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Resuscitation fluids
Fluids have been administered intravenously, subcutaneously, and per rectum since the 1600s. The modern description of the circulatory system in 1638 by William Harvey allowed the concept to slowly progress. William O’Shaughnessy theorized that patients suffering from volume loss secondary to cholera would benefit from restoration of blood to its natural specific gravity by replacing its “deficient saline.” This became the first concept of contemporary intravenous (IV) fluid therapy. Thomas Latta was credited with applying O’Shaughnessy’s theory and treating victims of cholera in 1832. Later in the 19th century, Sydney Ringer described a physiologic solution with a focus on electrolyte concentrations in his isolated frog heart models. Hartman modified this solution by the addition of lactate as a buffer. Many of these concepts were criticized and largely forgotten until the 20th century. The advent of modern surgery was associated with increased recognition of the importance of maintaining intravascular volume and led to investigation of the use of IV fluids for that purpose.
World War I provided tremendous experience with resuscitation of hemorrhagic shock. Walter Cannon’s work eloquently described the natural history and presentation of shock with primary accounts of battlefield victims. His work suggested that a delay in surgical control of bleeding was accompanied by a large increase in fatality. Furthermore, he indicated that aggressive resuscitation without surgical control could worsen hemorrhagic shock. He also indicated that resuscitation with saline could worsen existing acidosis. In subsequent decades, however, much of his work was forgotten or ignored. Then in World War II and the Korean War, practice shifted to resuscitation with plasma and blood. Blalock supported this based on his dog studies, suggesting that crystalloid fluids were rapidly lost from the intravascular space. In 1963, Shires showed that shock is accompanied by a shift of interstitial fluid into the vasculature, and he posited that crystalloid replaced the depleted interstitial space. This discovery brought renewed interest in salt solution therapy ( Table 1 ). The Vietnam era witnessed large-volume crystalloid resuscitation and increased survival rates. However, these practices also led to an increase in volume overload-related complications such as acute respiratory distress syndrome or Da Nang lung. Subsequent decades have been characterized by further optimization in aggressive resuscitation. Specific gains have been made in the realm of intensive care, monitoring, IV access, and end points of resuscitation. Despite these advances, many controversies and questions remain. Choice of fluid has remained controversial. The study of the mechanism of shock has provided a vast amount of information at the cellular and molecular level, but this has yet to translate into a directly applicable clinical treatment. More importantly, the complications of modern resuscitation are commonly seen in trauma intensive care units (ICUs).
TABLE 1:
Composition of Balanced Salt Solutions (mEq/L)
Modified from Miller RD: Miller’s Anesthesia, 7th ed. Philadelphia, Elsevier, 2010, and consulting editors, Micromedex 2.0 5/2/2012.
| Solutions | Glucose (g/L) | Na + | Cl − | |
K + | Ca 2 + | Mg 2 + | |
NH 4 + |
|---|---|---|---|---|---|---|---|---|---|
| Extracellular fluid | 1000 | 140 | 102 | 27 | 4.2 | 5 | 3 | 3 | 0.3 |
| 5% dextrose and water | 50 | ||||||||
| 0.21% sodium chloride (0.25 NS) | 34 | 34 | |||||||
| 0.45% sodium chloride (0.5 NS) | 77 | 77 | |||||||
| 0.9% sodium chloride (NS) | 154 | 154 | |||||||
| 3% sodium chloride (HS) | 513 | 513 | |||||||
| 7.5% sodium chloride (HS) | 1283 | 1283 | |||||||
| Lactated Ringer’s solution | 130 | 109 | 28 * | 4 | 2.7 |
HS, hypertonic saline; NS, normal saline.
* Present in solution as lactate, but is metabolized to bicarbonate.
