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(Chest. 2002;122:445-450.)
© 2002 American College of Chest Physicians

Cerebral Oxygenation During Exercise in Patients With Terminal Lung Disease*

Gabrielle Jensen, MD; Henning Bay Nielsen, MD; Kojiro Ide, PhD; Per Lav Madsen, MD; Lars Bo Svendsen, MD; Ulrik Gerner Svendsen, MD, PhD and Niels Henry Secher, MD, PhD

* From the Department of Anesthesia (Drs. Jensen, Nielsen, Ide, Madsen, L.B. Svendsen, and Secher), Copenhagen Muscle Research Center, Copenhagen, Denmark; and the Pulmonary Clinic (Dr. U.G. Svendsen), The Heart Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Correspondence to: Henning Bay Nielsen, MD, Department of Anesthesia 2041, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark; e-mail: h.bay{at}dadlnet.dk


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: In patients with terminal lung disease who were exercising, we assessed whether improved arterial O2 saturation with an increased fraction of inspired oxygen (FIO2) affects cerebral oxygenation.

Design: Randomized, crossover.

Patients and methods: The cerebral changes in oxyhemoglobin ({Delta}HbO2) and changes in deoxyhemoglobin ({Delta}Hb) levels were evaluated using near-infrared spectrophotometry and the middle cerebral artery (MCA) mean velocity (Vmean) was determined by transcranial Doppler ultrasonography in 13 patients with terminal lung disease (New York Heart Association class III-IV). Patients were allocated to an FIO2 of either 0.21 or 0.35 during incremental exercise with 15 min between trials.

Results: Peak exercise intensity (mean [± SE], 26 ± 4 W) reduced the arterial O2 pressure (at rest, 64 ± 3 mm Hg; during exercise, 56 ± 3 mm Hg) and the arterial oxygen saturation (SaO2) [at rest, 92 ± 2%; 87 ± 2%; p < 0.05], while the arterial CO2 pressure was not significantly affected. The MCA Vmean increased from 49 ± 5 to 63 ± 7 cm/s (p < 0.05) as did the {Delta}Hb, while the {Delta}HbO2 remained unaffected by exercise. With an elevated FIO2, the SaO2 level (at rest, 95.8 ± 0.7%; during exercise, 96.0 ± 1.0%) and arterial O2 pressure (at rest, 102 ± 11 mm Hg; during exercise, 100 ± 8 mm Hg) were not significantly affected by exercise, and the levels of blood oxygenation remained higher than the values established at normoxia (p < 0.05). The MCA Vmean increased to a level similar to that achieved during control exercise (ie, to 70 ± 11 cm/s). In contrast to control exercise, {Delta}Hb decreased while {Delta}HbO2 increased during exercise with 35% O2 (p < 0.05).

Conclusion: An O2-enriched atmosphere enabled patients with terminal lung disease to maintain arterial O2 saturation during exercise. An exercise-induced increase in cerebral perfusion was not affected by hyperoxia, whereby the enhanced availability of oxygenated hemoglobin increases cerebral oxygenation. The clinical implication of the study is that during physical activity patients with terminal lung disease are recommended to use an elevated FIO2 to protect cerebral oxygenation.

Key Words: acidosis • arterial oxygen saturation • cycling • hyperoxia • lactate


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In patients with chronic respiratory failure, work capacity is limited by an impaired pulmonary O2 transport capacity.1 Yet, exercise-induced arterial hypoxemia is not a phenomenon that is restricted to patients with lung disease. In athletes, the O2 transport capacity of the lung appears to be limited in that the PaO2 and arterial oxygen saturation (SaO2) may decrease during maximal exercise.2 3 4 5 6 Such arterial hypoxemia reduces cerebral oxygenation, as determined by near-infrared spectrophotometry (NIRS),5 to such an extent that it may cause fainting.7 8 In the athlete, exercise-induced hypoxemia and cerebral O2 desaturation are restored with an elevated fraction of inspired oxygen (FIO2).5

