James E Fewell

Influence of carotid denervation on the arousal and cardiopulmonary response to rapidly developing hypoxemia in lambs

ABSTRACT: Experiments were done on five lambs to determine if carotid denervation influences the arousal and cardiopulmonary responses to rapidly developing hypoxemia during sleep. Each lamb was anesthetized and instrumented for recordings of electrocorticogram, electrooculogram, nuchal and diaphragm electromyograms, and measurements of arterial blood pressure and arterial hemoglobin oxygen saturation. The carotid chemoreceptors and baroreceptors were denervated, a tracheostomy was done, and a fenestrated tracheostomy tube was placed in the trachea so that the inspired oxygen mixture could be changed quickly. No sooner than 3 d after surgery, measurements were made in quiet sleep and active sleep during control periods when the animal was breathing 21% oxygen and during experimental periods of rapidly developing hypoxemia when the animal was breathing 5% oxygen. Rapidly developing hypoxemia was terminated during each epoch by changing the inspired gas mixture back to 21% oxygen once the animal aroused from sleep or once the arterial Hb oxygen saturation decreased to 30%. Arousal occurred during only 4 of 11 epochs in quiet sleep and during only 3 of 14 epochs in active sleep before the arterial Hb oxygen saturation decreased to 30%. These data provide evidence that the carotid chemoreceptors and/or carotid baroreceptors play a major role in causing arousal from sleep during rapidly developing hypoxemia in lambs.

Renal denervation eliminates the renal response to continuous positive-pressure ventilation.

Summary A study was conducted to describe the role of the renal nerves in mediating the reflex antidiuresis and antinatriuresis associated with the application of continuous positive pressure ventilation (CPPV). Experiments were performed on seven dogs 4-5 days after they had undergone surgical de-nervation of the left kidney. The nerves to the right kidney were left intact. Urine flow (V), sodium excretion (UnaV), effective renal plasma flow (ERPF), and glomerular filtration rate (GFR) were determined for both the intact and denervated kidneys. In the right kidney with intact renal nerves, application of CPPV caused statistically significant (P <0.05) decreases from control levels in V, UnaV, ERPF, and GFR. In the left denervated kidneys, however, CPPV did not produce any statistically significant changes in V, UnaV, ERPF, or GFR. These data suggest that the renal nerves participate in mediating the antidiuresis and antinatriuresis associated with elevation of the expiratory pressure.

Influence of repeated upper airway obstruction on the arousal and cardiopulmonary response to upper airway obstruction in lambs.

ABSTRACT: Experiments were done on five Iambs to determine if repeated obstruction of the upper airway influences the arousal and cardiopulmonary response to upper airway obstruction. Each lamb was anesthetized and instrumented for recordings of electrocorticogram, electrooculogram, nuchal and diaphragm electromyograms, and measurements of arterial blood pressure and arterial hemoglobin oxygen saturation. A tracheostomy was done and a fenestrated tracheostomy tube placed in the trachea. The animals were studied after a 3-day recovery period. During a study, a 5F balloon-tipped catheter was inserted into the tracheostomy tube so that air flow could be obstructed by inflating the balloon. The balloon was inflated each time the animal went to sleep for approximately 100 consecutive epochs (17 to 30 h) and the time to arousal and the arterial hemoglobin oxygen saturation at arousal were recorded. Upper airway obstruction was terminated by deflating the balloon once the animal aroused from sleep. Arousal occurred from both sleep states during upper airway obstruction but was delayed in active sleep compared to quiet sleep. The time to arousal and the decrease in arterial hemoglobin oxygen saturation were significantly increased with repeated upper airway obstruction only during active sleep. Inasmuch as it is possible that alterations in the arousal response to respiratory stimuli play a role in sudden infant death, studies to investigate the mechanisms of the state-specific changes in the arousal response to upper airway obstruction are warranted.

Influence of carotid denervation on the arousal and cardiopulmonary responses to upper airway obstruction in lambs.

ABSTRACT: Experiments were done on five lambs to determine if carotid denervation influences the arousal and cardiopulmonary responses to upper airway obstruction during sleep. Each lamb was anesthetized and instrumented for recordings of electrocorticogram, electro-oculogram, nuchal and diaphragm electromyograms. and measurements of arterial blood pressure and arterial Hb oxygen saturation. A tracheotomy was done and a fenestrated tracheotomy tube placed in the trachea. During the study, a 5 F balloon-tipped catheter was inserted into the tracheotomy tube so that air flow could be obstructed by inflating the balloon. No sooner than 3 d after surgery, measurements were made in quiet sleep and active sleep during control periods when the animal was breathing room air and during experimental periods of upper airway obstruction. Carotid denervation significantly affected the arousal response to upper airway obstraction. Arousal occurred during 14 of 14 epochs in quiet sleep and during 12 of 13 epochs in active sleep before the arterial Hb oxygen saturation decreased to 30%. However, the time to arousal was increased and the arterial Hb oxygen saturation at arousal was decreased in carotid-denervated lambs compared with what we have previously observed in carotid-intact lambs. These data provide evidence that the caroid chemoreceptors and/or carotid baroreceptors play a major role in causing arousal from sleep during upper airway obstruction in lambs. Our results may have implications for sudden infant death syndrome, because it is possible that alterations in the arousal response to respiratory stimuli play a role in sudden infant death.

