causes and treatment of chronic respiratory failure

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UMEÅ UNIVERSITY MEDICAL DISSERTATION

New series No 1142 ISSN 0346-6612 ISBN 987-91-7264-455-7

From the Department of Public Health and Clinical Medicine Respiratory Medicine and Allergy

Umeå University, Sweden

Causes and Treatment of Chronic Respiratory Failure

Experience of a National Register

Torbjörn Gustafson

Umeå 2007

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Copyright © 2007 by Torbjörn Gustafson

ISSN 0346-6612, ISBN 987-91-7264-455-7

Printed by: Solfjädern Offset AB, Umeå Cover: Blå Jungfrun, Kalmarsund

Department of Public Health and Clinical Medicine

Respiratory Medicine and Allergy Umeå University

SE-901 85 Umeå, Sweden

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To Jonas, Helena, Emma and Ulla, my dear family!

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TABLE OF CONTENTS

Abstract .................................................................................................................... 5

Swedish summary ..................................................................................................... 6

Original papers ......................................................................................................... 9

Abbreviations .......................................................................................................... 10

Introduction ............................................................................................................. 11

Aims ........................................................................................................................ 21

Material and methods ............................................................................................. 22

Study design ..................................................................................................... 22

Study populations ............................................................................................. 22

Data analyses ..................................................................................................... 25

Statistical methods ........................................................................................... 25

The individual papers ...................................................................................... 27

Results ..................................................................................................................... 40

Sex-related differences in LTOT in COPD (Paper I) ....................................... 40

Occupation and pulmonary fibrosis (Paper II) ................................................. 44

Ventilation or oxygen in kyphoscoliosis (Paper III) ......................................... 49

Quality in long-term oxygen therapy (Paper IV) .............................................. 52

Discussion of methodology ...................................................................................... 55

Discussion of main results ....................................................................................... 57

Conclusions ............................................................................................................. 70

Future perspectives ................................................................................................. 71

Acknowledgements .................................................................................................. 73

References ............................................................................................................... 75

Papers I – IV ............................................................................................................. 86

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ABSTRACT Causes and treatment of chronic respiratory failure - experience of a national register Long-term oxygen therapy (LTOT) or home mechanical ventilation (HMV) can improve survival time in chronic respiratory failure. A national quality register could be an aid to identifying risk markers and optimizing therapy for respiratory failure.

Aims: ▪To identify risk markers for chronic respiratory failure, especially when triggered by chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). ▪To predict sex-related differences in the future need of LTOT for COPD and to study sex related survival rate in COPD patients starting LTOT. ▪To investigate if HMV is more effective than LTOT alone in treating chronic respiratory failure caused by kyphoscoliosis. ▪To evaluate the use of quality indicators in LTOT.

Methods: Swedish national registers for LTOT and HMV were established in 1987 and 1996 respectively. They were reconstructed in 2004 to form the web-based register Swedevox. Indications for LTOT were based on the guidelines from the Swedish Society for Respiratory Medicine. The incidence and prevalence of LTOT for COPD were measured annually from 1987 to 2000, and the future need for LTOT was estimated on the basis of the frequency of ever smoking in Sweden in 2001 in different age groups. A postal questionnaire on occupational exposures was completed by 181 patients with severe pulmonary fibrosis who started LTOT between 1997 and 2000, and by 757 controls. Odds ratios (ORs) were calculated. Time to death was evaluated in kyphoscoliotic patients starting HMV or LTOT alone in 1996-2004. Ten quality indicators were defined and evaluated based on data from patients starting LTOT in 1987-2005.

Results: The incidence each year of LTOT in COPD patients increased more rapidly in women than in men (from 2.0 and 2.8/100,000 in 1987 to 7.6 and 7.1/100,000 in 2000 respectively, (p < 0.001)). Women ran a 1.9 times higher risk than men to develop chronic hypoxemia from COPD and had a higher survival rate during LTOT. In men, IPF was associated with exposure to birch dust with an OR 2.7, (95% confidence interval (CI) 1.30–5.65) and with hardwood dust, OR 2.7 (95% CI 1.14–6.52). Patients with kyphoscoliosis showed a better survival rate with HMV than with LTOT alone with a hazard ratio of 0.30 (95%CI 0.18-0.51), adjusted for age, sex, concomitant respiratory diseases, and blood gas levels. There were improvements in the following eight quality indicators for LTOT: access to LTOT, PaO2 ≤ 7.3 kPa without oxygen, no current smoking, low number of thoracic deformity patients without concomitant HMV, LTOT > 16 hours of oxygen/day, mobile oxygen equipment, reassessment of hypoxemia when LTOT was not started in a stable state COPD, and avoidance of continuous oral steroids in COPD. There was a decline in the indicator PaO2 > 8 kPa on oxygen. First-year survival rate in COPD was unchanged.

Conclusions: The incidence and prevalence of LTOT increase more rapidly in women than in men. Survival rate during LTOT in COPD is better in women than in men. Exposure to birch and hardwood dust may contribute to the risk of IPF in men. Survival rate in patients with kyphoscoliosis was three times better with HMV than with LTOT alone. The national quality register for LTOT showed improvements in eight out of ten quality indicators. Levels for excellent quality in the indicators are suggested. Key words: Chronic obstructive pulmonary disease; pulmonary fibrosis; kyphoscoliosis; respiratory failure; sex; smoking; occupation; survival; long-term oxygen therapy; mechanical ventilation.

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SAMMANFATTNING PÅ SVENSKA Vid kronisk andningssvikt är tiden för överlevnad kort, men den kan förlängas med långtids behandling med syrgas (LTOT) eller hemrespiratorbehandling (HMV). Det är därför viktigt att identifiera riskfaktorer och att optimera behandlingen. Rökning, den huvudsakliga riskfaktorn för kroniskt obstruktiv lungsjukdom (KOL), har blivit vanligare hos kvinnor än hos män. Exponeringar i yrkesmiljö kan delvis ligga bakom utveckling av idiopatisk lungfibros (IPF), ett tillstånd med allvarlig ärrbildning i lungorna, vars orsak till stor del är okänd. Vid andningssvikt på grund av kyfoskolios spelar underventileringen på grund av deformeringen av bröstkorgen stor roll. Trots att mycket talar för att HMV är effektivare än enbart LTOT mot andningssvikt vid kyfoskolios, så erhåller en hel del kyfoskoliospatienter enbart LTOT. Det finns välkända svårigheter att få riktlinjer för LTOT genomförda. Ett nationellt kvalitetsregister kan tjäna som grund för utvärdering och förbättring av urval av patienter till samt genomförande av syrgasbehandling.

Målsättning: ▪ Att identifiera riskmarkörer för kronisk andningssvikt orsakad av kroniskt obstruktiv lungsjukdom (KOL) eller idiopatisk lungfibros (IPF). ▪ Att förutsäga könsrelaterade skillnader vad gäller behov av LTOT mot KOL inom en nära framtid och att studera könsrelaterade skillnader i överlevnad hos KOL-patienter, vilka påbörjar LTOT. ▪ Att studera om HMV är effektivare än enbart LTOT vid behandling av kronisk andningssvikt orsakad av kyfoskolios. ▪ Att utvärdera effekten av ett nationellt kvalitetsregister och att föreslå utmärkt kvalitet på kvalitetsindikatorer vid LTOT.

Metoder: Svenska nationella kvalitetsregister för LTOT och HMV etablerades respektive 1987 och 1996. Dessa rekonstruerades 2004 till att bilda det webbaserade registret Swedevox. Indikationerna för LTOT baseras på riktlinjer från Svensk Lungmedicinsk Förening. Dessa säger att LTOT är indicerat vid svår kronisk syrebrist, eller måttlig kronisk syrebrist komplicerad med högerhjärtsvikt eller förhöjt antal röda blodkroppar. Grundsjukdomen skall ha varit stabil i minst tre veckor. I vissa fall behöver dock LTOT påbörjas under en försämringsepisod av KOL och då skall skälet till LTOT omprövas de närmaste tre månaderna. Rökstopp är ett krav för att påbörja syrgasbehandling. Påbörjade LTOT och pågående LTOT på grund av KOL mättes varje år från 1987 till 2000 och det framtida behovet av LTOT hos män respektive kvinnor beräknades på basen av rökning någonsin i Sverige under 2000 i olika åldersgrupper. En postenkät om yrkesexponeringar fylldes i av 181 patienter med svår lungfibros, vilka påbörjade LTOT mellan 1997 och 2000, samt av 757 kontrollpersoner. Oddskvoter (OR) beräknades avseende riskmarkörer. Tiden till död utvärderades hos kyfoskoliospatienter som påbörjade HMV eller enbart LTOT under 1996-2004. Tio kvalitetsindikatorer definierades och utvärderades baserat på data från patienter, som påbörjade LTOT från 1987 till och med 2005.

Resultat: Det årliga antalet påbörjade LTOT hos KOL-patienter ökade snabbare hos kvinnor än hos män (från 2,0 och 2,8/100 000 under 1987 till 7,6 och 7,1/100,000 under 2000 respektive (p < 0,001)). Kvinnor löpte en 1,9 gånger högre risk än män att utveckla kronisk syrebrist på grund av KOL. Allt fler kvinnor med KOL beräknas påbörja LTOT under de närmaste åren och ännu fler kommer att ha pågående LTOT på grund av KOL. Hos män var IPF associerat med exponering för björkdamm, OR 2,7, (95 % konfidensintervall (CI) 1,30–5,65) och med damm av ädelträ, OR 2,7 (95 % CI 1,14–6,52). Patienter med kyfoskolios, vilka erhöll HMV, hade bättre överlevnadsgrad än de som behandlades med enbart syrgas med en riskkvot på 0,30 (95 % CI 0,18–0,51), korrigerat för ålder, kön, samtidig luftvägssjukdom samt blodgasnivåer. Det blev förbättring i följande åtta kvalitetsindikatorer

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för LTOT: Tillgång till LTOT, arteriellt syretryck (PaO2) ≤ 7,3 kPa med luftandning, ingen pågående rökning, HMV till alla kyfoskoliospatienter som erhåller LTOT, > 16 timmar med syrgas per dygn, portabel syrgasutrustning, omprövning av indikationen för LTOT, om den har påbörjats när KOL inte var i stabil fas samt undvikande av underhållsbehandling med kortisontabletter vid KOL. Det blev minskning i indikatorn PaO2 > 8 kPa vid andning av syrgas. Överlevnadsgraden första året vid KOL var oförändrad. Under 2005 förmådde > 80 % av länen uppfylla fyra kriterier för LTOT.

Slutsatser: Påbörjade behandlingar med LTOT och pågående LTOT ökar snabbare hos kvinnor än hos män. Överlevnaden vid LTOT på grund av KOL är bättre hos kvinnor än hos män. Exponering för damm av björk och ädelträ kan bidra till ökad risk för IPF hos män. Kyfoskoliospatienter hade tre gånger bättre överlevnad med HMV än med enbart syrgas. Det nationella kvalitetsregistret för LTOT visade förbättring i åtta av tio kvalitetsindikatorer. Nivåer föreslås för utmärkt kvalitet för de tio indikatorerna.

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CAUSES AND TREATMENT OF CHRONIC RESPIRATORY FAILURE – EXPERIENCE OF A NATIONAL REGISTER

ORIGINAL PAPERS

I Franklin KA, Gustafson T, Ranstam J, Ström K. Survival and future need of long-term oxygen therapy for chronic obstructive pulmonary disease - gender differences.

Respir Med 2007; 101:1506-1511

II Gustafson T, Dahlman-Höglund A, Nilsson K, Ström K, Tornling G, Torén K. Occupational exposure and severe pulmonary fibrosis.

Respir Med 2007; 101:2207-2212

III Gustafson T, Franklin KA, Midgren B, Pehrsson K, Ranstam J, Ström K. Survival of

patients with kyphoscoliosis receiving mechanical ventilation or oxygen at home.

Chest 2006; 130:1828-1833

IV Gustafson T, Löfdahl K, Ström K. A model of quality assessment in patients on long-term oxygen therapy.

Manuscript Permission to print the original papers in this thesis has been granted from the Editorial epartments of Respiratory Medicine and Chest The Tables 2 and 3 and the Figures 8-12 in this thesis were published in Respiratory Medicine, Volume 101, Franklin KA, Gustafson T, Ranstam J, Ström K, Survival and future need of long-term oxygen therapy for chronic obstructive pulmonary disease - gender differences, Page 1506-1511, Copyright Elsevier (2007). The Tables 4, 5 and 8-11 and the Figure 4 in this thesis were published in Respiratory Medicine, Volume 101, Gustafson T, Dahlman-Höglund A, Nilsson K, Ström K, Tornling G, Toren K, Occupational exposure and severe pulmonary fibrosis, Page 2207-2212, Copyright Elsevier (2007). The Tables 6, 12 and 13 and the Figures 13-15 in this thesis were published in Chest, Volume 130, Gustafson T, Franklin KA, Midgren B, Pehrsson K, Ranstam J, Ström K. Survival of patients with kyphoscoliosis receiving mechanical ventilation or oxygen at home, Page 1828- 1833. Copyright American College of Chest Physicians (2006).

