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J Appl Physiol 83: 1184-1191, 1997;
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Journal of Applied Physiology
Vol. 83, No. 4, pp. 1184-1191, October 1997
CONTROL OF BREATHING, CIRCULATION, AND TEMPERATURE

Hemodynamics, cerebral circulation, and oxygen saturation in Cheyne-Stokes respiration

Karl A. Franklin1, Erik Sandström2, Göran Johansson3, and Eva M. Bålfors3

1 Departments of Pulmonary Medicine, 2 Thoracic Surgery, and 3 Anesthesia and Critical Care Medicine, University Hospital, S-901 85 Umeå, Sweden

ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES

ABSTRACT

Franklin, Karl A., Erik Sandström, Göran Johansson, and Eva M. Bålfors. Hemodynamics, cerebral circulation, and oxygen saturation in Cheyne-Stokes respiration. J. Appl. Physiol. 83(4): 1184-1191, 1997.---Because cardiovascular disorders and stroke may induce Cheyne-Stokes respiration, our purpose was to study the interaction among cerebral activity, cerebral circulation, blood pressure, and blood gases during Cheyne-Stokes respiration. Ten patients with heart failure or a previous stroke were investigated during Cheyne-Stokes respiration with recordings of daytime polysomnography, cerebral blood flow velocity, intra-arterial blood pressure, and intra-arterial oxygen saturation with and without oxygen administration. There were simultaneous changes in wakefulness, cerebral blood flow velocity, and respiration with accompanying changes in blood pressure and heart rate ~10 s later. Cerebral blood flow velocity, blood pressure, and heart rate had a minimum occurrence in apnea and a maximum occurrence during hyperpnea. The apnea-induced oxygen desaturations were diminished during oxygen administration, but the hemodynamic alterations persisted. Oxygen desaturations were more severe and occurred earlier according to intra-arterial measurements than with finger oximetry. It is not possible to explain Cheyne-Stokes respiration by alterations in blood gases and circulatory time alone. Cheyne-Stokes respiration may be characterized as a state of phase-linked cyclic changes in cerebral, respiratory, and cardiovascular functions probably generated by variations in central nervous activity.

ultrasonography; Doppler; transcranial; blood pressure; transcutaneous blood-gas monitoring; cerebrovascular circulation

INTRODUCTION

CHEYNE-STOKES RESPIRATION is characterized by a regular waxing and waning breathing pattern followed by a central apnea (7, 11). It occurs among patients with congestive heart failure and in patients who have experienced a stroke (7, 8, 11, 17, 20, 24).

The increased arterial circulation time observed in patients with heart failure has been suggested as the primary cause of Cheyne-Stokes respiration because it delays the chemoreceptor response to changes in arterial PCO2 (PaCO2) (23, 27). By the use of analytical models, it has been proposed that an increased gain of the respiratory chemical control feedback loop produces respiratory system instability, with Cheyne-Stokes respiration as a result (9, 10, 22). Increased arterial circulatory time because of heart failure alters the loop gain in a direction that makes respiratory oscillations more likely to occur, and the controller tends to produce "the wrong response at the wrong time" (22). Hypoxemia and simultaneously occurring cerebrovascular disease are supposed to enhance the sensitivity for changes in PaCO2. However, these models have not taken into consideration that prolonged lung-to-artery circulation time occurs in patients with congestive heart failure regardless of Cheyne-Stokes respiration (8, 18, 26). Oxygen administration reduces central apneas in patients with Cheyne-Stokes respiration, but the mechanisms remain unknown (2, 12, 16).

Increased circulatory time and changes in blood gases cannot explain why Cheyne-Stokes respiration occurs in only a fraction of patients with heart failure or in patients without heart failure who have experienced a stroke.

Changes in blood gases and their relationship to respiration have been regarded as vital in the pathogenesis of Cheyne-Stokes respiration, yet on-line intra-arterial blood-gas measurements during apnea have not been performed in these patients.

