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Biomedical subjects

John E Remmers

Publications and source records attributed to John E Remmers.

15 recordsLinked to original sources
PubMed2006

Lung and buccal ventilation in the frog: uncoupling coupled oscillators.

The frog, with two distinct ventilatory acts, provides a useful model to investigate the prospective interaction of two oscillators in generating the respiratory rhythm. Building on evidence supporting the existence of separate oscillators generating buccal and lung ventilation, we have attempted to uncouple the two rhythms in the isolated brain stem preparation. Opioid preferentially inhibits the lung rhythm, suggesting an uncoupling of the lung from the buccal oscillator. Reduction of the superfusate chloride concentration alters both the buccal and the lung rhythms. Joint application of opioid and reduced-chloride superfusate leads to an increase in the variability of the buccal burst-to-lung burst intervals. This increase in variability suggests that chloride-mediated mechanisms are involved in coupling the buccal oscillator to the lung oscillator. Given the results from these interventions, we propose a simple schematic model of the frog respiratory rhythm generator, outlining the coupling of the lung and buccal oscillators.

Animals↗
PubMed2006

Phylogeny of vertebrate respiratory rhythm generators: the Oscillator Homology Hypothesis.

A revolution is underway in our understanding of respiratory rhythm generation in mammals. Until recently, a major focus of research within the field has centered around the question of locating and elucidating the mechanism of rhythmogenesis of a single respiratory neuronal oscillator which is reiterated bilaterally within the brainstem. Now it appears that each hemisection may contain at least two oscillators that interact to generate the respiratory rhythm in mammals. Comparative studies have hinted at the existence of multiple respiratory oscillators in non-mammalian vertebrates for some time, raising the possibility of homologous oscillators. Here, we consider available tools to identify neuronal oscillators and critically review the evidence for the importance and existence of multiple respiratory oscillators in vertebrates. First focusing on a comparison between frogs and mammals, we then evaluate the hypothesis that ventilatory oscillators in extant tetrapods evolved from ancestral oscillators present in fish (the Oscillator Homology Hypothesis). While supporting data are incomplete, the Oscillator Homology Hypothesis will likely serve as a useful framework to motivate further studies of respiratory rhythm generation in lower vertebrates.

Animals↗
PubMed2006

Model based analysis of sleep disordered breathing in congestive heart failure.

We employed a computational model of the respiratory control system to examine which of several factors, in isolation and in combination, can contribute to or explain the development of Cheyne-Stokes breathing (CSB). Our approach uses a graphical method for stability analysis similar, in concept, to the phase plane. The results from the computer simulations indicate that a postulated three-fold increase in the chemosensitivity of the central chemoreflex (CCR) loop may, by itself, explain development of CSB. By contrast, a similar increase in the chemosensitivity of the peripheral chemoreflex (PCR) loop cannot, by itself, account for CSB. The analysis reveals that the system is more readily destabilized by increasing the gain of only one chemoreflex loop than by a combined increase in gain of both loops. Reduction in the cardiac output or cardiomegaly decreases the size of the stability region. We conclude that development of CSB is the result of a complex interaction between CCR and PCR loops which may, in turn, interact with decreased cardiac output and cardiomegaly.

Blood Gas Analysis↗
PubMed2005

Ancient gill and lung oscillators may generate the respiratory rhythm of frogs and rats.

Though the mechanics of breathing differ fundamentally between amniotes and "lower" vertebrates, homologous rhythm generators may drive air breathing in all lunged vertebrates. In both frogs and rats, two coupled oscillators, one active during the inspiratory (I) phase and the other active during the preinspiratory (PreI) phase, have been hypothesized to generate the respiratory rhythm. We used opioids to uncouple these oscillators. In the intact rat, complete arrest of the external rhythm by opioid-induced suppression of the putative I oscillator, that is, pre-Bötzinger complex (PBC) oscillator, did not arrest the putative PreI oscillator. In the unanesthetized frog, the comparable PreI oscillator, that is, the putative buccal/gill oscillator, was refractory to opioids even though the comparable I oscillator, the putative lung oscillator, was arrested. Studies in en bloc brainstem preparations derived from both juvenile frogs and metamorphic tadpoles confirmed these results and suggested that opioids may play a role in the clustering of lung bursts into episodes. As the frog and rat respiratory circuitry produce functionally equivalent motor outputs during lung inflation, these data argue for a close homology between the frog and rat oscillators. We suggest that the respiratory rhythm of all lunged vertebrates is generated by paired coupled oscillators. These may have originated from the gill and lung oscillators of the earliest air breathers.

