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R E S U S C I T A T I O N 185 (2023) 109748

Available online at ScienceDirect

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

chemistry tests, and computed tomography (CT) findings of NOMI


Introduction are non-specific.3 Novel biomarkers are emerging, and intestinal
fatty acid binding protein (IFABP) is one of the most widely studied
Organ dysfunction after out-of-hospital cardiac arrest (OHCA) is biomarkers for small bowel injury.6 IFABP is a cytosolic protein of
common and carries a high mortality rate.1 The organ dysfunction enterocytes and is released rapidly into the bloodstream if the muco-
is caused by whole-body ischaemia–reperfusion injury and include sal tissue becomes ischaemic.7–8 The incidences of NOMI after car-
neurologic, circulatory and respiratory functions.2 Ischaemia- diac arrest have been reported to be low.9–10 However, due to the
reperfusion in OHCA may also injure the intestines, and both gastric diagnostic limitations, intestinal injury may be underreported. A
regurgitation and early diarrhea after OHCA has been shown to pre- higher incidence of intestinal injury after cardiac arrest is supported
dict poor neurological outcome.3–5 by an elevated level of IFABP in most of these patients.11–12
The most severe forms of intestinal ischaemia are termed ´non- In two previous reports IFABP was associated with high doses of
occlusive mesenteric ischaemia´ (NOMI), a syndrome caused by adrenaline (epinephrine) given during resuscitation, but not with time
hypoperfusion.3 However, clinical findings, current clinical-

* 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

Second, to assess organ dysfunction, we compared SOFA score, Results


haemodynamic variables, and clinical-chemistry tests between the
high and low IFABP group. Thirty-day mortality was evaluated in uni- Among 65 consecutive patients assessed for eligibility, 15 patients
variable logistic analyses. Because of the low sample size, we were excluded. Seven patients due to immediate withdrawal of life-
assessed the three variables with the lowest p-values in a multivari- support, two had septic etiology, two patients were not in need of
able model after confirming that they were clinically important. ICU admission, three patients received VAD or ECMO and one
Finally, we performed sensitivity analyses on the multivariable patient underwent immediate surgery. Fifty patients were included
models by analysing all variables with p < 0.1 in univariable analyses in the study.18 Demographic data are provided in Table 1. Mean
independently and together, and by exchanging lactate for base length of day zero was 11 hours. At start of day two, seven patients
deficit. had died, all in the high IFABP group, and six patients had been
All tests were two-sided and statistical significance was defined transferred to ward, all in the low IFABP group (Fig. 1).
as p < 0.05. Data were extracted with the software Matlab (Math-
works Inc., Natick, MA), and the statistical analyses were performed Plasma intestinal fatty acid binding protein (IFABP)
with Stata 17.0 (StataCorp LCC, Collage Station, TX). No adjustment The mean IFABP level was 28.2 ng/mL (SD 12.9) at admission
for multiplicity were made. (Table 1). The levels declined rapidly, with low values by day two
(Fig. 2). The mean IFABP in the 18 healthy controls was 1.2 ng/
Sample size mL (data not shown).
No formal sample size was calculated, as described in the protocol
article for the main study.19 Association between cardiac arrest and IFABP at admission
Patients in the high IFABP group had more often non-shockable
Ethics initial rhythm, longer time to ROSC, higher doses of adrenaline,
The Regional Committee for Medical and Health Research Ethics, base deficit, and lactate, but lower pH (Table 1). Presumed non-
Central Norway Health Region (REK Midt, No. 2015/1807) approved cardiac etiology together with circulatory shock and comatose
the study. Participants or their proxies provided written consent. The state in emergency room were also more frequent in the high
study is registered in ClinicalTrials.gov (Identifier: NCT02648061). IFABP group.

Table 1 – Characteristics on admission of successfully resuscitated OHCA patients.