The present study was designed to determine the temporal relationship among wakefulness, cerebral circulation, blood pressure, heart rate, respiration, and intra-arterial oxygen saturation (SaO2) with and without oxygen administration during Cheyne-Stokes respiration.

METHODS

Subjects. Ten men with Cheyne-Stokes respiration and frequent central sleep apneas according to previous polysomnographic recordings were included in the study. All the patients were in the normal range for arterial PO2 (PaO2), PaCO2, pH, and base excess when awake. Five patients had congestive heart failure, and two had experienced a stroke. Three patients had both heart failure and a previous stroke. Patient characteristics and ongoing medical treatment are shown in Tables 1 and 2.

Table  1.   Patient characteristics
Subject No. Age, yr BMI, kg/m2 Left Ventricular Function CHF, Class (NYHA) Cerebral Disorder
1 74 30 Poor III
2 73 25 Impaired II
3 72 32 Poor III Stroke
4 67 32 Poor III Stroke
5 61 47 NA  --- Stroke
6 62 20 Normal  --- Stroke
7 58 32 Impaired III
8 78 22 Poor III
9 59 33 Poor III Stroke
10 67 25 Impaired II
Mean ± SD 67 ± 7 30 ± 8
BMI, body mass index; CHF, congestive heart failure; NYHA, New York Heart Association; NA, not available. Left ventricular function was visually scored by echocardiography.

Table  2.   Patient medication
Subject No. Total Daily Dosage
1 5 mg Diazepam, 0.13 mg digoxin, 5 mg enalapril, 80 mg furosemide
2 5 mg Amiloride, 40 mg furosemide, 0.1 mg levothyroxin, 75 mg salicylic acid
3 150 mg Captopril, 0.25 mg digoxin, 80 mg furosemide, 60 mg nitroglycerine
4 40 mg Furosemide, 50 mg metoprolol, 40 mg nitroglycerine, 30 mg paroxetine
5 7.5 mg Amiloride, 20 mg baclofen, 600 mg carbamazepine, 400 mg meprobamate, 1 mg prazosin, 75 mg salicylic acid
6 20 mg Baclofen, 0.13 mg digoxin, 5 mg felodipine
7 40 mg Furosemide, 1,200 mg gemfibrozil, 200 mg metoprolol, 13 mg nitroglycerine, 160 mg salicylic acid
8 0.13 mg Digoxin, 80 mg furosemide, 40 mg nitroglycerine, 50 mg spironolacton
9 5 mg Felodipine, 60 mg furosemide, 12.5 mg propiomazine, 50 mg spironolacton
10 20 mg Enalapril, 10 mg simvastatin, 75 mg salicylic acid, 160 mg sotalol

Protocol. The study was performed during sleep in the daytime with the patient in the supine position and without use of additional sedatives. Four patients were prophylactically treated with Warfarin after a stroke. The dose of Warfarin in these patients was reduced to an international normalized ratio of 1.4-1.6 on the day of examination. Recordings were first obtained without oxygen and then with nasal oxygen at 5 l/min.

The study protocols were approved by the Umeå University Ethics Committee for human studies.

Polysomnographic recordings were made on a 16-channel paper printer (Gould TA 5000, Gould T&M, Valley View, OH) at a speed of 5 mm/s. They included cerebral blood flow velocity (CBFV) by transcranial Doppler signals from the middle cerebral artery (TC2-64B, EME, Überlingen, Germany); continuous recording of arterial blood pressure by an arterial cannula with an internal diameter of 1.0 mm in the radial artery of the nondominant hand (2 DT-XX, Ohmeda, Monroeville, CO); on-line SaO2 by using a 4-Fr fiber-optic catheter inserted in the femoral artery with oxygen saturation computed each second from a running average of 5 s (Opticath U425C and Oximetrix, Abbott, North Chicago, IL); finger oximetry with a continuous averaging period of 3 s (Biox 3740, Ohmeda); transcutaneous PCO2 (PtcCO2; TINA-TCM3, Radiometer, Copenhagen, Denmark); electroencephalogram (C3-A2), electrooculograms, chin-electromyogram, and nasal and oral airflow (3-port thermistor); abdominal movements (Resp-EZ, EPM Systems, Midlothian, VA); and heart rate from the electrocardiogram (V5). Two patients were excluded from the intra-arterial oximetry measurements, one because of a previous aortofemoral graft and one because of technical problems.

