Hypertonic Saline Solutions for the Initial Treatment of Patients with Traumatic Injuries

Early and aggressive fluid resuscitation of patients with hypotension and traumatic injuries may impact morbidity and mortality. Which fluid to use, if any, is controversial. Hypertonic saline solutions (HS) have recently undergone a series of randomized and blinded clinical trials in this patient population. These studies tend to show an improvement in survival of those patient initially infused with HS, specifically hypertonic saline dextran (HSD). The greatest benefit is reported in patients subsequently requiring emergent surgery, or with a poor predicted survival. HS appears to work by rapidly correcting blood volume, lost due to hemorrhage, returning oxygen delivery to normal. There is also an arresting of the adverse immunological cascade, associated with tissue hypoperfusion, that may effect survival. In addition there is a growing interoperative use of HS adding to the literature on safety. The use of hypertonic saline solutions, such as HSD, appears safe and is of benefit to the patient by increasing chances of survival. The use of hypertonic solutions is warranted for the initial resuscitation of patients with hypotension and traumatic injuries.

Fluid resuscitation of the patient with hypotension and severe traumatic injuries has acute effects as to immediate survival, as well as on the occurrence of later complications, which ultimately effecting quality of life and long-term survival. Trauma remains one of the leading causes of death in individuals under the age of forty <|[1]|>. Hemorrhage, the loss of blood, is a major contributor to injury related morbidity and mortality. Therefore, the goal of fluid resuscitation is to restore blood volume and reestablish blood flow to critical organs, with the definitive outcome being survival.

Early and aggressive fluid resuscitation of a victim of trauma to correct for blood loss due to hemorrhage is controversial <|[2-9]|>. Factors which must be considered in the overall effectiveness of resuscitation solutions are the resulting effect on the rela-tionship of oxygen delivery and the metabolic demand for oxygen, possible aggravation of internal bleeding and additional loss of blood, and the time delay due to gaining intravenous access and fluid administration before the initiation of definitive inter-ventions, such as surgery if necessary. Thus, the ideal resuscitation fluid should expand vascular volume, be able to transport oxygen or reduce oxygen demand, not increase bleeding, and be able to be administered rapidly. At present no available solu-tion meets all of these criteria.

Of the presently used solutions for the replacement of blood loss nonehas undergone extensive clinical and regulatory inves-tigations. Recently, questions have been raised as to the efficacy, in light of associated risk and cost, of most available solutions, including whole blood <|[9-17]|>. Thus, over the past twenty years there has been an concerted effort to develop new resuscitation solutions.

Recently, there have been a number of clinical investigations as to the use of hypertonic (2,400 mOsm/kg) saline solutions as the initial fluid for resuscitation of victims of trauma <|[18-34]|>. These hypertonic solutions usually are a 7.5% NaCl solution often combined with hyperoncotic colloids, such as 6% Dextran 70 or hetastarch. The imputes for the clinical use of hyperto-nic saline solutions is based on an extensive basic science literature elucidating the mechanisms of action of the solutions, and a growing positive clinical experience.

PHYSIOLOGICAL PROPERTIES

Survival

The initial incentive for the clinical study of hypertonic saline solutions was the early work on survival of animals <|[35-37]|>. In 1981 Velasco et. al <|[35]|> reported that in dogs, who were lightly anesthetized and hemorrhaged to a blood pressure of 40 mmHg and sustained for 30 minutes, the administration of 4 ml/kg (10% of the blood lost) of a 7.5% hypertonic saline (HS) solution rapidly restored blood pressure and improved survival. In the treated animals 100% survived, while none of the control animals lived beyond seven hours. Maningas and coworkers <|[36]|> conducted studies using conscious pigs that were hemorrha-ge 70% of their estimated blood volume. This model resulted in death if not treated. Of the animals treated with 11 ml/kg HS intravenously about 50% survived, while 100% of the animals survived who received an equal volume of the hypertonic saline dextran (HSD) solution. The findings of improved survival with the administration of small volumes of hypertonic solutions stimulated additional work into the mechanisms of action of these solutions.

