UMEM Educational Pearls - Critical Care Literature Update

Balanced crystalloids:  So Hot Right Now

Brief Read:

The use of balanced crystalloids has been the subject of several RCTs with conflicting results. However, recent post-hoc and meta-analyses of these same trials suggest that balanced crystalloids may be the best choice initially. See nice summary at: https://www.atsjournals.org/doi/full/10.1164/rccm.202203-0611ED.

Long Read:

While I had thought about summarizing the recently published data on EPR from the CRITICAL trial in Japan, JournalFeed today covered the recent post-hoc analysis of the BaSICS trial originally seen on CC Pearls back in August 31, 2021 by Dr. Sjelocha. This subject is as important as it is confusing. There are large and relatively well done RCTs that point in opposite and sometimes strange directions. However, as the authors of the SMART trial summarized, even an NNT of 94 in this population could be a huge number of patients!

The use of balanced crystalloids (e.g. Plasmalyte) has been the subject of several previous RCTs (SMART and SALT-ED) with conflicting results. Recently the PLUS RCT and BaSICS trials seemed to push the literature towards to concluding there was no difference, but there are caveats for both trials now in the literature:

• While the PLUS RCT found no difference, a concurrently published meta-analysis seemed to conclude the opposite (https://doi.org/10.1056/EVIDoa2100010).
• Further confusing the issue, apost-hoc analysis of the similarly negative BaSICS RCTcame out in March 2022 suggesting that overall there was a benefit for patients who received balanced crystalloid when they hit the door, but that those who arrived with sepsis and were unplanned admissions benefited most!
  • The authors note that their original analysis is likely affected by the fact that 68% of the original BaSICS study population had already received balanced fluid, saline, or both before randomization.

This paper makes a nice point which I think is important for us in the ED: the evidence is suggesting a commonality in many critical care concepts, which is that decisions made in early resuscitation may have an outsized impact on patient outcomes. However, this will not be the last we hear on this subject, but for the time being, I agree with Dr. Lacy that “It might not matter as much what fluids you choose when patients are on their third, fourth, or fifth liter of fluid – but especially for the sickest patients, it sure seems like the initial resuscitation fluid makes a difference.”

BaSICS post hoc: https://www.atsjournals.org/doi/full/10.1164/rccm.202111-2484OC (See JournalFeed post from today and the accompanying editorial)

• 68% (10,520) of enrolled patients had balanced crystalloids (3,202), saline (2,096), or both (1,862) prior to enrollment
• “There was a high probability that balanced solution use was associated with lower 90-day mortality in patients who exclusively received balanced solutions before study enrollment.”

BASICS: https://jamanetwork.com/journals/jama/fullarticle/2783039 (summary stolen from Dr. Sjeklocha’s  August 31, 2022 CC Pearl)

• No difference in 90 days mortality (P-Lyte 26.4% v NS 27.2, aHR p=0.47), AKI or RRT out to 7-days, or in duration of MV, ICU LOS or hospital LOS
• Signal for possible harm in TBI population with balanced crystalloids compared to normal saline

PLUS: https://www.nejm.org/doi/10.1056/NEJMoa2114464

• 5,037 critically ill patients
• No statistically significant difference in the primary outcome of death within 90 days of randomization in the BMES group compared to the saline group (21.8% vs 22.0%, 95% CI -3.6 to 3.3; P=0.90).
• Subgroup analyses were conducted based on illness severity before randomization, presence of sepsis, kidney injury, age, sex, and ICU admission after surgery, and did not show a significant difference between the two groups.

SMART: https://www.nejm.org/doi/full/10.1056/nejmoa1711584

• 7942 patients in the balanced-crystalloids group,
• Balanced: 1139 (14.3%) versus Saline: 1211 of 7860 patients (15.4%) had a major adverse kidney event in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04).
• “Our results suggest that the use of balanced crystalloids rather than saline might prevent 1 patient among every 94 patients admitted to an ICU from the need for new renal-replacement therapy, from persistent renal dysfunction, or from death.”

SALT-ED: https://www.nejm.org/doi/full/10.1056/nejmoa1711586

• 13,347 patients
• The number of hospital-free days did not differ between the balanced-crystalloids and saline groups (median, 25 days in each group; adj. OR, 0.98; 95% CI, 0.92 to 1.04; P=0.41).
• Balanced crystalloids resulted in a lower incidence of major adverse kidney events within 30 days than saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P=0.01).

https://journalfeed.org/article-a-day/2022/back-to-basics-first-fluid-choice-matters-a-reanalysis-of-the-basics-rct/

Background:

· Empiric broad spectrum antibiotic therapy is a mainstay of the management of critically ill patients with septic shock.

