation database from 2007 to 2010,
pathogenesis of sepsis-associated cardiac arrest. We therefore sought “septicemia” carried an odds ratio of survival to discharge of 0.65
to review the epidemiology and pathogenesis of sepsis-associated (95% CI: 0.59, 0.71) and was incorporated into a risk-standardization
IHCA and to use these data to generate hypotheses regarding potential model for predicting survival following IHCA [5].
targeted therapeutic strategies to enhance CPR and improve outcomes Limited data suggest that those patients with sepsis who survive CPR
in this population. are prone to higher post-resuscitation mortality rates than their coun-
terparts without sepsis. One early study included 73 patients with sep-
sis-associated cardiac arrest, of whom 45% were initially resuscitated
2. Epidemiology but only one of whom survived to discharge as compared to 7.8% of pa-
tients without sepsis [21]. Using data from the National Registry of Car-
2.1. Prevalence of sepsis-associated IHCA diopulmonary Resuscitation (NRCPR) between 2000 and 2004, Larkin et
al. found that sepsis was not associated with increased risk of death at
Initial epidemiologic reports linking sepsis to risk of IHCA were the time of the CPR event (odds ratio 1.00; 95% CI 0.94, 1.05). However,
single-institution retrospective studies of cardiac arrest published sepsis was associated with increased risk of subsequent in-hospital
in the 1980s and 1990s [8-11]. More recent studies have relied on mortality, with an unadjusted odds ratio for in-hospital mortality of
multicenter IHCA registry data [3-6,8,9]. Across these studies, the 2.50 (95% CI 2.27, 2.75) that remained significant after adjustment for
prevalence of sepsis among adults with IHCA has ranged from 13 to other patient and event characteristics (1.25; 95% CI 1.10, 1.44) [6].
27% (Table 1). In children, single institution studies have identified In early pediatric literature, one children's hospital in the United
sepsis in 9–48% of cases with IHCA [7,10-12], while the prevalence States reported that none of the 44 patients with sepsis-associated
in multicenter and registry-based pediatric studies ranges from 14 IHCA survived to 1 year [7]. A Brazilian children's hospital reported
to 34% (Table 2) [4,13-20]. that 16.3% of septic patients survived for 24 h after IHCA, compared to

Table 1
Adult cardiopulmonary resuscitation publications that include data regarding incidence and/or outcomes related to sepsis.

Year Author Database/institution Survival (All IHCA) Incidence of sepsis Survival (sepsis-associated IHCA)

1983 Bedell Single institution 41/294 (14%) to hospital discharge 42/294 (14.3%) 0/42 (statistical significance not provided)
[23]
1988 Taffet Single institution 21/329 (6.4%) 73/329 (22.2%) 45% with ROSC; 1/73 (1.4%) survival to
[21] hospital discharge vs. 20/256 (7.8%) in
patients without sepsis; p = 0.03
1992 Blackhall Single institution 22/131 (16.8%) to 24 h; 4/131 (3.1%) to 22/131 (17%) 0/22
[24] hospital discharge
1994 Ballew Single institution 50/313 (16.0%) of those who received CPR 62/313 (19.8%) 0/62; p b 0.001
[22]
a
2003 Peberdy NRCPR 17% to hospital discharge 26% with pneumonia, septicemia, or n/a
[8] other infection
2006 Nadkarnic NRCPRa 18% to hospital discharge 10,100/36902 (27%) with pneumonia, n/a
[4] septicemia, or other infection
2010 Larkin [6] NRCPRa 15.9% to hospital discharge 6429/49130 (13.1%) 7.6% to hospital discharge. OR of
pre-discharge mortality: 2.50 (2.27, 2.75)
b
2012 Carr [64] GWTG-Resuscitation 19.7% of patients without pneumonia and Bacteremia in 11.5% without n/a
14.9% of patients with pneumonia pneumonia and in 28.6% with
survived to hospital discharge pneumonia (p b 0.001)
2012 Girotra GWTG-Resuscitationb 13.7% to hospital discharge in 2000; 22.3% 2000–2003: 3367/23633 (14.2%); n/a
[3] to hospital discharge in 2009 2004–2006: 6037/32603 (18.5%);
5363/28389 (18.9%); p b 0.001)
2013 Chan [5] GWTG-Resuscitationb 10,290/48841 (21.1%) to hospital 8296/48841(17.0%) 9.3% vs.19.1%; p b 0.001
discharge
a
National Registry of Cardiopulmonary Resuscitation.
b
Get with the Guidelines – Resuscitation Database.
c
Publication includes both adult and pediatric cardiac arrest data; only adult data included in this table.
