Open AccessPopulation Pharmacodynamic Modeling and Simulation of the Respiratory Effect of Acetazolamide in Decompensated COPD Patients
Author(s) -
Nicholas Heming,
Saı̈k Urien,
Virginie Fulda,
Ferhat Meziani,
Arnaud Gacouin,
M. Clavel,
Benjamin Planquette,
Christophe Faisy
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0086313
Subject(s) - acetazolamide , medicine , copd , anesthesia , ventilation (architecture) , tidal volume , population , respiratory minute volume , respiratory system , respiratory alkalosis , mechanical ventilation , metabolic acidosis , mechanical engineering , environmental health , engineering
Background Chronic obstructive pulmonary disease (COPD) patients may develop metabolic alkalosis during weaning from mechanical ventilation. Acetazolamide is one of the treatments used to reverse metabolic alkalosis. Methods 619 time-respiratory (minute ventilation, tidal volume and respiratory rate) and 207 time-PaCO 2 observations were obtained from 68 invasively ventilated COPD patients. We modeled respiratory responses to acetazolamide in mechanically ventilated COPD patients and then simulated the effect of increased amounts of the drug. Results The effect of acetazolamide on minute ventilation and PaCO 2 levels was analyzed using a nonlinear mixed effect model. The effect of different ventilatory modes was assessed on the model. Only slightly increased minute ventilation without decreased PaCO 2 levels were observed in response to 250 to 500 mg of acetazolamide administered twice daily. Simulations indicated that higher acetazolamide dosage (>1000 mg daily) was required to significantly increase minute ventilation ( P <.001 vs pre-acetazolamide administration). Based on our model, 1000 mg per day of acetazolamide would increase minute ventilation by >0.75 L min −1 in 60% of the population. The model also predicts that 45% of patients would have a decrease of PaCO2>5 mmHg with doses of 1000 mg per day. Conclusions Simulations suggest that COPD patients might benefit from the respiratory stimulant effect after the administration of higher doses of acetazolamide.