Strategies for Small Volume Resuscitation Recently, studies have provided conflicting conclusions about the effects of hypertonic saline and HSD infusion on cardiac function showing that infusion of hypertonic saline solution into the circulation or directly into coronary vessels causes increased contractility [53, 54], little effect on contractility [55-58], or decreased contractility [59, 60]. Some of the negative reports may be the result of studying very high doses or very fast infusion rates. Rapid infusions or inappropriately high doses cannot only cause fluid overload, but also arrhythmias [50, 61, 62]. Such doses or infusion rates can transiently cause very high concentrations of extracellular sodium or osmotic pressures and this is further rationale for slower infusions.

2.3 Rate of Infusion

More efficient volume expansion should not be a contraindication for trauma care, particularly for the combat casualty care, but rather optimal use of hypertonic fluids may require different infusion guidelines as to infusion rate. If the physician or medic appreciates the volume equivalency illustrated and estimated in Figure 2 and considers administering 250 mL of HSD in a regimen similar to 3 liters of LR the likelihood of misuse may be reduced. On the other hand, most of the clinical trauma trials of HSD were performed in the early 1990s when aggressive resuscitation was the standard of care. When HSD was infused rapidly per prehospital resuscitation protocols of the day, there was a survival benefit in these civilian trauma patients most representative of combat injuries and penetrating trauma requiring surgery [1, 63].
2.4 Peripheral Circulatory Effects
The effects of infusing hyperosmotic-hyperoncotic solutions on the peripheral vasculature and the microcirculation are generally to induce changes that augment flow. These are a reduction in peripheral vascular resistance, which is primarily due to arteriolar vasodilation [64]. Capillary perfusion may be further augmented by the ability of HSD to reverse specific cellular effects of ischemia and ischemia-reperfusion. HSD infusion shrinks endothelial cells that are swollen by hemorrhagic shock [16].
2.5 Immune Modulation of Hypertonicity
In the last 10 years there has been a growing body of evidence on the immune modulation of hypertonic resuscitation. In vitro and in vivo effects of hypertonicity on white cells suggest that a hyperosmolarity above 330 mOsm can down-regulate the initial inflammatory activation of neutrophils and upregulate immunological protection provided by lymphocytes [65-67]. Most recently, the down regulation of inflammatory cytokines and neutrophil activity along with proliferation of lymphocytes counts have been demonstrated in trauma patients treated with HSD [68]. Such data have resulted in one NIH sponsored injury trials of blunt trauma focusing on immune function as well as clinical outcome [69]. The strong and elegant science behind hypertonic immune modulation has suggested to some that HS and HSD be considered primarily as an anti-inflammatory drug and not a volume expander. From this consideration, HS alone is likely to be as efficacious as HSD. This may be a shortsighted viewpoint in that it negates the proven physiologic value to restoring vascular volume, perfusion and oxygen delivery in trauma patients. Physicians and medics administer fluids to trauma patients with an immediate need for augmentation of volume expansion and tissue oxygen delivery. The extensive animal work on HS versus HSD and the outcomes from clinical trials support the rationale for providing better volume expansion and associated hemodynamics of HSD compared to HS.

Table 1: All HS.

Human Trials/Experiences with 7.5% NaCl Author 9 DeFelippe, 80 Holcroft, 87 Younes, 87 Auler, 87 Younes,89,92 Holcroft,89 Auler, 89 Holcroft, 89 Maningas, 89 HS HSD HS HS Sol. Dose 4 mL/kg 250 mL 4 mL/kg 4 mL/kg Site PH OR OR ER ER PH PH ER OR PH Patients trauma aneurysm aneurysm trauma trauma 15 trauma trauma trauma cardiac surgery trauma 16 HS HSD HSS Iso
Reference The Lancet 1980;Nov 8:1002-1004.

ICU refractory shock

10 Ann Surg 206:279-Rev Ass Med Brasil 8;34:150-155 5

Surgery 101:594-601.

