Sodium Bicarbonate for Critically Ill Patients With Metabolic Acidosis and Acute Kidney Injury (ESCALATE)

Evaluating the Clinical Effectiveness of Sodium Bicarbonate for Critically Ill Patients With Metabolic Acidosis and Acute Kidney Injury (ESCALATE)

The study investigates whether sodium bicarbonate is able to reduce the occurrence of major adverse kidney events on day 90 (MAKE90) in critically ill patients with metabolic acidosis and acute kidney injury (AKI). While its efficacy in this context has been suggested in a subgroup analysis of the BICAR-ICU trial it has not been confirmed in a double-blinded randomized controlled trial to date.

Study Overview

• Status: Not yet recruiting
• Conditions: Critical Illness; Acute Kidney Injury; Metabolic Acidosis
• Intervention / Treatment: Drug: Sodium Bicarbonate 8.4% Solution for Injection; Drug: Balanced crystalloid solution

Detailed Description

Each year > 200 000 adult patients are admitted to intensive-care units (ICUs) in Germany of which around half develop acute kidney injury (AKI). AKI markedly increases morbidity, mortality, ICU/hospital length of stay, and the risk of progression to chronic kidney disease.2-4 Metabolic acidosis significantly raises hospital mortality, the need for kidney-replacement therapy (KRT), and the incidence of major adverse kidney events within 30 days (MAKE30).5,6 When AKI and metabolic acidosis coexist, 90-day mortality ranges from 53 % to 59 % (vs 26 % for AKI alone).

Acidaemia depresses cardiovascular function through reduced myocardial contractility, impaired catecholamine responsiveness, hyperkalaemia, pulmonary vasoconstriction and arrhythmogenesis.7,8 Restoring extracellular pH is therefore biologically plausible as a strategy to improve organ perfusion and outcomes.

Sodium bicarbonate is the most widely used buffer in clinical practice, yet high-quality evidence for its benefit in AKI with metabolic acidosis is lacking. To date, despite numerous calls for appropriately designed studies, there have only been two RCTs primarily addressing the effects of sodium bicarbonate in critically ill patients with severe acidosis.1,9 Due to methodological limitations (open-label study design, selection bias, risk of confounding) and lack in generalizability, the question on using sodium bicarbonate in critically ill patients with AKI and metabolic acidosis cannot be answered with certainty.

The "Evaluating the clinical effectiveness of sodium bicarbonate for critically ill patients with metabolic acidosis and acute kidney injury" trial is a multicenter, double-blinded, randomized controlled trial. It is designed to determine whether treatment with intravenous 8.4% weight/volume (w/v) sodium bicarbonate is superior to placebo in terms of the composite endpoint major adverse kidney events (MAKE) at day 90 (composite of death from any cause, receipt of any KRT within the 90-day period, or persistent renal dysfunction (defined as a creatinine value ≥200% of the baseline value) at day 90) in critically ill patients with AKI (KDIGO stage 2 or 3) and metabolic acidosis. The findings of the ESCALATE trial are expected to have significant implications for clinical practice and patient outcomes, both in Germany and internationally, by providing high-quality evidence to guide the management of a critically ill population with high risk of mortality.

• Study Type: Interventional
• Enrollment (Estimated): 660
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Alexander Zarbock, MD; Phone Number: +49251-8347255; Email: ESCALATE@ukmuenster.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult ≥ 18 years
2. Critically ill patients (requiring treatment on an ICU or IMC)

3. Metabolic acidosis, defined as all of the following:

   1. Arterial pH ≤7.25
   2. PaCO2 < 6.5kPa (<49 mmHg)
   3. Standard bicarbonate ≤20 mmol/L
   4. Standard Base Excess <-2
4. AKI stage 2 or 3 of the KDIGO classification
5. Written informed consent of the patient or legal representative or authorized representative or emergency inclusion (according to Article 35 EU-Regulation 536/2014)

Exclusion Criteria:

1. Pregnant or breastfeeding patients
2. Respiratory acidosis (acute or chronic) [dynamic, and if corrected, patient may be reconsidered for the trial]
3. Patients on KRT, or KRT immediately indicated and treating clinician(s) unwilling to defer
4. Deemed unsuitable for KRT
5. High output stoma/ileostomy
6. Percutaneous biliary drainage
7. End stage kidney failure defined as documented eGFR <15ml/min/1.73m 2 prior to onset of this acute illness or end stage kidney disease (ESKD) on dialysis
8. Known renal tubular acidosis
9. Diabetic ketoacidosis
10. High anion gap acid poisoning (e.g. polyethylene glycol (PEG), aspirin, methanol)
11. Symptomatic hypocalcaemia (Ionized calcium <1.05 mmol/L)[dynamic, and if corrected, patient may be reconsidered for the trial]
12. Hypernatremia (plasma sodium >150 mmol/L)[dynamic, and if corrected, patient may be reconsidered for the trial]
13. Severe hypokalemia (potassium <3.0 mmol/L)[dynamic, and if corrected, patient may be reconsidered for the trial]
14. Death perceived as imminent
15. Known hypersensitivity to sodium bicarbonate or EDTA (Disodiumedetate)
16. Previously randomized into ESCALATE

