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Visual attention in patients with chronic obstructive pulmonary disease
BIOLOGICAL PSYCHOLOGY ELSEVIER
Biological Psychology41 (1995) 295-305
Visual attention in patients with chronic obstructive pulmonary disease Petra J.E. Vos, Hans T.M. Folgering, Cees L.A. van Herwaarden Department of Pulmonary Diseases, University of Nijmegen, Medical Centre Dekkerswald, P.O, Box 9001, 6.~60 GB Groesbeek, The Netherlands
Received 12 August 1992; accepted 7 July 1995
A~tract
The ~lective visual attention of 39 patients with chronic obstructive pulmonary disease (COPD) was measured by the Bourdon-Vos test and compared with the attention performance of 38 healthy controls of the same age range. The correlation betw~n the attention of the COPD patients and day- and night-time parameters was determined. Furthermore, in 44 other COPD patients with daytime hypoxaemia, the effect of one night of oxygen supplementation and of a 7-day treatment with two respiratory stimulants (chlormadinone amtato) (CMA) or acetazolamide (ACET) on attention performance was studied. The results showed that the attention performance of COPD patients was lower than that of controls. Significant correlations were found between the mean line time (attention parameter) and the tbllowing parameters: age, inspiratory vital capacity (IVC), hy~rcapnic ventilatory response (HCVR), daytime arterial oxygen saturation (Sao~, daytime arterial oxygen pressure (Pa~, daytime arterial carbon dioxide pressure (Pac02), mean nocturnal Sa02, lowest nocturnal Sa02 and the standard deviation of the mean nocturnal Sa02. Multiple linear regression analysis sho~ved that, apart from age, only the nadir of the nocturnal Sa02 contributed to the prediction of the attention. No clinically important short-term effect of oxygen or respiratory stimulating t~..erapy on the attention performance was found. Keywords: Chronic obstructive pulmonary disease; Cognitive function; Hypoxaemia
* Corresponding author. 0301-0511195/$09.50 © 1995 Elsevier Science BV. Aii rights reserved $$D1 0301-05 i I f95)05140-6
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1. latroduetion Patients with chronic obstructive pulmonary disease (COPD) have a lower neuropsychological performance than healthy controls and many of their neuropsychological functions correlate inversely with the daytime arterial oxygen tension (PaO2) (Grant et al., 1982, 1987; Krop et al., 1973; Prigatano et al., 1983). Moreover, the impaired mental function appears to be partly reversible with longterm oxygen therapy (Block, 1983; Heaton et al., 1983). Results from studies examining the short-term effect of oxygen supplementation on cognitive function in other (non-COPD) patients are inconsi:t:nt (Raskin et al., 1978; Wilson et al., 1985). Since the correlation between tht neuropsychological function and the PaO2 was found to be low in previous literature (r = 0.2 (Grant et al., 1982, 1987) and r = 0.3 (Prigatano et al., 1983)), there must be other factors that contribute to the impaired cognitive function in COPD patients. Parameters of pulmonary function appear not to correlate significantly with the cognitive performance (Grant et al., 1982; Prigatano et al., 1983). The additional hypoxaemia that occurs in COPD patients during sleep may be involved (Douglas & Flenley, 1990; Grant et al., 1982). This hypothesis has not been directly investigated although in heavy snorers and in patients with t~e obstructive sleep apnoea syndrome, it has been indicated that nocturnal hypoxaemia is related to the cognitive performance (Findley et al., 1986; Greenberg et al., 1987; Televaki et al., 1988). Another factor that has been suggested to affect cognitive function is the presence of hypercapnia, although significant correlations have not been found (Grant et al., 1982, 1987). The effect that therapeutic interventions with respiratory stimulants such as chiormadinone acetate and acetazolamide have on cognitive function has not been studied yet. These respiratory stimulants influence ventilation in COPD patients which may result in a decrease of the arterial carbon dioxide tension (PaCO2) and in an increase in oxygen tension (Pao2). Chlormadinone acetate (CMA) is a synthethic pr0gestagen which raises PaO2 and reduces PaCo2 by central stimulating effects (Skatrud & Dempsey, 1983; Vos et al., 1994). Acetazolamide (ACET) is a carbonic anhydrase inhibitor which increases ventilation by inducing a metabolic acidosis; metabolic acidosis may stimulate both the peripheral and the central chemoreceptors (Friberg et al., 1990; Skatrud & Dempsey, 1983; Vos et al., 1994). In the current study these factors are explored using selective attention, or mental concentration, as a parameter of cognitive function, since it is probably one of the first cognitive abilities which is affected by hypoxaemia (Gibson et al., 1981). Specifically, the Bourdon-Vos test was used to investigate cognitive function in this study (Vos, 1992). Since it is not feasible to perform a whole battery of neuropsychological tests in a pulmonary clinic, this short 10-min test was used as it would also be practical in clinical situations. The aims of this study were the following: first, to determine if COPD patients indeed have impaired attention compared to healthy controls of the same age range; second, to determine the correlation between the attention performance of COPD patients and age, body mass index, daytime blood gas values, pulmonary function
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and night-time oxygenation; and third, to examine the effect of one-night oxygen supplementation on attention performance in COPD patients with daytime hypoxaemia, as well as the effect of a 7-day treatment with respiratory stimulants (chlormadinone acetate and acetazolam,.'de) to decrease the arterial carbon dioxide tension. 2. Methods
2.1. Subjects Healthy subjects and patients with COPD were studied. All subjects with obvious conditions that would interfere with the results, such as psychiatric disorders, alcoholism, cerebral vascular disease, use of benzodiazepines, poor sight or shaking hands were excluded. In this study two different groups of COPD patients participated. The first group consisted of 39 COPD patients; 31 men and eight women. The mean age (±S.D.) was 65.9 years ( ± 5). The second group of 44 COPD patients included only patients with daytime hypoxaemia, defined as a PaO2 value below 8.5 kPa. Their mean age ( i S . D . ) was 64.7 years (4-5). The 44 hypoxaemic patients already received oxygen therapy at home. All COPD patients were in a stable clinical condition and received optimal bronchodilator treatment. Their FEVI (forced expiratory volume in 1 s) value had to be less lthan 65% of the predicted value (Quanjer, 1993). The characteristics of the COPD patients are shown in Table 1. Thirty-eight healthy subjects (16 men, 22 women) were randomly recruited from a general practice. Exclusion criteria were any signs of relevant disease according to Table i Characteristics of two groups of COPD patients (S.D.) Characteristic
Body mass index (S.D.) FEV I as % predicted (S.D.) IVC as % predicted (S.D.) TLC as % predicted (S.D.) FRC as % predicted (S.D.) RV as % predicted (S.D.) HCVR in Fmin/kPa (S.D.) PaC02 daytime in kPa (S.D.) Paco 2 daytime in kPa (S.D.) Mean nocturnal SaO2 % (S.D.) S.D. of mean nocturnal S~02 (S.D.) Lowest nocturnal SaO2 in % (S.D.)
