Renal Hemodynamics and Function in Experimental Hemorrhagic Hypotension: Effects of Osmotic Diuresis

Vol. D.1, Printed h1, L

TttE JouRK,\L OF UROLOGY

Cop~,Tight :~0 1965 by The VVilliarns & \Vilkins Co.

REXAL HEl\lODYNAl\UCS A~D .FUNCTIO:N IN EXPERil\IENTAL HEA10RRHAGIC HYPOTENSION: EFFECTS OF OSJ\IOTIC DIURESIS GERALD P iVJURPHY,* JOHN A. GAGNON, GERALD S ..JOHNSTOX PAUL E. TES CHAN

.,Nn

Vrnin the Department of Surgical Physiology, Division of Basic Surgical Research, }Faller Recd Army Institute of Research, Washington, D. C.

The functional integrity of the kidney in the presence of hemorrhagic hypertension is thought to depend on a number of critical factors which include: renal blood flow glornerular filtration rate (GFR), and vascular resistance. Clinitally, the degree of the renal circulatory adjustn1ents to hemorrhagic hypotension has been considered a major determinant in whether acute renal failure subsequently develops. vVe have quantitated the functional renal alterations in experimental hemorrhagic hypotension and have studied these alterations after t,he induction of os1notic diuresis. While the capacity of the kidney to increase urine flow has been considered critical in the production of some varieties of acute renal failure,1 correlation of this factor with other tests of tubular, glomerular, and vascular alterations in hvnn11-
to and during osmotic diuresis by means of a freebleed-out device. 2 Direct renal blood f!(w, (DRBP), CPAH, urine flow rate eral arterial hematocrit value, and mean aortic blood pressure were measured directly, as ck:termined in hepa.rinized animals (3 to 5 in the manner previously described. 3 The rena,I extractions of the clearance substances ,vere also obtained. Osmolar clearances and T'°H,C) (net tubular reabsorption of solute free water or Cos1v1 ·- V) were calculated . Urine and osmolarities were deterrnined with the aid of a Fiske osrn.ometer. Following induction and main tenance of a hernorrhagic h:ypotensive state, an osmotic diuretic (8 per cent urea or 20 per cent mannitol) was administered rates of 1 to 5 ml. per minute. A. similar dose of antidiuretic hormorn, was also used. In some experiments vasopressin (ADH di luted in normal saline) 5 to 10 per hour was added to the infusate. RESULTS

METHODS

We h,rrn studied over 60 healthy adult male and fernale mongrel dogs in a normally hydrated state and the results are reported. The principles and of the N ationaJ Society for Medical Research for animal care were observed. Control states of hemorrhagic hypotension at pre-selected blood pressure (BP) levels (mean aortic BP 50 to 77 mm. Hg.) were maintained prior 1964. Accepted for publication October Read, in part, at annm1l meeting American !\Iedical Association, San Francisco, California, June 21--25, 1964. * Present address: Brady Hesearch Laboratory, Johns Hopkins Hospital, Baltimore, Maryland. 1 Barry, K. G. and Malloy, J. P. · Oliguric renal failure; evaluation and therapy by the intravenous infusion of rnannitol J.A.l\LA., 179: 510-

Anuric hemorrhagic hypotension (BI' grel dogs subjected to sustained hypotension at 50 BP for l to 3 hours, (11 of 12 dogs) developed anuria after 30 rninute,; of hypotension. During anuric clearance of para-aminohippuric acid creatinine and inulin was zero, while DRB.F con. tinned at an average of 23 ml. per minute 11 to ,55). The extraction of creatinine came negative in all animals, preceding in most instances a negative PAH extraction 15 to 20 minutes. The inulin extraction (Em) lw came negative in two of six anuric animals. F'oI2 Einheber, A. and Clarke, R. W.: Blood pres sure stabilizing device and blood reservoir for inducing hemorrhagic hypotension. J. AppL Physiol., 11: 493-495, 1957. 3

J\lurphy, G. P.i Gagnon, ,J. i'L and l'escha.11 1 _p.

E.: :Measurement of renal function in hypo tension: Effect of nrnnnitol J. (TroL, 133-138. 1963.

5l3, 1962.

