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NEUROSURGICAL ANESTHESIA

The Effect of Treatment with Albumin, Hetastarch, or Hypertonic Saline on Neurological Status and Brain Edema in a Rat Model of Closed Head Trauma Combined with Uncontrolled Hemorrhage and Concurrent Resuscitation in Rats

Israel Eilig, MD^*, Maxim Rachinsky, MD^*, Alan A. Artru, MD, Andrei Alonchin, MD, Vadim Kapuler, MD^§, Alexander Tarnapolski, MD^*, and Yoram Shapira, MD PhD^*

*Division of Anesthesiology, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Department of Anesthesiology, University of Washington School of Medicine, Seattle, Washington; and the Departments of Neurosurgery and §Pediatric Surgery, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Address correspondence to Alan A. Artru, MD, Department of Anesthesiology, Box 356540, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195-6540. Address e-mail to artruaa{at}u.washington.edu Reprints will not be available from the author.

	Abstract

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In rats subjected to closed head trauma (CHT) plus uncontrolled hemorrhage, giving 0.3 mL of 0.9% saline per 0.1 mL of blood lost did not restore mean arterial blood pressure (MAP) or improve neurological severity score (NSS). In CHT without hemorrhage, giving 20% albumin or 10% hetastarch improved NSS. We hypothesized that these latter treatments would also improve NSS after CHT plus uncontrolled hemorrhage. Rats were randomly assigned to one of seven groups. Experimental conditions were CHT (yes or no), uncontrolled hemorrhage (yes or no), and fluid given to replace blood loss (none; 10% hetastarch, 20% albumin, or 3% saline [0.1 mL per 0.1 mL of blood lost]; or 0.9% saline [0.3 mL per 0.1 mL of blood lost]). NSS (0–25 scale, where 0 = no impairment) was determined at 1, 4, and 24 h, and brain water content was determined at 24 h after CHT. NSS (median ± range) at 24 h was 11 ± 6 when no fluid was given; 16 ± 5 with 10% hetastarch; 14 ± 5 with 20% albumin; 12 ± 4 with 3% saline; and 13 ± 4 with 0.9% saline given (not significant). In addition, brain water content and MAP did not differ among the groups receiving CHT with or without uncontrolled hemorrhage. In our model of CHT plus uncontrolled hemorrhage in rats, giving 10% hetastarch, 20% albumin, 3% saline, or 0.9% saline failed to improve NSS, brain water content, or MAP.

Implications: In previous studies of closed head trauma (CHT) without hemorrhage, giving 20% albumin or 10% hetastarch improved neurological severity scores (NSSs). We hypothesized that these treatments also might be beneficial in CHT plus uncontrolled hemorrhage. We found that giving 10% hetastarch, 20% albumin, 3% saline, or 0.9% saline failed to improve NSS, brain water content, or mean arterial blood pressure.

	Introduction

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Uncontrolled hemorrhage in a rat model of closed head injury (CHT) decreased mean arterial blood pressure (MAP) and worsened the neurological severity score (NSS) at 4 and 24 h (1,2). Giving 0.3 mL of 0.9% saline IV for each 0.1 mL of blood lost did not improve MAP or NSS, and giving larger volumes of 0.9% saline worsened NSS and survival rate. In a rat model of CHT without induced hemorrhage, giving 20% human serum albumin or 10% hydroxyethyl starch improved NSS (3). On the basis of the results of this latter study, we hypothesized that giving 20% human serum albumin or 10% hydroxyethyl starch would improve MAP and NSS in a model of CHT plus uncontrolled hemorrhage.

Accordingly, this study was designed to examine the effect of treatment with 20% human serum albumin or 10% hydroxyethyl starch on NSS at 4 and 24 h after CHT plus uncontrolled hemorrhage. Treatment with 3% saline was also examined as a comparison treatment to 20% human serum albumin and 10% hydroxyethyl starch. The administration of 0.9% saline was examined as a control treatment and also to ensure that the effects of 0.9% saline on NSS in the present model were similar to those previously reported with 0.9% saline (1,2). Further, brain water content was determined as a measure of cerebral edema 1) to ensure that the effects of 0.9% saline in the present model were similar to those previously reported with 0.9% saline (1,2) and 2) to determine whether, in the event that 20% human serum albumin, 10% hydroxyethyl starch, or 3% saline improved NSS, reduction of cerebral edema might play a role in that improvement.

