Category: Sepsis

Procalcitonin, Still Auditioning For a Role in Neonatal Sepsis

A single test to rule out bacteria infection would be a lovely invention.  But, in the absence of such, we’ll settle for a test to rule out serious bacterial infection.  But, alas, procalcitonin – despite its sponsored proponents – is not that test.

This is a systematic review and meta-analysis pooling 2,317 patients from seven studies evaluating its use in detection of SBI in a neonatal population of less than 91 days of life.  Most commonly, the discriminatory value reported used was 0.3 ng/mL, with five studies reporting this data and the other two providing this data upon request.  All told, infants with PCT >0.3 ng/mL had a 42.7% prevalence of SBI, while those with PCT below the cut-off had a 12.5% prevalence.

So, this works out to a relative risk of 3.97 (95% CI 3.41 to 4.62) given a PCT greater than the cut-off.  Unfortunately, a prior review of the “Rochester criteria” for infants aged 29 to 90 days noted this cohort of low-risk patients had a prevalence of SBI of only 2.7%, with a RR for SBI of 30.6 (95% CI 7.0-68.13).  Noting 2.7% to be superior to 12.5% as a rule-out mechanism, it would seem prudent to retain the Rochester criteria rather than rely on PCT.

It may be reasonable to incorporate PCT into future decision instruments for risk-stratification, but such validated rules are not yet available.

“Use of Serum Procalcitonin in Evaluation of Febrile Infants: A Meta-Analysis of 2,317 Patients”
http://www.ncbi.nlm.nih.gov/pubmed/25281186

ARISE, and Cast Off the Shackles of EGDT

The sound you hear is a sigh of relief from Emergency Physicians and intensivists regarding the outcomes of the Australasian Resuscitation in Sepsis Evaluation (ARISE).

As ProCESS suggested, and as many have suspected all along, it seemed the critical intervention from Early Goal-Directed Therapy was the early part – and less the SCO2 monitoring and active management of physiologic parameters using dobutamine and blood transfusion.  Now, we have a second study, in addition to ProCESS, supporting the same general conclusions.

ARISE enrolled patients with confirmed or suspected sepsis, and either hypotension refractory to 1L crystalloid fluid challenge or a lactate level of 4.0 mmol/L or more.  31 centers randomized 1,600 patients to undergo either EGDT or “usual care”, which entailed routine local clinical practice, excepting measurement of SCVO2 was forbidden.  EGDT, however, was provided by specially coordinated teams to ensure all patients received the intervention.  The primary outcome was death from any cause within 90 days, powered to detect an absolute risk-reduction of 7.6%.

Baseline characteristics between the two groups were quite similar, few patients dropped out of each arm, and, finally, there was no difference in the primary outcome – 18.6% vs. 18.8% (does it matter which is which?)  Indeed, of all the outcomes measured, only two differed in statistically significant fashion: the EGDT cohort departed the Emergency Department 30 minutes more quickly, and the EGDT cohort received greater vasopressor support – attributable entirely to the use of dobutamine in 15.4% of patients vs. 2.6% in the usual care arm.

As expected, resource utilization unique to EGDT, of course, was different – more and different types of central venous catheters, more arterial catheters, and more frequent use of blood products.  And, as we’re seeing – all of this is unnecessary.  As with ProCESS, “usual care” has become EGDT, excepting these elements.  Both groups received substantial, early crystalloid resuscitation, early appropriate antibiotic coverage, and departed the Emergency Department to a critical care setting quite quickly.

EGDT receives credit for making us aware the impact early identification and intervention can have on mortality.  However, it is time to leave EGDT behind and identify new resuscitation targets and sensible strategies for achieving them.

