Journal of Critical Care 43 (2018) 122–127

Contents lists available at ScienceDirect

Journal of Critical Care

journal homepage: www.jccjournal.org

Cardiorenal syndrome in sepsis: A narrative review

Aditya Kotecha, MBBS a, Saraschandra Vallabhajosyula, MBBS b,c,
Hongchuan H. Coville, MD d, Kianoush Kashani, MD MSc FCCP FASN c,e,⁎
a
Department of Medicine, Detroit Medical Center/Wayne State University, Detroit, MI, United States
b
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States
c
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, United States
d
Department of Medicine, University of Central Florida College of Medicine, Gainesville, FL, United States
e
Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, United States

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

Keywords: Multi-organ dysfunction is seen in nearly 40–60% of all patients presenting with sepsis, including renal and car-
Cardiorenal syndrome diac dysfunction. Cardiorenal syndrome type-5 reflects concomitant cardiac and renal dysfunction secondary to a
Sepsis systemic condition that primarily affects both organs, such as sepsis. There are limited data on the etiology, path-
Septic shock ogenesis and clinical implications of cardiorenal syndrome in sepsis. Cardiac dysfunction and injury can be mea-
Acute kidney injury sured with cardiac biomarkers, echocardiographic dysfunction, and hemodynamic parameters. Acute kidney
Troponin-T
injury is systematically evaluated using serum creatinine and urine output criteria. This review seeks to system-
Echocardiography
atically describe the epidemiology, risk factors, pathogenesis, diagnosis and management of cardiorenal
syndrome type-5 in the setting of sepsis.
© 2017 Elsevier Inc. All rights reserved.

Contents

1. Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
1.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
1.2. Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
2. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
3. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
3.1. Cardiac dysfunction in sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
3.2. Kidney injury in sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
3.3. Organ cross talk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
4. Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
5. Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
5.1. Cardiac dysfunction and injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
5.2. Renal injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
6. Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

Abbreviations: AKI, acute kidney injury; CRRT, continuous renal replacement therapy; CRS, cardiorenal syndrome; cTnI, cardiac troponin-I; cTnT, cardiac troponin-T; KDIGO, Kidney
Disease Improving Global Outcomes; LV, left ventricle; LVEF, left ventricular ejection fraction; NGAL, neutrophil gelatinase-associated lipocalin; RV, right ventricle; SCM, septic
cardiomyopathy.
⁎ Corresponding author at: Divisions of Nephrology/Hypertension and Pulmonary/Critical Care Medicine, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN
55905, United States.
E-mail address: Kashani.Kianoush@mayo.edu (K. Kashani).

