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

30 Participants Needed

Trial Summary

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 diazoxide safe for use in humans?

There is a report of a nondiabetic patient experiencing prolonged coma due to high blood sugar after receiving diazoxide during surgery, suggesting that it can cause significant blood sugar issues when combined with anesthesia and surgical stress. ^{1 2 3 4 5}

How does the drug Diazoxide differ from other treatments for heart surgery?

Diazoxide is unique because it works by opening potassium channels in the heart, which helps to protect the heart muscle during surgery, unlike other treatments that primarily focus on controlling blood sugar levels. ^{3 4 6 7 8}

What is the purpose of this trial?

This study aims to confirm the safety and efficacy of diazoxide as an additive to hyperkalemic cardioplegia in patients undergoing cardiac surgery with cardiopulmonary bypass. The investigators hypothesize that diazoxide combined with hyperkalemic cardioplegia provides superior myocardial protection and reduced myocardial stunning compared with standard cardioplegia alone. Thirty patients will receive treatment. Safety will be assessed by comparing mean arterial blood pressure measurements, glucose levels and incidence of adverse events between the two groups. Efficacy will be assessed by comparing right and left ventricular function in pre-operative vs post-operative transesophageal echocardiograms, need for mechanical circulatory support, ease of separation from bypass and Vasoactive Inotrope Score (VIS) between the two groups. The information gained could pave the way for the use of Katp (Potassium-atp) channel openers to prevent stunning, improve patient outcomes, and reduce health care costs related to myocardial stunning that requires inotropic and mechanical support following cardiac surgery.

Research Team

Jennifer Lawton, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

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

Hyperglycemic hyperosmolar nonketotic coma following diazoxide, anesthesia and operation. [2019]

2. India 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. [2021]

3. India pubmed.ncbi.nlm.nih.gov

Comparison of intensive insulin therapy and conventional glucose management in patients undergoing coronary artery bypass grafting. [2022]

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

Perioperative Glycemic Management in Cardiac Surgery: A Narrative Review. [2023]

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

Perioperative Management of Hyperglycemia and Diabetes in Cardiac Surgery Patients. [2022]

6. France pubmed.ncbi.nlm.nih.gov

Does the Type of Cardioplegia Solution Affect Intraoperative Glucose Levels? A Propensity-Matched Analysis. [2018]

7. United States 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. [2011]

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

Glucose and insulin changes in infants and children undergoing hypothermic open-heart surgery. [2019]