Peripheral Chemoreceptor
Responsiveness and Hypoxic
Pulmonary Vasoconstriction
Tyler J. Albert, M.D.
Senior Medical Resident
Chief of Medicine Rounds
November 23, 2010
3 Years of Preparation

Intern year:


R2 year:


Transformed outpatient rotations into
transthoracic echocardiogram (TTE) practice
sessions
Successfully ran the gauntlet of the VA IRB from
Boise, ID
R3 year:

8 weeks of research
Important Terminology

Hypoxic ventilatory response (HVR):



Isocapnic HVR:


Increase in ventilation due to a decrease in PaO2
Mediated by peripheral chemoreceptors in the
carotid body and aortic arch
Fixed CO2 levels, isolating hypoxemia
Poikilocapnic HVR:

Variable CO2 levels, physiologic but confounding
Hypoxic Pulmonary
Vasoconstriction (HPV)


Vasomotor response to alveolar hypoxia
Mediates ventilation/perfusion (V/Q) matching




optimizes PaO2 by reducing low V/Q fraction
Intrinsic to the lung
Focal with disease (PNA, atelectasis)
Global with hypoxia (altitude, hypoventilation)
Hypoxic Pulmonary
Vasoconstriction
Background
Denervation of peripheral chemoreceptors in
animals, diminishing HVR, increases HPV
Carotid body ablation
Naeije et al. JAP 66:42, 1989
Chemical sympathectomy
Hypothesis
Individuals with high HVR
have less HPV in response to
low alveolar oxygen (PAO2).
Methods: Measuring HVR



Recorded HVR (∆ minute ventilation/∆ SaO2)
over 15 min of poikilocapnic hypoxia (0.21 to
0.12 FIO2)
Used nitrogen to drop the FIO2
Monitored:
- SaO2
- HR
- BP
- Minute ventilation
- End-tidal CO2 (EtCO2)
- ECG
Measuring HVR
Methods: Measuring HPV


Screened for tricuspid regurgitation with TTE
Pulmonary artery systolic pressure (PASP)
recorded by echosonographer




Bernoulli’s equation (∆P=4V2)
Subjects randomly at FIO2 = 0.21, 0.18, 0.15 and
0.12, each x 15 min
Echosonographer blinded to FIO2
PASP recorded at SaO2 = 85%

Provided a common PAO2 stimulus, using SaO2
as a surrogate for alveolar oxygenation
Measuring HPV
Results

15 healthy subjects





11 men, 4 women
Age: 26-37, mean 29.4 years
Baseline SaO2: 95-98, mean 97%
Baseline EtCO2: 37-42, mean 39 mmHg
Baseline PASP: 14-30, mean 23 mmHg
Results

Good range of HVRs (0.05-0.3 L/min/%SaO2)


Correlates with previously published data
EtCO2 dropped as expected with increasing
HVR (p=0.035)
HPV (PASP @ 85% SaO2)
HVR correlates with HPV
p = 0.01
R2 = 0.41
50
40
30
20
10
0
0
0.05
0.1
0.15
0.2
0.25
0.3
Poikilocapnic HVR (L/min/%SaO2)
0.35
Conclusion

HVR and HPV are inversely related



Direct correlation between peripheral
chemoreceptor response and hypoxic pulmonary
vasoconstriction in healthy subjects
Consistent with animal models showing a
modulating influence on HPV by peripheral
chemoreceptor activation
First demonstration of this phenomenon in
humans
Limitations

Poikilocapnic HVR



Confounding from low CO2
Hypocapnia itself lowers HPV
Inaccuracy of TTE


Variable correlation with PASP by catheterization,
does not measure pulmonary vascular resistance
VA IRB and subjects (co-residents) less likely to
approve Swan-Ganz catheter
What’s Next

We identified a contributor to HPV, which
could lead to targeted therapies



If isolated, we could stimulate breathing and alter
pulmonary resistance in pulmonary hypertension,
high altitude pulmonary edema, etc.
Almitrine: evidence for evoking increased carotid
body activity
Oxford: customized chamber for isocapnic
HVR and HPV measurement
References







Naeije R, LeJeune P, Leeman M, Melot C, Closset J. Pulmonary vascular
responses to surgical chemodenervation and chemical sympathectomy in
dogs. J Appl Physiol. 1989 Jan;66(1):42-50.
Steinback CD, Poulin MJ. Ventilatory responses to isocapnic and
poikilocapnic hypoxia in humans. Respir Physiol Neurobiol. 2007 Feb
15;155(2):104-13.
Dorrington KL, Talbot NP. Human pulmonary vascular responses to hypoxia
and hypercapnia. Pflugers Arch. 2004 Oct;449(1):1-15.
Duffin J. Measuring the ventilatory response to hypoxia. J Physiol. 2007 Oct
1;584(Pt 1):285-93.
Moudgil R, Michelakis ED, Archer SL. Hypoxic pulmonary vasoconstriction.
J Appl Physiol. 2005 Jan;98(1):390-403.
Teppema LJ, Dahan A. The ventilatory response to hypoxia in mamals:
mechanisms, measurement, and analysis. Physiol Rev. 2010;90:675-754.
Aaronson PI, Robertson TP, Knock GA, et al. Hypoxic pulmonary
vasoconstriction: mechanisms and controversies. J Physiol.
2006;570(1):53-58.
Thank you





Erik Swenson
Patricia Sills
VA Respiratory Therapists
New Saigon Deli
Andy Luks