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A randomized trial of Plasma-Lyte A and 0.9 % sodium chloride in acute pediatric gastroenteritis Allen, Coburn H; Goldman, Ran D; Bhatt, Seema; Simon, Harold K; Gorelick, Marc H; Spandorfer, Philip R; Spiro, David M; Mace, Sharon E; Johnson, David W; Higginbotham, Eric A; Du, Hongyan; Smyth, Brendan J; Schermer, Carol R; Goldstein, Stuart L Aug 2, 2016

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RESEARCH ARTICLE Open AccessA randomized trial of Plasma-Lyte A and0.9 % sodium chloride in acute pediatricgastroenteritisCoburn H. Allen1*, Ran D. Goldman2, Seema Bhatt3, Harold K. Simon4, Marc H. Gorelick5, Philip R. Spandorfer6,David M. Spiro7, Sharon E. Mace8, David W. Johnson9, Eric A. Higginbotham1, Hongyan Du10, Brendan J. Smyth11,Carol R. Schermer10 and Stuart L. Goldstein3AbstractBackground: Compare the efficacy and safety of Plasma-Lyte A (PLA) versus 0.9 % sodium chloride (NaCl)intravenous (IV) fluid replacement in children with moderate to severe dehydration secondary to acutegastroenteritis (AGE).Methods: Prospective, randomized, double-blind study conducted at eight pediatric emergency departments(EDs) in the US and Canada (NCT#01234883). The primary outcome measure was serum bicarbonate level at 4 h.Secondary outcomes included safety and tolerability. The hypothesis was that PLA would be superior to 0.9 %NaCl in improvement of 4-h bicarbonate. Patients (n = 100) aged ≥6 months to <11 years with AGE-inducedmoderate-to-severe dehydration were enrolled. Patients with a baseline bicarbonate level ≤22 mEq/L formed themodified intent to treat (mITT) group.Results: At baseline, the treatment groups were comparable except that the PLA group was older. At hour 4, thePLA group had greater increases in serum bicarbonate from baseline than did the 0.9 % NaCl group (mean ± SDat 4 h: 18 ± 3.74 vs 18.0 ± 3.67; change from baseline of 1.6 and 0.0, respectively; P = .004). Both treatment groupsreceived similar fluid volumes. The PLA group had less abdominal pain and better dehydration scores at hour 2(both P = .03) but not at hour 4 (P = 0.15 and 0.08, respectively). No patient experienced clinically relevant worsening oflaboratory findings or physical examination, and hospital admission rates were similar. One patient in each treatmentgroup developed hyponatremia. Four patients developed hyperkalemia (PLA:1, 0.9 % NaCl:3).Conclusion: In comparison with 0.9 % NaCl, PLA for rehydration in children with AGE was well tolerated and led tomore rapid improvement in serum bicarbonate and dehydration score.Trial registration: NCT#01234883 (Registration Date: November 3, 2010).Keywords: Balanced fluid therapy, Dehydration, Hyperchloremic metabolic acidosis, Plasma-Lyte A, Rehydration,Gastroenteritis* Correspondence: challen@seton.org1Department of Pediatrics, Dell Medical School at University of Texas atAustin, 4900 Mueller Blvd, Austin, TX 78746, USAFull list of author information is available at the end of the article© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe 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.Allen et al. BMC Pediatrics  (2016) 16:117 DOI 10.1186/s12887-016-0652-4BackgroundAcute gastroenteritis (AGE) complicated by dehydrationremains a major cause of childhood morbidity and mortal-ity, requiring significant healthcare expenditure worldwide[1–3]. Approximately 179 million cases of AGE occur inthe US each year [4–6]. Despite a decrease in positive la-boratory diagnoses of AGE, likely attributable to rotavirusvaccination availability since 2006 [7], substantial diseaseremains. The fluid loss associated with AGE not onlycauses dehydration, but can lead to metabolic acidosis andelectrolyte disturbances [1, 6, 8, 9].Intravenous fluid therapy (IVT) is the mainstay oftreatment for severe pediatric dehydration, and the re-quirement for continued IVT is the leading indicationfor hospitalization. However, recommendations for IVTare poorly standardized, and significant controversy ex-ists as to the optimal fluid for use in children [10, 11]. Ingeneral, isotonic fluids are advised for acute rehydrationwith the most commonly administered fluids being0.9 % sodium chloride (NaCl) and Lactated Ringer’s(LR) solution [12]. However, 0.9 % NaCl, which contains asupraphysiologic chloride concentration, can inducehyperchloremic metabolic acidosis (HCA), which canexacerbate the low serum bicarbonate levels often associ-ated with diarrhea and poor perfusion from dehydration[13]. To prevent HCA, clinicians use LR, but concerns ofhyponatremia due to low sodium concentration limitits use [12]. Thus, there is