Washington University Emergency Medicine Journal Club– April 28th, 2022
It’s another busy day TCC, when an elderly female rolls in from triage with fever, cough, and a new oxygen requirement. Her vitals are T 38.3 BP 90/42, HR 115, RR 24, Sp02 88% on RA. Even before you see the patient you are concerned for pneumonia with severe sepsis. You institute early antibiotics, fluids, serial lactates and systematically begin to aggressively resuscitate her. The patient requires nearly five liters of normal saline before her blood pressure stabilizes. Proud of your resuscitation, you tweet out #crushingsepsis and #normalsaline4life which gets an immediate response from Dr. Evan Schwarz, who happened to be trolling your twitter feed. He tweets “More like #increaseddrenalfailure and #trybalancedfluids.” Inspired by his tweets (and his article published in EPMonthly) you perform a brief literature review on the topic of ‘balanced fluid’ resuscitation to see if there is any evidence supporting balanced fluid use over saline in general, in sepsis specifically, or in any other specific patient population…
Population: Adult patients receiving IV crystalloid (admitted patients, critically ill
patients, patients with severe sepsis or septic shock, patients with diabetic
Intervention: Balanced (chloride-restricted) crystalloids such as Lactated Ringer’s
Comparison: Normal Saline
Outcome: Mortality, resolution of septic shock, development of septic shock, ICU
and hospital length of stay, duration fo mechanical ventilation, need for renal
In addition to the recently published PLUS Study, two large studies covered in our
previous journal club on this topic were selected. The fourth article selected was a
subgroup analysis of the two older studies that only included patients with diabetic
Article 2: Self WH, Evans CS, Jenkins CA, et al; Pragmatic Critical Care Research Group. Clinical Effects of Balanced Crystalloids vs Saline in Adults With Diabetic Ketoacidosis: A Subgroup Analysis of Cluster Randomized Clinical Trials. JAMA Netw Open. 2020 Nov 2;3(11):e2024596. Answer Key.
Article 3: 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 Mar 1;378(9):829-839. Answer Key.
Article 4: Finfer S, Micallef S, Hammond N, et al; PLUS Study Investigators; Australian New Zealand Intensive Care Society Clinical Trials Group. Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults. N Engl J Med. 2022 Mar 3;386(9):815-826. Answer Key.
Normal saline has long been the “go to” fluid of choice for resuscitation in the ED for critically ill patients. However, the use of such “chloride rich” or “unbalanced” fluids has been controversial for decades, with many calling for the use of fluids that more closely resemble the tonicity of human blood. Aggressive resuscitation with isotonic saline has been shown to decrease serum pH, without affecting serum osmolality (Williams 1999), and has been suggested to increase the risk of renal dysfunction (Lobo 2014). The clinical significance of these and similar effects has been called into question over the last decade. We sought to evaluate the evidence for and against the use of balanced fluid resuscitation in ED patients, particularly those with severe sepsis or septic shock.
Two large cluster-randomized studies looking at the use of balanced fluids were published out of Vanderbilt University Medical Center in 2018. The first of these (Self 2018) enrolled patients receiving at least 500 mL of intravenous isotonic crystalloid in the ED who were later admitted to a non-ICU bed (i.e. non-critically ill patients). Patients were “randomized” based on calendar month, alternating between saline and balanced cystalloids. There was no difference in the primary outcome (number of hospital-free days to day 28) between the two groups. There was small decrease in risk of the secondary outcome, major adverse renal events—a composite of doubling of creatinine from “baseline,” need for renal replacement therapy, and death—with an adjusted odds ratio of 0.82 (95% CI 0.70-0.95), a risk reduction of 0.9%, and a NNT of 111. This slight difference was entirely driven by the decreased risk of a doubling of the creatinine, with no actual difference in need for renal replacement therapy or death. In fact, the statistical significance achieved was also entirely due to the use of a composite outcome to increase the incidence of any outcome (thereby narrowing the 95% CI), with no actual statistically significant difference in the risk of doubling of creatinine when looked at in isolation (RR 0.86, 95% CI 0.73-1.01). It should not be surprising that no difference in patient-centered outcomes was observed in this study, given that these were relatively healthy patients receiving a rather small amount of fluid (median volume of ~ 1 liter during the entire hospitalization). The results are made even more suspect by the fact that over a third of patients did not have a baseline creatinine in the system for comparison, but rather had a baseline creatinine estimated based solely on age, race, and gender.
