Dose-response Study of Sodium Nitroprusside in Children Requiring Controlled Hypotension in the Operating Room

A Phase 2 Multicenter, Randomized, Double-blind, Parallel Group, Dose-ranging, Effect-controlled Study to Determine the Pharmacokinetics and Pharmacodynamics of Sodium Nitroprusside in Pediatric Subjects

Sodium nitroprusside (SNP) has been approved for control of blood pressure in adults, yet there are no controlled studies in children. The purpose of this study is to determine the efficacy and safety of sodium nitroprusside in children who will be having surgery, and who require blood pressure lowering in order to decrease the amount of blood loss during their surgery.

Study Overview

• Status: Completed
• Conditions: Hypotension
• Intervention / Treatment: Drug: Nitroprusside; Drug: Nitroprusside; Drug: Nitroprusside

Detailed Description

The trial is a multicenter randomized, double-blind, parallel group, dose-ranging, effect-controlled study examining the effects of sodium nitroprusside in pediatric subjects requiring relative hypotension during a surgical or medical procedure. The goal is to establish the starting and maximum infusion rates that afford optimum blood pressure control in children and a safe dosing regimen in children. The objective is to describe the relationship between the infusion rate of nitroprusside and changes in blood pressure.

The specific aims of this trial are:

1. To define the onset and offset of blood pressure lowering effects of nitroprusside to obtain adequate instructions for dose titration in the pediatric population.
2. To construct a dose-response model that defines the relationship between nitroprusside infusion rate and changes in blood pressure in pediatric subjects.
3. To assess the safety of nitroprusside administration in pediatric subjects requiring controlled reduction of blood pressure.

• Study Type: Interventional
• Enrollment (Actual): 211
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305-5401
      • Stanford University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Study subjects must meet all of the following criteria:

• Subject is less than 17 years of age
• Neonates must be full-term gestation and have a body weight of at least 2.5 kg
• Subject requires pharmacologically-induced hypotension for acute blood pressure management for surgery or other invasive procedure, e.g., cerebral artery embolization
• Duration of the subject's controlled hypotension is expected to be ≥ 2 hours
• Subject requires general anesthesia with endotracheal intubation
• Subject requires placement of intra-arterial line during the surgical or medical procedure
• The subject's parent or legal guardian gives permission (informed consent) and subject gives assent when appropriate.

Exclusion Criteria:

Subjects will be excluded if any of the following criteria exist:

• Subject has a known allergy to SNP
• Subject has a known mitochondrial cytopathy with a disorder of oxidative phosphorylation or of respiratory chain enzymes
• Subject has a contraindication to vasodilator therapy for control of blood pressure during surgery or procedures
• Subject has participated in other clinical trials for investigational drugs and/or devices within 30 days prior to enrollment
• Subject has any serious medical condition which, in the opinion of the investigator, is likely to interfere with study procedures
• Subject is moribund (death likely to occur within 48 hours)
• Subject has a positive result for the urine or serum human chorionic gonadotropin (HCG) test administered at screening.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 0.3 mcg/kg/min; Infusion of Sodium Nitroprusside began only after a 5-minute period of stable anesthesia or sedation (no changes in dosages). The infusion rate during the blinded study drug period was increased in a step-wise fashion to the full dose rate as follows: 5 ± 1 minutes at 1/3 of the full rate; 5 ± 1 minutes at 2/3 of the full rate; and 20 minutes at the full dose rate (ie, 30 minutes total). The full infusion rate was 0.6 mL/kg/hr; 2/3 of the full rate was 0.4 mL/kg/hr; and 1/3 of the full rate was 0.2 mL/kg/hr. After titration to the full dose of blinded study drug, blinded infusion dosage adjustments were not permitted during the blinded study drug administration period. The blinded infusion dosage continued for the 30 minutes unless clinical events demanded a change for safety reasons.	Drug: Nitroprusside; Study drug was infused via a dedicated peripheral intravenous catheter or via a dedicated lumen of a multi-orifice central venous catheter. Infusion pumps capable of reliable delivery at low infusion rates (to 0.1 mL/hr) were used.Study drug was dispensed to the sites in 2 mL vials containing 25 mg/mL of sodium nitroprusside. The pharmacist prepared and dispensed the study drug, and supplied blinded study drug for each subject according to a randomization assignment generated by the IVRS (Interactive Voice Response System).; Other Names: Sodium Nitroprusside IV infusion 0.3 mcg/kg/ min; Drug: Nitroprusside; Study drug was infused via a dedicated peripheral intravenous catheter or via a dedicated lumen of a multi-orifice central venous catheter. Infusion pumps capable of reliable delivery at low infusion rates (to 0.1 mL/hr) were used.Study drug was dispensed to the sites in 2 mL vials containing 25 mg/mL of sodium nitroprusside. The pharmacist prepared and dispensed the study drug, and supplied blinded study drug for each subject according to a randomization assignment generated by the IVRS.; Other Names: Sodium Nitroprusside IV infusion 2 mcg/kg/ min; Drug: Nitroprusside; Study drug was infused via a dedicated peripheral intravenous catheter or via a dedicated lumen of a multi-orifice central venous catheter. Infusion pumps capable of reliable delivery at low infusion rates (to 0.1 mL/hr) were used.Study drug was dispensed to the sites in 2 mL vials containing 25 mg/mL of sodium nitroprusside. The pharmacist prepared and dispensed the study drug, and supplied blinded study drug for each subject according to a randomization assignment generated by the IVRS; Other Names: Sodium Nitroprusside IV infusion 3 mcg/kg/ min
Active Comparator: 1 mcg/kg/min; Infusion of Sodium Nitroprusside began only after a 5-minute period of stable anesthesia or sedation (no changes in dosages). The infusion rate during the blinded study drug period was increased in a step-wise fashion to the full dose rate as follows: 5 ± 1 minutes at 1/3 of the full rate; 5 ± 1 minutes at 2/3 of the full rate; and 20 minutes at the full dose rate (ie, 30 minutes total). The full infusion rate was 0.6 mL/kg/hr; 2/3 of the full rate was 0.4 mL/kg/hr; and 1/3 of the full rate was 0.2 mL/kg/hr. After titration to the full dose of blinded study drug, blinded infusion dosage adjustments were not permitted during the blinded study drug administration period. The blinded infusion dosage continued for the 30 minutes unless clinical events demanded a change for safety reasons.	Drug: Nitroprusside; Study drug was infused via a dedicated peripheral intravenous catheter or via a dedicated lumen of a multi-orifice central venous catheter. Infusion pumps capable of reliable delivery at low infusion rates (to 0.1 mL/hr) were used.Study drug was dispensed to the sites in 2 mL vials containing 25 mg/mL of sodium nitroprusside. The pharmacist prepared and dispensed the study drug, and supplied blinded study drug for each subject according to a randomization assignment generated by the IVRS (Interactive Voice Response System).; Other Names: Sodium Nitroprusside IV infusion 0.3 mcg/kg/ min; Drug: Nitroprusside; Study drug was infused via a dedicated peripheral intravenous catheter or via a dedicated lumen of a multi-orifice central venous catheter. Infusion pumps capable of reliable delivery at low infusion rates (to 0.1 mL/hr) were used.Study drug was dispensed to the sites in 2 mL vials containing 25 mg/mL of sodium nitroprusside. The pharmacist prepared and dispensed the study drug, and supplied blinded study drug for each subject according to a randomization assignment generated by the IVRS.; Other Names: Sodium Nitroprusside IV infusion 2 mcg/kg/ min; Drug: Nitroprusside; Study drug was infused via a dedicated peripheral intravenous catheter or via a dedicated lumen of a multi-orifice central venous catheter. Infusion pumps capable of reliable delivery at low infusion rates (to 0.1 mL/hr) were used.Study drug was dispensed to the sites in 2 mL vials containing 25 mg/mL of sodium nitroprusside. The pharmacist prepared and dispensed the study drug, and supplied blinded study drug for each subject according to a randomization assignment generated by the IVRS; Other Names: Sodium Nitroprusside IV infusion 3 mcg/kg/ min
Active Comparator: 2 mcg/kg/min; Infusion of Sodium Nitroprusside began only after a 5-minute period of stable anesthesia or sedation (no changes in dosages). The infusion rate during the blinded study drug period was increased in a step-wise fashion to the full dose rate as follows: 5 ± 1 minutes at 1/3 of the full rate; 5 ± 1 minutes at 2/3 of the full rate; and 20 minutes at the full dose rate (ie, 30 minutes total). The full infusion rate was 0.6 mL/kg/hr; 2/3 of the full rate was 0.4 mL/kg/hr; and 1/3 of the full rate was 0.2 mL/kg/hr. After titration to the full dose of blinded study drug, blinded infusion dosage adjustments were not permitted during the blinded study drug administration period. The blinded infusion dosage continued for the 30 minutes unless clinical events demanded a change for safety reasons	Drug: Nitroprusside; Study drug was infused via a dedicated peripheral intravenous catheter or via a dedicated lumen of a multi-orifice central venous catheter. Infusion pumps capable of reliable delivery at low infusion rates (to 0.1 mL/hr) were used.Study drug was dispensed to the sites in 2 mL vials containing 25 mg/mL of sodium nitroprusside. The pharmacist prepared and dispensed the study drug, and supplied blinded study drug for each subject according to a randomization assignment generated by the IVRS (Interactive Voice Response System).; Other Names: Sodium Nitroprusside IV infusion 0.3 mcg/kg/ min; Drug: Nitroprusside; Study drug was infused via a dedicated peripheral intravenous catheter or via a dedicated lumen of a multi-orifice central venous catheter. Infusion pumps capable of reliable delivery at low infusion rates (to 0.1 mL/hr) were used.Study drug was dispensed to the sites in 2 mL vials containing 25 mg/mL of sodium nitroprusside. The pharmacist prepared and dispensed the study drug, and supplied blinded study drug for each subject according to a randomization assignment generated by the IVRS.; Other Names: Sodium Nitroprusside IV infusion 2 mcg/kg/ min; Drug: Nitroprusside; Study drug was infused via a dedicated peripheral intravenous catheter or via a dedicated lumen of a multi-orifice central venous catheter. Infusion pumps capable of reliable delivery at low infusion rates (to 0.1 mL/hr) were used.Study drug was dispensed to the sites in 2 mL vials containing 25 mg/mL of sodium nitroprusside. The pharmacist prepared and dispensed the study drug, and supplied blinded study drug for each subject according to a randomization assignment generated by the IVRS; Other Names: Sodium Nitroprusside IV infusion 3 mcg/kg/ min
Active Comparator: 3 mcg/kg/min; Infusion of Sodium Nitroprusside began only after a 5-minute period of stable anesthesia or sedation (no changes in dosages). The infusion rate during the blinded study drug period was increased in a step-wise fashion to the full dose rate as follows: 5 ± 1 minutes at 1/3 of the full rate; 5 ± 1 minutes at 2/3 of the full rate; and 20 minutes at the full dose rate (ie, 30 minutes total). The full infusion rate was 0.6 mL/kg/hr; 2/3 of the full rate was 0.4 mL/kg/hr; and 1/3 of the full rate was 0.2 mL/kg/hr. After titration to the full dose of blinded study drug, blinded infusion dosage adjustments were not permitted during the blinded study drug administration period. The blinded infusion dosage continued for the 30 minutes unless clinical events demanded a change for safety reasons	Drug: Nitroprusside; Study drug was infused via a dedicated peripheral intravenous catheter or via a dedicated lumen of a multi-orifice central venous catheter. Infusion pumps capable of reliable delivery at low infusion rates (to 0.1 mL/hr) were used.Study drug was dispensed to the sites in 2 mL vials containing 25 mg/mL of sodium nitroprusside. The pharmacist prepared and dispensed the study drug, and supplied blinded study drug for each subject according to a randomization assignment generated by the IVRS (Interactive Voice Response System).; Other Names: Sodium Nitroprusside IV infusion 0.3 mcg/kg/ min; Drug: Nitroprusside; Study drug was infused via a dedicated peripheral intravenous catheter or via a dedicated lumen of a multi-orifice central venous catheter. Infusion pumps capable of reliable delivery at low infusion rates (to 0.1 mL/hr) were used.Study drug was dispensed to the sites in 2 mL vials containing 25 mg/mL of sodium nitroprusside. The pharmacist prepared and dispensed the study drug, and supplied blinded study drug for each subject according to a randomization assignment generated by the IVRS.; Other Names: Sodium Nitroprusside IV infusion 2 mcg/kg/ min; Drug: Nitroprusside; Study drug was infused via a dedicated peripheral intravenous catheter or via a dedicated lumen of a multi-orifice central venous catheter. Infusion pumps capable of reliable delivery at low infusion rates (to 0.1 mL/hr) were used.Study drug was dispensed to the sites in 2 mL vials containing 25 mg/mL of sodium nitroprusside. The pharmacist prepared and dispensed the study drug, and supplied blinded study drug for each subject according to a randomization assignment generated by the IVRS; Other Names: Sodium Nitroprusside IV infusion 3 mcg/kg/ min

