Dextran

The effects of hypertonic saline/dextran (HSD) on hemodynamics and on rebleeding were studied during an uncontrolled intra-abdominal hemorrhage combined with a high-energy gunshot wound (GSW) in the hind limb of anesthetized swine. The GSW had instant effects on the central hemodynamics, which were aggravated when the internal hemorrhage was induced. Compared with baseline, cardiac output decreased to about 42%, mean arterial pressure decreased to 52 +/- 44%, and mean flow rates in the splanchnic region, in the upper aorta, and in the kidney decreased to 51 to 15%. The injection of HSD at 10 minutes was followed by a prompt increase in blood flow rates, but rebleeding occurred in five of eight animals, although only two died. In conclusion, GSW induced instant changes in hemodynamics at distance from the injury. When HSD treatment was given in a bolus injection, rebleeding occurred in five of eight animals, although the second hemorrhage became fatal in only one animal.

Introduction

Early prehospital treatment of hemorrhagic shock with intravenous fluid replacement in the presence of uncontrolled bleeding remains an issue. The detrimental effects of the rapid infusion of Ringer's lactate caused by rebleeding have been observed in animals by several authors.1-5 Similar effects on hemorrhage attributable to rebleeding have been observed by others using low-volume substitution with hypertonic saline/ dextran (HSD).6-9 In all of these animal studies, a standard vascular lesion has been created by inducing either a longitudinal slit or a transverse cut in an artery. These models involve a single vascular lesion that can be considered to be of a lowenergy type with moderate interference from other injury mechanisms. In a military setting, however, these types of injuries are rare and the wounds observed are more frequently multiple and complicated.10-12 Shrapnel or bullets of different sizes will penetrate the body at different sites and with different velocities, and the energies transferred to the total organism vary considerably. Immediate changes in both regional and central hemodynamics were observed when a high-velocity gunshot wound (GSW was inflicted on a leg of anesthetized dogs.13,14 In addition, others have observed changes in the fibrinolytic system with the same trauma model.15 Consequently, these compliGated injuries may activate different hemodynamic defense mechanisms that influence internal hemorrhage and hemostasis. Therefore, we were particularly interested in studying the effects of a low-volume intravenous shock treatment with HSD 10 minutes after injury when an intra-abdominal aortic lesion had been combined with a high-energy GSW in the hind limb.

Materials and Methods

Sixteen pigs with a body weight of 19 to 27 kg (mean, 23 kg) were studied. The protocol was approved by the appropriate Animal Ethics Committee (UmeA, Sweden).

After fasting overnight, the animals were premedicated with ketamine and anesthesia was induced with an intravenous injection of pentobarbital 180 to 220 mg. Tracheotomy was performed, and the pigs were ventilated with a Siemens Servo Ventilator 900C (Siemens-Elema, Solna, Sweden) to achieve normocapnia. To reduce the depressant effect of general anesthesia on the hemodynamic results,16 the anesthesia was maintained by a continuous infusion of 700 to 800 mg/h of ketamine hydrochloride. A midline ventral celiotomy was performed to allow continuous measurement of blood flow rates by four perivascular ultrasonic flow probes connected to two Transonic T 208 devices (Transonic System, New York, NY). The blood flows in the portal vein, the left renal artery, and the abdominal aorta proximal and distal to an aortic injury were measured. Between the two aortic probes, the ventral abdominal aorta was exposed and, using the technique described by Bickell et al.,17 a 4-0 stainless steel surgical wire was passed through the anterior aortic wall with a distance of 5 mm between the entry and the exit of the wire. The free ends of the wire were brought through the abdominal wall via a separate incision, and the abdominal midline incision was then closed. The left external jugular vein was catheterized for infusing fluids and ketamine, and the left common carotid artery was catheterized for blood sampling and pressure monitoring. A flow-directed thermodilution Swan-- Ganz catheter was inserted into the right external jugular vein and positioned with the distal port in the pulmonary artery to measure pulmonary artery pressure, cardiac output (CO), and mixed venous saturation.

Samples for measuring arterial blood gases and the blood hemoglobin (B-Hb) level were also obtained from the arterial catheter. Arterial blood gases were measured with either a BGE analysor or a GEM Premier Plus analysor (Instrumentation Laboratory, Milano, Italy), and mixed venous saturation was measured with an Oximetrix 3 (Abbott Critical Care System, Abbott Laboratories, Chicago, IL). The B-Hb concentration and the arterial oxygen saturation were measured with a CO oximeter 482 (Instrumentation Laboratory). Finally, a urinary catheter (Foley) was inserted into the bladder.