· Vancomycin is widely used for the coverage of potential MRSA infection

• PROS: cheap, widely available, relatively widespread tissue penetration when given IV, and is generally well-tolerated

• CONS: has a complicated dosing regimen requiring specifically-timed serum concentration sampling and subsequent dose changes, frequently subtherapeutic, carries a risk of AKI especially when used concomitantly with piperacillin/tazobactam,¹ as it commonly is during empiric therapy for septic shock.         

· Continuous infusion of vancomycin has been repeatedly demonstrated to reach target serum concentrations faster, maintain consistent serum vancomycin levels better, with fewer serum concentration sampling required, and less overall vancomycin required to do so, in both adult and pediatric populations.^2-5

Current Article: 

Flannery AH, Bissell BD, Bastin MT, et al. Continuous Versus Intermittent Infusion of Vancomycin and the Risk of Acute Kidney Injury in Critically Ill Adults: a Systematic Review and Meta-Analysis. Crit Care Med. 2020;48(6):912-8.

· Systematic review and meta-analysis of 11 studies for a total of 2123 patients

· Comparing continuous versus intermittent vancomycin infusion.

· Primary outcome of AKI, secondary outcome of mortality

· Found a reduction in the incidence of AKI in the continuous infusion cohort:

• OR 0.47 (95% CI 0.34-0.65) even when taking into account trough levels /area under the curve concentrations and the severity of AKI examined by the individual studies.

· No association between infusion strategy and mortality

Considerations:

· Initial loading dose used in most of the studies (15 mk/kg) probably underdosed, current recommendation for 25mg/kg initial loading dose⁷ (which is not even always effective by itself)⁸ (Reardon)

· Continuous infusion may be difficult with limited IV access

· AKI associated with increased hospital stay, costs, mortality (although didn’t pan out in study) – worth preventing if possible.

Take Home:

· Give a 25-30mk/kg loading dose of vancomycin in critically ill patients with suspicion of MRSA to achieve target serum concentrations sooner.

· Continuous vancomycin is a viable option and could be considered in ED boarders, especially if there is concern for impending renal injury.

Show References

2. Distinguish artery from vein with compression and/or Doppler.* 

3. Sterilely prep the site and ultrasound probe.

4. Cannulate the vein in the transverse or longitudinal plane.

Show References

A single episode of hypotension portends a worse outcome for septic patients.  The restrospective analysis by Marchick et al of 700 patients showed that mortality was 10% vs 3.6% for septic patients whose SBP dropped below 100 even once.  It was also noted that the lower the SBP, the worse the in-hospital mortality.

So, not only do we need to remember to watch blood pressure closely for head-injured patients, but for septic patients as well!

Show References

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Since all of us are taking care of critically ill patients for longer periods of time, I think it is important to be familar with current critical care literature.  Often, we are the first "intensivist" a patient sees when they arrive to the hospital.  To keep us up to date, I am going to be sending out critical care literature updates every couple of weeks similar to Amal's cardiology updates.   Please email me with any questions, comments, or feedback.

Mike

Recent Articles from the 2008 Critical Care Literature

Hydrocortisone therapy for patients with septic shock.

Sprung CL, Annane D, Keh D, Moreno R, Singer M, et al. NEJM 2008;358:111-24.

            Corticosteroid therapy for patients with septic shock seems to change favor every couple of years.  In the first publication of the Surviving Sepsis Campaign Guidelines, steroids were given a favorable recommendation based largely upon the results of one multicenter, randomized, controlled trial. (Annane, et al. JAMA 2002;288:862-71) In this study, Annane reported a reduction in the likelihood of death in patients who did not respond to the corticotropin stimulation test and were given steroids (hydrocortisone and fludrocortisone).

            The current study is from the CORTICUS Study Group and is a multicenter, randomized, double-blind, placebo-controlled study conducted in 52 ICUs from March 2002 to November 2005.  Enrolled patients had to have clinical evidence of infection, a systemic response to infection, organ dysfunction attributable to sepsis, and the onset of shock within 72 hours (SBP < 90 mmHg despite fluids or vasopressors).  Patients were randomized to receive either hydrocortisone or placebo for 5 days.  Doses were then tapered over the next 6 days for a total duration of therapy of 11 days.  A lack of response to corticotropin was defined as an increase in cortisol of no more then 9 mcg/dL.  The primary end point of the study was the rate of death from any cause at 28 days in “non-responders”.  Some important secondary end-points included the rate of death at 28 days in “responders”, time to reversal of shock, duration of ICU and hospital stay, and rates of death at 1 year.

            Four-hundred ninety nine patients were enrolled in the study.  Of these, 233 were identified as “non-responders”.  In this group, 125 were randomized to receive hydrocortisone and 108 received placebo.  The demographic and clinical characteristics of patients in each group were similar.  Over 90% of patients in each group were vented and all were receiving vasopressors, the most common being norepinephrine.  With respect to the primary outcome, there was no significant difference in the rate of death at 28 days between the study groups.  For the secondary end points, there was also no significant difference in the rate of death in “responders”, duration of ICU or hospital length of stay, or death at 1 year.  The only difference that was found in those receiving hydrocortisone was a reduction in the time to reversal of shock.  Importantly, this did not translate into improved mortality.  Lastly, the authors reported an increase in new episodes of sepsis and septic shock in those receiving hydrocortisone but the absolute numbers are small.

