Key words: hypercapnia; hypoxia; nasal continuous positive airway pressure; obstructive sleep apnea; ventilatory response

Transcription

1 Original Research SLEEP MEDICINE Effect of Treatment With Nasal Continuous Positive Airway Pressure on Ventilatory Response to Hypoxia and Hypercapnia in Patients With Sleep Apnea Syndrome* Lucia Spicuzza, MD, PhD, FCCP; Luciano Bernardi, MD; Rossella Balsamo, MD; Nicola Ciancio, MD; Riccardo Polosa, MD, PhD; and Giuseppe Di Maria, MD, FCCP Background: The increase in peripheral chemoreflex sensitivity in patients with obstructive sleep apnea (OSA) is associated with activation of autonomic nervous system and hemodynamic responses. Nasal CPAP (ncpap) is an effective treatment for OSA, but little is known on its effect on chemoreflex sensitivity. Objectives: To assess the effect of ncpap treatment or placebo (sham ncpap) on ventilatory control in patients with OSA. Setting: Sleep laboratory of Azienda Ospedaliera Garibaldi. Patients: Twenty-five patients with moderate-to-severe OSA. Design and measurements: Patients were randomly assigned to either therapeutic ncpap (use of optimal pressure, n 15) or sham ncpap (suboptimal pressure of 1 to 2 cm H 2 O, n 10) in a double-blind fashion and treated for 1 month. A rebreathing test to assess ventilatory response to normocapnic hypoxia and normoxic hypercapnia was performed at basal condition and after 1 month of treatment. Results: The use of therapeutic ncpap or sham ncpap did not affect daytime percentage of arterial oxygen saturation (SaO 2 %) or end-tidal PCO 2. The normocapnic hypoxic ventilatory response was reduced after 1 month of treatment with ncpap (the slope was L/min/SaO 2 % at basal condition and L/min/SaO 2 % after 1 month of treatment, p 0.008) [mean SD], but not in patients treated with sham ncpap (slope, L/min/SaO 2 % and L/min/SaO 2 % at basal condition and after 1 month, respectively). The normoxic hypercapnic ventilatory response remained unchanged after 1 month in both groups. No changes in ventilatory response to either hypoxia or hypercapnia were observed after a single night of ncpap treatment. Conclusion: The ventilatory response to hypoxia is reduced during regular treatment, but not after short-term treatment, with ncpap. Readjusted peripheral oxygen chemosensitivity during ncpap treatment may be a side effect of both reduced sympathetic activity and increased baroreflex activity, or a possible continuous positive airway pressure-related mechanism leading to a reduced activation of autonomic nervous system per se. (CHEST 2006; 130: ) Key words: hypercapnia; hypoxia; nasal continuous positive airway pressure; obstructive sleep apnea; ventilatory response Abbreviations: AHI apnea-hypopnea index; BMI body mass index; CPAP continuous positive airway pressure; ncpap nasal continuous positive airway pressure; NS not significant; OSA obstructive sleep apnea; Petco 2 end-tidal Pco 2 ;Sao 2 % percentage of arterial oxygen saturation 774 Original Research

2 Abnormalities in the chemoreflex ventilatory response have been shown to occur in patients with obstructive sleep apnea (OSA) and to interact with cardiovascular function, increasing the cardiovascular risk in these patients. 1 Studies 2,3 investigating peripheral chemoreflex responses have reported conflicting results showing an increased, decreased, or normal response. However, in most of these studies, results were affected by confounding factors such as the presence of hypertension and diabetes, which are present in a large number of patients with OSA and which are known to affect the ventilatory response. Narkiewicz et al 3 showed for the first time that in patients with OSA, peripheral chemoreflex sensitivity to hypoxia is increased in the absence of confounding factors. The increase in peripheral chemoreflex sensitivity was associated with a selective potentiation of autonomic and hemodynamic response. 3 Nasal continuous airway positive pressure (ncpap) is considered the first-choice treatment for patients with OSA, inducing a reduction in nocturnal respiratory events, symptoms, and cardiovascular morbidity. 4,5 Little is known about the effect of ncpap on ventilatory control in patients with sleep apnea. As ncpap is known to reduce autonomic activation and baroreflex activity, 6 it is possible that one of the mechanisms by which this impairment occurs is by affecting peripheral chemoreflex. The aim of this study was therefore to assess the effect of regular treatment with ncpap on ventilatory control in patients with sleep apnea. In order to do this, we assessed the normocapnic hypoxic and the hypercapnic normoxic chemoreflex response, at basal condition and after 1 month of treatment, in a group of patients with OSA treated with regular ncpap and in a group of patients treated with sham ncpap (suboptimal treatment pressure), all in the absence of confounding factors. *From Dipartimento di Medicina Interna e Medicina Specialistica (Drs. Spicuzza, Balsamo, Polosa, and Di Maria), Sezione di Malattie Respiratorie, Università di Catania, Catania; Unità Operativa di Clinica Pneumologica e Medicina Respiratoria del Sonno (Dr. Ciancio), Azienda Ospedaliera Garibaldi, Catania; and Dipartimento di Medicina Interna e Patologia (Dr. Bernardi), IRCCS S. Matteo, Università di Pavia, Pavia, Italy. None of the authors have any conflict of interest to disclose. Manuscript received November 30, 2005; revision accepted February 28, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Lucia Spicuzza, MD, Dipartimento di Medicina Interna e Medicina Specialistica, Sezione di Malattie Respiratorie, Via Passo Gravina 187, Catania, Italy; luciaspicuzza@tiscali.it DOI: /chest Study Subjects Materials and Methods We studied a total of 25 patients with moderate-to-severe OSA evaluated in our sleep laboratory (Table 1). None of the patients had received treatment for sleep apnea. Exclusion criteria included the presence of hypertension and/or other cardiovascular diseases, diabetes, thyroid disorders, chronic obstructive/restrictive lung diseases or chronic respiratory failure, and smoking habit. None of the patients had a history of drug/alcohol abuse or addiction. Study Protocol After the diagnosis of sleep apnea was made, a total of 15 patients were treated with ncpap for 1 month, after 1 night of ncpap titration in order to establish optimal treatment pressure, to abolish snoring and respiratory events. In the control group were included 10 patients who (after 1 night of ncpap titration) were treated with sham ncpap (subtherapeutic pressure, 1 to 2 cm H 2 O) for 1 month. All patients were informed that they were participating in a study and gave informed consent. The protocol study was double blind, as neither patients nor the staff in contact with them knew which group the patient was assigned. The patients were aware of the fact that the average waiting time for our local health system to provide them with their own ncpap device was, on average, 2 months, so they were not concerned about not being treated (if in the placebo group) for the month they were included in the study. Ventilatory response was assessed in basal condition and after 1 month (in the morning in each occasion) in both treated and untreated groups. In a subset of patients (n 6), the ventilatory response was measured after 1 single night of ncpap treatment with optimal pressure established in the titration night study. Compliance to and regular use of ncpap was assessed by using ventilators able to store each night data such as the number of hours with ncpap on, respiratory events, and mean pressure. In addition, patients were asked to keep a log to record the effective use of ncpap every night. The protocol was approved by the local ethics committee. Polysomnography Patients underwent overnight standard polysomnography performed in our sleep laboratory using a computerized system (CompuMedic S-Series Sleep System; CompuMedic; Abbotsford, Australia). Sleep stages were identified by EEG (C3/A2 and C4/A1), electrooculography, and bipolar submental electromyography; all recordings were obtained from surface electrodes. The staging was performed according to standard criteria. 7 Thoracic and abdominal excursions were detected by inductance plethysmography bands. Airflow was detected by a nasal-oral thermocouple, and percentage of arterial oxygen saturation (Sao 2 %) was determined using finger pulse oximetry. ECG was monitored from precordial leads. Obstructive apneas were defined as a complete cessation of airflow in the presence of rib cage and abdomen motion for at least 10 s, and hypopneas were defined as a 50% decrease of airflow, respectively, for at least 10 s associated with a decrease in Sao 2 % 4%. Central apneas were defined as the cessation of airflow and respiratory effort for at least 10 s. Apnea-hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of sleep. The diagnosis of sleep apnea was made when the AHI was 5 (mild when the AHI was 20, moderate when the AHI was 20 to 50, and severe when the AHI was 50). CHEST / 130 / 3/ SEPTEMBER,

3 Table 1 Demographic and Clinical Data of Patients* Variables Patients Treated With ncpap Patients Treated With Sham ncpap p Value Male/female gender, No. 12/3 8/2 Age, yr NS BMI, kg/m NS AHI, basal NS AHI, during ncpap Pao 2,mmHg NS Paco 2,mmHg NS FEV 1, % of predicted NS FVC, % of predicted NS Systolic BP, mm Hg NS Diastolic BP, mm Hg NS Heart rate, beats/min NS CPAP, cm H 2 O Hours of CPAP per night NS *Data are presented as mean SD unless otherwise indicated. Hypoxic and Hypercapnic Ventilatory Response Classic rebreathing tests in a closed circuit were performed at sea level at 21 C and 60% relative humidity. The subjects (who were asked to refrain from smoking and drinking caffeinated beverages for at least 2 h before the experiment) were seated and connected to a rebreathing circuit through a mouthpiece, similarly to previously described and validated works Briefly, rebreathing into a closed circuit causes a progressive reduction of inspired oxygen and increases in carbon dioxide, both of which stimulate ventilation. When the ventilatory response to hypoxia was to be assessed, end-tidal Pco 2 (Petco 2 ) was kept at a constant level by passing a portion of the expired air into a scrubbing circuit before returning it to the rebreathing bag. When ventilatory response to normoxic hypercapnia was assessed, exogenous O 2 was added to the rebreathing circuit in order to maintain the Sao 2 % at approximately 96%. Before each rebreathing test, the subjects breathed room air through the same mouthpiece in order to collect baseline data. In each condition, we continuously measured Petco 2 with a capnograph connected to the mouthpiece (COSMOplus; Novametrix; Wallingford, CT) and the Sao 2 % by pulse oximetry (model 3740; Ohmeda; Englewood, CO). The flow was continuously measured by a heated Fleisch pneumotachograph (Metabo; Epalinges, Switzerland), connected to a differential pressure transducer (RS part N ; RS Components; Corby, UK), connected in series in the expiratory part of the rebreathing circuit. Breathing rate, tidal volume, and minute ventilation relative to each breath were recognized, with their corresponding values of Sao 2 % and Petco 2. The chemoreflex sensitivity to hypoxia or hypercapnia was obtained from the slopes of the linear regression of minute ventilation vs Sao 2 %orpetco 2, respectively. Statistical Analysis Data are presented as mean SD. Statistical analysis was performed using a statistical package (Graphpad Prism; Graphpad; San Diego, CA). Differences between groups were analyzed using an unpaired t test or analysis of variance. Differences in variables within the same group were analyzed using a paired t test Results Demographic and functional data were similar in the two groups (body mass index [BMI] was 30 kg/m 2 in 8 of 15 patients treated and in 9 of 10 control subjects) and are shown in Table 1. Rebreathing maneuvers induced a significant increase (p 0.01) in minute ventilation to either a decrease in Sao 2 % or to an increase in Petco 2. The normocapnic hypoxic ventilatory response and the normoxic hypercapnic ventilatory response at basal conditions were similar in the treated and untreated groups (Table 2). Treatment with ncpap but not sham ncpap induced a significant reduction in AHI (from to ) and improvement of daytime and nighttime symptoms. The use of ncpap or sham ncpap did not affect daytime Sao 2 % or Petco 2, and no change was observed in BMI. The normocapnic hypoxic ventilatory response was significantly reduced after 1 month in patients treated with ncpap (the slope was L/min/ Sao 2 % at basal condition and L/min/ Sao 2 % after treatment, p 0.008) but not with sham ncpap (basal slope, L/min/Sao 2 %; after 1 month, L/min/Sao 2 %, p not significant [NS]) [p 0.01, analysis if variance; Table 2; Fig 1]. The normoxic hypercapnic ventilatory response remained unchanged after 1 month in both treated (the slope was L/min/mm Hg Petco 2 at basal condition and L/min/mm Hg Petco 2 after 1 month, p NS) and untreated patients (basal slope, L/min/mm Hg Petco 2 ; after 1 month, L/min/mm Hg Petco 2 ;p NS; Table 2). In a group of normal subjects (AHI 5, n 10) matched for BMI ( kg/m 2 ) and age ( years), the mean slope was L/min/Sao 2 % (range, 0.2 to 1.1 L/min/Sao 2 %). In order to assess a possible short-term effect of ncpap on ventilatory control, in a subset of patients the ventilatory response was assessed after a single night of treatment with ncpap at the optimal 776 Original Research

4 Table 2 Respiratory Data* Treatment With Effective ncpap Treatment With Sham ncpap Variables Basal After 1 mo p Value Basal After 1 mo p Value Normocapnic hypoxic ventilatory response Slope, L/min/Sao 2 % NS Sao 2 % Baseline NS NS End-rebreathing NS Petco 2,mmHg Baseline NS NS End-rebreathing NS NS Minute ventilation, L/min Baseline NS NS End-rebreathing NS Hypercapnic normoxic ventilatory response Slope, L/min/mm Hg Petco NS NS Sao 2 % Baseline NS NS End-rebreathing NS NS Petco 2,mmHg Baseline NS NS End-rebreathing NS NS Minute ventilation, L/min Baseline NS NS End-rebreathing NS NS *Data are presented as mean SD. NS vs basal slope of patients treated with ncpap. pressure. Although a single night of treatment significantly reduced AHI, no changes were observed in normocapnic hypoxic ventilatory response (the slope was L/min/Sao 2 % at basal condition and L/min/Sao 2 % after 1 night of treatment, p NS; n 6). Discussion In this study, we have shown that 1 month of regular treatment with ncpap reduces the ventilatory response to hypoxia but not to hypercapnia in patients with moderate-to-severe sleep apnea. To our knowledge, this is the first study controlled vs placebo (sham ncpap) and excluding patients with comorbidities. A first observation is that treatment with ncpap in OSA patients (all eucapnic) did not change basal minute ventilation, Sao 2 %, and Petco 2 ; thus, is clear that changes in chemoreflex sensitivity do not simply reflect changes in blood gases. In addition, we can rule out the confounding effect of comorbidities such as hypertension and diabetes, which are common in patients with sleep apnea and which are known to affect the ventilatory response. 11 We also ruled out the effect of cigarette smoking, which by itself increases chemoreflex sensitivity, and we observed no changes in BMI after 1 month, another potential cause of alteration in the Figure 1. Effect of 1 month of treatment with ncpap (left) or sham ncpap (right) on normocapnic hypoxic ventilatory response. VE minute ventilation. CHEST / 130 / 3/ SEPTEMBER,

5 ventilatory control. Although many studies assessing peripheral chemoreflex response in OSA have reported conflicting results, 12 the only study 3 controlling for confounding factors has shown that peripheral, but not central, chemoreflex sensitivity is increased in eucapnic patients with OSA. Our observation that a restoration of normal nocturnal respiratory conditions obtained with ncpap treatment reduces the peripheral, but not central chemoreflex sensitivity, is somehow in agreement with this previous study. 3 The mechanism underlying alteration of chemoreflex sensitivity to hypoxia and the recover after ncpap remains unclear. The most likely explanation is that episodes of intermittent hypoxia may alter or reset the sensitivity of the carotid body, and this is supported by a large body of evidence. Chronic exposure to intermittent hypoxia increases the chemosensory and ventilatory response to hypoxia in animals and in humans. 13 In addition, physiologic studies 14 have shown that acute intermittent hypoxia, but not sustained hypoxia, induces longterm augmentation of respiratory motor output. From animal models, it seems that the long-term facilitation is associated not only with episodic activation of chemoafferent neurons in the carotid sinus but is attributable also to the hypoxic effects on the CNS. 14 Moreover, it has been reported that in patients with OSA, the isocapnic hypoxic ventilatory response positively correlates with both the number of apneas and the lowest nocturnal Sao 2 %. 15 Therefore, it is conceivable that normalization of nocturnal levels of Pao 2 may result in recovery of carotid bodies sensitivity. Another possible mechanism is the effect of repetitive apneas on autonomic cardiovascular control. Sleep apnea is known to increase sympathetic nerve activity and to reduce arterial baroreflex sensitivity both during the day and the night. 1,16,17 A reciprocal influence exists between baroreflex and chemoreflex activity. In fact, arterial baroreflex activation in the human potently inhibits the sensitivity of peripheral but not central chemoreceptors, whereas chemoreceptor stimulation causes a significant increase in sympathetic activity (thus depression of vagal baroreflex response). 6,12 It is possible that the chronic reduction in baroreflex sensitivity observed in OSA patients may be linked with increased chemoreflex sensitivity. Therefore, treatment with nocturnal ncpap, known to decrease sympathetic activity 6 and increase baroreflex sensitivity, 18 may be associated with a decrease in chemoreflex sensitivity. Involvement of autonomic control on modulation of ventilatory response is further confirmed by the observation that in our study, hypercapnic ventilatory response was not affected by ncpap. In fact baroreflex activation in human is strongly correlated with peripheral but not central chemoreceptor activation. 19 The observation that treatment with ncpap did not affect the hypercapnic response is somehow expected. It has been reported that central chemoreflex activity is not altered in normocapnic patients with sleep apnea, 20 and treatment with ncpap may reset the ventilatory response in hypercapnic OSA (changes in the position, but not in the slope) without effect in eucapnic OSA. 21 Few previous studies have addressed the effect of continuous positive airway pressure (CPAP) on ventilatory response, with conflicting results. However none of these studies were controlled vs placebo, and none excluded confounding factors. Compatible with our data, Tun et al 22 showed that the ventilatory response to hypoxia decreased from 0.8 to 0.6 L/min/ Sao 2 % after 2 weeks of CPAP; however, the depression was accompanied by a decrease in basal level of Paco 2, and this might itself decrease the response to hypoxia. 19 Lin 23 found that CPAP increased the ventilatory response to hypoxia in hypercapnic patients with OSA but not in eucapnic patients. From our study, is clear that changes in chemoreflex activity do not occur acutely, after a single night of sleep with ncpap, even in the absence of respiratory events and normal gas exchange. Therefore, if ncpap-induced changes in chemoreflex control represent an adaptive response to the disappearance of nocturnal respiratory events, (without effect of CPAP per se), it is clear that this process needs a longer time to occur, from 2 weeks 22 to 1 month as shown by our study. Strengths of our study include that patients were not affected by comorbidities that may alter, per se, chemoreflex response, and that results were controlled vs placebo in identical experimental conditions. Furthermore, all cases were newly diagnosed and the patients were never treated before. A limitation of the study is that we did not measure P 0.1 to assess neural drive. Indeed, the effect of ncpap on the ventilatory response to hypoxia may help explain some clinical beneficial effects of this ventilatory treatment. In fact, reduction of sympathetic activity and improvement in baroreflex response is an important mechanism by which CPAP treatment reduces cardiovascular risk. Therefore, considering that the inverse correlation between chemoreflex and baroreflex activity is now well acquired, one possible mechanism by which CPAP may reduce cardiovascular risk is modulation of peripheral chemoreflex sensitivity. Readjusted peripheral oxygen chemosensitivity during ncpap treatment may be either a side effect of both reduced sympathetic activity and increased baroreflex 778 Original Research

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