UMEM Educational Pearls - Critical Care Literature Update

Category: Critical Care Literature Update

Title: Balanced crystalloids: So Hot Right Now

Keywords: balanced crystalloid, saline, resuscitation, kidney injury (PubMed Search)

Posted: 7/14/2022 by William Teeter, MD
Click here to contact William Teeter, MD

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:


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 (
  • 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: (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: (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


  • 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.


  • 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.”


  • 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).


Category: Critical Care Literature Update

Title: Continuous Vancomycin Infusion & Decreased AKI in Critically Ill Patients

Keywords: sepsis, septic shock, acute renal failure, acute kidney injury, nephrotoxicity, vancomycin, MRSA, IV antibiotics (PubMed Search)

Posted: 5/27/2020 by Kami Windsor, MD
Click here to contact Kami Windsor, MD



· 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



· 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

Category: Critical Care Literature Update

Title: Ultrasound-Guided Subclavian CVC

Keywords: Subclavian,ultrasound, cvc, central venous catheter (PubMed Search)

Posted: 8/17/2010 by Haney Mallemat, MD (Updated: 4/24/2024)
Click here to contact Haney Mallemat, MD

Evidence suggests subclavian central venous catheters have fewer complications (e.g., less thrombosis and infection) compared to catheters at other sites. The benefits come at increased risk for potential complications during placement using the landmark technique (e.g., pneumothorax and arterial puncture). Ultrasound-guided subclavian cannulation is gaining popularity and is actively being studied. 
How to do it:
1. Find the axillary vein; located caudal to the distal third of the clavicle (see reference).

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.

*Note: Some recommend following the axillary vein medially until it becomes the subclavian vein and cannulating this site.

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

Category: Critical Care Literature Update

Title: Etomidate and adrenal suppression

Keywords: etomidate, adrenal insufficiency (PubMed Search)

Posted: 7/7/2008 by Mike Winters, MD (Updated: 4/24/2024)
Click here to contact Mike Winters, MD

Recent Articles from the Critical Care Literature

Duration of adrenal insufficiency following a single dose of etomidate in critically ill patients

Vinclair M, Broux C, Faure P, Brun J, Genty C, et al. Intensive Care Med 2008;34:714-9.
            Etomidate has become a favored first-line induction agent for intubation in the emergency department.  Given its excellent hemodynamic tolerance, etomidate is especially useful in hemodynamically unstable patients. A known side effect of etomidate is adrenal suppression, due to inhibition of 11β-hydroxylase, the enzyme that converts 11β-deoxycortisol into cortisol. As a result, recent literature has raised concerns that etomidate may worsen patient outcomes in those with relative adrenal insufficiency, namely those with septic shock.
            The current study is a prospective, observational study conducted in France from October 2005 to January 2006. The purpose of the study was to assess the duration of adrenal suppression following a single dose of etomidate, given either in the field or in the emergency department for RSI. Importantly, patients with septic shock, or those with preexisting adrenal insufficiency, were excluded from this study. To diagnose adrenal insufficiency, the investigators measured total cortisol and 11β-deoxycortisol following a high-dose cosyntropin stimulation test (250 mcg). Values were obtained at 12, 24, 48, and 72 hours following etomidate administration. An accumulation of 11β-deoxycortisol with a lack of cortisol rise was used to establish etomidate-related adrenal insufficiency.
            A total of 40 patients were included in this study. The majority of patients required intubation as a result of either trauma or subarachnoid hemorrhage. At hour 12, 80% of patients fulfilled the investigators definition of etomidate-related adrenal insufficiency, whereas by hour 48, only 9% met criteria. In addition, at hour 24, patients with etomidate-related adrenal suppression required larger doses of norepinephrine that those without adrenal inhibition. From their data, the authors conclude that a significant proportion of patients without septic shock have adrenal suppression for at least 12 hours following a single dose of etomidate. This effect, however, appeared reversible in that most patients recovered adrenal function by hour 48. Finally, the authors recommend that systemic steroid supplementation be considered during the first 48 hours in hemodynamically unstable patients who have received etomidate for intubation.
            There are a number of limitations with this study. The most important limitation is, perhaps, the authors’ definition of etomidate-related adrenal insufficiency. Diagnosing adrenal insufficiency in critically ill patients remains controversial. The cosyntropin test (high- or low-dose) has many recognized limitations. In addition, measurement of 11β-deoxycortisol is difficult because reference values for critically ill patients are rare. The authors also chose to measure total serum cortisol, rather than the more biologically active free serum cortisol. Lastly, data for all 40 patients at 72 hours was not complete.
            Take Home Points: This small, observational study found a high incidence of adrenal suppression for at least the first 12 hours in unstable patients receiving etomidate for intubation. Importantly, this study excluded patients with sepsis or septic shock. Given the limited number of patients and the difficulty in defining adrenal insufficiency in the critically ill, this study provides some interesting results and is hypothesis-generating at best. Their recommendation for systemic steroid supplementation during the first 48 hours following etomidate administration in unstable patients cannot be supported by this study.