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Mean Arterial Pressure (MAP) From the Baseline MAP	From the Baseline MAP until the end of the blinded phase; scheduled for 30 min	Approximately 30 minutes
Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population	Treatment-emergent AEs (TEAEs) were defined as an AE experienced by the patient that was either first observed after the initiation of study drug (blinded or open-label) or represented an exacerbation (usually in severity) of a pre existing condition observed prior to treatment. Subjects will be followed for 30 days after discontinuation of study drug. The occurrence of Serious Adverse Events (SAEs) will be monitored for 30 days.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion;	Change From Baseline in MAP (mmHg) After 20 and 25 Minutes Double-Blind Infusion (Overall) for ITT Efficacy Evaluable Population.	25 minutes
Infusion Rate of Sodium Nitroprusside That Reduces MAP to a Predetermined Clinically Meaningful Target Value +/- 10%;	Infusion rate of sodium nitroprusside at which a predetermined clinically meaningful target value (+/- 10%) of MAP was achieved during study drug administration	Up to the end of open label treatment (Approximately 120 minutes)
Number of Participants Who Reach Target MAP;	Blinded Study Drug Administration Period: Started with study drug administration following stabilization of anesthesia. Patients were administered a blinded dose of SNP for up to 30 mins. This period ended at the start of open-label study drug infusion or at the completion of the blinded infusion if no open-label study drug was given. The follow-up period immediately followed for those patients not receiving open-label infusion. Blinded Treatment Phase II - gap between the end of blinded study drug infusion and the start of open-label study drug infusion Open-label treatment phase began with the start of open-label study drug infusion and was at least 90 mins in duration. SNP was initiated at a dose deemed appropriate by the investigator and was gradually adjusted to reach a target MAP based on clinical presentation and needs of the patient. Target MAP was not to be < 50 mmHg (40 mmHg for patients < 30 days of age). This period ended at the completion of open-label infusion.	To the end of open label treatment (approximately 120 minutes)

