Brain edema and intracranial hypertension in rats after total hepatectomy

GASTROENTEROLOGY1995;108:1097-1103

Brain Edema and Intracranial Hypertension in Rats After Total Hepatectomy SIGURDUR OLAFSSON, JEANNE GOTTSTEIN, and ANDRES T. BLEI Department of Medicine, Lakeside Veterans Administration Medical Center, and Department of Medicine, Northwestern University,Chicago, Illinois

B a c k g r o u n d / A i m s : Glutamine, generated from ammo-

nia in astrocytes, may account for brain edema in acute liver failure. Recent studies showing decreased intracranial pressure after hepatectomy in humans suggest that factors released by the necrotic liver could play a pathogenic role in brain swelling. The aim of this study was to examine whether brain edema and intracranial

hypertension develop in hepatectomized rats. Methods: Rats underwent a portacaval anastomosis or a sham operation. At 24 hours, animals underwent a second sham operation or a total hepatectomy. Intracranial pressure was continuously monitored, and cortical water and glutamine contents were measured after the rats were killed. In a second experiment, hepatectomized and devascularized (portacaval anastomosis plus hepatic artery ligation) rats were killed every 2 hours and at the t i m e of intracranial hypertension. Results: Although brain edema developed in both groups with liver failure, devascularization resulted in a higher brain water content in spite of an equivalent increase in glutamine concentration. Intracranial pressure increased to a similar degree in both groups, but all parameters increased earlier in anhepatic rats. Conclusions: Hepatectomized rats develop brain edema and intracranial hypertension. The temporal sequence in this model supports the role of glutamine as an organic osmolyte. In addition, other factors (e.g., brain volume) may contribute to intracranial hypertension in hepatectomized rats.

A pathogenic role for glutamine implicates ammonia, possibly of gut origin, in the genesis of brain edema. However, recent clinical observations indicate that hepatectomy in some patients with FHF and neurological symptoms appeared to stabilize their course and control the intracranial hypertension. <7 This raises the possibility that factors derived from the necrotic liver are directly responsible for the generation of cerebral swelling. If correct, these observations could implicate products of cellular membranes or soluble inflammatory cytokines in the genesis of brain edema. We designed an experiment to test the hypothesis that removal of a liver would not result in the development of brain edema. Hepatectomized rats were compared with rats having undergone hepatic devascularization, a model well characterized for the development of brain edema and intracranial hypertension, s'9 Although the vascular supply to the liver is interrupted in the devascularized model, there is still release of cellular contents from the liver into the circulation, as evidenced by the high level of serum aminotransferases. 1° Body temperature, a critical variable, 8'~° was rigorously controlled. Our results indicate that both brain edema and intracranial hypertension develop after hepatectomy, although the pathogenic mechanisms appear to differ in the two models. Materials

and Methods

Surgical Procedures rain edema, leading to intracranial hypertension, is a leading cause of death in fulminant hepatic failure (FHF). Recently, several reports have implicated an accumulation of glutamine in the brain in its pathogenesis. ~-3 In this hypothesis, glutamine, a product of ammonia detoxification in cortical astrocytes, 4 acts as an osmolyte, resulting in the accumulation of water in the brain. Indeed, inhibition of glutamine synthesis prevents the development of ammonia-induced brain edema in vivo 2'3 and the swelling of isolated glial cells in vitro. 5

B

Male Sprague-Dawley rats (Charles River Breeding Laboratories, Wilmington, MA), weighing 350-450 g, were used. On receipt, rats were kept on a 12/12 hour light/dark cycle and fed a cereal-based chow diet with free access to water. After 1 week, they were anesthetized with methoxyflurane, and an end-to-side portacaval anastomosis (PCA) was conAbbreviations used in this paper: FHF, fulminant hepatic failure; HEP, hepatectomy (group); ICP, intracranial pressure; ISCH, ischemic hepaticfailure (group); MAP, mean arterial pressure; PCA, portacaval anastomosis (group). This is a U.S. government work. There are no restrictionson its use. 0016-5085/95/S0.00