Number of patients First group 39
Second group 44
23 (4) 33 (!0) 81 (17) 99 (23) ! 31 (36) 144 (45) 3.7 (4) 8.9 0.4) 5.7 (i.0) 88.5 (5) 2.6 (2) 78.3 (10)
24 (4) 30 (!0) 80 (14) IO0 (18) ! 34 (30) 154 (46) 2.4 (2) 7.5 (l.O) 6.4 (I.2) 85.1 (i0) 3.4 (2) 74.0 (15)
FEV I, forced expiratory volume in I s; IVC, inspiratory vital capacity; TLC, total lung capacity; FRC, functional residual capacity; RV, residual capacity; HCVR, hypercapnic ventilatory response; PaO2, arterial caygen pressure; PaCO2, arterial carbon dioxide pressure; SaO2, arterial oxygen saturation.
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the history and medical data of the general practitioner. Since these healthy controls had no history of pulmonary disease, their lung function was presumed to be normal. Oxygen saturation was checked in all patients at home with an ambulant oxymeter (Oxyshuttle, SensorMedics). The inclusion criterion was that patients be aged between 55 and 77 years. The mean age (±S.D.) of this group was 64.8 (~-5) years. The healthy subjects were studied at home and the COPD patients in hospital, all at 10:00 h.
2.2. Techniques Selective attention was measured by the Bourdon-Vos test (Fig. 1, 60% reduced scale). This is a recently modified version of the traditional Bourdon test (Bourdon, 1895; Vos, 1992). The Bourdon-Vos test measures sustained selective attention by measuring simple reaction time. This goal is achieved by selective reaction to fourdot targets in two different patterns (square and diamond) and by ignoring nontargets (three- and five-dot targets). The test consists of 33 lines each with 24 configurations. Patients were instructed to mark all configurations of four dots as quickly as possible. Omissions, as a parameter of accuracy, and the time of each line, which indicated speed, were recorded. All versions of the Bourdon-Vos test are the same. Every person performed the test at least twice on separate days. The results of the first and the second test (1-10 days after another) were compared in view of the expected practice effect (Vos, 1992). Drinking coffee was forbidden within 3 h before performing the test. The Bourdon-Vos test has succesfully been used in several other studies (Unrug-Neervoort et al., 1992). The validity and sensitivity of the Bourdon-Vos test has been checked by the Dutch Institute for Psychologists (COTAN/NIP), which is a common procedure for such tests in The Netherlands. According to this institute the validity, sensitivity and reliability of the test appeared to be highly acceptable. In all patients with COPD the pulmonary function, including the hypercapnic ventilatory response, was measured and arterial blood gas samples were taken. Oxygen saturation was recorded from 22:00 h to 06:00 h by a pulse-oximeter (Oxyshuttle, SensorMedics). The saturation data of the whole night were stored, digitised and analysed by a computer (Apple Ile) to provide the mean and the lowest saturation of each night as well as the standard deviation of the mean saturation.
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2.3. Protocol (Fig. 2) The first test was designed as a practice test in all subjects. The attention performance of the group of 39 COPD patients was compared with the performance of the healthy subjects with the same age range. Because of the different gender composition of the COPD and the control group, the difference in attention performance between men and women in both groups was determined. The data of the group of 39 COPD patients were used to determine the correlation between attention performance and age, body mass index, daytime blood gas values, pulmonary function and night-time oxygenation. The effect on attention performance of therapeutic interventions (02, CMA, ACET), aiming at an improvement of the arterial P02 or Pc02, was studied in the group of 44 COPD patients with daytime bypoxaemia. Thirty-one of these patients receive~ nocturnal oxygen su~tdementation and were tested the next day while breathing room air. The other 13 patients received day- and night-time oxygen treatment so they performed the third attention test while breathing supplemental oxygen. Oxygen supplementation was delivered through a nasal cannula at 1 l/min. iqext, eleven of the group of 31 hypoxaemic COPD patients were treated with 25 mg of chlormadinone acetate twice a day for 1 week. Nine hypoxaemic patients received 250 mg of acetazolamide twice a day during 1 week. The other 11 patients received placebo twice a day in identical capsules as the respiratory stimulants. These latter data, were used in order to determine the long-term reproducibility of the test. The drugs were randomised and given in a double blind fashion.
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2.4. Statistical analysis Statistical analysis was performed using the Wilcoxon test. Spearman correlations were computed. Stepwise multiple linear regression was used to explore the simultaneous contribution of several parameters. P-values of 0.05 or less were considered to be significant; due to the exploratory nature of most tests, no effort was made to protect the overall error rate. 3. Remits
3.1. Practice effect The line times of the second attention test were significantly shorter than those of the first test, in the healthy controls as well as in the patients with COPD. The mean line time of the control group decreased from 13.6 (S.D. = 3) s to 12.6 (S.D. = 2) s. In the COPD group the mean line time changed from 15.0 (S.D. = 3) to 14.1 (S.D. = 2) s. In addition, in the patients with COPD, significantly fewer omissions were recorded in the second test than in the first test (10 and 14, respectively). No significant difference was found between the results of the second and the third tests.
3.2. Comparison of patients with COPD and healthy controls The results of the attention test of the first group of 39 patients with COPD aud the healthy controls of the same age range are shown in Table 2. The coatrol group had significantly shorter line times than the COPD patients. No significant difference in attention performance between men and women was evident in either the COPD group or the control group.
