Circulatory dynamics of pregnancy

OBSTETRICS Circulatory dynamics of pregnancy I. Fluid shifts following saline infusion

BEN H. DOUGLAS, PH.D. THOMAS G. COLEMAN, PH.D. Jackson, Mississippi

The ability of pregnant and nonpregnant animals to handle a standard infusion of physiologic saline was determined. Infused fluid leaves the circulatory system of pregnant animals and enters the extravascular space at a relatively slower rate. This becomes apparent when pregnant animals are subjected to nephrectomy prior to infusion and their response compared to that of the nonpregnant animals which had nephrectomy prior to infusion. An analogue model of the system suggests that this may be due to a lesser degree of dilution of the pregnant animal's plasma proteins following saline infusion.

A N u M B E R of physiologic changes occur in the circulatory system during normal pregnancy. During the first and second trimesters of pregnancy, the arterial pressure tends to decrease. 1 • 2 • 3 There is a disproportionate decrease in diastolic pressure which frequently produces capillary pulsations. The venous pressure in the upper extremities remains fairly constant but tends to increasP in the lower extremities.~ The blood volume increases during pregnancy due to increases in plasma volume and red cell mass. 5 • 6 The blood viscosity and circulation time decrease due to the increase in plasma volume. The mean systemic pressure increases during pregnancy. 7 Cardiac output rises during pregnancy but reportedly returns to near normal at term. 8 • 9 • 10 Edema is common during pregnancy and

has been attributed to obstruction to lymphatic and venous return from the lower extremities, reduction in plasma oncotic pressure, and retention of sodium and fluids. 11 It appears, for a variety of reasons, that the pregnant animal is more susceptible to edema formation than the nonpregnant animal. If the pregnant animal is more susceptible to edema fmmation, this indicates that there is a change in capillary dynamics. This study was designed to examine this change in capillary dynamics by determining the relative rates of disappearance of fluid from the circulatory system of pregnant and nonpregnant animals. A model of the system was used to relate some of the other circulatory changes during pregnancy to capillary dynamics.

From the Departments of Medicine and Physiology and Biophysics, University of Mississippi Medical Center.

Methods Forty-five Holtzman albino rats weighing approximately 250 grams were used in this

Supported by NIH Grant HE-09192.

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study. The first group of 15 animals was treated as follows: They were anesthetized with 30 mg. per kilogram sodium pentobarbital and the external jugular vein was cannulated for fluid administration. Control Five of the animal~ were then infused with 1 mi. saline per 100 grams body weight, 5 were infused with 2 ml. saline per 100 grams body weight, and 5 were infused with 3 mi. saline per 100 grams body weight. The saline was infused over a 2 minute period and hematocrits were taken at 1, 5, 10, 20, and 30 minute intervals following infusion. The second group of 15 animals had nephrectomy. Following nephrectomy they underwent the same procedure. The third group of 15 animals was pregnant and was treated as follows: Control hematocrits were taken on 5 of the animals, they were infused with 2 mi. saline per 100 grams body weight, and hematocrits were taken at 1, 5, 10, 20, and 30 minute intervals. The gravid uterus was removed from 5 animals, they were infused with saline as above and their hematocrits taken. The remaining 5 pregnant animals were subjected to nephrectomy and the procedure repeated. A mathematical model of the circulatory system was designed with special emphasis on fluid volumes and capillary dynamics. The §ystem response to saline infusion in both pregnant and nonpregnant states was studied. Hematocrit, interstitial fluid volume, blood volume, mean systemic pressure, cardiac output, capillary pressure, plasma colloid osmotic pressure, tissue colloid osmotic pressure, tissue pressure, and the rate of change of interstitial fluid volume were recorded. Results

