Gastrointestinal failure affects outcome of intensive care

Accepted Manuscript Gastrointestinal failure affects outcome of intensive care

Martin Padar, Joel Starkopf, Gerli Uusvel, Annika Reintam Blaser PII: DOI: Reference:

S0883-9441(18)31801-X https://doi.org/10.1016/j.jcrc.2019.04.001 YJCRC 53226

To appear in:

Journal of Critical Care

Please cite this article as: M. Padar, J. Starkopf, G. Uusvel, et al., Gastrointestinal failure affects outcome of intensive care, Journal of Critical Care, https://doi.org/10.1016/ j.jcrc.2019.04.001

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ACCEPTED MANUSCRIPT Title Gastrointestinal failure affects outcome of intensive care Author names and affiliations Martin Padara,b – [email protected]; corresponding author Joel Starkopfa,b – [email protected]

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Gerli Uusvel b – [email protected] Annika Reintam Blasera,c – [email protected]

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a – Department of Anaesthesiology and Intensive Care, University of Tartu, 50406 Tartu, Estonia b – Department of Anaesthesiology and Intensive Care, Tartu University Hospital, L. Puusepa 8, 50406 Tartu, Estonia

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c – Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, Lucerne Cantonal Hospital, Spitalstrasse, 6000 Lucerne, Switzerland

ACCEPTED MANUSCRIPT Abstract

Purpose. Goal of this study was to describe incidence and outcome of gastrointestinal failure (GIF) in ICU patients, evaluate its additive role to SOFA score in mortality prediction and describe GIF according to etiology.

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Materials and methods. A retrospective study with prospective data collection was conducted in mixed adult ICU patients admitted 2004-2015. GIF was considered present if ≥ 3 of following 6 symptoms occurred in one day: maximum gastric residual volume ≥ 500 mL; absent bowel sounds; vomiting or regurgitation; diarrhea; suspected or radiologically confirmed bowel distension; gastrointestinal bleeding. Division into primary (gastrointestinal pathology causing GIF) and secondary (due to other conditions) GIF was made based on origin of syndrome.

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Results. GIF developed in 413 (10.4%) of 3959 patients. Primary GIF occurred in 61.3% and secondary GIF in 38.7% of patients. Development of GIF was associated with longer mechanical ventilation, ICU stay and higher ICU, 30-day and 90-day mortality. Outcomes of patients with primary and secondary GIF were similar. All SOFA sub-scores and number of gastrointestinal symptoms on admission day independently predicted 90-day mortality.

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Conclusions. Gastrointestinal failure, independent of origin, is associated with worse ICU outcome. Similar to other organ failures included in SOFA score, GIF independently predicts mortality.

Keywords

Funding

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Gastrointestinal failure, gastrointestinal dysfunction, gastrointestinal symptoms, intensive care, critically ill

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This study was funded with an institutional grant from the Ministry of Education and Research of Estonia (IUT34-24).

ACCEPTED MANUSCRIPT Introduction Gastrointestinal (GI) dysfunction is common in intensive care patients and related to worse outcomes, regardless of exact definition [1-4]. However, previous definitions are not well validated and have not yielded a readily applicable graded severity score [5]. Widely used organ dysfunction scores, such as the Sequential Organ Failure Assessment (SOFA) score [6], do not take GI system into account.

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In clinical practice, GI dysfunction is mainly assessed by clinical observation of different GI symptoms and measurement of gastric residual volumes (GRV). Attempts have been made to include these into scoring systems to predict patient outcome. A previous prospective multicentre study showed that a higher number of GI symptoms as well as presence of gastrointestinal failure (GIF), defined as 3 or more concomitant GI symptoms, on admission to ICU were independent predictors of mortality. However, score that could significantly improve mortality prediction of SOFA could not be developed. [4] Authors of that study underline important limitations of their dataset (selected patients with low number of patients per site).

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The main goal of this study was to describe the incidence and outcome of gastrointestinal failure in consecutive ICU patients and evaluate its possible additive role in mortality prediction of the SOFA score. Further, we aimed to describe GIF according to etiology differentiating primary and secondary GIF. We hypothesized that similar to different origins of intra-abdominal hypertension [7] secondary GIF is associated with worse outcome than primary GIF.