3.& Correlation of attention with patient characyeristics Table 3 shows the correlation between the attention parameters and characteristics of the group of 39 COPD patients. The mean line time was significantly correlated with age, inspiratory vital capacity, hypercapnic ventilatory response, daytime Sao2, daytime PaO2, daytime PaCO2, mean nocturnal SaO2, lowest nocturnal SaO2 and with the standard deviation of the mean nocturnal SaO2. The number c_" omissions was significantly correlated with the waking SaO2. Stepwise Table 2 Results of the attention test of 39 COPD patients compared to those of 38 controls of the same age range
Overall mean linetime (s) (S.D.) Mean line time 0-11 (s) (S.D.) Mean line time 11-22 (s) (S.D.) Mean line time 22-33 (s) (S.D.) Total omissions (number) (range) *P < 0.05.
COPD
Controls
14.1 (3) 14.4 (3) 13.9 (3) 14.0 (3)
12.6 (2)* 12.7 (2)* 12.4 (2)* 12.7 (2)*
1o (0-57)
7 (0-28)
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Table 3 Correlation coefficientsbetween attention and daytime/nighttimeparameters
Age IVC (% predicted) HCVR (I/min/kPa) Sao2 awake (%)
PaO2awake (kPa) PaCO2awake (kPa) Mean nocturnal SaO2 (%) S.D. of mean nocturnal Sao2 Lowestnocturnal SaO2 (%)
Mean linetime
Omissions
0.33* -0.35 -0.43 -0.33 -0.28 0.31 -0.33* 0.42* -0.33*
0.28 0.13 0.01 -0.33* -0.59 0.!5 -0.19 0.06 0.02
No significantcorrelationswere found with body mass index, FEVI, TLC, RV and FRC. *P <0.05.
multiple linear regression explored the contribution of the parameters mentioned above to the prediction of the mean line time (LT). Only age (A) (11%; P = 0 . ~ on entry) and the lowest nocturnal SaO2 (SaO2 Low) (9%; P = 0.05 on entry) contributed significantly (overall P = 0.02) to the total variance. The regression equation was: LT = 10.6 + 0.16A -0.09 SaO2 Low. 3. 4. Short-term effect o f oxygenation and respiratory stimulants The mean daytime PaO2 of the hypoxaemic patients with COPD increased during oxygen supplementation from 7.4 to 9.9 kPa. The mean daytime PaCO2 increased from 6.4 to 7.0 kPa. Table 4 shows the results of the patients tested with and without oxygen supplementation. No significant difference in attention performance was seen after one night breathing room air compared to the results after one night's oxygen supplementation. Measures of attention were not affected by daytime hypoxaemic condition (33 patients) or by daytime oxygenated condition (13 patients). After a l-week Ueatment with chlormadinone acetate the mean daytime PaO2 increased from 7.2 to 7.8 kPa and the Paco2 decreased from 6.5 to 5.8 kPa. Acetazolamide increased the Pao2 from 7.5 to 9.4 kPa, and decreased the PaCO2 from 6.4 to 5.9 kPa. The lowest nocturnal SaO2 did not change during chlormadinone acetate treatment, and during acetazolamide an increase from 70 to 77% was found. The results of the attention test are shown in Table 4. During chlormadinone acetate therapy a positive trelid in attention performance was seen, However, this was only significant in the mean time of the last 11 lines.
4. Discussion This study showed that patients with COPD had an impaired visual attention performance compared to healthy controls of the same age. This finding is consistent with those of others (Grant et al., 1982, 1987; Krop et al., 1973; Prigatano et al., 1983). The COPD group and the control group were not matched for education since
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no significant influence is known between education and the performance of the Bourdon-Vos test (Vos, 1992). It was assumed that the gender difference between the COPD and the control group had no effect on the results since no difference could be found in attention performance between men and women. The attention of the COPD patients was significantly inversely related to oxygenation in the current study. In other words, hypoxaemia seemed to have an adverse effect on the brain function. This was also shown in healthy subjects in previous research at high altitude (Gibson et al., 1981). This is reasonable since oxygenation is essential for the neural biosynthetic processes (Adams et al., 1980; Blass & Gibson, 1979; Gibson et al., 1981). However, only a low correlation coefficient (r = -0.3) of the attention with daytime oxygenation was found in this study and in those of others (Grant et al., 1982, 1987; Prigatano et al., 1983). The current study also found a correlation with nighttime oxygenation. A similar correlation had been shown in patients with obstructive sleep apnoeas (Findley et al., 1986). Moreover, linear regression analysis in this study showed that besides age, only the lowest nocturnal SaO2 contributed to the prediction of the attention performance. Perhaps the extra hypoxaemia itself is responsible for the deterioration in visual attention or perhaps the arousals caused by the nocturnal hypoxaemia play a role. The latter explanation is less likely since no significant relationship could be found between arousals and cognitive function in studies with patients with the sleep apnoea syndrome (Findley et al., 1986). Since hypoxaemia adversely influences attention, one would expect some benefit of reversal of the hypoxia. It has been shown that short-term oxygen augmented oxygen-dependent enzymes are necessary for the stimulation of neurotransmitters (Gibson et al., 1981). Nevertheless, in our group of 41 hypoxaemic patients, no effect on attention performance was evident after treatment with oxygen for one night, either when they were tested in a hypoxaemic or in an oxygenated condition. This was consistent with results of others in non-COPD patients (Raskin et al., 1978; Wilson et al., 1985). Perhaps the fact that our hypoxaemic COPD patients were already treated with oxygen supplementation at home influenced the results. Hence, perhaps the attention performance of patients with long-term hypoxaemia may be influenced with supplemental oxygen. There was no significant effect of acetazolamide therapy on attention either. In the chlormadinone acetate group, a tendency for improvement in attention could be detected. This positive effect cannot be explained by the practice effect since this study has shown that the second and third performances are reliably stable. Also, it is not likely that the correction of the hypercapnia was the reason for the trend of improved attention performance since the acetazolamide group did not show this partial improvement. Perhaps the positive effect of chlormadinone acetate on disordered breathing during sleep and therefore the effect on sleep fragmentation is part of the explanation (Hensley et al., 1980). Yet, it is stressed that the number of patients tested with respiratory stimulants is very small. The mean line times during room air of the group of 39 COPD patients and those of the 31 and 13 hypoxaemic patients differed slightly (Tables 2, 4). The reason for this difference may be because of the different ages oi~the groups which were 65.9, 63.9 and 66.7 years, respectively.