Action Potentials↗
PubMed2004

Remotely controlled mandibular positioner predicts efficacy of oral appliances in sleep apnea.

Anterior mandibular positioners (AMPs) have become increasingly popular as alternatives to continuous positive airway pressure for the treatment of obstructive sleep apnea. However, widespread acceptance of AMP is limited by an efficacy rate of 50-80% and an inability to predict which patients will respond to therapy. We evaluated 23 patients with obstructive sleep apnea (respiratory disturbance index [RDI] >/= 15 h(-1)) with a remotely controlled mandibular positioner (RCMP), a temporary oral appliance that can advance or retract the mandible in a process analogous to changing the mask pressure during a continuous positive airway pressure titration study. We hypothesized that the elimination of respiratory events and significant nocturnal oxygen desaturation during an RCMP overnight study would predict AMP efficacy, as defined by an absolute reduction in RDI to less than 15 h(-1), a relative reduction in RDI of more than 30% from baseline, and a subjective improvement in symptoms. AMP compliance was 82%, and therapeutic efficacy was 53%. Among compliant patients, the positive and negative predictive value of an RCMP study in predicting AMP treatment success was 90% and 89%, respectively. An overnight RCMP study is highly predictive of AMP response.

Adult↗
PubMed2004

A computational model of the human respiratory control system: responses to hypoxia and hypercapnia.

Although recent models offer realistic descriptions of the human respiratory system, they do not fulfill all characteristics of a stable, comprehensive model, which would allow us to evaluate a variety of hypotheses on the control of breathing. None of the models offer completely realistic descriptions of the gaseous components of blood, and their description of delays associated with the propagation of changes in partial pressures of respiratory gases between the lungs and brain and tissue compartments have shortcomings. These deficiencies are of particular significance in an analysis of periodic breathing where dynamic alterations in the circulation and in blood chemical stimuli are likely to assume considerable importance. We developed a computational model of the human respiratory control system which is an extension of the model of Grodins et al. (F. S. Grodins, J. Buell, and A. J. Bart. J. Appl. Physiol. 22(2):260-276, 1967). Our model combines an accurate description of a plant with a novel controller design that treats minute ventilation as a sum of central and peripheral components. To ensure that the developed model is stable and sufficiently robust to act as a test platform for hypotheses about control of ventilation, we simulated a series of challenging physiological conditions, specifically, the response to eucapnic hypoxia, the development of periodic breathing during hypocapnic hypoxia, and the open loop response to hypercapnic step. These steady state and transient responses of the model were compared with results from similar physiological experiments. Our simulations suggest that for a particular value of arterial Po2, the steady state difference between brain and arterial Pco2 remains approximately constant as a function of arterial Pco2. The model indicates that hypoxia-induced changes in cerebral blood flow contribute significantly to the ventilatory decline observed during eucapnic hypoxia. The model exibits hypoxic-induced periodic breathing, which can be eliminated by small increases in F(I)co2. The dynamics of the model's open loop hypercapnic ventilatory response approximates experimental data well.

Computer Simulation↗
PubMed2003

A decision rule for diagnostic testing in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is traditionally diagnosed using overnight polysomnography. Decision rules may provide an alternative to polysomnography. A consecutive series of patients referred to a tertiary sleep center underwent prospective evaluation with the upper airway physical examination protocol, followed by determination of the respiratory disturbance index using a portable monitor. Seventy-five patients were evaluated with the upper airway physical examination protocol. Historic predictors included age, snoring, witnessed apneas, and hypertension. Physical examination-based predictors included body mass index, neck circumference, mandibular protrusion, thyro-rami distance, sterno-mental distance, sterno-mental displacement, thyro-mental displacement, cricomental space, pharyngeal grade, Sampsoon-Young classification, and over-bite. A decision rule was developed using three predictors: a cricomental space of 1.5 cm or less, a pharyngeal grade of more than II, and the presence of overbite. In patients with all three predictors (17%), the decision rule had a positive predictive value of 95% (95% confidence interval [CI], 75-100%) and a negative predictive value of 49% (95% CI, 35-63%). A cricomental space of more than 1.5 cm (27% of patients) excluded OSA (negative predictive value of 100%, 95% CI, 75-100%). Comparable performance was obtained in a validation sample of 50 patients referred for diagnostic testing. This decision rule provides a simple, reliable, and accurate method of identifying a subset patients with, and perhaps more importantly, without OSA.