130 R.W. Morgan et al. / Journal of Critical Care 40 (2017) 128–135

Table 2
Pediatric cardiopulmonary resuscitation publications that include data regarding incidence and/or outcomes related to sepsis.

Year Author Database/institution Survival (all IHCA) Incidence of sepsis Survival (sepsis-associated IHCA)

1997 Torres [7] Single institution 33/92 (36%) survival to 24 h; 9/92 (10%) to 1 44/92 (48%) 0/44 to 1 year
year
2002 Reis [11] Single institution 83/129 (64%) with ROSC; 43/129 (33%) survival 43/129 (33%) 7/43 (16.3%) to 24 h. RR of death
to 24 h; 24/129 (19%) to 30 days; 19/129 (15%) =1.35 (1.08–1.68); p = 0.03
to 1 year
2006 Nadkarnie [4] NRCPRa 27% survival to discharge 259/880 (29%) with n/a
pneumonia, septicemia, or
other infection
2006 Rodriguez-Nunez Spanish Study Group for 59.5% with ROSC; 34.5% survival to 1 year 26/116 (22.4%) 19.2% to hospital discharge; RR of
[14] Cardiopulmonary Arrest in mortality: 1.35 (CI95: 1.02–1.78; p b
Children 0.05)
2006 Tibballs [12] Single institution 40/111 (36%) survival to discharge 10/111 (9.0%) n/a
2009 Meert [19] PECARNb 172/353 (48.7%) of patients with ROSC survived Septic shock in 5.4% of 9/28 (32.1%)d
d
to hospital discharge. survivors and 10.6% of
non-survivorsd
2013 Girotra [20] GWTG-Resuscitationc 14.3% survival to discharge in 2000; 39.4% to 12.8% in 2000–2003; 18.3% n/a
discharge in 2009 in 2004–2006; 14.5% in
2007–2009
2013 Lopez-Herce [15] Iberoamerican Pediatric 69.5% with ROSC; 39.2% survival to discharge 104/502(20.7%) n/a
Cardiac Arrest Study
Network
2014 del Castillo [16] Iberoamerican Pediatric 172/250 (69.1%) with ROSC; 101/250 (40.4%) 37/250 (14.8%) 13.5% survival to discharge; RR 8.25
Cardiac Arrest Study survival to discharge (CI95: 2.93–23.19; p = 0.000)
Network
2014 Jayaram [18] GWTG Resuscitationc 543/1551 (35.0%) survival to discharge 220/1551(14.2%) 55/220 (25%) survival to discharge;
OR for survival to discharge: 0.65
(0.46–0.94)
2015 Matamoros [17] Multicenter study 33/146 (22.6%) to hospital discharge 49/146 (33.5%) with sepsis 9/49 (18.4%) survival; RR of death:
as etiology of arrest 2.29 (0.90–5.80)
a
National Registry of Cardiopulmonary Resuscitation.
b
Pediatric Emergency Care Applied Research Network.
c
Get with the Guidelines – Resuscitation Database.
d
Only patients with N20 min of ROSC included in study.
e
Publication includes both adult and pediatric cardiac arrest data; only pediatric data included in this table.

33% of all IHCA patients (RR 1.35 [1.08–1.68]; p = 0.03) [11]. A 1997
study of IHCA in 32 pediatric ICUs detailed survival to discharge in
only 6.8% of patients with infectious diagnoses [13]. More recently, pe-
diatric data from the GWTG-Resuscitation database demonstrated an
odds of survival to discharge of 0.65 (95% CI: 0.46, 0.94) for children
with sepsis-associated IHCA [18]. The multinational Iberoamerican Pe-
diatric Cardiac Arrest Study Network found a relative risk of mortality
of 8.25 (95% CI: 2.93, 23.19) for children in ICUs with sepsis-associated
IHCA compared to those without sepsis at the time of IHCA [6,16].
Therefore, we believe that septic shock should be specifically identified
and studied rather than broader groups of sepsis-related diagnoses that
may or may not be as clinically relevant at the time of cardiac arrest. Fu-
ture cardiac arrest studies could specifically report on the presence of
septic shock in the hours preceding cardiac arrest. Although this under-
taking is complicated by controversies regarding definitions of sepsis
and septic shock in the adult and pediatric populations, the definitions
in cardiac arrest studies should be consistent with the most up-to-
date international recommendations [25-29].