HS/HSD 250 mL HS/HSD 250 mL HS/HSD 4 mL/kg HSD HSD HS HSS HSS HSS HS HSS HSD HSS HSS HSS HSS HSD 250 mL 250 mL 250 mL 4.5 mL/kg 4 mL/kg 4 mL/kg 2-4 mL/kg 4 mL/kg 250 mL 2-5 mL/kg 210 mL 3.1 mL/kg 3.8 mL/kg 250 mL
35 Surgical Forum 39:70-72; 16 Braz J Med Biol Res 22:291294

Brazilian Journal 1989.

ICU post cardiac bypass
31 Perspectives-Shock Res, Alan R. Liss: NY.p. 331-Am J Surg 1157:528-533. 51 Arch Surg 125:1309-1316
Anaesthesia 45:928-934 Prcdgs. - 4th Int Sym Hypertonic Resus. 1990:34 Prcdgs. - 4th Int Conf Hypertonic Resus 1990:45 Circulatory Shock 37:220-225. Critical Care Med 18:S205
10 Vassar, Boldt, 90a, 90b 12 Kuss, Kroll, 90,Ramires, 90,Hannemann, Chavez-Negrete, Meier-Hellman, Boldt, Boldt, Boldt, Vassar, 91
ICU sepsis ICU right heart failure ICU sepsis/resp. failure ER OR OR OR PH hypovol. GI bleed. cardiac surgery cardiac surgery cardiac surgery trauma ICU head injury
23 Eur Surg Res 23:123-129.
Prcdgs. - 4th Int Sym Hypertonic Resus. 1990:27 Ann Thorac Surg 51:610-615 Br J Anaesth 67:595-602 J Cardiothorac Vasc Anesth 5:23-28
83 Arch Surg 126:1065-1072.
Author 22 Mattox, Vassar, Majluf,92 (abs) 26 Schaffartzik, 92 (abs) 27 Fabian, 93 (abs) 28 Keller, 93 (abs) 29 Vassar, Gong, Prien, Rocha e Silva, Rudin, 94 (abs) 34 Ellinger, Frey, 94, 36 Albrecht, Stehtzer, Goertz, Sztark, Oliveira, Jovanovici, Bonazzi, Walz, Tllfsrud, Dahlqvist, 96

Sol. HSD

Dose 250 mL 250 mL 250 mL 4 mL/kg 1.5 mL/kg

Site PH PH ER

Patients trauma trauma hypovolemic shock

HSD 11 25

Reference
211 Ann Surg 213:482-491. 84 Arch Surg 128:1003-1013
Prcdgs. - 5th Internat Conf Hypertonic Resus Prcdgs. - 5th Internat Conf Hypertonic Resus

HS/HSD 250 mL HSD HSS HS

24 Chavez-Negrete,92(abs) HSD
ICU acute MI ICU septic shock ICU head injury OR PH OR ER OR oral surgery trauma cardiac surgery trauma ortho-surgery cardiac surgery 11
Prcdgs. - 5th Internat Conf Hypertonic Resus Unpub abstr, see Surgery 122:609-16 Prcdgs. - 1993 Gulf Atlantic Anes, Res. Conf
HSS 5 mL/kg HS/HSD 250 mL HS/HSD 30 mL HSS HSD HSD HSS HSD HSS HSS HSS HS HSD HSD HS HS HSD HS 250 mL 250 mL 4 mL/kg 250 mL 4 mL/kg 4 mL/kg 4mL/kg 235 mL 4-5 mL/kg 3.5 mL/kg 4 mL/kg 4 mL/kg

45 J Trauma 34:622-633;

J Am Soc Nephrol 13:1808-1812

Clin dialysis

19 Zentralblatt fur Chirurgie 118:257-Shock 1994;1 (Suppl):2 (no. 7). 7
Prcdgs. 6th Internat Conf Hypertonic Resus

mL OR OR OR OR OR OR OR

20 Shock 3:167-172. 22 Personal communication 1994. 12 Shock 3:152-156.
ICU sepsis aneurysmectomy minor surgery organ donors cardiac surgery polytruama aneurysm repair ICU sepsis

