Anesth Analg 1999;89:950
© 1999 International Anesthesia Research Society
NEUROSURGICAL ANESTHESIA
Treatments to Support Blood Pressure Increases Bleeding and/or Decreases Survival in a Rat Model of Closed Head Trauma Combined with Uncontrolled Hemorrhage
Daniel Talmor, MD*,
Vlademir Merkind, MD
,
Alan A. Artru, MD
,
Oleg Shapiro, MD*,
Daniel Geva, MD§,
Leonid Roytblat, MD*, and
Yoram Shapira, MD, PhD*
Divisions of
*Anesthesiology and
Neurosurgery, Ben-Gurion University of the Negev, Faculty of Health Sciences, Soroka Medical Center, Beer Sheva, Israel;
Department of Anesthesiology, Kaplan Hospital, Rehovot, Israel; and
§Department of Anesthesiology, University of Washington, Seattle, Washington
Address correspondence and reprint requests to Alan A. Artru, MD, Department of Anesthesiology, Box 356540, University of Washington School of Medicine, Seattle, WA 98195-6540. Address e-mail to artruaa{at}u.washington.edu
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Abstract
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Hemorrhagic hypotension may aggravate the detrimental effects of head trauma on neurologic outcome. Our study examined whether using phenylephrine or large volumes of saline IV to increase mean arterial blood pressure (MAP) to 70, 80, or 90 mm Hg during the combination of head trauma and uncontrolled hemorrhage would improve neurologic outcome. Rats were assigned to one of 17 groups. In Groups 1–5, the variables were head trauma (yes/no), hemorrhage (yes/no), 0 or 3 mL saline per milliliter of blood lost, and no target MAP. In Groups 6–11, hemorrhage was or was not combined with head trauma, and large volumes of saline were given IV to achieve target MAPs of 70, 80, or 90 mm Hg. Groups 12–17 were similar to Groups 6–11 except that phenylephrine was used rather than saline to achieve target MAPs. Saline increased blood loss at 2 h to approximately 16 and 25 mL at a MAP of 80 and 90 mm Hg respectively, increased (worsened) the neurodeficit score but not cerebral edema at 24 h, and decreased survival rate at 2 and 24 h. Because phenylephrine was fatal for 62 of 63 rats, group mean values for blood loss, neurodeficit score, and brain tissue specific gravity could not be calculated. We conclude that supporting MAP with either phenylephrine or large volumes of saline worsened the neurodeficit score and/or survival and did not affect cerebral edema formation in our rat model of head trauma combined with hemorrhage.
Implications: The results of this study indicate that maintaining mean arterial blood pressure at 70, 80, or 90 mm Hg with either phenylephrine or large volumes of saline worsened the neurodeficit score and/or survival and did not affect cerebral edema formation in our rat model of head trauma combined with hemorrhage.
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Introduction
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Traumatic head injury, when severe, causes a decrease in neurologic status and may result in permanent neurologic injury. If, in addition, the trauma causes uncontrolled bleeding, the resultant hypotension may further worsen the posttraumatic neurologic status and increase the risk for permanent neurologic injury (1). Two approaches to the treatment of hemorrhagic hypotension are replacement of blood loss with IV fluid and the use of vasoactive drugs.
Previous reports suggest that saline may be a useful IV fluid for treating hemorrhagic hypotension after traumatic head injury. Small volumes of saline (0.025 mL/g, intraperitoneally) given to rats 1 h after head trauma did not increase the permeability of the blood-brain barrier to Evans blue dye, decrease the specific gravity or increase the water content of brain tissue adjacent to the area of injury, or worsen the neurodeficit score at 4 h or 24 h after head trauma (2). Large volumes of saline (0.25 mL/g, IV) given to rats 1 h after head trauma reversed the decrease of mean arterial blood pressure (MAP) that was present during the 0–1 h time period after head trauma without significantly altering brain tissue specific gravity or water content, or neurodeficit score (3).
However, moderate volumes of saline have not been reported to be beneficial in the treatment of hemorrhagic hypotension alone or in combination with head trauma. Moderate volumes of saline (3 mL IV for each 1 mL of blood lost) given to rats after the onset of a 2-h period of hemorrhagic hypotension (tail resection) failed to reverse the decrease of MAP and increased the volume of blood lost (4,5). Moderate volumes of saline (3 mL IV for each 1 mL of blood lost) given to rats after the combination of head trauma and hemorrhagic hypotension also failed to reverse the decrease of MAP and increased the volume of blood lost, and worsened the neurodeficit score (4,5). We hypothesized that moderate volumes of saline were not beneficial in these latter studies because the volume of saline used was not large enough to restore MAP to near baseline values. Accordingly, one aim of our present study was to examine the effects of saline in a model of head trauma combined with uncontrolled hemorrhage when saline was given to achieve target MAPs of 70, 80, and 90 mm Hg.
As a comparison treatment to saline, we selected IV infusion of phenylephrine to achieve target MAPs of 70, 80, and 90 mm Hg. IV infusion of phenylephrine for 15 min after middle cerebral artery occlusion in rats previously was reported to improve local cerebral blood flow (6). Although IV infusion of phenylephrine for 15 min after head trauma in rats did not increase brain tissue specific gravity, decrease the volume of injured brain tissue, or improve the neurodeficit score (7), it was subsequently speculated that the duration of phenylephrine infusion was too short to be effective (8). Accordingly, a second aim of our study was to examine the effects of phenylephrine when it was infused IV to achieve MAPs of 70, 80, and 90 mm Hg for 2 h during the combination of head trauma and hemorrhage.
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Methods
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All experiments were approved by the Ben-Gurion University of the Negev Animal Care Committee. A description of the surgical preparation, head trauma, and neurodeficit score used in the present study was published previously (7). In brief, a midline scalp incision was made to expose the calverium, blunt impact of 0.5 J was delivered over the left hemisphere by a stereotaxically guided plate, and the neurodeficit score was determined using the Neurological Severity Score scale which assesses mobility, reflexes, behavior (seeking), and function (beam walking/balance) using a 25-point scale in which 0 indicates no neurologic deficit and 25 indicates the most severe impairment. In our present study, 226 male Sprague-Dawley rats weighing 296 ± 31 g (mean ± SD) were anesthetized with halothane. One hundred forty-three rats received head trauma and 83 rats did not (sham rats). Within the first 5 min after head trauma, 10 rats became apneic and died and four others suffered from massive bleeding and died. In five other rats, the neurodeficit score at 1 h was <10 or >20. All 19 of these rats were excluded from the study. The remaining 207 rats were studied. The first 136 rats initially were randomly assigned to the 17 experimental groups (Table 1). In all groups except Group 1, one or more rats died during the study. Therefore, rats continued to be assigned to Groups 2–17 until there were eight survivors at 24 h in a given group, or until 10 rats in a row assigned to a given group all died. At the conclusion of scalp incision plus sham or scalp incision plus head trauma, 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. At 1 h after head trauma or sham, the neurodeficit score of each rat was determined.
The rats were then reanesthetized with halothane. A 23-gauge catheter was inserted into a femoral vein for fluid administration (where indicated). A 23-gauge catheter was inserted into a femoral artery for blood sampling and blood pressure and pulse rate measurements. After determining baseline circulatory (MAP and pulse rate) and laboratory (blood gas tensions, electrolyte concentrations, and hematocrit) values, the rats were placed on a small platform. The base of the tail was injected with 2% lidocaine, and halothane was discontinued. Uncontrolled hemorrhagic hypotension was then induced in all rats except in Group 3. To induce hypotension, a previously established model was used (9,10). Hypotension was achieved by resecting the distal 25% of the rat’s tail. Blood loss from the proximal portion of the tail was immediately directed into a graded tube, and blood loss was measured (10). The amount of bleeding was recorded at 15, 30, 60, 90, and 120 min after tail resection.
