Gastrointestinal dysmotility syndromes are quietly common in critically ill patients, especially in mechanically ventilated- medically/surgically Intensive Care Units (MV-MSICUs) admitted patients. These dysmotility syndromes are clinically manifested by daily inspections of an array of signs before these diagnoses are radiologically/non-radiologically confirmed [1]. Although GIT related dysmotilities in MV-MSICU patients are multifactorial in causing and multidimensional in manifestation, Opioids Induced Constipation (OIC) is the most alarming sound in ICU patients due to its array of manifestation signs and symptoms, including but not excluded to; constipation accompanied with an abdominal pain, slowing gastric emptying rate, elevated Gastric Residual Volume (GRV), nausea/vomiting and gastroesophageal refluxes [2,3]. 

While opioids are so quietly used in MV-MSICU patients, as best ever seen analgosedative agents, opioids related bowel dysmotility are frequently diagnosed with a multi-faceted clinical negative impacts, in particular of delaying gastric emptying, decreasing overall enteral intakes, delaying discharge propensity, hindering enterocyte functionality and integrity, increasing susceptibility to Enterobacteriaceae translocation and consequentially to GIT related sepsis and exaggerating overall ICU complications and inevitably, mortality rates [4,5].

Although a single consensus definition of OIC is yet to be elucidated and therefore inaccurately incidences assessment, its widely prevalence [reaching up to 70%-80% according to some pilot studies] and its short and long terms debilitating consequences may clinically and economically burden overall health system in any country if it isn’t early diagnosed and promptly treated [6-8].                

Three types of opioid receptors that mediate the enteric nervous system (ENS) inhibitory effects, have been profusely studied. Once morphine or other like agents agonizes opioid receptor, primarily μ-receptors, a non-propulsive contraction accompanied with sphincters hypertonicity is predominated which result in transit time prolongation and inevitably, GIT stasis and constipation [9-11].

So, prevention or antagonizing or at least mitigation this opioid negative GIT consequences are undoubtedly of value in re-establishing GIT emptying and integrity functions and consequently restoring enteral feeding, preserving enteric immunity and improving overall ICU patients’ clinical status [12-13]. Similarly, to OIC, Chronic Idiopathic Constipation (CIC) had been investigated in many studies and a consensus results concluded that soluble fibers is more effective than insoluble fiber in managing CIC [14].

Nondigestible Oligosaccharides (NDOs) occur naturally in many plants, mainly vegetables, whole grains and fruits. They can also be enzymatically synthesized from monomeric or dimeric sugars or enzymatically hydrolyzed from polysaccharides. As a rule of thumb, NDOs are broad class of indigestible, non-absorbable, while fermentable water-soluble carbohydrate-based agents with a wide range of physiological advantages, particular                      rly in enterocytes nourishment via microbiota yielding short chain fatty acids. Hence, they are biochemically classified within prebiotics family. Fructo-Oligosaccharides (FOS) and Galacto-Oligosaccharides (GOS) are the two important groups of prebiotics and since low quantities of FOS and GOS naturally exist in foods, scientists are attempting to produce them on an industrial scale [15-20].

Addressing and preventing the adverse effects of medications as common as opioids in MV-MSICUs is essential to patient care. In this study we aim to assess the daily Fructo-Oligosaccharides (FOSs) proactively supplementation effectiveness on opioid induced constipation and its related positive biochemical and clinical outcomes in MV-MSICU admitted patients.

This study trial was a single-center, non-funded and non-sponsored retrospective study, conducted in our multidisciplinary, MSICU within King Hussein Medical Hospital (KHMH) at Royal Medical Services (RMS) in Jordan for OIC affected MV-MSICU admitted patients between Jan 2018 and May 2021.

Ethical approval was signed from our Institutional Review Board (Ref #48, 9/2021) and the requirement of consent was waived owing to its retrospective design. Retrievable data were retrospectively collected from our Electronic Medical Record System (Hakeem), including but not excluded to, baseline demographics, anthropometrics, analgosedative rates, GIT related data and some nutrition indices.

This study targeted all eligible adult MV-MSICU admitted patients who were on a regular titratable morphine infusion [with or without supplemented doses of sedative agents] to keep Richmond Agitation Sedative Scale (RASS) between -2 and -1 for at least 48 hours and had reduced frequency of bowel movements accompanied with an absence of any stool evacuation in the prior 2 days while keeping our institutional protocolized bowel management care [primarily composed of actively using Glycerin 2.8 g suppositories with/without enteral polyethylene glycol 13.8 g]. Also, all our study eligible patients should be on enteral feeding or scheduled to be enterally fed via Nasogastric (NG) tube, at least on trophic feeding dose (10-20 ml/hr). 