	Methods

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This study was approved by the Animal Care Committee of Ben-Gurion University of the Negev, Beer-Sheva, Israel. Seventy halothane-anesthetized, adult Sprague-Dawley rats, 222 ± 35 g (mean ± SD), were initially used in this study. Rats spontaneously breathed halothane (2.0%–2.5% inspired in oxygen) via a face mask. The model of CHT used in this study delivers an impact of 0.5 J by using a free-falling plate, from the center of which protrudes a silicone-tipped rod that impacts the skull, as previously described (4,5).

Rats received CHT (n = 62) or did not receive CHT (n = 8). Among the rats receiving CHT, eight rats became apneic and died, and another six animals had NSS <10 or 20. These 14 rats were excluded from the study on the basis of previous results with this model (with NSS <10, the neurological impairment is so minor that "protective" treatment cannot significantly decrease NSS, whereas with NSS >20, the injury is so severe that no treatment can prevent worsening impairment) (3). The 8 rats not receiving CHT were assigned to one experimental group, and the 48 rats that survived CHT and met inclusion criteria were randomly assigned to one of six other experimental groups. Experimental conditions for the seven groups are summarized in Table 1. Group 1 (sham) included rats in which the scalp was incised and no cranial impact was delivered. Groups 2–7 included rats in which the scalp was incised and CHT was delivered. After scalp incision with or without CHT, the skin edges of the scalp incision were injected with 2% lidocaine, and the incision was sutured closed. Halothane was discontinued and, once awake, rats were returned to their cages, where they were allowed free access to food and water.

Groups 4–6 received 10% hydroxyethyl starch, 20% human serum albumin, and 3% saline, respectively, during the 2-h period of uncontrolled hemorrhage. In these groups the volume of fluid given was 0.1 mL for each 0.1 mL of blood lost. Group 7 received 0.9% saline during the 2-h period of uncontrolled hemorrhage. In this group, the volume of fluid given was 0.3 mL for each 0.1 mL of blood lost. In all four groups, fluid given during the period of 0–15 min after tail resection was based on blood lost during that time; fluid given during 15–30 min was based on blood lost during that time; and so forth for the 30–60-, 60–90-, and 90–120-min time periods.

Twenty percent human serum albumin was supplied by Kamada Ltd (Kibbutz Beit Kama, Israel). The formulation of 10% hydroxyethyl starch given was Haes-steril^® 10%, polystarch; 10% hyperoncotic medium molecular weight hydroxyethyl starch in 0.9% sodium chloride solution (Fresenius, Honburg, Germany) (1 L contains poly(0-2-hydroxyethyl) starch [hydroxyethyl starch; molecular substitution 0.4–0.55] of average molecular weight [nominal] 200,000 d); and sodium chloride 9 g (sodium 154 mEq/L, chloride 154 mEq/L, and osmolality 309 mOsm/L). Approximate osmolarities of 10% hydroxyethyl starch, 20% human serum albumin, and 3% saline were 308, 283, and 1030 mOsm/L, and approximate oncotic pressures were 68, 68, and 0 mm Hg, respectively.

MAP was determined before tail resection (baseline) and at 15, 30, 60, 90, and 120 min afterward. Blood gas tensions and osmolality, and sodium, glucose, and hemoglobin concentrations, were determined before (baseline) and at 120 min after tail resection. At 2 h after tail resection, the cut end of the tail was tied to stop the bleeding. The femoral artery catheter was removed and, upon completion of IV fluid administration, the femoral vein catheter was also removed. All rats were returned to their cages, where unlimited food and water were supplied. Mortality was recorded during the 2-h experimental period and after 22 h, i.e., for a total of 24 h.