Cerebral oxygenation has not been determined in patients with chronic lung disease. We hypothesized that chronic hypoxemia is of consequence for cerebral oxygenation, particularly during exercise. In patients with chronic lung disease, hypoxemia becomes aggravated during exercise,9 10 and breathing O2-supplemented air could improve cerebral oxygenation.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Thirteen patients participated in the study after written informed consent was obtained, as approved by the Ethics Committee of Copenhagen (case No. KF 01–308-98) [Table 1 ]. The patients had severe pulmonary disease to such an extent that it placed them in New York Heart Association class III-IV. Thus, they presented with such deteriorated lung function (Table 2 ) that lung transplantation was considered necessary, and five of the patients required long-term O2 therapy.1


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  		Table 1.. Anthropometric Data*

 

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  		Table 2.. Functional Lung Data*

 
The patients were randomized in a single-blinded manner to an FIO2 of either 0.21 or 0.35 in a crossover study design with periods of rest between trials. A catheter (1.0 mm internal diameter, 19-gauge) was inserted into the radial artery of the nondominant arm. Positioned at the level of the heart, the catheters were connected to a pressure monitoring kit (Baxter Healthcare Corporation; Maurepas, France) with continuous infusion of isotonic saline solution (3 mL/h). The patients were seated with the upper body elevated 60°, the legs placed almost horizontally, and the feet fastened to the pedals of a modified Krogh cycle ergometer.11 After 2 to 3 min of rest, the first workload was at 6 W, and it was maintained for 3 min. Every third minute thereafter, the work rate was increased by 6 W until the patient became exhausted. After exercise, the patients recovered for about 20 min, and the exercise then was repeated with the alternative FIO2. After exercise, the perceived exertion was expressed on a visual scale.12

The subjects breathed through a two-way, low-resistance T-valve (model 2700; Hans Rudolph; Kansas City, MO) with humidified air delivered from a Douglas bag. First, the subject breathed ambient air for 5 min to stabilize ventilation. Thereafter, the subject breathed the air that had been allocated by randomization.

Arterial blood samples and lactate levels were obtained anaerobically (QS50; Radiometer; Copenhagen, Denmark). Samples were taken at rest and at the end of each work rate episode to be stored on ice and analyzed within 15 min (ABL-615; Radiometer). The O2 content in arterial blood (CaO2) was the sum of the bound O2 (1.39 x hemoglobin x SaO2) and the dissolved O2 (0.003 x PaO2). Arterial BP and heart rate were assessed through the arterial line connected to a monitor (Danica; Copenhagen, Denmark).

A continuous-wave NIRS photometer was used to determine the changes in oxyhemoglobin ({Delta}HbO2) and deoxyhemoglobin ({Delta}Hb) [model NIRO500; Hamamatsu Phototonics; Hamamatsu, Japan]. The optodes were placed on the forehead just below the hairline. Light was transmitted via a fiberoptic cable, and reflected light was delivered via a second cable to a photomultiplier. With NIRS of the brain, the photons pass through the scalp, the skull, and into the frontal lobe to a depth of several centimeters with only minimal influence from skin blood flow.13 Black-rubber pads attached by tape attenuated the background light and also helped to maintain a distance of 4 cm between the optodes.

The photometer operates at four wavelengths, whereby the change in the chromophore concentration is measured. The optical densities (ODs) for the four wavelengths were acquired with a sampling time of 2 s. The {Delta}Hb and {Delta}HbO2 were calculated from experimentally determined OD values using computer software (ONMAIN; Hamamatsu Phototonics).14 The algorithm is based on a modified Lambert-Beer’s law as follows: A = {alpha} x c x d x B + G, where A is the attenuation in OD, {alpha} is the specific extinction coefficient of the absorbing compound (in micrometers per centimeter), c is the concentration of the absorbing compound (in micrometers), d is the distance between the optodes on the skin surface (4 cm), B is the differential pathlength factor, and G is a factor introduced to account for the scattering of light in the tissue. The factor G was assumed to remain constant, and the differential pathlength factor adopted for the brain was 5.93.15 The concentration change of total volume of hemoglobin ({Delta}HbT) was the sum of {Delta}HbO2 and {Delta}Hb with values expressed relative to rest. To stabilize the data, cerebral oxygenation was followed with the subject breathing room air. Prior to treatment with the first of the two FIO2 levels, the values were zeroed.