The second study out of Vanderbilt (Semler 2018) was similar in methodology, but enrolled only adult patients admitted to one of five participating ICUs. In this case, the primary outcome was the composite incidence of major adverse renal events, as defined in the previous study. The authors again found a small reduction in the incidence of major adverse renal events, with an adjusted OR of 0.90 (95% CI 0.82-0.99), a risk reduction of 1.1%, and a NNT of 91. As in the prior study, there was no statistically significant difference for any of the individual components of this composite outcome; by combining outcomes, the authors were able to increase the incidence and hence decrease the 95% CI, allowing them to achieve statistical significance. In this case, the difference was only observed after statistical adjustment for known confounders; in the unadjusted data there was no statistically significance difference (RR 0.93, 95% CI 0.86-1.00). Interestingly, the median volume of fluid administer was about 1 liter, similar to the study conducted on non-critically ill patients, and it is possible that a more pronounced effect would be seen in patients receiving a larger volume of fluid.
Two subgroup analyses of data from these studies has been published. The first (Brown 2019) included 1,641patients from there SMART study who were admitted to the medical ICU with a diagnosis of sepsis. Thirty-day in-hospital mortality (the primary outcome) occurred in 26.3% of patients in the balanced crystalloids group and 31.2% in the saline group (adjusted odds ratio 0.74; 95% CI, 0.59-0.93). Patients in the balanced group also experienced a lower incidence of major adverse kidney events within 30 days (aOR, 0.78; 95% CI, 0.63-0.97) and a greater number of renal replacement therapy-free days (20 ± 12 vs. 19 ± 13; aOR, 1.35; 95% CI, 1.08-1.69) compared with the saline group.
A second subgroup analysis (Self 2020) included 172 patients from the SMART and SALT-ED studies were diagnosed with diabetic ketoacidosis (DKA). Time to DKA resolution was shorter in the balanced fluid group than the saline group (median 13.0 hours, IQR 9.5-18.8 vs. median 16.9 hours, IQR 11.9-34.5; adjusted hazard ratio [aHR] 1.68, 95% CI 1.18-2.38). The median duration of insulin drip was also shorter in the balanced fluid group (9.8 hours vs. 13.4 hours; aHR 1.45, 95% CI 1.03-2.03. Incidences of death, major adverse kidney events, and mechanical ventilation were low and not significantly different between groups.
Finally, the recently published PLUS study compared fluid resuscitation with Plasma-Lyte to normal saline among ICU patients at multiple ICUs in New Zealand and Australia. After enrolling just over 5000 patients (out of a planned 8800), the authors found no difference in the primary outcome of 90-day all-cause mortality (absolute difference -0.15% (95% CI -3.60 to 3.30%), maximum serum creatinine within 7 days, maximal increase in creatinine in the ICU, or need for new renal replacement therapy.
While there is, at this time, no compelling evidence that use of balanced fluids for resuscitation improves patient-centered outcomes, there is also no evidence of harm. While Plasmalyte and lactated ringers are slightly more expensive than normal saline ($4.50 vs $2 per liter), this difference is marginal and would be dwarfed by other costs of hospitalization. Given the potential for improved renal function with LR use seen in the SALT-ED and SMART trials, it is certainly reasonable to choose balanced fluids when large volume resuscitation is anticipated, it is unlikely that most patients would see any benefit over the use of normal saline.