Mannitol hemodilution-perfusion: The kinetics of mannitol distribution and excretion during cardiopulmonary bypass

Journal of Surgical Research

MANNITOL OF

Clinical

and Laboratory

Volume

7 Number

10,

Investigation October 1967

HEMODILUTION-PERFUSION: MANNITOL DISTRIBUTION DURING CARDIOPULMONARY GEORGE JEAN

A. KIMSEY,

PORTER,

M.D., B.S.,

AND

IN 1960 we began adding hypertonic mannitol to the perfusate of selected patients undergoing cardiopulmonary bypass. By inducing an osmotic diuresis we hoped to prevent or modify the occurrence of acute tubular necrosis, which in our past experience [19] had complicated the postoperative course in 14% of patients surviving valvereplacement surgery. Normally, total body perfusion is accompanied by oliguria and occasionally by anuria [lo]. In addition, significant hemolysis is a recognized hazard of open-heart surgery. In dogs the acute tubular necrosis induced by blood pigments can be intensified by oliguria, while mannitol administration offers significant protection [ 181. Goldberg extended the observations on pigment-produced acute renal failure of dogs by collecting evidence favoring direct tubular damage and intraluminal obstruction in the absence of renal ischemia as etiological factors [ 111. Thus, during cardiopulmonary bypass where hemolysis is couFrom the Division of Cardiovascular-Renal Disease of the Department of Medicine and the Division of Cardiovascular Surgery of the Department of Surgery of the University of Oregon Medical School, Portland, Ore. This work was supported by Cardiovascular Clinical Research Center Grant HE-06336 from the National Heart Institute, National Institutes of Health, U.S. Public Health Service; and the Oregon Heart Association. Submitted for publication Nov. 15, 1966.

THE KINETICS EXCRETION BYPASS

AND

ALBERT HELEN

STARR, LENERTZ,

M.D., B.S.

pled with expected oliguria, there exists a situation which would accentuate any tendency for luminal deposition of hemoglobin. By inducing an osmotic diuresis, tubular flow rates would increase, thus minimizing the opportunity for such deposition. Additional advantages to the use of hypertonic mannitol under conditions of total body perfusion are that it allows reliable renal clearance mea::urements despite the occurrence of hypotension [9], and at the same time it improves renal blood flow by decreasing renal vascular resistance [4]. In a preliminary report we documented a significant decrease in the rate of hemolysis during cardiopulmonary bypass when hypertonic mannitol was added to the perfusate [22]. Recently we have reported evidence indicating that hypertonic mannitol was a significant factor .in reducing our incidence of postbypass renal failure [ 191. This report will present, along viith information regarding the kinetics, our current method of administering mannitol during cardiopulmonary bypass, the distribution and excretion of mannitol, and its effects on electrolyte composition of the blood and urine METHOD All patients :ncluded in the study were adults with either congenital or acquired val447

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vular heart disease. The protocol employed was as follows: Prior to entering the operating room, an indwelling bladder catheter was inserted and the bladder drained of residual urine followed by two air rinses. After induction of anesthesia, the prebypass urine collection was begun and continued until the start of total body perfusion. During bypass, urine volumes were collected at 30-minute intervals, Upon completion of cardiopulmonary bypass, urine volumes were collected for three consecutive S-hour intervals, followed by a 24-hour collection. Blood samples were timed to bracket each urine collection. Determination performed on appropriate samples included: (1) hematocrit using an International microcapillary centrifuge, model MB; (2) creatinine according to the method of Haugen [12]; (3) mannitol using the procedure of Corcoran and Page [6]; ( 4) osmolality using a Fiske osmometer; (5) sodium and potassium using a Baird flame photometer with a lithium internal standard; and ( 6) inulin by the technique of Roe et al. [24] corrected for blood glucose content. Calculation of the amount of mannitol to be administered during surgery has been simplified since our original report [22]: Mannitol

for priming pump oxygenation:

10 ml. per kilogram of 10% mannitol + 4 ml. per 100 ml. oxygenator capacity Mannitol for replacement: 2 ml. per minute of 10% mannitol solution given as a constant infusion Administered in this manner a plasma level of approximately 500 mg. per 100 ml. can be maintained throughout the period of extracorporeal circulation.

