Tag Archives: Sepsis

“The third international consensus definitions for sepsis and septic shock (sepsis-3),” JAMA 315: 801, 2016, SCCM sepsis definitions task force

Intro:

• initial definitions of sepsis, severe sepsis, and septic shock from 1991; defined severe sepsis as sepsis complicated by organ dysfx which could progress to septic shock, defined as hypotension despite adequate fluid resuscitation; revisited in 2001
• the definitions of sepsis, severe sepsis, and septic shock have remained largely unchanged for more than 2 decades

Process of developing new definitions:

• recognizing the need to reexamine current definitions, the euro society of critical care medicine and the society of critical care medicine convened a task force (TF) of 19 experts in critical care, ID, surgery, and pulmonology (no EM) in jan 2014
• existing definitions were revisited in light of an enhanced appreciation of the pathobiology and the availability of large EMR databases and pt cohorts
• expert consensus process forged agreement on updated definitions and the criteria to be tested in the clinical arena
• the agreement between potential clinical criteria and the ability of the criteria to predict outcomes (eg ICU admission, mortality) were then tested in multiple large EMR databases
• systematic lit review/metaanalysis and delphi consensus methods were also used for the definition and clinical criteria describing septic shock
• when compiled, the TF recommendations were circulated to major international societies and other relevant bodies for peer review and endorsing (a total of 31 endorsing societies) (again, no EM)

 Challenges and opportunities:

• because no gold standard diagnostic tests exist for sepsis, the TF sought definitions and supporting clinical criteria that were clear and fulfilled multiple domains of usefulness and validity
• the original conceptualization of sepsis as infection + ³2 SIRS criteria focused solely on inflammatory excess; sepsis is now recognized to involve early activation of both pro- and anti-inflammatory responses, along with major modifications in nonimmunologic pathways such as cardiovascular, neuronal, autonomic, hormonal, bioenergetic, metabolic, and coagulation, all of which have prognostic significance; a broader perspective also emphasizes the significant biological and clinical heterogeneity in affected individuals
• the current ³2 SIRS criteria to identify sepsis was unanimously considered by the TF to be unhelpful
• the “sequential organ failure assessment” (SOFA) score looks at severity of organ dysfx via the following variables: P/F ratio (resp), platelets (coag), bili (liver), BP (cardiovascular), GCS (neuro), creat and UO (renal); a higher SOFA score is associated with increased mortality, but outside the critical care community the score is not well known + cumbersome to use
• multiple definitions for septic shock are currently in use resulting in significant heterogeneity in reported mortality
• the public needs an understandable definition of sepsis and health care providers require improved clinical prompts and diagnostic approaches to facilitate earlier identification and an accurate quantification of the burden of sepsis

Results/recommendations:

Definition of sepsis:

• sepsis is defined as life-threatening organ dysfx caused by a dysregulated host response to infection
• under this definition (“life-threatening organ dysfx”), the term “severe sepsis” becomes superfluous

Clinical criteria to identify pts with sepsis:

• the TF evaluated which clinical criteria best identified pts most likely to have sepsis; this objective was achieved by interrogating large datasets of hospitalized pts with presumed infection, assessing agreement among existing scores of inflammation (SIRS) or organ dysfx (SOFA), and delineating their correlation with subsequent outcomes; in addition, multivariable regression was used to explore the performance of 21 bedside and lab criteria proposed by the 2001 TF
• the EMR included 150,000 pts with suspected infection (from 12 hosps within the univ of pittsburgh system); two outcomes – ICU stay ³3 days and mortality – were used to assess predictive validity
• for ICU pts, a change in SOFA score ³2 from baseline was superior to SIRS criteria; the TF recommends the use of SOFA score ³2 from baseline to identify life-threatening organ dysfx and, thus, sepsis
• for non-ICU pts, the TF found that 2 or more of the following clinical variables – altered mental status, syst BP £100, and RR ³22 – offered good predictive validity; this new measure is termed qSOFA (for quick SOFA) and provides simple bedside criteria to identify life-threatening organ dysfx and, thus, sepsis; the TF recommends that qSOFA criteria be used to prompt clinicians to further investigate organ dysfx, to initiate or escalate therapy as appropriate, and to consider referral to critical care specialists
• thus, for ER pts, the TF recommends the following for identification of pts with sepsis: ³2 of the qSOFA criteria: altered MS, syst BP £100, RR ³22

