peripheral chemoreceptor responsiveness and hypoxic pulmonary vasoconstriction tyler j. albert, m.d....
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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: Transformed outpatient rotations into
transthoracic echocardiogram (TTE) practice sessions
R2 year: Successfully ran the gauntlet of the VA IRB from
Boise, ID R3 year:
8 weeks of research
Important Terminology
Hypoxic ventilatory response (HVR): Increase in ventilation due to a decrease in PaO2
Mediated by peripheral chemoreceptors in the carotid body and aortic arch
Isocapnic HVR: 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
Carotid body ablation Chemical sympathectomy
Naeije et al. JAP 66:42, 1989
Denervation of peripheral chemoreceptors in animals, diminishing HVR, increases HPV
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 - Minute ventilation
- HR - End-tidal CO2 (EtCO2)
- BP - 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)
p = 0.01R2 = 0.41
HVR correlates with HPV
0 0.05 0.1 0.15 0.2 0.25 0.3 0.350
10
20
30
40
50
Poikilocapnic HVR (L/min/%SaO2)
HP
V (
PA
SP
@ 8
5%
SaO
2)
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