Hypertonic Saline Dextran Trial on Trauma Patients

[Spock]

I read about this in the newspaper so my information is not scientific but the article said there was funding for a multicenter study including Canada and the USA. I was under the impression that some services in Pittsburgh were going to be part of the study but I have heard nothing since reading the article a few weeks ago. Has the study started?

We do interventional neuroradiology procedures at my hospital and sometimes use hypertonic saline. The physician is an MD/PhD and is so bloody intelligent that a normal conversation is difficulty even though he is a nice guy. I haven't done a procedure with him where he asked for hypertonic saline but if I ever do I'm going to ask alot of questions.

Live long and prosper.

Spock

[chbare]

"You should try one of those 'Dial-A-Nurse,' Hotlines, i hear they are skilled at finding all sorts of things that don't exist...

ACE844"

ACE844, we had a semester of "finding things that don't exist" in nursing school and even did a 300 hour clinical rotation in the Land of OZ to compliment our didactic education.

Take care,

chbare.

[AZCEP]

:shock: That sure explains a lot of the questions that nursing staff ask, now doesn't it. :shock:

[Ace844]

Here's the Full text stucy on this topic...

(A Single Bolus of 3% Hypertonic Saline with 6% Dextran Provides Optimal Initial Resuscitation After Uncontrolled Hemorrhagic Shock

[Original Articles)

Watters, Jennifer M. MD; Tieu, Brandon H. MD; Differding, Jerome A. BS; Muller, Patrick J. BS; Schreiber, Martin A. MD

From the Oregon Health & Science University, Portland, Oregon.

Submitted for publication January 25, 2006.

Accepted for publication March 29, 2006.

This work was supported in its entirety by the US Army Medical Research Acquisition Activity Award W81XWH-04-1-0104.

Presented at the Northwest Regional Committee on Trauma Resident Paper Competition, December 11, 2004, Centralia, Washington, and the 35th Annual Meeting of the Western Trauma Association, February 27–March 5, 2005, Jackson Hole Wyoming.

Address for reprints: Jennifer M. Watters, MD, 3181 SW Sam Jackson Park Road, Mail Code L223A, Portland, OR 97239; email: wattersj@ohsu.edu.]

Abstract

Background: The optimal fluid for early resuscitation of hemorrhagic shock would restore perfusion without increasing blood loss, hypothermia, acidosis, or coagulopathy. This study examined effects of a single bolus of hypertonic saline (HTS) with or without (±) dextran (D) after uncontrolled hemorrhage (UH) and determined optimal fluid composition.

Methods: Fifty swine were anesthetized and underwent invasive line placement, celiotomy, splenectomy, suprapubic catheterization, and grade V liver injury. After 30 minutes of UH, blinded fluid resuscitation was initiated with a 250-mL bolus. Animals were randomized to five groups: normal saline (NS), 3% HTS (3%), 3% HTS/6% D (3% D), 7.5% HTS (7.5%), or 7.5% HTS/6% D (7.5% D). Mean arterial pressure (MAP) and tissue oxygen saturation (StO2) were recorded. Laboratory and thrombelastography (TEG) data were collected every 30 minutes. Animals were sacrificed 120 minutes after injury. Analysis of variance was used to compare groups. Significance was defined as p < 0.05.

Results: Baseline characteristics and laboratory values were similar in all groups. All groups achieved a similar degree of shock. Two NS and two 3% animals did not survive to 120 minutes. Fluids containing dextran produced a significantly greater increase in MAP (p < 0.02). Animals receiving 3% D maintained a higher MAP 90 minutes after fluid bolus. Also, 7.5% ± D produced a significantly greater initial increase in StO2 (p < 0.05). This effect declined after fluid bolus while 3% D continued to improve tissue oxygenation. Significant differences developed between groups in TEG values, hematocrit, fibrinogen, urine sodium, serum sodium, serum chloride, and urine output.

Conclusions: A single bolus of 3% D after uncontrolled hemorrhagic shock produces an adequate and sustained rise in MAP and StO2 and attenuates hypercoagulability. Resuscitation with 7.5% ± D produces significantly increased urine output accompanied by a decline in MAP and StO2 over time. A single bolus of 7.5% D results in significant dilutional anemia and relative hypofibrinogenemia.