13 Anes 82: 1389-95, 96

Transplantation Prcdgs. 27:2473
10 Shock 3:391-394. 20 Intensive Care Medicine, 21( Suppl 1):S156
Intensive Care Medicine, 21( Suppl 1):S223 Intensive Care Medicine, 21( Suppl 1) Shock 6(Suppl): 30 Shock 6(Suppl): 30-31
0.5-1.0mL/kg ICU elevated ICP Clin healthy volunteers ICU critically ill
Author 46 Strecker, Kroll, Kroll, Kroll, Izmail, Rask, Hanneman, Younes, Christ, Gemma, Swensen, Hartl, Horn, Schwartz, Tllfsrud, Tllfsrud, Wiklund, Sireix, Christ, Murphy Durasnel, Krenn, Wall, Jarvela, 01 HS
Sol. HSS HSS HSS HSS HS HSS HSD HS HS HSS HSS HSS HSD HSD HSS HSS HSD HS HSS HSD HS
Dose 250 mL 250 mL 250 mL 250 mL 250 mL 5 mL/kg 2-4 mL/kg 250 mL 100 mL 3 mL/kg 2-12 mL/kg 100 mL 4 mL/kg 4 mL/kg 250 mL 250 mL 4 mL/kg 100 mL 4 mL/kg 250 mL 4 mL/kg

Site OR OR OR

Patients

resected pheochrom.

HSS 4 9
Shock 6(Suppl): 31 Shock 6(Suppl): 31
Clin healthy volunteers anesthetized pts anesthetized pts Clin healthy volunteers ICU sepsis ICU septic shock ER OR OR trauma aneurysm repair neurosurgery 101 9
Shock 6(Suppl): 31-32 Shock 6(Suppl): 31-32 Shock 6: 31-32, 1996 Ugeskrift for Laeger 158:607-09 Shock 5:130-4
111 Shock. 7:79-Acta Anaesthesiologica, Scandinavica 41:62-70

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Table 2: 30 Day Mortality Outcomes of Hypertonic Resuscitation Trials for Trauma & Hemorrhage.
Hypertonic Saline (HS) alone, total n=948 Reference HS, n=454 Younes, 92[76] 20.0% Vassar, 90[1] 53.1% Vassar, 93[77] 14.1% Vassar, 93[78] 40.0% Fabian, 94[79] 35.8% Fabian, 94[79] 35.2% Cooper,04[80] 44.7% all HS trials 35.4% HS vs SOC Hypertonic Saline Dextran (HSD), total n=1284 Reference HSD, n=641 Younes, 92[76] 20.0% Maningas, 89[81] 13.0% Vassar, 90[82] 52.2% Vassar, 91[77] 36.1% Mattox, 91[1] 16.6% Chavez-N., 91[83] 3.8% Vassar, 93[78] 22.5% Vassar, 93[84] 44.0% Younes, 97[85] 26.7% all HSD trials 24.5% HSD vs SOC
SOC, n= 494 22.9% 37.0% 16.7% 51.1% 37.3% 28.3% 50.4% 34.4% -0.7% SOC, n=641 22.9% 20.0% 54.2% 41.0% 19.9% 21.7% 16.7% 51.1% 36.0% 28.7% -4.2%
2.7 HS and HSD Trauma Trials
Table 2 shows the 30 day mortality data of all trauma and hemorrhagic shock trials in which 7.5% NaCl (HS) alone or 7.5%NaCl-6% dextran (HSD) have been used to teat trauma. The trails were blinded and randomized with one exception [83] as to treatment with HS or HSD compared to an equal volume of the standard of care solutions (SOC; normal saline, Ringers solution or Plasmalyte A). All solutions have been evaluated at 250 mL dose with additional fluids and medical care given as deemed clinically necessary. It should be made clear that these solutions were given in addition to all of the normal and subsequent care the patient required per trauma center protocol. No treatment was withheld. Trauma trials with 7.5% HS without a colloid have overall shown less efficacy than trials with HSD as reviewed in a meta-analysis [86]. There were no statistically significant differences with the overall mortality being 0.7% less with the HS treatment, Table 2. A recent randomized study of the use of HS to treat traumatic head injury showed a 5.5% difference favoring HS, but this was not statistically significant [80]. On the other hand, the outcomes in the trauma trials with HSD more strongly support efficacy as shown in Table 2 and by an extensive individual patient data meta-analysis [63, 87, 88]. Most all of these trials documented an improvement in blood pressure, and several documented reduction in total volume needs.