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All parameters studied together could account for only 20% of the variance in attention. Concomitant diseases such as heart failure and atherosclerosis might be influential as well as depression and fatigue which is often shown in patients with chronic diseases (Parsons & Prigatano, 1978). Bronchodilators may influence the central nervous system and therefore the attention performance. Finally, perhaps sleep fragmentation due to nocturnal coughing and dyspnoea also played a role. It can be concluded that the attention performance of COPD patients is lower than that of the controls. Multiple linear t-egression analysis showed that, apart from age, only the nadir of the nocturnal SaG2contributed to the prediction of the attention in patients with COPD. Unfortunately, neither one night of oxygen suppletion nor l-week chlormadinone acetate or acetazolamide improved the attention performance in hypoxaemic patients with COPD. Aeimowledgements This study was supported by a grant from the Dutch Asthma Foundation. We gratefully acknowledge the statistical assistance of Dr T.M. de Boo and Mr W.A.J.G. Lemmens (Department of Medical Statistics) and the advice of Dr P.G. Vos (Department of Psychology). References Adams, K., Sawyer, J. & Kvale, P. (1980). Cerebral oxygenation and neuropsychological adaptation. Journal of Clinical Neuropsychology, 3, 189-208. Blass, J. & Gibson, G. (1979). Consequences of mild graded hypoxia. Advances in Neurology, 26, 225-250. Block, A. (1983). Neuropsycho|oglcal aspects of oxygen therapy. Respiratory Care, 28, 885-888. Bourdon, B. (1895). Observations comperatives sur la reconaissance, la discrimination et I'association. Revue Philosophique de ia France et de l'Etranger, 40, 153-185. Douglas, N. & Flenley, D. (1990). Breathing during sleep in patients with chronic obstructive lug disease. State of the art. American Review of Respiratory Diseases, 141, 1055-1070. Findley, L., Barth, J., Powers, D., Wiihoit, S., Boyd, D. & Suratt, P. (1986). Cognitive impairment in patients with obstructive sleep apnoea and associated hypoxaemia. Chest, 90, 686-690. Friberg, L., Kastrup, J., Rizzi, D., Jensen, J. & Lassen, N. (1990). Cerebral blood flow and end tidal PCO2 during prolonged acetazola~de treatment in humans. American Journal of Physiology, 258, H954-H959. Gibson, G., Pulsinelli, W., Blass, J. & Duffy. T. (1981). Brain dysfunction in mild to moderate hypoxia. American Journal of Medicine, 70, 1247-1254. Grant, I., Heaton, g., McSweeny, A., Adams, K. & Timms, R. (1982). Neuropsychologic findings in hypoxaemic chronic obstructive pulmonary disease. Archives of Internal Medicine, 142, 1470-1476. Grant, I., Prigatano, G., Heaton, R., McSweeny, A., Wright, E. & Adams, K. (1987). Progressive neuropsychologi¢ impairment and hypoxaemia. Archives of General Psychiatry, 44, 999-1006. Oreenber8, G., Watson, R. & Deptula, D. (1987). Neuropsychologlcal dysfunction in sleep apnoea. Sleep, I0, 254-262. Heaton, R., Grant, I.,McSweeny, A., Adams, K. & Petty,T. 0983). Psychologiceffectsof continuous and nocturnal oxygen therapy in hypoxaemic chronic obstructive pulmonary disease. Archives of Internal Medicine, 143~ 1941-1947. Hensley, M., Saunders, N. & Strohl, K. (1980). Medroxyprogesterone treatment of obstructive sleep apnoes. Sleep, 3, 441-446. Krop, H., Block, A. & Cohen, E. (1973). Neuropsychologlc effects of continuous oxygen therapy in chronic obstructive pulmonary disease. Chest, 64, 317-322.
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Parsons, O. & Prigatano, G. (1978). Methodological considerations in clinical neuropsychology research. Journal of Consulting and Clinical Psychology, 46, 608-619 Prigatano, G., Parsons, O., Wright, E., Thevin, D. & Hawryluk, G. (1983). Neuropsychologic test performance in mildly hypoxaemic patients with chronic obstructive pulmonary disease. Journal of Consulting and Clinical Psychology, 51, 108-116. Quanjer, P. (1993). Standardised lung function testing. European Respiratory Journal, 6, Suppl 16. Raskin, A., Gershon, S., Crook, T., Sathananthan, G. & Ferris, S. (1978). The effects of hyperbaric and normobaric oxygen on cognitive impairment ink the elderly. Archives of General Psychiatry, 35, 50-56. Skatrud, J. & Dempsey, J. 0983). Relative effectiveness of acetazolamide versus medroxyprogesterone acetate in correction of chronic carbon dioxide retention. American Review of Respiratory Diseases, 127, 405-412. Telakivi, T., Kajaste, S., Partinen, M., Koskenvuo, M., Salmi, T. & Kaprio, J. (1988). Cognitive function in middle-aged snorers and controls: role of excessive daytime somnolence and sleep-related hypoxic events. Sleep, !!, 454-462. Unrug-Neervoort, A., Van Luijtelaar, G. & Coenen, A. (1992). Cognition and vigilance: differential effects of diazepam and bispirone on memory and psychomotor performance. Neuropsychobiology, 26, 146-150. Vos, P. (1992). Bourdon.Vos test, the manual, 2nd edn. Lisse: Swets & Zeitlinger. Vos, P., Folgering, H., De Boo, T., Lemmens, W. & Van Herwaarden C. (1994). Effects ofchlormadinone acetate, acetazolamide and oxygen on awake and asleep gas exchange in patients with chronic obstructive pulmonary disease (COPD). European Respiratory Journal, 7, 850-855. Wilson, D., Kaplan, R., Timms, R. & Dawson, A. (1985). Acute effects of oxygen treatment upon informatien processing in hypoxaemic COPD patients. Chest, 88, 239-243.