Fig. 1, A shows the effect on hematocrit of infusing 1, 2, or 3 mi. saline per 100 grams body weight. The hematocrit of the animals which received 1 ml. saline per I 00 grams body weight (solid line) decreased from 4 7 ± 1 per cent to 44 ± 1 per cent following infusion of the saline. Within

approximately 5 minutes the hematocrit returned to control levels. The hematocrit of the animals which received 2 mi. saline per 100 grams body weight (broken line) decreased from 4 7 ± 1 per cent to 42 ± 2 per cent follovving infusion of the saline. The hematocrit of these animals did not reapproach control levels as raoidlv as did thP hematocrit of the first group, but within 10 minutes it had returned approximately to control levels. The hematocrit of the animals which received 3 ml. saline per 100 grams body weight (dotted line) decreased from 48 ± 2 per cent to 40 ± 2 per cent following infusion of the saline. The hematocrit of these animals did not reapproach control levels as rapidly as did the hematocrit of the first group but it reached approximate control levels within 10 to 20 minutes. Fig. 1, B shows that total nephrectomy had little effect on the shape of the curves, at least during the first 5 to I 0 minutes following infusion of the saline. The hematocrit of the animals which received 1 ml. saline per 100 grams body weight (solid line) decreased from 52 ± 2 per cent to 49 ± 1 per cent, the hematocrit of the animals which received 2 ml. saline per 100 grams body weight (broken line) decreased from 50 ± 2 per cent to 44 ± 1 per cent, and the hematocrit of the animals which received 3 ml. saline per 100 grams body \veigh t (dotted line) decreased from 49 ± 1 per cent to 41 ± 2 per cent. The magnitude of decrease in hematocrit of the nephrectomized animals was approximately the same as that of the control animals. The hematocrits also returned to control levels in approximately the same periods of time. Fig. 2 shows the effect on hematocrit of infusing saline into pregnant animals. All of these animals received 2 mi. saline per 100 grams body weight. This was somewhat of a compromise since 1 mi. saline per 100 grams decreased the hematocrit approximately 3 points, and since 3 mi. saline per 100 grams body weight was not well tolerated by the animals. The hematocrit of the control pregnant animals which were infused (solid line) decreased from 45 ± 2 per cent .._

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Fig. 1. The effect on hematocrit of infusing 1, 2, or 3 mi. saline per 100 grams body weight into control animals (A) and nephrectomized animals (B) is shown. Standard errors of the mean are indicated.

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June 15, 1970

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Fig. 2. The effect on hematocrit of infusing 2 mi. saline per 100 grams body weight into pregnant animals, pregnant animals following hysterectomy, and pregnant animals following m·phrectomy is shown. Standard errors of the mean are indicated.

to 40 ± 1 per cent but reapproached control levels within approximately 10 minutes. Removal of the gravid uterus did not change this pattern of response as the hematocrit of these animals (broken line) following infusion of saline decreased from 42 ± 2 per cent to 37 ± 1 per cent. The pregnant animals which had nephrectomy prior to saline infusion exhibited a somewhat different response. Their hematocrit following saline infusion decreased from 45 ± 2

per cent to 36 ± 3 per cent. lVhile this decrease appears to be greater in magnitude than that of the other pregnant animals, the difference is not significant. However, the hematocrit of these animals did not rcapproach control levels as rapidly as did the hematocrit of the other pregnant animals. It was only after 20 to 30 minutes that the hematocrit of these animals began to reapproach control levels. Fig. 3 shows a block diagram of the

Circulatory dynamics m pregnancy

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circulatory model. The model shows that the net rate of change in plasma volume is equal to the rate of infusion minus the movement into the interstitial spaces. The net rate of change in plasma volume is then integrated to give plasma volume. The plasma volume is summed with the red cell volume to give blood volume. The red cell volume divided by blood volume gives the hematocrit ratio. The functional reiationship of blood volume to mean systemic

tissue protein divided by the interstitial fluid volume gives tissue protein concentration. Tissue protein concentration multiplied by K., is the tissue colloid osmotic pressure. The relationship of interstitial fluid pressure to interstitial fluid volume is used to calculate interstitial fluid pressure. Then, interstitial fluid pressure, capillary pressure, tissue colloid osmotic pressure, and plasma colloid osmotic pressure are summed to give the change in pressure at the capillary. The