All (n = 50) Low IFABP (n = 25) High IFABP (n = 25) p-value


Demographic
Age 67 [54–76] 67 [54–73] 65 [52–76] 0.94
Sex, male 40 (80%) 22 (88%) 18 (72%) 0.29
Charlson Comorbidity Index 3 [2–4] 4 [2–5] 3 [1–4] 0.23
Prehospital Utstein variables
Witnessed cardiac arrest 42 (84%) 22 (88%) 20 (80%) 0.70
Bystander CPR 44 (91.7%) 23 (100%) 21 (84%) 0.11
Time to ACLS (min) 10 [5–13] 9 [5–12] 10 [5–16] 0.47
Shockable initial rhythm 39 (78%) 24 (96%) 15 (60%) 0.005
Number of defibrillations 2 [1–4] 2 [1–3] 2 [0–4] 0.95
Adrenaline, total dose in mg 0 [0–2] 0 [0–0] 2 [1–3] <0.001
Time to ROSC (min) 24 [14–32] 18 [10–28] 28 [20.5–35.5] 0.009
Presumed cardiac etiology 42 (84%) 24 (96%) 18 (72%) 0.05
At admission
Circulatory shock in ER* 17 (36%) 4 (16%) 13 (52%) 0.02
Comatose at admission (GCS < 8) 42 (84%) 18 (72%) 24 (96%) 0.05
Initial pH 7.24 [7.09–7.28] 7.28 [7.25–7.31] 7.09 [7.02–7.24] <0.001
Initial Base deficit 10.4 [6–13.8] 6.3 [3.4–10.4] 13.8 [8.7–17.5] <0.001
Initial arterial lactate (mmol/L) 6.2 [3.1–9.6] 3.8 [2.1–6.6] 9.3 [5.2–12] <0.001
SAPS II score 64 (53–73) 60.5 (41.5–69.5) 67 (58–75) 0.06
Creatinine (micromol/L) 96.4 (30.6) 96.4 (30.6) 101.4 (25.8) 0.57
IFABP (ng/mL) 28.2 (12.9) 18.3 (10.3) 38.2 (5.9) NA
CPC 1–2 at discharge 31 (62%) 23 (92%) 8 (32%) <0.001
Dichotomous variables are summarized as counts and percentages and compared by Fisher’s exact test. Normal distributed variables are expressed as mean and
standard deviation and compared by Student’s T-Test. Other continuous variables and categorical variables are expressed as median and interquartile range (IQR)
and compared by Wilcoxon rank-sum test.
*Shock defined as systolic blood pressure <90 mmHg or in need of fluids and/or vasopressors to maintain systolic blood pressure >90 mmHg.
OHCA: Out-of hospital cardiac arrest. CPR: Cardiopulmonary resuscitation. ACLS: Advanced cardiac life support. ROSC: Return of spontaneous circulation. ER:
Emergency room. GCS: Glasgow Coma Scale. SAPS II: Simplified Acute Physiology Score II. IFABP: Intestinal Fatty Acid Binding Protein. CPC: Cerebral
performance category.
4 R E S U S C I T A T I O N 185 (2023) 109748

