Pantoprazole for Acute Kidney Injury in Hemorrhagic Shock

(Trauma AKI PPI Trial)

Overseen By Yafen Liang, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: The University of Texas Health Science Center, Houston

Must be taking: Proton pump inhibitors

Disqualifiers: Renal replacement therapy, Cardiac arrest, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2 days

100 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is the drug pantoprazole effective in preventing kidney injury?

Research suggests that pantoprazole may help protect against kidney injury caused by cisplatin, a chemotherapy drug, as it prevented increases in kidney injury markers in patients receiving cisplatin treatment. ^{1 2 3 4 5}

Is pantoprazole generally safe for humans?

Pantoprazole is generally considered safe and has been used for over 13 years in more than 100 countries with an excellent safety profile. However, rare side effects have been reported, including liver toxicity, a significant drop in platelet count (thrombocytopenia), and drug-induced fever. These side effects are uncommon, but they should be considered when using pantoprazole. ^{2 6 7 8 9}

How does the drug pantoprazole differ from other treatments for acute kidney injury in hemorrhagic shock?

Pantoprazole is unique because it is a proton pump inhibitor (PPI) that can be administered intravenously, making it suitable for acutely ill patients who cannot take oral medications. It also has anti-inflammatory effects, which may help reduce kidney damage in conditions like renal ischemia/reperfusion injury, potentially offering benefits beyond its primary use for acid-related disorders. ^{10 11 12 13 14}

What is the purpose of this trial?

The investigators propose a single-center, randomized, controlled trial to determine whether early initiation of proton pump inhibitor (PPI), pantoprazole, will decrease acute kidney injury (AKI) for trauma patients presenting with hemorrhagic shock compared to routine timing of initiation of PPI. Kidney injury will be assessed by the urinary kidney injury biomarkers, and the incidence, severity and AKI-free days within first week and major adverse kidney events (MAKE) at day 30. The specific aims of the study will be achieved by a cohort of 100 patients to receive either early(study) or routine (control) administration of pantoprazole for 2 days after the initial injury insult.

Research Team

Yafen Liang, MD

Principal Investigator

The University of Texas Health Science Center, Houston

Eligibility Criteria

This trial is for trauma patients who have experienced hemorrhagic shock and are at risk of acute kidney injury. Participants must be within a specific cohort of 100 patients to receive either early or routine pantoprazole treatment after their initial injury.

Inclusion Criteria

I was in shock due to severe bleeding with very low blood pressure and a fast heart rate when I arrived at the emergency department.

Exclusion Criteria

I had a cardiac arrest before getting to the ER or am expected to live less than 24 hours.

I am currently on dialysis.

History of PPI sensitivity or allergy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either early or routine administration of pantoprazole for 2 days after the initial injury

2 days

Daily monitoring in the intensive care unit

Initial Follow-up

Participants are monitored for urinary kidney biomarker levels and AKI staging for 5 days after enrollment

5 days

Daily assessments

Extended Follow-up

Participants are monitored for major adverse kidney events (MAKE) 30 days after the initial injury

30 days

Treatment Details

Interventions

• Pantoprazole

Trial Overview The study tests if giving the proton pump inhibitor pantoprazole early can reduce kidney damage in trauma patients with hemorrhagic shock, compared to standard timing. It measures kidney health by checking biomarkers and tracking adverse events up to day 30.

Participant Groups

Group I: Early Initiation Experimental Treatment 1 Intervention

Within 2 hours of emergency department (ED) admission after inclusion criteria is met, administer 1st dose of Protonix (pantoprazole) 40 mg, then followed by 40 mg q12hrs for 2 additional days

Group II: Usual Care Active Control 1 Intervention

Administer 1st dose of 40 mg Protonix (pantoprazole) at the usual timing (current practice: in the intensive care unit), then followed by 40 mg daily for 2 additional days.

Pantoprazole is already approved in United States, European Union, Canada, Japan, China, Switzerland for the following indications:

Approved in United States as Protonix for:

• Erosive esophagitis
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome

Approved in European Union as Pantoprazole for:

• Erosive esophagitis
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome
• Peptic ulcer disease

Approved in Canada as Pantoprazole for:

• Erosive esophagitis
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome

Approved in Japan as Pantoprazole for:

• Erosive esophagitis
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome

Approved in China as Pantoprazole for:

• Erosive esophagitis
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome

Approved in Switzerland as Pantoprazole for:

• Erosive esophagitis
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome

Who Is Running the Clinical Trial?

The University of Texas Health Science Center, Houston

Lead Sponsor

Trials

974

Recruited

361,000+

The University of Texas Health Science Center at San Antonio

Collaborator

Trials

486

Recruited

92,500+

Findings from Research

Intermittent intravenous pantoprazole effectively maintains gastric pH levels above 4.0 in ICU patients at risk for upper gastrointestinal bleeding, showing improved control from day 1 to day 2 compared to continuously infused cimetidine.