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ABBREVIATIONS

ATS American Thoracic Society

CI Confidence interval

COPD Chronic obstructive pulmonary disease

ERS European Respiratory Society

FEV1 Forced expiratory volume in one second

FVC Forced vital capacity

HMV Home mechanical ventilation

HR Hazard ratio

IPF Idiopathic pulmonary fibrosis

ILD Interstitial lung disease

kPa kilopascal

LTOT Long-term oxygen therapy

MRC Medical Research Council

NOTT Nocturnal Oxygen Therapy Trial

OR Odds Ratio

PaCO2 Arterial carbon dioxide tension

PaO2 Arterial oxygen tension

PF Pulmonary fibrosis

SD Standard deviation

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INTRODUCTION

Chronic respiratory failure

Chronic respiratory failure (arterial partial pressure of oxygen (PaO2) < 8.0 kPa, with or

without arterial partial pressure of carbon dioxide (PaCO2) > 6.7 kPa while breathing air at

sea level),1 is a serious complication of several pulmonary diseases, chronic obstructive

pulmonary disease (COPD) being the most common of them.2-5 Other major causes include

interstitial lung disease (ILD), pulmonary vascular disease and damage to the lungs and

bronchi after pulmonary tuberculosis.2-5 Chronic respiratory failure can also be caused by

thoracic deformity, such as kyphoscoliosis and sequelae after pulmonary tuberculosis. In

thoracic deformity, hypoventilation with carbon dioxide retention requires special

attention.2,3,6 Hypoxemia, the main component of respiratory failure, is the result of various

combinations of four mechanisms: ventilation-perfusion inequality, hypoventilation, diffusion

impairment and shunt, of which ventilation-perfusion inequality is the most important.7,8

Hypoxemia is dangerous, since it results in tissue hypoxia, causing damage to the internal

organs.7

Long-term oxygen therapy

The consequence of chronic hypoxemia in COPD is a poor prognosis with reduced time to

death.9 Oxygen has been used in the treatment of pulmonary diseases since the 1920s.10,11

Long-term administration of oxygen (LTOT) to COPD patients with respiratory failure was

introduced in the 1950s, based on the results of some largely observational studies with small

numbers of subjects.12,13

The results of two large randomised controlled studies confirmed the improvements in

survival time after LTOT in COPD patients with severe chronic hypoxemia.14,15 The

Nocturnal Oxygen Therapy Trial (NOTT) from the US randomised 203 patients with COPD

and hypoxemia (PaO2 ≤ 7.3 kPa or PaO2 ≤ 7.9 kPa together with pulmonary hypertension or

polycythemia) to nocturnal oxygen of 12 hours per 24 hours or continuous oxygen for 24

hours per day. After a mean of 19 months (range 12-24 months), the mortality was 1.94 times

higher (p = 0.01) in the nocturnal oxygen group vs. continuous oxygen.

In the British study from the Medical Research Council (MRC), oxygen for at least 15 hours

per day at a flow rate of 2 l/min or higher if required to reach a PaO2 of > 8 kPa was

INTRODUCTION

12

compared with no oxygen at all in 87 COPD patients with PaO2 between 5.3 and 8.0 kPa.

Most patients were men and 37% were smokers. At 5 years of follow-up, 19/42 patients had

died in the oxygen group vs. 30/45 patients in the control group. There was no effect on

mortality in men within 500 days.

Later, a study in Poland demonstrated that LTOT had no influence on survival time in COPD

patients with mild-moderate hypoxemia, which so far is the only performed study in that

area.16 There was no difference in cumulative survival time over three years between LTOT

and no oxygen in 135 COPD patients with PaO2 between 7.4 and 8.7 kPa.

These controlled trials on hypoxemic COPD constitute the scientific evidence for several

recommendations on the use of LTOT.1,17-21

Long-term oxygen therapy is one of the two interventions with positive prognostic effects in

COPD, the other being smoking cessation.22-25 LTOT actually doubles survival time when

administered continuously to severely hypoxemic COPD patients.14,15 In contrast, a large

recently published study did not clearly show that the combination of inhaled steroid and

long-acting beta-2-agonist had life-prolonging effects on COPD.26

There is no evidence that LTOT has effects in terms of survival time in other underlying

conditions with chronic hypoxemia than COPD. Still, oxygen is believed to reduce dyspnoea

and to attenuate the harmful effect of hypoxemia on the internal organs.27 Therefore oxygen is

recommended when hypoxemia occurs in patients with idiopathic pulmonary fibrosis (IPF)

and pulmonary hypertension (PAH) or other disease processes with similar indications as in

COPD.2,21,28

Despite the doubling of survival time with LTOT administered for chronic severe hypoxemia

in COPD, survival time during LTOT is poor, particularly in pulmonary fibrosis and

pulmonary hypertension.3-5 In COPD, the excess mortality attributable to hypoxemia is

eliminated by LTOT29 but the mortality attributable to severe obstruction and cardiovascular

disease associated with COPD remains.30 Therefore, identifying risk markers for chronic

respiratory failure and hypoxemia is an important task for improving prevention.

Furthermore, the survival time benefit is only observed in patients with severe hypoxemia.14-16

Therefore, it is essential to have adequate patient selection criteria for LTOT. The survival

INTRODUCTION

13

benefit was doubled when continuous oxygen therapy was administered, as compared with

nocturnal treatment. Adequate LTOT, including hours of oxygen use and oxygenation, is also

essential to obtain maximum benefit. Adequate LTOT is also decisive to obtain improvements

in quality of life.31

A small improvement in quality of life is obtained with LTOT in hypoxemic COPD, but

quality of life remains poor during LTOT.31-34 To obtain the benefit of improving quality of

life, mobile equipment is decisive for patients active outside home.31 Dyspnoea at exertion

can be incapacitating in respiratory failure and oxygen has a limited effect on this symptom.35-

38

The aims of this thesis were to study sex as a risk factor for hypoxemic COPD and

occupational exposure as a risk factor for pulmonary fibrosis with severe hypoxemia, to

identify whether HMV or LTOT is the best treatment in kyphoscoliosis with respiratory

failure and to evaluate quality indicators for LTOT. The quality indicators were based on

existing evidence and guidelines and our experience of a national register on LTOT.

Sex-related differences in COPD

Tobacco smoking and occupational risk factors, as well as malnutrition, poor water supply,

sanitation, personal and domestic hygiene, unsafe sexual behaviour, alcohol use,

hypertension, physical inactivity, illegal drugs, and air pollution have been identified as major

risk factors for death and disability worldwide.39

Tobacco smoking is the dominant risk factor for COPD,19,40,41 after age.42 Smoking is

increasing in a global perspective.43 The cigarette consumption per capita worldwide is slowly

decreasing, but total smoking has increased continuously over the last decades, mainly owing

to population growth. Cigarette consumption is still higher per capita in developed countries,

but it is increasing dramatically in the developing part of the world.43 Chronic obstructive

pulmonary disease is expected to rise from the twelfth to the fifth leading cause of disability

from 1990 to 2020 and from the sixth to the third leading cause of death from 1990 to 2020.44

The tobacco industry has studied smoking patterns and preferred tobacco products among

women in detail, and has used this information to make tobacco products specially designed

to support recruitment of female smokers.45,46 Tobacco advertising contributes to initiation of

INTRODUCTION

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smoking in the population.47-50 It is believed that deaths attributable to tobacco use would

continue to rise even if comprehensive tobacco control policies were immediately

implemented worldwide.43

Women are more sensitive than men to the harmful effects of tobacco smoke, according to

several studies,24,51-53 and may also be more disposed to developing severe form of COPD.54

Moreover, in severe COPD the prognosis is worse for women than for men.55,56 The effects of

long-term oxygen on survival time in women with severe COPD have been less studied than

among men. Only 21%-24% of the patients included in previous studies of LTOT and

survival time were women.14-16

For many years, the prevalence of COPD has been higher for men than for women. This

pattern has been changing in recent years.57 In Sweden, smoking has decreased gradually

since 1980 and since 1990 fewer men than women smoke. In 2005, 14% of men and 18% of

women in Sweden were current smokers, or less than 16% of the adults in total.58 The ratio in

a country of prevalence of smoking in younger women to that of older women is thought to be

an indicator of the future prevalence of smoking in that country.59

The mechanism behind pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common disorder in the group of idiopathic

interstitial pneumonias which, in turn, is a subgroup of the diffuse parenchymal lung

diseases.60 The histological pattern is usual interstitial pneumonia (UIP), not specific for IPF.

It is a serious disease with poor response to treatment.61 Idiopathic pulmonary fibrosis is

clinically comparable to diffuse interstitial pneumonia (DIP) and nonspecific interstitial

pneumonia (NSIP), which carry less severe prognoses than IPF. These are the main

alternative interstitial lung diseases (ILD) to IPF.62,63 The recommended procedure for

differentiation of IPF from the other ILDs is surgical lung biopsy. When it is not possible to

perform, the differential diagnosis may rest on accepted major and minor criteria, based on

non-invasive techniques.61 In reality, open lung biopsy is only performed in a small

proportion of patients with PF.64,65

The mortality in IPF is high and is increasing.62,66,67 Median survival time is 3-5 years after

diagnosis and there is evidence that mortality rates may now be higher than in several

INTRODUCTION

15

malignancies.61,67 When PF is complicated by respiratory failure, survival time is

considerably shorter than in COPD with respiratory failure.3,5

Figures for prevalence/incidence are not entirely reliable, owing to a shortage of reports, a

low proportion of biopsy verifications of the diagnosis, and reclassification.61 The previous

highest prevalence (20.2 per 105 in men and 14.3 per 105 in women) and incidence (10.7 per

105 in men and 7.4 per 105 in women per year) was found in a New Mexico county.68 A

recent survey demonstrated a more than doubling of the incidence between 1990 and 2003 in

the United Kingdom.64 This increase could not be explained in terms of ageing in the

population or improved diagnostic accuracy.

There are several risk factors for IPF, including genetic predisposition and environmental

agents.61 The knowledge about potentially harmful occupational exposures is largely based on

six case-control studies in three countries.69-74 According to a meta-analysis of these studies,65

there are significant associations between six types of exposure and IPF: ever smoking (1.58

[1.27–1.97]), agriculture/farming (1.65 [1.20–2.26]), livestock (2.17 [1.28–3.68]), wood dust

(1.94 [1.34–2.81]), metal dust (2.44 [1.74–3.40]), and stone/sand (1.97 [1.09–3.55]). There is

no study from northern Europe on occupational exposure in patients with PF where, for

example, occupational exposure to soft wood may be frequent.

Respiratory failure in kyphoscoliosis

In respiratory failure, ventilation-perfusion mismatch, reduced area for gas diffusion and

alveolar hypoventilation contribute in varying proportions to this physiological disturbance,

depending on the underlying disease.7,8 Kyphoscoliosis causes impaired ventilatory

mechanics, which may result in considerable alveolar hypoventilation, especially during

sleep.75-79 It has been demonstrated that breathing at low lung volumes often leads to airway

obstruction.80-82 Many of these patients therefore have both a restrictive and obstructive

respiratory disorder and may develop both hypercapnia and hypoxemia in varying

combinations. Therefore, the selection criteria for both LTOT and for HMV are often

fulfilled. The respiratory and cardiac failure caused by kyphoscoliosis results in a poor

prognosis.

Several studies suggest that early initiation of HMV in kyphoscoliotic patients may prevent

the onset of overt respiratory failure.83,84 The mechanisms for the effect seem to be improved

respiratory drive,85,86 improved respiratory muscle function,87-89 but not necessarily affecting

of sleep architecture.90 Consequently, there is a positive effect on daytime blood gases from

INTRODUCTION

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HMV during the night to patients with hypoventilation, which is observed early in the

treatment.91 The benefits of HMV as compared with LTOT has recently been shown in a

small retrospective follow-up by Buyse et al..92

Earlier studies comparing LTOT with HMV in patients with severe thoracic spine deformity

are either short-term or retrospective, and small in terms of number of subjects. Randomised

controlled trials on this issue are generally considered ethically difficult to justify.92

According to figures from quality registers in Sweden and France, LTOT is prescribed for a

substantial number of patients with respiratory failure caused by kyphoscoliosis.3,5,6 In the

Swedish Oxygen Register the annual number of new patients with kyphoscoliosis registered

when starting LTOT remained stable since 1987. This was a matter of concern, since the

Swedish Society of Respiratory Medicine has recommended HMV for these patients since

1993. Since several patients with severe thoracic spine deformity are prescribed LTOT

without concomitant HMV we found it important to compare the impact on survival time of

the different treatment modes in a large patient group.