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Strategies for Small Volume Resuscitation Only one trial was statistically significant alone [85] and also suggested that the greatest survival benefit of HSD was in the patients with the lowest entry blood pressures. The view that HSD is more beneficial in severely injured has been borne out in several subgroup analyses of the more severely injured patients who often did show statistically significant increased survival in trauma patients with head injury [87], dehydration [89] and penetrating injury [1, 63]. Taken as a whole the HS and HSD studies suggest safety, volume sparing and improved outcome. Based on the randomized controlled trauma trials, Table 2, HSD appears to reduce mortality of hypotensive trauma. Over all the difference can be considered small, a 4.2% patient weighted mean change, or a 15% reduction of mortality. The largest subset of hypotensive trauma patients would survive without treatment and a smaller subset would die regardless of treatment. Only a small subset of perhaps 10-20% can benefit or be harmed by fluid therapy. Taken in light of this argument the benefit seems profound. However, treatment effects in randomized control trials can be greater or less than in standard clinical usage. Perhaps more important than a new round of controlled trials is to encourage post regulatory approval monitoring in those countries where HSD is approved for use. If civilian trauma centers can be matched as to general patient population, and a form of standardized outcome data collection can be generated, such data might be more valuable than a clinical trial because it could provide real world outcome effects. New trauma trials sponsored by the NIH and with military funding from the US, Canada and Great Britain has recently started or in final planning. Such trials may lead to US regulatory approval and/or use by US Armed forces. On the other hand, HSD has regulatory approval in most of the NATO countries and hypertonic saline hetastarch (HSS) in a growing number of them. Thus, many NATO military units could evaluate hypertonic resuscitation. Military surgeons and anesthesiologists in countries for which HSD or HSS is approved should be encouraged to become familiar with the extensive backgrounds of such products and use them electively in their homeland practices. Product placement with selective combat medical units along with a post regulatory monitoring program would provide the first real combat experience of small volume resuscitation and should be encouraged. The outcomes from case reports of units deployed with and without hypertonic formulations could be compared by an expert panel.

2.8 HSD versus HSS

Early studies comparing HSD versus HSS formulations suggested equivalent physiologic effects. HSD has had more extensive US exposure and use in trauma trials, while HSS has more European exposure and is most often used in intraoperative trials, particularly for cardiac surgery. In the small volume formulations the particular benefit or any side effect of the type of colloid is likely to be negligible. HSD had been show to be devoid of any apparent effect on coagulation or blood typing or inflammation in the trials to date. An extensive record of clinical safety has been established for HSS in Austria where it has been approved since 1991 and used in over 56,000 patients [90]. The primary indications for its use have been head injury, trauma, and intraoperative volume sparing.
2.9 Hypertonicity, Inflammation and Organ Failure
The renewed interest in HSD or HS alone has resulted from the pioneering studies of Junger and Hoyt who first established profound anti-inflammatory properties of a hypertonic bolus [91, 92]. Studies in cell culture and rodent models have suggested efficacy as survival is improved and organ failure (histology) greatly attenuated by hypertonic resuscitation [93, 94]. Thus, the concept of hypertonic therapy as a drug is intriguing. Indeed, incidents of organ failure (ARDS, renal failure, etc) were reduced in the USA multi-center trial 5/211 with HSD vs 20/211 with SOC as well as in incidents of MOF in the individual patient meta-analysis [88].

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2.10 Combat Casualty Care
Despite all of the new hypertonic publications on inflammation and the older publications on the physiology of resuscitation the most straightforward rationale for its use of any fluid combat casualty care can be summarized in Figure 2. Even if HS alone is as effective at reducing inflammation as HSD the better volume expansion with HSD or HSS versus HS alone is sufficient rationale for choosing HSD or HSS over HS. Better volume expansion also equates with better cardiac output and blood pressure thus, periods of hypotension are less likely with head injury. The only rationale for choosing HS alone over HSS or HSD would be cost or untoward clinical results with HSD. However, taken as a whole the extensive clinical record of HSD and HS in trauma suggests, but does not prove, that HSD and probably HSS may be superior with respect to outcomes. The early volume expansion properties of HSD are about 10-fold greater than that of standard crystalloids [95, 96]. Figure 2 provides the main rationale for use of HSD for combat casualty care volume sparing. More efficient volume expansion provides the rationale for its use in situations where hypovolemia impairs oxygen delivery. In situations where over resuscitation is a concern due to uncontrolled hemorrhage and or cardiac insufficiency the experimental record suggests that the solutions should be infused slowly and/or titrated to effect. If the medic appreciates the 10:1 volume equivalency and considers administering 250-mL dose in a regimen similar to how they would administer 2.5 liters the potential for misuse could be lessened. Three special patient populations to consider for combat casualty care are the safety and efficacy of hypertonic resuscitation with pre-existing dehydration, traumatic brain injury or penetrating injury.