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structed using a continuous suture technique (7-0 Surgilene; Davis-Beck, Danbury, CT). The anastomosis was completed within 5 minutes; patency of the shunt was confirmed at the time the experiment was completed. In sham-operated rats, the portal vein and inferior vena cava were clamped for 5 minutes. The abdomen was sutured in two layers, and rats were returned to their individual cages. Feeding and water ingestion were promptly resumed. A period of 24 hours elapsed after the first surgical procedure to ensure survival from the PCA procedure itself. At that time, the animals were again anesthetized with methoxyflurane and underwent either hepatectomy, hepatic devascularization, or a second sham operation. Hepatectomy was performed after tying off the hepatic artery and common bile duct. The vascular supply to each lobe was then ligated, and the tissue was resected. To avoid interruption of the inferior vena cava, a minimal amount of liver tissue was left around the vessel. Estimated liver blood volume loss 11 was replaced by 1.5 mL of saline intravenously. In animals not undergoing hepatectomy, 1.5 mL of blood was drawn and replaced by saline. Hepatic devascularization was achieved by ligating the hepatic artery. In rats undergoing a second sham operation, the abdomen was reopened and structures were identified. Catheters (PE-50, Intramedic; Clay-Adams, Parsippany, NJ) were placed in the femoral artery and femoral vein. Through a small posterior scalp incision, a PE-10 catheter was placed in the cisterna magna as described. ~2

Experimental Preparation The arterial and intracisternal catheters were connected to pressure transducers (PE-23; Statham Gould, Oxnard, CA), and values of mean arterial pressure (MAP) and intracranial pressure (ICP) were continuously inscribed in a Sensormedics R611 recorder (Anaheim, CA); zero was placed at the level of the heart. Body temperature was continuously monitored via an intra-abdominal thermistor wire (model BAT 8; Physitemp Instruments, Clifton, NJ) and maintained at 37.5 -+ 5.0°C. Arterial blood gases (model 1302; Instrumentation Laboratory, Chicago, IL) were measured when animals had recovered from the second anesthesia and before death. Blood glucose level was measured every 2 hours from femoral artery samples with the use of Dextrostx reagent strips (Miles Inc., Elkhart, IN). Animals were kept euglycemic by a continuous glucose infusion (0.038 mL/min) via a femoral vein catheter. Once the experiments were completed, rats were injected with an overdose of pentobarbital and immediately decapitated, and the brain was quickly removed. One cerebral hemisphere was kept at 4°C, and cortical brain water content was measured within 30 minutes of death using the gravimetry technique. 13 The brain was cut into 2-ram slices, and 1-mm punch biopsy specimens were obtained from the gray matter of the cortex. Water content of each specimen was measured gravimetrically using a density gradient of bromobenzene-kerosene precalibrated with K 2 S O 4 as previously described.* The cortical samples were placed into the fluid column, and the

GASTROENTEROLOGY Vol. 108, No. 4

equilibrium point was measured at 2 minutes. The specific gravity of the tissue was calculated,8'14 and results were expressed as percentage of water content. Six to eight measurements were made per animal, and values were arithmetically averaged. The other hemisphere was stored at - 7 0 ° C for subsequent measurement of glutamine content. Gray matter of the cortex was homogenized in 8 vol 1.2 mol/L HC104. The supernatant fluid was neutralized with 15% KOH in 0.1 mol/L K2HPO4 and centrifuged, and the supernatant was used to measure glutamine enzymatically)5 Plasma ammonia level was measured before the rats were killed using an adaptation of a commercial kit (Technicon Instruments Corp., Valhalla, NY) as reported. 16 Serum osmolality was measured at baseline and before death with a microosmometer (model 3MO; Advanced Instruments Inc., Needham Heights, MA). Hematocrit was measured at baseline and before death.