ACCEPTED MANUSCRIPT Materials and methods General

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A single-centre, retrospective study with prospective data collection was conducted. The 1st Intensive Care Unit of Tartu University Hospital is a 10-bed mixed medical-surgical ICU, offering tertiary level care to predominantly adult patients. All adult patients, readmissions included, admitted to the study unit in 2004 – 2015 were included in the study. For the analyses, prospectively collected data from a local electronic patient database were used. Mortality data were retrieved from the national Population Register. Ethics

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The study was approved by the Research Ethics Committee of the University of Tartu with waived informed consent (permit no. 264/T-4).

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Definitions

Gastrointestinal symptoms were defined and assessed as follows:

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1. Absent bowel sounds – Bowel sounds were not heard on auscultation, assessed by a senior intensive care physician in a non-protocolized manner. 2. Bowel distension – either suspected clinically or confirmed radiologically in any bowel segment. 3. Vomiting – visible vomiting or regurgitation in any amount. 4. Gastrointestinal bleeding – a visible amount of blood in stomach contents or stool. 5. Diarrhoea – the occurrence of liquid stool more than 3 times in a day. 6. High gastric residual volumes (GRV) – a total daily volume greater than 500 mL (GRV measurement described in detail later).

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The sum of GI symptoms signifies the number of symptoms present in one day. Gastrointestinal failure was considered present if a patient experienced 3 or more GI symptoms in one day. Primary GIF was defined as GIF occurring in a patient with a primary GI pathology (including oesophageal, gastric, hepatic, pancreatic, gallbladder, small and large intestine sites of illness, trauma or surgery) and secondary GIF in a patient without primary GI pathology, occurring secondary to some other pathology.

Sepsis was defined as confirmed or suspected infection, and at least two systemic inflammatory response syndrome criteria, i.e. any two of the following: temperature >38°C or <36°C; heart rate >90 beats/min; respiratory rate >20 breaths/min, PaCO2 < 32 mmHg or mechanically ventilated; white cell count >12,000 cells/mm3, <4,000 cells/mm3 or with >10% immature (band) forms. Severe sepsis was defined as sepsis with at least 1 organ failure. Septic shock was defined as sepsis-induced hypotension persisting despite adequate fluid replacement, requiring the initiation of vasopressor therapy. [8]

ACCEPTED MANUSCRIPT The diagnostic category was defined as surgical or medical according to diagnoses at ICU admission. Admission characteristics and outcome variables

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Patient characteristics included the number of patients, age, sex, BMI, diagnostic category, abdominal or other surgery, presence or absence of sepsis, severe sepsis or septic shock, Acute Physiology and Chronic Health Evaluation II (APACHE II)[9] and SOFA scores, vasopressor or inotrope treatment and mechanical ventilation (MV) on the day of ICU admission. Outcome variables were length of ICU stay and MV; ICU, 30- and 90-day mortality.

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GRV measurement

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Intra-abdominal pressure (IAP) measurement

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To measure gastric residual volume (GRV), enteral feeding was stopped, and the nasogastric tube was held closed for 30 minutes. The tube was then opened and remained open for 30 minutes with a collection bag mounted to the bed well under the level of the stomach, allowing for the free flow of gastric content. Evacuated content was discarded. Initially, after starting enteral nutrition (EN), GRV measurements were performed every 6 hours. Further measurements were made every 12 hours, if two consecutive measurements had yielded less than 200 mL. Total amount of GRV per day was documented.

Statistical methods

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IAP was recorded daily in selected patients who were considered at risk for intra-abdominal hypertension (IAH) according to local routine. In those patients, IAP was measured intermittently every 6 to 12 hours with a pressure measurement technique in accordance with the clinical practice guidelines of the World Society of the Abdominal Compartment Syndrome [10]. IAH grades were defined as follows: grade I – IAP 12-15 mmHg; grade II – 1620 mmHg; grade III – 21-25 mmHg; grade IV – >25 mmHg.

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Categorical variables were compared using chi-square or Fisher’s exact test. Normality of distribution for continuous variables was evaluated by Kolmogorov-Smirnov test. Continuous variables are described as median and inter-quartile range if not stated otherwise. Comparisons of continuous variables were performed using the independent samples median test. As we aimed to compare a set of GI symptoms as a descriptor of dysfunction of GI system to assessment of dysfunction of other organ systems, we chose to use regression models with SOFA sub-scores and GI symptoms. Prediction of mortality of our study population was not an aim per se. Logistic regression analyses were performed to identify whether the number of GI symptoms predicted mortality independently and together with the SOFA sub-scores. Nagelkerke R Square test was used to evaluate the power of the prediction models. Kaplan-Meier curve and log-rank test was used to compare survival of patients with and without GIF.

