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Biomedical subjects

C P O'Donnell

Publications and source records attributed to C P O'Donnell.

At least 19 recordsLinked to original sources
PubMed2006

Association between lipid peroxidation and inflammation in obstructive sleep apnoea.

In the present study, the authors examined the relationship between lipid peroxidation and inflammation in patients with obstructive sleep apnoea (OSA). A total of 40 obese patients with OSA were studied, along with 18 obese and 12 lean subjects without OSA. Overnight excretion of 8-isoprostane in urine and serum levels of high-sensitivity C-reactive protein (hsCRP) were measured. In addition, the effects of 3 months' treatment with nasal continuous positive airway pressure (nCPAP) were studied in 20 obese patients with moderate-to-severe OSA. Overnight urinary excretion of 8-isoprostane and serum levels of hsCRP were significantly higher in patients with moderate-to-severe OSA compared with patients with mild OSA and obese or lean subjects without OSA. Overnight urinary excretion of 8-isoprostane significantly correlated with apnoea-hypopnoea index, duration of hypoxia during sleep, body mass index, and serum levels of hsCRP in patients with OSA. The severity of OSA was an independent factor predicting the urinary excretion of 8-isoprostane. nCPAP significantly decreased urinary excretion of 8-isoprostane and serum levels of hsCRP. In conclusion, these results suggest that both obstructive sleep apnoea severity and obesity can independently contribute to elevations in urinary excretion of 8-isoprostane. Therefore, obstructive sleep apnoea may increase the risks of cardiovascular morbidity in obese patients.

C-Reactive Protein↗
PubMed2005

Acute and chronic cardiovascular effects of intermittent hypoxia in C57BL/6J mice.

We investigated the effects of 1) acute hypoxia and 2) 5 wk of chronic intermittent hypoxia (IH) on the systemic and pulmonary circulations of C57BL/6J mice. Mice were chronically instrumented with either femoral artery or right ventricular catheters. In response to acute hypoxia (4 min of 10% O2; n = 6), systemic arterial blood pressure fell (P < 0.005) from 107.7 +/- 2.5 to 84.7 +/- 6.5 mmHg, whereas right ventricular pressure increased (P < 0.005) from 11.7 +/- 0.8 to 14.9 +/- 1.3 mmHg. Another cohort of mice was then exposed to IH for 5 wk (O2 nadir = 5%, 60-s cycles, 12 h/day) and then implanted with catheters. In response to 5 wk of chronic IH, mice (n = 8) increased systemic blood pressure by 7.5 mmHg, left ventricle + septum weight by 32.2 +/- 7.5 x 10(-2) g/100 g body wt (P < 0.015), and right ventricle weight by 19.3 +/- 3.2 x 10(-2) g/100 g body wt (P < 0.001), resulting in a 14% increase in the right ventricle/left ventricle + septum weight (P < 0.005). We conclude that in C57BL/6J mice 1) acute hypoxia causes opposite effects on the pulmonary and systemic circulations, leading to preferential loading of the right heart; and 2) chronic IH in mice results in mild to moderate systemic and pulmonary hypertension, with resultant left- and right-sided ventricular hypertrophy.

Acute Disease↗
PubMed2003

Hypercapnic duty cycle is an intermediate physiological phenotype linked to mouse chromosome 5.

We hypothesized that upper airway obstruction (UAO) leads to a compensatory increase in the duty cycle [ratio of inspiratory time to respiratory cycle length (Ti/Tt)], which is determined by genetic factors. We examined the compensatory Ti/Tt responses to 1). UAO and hypercapnia among normal individuals and 2). hypercapnia in different inbred strains, C3H/HeJ (C3) and C57BL/6J (B6), and their first- and second-generation (F2) offspring. 3). We then used the compensatory Ti/Tt response in the F2 to determine genetic linkage to the mouse genome. First, normal individuals exhibited a similar increase in the Ti/Tt during periods of hypercapnia (0.11 +/- 0.07) and UAO (0.09 +/- 0.06) compared with unobstructed breathing (P < 0.01). Second, the F2 offspring of C3 and B6 progenitors showed an average Ti/Tt response to 3% CO2 (0.42 +/- 0.005%) that was significantly (P < 0.01) greater than that of the two progenitors. Third, with a peak log of the odds ratio score of 4.4, Ti/Tt responses of F2 offspring are genetically linked to an interval between 58 and 64 centimorgans (cM) on mouse chromosome 5. One gene in the interval, Dagk4 at 57 cM, is polymorphic for C3 and B6 mice. Two other genes, Adrbk2 at 60 cM and Nos1 at 65 cM, have biological plausibility in mechanisms of upper airway patency and chemosensitivity, respectively. In summary, Ti/Tt may serve as an intermediate physiological phenotype for compensatory neuromuscular response mechanisms for maintaining ventilation in the face of UAO and hypoventilation and to help target specific candidate genes that may play a role in the expression of sleep-disordered breathing.