Mechanically ventilated critically ill patients who had antibiotic or non-antibiotic associated diarrhea in the past 48 hours, radiologically confirmed mechanical or non-mechanical ileus, ileostomy or colostomy, recent gastro-intestinal surgery or active inflammatory status, gastro-residual volume (GRV) >150 ml despite prior administration of prokinetic(s) [either erythromycin or metoclopramide or both], early mortality or extubation or discharging before completing at least 7 ICU admission days and non-retrievable data were excluded from this study. 

Finally, this study was conducted on 188 Eligible OIC affected MV-MSICU patients, which were grouped to 2 comparative cohorts; OIC affected MV-MSICU patients who were on daily FOS proactively supplementation (Cohort I) and OIC affected MV-MSICU patients who were on our institutional protocolized bowel care management (Cohort II). An Independent and One Sample T-Tests were used to analyze all non-dichotomous comparative investigated variables and the analysis outcomes were expressed as Mean ± SD or Mean difference ± SEM. For dichotomous comparative variables, a Chi Square Test were used to express the comparative analysis results as Number (Percentage). Statistical analyses were performed using the IBM SPSS version. 25 (IBM Corp., Armonk, NY, USA) and p-values ≤0.05 were considered statistically significant.

This study finally included 188 eligible OIC affected MV critically ill patients admitted to our adult MSICU at KHMC/RMS/Amman/Jordan between Jan 2018 and May 2021 via the Emergency Department (ED) or via other hospital wards with any medical or surgical problem. Totally, 1967 ICU patients were excluded from our study because they had one or more of the exclusion clinical criteria during the study period. 

The mean age of the whole studied OIC affected patients was 58.94±10.37 years and Group I patients were insignificantly older than Group II patients (59.17±10.225 years versus 58.72±10.56 years, respectively, p-value = 0.764). Male patients were significantly distributed in the study in approximately 2.29: 1 ratio to female patients (131 (69.7%) versus 57 (30.3%), respectively, p-value = 0.023) in which 76.8% (73 Men) and 23.2% (22 Women) belonged to Group I compared to 42.3% (58 Men) and 37.6% (35 Women) in Group II. There were an overall 104 (55.32%) medically and 84 (44.68%) surgically ICU patients which respectively distributed to 55 (59.14%) and 38 (40.86%) in Group I versus 49 (51.58%) and 46 (48.42%) in Group II. with an odd ratio of 1.31 (95% CI; 0.62-2.79).

The overall 28-day ICU mortality was detected in 76 OIC affected MV-MSICU patients with an overall incidence rate of 40.4% during an average of 12.76±4.95 days and 17.07±6.98 days of ICU and overall hospital admission days, respectively. 

Table 1: The comparative variables of the OIC affected mechanically ventilated critically ill patients across Group I (on daily FOS proactively supplementation) and Group II (on our institutional protocolized bowel care management**).

The comparative non-dichotomous variables between Group I and Group II were statistically analyzed by Independent T- Test and the results were expressed as Mean ± SD and as Mean difference ± SEM. While the comparative variables for the total sample were analyzed by One Sample T-Test and the results were also expressed as Mean ± SD. For dichotomous data, a Chi Square Test was used to express the analysis outcomes as Number (Percentage) (at p-value< 0.05*): Group I: OIC affected MSICU patients who were on daily FOS proactively supplementation, Group II: OIC affected MSICU patients who were on our institutional protocolized bowel care management, **: Actively using Glyceri n 2.8 g suppositories with/without enteral polyethylene glycol 13.8 g. N: Number of Patients, BW: Body Weight, BMI: Body Mass Index, ICU: Intensive Care Unit, 0: Baseline, %∆: Percentage changes, CRP: C-Reactive Protein, ALB: Albumin level, CRP: ALB: CRP to ALB ratio, GRV: Gastric Residual Volume, LOS: Length of stay, 1: After intervention.

Table 2: The comparative variables of the OIC affected mechanically ventilated critically ill patients across Group I (on daily FOS proactively supplementation) and Group II (on our institutional protocolized bowel care management**).

