Category: Sepsis

Intermediate Lactate Values, Lowering the Bar for Cryptic Shock

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.

Serum lactate has been the darling of Emergency Medicine/Critical Care since Manny Rivers first introduced EGDT to the Emergency Department. Since then we have used it as a screening tool, a means to guide therapy and even to prognosticate outcomes. Despite our universal acceptance of its utility, very little high quality data has been published on its diagnostic properties. I reviewed this evidence in more depth in a past post and will limit this to the question, “Can serum lactate identify a group of patients who are in cryptic shock, despite clinically appearing well?” The Surviving Sepsis Campaign recommends using a lactate level of 4 mmol/L as the threshold for identifying cryptic shock, but lactate has a continuous curvilinear association with mortality and a 4 mmol/L threshold seems like an arbitrary cutoff.

In an attempt to answer this question Puskarich et al conducted a systematic review, published in the Journal of Critical Care, examining the ability of intermediate lactate values (2.0-3.9 mmol/L) to predict cryptic shock and death. Eight studies were included in this review. A total of 11,062 patients with intermediate lactate levels were examined. The authors appropriately decided that given the heterogeneity of these datasets, a formal meta-analysis was not appropriate. Instead they settled for descriptive statistics of each individual trial. In summary they found patients with intermediate lactate values who were normotensive had a 30 day mortality rate of 14.9% (mortality in individual trials ranged from 3.2-16.4%). Obviously the patients with intermediate lactate levels that were concurrently hypotensive fared far worse (30 day mortalities of 35-37%).

This review fails to define the clinical utility of the association between elevated lactate levels and risk of death.  In the few studies included in this review which published diagnostic test characteristics, lactate performed surprisingly poorly. Howell et al found lactate had an AOC of 0.71 for predicting 30 day mortality. Shapiro et al reported a similar AOC of 0.67. In fact in the Shapiro study when a cutoff of 2.5 mmol/L was used as screening tool for cryptic shock, it had a sensitivity of 59% and a specificity of 71%. Even a threshold of 4 mmol/L though very specific (92%) had a sensitivity of 36%, a far lower sensitivity than one would be traditionally accepted for a screening test.

More importantly, this data does not allow us to determine how a lactate threshold of 2.5 mmol/L  performs in the true cryptic shock patient. This is the patient who has end organ hypoperfusion without any clinically obvious signs. In most of the patients with elevated lactates, they appear clinically ill and thus the lactate is only confirming what we already know, that this patient needs aggressive intervention. If lactate is to prove useful as a true screening tool (at whatever threshold), it should be able to identify the patient clandestinely experiencing septic shock before any obvious signs of of end-organ damage (AMS, hypotension, AKI) become apparent. Unfortunately we have little data supporting its use in this manner. Even the secondary analysis of the Jones trial, finding similar mortalities between hypotensive patients and normotensive patients with elevated lactate (above 4mmol/L), fails to impress. Although the cryptic shock patients were not hypotensive in the strictest sense, they were by no means physiologically normal. On the contrary they were older, more tachycardic, with faster respiratory rates, and experienced significantly more intra-abdominal infections (30% vs 16%) than their hypotensive counterparts. And though they were not hypotensive (<90 mmHg), their blood pressures were not necessarily normal. The median blood pressure in the cryptic shock group was 108mmHG with an IQR of 92-126. To put it simply, these patients were sick. They did not require a lactate level to identify them as in need of aggressive therapy. There was nothing cryptic about them….

“Prognosis of Emergency Department Patients with Suspected Infection and Intermediate Lactate Levels: A Systematic Review”
http://www.jccjournal.org/article/S0883-9441(14)00002-1/abstract

Sepsis, NHAMCS, and Non-Truths

“… our results provide a worrisome view of the quality of care of septic patients in U.S. EDs.”

Crikey.

This is serious business.  Tell me more.

“Our data suggest that many emergency department patients (31%) with sepsis do not receive antibiotics until they arrive on the inpatient unit.”