            Things to Consider:  Investigators had planned to enroll 800 patients but stopped at 499 due to slow recruitment, termination of funding, and expiration of the study drug.  In addition, the mortality rate in the placebo group was lower than what would be expected.  As a result, the study is inadequately powered.  In contrast to the Annane study, enrollment of patients could be up to 72 hours after the onset of shock, raising the question of timing of steroids administration.  Furthermore, the majority of patients in this study were older, Caucasian males who required emergency surgery – not typical of the septic shock population at UMMC.  Importantly, patients who were receiving long-term corticosteroids within the past 6 months, or short-term steroids within the past 4 weeks, were excluded – the patients we would typically give stress dose steroids to during refractory shock. 

            Take Home Point: Although CORTICUS is underpowered, it is one of the largest trials to date on corticosteroids in patients with septic shock.  The results indicate that corticosteroid therapy in this patient population of “non-responders” had no effect on mortality.  Based upon this study, the latest version of the Surviving Sepsis Campaign Guidelines has downgraded their recommendation on corticosteroids.  It appears that the pendulum regarding steroids may now be swinging back in the negative direction.

Intensive insulin therapy and pentastarch resuscitation in severe sepsis.

Brunkhorst FM, Engel C, Bloos R, Meier-Hellmann A, Ragaller M, et al. NEJM 2008;358:125-139.

            The concept of “tight glucose control” in critically ill patients primarily began with the Van de Berghe study in 2001.  In this study, investigators found a reduction in mortality in critically ill patients whose glucose was maintained between 80 – 110 mg/dL. (Van de Berghe G, et al. NEJM 2001;345:1359-67.)  The benefit was primarily seen in cardiac surgery patients who had multiple organ failure from sepsis.  Furthermore, these patients were given a high glucose challenge immediately after surgery – not a common practice.  More recently, the same investigators evaluated MICU patients who had not undergone surgery nor received a glucose challenge.  (Van de Berghe G, et al. NEJM 2006;354-449-61.)  In this latter study there was no benefit to intensive insulin therapy.

            The current study is a multicenter, randomized, open-label study of both intensive insulin therapy and hydroxyethyl starch in patients with severe sepsis.  The study was conducted from April 2003 to June 2005 in 18 multidisciplinary ICUs at academic tertiary hospitals in Germany.  The study was designed to detect a decrease in mortality from 40% to 30% at 28 days.  Enrolled patients had to have the onset of severe sepsis or septic shock either 24 hours before ICU admission or less than 12 hours after ICU admission.  The primary end points were the rate of death from any cause at 28 days and morbidity.  Since we do not use HES in the ED for volume resuscitation, I will focus on intensive insulin therapy.

            The insulin arm of the study compared intensive insulin therapy to conventional insulin therapy.  In the conventional group, insulin was given when glucose values were > 200 mg/dL, with the goal of maintaining glucose between 180 – 200 mg/dL.  In the intensive insulin group, insulin was given when glucose values were > 110 mg/dL, with the goal of maintaining glucose between 80 – 110 mg/dL.  Treatment ended at either discharge from the ICU, death, or a total of 21 days of therapy were reached.

            Five hundred thirty seven patients were enrolled, 290 in the conventional insulin group and 247 in the intensive insulin group.  Baseline patient characteristics including age, pre-existing co-morbidities, sites of infection, lab values, and hemodynamic variables were similar between the groups.  Total nutritional intake, including glucose, was similar in both groups.  Interestingly, the majority of patients had nosocomial acquired infections and over 60% in both groups were given hydrocortisone.  Overall, there was no significant difference in the rate of death between the intensive and conventional insulin therapy groups.  Furthermore, there was no significant difference in morbidity between the two groups.  As one might expect, there was significantly more hypoglycemic episodes in the intensive insulin therapy group (17% vs. 4.1%).  Although no deaths were attributable to hypoglycemia, there were more “life threatening” episodes of hypoglycemia in the intensive insulin group.  As a result of the increase in hypoglycemic episodes the study was stopped early.

            Take Home Point:  In this patient population with severe sepsis, intensive insulin therapy, using a continuous infusion, to maintain glucose between 80 – 110 mg/dL did not improve mortality.  It did, however, result in significantly more hypoglycemic episodes (glucose < 40 mg/dl).  Many EDs across the country are now developing and implementing sepsis protocols primarily based upon the SSC Guidelines.  Based upon this study, intensive insulin therapy may not be a necessary component to the ED management of patients with severe sepsis or septic shock.