Quality in long-term oxygen therapy

The main goal of LTOT in relation to hypoxemic COPD is to improve survival time. To attain

this goal, patient selection and performance are of utmost importance. Long-term oxygen

therapy is effective in COPD with severe hypoxemia. This treatment method is complicated,

and the portable oxygen is fairly expensive. Therefore, it is important to assure the quality of

LTOT with use of a number of appropriate quality parameters, and guidelines constitute the

first step in this direction.

Guidelines on LTOT

The indications for LTOT are described in a number of guidelines, among them the Global

Strategy for the Diagnosis, Management, and Prevention of COPD, and in the statement from

the American Thoracic Society (ATS) and the European Respiratory Society (ERS).1,19

Guidelines consist of patient selection criteria and criteria for performance of LTOT.

According to the guidelines from the Swedish Society of Respiratory Medicine, LTOT is

indicated for patients with:17,18,20,21

• chronic hypoxemia owing to COPD or other diseases,

INTRODUCTION

17

• a stable disease course on optimum medical therapy for at least three weeks, and

• arterial oxygen tension (PaO2) when breathing room air ≤ 7.3 kPa (< 7.0-7.5 kPa before

1993) or signs of cor pulmonale or haematocrit > 50 % plus

room air PaO2 of 7.4-8 kPa (around 7.5 kPa before 1993).

The prescription of LTOT to current smokers is discouraged.

Arterial blood gas samples are taken with the patient at rest and after having breathed air for a

minimum of 20 minutes. Arterial blood gas samples are taken on oxygen after having

breathed the prescribed flow of oxygen for a minimum of twenty minutes.

Performance of LTOT

According to the Swedish guidelines, oxygen should be prescribed as many hours as possible

per day, preferably 24 hours.21 A resting PaO2 of above 8 kPa when breathing oxygen is

recommended.

The stationary oxygen supply through the concentrator should be supplemented with mobile

equipment in patients with outdoor activity.

Reassessment of the indication for LTOT should be performed after one and three months,

when LTOT is initiated owing to an exacerbation of COPD.20

Quality indicators

Patient selection criteria

Access to LTOT – Given above, it is important to identify and provide LTOT to patients who

fulfil the selection criteria. In the mid 1980s there were large variations in the number of

LTOT patients among the different counties in Sweden, which caused concern among

respiratory physicians and was the rationale for the start of the Swedish Oxygen Register in

1987.2

Level of hypoxemia – Contrary to severe hypoxemia, patients with mild to moderate

hypoxemia should not be prescribed long-term oxygen, unless the hypoxemia is accompanied

by pulmonary hypertension or raised haematocrit levels.1,17-19 Consequently, the selection of

appropriate patients should be essential in LTOT.14-16

Smoking - According to the Swedish guidelines for LTOT, current smoking is an obstacle to

prescription of LTOT, because of the risk that ongoing smoking will jeopardize the treatment

INTRODUCTION

18

results. Cigarette smoking has been shown to inhibit the benefits of oxygen on secondary

polycythemia,93 and a previous study demonstrated association between continued smoking

during LTOT and increased mortality.3 There is also a risk of fire accidents, of which there

are a few reports.94-96

Kyphoscoliosis - Since alveolar hypoventilation is an important pathophysiological

mechanism when kyphoscoliosis is the reason for chronic hypoxemia,75-79 oxygen alone is

insufficient as therapy in these patients. Instead, HMV during the night is often recommended

as the first treatment,97 since it has favourable physiological effects, including improved

daytime blood gases.83-89,91 Many patients with kyphoscoliosis and respiratory failure receive

supplemental oxygen2,3,5,6 especially those who also have concomitant respiratory disease, but

the mortality is higher when oxygen is given without concomitant HMV, according to data

from a large French register and a Belgian retrospective follow-up study.5,92

Performance of LTOT

Correction of hypoxemia – The target for resting arterial oxygen tension is chosen from the

procedure in the NOTT and the MRC studies, where the subjects were given a flow rate of

oxygen sufficient to reach PaO2 60-80 mmHg (equal to 5.3-8.0 kPa) and 60 mmHg,

respectively.14,15 The level of oxygen in the arterial blood has to be raised to alleviate hypoxia

in the body tissues, and the results of LTOT thus depend on adherence to adequate

achievement of arterial oxygenation. In some patients, retention of carbon dioxide can make it

difficult to reach adequate oxygenation with the oxygen supply.27

Treatment time per day – Appropriate duration of treatment with oxygen per day is also

important for the outcome of LTOT, according to the findings in the NOTT and the MRC

studies.14,15 Oxygen should be supplied for at least 15 hours per day, and the effects on

survival time are increased if the treatment time is extended beyond that, up to 24 hours per

day.

Portable oxygen equipment – The possibilities of reaching appropriate treatment time

increases if the patient has suitable equipment. For this purpose, addition of portable oxygen

equipment to the stationary equipment has a positive effect in patients who spend time outside

their home.31,98,99

INTRODUCTION

19

Reassessment of LTOT after initiation during COPD exacerbation – It is often necessary to

start LTOT during recovery from an exacerbation of COPD instead of awaiting the stable

level of oxygenation. Some patients will then experience improved arterial oxygen levels

during a three-month period, making LTOT no longer needed. Under those circumstances,

recent guidelines recommend a recheck of arterial blood gases after 30-90 days.19,100,101

Concomitant treatment

Avoidance of continuous oral glucocorticosteroids in COPD – Temporary treatment with oral

glucocorticosteroids in acute exacerbations has beneficial effects on recovery time, lung

function and hypoxemia1,19 but long-term treatment with oral glucocorticosteroids is not

recommended in COPD, because no treatment effects have been shown and there are serious

side effects.1 An association has been found between oral steroid medication and increased

mortality in female LTOT patients3,102 and higher mortality in LTOT patients with high body

mass index receiving oral glucocorticosteroids has also been demonstrated.103

Results of treatment

Survival time – According to the results from the NOTT and MRC studies, LTOT can double

survival time in COPD patients with severe hypoxemia.14,15 Those studies were performed on

selected patients, who were younger and had fewer co-morbidities than the average patients

who have later received LTOT.104 The survival time in COPD patients may be lower in

clinical practice than in the randomised controlled trials,14,15 according to the findings of an

Australian study,104 where the patients were older and had multiple co-morbidities. However,

when selected according to similar criteria as in the NOTT and MRC studies, survival time in

Swedish COPD patients receiving LTOT was similar.102,105

Implementing guidelines for management of LTOT are recognized as being difficult.106,107

Adherence to the LTOT guidelines varies in different countries and different areas in the

countries.3,98,108-110 A national register provides a basis for evaluation and subsequent

improvement.

21

AIMS

The objectives of this thesis were to identify possible strategies for the prevention and

postponement of the development of chronic respiratory failure as well as to assure the quality

of treatment of chronic respiratory failure.

The specific aims were

- To identify risk markers for chronic respiratory failure, particularly female sex in chronic

obstructive pulmonary disease and occupational exposure in pulmonary fibrosis.

- To predict the future incidence and prevalence of chronic hypoxemia in chronic obstructive

pulmonary disease on the basis of sex-related prevalence in smoking.

- To study sex related survival time in COPD patients who start LTOT.

- To identify the best treatment of chronic respiratory failure caused by kyphoscoliosis,

comparing home mechanical ventilation or long-term oxygen alone.

- To evaluate the effects of a national quality assurance register and to suggest levels for

excellent quality for quality indicators in long-term oxygen therapy.

22

MATERIAL AND METHODS

STUDY DESIGN

Paper I: Register study of cohorts as well as cross-sectional data

Paper II: Retrospective case control study

Paper III: Cohort study

Paper IV: Prevalence study on county level and national level

STUDY POPULATIONS

The Swedish Oxygen Register

The Swedish Oxygen Register was established in 1987 with the two main purposes of gaining

knowledge of treatment effects and long-term prognosis in LTOT and improving the quality

of LTOT in chronic hypoxemia. The principal quality aspects were to optimize: access to

therapy, adherence to national guidelines for LTOT and performance of LTOT. The register is

used for a prospective cohort study of patients receiving oxygen for chronic hypoxemia at the

start of LTOT, including patients who were already on LTOT when the register was

established. The LTOT patients are reported from the responsible physicians at the Swedish

centers for LTOT, one or more in each Swedish county. Follow up is recorded one year after

inclusion.

Specially trained physicians and nurses are responsible for the LTOT in each county, which is

the relevant unit. Annual meetings are held for reporting of the results from the register, for

training, and thereby to achieve gradual improvements in LTOT. The statistics from the

register are also annually distributed in written forms.

A large number of variables for each patient are were registered at inclusion, when their

LTOT is started. A selection of these variables has been registered since the start of the

Register and others during limited periods.


23

Table 1. Registered data in patients receiving LTOT (selection)

Inclusion record form Follow up record form Swedish census registration number Swedish census registration number Sex County County Number of in-hospital days Arterial blood gas tensions Reason of withdrawal of oxygen PaO2 (air) Date for withdrawal of oxygen PaCO2 (air) PaO2 (oxygen) PaCO2 (oxygen) Cause(s) of hypoxemia Smoking history Current medication Presence of ankle oedema WHO performance status FEV1 and FVC Oxygen therapy Equipment Prescribed flow rate Prescribed daily treatment time FEV1: forced expiratory volume in one second; FVC: forced vital capacity

Figure 1. Causes of hypoxemia in patients receiving LTOT 1987-2005 according to sex.


24

Register coverage

Sweden had a population of 8.4 million in 1987 and 9.1 million in 2006. The register covers

approximately 85% of the LTOT patients.2 The coverage is internally validated with surveys

to the reporting centers about every other year. Four of the 24 counties were unable to report

all LTOT patients to the register, owing to shortages of staff during some part of the period

1987-2000.111 Data from the Swedish Oxygen Register were used in Papers I-IV

The Swedish Home Ventilator Register

The Swedish HMV Register was established 1996 with the purpose of allowing international

and national comparisons of indications, dissemination of methods and results. All the

Departments of Respiratory Medicine and all other medical units prescribing oxygen or home

mechanical ventilation in all Swedish counties report all patients who start HMV, and they are

then followed prospectively with survival time as a primary outcome. Among the data

registered is Swedish census registration number, sex, arterial blood gas tensions when

breathing air, and presence of a concomitant respiratory disease.

Register coverage

The Register covers at least 90% of the Swedish patients treated with HMV according to

repeated internal validations.

Data from the Swedish HMV Register were used in Paper III.

In November 2004, the Swedish Oxygen Register and the Swedish HMV Register were

reconstructed and merged to form the Swedevox Register, which is entirely web-based.

The Swedish Oxygen Register and the Swedish HMV Register were approved by all regional

ethic committees and by the Swedish Data Inspection Board. The registers were funded by the

Swedish National Board of Health and Welfare as national quality assurance registers.

The Causes of Death Register is kept by the Swedish National Board of Health and Welfare,

and comprises all deceased Swedish citizens during a calendar year. Among the information

in the register are Swedish census registration numbers, cause or causes of death, time of


25

death and results of autopsy if performed. The International Classification of Diseases (ICD)

is used for classification of causes of death.

Official statistics in Sweden are produced by the government agency Statistics Sweden, or

Statistiska centralbyrån (SCB), housing the Swedish Population Register, which also contains

information about date of death for people living in Sweden.

Data analyses

In Paper I, we analysed data from the Swedish Oxygen Register, comparing this data with the

dates of death from the Swedish Causes of Death Register.

In Papers III and IV, we analysed data from the Swedish Oxygen and HMV registers with

dates of death from the Swedish Population Register. In the COPD patients in Paper IV, we

investigated the survival rates during the first year of LTOT, adjusted for age and sex. We

also analysed the age-adjusted overall survival according to the year of starting LTOT and

sex.

Statistical methods

The Chi-squared test was used in Papers I and III for comparisons of categorical data.

The Student’s t-test was used in Paper I for comparisons of continuous data.

Analyses of variance were used in Paper III for comparison analyses of continuous data.

Cox regression analysis was used in Paper I to analyse time to death adjusted for age, in Paper

III to assess the effects of treatment method on survival rate and in Paper IV to assess first-

year and overall survival rates standardised for sex and age 70 years.

The Mantel-Haenszel chi-squared test was used in Paper II to calculate odds ratios for PF and

IPF.

Linear regression analyses were used for adjustment of age and other confounders in time-

trend analyses of continuous variables in Paper I.

Logistic regression analysis was used in Paper I for age-adjusted analyses of category

variables and in Paper II to adjust for overlapping exposures between occupations.