Definition of septic shock:

• septic shock is a subset of sepsis in which underlying circulatory and cellular metabolic abnormalities are profound enough to substantially increase mortality

Clinical criteria to identify septic shock:

• 3 variables were identified to test in cohort studies – MAP <65, lactate >2, and need for vasopressor(s) to maintain MAP ³65 after volume resuscitation
• the first database interrogated was the surviving sepsis campaign’s international multicenter registry; a total of 20,000 septic pts; the mortality for septic pts with all 3 variables was >40%
• these same 3 variables were then used to interrogate 2 unrelated large EMR datasets – univ of pittsburgh (12 hosps, 6,000 pts) and kaiser (20 hosps, 54,000 pts); the mortality for septic pts with all 3 variables was 35-55%
• thus, the TF recommends the following criteria for identification of pts with septic shock: MAP <65, lactate >2, and need for vasopressor(s) to maintain MAP ³65 after volume resuscitation

Controversies – lactate levels:

• because lactate offered no meaningful change in the predictive validity beyond ³2 of the qSOFA criteria in the identification of pts with sepsis, the TF could not justify adding the complexity/cost of lactates alongside these simple bedside criteria
• the TF recommendations should not, however, constrain the monitoring of lactate as an indicator of illness severity or as a guide to therapeutic response
• some TF members suggested that elevated lactate represents an important marker of “covert shock” in the absence of hypotension

Implications:

• simple clinical criteria (qSOFA) that identify pts with sepsis (ie pts with evidence of infection who are likely to have a prolonged ICU course +/- death) have been developed and validated
• there is potential conflict with current organ dysfx scoring systems, early warning scores, ongoing research studies, and pathway developments

“Editorial: new definitions for sepsis and septic shock: continuing evolution but with much still to be done,” wake forest

• the TF assessed the predictive validity of SOFA, SIRS, and qSOFA in a primary cohort that included 150,000 pts with suspected sepsis and a confirmatory analysis that included 700,000 pt encounters at 156 US and non-US hosps
• for identifying pts with sepsis: the investigators found that in the ICU the best predictive value was found with change in SOFA score >2 from baseline; in non-ICU settings, the best predictive value was found with the qSOFA score
• for identifying pts with septic shock: the TF conducted a systematic review and metaanalysis of 92 studies informing a delphi process that created the new definition, then tested the variables identified by the delphi process in cohort studies using datasets from the surviving sepsis registry, univ of pittsburgh hosps, and kaiser hosps
• according to the new recommendations:
  • sepsis is now identified by evidence of infection + life-threatening organ dysfx, clinically characterized by an acute change in the SOFA score ³2 from baseline (ICU pts) or ³2 of the 3 clinical variables of the qSOFA score (nonICU pts)
  • septic shock is now identified by MAP <65, lactate >2, and the need for vasopressor(s) to maintain MAP >65 after volume resuscitation
• there is no longer any mention of the SIRS criteria (HR >90, RR >20, T >38° or <36°, WBC >12K or bands >10%)
• there remain concerns with the quality of the information used to generate the updated criteria
• regarding the new qSOFA score: because this score was retrospectively derived from databases that had substantial gaps in clinical info for pts treated outside ICUs, qSOFA will require prospective real-world validation before it should enter routine clinical practice

“Levosimendan for the prevention of acute organ dysfunction in sepsis,” NEJM, 2016, UK

Background: Levosimendan is a calcium-sensitizing drug marketed under the trade name Simdax that is approved in Europe and South American for use in acute decompensated heart failure. It increases cardiac contractility through calcium sensitization of troponin C and vasodilates by opening potassium channels in vascular smooth muscle cells. It is felt to only minimally increase myocardial oxygen demand. Small trials have suggested that it may improve organ perfusion and hemodynamics in sepsis.

Question: Does the addition of levosimendan to standard care in patients with septic shock reduce the severity of organ dysfunction?

Study Type: Multicenter, randomized, double-blind, placebo-controlled trial in 34 ICUs in the UK.