“Goal-Directed Resuscitation for Patients with Early Septic Shock”
http://www.nejm.org/doi/full/10.1056/NEJMoa1404380

Still Adrift in Ignorance Over Blood Cultures

While supervising residents, one of the frequent diagnostic suggestions in undifferentiated febrile patients is: blood cultures.  As an Emergency Physician, the utility of blood cultures – short of diagnosing endocarditis or another primary hematogenous source – is vanishingly small.  After all, the source of infection is nearly universally somewhere else – lung, urine, CSF, skin & soft tissue – and relying on the blood to give you the answer two days later is an unreliable and impractical proposition.

This study is yet another attempt at identifying patients with high likelihood of bacteremia, retrospectively analyzing 5,499 patients at Odense University Hospital for whom blood cultures were drawn.  This cohort, representing roughly half of all patients presenting to the Emergency Department, had positive blood culture results 7.6% of the time.  CRP, temperature, and SIRS criteria were evaluated as potential predictive variables – and, unfortunately, the positive likelihood ratios of each were only between 2 and 3, and the negative likelihood ratios associated with each were all 0.4.  The authors combine these criteria and promote their absence as a rule-out, with a negative predictive value of 99.5% – but, common sense ought obviate trying to diagnose bacteremia in an afebrile patient with no SIRS criteria, and the NPV performance is more related to the low prevalence of disease than the utility of their criteria.

Really, the most interesting element of this study: the massive volume of blood cultures performed, with 92% of them true negative or false positive.  Costs for blood cultures vary by facility, and range from $15-$50, with patient charges typically a significant multiplier beyond.  A low yield might be important if the diagnoses were changing management and improving outcomes, but the vast majority of culture results are clinically unimportant.  These authors have not described particularly strong positive predictors – but they’ve illustrated the massive scope of the problem.

“How do bacteraemic patients present to the emergency department and what is the diagnostic validity of the clinical parameters; temperature, C-reactive protein and systemic inflammatory response syndrome?”

Nitric Oxide Supplies No Miracles in Sepsis

An interesting context to end-organ dysfunction in sepsis stems from microcirculatory dysfunction, secondary to endothelial activation and vascular disruption as part of the inflammatory cascade.  Even though abnormal vasoconstriction in sepsis may be pharmacologically ameliorated, microcirculatory perfusion remains impaired.

This interesting trial attempted to modulate microcirculation through the use of inhaled nitric oxide.  Authors enrolled patients whose macrocirculation had been optimized, using objective targets consistent with contemporary care in septic shock, and randomized them to inhaled nitric oxide or sham.  Using a custom device for 40 ppm nitric oxide inhalation – for which authors all deny COI – an enrollment of 138 patients was planned.

However, after 49 patients, the trial was stopped due to futility.  The device was a success – as measured by circulating nitrite levels.  Unfortunately, from a microcirculation perfusion endpoint, there was no difference.  Likewise, there were no obvious differences or trends in secondary clinical outcomes.  There were, at least no obvious harms related to therapy.

Next steps in evaluation of this therapy – if any – are as of yet unclear.

“Randomized Controlled Trial of Inhaled Nitric Oxide for the Treatment of Microcirculatory Dysfunction in Patients With Sepsis”
http://www.ncbi.nlm.nih.gov/pubmed/25080051

The Broken ED Sepsis Quality Measure

Are there yet sufficient mandates in the Emergency Department?  Door-to-physician times, door-to-CT time in acute ischemic stroke, door-to-analgesia for long bone fractures – and, on the horizon, National Quality Forum proposed measures for delivery of sepsis bundle components within 3 and 6 hours.

The problem? As these authors discover, even for patients ultimately receiving a diagnosis of severe sepsis and septic shock, many do not meet those criteria within 3 hours, or in the Emergency Department.  These authors perform a retrospective review of 113 patients from a public Level 1 trauma center and 372 from a university teaching hospital who received who received at least a provisional diagnosis of severe sepsis or septic shock.  According to their review, 9.8% of patients at the trauma center and 15.3% of patients did not meet criteria for severe sepsis or septic shock within 3 hours of arrival.