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Data were analysed using SPSS software (IBM SPSS Statistics for Windows, Version 23.0. 2015, Armonk, NY: IBM Corp).

ACCEPTED MANUSCRIPT Results

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3959 patients were included in the study. On admission day, more than 80% of patients were mechanically ventilated. Sepsis, severe sepsis or septic shock were present in 30% of patients. 46% of patients were of surgical profile and 17% had undergone gastrointestinal surgery. Median SOFA and APACHE II scores were 6 (IQR 4-10) and 14 (IQR 9-21) on admission day, respectively. Complete data of admission day characteristics is shown in Table 1. Overall prevalence of sepsis was 34.1% (including severe sepsis 3.3% and septic shock 24.8%).

GIF vs no GIF

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GIF developed in 413 (10.4%) of all patients at some time during their ICU stay and was present on the day of ICU admission in 181 (4.5%) patients. Patients with GIF were older and more frequently male than those without GIF. Patients with GIF were more severely ill on admission day to ICU, demonstrated by higher SOFA and APACHE II scores. Those developing GIF were more often admitted with a surgical diagnosis and after gastrointestinal surgery.

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Patients with GIF stayed in the ICU longer and experienced a longer period of mechanical ventilation. ICU mortality, and mortality at 30 and 90 days was also higher in patients that developed GIF. Complete comparison is shown in Table 1. Overall prevalence of sepsis was 61.1% (including severe sepsis 12.6%, septic shock 39.6%) in patients with GIF and 31.0% (severe sepsis 2.5%, septic shock 23.1%) in patients without GIF (P < 0,001 for all).

Primary vs secondary GIF

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GIF with a primary, gastrointestinal etiology occurred in 253 (61.3%) patients, while non-GI pathology lead to GIF in 160 (38.7%) patients. Admission diagnosis of patients with primary GIF was gastrointestinal in 47.0%, peritonitis and pancreatitis in 16.2% each and oncological in 5.1% of patients. Other diagnostic groups underlying primary GIF included: polytrauma, infection, intoxication, post-reanimaton state, vascular, respiratory, renal and other pathologies. For patients with secondary GIF, most common admission diagnoses were cardiovascular (21.3%), intoxication (11.4%), post-reanimation state (10.8%) and pulmonological or nephrological/urological (both 10.1%). Other diagnostic groups underlying secondary GIF were polytrauma, infections, physical causes (hypo- and hyperthermia etc), neurological, orthopaedic, oncological, ENT or maxillofacial surgical, gastroenterological and other pathologies. There was no difference in age between the groups, but patients with secondary GIF were more frequently male. On the day of admission to ICU, patients developing secondary GIF were more severely ill than those who developed primary GIF according to higher presence septic shock, higher lactate levels and fluid gain on admission day as well as higher median SOFA and APACHE II scores. Patients developing primary GIF

ACCEPTED MANUSCRIPT were more frequently of surgical profile (68.8 vs 45.6%; p < 0,001) and 140 (55.3%) of them had gastrointestinal surgery. Overall prevalence of sepsis was 64.0% (including severe sepsis 13.7%, septic shock 44.4%) in patients with primary GIF and 56.6% (severe sepsis 11.1%, septic shock 32.1%) in those with secondary GIF (P < 0,05 for septic shock only). There were no differences in outcomes between patients with primary vs secondary GIF. Complete comparison of patients developing primary and secondary GIF is shown in Table 2.

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Gastrointestinal symptoms

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The maximal number of GI symptoms experienced by patients was 4 on admission day and 6 during whole stay. During the first week in ICU, patients with primary GIF experienced more gastrointestinal symptoms than those with secondary GIF on days 1, 3 and 4. (Figure 1). Cumulative incidence of primary vs seconday GIF is shown in Figure 2, with cases of primary GIF occurring more often in the first 8 days.