--------------------------------------------------------------------------------

Although traumatic injury accounts for the largest number of deaths for persons aged 1 to 44 years,1 many questions remain unanswered about initial, field, or prehospital management of trauma victims. Although therapeutic intervention for the treatment of hemorrhagic shock invariably includes the administration of fluids, the optimal timing, fluid composition, and quantity to infuse are not known. Fluid resuscitation is often the first and only treatment for hypotensive patients available to early responders in the field. However, the mortality benefit of aggressive early fluid resuscitation has been questioned in the presence of uncontrolled hemorrhage in both animal models and human trials.2,3 Although overly aggressive fluid resuscitation may be harmful, adequate resuscitation decreases organ damage and improves survival.4 In addition, many victims of trauma suffer multiple injuries including traumatic brain injuries. It may be difficult or impossible for first responders to rule out a traumatic brain injury, which can be worsened by even a single episode of hypotension,5 but large volume fluid resuscitation is associated with increased intracranial hypertension.6 To further complicate early resuscitation, determinants of adequate initial resuscitation are still debated.

Numerous studies have been conducted examining the efficacy of hypertonic saline in initial trauma resuscitation. The ideal initial resuscitation fluid would restore and maintain tissue perfusion while not increasing intracranial pressure, blood loss, hypothermia, or acidosis and mitigating late complications attributed to hypercoagulability. The most widely studied has been 7.5% saline with and without dextran. Hypertonic saline has been shown to rapidly restore blood pressure, improve cardiac performance,7 reduce intracranial pressure and improve cerebral perfusion pressure,8 and may attenuate the proinflammatory response.9

This study sought to examine the effects of a single bolus of hypertonic saline (HTS) after uncontrolled hemorrhagic shock (UHS) from solid organ injury in a clinically relevant model, and to determine the optimal fluid composition by using solutions of varying tonicity with and without (±) the addition of dextran (D). Although dextran has been associated with anaphylaxis and coagulopathy,10,11 a study examining the effects of a single prehospital bolus of 7.5% HTS with 6% dextran-70 did not report any cases of dextran-related anaphylaxis or coagulopathy.6 Our hypotheses were that a single bolus of HTS after UHS in a prehospital model would provide adequate restoration of blood pressure and tissue perfusion and that these effects would increase with increasing tonicity and the addition of dextran to the solutions.

MATERIALS AND METHODS

The study design was a randomized, blinded, controlled trial conducted in a large animal model. The Institutional Animal Care and Use Committee at Oregon Health & Science University approved the protocol. This facility adheres to the National Institutes of Health guidelines for the care and use of laboratory animals.

Uncontrolled Hemorrhagic Shock Model

Fifty female Yorkshire crossbred swine with a mean weight of 33 kg were obtained from a commercial breeder. Animals underwent a 16-hour preoperative fast except for water ad libitum. Animals were preanesthetized with 8 mg/kg intramuscular Telazol (Fort Dodge Animal Health, Fort Dodge, IA), oral-endotracheally intubated with a 6.5- to 7.5-mm tube, and mechanically ventilated. Volume control ventilation was used with tidal volumes set at 12 ± 2 cc/kg. Respiratory rate was adjusted to maintain end-tidal CO2 and Pco2 of 40 ± 4 mm Hg. Anesthesia was maintained with isoflurane (Abbott Laboratories, North Chicago, IL) and an independent animal technician assessed adequacy by monitoring jaw laxity and painful stimuli to the nasal septum and forefoot. Euthermia (38.0 ± 1.5°C) was preserved using warmed fluids and external warming devices. Monitoring devices were placed including a left common carotid arterial catheter, left external jugular catheter, esophageal thermometer, and a cutaneous InSpectra Tissue Spectrometer (Hutchinson Technology, Hutchinson, MN) on the left hind limb. The arterial catheter was used for continuous mean arterial blood pressure (MAP) recording and blood sampling. The venous catheter was used for administration of resuscitation fluids. Continuous tissue oxygen saturation (StO2) data were obtained and recorded using the tissue spectrometer.

