In designing a resuscitation strategy that is beneficial it is important to recognize that certain lethal injuries can be defined.  These include severe head injuries, life threatening airway injuries, significant chest injuries to the heart and great vessels with exsanguination, massively disruptive abdominal visceral injuries with exsanguination and injuries with significant exsanguinating retroperitoneal bleeding such as massive pelvic fractures.  Resuscitation aimed at these patients will unlikely be associated with improved outcomes. 

When one reviews the development of trauma systems and the effects of fluid resuscitation, it is difficult to evaluate the data. Reports vary by where death occurs (in the field, in the hospital, or in the operating room) and it is also difficult to sort out the effects of transport times, the presence of airway control and ventilation, the type and degree of fluid resuscitation or use of MAST suits, and the impact of surgery. 

The first true useful study that identified the timeliness of care relative to bleeding came from the Birmingham Accident Hospital in 1968.¹  Sevitt demonstrated in review of 250 patients over 5 years that 28% of patients died in less than 6 hours and this was the first indication of patients who were bleeding to death rapidly.  This suggested that early fluid resuscitation for bleeding has to be focused on the earliest outcomes, and that when you bleed enough to die you do so in less than 6 hours. 

An epidemiologic evaluation of traumatic deaths following trauma system implementation in San Diego reveals the majority of patients die within 6 hours from exsanguination.² An almost identical study from Denver identified the critical time of 6 hours for death from exsanguination.³ 

Should We Resuscitate

Canon pointed out the disadvantage fluid resuscitation in 1910 and emphasized that increases in blood pressure prior to surgical hemostasis would “pop the clot” and increase bleeding with potential exsanguination.  This has led to much controversy over fluid resuscitation in injured patients.⁴

What We Have Learned

·  There are certain injuries that will be deadly and refractory to fluid therapy care.

· Excessive fluid resuscitation prior to surgical hemostasis will be accompanied by increased bleeding

·   Patients who are bleeding will exsanguinate immediately or stop bleeding spontaneously at approximately 6 hours. 

Which Fluid?

Resuscitation strategies recently have focused on concerns regarding the use of Ringer’s lactate, the reemergence of the evaluation of hypertonic saline, the use of colloids, the use of alternative crystalloids, and the use of oxygen carrying solutions or hemoglobin solutions.

A recent report of the Institute of Medicine raised concerns with crystalloid resuscitation using Ringer’s lactate and concerns have been raised regarding colloid resuscitation.⁵

Increasingly, hypertonic saline has been attractive and is able to achieve higher pressure resuscitation for equivalent volumes and may have an immuno-modulatory role.  Hypertonic saline (7.5%) is currently not FDA approved.

The advantages of hypertonic saline resuscitation include its hemodynamic effects, its effects on lowering ICP in brain injured patients, and most recently multiple studies which have suggested benefits in modulating the inflammatory response.  Concerns have been raised about the effects of enhanced blood pressure restoration using hypertonic saline and the effect on primary hemostasis.⁶ Recent data suggests in a well designed animal model that retroperitoneal bleeding is less following HTS resuscitation with less percent bleeding.  Although concern has been raised regarding aggravation of bleeding, this recent study suggests this is not a significant problem.  As such, hypertonic saline should be evaluated.⁷

The advantages of hypertonic saline in head injury have been recently reviewed.⁸  It is clear that in animal models HTS decreases intracranial pressure, and prevents the intracranial pressure increases that follow shock.  These changes occur primarily in areas of the brain that maintain intact blood brain barriers.  Human studies have been few in number in head injury and a uniform concentration has not been studied.  It does appear, however, that the use of hypertonic saline is accompanied by a reduction in intracranial pressure and that this is particularly beneficial in children.⁹

HTS Immunologic Changes

The discovery of the immunologic properties of hypertonic saline occurred following observations of immunosuppression in in vitro T-cell blastogenesis by high extracellular salt concentrations.¹⁰ Subsequent analysis revealed that lower concentrations achievable clinically, were immuno stimulatory.

Much work by many groups has evaluated the mechanisms in a variety of cells.  Significant observations include the ability to reduce organ dysfunction and improve survival in animal models including hemorrhage and subsequent infection following hypertonic saline resuscitation.^{11, 12} The mechanisms by which this occurs have been explored in great detail.  There appears to be a membrane associated effect of hypertonic saline leading to activation of protein tyrosine kinases (essential intracellular second messengers) which lead to nuclear activation protein synthesis, and proliferation.^{13, 14, 15}  The timing of HTS is important.

The mechanism of hypertonic saline on polymorphonuclear leukocyte function appears to be multifactorial but importantly adhesion to the microcirculation is significantly different between hypertonic saline and Ringer’s lactate and this is accompanied by decreased adhesion molecule expression and reduced organ failure in animal models.  It appears that the restoration of adhesion molecule regulation can occur if the osmotic environment is normalized and be reestablished by giving a second dose or recreating the hypertonic environment.^{16, 17} This suggests that the manipulation of resuscitation fluids may, in fact, be much like dosing a drug and establishes the research need for further exploration in the future.  Recent data suggests that direct involvement of hypertonic environments with the cytoskeleton and the induction of cytoskeletal polymerization is a fundamental mechanism by which adhesion molecule expression and oxidative injury are affected.^{18, 19}

Human studies have shown preliminary evidence that immune variables demonstrated in animals can be demonstrated following infusion to human volunteers.²⁰  Previous multicenter trials, however, comparing Ringer’s lactate and hypertonic saline with Dextran were unable to show overall differences in survival.  Of interest, however, there was a survival advantage in patients who required surgery and it would appear that the hypertonic saline Dextran group had fewer complications.²¹  A multicenter trial looking at patients transported by helicopter suggested a mortality advantage in head injured patients.