Role of Sinoaortic Baroreceptors in Initiating the Renal Response to Continuous Positive-pressure Ventilation in the Dog

Experiments were conducted to determine the role of cardiopulmonary receptors with vagal afferents and sinoaortic baroreceptors in initiating the reflex antidiuresis and antinatriuresis during continuous positive-pressure ventilation (CPPV). CPPV was applied to 18 dogs: seven control, five that underwent bilateral vagotomy; and six that underwent sinoaortic baroreceptor denervation. The dogs were anesthetized with pentobarbital, paralyzed with succinylcholine, and their lungs were mechanically ventilated with a volume ventilator. Renal function and systemic hemodynamics were monitored by clearance methods and pressures, respectively. After two 30-min control periods of intermittent positive-pressure ventilation (IPPV), CPPV using 10 cm H2O positive end-expiratory pressure was applied for two 30-min experimental periods. Three 30-min recovery periods of IPPV followed. In dogs of the control group and vagotomy group, CPPV caused statistically significant decreases from control levels in urinary flow, sodium excretion, and glomerular filtration rate. However, in the dogs of the sinoaortic baroreceptor denervation group, CPPV did not produce any significant change in these variables. Therefore, the results do not support the hypothesis that cardiopulmonary receptors mediate the renal response to CPPV. Rather, the data indicate that the aortic arch and carotid sinus baroreceptors participate in initiating the reflex antidiuresis and antinatriuresis during CPPV.

Repeated exposure to rapidly developing hypoxemia influences the interaction between oxygen and carbon dioxide in initiating arousal from sleep in lambs.

ABSTRACT: Experiments were done on 12 lambs to determine if repeated exposure to hypoxemia influences the interaction between oxygen and carbon dioxide in causing arousal response from sleep. Each lamb was anesthetized and instrumented for sleep staging and measurements of arterial Hb oxygen saturation. No sooner than 3 days after surgery, measurements were made in quiet and active sleep during control periods when the lambs were breathing 21% oxygen and during experimental periods when the lambs were breathing either 5% O2-0% CO2, 5% O2-5% CO2 or 5% O2-10% CO2. Each experimental period was terminated during each epoch by changing the inspired gas mixture back to 21% oxygen once the animal aroused from sleep. The lambs were divided into two groups. One group (n = 7) was studied without prior exposure to hypoxemia and the other group (n = 5) was studied after exposure to 5% oxygen during ∼100 epochs of sleep until they aroused. In lambs not previously exposed to hypoxemia, there was evidence for a slight interaction between oxygen and carbon dioxide in initiating arousal but only from quiet sleep. Repeated exposure to hypoxemia resulted in an arousal response decrement to hypoxemia. In lambs previously exposed to hypoxemia, there was evidence for an interaction between oxygen and carbon dioxide in initiating arousal from both quiet and active sleep (i.e. the time to arousal decreased and the saturation at arousal increased as increasing amounts of carbon dioxide were added to the hypoxic gas mixture). Thus, our data provide evidence that a greater interaction exists between oxygen and carbon dioxide in initiating arousal—particularly in active sleep—once an arousal response decrement has developed to hypoxemia alone.

Arousal from Sleep during Rapidly Developing Hypoxemia in Lambs

ABSTRACT. Arousal is an important protective response that may prevent severe hypoxemia and death during sleep. However, very little is known about arousal from sleep in response to respiratory stimuli in newborns. Experiments were therefore done to investigate the arousal response from sleep to rapidly developing hypoxemia in eight lambs. Each lamb was anesthetized and instrumented for recordings of electrocorticogram, electrooculogram, nuchal and diaphragm electromyograms, and measurements of arterial hemoglobin oxygen saturation. A tracheotomy was done and a tracheostomy tube placed in the trachea so that the fraction of inspired oxygen could be changed quickly. No sooner than 3 days after surgery, measurements were made in quiet sleep and active sleep (AS) during 30-s control periods when the animals were breathing 21% oxygen and during experimental periods of hypoxemia when the animals were breathing either 10, 5, or 0% oxygen in nitrogen. During quiet sleep, arousal occurred at similar arterial hemoglobin oxygen saturations (81 ± 6% on 10% O2, 80 ± 5% on 5% O2 and 83 ± 5% on 0% O2) suggesting that arousal was independent of the rate of change of arterial oxygen. However, during AS arousal occurred at different arterial hemoglobin oxygen saturations (76 ± 6% on 10% O2, 55 ± 11% on 5% O2, and 44 ± 17% on 0% O2) suggesting that arousal was dependent on the rate of change of arterial oxygen. During some epochs of AS, electrocortical signs of cerebral hypoxia and primary apnea occurred before arousal. These data provide evidence that arousal from quiet sleep in response to hypoxemia occurs once an arousal threshold has been reached. However, during AS, arousal appears to follow an arousal latency once an arousal threshold has been reached. Furthermore, if the rate of change of oxygen is great enough during AS, signs of cerebral hypoxia and primary apnea may precede arousal. These data would allow one to speculate that if the rate of change of arterial oxygen is great enough during apnea in AS, arousal may fail to occur before hypoxic cerebral depression and ultimately death ensue.

