Effect of Ventilatory Drive on Carbon Dioxide Sensitivity below

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					Effect of Ventilatory Drive on Carbon Dioxide Sensitivity
below Eupnea during Sleep
Hideaki Nakayama, Curtis A. Smith, Joshua R. Rodman, James B. Skatrud, and Jerome A. Dempsey
The John Rankin Laboratory of Pulmonary Medicine, Departments of Population Health Sciences and Medicine, University of Wisconsin School of
Medicine; and Middleton Memorial Veterans Hospital, Madison, Wisconsin



We determined the effects of changing ventilatory stimuli on the                          ure (CHF) (10–13) tended to coincide with relatively high degrees
hypocapnia-induced apneic and hypopneic thresholds in sleeping                            of ventilatory responsiveness to hypoxia and/or CO2. Third, the
dogs. End-tidal carbon dioxide pressure (PETCO2) was gradually re-                        occurrence of CSR with central apnea in CHF patients was
duced during non–rapid eye movement sleep by increasing tidal                             shown to correlate positively with the level of hypocapnia during
volume with pressure support mechanical ventilation, causing a                            eupneic breathing in wakefulness and/or sleep (6, 8, 14, 15).
reduction in diaphragm electromyogram amplitude until apnea/                              Finally, raising PaCO2 via augmented fraction of inspired CO2
periodic breathing occurred. We used the reduction in PETCO2 be-                          (FICO2) alleviates apnea and periodic breathing in healthy sub-
low spontaneous breathing required to produce apnea ( PETCO2)
                                                                                          jects sleeping in hypoxia (16), in patients with CHF and with CSR
as an index of the susceptibility to apnea. PETCO2 was 5 mm Hg
                                                                                          (5, 17–19), and in central apnea syndrome (20, 21).
in control animals and changed in proportion to background venti-
                                                                                              Paradoxically, driving ventilation higher and reducing steady-
latory drive, increasing with metabolic acidosis ( 6.7 mm Hg) and
nonhypoxic peripheral chemoreceptor stimulation (almitrine; 5.9
                                                                                          state background PaCO2 can also alleviate central apnea and/or
mm Hg) and decreasing with metabolic alkalosis ( 3.7 mm Hg). Hy-                          periodic breathing during sleep. For example, acetazolamide
poxia was the exception; PETCO2 narrowed ( 4.1 mm Hg) despite                             administration causes metabolic acidosis and hyperventila-
the accompanying hyperventilation. Thus, hyperventilation and                             tion, and this reduces the amount of periodic breathing during
hypocapnia, per se, widened the PETCO2 thereby protecting                                 sleep in hypoxia (22). The magnitude of hypoxia-induced peri-
against apnea and hypopnea, whereas reduced ventilatory drive                             odic breathing is also reduced over the time course of acclima-
and hypoventilation narrowed the PETCO2 and increased the sus-                            tization to hypoxia as eupneic ventilation increases, and PaCO2
ceptibility to apnea. Hypoxia sensitized the ventilatory responsive-                      falls further with time (16, 23, 24). Similarly, theophylline or
ness to CO2 below eupnea and narrowed the PETCO2; this effect of                          acetazolamide administration to CHF patients with CSR or
hypoxia was not attributable to an imbalance between peripheral                           central apnea alleviates much of the patients’ apnea and peri-
and central chemoreceptor stimulation, per se. We conclude that                           odicity even in the face of further reductions in spontaneous
the PETCO2 and the ventilatory sensitivity to CO2 between eupnea                          background PaCO2 (25–27). Finally, patients with interstitial
and the apneic threshold are changeable in the face of variations                         lung disease do not show an increased prevalence of sleep ap-
in the magnitude, direction, and/or type of ventilatory stimulus,                         nea despite the presence of chronic hyperventilation (28).
thereby altering the susceptibility for apnea, hypopnea, and peri-                            Clearly, the compatibility of these two sets of observations
odic breathing in sleep.                                                                  would require that the apneic PCO2 threshold change in re-
Keywords: sleep apnea; chemoreceptors; hyperventilation; hypoventi-
                                                                                          sponse to sustained hyperventilation. Furthermore, given the
lation; apneic/hypopneic thresholds                                                       varying susceptibility to apnea and periodic breathing experi-
                                                                                          enced with the various types of ventilatory stimuli, it would
There is considerable evidence that hypocapnia is a major con-                            appear that not all types of stimuli affect the threshold in a
tributor to the genesis of central apnea and periodic breathing                           similar way. To date, only limited findings are available on this
during sleep in humans. First, studies using mechanical ven-                              question of a changing apneic threshold. Older studies used an
tilation to lower PaCO2 reveal that non–rapid eye movement                                extrapolation of the hypercapnic ventilatory response to zero
                                                                                           ·
(NREM) sleep unmasks a highly sensitive apneic threshold in-                              V E intercept to estimate the apneic threshold; but these ex-
duced by reductions in arterial carbon dioxide pressure (PaCO2)                           trapolations are highly uncertain because of the unknown shape
that were only 2–4 mm Hg less than eupneic PaCO2 (1–4). Second,                           of the CO2 response near and below eupnea (29, 30). Mechan-
the occurrence of central apneas in patients with Cheyne–Stokes                           ical ventilation may be used to lower PaCO2 and provide a di-
respiration (CSR) was shown to be preceded by transient hyper-                            rect measure of the hypocapnia-induced apneic threshold
pnea and hypocapnia (5–8); and in healthy subjects sleeping in                            (2, 4). Using variations of this technique in anesthetized rats,
hypoxia the apneic periods during periodic breathing coincided                            acute CO2 inhalation was shown to raise both eupneic and ap-
with reductions in end-tidal carbon dioxide pressure (PETCO2),                            neic threshold PCO2 and to increase the difference between
which approximated the subjects’ independently determined ap-                             them (31); and in sleeping healthy humans, mild hypoxia caused
neic threshold for PCO2 (1). In addition, the susceptibility to peri-                     a slight hyperventilation and a narrowing of the difference be-
odic breathing in hypoxia (9) or to CSR in congestive heart fail-                         tween eupneic PETCO2 and the apneic threshold PETCO2 (32).
                                                                                              We examined the effects of several types of stimuli and in-
                                                                                          hibitors to respiratory motor output on the apneic threshold,
                                                                                          using a mechanical ventilator in the pressure support mode to
( Received in original form October 10, 2001; accepted in final form February 1, 2002 )   increase VT, reduce PaCO2, and cause hypopnea and eventually
This research was supported by grants from the NHLBI and Veterans Administra-             apnea and periodic breathing in a chronically instrumented,
tion Merit Review.                                                                        sleeping dog model. We used the difference in PETCO2 between
Correspondence and requests for reprints should be addressed to Dr. J. A. Demp-           the prevailing spontaneous eupneic PETCO2 and the apneic (or
sey, The John Rankin Laboratory of Pulmonary Medicine, 504 North Walnut                   hypopneic) threshold PETCO2 (i.e., PETCO2          PCO2 at apneic
Street, Madison, WI 53705. E-mail: jdempsey@facstaff.wisc.edu
                                                                                          (or hypopneic) threshold         PCO2 spontaneous breathing) as
Am J Respir Crit Care Med Vol 165. pp 1251–1259, 2002
DOI: 10.1164/rccm.2110041                                                                 an index of the susceptibility to apnea (or hypopnea). This in-
Internet address: www.atsjournals.org                                                     dex is useful in determining the susceptibility to apnea be-
1252                                                      AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE                 VOL 165    2002


