Dataset Information

Rapid versus standard intravenous rehydration in paediatric gastroenteritis: pragmatic blinded randomised clinical trial.

ABSTRACT:

Objective

To determine if rapid rather than standard intravenous rehydration results in improved hydration and clinical outcomes when administered to children with gastroenteritis.

Design

Single centre, two arm, parallel randomised pragmatic controlled trial. Blocked randomisation stratified by site. Participants, caregivers, outcome assessors, investigators, and statisticians were blinded to the treatment assignment.

Setting

Paediatric emergency department in a tertiary care centre in Toronto, Canada.

Participants

226 children aged 3 months to 11 years; complete follow-up was obtained on 223 (99%). Eligible children were aged over 90 days, had a diagnosis of dehydration secondary to gastroenteritis, had not responded to oral rehydration, and had been prescribed intravenous rehydration. Children were excluded if they weighed less than 5 kg or more than 33 kg, required fluid restriction, had a suspected surgical condition, or had an insurmountable language barrier. Children were also excluded if they had a history of a chronic systemic disease, abdominal surgery, bilious or bloody vomit, hypotension, or hypoglycaemia or hyperglycaemia.

Interventions

Rapid (60 mL/kg) or standard (20 mL/kg) rehydration with 0.9% saline over an hour; subsequent fluids administered according to protocol.

Main outcome measures

Primary outcome

clinical rehydration, assessed with a validated scale, two hours after the start of treatment.

Secondary outcomes

prolonged treatment, mean clinical dehydration scores over the four hour study period, time to discharge, repeat visits to emergency department, adequate oral intake, and physician's comfort with discharge. Data from all randomised patients were included in an intention to treat analysis.

Results

114 patients were randomised to rapid rehydration and 112 to standard. One child was withdrawn because of severe hyponatraemia at baseline. There was no evidence of a difference between the rapid and standard rehydration groups in the proportions of participants who were rehydrated at two hours (41/114 (36%) v 33/112 (30%); difference 6.5% (95% confidence interval -5.7% to 18.7%; P=0.32). The results did not change after adjustment for weight, baseline dehydration score, and baseline pH (odds ratio 1.8, 0.90 to 3.5; P=0.10). The rates of prolonged treatment were similar (52% rapid v 43% standard; difference 8.9%, 21% to -5%; P=0.19). Although dehydration scores were similar throughout the study period (P=0.96), the median time to discharge was longer in the rapid group (6.3 v 5.0 hours; P=0.03).

Conclusions

There are no relevant clinical benefits from the administration of rapid rather than standard intravenous rehydration to haemodynamically stable children deemed to require intravenous rehydration. Trail registration Clinical Trials NCT00392145.

SUBMITTER: Freedman SB

PROVIDER: S-EPMC3219422 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDespite treatment recommendations from various organizations, oral rehydration therapy (ORT) continues to be underused, particularly by physicians in high-income countries. We conducted a systematic review of randomised controlled trials (RCTs) to compare ORT and intravenous therapy (IVT) for the treatment of dehydration secondary to acute gastroenteritis in children.MethodsRCTs were identified through MEDLINE, EMBASE, CENTRAL, authors and references of included trials, pharmaceutical companies, and relevant organizations. Screening and inclusion were performed independently by two reviewers in order to identify randomised or quasi-randomised controlled trials comparing ORT and IVT in children with acute diarrhea and dehydration. Two reviewers independently assessed study quality using the Jadad scale and allocation concealment. Data were extracted by one reviewer and checked by a second. The primary outcome measure was failure of rehydration. We analyzed data using standard meta-analytic techniques.ResultsThe quality of the 14 included trials ranged from 0 to 3 (Jadad score); allocation concealment was unclear in all but one study. Using a random effects model, there was no significant difference in treatment failures (risk difference [RD] 3%; 95% confidence intervals [CI]: 0, 6). The Mantel-Haenzsel fixed effects model gave a significant difference between treatment groups (RD 4%; 95% CI: 2, 5) favoring IVT. Based on the four studies that reported deaths, there were six in the IVT groups and two in ORT. There were no significant differences in total fluid intake at six and 24 hours, weight gain, duration of diarrhea, or hypo/hypernatremia. Length of stay was significantly shorter for the ORT group (weighted mean difference [WMD] -1.2 days; 95% CI: -2.4,-0.02). Phlebitis occurred significantly more often with IVT (number needed to treat [NNT] 33; 95% CI: 25,100); paralytic ileus occurred more often with ORT (NNT 33; 95% CI: 20,100). These results may not be generalizable to children with persistent vomiting.ConclusionThere were no clinically important differences between ORT and IVT in terms of efficacy and safety. For every 25 children (95% CI: 20, 50) treated with ORT, one would fail and require IVT. The results support existing practice guidelines recommending ORT as the first course of treatment in appropriate children with dehydration secondary to gastroenteritis.