After placement of monitoring devices, animals underwent midline celiotomy, splenectomy, and suprapubic catheterization. Splenectomies are performed in swine hemorrhage models because of the variability of the spleen's distensibility and the resultant variable amounts of sequestered blood. Splenic blood volume was replaced with normal saline (NS) 3 mL/g spleen weight. After a 15-minute stabilization period, preweighed sponges were placed in the pelvis and inferior left and right pericolic gutters to facilitate blood collection and blood loss measurement. Sponges were not in contact with the liver and should not have affected blood loss.

Standardized grade V liver injuries were created using a specially designed clamp. The clamp, closed over the central portion of the liver, creates a reproducible injury with extensive parenchymal damage as well as laceration of one or more central hepatic veins, consistent with the AAST Injury Scaling and Scoring System for a grade V hepatic injury.12 Autopsies were performed after animal sacrifice to ensure comparable injuries by determining the number of central hepatic veins injured. Figure 1 is a representative injury demonstrating a large laceration of the left hepatic vein.

--------------------------------------------------------------------------------

[Help with image viewing]

[Email Jumpstart To Image] Fig. 1. Grade V liver injury. This photograph demonstrates a representative grade V liver injury. Use of a specially designed clamp results in extensive parenchymal damage and injury to one or more central hepatic vein. The clamp is passing through a large laceration of the left hepatic vein.

--------------------------------------------------------------------------------

Animals were allowed to hemorrhage for 30 minutes. During the hemorrhage period, blood loss was collected by suction as well as with the preweighed sponges and was reported as a mean for each group. Visible hemorrhage ceased in all animals without intervention after reaching similar nadir MAPs. At 30 minutes postinjury, sponges were removed and reweighed and the abdomen was closed.

Animals were randomized to one of five fluid groups and blinded resuscitation was initiated. A single 250-mL bolus (7.2 ± 0.8 mL/kg to 7.6 ± 0.7 mL/kg) of study fluid was infused over 10 minutes. Fluids administered were: normal saline (NS), 3% saline (3%), 3% saline with 6% dextran-70 (3% D), 7.5% saline (7.5%), and 7.5% saline with 6% dextran-70 (7.5% D). NS and 3% were commercially prepared (Baxter, Deerfield, IL: NS, pH 4.5–7.0, 154 mEq/L sodium, 154 mEq/L chloride; 3%, pH 5.0, 513 mEq/L sodium, 513 mEq/L chloride) and the remaining fluids (3% D, 513 mEq/L sodium, 513 mEq/L chloride, 60 gm/L dextran-70; 7.5%, 1283 mEq/L sodium, 1283 mEq/L chloride; 7.5% D, 1283 mEq/L sodium, 1283 mEq/L chloride, 60 gm/L dextran-70) were compounded in our laboratory using sodium chloride (Fisher Chemicals, Fairlawn, NJ) and dextran-70 from Leuconostoc mesenteroides (Sigma-Aldrich, Inc., St. Louis, MO) and passed through a 0.22-µm filter to eliminate any bacterial or viral contaminants. MAP and StO2 monitoring continued for a total of 120 minutes before animal sacrifice. Laboratory and thrombelastography (TEG) data were collected at baseline and every 30 minutes. Secondary blood loss was measured at 120 minutes by reopening the abdomen and collecting all blood with suction and a new set of preweighed laparotomy sponges and was reported as a mean for each group.

Statistical Analysis

Anaylsis of variance (ANOVA) and repeated measures ANOVA were used to compare groups using a statistical software package for personal computers (SPSS, Windows Version 13.0, SPSS, Inc., Chicago, IL). Paired t tests were used to make comparisons within groups. Significance was defined as p < 0.05.

RESULTS

Two NS and two 3% animals did not survive to 120 minutes. Nonsurvivors' data were included in the analysis until the time of their deaths. All animals had similar injuries (2.1 ± 0.9 vessels) determined by autopsy. Baseline characteristics and end of study data including weight and temperature were similar for all groups (p > 0.2). Hemodynamic and urine output data are presented in Table 1. Despite equal blood loss and resuscitation volumes, animals receiving 7.5% ± D produced considerably more urine than animals receiving 3% ± D or NS, p < 0.03.

