The Death of the Hypoxic Drive Theory

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The Death of the Hypoxic Drive Theory
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The Death of the Hypoxic Drive Theory
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Oxygen Bars
"If they inhale too much oxygen, they can stop
breathing."
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A Real Order
RISING CO2
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What is Hypoxic Drive?
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Quincy, the missing Oxygen episodes
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Hes a Retainer
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Thats Where He Lives..
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He in the 50/50 Club
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Overview of Talk

• Control of breathing, Hypoxic Drive
• P0.1 Occlusion Pressure
• V/Q mismatch and Haldane Effect
• History of traditional theory
• Studies pro and con
• Other studies, more O2 may be goal
• Specific OSA/Pickwickian concerns
• Where to go from here?

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The Control of Breathing
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Carotid Bodies
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Carotid Body Diagram
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Ventilatory Response to Hyppoxemia
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Ve Response to Hypoxemia
Normal Hypoxic Drive
10-15
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High CO2, Low O2 Double-whammy
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Alveolar AIR Equation

• See-Saw of O2, CO2 in alveoli (RA)
• PAO2 40 and a PACO2 of 70
• If PACO2 climbs to 90 without any supp. O2
  given..
• The PAO2 would drop to about 20 per alv. Air
  equation
• Death..

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High CO2, Low O2
PaO2 40
PaCO2 70
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If PaO2 200
Ve
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P0.1 The Occlusion Pressure

• Pressure drop first 1/10th sec. insp.
• Before conscious perception or reaction can occur
• Reliable measure of neural output.
• Imagine what yours would be if you sprinted up
  two flights of stairs.

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P0.1 The Good, The Bad, and The Ugly
In normal subjects.. P0.1 of 8.0 assoc. with MV
of 50-70 L/M Unsustainable for the long haul
gt4
3

• 1

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P0.1 The Good, The Bad, and The Ugly
In normal subjects.. P0.1 of 8.0 assoc. with MV
of 50-70 L/M Unsustainable for the long haul
gt4
3

• 1

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P0.1/MIP relationship fatigue setting in?
Start of SBT
End of SBT

• P0.1 2.5
• MIP 68

• P0.1 5.6
• MIP 34

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How Oxygen Can Increase CO2

• Reduction of normal hypoxic drive (not a
  respiratory drive abnormality)
• Worsening of ventilation/perfusion matching via
  regional release of hypoxic pulmonary
  vasoconstriction
• The Haldane Effect

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Each alveoli has its own equation
Imagine the worst one

• 760 minus 47 for the water, 713
• 713 X FIO2
• Room Air 150, 100 O2 713
• If alveolar PACO2 is 120 (worst unit)
• RA PAO2 would be 30
• But if on 100 O2---- PAO2 would be 593

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PACO2 30
PA 100 or 600 incoming
Huh Huh, Heh Heh
PACO2 120
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Regional release of HPV
HPV
Room Air
CO2 120
PAO2 lt60
CO2 120
100 O2
PAO2 600
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Rising PaCO2.
Break out the ET tray?
Stop the O2 Spray?
Or permissive hypercapna?
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CO2 Transport Binding

• CO2 diffuses into blood from cells
• 7 remains dissolved in blood plasma as PaCO2
• 15-20 bound to Hgb
• Rest is converted to bicarb

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At the tissues
Bohr Effect

• Rising CO2 levels help to drive off O2 from
  Hemoglobin.
• Rightward shift of O2 disassociation curve

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In the Lungs
Haldane Effect

• Oxygen displaces carbon dioxide from hemoglobin.
  
• Helps with ventilaton
• Shift to the left..

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Haldane Effect
CO2
O2
O2
CO2
O2
CO2
The Haldane Effect
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Hgb and CO2, To carry or not to carry? That is
the question.

• 15-20 of total CO2 attached to Hgb
• Elevated Hgb levels in hypoxemic COPD
• 50/50 club member has arterial blood normally
  carrying an extra CO2 load
• Now arrives in ER in resp. failure
• Increasing SpO2 will drive CO2 off Hgb

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into your waiting ABG syringe
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Knock out of hypoxic drive..?
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Or, drive in a hypercarbic potential?
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1997 CCM
Sept., 1997 CCM

• Dr. Hoyt

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In the beginning..
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The Way We Were.
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The Way We Were.
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First Shot Across the Bow
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Aubier, et al 1980

• Effects of the Administration of O2 on
  Ventilation and Blood Gases in Patients with
  Chronic Obstructive Pulmonary Disease During
  Acute Respiratory Failure
• American Review of Respiratory Disease Vol. 122
  pages 747-754, 1980

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Methods

• 22 patients in acute resp failure
• 15 minutes of 100 O2
• Measured Ve and ABGs before and after

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Time Course, change in Ve
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What Happened? Changes on 100 O2

• PaO2 from 38 to 225
• PaCO2 from 65 to 88
• pH from 7.34 to 7.25
• RR 32 to 31
• VT 341 to 323 ccs
• VD/VT .77 to .82

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Why the PaCO2 went up?

