SEPTIC SHOCK is the leading cause of morbidity and mortality in intensive care units. The importance of early volume resuscitation of a patient with sepsis has been shown in several recent studies. The type of fluid used has received much debate over the years. Newer methods of fluid resuscitation offer potential benefits in comparison with those currently being used. Hypertonic saline is one type of fluid that has potential to be used successfully in patients who have septic shock. This review will discuss the current state of the art regarding fluid resuscitation as well as the evidence supporting the use of hypertonic saline.

The fundamental derangement in sepsis is maldistribution of blood flow. An inciting event results in a local inflammatory response, which is characterized by vasodilation, increased capillary permeability, and inflammatory cell migration into the tissues. Neutrophil activation leads to the release of vasoregulatory mediators (eg, nitric oxide and arachidonic acid metabolites) and proteases (eg, elastase and matrix metalloproteinases), which in turn lead to the increased endothelial permeability. Based on these pathophysiologic changes, significant hemodynamic alterations can occur resulting in hypotension, tachycardia, decreased cardiac output, and eventually death.1

In an attempt to overcome (or even prevent) this complex cascade of events resulting in these hemodynamic derangements, high-volume resuscitation with crystalloid solutions (ranging from 6 to 10 L) is often used during the initial resuscitation of a patient with sepsis. Early resuscitation, including the administration of intravenous fluids, with restoration of the circulation and maintenance of cardiac output and oxygen delivery has been shown to reduce morbidity, mortality, and healthcare resource consumption in patients with septic shock.2,3 Other types of solutions (eg, colloid solutions) have also been used, and debate is ongoing as to which solution would offer the most benefit.

CRYSTALLOID SOLUTIONS

Crystalloid infusates (eg, 0.9% sodium chloride or lactated Ringer's solution) are the most common type of fluid administered during the treatment of septic shock. Expansion of plasma volume occurs and is beneficial in the resuscitation scheme. Potential alterations in hemodynamic stability can result however. Only one quarter of the infused amount remains in the intravascular space with the remaining 3 quarters distributed into the extravascular space resulting in only a transient increase in plasma volume. Significant hemodilution of plasma proteins and a decrease in colloid osmotic pressure, along with a generalized increase in microvascular permeability (from both a pulmonary and systemic basis), may occur. The expansion of plasma volume results in decreased plasma levels of various neurohormones (eg, adrenocorticotropic hormone, cortisol, and aldosterone) and endogenous pressors (eg, norepinephrine, epinephrine, cortisol, vasopressin, and rennin) contributing to the alterations in hemodynamic stability.

COLLOID SOLUTIONS

Colloid solutions, in the form of synthetic or nonsynthetic compounds (eg, hydroxyethyl starch and albumin), generate protein or colloid osmotic pressure and have the theoretical advantage of causing greater volume expansion per unit infused than a crystalloid solution. Colloid use, however, has the potential for a greater number of adverse effects (eg, renal tubular injury following hydroxyethyl starch infusion, decrease in factor VIII levels, and prolongation of the partial thromboplastin time).4,5 Colloid solutions are also more expensive to administer than are crystalloid solutions.

CRYSTALLOID VERSUS COLLOID

The choice of fluid (eg, crystalloid or colloid) used to resuscitate a patient with septic shock remains controversial. Reports from animal models of sepsis demonstrate no increase in extravascular lung water when hydrostatic pressures are maintained at low levels, indicating that in sepsis the primary determinant of extravascular fluid flux appears to be microvascular pressure rather than colloid osmotic pressure. Thus, when lower filling pressures are maintained, there is no significant difference in the development of pulmonary edema with crystalloids or colloids. However, if higher filling pressures are required to optimize cardiac performance, colloids may mitigate with extravascular fluid flux. A clinical trial comparing the use of either crystalloid or colloid solutions for resuscitation has shown similar outcomes (at 28 days) with either type of fluid that was administered.6 Given these results and the expense of colloid solutions, the routine use of colloid solutions for the resuscitation of a patient with septic shock is avoided.

HYPERTONIC SALINE SOLUTIONS

The use of alternative types of fluids for the resuscitation of a patient with septic shock has been proposed. Hypertonic saline is one such type of fluid. It can cause a rapid plasma volume expansion induced by mobilization of fluids from the intracellular compartment through the extravascular fluid space. This results in an increase in the overall plasma volume up to 4-fold that of the actual infused volume; however, these effects are only short lived. The addition of colloids to the hypertonic saline solution prolongs the duration of volume expansion and therefore accentuates these effects on central and regional circulation. Hypertonic saline admixed with dextran has been studied in the fluid resuscitation of experimental animals and humans who have hemorrhagic or traumatic shock.7,8 Based on these results, interest in the use of hypertonic saline in the management of sepsis has arisen. Studies using hypertonic saline solutions (admixed with a colloid) on the effects on hemodynamic function, intravascular volume expansion, immune system function, and endothelial function have been performed.