Blood volume

Improvements in outcome were associated with increases in blood pressure due to the expansion of blood volume, due to mobilization of cellular water into the plasma. With the administration of HS there is a rapid expansion of blood volume which is even greater if HSD is used <|[35-51]|>. Recent studies of these solutions in human volunteers have shown the for the volume of HS administered there is a near equal expansion of plasma volume <|(Figure 1)|> <|[49-51]|>. When dextran is added to HS the expansion ratio is greater and sustained for a longer period. For conventional solutions such as isotonic saline the ratio of plas-ma volume expansion per volume of fluid administered is 0.2 ml/ml, and for Dextran is 0.6 ml/ml. Thus, expansion of blood volume for a given volume of solution infused is greater when hypertonic solutions are used and this is sustained for a longer period of time if HSD is administered.

Cardiac function

The expansion of blood volume following hemorrhage resuscitation by administration of HS is associated with increases in blood pressure and cardiac output, and a reduction in total peripheral resistance <|[38-48]|>. Together these effects cause an impro-vement in organ blood flow <|[51-55]|>. Of note is that for a given increase in plasma volume the increase in cardiac output is grea-ter when HS is administrated <|[39-44]|>. This improvement in cardiac output for a given plasma volume expansion is multifacto-rial and may be related to enhancement of left ventricular contractile force by the increase in plasma osmolality and a greater preload due to the expansion of blood volume <|[38-48, 56]|>. Also arteriolar vasodilatation results in a reduction in total periphe-ral resistance, therefore decreasing afterload <|[57]|>. The increase in preload, coupled with the reduction in afterload, facilitates an increase in cardiac output. The proportional increase in cardiac output exceeds that of the reduced oxygen carrying capaci-ty due to blood volume expansion and hemodilution. The net effect of these changes is an increase in oxygen delivery and cor-rection of the metabolic alterations induced by hemorrhage <|[39-44]|>. Therefore, with the infusion of hypertonic saline solutions, cardiac output, perfusion of vital organs and oxygen delivery are improved beyond what would be predicted for the level of expansion of blood volume.

The improved tissue blood flow and reduction in total peripheral resistance after HS infusion is in part the result of a alleviation of endothelial swelling <|[58-60]|>. In response to hyoperfusion the endothelial cell of skeletal muscle blood vessels swell, resulting in narrowing the diameter and restricting flow. The infusion of hypertonic solutions results in an resumption in micro-circulatory blood flow as vessel diameter is increased. The infusion of hypertonic solutions causes an immediate reduction in the size of the endothelial cells, reducing peripheral resistance and pronounced improvement in tissue blood flow.

Immune function

The marked increase in flow in the microvasculature that occurs with infusion of HS is associated with a reduction of neutrophils rolling and sticking to the endothelial cells of blood vessels <|[58-67]|>. In response to hypoperfusion and subsequent reper-fusion there an activation of adherent leukocytes which release cytotoxic substances and reactive oxygen species damaging the endothelial barrier. With this damage comes leakage of fluid and macromolecules into the extravascular space. Hypertonicity inhibits leukocyte adherence and activation <|[61-57]|>. Recent studies have identified a number of immune pathways in which are mediated by hypertonicity <|[61-67]|>. Of note, is that many of these responses can be demonstrated in vitro suggesting that HS has a direct effect on immune cells. It appears that the administration of HS and resultant hypertonicity elicits a cellular signal which modulates and inhibits the immune cascade normally associated with reperfusion injury. Administration of HS resulting in suppression of this cascade may impact long-term morbidity and survival. Further, recent findings suggest that once this cas-cade is initiated the beneficial effects of administration of hypertonic solutions will be diminished <|[62]|>. Together these data suggest initial or early hypertonic saline resuscitation would be of greater benefit than infusion after a period of conventional fluid administration.

There has been an extensive effort as to the toxicology, pharacokenitic, and stability of HSD and it components, hypertonic saline (7.5% NaCl) and 6% Dextran 70 <|[31, 68-74]|>. These studies have also addressed interference in clinical laboratory procedures, blood cross typing, and coagulation <|[70-72]|>. For this reason HSD has become the most commonly studied hypertonic hyperoncotic solution <|[29, 32]|>. HSD is presently approved for clinical use in a number of countries <|[27, 29]|>.

The physiological mechanism of hypertonic solutions in the treatment of hypotension and hypoperfusion would logically result in a better outcome. Blood volume expansion is greater than other solutions give at equal volumes. The sustained improvement in cardiac output, and subsequently oxygen delivery, is superior to other solutions even at an equal expansion of blood volume. The modulation of immune function by HS would favor a reduction in secondary complications. In addition HS, spe-cifically HSD, does not appear to effect a number of clinical procedures important in the care of patients.

