AD-A266 475 INSTITUTE REPORT NO. 474 Delayed Resuscitation with Hypertonic Saline/Dextran From Uncontrolled Aortotomy Hemorrhage in Swine D T 1ECT DJohn D. O'Benar ELECT and JUL 0 6 1993 Stephen P. Bruttig A Division of Military Trauma Research T his document has been approved for Public release and sale; it distribution is unrLzited. January 1993 (cid:127).(cid:127)Zi..'7h'. ARMY INSTITUTE OF RESEARCR PRFSID0O OF SAN FRANCISCO CALIFORNIA 94129 Delayed resuscitation with hypertonic saline/dextran from uncontrolled aortotomy hemorrhage in swine -- J.D. O'Benar and S.P. Bruttig This document has been approved for public release and sale; its distribution is unlimited. Destroy this report when it is no longer needed. Do not return to the originator. Citation of trade names in this report does not constitute an official endorsement or approval of the use of such items. The experimental studies of the author described in this report were reviewed and approved by the Institutional Review Committee/Animal Care and Use Committee at Letterman Army Institute of Research. The manuscript was peer reviewed for compliance prior to submission for publication. In conducting the research described here, the author adhered to the "Guide for the Care and Use of Laboratory Animals," DHEW Publication (NIH) 86-23. This material has been reviewed by Letterman Army Institute of Research and there is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. (AR 360-5) R. (dat e) I'OL, MC iommanding UNCLASS IF IED SECURTY CLASSIFiCATiON OC THiS PAGE Form Approved REPORT DOCUMENTATION PAGE OMB NO 07o0-0o8 la REPORt SECiR.Tr C,.ASStFCAriON Io 'S!,(CTiV MAPiK,%G$ 2 SECURITY CLASSIICATiON AtHORITy 3 OSTPSTIoNAVALABL'y 0' R UR .. . 2b DECLASSIFICATION /DOWNGRADING SCHEDULE Approved .or pu-4c reease is u lim ited. 4 PERFORMING ORGANIZATION REPORT NUMBER(S) 5 MONITORING ORGAN'ZATiO.' REFOR NiMBER(S) Institute Report No. 474 6a- NAME OF PERFORMING ORGANIZATION 6o OFFICE SYMBOL 7a NAME OF MONITORING ORGA.YZATtON T1ra-u-1m- 4tar (If applicable) Arm--, .Veica'_ Research andý flvison o Y~viis~lo~noaf ryTraumia SGR~D- UL.-MTDeeoen o n I ~ ~Deyelo=zernt =n 6c. ADDRESS (CityS.ta te, and ZIP Code) 7o * DRE.SSý(Cs',~ ite, anol ZIP Coae) L.e,,tera (cid:127),..z, :. _st"ue of Research .. Tresidio af FFarna ncisco, CA 94129-6800 Frederick, YD 2"7;?'-75-2 8a NAME O0 FJNDiNG-/SPONSOR.NG 80 OFFICE SYMBOL 9 PROCUREMENT INSTR(cid:127)JMEN- ;DENT FCA7,% NNBaEP ORGANIZATION (if applicable) 6c. ADDRES'S'C ity, State, and ZIP Code) 10 SOJRCE OF ;LýNDIG N(cid:127),AQiCj PROGRAM PROJECT TASK WO (cid:127),j i ,, ELEMENT NO NO NO ACCESS'OfN NO 61102A BE14 (1U. ;T ITLEie (=invcl-u:d:e, SReceursituy sCclaistsaiftiicoatnio n)with HRypertonic Saline/Dextran from Unczntrcl"ed Acrc-o=-." hezorrag7e in Swine 12- PERSONA. "JTHORS;. C'Bernar. ýr D. a:4d ruittig, Stephen P. 13a TYPE O REPORT 73b TIME COVERED :4 DATE OF REPORT (Ye,#r, Month, Day) 15 PAGE COLuNT n=. .....i t-e . I FROM T- 93 Jan 29 4 16. SUPPLEMENTARY NOTATION 17_ COSATI CODES 18. SUBJECT TERMS (Continue on reverse it necessary anc Identity by Clock numoer) FIELD I GROUP SUB-GROUP (U) Hemorrhage, hypertonic saline/dextran, pigs, a'"c- .... resuscitation 19. ASSTRXZ7 ( C.ontinue On reverse if necesaryarg identity by block number) Immediate resuscitation from hemorrhage, a common therapy in clinical practice, is associated with high mortality in laboratory models of uncontrolled hemorrhage. We hypothesized that a delayed resuscitation might improve survival, and that gradual repletion of vascular volume might be the most beneficial treatment. To investigate delayed resuscitation, we subjected anesthetized swine weighing 35 to 45 kg to wire suture abdominal aortotomy which resulted in an uncontrolled hemorrhage. After a 30 min delay, they were injected with 4 ml/kg intravenous hypertonic saline dextran solution (7.5% saline in 6% Dextran 70) administered either as a bolus over I minute or as a slow infusion over 12 minutes. Survival was enhanced to 63%, 5/8, in the bolus groups and 78%, 7/9, in the slow infusion group over a survival rate of 57%, 8/14, in the untreated controls. These differences in survival were not statistically significant. However there was a tendency for treatment to increase blood loss (817 + 95 ml in the bolus group, 645 + 86 ml in the slow infusion group versus 520 + 42 ml in Ehe control group). Hypertonic ialine/dextran increased cardiac output