Adult↗
PubMed2003

Nitric oxide mediates metabolism as well as respiratory and cardiac responses to hypoxia in the snail lymnaea stagnalis.

Lymnaea stagnalis were exposed to hypoxic and chemical challenges while ventilation, heart rate and metabolism were monitored. Hypoxia increased ventilatory behavior, but this response was eliminated by immersion in 0.75 mM nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7 NI). 7 NI also suppressed ventilatory behavior under normoxia. 10.0 mM L-arginine (ARG, the NOS substrate) increased ventilatory behavior under normoxia, but dampened the hypoxic response. The heart-rate response to NOS inhibition exhibited dose-dependent contradictory characteristics. Under both normoxia and hypoxia 0.25 mM 7 NI increased heart rate, while 0.75 mM 7 NI suppressed it. The effect of 0.50 mM 7 NI depended on whether normoxia or hypoxia was coincident; under normoxia 0.50 mM 7 NI increased heart rate, while under hypoxia this concentration suppressed heart rate. Exposure to ARG did not elicit dose-dependent contradictory responses. Heart rate increased when treated with 10.0 mM ARG under normoxia and hypoxia, while 1.0 mM ARG increased heart rate only under hypoxia. Metabolic responses to NOS inhibition also exhibited dose-dependent contradictory changes. V.O2 decreased over 60% in response to 0.75 mM 7 NI, and baseline V.O2 was restored when exposure ceased. In contrast, 0.25 mM 7 NI increased V.O2 10%, and the increase continued after exposure ceased. 0.50 mM 7 NI decreased V.O2 40%, but V.O2 increased when exposure ceased. ARG had only the effect of increasing V.O2, and only at 10.0 mM concentration. Based on these results and on NO's known role as a neuromodulator, we conclude that the cardio-respiratory responses to hypoxia are, in part, mediated by NO.

Animals↗
PubMed2003

Comparison of home oximetry monitoring with laboratory polysomnography in children.

STUDY OBJECTIVES: To measure the accuracy and reliability of a portable home oximetry monitor with an automated analysis for the diagnosis of obstructive sleep apnea (OSA) in children. DESIGN: Prospective cohort study. SETTING: Alberta Lung Association Sleep Center, Alberta Children's Hospital Sleep Clinic. STUDY SUBJECTS: Consecutive, otherwise healthy children, aged 4 to 18 years, presenting to the Pediatric Sleep Service at the Alberta Children's Hospital for assessment of possible OSA. INTERVENTIONS: All subjects underwent 2 nights of monitoring in the home with an oximetry-based portable monitor with an automatic internal scoring algorithm. A third night of monitoring was done simultaneously with computerized laboratory polysomnography according to American Thoracic Society guidelines. MEASUREMENTS AND RESULTS: Both test-retest reliability of the portable monitor-based desaturation index (DI) between 2 nights at home and between laboratory and home were high using the Bland and Altman analysis (mean agreement, 0.32 and 0.64; limits of agreement, - 8.00 to 8.64 and - 0.75 to 6.50, respectively). The polysomnographic apnea-hypopnea index (AHI) agreed poorly with the portable monitor DI (mean difference, 1.27; limits of agreement, - 12.02 to 15.02). The sensitivity and specificity of the monitor for the identification of moderate sleep apnea (polysomnography AHI > 5/h) were 67% and 60%, respectively. CONCLUSION: Portable monitoring based only on oximetry alone is not adequate for the identification of OSA in otherwise healthy children.

Adolescent↗
PubMed2002

Central respiratory activity of the tadpole in vitro brain stem is modulated diversely by nitric oxide.

Nitric oxide (NO) is a potent central neuromodulator of respiration, yet its scope and site of action are unclear. We used 7-nitroindazole (7-NI), a selective inhibitor of endogenous neuronal NO synthesis, to investigate the neurogenesis of respiration in larval bullfrog (Rana catesbeiana) isolated brain stems. 7-NI treatment (0.0625-0.75 mM) increased the specific frequency of buccal ventilation (BV) events, indicating influence on BV central rhythm generators (CRGs). The drug reduced occurrence, altered burst shape, and disrupted clustering of lung ventilation (LV) events, without altering their specific frequency. LV burst occurrence and clustering also differed between pH conditions. We conclude that NO has diverse effects on respiratory rhythmogenesis, being necessary for the expression of respiratory rhythms, inhibiting the frequency of BV CRG, and affecting both shape and clustering of LV bursts through conditional modulation of LV CRG. We confirm central chemosensitivity in these preparations and demonstrate chemomodulation of LV burst clustering and occurrence but not specific frequency. Results support distinct oscillators underlying LV and BV CRGs.

