Effect of hemodilution on cochlear blood flow measured by laser-doppler flowmetry

Am t Otolaryngol 8:16-22, 1.q87

Effect of Hemodilution on Cochlear Blood Flow Measured by Laser-Doppler Flowmetry ELISABETH HULTCRANTZ,MD, PHD, AND ALFRED L. NUTTALL, PHD The effect of hemodilution on cochlear blood flow was studied in guinea pigs. Hypervolemic hemodilution was accomplished by infusion of 10 mg/kg of body weight of dextran 40 (as a 10% solution in normal saline), which resulted in an average hematocrit decrease from 43 to 32%. Normovolemic hemodilution was accomplished by repeated exchange of 3 ml of whole blood with 3 ml of dextran 75 (6% solution in normal saline) every 5 minutes until the hematocrit reached approximately 5%. The cochlear blood flow was measured by laser-Doppler flowmetry. Irrespective of the dilutional technique, the cochlear blood flow increased as hematocrit decreased to a maximum of approximately 200% of original value at a hematocrit near 20%. The blood pressure was not significantly influenced by the hemodilution until hematocrit values below 15% were reached. The enhancement of cochlear blood flow is consistent with the expected reduction of blood viscosity and increase of cardiac output. Normovolemic hemodilution with dextran 75 causes a smaller disturbance of systemic circulation physiology and has a more lasting effect than dextran 40 infusion.

To treat patients with s u d d e n hearing loss, attempts have been made to increase tile blood circulation in the cochlea, thus enhancing oxygenation. Vasodilators, anticoagulants, sympathetic nerve inhibition (stellate ganglion), and hyperbaric oxygen administration are still used as treatments2 ,8-1~ The results of the different interventions are difficult to evaluate, since the disease has a high spontaneous remission tendency. However, the rationales for these treatments have been supported by Fisch et al., 12 who developed a technique to measure perilymphatic oxygen tension in humans and in a later investigation demonstrated low perilymphatic oxygenation in patients with sudden hearing loss. 13 Low-molecular-weight (MW) dextran, dextran 40 (mean MW, 40,000), has been w i d e l y used by intravenous infusion in the treatment of tissue ischemia and of hearing lOSS. 14-1t~ By infusing dextran 40 (which, as a 10% solution, is slightly hyperoncotic with respect to plasma), a condition of hypervolemic hemodilution is created that decreases blood viscosity and thereby increases tissue blood flow. Alternatively, D a u m a n et al. 17 have presented promising results for treating sudden hearing loss patients with normovolemic hemodilution, substituting the removed blood with dextran 60 (mean MW, 60,000). The purpose of the present investigation was

The cochlear arterial blood supply is an endarterial system derived from the vertebrobasilar complex. ~ Within the cochlea, radiating arterioles supply capillary beds in the spiral ligament, stria vascularis, and the osseous spiral lamina in parallel networks, but there are extensive possibilities for anastomoses in the periphery. 2 If a vascular accident (e.g., thrombosis, embolism, or rupture of a vessel) s h o u l d occur within the cochlear vascular system, the clinical picture of a " s u d d e n hearing loss" m a y theoretically be expected. The degree of hearing loss and the extent to which a remission might be possible should depend on the site of the vascular accident. Sudden hearing loss m a y be caused by a variety of other insults to the cochlea including viral infections, 3 intracochlear membrane ruptures or perilymphatic fistulas, 4,5 as well as vascular accidents, e.7 Received May 19, 1986, from the Department of Otorhinolaryngotogy, University Hospital, Uppsala, Sweden (Dr. Hultcrantz), and the Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan (Dr. Nuttalt}, Accepted for publication July 9, 1986. Supported by the U.S. Public Health Service grant NIH NS11731. Address reprint requests to Dr. Hultcrantz: Department of Otorhinolaryngoiogy,UniversityHospital, S-75185, Uppsala, Sweden. 0196-0709/87 $0,00 + .25 16

