Balanced crystalloids for septic shock resuscitation

Timely fluid administration is crucial to maintain tissue perfusion in septic shock patients. However, the question concerning which fluid should be used for septic shock resuscitation remains a matter of debate. A growing body of evidence suggests that the type, amount and timing of fluid administration during the course of sepsis may affect patient outcomes. Crystalloids have been recommended as the first-line fluids for septic shock resuscitation. Nevertheless, given the inconclusive nature of the available literature, no definitive recommendations about the most appropriate crystalloid solution can be made. Resuscitation of septic and non-septic critically ill patients with unbalanced crystalloids, mainly 0.9% saline, has been associated with a higher incidence of acid-base balance and electrolyte disorders and might be associated with a higher incidence of acute kidney injury. This can result in greater demand for renal replacement therapy and increased mortality. Balanced crystalloids have been proposed as an alternative to unbalanced solutions in order to mitigate their detrimental effects. Nevertheless, the safety and effectiveness of balanced crystalloids for septic shock resuscitation need to be further addressed in a well-designed, multicenter, pragmatic, randomized controlled trial.


INTRODUCTION
Septic shock is characterized by intense systemic vasodilation with varying degrees of hypovolemia. (1) Timely fluid administration is crucial to improve cardiac output, restore oxygen delivery and reverse tissue hypoxia. (1) As a result, cellular and mitochondrial dysfunction as well as progression to multiple organ dysfunction syndrome secondary to systemic inflammation and tissue hypoperfusion are mitigated. (1) Therefore, fluid administration is recommended as a first-line intervention to resuscitate septic shock patients. (2) A growing body of evidence suggests that the type, amount and timing of fluid administration during the course of sepsis may affect patient outcomes. (3) While early fluid administration has been associated with decreased in-hospital mortality, (4) delayed resuscitation has been associated with a pronounced release of inflammatory mediators and decreased skeletal muscle adenosine triphosphate content and mitochondrial dysfunction. (5) Furthermore, liberal fluid administration to septic shock patients yields a net positive fluid balance, which may contribute to organ failure and poor outcomes. (6)  Timely fluid administration is crucial to maintain tissue perfusion in septic shock patients. However, the question concerning which fluid should be used for septic shock resuscitation remains a matter of debate. A growing body of evidence suggests that the type, amount and timing of fluid administration during the course of sepsis may affect patient outcomes. Crystalloids have been recommended as the first-line fluids for septic shock resuscitation. Nevertheless, given the inconclusive nature of the available literature, no definitive recommendations about the most appropriate crystalloid solution can be made. Resuscitation of septic and non-septic critically ill patients with unbalanced crystalloids, mainly 0.9% saline, has been associated with Conflicts of interest: None.
Submitted on June 22, 2016 Accepted on August 8, 2016 a higher incidence of acid-base balance and electrolyte disorders and might be associated with a higher incidence of acute kidney injury. This can result in greater demand for renal replacement therapy and increased mortality. Balanced crystalloids have been proposed as an alternative to unbalanced solutions in order to mitigate their detrimental effects. Nevertheless, the safety and effectiveness of balanced crystalloids for septic shock resuscitation need to be further addressed in a well-designed, multicenter, pragmatic, randomized controlled trial.
Many types of fluids are available for clinicians at the bedside. (3) Nevertheless, since the type and amount of administered fluids affect patient-centered outcomes, (7,8) such drugs should be prescribed with caution. (3) Moreover, it is important to emphasize that fluid administration should be indicated only for those who have impaired tissue perfusion and are deemed fluid responsive (i.e., patients with a high likelihood of improving cardiac output after fluid administration). (9) Whenever fluids are judged necessary, clear endpoints of efficacy and safety must be defined in advance in order to maximize the efficacy of the fluids administered and minimize their potential detrimental effects. (9) The question concerning which fluid should be used during septic shock resuscitation remains a matter of debate. (10) The current Surviving Sepsis Campaign Guidelines recommend crystalloids as first-line fluids for septic shock resuscitation. (2) Nevertheless, no consensus has been reached regarding which crystalloid, i.e., unbalanced or balanced, is the most appropriate in this context. (11) This narrative review briefly discusses the main physicochemical properties of unbalanced and balanced crystalloids as well as their main advantages and drawbacks. It also presents evidence supporting balanced crystalloids as the fluids of choice for septic shock resuscitation. ). (12) The search retrieved 433 references. After title and abstract screening, we selected the full-text versions of 95 relevant citations for a thorough analysis. We also searched reference lists of the retrieved manuscripts to identify other relevant studies.