a substantial need to furtherevaluate alternative isotonic crystalloids as a treatmentfor AGE [10].Plasma-Lyte A (PLA, Baxter Healthcare, Deerfield, IL),a balanced isotonic crystalloid, contains physiologic so-dium, chloride, potassium, magnesium, and bicarbonateprecursors in mEq/L: Na 140, K 5, Cl 98, Mg 3, Acetate27, and gluconate 23, pH 7.4). It is utilized as a sourceof water and electrolytes or as an alkalinizing agent. Sev-eral studies in adults have reported a reduction in the in-cidence of hyperchloremia and metabolic acidosis withbalanced solutions (eg, LR and PLA) over 0.9 % NaCl[14–16]. The osmolarity of Plasma-Lyte A is 294 mOs-mol/L, within the pediatric reference range [17]. Of note,isotonic Plasma-Lyte has different naming conventionsaround the globe and hence different publications mayrefer to Plasmalyte A, Plasmalyte, or Plasmalyte 148. Inthe Unites States, there are 2 naming formulations whichare identical in ionic composition but which differ in solu-tion pH: Plasma-Lyte A (used here) which has a pH of 7.4and Plasma-lyte 148 which has a pH of 5.5.Plasma-Lyte A has not previously been studied spe-cifically in the pediatric population. In addition to thephysiologic chloride level, PLA contains acetate andgluconate, which serve as buffering agents. It may bepreferred for children with AGE because it replaces waterand electrolytes lost due to diarrhea and vomiting as wellas bicarbonate lost in stool. PLA has the potential to re-verse the acidosis that may contribute to the physicalsymptoms of nausea, vomiting, diarrhea, and abdominalpain [18, 19].The hypothesis of this study was that PLA would besuperior to 0.9 % NaCl in improvement of 4-h bicarbon-ate level and result in faster resolution of clinical signsand symptoms in children with AGE and dehydration.MethodsThis prospective, randomized, triple-blind, company-sponsored, active-controlled study was conducted at 8pediatric emergency departments (ED) in the US andCanada (NCT#01234883). Institutional ethics approval wasobtained from each institution (Additional file 1: Table S1),and written informed consent was obtained from the par-ent/legal guardian of all children before randomization.Safety data were periodically monitored by an independentconsultant (pediatric nephrologist, SLG) who was not in-volved in patient recruitment or management.Patients ≥6 months to <11 years of age were eligiblefor enrollment if they presented to the ED with moderate-to-severe dehydration due to AGE, defined as ≥3 episodesof diarrhea or nonbilious vomiting within the previous24 h and a Gorelick dehydration score ≥4 [20]. Screenedpatients had blood drawn for serum chemistry. A preran-domization fluid bolus of ≤20 mL/kg in the 4 h prior toenrollment was permitted. Exclusion criteria includedAGE that did not require IVT per clinicians’ judgment,chronic health conditions such as renal failure affectingthe ability to tolerate fluids or those that result in electro-lyte abnormalities, or the use of prohibited medications(eg, antacids/anti-diarrhea or systemic corticosteroids within24 or 72 h prior to presentation, respectively).During the prestudy period, all patients received routinecare, and oral rehydration therapy and IVT per clinicianjudgment. Screening included review of inclusion/exclu-sion criteria, complete medical history and physical exam,Gorelick score, abdominal pain assessment, and assess-ment of volume and type of prestudy IVT.Concealed treatment allocation was via an InteractiveVoice Recognition System/Interactive Web-based System.Eligible patients were randomly assigned in a 1:1 ratioto receive concealed bolus therapy with PLA (MultipleElectrolyte Injection, Type 1) or 0.9 % NaCl. Followingrandomization, hour 0 was defined as the beginning ofinfusion of the first bolus of blinded study treatment.Patients were assessed at baseline, hour 4 (±1), and 48 ±6 h. The study treatment period was for up to 8 h. If thepatient continued to require IVT beyond the study treat-ment period, the clinician ordered standard-of-care rehy-dration IVT. The safety follow-up period was definedfrom the end of the last blinded study bolus to 48 ± 6 h.The protocol recommended 20 mL/kg for the first studyAllen et al. BMC Pediatrics  (2016) 16:117 Page 2 of 9treatment IV bolus, but the ordered dose was left to pro-vider discretion [21].The primary outcome was the change in venous serumbicarbonate, as measure by total carbon dioxide by clin-ical chemistry automated analyzers via local laboratories,between baseline (hour 0) and hour 4. Secondary out-comes included assessments of the Gorelick score; theBaxter Animated Retching Face (BARF) [22] score fornausea/vomiting; pain (FLACC scale for ages six monthsto three years, FACES scale for ages 3–11 years); volumeand duration of IVT; time to clinical rehydration, andlength of stay in the ED. Safety assessments includedphysical examinations, laboratory assessments, and anyreported or observed adverse events (AEs). At the safetyfollow-up, information was obtained regarding AEs, un-planned return visits, and hospital admission.The intent-to-treat (ITT) population included all patientswho were randomized to receive study treatment and wasused to assess safety. For the primary and secondary out-comes, a modified intent-to-treat (mITT) analysis was usedto focus on only those patients with a baseline serum bicar-bonate level ≤22 mEq/L. This was necessary in order toallow clinicians to initiate the first study treatment bolusper standard of care prior to receipt of initial laboratorytest results. However, only patients with baseline serumbicarbonate level ≤22 mEq/L continued study treatmentin 10-to-20 mL/kg allotments until clinical rehydrationwas achieved or hour 8 transpired, whichever occurredfirst and was considered the “end of study” treatment. En-rolled patients with baseline bicarbonate >22 mEq/L hadthe study infusion stopped and were considered “earlytreatment release (ETR).” They did not undergo 4-h la-boratory testing but were followed for safety parameters.Sample size determination was made assuming a 25 %coefficient of variation and a 15 % difference betweenPLA and 0.9 % NaCl for serum bicarbonate level, follow-ing a log-normal distribution. A sample size of 80 evalu-able mITT patients (40 per treatment group) had a powerof 80 % to detect such a difference with a 1-sided alpha of0.05. Planned enrollment for this study was approximately112 subjects (56 subjects per treatment group to ensure40 evaluable mITT subjects per treatment group), with anestimated 30 % attrition rate. The superiority of PLA inmaintaining the baseline serum bicarbonate levels wasestablished if the one-sided 95 % lower limit of the changefrom hour 0 to hour 4 geometric mean ratio of test/con-trol was greater than one. Stratified analyses by age rangeand severity of baseline serum bicarbonate level for theprimary outcome were planned a priori. For continuousefficacy and safety variables, descriptive summary statisticswere provided by treatment group and time, whereasbetween-treatment comparisons at the post-baseline visitswere performed with respect to difference or geometricmean ratio from baseline. All data are reported, butno statistical comparisons were performed for groupswith <10 subjects. SAS procedures MIXED, GENMOD,and LOGISTIC (SAS OnlineDoc®, SAS Institute Inc., Cary,NC) were used to carry out all analyses. No interim ana-lyses were planned or performed.ResultsPatient disposition is shown in Fig. 1. The study enroll-ment period was from January 20, 2011, through February4, 2013, during which approximately 2,669 patients wereprescreened for study inclusion. The exact number ofpatients seen is an estimate, due to different screeningFig. 1 Patient dispositionAllen et al. BMC Pediatrics  (2016) 16:117 Page 3 of 9processes between the centers. The study was stoppedearly due to slow recruitment after 100 patients were en-rolled with 77 evaluable mITT subjects. The ITT group wasformed by 100 patients who were randomized to receive ei-ther PLA (n = 51) or 0.9 % NaCl (n = 49). ETR occurred in23 patients due to baseline bicarbonate >22 mEq/L. Therewere 77 patients (PLA: 39; 0.9 % NaCl: 38) in the mITTgroup for assessment of the primary outcome.Pre-study Treatment Period ComparisonBaseline comparison of the mITT treatment groups ispresented in Table 1. Of note, patients in the PLA groupwere older. Both groups exhibited similar Gorelick dehy-dration scores, as well as similar FLACC, FACES, andBARF scores. In addition, both groups had similar weight-based fluid administration prior to receipt of study fluid(PLA: 17.98 ± 11.17 ml/kg vs 0.9 % NaCl: 15.38 ± 6.55 ml/kg; Additional file 1: Table S2).Treatment and outcomesThere were no significant differences in volume, durationof fluid administration, or maintenance IVT betweengroups. The number of boluses was 1.9 for both groups,dose of study treatment was 38.4 mL/kg vs 39.6 mL/kg,duration of administration was 104.3 min vs 93.7 min andmaintenance fluid was 12.2 vs 12.3 mL/kg PLA vs 0.9 %NaCl respectively, all P > .05. Twelve patients in the PLAgroup received concomitant maintenance IV fluid vs 11 inthe 0.9 % NaCl group.Outcome comparisons between the two groups arepresented in Table 2. Patients receiving PLA