Intra-abdominal hypertension

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Outcome prediction

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IAP was measured in 46.3% of all patients. When GIF was present on the day of admission, IAP measurement was instituted in 88.5% of primary and 64.4% of secondary GIF cases. For all cases of GIF, IAP was measured in 86.2% of cases and measurement rates for primary and secondary GIF were 90.9% and 78.7%, respectively. IAH was detected in 22.3% of patients: 59.3% of those with GIF and in 17.9% of those not developing GIF. Occurrences of IAH in patients experiencing primary or secondary GIF at any time, were 65.6% and 49.4%, respectively. IAP values > 20 mmHg (grades III and IV) were measured in 23 patients (9.1%) with primary GIF and 6 patients (3.7%) with secondary GIF.

A higher number of gastrointestinal symptoms on the day of ICU admission was associated with longer ICU stay, longer mechanical ventilation and increased mortality (Table 3). The differences were significant in all outcomes between the groups in growing order, except mortality did not differ in patients presenting with 1 vs 2 GI symptoms on the day of ICU admission (Table 3). Cumulative survival of patients with and without GIF are presented in Figure 3, where the two survival curves split during the first week after ICU admission demonstrating higher mortality in patients with GIF. In our model of logistic regression analysis, all admission day SOFA sub-scores and number of concomitant GI symptoms independently predicted 90-day mortality. When added to SOFA score, a higher number of GI symptoms on admission day improved the predictive value of the former. (Table 4)

ACCEPTED MANUSCRIPT Discussion

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This study demonstrated that gastrointestinal failure, defined as concomitant occurrence of ≥ 3 gastrointestinal symptoms, is relatively frequent in a mixed ICU population, taking place in one tenth of patients. Presence of GI symptoms on the day of admission to ICU is associated with worse outcomes. A higher number of GI symptoms on admission day independently predicts mortality. When added to SOFA score, a GI dysfunction sub-score based on the number of symptoms improves mortality prediction.

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The incidence of GI failure in ICU patients ranges from 2.6 – 13.6% in previous studies [2– 4,11], though various definitions have been used. In a single centre study demonstrating a 2.6% incidence, GIF was defined as GI bleeding requiring significant transfusion [11]. This low incidence could be attributed to the fact that overt GI bleeding is rare in ICU patients . Also, the study population was mostly elective cardiac surgery patients with few patients admitted with acute abdominal pathologies. A prospective multicentre study the first time proposing a definition of GIF as ≥3 concomitant GI symptoms observed an incidence of 6.4% [4]. Compared to our population, patients in that study were more severely ill according to SOFA and APACHE II scores on admission and ICU mortality (31 vs 20%). Therefore, the difference in GIF incidence could not be attributed to GIF occurring together with other organ failures or an overall higher illness severity. Their cohort also had more surgical, including abdominal surgery patients, in whom a higher incidence of GI symptoms and GIF could be expected. This, together with our findings may actually suggest that a significant part of cases of GIF occur later in the course of critical illness after survival from the acute pathology which necessitated ICU admission. Around one fifth of our GIF cases occurred beyond the first week. Most importantly, we included all consecutive patients admitted, which was not the case in the previous multicentre study [4].

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Our distinction of primary and secondary GIF is in keeping with the terminology suggested to distinguish types of acute gastrointestinal injury (AGI) by the Working Group on Abdominal Problems of the European Society of Intensive Care Medicine [12]. In our study, about 2/3 of cases of GIF were of primary origin. Primary GIF was mostly observed in surgical patients, half of them having had an operation on GI tract. Secondary GIF developed in patients with various pathologies, mostly of medical category. These patients were more severely ill on the day of admission (higher SOFA and APACHE II scores and lactate levels). Mortality at different time points was consistently higher in the secondary GIF group, but with no statistical significance. Interestingly, septic shock, usually associated with higher mortality, was significantly more frequent on admission in patients that had or developed primary GIF (38 vs 26%). Zhang et al recently reported that patients with secondary AGI were older, had more comorbidities and a higher 28-day mortality compared to primary AGI, whereas the overall prevalence of AGI was not reported [13]. Similarly to our previous observations regarding primary and secondary IAH [7] we hypothesize that if abdominal sepsis is immediately and efficiently treated, the outcome is better compared to cases where source control is less efficient. Of note, during the study period Sepsis-3 definitons [14] were not yet available, and previous definition was used during prospective data collection [8].

