Fluid Management in Critically Ill Surgical Patients

The administration of intravenous (IV) fluids for resuscitation and shock management is a fundamental component of the management of almost all surgical and critically ill patients in intensive care units (ICU). However, there is still longstanding debate over the optimal composition of IV fluids that should be used in the resuscitation of acutely and critically ill patients.

When the cause of shock is hemorrhagic, the PROPPR (Pragmatic, Randomized Optimal Platelet and Plasma Ratios) randomized control trial confirmed that the ideal resuscitation strategy is balanced hemostatic resuscitation with the administration of packed red blood cells, fresh frozen plasma, and platelets.¹ When hypotension is not caused by blood loss, but instead most commonly due to hypovolemia and sepsis, significant debate remains over the optimal IV resuscitation fluid that should be given. Many different IV fluids with different compositions are available for use in fluid resuscitation (see Table 1). Crystalloid solutions with electrolyte compositions closer to that of plasma (balanced crystalloids, such as lactated Ringer’s solution or PlasmaLyte) represent an increasingly used alternative to saline in critically ill patients.

For patients undergoing major surgery, randomized trials have confirmed that balanced crystalloids cause less hyperchloremic metabolic acidosis and reduce the need for vasopressors²; however, no difference in the rate of acute kidney injury or mortality was found in three randomized clinical trials.^3-5

In contrast, observational^6,7 and retrospective⁸ studies in critically ill patients found that IV 0.9 percent saline resuscitation was associated with hyperchloremic metabolic acidosis, higher rates of acute kidney injury, need for renal replacement therapy, and death. The use of balanced crystalloids in critically ill patients was associated with lower rates of acute kidney injury, renal-replacement therapy, and death.  A meta-analysis of studies (21 studies, n=6253) in 2015 comparing high-chloride versus low-chloride content crystalloids in perioperative and critical care fluid resuscitation reported that high-chloride fluids were associated with significantly higher risk for acute kidney injury (RR 1.64, CI 1.27 to 2.13; P < 0.001) and hyperchloremia/metabolic acidosis (RR 2.87, CI 1.95 to 4.21; P < 0.001), but no difference in mortality.⁹

The recent publication of multiple large randomized clinical trials that compared fluid resuscitation using balanced crystalloid solutions with 0.9 percent sodium chloride in critically ill adult patients (including surgical patients) has provided additional high-quality data on this important topic (Table 2 and 3). In this article, we will discuss the results of these trials to inform our optimal clinical practice.

IV Fluid Composition Studies

SPLIT Trial

The SPLIT (0.9 percent Saline vs Plasma-Lyte 148 (PL-148) for ICU fluid Therapy) trial¹⁰ was a double-blind RCT that randomized adult ICU patients (n=2,278) across four ICUs in New Zealand to receive PlasmaLyte versus 0.9 percent saline. There was a median two liters IV fluid administered in each arm. No difference in 90-day acute kidney injury, renal replacement therapy, or in-hospital mortality was identified.  

SALT and SALT-ED Trials

The SALT (Saline against Lactated Ringer’s or Plasma-Lyte) trial¹¹ was a pilot study that compared balanced crystalloids versus saline in 974 adult patients in a single medical ICU, most admitted from the emergency department with sepsis. No difference in mortality was noted, but there was a lower rate of Major Adverse Kidney Event at 30 days (MAKE30, death from any cause, new renal-replacement therapy, or persistent renal dysfunction) with balanced crystalloids in sepsis patients and those who received larger volumes of IV fluids. The SALT-ED (Saline against Lactated Ringer’s or Plasma-Lyte in the Emergency Department) trial¹² randomized 13,347 emergency department patients at a single center who required IV fluid resuscitation to balanced crystalloids or saline.  No difference in the primary outcome of hospital-free days was noted, but balanced crystalloids had a significantly lower rate of MAKE30, and this was greatest among the subgroup of patients who had an elevated plasma creatinine on presentation and in patients with hyperchloremia. Limitations of these two trials include the open label design and initiation of renal replacement therapy (RRT) was determined by the treating clinicians.