After surgical preparation, the animals were allowed to stabilize for 30 minutes. The baseline hemodynamic features were measured, and the animal was fixed in the standardized "Swedish missile trauma model" to induce the high-energy GSW (Fig. 1).18 The weapon used was a smooth-bore rifle, caliber 6.02 mm, and the projectiles were steel spheres (O, 6.0 mm; mass, 0.88 g). The impact velocity was measured by means of two ring magnets, spaced 150 mm apart, connected to an electric counter and a pulse generator to measure the projectile passage time. The projectile struck the lateral aspect of the right thigh posterior to the femur and the femoral artery. The length of the trajectory of the projectile through the right thigh was measured with calipers. The kinetic energy transferred from the projectile to the tissues was calculated based on the known characteristics of the projectile, the velocity, and the length of the trajectory.19,20

Approximately 20 seconds after the gunshot, the stainless steel wire was removed by pulling both ends of it simultaneously and thereby causing an uncontrolled intra-abdominal hemorrhage. The blood flows above and below the aortic laceration, as well as the blood flows of the left renal artery and the portal vein, were recorded every 15 seconds between 0 and 5 minutes and 11 and 16 minutes and every other minute during the 120-- minute period. The arterial and pulmonary pressures, heart rate (HR), and CO were recorded at approximately 15 seconds after the gunshot, which was before the induction of the aortic lesion. These parameters were measured subsequently at 5 minutes after the initial bleed and every 10 minutes during the experiment.

At 10 minutes after the induction of the aortic injury, the treatment with HSD 4 mL/kg body weight was given intravenously as a bolus injection during 1 minute. Simultaneously, the GSW was packed with compresses that were weighed before and at the end of the study.

Results

The Effects of the Gunshot

The energy transmitted from the gunshot to the soft tissue of the right thigh was calculated to be 574 +/- 10 J in the treated group and 586 +/- 13 J in the control group. No large vessel or bone structure was hit, and the weighed blood loss from the wounds was 22 +/- 3 mL (control, 18 +/- 2 mL) at the end of the experiments.

In all animals, approximately 15 seconds after the gunshot, mean arterial pressure (MAP) had decreased to 85 5% (p

Initial Blood Loss

The blood flow rates decreased rapidly when the steel wire was pulled and the aortic bleeding started (Fig. 2, top). The bleeding stopped at 2.9 +/- 0.3 minutes and amounted to 520 +/55 mL for all animals. The mean calculated initial blood loss was higher in the control group than in the treatment group, but the difference was not significant (523 +/- 73 mL vs. 365 +/- 37 mL).

In all animals, compared with the baseline flow, the mean flow rate between 1 and 10 minutes after the onset of aortic bleeding amounted to 51 +/- 4% in the splanchnic region (p

At 5 minutes after the aortic injury, CO had decreased to 42 +/4% (p

Injection of HSD

In the treatment group, the blood flow rates increased promptly after HSD had been given between 10 and 11 minutes after the onset of aortic bleeding. The peak flow occurred at 12.1 +/- 0.4 minutes without any significant differences between the flow probes (Fig. 2, top). CO increased by 80 +/- 12% (p

Postinfusion Period

In the HSD group, all flow probes recorded higher mean flow rates during the period 11 to 40 minutes than during the initial 1 to 10 minutes of the study (p

In the HSD group, CO was 81 12%, MAP was 65 8% (p

The blood flow rates obtained between 11 and 120 minutes of the study are shown in Table I. The hemodynamic data obtained late in the study are not reported further because they were influenced by the fact that some of the animals were dying.

Rebleeding and Death

Four animals died, two from each group. Three of these showed a progressive aggravation of the oxygen distribution leading to acidosis. One animal in the treatment group aggravated rapidly after a second episode of hemorrhage. The four animals that died before the end of the study tended to have a greater total blood loss than the survivors, 688 +/- 112 mL and 591 +/- 42 mL, respectively.

Rebleeding occurred after HSD injection in five of the eight animals and amounted to 128 +/- 56 mL, with a maximum of 343 mL. The first period of rebleeding started at 0.7 +/- 0.2 minutes and stopped at 4.1 +/- 1.4 minutes after the completion of the injection of HSD. A second episode of rebleeding was observed in one of these animals, starting 13 minutes and ending 14 minutes after the HSD treatment was given. The total volume of rebleeds was 133 +/- 61 mL, or 37 +/- 16% of the initial blood loss, but it never exceeded the initial hemorrhage. In the control group, no period of rebleeding was observed.

D^sub 2^ decreased to 39 +/- 0.03% of baseline after the initial bleeding in all animals without any significant difference between the groups (Fig. 3). Between 11 and 40 minutes, DO^sub 2^ was 59 +/-10% of baseline in the treatment group compared with 36 +/- 0.02% in the control group (p

There was a significant correlation between the amount of blood lost, as calculated from the difference in blood flow proximal and distal to the aortic lesion, and the weighed abdominal blood at autopsy (r = 0.56; p