Biological Psychology41 (1995) 295-305
Visual attention in patients with chronic obstructive pulmonary disease Petra J.E. Vos, Hans T.M. Folgering, Cees L.A. van Herwaarden Department of Pulmonary Diseases, University of Nijmegen, Medical Centre Dekkerswald, P.O, Box 9001, 6.~60 GB Groesbeek, The Netherlands
Received 12 August 1992; accepted 7 July 1995
A~tract
The ~lective visual attention of 39 patients with chronic obstructive pulmonary disease (COPD) was measured by the Bourdon-Vos test and compared with the attention performance of 38 healthy controls of the same age range. The correlation betw~n the attention of the COPD patients and day- and night-time parameters was determined. Furthermore, in 44 other COPD patients with daytime hypoxaemia, the effect of one night of oxygen supplementation and of a 7-day treatment with two respiratory stimulants (chlormadinone amtato) (CMA) or acetazolamide (ACET) on attention performance was studied. The results showed that the attention performance of COPD patients was lower than that of controls. Significant correlations were found between the mean line time (attention parameter) and the tbllowing parameters: age, inspiratory vital capacity (IVC), hy~rcapnic ventilatory response (HCVR), daytime arterial oxygen saturation (Sao~, daytime arterial oxygen pressure (Pa~, daytime arterial carbon dioxide pressure (Pac02), mean nocturnal Sa02, lowest nocturnal Sa02 and the standard deviation of the mean nocturnal Sa02. Multiple linear regression analysis sho~ved that, apart from age, only the nadir of the nocturnal Sa02 contributed to the prediction of the attention. No clinically important short-term effect of oxygen or respiratory stimulating t~..erapy on the attention performance was found. Keywords: Chronic obstructive pulmonary disease; Cognitive function; Hypoxaemia
* Corresponding author. 0301-0511195/$09.50 © 1995 Elsevier Science BV. Aii rights reserved $$D1 0301-05 i I f95)05140-6
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1. latroduetion Patients with chronic obstructive pulmonary disease (COPD) have a lower neuropsychological performance than healthy controls and many of their neuropsychological functions correlate inversely with the daytime arterial oxygen tension (PaO2) (Grant et al., 1982, 1987; Krop et al., 1973; Prigatano et al., 1983). Moreover, the impaired mental function appears to be partly reversible with longterm oxygen therapy (Block, 1983; Heaton et al., 1983). Results from studies examining the short-term effect of oxygen supplementation on cognitive function in other (non-COPD) patients are inconsi:t:nt (Raskin et al., 1978; Wilson et al., 1985). Since the correlation between tht neuropsychological function and the PaO2 was found to be low in previous literature (r = 0.2 (Grant et al., 1982, 1987) and r = 0.3 (Prigatano et al., 1983)), there must be other factors that contribute to the impaired cognitive function in COPD patients. Parameters of pulmonary function appear not to correlate significantly with the cognitive performance (Grant et al., 1982; Prigatano et al., 1983). The additional hypoxaemia that occurs in COPD patients during sleep may be involved (Douglas & Flenley, 1990; Grant et al., 1982). This hypothesis has not been directly investigated although in heavy snorers and in patients with t~e obstructive sleep apnoea syndrome, it has been indicated that nocturnal hypoxaemia is related to the cognitive performance (Findley et al., 1986; Greenberg et al., 1987; Televaki et al., 1988). Another factor that has been suggested to affect cognitive function is the presence of hypercapnia, although significant correlations have not been found (Grant et al., 1982, 1987). The effect that therapeutic interventions with respiratory stimulants such as chiormadinone acetate and acetazolamide have on cognitive function has not been studied yet. These respiratory stimulants influence ventilation in COPD patients which may result in a decrease of the arterial carbon dioxide tension (PaCO2) and in an increase in oxygen tension (Pao2). Chlormadinone acetate (CMA) is a synthethic pr0gestagen which raises PaO2 and reduces PaCo2 by central stimulating effects (Skatrud & Dempsey, 1983; Vos et al., 1994). Acetazolamide (ACET) is a carbonic anhydrase inhibitor which increases ventilation by inducing a metabolic acidosis; metabolic acidosis may stimulate both the peripheral and the central chemoreceptors (Friberg et al., 1990; Skatrud & Dempsey, 1983; Vos et al., 1994). In the current study these factors are explored using selective attention, or mental concentration, as a parameter of cognitive function, since it is probably one of the first cognitive abilities which is affected by hypoxaemia (Gibson et al., 1981). Specifically, the Bourdon-Vos test was used to investigate cognitive function in this study (Vos, 1992). Since it is not feasible to perform a whole battery of neuropsychological tests in a pulmonary clinic, this short 10-min test was used as it would also be practical in clinical situations. The aims of this study were the following: first, to determine if COPD patients indeed have impaired attention compared to healthy controls of the same age range; second, to determine the correlation between the attention performance of COPD patients and age, body mass index, daytime blood gas values, pulmonary function
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and night-time oxygenation; and third, to examine the effect of one-night oxygen supplementation on attention performance in COPD patients with daytime hypoxaemia, as well as the effect of a 7-day treatment with respiratory stimulants (chlormadinone acetate and acetazolam,.'de) to decrease the arterial carbon dioxide tension. 2. Methods
2.1. Subjects Healthy subjects and patients with COPD were studied. All subjects with obvious conditions that would interfere with the results, such as psychiatric disorders, alcoholism, cerebral vascular disease, use of benzodiazepines, poor sight or shaking hands were excluded. In this study two different groups of COPD patients participated. The first group consisted of 39 COPD patients; 31 men and eight women. The mean age (±S.D.) was 65.9 years ( ± 5). The second group of 44 COPD patients included only patients with daytime hypoxaemia, defined as a PaO2 value below 8.5 kPa. Their mean age ( i S . D . ) was 64.7 years (4-5). The 44 hypoxaemic patients already received oxygen therapy at home. All COPD patients were in a stable clinical condition and received optimal bronchodilator treatment. Their FEVI (forced expiratory volume in 1 s) value had to be less lthan 65% of the predicted value (Quanjer, 1993). The characteristics of the COPD patients are shown in Table 1. Thirty-eight healthy subjects (16 men, 22 women) were randomly recruited from a general practice. Exclusion criteria were any signs of relevant disease according to Table i Characteristics of two groups of COPD patients (S.D.) Characteristic
Body mass index (S.D.) FEV I as % predicted (S.D.) IVC as % predicted (S.D.) TLC as % predicted (S.D.) FRC as % predicted (S.D.) RV as % predicted (S.D.) HCVR in Fmin/kPa (S.D.) PaC02 daytime in kPa (S.D.) Paco 2 daytime in kPa (S.D.) Mean nocturnal SaO2 % (S.D.) S.D. of mean nocturnal S~02 (S.D.) Lowest nocturnal SaO2 in % (S.D.)