demonstratedsignificantly greater increase in serum bicarbonate levelsfrom baseline to hour 4 compared with patients receiving0.9 % NaCl. When stratified by bicarbonate level severity,PLA showed superiority over 0.9 % NaCl treatment forbicarbonate ranges ≥12 to 16. Although PLA patientsin the >16 to 22 mEq/L bicarbonate range had a statis-tically significant increase in serum bicarbonate levels(P < .05), the increase in the PLA group was not signifi-cantly different from the 0.9 % NaCl group (P = .11)for this bicarbonate range. None of the patients re-ceiving 0.9 % NaCl had baseline serum bicarbonatelevel <12 mEq/L. The three patients with severe acid-osis who received PLA demonstrated a mean improve-ment in serum bicarbonate level from 9.3 ± 0.6 mEq/Lto 14.3 ± 4.2 mEq/L.Comparison by age strata demonstrated PLA superior-ity for the >2 years to ≤5 years age range (mean 17.16 to18.31; P < .05). Although the >5 years to <11 years agerange had a significant increase in serum bicarbonate levelfor PLA patients (P < .05), superiority over 0.9 % NaCl wasnot calculated due to the small number of older subjectsin the 0.9 % NaCl group. Patients receiving PLA dem-onstrated significant improvements in clinical status asmeasured by the hour 2 Gorelick score and FLACCpain scales. Patients in the PLA group had improve-ment in BARF scores from baseline to hour 2 (meanchange −3.6 ± 5.1; P = .005) and hour 4 (mean change−4.8 ± 3.97; P = .005). Patients in the 0.9 % NaCl groupdid not show similar BARF score improvements at hour2 (mean change−2.1 ± 4.0; P = .08) but did at hour 4 (meanchange −2.9 ± 3.88; P = .02). However, between-groupBARF scores were not significant. No other differences insecondary outcome measures were observed.Safety outcomesThe shift in potassium and sodium levels from baselineto hour 4 is presented in Figs. 2 and 3. There were noepisodes of hyponatremia (<130 mEq/L) or hypernatre-mia (>155 mEq/L) in either group. Some patients ineach group presented with hyponatremia that was alsodocumented at hour 4 (PLA: 8/13; 0.9 % NaCl: 4/8), andone patient in each group developed mild hyponatremia(131–135 mEq/L). Hypokalemia (<3.5 mEq/L for ages≥6 months to ≤2 years and <3.0 mEq/L for ages 2–11years) and hyperkalemia (>5.6 mEq/L for ages ≥6 monthsTable 1 Baseline clinical and biochemical characteristics(mITT population)Plasma-Lyte A 0.9 % NaCln = 39 n = 38Age*, months, mean 45.9 34.2Age group, n (%) ≥6 months to ≤2 years 8 (21) 20 (53)>2 to ≤5 years 21 (54) 11 (29)>5 to <11 years 10 (26) 7 (18)Weight*, kg 15.8 ± 5.18 13.5 ± 6.80Vomiting episodes 8.9 ± 8.53 6.1 ± 5.92Diarrhea episodes 4.8 ± 4.77 6.8 ± 6.77Capillary refill time*, seconds 3.3 ± 0.50 2.8 ± 0.26Bicarbonate, mEq/L 16.9 ± 3.51 17.8 ± 2.82Sodium, mEq/L 137.0 ± 4.07 136.9 ± 2.93Potassium, mEq/L 4.4 ± 0.80 4.2 ± 0.67Chloride, mEq/L 103.0 ± 4.74 103.5 ± 4.19BUN, mg/dL 16.5 ± 7.17 14.6 ± 6.33Creatinine*, mg/dL 0.43 ± 0.13 0.37 ± 0.10Glucose, mg/dL 70.3 ± 21.26 74.4 ± 21.62Gorelick dehydration scale, median (IQR) 5 (5–6) 5 (5–6)Ondansetron 36 (92) 29 (76)All analgesicsa 25 (64) 23 (61)BUN blood urea nitrogen, IQR interquartile rangeAll data are presented as mean ± standard deviation unlessotherwise indicatedaAcetaminophen, nonsteroidal anti-inflammatory drugs, and narcoticsadministered orally and/or by intravenous infusion*P <0.05 PLA vs 0.9 % NaClAllen et al. BMC Pediatrics  (2016) 16:117 Page 4 of 9to ≤2 years and >5.5 mEq/L for ages 2–11 years) wereboth assessed. Two patients in the PLA group vs 6 inthe 0.9 % NaCl group became hypokalemic at hour 4.Four patients in the study developed hyperkalemia (PLA:1/39 vs 0.9 % NaCl: 3/38) by hour 4. All samples showinghyperkalemia demonstrated hemolysis, all of which weredeemed clinically insignificant by the investigators.DiscussionThis prospective, randomized, triple-blind, multicentertrial comparing PLA to 0.9 % NaCl in children with de-hydration secondary to AGE determined that PLA wassuperior to 0.9 % NaCl for improving the metabolic acidosis(change from baseline in bicarbonate of 1.6 mEq/L for PLAvs 0.0 mEq/L for 0.9 % NaCl) despite comparable initialTable 2 Primary and secondary outcomes (mITT population)Plasma-Lyte A 0.9 % NaCl P valuen = 39 n = 38Bicarbonate <23 mEq/LBaseline (hour 0) 16.9 ± 3.51 17.8 ± 2.82 .004Hour 4 18.5 ± 3.74 18.0 ± 3.67Bicarbonate <12 mEq/LBaseline (hour 0) (n) 9.3 ± 0.58 (3) – (0) NAbHour 4 (n) 14.3 ± 4.16 (3) – (0)Bicarbonate ≥12–16 mEq/LBaseline (hour 0) (n) 14.5 ± 1.34 (13) 14.6 ± 1.29 (13) .04Hour 4 (n) 16.1 ± 2.28 (12) 14.7 ± 2.90 (11)Bicarbonate >16–22 mEq/LBaseline (hour 0) (n) 19.23 ± 1.86 (23) 19.51 ± 1.68 (25) .11Hour 4 (n) 20.35 ± 3.18 (22) 