SGEM#368: Just A Normal Saline Day in the ICU – The PLUS Study

Date: June 12th, 2022 Reference: Finfer et al. Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults. NEJM 2022. Guest Skeptic: Dr. Aaron Skolnik is an Assistant Professor of Emergency Medicine at the Mayo Clinic Alix School of Medicine and Consultant in the Department of Critical Care Medicine at Mayo Clinic Arizona.  He is board certified in Emergency Medicine, Medical Toxicology, Addiction Medicine, Internal Medicine-Critical Care, and Neurocritical Care.  Aaron is a full-time multidisciplinary intensivist.  He is the Medical Director of Respiratory Care for Mayo Clinic Arizona and is most proud of his position as medical student clerkship director for critical care. Case: A 62-year-old man is brought in by EMS from home with lethargy and hypotension.  Chest x-ray is clear, labs are remarkable for a leukocytosis of 16,000 with left shift; exam is notable for left flank pain and costovertebral tenderness.  Straight catheter urinalysis is grossly cloudy, and pyuria is present on microscopy.  Blood pressure is 85/50 mmHg.  You wonder which IV fluid should you order? Background:  There has been a longstanding debate about which intravenous fluid is the best for volume resuscitating critically ill patients.  We’ve known for some time that albumin is bad for injured brains, and that hydroxyethyl starch solutions have been associated with kidney injury and mortality.  Since then that debate has broadly centered on the choice between what we will call “abnormal saline” (0.9% sodium chloride), and balanced crystalloid solutions, meaning those with a chloride composition closer to plasma such as lactated ringer’s or Plasma Lyte 148. Early work suggested potential harm from 0.9% saline, that may be partly driven by kidney injury associated with the administration of high-chloride content IV fluids. In the last few years, the pendulum has swung back and forth.  Two large, cluster-randomized trials (SMARTand SALT-ED) showed a small benefit to the use of balanced crystalloids in preventing a composite outcome of Major Adverse Kidney Events within 30 days (aka MAKE-30). Then, the BaSICS trial (a multicentred RCT done in 75 Brazilian ICUs) came along and compared saline to Plasma-Lyte at what the authors deemed slow and fast infusion rates.  We reviewed that last time on SGEM#347. There was no interaction between fluid type or rate of infusion with the primary outcome of 90-day survival.  Among 19 secondary outcomes, which should only be considered hypothesis generating, SOFA scores and neuro SOFA scores at day seven were worse in the balanced crystalloid group. Now we have the PLUS trial, from Australia and New Zealand to add to the medical literature on this issue. Clinical Question: Is the 90-day mortality in critically ill adult patients lower with the use of Plasma-Lyte 148, a balanced crystalloid solution, for fluid resuscitation and therapy, than with the use of normal saline? Reference:  Finfer et al. Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults. NEJM 2022. Population: Patients 18 years or older, admitted to 53 ANZ ICUs over 38 months, whom the treating clinician deemed to need fluid resuscitation and were expected to be in the ICU on three consecutive days. Exclusions: Patients with specific ICU fluid requirements, those who received disqualifying fluid prior to enrollment (> 500 mL in the ICU), those at imminent risk for death or with life expectancy < 90 days, and those at risk for cerebral edema. Intervention: Plasma-Lyte 148 for all resuscitation episodes while in ICU for up to 90 days after the first episode of fluid resuscitation Comparison: 0.9% saline for all resuscitation episodes while in ICU for up to 90 days after the first episode of fluid resuscitation Outcome: Primary Outcome: All-cause mortality within 90 days after randomization Secondary Outcomes: Peak serum creatinine level during the first seven days after randomization, the maximum increase in creatinine level during ICU stay, receipt of new renal-replacement therapy, receipt and duration of treatment with vasoactive drugs, duration of mechanical ventilation in the ICU, length of ICU and hospital stays, and death from any cause during ICU stay, during hospital stay, and within 28 days after randomization. Trial: Double-blind, parallel-group, randomized, controlled trial. Authors’ Conclusions: “We found no evidence that the risk of death or acute kidney injury among critically ill adults in the ICU was lower with the use of [Plasmalyte 148] than with saline.