Choice of fluids
The use of crystalloids versus colloids in critically ill patients has been an ongoing debate for decades ( Fig. 1 ). In the Vietnam War, isotonic crystalloids were used when laboratory work from the 1960s by Shires and others showed larger-volume resuscitation with isotonic crystalloids resulted in improved survival. They noted that extracellular fluid redistributed into both intravascular and intracellular spaces during shock, and rapid correction of this extracellular deficit required an infusion of a 3:1 ratio of crystalloid fluid to blood loss. Using this resuscitation strategy, the overall rate of mortality and the rate of acute renal failure decreased but a new entity of shock lung, now better known as acute respiratory distress syndrome, was encountered.
Colloid
There are a number of theoretic advantages to the use of colloids for fluid resuscitation. Colloids increase the plasma volume and oncotic pressure immediately after being given. It has been commonly assumed that this effect lasts for a clinically significant amount of time, but animal studies have suggested that this effect might be short-lived and that colloid molecules may diffuse into the extravascular space within seconds of administration. It has also been commonly assumed that administration of colloids leads to less tissue edema than with crystalloids. However, the shift and the eventual change of interstitial osmotic pressure could potentially worsen edema and have the opposite of the intended effect. The benefits have never been verified in the clinical setting, and clinical trials show that extravascular fluid volume and requirement for mechanical ventilation are equivalent after administration of colloid or crystalloid.
The number of published clinical studies comparing colloids versus crystalloid administration in critically ill patients has grown. The Colloids versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) Trial prospectively randomized 2857 patients with hypovolemic shock to receive colloids or crystalloids for resuscitation. Colloids in this study included gelatins, 4%, 5%, 20% or 25% albumin, dextrans, and hydroxyethyl starches. There was no significant difference in 28-day mortality between the colloids versus crystalloid group, 25.4% versus 27.0%, respectively. The CRISTAL study group then performed a subgroup analysis on 741 critically ill surgical patients and found similar results in the surgical population. Colloids provided no survival benefit compared with crystalloids for the resuscitation of these patients.
The Saline versus Albumin Fluid Evaluation (SAFE) study randomized 6997 ICU patients to receive 4% albumin or normal saline (NS). The study population was heterogeneous and included 43% surgical patients and 17.4% trauma patients. Physicians were blinded and were allowed to determine the rate and amount of fluid infusion depending on the clinical circumstances. There were no significant differences in mortality rate, ICU days, days of mechanical ventilation, or days of renal replacement therapy. The SAFE investigators later performed a post hoc analysis of the patients with traumatic brain injury (TBI) in the original cohort and found that the use of albumin significantly increased mortality rate. Among patients with severe TBI, 41.8% of the patients in the albumin group died versus 22.2% in the saline group. Because there was no difference in resuscitation end points between groups, it was hypothesized that vasogenic or cytotoxic cerebral edema might be exacerbated by albumin.
A Cochrane Collaboration meta-analysis examined randomized controlled trials in critically ill patients receiving colloid or crystalloid for resuscitation and found no advantage to the use of colloid. Albumin, hydroxyethyl starch, modified gelatin, and dextran were each examined individually, and in each case, the relative mortality risk for patients receiving colloid was between 0.91 and 1.24. Other meta-analyses have either shown no benefit to the use of colloids or have suggested that some patient populations may have a worse outcome. Other possible disadvantages are an increased incidence of allergic reactions and renal failure (dextrans), altered platelet function (dextrans, hetastarches), hyperchloremic acidosis (hetastarch), and greater expense. In summary, there is no clinical evidence to support giving colloid products over crystalloid solutions for fluid resuscitation.
In the setting of end-stage liver failure, albumin products have been used extensively for the purposes of replacing ascites lost in a controlled or uncontrolled fashion. Limited studies have demonstrated benefit in avoiding renal failure in the setting of large-volume paracentesis. While postoperative protocols continue to use albumin, data remain limited. The critical care practitioner should be aware of the potential for volume overload and should consider end points for continued use including the normalization of the plasma albumin level.
