Laxative use and mortality in patients on haemodialysis: a prospective cohort study.

BACKGROUND: Patients on haemodialysis (HD) are often constipated. This study aimed to assess the relationship between constipation and mortality in such patients. In this study, constipation was defined as receiving prescription laxatives, based on the investigation results of "a need to take laxatives is the most common conception of constipation" reported by the World Gastroenterology Organization Global Guidelines. METHODS: This cohort study included 12,217 adult patients on HD enrolled in the Japan-Dialysis Outcomes and Practice Patterns study phases 1 to 5 (1998 to 2015). The participants were grouped into two based on whether they were prescribed laxatives during enrolment at baseline. The primary endpoint was all-cause mortality in 3 years, and the secondary endpoint was cause-specific death. Missing values were imputed using multiple imputation methods. All estimations were calculated using a Cox proportional hazards model with an inverse probability of treatment weighting using the propensity score. RESULTS: Laxatives were prescribed in 30.5% of the patients, and there were 1240 all-cause deaths. There was a significant association between laxative prescription and all-cause mortality [adjusted hazard ratio (AHR), 1.12; 95% confidence interval (CI): 1.03 to 1.21]. Because the Kaplan-Meier curves of the two groups crossed over, we examined 8345 patients observed for more than 1.5 years. Laxative prescription was significantly associated with all-cause mortality (AHR, 1.35; 95% CI: 1.17 to 1.55). The AHR of infectious death was 1.62 (95% CI: 1.14 to 2.29), and that of cancerous death was 1.60 (95% CI: 1.08 to 2.36). However, cardiovascular death did not show a significant inter-group difference. CONCLUSIONS: Constipation requiring use of laxatives was associated with an increased risk of death in patients on HD. It is important to prevent patients receiving HD from developing constipation and to reduce the number of patients requiring laxatives.

Impact of persistent constipation on health-related quality of life and mortality in older community-dwelling women.

OBJECTIVES: Very little is known about whether the reported health-related impact of constipation is worse in people who experience constipation over a long period of time vs. those with more transient symptoms. We aimed to determine the impact of persistent vs. transient constipation on health-related quality of life (QOL), depression, and mortality. METHODS: We analyzed data from 5,107 women (aged 70-75 years in 1996) who answered "Have you had constipation in the past 12 months?" in all five surveys sent out every 3 years of the Australian Longitudinal Study on Women's Health. RESULTS: Of the 5,107 women, 20.9, 54.1, and 24.7% reported having persistent constipation on at least 4 out of 5 surveys, transient constipation reported on 1-3 surveys, or none reported over the 15-year time frame, respectively. Women who reported persistent constipation had significantly lower scores for all domains of QOL on the SF-36 except role-emotional, and had higher levels of self-reported depression, even after adjusting for number of chronic illnesses and fluid intake. Mortality rates were increased when comparing women with no reported constipation with persistently reported constipation (8.2% vs. 11%, odds ratio = 1.32, 95% confidence interval 1.0, 1.74, P = 0.05) controlling for specific chronic illnesses. CONCLUSIONS: Persistent constipation among older women is associated with poor health outcomes.

Surgery for constipation in patients with prior spinal cord injury: the Department of Veterans Affairs experience.

