Tezko dihanje -

Dyspnea in patients with advanced disease

Ljubjana, 20.102017

Gudrun Kreye

Division for Palliative Care, 2. Medizinische Abteilung, University Hospital Krems

No conflict of interest to declare

Patient F. M., 10.5.1975

• Osteosarcoma of the right hip

• Lung metastases

• Multiple chemotherapies

• Fluidopneumothorax right side

• Surgical procedure for fluidopneumothorax

• Pneumonia both sides

Patient F. M., 10.5.1975

Patient F. M., 10.5.1975 –Treatment options in

this acute situation?

• Immediate 6th-line chemotherapy

• Therapy with checkpoint-inhibitor therapy

• Opioids

• Palliative sedation

• Another surgical procedure

Patient F. M., 10.5.1975 –Treatment options in

this acute situation?

• Immediate 6th-line chemotherapy

• Therapy with checkpoint-inhibitor therapy

• Opioids

• Palliative sedation

• Another surgical procedure

Patient O.K. ,81 years

• Advanced lung cancer

• Acute dyspnea

• Symptoms of angina pectoris

• X-ray of the lung: stable, no new lesions

• Hb 5,6 g/dl

• Patient wants every treatment possible

Therapy??

Patient O.K. ,81 years -Therapy

• Immediate start of chemotherapy

• Furosemide

• Opioids

• Immediate blood transfusion

• Benzodiazepines

Patient O.K. ,81 years -Therapy

• Immediate start of chemotherapy

• Furosemide

• Opioids

• Immediate blood transfusion

• Benzodiazepines

Female patient A.S., 63

• Advanced breast cancer

• ECOG 3

• Lymphangiosis carcinomatosa

• Chronic dyspnea

Therapy??

Female patient A.S., 63

• Another chemotherapy

• Opioids

• Corticosteroids

• Furosemide

• Blood transfusion

Female patient A.S., 63

• Another chemotherapy

• Opioids

• Corticosteroids (although low

evidence)

• Furosemide

• Blood transfusion

Definition of Dyspnea

American Thoracic Society defines dyspnea

as an individual’s sensation of breathing

discomfort arising from various physiological,

psychological, social, and environmental

circumstances

Dyspnea ATSCo. Dyspnea. Mechanisms, assessment, and management: aconsensusstatement. AmJRespirCritCareMed.

1999;159(1):321–40

Physiology of breathing

• Defined as the movement of oxygen from the outside

environment to the cells within tissues, and the transport of

carbon dioxide in the opposite direction

• Most important internal impulse : pCO², pH - blood

• Less important: pO² in arterial blood

Receptors for pH-value and hypoxemia

• Less important as breathing stimulator

• Localisation:

– Aortic arch

– Bifurcation of carotis

– Breathing center in the brain

Other stimuli for breathing: :

• Expansion of the lung (Hering-Breuer-Reflex)

• Consciousness

Physiology of breathing

Quantification of Dyspnea

Goldstandard: ?

*JR Thomas and v Gunten C, Lancet Oncology 2002

Respiratory rate?

Quantification of Dyspnea

• Goldstandard:

– Subjective report of the patient

• Respiratory rate, oxygensaturation, blood

gas analysis:

– Do not correlate with severity of dyspnoea

– No measurement tool for patients

*JR Thomas and v Gunten C, Lancet Oncology 2002

• Visual analogue scale*

•

• Borg Scale**

•

• Edmonton Rating Scale***

* Adams L et al, Clin Sci 1985

** Med Sci Sports Exerc 1982

*** Driver LC et al, MD Anderson Palliative Care Handbook 2002

Quantification of dyspnea for palliative care patients

Dyspnoea in palliative care

• Cancer

• Neurologic diseases

• Pneumologic diseases

• Cardial diseases

Prevalence of dyspnea in palliative care patients

• COPD: 90–95 %

• Chronic heart failure: 60–88 %

• Advanced cancer: ca. 50 %.1, 2 according to stage 19-

76%

• Pulmonal hypertension

• Increasing with disease progression 49-94%3, 4

Ripamonti et al. Supp Care Cancer 1999

Muers MF et al, Thorax 1993,

Higginson I et al, JR Soc Med 1989;

