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Drawing Impairment Predicts Mortality in Severe COPD
CHEST
Original Research COPD
Drawing Impairment Predicts Mortality in Severe COPD* Raffaele Antonelli-Incalzi, MD; Andrea Corsonello, MD; Claudio Pedone, MD; Luigi Trojano, MD; Domenico Acanfora, MD; Aldo Spada, MD; Orsola Izzo, PsyD; and Franco Rengo, MD
Background: Cognitive impairment frequently occurs in elderly COPD patients, but little is known about its prognostic implications. We aimed at evaluating the prognostic role of cognitive impairment in patients with severe COPD. Methods: Our series consisted of 149 stable patients (mean [ⴞ SD] age, 68.7 ⴞ 8.5 years) with COPD and a PaO2 of < 57 mm Hg at rest (n ⴝ 97) or at the end of the 6-min walking test (n ⴝ 37) who were enrolled in a prospective observational study. After a multidimensional baseline assessment, patients were followed up by telephone calls for a mean duration of 32.5 ⴞ 9.2 months (minimal follow-up duration, 24 months); 134 patients were successfully tracked. We used multivariable Cox proportional hazard analysis to identify predictors of death among clinical/ functional variables that previously were shown to have prognostic implications and among neuropsychological indexes selected on the basis of univariate analysis. Results: We observed 29 deaths over a median follow-up time of 32 months. Only the two following variables were independently associated with the outcome: an abnormal score on the copy with landmark test (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.34 to 6.39); and a 6-min walk distance of < 300 m (HR, 3.46; 95% CI, 1.15 to 10.5). A PaO2 of < 57 mm Hg at rest (HR, 2.19; 95% CI, 0.93 to 5.18) and an FEV1 of < 40% predicted (HR, 2.74; 95% CI, 0.99 to 7.57) were nearly significantly associated with the outcome, while PaCO2, body mass index, physical dependence, comorbid diseases, and the impairment of cognitive domains other than drawing impairment were unrelated to the outcome. Conclusions: Drawing impairment is a risk factor for mortality and might improve the assessment of hypoxemic COPD patients. (CHEST 2006; 130:1687–1694) Key words: cognitive impairment; COPD; drawing impairment; mortality Abbreviations: BADL ⫽ basic activity of daily living; BMI ⫽ body mass index; CI ⫽ confidence interval; IADL ⫽ instrumental activity of daily living; MMSE ⫽ mini-mental state examination; OSA ⫽ obstructive sleep apnea; 6MWD ⫽ 6-min walk distance
impairment is one of the most common C ognitive nonrespiratory effects of COPD, and its prevalence dramatically increases with the worsening of *From Geriatric Medicine (Drs. Antonelli-Incalzi and Pedone), University Campus Bio-Medico, Rome, Italy; the Italian National Research Center on Aging (Dr. Corsonello), Cosenza, Italy; the Department of Psychology (Dr. Trojano), Second University of Naples, Caserta, Italy; Salvatore Maugeri Foundation (Drs. Acanfora and Izzo), Institute of Care and Scientific Research, Rehabilitation Institute of Telese, Benevento, Italy; the San Raffaele Foundation (Dr. Spada), Cittadella della Carita`, Taranto, Italy; and Chair of Geriatric Medicine (Dr. Rengo), “Federico II” University School of Medicine, Naples, Italy. This study was supported by a grant from the Italian Ministry of Health (Conv. N. ICS 030.8/RF99.42). www.chestjournal.org
hypoxemia and the onset of hypercapnia.1–3 It involves several cognitive domains and, despite regular oxygen therapy, is associated with depressed cerebral metabolism of primary areas, which mimics that All authors have no conflict of interest in the subject matter of the manuscript. Received May 18, 2006; revision accepted July 19, 2006. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Andrea Corsonello, MD, Viale della Resistenza Pal Alfa Scala H, I-87036 Rende (CS), Italy; e-mail: [email protected] DOI: 10.1378/chest.130.6.1687 CHEST / 130 / 6 / DECEMBER, 2006
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observed in Alzheimer disease patients, and, to a lesser extent, associative areas.2,3 These findings suggest that cognitive impairment is an important index of COPD severity. Furthermore, cognitive impairment might contribute to the limitation of For editorial comment see page 1636 personal independence in selected instrumental activities of daily living (IADLs), such as managing money or self-administering drugs.3,4 Thus, cognitive impairment should be considered a primary component of the syndrome related to severe COPD. The last years of the natural history of COPD are characterized by a dramatic physical and psychological decline enhancing both the classificatory and discriminative capacity of indirect measures of disease severity, such as indicators of performance and health status.5,6 These indirect measures are also related to the prognosis.7 Cognitive impairment efficiently discriminates elderly COPD patients with different health status,8 but there is a distinct lack of information on whether it also has prognostic implications. We used longitudinal data from a population of patients with severe COPD to evaluate the impact of cognitive impairment on survival.
Materials and Methods From October 2000 to May 2002, we consecutively enrolled 149 COPD patients who had undergone a period 40 to 60 days of in-hospital rehabilitation following an acute exacerbation of COPD. At the time of data collection, participants were in stable condition, and their Pao2, Paco2, and personal independence were comparable to those reported before the exacerbation in the ambulatory records. The diagnosis of COPD was made according to American Thoracic Society standards.9 Only patients with a Pao2 of ⱕ 56 mm Hg either at rest or at the end of a 6-min walking test were selected because cognitive impairment is highly prevalent and clinically important in hypoxemic COPD patients.1,2 Probable Alzheimer disease,10 vascular dementia,1 or other diseases known to affect cognitive status11 were criteria of exclusion from the study. Obstructive sleep apnea (OSA) was excluded on the basis of a structured interview but not of a sleep study. The study protocol was approved by the ethics committees of the participating institutions. Patients gave an informed, written consent to be enrolled in the study. Clinical and neuropsychological assessment instruments relevant to the present study are described in Table 1.9,12–21 Follow-up and Analytic Approach Patients were followed up with a yearly telephone call. The mean (⫾ SD) duration of follow-up was 32.5 ⫾ 9.2 months. For survivors, the minimal duration of follow-up, corresponding to patients who were discharged from the hospital at the end of the
Table 1—Clinical and Neuropsychological Assessment Tools* Tools Clinical assessment Spirometry
Arterial blood gases 6-min walking test Comorbidity Personal independence
Neuropsychological assessment19–21 MMSE
MDB
Description
9,12–18
Spirometry with a bronchodilator test was performed by a computerized system (MedGraphics 1070; Medical Graphics Corporation; St. Paul, MN) and had to meet American Thoracic Society criteria of acceptability and reproducibility of curves9 Arterial blood gases were measured (Radiometer ABL 500; Diamond Diagnostics; Holliston, MA) while the patient was breathing room air for at least 1 h The 6-min walking test was performed according to the standardized protocol of Butland et al,12 and the 6MWD was expressed either as an absolute value or as the percent predicted13 Comorbid diseases were classified according to the ICD-9-CM14; coronary artery disease and renal failure were diagnosed according to clinical recommendations15,16 Personal independence was rated according to BADLs (ie, bathing, dressing, toileting, transferring, continence, and eating) and IADLs (ie, telephoning, outdoor moving and grocery shopping, traveling, taking medicine, and managing money)17,18; given that the vast majority of patients were men, data on housework-related IADLs were not collected The MMSE assesses the patient’s mental status in the following 5 areas: orientation to time and to place; primary verbal memory; attention calculation; secondary verbal memory; verbal attainment; and constructional ability. Scoring ⱖ 25 on the MMSE is considered to be diagnostic of normal cognitive status19; the instrument has been validated in the Italian population21 The MDB is a well-standardized battery that explores the following five cognitive domains through eight neuropsychological tests20: visual-spatial intelligence (Raven colored progressive matrices); controlled verbal production (verbal fluency test) and verbal competence (sentence construction); primary and secondary verbal memory (Rey auditory 15-word learning test); simple constructional function (copying of drawings: simple copy) and complex constructional function (copying of drawings: copy with landmarks); and visual memory (immediate visual memory); MDB scores range between 0 and 8, and a score of ⬍ 4 is considered to be diagnostic of dementia20; raw neuropsychological scores were corrected for age and education according to procedures standardized and validated for the Italian population20
*MDB ⫽ mental deterioration battery; ICD-9-CM ⫽ International Classification of Diseases, 9th revision, clinical modification. 1688
Original Research
last month of recruitment, was 24 months. The municipal registers were consulted when neither patients nor relatives or caregivers could be contacted (n ⫽ 13). For 15 patients, we had no follow-up information. We evaluated the hypothesis that cognitive impairment may represent an independent predictor of mortality. We selected for multivariable modeling the following three sets of variables: (1) variables having a known relationship with the outcome (ie, age, gender, post-bronchodilator therapy FEV1, body mass index [BMI], 6-min walk distance [6MWD], chronic renal failure, coronary artery disease, basic activities of daily living [BADLs], and IADLs); (2) neuropsychological indexes associated with the outcome; (3) indexes of disease severity (ie, Pao2 and Paco2). Since age and BMI were already accounted for in the model, we entered the 6MWD as the absolute value, not as a percent predicted value. To dichotomize continuous variables, we used cutoff values that were identified by the receiver operating characteristic.22 In univariate analysis, the incidence rate ratio and the corresponding 95% confidence interval (CI) were calculated. Proportional hazard Cox regression multivariable analysis was performed to estimate hazard ratios and 95% CIs. The proportional hazard assumption was tested analyzing the plot of the log-minuslog survival against the log of time. Since hypoxemia is a potential effect modifier of the association between neuropsychological deficit and survival, we compared mortality in people with hypoxemia without neuropsychological deficit, mortality in people with neuropsychological deficit without hypoxemia, and both risk factors compared with the mortality of people with neither risk factor. We used the Kaplan-Meier method to graphically display the risk of death, and we quantified the interaction between these factors using the synergy index.23,24 Statistical analysis was performed using a statistical software package (SPSS, version 10.0; SPSS Inc; Chicago, IL).