ACCEPTED MANUSCRIPT Some similarities exist with results of a study by Zhang et al, looking at clinical characteristics and prognosis of patients with primary or secondary AGI [14]. General ICU population is not described in the study and thus, overall prevalence of AGI is not known. However, patients with GIF in our current study and those with AGI in the study by Zhang et al are comparable regarding age, gender mix and SOFA and APACHE II scores on admission to ICU. Patients with secondary AGI were older, had more comorbidities and had a higher 28-day mortality. These results are somewhat in line with ours, highlighting that GIF caused by a primary insult may respond better to therapeutic or surgical interventions.

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Patients with primary GIF have more GI symptoms in the first days of ICU stay, possibly making primary GIF more evident in its clinical presentation. Also, a higher proportion of all cases of primary GIF occur during the first week, in closer temporal connection to the pathology that necessitated ICU admission. However, for both primary and secondary GIF a significant part, about 1/5 of all cases, takes place later.

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Intra-abdominal pressure was measured in nearly half of all patients at some time during their stay. In those with GIF, IAP was measured in a great majority of cases, especially when GIF was caused by a GI pathology. IAH occurred in 22% of patients, a rate similar to the previously observed 20-40% in ICU patients [15]. However, about two thirds of patients with primary GIF and half of those with secondary GIF developed IAH at some time during ICU stay. Even though IAP was frequently measured in patients with GIF in our population, it must be kept in mind that these are patients demonstrating 3 or more GI symptoms in the same day, a clinically evident problem. It can be reasoned that IAP measurements, if possible, should be routine in such patients as the possibility of IAH is high. Many cases of IAH may have been missed, especially in patients with secondary GIF.

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A higher number of simultaneous GI symptoms was associated with worse outcomes including mortality, as also demonstrated in earlier research [4]. The presence of GIF on the day of admission was associated with a near 50% mortality at 30 days. In our population, all SOFA sub-scores performed well, independently predicting mortality in our regression model. A five-grade organ failure score, similar to SOFA sub-scores, could be formed for the GI tract, using 0-4 symptoms as stages of dysfunction. Addition of this score Addition of the number of GI symptoms as a seventh variable to SOFA slightly improved mortality prediction of the latter. This study again highlights that GI problems in ICU patients translate into worse outcomes, irrespective of cause. However, subjectivity in assessment and different nature of GI symptoms most likely resulting in different impact on outcome makes any scoring system based solely on GI symptoms imprecise. However, subjectivity in assessment of GI symptoms makes such kind of scoring system imprecise and search for a more reliable scoring system (e.g. including biomarkers) of GI function needs to continue. Importantly, GI symptoms used in our study are fairly different and their impact outcome is most likely of different magnitude. In fact, several of the symptoms used in current study have been criticized and it has been suggested to omit using assessment of peristalsis and GRVs in daily practice [1618]. Whereas we fully agree that absent peristalsis should not lead to withholding of EN, assessment of peristalsis together with other GI symptoms may still help to gain a very rough

ACCEPTED MANUSCRIPT estimation of GI dysfunction, with current study confirming the findings of previous research [12,19]. Similarly, measuring GRVs to guide fully established EN [16] is most likely obsolete, but GRV may still have a role in assessing GI dysfunction in patients not yet tolerating full EN. Taken together, awaiting further developments in this area, GI symptoms still remain the main tool to assess GI dysfunction in daily practice. Moreover, future scores may also consider including GI symptoms as a trigger for more precise but also more costly diagnostics for GI dysfunction.

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Strengths of this study are a considerably large patient population including all consecutive patients and prospective data collection with emphasis on gastrointestinal signs and symptoms. Some limitations should be noted. First, a single centre design in a mixed ICU decreases the generalizability of results. Second, a long time span needed to acquire this number of patients in one study centre also carries a possibility of practice changes, which may influence patient outcomes. Third, the problem of subjectivity remains when using only symptoms to define gastrointestinal failure.

ACCEPTED MANUSCRIPT Conclusions

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Gastrointestinal failure, defined based on presence of GI symptoms, is associated with worse ICU and 90 days outcome. This effect is independent of whether GIF occurred due to primary GI pathology or was of secondary origin. Similar to other organ failures included in the SOFA score, GIF independently predicts mortality.