Arterial blood samples were taken in the awake state at the start and during oxygen treatment at the end of the recordings.

Sleep stages were scored manually according to Rechtschaffen and Kales (28). The shift among sleep, arousal, and awake periods was evaluated continuously. An arousal was scored when sleep was interrupted by continuous alpha activity and increased electromyographic activity over 3 s (6). A central apnea was defined as a cessation of airflow for at least 10 s without any respiratory movements. A Cheyne-Stokes respiratory cycle length was defined from the end of one apnea to the termination of the following apnea (26). Lung-to-artery circulation time was defined as the time from the end of apnea to minimum intra-arterial oxygen desaturation (18, 26). Baseline values for CBFV, mean arterial pressure (MAP), heart rate, finger SaO2, and intra-arterial SaO2 were obtained during regular respiration in the awake state. The PtcCO2 device was calibrated in vivo to arterial blood gases. Because of the drift in the TINA-TCM3, the baseline value for PtcCO2 was rated as the value immediately preceding each apnea. Maximum and minimum values for CBFV, MAP, heart rate, finger SaO2, intra-arterial SaO2, and PtcCO2 before, during, and after 10 consecutive apneas were obtained in each patient and calculated as the percent change from baseline. Values at the start of and at the termination of apnea were also plotted. The mean value for these parameters was calculated for all 10 cycles in each patient. The mean (±SD) for all patients was then calculated. The target was to also obtain data from 10 consecutive apneas during oxygen administration, but fewer cycles were obtained in a number of cases.

Student's t-test for paired observations was used to test the influence of oxygen administration. Pearson's correlation coefficient was calculated for the relationship among apnea, hyperpnea, and oxygen desaturations on maximum and minimum CBFV, MAP, and heart rate for all values and also for values in each patient. The null hypothesis was rejected at the 5% level (P < 0.05). All results are expressed as means ± SD.

RESULTS

Without oxygen. The mean PaO2 of awake subjects during regular respiration was 10.5 ± 1.3 kPa, and the PaCO2 was 4.9 ± 0.5 kPa. The breathing frequency was 17 ± 4 breaths/min. The recording time was 158 ± 40 min, and there was a mean of 57 ± 18 apneas/h of sleep.

The average Cheyne-Stokes cycle length was 52 ± 6 s. It included a hyperpnea of 29 ± 6 s and a succeeding apnea of 23 ± 6 s. Tidal volume changed in a crescendo-decrescendo pattern with a maximum in midhyperpnea. The maximum and minimum absolute values of hyperpnea, apnea, CBFV, MAP, and heart rate in each patient are shown in Fig. 1 and Tables 3, 4, 5, 6. The maximum and minimum mean values for all patients in the form of the percent change from baseline for CBFV, MAP, heart rate, and blood gases and their temporal relationship to respiration are shown in Fig. 2.
Fig. 1. Typical changes in heart rate, respiration, blood gases, arterial blood pressure (Pa), mean arterial pressure (MAP), and cerebral blood flow velocity (CBFV) without oxygen administration in subject 8 at a low paper speed (1 mm/s). ECG, electrocardiogram; Abd, abdominal movements; SaO2, arterial O2 saturation; ia, intra-arterial.
[View Larger Version of this Image (49K GIF file)]

