Nitric Oxide for Congenital Heart Disease

Recruiting in Palo Alto (17 mi)

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Children's Hospital Medical Center, Cincinnati

Must not be taking: Steroids, Inhaled NO, others

Disqualifiers: Preoperative AKI, Cardiac arrest, others

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

Acute kidney injury (AKI) following cardiac surgery for congenital heart defects (CHD) in children affects up to 60% of high risk-patients and is a major cause of both short- and long-term morbidity and mortality. Despite effort, to date, no successful therapeutic agent has gained widespread success in preventing this postoperative decline in renal function. Nitric oxide is an intricate regulator of acute inflammation and coagulation and is a potent vasodilator. The investigators hypothesize that nitric oxide, administered during cardiopulmonary bypass (CPB), may reduce the incidence of AKI.

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 have recently been treated with steroids or are using inhaled nitric oxide (iNO) before surgery.

What evidence supports the effectiveness of the drug nitric oxide for congenital heart disease?

Inhaled nitric oxide is shown to be beneficial as a selective pulmonary vasodilator (a drug that widens blood vessels in the lungs) for treating pulmonary hypertension (high blood pressure in the lungs) in newborns with congenital heart disease, providing hemodynamic benefits (improvements in blood flow and pressure). However, these benefits have not been confirmed in randomized, placebo-controlled studies.

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Is nitric oxide generally safe for use in humans?

Nitric oxide is involved in many body processes and has been studied for various conditions. It can cause side effects like headaches and low blood pressure due to its ability to widen blood vessels. However, it is generally considered safe when used appropriately, although targeting its effects to specific tissues remains a challenge.

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How is the drug nitric oxide unique in treating congenital heart disease?

Nitric oxide is unique because it is inhaled and acts as a selective pulmonary vasodilator, meaning it specifically relaxes the blood vessels in the lungs, which can help manage pulmonary hypertension (high blood pressure in the lungs) in patients with congenital heart disease. This targeted action helps improve blood flow and oxygen delivery without affecting the rest of the body, unlike some other treatments.

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Eligibility Criteria

This trial is for newborns (up to 31 days old) who need heart surgery with cardiopulmonary bypass for congenital heart defects. They must weigh over 2 kg and be at least 36 weeks gestational age. Babies can't join if they've had a recent cardiac arrest, preoperative AKI, certain lung or kidney conditions, steroid treatments, or are on other trials.

Inclusion Criteria

My newborn is having heart surgery with CPB for congenital heart disease.

Exclusion Criteria

Non-English speakers

My kidney ultrasound showed structural abnormalities.

I need surgery urgently.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Nitric oxide is administered during cardiopulmonary bypass (CPB) to reduce the incidence of AKI

Intraoperative

1 visit (in-person, surgical procedure)

Follow-up

Participants are monitored for AKI and other outcomes postoperatively

72 hours

Continuous monitoring during hospital stay

Extended Follow-up

Participants are monitored for long-term kidney function and recovery

4 weeks

Participant Groups

The study tests whether nitric oxide given during heart surgery can lower the risk of acute kidney injury in newborns with congenital heart defects. It's exploring if this gas helps protect the kidneys by reducing inflammation and improving blood flow during surgery.

Group I: Nitric Oxide Experimental Treatment 1 Intervention

Intraoperative NO entrained at 20 ppm into the oxygenator of the CPB circuit with standard care

Group II: Oxygen Placebo Group 1 Intervention

Standard CPB without NO administered at any point intraoperatively

Nitric Oxide is already approved in United States, United States, United States for the following indications:

🇺🇸 Approved in United States as Inomax for:

• Hypoxic respiratory failure in term and near-term neonates with pulmonary hypertension

🇺🇸 Approved in United States as Noxivent for:

• Hypoxic respiratory failure in term and near-term neonates with pulmonary hypertension

🇺🇸 Approved in United States as GeNOsyl for:

• Hypoxic respiratory failure in term and near-term neonates with pulmonary hypertension

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Cincinnati Children's Hospital Medical Center Cincinnati, OH

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati Lead Sponsor

Mallinckrodt Industry Sponsor

Indiana University Collaborator

References

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

Inhaled nitric oxide in the neonate with cardiac disease. [2022] As a selective pulmonary vasodilator, inhaled nitric oxide is an important diagnostic and therapeutic agent for the treatment of pulmonary hypertension in patients with congenital heart disease. Among 400 patients treated in our center with nitric oxide, 37% were newborns. Hemodynamic benefit was shown in newborns with total anomalous pulmonary venous connection, in those with congenital mitral stenosis, and in postoperative patients with preexisting left to right shunts and other lesions. It can be used to help discriminate anatomic obstruction to pulmonary blood flow from pulmonary vasoconstriction, and it may be used in the treatment or prevention of pulmonary hypertensive crises after cardiopulmonary bypass. However, none of the purported benefits of inhaled nitric oxide in children with congenital heart disease have been studied in a randomized, placebo-controlled manner.