http://dx.doi.org/10.1016/j.jcrc.2017.08.044
0883-9441/© 2017 Elsevier Inc. All rights reserved.
 A. Kotecha et al. / Journal of Critical Care 43 (2018) 122–127
1. Background
1.1. Introduction
Sepsis continues as a leading cause of mortality and morbidity. In a
report from 2008, it accounted for 1,141,000 hospital admissions [1].
Despite recent advances in clinical care, mortality in septic shock re-
mains N40% in contemporary practice [2]. Multi-organ dysfunction is
seen in up to 45% of patients presenting with sepsis/septic shock and
is associated with worse short-term outcomes and long-term organ
dysfunction [3,4]. Sepsis is frequently associated with cardiovascular
and renal dysfunction and injury either in isolation or in combination.
However, there are limited data on cardiorenal syndrome (CRS) in sep-
tic patients.
CRS is defined as the primary dysfunction of either the heart or kid-
ney resulting in secondary dysfunction or injury to the other organ and
is classified into five types based on the chronicity and direction of
‘organ cross-talk’ [5]. CRS type 5 (CRS-5) reflects concomitant cardiac
and renal dysfunction secondary to a systemic condition that affects
both organs. Sepsis, cirrhosis, systemic lupus erythematosus, sarcoido-
sis, systemic sclerosis, amyloidosis, and toxins are all well-established
causes of CRS-5 [5,6]. In this review, we seek to systematically examine
the etiopathogenesis, clinical features, diagnosis, and management of
septic CRS-5.
1.2. Definitions
According to the recent Sepsis-3 guidelines, sepsis is defined as a
‘life-threatening organ dysfunction due to a dysregulated host response
to infection’ [2]. In the intensive care unit, sepsis is diagnosed by N 2
points rise in the Sequential Organ Failure Assessment score [2]. Cardio-
vascular dysfunction in sepsis can manifest as circulatory failure, septic
cardiomyopathy (SCM) and autonomic dysregulation [7]. Traditionally,
hemodynamic measurements of biventricular function using pulmo-
nary artery catheter have been used to define cardiac dysfunction [8].
However, the advent of critical care echocardiography has resulted in
widespread adoption of echocardiographic definitions of myocardial
dysfunction [9]. Cardiac injury in the current era is almost exclusively
defined by elevations in cardiac troponin-T (cTnT) and/or troponin-I
(cTnI), and these biomarkers have been validated as mortality predic-
tors in the septic population [10,11]. Increase in cTnT or cTnI
≥ 0.01 ng/mL or an upward change in cTnT of ≥ 0.03 ng/mL has been
used to define cardiac injury in sepsis [12].
Historically acute kidney injury (AKI) was diagnosed using the Risk,
Injury, Failure, Loss and End-Stage criteria that was subsequently up-
dated to AKI Network criteria in 2007 [13,14]. Kidney Disease Improving
Global Outcomes (KDIGO) criteria combines the prior definitions and
defines AKI as an absolute increase in serum creatinine ≥ 0.3 mg/dL
(26.5 μmol/L) within 48 h or by a 50% increase in serum creatinine
from baseline within 7 days, or a urine volume of b0.5 mL/kg/h for at
least 6 h [15].
2. Epidemiology
The knowledge of the relationship between CRS-5 and systemic con-
ditions in septic patients is limited [16]. AKI occurs with an incidence of
16–41% in septic patients, with a higher incidence noted in older pa-
tients and those with higher prior comorbidity. Attributable mortality
to AKI varies from 0 to 41%, and factors including delayed diagnosis,
multi-organ involvement, and processes of care contribute to the re-
ported variability in this relationship [17-19]. Nearly 20–60% of patients
with sepsis and septic shock develop SCM and have a worse prognosis
as compared to those without SCM [9,20]. Myocardial injury as demon-
strated by elevation in cTnT or cTnI is seen in about 60% of septic pa-
tients [11]. The incidence and prevalence of CRS-5 and its individual
123
