Quantal breathing frequency variation in halothane anaesthetised neonatal rats

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Abstract

We examined the changes in cardioventilatory synchronisation and breathing frequency variability that occur during early postnatal development in anaesthetised rats. Five-minute periods of heart rate and inspiratory timing data were recorded from 26 halothane anaesthetised, spontaneously breathing rats aged 2–14 days. The presence of cardioventilatory synchronisation was determined by examining the timing relationship between inspiratory onset and the preceding ECG R waves. We observed synchronisation at all ages, and the degree of synchronisation present (measured as the Shannon entropy of the interval between inspiration and the immediately preceding R wave) did not correlate with age. Frequent apnoeas were observed in the respiratory frequency time series. The duration of these apnoeas was close to either one or two times the duration of the immediately preceding breath. We suggest that these “dropped breaths” may be the consequence of a resetting of the respiratory oscillator just prior to initiation of the breath, or a gating process beneath the oscillator that intermittently blocks the mechanical initiation of breaths. Dropped breaths were seen commonly in rats up to 11 days of age, but rarely in 11–14-day old rats, and were not associated with the presence or absence of cardioventilatory synchronisation.

Introduction

In 1995, Goodman described quantal patterns of breathing frequency variation in adults during spontaneously breathing propofol anaesthesia (Goodman, 1995). Subsequently we have shown that the described quantal variations are attributable to a form of cardio-respiratory interaction, which has been called cardioventilatory coupling or synchronisation. Cardioventilatory synchronisation is a triggering of inspiratory onset by a cardiovascular afferent associated with a preceding heart beat (Galletly and Larsen, 1997, Galletly and Larsen, 2001, Larsen et al., 1999a, Larsen et al., 1999b). Synchronisation occurs in a range of mammalian species, during anaesthesia, sedation, and in the awake resting state (Larsen and Galletly, 1999, Tzeng et al., 2003). Although the pathway by which the triggering effect of synchronisation is achieved is not known, synchronisation results in several forms of quantal breathing frequency variability (Galletly and Larsen, 1999). The simplest quantal change in ventilatory period occurs when the entrainment ratio between heart beats and breaths changes that is when consecutive breaths are triggered after different numbers of heart beats. Other synchronisation-related quantal variations in breathing frequency occur when the ratio of heart rate to breathing frequency falls within certain regions (known as Arnold tongues) and breath-to-breath changes occur in synchronisation interval (the interval between the inspiratory onset and the triggering cardiac beat). Cardioventilatory synchronisation is a major cause of breath-to-breath breathing rate irregularity during spontaneous breathing anaesthesia in humans (Galletly and Larsen, 1999).

In a recent paper, Mellen et al. (2003) observed that following administration of opiods to awake neonatal rats, respiratory period jumped to integer multiples of the control respiratory period, which they referred to as “quantal slowing”. The authors suggested that this quantal variation may be due to noisy coupling between two brainstem oscillators, or alternatively to a random failure in transmission of respiratory drive. In contrast to the quantal fluctuations that we have previously observed during cardioventilatory synchronisation (in which breath-to-breath respiratory intervals fluctuate in increments of the heart period), the quantal variations observed by Mellen et al. were in multiples of the respiratory period itself; that is, one or more breaths failed to be initiated.

In this study we examined the presence of cardioventilatory synchronisation in neonatal rats (aged 2–14 days), and sought to identify whether this was associated with quantal (respiratory period multiples) fluctuations in respiratory period.

Section snippets

Animals and data acquisition

After gaining ethics approval we studied 26 Wistar rats, two at each day of age from 2- to 14-days old. Anaesthesia was induced by inhalation of 1.5% halothane in oxygen, and was maintained by inhalation of 1% halothane in oxygen via facemask. All preparations were maintained at 37 °C. Using subcutaneous needle electrodes an ECG with large positive R wave signal was obtained. Respiratory activity was recorded by placing a saline-filled PE 50 cannula connected to a pressure transducer into the

Results

Cardioventilatory synchronisation apparent as horizontal banding within the RI interval plot was observed in 24 of 26 rat pups (an example is shown in Fig. 1). In general, synchronisation was seen intermittently, for periods of 30–60 s at a time, rather than consistently over the 5 min data period (Fig. 1), and both patterns I and IV synchronisation were observed. We did not observe any periods of pattern II synchronisation, and therefore there were no examples of quantal respiratory variability

Discussion

In this study we have observed the presence of cardioventilatory synchronisation in rats from 2 to 14 days of age. In addition we observed quantal variation of respiratory frequency associated with one or more missed breaths. This quantal variation was seen most frequently rats less than 12-days old. This form of quantal variation was not related to cardiac influences on inspiratory timing as occurs with quantal variation in respiratory frequency associated with cardioventilatory

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