The Rats were assigned to the 17 experimental groups as described previously and as outlined in Table 1. In brief, rats in which hypotension was induced received either head trauma or sham surgery before hypotension, and were either untreated or given saline or phenylephrine IV to maintain MAP at 70, 80, or 90 mm Hg during hemorrhage. Specifically, in Groups 2 and 5–11, warmed saline was infused IV to replace blood lost and to keep MAP at 70 mm Hg (Groups 6 and 9), 80 mm Hg (Groups 7 and 10), or 90 mm Hg (Groups 8 and 11) during hemorrhage. Groups 12–17 were treated with phenylephrine to keep MAP at 70 mm Hg (Groups 12 and 15), 80 mm Hg (Groups 13 and 16), or 90 mm Hg (Groups 14 and 17) during hemorrhage. In Groups 2 and 5, the total volume of saline IV was equal to 3 times the total amount of blood lost. In all groups receiving saline, the IV fluid was administered over the 2-h period after the onset of hemorrhage. MAP and pulse rate were determined before tail resection (baseline) and at 1, 3, 5, 15, 22.5, 30, 60, 90, and 120 min afterward. Blood gas tensions, electrolyte concentrations, and hematocrit 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 of the 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.
Values for the neurodeficit score are given as median ± range. These data were compared within and among groups by the Kruskal-Wallis test with post hoc testing using the Mann-Whitney U-test for nonparametric data. Values for parametric data are presented as the mean ± SD. One-way analysis of variance was used to determine if a variable changed among groups, and was followed by Student-Newman-Keuls multiple comparison test. For all statistical analysis, a P value <0.05 was considered significant.
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Results
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In the groups that received no saline during hemorrhage (Groups 1 and 4), blood loss was greater during the initial 15-min period than during any subsequent 15- or 30-min period (Figure 1). In the groups that received 3 mL of saline for each milliliter of blood lost (Groups 2 and 5), blood loss for the 2 h of hemorrhage was greater than in Groups 1 and 4 (Table 2). In the groups that received no saline or 3 mL of saline for each milliliter of blood lost, MAP was decreased during hemorrhage (Groups 1, 2, 4, and 5) as compared with no hemorrhage (Group 3) (Figure 2). In the saline-treated groups, the volume of saline needed during hemorrhage to achieve MAPs of 70, 80, and 90, respectively, increased as the target MAP increased. In these groups, mean blood loss increased (approximately 9, 16, and 25 mL, respectively) as MAP was increased to 70, 80, and 90 mm Hg, respectively.
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Figure 1. The cumulative volume of blood loss (mean value for each group expressed as milliliters) during 2 h of uncontrolled hemorrhage is shown for the groups in which uncontrolled hemorrhage was induced and at least one rat in that group survived for the entire 2-h period. For clarity, standard deviation for each mean value is omitted.
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Table 2. MAP, Volume of Blood Lost, and Volume of Fluid Given During Hemorrhage, and Brain Tissue Specific Gravity at 24 h After Closed Head Trauma
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Figure 2. Mean arterial blood pressure (MAP) during the 2-h experimental period is shown for the groups that did not receive large volumes 0.9% saline or phenylephrine IV to maintain MAP at 70, 80, or 90 mm Hg. Values are presented as mean ± SD. Baseline MAP values in these five groups (92 ± 7, 90 ± 8, 89 ± 6, 94 ± 7, and 91 ± 6 mm Hg, respectively) did not differ significantly among the groups or among baseline MAP values in Groups 6–17 (not shown). With the onset of uncontrolled hemorrhage in Groups 1, 2, 4, and 5, MAP decreased as compared with baseline values. MAP during the 2-h experimental period did not decrease in Group 3 (no uncontrolled hemorrhage).
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The neurodeficit score at 1 h after head trauma and before hemorrhage did not differ among groups (Figure 3). At 24 h after head trauma, the neurodeficit score decreased (improved) from 16 ± 2 (1 h) to 12 ± 2 (24 h) in the group that did not receive hemorrhage (Group 3). At 24 h after head trauma and hemorrhage, the neurodeficit score was not significantly different from the neurodeficit score at 1 h in Groups 4 and 5. In the groups in which head trauma plus hemorrhage was treated with large volumes of saline, the neurodeficit score increased (worsened) at 24 h in comparison with the neurodeficit score at 1 h.
