Effect of the Buteyko Method on Resting Ventilation and Asthma Control in Asthma …°... · 2019. 3. 18. · 5 Abstract Background: The Buteyko method (BM) seems to change breathing

Effect of the Buteyko Method on Resting Ventilation

and Asthma Control in Asthma Patients

Monique van Oosten

Ritgerð til meistaragráðu Háskóli Íslands

Læknadeild Námsbraut í Lýðheilsuvísindum

Heilbrigðisvísindasvið

Áhrif Buteyko aðferðinnar á hvíldaröndun og stjórnun astmasjúkdómsins hjá astmasjúklingum

Monique van Oosten

Ritgerð til meistaragráðu í Lýðheilsuvísindum

Leiðbeinandi: Marta Guðjónsdóttir

Meistaranámsnefnd: Marta Guðjónsdóttir, Auðna Ágústsdóttir og Björn Magnússon

Læknadeild

Námsbraut í Lýðheilsuvísindum

Heilbrigðisvísindasvið Háskóla Íslands

Mars 2017

Effect of the Buteyko Method on Resting Ventilation and Asthma Control in Asthma Patients

Monique van Oosten

Thesis for the degree of Master of Science

Supervisor: Marta Guðjónsdóttir

Masters committee: Marta Guðjónsdóttir, Auðna Ágústsdóttir and Björn Magnússon

Faculty of Medicine

Department of Public Health

School of Health Sciences

March 2017

Ritgerð þessi er til meistaragráðu í lýðheilsufræði og er óheimilt að afrita ritgerðina á

nokkurn hátt nema með leyfi rétthafa.

© Monique van Oosten 2017

Prentun: Háskólaprent

Reykjavík, Ísland 2017

3

Ágrip

Bakgrunnur. Buteyko meðferðin (BM) virðist breyta öndun, bæta lífsgæði og astma stjórnun hjá astma

sjúklingum. Rannsóknir hafa fram að þessu ekki skilgreint nægilega vel lífeðlisfræðileg áhrif

meðferðarinnar.

Markmið þessarar rannsóknar er að skoða lífeðlisfræðileg áhrif BM á hvíldaröndun og stjórnun astma í

hóp astmasjúklinga.

Aðferð. Í þessari framskyggnu, íhlutandi rannsókn með samanburðarhópi voru astmasjúklingar mældir

þrisvar sinnum í algjörri hvíld, með 6 mánaða millibili. Þeir voru paraðir miðað við aldur, kyn og

líkamsþyngdarstuðul (BMI) við heilbrigðan samanburðahóp. BM var kennd eftir fyrstu 6 mánuðina. Síðan

var hópnum fylgt eftir og mældur að nýju 6 mánuðum síðar. Hvíldaröndun (öndunartíðni og andrýmd

(VT)), næmni öndunarstöðva metin út frá viljastýrðu öndunarstoppi, efnaskipti, og astma control

spurningalisti (ACT) voru skoðuð. Hlutfall milli heildaröndunar (VÉ) og koltvísýringsútskilnaðar

(VÉ/VĆO2) var reiknað út. Fráblástursgeta á einni sekúndu (FEV1) var mæld og reiknuð sem hlutfall af

hámarksandrýmd (FEV1/FVC).

Niðurstöður: 22 (61%) af þeim 36 astmasjúklingum sem hófu rannsóknina og 20 þátttakendur í

samanburðarhópi luku þátttöku. Í byrjum rannsóknarinnar voru hóparnir eins varðandi aldur, kyn og BMI,

en FEV1/FVC hlutfallið var lægra og viljastýrða öndunarstoppið styttra hjá astmahópnum (p<0.05). Eftir

BM hjá astmahópnum hafði hlutþrýstingur koltvísýrings við lok útöndunar (PETCO2), VÉ/VĆO2, og stig

fyrir ACT aukist (p<0.05) og viljastýrða öndunarstoppið hafði lengst (p<0.001). Eins hafði hlutþrýstingur

súrefnis við lok útöndunar (PETO2), VÉ, VT og efnaskipti minnkað en BMI hafði hækkað (p<0.05).

FEV1/FVC var óbreytt.

Umræða: Í upphafi var hvíldaröndun svipuð hjá hópunum en næmni öndunarstöðva var meiri hjá

astmahópnum. BM virðist minnka næmni öndunarstöðva þar sem viljastýrða öndunarstoppið verður

lengra. Hærra PETCO2 og lægra PETO2 bendir til að hlutfall milli alveolar öndunar (VÁ) og VĆO2 (VÁ/

VĆO2) hafi minnkað, þrátt fyrir hærra VÉ/VĆO2. Því má álykta að lægra VT hafi aukið öndun í

dauðarýminu. BM bætir stjórnun á astma án þess að hafa breytt FEV1/FVC.

4

5

Abstract

Background: The Buteyko method (BM) seems to change breathing patterns, increase quality of life

and asthma control in asthmatics. Until now, studies have not been able to identify sufficiently the

physiological mechanism behind the BM.

The aim of this study is to evaluate the physiological effect of BM on resting ventilation and asthma

control in an asthma group.

Methods: In this prospective, intervention study, asthmatics were measured 3 times at complete rest,

at a 6-month interval. They were matched by age, gender, and body mass index (BMI) to control

subjects. The first 6-month interval was the control period. The BM was taught to the asthmatics after

the control period. Asthmatics were followed up and measured again after 6 months. Resting ventilation

(respiratory rate and tidal volume (VT)), respiratory chemosensitivity evaluated by breath holding time

(BHT) and metabolism were assessed, and the asthma control test questionnaire (ACT) was applied.

The equivalent of pulmonary ventilation (VÉ) for carbon dioxide output (VÉ/VĆO2) was calculated. The

forced expiratory volume in one second (FEV1) was measured and calculated as a percentage of the

forced vital capacity (FEV1/FVC).

Results: 22 (61%) of 36 asthmatics and 20 control subjects finished the study. At baseline, groups were

comparable regarding age, gender and BMI. In the asthma group, FEV1/FVC was lower and BHT was

shorter (p<0.05). After BM in the asthma group, partial pressure of end-tidal carbon dioxide (PETCO2),

VÉ/VĆO2, BMI and scores for the ACT had increased (p<0.05) and BHT had become longer (p<0.001).

Partial pressure of end-tidal oxygen (PETO2), VÉ, VT and metabolism had decreased (p<0.05). FEV1/FVC

remained the same.

Discussion: At baseline, resting ventilation was alike between the groups, but respiratory

chemosensitivity was higher in the asthma group as seen in shorter BHT. BM effected resting ventilation

by decreasing respiratory chemosensitivity for CO2 as evaluated by longer BHT. It could be concluded

that the equivalent of alveolar ventilation (VÁ) for VĆO2 (VÁ/VĆO2) had decreased, evidenced by

higher levels of PETCO2 and lower levels of PETO2. However, VÉ/VĆO2 had increased, implying greater

dead space ventilation as a result of decreased VT. BM improved asthma control without altering

FEV1/FVC.

6

7

Acknowledgements

First of all, I would like to express my deepest gratitude to my supervisor, Marta Guðjónsdóttir for carrying

out this research project with me, and for all her guidance, support, encouragement, patience, and, most

of all, her excellent teaching.

I am very grateful to my master’s committee, Auðna Ágústsdóttir and Björn Magnússon, for

supporting me in this work and for sharing their expertise.

I am grateful to Reykjalundur for giving us the opportunity to perform our research in their laboratory.

Finally, I would like to thank all my family and friends for their mental support, and last, but not least,

my beloved daughter Katrín Möller, for her invaluable help.

This project was financially supported by the Asthma and Allergy Foundation, the Icelandic

Physiotherapy Society and the Oddur Ólafsson Foundation.

8

Table of contents

Ágrip ........................................................................................................................................................ 3

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

Acknowledgements.................................................................................................................................. 7

Table of contents ..................................................................................................................................... 8

List of Figures ........................................................................................................................................ 10

List of tables ........................................................................................................................................... 11

List of abbreviations ............................................................................................................................... 12

1 Introduction .................................................................................................................................... 14

1.1 What is asthma? .................................................................................................................... 14

Diagnosis ................................................................................................................... 14

Risk factors and allergies ........................................................................................... 15

1.2 Asthma control ....................................................................................................................... 15

Control-based asthma management ......................................................................... 16

Psychological factors. ................................................................................................ 17

Posture and physical condition .................................................................................. 17

1.3 Ventilation at rest ................................................................................................................... 18

The Respiratory system ............................................................................................. 18

Pulmonary ventilation ................................................................................................ 22

Alveolar ventilation ..................................................................................................... 22

Dead space ventilation .............................................................................................. 23

The bicarbonate buffer system .................................................................................. 24

Spirometry.................................................................................................................. 25

Ventilation musculature ............................................................................................. 25

Breathing control ........................................................................................................ 26

Chemosensors ........................................................................................................... 28

Physiological efficient and functional ventilation........................................................ 29

Metabolism................................................................................................................. 30

1.4 Asthma and resting ventilation .............................................................................................. 30

Asthma and breathing therapy................................................................................... 31

1.5 The Buteyko method .............................................................................................................. 32

Research on BM ........................................................................................................ 33

Breath holding and the Buteyko method ................................................................... 34

2 Aims and Objectives ...................................................................................................................... 36

3 Methods ......................................................................................................................................... 37

3.1 Participants ............................................................................................................................ 37

9

3.2 Protocol .................................................................................................................................. 38

Measures ................................................................................................................... 39

3.3 Procedure .............................................................................................................................. 40

3.4 Statistical analysis ................................................................................................................. 41

4 Results ........................................................................................................................................... 43

4.1 Ventilation .............................................................................................................................. 43

4.2 Asthma control ....................................................................................................................... 45

4.3 Metabolism ............................................................................................................................ 46

4.4 Breath holding time ................................................................................................................ 46

5 Discussion ..................................................................................................................................... 47

5.1 Pre-intervention ..................................................................................................................... 47

5.2 Post-intervention .................................................................................................................... 49

5.3 Strength and limitations ......................................................................................................... 51

5.4 Future studies ........................................................................................................................ 53

6 Conclusion ..................................................................................................................................... 53

References ............................................................................................................................................ 55

Appendix A ............................................................................................................................................ 63

Appendix B ............................................................................................................................................ 64

Appendix C ............................................................................................................................................ 66

Appendix D ............................................................................................................................................ 70

Appendix E ............................................................................................................................................ 72

Appendix F ............................................................................................................................................. 73

10

List of Figures

Figure 1. The respiratory system. ..................................................................................................... 19

Figure 2. Airway branching in the lower respiratory tract. ................................................................ 20

Figure 3. Normal bronchial tube at left side and narrowing of the bronchial tube in asthma ........... 21

Figure 4. The hemoglobine saturation curve for partial pressures of oxygen. ................................. 22

Figure 5. Hypo- and hyperventilation ............................................................................................... 23

Figure 6. The anatomic dead space. ................................................................................................ 24

Figure 7. Spirometry, a volume-time graph. ..................................................................................... 25

Figure 8. Muscles of breathing. ........................................................................................................ 26

Figure 9. A control system has three interconnecting components. ................................................ 27

Figure 10. Central (left-side of picture) and peripheral chemosensors (right-side) .......................... 28

Figure 11. Flowchart of procedure and participants ......................................................................... 40

Figure 12. Measurements performed for both groups at M1, M2 and M3 ....................................... 41

Figure 13. Partial pressures of end-tidal carbon dioxide (PETCO2) and oxygen (PETCO2) ............... 44

Figure 14. Results from the ACT. ..................................................................................................... 45

Figure 15. SABA usage before and after the Buteyko method. ....................................................... 45

Figure 16. Breath holding time measures ........................................................................................ 46

Figure 17.∆ BHT Line Fit Plot without extreme case ........................................................................ 47

11

List of tables

Table 1. Potential risk factors for asthma15 ...................................................................................... 15

Table 2. Randomized control trials involving BM ............................................................................. 33

Table 3. Asthma history and medication usage at M1 ..................................................................... 38

Table 4. Measures of age, gender and BMI for all participants at M1 ............................................. 43

Table 5. Ventilation measurements at M1 ........................................................................................ 43

Table 6. Body mass index, lung function and ventilation parameters. ............................................. 44

12

List of abbreviations

ANS Autonomic nerve system

APC Antigen-presenting immune cell

BHT Breath holding time

BM Buteyko Method

BTS/ACPRC guideline Guidelines for the physiotherapy management of the adult, medical, spontaneously breathing patient

C3 Cervical vertebra number 3

Cl- Chloride ion

CO2 Carbon dioxide

COPD Chronic obstructive pulmonary disease

CPG Central pattern generator

CSF Cerebral spinal fluid

DALYs Disability-adjusted life years

DB Dysfunctional breathing

DRG Doral respiratory generator

ECF Extracellular fluid

ECRHS The European Community Respiratory Health Survey I and II

EMG Electromyography

f Frequency of breathing

FEV1 Forced expiratory volume in one second

FVC Forced vital capacity

GERD Gastroesophageal reflux disease

GINA15 Global Initiative for Asthma 2015

GOLD Global Initiative for Chronic Obstructive Lung Disease

H2CO3 Carbonic acid

H2O Water

Hb Hemoglobin

HbO2 Oxyhemoglobin

HCO3- Bicarbonate

HHb Deoxyhemoglobin

HV Hyperventilation

ICS Inhaled corticosteroids

IgE Immunoglobulin E

ISAAC The International Study on Asthma and Allergies in Childhood

13

L Liters

LABA Long-acting beta2-agonist

Log Logarithm

Min Minutes

Ml Milliliter

mmHg Millimeter of Mercury

Mmol Millimole

NAEPP National Asthma Education and Prevention Program

NTS Nucleus tractus solitaries

O2 Oxygen

PaCO2 Arterial pressure of carbon dioxide

PaHCO3- Arterial pressure of bicarbonate

PaO2 Arterial partial pressure of oxygen

PCO2 Partial pressure of carbon dioxide

PEF Peak expiratory flow

pH -log[H+]; measure of hydrogen ion activity

pK logarithm of dissociation constant, K

PO2 Partial pressure of oxygen

PRG Pontine respiratory generator

RR Respiratory rate

SABA Short-acting beta2-agonist

SHR Sensory hyperactivity

SIGN British guidelines on management of asthma

U-BIOPRED Unbiased BIOmarkers for the PREDiction of Respiratory Disease Outcome.

V’A Alveolar ventilation

V’E Pulmonary ventilation

V´D Dead space ventilation

VRG Ventral respiratory generator

VT Tidal volume

WHO World Health Organization

14

1 Introduction

Over 2000 years ago, the Greek Hippocrates (460-377 BC) recognized symptoms of abnormal breathing

and named these symptoms as a disease asthma.1 Asthma is nowadays a highly prevalent chronic

illness, affecting approximately 300 million individuals worldwide, and the incidences are increasing.

Global prevalence of asthma ranges from 1 16 %. In Iceland, prevalence of asthma is about 10% in

children2 and 5-7% in adults.3 Almost 14 million disability-adjusted life years (DALYs) are lost annually

worldwide, due to asthma. This represents 1.8% of the total global disease burden4 and is similar to

diabetes.5 Both morbidity and mortality from asthma are significant, and it is estimated that 346.000

individuals die worldwide every year because of asthma.4 The World Health Organisation (WHO)

estimates that asthma deaths will increase over the next ten years if urgent action is not taken.6

Asthma is ineffectively treated despite a better understanding of pathophysiology and new

pharmacological strategies.4 According to WHO, access to cost-effective strategies and asthma

medication should be improved to prevent asthma attacks and asthma-related death.6 Non-

pharmacological therapies such as breathing therapies have shown to increase asthma control and

quality of life. One of them, the Buteyko method (BM) has garnered interest in the asthmatic population

worldwide.7, 8 BM is a technique that uses breath control to treat asthma and is believed to be connected

to low levels of carbon dioxide (CO2) in the body.9, 10 There is little scientific evidence that supports the

CO2 theory of BM. In this study, physiological mechanisms behind the theory such as resting ventilation

and chemosensitivity for CO2 are examined.

1.1 What is asthma?

Asthma is an umbrella term for a heterogeneous disease and is characterized by variable airflow

limitation, both in time and in intention, due to bronchial contraction, bronchial swelling and mucus

accumulation. These can cause various and variable respiratory symptoms, such as wheezing, shortage

of breath, chest tightness, and coughing. Chronic inflammation and hyper-responsive airways are

common features of asthma.4

Diagnosis

The diagnosis of asthma is made according to family and medical history, physical examination, and

lung function tests, such as spirometry and peak flow tests (PEF). To diagnose inflammation in the

airways, a bronchoprovocation, or challenge, test is done to trigger symptoms and confirm the variable

expiratory airflow limitation.

A thorough diagnosis is necessary for good asthma control and management. Asthma is easily

confused with asthma-related disorders, like vocal cord dysfunction, airway sensory hyperactivity (SHR),

hyperventilation, dysfunctional breathing, non-obstructive dyspnoea, and gastroesophageal reflux

disease (GERD). Asthma medications do not offer relief in these asthma-like disorders.11

15

Risk factors and allergies

Fundamental causes of asthma are difficult to establish. Genetic predisposition12 seems to be a part,

but does not explain the increase in asthma prevalence alone.13 The Unbiased BIOmarkers for the

PREDiction of Respiratory Disease Outcome (U-BIOPRED) project, set up in 2009, aimed to identify

the heterogeneity of asthma in so-called phenotypes, leading to new treatment targets and better

approaches to asthma therapy.14 Certain risk factors can have an influence on the development and

severity of asthma (see Table 1).15 Asthma often involves an inflammatory disorder of the lungs and

inflammation can be found in all airways, including the nose, called rhinitis. For example, 80% of

asthmatics have rhinitis, and 20-50% of those with rhinitis have asthma.4, 16

Table 1. Potential risk factors for asthma15

Host factors

Age

Gender15

Genetic predisposition12

Atopy

Environmental Factors

Early life and social factors

Indoor environment

Outdoor environment

Stress

Lifestyle Factors

Smoking

Diet

Obesity and physical activity17

Gastroesophageal reflux

Occupational Factors

Work exposures

It is difficult to understand how these risk factors in Table 1 contribute to the development of asthma.

