Journal Club Podcast #44: July 2018
A (somewhat)restrained rant on the importance of looking at the details and not combining outcomes to improve precision...
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Article 2: 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 3: Raghunathan K, Shaw A, Nathanson B, Stürmer T, Brookhart A, Stefan MS, Setoguchi S, Beadles C, Lindenauer PK. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis. Crit Care Med. 2014 Jul;42(7):1585-91. Answer Key.
Article 4: Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012 Oct 17;308(15):1566-72. Answer Key.
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, SpO2 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 #increasedrenalfailure 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.
Population: Adult patients receiving IV crystalloid (admitted patients, critically ill patients, patients with severe sepsis or septic shock)
Intervention: Balanced (chloride-restricted) crystalloids such as Lactated Ringer’s or Plasma-Lyte
Comparison: Normal Saline
Outcome: Mortality, renal failure, need for renal replacement therapy
Two recently published, highly publicized articles (Self 2018 and Semler 2018) were chosen for inclusion. In order to identify two additional articles, the previous journal club covering this topic (November 2015) was searched and the two most relevant articles chosen.
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.
The first paper we reviewed was a retrospective before-and-after study conducted at a single ICU in Melbourne Australia (Yunos 2012). This study demonstrated an decreased risk of acute kidney injury (OR 0.52, 95% CI 0.37-0.75) and need for renal replacement therapy(OR 0.52 95% CI 0.35-0.76) with the use of balanced fluids. Unfortunately, this study was not only limited by its methodological design, but is not externally valid to our patient population, as only 22% of patients were admitted from the ED, half were post-operative, and nearly a third were admitted following elective surgery
A less methodologically robust, retrospective study was identified that at least enrolled patients more similar to those in our setting (Rhagunathan 2014). This study was conducted using a retrospective cohort of patients from 360 US ICUs with sepsis requiring vasopressor therapy. Unfortunately, as this was retrospective, the two treatment groups were unbalanced, and statistical methods had to be employed to balance the two cohorts. Patients receiving any amount of balanced fluid were propensity matched to patients receiving only unbalanced fluids during the same time period. Patients who received some balanced fluids saw a decrease in in-hospital mortality (RR 0.86, 95% CI 0.78-0.94; NNT 31) with no difference in AKI or need for dialysis. A dose-response relationship was also observed, in which the relative risk of in-hospital mortality was lowered an additional 3.4% on average for every 10% increase in in the proportion of balanced fluids received.
More recently, two large quasi-randomized studies looking at the use of balanced fluids were published out of Vanderbilt University Medical Center. 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 0.98 (95% CI 0.92-1.04), 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 shouldn’t be surprising that no real difference in 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 for 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 confounder; when looking at unadjusted data, there was no statistically significance difference between the groups (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 quite likely that a more pronounced effect would be seen in patients receiving a larger volume of fluid. In fact, a fairly large treatment effect was observed in subgroup analysis of patients with sepsis, with a risk difference of 5.1% (NNT ~20).
The bulk of this evidence suggests that when administered broadly, the use of saline versus balanced fluids does not have any real impact on meaningful outcomes. However, when larger volumes of fluid are administered (such as in patients with sepsis), there does seem to be a trend, at least, towards improved outcomes. Rather than continue to research the use of balanced fluids in non-critically ill patients or in all patients admitted to an ICU, regardless of medical condition, further research should attempt to confirm the apparent benefit in those patients likely to receive a larger volume of IV fluids. Likewise, despite the low cost and lack of harm associated with Lactated Ringer’s solution, it would be difficult to broadly recommend its use over normal saline, but rather to consider its use when two or more liters of fluid are expected to be given.