Randomised control trial
Richalet JP, Rivera M, Bouchet P, Chirinos E, Onnen I, Petitjean O, Bienvenu A, Lasne F, Moutereau S, León-Velarde F.Acetazolamide: a treatment for chronic mountain sickness.
American Journal of Respiratory and Critical Care Medicine.
2005 Dec 1;172(11):1427-33.
- Submitted by:Amy Kule - Medical Student
- Institution:Rush Medical College
- Date submitted:8th May 2009
1
Objectives and hypotheses
1.1
Are the objectives of the study clearly stated?
Objective of the study was to evaluate the efficacy of acetazolamide in the treatment of chronic mountain sickness and the importance of nocturnal hypoxemia in its pathophysiology.
2
Design
2.1
Is the study design suitable for the objectives
Yes. Double-blinded placebo-controlled study was utilized.
2.2
Who / what was studied?
Thirty male patients suffering from chronic mountain sickness (Monge's disease) and 10 normal subjects from Cerro de Pasco, Peru(4,300 m).
2.3
Was this the right sample to answer the objectives?
Yes. All subjects were high-altitude natives and resided permanently in the same area of Peru.
2.4
Is the study large enough to achieve its objectives? Have sample size estimates been performed?
Yes. However, conclusion made from homogenous sample population was questioned to be widely implemented across other high-altitude regions. No sample size estimates were performed.
2.5
Were all subjects accounted for?
Yes. Thirty patients were randomized. However, two patients (one each from the D250 and D500 groups) left the study fro personal reasons and were not available for the posttreatment measurements.
2.6
Were all appropriate outcomes considered?
Yes. Measurements and comparisons were made in various categories: hematocrit, erythropoietin, ferritin, soluble transferrin receptor concentrations, nocturnal arterial oxygen saturation, nocturnal heart rate, apnea-hypopnea index (AHI), systolic and diastolic arterial pressure and chronic mountain sickness (CMS) clinical score, which was based on breathlessness, sleep disturbance, cyanosis, paresthesias, heachache and tinnitus.
2.7
Has ethical approval been obtained if appropriate?
Yes. All 40 subjects gave their informed consent to participate in this study, which was approved by the ethics committee of the Universidad Peruana Cayetano Heredia (Lima, Peru).
2.8
Were the patients randomised between treatments?
Yes.
2.9
How was randomisation carried out?
Allocation to treatment was done randomly through computer-generated random numbers balanced between the three treatment groups (n, age in years, weight in kilograms, and height in centimeters).
2.10
Are the outcomes clinically relevant?
Yes. Improvements of hematocrit, erythropoietin, soluble transferrin receptor concentration, ferritin, nocturnal arterial oxygen saturation, nocturnal heart rate, apnea-hypopnea index (AHI), systolic and diastolic arterial pressure and CMS clinical score were assessed.
3
Measurement and observation
3.1
Is it clear what was measured, how it was measured and what the outcomes were?
Yes.
[Blood sample obtained from antecubital vein in supine position immediately when subjects woke up in morning.]
1. Hematocrit - obtained by centrifugation.
2. Erythropoietin - measured by enzyme-linked immunosorbent assay (ELISA).
3. Ferritin - determined by Nichols Advantage ferritin reagent cartridges.
4. Soluble transferrin receptors - determined by Nichols Advantage soluble transferrin receptor cartridges.
5. Nocturnal arterial oxygen saturation - measured with Poly-Mesam MAP recording system using thoracic and abdominal strain gauges for recording of ventilation, nasal thermistors for nasal flux and transcutaneous oximetry at the finger tip for continuous measurement of SaO2.
6. AHI - calculated as mean number of events per hour of night recording. Apnea and hypopnea events defined as decrease in ventilation of more than 80 and 50% from basal value, respectively. AHI value above 5 considered pathologic and risk factor for cardiovascular disease.
7. Heart rate - obtained from ECG recordings from three precordial electrodes.
8. Systemic arterial pressure - measured by sphygmomanometry after 15-minute rest in supine position.
9. CMS clinical score - based on symptoms of breathlessness, sleep disturbance, cyanosis, paresthesias, headache and tinnitus.
All outcomes for these factors were discussed.
[Blood sample obtained from antecubital vein in supine position immediately when subjects woke up in morning.]
1. Hematocrit - obtained by centrifugation.
2. Erythropoietin - measured by enzyme-linked immunosorbent assay (ELISA).
3. Ferritin - determined by Nichols Advantage ferritin reagent cartridges.
4. Soluble transferrin receptors - determined by Nichols Advantage soluble transferrin receptor cartridges.
5. Nocturnal arterial oxygen saturation - measured with Poly-Mesam MAP recording system using thoracic and abdominal strain gauges for recording of ventilation, nasal thermistors for nasal flux and transcutaneous oximetry at the finger tip for continuous measurement of SaO2.