cause a small PCO2 means that one is breathing very close to                 Use of PSV to Define the Apneic and Hypopneic Thresholds
the apneic threshold and further transient increases in ventila-             Dogs breathed room air spontaneously through the open port in the
tion would cause apnea, whereas a large PETCO2 means one is                  balloon valve (see EXPERIMENTAL SETUP AND MEASUREMENTS). The me-
further from their apneic threshold during spontaneous eupnea                chanical ventilator (Veolar, Hamilton Medical) was set in the pres-
and thus less susceptible to hypocapnic inhibition.                          sure support mode and the trigger sensitivity was set as low as possible
                                                                             ( 1.5 cm H2O). When the balloon was inflated and the low resistance
                                                                             shunt to the room sealed, the ventilator delivered preset levels of in-
METHODS                                                                      spiratory pressure support whenever the trigger threshold was reached
Studies were performed on six unanesthetized female mixed-breed              (i.e., a dog set its own frequency; increased pressure support resulted
dogs (20–25 kg) during NREM sleep. The dogs were trained to sleep            in increased VT). The expiratory positive airway pressure was set at
in an air-conditioned (19–22 C) sound-attenuated chamber. Throughout         0 cm H2O. Each pressure support level was maintained for 2 minutes
all experiments, the dogs’ behavior was monitored by an investigator         and then the balloon was deflated and the dog was allowed to breathe
seated within the chamber and also by closed-circuit television. The         spontaneously again. At least 2 minutes elapsed before another PSV
Animal Care and Use Committee of the University of Wisconsin ap-             trial was performed. PSV was increased in steps of 1–2 cm H2O (range
proved the surgical and experimental protocols for this study.               3–35 cm H2O depending on conditions) until apneas and periodic
                                                                             breathing were observed. TE was measured from the end of the in-
Chronic Instrumentation                                                      spiratory flow to the onset of the next EMGdi burst. Periodic breath-
                                                                             ing was identified visually by the presence of at least three cycles of
Our preparation required two surgical procedures performed under
                                                                             hyperpnea and apnea as judged by EMGdi with a consistent periodic-
general anesthesia with strict sterile surgical techniques and appropri-
                                                                             ity (see RESULTS). Further, the apnea lengths had to be at least three
ate postoperative analgesics and antibiotics. In the first procedure, a
                                                                             standard deviations greater than the baseline TE. The apneic thresh-
chronic tracheostomy was created; diaphragm EMG electrodes and a
                                                                             old was taken to be the PETCO2 observed in the breath immediately
5-lead EEG montage were also installed. After at least 3 weeks’ re-
                                                                             preceding the start of periodic breathing. Once apneas were observed,
covery, a second procedure was required to install indwelling cathe-
                                                                             PSV trials were repeated within 1–2 cm H2O PSV and the mean of
ters in the abdominal aorta and abdominal vena cava. Catheters and
                                                                             these three to five periodic breathing trials taken as the apneic thresh-
electrode wires were tunneled subcutaneously to the cephalad portion
                                                                             old PETCO2 for that animal in the specific condition under study.
of the dog’s back where they were exteriorized. This chronically in-
                                                                                 A hypopneic threshold was determined from PSV trials in which
strumented model is described in detail elsewhere (33).
                                                                             periodic breathing did not occur. Hypopnea was defined as a reduc-
                                                                             tion in the mean electrical activity (MEA) of the diaphragm EMG
Experimental Setup and Measurements                                          greater than two standard deviations from the mean MEA obtained
The dogs breathed via a cuffed endotracheal tube (10.0 mm outer di-          during baseline eupnea of a given trial. The hypopneic threshold was
ameter; Shiley, Irvine, CA), which was inserted into the chronic tra-        taken to be the PETCO2 observed in the breath immediately preceding
cheostomy. Airflow was measured via a heated pneumotachograph                the start of a hypopneic breath. For each dog, each of the five experi-
system (model 3700; Hans Rudolph, Kansas City, MO, and model                 mental conditions (see below) provided an average of 32 (range 11–
MP-45-14-871; Validyne, Northridge, CA) connected to the endotra-            41) inspiratory efforts that reached a hypopneic threshold within the
cheal tube. The pneumotachograph was calibrated before each study            2-minute observation period. The mean PETCO2 associated with the re-
with four known flows. Tracheal pressure (Ptr) was measured at a             duced EMGdi was used to represent the hypopneic threshold in that
port in the endotracheal tube that was connected to a pressure trans-        animal for that condition. Some trials at low levels of pressure support
ducer (model MP-45-14-871; Validyne) by means of 1.7 mm inner di-            never achieved a hypopneic threshold. Trials in which there was a
ameter high durometer PVC tubing (Abbott Laboratories, North Chi-            state change or sigh were excluded from analysis.
cago, IL). The pressure transducer was calibrated before each study
by applying six known pressures. Airway PO2 and PCO2 were moni-              Changing Background Ventilatory Drive
tored by a mass spectrometer (model MGA-1100; Perkin-Elmer, Nor-             Acetazolamide. Acetazolamide (31.3–62.5 mg) was given orally 5
walk, CT) through a second port in the endotracheal tube. Three to           hours before the study. A stable metabolic acidosis and hyperventila-
six 1-ml arterial samples were obtained at the start of each experiment      tion (pHa 7.34; PaCO2 30 mm Hg) was achieved for the duration
from the aortic catheter and analyzed for pH, PO2, and PCO2 on a             of the PSV trials (2–2.5 hours).
blood-gas analyzer (model ABL-505; Radiometer, Copenhagen, Den-                  Sodium bicarbonate. NaHCO3 solution was infused through the
mark). The blood-gas analyzer was validated daily with dog blood             indwelling venous catheter at a rate of 0.08 mEq/kg/min for 45–60
tonometered with three different combinations of PO2 and PCO2 cover-         minutes to achieve a stable metabolic alkalosis and hypoventilation
ing the range encountered in the experiments. Samples were cor-              (pHa 7.51; PaCO2 44 mm Hg).
rected for both body temperature and systematic errors revealed by               Hypoxia. Moderate hypoxia (PETO2 47 mm Hg) was applied by de-
tonometry. The inspiratory and expiratory tubes of the ventilator were       creasing FIO2. PSV trials were begun after 10–15 minutes of hypoxic expo-
connected to the pneumotachograph using a Y-connector. A silent              sure. Hypoxia was maintained throughout the PSV trials (up to 1.5 hours).
balloon valve was placed between the pneumotachograph and the                    Almitrine bismesylate. Was used as a nonhypoxic peripheral chemore-
Y-connector such that the dog could breath spontaneously from room           ceptor stimulus to ventilation based on evidence that carotid body
air or abruptly switched to pressure support ventilation (PSV) by in-        denervation eliminated about two-thirds of the ventilatory response
flation of the balloon. All signals were digitized (128-Hz sampling fre-     to almitrine in the awake cat (34) or sleeping dog (unpublished find-
quency) and stored on the hard disk of a personal computer for subse-        ings—author’s laboratory) and that carotid body denervation plus
quent analysis. Key signals were also recorded continuously on a polygraph   vagotomy (and therefore aortic body denervation) completely elimi-
(Gould ES 2000, Cleveland, OH or AstroMed K2G, West Warick, RI).             nated the ventilatory response to almitrine in the anesthetized dog
All ventilatory and blood pressure data were analyzed on a breath-by-        (35). An intravenous bolus of 14-ml (1 mg/ml) almitrine was adminis-
breath or beat-by-beat basis by means of custom analysis software de-        tered over 60 seconds followed by a continuous infusion at a rate of
veloped in our laboratory.                                                   0.2–0.4 ml/minute for the duration of the PSV trials (1–1.5 hours).
                                                                             This bolus-infusion protocol resulted in a hyperventilation (PaCO2
Experimental Protocol                                                        30 mm Hg) within 5 minutes, which remained stable for the duration
Studies were performed over several days during NREM sleep. The              of the PSV trials. PSV trials were begun 15 minutes after the start of
animals were unrestrained during the experiments and the body posi-          almitrine infusion.
tion in which they chose to sleep was not restricted. The apneic
threshold for CO2 was determined by means of PSV under five differ-          Nonchemical Effects of PSV
ent steady-state levels of background ventilatory drive produced in          Nonchemical effects of PSV have been shown to include a significant
various ways: normoxia (control), metabolic acidosis, metabolic alka-        reduction in the amplitude of respiratory motor output in sleeping hu-
losis, hypoxia, and almitrine.                                               mans (36). In the present study, the nonchemical effects of PSV on di-
Nakayama, Smith, Rodman, et al.: CO2 Sensitivity Below Eupnea                                                                                       1253