529

530

MURPHY AND ASSOCIATES TABLE

1. Typical renal functional and hemodynamic events during hemorrhagic hypotension * Length of

Period

Vt

Period (mins)

U1

Control

:,:;

I I

I

REF EPAH DRBF

CrN

I

~ U

---;;-,~ 51 - - 1

- - - · - - - - - - - - ~ - _23 _ _ ~ W.O.t 16 .06 Hemorrhage (with 37 . 01 controlled bleed-out U3 device) U4 26 I .04 U5 28 .07

52 4 16 18

Ern

--

Mean Aortic

UosM u 0 ,m/ ml.

BP (mm. Hg.)

----=---- ~~ 2 6 6

69 69 70

Ij

TcH,0 [

~~1~

--;;--- 148

-

Cos"

I~

1

1,02~~ I 81 618 .08 .02 518 .12 .05

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

Hemorrhage +8% urea-ADH 4 ml./ min. I.V. Left renal vein cannulated

Hemorrhage +20% mannitol ADH 4 ml./min. I.V.

U6 U7

us

I

W.O. U9 UlO Ull

.15 .28 .53 .62 .17 1.02 1.15

20 20 21 17 21 21 20

23 33 30 -

:

9 8 10 -

70 70 70 69 68

484 527 544 -

I

I

.23 .44 .86

.08 .16 .33

-

--

41 49 1.04 .33 8 .21 61 1.52 490 1.44 .42 9 .26 GS 59 .561 42 55 .56 46 10 .25 68 486 1.62 .47 ------- --- -- -- --- --- -- --- - - - - - --- - Ul2 .18 20 1.36 23 59 .52 68 444 1. 72 .36 .43 .09 2.08 26176 .45 401 2.31 .23 .07 68 Ul3 24 23 24 23

1

* Values are for left kidney only.

t V = Urine flow ml./min. t W.O. = Washout. lowing the period of anuria in this group, hypertonic rn.annitol (20 per cent) infusion was continued for 45 to 60 minutes. Associated with the mannitol infusion was a resumption of measurable urine flow (average 0.71 ml. per minute), and a urinary washout of some of the clearance material, notably P AH and creatinine in the manner as previously described. 3 • 4 This resulted in a transient overshoot in REF calculated renal blood flow. ( REF = CP~ X EPAH 1

l

Hct.

)

which exceeded DRBF by 93 per cent during a 40-minute average period after start of the infusion. Later, when a steady state had been achieved (at the same constant hypotensive BP of 50),DRBF had increased from 23 to 44 ml. per minute (average). This value represents about 40 per cent of the average control normotensive 4 Murphy, G. P., Gagnon, J. A. and Teschan, P. E.: Renal hemodynamic effect of mannitol in normotension and hypotension. Surg. Forum., 14:

99-100, 1963.

DRBF of 111 ml. per minute. Associated with these alterations was the restoration of EcR and Em to positive values, and the maintenance thereafter of an average EPAH of a value of 0.51. The maximal values for CcR and Cm during osmotic diuresis at this blood pressure level (50) were 4 and 9 ml. per minute. Oliguric hemorrhagic hypotension (BP 65 to 77). In dogs bled to a mean aortic BP of 65 to 77 mm. Hg. measurable, although low, urine flow persisted. The average value from one group of 5 dogs was .04 ml. per minute during this period. Concmnitantly there occurred average decreases of 80 per cent in CPAH, 73 per cent in RBF, and 70 per cent in DRBF. The DRBF averaged 36 ml. per minute during this time. Decreases (not greater than 20 per cent) in EPAH, EcR, and Em were also noted. Infusion of mannitol in these controlled states resulted in a brisk average urinary flow rate of 2.2 ml. per minute. After the initial urinary washout period, and during a steady state, RBF and DRBF averaged 70 1nl. per rn.inute. These two values were about 55 per cent of the normotensive

531

EFFECTS OF OSMOTIC DIURESIS

_j

0 0: I-

z u

0

60 0

50

w

. . .

.

2'. z 40 w


I0

::; 0: 0

z

30

0

lL

,,. 0

-

20

0:

10

0

z

!:I° lL

e,

0

10

20

30

40

50

60

70

80

100

90

130

140

Tc H 2 0 % OF NORMOTENSIVE CONTROL •

Hypotension BP (Mean Aortic mmHg • 68-77)

0 Hypotension + 20 % Manni to/ 5 ml./min. 1.V. •

Hypotension + 8 % Urea 4 ml./min. LV.