Results We had follow-up information for 134 of 149 participants (90% of the baseline cohort). Patients
who were lost to follow-up and those who were successfully tracked had comparable respiratory function test results, clinical/neuropsychological characteristics, and performance status, but patients lost to follow-up were older (mean age, 74.2 ⫾ 5.1 vs 69.0 ⫾ 8.6 years, respectively; F ⫽ 3.746 [by analysis of variance]; p ⫽ 0.057). Over a cumulative observation period of 4,362 months, 29 participants died. Demographic, clinical, and respiratory function characteristics of the patients considered in the analysis are reported in Table 2. Ninety-seven patients had a Pao2 of ⬍ 57 mm Hg at rest and, then, received oxygen therapy for 20 h daily; the remaining 37 patients had effort-induced hypoxemia. The mean age was nearly 70 years, and the majority of patients were men. Dependence in BADLs/IADLs was highly prevalent, as were coronary artery disease and renal failure. The mean 6MWD was ⬍ 300 m, which corresponds to ⬍ 60% of the predicted value. Spirometric and blood gas analysis values were consistent with severe COPD. Nonsurvivors were less educated and more frequently dependent in BADLs/IADLs than survivors, while age, gender distribution, BMI, and comorbidity did not differ among the groups. Nonsurvivors had lower Pao2, FEV1 percent predicted, and 6MWD with respect to survivors. The neuropsychological profile of patients is reported in Table 3. The prevalence of overall cognitive impairment, as expressed by a mini-mental state examination (MMSE) score of ⬍ 25, was 32.8%, and that of severe cognitive impairment, corresponding to a defective performance on more than four components of the mental deterioration battery, was
Table 2—Demographic, Clinical, and Respiratory Function Characteristics of the Patients Studied* Variables Age, yr Education, yr Female gender BMI, kg/m2 Dependent in at least 1 BADL Dependent in at least 1 IADL Coronary artery disease Renal failure 6MWD m % predicted FEV1, % pH Pco2, mm Hg Po2, mm Hg Sao2, %
All Patients (n ⫽ 134)
Survivors (n ⫽ 105)
Nonsurvivors (n ⫽ 29)
68.7 ⫾ 8.5 6.8 ⫾ 3.8 22 (16.4) 27.1 ⫾ 6.1 49 (36.6) 86 (64.2) 26 (19.4) 24 (17.9)
68.9 ⫾ 8.5 7.0 ⫾ 3.9 17 (16.2) 27.1 ⫾ 5.7 34 (32.4) 65 (61.9) 20 (19.0) 19 (18.1)
67.8 ⫾ 8.3 6.0 ⫾ 3.2 5 (17.2) 27.1 ⫾ 7.3 15 (51.7) 21 (72.4) 6 (20.7) 5 (17.2)
274 ⫾ 110 57.9 ⫾ 25.8 36.5 ⫾ 18.0 7.41 ⫾ 0.04 44.0 ⫾ 8.2 57.8 ⫾ 8.4 89.6 ⫾ 5.8
289 ⫾ 111 61.0 ⫾ 26.8 37.8 ⫾ 19.6 7.41 ⫾ 0.03 43.7 ⫾ 8.3 58.8 ⫾ 8.1 90.2 ⫾ 4.8
216 ⫾ 82 46.7 ⫾ 18.4 31.3 ⫾ 8.1 7.41 ⫾ 0.04 45.2 ⫾ 8.2 54.2 ⫾ 8.4 87.3 ⫾ 8.0
F-Statistic†
2
0.412 1.745 0.018 0.001 3.665 1.092 0.039 0.011 10.77 7.066 2.736 0.190 0.733 7.198 5.959
p Value 0.522 0.189 0.892 0.979 0.056 0.296 0.843 0.915 0.001 0.009 0.100 0.664 0.393 0.008 0.016
*Values are given as the mean ⫾ SD or No. of cases (%), unless otherwise indicated. †One-way analysis of variance. www.chestjournal.org
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Table 3—Prevalence of Abnormal Scores in Neuropsychological Tests* Variables Raven progressive matrices Verbal fluency Visual span Verbal span Verbal memory Short term Long term Copying drawings Copying drawings with landmarks Immediate visual memory Sentence construction MDB score MMSE score
All Patients (n ⫽ 134)
Survivors (n ⫽ 105)
Nonsurvivors (n ⫽ 29)
2
p Value
15 (11.2) 10 (7.5) 20 (14.9) 3 (2.2)
13 (12.4) 9 (8.6) 13 (12.4) 2 (1.9)
2 (6.9) 1 (3.4) 7 (24.1) 1 (3.4)
0.688 0.864 2.474 0.247
0.407 0.353 0.116 0.619
50 (37.3) 35 (26.1) 9 (6.7) 54 (40.3) 17 (12.7) 14 (10.4) 14 (10.4) 44 (32.8)
40 (38.1) 24 (22.9) 7 (6.7) 37 (35.2) 13 (12.4) 11 (10.5) 13 (12.4) 33 (31.4)
10 (34.5) 11 (37.9) 2 (6.9) 17 (58.6) 4 (13.8) 3 (10.3) 1 (3.4) 11 (37.9)
0.127 2.676 0.002 5.164 0.041 0.001 1.938 0.436
0.722 0.102 0.965 0.023 0.840 0.984 0.164 0.509
*Values are given as No. of cases (%), unless otherwise indicated. See Table 1 for abbreviation not used in the text.