This is somewhat concerning data.  Of course, some patients can have sepsis from viremia, and would not warrant antibiotics – but, I think most admitted patients with SIRS and a suspected infectious source ought to receive treatment.

But, unfortunately, for this study, the question is less the quality of ED care, and more the quality of the data source.  The National Hospital Ambulatory Medical Care Survey is a lovely data set, whose quality is only increasing as coding and structured data become more prevalent – but a retrospective analysis of these data is not appropriate substrate to make sweeping generalizations regarding the care in the Emergency Department.

From the ~400 Emergency Departments providing yearly data to NHAMCS, 0.32% of patients met their definition of sepsis.  That meant these data reflect a sample of 1,141 patients, and the admitted limitation of “studies relying on NHAMCS data are vulnerable to errors of omission in data collection.”  These authors lack information regarding previously administered antibiotics from transferred patients, and admit some patients – those spending <1 hour in the ED – may simply have left the ED before antibiotic administration could be completed.

Quite simply, it’s (mostly) garbage in and (mostly) garbage out.

The authors also attempt an assessment of antibiotic appropriateness from this retrospective chart abstraction.  It is so egregiously flawed it doesn’t even warrant comment.

“Sepsis Visits and Antibiotic Utilization in U.S. Emergency Departments”
http://www.ncbi.nlm.nih.gov/pubmed/24201179

What to Make of Esmolol in Septic Shock?

This is the new hotness in critical care discussions – the co-administration of intravenous esmolol to critically ill folks on high-dose vasopressor support in the ICU.  It’s a fascinating thought – considering the alpha- and beta-stimulation of norepinephrine necessary to maintain central perfusion, co-administration of a sympatholytic seems self-defeating, in a sense.

However, this may not be the case.  There are multiple dose-dependent effects of catecholamines on different tissues, as well as concern the tachycardia resulting from sympathomimetic myocardial stimulation in sepsis results in adverse outcomes.  Based on prior observational evidence, these authors performed a randomized, open-label trial of esmolol co-administration in a cohort of critically ill patients on vasopressor support.

They randomized 154 patients with HR >95 and septic shock to esmolol, titrated to a HR between 80 and 94 bpm, vs. usual care.  The hemodynamic variables showed, despite the use of esmolol, norepinephrine dosage was not significantly increased in order to maintain MAP.  Improvements in stroke volume compensated for a lower heart rate, resulting in non-significantly lower cardiac index.  However, what has everyone fascinated – the control group had 90% in-hospital mortality, compared with 67% for the esmolol group.  I don’t think anyone disagrees this is statistically significant and clinically important.

There were differences in baseline variables between groups.  The etiology of sepsis was substantially tilted towards peritonitis in the esmolol group, with obviously different causative organisms.  Lactic acid, base excess levels, and SAPS II scores favored the esmolol group.  The lead author and one co-author also have financial conflicts of interest with Baxter, the makers of esmolol (Brevibloc).  Financial conflicts, open-label, and the size of the study all make me wary of reproducibility and the magnitude of the effect size.

So, there are problems warranting additional and independent confirmation.  That said, the mortality benefit observed in this study is large enough I wouldn’t contest anyone who wanted to go ahead and start trying this in their highest-predicted mortality subset.  However, I’d also consent patients/families to this therapy as experimental and prospectively collect data for at least retrospective pre-/post- comparisons.

“Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock A Randomized Clinical Trial”
www.ncbi.nlm.nih.gov/pubmed/24108526

Chloride-Restriction & More JAMA Inadequacy

“The implementation of a chloride-restrictive strategy in a tertiary ICU was associated with a significant decrease in the incidence of AKI and use of RRT.”

Pretty clear, eh?  This article is one of several in a line of folks working to divorce us from normal saline.  The argument is that this hypernatremic, hyperchloremic solution, when given for large-volume resuscitation in the critically ill, leads to metabolic acidosis and decreased urine output.  This study, sponsored by Baxter, the makers of Plasma-Lyte, is an open-label, before-and-after design.  One year, they gave whatever fluid they wanted – mostly saline.  The next year, saline-containing fluids were restricted, and they used 20% albumin, lactated ringers (Hartmann’s solution), or Plasma-Lyte.