--------------------------------------------------------------------------------

[Help with image viewing]

[Email Jumpstart To Image] Table 1 Baseline and End-of-Study Data

--------------------------------------------------------------------------------

Continuous MAP data are presented in Figure 2. Injuries were created at time zero (T0). All animals experienced a precipitous drop in MAP to similar nadirs followed by a period of autoresuscitation to a significantly higher MAP compared with nadir MAP (p = 0.001). The single fluid bolus was administered over 10 minutes beginning 30 minutes after injury. 7.5% saline solutions initially caused a brief drop in the MAP, which was more pronounced with the fluid containing dextran. The 3% D group produced a significantly greater overall increase in MAP compared with all other fluids except 7.5% D (p < 0.02). However, the overall increase in MAP in the 7.5% D group was not significantly higher than the MAP increase with NS (p = 0.06). Twelve of 50 animals (24%) returned to their baseline MAP after fluid administration. Animals reaching baseline MAP by group: NS, 0/10; 3%, 1/10; 3% D, 5/10; 7.5%, 2/10; 7.5% D, 4/10. Of animals receiving dextran, 9/20 (45%) returned to baseline MAP. There was no significant difference in rate of return to baseline blood pressure between the two groups receiving dextran (p = 1). Compared with NS, 3% D animals returned to their baseline MAP at a significantly higher rate (p = 0.03). With larger cohorts, statistically important differences may have developed compared with other fluids.

--------------------------------------------------------------------------------

[Help with image viewing]

[Email Jumpstart To Image] Fig. 2. Continuous mean arterial pressure. Data presented are the average mean arterial pressures for each group. Injuries were created at time zero (T0). All animals reached similar MAP nadirs followed by significant autoresuscitation (p= 0.001). Fluid bolus administration began 30 minutes after injury. 3% D produced a significantly greater overall increase in MAP compared with all fluids except 7.5% D (p< 0.02).

--------------------------------------------------------------------------------

Continuous StO2 data are presented in Figure 3. After injury, tissue oxygen saturation dropped precipitously, mirroring MAP. Likewise, all animals reached similar StO2 nadirs followed by a period of autoresuscitation. The four groups receiving HTS began improving StO2 immediately with fluid administration. 7.5% ± D solutions produced a greater initial increase in StO2. However, this effect began declining within 5 minutes of completing the fluid bolus. The decline was more rapid in the 7.5% group. On the contrary, 3% D continued to improve StO2 during the 90-minute resuscitation period.

--------------------------------------------------------------------------------

[Help with image viewing]

[Email Jumpstart To Image] Fig. 3. Continuous tissue oxygen saturation. Average mean StO2 for each group is presented. The StO2 for each group declined after injury mirroring the drop in MAP. All animals reach similar nadirs followed by a period of autoresuscitation. StO2 improved with fluid administration in all groups. 7.5% ± D solutions produced a greater initial increase in StO2. Upon completing the fluid bolus, StO2 declined in all groups except the 3% D group.

--------------------------------------------------------------------------------

Baseline laboratory results were similar for all groups. At 120 minutes, platelet count (299 ± 117), partial thromboplastin time (PTT; 15.5 ± 2.2), prothrombin time (PT; 14.2 ± 1.3), pH (7.39 ± 0.05), pCO2 (48 ± 4), pO2 (481 ± 99), serum lactate (2.4 ± 1.8), and base excess (5.1 ± 3.8) remained similar for all groups. Baseline laboratory data and data at 120 minutes showing significant differences between groups and from baseline are listed in Table 2. Groups receiving HTS developed hypernatremia with Na levels peaking 30 minutes after fluid infusion. Serum Na levels remained significantly different at T120. HTS groups also developed significant hyperchloremia. The degree of hypernatremia and hyperchloremia correlated with the infused fluid's NaCl concentration. Significant anemia and relative hypofibrinogenemia developed in HTS groups, and was exacerbated by the addition of dextran. HTS groups developed elevated urine Na levels corresponding to serum Na. Table 3 displays additional laboratory data comparing end of study with baseline for each group. Although no differences were seen in these data between groups at T120, within each group several of these results differed significantly from baseline data. A significant drop in pH occurred in the NS, 3%, and 7.5% groups. However, a significant increase in lactate was only seen in the 3% group.