However, it is known that some risk factors, also called triggers, have an unyielding influence on asthma.

These can be indoor allergens (house mites, pollution, and pet dander), outdoor allergens (pollen and

mold), and tobacco smoke. It is estimated that 15% of asthma cases among adults of working age are

due to chemical irritants in work places (occupational asthma).4, 18 When one is exposed for a long time

to these risk factors, structural changes in the airways, also called airway modelling, are seen and are

often associated with chronic allergic inflammation.19

1.2 Asthma control

Asthma control is defined as the “effective management of the clinical characteristics of the disease,

including symptoms (such as dyspnea, cough and wheezing), nocturnal awakening, reliever medication

16

use, activity limitation and lung function”, according to the Global Initiative for Asthma (GINA16)4.

GINA16 defines three levels of asthma control, “controlled/well controlled, partially controlled/ not well-

controlled, and uncontrolled/very poorly controlled”.4

To assess levels of asthma control, the Asthma Control TestTM questionnaire (ACT; Quality Metric

Inc., Lincoln, RI, , USA) was concluded to be reliable, valid, and preferred in clinical practice according

to a recent review.20 The ACT is a five question, self-administered health survey used to measure

asthma control in individuals 12 years of age and older. It has a four-week recall period. The ACT has

a cut-off score of 19. Asthma is well-controlled with scores above 19, and not well-controlled with 19 or

below. Diary cards are used in studies together with the ACT to recognize fluctuations by recording

symptoms, medication usage, or other required measurements.21-23

Control-based asthma management

The goal of asthma management is to obtain and maintain control of the disease, with the minimum and

adequate level of therapy and minimum side effects. As the variable character of asthma can make it

difficult for health care professionals, and asthmatics themselves, to control symptoms, guidelines are

focused on levels of asthma control, rather than disease severity.24 Proper diagnosis by trained health

care professionals, a good patient-doctor relationship, patient education, self-management, avoidance

of exposure to triggers and adherence to treatment are recommended to achieve control and reduce

asthma-related deaths, according to WHO.6

Asthma management should prevent exacerbations, decreased lung function, and adverse side

effects of medications by using the lowest possible medication dosage. Supervised medication

management is required based on guidelines. These guidelines mostly provide a stepwise medication

strategy according to levels of control. As for the bronchoconstriction component, asthma is managed

by a combination of short-acting B2-agonist (SABA) and/or long-acting B2-agonist (LABA). For the

inflammatory component, asthma is controlled by inhaled and/or oral corticosteroids as a treatment or

as a preventative measure.4

Demoly et al.25 showed that 6.1% of the adult population in five countries in Europe (about 15 million

people) are diagnosed with asthma. Of these, 57% of asthmatics who were treated for their asthma

were not well-controlled. As asthma control decreased, direct costs (hospital admission and increased

use of medication) and indirect costs (time lost from work and premature death) for asthmatics

increased.5, 25 Papaioannou et al.24 concluded that, world-wide, asthma is controlled only in a small

percentage of patients. Reasons for this are a lack of understanding or misunderstanding of disease

mechanisms, inadequate adherence to treatment, and a lack of good patient-doctor relationships. Also,

continuous exposure to irritants and the presence of comorbidities are suggested to be causes of not

well-controlled asthma. To access effective management and achieve better control, specialized

healthcare and, most importantly, a better understanding of disease mechanisms are required. Severe

asthma is an important problem, which needs to be focused on.24

In a meta-analysis of placebo-controlled trials of asthma medication dosages, Salpeter et al.26

concluded that regular B2-agonist usage over one week resulted in tolerance to its effects and poorer

disease control. In this analysis, some of the investigated research was funded or sponsored by

17

pharmaceutical companies and some was not. Of this, 73% of the funded research concluded that B2-

agonist usage was of benefit for asthmatics. Only 10% of the unfunded research confirmed B2-agonist

usage to be of benefit for asthmatics. In a recent Cochrane overview of reviews27 it is concluded, that

regular B2-agonist medication usage increased the risk of fatal and non-fatal serious adverse events for

adults or adolescents with asthma.

Psychological factors.

Emotional disorders, such as anxiety and depression can have an impact on asthma control.28 These

disorders are more frequent among asthmatics and can make asthma symptoms more prominent,

although asthma is not a psychosomatic disorder. Vice versa, asthma symptoms themselves can

increase anxiety and panic, and worsen psychosomatic disorders. This process might result in, or be

the result of, disproportionate breathing behaviours, or dysfunctional breathing.29, 30 Pbert et al.31,

suggested that relaxation techniques (mindfulness-based stress reduction) improved the asthma-related

quality of life, and this was seen without decline of lung function. Unfortunately, there is no validated

method to evaluate psychological effects on asthma control.29, 32 When emotional stress makes asthma

worse, GINA16 advises the use of relaxation techniques and breathing exercises to achieve better

asthma control.4

Posture and physical condition

Posture and physical condition are important for the functionality of ventilation in rest. They influence

the mechanical interaction of lung, chest wall, and intra-abdominal pressure, and the vulnerable process

of synchronized activation of the diaphragm and inspiratory muscles.33 Breathing becomes dysfunctional

when this biomechanical function is inappropriate and inefficient due to bad posture and bad physical

condition, and this influences asthma control.34

The diaphragm is the main inspiratory muscle. The synchronous transmutation of the diaphragm

from parachute shape to disk form and back is restricted by many factors because of a lack of stability

in this movement. The tension provoked by the push-pull mechanics of organs above and below the

diaphragm is the only stabilization for the diaphragm. This explains the vulnerability of the efficiency of

the diaphragm and mostly depends on posture and the elastic firmness of tissues such as the diaphragm

itself, the respiratory and pelvic floor muscles, the abdomen viscera, and of the rib cage.35, 36

In asthma, the slightest tension and/or mucus accumulation in the bronchi increases deep

inspirations. The auxiliary muscles, as scalenii, the sternocleidomastoids, and the trapezuis, become

more activated and try to decrease the feeling of dyspnea, leading to higher costal and dysfunctional

breathing patterns. Van Dixhoorn et al.36 explained that dysfunctional breathing patterns create a

continuous range of adaptations and adjustments of respiratory muscles and muscular activity in the

whole body, resulting in bad posture. By correcting bad posture habits and training straight posture, the

functionalilty of the biomechanics of breathing improves. Hodges et al.33, 37 demonstrated that the

efficiency of the diaphragm is reduced when the central ventilatory drive is increased. Deep inspirations

resulted in increased tension of the diaphragm, changed posture, and an increased central ventilatory

drive is related to dysfunctional breathing.

18

1.3 Ventilation at rest

Ventilation has multidimensional functions which are interactive. It has both psychological and

physiological components, either of which can become disturbed and result in dysfunctional breathing.38

Thomas et al.39 concluded that 30% of asthmatics are affected by dysfunctional breathing in terms of

breathing in excess of metabolism or hyperventilation. However, the pathophysiology of hyperventilation

is not completely understood yet38, 40-42 and difficult to relate to asthma. One of the main symptoms of

asthma is breathlessness or dyspnea. When in dyspnea, asthmatics feel the need to breathe more43

and studies have shown hyperventilation to be present in asthma attacks44 and in asthmatics.39, 45-47 In

order to explore what is known about ventilation and asthma, the physiology of resting ventilation is

examined and related to asthma. Chemosensitivity to CO2 in breathing control and the relation between

asthma and CO2 are emphasized to assess whether or not asthmatics hyperventilate at rest.

The Respiratory system

Function of the respiratory system

The respiratory system has two primary functions. The first function is respiration, which can be divided

into external and cellular respiration (see Figure 1). External respiration is the gas exchange of oxygen

(O2) and CO2. It occurs together with the circulatory system and between the atmosphere and the body.

External respiration can be separated in four processes, a) the exchange of CO2 and O2 between the

atmosphere and the airways, or ventilation, b) the diffusion of O2 and CO2 between the airways and the

pulmonary capillaries, c) the transport of O2 and CO2 in the blood, and d) the diffusion of these gases

between the blood and the cells.

19

Figure 1. The respiratory system. One main function of the respiratory system is the gas exchange in 4 phases: ventilation, transport, diffusion to cells, and oxidation in cells. The other main function is the maintenance of the acid-base balance (pH).48

Cellular respiration is when oxygen reacts in the cells with nutrients like fatty acids, carbohydrates

(glucose) and amino acids. The reaction provides energy and creates carbon dioxide, water, and waste

products. The purpose of cellular respiration is to obtain energy by burning oxygen in the cells. The

other primary function of the respiratory system is to maintain the acid-base balance (pH) in the blood

stable, together with buffer- and renal system.49

Structure of the respiratory system

The respiratory system is not simply the airways, the lungs and the muscles of respiration. It also

includes the chest wall, important because of the mechanical interaction with the lungs, and the central

nervous system that is concerned with the control of ventilation.

The airways may be divided into two parts: the upper and lower respiratory tracts. Air enters through

the nose and/or mouth. The upper airway: mouth, nasal cavity, pharynx, and larynx, are essential for

conditioning the air before it reaches the lungs and alveoli. Breathing through the mouth is not nearly as

effective as breathing through the nose; the nasal cavity filters out bacteria, viruses and other unwanted

material. It warms outside air to body temperature (37º) and adds water or vapour until the air reaches

100% humidity, so that the inner surface (epithelium) of the lungs do not dry out.49, 50 It matters whether

asthmatics breathe through the nose or mouth. Oral breathing can cause a decrease in lung function in

mild asthmatics at rest. It can initiate asthma symptoms in some, and it may play a role in the

20

pathogenesis of acute asthma exacerbations.51, 52 Nasal breathing is important for asthmatics. It is

shown that impaired nasal function affects the lower airways in asthmatics.16

The lower respiratory tract consists of the trachea and two primary bronchi, each dividing from 10 to

23 times before terminating in a cluster of alveoli in the lungs (see Figure 2). The first 16 bronchioles, or

the conductive zone, contain no alveoli and their walls are too thick for gas exchange with venous blood.

The area from the beginning of the mouth and nose through the conductive zone is called the anatomic

dead space. The structure of the airways varies, dependent on their location in the tracheobronchial

tree. The trachea is a fibromuscular tube, supported by C-shaped cartilage. The cartilage support

diminishes progressively in distal airways. Cartilage support disappears in airways with a diameter of 1

mm, called bronchioles.49

Figure 2. Airway branching in the lower respiratory tract. The conducting system is part of the anatomic dead space where there is no gas exchange. The exchange surface is for diffusion of gases.48

The diameter of these bronchioles is regulated primarily by the autonomic nervous system and

locally, among other factors, by levels of CO2 in air passing through them. If levels of CO2 fall, as in

breathing in excess of metabolism or hyperventilation, the bronchioles constrict. If levels rise, they

dilate.49 Most of the respiratory tract is coated by mucus-covered, ciliated epithelium. When asthma

symptoms are present, the epithelium often produces more mucus and is thickened, diminishing the

radius of the bronchioles and narrowing the respiratory tract (see Figure 3).49

21

Figure 3. Normal bronchial tube at left side and narrowing of the bronchial tube in asthma at right side of picture.53

Diffusion of O2 and CO2 takes place through the alveoli and their associated pulmonary capillaries,

or the alveolar-capillary interface. The ventilation/perfusion ratio (V’/Q’ ratio) in respiratory physiology is

a ratio used to assess the efficiency and adequacy of the matching of two variables: V’, ventilation or

the air that reaches the alveoli and Q’, perfusion or the blood that reaches the capillaries surrounding

the alveoli. The surface area and thickness of the alveolar-capillary membrane is important for

diffusion.49

The transport of oxygen and carbon dioxide.

Less than 2% of O2 is transported dissolved in the blood. About 98% is chemically bound to the protein

hemoglobin (Hb), situated in the red blood cells, or erythrocytes. The amount of Hb present in blood is

important for the capacity and the content of O2 in blood. The percent saturation (% Hb saturation)

expresses the proportion of Hb bound to oxygen. The affinity of Hb for O2 is expressed in the

oxyhemoglobin (HbO2) dissociation curve.

Several mechanisms have an effect on the percentage of Hb saturation and the availability of O2 for

metabolism. It starts to be critical when the partial pressure of oxygen (PO2) falls below 60 mm Hg. At

this state, Hb is 90% saturated (see Figure 4), with a normal partial pressure of CO2 (PCO2) of 40 mm

Hg.49

22

Figure 4. The hemoglobine saturation curve for partial pressures of oxygen. The effect of different partial pressures of CO2 (PCO2) on hemoglobine saturation.48

However, in situations of hyperventilation (PCO2 is 20 mm Hg), the dissociation curve shifts to the left

(see Figure 4). Hyperventilation increases the affinity of Hb for O2 and off-loading of O2 on the tissues

will be reduced.49

The tissues are vascularized by a fine capillary network. There, the exchange of O2 and nutrients

diffuse out of the blood into the cells. About 5-10% of the CO2 is transported in the blood dissolved in

the plasma, 20% bound to Hb and 70% as bicarbonate (HCO3 ), an important buffer for the pH in blood.

Venous blood returning from body tissues containing a high concentration of CO2 and a low

concentration of O2 is pumped from the right ventricle of the heart into the lungs, where CO2 is exhaled

and O2 is inhaled.49, 54

Pulmonary ventilation

In physiology, the exchange of gas between the lungs and the atmosphere is called the pulmonary

ventilation (V’E), measured as litres per minute (L/min). Pulmonary ventilation is a combination of gas

that exchanges with pulmonary blood, or alveolar ventilation, plus gas that does not exchange with

pulmonary blood, or dead space ventilation. Ventilation is dependent on the tidal volume, or the amount

of air inhaled within each breath, (VT, L) and the frequency of breathing (f, breaths /minute), described

with the formula VÉ = VT x f. Pulmonary ventilation at rest ranges much or from 4-7 L/min.49 It is important

to relate resting ventilation to metabolism, as big men have to breathe more air than small women.49

Some studies55-57 have examined resting ventilation in asthmatics, but they have not related these

measures to metabolism. Such results are difficult to evaluate.

Alveolar ventilation

Alveolar ventilation (V’A) is the airflow that enters the alveoli, measured as litres per minute (L/min). It

represents inspired air with 20-21% of O2 and 0.03% of CO2, and in a similar volume of expired air, with

16-17% of O2 and 3-4 % of CO2 leaving the functioning alveoli at rest. When V’A is high

(hyperventilation), PO2 increases and PCO2 decreases in the alveoli. When VÁ is low (hypoventilation),

23

the PO2 decreases and PCO2 increases (see Figure 5). Functionally, VÁ should be examined relative

to what is required by metabolic demands. In rest, hyperventilation is when V’A is more than metabolic

demands, as for example in stressful and emotional situations.49

Figure 5. Hypo- and hyperventilation. In hyperventilation, alveolar partial pressure of oxygen is higher and of carbon dioxide is lower than in normal ventilation. And vice versa in hypoventilation.48

Dead space ventilation

Gas that does not exchange with pulmonary blood, or dead space ventilation is not included in alveolar

ventilation. Alveolar ventilation is pulmonary ventilation without dead space ventilation. The dead space

is composed of two parts: anatomic and alveolar dead space. Anatomic dead space is the area from the

beginning of the mouth or nose through the conductive zone (see Figure 2). After each inspiration, an

amount of air stays in the conductive zone i.e. dead space volume (VD) and this fresh air has the same

composition as the outside air. After each expiration, an amount of air does not leave the lungs and that

air has the same composition as the alveolar air (see Figure 6). Studies have tried to estimate this space

with non-invasive methods.54, 58 In asthma, this space can alter as the tension in the bronchi changes.

Additionally, traction or compression (as sitting straight or bending) increases and decreases anatomic

dead space respectively. The smaller the tidal volume, the greater the percentage lost to anatomic dead

space ventilation for each breath.59

The alveolar dead space refers to ventilated but non-perfused alveoli in the lungs. Alveolar dead

space is most often more in asthmatics although it varies considerably, because of the variable

ventilation-perfusion (V’A/Q’) mismatch in the alveolar-capillary unit caused by bronchoconstriction.58, 60

The V’A/Q´mismatch is an important factor when interpreting values of resting partial pressure of end-

tidal CO2 (PETCO2) in asthmatics. Measures of PETCO2 are used to estimate measures of partial

pressures of arterial CO2 (PaCO2) for normal subjects.41, 54, 60 Measures of PETCO2 are taken at the end

of quiet exhalations, providing the best conditions to resemble PaCO2. For asthmatic subjects, the

24

relation between PETCO2 and PaCO2 has differed because of the ventilation and perfusion mismatch

(VÁ/Q’) in the alveoli. Depending on the severity of this mismatch, differences can be seen in lower

values of PETCO2 than real values of PaCO2. To make precise measures in asthmatics, a blood gas

sample is needed to get exact measures of PaCO2.58

Physiologic dead space is the sum of alveolar and anatomic dead space. Inspired air from these

areas will leave the body as it entered, contributing no CO2 to exhaled air. Thus, the greater the

physiologic dead space, the less the CO2 in exhaled air.49 Dead space ventilation has no physiologic

advantage and, if increased, more energy must be wasted to move additional gas so that alveolar

ventilation can be maintained. This conforms to breathing ineffectively and dysfunctional.

Figure 6. The anatomic dead space. After each inspiration, an amount of air stays in the conductive zone. During expiration, the air in these conductive zones has the same composition as the inspired air. After each expiration, an amount of air does not leave the lungs.48

The bicarbonate buffer system

The bicarbonate buffer system helps, together with the respiratory and renal system, to maintain a

constant internal environment in the cells and the body (homeostasis) by keeping a balance between

acids and bases.

