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Published on in Vol 15 (2026)

Preprints (earlier versions) of this paper are available at https://preprints.jmir.org/preprint/95459, first published .
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Oral vs Intravenous Fluid Therapy in Emergency Department Patients: Protocol for a Randomized Controlled Feasibility and Noninferiority Trial

Oral vs Intravenous Fluid Therapy in Emergency Department Patients: Protocol for a Randomized Controlled Feasibility and Noninferiority Trial

Authors of this article:

Peter Biesenbach1 Author Orcid Image ;   Mette Rahbek Kristensen1 Author Orcid Image ;   Mikkel Brabrand2 Author Orcid Image ;   Christian Backer Mogensen3 Author Orcid Image ;   Line Emilie Laugesen1 Author Orcid Image
Article Authors Cited by Tweetations Metrics

    Protocol

    1Department of Emergency Medicine, Esbjerg Hospital, University of Southern Denmark, Esbjerg, South Denmark, Denmark

    2Department of Emergency Medicine, Odense University Hospital, University of Southern Denmark, Odense, South Denmark, Denmark

    3Department of Emergency Medicine, Hospital Sønderjylland, University of Southern Denmark, Aabenraa, South Denmark, Denmark

    Corresponding Author:

    Peter Biesenbach, MD

    Department of Emergency Medicine

    Esbjerg Hospital

    University of Southern Denmark

    Finsensgade 35

    Esbjerg, South Denmark, 6700

    Denmark

    Phone: 45 53861985

    Email: peter.biesenbach@rsyd.dk


    Background: Intravenous fluid therapy is widely used in emergency departments (EDs) to treat hypovolemia and hypotension. However, its hemodynamic effects are often modest and short-lived. Intravenous fluid therapy requires a peripheral venous catheter, which increases the risk of complications such as catheter failure and phlebitis. Oral fluid therapy represents a simple, noninvasive alternative that has been shown in physiological studies to expand plasma volume and increase blood pressure. No randomized trial has compared oral with intravenous fluid therapy in a general adult ED population. Evidence regarding the feasibility of randomized comparisons of fluid administration modes and whether oral fluid administration can reliably deliver the prescribed volume remains limited.

    Objective: This study aims to evaluate the feasibility of conducting a randomized controlled trial of oral vs intravenous fluid therapy in ED patients requiring fluid replacement and to determine whether oral fluid therapy is noninferior to intravenous fluid therapy in achieving the prescribed fluid volume.

    Methods: This investigator-initiated, multicenter, open-label randomized controlled feasibility and noninferiority trial will enroll 250 adult ED patients prescribed ≥1000 mL of intravenous crystalloid therapy. Participants will be randomized 1:1 to receive either oral fluids or intravenous crystalloid. The primary feasibility outcome is protocol adherence, defined as the proportion of randomized participants who receive the allocated route of administration without a major protocol deviation. The primary clinical outcome is the proportion of patients achieving the prescribed fluid volume during the ED stay, censored at 48 hours after randomization and analyzed using a noninferiority framework. Noninferiority of oral fluid therapy will be tested against the null hypothesis that the intravenous proportion exceeds the oral proportion by at least the noninferiority margin of 15 percentage points, using the difference in proportions with a 1-sided 97.5% CI (equivalent to a 2-sided 95% CI) from an exact proportion test. The sample size of 250 will provide 90% power at a 1-sided α of .025 under an assumed proportion of 85% in both arms.

    Results: The study was funded by the Region of Southern Denmark in May 2024. Recruitment began in October 2025 at 3 Danish EDs, and 85 participants have been recruited as of September 2026. Recruitment is projected to close in October 2026, with final 30-day follow-up projected for November 2026. No amendments to the protocol have been made. Results are expected to be published in summer 2027.

    Conclusions: This trial will evaluate whether a randomized trial comparing intravenous and oral fluid therapy is feasible in ED patients and whether oral fluid therapy can achieve prescribed fluid volumes comparable to those achieved with intravenous therapy. The findings will inform the design of a future definitive effectiveness trial.

    Trial Registration: ClinicalTrials.gov NCT07361952; https://clinicaltrials.gov/study/NCT07361952

    International Registered Report Identifier (IRRID): DERR1-10.2196/95459

    JMIR Res Protoc 2026;15:e95459

    doi:10.2196/95459

    Keywords

    emergency medicine; fluid therapy; oral fluid; resuscitation; fluid methods; rehydration solutions; infusions; intravenous; crystalloid solutions; randomized controlled trial; hypovolemia 


    Background

    Intravenous fluid therapy is among the most frequently administered interventions in emergency departments (EDs) and critical care settings [1,2]. It is routinely used to improve organ perfusion in patients with hypotension and hypovolemia; however, the hemodynamic effects of fluid therapy are often modest and short-lived [3]. Evidence guiding fluid therapy strategies remains inconclusive in several key areas. Large clinical trials have failed to demonstrate consistent differences in outcomes between balanced crystalloids and isotonic saline [4,5] as well as between restrictive and liberal fluid strategies [6-8]. Liberal intravenous fluid administration may also contribute substantially to health care resource use [9]. Despite the uncertainty, intravenous fluid therapy remains a cornerstone of ED treatment in acute illness [10,11].

