The impact of two different dosing courses of acetazolamide on ventilatory sensitivity to hypoxia and hypercapnia in a young and old Cohort – a comparison study

Bradley, Christopher James (2020). The impact of two different dosing courses of acetazolamide on ventilatory sensitivity to hypoxia and hypercapnia in a young and old Cohort – a comparison study. University of Birmingham. M.Sc.

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Abstract

Introduction – Acetazolamide (Az) is a carbonic anhydrase (CA) inhibitor used to treat acute mountain sickness (AMS). Current dose recommendations are to take 250mg of Az twice daily (BD) for 48 hours. However, evidence indicates that, due to impaired renal function, older people may require less to get the same protective effect. The present study aimed to assess this hypothesis by testing the hypoxic ventilatory response (HVR) and hypercapnic ventilatory response (HCVR) following the administration of Az at two different doses in young and older individuals.
Methods – 13 participants were recruited (7 young, M = 24.3 ± 3.1 and 6 old, M = 71 ± 2) and performed a HVR and HCVR using a steady state method on 3 occasions: a no drug control, after 125mg Az BD for 48 hours and after 250mg Az BD for 48 hours. Az-induced alterations in acid-base balance were confirmed via blood gas sampling on each visit.
Results – Both doses of Az caused significant reductions in bicarbonate (HCO3-), pH and base excess whilst also stimulating resting ventilation in both groups (p<0.001 for all). Hypoxic sensitivity was significantly blunted in the older group on Az (p=0.031). In contrast it was the young group that developed a blunted hypercapnic hypoxic response on Az, with a significant reduction in the slope (-0.013x ± 0.007x vs -0.0098x ± 0.006x, p=0.025) and intercept (1.01 ± 0.5 vs 0.77 ± 0.4, p=0.019) of the ventilation line of best fit. Estimated glomerular filtration rate (eGFR) was significantly lower in the older group (125.2 ± 17.8ml/min/1.73m2 vs 87.7 ± 8.1ml/min/1.73m2, p=0.001).
Discussion – Alterations to acid-base balance were caused by 125mg Az BD in both cohorts, indicating the effectiveness of Az at inhibiting renal CA at 125mg BD. The lower eGFR recorded in the older participants would reduce the clearance of Az of the older participants. The impaired clearance of Az most likely caused the blunting effect of the HVR seen within the older group, as Az would accumulate in the circulation and inhibit off-target CA isoforms within the peripheral chemoreceptors (PCR), reducing the ventilatory drive. In contrast, it was the young cohort who experienced a blunted HCVR after using Az. Inhibition of CA in the red blood cells (RBC) causes CO2 retention and so may reduce the offloading of CO2 at the blood brain barrier (BBB) causing this blunting effect. Compensation for this action may arise through a separate mechanism in the older participants.

Type of Work:

Thesis (Masters by Research > M.Sc.)

Award Type:

Masters by Research > M.Sc.

Supervisor(s):