Experimental Design Two series of experiments were performed. In the first experiment, three groups of animals were studied (8 animals in each group): PCA/hepatectomized (HEP); (2) PCA/sham (PCA); and (3) sham/sham (SHAM). SHAM and PCA rats were killed at equivalent times to that of HEP rats. (Although a theoretical design would include a sham/hepatectomized group, a one-stage hepatectomy is not a viable preparation in our experience.) In the second experiment, the temporal relation between cortical glutamine and brain water contents over the course of FHF was examined in two models of liver failure: hepatectomized rats and animals after hepatic artery ligation (ischemic liver failure, ISCH). Animals (4 animals in each group) were killed at 2,4,6 (HEP and ISCH), and 8 hours (ISCH). (Hepatectomized rats did not have measurements at 8 hours because they develop intracranial hypertension sooner). A group of rats (n = 4) killed 24 hours after PCA served as a baseline. In addition, groups (8 animals in each group) of hepatectomized rats and devascularized animals were studied until the development of intracranial hypertension and killed once ICP waves, an indication of imminent brain herniation,9 were noted.

Statistical Analysis Comparison between groups was made with analysis of variance (ANOVA); for comparison between groups in the first experiment, Tukey's test was used for testing differences between means. Both FHF models were compared with an unpaired Student's t test. Results were expressed as mean _+ SEM. Significance was set at a P value of < 0.05. The study was approved by the Animal Care Committee at the Lakeside Veterans Administration Medical Center.

Results General Aspects Body weights were similar in all groups (Tables 1 and 2). H E P rats had a significantly higher final heart

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Table i .

BRAIN EDEMA IN RATS AFTER HEPATECTOMY

1099

H e p a t e c t o m i z e d R a t s V e r s u s S h a m and PCA R a t s

Group (n = 8)

Body wt (g)

Arterial blood pH

MAP

Heart rate

(ram Hg)

(bpm)

SHAM PCA HEP

400 + 13 414 ± 8 385 _+ 18

7.44 + 0.01 7.44 _+ 0.01 7.51 ± 0.02 a

107 + 1 99 + 3 90 ± 12

349 ± 9 380 _+ 16 460 ± 20 a

ICP

(mm Hg)

3.7 _+ 0.5 3.7 _+ 0.2 11.6 ± 1.5 a

Brain glutamine level

Brain water content (%)

(l,zmol/g)

8 0 . 2 5 _+. 0.05 80,27 ± 0.06 8 0 . 7 6 + 0.08 a

6.34 ± 1.73 12.83 _+ 1.07 a 24,80 ± 1.72 ~

NOTE. Results are mean ± SE. "P < 0.01 vs. all groups, ANOVA with a Tukey's test.

rate (460 + 20 beats/min) than SHAM (349 + 9) and PCA rats (380 + 16 beats/min). Devascularized rats had a progressive increase in MAP, which exceeded 140 m m H g at the time of death (Figure 1). No animal had evidence of acidosis or hypercarbia; respiratory alkalosis developed in hepatectomized and devascularized rats. H E P rats were killed at 436 + 66 minutes and ISCH rats at 602 + 55 minutes (P = NS). Baseline serum osmolality was 292 ± 2.9 mOsm/L. Final osmolality for H E P and ISCH rats was 295 --- 4.4 and 293 --- 2.7 mOsm/L, respectively (P = NS compared with baseline). Baseline hematocrit was 0.36% + 0.01% compared with final hematocrit of 0.40% +_ 0.01% for H E P and 0.39% -+ 0.01% for ISCH rats (P = NS).

Plasma Ammonia Maximal elevations in plasma ammonia were observed in H E P rats at 2 hours (0.87 + 0.13 mmol/L) and ISCH rats at 6 hours (0.88 _+ 0.14 mmol/L) vs. baseline (0.48 + 0.08 mmol/L; PCA alone), which did not reach the significance level (P = 0.06; n = 4).

