Ventilation in anemia and polycythemia

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  • Ventilation in anemia and pol ycythemia'

    Cardiopubnonar Research I ~ b o r a t ~ r y , Departnae~at of Pediatrics, University of Cokor.ads l%ifedica& Center, Derever, CoIorado

    Received December 4, 6969

    Dedicated to Dr. A. C. Burton as he retires as Chairman of the Departmegzt of Biophysics, U~iversity of Western Ontario

    CROPP, G. I. A. 31978. Ventilation in anemia and pslycythernia. Can. I. Physiol. Pharmaml. 48,382-393.

    Pulmonary ventilation was measured during breathing s f loo%, 20%, and 68% oxygen in lightly anesthetized dogs. The animals were divided inas three groups; dogs in each group were studied at their normal hematscrit and after complete recovery from exchange transfusions with either plasma, packed red cells, or norn~al blood. Exchange transfusions with normal blood or elevating the hematocrit to a mean of 54% did not alter minute ventilation at any of the inspired oxygen concentrations tested. When dogs were made anemic (mean hematocrit 11 9% ), they consistently ventilated more at all inspired oxygen csncentrations, and they had a faster and approximately 40% greater ventilatory response to hypoxia than before they were 111ade anemic. At a given inspired oxygen concentration Pao, was the same, but PGo2 was consistently louer in anemic than in non-anemic animals. Ventilation increased as PVo, fell, and this relation was independent sf existing laematocrits. A hypothesis has been prspssed that pulmonary ventilation may, in part, be regulated by average tissue Po, and systemic vascular resistance, with baroreceptors acting as tlae mediators of the response. Wc also observed that hemoglobin levels and hematocrits rose significantly during acute hypoxia in non-splenecto- mized dogs, causing an increase in the oxygen-carrying capacity of approximately 25% in anemic, of 6% in normal, and of 3 % in polycythernic dogs.

    Introduetisn who had no ~nycscardial disease (Cropp 1949b).

    Measurements of pulmollary ventilation in Experiments i;y Cornroc and ~chmihi ( 1938) 9

    anemia have given somewhat cdnflictinS results. Cbicsdi et a&. ( 1941 ), arncl Clark and associates

    WBurngart and Altschule ( 1948), in an extew- ( 1943 ) indicated that acute reductisms of

    slve review of the pathophysiology of anemia, oxygen-carrying capacity of blood by poiscsning

    listed increases in minute verstilation, decreases of hemoglobin with carbon monoxide or aniline

    in vital capacity, and decreases in arterial oxy- dyes did not change pulmo14ary ventilation.

    gel1 saturation during exercise as common find- Cornroe ( 1964) also stated that anemic sub-

    ings in patients v d h severe anemia. There jects did not hyperventilate. These observations

    was, however, great variability in the ventila- suggest that acute or moderate decreases

    tory adjustments to anemia among different in the oxygen-carrying capacity of blood do not

    subjects, and it is possible that the presence of affect respiration, but that severe anemia may

    clinical complications such as heart failure, increase miuutc ventilation moderately. We,

    pulmonary edema, or generalized systemic dis- therefore, designed experiments in lightly anes-

    ease influenced the way in whicll ventilation thetized dogs in which pulmonary ventilation was in was asscsed at various inspired oxygen con-

    observed hypcrventllation (low Paco,) wi thu t ccntraticsns at normal hematocrits, in severe

    alkalosis in several severely anemic children anemia, and in mild polycytl~emia. - -- -

    'This work was supported by grants from the Methods U.S.P.H.S. (HE 06895-08, HE 03554-02, and Career Mongrel dogs, weigfning 5.6 to 9.9 kg, were anes- Development Award HE 35249-03). thetized avitfn intravenous sodium pentobrrrbital (30

    "Present address: Cardiopulnaonary Research Lab- nag/kg, the minimum effective dose in dogs 0% this oratory, Department sf Pediatrics, University of size). Anesthesia was supplemented :is necessary Colorado Medical Center, 4200 E. 9th Ave., Denver, when the animals showed sign\ of awakening. The Colorado 80220, U.S.A. trachea was intubated with a cuffed tube. An external

