Effects of Theophylline on Ventilatory Poststimulus Potentiation in Patients with Brain Damage

Abstract

Patients with brain damage, in contrast to normal subjects, exhibit a significant ventilatory undershoot when brief hypocapnic hypoxia is terminated abruptly by hyperoxia. This has been attributed to an impairment of activation of short-term potentiation, a brain stem mechanism promoting breathing stability. We hypothesized that in these patients theophylline, a drug that stabilizes breathing, may affect short-term potentiation. Eight stable patients with brain damage and 10 normal adults were studied. Activation of short-term potentiation was examined by brief exposure to hypoxia followed by hyperoxia after pretreatment with placebo or theophylline. Both in patients and normal subjects at the end of hypoxia ventilation increased to a similar magnitude with and without theophylline. In normal subjects independent of pretreatment, when hypoxia was terminated abruptly by hyperoxia, ventilation declined slowly to baseline without an undershoot, indicating activation of short-term potentiation. In patients with placebo, ventilation upon switching to hyperoxia exhibited a significant undershoot. This undershoot was significantly attenuated by theophylline, although compared with normal subjects, a slight hypoventilation was observed. We conclude that in patients with brain damage, theophylline largely prevents the hyperoxic drop of ventilation, presumably by affecting the activation of short-term potentiation. This may underlie the beneficial effect of theophylline on breathing stability.

Non-linear dynamics of human periodic breathing and implications for sleep apnea therapy

“…8 as well as an ''off'' transient time constant of 22 s. That STP can involve rate sensitivity during the ''off'' transient has not been previously emphasized. However, rate sensitivity is consistent with ventilatory undershoots [15] which have been observed in patients and felt to be tied to STP. Rate sensitivity during the ''off'' ventilatory transient is the simplest explanation of undershoots and is consistent with known chemoreceptor properties.…”

“…Only with prolonged ventilatory stimulation has a lengthened ''off'' transient and apparent rate sensitivity appeared [21,24]. Rate sensitivity or undershoot of the ''off'' ventilatory transient have also been observed in brain damaged subjects [15]. Rate sensitivity of any kind during apnea has to the author's knowledge never been reported.…”

“…Differences in ''on'' and ''off'' transient time constants of carotid stimulation have been reported [24] and prolongation of the ''off'' transient has been attributed to central neural processing and called STP. STP has been postulated to exert a stabilizing effect by minimizing hypocapnic inhibition and can be targeted therapeutically with theophylline [15]. Carotid stimulation during expiration leads to prolongation of expiration [27] in what is considered neural STD.…”

“…Other modifications included the inclusion of P aCO 2 rate sensitivity for the peripheral chemoreceptors and dynamically variable on and off first order rate constants. The latter modifications made it possible to model unidirectional rate sensitivity or chemoreceptor adaptation [4,10], shortterm potentiation of respiration [7,15,21,24], and inhibitory dynamics during apnea [3]. Total respiratory drive is considered to be provided by the summation of inputs from central (V c ) and peripheral (V p ) chemoreceptors with separate P aCO 2 thresholds a and b, respectively.…”

“…Thus, g rc+ was set to zero for most simulation runs for the present study. However, evidence for a negative rate sensitivity in humans is provided by ventilatory undershoots observed during posthyperventilation transients in a normal subject [21] and patients with brain damage [15].…”