"Respiratory-related heart rate variability persists during central apnea in dogs: mechanisms and implications".

RICHARD HORNER ET AL. (5) have used mechanical ventilation in unanesthetized dogs to show that the respiratory sinus arrhythmia (RSA) present during hypocapnic mechanical ventilation persists during the apneic period following cessation of the mechanical ventilation. During this postmechanical ventilation apneic period, RSA was clearly present in the same time period (as during mechanical ventilation breaths) in the first one or two “phantom” breaths of the apnea, although the RSA amplitude was reduced and phase was altered. Thereafter, as apnea proceeded, the RSA was markedly reduced in amplitude but then came back strongly toward the termination of the apneic period and was in phase with the postapneic spontaneous breaths. This persistent RSA at the onset of central apnea was perceived as a lingering time-dependent “memory” effect from the preceding respiratory-related events. The concept of memory in the respiratory control system has been demonstrated under a variety of conditions and should be considered an integral part of the total response to excitatory or inhibitory influences that affect ventilatory control. The excitatory shortterm potentiation (STP) of phrenic nerve activity that follows withdrawal of heightened chemoreceptor input was described over 50 years ago (2). Eldridge and Millhorn (2) have added substantially in the past two decades to our understanding of this phenomenon by demonstrating that the STP occurs in response to a variety of sensory stimuli and that it represents an important component of the behavior of the brain stem respiratory control mechanism. This STP is also manifested in a slowly dissipating enhanced ventilatory output following chemoreceptor stimulation in awake, sleeping, and exercising humans (4). Furthermore, ongoing subthreshold oscillatory respiratory nervous activity has also been shown to persist, even in the absence of rhythmic respiration. This was nicely demonstrated by Horner et al. (5) in the continuing respiratory sinus arrhythmia in unanesthetized dogs. It has also been shown previously in more reduced preparations by continued oscillatory activity in laryngeal nerves, glossopharyngeal nerves, and in some inspiratory and expiratory premotor medullary neurons during phrenic silence (1). Apnea in the study of Horner et al. (5) was induced by hypocapnia via mechanical ventilation, but memory effects of inhibitory influences may also cause and prolong apnea independently of, and even despite, chemical stimuli. For example, electrical stimulation of the central cut end of the vagus nerve or the superior laryngeal nerve in anesthetized animals caused phrenic apnea that persisted well beyond the period of electrical stimulation. The duration of the poststimulation phrenic inhibition was markedly influenced by the duration of the preceding stimulus (9). The apnea that followed augmented inspirations in dogs (7) and cats (12) may be another example of an inhibitory memory-like effect related to lung stretch. Similarly, short apneas also occur after brief periods of normocapnic hypoxic-induced hyperpnea in the awake intact dog, and these apneas were prevented by cervical vagal blockade (15). Apparently, in these studies involving one or more actively augmented inspirations or increased tidal volumes, both an excitatory STP and inhibitory mechanoreceptor memory effect occurred simultaneously; however, when the vagi were intact, the inhibitory effect prevailed and ventilation was inhibited. Inhibitory memory effects have also been induced in humans by nonchemical mechanoreceptor influences. Over 40 years ago, Fowler (3) showed that brief interspersed periods of rebreathing would prolong breath-holding time. More recently, sleeping and waking subjects mechanically ventilated at high tidal volumes and frequencies for long periods with end-tidal pressure of CO, held at normocapnia (10) experienced prolonged apneas on cessation of the mechanical ventilation. Whether these inhibitory effects in humans are purely reflexive in nature, as they apparently are in dogs and cats, has not been shown conclusively; in fact, these effects have only been shown thus far to occur after very long durations of normocapnic mechanical ventilation. These inhibitory memory effects may involve a central reorganization or habituation of central neural output (12). Apnea (i.e., phrenic silence) is often accompanied at its onset by tonic expiratory activity in late augmenting expiratory medullary cells following augmented inspirations in awake cats (12) and in early expiratory medullary cells after electrical stimulation of the superior laryngeal nerve or vagi in the anesthetized cat (13). Similarly, tonic activation of expiratory