RESOLUTION OF MUSCLE WASTING DURING AN ACUTE E.X.4CERBATION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

A thesis submitted to the Faculty of Graduate Studies and Research in partial fùlfillment of the requirements of the degree of Master of Science

Colleen Frances Reavell School of Dietetics and Human Nutrition

McGill University Montreal, Quebec

November, 1 999

Copyright O 1999 by Colleen Frances Reavell

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To my supervisor Dr. Katherine Gray-Donald, who initially sparked my interest in

research and inspireci me to do a Masters degee. Thank you for your continuous support

and guidance to me as a student and more importantly as an individual. Your insight

never failed to intrigue and enlighten me and allowed me to achievc my goal.

1 want to thank my cornmittee members, Dr. K. G. Koski and Dr. J. G Martin for ail of

their expertise and advice related to my research.

Thank you to Dr. Jean Bourbeau at the Montreal Chest Institute for al1 of his support and

interest in this research project.

Thank you to the research assistants at the Montreal Chest Institute for a11 the t h e they

dedicated to screening patients. 1 could not have done this project without their help.

Thank you to al1 of the patients who consented to be in this study. It is because of your

understanding for the importance of research and your willingness to participate that

makes research projects Iike this possible.

A special thank you to my mom and dad, and my two sisters, Jennifer and Jaimee. It is

your love and faith in me that gives me the strength to be who I am and accomplish ail of

my dreams. 1 am al1 that 1 am because of you.

Thank you to rny boyfnend Thierry, whose patience and support allowed me to take as

much time as 1 needed to always do my best.

Thank you to Heidi, Krista and Isabelle for always being there and sharing al1 of Our

successes and stmggles as graduate students!

Weiçht loss and depletion of fat-& mass commonly occun in patients with

COPD. The objective of the study was to determine the magnitude and duration of protein

depletion during an episode of acute exacerbation. Fifieen patients (9 women and 6 men)

admitted for an acute exacerbation of COPD participated in a descriptive study that

prospectively measured individual nitrogen balance over a 6-week followv-up period using

repeated nitrogen balance tests.

The mean nitrogen balance in hospital was -1 3.2W 1 1 -63 g N/day. Onl y 2

patients achieved a positive nitrogen balance by 2 weeks pst-admission and 4 more

patients by 4 weeks pst-admission. At 6-weeks pst-admission. 7 patients (47%) were

still in negative nitrogen balance (- 10.7519.34 g N/&y ). Protein and energy intakes were

significantly higher in patients who achieved a positive nitrogen balance (1.7*0.5 g

protein/kg/day and 1 2W30% of estimated energy expenditure ( 1 -7 x REE)) than patients

who remained in a negative nitrosen balance ( 1 -310.6 g proteidkgday and 70*20% of

estimated energy expenditure). There were no signifiant changes in Lveight or handgrip

strength over the follow-up period. No effect of cumulative or daily corticosteroid doses

on nitrogen balance or changes in handgrip strength were found.

In conclusion, the catabolic stress of an acute exacerbation on nutitional status is

rernarkable. Patients admitted for an acute exacerbation of COPD are in severe negative

nitrosen balance. which improves very slowly postdischarge. A negative nitrogen

balance is prolonged in patients who have a decreased protein and energ intake.

Résumé

La perte de poids et la déplétion de la masse non pisseuse survient chez los

patients COPD. Le but de cette étude était de déterminer la durée du rapport négatif

de nitrogène chex les patients aprês une e.xacerbation aigw de COPD et l'estimation

de la perte nette de protéines. Quinze ( 15) patients (9 femmes et 6 hommes) admis

pour une exacerbation aigue de COPD ont participt5s à une étude descriptive avec la

perspective de mesurer la balance de nitrogène individuelle sur une période de 6

semaines en utilisant les essais de rapport répétés de nitrogène.

La moyenne de rapport de nitrogêne à l'hôpital était -13.20r 1 1.63 g N/jour.

Seulement 1 patients ont obtenus un rapport positif de nitrogène aprês 2 semaines

d'admission et 4 patients de plus à leur 4 semaine d'admission. Six semaines

après leur admission, 7 patients (47%) avaient toujours un rapport négatif de

nitrogène (- fO.7519.34 g N/jour). La prise de protéines et d'énergie était de façon

significative plus importante chez les patients avec un rapport positif de nitrogene

( 1.7*O.5 g protéine/kg/jour et 1 2&30% de dépense énergitique estimée) ( 1.7 x REE)

que chez les patients restant avec un rapport négatif de nitrogène (1.310.6 g

protéine/kg/jour et 70120% de dépense énergitique estimée). II n'y avait pas de

changements significatifs dans le poids ou la force de la poignée de main durant la

période de suivi. Aucun effet de la dose cumulative ou quotidienne de corticostéroide

n'a été touvé dans le rapport de nitrogène ou dans le changement de la force de la

poignée de main.

En conclusion, le stress catabolique d'une excerbation aigue sur le statut

nutritionnel est remarquable. Les patients admis pour une excerbation aigue du COPD

ont un rapport négatif sévère de nitrogène qui s'arnéliore très lentement apres leur

congé de l'hôpital. La déplétion de protéines est prolongée chez les patients avec une

diminution de la prise de protéines et d'énergie.

Table of Contents

Acknowledgments

A bstract ---- Résumé --CIIIIU------I---------

Table of Contents

L ist C J ~ Tubfe-s - L isf of Figures

Introduction

Literature Review

I

. . 11

. . . 111

iv-vi

vi i ...

Vl l l

t

2

Natural History and Clinical and Nutritional Predictom of Mortality - 2

Nutn'tionaI Stutus & Respiraioq and Perîpheral Musele Strengîh 1 O

Nutn'tiona! Status and Erercise Performance --________ 10

Causes of Weight Loss in COPD Patients --- I I

I n c r e d Energy mpendi'ure 1 1

Proin/mmatory Cytokines --- H I - - - - 14

/ncreuCIsed Meluho / ic I&e 16

A lt ered Suhstrufe Mefuhdi.m: Infectif~n verstl,. Sfurvu~ion 1 6

Ta blc of Contents

Table o f Contents

Sadr Population -- 3 1

Discussion 47

Conclusion 52

Bibliography 53

Appendices Patient Consent F o m

Initial Questionnarie

List of Tables

Table 1.

Table 2.

Table 3.

Table 4.

Table 5.

Table 6.

Table 7.

Table 8.

Summary of Nutritional Status Studies in COPD

Summary of Studies Measunng Components of Energy

Expenditure in COPD Patients

Study Schedule

Baseline Characteristics of 15 male and female COPD Patients

Admitted for an Acute Exacerbation of COPD

Dietary Intalie and Nutritional Status of 15 Male and Female COPD

Patients Admitted for an Acute COPD Exacerbation Over a 6-week

Follow-up Period 35

Summary of Admissions and Nitrogen Balances of 15 Patients

Admitted for an Acute Exacerbation Over a 6-week Follow-up Penod 36

Correlations between Nitrogen balance and dietaxy intake

During a 6-week Follow-up Period in 15 Male and Female

COPD Patients Admitted for an Acute COPD Exacerbation

Correlations between Cumulative, Additional, and Daily

Corticosteroid Doses and Nitrogen Balance and Handgrip

Strength in 15 Male and Female COPD Patients Admitted for an 45

Acute COPD Exacerbation Over a 6-Week Follow-up Period

L is t of Figures

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6

Figure 7.

Figure 8.

The Relationship of FEVIT Ase, and Smoking and Mortality 3

Relationship of Factors lnvolved in Weight Loss in COPD 12

Nitrogen Balance of 9 Female Patients Admitted for an Acute COPD

Exacerbation Over a 6-Week Follow-Up Period 32

Nitrogen Balance of 6 Male Patients Admitted for an Acute COPD 33

Exacerbation Over a 6-Week Follow-Up Period

Correlation Between Protein Intake and Nitrogen Balance During

A 6-Week Follow-Up Period in 9 Female COPD Patients

Adrnitted for an Acute COPD Exacerbation

Correlation Between Protein Intake and Nitrogen Balance Dunng

A 6-Week Follow-Up P e r d in 6 Male COPD Patients

Adrnitted for an Acute COPD Exacerbation

Body Weights of 9 Female COPD Patients Adrnitted for an Acute 42

Exacerbation of COPD Over a 6-Week Follow-Up Period

Body Weights of 9 Female COPD Patients Admitted for an Acute 43

Exacerbation of COPD Over a 6-Week Follow-Up P e n d

Introduction

Chronic obstructive pulmonary disease (COPD) is definrd by prob~essive

irrevenible airflow obstruction and is characterized by wo conditions: chronic bronchitis

and emphyserna Chronic bronchitis is diagnosed by chronic recurrent productive cough

and emphyserna is associated with destruction and enlargement of the alveol i (Canadian

Thoracic Society, 1992). In Nonh Amenca, COPD is the fourth leading cause of death,

and mortality and prevalence rates are increasing (European Respiratory Society (ERS),

1995). A decline in lung function is the primary predictor of mortality in COPD (Traver,

1979). Tobacco smoking accounts for 80 to 90% of the risk of developing COPD

(Amencan ïhoracic Society (ATS), 1995). Srnoken have an increased rate of decline of

Iung function leading to higher mortality rates (ATS, 1995).

Poor nutritional status also has an independent adverse effect on prognosis (Gray-

Donald, 1996; Schols, 1998; Wilson, 1989). The prevalence of nutritional depletion in

COPD ranges fiom 20% in stable outpatients (Engelen, 1994) up to 47% in hospitalized

patients (Hunter, 1981). Several factors associated with a low body weight and.or

depletion of muscle mass are reduced respiratory and peripheral muscle strength and

exercise performance (Eflhimiou, 1988; Engelen, 1994; Gray-Donald, 1989; Schols,

199 1 b; Whittaker, 1990).

It is still uncertain whether weight loss occurs gradually over the course of the

disease, or in a stepwise pattern consistent with episodes of acute exacerbation. A higher

prevalence of nutritional depletion in hospitalized patients has stimulated interest towards

the adverse effects an acute exacerbation has on nutritional status. Saudny-Unterberger et

al. (1997) reported net nitrogen (N) losses of 6 . 4 6 f 1.99 g N/&y in COPD patients

admitted for an acute exacerbation despite aggressive nutritional intervention. The

objective of this study was to detemine how long patients remain in negative nittogen

balance following an acute exacerbation of COPD and to estimate the net protein losses

over a 6-week follow-up penod. Several factors including dietary intake and cumulative

corticosteroid medications that are associateci with a negative nitrogen balance were also

examined.

Litera ture Revicw

Natural History and Clinical and Nutritional Predictors of Mortality

Decfine in Lung Functrœon

Lung Function Tèsîs

Lung function tests are used in the diaposis of COPD as well as in the

assessment of its severity, progression and prognosis (ERS, 1995). The forced expiration

is one of the most informative lung function tests. AAer a full inspiration, the forced

expiratory volume of gas exhaled in one second (FE&) and the forced vital capacity

(FVC), the total volume of bas exhaled, are measured frorn a forced expiration. The

normal ratio of FEV, to FVC is about 80% in healthy subjects (West, 1997).

Forced Erpiratory Vofume in one second (FE VI)

FEV! is the primary predictor of mortality for COPD (Traver, 1979). As seen in

Figure 1, FEVl fails gradually over a Iifetime beginning at approximately age 30. In

moderate to severe disease, prognosis is best assessed by FEVl in relation to reference

values. The 5-year survival rate of patients with an FEV, of approximately 1.0 L,

indicative of severe airflow obstruction, is around 50% (ATSI 1995).

Risk Factors

Exposure to tobacco smoke is the primary risk factor for COPD. Tobacco

smoking accounts for 80 to 90% of the risk of developing COPD (ATS, 1995). Figure 1

demonstrates that smokers have an increased rate of decline in FEVI, with heavier

smokers having an even higher rate. Ex-smoken have an improved prognosis regardless

of age. Increased mortality rates in men from COPD have already been attributed to p s t

trends in tobacco smoking ( Man fieda, 1 989).

Age is also a risk factor for a more rapid decline of lung function (ATS, 1995)

however age cannot readily be sepmted fiom the number of years of exposure to tobacco

smoking as most smoken started at approximately the same age.

Normal Range Non-smoker or not susceptible to smoke

\

susceptible to smoke \C

50

ACE (Years)

Figure 1. The Relationsbip of FEV,, Age, and Smoking and or ta lit^'^

I American ïhoracic Society. (1 995). Definit ions. E pidemiology, Pat hoph y siology, Diagnosis, and Staging. American Journal of Res~iratory and Cntical Care Medicine. 1 52 (Suppl.). 78- 12 1 . 2 Fletcher, C. ( 1977). The natural history of chronic airfiow obstrucion. British Medical Journal. 1 , 1645- 1648.

Episodes of acute esacerbation are one of the most cornmon complications in the

rvolution of COPD and are the principlc: indication for hospitalization (ATS. 1995).