components of AKI and SCM/cardiac injury vary across literature due
to the following reasons:
a) Inconsistent definitions: Prior to the development of the KDIGO def-
inition of AKI, the prevalence of AKI was reported to be 16–67% [21].
Standardization of the AKI definitions has led to greater applicability
across health care systems. The optimal research definition of cardi-
ac dysfunction in sepsis is still lacking. Current echocardiographic
definitions are extrapolated from heart failure literature and lack
precision in septic patients [22,23]. cTnT has high specificity for min-
imal myocardial injury. However, the role of serial cTnT testing in
this population has not been validated.
b) Use of electronic health records: Ability to compile longitudinal data,
electronic ‘alerting’ systems and use of quality control initiatives has
all improved recognition and prevention of AKI and SCM [24].
c) Use of non-invasive technology: Advances in echocardiography and
use of modern methods has aided in the detection of subtle SCM. Ad-
ditionally, the development of high-sensitivity cTnT has increased
the rate of myocardial injury identification [25].
d) Processes of care: Improvement in the processes of care, faster rec-
ognition of sepsis, and prevention of therapeutic harm have all re-
sulted in greater attention to prevention of organ injury [26].
3. Pathophysiology
Sepsis is a pro-inflammatory state causing microvascular changes,
pathological vasodilatation and multiorgan failure. Alterations in phys-
iology can occur from sepsis systemic effects, heart and kidney cross
talk, and the impact of care processes (Fig. 1 and Table 1) [6].
3.1. Cardiac dysfunction in sepsis
SCM is a consequence of hemodynamic alterations and changes in
myocardial blood flow, in addition to direct myocardial toxicity from
bacterial toxins [27]. Under-resuscitation using intravenous fluids has
been recognized to contribute to the traditional ‘cold shock’ in sepsis.
However, modern literature has emphasized the role of judicious fluid
resuscitation. Often restoration of vascular tone and adequate fluid
loading unmasks left ventricular (LV) systolic dysfunction [28]. Ade-
quate fluid loading can worsen new or pre-existing diastolic dysfunc-
tion leading to inability to maintain hemodynamic stability. The right
ventricle (RV) is exquisitely sensitive to increase in afterload due to pul-
monary vasoconstriction and use of positive pressure ventilation [29]. In
addition to these hemodynamic alterations, sepsis is associated with
changes in coronary blood flow induced by inflammatory mediators
such as nitric oxide, endothelin-1, calcium channels and cytokines
[27]. A full review of these mechanisms has been elegantly described
by Antonucci et al. and is beyond the scope of this review [27]. Classic
LV systolic dysfunction as defined by LV ejection fraction (LVEF) of
b50% is present in 14–27% of patients with sepsis and septic shock [9,
30]. Additionally, sepsis is associated with tachycardia due to autonomic
dysreflexia that contributes to impaired diastolic filling, worsening ar-
rhythmias and decreased cardiac output.
3.2. Kidney injury in sepsis
Sepsis-associated AKI is a multifactorial phenomenon and involves
derangements in renal vascular tone, renal blood flow, and direct
renal toxicity from infection and inflammation. A complete review of
pathophysiological mechanisms is beyond the scope of this review
[21]. In a meta-analysis of 160 studies on sepsis, normal or increased
renal blood flow was noted in nearly 30% of the patients [31]. Wan et
al. showed that there might be a diversion of renal blood flow towards
the renal cortex resulting in relative renal medullary hypoxia [32]. In-
flammatory mediators in sepsis cause renal dysfunction by apoptosis
of tubular cells [33]. Patients with higher endotoxin activity in CRS-5
124 A. Kotecha et al. / Journal of Critical Care 43 (2018) 122–127