aphragm electromyogram (EMGdi) and breath timing were quantified               support. This reduction in EMGdi is an example of a non-CO2 re-
in two ways. First, we analyzed the effects of the first breath of pressure    lated, neuromechanical inhibition (also see Figure 4 for mean val-
support in all PSV trials, assuming that any observed effects on EMGdi         ues and Figure 5 for further evidence of neuromechanical inhibi-
would have occurred before any change in chemoreceptor PCO2. Sec-              tion during PSV). In Figure 1B, conducted at a higher level of
ond, we conducted 29 PSV trials in four dogs in which PETCO2 was pre-
                                                                               pressure support and increased VT and with further reductions in
vented from falling by increasing FICO2.
                                                                               PETCO2, EMGdi mean electrical activity (MEA) was now reduced
Data Collection and Analysis                                                   further to greater than 2 SD or 40–70% below eupnea in the ma-
Sleep staging. Sleep state was determined from the polygraph record of         jority of breaths. TE was prolonged consistently but only by
each study. NREM sleep was defined as a synchronized low-frequency             30% or 1 second greater than baseline spontaneous eupnea TE. In
( 10 Hz) EEG associated with an absence of rapid eye movements.                Figure 1C, conducted at 11 cm H2O pressure support, PETCO2 was
EEG arousal was defined as desynchronization and speeding ( 10                 reduced 4–5 mm Hg below baseline eupnea. A greatly reduced
Hz) of the EEG for more than 3 seconds. Any PSV trials in which the            EMGdi and inspiratory effort that were insufficient to trigger the
dog changed sleep state were excluded from further analysis.                   ventilator are shown at      1 minute, 15 seconds into this trial,
   Statistics. The group means for all dogs were compared by means             again with little prolongation of TE. Thereafter, regularly appear-
of one-way repeated measures analysis of variance (ANOVA) with                 ing apneas (TE 3 baseline eupnea) and periodic, cluster-type
the Tukey post hoc test for multiple comparisons. Differences were
                                                                               breathing was observed for the remainder of the trial. This abrupt
considered significant if p 0.05.
                                                                               transition from a gradually reduced amplitude of EMGdi with lit-
                                                                               tle change in breath timing, to substantial TE prolongation and
RESULTS
                                                                               periodic breathing pattern was a consistent feature of achieving
Progression of Ventilatory Inhibition Below Eupnea                             the apneic threshold during progressive hypocapnia via PSV.
during PSV
                                                                               Effects of Changing Background Ventilatory Drive on the
Typical examples of the progressive inhibitory effects of PSV
                                                                               Apneic/Hypopneic Threshold
on EMGdi amplitude and timing are shown for the same dog
in Figures 1A–1C under background control conditions of                        Normoxic/normocapnic control. When the dogs breathed room
normoxic normocapnia.                                                          air spontaneously during NREM sleep, they maintained typical
                                                                                                                                      ·
   First, in Figure 1A note that EMGdi amplitude was reduced                   canine values of ventilatory and blood gas variables ( VI 3.3
30% with no change in TI or TE on the first breath of pressure                 L/min; PETCO2 38.6 mm Hg; pHa 7.378; [HCO3 ] 21.8