CALCULATIONS Clearance rates were computed by the standard formula [26]. Mannitol space was calculated using the Robson et al. [23] formulation when a single priming dose was administered. For patients receiving a re448

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placement infusion the formula was modified as follows :

v = Vl Cl + Lt - umt t - PV pump. Ct VlCl= grams of mannitol prime. I,t = grams of mannitol infused during time t. Umt = grams of mannitol excreted during time t. C t = concentration of mannitol (gm./ L. ) in the plasma at the conclusion of the measured interval t. PV pump = plasma volume of pump Vt = mannitol space of patient (L) at conclusion of measured interval t. For comparative purposes, the mannitol space was expressed as a percent of body weight in kilograms. The above formula was also used to compute inulin space.

RESULTS Evaluation of Chemical Detection of Mannitol The maximum variation in thirty-four duplicate plasma determinations was 1.2~~ while for twenty-two duplicate urine determinations 0.5% was the maximum difference recorded. Neither variation was significant when the “t” test for paired observations was applied [28]. On the average the mannitol content of arterial blood exceeded the venous content by 4%. Although this arteriovenous difference was not statistically significant, for convenience all reported plasma mannitol values are arterial samples. When known amounts of mannitol were added to plasma and urine, from 98% to 103% was recovered. On five different occasions blood samples were taken from the pump-oxygenator every 15 minutes for 1 hour after the patient had been removed from the circuit. There was no evidence of loss of mannitol from the closed system, and the maximum variation for any one run was less than 3%. Finally, the influence of various forms of sample storage was tested. After 24 hours at room temperature

PORTER

ET

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MANNITOL

DISTRIBUTION

(23”C.), 100.5% of th e initial mannitol content remained in both plasma and urine. 100.17, was recovered after either 48 or 72 hours of refrigeration (4”C.), while one or two weeks of freezing yielded a 99.8% reof a protein-free filtrate covery. Preparation prior to storage did not prove superior to plasma; the difference in recovery was less than 0.3%. Inulin, paraaminohippurate and glucose did not interfere with the calorimetric determination for mannitol.

hlannitol

AND

EXCRETION

IN

CARDIOPULhlONARY

BYPASS

(calculated according to the formulation of Robson et al. [23] ) in each of the 7 patients is plotted at various time intervals during bypass. The progressive expansion of the calculated distribution volume precludes the use of the plasma disappearance curve for evaluating mannitol clearance rates under the conditions of total body perfusion. As an alternative to the single-injection method the periodic volume of distribution of mannitol was computed in 29 patients undergoing valve-replacement surgery in which a constant plasma level of mannitol was maintained by a replacement infusion. The mean values for both male and female patients are shown in Table 1. The expected difference between men and women did not persist after the first hour of cardiopulmonary bypass. As can be seen there is a progressive increase in the measured mannitol volume throughout the 2 hours of study. In order to extend the number of observations for a given patient, the changes in mannitol space in 8 patients whose period of total body perfusion was in excess of 3 hours were plotted separately (Fig. 3). By the second bypass interval (69 min.) the major distribution phase had been

Distribution

In 7 patients undergoing valve replacement surgery the mannitol was given as a single bolus, so that the plasma disappearance curve could be determined. Sequential mean plasma mannitol levels for these patients are shown in Figure 1. When the resulting exponential curve, shown in Figure 1 (A), was replotted on a semilogarithmic paper, a two-slope function was derived, as shown in Figure 1 (B). The slope a can be used to approximate the renal clearance of mannitol provided there is no extrarenal loss and that the volume of distribution is relatively constant. In Figure 2 the apparent volumes of mannitol distribution A

100 t 0" 0

30

,IJ'IfI 60

90

120 Time

0 on

30

60

90

120

bypass-mio

Fig. 1. (A) M ean plasma mannitol concentrations following a single injection of hypertonic mannito1 in 7 patients during cardiopulmonary bypass. The bars include one standard error of the mean. (B) RepIot of mean plasma mannitol concentration shown in (A) using a semilogarithmic scale. a refers to the slope of the second distribution phase, while 6 refers to the slope of the derived primary distribution phase after the method of Dominguez et al. [7]. 449

