Daily laxative therapy reduces organ dysfunction in mechanically ventilated patients: a phase II randomized controlled trial

de Azevedo et al. Critical Care (2015) 19:329 DOI 10.1186/s13054-015-1047-x RESEARCH Open Access Daily laxative therapy reduces organ dysfunction in mechanically ventilated patients: a phase II randomized controlled trial Rodrigo Palacio de Azevedo, Flávio Geraldo Resende Freitas, Elaine Maria Ferreira, Luciano Cesar Pontes de Azevedo and Flávia Ribeiro Machado* Abstract Introduction: Constipation is a common problem in intensive care units. We assessed the efficacy and safety of laxative therapy aiming to promote daily defecation in reducing organ dysfunction in mechanically ventilated patients. Methods: We conducted a prospective, randomized, controlled, nonblinded phase II clinical trial at two general intensive care units. Patients expected to remain ventilated for over 3 days were randomly assigned to daily defecation or control groups. The intervention group received lactulose and enemas to produce 1–2 defecations per day. In the control group, absence of defecation was tolerated up to 5 days. Primary outcome was the change in Sequential Organ Failure Assessment (SOFA) score between the date of enrollment and intensive care unit discharge, death or day 14. Results: We included 88 patients. Patients in the treatment group had a higher number of defecations per day (1.3 ± 0.42 versus 0.7 ± 0.56, p < 0.0001) and lower percentage of days without defecation (33.1 ± 15.7 % versus 62.3 ±24.5 %, p < 0.0001). Patients in the intervention group had a greater reduction in SOFA score (–4.0 (–6.0 to 0) versus –1.0 (–4.0 to 1.0), p = 0.036) with no difference in mortality rates or in survival time. Adverse events were more frequent in the treatment group (4.5 (3.0–8.0) versus 3.0 (1.0–5.7), p = 0.016), including more days with diarrhea (2.0 (1.0–4.0) versus 1.0 (0–2.0) days, p < 0.0001). Serious adverse events were rare and did not significantly differ between groups. Conclusions: Laxative therapy improved daily defecation in ventilated patients and was associated with a greater reduction in SOFA score. Trial registration: Clinical Trials.gov NCT01607060, registered 24 May 2012. Introduction Constipation is a frequent problem in intensive care units (ICUs) and has often been overlooked [1]. A number of factors can contribute to constipation in critically ill patients, including immobility, dehydration and the use of sedatives, opioids and vasopressors [1–3]. The reported incidence of constipation in this population varies from 5 to 84 % [4–9]. * Correspondence: Disciplina de Anestesiologia, Dor e Terapia Intensiva, Universidade Federal de São Paulo, Rua Napoleão de Barros, 715 - 6° andar - Vila Clementino, CEP: 04024-002 São Paulo, SP, Brazil Constipation may be part of a broader context of acute intestinal dysfunction [10]. Recent studies have identified constipation as an independent prognostic factor in critically ill patients [1, 2, 9, 11, 12], suggesting that its treatment would improve outcome [13]. Bowel dysfunction can lead to complications, such as bacterial translocation, abdominal distension, delayed gastric emptying, vomiting, intestinal obstruction and perforation [14–17] and may be associated with worsened prognosis [18]. However, it remains unclear whether constipation is merely a marker of disease severity or an organ dysfunction to be treated. © 2015 de Azevedo et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. de Azevedo et al. Critical Care (2015) 19:329 Page 2 of 9 Given the absence of relevant studies, we conducted this phase II study to assess the effects of a laxative therapy protocol aimed at promoting daily defecation on organ dysfunction in mechanically ventilated patients. We hypothesized that daily defecation would reduce bacterial translocation and improve intra-abdominal pressure by reducing abdominal distention and enhancing gastric emptying, thus contributing to a reduction in overall organ dysfunction. We also aimed to evaluate the efficacy of the protocol in promoting daily defecation and the safety of this intervention by assessing its associated adverse events. the intervention group received lactulose (667 mg/ml; Lactulona®, Daiichi Sankyo, Barueri, SP, Brazil) at an initial dose of 20 ml every 8 hours. The goal was for the patient to produce 1–2 defecations per day. Lactulose was discontinued in patients with diarrhea. In the control group, the absence of defecation was tolerated for up to 5 days, unless symptoms of obstipation were present. Rectal examination and enemas were prescribed as needed, and lactulose use was discouraged. The general treatments and procedures for weaning from MV for both groups were based on local protocols. Nutritional support was also based on local protocols and is briefly described in Additional file 1. Methods Measurements Study design Our primary outcome was the change in Sequential Organ Failure Assessment (SOFA) score between the date of enrollment (day 0) and the day of ICU discharge, death or day 15 of the study, whichever came first (termed ΔSOFA). The secondary outcomes were the ventilator-free days within 28 days, and the length of ICU and hospital stays. We determined the 28-day, ICU and hospital mortality rates. For those patients discharged from the hospital before day 28, survival status was determined by consulting with the hospital register for reports of outpatient clinic visits, hospital readmissions or phone calls. We used the daily Therapeutic Intervention System Score (TISS)-28 [19] to assess nurse workload, and the data were reported as the mean values of the daily TISS28 and the total TISS-28 during the study period. We also recorded the occurrence of new infections, considering only pneumonia, catheter-related bloodstream infections and urinary tract infections, the presence of bacteremia, new episodes of severe sepsis or of septic shock, and the occurrence of new organ dysfunctions, according to the definitions available in Additional file 1. For all patients, we recorded the general descriptive data as described in Additional file 1. The effectiveness of the protocol was assessed throughout the treatment period, primarily by the number of defecations per day, which was defined as the total number of defecations occurring during the treatment period divided by the total days of observation. We measured the percentage of days without evacuation during the observation period and the time to the first defecation. For patients who did not (...truncated)