Project description:BACKGROUND:The World Health Organization (WHO) recommends rapid intravenous rehydration, using fluid volumes of 70-100mls/kg over 3-6 h, with some of the initial volume given rapidly as initial fluid boluses to treat hypovolaemic shock for children with acute gastroenteritis (AGE) and severe dehydration. The evidence supporting the safety and efficacy of rapid versus slower rehydration remains uncertain. METHODS:We conducted a systematic review of randomised controlled trials (RCTs) on 11th of May 2017 comparing different rates of intravenous fluid therapy in children with AGE and moderate or severe dehydration, using standard search terms. Two authors independently assessed trial quality and extracted data. Non-RCTs and non-English articles were excluded. The primary endpoint was mortality and secondary endpoints included adverse events (safety) and treatment efficacy. MAIN RESULTS:Of the 1390 studies initially identified, 18 were assessed for eligibility. Of these, 3 studies (n?=?464) fulfilled a priori criteria for inclusion; most studied children with moderate dehydration and none were conducted in resource-poor settings. Volumes and rates of fluid replacement varied from 20 to 60 ml/kg given over 1-2 h (fast) versus 2-4 h (slow). There was substantial heterogeneity in methodology between the studies with only one adjudicated to be of high quality. There were no deaths in any study. Safety endpoints only identified oedema (n?=?6) and dysnatraemia (n?=?2). Pooled analysis showed no significant difference between the rapid and slow intravenous rehydration groups for the proportion of treatment failures (N?=?468): pooled RR 1.30 (95% CI: 0.87, 1.93) and the readmission rates (N?=?439): pooled RR 1.39 (95% CI: 0.68, 2.85). CONCLUSIONS:Despite wide implementation of WHO Plan C guideline for severe AGE, we found no clinical evaluation in resource-limited settings, and only limited evaluation of the rate and volume of rehydration in other parts of the world. Recent concerns over aggressive fluid expansion warrants further research to inform guidelines on rates of intravenous rehydration therapy for severe AGE.

Project description:BackgroundThe World Health Organization (WHO) rehydration management guidelines (Plan C) for children with acute gastroenteritis (AGE) and severe dehydration are widely practiced in resource-poor settings, yet have never been formally evaluated in a clinical trial. A recent audit of outcome of AGE at Kilifi County Hospital, Kenya noted that 10% of children required high dependency care (20% mortality) and a number developed fluid-related complications. The fluid resuscitation trial, FEAST, conducted in African children with severe febrile illness, demonstrated higher mortality with fluid bolus therapy and raised concerns regarding the safety of rapid intravenous rehydration therapy. Those findings warrant a detailed physiological study of children's responses to rehydration therapy incorporating quantification of myocardial performance and haemodynamic changes. Methods: GASTRO is a multi-centre, unblinded Phase II randomised controlled trial of 120 children aged 2 months to 12 years admitted to hospital with severe dehydration secondary to AGE. Children with severe malnutrition, chronic diarrhoea and congenital/rheumatic heart disease are excluded. Children will be enrolled over 18 months in 3 centres in Kenya and Uganda and followed until 7 days post-discharge. The trial will randomise children 1:1 to standard rapid rehydration using Ringers Lactate (WHO plan 'C' - 100mls/kg over 3-6 hours according to age, plus additional 0.9% saline boluses for children presenting in shock) or to a slower rehydration regimen (100mls/kg given over 8 hours and without the addition of fluid boluses). Enrolment started in November 2016 and is on-going. Primary outcome is frequency of adverse events, particularly related to cardiovascular compromise and neurological sequelae. Secondary outcomes focus on clinical, biochemical, and physiological measures related to assessment of severity of dehydration, and response to treatment by intravenous rehydration.DiscussionResults from this pilot will contribute to generating robust definitions of outcomes (in particular for non-mortality endpoints) for a larger Phase III trial.