Crystalloid
The choice of crystalloid has also been a source of controversy in critically ill patients. Randomized trials have aimed to identify the clinical benefits of balanced crystalloid administration with lactated Ringer’s (LR) or Plasma-Lyte compared to NS. Traditionally, NS has been used for the initial fluid resuscitation of trauma patients. NS is composed of 154 mEq/L of sodium and 154 mEq/L of chloride. It has been chosen by some trauma systems in part because of the concern that lactated Ringer’s (LR) solution may lead to clotting of blood filters when given with red blood cell (RBC) transfusions due to chelation of calcium by the citrate anticoagulant. This clotting phenomenon has not been well described and has not been problematic in centers primarily using LR. NS also has higher osmolarity than LR solution and therefore has a potential benefit in patients with severe brain injuries. However, large-volume resuscitation with NS can lead to hyperchloremic metabolic acidosis. Studies in elective surgical patients showed that patients receiving NS required more bicarbonate and had lower pH values after surgery than those receiving LR solution.
Ringer’s solution was originally developed by Sydney Ringer after laboratory experiments involving isolated frog hearts suspended in sodium chloride became contaminated with inorganic salts from the Thames River, and it was noticed that potassium and calcium increased contractility. The solution was later modified by Hartman by the addition of sodium lactate and is now known as LR solution. Use of LR solution for fluid resuscitation avoids the hyperchloremic metabolic acidosis that can result from NS. Clinical trials in elective surgical patients suggest that use of LR solution may lead to less blood loss compared with NS. Animal models of uncontrolled hemorrhagic shock show that LR solution resuscitation leads to less blood loss and more favorable effects on extravascular lung water index compared with resuscitation with NS.
LR solution is not approved by the American Association of American Blood Banks for infusion with packed RBCs because of the concern that calcium in the fluid may be chelated by citrate in the blood, leading to clotting of the filters. The clinical significance of this is unclear, and studies suggest that simultaneous LR solution resuscitation and rapid RBC infusion does not lead to increased clotting. In the 1980s, LR solution was found to cause neutrophil activation and studies subsequently showed that the d-isomer of lactate, which is not a part of normal human metabolism, was responsible for this activation. All currently used LR solutions contain only the l-isomer.
Plasma-Lyte is a balanced crystalloid solution that is sold commercially using a variety of different formulations around the world. It was designed to be a balanced solution and most formulations contain sodium, potassium, magnesium, and chloride, but not calcium. Acetate, gluconate, or lactate is present as a bicarbonate precursor. It does not lead to hyperchloremic acidosis and is safe to give with medications or blood products. Initial clinical studies focused on the use of Plasma-Lyte in cardiac surgery and transplant patients. There is no evidence that its theoretic advantages lead to improved outcomes in trauma patients compared with other crystalloids.
The Isotonic Solutions and Major Adverse Renal Events Trial (SMART) investigators studied the benefits of balanced fluid administration compared to NS in critically ill and non–critically ill patients. In their pragmatic, cluster-randomized, multiple-crossover trial of 15,802 patients, administration of NS was associated with major adverse kidney events, a composite outcome that included death from any cause, new renal-replacement therapy, or persistent renal dysfunction. The SALT-ED study group conducted a concurrent study at the same institution evaluating the impact of balanced crystalloid (LR or Plasma-Lyte) administration compared with NS on hospital-free days in patients who did not require ICU admission. In their study of 13,347 non–critically ill patients, there was no difference in hospital-free days between the balanced crystalloid group and the NS group. Secondary outcomes included major adverse kidney events within 30 days. Similar to the SMART study, balanced crystalloid administration was associated with a lower incidence of major adverse kidney events within 30 days.