Vilkrnan et al. (1997) studied the prognosk of COPD patients afier tirst hospitai

admission using retrospective data that was collected on 1,648 nrwly diagnosed male

COPD patients and 589 newly diagnosed temale COPD patients, q e s 65 to 69 yean. who

were followed between 1986 and 1992. Patients were hospitalized for COPD on average

3.27 + 4.53 times (3.49 + 4-88 for males, and 2.66 + 3.22 for femaies) over the 6-year

follow-up period. AAer first admission, the median survival time for ail patients was 5.7 1

years. Twenty-five percent of males and fernales died within 1.90 years and 3.46 years,

respectively. The 5-year survival rate was 50% for males and 70% for females.

Connoa et ai. ( 1996) reported fkorn a large population of 1 ,O 16 patients who were

admitted for an acute e.xacerbation of severe COPD I - and 2-year survival rates of 57%

and 5 1%- respectively. However, readmission was associated with increased mortality.

Readmission to hospital within 6-months was associated with mortality rates of Z7%,

3 1 %, and 36% for patients who had 1, 2, or more than 2 readmissions. respectively.

Weight L o s ~ o w Body Weigirt

Weight loss is a comrnon clinical feature of COPD. In the past, malnutrition

seemed to be an inevitable process related to the severity of the dise= (Vandenbergh,

1966). Recent s u ~ v a l studies have shown that weight loss leading to a low body weight

has an adverse impact on the prognosis of COPD that is independent of lung function

(Gray-Donald, 1996; Schols, 1998; Wilson, 1 989).

Body weight can be expressed as a percentage of Ideal Body Weight (IBW) or as

a ratio to height using the Body Mass Index (BMI) (Gibson, 1990). An IBW less than

90% or a BMI less than 20 kg/m2 are standard cutoRs used to determine undenveight

(Gibson, 1990). For the elderly, the healthy range of 22 to 27 kg/m2 has been suggested

(Cornoni-Huntley, 1991). Studies have shown that a BMI greater than 22 kdm'

improves survival for COPD patients (Connors, 1 996).

In the advanced stages of the diseiise, Vandenkrgh et al. ( 1966) found thsit wight

loss sigificantly decreased the survival rite. Among 71 out of 100 patients \vho had

weight loss greater than 10% of their initial weight, 35 died, with 50% of them haviny

weight loss greater than 10°6 of their initial weight The 3- and 5-yenr survival nies for

patients with weight losses greater than 10% of their initial weight were 67% and 4946

cornpared to 87% and 7690 for the 19 patients without weight loss. respectively.

In the study by Wilson et al. (1989), the relationship benveen low body weight

and survival was cornpared between groups of patients with similar xverity of airtlow

obstruction. Using data fiom the National Institute of Health Intermittent Positive-

Pressure Breathing (NIHIPPB) clinical trial, 779 male COPD patients were categorized

into 3 groups based on degree of airflow obstruction (mild FEV, < 35%, moderate FEVl

35 to 47%, severe FEVl >J7%) and IBW (low <90°h, normal 90 to 1 IO%, high >110?6).

Not on1 y was there an independent effect of low body weight on mortality in each goup,

the relationship was strongest in patients with an FEVl above 4796 of predicted.

Using the BMI as an indicator of nutritional statu, Gray-Donald et al. ( 1996)

followed 348 patients with severe COPD, age 30-75 years during a 3- to 5-year follow-up

period in order to determine the role of Iow body weight on the prognosis of COPD

patients. Out of the 162 deaths, 72% were caused by respiratory failure. Both BMI and

FEVl were significantly lower in those patients who died. Using multivanate analysis,

BMI was fowd to have an independent effect on sunival. The probabilities of survival at

3- and 5-years for patients with a BMI 4 0 kg/m2 were 55% and 20%, respectively.

These probabilities increased to 6596 and 35% for patients with a BMI in the range 20 to

27 kg/m2 and up to 85% and 50% for patients with a BMi above 27 kglm'.

Furthemore, a retrospective Cyear survival analysis study by Schols et al. (1998)

involving 400 rehabilitation patients provides more evidence that low body weight is

significantly related to a decreased survival. In a Cox proportional hazards model, %MI

was a sipificant predictor of survival (~0.0001). In a Cox regression survival plot,

patients in the quintiles below a BMI of 25 kg/m2 had a significantly lower survival rate.

The probability of survival at 3-years was 35% for patients with a BMI <20 kg/m2. 40%

for patients with a BMI 20-24 kg/m2, and 75% for patients with a BMI >29 kdm'.

Nutritional Status of COPD Patients

Table 1 provides a summa- of the studies that have evaluated the nutritional

status of COPD patients. The results demonstrate that nutritional deplaion begins early

in the disease and as the disease progresses, the prevalence of malnutrition increases.

Body Weight

Studies using the standard cut off of an IBW<90% to identifi the prevalence of

underweight in COPD have shown that weipht progressive1 y declines as the disease

advances. In stable outpatients the prevalence of undenveight patients has been reported

to range fiom 17% (Engelen, 1994) to 24% (Sahebjarni, 1993). A highcr prevalence of

35% (Schols, 1993) to 63% (Braun, 1984) has been reported for patients entenng

rehabilitation programs. In hospitalized patients, Laaban et al. ( 1993) classified 34% of

patients as king underweight (<9O%IBW) with 10% of those patients having an

IBWc70%. Hunter et al. (1981) reported that 50% of hospitalized patients had

significantly lower ( ~ 0 . 0 0 1 ) actual weights versus usual weights, which were 6 1 to 90%

of their usual weight.

Body Conipositiorr

Although body weight is informative, it is a crude measure of nutritional status.

Weight changes can go unrecognized due to shifis in fluid balance, which can mask any

body compositional changes that occur (Barrends, 1997b). One method of determining

body composition is performing anthropometic rneasurements. Triceps skinfold

thickness (TSF) and mid-am muscle circumference (MAMC) are commonly used to

measure subcutaneous fat stores and skeietal muscle mass depletion, respectively

(Gibson, 1990). More recently the bioelectical impedence assay (BIA) has been

validated in stable COPD patients for measuring FFM (Schols, 199 1 d).

Anrlrropomutn'c Measurelllytits

Patients with a history of weight loss and who are undenveight have sigiiicantly

lower anthropometric measurements of both TSF and MAMC compred to patients

without weight loss (Braun, 1984; Hunter, 1981: Sahebjami, 1993), which demonstrates

that weight loss leads to fosses of both fat and fat-fiee mas.

Measurements of MAMC in di fferent COPD populations have revealed t hat

COPD patients suffer fiorn moderate muscle mass depletion (60 to 9096 of standard).

This has been found to occur in 53% of patients entering rehabilitation pro-mms (Braun,

1984) and 50% of hospitalized patients (Hunter, 198 1 ). Severe muscle mass depletion

(60% of standard) has k e n identitied in patients admitted for acute respiratory failure,

with 6% king severely depleted and 36% having moderate muscle mass depletion (60 to

79% of standard) (Laaban, 1 993).

Severe depletion of fat mass (<60% of standard) is more prevalent in COPD

patients. Severe fat mass depletion occurs in 33% of patients entering rehabilitation

programs (Braun, 1984), 50% of hospitalized patients (Hunter, 1981), and in 52% of

patients admitted for acute respiratory failure (Laaban, 1993).

Skinfold anthropometry has several limitations in the elderly population due to the

centralizatton of body fat that occurs with aging. Schols et al. ( 199 16) found that skinfold

anthropometry significantly (p<0.001) overestimated FFM compared to BIA, which

would lead to an underestimation of fat mass.

BioeIectnCal hpedance Assay (BL4)

Two recent studies used BIA in stable COPD patients in order to detennine more

accurately the prevalence of nutritional depietion. Both studies classified patients into

one of four groups based on an IB Wc9O% and FFM/%IB W of <63% for females and

<67% for males. In the first study, Schols et al. ( 1993) studied 255 patients admitted to a

rehabilitation program. Ovenll, 35% of patients were underweight with 74% funher

k ing classified as depleted and 26% not depleted. Sixty-five percent of patients were

normal weight with 15% being depleted and 85% not depleted. Creatinine height index

(CHI) measures were significantl y lower in the depleted patients with an overall average

for al1 patients of 60.7 + 15-696, indicatinp severe muscle mass depletion. Overall. 45%

of patients suffered fiom nutritionid depletion of either weight loss. muscle mas, or both.

In the second study. Enplen et al. ( 1994) studied the prevalence of nutritional

depletion in 72 outpatients. The overali patîems of nutitional depletion were similar to

that found by Schols et al. (1993) except less nutritional depletion (2 1%) was seen in this

population. Seventeen percent of patients were underweight with 8391, having a depieted

FFM and 17% having a nomal FFM. Eighty-three percent were found to be normal

weight with 5% of these patients having a depleted FFM and 9506 a normal FFM.

Biochemical Indicators

Visceral protein status can be assessed using serum proteins such as albumin,

prealbumin and transferrin (Gibson, 1990). However, studies have shown that serum

proteins are not sensitive to the nutritional depletion in COPD patients. Despite evidence

of moderate muscle mass depletion, serum proteins remain within the normal range

(Braun, 1984; Hunter, 198 1; Schols, 1993). Even in the 42.6 of patients that had

moderate muscle m a s depietion with 6% having severe muscle mass depletion, only 4%

had albumin levels and 2% had transfemn levels that were below normal values (Laaban,

1993).

Effects of Nutritional Status on Functional Status

Nutritionai Status and Lung Function

The relationship betwveen nutritional status and lung Function has long been

recognized. A moderate correlation of -0.699 (p<O.O03) between FEVl (Ob predicted)

and IBW has been reportrd (Openbrier, 1983). However, both of these factors have an

independent effect on the proposis in COPD.

Nuttitiond Status and Respiratory and Pedpkerai Muscle Strengtli

Malnutrition is associated wit h weaker respiratory muscle strength. In patients

with an iBW<80%, Whittaker et al. (1990) reported an average Pui~x of 80% predicted

and PEMAX of 53% predicted. Using the sarne cut off for body weight, Nishimura et al.

( 1995) found that undenveight COPD patients had a significantly lower (p=O.O5) PIMAX

and PEMAX compared to normal weight patients and controls. Nishimura et al. (1995)

also found significant positive correlations between lean body mass and P~MAX (r0.66,

p~0.00 1 ) and PEMAX (r=0.59, ~ 0 . 0 1 ) in COPD patients when underweight and normal

weight patients were analyzed together. Gray-Donald et al. (1996) found a weak

association between IBW and PIMAX (r=0.20, p=0.01) and PEMAX (r4.39, p=O.01).

Although Engelen et al. (1994) observed lower PM and PEMAX in depleted patients,

these relationships did not reach statistical significance. However, depleted patients had

significantly lower rneasurements of handgrip strength (pcO.0 1 ), a mesure of peripheral

muscle strength, than nondepleted patients (Engelen, 1994). Efthimiou, et al. ( 1988) also

found that patients with an IBW<90% had significantly lower (p=0.05) handgrip strength

measures than patients with an iBW>90?6.

Nutn2iomai S~onts and Exercise Performance

Depletion of FFM can impair exercise performance. Schols et al. ( 199 1 b) found

significant correlations between FFM (r=0.73, p<0.00 1 ) and body weight (-0.6 1,

1 O

p=û.001) and the distance walkrd durin3 the 12-minute walking test. This relationship

was independent of lung function. In a subgroup of the undenveight patients only the

correlation between FFM and exercise performance remained signi ficont. In a Iater study,

Schols et al. (1993) were able to see this relationship when they found that undenveight

patients (IBW<90%) with depleted FFM had significantly decreased (p~O.02) walking

distances during the l'-minute walking test than non-depleted patients within

underweight and normal weight patients. Exercise performance, as measured by the 6-

minute walking test. did not seem to be affected in underweight patients (IBW<90%)

compared to normal weight patients in two studies by Gray-Donald et al. (1989) and

EAhimiou et al. ( 1988). These studies used body weight to evaluate nutritional status and

not FFM, which may explain why no correlation was found. As well, the effects of

nutritional status on exercise performance would be more obvious with the 12-minute

walking test.

Causes of Weight Loss in COPD Patients

Although the causes of weight loss in COPD are still not clarified, many factors

are known to be involved. Figure 2 is a diagram of the relationship of these factors and

weight Ioss.

A major cause of weight loss is an imbalance between energy intake and energy

expenditure. Total &ily energy expenditure (TDE) can be divided into three components.

The largest component is REE constituting 60 to 75% of TDE. Diet-induced

thermogenesis (DIT) accounts for approximately 10% of TDE. The most variable

cornponent of TDE is the energy expended for activity [TDE-(REE + DIT)]. DIT does

not seem to be significantly eievated in COPD patients (Doré, 1997) however, the studies

in Table 2 reveal that both REE and the energy expended for activity are significantly

elevated in COPD patients.