Table  3.   Hypernea and apnea duration during 10 cycles of Cheyne-Stokes respiration in each subject without oxygen
Subject No. Hyperpnea, s Apnea, s
1 30 ± 3 34 ± 6
2 26 ± 10 24 ± 7
3 33 ± 9 20 ± 4
4 30 ± 6 26 ± 5
5 20 ± 2 24 ± 4
6 25 ± 4 23 ± 4
7 25 ± 8 17 ± 4
8 29 ± 5 25 ± 5
9 34 ± 8 19 ± 8
10 40 ± 10 17 ± 2
Mean ± SD 29 ± 6 23 ± 5

Table  4.   Maximum and minimum heart rate during 10 cycles of Cheyne-Stokes respiration in each subject without oxygen
Subject No. Baseline Value, beats/min Maximum Before Apnea, beats/min Time Before Apnea Onset, s Minimum in Apnea, beats/min Time After Apnea Onset, s
1 65 71 ± 2 10 ± 3 50 ± 0 12 ± 5
2 60 61 ± 3 4 ± 2 53 ± 2 12 ± 4
3
4 72 78 ± 2 0 ± 0 69 ± 1 27 ± 5
5 80 83 ± 2 1 ± 3 82 ± 2 19 ± 8
6 60 63 ± 4 5 ± 6 52 ± 3 7 ± 8
7 75 79 ± 3 11 ± 9 71 ± 2 12 ± 6
8 70 76 ± 2 7 ± 6 69 ± 1 11 ± 4
9 68 70 ± 2 4 ± 5 61 ± 2 15 ± 6
10 45 48 ± 1 13 ± 6 42 ± 1 7 ± 3
Mean ± SD 66 ± 10 70 ± 11 6 ± 5 61 ± 13 14 ± 6
Subject 3 had atrial flutter.

Table  5.   Maximum and minimum mean arterial pressure during 10 cycles of Cheyne-Stokes respiration in each subject without oxygen
Subject No. Baseline Value, mmHg Maximum Before Apnea, mmHg Time Before Apnea Onset, s Minimum in Apnea, mmHg Time After Apnea Onset, s
1 70 76 ± 1 4 ± 2 63 ± 2 22 ± 6
2 90 96 ± 7 5 ± 5 79 ± 9 14 ± 9
3 90 100 ± 4 10 ± 6 83 ± 3 15 ± 5
4 110 119 ± 3 3 ± 6 101 ± 3 29 ± 2
5 110 121 ± 5 6 ± 2 94 ± 4 8 ± 3
6 97 106 ± 3 5 ± 4 89 ± 4 14 ± 6
7 92 105 ± 3 11 ± 7 87 ± 5 11 ± 2
8 78 80 ± 1 5 ± 8 73 ± 2 21 ± 6
9 80 85 ± 3 10 ± 8 74 ± 3 18 ± 5
10 85 90 ± 3 24 ± 11 75 ± 3 9 ± 7
Mean ± SD 90 ± 13 98 ± 15 8 ± 6 82 ± 11 16 ± 6

Table  6.   Maximum and minimum cerebral blood flow velocity during 10 cycles of Cheyne-Stokes respiration in each subject without oxygen
Subject No. Baseline Value, cm/s Maximum Before Apnea, cm/s Time Before Apnea Onset, s Minimum in Apnea, cm/s Time After Apnea Onset, s
1 25 30 ± 1 9 ± 2 21 ± 1 12 ± 4
2 65 72 ± 6 14 ± 5 56 ± 8 4 ± 4
3 20 22 ± 2 15 ± 6 15 ± 3 4 ± 6
4 30 38 ± 3 12 ± 3 26 ± 2 12 ± 7
5 30 40 ± 3 11 ± 3 25 ± 2 3 ± 2
6 50 66 ± 2 12 ± 3 41 ± 4 6 ± 2
7 30 33 ± 3 16 ± 7 26 ± 1 4 ± 3
8 50 63 ± 3 12 ± 8 43 ± 3 11 ± 5
9 45 52 ± 4 21 ± 7 35 ± 5 10 ± 6
10 37 46 ± 3 29 ± 11 31 ± 2  -4 ± 7*
Mean ± SD 38 ± 14 46 ± 17 15 ± 6 32 ± 12 6 ± 5
* Minimum values occurred at 4 ± 7 s before apnea onset.