A buffer system is a mixture of an acid and a base that resists changes in its pH. The bicarbonate

buffer system is closely linked to pH through the bicarbonate buffer formula, CO2 + H2O ↔ H2CO3 ↔ H+

+ HCO3 . Weak carbonic acid (H2CO3) and an HCO3 base are a buffer pair. The buffer value is expressed

by the Henderson-Hasselbach equation: pH = pK + log [HCO3 ] / [CO2 + H2CO3] where K is the

dissociation constant and [HCO3 ] is the plasma bicarbonate concentration. Because it is a weak acid,

25

the H2CO3 concentration is negligible. The ability of this buffer system depends on V’E, as V’E controls

the levels of CO2 in the body.49 Higher pH values are seen in acute hyperventilation, but with chronic

hyperventilation pH values are stable and approach normal values.61, 62

Spirometry

Spirometry testing is done to assess lung function (see figure 7). Spirometry values are compared to

predicted values according to the gender, age, height, mass, and ethnicity of the participant. The most

common spirometry values are the forced vital capacity (FVC) and the forced expiratory volume in one

second (FEV1). FVC measures the amount of air from the start of a maximal inspiration until the end of

a maximal forced expiration. The volume of air expired in the first second is a good index of expiration

airways resistance, especially when expressed as ratio with FVC.

Figure 7. Spirometry, a volume-time graph. The proportion of the amount of air, starting after a maximal inspiration, of forced expiration in one second to forced vital capacity (FEV1/FVC).48 FET= forced expiratory time.

In asthma, values lower than 0.7 of the ratio FEV1/FVC indicate obstruction of the expiratory airflow.4

Measures of FEV1 compared to predicted values lower than 80%, indicate the severity of the

obstruction.63 Meuret et al.61 showed that deep and fast breathing, as in spirometry, can lead to airway

obstruction and increase asthma symptoms in asthmatics, while deep inhalations provoke

bronchodilation in healthy airways.64

Fenger et al.65 demonstrated, that changes in weight had an impact on lung function testing.

Increasing adiposity resulted in a decline of FEV1 and FVC, but not FEV1/FVC. The opposite was also

true, decreasing adiposity increased FEV1 and FVC but not FEV1/FVC.

Ventilation musculature

The respiratory muscles are skeletal muscles (see Figure 8). The group of inspiratory muscles includes

the diaphragm, the external intercostal, parasternal, sternocleidomastoid, and scalene muscles. The

group of expiratory muscles includes the internal intercostal muscles, the rectus abdominis, the external

and internal oblique muscles, and the transverse abdominal muscles. During ventilation at rest, only the

inspiratory muscles are active. During increased breathing efforts, the expiratory muscles become active

as well. At this time, respiration is coordinated by a combination of diaphragm and transverse abdominal

26

muscle activitiy.33 The respiratory muscles themselves use 5% of total oxygen uptake, can get tired, and

can be trained.66, 67

The main work of breathing by respiratory muscles, is to overcome the elastic recoil of the lungs and

chest wall, but also the resistance to air flow. Airway resistance is about 35% to 50% in the upper

airways. Airway resistance is higher while breathing through the nose than through the mouth. In normal

conditions, the radius of the bronchi decides the resistance of the airways. In asthma, the bronchi with

the smallest radius causes the highest resistance (see Figure 3).49

Figure 8. Muscles of breathing. Muscles of the thorax, neck, and abdomen create the pressure difference to move air during ventilation.48

Breathing control

Control of breathing is of vital importance to keep the internal environment of our cells constant, one of

the most important physiologic functions of the body. Failure is not an option. Normally, the human body

cannot be without ventilation for more than three minutes. In comparison, we can be without food for

about three weeks and without water for about three days.49

Ventilation is spontaneously triggered in the central nervous system. It is controlled by a fine-tuned

system, aiming at an efficient utilization of blood gases such as CO2 and O2 to keep the pH constant.

The goal of this system is an effective, functional breathing mechanism with a minimum of work and a

minimum of metabolic cost of each breath.

27

Figure 9. A control system has three interconnecting components. Central respiratory centers in medulla oblongata change ventilation by controlling respiratory muscles, according to inputs from chemosensors, the lungs, and other receptors.49

The respiratory control system has three, interconnecting components (see Figure 9). The first

component (central controller) are the respiration centers, which are distributed in the reticular formation

of the medulla oblongata. A complicated synaptic interaction between several neurons in these

medullary respiratory control centers effectively change and adapt ventilation. Pacemaker-like neurons

in the pre-Bötzinger complex, called the central pattern generator (CPG), are situated in the ventral

respiratory groups of the medulla. They generate the timing and the amplitude of respiratory muscles

with a highly regulated lability, modulated by pontine and other inputs.68, 69 The CPG is automatically

modified while talking, singing, or blowing. Dysfunctions of the CPG can result in diseases.48, 68

Secondly, sensory inputs (sensors) from higher brain centers and from central and peripheral

chemosensors consistently influence these respiratory control centers in the brain. Other contributors

are sensory inputs from the lungs, the cardiovascular system, the skeletal muscles, and tendons of

respiratory muscles. The third component (effectors) is the synchronized distribution of motor output to

the respiratory musculature controlling ventilation. The respiratory control system needs further

exploration in order to be able to evaluate how breath control and chemosensitivity for CO2 are related.70

The underlying mechanisms of neural control of ventilation are still not completely understood.49, 68

The spontaneous central pattern generation of respiration can be overwhelmed by centers from the

cortex and human will. They may have a direct influence on the muscles of breathing (diaphragm and

auxiliary muscles), as with breath holding. Other cortex centers, where experiences of stress and

emotions as depression, anxiety, and happiness arise, can initiate widespread ventilatory responses

throughout the body. Emotions and respiration are closely linked in a complex feedback system through

the autonomic nerve system (ANS). Severe and persistent emotional states can cause chronic

hyperventilation, resulting in a sympathetic dominance of the ANS. During meditation and breathing

practices, there is a shift from sympathetic to parasympathetic dominance in the ANS. This results in

decreased respiratory activity and reduced negative emotions.71-74

28

Chemosensors

According to physiology, a respiratory chemosensor is a receptor that detects alterations of its direct

chemical environment and adjusts respiratory activity through the central nervous system.49 Control of

breathing by chemosensors can be seen as a feedback control system.75 VÉ controls levels of PaCO2

and PaO2, and respiratory chemosensor reflexes control VÉ, apart from influences of higher brain

centers. The respiratory chemosensor reflexes are responsible for controlling PaCO2 and keeping

hydrogen ion concentrations (H+) within certain values. There are two types of chemosensors, the

central chemosensors, located distributed in the medulla, and the peripheral chemosensors, located in

the carotid and aortic bodies.

Figure 10. Central (left-side of picture) and peripheral chemosensors (right-side). CO2 flows into the cerebrospinal fluid through the blood barrier, a highly selective permeable membrane, separating arterial blood from cerebrospinal fluid, keeping the brain safe. This increases ventilation through the reduced pH, sensed by the central chemoreceptors, activating the respiratory control center. Increased PaCO2 also stimulates peripheral chemoreceptors, activating respiratory control centers. Through a negative feedback system of higher amount of O2, and lower amount of CO2, the respiratory control center is inactivated.48

Central respiratory chemosensors lie in brain extracellular fluid (ECF) and are surrounded by

cerebrospinal fluid (CSF). They are effected by local metabolism (see Figure 10). The blood-brain barrier

separates respiratory chemosensors from arterial blood and is highly permeable for PaCO2. It is difficult

for HCO3- and H+ to cross this barrier. Hence, the respiratory chemosensors are not sensitive to CO2,

but to H+ concentrations. When V’E changes, PaCO2 and pH change in the blood, resulting in changes

29

in levels of CO2 in the CSF. In CSF pH changes also, according to the bicarbonate buffer system formula

↕CO2 H2O ↔ H2CO3 ↔ ↕H+ + HCO3 . In response to changes in pH, the central chemosensors

stimulate/inhibit the respiratory centers, controlling respiratory activity through this feedback system.49

It is very important to maintain pH, or H+, levels within certain limits in the CSF. Maintaining pH is done

by keeping the ratio of CO2 to HCO3- constant, as expressed by the Henderson-Hasselbach equation

H+ = CO2/ HCO3 or pH = pK + log (HCO3 /CO2). Regulation of pH in the CSF is made more rapidly than

blood pH (because of a lack of hemoglobin in the CSF).

Under resting conditions ventilation is mostly regulated by CSF pH, directly reflexing PaCO276, and

pH disturbances in CSF are resisted by modulating V’E. In other words, ventilation is a mechanism for

regulating the acidity of the blood and of the CSF through the controlled release of CO2. Furthermore,

the ventilatory drive is dependent on the threshold values of CO2, which stimulates or inhibits breathing

at the central level. With breath holding, levels of PaCO2 increase until the threshold value of CO2 has

been reached, expressing the chemosensitivity of the ventilatory drive. Because VÉ controls PaCO2,

persistent changes in VÉ can alter the ventilatory recruitment threshold of PaCO2. Where habitually or

chronic hyperventilation develops, the central respiratory control centers become more sensitive for CO2

as a state of chemo hypersensitivity. They trigger breathing at lower levels of PaCO2, maintaining a

hypocapnic state (low PaCO2).75 Laffey et al.62 related asthma to hyperventilation and to causes of

hypocapnia. This state can be intermittent or persistent as asthma symptoms fluctuate widely.

Kassabian et al.77 showed a raised respiratory control sensitivity in asthma and Hide et al.78

demonstrated that the central respiratory control centers have a key role in determining the severity of

asthma.

The peripheral chemoreceptors, located in the carotid and aortic bodies, lie at the fork of the common

carotid arteries that supply the brain with blood. They are sensitive to low PaO2, low pH, and high PaCO2.

They are maximally stimulated when PaO2 decreases below 50-60 mmHg, as can be the case with

severe asthma attacks. The reflex of the peripheral chemoreceptors increase ventilation and constrict

the bronchi but dilate upper airways.76 The peripheral chemoreceptors sensitize the central pattern

generator through both ventilation and sympathetic nerve activity, even for a prolonged time after

cessation of input. The ventilator control system is highly flexible in response to this chemoreceptor

stimuli, even during exercise and sleep.68

A large number of other sensors located in the lungs, the muscles, tendons, and skin have an

influence on the respiratory control centers. Pulmonary stretch receptors decrease respiration through

the central nervous system. Receptors in the nose, mouth, and upper airways (irritant receptors) keep

the airways open when pressure falls in the upper airways (with cough and sneezing reflexes).

Temperature increases respiratory rate, and sudden pain decreases it. Prolonged pain, on the other

hand, increases respiratory rates.49

Physiological efficient and functional ventilation

Efficient ventilation should be assessed in relation to metabolism. There has to be a balance between

metabolism and ventilation or between O2 demand and supply at the tissue level. Ventilation is normal

when a balance between metabolism and ventilation is achieved without compensation mechanisms

30

(such as bronchoconstriction) i.e. when there is a balance between CO2 production and CO2

exhalation.9, 49

Courtney et al.79 examined the functionality of ventilation at rest. Comprehensive evaluation of the

various aspects of ventilation should include physiological measures, breathing symptom questionnaires

and tests of breathing function such as BHT. The function of the biomechanics of ventilation at rest can

be influenced by posture37, physical conditions80, and breathing techniques81. The efficiency of the

biomechanics of ventilation can have an influence on asthma control. Straight posture, ensuring optimal

diaphragmatic breathing and good physical condition are contributory to asthma control.34 Measures

such as VÉ and PaCO2, are essential to evaluate the functionality of ventilation at rest, because of their

key role in central respiratory control and the balance between CO2 production and CO2 exhalation.49,

62

Metabolism

To interpret the efficiency of ventilation at rest, it should be corrected to metabolism. Metabolism is al

biochemical processes that occur in the body in order to provide the cells with their needs and to

maintain homeostasis. Metabolic rate is mostly dependent on gender, age, surface of the skin, and

muscle mass. Gas exchange, O2 consumption (V’O2), and CO2 output (V’CO2), are indicators of

metabolism. An important measure of ventilation is the ratio between the volume of gas breathed out

(V’E) in litres per minute to VĆO2 (V’E /V’CO2) in litres per minute. This ratio is called the ventilatory

equivalent of CO2 and is meant to reflect the efficiency of ventilation. Normal values of the ventilatory

equivalent at rest have not yet been established. Habedank et al.82 found lower rates of V’E/V’CO2 at

rest for men than for women (50.5 ± 8.8 versus 57.6 ± 12.6, p < 0.05). Ventilatory efficiency at rest was

depended primarily on age and gender in that study. If ventilation is in excess to our metabolic rate, we

hyperventilate. When hyperventilating, the ventilatory equivalent will increase, PaCO2 will decrease, and

PaO2 will increase. It is presumed that the ratio of V’A /V’CO2, compared to V’E V’CO2 gives an indication

of ventilation in physiologic dead space at rest. The greater the difference between V’A /V’CO2 and V’E

V’CO2, the more energy is wasted in dead space ventilation. This could indicate dysfunctional breathing.

Hence, to obtain precise measures of VÁ, blood gas samples are needed.

Meditation and SABA use have an influence on resting metabolism. Wallace et al.83 and Wolkove et

al.74 showed that reducing ventilation regularly, as in meditation, can result in lower metabolic rates.

Agha et al.84 demonstrated a direct positive correlation between metabolic rate at rest, asthma severity,

and impairment of lung function. They showed that B2-agonist medication increased the metabolic rate

of asthmatics, and more studies85, 86 have confirmed metabolic side effects of B2-agonists in asthma.

1.4 Asthma and resting ventilation

How do asthmatics breathe in rest when they are symptomatic? Do asthma symptoms cause

hyperventilation, or does hyperventilation cause asthma symptoms? Normally, when asthma symptoms

occur, ventilation increases because of the feeling of dyspnea caused by bronchoconstriction. Irritant

receptors in the airways, stimulated by increased mucus, also causes increased ventilation, that result

31

in hypocapnia and a disturbance in pH.49 According to this, asthma symptoms cause hyperventilation.

Only very severe asthma attacks cause high values of CO2 (hypercapnia) and low values of O2

(hypoxia). Due to severe bronchospasm and dyspnea, it is difficult for people with severe asthma

symptoms to do the work of breathing. Severe bronchospasm and dyspnea result in a cycle of

progressive hypoxia (stimulating the peripheral chemoreceptors68), hypercapnia, fatigue, and respiratory

failure.62 Hyperinflation can be a consequence of chronic severe asthma.87

Can hyperventilation cause asthma symptoms? Laffey et al.62 explained how hyperventilation is

related to low baseline levels of PaCO2 (hypocapnia). Hypocapnia is expressed by the equation: PaCO2

= CO2 production/ CO2 exhalation + inspired CO2. As the production of CO2 is not the cause of low

PaCO2 levels, and inspired CO2 is negligibly low, the principle physiologic cause of hypocapnia is

related to hyperventilation. Studies40, 88 have shown that levels of PETCO2 in rest can be normal in people

with symptomatic hyperventilation. It seems more likely, that during symptomatic hyperventilation, levels

of PETCO2 fluctuate rather than becoming chronically low.89, 90 Experimental evidence supports the

potential role of hypocapnia in asthma. Van den Elshout et al.91 found a relation between hypocapnia

and respiratory resistance in asthmatics, caused by bronchoconstriction. Decreased PETCO2, 7.5

mmHg, resulted in 13% increased respiratory resistance in asthmatics, but not in non-asthmatic

subjects, demonstrating that hypocapnia is a possible cause of asthma symptoms. When PETCO2 was

increased, respiratory resistance reduced in both healthy and asthmatic subjects. Hypocapnia also shifts

the oxyhemoglobin curve to the left (see Figure 4), restricting offloading of oxygen to the cells, resulting

in less oxygen supply to the cells (Bohr effect), or tissue hypoxia. Hypocapnia may create a more

anaerobic metabolism, causing the accumulation of organic acids. In other words, the more we breathe,

the less oxygen we have for metabolism.41, 62 This evidence suggests that there is a link between

hyperventilation and decreased oxygen supply at the cellular level. Finally, when hyperventilation

becomes chronic, the central respiratory control centers seem to become more sensitive, triggering

breathing at lower levels of CO2.62, 75 As seen before, raised central respiratory control sensitivity has

been related to asthma.62, 77, 78 Other studies have examined the role of CO2 in asthma and shown

asthma to be related to hypocapnia. Hence, evidence of hyperventilation in asthma is not clear and

further studies are needed.7, 47, 60, 62

Asthma and breathing therapy

Non-pharmaceutical therapies for asthma used with or instead of conventional therapies, have garnered

growing interest in a group of the asthmatic population.92 Concerns and dislikes about medications,

particularly of inhaled and oral corticosteroids, have caused poor medication compliance.46, 93 Plus,

severe asthma has shown to be difficult to control. 93, 94 People with uncontrolled asthma are more likely

to use non-pharmaceutical therapies.92

Studies92-95 have shown that breathing therapies are the most used complementary, non-

pharmaceutical therapies for asthma. GINA164 recommends breathing therapies as a complement to

conventional asthma management. Slader et al.81 suggested that features of breathing therapies, such

as relaxation, voluntary reduction of rescue medication, and self-efficacy, were the primary reasons for

32

improvement in asthma control and not the breathing exercises themselves. GINA164 discusses the

need for high quality studies to test the efficacy of breathing therapies.

