Procalcitonina y sepsis
2
Procalcitonin as a Sepsis Biomarker Opposing authors provide succinct, authoritative discussions of controversial issues in emergency medicine. Authors are provided the opportunity to review and comment on opposing presentations. Each topic is accompanied by an Editor’s Note that summarizes important concepts. Participation as at authoritative discussant is by invitation only, but suggestions for topics and potential authors can be submitted to the section editors. Editor’s Note: Procalcitonin has been promoted as an effective biomarker for patients with suspected sepsis, but it is unclear whether assessing procalcitonin levels leads to improved patient outcomes. In this Clinical Controversies series, our discussants present the pros and cons of using procalcitonin to identify and manage patients with suspected sepsis. PROCALCITONIN: AN EFFECTIVE SCREENING TOOL AND SAFE THERAPEUTIC DECISIONMAKING AID FOR EMERGENCY DEPARTMENT PATIENTS WITH SUSPECTED SEPSIS Philipp Schuetz, MD, MPH; Beat Mueller, MD Medical University Department, Internal Medicine and Emergency Medicine, Kantonsspital Aarau, Aarau, Switzerland Today’s standard sepsis definition is based on the long-established recognition that the host response is an important aspect of the sepsis syndrome. Unfortunately, the systemic inflammatory response syndrome criteria have been less useful to diagnose sepsis than anticipated, lacking sensitivity, specificity, and ease of clinical application. 1 Had the host-response biomarker procalcitonin been available by then, it would certainly have been preferred over the WBC count as the laboratory-based systemic inflammatory response syndrome criterion, considering procalcitonin’s advantages, outlined below. Although not a “perfect sepsis biomarker,” procalcitonin is currently the best such biomarker in regard to diagnosis, therapeutic guidance, and risk stratification. Unlike any other sepsis markers, numerous clinical studies have documented that procalcitonin-guided sepsis care results in cost-effective and targeted management of patients. Several arguments support its use in daily clinical practice. First, because of its regulation, procalcitonin is more specific toward bacterial infections than other inflammatory biomarkers. Procalcitonin is up-regulated by microbial toxins and certain proinflammatory mediators (eg, interleukin-1b, tumor necrosis factor-a, interleukin-6) and down-regulated as these substances subside during recovery. Conversely, procalcitonin expression is attenuated by cytokines typically released during viral infection (eg, interferon-g). 2 By flagging the presence and tracking the status of systemic bacterial infection, procalcitonin measurements aid in determining bacterial sepsis risk and course, as well as bacterial sepsis treatment efficacy. 3,4 Second, procalcitonin is helpful in identifying sepsis and bacteremia risk. A 2007 meta-analysis including 17 observational sepsis studies totaling greater than 2,000 patients found a high discriminatory value of procalcitonin (area under the curve 0.84) for bacteremia, with blood culture as the reference standard. 5 In accordance with a large pneumonia cohort, low initial procalcitonin levels were estimated to make bacteremic disease highly unlikely. 6 Applying this finding to decisionmaking about blood culture could substantially cut the number of negative culture results. 6 For patients with coagulase-negative staphylococcus growth in blood cultures, low procalcitonin level effectively rules out true bacteremia and points to culture contamination. 7 Third, for patients presenting with systemic inflammatory response syndrome, procalcitonin level differentiates true infection from other causes with high diagnostic accuracy. A recent meta-analysis including 30 high-quality observational studies totaling greater than 3,200 patients found procalcitonin to have an overall area under the curve of 0.85 to differentiate sepsis versus systemic inflammatory response syndrome in different settings. 8 Results were similar for medical, surgical, or pediatric patients, with sensitivities and specificities of approximately 75% to 80%. Despite heterogeneity in underlying sepsis studies, these results illustrate that procalcitonin is the most promising biochemical marker for sepsis diagnosis. Fourth, procalcitonin is the only widely available biomarker that improves choices about initiation and duration of antibiotic treatment in patients with respiratory infections. Interventional evidence demonstrates that in mostly septic patients with pneumonia or other respiratory infection, procalcitonin protocols 9 led to significant 318 Annals of Emergency Medicine Volume 66, no. 3 : September 2015 CLINICAL CONTROVERSIES
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Procalcitonina y sepsis
Transcript of Procalcitonina y sepsis
CLINICAL CONTROVERSIES
Procalcitonin as a Sepsis Biomarker
318 A
Opposing authors provide succinct, authoritative discussions of controversial issues in emergency medicine.Authors are provided the opportunity to review and comment on opposing presentations. Each topic isaccompanied by an Editor’s Note that summarizes important concepts. Participation as at authoritativediscussant is by invitation only, but suggestions for topics and potential authors can be submitted to the sectioneditors.