26

The photograph in the printed version has been removed in the electronic version

Figure 2. Young girls smoking cigarettes


27

PAPER I – Sex-related differences in LTOT in COPD

Patient population

We included all LTOT patients aged 18 and over with hypoxemia attributable to COPD who

were registered between 1 January 1987 and 31 December 2000 (n=5,689). We acquired the

vital statistics on each patient through 31 December 2003 and the dates of death from the

Causes of Death Register at the Swedish National Board of Health and Welfare.

Women were slightly younger than men at the start of LTOT (p < 0.001). The mean age of

both sex increased during the study years. In 1987, the mean age of the women was 66 ± 8

years and that of the men 67 ± 9 years. In 2000, the mean age of women had increased to 73 ±

9 years (p < 0.001) and the mean age of men to 74 ± 8 years (p < 0.001). Seventy-three per

cent of the women and 70% of the men had PaO2 < 7.3 kPa at the onset of oxygen therapy.

Three hundred and ninety-four patients were excluded since they were registered in the four

counties that withdrew from the study for part of the time. They did not differ in age and sex

from the included patients.

Mean arterial PaO2 was slightly lower and mean PaCO2 was higher in women than in men

when starting oxygen therapy. Mean PaCO2 at the start of treatment gradually decreased in

men from 1987 to 2000, but remained stable in women.

Table 2. Baseline characteristics of COPD patients at start of LTOT.

Women n = 2,894

Men n = 2,795 p-value

Age (years) 70 ± 9 72 ± 9 < 0.001

PaO2 (kPa) 6.6 ± 1.0 6.7 ± 0.9 < 0.001

PaCO2 (kPa) 6.6 ± 1.2 6.1 ± 1.2 < 0.001

PaO2 (oxygen) (kPa) 9.0 ± 1.1 9.0 ± 1.2 0.95

PaCO2 (oxygen) (kPa) 6.9 ± 1.2 6.4 ± 1.2 < 0.001

FEV1 (liters) 0.6 ± 0.3 1.0 ± 0.5 < 0.001

FVC (liters) 1.4 ± 0.5 2.1 ± 0.9 < 0.001

Peripheral oedema (%) 58 52 < 0.001 Smoking history (%) Current Past Never

4 85 11

3 90 6

< 0.001

Values are presented in per cent or as the means ± SD


28

The predicted incidence and prevalence of the need for LTOT was calculated from the

frequency of ever smoking in Sweden in 2001 in different age groups, according to Statistics

Sweden:

Table 3. Ever smoking in men and women according to age in 2001.

Ever smoking (%)

Age Men Women

16-24 23.5 30.1

25-34 33.6 37.9

35-44 43.4 52.4

45-54 63.9 59.5

55-64 69.9 54.0

65-74 64.1 41.8

75-84 66.3 30.3

In the prediction of future need for LTOT, we assumed that age at the start of treatment for

men and women would be the same as in 2000 and that the relation between the prevalence

and incidence would continue to be the same as from 1987 to 2000.

The incidence of LTOT was calculated as in the following example:

The mean percentage of ever smoking in Sweden in women in the age group of 64-84 years

old of was 36.4% in 2001. This age group corresponds closely to the age range of women

receiving oxygen in 2000 (73 ±9 years). Five years later, in 2006, there would thus be 41.8%

of women who had ever smoked among women in the age group for starting LTOT, and the

incidence of LTOT was therefore calculated as being 1.15 times higher (41.8/36.4) in 2006

than in 2000 (when the incidence was 7.65 per 100,000) which would have been 8.78 per

100,000. Fifteen years later, in 2016, the incidence would be 1.48 times higher (54.0/36.4)

than in 2000.

Prevalence of LTOT was calculated as in the following example:

We first calculated the annual quotient between prevalence and incidence which, in women,

was 2.76 per 100,000 in 1988 and 3.47 per 100,000 in 2000. The mean increase for every year


29

was 0.054. The prevalence of oxygen in the year of 2006 was therefore calculated as the

predicted incidence in 2006 (in women: 8.78 per 100,000) multiplied by the expected quotient

in 2006 i.e. the quotient in 2000 plus 6 x 0.054 (in women 3.79 per 100,000). This gave an

expected prevalence of 8.78 x 3.79 = 33.28 per 100,000 in women in the year of 2006.

The mathematical model is therefore: Expected prevalence year X = expected incidence year

X x ((prevalence year 2000/incidence year 2000) + (X-2000 x ((prevalence year

2000/incidence 2000) – (prevalence year 1987/incidence 1987))/13)).


30


Figure 3. Inside a timber industry.


31

PAPER II - Occupation and pulmonary fibrosis

We included as cases all patients (n=241) registered when starting LTOT for chronic

hypoxemia triggered by PF between 1 February 1997 and 4 April 2000. In the analysis, we

divided the cases into two groups, namely all cases (the PF sample), and a restricted sample of

cases (the IPF sample), after exclusion of all subjects with known aetiology of their fibrosis.

The data from the Oxygen Register and the questionnaires did not allow verification of IPF

according to accepted major and minor criteria.61 When identifying the IPF patients we

therefore excluded all patients with host susceptibility or known external agents. We then

assumed that the remaining patients had IPF, being the largest group of the idiopathic

interstitial pneumonias serious enough to cause chronic respiratory failure.

We selected as controls a random sample (n=1,000) from the general population of Sweden

with the same age range as the cases. We sent an extensive postal questionnaire to the cases

and the controls, described below.

The questionnaire was completed by 193 PF patients (cases). Twelve (6%) were excluded due

to erroneous diagnosis in the Oxygen Register. Hence, 181 subjects were included in the PF

sample. From this sample we excluded 27 subjects because of rheumatoid arthritis (n=14),

scleroderma (n=4), Sjögren’s syndrome (n=2) and other diseases such as systemic sclerosis

and systemic lupus erythematosus (n=7). An additional 14 cases were excluded because of

known aetiology, viz. asbestosis (n=6), silicosis (n=5), and irradiation or drug-induced PF

(n=3). Hence, 140 cases were included in the IPF sample. Of the 1,000 controls being sent the

questionnaire, 757 responded.

For each patient answering the questionnaire, the responsible physician was sent a

questionnaire about drugs used the ten years before debut of the disease, any irradiation

treatment, year of first symptoms and diagnosis, investigations performed, grounds for

diagnosis and the physician’s opinion of the possible aetiology of the PF. In the IPF sample,

75 had been examined with high resolution computer tomography of the lungs and ten had

lung biopsy, open or video assisted.


32

These are the baseline data for the cases and controls with regard to age and smoking status.

Table 4. Description of the study population. The cases were the subjects in the PF sample (n=181), where the IPF sample (n=140) was included. Men Women

Cases n=114

Controls n=349

Cases n=67

Controls n=408

Age (yrs) 74.4 64.2 72.0 63.4

Never-smokers (%) 15.7 38.7 54.5 52.6

Ex-smokers (%) 80.6 46.2 43.8 27.4

Current smokers (%) 3.7 15.1 1.7 20.0

Figure 4. Flow chart showing the selection of cases and controls for the study.

The postal questionnaire sent to the cases and controls included details about their occupation,

specific occupational exposure, drugs used and smoking habits. The wording of the items in

the questionnaire was as follows, covering 29 different types of occupational exposure:


33

Table 5. Questions about occupational exposure in the questionnaire.

Have you ever been exposed to welding fumes? mineral dust? coal dust or graphite dust? man-made mineral fibres? ceramics dust? asbestos? grain dust? flour dust? dust from pine or fir? dust from birch? dust from hardwood? paper dust? textile dust? radiation? fire fumes? engine exhausts? irritating gases (ammonia, chlorine dioxide, chlorine gas, sulphur dioxide)? environmental tobacco smoke? Have you worked with grinding, polishing, milling, turning or other processing of metals? soldering? blasting? chrome-platering or nickel-platering? birds? moldy hay or straw? solvents? cutting oils/fluids? rapid glues (Loctite, cyanoacrylates or Omnifit)? Have you worked as a dentist, dental technician or dental nurse?

The cases and referents were divided into the following three groups according to year of

birth: 1906–1923, 1924–1936 and 1937–1969. The cases were diagnosed in 1968–1999. We

further divided them into three groups according to their year of diagnosis, as follows: 1968–

1986 (41%), 1987–1993 (28%) and 1994–1999 (31%).

Relevant exposure was exposure that had occurred before the onset of PF, approximated as

the year of diagnosis. It was also necessary to define an anchor point in time for each control.

Hence, in each birth year group the controls were randomly assigned to a year of diagnosis

group. The number of controls allocated to each year of diagnosis group was weighted by the

number of actual cases. Each control was then assigned the mid-year in his or her year of

diagnosis group as the anchor year.


34

Subjects had to report exposure five years or more before diagnosis to be classified as

exposed. Consequently, exposure occurring during the 5-year period immediately prior to the

diagnosis was not included in the analysis. Exposures were merged into five categories in the

final analysis: occupational, organic dust, wood dust, inorganic dust, and metal dust.

Two groups of cases were analysed, the whole group of cases (the PF sample) and the

restricted sample (the IPF sample). The cases and controls were stratified for sex, age group,

and birth year group. Odds ratios (ORs) were calculated. Only exposure categories with five

or more exposed cases were considered in the final analysis.


Figure 5. A woman with kyphoscoliosis.


35

PAPER III – Ventilation or oxygen in kyphoscoliosis

All men and women with respiratory failure caused by non-paralytic kyphoscoliosis, i.e.

scoliosis not related to neuromuscular disorders, registered when starting LTOT or HMV

between 1 January 1996 and 31 December 2004 were included (n=244). We acquired the vital

statistics before 15 February 2006 and the dates of death from the Swedish Population

Register.

The mean age of all patients was 69 ± 11 years. One hundred and sixty-seven were women

and 77 were men. Twenty-seven of the 100 patients who received HMV also received

supplementary oxygen therapy. Three patients were ventilated via tracheostomy and the rest

with nasal or oro-nasal masks. Mechanical ventilation was prescribed during sleep, i.e. for

less than eight hours to 75% of the patients and for more than 12 hours to only two per cent of

patients. All of 144 patients who received oxygen therapy alone were prescribed oxygen for

16 to 24 hours per day. Five patients who started with oxygen alone and later received

supplementary mechanical ventilation were grouped according to the initial treatment.

Table 6. Baseline characteristics of patients with kyphoscoliosis starting treatment with home mechanical ventilation or oxygen in Sweden, 1996-2004.

Characteristics HMV (n = 100)

LTOT alone (n = 144) p-value

Age (years) 62.4±12.7 73.5±8.9 < 0.001

Women (%) 68 69 0.95

Concomitant respiratory disease (%) 33 65 < 0.001

PaO2 (kPa) 7.5±1.7 6.4±0.9 < 0.001

PaCO2 (kPa) 7.6±1.2 6.9±1.3 0.002


36


Figure 6. A man with portable oxygen equipment.


37

PAPER IV - Quality in long-term oxygen therapy

We prospectively followed all registered adults starting LTOT for chronic hypoxemia before

1 January 2006 until death or 31 December 2006 (n=12,187). We did not include patients

receiving LTOT for a short period as part of palliative treatment for cancer of the lung,

whether primary or secondary.

Our quality indicators


From 1987 and onwards:

- Access to LTOT as the number of LTOT patients per 100,000 inhabitants

- Percentage of patients with PaO2 ≤ 7.3 kPa when breathing air, daytime at rest

- Percentage of patients who are not current smokers


- Small number of patients with thoracic deformity without concomitant HMV

Performance of LTOT


- Percentage of patients with PaO2 > 8 kPa when breathing oxygen

- Percentage of patients with prescribed dosage of oxygen > 16 hours per day

1989-2004:

- Percentage of patients with access to mobile oxygen equipment, registered at follow-up after

one year


- Percentage of COPD patients with reassessment of hypoxemia when breathing air if LTOT

was not started in a stable state, registered at follow up after one year

Concomitant treatment:

1987-1989 and from 1995 and onwards:

- Percentage of COPD patients without continuous oral glucocorticosteroids

Result of treatment: First-year survival rate in COPD

1987-2004:

- First-year survival rate among COPD patients


38

Use of quality indicators

The county level of achievement for each quality indicator was given for comparisons with

the national level reached by all participating centers in the annual reports and from the start

of the web-based Swedevox register. With the individual levels obtained from these centers as

guidance, a recommended level of achievement was chosen as a marker of excellent quality,

according to the individual levels obtained from the centers, e.g. XX% of patients have PaO2

> 8 kPa when breathing oxygen (Table 14).

Each quality indicator was analysed by comparing data from 1987 and 2005, or at some other

start and end year, as described above.

Table 7. Baseline characteristics of patients starting LTOT 1987-2005.