Reuben DB et al. Chest 1986)

Solano JP et al., J Pain Symptom Manage 2006

Altfelder N et al., Palliative Medicine 2010

Currow DC et al., J Pain Symptom Manage 2010

Bausewein C et al., Palliat Med 2010

Physician attitudes toward palliative care for patients with pulmonary

arterial hypertension: results of a cross-sectional survey

Fenstad ER et al. Pulm Circ. 2014

Physician attitudes toward palliative care for patients with pulmonary

arterial hypertension: results of a cross-sectional survey

Fenstad ER et al. Pulm Circ. 2014

“The most frequent reasons for not referring patients to PC included nonapproval

by the patient/family (51%) and concern that PC is "giving up hope" (43%)”

• Present in 70% of all patients in their last weeks of life

• Severe in 25 % of all cancer patients *

• Dyspnea = independent prognostic parameter for shorter

survival*

* Reuben DB et al, Archives of Internal Medicine 1988

Prevalence of dyspnea in cancer care patients

Dyspnea: independent prognostic parameter for shorter survival *

Arrieta O et al., Lung Cancer 77, 2012, 205–211

Case report dyspnea

Case report dyspnea

Case report dyspnea

Investigations in palliative care patients with dyspnea

suggested by medical students

G. Pohl, WMW 2011

Case report dyspnea

Case report dyspnea

Treatment options for palliative care patients as selected by

medical students

G. Pohl, WMW 2011

Treatment options for palliative care patients

Non-pharmacological treatment of dyspnoea

• Try to be calm

• Prepare emergency plan in advance

• Psychological help

• Physiotherapy

• Change position

• Breathing

• Relaxation techniques

• Stay with the patient- avoid isolation

• Technical aids: ventilator, fan,

• Open window

Nava S. et al. Lancet Oncol. 2013

Pharmacological treatment of dyspnea

Opioids

Benzodiazepines?

Other drugs Anxiolytics/Antidepressants

Neuroleptic drugs?

Corticosteroids?

Kamal AH et al. J Palliat. Medicine 2012

Booth S. Palliat. Med. 2013

Ekström et al. BMJ 2015

Opioide-Rationale

• Reduce ventilatory drive to hypercapnia, hypoxia and

exertion

• Activation of µ und d-opioidreceptors reduces

inspiratory volume and volume per minute

*Bianchi A et al. J Pain and Symptom management, 1995)

Opioids – mechanism of action

• Still unclear

• Naloxon enhances dyspnea* - role of endogeneous opioids?

• PET-Scan: cortical areas correlating with dyspnea**

* Akiyama et al., J Appl Physiol 1993

** Peiffer et al. Am J Respir Crit Care Med 2001

Opioids in palliative care patients withs dyspnea

• Pharmacological firstline-therapy

• Only therapy with benefit

• No signs for respiratory depression when adequately

titrated

• No significant chances in oxygen saturation

• No significant elevations of carbon dioxide

Jennings AL et al. Thorax 2002

Abernethy et al. BMJ 2003

Currow DC et al., J Pain Symptom Manage 2011

Ben-Aharon I et al. Acta Oncol 2012

Kamal AH et al. J Palliat. Medicine 2012

Booth S. Palliat. Med. 2013

Abernethy et al. BMJ 2015

Lopez-Saca JM et al. Curr Opp Supp Pall Care 2014

Bausewein C. Internist (Berl). 2016 Oct;57(10):978-982.

Chin C, Booth. Postgrad Med J. 2016 Jul;92(1089):393-400. doi:

10.1136/postgradmedj-2015-133578. Epub 2016 Apr 6.