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  • GROPP: VENTILATION IN ANEMIA AND POLYGYTHEMIA 383

    jugular vein and femoral artery were isolated under sterile conditions, and polyethylene catheters (PE 190) were inserted and advanced to the main pul- monary artery and aorta respectively. The tracheal tube was connected to a two-way low resistance valve with 18 ml dead space. The inspired gas passed through a pneumotachograph which was connected to a differential pressure transducer. The undamped differential pressure signal increased linearly as in- spiratory flow rates increased to 3000 ml/s. a value far exceeding peak flow rates encountered in these experiments. The inspiratory flow signals were elec- tronically damped by a filter capacitor with a time constant of 4 s. Inspired minute volume was obtained from the mean inspiratory flow rate, derived by in- tegrating the damped inspired flow rate signal, re- corded at a speed of 80 mm/s, over complete respiratory cycles during a 30- to 60-s period. In- tegration was performed with a planimeter, which on repeated tests measured known areas with an error of less than 1%. Zero flow rates were intermittently checked by disconnecting the respiratory valve from

    the tracheal tube. The mean inspiratory flow rates were recorded on a direct-writing recorder.

    Minute ventilation was measured during breathing of 100%, 20%, and 10% oxygen in nitrogen. At the altitude of Denver (1600 m above sea level) com- pressed dry 100% and 10% oxygen provides average inspired oxygen tensions of 628 and 63 mm Wg respectively; partly humidified room air has a Po2 of approximately 123 mm Hg at room temperature. Dry 10% and 100% oxygen was breathed from meteoro- logical balloons, connected by a multidirectional stop- cock to the inspiratory tube. Air and 100% oxygen were breathed for at least 10 min, and 10% oxygen for I0 to 12 rnin before minute ventilation was measurecl. 'Ihe lungs of the dogs were intermittently hyperinflated to prevent atelectasis, and secretions were aspirated from the trachea and major bronchi when necessary. The sequence in which air, 10% oxygen, and 100% oxygen were breathed was ran- domized.

    The inspired minute volume (eI ) was converted to minute ventilation at body temperature and full saturtation ( k'rDT,,) as follows:

    . (273 + rectal temp.) (barometric press. - 0.48PvR) - -

    ''BT~S = ' I ( ? m o o n ~ temp.) (barometric press. - PV.) where 0.48 was the average relative humidity in our laboratory during the period in which these studies were conducted (range 43-56% ), Pv, was water vapor pressure (mm Hg) at room temperature ( "C), and P I , was water vapor pressure (nmm Hg) at rectal temperature ("C). The correction factor for water vapor affected measurements of minute ventilation by less than 1 % when relative humidity changed from 40 to 60%; for this reason the average relative humidity factor of 0.48 was used for all calculations. When the inspired gas was dry, the relative humidity factor equaled zero.

    The volume of inspired gas only equals the expired volume when the respiratory quotient is 1.0. During hyperventilation of acute hypxia, excess COz is eliminatecl and the respiratory quotient (W.Q.) in- creases transiently. We crilcufated by how much the expired volume would differ from the inspired vol- ume when the R.Q. increased temporarily from 1.0 to 1.5. The results showed that such a change in R.Q. resulted in diaerences of less than d % between in- spired and expired minute volume. For these reasons the R.Q. correction was omitted, q d VrBTp, was eqliztted to TfE:BPPS. Measurements of VE,,,, were ex- pressect per kilogram body weight, to adjust for dif- ferences in body size of the experimental animals.

    Systemic arterial and mixed venous blood samples were obtained through aortic and pulmonary artery catheters respectively. Oxygen and GO2 tensions and pH were meas~ared on 1- to 2-ma1 samples, stored in ice water until determinations were made. Measure- ments were done within less than 10 rnin of collection on blood gas and pH electrodes. Temperature correc- tions for differences between instrumental and body temperatures were made with a blood gas calculator (Severinghatis 1966). Blood samples were mixed gently before blood gases and pH were measured; the

    remainder of the samples served for determinations of he~noglobin concentration by the cyanmethemoglobin method and of hematocrits by the capillary tube t echniqale.

    Anemia and polycythemia were induced by iso- volumetric exchange transfusions with plasma m d red cells respectively. Exchange transfusions were performed by simultaneously withdrawing arterial blood from the dog through the aortic catheter and infusing donor blood or plasma into the external jugular vein. We used a Holter pump (model #RL 175. Extracorporeal Med. Specialties, Inc., Mt. Laurel Township, N.J., U.S.A.) with two silicone elastomer pumping chambers (PC 7250); one chamber contin- alally infused donor blood while the other withdrew arterial blood. The bottles containing donor blood and receiving the removed blood were suspended from a scale. As long as the combined weight remained unchanged, identical amounts of blood were removed from and infused into the dog. When imbalances de- keloped, a screw clamp was used to adjust blood removal from or infusion into the dog to an appro- priate rate. At the end of the exchange transfusion we transfused a volume of plasnna or blood equal to the volume of all the blood sanaples removed during a study.