No cases of upper gastrointestinal bleeding were reported in any treatment group, and the incidence of adverse events, including pneumonia, was similar between patients treated with pantoprazole and those treated with cimetidine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent intravenous pantoprazole and continuous cimetidine infusion: effect on gastric pH control in critically ill patients at risk of developing stress-related mucosal disease. Somberg, L., Morris, J., Fantus, R., et al.[2022]

Pantoprazole, a commonly used proton pump inhibitor for stress-related mucosal disease in ICU patients, was associated with a significant drop in platelet count (over 70%) in a 51-year-old male patient, indicating a potential adverse effect of the drug.

The thrombocytopenia observed was severe enough to require transfusions and corticosteroid treatment, but these interventions were ineffective, suggesting that the mechanism behind pantoprazole-induced thrombocytopenia may be non-immune.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pantoprazole-induced Thrombocytopenia: Unresponsive to Corticosteroid and Thrombocyte Concentrate Transfusion. Widyati, ., Latifah, N., Ramadhani, M.[2023]

In a post hoc analysis of the SUP-ICU trial involving 1140 patients with a high Simplified Acute Physiology Score (SAPS II > 53), those treated with pantoprazole had a higher 90-day mortality rate (47%) compared to those receiving placebo (41%), suggesting potential safety concerns with pantoprazole in this high-risk group.

Patients on pantoprazole also experienced fewer days alive without life support compared to the placebo group, indicating that the use of pantoprazole may be associated with worse outcomes in critically ill patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pantoprazole prophylaxis in ICU patients with high severity of disease: a post hoc analysis of the placebo-controlled SUP-ICU trial. Marker, S., Perner, A., Wetterslev, J., et al.[2020]

In a study of 60 head and neck cancer patients, pantoprazole significantly reduced nephrotoxicity caused by cisplatin, with no cases of kidney injury in the high-dose pantoprazole group and only 3 cases in the low-dose group, compared to 6 cases in the control group.

The use of pantoprazole was associated with lower levels of kidney injury biomarkers (KIM-1, NGAL, and sFasL) after cisplatin treatment, suggesting it effectively protects against acute kidney injury in patients undergoing chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible protective effect of pantoprazole against cisplatin-induced nephrotoxicity in head and neck cancer patients: a randomized controlled trial. Ghonaim, E., El-Haggar, S., Gohar, S.[2022]

Drugs that inhibit acid secretion or eradicate Helicobacter pylori are important for treating peptic ulcers, especially in patients with renal failure, as their pharmacokinetics can be affected by kidney function.

Histamine H2-receptor antagonists and pirenzepine require dosage adjustments in patients with renal insufficiency, while proton pump inhibitors and misoprostol do not, highlighting the need for careful medication management in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic optimisation of the treatment of peptic ulcer in patients with renal failure. Gladziwa, U., Koltz, U.[2018]

Hepatotoxicity from proton pump inhibitors (PPIs) like pantoprazole is very rare, but it can occur, as demonstrated in a case involving a 35-year-old man treated for acute gastritis.

The patient's liver function improved one week after stopping pantoprazole, indicating that while hepatotoxicity is infrequent, discontinuation of the drug can lead to full recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver hepatotoxicity associated with pantoprazole: a rare case report. Aslan, M., Celik, Y., Karadas, S., et al.[2021]

A case report highlights a rare instance of an acute drug-induced fever and leukocytosis caused by pantoprazole, a type of proton pump inhibitor (PPI).

This reaction was identified as an idiosyncratic inflammatory response, indicating that while PPIs are generally safe, they can occasionally trigger hypersensitivity reactions without cross-sensitivity to other PPIs like esomeprazole.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug fever due to a single dose of pantoprazole. Schiller, D., Maieron, A., Schöfl, R., et al.[2018]

Pantoprazole is an effective proton pump inhibitor used to treat various acid-related conditions, including gastroesophageal reflux disease and peptic ulcer disease, and has been safely used for over 13 years in more than 100 countries.

It has a strong safety profile with low risk for drug interactions, making it suitable for patients across all age groups, although it is officially indicated only for adults and adolescents in Europe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pantoprazole: a proton pump inhibitor with oral and intravenous formulations. Devault, KR.[2018]

In a study involving male CD2F1 mice, pantoprazole significantly increased lethality and gastrointestinal toxicity after total body irradiation (TBI), reducing median survival from 22 days to 12 days at a dose of 9.0 Gy.