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

In this study time to ROSC and initial lactate concentrations after


OHCA were significant risk factors for intestinal injury as reflected
by IFABP at admission. High levels of IFABP were associated with
multiple organ dysfunction at day two and increased mortality. Nota-
bly, at the start of day two, all patients who had died were in the high
IFABP group, while all patients who had been transferred to ward
were in the low IFABP group.
We found that several clinical markers of whole body ischaemia–
reperfusion injury were associated with high IFABP levels. Multivari-
able analysis identified time to ROSC and lactate serum concentra-
tions as significant predictors of IFABP levels. In contrast, the dose
of adrenaline given during resuscitation did not contribute signifi-
cantly to raised IFABP. The sensitivity analyses did not alter this find-
Fig. 1 – Status of patients at start of each day (0600 ing. This result is contrary to two previous studies, which found that
hours), day zero is of variable length. Only patients still multiple doses of adrenaline, and not duration of cardiac arrest, were
treated in the ICU were included in the statistical associated with higher IFABP levels.11,13 Doses of adrenaline in the
analyses of organ dysfunction. IFABP: Intestinal Fatty report by Krychtiuk et al. were comparable to our study and both
Acid Binding Protein. ICU: Intensive Care Unit. studies had comparable eligibility criteria except for inclusion of both
OHCA and IHCA patients.11,13 IHCA represent a different population,
which is more frequently witnessed by health professionals.27
Evaluated as a continuous variable in univariable linear regres- Indeed, Krychtiuk et al. found shorter time to ROSC and an initial
sion analyses, IFABP levels increased significantly with increasing median lactate value of only 1.9 mmol/l compared to 5.2 mmol/l in
time to advanced life support, time to ROSC, dose of adrenaline, our cohort.13 This may indicate higher load of ischaemia in our study
higher Simplified Acute Physiology Score (SAPS) II score, pH, lac- which could contribute to more severe intestinal injury and higher
tate, and base deficit. Also, circulatory shock and comatose state IFABP levels. However, IFABP was measured by a different kit in
in emergency department were associated with higher IFABP levels our study making absolute values of IFABP, and thus severity of
(Supplementary Table 2). intestinal ischaemia, difficult to compare.6
In multivariable regression analysis IFABP increased significantly Intuitively, it would be surprising if intestinal ischemic injury was
with longer times to ROSC and higher levels of lactate, but not with not related to duration of cardiac arrest. In other studies of gastroin-
increasing dose of adrenaline (Table 2). For adrenaline, the rate of testinal injury after cardiac arrest, two of NOMI and two of endo-
rise in IFABP was higher for patients given 1–2 mg adrenaline than scopic lesions, three out of four studies found an association with
for those receiving  3 mg, but with wide and overlapping confidence time to ROSC.9–10,28–29 In multivariable analysis, cardiac arrest dura-
intervals (11.5, 95% CI 4.4–18.7, and 7.9, 95% CI 0.2–15.7, respec- tion but not dose of adrenaline was associated with NOMI, but vice
tively). The results were not notably different in the sensitivity analy- versa in a recent study of endoscopic lesions.10,29 These results
ses (Supplementary Table 3). may reflect that time to ROSC and total dose of adrenaline are clo-
sely related and it will vary which of these factors that are identified in
Associations between IFABP at admission and organ a multivariable analysis.
dysfunction Organ dysfunction at day two occurred more frequently in the
At the start of day two, 37 patients were still treated in ICU and high IFABP group. To our knowledge, this is the first study of OHCA
included in the analyses of organ dysfunctions. Total SOFA score to show a correlation between intestinal injury and the degree of mul-
and the sub-scores of renal and respiratory functions at day two were tiple organ dysfunction. In conditions other than OHCA, however, the
significantly higher in the high IFABP group (Supplementary Table 1). association between IFABP and organ dysfunction has been
Neither of the other SOFA sub-scores nor other clinical-chemistry reported previously.30–33 We observed that patients with high IFABP
tests differed between the two groups (Supplementary Table 1). How- had more frequent renal and respiratory organ dysfunction, but nei-
ever, all six patients receiving inotropic drugs were in the high IFABP ther higher circulatory SOFA score nor higher dose of noradrenaline
group (p = 0.009, Supplementary Table 1). The evolution of organ dys- at day two. The incidences of circulatory dysfunction have been
function and support are shown in Fig. 2 and Supplementary Fig. 1. reported to be high following both NOMI and cardiac arrest.2,34
Therefore, we would expect to find a difference in severity of circula-
IFABP at admission and mortality tory dysfunction between the high and low IFABP group. Indeed, our
Lactate and IFABP contributed significantly to 30-day mortality in the findings do not exclude a correlation between high IFABP and circu-
multivariable logistic analysis, but not non-shockable rhythm, as pre- latory dysfunction for several reasons. Firstly, all patients receiving
R E S U S C I T A T I O N 185 (2023) 109748 5

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.

Variable Univariable Multivariable


Adjusted R2 = 0.37

Unadjusted coefficient 95% CI Adjusted Coefficient 95% CI p-value


Time to ROSC (min) 0.52 0.33–0.71 0.35 0.11–0.59 0.006
Adrenaline (mg) 2.86 1.09–4.63 0.53 1.32–2.37 0.57
Lactate (mmol/l) 1.26 0.51–2.00 0.76 0.03–1.49 0.04
IFABP: Intestinal Fatty Acid Binding Protein. ROSC: Return of spontaneous circulation.

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.

Univariable analysis Multivariable analysis

Variables OR 95% CI p-value OR 95% CI p-value


Lactate, per SD 7.15 2.43–21.00 <0.001 7.81 1.67–36.57 0.009
Non-shockable initial rhythm 20.57 3.62–116.83 0.001 18.05 0.91–359.22 0.06
IFABP at admission, per SD 12.23 2.46–60.76 0.002 16.90 1.10–261.27 0.04
Time to ROSC, per SD 2.49 1.18–5.27 0.02
SAPS II, per unit 1.05 1.00–1.09 0.03
Time to ACLS, per SD 1.84 0.99–3.43 0.05
Shock in emergency room* 2.78 0.80–9.61 0.11
Dose of adrenaline, per mg 1.22 0.90–1.66 0.19
Bystander CPR 0.47 0.06–3.66 0.47
OR: Odds ratio, CI: Confidence interval, SD: Standard Deviation, IFABP: Intestinal fatty acid binding protein, ROSC: Return of spontaneous circulation, SAPS II:
Simplified Acute Physiology Score II, ACLS: Advanced cardiac life support, CPR: Cardiopulmonary resuscitation.
*Shock defined as systolic blood pressure <90 mmHg or in need of fluids and/or vasopressors to maintain systolic blood pressure >90 mmHg.