    Donor blood was collected sterilely under light sodium pentobarbital anesthesia from the femoral artery of donor dogs into 250-ml polycarbonate cen- trifuge bottles, containing 20-40 mg heparin each. The collected blood was centrifuged at 2200 r.g.m. for 10-12 rnin in a refrigerated centrifuge. The plasma and red cells were separated and stored in sterile plastic containers in the refrigerator at 4 "C. The exchange transfusions were performed after the initial control study at normal hematocrit had been com-

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  • 384 CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY. VOL. 48: 1970

    pleted. The volumes exchanged ranged from 500 to 850 m8, and the exchange transfusions were com- pleted in 30-45 min. After the exchange transfusions vilere finished, catheters were removed, vessels were tied off, and the skin was closed. The dogs were given 400 000 units penicillin G and 0.5 g streptomycin inrramusckilarly and 15-20 mg protarnine sulfate in- travenously. The dogs were given antibiotics (same dose as above) once daily for 2 to 3 days. Three groups of dogs were studied:

    Group I consisted of nine dogs, exchange-transfused with plasma and restudied in the anemic state; group 81 had eight dogs, exchange-transfused with packed cells and restudied when polycythernic; group 111 had eight dogs which were studied before and following an exchange transfusion with whole blood. The second study was performed 3-7 days after the first one. Every dog was exposed at least twice to each breath- ing-gas mixture during pre- and post-exchange studies, and the mean values for aninrate ventilation, blood gases, hernatocrits, and hemoglobins at every inspired oxygen concentration were calculated for each dog and for both the pre- and the post-exchange studies. Since each dog was studied twice, we used each ani- mal as his own conti-08; we, therefore, calculated how much the various parameters had changed in each dog from the pre-exchange to the post-exchange period, and by the use of Student's t test we determined whether the mean changes were significantly different from zero. Group 111 (dogs exchange-transfused with whole blood) served as a procedural control group to show whether submitting a dog to an exchange trans- fusion, witlaout altering its hernatocrit, would affect its ventilatory response to various inspired oxygen concentrations. Changes were considered insignificant when the p values exceeded 0.05.

    Results

    Table I shows that exchange transfusions wi t l ~ plasma produced severe anemia (mean hematocrit (Hct) 1 1.3 % ) , while exchange transfusions with packed cells raised the hema- tocrit on the average by 10.2%. Exchange transfusions with normal blood did not induce sigr~ificant changes in either hemoglobin con- centration csr hematocrit. At the time of the second study all dogs were in good health, none of the anemic dogs were in heart failure, and the average weight for the dogs in each group had not changed significantly.

    Following the completion of the second study, the dogs were killed and their lungs ex- amined immediately. There were no macro- scopic signs of pneumoilia or atelectasis in any of the animals examined. When dogs were exchange-transfused with plasma the hcmo- globin and hcmatocrit levels, measured im- mediately following exchange transfusions,

    TABLE I Hemoglobin concentrations and hematocrits during 1100 % oxygen breathing before and after exchange