10.4%. Drawing skills and verbal memory were the most frequently impaired cognitive domains (Table 3). Among neuropsychological tests, only the copying of a drawing with landmarks, which taps the integration of visuospatial and executive functions, was significantly associated with the mortality outcome in univariate analysis (Table 4). Results from multivariable analysis are reported in Table 5. After adjusting for potential confounders, 6MWD and drawing impairment were still associated with mortality, and we observed a weaker association of a Pao2 of ⬍ 57 mm Hg and an FEV1 of ⬍ 40% predicted. The cumulative survival of hypoxemic patients with or without drawing impairment was lower than that of nonhypoxemic patients (Mantel-Cox, 6.49 [p ⫽ 0.011]; Breslow, 6.40 [p ⫽ 0.011]). The survival curves of patients grouped according to the presence
Table 4 —Relationship Between Abnormal Performance on Individual Neuropsychological Tests and Mortality* 95% CI Limits Variables
IRR
Lower
Upper
Raven progressive matrices Verbal fluency Visual span Verbal span Verbal memory Short term Long term Copying drawings Copying drawings with landmarks Immediate visual memory Sentence construction MDB ⬍ 4 MMSE score ⬍ 25
0.56 0.41 2.08 1.95
0.13 0.05 0.89 0.26
2.37 3.0 4.88 14.3
0.88 1.83 0.93 3.46 1.14 1.04 0.28 1.47
0.41 0.86 0.22 1.65 0.40 0.31 0.04 0.69
1.90 3.87 3.91 7.24 3.28 3.43 2.06 3.11
*IRR ⫽ incidence rate ratio. See Table 1 for abbreviation not used in the text. 1690
of drawing impairments, hypoxemia, or both are shown in Figure 1. The contemporary presence of hypoxemia and drawing dysfunction was associated with a dramatic increase in mortality. This increase, however, was approximately equal to the sum of the risk associated with each factor, with only a weak synergic effect (synergy index, 1.7). Discussion We found that in patients with severe COPD two nonrespiratory indexes of health status (ie, a low score on the copying of a drawing with landmark test and a low 6MWD) predict mortality. The effect of neuropsychological dysfunction on mortality was independent of arterial hypoxemia, a nearly significant predictor, and the two factors showed only a weak synergy, indicating that the increase in risk in people with both factors is roughly equal to the sum of the risks associated with each of them. Likely due to a floor effect, neither age nor the severity of bronchial obstruction were associated with the outcome. The drawing skills, as explored by the copying of a drawing with landmark test, rely on both visuospatial and executive abilities. He´caen and Assal25 found that patients with lesions of the right hemisphere perform worse than those with lesions of the left hemisphere on this task, while Pillon26 demonstrated that patients with frontal lesions (ie, with likely executive dysfunction) are relatively impaired in performing the copying of a drawing with landmarks compared to patients with posterior cerebral lesions. Neurofunctional studies27 have shown that the drawing process is associated with activation of both the parietal and frontal cortexes (ie, with a frontoparietal network). Subcortical structures are part of such a network.28 Accordingly, not only frontal and parietal lesions, but also subcortical lesions likely are responOriginal Research
Table 5—Multivariable Cox Proportional Hazard Analysis To Identify Predictors of Mortality* 95% CI Limits Variables
HR
Lower
Upper
Age ⬍ 70 yr Female gender BMI ⬍ 20 kg/m2 FEV1 ⬍ 40% Po2 ⬍ 57 mm Hg Pco2 ⬍ 45 mm Hg Coronary artery disease and/or renal failure Dependence in at least 1 BADL Dependence in at least 1 IADL 6MWD ⬍ 300 m Impaired copying drawings with landmarks Normal copying drawings with landmarks and no hypoxemia Impaired copying drawings with landmarks and no hypoxemia Normal copying drawings with landmarks and hypoxemia Impaired copying drawings with landmarks and hypoxemia
0.86 1.16 1.15 2.74 2.19 1.44 1.43 1.78 1.62 3.46 2.93 Ref. 2.83 2.11 6.36
0.37 0.39 0.36 0.99 0.93 0.60 0.61 0.70 0.58 1.15 1.34
2.03 3.46 3.62 7.57 5.18 3.45 3.31 4.54 4.48 10.5 6.39
0.82 0.57 1.88
9.72 7.86 21.5
*HR ⫽ hazard ratio.
sible for defective drawing.29 The exact role of frontal lobes awaits definition, but the intracortical recording of prefrontal activation during drawing in monkeys30 and the involvement of the ventral premotor area in the preparation of copying movements in humans31 are consistent with a primary role. This bulk of evidence demonstrates that the drawing relies on the integration of parietal and frontal activities of the brain mediated through subcortical structures and cannot be considered a merely executive or merely visuospatial test. In the present
study, survivors could not be distinguished from nonsurvivors on the basis of the results of either a simple copying test or the copying of pentagon item on the MMSE (as demonstrated by an additional analysis not reported in this study). This fact could suggest that the completion of a constructional task that requires the integration of both visuospatial and executive abilities is specifically associated with higher mortality risk in our sample of COPD patients. In this respect, the strong association between executive dysfunction and the inability to correctly
Figure 1. Cumulative survival rate of patients grouped according to the absence or presence of a combined abnormal score on the copying a drawing with landmarks test and hypoxemia. www.chestjournal.org
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manage the inhalers further points at such a dysfunction being a marker of COPD severity.32 The executive dysfunction has been extensively studied and has proved to be a primary determinant of personal independence in non-COPD patients. It explains 56% of the variance in the ability to give informed consent for medical care by Parkinson disease patients and 70% of the variance in functional autonomy among persons in a community of elderly residents.33,34 Furthermore, in healthy elderly persons the executive dysfunction heralds worsening personal independence and contributes to the explanation of the negative effect of declining verbal memory on functional status.35,36 It also qualified as a risk factor for needing formal health care and for death in an independent elderly population.37 Finally, executive dysfunction is the dominant trait of frontal type dementia and is among the earliest manifestations of various types of secondary dementia.38,39 In COPD patients, executive dysfunction likely reflects the malfunctioning of neuronal circuits integrating subcortical and cortical parietal/ frontal areas.40 Interestingly, depressed frontal and anterior subcortical metabolism is a well-recognized correlate of COPD severity and COPD-related cognitive impairment, likely because deeply located regions and white matter are at a greater risk of hypoxia-related injury.2,41 Furthermore, hypertension and diabetes mellitus, which are highly prevalent comorbidities in populations of COPD patients, are risk factors for frontal type cognitive dysfunction.42 Defective prefrontal perfusion has also been documented in diabetic patients experiencing recurrent hypoglycemic crises.43 All of these reasons might explain the high prevalence of a defective copying of a drawing with landmarks test and its role as an indicator of disease severity in patients with advanced COPD. Finally, it is worth underlining that performance on the copying of a drawing with landmarks test, which strongly requires the interaction between visuospatial and executive skills through a widely distributed frontoparietal neural network, outweighs performance on “purer” constructional tests (ie, simple copying) and executive tests (ie, verbal fluency and Raven progressive matrices) as prognostic indicators. Confirming previous observations,44,45 the 6MWD results predicted survival, while BADLs/IADLs lacked prognostic implications. The only study46 testing activities of daily living as a prognostic marker in COPD patients found that they lacked predictivity in the multivariable model. However, the 6MWD and the level of independence in BADLs/IADLs are strictly related.47 Thus, BADLs/IADLs are candidates for markers with which to predict survival. This did not occur likely because the continuous distribu1692
tion and a very large range of possible values enhance the classificatory capacity and, then, the predictivity of the 6MWD. Indeed, walking capacity declines continuously with decreasing aerobic fitness,48 while the ability to perform BADLs is retained until the maximal oxygen uptake drops to ⬍ 750 mL/min.49 Evidence suggests that a structured screening of cognitive function should be a routine component of the assessment of elderly COPD patients, either for identifying those at risk of poor compliance or for prognostic purposes.2,3,50 However, the assessment of executive function is marginal or absent in some of the most popular screening instruments such as the abbreviated mental test51 and the short portable mental status questionnaire.52 On the other hand, a patient with executive dysfunction might score normally even on a screening instrument assessing such a domain (eg, the MMSE) because the score reflects the overall cognitive performance. Accordingly, classificatory and predictive properties of screening tests that focus on executive function but are able to distinguish executive from praxic dysfunction, such as in the clock-drawing test, seem worthy of assessment in COPD patients.53 This study has some limitations. First, the patients who were lost to follow-up were older than those who were tracked. Thus, we likely underestimated mortality and the prognostic role of malnutrition. Second, OSA was excluded on the basis of the results of a sleep questionnaire and not the results of a sleep study. Theoretically, some cases of overlap syndrome might have remained unrecognized, thus increasing the prevalence and/or severity of executive dysfunction. Third, all of the patients regularly attended the outpatient respiratory departments at the two institutions where they were initially studied. While this guarantees for an accurate definition of stable COPD, results might not completely apply to the heterogeneous home-dwelling COPD population. Finally, at the time the study was designed we had not specifically hypothesized that executive dysfunction played a primary prognostic role, and thus we did not assess “frontal” functions by means of neuropsychological tests tapping their multifaceted aspects. In conclusion, the copying of a drawing with landmarks test can be used as a prognostic marker in COPD patients. Future research should verify whether this finding reflects a distinctive impairment of executive dysfunction in patients with severe COPD or, alternatively and mimicking the early stages of Alzheimer disease, a constructional dyspraxia due to right insular involvement.54 Research is also needed to assess whether the observed neuropsychological dysfunction is a clue to detecting conOriginal Research
