SUMMARY1. Ventilation was studied during wakefulness and sleep in six healthy humans in normoxia (mean barometric pressure (PB) = 740 torr), and in hypobaric hypoxia (AB = 455 torr).2. Hypoxia caused hyperventilation and hypocapnic alkalosis (APpao2 =c-7 torr)during wakefulness and in all sleep states. 3. Periodic breathing was the predominant pattern of breathing in all stages of non-rapid eye movement (non-r.e.m.) sleep in hypoxia, but was rarely observed during wakefulness or r.e.m. sleep.4. Periodic breathing was composed of repetitive oscillations of reproducible cycle length characterized by clusters of breaths with augmented inspiratory effort (VT/TI) and highly variable distribution of breath-to-breath minute ventilation (VE) and tidal volume (VT), which alternated regularly with prolongations of the expiratory pause of the last breath of each cluster (apnea duration = 5-18 see). 5. Hypoxia-induced periodic breathing was eliminated by: (a) acute restoration of normoxia coincident with a 3-6 torr increase in PaIc2; and (b) augmented F1,c2(at constant arterial oxygen saturation) which rapidly and reversibly eliminated apneas and stabilized breathing pattern with a < 2 torr increase in Paco2. If hypocapnia was prevented (by augmented F1,co,) during acute induction of hypoxia in non-r.e.m. sleep, periodic breathing was also prevented. 6. We propose that the genesis of hypoxia-induced periodic breathing requires the combination of hypoxia and hypocapnia. Periodicity results from oscillations in CO2 about a C02-apnea threshold whose functional expression is critically linked to sleep state.

Ischemia/reperfusion injury and delayed graft function (DGF) following organ transplantation adversely affect graft function and survival. A large animal model has not been characterized. We developed a pig kidney allograft model of DGF and evaluated the cytoprotective effects of inhaled carbon monoxide (CO). We demonstrate that donor warm ischemia time is a critical determinant of DGF as evidenced by a transient (4-6 days) increase in serum creatinine and blood urea nitrogen following transplantation before returning to baseline. CO administered to recipients intraoperatively for 1 h restored kidney function more rapidly versus air-treated controls. CO reduced acute tubular necrosis, apoptosis, tissue factor expression and P-selectin expression and enhanced proliferative repair as measured by phosphorylation of retinol binding protein and histone H3. Gene microarray analyses with confirmatory PCR of biopsy specimens showed that CO blocked proinflammatory gene expression of MCP-1 and heat shock proteins. In vitro in pig renal epithelial cells, CO blocks anoxia-reoxygenation-induced cell death while promoting proliferation. This large animal model of DGF can be utilized for testing therapeutic strategies to reduce or prevent DGF in humans. The efficacy of CO on improving graft function posttransplant validates the model and offers a potentially important therapeutic strategy to improve transplant outcomes.

Ventilatory and timing responses to repetitive and sustained inspiratory resistive loading were assessed in six naive male subjects during wakefulness (AW) and non-REM sleep (NREM). In five of six subjects, tidal volume (VT) was maintained or increased with repetitive five-breath loading periods during wakefulness. In these five subjects, mouth occlusion pressure (P100) increased with loading during AW (1.8 +/- 0.5 control vs. 2.2 +/- 0.4 cmH2O loaded, P less than 0.05), but not during NREM (2.1 +/- 1.5 control vs. 2.1 + 1.5 cmH2O loaded). For each state, VT and frequency (f) responses to sustained loads were similar to responses to five-breath loads. During sustained loading; a) VT increased 35% during AW, decreased 28% during NREM, b) f decreased 35% during AW, increased 6% during NREM, c) minute ventilation (VE) decreased 12% during AW, decreased 23% during NREM. Ventilatory responses persisted until arousal (0.4--1.7 min) in NREM. With repetitive loading: a) inspiratory duration (TI) increased during AW but did not change during NREM, b) "duty cycle" (TI/TT) increased with loading in both states. These findings suggest that a) NREM abolishes between-breath augmentations in P100, b) within-breath load compensation is operant during both AW (preserved VT) and NREM (failure of predicted TI prolongation) by differing mechanisms, c) arousal may be a ventilatory compensation to inspiratory resistive loading in NREM.

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