Characteristic

No patients 12 187

% men 49

Age, years 71+9

Cause(s) of hypoxaemia, no patients

COPD 8446

Pulmonary fibrosis 1431

Thoracic deformity 605

Pulmonary vascular disease 461

Sequelae of pulmonary tuberculosis 262

Other causes 982

Arterial blood gas tensions, kPa

PaO2 (air) 6.6+1.0

PaCO2 (air) 6.2+1.3

PaO2 (oxygen) 9.0+1.3

PaCO2 (oxygen) 6.5+1.3


39

Figure 7. Age of COPD patients at the start of LTOT according to starting year and sex.

40

RESULTS

PAPER I – Sex-related differences in LTOT in COPD

Observed and predicted incidence and prevalence

The incidence of LTOT increased among women from 2.0/100,000 in 1987 to 7.6/100,000 in

2000 (p < 0.001), and among men from 2.8/100,000 in 1987 to 7.1/100,000 in 2000

(p < 0.001). From 1997 and onwards, more women than men started LTOT each year.

Figure 8. Incidence of COPD patients starting LTOT according to start year and sex.

0

1

2

3

4

5

6

7

8

9

1985 1990 1995 2000 2005

Per

100

,000

WomenMen

The prevalence of women on LTOT increased more rapidly than that of men. In 1987, 50% of

the COPD patients were women, and in 2000, 58%. Among the women, the prevalence of

LTOT increased from 5.5/100,000 in 1986 to 26.5/100,000 in 2000 (p < 0.001), and among

the men LTOT prevalence rose from 5.7/100,000 to 19.3/100,000 during the observation

period (p < 0.001).

Year of start of LTOT

RESULTS

41

Figure 9. Prevalence of COPD patients starting LTOT according to start year and sex.

0

5

10

15

20

25

30

1985 1990 1995 2000 2005

Per

100

,000

WomenMen

Risk for need of LTOT in women

In the age group receiving oxygen, i.e. ages 65-84 years, the overall frequency of ever

smoking in Sweden was 36.4% in women and 65.0% in men in 2001.112 The incidence of

LTOT for the indication COPD was, however, slightly higher in women in 2000, indicating

that women with COPD ran a 1.9 times higher risk of needing LTOT to treat respiratory

failure. The frequency of ever smoking decreased with age among women, while the opposite

trend was seen in men (Table 3).

Future perspectives

We predict that the incidence and prevalence of LTOT will increase in women from 2006 to

2036, since smoking frequency is increasing among middle-aged women and since smoking

women have a high risk of developing end-stage COPD requiring oxygen therapy.


RESULTS

42

Figure 10. Registered and predicted incidence of COPD patients receiving LTOT according to year and sex. The dotted lines indicate the predicted incidence.

We also predict that about 70% of patients on oxygen in 2026 will be women, with a

prevalence of 61 per 100,000 women as compared with 29 per 100,000 men.

Figure 11. Registered and predicted prevalence of COPD patients receiving LTOT according to year and sex. The dotted lines indicate the predicted prevalence.



RESULTS

43

Hours of oxygen and survival time

In 1987, 42% of patients were prescribed oxygen from compressed gas cylinders and 58%

were prescribed oxygen from concentrators. The percentage of patients using concentrators

rose rapidly, to 97% in 2000. Liquid oxygen was prescribed in 2-3% of patients after 1993,

when it was introduced in Sweden. Slightly more men than women were prescribed oxygen

for > 20 hours per day, p=0.041. Two per cent of women were prescribed oxygen for less than

15 hours per day, 60% for 15-17 hours per day, 9% for 18-19 hours per day and 29% for 20-

24 hours per day. In the case of men, 2% were prescribed oxygen for less than 15 hours per

day, 59% for 15-17 hours per day, 8% for 18-19 hours per day and 31% for 20-24 hours per

day.

The median (1st and 3rd quartile) survival time after the start of treatment was 2.8 (2.6-2.9)

years in women and 2.0 (1.9-2.1) years in men (Figure 12). First-year survival rate was 77%

(95% CI 75-79%) in women and 69% (95% CI 67-71%) in men. The relative risk of death for

men vs. women was 1.21 (95% CI 1.14-1.28) according to a Cox regression adjusted for age.

In patients who were withdrawn from LTOT within one year from the start of treatment, death

was the reason for withdrawal in 88% of women and 91% of men. Improvement in

oxygenation breathing ambient air, and non-compliance were other reasons for withdrawal

during the first year of treatment.

Figure 12. Survival rate in men and women receiving LTOT 1987 -2000.

RESULTS

44

PAPER II - Occupation and pulmonary fibrosis

Subjects with occupational exposure had an increased risk for PF, but not for IPF. Exposure

to wood dust increased the risk for PF but not for IPF. There was no increased risk for either

PF or IPF in relation to exposure to metal dust.

Table 8. Odds ratio, stratified by sex, year of diagnosis, birth year and smoking, for the PF sample (n=181) and the IPF sample (n=140) according to occupational exposure. Exposure PF sample IPF sample

n* OR 95% CI n* OR 95% CI

Any occupational exposure 123 1.6 1.06–2.37 86 1.1 0.71–1.72

Organic dust 69 1.4 0.98–2.12 49 1.1 0.74–1.76

Wood dust 34 1.7 1.03–2.95 22 1.2 0.65–2.23

Inorganic dust 57 1.2 0.79–1.97 35 0.9 0.53–1.49

Metal dust 37 1.0 0.62–1.69 25 0.9 0.51–1.59

When stratifying the analyses for sex, we observed the highest risks of developing PF among

men. Exposure to wood dust among men doubled the risk of developing PF.

Table 9. Odds ratio, stratified by year of diagnosis, birth year and smoking, for the PF sample divided into men (n=114) and women (n=67), according to occupational exposure. Exposure Men, PF Women, PF

n* OR 95% CI n* OR 95% CI

Any occupational exposure 89 1.7 0.95–3.12 34 1.5 0.84–2.55

Organic dust 54 1.7 1.04–2.70 15 1.1 0.56–2.10

Wood dust 33 2.1 1.18–3.65 – n.a. –

Inorganic dust 54 1.4 0.84–2.23 – n.a. –

Metal dust 34 1.1 0.62–1.79 – n.a. –

We then analysed the risks of developing PF and IPF according to all the detailed exposures.

These analyses were performed in men and women together, and were restricted to exposures

affecting five or more cases. The exposure categories are not mutually exclusive. An

increased risk of PF was associated with exposure to mineral dust, birds, flour dust, dust from

pine or fir, birch dust, hardwood dust and fire fumes. In cases of IPF the exposures giving

RESULTS

45

increased risk were only birch dust and hardwood dust. The OR for flour dust and IPF were

just below significance level.

46

Table 10. Odds ratio for the PF sample and the IPF sample according to occupational exposure, stratified by sex. Only exposures with five or more exposed cases were considered. Number of controls exposed for each occupational exposure, divided into men and women. Exposure PF

(n=181) IPF

(n=140) Controls, men

(n=349) Controls, women (n=408)

n OR 95% CI n OR 95% CI n n

Welding fumes 24 1.1 0.64–1.78 15 0.8 0.42–1.42 70 1 Grinding, polishing, milling or turning or other processing of metals

22

1.0

0.57–1.64

15

0.8

0.43–1.44

62

13

Soldering 13 0.9 0.47–1.65 9 0.7 0.31–1.38 44 8

Blasting 7 3.2 1.10–9.32 – n.a. – 7 0

Mineral dust 27 2.4 1.39–4.06 14 1.4 0.74–2.72 39 2

Coal dust or graphite dust 11 1.8 0.83–3.82 9 1.8 0.80–4.07 18 3

Artificial mineral fibres 22 1.2 0.67–2.00 14 0.8 0.45–1.57 60 4

Asbestos 26 1.2 0.72–2.00 15 0.8 0.44–1.47 66 6

Birds 16 2.3 1.22–4.34 10 1.7 0.82–3.62 11 22

Moldy hay or straw 12 1.4 0.68–2.68 8 1.1 0.50–2.48 23 10

Grain dust 17 1.3 0.70–2.21 12 1.1 0.57–2.15 32 22

Flour dust 18 2.1 1.14–3.76 13 1.9 0.98–3.74 19 18

Pine or fir dust 32 2.1 1.31–3.47 20 1.4 0.82–2.52 48 9

Birch dust 16 2.6 1.32–5.18 13 2.4 1.18–4.92 18 4

Hardwood dust 10 2.4 1.05–5.69 9 2.5 1.06–5.89 12 2

47

Paper dust 9 1.3 0.60–2.91 6 1.1 0.43–2.70 17 8

Textile dust 13 1.4 0.74–2.72 10 1.3 0.64–2.70 12 33

Radiation 6 0.9 0.36–2.28 5 0.9 0.32–2.28 16 8

Solvents 28 1.3 0.79–2.05 19 1.0 0.60–1.77 64 14

Fire fumes 8 2.9 1.10–7.58 5 2.3 0.74–6.97 9 0

Engine exhausts 24 0.9 0.54–1.50 15 0.7 0.39–1.27 74 11 Irritating gases (ammonia, chlorine dioxide, chlorine, sulphur dioxide)

13

1.5

0.79–3.00

10

1.5

0.71–3.06

22

10

Environmental tobacco smoke 53 1.0 0.71–1.45 40 0.9 0.61–1.36 117 90

Cutting oils/fluids 8 1.0 0.43–2.23 5 0.8 0.28–2.01 25 0 Rapid glues (Loctite, cyanoacrylates or Omnifit)

6

1.0

0.37–2.45

6

1.9

0.38–2.37

18

2

RESULTS

48

When we analyzed men and women separately with five or more exposed subjects to a group,

risks remained increased for IPF in men exposed to birch dust (OR 2.7, 95% CI 1.30–5.65)

and hardwood dust (OR 2.7, 95% CI 1.14–6.52). Men with IPF also had an increased OR

associated with birds (OR 2.7, 95% CI 1.00–7.06). There was no increased risk for any of the

exposure subgroups in women.

Ten patients with PF reported occupational exposure to hardwood dust. There was also

information about occupations in the questionnaire. The occupations with the longest duration

of exposure to hardwood dust were wood products machine operator, forester, cabinet

makers, machine operator, telephone service worker and blacksmith. There were also two

carpenters and two subjects who did not report their occupation.

We also analysed the material using a latency period of 10 years instead of 5 years, with

similar results. The same exposures were associated with increased risks, but the risks were

slightly higher. In order to explore a cohort effect, we ran the analyses with the population

divided into two groups according to the mean birth year, 1930. We found no clear indication

of any cohort effect.

With the logistic regression models, we observed similar results. Exposure to organic dust

(and wood dust) increased the risk of PF, especially among men. No significant associations

were found when we modelled IPF as the dependent outcome.

Table 11. Logistic regression models for the PF sample giving odds ratios (and 95% confidence intervals) adjusted for sex, smoking, year of birth and year of diagnosis.

Predictor All PF patients (n=181) Men Women

Inorganic dust 1.1 (0.70–1.68) 1.1 (0.70–1.83) 0.55 (0.12–2.53)

Organic dust 1.5 (1.00–2.15) 1.7 (1.06–2.8) 1.2 (0.60–2.22)

Metal dust 0.98 (0.61–1.58) 0.97 (0.58–1.63) 0.82 (0.17–3.82)

Wood dust 1.9 (1.12–3.15) 2.1 (1.22–3.75) 0.50 (0.06–4.11)

RESULTS

49

PAPER III – Ventilation or oxygen in kyphoscoliosis

More patients started LTOT alone than HMV during the whole study period (Figure 13).

Figure 13. The annual number of patients starting HMV or LTOT 1996-2004.

Thirty-two of the 100 (32%) patients on home mechanical ventilation and 110 of the 144

(76%) patients on oxygen therapy alone had died at follow-up. Age above 70 years, suffering

from concomitant respiratory disease, low PaO2 and low PCO2 were related to an increased

risk of early death in the univariate analysis.

Table 12. Univariate analysis of relative risk of death among patients with kyphoscoliosis. Hazard ratio 95% CI p-value Mechanical ventilation vs. oxygen therapy alone 0.22 0.15-0.33 < 0.001

Age > 70 years 3.34 2.31-4.82 < 0.001

Concomitant respiratory disease 2.43 1.72-3.44 < 0.001

Female sex 1.33 0.93-1.93 0.118

PaO2 (mm Hg)* 0.97 0.96-0.99 < 0.001

PaCO2 (mm Hg)* 0.98 0.96-0.99 < 0.01 *Continuous variables

RESULTS

50

Table 13. Multivariate analyses of relative risk of death among patients with kyphoscoliosis.

Hazard ratio 95% CI p-value

Oxygen therapy alone 1

Home mechanical ventilation 0.30 0.18-0.51 < 0.001

Age > 70 years 2.63 1.74-3.98 < 0.001

Female sex 1.27 0.85-1.92 0.24

Concomitant respiratory disease 1.43 0.96-2.12 0.078

PaO2 (mm Hg) 0.99 0.97-1.02 0.70

PaCO2 (mm Hg) 0.99 0.98-1.02 0.95

Patients treated with HMV experienced better survival rate than patients treated with oxygen

alone, even when adjusting for age, sex, concomitant respiratory diseases and blood gases.