19.53 ± 2.95 (24)Chloride, mmol/LBaseline 103.03 ± 4.74 103.53 ± 4.19 <0.001Hour 4 104.49 ± 3.18 108.51 ± 4.87Gorelick dehydration scaleBaseline (hour 0) 5.2 ± 0.93 5.3 ± 1.11 .03Hour 2 2.0 ± 1.45 2.8 ± 1.74Hour 4 0.81 ± 0.84 1.41 ± 1.08 .08FLACC pain scaleBaseline (Hour 0) 2.0 ± 1.91 1.7 ± 2.00 .03Hour 2 0.6 ± 0.98 1.7 ± 2.59Hour 4 1.44 ± 2.18 0.68 ± 1.35 .15FACES pain scaleBaseline (Hour 0) 2.3 ± 1.86 3.2 ± 1.90 .31Hour 2 1.1 ± 1.55 1.9 ± 1.60Hour 4 0.37 ± 0.60 1.11 ± 1.54 NABARF ScaleBaseline (Hour 0) 5.10 ± 4.02 4.43 ± 3.86 .27Hour 2 1.5 ± 3.10 2.00 ± 2.58 .55Hour 4 0.3 ± 0.98 1.23 ± 2.24 .12Time to Rehydrationa, h 6.1 ± 1.75 7.0 ± 2.7 .13Hospitalized, n (%) 12 (31) 11 (29) .86BARF, Baxter animated retching faces; FLACC, face, legs, activity, cry, consolability pain assessment scale for childrenAll data are presented as mean ± standard deviation unless otherwise indicatedaRehydration was defined as the time the clinician determined no further bolus fluid therapy was indicatedbNot available due to sample size (n <10)Allen et al. BMC Pediatrics  (2016) 16:117 Page 5 of 9serum bicarbonate levels and comparable volumes of IVT.In addition to acidosis, pain as assessed by the FLACCscale, and dehydration score significantly improved at hour2 in patients receiving PLA. The clinical significance of theimproved dehydration scores at hour 2 is unclear as thedehydration scores were not significantly improved athour 4 in patients receiving PLA. It may be that oncethe intravascular fluids redistributed, the clinical picturewas similar between the two treatment groups. Importantly,neither PLA nor 0.9 % NaCl induced significant hyponatre-mia or hyperkalemia. In fact, the frequency of conversionto abnormal laboratory values was similar between groups.Although randomization was performed at the centerlevel, the distribution of the children’s age and weightFig. 2 Change in sodium levels from baseline to hour 4Fig. 3 Change in potassium levels from baseline to hour 4Allen et al. BMC Pediatrics  (2016) 16:117 Page 6 of 9was dissimilar between groups, precluding some testcomparisons due to small sample size. However, therewere no differences in weight-based rehydration volumesor time despite baseline differences in age and capillaryrefill. Age stratification demonstrated a similar treatmenteffect across age groups.We tested serum bicarbonate as the primary outcome ofthis study based on evidence suggesting that dehydrationseverity is related to bicarbonate [23]. Low serum bicar-bonate levels are the most common electrolyte abnormal-ity occurring in children with AGE, and dehydrationseverity has been found to be related to the bicarbonateconcentration on admission [24, 25]. Bicarbonate is alsothe electrolyte most likely to alter care [25] in that it corre-lates with extended stay, admission to the observationunit, and administration of more IVT. Bicarbonate is aquantifiable, objective determinant, thus it is ideal for stat-istical power determination [9]. The European Society forPaediatric Gastroenterology, Hepatology, and Nutrition/European Society for Paediatric Infectious Diseasesrecommends that serum bicarbonate laboratory testsbe considered in dehydrated children if IVT is started[26]. These guidelines also recommend rapid rehydrationwith 20 mL/kg/h of 0.9 % saline solution for 2 to 4 h.The high level of chloride in 0.9 % NaCl is known tobe associated with hyperchloremic metabolic acidosis.Therefore, it is not surprising that despite its ability torehydrate in this study, 0.9 % NaCl did not improvemetabolic acidosis. Our study determined that correctingacidosis and fluid status was associated with clinicallyrelevant outcomes of significant improvement in dehy-dration scores and abdominal pain. In addition, althoughthe study was not powered to detect a difference in timeto rehydration, the data suggest that there may be a clin-ically meaningful difference of nearly 1 h (P = .13) andmay warrant further study with a larger sample.Interestingly, 0.9 % NaCl induced hyperchloremia with-out an associated change in bicarbonate. This finding is incontrast to studies in children with severe AGE [12] whereit increased bicarbonate, and in contrast to adult studiesthat show when 0.9 % NaCl is used as a resuscitative fluid,it generally decreases serum bicarbonate [27–29].When 0.9 % NaCl is used to treat children with acutediarrhea and severe dehydration, pH may decrease des-pite improvement in clinical signs of rehydration [30] Inthe present study the finding that 0.9 % NaCl caused asignificant increase in serum chloride levels suggests that0.9 % NaCl may exacerbate AGE acidosis via