• Average Ve decrease by 7---account for 5 torr
• Haldane effect ---account for 7 torr
• VD/VT change effect ----12 torr

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Conclusions

• No overall significant change in VE
• Increase in PaCO2 mainly secondary to VD/VT
  changes (removal of regional HPV)

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However,one patient

• had a increase in PaCO2 of 76
• VE reduction of 26,
• VT reduction .301 to .189
• RR increase from 28 to 35

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The Valley of the Studies
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The Bohr Effect and The Bore Effect
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whitnack_at_pacbell.net
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Hyperoxic-induced Hypercarbia in Stable COPD
Sassoon, et al Am Rev Res Dis 1997 135907-911

• 17 ambulatory COPD patients
• 15 minutes of alternating O2 or air breathing
• Measured PaCO2, VE indices, VD/VT, VCO2

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Air O2

• PaCO2 46 mmHg
• VE 13.5 Liters
• VD/VT .49

• PaCO2 49 mmHG
• VE 12.8 Liters
• VD/VT .53

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Conclusion

• ..our study suggests that hyperoxic-induced
  hypercapnia in patients with COPD is not
  primarily related to either hypercapnic or
  hypoxic drive, but that impairment in gas
  exchange appears to be the predominant factor
  contributing to the hypercapnia.

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Inter-individual Variability of the Response to
Oxygen Administration in Hypercapneic Patients,
Gasparini, et al, Eur J of Resp Dis., 1986 69

• 16 patients
• COPD, hypercapnic STABLE
• Behavior of PaCO2, VE, V/Q ratios with different
  s O2

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Methods/Results

• 5 consecutive days
• O2 s RA, 28, 40, 60, 100 X 30 minutes
• Each dayfirst RA then O2
• Measured VE mechanics ABGs on both
• No correlation between incr. PaCO2 VE
• Significant correlation between increased PaCO2
  and increase in VD/VT
• At 60 and 100 O2 there was a small decrease in
  VT, but not RR. (No one stopped breathing)

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Conclusions

• Constant increase in PaCO2 with each increase in
  O2 concentration
• PaCO2 increase appears clinically not relevant in
  stable state (COPD) patients
• The increase in PaCO2 is due to VD/VT changes

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O2-Induced Change in VE VE Drive in COPD
Dick, Liu, Sassoon, Berry, Mahutte Am J Resp Crit
Care Medicine 1997 Vol.155, pages 609-614

• Examined the role of respiratory control during
  O2 induced hypercarbia in stable COPD patients
• Compared observed changes with predicted

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Methods

• 11 ambulatory outpatient COPD patients
• Hypoxemic, mean RA PaO2 63/-11
• One had baseline SaO2 of 76
• 3 had SpO2s of 92, 93 94 each
• Hypercarbic, mean RA PaCO2 53
• PaCO2 ranged from 42-68
• Studied before and after 15 min. 100 O2

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Measured/Calculated

• Measured O2 induced changes in VE, PaCO2, SaO2
• Hypercapnic and hypoxic ventilatory response
  curves
• Observed change was compared with predicted

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Observed Predicted VE Changes
One foot on the brake, one on the gas pedal
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Conclusion
We conclude that the O2-induced change in
Ventilation observed is equal to that expected
from the ventilatory drives and the changes in
PaCO2 and SaO2
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Conclusion.
and that O2-induced hypercarbia does not indicate
a failure of respiratory control mechanisms in
the maintenance of PaCO2 homeostasis.
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Conclusion

• NO
• DRIVE
• ABNORMALITY

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Now looking for outcomes, not causation

• Oxygen therapy for hypercapnic patients with
  chronic obstructive pulmonary disease and acute
  respiratory failure A randomized, controlled
  pilot study
• CRITICAL CARE MEDICINE 200230113-116
• Gomersall, et al

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• 34 Patients Studied
• Target PaO2 gt50 mm Hg vs.
• Target PaO2 gt70 mm Hg
• Main outcome variable was need for mechanical
  ventilation (invasive or non-invasive)

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Editorial, same issue

• Target Low PaO2 gt 50
• Actual low average PaO2 of 6368 mm Hg
• Target high gt 70
• Actual high average PaO2 of 97115 mm Hg

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Outcome
There was no significant difference in PaCO2 or
pH
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Conclusion

• Traditional teaching related to oxygen therapy
  for hypercapnic patients with an acute
  exacerbation of chronic obstructive pulmonary
  disease may be incorrect. A large randomized,
  controlled study is required to confirm this
  impression.