2.11 Safety and Efficacy of 7.5% NaCl with Pre-existing Dehydration
A special problem of combat casualty care is that wounded combatants are almost always dehydrated. The anticipation is that at some level preexisting dehydration negates the safety and clinical effectiveness of hypertonic infusions. This concern motivated several studies that analyzed the safety and effectiveness of HSD in dehydrated animals and patients. Hemorrhaged and dehydrated rats infused with hypertonic saline after occlusion of the renal artery showed an increase in incidence of renal failure and a high mortality rate compared to groups treated with isotonic fluid [97]. However, these results were not confirmed in more realistic long-term studies of renal function in large-animal models with a 4 mL/kg dose of 7.5% NaCl dextran [98-101]. The beneficial volume expansion and cardiovascular effects of HSD were still apparent after water restriction over 2 to 4 days and increased preinfusion osmolalities of 325-340 mOsm/L in dehydrated sheep and swine [98, 99, 101] subjected to moderate to severe hemorrhage. Of relevance to dehydration is the effectiveness of HSDs ability to increase survival in trauma patients with high preinfusion serum sodium [100]. Presumably, this patient population has pre-existing dehydration. Survival rates were low in this group when they were administered standard of care solutions, but survival was greatly and significantly improved in the HSD group. Counter intuitively, HSD has been used to effectively treat experimental dehydration in US Army sponsored studies [102, 103].
2.12 HSD and HS for Treatment of Head Injury
There is a strong physiological rationale for the use of hypertonic fluids to treat head injury particularly in the presence of hypotensive hypovolemia. Increased plasma hyperosmolality can translocate CSF and cellular water out of the brain and reduce the intracranial pressure associated with head injury. This edema lessening effect occurs in the regions of brain less traumatized, but a global reduction in ICP increased perfusion throughout the brain [104]. In animals with experimental mass lesions hypertonic resuscitation reduced ICP

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Strategies for Small Volume Resuscitation and improved blood flow [105]. Again, at first this would suggest that HS would be expected to be as beneficial as HSD for these patients and this is likely true for the effects on ICP. But a key component of mortality in patents with traumatic brain injury is the prevention of hypotension. Chesnut et al showed that episodes of hypotension were significant predictors of outcome in head injured patients [106]. A single episode of systolic pressure below 90 mmHg doubled the mortality. The ability of HSD to restore and sustains volume expansion, cardiac output and blood pressure better than HS alone has been well demonstrated in animal trials and clinical trials and is the rationale for why HSD may be particularly effective in patients with head trauma. Wade et al performed a cohort analysis of individual patient data on patients with traumatic brain injury [87]. Treatment with HSD resulted in a survival until discharge of 37.9% (39 of 103) compared with 26.9% (32 of 119) with standard of care (p = 0.080). Using logistic regression, adjusting for trial and potential confounding variables, the treatment effect can be summarized by the odds ratio of 2.12 (p = 0.048) for survival until discharge. Practically, this means that patients who have traumatic brain injuries in the presence of hypotension and receive HSD are about twice as likely to survive as those who receive standard of care. A recent prehospital trial of HS alone for treatment of head injury showed a small, but statistically insignificant 5% difference in outcomes favoring HS [80]. It is likely that the clinical benefit of HSD shown in trauma trials results from both the direct affect on lowering ICP as well as the indirect affect of improving arterial pressure and cerebral perfusion.