an ensuingnon-anion gap metabolic acidosis, due to a rapid rise inserum chloride levels relative to sodium [29].The majority of children were rehydrated with ap-proximately 40 mL/kg of treatment fluid. Although weallowed treatment for up to 8 h, most were rehydratedwith bolus infusions of less than 2 h and independent ofIVT type, approximately one-third in each group neededobservation/inpatient admission for continued hydration.We also found that electrolyte abnormalities post-treatment were similar between the two treatment groups,alleviating concerns of using a solution that contains alower sodium concentration than 0.9 % NaCl and thatcontains potassium.While common practice does not introduce potassiumuntil urine output is observed, this study supports thesafe use of a fluid containing physiologic amounts ofpotassium. In fact, the amount of potassium deliveredby PLA treatment during the study is surprisinglysmall–PLA contains 5 mEq/L of potassium. The averagechild in the PLA group weighed approximately 16 kg. At40 mL/kg, the average child received a total of 3.2 mEq ofpotassium via PLA, which is equivalent to about one-thirdof a banana.The strengths of this study were its randomization,effective blinding, clinical equipoise, and multicenterdesign. Limitations were its relatively small sample sizeand the resultant inability to detect some clinically import-ant secondary outcomes. Although the primary objectivewas achieved despite a lower-than-planned enrollment,not meeting planned enrollment may have impaired ourability to detect some of the secondary outcomes. More-over, although the random assignment was not similar interms of age or weight, the weight-based volumes deliv-ered were similar. The planned evaluation of the impact ofPLA by severity of baseline acidosis as measured by thebicarbonate strata was limited by the lack of severelydehydrated children in the 0.9 % NaCl group.ConclusionThis study adds new information for the treatment ofAGE-induced dehydration. PLA is an appropriate alterna-tive to 0.9 % NaCl because it provides the necessary waterand electrolyte replacement, and as an alkalinizing agentit may ameliorate the clinical sequelae of AGE-inducedacidosis. Both PLA and 0.9 % NaCl were effective andwell tolerated and had similar safety profiles. Plasma-Lyte Awas more effective than 0.9 % NaCl at correcting acidosis,in particular in patients with moderate acidosis on admis-sion, and led to improved clinical findings of dehydration.Additional fileAdditional file 1: Table S1. Ethics Committees. Table S2. IVF bolusduring screening and safety follow-up visits (mITT population). (DOCX 15 kb)AbbreviationsAGE, Acute gastroenteritis; BARF, Baxter Animated Retching Face; ED,Emergency department; FLACC, Face, legs, activity, cry, consolability painassessment scale for children; HCA, Hyperchloremic metabolic acidosis;IVT, Intravenous fluid therapy; LR, Lactated Ringer’s; mITT, Modified intent-to-Allen et al. BMC Pediatrics  (2016) 16:117 Page 7 of 9treat; NaCl, Sodium chloride; PLA, Plasma-Lyte A (sodium chloride, sodiumgluconate, sodium acetate, potassium chloride and magnesium chlorideAcknowledgementsThe authors gratefully acknowledge the editorial assistance provided by EdShifflett, PhD; and Elizabeth Rosenberg, PhD; of AlphaBioCom, LLC, King ofPrussia, PA, which was funded by Baxter Healthcare Corporation.BJS and CRS were employees of Baxter Healthcare Corporation during thestudy design, completion, and manuscript development.FundingBaxter Healthcare Corporation funded this study.Availability of data and materialsDataset (s) supporting the conclusions of this article are included within thearticle and are available at clinicaltrials.gov [https://clinicaltrials.gov/ct2/show/results/NCT01234883?term=plasma-lyte+and+baxter&rank=4]. Due to privacyand consent, patient-level data are not posted in a public repository. However,proposals for data requests can be sent to Baxter for review.Authors’ contributionsSLG served as the safety monitor for the study, co-wrote the first draft, andsaw and approved the final version of the manuscript. HD was the statisticianfor the study and saw and approved the final version of the manuscript.CHA co-wrote the first draft; was one of the site principal investigators forthe study and contributed to data collection, data review and manuscriptwriting and revisions; and saw and approved the final version of the manuscriptfor submission. CRS co-wrote the first draft and saw and approved the finalversion of the manuscript for submission. BJS co-wrote the first draft and sawand approved the final version of the manuscript for