Water Content of Cortical Gray Matter At the time of death, brain edema was detected in H E P animals (Figure 2), whereas no difference in water content was noted between PCA (80.27% _+ 0.06%) and SHAM (80.25 ___ 0.05) rats. Although brain water content increased earlier in hepatectomized rats, with a significant increase at 6 hours, hepatic devascularization resulted in a significantly higher final brain water content

(81.12 + 0.09 vs. 80.76 + 0.08; P < 0.007; Figures 2 and 3).

Cortical Gray Matter Glutamine At the time of death, H E P rats developed a fourfold increase (24.80 + 1.72 mmol/L) in brain glutamine concentration compared with the SHAM group (Table 1). PCA rats had a twofold increase in glutamine concentration (12.83 + 1.07) compared with SHAM rats (6.34 + 1.73; P < 0.01). W h e n observed over time, a significant elevation was noted already at 4 hours in H E P and ISCH rats (22.4 _+ 2.0 and 16.9 +-_ 1.1, respectively) compared with baseline (11.4 _+ 1.1; P < 0.025; Figure 3). Final glutamine levels in rats that underwent hepatectomy were similar to those in the devascularized group (Table 2).

ICP Both hepatectomized and devascularized rats developed intracranial hypertension (Figure 4). In the hepatectomized group, ICP increased earlier and remained significantly higher during most of the course; however, the difference at death (11.6 + 1.5 vs. 8.6 _+ 1.2 m m Hg) did not reach statistical significance. ICP did not increase in SHAM or PCA rats.

Discussion The results of this study indicate that rats develop brain edema and intracranial hypertension after total hepatectomy. Although earlier animal studies had noted the

Table 2. H e p a t e c t o m y V e r s u s I s c h e m i c Liver Failure a t t h e T i m e o f I n t r a c r a n i a t H y p e r t e n s i o n Brain glutamine level (llmol/g)

Brain water content (%)

ICP

Time of death

(bpm)

Arterial blood pH

(mm Hg)

(min)

460 + 20 390 + 28

7,51 + 0.02 7.53 ± 0.01

24.80 + 1.72 23.80 +_ 3.36

8 0 , 7 6 + 0.08 ~ 8 1 . 1 2 ± 0.09

11.6 ~_ 1.5 8.6 _+ 1.2

436 ± 66 602 ÷ 55

Group (n = 8)

Body wt (g)

MAP

Heart rate

(mm Hg)

HEP ISCH

385 ± 18 414 ± 9

90 ± 12 a 165 ± 12

NOTE. Results are mean ± SE. aP = 0 . 0 0 1 vs. ISCH; bp = 0,007.

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OLAFSSON ET AL.

GASTROENTEROLOGY Vol. 108, No. 4

81.5

180

#

160

81.0

140

i

100 (

80.5

80

60

-6

I -5

I -4

I -3

I -2

I -1

80.0

Sham

0

Time until Sacrifice (hours) Figure 1. MAP. Results are expressed as mean _+ SE. Time O, death. Ischemic rats had a progressive increase in MAP during the last 6 hours, although MAP exceeded 140 mm Hg only at the last measurement. Significant differences (P < 0.05 vs. all groups) were observed at - 2 , - 1 , and 0 hours. O, ICSH group; I , HEP group; ©, SHAM and PCA groups.