Number of patients First group 39
Second group 44
23 (4) 33 (!0) 81 (17) 99 (23) ! 31 (36) 144 (45) 3.7 (4) 8.9 0.4) 5.7 (i.0) 88.5 (5) 2.6 (2) 78.3 (10)
24 (4) 30 (!0) 80 (14) IO0 (18) ! 34 (30) 154 (46) 2.4 (2) 7.5 (l.O) 6.4 (I.2) 85.1 (i0) 3.4 (2) 74.0 (15)
FEV I, forced expiratory volume in I s; IVC, inspiratory vital capacity; TLC, total lung capacity; FRC, functional residual capacity; RV, residual capacity; HCVR, hypercapnic ventilatory response; PaO2, arterial caygen pressure; PaCO2, arterial carbon dioxide pressure; SaO2, arterial oxygen saturation.
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the history and medical data of the general practitioner. Since these healthy controls had no history of pulmonary disease, their lung function was presumed to be normal. Oxygen saturation was checked in all patients at home with an ambulant oxymeter (Oxyshuttle, SensorMedics). The inclusion criterion was that patients be aged between 55 and 77 years. The mean age (±S.D.) of this group was 64.8 (~-5) years. The healthy subjects were studied at home and the COPD patients in hospital, all at 10:00 h.
2.2. Techniques Selective attention was measured by the Bourdon-Vos test (Fig. 1, 60% reduced scale). This is a recently modified version of the traditional Bourdon test (Bourdon, 1895; Vos, 1992). The Bourdon-Vos test measures sustained selective attention by measuring simple reaction time. This goal is achieved by selective reaction to fourdot targets in two different patterns (square and diamond) and by ignoring nontargets (three- and five-dot targets). The test consists of 33 lines each with 24 configurations. Patients were instructed to mark all configurations of four dots as quickly as possible. Omissions, as a parameter of accuracy, and the time of each line, which indicated speed, were recorded. All versions of the Bourdon-Vos test are the same. Every person performed the test at least twice on separate days. The results of the first and the second test (1-10 days after another) were compared in view of the expected practice effect (Vos, 1992). Drinking coffee was forbidden within 3 h before performing the test. The Bourdon-Vos test has succesfully been used in several other studies (Unrug-Neervoort et al., 1992). The validity and sensitivity of the Bourdon-Vos test has been checked by the Dutch Institute for Psychologists (COTAN/NIP), which is a common procedure for such tests in The Netherlands. According to this institute the validity, sensitivity and reliability of the test appeared to be highly acceptable. In all patients with COPD the pulmonary function, including the hypercapnic ventilatory response, was measured and arterial blood gas samples were taken. Oxygen saturation was recorded from 22:00 h to 06:00 h by a pulse-oximeter (Oxyshuttle, SensorMedics). The saturation data of the whole night were stored, digitised and analysed by a computer (Apple Ile) to provide the mean and the lowest saturation of each night as well as the standard deviation of the mean saturation.
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2.3. Protocol (Fig. 2) The first test was designed as a practice test in all subjects. The attention performance of the group of 39 COPD patients was compared with the performance of the healthy subjects with the same age range. Because of the different gender composition of the COPD and the control group, the difference in attention performance between men and women in both groups was determined. The data of the group of 39 COPD patients were used to determine the correlation between attention performance and age, body mass index, daytime blood gas values, pulmonary function and night-time oxygenation. The effect on attention performance of therapeutic interventions (02, CMA, ACET), aiming at an improvement of the arterial P02 or Pc02, was studied in the group of 44 COPD patients with daytime bypoxaemia. Thirty-one of these patients receive~ nocturnal oxygen su~tdementation and were tested the next day while breathing room air. The other 13 patients received day- and night-time oxygen treatment so they performed the third attention test while breathing supplemental oxygen. Oxygen supplementation was delivered through a nasal cannula at 1 l/min. iqext, eleven of the group of 31 hypoxaemic COPD patients were treated with 25 mg of chlormadinone acetate twice a day for 1 week. Nine hypoxaemic patients received 250 mg of acetazolamide twice a day during 1 week. The other 11 patients received placebo twice a day in identical capsules as the respiratory stimulants. These latter data, were used in order to determine the long-term reproducibility of the test. The drugs were randomised and given in a double blind fashion.
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2.4. Statistical analysis Statistical analysis was performed using the Wilcoxon test. Spearman correlations were computed. Stepwise multiple linear regression was used to explore the simultaneous contribution of several parameters. P-values of 0.05 or less were considered to be significant; due to the exploratory nature of most tests, no effort was made to protect the overall error rate. 3. Remits
3.1. Practice effect The line times of the second attention test were significantly shorter than those of the first test, in the healthy controls as well as in the patients with COPD. The mean line time of the control group decreased from 13.6 (S.D. = 3) s to 12.6 (S.D. = 2) s. In the COPD group the mean line time changed from 15.0 (S.D. = 3) to 14.1 (S.D. = 2) s. In addition, in the patients with COPD, significantly fewer omissions were recorded in the second test than in the first test (10 and 14, respectively). No significant difference was found between the results of the second and the third tests.
3.2. Comparison of patients with COPD and healthy controls The results of the attention test of the first group of 39 patients with COPD aud the healthy controls of the same age range are shown in Table 2. The coatrol group had significantly shorter line times than the COPD patients. No significant difference in attention performance between men and women was evident in either the COPD group or the control group.
