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Biomedical subjects

E C Fletcher

Publications and source records attributed to E C Fletcher.

At least 37 records · Page 2Linked to original sources
PubMed1998

Stimulation of breathing by activation of pulmonary peripheral afferents in rabbits.

Respiratory response to selective activation of vagal afferents in the peripheral airways was investigated in anesthetized, open-chest, and artificially ventilated rabbits. Phrenic activity was used as an index of central respiratory drive before and after injection of hypertonic saline (8.1%, 0.1 ml) into the periphery of the lung to stimulate the afferents. The amplitude of "integrated" phrenic activity and phrenic burst rate increased by 19 +/- 3.4 and 53.7 +/- 12.7% (n = 23; P < 0.001), respectively. The response peaked at 5.5 +/- 1.6 s and returned to the baseline at 7 min (median) after the injection. The magnitude of the response was positively related to the concentration of injected NaCl. The response could not be elicited by injection of normal saline and was abolished by vagotomy. Because artificial ventilation caused phrenic activity to be entrained with the ventilator, respiratory drive was further assessed after the ventilator was stopped. Again, neural hyperpnea and tachypnea were observed. Because activation of a small fraction of the pulmonary peripheral afferents resulted in vigorous stimulation of respiratory drive, we speculate that initiation of this reflex may contribute to hyperpnea and tachypnea under both physiological and pathophysiological conditions.

Afferent Pathways↗
PubMed1998

Bronchial foreign bodies simulating endobronchial malignancy.

Reported are two cases of benign endobronchial lesions with granulomatous reactions that led to complete airway obstruction. Combined with a long history of cigarette smoking and the appearance of a hilar mass, these lesions appeared clinically to be bronchogenic carcinomas. Both cases went to thoracotomy, but in each case the requirement that malignant tissue be identified, allowed recognition of a foreign body in one case, and broncholith in the second, avoiding pneumonectomy in both cases.

Aged↗
PubMed1998

Upper airway resistance syndrome.

Many clinicians are familiar with the clinical symptoms and signs of obstructive sleep apnea (OSA). In its most blatant form, OSA is complete airway obstruction with repetitive, prolonged pauses in breathing, arterial oxyhemoglobin desaturation; followed by arousal with resumption of breathing. Daytime symptoms of this disorder include excessive daytime somnolence, intellectual dysfunction, and cardiovascular effects such as systemic hypertension, angina, myocardial infarction, and stroke. It has been recently recognized that increased pharyngeal resistance with incomplete obstruction can lead to a constellation of symptoms identical to OSA called "upper airway resistance syndrome" (UARS). The typical findings of UARS on sleep study are: (1) repetitive arousals from EEG sleep coinciding with a (2) waxing and waning of the respiratory airflow pattern and (3) increased respiratory effort as measured by esophageal pressure monitoring. There may be few, if any, obvious apneas or hypopneas with desaturation, but snoring may be a very prominent finding. Treatment with nasal positive airway pressure (NCPAP) eliminates the symptoms and confirms the diagnosis. Herein we describe two typical cases of UARS.

Adult↗
PubMed1997

Treatment of severe systemic inflammatory response syndrome and sepsis with a novel bradykinin antagonist, deltibant (CP-0127). Results of a randomized, double-blind, placebo-controlled trial. CP-0127 SIRS and Sepsis Study Group.

OBJECTIVE: To test the effect of a novel bradykinin antagonist, deltibant (CP-0127), on survival, organ dysfunction, and other outcomes in patients with the systemic inflammatory response syndrome (SIRS) and presumed sepsis. DESIGN: Multicenter, randomized, placebo-controlled, double-blind, parallel, dose-ranging trial. Follow-up for 28 days or until death. SETTING: A total of 47 US referral hospitals. PATIENTS: A total of 504 patients with SIRS and documented evidence of infection plus either hypotension or dysfunction of 2 organ systems. INTERVENTIONS: Three-day continuous intravenous infusion of either placebo or 1 of 3 doses (0.3, 1.0, or 3.0 microg x kg(-1) x min(-1)) of deltibant. Concurrent therapy at the discretion of the treating physician. MAIN OUTCOME MEASURE: Risk-adjusted, 28-day, log-normal intent-to-treat survival analysis. Risk adjustment was performed using a study-specific risk model derived from the APACHE III database. RESULTS: Deltibant had no significant effect on risk-adjusted 28-day survival. In a posthoc analysis, risk-adjusted 7-day survival showed a nonsignificant trend toward improvement (P=.09). The 28-day risk-adjusted survival in the prospectively defined subset of patients with gram-negative infections showed a statistically significant improvement (P=.005). CONCLUSIONS: Deltibant may have some effect on survival in patients with SIRS and gram-negative sepsis; however, additional studies would be required to prove this.