2.3. Limitations of sepsis-associated IHCA epidemiological data 3. Pathophysiology of sepsis-associated cardiac arrest

A notable limitation of most studies to date on the prevalence and
outcomes of patients with sepsis who develop IHCA is that these data
have been extrapolated from broader cardiac arrest studies, with few
specifying sepsis as a subgroup of interest a priori. While numerous
studies retrospectively report the proportion of patients with sepsis or
related disease categories in their respective study cohorts, the majority
do not clearly define the entity. The studies that include such definitions
differ in regard to these categorizations, which include septic shock [11],
“sepsis syndrome” with unspecified criteria [7,11], a “pneumonia, septi-
cemia, or other infection” category [4], and a primary diagnosis of “in-
fectious disease” [13].
The lack of a consistent definition of sepsis in these reports precludes
studying the epidemiology of sepsis-associated cardiac arrest in a sys-
tematic fashion and potentially hinders the application of existing epi-
demiologic data to clinical practice. Given the impact of sepsis on
cardiac arrest outcome and the paucity of relevant high-quality data,
the use of a more standardized definition of sepsis in studies of IHCA
would help ensure that data about prevalence and outcome are collect-
ed and reported in a more uniform and comparable manner. When sep-
tic shock is present at the time of cardiac arrest, it greatly affects
physiology and provides for physiologic targets during cardiac arrest.
The precise mechanisms by which septic shock leads to cardiac ar-
rest have not been explicitly characterized [30]. However, the cardinal
manifestations of septic shock, including vasodilation, hypovolemia,
and myocardial dysfunction, along with concurrent hypoxemia, acido-
sis, and metabolic derangements likely form the basis of the complex
pathophysiologic pathways that both contribute to cardiac arrest and
impede successful ROSC in these patients (see Fig. 1).
3.1. Derangements of vascular tone
Systemic inflammation is a central component of sepsis and leads to
abnormalities in vascular tone and distributive shock [31]. A substantial
proportion of patients with septic shock, especially children, have path-
ologically elevated vascular tone and systemic vascular resistance [32].
This leads to an abnormal distribution of blood flow among circulatory
beds and increases cardiac afterload, thereby increasing stress on the
myocardium and potentially predisposing to cardiac arrest. Patients
with sepsis may alternatively develop vasodilation and low systemic
vascular resistance. This is mediated locally by increased production of
nitric oxide and other modulators and, in some cases by decreased en-
dogenous vasopressin [33,34]. Vasodilation leads to hypotension and
 R.W. Morgan et al. / Journal of Critical Care 40 (2017) 128–135
Fig. 1. Pathophysiology of sepsis-associated cardiac arrest. Diagram depicting the pathophysiologic components of septic shock and their influence on intra-arrest physiology.
inadequate tissue perfusion. The consequent fall in diastolic blood pres-
sure can decrease coronary perfusion pressure and, along with reduced
time in diastole due to tachycardia, can induce myocardial ischemia and
cardiac arrest. Once cardiac arrest occurs, the generation of coronary
perfusion pressure, determined by the difference between the aortic
and right atrial pressures during diastole, is vital to successful CPR
[35]. In the setting of vasodilatory shock with low systemic vascular re-
sistance, the inability to generate adequate systemic diastolic blood
pressures and coronary perfusion pressures during CPR precludes ROSC.
3.2. Derangements of volume status
Depending largely on the stage of illness, patients with septic
shock may be total body fluid deplete (e.g., upon presentation) or
fluid overloaded (e.g., after fluid resuscitation). Regardless, in the
setting of pathologic vasodilation with increased vascular
capacitance and capillary leak syndrome with transudative loss of
intravascular fluid, patients will frequently have a low relative
intravascular volume status [36]. Inadequate ventricular end-dia-
stolic volume due to hypovolemia results in diminished stroke
volume and cardiac output, predisposing to myocardial ischemia
and cardiac arrest [37,38]. Additionally, recent epidemiologic studies
have shown that 84% of adults with septic shock [39] and 74% of
children with severe sepsis require endotracheal intubation and
mechanical ventilation [40]. In patients with hypovolemia at the
time of intubation, the alterations in cardiopulmonary interactions
that occur with initiation of invasive positive pressure ventilation
can directly precipitate cardiac arrest [41,42]. During CPR,
insufficient preload further compromises the generation of the
necessary coronary perfusion pressures to achieve ROSC.