--------------------------------------------------------------------------------

[Help with image viewing]

[Email Jumpstart To Image] Table 2 Baseline (T0) and End-of-Study (T120) Laboratory Data

--------------------------------------------------------------------------------

--------------------------------------------------------------------------------

[Help with image viewing]

[Email Jumpstart To Image] Table 3 Baseline (T0) versus End-of-Study (T120) Laboratory Data

--------------------------------------------------------------------------------

TEG data are shown in Figure 4. Reaction ® time represents the time to onset of clot formation. A significant decrease in R time occurred in all groups except 3% D. The alpha angle represents the rapidity of fibrin buildup and cross-linking. The alpha angle did not increase in animals receiving dextran. Maximum amplitude (MA) is a measurement of clot strength and is affected by platelet number and function as well as by fibrinogen level. The MA decreased significantly in animals receiving dextran. Clotting index (CI) is a calculated measurement of overall coagulation function derived from all measured values. CI increased significantly in all animals except those receiving 3% D.

--------------------------------------------------------------------------------

[Help with image viewing]

[Email Jumpstart To Image] Fig. 4. Thrombelastography data. Comparisons are made between baseline and end of study data. (A) A significant decrease in reaction time occurred in all groups except 3% D. ( Alpha angle did not increase in animals receiving dextran. © Maximum amplitude decreased significantly in animals receiving dextran. (D) Clotting index increased significantly in all animals except those receiving 3% D. p < 0.05, *v. preinjury and **v. 3% D and 7.5% D.

--------------------------------------------------------------------------------

DISCUSSION

Historically, large-volume resuscitation has been advocated for the hypotensive trauma victim. This approach may increase mortality in the setting of uncontrolled hemorrhage and may lead to increased acidosis, hypothermia, coagulopathy, abdominal compartment syndrome, elevated intracranial pressure, and a host of poorly understood immunologic consequences. The ideal fluid for early resuscitation would restore tissue perfusion and avoid this myriad of ill effects. Hypertonic saline has been shown to rapidly restore blood pressure and improve cardiac performance.7 Studies report a reduction in intracranial pressure and an improvement in cerebral perfusion pressure after resuscitation with hypertonic saline.8 In addition to excellent physiologic performance, hypertonic saline may attenuate the pro-inflammatory response.9 Decreasing dysfunctional inflammation after traumatic injury could profoundly effect the development of late sequelae such as acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS). Prior work in our lab demonstrated that up-regulation of pro-inflammatory cytokines in the lung after grade V liver injury and uncontrolled hemorrhage does not occur if fluid resuscitation is withheld.13 Our results suggest that fluid resuscitation of any kind may be responsible for the dysfunctional inflammatory response to traumatic injury. However, the risks of prolonged hypotension and shock are well known. Our study was limited to a short time course and additional work needs to be completed to determine whether this dysfunctional response persists and whether the timing of fluid resuscitation affects the inflammatory response. In addition, our findings motivated the current study to determine whether adequate initial field resuscitation could be achieved and maintained with a single bolus of fluid, avoiding large volume resuscitation during initial intervention.

Because we were not performing goal directed resuscitation, such as to a predetermined mean arterial pressure (MAP), we used a near-infrared tissue spectrometer (NIRS) to assess regional tissue oxygenation in hind limb muscle as a marker of resuscitation adequacy. NIRS is noninvasive, provides continuous data, and several previous studies have shown that NIRS is capable of determining local tissue oxygenation under a variety of clinical scenarios.14–16 In swine, hind limb muscle tissue oxygenation reflects both the severity of shock and the adequacy of resuscitation 17 and may be used as a surrogate marker of splanchnic perfusion.18

Our data indicate that a 250-mL bolus of 3% D restores both MAP and StO2 and maintains adequate perfusion for 90 minutes after infusion. The addition of dextran is important for both achieving and maintaining adequate resuscitation. In previous animal studies, it has been shown that the addition of a 6% dextran to 7.5% NaCl resulted in a significantly higher and more sustained cardiac output, mean arterial pressure, lower arterial peripheral resistance,19 and increased survival 20 compared with hypertonic saline and dextran alone. The increase in MAP and StO2 achieved with 3% D is not associated with increased secondary bleeding. Ideally, within 90 minutes, a patient would reach the trauma surgeon who could initiate definitive care including operative intervention and ongoing resuscitation.