CLINICAL TRIALS

The reported number of patients treated with hypertonic saline solutions (HS) continues to expand <|[32, 33, 75]|>. The formu-lation of solutions has been diverse with the sodium concentration ranging from 1.5 to 7.5% with the addition of colloids such as dextran or hetastarch. HS solutions have been used in a number of clinical settings: intra-operatively for volume expansion, <|[75-89]|> to attenuate hypotension after aortic cross clamping <|[78-81, 90, 91]|> and during renal dialysis, <|[92]|> treat hypotension due to bleeding gastric ulcers <|[19, 93]|>, fluid maintenance of patients with burn injuries or sepsis <|[93-96]|>, to reduce intracranial pressure and improve cerebral blood flow <|[23, 24, 98, 99]|>, and in the resuscitation of patients with hypotension and injuries due to trauma <|[18-26]|>. This last application is the one with the most extensive data base and will be discussed further.

The points of discussion will focus on the uniformity of the response to hypertonic solutions, specifically hypertonic saline dextran (HSD). The points that will be considered are survival until discharge, improvement in blood pressure, increased blee-ding, conservation of fluids, and complications.

Hypertonic solutions have been used in doubled blinded studies of patients who are hypotensive and have traumatic injuries <|[18-26]|>. What is amazing is the range of patients that have been treated in a variety of settings. The settings have included admi-nistration in the field at the site of the accident, in the transport vehicles (ambulance and helicopter) and in the emergency room. The criteria for entry has employed measurements that can be attained in the initial minutes of treatment. These include the pre-sence of traumatic injuries, hypotension, and determination of a trauma score (assessment of respiratory rate, blood pressure and cognitive function) <|[100, 101]|>. While these factors are used to enroll a patient, unlike many clinical trials employing only surrogate clinical or physiological endpoints, the efficacy endpoint of all of the studies of hypertonic solutions has been survival. Thus, studies of hypertonic saline solutions in the treatment of trauma have involved the extremely heterogeneous population, that is patients with traumatic injuries and hypotension, who may have a very low or very high probability of survival.

A number of formulations of hypertonic solutions have been evaluated. By far the most extensive data base for the treat-ment of patients with hypotension and traumatic injuries is available for the formulations of hypertonic saline (HS; 7.5% NaCl) and hypertonic saline dextran (HSD; 7.5% NaCl in 6% Dextran 70). The trails were blinded and randomized 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) <|[18-26]|>. All solutions have been evaluated at 250 ml 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 with held.

Survival

The outcomes of studies of HS or HSD compared to standard of care (SOC) are presented in <|Table 1|> and <|Table 2|> <|[18-26]|>. On the whole the use of HS or HSD in the resuscitation of patients with traumatic injuries has been favorable. In a recent meta-analysis of studies of patients with traumatic injuries Wade and coworkers <|[26]|> found there to be little effect of hypertonic saline alone on survival until discharge. Of the six studies, involving 719 patients distributed between HS alone ( 3 4 0 patients) and standard of care (SOC; 379 patients), there was a weighted mean difference in discharge survival of only -0.6%. There was no significant difference between treatment groups (p = 0.919). When the combination solution of HSD was evaluated in 615 patients compared to SOC in 618 patients there was a 3.6% increase in survival.

This equates to a 13% reduction in mortality. The odds ratio was 1.20 in favor of the use of HSD, with a 95% confidence interval of 0.94 to 1.57. While not significant (p = 0.142, two tailed; p = 0.071, one-tailed) the meta-analysis suggested a favorable benefit on discharge survival for the use of HSD treatment of hypotension in the presence of traumatic injuries. When patients who received a test solution as the initial resuscitation solution were evaluated using a meta-analysis of indi-vidual patient data from six studies the odds ratio was 1.47 (95% CV 1.04, 2.08; p < 0.05) favoring a significant improve-ment in survival in patients infused with HSD <|[104]|>. These finding suggest the timing of the administration of HSD is important in the determination of subsequent outcome.