SMART Trial

The SMART (Isotonic Solutions and Major Adverse Renal Events) trial¹³ was a non-blinded RCT that randomized critically ill adults (n=15,802) across five ICUs in a single U.S. academic center (Vanderbilt). IV fluids were alternated monthly between balanced crystalloid (lactated Ringer’s solution or PlasmaLyte A) and 0.9 percent saline, beginning in the emergency department and continued in the ICU. Balanced crystalloids resulted in a lower rate of the composite outcome MAKE30 compared to saline (14.3 percent versus 15.4 percent, OR 0.91, p = 0.04). Interestingly, the difference in the composite outcome (MAKE30) was driven by death (OR 0.9; 95 percent CI 0.80 – 1.01) and RRT (OR 0.84; 95 percent CI 0.68-1.02) and not by changes in creatinine. No difference in need for dialysis (2.9 percent saline versus 2.5 percent) or persistent renal dysfunction (6.6 percent versus 6.4 percent) was noted. In the surgical patient planned subgroup analysis, no difference in MAKE30 was identified (11.4 percent versus 12.2 percent).

Subgroup analysis confirmed that normal saline was associated with increased mortality among patients with sepsis (29.4 percent versus 25.2 percent; p=0.02) or chronic dialysis (18.4 percent versus 12.2 percent; p=0.01). Furthermore, the difference in outcomes between balanced crystalloids and saline was greater for patients with sepsis and patients who received larger volumes of crystalloid. A post-hoc analysis of sepsis medical ICU patients (n=1,641) reported higher 30-day in-hospital mortality in the saline group (31.2 percent versus 26.3percent, OR 0.74, CI 0.59 – 0.93, p = 0.001), with a number needed to treat with balanced crystalloids to prevent one death of 20.¹⁴  

BaSICS Trial

The BaSICS (Balanced Solution versus Saline in Intensive Care Study) trial¹⁵ was conducted in hopes to settle the divergent results of the SPLIT and SMART trials discussed above. BaSICS was a multicenter double-blind RCT that randomized adult ICU patients (n=11,052) on the first ICU day in 75 ICUs in Brazil to balanced crystalloid (PlasmaLyte 148) versus 0.9 percent saline for all ICU fluid administration (boluses, maintenance, and carriers) with a primary outcome measure of 90-day all-cause mortality.  There was no significant different in 90-day mortality (26.4 percent PlasmaLyte versus 27.2 percent 0.9 percent saline; p=0.47). Subgroup analysis showed no statistically significant difference in acute kidney injury (27 percent versus 27 percent) or need for dialysis (1 percent versus 1 percent). Subgroup analysis also confirmed higher mortality in patients with traumatic brain injury who received balanced crystalloids (31.3 percent PlasmaLyte 148 versus 21.1 percent normal saline; hazard ratio 1.48, 95 percent CI 1.03 – 2.12, p=0.02).

Unlike the SMART trial, the BaSICS trial failed to demonstrate decreased mortality, AKI, or need for RRT with the use of balanced crystalloid. Significant limitations of the BaSICS trial are the low volume of IV fluid administered (median 1.5 L on the first ICU day), low severity of illness and approximately 80 percent compliance with study fluid administration (compared to 95 percent in the SMART trial). Additionally, 48 percent of the cohort were ICU admissions after elective surgery, with low severity of illness and low risk of acute kidney injury. In contrast, the SMART trial enrolled mostly unplanned ICU admissions with higher severity of illness and fewer elective surgical patients. The BaSICS trial, however, had a much higher in-hospital mortality rate (23 percent) compared to the SMART trial (11 percent). 

Rate of IV Fluid Administration

The BaSICS trial¹⁶ also studied the rate of bolus IV crystalloid infusion (333 versus 999 ml/hr), and there was no significant difference in 90-day mortality between the slower infusion group versus the rapid infusion cohort (26.6 percent versus 27 percent; p=0.46).

Systematic Reviews

A systematic review of intervention trials of critically ill adult patients (n=26,351 in 58 trials) who required fluid resuscitation separately examined outcomes in surgical, trauma, traumatic brain injury, and sepsis patient cohorts. For surgery and sepsis patients, balanced crystalloids and albumin were associated with increased survival, decreased red blood cell transfusion volume, and decreased acute kidney injury. In patients with traumatic brain injury, saline was associated with decreased mortality compared to albumin and balanced crystalloids.¹⁷  This systematic review, however, did not include the recently published BaSICS trial.