Fig. 2. Subjects without oxygen administration. Mean changes in maximum and minimum percent change from baseline for CBFV, MAP, heart rate, and SaO2 and their temporal relationship to apnea. Values are means ± SD; n = 10 subjects. Baseline values were obtained during normal respiration of subjects in awake state.
[View Larger Version of this Image (23K GIF file)]

There were cyclic variations in CBFV, arterial pressure, and heart rate with a maximum during hyperpnea and a minimum during apnea in all patients. Heart rate changes could not be estimated in one patient with atrial flutter. The maximum CBFV occurred in the middle of hyperpnea when the tidal volume was greatest and 6.8 ± 2.4 s before the maximum MAP (P < 0.001) and 10.0 ± 3.0 s before the minimum intra-arterial SaO2 (P < 0.001). The minimum CBFV occurred 5.5 ± 3.9 s before midapnea (P < 0.001), 10.0 ± 3.3 s before the minimum MAP (P < 0.001), and 6.6 ± 6.3 s before the minimum heart rate (Fig. 2).

The duration of apnea, hyperpnea, or the degree of oxygen desaturation were not related to the magnitude of changes in CBFV, MAP, or heart rate. Moreover, there was no correlation among the magnitude of changes in CBFV, MAP, and heart rate.

The patients fell asleep 0.4 ± 2.6 s after the onset of apnea and were again aroused 0.5 ± 1.4 s after the termination of apnea in 78 of the 100 Cheyne-Stokes cycles investigated, i.e., arousals occurred during hyperpnea and sleep during apnea. Sleep stage 1 continued during both hyperpnea and apnea in 5 of all the 100 cycles, and the patients were awake during the remaining 17 cycles.

The nadir intra-arterial SaO2 was 87 ± 4% at 21 ± 6 s after the end of apnea. Intra-arterial desaturations were greater and occurred earlier than the nadir finger SaO2 of 91 ± 4% at 31 ± 8 s after the termination of apnea (P < 0.01). Changes in PtcCO2 were minor but still significant, with a decrease of 2 ± 1% below baseline 36 ± 5 s after apnea onset and an increase of 1 ± 1% above baseline 36 ± 6 s after the termination of apnea (P < 0.01).

Lung-to-artery circulation time, defined as the time from the termination of apnea to nadir intra-arterial SaO2, correlated with the cycle length (hyperpnea + apnea time; r = 0.81; P < 0.05).

With nasal oxygen. Three patients were excluded from the analysis because they did not fall asleep during the administration of oxygen.

In the seven remaining patients who were given oxygen, the average PaO2 in awake subjects increased from 10.3 ± 1.4 to 22.7 ± 6.7 kPa (P < 0.01) according to arterial blood samples, but the PaCO2 did not change. The breathing frequency increased slightly from 15 ± 1 to 16 ± 1 breaths/min (P < 0.05). Baseline values for heart rate, MAP, and CBFV did not change. The recording time was 45 ± 19 min. The number of apneas per hour of sleep among the seven patients decreased from a mean of 63 ± 5 to 47 ± 12 (P < 0.01).

On average, 7 ± 2 cycles (range 3 to 10 cycles) of Cheyne-Stokes respiration were recorded in each of the seven patients. Mean changes in maximum and minimum percent change from baseline for CBFV, MAP, heart rate, and SaO2 and their temporal relationship to respiration during oxygen administration are shown in Fig. 3. The cycle length (hyperpnea + apnea time) increased from 50 ± 5 to 63 ± 14 s during oxygen treatment (P < 0.05), with a tendency toward longer apneas (P = 0.054).
Fig. 3. Subjects with nasal oxygen administration. Mean changes in maximum and minimum percent change from baseline for CBFV, MAP, heart rate, and SaO2 and their temporal relationship to apnea. Values are means ± SD; n = 7 subjects. Baseline values were obtained during normal respiration of subjects in awake state.
[View Larger Version of this Image (22K GIF file)]

Oxygen desaturations were reduced by oxygen administration (P < 0.01), but the cyclic variations in CBFV, MAP, and heart rate did not change (Fig. 3). The nadir intra-arterial SaO2 was 97 ± 2% at 14 ± 4 s after the end of apnea, and the nadir finger SaO2 was 98 ± 1% at 29 ± 8 s after the termination of apnea. Changes in PtcCO2 were minor and did not change with oxygen.