As outlined above, NSS was determined at 1 h after CHT (or sham), and the 2-h period of uncontrolled hemorrhage then was begun. NSS was again determined at 4 and 24 h after CHT. The NSS was developed to assess the clinical condition of the rats after CHT (6). Points are assigned for motor functions as well as behavior. The following are assessed: ability to exit from a circle (3-point scale), gait on a wide surface (3-point scale), gait on a narrow surface (4-point scale), effort to remain on a narrow surface (2-point scale), reflexes (5-point scale), seeking behavior (2-point scale), beam walking (3-point scale), and beam balance (3-point scale). The NSS measures directly the deterioration of observable neurological status such that a low score represents nearly intact neurological status (minimal score = 0) and a high score represents severe neurological dysfunction (maximum = 25).

After the 24-h assessment of NSS, all animals were killed by decapitation. The entire brain (excluding the cerebellum) was immediately removed (36 ± 7 s) and placed on a frozen plate. Brain tissue samples up to 50 mg were cut from areas just adjacent to the zone of maximal macroscopic damage in the left hemisphere and from the corresponding area in the right hemisphere of the CHT groups (2–5,7,8). In the sham group (Group 1), brain tissue samples were taken from the corresponding left and right hemisphere areas. Brain tissue water content was determined by placing each sample on a preweighed piece of aluminum foil and weighing tissue wet weight (WW). Samples were then dried in a desiccating oven at 105°C for 24 h and reweighed to obtain dry weight (DW). Tissue water concentration (H₂O%) was calculated as (WW - DW)(100)/WW.

MAP, brain tissue water content, volumes of blood lost and fluid given, and laboratory results were tabulated as mean ± SD. These data were compared within and among groups by using repeated- measures analysis of variance followed by post hoc evaluation with the Student-Newman-Keuls test. The NSSs were tabulated as median ± range (25th and 75th percentiles) and were compared within and among groups by using the Kruskal-Wallis test with post hoc evaluation by using the Mann-Whitney U-test. For all statistical tests, a probability value of <0.05 was considered significant.

	Results

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The NSS of all rats in which cranial impact was delivered (Groups 2–7) are shown for 1, 4, and 24 h after CHT in Table 2. Within-group comparisons indicated that NSS at 24 h improved significantly in comparison with NSS at 1 h in the group receiving CHT without hemorrhage (Group 2) but not in any of the groups receiving CHT plus uncontrolled hemorrhage (Groups 3–7) with or without IV fluid therapy. In the group receiving 20% human serum albumin, NSS was increased (worse) at 4 h as compared with 1 or 24 h, and in the group receiving 3% saline, NSS was increased at 4 h as compared with 24 h. Between-group comparisons indicated that NSS at 1 h did not differ significantly among the groups receiving CHT (Groups 2–7). At 4 h, NSS decreased to significantly lower values (i.e., greater improvement in neurologic status) in the group receiving CHT without hemorrhage (Group 2) as compared with the groups receiving CHT plus uncontrolled hemorrhage, which were treated with 10% hydroxyethyl starch or 20% human serum albumin. At 24 h, NSS was lower in the group receiving CHT without hemorrhage (Group 2) as compared with all of the groups receiving CHT plus uncontrolled hemorrhage.

View larger version (16K): [in this window] [in a new window]   Figure 1. Mean percentage of brain water content in the injured (left) hemisphere is shown for each of the experimental groups. Vertical lines above each bar indicate the standard deviation from the mean. CHT = closed head trauma; H = hemorrhage; HES = 10% hetastarch; HSA = 20% human serum albumin; 3% S = 3% saline; 0.9% S = 0.9% saline. Mean brain water content was increased in all the CHT groups (*) as compared with the control group (which did not receive CHT, H, or IV fluid). P < 0.05.