Several reviews7, 8, 96 showed that breathing therapies may decrease the use of SABA, and that they

may improve symptoms, quality of life, and psychological outcomes, but not physiological outcomes. All

methods provide instructions on nose and diaphragmatic breathing, reduced ventilation, and daily

training. Offering breathing therapies by physicians is effective for asthma management.8 However, it is

still uncertain what the best and most efficient training method is. Inconsistent outcome measurements

at baseline, and after a retraining intervention, make it difficult to point out a single, best therapy,

according to the review of Bruton et al.7 The most frequently mentioned breathing exercise program in

studies is the Buteyko Method.8, 97-102

1.5 The Buteyko method

The Buteyko method (BM) is a structured, health-promoting method for children and adults with asthma9,

10. BM shows no evidence of adverse effects.21 It is acknowledged by the GINA164, the British guidelines

on management of asthma (SIGN 141)103, and by guidelines for the physiotherapy management (joint

BTS/ACPRC guideline).104 The method is complemental to conventional therapy strategies and does

not conflict with medication use.4, 103, 104 Systemic reviews of breathing methods also suggested BM to

be efficient for asthma management.7, 8, 104

The BM is focused on reducing ventilation gradually, tidal volume at first and frequency when

advanced in the trainings. The BM is based on the theory that asthma can be reversed. It claims hidden

hyperventilation leads to excessive losses of CO2, and this is a fundamental cause of asthma. To adjust

the CO2 balance, the asthmatic body develops defensive reactions such as asthma. The aim of BM is

to normalize levels of CO2 systematically by gradually decreasing ventilation, and matching it with

metabolic needs. Progress or lack of progress is evidenced by breath holding time (BHT), a non-effort

demanding measurement that is standardized in this method. BHT is an indicator of the chemosensitivity

of CO270, but also gives valuable feedback for asthmatics about their health level, risk estimations of

symptom recurrence, and exacerbations.9, 10 The BM differs from other breathing techniques, because

of the BHT feedback system.

The overall complex treatment procedure consists of a combination of breathing instructions, with

both mental and physical components. These include awareness, breathing- and relaxation therapies,

together with common, and also individual advice about nutrition, physical activity and general health.

By these direct and indirect techniques, the BM gradually and unconsciously resets breathing patterns.

The essence of the technique of the method is decreasing the depth of breathing. This is done in daily

training sessions by relaxing conscious and unconscious all the muscles that potentiate the breathing

action until a very slight lack of air is felt. The sensation of slight breathlessness is maintained by keeping

the breathing muscles relaxed, particularly around the shoulders and chest, and by a slight tension of

the transverse abdominal muscle. Sitting straight and breathing through the nose while training is

essential to obtain success.

In a formal Buteyko session, training starts and ends with measuring BHT. A session has been

successful when BHT is longer at the end of the session. Formal training session duration is 15 to 30

33

minutes. Training should be done at least twice a day, upon waking and before sleep. Some common

advice to prevent deep breathing in daily life is included. For example, to control and prevent deep

breathing while sleeping, it is advised to wrap a non-elastic tissue tight around the upper chest.

Asthmatics themselves have found it useful while sleeping to close the mouth loosely and carefully with

a light adhesive tape, to avoid breathing through the mouth. Sometimes it is even necessary to

encourage awakening at night to prevent nocturnal asthma symptoms. Coughing and talking techniques

are taught when needed, aimed at reduced breathing. Coughing should be performed calmly and

efficiently and followed by a holding the breath for a very short period without discomfort afterwards.

Talking should be done calmly, with inspirations through the nose. Physical activity is advised according

to BHT measurements. When BHT is below 10 seconds, only very light physical activity is advised as

walking slowly. When BHT is between 10 to 20 seconds, light physical activity is encouraged as walking

and cycling with nose breathing. When BHT has reached over 20 seconds light moderate training is

advised daily, with intervals if necessary in the beginning to keep up nose breathing. When physical

activity leads to dyspnea, exercise intensity should be lowered. In general, until BHT has reached 60

seconds, physical training should always be guided with BHT measuring and should lead to higher BHT

after training. This is important advice for asthmatics in order to be able to increase their BHT over time.

Research on BM

Several studies on BM have been published.21, 34, 55, 105-111 They mainly investigated the clinical

effectiveness of treatment for asthma. Six of them were randomised, controlled trials (Table 2).

Table 2. Randomized control trials involving BM

First author (date) Study participants Study design Significant Results of BM

1) Bowler (1998)55 39 adults in 2 groups 1. BM vs. ↓Medication use

2. Relaxation + breathing exercises

↓MV

2) Opat (2000)109 36 adults in 2 groups 1. BM video vs. ↓Medication use 2. Placebo video ↑QoL 3) Cooper (2003)106 90 adults in 3 groups 1. BM vs. ↓Symptoms 2. Yoga device vs. ↓Medication use 3. Placebo device 4) McHugh (2003)108 38 adults in 2 groups 1. BM vs. ↓Medication, also ICS use 2. Education +relaxation 5) Abramson(2004)105 95 adults in 4 groups 1. BM + placebo video vs. ↑PETCO2 (4 vs. 3)

2. Asthma education + Buteyko video vs.

↓Medication use

3. Asthma education + placebo video vs.

4. BM + Buteyko video 6) Cowie(2008)21 56 adults in 2 groups 1 .BM vs ↓Symptoms 2. Physiotherapy ↓Medication, also ICS use 7) Prem (2012)110 120 adults in 3 groups 1. Buteyko vs. ↓ Qol 2. Pranayama yoga ↓ Symptoms 3. Control group ↓ Medication use

MV=minute ventilation; QoL=quality of life; ICS=inhaled corticosteroid; PETCO2= partial pressure of end-tidal carbon dioxide; vs. =versus

34

They all demonstrated substantially reduced reliever usage (SABA) and most of them showed increased

quality of life, without impairment of lung function (spirometry). Two studies, (4, 6) also showed reduced

inhaled corticosteroid usage. Cooper et al. (3) compared the method with placebo and the Pink City

Lung Exerciser.

In a non-randomised but controlled study Hassan et al.107 showed, that BHT increased and peak

expiratory flow in one second (PEF1) improved significantly after BM. The study of Bowler et al. (1)

examined therapeutic mechanisms behind the method. They measured lower levels of PETCO2 at

baseline as compared to the control group. They showed a decrease in pulmonary ventilation (VÉ) after

the method, but without changes in PETCO2. They also found a correlation between decreased SABA

usage and lower levels of VÉ (r2 = 0, 51). The study of Abramson et al. (5), published as an abstract,

reported lower levels of PETCO2 and a marginal reduction in the ventilatory response to CO2 after BM.

Courtney et al.34, showed a significant correlation between short BHT and a thoracic-dominant breathing

pattern, but a negative correlation between PETCO2 and BHT. Another research of Cooper et al.111

demonstrated that mouth-taping without BM had no influence on asthma control in symptomatic

asthmatics.

Until now, research on BM has not been able to fully support the CO2 theory. Thomas et al.32, support

the theory somewhat. They surveyed 210 asthmatic adults using the Nijmegen Questionnaire, a

validated questionnaire that differentiates hyperventilation and dysfunctional breathing. They showed

that hyperventilation is more common in women and in almost 30% asthmatic adults. Further exploration

of the control of respiration and other mechanisms behind the method is needed.112

Breath holding and the Buteyko method

Breath holding competence is an essential part of self-management in BM. BHT is not used for

therapeutic purposes. It is not an exercise, but it gives feedback about risk estimations of symptom

recurrence and exacerbation.9,10 It is also relevant to the respiratory chemosensitivity of CO2.70

Additionally, BHT is shown to have a relation with abnormal spirometry34, PACO2 (Karsten-Voets HMM.

unpublished master thesis, 2006), dysfunctional breathing79, and hyperventilation.113 Success in BM is

evidenced by progressively longer BHT, as chemosensitivity for CO2 decreases and levels of CO2 rise.

However, only a limited amount of research has been done with BHT.

Breath holding measurements are performed differently by different researchers and can possibly

have training effects.79 Nishino et al.70 have investigated different methods of BHT and showed different

training effects (that is, improvements after successive tests), on two distinct periods in the process of

voluntary breath-holding. A first period showed no training effect, and a second period when on-going

breath holding indicated a training effect.

The first period of BHT was hardly influenced by the stress of breath-holding and the activity of the

respiratory muscles. Precise instructions have to be followed to determine a correct BHT. It is measured

while sitting straight, starting after a gentle expiration and lasting until the first desire to breathe again.

This measurement is performed correctly when tidal volume (VT) and frequency (f) are the same before

and after breath holding.9 When breath holding, CO2 accumulates in the blood. The greater the

35

ventilatory response to CO2, the shorter the period of no respiratory sensation during breath holding. A

significant correlation between the first breath-holding period and CO2 chemosensitivity was observed,

and this measure was concluded to be useful in studies for clinical testing causes of dyspnea.70 The BM

uses this BHT protocol and is considered fairly standardized.79 It is mapped in BM and relates to the

extent of ventilation dysfunction.9

The second period of ongoing breath holding after the first period was shown to be influenced by

physiological and non-physiological factors. It improved with successive trials, showing a training effect.

To obtain the ventilatory CO2 response curve, a rebreathing test using a modified Read’s technique 114

was performed for the two periods separately. These tests showed the first “post-expiratory period of no

respiratory sensation” to be below a certain “central threshold of the centrally generated respiratory

motor command signal”.70

Reducing ventilation, as done in BM, is concluded to be a reasonable approach to increase asthma

control.115 Still, there is a need for physiological based explanations of the mechanisms behind the

positive results of BM.4 Studies with detailed ventilation measures at baseline and after a breathing

intervention are proposed.7 Respiratory chemosensitivity for CO2 is recommended as one of the primary

outcome measures of ventilation.7, 115 Research has shown that continually reducing VÉ may increase

the ventilatory recruitment threshold of PaCO275, and the protocol of BHT in BM is a significant indicator

for the respiratory chemosensitivity of CO2.70

36

2 Aims and Objectives

The aim of this study is to assess the effects of BM on resting ventilation and asthma control in a group

of asthmatics.

Objectives are to assess the effects of BM on

• Resting ventilation as measured by V’E, PETCO2 and PETO2.

• Perceived asthma control as measured by the ACT and SABA usage.

• Metabolism as measured by V’CO2 and V’O2.

• Respiratory chemosensitivity for CO2 as evidenced by BHT.

37

3 Methods

This was a prospective, controlled, intervention study with 6-month intervention period.

3.1 Participants

We recruited 36 asthmatics from medical centres, the Icelandic Asthma and Allergy Association, general

practitioners, and from pulmonary specialists. All the participants were 18 years or older. To be included,

the asthmatics had to have a physician diagnosis of asthma. They had to have benefited from SABA

use in the four weeks prior to the start of the study. The asthmatics were divided into three groups

according to their SABA use: very mild, when SABA usage was less than or once a month (≤ 1/month);

mild, when SABA usage was less than once a day (<1/day); and moderate, once a day or more (≥

1/day). They also had to be willing to participate in BM. In addition, they gave their oral agreement to be

prepared to do breathing exercises twice a day. Smokers (2 participants) and ex-smokers (1 participant)

were not excluded. Diagnosis of other respiratory diseases, including chronic obstructive pulmonary

disease (COPD) (1 participant) and co-morbidities such as depression, GERD, high cholesterol,

fibromyalgia and obesity were allowed (see Table 3). To evaluate if the groups were comparable, we

paired 20 healthy control participants for gender, age and BMI with 22 asthmatics, who finished the

study. The healthy control participants were obtained by approaching friends, family and employees of

Reykjalundur. They had no history of obstructive airway disorders as asthma nor dyspnea, they did not

use any health related medication and did not know anything about the BM. Smokers were allowed (3

participants). Approval of the National Bioethics’ Committee was obtained before starting this study (see

Appendix A, number VSNb2012010044/03.7). The participants received an introduction letter before

participating to the study (see Appendix C). Participants were provided with written informed consent

forms that they signed in order to participate in this study (see Appendix B).

38

Table 3. Asthma history and medication usage at M1

Gender Age

(years)

Years since

initial

diagnosis

Comorbidity Steroid and

LABA

Steroid

usage SABA

SABA

usage

F 41 Childhood Allergy Pulmicort 1/day Bricanyl* 3/day"

F 45 12 Depression/

GERD Pulmicort 2/day Ventolin 3/day

F 44 Childhood Fibromyalgia/

Rhinitis Flixotide 2/week Ventolin 1/week"

M 21 Childhood N n n Ventolin 3/week"

F 61 21 Allergy Seretide 1/day Ventolin 3/week

F 23 7 n n n Ventolin* 2/day"

F 42 Childhood Obese/

Rhinitis Seretide 2/day Ventolin 3/day

M 71 26 n Flixotide 1/day Bricanyl* 2/day

F 57 28

Fibromyalgia/

Depression/

Rhinitis

Seretide 1/day Ventolin 3/week

F 61 Childhood Adison disease Dexamethasone 0, 5/day Ventolin 2/day"

F 22 Childhood Obese

/Fibromyalgia Symbicort 1/day Ventolin 2/day

M 38 Childhood GERD

/Blood pressure Symbicort 3/week Bricanyl 2/day

F 55 Childhood Mould

/Rhinitis n n Ventolin 2/day

F 64 20 GERD/

Rhinitis n n Ventolin <1/month

M 40 3 Depression/

GERD Seretide 1/day Ventolin 2/day

M 31 25 n Relvar 1/day Bricanyl 2/day

F 33 26 Rhinitis Seretide 1/day Ventolin 3/week"

F 53 Childhood

COPD/

Chrone’s disease/

Diabetes

Seretide 4/day Ventolin* 1/week"

F 21 5 Xolair- injections/

Rhinitis Relvar 2/day Ventolin 3/day

F 56 4 GERD/

Fibromyalgia Flixotide 2/day Ventolin* 3/week"

F 54 Childhood High cholesterol Flixotide n Ventolin 3/week

M 69 62

GERD/

Hypertension/

Rhinitis

Decortin 1/ day Ventolin* 1/week

n = never; F= female; M = male; COPD= chronic obstructive pulmonary disease; GERD= gastroesophageal reflux disease. * = Nocturnal symptoms 1-2 a week “= Limitation of exercises, SABA use not included

3.2 Protocol

Particular emphasis was placed on measuring at complete rest to ensure the least provocation of the

central respiratory centers. Measurements described below were taken at the laboratory in

Reykjalundur, on the weekends, in the early mornings, and before breakfast. While measuring

39

ventilation, all participants sat straight and listened to the same relaxing audio. No food, medication,

alcohol, caffeine, nor physical activity was allowed at least eight hours before measuring. Measurements

were performed in the following order: weight and height, blood pressure and pulse, resting ventilation

and metabolism, BHT, spirometry, and the ACT (see Figure 12). Care was taken to make certain that

all participants were examined with the same protocols and in the order described. Seasonal influences

were taken into account. Measurements of the participants were spread over the year, as asthma

symptoms can be triggered by the changing of seasons.

Measures

To be able to assess our aim and objectives, the following measurements were taken:

Ventilation at rest, metabolism and spirometry

Measurements of resting ventilation (V’E), end-tidal carbon dioxide (PETCO2), end-tidal oxygen (PETO2),

tidal volume (VT), respiratory rate (RR), carbon dioxide output (V’CO2) and oxygen consumption(V’O2),

were sampled. This was done while participants were connected to a metabolic cart device (Vmax

Encore 29, Sensormedics, CA, USA). They were sitting in a straight position and listened to relaxing

audio for 15 minutes while wearing a facemask. The average of the last four minutes of measurements

were used for statistics. The ventilatory equivalent for CO2 output (V’E V’CO2) was calculated. Measures

of lung function variables, including FEV1 and FVC, were made with the same device and were

expressed as percentages predicted for gender, age, height, mass, and ethnicity.49

Asthma control

The ACT was used to measure asthma management.20, 116, 117 (see Appendix D and E). The ACT

involves 5 items assessing asthma symptoms (daytime and nocturnal), the use of rescue medications,

and the effect of asthma on daily functioning. Each item includes 5 response options corresponding to

a 5-point, Likert-type rating scale. Responses for each of the 5 items are summed to yield a score

ranging from 5 (uncontrolled asthma) to 25 (controlled asthma). A score > 19 points indicates well-

controlled asthma.

Symptoms, SABA use and severity.

Asthmatics had to fill out diary cards (see Appendix F). Diary cards supported the asthmatics in

evaluating their asthma and in completing the ACT. They could recognize fluctuations of asthma control

by registering symptoms such as coughing, breathlessness, and chest tightness, and by registering

waking at night, symptom related restrictions in physical activity, missed school/work days, and visits to

their physician or to an emergency department. Symptoms of allergies, medication use, and asthma

exacerbations had to be registered on these cards.

Breath holding time protocol

BHT in BM is the time after a normal exhalation until the very first sensation of shortage of air.

Participants had to sit straight, and, after a gentle expiration, they had to stop breathing by pinching their

nose with mouth closed, until the first desire to breathe again. The measurement was performed

correctly, if VT and f were the same before and after holding their breath. BHT measurements were

40

repeated three times, with one-minute intervals, and the mean was used for statistics. Time

measurements were done with a stopwatch that measures 0.01 of a second.

3.3 Procedure

Data collection was conducted from June 2012 through January 2016. The asthmatics were measured

three times; 6 months before the intervention (M1), just before the beginning of the intervention (M2),

and 6 months later (M3). The first period (M1-M2) was the control period for the asthmatics. The control

group were measured two times, at M1 and M2 (see Figure 11). Fourteen asthmatics, or 39%, did not

finish the study. Five (36%) of them did not attend the BM classes because of personal problems not

related to the study, five (36%) dropped out directly after the classes because of a lack of interest in the

method, and four (28%) of them tried to keep exercising but resigned as they were unable to follow

instructions and do the exercises.

Figure 11. Flowchart of procedure and participants. Measurements were performed for 36 asthmatics. 14 (39%) of them dropped out of the study. The 22 asthmatics left were compared to 20 healthy controls

The asthmatics had to complete the ACT at M1, M2 and M3 and once a month, from M1-M2 (6

times), from M2-M3 (6 times). They also had to fill out diary cards during M1-M2 and M2-M3 (see Figure

12). For examining SABA use at M1, we used their responses to question 4 on the ACT completed at

M1. For examination of SABA usage at M3, we calculated the average use of SABA in the two months

before M3 from their diary cards, when available. When not available, we used the response to question

4 from their ACT.

41

Figure 12. Measurements performed for both groups at M1, M2 and M3

The intervention

The asthmatics were taught BM after M2. According to their registrations, 6 groups of 4-7 participants

were formed. Instructions of the BM were provided in 5, 2-hour sessions over 3 weeks for each group.