to 4.7 + 0.37 L/min in the slow infusion group and 3.4 + 0.33 L/min in the bolus group at 30 min afte-r treatment over 2.4 + 0.20 L/min in the control group. Mean arterial pressure was sustained at 63 + 5 mmHg in the slow infusion group, 43 + 3 mm~g DISTRIBUTION/ AVAILABILITY OF ABSTRACT 21 ABSTRA~C 44~~,SSIFICATiON '20 CUlN .LASSIFIEODiUNLIMITED [0 SAME AS RPT Q OTIC USERS 9K415 565116 John K. Hess, COL. )D Form 1473, JUN 86 Previouseditionsareo bsol te. SECR'TY CLASSIFICATION OF TH(cid:127)IS PAý5C in the bolus group, versus 49 + 4 mmHg in the control group. These results are consistent with the hypothesis that hypertonic saline dextran is an effective resuscitation solution for uncontrolled hemorrhage when administered 30 minutes after the insult, especially as a slow infusion. ABSTRACT Immediate resuscitation from hemorrhage, a common therapy in clinical practice, is associated with high mortality in laboratory models of uncontrolled hemorrhage. We hypothesized that a delayed resuscitation might improve survival, and that gradual repletion of vascular volume might be the most beneficial treatment. To investigate delayed resuscitation, we subjected anesthetized swine weighing 35 to 45 kg to wire suture abdominal aortotomy which resulted in an uncontrolled hemorrhage. After a 30 min delay, they were injected with 4 ml/kg intravenous hypertonic saline/dextran solution (7.5% saline in 6% Dextran 70) administered either as a bolus over 1 minute or as a slow infusion over 12 minutes. Survival was enhanced to 63%, 5/8, in the bolus groups and 78%, 7/9, in the slow infusion group over a survival rate of 57%, 8/14, in the untreated controls. These differences in survival were not statistically significant based on the chi-square test. However there was a tendency for treatment to increase blood loss (817 + 95 ml in the bolus group, 645 + 86 ml in the slow infusion group versus 520 + 42 ml in the control group). Hypertonic saline/dextran significantly increased cardiac output to 4.7 + 0.37 L/min in the slow infusion group and 3.4 + 0.33 L/min in the bolus group at 30 min after treatment over 2.4 + 0.20 L/min in the control group. Mean arterial pressure was sustained at 63 + 5 mmHg in the slow infusion group, significantly different from 43 + 3 mmHg in the bolus group, versus 49 + 4 mmHg in the control group. These results are consistent with the hypothesis that hypertonic saline/dextran is an effective resuscitation solution for uncontrolled hemorrhage when administered 30 minutes after the insult, especially as a slow infusion. Key Words: Hemorrhage, hypertonic saline/dextran, pigs, aortotomy, resuscitation Acsy~iofl For F:Tu C(cid:127)A&I1 I;7i6';! i . . . ... .. . S.. . ... .. . .. /1 If. " . Delayed Resuscitation with Hypertonic Saline/Dextran From Uncontrolled Aortotomy Hemorrhage in Swine -- John D. O'Benar, Ph.D. & Stephen P. Bruttig, Ph.D. For the past five years, we have investigated the use of hypertonic saline/dextran (HSD 7.5% NaCI in 6% Dextran 70) as a resuscitation fluid to treat hemorrhagic shock. Maningas et al. (1) found that in controlled blood loss (46 ml/kg over 15 min) in pigs, HSD in a dose of 11.5 ml/kg was capable of producing 100% survival in a model which was 100% lethal if left untreated. Subsequent studies by this group have shown that 4 ml/kg of HSD is the minimal effective dose of this resuscitation fluid. Bickell et al., by contrast, studied pigs in which an uncontrolled blood loss was produced by aortotomy (2). In this model, which was 100% survivable if left untreated, PSD (at 4 ml/kg) was lethal if administered within 5 min following hemorrhage. These authors attributed lethality to the increased systemic blood pressure and hemodilution produced by HSD. The increased systemic blood pressure disrupted the developing thrombus at the aortotomy site and re-initiated the hemorrhage which, coupled with hemodilution, prevented reformation of the mural thrombus. This explanation is further supported by experiments in rats in which early hypertonic saline infusion in a model of "uncontrolled" hemorrhagic shock led to an increased blood loss from injured vessels, a fall in mean arterial pressure and early mortality (3,4). The question remains: What would be the effect of HSD in the uncontrolled hemorrhage if HSD were administered more gradually and at a more clinically realistic time, i.e., 30 min post injury? This study was designed to