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INVITED REVIEWS: David E. Leaf and David S. Goldfarb Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness J Appl Physiol 2007; 102: 1313-1322 [Abstract] [Full text] [PDF]

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The mixed peripheral stimulus and central inhibition of ventilation in acute hypoxia.

Christopher B. Wolff   (19 October 2009)

Author's reply to Letter by Chris Wolff

David Evan Leaf, MD, David S Goldfarb, MD (New York University)   (19 October 2009)

The mixed peripheral stimulus and central inhibition of ventilation in acute hypoxia. 19 October 2009
Christopher B. Wolff, Anaesthetic Laboratory and Clinical Pharmacology Barts & the London Hospital Medical School, LONDON Send letter to journal: Re: The mixed peripheral stimulus and central inhibition of ventilation in acute hypoxia. chriswolff{at}doctors.org.uk Christopher B. Wolff	Acute hypoxia increases cerebral blood flow (3) which lowers cerebral extra-cellular fluid (ECF) PCO2. As a result there is centrally mediated inhibition of ventilation (1). The central inhibition reduces, or even eliminates, the ventilatory stimulus effect from the peripheral arterial chemoreceptor (PCR) in the mild range (5,6,7). Hence, ventilation in acute hypoxia is influenced positively by the peripheral arterial chemoreceptor and negatively by the central chemoreceptor. This explains why the ventilatory response to mild hypoxia (PaO2 50-100 mm Hg) is virtually non- existent. It is therefore misleading to assume that the ventilatory response to hypoxia represents the sensitivity of the peripheral arterial chemoreceptor. It is an assumption which is widely made appearing, for example, in the comprehensive review of acetazolamide inhibitory mechanisms by Leaf and Goldfarb (4). Dejours and his colleagues revealed the true PCR drive in acute hypoxia (2). They gave two breaths of oxygen and observed progressively greater temporary reductions in ventilation the lower the background hypoxic arterial PO2. Hence, peripheral arterial chemoreceptor drive in acute hypoxia is greater than is apparent from the ventilatory response. The processes involved in the evolution of acclimatization can then be examined (6,7) with many interesting questions remaining, such as ‘How are the processes achieved?’. REFERENCES 1. CUNNINGHAM, D. J. C., P. A. ROBBINS, AND C. B. WOLFF. Integration of respiratory responses to changes in alveolar partial pressures of CO2 and O2 and in arterial pH. In: Handbook of Physiology. Section 3, The Respiratory System Bethesda, MD: Am. Physiol. Soc., 1986, sect. 3, vol. II, pt. 2, chapt. 15, p. 475-528. 2. DEJOURS P., Y. LABROUSSE, J. RAYNAUD, F. GIRARD AND A. TEILLAC. Stimulus oxygène de la ventilation au repos et au cours de l’exercice musculaire a basse altitude (50m) chez l’homme. Rev. Franc. Études Clin. Biol., 3: 105-123, 1958. 3. JENNETT S., L.H. PITTS AND J.B. NORTH. Rapid cerebral vasodilatation in brief hypoxia in anaesthetized animals. Quarterly J. Exper. Physiol., 66: 447-463, 1981. 4. LEAF D.E. AND D.S. GOLDFARB. Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness. J. Appl. Physiol., 102: 1313-1332, 2007. 5. MASON N.P. The physiology of high altitude an introduction to the cardiorespiratory changes occurring on ascent to altitude. Curr. Anaesthesia Crit. Care, 11: 34-41, 2000. 6. WOLFF C.B. The physiological control of respiration. Mol. Aspects of Medicine., 13(6): 445-567. 1992. 7. WOLFF, C.B. The control of ventilation in hypoxia – I. normal adjustments. Mountain Medicine News, 8 (1): 3-6, 1997/8. CHRIS WOLFF Anaesthetics Laboratory, William Harvey Research Institute, Barts & The London Hospitals Medical School, Little Britain, London, EC1A 7BE.
Author's reply to Letter by Chris Wolff 19 October 2009