OBJECTIVE: Patients with spinal cord injury (SCI) typically have difficulty with constipation. Some undergo surgery for bowel management. We predicted that SCI patients would have higher mortality and/or morbidity rates following such surgery than neurally intact patients receiving the same procedures. We sought to evaluate this using a large population-based data set. METHODS: Patients receiving care at Department of Veterans Affairs Medical Centers (DVAMCs) with computer codes for SCI and constipation who later underwent colectomy, colostomy, or ileostomy during fiscal years 1993-2002 were identified. Charts were requested from the VAMCs where the surgery had been performed and a retrospective chart review of these charts was done. We collected data on patient demographics, six specific pre-operative co-morbidities, surgical complications, and post-operative mortality. Comparisons were made to current literature evaluating a population receiving total abdominal colectomy and ileorectal anastomosis for constipation but not selected for SCI. RESULTS: Of 299 patients identified by computer search, 43 (14%) had codes for SCI and 10 of 43 (24%) met our inclusion criteria. All were symptomatic and had received appropriate medical management. Co-morbid conditions were present in 9 of 10 patients (90%). There were no deaths within 30 days. The complication rate was zero. The mean post-operative length of stay was 17 days. CONCLUSIONS: Patients with SCI comprise about 14% of the population who receive surgery for severe constipation in the Department of Veterans Affairs system. The mortality and morbidity rates in these patients are similar to those reported in other constipated patients who have surgery for intractable constipation. Our data suggest that stoma formation ± bowel resection in patients with SCI is a safe and effective treatment for chronic constipation.

Hirschsprung's disease associated with Down syndrome: a meta-analysis of incidence, functional outcomes and mortality.

PURPOSE: Down syndrome (DS) is the most frequent chromosomal abnormality associated with Hirschsprung's disease (HD). It has often been suggested that this association results in poorer outcomes with regard to postoperative complications, continence and mortality. On the other hand, the results after surgical treatment of HD in patients with DS are reportedly similar to those in cases with HD alone. The objective of this study was to determine the incidence of DS in cohorts with HD, and to compare pre-/postoperative complications, functional outcome and mortality between cohorts with and without coexisting DS. METHODS: A systematic literature-based search for relevant cohorts was conducted using multiple online databases. The number of DS cases in HD cohorts was recorded and data on pre-/postoperative complications, functional outcome and mortality were extracted. Pooled odds ratios with 95% confidence intervals were calculated using meta-analysis methodology. RESULTS: Sixty-one articles met defined inclusion criteria, comprising data from 16,497 patients with HD. The overall incidence of DS among them was 7.32%. Vice versa, the incidence of HD in 29,418 patients with DS was 2.62%. There were no significant differences regarding the male-to-female ratio between cohorts with and without coexisting DS (4:1 vs. 3:1 respectively; P = 0.5376). The rate of additional comorbidities was significantly higher in HD associated with DS (P < 0.0001). Recto-sigmoid HD was in both cohorts the most common type of HD (P = 0.8231). Long-segment HD was significantly more frequent in HD with coexisting DS (P = 0.0267), while total colonic aganglionosis occurred significantly more often in HD without DS (P = 0.0003). There were no significant differences in preoperative constipation/obstruction (P = 0.5967), but the rate of preoperative enterocolitis was significantly higher in HD associated with DS (P = 0.0486). Postoperative complications such as recurrent enterocolitis (P = 0.0112) and soiling (P = 0.0002) were significantly more frequent in HD with coexisting DS. Although not statistically significant, fecal incontinence (P = 0.1014) and persistent constipation (P = 0.1670) occurred more often after surgical treatment of HD with DS. The mortality rate was significantly higher in HD associated with DS (P < 0.0001). CONCLUSIONS: The association of HD with DS is well-recognized with an incidence of 7.32%. A large number of patients with DS continue to have persistent bowel dysfunction after surgical treatment of HD. Our data provide strong evidence that the coexistence of HD and DS is associated with higher rates of pre-/postoperative enterocolitis, poorer functional outcomes and increased mortality.

Constipation in long-term ventilated patients: associated factors and impact on intensive care unit outcomes.