presence of astrocyte swelling 17 and an increased water content in small brain samples in hepatectomized animals, 17'18 the effect of hepatectomy on the evolution of brain edema and intracranial hypertension has not been previously examined. Furthermore, prior studies have mainly investigated the effect of hepatectomy on survival. Mazziotti e t al. 19 reported that hepatectomized pigs survived longer than animals undergoing hepatic devascularization. However, body temperature was not monitored in these studies. Hepatectomy results in profound hypothermia, 1° which is known to reduce brain edema and prolong survival in animal models of FHF. 8'1° Animals in our study were purposely kept normothermic. In agreement with the current study, Peignoux et al. found no difference in survival between hepatectomized and devascularized rats when the animals were kept normothermic1°; survival in both groups was prolonged during hypothermia. Despite a lesser degree of brain edema at death, hepatectomized rats developed a similar degree of intracranial hypertension than animals with ischemic liver failure. This suggests that other factors may be contributing to the increase in ICP in hepatectomized rats. ICP may arise from expansion of one of three compartments2°; brain tissue, cerebrospinal fluid space, and cerebral blood volume. Expansion of brain tissue, brain edema, is clearly

PCA

HEP

ISCH

Figure 2. Water content of cortical gray matter at the time of death. Brain water content (%) was significantly increased in both HEP and ISCH rats at the time of intracranial hypertension; however, hepatectomy resulted in a smaller increase in brain water content. No difference was noted between PCA and SHAM animals. *P < 0,01 vs. PCA and SHAM groups; #P < 0.007 vs. HEP group.

82.0

HEP

HEP

- 3o "6

81,5 81,0

-

25

E

-

20

__.

-

z_

-15

=,

-10

O z

-5

~

~ 80.580.0 -

/,

79.5 MEAN +/- SE

82.0 -

ISCH

- 30

ISCH

g 815-

-25

.~ 81.o15 i 80.o 79.5

-

-

2

4

4

/~,~

lo 5

.~ ~<

i z

-0

Time untilsacrifice(hours) Timeuntilsacrifice(hours) MEAN+/- SE

Figure 3. Temporal relation between glutamine level in cortical gray matter and water content in cortical brain in the two models of FHF. Results are expressed as mean _+ SE. In HEP rats, cortical water content was maximal at 6 hours after removal of the liver, whereas cortical glutamine level had already plateaued at 4 hours (P < 0.025). In ISCH rats, brain water content increased significantly (P < 0.01) at the time of final measurements (mean, 602 minutes), whereas brain glutamine levels, which were significantly elevated at 4 hours (P < 0.025), had a maximal level at 8 hours. In both models, the increase in brain glutamine level preceded the elevation in brain water content. The course was shorter in HEP rats.

April 1 9 9 5

BRAIN EDEMA IN RATS AFTER HEPATECTOMY

1,I 12

10

8 #

#

6

o -6

-5

-4

-3

-2

-1

o

Time until Sacrifice (hours~ Figure 4. Development of intracranial hypertension. Results are expressed as mean _+ SE. Time O, death. ICP increased earlier in HEP rats and was significantly higher than in ISCH rats through most of the course. ICP did not increase in SHAM or PCA rats. *P < 0.025 vs. ISCH rats; tp < 0.001 vs. ISCH rats; #P < 0.01 vs. PCA and SHAM rats. II, ISCH rats; 0 , HEP rats; ©, SHAM and PCA rats.

present in experimental FHF. 2~ On the other hand, expansion of cerebrospinal fluid volume is unlikely to be of significance, as evidenced by the lack of ventricular enlargement in this syndrome. = Therefore, it seems likely that, in addition to brain edema, an increased brain blood volume contributed to the intracranial hypertension of the hepatectomized group. Normally, the effect of brain blood volume on ICP is minimal. However, in the presence of a swollen brain, slight increases in brain blood volume can cause a dramatic increase in ICP. 2° Although human 23 and animal studies 24 have shown for the most part a reduction in cerebral blood flow in FHF, this finding is not inconsistent with a concomitant increase in brain blood volume. Indeed, it has been postulated that the progressive reduction in flow that results from high ICP triggers a vasodilatory response in the cerebral microvasculature, increasing brain blood volume. 25 The lower arterial pressure (Figure 1) and the higher values of ICP throughout the evolution (Figure 4) support the possibility that vasodilation is present even at an earlier state in hepatectomized rats. Ammonia, through the generation of glutamine in astrocytes, has been implicated in the pathogenesis of brain edema in F H F . 2'3'26 Swelling of astrocytes has been noted in hyperammonemic states such as in the rat after PCA 27 and animal models of FHF. 2. High levels of brain