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Table 4: Selected HBOC Trials.
Transfusions Trial subjects indication Hemopure (Biopure) orthped. Surgery[115] cardiac surgery[116] surgery patients[117] aortic repair[118] preop hemodilut. [119] preop hemodilut. [120] exercise volunteers[121] Hemolink (Hemosol) autologous donation[122] cardiac surgery[123] cardiac surgery[124] Polyheme (Northfield) trauma surgery trauma surgery[125] Hemassist (Baxter) major surgery[126] prehospital trauma[127] major surgery[128] cardiac surgery[129] aortic surgery[130] ER trauma[111] stroke[131] RBC (89) RBC (63) RBC (12) RBC (105) RBC (46) saline (45) 3.1L similar 4.7L 67% 100% 81% 100% 87% 100% 171 historical 21 RBC (23) 7.8u 11.3u 149 pstarch (150) 0.3u 30 pstarch (30) 0.7u 56% 76% 10% 47% 55% 82% 350 RBC (338) RBC, (49) LR, (26) RBC, (24) hespan (12) hespan (6) RBC (6) 10% 47% 1.4u 1.7 u 3.3 u 3.1u 2.2 u 3.7u 73% 100% 30% 100% 66% 100% patients (n=) HBOC Cont. units/patient % patients

Physiology

HBOC Cont. HBOC Cont. BP SVR CI DO2

104 RBC (105)

3.4 Clinical Trials
Table 4 lists selected clinical trials of Polyheme, Hemopure, Hemolink and HemAssist (DCLHb). The Hb substrate used by the different pharmaceutical companies comes from outdated human and bovine blood.

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Strategies for Small Volume Resuscitation Northfield Laboratories Polyheme and Biopures Hemopure, and Hemosols Hemolink have advanced to large scale FDA Phase 3 trials [132, 133]. However, research setbacks and disappointing trials have occurred more often than not. Diaspirin cross-linked hemoglobin (DCLHb) developed by the US Army and Baxters Hemoglobin Therapeutics is the best-studied RBC substitute. DCLHbs development was cancelled after it exhibited a high mortality rate in trauma trials [110]. Somatogen cancelled development of Optro after cardiac surgery trials of its product produced adverse events. Hemosols phase III trial of Hemolink has been halted to evaluate an imbalance in adverse events. Nothfield and Biopure continue with their phase III clinical research. Prehospital trauma trials have just started for Polyheme and are planned for Hemorpure. The FDA halted Biopures US clinical trials in 2003 pending some key animal experiments to address specific questions. Because of the dramatic failures in safety issues the FDA is likely to be cautious and conservative before granting marketing approval to a RBC substitute. A commercially available blood substitute will likely not be available in the next two years.
3.5 Plasma Volume Expansion
Fischer et al compared plasma volume expansion (PV) after a 30-min infusion of 20 mL/kg 6% DCLHb, isooncotic 7.8% human albumin versus 60 mL/kg of LR in conscious sheep under conditions of normovolemia and hemorrhagic hypovolemia [134]. The PV for DCLHb calculated from Evans blue indicator dilution and Hct dilution was nearly 2x greater than for albumin. The relatively increased expansion of 10% DCLHb versus 7.8% human albumin is quite surprising as the albumin was made-up to be an iso-oncotic control to the DCLHb. The explanation for the enhanced volume expansion of DCLHb is unknown, but several mechanisms can be hypothesized. PV enhancement could be due to a reduction in capillary pressure due to arteriolar vasoconstriction. Alternatively, increased lymphatic pumping could return interstitial protein into the circulation and augment the plasma colloid osmotic pressure and expansion. Indeed, Fischer et al. did report an increased plasma protein concentration, increased total vascular plasma protein and increased COP in the DCLHb group despite the albumin and DCLHb being matched for volume infused and colloid osmotic pressure [134]. Oxyglobin is a FDA approved veterinary product made from bovine hemoglobin (Biopure) but has a higher colloid osmotic pressure (~40 mmHg) than the human product, Hemopure. Oxyglobin was also found to be a potent volume expander increasing blood volume more than hespan in hemorrhaged rabbits. There is little data in the literature that we are aware of on the volume expansion effects of Hemopure, Polyheme or Hemolink. No direct comparisons have been made with the products under clinical evaluation of volume expansion, Table 3.