The complication of studying a trauma population is that there is a group of patients with severe injuries that are going to die irrespective of the interventions used, and there is another group with minor injuries who are going to live irrespective of the intervention. Therefore a trauma treatment can only impact outcome in a small portion of the total population. An example of this issue can be derived from the frequency distribution of TRISS scores in the study by Vassar et al <|[24, 102]|>. TRISS score is equivalent to the probability of survival <|[102]|>.

From this data over 55% of the patients had a probability of survival of greater of 95% <|(see Figure 2)|>. The impact of this problem can be seen in the observed versus predicted survival in the study by Vassar et al <|[24]|> <|(see Table 3)|>. For patients with a high predicted survival the majority survived with no difference between treatments. In the patient popula-tion with a poor predicted outcome, less than 15% of the study population, the majority of the patients dies. Therefore, in patients with traumatic injuries when assessing the efficacy of a treatment as to survival one must realize that the size of the population which can truly be effected is much smaller than the total population making an impact of treatment difficult to demonstrate.

For the above reasons investigators have evaluated sub-populations within their studies to assess the benefits of HSD admi-nistration. These have included stratification of the data based on initial blood pressure, injury type, presence of head injuries, requirement of blood transfusion or emergent operative care, and predicted outcome. 3) 44.0% 51.1%

Initial blood pressure

Patients who have a lower blood pressure are assumed to have a more sever loss of blood. Thus, some investigators have used the blood pressure at the time of treatment as a subgroup. Vassar et al <|[21]|> found similar rates of survival, about 70%, for patients with SBP ≥ 80 mmHg. For patients with a SBP ≤ 79 treatment with SOC resulted in a 47% survival compared to 57% when administer HSD. In a subsequent study they found patients who had an unobtainable blood pressures prior to treatment had an improved survival compared to the predicted survival if treated with HSD <|[24]|>. No difference was noted with SOC or HS. Younes et al <|[25]|> reported that in patients with an initial mean arterial pressure of less than 70 mmHg the use of HSD had a significant effect on long term survival. It appears that when blood pressure is used to stratify the patient population those patients with an initial low blood pressure benefit from the administration of HSD.

Injury type

In studies of HSD the focus has been on patients with traumatic injuries. In six of the eight studies enrollment was based on injuries due to trauma <|[18, 20-24]|>. In the other two studies by Younes et al <|[19, 25]|> the criteria was hypovolemic shock. Of the patients enrolled in these two studies the majority (96% and 85%) had traumatic injuries. In all of the studies there were blunt injuries, primarily from vehicle accidents, and penetrating injuries, due to gunshot or stab wounds. The ratio of penetrating to blunt injuries was 624 to 588, or 51% of the patients. In the United States the expected percentage of patients with pene-trating injuries would be on the order of 21% <|[103]|>. The patient injury distribution in studies of hypertonic solution have an increased incidence rate of penetrating injuries, which is reflective on the large urban hospitals where these studies were conducted. An influencing factor in the selection of patients with penetrating injuries may also be the requirement in all of the studies that the patients be hypotensive prior to enrollment.

The most common segregation of the population is based on the type of injury, blunt versus penetrating. As mentioned above the patient with a penetrating injury is suggested to lose more blood though outcome is better. Maningas et al <|[18]|> excluded patients with blunt injuries in order to maintain some uniformity of the injuries encountered. Vassar et al <|[21]|> reported similar survivals until discharge of patients with blunt injuries for SOC (60%) and HSD (61%). For patients with penetrating injuries there was a trend for improvement with HSD (77%) compared to SOC (53%). In a later study of patients treated with SOC, HS or HSD, Vassar et al <|[24]|> could not identify a difference in outcome between treatments based on injury type. In another study they found HS to improve outcome compare to predicted survival in patients with blunt or penetrating injuries, while with HSD a difference was only noted for patients with blunt injuries <|[23]|> The selective used of hypertonic solutions based on injury type does not appear warranted.