    Another aspect of fluid administration has not yet been explored in the ED setting: whether it is at all necessary to administer a fluid bolus intravenously, as an infusion. Intravenous therapy requires a peripheral intravenous catheter, which carries the risk of complications such as occlusion, dislodgement, phlebitis, and bacteremia [12,13]. A large number of ED patients receive peripheral venous catheters despite not strictly requiring them [14,15].

    Oral fluid administration represents a simple, noninvasive alternative. Beyond its practicality, oral fluid administration exerts distinct physiological effects. Previous data suggest that oral fluids induce expansion of the circulating plasma volume, recruitment of splanchnic blood volume, peripheral vasoconstriction [16,17], increased cerebral blood flow [18], and increased blood pressure [19]. Collectively, these findings indicate that oral fluid therapy induces a range of cardiovascular responses associated with sympathetic activation, although the precise underlying mechanisms remain incompletely understood [20].

    Despite these physiological observations, prospective clinical evidence remains limited. In a randomized crossover trial conducted by our group in healthy participants, oral fluid therapy resulted in a significantly greater and more sustained increase in mean arterial pressure than intravenous fluids [21]. Similarly, a greater increase in blood pressure was also reported in intensive care patients in shock when fluids were administered via a nasogastric tube [22]. A meta-analysis published in 2018 found oral hydration to be as effective as intravenous hydration in preventing contrast-induced nephropathy [23]. A trial showed no difference in outcome for acute pancreatitis between nasojejunal and intravenous fluid therapy [24]. In pediatric populations, a randomized trial demonstrated that oral fluid therapy was not inferior to intravenous fluid therapy [25], and a meta-analysis of 16 randomized controlled trials investigating gastroenteritis reported shorter hospital stays and fewer serious adverse events in the oral group [26].

    Despite these findings, no prospective randomized controlled trials have compared oral and intravenous fluid therapy in adult ED populations. Intravenous fluids are frequently administered to patients who are alert, cooperative, and able to swallow. Yet it remains uncertain whether oral administration can reliably deliver prescribed fluid volumes in routine emergency care. The advantage postulated for oral fluid therapy is not that it delivers fluid better than the intravenous route, but that it delivers fluid at similar rates. Establishing feasibility and exploring noninferiority in volume delivery are therefore necessary steps before conducting a definitive effectiveness trial.

    Objectives

    The aim of this study is to evaluate the feasibility of conducting a randomized controlled trial comparing oral and intravenous fluid therapy in ED patients requiring fluid replacement and to determine whether oral fluid therapy is noninferior to intravenous fluid therapy in achieving the prescribed fluid volume during the trial period, defined as the ED stay censored at 48 hours after randomization.


    Study Design

    This study is an investigator-initiated, multicenter, open-label, randomized controlled feasibility and noninferiority trial. The study protocol is reported in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement [27]. A flow diagram of the study design is shown in Figure 1.

    The trial has 2 primary objectives. The primary feasibility objective is to evaluate the feasibility of administering oral fluid therapy in the ED setting, assessed by protocol adherence. The primary clinical objective is to determine whether oral fluid therapy is noninferior to intravenous fluid therapy in achieving the prescribed fluid volume during the trial period, defined as the ED stay censored at 48 hours after randomization. The study is designed as a pragmatic trial to reflect routine clinical practice.

    ‎
    Figure 1. Participant flow through the trial, showing screening, randomization, allocation, the trial period, follow-up, and analysis populations. ED: emergency department; GCS: Glasgow Coma Scale.

    Study Setting

    The trial is being conducted at 3 Danish EDs in the Region of Southern Denmark. Participants are recruited from the EDs at the University Hospitals of Aabenraa, Esbjerg, and Odense. The combined catchment area is around 950,000 inhabitants.

    Research personnel will recruit participants and collect data. All research personnel will follow standardized protocols for screening and patient inclusion, as well as follow-up and data collection. The study originates from the research unit for emergency medicine in Esbjerg.

    Study Period

    Recruitment began in October 2025 and is expected to continue until October 2026.

    Population and Eligibility Criteria

    Adults aged ≥18 years presenting to the ED for any reason will be invited to participate in the study if the treating physician prescribes a minimum of 1000 mL of crystalloid intravenous fluid therapy during the ED stay. Only patients able to provide informed consent will be included. A patient can participate in the study only once.

    Patients are excluded if they fulfill any of the following criteria: Glasgow Coma Scale score ≤12 (altered mental state prohibiting oral fluid intake), pregnancy, contradictions to oral fluids, hyponatremia <120 mEq/L, or a requirement for treatment in the intensive care unit.

    Recruitment and Informed Consent

    Research personnel identify eligible participants presenting to the ED through electronic health records during weekdays between 08:00 AM and 4:00 PM. The treating clinician is contacted as soon as intravenous fluid treatment has been prescribed. If the patient meets the eligibility criteria, research personnel will inform the patient about the study details and invite them to participate in the study. All screened patients are recorded in a screening log, including those meeting an exclusion criterion, those for whom the treating physician declines an approach, and those declining participation, with the reason for noninclusion in each case.