Editor’s Note: Procalcitonin has been promoted as aneffective biomarker for patients with suspected sepsis, butit is unclear whether assessing procalcitonin levels leads toimproved patient outcomes. In this Clinical Controversiesseries, our discussants present the pros and cons of usingprocalcitonin to identify and manage patients withsuspected sepsis.
PROCALCITONIN: AN EFFECTIVE SCREENINGTOOL AND SAFE THERAPEUTICDECISIONMAKING AID FOR EMERGENCYDEPARTMENT PATIENTS WITHSUSPECTED SEPSIS
Philipp Schuetz, MD, MPH; Beat Mueller, MD
Medical University Department, Internal Medicine andEmergency Medicine, Kantonsspital Aarau, Aarau,Switzerland
Today’s standard sepsis definition is based on thelong-established recognition that the host response is animportant aspect of the sepsis syndrome. Unfortunately,the systemic inflammatory response syndrome criteria havebeen less useful to diagnose sepsis than anticipated, lackingsensitivity, specificity, and ease of clinical application.1 Hadthe host-response biomarker procalcitonin been availableby then, it would certainly have been preferred over theWBC count as the laboratory-based systemic inflammatoryresponse syndrome criterion, considering procalcitonin’sadvantages, outlined below. Although not a “perfectsepsis biomarker,” procalcitonin is currently the bestsuch biomarker in regard to diagnosis, therapeuticguidance, and risk stratification. Unlike any other sepsismarkers, numerous clinical studies have documented thatprocalcitonin-guided sepsis care results in cost-effectiveand targeted management of patients. Several argumentssupport its use in daily clinical practice.
First, because of its regulation, procalcitonin ismore specific toward bacterial infections than otherinflammatory biomarkers. Procalcitonin is up-regulated bymicrobial toxins and certain proinflammatory mediators
nnals of Emergency Medicine
(eg, interleukin-1b, tumor necrosis factor-a, interleukin-6)and down-regulated as these substances subside duringrecovery. Conversely, procalcitonin expression is attenuatedby cytokines typically released during viral infection (eg,interferon-g).2 By flagging the presence and tracking thestatus of systemic bacterial infection, procalcitoninmeasurements aid in determining bacterial sepsis riskand course, as well as bacterial sepsis treatment efficacy.3,4
Second, procalcitonin is helpful in identifying sepsis andbacteremia risk. A 2007 meta-analysis including 17observational sepsis studies totaling greater than2,000patientsfound a high discriminatory value of procalcitonin (area underthe curve 0.84) for bacteremia, with blood culture as thereference standard.5 In accordance with a large pneumoniacohort, low initial procalcitonin levels were estimated to makebacteremic disease highly unlikely.6 Applying this finding todecisionmaking about blood culture could substantially cutthe number of negative culture results.6 For patients withcoagulase-negative staphylococcus growth in blood cultures,low procalcitonin level effectively rules out true bacteremiaand points to culture contamination.7
Third, for patients presenting with systemic inflammatoryresponse syndrome, procalcitonin level differentiates trueinfection from other causes with high diagnostic accuracy. Arecent meta-analysis including 30 high-quality observationalstudies totaling greater than 3,200 patients foundprocalcitonin to have an overall area under the curve of 0.85to differentiate sepsis versus systemic inflammatory responsesyndrome in different settings.8 Results were similar formedical, surgical, or pediatric patients, with sensitivities andspecificities of approximately 75% to 80%. Despiteheterogeneity in underlying sepsis studies, these resultsillustrate that procalcitonin is the most promisingbiochemical marker for sepsis diagnosis.
Fourth, procalcitonin is the only widely availablebiomarker that improves choices about initiation andduration of antibiotic treatment in patients with respiratoryinfections. Interventional evidence demonstrates that inmostly septic patients with pneumonia or other respiratoryinfection, procalcitonin protocols9 led to significant
Volume 66, no. 3 : September 2015
Clinical Controversies
diminution in antibiotic (over)exposure. Protocols usingserially measured procalcitonin to guide early antibiotictreatment discontinuation resulted in sharp reductions(30% to 70%) in antibiotic courses. A recent individualpatient data meta-analysis including greater than 4,200patients found that antibiotic exposure decreased from(median) 8 days to 4 days in procalcitonin arms versuscontrol arms. Mortality in procalcitonin arms was similar,and treatment failure risks were significantly lowercompared with when procalcitonin was not applied toantibiotic-related decisionmaking.3,10 These studies led toprocalcitonin’s inclusion in the current sepsis guidelines,which suggest that a low procalcitonin measurement willassist clinicians in discontinuing empiric antibiotics whenno evidence of infection is found.11
Fifth, procalcitonin has prognostic implicationsassociated with clinical outcome. Procalcitonin levelperformed better than WBC count or C-reactive protein(CRP) level in detecting serious bacterial infectionamong children with fever of no apparent source. A USstudy found an approximately 90% negative predictivevalue for sepsis mortality when procalcitonin leveldecreased by greater than or equal to 80% within 72hours of ICU admission.12 When procalcitonin level didnot decrease or even increased, positive predictive valuesfor mortality were approximately 36% to 48%. The highprognostic value of procalcitonin level in identifyingpatients at high risk for adverse outcomes was also foundin a large Danish study.13 Although antibiotic therapyescalation in patients with persistently increasedprocalcitonin level did not decrease mortality in thisstudy, this likely illustrates the limitations of currentsepsis treatment rather than a limitation in theprognostic ability of the test.