    transfusions with plasma, packed cells, si- normal blood

    - - - - - - - - - -- - - - - - - - - - - - - - -- -

    Mean [Hb] (g/100 rnl Mean Hct

    blood -t S.E.) (% -t S.E.) -- -- -- - - -- -- - - - - - --

    Group I Pre-exchange

    (normal Hct) 12.9_+0.41 38.821.36 Post exchange

    (anemia) 3 .710 .35 11.3k0.76 Group I1

    $re-exchange (normal Hct) 14.7 1 0 . 4 6 43.751.17

    Post-exchange (polycythemia) I 8 . 4 _6 8.52 53.9k 1.24

    Group 11% Pre-cxchange

    (normal Hct) 13.5 -t 0.50 39.5k1.50 Post-exchange

    (normalHc4) 12.4k0.35 36.9k0.49

    werc not significantly different from those ob- served at the time of the second study. How- ever, when dogs were exchange-transfused with packed red cells, the post-exchange hemto- crits were higher than those observed several days later (60-75 % versus 48-63 % 1. There were no visible signs of hernolysis in plasma, collected I to 7 days after the initial study. When the dogs were killed at the end of the second study, the spleens of polycythemic ani- mals appeared to be of similar size to those of dogs with normal or low hernatocrits. Blood volaames, measured by the Evans Blue dye method, were on the average 9% larger in the pslycythcmic dogs than in the same dogs be- fore they were exchange-transfused; this dif- fcrcncc could account for approxhnatdy half of the fall in hcrnatocrit subsequent to the ex- change transfusions. It appears, therefore, that some red cells were destroyed after the ex- change transfusions with packed cells, and the released hemoglobin or its breakdown products were excreted before the time of the second study.

    Table 11 and Fig. I show that before ex- change transfusions all three groups of dogs had similar minute ventilation at the various inspired oxygen concentrations tested and an approximately equal increase in ventilation in response to acute hypoxia. When nine dogs were rendered anemic, they incrcascd their

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  • CROPP: VENTILATION IN ANEMIA AND POLYCYTWEMIA

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  • CANADIAN JOURNAL 8%: PHYSIOLOGY AND PKARR-ZACOLOGY. VQL. 48, 1990

    nsp i red Oxygen *----+ - -

    A n e m i c B o g s N o r m a l H c t P o l y c y t k e r n i c D o g s

    FIG. 1. Mean minute ventilation in three groups of dogs at lgB0%, 2096, and 16% inspired oxygen before and after exchange transfusions. Each group was first studied at its normal hematocrit (control) and then after being rendered anemic ( la) or polycythemic ( I b ) , or after being exchange-transfused with whole blood which did not dter hematocrit ( Ic ) . Anemic dogs always ventilated more than now-anemic dogs at all inspired oxygen coneentra- tions. The ventilatory response to 10% Oz was also significantly greater in anemia. Pc~Iyey- thcmia and cxshamge transfusions with normal blood did not affect ventilation or the ventilatory response to hypoxia significantly.

    minute ventilations at all inspired oxygen con- centrations, and they had a 40% greater venti- latory response to hypoxia than before they were made anemic. The increased responsive- ness to hypoxia was statistically significant ( p < 0.0 1 ) . Tt was regularly noted that ventilation increased at a faster rate at the onset of hypoxia in anemic than in non-anemic dogs.

    The results in Table II and Fig. 1 show that mild ~rolycythemia (group HI) did not affect minute ventilation or the ventilatory response to hypoxia in the dog. They also suggest that submitting dogs to an initial experiment and an exchange transfusion will not alter their minute ventilation or ventilatory response to hypoxia at the time of the second study.

    Inspection of Fig. 2 and Table 11% confirms that when dogs were made anemic they hyper- ventilated, as indicated by lower Pco2 and higher pH values than before they were made ancmic. Acute hypoxia tended to decrease Pa(yo, and increase pHa more in anemic than in nsn-anemic dogs, suggesting a larger than normal increase in ventilation in ancmic dogs in response to hypoxia. In mild polycythcm~a or after mere exchange transfusions with whole blood the arterial or-venous pH or PCOB were

    the same as during the pre-exchange phase of the experiment.

    Arterial P,, values were not changed by the exchange transfusions in any of the three groups of dogs. Mixed venous Po2 was always less in anemic than non-anemic dogs, at any inspired oxygen concentration. Mild polycyth- cmia or exchange transfusions with normal blood did not alter the Pvo, at any given in- spired oxygen concentration.

    The relation between Pao, apd PVo2 on orle hand and ventilation on the other is shown in Fig. 3. The fi galre indicates that at any given Pao2, post-exchange animals with normal or elevated hcmatscrits had essentially the same ventilation, while anemic dogs ventilated more. When, however, the re la ti or^ between minute vuntiiation and mixed venous Po, is examined, there is no strikir~g difference in ventilation be- tween anemic andnon-anemic dogs at any one PVo,, and ventilation seemed to increase at a progressively faster sate as Eo, fell to low values.

