Population pharmacodynamic modeling and simulation of the respiratory effect of acetazolamide in decompensated COPD patients.
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-PaCO2 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 PaCO2 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 PaCO2 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.
Service de Réanimation Médicale, Hôpital Européen Georges Pompidou, Université Paris Descartes, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Paris, France.
Nicholas
N
Heming
CIC-01109 Cochin-Necker INSERM, Unité de Recherche Clinique, Hôpital Tarnier, Université Paris Descartes, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Paris, France.
Saïk
S
Urien
Centre Régional de Pharmacovigilance, Hôpital Européen Georges Pompidou, Université Paris Descartes, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Paris, France.
Virginie
V
Fulda
Service de Réanimation Médicale, Hôpital Civil, Strasbourg, France.
Ferhat
F
Meziani
Service de Réanimation Médicale et Infectieuse, Hôpital Pontchaillou, Rennes, France.
Arnaud
A
Gacouin
Service de Réanimation Polyvalente, CHU de Limoges, Limoges, France.
Marc
M
Clavel
Service de Réanimation Médico-Chirurgicale, Hôpital André Mignot, Le Chesnay, France.
Benjamin
B
Planquette
Service de Réanimation Médicale, Hôpital Européen Georges Pompidou, Université Paris Descartes, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Paris, France.
Christophe
C
Faisy
D000086:Acetazolamide / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology*; D012119:Respiration / Q000187:drug effects*; D012121:Respiration, Artificial; D013990:Tidal Volume / Q000187:drug effects
D000086:Acetazolamide