No one disputes early recognition and treatment of sepsis is a cornerstone of quality Emergency Department care.  However, retrospective application of sepsis definitions to the initial time period of presentation is clearly a Quixotic quest.  Chasing every last potential severe sepsis patient will only lead to further unintended consequences, inappropriate care, and resource over-utilization – particularly because most patients with SIRS in the Emergency Department are never diagnosed with an infection.

Just as with OP-15, we should continue to work against implementation of this measure.

“Many Emergency Department Patients With Severe Sepsis and Septic Shock Do Not Meet Diagnostic Criteria Within 3 Hours of Arrival”
http://www.ncbi.nlm.nih.gov/pubmed/24680548

SIRS is Rarely Sepsis

You already knew this – but that hasn’t stopped your hospital from purchasing the “Sepsis Alert” tool for your electronic health record.  Now, you and your nurses get blasted with computerized interruptions every time a patient is tachycardic and has an elevated WBC count.  And, you ignore it – because it’s 1) wrong, or 2) you placed a central line and admitted the patient to the ICU half an hour ago.

But, just how often do these sepsis alerts, based on systemic inflammatory response criteria, fire erroneously?  That is the question asked by this group from Harbor-UCLA and UC Davis.  Using the National Hospital Ambulatory Medical Care Survey from 2007 to 2010, these authors attempted to estimate the frequency of true infection in the setting of SIRS.  Unfortunately, while the NHAMCS set now includes vital signs obtained at triage, it does not include results of tests, such as the WBC.  Therefore, these authors – and this is where the study breaks down a bit – were required to mathematically conjure up a range of estimates for the frequency with which patients would meet the WBC criterion for SIRS.  Based on minimum and maximum estimates, the percentage of Emergency Department visits estimated to have SIRS ranged from 9.7% to 26.0%, and the authors ultimately split the difference at 17.8% for their analysis.

Based on their estimate, there were approximately 66 million visits to Emergency Departments meeting SIRS criteria, and the largest cohort of eventual diagnoses for these patients was indeed infection – but this constituted a mere 26% of all SIRS.  The remaining diagnoses were scattered among trauma, mental disorders, respiratory diseases, and other non-specific, organ-system dysfunction, catch-all ICD-9 codes.  While the interruptions and low specificity of SIRS alert tools are the obvious problem addressed by this study, the other implication is the troubling scope of the problem:  after trauma and infection are excluded, there are approximately 42 million other ED visits that may erroneously trip institutional protocols, costly unnecessary testing, and additional resource utilization targeting sepsis.

This is the sort of decision-support that simply doesn’t add any proven value, and another venue of encroachment into efficient and effective care.

“Epidemiology of the Systemic Inflammatory Response Syndrome (SIRS) in the Emergency Department”
http://www.ncbi.nlm.nih.gov/pubmed/24868313

Colloids Will Never Die

People love colloids.  Gross fluid resuscitation with crystalloids makes folks uncomfortable; the general dilutional effects and lack of oncotic pressure associated with crystalloids portends suboptimal volume replacement.

Yet, as we see again, the theoretical advantages of colloids are just that:  theoretical.

In this multi-center study from Europe, ICU patients were randomized – following initial resuscitation – to further resuscitation with crystalloids alone or crystalloids supplemented with albumin to a serum albumin target of 30g/L.  Groups were well-matched at baseline, in medical/surgical comorbidities, organ dysfunction, physiologic parameters, and pre-randomization resuscitation.  This excerpt from the authors’ conclusions condenses the results most simply:

“… the use of albumin in addition to crystalloids to correct hypoalbuminemia, as compared with the use of crystalloids alone, in patients with severe sepsis during their stay in the ICU did not provide a survival benefit at 28 or 90 days, despite improvements in hemodynamic variables.”