Fig. 1. Pathogenesis of cardiorenal syndrome in sepsis. Legend: Black boxes and arrows demonstrate the effects of sepsis pathophysiology and colored arrows highlight the effects of
processes of care on the development of cardiorenal syndrome. Abbreviations: ARDS: acute respiratory distress syndrome; CBF: coronary blood flow; RV: right ventricular; SCM: septic
cardiomyopathy.

demonstrated greater renal apoptosis than those without high endotox- mandate increasing doses of vasopressors and consequently renal hy-
in activity [16]. Additionally, in septic patients decreased cardiac output poperfusion and ischemia. AKI, on the other hand, is associated with
due to extrinsic compression from abdominal compartment syndrome worsening acidosis with impact on decreased efficacy of vasopressors
and/or positive pressure ventilation can result in decreased renal perfu- [37]. Excessive intravenous fluids during resuscitation can cause visceral
sion [34,35]. edema and abdominal or kidney intra-capsular compartment syn-
drome, with a further decline in the renal blood flow [38]. On the
3.3. Organ cross talk other hand, fluid overload has direct influence in worsening of cardiac
function by elevation of cardiac filling pressures.
Multiple pathophysiological mechanisms and processes of care af-
fect both organ systems (Fig. 1 and Table 1). Macrovascular hemody-
4. Risk factors
namic alterations in sepsis can result in selective hypoperfusion of the
renal medulla and hence ischemic AKI and acute tubular necrosis [32].
There are limited data highlighting the risk factors for the develop-
Conversely, renal ischemia leads to in increased inflammatory media-
ment of CRS-5 in sepsis. Advanced age, higher comorbidity and septic
tors in the heart that result in an enhanced LV dimensions and therefore
shock are shared risk factors for cardiac and renal dysfunction in sepsis
declined systolic function [36]. Worsening circulatory failure would also
[9,39]. In a prospective study of 29 septic patients, patients requiring
renal replacement therapy had a lower LVEF compared to those not re-
Table 1 quiring renal replacement therapy (34.7 ± 4.1% vs. 42.8 ± 3%, p b 0.001)
Factors contributing to organ cross-talk in cardiorenal syndrome. [40]. Patients with SCM were dialyzed more frequently than patients
Primary pathology Mechanism of organ cross-talk without SCM (94% vs 16%, p b 0.001). The group with SCM also exhibited
higher severity of AKI [40]. Older age, hypertension and coronary dis-
Cardiovascular
Excessive fluid resuscitation Renal hyperemia and reno-venous congestion ease were predictive of new-onset LV diastolic dysfunction, but not sys-
Right ventricular failure Reno-venous congestion, renal edema tolic dysfunction [9]. In a multi-center prospective observational study
Under-resuscitation Renal ischemia, ATN conducted in 23 countries, Bagshaw et al. demonstrated the severity
Left ventricular failure Decreased renal perfusion, renal ischemia, ATN of illness, concomitant non-renal organ dysfunction, need for vasopres-
Tachycardia/tachyarrhythmia Impaired cardiac output, increased vasopressor
use causing renal ischemia and toxicity
sors and mechanical ventilation to be risk factors for the development of
Refractory circulatory shock Vasopressor toxicity, excessive reno-vascular septic AKI [41]. Emergent surgical admission and delayed time to antibi-
constriction otic therapy were associated with greater AKI in patients with sepsis
Renal
[42,43].
Metabolic acidosis Worsening shock, decreased vasopressor efficacy
Protein, immunoglobulin loss Decreased immunity, worsening inflammation
Microvascular derangements Worsening capillary leak, decreased preload 5. Diagnosis
Decreased RAAS activation Circulatory failure
Need for renal replacement Catheter-related infections, increased vasopressor The timeline of CRS-5 development is divided into five phases from
therapy use the onset of sepsis: hyperacute (0–72 h), acute (3–7 days), subacute (7–
Abbreviations: ATN: acute tubular necrosis; RAAS: renin-angiotensin-aldosterone system. 30 days) and chronic (≥30 days) [6]. CRS-5 is a clinical diagnosis, which
 A. Kotecha et al. / Journal of Critical Care 43 (2018) 122–127
is characterized by concomitant presence of acute kidney and heart dys-
function and/or injury in the setting of sepsis.
5.1. Cardiac dysfunction and injury
SCM is described by echocardiographic evidence of new-onset LV
systolic, LV diastolic or RV dysfunction [9]. American Society of Echocar-
diography definitions are used to classify ventricular dysfunction. Vary-
ing cut-offs of LVEF from 45 to 55% have been used in literature to define
LV systolic dysfunction [22,44]. Due to the dynamic nature of LVEF, the
incidence of reduced LVEF may increase over time based on afterload
conditions and fluid resuscitation [45,46]. More recently, various au-
thors have used strain imaging to define systolic dysfunction that has
demonstrated greater correlation with clinical outcomes [47,48]. LV
diastolic dysfunction is defined as grades II-IV dysfunction on tissue
Doppler imaging [49]. The traditional criteria employ multiple pa-
rameters that might not be applicable or measurable in acute critical