    We regularly observed significant increases in hemoglobin concentrations and hematocrits when dogs were chamgcd from breathing 100% oxygen or air to 10% oxygen. The mean

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  • GROPP: VENTILATION IN ANEMIA AND POLYCYTHEMIA

    Mixed Venous 0

    O h Insp i red Oxygen g - - - - - - - - - *

    A n e m i a ( P o s t - E a c h . ]

    K+---------------------4

    N o r m a l H e t ( P r e - E x c h . ]

    FIG. 2. Mean values for blood gases and pH during 100%, 20%, and 10% 8. breathing in dogs before and after they were made anemic. Note evidence of hyperventilation in anemia (relatively law Pacyo2 and high pMa). PVoa was significantly less in anemic than nsn-anemic dogs at all inspired 0? concentrations.

    changes noted on switching from 100% to 10% oxygen are summarized in Table TV. The increases tended to be most marked in anemic animals. There were no significant increases in either heinatascrit or he~noglobin concentra- tion when the inspired gas was changed from 180% oxygen to air. The rise in hemoglobin concentration during hypoxia increased the oxygen-carving capacity by approximately 25% in anemic dogs, by 6% in dogs with normal hematocrits, and by 3% in polycythe- mic animals.

    Discassion The most important observation in this

    study was that anemic dogs ventilated more at any inspired oxygen concentration and showed a greater ventilatory response to hypoxia than non-anemic dogs.

    The arterial P,,, at any given inspired oxygen concentration was the same in anemic and nsn- anemic animzls; we, therefore, conclaaded that alterations in Pao, were not thc likely cause for the observed increases in minute vcntila- tion in anemia and that systemic chemorecep-

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  • CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY. VOL. 48, 1970

    TABLE III Effect of anemia, pslycythemia, and exchange transfusions alone on mean blood gases and pH - - - - -. - - - - - - - - - -- --

    Group I ~ r o u p II Group nr Significance

    Inspired Pre- of change Pre- Poly- Pre- Psst- gas exchange Anemia Change ( p value) exchange cythernia exchange exchange

    pao, 100% 0, Air 10% 0 2

    P ~ c o , 100% 0 2 Air 10% Oa

    pHa 100% O2 Air 10% 0 2

    Pvo, 100% 0 2 Air 10% 0 2

    pHv 100% 0 3 Air 10% 0 2

    NOTE: All blood gas tensions in millimeters of Hg.

    TABLE IV Mean increases in hemoglobins and hematocrits during acute hypoxia before and after exchange transfusions

    for each of three experimental groups -. - -- - - - --

    Significance Significance Mean [Hb] Change in [Hb] of change Change ian Hct of change

    Group (g/100 ml) (glI00 ml _+ S.E.) ( p value) (%, + S.E.) ( p value) -- - - . --

    I : Pre-exchange 12.9 +0 .5+0 .15

  • CROPP : VENTILATION IN ANEMIA AND POLYCYTHEMIA

    0 - - - - - I aP---=a - A n e m i c B o g s N o r m a l D o g s P o l y c y t h e m i c D o g s

    FIG. 3. Relation between minute ventilation (liE/kg) and arterial and mixed venous Po2 in post-exchange dogs. At a given Pao,, anemic dogs tended to ventilate more than non-anemic animals. V. increased as PVoz fell. At a given PCo, ventilation was the same in dogs with high, low, or normal hematscrits.

    tion. The findings were interpreted by these authors in the following way: the arterial oxygen content of blood supplying systemic chemoreceptors, rather than its Po,, is impor- tant to their function. It should be noted that Mills and Edwards did not measure pulmonary ventilation, and chemoreceptor discharges can- not be equated with ventilation. While these authors suggested that in the older CO experi- ments the central nervous svstem mav have

    J J

    been depressed by carbon monoxide, it is equally possible that in their experiments car- bon monoxide stimulated chemareceptors in a pharmacological, but not physiological way.

    Since the arterial pH was higher during the hyperpnea of anemia, it is unlikely that the observed hyperventilation was a compensatory effort to correct a metabolic acidosis; on the contrary, it appears that severe anemia elicited a mild primary respiratory alkalosis.

    We were unable to confirm in the dog the

    observations of ventilatory depression in poly- cythernia made by Hornbein and Roos ( 1958) and Risgard et al. (1969) in man and calves respectively. Our findings correspond to those of Eisele et al. ( 19&9), who also studied dogs; the disagreement with Hornbein and Bisgard may be due to species differences, to too moder- ate a degree of polycythemia, or to changes in ventilation which were beyond detection in our ex~eriments.