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. Yes The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). Yes The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes All groups were treated equally except for the intervention. No Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. Yes Financial conflicts of interest. Yes Results: They recruited 5,037 patients from 53 ICUs in Australia and New Zealand. The mean age was 62 years, 39% female, 76% had invasive mechanical ventilation, and a median APACHE score of 19. Key Result: No statistical difference in all-cause mortality within 90 days. Primary Outcome: All-cause mortality within 90 days after randomization 21.8% Plasma-Lyte 148 group vs 22.0% saline group Absolute difference of −0.15 percentage points (95% CI, −3.60 to 3.30; P=0.90) Odds Ratio of 0.99 (95% CI, 0.86 to 1.14) Secondary Outcomes: Over the first seven days after randomization, arterial blood pH was higher, and the serum chloride level was lower in the balanced crystalloid group. Both achieved statistical significance, though the absolute difference was probably not clinically meaningful.  Over that same time period, there were no significant differences in mean heart rate, mean arterial pressure, mean central venous pressure, creatinine, hemoglobin, and lactate between groups. Measures of organ failure including rise in creatinine and need for renal replacement therapy were similar between groups.  There was also no significant difference in days alive free of the vent, free of renal replacement, outside of the ICU, or outside of the hospital.  Adverse events did not differ between groups. We reached out to the lead author Dr. Simon Finfer. He was kind enough to send a brief responses to our five nerdy questions. 1) Recruitment: The trial was originally designed to recruit a sample size of 8,800 patients.  Due to COVID-19, the recruitment stopped at just over 5,000 patients.  Do you think this influenced the trial results in any meaningful way? “NO - this was covered in paper and supplementary figure S11 2) Fluids: More than half of the patients in the balanced crystalloid group received more than 500 mL of normal saline, mostly because of medications that could not be mixed in balanced solution.  How might this have swayed the trial result and what did the authors do to account for this? “We did several secondary analyses that did not alter the results. They are all in table 2 - see attached which is convincing that going on further to 8800 or even more would not have produced a different result” 3) Brain Injury: The authors didn’t test balanced crystalloid solution in TBI patients or others thought to be at risk for cerebral edema.  What do you think about balanced versus saline in this group?  Is this population the clinical stronghold of normal saline? “The BaSICS study validates our decision not to expose patients with TBI to PL148 which has higher tonicity than other balanced fluids but still lower than NS. Patients with TBI should get NS. 4) Small Effect Size: The trial is a “negative” one, but as the authors point out in their discussion, their results also allow for up to a 3% increase or decrease in the risk of death or new renal replacement associated with balanced crystalloid administration.  Is that an acceptable level of uncertainty about effect?  How do you apply those confidence intervals to patient care? “See answer to point 1 and below”  5) Other Evidence: There is a recent systematic review and meta-analysis published in NEJM Evidence examining 13 RCTs and over 35,000 patients comparing balanced crystalloid to saline in critically ill adults.  That SRMA concluded “The estimated effect of using balanced crystalloids versus saline in critically ill adults ranges from a 9% relative reduction to a 1% relative increase in the risk of death, with a high probability that the average effect of using balanced crystalloids is to reduce mortality.”  What do you think of the SRMA and how do you integrate all of this recent evidence into your clinical practice? “Well, as I am the corresponding author for that paper, I think it is quite good. The overall message is that balanced solutions are probably better overall, but the effect is small, for patients with a low risk of death the absolute effect is very small indeed. Patient with TBI and possibly other acute brain pathologies should get normal saline or a fluid of equal tonicity. We are conducting a patient level meta-analysis which will allow us to look at subgroups’ effects in more detail (I am the senior author for that as well). We have all the data and hope to publish by the end of this year.”