One can conclude from the data to date that from basic research data there appears to be improved microvascular flow, less organ dysfunction, and in some uncontrolled bleeding models there is no exaggeration of bleeding.  That hypertonic saline controls intracranial pressure and brain edema and has immunomodulatory value is also clear.  When one looks at clinical applicability, there are currently no good studies of the infectious or inflammatory complications that might be affected by hypertonic resuscitation.  The only demonstrated mortality advantage has been in head injured patients.  Given the important new information that has occurred in the last 10 years, it is critically important that these fluids be reevaluated in clinical trials.

References

1.             Sevitt S:  Fatal road accidents.  Brit J Surg 55(7):481-505, 1968.

2.             Shackford SR, Mackersie RC, Holbrook TL, et al:  The epidemiology of traumatic death. Arch Surg 128:571-575, 1993.

3.             Sauaia A, Moore FA, Moore EE, et al:  Epidemiology of trauma deaths:  a reassessment.  J Trauma 38(2):185-193, 1995.

4.             Bickell WH, Wall Jr. MJ, Pepe PE, et al:  Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries.  N Engl J Med 331:1105, 1994

5.             Pope A, French G, Longnecker DE (Eds): Fluid Resuscitation. State of the Science for Treating Combat Casualties and Civilian Injuries.  National Academy Press, Washington, D.C., 1999.

6.             Matsuoka T, Hildreth J, Wisner DH: Uncontrolled hemorrhage from parenchymal injury:  Is resuscitation helpful? J Trauma 40(6):915-921, 1996.

7.             Cruz RJ, Perin D, Silva LE, et al:  Radioisotope blood volume measurement in uncontrolled retroperitoneal haemorrhage induced by a transfemoral iliac artery puncture. Injury 32(1):17-21, 2001.

8.             Doyle JA, Davis DP, Hoyt DB:  The use of hypertonic saline in the treatment of traumatic brain injury.  J Trauma 50(2):367-383, 2001.

9.             Pfenninger J, Wagner BP: Hypertonic saline in severe pediatric head injury.  Crit Care Med 29(7):1489, 2001.

10.         Junger WG, Liu FC, Loomis WH, Hoyt DB: Hypertonic saline enhances cellular immune function. Circ Shock 42:190-196, 1994.

11.         Coimbra R, Hoyt DB, Junger WG, et al: Hypertonic saline resuscitation decreases susceptibility to sepsis following hemorrhagic shock.  J Trauma 42(4):602-607, 1997.

12.         Rizoli SB, Kapus A, Parodo J, et al: Immunomodulation is reversible and accompanied by changes in CD11b expression.  J Surg Res 83(2):130-135, 1999

13.         Junger WG, Herdon-Remelius C, Junger H, et al: Hypertonicity regulates the function of human neutrophils by modulating chemoattractant receptor signaling and activating mitogen-activated protein kinase p38. J Clin Invest 101(12);2768-2779, 1998.

14.         Rizoli SB, Kapus A, Parodo J, Rotstein OD: Hypertonicity prevents lipopolysaccharide-stimulated CD11b/CD18 expression in human neutrophils in vitro: role for p38 inhibition. J Trauma 46 (5):794-798, 1999.

15.         Ciesla DJ, Moore EE, Biffl WL, et al: Hypertonic saline activation of p38 MAPK primes the PMN respiratory burst.  Shock 16(4):285-289, 2001.

16.         Ciesla DJ, Moore EE, Biffl WL, et al:  Attenuation of the neutrophil cytotoxic response is reversed upon restoration of normotonicity and reestablished by repeated hypertonic challenge.  Surgery 129(5):567-575, 2001.

17.         Ciesla DJ, Moore EE, Zallen G, et al: Hypertonic saline attenuation of polymorphonuclear neutrophil cytotoxicity: time is everything. J Trauma 48(3):388-395, 2000.

18.         Rizoli SB, Rotstein OD, Parodo J, et al: Hypertonic inhibition of exocytosis in neutrophils: central role of osmotic actin skeleton remodeling. Am J Physiol Cell Physiol, 279(3):C619-C633, 2000.

19.         Ciesla DJ, Moore EE, Musters RJ, et al: Hypertonic saline alteration of th PMN cytoskeleton: Implications for signal transduction and the cytotoxic response.  J Trauma 50(2):206-212, 2001.

20.         Angle N, Cabello-Pasini R, Hoyt DB, et al: Hypertonic saline infusion: Can it regulate human neutrophil function? Shock 14(5):503-508, 2000.

21.         Mattox KL, Maningas PA, Moore EE, et al: Prehospital hypertonic saline/dextran infusion for post-traumatic hypotension. A U.S.A. Multicenter Trial. Ann Surg 213(5):482-491, 1991.