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Figure 3. The neurodeficit score (assessed using the Neurological Severity Score scale), expressed as median ± range, is shown for the groups that received closed head trauma. Solid (black) columns represent the neurodeficit score at 1 h after head trauma and hatched (gray) columns represent the neurodeficit score at 24 h after head trauma. A neurodeficit score of 0 represents no neurologic damage and a neurodeficit score of 25 represents severe neurologic damage. At 1 h after head trauma, the neurodeficit scores (16 ± 2, 16 ± 2, 15 ± 2, 16 ± 3, 15 ± 3, 16 ± 2, 16 ± 3, and 16 ± 3, respectively) did not differ significantly among the groups. At 24 h after head trauma, the neurodeficit score decreased (improved) to 12 ± 2 in Group 3 (head trauma but no uncontrolled hemorrhage), as compared with the neurodeficit score at 1 h (indicated by the asterisk). The neurodeficit score at 24 h was not significantly different from the neurodeificit score at 1 h in Groups 4 (head trauma + hemorrhage, no 0.9% saline given, neurodeficit score = 16 ± 2) and 5 (head trauma + hemorrhage, 3 mL 0.9% saline given IV for each milliliter of blood lost, neurodeficit score = 14 ± 2). The neurodeficit score at 24 h increased (worsened) in Groups 9 (head trauma + hemorrhage, large volume of 0.9% saline given IV to maintain mean arterial blood pressure [MAP] at 70 mm Hg, neurodeficit score = 20 ± 2) and 10 (head trauma + hemorrhage, large volume of 0.9% saline given IV to maintain MAP at 80 mm Hg, neurodeficit score = 22 ± 3) as compared with the neurodeficit score at 1 h (indicated by the dagger). All rats that received head trauma plus hemorrhage and were treated with either large volume of 0.9% saline IV to maintain MAP at 90 mm Hg or phenylephrine IV to maintain MAP at 70, 80, or 90 mm Hg died (Groups 11, and 15–17).
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In the group that received head trauma and no saline as replacement for blood loss during hemorrhage (Group 4), brain tissue specific gravity in the injured (left) hemisphere was decreased in comparison with that in the group that received no head trauma and no saline as replacement for blood loss (Group 1). The administration of large volumes of saline IV as replacement for blood loss in groups that received no head trauma (Groups 6 and 7) caused no change in brain tissue specific gravity as compared with Group 1. In the group that received head trauma and 3 mL of saline as replacement for each milliliter of blood loss during hemorrhage (Group 5), brain tissue specific gravity in the injured (left) hemisphere was decreased in comparison with that in the group that received no head trauma and 3 mL of saline replacement for each milliliter of blood loss during hemorrhage (Group 2). The administration of large volumes of saline IV (>3 m for each milliliter of blood lost) in groups that received head trauma (Groups 9 and 10) resulted in a decrease in brain tissue specific gravity that was not significantly different from that which occurred in Group 5.
In rats that received head trauma, hemorrhage, and 3 mL of saline for each milliliter of blood lost (Groups 4 and 5), survival rate was 91%–100% at 2 h and 73% at 24 h (Table 1). The survival rate decreased in groups in which target MAPs of 70, 80, and 90 mm Hg were achieved by giving either >3 mL of saline for each milliliter of blood lost (44%, 24%, and 0% in Groups 9–11, respectively), or phenylephrine (0%, 0%, and 0% in Groups 15–17, respectively). In rats that received hemorrhage but no head trauma, the administration of large volumes of saline also produced a dose-related decrease of survival rate at 2 h (100%, 79%, and 0%) and at 24 h (89%, 57%, and 0%) in Groups 6–8, respectively. The administration of phenylephrine produced extremely low survival rates regardless of phenylephrine dose (8%, 0%, and 0% in Groups 12–14, respectively, at both 2 and 24 h).
