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Date: September 28th, 2021
Reference: Zampieri et al. Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA 2021
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. Board certified in Emergency Medicine, Medical Toxicology, Addiction Medicine, Internal Medicine-Critical Care, and Neurocritical Care, Aaron practices full time as a multidisciplinary intensivist. He is the Medical Director of Respiratory Care for Mayo Clinic Arizona and serves proudly as the medical student clerkship director for critical care medicine.
Case: A 66-year-old woman 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 mm Hg. You wonder which intravenous (IV) fluid should you order?
Background: In ten seasons of the SGEM we have not covered the issue of which IV solution is the best in critical ill patients. That includes both trauma patients and septic patients. The controversy has been long standing with the standard joke being that there is nothing “normal” about normal saline. Saline is a hypertonic acidotic fluid.
Many critically ill patients receive intravenous crystalloids for volume expansion as part of their resuscitation. Some bench work, observational studies, and now two large, unblinded, cluster-randomized single-center trials (SMART and SALT-ED) suggested a benefit to using balanced crystalloids (i.e. Lactated Ringer’s or Plasmalyte 148) over 0.9% saline.
In the two large trials, this benefit was seen as a reduction in a composite outcome of major adverse kidney events within 30 days (MAKE-30). In the non-blinded SMART trial, there was no statistical difference in the individual components of the composite outcome (in-hospital death before 30 days, new renal replacement therapy or in creatinine >200% of baseline).
The SALT-ED trial was also a single-centre unblinded trial, but the primary outcome was hospital free days. They reported no statistical difference between the two groups. Their secondary composite outcome of death, new renal-replacement therapy, or final serum creatinine >200% of baseline, was statistically better with balanced crystalloid vs saline. However, there was not a statistical difference in any of the individual components of the composite outcome.
The BaSICS trial attempts to answer whether balanced solutions are superior to saline using a large, double-blind, factorial, multi-center randomized trial.
Clinical Question: Does administration of a balanced solution (Plasma-Lyte 148) during intensive care unit (ICU) stay, compared with saline solution, result in improved 90-day survival in critically ill patients?
Reference: Zampieri et al. Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA 2021
- Population: Adult patients admitted the ICU for more than 24 hours, needing at least one fluid expansion and with at least one risk factor for acute kidney injury (age over 65, hypotension, sepsis, required mechanical ventilation or non-invasive ventilation, oliguria or increased serum creatinine level, cirrhosis or acute liver failure)
- Exclusions: Required or expected to require renal replacement therapy within 6 hours of admission, severe electrolyte disturbances (sodium < 120 mmol/L or > 160 mmol/L), death considered imminent within 24 hours, suspected or confirmed brain death, palliative or comfort care only or patients previously enrolled in the trial. During the study, hyperkalemia (K+ > 5.5 mEq/L) was removed as an exclusion criteria, after the second interim analysis.
- Intervention: Plasmalyte 148 solution at either slow (333 mL/hr) or fast (999 mL/hr) infusion rate.
- Comparison: 0.9% sodium chloride solution at either slow (333 mL/hr) or fast (999 mL/hr) infusion rate.
- Outcomes:
- Primary Outcome: 90-day survival
- Secondary Outcomes: Need for renal replacement therapy up to 90 days after enrollment, occurrence of acute kidney injury, for patients without acute kidney injury at enrollment, SOFA score and, number of days not requiring mechanical ventilation within 28 days
- Trial Design: Double-blind, factorial, randomized clinical trial conducted at 75 ICUs in Brazil.
Authors’ Conclusions: “Among critically ill patients requiring fluid challenges, use of a balanced solution compared with 0.9% saline solution did not significantly reduce 90-day mortality. The findings do not support the use of this balanced solution.”
Quality Checklist for Randomized Clinical Trials:
- The study population included or focused on those in the emergency department. No
- 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). Unsure
- 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. Unsure
Results: A total of 10,520 patients were randomized and available for analysis. The mean age was 62 years, 44% were female, 48% admitted after elective surgery, 68% had received crystalloid bolus before ICU admission (45% getting > 1 litre), 60% were hypotensive or getting vasopressors, 44% required mechanical ventilation and median volume of fluid was 1.5 litres during the first day of enrollment.
Key Results: No significant interaction between fluid type or infusion rate for the primary outcome of death at 90 days.
