Population pharmacodynamic model of bicarbonate response to acetazolamide in mechanically ventilated chronic obstructive pulmonary disease patients

Heming, Nicholas; Faisy, Christophe; Urien, Saı̈k

doi:10.1186/cc10448

Cited by 28 publications

(24 citation statements)

References 26 publications

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“…This study is a continuation of our previous published work [15]. The results of the present study suggest that higher doses of acetazolamide are necessary to induce a substantial increase in minute ventilation and hence a decrease in PaCO 2 in alkalotic mechanically ventilated COPD patients.…”

Section: Discussionsupporting

confidence: 82%

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Population Pharmacodynamic Modeling and Simulation of the Respiratory Effect of Acetazolamide in Decompensated COPD Patients

et al. 2014

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BackgroundChronic 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.Methods619 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.ResultsThe 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.ConclusionsSimulations suggest that COPD patients might benefit from the respiratory stimulant effect after the administration of higher doses of acetazolamide.

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Section: Discussionsupporting

confidence: 82%

“…This cohort has been previously described [15]. Due to the observational design, patient consent was waived, in accordance with French bioethics laws.…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacodynamic Modeling and Simulation of the Respiratory Effect of Acetazolamide in Decompensated COPD Patients

et al. 2014

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“…It has also been reported that non-responders to acetazolamide (defined by a reduction of PaCO 2 of less than 5 mm Hg) have a more severe airflow limitation than responders [48]. This finding has not been confirmed in later studies [16]. …”

Section: Clinical Datamentioning

confidence: 95%

“…Mixed acid-base balance disturbances (the association of chronic respiratory acidosis and metabolic alkalosis) can also be observed. Indeed, in mechanically ventilated patients with COPD, the most frequently observed acid-base disorders are mixed [15,16]. In this context, respiratory acidosis is the consequence of hypercapnia.…”

Section: Metabolic Alkalosis In the Intensive Care Unitmentioning

confidence: 99%

Acetazolamide: a second wind for a respiratory stimulant in the intensive care unit?

2012

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Patients with chronic obstructive pulmonary disease (COPD) are affected by episodes of respiratory exacerbations, some of which can be severe and may necessitate respiratory support. Prolonged invasive mechanical ventilation is associated with increased mortality rates. Persistent failure to discontinue invasive mechanical ventilation is a major issue in patients with COPD. Pure or mixed metabolic alkalosis is a common finding in the intensive care unit (ICU) and is associated with a worse outcome. In patients with COPD, the condition is called post-hypercapnic alkalosis and is a complication of mechanical ventilation. Reversal of metabolic alkalosis may facilitate weaning from mechanical ventilation of patients with COPD. Acetazolamide, a non-specific carbonic anhydrase inhibitor, is one of the drugs employed in the ICU to reverse metabolic alkalosis. The drug is relatively safe, undesirable effects being rare. The compartmentalization of the different isoforms of the carbonic anhydrase enzyme may, in part, explain the lack of evidence of the efficacy of acetazolamide as a respiratory stimulant. Recent findings suggest that the usually employed doses of acetazolamide in the ICU may be insufficient to significantly improve respiratory parameters in mechanically ventilated patients with COPD. Randomized controlled trials using adequate doses of acetazolamide are required to address this issue.

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“…Moreover, several factors, such as co-administration of furosemide or systemic steroid, can interfere with ACET pharmacokinetics (5). In the study performed by Rialp Cervera et al (1), co-treatments with diuretics (69% vs. 71%), steroids (4% vs. 13%), catecholamines (35% vs. 50%), were not used in the same proportion in the two groups (although the difference has no statistical significance), theses therapeutics can interfere with ACET pharmacokinetics and affect ACET's effectiveness (5).…”

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confidence: 99%

Effects of early administration of acetazolamide on the duration of mechanical ventilation in patients with chronic obstructive pulmonary disease: still far from the truth?

Bahloul¹,

Ammar²,

Bouattour³

et al. 2017

J. Thorac. Dis.

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In this study, Rialp Cervera et al.(1) have randomly assigned patients with chronic obstructive pulmonary disease (COPD) or obesity hypoventilation syndrome (OHS) with acute respiratory failure requiring mechanical ventilation (MV) <72 h to receive either acetazolamide 500 mg or placebo. All patients had initial bicarbonate >28 mmol/L and pH >7.35. Test-treatment, ACTZ 500 mg or placebo, was daily administered if pH >7.35 and bicarbonate >26 mmol/L. Clinical, respiratory and laboratory parameters were recorded on a daily basis.This was a multicenter, randomized, placebo-controlled, phase III, double-blind study held in seven intensive care units in Spain. Patients with COPD or OHS, requiring invasive MV due to acute respiratory failure for less than 72 h and who showed metabolic alkalosis with pH >7.35 and with plasmatic bicarbonate >28 mmol/L, while being on invasive MV, were consecutively included from November 2011 to February 2014. Forty seven patients (36 men) were randomized as ACTZ (+) or placebo: 23 patients in placebo group, and 24 in ACTZ (+) group. There were no significant differences between groups in comorbidities, baseline characteristics or arterial blood gases at inclusion. At inclusion, SOFA score, proportion of patients with noninvasive ventilation (NIV) failure before inclusion, reason of invasive MV, laboratory serum tests, blood gas analysis and respiratory parameters did not show any significant differences between groups.This study (1) showed no significant decreases in the duration of MV and weaning, or in the length of ICU and hospital stay with acetazolamide treatment compared with placebo in intubated patients with COPD or OHS and metabolic alkalosis. Moreover, patients treated with acetazolamide showed a significant reduction in bicarbonate concentration and PaCO 2 values at discontinuation of MV, with 33% of them having recovered from their metabolic alkalosis, whereas no patient in the placebo group did so. Moreover, respiratory rate and minute volume did not show any significant differences throughout the MV period although minute volume tended to increase over time in the acetazolamide group [minute volume 9.7 (8.9-10.4) vs. 10.6 (9.2-12.0) L/min, P=0.26].In conclusion, this study showed that in severe exacerbation of COPD or OHS requiring intensive care admission and invasive MV, despite the fact that acetazolamide is used to reverse metabolic alkalosis, this therapy does not help reduce the duration of MV and/or make the weaning process easier.Nevertheless, this study-as mentioned by authorssuffers from many limitations. First, a sample size of 98 patients was estimated to have a power of 80% with an alpha error of 5% to detect a 3-day difference between groups in the duration of MV. However, the study was stopped prematurely due to slow patient recruitment. In fact, only 47 patients were included in the study, 23 patients in the placebo group and 24 in the acetazolamide one. Consequently, this study did not detect any significant J Thorac Dis 2017;9(6):1393-1395 jtd.amegroups....

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Population pharmacodynamic model of bicarbonate response to acetazolamide in mechanically ventilated chronic obstructive pulmonary disease patients

Cited by 28 publications

References 26 publications

Population Pharmacodynamic Modeling and Simulation of the Respiratory Effect of Acetazolamide in Decompensated COPD Patients

Population Pharmacodynamic Modeling and Simulation of the Respiratory Effect of Acetazolamide in Decompensated COPD Patients

Acetazolamide: a second wind for a respiratory stimulant in the intensive care unit?

Effects of early administration of acetazolamide on the duration of mechanical ventilation in patients with chronic obstructive pulmonary disease: still far from the truth?

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