current OSA, the poor quality of oxygen therapy, or the poor control of comorbid diseases such as diabetes mellitus. Clarifying these issues will enable us to define the clinical meaning of the present findings and, hopefully, to improve the care of COPD patients. References 1 Antonelli Incalzi R, Gemma A, Marra C, et al. Chronic obstructive pulmonary disease: an original model of cognitive decline. Am Rev Respir Dis 1993; 148:418 – 424 2 Antonelli Incalzi R, Marra C, Giordano A, et al. Cognitive impairment in chronic obstructive pulmonary disease: a neuropsychological and SPECT study. J Neurol 2003; 250:325– 332 3 Antonelli Incalzi R, Gemma A, Marra C, et al. Verbal memory impairment in COPD: its mechanisms and clinical relevance. Chest 1997; 112:1506 –1513 4 Antonelli Incalzi R, Corsonello A, Pedone C, et al. Construct validity of activities of daily living scale: a clue to distinguish the disabling effects of COPD and congestive heart failure. Chest 2005; 127:830 – 838 5 Almagro P, Julia J, Sanjaume M, et al. Mortality after hospitalization for COPD. Chest 2002; 121:1441–1448 6 Sprenkle MD, Niewoehner DE, Nelson DB, et al. The Veterans Short Form 36 questionnaire is predictive of mortality and health-care utilization in a population of veterans with a self-reported diagnosis of asthma or COPD. Chest 2004; 126:81– 89 7 Domingo-Salvany A, La Marca R, Ferrer M, et al. Healthrelated quality of life and mortality in male patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166:680 – 685 8 Antonelli Incalzi R, Bellia V, Catalano F, et al. Evaluation of health outcomes in elderly patients with asthma and COPD using disease-specific and generic instruments: the Salute Respiratoria nell’Anziano (Sa.R.A.) Study. Chest 2001; 120: 734 –742 9 American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152:s77–s120 10 McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDSADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34:939 –944 11 American Medical Association. Consensus Conference. Differential diagnosis of dementing diseases. JAMA 1987; 258: 3411–3416 12 Butland RJA, Pang J, Gross ER, et al. Two, six, and 12 minute walking tests in respiratory disease. BMJ 1982; 284:1607– 1608 13 Enright PL, Sherrill DL. Reference equations for the sixminute walk in healthy adults. Am J Respir Crit Care Med 1998; 158:1384 –1387 14 World Health Organization. PHS-HCF: international classification of diseases: 9th revision; clinical modification. Washington, DC: Public Health Service, Health Care Financing Administration, 1980 15 Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACPASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations; a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Comwww.chestjournal.org
16
17
18
19
20
21
22 23 24 25 26 27 28
29 30 31 32 33 34
35
36
mittee on Management of Patients with Chronic Stable Angina). Circulation 1999; 99:2829 –2848 Mendelssohn DC, Barrett BJ, Brownscombe LM, et al. Elevated levels of serum creatinine: recommendations for management and referral. Can Med Assoc J 1999; 161:413– 417 Katz S, Ford AB, Moskowitz RW, et al. Studies of illness in aged: the index of ADL, a standardized measure of biological and psychosocial function. JAMA 1963; 185:94 –106 Lawton MP, Brody EM. Assessment of older people: selfmaintaining and instrumental activities of daily living. Gerontologist 1969; 9:179 –186 Folstein MF, Folstein SE, McHigh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189 –198 Carlesimo GA, Caltagirone C, Gainotti G. The mental deterioration battery: normative data, diagnostic reliability and qualitative analyses of cognitive impairment; the Group for the Standardization of the Mental Deterioration Battery. Eur Neurol 1996; 36:378 –384 Magni E, Binetti G, Bianchetti A, et al. Mini-mental state examination: a normative study in Italian elderly population. Eur J Neurol 1996; 3:1–5 Hanley JA, McNeil BJ. The meaning and use of the area under a receiver-operating characteristics (ROC) curve. Radiology 1982; 143:29 –36 Rothman KJ. Epidemiology: an introduction. New York, NY: Oxford University Press, 2002 Rothman KJ, Greenland S. Modern epidemiology. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 1998 He´caen H, Assal G. A comparison of constructive deficits following right and left hemispheric lesions. Neuropsychologia 1970; 8:289 –303 Pillon B. Visuo-constructive problems and methods of compensation: results for 85 patients with brain lesions. Neuropsychologia 1981; 19:375–383 Ino T, Asada T, Ito J, et al. Parieto-frontal networks for clock drawing revealed with fMRI. Neurosci Res 2003; 45:71–77 Makuuchi M, Kaminaga T, Sugishita M. Both parietal lobes are involved in drawing: a functional MRI study and implications for constructional apraxia. Brain Res Cogn Brain Res 2003; 16:338 –347 Shulman KI. Clock-drawing: is it the ideal cognitive screening test? Int J Geriatr Psychiatry 2000; 15:548 –561 Averbeck BB, Chafee MV, Crowe DA, et al. Parallel processing of serial movements in prefrontal cortex. Proc Natl Acad Sci U S A 2002; 99:13172–13177 Krams M, Rushworth MF, Deiber MP, et al. The preparation, execution and suppression of copied movements in the human brain. Exp Brain Res 1998; 120:386 –398 Allen SC, Jain M, Ragab S, et al. Acquisition and short-term retention of inhaler techniques require intact executive function in elderly subjects. Age Ageing 2003; 32:299 –302 Dymek MP, Atchinson P, Harrel L, et al. Competency to consent to medical treatment in cognitively impaired patients with Parkinson’s disease. Neurology 2001; 56:17–24 Grace AN, Baker PS, Allman RM. Neurocognitive correlates of lifespace [abstract]. Presented at the annual meeting of the American Geriatric Society, Philadelphia, PA; May 20 –23, 1999; 95 Royall DR, Palmer R, Chiodo LK, et al. Declining executive control in normal aging predicts change in functional status: the Freedom House Study. J Am Geriatr Soc 2004; 52:346 – 352 Royall DR, Palmer R, Chiodo LK, et al. Executive control mediates memory’s association with change in instrumental CHEST / 130 / 6 / DECEMBER, 2006
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38 39 40 41 42
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activities of daily living: the Freedom House Study. J Am Geriatr Soc 2005; 53:11–17 Lavery LL, Starenchak SM, Flynn WB, et al. The clock drawing test is an independent predictor of incident use of 24-hour care in a retirement community. J Gerontol A Biol Sci Med Sci 2005; 60:928 –932 Royall DR. Executive cognitive impairment: a novel perspective on dementia. Neuroepidemiology 2000; 19:293–299 Buracchio T, Arvanitakis Z, Gorbien M. Dementia with Lewy bodies: current concepts. Dement Geriatr Cogn Disord 2005; 20:306 –320 Boone KB, Miller BL, Lesser IM, et al. Neuropsychological correlates of white-matter lesions in healthy elderly subjects: a threshold effect. Arch Neurol 1992; 49:549 –554 Shim TS, Lee JH, Kim ST, et al. Cerebral metabolic abnormalities in COPD patients detected by localized proton magnetic resonance spectroscopy. Chest 2001; 120:1506 –1513 Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment: beyond controversies, towards a consensus; report of the International Working Group on Mild Cognitive Impairment. J Intern Med 2004; 256:240 –246 MacLeod KM, Hepburn DA, Deary IJ, et al. Regional cerebral blood flow in IDDM patients: effects of diabetes and of recurrent severe hypoglycaemia. Diabetologia 1994; 37: 257–263 Gerardi DA, Lovett L, Benoit-Connors ML, et al. Variables related to increased mortality following outpatient pulmonary rehabilitation. Eur Respir J 1996; 9:431– 435 Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension: comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 2000; 161:487– 492
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46 Yohannes AM, Baldwin RC, Connolly MJ. Predictors of 1-year mortality in patients discharged from hospital following acute exacerbation of chronic obstructive pulmonary disease. Age Ageing 2005; 34:491– 496 47 Bendstrup KE, Ingemann Jensen J, Holm S, et al. Outpatient rehabilitation improves activities of daily living, quality of life and exercise tolerance in chronic obstructive pulmonary disease. Eur Respir J 1997; 10:2801–2806 48 Cahalin L, Pappagianopoulos P, Prevost S, et al. The relationship of the 6-min walk test to maximal oxygen consumption in transplant candidates with end-stage lung disease. Chest 1995; 108:452– 459 49 Posner JD, McCully KK, Landsberg LA, et al. Physical determinants of independence in mature women. Arch Phys Med Rehabil 1995; 76:373–380 50 Burgess A, Kunik ME, Stanley MA. Chronic obstructive pulmonary disease: assessing and treating psychological issues in patients with COPD. Geriatrics 2005; 60:18 –21 51 Rocca WA, Bonaiuto S, Lippi A, et al. Validation of the Hodkinson Abbreviated Mental Test as a screening instrument for dementia in an Italian population. Neuroepidemiology 1992; 11:288 –295 52 Pfeiffer E. A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients. J Am Geriatr Soc 1975; 23:433– 441 53 Royall DR, Cordes JA, Polk M. CLOX: an executive clock drawing task. J Neurol Neurosurg Psychiatry 1998; 64:588 – 594 54 Royall DR, Gao JH, Kellogg DL Jr. Insular Alzheimer’s disease pathology as a cause of “age-related” autonomic dysfunction and mortality in the non-demented elderly. Med Hypotheses 2006; 67:747–758
Original Research
Original Research COPD
Drawing Impairment Predicts Mortality in Severe COPD* Raffaele Antonelli-Incalzi, MD; Andrea Corsonello, MD; Claudio Pedone, MD; Luigi Trojano, MD; Domenico Acanfora, MD; Aldo Spada, MD; Orsola Izzo, PsyD; and Franco Rengo, MD