    I

    We observed that in dogs with high, normal, or low hematocrits, ventilation increased as Pvo2 fell. If there is a relation between PvO, and ventilation, anemic animals would be ex- pected to breathe more than non-anemic ones, since their Pv,,, is always lower than that of non-anemic dogs at a given inspired oxygen concentration. Since Pvo, falls lower during hypoxia in anemic than in non-anemic dogs, it would also be expected that hypoxia would elicit a greater ventilatory response in the ane-

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  • CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY. VOL. 48, 1970

    I PERIPHERAL VASODILATION [

    I MEDULLARY CENTERS (Vasomotor and Respiratory) I

    I OXYGENATION SUPPLY TO TISSUES I FIG. 4. Schema for a hypothetical mechanism by which respiration may be regulated in

    anemia.

    mic than in the non-anemic state; this was, in fact, observed. The question arises whether there are chemoreceptors in the pulmo~lary cir- culation which sense changes in Pvo, and cause respiratory stimulation whenever mixed venous Po, falls below a critical level. Duke et aH. (1963) suggested that such receptors may exist on the basis of neurophysiological, but not ventilatory studies. The work of many other investigators has failed to show that there are functionally significant chemoreceptors in the pulmonary circulation which detect either de- creases in Pvo, or pH, or increases in (Heymans and Heymans 1927; Bejours et al. 1955; Gropp and Comroe 196% ). We, there- fore, consider it unlikely that the low Pvo, in anemia stimulated mixed venous chemorecep- tors.

    A decrease in mixed venous oxvgen tensions J L7

    suggests that the average tissue oxygen tension has fallen. Jnvestirrations bv several workers have indicated t ha i tissue hipoxia can lcad to vasodilation and low vascular resistance (Bar- croft et al. 1952; Ross et al. 1962). Low sys- temic vascular resistance has been repeateOly

    demonstrated in patients with anemia (Bran- non et a/. 1945; Roy et al. 1963; Duke and Abelmann 1969; Gropp 1969a). The findings of Duke and Abelmann (1969) and Cropp (19696) suggested that the low systemic vas- cular resistance in anemia was due to vasodila- tion and not to low blood viscosity. We re- cently proposed that the cardiovascular ad- justme~~ts in anemia are aimed at maintaining systemic arterial blood pressure, and that baro- receptors may be involved in this regulatioi~ (Gropp 1969b). We would like to suggest that the same negative feedback system may also be responsible for the stimulation of respiration in anemia. A hypothetical schema which sum- marizes our ideas is shown in Fig. 4. As tissue hypoxia causes peripheral vasodilation, baro- stretch receptors detect a fall in arterial blood pressurc, discharge fewer inhibitory impulses, and allow vasomotor and respiratory centers to discharge more. The described feedback loop attempts to maintain systemic arterial pressure and also stimulates ventilation; in this loop arterial pressure is the controlled variable and baroreceptors are the mediators or sensors.

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  • CROPP: VENTILATION IN ANEMIA AND POLYCYTHEMIA 391

    Aviado and Schmidt ( 1955) stated that stimu- lation of efferent carotid sinus nerves or in- creased sinus perfusion pressures caused res- piratory inhibition, while denervation or sinus hypotension tended to stimulate ventilation. It, therefore, seems possible that the low systemic vascular resistance in anemia stimulated rcs- piration. The anemic dogs examined in this study had significantly decreased peripheral vascular resistances, in comparison with their non-anemic state (unpublished observations), indicating that the physiological changes nec- essary for decreased baroreceptor discharge had occurred. The proposed mechanism of respiratory stimulation secondary to tissue hy- poxia may also contribute to the ventilatory drive in such hypermetabolic states as fever, artificial h yperthermia, hyperthyroidism, and exercise, and in shock where lack of barorecep- tor discharges releases vasomotor and respira- tory centers from inhibition. Bejours (1964) speculated that baroreceptors may be important in the respiratory control of exercise.

    The aim of increased ventilation in anemia is to .raise the alveolar oxygen tension and oxygen delivery to the tissues. When the in- spired oxygen tension is high and hemoglobin leaves the lung fully saturated with oxygen, the benefits derived from hyperventilation are small; however, when inspired gas mixtures have low oxygen tensions, as, for instance, at altitude, the small increase in alveolar P,,, pro- duced by hyperventilation can elicit a consid- erable rise in the concentration of oxyhemo- globin in systemic arterial blood. The baro- receptor drive of ventilation is, therefore, probably only of secondary importance in the control of ventilation under normal, resting, physiological conditions in comparison wich central and chemoreceptor drives, but it may gain in significance when tissue hypoxia, re- gardless of its cause, becomes severe. The baroreceptor-regulated part of respiratory drive will be maximal at a systemic arterial pressure of 60 mm Hg or less when the baroreceptors become functionally inactive. The vasomotor and respiratory stimulation initiated by low systemic vascular resistance and small decreases in mean arterial pressure will be partly offset by the high pulse pressure observed in anemia.