    Assignment of Interventions

    Randomization is performed stratified per site using block randomization with a 1:1 allocation to the intervention or control group, using the electronic randomization system accessible through REDCap (Vanderbilt University) via the Open Patient Data Explorative Network (OPEN; Odense University Hospital [OUH]) [28]. After obtaining written consent from the participant, the research staff will create a new record and randomize the patient within the program, automatically assigning the patient to a treatment arm. Personnel who will enroll participants and those who will assign participants to the interventions will not have access to the random allocation sequence.

    Concealment

    Due to the type of intervention, it is not possible to blind the allocation of treatment to the participants or study representatives. The biostatistician performing the analysis will be blinded to the allocation.

    Intervention (Oral Fluids)

    The treatment consists of clear fluids administered orally of any type (eg, tap water or tea). The fluid temperature will not be specified for the trial. The fluids will be administered via regular single-use cups available in the ED. The bedside nurse encourages the patient to drink if necessary to achieve the prescribed fluid volume. During the trial period, the patient receives any prescribed fluid volume orally over a predefined time frame decided by the attending physician. Patients are allowed to drink additional fluids. Participation in the oral fluid administration arm will be ended in the event of >2 episodes of vomiting refractory to medication.

    Control (Intravenous Fluids)

    The type of intravenous fluid is chosen by the physician from the standard repertoire of crystalloid infusions available at the ED. These include Ringer’s lactate, 0.9% sodium chloride, and Ringer’s acetate. The crystalloid infusions are stored at room temperature in the medical storage room or within the patient’s room and are also administered at room temperature. Empty fluid packages are not stored after use. During the trial period, the patient receives any prescribed fluid volume intravenously over a predefined time frame decided by the attending physician. Patients are allowed to drink additional fluids.

    Trial Period

    The trial period is limited to the stay in the ED. In the case of discharge to home, admission to the ward, or transfer to another medical facility, the trial period stops. Furthermore, 48 hours after inclusion, the trial period stops, even if the patient is still boarded in the ED. Transport within the ED for any reason, including X-rays, computed tomography imaging, or echocardiography, does not affect participation. In both groups, the total fluid volume as well as the rate of fluid administration during the ED stay will be decided by the physician, and repeat fluid boluses are not limited. The study does not limit additional care, including other types of oral or intravenous fluids such as antibiotics or transfusions.

    Outcomes

    Overview

    All outcomes are summarized in Tables 1 and 2.

    Table 1. Feasibility outcome measures.
    OutcomesDefinitionsMetricsTime points
    Primary feasibility outcome: protocol adherenceProportion of participants with no major protocol deviation. Major protocol deviations are defined as follows: (1) enrollment of a participant who met an exclusion criterion, (2) randomization without valid informed consent, or (3) administration of intravenous crystalloid for volume replacement to a participant allocated to the oral arm. Oral intake is permitted in both arms and does not constitute a protocol deviation. Discontinuation of the oral arm under the prespecified stopping rule (>2 episodes of vomiting refractory to medication) is considered protocol-adherent.Proportion with 95% CI, overall and by siteEDa stay (censored at disposition or 48 hours)
    Secondary feasibility outcomes

    		Recruitment rateNumber of participants recruited over time at each site, relative to the catchment populationDescriptive (count; rate per site-month)Enrollment period

    		Data collection feasibilityExtent, pattern, and reasons for missing source dataDescriptive (proportion missing by variable, with reasons)Throughout the study

    		Study completion rateProportion of participants completing the study through day 30Descriptive (proportion with 95% CI)Day 30

    		Resource requirementsTime, staff, and financial resources required to conduct the trialDescriptiveThroughout the study

    		Fidelity rateConsistency of intervention delivery across sitesDescriptive (proportion adherent by site)ED stay

    		Recruitment cascadeNumbers screened, excluded by criterion, not approached at the treating physician’s request, declining consent, randomized, and withdrawn during the trial period or before day 30, with reasonsDescriptive; CONSORTb flow diagramScreening through day 30

    aED: emergency department.

    bCONSORT: Consolidated Standards of Reporting Trials.

    Table 2. Clinical outcome measures.
    OutcomesDefinitionsMetricsTime points
    Primary clinical outcome: achievement of prescribed fluid volumeProportion of participants achieving the prescribed fluid volume by the allocated route during the trial periodRisk difference (oral minus IVa) with 2-sided 95% CI (exact proportion test); noninferiority will be concluded if the lower limit exceeds −15 percentage points in both the intention-to-treat and per-protocol populationsEDb stay (censored at disposition or 48 hours)
    Secondary clinical outcomes

    		Fluid received during the ED stayIV, oral, and total fluid volume received during the entire ED stayMean (SD) or median (IQR); t test or Mann-Whitney U test, according to distributionED stay

    		Fluid received during the study periodIV, oral, and total fluid volume received during the trial periodMean (SD) or median (IQR); t test or Mann-Whitney U testTrial period (≤48 hours)

    		Change in blood pressureChange in systolic and mean arterial pressureMean change with 95% CI; t test or Mann-Whitney U testBaseline to 8 hours or discharge, whichever occurs first

    		Hospital-free days aliveDays alive and out of hospital, dichotomized as event-free at 30 daysProportion; chi-square test or Fisher exact test; RRc with 95% CIDay 30

    		MortalityAll-cause mortalityProportion; chi-square test or Fisher exact test; RR with 95% CIDay 30