Table 2. Summary of Studies hleasuring Resting Energy En

Authors

- pp - - - -

Schols et al. (1991~)

Schols et al. (1991ri)

Crcutzbtrg et al. ( 1998)

Hugli et al. (19%)

Baarcnds et al. (1 19978)

Barrends et al. ( 1 997c)

Pulmonriry il Study Met hads

Obiectives Iiidirect caloriitietry-VH

Measiired REE BIA & Aiitliropoinetry

- Iiidii.c.çt ~doriiiictiy-VI 1

Measiired REE BI A

Meiisured REE Iiidircct caloriineiry-VI4 BI A

1

REE and TDE 1 Iiidirect caloriinetry-

Doihly tabelcd water REE aiid TDE ltidiixci cnloi.iiiietry-VI-l

enditure und Total Daily Energy Exlwnditure in Chronic ~bstructivo ieiise (COPI)) Patients*

- --

Study Design

WL and WS COPD patieiiis (11=8O)

W I, riiid WS COPI) pntictits (11-68) Agc & scx-iiiatclicd coiii rols ( 1 ~ 3 4 )

Stable COPD patieiits (11- 1 72) Age-iiiaiched con trols (ii=92)

Stable COPD pctieiits (n= 16)

Age & sex-inotçlied controls (ilS 1 2)

Stable COIID patients (ii-8)

Aye, sex, aiid RMI-itintclied coiitrols (ii=8)

Stable COPD pritieiits (n=20; 10 willi ? REE, 10 wdli noiriial REE)

Results

? REElFFM in WL rs . WS (p~0.005)

? R EL:/I:I:M iii pu~ieiits vs. cont rols (p<O.OS) ? adjusted REE in W L vs. WS patients (p<O.O 1 ) ? REE/FFM in COPD patients vs. controls (p4.0 1 )

Siiiiilar TDE brtweeii groups Activity was sigiiificatitly lower (p-0.03) in C'OPD patients 7 REE/PI:M iii C'OPD.)ici~ts (pCO.0 I ) H EE (rl>solute) w & h signi ficiii~tl y di flcrciit hct wecn groiips

TDElREE for FFM in COPD patients :. ? (p=O.O I ) pliysical-activiiy cuinponent 10 TDE (TDE-REE) TDE is tioi rclaied to '!' Kl'.E/I:I:M 'l'DE was siiiiilar iii botli graups(p-0.08)

h

*Abbreviations: REE, resting rnergy exppcdi ture; TDE, tutal dai ly aciergy expendit urr; DIA, hioelactrical iinpedeiice assry; BMI, body inass index; FFM, Fat-free mass; WL, weight-losing; WS, weight-stable; VH, ventilatcd-hood system.

Contrary to the decline in REE that naturally occun with nging (Poehlman. 1992:

VauSan, 199 1 ). REE adjusted for FFM (REWFFM) is si~miticmtly elrvatcd in stable

COPD patients compared to controls (Creutzberg, 1998; Hugli. 1 996: Schols. 199 1 a). In

the large goup of stable COPD patients studied by Creutzberg et al. (1998), the

prevalence of an elevated REE, defined as REE/FFM >110%. \\-as 2696. Schols et al.

( 199 la, 199 1c) reported that weight losing (WL) COPD patients had signiticantly

elevated REUFFM versus weight stable (WS) COPD patients, sugsesting that an elevated

REE contributes to weight loss. However, Barrends et al. ( 1997~) and Hugli et al. ( 1996)

estabiished that an elevated REE was not strongly related to TDE in COPD patients.

TDE was similar behveen normo- and hypermetabolic patients (Banends, 1997~) and

hypemetabolic patients and controls (Hugli, 1996). As well, Creutzberg et al. ( 1998)

reported that the prevalence of FFM depletion was not signi ficantly different between

nonno- and hyperrnetabolic patients (36% venus 33%, respectively), which suggests that

an elevated REE does not directly contribute to a negatïve energy balance in COPD.

Two studies have k e n able to establish that the variarion in TDE is directly

related to the increased energy expended for activity. Hugli et al. ( 1996) reported similar

TDE between COPD patients and controls, as measured in a respiratory chamber,

however, the patients had a significantly reduced activity. Using the doubly labeled water

technique, Banends et al. (1997a) found that for equal amounts of activity, COPD

patients expended more energy. Although physical activity may be decreased in COPD

patients the energy expended for activity is elevated and therefore remains a sigiificant

component of TDE.

Proin/lrnmatory Cytokines

Many patients with severe COPD experience recunent illnesses such as acute

bronchitis or pnewnonia, which are common indications for hospitalization (ATS, 1995).

Bacterial and viral infections are potent stimuli for the production of cytokines such as

tumor necrosis factor (TNF-a) and interleukins (IL), which modulate al1 of the hast's

metabolic responses that occur during an infection such as increase metabolic rate and

alter substratr metabolism (VAN DER Poli, 1993). As weii. cytokines r t k t enerky intake

via their anorectic effect which also compromises enerby balance (Grunkld, 199 1 ).

Elevated TNF-a blood levels have k e n documented in various human diseases

associated with cachexia including cancer and acquired immunodeticiency syndrome

(AIDS) (Manhys, 1997) and have recently k e n postulated to play a major role in the

etiology of wasting in COPD patients. Di Francia et al. (1994) tirst linked TNFa with

weight loss in COPD patients by discovering elevated serum TNF-a in a subgroup of

undeweight patients, who otherwise had no reason for elevated serum TNF-a levels.

None of the 30 mde patients recruited into the study received corticosteroids or had an

exacerbation during the previous 3 months, or had a cumnt infection. Serum TNFu

levels were significantly higher in the underweight patients (<90°hIBW) venus the

normal weight patients (>90%IBW) and controls. However, 5 of the 16 underweight

patients had semm TNF-a values within the upper Iimit of the normal mge. Although

no correlation between TM-a and weight loss was found, TNF-a was elevated in

undenveight patients only, which tint suggested that the production of T N F a might be

elevated in underweight COPD patients.

The inability of this author and othea (Godoy, 1996; Schols, 1996) to find an

association between serurn TNF-a levels and weight loss is probably because TNF-a is

only transiently elevated in the s e m afler production until it foms complexes with

s e m TNF receptors on target cells (Tracey, 1993). TNF-a is produced by macrophages,

which are cells transformed fiom monocytes. During a 6-month follow-up study Godoy

et al. (1996) cross-sectionally compared lipopolysaccharide (LPS)-stimulated T N F a

production by peripheral blwd monocytes in WL COPD patients, who had weight losses

>5% in the p s t year, with WS patients and age-matched healthy controls. Although

LPS-stimulated TNF-a production by monocytes was significantly increased in WL

patients compared to WS patients and controls at baseline, production was not

significantly increased at the 2, 4 and 6-rnonth follow-up visits during which time

originally WL COPD patients managed to maintain their weight. Although no cause-

effect relationship could be concluded, these results suggest that ongoing weight loss may

involve elevated TNF-a production.

There is evidence that it is the chronic intlarnmation of the aînvays in COPD

patients that stimulates the production of cytokines local1 y. act ivating the in flarnmatory

response. Using the spuhirn induction technique Keatings et al. ( 1996) found that COPD

patients had significantly increased concentrations of both T N F a and IL-8 in their

sputum compared to controls. Neutrophii counts were also significantly higher in COPD

patients, which is strong evidence that the elevated levels of IL-8 and TNF-+r are

stimulating the inflammatory response, since both are required. respectively for the

recruitment and activation of neuîrophils and their m ip t ion through the epithelial cells

into the lungs.

lncreased Metubolic Rate

Cytokines rnay also be responsible in part for the increased REE characteristic of

COPD patients. Schols et al. (1996) investigated the possible relationship between an

increased REE and the systemic inflammatory response as reflected by raised levels of

cytokines (TNF-a, IL-6. IL-8), TNF-a receptors (TNF-R55 and TNF-R75), and acute

phase proteins: lipopolysacchm*de binding protein (LBP) and C-reactive protein (CRP) in

30 patients with moderate to severe COPD versus controls. REE was measured by

indirect calorimetry and aâjusted for FFM, which was measured by BIA. Only one of the

TNF-a receptors, TNF-R75 was increased in the COPD patients. I L 4 and -8 were

increased in some patients, while acute phase proteins were significantly increased in ail

the COPD patients venus controls. Only an increased REE was significantly related to

nised levels of the acute phase proteins (CRP, LBP). The acute phase response was

present in 50% of the hypermetabolic patients and was aswciated with significantly

increased levels of sTNF receptors - sTNF-RS and sTNF-R75. This study suggests that

the elevated REE in stable COPD patients may be due to the inflammato~ response that

is initiated by cytokines in response to the chronic inflammation of the airways.

Aiîered Substrate MmoboI&m Infection wmus Stotvatlon

The metabolic disturbances of infection mediated by TNF-a leads to a catabolic

state, which is very different front the adaptive processes involved during starvation (Van

Der Poll, 1993). 16

During earl y starvat ion, t here is npid proteol ysis from slieletal muscle whereby

amino acids are taken-up by the liver and used as substrates for gluconeogenesis. Urinary

urea nitrogen is the main by-proâuct, with losses of about 12 g prr day, which is

equivalrnt to the loss of approximately 75 g of muscle protein per d q . During prolonçed

starvation there is an adaptation period. The adaptive response to stan-ation involves a

decrease in REE and utilization of fat as the major source of fuel in order to conserve lean

body mass (Edes, 199 1 )

During infection there is no adaptive response. Although TNF-a stimulates

lipolysis and hepatic lipogenesis. it also downregulates lipoprotein lipase (LPL) impairing

the metabolkm of lipoproteins (VLDL) resulting in hypertriglyceridaemia (Grunfeld,

1991, 1992). This futile cycling of FFA forces the host to continue using protein as the

main source of fuel. RJF-a induces protein turnover by increasing both muscle

proteolysis and hepatic protein synthesis in order to provide precursors for the energy and

amino acid requirements of the mesxd host (Grunfeld, 199 1, 1992). The fiee amino

acids released by protein catabolism are used either for gluconeogenesis or new protein

synthesis, which is essential for leukocyte proliferation, acute phase protein synthesis, and

tissue repair (Grunfeld, 1 99 1, 1 992). However, protein catabol isrn exceeds protein

synthesis therefore a negative nitrogen balance persists (Grunfeld, 199 1, 1992). If the

inflarnrnatoiy response is exaggerated, excessive wasting of lean body mass continues.

The use of corticosteroids is part of the standard therapy and management of

patients with COPD, both during exacerbations and during interim periods of stability

(ATS, 1995) to improve FEVl Corticosteroids are known for their catabolic effects

(McEvoy, 1997). In situations of high-dose corticosteroid therapy such as in dunng

rheumatoid arthritis, Roubenoff et al. (1990) reported that corticosteroids produced a

signifkant negative nitrogen wasting that persisted for 4 days afier the corticosteroid

treatrnent was discontinued.

Decramer et al. (1992) previously described three case reports, one patient with

COPD and two with asthma, who al1 developed severe muscle myopathy involving both

respiratory ( PIM AX and PEMAY) and priphenl (quadriceps force) muscle wveakness

during treatmcnt with high doses of corticosteroids. It brcarne rvidrnt fiom the data

presentrd that the respiratory and peripheral muscle myopathy was cauxd by the steroid

treatment since muscle strength gradually improved as corticosteroid doses were tapered

off.

A dose response and long-term usage of corticosteroid therapy are both likely to

be involved in muscle wasting. Decramer et al. (1994) looked at the effect of long-term

use of corticosteroids and how they affected muscle weakness in COPD patients. A total

of 2 1 patients ( 15 COPD, 6 asthmatics), who were admitted for an acute exacerbation and

required treatment with corticosteroids were included in the study. The average daily

dose of cotticosteroids was calculated for the previous 6 rnonths. One patient was on

continuous corticosteroid therapy while the rernaining subjects received repeated bursts

during exacerbations of their disease. The number of previous e.wcerbations for the

group mged from I to 4 per patient. The average daily dose was low, ranging fiom 1.4

to 2.1 mg/day, averaging 4.3 mg/day. Quadriceps force was in the normal range for 13

patients who had a mean corticosteroid dose less than 4 mg/day. For the remaining 8

patients (7 with COPD) with an average daily corticosteroid dose greater than 4mg/day,

quadriceps force fell below the normal range. Long-term steroid treatment correlated

significantly with al1 of the muscle strength measurements, whereas present steroid

therapy in hospital did not affect muscle strength. Measures of PIMAX and PEMAX and

quadriceps force conelated well with each other, although the contri-bution of steroid

treatment was independent.

hadequate Dietary Intake

Weight loss occurs when a patient's energy intake is less than their energy

expenditure resulting in a negative energy balance. There is strong evidence that energy

expenditure is abnormally high in COPD patients, which means that energy reguirements

are also increased. Up until recently it was assumed that the dietary intake of COPD

patients was sufficient. This presumption was based heavily on the study by Hunter et al.