Sixth, an individual patient data meta-analysis foundprocalcitonin-guided care to be cost-effective.14 Althoughinitial costs of procalcitonin testing are higher compared withthat of older biomarkers such as CRP, procalcitonin-guidedcare still results in important cost savings because of improvedpatient care and shorter antibiotic courses. Similar cost data arenot available for CRP, lactate, and other infection markers.
Sepsis is not a well-defined disease, but rather a complexsyndrome developing from heterogeneous underlyinginfections. Consequently, current sepsis markers have lowerdiagnostic performance compared with that of otherdiagnostic markers such as troponin and D-dimer usedin other clinical conditions. Instead of evaluating novelsepsis markers according to their ability to diagnose thesyndrome with the arbitrary sepsis definition establishedmore than 25 years ago,4 we should focus on the results of
Volume 66, no. 3 : September 2015
comparative efficacy research trials. These trials willmeasure whether a potential sepsis biomarker ultimatelyimproves identification of at-risk patients by assessingeffects on antibiotic exposure and clinical outcomes. As adiagnostic and prognostic tool, procalcitonin has been putto the test and the results are encouraging. The convergingcrises of increasing resistance and collapse of antibioticresearch need urgent action. More widespreadprocalcitonin use in sepsis patients is an evidence-based firststep to limit prolonged courses of unnecessaryantimicrobials, blunt the further development ofantimicrobial resistance, and cut costs while maintainingsignificant gains achieved in reducing sepsis mortality.
http://dx.doi.org/10.1016/j.annemergmed.2015.03.029
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3. Schuetz P, Muller B, Christ-Crain M, et al. Procalcitonin to initiate ordiscontinue antibiotics in acute respiratory tract infections. CochraneDatabase Syst Rev. 2012;(9):CD007498.
4. Schuetz P, Christ-Crain M, Muller B. Procalcitonin and otherbiomarkers to improve assessment and antibiotic stewardship ininfections—hope for hype? Swiss Med Wkly. 2009;139:318-326.
5. Jones AE, Fiechtl JF, Brown MD, et al. Procalcitonin test in thediagnosis of bacteremia: a meta-analysis. Ann Emerg Med.2007;50:34-41.
6. Muller F, Christ-Crain M, Bregenzer T, et al. Procalcitonin levels predictbacteremia in patients with community-acquired pneumonia: aprospective cohort trial. Chest. 2010;138:121-129.
7. Schuetz P, Mueller B, Trampuz A. Serum procalcitonin fordiscrimination of blood contamination from bloodstream infection dueto coagulase-negative staphylococci. Infection. 2007;35:352-355.
8. Wacker C, Prkno A, Brunkhorst FM, et al. Procalcitonin as a diagnosticmarker for sepsis: a systematic review and meta-analysis. LancetInfect Dis. 2013;13:426-435.
9. Schuetz P, Chiappa V, Briel M, et al. Procalcitonin algorithms forantibiotic therapy decisions: a systematic review of randomizedcontrolled trials and recommendations for clinical algorithms. ArchIntern Med. 2011;171:1322-1331.
10. Schuetz P, Mueller B. It is all about risk-adapted algorithms. Crit CareMed. 2013;41:e27.
11. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign:international guidelines for management of severe sepsis and septicshock, 2012. Intensive Care Med. 2013;39:165-228.
12. Schuetz P, Maurer P, Punjabi V, et al. Procalcitonin decrease over 72hours in US critical care units predicts fatal outcome in sepsispatients. Crit Care. 2013;17:R115.
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14. Schuetz P, Balk R, Briel M, et al. Economic evaluation of procalcitonin-guided antibiotic therapy in acute respiratory infections: a US healthsystem perspective. Clin Chem Lab Med. 2015;53:583-592.
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