    		PIVCd hoursNumber of hours with a peripheral IV catheter in situMedian (IQR); Mann-Whitney U testED stay through PIVC removal

    		PIVC avoidanceProportion of participants without any PIVC during the study periodProportion; chi-square test or Fisher exact test; RR with 95% CITrial period (≤48 hours)

    		Acute kidney injuryAcute kidney injury according to RIFLEe criteria within 48 hoursProportion; chi-square test or Fisher exact test; RR with 95% CI (exploratory safety)Within 48 hours

    		Severe electrolyte derangementSodium <120 or >160 mmol/L, potassium <3 or >6 mmol/L, or chloride <90 or >110 mmol/L within 48 hoursProportion; chi-square test or Fisher exact test; RR with 95% CI (exploratory safety)Within 48 hours
    Substudy outcomes

    		Continuous hemodynamics (substudy 1)Blood pressure, cardiac output, stroke volume, pulse, and systemic vascular resistance index measured noninvasively using Edwards HemoSphere; 10 participants per armDescriptive (summary statistics); not powered for comparisonFirst 4 hours of fluid therapy

    		Health-related quality of life (substudy 2)36-item Short Form Health Survey, comprising 8 domains; 10 participants per armDescriptive (domain scores); not powered for comparisonDay 30

    		Anxiety and depressive symptoms (substudy 2)Hospital Anxiety and Depression Scale, comprising 14 items; 10 participants per armDescriptive (subscale scores); not powered for comparisonDays 7 and 30

    aIV: intravenous.

    bED: emergency department.

    cRR: relative risk.

    dPIVC: peripheral intravenous catheter.

    eRIFLE: risk, injury, failure, loss of kidney function, and end-stage kidney disease.

    Substudy 1: Continuous Blood Pressure Monitoring

    In 10 patients receiving the intervention and 10 patients from the control group, we will measure hemodynamic parameters (blood pressure, cardiac output, stroke volume, pulse, and systemic vascular resistance index) continuously via a noninvasive device (Edwards HemoSphere; Becton, Dickinson and Company) over the first 4 hours of fluid therapy.

    Substudy 2: Patient Satisfaction

    Ten patients from each group, for a total of 20 patients, will receive an electronic questionnaire measuring quality of life on day 30, the 36-item Short Form Health Survey, a patient-reported questionnaire that covers 8 health domains and has been validated in a Danish general-population sample [29]. Patients are also provided with the Hospital Anxiety and Depression Scale to complete on days 7 and 30, a self-assessment scale for detecting states of depression and anxiety in the hospital setting with established validity in patients with medical illness [30]. All questionnaires will be delivered to the patient through electronic or standard mail if consent is given.

    Data Collection Methods

    Data collection will be carried out by dedicated and trained research personnel. Data collected will be entered by research personnel into the electronic database REDCap via OPEN at OUH, and/or uploaded and stored on a secure SharePoint site. Patients who are screened but not randomized are not entered into the trial database; only the screening log entry and the reason for noninclusion are retained. Participants may withdraw at any time without giving a reason. For participants who withdraw after randomization, data collected up to the point of withdrawal are retained and analyzed unless deletion is requested, in which case the record is deleted.

    Data Collected

    A schedule of measurements is provided in Figure 2. Information necessary for assessing eligibility of potential participants prior to obtaining informed consent is disclosed to the investigator in accordance with applicable data protection regulations. For screening, the following parameters are assessed without patient consent: social security number, name, admission blood tests, pregnancy test, prescriptions ordered by the physician, and vital signs (systolic and diastolic blood pressure, mean arterial pressure, heart rate, peripheral oxygen saturation, Glasgow Coma Scale score, and ear temperature).

    After consent is given, we collect additional data, including feasibility measures (recruitment rate, data collection feasibility, study completion rate, and protocol adherence; the journal information collected is restricted to the duration from admission to the ED until 30 days after inclusion), clinical parameters (patient characteristics and demographics, such as date of birth, sex, name, and comorbidities [Charlson Comorbidity Index]), and any vital signs recorded as part of standard patient management during the stay in the ED (systolic and diastolic blood pressure, mean arterial pressure, heart rate, peripheral oxygen saturation, Glasgow Coma Scale score, and tympanic temperature). All fluids administered both orally and intravenously will be documented.

    The time and date of admission and discharge will be collected for the first 30 days. The time and date of any readmission or death will be collected for the first 30 days. The time and date of insertion and removal of any peripheral cannula will be documented, as well as the reason for removal. Blood tests for sodium, chloride, potassium, and creatinine from admission until 48 hours after inclusion will be collected.

    ‎
    Figure 2. Schedule of enrollment, interventions, and assessments. Vital signs included systolic and diastolic blood pressure, mean arterial pressure, heart rate, peripheral oxygen saturation, Glasgow Coma Scale score, and tympanic temperature. Blood tests included sodium, chloride, potassium, and creatinine. Substudy 1 for continuous hemodynamics included 10 participants per arm and assessed blood pressure, cardiac output, stroke volume, pulse, and systemic vascular resistance during the first 4 hours. Substudy 2 for vital status and readmission included 10 participants per arm and assessed vital status, readmission, and hospital-free days through day 30. ED: emergency department; HADS: Hospital Anxiety and Depression Scale; IV: intravenous; PIVC: peripheral intravenous catheter; SF-36: 36-item Short Form Health Survey.