( 198 1 ), who concluded that the nutrient intakes of hospitalized patients were significantly

~Teater than or comparable to the 1974 Recomrnended Dietary Allowances and that

nutrient requirements were k ing met. However, the dietary histones pertormed

represented only the usual intake of the patient at home dunng the past year and excluded

intake prior to or during any hospitalizations when energy requirements are increased-

Despite the fact that 509'0 of the COPD patients had weight losses greater than 10Y0 of

their usual weight, Hunter et al. (1 98 1 ) concluded that dietary intakes were adequate to

meet estirnated energy requirements.

Braun et al. (1984) also reported that the dietary intakes, rneasured from a May

food record, of 60 COPD outpatients appeared to be adequate based on energy

requirements detemined from basal energy expenditure using the Harris Benedict

equations. However, when the authors calculated energy expendi t ure from resting V@,

they realized that energy intake did not even meet the eievated REE, which is only one

component of TDE.

More recently, Schols et al. (1991~) found that WL patients had significantly

higher REE/FFM whereas absolute dietary intake was not significantly different from WS

patients. Although there was a significant correlation ( d . 4 8 ; pc0.00 1 ) between energy

intake and REEFFM, energy intake became hampered as the disease seventy worsened.

Classification of patients by disease severity revealed that WL patients had the rnost

compromised lung function and had a more pronounced negative energy balance leading

to weight loss.

Depression and Dl'mary Intake

Depression caused by a decrease in functional status has also been irnplicated to

play a role in poor dietary intake. EngstMm et al. (1996) reported that COPD patients

with the most advanced disease reported the wont dysfunction in everyday life, which

had a large impact psychologically on patients. lncreased anxiety and depression were

two factors that affected habits of COPD patients including eating. Braun et al. ( 1984)

showed that depression was directly related to %iBW, which suggests that depression has

a large impact on dierary intake and may contribute to weight loss as the disease

progresses.

Qua/@ of üfe (QOL) anâ Dit?lary Intuke

COPD patients have a poor QOL and as the severity of the disease wonens,

functional status is significantly impaired. Using the Sickness Impact Profile (SIP) to

mesure functional status and the Mood Adjective Check List (MACL) and Hospital

Anxiety and Depression Scale (HAD) to measure emotional status. Engsndrn et al. ( 1996)

cross-sectionally studied a group of 68 COPD patients in order to describe their QOL.

Patients with the most advanced disease (FE& ~ 5 0 % of predicted) reported the worst

dysfunction in everyday activities that required physical activity such as ambulation,

mobility, recreatiodpastimes, and eating.

Using multivariate analysis, Monso et al. (1998) found that lung function

explained 50% of the variation in QOL followed by dyspnea explaining an additional 6 to

-4%. No correlations between respiratory or peripheral muscle strength or nutritionai

status, measured by TSF and W C , and QOL were found. However, on1 y 4% of the

patients in this study were classified as being malnourished and PIMAX, PEMAX and

handgn'p strengths were al1 within nonnal range.

Shoup et al. ( 1997) were able to see an association between a poorer health related

quality of life (HRQL) and a decreased lean body mass (LBM) but when dyspnea was

added to the analysis model, LBM was no longer significant. However, dyspnea is a

symptom caused by a decreased functional status, in which nutitional status has an

underl ying effect.

Nutn'tonal Intervention in Stable COpD Pan'e~~ts

Goldstein et al. (1986), and Whittaker et al. (1990) were both successful in

improving nutitional and functional status in moderatel y malnourished ( IB W<90%)

COPD patients providing energy intakes of 1.7 x REE during inpatient refeeding trials

afier 14-days and Iodays, respectively. A signiticant weight gain of 2.4 kg (Whittaker,

1 990) along with signi ticant improvements in respiratory musc le strength and endurance

(Whittaker, 1990), and peripheral muscle strength and endurance (Goldstein, 1986) were

reported.

Two studies have investigated the impact of outpatient supplementation propms

in COPD. During r 3-month controlled trial. Eflhimiou et al. (1988) rrporîrd signiticûnt

improvements in weight gain (4.2 kg), TSF and MAMC, respiratory (PIMAX and PEMAx)

and pen phenl (handgip strenfh) muscle strength, and exercise pertormancr (6-minute

walking test) in the 7 malnourkhed (lBW<90?6) COPD patients who ivere supplemented.

Oral supplementation sihmificantly increased energy intake to 2,500 kcal and 90g of

protein in the men and 1,300 kcal and 80g of protein in the women. Unfortunately by 3-

months after the 3-month supplementation period, dunng which time patients returned to

their usual dietary intake, patients experienced weight loss, and respiratory and peripheral

muscle strengths and exercise performance retumed to baseline values.

Rogers et al. ( 1992) reported similar results as Efihimiou et al. ( 1988) in a 4-

month randornized refeeding trial consisting of an initial 3-week inpatient phase followed

by a 3-month outpatient phase. During the inpatient phase 15 patients received oral

supplernentation that provided an energy intake of 1.7 x REE and a protein intake of

1.5gkdday and nutritional education. Upon discharge patients were given a supply of

supplements and a personal meal plan to follow along with nutrition counseling to try to

maintain target energy and protein intakes during the outpatient phase. The mean total

energy intake during the outpatient phase was 1.73 x REE in the supplemented patients.

At 4 months patients had significant improvements in peripheral muscle saength

(handgrip strength), respiratov muscle strength (PEMAX), and exercise performance ( 1 Z-

minute walking test). Patients had a rnean weight gain of 1.7 kg afier the inpatient phase

with an additional weight gain of 0.7 kg during the outpatient phase. Although patients

maintained caloric intake during the outpatient phase, weight gain was not significant.

Many patients including controls lost weight periodically dunng the outpatient phase,

which seemed to correspond with acute exacerbations of COPD. Rogers et al. calculated

a mean weight loss of 1.5 kg per exacerbation.

Acute Exacerbation of COPD

The individual effects of each of the factors involved in weight loss are

compounded during an acute exacerbation. Vermeeren et al. (1997) were the tint to

2 1

investigate the effects of an acute exacerbation on the nutntional and meiabolic protile of

patients with COPD. A total of 23 patients who were admitted to hospitd for an acute

exacerbation were followed during hospitalization and were invitrd for a follow-up

consultation at 3 months after discharge when they were in stable condition. Dietq

interviews revealed that intakes prior to admission significantly decreased and durinp the

first few days of hospitalization, a negative energy balance persisteci. Many symptoms

seem to be associated with a decrease in dietary intake including bloating nausea and

vomiting, dyspnea while eating, loss of appetite, and early satiety. By discharge most

sym ptoms im proved and dietary intake retumed to habi tua1 in take. During

hospitalization, there \vas no change in weight or FFM, as measured by BIA, which can

be expected during an acute state due to fluid shifts. REE was measured by indirect

calorimetry the day after admission and at discharge. Al1 patients had an elevated REE

on admission and 10 patients still had an elevated REE at discharge. Only 10 out of 13

patients volunteered to participate in the 3-month follow-up evaluation. These patients

happened to have better lung fùnctions and weighed more at discharge. This subgroup's

dietary intake resumed to habituai and they had a significant mean weight gain of 1.65-1

kg However, these results are most likely confounded because these patients were most

likely the healthiest patients. A major limitation of this study was that the follow-up

evaluation was not until 3-months pst-discharge and less than half of the patients

participated. Although this study concludes that dietary intake resumes to habitual intake,

weight histones were not taken in order to know whether habitual intake was adequate.

Refeeding studies have established that the usual intake of COPD patients is inadequate

to maintain nutritional status (Efihirniou, 1988; Rogers, 1992). It is still unknown what

the energy requirements of COPD patients are during an acute exacerbation of COPD or

whether patients are able to achieve a positive energy balance afier an acute exacerbation.

Nutn'tionaI Suppott during un Acute ~acerbutlon

Only one study by Saudny-Unterberger et al. ( 1997) has evaluated the impact of

aggressive nutritional support during an acute exacerbation of COPD. During a 14 &y

randornized controlled study, 14 patients were randomized to the supplemented group to

receive a mean ratio of energy intakelHam-s Benedict equation of 1.5 X REE or 1.7 x

REE depending if their BMI was 10 to 27 kg/m2 or ~ 2 0 kg/m2. These patients receivcd

oral supplements and snacks in addition to the regular hospital menu in order to meet

their estirnated energy requirements. Ten control patients were randornized to receive the

regular hospital menu. Calorie counts were used daily in hospital to mesure dietary

intake and to assure that the supplemented patients consumed their estimated energy

requirements. Dietary intake was verified by 24-hour recalls, which were conducted by

the same dietitian every other &y. Patients who received oral supplements were able to

increase their mean ratio of energy intakdHarris Benedict equation to 1.89 x REE, which

was significantly higher (p=0.004) than the control goup's mean ratio of 1.47 x REE.

Nitrogen balance studies were conducted on approximatel y day six of hospital izat ion.

The average nitrogen losses for the treatment and control groups were -6.46 t 1.99 g

N/day and -5.10 f 1 -60 g N/day, respectively. A nitrogen loss of 6 g of N/day would

result in a loss of 37.5 g proteidday. One important factor that was found to significantly

correlate with the negative nitrogen balances was cumulative corticosteroid medications

(r=-0.73, p=-û.0048). After 14 days of supplementation, no significant improvements in

respiratory muscle strength (PIMAX, PEMAX), 1 ung function (FEV 1 ), peripheral muscle

strength (handgrip strength), or exercise performance @-minute walking test) were

reported within or between groups. Only FVC significantly improved in the

supplemented group. The average length of hospitalization was 14 days and ranged fiom

8 to 33 days, which means that most patients were in hospital during the entire study

period. Although al1 patients were in negative nitrogen balance in hospital despite such

aggressive nutritional support, the importance of nutritional support should not be

diminished. The catabolic processes invoived during an acute e.xacerbation rnay be

impossible to halt during this acute phase, however, nutritional support may be important

in resolving the catabolic state as quickly as possible. The fact that there were no

significant improvements in functional status by 2 weeks post-admission does not mean

that nutritional support is not more effective with time. This study supports the need for

prospective studies to determine how long patients remain in negatiw nitrogen balance

following an acute exacerbation of COPD and what factors including dietary intake and

corticosteroid medications are associated with a negative nitrogen balance. Shiyal et al.

(1992) has already clearly demonstrated how dificult it is for older subjects to regain

FFM once it is lost. With aging, more energy is mquired to improve nutritional status and

any bqin in FFM occun at a much slower rate then younger subjects. The mqmitude and

duration of the catabolic effects of an acute exacerbation need to be determined in order

to prevent any senous losses of muscle mass.

Study Rationale

Weight loss is a common clinical feature of COPD and is associated with muscle

wasting Patients with a low body weight and/or depletion of muscle mass have reduced

respiratory and peripheral muscle strength, and exercise performance. These patients ais0

have a poorer prognosis, which is independent of the degree of airflow obstruction.

Although the underlying mechanisms of weight loss remain unclear, refeeding tials have

show that the usual dietary intake of COPD patients is inadequate to maintain or

improve nutritional status. It has also been established that energy expenditure is

increased mostly due to an increase in energy expended for activity. It is still unknown

whether weight loss in COPD patients penists wgadualIy over time or if it occurs in a

stepwise pattern consistent with acute exacerbations as observed by Rogers et al. (1993).

Higher prevalence rates of nutritional depletion in hospitalized patients have stimulateci

interest towards the adverse effects an acute exacerbation has on nutritional status. The

rationale for this study was based on the findings in a recent study by Saudny-Unterberger

et al. (1997), who reported that COPD patients admitted to hospital for an acute

exacerbation had a mean negative nitrogen balance of -6.4611 -99 g N/day despite

successfitl agressive nutritional intervention. The catabolic stress of an acute

exacerbation has never been studied prospectively and therefore it is unknown how long

patients rernain in a negative nitrogen balance or the magnitude of protein catabolism.

This is the first study to mesure nitrogen balance prospectively through consecutive

nitrogen balance tests in individual COPD patients admitted for an acute exacerbation

during a 6-week follow-up study. The objective of this study was to determine how long

patients remain in negative nitrogen balance following an acute exacerbation of COPD

and to estimate the net protein losses over a dweek follow-up period. Factors that may

be associated wi-th a neçative nitrogen balance including dieta? intalie and cumulative

corticosteroid medications were also examined-

Hypothesis

Negative nitrogen balance will not be resolved by 6-weeks post-admission for an

acute exacerbation of COPI).

Study Objectives

1. To estimate nitrogen balance from serial masures during hospitalization and up

to 6-weeks pst-admission

2. To measure energy and protein intakes during an acute exacerbation in hospitai

and up to 6-weeks pst-admission.