3.11 HBOC Conclusion and Recommendations
Hemoglobin based oxygen carriers are potent plasma expanders with a modest vascular half-life. Both properties may be a limitation for use as a blood substitute, but may have utility and advantages as an acute resuscitative fluid. The limited amount of independent experience with the HBOC solutions currently under development makes conclusions difficult. Infusion regimens for HBOCs will likely be different than for packed RBCs or asanguineous fluids due to the unique physical properties and physiological effects of HBOCs. At present it is not clear if such solutions will offer an improvement in standard of care. Safe and effective oxygen carrying plasma expander remains an attractive goal. It is likely that effective Hb molecular structure, optimal concentrations, and carrier solutions will be developed. Such development and clinical utility will take substantial preclinical and clinical study to define the safety and efficacy and the optimal therapeutic regimens of such formulations.
4.0 TITRATED CLOSED-LOOP RESUSCITATION
One approach to reducing volume needs may be to provide automated computer controlled fluid resuscitation, which can be tailored to individual patient needs and frees up clinical personnel. Severe hemorrhagic hypotension must be quickly addressed and corrected to prevent cardiac arrest, ischemic injury and organ dysfunction. On the other hand, the ideal system would eliminate wasteful and excessively rapid resuscitation that could be deleterious. The rationale is that rapid increases in blood pressure can lead to additional bleeding. A method to accurately guide and control fluid resuscitation of hemorrhage could improve outcomes by reducing incidences of both excessive and inadequate resuscitation.

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Strategies for Small Volume Resuscitation Endpoint resuscitation occurs when fluid therapy is titrated proportional to the measured values of a specific physiological variable or endpoint. The use of endpoint resuscitation has largely been restricted to the intensive care unit and operating room environments where continuous monitoring and staffing allow careful titration of therapy to a target variable level or range. With the development of new portable monitoring technologies and computer-controlled infusion pumps, automated closed-loop" titrated endpoint resuscitation may be feasible for prehospital and emergency room use. Fred Pearce of Walter Reed has historically been an advocate of early closed-loop control for combat casualty care. An effective "Resuscitation System" would need to fulfill several requirements. We have been using automated resuscitation systems both to facilitate our research, but also as a means to test the concept of closed-loop fluid therapy in hemorrhage and burns [159162]. The first report of closed-control of fluid therapy we are aware of is that of Bowman and Westenskow who built and tested, in dogs and patients, a system that provided microprocessor-controlled fluid resuscitation of burn shock using urinary output as an endpoint [163]. Kramer et al. have designed and tested a similar system in sheep [162] and have begun evaluating a fluid balance monitor in burn-injured patients as a first step in doing closed-loop clinical trials. Burn injury is one scenario where excessive fluid therapy has become common [164] and a system of tightly controlling fluid therapy to achieve, but not exceeding urinary output targets may ultimately reduce morbidity of fluid overload. Such a fluid therapy system lends itself to initial care through enroute care and the first hours. Burn resuscitation is a relatively slow process that occurs over many hours to days. Hemorrhagic shock typically provides a more acute life threatening challenge than burn injury. In hemorrhage, fluid therapy is needed in a manner of minutes and stabilization must occur in a manner of a few hours or less. Urinary output is not a useful endpoint for acute resuscitation of hemorrhage. In order to perform initial closed-loop resuscitation of hemorrhage, measurement of rapidly responsive endpoints (arterial pressure, cardiac output or skeletal muscle oxygenation) have been evaluated [159-161]. Resuscitation System prototypes have used a LabView controller with preprogrammed algorithms that convert the value of an endpoint variable into a specific infusion rate. We suggest that such algorithms, which define infusion rate as a function of an endpoint variable, may not be optimized by a linear relationship. Thus, we designed non-linear decision table algorithms that infuse fluid quickly when the endpoint variable is low near an a priori defined critical level, but then greatly reduce infusion rate as the defined stable level was approached [159]. Such a system can be designed to provide different algorithms for different clinical scenarios. For example, with penetrating injury hypotensive resuscitation might be optimal to reduce risk of rebleeding, while with head injury normotensive resuscitation would likely be needed since periods of hypotension increase morbidity and mortality with head trauma. Further, different endpoints and different targets might be used to provide initial care, e.g., blood pressure versus sustained care in which lactate and urinary output might be more useful indices. A secondary goal of such an approach is to reduce fluid volumes required for combat casualty care. This approach did appear to reduce the extend of rebleeding when compared against aggressive fluid therapy such as has been show to increase bleeding and death in sheep and swine models of uncontrolled aortic bleeding.[161, 165] However, much research and development remains to determine if such closed-loop resuscitation has real clinical applicability or if it will remain a laboratory tool.