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3or

0’

r

,

I

0

30

60

Time

I

90 on bypass-min

I

I

120

150

completed, and from this point on a gradual but progressive increase in the measured mannitol space was recorded. Since the change between the second and the sixth sampling intervals was nearly linear, an expansion rate of approximately l.OyO per hour could be computed. In 6 of the 8 patients who compose Figure 3, simultaneous inulin and mannitol space determinations were performed at 30-minute intervals during bypass. Mannitol space always exceeded inulin space, most notabIy during the early bypass intervals (Fig. 4). After 3 hours inulin space measured approximately 85% of the mannitol space. In a 4%year-old male who underwent aortic and mitral valve replacement, mannitol and inulin were infused for 2% hours before starting bypass-when the eight cardiopulmonary simultaneous space measurements performed during the cardiopulmonary bypass were 1.

Changing

60

Time

Mannitol of

No.

l/2

Adults Females Males P”

29 13 16

19.6 18.0 k 0.9 20.9 c 0.9

450

<0.05 groups

150

(80

compared, inulin space averaged 93% * 12% of the mannitol space. Mannitol Excretion Table 2 summarizes the percentage of administered mannitol recovered during the various sampling intervals. When the data were subdivided as to duration of cardiopulmonary bypass, significantly less mannitol was recovered from the patients whose bypass exceeded 2 hours. The percentage of mannitol recovered during the period of bypass includes the mannitol which remained in the pump oxygenator at the time of decannulation. The 48-hour recovery for 29 patients was 85.6yL. The renal tubular handling of mannitol was compared to inulin by a correlation plot of the respective urine to plasma (U/P) ratios. These data are shown in Figure 5. The

Space ( vO Body Weight) Cardiopulmonary Bypass

Patients

of two

120

Mean mannitol space plotted as a function of time on bypass in 8 patients undergoing valve-replacement surgery. The calculation of mannitol space during constant infusion equilibration is outlined in the section on methods. The bars represent one standard error on the mean.

According

Bypass Time

a p = Probability

90 on bypass-min

Fig. 3.

Fig. 2. Plot of the individual trends of mannitol space as a function of time on bypass in the 7 patients shown in Figure 1. Mannitol space was calculated according to the method of Robson et al. [23].

Table

30

being

the same.

to Duration

(hr.)

1

1 l/2

2

22.9 21.2 k 1.0 24.3 k 1.1

24.2 22.9 ‘- 1.0

25.4 24.3 k 1.3 26.2 f 1.1

<0.05

25.2 k <0.20

1.2

<0.30

PORTER

0

I

30

ET

AL.:

MANNITOL

I

I

DISTRIBUTION

I

60 90 Time on bypass-min

120

I

150

180

Fig. 4. Simultaneous plot of inulin/mannitol space as a function of time on bypass in 6 patients undergoing cardiopulmonary bypass.

I

I

I

5

IO

15

U/P

EXCRETION

IN

CARDIOPULMONARY

BYPASS

13 of the 29 patients who had bypass period of 2 hours. The addition of lOy$ mannitol produces significant hemodilution, as reflected by the decreases in hematocrit and serum sodium. The induced hyperosmotic state was maintained throughout cardiopulmonary bypass by the constant infusion of mannitol. The concentration of sodium in the urine was one-third or less of that in the serum. The net loss of either urinary sodium or potassium did not correlate with the urinary mannitol excretion, potassium loss being the more consistent of the two electrolytes. When urinary sodium and potassium excretion was related to total solute excretion, the initial 30 minutes of bypass were associated with a relative increase in this ratio, following which there was a substantial decline during subsequent bypass interval (Fig. 6). The accumulated loss of sodium in the urine for these 13 patients averaged 10.0 mEq., while the accumulated loss of urinary potassium averaged 16.5 mEq. The urinary flow rates averaged 4.15 ml. per minute for the 2 hours of bypass.