The patients fell asleep 0.3 ± 1.9 s before the onset of apnea and were aroused 0.4 ± 1.0 s after the end of apnea in 40 of 49 Cheyne-Stokes respiratory cycles. During two of the remaining nine cycles, the patients were asleep, whereas they were awake during three cycles. The stage of wakefulness could not be determined during four Cheyne-Stokes respiratory cycles.

The cycle length divided by the circulation time (time from the end of apnea to nadir intra-arterial SaO2) increased during oxygen treatment from 2.5 ± 0.6 s (range 1.8 to 3.3 s) to 3.9 ± 1.5 s (range 2.9 to 6.8 s) (P < 0.05).

DISCUSSION

A novel finding in the present study is the occurrence of simultaneous changes in CBFV, respiration, and wakefulness, followed by changes in blood pressure and heart rate an average of 10 s later, during a Cheyne-Stokes respiratory cycle. These parameters all had a minimum in apnea and a maximum during hyperpnea. Sleep prevailed during apnea and arousal during hyperpnea. Therefore, Cheyne-Stokes respiration in these patients consisted not only of a typical breathing pattern but also of phase-linked cyclic changes in cerebral function and the cardiovascular system.

Oxygen administration reduced the frequency of apneas and increased the cycle length of Cheyne-Stokes respiration. The treatment time was, however, short, and other studies have showed larger reductions in apnea with nocturnal oxygen administration (2, 12, 16). The results nonetheless revealed that fluctuations in CBFV, blood pressure, and heart rate were not an effect of apnea-induced hypoxemia because hemodynamic changes continued despite oxygen treatment and minor desaturations.

This is the first study that analyzes reliable on-line oxygen saturation by intra-arterial oximetry during Cheyne-Stokes respiration. Intra-arterial oxygen desaturations were more severe and occurred earlier than those recorded with finger oximetry. The actual difference was probably a bit longer because the averaging period of the intra-arterial oximetry was 5 s, and the finger oximetry only 3 s.

It has been reported that maximum PaCO2 occurs simultaneously with the minimum PaO2 during Cheyne-Stokes respiration (3, 23, 25, 27). Nadir intra-arterial SaO2 occurred late in hyperpnea and ~10 s after the maximum CBFV in the present study. If maximum PaCO2 occurs simultaneously with minimum SaO2, our results indicate that the resumption of respiration after apnea was not initiated by increased PaCO2 because minimum intra-arterial SaO2 occurred at the end of hyperpnea.

The large fluctuation in CBFV observed during central apnea and Cheyne-Stokes respiration and its close temporal relationship to changes in wakefulness and respiration have not previously been described. CBFV decreased simultaneously with respiration and preceded the apnea that was initiated at the onset of sleep, indicating a reduction in cerebral activity. Decreased cerebral activity decreases the demand for oxygen and thereby cerebral blood flow (19).

Flow velocity in the middle cerebral artery reflects changes in the total cerebral blood flow because this artery carries 80% of the hemispheric blood (1). One limitation of the Doppler technique is that flow velocity and not actual flow is measured. Even so, electromagnetic measurements of cerebral blood flow have shown a close correlation with CBFV measured by transcranial Doppler (5, 30). Karp et al. (21) found that the cerebral arteriovenous circulation time increased from 14 s during hyperpnea to 17 s during apnea in Cheyne-Stokes respiration measured with Evan's blue. This supports the hypothesis that the reduction in CBFV during apnea in our study represents an actual decrease in the total cerebral blood flow as well.