investigate this question by determining the efficacy of HSD in a model in which resuscitation was delayed and gradual. We thus sought to determine whether delay and gradual HSD administration would improve hemodynamics and survival. Preliminary experiments in rabbits have shown successful resuscitation if the HSD treatment is delayed 30 min after aortotomy (5). Therefore, we proposed to resolve these differences in administration, and more importantly, outcome, by determining the effect of delayed administration of HSD on survival and function following an uncontrolled (aortotomy) hemorrhage. Bolus and gradual infusions 2 -- J.D. O'Benar and S.P. Bruttig were compared to determine if one mode of administration is to be preferred over the other. The logistic advantage of HSD, i.e., 'he small volume required to resuscitate and the short time required to administer HSD, coupled with the potential enhancement of survival from massive hemorrhage, make HSD administration a particularly attractive therapy in combat casualty care. However, questions remain concerning its efficacy after traumatic injury, especially that involving uncontrolled truncal vascular hemorrhage. Consequently, the present experiments evaluated the effects of time delay (30 min) and type of administration (gradual vs. bolus) in improving the effectiveness of HSD as a potential resuscitation solution. Materials and Methods Forty-four female swine weighing 35-45 kg were entered into the study. After an overnight fast, they were premedicated with an intramuscular injection of 2.2 mg/kg ketamine, 2.2 mg/kg xylazine and 0.08 mg/kg atropine, followed by halothane anesthesia via a face mask. After endotracheal intubation, anesthesia was maintained with oxygen, 12% nitrous oxide and 1-2% halothane via respirator. A neck incision was performed and a Swan-Ganz cannula was placed via the internal jugular vein for measurement of cardiac output, central venous and pulmonary artery pressure. An external jugular catheter was inserted for sampling and injection and a carotid catheter for sampling and systemic arterial pressure measurement. Next, splenectomy was performed through a midline laparotomy with ligation of all vascular pedicles. The abdominal aorta was exposed, using warm saline-soaked towels to retract the viscera. The aorta was marked with two points 5 mm apart approximately 10 cm proximal to the iliac artery bifurcation. A 4-0 surgical wire was threaded through the ventral aortic wall, into the lumen and back out again at these points using a curved 27 gauge needle as a guide. The free ends of the surgical wire were then exteriorized through a small hole in the abdominal wall and the abdominal incision J.D. O'Benar and S.P. Bruttig -- 3 was sewn closed. The nitrous oxide was discontinued and the animal spontaneously breathed a mixture of oxygen and 1.0 - 1.5 per cent halothane. After a ten minute stabilization period, two control samples were taken ten minutes apart. Samples consisted of hemodynamic data: phasic and mean pulmonary wedge and systemic pressures, central venous pressure, cardiac output and ECG; complete blood gases, including complete co-oximeter readings and blood chemistries, including lactate, albumin, total protein, and blood glucose measurements. Arterial and venous hematocrits were also determined. If the hemodynamic readings were unstable (did not agree within 10%) an additional ten minute period was allowed and measurements were retaken. Aortotomy (hemorrhage) was then accomplished by pulling out the wire suture through the abdominal wall. This caused a 5 mm slit-like tear in the long axis of the ventral abdominal aortic wall. Hemodynamic variables were measured and samples were taken at 5, 15, 30, 42, 60, 90 and 120 min post aortotomy. Animals were alternately assigned to one of four treatment groups and treatment was begun immediately after the 30 min sample. In Group A (the control group, N=14), no fluid was given. In Group B (slow infusion group, N=9), hypertonic saline/dextran (7.5% NaCI in 6% Dextran-70, HSD) was administered slowly, at 4 ml/kg, over a period of 12 min. In Group C (bolus infusion group, N=8), the same dose of HSD was administered in approximately 1 min. Group D (N=4), which served as non-hemorrhage controls, consisted of shai.i-operated time controls in which the aortotomy suture was placed but never pulled. After the last sample at two hours