Figure 14. Cumulative proportion of surviving patients receiving HMV or LTOT alone.

RESULTS

51

Survival time was longer in patients with a concomitant disease receiving mechanical

ventilation than in patients without a concomitant respiratory disease on oxygen therapy

(p=0.03):

Figure 15. Cumulative proportion of surviving patients receiving HMV or LTOT alone, subdivided according to the presence of concomitant respiratory disease.

RESULTS

52

PAPER IV - Quality in long-term oxygen therapy

Quality indicators at national level

We found improvements in eight of the ten quality indicators. The achievement of adequate

oxygenation (PaO2 > 8 kPa) when breathing oxygen was impaired and first-year survival rate

was unchanged.

Table 14. Achieved performance at national level in ten quality indicators according to the proposed levels for excellent quality, first and latest-year of use of indicator.

Quality indicator Proposed excellent quality level

Achieved performance level first-year cohort and latest-year cohort Year Level


1. Access to LTOT (patients/100,000 inhabitants) > 30 1987) 7 2005) 31

2. PaO2 ≤ 7.3 kPa (% of patients) > 85 1987) 76 2005) 85

3. Non-smokers (% of patients) ≥ 95 1987) 96 2005) 99

4. LTOT patients with thoracic wall deformity without HMV (n) None 1993) 30

2005) 5 Performance of LTOT

5. PaO2 > 8 kPa on oxygen (% of patients) > 90 1987) 86 2005) 80

6. More than 16 hours per day (% of patients) > 95 1987) 91 2005) 97

7. Mobile oxygen equipment (% of patients) > 50 1989) 48 2004) 65

8. Reassessment of LTOT one to three months after initiation during a COPD exacerbation (% of patients) > 95 2002) 0

2005) 30 Concomitant treatment 9. Avoidance of continuous oral glucocorticosteroids in COPD (% of patients) ≥ 80 1987) 54

2005) 81 Result of treatment

10. First-year survival rate in COPD patients > 0.65 1987) 0.73 2004) 0.75

Access to therapy increased in terms of the number of patients on LTOT and there was a

decrease in the variations among the counties. On 1 January 1987, the number of ongoing

patients on LTOT varied between 1.3 and 19.6 per 100,000 (a factor of 15) in the different

counties, whereas on 31 December 2005 it varied between 21.0 and 76.0 per 100,000 (a factor

RESULTS

53

of 3.6.) At national level, the total number of LTOT cases increased from 565 to 2,871 per

these dates.

The dominant underlying diseases for respiratory failure were COPD and PF.

Figure 16. Number of new patients (n) with long-term oxygen therapy in 1987-2005 divided by reasons for hypoxemia. : Chronic obstructive pulmonary disease; : Pulmonary fibrosis; : Thoracic cage deformity; : Other diseases.

The first-year survival rate in COPD patients did not change.

Figure 17. First-year survival rate in patients with COPD according to year of start of LTOT.

RESULTS

54

County quality achievement

At the end of the study period, all the counties reached our proposed excellent quality levels

for first-year survival rate, the prescription of oxygen for more than 16 hours per day, 90% for

LTOT to non-smokers and 80% for providing the patients with mobile equipment.

Conversely, only 25% of the counties managed to reach the quality levels for the

reassessment of LTOT one to three months after initiation during a COPD exacerbation and

25% for PaO2 > 8 kPa on oxygen. For this quality indicator, there was a decline in

achievement among the counties. There were improvements in the other quality indicators,

apart from avoiding LTOT to current smokers, which emerged as unchanged.

Table 15. Achievement among the counties (%) in excellent quality level by quality indicator, first and latest-year of use of indicator.

Proposed excellent quality level

Counties achieving excellent quality level first and latest-year of use of indicator Year %


> 30 patients/100,000 inhabitants with access to LTOT 1987) 0 2005) 60

> 85% of patients with PaO2 ≤ 7.3 kPa 1987) 35 2005) 65

≥ 95% of patients who were non-smokers 1987) 90 2005) 90

HMV to all patients with thoracic wall deformity 1993) 30 2005) 75

Performance of LTOT

> 90% of patients with PaO2 > 8 kPa on oxygen 1987) 50 2005) 25

> 90% of patients with more than 16 hours per day 1987) 70 2005) 100

> 50% of patients with mobile oxygen equipment 1989) 60 2004) 80

> 95% of patients with reassessment of LTOT one to three months after initiation during a COPD exacerbation

2002) 0 2005) 25

Concomitant treatment ≥ 80% of COPD patients without continuous oral glucocorticosteroids

1987) 25 2005) 50

Result of treatment

> 0.65 first-year survival rate in COPD patients 1987) 70 2004) 100

55

DISCUSSION OF METHODOLOGY

A national quality assurance register, as the Swedish Oxygen Register and the Swedish Home

Mechanical Ventilation Register, now merged to become Swedevox, offers the advantage of

following the diagnosis and treatment outcome in the vast majority of patients over a long

period of time, making it possible to compare the medical service among the reporting units.

There are two major drawbacks to register studies: patients are not randomised to treatment

mode and there is no control group. The treatments among the patients in a register are

decided on the basis of the preferences of the doctor and patient. However, there is also an

advantage: the patients in the registers do not represent a small selected group, but rather the

majority of the Swedish patients as in this case treated with LTOT and HMV. Therefore, a

study based on data from the Swedish Oxygen Register gives different information than the

NOTT and MRC studies,14,15 since many of our patients would have been excluded from

those studies.

A quality register runs the risk of bias from under-reporting. For the Oxygen Register, an

external validation comparing patient registrations with data from manufacturers and

pharmacies was performed in 1986-1987.2 This validation showed that the coverage of the

register was 85%. Later, an internal validation of the coverage of registration was performed

approximately every second year by sending questionnaires to participating clinics.

We do not believe that there were selective reporting losses to the Oxygen Register, since the

interruptions in reporting applies to the entire counties, and were caused by shortages of staff.

For example from 1987 until 2000, in periods there were no reports from four counties. We

have not performed any analysis of dropout rates, but we advised the units against reporting

only surviving patients, when average coverage reporting resumed from a county.

The unique Swedish census registration numbers enable linkage with other registers that are

important for follow up and analyses, especially the Swedish Population Register for vital

status.113 This system may not altogether cover follow up correctly, owing to some difficulties

in the census registration number system. Statistics Sweden estimates, for example, that some

4,000 personal identification numbers are annually “recycled” from a small number of

persons. Also, some people emigrate without informing the authorities. Consequently, it is

DISCUSSION

56

sometimes difficult to obtain the correct date of death. Before the introduction of the web-

based registration system in 2004, the register forms occasionally contained an erroneous

census registration number. The patients have been known and followed by the reporting

clinic, which have reported the date of death or date of withdrawal for other reasons for these

patients. The number of erroneous census registration numbers was less than 1%. In all, we

believe that the cases without follow up have been few and may only have resulted in

negligible errors. Data collection is promoted by the uniformly organised medical care system

in Sweden and by the good quality of official statistics related to medical diagnoses,

treatments and causes of deaths.

How to improve quality of LTOT

One of the main objectives for a quality assurance register is to promote the improvement of

quality of care, e.g. patient selection and performance of treatment by feed back to the

reporting centers. To achieve this goal we have held annual meetings for the responsible

physicians and nurses since the start of the Swedish Oxygen Register 1987, where they also

received reports on the Swedish Home Mechanical Ventilation Register since its start in 1996.

Since 2004, data from the merged register Swedevox is entirely web-based, and the reporting

clinics have continuous access to their reported data. The annual reports and quality indicators

are accessible to each participating clinic and, when relevant, to the public. Some indicators

from small counties are subject to large annual variation and are therefore not accessible to

the public on an annual basis.

57

DISCUSSION OF MAIN RESULTS

Sex-related differences in LTOT in COPD

Our results indicate that over the next 20 years there will be an increasing female dominance

in patients receiving LTOT for chronic hypoxemia attributable to COPD. We estimate that in

Sweden in 2026, more than twice as many women as men will be on LTOT to treat COPD

with chronic hypoxemia. This assumption is based on our findings that incidence and

prevalence of LTOT increased among women as compared with men over 15 years, and on

the present smoking habits of middle-aged women and men. We believe that the increase in

prevalence of LTOT in women as compared with men will be more pronounced than the

increase in incidence, since we found significantly lower mortality after start of LTOT in

women than men in our study.

Several studies have demonstrated that women are more sensitive than men to the harmful

effect of tobacco smoke.51,54,114-116 It has long been known that there are sex-related

differences in the natural behaviour of the airways during a person’s life span, both in

biological and socio-cultural respects.117 Starting smoking in childhood is especially serious,

since it increases the likelihood of becoming a persistent adult smoker, and thus the risk of

developing obstructive airway disease.115 Moreover, lung function develops more slowly in

smoking girls than in smoking boys, and women who begin to smoke in childhood experience

a greater risk of lung function reduction and obstructive airway disease later than men who

smoke from childhood.114,115

Women may also be more susceptible than men to the development of severe COPD.

A study of patients with severe, early onset COPD revealed that current or ex-smoking female

first-degree relatives of these patients had a greater risk of reduction of FEV1 and of relevant

response to bronchodilator than male relatives.54 Analysis of data in two independent

population studies showed that smoking women ran a higher risk than smoking men of

needing admittance to hospital for COPD,51 but this finding was not reproduced in the

Confronting COPD International Survey.118 A Spanish investigation of COPD patients who

attended a pulmonary clinic, 53 FEV1-matched men and women, showed that the women

were younger and smoked less than the men.119 The women had more exacerbations in the

last year, poorer performance in walking distance and worse quality-of-life scores than the

DISCUSSION

58

men. Our new finding indicates that smoking women are substantially more likely than

smoking men to develop respiratory failure that necessitates LTOT.

We found a higher survival rate in women than in men after the start of LTOT. First-year

survival rate was 77% (95% CI 75–79%) and 69% (95% CI 67–71%), respectively, and

median survival rate was 2.8 years in women and 2.0 years in men. Similar survival data were

noted in an Australian study of 249 men and 256 women with COPD or chronic airflow

limitation treated with long-term oxygen.104 Their overall first-year survival rate was 75% and

median survival rate was 28 months in women and 22 months in men. Three other studies

reported higher survival rates after the onset of oxygen therapy. Miyamoto et al. found, in a

large study, a mean survival rate of 5.2 ± 0.2 years among women and 4.8 ± 0.2 in men after

the start of LTOT.4 Their first-year survival rates were 93.3% for women and 90.0% for men.

In a study by Chailleux et al. on the French quality register ANTADIR Observatory, the mean

survival time for COPD patients on LTOT was three years.5 Machado et al. found, in contrast

to several other authors, a higher risk of death among women than men with oxygen-

dependent COPD.56

When interpreting these results, patient selection and sex distribution among patients should

be taken into account. Women represented 51% of the subjects both in our study and in the

study by Crockett at al., while only 25% of the participants were women in the Japanese

study.4,104

The similarity in the results between our study and the Australian study104 can partly be

explained by the fact that all patients receiving LTOT were included in these studies, in

contrast to the studies by Chailleux et al and Miyamoto et al., who excluded patients for

various reasons and had higher survival rates.4,5

When patients with a poor WHO performance status were excluded from the Swedish

Oxygen Register, similar survival time as in the randomized controlled studies14,15 and in the

studies on Japanese and French LTOT patients4,5 was found.105

On the other hand, the daily hours of oxygen use should also affect the survival time,

according to the results in the “NOTT” study, where treatment 24 hours per day was more

effective than 12 hours per day.14 In the Japanese study, 63% of the patients were prescribed

oxygen for at least 20 hours per day,4 as compared with only 30% of the patients in our study.

This could very well contribute to the lower survival rate for our patients. The lower survival

DISCUSSION

59

rate in our material probably depends both on the inclusion of all patients, regardless of

performance status, and the shorter treatment time with oxygen per 24 hour period.

The mathematical model used to predict the future incidence and prevalence of LTOT in

COPD is based on two assumptions: the age at the start of LTOT is stable and quitting

smoking will not affect the model. The mean age at the start of LTOT increased gradually in

the period 1987-2005. We are happy enough to have a high smoking cessation rate.58 A high

cessation rate in patient cohorts reaching the age of 60-80 years during the period 2007-2035

will probably reduce or postpone the onset of chronic hypoxemia and need of LTOT in this

group.