3. To examine total protein and energy intake in relation to nitrogen balance

4. To correlate cumulative corticosteroid dose with nitrogen balance and peripheral

muscle strength

5. To evaluate changes in peripheral muscle strength and weight in relation to

nitrogen balance, cumulative corticosteroid dose, and dietary intake.

Smdv Design

This was a descriptive study that prospectively measured nitrogen balance over a

6-weck follow-up period usinp repeated nitrogen balance tests in individual COPD

patients admitted to hospital for an acute exacerbation. Factors associated with an acute

exacerbation that are invo lved in negative nitrogen balance were also rxamined.

Sntdy Subjects

EIigt0biIity Cn'teRa

Eligible patients had to have a clinical diagnosis of COPD as defined by an FEV,

5 75% (predicted) and an FEVI/FVC < 70% (absolute) in the 1st two years and be

adrnitted for an acute exacerbation of COPD seconâary to a respiratory tract infection or

any secondary causes. Patients had to be between 50 and 85 years of age, be a curent or

ex-smoker, and speak English andor French. Patients with a diagnosis of lung cancer in

the past year, renal failure, or dementia were excluded fiom the study.

Recnrr'rment

Between June 1998 and Apnl 1999, al1 patients admitted to the Montreal Chest

[nstitute's fifth flwr and &y hospital were screened and al1 patients that met the above

eligibility cnteria were approached and informed of the study protocol. Oniy those

patients who gave signed consent participated in the study (Appendix A). Screening and

recruitrnent was done by Colleen Reavell. Research assistants at the Montreal Chest

Institute also helped with the initial screening. This study was approved by the ethics

cornmittee of the Montreal Chest Institute.

The study consisted of four visits that took place over a 6-week follow-up peiod.

Visit one was in hospital and took place within 72 hours of admission (Appendix B). The

foilow-up visits took place at 2-, 4-, and 6-weeks pst-admission either in hospital or at

the patient's home after the patient was discharged (Appendix C). All visits were 26

conducted by the same dietitian (Colleen Rravell). The study schedule is outlined in

Table S.

1 Table 3. Resolution of Musde Wasting During an Acute Exacerbation of COPD Study Sched&

1 VISIT 1 Hospital 2 weeks 1 4 weeks 1 6 weeks

QUESTIONNAIRE: Contact information 1 4

b 1 1

Sociodemographic infornation J Smoking histow J 1

. Dyspnea scale J 1 Spirometry J Stabil ity of COPD: Medication 4 J J 4 Stability of COPD: Symptoms J J J Exercise 1 J J J Respiratory aggravations / health problems 1 I ' I J LM EASUREMENTS: Weight J 1 J J J

I I 1

Handgrip strength J 4 J J

Dietary intervie\v-24 hour recall JJ 4J J J 44 Nitrogen balance test J 1 J J 4

Meawremenlir Nitrogen Bdance

Al though limi rations do exist in the estimation of nitrogen balance including

incomplete urine collections, underestimation of urinary nitrogen losses, and/or

underestimation of dieîary nitrogen, many precautions were taken to assure appropriate

techniques, measurements and procedures were followed to minimize error.

In hospital the twenty-four hour urine collections were ordered by the doctor and

collected by the nuning staff. At discharge, patients were sent home with a urine

collection container for the tint follow-up visit In order to ensure that that the 24-hour

urine collections were complete at home, patients were contacted by phone by the

dietitian prior to each follow-up visit. The 24-hour urine collections were scheduled on

days when patients expected to be at home and had no appointments. The follow-up visit

was scheduled for the day afier. The collection period was fiom 8 am on the scheduled 27

collection day to 8 am the following day, the day of the follow-up visit. Patients wrre

asked to keep the urine collection in the fi-idge during the cntire collection priod until the

dietitian picked it up at the visit. Patients were contacted on the collection day to confirm

that the urine collection \vas started and that there were no problems. A new urine

collection container wvs lefi with the patient for the next follo~v-up visit. Unnaiy

creatinine excretion was used as an index ~Fcompleteness of urine collections.

The twventy-four hour urine collections were delivered directly IO the Biochemistry

laboratory at the Royal Victoria Hospital. Urinary urea nitrogen (UUN) was measured

using the Beckman S-ynchron CX7 instrument to estimate TUN. Although estimatins

TUN from UüN may not be the most accurate, Milner et al. (1993) found a strong

conelation r=0.98 (p=O.00 1 ) between T W and ULM in critically il1 patients. In severely

critical burn and hip fracture patients, Larsson et al. ( IWO) reported that more than 9006

of the TUN excreted was UUN. Total urinary nitrogen ( T m ) was estimated from UUN

by adding a correction factor of 2 grams for non-urea nitrogen componems of the urine

(uric acid ammonia, and creatinine) and 2 grams for dermal and fecal losses of nitrogen

(Gibson, 1990). Nitrogen balance was calculated using the equation:

Protein intake (g)/6.25 - [(UUN (g) + 4 g)]

Dimory Irirake

Protein and ener_gy intakes were detennined using the 24-hour recall method. A11

interviews conducted were by the same dietitian, Colleen Reavell. Two consecutive

recalls were performed at each visit using a standard interview kit. In hospital both 24-

hour recalls were conducted in person. Once the patient was discharged, follow-up visits

took place at the patient's home. One 24-hour recall was conducted during the visit and

the second 24-hour recall was conducted over the phone the following day. The two

consecutive 24-hour recalls represented the intakes for the 24 hours the urine collection

was being collected and the following day. The mean protein and energy intakes fiom the

two days were calculated using the Food Processor nutrient analysis program.

Nutniional Stancs

Body weight was measured at each visit using the same portable scale (Seca

Optima 760, Germany). Patients were weighed without shoes and wearing only a

hospital g o w in hospital or light clothinç at home. Height was measured in hospital

using a balance beam scale (Detecto Scales tnc., Brooklyn, NY, USA) to calculate BMI.

A BMI between 22 and 27 kgm' has k e n estabtished as the healthy weight range for the

eiderly (Cornoni-Huntley, l99 1). Patients with a BMI below 22 kdrn' were classified as

underweight and above 27 kg/m2 as ovenveipht.

Urinary creatinine excretion was also measured from the 24-hour urine

collections. CHI was calculated by dividing the Mhour unnary creatinine excretion of

the patient by the expected age-corrected creatinine excretion for height (Gibson, 1990).

A CHI of 60% to 80% of standard represents a moderate deficit in body muscle mass.

Penpheral Mmle Strength

Handgrip strength is a validated masure of upper body strength and is strongly

correiated with muscle mass (Frontera, 1 99 1 ; Ka1 Iman, 1990; Reed, 1 99 1 ). Handgrip

strength was measured on the dominant hand using a Jamar Hand Dynanometer. Patients

were asked to sit comfortably with their shoulder adducted and neutrally rotated, elbow

flexed at a 90 degree angle, and forearm and h s t in a neutral position (standard

procedure). The mean of three attempts was used.

CorSl'cosîeroid Treaîment

Daily corticosteroid doses were recorded fiom admission up to the end of the 6-

week study period. Because of differences in potencies beîween corticosteroids,

corticosteroids were converted to an equivalent dose of methylprednisone (Gilman,

1985). Cumulative dose and daily dose were calculated for each visit. Total cumulative

dose over the p s t 2 years was also recorded fiom medical records since there is evidence

that long term steroid treatrnent correlates with respiratory and peripheral muscle

weakness (Decramer, 1 994).

Meam and Standard Lkviotions

Group means and standard deviations were calculated for men and women

separately for baseline charactenstics and for al1 variables measured at each visit. The

variables included: age, weight, height, BMI, FEV, (?/a predicted), FEVl/FVC (%),

hospital and day hospital iength of stay, nitrogen balance, protein intake (&y,

g/kg/day), enerbT intake (kcaldday, % estimated energy expenditure), handgrip strength,

and CHi.

Paired !-tests

Paired t-tests were used to test for differences in weight, nitrogen balance, protein

and energy intake, handgrip strength, and CHI between visit I and visit 2, 3, and 4 for

females and males separately. Repeated measures ANOVA was not used because four

patients missed a visit and this analysis will not analyze observations with missing data,

the sample size would be too restricted.

Strrdent t4est.s

Student t-tests were used to test for differences in protein and energy intake, body

weight, handgrip strength, and corticosteroid doses between patients who achieved a

positive nitrogen balance and patients who remained in negative nitrogen balance.

Pearson CorreIations

Pearson correlations were used to examine the relationships between cumulative

corticosteroid dose and nitrogen balance, cumulative corticosteroid dose and muscle

strength, nitrogen balance and protein and energy intakes, nitrogen balance and muscle

strength, protein and energy intakes and muscle strength, nitrogen balance and weight,

and weight and muscle strength.

Resu Its

Study Population

Between June 1998 and April 1999, 1 16 patients admitted with a COPD

exacerbation to the Montreal Chest Institute's 5th tloor and day hospital were screened.

Fony patients did not meet the eligibility criteria. Fifieen patients did not speak English

or French, 12 patients were oider than 85 yean of age, 6 patients had at least one co-

morbidity, 5 patients did not meet the definition for COPD and or acute exacerbation, and

2 patients were discharged too soon therefore could not be included.

Seventy-six patients were eligible however 56 refused. Although most patients

did not explain why they did not want to participate, 3 main reasons were the length of

the study, the 24-hour urine collections at home, and home visits. Twenty patients

accepted to participate but only 15 patients completed the study. Three patients withdrew

from the study because they felt too sick to continue, one patient suffered from chronic

heart failure and was admitted to another hospital for the remainder of the follow up

period, and one patient died.

All 4 visits were completed by I I of the 15 patients. One female and one male

patient missed visit 2 and 3 due to the flu and a cataract operation, respectively. Visit 4

\vas not completed by 2 male patients, both who felt too well to stay home for the final

24-hour urine collection.

B~seline Characteristics

The study was completed by 15 patients (6 males, 9 females) aged 65 to 85 years.

Baseline characteristics are summarized in Table 4. These patients suffered fiom

moderate to severe COPD as indicated by their lung function tests (FEV, and

FEVI/FVC). Hospitalization is required in the management of al1 severe exacerbations.

Eight out of the 9 female patients and 3 out of the 6 male patients were hospitalized for

their COPD exacerbation. Three male patients and one female patient required admission

to the Day Hospital oniy for their acute exacerbation.

Four male patients and one female patient (33%) were undenveight (BMI ~ 2 2

kg/m2). Eight patients (53%) fell within the healthy rang (BMI 12-27 kdrn2). Two

female patients (14%) had n BMI tell above 27 kg/m2.

Table 4. Badine characteristics of 15 male and &male patients admitted for an acute exacerbation of COPD

C haracteristics Sex Al& years Weigbt, kg Height, cm BMI, kg/mf FEVI (% predicted) FEVaIFVC (%)

Ninogen balance

Hospital length stay (LOS), days Day Hospital LOS, days

Figures 3 and 4 gmph the nitrogen balance values of the 15 patients over the 6-

Mean i SD Men (n=6) Women (n=9)

9.33 k 1 1 -02 (n=3)+ 1 10.37 t 6-80 (n=8)* 2.20 f 1.30 (n=5)* 1 3.0 i 1.4 1 (n=2)*

week follow-up period. The rnean Ntrogen balances at each point in time are reported in

76 k 6.78 61.42 f 10.36

* Sarnpie sizes do not add up because some patients were admitted to both the day hospital and th 5" floor during hospitalization

Table 5. Al1 patients were in negative nitrogen balance during hospitalization, with an

74.67 I 6.14 64.56 k 2 1 -42

ovedl mean nitrogen loss of - 13.20 f 1 1.63 g N/day (- 10.14 i 12.76 g N/day for men

and -6.87 * 10.56 g Nlday for women). Nitrogen balances improved slowly over the 6-

169.5 .t 2.95 1 157.88 f 5.07

week follow-up p e n d Only 8 patients achieved a positive nitrogen balance by 6-weeks

2 1.39 + 3.72 38.34 I 10.36

post-admission. Two patients (patients I and 12) achieved positive nitrogen balance by

26.1 1 k 8.26 53.1 1 f 12.73

two weeks, 4 more patients (patients 4, 10, 13, and 14) by Cweeks, and only 2 more

36.33 + 6.3 1 1 53-34 f 12.65

(patients 5 and 7) by 6-weeks. Seven patients (2, 3,6,8, 9, 1 1, and 15) still remained in

negative nitrogen balance 6 weeks after their initial hospitalization.