APACHE↗
PubMed1997

Hypertension caused by chronic intermittent hypoxia--influence of chemoreceptors and sympathetic nervous system.

BACKGROUND: The sleep apnea syndrome (SAS) is a common health problem with a 30% prevalence among patients with so-called essential hypertension. OBJECTIVE: Prompted by this epidemiologic link we tried to find out whether there is a cause-effect relationship between SAS and systemic hypertension. DESIGN: We developed an animal model to simulate defined aspects of the SAS. Rats were exposed to chronic repetitive hypoxia for 7 h per day and their blood pressure was measured by invasive methods. RESULTS: We found that 30 days of intermittent hypoxia sufficed for the development of a significant elevation of blood pressure. The co-exposure to hypoxia and hypercapnia had no additional effect. Surgical denervation of peripheral chemoreceptors prevented the increase in arterial blood pressure. Adrenal demedullation and chemical denervation of the peripheral sympathetic nervous system by 6-hydroxy dopamine also prevented the increase. CONCLUSIONS: Our data imply that repetitive hypoxemia in SAS is probably the cause of the high prevalence of systemic hypertension in this population and that peripheral chemoreceptors and the sympathetic nervous system play important roles in this pathophysiologic process.

Adrenal Medulla↗
PubMed1997

Acute blood pressure elevation during repetitive hypocapnic and eucapnic hypoxia in rats.

Using a rat model, we investigated whether episodic eucapnic hypoxia was a more potent stimulus to acute blood pressure (BP) elevation and bradycardia than episodic hypocapnic hypoxia. We also investigated the role of sympathetic and parasympathetic nervous system in this cardiovascular response. Sprague-Dawley (SD) and Wistar Kyoto (WKY) rats were exposed to repetitive 30-s cycles of hypocapnic or eucapnic hypoxia before and after intravenous injection of the alpha1-adrenergic blocker prazosin, alpha2-adrenergic blocker yohimbine, or atropine. Eucapnic hypoxia caused a threefold elevation in systolic BP from baseline (83.5 +/- 3.5 mmHg in WKY, 70.6 +/- 4.6 mmHg in SD) and greater bradycardia (-178 +/- 20 beats/min in WKY, -178 +/- 21 beats/min in SD) compared with hypocapnic hypoxia (29.8 +/- 3.6 mmHg and -43 +/- 15 beats/min in WKY, 19.0 +/- 4.1 mmHg and -45 +/- 12 beats/min in SD). After prazosin, the BP increase from eucapnic hypoxia was blunted, yohimbine showed no effect, and atropine blocked the bradycardia. Direct measurement of sympathetic nerve activity confirmed that adding CO2 to the hypoxic gas mixture caused a 61% increase in sympathetic nerve activity. WKY rats seem more vulnerable than SD rats to both hypoxia exposures in terms of the elevation in BP. We conclude that, in the rat, eucapnic hypoxia is a more potent stimulus to acute BP elevation and bradycardia than is hypocapnic hypoxia. An increased sympathetic tone appears to be involved in the BP response to acute episodic hypoxia.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1997

Blood pressure response to chronic episodic hypoxia: role of the sympathetic nervous system.

Previous studies in several strains of rats have demonstrated that 35 consecutive days of recurrent episodic hypoxia (7 h/day) cause an 8- to 13-mmHg persistent increase in diurnal systemic blood pressure (BP). Carotid chemoreceptors and the sympathetic nervous system have been shown to be necessary for development of this BP increase. The present study was undertaken to further define the role of renal artery sympathetic nerves and the adrenal medulla in this BP increase. Male Sprague-Dawley rats had either adrenal medullectomy, bilateral renal artery denervation, or sham surgery. Rats from each of these groups were subjected to episodic hypoxia for 35 days. Control groups received either compressed air or were left unhandled. Adrenal demedullation or renal artery denervation eliminated the chronic diurnal mean BP response (measured intra-arterially) to episodic hypoxia, whereas sham-operated controls continued to showed persistent elevation of systemic BP. Plasma and renal tissue catecholamine levels at the end of the experiment confirmed successful adrenal demedullation or renal denervation in the respective animals. The chronic episodic hypoxia-mediated increase in diurnal BP requires both intact renal artery nerves as well as an intact adrenal medulla.

