Sacral nerve stimulation for constipation and fecal incontinence in children: Long-term outcomes, patient benefit, and parent satisfaction.

OBJECTIVE: To evaluate the long-term efficacy of sacral nerve stimulation (SNS) in children with constipation and describe patient benefit and parent satisfaction. METHODS: Using a prospective patient registry, we identified patients <21 years old with constipation treated with SNS for >2 years. We compared symptoms, medical treatment, PedsQL Gastrointestinal Symptom Scale (GSS), Fecal Incontinence Quality of Life Scale (FIQL), and Fecal Incontinence Severity Index (FISI) before SNS and at follow-up. We contacted parents to administer the Glasgow Children's Benefit Inventory (GCBI) and a parent satisfaction questionnaire. KEY RESULTS: We included 25 children (52% male, median age 10 years): 16 had functional constipation, six anorectal malformation, two tethered spinal cord, and one Hirschsprung's disease. Defecation frequency did not change after SNS but patients reporting fecal incontinence decreased from 72% to 20% (P<.01) and urinary incontinence decreased from 56% to 28% (P=.04). Patients using laxatives decreased from 64% to 44% (ns) and patients using antegrade enemas decreased from 48% to 20% (P=.03). GSS, most FIQL domains, and FISI were improved at follow-up. Six (24%) patients had complications requiring further surgery. Of the 16 parents contacted, 15 (94%) parents indicated positive health-related benefit and all would recommend SNS to other families. CONCLUSIONS & INFERENCES: Sacral nerve stimulation is a promising and durable treatment for children with refractory constipation, and appears particularly effective in decreasing fecal incontinence. Although a quarter of patients experienced complications requiring additional surgery, nearly all parents reported health-related benefit. Future studies to identify predictors of treatment response and complications are needed.

Segmental colonic dilation is associated with premature termination of high-amplitude propagating contractions in children with intractable functional constipation.

BACKGROUND: Colonic dilation is common in children with intractable functional constipation (FC). Our aim was to describe the association between segmental colonic dilation and colonic dysmotility in children with FC. METHODS: We performed a retrospective study on 30 children with intractable FC (according to the Rome III criteria) who had undergone colonic manometry and contrast enema within a 12-month time period. Colonic diameter was measured at 5 cm intervals from the anal verge up to the splenic flexure. Moreover, the distance between the lateral margins of the pedicles of vertebra L2 was measured to provide a ratio (colonic diameter or length/distance between the lateral margins; "standardized colon size" [SCS]). All manometry recordings were visually inspected for the presence of high-amplitude propagating contractions (HAPCs); a parameter for colonic motility integrity. The intracolonic location of the manometry catheter sensors was assessed using an abdominal X-ray. KEY RESULTS: Colonic segments with HAPCs had a significantly smaller median diameter than colonic segments without HAPCs (4.08 cm vs 5.48 cm, P<.001; SCS 1.14 vs 1.66, P=.001). Children with prematurely terminating HAPCs had significantly larger SCS ratios for colonic diameter than children with fully propagating HAPCs (P=.008). SCS ratios for the length of the rectosigmoid and the descending colon and the SCS ratio for sigmoid colon diameter were significantly larger in children with FC compared to a previously described normative population (P<.0001, P<.0001 and P=.0007 respectively). CONCLUSIONS & INFERENCES: Segmental colonic dilation was associated with prematurely terminating HAPCs and may be a useful indicator of colonic dysmotility.

The relevance of practice misalignments to trials in transfusion medicine.

Practice misalignments can occur in any clinical trial investigating a pre-existing therapy that is typically adjusted based on clinical characteristics outside of the trial setting. To eliminate the heterogeneity in clinical practice, recent trials investigating titrated therapies have randomized patients to fixed-dose regimens without including a routine care control group receiving titrated therapy. In these trials, the normal relationships between clinically important characteristics and therapy titration are disrupted. Within each arm of the trial, randomization creates subgroups of patients receiving levels of therapy inconsistent with current practices outside of the trial. These practice misalignments may have outcomes worse than routine care and may compromise patient safety. In addition, comparisons of trial arms with practice misalignments have limited interpretability and generalizability. In this review, we use examples from the literature to discuss how practice misalignments can impact the safety, results and conclusions of clinical trials. In addition, we discuss methods to characterize relationships between therapy titration and clinical characteristics and trial design strategies that may minimize practice misalignments.