EFFECT OF HEMODILUTION ON COCHLEAR BLOOD FLOW

to study, first, whether and to what extent infusion of dextran 40 (in an amount equivalent to that used clinically) influences the cochlear blood flow and, second, the effect of normovolemic hemodilution on cochlear blood flow when either dextran 75 or dextran 40 [as iso-oncotic solutions) was used as a substitute for the removed blood. MATERIALS AND METHODS Twenty-seven pigmented guinea pigs weighing 300 to 600 g were used. Anesthesia was induced by diazepam (1 mg/kg intraperitoneally or intramuscularly) and fentanyl [given 15 minutes later at a dosage of 0.32 mg/kg intramuscularly). A fentanyl dose was repeated (0.16 mg/kg) about every 30 minutes and the diazepam dose (0.5 mg/kg) every 2 hours. The animals were tracheotomized but did not require artificial ventilation. The right carotid artery was cannulated for continuous blood pressure measurement, and the right iugular vein was cannulated for blood withdrawal and dextran infusions. Heart rate was continuously monitored. Body temperature was measured rectally and kept constant at 38~ by a regulated heating pad. The head was rigidly fixed in a heated headholder, and the left bulla was opened from a ventral surgical approach with preservation of the ossicular chain and tympanic membrane. The laser Doppler probe (1.7 mm diameter) of a laser Doppler blood perfusion instrument was placed over the lateral wall of the second turn of the cochlea to monitor the blood flow through the spiral ligament, the vascular stria, and the modiolar areas. A second laser Doppler probe was attached by adhesive tape to the shaved abdominal skin to monitor the skin blood flow. This probe was held within a heated (38~ fixture for controlling skin temperature during skin perfusion measurements. Several studies by others have given details of the laser Doppler method. 18-2~ Infusion of 10% dextran 40 in saline (10 mg/kg) over a 1-hour period was carried out in 11 animals. In some cases the readings of cochlear blood flow and blood pressure were continued for up to I hour after the infusion. Hernatocrit was measured in venous blood samples taken before and after the infusion. In this study, data are used only from animals that had initial and stable systemic blood pressure />8 kPa (60 mm Hg), because Hultcrantz et al. z~ have shown that cochlear autoregulation is lost for systemic blood pressure below about 8 kPa. Thus, data are ana-

lyzed from six of the 11 dextran 40-infused guinea pigs and eight of 16 dextran 75-infused guinea pigs. Following the 1-hour period of dextran 40 infusion, three animals were normovolemic hemodiluted in stepwise increments down to a hematocrit of about 15% by withdrawal of 3 ml of blood at each step and replacement with 5% dextran 40 in saline (isosmotic solution). For the eight guinea pigs that were normovolemic hemodiluted down to a hematocrit of 5% using 6% dextran 75 for replacement, successive exchanges of 3-ml volumes spaced approximately five minutes apart were done. In four of these eight animals, the initial exchange of 3 ml of blood for 3 ml of dextran 75 was followed b y a 1-hour lapse before the second and subsequent exchanges. The effect on cochlear blood flow, blood pressure, and hernatocrit was studied during the 1-hour period and as normovolemic hemodilution was continued.

RESULTS Of the 27 animals used, 13 were excluded from the analysis due to initial blood pressures below 8 kPa. Although dextran infusion had a tendency to increase the blood pressures of these animals, the rise was generally not up to 8 kPa. The cochlear blood flow response, however, was quantitatively the same in the animals with low blood pressure as in the high blood pressure group. The six hypervolemic hemodiluted animals did not show any significant change in blood pressure during a 1-hour infusion of dextran 40; the cochlear blood flow increased to about 160% of the original value (Fig. 1A). Most of the increase occurred over the first 30 minutes and reached a steady state (Fig. 1B). Specific examples of continuously increasing flow can, however, be seen in Figure 1A. The range of initial hematocrit was 40 to 45% [mean 43%, which fell to 18 to 35% (mean 32%) during the infusion. One animal was observed for 1 hour following the dextran 40 infusion and exhibited little or no significant change in blood pressure or cochlear blood flow during the postinfusion period [Fig. 2). The three animals that were normovolemic hernodiluted with dextran 40 showed a continuous increase of cochlear blood flow to a peak value of near 200% at a hematocrit of about 15% (Fig. 3). Skin blood flow was more variable than co-