The asthmatics were taught the BM by a trained and internationally accredited Buteyko practitioner and

physiotherapist. They were taught techniques designed to reduce their breathing direct and indirect,

according to components of the method. These included awareness, relaxation, nose- and low tidal

volume breathing techniques. Besides other exercises, they received individual management and

guidance on how to avoid deep breathing in daily life.

The participants had to train twice a day; once in the mornings and once in the evenings and register

BHT on diary cards.9, 10 Breath holding measures were taken before and after exercises to evaluate both

the training and progress. To achieve normal ventilation, BHT set-points had to be assessed with an

end goal of 60 seconds. According to BM, physical activity other than walking was not yet advised during

the study. To be able to increase physical activity, BHT had to be over 20 seconds. The asthmatics were

encouraged to stay on their medication regime, as advised by their physician. If they wished to change

their asthma medication, they were advised to discuss this with their physician.

Intervention period

The second period (M2-M3) was the intervention period for the asthmatics. The evaluation day for

assessing progress and training motivation was in the middle of the intervention period. End measures

were taken at the end of the six months intervention period M3, a year after M1 (see Figure 11).

3.4 Statistical analysis

Data was entered into a statistical program (StatView) and was checked for any abnormalities or errors.

Summary statistics were used to analyse the characteristics of the groups. Descriptive statistics were

42

used to identify trends in outcomes, as measures of resting VÉ, ACT, spirometry, PETCO2, BMI, and

BHT. We used unpaired students’ t -tests to compare means of measures between groups. Linear

regression was used to find a correlation between changes in BHT and PETCO2. To detect a within

patient change from M1 to M2 to M3 for measures of resting ventilation, ACT, spirometry, PETCO2, BMI

and BHT, ANOVA for repeated test was used with Fisher post hoc analysis, to correct for repeated

comparisons. To detect changes in control group from M1 to M2, paired t-test was used. To test for

differences in changes between the groups from M1-M2 for measured parameters, an unpaired t-test

was used. Responses were expressed as mean ± SD. Statistical significance was set at p < 0.05.

43

4 Results

To evaluate parameters for the 22 asthmatics who finished the study during the control period, their

measurements were compared between M1 and M2. To assess if the asthma group was comparable

to the healthy control group, we compared measurements of the 22 asthmatics to measurements of the

20 healthy control participants at M1 and at M2 and between M1 and M2. To assess the effects of BM,

measurements of the 22 asthmatics performed at M1 and M2 were compared to their measurements at

M3.

Participants

After matching for age, gender, and BMI, there were no significant differences between the asthma and

healthy control groups (see Table 4). A rough examination shows dropouts in the asthma group not to

be different from those who participated in the study.

Table 4. Measures of age, gender and BMI for all participants at M1

M1 Asthmatics (22) Controls (20) p- value

Age (years) 46.1±14.6 45.1±15 NS

Gender(F/M) 16/6 16/4 NS

BMI 27.9±5.3 26.5±5 NS

BMI = body mass index; F = female; M = male; NS= nonsignificant.

Between M1 and M2, there were no significant differences in or between groups in regards to BMI.

Between M1 and M3, the mean of measured BMI had increased in the asthma group (see Table 6).

4.1 Ventilation

Between M1 and M2, no differences were found between the groups for the means of the measured

parameters of ventilation (see Table 5 and 6). Lung function was in the normal range for both groups,

and no significant difference was observed for FEV1 or FVC. However, the FEV1/FVC ratio was

significantly lower in the asthma group, compared to the control group (see Table 5).

Table 5. Ventilation measurements at M1

M1 Asthmatics (22) Controls (20) p- value

VÉ 6.7±1.7 6.4±1.3 NS

FEV1(L) 3.06±1.1 3.36±1.0 NS

FEV1(% pred) 96.6±21.2 105.8±14.1 NS

FVC(L) 4.04±1.1 4.20±1.3 NS

FVC (% pred) 108.6±17.1 112.3±17.7 NS

FEV1/FVC 74±1 80±1 0, 04

VÉ = pulmonary ventilation; BHT = breath holding time; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; pred. = predicted; L = litre; NS = non-significant

At M3, in the asthma group, the means of measured FEV1 and FVC decreased, but the ratio of

FEV1/FVC did not change (see Table 6).

44

PETCO2 and PETO2 were measured to examine alveolar ventilation. In the asthma group, significant

changes were seen between the means of measures from M1 to M3 and from M2 to M3, as PETCO2

increased and PETO2 decreased (see Figure 13).

Figure 13. Partial pressures of end-tidal carbon dioxide (PETCO2) and oxygen (PETCO2) of the asthma group (blue) versus the control group (blue) at three different time points. Points represent mean values and standard deviations for the asthma group and the control group. *= p<0.05 in M3 versus previous

In the asthma group, the means of measures of V‘E and VT decreased between M1 and M3, and M2 and

M3, but the mean of RR remained the same (see Table 6).

Table 6. Parameters before (M1), after the control period and before intervention (M2), and after intervention period in the asthmatic group (M3) as compared to their controls.

Asthmatics (n=22) Controls (n=20)

M1 M2 M3 M1 M2

BMI 27.9±5.3 28.3±5.5 28.7±5.9* 26.5±5 26.4±5.1

FEV1 (% pred.) 96.6±21.2 99.05±19.5 93.8±18.2* 105.8±14.08 105.2±14.34

FVC(% pred.) 108.6±17.1 109.9±18, 1 104.5* 112.3±17.67 112.2±19

FEV1/FVC 74±1 75±1 75±1 80±0.7¥ 80±0.7

V‘O2 L/min 0.180±0.07 0.187±0.06 0.146±0.06* 0.191±0.06 0.196±0.05

V‘CO2 L/min 0.148±0.06 0.16±0.06 0.118±0.05* 0.152±0.05 0.153±0.04

VÉ L/min 6.65±1.74 6.88±2.00 5.69±1.70* 6.38±1.3 6.43±1.4

VT(L) 0.58±0.21 0.68±0.27 0.49±0.16* 0.67±0.27 0.66±0.18

RR(per minute) 12.2±2.7 11.1±2.9 12.2±3 10.9±3.5 10.7±2.9

V‘E/V‘CO2 48.3±10.5 44.4±7.7 52.2±13.3* 43.9±9.9 43.3±7.8

FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; pred. = predicted; V’O2 = oxygen consumption; VĆO2 = carbon dioxide output; VÉ = pulmonary ventilation, VT = tidal volume, RR = respiratory rate, V’E/V’CO2 = ventilatory equivalent for carbon dioxide. * = p<0.05 in M3 versus previous measurements, ¥ = p<0.05 in control versus asthmatics.

45

4.2 Asthma control

To interpret asthma control, scores from the ACT were examined. At M1 and M2, the asthmatics were

not well controlled, with mean scores of 16.7 and 18.6 respectively. At M3, the mean score was 21.3,

indicating well-controlled asthma (see Figure 14).

Figure 14. Results from the ACT. Bars represent mean values of scores with standard deviations. Scoring > 19 points indicates well-controlled asthma. * = p<0.05 in M3 versus previous measures.

The number of asthmatics with SABA usage ≤ 1/month, or very mild, increased from 1 to 14. Participants

from the asthma group with SABA usage < 1/day, or mild, decreased from 9 to 7. The subgroup with

usage ≥ 1/day, or moderate, decreased from 12 to 1 (see Figure 15). This is calculated to an 85% drop

in SABA usage in the 22 asthmatics. Precise measures of combinations of LABA and inhaled and/or

oral corticosteroids were not performed in this study, but an estimation indicated a decrease of 45%.

Figure 15. SABA usage before and after the Buteyko method. Number of participants according to their SABA use before and after BM. Very mild = ≤ 1/month; mild = < 1/day ; moderate = ≥ 1/day.

46

4.3 Metabolism

To be able to evaluate metabolism, measures of VÓ2 and VĆO2 were examined. Between M1 and M2,

the means of these measures did not show differences between the groups (see Table 6). At M3, the

means of measured VÓ2 and VĆO2 decreased. As these metabolic measures decreased more than

VÉ after the intervention (p < 0.05), values of V’E/V’CO2 increased significantly between M2 and M3.

(see Table 6).

4.4 Breath holding time

BHT was measured to evaluate respiratory chemosensitivity for CO2. At M1 and M2, the results showed

that the asthma group had significantly shorter BHT than the control group. At M3, the mean of BHT

measures became longer in the asthmatic group (see Figure 16).

Figure 16. Breath holding time measures for the asthma group (blue) versus the control group (orange), at three different time points. Points represent mean values and standard deviations for the asthma group and the control group. ¥ = p<0.05 in control group versus asthma group; ¤ = p<0.0001 M3 versus previous measure.

The correlation for changes of measured BHT and PETCO2 was evaluated. A significant correlation

was found when one extreme case with highly variable PETCO2 and BHT levels was excluded. This case

was taken out, as the cause of these extreme values could have been a high dosage of oral steroid use

at M2. The coefficient of determination between the changes in BHT and changes in PETCO2 was r2 = 0,

2772, p<0.02 (see Figure 17).

47

Figure 17.∆ BHT Line Fit Plot without extreme case. A significant correlation was found for changes in BHT and PETCO2 when the extreme case was excluded (r 2 = 0.2772, p<0.02).

In summary, the effects of BM were visible in changed means of measures of resting ventilation, higher

levels of PETCO2, lower levels of PETO2, together with increased asthma control and reduced respiratory

chemosensitivity for CO2 in asthmatics.

5 Discussion

The results showed no difference in resting ventilation in asthmatics at baseline as compared to their

healthy controls. However, BHT among the asthmatics was shorter before BM, indicating higher

respiratory chemosensitivity for CO2. Values of BHT were longer after BM, which is in accord with lower

respiratory chemosensitivity for CO2. Higher values of PETCO2 and lower values of PETO2 were measured

after BM, indicating decreased values of VÁ/VĆO2. Both VÉ and metabolism decreased after the

intervention, the latter more than the former, resulting in increased VÉ/VĆO2. Higher values of

VÉ/VĆO2 and PETCO2 and lower values of PETO2 implied more dead space ventilation, due to changes

in breathing patterns, i.e., lower VT. Asthma was not-well controlled before, but well controlled after, BM.

Lung function measures such as FEV1 and FVC decreased, but their ratio stayed the same after the

intervention.

5.1 Pre-intervention

Ventilation was examined at utmost rest in our participants, with the least provocation of respiratory

control. In these conditions, no marked increase in ventilation is shown in the asthma group. Increased

ventilation is expected from past studies and from the theory of the BM.39, 45, 60, 118, 119 Thomas et al.32, 39

tried to evaluate hyperventilation in asthmatics using the Nijmegen questionnaire (NQ)120, a validated

screening tool to distinguish people who hyperventilate from people who do not.38 They reported that

one third of asthmatic women and one fifth of asthmatic men had symptoms associated with

hyperventilation or dysfunctional breathing.39 Bowler et al.55 confirmed significantly lower levels of

PETCO2 at rest in asthmatics as compared to a normal group, without evidence of clinically increased

breathing. In a controlled study of 23 mild and stable asthmatics, Osborne et al.60 reported significant

lower levels of PETCO2 and PaCO2 at rest in asthmatics, compared to healthy controls. Still, they could

48

not show clinically significant hyperventilation. It is difficult to understand the exact reasons for these

findings as they did not measure metabolism. Also, as Osborne et al. themselves noticed, measures

were taken with a mouthpiece and nose clip, which could have influenced breathing.121 Furthermore, it

may be argued whether patients were measured at complete rest in the study of Osborne et al. Although

participants were not allowed to use caffeine nor bronchodilators eight hours before measuring, other

features could have influenced their ventilation such as emotional state, recent physical activities, food

intake, and posture.122, 123 In our study, by measuring in protocolled optimal resting circumstances, with

the least physical and psychological challenges, we tried to normalize conditions pertinent to the disease

and reduce variability that could contribute to our findings for both groups. Hormbrey et al.45 examined

breathing patterns in symptomatic asthmatics, in people with symptoms of hyperventilation and in

healthy subjects. At rest, the asthmatics had significantly higher VÉ and lower levels of PETCO2 (37

mmHg), compared to people who were supposed to hyperventilate (40 mmHg) and healthy subjects (41

mmHg). However, there were only 6 participants in each group. In this study, hyperventilation was

related to changes in CO2 levels rather than long-term CO2 levels. William N. Gardner41 explained that

voluntary hyperventilation can result in a drastic removal of alveolar CO2 (PACO2), primarily coming from

alveolar gas, then from blood in pulmonary veins, from the left side of the heart, and, finally, from the

first part of systemic circulation. Hence, a few minutes after hyperventilating, partial pressure of PACO2

had returned to normal. A new balance had been achieved between a wash-out from the lungs and the

tissues with same PACO2 levels, corresponding to “a 50% change of CO2 content of the body tissues

with a change of 5 minutes in PACO2”. The reviews of Bruton et al.115 and Meuritz et al.61 have shown

asthmatics to have a tendency of lower levels of PaCO2, compared to healthy subjects. Also, Dr.

Konstantin Buteyko, who developed the BM, claimed that hidden hyperventilation is one of the causes

of asthma. The primary goal of BM is to decrease ventilation, balance it with metabolism, thereby raising

levels of CO2.9 Hence, other factors need to be sought to explain the theory of the BM.

Asthma in the study subjects was not-well controlled at baseline, according to the mean scores from

the ACT. This finding is somewhat similar to the results of the study of Demoly et al.25, where they also

used the ACT to evaluate asthma control. They concluded that asthma was not well controlled in more

than half of the treated asthmatics in 5 countries in Europe. Furthermore, Papaioannou et al.24 explained

that, world-wide, asthma is only controlled in a small percentage of patients. Most of the asthmatics in

our study were asymptomatic during the measurements, but they were symptomatic during the study.

The severity of their symptoms during the M1-M2 period varied widely. As their SABA use varied from

once a month to more often than once a day, they were divided in three subgroups, corresponding with

very mild (≤ 1/month), mild (< 1/day) to moderate (≥1/day) SABA use, according to the study of Osborne

et al.60 At baseline, 4.5% were very mild, 41% were mild, and 54.5% were moderate.

The mean values of FEV1/FVC were lower for the asthmatics in our study, confirming decreased lung

function as compared to the healthy control group. Ventilation per metabolism (V’E/V’CO2) was higher

for the asthmatics in our study, but not significantly so. These differences of V’E/V’CO2 between

asthmatics and the healthy control group may have become clearer with a larger number of participants.

BHT for the asthmatics was shorter (14.1± 8.2 sec, p< 0.05), compared to the healthy controls, (19±

7.1 sec). According to Nishino et al.70, shorter BHT is related to increased dyspnea and greater

49

respiratory chemosensitivity for CO2. The longer the breath can be held, the better the accumulation of

CO2 is tolerated, the lower respiratory chemosensitivity for CO2. This result conforms to the results in

the review of Hida et al.78, where they indicated that the ventilatory drive in asthmatics is affected by

respiratory chemosensitivity for CO2. They also showed in this review, that the ventilatory drive is related

to asthmatics with both a decreased sensation of dyspnea (as in asthmatics who have experienced near

fatal asthmatic periods) and an increased sensation of dyspnea (as in asthmatics who did not have

experienced near fatal asthmatic periods). They concluded that the ventilatory drive has a fundamental

role in determining the severity of asthma. Also, Kassabian et al.77 showed an increased respiratory

chemosensitivity for CO2 in asthma. Still, in their study PETCO2 and PETO2 were similar to the control

group at baseline, showing no evidence of increased VÁ at rest. In literature, it is suggested that PETCO2

can be normal in people with symptomatic hyperventilation at rest.40 Han et al.89, did not find changes

of PETCO2 at rest for people suffering from hyperventilation and anxiety, as compared to people who did

not had those issues. They characterized people who hyperventilate as having a respiratory control

system that is more sensitive to provocation and with unstable breathing patterns. Macnutt et al.124

showed chemosensitivity for CO2 to be higher in women than in men.

It is an attractive proposition to hypothesize that the asthmatics with shorter BHT in this study have

an inefficient or dysfunctional way of breathing; the underlying central respiratory rhythm will regenerate

quicker but only when provoked, resulting in more quickly increased ventilation as when symptomatic.

Increased ventilation decreases levels of PaCO2 and triggers dyspnea sooner compared to subjects

with longer BHT.62, 75 Furthermore, the relation between levels of PETCO2 and bronchodilation/-

constriction is well known in physiology49 and this relation is confirmed by experimental studies of OĆain

et al.125, van den Elshout et al.91 and other studies.47, 61, 91

5.2 Post-intervention

This study evaluated the effect of the BM on resting ventilation and asthma control in asthmatics. Our

findings showed that asthmatics had retrained their breathing patterns without any study-related adverse

effects. At M3, the asthmatics had become more aware of their breathing and had avoided deep

breathing. Some had even experienced changes in their breathing patterns, such as being aware of

greater breath suspension episodes in daily life, indicating slower RR. However, our data showed no

significant change in RR, but a significant change in VT. This is consistent with the study of Wolkove et

al.74, when they investigated the physiology of ventilation during transcendental meditation (TM) as a

relaxation method. Their results showed minute volume (V’E) to decrease due to a decreased tidal

volume (VT). In their study, VT was smaller at same levels of PETCO2 compared to controls, and these

findings were associated with the chemical and neural regulation of ventilation. Our data also showed

increasing levels of PETCO2 together with decreasing levels of PETO2. According to physiology, these

are indicators of lowered values of VÁ in relation to VĆO2. Bowler et al.55 showed reduced VÉ after BM

(14 ± 6.5 versus 9.6 ± 3.1 L/min), but without measuring metabolism and with unchanged low levels of

PETCO2. Abramson et al.105 were able to show increased PETCO2 levels after BM. Ritz et al.47 showed

higher levels of PETCO2 after a capnometry assisted respiratory training (CART), but not after slow

breathing and awareness training (SLOW). These trainings were not according to the BM, but they were

50

based on the hypothesis that raised levels of CO2 could increase asthma control. Still, subjects in both

studies increased asthma control, implying that the results only partially supported the hypothesis that

CO2 is related to asthma control.

