PIIS0300957223000618
PIIS0300957223000618
PIIS0300957223000618
Resuscitation
journal homepage: www.elsevier.com/locate/resuscitation
Clinical paper
Intestinal injury in cardiac arrest is associated
with multiple organ dysfunction: A prospective
cohort study
Bjørn Hoftun Farbu a,b,c,*, Halvor Langeland a,b, Thor Ueland d,e,f, Annika E. Michelsen e,f,
Andreas Jørstad Krüger b,c,g, Pål Klepstad a,b, Trond Nordseth a,b
Abstract
Background: The impact of intestinal injury in cardiac arrest is not established. The first aim of this study was to assess associations between
clinical characteristics in out-of-hospital cardiac arrest (OHCA) and a biomarker for intestinal injury, Intestinal Fatty Acid Binding Protein (IFABP).
The second aim was to assess associations between IFABP and multiple organ dysfunction and 30-day mortality.
Methods: We measured plasma IFABP in 50 patients at admission to intensive care unit (ICU) after OHCA. Demographic and clinical variables
were analysed by stratifying patients on median IFABP, and by linear regression. We compared Sequential Organ Failure Assessment (SOFA)
score, haemodynamic variables, and clinical-chemistry tests at day two between the “high” and “low” IFABP groups. Logistic regression was applied
to assess factors associated with 30-day mortality.
Results: Several markers of whole body ischaemia correlated with intestinal injury. Duration of arrest and lactate serum concentrations contributed
to elevated IFABP in a multivariable model (p < 0.01 and p = 0.04, respectively). At day two, all seven patients who had died were in the “high” IFABP
group, and all six patients who had been transferred to ward were in the “low” group. Of patients still treated in the ICU, the “high” group had higher
total, renal and respiratory SOFA score (p < 0.01) and included all patients receiving inotropic drugs. IFABP predicted mortality (OR 16.9 per stan-
dard deviation increase, p = 0.04).
Conclusion: Cardiac arrest duration and lactate serum concentrations were risk factors for intestinal injury. High levels of IFABP at admission were
associated with multiple organ dysfunction and mortality.
Trial registration: ClinicalTrials.gov: NCT02648061.
Keywords: Cardiac arrest, Intestinal ischaemia, Intestinal fatty acid binding protein, IFABP, Multiple organ dysfunction, Organ failure
* Corresponding author.
E-mail address: bjorn.hoftun.farbu@stolav.no (B. Hoftun Farbu).
https://doi.org/10.1016/j.resuscitation.2023.109748
Received 12 January 2023; Accepted 20 February 2023
0300-9572/Ó 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/
licenses/by/4.0/).
2 R E S U S C I T A T I O N 185 (2023) 109748
to ROSC.11,13 Further, increases in IFABP were associated with and/or vasopressors to maintain systolic blood pressure
higher mortality and poor neurological outcome.11,13 These studies >90 mmHg.22 We scored Glasgow Coma Scale at admission, Simpli-
included patients with both in-hospital cardiac arrest (IHCA) and fied Acute Physiology Score II (SAPS II) 24 hours after admission,
OHCA. The high levels of plasma IFABP at admission declined and Sequential Organ Failure Assessment (SOFA) daily.23–25
rapidly.11 However, injured intestines may enhance bacterial translo- A pulmonary artery catheter (Swan-Ganz CCOmbo, Edwards
cation or release pro-inflammatory mediators, in addition to IFABP, Lifesciences, USA) for continuous central haemodynamic measure-
contributing to subsequent and prolonged multiple organ ments was inserted in all comatose patients who did not have con-
dysfunction.14 traindications. Medication and all haemodynamic variables were
Risk factors for intestinal injury, and the potential relation gathered from the electronic critical care information system (Picis
between intestinal injury and organ dysfunction are highlighted as CareSuite, Optum Inc., USA). The haemodynamic variables were
research priorities by the European Society of Intensive Care cardiac output, proportion of patients receiving inotropic drugs (adre-
Medicine.15 Thus, the first aim of this study was to assess associa- naline, dobutamine, dopamine), dose of noradrenaline and amount
tions between OHCA characteristics and IFABP at admission. The of fluid infusion. Cardiac output and dose of noradrenaline reported
second aim was to assess possible associations between IFABP are the mean value over the period starting 30 minutes before and
at admission and organ dysfunctions and 30-day mortality. ending 30 minutes after each blood sample collection. Amount of
fluid infusion is the mean for the previous day.
