Diazoxide for Heart Surgery

Overseen By Jennifer Lawton, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Johns Hopkins University

Must not be taking: Sulfonylureas, Diphenylhydantoin

Disqualifiers: Diabetes, LVAD, Ejection fraction < 30%, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Day of surgery

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding diazoxide (a medication for low blood sugar and high blood pressure) to a commonly used heart surgery solution can better protect the heart during surgery. Researchers aim to determine if this new mix can prevent heart muscle damage and improve recovery post-surgery. It targets individuals undergoing planned heart surgery with a heart-lung machine. Those with very low heart function or requiring specific heart devices are not eligible. This study could lead to better heart surgery outcomes and reduce the need for additional heart support after surgery. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking heart surgery advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on sulfonylurea medications for diabetes or if you have seizure disorders controlled by diphenylhydantoin.

Is there any evidence suggesting that diazoxide is likely to be safe for humans?

Research has shown that diazoxide is generally safe for individuals undergoing heart surgery. One study found that patients who took diazoxide did not experience serious issues such as deaths, strokes, or heart attacks. They received an average dose of about 36 mg, and their safety outcomes were similar to those who took a placebo, indicating no major safety differences. Another study also supported the safety and practicality of using diazoxide during heart surgery. These studies suggest that diazoxide is well-tolerated. However, as this is an early-phase trial, the researchers are still gathering safety information, and further research is needed for complete assurance. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Diazoxide is unique because it is being explored as an additive to hypothermic hyperkalemic cardioplegia, a technique used during heart surgery to protect the heart. Unlike traditional approaches that primarily focus on simply stopping the heart and reducing its temperature, diazoxide may have protective effects at the cellular level by opening potassium channels in the mitochondria. This mechanism could potentially reduce heart tissue damage during surgery, offering a new layer of protection that existing treatments don't provide. Researchers are excited because this could lead to improved outcomes and quicker recovery times for patients undergoing heart surgery.

What evidence suggests that diazoxide might be an effective treatment for myocardial protection during heart surgery?

Research shows that diazoxide, which participants in this trial will receive, can greatly improve heart function after surgery. Studies have found that diazoxide reduces damage to heart tissue in animals like rodents and pigs. In one study, patients who received diazoxide had heart function that was 27% better than those who did not. Adding diazoxide to heart surgery has proven safe, with no major side effects such as heart attacks or strokes reported. Overall, early evidence suggests that diazoxide helps protect the heart during surgery and aids in recovery. ^{4 6 7 8 9}

Who Is on the Research Team?

Jennifer Lawton, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for patients undergoing cardiac surgery who require cardiopulmonary bypass. It's designed to see if adding diazoxide to the heart-protecting solution used during surgery can help reduce heart muscle damage.

Inclusion Criteria

I am scheduled for a planned heart surgery.

I am scheduled for heart surgery that will use a heart-lung machine and stop my heart.

I agree to use effective birth control for six days after my diazoxide dose.

Exclusion Criteria

Patients with a history of cold agglutinins

I am scheduled for a heart pump implant or heart transplant.

Allergy to Thiazide and its derivatives

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive IV Diazoxide as an additive to hypothermic hyperkalemic cardioplegia during cardiac surgery

Day of surgery

1 visit (in-person)

Immediate Post-operative Monitoring

Participants are monitored for safety and efficacy, including blood pressure, glucose levels, and adverse events

48 hours post-operatively

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and mechanical circulatory support

7 days post-operatively or until discharge

What Are the Treatments Tested in This Trial?

Interventions

• Diazoxide

Trial Overview The study tests whether IV diazoxide added to hyperkalemic cardioplegia (a technique to protect the heart during surgery) is safe and more effective than standard protection alone in reducing myocardial stunning after cardiac surgery.

How Is the Trial Designed?

Group I: Diazoxide Experimental Treatment 1 Intervention

IV Diazoxide as additive to hypothermic hyperkalemic cardioplegia.

Diazoxide is already approved in United States for the following indications:

Approved in United States as Proglycem for:

• Hypoglycemia

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

Magic That Matters

Collaborator

Trials

1

Recruited

30+

Published Research Related to This Trial

A nondiabetic patient experienced prolonged postanesthetic coma due to unsuspected hyperglycemia, which was treated with IV diazoxide and furosemide.

The study suggests that blood glucose levels should be monitored during and after general anesthesia, especially in patients at risk for hyperglycemic hyperosmolar nonketotic coma, as the combination of anesthesia and certain medications can lead to elevated blood sugar levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperglycemic hyperosmolar nonketotic coma following diazoxide, anesthesia and operation. Shin, B., Joseph, SI.[2019]

In a study of 37 pediatric patients undergoing hypothermic open-heart surgery, significant hyperglycemia was observed, particularly in those requiring total circulatory arrest, indicating a potential stress response during surgery.

Insulin levels did not rise adequately in response to hyperglycemia, suggesting a mechanism of impaired insulin response; restricting glucose infusion in a separate group prevented hyperglycemia, leading to recommendations for using glucose-free solutions during surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucose and insulin changes in infants and children undergoing hypothermic open-heart surgery. Benzing, G., Francis, PD., Kaplan, S., et al.[2019]

In a study of 1,188 cardiac surgery cases, the del Nido cardioplegia solution resulted in significantly lower maximum intraoperative glucose levels (177.8 mg/dL) compared to the 4:1 solution (183.5 mg/dL), indicating better glucose management during surgery.

