Safety Study of Nebulized Sodium Nitroprusside in Adult Acute Lung Injury

A Phase 1 Study: The Determination of the Maximum Tolerable Dosage of Nebulized Sodium Nitroprusside in Adult Acute Lung Injury

Acute lung injury (ALI) is caused by a wide variety of conditions, but always characterized by hypoxia and non-cardiogenic pulmonary edema. Current treatment of ALI is supportive and treatment of the underlying cause. New therapies to treat severe ALI have not been shown to improve survival, and are limited by financial and logistical resources.

The investigators propose to investigate the role of inhaled sodium nitroprusside (iSNP) in ALI. Sodium nitroprusside (SNP) is a vasodilator. When inhaled, SNP may travel to areas of the lung participating in gas exchange, and cause the blood vessels surrounding these areas to enlarge. This may result in an increase of blood vessels to these areas of the lung, and improve oxygenation. Currently, iSNP has not been studied in the adult population. Therefore, this study is intended to find the safety profile of varying doses of iSNP.

Study Overview

• Status: Unknown
• Conditions: Hypoxia; Respiratory Failure; Acute Respiratory Distress Syndrome; Acute Lung Injury; Sodium Nitroprusside
• Intervention / Treatment: Drug: Sodium Nitroprusside

Detailed Description

Acute lung injury (ALI) is a syndrome characterized by acute hypoxemic respiratory failure with bilateral pulmonary infiltrates that are not attributed to left atrial hypertension. ALI is responsible for significant mortality and morbidity in the critically ill population.

Novel rescue therapies used to support oxygenation in severe ALI include inhaled nitric oxide and high frequency oscillatory ventilation; however, neither have been shown to reduce mortality and both are limited by logistical and financial challenges.

Inhaled sodium nitroprusside (iSNP) is a vasodilator which causes local vasodilation of pulmonary capillaries surrounding functional alveoli, resulting in improved oxygenation by redistributing pulmonary blood flow to areas with better ventilation-perfusion ratios. As iSNP can be administered by a low-cost nebulizer and is relatively inexpensive compared to other novel rescue therapies, this modality may be an alternative therapy for patients with severe hypoxemia. Two pediatric studies support the use of iSNP in ALI; however, iSNP has not been studied in the adult ALI population. To determine whether iSNP can improve oxygenation in adult ALI, the maximum tolerable dose (MTD) must first be determined.

Our study aims to determine the MTD of iSNP in adult ALI through an open-label, non-randomized, single centered, dose escalation study design, whereby subjects will receive iSNP for thirty minutes and have various physiologic variables recorded.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X5
      • Recruiting
      • Mount Sinai Hospital, University of Toronto
      • Principal Investigator: Sangeeta Mehta, MD FRCPC
      • Principal Investigator: Terence Ip, MD
      • Sub-Investigator: Lisa Burry, PharmD
      • Sub-Investigator: Cynthia Harris, RRT
      • Sub-Investigator: John Traill, RRT
      • Sub-Investigator: Niall Ferguson, MD, FRCPC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18
2. Negative β-hCG in women of child bearing age (age ≤ 50)

3. Developed ALI within past 72 hours:

   • PaO2/FiO2 < 300;
   • Bilateral infiltrates on CXR;
   • No clinical evidence of elevated left atrial pressure ie. Heart failure as the cause of hypoxia and bilateral infiltrates; and
   • Recognized risk factor for ALI such as: pneumonia, aspiration pneumonitis, acute pancreatitis, massive blood transfusion, or sepsis
4. FiO2 ≥ 0.5
5. PEEP ≥ 8 cm H2O
6. Invasive arterial blood pressure line
7. Endotracheal intubation or tracheostomy
8. Conventional mechanical ventilation
9. Mean Arterial Pressure (MAP) ≥ 65 mmHg with or without use of vasopressors (stable for at least more than 1 hour)
10. Arterial pH ≥ 7.15

Exclusion Criteria:

1. Chest tube with active leak (eg. bronchopulmonary fistula),
2. Prone ventilation, inhaled nitric oxide, inhaled prostacyclin, high frequency oscillatory ventilation,
3. Lack of consent,
4. Untreated coarctation of aorta, symptomatic or severe/critical aortic stenosis as documented by echocardiogram or clinical history,
5. Evidence of increased intracranial pressure (eg. dilated pupils, known intracranial trauma or mass on head CT),
6. SpO2 <90%,
7. Contraindication to SNP i.e. hypersensitivity, congenital optic atrophy, tobacco amblyopia,
8. Active treatment with IV or transdermal nitroglycerin,
9. G6PD deficiency
10. CrCl < 30 ml/min or receiving renal replacement therapy, or
11. Total bilirubin > 68 µmol/L and AST or ALT level 2 times the upper limit of normal.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Nebulized sodium nitroprusside

Drug: Sodium Nitroprusside; Each subject will receive one of five possible dosages of nebulized sodium nitroprusside. The dosage will be determined by the 3 + 3 dose escalation design. Only a maximum of six patients will be given a particular dosage. Arterial blood gases will be drawn at 0 min, 15 min, 30 min and 45 min during nebulized sodium nitroprusside administration. Vitals signs will be recorded every five minutes. No changes to ventilator settings or vasopressor dosage or fluid administration will be allowed.; Other Names: Nipride, Nitropress

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The maximum tolerable dosage of nebulized sodium nitroprusside. This will be determined by the 3 + 3 dose finding design.	Participants will be followed for the duration of the intervention of 45 min. . It is anticipated it will take up to 1 year to recruit the required number of participants to determine the maximum tolerable dose of nebulized sodium nitroprusside.	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
The change in measures of oxygenation (PaO2,SaO2,oxygenation index) during iSNP administration.	0 min, 15 min, 30 min, and 45 min
The change in heart rate (HR), mean blood pressure (MAP) during iSNP administration.	0 min, 15 min, 30 min, and 45 min
The presence or absence of lactate, and/or methemoglobin.	0 min, 15 min, 30 min, and 45 min

Collaborators and Investigators

• Sponsor: Mount Sinai Hospital, Canada
• Investigators: Principal Investigator: Sangeeta Mehta, MD FRCPC, Department of Critical Care Medicine, University of Toronto; Principal Investigator: Terence Ip, MD, Department of Critical Care Medicine, University of Toronto

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Anticipated): June 1, 2013
• Study Completion (Anticipated): June 1, 2013

Study Registration Dates

• First Submitted: May 29, 2012
• First Submitted That Met QC Criteria: June 12, 2012
• First Posted (Estimate): June 14, 2012

Study Record Updates

• Last Update Posted (Estimate): June 14, 2012
• Last Update Submitted That Met QC Criteria: June 12, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: Safety; adult; Phase 1; lung injury; Acute Respiratory Distress Syndrome; Dose Finding; nitric oxide; High-Frequency Ventilation; Acute Lung Injury; Sodium Nitroprusside; 3 + 3 design; Nebulizers and Vaporizers; Pulmonary Gas Exchange; Pulmonary Alveoli
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Signs and Symptoms, Respiratory; Infant, Premature, Diseases; Thoracic Injuries; Respiratory Insufficiency; Wounds and Injuries; Hypoxia; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Lung Injury; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Nitric Oxide Donors; Nitroprusside
• Other Study ID Numbers: 10-0102-A