illness, leading to the development of modified definitions by some
authors [23,50]. Semi-quantitative echocardiography and strain im-
aging have been used to measure RV function [9,51]. B-type natri-
uretic peptide and N-terminal pro-B-type natriuretic peptide are
strong biomarkers of ventricular dysfunction and mortality in septic
patients [52]. However, the optimal cut-offs of these peptides are
poorly defined. Haines et al. demonstrated natriuretic peptides to
be predictive of maximum stage of AKI and need for renal replace-
ment therapy [53].
Myocardial injury, on the other hand, is usually classified using cTnT
or cTnI. Up to 85% of patients with sepsis and septic shock have detect-
able cTnT levels using standard troponin assays and troponin levels
have demonstrated a strong association with mortality [11]. cTnT levels
correlate with the presence of LV systolic and diastolic dysfunction and
RV dysfunction on echocardiography [25]. cTnT levels in patients with
sepsis correlate with duration of hypotension and extent of vasopressor
support [54]. cTnT ≥0.01 ng/mL have been associated with higher mor-
tality in sepsis and septic shock [12]. Landesberg et al. demonstrated
high sensitivity cTnT values to correlate with LV diastolic dysfunction
and RV dysfunction at higher cutoff values, alluding to a likely etiology
of troponin release in these patients [25]. Use of troponin for the diagno-
sis of CRS presents a diagnostic dilemma in patients on chronic hemodi-
alysis as about two-third of these patients have elevated troponin in the
absence of cardiac dysfunction [55]. Pro-inflammatory cytokines such as
interleukins 1 and 6 are highly sensitive for myocardial cell injury; how-
ever, their nonspecific elevation in inflammatory conditions and the in-
creased specificity of cTnT and cTnI have decreased their use in clinical
practice.
5.2. Renal injury
AKI is diagnosed by KDIGO criteria using clinical and laboratory
markers and has been detailed in Section 1.2. Use of biomarkers to de-
tect sub-clinical and early AKI is rapidly evolving. In septic patients, neu-
trophil gelatinase-associated lipocalin (NGAL), is not only sensitive to
detect AKI but also has a high correlation with severity of sepsis. NGAL
is also specific for septic AKI as compared to AKI due to other causes
and is predictive of need for intensive care admission and renal replace-
ment therapy [42]. However, the external validity of NGAL has not been
confirmed as the source of data is from homogenous populations and
single centers. Urine Insulin-like growth factor-binding protein 7 and
tissue inhibitor of metalloproteinases-2, both inducers of G1 cell cycle
arrest are superior to other biomarkers in predicting development of
moderate-severe AKI (KDIGO stage 2 or 3) in septic patients within
12 h [56]. Other novel biomarker for early AKI such as N-acetyl-beta-
glucosaminidase, kidney injury molecule-1, interleukin-18 and
cystatin-C need further validation in human studies [57].
125
6. Management
Due to the limited data on the etiopathogenesis, temporal course
and clinically robust definitions of CRS-5, the diagnosis, and manage-
ment of CRS-5 is varied and inconsistent. In CRS-5 where it is second-
ary to systemic process like sepsis, the cornerstone of management is
the treatment of underlying disease [4,58]. Early antibiotics and
early judicious fluid resuscitation are the cornerstone of sepsis man-
agement with concurrent vasopressor therapy for septic shock [4].
Implications of management strategies, and mutual worsening of
cardiac and renal function were highlighted in Fig. 1 and Table 1.
Source control, blood product administration and mechanical venti-
lation are therapeutic adjuncts that are used as mandated by the
clinical context.
Fluid and vasopressor therapy are used to stabilize the hemodynam-
ic alterations. Current guidelines recommend fluid loading with
30 mL/kg body weight of crystalloids prior to initiation of vasopressors.
Patients with chronic heart failure and kidney disease have a high risk of
under-resuscitation due to concerns for fluid overload [59]. Patients
with CRS-5 likely suffer from the same biases by treating intensivists
resulting in potential under-resuscitation and persistence of circulatory
failure. The use of ‘balanced’ crystalloids in sepsis is associated with im-
proved outcomes, especially in patients with severe metabolic acidosis
[60]. Use of high-chloride containing fluids is associated with the devel-
opment of normal anion gap metabolic acidosis in addition to high
anion-gap metabolic acidosis (from lactic acidosis). This results in de-
creased efficacy of vasoactive medications and antibiotics causing po-
tentially prolonged and more severe circulatory failure [37].
Management of acidosis is further complicated by co-existing AKI, po-
tentially necessitating renal replacement therapy. Over-zealous fluid re-
suscitation often results in visceral edema, renal vascular congestion
and intra-abdominal hypertension all of which potentially decrease
renal blood flow and impair venous return. The use of diuretics to opti-
mize fluid management in these patients is limited by the development
of AKI. The consequent fluid accumulation results in worse outcomes
