Adding Nebulized Salbutamol to Intravenous Atropine and Oxygen in OP Poisoning (SalbutamolOP)

Effect of Adding Nebulized Salbutamol to Intravenous Atropine and Oxygen During Resuscitation of OP Pesticide Poisoned Patients

We hypothesize that salbutamol will speed removal of alveolar fluid compared to atropine alone in OP poisoned patients. We propose to compare the effect of two stat doses of nebulized salbutamol (2.5 mg; 5.0 mg), with nebulized saline placebo, in symptomatic patients receiving standard resuscitation with atropine, oxygen, and fluids after poisoning with OP pesticides. 25 patients will be randomised to each arm (total 75 patients). Primary outcome will be oxygen saturation's over the following 60 min during resuscitation. Secondary outcomes will include atropine dose administered, speed to stabilization, aspiration or pneumonia, intubation, tachydysrhythmias, and mortality. A positive outcome will result in design of a large definitive phase III study.

Study Overview

• Status: Completed
• Conditions: Organophosphate Poisoning
• Intervention / Treatment: Drug: Standard care; Drug: Standard care+ 2.5 mg Salbutamol; Drug: Standard care+ 5 mg Salbutamol

Detailed Description

Pesticide self-poisoning kills over 300,000 people every year (1). Most deaths occur in rural Asia where widespread use of pesticides to boost food production allows easy access at stressful times. The WHO now recognizes pesticide poisoning to be the single most important global means of suicide (2) Amongst pesticides, organophosphorus (OP) and carbamate insecticides are of most concern, causing about 2/3 of deaths (1,3). These insecticides inhibit the enzyme acetylcholinesterase (AChE), producing an 'acute cholinergic crisis' with reduced consciousness, bradycardia, hypotension, and acute respiratory failure. On arrival at hospital, patients are resuscitated with atropine and, for OPs, an oxime AChE reactivator (4). Unfortunately, this treatment is often inadequate and many still die (5). A recent Bangladeshi RCT showed that rapid resuscitation of patients with atropine saves lives (6). This study compared a faster 'doubling dose' method of atropinisation with a standard bolus method during resuscitation. It reported quicker stabilisation and a 14% absolute reduction in mortality.

Rationale: Atropine only stops production of fluid and does not speed its removal from the lung. Therefore a treatment that increases removal, to complement atropine-induced cessation of production, could reduce fluid in the lungs and speed return effective oxygen exchange. A single nebulised dose of the beta-adrenergic agonist salbutamol may increase removal since it increases alveolar fluid removal via the epithelial sodium channel. A pilot clinical study is required to test the hypothesis and to provide data for powering a large phase III RCT.

Research question: Will addition of the beta-adrenergic agonist salbutamol to atropine during resuscitation improve oxygenation, reduce the need for atropine, and speed stabilisation?

Objectives:General Objectives: To test the efficacy of salbutamol at increasing oxygenation and speeding resuscitation.

Specific Objectives: To test whether salbutamol alters dose of atropine administered and incidence of tachydysrhythmias.

Total duration of the study will be one year and all patients aged 12 years or older with clinical features of OP/carbamate poisoning requiring oxygen and atropine will be enrolled. The study will be done in three arms.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bangladesh
  • Sylhet, Bangladesh, 3100
    • Sylhet M.A.G.Osmani Medical College Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age 12 yrs or older
• clinical features of OP poisoning
• requiring oxygen and atropine and give consent

Exclusion Criteria:

• age 11 yrs or younger
• no requirement for atropine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 'Standard care'; Standard care= Intravenous fluids, Oxygen by face mask, Intubation if necessary, Mechanical ventilation (Engstrom Pro by GE) if necessary, Cardiac monitor (Infunix IP4050), Atropine (anti-muscarinic drug; G-Atropine) by intravenous route, Pralidoxime (acetylcholinesterase reactivating oxime drug; PAM-A) by intravenous route.	Drug: Standard care; Standard management for OP poisoning; Other Names: Intravenous fluids; Intubation if necessary,; Mechanical ventilation if necessary (Engstrom Pro); Atropine (anti-muscarinic; G-Atropine); Pralidoxime (acetylcholinesterase reactivating oxime; PAM-A); Oxygen by face mask by intravenous route,
Experimental: 'Standard care+ 2.5 mg Salbutamol'; Standard care+ 2.5 mg Salbutamol= Nebulized salbutamol (Ventolin respiratory solution) 2.5 mg stat and once only with standard care	Drug: Standard care+ 2.5 mg Salbutamol; Ventolin respiratory solution 2.5 mg; Other Names: Ventolin
Experimental: 'Standard care+ 5 mg Salbutamol'; Standard care+ 5 mg Salbutamol= Nebulized salbutamol (Ventolin respiratory solution) 5 mg stat and once only with standard care	Drug: Standard care+ 5 mg Salbutamol; Ventolin respiratory solution 5 mg; Other Names: Ventolin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement of oxygen saturation	Improvement of oxygen saturation from the base line to normal level after adding nebulized salbutamol to regular I/V atropine and oxygen therapy.	60 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate, respiratory rate and Blood pressure	Settlement of heart rate, respiratory rate and blood pressure to normal range after adding salbutamol to regular management.	60 minutes

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Atropine dose	Requirement of total atropine dose until full atropinization (before put in to maintenance dose) after adding nebulized salbutamol	120 minutes

Collaborators and Investigators

• Sponsor: Sylhet M.A.G.Osmani Medical College
• Collaborators: University of Edinburgh
• Investigators: Principal Investigator: Fazle R Chowdhury, FCPS, Consultant, Medicine, Sylhet M.A.G.Osmani Medical Collge, Sylhet, Bangladesh; Principal Investigator: Michael Eddleston, PhD, Professor of Clinical Toxicology, University of Edinburgh

Publications and helpful links

General Publications

• Abedin MJ, Sayeed AA, Basher A, Maude RJ, Hoque G, Faiz MA. Open-label randomized clinical trial of atropine bolus injection versus incremental boluses plus infusion for organophosphate poisoning in Bangladesh. J Med Toxicol. 2012 Jun;8(2):108-17. doi: 10.1007/s13181-012-0214-6.
• Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute organophosphorus pesticide poisoning. Lancet. 2008 Feb 16;371(9612):597-607. doi: 10.1016/S0140-6736(07)61202-1.
• Gunnell D, Eddleston M, Phillips MR, Konradsen F. The global distribution of fatal pesticide self-poisoning: systematic review. BMC Public Health. 2007 Dec 21;7:357. doi: 10.1186/1471-2458-7-357.
• Eddleston M. Patterns and problems of deliberate self-poisoning in the developing world. QJM. 2000 Nov;93(11):715-31. doi: 10.1093/qjmed/93.11.715.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: June 7, 2014
• First Submitted That Met QC Criteria: June 9, 2014
• First Posted (Estimate): June 10, 2014

Study Record Updates

• Last Update Posted (Estimate): December 29, 2015
• Last Update Submitted That Met QC Criteria: December 28, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: Organophosphate, insectiside, Salbutamol, Atropine
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Poisoning; Organophosphate Poisoning; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Protective Agents; Adrenergic Agonists; Adjuvants, Anesthesia; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Antidotes; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Mydriatics; Cholinesterase Reactivators; Enzyme Reactivators; Albuterol; Atropine; Pralidoxime
• Other Study ID Numbers: Medicine SOMCH