The effect of anemia on the ventilatory response to transient and steady-state hypoxia. T V Santiago, … , N H Edelman, A P Fishman J Clin Invest. 1975;55(2):410-418. https://doi.org/10.1172/JCI107945. Research Article The effects of anemia upon the ventilatory responses to transient and steady-state hypoxia were studied in unanesthetized goats. Responses to transient hypoxia (inhalation of several breaths of nitrogen) were considered to reflect peripheral chemoreceptor and non-chemoreceptor influences of hypoxia upon ventilatory control. In all goats, severe anemia (hemoglobin 3.1-4.8 g/100ml) markedly heightened the responses to transient hypoxia (from a mean of 0.27 to a mean of 0.75 liter/min/percent fall in SaO2). This phenomenon was substantially reversed by alpha-adrenergic blockade (phenoxybenzamine, 5 mg/kg). In contrast, the ventilatory responses to steady-state hypoxia were unaffected by severe anemia. These data suggest that severe anemia enhances the peripheral chemoreceptor-mediated response to hypoxia through a mechanism involving the alpha-adrenergic system. It also appears that a ventilatory depressant effect of hypoxia which is not mediated by the peripheral chemoreceptors is also enhanced by severe anemia, thereby preventing an increase in the steady-state ventilatory response to hypoxia. Finally, experiments involving variation in oxygen affinity of hemoglobin suggested that O2 tension rather than O2 availability in arterial blood is the major determinant of peripheral chemoreceptor activity. Find the latest version: https://jci.me/107945/pdf The Effect of Anemia on the Ventilatory Response to Transient and Steady-State Hypoxia TEODORO V. SANTIAGO, NORMAN H. EDELMAN, and AMnRE P. FISHMAN From the Pulmonary Diseases Division, Department of Medicine of the College of Medicine and Dentistry of New Jersey-Rutgers Medical School, Piscataway, New Jersey 08854, and Cardiovascular-Pulmonary Division, Department of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania 19104 A B S T R A C T The effects of anemia upon the ventila- of arterial blood (1). There is also considerable un- tory responses to transient and steady-state hypoxia were certainty concerning the effects of anemia upon ventila- studied in unanesthetized goats. Responses to transient tion per se and upon the ventilatory response to hypoxia hypoxia (inhalation of several breaths of nitrogen) were (2, 3). This issue is of clinical interest since new modes considered to reflect peripheral chemoreceptor-mediated of therapy for patients with hematologic malignancies reflexes whereas responses to steady-state hypoxia were and chronic renal failure have increased the prevalence considered to reflect both the chemoreceptor and non- of individuals with severe chronic anemia who are likely chemoreceptor influences of hypoxia upon ventilatory to encounter hypoxia-producing respiratory disorders. control. In all goats, severe anemia (hemoglobin 3.1-4.8 One basis for the disparate results obtained in previ- g/100 ml) markedly heightened the responses to transi- ous studies of the ventilatory response to hypoxia in ent hypoxia (from a mean of 0.27 to a mean of 0.75 liter/ anemia may be the use of steady-state methods. This min/percent fall in SaO2). This phenomenon was sub- reservation stems from the fact that ventilatory responses stantially reversed by alpha-adrenergic blockade (phe- to all but exceedingly brief periods of hypoxia prob- noxybenzamine, 5 mg/kg). In contrast, the ventilatory ably reflect the combined effects of stimulation of the responses to steady-state hypoxia were unaffected by peripheral chemoreceptors and of depression of ventila- severe anemia. These data suggest that severe anemia tion via a direct effect upon the central nervous system enhances the peripheral chemoreceptor-mediated re- (4). Anemia could complicate the situation by decreas- sponse to hypoxia through a mechanism involving the ing oxygen delivery to both the peripheral chemore- alpha-adrenergic system. It also appears that a ventila- ceptors and the brain. tory depressant effect of hypoxia which is not mediated The protocols of the present study were, therefore, by the peripheral chemoreceptors is also enhanced by designed to evaluate separately the peripheral chemo- severe anemia, thereby preventing an increase in the receptor and the direct central nervous ventilatory ef- steady-state ventilatory response to hypoxia. Finally, ex- fects of hypoxia in intact unanesthetized animals. In periments involving variation in oxygen affinity of hemo- order to make this distinction, we took advantage of the globin suggested that O tension rather than 02 avail- fact that the peripheral chemoreceptor stimulation of ability in arterial blood is the major determinant of ventilation occurs within 2-10 s after exposure to acute peripheral chemoreceptor activity. hypoxia (5), whereas the centrally mediated depression of ventilation by acute hypoxia takes 40-60 s to become INTRODUCTION manifest (6, 7). We, therefore, assessed the peripheral chemoreceptor