Head injuries

Patients with hypotension and traumatic brain injury have a poor survival. The probability of survival is about half of that with only one of the injury components. The occurrence of head trauma associated with blunt trauma led Vassar et al <|[21, 23, 24]|> to evaluate this subgroup of patients in their studies of resuscitation of patients with hypotension. A consistent finding by this group is that HSD treatment significantly improves survival of patients with brain injury and in those patients with a Glasgow coma score of ≤ 8. In addition, the quality of life after discharge from the hospital appears to be improved in the patients. Recent work by Shackford and colleges <|[98]|> using 3% HS failed to show an improved outcome in patients with head injury. However, this treatment was delayed compared to the earlier HSD trials. Wade et al <|[99]|> in retrospective analysis of patients with hypotension and traumatic brain injury found survival until discharge to be 38% for patients administered HSD compared to 27% for SOC. This difference in survival was not significantly different (p = 0.080) until adjustments were made for trial effects (p = 0.048). The odds ratio (2.12; 95% CV 1.01, 4.49) suggest patients with traumatic brain injury who are trea-ted with HSD are more likely to survive than those administered SOC.

Blood transfusion

Patients who require the transfusion of whole blood or packed red cells are presumed to be in an extreme state of hypovolemia that could be life treating. The necessity of blood replacement is correlated with the severity of the injury and more com-mon with penetrating injuries <|[24]|>. The amount of blood infused is on the order of 1-2 liters <|[23, 24]|>. In a meta-analysis of individual patient data from six of the previous studies of HSD Wade et al <|[104]|> found that in patients requiring a blood transfusion that the odds ratio (1.60; 95% CV 0.95, 2.81) favored HSD improving survival until discharge. This finding however was not significant. Vassar et al <|[24]|> reported the estimated blood loss and replacement requirements of patients undergoing emergent surgical procedures. There was no significant difference in the amount of blood required, 1.5 2.7 Lfor SOC and 1.2 1.8 L with HSD, but in the HSD group survival was improved compared to predicted outcome. Patients requiring blood transfusion are believed to be at risk of dying, and the administration of HSD tends to increase the probability of survival.

Emergent surgery

Mattox et al <|[22]|> found that in patients requiring surgery there was a significant treatment effect favoring the use of HSD. In patients requiring emergent operative procedures Vassar et al <|[24]|> found HSD to improve survival compared to predicted survival. In comparison to SOC there was no difference. In a later study Vassar et al <|[23]|> again found HSD to improve survival (56%) compared to the predicted level (45%). However, in a direct comparison to SOC (52%) no difference was noted. In a meta-analysis of individual patient data Wade et al <|[104]|> found the odds ratio (1.60, 95% CV 0.96, 2.27) to favor HSD compared to SOC, but the improvement was not statistically significant. Though the results encourage the use of HSD in patients who subsequent-ly require emergent operative procedures this condition can not be identified at the time of initial administration of fluids.

Predicted outcome

As noted above the patient population with traumatic injuries which can benefit from fluid resuscitation is limited. Vassar et al <|[23,24]|> have focused on those patients with a poor predicted survival <|(Table 3)|>. This prediction is based on the TRISS evaluation <|[102]|>. In patients with a predicted survival of < 25% administration of isotonic saline did not alter the observed survival from the predicted value. The administration of HS or HSD resulted in significant improvements above the predicted value. This trend was also observed in a subsequent study <|[23]|>. Thus, the use of hypertonic solutions appears to be of greater benefit to those patients who have more severe injuries resulting in a poorer predicted survival.

Improved blood pressure

In the majority of the studies of patients who were hypotensive a systolic blood pressure on less than 90 mmHg was used as an entry criteria <|[26]|>. It is assumed that patients with a blood pressure that is sustained at a low level for an extended period of time will have a poor outcome. This is supported in the work of Vassar et al <|[24]|> where in those patients that did not survive blood pressure was not increased to the extent of those who did survive <|(see Table 4)|>. If this holds true the use of hypertonic saline solutions is beneficial as there is a consistent finding of an greater increase in blood pressure following administration compared to SOC <|[18, 19, 22, 23, 25]|>. For the majority of patients the increase in SBP with HS or HSD administration is on the order of 10 mmHg greater than that observed with SOC. If it is assumed that an increa-se in blood pressure is beneficial, resulting in increased survival, the administration of HS or HSD would be favored.

Uncontrolled bleeding

An increase in blood pressure has been purported to induce an increase in bleeding in the presence of uncontrolled hemor-rhage <|[9]|>. In animals models the increase in blood pressure associated with the administration of fluid to sustain an increase in blood pressure leads to increased blood loss and ultimately death <|[105, 106]|>. This has been show to occur in animals with the administration of HS and HSD, thus raising concerns as to increased bleeding and mortality with these fluids <|[51, 107, 108]|>.