    Data Monitoring Committee and Trial Monitoring

    No data monitoring committee has been established for this trial. The interventions involve administration of fluid therapy, which is routinely used as part of standard clinical care in the ED and considered a low-risk intervention. A data monitoring committee was deemed unnecessary. Trial oversight is instead provided by the local investigators responsible for trial conduct, participant safety, and protocol adherence.

    Data Analysis

    Data will be stored for 10 years in accordance with Danish regulatory requirements. Data are stored in pseudonymized form and will be managed and analyzed using Stata (version 18; StataCorp) in collaboration with an independent biostatistician. We will not conduct any interim analyses. The primary analysis will be performed on both the intention-to-treat and per-protocol populations, as recommended for noninferiority trials. Missing data will not be imputed. Feasibility outcomes will be analyzed descriptively.

    Statistical Analysis

    Data are stored in pseudonymized form for 10 years in accordance with Danish regulatory requirements and are managed and analyzed in R (version 4.6.1; R Foundation for Statistical Computing) in collaboration with an independent biostatistician blinded to allocation. No interim analysis is planned.

    The primary analysis will be performed on both the intention-to-treat population (all randomized participants, regardless of the treatment received) and the per-protocol population (participants who completed the allocated route without a major protocol deviation). For a noninferiority trial, concordant results in both populations are required for the conclusion to be considered robust; a discordant result will be reported as inconclusive.

    For the primary clinical outcome, let Poral and PIV denote the proportions achieving the prescribed volume in the 2 arms. Noninferiority will be assessed against the null hypothesis that PIV−Poral is at least the noninferiority margin of 15 percentage points (absolute scale). The difference in proportions will be estimated with a 1-sided 97.5% CI (equivalent to a 2-sided 95% CI) using an exact proportion test (prop.test in R); noninferiority will be concluded if the lower confidence limit excludes a difference in favor of intravenous fluids of >15 percentage points.

    Secondary binary outcomes will be compared using chi-square or Fisher exact tests, with relative risks and 95% CIs. Secondary continuous outcomes will be compared using independent t tests or Mann-Whitney U tests according to distribution, assessed by the Shapiro-Wilk test. Hospital-free days will be dichotomized as event-free at 30 days (yes or no) and analyzed as a binary outcome. Feasibility outcomes will be summarized descriptively. The planned presentation of the principal results is shown in Table 3.

    Table 3. Template for presentation of the principal trial results.
    OutcomesOral fluid therapy (n=125)Intravenous fluid therapy (n=125)Difference (95% CI)P value
    Primary outcome: achieved fluid volume, (%)n (%)n (%)Risk difference (lower limit-upper limit)PNIa
    30-day mortalityn (%)n (%)RRa (lower limit-upper limit)P
    Mean fluid received (mL)Mean (SD)Mean (SD)Mean difference (lower limit-upper limit)P
    Acute kidney injuryn (%)n (%)RR (lower limit-upper limit)PAKIc

    aNI: noninferiority.

    bRR: relative risk.

    cAKI: acute kidney injury.

    Sample Size

    A feasibility trial does not require a sample size calculation. The sample size is therefore determined by the primary clinical (noninferiority) outcome. No published data describe the proportion of adult ED patients who receive the full prescribed volume of fluids before disposition, and we identified no directly comparable benchmark. We expect 85% of patients in both arms to achieve the prescribed fluid volume. This assumption was established by structured consensus among the treating clinicians at the participating sites, informed by pediatric enteral-rehydration literature, in which failure of the oral route occurs in approximately 10% of children [26]. Estimating this proportion in adult ED patients is one of the objectives of the trial, and the observed proportion in the intravenous arm will be used to specify the sample size of any subsequent definitive trial. Under this assumption, for a binary outcome analyzing noninferiority of oral fluids, 240 patients in total are required with 90% power and a 1-sided α of .025 to exclude a difference in favor of the intravenous fluids of >15 percentage points. This margin was chosen based on clinical judgment that a difference of <15 percentage points would not be considered clinically relevant, given the advantages of oral administration. To accommodate dropouts, a total of 250 patients will be included.

    Ethical Considerations

    The trial was registered at ClinicalTrials.gov (NCT07361952) on December 29, 2025, after recruitment had commenced on October 3, 2025. Registration was delayed unintentionally; the trial was approved by the Regional Committees on Health Research Ethics for the Region of Southern Denmark (S-20250042) on September 8, 2025. The processing of personal data was registered with the Region of Southern Denmark internal registry as required under the European Union General Data Protection Regulation and Danish Data Protection Agency regulations. Signed informed consent will be obtained for all participants after the study has been explained both in writing and orally. Only the sponsor and local investigators will have access to the final trial dataset. Other researchers may be granted access to the anonymized data for analysis upon reasonable request.

    Patient Involvement

    No involvement of patients or the public in the design or reporting of the study has been planned.