Analysis of Variance↗
PubMed2002

Mechanical properties of the passive pharynx in Vietnamese pot-bellied pigs. I. Statics.

The static mechanical properties of the passive pharynx were investigated in Vietnamese pot-bellied pigs by using an isolated upper airway preparation. During general anesthesia and neuromuscular blockade, cross-sectional area (A) of the pharynx was measured while airway pressure (Paw) was held at various pressures in the absence of airflow. The static A-Paw relationship was measured during application of 0, 1, and 2 cm of caudal tracheal displacement. Relative to humans, closing pressures (Pclose) of the pig pharynx were very low (-15 to -35 cmH(2)O). Tracheal displacement significantly decreased compliance of the hypopharynx (from 0.074 +/- 0.02 cm(2)/cmH(2)O with no displacement to 0.052 +/- 0.01 cm(2)/cmH(2)O with 2 cm of displacement) and decreased Pclose of the oropharynx (from -18.2 +/- 9.9 cmH(2)O to -24.1 +/- 10.5 and -28.7 +/- 12.3 cmH(2)O with 1 and 2 cm of displacement, respectively). Tracheal displacement did not affect A of the pharyngeal segments. In conclusion, tracheal displacement decreased collapsibility of the passive pharynx. The pharynx of the pot-bellied pig is structurally more resistant to collapse than the human pharynx.

Anatomy, Cross-Sectional↗
PubMed2002

Mechanical properties of the passive pharynx in Vietnamese pot-bellied pigs. II. Dynamics.

We described the dynamic mechanical properties of the passive pharynx in Vietnamese pot-bellied pigs and the effects of caudal tracheal displacement. During general anesthesia and neuromuscular blockade, airflow through the upper airway (V) and pharyngeal cross-sectional area were measured during ramp decreases in pressure downstream from the pharynx (Pdown). Measurements were made with 0, 1, and 2 cm of caudal tracheal displacement. Airflow limitation and/or negative pressure dependence (NPD) were observed in all animals. Tracheal displacement (2 cm) increased maximal V (V(max)) by 205.1 +/- 105.1% (P < 0.05) relative to the value with no displacement and increased the magnitude of NPD, expressed as percent decrease in V from V(max), from 22.9 +/- 27.4 to 56.6 +/- 37.5% (P < 0.05). Initial decreases in Pdown narrowed all levels of the pharynx, but, once V(max) was reached, further decreases in Pdown narrowed the hypopharynx but not the nasopharynx and oropharynx. We conclude that the hypopharynx is the flow-limiting site in the pig pharynx. Tracheal displacement not only improved airflow dynamics as V(max) increased but also resulted in pronounced NPD.

Airway Resistance↗
PubMed2002

Hypoxemia and low Crs in vagally denervated lambs result from reduced lung volume and not pulmonary edema.

Vagal denervation performed in the intrathoracic region in newborn lambs leads to hypoxemia and decreased respiratory system compliance (Crs), which could result from atelectasis and/or pulmonary edema. The objective of the present study was to quantify the relative roles of alveolar derecruitment and pulmonary edema as underlying cause(s) of respiratory failure. Vagal denervation was performed in the intrathoracic region and below the recurrent laryngeal nerves in six newborn lambs within 24 h of birth, whereas six were sham operated. Pre- and postinflation Crs was measured to investigate the presence of alveolar derecruitment. Pulmonary edema was assessed with lung wet-dry-to-wet and lung tissue wet-to-dry ratios, total protein, and FITC-BSA recovery in lung tissue and bronchoalveolar lavage. Compared with that in the sham-operated animals, Crs was significantly lower in vagally denervated animals. However, postinflation, pulmonary system compliance obtained by quasi-static lung inflation and deflation to 30 cmH2O showed no significant difference between the sham-operated and denervated lambs. The lung wet-dry-to-wet and lung tissue wet-to-dry ratios, total protein, and FITC-BSA recovery in lung tissue and bronchoalveolar lavage were similar in denervated and sham-operated groups. We provide evidence that reduced lung volume and not pulmonary edema is associated with intrathoracic vagal denervation and is the likely underlying mechanism for hypoxemia and low Crs.

Afferent Pathways↗