An improvement in cardiovascular function and splanchnic perfusion was noted in a model of Escherichia coli-induced sepsis in dogs. Comparing lactated Ringer's solution and hypertonic saline, both were shown to transiently improve both systemic and regional blood flow. Hypertonic saline, however, was associated with a significant (and sustained) reduction in systemic and mesenteric oxygen extraction without worsening of other markers of perfusion.9

Repletion of intravascular volume in experimentally induced sepsis also occurs with the use of a hypertonic saline/colloid infusion. Following induced shock from E coli endotoxin infusion, a hypertonic saline/hetastarch infusion resulted in an increase in plasma volume, arterial pressure, cardiac output, and stoke volume. The effects were only transient however.10 In another study of endotoxin-induced shock, the use of a hypertonic saline/dextran solution enhanced cardiac contraction and relaxation more than did the use of lactated Ringer's solution.11 In an isolated, perfused rat heart preparation, perfusion with the hypertonic saline/dextran solution improved myocardial contractility unrelated to changes in coronary blood flow of myocardial oxygen consumption.12

Various immunomodulatory effects have also been described following the use of hypertonic saline in the treatment of sepsis. Significantly reduced bacterial colony counts along with an enhancement of both intracellular bacterial killing and superoxide generation were noted in those animals resuscitated with hypertonic saline compared with controls resuscitated with normal saline.13 Thermal injury-induced bacterial translocation in a rat model of burn injury with septic challenge has been demonstrated with the use of hypertonic saline. Increased bacterial clearance, phagocytic activity, and Toll-like receptor expression of peritoneal cells were shown following the administration of hypertonic saline in this model.14 Other immunomodulatory effects have been shown in various models of traumatic or hemorrhagic shock including enhancement of cellular immune function (increased T-cell proliferation, cell-mediated immune function, blunted neutrophil activation, reduction in tumor necrosis factor alpha production) but have yet to be studied in septic shock models.15,16

The use of hypertonic saline in the resuscitation of humans with septic shock has received little study. There is only 1 clinical study published to date, evaluating the acute hemodynamic effects following the use of a hypertonic saline solution. In stable patients (n = 29) with sepsis, administration of a hypertonic saline (NaCl 7.5%)/dextran solution was compared with that of a normal saline. Patients with a pulmonary artery wedge pressure measurement of less than 12 mm Hg were randomized to receive either 250 mL of a hypertonic saline/dextran or a normal saline solution. In these patients treated with hypertonic saline/dextran, there were significant increases in cardiac index, pulmonary artery occlusion pressure, and stroke volume index lasting for up to 120 minutes following the infusion without any significant side effects.17

The mechanisms behind the resultant improvement in hemodynamic status are likely multifactorial. Rapid increase in the intravascular volume through the mobilization of water (from the intracellular space, microvascular endothelium, and red blood cells) into the interstitial and intravascular spaces occurs. A reduction in the endothelial edema and a decrease in hydraulic resistance occur, all of which promote tissue perfusion. Cardiac contractility may also improve through a direct hyperosmolar effect and through the decrease in myocardial edema that is unrelated to changes in coronary blood flow.18,19

SUMMARY

Septic shock remains an important cause of morbidity and mortality. A cascade of inflammatory events results in the release of mediators that cause a maldistribution of blood flow with resultant disturbance in end organ perfusion. Early restitution of the circulation has been shown to improve tissue oxygen delivery and to increase survival. Fluids administered as either crystalloid or colloid solution are the mainstay of treatment for the resuscitation of a patient with septic shock. Yet the complications of volume overload, systemic and pulmonary edema, and hemodilution have led to the search for alternative means of fluid resuscitation.

Hypertonic saline offers a theoretically viable option for resuscitation of such patients. The effects of hypertonic saline as shown in various experimental models of sepsis (eg, rapid plasma volume expansion, improvement in myocardial contractility and performance, reduction in endothelial and myocardial edema, and enhancement of immune function) may also well occur in human; however, data are lacking in this regard. The benefits and potential risks (eg, volume overload, hypernatremia) of the use of hypertonic saline solutions must be evaluated in future studies. Randomized clinical trials are necessary to more completely evaluate the effectiveness of this type of fluid resuscitation of patients with septic shock.

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