- Secondary Outcomes: There were 19 secondary outcomes evaluated. Of those, two met the threshold for statistical significance with both reporting harm with the balanced solution. Specifically, SOFA score at day 7 (absolute difference 0.27 [0.08-0.45]) and neurological SOFA score > 2 at day 7 (32.1% vs 26.0% for the saline solution group; odds ratio, 1.40 [95% CI, 1.18-1.66]).
1) External Validity: This study was conducted in 75 ICUs in Brazil. Half of the patients were admitted after elective surgery and 44% were on mechanical ventilation. The median APACHE II score was 12 and the median SOFA score was 4. Are these the same patients you see in your ICU?
2) Fluids: Almost half of patients had received more than 1 litre of IV fluids prior to enrollment. More of the patients received balanced solution compared to saline solution. This could have impacted the results.
The total volume of crystalloids received by patients in the trial was small. The median volume of fluid was 1.5 litres during the first day of enrollment. During the first three days after enrollment the accumulated median fluid administered (including study fluid and non-study fluid) was 4.1 L (SD, 2.9 L) and the median study fluid administered during the same period was 2.9 L (SD, 2.4 L).
3) Power Calculation. The sample size was calculated based on an estimated 90-day mortality of 35% in the saline group. Actual mortality was lower (around 27%) in both groups. The authors say that this may have resulted in a lower power to observe a clinically important difference.
Power calculation is mainly dependent on two things: the effect size, and the sample size. The effect size is the delta, the difference between intervention and the control or comparison group. The sample size is the number of participants in the cohort.
You will read papers that say the study was underpowered to find a difference. I’ve probably said this before and been in error. Once you have run the experiment the results are as reported. An assumption was made a priori as to effect size. You no longer have an assumption for the magnitude of effect. Now you have a data set with the “actual” effect size in that population. This is probed for analyzed for statistical significance with the appropriate tools. No more assumptions on effect size needs to be made and what you see is what you get.
4) Secondary Outcomes or Subgroup Analyses: They found two of 19 secondary outcomes that were statistically significant. Both showed increased harm with balanced solution compared to saline The authors say: “all of the subgroup and secondary outcome analyses should be considered as only hypothesis-generating”.
The authors are correct that it is hypothesis generating. We should not over-interpret secondary outcomes or subgroups. We have seen in other trials where these statistical differences are highlighted (CRASH-3) because of the potential positive patient impact. I think this could be an example of intervention bias (Foy and Filippone 2013). I doubt we will see people advocating for “normal” saline in the ICU for these secondary outcomes
5) Industry Involvement: Baxter supported this large trial by providing the fluids. There were some financial conflicts of interest declared with some of the authors. However, Baxter did not have a role in the design and conduct of the study.
Funding and fCOIs are just additional data points that need to be considered. They occur on a spectrum from no industry involvement to being designed, conducted, analysed, and written by employees of a company. None of that makes the information incorrect but our skepticism should be proportional to the degree of industry involvement.
Comment on Authors’ Conclusion Compared to SGEM Conclusion: We would have modified the conclusion to: “Among adult patients admitted the ICU for more than 24 hours, needing at least one fluid expansion and with at least one risk factor for acute kidney injury use of a balanced solution compared with 0.9% saline solution did not significantly reduce 90-day mortality. The findings do not support the use of this balanced solution in this cohort of patients.”
SGEM Bottom Line: In adult ICU patients at risk for kidney injury, administering modest volumes of Plasmalyte 148 versus normal saline, at fast or slow infusion rates, did not influence 90-day mortality.
Case Resolution: You only have ready access to 0.9% saline in your emergency department. You administer a total of one liter before the patient is transferred to the ICU.
Clinical Application: When resuscitating critically ill patients in the emergency department, the type of crystalloid and rapidity of infusion do not likely influence 90-day mortality, at least at low total volumes administered.
Dr. Aaron Skolnik
What Do I Tell the Patient? You have a severe urine infection. We are going to give you some IV antibiotics to treat the infection. Your blood pressure is low and that can be dangerous. We are going to also give you some IV fluids to bring your blood pressure up. You will be admitted to the intensive care unit where than can continue the treatment and watch you closely.
Keener Kontest: There was no winner last week. According to the CDC, one in three patients who dies in a hospital has sepsis.
Listen to the SGEM podcast this week to hear the trivia question. If you think you know the answer, send an email to thesgem@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.
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