Background: Cognitive impairment frequently occurs in elderly COPD patients, but little is known about its prognostic implications. We aimed at evaluating the prognostic role of cognitive impairment in patients with severe COPD. Methods: Our series consisted of 149 stable patients (mean [ⴞ SD] age, 68.7 ⴞ 8.5 years) with COPD and a PaO2 of < 57 mm Hg at rest (n ⴝ 97) or at the end of the 6-min walking test (n ⴝ 37) who were enrolled in a prospective observational study. After a multidimensional baseline assessment, patients were followed up by telephone calls for a mean duration of 32.5 ⴞ 9.2 months (minimal follow-up duration, 24 months); 134 patients were successfully tracked. We used multivariable Cox proportional hazard analysis to identify predictors of death among clinical/ functional variables that previously were shown to have prognostic implications and among neuropsychological indexes selected on the basis of univariate analysis. Results: We observed 29 deaths over a median follow-up time of 32 months. Only the two following variables were independently associated with the outcome: an abnormal score on the copy with landmark test (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.34 to 6.39); and a 6-min walk distance of < 300 m (HR, 3.46; 95% CI, 1.15 to 10.5). A PaO2 of < 57 mm Hg at rest (HR, 2.19; 95% CI, 0.93 to 5.18) and an FEV1 of < 40% predicted (HR, 2.74; 95% CI, 0.99 to 7.57) were nearly significantly associated with the outcome, while PaCO2, body mass index, physical dependence, comorbid diseases, and the impairment of cognitive domains other than drawing impairment were unrelated to the outcome. Conclusions: Drawing impairment is a risk factor for mortality and might improve the assessment of hypoxemic COPD patients. (CHEST 2006; 130:1687–1694) Key words: cognitive impairment; COPD; drawing impairment; mortality Abbreviations: BADL ⫽ basic activity of daily living; BMI ⫽ body mass index; CI ⫽ confidence interval; IADL ⫽ instrumental activity of daily living; MMSE ⫽ mini-mental state examination; OSA ⫽ obstructive sleep apnea; 6MWD ⫽ 6-min walk distance
impairment is one of the most common C ognitive nonrespiratory effects of COPD, and its prevalence dramatically increases with the worsening of *From Geriatric Medicine (Drs. Antonelli-Incalzi and Pedone), University Campus Bio-Medico, Rome, Italy; the Italian National Research Center on Aging (Dr. Corsonello), Cosenza, Italy; the Department of Psychology (Dr. Trojano), Second University of Naples, Caserta, Italy; Salvatore Maugeri Foundation (Drs. Acanfora and Izzo), Institute of Care and Scientific Research, Rehabilitation Institute of Telese, Benevento, Italy; the San Raffaele Foundation (Dr. Spada), Cittadella della Carita`, Taranto, Italy; and Chair of Geriatric Medicine (Dr. Rengo), “Federico II” University School of Medicine, Naples, Italy. This study was supported by a grant from the Italian Ministry of Health (Conv. N. ICS 030.8/RF99.42). www.chestjournal.org
hypoxemia and the onset of hypercapnia.1–3 It involves several cognitive domains and, despite regular oxygen therapy, is associated with depressed cerebral metabolism of primary areas, which mimics that All authors have no conflict of interest in the subject matter of the manuscript. Received May 18, 2006; revision accepted July 19, 2006. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Andrea Corsonello, MD, Viale della Resistenza Pal Alfa Scala H, I-87036 Rende (CS), Italy; e-mail: [email protected] DOI: 10.1378/chest.130.6.1687 CHEST / 130 / 6 / DECEMBER, 2006
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observed in Alzheimer disease patients, and, to a lesser extent, associative areas.2,3 These findings suggest that cognitive impairment is an important index of COPD severity. Furthermore, cognitive impairment might contribute to the limitation of For editorial comment see page 1636 personal independence in selected instrumental activities of daily living (IADLs), such as managing money or self-administering drugs.3,4 Thus, cognitive impairment should be considered a primary component of the syndrome related to severe COPD. The last years of the natural history of COPD are characterized by a dramatic physical and psychological decline enhancing both the classificatory and discriminative capacity of indirect measures of disease severity, such as indicators of performance and health status.5,6 These indirect measures are also related to the prognosis.7 Cognitive impairment efficiently discriminates elderly COPD patients with different health status,8 but there is a distinct lack of information on whether it also has prognostic implications. We used longitudinal data from a population of patients with severe COPD to evaluate the impact of cognitive impairment on survival.
Materials and Methods From October 2000 to May 2002, we consecutively enrolled 149 COPD patients who had undergone a period 40 to 60 days of in-hospital rehabilitation following an acute exacerbation of COPD. At the time of data collection, participants were in stable condition, and their Pao2, Paco2, and personal independence were comparable to those reported before the exacerbation in the ambulatory records. The diagnosis of COPD was made according to American Thoracic Society standards.9 Only patients with a Pao2 of ⱕ 56 mm Hg either at rest or at the end of a 6-min walking test were selected because cognitive impairment is highly prevalent and clinically important in hypoxemic COPD patients.1,2 Probable Alzheimer disease,10 vascular dementia,1 or other diseases known to affect cognitive status11 were criteria of exclusion from the study. Obstructive sleep apnea (OSA) was excluded on the basis of a structured interview but not of a sleep study. The study protocol was approved by the ethics committees of the participating institutions. Patients gave an informed, written consent to be enrolled in the study. Clinical and neuropsychological assessment instruments relevant to the present study are described in Table 1.9,12–21 Follow-up and Analytic Approach Patients were followed up with a yearly telephone call. The mean (⫾ SD) duration of follow-up was 32.5 ⫾ 9.2 months. For survivors, the minimal duration of follow-up, corresponding to patients who were discharged from the hospital at the end of the
Table 1—Clinical and Neuropsychological Assessment Tools* Tools Clinical assessment Spirometry
Arterial blood gases 6-min walking test Comorbidity Personal independence
Neuropsychological assessment19–21 MMSE
MDB
Description
9,12–18
Spirometry with a bronchodilator test was performed by a computerized system (MedGraphics 1070; Medical Graphics Corporation; St. Paul, MN) and had to meet American Thoracic Society criteria of acceptability and reproducibility of curves9 Arterial blood gases were measured (Radiometer ABL 500; Diamond Diagnostics; Holliston, MA) while the patient was breathing room air for at least 1 h The 6-min walking test was performed according to the standardized protocol of Butland et al,12 and the 6MWD was expressed either as an absolute value or as the percent predicted13 Comorbid diseases were classified according to the ICD-9-CM14; coronary artery disease and renal failure were diagnosed according to clinical recommendations15,16 Personal independence was rated according to BADLs (ie, bathing, dressing, toileting, transferring, continence, and eating) and IADLs (ie, telephoning, outdoor moving and grocery shopping, traveling, taking medicine, and managing money)17,18; given that the vast majority of patients were men, data on housework-related IADLs were not collected The MMSE assesses the patient’s mental status in the following 5 areas: orientation to time and to place; primary verbal memory; attention calculation; secondary verbal memory; verbal attainment; and constructional ability. Scoring ⱖ 25 on the MMSE is considered to be diagnostic of normal cognitive status19; the instrument has been validated in the Italian population21 The MDB is a well-standardized battery that explores the following five cognitive domains through eight neuropsychological tests20: visual-spatial intelligence (Raven colored progressive matrices); controlled verbal production (verbal fluency test) and verbal competence (sentence construction); primary and secondary verbal memory (Rey auditory 15-word learning test); simple constructional function (copying of drawings: simple copy) and complex constructional function (copying of drawings: copy with landmarks); and visual memory (immediate visual memory); MDB scores range between 0 and 8, and a score of ⬍ 4 is considered to be diagnostic of dementia20; raw neuropsychological scores were corrected for age and education according to procedures standardized and validated for the Italian population20
*MDB ⫽ mental deterioration battery; ICD-9-CM ⫽ International Classification of Diseases, 9th revision, clinical modification. 1688
Original Research
last month of recruitment, was 24 months. The municipal registers were consulted when neither patients nor relatives or caregivers could be contacted (n ⫽ 13). For 15 patients, we had no follow-up information. We evaluated the hypothesis that cognitive impairment may represent an independent predictor of mortality. We selected for multivariable modeling the following three sets of variables: (1) variables having a known relationship with the outcome (ie, age, gender, post-bronchodilator therapy FEV1, body mass index [BMI], 6-min walk distance [6MWD], chronic renal failure, coronary artery disease, basic activities of daily living [BADLs], and IADLs); (2) neuropsychological indexes associated with the outcome; (3) indexes of disease severity (ie, Pao2 and Paco2). Since age and BMI were already accounted for in the model, we entered the 6MWD as the absolute value, not as a percent predicted value. To dichotomize continuous variables, we used cutoff values that were identified by the receiver operating characteristic.22 In univariate analysis, the incidence rate ratio and the corresponding 95% confidence interval (CI) were calculated. Proportional hazard Cox regression multivariable analysis was performed to estimate hazard ratios and 95% CIs. The proportional hazard assumption was tested analyzing the plot of the log-minuslog survival against the log of time. Since hypoxemia is a potential effect modifier of the association between neuropsychological deficit and survival, we compared mortality in people with hypoxemia without neuropsychological deficit, mortality in people with neuropsychological deficit without hypoxemia, and both risk factors compared with the mortality of people with neither risk factor. We used the Kaplan-Meier method to graphically display the risk of death, and we quantified the interaction between these factors using the synergy index.23,24 Statistical analysis was performed using a statistical software package (SPSS, version 10.0; SPSS Inc; Chicago, IL).