To indicate changes in cerebral blood flow, the mean blood velocity (Vmean) of the proximal segment of the right middle cerebral artery (MCA) was located (Multidop X; DWL; Sipplingen, Germany) through the posterior temporal window.16 17 Once the optimal signal-to-noise ratio was obtained, the probe was covered with adhesive ultrasonic gel and was secured to the subject with a headband.

The data are expressed as the mean ± SE. Comparisons among multiple samples were evaluated by the Friedman analysis of variance (SYSTAT; Evanston, IL). Significant effects resulted from the use of the Wilcoxon signed rank test for locating pair-wise differences, and a p value of < 0.05 was considered to be statistically significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
With an FIO2 of 0.21, the time to exhaustion was 12.5 ± 2.0 min, corresponding to a peak work rate of 26 ± 4 W, and was associated with a perceived exertion (using a visual Borg scale) of 17 (range, 15 to 20).

Before exercise, the PaO2 was low with a further decrease during exercise to reach the lowest value of 44.7 mm Hg (Table 3 ). The concentration of lactate increased only a little, with the highest level at only 3.8 mmol/L, and the arterial pH remained stable. The PaCO2 was not affected at peak exercise, at which point SaO2 reached its lowest value. Thus, although the concentration of hemoglobin increased, CaO2 decreased by 2.5 ± 0.9%.


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  		Table 3.. Effects of O2 Supplementation in Patients With Terminal Lung Disease in Response to Cycling*

 
Heart rate and BP increased during exercise, as did the MCA Vmean, corresponding to an increase of 31 ± 9% at exhaustion. The {Delta}Hb increased at the low exercise intensity (6 W) and increased further during peak exercise (Fig 1 ). In contrast, the {Delta}HbO2 was not significantly affected by exercise, and therefore {Delta}HbT increased.



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  		Figure 1.. {Delta}HbT, {Delta}HbO2, and {Delta}Hb concentrations in the brain in patients with end-stage pulmonary disease at rest, and during low-workload (6 W) and moderate-workload (16 ± 1 W) cycling until exhaustion (peak workload, 26 ± 4 W). Measurements are with FIO2 levels of 0.21 ({circ}) and 0.35 (•). * = different from rest; {dagger} = different from normoxic exercise (p < 0.05).

 
An FIO2 of 0.35 did not affect the time to exhaustion (12.1 ± 1.7 min), the peak work rate (28 ± 4 W), or the perceived exertion (16; range, 12 to 20).

At rest, PaO2 and SaO2 increased, and arterial oxygenation was not affected during exercise (Table 3) . The concentration of hemoglobin reached values similar to those established during exercise when subject were in normoxia, and therefore CaO2 increased by 2.3 ± 1.0%. The concentration of lactate was similar to that established during exercise with an FIO2 of 0.21, and pH decreased only at the highest intensity. Heart rate and BP increased to levels similar to those developed during control exercise.

At rest (vs during exercise), an FIO2 of 35% reduced {Delta}Hb (-0.7 ± 0.6 vs 1.8 ± 0.6 µmol/L, respectively; p < 0.05), but neither {Delta}HbO2 (4.6 ± 1.8 vs 4.6 ± 1.6 µmol/L, respectively) nor {Delta}HbT (3.9 ± 2.1 vs 6.4 ± 2.3 mmol/L, respectively) were significantly affected. In contrast to control exercise, the {Delta}Hb decreased below the resting level and {Delta}HbO2 increased to above the level established in normoxia (Fig 1) . The {Delta}HbT reached the same increase as during control exercise, and the elevation in MCA Vmean was also similar to that established during exercise with an FIO2 of 0.21 (Table 3) .


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Performed in patients with terminal lung disease, this study demonstrated the following: (1) during exercise the NIRS-determined cerebral hemoglobin concentration increases corresponding to the increase in cerebral perfusion; (2) in normoxia, the cerebral oxygenation decreases as deoxyhemoglobin becomes elevated with an unchanged concentration of oxyhemoglobin; and (3) an elevated FIO2 increases both the SaO2 and the oxygenation of the brain. These results indicate that it is possible to assess the effect of O2 therapy on tissue oxygenation.

