Hypercapnic Ventilatory Response Slope Research Articles

Interictal respiratory variability predicts severity of hypoxemia after generalized convulsive seizures.

Severe respiratory dysfunction induced by generalized convulsive seizures (GCS) is now thought to be a common mechanism for sudden unexpected death in epilepsy (SUDEP). In a mouse model of seizure-induced death, increased interictal respiratory variability was reported in mice that later died of respiratory arrest after GCS. We studied respiratory variability in epilepsy patients as a predictive tool for severity of postictal hypoxemia, a potential biomarker for SUDEP risk. We then explored the relationship between respiratory variability and central CO2 drive, measured by the hypercapnic ventilatory response (HCVR). We reviewed clinical, video-electroencephalography, and respiratory (belts, airflow, pulse oximeter, and HCVR) data of epilepsy patients. Mean, SD, and coefficient of variation (CV) of interbreath interval (IBI) were calculated. Primary outcomes were: (1) nadir of capillary oxygen saturation (SpO2 ) and (2) duration of oxygen desaturation. Poincaré plots of IBI were created. Covariates were evaluated in univariate models, then, based on Akaike information criteria (AIC), multivariate regression models were created. Of 66 GCS recorded in 131 subjects, 30 had interpretable respiratory data. In the multivariate model with the lowest AIC value, duration of epilepsy was a significant predictor of duration of oxygen desaturation. Duration of tonic phase and CV of IBI during the third postictal minute correlated with SpO2 nadir, whereas CV of IBI during non-rapid eye movement sleep had a negative correlation. Poincaré plots showed that long-term variability was significantly greater in subjects with ≥200 s of postictal oxygen desaturation after GCS compared to those with <200 s desaturation. Finally, HCVR slope showed a negative correlation with measures of respiratory variability. These results indicate that interictal respiratory variability predicts severity of postictal oxygen desaturation, suggesting its utility as a potential biomarker. They also suggest that interictal respiratory control may be abnormal in some patients with epilepsy.

A biomarker of opioid-induced respiratory toxicity in experimental studies

Opioids are commonly used painkillers and drugs of abuse and have serious toxic effects including potentially lethal respiratory depression. It remains unknown which respiratory parameter is the most sensitive biomarker of opioid-induced respiratory depression (OIRD). To evaluate this issue, we studied 24 volunteers and measured resting ventilation, resting end-tidal PCO2 (PETCO2) and the hypercapnic ventilatory response (HCVR) before and at 1-h intervals following intake of the opioid tapentadol. Pharmacokinetic/pharmacodynamic analyses that included CO2 kinetics were applied to model the responses with focus on resting variables obtained without added CO2, HCVR slope and ventilation at an extrapolated PETCO2 of 55mmHg ( 55). The HCVR, particularly 55 followed by slope, was most sensitive in terms of potency; resting variables were least sensitive and responded slower to the opioid. Using 55 as biomarker in quantitative studies on OIRD allows standardized comparison among opioids in the assessment of their safety.

Hypercapnic ventilatory response in epilepsy patients treated with VNS: A case-control study.

Central CO2 chemoreception (CCR), a major chemical drive for breathing, can be quantified with a CO2 re-breathing test to measure the hypercapnic ventilatory response (HCVR). An attenuated HCVR correlates with the severity of respiratory dysfunction after generalized convulsive seizures and is a potential biomarker for sudden unexpected death in epilepsy (SUDEP) risk. Vagus nerve stimulation (VNS) may reduce SUDEP risk, but for unclear reasons the risk remains higher during the first 2 years after implantation. The vagus nerve has widespread connections in the brainstem, including key areas related to CCR. Here we examined whether chronic electrical stimulation of the vagus nerve induces changes in CCR. We compared the HCVR in epilepsy patients with or without an active VNS in a sex- and age-matched case-control study. Eligible subjects were selected from a cohort of patients who previously underwent HCVR testing. The HCVR slope, change in minute ventilation (VE) with respect to change in end tidal (ET) CO2 (∆ VE/ ∆ ETCO2) during the test was calculated for each subject. Key variables were compared between the two groups. Univariate and multivariate analyses were carried out for HCVR slope as dependent variable. A total of 86subjects were in the study. HCVR slope was significantly lower in the cases compared to the controls. Cases had longer duration of epilepsy and higher number of anti-epileptic drugs (AEDs) tried during lifetime. Having active VNS and ETCO2 were associated with a low HCVR slope while high BMI was associated with high HCVR slope in both univariate and multivariate analyses. We found having an active VNS was associated with relatively attenuated HCVR slope. Although duration of epilepsy and number of AEDs tried during lifetime was significantly different between the groups, they were not predictors of HCVR slope in subsequent analysis. Chronic electrical stimulation of the vagus nerve by VNS may be associated with an attenuated CCR [Correction added on 24 November 2021, after first online publication: The preceding sentence has been revised from “Chronic electrical stimulation of VNS nerve by VNS…”]. A larger prospective study may help to establish the time course of this effect in relation to the time of VNS implantation, whether there is a causal relationship, and determine how it affects SUDEP risk.

Acetazolamide Attenuates Hunter-Cheyne-Stokes Breathing but Augments the Hypercapnic Ventilatory Response in Patients with Heart Failure

Acetazolamide has been used to attenuate Hunter-Cheyne-Stokes breathing with central sleep apnea (CSA) associated with heart failure. However, the mechanisms underlying this improvement remain to be fully elucidated. We hypothesized that acetazolamide stabilizes CSA by attenuating the ventilatory sensitivity to CO2, which is increased in patients with heart failure and is thought to be the major mechanism mediating CSA. Six consecutive male patients with stable systolic heart failure and CSA (apnea-hypopnea index [AHI] ≥ 15 episodes/h) were randomized to a double-blind crossover protocol with acetazolamide or placebo received 1 hour before bedtime for six nights with 2 weeks of wash-out. Under both conditions, we measured the hypercapnic ventilatory response (HCVR), arterial blood Pco2, steady-state metabolic CO2 production, overnight attended polysomnography, and also assessed cardiac and pulmonary function. Compared with placebo, acetazolamide significantly decreased the AHI (65 ± 32 vs. 31 ± 19 events/h, mean ± SD). Acetazolamide increased the HCVR slope by 55% (3.3 ± 1.7 vs. 5.1 ± 2.4 L/min/mm Hg; P = 0.03), an increase that far exceeded the 12% fall in arterial Pco2 (P = 0.02). The acetazolamide-induced change in the balance of these effects (ΔHCVR × Pco2) was inversely associated with the reduction in AHI (r = 0.8; P = 0.045). This placebo-controlled study indicates that acetazolamide improves CSA in patients with heart failure despite an increase in the slope of the HCVR. However, because the degree of HCVR elevation inhibits the improvement in unstable breathing, an increased CO2 chemosensitivity may be a key mechanism underlying an incomplete resolution of CSA with acetazolamide.

A quick and easy method of measuring the hypercapnic ventilatory response in patients with COPD

Hypercapnic ventilatory response (HCVR) techniques have not previously been adequately validated in patients with chronic obstructive pulmonary disease (COPD). We have tested the hypothesis that end-tidal PCO(2) may be used to test the HCVR in COPD during non-steady-state rebreathing, despite the fact that large (arterial-end-tidal) PCO(2) differences (P(a-et)CO(2)) exist during air breathing. Eight patients and 11 healthy volunteers underwent steady-state HCVR testing and non-steady-state rebreathing HCVR testing, using Pa and PetCO(2). In COPD patients, PetCO(2) was lower than PaCO(2) by a constant amount throughout steady-state HCVR, but equalised with PaCO(2) during non-steady-state HCVR. Consequently there were no differences in HCVR slope using either method (steady-state p=0.91; rebreathing p=0.73), or HCVR intercept in rebreathing (p=0.68) whether PaCO(2) or PetCO(2) was used. The steady-state HCVR intercept using PetCO(2) was greater than that using PaCO(2) (p=0.02). In healthy volunteers PetCO(2) equalised with PaCO(2) during steady-state HCVR, but was progressively greater than PaCO(2) during non-steady-state. Consequently, there was no difference in HCVR slope (p=0.21) or intercept (p=0.46) whether PaCO(2) or PetCO(2) was used. During non-steady-state there was a P(a-et)CO(2) difference in slope (p=0.03) and intercept (p=0.04). In COPD patients non-steady-state HCVR using PetCO(2) is well tolerated, which is as accurate as PaCO(2). HCVR slope may be derived using PetCO(2) during steady-state testing, though there may be errors in intercept compared to use of PaCO(2). In healthy volunteers PetCO(2) may be used to estimate PaCO(2) during steady-state but not rebreathing HCVR.

The effect of upper airway structural changes on central chemosensitivity in obstructive sleep apnea-hypopnea.

We examined the efficiency of upper airway structural changes in uvulopalatopharyngoplasty and/or tonsillectomy on central chemosensitivity, and whether the outcome of such surgeries can be predicted by the central chemosensitivity in obstructive sleep apnea-hypopnea syndrome (OSAHS) patients. In 11 patients with OSAHS group, the average of the hypercapnic ventilatory response (HCVR) slope was 1.93 +/- 0.20 L/min/mm Hg preoperatively and 1.78 +/- 0.22 L/min/mm Hg postoperatively. The average of the mouth occlusion pressure at 0.1 second after the onset of inspiration (P (0.1)) slope was 0.47 +/- 0.06 cm H (2)O/mm Hg and 0.44 +/- 0.08 cm H (2)O/mm Hg, before and after surgery, respectively. There were no significant differences before and after treatment, although OSAHS was improved by these surgeries. In control group with 5 patients, the HCVR slope and P (0.1) slope also showed no significant difference before and after the procedure. When we divided the 11 OSAHS patients into 7 responders (apnea-hypopnea index < 20 events/h and > 50% reduction) and 4 poor responders, there was a significant difference between the average HCVR slope of responders (1.59 +/- 0.21 L/min/mm Hg) and that of poor responders (2.52 +/- 0.20 L/min/mm Hg). We saw no significant difference in physiologic (age, body mass index, one-piece tonsil weight), blood gas values, cephalometric, spirometric, or sleep parameters.

Explained and unexplained variability of CO2-sensitivity in humans.

When modeling the respiratory control system, it is useful to know the inherent noise in the variables of interest, such as the arterial PCO2 and the sensitivity of the hypercapnic ventilatory response (HCVR). These variables can be greatly affected by behavioral and environmental conditions including fluctuations in arousal level, emotion, cognitive activity, subject-experimenter interaction, light, noise and temperature. For instance, even when in an ostensible steady-state, merely opening one’s eyes results in systematic increases in breathing frequency, ventilation and HCVR slope (reviewed by Shea1). In addition, challenges to the respiratory control system (e.g., added loads, hypoxia or hypercapnia) can result in adaptation such that subsequent measurements are affected by prior measurements (e.g., Powell et al2). Furthermore there can be non-physiological variability that is intrinsic to the measurement technique itself (e.g., instability of sensors). Overall, influences from behaviors, arousal, the environment, adaptation and the measurement technique contribute to the ‘noise’ in the measured data.

The Effects of Large-Dose Flumazenil on Midazolam-Induced Ventilatory Depression

Flumazenil, a benzodiazepine antagonist, clearly reverses midazolam-induced sedation; reversal of ventilatory depression has not been as well demonstrated. Thirty-two subjects completed this randomized, double-blind, placebo-controlled study investigating the dose-response relationship and duration of flumazenil's effects on ventilatory depression and hypnosis induced by a continuous midazolam infusion. A computer-controlled infusion of midazolam was used to titrate the predicted midazolam plasma concentration to a level at which subjects were unresponsive to verbal commands and then to maintain that concentration. Measurements of ventilation and hypnosis were repeated at predetermined intervals: before midazolam administration, before test drug (flumazenil [1, 3, or 10 mg] or placebo), and 5, 30, 60, 120, and 180 min after test drug administration. Ventilation and tidal volume were measured during an isocapnic hyperoxia clamp at a PETCO2 of 46 mm Hg (VE46 and VT46, respectively). A pseudo-rebreathing technique was used to measure the hypercapnic ventilatory response (HCVR) slope and ventilation intercept at a PETCO2 of 58 mm Hg (VE58). Midazolam reduced VE46, VT46, and VE58, as well as hypnosis scores, in all test drug groups. The reduction in HCVR slope, however, was significant only when all 32 subjects were considered in aggregate. All three doses of flumazenil reversed hypnosis and also reversed the reduction in VE46 and VT46 within 5 min. The reduction in VE58, however, was reversed less consistently. Flumazenil's effect on VE46 and VT46 lasted at least 30 min after 1 mg and at least 60 min after 3 mg, paralleling the effect of these doses on hypnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory interaction after spinal anesthesia and sedation with midazolam.

The combined use of midazolam and spinal anesthesia is common in clinical practice. Despite the known potential for each to alter ventilation, the effect of their interaction has not been examined. Nineteen healthy volunteers were studied to assess the impact of intravenous midazolam (0.05 or 0.075 mg/kg), spinal anesthesia (T3-T8; mean level, T6), and their combination on resting ventilation and ventilatory responses to progressive hyperoxic hypercapnia. Resting ventilatory pattern was altered significantly by each condition. Midazolam caused a 29% decrease in resting tidal volume and a 24% decrease in mean inspiratory flow rate, while respiratory frequency increased by 14% and minute ventilation remained unchanged. By contrast, spinal anesthesia alone caused a 32% increase in tidal volume, a 24% increase in mean inspiratory flow rate, and a 13% increase in minute ventilation accompanied by a 14% decrease in respiratory frequency. The combination of midazolam and spinal anesthesia caused a significant decrease in minute ventilation (19%), tidal volume (28%), and mean inspiratory flow rate (27%), all of which were significantly more than the predicted sum of the individual interventions. Midazolam and spinal anesthesia each produced a significant decrease in hypercapnic ventilatory response slope, whereas their combination provoked no net change in hypercapnic ventilatory response slope. Interpretation of the hypercapnic ventilatory response data was complicated by shifts in the position of the ventilatory response curve, particularly under the spinal anesthesia condition. It is concluded that intravenous midazolam depresses resting ventilation, spinal anesthesia stimulates resting ventilation, and their combination has a modest synergistic effect of depressing resting ventilation.

Defining origin of positive slope in hypercapnic ventilatory response curve

The sensitivity to CO2 as a respiratory stimulant has traditionally been studied by exposing organisms to progressively increasing levels of inspired CO2 while measuring the corresponding increase in minute ventilation (V). Plots of V as a function of end-tidal CO2 concentration reveal a complex function with a "dogleg" shape. Only the positive slope of the V function is taken as an index of chemosensitivity, but the starting points for such analyses are often chosen arbitrarily. This paper examined the hypotheses that the range of CO2 concentrations over which V slopes are compared may be mathematically defined and that arbitrary choices of this analytic range may influence conclusions about the hypercapnic ventilatory response (HCVR). Three mathematical models attempted to define the origin of the positive slope for the HCVR curve using empirically derived data. The results revealed good agreement that the origin of the positive HCVR slope may be reliably defined by a point that joins the horizontal and positive slope of the HCVR curve. In addition to identifying the "joint-point" statistic, the results suggest that arbitrarily defining the range of CO2 values over which V is analyzed can be replaced by quantitative approaches for identifying the origin of the ventilatory response to hypercapnia.

Sensation and control of breathing: A dynamic model

A dynamic model of the CO2 respiratory control system is proposed, which can provide a qualitative basis for predicting breathing sensations. The discomfort index, which represents breathing sensations, is assumed to be composed of two sources: the arterial CO2 level and the respiratory motor command. The respiratory controller receives inhibitory neuromechanical and excitatory CO2 signals from the plant. The CO2 signal is enhanced by exercise stimuli. This dynamic multiplicative-type controller is used in simulations of key experiments: exercise and CO2 rebreathing with and without resistive loading. The dynamics of the discomfort index, the respiratory motor command, ventilation, and arterial CO2 concentration conform to the experimental data. The perceptual sensitivity to CO2 relative to respiratory effort is significantly correlated with the slope of hypercapnic ventilatory response. This result shows a clear linkage between ventilatory response and breathing sensations. Although it is shown that the automatic controller effectively minimizes the discomfort index for perturbations about an operating point under certain conditions, the discomfort index itself does not seem to be an underlying control principle of the proposed automatic controller model. Rather, breathing sensations may influence ventilatory responses by modifying the output of the automatic controller.

Ventilatory responses to hypercapnia and hypoxia in patients with eucapnic morbid obesity before and after weight loss

1. To examine the relationship between eucapnic morbid obesity and ventilatory responsiveness to chemical stimuli, we measured hypercapnic and hypoxic ventilatory responses in 29 patients (26 women, three men) before and 3-6 months after gastroplasty. No subject demonstrated resting awake hypercapnia and non suffered from sleep-disordered breathing. 2. Mean weight fell significantly (122.8 +/- 21.4 vs 102.2 +/- 22.8 kg, P less than 0.0001) and functional residual capacity rose slightly but significantly (1.94 +/- 0.58 vs 2.18 +/- 0.64 litres; P less than 0.05) after weight loss. 3. The hypercapnic ventilatory response slope fell significantly after weight loss (2.88 +/- 2.27 vs 2.24 +/- 1.06 litres min-1 mmHg-1, P less than 0.05) with a significant shift of the ventilatory response curve to the right. There were no statistically significant changes in the patterns of ventilatory response. 4. In addition, isocapnic hypoxic ventilatory response slopes, measured at two levels of carbon dioxide partial pressure, fell significantly after weight loss. These changes were accompanied by significant shifts of the ventilatory response curves to the left, such that, for a given oxygen saturation, mean ventilation was significantly lower in the less obese state. Similarly to hypercapnic responses, there were no statistically significant changes in ventilatory pattern despite the changes in overall ventilatory response. 5. We conclude that ventilatory responsiveness to chemical stimuli is increased in obese subjects who maintain adequate alveolar ventilation while awake.

夏期と冬期における炭酸ガス‐換気量応答曲線の比較

Ventilatory response to carbon dioxide in the summer and winter was measured on healthy 9 male subjects by means of CO2 rebreathing method; the subject rebreathed a gas mixture (about 7% CO2 in O2) of 6 liters for 4 min after the subjects rested in a sitting position for about 20 min. During rebreathing, CO2 concentration of expired air and tidal volume were determined continuously using an infrared CO2, analyzer and respirometer, respectively. The mean and standard deviations for the slope of the ventilatory response line in the summer and winter were 2.42i±0.75 and 2.45±1.03 1·min1'mmHg1. There were no significant differences in the slope of hypercapnic ventilatory response in the summer and winter. However, ventilation corresponding to alveolar CO2 pressure of 60mmHg calculated from regression equation of ventilatory response line were 35.2±15.6 in summer and 25.4±15.2 1·min1 in winter, the difference being significant.

The influence of body size on the ventilatory response to hypercapnia.

The slope of ventilatory response to hypercapnia at rest was determined in 77 healthy male students by means of the CO2 rebreathing method. It was found that the hypercapnic ventilatory response slope (S) was significantly lower in the lean group with BMI (body mass index) below 19 than that in the normal group, while there were no significant correlation between S and body weight or height. These results indicate that sensitivity of hypercapnia in the lean subjects differed from that of normal and overweight subjects.

Effect of short-term sleep loss on breathing.

Loss of sleep is common among patients with respiratory disorders. We studied ventilatory performance in 15 normal subjects to determine whether a single night of sleep loss would have any detectable effect on breathing. Spirometry and hypercapnic ventilatory response testing were performed daily for 3 consecutive days with no sleep permitted between testing on days 1 and 2. We found a small but significant decline in forced vital capacity and maximal voluntary ventilation and a 20% decrease in hypercapnic ventilatory response slope after sleep loss (P less than 0.05). We conclude that sleep loss results in a significant deterioration in ventilatory performance, which may be clinically important to patients with respiratory diseases.