CRYSTALLOIDS
Solutions containing water and freely permeable ions, mainly sodium and chloride, are classified as crystalloids (Table 1). (3) Some of these solutions have other ions, such as potassium, calcium or magnesium, and may have buffers, most commonly bicarbonate, lactate, acetate or gluconate, to maintain electroneutrality (balance between positive and negative ions). (3) Crystalloid solutions may be hypotonic, isotonic or hypertonic in relation to human plasma. (3) A crystalloid solution is considered balanced when it has a strong ion difference (SID) close to 24mEq/L, (13) which can be achieved by replacing varying amounts of chloride from 0.9% saline with bicarbonate, lactate or acetate (Table 1). (3)
Healey et al. (15) Moderate hemorrhage and massive hemorrhage (35% and 218% of TBV removed, respectively) in rats 0.9% saline Ringer's lactate No acid-base difference in moderate hemorrhage. In massive hemorrhage, less acidosis and improved survival with Ringer's lactate compared to 0.9% saline.
Todd et al. (17) Uncontrolled hemorrhagic shock in pigs 0.9% saline Ringer's lactate Less Ringer's lactate than 0.9% saline was necessary to restore baseline MAP. Higher urinary output with 0.9% saline than Ringer's lactate. Higher incidence of hyperchloremic acidosis and lower fibrinogen levels with 0.9% saline than with Ringer's lactate.
Noritomi et al. (18)   charge to sustain the electrical neutrality (Law of electroneutrality). The balancing anionic charge is derived from nonvolatile weak acids, mainly albumin and phosphate. (43) Infusion with large amounts of 0.9% saline produces hyperchloremic metabolic acidosis in healthy volunteers and in different populations of critically ill patients (Table 3). Hyperchloremic metabolic acidosis occurs because 0.9% saline contains strong cations and strong anions in the same quantity (SID equal to zero). When the plasma chloride concentration increases after 0.9% saline infusion, the net positive charge of plasma (SID) is reduced. Conversely, compensatory mechanisms designed to maintain the plasma electro-neutrality are activated, thus increasing the plasma positive charge (H + ) while decreasing the arterial pH. (43)

Balanced crystalloids
Balanced crystalloids have been proposed as an alternative to unbalanced solutions in order to mitigate their detrimental effects. (3) The most commonly available balanced crystalloids are presented in table 1. Ringer's lactate is produced by adding sodium lactate as a buffer to Ringer's solution to reduce its chloride concentration ( Table 1). Concerns that large amounts of Ringer's lactate infusion can increase plasma lactate levels in critically ill patients have led to the development of Ringer's acetate, in which the lactate buffer is replaced by acetate. (30) Thus, the composition of Ringer's lactate and Ringer's acetate is almost identical with the exception of the added buffer (lactate or acetate, respectively) ( Table 1).
Plasma-Lyte is another balanced solution with an osmolality of 294mOsm/L and sodium and chloride concentrations of 140mmol/L and of 98mmol/L, respectively. Other electrolytes and buffers present in this solution include potassium, magnesium, acetate and gluconate (Table 1). In the next sections, the current evidence comparing balanced and unbalanced crystalloids in experimental models ( Table 2) as well as in clinical studies involving healthy volunteers and septic and nonseptic critically ill patients (Table 3) is presented.
Plasma-Lyte was compared to 0.9% saline only in one experimental model of abdominal sepsis ( Table 2). (14) In this study, rats were randomly allocated to resuscitation with either Plasma-Lyte or 0.9% saline, subcutaneously, eighteen hours after a cecal ligation and puncture. (14) Resuscitation with Plasma-Lyte was associated with maintained plasma chloride levels and arterial pH, lower plasma creatinine, lower urinary cystatin C, lower neutrophil gelatinase-associated lipocalin (NGAL), lower plasma interleukin-6 (IL-6), lower incidence (and severity) of acute kidney injury and a higher survival rate than animals resuscitated with 0.9% saline. Serum potassium levels, which are a major concern related to balanced crystalloids containing potassium, did not differ between the groups. (14)

