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: Intern year: Transformed outpatient rotations into transthoracic echocardiogram (TTE) practice sessions Transformed outpatient rotations into transthoracic echocardiogram (TTE) practice sessions R2 year: R2 year: Successfully ran the gauntlet of the VA IRB from Boise, ID Successfully ran the gauntlet of the VA IRB from Boise, ID R3 year: R3 year: 8 weeks of research 8 weeks of research

3. Important Terminology Hypoxic ventilatory response (HVR): Hypoxic ventilatory response (HVR): Increase in ventilation due to a decrease in P a O 2 Increase in ventilation due to a decrease in P a O 2 Mediated by peripheral chemoreceptors in the carotid body and aortic arch Mediated by peripheral chemoreceptors in the carotid body and aortic arch Isocapnic HVR: Isocapnic HVR: Fixed CO 2 levels, isolating hypoxemia Fixed CO 2 levels, isolating hypoxemia Poikilocapnic HVR: Poikilocapnic HVR: Variable CO 2 levels, physiologic but confounding Variable CO 2 levels, physiologic but confounding

4. Hypoxic Pulmonary Vasoconstriction (HPV) Vasomotor response to alveolar hypoxia Vasomotor response to alveolar hypoxia Mediates ventilation/perfusion (V/Q) matching Mediates ventilation/perfusion (V/Q) matching optimizes P a O 2 by reducing low V/Q fraction optimizes P a O 2 by reducing low V/Q fraction Intrinsic to the lung Intrinsic to the lung Focal with disease (PNA, atelectasis) Focal with disease (PNA, atelectasis) Global with hypoxia (altitude, hypoventilation) Global with hypoxia (altitude, hypoventilation)

5. Hypoxic Pulmonary Vasoconstriction

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

7. Hypothesis Individuals with high HVR have less HPV in response to low alveolar oxygen (P A O 2 ).

8. Methods: Measuring HVR Recorded HVR (∆ minute ventilation/∆ S a O 2 ) over 15 min of poikilocapnic hypoxia (0.21 to 0.12 F I O 2 ) Recorded HVR (∆ minute ventilation/∆ S a O 2 ) over 15 min of poikilocapnic hypoxia (0.21 to 0.12 F I O 2 ) Used nitrogen to drop the F I O 2 Used nitrogen to drop the F I O 2 Monitored: Monitored: - S a O 2 Minute ventilation - S a O 2 - Minute ventilation - HR - End-tidal CO 2 (EtCO 2 ) - BP ECG - BP - ECG

9. Measuring HVR

10. Methods: Measuring HPV Screened for tricuspid regurgitation with TTE Screened for tricuspid regurgitation with TTE Pulmonary artery systolic pressure (PASP) recorded by echosonographer Pulmonary artery systolic pressure (PASP) recorded by echosonographer Bernoulli’s equation (∆P=4V 2 ) Bernoulli’s equation (∆P=4V 2 ) Subjects randomly at F I O 2 = 0.21, 0.18, 0.15 and 0.12, each x 15 min Subjects randomly at F I O 2 = 0.21, 0.18, 0.15 and 0.12, each x 15 min Echosonographer blinded to F I O 2 Echosonographer blinded to F I O 2 PASP recorded at S a O 2 = 85% PASP recorded at S a O 2 = 85% Provided a common P A O 2 stimulus, using S a O 2 as a surrogate for alveolar oxygenation Provided a common P A O 2 stimulus, using S a O 2 as a surrogate for alveolar oxygenation

11. Measuring HPV

12. Results 15 healthy subjects 15 healthy subjects 11 men, 4 women 11 men, 4 women Age: 26-37, mean 29.4 years Age: 26-37, mean 29.4 years Baseline S a O 2 : 95-98, mean 97% Baseline S a O 2 : 95-98, mean 97% Baseline EtCO 2 : 37-42, mean 39 mmHg Baseline EtCO 2 : 37-42, mean 39 mmHg Baseline PASP: 14-30, mean 23 mmHg Baseline PASP: 14-30, mean 23 mmHg

13. Results Good range of HVRs ( 0.05-0.3 L/min/%SaO2 ) Good range of HVRs ( 0.05-0.3 L/min/%SaO2 ) Correlates with previously published data Correlates with previously published data EtCO 2 dropped as expected with increasing HVR (p=0.035) EtCO 2 dropped as expected with increasing HVR (p=0.035)

14. p = 0.01 R 2 = 0.41 HVR correlates with HPV

15. Conclusion HVR and HPV are inversely related HVR and HPV are inversely related Direct correlation between peripheral chemoreceptor response and hypoxic pulmonary vasoconstriction in healthy subjects 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 Consistent with animal models showing a modulating influence on HPV by peripheral chemoreceptor activation First demonstration of this phenomenon in humans First demonstration of this phenomenon in humans

16. Limitations Poikilocapnic HVR Poikilocapnic HVR Confounding from low CO 2 Confounding from low CO 2 Hypocapnia itself lowers HPV Hypocapnia itself lowers HPV Inaccuracy of TTE Inaccuracy of TTE Variable correlation with PASP by catheterization, does not measure pulmonary vascular resistance 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 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 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. 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 Almitrine: evidence for evoking increased carotid body activity Oxford: customized chamber for isocapnic HVR and HPV measurement 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. 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. 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. 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. 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. 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. 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. 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 Erik Swenson Patricia Sills Patricia Sills VA Respiratory Therapists VA Respiratory Therapists New Saigon Deli New Saigon Deli Andy Luks Andy Luks