Variability of the ventilatory response to Duffin's modified hyperoxic and hypoxic rebreathing procedure in healthy awake humans

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Abstract

We quantified the magnitude of within- and between-day, within-subject variability of the ventilatory response to Duffin's modified rebreathing procedure in 20 healthy humans. The PETCO2 at which ventilation increased with progressive increases in PETCO2 during rebreathing was identified as the ventilatory recruitment threshold (VRTCO2); the ventilatory response below and above the VRTCO2 was taken as an estimate of non-chemoreflex drives to breathe (V˙EB) and chemoreflex sensitivity (V˙ES), respectively. Within- and between-day intraclass correlation coefficients for each of these parameters were >0.60 (range: 0.62–0.93), indicating good-to-excellent test–retest reliability. Within- and between-day, within-subject coefficients of variation for hyperoxic and hypoxic V˙EB (range: 24.6–30.7%) and V˙ES (range: 18.5–32.7%) were relatively high but acceptable, while those for the VRTCO2 were very small (range: 3.0–3.8%). In conclusion, Duffin's modified rebreathing procedure, in both its hyperoxic and hypoxic form, is a highly reliable tool for measurement of chemoreflex and non-chemoreflex ventilatory control characteristics over short and long periods of time in healthy humans.

Introduction

Resting steady-state minute ventilation (V˙E) and arterial PCO2 (PaCO2) depend on central chemoreflex, peripheral chemoreflex and ‘other’ non-chemoreflex drives to breathe and their intersection with the metabolic hyperbola (Fig. 1) (Cunningham et al., 1986, Mahamed et al., 2001). Thus, any change in resting V˙E and PaCO2 may be accounted for by a change in any one or combination of the following: metabolic rate (V˙CO2); central and/or peripheral ventilatory chemoreflex sensitivity (V˙ES); central and/or peripheral chemoreflex ventilatory recruitment threshold for CO2 (VRTCO2), secondary to alterations in arterial and central (or brain tissue) acid–base status; non-chemoreflex drives to breathe (V˙EB); and cerebral blood flow/cerebrovascular CO2 reactivity (Duffin, 2005, Xie et al., 2006, Xie et al., 2008, Ainslie and Duffin, 2009) (Fig. 1).

Several techniques, including Read's (1967) original rebreathing procedure, the steady-state procedure either by end-tidal forcing (Robbins et al., 1982) or by prospective targeting (Slessarev et al., 2007) and the progressive isocapnic hypoxia procedure (Weil et al., 1970, Rebuck and Campbell, 1974), have been developed to estimate central and peripheral ventilatory chemoreflex sensitivity. However, only Duffin's modification of Read's rebreathing procedure (Casey et al., 1987, Duffin and McEvoy, 1988, Mohan and Duffin, 1997, Duffin et al., 2000), which includes 5-min of prior voluntary hyperventilation and maintenance of a constant (isoxic) hyperoxic or hypoxic end-tidal PO2 (PETO2), permits measurement of (i) V˙EB and (ii) both central and peripheral chemoreflex V˙ES and VRTCO2. For simplicity and clarity, we propose the use of the term “Duffin's modified rebreathing procedure” to describe these tests.

The informed application of any experimental technique used to investigate a specific research question, including the interpretation of study results, requires a clear characterization of the variability associated with the physiological parameter(s) being measured over short (e.g., hours) and long (e.g., days, weeks, months) periods of time. Numerous published studies in awake humans have described the variability associated with measurement of central and peripheral chemoreflex sensitivity using either Read's rebreathing method (Read, 1967, Jennett, 1968, Strachova and Plum, 1973, Hirshman et al., 1975, Lederer et al., 1977, Sahn et al., 1977, Tobin et al., 1988, Berkenbosch et al., 1989, Beidlman et al., 1999, Spengler and Shea, 2001) or the steady-state procedure (Nishimura et al., 1991, Semple and McConnell, 1992) and the progressive isocapnic hypoxic procedure (Hirshman et al., 1975, Sahn et al., 1977, Nishimura et al., 1991, Garcia-Rio et al., 1998, Beidlman et al., 1999, Zhang and Robbins, 2000, Fahlman et al., 2002, Terblanche et al., 2004, Koehle et al., 2005), respectively.

However, only Mahamed and Duffin (2001) have reported on the variability of the ventilatory response to Duffin's modified hyperoxic and hypoxic rebreathing tests measured once daily for 14 consecutive days in a small group of only 7 healthy volunteers. In that study, within-subject coefficients of variation (CV) over the 14 days for V˙EB (86.6% and 83.3%) and V˙ES (85.9% and 59.9%) were high, while those for the VRTCO2 were dramatically less (7.6% and 7.6%) for hyperoxic and hypoxic tests, respectively.

The purpose of the present study was to extend these observations by quantifying and comparing, for the first time, the magnitude of within- and between-day, within-subject variability of the ventilatory response to Duffin's modified hyperoxic and hypoxic rebreathing tests in 20 healthy, young, awake volunteers under strictly controlled experimental conditions.

Section snippets

Subjects

Twenty, healthy, young (20–30 years), regularly active, non-smoking, men (n = 12) and women (n = 8) with no history of cardiorespiratory disease completed this study. Female participants were nulliparous, eumennorheic (confirmed by serum progesterone ([P4]) and 17β-estradiol ([E2]) concentrations) and had not used oral contraceptives for ≥6 months prior to study participation. The study protocol and consent form were approved by the Queen's University and Affiliated Teaching Hospitals Health

Subjects

Baseline measurements are presented in Table 1. All subjects were healthy, regularly active, non-smokers with normal resting pulmonary function as determined by routine spirometry. Female volunteers 1, 2, 3, 4, 5, 6, 7 and 8 began experimental testing (Day 0) exactly 5, 25, 3, 20, 17, 5, 18 and 6 days from the first day of menstruation, respectively (Table 1). Accordingly, and by design, mean circulating [P4] (p = 0.305) and [E2] (p = 0.458) were not significantly different across days.

Modified rebreathing responses

Ventilatory

Discussion

The major findings of this study were: (1) little/no systematic variation occurs in the ventilatory response to Duffin's modified hyperoxic and hypoxic rebreathing tests measured repeatedly over short and long periods of time in healthy awake humans; and (2) Duffin's modified rebreathing procedure, in both its hyperoxic and hypoxic form, is a highly reliable tool for within- and between-day measurement of chemoreflex and non-chemoreflex ventilatory control characteristics.

Acknowledgements

We would like to acknowledge Dr. James Duffin (Departments of Anaethesia and Physiology, University of Toronto) for his constructive comments, which were helpful in the preparation of the manuscript. This work was supported by the William M. Spear Endowment Fund for Respiratory Research at Queen's University. D. Jensen was supported by a John Alexander Stewart Post-Doctoral Research Fellowship (Department of Medicine, Queen's University and Kingston General Hospital); a Queen's University

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