Adult↗
PubMed2002

Ventilating with tracheal gas insufflation and periodic tracheal occlusion during sleep and wakefulness.

INTRODUCTION: The current invasive and noninvasive methods for delivering long-term ventilatory support rely on cumbersome patient interfaces that may interfere with upper airway function. To overcome these limitations, a novel system was developed to ventilate conscious, spontaneously breathing dogs through a self-contained cuffed cannula that was used for tracheal gas insufflation (TGI) and periodic tracheal occlusion (PTO). We hypothesized that TGI + PTO would provide greater ventilatory support than would TGI alone and that its effect would be more pronounced during sleep than wakefulness. METHODS: Chronically tracheostomized dogs were monitored for sleep (ie, EEG, electro- oculogram, and nuchal electromyogram) and breathing (ie, tracheal pressure [Ptr] and upper airway flow via snout mask). A thin transtracheal cannula housed within a cuffed tracheostomy tube was used for TGI and PTO monitoring. E, gas exchange, and breathing patterns were examined during sleep and wakefulness at baseline (ie, no TGI) and during the application of TGI alone (at 5, 10, and 15 L/min) and the application of TGI + PTO. RESULTS: Compared to baseline breathing without TGI, TGI at 5, 10, and 15 L/min decreased minute ventilation without influencing PaCO(2). In contrast, TGI + PTO led to progressive increases in ventilation, positive Ptr swings, and decreases in PaCO(2) as the flow rate was increased during sleep and wakefulness. Moreover, spontaneous breathing efforts ceased during TGI + PTO at flow rates of 10 and 15 L/min during wakefulness, and at all flow rates during sleep. CONCLUSIONS: The findings indicate that TGI + PTO can fully support ventilation in a spontaneously breathing canine model during sleep and wakefulness. Its streamlined interface could ultimately prove to be clinically significant, once technical concerns are addressed.

Animals↗
PubMed2001

Female gender exacerbates respiratory depression in leptin-deficient obesity.

Obese females are less predisposed to sleep-disordered breathing and have higher serum leptin levels than males of comparable body weight. Because leptin is a powerful respiratory stimulant, especially during sleep, we hypothesized that the elevated leptin level is necessary to maintain normal ventilatory control in obese females. We examined ventilatory control during sleep and wakefulness in male and female leptin-deficient obese C57BL/6J-Lep(ob) mice, wild-type C57BL/6J mice with dietary-induced obesity and high serum leptin levels, and normal weight wild-type C57BL/6J mice. Both male and female C57BL/6J-Lep(ob) mice had depressed hypercapnic ventilatory response (HCVR) in comparison with wild-type animals. In comparison with male C57BL/6J-Lep(ob) mice, female C57BL/6J-Lep(ob) mice had reduced HCVR and respiratory drive (a ratio of tidal volume to inspiratory time) both during non-rapid eye movement (NREM) sleep and wakefulness. In contrast, the HCVR did not differ between sexes in wild-type mice during NREM sleep and wakefulness, but was lower in females during REM sleep. Thus, leptin deficiency in female obesity is even more detrimental to hypercapnic ventilatory control during wakefulness and NREM sleep than in obese, leptin-deficient males.

Animals↗
PubMed2001

A model of sleep-disordered breathing in the C57BL/6J mouse.