due to persistent positive pressure balance [61]. The initial premise
that patients with sepsis all require 30 ml/kg fluid resuscitation has sub-
sequently been challenged, especially in patients with SCM. Ongoing
studies evaluating the role of echocardiography-directed fluid resuscita-
tion (NCT02354742) will likely help guide clinicians on fluid manage-
ment in CRS-5.
Norepinephrine is the recommended first line vasoactive agent in
these patients due to its cardiac-sparing effects and effective restoration
of vascular tone [4]. However, in patients with CRS-5, there is concern
for norepinephrine toxicity due to excessive renal vascular constriction
and renal medullary hypoxia [62]. Use of inotropes in the management
of septic shock has declined over the past decade, despite the initial en-
thusiasm generated by the Early Goal-Directed Therapy Guidelines [26].
The specific role of inotropes in the management of SCM remains to be
explored. Augmentation of cardiac index to supra-normal levels using
inotropes did not achieve any reduction in mortality or morbidity in pa-
tients with septic shock [63]. SCM is considered by some authorities as a
survival adaptation and increasing the beta-receptor stimulation could
contribute to worse outcomes [64]. Levosimendan has shown promis-
ing results in patients with acute heart failure; however, it did not dem-
onstrate a difference in outcomes in sepsis [65]. Levosimendan has
shown improvement in physiological LV and RV parameters, and
needs further study specifically in septic patients with SCM [66,67]. Cur-
rent guidelines do not recommend levosimendan for renal protection in
patients with sepsis [68]. The ideal combination of vasopressors,
inotropes and fluid therapy in the CRS-5 remains to be defined due to
the complex interactions between the therapeutic strategies and the
organ systems. Fluid and vasopressor therapy should be used to restore
perfusion pressure with a consideration for a higher mean arterial pres-
sure goal in patients with chronic hypertension [69]. However, these
higher blood pressure targets often are associated with greater
126 A. Kotecha et al. / Journal of Critical Care 43 (2018) 122–127
vasoactive medication use and its consequent toxicity, necessitating a
fine clinical balance.
Loop diuretics such as furosemide have been used to increased uri-
nary output, but as it can worsen renal function [42]. Current guidelines
recommend against using loop diuretics to prevent AKI solely. However,
diuretics could be utilized to control or avoid fluid overload [68]. In case
of refractory AKI in spite of achieving normal blood pressure, continuous
renal replacement therapy (CRRT) should be considered [70]. CRRT may
also help clear inflammatory cytokines, which could improve hemody-
namics in septic patient and decrease myocardial strain [71]. Currently,
there is a lack of unanimity amongst intensivists regarding early vs late
initiation of CRRT; however more recent literature has favored early
start, especially in post-surgical patients [72,73]. In a multicenter trial,
patients receiving CRRT had better renal recovery than patients receiv-
ing intermittent hemodialysis [74]. Convective CRRT has been shown to
decrease the need for vasopressor support over the first week of therapy
as compared to diffuse CRRT; however, this has not been specifically
evaluated in CRS-5 [75]. In sepsis, there are multiple pro and anti-in-
flammatory mediators and selectively blocking one mediator has not
been shown to improve outcomes. The ‘peak concentration hypothesis’
conceptualizes the prevention of peak concentration of mediators via
continuous filtration. CRRT, by virtue of continuously removing all of
the pro and anti-inflammatory mediators improves outcomes [76].
7. Conclusion
Sepsis is a leading cause of acute CRS-5; however, there are limited
data in this patient population. CRS-5 secondary to sepsis is a constella-
tion of clinical scenarios causing concomitant cardiac and renal dysfunc-
tion and it is tough to delineate a single pathophysiological pathway [6].
The clinical course of CRS-5 depends on the severity of sepsis and the
baseline level of cardiac and renal function. Prompt diagnosis and treat-
ment of underlying sepsis are essential for improved outcomes. Due to
the evolution of cardiac biomarker assays and echocardiographic tech-
niques, there is a critical need to define cardiovascular injury in sepsis
and thereby cardiorenal syndrome optimally. Appropriate management
strategies for fluid and vasopressor management and timing of renal re-
placement therapy are potential avenues for clinical and translational
research.
Acknowledgements
Conflicts of interest: All authors report no financial disclosures and
conflicts of interest relevant to the current submission.
Funding: This research did not receive any specific grant from
funding agencies in the public, commercial, or not-for-profit sectors.
Contributions: Study design, literature review: AK, SV, HHC, KK.
Data analysis, drafting manuscript: AK, SV, HHC.
Manuscript revision, intellectual revisions, mentorship: SV, KK.
Final approval: AK, SV, HHC, KK.
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