Frn. 1. Effect of hemorrhagic hypotension and osmotic diuresis upon GFR and T H,O alterations 0

control values. CcR and Crn also increased slightly during the period of osmotic diuresis. Table 1 gives the results obtained in a typical dog subjected to oliguric hemorrhagic hypotension and subsequently treated with both 8 per cent urea-ADH and 20 per cent mannitol-ADH solutions. The results of this treatment emphasize the differences in physical properties of each agent. Urea, a freely-diffusable solute, increases the tubular reabsorption of water (T 0 H,O), raises the osmolar clearance rate, and increases the urinary concentration. Mannitol, a non-reabsorbable solute, in these experiments increases the urinary fl.ow rate to a greater degree than urea, although the urine is more dilute, and T H,O is decreased. Other observers 5 have noted a fall in the U /P osmolar ratio following hemorrhage in hydropenic dogs. This decrease has been attributed to a washout of papillary sodium concentration. A concomitant reduction in T 0 H,O is explained by the same observations. In dogs which we have bled and maintained at a constant BP of 68 to 70 mm. Hg. the following average urinary concentration values have been obtained: U /P osmolar ratio (control) of 5.33, and T"H,O of 0.31 (control) fell to average U /P values of 2.8 and T 0 H20 of 0.10. During a subsequent mannitol infusion the U /P ratio fell farther to an average of 1.4 and T 0H 20 averaged 0.38. These results substantiate the previous observations 5 on renal medullary 0

5 Selkurt, E. E.: Osmolar and free water clearance during hemorrhagic shock in the dog. Proc. Soc. Exp. Biol. & Med., 111: 626-629, 1962.

sodium washout during hemorrhage. The results of treatment will be presented in further detail in the next section. Tubular function during hemorrhagic hypotension. During hemorrhagic hypotension, tubular cellular dysfunction might have been severely affected in a number of secretory and reabsorptive activities. 6 If this were generally true the urinary composition would be expected to resemble glomerular filtrate. In figure 1 the relationships are presented between the reduction in GFR and T 0 H,O during hemorrhagic hypotension and subsequent treatment with an osmotic diuretic. These results are from 3 animals. The control periods of hemorrhage ranged from 1 to 2 hours. The acute variations in T 0 H20 during the measured reductions in GFR at similar levels of hemorrhage and hypotension in these dogs provide evidence against the hypothesis that the renal tubules have become inert conduits of filtrate. However, these control values do not demonstrate any clear evidence for the phenomenon of a relative augmentation in tubular water reabsorption in the presence of a reduction of GFR. 6 The results of treatment indicate that a wide range of tubular water reabsorption is still possible in hypotension during osmotic diuresis without a change in measured GFR or BP. The greatest increase in T H,O was obtained with 8 per cent urea. 5 Coelho, J. B. and Bradley, S. E.: Function of the nephron population during hemorrhagic hypotension in the dog with special reference to the effects of osmotic diuresis. J. Clin. Invest., 43: 3860

400, 1964.

532

1IURPHY AND ASSOCIATES

30

c

'

E

25

>

uo 20 w u

o Hemorrhage (BP Mean Aor!1c rnmHg 68-77]

z

;;,

8 a:

50

""'

15

D.

Hemorrhage+ 8% Url!o + ADH

•

Hemorrhage+ 20% Monrtitol

.t. Hemorrhage+ 20% Monnitol+ADH

10 05

0

02

04

06

08

10

12

14

1.6

18

URINE FLOW (V)

2.0

22

24

26

28

30

ml /min.