VoJume 8 Number 1 Janua~ 1987 17

EFFECT OF HEMODILUTION ON COCHLEAR BLOOD FLOW

A

225

200

t75

.~j...~_.:- ....... .....~......o.:::...,..:::::::::::::::::::::::::::::::::

t50

8~,oo S ~

0 ~

200

I

1

I

I

l

I

I

I

I

I

I

5

i0

15

20

25

30

35

40

45

50

55

B

~,o~=

..... ~ ..... E..... E ..... ~ ..... E ..... E ..... E ..... E ..... E ..... E ..... E ..... E

170

~o U ~

tiii

i40

itO t00

I

I

I

I

I

I

I

I

I

I

I

I

5

i0

i5

20

25

30

35

40

45

50

55

60

g5

TIME (min) t00 9O

ao

9

7o

~

i

1.so

..... " "

' _ E , ~

I

"...... I

I

I

'9

I

I

I

I

I

I

I

tO

20

30

40

50

60

70

80

90

t00

i iO

Time

(rain)

u.~ r

2oo i75

i25

..........2:Y

.J

American O Journal of Ofolaryngology 18

I~Eb"

2~

O

10

O

o~

4o

iO0 75

- I 5O

'"

| --

4O

I

I

I

I

I

35

30

25

2O

15

H E M A T O C R I T (%i

0

i20

Figure I (top). The change in cochlear blood flow and m e a n systemic blood pressure during a 1-hour intravenous infusion of dextran 40. A, the percentage change i n cochlear blood flow for six individual guinea pigs. B, the m e a n percentage change of cochlear blood flow for the six animals o[ part A (solid line) and the mean systemic blood pressure (dotted line). Vertical bars are - 1 SEM. Figure 2 (center). The change i n cochlear blood flow (light dotted line) and systemic blood pressure (solid line) during a 1-hour intravenous infusion of dextran 40 and for the 1 hour following the infusion. Figure 3 (bottoml. The percentage change in cochlear blood flow for three guinea pigs during normovolemic hemodilntion wifl~ dextran 40.

HULTCRANTZ AND NUTTALL

~.oo 9o

LU

A

8 t~

to O

1

i

'

I

#

I

-

;

;

I

4B-43 42-39 38-35 34-31 30-27 2B-23 22-ig

Figure 4. A, mean systemic blood pressure (• SEM) during normavolemic hemodilution with dextran 75. 13, the percentage change in cochlear blood flow for seven individual guinea pigs of part A,

B

..a.

~" ~ x ' . / "E

i8-i5

,/~

,,~

8 75

50

t

I

I

I

I

45

40

35

30

25

I

20

t5

HEMATOCRIT (%) chlear blood flow but showed the same general pattern during dextran 40 infusion, i.e., increasing to a maximum of approximately 150% of its original value. Normovolemic hemodilution with dextran 75 in eight animals did not significantly change the blood pressure, but the cochlear blood flow rose successively in relation to the decrease of the hematocrit to a maximum near 180% at a hematocrit of 15% (Fig. 4). The hemodilution continued until the animal died, usually at a hematocrit between 5 and 10%. During that late phase of the experiments, the blood pressure fluctuated greatly, and the cochlear blood flow showed changes often correlated with blood pressure. Figure 5 shows an example of a sharp decline in cochlear blood flow that occurred during the final phase of blood pressure collapse below a hematocrit of 10%. The skin blood flow showed a greater variation during the normovolemic hemodilution with dextran 75 but the same tendency as the cochlear blood flow (Fig. 6).