Alternatively, patients who have been fluid resuscitated and are
volume overloaded, especially those with concomitant myocardial
dysfunction, may have intravascular volume overload. This can lead
to increased right atrial pressure and may compromise myocardial
perfusion by raising the downstream pressure to the coronary
circulation.
131
3.3. Myocardial dysfunction
Myocardial dysfunction occurs in approximately half of patients
with septic shock [43,44]. It is classically characterized by impairment
of contractility, but diastolic dysfunction, characterized by diminished
left ventricular compliance and filling, has been increasingly described
[44-48]. In general, IHCA victims with diminished ejection fraction
prior to arrest are less likely to survive to discharge than those with nor-
mal cardiac function [49]. The mechanisms responsible for myocardial
dysfunction are complex and not entirely elucidated, but include cyto-
kine-mediated myocardial depression [50,51], activation of inducible
nitric oxide synthase (NOS) [52-54], excessive beta-adrenergic stimula-
tion by both intrinsic and pharmacologic catecholamines [55,56], alter-
ations in intracellular calcium trafficking [57-59], and direct
mitochondrial injury [60,61]. Furthermore, many older adults with sep-
sis have underlying coronary artery disease [62]. The hemodynamic al-
terations of sepsis can worsen already tenuous myocardial perfusion in
these patients and result in cardiac arrest.
3.4. Hypoxemia/acidosis/metabolic derangements
Hypoxemia, due to pneumonia and/or acute respiratory distress
syndrome, is common in patients with septic shock [4,40,43,63,64].
Hypoxemia contributes to tissue hypoxia in these patients and can spe-
cifically lead to myocardial hypoxia that predisposes to cardiac arrest.
When alveolar oxygen tension is diminished at the time of cardiac
arrest, oxygen delivery during CPR is further compromised [65]. This
has the potential to impact the likelihood of ROSC and the degree of
post-arrest organ dysfunction.
Acidemia, as a result of tissue hypoxia, hypercarbic respiratory fail-
ure, or other organ dysfunction during septic shock, indirectly compro-
mises myocardial function and can be arrhythmogenic, thus potentially
predisposing to cardiac arrest [66]. During cardiac arrest, the impact of
acidosis on outcome remains unclear. Acidosis decreases hemoglobin's
affinity for oxygen, enhancing unloading of oxygen at the tissue level,
but potentially compromising oxygen uptake in the lungs in the
132 R.W. Morgan et al. / Journal of Critical Care 40 (2017) 128–135
presence of coexistent pulmonary disease or with the relatively low
minute ventilation provided during CPR.
Multiple organ dysfunction syndrome can result in electrolyte dis-
turbances such as hypocalcemia and hyperkalemia that directly impact
cardiac contractility and predispose to arrhythmias. Failure to correct
such metabolic derangements during cardiac arrest impedes successful
resuscitation efforts.
3.5. Pulmonary hypertension and right ventricular failure
Right ventricular dysfunction occurs as frequently as left ventricular
dysfunction in sepsis [33,45]. Pulmonary hypertension has been de-
scribed in humans with septic shock and is frequently reported in ani-
mal models of lipopolysaccharide-induced septic shock [67-69].
Pulmonary hypertension likely contributes to right ventricular dysfunc-
tion and diminished trans-pulmonary blood flow with resultant low
cardiac output prior to cardiac arrest. During cardiac arrest, pulmonary
hypertension causes decreased aortic blood pressure and increased
right atrial pressure, which together further decrease coronary perfu-
sion pressure, inhibit myocardial blood flow, and impede successful
resuscitation.
4. Prevention of sepsis-associated IHCA
Prompt recognition and treatment of septic shock are the first steps
in preventing IHCA in these patients. Early goal-directed therapy aimed
at optimizing intravascular volume status and correcting metabolic de-
rangements, in addition to timely administration of antimicrobials and
other source control measures can reduce mortality in septic shock
[37,38,70,71]. Recognition of sepsis-associated cardiac dysfunction, like-
ly a major precipitator of cardiac arrest, is important. This can be accom-
plished through clinical examination, measurement of serum levels of
natriuretic peptides, and echocardiography, and should trigger the use
of inotropic support in addition to vasopressors [43,72].
