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Hypertonic fluids have an osmotic content that is higher than in the body fluids. When this content remains in the extracellular fluid space, such as with saline, the volume effect becomes very powerful owing to osmotic allocation of fluid from the intracellular to the extracellular fluid space. These fluids have also been found to favorably modulate the inflammatory response. The most studied preparations are saline 7.5% with and without a colloid (dextran or hydroxyethyl starch) added.
This chapter reviews the current clinical evidence regarding the use of hypertonic fluids for the early resuscitation of injured patients and for perioperative indications for a variety of procedures. While there is a wealth of preclinical data suggesting potential benefit from this resuscitation strategy, the clinical trial data have failed to show any clear benefit to the prehospital administration of these fluids in trauma patients, and the data for perioperative use is limited. More study is needed to define the best use of these fluids in a variety of patient populations and surgical procedures.*
Hypertonic fluids have been under investigation for the resuscitation of injured patients for over 30 years. Several studies have suggested that the use of these fluids is of potential benefit in the resuscitation of patients with hypovolemic shock and traumatic brain injury.[1–3] More recent studies, however, have failed to show a mortality benefit for early treatment in these patient cohorts.[4–6] In addition, there have been a number of reports describing the use of hypertonic fluids in the perioperative setting, including aortic surgery, cardiac surgery, transplant surgery, and spinal surgery.[7,8]
Hypertonic fluids include a wide spectrum of products with a range of hypertonic saline (HTS) solutions varying from 1.6% to 23.4% sodium chloride. In addition, HTS is also available coupled with a variety of colloid solutions including dextran 70 and hetastarch.
This review seeks to describe the mechanisms of action of hypertonic fluids that may offer benefits for acute resuscitation and perioperative management of patients undergoing major surgery, and to review the current clinical trial evidence in this regard.
Mechanism of action
Hypertonic fluids have several physiological and immunological effects that suggest potential benefit in management of severely injured patients. Because these agents have an osmotic effect, when administered intravenously they draw interstitial fluid into the intravascular space, thus restoring tissue perfusion in the setting of hypovolemic shock. This allows improvement in blood pressure with a smaller volume of fluid than traditional isotonic crystalloid solutions. Furthermore, several in vitro and animal studies suggest that these fluids reduce endothelial cell edema and enhance microcirculatory flow following hemorrhagic shock.
In addition to these physiological changes, a wide body of literature describes the significant impact of hypertonic solutions on the inflammatory response. Several animal studies have demonstrated that resuscitation with hypertonic solutions attenuates the activation of neutrophils after injury and reduces remote inflammatory lung injury. This effect appears to be due to down-regulation of the adhesion molecule CD 11b and enhanced shedding of L-selectin.
These observations have also been made in humans receiving HTS early after severe injury.[9,10] Modulation of circulating monocyte function has also been described, which may down-regulate the production of pro-inflammatory cytokines and enhance production of anti-inflammatory cytokines such as interleukin (IL)-10. This suppression of the innate immune response appears to be transient and resolves once the serum osmolarity returns to normal. While the innate immune response appears to be inhibited, the cellular response, as manifested by changes in T-cell function, appears to be enhanced. Extensive work by Junger et al. has demonstrated that hypertonicity increases T-cell proliferation, enhances mitogen-stimulated IL-2 production, and rescues T-cells from suppressive cytokines.[11–13] Taken together, these studies suggest a potential role for hypertonic fluids in modulating the immunosuppressive response observed after severe injury or insult.
Finally, a large body of research has focused on the mechanism of action of hypertonic fluids to reduce cerebral edema and improve cerebral perfusion after brain injury. In addition to the obvious physiological effects, hypertonic fluids have been associated with improved cerebral vasoregulation resulting in reduced vasospasm, modulation of cerebral leukocytes, and inhibition of the sodium glutamate exchanger, leading to reduced extracellular accumulation of glutamate, which is neurotoxic.[14] These studies, coupled with animal models showing reduction of intracranial pressure (ICP) in brain-injured animals, have led to a number of clinical studies of these fluids for the management of patients with severe traumatic brain injury.
In summary, there is compelling preclinical scientific evidence that hypertonic fluids have physiological and anti-inflammatory effects that may prove beneficial for the management of a number of perioperative concerns including resuscitation of hypo-volemic shock, management of traumatic brain injury, and management of ischemia and reperfusion injury such as occurs following cardiopulmonary bypass or transplant surgery. This has led to numerous clinical reports.
Clinical trial experience
Clinical studies of hypertonic solutions have largely been focused on three areas: early resuscitation of hemorrhagic shock in the prehospital or emergency department setting, management of increased ICP largely in the intensive care unit setting, and operative reports in a variety of major surgical interventions. Each of these areas is addressed separately.