As previously mentioned, the national ratio of prevalence of smoking in younger women to

that of older women is thought to be an indicator of the future prevalence of smoking in that

country.59 Despite this uncertainty, the increased sensitivity of the female lung to tobacco

smoke and the high numbers of smoking women will lead to an increased need for LTOT in

the future, which will probably be even more pronounced worldwide than in Sweden, if our

predictions prove correct.43,44,120

Methodological considerations

The future incidence and prevalence of LTOT in COPD may develop in other directions than

predicted if various conditions turn out to be other than anticipated using our method. Lower

incidence and prevalence may occur if smoking decreases more rapidly than we believe and if

prevention and treatment of COPD improves more rapidly than it has so far. The prevalence

of LTOT may increase if cardiovascular mortality continues to decrease,121,122 if the attention

to respiratory failure increases and if the LTOT becomes more effective with increased hours

of oxygen per day.14

DISCUSSION

60

Occupation and pulmonary fibrosis

We report the association in men between IPF and exposure to birch dust and hardwood dust

as the main finding in our case-control study. The risk of IPF with these exposures was more

than doubled, and the risk of PF, without exclusion of cases with other probable reason for

fibrosis, was doubled in men with exposure to unspecified wood dust. In addition to birch

dust and hardwood dust, the patients with PF, men and women together, also had increased

odds ratios for blasting, mineral dust, birds, flour dust, and dust from pine or fir and fire

fumes.

We studied a different selection of cases than in the previous case-control studies, namely

severe PF including IPF as the largest subgroup. In this procedure, we could estimate the risk

of the studied exposures in the patients with already known external cause of their PF,

asbestos being the most common, and other diseases known to be associated with PF,

rheumatoid arthritis being the largest group. The previous case-control studies on risk of

environmental exposures did not include patients with other forms of ILD than IPF.69-74 We

found associations with more exposures in PF than in IPF, namely: blasting, mineral dust,

birds, flour dust, dust from pine or fir, birch dust, hardwood dust and fire fumes. The

increased odds ratios for blasting and mineral dust might represent undiagnosed silicosis. It is

also possible that some of the patients with known cause of PF actually had IPF, since IPF is

the most common of the idiopathic interstitial pneumonias.63,123 The cohort we studied was a

national sample of PF patients in advanced stage with chronic hypoxemia. They represent 8-

9% of the Swedish patients with ongoing LTOT for chronic hypoxemia, the second largest

group after COPD. As expected, the majority of the PF patients in our study, 77%, had

IPF.63,123 The fibrosis in PF patients was explained by external agents in 8% and by

association with other disease in 15%. Yet it is possible that some of the remaining 23% also

had IPF, since IPF is not only the most common ILD but also the most serious one.123 The

diagnosis of IPF was based on other data than lung biopsy in the majority of our patients, as

in a recent study from the UK on incidence and mortality of IPF.64

The main difference between our results and those of previous studies of environmental

exposure in IPF was that we did not find an increased risk with exposure to metal dust as was

found in five other case-control studies.69-71,73,74 In a UK study on standardised mortality

ratios, no association with exposure to metal dust was found.124 The patients in our cohort

may have been less severely exposed to dust from hard metal and they may have had less

DISCUSSION

61

harmful working environments than the patients in previous studies. A difference in patient

selection may also have played a role. Our patients represented a national sample and were

not recruited from a specific region, as in two of the other case-control studies.69,71


The cases in the PF sample, which included the IPF sample, were selected in the sense that

they represented a late stage in the disease and that current smoking was an exclusion

criterion, when they were prescribed LTOT. On the other hand, the cases were recruited from

the whole country, and can thus be assumed to be representative of Swedish patients with IPF,

with knowledge of the poor prognosis of that disease. In a retrospective case-control study

like this one, there is a risk of recall bias. People with a disease may be more inclined to recall

certain exposures than control persons without the disease.125 This problem could be solved

by interviews from experts to achieve higher accuracy, but for practical and financial reasons

that is not possible in a large study like this.126 Among people with respiratory disorders,

higher sensitivity and lower specificity have been demonstrated than in persons without

respiratory problems to self-reported dust or gas exposure.127 For common exposures, as in

our study, bias in terms of sensitivity is more important than bias specificity to cause

misclassification.128 We have found support for the validity of the self-reported exposures

when comparing with details about occupations among the ten patients who reported exposure

to dust from hardwood. An even more accurate check of validity of the reported exposures

could be achieved by using a job exposure matrix, as in a recent study on adult asthma

incidence.129

DISCUSSION

62

Ventilation or oxygen in kyphoscoliosis

The results of our prospective study from two national quality assurance registers suggest that

HMV is a more effective improver of survival rates than LTOT alone in patients with

respiratory failure owing to kyphoscoliosis. Our results also indicate that survival rate is not

influenced by the degree of hypoxemia or hypercapnia, once corrected with HMV or a

combination of HMV with LTOT. The presence of concomitant respiratory disease, in 66% of

the patients, mainly COPD, does not seem to have as negative an impact on survival time as

found in two previous studies.5,6

There is abundant documentation on the effectiveness and uses of mechanical ventilation in

kyphoscoliosis.83,89,92,130 It’s utility has also been demonstrated in a French survey.5

Consequently, home mechanical ventilation and not LTOT is the recommended treatment for

hypercapnic respiratory failure, as seen in kyphoscoliosis.97 There is no documentation that

supports treatment with oxygen to these patients. The reasons for which a considerable

proportion of the Swedish kyphoscoliotic patients are treated with LTOT instead of HMV

might be that the responsible physicians have assessed the concomitant disease as mainly

responsible for the respiratory failure, and the hypoxemia has been regarded as more serious

than the hypercapnia. However, our results show that this treatment strategy is erroneous in

patients with kyphoscoliosis and respiratory failure. The hypoventilation or impending

hypoventilation is the greatest risk factor and should always be corrected first.

Concomitant respiratory disease is common in patients with kyphoscoliosis5,6 and this may be

partly explained as an airway complication attributable to small lung volume.80,81 Recent

research demonstrates that a restriction of lung volume and chronic breathing at low lung

volumes might increase the rate of stress generation in airway smooth muscle,82 as has also

been demonstrated in mechanical strain in cultured airway smooth muscle cells.131 In obese

patients there is an increased prevalence of wheezing and airway hyperresponsiveness81,132-134

and several studies have observed an association between high body mass index and

asthma.135-141 Patients with kyphoscoliosis breathe at low lung volumes, which might explain

the high frequency of airway disease in patients with kyphoscoliosis and respiratory failure,80

as in patients with lung function affected by chronic cervical spinal cord injury.142

Furthermore, airway obstruction in kyphoscoliosis can also be caused by bronchial torsion

secondary to the thoracic deformity.143

DISCUSSION

63

Among the kyphoscoliotic patients treated with LTOT, 54% had a diagnosis of COPD, and

only 75% of these patients with kyphoscoliosis and COPD had ever smoked. This finding

supports the hypothesis that the kyphoscoliosis or relatively low lung volumes might explain

some of the airways disease diagnosed as COPD and thought to motivate LTOT.80

Improvement in vital capacity and arterial blood gas oxygen has been shown to occur when

patients with kyphoscoliosis are treated with nocturnal nasal intermittent positive pressure

ventilation.92

The strongest confounding factor in our study was the older mean age in the LTOT group.

When entered in a multiple regression analysis, age and treatment turned out to have

independent impacts on survival time. When considered alone, hypoxemia and concomitant

respiratory disease was associated with poorer survival time, but since these factors were

closely related to advanced age, they lost their statistical significance when entered in the

multivariate analysis. Moreover, survival time was not affected by levels of carbon dioxide or

vital capacity. No effect of initial PaO2 is expected, since both therapies aim at correcting

hypoxemia. Since nocturnal mechanical ventilation corrects daytime hypercapnia,91 which

was most pronounced in the HMV groups, any negative effect of hypercapnia on survival

time is abolished by this treatment. The prognosis for patients with a combination of HMV

and LTOT was about the same as with HMV alone, which is in accordance with the results of

Buyse et al. in a study on a smaller patient material.92


A joint register would have strengthened our results, but since the two registers have been

supervised by the same scientific society and in most instances receive reports from the same

clinicians, we believe that our results give a true description of the outcome for the two

treatment modalities. Our study is not randomised or controlled, which would probably not be

ethically possible in relation to this problem.92 The patients were actually selected for one of

the studied treatment methods. Patients prescribed LTOT and HMV differed at the start of

treatment for respiratory failure, the main difference being that patients prescribed LTOT had

a mean age of twelve years older. They also had more pronounced hypoxemia and less

hypoventilation or hypercapnia than the patients prescribed HMV. They also had slightly

higher vital capacity. Clearly, LTOT was selected for a subset of patients with more

hypoxemia than explained by hypoventilation only, and hypercapnia was an indication for

starting HMV. Yet the results of this study demonstrate that when the main disease is a severe

DISCUSSION

64

thoracic spine deformity, patients receiving HMV have a better outcome than patients on

LTOT, and our results add support to the consensus statement on therapy in kyphoscoliosis.97

DISCUSSION

65

Quality in long-term oxygen therapy

We found improvement in eight of the ten quality indicators which we had selected for follow

up during the 19 years of quality registration. Patient selection was improved regarding access

to therapy, and there was an increase in the proportion of patients with severe hypoxemia and

a decrease in the proportion of current smokers. There were improvements both on the

national level and in the individual counties. Yet, there was a worsening in terms of achieving

the treatment goal of oxygenation with supplementary oxygen. That quality indicator was

poorly fulfilled at the end of the observation period as was the activity of reassessment of

LTOT when it was started during an exacerbation of COPD. However, the latter quality

indicator was introduced late in the observation period and improvement might have been

slow. From the start of the study the register data was used for feed back to the responsible

physicians and nurses in annual reports and at training meetings. In this way, the register has

served as a benchmarking tool for quality assurance, as can be seen in that there were

improvements in most of the quality indicators.

Patient selection in LTOT

Initiation of LTOT increased considerably during the study, almost entirely on the indication

of COPD. The reason for this is probably increased attention to patients requiring LTOT and

the time course of smoking habits rather than selection of patients with doubtful indications,

since the proportion of patients with severe hypoxemia increased. A Danish study showed

increased prevalence of LTOT to COPD patients from 27 per 100,000 inhabitants in 1994 to

42 per 100,000 in 2000.144 The highest prevalence was found in the counties where general

practitioners took part in the prescription of LTOT, and the adherence to the criteria for the

treatment was lower in those counties. In our study, all responsible physicians, mainly

pulmonologists, were specially trained for LTOT. We found a fourfold variation between the

counties in the incidence of LTOT prescriptions in 2005. Differences in attention could

possibly contribute to this, but the differences are probably caused by variations in respiratory

failure owing to smoking related diseases, as can be seen by the fact that there was also a

fourfold variation in the incidence of lung cancer in Sweden, according to the Cancer Register

of the National Board of Health and Welfare.145

There was an adherence to the indicator severe hypoxemia when breathing room air of 76% in

the patients who were prescribed LTOT from the beginning of the study, and this rose to 85%.

The adherence to the Swedish guidelines for LTOT is likely to have been higher, since some

DISCUSSION

66

of the patients with PaO2 > 7.3 kPa probably had pulmonary hypertension or polycythemia as

an additional reason for LTOT. In a Danish study on COPD patients receiving LTOT, 462 of

822 (56%) patients had adherence to the criteria for hypoxemia.146 There were no data on

PaO2 on room air in 169 of the patients and there was adherence to the hypoxemia criteria in

70.6% of the other 653 patients. The limit at which LTOT is effective in treating hypoxemia

is addressed as a research field in a recent NHLBI workshop report.36 The report emphasizes

that the average use of oxygen was only 13.5 hours per day in the study by Górecka et al.,

which may have lowered the possibility of establishing an effect on survival time in mild to

moderate hypoxemia, and that LTOT might have other effects than prolonged survival time in

these patients.

The Swedish guidelines include a strong recommendation that LTOT should be avoided in

patients who have not stopped smoking. The reason is that smoking probably interferes with

the treatment result and that there is a risk of fire accidents.94-96 Current smokers have

increased mortality during LTOT,3 but it is still possible that LTOT is beneficial on survival

time in these patients. This is an ethical issue for further investigation according to the

NHLBI workshop.36

At the end of our study, as many as 99% of the patients were non-smokers when starting

LTOT. This adherence to guidelines for LTOT has varied in other countries between 49% in

the US and 93% in Turkey.147,148 Other examples of proportion of non-smoking LTOT

patients are 79% in Denmark and 86% in Scotland.108,110

When respiratory failure is caused by deformity of the thoracic cage, LTOT is often

prescribed, especially when there is a concomitant respiratory disorder.2,3,5,6,149 However,

HMV is physiologically more effective in these patients.83-89 Home mechanical ventilation

alone is sufficient in some cases, but LTOT alone results in a poorer survival rate.92,149

After the presentation of the results of Paper III, the prescription of LTOT alone to patients

with deformity of the thoracic cage dwindled to a few registered cases annually in Sweden.