5. Cardiopulmonary resuscitation in sepsis-associated IHCA
High-quality CPR with emphasis on appropriate chest compression
rate, depth, and recoil; vasopressor administration; and timely defibril-
lation has been shown to increase the likelihood of ROSC, survival to
hospital discharge, and satisfactory neurologic recovery following
IHCA [2,3]. Given the higher rate of adverse outcomes from IHCA in
the setting of septic shock, further work is necessary to identify targeted
therapeutic interventions to enhance CPR and improve outcomes spe-
cifically in sepsis-associated IHCA. The complex pathophysiologic mech-
anisms in patients with septic shock are especially problematic during
resuscitation of cardiac arrest. In addition to the standard therapies of
advanced cardiac life support (ACLS), several potential intra-arrest
treatments could be used early in the algorithmic approach to specifical-
ly target vasodilation, hypovolemia, myocardial dysfunction, metabolic
abnormalities, and pulmonary hypertension.
5.1. Derangements of vascular tone
The major determinant of CPR success is the generation of adequate
coronary perfusion pressure, determined by the difference between the
aortic blood pressure and right atrial pressure during diastole [35,73].
Low intra-arrest diastolic blood pressures hinder the generation of myo-
cardial blood flow during CPR. Administration of appropriate vasopres-
sors during CPR could theoretically allow for enough improvement in
diastolic pressures to generate sufficient coronary perfusion to facilitate
ROSC. “Relative vasopressin deficiency” occurs during septic shock and
exogenous vasopressin is recommended as a second-line vasopressor
for refractory hypotension during septic shock [37,55,74]. However, in
a recently published large animal sepsis-associated cardiac arrest
study, there was no advantage of adding vasopressin to epinephrine
[75]. Since a proportion of patients with septic shock have elevated sys-
temic vascular resistance, it is possible that vasopressor administration
with further elevation of left ventricular afterload may actually be dele-
terious in some cases. Importantly, monitoring the patient's hemody-
namic response to vasopressor administration during cardiac arrest
and targeting that response with additional therapies holds great prom-
ise [76].
5.2. Derangements of volume status
Intra-arrest intravascular volume expansion with crystalloid fluids is
a potentially advisable therapy in patients with septic shock who prog-
ress to cardiac arrest since aortic diastolic pressure is partly dependent
upon adequate ventricular filling. However, since the downstream pres-
sure of the myocardial vasculature is the right atrium, aggressively vol-
ume-loading this chamber in the setting of the poor right ventricular
output of cardiac arrest may be deleterious to the generation of coro-
nary perfusion pressure during CPR. While the optimal intra-arrest
fluid administration strategy in the patient with septic shock is un-
known, it is reasonable to assume that personalizing the approach to pa-
tient status and measures of response could be beneficial. This would
include the assessment of preload (e.g., central venous pressure, real-
time echocardiography) and coronary perfusion pressure. Since most
patients with IHCA are in an ICU setting, such monitoring is frequently
possible [77,78].
5.3. Myocardial dysfunction
Knowledge of the pathophysiology of impaired cardiac contractility
in septic shock allows for hypotheses regarding intra-arrest therapeutic
targets. While administration of calcium during cardiac arrest has not
been associated with favorable outcomes, the altered calcium trafficking
within the septic cardiomyocyte could provide a physiologic circum-
stance in which exogenous calcium administration might be beneficial
[57,58,79,80]. Likewise, some of the detrimental effects of excessive en-
dogenous nitric oxide can be tempered in sepsis with the use of NOS in-
hibition, affording another potential intra-arrest target, though no
favorable mortality benefits have been demonstrated to date [81].
5.4. Hypoxemia/acidosis/metabolic derangements
As with cardiac arrest of any etiology, contributing factors such as
hypoxemia, hypercarbia, acidosis, and hyperkalemia, should be consid-
ered. Patients with septic shock progressing to cardiac arrest may have
several of these derangements present simultaneously and failure to re-
verse them may preclude ROSC. As such, clinicians should systematical-
ly and thoroughly address such factors early in the resuscitation effort.
Routine administration of sodium bicarbonate is not recommended
during cardiac arrest for the empiric treatment of acidosis, but there
may be sub-populations, such as those with septic shock and multiple
organ dysfunction, in whom it is beneficial; further work is needed to
identify these groups [82,83].