Asthma was well-controlled after the BM, as average scores for the ACT reached above the set-point

of 19. In the BM, asthmatics were not encouraged to diminish their medication usage unless advised by

their physician. They were instructed to use the BM techniques before using rescue medication. Asthma

control increased in all other research that investigated the effectiveness of the method.21, 55, 81, 106, 108,

109, 126 In our study, after BM, SABA usage had decreased for 85% of the participants. Of those, 63.6%

were with very mild, 31.8% were with mild and 4.6% with moderate SABA usage. Bowler et al.55 also

showed a reduction of SABA usage and found a correlation with reduced VÉ, r2= 0, 51 p < 0.004.

Although FEV1 and FVC decreased significantly for the asthmatics, the FEV1/FVC ratio remained the

same after BM. These results resembled the results from Fenger et al.65, where they concluded changes

of adiposity altered levels of FEV1 and FVC, but values for the FEV1/FVC ratio stayed the same.

Metabolism in the asthmatics had reduced at M3, as both values of V’O2 (0.180 ± 0.07 vs. 0.146 ± 0.06

L/min; p < 0.05) and V’CO2 (0.148 ± 0.06 vs 0.118 ± 0.05 L/min; p < 0.05) had decreased. The results

also showed that asthmatics gained weight at M3 as compared to M1. It can be assumed that these

findings are correct as metabolism remained the same in M1-M2 for both groups. A possible explanation

for asthmatics gaining weight could be decreased SABA or B2-agonists usage. Studies84-86 have

confirmed metabolic side effects of B2-agonists in asthma and have suggested these to increase the

metabolic rate in asthmatics. Agha et al. concluded that asthmatics have higher basal metabolic rates

than normal subjects.84 Less B2-agonist usage could possibly have caused weight gain, however slight,

in our study. Increased asthma control and decreased SABA usage was accomplished by reduced

breathing according to our results. The study of Wallace et al.83 showed that meditation reduced

metabolic rates. Other studies examining meditation and relaxation therapies have shown a shift from

sympathetic to parasympathetic dominance in the ANS, together with reduced breathing.71-74 In addition

to this, Matsumoto et al.127 concluded that the bronchodilation effect of B2-agonist medication is through

activation of the sympathetic nervous system. For these reasons, it is suspected that the nervous system

has an impact on the weight gaining effect of reduced breathing and reduced B2-agonist usage.

V’E decreased, but when we corrected V’E for metabolism, we found an increase in values of

V’E/V’CO2 (44.4 ± 7.7 vs. 52.2 ± 13.3; p < 0.05) after BM. Although both VÉ and metabolism decreased,

VÉ decreased less than metabolism. At the same time values of PETCO2 increased and PETO2

decreased, which is considered supportive for lower values of V’A/CO2. Higher values of V’E/V’CO2 and

estimated lower values of V’A/CO2 after BM, indicate that more energy is wasted in dead space

ventilation. An explanation could be that these changes are derived from a decline in VT, without

changes of RR. The percentage of breathing lost in dead space ventilation (V´D) increases when VT

decreases. In this phase of BM, it could be said that the asthmatics (still) breathe ineffectively or

dysfunctionally. They are in the middle of changing their breathing patterns and life style. They still have

a long way to go to reach the 60-second BHT end-goal of BM, and reducing their RR will very likely be

a part of it.

51

In this study, asthmatics reached the BHT set-point of 20 seconds at M3 (25 ± 8.7 sec). These

measures became similar to measurements from the control group (21.5 ± 11.3 sec). They were similar

to measurements from BHT (13.4 ± 5.19 vs. 22.67 ± 7.38, p < 0.0005) after BM in the study of Hassan

et al.107, when they examined BM on patients with bronchial asthma. Our study presented a positive,

significant correlation for the changes in BHT and PETCO2. The coefficient of determination (r2) between

the changes in BHT and the changes in PETCO2 is r2 = 0, 2772, p< 0.02, indicating that almost 30% of

higher levels of PETCO2 were due to less respiratory chemosensitivity for CO2, as evidenced by higher

BHT. According to Ninisho et al.70, this implicated less dyspnea. In the context of these results, it could

be said that breathing less means less breathlessness.

Our results could be considered supportive for the theory of the BM in that they provides evidence

that confirms reduced breathing to increase asthma control. Higher levels of PETCO2, lower levels of

PETO2, together with increased asthma control may be fundamental to the pathophysiology of asthma.

BM, apparently, reduced the chemosensitivity for CO2 and this might have taken away the underlying

causes of asthma. This study also indicated that breathing patterns may be altered and that the steady

state of ventilation can be reset.

There were undoubtedly nonspecific intervention and professional attention effects that could cause

spontaneous improvements of symptomatic asthmatics, as mentioned in Gina16 and other studies.4, 98,

112 Factors such as relaxation, self-efficacy, and voluntary reduce of medication could partially have

caused the results of the intervention. The techniques used in the BM gave the asthmatics a feeling of

control, reducing their anxiety about their symptoms. The BHT in BM gave asthmatics information about

their progress and results, and improvements might have enhanced their self-efficacy.21, 46, 81, 109

5.3 Strength and limitations

Complex interventions like these were methodologically difficult to control. Our design of comparing an

asthmatic group to themselves as their own control group and comparing them to healthy participants

provided a credible control procedure. Therefore, our results can be related to aspects of the

intervention.

We examined asthma control and ventilation at rest in people with asthma who found relief from

medication. Our most important preselection was that the asthmatics had to have benefited from the

use of rescue reliever medication in the last month. We measured in protocolled optimal resting

circumstances, with minimal physical and psychological challenges. We tried to normalize conditions

pertinent for the disease and reduced variability that could contribute to our findings for both groups. We

tried to assess seasonal effects involving different risk factors on asthma by measuring the groups at

different times of the year. Allergies in summertime and cold dry air in wintertime are the most observed

triggers in this study. The BM was unknown in Iceland, and it was possible that asthmatics could have

found information about the method on the internet or elsewhere, as it was mentioned in our

advertisements for participants.

Limitations

Although a sample size of 20 participants in each group was statistically predicted to be sufficient, bigger

sample sizes would have given even more reliable results.

52

Having more asthmatics participate in the study and randomising them for a BM group and an

untreated group would have made the study a randomised trial. Finding asthmatics willing to participate

was difficult, and this would have taken too long time. The BM is a complemental treatment to initial

treatment strategies, according to guidelines of asthma management. Physicians and lung specialists

in Reykjavík were informed about the BM, but it was difficult to encourage them to help us to find the

right participants. Only two of the subjects had been encouraged by their physician to participate in this

study, but most of the participants had seen recruitment material in pharmacies or medical centers. The

Buteyko method is still unknown on Iceland and, one could say, revolutionary. That could be one of the

reasons why it was difficult to find participants in a small society like Iceland. Further on, it would have

been appropriate for the researcher to inform the family physicians of the asthmatics of their participation

in the study to keep the physicians informed.

We have not been able to assess hyperventilation or dysfunctional breathing in our asthmatics with

the Nijmegen Questionnaire, 38 as this questionnaire has not yet been translated into Icelandic and

tested in Iceland. The inclusion criteria of benefitting from SABA use in the last month was subjective. It

would have had more significance if benefitting from SABA was confirmed in lung function testing. Also,

it would have been interesting to examine psychiatric disorders such as depression and anxiety

assessments. Other studies have evaluated psychiatric disorders and suggested a relationship between

anxiety, depression, and asthma control.29, 60 This could have contributed to the examination of who

benefits the most from these breathing methods.

As nasal breathing is emphasized, it is likely to have affected NO levels in our participants. NO is

produced in many cells in the body and also in the endothelium of the paranasal sinuses. NO is involved

in a large number of physiological processes; it has both local effects such as host-defence by keeping

the nasal sinuses sterile, and distal effects such as bronchodilation, vasodilatation, improving

ventilation/perfusion matching, O2 transport, and immune responses.50, 128

A considerable number of participants dropped out of the study, or 14 (39%) of the 36 asthmatics.

This was not unexpected as participation required a long-term commitment of the participants. The

intervention was complex, involving lifestyle changes and most participants were in their forties. These

could be important limitations, as young people might change their lifestyles more easily. The two

youngest people in our study, 19 and 21 years old, demonstrated significant positive results shortly after

the intervention. Further explanations could be that participants did not pay for the Buteyko method, nor

were they rewarded in any way. The method is unknown, revolutionary and not encouraged by

physicians and this could have an influenced their enthusiasm in compliance with exercising.

Actual compliance with the daily exercises and diary cards was not closely monitored. These

trainings require considerable commitment from the individual patients, in terms of time and effort. The

BM is best suited to people who do not want a quick fix, are not content with medication use, and are

prepared to change life habits. The belief in therapy efficacy grew among the asthmatics who completed

the study, in response to experiencing improvements in their condition. All of the 22 participants reached

the 20-second set point of BHT.9, 10 To reach the 60-second end-goal of the BM, longer follow ups are

required. Then, physical exercise would also become part of the instructions.

53

5.4 Future studies

Asthma diagnose involves a variety of phenotypes. Different therapies may be effective for different

people, and it is not known who benefits most from breathing exercise methods. This study has not

approached this knowledge. Further investigations with breathing methods such as BM are needed.

Longer follow ups are preferable, at least until the BM end-goals are reached for each participant. A

measure of commitment for being prepared to train breathing should be one of the criteria included.

Also, measurements evaluating inflammatory biomarkers, bronchial reactivity, and hyperventilation

assessments, with questionnaires such as the Nijmegen questionnaire38, and blood gas tests are

preferable. This is important for correctly diagnosing and targeting who (according to personality and

breathing style) would benefit most. It would be interesting to investigate the method with children. Two

studies with children have been done and have shown excellent results.129, 130 Studies with severe

asthma offer interesting options to examine whether severe asthmatics can obtain better control with

the method. One study131 examined BM and physical exercise and another is on-going in Germany. It

would be important to investigate if, and what type of asthmatic, hyperventilates during physical

exercise, by examining blood gases. All this is crucial in assuring that the method will become a

responsible and cost-effective part of overall asthma management.

6 Conclusion

In summary, this study provided detailed information about the physiology of ventilation at rest and

asthma control in asthmatics, before and after the Buteyko method. This study showed no evidence of

dissimilar ventilation or PETCO2 at baseline, when measured at utmost rest, compared to a healthy

control group. Asthma was well-controlled after the method, as evidenced by scores from the ACT.

Symptoms decreased and medication use reduced: SABA use by 85% and a combination of

LABA/steroid use was reduced by approximately 45%. The study suggested that asthmatics have

greater respiratory chemosensitivity to CO2, as evidenced by shorter BHT. VÉ, chemosensitivity and

metabolism at rest decreased after BM, but VÉ/CO2 increased. Values of PETCO2 increased and values

of VÉ and PETO2 decreased, indicating decreased values of VÁ/CO2 after the BM. As the distance

between estimated VÁ/CO2 and VÉ/CO2 increased after BM, it may be concluded that dead space

ventilation also increased. Increased dead space ventilation is assumed to be a result of decreased tidal

volumes. Measures of lung function as FEV1 and FVC decreased, probably because of lower metabolic

rates, but their ratio (FEV1/ FVC) remained the same.

In this study, we have tried to give information about the plasticity of chemical ventilatory control and

we suggested the BM to have affected the underlying pathophysiology of asthma without disturbing lung

function. These results could be important for evaluating therapies for asthma and influencing public

health regimes for the management of asthma. Still, asthma is often poorly controlled, despite broadly

endorsed management guidelines. It is important for physiotherapists to be able to offer asthmatics a

scientifically based and acknowledged103 breathing exercising method. SABA usage diminished

enormously. Since medication costs for asthmatics are increasing and safety profiles of these

medications have come under scrutiny, adequate usage and reduction of medication implies a

54

pharmacy-economic benefit for asthmatics and Iceland. These results could also encourage clinicians

to offer qualified, physiotherapy support to patients with asthma for better control of their asthma.

Breathing less means less breathlessness.

55

References

1. Diamant Z, Diderik Boot J, Christian Virchow J. Summing up 100 years of asthma. Respiratory Medicine 2007;101:378-88.

2. Börn og astmi. Iceland: Astma og ofnæmisfélagið. (Accessed November 2016, 2016, at http://www.ao.is/images/pdf/greinar/AO_2009-2_born_med_astma.pdf.)

3. Astma og erfðir. Iceland: Astma og ofnæmisfélag. (Accessed November 19, 2016, at http://www.ao.is/images/pdf/greinar/AO_erfdir.pdf.)

4. Appendix to Global Initiative for Asthma-GINA. 2016. (Accessed November 19, 2016, at http://ginasthma.org/2016-online-appendix-global-strategy-for-asthma-management-and-prevention/.)

5. Bulletin of the World Health Organization Past issues 2005. (Accessed May 30, 2016, at http://www.who.int/bulletin/volumes/83/7/bousquetabstract0705/en/. .)

6. WHO/Asthma. 2016. (Accessed November 19, 2016, at http://www.who.int/topics/asthma/en/.)

7. Bruton A, Thomas M. The role of breathing training in asthma management. Curr Opin Allergy Clin Immunol 2011;11:53-7.

8. Burgess J, Ekanayake B, Lowe A, Dunt D, Thien F, Dharmage SC. Systematic review of the effectiveness of breathing retraining in asthma management. Expert Rev Respir Med 2011;5:789-807.

9. Novozhilov A. Living without Asthma. 2 ed: Germany: Mobiwell Verlag; 2003.

10. Stalmatski A. MB. Freedom from Asthma. 1 ed: London: Kyle Cathie Limited; 1999.

11. Lowhagen O. Diagnosis of asthma - new theories. J Asthma 2015:1-7.

12. Davies ER, Kelly JF, Howarth PH, et al. Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life. JCI insight 2016;1.

13. Tattersfield AE, Knox AJ, Britton JR, Hall IP. Asthma. Lancet 2002;360:1313-22.

14. Lefaudeux D, De Meulder B, Loza M, et al. The first U-BIOPRED sputum handprint of severe asthma. European Respiratory Journal 2015;46.

15. Asthma and Respiratory Symptoms in Nordic Countries, Environmental and Personal Risk Factors. Digital Comprehensive Summaries of Uppsala Dissertations form the Faculty of Medicine 159.73, 2006. (Accessed November 2016, 2016, at http://www.diva-portal.org/smash/get/diva2:168618/FULLTEXT01.pdf2006.)

16. Braunstahl GJ. United airways concept: what does it teach us about systemic inflammation in airways disease? Proceedings of the American Thoracic Society 2009;6:652-4.

17. van Huisstede A, Castro Cabezas M, van de Geijn GJ, et al. Underdiagnosis and overdiagnosis of asthma in the morbidly obese. Respir Med 2013;107:1356-64.

18. Balmes J, Becklake M, Blanc P, et al. American Thoracic Society Statement: Occupational contribution to the burden of airway disease. Am J Respir Crit Care Med 2003;167:787-97.

56

19. Meurs H, Gosens R, Zaagsma J. Airway hyperresponsiveness in asthma: lessons from in vitro model systems and animal models. Eur Respir J 2008;32:487-502.

20. Nathan RAS, C. A. Kosinski, M. Schatz, M. Li, J. T. Marcus, P. Murray, J. J. Pendergraft, T. B. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol 2004;113:59-65.

21. Cowie RL, Conley DP, Underwood MF, Reader PG. A randomised controlled trial of the Buteyko technique as an adjunct to conventional management of asthma. Respir Med 2008;102:726-32.

22. Gallefoss F, Bakke PS, Rsgaard PK. Quality of life assessment after patient education in a randomized controlled study on asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159:812-7.

23. Ignacio-García J-M, Pinto-Tenorio M, Chocrón-Giraldez MJ, et al. Benefits at 3 yrs of an asthma education programme coupled with regular reinforcement. European Respiratory Journal 2002;20:1095-101.

24. Papaioannou AI, Kostikas K, Zervas E, Kolilekas L, Papiris S, Gaga M. Control of asthma in real life: still a valuable goal? European Respiratory Review 2015;24:361-9.

25. Demoly P, Gueron B, Annunziata K, Adamek L, Walters RD. Update on asthma control in five European countries: results of a 2008 survey. European Respiratory Review 2010;19:150-7.

26. Salpeter SR, Ormiston TM, Salpeter EE. Meta-analysis: respiratory tolerance to regular beta2-agonist use in patients with asthma. Annals of internal medicine 2004;140:802-13.

27. Cates CJ, Wieland LS, Oleszczuk M, Kew KM. Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews. Cochrane Database Syst Rev 2014:Cd010314.

28. Scott KM, Von Korff M, Ormel J, et al. Mental disorders among adults with asthma: results from the World Mental Health Survey. General hospital psychiatry 2007;29:123-33.

29. Yii AC, Koh MS. A review of psychological dysfunction in asthma: affective, behavioral and cognitive factors. J Asthma 2013;50:915-21.

30. Carr RE. Panic disorder and asthma: causes, effects and research implications. J Psychosom Res 1998;44:43-52.

31. Pbert L, Madison JM, Druker S, et al. Effect of mindfulness training on asthma quality of life and lung function: a randomised controlled trial. Thorax 2012;67:769-76.

32. Thomas M, McKinley RK, Freeman E, Foy C, Price D. The prevalence of dysfunctional breathing in adults in the community with and without asthma. Prim Care Respir J 2005;14:78-82.

33. Hodges PW, Gandevia SC. Changes in intra-abdominal pressure during postural and respiratory activation of the human diaphragm. J Appl Physiol 2000;89:967-76.

34. Courtney R, Cohen M. Investigating the claims of Konstantin Buteyko, M.D., Ph.D.: the relationship of breath holding time to end tidal CO2 and other proposed measures of dysfunctional breathing. J Altern Complement Med 2008;14:115-23.