    Risk and Side Effects

    Overall, the risk to participants is minimal. All participants are prescribed fluids by a physician; the volume is not changed as part of the trial; oral fluids are safe and regularly used in clinical care for hydration. The only risk is the potential inability of certain patients to drink the amount of fluid prescribed by the attending physician within the defined time frame. But regular re-evaluation of the patient’s fluid intake, hydration status, and vital signs every 8 hours is part of the standard monitoring in the ED and will ensure that fluid management is adjusted by the attending physician if necessary. There is no evidence suggesting that oral fluid administration endangers patient safety, and intravenous fluid therapy remains available as a rescue option. Furthermore, the study does not restrict any other aspect of routine clinical care, including medications or additional fluid types. Participants in clinical trials are covered by the Danish patient compensation system administered by Patienterstatningen.

    Dissemination

    The results of the study will be published in peer-reviewed scientific journals and disseminated through participation in academic conferences. Positive and negative results will be published according to the CONSORT (Consolidated Standards of Reporting Trials) statement for parallel-group randomized trials [31]. The author panel will include study members in accordance with the International Committee of Medical Journal Editors (ICMJE) criteria.

    Protocol Amendments

    Protocol modifications will be communicated to the clinical trial registry and scientific ethics committee and described in future publications.


    Overview

    The study was funded by the Region of Southern Denmark in May 2024. Recruitment for the trial began on October 3, 2025, at the participating EDs in Esbjerg, Odense, and Aabenraa. As of September 2026, a total of 85 patients have been randomized to 1 of the 2 treatment arms, corresponding to 34% of the target sample. The trial plans to include 250 participants in total. Recruitment is expected to be completed in October 2026, with final follow-up anticipated in November 2026. Results are expected to be published in summer 2027.

    Progress and Protocol Deviations

    Enrollment has proceeded without any amendments to the eligibility criteria, intervention, outcome definitions, or statistical analysis plan. No serious adverse events attributable to the study intervention have been reported to the investigators. No interim analysis has been performed, and no comparative analysis of trial data has been undertaken; accordingly, no results of the primary or secondary outcomes are reported here.


    Principal Anticipated Findings

    We anticipate that a randomized comparison of oral and intravenous fluid therapy can be delivered in routine emergency care and that most alert adults prescribed intravenous crystalloid will drink the prescribed volume when asked to. If protocol adherence is acceptable and the lower confidence bound for the difference in the proportion achieving the prescribed volume lies within 15 percentage points, a definitive effectiveness trial will be warranted. Two negative results would be equally informative. If clinicians decline to randomize eligible patients or if participants allocated to the oral route are frequently converted to intravenous administration, the obstacle lies in clinician equipoise rather than patient tolerance and must be addressed before a larger trial is attempted. If patients accept randomization but many cannot drink the prescribed volume, the definitive trial will require a narrower eligibility definition than the deliberately broad one used here. In either case, the trial will have identified the constraint that a larger trial must be designed around.

    Comparison With Prior Work

    The physiological case for oral fluid therapy is more secure than its clinical evidence base. Water ingestion produces plasma volume expansion, splanchnic recruitment, peripheral vasoconstriction, and a rise in arterial pressure in healthy volunteers, in autonomic failure, and in shock [17-21], and our own crossover trial found a greater and more sustained rise in mean arterial pressure after oral than after intravenous fluid [22]. Clinically, enteral hydration has performed at least as well as the intravenous route wherever the 2 routes have been compared: in pediatric gastroenteritis, where a meta-analysis of 16 randomized trials reported shorter hospital stays and fewer serious adverse events [27]; in bronchiolitis [26]; in predicted severe acute pancreatitis [25]; and in the prevention of contrast-associated acute kidney injury [24].

    But these settings are narrow, each concerning a single diagnosis, and several concern children. The adult ED is different, with an undifferentiated population in which the intravenous route is the default not because it is superior but because a catheter is easily available. This trial therefore tests not a physiological hypothesis but an assumption on which everyday practice rests and for which no direct evidence exists.

    Strengths

    Site-stratified randomization removes the potential for confounding by site. The design is pragmatic and inclusive, with eligibility defined by the prescription rather than the diagnosis, physician discretion over fluid type, volume, and rate, no restriction on concurrent care, and intravenous rescue always available. The feasibility framework gives the trial a useful answer in either direction: it will enable a definitive trial or specify what must change before one can be run.

    Limitations

    The trial is not powered for patient-centered outcomes, and no conclusion about mortality, organ dysfunction, or length of stay may be drawn from it; acute kidney injury and severe electrolyte derangement are exploratory safety signals, not tested hypotheses.

    The intervention cannot be blinded, which may bias adherence; we mitigate this by blinding the analyzing statistician, prespecifying outcome definitions, and drawing volumes from routine nursing documentation. Oral intake is intrinsically less precisely measured than an infused volume, a limitation shared by all trials of enteral hydration; its extent is quantified through the data collection feasibility outcome and through the reporting of missingness, since the analysis is based on complete cases.

    ED length of stay is a competing event that closes the observation window, and because oral administration is slower, early disposition may limit delivery in the oral arm more frequently.

    The 15-percentage point margin was set by clinical consensus and is permissive: a noninferiority conclusion under it excludes only a large shortfall in fluid volume delivery. The assumed 85% baseline proportion is a working assumption, not an empirical estimate, as no published data describe it in adult ED patients; if the true proportion differs materially, the clinical comparison will be underpowered or overpowered, although the feasibility outcomes, being estimated descriptively, remain valid.

    Selection bias arises from limited screening hours, the requirement for capacity to consent, and the treating clinician’s discretion to decline an approach. Consent is sought in an environment in which patients may feel unable to refuse.