Future Studies

Additional data will soon be available from the multicenter Plasma-Lyte 148 versUs Saline Study (PLUS) from the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS), as it has recently completed enrollment (n=5,037).  Adult ICU patients receiving an IV fluid bolus for evidence of hypovolemia were randomized to receive either PlasmaLyte 148 or 0.9 percent normal saline for all crystalloid therapy and all resuscitation episodes for up to 90 days after randomization. The primary outcome measure of the PLUS multicenter blinded RCT is all-cause 90-day mortality, so it will provide comparable data to the BaSICS trial.^18-20 Importantly, the PLUS study excluded patients with traumatic brain injury and those at risk for developing cerebral edema based on potential harm with balanced crystalloids identified in the other clinical trials. Another study, BEST-FLUIDS (Better Evidence for Selecting Transplant Fluids), is a multicenter, double-blind RCT comparing PlasmaLyte 148 versus 0.9 percent saline on the incidence of delayed graft function in deceased donor kidney transplant recipients (n=800).²¹

Conclusion and Clinical Recommendations

Almost all patients in the ICU receive IV fluids, but what fluids are best based on the studies to date? Given the divergent outcomes of the two largest trials (SMART and BaSICS) with different primary outcome measures (MAKE30 versus 90-day mortality) and enrollment of different patient populations (higher severity of illness, less elective surgical patients in SMART versus lower severity of illness and more elective surgical patients in BaSICS), how should these data impact our clinical practice?

First, all trials to date and the latest systematic review have confirmed a clear significant benefit to 0.9 percent saline in traumatic brain injury (TBI) patients (Figure 1). Second, if the patient is likely to receive two liters of IV fluid or less and has no risk factors for acute kidney injury (like many of our elective surgical patients), then either crystalloid (balanced or saline) is likely safe.   

Figure 1. Optimal Resuscitation IV Fluids in Adult Critical Care

Importantly, current evidence points towards using balanced crystalloid over saline for resuscitation in the most acutely and critically ill patients who will require greater than two liters or have risk for AKI (emergent surgical patients, unplanned ICU admission), with the exception of those with traumatic brain injury. SMART also confirmed a significant benefit to balanced crystalloids in medical, sepsis, and previous RRT patients.

Given the findings of the SMART and SALT-ED trials (increased risk of acute kidney injury with the use of 0.9 percent saline compared to Lactated Ringer’s/Hartmann’s) and no difference in overall mortality or AKI in the SPLIT and BaSICs trials (both used Plasmalyte), it may be that the specific type of balanced crystalloid (Plasmalyte or Lactated Ringer’s) also affected outcomes. The upcoming results of the PLUS trial, which compared Plasmalyte to saline, will provide additional information regarding this important issue.  

Critiques of all of these trials point to the low level of illness severity among participants, the low volumes of resuscitation fluid administered, relatively low risk of acute kidney injury, and differences in study fluid adherence amongst the trials. Understanding the nuances of these trial results is important, and we eagerly await the results of additional large clinical trials investigating this very important topic that impacts almost all of our surgical and critically ill and injured patients.