pressure is then used to calculate mean sys~

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temic pressure. The mean systemic pressure multiplied by K, a constant, gives the cardiac output. The cardiac output multiplied by the venous resistance equals capillary pressure. The model also shows that plasma protein concentration is equal to plasma proteins divided by plasma volume. Plasma protein concentration multiplied by K 2 is the plasma colloid osmotic pressure. The

plied by K 3 gives the rate of shift of fluid to the interstitial spaces. The model's predictions of the effect of saline infusion on hematocrit, plasma volume, and interstitial fluid volume are shown in Fig. 4. When saline is infused, the plasma volume expands, causing the hematocrit to decrease. As fluid leaves the circulatory system and enters the interstitial spaces, the interstitial fluid volume expands. As the interstitial fluid

June 15, 1970

556 Douglas and Coleman

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Circulatory dynamics m pregnancy

volume increases, the hematocrit and plasma volume return to near control levels. These curves are for a nonpregnant, 62 kilogram female. Figs. 5 and 6 show all the variables of the model and compare the pregnant with the nonpregnant. The model's predictions of the effect of saline infusion (2 ml. per 100 grams body weight) on blood volume of pregnant females are shown in Fig. 5, A (control values from Pritchard 12 ). The blood volume expands and returns to near control levels within 30 minutes. Fig. 5, B shows the effect

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of saline infusion on the plasma volume of pregnant and nonpregnant females. The plasma volumes also return to near control levels within 30 minutes. Fig. 5, C shows the effect on hematocrit of infusing saline into pregnant and nonpregnant females. These curves show that if each receives 2 mi. saline per 100 grams body weight, there is less decrease in hematocrit in the pregnant subjects. Also, the hematocrit returns to control levels at a slower rate. Fig. 5, D shows the effect of saline m-

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558 Douglas and Coleman

fusion on mean systemic pressure of pregnant and nonpregnant subjects. The mean systemic pressure increases following saline infusion7· 13 · 14 • 15 and returns toward control levels as fluid leaves the circulatory system. The increased mean systemic pressure results in an elevated cardiac output (Fig. 5, E) with concomitant elevation of capillary pressure (Fig. 5, F). As saline is infused, the plasma colloid osmotic pressure (Fig. 6, A) of pregnant and nonpregnant subjects decreases. It decreases relatively more in the nonpregnant subjects ( l'ontrol values are from Mackl 6 ). As the interstitial fluid volume increases (Fig. 6, B) the tissue colloid osmotic pressure decreases (Fig. 6, C), and the tissue pressure increases !fig. 6, D) .17 • 18 Fig. 6, D also shows that when the tissue pressure is high, very large quantities of fluid must pass into the interstitial spaces to further increase it. Fig. 6, E shows the rate of change of interstitial f1uid volume with respect to time when saline is infused into pregnant and nonpregnant subjects. The infused fluid enters the interstitial spaces of the pregnant subjects at a relatively slower rate. Comment

When saline is infused into nonpregnant animals it quickly leaves the circulatory system as evidenced by the rapid return of the hematocrits to control levels. Total nephrectomy of nonpregnant animals has little influence on the rate at which the infused fluid leaves the circulatory system, at least during the first few minutes following infusion. This indicates that the fluid passes rapidly into the extravascular space. Pregnant animals respond in essentially the same manner when both kidneys are intact. The hematocrit of the pregnant nephrectomized animals does not reapproach control levels as rapidly as in the pregnant animals with both kidneys intact. Thus, the infused saline does not pass into the extravascular space of pregnant animals as rapidly as it does in the nonpregnant animals. Evidently the kidneys of the pregnant animals must remove, initially, some of the

June 15, 1970 Amcr.