submission. RDG was oneof the site principal investigators for the study and contributed to datacollection, data review and manuscript writing and revisions; and saw andapproved the final version of the manuscript for submission. SB was one ofthe site principal investigators for the study and contributed to data collection,data review and manuscript writing and revisions; and saw and approved thefinal version of the manuscript for submission. HKS was one of the site principalinvestigators for the study and contributed to data collection, data review andmanuscript writing and revisions; and saw and approved the final version of themanuscript for submission. MHG was one of the site principal investigators forthe study and contributed to data collection, data review and manuscriptwriting and revisions; and saw and approved the final version of the manuscriptfor submission. PRS was one of the site principal investigators for the study andcontributed to data collection, data review and manuscript writing and revisions;and saw and approved the final version of the manuscript for submission. DMSwas one of the site principal investigators for the study and contributed to datacollection, data review and manuscript writing and revisions; and saw andapproved the final version of the manuscript for submission. SEM was oneof the site principal investigators for the study and contributed to datacollection, data review and manuscript writing and revisions; and saw andapproved the final version of the manuscript for submission. DWJ was oneof the site principal investigators for the study and contributed to datacollection, data review and manuscript writing and revisions; and saw andapproved the final version of the manuscript for submission. EAH was oneof the site principal investigators for the study and contributed to datacollection, data review and manuscript writing and revisions; and saw andapproved the final version of the manuscript for submission.Authors’ informationNot applicable.Competing interestsCHA has received industry-funded clinical research from Venaxis, Salter Labs,Cerexa, AstraZeneca, and Baxter. Dr. Simon has received grant funding fromAspen Pharma/Venaxis Pharma. MHG has received funding as a co-investigatorfrom AHRQ. PRS has received research funding from AspenBioPharma andBaxter. SEM has received research grants from Durata, Shire Orphan Therapies,Aspen Biopharma, Baxter Healthcare, Halozyme, Luitpold Pharmaceuticals,Roche, Ischemia Care, and Gebauer processed through the hospital, ClevelandClinic Foundation. EAH has received industry funded clinical research from CSLBehring, Baxter, Durata Therapeutics. SLG has received industry funded clinicalresearch from Baxter and Gambro. HD is an employee of Baxter. BJS and CRSwere employees of Baxter at the time of this study. DMS, DWJ, RDG and SBdeclare that they have no competing interests.Consent for publicationNot applicable.Ethics approval and consent to participateInstitutional ethics approval was obtained from each institution (Additional file1: Table S1), and written informed consent was obtained from the parent/legalguardian of all children before randomization.Author details1Department of Pediatrics, Dell Medical School at University of Texas atAustin, 4900 Mueller Blvd, Austin, TX 78746, USA. 2Department of Pediatrics,British Columbia Children’s Hospital, University of British Columbia,Vancouver, BC, Canada. 3Department of Pediatrics, Cincinnati Children’sHospital Medical Center, Cincinnati, OH, USA. 4Departments of Pediatrics andEmergency Medicine, Emory University/Children’s Healthcare of Atlanta,Atlanta, GA, USA. 5Pediatric Emergency Medicine, Children’s Hospital ofWisconsin, Milwaukee, WI, USA. 6Pediatric Emergency Medicine Associates,Children’s Healthcare of Atlanta, Atlanta, GA, USA. 7Pediatric EmergencyServices, Oregon Health and Science University, Portland, OR, USA.8Department of Emergency Medicine, Cleveland Clinic, Cleveland, OH, USA.9Departments of Pediatrics, Pharmacology and Physiology, Alberta Children’sHospital, Calgary, AB, Canada. 10Research and Development, BaxterHealthcare Corporation, Deerfield, IL, USA. 11Bristol-Myers Squibb,Pennington, NJ, USA.Received: 26 August 2015 Accepted: 19 July 2016References1. 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Epidemiol Infect. 2007;135:293–301.6. Graves NS. Acute gastroenteritis. Prim Care. 2013;40:727–41.7. Tate JE, Burton AH, Boschi-Pinto C, Steele AD, Duque J, Parashar UD, et al.2008 estimate of worldwide rotavirus-associated mortality in childrenyounger than 5 years before the introduction of universal rotavirusvaccination programmes: a systematic review and meta-analysis. LancetInfect Dis. 2012;12:136–41.8. Gennari FJ, Weise WJ. Acid–base disturbances in gastrointestinal disease.Clin J Am Soc Nephrol. 