1101

glutamine are reported in animals 29 and humans with FHF. ~° To further support a role for glutamine as an osmolyte, administration of methionine sulfoximine, a glutamine synthetase inhibitor, to normal 31 and PCA 3 rats ameliorates brain edema and prevents an increase in ICP during an ammonia infusion. 3 In the current study, both models showed an increase in plasma ammonia level that was followed by an increase in cortical glutamine level, which in turn preceded an increase in brain water content and ICP. This temporal sequence, with plateauing glutamine levels attained several hours before the increase in brain water content, supports the role of glutamine as an osmolyte in the genesis of brain edema in FHF. However, despite similar levels of glutamine in the cortical gray matter, the hepatectomized group had less brain edema than the devascularized rats at death; although the difference appears small, it is highly significant. This indicates that accumulation of glutamine may not be the only factor causing brain edema in these animal models of FHF. Serum osmolality did not differ between the groups with liver failure. A higher brain water content in devascularized animals could result from the accumulation or decreased efflux of other osmolytes. In the devascularized model, efflux of taurine, an organic osmolyte, into the cerebrospinal fluid indicates a mechanism that may be insufficient to compensate for the osmotic effects ofglutamine generated in glial cell. 32 However, vasogenic mechanisms may also be present. The increase in systemic blood pressure in devascularized animals may have exceeded the autoregulatory range of the cerebral vasculature at the end of the experiments, causing an increased brain capillary water filtration and slightly higher final brain water content in that group. This increase in MAP, with maximal values attained at the time of intracranial hypertension, is most likely a manifestation of the Cushing's reflex. MAP did not increase in the hepatectomized rats. Several investigators report stabilization of hemodynamics, renal function, and metabolic abnormalities in patients with FHF or primary nonfunction after liver transplantation following hepatectomy. <33'34 In fact, this approach has been used to temporarily improve the treatment of these patients while awaiting liver transplantation. Rozga et al. recently reported a case of FHF in which hepatectomy resulted in a dramatic reduction of ICP. 7 However, the patient was maintained hypothermic and underwent plasma volume exchange followed by artificial liver treatment, making it difficult to separate the contribution of each therapy. These observations in humans are at variance with our findings. There are several

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possible explanations for this discrepancy: (1) the reported benefits of hepatectomy on the neurological status in humans may be due to hypothermia; (2) the setting of our animal study (hepatectomy from the onset) is different from the one applied to patients (hepatectomy at the time of elevated ICP); or (3) the effect of liver necrosis on the brain may depend on the etiology of FHF (ischemic in our rats vs. toxic and/or infectious in the human subjects). In conclusion, our study shows that both brain edema and intracranial hypertension develop in hepatectomized rats but the mechanisms appear to differ from a model of FHF in which the devascularized liver is left in situ (ischemic FHF). A similar increase of intracranial hypertension developed in the hepatectomized rats despite significantly lesser brain edema, suggesting a role for increased brain blood volume in the pathogenesis of intracranial hypertension. Furthermore, despite the difference in water content in the brain between the two models, glutamine levels in the cortical gray matter were similar, suggesting that other mechanisms may play a role in the development of brain edema in these models. Further studies identifying such mechanisms and the role for changes in brain blood volume may provide new insights into pathogenesis and new approaches to the management of FHF.

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Received December 28, 1993. Accepted December 14, 1994. Address requests for reprints to: Andres T. Blei, M.D., Department of M e d i c i n e / l l l E , Lakeside Veterans Administration Medical Center, 333 East Huron Street, Chicago, Illinois 60611. Fax: (312) 9080036. Supported by Merit Review from the Veterans Administration Research Service.