OBJECTIVES: To characterize the factors associated with delayed defecation in long-term ventilated patients and to examine the relationship between delayed defecation and logistic organ dysfunction scores, acquired bacterial infections, and mortality in the intensive care unit. DESIGN: Prospective observational cohort study. SETTING: A 21-bed polyvalent intensive care unit in a university hospital. PATIENTS: A total of 609 adult patients admitted over a 41-month period who underwent mechanical ventilation for ≥ 6 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three hundred fifty-three patients (58%) passed stools ≥ 6 days after they were admitted to the intensive care unit ("late" defecation). Patients with early and late defecation had similar general characteristics when admitted to the intensive care unit and had similar logistic organ dysfunction scores on the first day of mechanical ventilation. Several variables were independently associated with a delay in defecation: a Pao2/Fio2 ratio of less than 150 mm Hg (adjusted hazard ratio 1.40; 95% confidence interval: 1.06-1.60; p = .0073), a systolic blood pressure between 70 and 89 mm Hg (adjusted hazard ratio 1.48; 95% confidence interval: 1.17-1.79; p = .002), and systolic blood pressure < 68 mm Hg (adjusted hazard ratio 1.29; 95% confidence interval: 1.01-1.60; p = .03). Logistic organ dysfunction scores were significantly higher on the fourth and ninth days of mechanical ventilation in patients with late defecation than in those with early defecation. The crude intensive care unit mortality rate was 18% in patients with early defecation and 30% in patients with late defecation (p < .001). Acquired bacterial infections at any site occurred in 34% of patients with early defecation and 66% of patients with late defecation (p < .001). CONCLUSION: A Pao2/Fio2 ratio of < 150 mm Hg and systolic blood pressure of < 90 mm Hg during the first 5 days of mechanical ventilation were independently associated with a delay in defecation. Our results suggest that constipation is associated with adverse outcomes in long-term ventilated patients.

New-onset constipation at acute stage after first stroke: incidence, risk factors, and impact on the stroke outcome.

BACKGROUND AND PURPOSE: The prevalence of constipation after stroke varies from 30% to 60%. The incidence of new-onset constipation during the early stage of stroke remains uncertain. The present study was designed to investigate the prevalence of new-onset constipation, its risk factors, and its impact on stroke outcome in patients with their first stroke at acute stage. METHODS: This is a prospective cohort study of 154 patients admitted with their first stroke. New-onset constipation during the first 4 weeks of stroke was recorded, using the Rome II criteria for constipation. Demographics, characteristics of the stroke, laboratory parameters, and use of medications were evaluated as risk factors for constipation. Death, recurrent stroke, and handicap at 12 weeks were regarded as poor outcome. The impact of constipation on poor outcome was also studied. RESULTS: The cumulative incidence of new-onset constipation was 55.2% at 4 weeks poststroke. The occurrence of constipation was associated with dependence (P<0.01) and use of bedpan for defecation (P<0.05). Among patients with moderate stroke severity (NIHSS 4 to 11) at baseline, constipation at 4 weeks was associated with a poor outcome at 12 weeks. CONCLUSIONS: New-onset constipation is a common complication of acute stroke. Its occurrence is associated with dependence and use of bedpan for defecation. Its development may predict a poor outcome at 12 weeks in patients with moderately severe stroke.

Fatalities associated with clozapine-related constipation and bowel obstruction: a literature review and two case reports.

BACKGROUND: Constipation is an exceedingly common side effect of treatment with clozapine. In rare cases, this side effect has resulted in fatal complications. OBJECTIVE: The authors review the literature on fatal complications of clozapine-related constipation and bowel obstruction. METHOD: The authors provide two new case reports of patients who died of similar causes. RESULTS: There were seven reports of deaths from clozapine-related bowel obstruction in the literature, with the most common mechanisms of death being severe impaction leading either to feculent vomiting or bowel necrosis. DISCUSSION: The discussion outlines potential mechanisms and management of clozapine-related constipation.

Constipation and risk of death and cardiovascular events.