    Finally, the 3 Danish EDs located within a publicly funded system, and the deliberately heterogeneous cohort may limit generalizability and preclude identification of which diagnostic groups benefit; that question is deferred to the definitive trial.

    Future Directions

    The outputs that matter most are design parameters: the proportion of adult ED patients who actually receive their prescribed volume by either route, the screening-to-randomization ratio, the frequency and reasons for crossover, and the catheter hours an oral strategy might avoid. We anticipate that the definitive trial’s primary end point should be patient-relevant rather than volume-related, since it is not in delivering the fluid that the oral route is hypothesized to confer benefit. A trial-based economic evaluation is a natural extension.

    Acknowledgments

    The authors thank the health care professionals and administrators at the 3 study sites, as well as the Open Patient Data Explorative Network (OPEN), for their assistance. The authors also thank the Region of Southern Denmark for financial support. The authors declare the use of generative AI (GAI) in the research and writing process. According to the Generative Artificial Intelligence Delegation Taxonomy (2025), the following tasks were delegated to GAI tools under full human supervision: visualization and reformatting (table generation). The GAI tool used was Claude Opus (version 4.8; Anthropic PBC). Responsibility for the final manuscript lies entirely with the authors. GAI tools are not listed as authors and do not bear responsibility for the final outcomes.

    Funding

    This project is supported by the Region of Southern Denmark Fri og Strategisk Forskningsfund (grant 2024-0061). The financial sponsorship will have no influence on data collection, analysis, or publication.

    Data Availability

    The data collected in this study are available from the corresponding author on reasonable request, in accordance with Danish data protection laws.

    Authors' Contributions

    PB and LEL conceptualized the study. PB reviewed the literature. All authors designed the study, and all authors participated in data collection. MRK supervised data collection and submitted documents to the relevant institutions. PB, LEL, CBM, and MB will analyze the study results and data quality. PB and LEL will conduct the statistical analysis. PB will write the main manuscript. All authors will critically review and approve the manuscripts before submission. All listed authors meet authorship criteria and confirm that no others meeting the criteria have been omitted.

    Conflicts of Interest

    None declared.