Visceral organ function and injury were assessed by the clinical-
Methods chemistry tests alanine aminotransferase (ALT), alkaline phos-
phatase (ALP), bilirubin, albumin (liver), lipase, amylase (pancreas),
Study design and setting and creatinine (renal). In addition, platelets were registered for the
This is a post hoc analysis of a prospective cohort consisting of 50 SOFA score. We obtained cerebral performance category (CPC) at
consecutive patients with ROSC after OHCA admitted to the Inten- discharge and vital status after 30 days from the medical records.26
sive Care Unit (ICU) at St. Olav’s University Hospital, Norway. The
circulatory characteristics and trajectories, together with develop- Blood sampling
ment of inflammatory biomarkers, have been published previ- Blood samples were drawn at inclusion and every morning during the
ously.16–18 Patients were included between January 2016 and ICU period. After gentle mixing, the blood samples were placed ver-
November 2017. tical for 30 minutes in ambient temperature and then centrifuged at
2200 g for 10 minutes. EDTA-plasma was frozen to 80 °C within
Participants 1 hour from sampling.
Both comatose and awake adult patients were assessed for eligibil- Levels of IFABP were measured in duplicate by enzyme
ity. Exclusion criteria were age <18 years, transferal from other hos- immunoassays (EIA) using commercially available antibodies (Cat#
pitals, assumed septic or anaphylactic aetiology, pregnancy, DY3078, R&D Systems, Minneapolis, MN, USA) in a 384-format
decision to limit life-sustaining therapy upon arrival, or the following using a combination of a SELMA (Jena, Germany) pipetting robot
before arrival in the ICU: cardiothoracic surgery, application of extra- and a BioTek (Winooski, VT, USA) dispenser/washer. Absorption
corporeal membranous oxygenation (ECMO) or a ventricular assist was read at 450 nm with wavelength correction set to 540 nm using
device (VAD). an ELISA plate reader (Bio-Rad, Hercules, CA, USA). Coefficients of
Patients were followed from admission to a maximum of five variation were <10%. We measured IFABP in blood samples from 18
days. The follow-up was terminated earlier if the patient died or healthy subjects for reference.
was transferred to ward, extracorporeal membrane oxygenation or
a ventricular assist device was applied, cardio-thoracic surgery Statistical analysis
was performed, or withdrawing of life-prolonging therapies was Normal distributed data are presented as mean ± standard deviation
decided. Day one started the morning after admission at 06:00, (SD), otherwise median with first and third quartile (Q1–Q3) or pro-
and therefore the admission day (“day zero”) had variable length. portions (%). We divided the population into “high” and “low” by the
median value of the IFABP concentration at admission. The distribu-
Early management tion of variables in the two groups were compared using Student t-
The hospital’s standard treatment of comatose patients was targeted test, chi-square test, Fisher exact test, and Wilcoxon rank-sum test,
temperature management at 36 °C for 24 hours. Percutaneous coro- as appropriate.
nary intervention was performed if indicated. Patients with hypoten- First, we evaluated risk factors for intestinal injury by comparing
sion and/or clinical signs of hypoperfusion were treated with fluids, the distributions of demographic, Utstein and clinical variables in
vasopressors and/or inotropic drug administration. Detailed informa- the “high” and “low” IFABP groups. The same variables were then
tion about the clinical care given has been published previously.19 analysed in a linear regression model with admission IFABP as a
continuous outcome variable. Due to concerns of non-linearity
Data sources and definitions between IFABP and dose of adrenaline given, we stratified patients
We obtained data according to the Utstein cardiac arrest template into three groups (no adrenaline, 1–2 mg and 3 mg adrenaline,
from the pre-hospital report.20 Charlson Comorbidity Index was cal- respectively) and applied the multivariable regression model per cat-
culated and clinical information on assessment and treatment were egory (with no adrenaline as the reference). The assumptions of lin-
gathered from the hospital record.21 Arterial blood gas variables earity, homoscedasticity and collinearity in the model were met.
(pH, base deficit, and lactate) were obtained from the first sample Because of low sample size, we only included the three variables
after hospital admission. Circulatory shock in emergency room was with the lowest p-values in univariate analyses in the multivariable
defined as systolic blood pressure <90 mmHg or in need of fluids model. These variables were judged to be clinically relevant.
R E S U S C I T A T I O N 185 (2023) 109748 3
sented in Table 3. The odds ratio was 16.9 per standard deviation
increase in IFABP (p = 0.04). The results were similar in the sensitiv-
ity analyses. Time to ROSC did neither contribute significantly nor
alter the order of the other variables when added to the model (Sup-
plementary Table 4).