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

Author BF has received PhD-funding by the Norwegian Air Ambu- 1. Nolan JP, Sandroni C, Bottiger BW, et al. European Resuscitation
Council and European Society of Intensive Care Medicine Guidelines
lance Foundation. All other authors declare that they have no conflict
2021: Post-resuscitation care. Resuscitation 2021;161:220–69.
of interest.
R E S U S C I T A T I O N 185 (2023) 109748 7

2. Roberts BW, Kilgannon JH, Chansky ME, et al. Multiple organ 24. Le Gall J-R, Lemeshow S, Saulnier F. A new simplified acute
dysfunction after return of spontaneous circulation in postcardiac physiology score (SAPS II) based on a European/North American
arrest syndrome. Read Online: Critical Care Medicine. Soc Crit Care multicenter study. J Am Med Assoc 1993;270:2957–63.
Med 2013;41:1492–501. 25. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related
3. Bjorck M, Koelemay M, Acosta S, et al. Editor’s Choice - Organ Failure Assessment) score to describe organ
Management of the Diseases of Mesenteric Arteries and Veins: dysfunction/failure. On behalf of the Working Group on Sepsis-
Clinical Practice Guidelines of the European Society of Vascular Related Problems of the European Society of Intensive Care
Surgery (ESVS). Eur J Vasc Endovasc Surg 2017;53:460–510. Medicine. Intensive Care Med 1996;22:707–10.
4. Früh A, Goliasch G, Wurm R, et al. Gastric regurgitation predicts 26. Jennett B, Bond M. Assessment of outcome after severe brain
neurological outcome in out-of-hospital cardiac arrest survivors. Eur damage. Lancet 1975;1:480–4.
J Intern Med 2021;83:54–7. 27. Høybye M, Stankovic N, Holmberg M, Christensen HC, Granfeldt A,
5. Schriefl C, Steininger P, Clodi C, et al. The association of early Andersen LW. In-Hospital vs. Out-of-Hospital Cardiac Arrest: Patient
diarrhea after successful resuscitation following out-of-hospital Characteristics and Survival. Resuscitation 2021;158:157–65.
cardiac arrest with neurological outcome: A retrospective 28. L’Her E, Cassaz C, Le Gal G, Cholet F, Renault A, Boles JM. Gut
observational study. Medicine (Baltimore) 2021;100:e28164. dysfunction and endoscopic lesions after out-of-hospital cardiac
6. Treskes N, Persoon AM, van Zanten ARH. Diagnostic accuracy of arrest. Resuscitation 2005;66:331–4.
novel serological biomarkers to detect acute mesenteric ischemia: a 29. Grimaldi D, Legriel S, Pichon N, et al. Ischemic injury of the upper
systematic review and meta-analysis. Intern Emerg Med gastrointestinal tract after out-of-hospital cardiac arrest: a
2017;12:821–36. prospective, multicenter study. Crit Care 2022;26:59.
7. Montagnana M, Danese E, Lippi G. Biochemical markers of acute 30. Piton G, Belon F, Cypriani B, et al. Enterocyte damage in critically ill
intestinal ischemia: possibilities and limitations. Ann Transl Med. patients is associated with shock condition and 28-day mortality. Crit
2018;6:341. Care Med 2013;41:2169–76.
8. Kanda T, Fujii H, Tani T, et al. Intestinal fatty acid-binding protein is a 31. Kastl SP, Krychtiuk KA, Lenz M, et al. Intestinal Fatty Acid Binding
useful diagnostic marker for mesenteric infarction in humans. Protein is Associated With Mortality in Patients With Acute Heart
Gastroenterology 1996;110:339–43. Failure or Cardiogenic Shock. Shock 2019;51:410–5.
9. Wurm R, Cho A, Arfsten H, et al. Non-occlusive mesenteric 32. Lieberman JM, Marks WH, Cohn S, et al. Organ failure, infection,
ischaemia in out of hospital cardiac arrest survivors. Eur Heart J and the systemic inflammatory response syndrome are associated
Acute Cardiovasc Care 2018;7:450–8. with elevated levels of urinary intestinal fatty acid binding protein:
10. Paul M, Bougouin W, Legriel S, et al. Frequency, risk factors, and study of 100 consecutive patients in a surgical intensive care unit. J
outcomes of non-occlusive mesenteric ischaemia after cardiac Trauma 1998;45:900–6.
arrest. Resuscitation 2020;157:211–8. 33. Osuka A, Kusuki H, Matsuura H, Shimizu K, Ogura H, Ueyama M.
11. Piton G, Belin N, Barrot L, et al. Enterocyte Damage: A Piece in the Acute intestinal damage following severe burn correlates with the