5.5. Pulmonary hypertension and right ventricular failure
The presence of pulmonary hypertension in animal models of
endotoxemia and right ventricular failure in human patients with septic
shock suggests that pulmonary vascular resistance could play a major
role in sepsis-associated cardiac arrest. This is compounded by the ad-
ministration of pulmonary vasoconstrictor agents (e.g. epinephrine)
during CPR. Measuring pulmonary vascular resistance during CPR and
evaluating potential therapeutics to reduce it, including the administra-
tion of selective pulmonary vasodilators, is a potentially exciting direc-
tion [68,84]. Additionally, some studies have established that
pulmonary vasodilation occurs in response to vasopressin administra-
tion, thus allowing for systemic vasoconstriction without the adverse
 R.W. Morgan et al. / Journal of Critical Care 40 (2017) 128–135
effect of pulmonary vasoconstriction and subsequent increase in right-
sided cardiac pressures seen with catecholamine administration [85,
86].
6. Post-cardiac arrest care
Post-cardiac arrest syndrome, characterized by brain injury, myocar-
dial dysfunction, systemic ischemia and reperfusion, and the persistent
precipitating pathology, has itself been described as a “sepsis-like” syn-
drome [87,88]. This pathophysiology is presumably exaggerated in the
setting of ongoing septic shock and likely accounts for some degree of
the higher rates of hospital mortality in patients with sepsis-associated
IHCA compared to those with IHCA not related to sepsis. In all likeli-
hood, the underlying processes that predisposed the patient to cardiac
arrest have not been reversed. As such, clinicians should focus on
reevaluating patients in their entirety, achieving source control, and
preventing subsequent hemodynamic deterioration.
The higher rates of post-ROSC mortality with sepsis-associated IHCA
[6,21] reflect the overall severity of disease and degree of multiple organ
dysfunction in these patients, which is not simply corrected with ROSC.
Derangements in vascular tone and intravascular volume status persist
and likely worsen after cardiac arrest. While aggressive fluid resuscita-
tion may have preceded or accompanied resuscitation from cardiac ar-
rest, relative intravascular hypovolemia can persist and further
volume administration may be indicated. The pre-arrest myocardial
dysfunction that is common among patients with sepsis places them
at especially high risk for more severe post-arrest myocardial dysfunc-
tion and resultant higher risk for subsequent death [49]. Post-arrest hy-
potension is associated with increased risk of mortality and poor
neurologic outcomes in those that survive [89,90]. This provides an op-
portune target for improving outcomes after an initially successful re-
suscitation by aggressively aiming to maintain adequate blood
pressure and systemic perfusion, utilizing both vasopressors for persis-
tent vasodilatory shock and inotropic agents for myocardial
dysfunction.
Therapies targeted at specific pathophysiologic features of the post-
cardiac arrest syndrome in patients with sepsis hold promise and war-
rant further investigation in the post-arrest period. Specific vasopres-
sors and inotropes can be utilized based on each patient's evolving
hemodynamic profile. Maintenance of adequate oxygenation in the set-
ting of evolving pulmonary injury due to sepsis or cardiac arrest is im-
perative. Lastly, with increasing data pointing to mitochondria as
central players in multi-organ injury related to both sepsis and cardiac
arrest, treatments targeting mitochondrial recovery hold great promise.
These include antioxidant therapies that protect against continued
stress and reperfusion injury, inhibitors of mitochondrial metabolism
in the immediate post-injury period, and stimulators of mitochondrial
biogenesis [91-94].
7. Conclusions
Current guidelines for resuscitation in cardiac arrest are applied to a
heterogeneous group of underlying pathophysiologic processes that re-
sult in cardiac arrest. Septic shock is responsible for a substantial pro-
portion of IHCAs and is associated with high mortality rates. Specific
pathophysiology present in sepsis, including systemic vasodilation, in-
travascular volume depletion, myocardial dysfunction, hypoxia, acidosis
and other metabolic derangements, and pulmonary hypertension likely
impact the progression to cardiac arrest and the difficulty in resuscitat-
ing patients with sepsis who suffer IHCA. Potential therapies aimed at
targeting these specific pathophysiologic disturbances include alterna-
tive vasopressor regimens, judicious intra-arrest volume expansion,
inotropic support, prompt reversal of underlying metabolic abnormali-
ties, and the application of selective pulmonary vasodilators. Experi-
mental conditions that model sepsis-associated IHCA need to be
developed to test novel CPR algorithms and post-resuscitative
133
therapies. Most importantly, sepsis-associated cardiac arrest provides
a prime example for the need to tailor therapies to the physiologic re-
sponse of the patient. Understanding and targeting sepsis-related path-
ophysiology before, during, and after cardiac arrest has great potential
to improve patient outcomes.
Conflicts of interest
None.
Financial disclosures
None.
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