Results We had follow-up information for 134 of 149 participants (90% of the baseline cohort). Patients
who were lost to follow-up and those who were successfully tracked had comparable respiratory function test results, clinical/neuropsychological characteristics, and performance status, but patients lost to follow-up were older (mean age, 74.2 ⫾ 5.1 vs 69.0 ⫾ 8.6 years, respectively; F ⫽ 3.746 [by analysis of variance]; p ⫽ 0.057). Over a cumulative observation period of 4,362 months, 29 participants died. Demographic, clinical, and respiratory function characteristics of the patients considered in the analysis are reported in Table 2. Ninety-seven patients had a Pao2 of ⬍ 57 mm Hg at rest and, then, received oxygen therapy for 20 h daily; the remaining 37 patients had effort-induced hypoxemia. The mean age was nearly 70 years, and the majority of patients were men. Dependence in BADLs/IADLs was highly prevalent, as were coronary artery disease and renal failure. The mean 6MWD was ⬍ 300 m, which corresponds to ⬍ 60% of the predicted value. Spirometric and blood gas analysis values were consistent with severe COPD. Nonsurvivors were less educated and more frequently dependent in BADLs/IADLs than survivors, while age, gender distribution, BMI, and comorbidity did not differ among the groups. Nonsurvivors had lower Pao2, FEV1 percent predicted, and 6MWD with respect to survivors. The neuropsychological profile of patients is reported in Table 3. The prevalence of overall cognitive impairment, as expressed by a mini-mental state examination (MMSE) score of ⬍ 25, was 32.8%, and that of severe cognitive impairment, corresponding to a defective performance on more than four components of the mental deterioration battery, was
Table 2—Demographic, Clinical, and Respiratory Function Characteristics of the Patients Studied* Variables Age, yr Education, yr Female gender BMI, kg/m2 Dependent in at least 1 BADL Dependent in at least 1 IADL Coronary artery disease Renal failure 6MWD m % predicted FEV1, % pH Pco2, mm Hg Po2, mm Hg Sao2, %
All Patients (n ⫽ 134)
Survivors (n ⫽ 105)
Nonsurvivors (n ⫽ 29)
68.7 ⫾ 8.5 6.8 ⫾ 3.8 22 (16.4) 27.1 ⫾ 6.1 49 (36.6) 86 (64.2) 26 (19.4) 24 (17.9)
68.9 ⫾ 8.5 7.0 ⫾ 3.9 17 (16.2) 27.1 ⫾ 5.7 34 (32.4) 65 (61.9) 20 (19.0) 19 (18.1)
67.8 ⫾ 8.3 6.0 ⫾ 3.2 5 (17.2) 27.1 ⫾ 7.3 15 (51.7) 21 (72.4) 6 (20.7) 5 (17.2)
274 ⫾ 110 57.9 ⫾ 25.8 36.5 ⫾ 18.0 7.41 ⫾ 0.04 44.0 ⫾ 8.2 57.8 ⫾ 8.4 89.6 ⫾ 5.8
289 ⫾ 111 61.0 ⫾ 26.8 37.8 ⫾ 19.6 7.41 ⫾ 0.03 43.7 ⫾ 8.3 58.8 ⫾ 8.1 90.2 ⫾ 4.8
216 ⫾ 82 46.7 ⫾ 18.4 31.3 ⫾ 8.1 7.41 ⫾ 0.04 45.2 ⫾ 8.2 54.2 ⫾ 8.4 87.3 ⫾ 8.0
F-Statistic†
2
0.412 1.745 0.018 0.001 3.665 1.092 0.039 0.011 10.77 7.066 2.736 0.190 0.733 7.198 5.959
p Value 0.522 0.189 0.892 0.979 0.056 0.296 0.843 0.915 0.001 0.009 0.100 0.664 0.393 0.008 0.016
*Values are given as the mean ⫾ SD or No. of cases (%), unless otherwise indicated. †One-way analysis of variance. www.chestjournal.org
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Table 3—Prevalence of Abnormal Scores in Neuropsychological Tests* Variables Raven progressive matrices Verbal fluency Visual span Verbal span Verbal memory Short term Long term Copying drawings Copying drawings with landmarks Immediate visual memory Sentence construction MDB score MMSE score
All Patients (n ⫽ 134)
Survivors (n ⫽ 105)
Nonsurvivors (n ⫽ 29)
2
p Value
15 (11.2) 10 (7.5) 20 (14.9) 3 (2.2)
13 (12.4) 9 (8.6) 13 (12.4) 2 (1.9)
2 (6.9) 1 (3.4) 7 (24.1) 1 (3.4)
0.688 0.864 2.474 0.247
0.407 0.353 0.116 0.619
50 (37.3) 35 (26.1) 9 (6.7) 54 (40.3) 17 (12.7) 14 (10.4) 14 (10.4) 44 (32.8)
40 (38.1) 24 (22.9) 7 (6.7) 37 (35.2) 13 (12.4) 11 (10.5) 13 (12.4) 33 (31.4)
10 (34.5) 11 (37.9) 2 (6.9) 17 (58.6) 4 (13.8) 3 (10.3) 1 (3.4) 11 (37.9)
0.127 2.676 0.002 5.164 0.041 0.001 1.938 0.436
0.722 0.102 0.965 0.023 0.840 0.984 0.164 0.509
*Values are given as No. of cases (%), unless otherwise indicated. See Table 1 for abbreviation not used in the text.