Firstly, the primary outcome doesn’t match their clinicaltrials.gov registration.  They’ve changed it from mean base excess during hospital stay to two primary outcomes that weren’t even both previously defined as secondary outcomes – increase in creatinine from baseline and incidence of acute kidney injury according to the RIFLE classification.

Then, they offer two positive results from their study – a decrease in the incidence of AKI and the use of renal replacement therapy.  The authors use RIFLE as their indicator of AKI – but they don’t pre-define which categories of RIFLE they use, and lump “Injury” and “Failure” together to a composite endpoint to gain statistical significance.  Otherwise, it’s a 7.4% control and 5.4% intervention difference in “Failure” that doesn’t reach statistical significance – and considering the mean baseline creatinine was lower in the intervention period, it ought to be expected to reach the failure definition less frequently.

The difference in rise of creatinine reaches statistical significance – but they’ve hidden the details in their online supplement  The mean serum creatinine in the baseline period rises from 10.4 mmol/L to 11.0 mmol/L, and in the intervention period from 10.3 mmol/L to 10.7 mmol/L.  This might be statistically significant, but hardly clinically significant.  Luckily, the authors use a skewed y-axis to distort and magnify the difference in their graph of these results.

Lastly, the RRT difference reported in their six-month study period is befuddling.  The overall rate of RRT in the entire year of their baseline period is 7.9%, while the rate of RRT in the entire year of their intervention period is 7.4%.  Yet, in the six months reported for this study, they report RRT use of 10% in the baseline period and 6.3% for the intervention period.  This implies the authors retrospectively selected their study period in order to magnify the effect of the RRT difference.  This difference in RRT also doesn’t match the 2% absolute difference in RIFLE classification for “failure” during the study period.  This implies the open-label nature of the study influenced the frequency of RRT use, as the authors may have exerted control over an outcome measure.

As far as patient-oriented outcomes go, after all this splitting of hairs, ICU length of stay was no different, the incidence of long-term dialysis was no different, and mortality was no different.  This is also a “bundle-of-care” study, with multiple different chloride-poor and chloride-rich fluids in use, which confounds the generalizability of the results.

Maybe chloride-sparing therapy is important.  But these authors are guilty of distorting and misleading with their presentation of results – and the JAMA editors, again, have failed us.

“Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults”
www.ncbi.nlm.nih.gov/pubmed/23073953

Credit for much of the insight into this article goes to Greg Press, who prepared this article for last month’s Journal Club at UT-Houston – but he is in no way responsible for this unhinged rant.

Eritoran, We Hardly Knew Ye

Endotoxin mediated circulatory collapse remains a theoretical target in the treatment of sepsis.

But, eritoran won’t be one of the agents used to ameliorate its effects.

After a phase II trial found sepsis patients randomized to eritoran had 37.5% mortality compared with 56.3% in the placebo group, the manufacturer sponsored a multi-national, multi-center phase III trial enrolling 1,951 patients.  And, in short – no mortality benefit overall, and no individual subgroups of severe sepsis with any indication of benefit.  The authors comments speak wistfully of the early favorable results before finally concluding: “Eritoran joins a long list of other experimental sepsis treatments that do not improve outcomes in clinical trials in these critically ill patients.”

Interestingly, the study concluded in 2010 – meaning it took 2 1/2 years for the results to reach publication.  The reader will have to derive their own interpretation regarding whether this had anything to do with being negative results from a manufacturer-sponsored trial.

“Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis”

JAMA & Procalcitonin

Someday, I’ll publish another article summary that doesn’t involve a conflict-of-interest skewering.  I’m really not as angry as Rob Orman says I am.  This article, at least, is directly relevant to the Emergency Department.