Two patients (patients 9 and II) in particular had extremely negative nitrogen

balances throughout the entire follow-up penod. Patient 9 was readmitted to hospita1

&ce for COPD and chronic heart failure over the 2- and 6-week visits perpetuating such

Table S. Dietary Intake and Nutritional Status of 15 Male and Female COPI) Patients Atlmitted for an Acute COPI) Exacerbation Over a bweek of Follow-ua Period

Va tiable Males Females (hlcrn f SD) In hospital 2 weeûs 4 weeûs 6 weeks In hospitiil 2 weekv 4 wwks 6 weeks

(n4 ) (n=6) (n=S) (n4) (n=9) (n=8) (n=9) (n=9) Energy,kcal/day 2551f1127 2100f417 2448 f 53 1 1766f649 1945f436U 1865f414 1470k291h 1689f472

Percent of EEE* 102 f 48 84f 17 98 f 27 87 f 27 83f 23 79 f 33 [REE x 1.7) Protein, dday 98 "9 1 837 83 î 22' 80 "5 63 f 1 6 ~ 71 f 16

---- ----- Protein, g/kg/dry 1.55 & 0.67 I .JO f 0.43 1.61 î 0.72 1.38 f0.80 1.41 f 0.57" 1.35 î0.52 1.13 î 0.57" 1.26 IO

Weight, kg I 63.5 f 12.3 1 62.6 f 14.4 1 64.6 f 21.4 65.3 * 23.1 1 64.0 & 22.0 1 64.5 f 21.8 I

Nitrogen balance, -1 1.69 î 12.32 -12.44 f 15.53 -5.94 f 13.37 -9.60 f -14.20 f -4.54 f 8.18~ -6.62 f 10.50 -1.87 f 8.49h g M a y 12.15 1 1,79" Handgrip 29.95I6.56 29.36f6.44 31.IOf:9.15 30.25 f 18.99 f 2.28 l9,25 f 3.15 19,69 f 2.95 19.55 f 2.68 strendh, kg force 10.24 CHI, "/o 18.88 f 7.30 19.70 17.60 17.43 f 9.81 17.36 i 7.14 22.03 f 8.2@ 16.75 f 7.47h 20.59 f 11.37 15.83 f 8 . 1 3 ~

h signilicantly different (p<O.OS) froin ' using paired t-tests *Al~hrrviati«ns: fiEl'., estiinatcd energy expnditure; RE13, restiny encqy expenditure; CI.11, creatinine height index

a highiy catabolic state. Patient I 1 had a very poor protein and enerLy intakr throughout

the follow-up pend so a negative nitrogen balance could br expected. The very negative

nitrogen balance o f patient 7 at 4 wtrks rulluwed an i8&y readmission for a COPD

exacerbation. The decline in nitrogen balance for patient 6 at 4- and 6-werks rnay be

related to the severity of his acute exacerbation. This patient was housebound due to his

persistent symptorns that did not improve over the followv-up period, which suggests that

the acute exacerbation resol ved slowl y prolonging the catabolic rffects. Two male

patients (patients 1 and 14) did not complete visit 4 because they both felt too well to stay

home for the final 24-hour urine collection. These two patients both achieved a positive

nitrogen balance by 4 weeks after their initial hospitaiization and resumed their activities.

Table 6 is a summary of the actual nitrogen balances of each patient over the

follow-up period. The nurnber of previous hospital admissions was examined to see if

there was any relationship with nitrogen balance. No correlation was found. The

correlation between nitrogen balance and readmission was examined however, i t is

difïicult to compare pst-admissions because patients were not al1 recruited at the same

time and therefore follow-up time afier the study p e n d was not equal.

Patient

6. Summary of Admissions and Nitrogen Balances of 15 Patients Admitted for an Acute COPD Exacerbation Over a 6wWeek Follow-up Period

Nitrogen Balances (g N/day) Hospital Admissioas Post 3 O O O 1 O 1 O 3 NA O O O O O

0.57f1.09

Hospital -1.12 -1 1.00 -15.86 -8.44 -10.11 4.69 -9.36 -13.14 -35.78 -8.68 -37.29 -0.94 -4.86 -5 -46

2 weeks 1 .O8 -3 .O4 -1.35 -2.80 -24.04 -5 -82 -2.13 -3.72 -38.67 NA -22.78

5 -99 -3 -23 4.14

4 weeùs 1 1.93 NA -4.56 0.22 -8.47 -13.02 -29.27 -7.7 1 -22.43 0.78

- 16.75 0.67 3-71 2.28 -6.70

4.38+11.09

6 weeks 1 Previous NA i 2 -3.68 1 I -6.00 1 3 5.38 i 16 2.% ! 1 -12.55 ! O 2.6 1 1 1 4.79 1 O -25.13 1 O 1.45 I NA

-21.64 I O 6.27 1 1

-29.20 -13.20fl1.63

1 -29 NA

-6.3 1 -7.93512.0

1 2

-1.43 1 O -4.25I9.94 1 2f4.13

Energ).

Refeedinp studies have found that energy intakes of at lest 1.7 x REE are

required in order to see any significant increases in weight, muscle snength, and exercise

performance in both stable inpatients and outpatients (Efihirniou. 1 988: Goldstein, 1 986;

Rogers, 1991; Whittaker, 1990). Following these recomrnendations. energy requirements

were calculated using the Hams Benedict equations ( 1 -7 x REE). which correlates very

wel l with energy expenditures of COPD patients rneasured by indirect calonmetry

(Moore, 1988). Energy requirements were compared to individual intakes as a percent-

The energy intakes and percent of energy intake to estimated enerp expendinire at each

time point are presented in Table 5. The lower energy intake at visit 4 for the males was

partly due to the fact that patients 1 and 14 did not complete visit 4 and therefore were not

included in the mean energy intake. These 2 patients both had average energy intakes of

150% of their estimated energy requirements.

It appean that both male and female patients had difficulty meeting their

estimated energy requirements during hospitaiization and follow-up. The average energy

intake for the males was 2255*759 kcals (10&40% of estimated energy requirements)

and 17391433 kcals (90*30% of estimated energy requirements) for the females. The

energy intake of the males did not significantly change over the 6-week follow-up. The

energy intake of the females was significantly lower at visit 4 only.

Eight patients (patients 1, 4, 5, 7, 10, 12, 13, 14) who even had energy intakes

greater than 1.7 x REE were unable to achieve a positive nitrogen balance in hospital.

However, these 8 patients were able to maintain their energy intake above 1.7 x M E

dunng the follow-up period and were the only patients who were able to achieve positive

nitrogen balance during the 6-week follow-up period. Patient 1 and 12 were able to

achieve positive nitrogen balance at 2 weeks, patient 14 by 4 weeks, and patient 5 by 6

weeks. These patients had a significantly (p<0.000 1 ) higher energy intake ( I20*3O% of

estimated energy requirements) than patients who remained in negati ve ni trogen balance

(70*20% of estimated energy requirements). Three male patients (patients 2, 6, and 9 )

and four female patients (patients 3, 8, 1 1, and 15) had energy intakes less than 80% of

their estimated energy requirements. These patients still remained in negative nitrogen

balance at 6 weeks. Four female patients (patients 4. 7, 10, and 13) had enerLy intakes

between 80 to 100% of their estimated energy requirements and were able to achieve

positive nitrogen balance starting at 4 weeks.

Table 7 provides the correlations between energy intake and nitrogen balance at

each visit. Although the correlation is borderline non-sibmificant in hospital, it is

statistically significant at 4 and 6 weeks. Adequate energy intake is an important factor in

resolving negative nitrogen balance. However, these correlations could be confounded by

an improved catabolic state resulting in an increased appetite as clinicd status of each

patient resolves.

Protein

Mean protein intakes expressed in g/day and g/kg/day are provided in Table 5.

The protein intake of the males did not significantly change over the 6-week follow-up.

The protein intake of the females was significantly lower at visit 4 only. which

corresponds to the decreased energy intake. The average protein intake for the males was

1 -510.6 g/kg/day and 1 -3k0.6 g/kg/day for the females. Patients who achieved a positive

nitrogen balance had a signi ficantly higher (~0.000 1 ) protein intake of 1.7*0.3g/kg/day

compared to 1.0kû.3 g/kg/day for patients who remained in a negaiive nitrogen balance.

The correlations between protein intake and nitrogen balance were exarnined

because one would not expect them to be correlated if protein requirements were king

met since a higher or a lower protein intake would still result in nitrogen balance.

However, strong positive correlations between protein intake and nitrogen balance are

evident as seen in Table 7 and Figures 5 and 6. The overall correlation between protein

intake and nitrogen balance for male and female patients together is d.34 (pe0.01).

Tabk 7. Correlations betwcen Nitrogen Balance and Dietary lntake During a 6- \Veek Follow-up Period in 15 Mak and Feaale COPD Patients .4dmitteâ for an

Acute COPD Exacerbation Independent Variables Nitmgen Balance

ln bospit.1 . 2 wetks 1 w e k s 6 week Energy Intakt (XREE* x 1.7) In hospital 1 0.4734

( ~ 0 . 0 143) 2 wecks -0.1905

1 (p4.5140) 4 weeks

WEE: Resting Energy Expendihire

Weight

Body weights were recorded at each visit and are shown in Figures 7 and 8.

Body weight did not significantly change for either the men or women over the bweek

follow-up period. Mean body weights are given in Table 5. A11 subjects were on

corticosteroids and 6 were also on diuretics rendering total body weight somewhat

unreliable.

Unnary creatinine excretion is highly conelated with lean body mass

(Heymsfield, 1983). Although there is an age-related decline in creatinine excretion,

Welle et al. (1996) found that the relationship between creatinine excretion and muscle

mass is not affected by age and therefore remains a useful index of muscle mass in the

Figure 8. Body Weights of 6 Male COPD Patients Admitted for an Acute Exacerbation of COPD Over a 6-Week Follow-Up Period

. . . .. -. . - _ - . .-. - - - - .. ._ .......-. . _._....- . - . - . _ _. . . <

~drnission 2 weeks

Visit

. .. .

4 weeks 6 weeks

1 -C Patient 1 +Patient 2 -t Patient 5 4- Patient 6 -t Patient 9 .C Patient 14

elderly. Although the creatinine excretions are much lower than the normal range of 15-

25 m&g/day (Tilkian, 1987))- it has been confirmeci that creatininc cxcretion rates below

10 mgkg/day occur kquently (36.8%) in critically il1 elderly patients and are consistent

with a lower muscle mass (Pesola, 1993).

Depletion of muscle mass can be estimated by the CHI. A CHI of 60% to 80% of

standard has been suggested to represent a moderate deficit in body muscle m a s

According to this standard, al1 15 patients can be classitied as severely depleted (40%)

based on age-corrected creatinine excretion rates that are available for calculating the CHI

(Gibson, 1 990).

Pen'pheraï muscle functio~t

Handgrip strengîh

As expected, men had sigificantly higher (p=0.0 1 ) handgrip strength measures

than the women- Handgrip strength rneasures for both men and women did not

significantly change over the follow up period (Table 5). Men had signiticantly lower

(p-0.02) and women had sirnilar handgrip strengths compared to reference values

reported by Bassey et al. (1993) obtained fiom a sample of 920 healthy men and women

of similar age to the study participants. However ideal muscle strengths for this age

group remains to be deterrnined.

No significant correlations were found between handgrip strength and nitrogen

balance, dietary intake, or weight at any t h e point. Handgrip measures can be unreliable

if patients who are sick do not perform the voluntary test reliably.

Corh'costeroid treatment

Cumulative corticosteroid dose was calculated during the follow up period.

Correlations between cumulative and daily corticosteroid dose and nitrogen balance are

presented in Table 8. Only correlations between daily dose of corticosteroids and

nitrogen balance were found at 4 and 6 weeks. There were no correlations between

cumulative corticosteroid dose or additional corticosteroid dose and change in handgrip

strength during the follow-up p e n d (Table 8).

Correlations with corticosteroid dose are very difficult to capture because there

was little variability in the chnical management during an acute exacerbation. In hospital,

patients were al1 on corticosteroids. By two weeks pst-admission most patients were

finished their tapering corticosteroid doses. At 4 and 6 weeks pst-admission, only two

patients who were readmitted to hospital were still on ~o~costeroids. The positive

correlations between daily corticosteroid doses at 4 and 6 weeks and nitrogen balance

were likely confounded by the severity of illness requiring readmission. To solve the

problem of low variability in corticosteroid treatment at any time point and to see if any

relationships do exist with nitrogen balance and handgrip strength, cumulative

corticosteroid doses over the previous two years were calculated for each individual

patient fiom their medical chart. No correlations between previous 6-month 1 Zmonth,

or 24-month cumulative corticosteroid doses and nitrogen balance or handgrip strength

were found. Nitrogen balance is a short-term measure and cumulative corticosteroid

intake is Iong-term therefore it is not surprishg that they do not correlate.

Discussion

This audy was designed to examine the impact of an acute esacerbation of COPD

on muscle wasting in COPD patients. The main objective of this study was to detennine

how long patients remain in negative nitrogen balance pst-admission and to estimate the

magnitude and describe the resolution of nitrogen balance over a 6-week foilow-up

period. A second objective was to rneasure dietary intake and cumulative corticosteroid

medications to determine whether they are significant factors associated with nitrogen

balance. A third objective was to detennine if any significant changes in muscle mass,

penpherai muscle strength and body weight occw in relation to nitrogen balance,

cumulative corticosteroid medications or dietary intake during the course of an acute

COPD exacerbation.