    The greater than normal ventilatory response to acute hypoxia in anemia may also be re-

    Iated to decreased baroreceptor activity. While noa-anemic dogs regularly and pro~ressively increased their systemic arterial pressure dur- ing acute hypox'la, our anemic dogs showed only a transient rise, followed by a return of pressure to pre-hypoxic levels (unpublished observations). Because of the relatively low distending pressures in the arterial barorecep- tors during hypoxia in anemic animals, medul- lary centers were also less inhibited and could discharge more; thus, the respiratory center could drive pulmonary ventilation during hyp- oxia more in anemic than non-anemic dogs. The ventilatorjl response to hypoxemia is, of course, primarily elicited by stimulation of systemic arterial chemoreceptors, but the response may be cnhanced by tissue hypoxia, low systemic vascular resistance, and decreased barorecep- tor discharge.

    While respiration in anemia may, in part, bc controlled by a mechanism shown in Fig. 4, and the circulation by a schema suggested re- cently by us (Cropp 1969b), oxygen delivery to the tissue is regulated primarily by increases in cardiac output and by favorable unloading conditions for oxygen in the tissues. This latter mechanism can be achievcd by moving the oxygen dissociation curve to the right. Mul- hausen et al. (1967) demonstrated such a shift in anemic patients, and it is probably related to higher than normal concentrations of 2,3-diphosphod ceric acid levels in the red

    b y cells of such subjects (Eaton and Brewer 1968).

    Reversible and rapid changes in hemoglobin concentrations and hematocrits during acute hypoxia were noted in anemic and non-anemic dogs. Gold and Murray (1969) showed that anemic dogs with a normal spleen increased their hematocrit when given a small dose of adrenaline, but that splenectomized dogs did not show such a response. Our dogs had intact spleens, and it is possible that, regardless of their hematocrit levels, they stored blood with very high hematocrit in their spleens which was released into the general circulation during hypoxia, causing a significant increase in large vessel hemoglobin concentrations. It is possible that adrenaline mediatcd the observed red cell release from the spleen. The increase in hema- tocrit tcndcd to be greater in anemic than non- anemic dogs, suggesting that in anemia slightly

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  • 392 CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY. VOL. 48, 1978

    more red cells entered the circulation during hypoxia than in the non-anemic state. The in- crease in hematocrit during hypoxia was of particular benefit to the anemic dogs, since it increased their oxygen-carrying capacity by approximately 25 % . This mechanism is prtab-. ably- of little importance in man, who has only a small and relatively non-reactive spleen. Another way in which hypoxia could have increased thc hematocrit was by a momentary decrease in plasma volumc. Ascent to high al- titude will causc a quick and brisk water diure- sis and a decrease in plasma volume in young human subjects (Lawrence et al. 1952; Nan- non et al. (969) .. Whether plasma volume can be altered within 10 min by hypoxia is not known, although rapid changes in hematocrit have been observed with alterations in body position (Pera and Berliner 1943; Cropp, un- published observations).

    The minute ventilations per kilogram body weight in our dogs with normal hematocrits were larger than those reported by others (Alt- man and Dittmer 1964). Wc attributed the larger ventilation to the relatively small size of our dogs (5-10 kg) and thc very light anesthe- sia used in these experiments. The dogs werc not hyperventilating during breathing of air or 100% oxygen as indicatcd by normal Paco, and pHa values.

    We believe that animals made anemic or polycythemic by exchange transfusions should be allowed to adjust to their new physiological state before hemodynamic or ventilatory studies are attempted. This seemed important since we frcqucntly observed a depression in their level of consciousness immediatelv after the cx-

    J

    change transfusions, and hemodynamic or res- piratory responses to hypoxia which were dif- fercnt from thosc noted after the animals had adjustcd to their anemic or polycythemic state.

    Acknowledgments

    The skilled technical assistance of Mrs. R. Babich and Mrs. E. Toyos, and the secretarial help of Mrs. D. Hoskins during the preparation of the manuscript were much appreciated.

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