3.& Correlation of attention with patient characyeristics Table 3 shows the correlation between the attention parameters and characteristics of the group of 39 COPD patients. The mean line time was significantly correlated with age, inspiratory vital capacity, hypercapnic ventilatory response, daytime Sao2, daytime PaO2, daytime PaCO2, mean nocturnal SaO2, lowest nocturnal SaO2 and with the standard deviation of the mean nocturnal SaO2. The number c_" omissions was significantly correlated with the waking SaO2. Stepwise Table 2 Results of the attention test of 39 COPD patients compared to those of 38 controls of the same age range
Overall mean linetime (s) (S.D.) Mean line time 0-11 (s) (S.D.) Mean line time 11-22 (s) (S.D.) Mean line time 22-33 (s) (S.D.) Total omissions (number) (range) *P < 0.05.
COPD
Controls
14.1 (3) 14.4 (3) 13.9 (3) 14.0 (3)
12.6 (2)* 12.7 (2)* 12.4 (2)* 12.7 (2)*
1o (0-57)
7 (0-28)
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Table 3 Correlation coefficientsbetween attention and daytime/nighttimeparameters
Age IVC (% predicted) HCVR (I/min/kPa) Sao2 awake (%)
PaO2awake (kPa) PaCO2awake (kPa) Mean nocturnal SaO2 (%) S.D. of mean nocturnal Sao2 Lowestnocturnal SaO2 (%)
Mean linetime
Omissions
0.33* -0.35 -0.43 -0.33 -0.28 0.31 -0.33* 0.42* -0.33*
0.28 0.13 0.01 -0.33* -0.59 0.!5 -0.19 0.06 0.02
No significantcorrelationswere found with body mass index, FEVI, TLC, RV and FRC. *P <0.05.
multiple linear regression explored the contribution of the parameters mentioned above to the prediction of the mean line time (LT). Only age (A) (11%; P = 0 . ~ on entry) and the lowest nocturnal SaO2 (SaO2 Low) (9%; P = 0.05 on entry) contributed significantly (overall P = 0.02) to the total variance. The regression equation was: LT = 10.6 + 0.16A -0.09 SaO2 Low. 3. 4. Short-term effect o f oxygenation and respiratory stimulants The mean daytime PaO2 of the hypoxaemic patients with COPD increased during oxygen supplementation from 7.4 to 9.9 kPa. The mean daytime PaCO2 increased from 6.4 to 7.0 kPa. Table 4 shows the results of the patients tested with and without oxygen supplementation. No significant difference in attention performance was seen after one night breathing room air compared to the results after one night's oxygen supplementation. Measures of attention were not affected by daytime hypoxaemic condition (33 patients) or by daytime oxygenated condition (13 patients). After a l-week Ueatment with chlormadinone acetate the mean daytime PaO2 increased from 7.2 to 7.8 kPa and the Paco2 decreased from 6.5 to 5.8 kPa. Acetazolamide increased the Pao2 from 7.5 to 9.4 kPa, and decreased the PaCO2 from 6.4 to 5.9 kPa. The lowest nocturnal SaO2 did not change during chlormadinone acetate treatment, and during acetazolamide an increase from 70 to 77% was found. The results of the attention test are shown in Table 4. During chlormadinone acetate therapy a positive trelid in attention performance was seen, However, this was only significant in the mean time of the last 11 lines.
4. Discussion This study showed that patients with COPD had an impaired visual attention performance compared to healthy controls of the same age. This finding is consistent with those of others (Grant et al., 1982, 1987; Krop et al., 1973; Prigatano et al., 1983). The COPD group and the control group were not matched for education since
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no significant influence is known between education and the performance of the Bourdon-Vos test (Vos, 1992). It was assumed that the gender difference between the COPD and the control group had no effect on the results since no difference could be found in attention performance between men and women. The attention of the COPD patients was significantly inversely related to oxygenation in the current study. In other words, hypoxaemia seemed to have an adverse effect on the brain function. This was also shown in healthy subjects in previous research at high altitude (Gibson et al., 1981). This is reasonable since oxygenation is essential for the neural biosynthetic processes (Adams et al., 1980; Blass & Gibson, 1979; Gibson et al., 1981). However, only a low correlation coefficient (r = -0.3) of the attention with daytime oxygenation was found in this study and in those of others (Grant et al., 1982, 1987; Prigatano et al., 1983). The current study also found a correlation with nighttime oxygenation. A similar correlation had been shown in patients with obstructive sleep apnoeas (Findley et al., 1986). Moreover, linear regression analysis in this study showed that besides age, only the lowest nocturnal SaO2 contributed to the prediction of the attention performance. Perhaps the extra hypoxaemia itself is responsible for the deterioration in visual attention or perhaps the arousals caused by the nocturnal hypoxaemia play a role. The latter explanation is less likely since no significant relationship could be found between arousals and cognitive function in studies with patients with the sleep apnoea syndrome (Findley et al., 1986). Since hypoxaemia adversely influences attention, one would expect some benefit of reversal of the hypoxia. It has been shown that short-term oxygen augmented oxygen-dependent enzymes are necessary for the stimulation of neurotransmitters (Gibson et al., 1981). Nevertheless, in our group of 41 hypoxaemic patients, no effect on attention performance was evident after treatment with oxygen for one night, either when they were tested in a hypoxaemic or in an oxygenated condition. This was consistent with results of others in non-COPD patients (Raskin et al., 1978; Wilson et al., 1985). Perhaps the fact that our hypoxaemic COPD patients were already treated with oxygen supplementation at home influenced the results. Hence, perhaps the attention performance of patients with long-term hypoxaemia may be influenced with supplemental oxygen. There was no significant effect of acetazolamide therapy on attention either. In the chlormadinone acetate group, a tendency for improvement in attention could be detected. This positive effect cannot be explained by the practice effect since this study has shown that the second and third performances are reliably stable. Also, it is not likely that the correction of the hypercapnia was the reason for the trend of improved attention performance since the acetazolamide group did not show this partial improvement. Perhaps the positive effect of chlormadinone acetate on disordered breathing during sleep and therefore the effect on sleep fragmentation is part of the explanation (Hensley et al., 1980). Yet, it is stressed that the number of patients tested with respiratory stimulants is very small. The mean line times during room air of the group of 39 COPD patients and those of the 31 and 13 hypoxaemic patients differed slightly (Tables 2, 4). The reason for this difference may be because of the different ages oi~the groups which were 65.9, 63.9 and 66.7 years, respectively.