Laboratory values did not differ among groups before uncontrolled hemorrhage. The averages of mean values at that time were hematocrit 41% ± 2%, pH 7.39 ± 0.04, PaCO2 47 ± 5 mm Hg, bicarbonate concentration 28 ± 2 mEq/L, calculated base excess 4.4 ± 1.0 mEq/L, PaO2 92 ± 8 mm Hg, sodium concentration 139 ± 5 mEq/L, potassium concentration 3.9 ± 0.1 mEq/L, and calcium concentration 1.1 ± 0.1 mmol/L. Two hours of hemorrhage decreased blood hematocrit, PaCO2, bicarbonate concentration, and calculated base excess (Table 3). The administration of large volumes of saline to achieve target MAPs of 80 or 90 mm Hg (Groups 7, 8, 10, and 11) further decreased hematocrit. The average of mean concentrations of electrolytes after 2 h of hemorrhage were sodium 136 ± 3 mEq/L, potassium 4.2 ± 0.7 mEq/l, and calcium 0.9 ± 0.2 mmol/L. Mean electrolyte values for each group were not significantly different from prehemorrhage values.
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Discussion
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Our principal findings were that large amounts of saline given IV produced a dose-related increase of blood loss and decrease of survival, and worsened the neurodeficit score in survivors. Treatment with phenylephrine produced even worse outcomes, with 62 of 63 rats dying within 24 hours after head trauma. These findings failed to support either of our two hypotheses, i.e., that (a) giving volumes of saline large enough to maintain MAP 
70 mm Hg, or (b) giving phenylephrine to maintain MAP 70 mm Hg during two hours of hemorrhage after head trauma would improve outcome. Multiple factors may have contributed to the failure of saline or phenylephrine treatment to improve outcome in our model.
MAP in the groups that received no saline (Groups 1 and 4) was not significantly different from that in the groups that received three milliliters of saline to replace each milliliter of blood lost (Groups 2 and 5). Thus, greater blood loss during hemorrhage in Groups 2 and 5 presumably did not occur because replacement with saline increased MAP. In the groups that did not receive head trauma, the increase of blood loss among the group that received saline (Group 2) and did not receive saline (Group 1) was not significantly different from the head trauma groups that received saline (Group 5) and did not receive saline (Group 4). Thus, it seems unlikely that injury to the central nervous system circulatory control centers significantly affected blood loss. Possible explanations for the greater blood loss in the groups that received saline include dilution of coagulation factors or dislodgment of thrombus at the site of bleeding (5,11). In the groups that did not receive head trauma (Groups 6–8), the MAP-related increase in blood loss was not significantly different from that in the groups that received head trauma (Groups 9–11), arguing against central nervous system injury as the principal factor controlling blood loss. Possible explanations for the MAP-related increase in blood loss include a MAP-related increase in intraluminal pressure within the tail artery at the site of bleeding, dilution of coagulation factors, or dislodgment of thrombus at the site of bleeding (5,11).
In the groups that survived two hours of hemorrhage after head trauma, the increase (worsening) of the neurodeficit score at 24 hours as compared with one hour (Groups 9 and 10) presumably did not occur as a result of saline-induced worsening of cerebral edema formation. To the contrary, brain tissue specific gravity in the groups that received no saline or 3 mL of saline for each milliliter of blood lost (Groups 4 and 5), was not significantly different from that in the groups that received more than three milliliters of saline for each milliliter of blood lost (Groups 9 and 10). The increase in the neurodeficit score in Groups 9 and 10 may have occurred because increased MAP and/or the greater volumes of saline given increased cerebral blood volume, in turn increasing intracranial pressure and decreasing cerebral perfusion pressure.