Hemorrhagic shock
There have been 10 clinical trials of hypertonic fluids for the management of hemorrhagic shock following injury (Table 5.1). These studies were conducted in the prehospital or early hospital setting. It was hypothesized that the earlier the fluid is given after injury the more likely one would be to observe a significant effect. These studies used a 7.5% saline solution with or without the addition of 6% dextran 70. The early investigations were largely too small to demonstrate a definitive difference in outcome. However, meta-analysis of the studies conducted before 1997 suggested an overall survival benefit from HTS with dextran (HSD), with an odds ratio of 1.47 (95% confidence interval 1.04–2.08).[3]
Human trials of hypertonic saline as a resuscitation fluid for hemorrhagic shock
| Reference | Population | Design | n | Hypertonic fluid | Outcome |
|---|---|---|---|---|---|
| Holcroft et al. (1987) [36] | Prehospital trauma pts | Prospective, randomized | 49 | 7.5% NaCl/6% dextran 70 | Improved SBP and overall survival |
| Holcroft et al. (1989) [37] | Hypotensive trauma pts in ED (SBP < 80) | Prospective, randomized | 32 | 7.5% NaCl/6% dextran 70 | No difference in survival |
| Vassar et al. (1991) [38] | Prehospital trauma pts (SBP < 100) | Prospective, randomized | 166 | 7.5% NaCl/6% dextran 70 | Improved SBP and improved survival for pts with traumatic brain injury |
| Mattox et al. (1991) [39] | Prehospital trauma pts (SBP < 90) 72% penetrating | Prospective, randomized | 359 | 7.5% NaCl/6% dextran 70 | Improved SBP, trend toward improved survival |
| Younes et al. (1992) [40] | Hypovolemic shock in ED (SBP < 80) | Prospective, randomized | 105 | 7.5% NaCl and 7.5% NaCl/6% dextran 70 | Improved SBP, no difference in survival |
| Vassar et al. (1993a) [41] | Prehospital trauma pts (SBP < 90) | Prospective, randomized | 258 | 7.5% NaCl and 7.5% NaCl/6% dextran 70 | Improved survival vs. predicted historical controls |
| Vassar et al. (1993b) [42] | Prehospital trauma pts (SBP < 90) | Prospective, randomized | 194 | 7.5% NaCl and 7.5% NaCl/6% dextran 70 | Improved survival vs. historical controls and for pts with traumatic brain injury |
| Younes et al. (1997) [43] | Hypovolemic shock in ED | Prospective, randomized | 212 | 7.5% NaCl/6% dextran 70 | Improved survival for pts with SBP < 70 |
| Bulger et al. (2008) [15] | Prehospital blunt trauma pts (SBP < 90) | Prospective, randomized | 209 | 7.5%NaCl/6% dextran 70 | No difference in ARDS-free survival |
| Bulger et al. (2011) [4] | Prehospital trauma pts (SBP < 70 or SBP 70–90, HR > 108) | Prospective, randomized | 895 | 7.5% NaCl and 7.5% NaCl/6% dextran 70 | No difference in 28-day mortality |
ARDS, acute respiratory distress syndrome; ED, emergency department; HR, heart rate; pts, patients; SBP, systolic blood pressure.
These early studies led to the regulatory approval of HSD in several European countries, but did not afford approval by the US Food and Drug Administration. Two subsequent studies have been conducted. The first was a study by Bulger et al., which focused on the impact of HSD on the development of acute respiratory distress syndrome (ARDS) in a blunt trauma population with evidence of hypovolemic shock.[15] This study closed after enrollment of 209 patients because of futility, with no overall difference in the rate of 28-day ARDS-free survival between the treatment groups.
A predefined subgroup analysis suggested a potential benefit in those patients at highest risk for ARDS as defined by the need for >10 units of blood transfusion in the first 24 hours. This led to a subsequent trial conducted by the Resuscitation Outcomes Consortium, a clinical trial network in the USA and Canada. This trial sought to enroll injured patients with more severe shock based on a prehospital systolic blood pressure of <70 mmHg or 70–90 mmHg with a heart rate >108 beats/min. This study was also closed before reaching its full proposed sample size after enrolling 895 patients randomized to either 7.5% saline (HS), HSD, or normal saline (NS). The results of this study show no difference in overall 28-day survival (HSD 74.5%, HS 73.0%, NS 74.4%, p = 0.91).[4]
In addition, there was a concern raised by the Data Safety Monitoring Board regarding a higher mortality seen among the post-randomization subgroup of patients who did not receive any blood transfusions in the first 24 hours. Subsequent analysis suggested a higher proportion of early deaths: some patients in the hypertonic groups died before blood products became available or were administered. This difference was no longer evident 6 hours after injury. A subsequent systematic review of the safety data demonstrated that HSD administration delayed the administration of blood products by altering standard transfusion triggers, such as systolic blood pressure, with no effect on survival.[16] Thus, despite a large number of clinical trials in this patient population, there remains no compelling evidence to support the routine use of hypertonic fluids in the early management of these patients in the civilian (non-military) community.
Traumatic brain injury
There have been a number of studies examining the use of hypertonic fluids ranging in concentration from 1.6% to 23.4%, given as both bolus and continuous infusions for the management of patients with intracranial hypertension. Most of these studies are case series or descriptive studies, which describe improved ICP with the use of hypertonic fluids in patients who have been refractory to conventional therapy. There have been few randomized controlled trials.