35. Dixhoorn Jan BB. Ademen wij vanzelf? 7 ed: Baarn: Bosch&Keuning N.V. ; 1993.

36. Courtney R, van Dixhoorn J, Greenwood KM, Anthonissen ELM. Medically Unexplained Dyspnea: Partly Moderated by Dysfunctional (Thoracic Dominant) Breathing Pattern. Journal of Asthma 2011;48:259-65.

57

37. Hodges PW, Heijnen I, Gandevia SC. Postural activity of the diaphragm is reduced in humans when respiratory demand increases. The Journal of physiology 2001;537:999-1008.

38. van Dixhoorn J, Folgering H. The Nijmegen Questionnaire and dysfunctional breathing. ERJ Open Research 2015.

39. Thomas M, McKinley RK, Freeman E, Foy C. Prevalence of dysfunctional breathing in patients treated for asthma in primary care: cross sectional survey. BMJ 2001;322:1098-100.

40. Folgering H. The pathophysiology of hyperventilation syndrome. Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace / Fondazione clinica del lavoro, IRCCS [and] Istituto di clinica tisiologica e malattie apparato respiratorio, Universita di Napoli, Secondo ateneo 1999;54:365-72.

41. Gardner WN. The pathophysiology of hyperventilation disorders. Chest 1996;109:516-34.

42. Hornsveld H, Garssen B. Hyperventilation syndrome: an elegant but scientifically untenable concept. The Netherlands journal of medicine 1997;50:13-20.

43. Salome CM, Thorpe CW, Diba C, Brown NJ, Berend N, King GG. Airway re-narrowing following deep inspiration in asthmatic and nonasthmatic subjects. Eur Respir J 2003;22:62-8.

44. McFadden ER, Lyons HA. Arterial-Blood Gas Tension in Asthma. New England Journal of Medicine 1968;278:1027-32.

45. Hormbrey J, Jacobi MS, Patil CP, Saunders KB. CO2 response and pattern of breathing in patients with symptomatic hyperventilation, compared to asthmatic and normal subjects. Eur Respir J 1988;1:846-51.

46. Thomas M, McKinley RK, Mellor S, et al. Breathing exercises for asthma: a randomised controlled trial. Thorax 2009;64:55-61.

47. Ritz T, Rosenfield D, Steele AM, Millard MW, Meuret AE. Controlling asthma by training of Capnometry-Assisted Hypoventilation (CATCH) vs slow breathing: a randomized controlled trial. Chest 2014;146:1237-47.

48. Silverthorne. Human Physiology, an integrated approach. 7 ed: Pearson education limited; 2016.

49. Levitzky MG. Pulmonary Physiology. 8 ed: USA: McGraw-Hill companies; 2013.

50. Bjermer L. The nose as an air conditioner for the lower airways. Allergy 1999;54 Suppl 57:26-30.

51. Hallani M, Wheatley JR, Amis TC. Enforced mouth breathing decreases lung function in mild asthmatics. Respirology 2008;13:553-8.

52. Hallani M, Wheatley JR, Amis TC. Initiating oral breathing in response to nasal loading: asthmatics versus healthy subjects. Eur Respir J 2008;31:800-6.

53. Astma. Tine Munk. (Accessed November 19, 2016, at https://www.nordsjaellandshospital.dk/afdelinger-og-klinikker/lunge-og-infektionsmedicinsk-afdeling/information-om-sygdom-og-behandling/Sider/astma.aspx.)

54. Zimmerman MI, Miller A, Brown LK, Bhuptani A, Sloane MF, Teirstein AS. Estimated vs Actual Values for Dead Space/Tidal Volume Ratios During Incremental Exercise in Patients Evaluated for Dyspnea. Chest 1994;106:131-6.

58

55. Bowler SD, Green A, Mitchell CA. Buteyko breathing techniques in asthma: a blinded randomised controlled trial. Med J Aust 1998;169:575-8.

56. Chalupa DC, Morrow PE, Oberdorster G, Utell MJ, Frampton MW. Ultrafine particle deposition in subjects with asthma. Environmental health perspectives 2004;112:879-82.

57. Johnson BD, Scanlon PD, Beck KC. Regulation of ventilatory capacity during exercise in asthmatics. J Appl Physiol (1985) 1995;79:892-901.

58. Wasserman K HJ, Sue DY, Stringer WW, Whipp BJ. Principles of Exercise Testing and Interpretation: including pathophysiology and clinical applications. 4 ed: Philadelphia: Lippincott Williams & Wilkins; 2005.

59. Brewer LM OJ, Pace NL. Anatomic dead space cannot be predicted by body weight. . Respir Care Journal 2008;53.

60. Osborne CA, O'Connor BJ, Lewis A, Kanabar V, Gardner WN. Hyperventilation and asymptomatic chronic asthma. Thorax 2000;55:1016-22.

61. Meuret AE, Ritz T. Hyperventilation in panic disorder and asthma: empirical evidence and clinical strategies. International journal of psychophysiology : official journal of the International Organization of Psychophysiology 2010;78:68-79.

62. Laffey JG, Kavanagh BP. Hypocapnia. New England Journal of Medicine 2002;347:43-53.

63. Urso DL, Daniele V, Formaro L, Urso G. [Diagnosis and treatment of asthma]. Recenti progressi in medicina 2012;103:284-7.

64. Fredberg JJ. Airway smooth muscle in asthma: flirting with disaster. Eur Respir J 1998;12:1252-6.

65. Fenger RV, Gonzalez-Quintela A, Vidal C, et al. The longitudinal relationship of changes of adiposity to changes in pulmonary function and risk of asthma in a general adult population. BMC pulmonary medicine 2014;14:208.

66. Gudjonsdottir MA, L. Baderna, P. Purro, A. Patessio, A. Vilianis, G. Pastorelli, M. Sigurdsson, S.B. Donner, C.F. Diaphragm fatigue during exercise at high altitude: the role of hypoxia and workload. European Respiratory Journal 2001;17:674-80.

67. Gudjonsdottir M, Thoroddsen E, Karlsdottir AE, Kristjánsdottir A, Jonasson MR, Asgeirsdottir M. Effect of exercise training on ventilation in patients with COPD or chronic heart failure. European Respiratory Journal 2012;40.

68. Dempsey JA, Smith CA. Pathophysiology of human ventilatory control. Eur Respir J 2014;44:495-512.

69. Feldman JL, Del Negro CA, Gray PA. Understanding the rhythm of breathing: so near, yet so far. Annu Rev Physiol 2013;75:423-52.

70. Nishino T, Sugimori K, Ishikawa T. Changes in the period of no respiratory sensation and total breath-holding time in successive breath-holding trials. Clinical science (London, England : 1979) 1996;91:755-61.

71. Jerath R, Crawford MW, Barnes VA, Harden K. Self-regulation of breathing as a primary treatment for anxiety. Appl Psychophysiol Biofeedback 2015;40:107-15.

72. Kreibig SD. Autonomic nervous system activity in emotion: a review. Biol Psychol 2010;84:394-421.

59

73. Farrow JT, Hebert JR. Breath suspension during the transcendental meditation technique. Psychosom Med 1982;44:133-53.

74. Wolkove N, Kreisman H, Darragh D, Cohen C, Frank H. Effect of transcendental meditation on breathing and respiratory control. J Appl Physiol Respir Environ Exerc Physiol 1984;56:607-12.

75. Duffin J. Role of acid-base balance in the chemoreflex control of breathing. J Appl Physiol (1985) 2005;99:2255-65.

76. Spyer KM, Gourine AV. Chemosensory pathways in the brainstem controlling cardiorespiratory activity. Philos Trans R Soc Lond B Biol Sci 2009;364:2603-10.

77. Kassabian J, Miller KD, Lavietes MH. Respiratory center output and ventilatory timing in patients with acute airway (asthma) and alveolar (pneumonia) disease. Chest 1982;81:536-43.

78. Hida W. Role of ventilatory drive in asthma and chronic obstructive pulmonary disease. Curr Opin Pulm Med 1999;5:339-43.

79. Courtney R, Greenwood KM, Cohen M. Relationships between measures of dysfunctional breathing in a population with concerns about their breathing. Journal of Bodywork and Movement Therapies 2011;15:24-34.

80. Bradley H, Dr. Esformes J. BREATHING PATTERN DISORDERS AND FUNCTIONAL MOVEMENT. International Journal of Sports Physical Therapy 2014;9:28-39.

81. Slader CA, Reddel HK, Spencer LM, et al. Double blind randomised controlled trial of two different breathing techniques in the management of asthma. Thorax 2006;61:651-6.

82. Habedank D, Reindl I, Vietzke G, et al. Ventilatory efficiency and exercise tolerance in 101 healthy volunteers. Eur J Appl Physiol Occup Physiol 1998;77:421-6.

83. Wallace RK, Benson H, Wilson AF. A wakeful hypometabolic physiologic state. The American journal of physiology 1971;221:795-9.

84. Agha MA, El Wahsh RA. Basal metabolic rate in bronchial asthma and chronic obstructive pulmonary disease patients. Egyptian Journal of Chest Diseases and Tuberculosis 2013;62:39-44.

85. Abramson MJ, Walters J, Walters EH. Adverse effects of beta-agonists: are they clinically relevant? American journal of respiratory medicine : drugs, devices, and other interventions 2003;2:287-97.

86. Haffner CA, Kendall MJ. Metabolic effects of beta 2-agonists. Journal of clinical pharmacy and therapeutics 1992;17:155-64.

87. Rebuck AS, Chapman KR. Asthma: 1. Pathophysiologic features and evaluation of severity. CMAJ: Canadian Medical Association Journal 1987;136:351-4.

88. Magarian GJ. Hyperventilation syndromes: infrequently recognized common expressions of anxiety and stress. Medicine (Baltimore) 1982;61:219-36.

89. Han JN, Stegen K, Simkens K, et al. Unsteadiness of breathing in patients with hyperventilation syndrome and anxiety disorders. Eur Respir J 1997;10:167-76.

90. Roth WT. Physiological markers for anxiety: panic disorder and phobias. International journal of psychophysiology : official journal of the International Organization of Psychophysiology 2005;58:190-8.

60

91. Van den Elshout FJ, Van Herwaarden CL, Folgering HTM. Effects of hypercapnia and hypocapnia on respiratory resistance in normal and asthmatic subjects. . Thorax 1991;46:28-32.

92. Chen W, FitzGerald JM, Rousseau R, Lynd LD, Tan WC, Sadatsafavi M. Complementary and alternative asthma treatments and their association with asthma control: a population-based study. BMJ Open 2013;3.

93. Slader CA, Reddel HK, Jenkins CR, Armour CL, Bosnic-Anticevich SZ. Complementary and alternative medicine use in asthma: who is using what? Respirology 2006;11:373-87.

94. George M, Topaz M. A systematic review of complementary and alternative medicine for asthma self-management. The Nursing clinics of North America 2013;48:53-149.

95. Ernst E. Complementary therapies for asthma: what patients use. J Asthma 1998;35:667-71.

96. Holloway E, Ram FS. Breathing exercises for asthma. Cochrane Database Syst Rev 2004:CD001277.

97. Agache I, Ciobanu C, Paul G, Rogozea L. Dysfunctional breathing phenotype in adults with asthma - incidence and risk factors. Clin Transl Allergy 2012;2:18.

98. Bruton A, Lewith GT. The Buteyko breathing technique for asthma: a review. Complement Ther Med 2005;13:41-6.

99. Freitas DA, Holloway EA, Bruno SS, Chaves GS, Fregonezi GA, Mendonca KP. Breathing exercises for adults with asthma. Cochrane Database Syst Rev 2013;10:CD001277.

100. Jones M, Harvey A, Marston L, O'Connell NE. Breathing exercises for dysfunctional breathing/hyperventilation syndrome in adults. Cochrane Database Syst Rev 2013;5:CD009041.

101. Morgan M. DYSFUNCTIONAL BREATHING IN ASTHMA: IS IT COMMON, IDENTIFIABLE AND CORRECTABLE? Thorax 2002;57:ii31-ii5.

102. O’Connor EP, C.D. Burda, B.U. Buckley, D.I. Whitlock, E.P. Breathing Exercises and/or Retraining Techniques in the Treatment of Asthma: Comparative Effectiveness. Comparative Effectiveness Reviews 2012 71.

103. The British Thoracic Society Scottish Intercollegiate Guidelines Network. SIGN, 2014. (Accessed November 19, 2016, at http://www.sign.ac.uk.)

104. Bott JB, S. Buxton, M. Ellum, S. Falconer, C. Garrod, R. Harvey, A. Hughes, T. Lincoln, M. Mikelsons, C. Potter, C. Pryor, J. Rimington, L. Sinfield, F. Thompson, C. Vaughn, P. White, J. Guidelines for the physiotherapy management of the adult, medical, spontaneously breathing patient. Thorax 2009;64 Suppl 1:i1-51.

105. Abramson M BB DC, Giolando F, Hartley F. A randomised controlled trial of the Buteyko Method for asthma. Int J Immunorehabil 2004.

106. Cooper S, Oborne J, Newton S, et al. Effect of two breathing exercises (Buteyko and pranayama) in asthma: a randomised controlled trial. Thorax 2003;58:674-9.

107. Hassan ZM, Riad NM, Ahmed FH. Effect of Buteyko breathing technique on patients with bronchial asthma. Egyptian Journal of Chest Diseases and Tuberculosis 2012;61:235-41.

108. McHugh P, Aitcheson F, Duncan B, Houghton F. Buteyko Breathing Technique for asthma: an effective intervention. N Z Med J 2003;116:U710.

61

109. Opat AJ CM BM, Abramson MJ. . A clinical trial of the Buteyko Breathing Technique in asthma as taught by a video. J Asthma 2000;37(7):557-64.

110. Prem V, Sahoo RC, Adhikari P. Comparison of the effects of Buteyko and pranayama breathing techniques on quality of life in patients with asthma - a randomized controlled trial. Clinical rehabilitation 2013;27:133-41.

111. Cooper S, Oborne J, Harrison T, Tattersfield A. Effect of mouth taping at night on asthma control--a randomised single-blind crossover study. Respir Med 2009;103:813-9.

112. Courtney R. Strengths, Weaknesses, and Possibilities of the Buteyko Breathing Method. Biofeedback; 2008:59-63.

113. Jack S, Rossiter HB, Pearson MG, Ward SA, Warburton CJ, Whipp BJ. Ventilatory Responses to Inhaled Carbon Dioxide, Hypoxia, and Exercise in Idiopathic Hyperventilation. Am J Respir Crit Care Med 2004;170:118-25.

114. Read DJ. A clinical method for assessing the ventilatory response to carbon dioxide. Australasian annals of medicine 1967;16:20-32.

115. Bruton A, Holgate ST. Hypocapnia and asthma: a mechanism for breathing retraining? Chest 2005;127:1808-11.

116. Jia CE, Zhang HP, Lv Y, et al. The Asthma Control Test and Asthma Control Questionnaire for assessing asthma control: Systematic review and meta-analysis. J Allergy Clin Immunol 2013;131:695-703.

117. Schatz M, Sorkness CA, Li JT, et al. Asthma Control Test: Reliability, validity, and responsiveness in patients not previously followed by asthma specialists. Journal of Allergy and Clinical Immunology 2006;117:549-56.

118. Buteyko clinic. 2016. (Accessed June 11, 2016, at http://buteykomoscow.ru/bkp/.)

119. Voronesz center. 2016. (Accessed June 11, 2016, at http://www.buteyko.ru/eng/sciizd.shtml.)

120. van Dixhoorn J, Duivenvoorden HJ. Efficacy of Nijmegen Questionnaire in recognition of the hyperventilation syndrome. J Psychosom Res 1985;29:199-206.

121. Hirsch JA, Bishop B. Human breathing patterns on mouthpiece or face mask during air, CO2, or low O2. Journal of Applied Physiology 1982;53:1281-90.

122. Pain MC, Biddle N, Tiller JW. Panic disorder, the ventilatory response to carbon dioxide and respiratory variables. Psychosom Med 1988;50:541-8.

123. Shershow JC, King A, Robinson S. Carbon dioxide sensitivity and personality. Psychosom Med 1973;35:155-60.

124. Macnutt MJ, De Souza MJ, Tomczak SE, Homer JL, Sheel AW. Resting and exercise ventilatory chemosensitivity across the menstrual cycle. J Appl Physiol (1985) 2012;112:737-47.

125. O'Cain CF, Hensley MJ, McFadden ER, Jr., Ingram RH, Jr. Pattern and mechanism of airway response to hypocapnia in normal subjects. J Appl Physiol Respir Environ Exerc Physiol 1979;47:8-12.

126. Strider JW, Masterson CG, Durham PL. Treatment of mast cells with carbon dioxide suppresses degranulation via a novel mechanism involving repression of increased intracellular calcium levels. Allergy 2011;66:341-50.

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127. Matsumoto K, Aizawa H, Fukuyama S, et al. Low-dose salbutamol suppresses airway responsiveness to histamine but not methacholine in subjects with asthma. Respiratory investigation 2013;51:158-65.

128. Lundberg JO, Weitzberg E. Nasal nitric oxide in man. Thorax 1999;54:947-52.

129. Elnaggar R, Shendy M. Efficacy of noninvasive respiratory techniques in the treatment of children with bronchial asthma: a randomized controlled trial. Bulletin of Faculty of Physical Therapy 2016;21:1-10.

130. McHugh P, Duncan B, Houghton F. Buteyko breathing technique and asthma in children: a case series. N Z Med J 2006;119:U1988.

131. Austin G, Brown C, Watson T, Chakravorty I. Buteyko Breathing Technique Reduces Hyperventilation-Induced Hypocaponea and Dyspnoea after Exercise in Asthma. Am J Respir Crit Care Med 2009;179:A3409.

63

Appendix A

64

Appendix B

FYLGISKJAL 3a

Vegna vísindarannsóknarinnar

„Hvernig hefur öndun áhrif á einkenni og stjórnun astma sjúkdómsins?“

Samþykkisyfirlýsing fyrir þátttakendur með astma.