In patients with terminal lung disease, exercise reduces arterial oxygenation,9 10 and an increase in cerebral perfusion was not able to compensate for the low arterial O2 content. With an FIO2 of 0.35, the SaO2 was maintained during exercise. With an unchanged increase in cerebral perfusion, cerebral oxygenation also increased during exercise. The clinical relevance of the present findings is to recommend an elevated an FIO2 to patients with terminal lung disease whereby well-being is likely to be enhanced.18

The patients represent several chronic diseases that, in the terminal state, are associated with deteriorated lung function. Thus, in the present study, PaO2 was reduced to a greater extent during exercise than that value reported for patients with stable COPD during exercise in another study.9 The SaO2 decreased to the same extent as that reported previously.10

During exercise, arterial desaturation reduced cerebral oxygenation, as evidenced by an increase in {Delta}Hb, while {Delta}HbO2 remained stable. This reduced cerebral oxygenation deviates from the response in healthy subjects, in whom both {Delta}HbO2 and {Delta}Hb increase during exercise.19 In the present study, even a small increase in work rate reduced PaO2 and SaO2, whereby {Delta}Hb increased by almost 2 µmol. An FIO2 of 0.35 maintained normal levels of PaO2 and SaO2 during exercise and also reversed exercise-induced cerebral hypoxemia. In fact, hyperoxic air appears to increase cerebral oxygenation above the resting level as {Delta}HbO2 increased by almost 6 µmol, whereas {Delta}Hb remained close to the level at rest. Thus, with normalized arterial O2 values, patients with terminal lung disease demonstrated the physiologic increase in cerebral oxygenation when the brain is activated.

An FIO2 of 0.35 could have influenced cerebral oxygenation through an increase in PaCO2 that is often noted in patients with terminal lung disease who are receiving O2. Hypercapnia affects not only cerebral blood flow, but also the MCA Vmean20 and cerebral oxygenation,7 21 which is in accordance with the "CO2 reactivity" of the brain.22 However, the present patients remained normocapnic during both control and hyperoxic exercise, with an increase in MCA Vmean that was similar to that established during cycling in healthy subjects.16 The expressed perceived exertion did not change in response to exercise with an FIO2 of 0.35; however, it was not thoroughly evaluated whether cerebral function improves by breathing O2-supplemented air.

In the patient with terminal lung disease, the supplementation of O2 may enhance exercise capacity,1 23 24 but the work rate was not elevated in the present study. The experience in healthy subjects is that the effect of O2 supplementation on exercise capacity is small5 25 and not always statistically significant.4 Reduced cerebral oxygenation may affect work capacity in the athlete.5 In the patient with terminal lung disease, atrophy of the skeletal muscles appears to be of importance for exercise capacity.26

With a low PaO2, arterial pH becomes critical for SaO2. During exercise in healthy subjects with the same experimental set-up as in the present study, pH decreased to about 7.3 as blood lactate approached 10 mmol/L.27 If lung patients also allowed lactate levels to increase to a concentration that would decrease pH during exercise, their SaO2 would become as low as 70%,28 with a reduction in O2 uptake by > 25%.4 5 Such calculations suggest that it is an advantage for the patient with a low PaO2 to work with only a marginal increase in blood lactate levels.

In patients with terminal lung disease, PaO2 becomes low even at an extremely low work rate. It appears to be of importance that pH is not reduced to a level where the Bohr effect influences SaO2. Thus, pH decreased only during exercise with an FIO2 of 0.35 when PaO2 was maintained. A reduction in SaO2 affects tissue oxygenation. Only with an elevated FIO2 were patients with terminal lung disease able to demonstrate the increase in cerebral oxygenation during exercise.

The main conclusions to be drawn from this study are that total cerebral hemoglobin levels increase with exercise, corresponding to an increase in cerebral blood velocity, while cerebral oxygenation depends on SaO2. An O2-enriched atmosphere maintains arterial oxygenation, and subsequently also cerebral oxygenation, in the patient with terminal lung disease.


   Footnotes
 
Abbreviations: CaO2 = O2 content in arterial blood; FIO2 = fraction of inspired oxygen; {Delta}Hb = change in deoxyhemoglobin; {Delta}HbO2 = change in oxyhemoglobin; {Delta}HbT = change of total volume of hemoglobin; MCA = middle cerebral artery; NIRS = near-infrared spectrophotometry; OD = optical density; SaO2 = arterial oxygen saturation; Vmean = mean blood velocity

Received for publication December 18, 2000. Accepted for publication February 11, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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