The last note is important, and reveals why this study will do nothing to change the use of natural and synthetic colloids for resuscitation:  clinicians love to make numbers look good, and colloids do that better than crystalloids.  Despite increased cost and no ultimate change in the primary outcome of mortality – or any secondary outcome of note – colloids improved hemodynamics in the short term.  Even though colloids are more costly, perhaps there are yet financial advantages to this small, early hemodynamic advantage?  Regardless, we are assured further research on this topic will continue apace.

My wife’s contribution to this post:  other important colloids people love include whipped cream, gravy, ketchup, and Jello®.

“Albumin Replacement in Patients with Severe Sepsis or Septic Shock”
http://www.ncbi.nlm.nih.gov/pubmed/24635772

MAPing Pressor Therapy, a Guide to Nowhere

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

Among the many questions in sepsis management, the proper use of vasopressors is one of the most vexing. Despite sparse evidence addressing their overall benefit in the management of septic shock, the use and misuse of vasopressors have been debated ad nauseam. And yet the precise time to begin pressor therapy and the ideal mean arterial pressure (MAP) to target are still very much uncertain.

Authors of the SEPSISPAM trial, or more commonly referred to as “the other sepsis trial published alongside ProCESS“, attempt to provide us with some guidance on the ideal MAP goal in septic shock. Pierre et al randomized 776 patients in septic shock, “refractory” to initial fluid bolus (30mL/kg), initiating vasopressor therapy at a MAP goal of either 65 or 85 mm Hg. The pressor used to achieve these MAPs was left to the discretion of the treating physician (though norepinephrine was the first-line pressor in the vast majority of the participating centers).

SEPSISPAM failed to find a difference between a MAP goal of 65 or 85 mm Hg in any of the many endpoints examined, with the exception of the pre-specified subgroup of patients with a history of hypertension. In those randomized to the 65 mm Hg group, they found a small increase in the amount of patients who experienced elevated creatinine levels and underwent renal replacement therapy within the first week of enrollment. Given that there was no difference in 28-day or 90-day mortality or the number of patients who survived to 28-days without organ support, its hard to imagine this momentary ascent into statistical significance as clinically relevant.

More important than the ideal MAP goal for pressor therapy, is how many of these patients should have been started on vasopressors in the first place? Patients were enrolled after they were found to be refractory to initially fluid bolus and then immediately started on pressors. And though the protocol allowed for physician judgment on additional fluid administration after the initial 30cc/kg bolus, if you examine the daily fluid administration during the first 24-hours of resuscitation, very little extra fluid was allotted. Though these patients received approximately 10 liters over the first 5 days of their resuscitation, only 3 liters were given within the first 24 hours. When compared to the ProCESS cohort, who received approximately 5 liters (depending on group allocation) within the first 6 hours, this resuscitation effort is entirely underwhelming.

It is impossible to make definitive conclusions when comparing outcomes from different trials, but these two cohorts appear fairly similar at the time of enrollment. In fact, the ProCESS cohort may have been slightly sicker (lower MAP, higher HR, higher initial blood lactate levels). These two very similar cohorts with almost identical pre-enrollment fluid administration demonstrated two very different resuscitative strategies.  The patients in the SEPSISPAM trial were given very little additional fluid after the initial bolus and were all immediately started on pressor therapy. Conversely, the ProCESS cohort were bolused generous amounts of additional fluid and only half were started on pressors within the first 6-hours of enrollment. The 28-day mortality in the SEPSISPAM cohort was 34% and 36.6% respectively. In contrast, the the ProCESS cohort found a 60-day mortality of 21.0%, 18.2% and 18.9% in the three resuscitative strategies.  Obviously not definitive data but a strong argument against the “Fear the Fluids” campaign that is so rampant in current ED and ICU management of septic shock.

“High versus Low Blood-Pressure Target in Patients with Septic Shock” http://www.nejm.org/doi/full/10.1056/NEJMoa1312173

Procalcitonin in Serious Bacterial Infection: Spoiler Alert – It Doesn’t Help Here Either

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

Over the years, numerous studies have been published attempting to show the benefit for serum markers in diagnosing sepsis or other infections. These markers include ESR, CRP and more recently, procalcitonin (PCT). Despite the reams of literature published, no study has shown a true patient centered outcome benefit to using these markers. Instead of doing an in depth review here of the literature on PCT, I recommend reading Rory Spiegel’s post here.