                                                                    Figure 1. (A) Polygraph record of one pressure support trial (7 cm H2O) in which
                                                                    apnea/periodicity was not achieved. Note that this level of PSV increased VT and
                                                                    decreased PETCO2 slightly; EMGdi amplitude was reduced at the onset of pressure
                                                                    support and throughout the trial, TE increased slightly but breathing pattern
                                                                    showed no tendency toward periodicity or apnea. (B) Polygraph record of one
                                                                    pressure support trial (9 cm H2O) in which PETCO2 is further reduced and EMGdi
                                                                    amplitude is reduced to greater than 2 SD below eupneic baseline control on
                                                                    most breaths; but apnea and periodic breathing are not present. Note that after
                                                                       2 minutes 15 seconds of continued pressure support in this trial, EMGdi ampli-
                                                                    tude was reduced on a single inspiration to such an extent ( 30% of baseline eu-
                                                                    pnea) that the spontaneous inspiratory effort was insufficient to produce enough
                                                                    pressure to trigger the ventilator to deliver the desired volume. (C) Polygraph
                                                                    record of one pressure support trial (11 cm H2O) in which apnea/periodicity was
                                                                    achieved (same dog, same test session as A). Note that a reduced EMGdi and in-
                                                                    spiratory effort on the seventh ventilator cycle was insufficient to trigger a ventila-
                                                                    tor breath. Clear periodicity developed after the ninth ventilator cycle. Arrow
                                                                    marks the PETCO2 considered to be the apneic threshold.
1254                                                                   AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE                                   VOL 165   2002

                TABLE 1. MEAN ( SD) VENTILATORY AND BLOOD GAS VALUES FOR ALL DOGS DURING NREM SLEEP
                WHEN BREATHING SPONTANEOUSLY UNDER VARYING LEVELS OF BACKGROUND VENTILATORY DRIVES
                                                                                                      ·
                                             TI                 TE           fb           VT          VI         PaCO2        PaO2                     [HCO3 ]a
                Condition           N    (seconds)          (seconds)    (b/minute)       (L)     (L/minute)    (mm Hg)     (mm Hg)        pHa          (mEq/L)

                Control,            6
                  normoxic,                1.45               3.52         13.0           0.26       3.3          38.2        106          7.378          21.8
                  normocapnic             (0.06)              (0.75)       (1.4)         (0.07)     (0.6)         (1.9)      (6.4)        (0.018)         (0.4)
                Met.                6      1.35                2.95        16.5           0.29       4.1          30.9        117          7.341          16.4
                  Acidosis                (0.33)              (1.2)        (6.7)         (0.12)     (0.7)         (2.1)      (5.0)        (0.023)         (1.8)
                Met.                5      1.61                3.56        12.3           0.24       2.9          44.2        101          7.507          34.6
                  Alkalosis               (0.29)              (0.63)       (2.2)         (0.07)     (0.5)         (2.1)      (5.2)        (0.021)         (1.7)
                Hypoxia             6      1.26                2.02        20.0           0.23       4.4          31.0         47          7.428          20.0
                                          (0.26)              (0.61)       (5.4)         (0.06)     (1.0)         (1.7)      (1.1)        (0.02)          (0.7)
                Almitrine           3      1.06                1.29        26.1           0.20       5.2          29.5        122          7.427          19.1
                                          (0.07)              (0.05)       (0.3)         (0.03)     (0.9)         (1.1)      (0.8)        (0.013)         (1.3)

                  Definition of abbreviations: fb breathing frequency; [HCO3 ]a arterial bicarbonate concentration; pHa              arterial pH; TE   expiratory
                                              ·
                time; TI inspiratory time; VI inspired minute ventilation; VT tidal volume.


                                               ·
mEq/L; Table 1). An increase in VI via increased VT from                                        7.507 versus 7.378; [HCO3 ] · 34.6 versus 21.8 mEq/L); Table
PSV sufficient to decrease the PETCO2 by 5.1 0.8 mm Hg (i.e.,                                   1) all dogs hypoventilated ( VI          2.9 versus 3.4 L/minute;
  PETCO2; PETCO2AT        PETCO2SPONTANEOUS) was required to                                    PETCO2      43.7 versus 38.6 mm Hg; Figure 3) indicating a sub-
produce apnea/periodicity (Figure 2). The average slope of the
               ·
                                                                                                stantial decrease in background ventilatory drive during NREM
reduction in VA per mm Hg reduction in PETCO2 was 0.68                                          sleep. To reach the apneic threshold in this background of de-
                                                                                                                                                   ·
0.11 L/mm Hg (Table 2). The PETCO2 from spontaneous eu-                                         creased drive and hypoventilation, an increase in VI via increased
pnea to hypopnea (MEAdi              2 SD or 62 7% of baseline                                  VT from PSV sufficient to reduce the PETCO2 to 40 mm Hg was re-
eupnea) was –4.6 1 mm Hg (Table 3).                                                             quired; i.e., there was a significantly narrowed PETCO2 ( 3.7
    Increased ventilatory drive: metabolic acidosis. After a stable                             1 mm Hg) in all dogs (Figure 2). A 1.3 mm Hg reduction also oc-
metabolic acidosis had been achieved (pH 7.341 versus 7.378;                                    curred in the PETCO2 for hypopnea (p 0.05). The gain of the
[HCO3 ] 16.4 versus 21.8 mEq/L; Table 1) all dogs mani-
                                   ·
                                                                                                slope of the ventilatory reduction to hypocapnia increased in all
fested stable hyperventilation (VI 4.8 versus 3.4 L/minute for                                  five dogs (average 24 35%) but did not achieve statistical
control; PETCO2 28.2 versus 38.6 mm Hg) indicating a substan-                                   significance (p 0.05) (Table 2). In one of the five dogs during
tial increase in background ventilatory drive during NREM                                       metabolic alkalosis, periodic breathing/apnea occurred sponta-
sleep. To reach the apneic threshold in this background of in-
                                 ·
                                                                                                neously during NREM sleep without PSV.
creased drive, an increase in VI (via increased VT from PSV)                                       Increased ventilatory drive: hypoxia. Moderate hypoxia dur-
sufficient to reduce the PETCO2 to 21.5 mm Hg was required.                                     ing NREM sleep (PETO2 47.2 mm Hg) resulted in stable hy-  ·
Thus, PETCO2 was 6.7 0.8 mm Hg, which represented a sig-                                        perventilation and respiratory alkalosis in all dogs ( VI      4.6
nificant widening over that in control conditions (Figure 2). The                               versus 3.4 L/minute; PETCO2 31.0 versus 38.6 mm Hg; pHa
average gain of the slope of the ventilatory reduction in re-                                   7.428 versus 7.378; [HCO3 ] 20.0 versus 21.8 mEq/L; Table
sponse to hypocapnia below eupnea was not significantly differ-                                 1) indicating a substantial increase in ventilatory drive. To
ent from normoxic eupnea (Table 2). The PETCO2 for hypo-                                        reach the apneic threshold in this background of increased
                                                                                                                        ·
pnea with metabolic acidosis was widened (Table 3) to a similar                                 drive an increase in VI via increased VT from PSV sufficient to
extent as was the PETCO2 for the apneic threshold.                                              reduce the PETCO2 to 26.9 mm Hg was required; i.e., relative to
    Decreased ventilatory drive: metabolic alkalosis. After a sta-                              control there was a significantly narrowed PETCO2 in all dogs
ble metabolic alkalosis had been achieved in NREM sleep (pHa                                    (mean         4.1    0.8 mm Hg; Figure 2). The average gain of