Opioids for patients with advanced COPD

• Systematic review/meta-analysis (Cochrane)

• 16 studies included

• 271 patients (95% with severe COPD)

• Sigificant reduction of dysnea by using opioids

Ekström M. et al. Effects of Opioids on Breathlessness and Exercise Capacity in Chronic Obstructive Pulmonary Disease: A Systematic

Review. Ann Am Thorac Soc. 2015 Mar 24

Pharmacological treatment of dyspnea with opioids

Opioidnaïve Opioid tolerant*

Mild dyspnea Hydrocodone (5-10 mg) or

Codeine (30 mg) p.o. every 4 h,

Then retarded formulation

Dose escalation 25%

to 50%

Severe dyspnea Morphine 5 mg p.o. every

4h oder

Oxycodone 5 mg every 4 h oder

Hydromorphon 1 mg every 4 h

Dose escalation 25%

to 50%

Parenteral Morphin 2.5 – 5mg s.c. or

i.v. 3-4 h or 10-30 mg/24h s.c. or

i.v.

Dose escalation 25%

to 50%

Titration Dose related escalation 30% Dose related escalation

30%

Jennings AL et al. Thorax 2002

Abernethy et al. BMJ 2003

Currow DC et al., J Pain Symptom Manage 2011

Fentanyl for dyspnea?? C.o. Thomas Sitte

Fentanyl forDyspnoe Simon ST et al., J Pain Symptom Management 2013

622 citations

13! Studies included

88 patients

69 lung cancer 16 COPD

Episodisch-kontinuierlich

Nebulized Fentanyl: 70

OFTC: 9

Intranasal: 5

Transdermal: 3

i.v.-Remifentanyl: 1

Only 2 RCTs!

Fentanyl for dyspnea Simon ST et al., J Pain Symptom Management 2013

• 622 citations

• 13 included

• Only 2 randomized controlled studies

• All studies showed improvement of dyspnea after application

• No respiratory depression by fentanyl!

• Large randomized studies necessary

Pharmacological treatment of dyspnea

Benzodiazepines

• Currently no benefit as firstline therapy

• No signs of respiratory depression

• Second or thirdline after opioid failure

•Simon, Bausewein et al. 2009

•Simon ST et al., Cochrane Database Syst Rev 2010

** JR Thomas and v Gunten C, Lancet Oncology 2002

** Mitchell-Heggs et al, QJM 1980

*** Woodcock AA, BMJ 1981

**** Man CG , Lancet 1993

° Gomutbutra P et al. J Pain Symptom Manag 2013

Pharmacological treatment of dyspnea

Benzodiazepines Dosage

• Lorazepam: 0.5-1mg /h p.o., then every 4-6h

• Diazepam: 5-10mg/h p.o., then every 6-8h

• Clonazepam: 0.25-2 mg p.o. every 12h

• Midazolam: 0.5 mg i .v. 15 min until symptom controllm then

continously

*JR Thomas and v Gunten C, Lancet Oncology 2002

Benzodiazepines for the relief of breathlessness in

advanced malignant and non-malignant diseases in adults.

Cochrane Database Syst Rev. 2016 Oct 20;10:CD007354. Bausewein

C et al.:

• There is no evidence for or against benzodiazepines for the relief of

breathlessness in people with advanced cancer and COPD.

• Benzodiazepines caused more drowsiness as an adverse effect

compared to placebo, but less compared to morphine.

• Benzodiazepines may be considered as a second- or third-line

treatment, when opioids and non-pharmacological measures have

failed to control breathlessness.

• There is a need for well-conducted and adequately powered studies.