There’s been significant research into biomarkers for infectious/inflammatory processes, with the goal of identifying a sufficiently sensitive assay to use as a “rule-out” for serious infection.  The goal is to use such an assay to prevent the overuse of antibiotics without increasing morbidity/mortality.  This is a good thing.

Procalcitonin is the latest darling of pediatrics and intensive care units.  However, to call the literature “inconclusive” is a bit of an understatement – which is why I was surprised to see an article in JAMA squarely endorsing procalcitonin-guided antibiotic-initiation strategies.  After all, I’ve previously covered negative trials in this blog (pubmed, pubmed).  However, these authors seem to have intentionally narrowed their trial selection to exclude these trials – and publish no methods regarding their systematic selection of articles.

The disclosures for all three authors includes “BRAHMS/Thermofisher”.  Who is this, you might ask?  Google points me to: http://www.procalcitonin.com – where BRAHMS/Thermofisher will sell you one of seven procalcitonin assays.  JAMA, third-ranked medicine journal in Impact Factor, reduced to advertising masquerading as peer-reviewed science.

“Clinical Outcomes Associated With Procalcitonin Algorithms to Guide Antibiotic Therapy in Respiratory Tract Infections”http://www.ncbi.nlm.nih.gov/pubmed/23423417

Normal Procalcitonin Rules-Out Line Sepsis

The use of procalcitonin in sepsis has been evolving rapidly in the recent literature.  The theory behind procalcitonin is that, typically, it is rapidly converted to calcitonin.  However, in the presence of gram-positive and gram-negative sepsis, circulating endotoxin results in a rapid rise in procalcitonin levels not seen during viral infection.  There’s a nice study showing use of procalcitonin levels allows for reductions in antibiotic use in the ICU, without a corresponding increase in mortality – which makes it a promising test to assist in antibiotic stewardship.

This is a little bit different spin on the question addressing the use of procalcitonin levels in a population that is febrile all the time – pediatrics.  Most of the time, when children are febrile, the infectious etiology is either readily identifiable as bacterial or presumed to be viral.  However, in the subset of children with indwelling central venous catheters – they’re treated presumptively as line sepsis until proven otherwise, despite the preponderance of viral etiologies.

This is a small case series of 62 children with indwelling lines, 14 of whom eventually grew positive blood cultures.  Using procalcitonin levels drawn in the Emergency Department to rule out bacteremia gave an AUC of 0.82 (0.70 to 0.93) with the “optimal” cutoff at 0.3 ng/mL giving a sensitivity of 93% and specificity of 63%.  I’m not sure I’d settle for anything less than 100% sensitivity for line sepsis, but there is a point at which the risks associated with healthcare delivery are equivalent to the risks of bloodstream infection.  This is a nice idea I wasn’t previously familiar with that hopefully will be confirmed in subsequent evaluation.

“Procalcitonin as a Marker of Bacteremia in Children With Fever and a Central Venous Catheter Presenting to the Emergency Department”
www.ncbi.nlm.nih.gov/pubmed/23023470

When Do Patients Need Blood Cultures?

Another lovely JAMA Rational Clinical Examination article relevant to the Emergency Department – this time regarding the utility of blood cultures.  Blood cultures are frequently requested for febrile inpatients, however, the incidence of false positive ranges between 2.5% and 8%.  This leads, unfortunately, to additional patient harms from additional treatment or observation.


This article is a systematic review of several studies gathering clinical features of patients for whom blood cultures were requested, as well as the clinical outcomes of the cultures, in an attempt to identify features predictive of positive or negative cultures.  They also examine a couple validated clinical decision instruments to determine their potential utility in stratifying the appropriateness of cultures.


Essentially, based on a few pieces of decent evidence and a few pieces of poor evidence, the authors determine a few general categories of infectious etiology with varying pretest probability for bacteremia.  These are:
 • Cellulitis, community-acquired pneumonia, community-acquired fever: low (<14%) probability
 • Pyelonephritis: mid (19-25%)
 • Severe sepsis, septic shock, bacterial meningitis: high (38-69%)


In general, however, no individual clinical feature had a positive or negative likelihood ratio of sufficient magnitude to guide testing.  Combinations of clinical features – such as patients with SIRS – were capable of excellent sensitivity & negative likelihood ratios, but only had specificities of 0.27 to 0.47.


