The Use of Isocapnic Hyperventilation (iHV) for Treatment of Methanol Poisoned Patients

Study Overview
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Brief Summary
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The projects investigate if treatment with isocapnic hyperventilation can eliminate methanol from the body in a similar manner to dialysis. This is achieved by administering the antidote (fomepizole) and let the patient breathe on a isocapnic hyperventilation device while samples of blood, urine and maybe the breath are collected to measure the contents of methanol and its metabolites.

Detailed Description
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Isocapnic hyperventilation (iHV) The normal physiology breathing is a careful balance between the number of breaths per minute (rate/min) and the depth of each breath (tidal volume, Vt). Together they make up the minute ventilation (MV), where MV= rate x Vt). To maintain stable homeostasis in the organism, the minute ventilation is closely regulated to maintain adequate uptake of oxygen and adequate elimination of the carbon dioxide (CO2) that is produced by the metabolism. Too low minute ventilation leads to a buildup of CO2 and decrease in blood pH (respiratory acidosis), while hyperventilation (too high minute ventilation) leads to an excess loss of CO2 and increase in blood pH (respiratory alkalosis). The same mechanism will also enable the organism to compensate any metabolic disturbances (up to a certain point): A metabolic acidosis will be counteracted by a hyperventilation, whereas a metabolic alkalosis will be counteracted by a hypoventilation, both with the ultimate goal of keeping the acidity (as given by the pH) as closely regulated as possible. The concept of isocapnic hyperventilation (iHV) allows the person to hyperventilate while keeping the CO2 within normal limits at the same time. The ClearMate (Thornhill Research Inc., Canada) adds CO2 to the inspired air to compensate to the increased loss induced by the increased minute ventilation. This means that hyperventilation can occur, and a wash-out of volatile substances such as methanol will happen without disrupting the important CO2 balance.

Official Title
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The Use of Isocapnic Hyperventilation (iHV) for Treatment of Methanol Poisoned Patients

Conditions
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Methanol Poisoning

Intervention / Treatment
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* Device: isocapnic hyperventilation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, men & women diagnosed with methanol poisoning Serum-methanol ≥ 50 mg/dL (16 mM) pH ≥ 7.0, and correctable by bicarbonate infusion no (newly developed) visual disturbances Exclusion Criteria: Acidosis requiring haemodialysis (pH <7.0), or acidosis that is not responding in spite of aggressive buffer (bicarbonate) treatment within maximum 1-2 hours. Comatose patients Newly developed visual disturbances ADH not fully blocked with antidotes, and not responding to additional dosing of fomepizole. Will be identified by a continuous or increasing anion gap (AG) or Base Excess (BE) on the blood gas machine.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective, single arm study Enrolment target: 30 evaluable patients Intervention: standard of care with sodium bicarbonate and fomepizole, plus iHV device treatment Rescue therapy: haemodialysis at investigators discretion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isocapnic hyperventilation (iHV)<br>Loading dose of fomepizole on clinical suspicion; A) History of intake of alcohol of unknown/illegal origin plus symptoms potentially occurring from methanol, or B) history as above and verified methanol poisonings among people drinking the same alcohol, or C) metabolic acidosis of unknown origin (where methanol cannot be excluded as the cause;or D) a combination of these. ● iHV started after a S-methanol concentration > 50 mg/dL is obtained (typically within 4 hours) and initial acidosis is partly or fully corrected by sodium bicarbonate (BD <15mM, HCO3- >10mM) | Device: isocapnic hyperventilation<br>* isocapnic hyperventilation (iHV) increases the elimination of methanol to the extent that it could replace haemodialysis for elimination purposes when haemodialysis is not required for the correction of acidosis, and alcohol dehydrogenase (ADH) is completely blocked by an antidote.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterization of methanol elimination kinetics, when iHV is utilized | T1/2 S-methanol (t1-t2) during iHV: Half-life of methanol in blood from start (t1) to end (t2) of treatment with iHV T1/2 S-methanol (t0-t1) before iHV): Half-life of methanol in blood from t0 to t1 before start of treatment with iHV for evaluation of individual differences in kinetics | 0-40 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterization of methanol elimination kinetics, prior to iHV is utilized | T1/2 S-methanol (t0-t1) before iHV): Half-life of methanol in blood from t0 to t1 before start of treatment with iHV for evaluation of individual differences in kinetics | 0-40 hours | 
| Serum formate kinetics | T1/2 S-formate before (t0-t1) before and after (t1-t2) (iHV): Half-life of formate in blood from t0 to t1 before start of treatment with iHV for evaluation of individual differences in kinetics | 0-40 hours | 
| Elimination ratio of methanol | Evaluation of elimination ratio of methanol through breath vs. urine with or without iHV | 0-40 hours | 
| Elimination ratio of formate | Evaluation of elimination ratio of formate through breath vs. urine with or without iHV | 0-40 hours | 
| Feasibility of use of iHV in Iran | iHV is new in Iran. The process requires training to be implemented correctly. This will be evaluated by assessing protocol deviations related to iHV equipment and by interviewing study workers on their perceived competency using the iHV equipment. This will not be reported in one value, but presented as text and used as an exploratory outcome to guide any future implementation of iHV in Iran | 0-40 hours | 
| Tolerability by self reporting by patient | Patient tolerability of iHV as self reported by patient This will be recorded using a five-level Likert Scale 1 Did not tolerate iHV at all 2: Tolerated iHV sin shorter periods, but below therapeutic level 3: Barely tolerated iHV enough for therapeutic level 4 Tolerate iHV enough for therapeutic level 5: No discomfort and good toleration of iHV | 0-40 hours | 
| Implementation of fomepizole in Iran | Perception of simplicity of use of fomepizole amongst doctors involved in the study This will be recorded using a five-level Likert Scale 1 Fomepizole can not be used in the Iranian healthcare system 2: Fomepizole is difficult and require significant extra efforts to be used in the Iranian healthcare system 3: Fomepizole may be used the Iranian healthcare system with some extra effort 4 Fomepizole can easily be used the Iranian healthcare system with little extra effort 5: Fomepizole can easily be used the Iranian healthcare system with no extra effort | through study completion, estimated 2 years | 
| Evaluation of fomepizole elimination during iHV | S-fomepizole analyzes from t1-t2. Pending availability of fomepizole analyzes | 0-4 hours | 
| Length of ICU- and hospital stay | Length during treatment with iHV | from stdy start to death or discharge ICU, expected average 30 hours | 
| Need for haemodialysis | Document type and degree of haemodialysis. Indication for such treatment is by the discretion of the local investigator. If S methanol >5mM after 26hrs (T1/2 50-80hrs during fomepizole treatment without haemodialysis (8)) or if patient becomes increasingly acidotic in spite of adequate antidote treatment. | 0- 40 hours | 
| Adverse events | Adverse events, including death, will be defined according to Good Clinical Practice guidelines by the International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use. All adverse events will be registered in this trial and reported in accordance with local regulations in Iran. Adverse events also include medical device deficiency of the isocapnic hyperventilation system | through study completion, estimated 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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isocapnic hyperventilation