Pharmacological treatment of dyspnea

Other drugs

• Anxiolytics/Antidepressants: – E.g. Buspiron, Mirtazapin, Sertralin

– No benefit

• Phenothiazine – e.g. Chlorpromazin, Promethazin oder Levomepromazin

– No benefit

Pharmacological treatment of dyspnea

Other drugs

• Inhaled Furosemid:

– Protective effect against bronchoconstrictionr*

– Reported benefit in review**

– In randomized trial: no benefit ***

• Corticosteroids: anecdotal benefit

– Lymphangitis carcinomatosa

– COPD

*Bianco S et al. Lancet 1988

**Booth S et al. Expert Reviews Resp Med 2009

***Wilcock A et al. Thorax 2008

Pharmacological treatment of dyspnea

Oxygen

• Dyspnea caused by hypoxemia: good response to oxygen (e.g.

COPD)*

• No difference between air and oxygen**

• Maybe placebo effect

• Cold air helps to reduce dyspnea

• Stimulation of N. trigeminus seems to have inhibitory effects

towards dyspnea ** *

• No benefit for oxygen****

• Sometimes „blind activism“ at the end of life*****

*Uronis HE et al. Thorax 2014

**Davis et al.Palliative care and rehabilitation of cancer patients

** * Liss HP et al. Am Rev Respir Dis 1988

*** * Cranston et al, Cochrane Database Syst Rev 2008

**** * Simon ST, Bausewein, 2009

Pharmacological treatment of dyspnea

Oxygen

• Individual attemt:

– 2l/min oxygen

– Titration

– Change to air after three days

– If benefit by oxygen continue

– If not, stop

Simon ST, Bausewein, 2009

Refractory dyspnea

• Dyspnea that can not be resolved after optimal treatment of the

underlying conditions is referred as refractory dyspnea

• *.

*S. T. Simon, V. Weingärtner, R. Voltz, C. Bausewein . Palliativmedizin, UIM 2/2013

Treatment of dyspnea Noninvasive ventilation

• Noninvasive ventilation is more efficient than oxygen and reduces

need for opioids in patients with advanced cancer

Nava S et al. Lancet Oncology 2013

• Patient K.J.

• 1974*, + 2014

• AML, KMT 2004

• Pleuroparenchymale

Fibroelastosis?

• Pulmonal cachexia

Dyspnea

Case report

Noninvasive ventilation, opioids and

benzodiazepines

Terminal dyspnea

• Shallow breathing, quick breathing

• Periods of apnoea

• Cheyne-Stokes-breathing

• Death rattle

Terminal dyspnea*

• Inform relatives about aspects of death rattle

• Low dose opioids and/or benzodiazepines

• Anticholinergic treatment

*JR Thomas and v Gunten C, Lancet Oncology 2002

Terminal dyspnea

• Anticholinergic treatment:

– Scopolamin 0.2-0.4mg s.c. every 4 h

– Or transdermal 1.5mg every 72 h

– oder 0.1-1 mg /h continous infusion

• Suctioning of mucus: often

counterproductive

Palliative Sedation

• If opioids are not enough to control symptoms

• Titration of benzodiazepines, neuroleptic

drugs until symptom control

Wein S, Oncology 2000

Beller EM et al. Palliative pharmacological sedation for terminally ill adults. Cochrane Database Syst Rev. 2015 Jan

Cherny NI et al. EAPC recommended framework for the use of palliative sedation. Palliative Medicine 23, 2009

Dyspnea in terminal heart failure

• Patient H. K.

• NYHA IV

• Several cycles of Simdax

• No HTX possible

• Terminal dyspnea, refractory to

opioids

• Treatment???

Sedierung in der Palliativmedizin - Leitlinie für den Einsatz sedierender Medikamente in der Palliativversorgung - European Association for Palliative Care (EAPC) Recommended Framework for the Use of Sedation in Palliative Care

übersetzt von B. Alt-Epping, T. Sitte, F. Nauck, L. Radbruch

Original von: Nathan I Cherny, Lukas Radbruch. EAPC recommended framework for the use of sedation in Palliative Care. Pall Med 2009; 23 (7): 581-593

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