10.4%. Drawing skills and verbal memory were the most frequently impaired cognitive domains (Table 3). Among neuropsychological tests, only the copying of a drawing with landmarks, which taps the integration of visuospatial and executive functions, was significantly associated with the mortality outcome in univariate analysis (Table 4). Results from multivariable analysis are reported in Table 5. After adjusting for potential confounders, 6MWD and drawing impairment were still associated with mortality, and we observed a weaker association of a Pao2 of ⬍ 57 mm Hg and an FEV1 of ⬍ 40% predicted. The cumulative survival of hypoxemic patients with or without drawing impairment was lower than that of nonhypoxemic patients (Mantel-Cox, 6.49 [p ⫽ 0.011]; Breslow, 6.40 [p ⫽ 0.011]). The survival curves of patients grouped according to the presence
Table 4 —Relationship Between Abnormal Performance on Individual Neuropsychological Tests and Mortality* 95% CI Limits Variables
IRR
Lower
Upper
Raven progressive matrices Verbal fluency Visual span Verbal span Verbal memory Short term Long term Copying drawings Copying drawings with landmarks Immediate visual memory Sentence construction MDB ⬍ 4 MMSE score ⬍ 25
0.56 0.41 2.08 1.95
0.13 0.05 0.89 0.26
2.37 3.0 4.88 14.3
0.88 1.83 0.93 3.46 1.14 1.04 0.28 1.47
0.41 0.86 0.22 1.65 0.40 0.31 0.04 0.69
1.90 3.87 3.91 7.24 3.28 3.43 2.06 3.11
*IRR ⫽ incidence rate ratio. See Table 1 for abbreviation not used in the text. 1690
of drawing impairments, hypoxemia, or both are shown in Figure 1. The contemporary presence of hypoxemia and drawing dysfunction was associated with a dramatic increase in mortality. This increase, however, was approximately equal to the sum of the risk associated with each factor, with only a weak synergic effect (synergy index, 1.7). Discussion We found that in patients with severe COPD two nonrespiratory indexes of health status (ie, a low score on the copying of a drawing with landmark test and a low 6MWD) predict mortality. The effect of neuropsychological dysfunction on mortality was independent of arterial hypoxemia, a nearly significant predictor, and the two factors showed only a weak synergy, indicating that the increase in risk in people with both factors is roughly equal to the sum of the risks associated with each of them. Likely due to a floor effect, neither age nor the severity of bronchial obstruction were associated with the outcome. The drawing skills, as explored by the copying of a drawing with landmark test, rely on both visuospatial and executive abilities. He´caen and Assal25 found that patients with lesions of the right hemisphere perform worse than those with lesions of the left hemisphere on this task, while Pillon26 demonstrated that patients with frontal lesions (ie, with likely executive dysfunction) are relatively impaired in performing the copying of a drawing with landmarks compared to patients with posterior cerebral lesions. Neurofunctional studies27 have shown that the drawing process is associated with activation of both the parietal and frontal cortexes (ie, with a frontoparietal network). Subcortical structures are part of such a network.28 Accordingly, not only frontal and parietal lesions, but also subcortical lesions likely are responOriginal Research
Table 5—Multivariable Cox Proportional Hazard Analysis To Identify Predictors of Mortality* 95% CI Limits Variables
HR
Lower
Upper
Age ⬍ 70 yr Female gender BMI ⬍ 20 kg/m2 FEV1 ⬍ 40% Po2 ⬍ 57 mm Hg Pco2 ⬍ 45 mm Hg Coronary artery disease and/or renal failure Dependence in at least 1 BADL Dependence in at least 1 IADL 6MWD ⬍ 300 m Impaired copying drawings with landmarks Normal copying drawings with landmarks and no hypoxemia Impaired copying drawings with landmarks and no hypoxemia Normal copying drawings with landmarks and hypoxemia Impaired copying drawings with landmarks and hypoxemia
0.86 1.16 1.15 2.74 2.19 1.44 1.43 1.78 1.62 3.46 2.93 Ref. 2.83 2.11 6.36
0.37 0.39 0.36 0.99 0.93 0.60 0.61 0.70 0.58 1.15 1.34
2.03 3.46 3.62 7.57 5.18 3.45 3.31 4.54 4.48 10.5 6.39
0.82 0.57 1.88
9.72 7.86 21.5
*HR ⫽ hazard ratio.
sible for defective drawing.29 The exact role of frontal lobes awaits definition, but the intracortical recording of prefrontal activation during drawing in monkeys30 and the involvement of the ventral premotor area in the preparation of copying movements in humans31 are consistent with a primary role. This bulk of evidence demonstrates that the drawing relies on the integration of parietal and frontal activities of the brain mediated through subcortical structures and cannot be considered a merely executive or merely visuospatial test. In the present
study, survivors could not be distinguished from nonsurvivors on the basis of the results of either a simple copying test or the copying of pentagon item on the MMSE (as demonstrated by an additional analysis not reported in this study). This fact could suggest that the completion of a constructional task that requires the integration of both visuospatial and executive abilities is specifically associated with higher mortality risk in our sample of COPD patients. In this respect, the strong association between executive dysfunction and the inability to correctly
Figure 1. Cumulative survival rate of patients grouped according to the absence or presence of a combined abnormal score on the copying a drawing with landmarks test and hypoxemia. www.chestjournal.org
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manage the inhalers further points at such a dysfunction being a marker of COPD severity.32 The executive dysfunction has been extensively studied and has proved to be a primary determinant of personal independence in non-COPD patients. It explains 56% of the variance in the ability to give informed consent for medical care by Parkinson disease patients and 70% of the variance in functional autonomy among persons in a community of elderly residents.33,34 Furthermore, in healthy elderly persons the executive dysfunction heralds worsening personal independence and contributes to the explanation of the negative effect of declining verbal memory on functional status.35,36 It also qualified as a risk factor for needing formal health care and for death in an independent elderly population.37 Finally, executive dysfunction is the dominant trait of frontal type dementia and is among the earliest manifestations of various types of secondary dementia.38,39 In COPD patients, executive dysfunction likely reflects the malfunctioning of neuronal circuits integrating subcortical and cortical parietal/ frontal areas.40 Interestingly, depressed frontal and anterior subcortical metabolism is a well-recognized correlate of COPD severity and COPD-related cognitive impairment, likely because deeply located regions and white matter are at a greater risk of hypoxia-related injury.2,41 Furthermore, hypertension and diabetes mellitus, which are highly prevalent comorbidities in populations of COPD patients, are risk factors for frontal type cognitive dysfunction.42 Defective prefrontal perfusion has also been documented in diabetic patients experiencing recurrent hypoglycemic crises.43 All of these reasons might explain the high prevalence of a defective copying of a drawing with landmarks test and its role as an indicator of disease severity in patients with advanced COPD. Finally, it is worth underlining that performance on the copying of a drawing with landmarks test, which strongly requires the interaction between visuospatial and executive skills through a widely distributed frontoparietal neural network, outweighs performance on “purer” constructional tests (ie, simple copying) and executive tests (ie, verbal fluency and Raven progressive matrices) as prognostic indicators. Confirming previous observations,44,45 the 6MWD results predicted survival, while BADLs/IADLs lacked prognostic implications. The only study46 testing activities of daily living as a prognostic marker in COPD patients found that they lacked predictivity in the multivariable model. However, the 6MWD and the level of independence in BADLs/IADLs are strictly related.47 Thus, BADLs/IADLs are candidates for markers with which to predict survival. This did not occur likely because the continuous distribu1692
tion and a very large range of possible values enhance the classificatory capacity and, then, the predictivity of the 6MWD. Indeed, walking capacity declines continuously with decreasing aerobic fitness,48 while the ability to perform BADLs is retained until the maximal oxygen uptake drops to ⬍ 750 mL/min.49 Evidence suggests that a structured screening of cognitive function should be a routine component of the assessment of elderly COPD patients, either for identifying those at risk of poor compliance or for prognostic purposes.2,3,50 However, the assessment of executive function is marginal or absent in some of the most popular screening instruments such as the abbreviated mental test51 and the short portable mental status questionnaire.52 On the other hand, a patient with executive dysfunction might score normally even on a screening instrument assessing such a domain (eg, the MMSE) because the score reflects the overall cognitive performance. Accordingly, classificatory and predictive properties of screening tests that focus on executive function but are able to distinguish executive from praxic dysfunction, such as in the clock-drawing test, seem worthy of assessment in COPD patients.53 This study has some limitations. First, the patients who were lost to follow-up were older than those who were tracked. Thus, we likely underestimated mortality and the prognostic role of malnutrition. Second, OSA was excluded on the basis of the results of a sleep questionnaire and not the results of a sleep study. Theoretically, some cases of overlap syndrome might have remained unrecognized, thus increasing the prevalence and/or severity of executive dysfunction. Third, all of the patients regularly attended the outpatient respiratory departments at the two institutions where they were initially studied. While this guarantees for an accurate definition of stable COPD, results might not completely apply to the heterogeneous home-dwelling COPD population. Finally, at the time the study was designed we had not specifically hypothesized that executive dysfunction played a primary prognostic role, and thus we did not assess “frontal” functions by means of neuropsychological tests tapping their multifaceted aspects. In conclusion, the copying of a drawing with landmarks test can be used as a prognostic marker in COPD patients. Future research should verify whether this finding reflects a distinctive impairment of executive dysfunction in patients with severe COPD or, alternatively and mimicking the early stages of Alzheimer disease, a constructional dyspraxia due to right insular involvement.54 Research is also needed to assess whether the observed neuropsychological dysfunction is a clue to detecting conOriginal Research