The most important finding was the magnitude and duration of negative nitrogen

balance that the patients experïenced during one acute exacerbation of COPD. Dietary

intake was found to be a significant factor associated with the resolution of nitrogen

balance. No correlations between cumulative corticosteroid doses and nitrogen balance

were found. Cumulative corticosteroid doses did not correlate with changes in peripheral

muscle strength, muscle mass, or weight, which did not significantly change over the 6

week follow-up period.

As anticipated, al1 15 patients were in negative nitrogen balance in hospital with a

mean nitrogen loss of -13.2W11.63 g N/day. This represents a protein loss of

approximately 82.5 g of protein per day based on the relationship that LBM is 20%

protein, which is equivalent to a loss of 4 12 g of LBM per day. In the context of other

nitrogen balance studies, the magnitude of the catabolic stress seen in this study of COPD

patients admitted for an acute exacerbation is greater than what has been reported in other

studies for patients hospitalized for severe trama and bums. Therefore the catabolic

stress of an acute exacerbation of COPD needs to be recognized and not taken lightly. In

a study of 14 steroid-treated head-injured patients, Clifton et al. (1984) reported a mean

negative nitrogen balance of -9.2f 10.87 g N/day during the first 9 days of hospitalization.

In a group of 39 patients suffering fiom multiple trauma and bums, Larsson et al. (1990)

reported a mean negative nitrogen balance of -13.8H.5 g N/&y durin?: the tint 8 d q s of

hospitalization. Mancusi-Ungaro et al. ( 1992) reported a mean negative nitrogen balance

of 4 - 5 2 1 -7 _r N/&y in bum patients suffering from total body surface area bums nnging

fiom 7% to 8396.

Only in a prospective study iike this one cm the resolution of nitrogen balance be

determined. Nitrogen balance improved very slowly over the 6-week follow-up period

with 7 patients (47%) still remaining in negative nitrogen balance (-10.75*9.34 g N/day)

at 6 weeks pst-admission. In a study of 63 elderly hip fracture patients, Pattenon et al.

(1992) reported that wvithin 8 to 10 days al1 patients achieved positive nitrogen balance.

Although the overall pattern of the resolution of nitrogen balance is reasonable.

two patients (patient 9 and 1 1 ) in particular have negative nitrogen balances that seem to

be exaggerated. One limitation in the estimation of nitrogen balance is how accurately

üUN is able to predict TUN. In stable condition, LTLM accounts for 80% to 90% of

TUN, which makes üUN very useful in estimating TUN. Under severe stress or trauma

Konstantinides et al. ( 199 1 ) found that üüN can overestimate TUN up to 1 12%, which

may explain why these two patients who seem to recover very slowly have such extreme

negative nitrogen balances. Excluding the nitrogen balances of patients 9 and 1 1, the

average nitrogen balance over 6-weeks was approximately 5 g N/day. This corresponds

to a cumulative Ioss of 1.3 kg of protein or 6.5 kg of LBM, which is very detrimental.

This study provides significant evidence that an adequate dietary intake is an

important factor involved in the resolution of nitrogen balance. Although 7 out of 15

patients still remained in negative nitrogen balance at 6 weeks pst-admission, these

patients had signiticantly lower energy and protein intakes then the 8 patients who

achieved positive nitrogen balance. Al1 patients were in negative nitrogen balance in

hospital, including the patients who had and energy intake above their estimated energy

requirements (1.7 x REE). The acute catabolic phase may be impossible to hait in

hospital. Patients who were able to achieve a positive nitrogen balance had a mean

energy intake of 120&30% of their estimated energy requirements (1 -7 x R E ) .

According to our findings, the energy requirements for an acute exacerbation are above

1.7 x REE. As seen in the study by Saudny-Unterberger et al. (1997), without nutritional

support most patients are unable to consume this level of energy intalie. Clevenger et al.

( 1992) reported that energy intakes of 1 -5 x REE for surgical patients and 1.75 x REE for

trauma patients and protein intakes of 1.5 to 2.0 g protein/day were required in stressed

genatric patients in hospital to improve nitrogen balance to -1.6 g N/day. Clifton et al.

( 19W) reported that a caloric intake of 1.6 1 to 2.40 x REE was required for patients with

severe head injury to achieve a positive nitrogen balance in hospital on three consecutive

days. The catabolic effects of an acute exacerbation are remarkable and although it may

be dificult to halt the catabolic processes during an acute exacerbation in hospital, the

catabolic state may be prolonged unnecessarily if an adequate dietary intake is not

achieved and maintained.

The chronic state of COPD patients also needs to be considered as an important

factor involved in weight loss and wasting of FFM. Bunker et al. (1987) perfomed

nitrogen balance studies in 24 healthy elderly people venus 20 housebound elderly with

chronic diseases, including patients with COPD. The patients with chronic diseases were

on varbus medications i ncl uding di uretics and corticosteroids. Housebound patients had

significantly lower protein and energy intakes venus the healthy elderly. Protein intake

was 46.3 g/day for men and 34.1 +y for women in the housebound elderly versus 69.4

g/day for men and 59.7 g/day for women in the healthy elderly. Energy intakes in the

housebound elderly were 22 kcals/kg/day for men and 19 kcals/kg/&y for women

compared to 29kcals/kg/day and for men and ZSkcalskg/day for females in the healthy

elderly. Housebound elderly had an average negative nitrogen balance of -1.6 g N/day

compared to healthy elderly who were in nitrogen balance (O g N/day). Some of our most

negative patients were housebound during the follow-up period. Although their nitrogen

balances may improve with time, they may remain in negative nitrogen balance, which

would certainly lead to serious Iosses of muscle mass over time. This study underscores

the importance of long-term nutritional support programs. Nutritional supplementation

programs need to be implemented in order to assure patients are able to meet elevated

energy requirements during an acute exacerbation, which would allow them to achieve a

positive nitrogen balance faster. In addition, it would also help patients maintain an

adequate energy level in order to irnprove nutritional and fûnctional staius in a stable

state, as seen in previous refeeding trials (EAhirniou. 1988; Rogers, 1992). 49

Corticosteroids are known for their catabolic effects. High doses of

corticosteroids have becn found to cause respiratory and periphenl muscle myopathy and

muscle weakness (Decramer, 1992). In addition, long-terni low doses of corticosteroids

correlate with muscle weakness (Decramer. 1994). Little variability in clinicd

management of corticosteroid therapy as well as the delay between the action of the dnig

and its rnetabolic efiects makes it dificult to see the effects on nitrosen balance and

muscle strength. In hospital al1 patients were on sirnilar doses of corticosteroids and

discharged on similar tapering doses. Only two patients were still on corticosteroids at 4

and 6 weeks. Both of these patients had been readmitted to hospital dunng the follow-up

period and were still in negative nitrogen balance. The two correlations at 4 and 6 weeks

were most likely confounded by the severity of the illness. No correlations between

change in handgri p strength and cumulative or addi tional corticosteroid doses between

visits were found. Long-tem low doses of corticosteroids have an independent effect on

peripheral muscle weakness (Decramer, 1994). No correlations between cumulative

corticosteroid dose over the previous 6 months, 12 months, or 24 months and handgrip

strength were fowid presumably because the change in handgrip strength is not a direct

measure of muscle mass. Although no correlations were found between corticosteroid

doses and nitrogen balance and muscle strength, it does not mean that they do not exist.

Despite such high negative nitrogen losses over the 6-week there were no

sipificant changes in body weight, muscle mass, or handgrip strength. During an acute

exacerbation body weight is a very crude measure of nutritional status due to disturbances

in fluid balance caused by corticosteroid treatment and diuretics. Fluid shiAs can also

occur during depletion of FFM (Barrends, 1997b), which may mask any weight changes.

Engelen et al. (1994) and Schols et al. (1993) both characterized a proportion of normal

weight patients to have a depleted LBM.

Unnary creatinine excretion did not significantly change over the follow-up

period indicati ng that muscle mass remained constant. Because creatinine was not used

in the estimation of TUN, it is possible that the protein losses are coming fiom sources

other than muscle in the body. Creatinine excretion is also very sensitive to changes in

the composition of dietary protein. The dietary composition of the diet was not controlled

and therefore creatinine excretion may not be reliable. The sources of the nitrogen losses

need to be examined hther.

Although handgrip stremgth is correlated with muscle mass. handgrip strenbqh did

not significantly change over the 6-week follow-up period. The preservation of upper

body strength seen in elderly patients who have a decreased physical activity (Frontera,

199 1 ) may be one reason why handgrip strength measures were preserved

Conclusion

This study clearly demonstrated that the catablic stress of an acute exacerbation

should be considered as serious as the catabolic effects of traumas and burns. An acute

exacerbation is a significmt factor involved in nitrogen loss. Although the catabolic

rffects of an acute exacerbation in hospital may be impossible to halt, resolution of

negative nitrogen balance is possible with dequate dietary intake. Efforts to implement

nutritional supplernentation programs for hospitalized patients should be a priority. The

implication of prolonged protein losses leading to serious losses of LBM is associated

with poorer prognosis. Although energy intakes above 1.7 x REE significantly improved

the resolution of nitrogen balance, the optimal energy requirements during an acute

exacerbation still need ta be determined. Nitrogen balance studies at home are possible

and could be a usehl methd in monitoring the nutritional status of COPD patients

regularl y.

Amencan Thoracic Society. ( 1995). Detinitions, Ep idemio lo~~. Pathophysiology, Diagnosis, and Staging. Amencan Journal o f Res~iratorv and Critical Care Medicine, 152 (Suppl.), 78-1 2 1 . -

Barrends. E. M., Schols A. M. W. J., P a ~ e m m s , D. L. E., Westerterp, K. R., & Wouten. E. F. M. ( 1997a). Total fiee living energy rrcpenditure in patients with severe chronic obstructive pulmonary disease. Amencan Joumal of Res~iratorv and Critical Care Medicine. 155,549-554.

Baarends, E. M., Schols, A. M. W. J., Van Marken Lichtenbelt, W. D., & Wouters, E. F. M. (1997b). Analysis of body water compartments in relation to tissue depletion in clinically stable patients with chronic obstructive pulmonary disease. Amencan Journal of Clinical Nutrition, 65,88-94.

Barrends, E. M., Schols, A. M. W. J., Westerterp, K. R., & Wouters, E. F. M. (1997~). Total daily energy expenditure relative to resting energy expenditure in clinically stable patients with COPD. Thorax. 52, 780-785.

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Braun, S. R., Keim, N. L., Dixon, R. M., Clagnaz, P., Anderegg, A., & Shargo, E. S. (1984). The prevalence and determinants of nutritional changes in chronic obstructive pulmonary disease. Chest, 86 (4), 558-563.

Bunker, V. W., Lawson, M. S., Stansfield, F., & Clayton, B. E. (1987). Nitrogen balance studies in apparently healthy elderly people and those who are housebound. British Journal of Nutrition, 57,2 1 1-22 1.

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Creutzberg E. C., Schols, A. M. W. J., Bothmer-Quaedvlieg, F. C. M.. & Wouters, E. F. M. (1998). Prevalence of an elevated resting energy expenditure in patients with chronic obstructive pulmonary disease in relation to body composition and lung function. European Journal of Clinical Nutrition, 52,396-401.

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Manfreda, J., Mao, Y., & Litven, W. ( 1989). Morbidity and mortality fiom chronic obstructive pulmonary disease. American Review of Res~iratorv Disease. 140 (Suppl.), 19-36.

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Openbrier, D. R., InMn, M. M., Rogers, R. M., Gottlieb, G. P., Dauber, J. H., Van Thiel, D. H., & Pennock, B. E. ( 1983). Nutritional status and lung function in patients with emphysema and chronic bronchitis. Chest. 83 ( 1 ), 1 7-22.

Patterson, B. M., Cornell, C . N., Carbone, B., Levine, B., & Chapman, D. (1992). Protein depletion and metabolic stress in elderly patients who have a fracture of the hip. The Joumal of Bone and Joint Surgerv, 74,25 1-260.

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Reed, R. L., Pearlrnutter, L., Yochurn, K., Meredith, K. E., & Mooradian, A. D. (1991). The relationship between muscle mass and muscle strength in the elderly. Journal of the American Geriatrics Societv. 39,555-56 1.

Rogers, R. M., Donahoe, M., Br Costantino, J. (1992). Physiologic effects of oral supplemental feeding in malnourished patients with COPD. Amencan Review of Res~iratorv Disease. 1 46, 1 5 1 1 - 1 5 1 7.

Roubenoff, R., Roubenoff, R. A., Ward, L. M., & Stevens, M. B. (1990). Catabolic effects of highdose corticosteroids persist despite therapeutic benefits in rheumatoid arthn'tis. Amencan Journal of Clinical Nutrition, 52, 1 1 13-1 1 17.