Discussion
Fig. 2 – Evolution of IFABP and variables of organ dysfunction and support, displayed as means, first five days after
admission. Day zero is of variable length. Only patients treated in the ICU at each time point are included in the
figure. SOFA scores and fluid infusion are based on previous 24 hours. Dose of noradrenaline and IFABP are obtained
at the time point given. Statistical tests were performed on day two only. IFABP: Intestinal Fatty Acid Binding
Protein. SOFA: Sequential Organ Failure Assessment.
Table 2 – Factors associated with IFABP at admission in multivariable linear regression model.
inotropic drugs were in the high IFABP group. Secondly, the lack of Whether intestinal injury, except in primary intestinal diseases,
an association with circulatory SOFA score may be due to many occurs in parallel with other organ dysfunctions or contributes to mul-
patients obtaining the highest score, which may be a type of ceiling tiple organ dysfunction, has not been clarified.15 This study was not
effect. Finally, only patients still treated in the ICU were included in designed to prove a contribution, but our findings do not exclude that
the statistical analysis of organ dysfunction. At the start of day two, important pathophysiological events could be mediated by the
thirteen patients had left the cohort. Of these, all patients with good intestines, either through bacterial translocation or inflammatory
outcomes were in the low IFABP group, and all the patients with poor cytokines.14,35–38
outcomes were in the high IFABP group (Fig. 1). Clearly, this could The association between IFABP and mortality in our study was
have attenuated the differences in organ dysfunction between the convincing. Indeed, all twelve patients who died the first five days
two groups. were in the high IFABP group (Fig. 1). This is in line with other
6 R E S U S C I T A T I O N 185 (2023) 109748
Table 3 – Factors associated with death within 30 days in logistic regression model.
reports, where gastrointestinal injury regardless of diagnostic modal- CRediT authorship contribution statement
ity is consistently associated with poor outcome after cardiac
arrest.4,9–11,13,28–29 IFABP, in specific, has been shown to predict Bjørn Hoftun Farbu: Conceptualization, Methodology, Investiga-
mortality in a variety of patient populations, including trauma, sepsis, tion, Formal analysis, Writing – original draft, Project administration.
acute heart failure and in unselected critically ill patients.30–31,39–42 Halvor Langeland: Conceptualization, Methodology, Investigation,
The present study has several limitations. Firstly, it is a small Formal analysis, Writing – original draft. Thor Ueland: Formal anal-
single-center study, although patients were consecutively included ysis, Writing – review & editing. Annika E. Michelsen: Formal anal-
and with a diversity in severity reflecting the OHCA population. Sec- ysis, Writing – review & editing. Andreas Jørstad Krüger:
ondly, IFABP is a novel biomarker and the validity in the cardiac Conceptualization, Methodology, Writing – original draft, Supervi-
arrest population has not yet been established. Thirdly, plasma sion. Pål Klepstad: Conceptualization, Methodology, Investigation,
IFABP is renally excreted and has short half-life.43 Even if blood Writing – original draft. Trond Nordseth: Formal analysis, Methodol-
samples were obtained shortly after hospital admission, both time ogy, Writing – review & editing, Supervision.
from ROSC to admission and from admission to blood sampling
may have influenced the observations. Fourthly, the selection of vari-
ables may not have been optimal to capture the potential multiple Appendix A. Supplementary material
organ dysfunction following intestinal injury. Finally, we divided our
cohort in two based on low and high IFABP levels. It is important Supplementary data to this article can be found online at https://doi.
to state that also patients in the low IFABP group had IFABP levels org/10.1016/j.resuscitation.2023.109748.
much higher than healthy volunteers. Thus, the comparison in our
study is not between intestinal uninjured versus injured patients, Author details
but more likely between two stages of intestinal injury.
a
Department of Anaesthesiology and Intensive Care Medicine, St.
Olav’s University Hospital, Trondheim, Norway bInstitute of Circula-
Conclusion
tion and Medical Imaging, Faculty of Medicine and Health Sciences,
Norwegian University of Science and Technology (NTNU), Trond-
We found that cardiac arrest duration and lactate were significant risk
heim, NorwaycNorwegian Air Ambulance Foundation, Department of
factors for intestinal injury at admission. High levels of plasma IFABP
Research and Development, Oslo, NorwaydK.G. Jebsen Thrombosis
at admission were associated with multiple organ dysfunction and
Research and Expertise Center, University of Tromsø, Tromsø,
high mortality. e
Norway Institute of Clinical Medicine, University of Oslo, Oslo,
f
Norway Research Institute of Internal Medicine, Oslo University
Hospital (Rikshospitalet), Oslo, Norway gDepartment of Emergency
Availability of data and materials
Medicine and Pre-Hospital Services, St. Olav’s University Hospital,
Trondheim, Norway
The datasets used during the current study are available from the
corresponding author on reasonable request.
R E F E R E N C E S
Conflict of interest
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