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sodium Bicarbonate; Experimental: Sodium Bicarbonate 8.4% w/v Intravenous infusion according to the treatment algorithm targeting a pH>7.30	Drug: Sodium Bicarbonate 8.4% Solution for Injection; Intravenous infusion according to the treatment algorithm. Infusion starts with 100ml/hr until a pH of 7.30 - 7.35 and a Base Excess of ≥ 0 is reached. Then, infusion is reduced to 25ml/hr and maintained for 5 hours. After 5 hours, infusion is titrated to a pH of >7.30.
Placebo Comparator: Balanced crystalloid solution; Placebo: Balanced crystalloid solution Intravenous infusion according to the treatment algorithm targeting a pH>7.30	Drug: Balanced crystalloid solution; Intravenous infusion according to the treatment algorithm. Infusion starts with 100ml/hr until a pH of 7.30 - 7.35 and a Base Excess of ≥ 0 is reached. Then, infusion is reduced to 25ml/hr and maintained for 5 hours. After 5 hours, infusion is titrated to a pH of >7.30.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
MAKE90 (consisting of mortality, dialysis within 90 days, persistent renal dysfunction (defined as serum creatinine ≥ 2x compared to baseline value at day 90)	90 days after randomization

Secondary Outcome Measures

Outcome Measure	Time Frame
90-day all-cause mortality (%)	90 days after randomization
Elevation of the creatinine level to ≥200% of base value at day 90 (one measurement between day 80 and 120 after randomization)	80 - 120 days after randomization
Receipt of any form of KRT within the 90-day time period after randomization	90 days after randomization
KRT-dependence on day 90	90 days after randomization
KRT-free days, defined as difference between number of days receiving KRT of any form between randomization and day 90 and number of days alive	90 days after randomization

Other Outcome Measures

Outcome Measure	Time Frame
Incidence of suspected unexpected serious adverse reactions (SUSARs)	from randomization until the end of treatment phase (up to day 7 OR Discharge from the intensive care unit, whatever comes first
ICU-Mortality (%)	90 days after randomization
Vasopressor-free days up to day 28	28 days after randomization
Vasopressor-free days up to day 90	90 days after randomization
Ventilator-free days up to day 28	28 days after randomization
Total hospital-free days up to day 90	90 days after randomization
Change in eGFR between baseline and day 90	90 days after randomization
Incidence of hospital acquired infections during ICU-stay	within initial ICU stay (up to 90 days after randomization)
Hospital Mortality (%)	90 days after randomization
KRT-free days up to day 28	28 days after randomization

Collaborators and Investigators

• Sponsor: Universität Münster
• Collaborators: German Research Foundation
• Investigators: Study Chair: Alexander Zarbock, MD, University Hospital Muenster, Dept. of Anesthesiology, Intensive Care Medicine and Pain Therapy

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: February 11, 2026
• First Submitted That Met QC Criteria: March 5, 2026
• First Posted (Actual): March 11, 2026

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Critical illness; Acute kidney injury; Metabolic acidosis; Sodium bicarbonate
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Disease Attributes; Metabolic Diseases; Renal Insufficiency; Acid-Base Imbalance; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Critical Illness; Acute Kidney Injury; Acidosis; Pharmaceutical Preparations; Therapeutics; Drug Administration Routes; Drug Therapy; Inorganic Chemicals; Sodium Compounds; Carbon Compounds, Inorganic; Carbonates; Carbonic Acid; Bicarbonates; Injections; Solutions; Sodium Bicarbonate
• Other Study ID Numbers: UniMS23_0017; 538117253 (Other Grant/Funding Number: Deutsche Forschungsgemeinschaft); 2025-523914-10-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this study, after deidentification (text, tables, figures, and appendices)
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication

IPD Sharing Access Criteria

With whom? Researchers who provide a methodologically sound proposal

By what mechanism will data be made available? Proposals should be directed to ESCALATE@ukmuenster.de. To gain access, data requestors will need to sign a data access agreement.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No