ACCEPTED MANUSCRIPT References

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[1] Chang RWS, Jacobs S, Lee B. Gastrointestinal dysfunction among intensive care unit patients. Crit Care Med 1987; 15:909–914. DOI: 10.1097/00003246-19871000000003 [2] Reintam A, Parm P, Redlich U, et al. Gastrointestinal failure in intensive care: a retrospective clinical study in three different intensive care units in Germany and Estonia. BMC Gastroenterol 2006; 6:19. DOI: 10.1186/1471-230X-6-19 [3] Reintam A, Parm P, Kitus R, et al. Gastrointestinal failure score in critically ill patients: a prospective observational study. Crit Care 2008; 12:R90. DOI: 10.1186/cc6958 [4] Reintam Blaser A, Poeze M, Malbrain ML, et al. Gastrointestinal symptoms during the first week of intensive care are associated with poor outcome: a prospective multicentre study. Intensive Care Med 2013; 39:899–909. DOI: 10.1007/s00134-013-2831-1 [5] Reintam Blaser A, Jakob SM, Starkopf J. Gastrointestinal failure in the ICU. Curr Opin Crit Care. 2016 Apr; 22(2):128-41. DOI: 10.1097/MCC.0000000000000286 [6] Vincent JL, de Mendonça A, Cantraine F, Moreno R, Takala J, Suter PM, Sprung CL, Colardyn F, Blecher S. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine. Crit Care Med 1998; 26(11):1793-800. DOI: 10.1097/00003246-19981100000016 [7] Reintam A, Parm P, Kitus R, Kern H, Starkopf J. Primary and secondary intra-abdominal hypertension--different impact on ICU outcome. Intensive Care Med 2008 Sep;34(9):1624-31. DOI: 10.1007/s00134-008-1134-4 [8] Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250-6. DOI: 10.1097/01.CCM.0000050454.01978.3B [9] Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 13 (10): 818–29. DOI:10.1097/00003246198510000-00009 [10] Kirkpatrick AW, Roberts DJ, De Waele J, Jaeschke R, Malbrain ML, De Keulenaer B, Duchesne J, Bjorck M, Leppaniemi A, Ejike JC, Sugrue M, Cheatham M, Ivatury R, Ball CG, Reintam Blaser A, Regli A, Balogh ZJ, D'Amours S, Debergh D, Kaplan M, Kimball E, Olvera C; Pediatric Guidelines Sub-Committee for the World Society of the Abdominal Compartment Syndrome. Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome. Intensive Care Med. 2013 Jul;39(7):1190-206. DOI: 10.1007/s00134-013-2906-z [11] Mayr VD, Duenser MW, Greil V, et al. Causes and determinants of outcome in critically ill patients. Crit Care 2006; 10:R14. DOI: 10.1186/cc5086 [12] Reintam Blaser A, Malbrain ML, Starkopf J, et al. Gastrointestinal function in intensive care patients: terminology, definitions and management. Recommendations of the

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ESICM Working Group on Abdominal Problems. Intensive Care Med. 2012 Mar; 38(3): 384–394. DOI: 10.1007/s00134-011-2459-y [13] Zhang D, Fu R, Li Y, et al. Comparison of the clinical characteristics and prognosis of primary versus secondary acute gastrointestinal injury in critically ill patients. J Intensive Care. 2017; 5: 26. DOI: 10.1186/s40560-017-0221-4 [14] Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. DOI:10.1001/jama.2016.0287 [15] Starkopf J, Tamme K, Reintam Blaser A. Should we measure intra-abdominal pressures in every intensive care patient? Ann Intensive Care. 2012; 2(Suppl 1): S9. DOI: 10.1186/2110-5820-2-S1-S9 [16] Reignier J, Mercier E, Le Gouge A, Boulain T, Desachy A, Bellec F, et al. Effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: A randomized controlled trial. JAMA. 2013;309:249–56. DOI: 10.1001/jama.2012.196377 [17] Read TE, Brozovich M, Andujar JE, Ricciardi R, Caushaj PF. Bowel Sounds Are Not Associated With Flatus, Bowel Movement, or Tolerance of Oral Intake in Patients After Major Abdominal Surgery. Dis Colon Rectum. 2017 Jun;60(6):608-613. DOI: 10.1097/DCR.0000000000000829. [18] Felder S, Margel D, Murrell Z, Fleshner P. Usefulness of bowel sound auscultation: a prospective evaluation. J Surg Educ. 2014 Sep-Oct;71(5):768-73. doi: 10.1016/j.jsurg.2014.02.003. Epub 2014 Apr 24. DOI: 10.1016/j.jsurg.2014.02.003 [19] Reintam A , Parm P, Kitus R, Kern H, Starkopf J. Gastrointestinal symptoms in intensive care patients. Acta Anaesthesiol Scand. 2009 Mar;53(3):318-24. DOI: 10.1111/j.1399-6576.2008.01860.x.