Decreased brain tissue specific gravity in the left (injured) hemisphere of rats that survived head trauma (Groups 3–5, 9, and 10) as compared with groups that did not receive head trauma (Groups 1, 2, 6, and 7) presumably did not occur as a result of (a) the volume of saline given, (b) the presence or absence of hemorrhage, or (c) MAP during the two-hour period of hemorrhage. These conclusions are supported by the observations that brain tissue specific gravity decreased (a) to approximately the same value in groups that received no saline (Groups 3 and 4), three milliliters of saline for each milliliter of blood lost (Group 5), and more than three milliliters of saline for each milliliter of blood lost (Groups 9 and 10); (b) to approximately the same value when the tail was not cut (Group 3) as when the tail was cut (Groups 4, 5, 9, and 10); and (c) to approximately the same value whether MAP was 55–56 mm Hg (Groups 4 and 5), 70 mm Hg (Group 9), or 80 mm Hg (Group 10). The likely explanation for the observation that brain tissue specific gravity decreased to the same extent in all groups that survived head trauma is that the head trauma itself exerts a greater influence on brain edema formation than does volume of saline given, hemorrhage, or MAP.
Decreased 24-hour survival rate in non-MAP–supported rats that received head trauma with or without hemorrhage (Groups 3–5) as compared with non-MAP–supported rats that received hemorrhage without head trauma (Groups 1 and 2) presumably did not occur as a result of differences among groups in MAP, volume of blood lost, or volume of saline given. As regards MAP, survival rate when MAP was 94 mm Hg (Group 3) was similar to that when MAP was 55–56 mm Hg (Groups 4 and 5), and survival rate was higher in Groups 1 and 2 than in Groups 4 and 5 even though MAP values were similar (55–57 vs 55–56 mm Hg, respectively). With respect to volume of blood lost, survival rate at 2 or 24 hours did not differ among groups with hemorrhage and no head trauma (Groups 1 and 2) even though blood loss was significantly increased in the latter group. Similarly, survival rate at 2 or 24 hours did not differ among groups with head trauma and hemorrhage (Groups 4 and 5) even though blood loss was significantly increased in the latter group. As for volume of saline given, survival rate at 2 or 24 hours did not differ among groups with hemorrhage and no head trauma (Groups 1 and 2) even though the volume of saline given was significantly increased in the latter group. Similarly, survival rate at 2 or 24 hours did not differ among groups with head trauma and hemorrhage (Groups 4 and 5) even though the volume of saline given was significantly increased in the latter group. The likely explanation for the observation that survival decreased when head trauma occurred with or without hemorrhage as compared with hemorrhage without head trauma is that head trauma exerts a greater negative effect on survival than does two hours of hemorrhage.
In groups that received saline to maintain MAP at 70, 80, or 90 mm Hg, survival rate at 2 and 24 hours was inversely related to MAP, volume of blood lost, and volume of saline given, and was directly related to head trauma. Thus, factors that may have contributed to mortality in these groups include hypervolemic circulatory failure, hypoxic brain and cardiac damage secondary to decreased oxygen-carrying capacity, and brain damage and negative circulatory effects resulting from head trauma. In the groups that received phenylephrine to maintain MAP at 70, 80, or 90 mm Hg, survival rate at 2 or 24 hours was inversely related to phenylephrine use. Thus, factors that may have contributed to mortality in these groups include circulatory failure secondary to high systemic vascular resistance superimposed on the above-mentioned effects.
In summary, in our model of head trauma plus hemorrhage, supporting MAP with volumes of saline up to two times the estimated blood volume or with phenylephrine increased bleeding and/or decreased survival. Possible explanations include increased intraluminal pressure or dislodgment of thrombus at the site of bleeding, dilution of coagulation factors, circulatory failure secondary to hypervolemia or high systemic vascular resistance, and brain and cardiac damage secondary to decreased oxygen-carrying capacity and, in brain, increased intracranial pressure and decreased cerebral perfusion pressure. Our results should not be misconstrued to argue against the important principle of supporting blood pressure in shock and head injury. Rather, our results indicate that the use of only 
-adrenergic stimulation or only massive volumes of saline IV are not beneficial methods of providing blood pressure support in these circumstances.
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Accepted for publication June 21, 1999.
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Abstract
Introduction