                TABLE 2. MEAN (          SD) VENTILATORY DATA OBTAINED AT THE APNEIC THRESHOLD*

                                                                                                            Apnea Duration (s)
                                                        VT (L)                                                     and
                                                                                                                                          ·
                Condition        P applied               and                 PETCO2          MEAdi           Apnea Duration               V A / PETCO2
                (N)              (cm H2O)          VT (% of baseline)      (mm Hg)        (% of baseline)     (% of baseline)    (L/minute/mm Hg eupnea)

                Normoxic       14.8     2.7          0.55      0.09        5.1     0.8       70    22          10.0   1.6                0.68     0.11
                  Control, 6                         207       50                                              286    70
                Met.           24.5     3.9†          1.2      0.84†       6.7†    0.8       57    19           9.0   2.7                0.70     0.07
                  Acidosis, 6                        421       171†                                            348    116
                Met.            9.0     0†           0.40      0.07        3.7†    1.0       69    19           8.4   1.5                0.84     0.24
                  Alkalosis, 5                       174       43                                              239    52
                Hypoxia, 6     15.7     4.1          0.56      0.08        4.1†    0.8       76    10           7.5   2.1                1.07     0.25†
                                                     249       59                                              356    104
                Almitrine, 4    27.0    4.0†         0.94      0.19        5.9†    0.8       74    24           6.3   1.2                0.77     0.08
                                                     438       24†                                              470   89†

                   Definition of abbreviations: PETCO2 difference in partial pressure of CO2 in end-tidal gas between spontaneous breathing and the ap-
                                  ·
                neic threshold; VA alveolar minute ventilation; VT tidal volume.
                   * PETCO2 was the difference between PETCO2 obtained from the breath immediately preceding the first apnea and the spontaneous
                PETCO2 during sleep for a given background ventilatory drive. Pressure applied at the airway opening (P applied), VT, and MEAdi, were ob-
                                                                                  ·                                           ·
                tained from the breaths immediately preceding apnea onset. VA / PETCO2 is the slope of the reduction in VA per mm Hg reduction in
                PETCO2 between spontaneous eupneic ventilation and the apneic threshold.
                   †
                     Significantly different from control (p 0.05).
Nakayama, Smith, Rodman, et al.: CO2 Sensitivity Below Eupnea                                                                                         1255

               TABLE 3. MEAN VALUES (                SD) AT THE HYPOPNEIC THRESHOLD

                                                                                   Hypopnea TE (s)
                                                                                         and
               Condition                      P applied                 PETCO2       Hypopnea TE           MEAdi            Minute ∫ EMGdi
               (N)                            (cm H2O)                (mm Hg)       (% of baseline)     (% of baseline)     (% of baseline)

               Normal, control (6)           10.9     2.7             4.5   1         4.6    1.2           62    7             53    5
                                                                                      138    18
               Met.                          18.6     4.5*            5.9   2.2       4.3    2.8           58    8             51   11
                 Acidosis, 6                                                          138    41
               Met.                           7.4     0.8             3.2   0.8*      4.1    0.3           66    4             66    15
                 Alkalosis, 5                                                         116    17
               Hypoxia, 6                     9.4     2.5             2.1   1*        2.6    0.9           64    12            64    19
                                                                                      127    21
               Almitrine, 4                  26.5     6.7*            4.6   1.1       2.3    0.9*          56    6             51    11
                                                                                      169    48

                 * Significantly different from control (p   0.05).