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Editorial Conclusion

• In earlier studies oximetry wasnt available
• an ad hoc standard for administering supplemental
  oxygen to COPD patients with acute respiratory
  insufficiency has evolved
• ..simple observational study would be a good
  starting point.
• continuous SpO2 monitoring..target 90-95

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One year period prevalence study of respiratory
acidosis in acute exacerbations of COPD
implications for the provision of non-invasive
ventilation and oxygen administrationP K Plant,
J L Owen, M W ElliottThorax 200055550-554
( July )
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Methods, Results

• aimed to determine the prevalence of respiratory
  acidosis in patients admitted with COPD
• During a 12 month period 983 patients were
  admitted with an acute exacerbation of COPD
• For hypercapnic patients a higher PaO2 was
  associated with worse acidosis
• Most of the hypercapnic patients with a PaO2 of
  gt75 mmHg were acidotic

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• Study only showed an association between acidosis
  and oxygen therapy rather than a causative
  relationship
• Focus was on preventing unnecessary NIV due to
  acidosis
• CONCLUSION
• PaO2 should be maintained below PaO2 75 with
  controlled oxygen to avoid the risk of acidosis
• (equates to an SaO2 of 85-92)

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The Role of Hypoventilation and
Ventilation-Perfusion Redistribution in
Oxygen-induced Hypercapnia during Acute
Exacerbations of Chronic Obstructive Pulmonary
Disease

• Am J Respir Crit Care Med 2000 Vol. 161
• Pages 1524-1529
• Robinson et al

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Methods

• 22 patients with acute excacerbation of COPD
• On RA and on 100 O2 Xs 20 minutes
• Measured VE, C.O., V/Q, PaCO2, PaO2
• Classification as retainers if PaCO2 increased
  over 3mmHg
• But some non-retainers had PaCO2 over 45 (one
  had a PaCO2 of 63)

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Of Note in Non-Retainers

• Initial PaCO2s on RA were.
• 63, 56, 61, 48, 55
• Half the non-retainers had elevated PaCO2
• PaO2 range 51-76
• No pH data given in study

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VE DECREASE RETAINERS ON 100 O2
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Conclusion

• ..our results suggest that the major mechanism
  differentiating retainers from nonretainers is
  depression of ventilation rather than the
  redistribution of blood flow caused by the
  release of hypoxic pulmonary vasoconstriction.

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5 Clinically Significant

• Subjects 13, 15, 17,18, 19
• 13 had PaCO2 increase of 18 and had initial
  PaO2 of 41, PaCO2 74
• 19 had a PaCO2 increase of 20, and had initial
  PaO2 of 46, PaCO2 of 78
• Others had increased PaCO2 of 8-11
• No pH data given

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Carbon dioxide responsiveness in COPD
patients with and without chronic hypercapnia

• by Scano et al
• European Respiratory Journal
• 1995 878-85(16)

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The Question.?

• To what extent does the reduced ventilatory
  response to a hypercapnic stimulus in COPD
  patients depend on a blunted chemoresponsiveness
  of central origin or to mechanical impairment.

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Wont?
Or Cant?
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The Method

• 17 COPD patients
• 9 nomocapnic, 8 hypercapnic
• 6 age matched normal subjects also as a control
• Given 93 O2, 7 CO2 for 3-5 minutes

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A model of hyperoxia and failure!
7 CO2
93 O2
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Measured in each group

• ABGs
• Spirometry
• P0.1
• MIP
• Electromyographic activity of the diaphram (Edi)

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Calculated relationships

• Change in P0.1/Change in PaCO2
• Change in P0.1/Change in PaCO2 relative to the
  P0.1/MIP relationship
• And many other relationships!!!
• In normals, in both COPD groups

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VE Increase
L/M
90
P0.1 as of MIP

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Change P0.1/Change PaCO2 as of MIP
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Conclusion
our data show that CO2 responsiveness is high
in normocapneics, whilst in hypercapneics, though
similar to that of the control group, it is
probably inadequate to sustain ventilation.
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The Long March of Ventilation
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Pit Stop
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Whats Goin On?