BACKGROUND AND AIMS: Constipation is one of the most frequent symptoms encountered in daily clinical practice and is implicated in the development of atherosclerosis, potentially through altered gut microbiota. However, little is known about its association with incident cardiovascular events. METHODS: In a nationally representative cohort of 3,359,653 US veterans with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 between October 1, 2004 and September 30, 2006 (baseline period), with follow-up through 2013, we examined the association of constipation status (absence or presence; defined using diagnostic codes and laxative use) and laxative use (none, one, or ≥2 types of laxatives) with all-cause mortality, incident coronary heart disease (CHD), and incident ischemic stroke. RESULTS: Among 3,359,653 patients, 237,855 (7.1%) were identified as having constipation. After multivariable adjustments for demographics, prevalent comorbidities, medications, and socioeconomic status, patients with (versus without) constipation had 12% higher all-cause mortality (hazard ratio [HR], 1.12; 95% CI, 1.11-1.13), 11% higher incidence of CHD (HR, 1.11; 95% CI, 1.08-1.14), and 19% higher incidence of ischemic stroke (HR, 1.19; 95% CI, 1.15-1.22). Patients with one and ≥2 (versus none) types of laxatives experienced a similarly higher risk of all-cause mortality (HRs [95% CI], 1.15 [1.13-1.16] and 1.14 [1.12-1.15], respectively), incident CHD (HRs [95% CI], 1.11 [1.07-1.15] and 1.10 [1.05-1.15], respectively) and incident ischemic stroke (HRs [95% CI], 1.19 [1.14-1.23] and 1.21 [1.16-1.26], respectively). CONCLUSIONS: Constipation status and laxative use are independently associated with higher risk of all-cause mortality and incident CHD and ischemic stroke.

Constipation incidence and impact in medical critical care patients: importance of the definition criterion.

BACKGROUND: Constipation incidence and impact remain controversial in the ICU. This may depend on the definition criterion used in the previous studies on the field. We aimed to determine the frequency and significance of constipation according to its definition criterion. METHODS: This is a prospective observational study. Adult patients without a cause of transit time modification and laxative intake within the first 3 days were screened. Constipation was defined by a first stool passage occurring after 3 days of ICU stay. Thereafter, we identified two subgroups of patients: absence of stool passage more than 3 days but less than 6 days (3-day subgroup), and no stool passage for 6 days or more (6-day subgroup). Survival, length of stay and time spent under mechanical ventilation (MV) were compared according to constipation status. RESULTS: Among 189 included patients [age 60.8 (49.5-74.2) years, SAPS II 44 (34-53)], 98 (51.9%) exhibited constipation (3-day subgroup n=53, 6-day subgroup n=45). Constipated patients were more likely to receive MV, sedation, vasopressors, enteral nutrition and neuromuscular blocking agents. ICU length of stay and time spent under MV was longer in the 6-day subgroup but not in the 3-day subgroup of patients. CONCLUSION: With regard to outcomes, defining constipation by the absence of stool passage less than 6 days after ICU admission does not identify a specific subset of population. Further studies on the management of this condition should focus on these 'long-term' constipated patients.

The relation of presenting symptoms with staging, grading, and postoperative 3-year mortality in patients with stage I-III non-metastatic colon cancer.

BACKGROUND/AIMS: To evaluate the association of presenting symptoms with staging, grading, and postoperative 3-year mortality in patients with colon cancer. MATERIALS AND METHODS: A total of 132 patients-with a mean (standard deviation; SD) age of 63.0 (10.0) years and of whom 56.0% were males-with non-metastatic stage I-III colon cancer were included. Symptoms prior to diagnosis were evaluated with respect to tumor localization, tumor node metastasis (TNM) stage, histological grade, and postoperative 3-year mortality. RESULTS: Constipation and abdominal pain were the two most common symptoms appearing first (29.5% and 16.7%, respectively) and remained most predominant (25.0% and 20.0%, respectively) up to diagnosis. The frequency of admission symptoms significantly differed with respect to tumor location, TNM stage and histological grade. The postoperative 3-year survival rate was 61.4%. Multivariate logistic regression revealed that melena and rectal bleeding increased the likelihood of 3-year mortality by 13.6-fold (p=0.001) and 4.08-fold (p=0.011), respectively. CONCLUSION: Our findings revealed differences in presenting symptom profiles with respect to the time of manifestation and predominance as well as to the TNM stage, histological grade, and tumor location. Given that melena and rectal bleeding increased the 3-year mortality risk by 13.6-fold and 4.08-fold, respectively, our findings indicate the association of admission symptoms with outcome among patients with colon cancer.

Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy.

OBJECTIVE: Clozapine is the preferred option for treatment-resistant schizophrenia. However, since 1975, clozapine has been known to cause agranulocytosis. In the clozapine screening guidelines, white blood cell count is mandatory. In the past 20 years, after its reintroduction, 3 other serious side effects, namely, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis have been documented but have so far failed to be incorporated in the screening guidelines. The objective of this review is to determine whether an update of the screening guidelines for serious side effects with clozapine is evidence based. DATA SOURCES: The English-language literature, available via MEDLINE or PubMed, on the incidence of 4 clozapine-related side effects, using clozapine, agranulocytosis, diabetic ketoacidosis, and gastrointestinal hypomotility as keywords, that have been published over the period 1976-2010, was collected. STUDY SELECTION: 16 studies that provided incidence rates or data from which these rates could be calculated were included. DATA EXTRACTION: We compared 1-year incidence rates, mortality rates in the whole study population and in the affected cases. When rates reflected longer periods of observation, the given rate was recalculated to obtain a 1-year incidence rate. RESULTS: The incidence of clozapine-induced agranulocytosis varies between 3.8‰-8.0‰. The mortality rate is 0.1‰-0.3‰, and the case-fatality rate is 2.2‰-4.2‰. In diabetic ketoacidosis, the incidence was calculated at 1.2‰-3.1‰, and the case-fatality rate was 20%-31%. In gastrointestinal hypomotility, the incidence was 4‰-8‰, and the case-fatality rate was 15%-27.5%. The discrepancy in incidence rates between Australia (7‰-34‰) and the rest of the world (0.07‰-0.6‰) impairs a general approach of this side effect. CONCLUSIONS: In 2 of the 3 studied side effects, diabetic ketoacidosis and gastrointestinal hypomotility, reduction of mortality to the level of agranulocytosis is both necessary and feasible. In order to obtain this outcome, the screening guidelines need to be modified; early detection of treatment-emergent hyperglycemia, that might-via diabetes mellitus-develop into diabetic ketoacidosis, requires obligatory monthly measurement of fasting plasma glucose. To prevent gastrohypomotility, and complications therefrom, the clinician should be required to choose between either weekly monitoring or standard coprescription of laxatives for prevention. The reported incidence of myocarditis (high in Australia, low in the rest of the world) is too divergent to allow for an overall recommendation outside Australia.

Safety assessment of prucalopride in elderly patients with constipation: a double-blind, placebo-controlled study.

Chronic constipation is common among nursing home residents. The aim of this study was to evaluate safety, tolerability and pharmacokinetics of the selective 5HT(4) receptor agonist prucalopride in elderly, chronically constipated patients in nursing homes. A multicentre, phase II, randomized, double-blind dose-escalation study in 89 elderly constipated nursing home residents treated with placebo, 0.5, 1 or 2 mg prucalopride once daily for 28 days was analysed. Adverse events, vital signs, ECG, Holter monitor and pharmacokinetics were assessed (Clinicaltrials.gov identifier: NCT00627692). Patients' mean age was 83 years; 88% had a history of cardiovascular diseases. Most frequent adverse events, at least possibly related to prucalopride, were diarrhoea and abdominal pain. Relative to placebo, there were no differences in vital signs, ECG corrected QT interval, ECG morphology parameters, or incidence of supraventricular or ventricular arrhythmias on Holter monitoring. Plasma prucalopride concentrations increased proportionally with administered dose. Prucalopride up to 2 mg once daily for 4 weeks was safe and well-tolerated by constipated elderly patients, with no differences vs placebo in ECG or a range of Holter-monitoring parameters.