                                                                                                    ·
the slope of the ventilatory reduction in response to hypocap-                     the fall in VA per mm Hg reduction in PETCO2 below eupnea
nia was increased 57        37% greater than control (p      0.05;                 (Figure 3B) was unchanged from control with metabolic aci-
Table 2). Hypoxia also caused a narrowing of the group mean                        dosis and almitrine, increased slightly but not significantly
hypopneic threshold PETCO2 to 2.1               1 mm Hg (p                         above control with metabolic alkalosis, and increased signifi-
0.05)(see Table 3); a reduction which was more than 50% be-                        cantly ( 40% greater than control) with hypoxia.
low normoxic control conditions and substantially greater                              Effect of PSV unloading, per se. PSV, per se, decreased the
than the average 20% fall in the apneic threshold PETCO2.                          amplitude of the integrated EMGdi 20       2% during the first
   Increased ventilatory drive via nonhypoxic peripheral chemore-                  PSV breath and prolonged TE an average of 32         18% (i.e.,
ceptor stimulation: almitrine. Infusion of almitrine bismesylate                   1.1     0.6 seconds     eupneic control; Figure 4). The first
(see METHODS) during NREM sleep resulted in a stable hyper-
                          ·
                                                                                   breath reduction in EMGdi did not differ across the five exper-
ventilation in all dogs (VI 5.2 versus 3.4 L/minute; PETCO2                        imental conditions. This response is too rapid to be mediated
28.8 versus 38.6 mm Hg; pHa 7.427 versus 7.378; [HCO3 ]                            by chemoreceptors (see Figures 1A–1C), indicating to us a neu-
19.1 versus 21.8 mEq/L; Table 1), indicating a substantial in-                     romechanical effect of unloading breathing via PSV. Moreover,
crease in ventilatory drive. To reach the apneic threshold in
                                                        ·
                                                                                   in 29 PSV trials during which normocapnia was maintained via
this background of increased drive, an increase in VI via in-                      increased FICO2, EMGdi was decreased throughout the trial
creased VT from PSV sufficient to reduce the PETCO2 to 22.9                        (see example in Figure 5); this effect was similar to that ob-
mm Hg was required; i.e., relative to control there was a sig-                     served on the first breath of hypocapnic PSV. Note these
nificantly widened PETCO2 in all dogs (mean             5.9    0.8                 nonchemical effects of PSV on reducing EMGdi or prolonging
mm Hg versus 5.1 0.8 control (p 0.05; Figure 2). The av-                           TE are substantially less than those observed at the hypopneic
erage gain of the ventilatory response to CO2 below eupnea                         (Table 3) or apneic (Table 2) thresholds, both of which are at-
was unchanged from control (Table 2). During almitrine ad-                         tributable primarily to hypocapnia.
ministration, the PETCO2 from eupnea to hypopnea was un-
changed from control.
   As summarized in Figure 3A, increased ventilatory drives                        DISCUSSION
of nonhypoxic origin tended to widen the PETCO2 required                           Our findings show that the hypocapnia-induced apneic thresh-
for apnea whereas decreased ventilatory drive tended to nar-                       old and, more importantly, the proximity of the spontaneous
row it. Hypoxia was the exception; the PETCO2 was narrower                         PCO2 to the apneic threshold PCO2 below eupnea (i.e., PETCO2)
than control and much narrower than one would predict from                         changed in proportion to the background ventilatory drive.
the substantial accompanying hyperventilation. The slope of                        The exception to this finding was hypoxia, during which the




                                                                                         Figure 2. Changes in the PETCO2 required to achieve the hypo-
                                                                                         pneic and apneic thresholds in dogs during NREM sleep (mean
                                                                                         SEM) during normal control conditions (normoxic, normocap-
                                                                                         nia), metabolic acidosis, metabolic alkalosis, hypoxia, and periph-
                                                                                         eral chemoreceptor stimulation with almitrine during NREM sleep
                                                                                         (mean SEM). Also see Tables 2 and 3.
1256                                                       AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE                VOL 165     2002


                                            Figure 3. (A) Mean data           subsequently, sufficient sensitivity to CO2 below eupnea must
                                            showing the PETCO2 from           be present in order for hypocapnia to depress central respira-
                                            spontaneous ventilation to        tory motor output and cause apnea or hypopnea. Modelers of
                                            the apneic threshold as a
                                            function of the spontaneous
                                                                              the ventilatory control system have identified two types of gain
                                            PETCO2 achieved during all        which predict predisposition to periodic breathing, namely:
                                            background ventilatory drive      “controller gain”, which indicates the strength of the chemore-
                                            conditions. Note the inverse      flex and is conventionally tested by the steady-state or tran-
                                            relationship between spon-        sient ventilatory response to increased CO2; and “plant gain”
                                            taneous PETCO2 and PETCO2         or the amplification with which any ventilatory overshoot is
                                            for all conditions except hy-
                                            poxia. (B) Mean slope of the
                                                                              translated into a reduction in PaCO2. The product of these two
                                            ventilatory response to re-       gains or “loop gain” is considered a sensitive determinant of
                                            duced PCO2 below eupnea           unstable ventilation (30).
                                               ·
                                            ( VA/ PETCO2) for all five ex-          PCO2 may be viewed as an integral part of the “controller
                                            perimental conditions. Note       gain” component because it defines the chemoreceptor gain to
                                            the large increase in gain dur-   hypocapnia below eupnea; whereas controller gain, as cur-
                                            ing hypoxia in contrast to
                                            the near-control values ob-
                                                                              rently conventionally defined, speaks only to the susceptibility
                                            served during acidosis and        to ventilatory overshoot and only to one potential determinant
almitrine at comparable levels of reduced spontaneous PETCO2 during           (i.e., sensitivity to hypercapnia) of the overshoot. Thus, the
spontaneous eupnea. Diamonds normal, squares acidosis, triangles              closer the proximity of eupneic PCO2 to the apneic or hypo-
alkalosis, circles hypoxia,
                ·               almitrine. * indicates a mean value for       pneic threshold PCO2 (i.e., the narrower the PCO2) the more
  PETCO2 or VA/ PETCO2 significantly different from control.                  likely it is that additional transient perturbations in ventilation
                                                                              above eupnea will precipitate significant ventilatory under-
                                                                              shoots. As mentioned previously, in addition to the change in
ventilatory sensitivity to CO2 below eupnea was markedly in-                    PCO2 with changing ventilatory drive, any change in the sus-
creased and PETCO2 was reduced significantly below control                    ceptibility to apnea would also be determined in part by the
despite a substantial increase in ventilatory drive and a reduc-              magnitude of the further increase in ventilation required to
tion in spontaneous PaCO2. In turn, this effect of hypoxia on                 achieve this PCO2 (i.e., “plant gain”).
  PETCO2 was not attributable to an imbalance between periph-                     Both of these determinants of apnea are shown together in
eral and central chemoreceptor stimulation per se; to the con-                Figure 6. For example, note that with an increase in nonhy-
trary, nonhypoxic peripheral chemoreceptor stimulation caused                 poxic background drive (metabolic acidosis or almitrine) the
an increase in PETCO2 similar to that attending the hyperven-                 protection against developing apnea is twofold. First, the re-
tilation of metabolic acidosis. The relevance of these findings               duction in PETCO2 required to cause apnea was increased by
to causes of apnea during sleep is discussed below.                           more than 30%. Second, this increase in PCO2 plus the move-
                                                                              ment of the eupneic PCO2 upward and to the left on the curvi-
                                                                                                       ·
 PETCO2 as a Determinant of Susceptibility to Apnea                           linear iso-metabolic VA:PaCO2 relationship, means that in met-
and Hypopnea                                                                  abolic acidosis a threefold greater than control transient
                                                                                             ·
During NREM sleep chemoreceptors provide the dominant                         increase in VA is required to lower the PETCO2 to the new ap-
control over central respiratory motor output (1, 37). In order               neic threshold. In contrast, when ventilatory drive is reduced
for apnea or hypopnea to develop during sleep, sufficient sen-                and eupneic PaCO2 increases (metabolic alkalosis), marked re-
sitivity of ventilatory responses and an adequate ventilatory                 ductions from control in both the PCO2 required for apnea
stimulus must be present to produce first, a transient ventila-               ( 30%) and the required increase in ventilation to reach the
tory overshoot above eupneic levels, commonly in response to                  new apneic threshold ( 40%) greatly enhance the probability
changes in sleep state and/or airway resistance (30, 38); and                 for the occurrence of apnea or hypopnea.