To investigate the pathophysiological sequelae of sleep-disordered breathing (SDB), we have developed a mouse model in which hypoxia was induced during periods of sleep and was removed in response to arousal or wakefulness. An on-line sleep-wake detection system, based on the frequency and amplitude of electroencephalograph and electromyograph recordings, served to trigger intermittent hypoxia during periods of sleep. In adult male C57BL/6J mice (n = 5), the sleep-wake detection system accurately assessed wakefulness (97.2 +/- 1.1%), non-rapid eye movement (NREM) sleep (96.0 +/- 0.9%) and rapid eye movement (REM) sleep (85.6 +/- 5.0%). After 5 consecutive days of SDB, 554 +/- 29 (SE) hypoxic events were recorded over a 24-h period at a rate of 63.6 +/- 2.6 events/h of sleep and with a duration of 28.2 +/- 0.7 s. The mean nadir of fraction of inspired O(2) (FI(O(2))) on day 5 was 13.2 +/- 0.1%, and 137.1 +/- 13.2 of the events had a nadir FI(O(2)) <10% O(2). Arterial blood gases confirmed that hypoxia of this magnitude lead to a significant degree of hypoxemia. Furthermore, 5 days of SDB were associated with decreases in both NREM and REM sleep during the light phase compared with the 24-h postintervention period. We conclude that our murine model of SDB mimics the rate and magnitude of sleep-induced hypoxia, sleep fragmentation, and reduction in total sleep time found in patients with moderate to severe SDB in the clinical setting.

Animals↗
PubMed2001

The impact of insulin-dependent diabetes on ventilatory control in the mouse.

Insulin-dependent diabetes mellitus (IDDM) can lead to ventilatory depression and decreased sensitivity to hypercapnia. We examined relationships between ventilation, plasma insulin, leptin, ketones, and blood glucose levels in two mouse models of IDDM: (1) streptozotocin-induced diabetes in C57BL/6J mice on a regular diet or with induced obesity from a high fat diet; and (2) spontaneous diabetes mellitus in NOD-Ltj mice. In both mouse models, IDDM resulted in depression of the hypercapnic ventilatory response (HCVR). This ventilatory depression was not associated with decreases in plasma insulin or leptin levels. There was, however, a strong association between the duration of hyperglycemia, the decline in HCVR, and increased glycosylation of the diaphragm. Hyperventilation was observed in only six of 14 C57BL/6J obese wild-type mice, despite a significant degree of diabetic ketoacidosis (DKA) in all 14 animals. In mice with DKA, there was a significant correlation between the increase in baseline minute ventilation (V E) and hyperleptinemia (r = 0.77, p < 0.01). In leptin-deficient C57BL/6J-Lep(ob) mice, low levels of both V E and ketones were observed. These results suggest that: (1) depression of the HCVR in IDDM is associated with hyperglycemia and glycosylation of the diaphragm; and (2) the hyperventilation of DKA is leptin dependent.

Animals↗
PubMed2000

Leptin, obesity, and respiratory function.

Leptin is a protein produced by adipose tissue that circulates to the brain and interacts with receptors in the hypothalamus to inhibit eating. The importance of this single peptide is vividly demonstrated by the profound obesity exhibited by the ob/ob mouse (C57BL/6J-Lep(ob)) which is unable to produce functional leptin. The measurement of respiratory function in the ob/ob mouse shows that the profound obesity is associated with impaired respiratory mechanics and depressed respiratory control, particularly during sleep. Longitudinal studies and leptin replacement studies in the ob/ob mouse indicate that leptin may act as both as a growth factor in the lung and as a neurohumoral modulator of central respiratory control mechanisms. Moreover, wildtype mice with diet-induced obesity have normal respiratory function associated with markedly elevated leptin levels. Human obesity, similar to obesity in wildtype mice, also causes an elevation in circulating leptin. However, unlike the tight relationship between obesity and elevated leptin present in an inbred strain of wildtype mice, human obesity is associated with more variable leptin levels for a given degree of adiposity. Thus, the possibility exists that a relative deficiency in leptin, or a leptin resistance, may play a role in obesity-related breathing disorders such as obesity hypoventilation syndrome (OHS) or obstructive sleep apnea (OSA).

Animals↗
PubMed2000

Effects of arousal and sleep state on systemic and pulmonary hemodynamics in obstructive apnea.