Project description:Background: Rehydration strategies in children with severe acute malnutrition (SAM) and severe dehydration are extremely cautious. The World Health Organization (WHO) SAM guidelines advise strongly against intravenous fluids unless the child is shocked or severely dehydrated and unable to tolerate oral fluids. Otherwise, guidelines recommend oral or nasogastric rehydration using low sodium oral rehydration solutions. There is limited evidence to support these recommendations. Methods: We conducted a systematic review of randomised controlled trials (RCTs) and observational studies on 15 th June 2017 comparing different strategies of rehydration therapy in children with acute gastroenteritis and severe dehydration, specifically relating to intravenous rehydration, using standard search terms. Two authors assessed papers for inclusion. The primary endpoint was evidence of fluid overload. Results: Four studies were identified, all published in English, including 883 children, all of which were conducted in low resource settings. Two were randomised controlled trials and two observational cohort studies, one incorporated assessment of myocardial and haemodynamic function. There was no evidence of fluid overload or other fluid-related adverse events, including children managed on more liberal rehydration protocols. Mortality was high overall, and particularly in children with shock managed on WHO recommendations (day-28 mortality 82%). There was no difference in safety outcomes when different rates of intravenous rehydration were compared. Conclusions: The current 'strong recommendations' for conservative rehydration of children with SAM are not based on emerging evidence. We found no clinical trials providing a direct assessment of the current WHO guidelines, and those that were available suggested that these children have a high mortality and remain fluid depleted on current therapy. Recent studies have reported no evidence of fluid overload or heart failure with more liberal rehydration regimens. Clinical trials are urgently required to inform guidelines on routes and rates of intravenous rehydration therapy for dehydration in children with SAM.

Project description:BackgroundDelays in treating anaesthesia-induced malignant hyperthermia increase risks of complications and death. NPJ5008 is a novel formulation of the indicated treatment, dantrolene sodium, developed to shorten preparation and administration times compared with the reference formulation Dantrium®. The two formulations have been compared preclinically.ObjectivesAssess bioequivalence of overall dantrolene (free acid) exposure of NPJ5008 versus Dantrium® and ascertain similarities in their pharmacokinetics and safety/tolerability profiles. Evaluate preparation/administration time savings for the new formulation.DesignPart 1 of this open-label trial in humans was a 1 : 1 randomised crossover study; part 2 was a single-arm study. Trial pharmacy data and laboratory simulations assessed preparation/administration step timings.SettingSingle clinical centre in the UK, April to July 2021.ParticipantsTwenty-one healthy male and female individuals.InterventionsPart 1: single intravenous 60 mg dose of NPJ5008 or Dantrium®, sequentially. Part 2: single intravenous 120 mg dose of NPJ5008. Simulation: five vials per formulation using paediatric and adult cannulas.Main outcome measuresOverall drug exposure to last measurable concentration (AUC 0 to last ) and extrapolated to infinity (AUC 0 to ∞ ) were primary endpoints. Other pharmacokinetic, clinical and muscle-function parameters, and adverse events, were monitored.ResultsAdjusted geometric mean ratios of NPJ5008 versus Dantrium® were 90.24 and 90.44% for AUC 0 to last and AUC 0 to ∞ , respectively, with the 90% confidence intervals (CI) within the 80 to 125% acceptance interval, establishing bioequivalence. No new safety issues emerged: any adverse events were of a similar magnitude across treatments and related to pharmacological properties of dantrolene. Pharmacy and simulation data revealed that every step in preparation and administration was 26 to 69% faster for NPJ5008 than Dantrium®.ConclusionNPJ5008 showed comparable pharmacokinetic and safety profiles to Dantrium®, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia.Trial registrationEudraCT Number: 2020-005719-35, MHRA approval.