responses to hypoxia by exposure of un- It has long been known that acute oxygen lack stimulates anesthetized goats to brief inhalations of nitrogen and, in ventilation. However, many facets of this reflex are still the same animals, we considered the responses to steady- obscure. It is not yet clear whether the peripheral ar- state hypoxia to provide a measure of the combined ef- terial chemoreceptors sense oxygen tension or content fects of the peripheral chemoreceptor and central ner- of Received for publication 14 February 1974 and in revised vous effects hypoxia. form 23 September 1974. From these experiments, we have been able to evalu- 410 The Journal of Clinical Investigation Volume 55 February 1975- 410 418 ate the roles of several factors in the overall ventilatory pressure to be recorded simultaneously as blood was with- response to hypoxia during chronic anemia. These in- drawn. It was shown that removal of 30-40 ml as during the transient hypoxia studies was without effect on the clude oxygen content of arterial blood, the degree of ventilation, blood pressure, and heart rate. Separate studies affinity of hemoglobin for oxygen, the level of sympa- comparing the effects of introducing the catheter via the thetic nervous system activity, and the effects of hypoxia carotid artery and the femoral artery also failed to disclose upon tissues other than the peripheral chemoreceptors. any difference in the observed data which might have been attributable to the different sites of cannulation. METHODS Steady-state hypoxia and hypercapnia The experiments were performed on 17 goats which ranged The same valving system was used to deliver air fol- in weight from 30 to 35 kg. 1 wk before the onset of the lowed by a mixture of 12% oxygen in nitrogen for 7 min study, under general anesthesia, an indwelling arterial can- each. Ventilation, blood pressure, and heart rate were re- nula was placed in the descending aorta via a carotid or corded continuously. Arterial blood was collected anero- femoral artery. During the week between the arterial can- bically after 6 min of breathing air and after 1.5 and 6 nulation and the experiments, the animals were trained min of breathing the hypoxic mixture. Expired gas was to the test procedures by exposure to mock experiments and collected for 1 min after 6 min of inhalation of each gas equipment in the laboratory. The animals were studied un- mixture. The blood samples were analyzed within 10 min anesthetized and were lightly restrained by fixing the using appropriate electrodes (Radiometer Co., Copenhagen, horns to a post while standing upright. Denmark) at 370C for Po2, Pco2, and pH. Oxygen satura- The experimental procedure involved the use of a snug tion and hemoglobin content were determined by spectro- mask, with a dead space of 100 ml, fitted to a Rudolph one- photometry (CO-Oximeter, Instrumentation Laboratory way breathing valve (0. C. Rudolph and Sons Inc., Cald- Inc., Lexington, Mass.). The volume of expired gas was well, N. J.). Wide-bore tubing at both ends of the valve measured with a calibrated dry-gas meter and samples made possible a switch from one inspired gas to another, were collected anerobically for determination of Po2 and or the collection of expired gas, without disturbing the Pco2 (Radiometer Co.). The accuracy of the analyzers was goat. Ventilation was measured using a Fleisch pneumo- checked periodically using the micro-Scholander technique tachograph that was interposed in the inspiratory line and (10). Oxygen consumption, carbon dioxide production, and attached to a differential pressure transducer (Statham respiratory quotient were calculated in the usual way (11). PM-15, Statham Instruments, Inc., Oxnard, Calif.). The The ventilatory response to inspired C02 was determined pressure signal was converted to a signal proportional to by administering an inspired gas mixture of 5% CO2 in tidal volume using an integrator circuit and records were 30% 02 plus N2 after a period of breathing a mixture of made using an oscilloscopic recorder (Electronics for Med- 30% 02 in N2. Each period lasted for 10 min. Expired icine, Inc., White Plains, N. Y.). Calibrations of volume gas and arterial blood were sampled during the last minute were made using a 2-liter syringe; these calibrations were of each period. The volume of expired gas and the pH, repeated three times during each experiment. Each calibra- Pco2, and Po2 of the arterial blood were measured as above. tion deviated by less than 10% from the average value. The ventilatory response to CO2 was expressed as the ratio of the increase in ventilation to the increase in arterial Transient hypoxia Pco:. The method for determining the ventilatory response to Groups of studies transient hypoxia was a modification of that originally described by Dejours (8). Before the start of the ex- Four groups of studies were done: (a) determination of perimental procedure, the goats were anticoagulated with the effects of anemia upon the ventilatory responses to heparin (2 mg/kg) administered i.v.