Collaborators and Investigators

• Sponsor: The Emmes Company, LLC
• Collaborators: Duke University; Stanford University
• Investigators: Principal Investigator: Gregory Hammer, MD, Stanford University; Principal Investigator: Scott Schulman, MD, Duke University

Publications and helpful links

General Publications

• Drover DR, Hammer GB, Barrett JS, Cohane CA, Reece T, Zajicek A, Schulman SR. Evaluation of sodium nitroprusside for controlled hypotension in children during surgery. Front Pharmacol. 2015 Jul 6;6:136. doi: 10.3389/fphar.2015.00136. eCollection 2015.
• Hammer GB, Connolly SG, Schulman SR, Lewandowski A, Cohane C, Reece TL, Anand R, Mitchell J, Drover DR. Sodium nitroprusside is not associated with metabolic acidosis during intraoperative infusion in children. BMC Anesthesiol. 2013 Apr 30;13:9. doi: 10.1186/1471-2253-13-9.

Study record dates

Study Major Dates

• Study Start: August 1, 2005
• Primary Completion (Actual): March 1, 2008
• Study Completion (Actual): February 1, 2009

Study Registration Dates

• First Submitted: August 25, 2005
• First Submitted That Met QC Criteria: August 25, 2005
• First Posted (Estimated): August 26, 2005

Study Record Updates

• Last Update Posted (Estimated): January 1, 2024
• Last Update Submitted That Met QC Criteria: December 12, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: safety; children; pharmacokinetics; efficacy; pharmacodynamics; dose-response; controlled hypotension; sodium nitroprusside
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypotension; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Nitric Oxide Donors; Nitroprusside
• Other Study ID Numbers: NICHD-2003-09-DR; N01HD43386-7-0-1 (U.S. NIH Grant/Contract)