Markmið og tilgangur rannsóknarinnar er að kanna hvort og hvernig Buteyko öndunarmeðferð hafi áhrif á einkenni og stjórnun á astmasjúkdómnum. Meðferðin byggir á því að með öndunaræfingum sé hægt að minnka astmi einkenni og lyfjanotkun. Niðurstöðurnar geta verið gagnlegar fyrir bættan skilning á astmasjúkdómnum.

Þátttaka í rannsókninni felur í sér að taka þátt í öndunarmeðferð í hópi og halda áfram reglubundnum æfingum samkvæmt leiðbeiningum í allt að sex mánuði. Jafnframt að halda dagbók um lyfjanotkun og líðan. Þátttakan felur einnig í sér að mæta alls þrisvar sinnum í mælingar á Reykjalund á árs tímabili, sem taka um hálfa klukkustund í senn.

Ég staðfesti hér með undirskrift minni að ég hef lesið upplýsingarnar um rannsóknina sem mér voru afhentar, hef fengið tækifæri til að spyrja spurninga um rannsóknina og fengið fullnægjandi svör og útskýringar á atriðum sem mér voru óljós. Ég hef af fúsum og frjálsum vilja ákveðið að taka þátt í rannsókninni.

Mér er ljóst að þó ég hafi skrifað undir þessa samstarfsyfirlýsingu, get ég hætt þátttöku hvenær sem er án útskýringa og án áhrifa á þá læknisþjónustu sem ég á rétt á í framtíðinni.

Mér er ljóst að rannsóknargögnum verður eytt að rannsókn lokinni og eigi síðar en eftir 5 ár frá úrvinnslu rannsóknargagna.

____________________

Dagsetning

___________________________________________________

Nafn þátttakanda

Undirritaður, starfsmaður rannsóknarinnar, staðfestir hér með að hafa veitt upplýsingar um eðli og tilgang rannsóknarinnar, í samræmi við lög og reglur um vísindarannsóknir.

Undirskrift:___________________________________ Dagsetning:____________________

65

FYLGISKJAL 3b

Vegna vísindarannsóknarinnar


Samþykkisyfirlýsing fyrir þátttakendur í samanburðarhópi.

Markmið og tilgangur rannsóknarinnar er að kanna hvort og hvernig Buteyko öndunarmeðferð hafi áhrif á einkenni og stjórnun á astmasjúkdómnum. Niðurstöðurnar geta verið gagnlegar fyrir bætann skilning á astmasjúkdómnum.

Þátttaka í rannsókninni felst í því að mæta í mælingar tvisvar sinnum á Reykjalund með 6 mánaða millibili. Hvor heimsókn tekur hálfa klukkustund og er þátttakanda að kostnaðarlausu.

Ég staðfesti hér með undirskrift minni að ég hef lesið upplýsingarnar um rannsóknina sem mér voru afhentar, hef fengið tækifæri til að spyrja spurninga um rannsóknina og fengið fullnægjandi svör og útskýringar á atriðum sem mér voru óljós. Ég hef af fúsum og frjálsum vilja ákveðið að taka þátt í rannsókninni.

Mér er ljóst að þó ég hafi skrifað undir þessa samstarfsyfirlýsingu, get ég stöðvað þátttöku mína hvenær sem er án útskýringa og án áhrifa á þá læknisþjónustu sem ég á rétt á í framtíðinni.

Mér er ljóst að rannsóknargögnum verður eytt að rannsókn lokinni og eigi síðar en eftir 5 ár frá úrvinnslu rannsóknargagna.

____________________

Dagsetning

___________________________________________________

Nafn þátttakanda

Undirritaður, starfsmaður rannsóknarinnar, staðfestir hér með að hafa veitt upplýsingar um eðli og tilgang rannsóknarinnar, í samræmi við lög og reglur um vísindarannsóknir.

Undirskrift:___________________________________

Dagsetning:____________________

66

Appendix C

FYLGISKJAL 2a

Upplýsingar vegna vísindarannsóknar.


Ábyrgðamaður rannsóknarinnar er : Dr.Marta Guðjónsdóttir, lífeðlisfræðingur, lektor við Læknadeild Háskóla Íslands og rannsóknastjóri á Reykjalundi.

Sími: 8679890 Tölvupóstfang: [email protected]

Aðrir rannsakendur eru: Monique van Oosten, sjúkraþjálfari, Buteykoþjálfari og meistaranemi í lýðheilsuvísindum.

Sími: 8998456. Tölvupóstfang: monique@centrum

Kæri viðtakandi.

Rannsóknin „Hvernig hefur öndun áhrif á einkenni og stjórnun astma sjúkdómsins“ er meistaraverkefni Monique van Oosten sjúkraþjálfara við námsbraut í Lýðheilsuvísindum við Læknadeild Háskóla Íslands. Leiðbeinandi hennar er Dr. Marta Guðjónsdóttir. Þér er boðið að taka þátt í rannsókninni þar sem þú hafðir samband við Monique í framhaldi af auglýsingu.

Tilgangur rannsóknarinnar er að kanna hvort og hvernig öndunarmeðferð (Buteyko) hafi áhrif á einkenni og stjórnun á astmasjúkdómnum. Buteyko öndunarmeðferðin er viðurkennd meðferð, hún hefur sýnt mjög góðan árangur og stangast ekki á við hefðbundnar meðferðir. Meðferðin byggir á því að með öndunarmeðferð sé hægt að minnka astmaeinkenni og lyfjanotkun.

Þér er boðin að taka þátt ef þú ert 18 ára og eldri, hefur greinst með astma sjúkdóminn, hefur haft þörf fyrir stuttverkandi berkjuvíkkandi lyf eins og Ventolin, einu sinni í viku eða oftar undanfarnar fjórar vikur og ert tilbúin að taka þátt í meðferð og stunda öndunaræfingar reglulega. Ekki verður greitt fyrir þátttöku en mælinga og meðferð verður þáttakendum að kostnaðarlausu. Ef þátttakandi óskar þess munu rannsakendur senda lækni viðkomandi niðurstöður mælinganna sem gerðar eru.

67

FYLGISKJAL 2a

Í hverju felst þátttakan? Þátttaka varir í 12 mánuði og gert er ráð fyrir:

� Þremur heimsóknum á Reykjalund, endurhæfingarmiðstöð SÍBS með 6 mánaða millibili. Hver heimsókn tekur um það bil 30 mínútur þar sem mæld verður öndun, blóðþrýstingur, hæð og þyngd. Því til viðbótar eiga þátttakendur að fylla út spurningarlista um astma með fimm spurningum sem tekur um 5-10 mínútur að svara. Lyfjanotkun verður skráð.

� Þátttöku í 8-9 manna hópi sem mætir í 5 skipti í öndunarmeðferð, í 2 klukkustundir í senn á tveggja og hálfs vikna tímabili. Eftirfylgd verður eftir þrjá mánuði til að meta árangurinn. Hugmyndafræði og Buteyko öndunaræfingar verða kenndar og gert er ráð fyrir að þátttakendur stundi æfingar heima í 15 til 30 mínútur daglega.

� Að halda dagbók um líðan og lyfjanotkun.

Monique van Oosten mun veita frekari upplýsingar í síma eða tölvupósti um meðferðina ef þörf krefur allt rannsóknartímabilið.

Áhætta og ávinningur: Áhætta af þátttöku er engin en beinn ávinningur er fyrir þátttakendur þar sem mjög góð reynsla er af öndunarmeðferðinni þar sem vísindarannsóknir benda til að meðferðin minnki verulega þörf astmasjúklinga fyrir lyf og auki lífsgæði þeirra. Auk þess fá þátttakendur mælingar sér að kostnaðarlausu. Niðurstöðurnar af rannsókninni geta verið gagnlegar fyrir bættan skilning á astmasjúkdómnum og meðferð við honum. Rannsókn þessi er gerð með samþykki Vísindasiðanefndar og hún hefur verið tilkynnt Persónuvernd.

Aðgengi að rannsóknargögum: Allar upplýsingar sem þátttakendur veita í rannsókninni, verða meðhöndlaðar samkvæmt ströngustu reglum um trúnað og nafnleynd og farið að íslenskum lögum varðandi persónuvernd, vinnslu og eyðingu frumgagna. Í tölfræðilegum úrvinnsluskrám koma ekki fram nöfn og kennitölur þátttakenda heldur fær hver og einn sitt númer sem ábyrgðamaður heldur einn skrá yfir. Rannsóknargögn verða varðveitt á öruggum stað hjá ábyrgðarmanni á meðan á rannsókn stendur og öllum gögnum verði eytt að rannsókn lokinni.

Þér er ekki skylt að taka þátt í rannsókninni og þú getur hætt við þátttöku hvenær sem er, án frekari útskýringa. Afstaða þín mun ekki hafa áhrif á þá þjónustu heilbrigðiskerfisins sem þú kannt að þurfa í framtíðinni.

Frekari upplýsingar: Ef þú hefur áhuga að taka þátt í rannsókninni eða fá frekari upplýsingar, vinsamlegast hafðu samband við Monique van Oosten, sjúkraþjálfara í síma 8998456

Með von um góða undirtektir,

Dr. Marta Guðjónsdóttir, lektor og ábyrgðarmaður rannsóknarinnar.

Monique van Oosten, sjúkraþjálfari, Buteykoþjálfari og meistaranemi í lýðheilsuvísindum.

________________________________

Ef þú hefur spurningar um rétt þinn sem þátttakandi í vísindarannsókn eða vilt hætta þátttöku í rannsókninni getur þú snúið þér til Vísindasiðanefndar, Hafnarhúsinu, Tryggvagötu 17, 101Reykjavík. Sími: 551-7100, fax: 551-1444, tölvupóstfang: [email protected].

68

FYLGISKJAL 2b

Upplýsingar vegna vísindarannsóknarinnar:


Ábyrgðamaður rannsóknarinnar er : Dr.Marta Guðjónsdóttir,

lífeðlisfræðingur, lektor við Læknadeild Háskóla Íslands og rannsóknastjóri á Reykjalundi, Sími: 8679890 Tölvupóstfang: [email protected]

Aðrir rannsakendur eru: Monique van Oosten, sjúkraþjálfari, Buteykoþjálfari og meistaranemi í lýðheilsuvísindum.

Sími: 8998456. Tölvupóstfang: monique@centrum

Kæri viðtakandi.

Rannsóknin, Hvernig hefur öndun áhrif á einkenni og stjórnun astma sjúkdómsins“ er meistaraverkefni Monique van Oosten sjúkraþjálfara við námsbraut í Lýðheilsuvísindum við Læknadeild Háskóla Íslands. Leiðbeinandi hennar er Dr. Marta Guðjónsdóttir. Þér er boðið að taka þátt í rannsókninni þar sem þú hafðir samband við Monique í framhaldi af auglýsingu.

Tilgangur rannsóknarinnar er að kanna hvort og hvernig öndunarmeðferð (Buteyko) hefur áhrif á einkenni og stjórnun á astmasjúkdómnum.

Þér er boðin að taka þátt ef þú ert 18 ára og eldri, hefur ekki greinst með astma sjúkdóminn, notar ekki heilsutengd lyf og hefur ekki tekið þátt í öndunarmeðferð eins og Buteyko meðferðinni.

69

FYLGISKJAL 2b

Þátttaka felst í tveim heimsóknum á Reykjalund, endurhæfingarmiðstöð SÍBS, með 6 mánaða millibili, þar sem hver heimsókn tekur um það bil 30 mínútur. Í heimsóknunum verður öndun, blóðþrýstingur, hæð og þyngd mæld. Ekki verður greitt fyrir þátttöku en mælingarnar verður þáttakendum að kostnaðarlausu. Áhætta og ávinningur: Áhætta af þátttöku er engin en ávinningur er að niðurstöður rannsóknarinnar geta verið gagnlegar fyrir bættan skilning á astmasjúkdómnum. Rannsóknin er unnin með samþykki Vísindasiðanefndar og hefur verið tilkynnt til Persónuverndar.

Aðgengi að rannsóknargögnum: Allar upplýsingar sem þátttakendur veita í rannsókninni, verða meðhöndlaðar samkvæmt ströngustu reglum um trúnað og nafnleynd og farið að íslenskum lögum varðandi persónuvernd, vinnslu og eyðingu frumgagna. Í tölfræðilegum úrvinnsluskrám koma ekki fram nöfn og kennitölur þátttakenda heldur fær hver og einn sitt númer sem ábyrgðamaður heldur einn skrá yfir. Rannsóknargögn verða varðveitt á öruggum stað hjá ábyrgðarmanni á meðan á rannsókn stendur og öllum gögnum verði eytt að rannsókn lokinni. Þér er ekki skylt að taka þátt í rannsókninni og þú getur hætt við þátttöku hvenær sem er, án frekari útskýringa. Afstaða þín mun ekki hafa áhrif á þá þjónustu heilbrigðiskerfisins sem þú kannt að þurfa í framtíðinni Frekari upplýsingar: Ef þú hefur áhuga að taka þátt í rannsókninni eða fá frekari upplýsingar, vinsamlegast hafðu samband við Monique van Oosten í síma 8998456 eða með tölvupósti: monique@centrum

Með von um góðar undirtektir,

Marta Guðjónsdóttir, lektor og ábyrgðarmaður rannsóknarinnar.

Monique van Oosten, sjúkraþjálfari, Buteykoþjálfari og meistaranemi í lýðheilsuvísindum.

________________________________________

Ef þú hefur spurningar um rétt þinn sem þátttakandi í vísindarannsókn eða vilt hætta þátttöku í rannsókninni getur þú snúið þér til Vísindasiðanefndar, Hafnarhúsinu, Tryggvagötu 17, 101Reykjavík. Sími: 551-7100, fax: 551-1444, tölvupóstfang: [email protected].

70

Appendix D

Mat á astmastjórn (ACTTM)

Sjúklinganúmer:___________________

Dagsetning:______________________

Eftirfarandi mat getur auðveldað fólki með astma (12 ára og eldra) að meta astmastjórn sína.

Alls eru FIMM spurningar. Dragðu hring um svarið þitt við hverri spurningu. Svaraðu eins

hreinskilningslega og hægt er.

Þú færð heildarniðurstöðu úr mati þínu á astmastjórnun með því að leggja saman stigin þín fyrir

hvert svar.

1. Síðastliðnar 4 vikur, hversu oft kom astminn í veg fyrir að þú kæmir jafn miklu í verk í vinnu, skóla eða heima?

1) alltaf

2) oftast

3) stundum

4) sjaldan

5) aldrei

2. Síðastliðnar 4 vikur, hve oft hefurðu fundið fyrir mæði? 1) Oftar en einu sinni á dag

2) Einu sinni á dag

3) 3 til 6 sinnum í viku

4) Einu sinnu til tvisvar í viku

5) Alls ekki

3. Síðastliðnar 4 vikur, hversu oft vaknaðir þú um nótt eða fyrr en vanalega að morgni vegna einkenna astmans (blásturshljóðs í lungum, hósta, mæði, þrengsla eða verkjar fyrir brjósti)?

1) 4 eða fleiri nætur í viku

71

2) 2 til 3 nætur í viku

3) Einu sinni í viku

4) Einu sinni eða tvisvar

5) Alls ekki

4. Síðastliðnar 4 vikur, hversu oft hefurðu notað neyðarúðann þinn eða innúðalyf (eins

og Ventolin®, Bricanyl® eða Salbutamol NM Pharma®)?

1) 3 eða oftar á dag

2) 1 sinni eða 2 á dag

3) 2 sinnum eða 3 í viku

4) Einu sinni í viku eða sjáldnar

5) Alls ekki

5. Hvaða einkunn myndirðu gefa astmastjórn þinni síðastliðnar 4 vikur? 1) Alls engin stjórn

2) Léleg stjórn

3) Nokkur stjórn

4) Góð stjórn

5) Algjör stjórn

Leggðu nú saman stigin þín.

Samtals:__________________stig. Stig: 25 – Til hamingju. Þú hefur haft algera stjórn á astmanum síðastliðnar 4 vikur. Þú hefur engin einkenni haft og

astminn hefur ekkert hamlað þér. Leitaðu til læknis eða hjúkrunarfræðings ef það breytist. Stig: 20-24 – Á réttri leið. Astmanum hefur e.t.v. verið STJÓRNAÐ VEL, síðastliðnar 4 vikur, en ekki STJÓRNAÐ

ALGERLEGA. Læknir eða hjúkrunarfræðingur gæti hjálpað þér að stefna að ALGERRI STJÓRN.

Stig: færri en 20 – Ekki á réttri leið. Astmanum hefur e.t.v. EKKI VERIÐ STJÓRNAÐ síðastliðnar 4 vikur. Læknir eða

hjúkrunarfræðingur getur mælt með aðgerðaráætlun til að takast á við astmann svo þú náir betri stjórn á honum.

Notað með leyfi GSK á Íslandi.

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Appendix E

ASTMA DAGBÓK

Þessi astma dagbók getur hjálpað okkur að halda utan um þína astmastjórnun.

� Skráðu sjúklingsnúmer og mánuð.

� Einkenni: Notaðu dagbókina til að skrá ef breyting er á einkennum þínum; Skráðu alvarleika: 1 = væg; 2 = meðallagi; 3 = alvarleg.

� Ofnæmisvakar: Skráðu og krossaðu við þegar þú hefur komið í snertingu við einn af mögulegum ofnæmisvökum þínum (t.d. gæludýr, reykingar, frjókorn o.s.frv.).

� Lyfjanotkun: Skráðu og krossaðu við þegar þú hefur tekið neyðarlyf. Skráðu og krossaðu einnig við þegar breyting er á lyfjanotkun sem þú tekur að staðaldri.

� Breath holding time: Þessi mæling byrjar þú að skrá þegar þú ert byrjaður/-uð að æfa samkvæmt öndunarmeðerðinni.

� Astma control test. Þetta fyllir þú út á sama tíma einu sinni á mánuði. Hér áttu að skrá tölustafi samkvæmt ACT leiðbeininum.

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Appendix F

Effect of the Buteyko Method on Resting Ventilation and Asthma Control in Asthma …°... · 2019. 3. 18. · 5 Abstract Background: The Buteyko method (BM) seems to change breathing

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