References

1. Holcomb JB, Tilley BC, Baraniuk S, et al; PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients in severe trauma: the PROPPR randomized control trial. JAMA. 2015; 313(5):471-482.
2. Pfortmueller CA, Funk GC, Reiterer C, et al. Normal saline versus a balanced crystalloid for goal-directed perioperative fluid therapy in major abdominal surgery: a double blind randomised controlled study. Br J Anaesth. 2018;120:274–283.
3. McIlroy D, Murphy D, Kasza J, Bhatia D, Wutzlhofer L, Marasco S. Effects of restricting perioperative use of IV chloride on kidney injury in patients undergoing cardiac surgery: the LICRA pragmatic controlled clinical trial. Intensive Care Med. 2017 Jun; 43(6):795-806.
4. Maheshwari K, Turan A, Makarova N, et al. Saline versus Lactated Ringer’s Solution. The Saline or Lactated Ringer’s (SOLAR) Trial. Anesthesiology. 2020; 132(4):614–624. 10.1097/ALN.0000000000003130
5. Weinberg L, Li MH, Churilov L, et al. The effects of 0.9 percent saline versus Plasma-Lyte 148 on renal function as assessed by creatinine concentration in patients undergoing major surgery: A single-centre double-blinded cluster crossover trial. PLoS One. 2021;16(5):e0251718. Published May 19, 2021. doi:10.1371/journal.pone.0251718
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7. Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9 % saline compared to Plasma-Lyte. Ann Surg 2012;255:821–829.
8. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive IV fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308:1566–1572.
9. Krajewski ML, Raghunathan K, Paluszkiewicz SM, Schermer CR, Shaw AD. Meta-analysis of high versus low-chloride content in perioperative and critical care fluid resuscitation. Br J Surg. 2015;102 (1):24-36. doi:10.1002/bjs.9651
10. Young P, Bailey M, Beasley R, et al. Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial. JAMA. 2015;314:1701–1710.
11. Semler MW, Wanderer JP, Ehrenfeld JM, et al.; SALT Investigators; Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in the intensive care unit: the SALT randomized trial. Am J Respir Crit Care Med. 2017;195:1362–1372.
12. Self WH, Semler MW, Wanderer JP, et al.; SALT-ED Investigators. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378:819–828.
13. Semler MW, Self WH, Wanderer JP, et al; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378:829–839.
14. Brown RM, Wang L, Coston TD, et al; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in sepsis: a secondary analysis of the SMART clinical trial. Am J Respir Crit Care Med. 2019;200:1487–1495.
15. Zampieri FG, Machado FR, Biondi RS, et al. Effect of IV Fluid Treatment with a Balanced Solution vs 0.9percent Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA. 2021;326(9):818–829. doi:10.1001/jama.2021.11684.
16. Zampieri FG, Machado FR, Biondi RS, et al. Effect of Slower versus Faster IV Fluid Bolus Rates on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA. 2021;326(9):830–838. doi:10.1001/jama.2021.11444
17. Tseng CH, Chen TT, Wu MY, Chan MC, Shih MC, Tu YK. Resuscitation fluid types in sepsis, surgical and trauma patients: A systematic review and sequential network meta-analyses. Critical Care. 2020;24:693. https://doi.org/10.1186/s13054-020-03419-y
18. https://clinicaltrials.gov/ct2/show/NCT02721654
19. https://www.georgeinstitute.org/projects/plasma-lyte-148r-versus-saline-plus-study
20. Hammond NE, Bellomo R, Gallagher M, et al. The Plasma-Lyte 148 v Saline (PLUS) study protocol: a multicentre, randomised controlled trial of the effect of intensive care fluid therapy on mortality. Crit Care Resusc. 2017;19:239–246.
21. Billot L, Bellomo R, Gallagher M, et al, on behalf of the PLUS Study Investigators and the ANZICS Clinical Trials Group. The Plasma-Lyte 148 versus Saline (PLUS) statistical analysis plan: A multicenter, randomized controlled trial of the effect of intensive care fluid therapy on mortality. Crit Care Resusc. 2021;23(1):24-31.
22. Collins MG, Fahim MA, Pascoe EM, BEST-Fluids Investigators and the Australasian Kidney Trials Network. Study Protocol for Better Evidence for Selecting Transplant Fluids (BEST-Fluids): A pragmatic, registry-based, multi-center, double-blind, randomized controlled trial evaluating the effect of IV fluid therapy with Plasma-Lyte 148 versus 0.9 percent saline on delayed graft function in deceased donor kidney transplantation. Trials. 2020 May 25;21(1):428. doi: 10.1186/s13063-020-04359-2. PMID: 32450917; PMCID: PMC7249430.

Leonard G. Gomella, MD, FACS is the Bernard W. Godwin Professor of Prostate Cancer; Chairman, Department of Urology; Senior Director Clinical Affairs, Sidney Kimmel Cancer Center, Thomas Jefferson University. Vice-president for Urology Jefferson Health, Philadelphia, PA.

Veda N. Giri, MD, is a professor, medical oncology, cancer biology, and urology; director, cancer risk assessment and clinical cancer genetics. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.

James Ryan Mark, MD, is an assistant professor, department of urology; director of clinical trials; medical director, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.

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