Hypertonic saline (HS) has been studied extensively over the last few decades as a resuscitation fluid. It raises the serum oncotic pressure, drawing fluid from the interstitial space into the intravascular space, leading to increased blood pressure and improved microcirculatory blood flow. A smaller volume of fluid is required than with isotonic crystalloids. The osmotic effect also reduces intracranial pressure in patients with severe brain injury and may modulate the systemic inflammatory response after injury. Numerous animal studies using 3% or 5% HS have been performed, but clinical data in patients with hemorrhagic shock are lacking. One study showed that hypotensive trauma patients receiving 3% HS had adequate restoration of blood pressure and urine output, and another small study using 5% HS showed a trend toward decreased mortality rate in patients with severe brain injury. Neither solution has been evaluated in recent years in a randomized controlled trial.
Hypertonic saline-dextran (HSD) has been investigated more extensively in clinical trials. It is a mixture of 7.5% NaCl and 6% dextran-70. Dextran was added in an attempt to prolong the hemodynamic effects of hypertonicity. A number of trials of prehospital administration of HSD showed a trend toward increased survival, but statistical significance was not reached. Three meta-analyses by Wade et al were later conducted. One analysis showed an overall survival benefit in the HSD group and another showed a survival benefit for hypotensive patients with TBI. In 2003, a randomized trial of HSD versus LR solution administered in the prehospital setting to blunt injured patients with hypovolemic shock began patient enrollment. The study was stopped in 2005 after the second interim analysis for futility. It was hypothesized that the lack of improvement in outcome was at least partially explained by enrollment of patients with transient hypotension who were not truly in hemorrhagic shock. A subsequent trial by the Resuscitation Outcomes Consortium randomized patents with either hypovolemic shock or severe TBI to receive 7.5% saline, HSD, or NS in the prehospital setting. Enrollment in the shock cohort was suspended due to futility and a potential safety concern in the hypertonic group. Enrollment in the TBI group was later suspended for futility as well. Currently, HSD has not shown a significant clinical benefit for fluid resuscitation in the civilian trauma setting.
In summary, recent data show potential benefit for balanced salt solutions. However, data for other crystalloid fluids are quite limited. The critical care practitioner should consider this lack of data and the potential cost of alternatives when making decisions on resuscitation protocols.
Blood products
The management of patients in hemorrhagic shock has significantly changed over the past two decades with clinical evidence that supports the use of goal directed, blood product resuscitation. Studies have shown that trauma patients are frequently coagulopathic on presentation, and resuscitation strategies should focus on the restoration of blood volume and correction of traumatic coagulopathy. This includes the more liberalized use of plasma and platelets in hemorrhagic shock patients. The PROMMTT study was a prospective cohort study performed at 10 trauma centers across the United States that included 1245 trauma patients who required at least 1 unit of blood within the first 6 hours after admission. The results demonstrated decreased mortality in patients who received higher plasma-to-packed RBC and platelet-to-packed RBC ratios. The PROPPR trial was a pragmatic, randomized clinical trial across 12 trauma centers in the United States. The trial randomized severely injured patients who required blood product resuscitation to receive either a 1:1:1 ratio or a 1:1:2 ratio of plasma, platelets, and packed RBCs. Overall mortality at 24 hours and 30 days was similar between the two groups; however, more patients in the 1:1:1 group achieved hemostasis and fewer patients died from exsanguination. The results from these studies have been vital for the development of massive transfusion protocols and a standard of care for the hemorrhaging trauma patient.
The use of low-titer liquid cold-stored whole blood (LTOWB) has become increasingly common in civilian practice. This resuscitation inherently follows the balanced resuscitation suggested by the PROPPR trial and represents a logistically simple method of replacing lost blood volume. Transfusion of large volumes of LTOWB has been shown to be safe (Malkin et al. 2021; Gallaher et al. 2020) and possibly improves outcomes (Shea 2020). The hemostatic efficacy of LTOWB is affected by the age of the blood and whether or not it has been leuko-reduced. For these reasons, the use of LTOWB for massive transfusion may require adjunctive therapies to include plasma, platelets, and cryoprecipitate.
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