• There is a hyperoxia-induced hypercarbia
• The lower the inital PaO2 and the higher the
  initial PaCO2, the greater the effect
• VD/VT changes and Haldane effect are the
  predominant reasons
• Small groups do drop VE 1426
• But in crisis and on 100 O2

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Central Abnormality or.

• Central Wisdom
• ??

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Lancet
Lancet
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Summation in Clinical Pulmonary Medicine,
Schiavi, May 98

• ....The traditional idea that oxygeninduces
  hypoventilation by suppressing hypoxic
  ventilatory drive at the level of peripheral
  chemoreceptors is no longer tenable.

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Reverse may true.

• Many studies used 100 O2 vs. RA but
• Oxygenating to high-normal may be beneficial
• Reduce P0.1 to sustainable level
• Reduce hyperinflation
• Price of mild hypercapnia

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Central Resp. Drive in ARF of Patients with COPD

• Aubier, et al
• Am Rev Resp Dis 1980
• Volume 122, 1980 pages 191-199

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Methods

• 20 patients in acute respiratory failure
• 12 of them later after recovery
• Before and after 5 l/m O2 for 20 minutes
• Measured VE, ABGs, P0.1

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ARF on RA ARF 5L/M O2

• PaO2 38
• PaCO2 61
• VE 11 Liters
• RR 32
• P0.1 8.3

• PaO2 120
• PaCO2 68
• VE 10 Liters
• RR 28
• P0.1 4.9

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Chronic on Air Acute on O2

• PaO2 54
• PaCO2 47
• VE 11Liters
• RR 21
• P0.1 3.9

• PaO2 120
• PaCO2 68
• VE 10 Liters
• RR 28
• P0.1 4.9

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Chronic on Air Chronic on O2

• PaO2 54
• PaCO2 47
• VE 11 Liters
• RR 21
• P0.1 3.9

• PaO2 158
• PaCO2 50
• VE 10 Liters
• RR 20
• P0.1 2.9

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PAO2 158!!
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Conclusion.

• ..in such patients, any rational therapeutic
  strategy should involve reduction of inspiratory
  muscle activity. In this context, the use of
  respiratory stimulants does not appear to be
  indicated on the other hand, the administration
  of O2-enriched air appears to meet this end.

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Acute effects of hyperoxia on dyspnea in
hypoxemia patients with chronic airway
obstruction at rest
Alvisi, et al Chest. 2003 Apr123(4)1038-46
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Methods

• 8 patients
• Studied on RA and on 30 O2
• Measured .
• Dyspnea
• P0.1
• Dynamic hyperinflation (via IC and EFL)

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Results . on 30 O2

• SpO2 increased from 93 to 97
• Less dyspnea on O2
• P0.1 decreased
• Less hyperinflation per increased Insp. Capacity

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Michel de Montaigne
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Ive Seen It Happen!
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Aubiers time course change
Those first minutes!
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Thunder and lightening
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Back to Hoys editorial
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Hoyt contd
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yes it may be true, but it is not important.

• COPD pts generally do quite well with a SaO2
  between 88-90 and dont need a higher PaO2..or
• No matter the mechanism, lets keep the same
  practice.

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Post-op Infection Reduction
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Wound healing, O2 collagen
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Cardiac autonomic regulation
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Nutrition and Oxygen levels
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It may be true, it may be important, but it is
no longer new
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The Emperor and his new clothes.
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Break-through breathing in the night
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Break-through breathing in the night
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Oximeters, cannulas, and masks, OH MY!
"She's melting, she got too much O2!"
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Fearless Vampire Killers!
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Still Taught, Still Believed
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Whats a Respiratory Therapist to Do?
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Studies Cited
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Mt. Everest...The ultimate in Hypoxic Drive
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• PaCO2s initially on Room Air
• 63 56 61 48 55
• 5 of 10 had elevated PaCO2 (no pH data)
• Mean PaO2 was 63,
• Lowest PaO2 was 51,
• Highest PaO2 was 76

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Causes of Hypercarbia with O2 Therapy in Patients
with COPD
Hanson, et al. Critical Care Medicine 1996
volume 24, pages 23-28

• Data from a computer model was compared with a
  previous case series (Aubier 1980)
• Simulated application of oxygen therapy
• Evaluated contribution of Haldane effect and
  changes in V/Q to CO2 retention in COPD

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Conclusions

• Quantitatively establishes the theoretical basis
  for these results. (Aubiers study)
• Changes in physiologic deadspace are sufficient
  to account for the hypercarbia developed

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Oxygen USA Oxygen Great Britain
VS.
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Geography and theory
OF O2
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CO2 7, O2 93 a Forced March
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Regional release of HPV
Room Air
100 O2
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The basic issue in this story is oxygen.