The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis.

A previous meta-analysis determined that the effects of steroids during sepsis were dose-dependent; since then, additional trials have been published. The current analysis updates our previous analysis examining the effects of steroids during sepsis. A literature search from 2004 to 2008 identified seven randomized controlled trials in adult patients; these were added to 14 previously identified trials. The effects of steroids on mortality were highly variable among the 21 trials (p <0.001, I(2) = 60%). In trials published before 1989, which involved short courses of high-dose steroids, steroids increased mortality (n = 8, I(2) = 14%, OR of death 1.39 (95% CI 1.04-1.86), p 0.03). In trials published after 1997, which involved longer courses of lower-dose steroids, steroids consistently improved shock reversal (n = 7, I(2) = 0%, OR of shock reversal 1.66 [95% CI 1.25-2.20), p <0.001), but demonstrated a more heterogeneous beneficial effect on mortality (n = 12, I(2) = 25%, OR of death 0.64 (95% CI 0.45-0.93), p 0.02). An inverse linear relationship between severity of illness and the effects of steroids on mortality was identified across all trials (p 0.03) and within the subgroup of trials published after 1997 (p 0.03); steroids were harmful in less severely ill patient populations and beneficial in more severely ill patient populations. There was no effect of response to adrenocorticotrophic hormone (ACTH) stimulation testing concerning the effects of steroids and no increase in steroid-associated adverse events. Low-dose steroids appear to improve mortality rates in patients with septic shock who are at high risk of death; however, additional trials in this subpopulation are necessary to definitively determine the role of low-dose steroids during sepsis.

Cardiopulmonary bypass primes polymorphonuclear leukocytes.

Polymorphonuclear leukocyte (PMN) superoxide (.O2-) production has been implicated in the pathogenesis of cardiopulmonary bypass (CPB)-related end organ injury. PMN "priming" has been described as an event which enhances the release of .O2- following a second, activating insult. We hypothesized that PMN priming occurs during CBP and is temporally related to the plasma level of complement (C3a), interleukin (IL)-6, and IL-8. PMNs were isolated from 10 CPB patients pre-bypass (preCPB), 5 min after protamine administration (PROT), and at 6 and 24 h post-CPB. PMN .O2- production was measured by a cytochrome c reduction assay in the presence or absence of either phorbol 12-myristate-13-acetate (PMA, 0.4 microgram/ml) or N-formyl-methionyl-leucyl-phenylalanine (FMLP, 1 microM) and also after priming with 2000 nM platelet-activating factor (PAF) followed by activation with either PMA or FMLP. Plasma levels of C3a, IL-6, and IL-8 were determined by enzyme-linked immunosorbent assay. PMA-activated PMN .O2- production was significantly elevated at 6 h post-CPB compared to pre-CPB levels (11.04 +/- 0.9 vs 7.62 +/- 0.57, P = 0.009), indicating that CPB is associated with in vivo PMN priming. When PMNs were primed in vitro with PAF and then activated with PMA or FMLP, .O2- release at 6 h post-CPB was also significantly greater than pre-CPB levels (16.04 +/- 0.74 vs 12.2 +/- 0.92, P = 0.038; and 17.33 +/- 1.38 vs 13.33 +/- 1.35, P < 0.05), indicating that CPB acts synergistically with PAF to prime PMNs. Levels of C3a rose significantly over pre-CPB levels at PROT (P = 0.001), and IL-6 and IL-8 rose over pre-CPB levels at 6 h post-CPB (P = 0.01 and P = 0.006, respectively). These findings demonstrate that CPB not only directly primes PMNs, but also potentiates priming of PMNs by PAF. This "primed" PMN state, which coincided with the increased plasma levels of inflammatory mediators, may suggest a mechanism of predisposition to organ dysfunction following CPB.