The greatly increased urine output in animals receiving 7.5% saline solution is likely secondary to hypernatremic natriuresis. Concomitant with these animals' increase in serum sodium was an increase in urine sodium and urine output. Excessive urine output may account for the subsequent decline in MAP and StO2 seen in these animals over time. 3% D resuscitation does not result in the same increase in urine output despite moderate increases in both serum and urine Na. This may explain the superior maintenance of MAP and StO2 in the 3% D group.

The data clearly demonstrate that all animals become relatively hypercoagulable after injury and fluid resuscitation as evidenced by decreased R time and increased clotting index. Dextran and specifically 3% saline with dextran attenuates this hypercoagulability. This attenuation is likely multifactorial but dilutional effects may be paramount. The decrease in maximum amplitude may be caused by relative hypofibrinogenemia. However, profound dilutional anemia may adversely affect platelet function by decreasing nitric oxide scavenging.21 Attenuation of the hypercoagulable response to traumatic injury may reduce the number of late thrombotic complications seen in this patient population. Without prophylaxis 58% of trauma patients will develop deep venous thrombosis.22 A hypercoagulable state is associated with the later development of ARDS and MODS.23 Of the fluids tested, 3%D produced the best physiologic and coagulation profile.

This study has several limitations. It was performed in anesthetized swine rather than awake human subjects. As such, the effects of general anesthesia on the physiologic parameters measured must be considered. However, performing this type of randomized blinded, controlled trial in humans would be a huge undertaking, both logistically and in cost, needing prior justification such as provided by this study. The study is limited to early intervention and is not extended to include survival data. The limited time course of the study precludes the identification of any late sequelae of limited initial resuscitation. Subsequent work should certainly be extended to capture that data. Animals did not have intracranial abnormality and intracranial pressures were not monitored, limiting the conclusions to be made about the fluid's use in patients with traumatic brain injuries. Adding a traumatic brain injury to the model and placing intracranial monitoring devices would be informative. Although pH decreased in three of five groups, none of our animals became severely acidotic, even in the NS group. The hepatic injury is extensive and animals lose 30 to 40% of their blood volume with nadir MAPs of 30 to 35 mm Hg. The lack of profound acidosis despite significant injury and blood loss is consistent with a moderate shock model representative of patients admitted to and resuscitated at trauma centers. However, our findings may be different if animals achieved a greater degree of shock or if fluid administration were delayed for up to 60 or 90 minutes.

CONCLUSIONS

After uncontrolled hemorrhagic shock, a single 250-mL bolus of 3% saline with 6% dextran-70 produces an adequate and sustained rise in both mean arterial pressure and tissue oxygen saturation while attenuating posttraumatic hypercoagulability. The sustained use of these fluids for resuscitation may be limited by the development of hypernatremia, hyperchloremic acidosis, increased bleeding as a result of vasodilatation, interference with platelet function, or the exacerbation of pulmonary edema or congestive heart failure caused by circulatory overload.

REFERENCES

1. Committee on Injury Prevention and Control, Institute of Medicine. Reducing the Burden of Injury: Advancing Prevention and Treatment. Bonne RJ, Fulco CE, Liverman CT, Eds. Washington, DC: National Academy Press; 1999;42–43. [Context Link]

2. Bickell WH, Bruttig S, Millnamow G, et al. The detrimental effects of intravenous crystalloid after aortotomy in swine. Surgery. 1991;110:529–536. Bibliographic Links [Context Link]

3. Bickell WH, Wall MJ, Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Eng J Med. 1994;331:1105–1109. [Context Link]

4. Wiggers CJ. Physiology of Shock. Cambridge: Harvard University Press; 1950;121–146. [Context Link]

5. Schreiber MA, Aoki N, Scott BG, et al. Determinants of mortality in patients with severe blunt head injury. Arch Surg. 2002;137(3):285–290. Ovid Full Text Bibliographic Links [Context Link]