The comparative non-dichotomous variables between Group I and Group II were statistically analyzed by Independent T- Test and the results were expressed as Mean ± SD and as Mean difference ± SEM. While the comparative variables for the total sample were analyzed by One Sample T-Test and the results were also expressed as Mean ± SD. For dichotomous data, a Chi Square Test was used to express the analysis outcomes as Number (Percentage) (at p-value< 0.05*): Group I: OIC affected MSICU patients who were on daily FOS proactively supplementation, Group II: OIC affected MSICU patients who were on our institutional protocolized bowel care management**, **: Actively using Glycerin 2.8 g suppositories with/without enteral polyethylene glycol 13.8 g, N: Number of Patients, %∆: Percentage Changes, 0: Baseline, 1: After intervention, BUN: Blood Urea Nitrogen, CCa: Corrected Calcium Level (CCa = Ca+0.8*(4-ALB)), Cal: Kcal, TCI: Total Calories Input, PD: Protein Density, K: Potassium level, BG: Blood Glucose Level, Var: Variation, Min: Minimum, Max: Maximum, Avg: Average

Cohort I patients compared to Cohort II patients, had an overall 28-day ICU mortality, ICU stay days and overall hospital admission days of 15 (15.8%), 14.59±5.20 days and 20.48±6.85 days compared to 61 (65.6%), 10.96±3.97 days and 10.96±3.97 days, respectively, P-value<0.05.

Regarding nutritional indices, Group I had a significantly higher Total Calories Input (TCI) and Protein Density Input (PDI) compared to Group II (1265.53±245.95 Cal/day and 4.85±0.71 g/100 Cal vs 1155.25±228.36 Cal/day and 3.90±0.55 g/100 Cal, respectively, p<0.05). This significantly higher Means ± SDs were conversely accompanied with significantly lower GRV and %∆GRV (150.59±7.09 ml and 7.84%±2.02% vs 181.28±6.83 ml and 21.68%±1.08%) despite the significantly higher morphine infusion rate in Group I versus Group II (3.62±0.73 mg/ hr. vs 3.23±0.14 mg/hr, respectively, +0.39±0.08 mg/dl, P-value<0.05). The mean differences ± SEMs across the two studied groups regarding the 3 tested nutritional indices were +110.28±34.60 Cal/day, +0.95±0.09 g/100 Cal, -30.69±1.02 ml and -13.84%±0.24%, respectively.

The %∆ in blood urea nitrogen (%∆BUN) was significantly lower in Group I compared with Group II (8.39%±33.24% vs 48.65%±49.87%) with Mean difference ± SEM of -40.26%±6.20%. Also, the %∆ of blood glucose variation (% BG var) and Total Daily Insulin (TDI) were significantly higher in Group I compared with Group II (55.92%±18.08% and 122.57±55.50 IU/day vs 45.21%±13.43% and 77.67±24.45 IU/day) with Mean differences ± SEMs of +10.71%±2.32% and +44.90±6.23 IU/day, respectively. There were also significantly higher %∆ALB and significantly lower %∆CRP: ALB in Group I versus Group II (45.62%±5.87% and 73.22%±25.02% vs 31.22%±4.00 and 94.84%±31.61%, respectively, p-value<0.05). There were insignificant differences in anthropometrics between the two aforementioned cohorts. The comparative variables of the OIC affected mechanically ventilated critically ill patients across Group I (on daily FOS proactively supplementation) and Group II (on our institutional protocolized bowel care management) were fully expressed in Table 1,2.

In this study, we compared two therapeutic strategies for proactively managements of OIC affected MV-MSICU admitted patients; OIC affected MV-MSICU patients managed proactively by regular enteral administration of reconstituted 1.7 grams FOS within 48 hours of morphine initiation (Group I) and OIC affected MV-MSICU patients managed actively by regular rectal administration of 2.8 grams glycerin suppositories with/without enteral administration 13.8 g PEG after morphine initiation (Group II). The uniqueness of our study, as we know, emphasized on its comparing intention regarding many issues; between proposed investigated agent and protocolized agent for bowel caring in our institution, between proactively management versus actively management, between two pre-defined cohorts using the same analgosedative agent Morphine, as the most popular used analgosedative agents in most global countries] and among mechanically ventilated, medically or surgically, admitted OIC affected critically ill patients who had complicated enteral feeding issues.