Medications used by the subjects in the present study may have an effect on the baseline levels of cerebral blood flow. However, transcranial Doppler is not a reliable method of obtaining absolute value of the blood flow. The study focused on rapid dynamics of CBFV, for which the transcranial Doppler is suitable. The dynamic changes were similar in all patients regardless of medication used.

Contrary to the present findings, the fluctuations in blood pressure and CBFV are simultaneous during obstructive apneas (4, 15). The changes in cerebral circulation during obstructive apneas are probably an immediate effect of changes in blood pressure because autoregulation is overridden (4). However, this could not be the cause in the present patients with central apneas because changes in CBFV preceded the changes in blood pressure. The different findings during obstructive and central apneas can probably be explained by the large fluctuations in intrathoracic pressure that only occur during an obstructive apnea. Moreover, it is likely that changes in cerebral activity and cerebral circulation induce central apnea, which may explain why changes in the cerebral blood flow occur before changes in the cardiovascular system.

Previous reports describe a decrease in heart rate at a late stage of apnea with its minimum in hyperpnea (29, 31). Goldenberger et al. (13) found a minimum heart rate during apnea and a maximum during hyperpnea, similar to our findings. Massumi and Nutter (25) reported that changes in heart rate and blood pressure occurred simultaneously and decreased during apnea, which is in accordance with our findings.

Survivors of a stroke or those with severe heart failure often have frequent central sleep apneas and Cheyne-Stokes respiration. They have cyclic changes in cerebral function and the cardiovascular system, with minimum activity during apnea. We speculate that Cheyne-Stokes respiration is a physiological mechanism for conserving oxygen like that in hibernating animals, who also exhibit periodic breathing. The demand for oxygen is lower during hibernation. Cheyne-Stokes respiration could, thus, be a physiological life-saving mechanism when a vital organ such as the heart or the brain has been severely damaged.

Circulation time, defined as the lung-to-artery circulation time and calculated from termination of apnea to minimum ear oximetry saturation or measured by dye methods, has been shown to correlate with the cycle length of Cheyne-Stokes respiration (3, 8, 26). This correlation was also observed in the present study; however, the cycle length of Cheyne-Stokes respiration increased during oxygen administration without any subsequent increase in circulation time. The lung-to-artery circulation time is probably increased during apnea because blood pressure and heart rate decrease during apnea because of a transient reduction in cardiac output. Thus estimates of circulation time by pulse oximetry responsiveness to apnea are probably inadequate because circulation time may alter during a Cheyne-Stokes respiratory cycle.

A limitation of the present study is the lack of reliable on-line PaCO2 measurements. The impact of carbon dioxide on Cheyne-Stokes respiration is still in doubt. Further studies involving reliable on-line recordings of rapid PaCO2 changes during Cheyne-Stokes respiration are desirable.

In conclusion, Cheyne-Stokes respiration is a state of phase-linked cyclic changes in cerebral, respiratory, and cardiovascular functions. It is unlikely that the modest changes in SaO2 and PCO2 observed in this study generate these cyclic fluctuations. Instead, we suggest that the prime generator is variations in central nervous regulatory activity, which, in turn, is influenced by factors such as heart failure and cerebrovascular lesions.

ACKNOWLEDGEMENTS

Thomas Bäcklund, Jan Nygren, and Carin Sahlin are acknowledged for their technical assistance. The authors also thank Hans Stenlund for statistical advice and Drs. Eva Svanborg, Peter Eriksson, and Björn Biber for valuable comments.

FOOTNOTES

   The study was supported by grants from the Swedish Heart and Lung Foundation, the Swedish Association for Heart and Lung Patients, and the AGA Co. medical research foundation.

Address for reprint requests: K. A. Franklin, Dept. of Pulmonary Medicine, Univ. Hospital, S-901 85 Umeå, Sweden.

Received 21 October 1996; accepted in final form 23 May 1997.

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