View larger version (19K): [in this window] [in a new window]   Figure 2. The mean cumulative volume of blood loss is shown at specific times during the 2-h period of uncontrolled hemorrhage for the experimental groups in which the distal 25% of the tail was resected (Groups 3–7). Vertical lines associated with each mean value indicate the standard deviation from the mean. Mean blood loss was more (*) at all time points in the group receiving 0.9% saline during uncontrolled hemorrhage (Group 7) as compared with the group receiving no IV fluid (Group 3). P < 0.05.

View larger version (23K): [in this window] [in a new window]   Figure 3. The mean change from baseline mean arterial blood pressure (MAP) is shown for the experimental groups receiving closed head trauma (Groups 2–7). Vertical lines associated with each mean MAP value indicate the standard deviation from the mean. Between-group comparisons indicated no significance among groups. Within-group comparisons indicated that in only two of the six groups (*) (Groups 3 and 6) and at only one time interval (120 min) was MAP significantly different (decreased) from baseline MAP. P < 0.05.

	Discussion

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Infusion of either hydroxyethyl starch, human serum albumin, or hypertonic saline decreases hematocrit (7). Decreased hematocrit reduces blood viscosity, which in turn decreases resistance to cerebral blood flow, especially in regions of relative stasis (8). Arguments in favor of hemodilution therapy for cerebral ischemia are based on observations that hemodilution improved cerebral blood flow and neurological outcome in animal models of, and in patients with, cerebral ischemia (9,10). In the previous study, in which 10% hydroxyethyl starch or 20% human serum albumin improved neurological status after CHT without uncontrolled hemorrhage, the hemodilution resulting from fluid administration was likely accompanied by significantly increased intravascular blood volume (3). In that study, the volume of fluid given IV was estimated to be equal to 15% of the total blood volume of the rat. Thus, any decrease of oxygen-carrying capacity caused by hemodilution presumably was more than offset by increased blood flow resulting from decreased viscosity of blood, and increased cardiac output and perfusion pressure resulting from hypervolemia. The net effect likely was increased oxygen and substrate delivery. In contrast, in this study, in which 10% hydroxyethyl starch, 20% human serum albumin, or 3% saline did not improve neurological status after CHT followed by uncontrolled hemorrhage, it is likely that the hemodilution resulting from fluid administration was not accompanied by increased intravascular blood volume. Thus, oxygen-carrying capacity was decreased for two reasons, i.e., hemodilution as a result of IV fluid administration and decreased hemoglobin resulting from uncontrolled hemorrhage. On the basis of the fact that the volumes of hydroxyethyl starch, human serum albumin, and 3% saline given just equaled the volume of blood lost and the observation that MAP was, for the most part, unchanged during this period, it seems likely that there was no increase of cardiac output or perfusion pressure and, consequently, no increase of oxygen and substrate delivery to offset the decrease caused by hemodilution and hemorrhage.

Another mechanism by which IV fluid therapy may affect neurological status after CHT with or without uncontrolled hemorrhage is by influencing cerebral edema formation. However, in a previous study of CHT plus uncontrolled hemorrhage, brain tissue specific gravity in the injured hemisphere did not differ among groups receiving no IV fluid and those receiving 0.9% saline (2). In a previous study of CHT without hemorrhage, brain tissue specific gravity in the injured hemisphere did not differ between groups receiving 0.9% saline and 10% hydroxyethyl starch or 20% human serum albumin (3). In this study of CHT plus uncontrolled hemorrhage, brain tissue water content in the injured hemisphere did not differ among groups receiving no IV fluid, 0.9% saline, 10% hydroxyethyl starch, 20% human serum albumin, or 3% saline. Thus, it seems likely that in these models, cerebral edema is not the major factor influencing the effect of IV fluids on neurological outcome after CHT. This conclusion is consistent with previous reports that the administration of large volumes of isoosmolar fluid IV does not interfere with brain edema in models of head injury (11,12), cold injury (13), or cerebral ischemia (14). Moreover, brain tissue water content is not significantly different after colloid administration from that after crystalloid administration (13,15,16). This suggests that, in the models studied, the blood-brain barrier was largely intact, so that the key determinant of water movement was total plasma osmolality rather than the small fraction attributable to colloid (13,16,17).