Four animals were hemodtluted by a 3-ml blood exchange with dextran 75, after which the skin and cochlear blood flow were recorded for I hour. Three of the animals showed an increase of up to 160 percent for the cochlear blood flow, which remained constant during the 1-hour postexchange period. The skin blood flow, however, did not increase significantly, and one animal exhibited a decline. DISCUSSION

Low-molecular-weight dextran has two effects on the circulatory system, both af which act in an antithrombotic way. First, dextran, which is only slowly excreted by the kidneys, has a hemodilutive effect while it stays in the vascular system. The hemodilutive effect is not only due to the infused volume b u t also depends on the concentration of dextran used. Concentrations above 3% are hyperoncotic and cause extracellnlar fluid to be drawn into the circulation. An infusion of dextran 40 (10 mg/kg as a 10% so-

Volume 8 Number 1 January 1987 19

EFFECT OF HEMODILUTION ON COCHLEAR BLOOD FLOW eo -

lU

A

eo

Oo4O I

O~

250

~1~

225 200 ~

0

I,

1

I

I

I

I

I,,

I

t

B

175

125 ,oo

75 50

t

.... Z

I

I

I

I

I

I

I

45

40

55

50

25

20

15

I0

5

(%)

HEMATOCRIT

Figure 5 (top). An example of the relationship of cochlear blood flow (B) I and mean systemic blood pressure during normoO volemichemodilutionwith dextran 75.

Figure 6 (bottom). The percentage change of skin blood [law during normovolemic hemodilution with dextran 75.

o:

z3~ I

46-4a

I

I

=

I

42-39 ~8-3s 34-3~ Hematocrit

I

I

I

30-27 26-23 22-i9

(%)

lution is saline) will consequently cause a hypervolemic hemodilution and a considerable drop of hematocrit. ~5 The decreased hematocrit causes a reduction in blood viscosity and an increase of the b l o o d shear rate. The result is an enhancement of tissue blood flow accompanied b y an increased cardiac o u t p u t . 22 According to Starling's law, the larger b l o o d volume will also contribute to the increase in cardiac output and blood pressure. Together with dextran, the extra fluid will be eliminated by the kidneys, and the net result will be a d e h y d r a t i o n of the body. If 10 percent dextran 40 is given in repeated infusions during a long period of time, an increasing risk for kidney failure develops and clinical fatalities have b e e n reported. 23,24 American Dextran also has an antithrombotic property Journal by its action on factor VIII, thereby reducing the of thrombocytes' adhesiveness, the so-called "coatOtolaryngology ing effect. ,,25 The coating effect is also dependent 20

I

~8-~5

on the elimination of dextran from the system, and a rebound effect with hypercoagulability may O c c u r . 26

Dextran 40 has a half-life of 5 hours in the circulation, and dextrans of higher molecular weight remain longer (e.g., dextran 75's half-life is 11 hours). Dextran 60 or 75 in 6% solution has nearly normal oncotic pressures and m a y be exchanged in equal volumes with whole blood. This procedure ameliorates some of the disadvantages and risks associated with the use of low-molecular-weight dextran given in a higher concentration. The circulating blood volume will be o n l y slightly increased, and no excess of fluid excretion will occur through the kidneys. The longer elimination time will give a more stable and lasting increase of tissue blood flow, and r e b o u n d effects on circulation and thrombocyte f u n c t i o n may be less prone to occur. Our present study on guinea pigs s h o w s that