STUDIES INVOLVING HEALTHY VOLUNTEERS
Four randomized crossover studies addressed the effects of 0.9% saline, Plasma-Lyte, Ringer's lactate or Hartmann's solution on acid-base balance and electrolyte disorders in healthy volunteers. (44)(45)(46)(47) All studies reported hyperchloremic metabolic acidosis following a 0.9% saline infusion. (44)(45)(46)(47) While 50mL/kg of Ringer's lactate infusion transiently decreased serum osmolality and increased venous pH in healthy volunteers, a lower urinary output was seen after the same amount of 0.9% saline infusion. (44) In another study, Reid et al. infused two liters of 0.9% saline or Hartmann's solution for two hours in healthy volunteers on two separate occasions. (45) In addition to a more pronounced and sustained intravascular volume expansion with 0.9% saline than with Hartmann's solution, urinary output was lower with 0.9% saline than with Hartmann's solution. (45) The same group compared 0.9% saline with Plasma-Lyte (two liters within one hour) in twelve healthy volunteers on two separate occasions (up to 10 days apart). (46) In this study, Plasma-Lyte and 0.9% saline produced similar intravascular volume expansion. Nevertheless, 0.9% saline yielded sustained hyperchloremia, reduced SID, increased extravascular volume (edema) and lowered diuresis compared with Plasma-Lyte. (46) Additionally, renal artery flow velocity and renal cortical perfusion assessed with magnetic resonance imaging were significantly lower after 0.9% saline administration than after Plasma-Lyte. There was no difference in urinary NGAL. (46)
A chloride-liberal strategy was compared with a chloride-restrictive strategy among critically ill adult patients in a before-after study. (50) During a six-month control period (chloride-liberal period), 760 patients received intravenous fluids (0.9% saline, 4% succinylated gelatin solution or 4% albumin) according to the clinician's preference. After a 6-month interval, 773 patients received only chloride poor fluids (Hartmann's solution, Plasma-Lyte or 20% albumin). (50) The authors demonstrated a significant decrease in acute kidney injury and failure (from 14.0% to 8.4%; p < 0.001) according to RIFLE classification and the need for RRT (from 10.0% to 6.3%; p = 0.005). No differences in in-hospital mortality or other clinical outcomes were observed. (50) Contradictory findings were presented in a retrospective cohort study including 53,448 septic patients. (48) In this observational study, resuscitation with balanced crystalloids, but not with unbalanced crystalloids, was associated with decreased risk of in-hospital mortality (RR, 0.86; 95%CI, 0.78 to 0.94; p = 0.001). Nevertheless, no significant difference in the incidence of acute kidney injury, need for RRT, and hospital and ICU lengths of stay was reported. (48) A propensity-matched cohort study with 3,116 hospitalized patients with a systemic inflammatory response syndrome (SIRS) showed that balance crystalloids (Plasma-Lyte or Normosol), compared with 0.9% saline, were associated with a lower rate of major complications (atrial fibrillation, congestive heart failure, acute respiratory failure, pneumonia, sepsis and coagulopathy), a lower frequency of electrolyte abnormalities and hyperchloremic acidosis, shorter length of hospital stay, less need for hospital re-admission, and lower in-hospital mortality. (51) Nevertheless, the incidence of acute kidney injury did not differ between the groups studied. (51) Several small randomized trials compared balanced crystalloids with 0.9% saline (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37) (Table 3). In most trials, 0.9% saline induced hyperchloremic metabolic acidosis compared with either Ringer's lactate or Plasma-Lyte (Table 3). The effect of 0.9% saline versus Plasma-Lyte on coagulation (thromboelastography) was recently evaluated in eighteen trauma patients. (27) The time from 2 to 20mm amplitude (K) was shorter, and the α angle higher after intravascular expansion with Plasma-Lyte than with 0.9% saline. (27) Coagulation derangements secondary to crystalloid infusion may have clinical implications, as suggested by another study involving 66 patients undergoing aortic reconstructive surgery. (24) In this study, patients who received 0.9% saline needed more platelets and blood product transfusion than did those who received Ringer's lactate. (24) The effect of intravascular volume expansion with low-chloride versus high-chloride content crystalloids in critically ill or surgical patients was recently addressed in a meta-analysis. (53) Twenty-one studies (15 randomized controlled trials) with 6,253 patients were included. Although high-chloride containing crystalloids did not affect mortality, they increased the risk of hyperchloremia and metabolic acidosis (risk ratio, 2.87; 95%CI, 1.95 to 4.21; p < 0.001) and the risk of acute kidney injury (risk ratio, 1.64; 95%CI, 1.27 to 2.13; p < 0.001). (53) Finally, there was an increase in blood transfusion volume following resuscitation with 0.9% saline compared with low-chloride crystalloids. (53) In summary, the current literature suggests that resuscitation of septic and non-septic critically ill patients with unbalanced crystalloids, mainly 0.9% saline, is associated with a higher incidence of acid-base balance and electrolyte derangements. Most importantly, resuscitation with unbalanced crystalloids might be associated with increased bleeding risk, an increased need for transfusion, a higher incidence of acute kidney injury, an increased need for RRT and increased mortality.

FUTURE DIRECTIONS
Although it appears that all crystalloid solutions have similar hemodynamic effects, (10) the impact of intravascular volume expansion with balanced solutions on regional and microcirculatory blood flow, tissue perfusion, mitochondrial function, systemic inflammation and coagulation need to be further evaluated in both experimental and clinical studies. (10) Furthermore, this review, as with any non-systematic narrative review, may have limitations in terms of the comprehensiveness of the search strategy used to identify relevant papers and the lack of standardization of methods for data extraction, analysis and interpretation. Thus, systematic reviews with meta-analysis on the subject are warranted.

CONCLUSION
Adequate fluid replacement is crucial to maintain perfusion pressure and, ultimately, tissue perfusion in septic shock patients. Although the current sepsis guidelines recommend crystalloids as first-line fluids for septic shock resuscitation, in the light of the inconclusive nature of the available literature, no definitive recommendations on the most appropriate crystalloid solution can be made. Therefore, the safety and efficacy of balanced solutions, compared with 0.9% saline, for septic shock resuscitation should be further evaluated in a large, multicenter, pragmatic, randomized clinical trial.