Study Population: Adult patients who required vasopressor support for ≥4hrs for septic shock were eligible for the trial. Exclusion criteria included >24 hrs of vasopressor support prior to enrollment, ESRD, Child-Pugh C liver disease, history of torsades, DNR, weight >125kg, and pregnancy.

Study Groups: Patients randomized to levosimendan or placebo for 24 hours. Additional inotropic medications were allowed if felt necessary by the treating clinician. Orion Pharmaceuticals provided the study drug but was not otherwise involved in the trial.

Primary Outcome: Mean daily SOFA score while in the ICU for a maximum of 28 days.

Results: 516 patients were randomized. The majority of screened patients were excluded because they were outside the 24hr window since meeting inclusion criteria. Notable baseline characteristics: Caucasian (93%), recent surgery (37%), APACE II (25), lung as primary source of infection (39%), beta-blockers at baseline (19%), mechanical ventilation (81%), dobutamine (9%). There was no difference in the mean SOFA score during ICU stay (6.68 +/-3.96 in the levosimendan group and 6.06 +/- 3.89 in the placebo group). Patients given levosimendan required more norepinephrine, were less likely to be liberated from mechanical ventilation, and more likely to experience SVT. Levosimendan did not improve outcomes in any of the pre-specified subgroups including patients with low cardiac output, impaired O2 delivery to tissue, and those on high-dose vasopressors. There was no difference in any mortality measure. Of note, cardiac index was similar throughout the trial in both groups (largely between 3.1-3.5 L/min/m2).

Caveats: Mostly Caucasian patients, does not answer the question of whether levosimendan may be helpful in the initial resuscitation of septic shock (median time from shock to randomization in this trial was 16 hrs), does not answer the question of whether a supranormal cardiac index is helpful in septic shock (both groups had a similar CI and very few patients in the intervention arm would have fit into the “cardiac index” arm of the 1995 NEJM trial we reviewed where CI goal was >4.5), does not answer the question of whether an inotrope is helpful in septic shock as the addition of levosimendan was offset in part by increased dobutamine use in the control arm, cardiac index was only measured in a subset of patients (30%) and measured using a variety of methods (PiCCO, esophageal Doppler, PAC) raising questions about generalizability and accuracy, more dobutamine use in the standard care arm then is seen at NMH.

Take-home Point: The addition of levosimendan to standard care in patients with septic shock does not improve outcomes and may be harmful.

Commentary: For me, an odd hypothesis to think that levosimendan would provide much physiologic benefit in this patient group: resuscitated septic patients who had been on vasopressors for a median of 16 hours and had adequate DO2 (as assessed by a median ScVO2 of 75 at the time of enrollment) especially as another inotrope was allowed in both arms. I would have been more interested in a protocol focused on early resuscitation, perhaps specifically in patients with a low ScVO2 or known cardiac dysfunction comparing levosimendan to placebo (without additional dobutamine) or a three-armed trial with levosimendan vs dobutamine vs placebo (as levosimendan’s ability to only minimally raise myocardial O2 demand offers some potential advantages over dobutamine). In any case, this trial, and others strongly suggest that a supranormal DO2 (or attempts to achieve one) are of little benefit in patients with sepsis. This trial is also a good reminder to take systematic reviews of small trials with a big grain of salt (see “Levosimendan reduces mortality in patients with severe sepsis and septic shock: a meta-analysis of randomized trials,” J Critical Care, 2015).

“Incidence, predictors, and outcomes of new-onset atrial fibrillation in critically ill patients with sepsis,” AJRCCM, 2017, Netherlands

Question: What is the incidence of new-onset atrial fibrillation/atrial flutter (AF) in ICU patients with sepsis and is the development of AF associated with mortality?

Study Type: Sub-study of a prospective cohort study at two hospitals in the Netherlands

Study Population: Adults admitted to the ICU with sepsis over a two-year period were included.  Exclusion criteria included a history of AF, recent cardiotomy, or cardiac arrest.

Study Groups: AF detection based on hourly recordings of the rhythm observed by the bedside nurse.  AF needed to be sustained for 1 hour or require pharmacologic treatment or cardioversion to be included.