                                                                                        Figure 4. Nonchemical effect of PSV on EMGdi mean elec-
                                                                                        trical activity (MEAdi) and TE obtained from the first pressure
                                                                                        support breath of all PSV trials. Note that unloading caused
                                                                                        a 20 2% decrease in the overall group mean MEAdi and a
                                                                                        32      18% increase in TE (relative to baseline spontaneous
                                                                                        breathing) within the first ventilator breath. Baseline control
                                                                                        TE averaged 2.9 seconds, thus the mean increase in TE was 0.9
                                                                                        second. Data from all pressure support levels for a given
                                                                                        background ventilatory drive condition are combined, as the
                                                                                        absolute level of pressure support was not correlated with the
                                                                                        magnitude of reduction in EMGdi amplitude.
Nakayama, Smith, Rodman, et al.: CO2 Sensitivity Below Eupnea                                                                         1257

                                                                           asleep (5–8, 15). We note that not all studies show chronic hy-
                                                                           perventilation in patients with CHF and CSR (39, 40). Based
                                                                           on these correlative data it has been suggested that the re-
                                                                           duced eupneic PaCO2 in these patients is moved closer to their
                                                                           apneic threshold and therefore renders the patient more sus-
                                                                           ceptible to apnea and periodic breathing. To the contrary, our
                                                                           results show that increases in ventilatory drive (via nonhy-
                                                                           poxic stimuli) that cause hyperventilation protect against ap-
                                                                           nea and periodic breathing by both widening the PCO2 and
                                                                                                                       ·
                                                                           requiring a greater further increase in VA for a given PCO2
                                                                           (see Figure 6). Alternatively, the decreased ventilatory drive
                                                                           and an increased eupneic PaCO2 that accompanied metabolic
                                                                           alkalosis sensitized the ventilatory depression in response to
                                                                           hypocapnia. For these same reasons, the present findings also
                                                                           explain why adding more ventilatory drive in subjects already
                                                                           experiencing apnea and/or periodic breathing (by means of
                                                                           theophylline or acetazolamide) results in a significant lessen-
Figure 5. Polygraph record of an isocapnic trial of PSV. Note the im-      ing or even elimination of apnea and periodic breathing (25–
mediate and persistent fall in EMGdi with little change in breath timing   27). Furthermore, perhaps even the reported effects of acutely
during PSV. The arrow indicates the first pressure support breath. FICO2   increasing PaCO2 via added FICO2 on removing central sleep ap-
was increased during PSV to prevent hypocapnia.                            nea and stabilizing breathing (5, 16, 17, 20, 21) may be due pri-
                                                                           marily to the nonspecific effects on PETCO2 of increasing
                                                                           background ventilatory drive and ventilation rather than to a
    With hypoxia-induced hyperventilation, (see Figure 6B)                 raised PaCO2, per se.
the protective effect of the greater further increase in ventila-              Whether or not increased ventilatory drive and/or reduced
tion required to produce a given reduction in PaCO2 (because               eupneic PaCO2 protects against and/or eliminates apnea and pe-
of the shift in position on the iso-metabolic hyperbola) was offset        riodic breathing on the one hand or may actually create condi-
by a narrowed PCO2 below eupnea. This was true in both the                 tions favorable to apnea on the other, may well depend on the
sleeping dog and especially in the human, in whom acute mild               specific stimulus causing the hyperventilation. We found that
hypoxia barely increased spontaneous ventilation and reduced               metabolic acidosis and pharmacologic stimulation of (prima-
the PaCO2 only 2–3 mm Hg, but PCO2 was reduced to less than                rily) the peripheral chemoreceptors (via almitrine) increased
one-half normoxic control conditions (32). Interestingly, in                 PETCO2 and protected against apnea, whereas hypoxia did not.
both the human and dog, hypoxia narrowed the PCO2 for hy-                  The cause of increased ventilatory drive in CHF patients with
popnea (below normoxic control) substantially more than the                CSR has been correlated (cross-sectionally and over time) to
  PCO2 for apnea (see reference 32 and Figure 2).                          increased pulmonary-capillary wedge pressure (40, 41). In
                                                                           turn, this increased drive to breathe is likely mediated by stim-
Alterations in the PCO2 from Eupnea to Apnea
                                                                           ulation of pulmonary C-fiber endings secondary to pulmonary
There are two potential reasons why the PCO2 from sponta-                  vascular congestion and edema in CHF (42). Perhaps hyper-
neous ventilation to the apneic threshold changes with chang-              ventilation caused primarily by sensory input from these recep-
ing background ventilatory drive. First, if only eupneic venti-            tors would—like hypoxia—increase the ventilatory sensitivity
lation increased and PaCO2 fell, i.e., with no change in true              to hypocapnia, and therefore reduce the PCO2 required to
ventilatory responsiveness to CO2 below eupnea (see below),                render the patient more susceptible to further transient venti-
then the PETCO2 must widen simply because a greater reduc-                 latory overshoots, which would lead to apnea, hypopnea, or
tion in PCO2 is required to cause the greater reduction in venti-          periodic breathing. The effects of several types of specific ven-
lation to produce apnea. This change in spontaneous eupneic                tilatory stimuli on the apneic threshold need to be determined.
ventilation was the major reason for the widened PCO2 that                 Recent findings in CHF patients with CSR do show a signifi-
accompanied the hyperventilation during metabolic acidosis                 cant reduction in the PETCO2 below eupnea (43).
or almitrine and the narrowed PCO2 found during the hy-
poventilation of metabolic alkalosis (see Figure 6).
    Second, an alteration in the gain of the slope of the fall in          Peripheral:Central Chemoreceptor Imbalance as a Risk Factor
ventilation in response to the reduced PCO2 below eupnea                   for Apnea/Hypopnea
    ·
( VA/ PETCO2) will also affect the magnitude of the PCO2.                  When carotid chemoreceptor stimulation—relative to that
These changes in sensitivity may even offset the above-men-                at the level of the medullary chemoreceptors—becomes the
tioned effects of changes in background spontaneous ventila-               dominant sensory input to the respiratory controller, this is
tion. For example, despite the comparable levels of hyperven-              believed to precipitate instability in breathing pattern. Several
tilation accompanying metabolic acidosis and hypoxia, the                  lines of evidence are commonly cited to support this hypothe-
  PCO2 was significantly greater than control in the former and            sis, including the periodic breathing produced in humans with
yet less than control in the latter. This difference in PETCO2
                           ·                                               carotid body stimulation via hypoxia (16, 44), adenosine infu-
occurred because the VA/ PETCO2 below eupnea was un-                       sion (45)—which has both a peripheral stimulatory and cen-
changed with metabolic acidosis and markedly increased (to                 tral depressant effect (46, 47), or in anesthetized animals via
50% control) with hypoxia.                                                 blockade of either the carotid chemoreceptor inhibitory neu-
                                                                           rotransmitter, dopamine (48), or the medullary chemorecep-
Role of Spontaneous Eupneic Pa CO2 and Increased Ventilatory               tors (49). Our present findings support the idea that hypocapnic
Drive as a Risk Factor for Apnea/Hypopnea                                  hypoxia enhances the susceptibility to apnea and hypopnea by
Several investigators have observed that CHF patients with                 reducing PETCO2. An additional question posed in the present
CSR have chronically reduced eupneic PaCO2, both awake and                 study was whether this apneic-producing effect of hypoxic hy-
1258                                               AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE                 VOL 165      2002