Puzzle of Post-Cardiac Arrest Syndrome. Shock 2015;44:438–44. development of multiple organ dysfunction syndrome: A prospective
12. Grimaldi D, Guivarch E, Neveux N, et al. Markers of intestinal injury cohort study. Burns 2017;43:824–9.
are associated with endotoxemia in successfully resuscitated 34. Stahl K, Busch M, Maschke SK, et al. A Retrospective Analysis of
patients. Resuscitation 2013;84:60–5. Nonocclusive Mesenteric Ischemia in Medical and Surgical ICU
13. Krychtiuk KA, Richter B, Lenz M, et al. Epinephrine treatment but not Patients: Clinical Data on Demography, Clinical Signs, and Survival.
time to ROSC is associated with intestinal injury in patients with J Intensive Care Med 2020;35:1162–72.
cardiac arrest. Resuscitation 2020;155:32–8. 35. Grimaldi D, Sauneuf B, Guivarch E, et al. High Level of Endotoxemia
14. Meng M, Klingensmith NJ, Coopersmith CM. New insights into the Following Out-of-Hospital Cardiac Arrest Is Associated With Severity
gut as the driver of critical illness and organ failure. Curr Opin Crit and Duration of Postcardiac Arrest Shock. Crit Care Med
Care 2017;23:143–8. 2015;43:2597–604.
15. Reintam Blaser A, Preiser JC, Fruhwald S, et al. Gastrointestinal 36. Ma Y, Zabell T, Creasy A, et al. Gut Ischemia Reperfusion Injury
dysfunction in the critically ill: a systematic scoping review and Induces Lung Inflammation via Mesenteric Lymph-Mediated
research agenda proposed by the Section of Metabolism, Neutrophil Activation. Front Immunol 2020;11 586685.
Endocrinology and Nutrition of the European Society of Intensive 37. Yi J, Slaughter A, Kotter CV, et al. A “Clean Case” of Systemic Injury:
Care Medicine. Crit Care 2020;24:224. Mesenteric Lymph after Hemorrhagic Shock Elicits a Sterile
16. Langeland H, Bergum D, Loberg M, et al. Characteristics of Inflammatory Response. Shock 2015;44:336–40.
circulatory failure after out-of-hospital cardiac arrest: a prospective 38. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial DAMPs
cohort study. Open Heart 2022:9. cause inflammatory responses to injury. Nature 2010;464:104–7.
17. Langeland H, Kristian Damas J, Eirik Mollnes T, et al. The inflammatory 39. Kitai T, Kim YH, Kiefer K, et al. Circulating intestinal fatty acid-binding
response is related to circulatory failure after out-of-hospital cardiac protein (I-FABP) levels in acute decompensated heart failure. Clin
arrest: a prospective cohort study. Resuscitation 2021. Biochem 2017;50:491–5.
18. Langeland H, Bergum D, Nordseth T, et al. Circulatory trajectories 40. Habes QLM, van Ede L, Gerretsen J, Kox M, Pickkers P.
after out-of-hospital cardiac arrest: a prospective cohort study. BMC Norepinephrine Contributes to Enterocyte Damage in Septic Shock
Anesthesiol 2021;21:219. Patients: A Prospective Cohort Study. Shock 2018;49:137–43.
19. Langeland H, Bergum D, Løberg M, et al. Transitions Between 41. Sekino M, Funaoka H, Sato S, et al. Intestinal fatty acid-binding
Circulatory States After Out-of-Hospital Cardiac Arrest: Protocol for an protein level as a predictor of 28-day mortality and bowel ischemia in
Observational, Prospective Cohort Study. JMIR Res Protoc 2018;7:e17. patients with septic shock: A preliminary study. J Crit Care
20. Perkins Gavin D, Jacobs Ian G, Nadkarni Vinay M, et al. Cardiac 2017;42:92–100.
Arrest and Cardiopulmonary Resuscitation Outcome Reports: 42. Timmermans K, Sir Ö, Kox M, et al. Circulating iFABP Levels as a
Update of the Utstein Resuscitation Registry Templates for Out-of- marker of intestinal damage in trauma patients. Shock
Hospital Cardiac Arrest. Circulation 2015;132:1286–300. 2015;43:117–20.
21. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a 43. Blaser A, Padar M, Tang J, Dutton J, Forbes A. Citrulline and
combined comorbidity index. J Clin Epidemiol 1994;47:1245–51. intestinal fatty acid-binding protein as biomarkers for gastrointestinal
22. Bernard G. The brussels score. Dordrecht; 1997. p. 43-4. dysfunction in the critically ill. Anaesthesiol Intensive Ther
23. Teasdale G, Jennett B. Assessment of coma and impaired 2019;51:230–9.
consciousness. A practical scale. Lancet 1974;2:81–4.

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