    1. Finfer S, Liu B, Taylor C, Bellomo R, Billot L, Cook D, et al. Resuscitation fluid use in critically ill adults: an international cross-sectional study in 391 intensive care units. Crit Care. 2010;14(5):R185. [FREE Full text] [CrossRef] [Medline]
    2. Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. Sep 26, 2013;369(13):1243-1251. [CrossRef] [Medline]
    3. Bihari S, Prakash S, Bersten AD. Post resusicitation fluid boluses in severe sepsis or septic shock: prevalence and efficacy (price study). Shock. Jul 2013;40(1):28-34. [CrossRef] [Medline]
    4. Zampieri FG, Machado FR, Biondi RS, Freitas FG, Veiga VC, Figueiredo RC, et al. Effect of intravenous fluid treatment with a balanced solution vs 0.9% saline solution on mortality in critically ill patients: the BaSICS randomized clinical trial. JAMA. Aug 10, 2021;326(9):1-12. [FREE Full text] [CrossRef] [Medline]
    5. Self WH, Semler MW, Wanderer JP, Wang L, Byrne DW, Collins SP, et al. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. Mar 01, 2018;378(9):819-828. [FREE Full text] [CrossRef] [Medline]
    6. McIntyre LA, Marshall JC. Intravenous fluids in septic shock - more or less? N Engl J Med. Jun 30, 2022;386(26):2518-2519. [CrossRef] [Medline]
    7. Myles PS, Bellomo R, Corcoran T, Forbes A, Peyton P, Story D, et al. Restrictive versus liberal fluid therapy for major abdominal surgery. N Engl J Med. Jun 14, 2018;378(24):2263-2274. [CrossRef] [Medline]
    8. Silversides JA, Perner A, Malbrain ML. Liberal versus restrictive fluid therapy in critically ill patients. Intensive Care Med. Oct 2019;45(10):1440-1442. [CrossRef] [Medline]
    9. Taylor C, Yang L, Finfer S, Machado FR, YouZhong A, Billot L, et al. An international comparison of the cost of fluid resuscitation therapies. Aust Crit Care. Jan 2021;34(1):23-32. [CrossRef] [Medline]
    10. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. Nov 08, 2001;345(19):1368-1377. [CrossRef] [Medline]
    11. ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. Oct 16, 2014;371(16):1496-1506. [FREE Full text] [CrossRef] [Medline]
    12. Trinh TT, Chan PA, Edwards O, Hollenbeck B, Huang B, Burdick N, et al. Peripheral venous catheter-related staphylococcus aureus bacteremia. Infect Control Hosp Epidemiol. Jun 2011;32(6):579-583. [CrossRef] [Medline]
    13. Austin ED, Sullivan SB, Whittier S, Lowy FD, Uhlemann AC. Peripheral intravenous catheter placement is an underrecognized source of staphylococcus aureus bloodstream infection. Open Forum Infect Dis. Apr 06, 2016;3(2):ofw072. [FREE Full text] [CrossRef] [Medline]
    14. Limm EI, Fang X, Dendle C, Stuart RL, Egerton Warburton D. Half of all peripheral intravenous lines in an Australian tertiary emergency department are unused: pain with no gain? Ann Emerg Med. Nov 2013;62(5):521-525. [CrossRef] [Medline]
    15. Göransson KE, Johansson E. Indication and usage of peripheral venous catheters inserted in adult patients during emergency care. J Vasc Access. 2011;12(3):193-199. [CrossRef] [Medline]
    16. Guinot PG, Nguyen M, Duclos V, Soudry-Faure A, Bouhemad B, Water Study Group. Oral water ingestion in the treatment of shock patients: a prospective randomized study. Intensive Care Med. Nov 2020;46(11):2111-2112. [CrossRef] [Medline]
    17. Cariga P, Mathias CJ. Haemodynamics of the pressor effect of oral water in human sympathetic denervation due to autonomic failure. Clin Sci (Lond). Sep 2001;101(3):313-319. [Medline]
    18. Schroeder C, Bush VE, Norcliffe LJ, Luft FC, Tank J, Jordan J, et al. Water drinking acutely improves orthostatic tolerance in healthy subjects. Circulation. Nov 26, 2002;106(22):2806-2811. [CrossRef] [Medline]
    19. Callegaro CC, Moraes RS, Negrão CE, Trombetta IC, Rondon MU, Teixeira MS, et al. Acute water ingestion increases arterial blood pressure in hypertensive and normotensive subjects. J Hum Hypertens. Jul 2007;21(7):564-570. [CrossRef] [Medline]
    20. Jordan J. Acute effect of water on blood pressure. What do we know? Clin Auton Res. Aug 2002;12(4):250-255. [CrossRef] [Medline]
    21. Poulsen MM, Laugesen LE, Kristensen M, Moradi M, Nielsen P, Wessels J, et al. Hemodynamic and biochemical effects of intravenous versus oral fluids in healthy volunteers – a protocol for a randomized crossover trial. Research Square. Preprint posted online on March 25, 2026. [FREE Full text] [CrossRef]
    22. Guinot PG, Nguyen M, Duclos V, Berthoud V, Bouhemad B, Water Study Group. Oral water has cardiovascular effects up to 60 min in shock patients. Front Cardiovasc Med. Dec 20, 2021;8:803979. [FREE Full text] [CrossRef] [Medline]
    23. Zhang W, Zhang J, Yang B, Wu K, Lin H, Wang Y, et al. Effectiveness of oral hydration in preventing contrast-induced acute kidney injury in patients undergoing coronary angiography or intervention: a pairwise and network meta-analysis. Coron Artery Dis. Jun 2018;29(4):286-293. [CrossRef] [Medline]
    24. Sharma V, Rana SS, Sharma R, Chaudhary V, Gupta R, Bhasin DK. Naso-jejunal fluid resuscitation in predicted severe acute pancreatitis: randomized comparative study with intravenous Ringer's lactate. J Gastroenterol Hepatol. Jan 2016;31(1):265-269. [CrossRef] [Medline]
    25. Babl FE, Franklin D, Schlapbach LJ, Oakley E, Dalziel S, Whitty JA, et al. Enteral hydration in high-flow therapy for infants with bronchiolitis: secondary analysis of a randomised trial. J Paediatr Child Health. Jun 2020;56(6):950-955. [CrossRef] [Medline]
    26. Fonseca BK, Holdgate A, Craig JC. Enteral vs intravenous rehydration therapy for children with gastroenteritis: a meta-analysis of randomized controlled trials. Arch Pediatr Adolesc Med. May 2004;158(5):483-490. [CrossRef] [Medline]
    27. Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. Jan 08, 2013;346:e7586. [FREE Full text] [CrossRef] [Medline]
    28. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. Apr 2009;42(2):377-381. [FREE Full text] [CrossRef] [Medline]
    29. Bjorner JB, Thunedborg K, Kristensen TS, Modvig J, Bech P. The Danish SF-36 Health Survey: translation and preliminary validity studies. J Clin Epidemiol. Nov 1998;51(11):991-999. [CrossRef] [Medline]
    30. Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res. Feb 2002;52(2):69-77. [CrossRef] [Medline]
    31. Hopewell S, Chan AW, Collins GS, Hróbjartsson A, Moher D, Schulz KF, et al. CONSORT 2025 statement: updated guideline for reporting randomised trials. Lancet (Forthcoming). Apr 14, 2025:S0140-6736(25)00672-5. [CrossRef] [Medline]

    ‎
    CONSORT: Consolidated Standards of Reporting Trials
    ED: emergency department
    ICMJE: International Committee of Medical Journal Editors
    OPEN: Open Patient Data Explorative Network
    OUH: Odense University Hospital
    SPIRIT: Standard Protocol Items: Recommendations for Interventional Trials

    Edited by A Schwartz; submitted 16.Mar.2026; peer-reviewed by G Keijzers, GJ Noordergraaf; comments to author 02.Jul.2026; revised version received 27.Aug.2026; accepted 31.Aug.2026; published 30.Sep.2026.

    Copyright

    ©Peter Biesenbach, Mette Rahbek Kristensen, Mikkel Brabrand, Christian Backer Mogensen, Line Emilie Laugesen. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 30.Sep.2026.

    This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on https://www.researchprotocols.org, as well as this copyright and license information must be included.