                                                                               Figure 6. Two principal determinants of apnea: (A) the
                                                                                  PETCO2 from spontaneous breathing to the apneic threshold;
                                                                               and (B) the change in ventilation above eupnea required to
                                                                               lower PETCO2 sufficiently to reach the apneic threshold ( PETCO2),
                                                                               are shown during conditions of control, metabolic acidosis and
                                                                               alkalosis, and in hypoxia in the dog (present study) and in
                                                                               normoxia and hypoxia in the sleeping human (32). The iso-
                                                                               metabolic line describing the relationship between PaCO2 and
                                                                                ·
                                                                               VA is theoretical and was constructed using an assumed
                                                                                           ·
                                                                               constant VCO2 of 150 ml/minute for both species and the
                                                                               measured PETCO2 during spontaneous eupneic breathing and
                                                                                                                      ·    ·
                                                                               at the apneic thresholds (PaCO2 VCO2/VA • k). For example,
                                                                               in the dog under control conditions the PETCO2 was 5.1         ·
                                                                               mm Hg below spontaneous eupnea and the increase in VA
                                                                               from spontaneous eupnea required to reach the apneic thresh-
                                                                               old was 0.5 L/minute. The diagonal dashed lines join eu-
                                                                               pneic and apneic points, and their slopes indicate the gain be-
                                                                               low eupnea of the ventilatory response to hypocapnia in each
                                                                                                                               ·
                                                                               condition. Note the increased slope of the VA:PaCO2 relation-
                                                                               ship between eupnea and the apneic threshold in hypoxia in
                                                                               both dogs and humans, whereas these slopes remained un-
                                                                               changed from control with metabolic acidosis and alkalosis.




pocapnia was attributable to the imbalance between periph-          from the carotid chemoreceptors that is specific to hypoxia
eral and central chemoreception.                                    (50); or a vasodilatory effect of hypoxia on the cerebral circu-
   We determined the effects of an imbalance between periph-        lation that would promote apnea and hypopnea by lowering
eral and central chemoreceptors on the apnea and hypopneic          medullary chemoreceptor PCO2 at any given arterial PCO2 (53).
thresholds PETCO2 by using a nonhypoxic peripheral chemo-
receptor stimulant, almitrine (35—also see METHODS), to cause       Summary
hyperventilation. Like hypoxia, almitrine increases the slope of    The PCO2 below spontaneous eupneic PaCO2 required for apnea
the ventilatory and/or the carotid sinus nerve response to hyper-   or significant reductions in EMGdi amplitude, as determined us-
capnia in most studies in humans and cats (50–52); although         ing pressure support ventilation, is an index of the propensity for
some indirect evidence suggests that hypoxia and almitrine          apnea and hypopnea during sleep. Our findings have shown that
might not have the same site and/or mechanism of stimulation of     the PCO2 during sleep changes in proportion to a changing back-
the carotid chemoreceptors (50). We found that, unlike hypoxia,     ground ventilatory drive. The exception was hypoxia during
almitrine-induced hyperventilation: (a) widened the PETCO2          which PCO2 was reduced to less than normoxic, normocapnic
similar to that found during metabolic acidosis-induced hyper-
                                                     ·              control despite an increase in background ventilatory drive. In
ventilation; and (b) caused a small increase in the VA/ PETCO2      contrast with some current concepts concerning causes of central
response slope below eupnea which was only about one-fifth          sleep apnea, our findings suggest that alveolar hyperventilation or
that observed in hypoxia (see Table 2). Furthermore, the re-        (nonhypoxic) peripheral chemoreceptor stimulation (in combina-
duced plant gain accompanying the hyperventilation induced by       tion with systemic and central alkalosis) all coincided with a wid-
almitrine combined with an increased PETCO2 required to reach       ened PETCO2 below eupnea, thereby protecting against (rather
the apneic or hypopneic thresholds would mean considerable          than enhancing) the occurrence of central apnea, hypopnea, and
protection against transient hypopneas or apneas in sleep.          unstable breathing. In contrast, reduced ventilatory drive and the
   So, the contrast of the apnea-producing effects of hypoxia       accompanying hypoventilation precipitated apnea and hypopnea.
versus the stabilizing effects of hypocapnic hyperventilation
induced via nonhypoxic peripheral chemoreceptor stimula-            Acknowledgment : The many contributions of Kathleen S. Henderson are
tion—means characteristics of hypoxia itself, rather than sim-      gratefully acknowledged. We acknowledge the Servier Pharmaceutical
                                                                    Company for supplying the almitrine.
ply an imbalance between peripheral and medullary chemore-
ceptor stimuli—is likely responsible for most of the marked
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