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.
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 grou...