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Table 1. Admission day characteristics and outcome data. No GIF

GIF

No of patients (%) Male gender, no of pt (%)

3959 (100) 2362 (59.7)

3546 (89.6) 2063 (58.2)

413 (10.4) 299 (72.4)

Age, years; median (range) Body mass index, kg/m2 Readmission, no of pt (%) APACHE II score, points

60 (18-98) 26 (23-30) 159 (4.0) 14 (9-21)

60 (18-98) 26 (23-29) 146 (4.1) 14 (8-21)

64 (18-92) 26 (23-31) 13 (3.2) 16 (11-23)

6 (4-10)

6 (3-9)

8 (6-11)

3235 (81.7)

2849 (80.3)

386 (93.4)

9 (6-12)

11 (8-14)

9 (6-12)

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Intra-abdominal pressure, mmHg

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Mechanical ventilation, no of pt (%)

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SOFA score, points

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All patients

70 (61-80)

71 (62-81)

66 (57-76)

2.6 (1.5-5.5)

2.5 (1.4-5.3)

3.4 (1.9-6.8)

Surgical profile, no of pt (%)

1815 (45.8)

1568 (44.2)

247 (59.8)

667 (16.8)

527 (14.9)

140 (33.9)

Vasopressor/inotrope, no of pt (%)

1453 (5002817) 2801 (70.8)

1326 (4302550) 2417 (68.2)

2975 (14305085) 384 (93.0)

Enteral feeding, no of pt (%)

1147 (29.0)

1087 (30.7)

60 (14.5)

226 (5.8)

184 (5.3)

42 (10.3)

Severe sepsis, no of pt (%)

89 (2.3)

65 (1.9)

24 (5.9)

Septic shock, no of pt (%)

879 (22.6)

744 (21.4)

135 (33.2)

Any sepsis, no of pt (%)

1194 (30.7)

993 (28.5)

201 (49.4)

ICU stay, days

4 (2-10)

4 (2-8)

11 (5-25)

Mechanical ventilation, days

2 (1-7)

2 (1-6)

9 (3-21)

ICU mortality, no of pt (%)

775 (19.6)

631 (17.8)

144 (34.9)

30 days mortality, no of pt (%)

1094 (27.8)

932 (26.5)

162 (39.6)

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Sepsis, no of pt (%)

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Gastrointestinal surgery, no of pt (%) Fluid gain in first 24 h, mL

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Abdominal perfusion pressure, mmHg Lactate, mmol/L

P value < 0.001 0.014 0.026 0.426 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001

ACCEPTED MANUSCRIPT 90 days mortality, no of pt (%)

1335 (33.9)

1132 (32.1)

203 (49.6)

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Note: Values provided are median (IQR), if not stated otherwise

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ACCEPTED MANUSCRIPT Table 2. Admission day characteristics and outcome data: primary vs secondary GIF.

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ICU stay, days Mechanical ventilation, days ICU mortality, no of pt (%) 30 days mortality, no of pt (%) 90 days mortality, no of pt (%)

10 (4-25) 8 (3-22) 82 (32.6) 92 (36.8) 116 (46.4)

P value

11 (5-26) 9 (4-21) 62 (38.7) 70 (44.0) 87 (54.7)

0.447 0.314 0.205 0.148 0.106

PT

Secondary GIF 160 (38.7) 130 (81.3) 64 (18-86) 26 (23-31) 1 (0.6) 20 (14-26) 9.5 (7-12) 149 (93.1) 11 (7-14) 68 (59-77) 3.9 (2.1-7.8) 73 (45.6) 0 2311 (1000-4968) 149 (93.1) 40 (25) 68 (42.80.7) 21 (13.2) 5 (3.1) 42 (26.4)

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No of patients (%) Male gender, no of pt (%) Age, years; median (range) Body mass index, kg/m2 Readmission, no of pt (%) APACHE II score, points SOFA score, points Mechanical ventilation, no of pt (%) Intra-abdominal pressure, mmHg Abdominal perfusion pressure, mmHg Lactate, mmol/L Surgical profile, no of pt (%) Gastrointestinal surgery, no of pt (%) Fluid gain in first 24 h, mL Vasopressor/inotrope, no of pt (%) Enteral feeding, no of pt (%) Any sepsis, no of pt (%) Sepsis, no of pt (%) Severe sepsis, no of pt (%) Septic shock, no of pt (%)