DISCUSSION

inulin

Fig. 5. Correlation plot of the urine/plasma (U/P) ratios of inulin and mannitol from the 6 patients shown in Figure 4. The identity line is indicated by the solid line, while the derived regressionline is shown by the dotted line, the slopeof which is 0.8 with a correlation coefficient of 0.9. solid line is the identity line and the dotted line the regression line derived from the leastsquares formula [28]. A correlation coefficient of 0.9 was derived for the regression line whose slope was 0.8. Effect on Electrolyte

AND

Excretion

Table 3 summarizes the mean electrolyte and mannitol excretion rates in the 29 patients shown in Table 2. No significant difference was evident when divided according to duration of cardiopulmonary bypass. Figure 6 is a composite of changes in urinary and serum electrolytes during surgery in

The inclusion of the extracorporeal circuit does not materially alter the kinetics of mannitol within the body as judged by the similarity between the plasma disappearance curves which we recorded (Fig. 1)) and those reported by Dominguez, Corcoran, and Page [7]. Despite the almost instantaneous mixing of mannitol when given by our techniques, initial distribution time averaged 46 minutes, as shown in Figure 1 (B) while for noncardiac patients the reported value is 29 minutes [7]. The longer interval for the initial phase of distribution between plasma and extracellular fluid space is not surprising, since the mannitol space in our patient was increased by at least 50~~ over the space reported for normal patients [7, 8, 16, 251. The 83% mannitol recovery during the first 24 hours after surgery compares favorably with the 79% to 857” recoveries reported in noncardiac patients [ 1, 3, 71. 451

29 14 15

Al1 Bypass< 2” Bypass> 2”

una v (mEq./min. ) u, v (mEq./min. ) u manv (mM./min.) uv (mL/min.)

No.

Patients

3.9 2 1.1 12.7 * 3.2 0 0.53 + .13

29

29

29

0.81

1.51 Ik

.22

350.0 f 39.3

547.8 2 130.8 3.73 c

27.1 -e 4.5

4.7

11.6

61.7 k

12.1 k

1st 8” 11.3 2 1.1 9.8 f 1.6 12.7 f 1.4

2d 8”

6.1

0.79 *

.07

140.7 -’ 25.6

36.0 r

12.3 Z!I 6.2

2d 8”

1st 24” Postoperative

and After Valve-Replucement

1st 8”

During

23.2 k 2.3 20.5 2 2.9 25.9 e 2.5

Mannitol Recovered ( % )

3d 8”

2.4 2 0.2 2.2 e 0.3 2.5 2 0.3

2d 24”

0.51 -+

.07

48.9 e 11.1

22.2 + 8.0

4.7 2 3.0

Surgey

3.5 + 0.5 3.1 ‘- 0.7 4.0 f 0.6

3d 8”

1st 24” Postoperative 45.0 Y!I2.4 53.4 2 3.3 37.1 k 1.9

Recovery

Bypass

Mannitol

in Patients

26.9

Bypass 66.3 k

2.

x P man. (mg. %) 461 -r- 24 468 +- 32 454 -c-36

Excretion

Man. km.) 97.8 k 6.1 85.6 c 7.6 109.3 f 8.6

The Electrolyte

8 4 4

F

Prebypass

3.

21 10 11

M

29

No.

Table

36.0 -c 2.2 35.9 f 3.5 40.0 f 2.9

Age

Sex

Table

0.65 r

5.5 ” 0 .08

20.5 IL 9.4

3.5 I!I 1.8

2d 24”

85.6 f 2.0 82.3 f 2.9 89.1 -c-2.5

Total

PORTER

ET

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MANNITOL

3,arSerum

Osmolality

,35

Sodium

Serum

r

DISTRIBUTION

5a Hemotocrit

r

O-S&J Prebypass

0 30 60 90 120 PostTimeon bypass-min bypass

AND

EXCRETION

rUrlne

K+/Urine

Urine

Nat/Urine

r

Urine/Plasma

IN

CARDIOPULMONARY

BYPASS

Solute

Solute

Sodium

PCbypass

Fig. 6.