David Evan Leaf, MD, Internal Medicine Columbia University Medical Center, David S Goldfarb, MD (New York University) Send letter to journal: Re: Author's reply to Letter by Chris Wolff DEL2128{at}columbia.edu David Evan Leaf, MD, et al.	The letter from Wolff contributes to the discourse regarding the effects of hypoxia on ventilation. We agree that the physiologic response to hypoxia is complex and likely represents the cumulative impact of multiple stimulatory and inhibitory pathways. Specifically, Wolff points out the importance of hypoxia-induced central ventilatory inhibition as a variable that, to an extent, masks the activity level of the peripheral arterial chemoreceptors. Normal human subjects display a biphasic response to an acute hypoxic stimulus, in which initial hyperpnea is followed by a subsequent decline in ventilation (9). The former phase is thought to represent carotid chemosensitivity, whereas the latter phase has been attributed, by some (9), to central ventilatory inhibition. Indeed, there is some evidence of hypoxia-induced depression of respiratory activity in cats following carotid chemodenervation (5). However, to our knowledge these findings have not been replicated in humans. In fact, studies in humans whose carotid bodies have been resected have consistently documented an absence of hypoxic ventilatory depression (1, 2, 4, 8, 10). To explain this perplexing constellation of findings, some investigators have proposed that central ventilatory inhibition may itself require input from the carotid bodies (3). Others have proposed that the absence of hypoxic ventilatory depression in humans following carotid body resection may reflect respiratory stimulation originating from the aortic bodies (9), incomplete carotid body resection (7), or regeneration of carotid chemosensitivity (6). Irrespective of etiology or mechanism, we agree with Wolff that the ventilatory response to acute hypoxia may not fully capture the activity level of peripheral chemoreceptors. References 1. Holton P, Wood JB. The effects of bilateral removal of the carotid bodies and denervation of the carotid sinuses in two human subjects. J Physiol 181: 365-378, 1965. 2. Honda Y. Respiratory and circulatory activities in carotid body- resected humans. J Appl Physiol 73: 1-8, 1992. 3. Khamnei S, Robbins PA. Hypoxic depression of ventilation in humans: alternative models for the chemoreflexes. Respir Physiol 81: 117- 134, 1990. 4. Lugliani R, Whipp BJ, Seard C, Wasserman K. Effect of bilateral carotid-body resection on ventilatory control at rest and during exercise in man. N Engl J Med 285: 1105-1111, 1971. 5. Millhorn DE, Eldridge FL, Kiley JP, Waldrop TG. Prolonged inhibition of respiration following acute hypoxia in glomectomized cats. Respir Physiol 57(3): 331-340, 1984. 6. Mitchell RA, Sinha AK, Mcdonald DM. Chemoreceptive properties of regenerated endings of the carotid sinus nerve. Brain Res 43: 681-685, 1972. 7. Timmers HJLM, Wieling W, Karemaker JM, Lenders JWM. Denervation of carotid baro- and chemoreceptors in humans. J Physiol 553: 3-11, 2003. 8. Vermeire P, de Backer W, van Maele R, Bal J, van Kerckhoven W. Carotid body resection in patients with severe chronic airflow limitation. Bull Eur Physiopath Respir 23(suppl 11): 165-166, 1987. 9. Whipp BJ. Carotid bodies and breathing in humans. Thorax 49(11): 1081-1084, 1994. 10. Whipp BJ, Ward SA. Physiologic changes following bilateral carotid-body resection in patients with chronic obstructive pulmonary disease. Chest 101: 656-661, 1992. David E. Leaf (1) and David S. Goldfarb (2,3) (1)Department of Medicine, Columbia University Medical Center, New York, NY (2)New York University School of Medicine, New York, NY (3)Nephrology Section, New York Harbor VA Medical Center, New York, NY