During obstructive sleep apnea (OSA), systemic (Psa) and pulmonary (Ppa) arterial pressures acutely increase after apnea termination, whereas left and right ventricular stroke volumes (SV) reach a nadir. In a canine model (n = 6), we examined the effects of arousal, parasympathetic blockade (atropine 1 mg/kg iv), and sleep state on cardiovascular responses to OSA. In the absence of arousal, SV remained constant after apnea termination, compared with a 4.4 +/- 1.7% decrease after apnea with arousal (P < 0.025). The rise in transmural Ppa was independent of arousal (4.5 +/- 1.0 vs. 4.1 +/- 1.2 mmHg with and without arousal, respectively), whereas Psa increased more after apnea termination in apneas with arousal compared with apneas without arousal. Parasympathetic blockade abolished the arousal-induced increase in Psa, indicating that arousal is associated with a vagal withdrawal of the parasympathetic tone to the heart. Rapid-eye-movement (REM) sleep blunted the increase in Psa (pre- to end-apnea: 5.6 +/- 2.3 mmHg vs. 10.3 +/- 1.6 mmHg, REM vs. non-REM, respectively, P < 0.025), but not transmural Ppa, during an obstructive apnea. We conclude that arousal and sleep state both have differential effects on the systemic and pulmonary circulation in OSA, indicating that, in patients with underlying cardiovascular disease, the hemodynamic consequences of OSA may be different for the right or the left side of the circulation.

Animals↗
PubMed2000

Neural and local effects of hypoxia on cardiovascular responses to obstructive apnea.

Obstructive sleep apnea (OSA) acutely increases systemic (Psa) and pulmonary (Ppa) arterial pressures and decreases ventricular stroke volume (SV). In this study, we used a canine model of OSA (n = 6) to examine the role of hypoxia and the autonomic nervous system (ANS) in mediating these cardiovascular responses. Hyperoxia (40% oxygen) completely blocked any increase in Ppa in response to obstructive apnea but only attenuated the increase in Psa. In contrast, after blockade of the ANS (20 mg/kg iv hexamethonium), obstructive apnea produced a decrease in Psa (-5.9 mmHg; P < 0.05) but no change in Ppa, and the fall in SV was abolished. Both the fall in Psa and the rise in Ppa that persisted after ANS blockade were abolished when apneas were induced during hyperoxia. We conclude that 1) hypoxia can account for all of the Ppa and the majority of the Psa response to obstructive apnea, 2) the ANS increases Psa but not Ppa in obstructive apnea, 3) the local effects of hypoxia associated with obstructive apnea cause vasodilation in the systemic vasculature and vasoconstriction in the pulmonary vasculature, and 4) a rise in Psa acts as an afterload to the heart and decreases SV over the course of the apnea.

Animals↗
PubMed2000

High-flow transtracheal insufflation treats obstructive sleep apnea. A pilot study.

To determine the effect of transtracheal insufflation (TTI) on obstructive sleep apnea (OSA), we examined breathing patterns in five tracheostomized patients with OSA at varying TTI flow rates when breathing with a closed tracheostomy. The breathing patterns and polysomnographic responses to air insufflation were studied as TTI was increased from 0 to 15 L/min for brief periods of non-rapid eye movement (NREM) sleep (Experiment 1). The frequency of sleep-disordered breathing episodes remained high at 0 and 5 L/min (87.0 +/- 33.7 and 79.4 +/- 24.4 episodes per hour NREM) and decreased significantly to 41.3 +/- 31.5 and 43.4 +/- 31.4 episodes/h NREM sleep at rates of 10 and 15 L/min, respectively (p = 0.003). At high levels of TTI (10 and 15 L/min), obstructive apneas and hypopneas decreased but periodic laryngeal obstructions were induced during stage 1 NREM sleep. To prevent laryngeal obstructions, a servo-control system was used to briefly interrupt TTI during these events. When this system was implemented for more prolonged periods of sleep (Experiment 2, total sleep time 176.6 +/- 12.5 min), high-flow TTI (hf-TTI, 15 L/min) led to an overall reduction in the combined frequency of obstructive apneas and laryngeal obstructions from 63.8 +/- 21.8 to 10.7 +/- 9.1 (p < 0.03) and was associated with a marked reduction in arousal frequency from 60.0 +/- 26.0 to 8. 3 +/- 5.4/h in NREM sleep, and from 67.5 +/- 3.5 to 0 +/- 0/h in rapid eye movement (REM) sleep. Our findings demonstrate that hf-TTI stabilized breathing patterns in apneic patients, and was safe and efficacious for prolonged periods of sleep.