6. AHI - calculated as mean number of events per hour of night recording. Apnea and hypopnea events defined as decrease in ventilation of more than 80 and 50% from basal value, respectively. AHI value above 5 considered pathologic and risk factor for cardiovascular disease.
7. Heart rate - obtained from ECG recordings from three precordial electrodes.
8. Systemic arterial pressure - measured by sphygmomanometry after 15-minute rest in supine position.
9. CMS clinical score - based on symptoms of breathlessness, sleep disturbance, cyanosis, paresthesias, headache and tinnitus.
All outcomes for these factors were discussed.
3.2
Are the measurements valid?
Yes.
3.3
Are the measurements reliable?
Yes.
3.4
Are the measurements reproducible?
Yes, except potentially CMS clinical score, which is subjectively based.
3.5
Were the patients and the investigators blinded?
Yes. Active and placebo tablets were identical in appearance. Treatment was double blind.
4
Presentation of results
4.1
Are the basic data adequately described?
Yes.
4.2
Were groups comparable at baseline?
Yes. (number, age in years, weight in kilograms, height in centimeters)
-Patients with CMS treated with placebo: n=10, 44+/-9, 63+/-3, 1.58+/-0.05
-Patients with CMS treated with 250 mg of ACZ daily (D250): n=10, 43+/-9, 65+/-9, 1.62+/-0.08
-Patients with CMS treated with 500 mg of ACZ daily (D500): n=10, 41+/-6, 67+/-10, 1.60+/-0.05
-A group of normal subjects (n=10, 39+/-9, 64+/-7, 1.60+/-0.05) living at the same altitude, with no apparent disease at examination and with a hematocrit at or below 55%, served as control subjects.
-Patients with CMS treated with placebo: n=10, 44+/-9, 63+/-3, 1.58+/-0.05
-Patients with CMS treated with 250 mg of ACZ daily (D250): n=10, 43+/-9, 65+/-9, 1.62+/-0.08
-Patients with CMS treated with 500 mg of ACZ daily (D500): n=10, 41+/-6, 67+/-10, 1.60+/-0.05
-A group of normal subjects (n=10, 39+/-9, 64+/-7, 1.60+/-0.05) living at the same altitude, with no apparent disease at examination and with a hematocrit at or below 55%, served as control subjects.
4.3
Are the results presented clearly, objectively and in sufficient detail to enable readers to make their own judgement?
Yes. All data obtained was clearly outlined as means and SD, and was provided additionally in graph form.
4.4
Are the results internally consistent, i.e. do the numbers add up properly?
Yes.
4.5
Were side effects reported?
The only mentioned adverse effects were slightly increased diuresis (three, three, and five subjects in placebo, D250, and D500 groups, respectively), paresthesias (two, four, and eight subjects in placebo, D250, and D500 groups, respectively), and altered taste of gaseous beverages (two, one, and no subjects in placebo,
D250, and D500 groups, respectively).
D250, and D500 groups, respectively).
5
Analysis
5.1
Are the data suitable for analysis?
Yes.
5.2
Are the methods appropriate to the data?
Yes. Data were compared by Student t test or nonparametric tests.
5.3
Are any statistics correctly performed and interpreted?
Yes. Student t test used for paired (effect of treatment) or unpaired (comparison of groups)
samples. Nonparametric tests were used for AHI (Wilcoxon for effect of treatment, Mann-Whitney for comparison of groups).
samples. Nonparametric tests were used for AHI (Wilcoxon for effect of treatment, Mann-Whitney for comparison of groups).
6
Discussion
6.1
Are the results discussed in relation to existing knowledge on the subject and study objectives?
Yes. Although previous studies have demonstrated the beneficial effects of acetazolamide on ventilation and SaO2 in subjects acutely exposed to hypoxia, the study presented in the article is the first to evaluate the effect of acetazolamide on nocturnal SaO2 and erythropoiesis in chronic hypoxia.
6.2
Is the discussion biased?
No. Limitations of the study, including placebo effect observed, were addressed in the discussion.
7
Interpretation
7.1
Are the authors' conclusions justified by the data?
Yes. The authors' conclusions regarding the pathophysiology of CMS as potentially due to nocturnal hypoventilation and acetazolamide as a proposed menthod of treatment is justified by the data presented.
7.2
What level of evidence has this paper presented? (using CEBM levels)
1b
7.3
Does this paper help me answer my problem?
Yes.
8
Implementation
8.1
Can any necessary change be implemented in practice?
Utilization of low-dose acetazolamide (250mg daily) can provide relief for those suffering from chronic mountain sickness and avoid incapacitating symptoms, as well as displacement to lower altitudes, resulting in social exclusion and psychological degradation.
8.2
What aids to implementation exist?
Few side effects. High prevalence of chronic mountain sickness in various high-altitude regions.
8.3
What barriers to implementation exist?
Relatively low-cost. Access to medications. Hard to access populations.