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58

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Appendix A. Patient Consent Form

Appendix B. Initial Questionnaire

Appendix C . FoIlow-up Questionnaire

3650 SI. Lirhain. .Clon1 r h l . Québec H2.ï l P 4 r ( 514) 849-5201 TZfcicopietrr f 5 14) 843-2088

Patients with emphysema or chronic bronchitis often lose weight and muscle strength during acute exacerbations of their condition. In order to better understrnd this loss and how best t o prevent these losses we are conducting this- study.

The study in which you are being asked to participate involves the following tests. You wil l be asked to have a 24-hour urine collection in hospital and three more times at home o f in hospital if you have not been discharged. A dietitian wil l visi t you on 4 occasions to ask about what you have been eating in the previous 24-hours. She will visit you at home at your convenience. At these rame 4 occasions, we will also measure the muscle strength of your hand by having you exert a force against a small measuring device. In order that we can record what medications you are on, we will be consulting your medical chart.

The dietitian who wil l evaluate your diet wi l l be very pleased to help you with any dietary problems and answer ony questions about the quality of your diet and give you suggestions for easy foods to prepare if you wish.

Should you wish to discontinue your participation a t any time, you are completely free to do so without any consequences to your care. This research is completely voluntary and may not lead to any improvements i n your health, but wil l help us find anrwers about caring for patients with emphysema and chronic bronckitis. A l l information obtained about you will be kept confidential.

1, , have read the above and agree to the tests and procedures outlined above. I understand that I am free to withdraw from the study at any time.

Signature o f patient Date

Witness

Un Institut de l'Hôpital Royal Victoria An Institute of the Royal Victoria Hospital affilié à l'Université McGiH affiliated with McGill University

3650 SI. Urbain. Montréal. Qrrgbec H2X P 4 (514) 849-5201 a Tdécopicvrr (51 4 ) 843-2068

Les patients souffrant d'emphysdme ou bronchite perdent du poids et de la force muscubire pendant l'hospitalisation. Afin de mieux pievenir ces pertes, nous avons planifid Btude P laquelle vous &tes invitées participer.

L'Btude comprend les tests suivants. Nous ferons une collecte d'urine pendant 24 heures B I'h6pit.l et trois collectes additionelles à b maison suite & votre retour. Une dietétitiste VOUS visitera une fois b I'hopital et trois fois d la maison pour vous questionner sur votre alimentation quotidienne. EElk mesurera aussi la force musculaire de votre main avec un petit appareil. Nous vous demandons également la permission de consulter votre dossier m6dical pour connaitre votre méâication.

La di&t&tiste qui 6valuera votm apport alimentaire sera en mesure de &pondre i toutes vos questions concernant votm alimentation et si vous le désirez, vous donner des suggestions de repas ou de collations faciles & ptdiparer.

Vous &tes entierement libre de discontinuer votre participation à tout moment sans aucun effet sur les soins que vous recevez. Votre participation à cette étude est volontaire et n'offre pas une amélioration directe de votm santé, cependant elle nous aidera P amelioier les soins offerts aux patients futurs. Tous les renseignement reçus seront gardés confidentiel.

Je, , ai lu ces informations et suis en accord avec les intewentions proposées. Je comprends que je peux terminer ma participation n'importe quel moment

Signature du patienqe)

Un institut de l'Hôpital Royal Victoria An Institute of the Royal Victoria Hospital affilié à I'Universit4 McGill affiliated with McGill University

1 CONTACT INFo-TION 1 Name:

Hospital number: Study numbcr:

Addres s : Phone nurnber:

Contact Person(s):

Name:

Relation:

Phone number:

Foflow up Notes:

Date:

Study number: 1 1 1

1 SOCIODEMOGRAPHIC INFORMATION 1 Date o f birth:

Gender: U Femaie 17 Male

Age: vears

Living Arrangements: iJ Alone [3 With others

Other:

Ethnic: O Caucasian/ White O Black O Hispanic O Asiatic

Employment Category : [7 Working full / part time

Not working O Other:

Past Medical History

ENT (Ears, Nose, Mouth) E yes Respiratory Disease Cardiovascular Disease Gastrointestinal Disease Genito-urinarv Disease Neurologie Disease Endocrinologie Disease Hematologic Disease Locomotor Disease Psychiatrie Disease Others:

Previous yes

Description no

Current y es

no

Study nurnber: 1 1

1 SMOWG HISTORY 1 1. Have you ever smoked?

Cigarettes O No O Yes (No means less than 20 packs of cigarettes or 400 -pans of tobacco in a lifetime or at least 1 a day for a year)

CigadCigarillo [7 No myes (Yes m m s more than 1 a week for a year) Pipe D N o O Yes (Yes means more than 1 Zoz of tobacco in a li fetime)

if "yes" go to question 2

2. Do you smoke now (as of 1 month aga)? 3. How much are you smoking now?

Cigarettes O No il Yes # Of cigarettes per &y Cigars/Cigacillo bIlNo [7 Yes # Of cigars/cigarillos per &y

Pipe O No O Yes # Of pouches (r 50 pams) of tobacco per week

I DYSPNEA SCALE 3 BREATHLESSNESS

Are you troubled by shorîness of breath when hurrying on the level or walking up a slight hill?

0 N/A O No m e s

Do you have to walk slower than people of your age do on the level because of the breath lessness?

O No Cl Yes

Do you ever have to stop for breath when walking at your own pace on the level?

O No a Yes

Do you ever have to stop for breath a h walking about 100 yards (300 feet) (or afier a few minutes) on the level?

O No O Yes

Are you too breathless to leave the house or breathless on dressing or undressing? UNo OYes

For how many years have you been breathless? yevs

Study number

1 SPIROMETRY 1 Lunc function test:

Date:

Fever on admission / fever on d q of urine collection? No CI Yes O C

FEVl

FVC

FEVI/FVC

ACTUAL PRED % PRED

-

1 INFORMATIONS PERSONNEL 1

Nom:

Numéro de I'hopital: Numéro de I 'éiudc: l-l--7

Adresse: Numéro de teleohone:

Personne contact:

Nom:

Relation:

Numero:

Notes de suivi:

Date:

Numéro de I'dtude: [ 1 1

1 INFORMATIONS SOCIODEMOGRAPHIQUE 3 Date de naissance:

Gendre: O Femme C] Homme

Avec qui vivez vous?: Seul

Cl Avec autres a Autres:

Ethnic: O Caucasiad Blanc

Noir 0 Hispanique

Asiatique

Langue( s):

Category d'emploie: O Travail temps pleidpartiel 0 Ne travaille pas 0 Autre:

Description

,

I

ONB (Orei lies, Nez, Bouche) Yeux Maladie Repiratoire Maladie Cardiovasc ulai re Maladie Gastrointestinale Maladie Geni to-urinaire Maladie Neurologique Maladie Endocrinologique Maladie Hematologique Maladie Locomoteur Maladie Psychiatrique Autres:

Courant oui

Passé non oui non

L'HISTOIRE DE FUMEZ 1 1. Avez-vous déji fumé?

Cigarettes O Non 01 Oui

Cigares/Cigarillos 0 Non O Oui Pipe CI Non 0 Oui

(Non veut dire moins que 20 paquets de cigarettes ou 400 gammes de tabac a vie ou au moins une/jour pour un a) (Oui veut dire plus d'une semaine pour un an) (Oui veut dire plus de 12 onze de tabac à vie)

Si "oui" allez à la question 2

2. Fumez vous maintenant (depuis 1 mois)? 3. Combien fumez vous maintenant?

Cigarettes O Non Oui +Y de cigarettes par jour Cigrires/Cigarillos O Non O Oui # de cigares/cigarillos par jour Pipe O Non O Oui if de sac (= 50 gammes) de tabac

par semaine

Devenez-vous essoufflé(e) quand vous vous dépechez sur un terrain plat ou quand vous montez une pente légère?

N/A O Non Cloui

Devez-vous marcher plus lentement que les gens de votre âge sur un terrain plat parce que vous devenez essoufflé(e)?

Non Ci Oui

Vous arrive-t-il de vous arrêter pou. reprendre votre souffle quand vous marchez à votre rythme sur un terrain plat?

0 Non R o u i

Vous amive-t-il de vous arrêter pour reprendre votre souffle apres avoir marché environ 100 verges (300 pieds) (ou après quelques minutes) sur un terrain plat?

Non O Oui

Ètes-vous trop essoumé(e) pour quitter la maison ou devenez-vous essoufIlé(e) en vous habillant ou en vous déshabillant?

0 Non O Oui

Depuis combien d'années êtes-vous essoumé(e) comme cela? # d'années

Tests de Fonctions Pulmonaires: Date:

Fièvre à l'admission :' fièvre le jour de la collection d'urine?

VEMS

CVF

VEMSIC VF

O No 0 Oui O C

PRED ACTUEL % PRED

I

1 STABILITY OF THE COPD 1 PRESENCE OF SYMPTOMS:

Since your last visit, your qmptoms are:

Have you been coughing in the last few &YS?

Have you had a lot of phlegm tiom the lungs?

Have you been out of breath the last few days?

Score for symptoms? O - None 1 - Easily tolerated 2 - Interfkring with your daily activities 3 - Incapacitating

Have you had a fever? CI No

Have you lost weight since hospitalization?

1 - Yes Las 2- No fiequent

(1-1

Yes

O No Yes

Had you Iost weight before that (i-e-past year)? u No Yes

If 'tes". Whv?

During the 1st 2 weeks have you done any exercise? O No 17 Yes

1 f "no", please i ndicate reason(s)?

If "yes", please complete the following table:

I I I I

*Walking. Bicyclins Swimming, Stretching, Yoga Tai chi, Other (speciQ)

Type o f exercise* (speci-) r

Number of times (per week)

Xpproximate duration each time (minutes)

1 WSPIRATOY AGGRAVATION OR 0- HEALTH PROBLEMS 1 Over the p s t 2 weeks have you had any unscheduled visits?

To p u r physician's offlce/clinic 17 No CI Yes If yes, how man? times'? -

To the ernergency room O No O Yes If yes, how rnany tirnes? -

By a health care professional: No Yes If yes, how many times? -

Over the fast 2 wveeks have you been hospitalized/to the day hospital? n N o [7 Yes

If "yes", what wvas the reason for admission? Total nwnber o f days?

Exacerbation or aggravation of your respiratory condition

Other medical condition:

O No O Yes

13 No I l Yes

Study nurnbcr - 7 - 1

1. llave your respiratory medications changed since the last visit? O No O Yes

If "yes", whnt are your new medications or doses?

MGDICATIONS HR DATE:

DIS:

DIS: 1 I -

DIS:

DIS :

~. -- ,---.

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I STABlLITE DE LA COPD 1

Par rapport à la Ier visite: est-ce que les symptômes de toux sont:

I -Oui Moins Semblables Pl us 2-Non fréquents fréquent

(1-1 (2-1 (34 Toussez-vous ces derniers jours? - O O O Ramenez-vous des crachats qui viennent des poumons ces derniers jours? O

jours?

Scores 0- 1 - 7- - 3 -

Devenez-vous essouf!fIé ces derniers (7 O O

pour les sympt6rnes: Aucun Symptomes facilement tolérables Symptômes qui intefierat dans les activités quotidiennes Symptômes incapacitants

Avez-vous eut de la fièvre? Ul Non 0 Oui 01 Pas mesuré

Avez-vous perdu du poids depuis l'hospitalisation? Non CI Oui

Avez-vous perdu du poids avants ça (i.e. années passées)? Non Ul Oui

Si "oui", raison?

Au cours des deux dernières sernmaines, avez-vous fait de l'exercice? a No 0 Yes

Si "non", S.V.P. indiques les raisons:

I I 1 _I

*Marche. Bicyclette. Nage, Etirement, Yoga Tai chi, Autres (specifiez)

Si "oui". S.V.P. completez le tableau suivant: Type d'exercise*

(speci fiez) Nombre de fois (par semaine)

Durée approimative à chaque fois (minutes)

1 AGGRAVEMENT RESPIRATOIRE OU AUTRES PROBLEMES DE SANTE 1 Au cours des 2 demieres semaines avez vous eut des visites qui noetaient pas céduleés?

Chez votre medicien (bureau, clinique)? O Non Oui Si oui, combien de fois? -

À l'urgence? O Non a Oui Si oui, combien de Fois? -

Par un professionnel de la santé? 17 Non Oui Si oui, combien de fois? -

Au cours des 2 demiere semaines avez vous été hospitalise~à l'hôpital de jour?

17 Non El Oui

Si oui, qu'elle était la raison de I'adrnission? L e nombre de jour total

Exacerbation ou aggravation de votre condition respiratorie? CI Non Oui

Autres conditions medicales: O Non D Oui

Nurndro de l'étude m l

. STABIL~TE DE LA COPD 1 1. Est ce que vos medicaments respiratoires ont change depuis la derniere visite?

Si "oui" qu'elle sont vos nouveaux medicaments ou dosages?

O Oui O Non

Mois 19 -