Primary GIF 253 (61.3) 169 (66.8) 63 (18-92) 27 (23-31) 12 (4.7) 14 (10-19) 7 (5-10) 237 (93.7) 11 (8-15) 65 (55-75) 3.1 (1.9-6.1) 174 (68.8) 140 (55.3) 3345 (1770-5125) 235 (92.9) 20 (7.9) 133 (53.6) 21 (8.5) 19 (7.7) 93 (37.5)

0.002 0.225 0.574 0.02 < 0.001 < 0.001 0.840 0.220 0.125 0.026 < 0.001 < 0.001 0.026 1,000 < 0.001 0.034 0.135 0.083 0.023

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Note: Values provided are median (IQR), if not stated otherwise. GIF gastrointestinal failure; APACHE acute physiology and chronic health evaluation; SOFA sequential organ failure assessment.

ACCEPTED MANUSCRIPT

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Figure 1.

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Caption: Primary vs secondary GIF: mean number of GI symptoms with 95% confidence intervals. GI gastrointestinal; GIF gastrointestinal failure.

ACCEPTED MANUSCRIPT Figure 2.

90% 80%

*

70%

*

*

4

5

*

*

*

*

60% 50%

*

PT

40%

30% 20%

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Cumulative percent of all cases

100%

10% 2

3

6

7 8 Day in ICU

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1

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0%

* P < 0.05

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Primary GIF

9

10

11

12

13

Secondary GIF

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Caption: Primary vs secondary GIF: cumulative incidence. GIF gastrointestinal failure.

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ACCEPTED MANUSCRIPT Table 3. Gastrointestinal symptoms on admission day and outcome. P-value

0

1

2

≥ 3 = GIF

GIF vs no GIF on day 1

Number of patients (%)

3959 (100)

2026 (51.2)

1361 (34.4)

391 (9.9)

181 (4.5)

-

MV, days; median (IQR)

2 (1-7)

1 (1-5)

3 (1-9)

4 (1-9)

4 (1-11)

< 0.001

ICU stay, days; median (IQR)

4 (2-10)

3 (2-8)

5 (2-11)

6 (2-12)

5 (2-12)

0.024

ICU mortality (%)

19.6

8.9

30.1

28.5

41.4

< 0.001

30-day mortality (%)

27.8

17.7

37.4

37.7

47.8

< 0.001

90-day mortality (%)

33.9

23.1

43.6

47.0

54.4

< 0.001

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All patients

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Number of GI symptoms on admission day

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Note: The differences were significant in all outcomes between the groups in growing order, except mortality at different time points did not differ in patients presenting with 1 vs 2 GI symptoms. GI gastrointestinal; GIF gastrointestinal failure.

ACCEPTED MANUSCRIPT

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Figure 3

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Caption: Survival: GIF vs no GIF. GIF gastrointestinal failure.

ACCEPTED MANUSCRIPT Table 4. SOFA sub-scores and number of GI symptoms Regression analysis for 90-day mortality Lower CI 95%

Upper CI 95%

Pvalue

SOFA respiratory

1.089

1.010

1.174

0.026

SOFA haematologic

1.184

1.096

1.278

< 0.001

SOFA hepatic

1.172

1.070

1.283

SOFA cardiovascular

1.446

1.361

1.535

SOFA neurological

1.443

1.375

SOFA renal

1.348

1.282

Number of GI symptoms

1.322

1.208

PT

OR

0.001

Nagelkerke R Squared for model

0.319 0.329

< 0.001

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SC 1.514

< 0.001

1.418

< 0.001

1.446

< 0.001

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Admission day variables

-

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Note: OR odds ratio; CI confidence interval; SOFA sequential organ failure assessment; GI gastrointestinal.

ACCEPTED MANUSCRIPT Highlights

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Gastrointestinal failure (GIF) was defined as presence of ≥3 GI symptoms in one day GIF occurred in 10.4% of 3959 mixed adult ICU patients GIF associated with longer mechanical ventilation, ICU stay and higher mortality No outcome difference noted in patients with different etiologies of GIF Like SOFA sub-scores, higher number of GI symptoms independently predicts mortality

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