Adult↗
PubMed2000

A model of obstructive sleep apnea in normal humans. Role of the upper airway.

We determined whether upper airway obstruction in normal individuals with intact reflexes could produce the syndrome of obstructive sleep apnea. Upper airway obstruction was produced in 12 normal individuals by lowering nasal pressure to -10 cm H(2)O during sleep. Full night polysomnography was performed during two consecutive nights of sleep with subatmospheric nasal pressure and compared with control nights before and after the negative pressure nights. We found that the application of negative pressure was associated with the development of recurrent obstructive apneas (non-REM-disordered breathing rate, 32.6 +/- 34.8 and 37.8 +/- 29.1 events/h during each of two negative pressure nights; p < 0.001) that were associated with oxyhemoglobin desaturation, arousals from sleep, and alterations in sleep stage distribution. Moreover, the median daytime sleep latency after two nights of sleep with subatmospheric pressure fell from 6.9 +/- 1.1 to 3.4 +/- 0.6 min, and rose significantly again to 8.1 +/- 1.5 min (p < 0.03) after the control night following subatmospheric pressure nights. Our findings suggest that a decrease in the pharyngeal transmural pressure alone is a sufficient condition for the production of the sleep apnea syndrome in normal individuals.

Adult↗
PubMed2000

Abbreviated method for assessing upper airway function in obstructive sleep apnea.

STUDY OBJECTIVES: Previous studies have shown that the level of flow through the upper airway in patients with obstructive sleep apnea (OSA) is determined by the critical closing pressure (Pcrit) and the upstream resistance (RN). We developed a standardized protocol for delineating quasisteady-state pressure-flow relationships for the upper airway from which these variables could be derived. In addition, we investigated the effect of body position and sleep stage on these variables by determining Pcrit and RN, and their confidence intervals (CIs), for each condition. DESIGN: Pressure-flow relationships were constructed in the supine and lateral recumbent positions (nonrapid eye movement [NREM] sleep, n = 10) and in the supine position (rapid eye movement [REM] sleep, n = 5). SETTING: University Hospital Antwerp, Belgium. PATIENTS: Ten obese patients (body mass index, 32.0+/-5.6 kg/m(2)) with severe OSA (respiratory disturbance index, 63.0+/-14.6 events/h) were studied. INTERVENTIONS: Pressure-flow relationships were constructed from breaths obtained during a series of step decreases in nasal pressure (34.1+/-6.5 runs over 3.6+/-1.2 h) in NREM sleep and during 7.8+/-2.2 runs over 0.8+/-0.6 h in REM sleep. RESULTS: Maximal inspiratory airflow reached a steady state in the third through fifth breaths following a decrease in nasal pressure. Analysis of pressure-flow relationships derived from these breaths showed that Pcrit fell from 1.8 (95% CI, -0.1 to 2.7) cm H(2)O in the supine position to -1.1 cm H(2)O (95% CI, -1.8 to 0.4 cm H(2)O; p = 0.009) in the lateral recumbent position, whereas RN did not change significantly. In contrast, no significant effect of sleep stage was found on either Pcrit or RN. CONCLUSIONS: Our methods for delineating upper airway pressure-flow relationships during sleep allow for multiple determinations of Pcrit within a single night from which small yet significant differences can be discerned between study conditions.

Airway Resistance↗
PubMed1999

Subclinical aortic perforation with the infant double-button patent ductus arteriosus occluder.

Modification of the double-button (Sideris) patent ductus arteriosus (PDA) occluder has resulted in a single-strut aortic component rather than the conventional cross-strut design. We report the use of this infant PDA occluder for transcatheter closure in three patients with PDA measuring 2 mm, 3.7 mm, and 4 mm. Subclinical aortic perforation with a small aortic aneurysm developed in two patients 1 year after occluder implantation. The third patient had developed a small aortic aneurysm without perforation at 3-month follow-up. All three patients had a residual shunt and underwent successful PDA surgical closure with aortic aneurysmal repair. Single-strut umbrella designs are not recommended for PDA transcatheter closure.

Aorta, Thoracic↗
PubMed1998

Effect of sleep/wake state on arterial blood pressure in genetically identical mice.