Discussion

The present study confirms that a high-energy gunshot to the soft tissue of the thigh almost instantly induces hemodynamic effects at some distance from the injury. The pathophysiology of this event is not clear; however, pressure waves from a peripheral high-velocity missile have been recorded in the abdomen22 as well as in the nervous system in pigs.23 In this study, a rapid decrease in systemic blood pressures was observed as early as 15 seconds after the GSW, thus before any major blood loss. This is in accordance with the findings of Rybeck and colleagues,13,14 who observed, using the same high-energy GSW model on anesthetized dogs, a significant and immediate increase in arterial blood flow to the traumatized leg and the opposite effect in the noninjured leg. This was accompanied by a slight decrease in arterial pressures, although HR remained at baseline levels during the whole study. In the present study, there was a rapid decrease in blood pressures. The CO could be properly recorded immediately after the GSW in 10 animals. It was slightly increased in 2 animals but decreased in 8 of them. This decreased CO could be attributed to a decrease in the stroke volume, because there was a moderate increase in HR. The same observations have been made by Rady et al.,24 although their recordings of CO were made 60 minutes after injury. This depressant effect on central hemodynamics could be an adequate mechanism to limit hemorrhage. In a previous study with a similar vascular injury model, we observed that the initial blood loss during the first minute of the bleeding was positively correlated with the initial blood pressure.25

The recommended dose of HSD (4 mL/kg body weight26,27) for the treatment of severe hemorrhagic shock produces powerful early hemodynamic effects in studies of controlled hemorrhagic shock28-31 as well as in uncontrolled intra-abdominal bleeding.6-9 This study shows that the same effects are seen when HSD is given in a model in which the uncontrolled hemorrhage is combined with a high-energy gunshot to the hind limb. A prompt increase in the aortic, splanchnic, and renal blood flows, as well as in CO, occurred within 15 seconds after the completion of the 1-minute injection of HSD, and the peak flow was reached within 1 minute. The blood flow rates and the MAP then returned to a fairly stable steady-state level, which was maintained for the subsequent 40 minutes. This resulted in a better restitution of the oxygen distribution compared with the control group, although this improvement in blood flow rates had only a short-lived effect on the standard bicarbonate concentration, base excess, and pH.

The ultrasonic method we used allows frequent measurements of the flow rates in the large abdominal vessels.32 It also permits us to calculate the difference between the blood flow rates proximal and distal to the aortic lesion and to identify the onset and the end of any bleeding. It is also possible to evaluate the amount of hemorrhage during that time. The validity of the calculated hemorrhage was confirmed by its correlation with the weighed blood losses, although the latter were 94 mL larger on average. This difference can probably be explained by postmortem leakage of blood when the autopsy is performed and by the fact that we report only obvious rebleeding events, although minor events may occur without being included in the calculations.

In this study, rebleeding occurred early after the HSD injection in five of eight animals, but the blood loss during rebleeding was calculated to be only 37% of the volume lost during the initial bleeding, which is in contrast with the figure of 62% reported in a similar previous study.9 Moreover, in the present study, only one animal presented with a third period of bleeding. The effects of the GSW seemed to reduce the total intra-abdominal blood loss, which probably explains why the treatment had a transient, but positive, effect on oxygen consumption.

Rebleeding has been attributed to many factors, including an increase in arterial pressure,2-4,8,9,33 an increase in vessel radius,8 and hemodilution.34 Also, a short lapse of time between the vascular injury and the start of hypertonic saline treatment increases the risk of rebleeding in experiments with cut rat tailS.35

The injection of HSD was followed by an increase in arterial pressures of at least 20 mm Hg and a definite increase in blood flows. In addition, the post-treatment hemodilution was also prominent. Regardless of the mechanism, there is evidence that the episodes of rebleeding encountered in the present study can be attributed to the HSD treatment itself.

Four animals died (25%), two from each group, during the 120-minute study. Three died partly as a result of larger hemorrhages after the initial vascular injury leading to progressive acidosis and shock, but only one animal from the HSD group had a second major blood loss during rebleeding. This is in contrast to 10 fatal outcomes among 16 animals (63%) in the previous study on HSD without the GSW.9 This finding may indicate a difference in hemodynamic defense mechanisms and total bleeding outcome depending on the type of trauma, even when the vascular injury is the same.

Regardless of the injury mechanisms, HSD given in a bolus injection caused rebleeding, which increased the blood loss and probably changed the course of events for the worse in one of the animals. However, when the additional blood loss remained moderate, the treatment had a positive effect on the hemodynamics and oxygenation. A different modality of administration of the HSD with a view to moderating the sudden increase in blood pressure and flows, therefore, may be beneficial. Consequently, the need for a continuous search for effective early resuscitation remains, particularly for use in the military environment, where the time between injury and definitive treatment is frequently prolonged. Moreover, the outcome of hemorrhage and shock is worsened by the presence of other injuries.36

Acknowledgments

We thank Prof. R.G. Hahn. for reading the paper and for his constructive ideas. We also thank Inga-Lisa Larsson and Elisabeth Malm for their skillful technical assistance.

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Guarantor: Louis Riddez, MD PhD

Contributors: Louis Riddez, MD PhD^; Holger Stahlberg, MD PhD^; Anders Suneson, MD PhD^^; Hans Hjelmqvist, MD PhD^^sec

*Department of Surgery, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.

^Department of Anesthesiology, Soder Hospital, SE- 118 83 Stockholm, Sweden.

^Defence Research Establishment, SE-172 90 Stockholm, Sweden.

secDepartment of Anesthesia and Intensive Care, Huddinge University Hospital, SE-141 86 Huddinge, Sweden.

This manuscript was received for review in October 1998. The revised manuscript was accepted for publication in January 2000.

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