A plot of the serial mean values for 13 patients who underwent 2 hours of cardiopulmonary bypass for valve-replacement surgery. When simultaneous inulin and mannitol clearance rates were measured on twentyeight occasions during cardiopulmonary bypass, the mannitol-to-inulin ratio was 0.80, which is comparable with 0.87 reported by Berger, Farber, and Earle in 8 normal controls [3]. Since mannitol enters the renal tubule only through filtration at the glomerulus [27], the lack of identical U/P ratios for inulin and mannitol (Fig. 5) indicates significant tubular reabsorption of mannitol under the conditions we studied. This factor, that is, an average reabsorption of 20% of the filtered mannitol, when added to the changing volume of distribution (Figs. 3, 4), invalidates the plasma disappearance curve as an estimate of renal clearance of mannitol. The distribution of mannitol within the body is dynamic, and following a single injection at least two phases can be identified, as shown in Figure 1 (B ) . The initial phase is quite rapid and represents primarily the movement from the plasma space into the extracellular space with only minimal renal loss. The second and much slower phase represents a composite of renal loss which depletes the plasma space leading to a secondary shift from the extracellular fluid space into the plasma and a continuing expansion of the volume of distribution. These factors must be

considered when one attempts to use mannito1 as a measure of extracellular fluid space. The gradient between plasma and interstitial space can be eliminated by the use of a constant infusion of mannitol; however, as can be seen from Figure 4, a small but definite increase in mannitol space, averaging 1% body weight per hour, is still recorded. In nephrectomized dogs, Mulrow, Oestreich, and Swan [ 151 demonstrated mannitol equilibration after 3 hours. Furthermore, they were able to detect measured changes in extracellular fluid volume by changes in the mannitol space. These same authors reported a reasonably good agreement between mannito1 and radiosulfate as a measure of extracellular fluid volume. This does not seem to be the case for inulin, since White and Rolf [33] found a constantly expanding distribution volume up to 72 hours after injection in nephrectomized rats, When they compared inulin space to radiochloride space, between 15 and 24 hours were required before inulin space equaled chloride space, while by 72 hours inulin space exceeded total body water in its distribution. In normal human subjects Elkinton [S] reported a constant volume of distribution for mannitol between 1 and 3 hours after injection, but in one patient with cardiac decompensation at least 4 hours were 453

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required. We have confirmed this prolongation of equilibration time by infusing mannito1 during the prebypass period. A representative study is shown in Table 3. Realizing the limitations of equating mannitol space with extracellular fluid space, the near linear rate of expansion between the second and sixth bypass intervals suggests that by selecting the midpoint, that is, the fourth interval, a meaningful estimate for comparing various patient groups can be obtained. For the 29 patients studied (Table 1) the mean mannito1 space after 2 hours was 25.4% of the body weight. This value is higher than the 20% mannitol space reported by Dominguez et al. [7] in the cardiac patient, but it is quite close to the 26.4% reported by Elkinton [S] in his patient with compensated congestive heart failure. Olesen [17], using radiobromide distribution, recorded an extracellular fluid space cf 27.2% of body weight in 24 nonedematous patients with heart disease. The increased rate of sodium excretion associated with osmotic diuresis during bypass (Table 4) is not unique to open-heart surgery, as Cheney et al. [5] reported similar findings in noncardiac surgery during mannitol-induced diuresis. Nor is the effect specific for mannitol, as Mielke and co-workers [14] reported increased rates of sodium excretion during cardiopulmonary bypass due to glucose-induced diuresis. The state of hydration which exists at the time of mannitol adminisTable