Fm. 2. Relationships between osmolar clearance and urine flow in controlled oliguric hemorrhagic hypotension before and after osmotic diuresis. Results obtained in 4 dogs. Figure 2 further illustrates that the wide range of TcH 20 alterations seen during treatment at a constant level of hemorrhagic hypotension is not detectably altered by concomitant vasopressin (ADH) administration. It is readily seen that relatively higher osmolar clearances and urine flow rates are obtained during mannitol diuresis. COMMENT

We have previously determined that the rise in RI3F during osmotic diuresis with mannitol in normotension and hypotension is induced by extrarenal factors. 7 • 8 In other experiments4 direct infusion of the agent into the renal artery has failed to demonstrate an intrarenal cause for the previously noted rise in RBF during mannitol diuresis. Similar results have been recently obtained by Kaye. 9 However, other important intrinsic intrarenal hemodynamic alterations can be induced by osmotic diuresis and can be more obviously related to other intrarenal events, e.g. a change in distribution of intrarenal blood flow, alterations in GFR, and changes in tubular func7 Johnston, G. S., Murphy, G. P. and Teschan, P. E.: The effect of systemic hematocrit value change on the direct renal blood flow in dogs with hemorrhagic hypotension. Invest. Urol., 1: 387-

393, 1964

8 Murphy, G. P., Pearson, W. T. and Johnston, G. S.: The acute cardiovascular and renal hemodynamic consequences of osmotic diuresis. Invest. Urol., 1: 394-402, 1964. 9 Kaye, M.: The effect on the kidney of mannitol injected into the renal artery (abst). Canad. Med. Assn. J., 90: 477-478, 1964.

tion. 3 • 4 Once a steady state is obtained and a washout of any intratubular clearance material has been eliminated,3· 4 valid conclusions can be drawn concerning the intrarenal hemodynamic alterations evoked by a particular osmotic agent in stable hypotensive states. The negative renal extraction values obtained for inulin, creatinine and P AH during the initial periods of hypotension have been examined in detail elsewhere. 3 We have concluded, despite the relative persistence of the negative EcR values and because of the positive Em values concomitantly obtained during anuric hypotension (1 to 3 hrs.), that there is evidence that glomerular filtration continues for an undetermined period. 3 • 4 GFR can be calculated in anuria by a direct method we have utilized previously. 3 • 4 When direct GFR is calculated (GFRmR = DRBF X Em X 1-HCT) evidence for some level of glomerular filtration is found in the presence of no urine flow. This method of calculation (GFRmR) obviously is determined independently of the urine flow rate and can be considered valid even in anuria. During these anuric states, as we have shown, if osmotic diuresis is induced, further measurable evidence of glomerular filtration can be obtained. These GFR values during osmotic diuresis are not of a greater magnitude than those observed in the preceding periods of hypotension. The induction of the diuresis in these hypotensive states by maintaining measurable outflow of urine is also regarded as beneficial in other

533

EFFECTS OF OSMOTIC DIURESIS

terms, such as the washout of unidentified damaging substances presumed to be present in the kidney due to the ischemic hypotension. 1 • 6 The degree of reabsorption of filtrate in the tubules as measured by T 0 H 20 could be seen in these ischemic hypotensive states as a possible determinant for the presence or absence of a local deposition of these materials to cytotoxic levels, and even to the production of localized tubulorrhexic lesions. 6 Hypertonic mannitol, because of its comparative superiority in increasing urinary flow rate and its lack of augmentative effect on T 0 H20, would appear to be a better agent than urea to use in these conditions to eliminate such substances. The desirability of restoring the reduced renal medullary sodium gradient in hemorrhagic hypotension remains a matter of conjecture at present. It should be recalled that 8 per cent urea solution was far more effective in restoring the medullary concentration gradient than was mannitol (table 1) in these experiments. Under the present control conditions of hemorrhagic hypotension the

use of vasopressin does not give additional detectable assistance in this regard. The relative augmentative renal hemodynamic effects of osmotic agents in hemorrhagic hypotension thus appear to be of less importance than do their individual molecular and tubular absorption characteristics and their effects on the renal concentrating mechanisms. SUMMARY

Renal hemodynamic and functional alterations have been studied in experiments in anuric and oliguric hemorrhagic hypotension in the dog. Significant levels of REF and GFR persisted in these hypotensive states. The persistence of a variable degree of tubular reabsorptive activity (T H20) in the presence of severe reductions of GFR (15 to 45 per cent of normotensive control values) was also noted. Two osmotic agents, urea and mannitol, have been compared in regard to their relative merit in producing the alterations in REF, GFR, T 0 H 20, osmolar clearance, and urine flow rate during hemorrhagic hypotension. 0