Adrenal Medulla↗
PubMed1996

Effects of chronic episodic hypoxia on monoamine metabolism and motor activity.

Chronic episodic hypoxia produces a wide array of cardiovascular dysfunctions in rats, including increases in blood pressure, heart rate, and sympathetic nerve activity. The action of episodic hypoxia might be related to low oxygen itself (hypoxemia) and/or combined with low CO2 (hypocapnia) resulting from hyperventilation. It is unknown whether or not the cardiovascular abnormalities are related to alterations in the central nervous system (CNS) that may be manifested as neurotransmitter and/or behavioral changes. In this study, we investigated effects of episodic eucapnic and hypocapnic hypoxia on monoamine metabolism in both CNS and adrenal glands, and on motor behavioral activity. Thirty-five male rats were divided into 3 groups. Experimental rats were exposed 8 h daily to varying fractional concentrations of inspired oxygen (FiO2) and carbon dioxide (FiCO2) for 35 days. These consisted of brief exposures (3-6s) of episodic (twice every min) eucapnic (3.5% FiO2 and 10% FiCO2, n = 6) or hypocapnic (3.5% FiO2 and 0% FiCO2, n = 14) hypoxia, or room air (21% FiO2 and 0.03% FiCO2, n = 15). Norepinephrine, dopamine, serotonin, and their metabolites in the hypothalamus, hippocampus, and adrenal glands were measured by high-performance liquid chromatography (HPLC). Spontaneous behavioral activity was assessed for 30 min by automated activity monitors. Episodic hypocapnic hypoxia produced a decrease in dopamine turnover and eucapnic hypoxia increased norepinephrine levels in the hypothalamus. Animals exposed to hypocapnic hypoxia also exhibited a consistent increase in horizontal (walking) and vertical (rearing) activity, as well as in total activity time. From these results, it is concluded that episodic eucapnic and hypocapnic hypoxia may affect metabolism of different neurotransmitters in the CNS.

Amines↗
PubMed1996

Can the treatment of sleep apnea syndrome prevent the cardiovascular consequences?

He et al. indicated that mortality is reduced in treated patients with OSA but the reasons for this are still speculative. CPAP eliminates the acute elevation of blood pressure (BP) that occurs during a night of obstructive apneas. In longer term studies hypertensive patients showed a fall in mean BP from baseline with CPAP both by day and by night. Noncompliant patients do not achieve this benefit and BP does not change in normotensive patients with OSA on CPAP. On the other hand, left ventricular mass does not seem to change in hypertensive OSA patients despite reduction in blood pressure. Some of the benefit in BP reduction may relate to other interventions such as successful weight loss. Clear answers as to the effects of intervention are difficult because of confounding factors such as antihypertensive medication and length of follow up as well as questions of compliance with treatment. Multicenter trials are being currently undertaken but will need some years to yield answers.

Humans↗
PubMed1996

Effect of episodic eucapnic and hypocapnic hypoxia on systemic blood pressure in hypertension-prone rats.

Repetitive episodic (18-24 s twice per minute) hypocapnic hypoxia (HH) administered chronically (7 h/day, 35 days) to Sprague-Dawley or Wistar-Kyoto rats results in a sustained increase in daytime blood pressure (BP). We examined acute and chronic BP response to episodic HH and eucapnic hypoxia (EH) in borderline hypertensive rats [first generation (F1) cross between spontaneously hypertensive and Wistar-Kyoto rats]. We hypothesized that episodic HH and EH would create a greater increase in acute and chronic BP in this breed of rat than in previously studied strains. We also examined neural mechanisms by which BP changes from hypoxia are induced. BP and heart rate were examined acutely in nine F1 rats during baseline, HH, EH, EH with prazosin, and EH with prazosin and atropine. Five groups of male F1 rats were studied after 35-day exposure to the following: Unhandled (n = 8): no treatment; Sham (n = 10): episodic compressed air; HH (n = 14): daily episodic hypoxia (2.7%); EH1 (n = 12); hypoxia 2.9%, CO2 8.4%; and EH2 (n = 11): hypoxia 2.8% and CO2 10.5%. Under acute conditions, HH caused a 34.2-mmHg and EH a 77.9-mmHg increase in mean BP. Prazosin partially blocked the increase in BP. Under chronic conditions, HH caused a 10.3-mmHg increase in daytime mean BP, whereas EH caused a fall in mean BP of 16.6 and 9.3 mmHg in the two separately studied groups. In the F1 rat, acute EH causes an elevation of BP but chronic EH causes a fall in BP. The acute response to EH is not predictive of what occurs after chronic exposure in the hypertension-prone F-1 rat.