post-aortotomy, humane euthanasia was performed on surviving animals with an overdose of barbiturate. The abdominal incision was then reopened and the total blood loss into the abdominal cavity was estimated by volumetric measurement of all available free blood and clot. The data were evaluated using an analysis of covariance with the 30 min post-aortotomy sample (pre- treatment) as the covariate. When the F ratio was significant, the Newman-Keuls test was used to identify 4 -- J.D. O'Benar and S.P. Bruttig the specific group and time differences. Reported values are expressed as means + standard error of the mean. Differences in survival were analyzed using a chi-square test. Differences were considered significant at p < 0.05. Results Most clear-cut were the survival data from these experiments. Survival was 57% (8/14) in untreated controls, and was enhanced to 63% (5/8) in the bolus group and 78% (7/9) in the slow infusion group. These differences were not statistically significant by a chi-squared test. This increased survival was cspite a tendency for treatment to increase blood loss (520 + 42 ml in control, 817 + 95 ml in bolus versus 645 + 86 ml in slow infusion). As expected, mean arterial pressure decreased markedly with aortotomy. (Fig.1) In the unresuscitated hemorrhage group, for example, mean arterial pressure decreased from 95 + 5 mmHg to 28 + 2 mmHg in 5 minutes. Other aortotomy groups showed similar declines. With resuscitation, the bolus group showed no discernable increase in arterial pressure with infusion. The slow infusion group, on the other hand, did show an increase in arterial pressure greater than that of the other groups to nearly 60 mmHg, and this increase was sustained in survivors throughout the 90 min recovery period. Cardiac output decreased predictably with hemorrhage with no difference between groups. (Fig. 2) Administration of HSD, either by the slow infusion or the bolus effected improvement in cardiac output. Improvements from slow infusion were both faster and greater, increasing to 4.7 + 0.37 L/min, a value greater than that of the time control group. Bolus resuscitation was adequate, however, and in both bolus and slow infusion groups, improvement was more or less sustained throughout the observation period. The mean pulmonary artery pressure (MPAP) decreased with aortotomy and increased again with resuscitation (Fig. 3). The slow infusion produced better recovery in MPAP J.D. O'Benar and S.P. Bruttig -- 5 than the bolus, the latter remaining below control values for most of the recovery period. The superiority of the slow infusion method of resuscitation was maintained throughout the observation period. Figure 4 shows data for total peripheral resistance. For the most part, this variable decreased with aortotomy and decreased again with resuscitation. This latter decrease in peripheral resistance is consistent with a vasodilator or rheologic effect of hypertonic saline/dextran (6). Except for an unexplained spike at 60 minutes, (slow infusion), these low resistance values were maintained until the termination of the experiment. Figure 5 shows oxygen delivery per kg body weight data. Resuscitation after aortotomy produced a sudden decline and negligible recovery in this variable. Perhaps this lack of recovery can be attributed to a lack of oxygen-carrying capacity due to the hemodilution caused by HSD infusion. Discussion Bickell, et al. (2) showed that significant bleeding was likely to be re-initiated with immediate resuscitation of aortotomy hemorrhage and that with the sudden increase in pressure, the thrombus would likely be eroded and blown off. The present study, on the other hand, allowed a 30 min delay for the thrombus to stabilize and thus be secure under the increase in pressure initiated by HSD. These studies are realistic in the sense that most resuscitation is begun only after the delays incurred during response by health care providers. We would estimate these delays to be minimally 30 minutes. Measurements of blood loss support this hypothesis. In the Bickell experiment the volume of hemorrhage in the hypertonic saline/dextran group was 1,340 + 230 ml versus 783 + 85 ml in the control. In our study, which added HSD, the hemorrhage volumes were also greater in the treatment groups than control group; volumes still did not approach those of the Bickell study and were apparently compatible with increased survival.