Operative Interval

4. Efect of Prolonged Mannitol Administration on Space Equilibration

Time p Mannitol Space Beginning Infusion (in liters) I

60

I 14.7 16.2 18.4 19.0 19.8

232 262 292 322 330

20.0 21.4 21.9 22.9 22.5

Prebypass

Bypass

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tration has been shown to influence the proportion of sodium in the total urinary solute. West and Bayless [32] found that by hydrating dogs prior to mannitol infusion the ratio of sodium to total solute excreted was not significantly altered during diuresis; however, when similar experiments were performed on hydropenic animals, mannitol diuresis was associated with a significant rise in the sodium per total solute ratio. Patients prior to surgery characteristically are restricted, so that relative hydropenia existed in all our patients prior to mannitol administration. When the sodium per total solute ratio was plotted (Fig. 6), a transient rise was noted during the first 30 minutes of bypass followed by a decline to a steady-state level below the values recorded in the preoperative period. From estimates of the mannitol space our patients appear to have an expanded extracellular fluid space, and thus their response more closely resembles that of the hydrated dogs cited above. In normal, noncardiac human volunteers when mannitol was given after the extracellular fluid space had been expanded by saline the excretory rate of sodium increased [34]. Under these conditions it was concluded that mannitol effect on sodium excretion could not be due to extracellular fluid volume expansion alone, and that a direct effect on the renal tubules must be present. In our patients the effect of anesthesia plus the stress response to surgery were present during the prebypass period, both being strong stimuli to renal retention of sodium. Our findings of an increased rate of sodium excretion during cardiopulmonary bypass are similar to those obtained by Mielke et al. [ 141, using a glucose hemodilution. However, they do not conform to the decrease in sodium excretion which Turner et al. reported in surgical patients who had been given mannitol [31]. The latter study did not employ extracorporeal circulation, and preoperative hydration was performed in all cases.Furthermore, they replaced the urine volume with a 1/2N saline solution. We feel that the observations made during the first 30 minutes reflect a transitional state regarding the renal response to osmotic diuresis. This conclusion is reinforced

PORTER

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DISTRIBUTION

by the pattern of creatinine and total solute washout which have been reported previously [20]. The degree of negative water balance in our patients can be adjusted, depending upon the amount of 1/3N saline used for electroIf only 10% mannitol is lyte replacement. administered during bypass, the average net water loss via urinary excretion is 2 cc. per minute. The total electrolyte quantities excreted are small, and the urinary sodium concentration never exceeds one-third of the plasma value. Factors common to the production of experimental renal failure in animals included: acidosis and/or dehydration, heme pigment loading, and renal ischemia and/or damage. When these factors are considered in the setting of cardiopulmonary bypass, all may b e present to varying degrees and thus enhance the opportunity for the occurrence of postoperative renal failure. The use of hypertonic mannitol to induce a sustained diuresis during cardiopulmonary bypass is ideally suited to counteract these problems without risk to the patient. Tubular urine flow is enhanced and in acidotic patients mannitol diuresis increases the urinary excretion of hydrogen ion [2]. In vitro studies have shown that inducing a mild increase in serum osmolality renders the erythrocytes less susceptible to mechanical trauma [30], and this has been confirmed in clinical practice using hypertonic mannitol 1221. Finally, recent reports by Lilien et al. [ 131, Braun and Lilienfield [4], Stahl [29], and ourselves [21] confirm that hypertonic mannitol leads to an increase in renal blood flow during times of hypotension. Thus, it is our belief that the inclusion of mannitol into the perfusate of the pump oxygenator not only has the protective characteristics outlined above but also reduces the amount of whole blood needed for priming the pump oxygenator.

SUMMARY The theoretical considerations which lead us to include hypertonic mannitol as part of

AND

EXCRETION

IN

CARDIOPULMONARY

BYPASS

the blood perfusion mixture in selected patients undergoing open-heart surgery are reviewed. In over 500 total body perfusions, mannitol has proven to be an effective, nontoxic substance which has significantly reduced our incidence of postoperative renal failure. The distribution of mannitol occurs in two phases and appears to be confined to the extracellular fluid space. Equilibration within this space requires more than 3 hours; 83cjc of the administered mannitol was recovered during the succeeding 24 hours. The plasma disappearance curve cannot be used to measure renal clearance, since the volume of distribution is constantly expanding during the period of observation plus the occurrence of renal tubular reabsorption of approximately 20% of the filtered mannitol. The saluresis induced by hypertonic mannitol during cardiopulmonary bypass was restricted to the interval of maximum osmotic diuresis and did not lead to postoperative hyponatremia. REFERENCES 1.