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

Identification of arginine as a precursor of endothelium-derived relaxing factor. [2022] Nitric oxide (NO) is a major endothelium-derived relaxing factor (EDRF) released in response to vasodilating amines, peptides, proteins, ionophores, and nucleotides. EDRF is an important regulator of smooth muscle tone and platelet aggregation and adhesion. Histamine and acetylcholine relax the intact norepinephrine-constricted guinea pig pulmonary artery by an EDRF-dependent mechanism in a medium free of amino acids. N omega-Monomethylarginine (N-MeArg; 0.25 mM) inhibited this relaxation by 64-73%. Inhibition by N-MeArg developed rapidly and was immediately and completely reversed by excess L-arginine but not by D-arginine or by citrulline. N-MeArg did not diminish relaxation induced by nitroprusside, an NO-generating agent, indicating that N-MeArg acts on endothelium rather than on smooth muscle. These observations strongly suggest that, in the intact guinea pig pulmonary artery, EDRF originates from enzymatic action on the guanido nitrogen(s) of an endogenous pool of arginine. This is strikingly similar to the origin of reactive nitrogen intermediates in activated macrophages.

3. Japan pubmed.ncbi.nlm.nih.gov

The role of nitric oxide in cardiac surgery. [2022] The release of nitric oxide (NO) from coronary endothelial cells is impaired following reperfusion; however, several experimental studies have found that it exerts a cardioprotective effect during myocardial ischemia-reperfusion. Thus, attempts have been made to supplement NO production exogenously during reperfusion when endogenous NO release may be diminished. Conversely, other studies suggest that NO exacerbates reperfusion injury by inducing the production of peroxynitrite. NO has also been reported to provide beneficial effects as a selective pulmonary vasodilator to relieve pulmonary hypertension. A loss of NO-mediated relaxation caused by the dysfunction of endothelial cells is characteristic of intimal hyperplasia, and nitrosovasodilators have proven efficient against atherosclerotic coronary heart disease, which may be attributable to their antiplatelet effects as well as to vasodilation. Furthermore, protamine sulfate, which is rich in L-arginine, is thought to augment NO production by supplying exogenous L-arginine, or to act on endothelial cell receptors to stimulate the production of NO. This review summarizes the current role of NO in cardiac surgery.

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

Endothelium-derived nitric oxide: actions and properties. [2022] Vascular smooth muscle relaxation in response to chemically diverse naturally occurring neurotransmitters and autacoids has been attributed to the formation and/or release of one or more vascular endothelium-derived relaxing factors (EDRFs) distinct from prostacyclin. The chemical, biochemical, and pharmacological properties of one such EDRF resemble closely the properties of nitric oxide (NO). Thus, both arterial and venous EDRFs as well as authentic NO cause heme-dependent activation of soluble guanylate cyclase, endothelium-independent vascular and nonvascular smooth muscle relaxation accompanied by tissue cyclic GMP formation, and inhibition of platelet aggregation and adhesion to endothelial cell surfaces. EDRF from artery, vein, and freshly harvested and cultured aortic endothelial cells was recently identified as NO or a labile nitroso species as assessed by chemical assay and bioassay. Endothelium-derived NO (EDNO) has an ultrashort half-life of 3-5 s due to spontaneous oxidation to nitrite and nitrate, both of which have only weak biological activity. EDNO can be synthesized from L-arginine and possibly other basic amino acids and polypeptides, perhaps by oxidative metabolic pathways that could involve polyunsaturated fatty acid-derived oxygen radicals. Inorganic nitrite could serve as both a stored precursor and an inactivation product of EDNO. EDNO and related EDRFs may serve physiological and/or pathophysiological roles in the regulation of local blood flow and platelet function.

5. Netherlands pubmed.ncbi.nlm.nih.gov

Endothelium-derived nitric oxide relaxes nonvascular smooth muscle. [2019] A bioassay cascade superfusion procedure was used to compare and contrast the actions of arterial and venous endothelium-derived relaxing factor (EDRF) with authentic nitric oxide (NO) on several nonvascular smooth muscle preparations. EDRF was released from human umbilical vein or bovine pulmonary artery by A23187 and allowed to superfuse two nonvascular and one vascular precontracted smooth muscle strips arranged in a cascade. NO or S-nitroso-N-acetylpenicillamine was delivered by superfusion. Both EDRF and NO relaxed bovine trachea, although artery was 10 times more sensitive than trachea to either relaxant. Similarly, rabbit taenia coli and rat fundus relaxed in response to high concentrations of NO or large amounts of EDRF released from umbilical vein. Vascular and nonvascular relaxant responses to both EDRF and NO were inhibited by oxyhemoglobin, methylene blue or superoxide, and were enhanced by superoxide dismutase. Perfusion of pulmonary artery or umbilical vein with A23187 resulted in contraction of guinea pig ileum and relaxation of pulmonary artery, whereas NO relaxed both preparations. Oxyhemoglobin enhanced the contractile and abolished the relaxant responses. Thus, ileum is more sensitive to endothelium-derived contracting factor(s) than to EDRF. NO raised cyclic GMP levels in all smooth muscle preparations, but a greater fold increase was observed in artery than in nonvascular smooth muscle. EDRF released from human umbilical vein was identified chemically as NO or a nitroso compound, as was done previously for EDRF from bovine pulmonary artery and vein. These observations support the view that one EDRF from artery and vein is NO or a labile nitroso compound.