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All parameters studied together could account for only 20% of the variance in attention. Concomitant diseases such as heart failure and atherosclerosis might be influential as well as depression and fatigue which is often shown in patients with chronic diseases (Parsons & Prigatano, 1978). Bronchodilators may influence the central nervous system and therefore the attention performance. Finally, perhaps sleep fragmentation due to nocturnal coughing and dyspnoea also played a role. It can be concluded that the attention performance of COPD patients is lower than that of the controls. Multiple linear t-egression analysis showed that, apart from age, only the nadir of the nocturnal SaG2contributed to the prediction of the attention in patients with COPD. Unfortunately, neither one night of oxygen suppletion nor l-week chlormadinone acetate or acetazolamide improved the attention performance in hypoxaemic patients with COPD. Aeimowledgements This study was supported by a grant from the Dutch Asthma Foundation. We gratefully acknowledge the statistical assistance of Dr T.M. de Boo and Mr W.A.J.G. Lemmens (Department of Medical Statistics) and the advice of Dr P.G. Vos (Department of Psychology). References Adams, K., Sawyer, J. & Kvale, P. (1980). Cerebral oxygenation and neuropsychological adaptation. Journal of Clinical Neuropsychology, 3, 189-208. Blass, J. & Gibson, G. (1979). Consequences of mild graded hypoxia. Advances in Neurology, 26, 225-250. Block, A. (1983). Neuropsycho|oglcal aspects of oxygen therapy. Respiratory Care, 28, 885-888. Bourdon, B. (1895). Observations comperatives sur la reconaissance, la discrimination et I'association. Revue Philosophique de ia France et de l'Etranger, 40, 153-185. Douglas, N. & Flenley, D. (1990). Breathing during sleep in patients with chronic obstructive lug disease. State of the art. American Review of Respiratory Diseases, 141, 1055-1070. Findley, L., Barth, J., Powers, D., Wiihoit, S., Boyd, D. & Suratt, P. (1986). Cognitive impairment in patients with obstructive sleep apnoea and associated hypoxaemia. Chest, 90, 686-690. Friberg, L., Kastrup, J., Rizzi, D., Jensen, J. & Lassen, N. (1990). Cerebral blood flow and end tidal PCO2 during prolonged acetazola~de treatment in humans. American Journal of Physiology, 258, H954-H959. Gibson, G., Pulsinelli, W., Blass, J. & Duffy. T. (1981). Brain dysfunction in mild to moderate hypoxia. American Journal of Medicine, 70, 1247-1254. Grant, I., Heaton, g., McSweeny, A., Adams, K. & Timms, R. (1982). Neuropsychologic findings in hypoxaemic chronic obstructive pulmonary disease. Archives of Internal Medicine, 142, 1470-1476. Grant, I., Prigatano, G., Heaton, R., McSweeny, A., Wright, E. & Adams, K. (1987). Progressive neuropsychologi¢ impairment and hypoxaemia. Archives of General Psychiatry, 44, 999-1006. Oreenber8, G., Watson, R. & Deptula, D. (1987). Neuropsychologlcal dysfunction in sleep apnoea. Sleep, I0, 254-262. Heaton, R., Grant, I.,McSweeny, A., Adams, K. & Petty,T. 0983). Psychologiceffectsof continuous and nocturnal oxygen therapy in hypoxaemic chronic obstructive pulmonary disease. Archives of Internal Medicine, 143~ 1941-1947. Hensley, M., Saunders, N. & Strohl, K. (1980). Medroxyprogesterone treatment of obstructive sleep apnoes. Sleep, 3, 441-446. Krop, H., Block, A. & Cohen, E. (1973). Neuropsychologlc effects of continuous oxygen therapy in chronic obstructive pulmonary disease. Chest, 64, 317-322.
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Parsons, O. & Prigatano, G. (1978). Methodological considerations in clinical neuropsychology research. Journal of Consulting and Clinical Psychology, 46, 608-619 Prigatano, G., Parsons, O., Wright, E., Thevin, D. & Hawryluk, G. (1983). Neuropsychologic test performance in mildly hypoxaemic patients with chronic obstructive pulmonary disease. Journal of Consulting and Clinical Psychology, 51, 108-116. Quanjer, P. (1993). Standardised lung function testing. European Respiratory Journal, 6, Suppl 16. Raskin, A., Gershon, S., Crook, T., Sathananthan, G. & Ferris, S. (1978). The effects of hyperbaric and normobaric oxygen on cognitive impairment ink the elderly. Archives of General Psychiatry, 35, 50-56. Skatrud, J. & Dempsey, J. 0983). Relative effectiveness of acetazolamide versus medroxyprogesterone acetate in correction of chronic carbon dioxide retention. American Review of Respiratory Diseases, 127, 405-412. Telakivi, T., Kajaste, S., Partinen, M., Koskenvuo, M., Salmi, T. & Kaprio, J. (1988). Cognitive function in middle-aged snorers and controls: role of excessive daytime somnolence and sleep-related hypoxic events. Sleep, !!, 454-462. Unrug-Neervoort, A., Van Luijtelaar, G. & Coenen, A. (1992). Cognition and vigilance: differential effects of diazepam and bispirone on memory and psychomotor performance. Neuropsychobiology, 26, 146-150. Vos, P. (1992). Bourdon.Vos test, the manual, 2nd edn. Lisse: Swets & Zeitlinger. Vos, P., Folgering, H., De Boo, T., Lemmens, W. & Van Herwaarden C. (1994). Effects ofchlormadinone acetate, acetazolamide and oxygen on awake and asleep gas exchange in patients with chronic obstructive pulmonary disease (COPD). European Respiratory Journal, 7, 850-855. Wilson, D., Kaplan, R., Timms, R. & Dawson, A. (1985). Acute effects of oxygen treatment upon informatien processing in hypoxaemic COPD patients. Chest, 88, 239-243.