HULTCRANTZ AND NUTTALL

the cochlear blood flow is positively correlated with the reduction in hematocrit value irrespective of the dilutional method, i.e., a hypervolemic hemodilution by dextran 40 infusion or a normovolemic hemodilution by direct exchange of w h o l e blood with dextran 75. The exchange of 3 ml of blood for 3 ml of dextran 75 gave almost the same increase of cochlear blood flow as the 1-hour infusion of dextran 40 (10 mg/kg), and the hematocrit reduction was similar. This exchange v o l u m e (3 ml) is about 10% of the circulating blood volume in these guinea pigs. It is similar in proportion to the amount of blood donors give in the blood banks (450 ml), which does not cause any harm to the subject. The expected effect of one blood exchange should not last for more than 24 hours, because the blood reserves in spleen and bone marrow are emptied to replace the loss. In a recent clinical study, 17 it was noticed that the hematocrit was restored to normal 24 hours after the hemodilution. Thus, a second blood exchange would probably be valuable to keep the cochlear blood flow high for a longer period of time. In the current study, no difference between the stability of cochlear blood flow increase induced by dextran 40 in relation to dextran 75 was seen. This is because the required observation time w o u l d be longer than the I to 2 hours over which these animals are in good systemic circulatory health. Generally, major surgery and anesthesia cause the blood pressure in guinea pigs to decline over time. Cochlear blood flow has a capability of autoregulation with respect to blood pressure. 21'27'2a At the blood pressures of these experiments (8 to 12 kPa or 60 to 90 mm Hg), cochlear blood circulation is expected to be in its autoregulatory range. Arturson and Thor~n 29 have shown that the systemic oxygen transport capacity of blood is improved as hematocrit is reduced from normal values to approximately 20%, and the maximum improvement is around a 30% hematocrit. In resting animals, therefore, normovolemic hemodilution, which does not increase the blood pressure, will not evoke the autoregulatory mechanism, is Normovolemic hemodilution reduces the blood viscosity and increases the cardiac output. These rheologic phenomena account for the expected finding of blood flow improvement in both the cochlea and the skin. The laser Doppler blood flow instrument measures the particle flux within a certain volume, ae Its output signal is proportional to the mean red blood cell velocity and to the total number of red

blood cells in the measured volume. Currently, for the cochlea, the method is qualitative and only increases and decreases compared to the original values can be determined. Since hemodilution results in a reduction of the total number of red blood cells in a given volume of whole blood, the increase of cochlear blood flow (including red cells and plasma), as given by the instrument, must be more than the measured 200% with regard to the velocity of the red cells. The variable readings of the cochlear blood flow at the end of the experiments w i t h hematocrits lower than 15% are probably d u e to a release from autoregulation during low blood pressure periods or an inability of regulation to follow the fast-changing pressure that occurs during circulatory collapse at these critical low hematocrit values. For clinical purposes, only the first part of the hemodilution curve is relevant, since the goal is to increase maximally the oxygenation of the cochlea, a point that presumably is reached when the systemic oxygen transport capacity is maximal, as it is with a hematocrit just below 30%. is,2~

Normovolemic hemodilution with dextran 75 of about 10% of the blood volume gives the same increase of the cochlear blood flow as an infusion of dextran 40 (10 mg/kg) and is a lesser strain on the circulatory system. Therefore, it might be recommended over dextran 40. The improved flow tends to be more stable and long-lasting. Dangerous rebound effects on rheologic dynamics seen for low-molecular-weight dextran would be reduced.

Acknowledgments. The authors wish to thank Josef M. Miller for valuable methodologic discussion, and ]. Nadine Brown and Michetie Grfffiths for technical assistance. They also acknowledge the gift of fentanyl, used for anesthesia in this study, from Jansen Pharmaceutica, Inc.

Refere1lces 1. Siebenmann F: Die Bluetegeffisse im Labyrinthe dos menschlichen Ohres. Wiesb J Bergmann, 1984 2. Axelsson A: The vascular anatomy of the cochlea in the guinea pig and man. Acts Otolaryngo| 3968; supp] 242, pp 54-102 3. Schuknecht HF, Kimura RS, Naufa] PM: The pathology of sudden deafness. Acta Oto]aryn6o] 1973;76:75-97 4. Coodhi]l V, Harris I, Brockman S], et a]: Sudden deafness

and labyrinthine window ruptures. Ann Otol Rhinol Laryngol 1973;82:2-12 5, Simmons FB: The double-membrane break syndrome in sudden hearing loss. Laryngoscope 1979;89:59-66 6. laffe BF: Hypercoagulation and other causes of sudden hearing loss. OtolaryngolClin North Am 1975;8:395-403

