Non-interventional Follow-up Versus Fluid Bolus in RESPONSE to Oliguria in the Critically Ill (RESPONSE)

Non-interventional Follow-up Versus Fluid Bolus in RESPONSE to Oliguria in the Optimization Phase of Fluid Therapy in the Critically Ill (the RESPONSE Trial)

Background: After hypotension, oliguria (urine output less than 0.5 mL/kg/h) was the most common trigger to administer fluid bolus in a multinational practice survey in intensive care. The effect of fluid bolus on cardiovascular variables can be very short-lived among patients in shock suggesting that fluid boluses in the optimization phase are unlikely to improve patient-centered outcomes. Moreover, a growing body of evidence suggests a poor renal response to fluid bolus.

Objective: To investigate, whether fluid bolus - as a standard of care - improves urine output in oliguric patients compared to a non-interventional follow-up approach without fluid bolus.

Design: Investigator-initiated, open, randomized, controlled study

Interventions:

1. Intervention group - follow-up without intervention
2. Control group - fluid bolus (500mL of balanced crystalloid over 30 minutes)

Randomization: 1:1 stratified according to the site, presence of acute kidney injury, and sepsis

Trial size: 130 patients randomized in 2 ICUs

Study Overview

• Status: Completed
• Conditions: Sepsis; Acute Kidney Injury; Critically Ill; Oliguria
• Intervention / Treatment: Other: follow-up without intervention; Other: fluid bolus

Detailed Description

Study hypothesis:

The investigators hypothesize that fluid bolus given due to oliguria does not improve urine output in a majority of patients, especially among those with acute kidney injury. Another study hypothesis is that patients receiving fluid bolus will have higher levels of endothelial damage biomarkers.

Intervention description:

Intervention group -follow-up without intervention; No intervention to increase the urine output within 2 hours will be done.

Standard group - Fluid bolus group: Patient will receive 500mL of balanced crystalloid intravenously over 30 minutes.

In both groups, if severe hemodynamic instability occurs, a rescue bolus of 500mL over 30 minutes may be given according to the decision of the treating clinician.

In both groups, all other ongoing infusions (nutrition and on-going clear fluids) will be held constant during the 2-hour period. Vasoactive medications, sedation, short-acting insulin, and other medications can be modified according the clinical need. No diuretics during the 2-hour study period are allowed. After two hours from randomization, treating clinician can modify the fluid and drug therapy according to the clinical needs of the patient. All administered fluids will be recorded 6 h from randomization.

Except for the study intervention period of 2 hours, no attempt to control fluid therapy will be done. During the study period, all other aspects of critical care will follow the ICU's standard operating procedures and clinician's prescription.

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Finland
  • Jyväskylä, Finland
    • Central Finland Central Hospital
  • Uusimaa
    • Helsinki, Uusimaa, Finland, 00290
      • Helsinki University Hospital, Meilahti

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age over 18
• Emergency admission to an ICU
• Mean arterial pressure (MAP) >65 mmHg (with vasopressors if needed) and initial fluid resuscitation for shock/hypovolemia has been given
• Oliguria (urine output less than 0.5mL/kg/h) for at least 2 consecutive hours

Exclusion Criteria:

• Marked fluctuations in hemodynamics within last 2 hours (cardiac arrhythmias, increase in norepinephrine need over 0.2ug/kg/min, need for initiation of inotrope/inodilator)
• Administration of furosemide within last 6 hours
• Chronic kidney disease (estimated pre-critical illness GFR < 60ml/min/1.73m2)
• Renal replacement therapy
• Among patients with acute kidney injury, urgent indications for commencing renal replacement therapy
• Fluid overload (cumulative fluid accumulation exceeds 10% of baseline body weight)
• Pulmonary edema (bilateral infiltrates in chest x-ray)
• Active bleeding (need for transfusion, platelets, or fresh frozen plasma)
• Suspected or known intra-abdominal hypertension (IAP >16mmHg)
• Pregnant or lactating
• Expected survival less than 24h
• Obtaining informed consent is not possible/consent is denied

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: follow-up without intervention; No intervention to increase the urine output within 2 hours will be done.	Other: follow-up without intervention
Active Comparator: Standard group - fluid bolus; Patient will receive 500mL of balanced crystalloid intravenously over 30 minutes.	Other: fluid bolus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in individual mean cumulative urine output (mL/kg/h)	Doubling of the urine output is defined as clinically meaningful response	2 hours after randomization compared to urine output 2 hours preceding randomization

Secondary Outcome Measures

Outcome Measure	Time Frame
The difference between groups in the change in individual urine output	2 hours after randomization compared to urine output 2 hours preceding randomization
Duration of consecutive oliguria (urine output <0.5 mL/kg)	during ICU stay, i.e. as long as urine output stays below 0.5 mL/kg/h while the patient is in the ICU (an average of 5 to 7 days) or until renal replacement therapy is commenced
Cumulative fluid balance	six hours from randomization

Other Outcome Measures

Outcome Measure	Time Frame
Number of patients receiving rescue boluses and the number of rescue boluses	study intervention period (i.e. 2 hours)
Highest stage of acute kidney injury	within 24 hours, 48 hours and during ICU stay (an average of 5 to 7 days or up to 30 days if patient is still in ICU)
Number of patients with one or several protocol violation(s) and number of those per patient	study intervention period (i.e. 2 hours)
Number of patients with adverse events	from randomization to next morning
Number of patients receiving renal replacement therapy	during ICU stay(an average of 5 to 7 days or up to 30 days if patient is still in ICU)
change in mean arterial pressure	from randomization to 2 hours post-randomization
change in heart rate	from randomization to 2 hours post-randomization

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital
• Collaborators: Central Finland Central Hospital
• Investigators: Principal Investigator: Suvi Vaara, MD, PhD, Helsinki University Central Hospital

Publications and helpful links

General Publications

• Inkinen N, Selander T, Pettila V, Valkonen M, Backlund M, Wennervirta J, Pulkkinen A, Hastbacka J, Vaara ST. Noninterventional follow-up vs fluid bolus in RESPONSE to oliguria-The RESPONSE trial protocol and statistical analysis plan. Acta Anaesthesiol Scand. 2020 Sep;64(8):1210-1217. doi: 10.1111/aas.13599. Epub 2020 Apr 28.

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2017
• Primary Completion (Actual): December 10, 2020
• Study Completion (Actual): December 10, 2020

Study Registration Dates

• First Submitted: August 1, 2016
• First Submitted That Met QC Criteria: August 8, 2016
• First Posted (Estimate): August 9, 2016

Study Record Updates

• Last Update Posted (Actual): December 14, 2020
• Last Update Submitted That Met QC Criteria: December 10, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: oliguria; fluid therapy; endothelial injury
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Urological Manifestations; Disease Attributes; Renal Insufficiency; Urination Disorders; Critical Illness; Acute Kidney Injury; Oliguria
• Other Study ID Numbers: 200/13/03/02/16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes