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* From the Pneumology (Drs. Delguste and Rodenstein) and EEG (Dr. Aubert and Mrs. Dury) Units, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium; Pneumology Unit (Dr. Jounieaux), Center Hospitalier Universitaire Sud, Amiens, France; and University Federal of Minas Gerais (Mrs. Parreira), Belo Horizonte, Brazil.
Correspondence to: Daniel O. Rodenstein, MD, PhD, Service de Pneumologie, Cliniques Universitaires Saint Luc, Avenue Hippocrate, 10, B-1200 Bruxelles, Belgique; e-mail: rodenstein{at}pneu.ucl.ac.be
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Abstract |
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Methods: We studied four healthy subjects during intermittent positive-pressure ventilation delivered through a nasal mask (nIPPV). Delivered minute ventilation (
Ed) was progressively increased to lower end-tidal carbon dioxide pressure (PETCO2) below the apneic threshold. Then, at different hypocapnic levels, nitrogen was added to induce falls in oxygen saturation, a hypoxic run (N2 run). For each N2 run, the reappearance of a diaphragmatic muscle activity and/or an increase in effective minute ventilation (E) and/or deformations in mask-pressure tracings were considered as a VRH, whereas unchanged tracings signified absence of a VRH. For the N2 runs eliciting a VRH, the threshold response to hypoxia (TRh) was defined as the transcutaneous oxygen saturation level that corresponds to the beginning of the ventilatory changes.
Results: Thirty-seven N2 runs were performed (7 N2 runs during wakefulness and 30 N2 runs during sleep). For severe hypocapnia (PETCO2 of 27.1 ± 5.2 mm Hg), no VRH was noted, whereas a VRH was observed for N2 runs performed at significantly higher PETCO2 levels (PETCO2 of 34.0 ± 2.1 mm Hg, p < 0.001). Deep oxygen desaturation (up to 64%) never elicited a VRH when the PETCO2 level was < 29.3 mm Hg, which was considered the carbon dioxide inhibition threshold. For the 16 N2 runs inducing a VRH, no correlations were found between PETCO2 and TRh and between TRh and both Ed and E.
Conclusion: During nIPPV, VRH is highly dependent on the carbon dioxide level and can be definitely abolished for severe hypocapnia.
Key Words: hypocapnia • hypoxia • noninvasive ventilation • ventilatory response
In 1990, our group reported recurrent episodes of desaturation occurring during sleep in patients undergoing intermittent positive-pressure ventilation delivered through a nasal mask (nIPPV).1 Because we have previously shown that nIPPV results in glottic narrowing in normal awake or asleep subjects, we do believe that these desaturations were probably due to complete glottic closure.2 3 These glottic apneas occurred during periods with absence of spontaneous diaphragmatic electromyogram activity (EMGDI) related to hypocapnic ventilatory inhibition.4 Indeed, in those observations,1 all patients were hyperventilated and severely hypocapnic with a carbon dioxide level far below the apneic threshold: transcutaneous PCO2 < 24 mm Hg. Glottic closure could last for up to 1 min, preventing delivered tidal volumes (VTs) insufflated through the nasal mask to reach the lungs. These glottic apneas resulted in deep falls in oxyhemoglobin saturation that, surprisingly, did not induced any reappearance of inspiratory muscle activity, even for extremely low transcutaneous oxygen saturation (SaO2) levels, as low as 60%.
Both hypoxia and hypercapnia are known to be potent stimuli of the ventilatory drive. Hypoxia increases minute ventilation (E) by stimulating the carotid body chemoreceptors, whereas carbon dioxide increases E mainly by stimulating the brainstem chemoreceptors. Hypercapnia also increases the ventilatory drive through stimulation of the peripheral chemoreceptors, and as much as 40% of the increase is a result of carotid-body stimulation.5
In animals, under hypoxic conditions, Fitzgerald and Lahiri6
have shown that the increased neural activity from the carotid body can be reduced dramatically, and sometimes virtually abolished, if hyperventilation results in severe hypocapnia, < 15 mm Hg. Thus, from our previous observations gathered in patients receiving nIPPV,1
we hypothesized that the ventilatory response to hypoxia (VRH) can be definitely abolished in humans by extreme hypocapnia. As it is now possible to provide noninvasive ventilation with nIPPV, we undertook this study in awake and asleep normal humans receiving noninvasive mechanical ventilation to evaluate their VRH at different hypocapnic levels below the apneic threshold.
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Materials and Methods |
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E due to an increase in VT and a decrease in the total duration of each breath (ie, an increase in respiratory frequency). The situation is different in a subject receiving passive mechanical ventilation with a noninvasive mode (ie, with his carbon dioxide level below the apneic threshold resulting in a silent EMGDI). When using volumetric ventilators in the controlled mode, both frequency and delivered VT (VTd) are fixed but the effective VT reaching the lungs and thus effective E are not at all fixed. This depends on several reasons: part of the VTd may leak back to the atmosphere through the mouth or between the mask and the skin, part of the VTd may leak to the stomach, and part of VTd may remain in the compliant pharyngeal airway. Finally, part of the VTd will reach the lungs, constituting the effective VT. The main determinant of the proportion of the VTd reaching the lungs is the glottic width.2
3
Thus, when using volumetric ventilators in the controlled mode, frequency and VTd are fixed, but the proportion of the VTd reaching the lungs is not necessarily fixed. If the glottic width remains stable, then effective VT (and effective E) will be stable. But if the glottic width changes, effective VT will be accordingly modified (increase with glottic widening and decrease with glottic narrowing). During hypoxia, either there is no response (ie, effective ventilation and mask-pressure curve tracings remain stable without any reappearance of phasic inspiratory muscle activity on EMGDI), or a ventilatory response will be seen in response to hypoxia. In this case, the reappearance of spontaneous respiratory muscle activity, which will per se activate glottic abductors, leads to glottic widening and increases in effective VT (despite the fact that the VTd is constant) with concomitant deformation of the mask-pressure curve, as previously shown.7
Population
Normal subjects were studied during nIPPV while their diaphragmatic muscle activity was continuously monitored through surface electromyography (EMG). The protocol of the study had been approved by the ethical committee of our hospital. Four healthy medical students (two women and two men) volunteered for the study. Their anthropometric characteristics are given in Table 1
. All gave written informed consent and received financial remuneration for their participation in the study. All subjects were without evidence of chronic cardiorespiratory disease, did not receive any medications, and all but one were nonsmokers. One female subject received an oral contraceptive pill, and the other female subject was in the luteal phase of the menstrual cycle. They were habituated to mechanical ventilation during two previous training sessions (3-h each), where they learned to relax their respiratory muscles.8
The subjects were aware that they would be submitted to hypoxia, but no detailed explanation of the aim of the study or of the expected response to hypoxia had been given to them.
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SaO2 and pulse rate were recorded by pulse oximetry (Nellcor N-100; Nellcor; Hayward, CA) using a finger probe. End-tidal carbon dioxide pressure (PETCO2) was measured from carbon dioxide recordings made with a small catheter passing through a small, plastic, hollow conical piece (Nasal Adapter Set; Datex; Helsinski, Finland) introduced in the right nare, so that the nare was kept open and the extremity of the catheter remained in the center of the airstream. The catheter was passed through a sealed orifice on the nasal mask and connected to the Normocap 200 (Datex), a carbon dioxide analyzer apparatus that draws a continuous gas sample from the subject’s airway. The pulse oximeter and carbon dioxide analyzer were calibrated with the incorporated internal calibrations modes or these devices. Pulse rate, SaO2, carbon dioxide, mask pressure, and rib cage and abdominal movements with their sum were recorded simultaneously on a second polygraph (electrostatic recorder Gould ES 1000; Gould Instruments S.A.F.; Ballainvilliers, France) at a paper speed of 5 mm/s. The Gould recorder lacked an internal clock, but two signals (mask pressure and VT) were displayed simultaneously on the two ink recorders for synchronization.
Procedure
Each subject was asked to sleep a maximum of 4 h during the night preceding the study. The subjects lay comfortably in bed with pillows on each side, securing a fixed position and avoiding any shift of the body during the night. Electrodes, the plethysmograph, and the finger sensor of the oximeter were then applied. Before setting the nasal mask (Nasal CPAP mask; Respironics; Monroeville, PA) over the nose, the carbon dioxide sampling device was introduced into the nostril. nIPPV was then started. Recordings were started 30 min after the beginning of nIPPV. Mechanical ventilation was delivered by volume respirators through the nasal mask. The accuracy of the delivered volume had been checked with a water-sealed spirometer. Subjects were started on controlled ventilation with a delivered E (Ed) of approximately 9 L/min. When subjects were asleep, Ed was progressively increased in order to abolish any spontaneous respiratory muscle activity. This was assessed from absence of phasic inspiratory activity on EMGDI, stability in mask pressure, and VT curves. Then, hyperventilation was obtained by increasing first the VTd up to a maximum of 1,200 mL, and then by increasing progressively the respirator frequency up to a maximum of 30 cycles per minute. The maximal ventilation delivered was never > 25 L/min. Progressive increases in Ed resulted in progressive decreases in PETCO2. Once a steady state of PETCO2 was achieved, nitrogen was added to the admission filter of the respirator to decrease the fraction of inspired oxygen without changing the Ed. Nitrogen was added until SaO2 reached 70% or an arousal occurred; this corresponded to a hypoxic run (N2 run). A new N2 run was not performed until returning to a stable state that allowed a new change in Ed and a new level of stable PETCO2.
Data Analysis
Vigilance status was scored according to standard criteria9
but using 60-s epochs. Movement arousal was defined as the abrupt appearance of an 
rhythm in the EEG during a sleep epoch, accompanied by an increase in submental chin EMG activity lasting for a least 2 s.10
Only the N2 runs preceded by at least 1 min of stable wakefulness or sleep state and stable ventilation with absence of EMGDI activity were considered for analysis. For each N2 run retained for analysis, all the breaths were analyzed from the beginning to the end of nitrogen admission. For each measured breath, the corresponding values for effective VT, SaO2 and PETCO2 were measured breath by breath, by hand, from the paper recordings of the Gould recorder. Effective VT corresponds to the volume measured from the sum signal of the plethysmograph records, and therefore corresponds to the volume effectively reaching the lungs, and not to the volume delivered by the respirator through the nasal mask (VTd). The VTd and the Ed were computed from the values noted from the respirator display. For each N2 run, the reappearance of a diaphragmatic muscle activity and/or an increase in effective E and/or deformations in mask-pressure tracings were considered as a VRH, whereas unchanged tracings signified absence of a VRH. The threshold response to hypoxia (TRh) was defined as the SaO2 level at which there was evidence of a VRH. For each N2 run, the lowest SaO2 that was reached (nadir SaO2) was evaluated.
Statistical Analysis
Data are presented as the mean ± SD. All volumes are expressed in body temperature and pressure saturation conditions. Nadir SaO2 and PETCO2 were compared between N2 runs that induced or did not induce a VRH by using the unpaired Student’s t test. Relationships between TRh and PETCO2 were tested using linear regression analysis for all N2 runs inducing a VRH. Relationships between TRh and Ed or E were also tested for all for N2 runs that induced a VRH by using linear regression analysis. A p value 
0.05 was considered to be significant.
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70% (Table 2
, Fig 2
). No difference in nadir SaO2 was found between the N2 trials that induced (n = 16) or did not induce (n = 21) a VRH (77.8 ± 5.7% vs 80.1 ± 6.3%, respectively; not significant).
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Ed given by the settings of the ventilator and the E that effectively reached the lung (E calculated from the plethysmograph records) on the TRh, for the N2 runs inducing a VRH. No relationships were found between TRh and, respectively, Ed and E. |
Discussion |
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VRH has never been previously studied during steady-state hypocapnic conditions below the apneic threshold. Because mechanical ventilation delivered through a nasal access allows patients to be noninvasively hyperventilated, we decided to test the ventilatory response to progressive hypoxia at different hypocapnic levels below the apneic threshold.4 11 12 In such situations, our data show that VRH can be abolished even for deep SaO2 falls, both during wakefulness and sleep (Table 2) . In our study, the value of PETCO2 below which it was impossible to induce a VRH during wakefulness (4 of 7 trials) or during sleep (17 of 30 trials) was 29.3 mm Hg (Fig 3) . This PETCO2 level corresponded in our study to the carbon dioxide inhibition threshold, which is lower than (and should be distinguished by definition from) the apneic threshold as described by Prechter et al.4 Indeed, all the N2 runs were performed in our study at a PETCO2 below the apneic threshold (passive hyperventilation with nIPPV). A 1999 study13 published only in abstract form, and using a very different methodology, found a very similar threshold for the disappearance of the VRH: 29 mm Hg. In our study, the carbon dioxide inhibition threshold was not the same for each subject; the respective levels were 34.1, 30.5, 29.3, and 33.8 mm Hg in subjects 1 to 4 (Table 2) . Indeed, due to definitions of the VRH that we used in this study, undetectable responses such as central activation (increase in tonic activity of respiratory muscles14 or activation of the peripheral chemoreceptors) cannot be ruled out in the N2 runs performed below 29.3 mm Hg PETCO2. Whereas we do not pretend to have excluded all neural responses in the N2 runs without any detectable VRH, the main point is that there is a carbon dioxide level below which no muscular response to hypoxia can be detected, irrespective of whether this is due to absence of neural activation in response to hypoxia, or to neural activation in conditions of too-low overall levels of excitation to result in spontaneous breathing.
Moreover, it is possible that the carbon dioxide inhibition threshold is different (within each subject) in wakefulness and in sleep. Previous data in animals15 and humans16 17 show that the slope of the VRH may change from wakefulness to sleep, although not all studies give the same results in animals18 or humans.18 19 20 21 Thus, as the slope of the VRH, the carbon dioxide inhibition threshold could also vary from wakefulness to sleep (and even within different sleep stages). In our study, we do not have enough data to compare the carbon dioxide inhibition threshold during wakefulness and during sleep for similar hypoxic levels in each subject, so that this point remains to be studied.
In 13 of the 16 N2 runs that resulted in a VRH, increases in VT and deformations of the mask-pressure tracings were accompanied by reappearance of inspiratory diaphragmatic muscle activity on surface EMGDI. In the three remaining N2 runs, increases in VT with deformations in mask-pressure waveforms were observed without any diaphragmatic muscle activation or triggered breaths. Such results may result from inaccurate assessment of signals; the absence of EMGDI activity could be related to the rather low-quality signal sensitivity of the surface EMGDI, and the absence of triggered breaths could be due to inspiratory muscle activity that is present during the mechanically delivered breath, but was either not present prior to the breath or was insufficient to trigger the breath. Another explanation could be an isolated glottic opening in response to hypoxia that results in an increase in effective VT. According to our previous observations,7 which reported similar tracings during nIPPV when using an esophageal bipolar electrode (to record accurately the EMG activity of the diaphragmatic muscle), we do believe that these increases in effective VT without any diaphragmatic muscle activation could be related to isolated glottic widening and be assimilated to a VRH. However, because we did not record the glottic width and the diaphragmatic muscle activity with an invasive method, this point remains to be confirmed.
As previous studies have demonstrated a neuromechanical inhibition of inspiratory motor output during normocapnic passive mechanical ventilation in awake22
and sleeping subjects,11
23
the inhibition threshold could depend not only on the carbon dioxide level but also on mechanical influences. In this study, we did not add carbon dioxide to the admission filter of the ventilator to test its direct influence on the inhibition threshold for a similar effective ventilation and a similar level of hypoxia. Indeed, in order to test the respective influences of neuromechanical inhibition and of chemical inhibition, one should test the subjects at a given mechanical condition and different carbon dioxide levels. However, at increasing carbon dioxide levels, it is not possible to maintain a fixed neuromechanical coupling during nIPPV, even if the parameters of the ventilator are left unchanged. In such situation, we have previously shown that the actual VT volume and effective E will change due to glottic widening despite fixed VTd and Ed.2
3
Therefore, this type of experiment would not allow separation of neuromechanical from chemical inhibition when using noninvasive ventilation. It seems obvious that in order to lower PETCO2, one has to increase effective ventilation, so that lower chemical stimuli (carbon dioxide) will be associated with higher mechanical stimuli (effective ventilation), both of which could inhibit the VRH. Although this was true in our study for subjects 1, 2, and 4, subject 3 showed a different pattern: on N2 run 11, the effective ventilation was 7.42 L/min, the PETCO2 was 29.2 mm Hg, and no VRH was recorded. On N2 run 32, the effective ventilation was much higher (13.55 L/min) for a similar level of PETCO2 (29.3 mm Hg), and a VRH was elicited (Table 2)
. Thus, we had a response despite a higher level of mechanical inhibition for a similar chemical stimuli. However, this is not a sufficient proof that the mechanical inhibition can be ruled out as associated with the chemical inhibition, since the subject was not in the same state of vigilance on the two occasions. Another way of tackling this problem is to consider whether the VRH can be abolished not only by a carbon dioxide threshold but by a E threshold. We were not able to find for effective E a clear-cut threshold below where no VRH could be elicited as we did for PETCO2. This suggests, without proving it, that the VRH seems to be mainly determined by chemical rather than by mechanical influences.
We conclude that in normal subjects receiving passive hyperventilation with nIPPV below the apneic threshold, the VRH depends mainly on the PETCO2 levels and can be definitely abolished by severe hypocapnia (carbon dioxide inhibition threshold of 29.3 mm Hg). We suggest that the VRH depends mainly on the carbon dioxide level when the latter is passively lowered below the apneic threshold down to the carbon dioxide inhibition threshold.
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Footnotes |
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Ed = delivered minute ventilation; E = minute ventilation; VRH = ventilatory response to hypoxia; VT = tidal volume; VTd = delivered tidal volume Partly supported by grants 9.4547.93 and 3.4533.98 from the Belgian Fonds de la Recherche Scientifique Médicale.
Received for publication September 19, 2000. Accepted for publication September 24, 2001.
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  V. Jounieaux, D. Rodenstein, M. Younes, and S. Corne Acknowledging Previous Work Is Part of Scientific Process Am. J. Respir. Crit. Care Med., May 1, 2004; 169(9): 1071 - 1072. [Full Text]
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