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Peripheral Chemoreceptor Responsiveness and Hypoxic Pulmonary Vasoconstriction

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:

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Peripheral Chemoreceptor Responsiveness and Hypoxic Pulmonary Vasoconstriction

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  1. Peripheral Chemoreceptor Responsiveness and Hypoxic Pulmonary Vasoconstriction Tyler J. Albert, M.D. Senior Medical Resident Chief of Medicine Rounds November 23, 2010

  2. 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

  3. 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

  4. 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)

  5. Hypoxic Pulmonary Vasoconstriction

  6. Background Denervation of peripheral chemoreceptors in animals, diminishing HVR, increases HPV Carotid body ablation Chemical sympathectomy Naeije et al. JAP 66:42, 1989

  7. Hypothesis Individuals with high HVR have less HPV in response to low alveolar oxygen (PAO2).

  8. 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

  9. Measuring HVR

  10. 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

  11. Measuring HPV

  12. 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

  13. 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)

  14. HVR correlates with HPV p = 0.01 R2 = 0.41

  15. 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

  16. 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

  17. 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

  18. 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. RespirPhysiolNeurobiol. 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.

  19. Thank you Erik Swenson Patricia Sills VA Respiratory Therapists New Saigon Deli Andy Luks

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