Unlike pantoprazole, the histamine type-2 (H2) receptor blocker cimetidine did not affect TBI-induced lethality, suggesting that pantoprazole's mechanism of action may exacerbate radiation damage, highlighting the need for caution in using proton pump inhibitors in radiation-exposed individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation lethality potentiation in total body irradiated mice by a commonly prescribed proton pump inhibitor, Pantoprazole sodium. Biju, PG., Gubrij, I., Garg, S., et al.[2021]

Pantoprazole is an effective proton pump inhibitor that, when used in combination with antibiotics, achieves Helicobacter pylori eradication rates of 71-93.8% in patients without known antibiotic resistance, making it a strong option for treating this infection.

In treating gastro-oesophageal reflux disease (GORD), pantoprazole is as effective as other PPIs and significantly better than histamine H(2)-antagonists, with good tolerability and minimal drug interactions, providing flexibility with both oral and intravenous formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pantoprazole: an update of its pharmacological properties and therapeutic use in the management of acid-related disorders. Cheer, SM., Prakash, A., Faulds, D., et al.[2022]

A case study of a 23-year-old man revealed that acute interstitial nephritis can develop after just 6 weeks of treatment with pantoprazole, a commonly prescribed proton-pump inhibitor.

The condition was diagnosed through a renal biopsy and successfully treated with corticosteroids and discontinuation of pantoprazole, highlighting the need for awareness of potential kidney-related side effects of PPIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pantoprazole-induced acute interstitial nephritis. Moore, I., Sayer, JA., Nayar, A., et al.[2018]

In a study involving male Wistar rats, pretreatment with pantoprazole at doses of 18 and 36 mg/kg significantly improved renal function by reducing serum creatinine and blood urea nitrogen levels after renal ischemia/reperfusion injury.

Pantoprazole also decreased oxidative stress markers and toll-like receptor 4 (TLR-4) expression in renal tissue, suggesting its protective effects against kidney damage are linked to its anti-inflammatory properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The protective effect of acute pantoprazole pretreatment on renal ischemia/reperfusion injury in rats. Kohansal, P., Rajai, N., Dehpour, AR., et al.[2019]

In a clinical trial involving 163 patients with duodenal ulcers, pantoprazole showed a significantly higher healing rate at 72% compared to 51% for ranitidine after 2 weeks, indicating its superior efficacy.

Both pantoprazole and ranitidine were well tolerated and safe, but pantoprazole also led to a faster reduction in pain for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Superiority of pantoprazole over ranitidine in the treatment of duodenal ulcer. Mexican clinical experience. Mexican Study Group of Pantoprazole++ in Duodenal Ulcer]. Dibildox, M., Rose, K., Tomás-Pons, J., et al.[2018]

Pantoprazole is the first parenteral proton pump inhibitor available in Canada, offering superior acid suppression compared to parenteral histamine 2 receptor antagonists without the risk of tolerance development.

It is safe for use in patients with renal or hepatic impairment and does not affect heart rate or blood pressure, making it a well-tolerated option for treating conditions like reflux esophagitis and upper gastrointestinal bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous pantoprazole: a new tool for acutely ill patients who require acid suppression. Trépanier, EF.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Intermittent intravenous pantoprazole and continuous cimetidine infusion: effect on gastric pH control in critically ill patients at risk of developing stress-related mucosal disease. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Pantoprazole-induced Thrombocytopenia: Unresponsive to Corticosteroid and Thrombocyte Concentrate Transfusion. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Pantoprazole prophylaxis in ICU patients with high severity of disease: a post hoc analysis of the placebo-controlled SUP-ICU trial. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Possible protective effect of pantoprazole against cisplatin-induced nephrotoxicity in head and neck cancer patients: a randomized controlled trial. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetic optimisation of the treatment of peptic ulcer in patients with renal failure. [2018]

6. Austria pubmed.ncbi.nlm.nih.gov

Liver hepatotoxicity associated with pantoprazole: a rare case report. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Drug fever due to a single dose of pantoprazole. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Pantoprazole: a proton pump inhibitor with oral and intravenous formulations. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Radiation lethality potentiation in total body irradiated mice by a commonly prescribed proton pump inhibitor, Pantoprazole sodium. [2021]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Pantoprazole: an update of its pharmacological properties and therapeutic use in the management of acid-related disorders. [2022]

11. Italy pubmed.ncbi.nlm.nih.gov

Pantoprazole-induced acute interstitial nephritis. [2018]

12. England pubmed.ncbi.nlm.nih.gov

The protective effect of acute pantoprazole pretreatment on renal ischemia/reperfusion injury in rats. [2019]

13. Mexico pubmed.ncbi.nlm.nih.gov

[Superiority of pantoprazole over ranitidine in the treatment of duodenal ulcer. Mexican clinical experience. Mexican Study Group of Pantoprazole++ in Duodenal Ulcer]. [2018]

14. Canada pubmed.ncbi.nlm.nih.gov

Intravenous pantoprazole: a new tool for acutely ill patients who require acid suppression. [2019]