Animals↗
PubMed1996

Obstructive sleep apnoea and cardiovascular morbidity.

Obstructive sleep apnoea (OSA) has been implicated through epidemiologic studies as a co-morbid factor in cardiovascular disease. There is a greater incidence of hypertension and atherosclerosis related diseases such as stroke, angina, and acute myocardial infarction in patients with OSA. However, obesity is a common problem in OSA as well as cardiovascular disease and is argued by some to be the etiologic factor for both OSA and cardiovascular morbidity. Clearly, there is shortened longevity in patients with untreated or inadequately treated OSA. Other factors which could account for this early mortality in OSA are sudden death during sleep (arrhythmia) or even fatalities from sleep related automobile accidents. The reason that the association between OSA and cardiovascular disease remains unclear is that the relationship thus far is demonstrated only by epidemiological association, not by mechanisms showing a cause-effect relationship. Some of these possible mechanisms are discussed below. Regardless of the mechanisms, the evidence is that OSA needs to be treated aggressively if patient morbidity and mortality from cardiovascular disease is to be reduced.

Cardiovascular Diseases↗
PubMed1996

The rat as a model of chronic recurrent episodic hypoxia and effect upon systemic blood pressure.

The systemic arterial blood pressure response to obstructive sleep apnea (OSA) in humans is usually repetitive (with each apnea) acute elevation with return to near baseline following the apnea. In addition, it is believed by most investigators that chronic diurnal elevation of systemic blood pressure may result from repetitive nightly apneas in humans, resulting in systemic hypertension in about 50-70% of sleep apnea patients. Mechanisms of the chronic elevation in blood pressure are difficult to investigate in humans because it may take many years of repetitive apneas for sustained daytime blood pressure to develop. The rat is an especially good animal to use to investigate these mechanisms because of its use as a model in many types of hypertension. The authors have examined the response to chronic episodic hypoxia (for 35 consecutive days) in several strains of rats, discovering that systemic blood pressure (BP) remains chronically elevated in the absence of hypoxic stimulation after this period. This manuscript reviews the findings in this model after various interventions in the neurochemical and neuroendocrine mechanisms controlling BP in this animal.

Animals↗
PubMed1995

The relationship between systemic hypertension and obstructive sleep apnea: facts and theory.

This article provides an in-depth overview of the relationship between primary hypertension and adult obstructive sleep apnea syndrome. The background data and research are taken from the English-language literature through 1993. Primary hypertension is a common cause of major medical illnesses, including stroke, heart disease, and renal failure, in middle-aged males. Its prevalence in the United States is around 20%, with the rate of newly diagnosed hypertensive patients being about 3% per year. Sleep apnea syndrome is common in the same population. It is estimated that up to 2% of women and 4% of men in the working population meet criteria for sleep apnea syndrome. The prevalence may be much higher in older, non-working men. Many of the factors predisposing to hypertension in middle age, such as obesity and the male sex, are also associated with sleep apnea. Recent publications describe a 30% prevalence of occult sleep apnea among middle-aged males with so called "primary hypertension." Is this association fortuitous, related to a high prevalence of both diseases in the same population, or is it caused by a factor common to both diseases, such as obesity? Should the diagnosis of apnea be actively sought with sleep studies in hypertensive populations? If a diagnosis of "asymptomatic" sleep apnea is made in a hypertensive person, should the apnea be treated? Current research data provide only partial answers to these and other questions regarding the association of apnea and hypertension. Logic dictates that clinically symptomatic patients in hypertensive clinics should receive appropriate evaluation for apnea, but broad populations of hypertensive individuals should not be referred for sleep studies.

Acute Disease↗
PubMed1995

Effect of recurrent episodic hypocapnic, eucapnic, and hypercapnic hypoxia on systemic blood pressure.