6. England pubmed.ncbi.nlm.nih.gov

Nitric oxide donor drugs: an update on pathophysiology and therapeutic potential. [2019] The discovery of the multiple physiological and pathophysiological processes in which nitric oxide (NO) is involved has promoted a great number of pharmacological researches to develop new drugs that are capable of influencing NO production directly and/or indirectly for therapeutic purposes (i.e, NO-releasing drugs, NO-inhibiting drugs, and phosphodiesterase V inhibitors). In particular, the so-called NO donor drugs could actually have an important therapeutic effect in the treatment of many diseases such as arteriopathies (atherosclerosis and its sequelae, arterial hypertension and some forms of male sexual impotence), various acute and chronic inflammatory conditions (colitis, rheumatoid arthritis and tissue remodelling), and several degenerative diseases (Alzheimer's disease and cancer). The old organic nitrates show some well-known pitfalls including the induction of tolerance and acute side effects related to abrupt vasodilation such as cephalea and hypotension, which limit their therapeutic indications. A low therapeutic index (i.e., peroxynitrite toxicity) has always characterised the sydnonimines class. A series of interesting new classes of NO donors are under intense pharmacological investigation and scrutiny (S-nitrosothiols, diazeniumdiolates and NO hybrid drugs), each characterised by a particular pharmacokinetic and pharmacodynamic profile. The most important obstacle in the field of NO donor drugs is represented by the difficulty in targeting NO release, and thereby its effects, to a particular tissue.

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

Endothelium-derived nitric oxide: pharmacology and relationship to the actions of organic nitrate esters. [2019] Vascular smooth muscle relaxation elicited by various endogenous substances results from their interaction with vascular endothelial cells to triger the formation of endothelium-derived relaxing factor (EDRF). EDRF from pulmonary and peripheral arteries and veins and from cultured and freshly harvested aortic endothelial cells has been identified pharmacologically and chemically as nitric oxide (NO) or a labile nitroso compound. Endothelium-derived NO (EDNO) and authentic NO activate the cytoplasmic form of guanylate cyclase by heme-dependent mechanism and thereby stimulate intracellular cyclic GMP accumulation in cells including vascular smooth muscle and platelets. Cyclic GMP functions as a second messenger to cause vascular muscle relaxation and inhibition of platelet aggregation and adhesion to vascular endothelial surfaces. EDNO is synthesized from L-arginine and perhaps arginine-containing peptides by an unidentified calcium-requiring process coupled to the occupation of extracellular endothelial receptors. The biological actions of EDNO are terminated by spontaneous oxidation to NO2- and NO3-. The biological half-life of the very lipophilic EDNO is only 3-5 sec and this allows EDNO to function locally as an autacoid. Nitroglycerin and other organic nitrate esters elicit endothelium-independent relaxation after entering vascular smooth muscle cells and undergoing denitration and formation of NO. The pharmacological actions of nitroglycerin are therefore essentially the same as those of EDNO, and the endogenous NO receptor is the heme group bound to soluble guanylate cyclase. EDNO may serve a biological role to modulate local blood flow and platelet function.

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

Inhaled nitric oxide in congenital heart disease. [2019] Congenital heart lesions may be complicated by pulmonary arterial smooth muscle hyperplasia, hypertrophy, and hypertension. We assessed whether inhaling low levels of nitric oxide (NO), an endothelium-derived relaxing factor, would produce selective pulmonary vasodilation in pediatric patients with congenital heart disease and pulmonary hypertension. We also compared the pulmonary vasodilator potencies of inhaled NO and oxygen in these patients.

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

Nitrates in different vascular beds, nitrate tolerance, and interactions with endothelial function. [2019] The favorable anti-ischemic effect of nitrates is based on the unique distribution pattern of vascular relaxation that they evoke in different vascular sections. Nitrovasodilators reduce cardiac preload and wall tension, and thus myocardial oxygen consumption. They increase precollateral coronary perfusion pressure, thereby augmenting oxygen delivery to ischemic sections, especially to the subendocardial layers. These vasodilator actions are caused by the nitric oxide (NO)-induced activation of soluble guanylyl cyclase, which augments vascular cyclic guanosine monophosphate (cGMP) levels to suppress intracellular Ca2+ concentrations. After some metabolic steps NO is finally cleaved from all nitrovasodilators and is probably identical with, or very closely related to, endothelium-derived relaxing factor (EDRF). A dinitrosyl-iron complex may serve under biologic conditions to stabilize the NO- radical, which has an extremely short half-life. NO derived from nitrovasodilators is used therapeutically to substitute for a deficient endothelium-mediated vascular control and autacoid production.