current OSA, the poor quality of oxygen therapy, or the poor control of comorbid diseases such as diabetes mellitus. Clarifying these issues will enable us to define the clinical meaning of the present findings and, hopefully, to improve the care of COPD patients. References 1 Antonelli Incalzi R, Gemma A, Marra C, et al. Chronic obstructive pulmonary disease: an original model of cognitive decline. Am Rev Respir Dis 1993; 148:418 – 424 2 Antonelli Incalzi R, Marra C, Giordano A, et al. Cognitive impairment in chronic obstructive pulmonary disease: a neuropsychological and SPECT study. J Neurol 2003; 250:325– 332 3 Antonelli Incalzi R, Gemma A, Marra C, et al. Verbal memory impairment in COPD: its mechanisms and clinical relevance. Chest 1997; 112:1506 –1513 4 Antonelli Incalzi R, Corsonello A, Pedone C, et al. Construct validity of activities of daily living scale: a clue to distinguish the disabling effects of COPD and congestive heart failure. Chest 2005; 127:830 – 838 5 Almagro P, Julia J, Sanjaume M, et al. Mortality after hospitalization for COPD. Chest 2002; 121:1441–1448 6 Sprenkle MD, Niewoehner DE, Nelson DB, et al. The Veterans Short Form 36 questionnaire is predictive of mortality and health-care utilization in a population of veterans with a self-reported diagnosis of asthma or COPD. Chest 2004; 126:81– 89 7 Domingo-Salvany A, La Marca R, Ferrer M, et al. Healthrelated quality of life and mortality in male patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166:680 – 685 8 Antonelli Incalzi R, Bellia V, Catalano F, et al. Evaluation of health outcomes in elderly patients with asthma and COPD using disease-specific and generic instruments: the Salute Respiratoria nell’Anziano (Sa.R.A.) Study. Chest 2001; 120: 734 –742 9 American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152:s77–s120 10 McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDSADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34:939 –944 11 American Medical Association. Consensus Conference. Differential diagnosis of dementing diseases. JAMA 1987; 258: 3411–3416 12 Butland RJA, Pang J, Gross ER, et al. Two, six, and 12 minute walking tests in respiratory disease. BMJ 1982; 284:1607– 1608 13 Enright PL, Sherrill DL. Reference equations for the sixminute walk in healthy adults. Am J Respir Crit Care Med 1998; 158:1384 –1387 14 World Health Organization. PHS-HCF: international classification of diseases: 9th revision; clinical modification. Washington, DC: Public Health Service, Health Care Financing Administration, 1980 15 Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACPASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations; a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Comwww.chestjournal.org
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19
20
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22 23 24 25 26 27 28
29 30 31 32 33 34
35
36
mittee on Management of Patients with Chronic Stable Angina). Circulation 1999; 99:2829 –2848 Mendelssohn DC, Barrett BJ, Brownscombe LM, et al. Elevated levels of serum creatinine: recommendations for management and referral. Can Med Assoc J 1999; 161:413– 417 Katz S, Ford AB, Moskowitz RW, et al. Studies of illness in aged: the index of ADL, a standardized measure of biological and psychosocial function. JAMA 1963; 185:94 –106 Lawton MP, Brody EM. Assessment of older people: selfmaintaining and instrumental activities of daily living. Gerontologist 1969; 9:179 –186 Folstein MF, Folstein SE, McHigh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189 –198 Carlesimo GA, Caltagirone C, Gainotti G. The mental deterioration battery: normative data, diagnostic reliability and qualitative analyses of cognitive impairment; the Group for the Standardization of the Mental Deterioration Battery. Eur Neurol 1996; 36:378 –384 Magni E, Binetti G, Bianchetti A, et al. Mini-mental state examination: a normative study in Italian elderly population. Eur J Neurol 1996; 3:1–5 Hanley JA, McNeil BJ. The meaning and use of the area under a receiver-operating characteristics (ROC) curve. Radiology 1982; 143:29 –36 Rothman KJ. Epidemiology: an introduction. New York, NY: Oxford University Press, 2002 Rothman KJ, Greenland S. Modern epidemiology. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 1998 He´caen H, Assal G. A comparison of constructive deficits following right and left hemispheric lesions. Neuropsychologia 1970; 8:289 –303 Pillon B. Visuo-constructive problems and methods of compensation: results for 85 patients with brain lesions. Neuropsychologia 1981; 19:375–383 Ino T, Asada T, Ito J, et al. Parieto-frontal networks for clock drawing revealed with fMRI. Neurosci Res 2003; 45:71–77 Makuuchi M, Kaminaga T, Sugishita M. Both parietal lobes are involved in drawing: a functional MRI study and implications for constructional apraxia. Brain Res Cogn Brain Res 2003; 16:338 –347 Shulman KI. Clock-drawing: is it the ideal cognitive screening test? Int J Geriatr Psychiatry 2000; 15:548 –561 Averbeck BB, Chafee MV, Crowe DA, et al. Parallel processing of serial movements in prefrontal cortex. Proc Natl Acad Sci U S A 2002; 99:13172–13177 Krams M, Rushworth MF, Deiber MP, et al. The preparation, execution and suppression of copied movements in the human brain. Exp Brain Res 1998; 120:386 –398 Allen SC, Jain M, Ragab S, et al. Acquisition and short-term retention of inhaler techniques require intact executive function in elderly subjects. Age Ageing 2003; 32:299 –302 Dymek MP, Atchinson P, Harrel L, et al. Competency to consent to medical treatment in cognitively impaired patients with Parkinson’s disease. Neurology 2001; 56:17–24 Grace AN, Baker PS, Allman RM. Neurocognitive correlates of lifespace [abstract]. Presented at the annual meeting of the American Geriatric Society, Philadelphia, PA; May 20 –23, 1999; 95 Royall DR, Palmer R, Chiodo LK, et al. Declining executive control in normal aging predicts change in functional status: the Freedom House Study. J Am Geriatr Soc 2004; 52:346 – 352 Royall DR, Palmer R, Chiodo LK, et al. Executive control mediates memory’s association with change in instrumental CHEST / 130 / 6 / DECEMBER, 2006
1693
37
38 39 40 41 42
43
44 45
activities of daily living: the Freedom House Study. J Am Geriatr Soc 2005; 53:11–17 Lavery LL, Starenchak SM, Flynn WB, et al. The clock drawing test is an independent predictor of incident use of 24-hour care in a retirement community. J Gerontol A Biol Sci Med Sci 2005; 60:928 –932 Royall DR. Executive cognitive impairment: a novel perspective on dementia. Neuroepidemiology 2000; 19:293–299 Buracchio T, Arvanitakis Z, Gorbien M. Dementia with Lewy bodies: current concepts. Dement Geriatr Cogn Disord 2005; 20:306 –320 Boone KB, Miller BL, Lesser IM, et al. Neuropsychological correlates of white-matter lesions in healthy elderly subjects: a threshold effect. Arch Neurol 1992; 49:549 –554 Shim TS, Lee JH, Kim ST, et al. Cerebral metabolic abnormalities in COPD patients detected by localized proton magnetic resonance spectroscopy. Chest 2001; 120:1506 –1513 Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment: beyond controversies, towards a consensus; report of the International Working Group on Mild Cognitive Impairment. J Intern Med 2004; 256:240 –246 MacLeod KM, Hepburn DA, Deary IJ, et al. Regional cerebral blood flow in IDDM patients: effects of diabetes and of recurrent severe hypoglycaemia. Diabetologia 1994; 37: 257–263 Gerardi DA, Lovett L, Benoit-Connors ML, et al. Variables related to increased mortality following outpatient pulmonary rehabilitation. Eur Respir J 1996; 9:431– 435 Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension: comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 2000; 161:487– 492
1694
46 Yohannes AM, Baldwin RC, Connolly MJ. Predictors of 1-year mortality in patients discharged from hospital following acute exacerbation of chronic obstructive pulmonary disease. Age Ageing 2005; 34:491– 496 47 Bendstrup KE, Ingemann Jensen J, Holm S, et al. Outpatient rehabilitation improves activities of daily living, quality of life and exercise tolerance in chronic obstructive pulmonary disease. Eur Respir J 1997; 10:2801–2806 48 Cahalin L, Pappagianopoulos P, Prevost S, et al. The relationship of the 6-min walk test to maximal oxygen consumption in transplant candidates with end-stage lung disease. Chest 1995; 108:452– 459 49 Posner JD, McCully KK, Landsberg LA, et al. Physical determinants of independence in mature women. Arch Phys Med Rehabil 1995; 76:373–380 50 Burgess A, Kunik ME, Stanley MA. Chronic obstructive pulmonary disease: assessing and treating psychological issues in patients with COPD. Geriatrics 2005; 60:18 –21 51 Rocca WA, Bonaiuto S, Lippi A, et al. Validation of the Hodkinson Abbreviated Mental Test as a screening instrument for dementia in an Italian population. Neuroepidemiology 1992; 11:288 –295 52 Pfeiffer E. A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients. J Am Geriatr Soc 1975; 23:433– 441 53 Royall DR, Cordes JA, Polk M. CLOX: an executive clock drawing task. J Neurol Neurosurg Psychiatry 1998; 64:588 – 594 54 Royall DR, Gao JH, Kellogg DL Jr. Insular Alzheimer’s disease pathology as a cause of “age-related” autonomic dysfunction and mortality in the non-demented elderly. Med Hypotheses 2006; 67:747–758
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