Barry, K. G., Doberneck, R. C., McCormick, G. J., and Berman, A. Kinetics of mannitol in man. (Symposium on the clinical and experimental use of mannitol. Walter Reed Army Inst. of Res.) Washington, D.C. 1962. P. 4. 2. Beck, R. N. Osmotic diuresis and the base sparing function of the kidney. Clin. Sci. 17:37, 1958. 3. Berger, E. V., Farber, S. J., and Earle, D. P., Jr. Renal excretion of mannitol. Proc. Sot. Exp. Biol. Med. 66:62, 1947. Lilienfield, L. S. Renal 4. Braun, W. E., and hemodynamic effects of hypertonic mannitol infusions. Proc. Sot. Exp. Biol. Med. 114:1, 1963. 5. Cheney, F. W., Jr., Rand, P. W., and Lincoln, J. R. Mannitol-induced diuresis. Ada. Surg. (Chicago) 88: 197, 1964. 6. Corcoran, A. C., and Page, T. H. Determination of mannitol in plasma and urine. J. Biol. Chem. 170: 165, 1947. 7. Dominguez, R., Corcoran, A. C., and Page, T. II. Mannitol: Kinetics of distribution, excretion and utilization in human beings. J. Lab. Clin. Med. 32:1192, 1947. 8. Elkinton, J. R. The volume of distribution of mannitol as a measure of the volume of extracellular fluid, with a study of the mannitol method. J. Clin. Invest. 26:1088, 1947. 455

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Gagnon, J. A., Murphy, G. P., and Teschan, P. E. Renal function in normotensive and hypotensive dogs during hypertonic mannitol and dextrose infusions. J. Surg. Res. 4:468, 1964. 10. Galletti, P. M., and Brecher, G. A. He&-lung Bypass, Principles and Techniques of Extracorporeal Circulation. New York: Grune & Stratton, 1962. P. 244. 11. Goldberg, M. Studies on the acute renal effects of hemolyzed red blood cells in dogs, including estimations of renal blood flow with kryptons5. J. Clin. Invest. 41:2112, 1962. 12. Haugen, H. N. The determination of endogenous creatinine in plasma and urine. Stand. .I. Clin. Lab. Invest. 5~48, 1953. 13. Lilien, 0. M., Jones, S. G., and Mueller, C. B. The mechanism of mannitol diuresis. Surg. Gynec. Obstet. 117:221, 1963. 14. Mielke, J. E., Hunt, J. C., Maher, F. T., and Kirklin, J. W. Renal performance during clinical cardiopulmonary bypass with and without hemodilution. J. Thoruc. Cardiov. Surg. 51:229, 1966. 15. Mulrow, P. J., Oestreich, H. M., and Swan, R. C. Measurement of extracellular fluid volume of nephrectomized dogs with mannitol, sucrose, thiosulfate and radiosulfate. Amer. .I. Physiol. 185: 179, 1956. 16. Newman, E. V., Bordley, J., III, and Winternitz, J. The interrelationships of glomerular filtration rate (mannitol clearance), extracellular fluid volume, surface area of body, and plasma concentration of manmtol. Bull. Hopkins Hosp. 75:253, 1944. 17. Olesen, K. H. Body composition in heart disease. Acta Med. Stand. 175:301, 1964. 18. Owens, K., Desautels, R., and Walters, C. W. Experimental renal tubular necrosis: The effects of pitressin. Surg. Forum 4:459, 1953. 19. Porter, G. A., Kloster, F. E., Herr, R. H., Starr, A., Griswold, H. E., and Kimsey, J. A. Renal complications associated with valve replacement surgery. J. Thorac. Cardiov. Surg. 53:145, 1967. 20. Porter, G. A., Kloster, F. E., Herr, R. J., Starr, A., Griswold, H. E., Kimsey, J., and Lenertz, H. The relationship between alterations in renal hemodynamics during cardiopulmonary bypass and postoperative renal function. Circulation 34: 1005, 1966. 21. Porter, G. A., Sutherland, D. W., McCord, C. W., and Starr, A. Changes in renal hemo-

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23.

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26. 27.

28. 29. 30.

31.

32.

33.

34.

1967

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