peripheral chemoreceptor responsiveness and hypoxic pulmonary vasoconstriction tyler j. albert, m.d....

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