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Mechanisms of dyspnea relief by inhaled furosemide

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Mechanisms of dyspnea relief by inhaled furosemide Powered By Docstoc
					What have we learnt from laboratory
induced breathlessness?


 Shakeeb H. Moosavi
 Sleep and Breathing
 Faculty of Medicine, NHLI
 Royal Brompton Hospital Campus
Breathlessness
1. Background (Definitions and terminology)

2. Generating dyspnoea in the laboratory
    •Neural pathways for different dyspnoeas

3. Theories about neurophysiology of dyspnoea
    •„Corollary discharge‟ hypothesis for air hunger
    •Does inhaled furosemide relieve air hunger?

4. „Multiple dimensions‟ of breathlessness
        Different diseases produce
        different dyspneas in patients
  Gasping

                     Difficult breathing
                                                 Short of breath

Elliott et al. (1991), Am Rev Respir Dis, 144;826-832
Simon et al. (1990), Am Rev Respir Dis, 142;1009-1014
Definitions and language

          • Breathlessness

      {   • Short of Breath (SOB)
          • Dyspnoea
                                        }   Synonymous


  “..a subjective experience of breathing discomfort that is
  comprised of qualitatively distinct sensations that vary in
  intensity” (ATS consensus statement 1999)



          • Air Hunger                      At least 3

     {    • Sense of Work/Effort
          • Chest tightness            }    distinguishable
                                            qualities
Generating specific forms of dyspnoea
          in the laboratory
  Different laboratory stimuli produce
  different dyspnoeas in normal subjects

Extreme     Constant PETCO2 = 41                  Constant VE = 10
            (n=5)                                 (n=16)


                                   work/effo rt

                                   air hunger




  Zero

            10     20     30                       40      45        50
          Voluntary VE (l/min)                       PETCO2 (Torr)
                                             *inferred from debriefing
     Lansing et al JRCCM 2000      Banzett et al. (1996) Resp Physiol 1996
 Typical air hunger stimulus response curves




Ventilation constrained:  =with mechanical ventilator; o =without ventilator
Steady state levels of air hunger
Air hunger sensitivity –
variable among subjects and consistent within subjects




                            Moosavi et al, JAP, 2002; Banzett et al, 1996
     Steady state levels of the sense of breathing work/effort

Tidal
Volume




PCO2
(mmHg)




WE
(%VAS)
     Specificity of stimuli for AH and WE
Breathing work



                         Breathing required more effort
   and effort
    cluster


                           Size of breaths felt too large
                         Breathing required more work
                                 Felt like heavy exercise
                 Felt tightness or constriction in chest
                            Breathing was comfortable
                         Size of breaths felt about right
                                     Felt short of breath
                 Feeling of suffocation or smothering
     Airhunger
       cluster




                           Felt an urge to breathe more
                              Felt a hunger for more air
                                      Felt starved for air
                                   Breaths felt too small
                                                             0   1   2     3   4     5   6   7
                                                                         Frequency
Testing theories about neurophysiology
              of dyspnoea
                  Research theme

   “We must look for the sensory receptors, sensory
  pathways, and thalamic or cortical centers which are
      responsible for the perception of respiratory
                      discomfort.”

                Comroe JH Jr. (1956)


              Research Strategy

Improve our knowledge of the mechanisms of breathlessness
     Through hypothesis driven laboratory experiments
signals indicating          signals indicating
demand for breathing        breathing achieved



                 Mismatch


                Dyspnoea

                                 “Neuroventilatory dissociation”

                                 “Efferent-reafferent mismatch”
         AH          Forebrain                         PCO2 
                                        ?

 Chen et al., 1992   Midbrain
                                                   Central
                                                Chemoreceptors
                     Brainstem
                     Resp. ctr
                                      Resp muscle activity not involved
                                      Banzett et al. , Respir Physiol 1990
     Lung            Respiratory      Gandevia et al. J physiol, 1993

Mechanoreceptors      muscles
                                   Harty et al J. Physiol. 1996
                       o
                                   Bloch-Salisbury et al, AJRCCM 1997
                      VE          Manning et al Resp. Physiol. 1992
                                   Shea et al Resp. Physiol. 1996
Work/       Forebrain
Effort

   Motor          ?
   Cortex
            Brainstem
            Resp. ctr

            Respiratory
             muscles

              o
             VE 
Corollary discharge hypothesis of air hunger



Hypoxic and hypercapnic drives to breathe
 generate equivalent levels of air hunger in
                 humans




                            (Moosavi et al., 2003)
      AH           Forebrain                PCO2 
                                 ?

                   Midbrain
                                           Central
                                        Chemoreceptors
                   Brainstem
                   Resp. ctr
                                       Peripheral
     Lung          Respiratory       Chemoreceptors
Mechanoreceptors    muscles

                     o
                                             PO2
                    VE 
(Moosavi et al., 2003, JAP)
 Corollary discharge hypothesis for airhunger




Time course of air hunger mirrors the biphasic
       ventilatory response to hypoxia




                              (Moosavi et al., 2004, JAP)
    Air hunger (%VAS)
                        100       Hypoxic stimulation
                         80
                         60
                         40
                         20
                          0
    VE (l/min)

                         20

                         10
.
                          0
PETO2 (torr)




                        150
                        100
                         50
                          0
     PETCO2 (torr)




                         40

                         20

                          0
                              0   5         10          15    20
                                       Time (min)
                                                             (Moosavi et al, 2004, JAP)
(Moosavi et al, 2004, JAP)
Testing novel interventions
     for dyspnoea relief
   (inhaled frusemide)
Inhaled furosemide modulates PSR activity




        From Sudo et al. (2000) Am J Resp Crit Care Med 162; 971-975
Inhaled furosemide relieves dypnoea in patients

•Stone et al. (1994)
   Inhaled furosemide relieves dyspnea in cancer patient

•Shimoyama and Shimoyama (2002)
   20mg Inhaled every 4 hrs
   eliminates dyspnea of terminal cancer- no side effects
•Ong et al. (2004)
   Exertional dyspnoea in COPD
Inhaled furosemide relieves dyspnoea in normals
                    After placebo                     After frusemide




Nishino et al. 2000, Am J Respir Crit Care Med 161:1963-1967
Moosavi et al, RPN, 2006
      AH           Forebrain         PCO2 


                   Midbrain
                                    Central
                                 Chemoreceptors
                   Brainstem
                   Resp. ctr

     Lung          Respiratory
Mechanoreceptors    muscles

                     o
                    VE 
                                      Sensitize
Further questions regarding inhaled frusemide

What are the sources of variability?

Do systemic effects have a role in relief?

Does it relieve sense of breathing „work/effort‟?

Can we predict which patients would benefit most?
Multidimensionality of dyspnoea
Multidimensional model of breathlessness?


                  Quality




    Sensory                   Sensory
    Intensity                 Affect
   Clinical significance



An extremely unpleasant sensation
     “..Of all forms of torture, asphyxiation is the strongest
     predictor of PTSD symptoms”
     (Basoglu and Mineka, unpublished)


     “…but if I felt I had to live my life feeling like that I would
     jump out the window”
Separate affective and sensory intensity
dimensions of dyspnoea?


    •Von Leopold et al, 2006, Respir Med
      - distraction specifically reduces the affective component of dyspnoea
Take home message….

  Laboratory-induced dyspnoea has contributed
   much to understanding neurophysiological
         mechanisms of breathlessness


    Raises many more interesting questions!


   Better informed for bench-bedside studies


  Utility of induced dyspnoea in clinical setting?

				
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posted:4/25/2011
language:English
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