The proposed mechanism for higher GI motility and subsequently less OIC in our study is extrapolated from the observed significantly lower Mean ± SD and Mean difference ± SEM regarding %∆GRV in Group I compared to Group II. Soluble fiber has been proven effective in preventing OIC in the animal model. Soluble fiber administration prevented OIC in rats treated with morphine by increasing cecal Short-Chain Fatty Acids (SCFA) concentrations [21]. SCFA are an end product of the saccharolytic fermentation of FOS by the colonic microbiota [22-24]. The role of SCFA in stimulating colonic motility has been well established. SCFA are believed to exert their effects by increasing colonic sodium and water absorption and stimulating propulsive contractions [25–26].

The lower mortality rate in Group I compared with Group II, may be partially explained by the significantly higher PD accompanied with significantly higher TCI in Group I, as a clinical consequence of significantly higher emptying rate [indirectly extrapolated from significantly lower GRV]. The significantly lower %∆GRV in Group I versus Group II may also explain the higher peaking of Blood Glucose Level (BG max) in Group I and hence, the higher insulin requirement, compared with Group II. Additionally, the significantly lower %∆BUN in Group I, despite dual significantly higher PD and CRP, may be attributed to the anti-catabolic effects of Insulin [27].

In conclusion, our study showed that the investigated soluble fiber, in the form of FOS 1.7 gram/30 ml, may be an innovative strategy in mitigation of an opioid analgosedative related inevitable negative clinical impacts while improving some of the biochemical and clinical positive outcomes in MV-MSICU admitted patients. This study is limited by its single-center, retrospective design and, a larger prospective study is needed to clarify the causations and establishing the clinical utility of soluble fiber in OIC affected MV-MSICU admitted patients. However, our center is an experienced and high-volume unit, so our data may be useful to other centers.

In this study, we compared two therapeutic strategies for proactively managements of OIC affected MV-MSICU admitted patients; OIC affected MV-MSICU patients managed proactively by regular enteral administration of reconstituted 1.7 grams FOS within 48 hours of morphine initiation (Group I) and OIC affected MV-MSICU patients managed actively by regular rectal administration of 2.8 grams glycerin suppositories with/without enteral administration 13.8 g PEG after morphine initiation (Group II). The uniqueness of our study, as we know, emphasized on its comparing intention regarding many issues; between proposed investigated agent and protocolized agent for bowel caring in our institution, between proactively management versus actively management, between two pre-defined cohorts using the same analgosedative agent [Morphine, as the most popular used analgosedative agents in most global countries] and among mechanically ventilated, medically or surgically, admitted OIC affected critically ill patients who had complicated enteral feeding issues.

The proposed mechanism for higher GI motility and subsequently less OIC in our study is extrapolated from the observed significantly lower Mean ± SD and Mean difference ± SEM regarding %∆GRV in Group I compared to Group II. Soluble fiber has been proven effective in preventing OIC in the animal model. Soluble fiber administration prevented OIC in rats treated with morphine by increasing cecal Short-Chain Fatty Acids (SCFA) concentrations [21]. SCFA are an end product of the saccharolytic fermentation of FOS by the colonic microbiota [22-24]. The role of SCFA in stimulating colonic motility has been well established. SCFA are believed to exert their effects by increasing colonic sodium and water absorption and stimulating propulsive contractions [25,26].

The lower mortality rate in Group I compared with Group II, may be partially explained by the significantly higher PD accompanied with significantly higher TCI in Group I, as a clinical consequence of significantly higher emptying rate [indirectly extrapolated from significantly lower GRV]. The significantly lower %∆GRV in Group I versus Group II may also explain the higher peaking of Blood Glucose Level (BG max) in Group I and hence, the higher insulin requirement, compared with Group II. Additionally, the significantly lower %∆BUN in Group I, despite dual significantly higher PD and CRP, may be attributed to the anti-catabolic effects of Insulin [27].

In conclusion, our study showed that the investigated soluble fiber, in the form of FOS 1.7 gram/30 ml, may be an innovative strategy in mitigation of an opioid analgosedative related inevitable negative clinical impacts while improving some of the biochemical and clinical positive outcomes in MV-MSICU admitted patients. This study is limited by its single-center, retrospective design and, a larger prospective study is needed to clarify the causations and establishing the clinical utility of soluble fiber in OIC affected MV-MSICU admitted patients. However, our center is an experienced and high-volume unit, so our data may be useful to other centers.

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