Volume 8 Number 1 January 1987

21

EFFECT OF HEMODILUTION ON COCHLEAR BLOOD FLOW 7. Johnson A, Hawke M, Berger G: Sudden deafness and vertigo due to inner ear hemorrhage--a temporal bone case report. J Otolaryngol 1984;13:210-207 8. Hibler N: Novacin als Therapeuticum in Hals-Nase-Ohren Gebiet. Mschr Ohrenheilk 1948; 82:441-453 9. Giger HL: Therapy of sudden deafness with 02- CO2 inhalation. HNO 1979;27:10-19 10. Goto F, Fujita T, Kitani Y, et ah Hyperbaric oxygen and stellate ganglion blocks for idiopathic sudden hearing loss. Acta Otolaryngol 1979;88:335-342 11. Mattox DE: Medicat management of sudden hearing loss. Otolaryngol Head Neck Surg 1980;88:111-113 12. Fisch U, Murata K, Hossli G: Measurement of oxygen tension in human perflymph. Acta Otolaryngol 1976;81'.278-282 13. Nagahara K, Fisch U, Nabuya Y: Perilymph oxygenation in sudden and progressive sensorineural hearing loss. Acta Otolaryngol 1983;9.6:57-68 14. Kellerhals B, Hippert F, Pfaltz CR: Treatment of acute a~oustie trauma with low molecular weight dextran. Pract Otorhino laryngol 1971;33:260-264 15. Messmer K, Schmid-Sch6nbein H: Hemodilution: Theoretical basis and clinical application, Basel, Karger, 1972 16. Wissen I, Aziz MYA: Erfahrungen in der Therapi der akuten Innenohrschwerh6rigkeit mit niedermolekularem Dextran, Pentoxifyllin and Nikotinsiiure. Laryngol Rhinol 1981;60:361-363 17. Dauman R, Cros AM, Mehsen M, et el: Hemodilution in sudden deafness: First results. Arch Otorhinolaryngol 1983;238:97-101 18. Miller 1M, Marks N], Goodwin PC: Laser Doppler measurement of cochlear blood flow. Hear Res 1983;11:385-394 19. Goodwin PC, Miller JM, Dengerink HA, et ah The laser

American Journal of Otolaryngology ~.2

20. 21. 22.

23. 24.

25. 26. 27. 28. 29. 30.

Doppler: A non-invasive measure of cochlear blood flow. Acta Otolaryngal 1984;98:403-412 Miller JM, Hultcrantz E, Short S, et el: Pharmacological effects on cochlear blood flow measured with laserDoppler technique. In press, Scand Audiol Hultcrantz E, Linder J, Angelborg C: Sympathetic effects on cochlear blood flaw at different blood pressure levels. INSERM 1977;68:271-278 Wood JH, Simeone FA, Kron RE: Rheological aspects of experimental hypervolemic hemodilution with low molecular weight dextran. Neurosurgery 1982; 11:739-753 Matheson N: Renal failure after administration of Dextran 40. Surg Gynecol Obstet 1970;131:661-665 Zaytouu GM, Schuknecht HF, Farmer HS: Fatality following the use of low molecular weight dextran in the treatment of sudden deafness. Adv Otorhinolaryngol 1983;31:240-246 Aberg M, Hedner U, Bergentz S-E: Effect of dextran on factor VIII. Ann Surg 1979;189:243-251 Laxenaire MC: Incidentes et accidentes observes lors l'utilsationdes macramolecules. Anesth Analg R~anim 1976;33;603-608 Hillerdal M, Engstr6m B, Hultcrantz E, et ah The effect of age and hypertension on cochlear blood flow. In press, Acta Otolaryngol Axelsson A, Angelborg C, Borg E, et ah Cochlear blood flow in spontaneous hypertensive (SH) rats subjected to noise. Manuscript. Arturson G, Thor~n L: Fluid therapy in shock. World J Surg 1983;7:573-580 Nilssan GE, Tenland T, Oberg PA: evaluation of laser Doppler flowmeter for measurement of tissue blood flow. I E E E Tr. Bio-Med Eng, BME-27 1980; 10:597-604