6. Mattox KL, Manigas PA, Moore EE. Prehospital hypertonic saline/dextran infusion for post-traumatic hypotension. The USA Multicenter Trial. Ann Surg. 1991;213:482–491. Bibliographic Links [Context Link]

7. Kramer GC, Perron PR, Lindsey DC, et al. Small volume resuscitation with hypertonic saline dextran solution. Surg. 1986;100:239–246. [Context Link]

8. Valet R, Albanese J, Thomachot L, et al. Isovolemic hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic intracranial hypertension: 2 mL/kg 7.5% saline is more effective than 2 mL/kg 20% mannitol. Crit Care Med. 2003;31:1683–1687. Ovid Full Text Bibliographic Links [Context Link]

9. Ciesla DJ, Moore EE, Biffl WL, Gonzalez RJ, Silliman CG. Hypertonic saline attenuation of the neutrophil cytotoxic response is reversed upon restoration of normotonicity and reestablished by repeated hypertonic challenge. Surgery. 2001;129:567–575. Bibliographic Links [Context Link]

10. Barron ME, Wilkes MM, Navickis RJ. A systematic review of the comparative safety of colloids. Arch Surg. 2004;139:552–563. Ovid Full Text Bibliographic Links [Context Link]

11. Roberts JS, Bratton SL. Colloid volume expanders: problems, pitfalls and possibilities. Drugs. 1998;55(5):621–630. Buy Now Bibliographic Links [Context Link]

12. Moore EE, Cogbill TH, Jurkovich GJ, et al. Organ injury scaling: spleen and liver (1994 revision). J Trauma. 1995;38:323–324. Ovid Full Text Bibliographic Links [Context Link]

13. Watters JM, Jackson T, Muller PJ, et al. Fluid Resuscitation Increases Inflammatory Response to Traumatic Injury. J Trauma. 2004;57:1378. Ovid Full Text [Context Link]

14. Cohn SM, Crookes BA, Proctor KG. Near-infrared spectroscopy in resuscitation. J Trauma. 2003;54:S199–S202. Ovid Full Text Bibliographic Links [Context Link]

15. Crookes BA, Cohn SM, Bloch S, et al. Can near-infrared spectroscopy identify the severity of shock in trauma patients? J Trauma. 2005;58:806–816. Ovid Full Text Bibliographic Links [Context Link]

16. Chaisson NF, Kirschner RA, Deyo DJ, et al. Near-infrared spectroscopy-guided closed-loop resuscitation of hemorrhage. J Trauma. 2003;54:S183–S192. Ovid Full Text Bibliographic Links [Context Link]

17. Crookes BA, Cohn SM, Burton EA, et al. Noninvasive muscle oxygenation to guide fluid resuscitation after traumatic shock. Surgery 2004;135:662–670. Bibliographic Links [Context Link]

18. Knudson MM, Lee S, Erickson V, et al. Tissue oxygen monitoring during hemorrhagic shock and resuscitation: A comparison of lactated Ringer's solution, hypertonic saline dextran, and HBOC-201. J Trauma. 2003;54:242–252. Ovid Full Text Bibliographic Links [Context Link]

19. Smith GJ. A comparison of several hypertonic solutions for resuscitation of bled sheep. J Surg Res. 1985;9:529–543. [Context Link]

20. Manigas PA, et al. Small volume infusion of 7.5% NaCl in 6% dextran 70 for the treatment of severe hemorrhagic shock in swine. Ann Emerg Med. 1986;15:1131–1137. Bibliographic Links [Context Link]

21. Valeri CR, Crowley JP, Loscalzo J. The red cell transfusion trigger: Has a sin of commission now become a sin of omission? Transfusion. 1998;38:602–608. Bibliographic Links [Context Link]

22. Geerts WH, Code KI, Jay RM, et al. A prospective study of venous thromboembolism after major trauma. N Eng J Med. 1994;331:1601–1606. [Context Link]

23. Gando S, Kameue T, Matsuda N, et al. Combined activation of coagulation and inflammation has an important role in multiple organ dysfunction and poor outcome after severe trauma. Thromd Haemost. 2002;88:943–949. [Context Link]