2008;3:1861–68.9. Yilmaz K, Karabocuoglu M, Citak A, Uzel N. Evaluation of laboratory tests indehydrated children with acute gastroenteritis. J Paediatr Child Health.2002;38:226–28.10. Freedman SB, DeGroot JM, Parkin PC. Successful discharge of children withgastroenteritis requiring intravenous rehydration. J Emerg Med. 2014;46:9–20.11. Neville KA, Verge CF, Rosenberg AR, O’Meara MW, Walker JL. Isotonic isbetter than hypotonic saline for intravenous rehydration of childrenwith gastroenteritis: a prospective randomised study. Arch Dis Child.2006;91:226–32.12. Mahajan V, Sajan SS, Sharma A, Kaur J. Ringers lactate vs Normal saline forchildren with acute diarrhea and severe dehydration- a double blindrandomized controlled trial. Indian Pediatr. 2012;49:963–68.13. Young JB, Utter GH, Schermer CR, Galante JM, Phan HH, Yang Y, et al. Salineversus Plasma-Lyte A in initial resuscitation of trauma patients: arandomized trial. Ann Surg. 2014;259:255–62.Allen et al. BMC Pediatrics  (2016) 16:117 Page 8 of 914. McFarlane C, Lee A. A comparison of Plasmalyte 148 and 0.9 % saline forintra-operative fluid replacement. Anaesthesia. 1994;49:779–81.15. Hadimioglu N, Saadawy I, Saglam T, Ertug Z, Dinckan A. The effect ofdifferent crystalloid solutions on acid–base balance and early kidneyfunction after kidney transplantation. Anesth Analg. 2008;107:264–69.16. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association betweena chloride-liberal vs chloride-restrictive intravenous fluid administration strategyand kidney injury in critically ill adults. JAMA. 2012;308:1566–72.17. Centers for Disease Control and Prevention. Guidelines for Management ofAcute Diarrhea: Disaster Safety. 2005. http://emergency.cdc.gov/disasters/disease/diarrheaguidelines.asp. Accessed 25 July 2016.18. Fields JM, Dean AJ. Systemic causes of abdominal pain. Emerg Med ClinNorth Am. 2011;29:195–210.19. Rosner MH. Metabolic Acidosis in Patients with Gastrointestinal Disorders:Metabolic and Clinical Consequences. Nutrition Issues in Gastroenterology,Series #73. Practical Gastroenterology. 2009. p. 42–52.20. Gorelick MH, Shaw KN, Murphy KO. Validity and reliability of clinical signs inthe diagnosis of dehydration in children. Pediatrics. 1997;99, E6.21. World Health Organization. World Health Organization (WHO) Guidelines onTreatment of Diarrhea. 2005. http://www.who.int/maternal_child_adolescent/documents/9241593180/en/ Accessed September 15, 2014.22. Baxter AL, Watcha MF, Baxter WV, Leong T, Wyatt MM. Developmentand validation of a pictorial nausea rating scale for children. Pediatrics.2011;127:e1542–49.23. Vega RM, Avner JR. A prospective study of the usefulness of clinical andlaboratory parameters for predicting percentage of dehydration in children.Pediatr Emerg Care. 1997;13(3):179–82.24. Reid SR, Bonadio WA. Outpatient rapid intravenous rehydration to correctdehydration and resolve vomiting in children with acute gastroenteritis.Ann Emerg Med. 1996;28:318–23.25. Wathen JE, MacKenzie T, Bothner JP. Usefulness of the serum electrolytepanel in the management of pediatric dehydration treated withintravenously administered fluids. Pediatrics. 2004;114:1227–34.26. Guarino A, Ashkenazi S, Gendrel D, Vecchio AL, Shamir R, Szajewska H.European society for paediatric gastroenterology, hepatology, and nutrition/European society for paediatric infectious diseases evidence-basedguidelines for the management of acute gastroenteritis in children ineurope: update 2014. J Pediatr Gastroenterol Nutr. 2014;59:132–52.27. Eisenhut M. Hyperchloraemic acidosis in patients given rapid isotonic salineinfusions. Arch Dis Child. 2007;92:560.28. Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled,double-blind crossover study on the effects of 2-L infusions of 0.9 % salineand plasma-lyte® 148 on renal blood flow velocity and renal cortical tissueperfusion in healthy volunteers. Ann Surg. 2012;256:18–24.29. Reid F, Lobo DN, Williams RN, Rowlands BJ, Allison SP. (Ab) normal salineand physiological Hartmann’s solution: a randomized double-blindcrossover study. Clin Sci (Lond). 2003;104:17–24.30. Juca CA, Rey LC, Martins CV. Comparison between normal saline and apolyelectrolyte solution for fluid resuscitation in severely dehydrated infantswith acute diarrhoea. Ann Trop Paediatr. 2005;25:253–60.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Allen et al. BMC Pediatrics  (2016) 16:117 Page 9 of 9


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