Primary Outcome: Incidence of new-onset AF

Results: 1,782 patients included in analysis.  Notable patient characteristics: Age (»62), immunosuppression (26%), malignancy (10%), lung as source of infection (62%), mechanical ventilation (83%), surgical admission (23%), 90-day mortality (34%).  The overall incidence of AF was 23%.  For patients with septic shock, the risk of AF was 40%.  The most common treatments administered were amiodarone (71%), magnesium (69%), electrical cardioversion (11%), and sotalol (8%).  After multivariable regression, AF remained associated with ICU mortality (HR 2.10; 95% CI, 1.61-2.73).  An AF risk score was developed (the “SAFE” score) and validated in an independent cohort.  The score can be accessed here: https://safescore.shinyapps.io/safe/.

Caveats: Unmeasured confounding a concern in observational studies, unable to prove AF has causal role in poor outcomes, relied on identification and classification of arrhythmia by bedside nurse so possible missed or misclassified episodes, data collected from only two centers.

Take-home Point: New-onset AF is common in ICU patients with sepsis and may lead to increased mortality.

Commentary 

–        Part of a growing body of literature helping to describe the incidence and significance of new-onset AF in critical illness.  Certainly notable that the incidence of AF in septic shock approaches 50%

–        The SAFE score still needs to be independently validated, but it is an interesting attempt by the authors to come up with a way to predict the development of sepsis-induced AF (and, in doing so, potentially identify a group of septic patients to enroll in trials of AF prophylaxis).​

“The timing of early antibiotics and hospital mortality in sepsis” AJRCCM, 2017, USA

Question: Does the timing of antibiotic administration in patients presenting with sepsis impact mortality?

Study Type: Retrospective study of a large healthcare database

Study Population: Adult patients presenting with sepsis (defined by ICD 9 codes + the receipt of abx within 6 hours of ED registration) to any of the 21 hospitals in the Kaiser Permanente Northern California system between 7/2010 and 12/2013.

Study Groups: Septic shock defined as need for vasopressors or initial serum lactate ³4; severe sepsis as a lactate ³2, ³1 instance of hypotension, need for invasive or non-invasive ventilation, or laboratory-determined organ dysfunction; all other patients classified as having sepsis. All vital signs obtained during the first hour were recorded and averaged. Abx administration calculated from the time of ED registration to the administration of the first abx in hours. Logistic regression was used to estimate the odds of hospital mortality based on abx timing and patient factors.

Primary Outcome: Hospital mortality

Results: 35,000 patients randomly selected. Notable patient characteristics: sepsis (35%), severe sepsis (52%), septic shock (13%), median age (73), mean first lactate (1.8), mechanical ventilation (1.4%), mortality of entire group (9.4%), mortality of patients with sepsis (3.9%), mortality of patients with severe sepsis (8.8%), mortality of patients with septic shock (26%). The fully adjusted odds ratio for hospital mortality based on abx timing was 1.09 (95% CI, 1.05-1.13) per elapsed hour after ED presentation. The absolute increase in mortality associated with a 1-hr delay in abx administration was 0.3% (95% CI, 0.01%-0.6%) for sepsis, 0.4% (95% CI, 0.1%-0.8%) for severe sepsis, and 1.8% (95% CI, 0.8%-3%) for shock.

Caveats: Retrospective, only able to describe an association not prove causation, no data provided on other aspects of early resuscitation which may impact outcome (IVF, did abx given cover causative pathogen, etc), only included patients presenting to the ED not patients who develop sepsis while hospitalized, relied upon ICD 9 codes to identify patients with sepsis.

Take-home Point: Among patients presenting to the ED with sepsis, severe sepsis, and septic shock, delays in abx administration are associated with increased mortality.

Commentary 

–        The most frequently cited paper on this subject is by Kumar (CCM, 2006) which retrospectively analyzed 2,731 patients with septic shock and found that for each hour delay in appropriate abx therapy after the onset of hypotension, mortality increased by 7.6%.

–        The result is less dramatic here (1.8% increase for each hour delay in patients with shock) and the authors highlight several methodological differences which may account for their findings.

–        The study has flaws, but it perhaps provides a more accurate look at the true mortality benefit of early abx in the modern era of sepsis management.