The first trial, by Shackford et al., randomized patients to HTS vs. lactated Ringer’s along with conventional therapies for increased ICP.[17] They were unable to demonstrate any major differences between the treatment groups but were hampered by the randomization of more severely injured patients into the HTS group.
Francony et al. compared equimolar doses of 20% mannitol and 7.45% HTS for management of patients with sustained elevations in ICP and found them to be equally effective.[18] Despite the lack of definitive data in this area, many neurosurgeons are now using HTS routinely for management of elevated ICP.
Three randomized controlled trials have specifically focused on the prehospital administration of HTS to patients with suspected traumatic brain injury. All of these studies utilized the Glasgow Outcome Score (GOS) as a measure of the long-term neurological outcome for these patients.
The first of these studies, by Cooper et al., enrolled injured patients with a prehospital Glasgow Coma Scale (GCS) value <8 and systolic blood pressure <100 mmHg.[6] This trial, which compared 7.5% saline with normal saline, was closed for futility (n = 229) with no difference in extended GOS between the treatment groups 6 months after injury. Because this study included patients who had both severe traumatic brain injury and shock, it was limited by a 50% mortality in the study cohort.
A second trial recently completed in Toronto, Canada was also closed with limitations in obtaining long-term outcome data.[19]
The largest trial in this patient population was recently completed by the Resuscitation Outcomes Consortium. The study was closed early for futility after enrolling 1,331 patients with no difference in the GOS at 6 months after injury.[5] Importantly, this trial enrolled patients with a GCS value <8 but no prehospital hypotension. Thus, like the hypovolemic shock studies, despite a large body of preclinical evidence supporting these resuscitation strategies, clinical trials have been unable to show convincing evidence of improved outcome.
Intraoperative and postoperative studies
A number of small studies have been reported regarding the use of hypertonic solutions in operative cases. Most of these have been conducted during either cardiac or aortic surgery. For patients undergoing cardiopulmonary bypass surgery, the most consistent finding has been a significant decrease in the positive fluid balance with the use of hypertonic fluids.[7] This finding was also noted in a recent Cochrane review of this literature.[8]
Many of these studies have also demonstrated improvement in cardiac index (CI) with hypertonic fluids, but the duration of this effect has been variable. Two studies noted improved CI up to 48 hours after surgery,[20,21] while others suggested a transient effect as short as 1–3 hours.[22,23] This variability may be due to variations in the dose of hypertonic fluids used and additional fluid given. These studies have been too small to identify any significant improvement in outcome.
Nine studies have examined the use of hypertonic solutions during aortic surgery. Like the studies in cardiac surgery, these studies also supported a lower overall fluid requirement in patients receiving hypertonic fluids. Auler et al. reported a small case series (n = 10) describing the administration of HTS vs. isotonic saline at the time of removal of the aortic clamp.[24] These authors report improved physiological endpoints and lower overall volumes of fluid required in the patients given HTS.
In another study, Shackford et al. randomized 58 patients undergoing elective aortic reconstruction to lactated Ringer’s vs. HTS (250 mEq sodium per liter) solution during operative repair.[25] The hypertonic group required on average half the amount of intraoperative fluid as the lactated Ringer’s group but there was no difference in clinical outcomes.
The most recent study by Bruegger et al. (n = 28) compared HTS with hydroxyethyl starch in normal saline for administration during the period of aortic clamping and found no difference between the groups.[26] Several other studies have also shown improved hemodynamic parameters (for review, see Azoubel et al. [7]), but none were large enough to demonstrate improved outcome.
Other operative scenarios explored have included transplantation, elective hysterectomy, and spinal surgery. One case series has been reported describing the use of 7.5% saline for patients with fulminant hepatic failure and Grade IV encephalopathy while undergoing orthotopic liver transplant.[27] These authors compare these patients with historical controls, and suggest that patients receiving HTS had more favorable hemodynamics and improved ICP. Another study examined the immune effect of HTS administration for patients undergoing elective hysterectomy and did not find any significant changes.[28]
One recent study examined the use of 3% saline infusions (30 cc/hour) in trauma patients following damage control surgery with open abdomens.[29] This was not a randomized trial, but patients receiving the hypertonic fluids demonstrated a shorter time to abdominal wall closure and higher rates of primary fascial closure, suggesting better management of post-operative tissue edema.
A recent meta-analysis also explored the intraoperative use of hypertonic solutions for elective neurosurgical procedures. These authors suggest that HTS may be superior to mannitol for brain relaxation during tumor resection.[30] A recent review highlights the many limitations in interpreting this literature.[31]
Finally, a retrospective, case-controlled study compared outcomes for patients undergoing major spinal surgery who received intraoperative HTS with those that did not, and suggested an association with lower postoperative infection rates.[32] A few studies have also examined the role of preloading patients undergoing spinal anesthesia with hypertonic fluids.[33–35] These studies have had mixed results, with some demonstrating improved hemodynamic parameters while others did not. All of these studies are limited by very small sample size.
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