Yet another factor that may have influenced neurological outcome in this study is plasma glucose concentration. This was significantly increased in Groups 3–7 at two hours after tail resection. In the same groups, NSS was worse at 24 hours than in Groups 1 and 2. It was previously reported that in this model, increased plasma glucose concentration worsened NSS after CHT (12,18).

Drummond et al. (19) examined brain water content after a 2.7-atmosphere parasagittal fluid percussion injury (FPI) in 436–501-gram rats. After injury, 16 milliliters of whole blood was removed and the red blood cells readministered after resuspension in 0.9% saline (0.2 milliliters for each 0.1 milliliters of plasma discarded) or 6% hydroxyethyl starch (0.1 milliliters for each 0.1 milliliters of plasma discarded). Plasma osmolality increased in both groups, and brain water content was not significantly changed in the traumatized or nontraumatized hemisphere in the 6% hydroxyethyl starch group but increased significantly in both hemispheres in the 0.9% saline group. That plasma osmolality increased with both IV fluids in the FPI study, but not in this study, probably reflects the larger volumes of 0.9% saline [18.8 milliliters, calculated as volume of blood removed x (1 - hematocrit) x 2] and 6% hydroxyethyl starch (9.4 milliliters) given in the FPI study. Comparison of the brain water content data is difficult because the FPI study contained no nontraumatized control group. Possible contributing factors to differences between the FPI study and this one include severity of injury (0.9% saline caused edema in both the traumatized and nontraumatized hemispheres in the FPI study), readministration of removed red blood cells (affecting the likelihood of ischemic damage by altering blood viscosity and oxygen-carrying capacity), and plasma osmolality (increased in the FPI study, affecting water movement across the blood-brain barrier).

Because analysis of brain water contents in the seven groups in this study confirmed that the effects of 0.9% saline were similar to those previously reported with 0.9% saline (1,2) but indicated no difference among 20% human serum albumin, 10% hydroxyethyl starch, 3% saline, and 0.9% saline in this study, it could be construed that the methods used to determine brain water content were not significantly sensitive to detect a change in brain water content had it occurred. Against that possibility are the results of two previous studies. The first indicated a time window between 15 minutes after CHT and up to two days after CHT during which cerebral edema could be detected (20). The second indicated that the administration of a hypotonic fluid worsened post-CHT cerebral edema within the aforementioned time window, demonstrating that this model is sufficiently sensitive to detect statistically significant cerebral edema (21). As regards this study, limitations include lack of monitoring of physiologic variables (such as MAP, PaO₂, plasma glucose concentration, etc.) during the first hour after CHT and lack of control of ventilation and brain temperature. Against the possibility that lack of monitoring of physiologic variables during the first hour after CHT was a major cause for differences in NSS and brain water content among groups is the observation that prehemorrhage MAP and blood values did not differ significantly among groups.

In summary, on the basis of a previous report that 10% hydroxyethyl starch and 20% human serum albumin improved NSS after CHT without hemorrhage, we hypothesized that these treatments might also improve NSS after CHT plus uncontrolled hemorrhage. We found that the above treatments, when given as 0.1 milliliters for each 0.1 milliliters of blood lost, and also treatment with 3% saline (0.1 milliliters for each 0.1 milliliters of blood lost) or 0.9% saline (0.3 milliliters for each 0.1 milliliters of blood lost) failed to improve NSS or brain water content. Further, treatment with 0.9% saline increased blood loss. It is possible that giving larger volumes of these fluids so as to increase MAP might improve NSS by increasing cerebral perfusion pressure.

	Acknowledgments

 
Supported in part by the Division of Anesthesiology, Soroka Medical Center.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Eilig, I. Articles by Shapira, Y. Search for Related Content PubMed PubMed Citation Articles by Eilig, I. Articles by Shapira, Y. Related Collections Trauma Neuroanesthesia