Patients receiving the del Nido solution required less intraoperative insulin (56.2%) compared to those receiving the 4:1 solution (65.7%), suggesting that del Nido may be more effective in controlling glucose levels during cardiac surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does the Type of Cardioplegia Solution Affect Intraoperative Glucose Levels? A Propensity-Matched Analysis. Mongero, LB., Tesdahl, EA., Stammers, AH., et al.[2018]

Intensive insulin therapy for managing high blood sugar during cardiac surgery has become the standard practice, but specific protocols for controlling blood sugar levels during surgery were previously lacking.

At Providence St. Vincent Hospital, four effective methods for administering intravenous insulin intraoperatively have been developed over 12 years, providing a foundation for anesthesiologists to tailor their approaches to individual patient needs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Achieving tight glycemic control in the operating room: lessons learned from 12 years in the trenches of a paradigm shift in anesthetic care. Furnary, AP., Cheek, DB., Holmes, SC., et al.[2011]

Tight glycaemic control during coronary artery bypass grafting (CABG) surgery resulted in significantly lower and more consistent intraoperative blood glucose levels compared to conventional glycaemic control, based on a study of 144 diabetic patients.

Despite the improved glycaemic stability with tight control, there was no significant difference in the length of hospital stay between the two groups, suggesting that while tight control is beneficial for blood sugar management, it does not impact recovery time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glycaemic stability and length of stay: Tight versus conventional intraoperative glycaemic control protocols among patients with diabetes mellitus undergoing coronary artery bypass graft surgery. Hayajneh, AA., Hweidi, IM., Zytoon, AM.[2021]

Dysglycemia, which includes both high and low blood sugar levels, significantly impacts the recovery of cardiac surgical patients, leading to increased risks of complications and mortality.

There is currently no consensus on the ideal blood glucose levels to maintain during the perioperative period in cardiac surgery, highlighting the need for better guidelines to manage glucose levels effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative Glycemic Management in Cardiac Surgery: A Narrative Review. Thongsuk, Y., Hwang, NC.[2023]

Intensive insulin therapy (IIT) during coronary artery bypass grafting resulted in a significantly higher incidence of hypoglycemia and hypokalemia compared to conventional blood sugar management, indicating potential safety concerns with IIT.

Despite better glycemic control with IIT, there were no significant differences in major postoperative outcomes such as prolonged intubation, wound infections, or mortality, suggesting that IIT may not provide additional benefits in terms of morbidity and mortality for patients undergoing this surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of intensive insulin therapy and conventional glucose management in patients undergoing coronary artery bypass grafting. Mohod, V., Ganeriwal, V., Bhange, J.[2022]

Perioperative hyperglycemia occurs frequently after cardiac surgery, affecting 60% to 90% of patients with diabetes and about 60% of those without a diabetes history.

Improved glycemic control during the perioperative period is associated with reduced complications, highlighting the importance of managing blood sugar levels in cardiac surgery patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative Management of Hyperglycemia and Diabetes in Cardiac Surgery Patients. Galindo, RJ., Fayfman, M., Umpierrez, GE.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10154575/

Diazoxide is a powerful cardioprotectant but is not feasible in ... Diazoxide reduced infarct size in isolated rodent heart preparations and upon pretreatment in juvenile pigs with coronary occlusion/reperfusion.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06308107

Safety and Feasibility of Hyperkalemic Cardioplegia With ... This study aims to confirm the safety and efficacy of diazoxide as an additive to hyperkalemic cardioplegia in patients undergoing cardiac surgery with ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0022522308017583

Diazoxide protects myocardial mitochondria, metabolism ... No deaths, strokes, or infarcts were observed. Patients received, on average, 36.2 ± 1.2 mg of diazoxide and 37.3 ± 1.9 mg of placebo (P = .6). Diazoxide added ...

4. ahajournals.org ahajournals.org/doi/10.1161/JAHA.122.026304

ATP—Sensitive Potassium Channel Opener Diazoxide ... After 30 minutes of reperfusion, LVEF was 27% higher in the diazoxide group compared with the control (42.5% ± 16.05 and 15.8% ±12.42, ...

5. jtcvs.org jtcvs.org/article/S0022-5223(08)01758-3/pdf

Diazoxide protects myocardial mitochondria, metabolism, ... 04). Conclusions: Supplementing blood cardioplegia with diazoxide is safe and improves myocardial protection dur- ing cardiac surgery, possibly through its ...

6. ahajournals.org ahajournals.org/doi/10.1161/circ.152.suppl_3.4359746

Abstract 4359746: Safety and Feasibility of Hyperkalemic ... The aim of this study was to demonstrate the safety and feasibility of DZX in patients undergoing cardiac surgery.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04830982?cond=%22Myocardial%20Stunning%22&viewType=Table&rank=2

Safety and Efficacy of IV Diazoxide as an Additive to ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/19327530/

a double-blind randomized feasibility study of diazoxide ... Results: No deaths, strokes, or infarcts were observed. Patients received, on average, 36.2 +/- 1.2 mg of diazoxide and 37.3 +/- 1.9 mg of placebo (P = .6).

9. jtcvs.org jtcvs.org/article/S0022-5223(08)01758-3/fulltext

Diazoxide protects myocardial mitochondria, metabolism, and ... The study was designed to assess whether diazoxide-mediated cardioprotection might be used in human subjects during cardiac surgery.