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Strategies for Small Volume Resuscitation [67] Coimbra R, Junger WG, Liu FC, Loomis WH, Hoyt DB: Hypertonic/hyperoncotic fluids reverse prostaglandin E2 (PGE2)-induced T-cell suppression. Shock 1995, 4(1):45-49. [68] Rizoli SB, Rhind SG, Shek PN, Inaba K, Filips D, Tien H, Brenneman F, Rotstein OD: The Immunomodulatory Effects of Hypertonic Saline Resuscitation of Traumatic Hemorrhagic Shock - A Pilot Randomized Controlled Trial. In Press 2004. [69] Bulger E: Hypertonic resuscitation may help victims of blunt trauma. In. Edited by Zalin L. Seattle: University of Washington (UW), Harborview Medical Center; 2003. [70] Wade C, Grady J, Kramer G: Efficacy of hypertonic saline dextran (HSD) in patients with traumatic hypotension: meta-analysis of individual patient data. Acta Anaesthesiol Scand 1997, 110(41):77-79. [71] Kramer GC, Poli de Figueiredo LF: Hypertonic 7.5% Saline: Evaluations of Efficacy and Safety from Human Trials. In: Third International Shock Congress: October 21-23, 1995 1996; Hamamatsu, Japan: Elsevier Science, Amsterdam; 1996: 363-368. [72] Kreimeier U, Messmer K: Small-volume resuscitation: from experimental evidence to clinical routine. Advantages and disadvantages of hypertonic solutions. Acta Anaesthesiol Scand 2002, 46:625638. [73] Boldt J, Kling D, Herold C, Dapper F, Hempelmann G: Volume therapy with hypertonic saline hydroxyethyl starch solution in cardiac surgery. Anaesthesia 1990, 45:928-934. [74] Oliveira SA, Bueno RM, Souza JM, Senra DR, Rocha-e-Silva M: Effects of hypertonic saline dextran on the postoperative evolution of Jehovah's Witness patients submitted to cardiac surgery with cardiopulmonary bypass. Shock 1995, 3(6):391-394. [75] Ramires JAF, Serrano CV, Jr., Cesar LAM, Velasco IT, Rocha e Silva MJ, Pileggi F: Acute hemodynamic effects of hypertonic (7.5%) saline infusion in patients with cardiogenic shock due to right ventricular infarction. Cir Shock 1992, 37:220-225. [76] Younes RN, Aun F, Accioly CQ, Casale LPL, Szajnbok I, Birolini D: Hypertonic solutions in the treatment of hypovolemic shock: a prospective, randomized study in patients admitted to the emergency room. Surgery 1992, 111(4):380-385. [77] Vassar JJ, Perry CA, Gannaway WL, Holcroft JW: 7.5% sodium chloride/dextran for resuscitation of trauma patients undergoing helicopter transport. Arch Surg 1991, 126(9):1065-1072. [78] Vassar MJ, Perry CA, Holcroft JW: Prehospital resuscitation of hypotensive trauma patients with 7.5% NaCl with added dextran: A controlled trial. J Trauma 1993, 34:622-633. [79] Fabian TC, Croce MA, Reynolds P, Castleman P, Kudssk KA: Hypertonic saline (7.5% NaCl) resuscitation: A prospective randomized trial in trauma patients (abs). unpublished (see Wade et al, Surgery 122:609-16) 1994. [80] Cooper D, Myles P, McDermott F, Laidlaw J, Cooper G, Murray L, Tremayne A, Bernard S, Ponsford J: Pre-hospital hypertonic saline resuscitation of patients with hypotension and severe traumatic brain injury. Randomized controlled trial. JAMA 2004, 291(11):1350-1357.

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ACKNOWLEDGEMENTS

Sponsored by: The Department of the Navy, Office of Naval Research (N00014-00-1-0362). The content does not necessarily reflect the position or policy of the U.S. government, and no official endorsement should be inferred.

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