In patients it is of interest that when the amount of blood loss is estimated, and the requirements of resuscitation fluids are examined, there is little difference between hypertonic saline solutions and conventional fluids <|[19, 23]|>. In the early study of Younes et al <|[19]|> the amounts of fluids, crystalloids and blood, required to maintain SBP at 100 mmHg was reduced signifi-cantly in patients initially administered HS or HSD.

This trend was consistently observed <|[18, 19, 22, 23]|>. The concerns associated with uncontrolled bleeding are focused on those patients with penetrating injuries to a major vessel that requires surgical interventions to control. It is interesting to note that in a number of studies the patient group that had the greatest improvement in discharge survival were those patients with penetrating injuries requiring surgery <|[22, 23]|>.

For example in the study of Mattox et al <|[22]|> in those patient with penetrating injuries requiring surgery the use of HSD was favored (p = 0.01) in improving survival over the first 24 hours.

Of note in the study of Mattox and colleagues <|[22]|> is the hospital with the highest enrollment of patients with penetrating injuries requiring surgery, Ben Taub General in Houston TX USA, the survival rates were 88% with HSD and 77% with SOC treatment (p = 0.06). This is the institution in which studies as to the benefits of with holding fluids in the field were conduc-ted <|[9]|>. Vassar et al <|[1, 23, 24]|> also noted an improved discharge survival in patients requiring urgent operative treatment if they had received HSD. Thus, if fluids are used for the emergent resuscitation of patients with hypotension and traumatic injuries hypertonic solutions do not appear to increase bleeding compared to standard solutions as hemoglobin concentrations, hemato-crites and estimated blood loss are not different between treatments <|[21-24]|>. In addition the population at greatest risk for increased bleeding are those patients with penetrating injuries requiring surgery. This subgroup had a significant improvement in survival with hypertonic saline infusions suggesting an overall benefit irrespective of any additional bleeding.

Reduced fluid requirements

HSD has been used in the post operative care of patients undergoing surgery <|[76, 84, 91]|>. In patients undergoing cardiac by-pass surgery there is a significant reduction in the fluid requirements over the 24 hour period following the administration of 250 ml of HSD compared to SOC <|[91]|>. In addition there was a significant increase in urine output resulting in a slightly reduced net fluid balance, while patients treated with SOC had a net increase in net fluid balance. In the earliest report of Younes et al <|[19]|> there was a significant reduction in the volume of fluids, both crystalloids and blood, required in those patients with hypotension who were initially administer HS or HSD. The reduction in fluid requirements was over 40%.

This study was conducted in the emergency room when the investigators controlled fluid administration to a SBP of 100 mmHg. In subsequent trials by other the administration of fluids was not as well controlled. However, there was still the trend for early fluid requirements to be reduced. In patients administered HSD the trend in 24 hour fluid administration was for a reduc-tion of about 1,000 ml <|[18, 21, 22, 25]|>. The magnitude of this reduction held irrespective of the total volume infused.

The magnitude of the reduction in fluid use, 1,000 ml, is of interest. In a model of a 70 kg human with a total body water of 42 L (28 L intracellular volume and 14 L extracellular volume) at a pre-infusion osmolality of 300 mOsm/kg the infusion of 2 5 0 ml of 7.5% saline (2,400 mOsm/kg) would increase total body osmolality to 312 mOsm/kg. If all of the NaCl is retained in the extracellular space the extracellular volume would be increased by 1,360 ml (250 ml infused plus about 1,000 ml drawn from the intracellular space). As standard of care solutions are distributed in the extrcellular space there would be a reduction in requi-red volume of about 1,000 ml if HS or HSD have been administered.

No difference in urine output between treatments has been noted <|[22]|>. Thus, administration of hypertonic saline solutions reduces overall resuscitation fluid requirements and net fluid balance compared to SOC.

Complications and considerations

Clotting Factors: Another factor possibly contributing to increased bleeding would be increased hemodilution with the hypertonic solutions. Hemodilution would lead to an increase in clotting time which would result in increased bleeding. The incidence of coagulopathies has been similar among the test solutions <|[22, 23]|>. In those studies in which prothrombin and par-tial thromboplastin times have been measured no difference has been noted between treatments. The dextran component of HSD has been reported to reduce clotting when administered in large volumes. Administration of 250 ml of HSD in studies in which the dextran concentration was increased up to 12% showed no difference in clotting factors <|[23]|>. Therefore, it appears that the use of HS or HSD does not alters clotting times.