Genetic determinants may contribute to the large variability in arterial blood pressure responses to changes in sleep/wake state in humans. In this study, we developed techniques to examine the relationship between sleep/wake state and mean arterial pressure (MAP) in unrestrained, genetically identical mice (C57BL/6J; n = 9). The left common carotid artery was catheterized, and arterial blood gases were analyzed 24-48 h postsurgery to verify normal respiratory and metabolic function. The animals were then allowed to cycle naturally through sleep/wake states over a 3- to 4-h period while continuous polysomnography and arterial pressure measurements were made. The MAP decreased from quiet wakefulness to non-rapid-eye-movement sleep (9.8 +/- 1.3 mmHg; P < 0.001) and further decreased from non-rapid-eye-movement to rapid-eye-movement sleep (9.7 +/- 1.8 mmHg; P < 0.001). We conclude that the inbred strain of C57BL/6J mice exhibits significant and consistent changes in MAP related to sleep/wake state. Future studies can compare responses in this strain of mice with those in other inbred or transgenic mice to determine whether specific genes regulate arterial blood pressure responses to sleep/wake state.

Animals↗
PubMed1998

The hypotonic upper airway in obstructive sleep apnea: role of structures and neuromuscular activity.

The structural properties of the upper airway determine its collapsibility during periods of muscle hypotonia. Both rapid-eye-movement (REM) sleep and increases in nasal pressure (PN) produce hypotonia, which persists even after nasal pressure is abruptly reduced. To determine the factors that influence the collapsibility of the hypotonic airway, the critical pressure (Pcrit) and nasal resistance upstream to the site of pharyngeal collapse (RN) were measured in the first three breaths after abrupt reductions in PN during non-REM and REM sleep. PN was reduced abruptly from 15.2+/-3.2 cm H2O (mean +/- SD) for three breaths in 19 apneic patients. Upper-airway pressure-flow relationships were analyzed to determine Pcrit for each breath in non-REM and REM sleep. We found that Pcrit rose (collapsibility increased, p < 0.001) and RN fell (p = 0.02) between the first and third breath after the decrease in PN, whereas no difference in Pcrit was detected between sleep stages. In six patients, genioglossus-muscle electromyograms (EMGs) were recorded. Peak phasic activity rose between the first and third breath (p = 0.03), but tonic and peak phasic EMG activity fell in REM as compared with non-REM sleep (p < 0.001). We conclude that the hypotonic upper airway becomes most collapsible by the third breath after an abrupt decrease in PN, regardless of sleep stage and despite an increase in genioglossus-muscle activity. Our findings suggest that predominantly mechanical rather than neuromuscular factors modulate the properties of the pharynx after abrupt reductions in nasal pressure.

Adolescent↗
PubMed1997

Endothelin causes portal and pulmonary hypertension in porcine endotoxemic shock.

A porcine model of endotoxemic shock was used to test the hypothesis that endothelins (ET) mediate the sustained increases in portal and pulmonary vascular resistances. Anesthetized pigs (n = 18) were instrumented and pretreated with 1) saline as a control; 2) indomethacin (Idm), a cyclooxygenase (Cox) inhibitor; or 3) Idm + bosentan (Bos), a mixed ET-receptor antagonist, and then were treated with endotoxin to produce shock and followed for 240 min. Global and regional hemodynamic parameters and plasma levels of ET-1 and thromboxane B2 were measured. The results show that 1) ET is independently responsible for the sustained increase in pulmonary vascular resistance; 2) ET and Cox products combine to increase portal venous resistance; 3) ET independently reduces cardiac output and attenuates or negates global systemic arterial vasodilation (presumptively mediated by nitric oxide) and exhibits regional differences, having little if any influence on the gut arterial bed. When considered with our prior study of nitric oxide regulation of the same beds in endotoxemic shock (N. Brienza, T. Ayuse, J. P. Revelly, C. P. O'Donnell, and J. L. Robotham, J. Appl. Physiol. 78: 784-792, 1995), the similarities between the portal venous and pulmonary arterial beds suggest that these two beds reflect phenomena occurring in microvascular and/or venous beds in multiple organs. The overall results suggest that a dynamic balance exists between NO and ET regulating arterial and microvascular and/or venous vasomotor activity during the evolution of endotoxemic shock.

Analysis of Variance↗