This recent article from Academic Emergency Medicine attempts to use PCT as an indicator of serious bacterial infection (SBI) in children under 3 years of age. They basically compared PCT with WBC, absolute neutrophil count (ANC) and absolute band count. PCT had the largest area under the curve (0.80 vs. 0.76 for WBC, 0.73 for ANC and 0.67 for absolute band count). Overall, the study found that all of these tests suffered from poor sensitivities but that specificity for PCT (92.7% at a cutoff of 0.6 ng/ml) coupled with its sensitivity (51.6% at the same cutoff) yielded the best positive likelihood ratio of any of these tests (+LR = 7.04). Based on this finding, the investigators conclude that PCT is a “more accurate marker than white blood count, absolute neutrophil count or absolute band count in identifying young febrile infants and children with serious bacterial infections.”
But, are we asking the right question? This study, as with many of the others, tries to use PCT to identify patients that we would otherwise miss as having a serious infection. However, they don’t compare PCT to physician clinical judgment. Or, more importantly, they do not investigate if PCT adds to clinical judgment. Instead, they compare it to markers we know are seriously lacking in their ability to predict (WBC, ANC and absolute band count).
Additionally, the investigators focus on the positive likelihood ratio and the high specificity. But we aren’t concerned about overworkup in febrile kids. As with all bad diseases, we want high sensitivity to make sure we miss as few SBIs as possible and a low negative likelihood ratio to aid in risk stratification. With a strong negative likelihood ratio (-LR < 0.10) we could use a PCT < 0.5 ng/ml to risk stratify patients to a low or very low risk of SBI and potentially send them home with follow up. Here, a PCT < 0.5 ng/ml had a – LR = 0.52. In this study, 13.3% (30/226) patients ultimately had an SBI. If you started with a pretest probability of 13.3% and apply a – LR of 0.52 using the Fagan Nomogram (below) you’d get a post-test probability of around 10%. This is nowhere near low enough for us to stop our workup.
Where does this leave us? Biomarkers will continue to be pushed since there are strong industry interests. Additionally, we want something concrete, objective and tangible to help us with our clinical decision-making. Future studies, though should focus on the additional benefit of markers to the clinician’s assessment and gestalt instead of looking at the biomarker in a vacuum. Show us this and we’ll all sit up and take notice. Until then, procalcitonin is simply another test without a clear indication.

Special thanks to Rory Spiegel (@CaptainBasilEM) and Mike Mojica for the help with this post.

Alas, EGDT, We Hardly Knew Ye

Twitter and the usual accelerated knowledge translation sites have been abuzz with the release of several important articles regarding resuscitation in severe sepsis.

The one garnering the most press is ProCESS, a 1:1:1 randomization of patients with severe sepsis into Early Goal-Directed Therapy, protocol-based aggressive fluid resuscitation, or “usual care”.  Many detailed analyses and sub-analyses will likely be written, but, the basic gist – it appears the critical innovation coming out out of Rivers’ EGDT is awareness of the importance of any aggressive early recognition and treatment.  The primary outcome – in-hospital mortality at 60-days – was similar across each group.  And, the minor variations in secondary outcomes probably support simply paying close attention to individual patient physiology.

This is not specifically practice-changing in many critical care settings – there has been plenty of skepticism regarding the specific interventions in the Rivers’ algorithm.  The search will certainly go on regarding ways to improve upon the 20% modern mortality in severe sepsis, but it is now easily defensible to eschew the Edwards’ catheter, blood transfusions, and dobutamine from Rivers’ specific protocol.

“A Randomized Trial of Protocol-Based Care for Early Septic Shock”
http://www.nejm.org/doi/full/10.1056/NEJMoa1401602