Cardiovascular and renal effects of dopamine and dobutamine in healthy, conscious piglets

The pharmacologic effects of dopamine and dobutamine (2 to 32 micrograms/kg.min) were evaluated in 12 1 to 2-month-old piglets. Dopamine increased cardiac output at 16 to 32 micrograms/kg.min (p less than .05) and increased heart rate (HR) at 4 to 32 micrograms/kg.min (p less than .05). Dobutamine produced an increased cardiac output at doses of 16 to 32 micrograms/kg.min (p less than .05), and increased HR at 32 micrograms/kg.min (p less than .05), decreased systemic arterial pressure and systemic vascular resistance at 16 to 32 micrograms/kg.min (p less than .05), decreased renal vascular resistance at 16 to 32 micrograms/kg.min, and increased renal blood flow at 4.8 and 32 micrograms/kg.min (p less than .05). We conclude that dopamine and dobutamine increase cardiac output in healthy, conscious piglets primarily by increasing HR. Neither agent was effective in increasing stroke volume, although a positive inotropic effect obscured by tachycardia cannot be ruled out. Dobutamine was the superior agent for renal vasodilation, whereas neither agent produced significant pulmonary vasodilation.

Effects of Hyperoxia on the Arousal Response to Upper Airway Obstruction in Lambs

ABSTRACT: Experiments were done to investigate the effects of increased inspired oxygen on the arousal response from sleep to upper airway obstruction in 10 newborn lambs. Each lamb was anesthetized and instrumented for recordings of electrocorticogram, electrooculogram, nuchal and diaphragm electromyograms, and measurements of systemic arterial blood pressure and oxygen saturation (fiberoptic catheter oximeter). A tracheotomy was performed and a fenestrated tracheostomy tube was placed in the trachea. A 5F balloon tipped catheter was inserted into the tube so that airflow could be obstructed by inflating the balloon. No sooner than 3 days after surgery, measurements were made during a control period and during an experimental period of upper airway obstruction; the inspired oxygen fraction was alternated hourly between 0.21 and 0.60. A total of 57 epochs of quiet sleep and 58 epochs of active sleep was obtained in eight lambs. Arousal was significantly delayed (p < 0.005) during active sleep (21 ± 6 s; mean ± 1 SD) compared to quiet sleep (7 ± 2 s) in room air. Increased inspired oxygen significantly delayed arousal (p < 0.05) during active sleep (47 ± 25 s), but had little effect on arousal in quiet sleep (10 ± 4 s). These results provide evidence that arousal from active sleep following upper airway obstruction in lambs is primarily initiated by a decrease in arterial oxygen. However, arousal from quiet sleep following upper airway obstruction in lambs appears to be initiated by other stimuli.

Pulmonary Vascular Response to Aerosolized Cromolyn Sodium and Repeated Epochs of Isocapneic Alveolar Hypoxia in Lambs

ABSTRACT: We investigated the effect of aerosolized cromolyn sodium (CS) on the pulmonary vascular response to isocapneic alveolar hypoxia in chronically instrumented Iambs aged 11–12 days. Each lamb underwent two operations: chest instrumentation for measurements of pulmonary arterial, systemic arterial, and left atrial pressures, and pulmonary blood flow; and a tracheotomy for drug administration. The animals were recovered 3 days before study. Each lamb receiver an aerosol of normal saline (placebo) and CS in paired experiments 24 h apart. In the first set of experiments (n = 8), placebo or CS (30 mg) was given, followed by four 15-min epochs of alveolar hypoxia (8% O2, 5% CO2, 87% N2) each separated by 30 min of alveolar normoxia (21% O2). During hypoxia after both placebo and CS, pulmonary arterial pressure and resistance increased. This response was unchanged with repeated epochs. In the second set of experiments (n = 8), normal saline or CS (30 mg) was administered three times over a 90-min period, followed by one 15-min epoch of hypoxia. Pulmonary arterial pressure and resistance increased during hypoxia after placebo, but did not change after CS. Thus, the single dose of aerosolized CS did not alter the pulmonary vascular response to alveolar hypoxia, whereas the triple dose of CS attenuated the response. Additionally, the pulmonary vascular response to hypoxia alone was not altered by repeated exposures to hypoxia. We conclude that CS interferes with the mechanism(s) responsible for hypoxic pulmonary vasoconstriction in newborn lambs.