Category: Critical Care Literature Update

Title: recombinant Factor VIIa for ICH

Keywords: intracerebral hemorrhage, recombinant factor VIIa (PubMed Search)

Posted: 7/6/2008 by Mike Winters, MD (Updated: 4/24/2024)
Click here to contact Mike Winters, MD


Recent Articles from the Critical Care Literature

Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage.

Mayer SA, Brun NC, Begtrup MSc, Broderick J, Davis S, et al. NEJM 2008;358:2127-37.
            Intracerebral hemorrhage (ICH) accounts for approximately 10% to 15% of all strokes, yet has the highest morbidity and mortality, with up to 40% of patients dying within 30 days. Aside from age, size, location, intraventricular extension, and GCS, hematoma expansion is an independent determinant of morbidity and mortality. Hematoma expansion is reported to occur in up to 70% of patients within the first several hours of the ICH. Recent research has focused on therapies to limit hematoma expansion. One such therapy is recombinant human activated Factor VII (rFVIIa). Excitement regarding this expensive drug came from a single phase 2 trial (Mayer SA, et al. NEJM 2005:352:777-85.) that demonstrated rFVIIa significantly reduced hematoma expansion and improved patient mortality.
            The FAST trial (Factor Seven for Acute Hemorrhagic Stroke), was a manufacture sponsored, phase 3 trial performed by the same investigators to confirm the findings of their previous phase 2 study. The FAST trial was a multi-center, randomized, double-blind, placebo-controlled trial conducted at 122 sites in 22 countries. Patients had to be at least 18 years of age with a spontaneous ICH documented by CT within 3 hours of symptom onset. Important exclusion criteria included GCS < 5 at presentation, secondary ICH (trauma, AVM), current anticoagulant therapy, thrombocytopenia, DIC, previous disability from CVA, or a thromboembolic event < 30 days prior to symptom onset. The primary end-point was disability or death defined by a modified Rankin score of 5 or 6 at day 90. The modified Rankin score evaluates global disability and handicap and ranges from 0 to 6. A score of 5 indicates a patient who is bed-bound and incontinent, whereas a score of 6 indicates death.
            Of 8,886 patients screened, 821 underwent randomization and received placebo, 20 mcg/kg of rFVIIa, or 80 mcg/kg of rFVIIa. Treatment had to start within 1 hour of the baseline CT and no more than 4 hours after the onset of symptoms. Patients then underwent a repeat CT at 24 hours and 72 hours to evaluate for hematoma expansion. Of note, the majority of the patients in this study were Caucasian males, older than 65 year of age who had deep gray matter ICHs. 
            As reported by the trial investigators, rFVIIa did reduce hematoma expansion at 24 hours compared to placebo. In the placebo arm, 26% of patients had hematoma growth, whereas only 11% of patients who received 80 mcg/kg of rFVIIa had hematoma expansion. In addition, the investigators report that the reduction in hematoma growth was even greater in those treated in less than 2 hours from onset of symptoms. However, when you look at the data for 72 hours, there was no significant difference in total hematoma volume or edema volume. More importantly, mortality at 90 days did not differ between placebo and the treatment groups. In fact, a higher percentage of patients who received 80 mcg/kg of rFVIIa had a worse outcome than compared with placebo. Furthermore, there was an absolute increase of 5% in the frequency of arterial thromboembolic serious events (MI, ischemia CVA) in the group receiving 80 mcg/kg of rFVIIa.
            Take Home Point: This phase 3 trial failed to demonstrate improved 90 day mortality in patients with spontaneous ICH who received rFVIIa. Although hematoma expansion was reduced at 24 hours in the rFVIIa groups, total lesion volume and edema volume at 72 hours remained unchanged. Although rFVIIa has been used in a variety of clinical settings, the results of this study indicate that it does improve mortality in patients with spontaneous ICH. Given the expense of the drug and lack of benefit, this should not be a drug we are using in the ED to treat patients with spontaneous ICH.

Category: Critical Care Literature Update

Title: Critical Care Literature Updates

Keywords: hydrocortisone, corticosteroids, insulin, sepsis (PubMed Search)

Posted: 2/28/2008 by Mike Winters, MD (Updated: 4/24/2024)
Click here to contact Mike Winters, MD

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.


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.