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infused saline. During the 30 minute period following infusion of the saline, the kidneys, if required to do so, could remove some of the infused iluid. It is apparently this critical quantity of fluid normally removed by the kidneys which is responsible for the prolonged decrease in hematocrit in the nephrectomized pregnant animals. Floyer observed a similar phenomenon in hypertensive animals. 19 After a standard infusion of physiologic saline into normotensive and hypertensive animals, the hematocrit of the hypertensive animals did not return to control levels as rapidly as it did in the normotensive animals. He also measured the interstitial fluid pressure of both groups and found that it rose more rapidly in the hypertensive animals following saline infusion. He suggested that this was the factor which led to a more prolonged expansion of plasma volume in the hypertensive animals. Our model indicates that other factors may be involved. It should be noted at this point, however, that certain variables were omitted from the model. For example the model does not include lymph flow to remoYe fluid and protein from the interstitial spaces. It also does not consider protein shifts across the capillary nor fluid loss to the gut. Other factors not included in the model arc stress-relaxation of the vascular

system. autoregulation of blood flow, arterial pressure changes, and urinary output. These factors were not included in the modrl in its present form because it was felt that they would make only minor qualitative contributions to fluid shifts during the relatively short time course of the study. The model does show that the interstitial fluid pressure may be elevated during pregnancy so that this may well be one of the factors which inhibits flow of fluid from the circulatory system into the interstitial spaces. Another factor is dilution of plasma proteins. When saline is infused into pregnant and nonpregnant on a weight basis, there is relatively less dilution of plasma proteins in the pregnant animals. Finally, since the hematocrit of the nephrectomized pregnant

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animals did not reapproach control levels as rapidly as did the hematocrit of the nephrectomized nonpregnant animals, urinary excretion of fluids may be an important factor.

REFERENCES

1. Adams, ]. Q.: AMER. J. OnsTET. GYNEC. 45: 66, 1943. 2. Burwell, C. S., Stayhorn, W. D., Flickering, D., Corlett, M. B., Bowerman, E. P., and Kennedy, ]. A.: Arch. Intern. Med. 62: 979, 1938. 3. Werko, L.: In Toxemias of Pregnancy, London, 1950, Ciba Symposium, p. 155. 4. Burwell, C. S.: Ann. Intern. Med. 11: 1305, 1938. 5. Caton, W. L., Roby, C. C., Reid, D. E., Caswell, R., Maletskos, C. ]., Fluharty, R. G., and Gibson, J. G., II.: AMER. ]. 0BSTET. GYNEC. 61: 1207, 1951. 6. Thompson, K. ]., Hirsheimer, A., Gibson, ]. G., II, and Evans, W. A., Jr.: AMER. ]. 0BSTET. GYNEC. 36: 48, 1938. 7. Douglas, B. H., Harlan, ]. C., Langford, H. G., and Richardson, T. Q.: AMER. J, OBsTET. GYNEC, 98: 889, 1967. 8. Bader, R. A., Bader, M. E., Rose, D. J., and Brauwald, E.: J. Clin. Invest. 34: 1524, 1955.

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We acknowledge the technical assistance of Mrs. JoAnn Douglas.

9. Palmer, A. J., and Walker, A. H. C.: J. Obstet. Gynaec. Brit. Emp. 56: 537, 1949. 10. Hamilton, H. F. H.: J. Obstet. Gynaec. Brit. Emp. 56: 548, 1949. 11. Mendelson, C. L.: In Obstetrics, Philadelphia, 1965, W. B. Saunders Company, p. 639. 12. Pritchard, J. A.: Clin. Obstet. Gynec. 31: 378, 1960. 13. Richardson, T. Q., Stallings, J. 0., and Guyton, A. C.: Amer. J. Physiol. 201: 471, 1961. 14. Guyton, A. C., Douglas, B. H., Langston, J. B., and Richardson, T. Q.: Circ. Res. 11: 431, 1962. 15. Richardson, T. Q., Harlan, ]. C., and Douglas, B. H.: ]. Surg. Res. 8: 84, 1968. 16. Mack, H. G.: Clin. Obstet. Gynec. 3: 336, 1960. 17. Guyton, A. C.: Circ. Res. 12: 399, 1963. 18. Douglas, B. H., Guyton, A. C., Langston, ]. B., and Bishop, V. S.: Amer. J. Physiol. 207: 669, 1964. 19. Floyer, M. A.: Proc. International Club on Arterial Hypertension, 1965, p. 440.