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Project description:BackgroundChildren hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea ( ≥3 watery stools/day) which is accompanied by poor outcomes. Rehydration guidelines for SAM are exceptionally conservative and controversial, based upon expert opinion. The guidelines only permit use of intravenous fluids for cases with advanced shock and exclusive use of low sodium intravenous and oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. Children managed in accordance to these guidelines have a very high mortality. The proposed GASTROSAM trial will reappraise current recommendations with mortality as the primary outcome. We hypothesize that liberal rehydration strategies for both intravenous and oral rehydration in SAM children with diarrhoea may reduce adverse outcomes.MethodsAn open Phase II trial, with a partial factorial design, enrolling children in Uganda, Kenya, Nigeria and Niger aged 6 months to 12 years with SAM hospitalised with gastroenteritis (>3 loose stools/day) and signs of moderate and severe dehydration. In Stratum A (severe dehydration) children will be randomised (1:1:2) to WHO plan C (100mls/kg Ringers Lactate (RL) with intravenous rehydration (IV) given over 3-6 hours according to age including boluses for shock), slow rehydration (100 mls/kg RL over 8 hours (no boluses)) or WHO SAM rehydration regime (ORS only (boluses for shock (standard of care)). Stratum B incorporates all children with moderate dehydration and severe dehydration post-intravenous rehydration and compares (1:1 ratio) standard WHO ORS given for non-SAM (experimental) versus WHO SAM-recommended low-sodium ReSoMal. The primary outcome for intravenous rehydration is mortality to 96 hours and for oral rehydration a change in sodium levels at 24 hours post-randomisation. Secondary outcomes include measures assessing safety (evidence of pulmonary oedema or heart failure); change in sodium from post-iv levels for those in Stratum A; perturbations of electrolyte abnormalities (severe hyponatraemia <125 mmols/L or hypokalaemia.DiscussionIf the trial shows that rehydration strategies for non-malnourished children are safe and improve mortality in SAM this could prompt revisions to the current treatment recommendations or may prompt future Phase III trials.

Project description:ImportanceDespite guidelines endorsing oral rehydration therapy, intravenous fluids are commonly administered to children with acute gastroenteritis in high-income countries.ObjectiveTo identify factors associated with intravenous fluid administration and hospitalization in children with acute gastroenteritis.Design, setting, and participantsThis study is a planned secondary analysis of the Pediatric Emergency Research Canada (PERC) and Pediatric Emergency Care Applied Research Network (PECARN) probiotic trials. Participants include children aged 3 to 48 months with 3 or more watery stools in 24 hours between November 5, 2013, and April 7, 2017, for the PERC study and July 8, 2014, and June 23, 2017, for the PECARN Study. Children were from 16 pediatric emergency departments throughout Canada (6) and the US (10). Data were analyzed from November 2, 2018, to March 16, 2021.ExposuresSex, age, preceding health care visit, distance between home and hospital, country (US vs Canada), frequency and duration of vomiting and diarrhea, presence of fever, Clinical Dehydration Scale score, oral ondansetron followed by oral rehydration therapy, and infectious agent.Main outcomes and measuresIntravenous fluid administration and hospitalization.ResultsThis secondary analysis of 2 randomized clinical trials included 1846 children (mean [SD] age, 19.1 [11.4] months; 1007 boys [54.6%]), of whom 534 of 1846 (28.9%) received oral ondansetron, 240 of 1846 (13.0%) received intravenous rehydration, and 67 of 1846 (3.6%) were hospitalized. The following were independently associated with intravenous rehydration: higher Clinical Dehydration Scale score (mild to moderate vs none, odds ratio [OR], 8.73; 95% CI, 5.81-13.13; and severe vs none, OR, 34.15; 95% CI, 13.45-86.73); country (US vs Canada, OR, 6.76; 95% CI, 3.15-14.49); prior health care visit with intravenous fluids (OR, 4.55; 95% CI, 1.32-15.72); and frequency of vomiting (per 5 episodes, OR, 1.66; 95% CI, 1.39-1.99). The following were independently associated with hospitalization: higher Clinical Dehydration Scale score (mild to moderate vs none, OR, 11.10; 95% CI, 5.05-24.38; and severe vs none, OR, 23.55; 95% CI, 7.09-78.25) and country (US vs Canada, OR, 3.37; 95% CI, 1.36-8.40). Oral ondansetron was associated with reduced odds of intravenous rehydration (OR, 0.21; 95% CI, 0.13-0.32) and hospitalization (OR, 0.44; 95% CI, 0.21-0.89).Conclusions and relevanceIntravenous rehydration and hospitalization were associated with clinical evidence of dehydration and lack of an oral ondansetron-supported oral rehydration period. Strategies focusing on oral ondansetron administration followed by oral rehydration therapy in children with dehydration may reduce the reliance on intravenous rehydration and hospitalization.Trial registrationClinicalTrials.gov Identifiers: NCT01853124 (PERC) and NCT01773967 (PECARN).