We have described a rat model that responds to chronic (8 h/day, 35 days) repetitive nonapneic episodic (cycled every 30 s) hypocapnic hypoxia with sustained increase in systemic blood pressure. Because the usual blood gas change of apnea is mildly increased CO2, we hypothesized that episodic hypoxia ranging from eucapnea to hypercapnia might cause a greater chronic increase in blood pressure than hypocapnic hypoxia in this model. Five groups of male Sprague-Dawley rats were studied: unhandled group received no treatment, sham group received compressed air in their chambers, hypocapnic hypoxic group received episodic hypoxia for 35 days, eucapnic hypoxic group received the same level of hypoxia but with 7-10% inspired fraction of CO2, and hybercarbic hypoxic group received hypoxia with 11-14% inspired fraction of CO2. Mean arterial blood pressure was measured in unrestrained conscious animals at baseline and after 35 days under their respective study conditions. Neither episodic eucapnic nor hypercarbic hypoxia had any additional effect on the changes in chronic diurnal blood pressure compared with hypocapnic hypoxia. These results suggest that the sympathetic nervous system or other neurohumoral systems contributing to chronic diurnal blood pressure elevation may be maximally stimulated by hypoxia or there may be some protective mechanism limiting the blood pressure response to asphyxia in this rat model.

Animals↗
PubMed1995

Acute systemic blood pressure elevation in obstructive and nonobstructive breath hold in primates.

Phasic blood pressure (BP) response during obstructive apnea (OA) in human sleep has been previously described as consisting of a slow incremental increase in BP to the point of apnea termination followed by a rapid rise and then fall in BP at the resumption of respiration. This rise in BP has been attributed to postapneic augmentation of cardiac output resulting after release of the marked negative intrathoracic pressure (NIP) of obstructed inspiration. Via an endotracheal tube, we created obstructed and nonobstructed breath hold (apnea) in chloralose-anesthesized baboons consisting of fixed-duration (30, 45, and 60 s) single OAs (mechanical obstruction) and nonobstructive (paralysis, ventilator cessation) apneas of matched duration and arterial desaturation. Systemic BP was measured before apnea (T0), during the last 5 s of apnea (T1), and during the first 5 s after resumption of respiration (T2). Despite wide fluctuations in NIP and BP during the T0 to T1 phase of OA, BP elevation in OA and nonobstructive apnea at T0, T1, or T2 did not differ for any duration apnea. At the release of obstruction, when resolution of NIP changes could theoretically increase cardiac output and accentuate BP, there was no difference in T1 and T2 pressures between the two conditions. We conclude that in this anesthesized animal model, mechanical (NIP) changes do not play a major role in overall maximum BP response to OA. Because of physiological differences between natural sleep in humans and the anesthetized state in animals, care must be taken in extrapolating these results to human sleep apnea.

Airway Obstruction↗
PubMed1995

The effect of body fat distribution on pulmonary function tests.

Although the influence of obesity on pulmonary function tests has been examined, the role of body fat distribution has received limited attention. Pulmonary studies of patients severely affected by upper body obesity suggest they have more severely compromised lung volumes than obese patients with lower body obesity. We examined 42 healthy but normal or mildly obese men to determine if body fat distribution influences pulmonary function tests. Multiple measures of adiposity showed a significant inverse relationship with both spirometry and static lung volumes. However, the biceps skinfold thickness had the strongest inverse relationship with total lung capacity (TLC) compared to other anthropometric measures. The waist-to-hip ratio (WHR) demonstrated a significant inverse relationship with static lung volumes only when controlling for cigarette smoking. However, comparing pulmonary function tests between patients with a WHR less than 0.950 (lower body fat distribution) and subjects with a WHR of 0.950 or greater (upper body fat distribution) revealed that FVC, FEV1, and TLC were significantly lower in the patients with upper body fat distribution. Stepwise multiple regression analysis was done using all anthropometric variables and age which generated predictive equations that included the biceps skinfold thickness for residual volume (RV) and TLC. This suggests that upper body fat distribution may be associated with a modest impairment of lung volumes in normal and mildly obese men. Until the findings of this study can be applied to a larger, ethnically and anthropometrically diverse population, and to women, we believe caution is warranted when standard equations are used to predict pulmonary function tests in an anthropometrically diverse population.

Adipose Tissue↗