Hypernatremia

A consistent finding with the use of hypertonic saline solutions is hypernatremia. The reported values indicated an increase on the order of 10-12 mmol/L if 250 ml of HS or HSD is administered to a patient with traumatic injuries <|[18-25]|>. There have been no adverse neurological reactions or neuropathological abnormalities found at autopsy that could be explained by the increase in sodium concentration <|[24]|>. Further in patients who died, in which autopsies were conducted, there were no incidence of central pontine myelinoysis <|[23, 24]|>. At present no adverse effects have been reported associated with increases in sodium concentrations of the magnitude reported with the administration of 250 ml of 7.5% NaCl. However, there is little information as to the used of hypertonic saline solutions in children which may be more susceptible to adverse effects of hypernatremia.

Medical complications

Studies of immunological function in human cells show improvements with the administration of hypertonic solutions <|[66, 67]|>. These improvements, coupled with an improvement in organ blood flow with adequate resuscitation, should lead to a reduction in medical complications secondary to hypoperfusion and reperfusion injury. The trend has been for a reduction in the incidence of complication when HSD is administered, and in the number of patients in which they are reported.

In the study of Mattox et al <|[22]|> there were seven patients (3%) treated with HSD who had complications, and 13 (6%) with complications who received the SOC. Of the patients with complication only one of the seven (14%) who was administered HSD died, while six (46%) of the SOC treated patients died. In the study of Vassar et al <|[24]|> of those who died the cause of death due to sepsis and organ failure was one for SOC, three for HS and three for HSD. In the recent study by Younes et al <|[25]|> the incidence of complications was similar among treatment groups. Adefinitive evaluation of the effect of hypertonic solutions on the incidence of medical complications is still necessary. The trend, however, is for there to be a reduction or no change in the rate of medical complications in patients administered HS.

Dose

The dose and rate of administration of hypertonic solutions that is recommended, 250 ml, followed by conventional fluids, is based on survival studies in animals <|[35]|>. Issues as to the safety of this dose and administration rate have been raised in intra-operative studies. Rapid administration of hypertonic saline hetastarch (HSS) to patients with a limited cardiac reserve undergoing cardiac surgery resulted in hypotension with transient hypovolemic left ventricular failure <|[89,109]|>. In trauma patients the rate of administration has been limited by the size of the infusion needle and the use of gravity to initiate flow <|[4, 7]|>.

A more rapid administration of hypertonic saline solutions has not been evaluated. There is little data to support an increase in volume or rate of administration of the present dose (250 ml), which has been show to be effective in the treatment of trauma patients. The recommended dose does raise a question as to body size. In all studies a uniform dose has been used over a wide body weight range. Unfortunately, in the present clinical trials body weight has not been reported.

As the majority of the patients have been young male adults body weight could vary from 50 to 150 kg, thus the dose by body weight covers a wide range, 5 to 1.6 ml/kg. The dose to be administered at present, 250 ml, favors safety and has not been associated with adverse events.

Timing of administration

In most of the available studies hypertonic solutions were administered within 2 hours following injury. In addition in there appears to be a greater benefit if HSD is administer as the first fluid used in resuscitation (see above). Recent animal studies support this observation <|[110]|>. Therefore, it is recommended that hypertonic saline solutions be the initial fluid administered to resuscitate a patient with hypotension and traumatic injuries.

Application and use of HSD

The administration of HSD, as well as other hypertonic saline solutions, to patients who are hypotensive with traumatic inju-ries appear be of benefit. In several patient subgroups there is a reduction in morbidity and mortality. In no subgroup that has been report is there an increase in mortality. Benefiting are those patients with head injuries or those requiring surgery. Indications are that patients having the greatest gain from HSD administration are those who are more severely injured, as jud-ged by degree of initial hypotension, subsequently requiring emergent surgery, or poor predicted survival. In order to capture these groups all patients should be treated. The solutions should be administered first and at a rate which is not rapid. As hyper-tonic saline solutions appears to be safe, with the possibility of advantages to the patient, the use of fluids, such as HSD, as the initial resuscitation solution administered to patients who have traumatic injuries and hypotension is warranted.

Appendix: 

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