Performance of LTOT

Attaining the desired level of PaO2 when breathing oxygen was the only quality indicator that

decreased during the study (from 86% to 80%). This was not explained by insufficient PaO2

in the patients with PF, in whom it can otherwise be difficult to reach appropriate oxygenation

levels. Nor was it explained by an increase in the mean PaCO2 from 1987 to 2005 on oxygen

DISCUSSION

67

in the LTOT patients. Yet another explanation could be insufficient titration of the oxygen

dosage, owing to shortening of the times for in-hospital treatment. In previous studies, the

adherence to improvement of the arterial oxygenation guidelines when breathing oxygen was,

for example, 45% in a Scottish study and 90% in an Australian study.110,150

Prescription of oxygen for more than 16 hours per day was high from the start in our study,

and improved further. It is possible that this was influenced by increased usage of portable

oxygen equipment.98,99,151 In a Greek study, only 27% of the patients with LTOT used oxygen

for more than 15 hours daily, as compared with 65% of the patients in a Danish study.99,152

We have studied the prescribed treatment time per day, rather than use of oxygen in reality,

since compliance has been deemed too difficult to follow in our large patient material, and

would seriously affect the possibilities for the staffs to report to the register. In an early

observation in the Swedish Oxygen Register, measuring of oxygen cylinder use and reading

of concentrator meters showed that approximately 70% of patients used oxygen for 15 hours

or more per day.3 Compliance of 65% with the treatment time > 15 hours per day was

demonstrated in both a Danish and a Dutch study.99,153 The use of mobile oxygen equipment

influenced compliance in both of these studies.

Adequate treatment time per day is important to the effects of LTOT in terms of survival

times,14,15 and mobile oxygen equipment has been shown to be important to enable patients

with outdoor activity, to have improved compliance.98 The use of mobile oxygen equipment

increased from 48% to 65% of the patients in our study between 1989 and 2004. The

corresponding figures have been between 20% and 67% in other countries.153-155 During the

same period, the oxygen equipment has also undergone developments, with lightweight

cylinders and demand pulsing delivery devices, making it easy to handle.156 We did not

measure the patients’ use of their mobile equipment, but according to the results in previous

studies, there is reason to suppose some degree of reduced compliance with the use of the

equipment.151,153

When severe hypoxemia occurs during an exacerbation of COPD, it may often be necessary

to initiate LTOT despite there not being a stable phase in the underlying disease. Reversal of

hypoxemia may take several weeks so initiating LTOT earlier has become more common

with earlier discharges from hospital.19,100,101 This early LTOT has been prescribed in such

cases for several years, and lately it has also been recommended in some guidelines.19,20

DISCUSSION

68

When LTOT is started during an exacerbation of COPD, it is recommended that the

indication be reassessed after one to three months.19,20 During the few years when we

registered adherence to the guidelines for this indicator, it increased from zero to 30% of the

relevant patients. In a Danish study from 1995, only 39% of the patients were followed up

properly after initiation of LTOT108 and the corresponding figure was 61% in a localised

British district in 1986-1987.157 Those studies dealt with all patients who received LTOT, and

to our knowledge, there is no other study of the follow up of only patients starting LTOT

during an exacerbation of COPD.

Concomitant treatment

A few studies have demonstrated increased mortality in COPD patients, associated with

maintenance therapy with oral glucocorticosteroids.102,103,158 In the study by Ström, female

COPD patients had increased mortality; in Ringbaek’s study the increased mortality was

limited to overweight COPD patients, while the increase in mortality was found to be dose

dependent for oral steroids in the study by Schols. Attention has been paid to this risk since

many years in Swedish COPD patients and the use of oral glucocorticosteroids decreased

from 46% to 19% during our study period. In some of these elderly patients, the indication for

corticosteroid maintenance therapy may well be other diseases than COPD.

Results of treatment

In our 19 year observation of COPD patients receiving LTOT, we found a stable level of the

first-year survival rate. We chose that measure for practical reasons. When comparing with

the national Causes of Death Register data, we did not find any significant change in overall

survival. It might be expected that improvements over the years in the performance of LTOT

would lead to somewhat improved survival times. One explanation for the fact that this did

not occur is probably that the patients have become steadily older at start of LTOT, which

could, in turn, be a result of improved overall care, with postponement of respiratory failure.

The decrease of smoking in the population during recent decades can also have influenced the

later start of respiratory failure. It is also possible that the prescription of oxygen for a

minimum of 16 hours per day results in many patients not striving to use oxygen for up to 24

hours per day. A continuous treatment 23-24 hours per day probably improves survival times

more than 15-16 hours per day in COPD patients with severe hypoxemia.14,15 Patients in our

study were older and patients with a very poor performance status or concomitant disease

DISCUSSION

69

were not excluded as in the NOTT and MRC studies,14,15,159 a fact that probably affected our

survival statistics.


We chose the ten quality indicators as a proposed instrument for accessing improvement of

LTOT, based on published evidence: PaO2 ≤ 7.3 kPa on air,14-16 HMV to patients with

thoracic deformity,92,97,149 PaO2 > 8 kPa on oxygen,14-16 more than 16 hours of oxygen per

day3,14,15 and reassessment of LTOT if started during a COPD exacerbation,19,100,101 and early

results on data from our register concerning access to LTOT,2 non-smoking status3 and

avoidance of continuous oral glucocorticosteroids in COPD.102,103,158 The suggested levels for

excellent quality of the indicators are based on the results in the individual counties and

reflect the current disease panorama and guidelines. Changes in epidemiology and scientific

progress will lead to a need for revision of the levels for excellent quality.36

70

CONCLUSIONS

Our results contribute to knowledge for preventing and postponing chronic obstructive

pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) and to improved quality

of treatment of respiratory failure.

Specific conclusions:

- Women with COPD experience a more rapid increase in incidence and prevalence for long-

term oxygen therapy (LTOT) than men with COPD.

- Exposure to wood dust, especially dust from birch and hardwood, may be a risk marker in

men for developing IPF.

- A substantial increase in the need for oxygen therapy will probably occur in women in the

immediate coming years.

- When they receive LTOT for COPD with severe hypoxemia, women have better survival

rates than men.

- Patients with kyphoscoliosis treated with home mechanical ventilation have better survival

rate than those treated with oxygen alone.

- We found improvements in eight of our ten quality indicators during 19 years of quality

registration. We propose a model for the quality assurance of LTOT, using indicators with

levels for excellent quality, based on our estimation of current knowledge.

71

FUTURE PERSPECTIVES

The two most important therapeutic implications of our studies are:

- Do not treat patients with respiratory failure due to kyphoscoliosis with oxygen alone.

- Encourage COPD patients with chronic hypoxemia to use the oxygen for as many hours as

possible during the every day and night.

The demonstrated female dominance in the increase of incidence and prevalence of LTOT

together with the increase in smoking in women as compared with men will constitute a

strong argument for increased efforts regarding smoking prevention and cessation. It is

important to target women for information and other measures to counteract the efforts by the

tobacco industry to recruit female smokers.160 Our model for prediction of future need for

LTOT can be validated by analyzing the future incidence and prevalence of LTOT.

The finding of wood dust as a probable risk marker for idiopathic pulmonary fibrosis (IPF)

will contribute to relevant preventive actions in manufacturing industries as well as in

handicrafts and private carpentries. It will be important to follow the future incidence of IPF,

and if it rises, it may be justifiable to repeat a case control study based on quality resister data

on risk markers for IPF. We also aim to evaluate cigarette smoking as a risk marker for IPF

by studying data on IPF patients reported to the Swedevox Register.161

Home mechanical ventilation (HMV) is the first line treatment when respiratory failure occurs

in patients with kyphoscoliosis. In selected cases, this treatment may be supplemented with

oxygen. After the presentation of Paper III to the participating centers the number of new

patients prescribed LTOT without HMV dropped to a few elderly patients who could not

learn to accept HMV. However, it is necessary to use data from the Swedevox Register to

assure that the prescription of LTOT without HMV to kyphoscoliotic patients stays on a low

level.

Evaluation of the implementation of the quality indicators for LTOT will serve as an

instrument for improvement of performance and outcome of LTOT. Scientific re-evaluation

of several of the indicators must be undertaken regularly to decide whether they should

remain as indicators or whether adjustments are needed.36 The optimal treatment time per 24

72

hours and the possible effect of LTOT in mild to moderate hypoxemia are areas that would

need further evidence.

Impaired health related quality of life is a very important aspect of respiratory failure and the

effect of LTOT has, so far, only been explored in a sample of our LTOT patients.31 Since

2006 we have included a short generic instrument for health related quality of life

measurement at the start and after the end of the first year of LTOT. The development of a

Swedish version of a specific instrument for health related quality of life in respiratory failure

will facilitate a better evaluation of the impact of treatment including the impact on LTOT in

this aspect.

The levels for excellent quality also need continuous updating according to new knowledge

and the changing epidemiology of respiratory failure.

73

ACKNOWLEDGEMENTS

First I want to express my gratitude to all those who developed the Swedish Oxygen Register and allowed me to analyze data from the Register - Kerstin Ström, my tutor, who developed the Register as one of the national quality registers, supported by the Swedish Board of Health and Welfare. You have generously supported me during many years, and you have shared your deep knowledge about long-term oxygen therapy with me. It has been a privilege for me to work with the register data under your supervision. Thank you for all enjoyable work meetings in Karlskrona, and for your and Thomas’ hospitality in your home at Långö! - The Swedish Society of Respiratory Medicine, the owner of the Register - The Swedish Heart-Lung Foundation, who supported the first Register and the transition of the Oxygen and HMV Registers to the web-based Swedevox Register - Jacob Boe, who initiated the Oxygen Register with a planned duration of five years - All colleagues in the Swedish Society of Respiratory Medicine and all “oxygen nurses” in Sweden who enthusiastically filled in all those report forms Karl Franklin, my co-supervisor, for all your generous support and for all the valuable advice in different aspects of my postgraduate studies. It is a pleasure to experience a speedy and effective transformation of a message in a text or a slide with your guidance Kjell Torén, my co-supervisor, for all your generous support and for everything you have taught me about occupational influences in pulmonary diseases. I have had several exciting weeks, working with our project at your institution. Thank you for all the lovely dinners in your home! Kurt Boman, my co-supervisor, for your all your generous support and helpful advice given at short notice whenever needed during work with my thesis. You introduced me to the science of magnesium in skeletal muscle many years ago. These studies were not possible to develop further, but we did not give up on my postgraduate studies Leif Rosenhall, my former Head of the Respiratory Department, for introducing me to respiratory medicine, for your wonderful leadership and for your friendship. Posthumous gratitude, I miss you very much Thomas Sandström, the head of the Umeå University Division of Respiratory Medicine and Allergy, for all your generous support and encouragement during this project and during my earlier study on magnesium and asthma Bengt Midgren, for co-authorship and for everything you have taught me in association with the Home Ventilator Register, nowadays Swedevox Kenneth Nilsson, for co-authorship and for all your generous support during many years of clinical work with interstitial lung diseases

74

Jonas Ranstam, for co-authorship and invaluable statistical advice Anna Dahlman-Höglund and Göran Tornling and Kerstin Löfdahl, for co-authorship Katarina Nylén, for all the encouragement you have given me to go on with this project, and for the care of many respiratory problems in our Department during my periods of absence Ellinor Ädelroth, the Head of the Department of Public Health and Clinical Medicine, for your periods providing back-up for me at our Outpatient Department, and for all your encouragement during this project and during many years prior to this All colleagues on the Department of Respiratory Medicine and Allergy at Umeå University Hospital, for your work with the respiratory problems in patients at Skellefteå hospital during my project. A special thanks to Håkan Törnqvist, for your periods of back-up for me at our Outpatient Department and to Eva Norrman; investigations around patients with tuberculosis can generate a lot of work Jan-Håkan Jansson, for all your much appreciated support on both details in this project as well as help in the clinical work Lars Johansson, for your generous support on details in this project and the many times that I have had computer problems Eva Åberg, the Head of Department of Medicine and Geriatrics, for allowing to me work with this project, for encouragement, and for working the years we have worked together in our Department Jeanette Kliger, Linda Schenck and Karin Axell, for your excellent linguistic revision Karin Burman and Lena Åström, for your important help with all practical items My dear family: Ulla, Jonas, Helena and Emma, for your patience with my absence from home in person or mentally. This was not a new phenomenon, but it has this time been worse than usual. The apartment on Språkgränd in Umeå has been a nice second home for me during the post graduate courses This work was generously supported by grants from the Swedish Heart-Lung Foundation, from the Västerbotten County Council and from the Foundation of Medical Research in Skellefteå The papers in this thesis have also been supported by grants from the Swedish National Board of Health and Welfare, the Blekinge County Council, and BREAS Medical AB.

75

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