However, the more important clinical aspect of blood cultures and bacteremia is not addressed in this article, which is how frequently the true positives even change clinical management.


“Does This Adult Patient With Suspected Bacteremia Require Blood Cultures?“

www.ncbi.nlm.nih.gov/pubmed/22851117

Put Hydroxyethyl Starch Away

The use of colloid solutions as volume expanders is tempting – massive crystalloid resuscitation suffers from third-spacing, limiting the practical intravascular volume provided.  Colloid resuscitation, in theory, uses the oncotic pressure of the solute to favor intravascular expansion.  One of the alternatives that I’d seen use, but was unaware it was widely used, are hydroxyethyl starches.  Earlier studies, at least, the ones I was familiar with, linked the high-molecular weight HES to renal failure.

This trial, from Denmark, evaluated a low-molecular weight HES (Tetraspan) with Ringer’s acetate resuscitation in an intensive care setting, enrolling patients diagnosed with sepsis in need of fluid resuscitation.  The trial was randomized and blinded, with the resuscitation fluids being hung in identical black bags.  Each enrolled patient could receive up to 33 mL per kg ideal body weight of the trial fluid, and additional fluid was unmasked Ringer’s acetate.

With 800 well-matched patients between groups, 51% of the HES group was dead at 90 days, compared with 43% in the Ringer’s acetate group (RR 1.17, CI 1.01 to 1.36).  Renal replacement therapy was needed in 22% of the HES group, compared with 16% of Ringer’s acetate group – and was a predictor of death.

Investigators did not see any particular fluid volume advantage to the HES solution, and the toxic effects of the hydroxyethyl starch molecules, unfortunately, were associated with greater morbidity and mortality.

Seems like another great-sounding idea that needs to be rapidly curtailed until a better safety profile and outcome benefit can be demonstrated.

“Hydroxyethyl Starch 130/0.4 versus Ringer’s Acetate in Severe Sepsis”
http://www.nejm.org/doi/full/10.1056/NEJMoa1204242

Lactate Clearance and ScvO2 Goals in Sepsis

Early goal-directed sepsis care is successful – but no one can say precisely what makes it successful.  Hawthorne effect?  Early antibiotics appear to have uncertain association with better outcomes.  Is it the blood?  Is it meeting the central venous oxygenation goal of >70%?

Other studies have shown equivalency in outcomes while performing serial lactic acid measurements, and this is another study in the same vein.  203 patients form the analysis cohort, in which 93 received management decisions based on lactate clearance and 110 which received management decisions based on the ScvO2.  All included patients had both values measured simultaneously, but were blinded to the opposition.

And, this is another study where the two measures are different but similar – which is probably why the analysis is so convoluted.  Of the 203 enrolled, 175 either fortuitously or by design met the ScvO2 goal, while 178 met the lactate clearance goal.  Meeting the ScvO2 goal led to a death rate of 21% and meeting the lactate clearance goal led to a death rate of 17%.  There was no difference in therapeutic interventions between the ScvO2 goal group and the lactate clearance group.

However, if you met the lactate clearance without meeting the ScvO2 goal, you had an 8% (2/25) mortality, while the ScvO2 group that didn’t clear lactate had a 41% mortality (9/22).  Unfortunately, there were a number of baseline differences between the groups, and it’s hard to draw any conclusions or hypotheses from this finding.  It’s also clear they didn’t identify any specific interventions that improved survival in their cohort – and, more appropriately, simply observed that poor lactate clearance simply portends a worse outcome, without any specific recommendation on how to address it.

“Prognostic Value and Agreement of Achieving Lactate Clearance or Central Venous Oxygen Saturation Goals During Early Sepsis Resuscitation”