Prognostication of Mortality in Critically 111 Patients With Severe Infections

      BACKGROUND

      The purpose of this study was to confirm the prognostic value of pancreatic stone protein (PSP) in patients with severe infections requiring ICU management and to develop and validate a model to enhance mortality prediction by combining severity scores with biomarkers.

      METHODS

      We enrolled prospectively patients with severe sepsis or septic shock in mixed tertiary ICUs in Switzerland (derivation cohort) and Brazil (validation cohort). Severity scores (APACHE [Acute Physiology and Chronic Health Evaluation] II or Simplified Acute Physiology Score [SAPS] II) were combined with biomarkers obtained at the time of diagnosis of sepsis, including C-reactive-protein, procalcitonin (PCT), and PSP. Logistic regression models with the lowest prediction errors were selected to predict in-hospital mortality.

      RESULTS

      Mortality rates of patients with septic shock enrolled in the derivation cohort (103 out of 158) and the validation cohort (53 out of 91) were 37% and 57%, respectively. APACHE II and PSP were significantly higher in dying patients. In the derivation cohort, the models combining either APACHE II, PCT, and PSP (area under the receiver operating characteristic curve [AUC], 0.721; 95% CI, 0.632-0.812) or SAPS II, PCT, and PSP (AUC, 0.710; 95% CI, 0.617-0.802) performed better than each individual biomarker (AUC PCT, 0.534; 95% CI, 0.433-0.636; AUC PSP, 0.665; 95% CI, 0.572-0.758) or severity score (AUC APACHE II, 0.638; 95% CI, 0.543-0.733; AUC SAPS II, 0.598; 95% CI, 0.499-0.698). These models were externally confirmed in the independent validation cohort.

      CONCLUSIONS

      We confirmed the prognostic value of PSP in patients with severe sepsis and septic shock requiring ICU management. A model combining severity scores with PCT and PSP improves mortality prediction in these patients.

      ABBREVIATIONS:

      APACHE ( Acute Physiology and Chronic Health Evaluation), AUC ( area under the curve), CRP ( C-reactive protein), IQR ( interquartile range), MCE ( misclassification error), PCT ( procalcitonin), PSP ( pancreatic stone protein), SAPS ( Simplified Acute Physiology Score), SOFA ( Sequential Organ Failure Assessment), SPE ( squared prediction error), suPAR ( urokinase plasminogen activator receptor)
      To read this article in full you will need to make a payment
      Subscribe to CHEST
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bernard GR
        • Vincent JL
        • Laterre PF
        • Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group
        • et al.
        Efficacy and safety of recombinant human activated protein C for severe sepsis.
        N Engl J Med. 2001; 344: 699-709
        • Vincent JL
        • Sakr Y
        • Sprung CL
        • Sepsis Occurrence in Acutely Ill Patients Investigators
        • et al.
        Sepsis in European intensive care units: results of the SOAP study.
        Crit Care Med. 2006; 34: 344-353
        • Vincent JL
        • Rello J
        • Marshall J
        • EPIC II Group of Investigators
        • et al.
        International study of the prevalence and outcomes of infection in intensive care units.
        JAMA. 2009; 302: 2323-2329
        • Dellinger RP
        • Levy MM
        • Rhodes A
        • Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup
        • et al.
        Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012.
        Intensive Care Med. 2013; 39: 165-228
        • Calandra T
        • Glauser MP
        • Schellekens J
        • Verhoef J
        Treatment of gram-negative septic shock with human IgG antibody to Escherichia coli J5: a prospective, double-blind, randomized trial.
        J Infect Dis. 1988; 158: 312-319
        • Abraham E
        • Anzueto A
        • Gutierrez G
        • NORASEPT II Study Group
        • et al.
        Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock.
        Lancet. 1998; 351: 929-933
        • Opal S
        • Laterre PF
        • Abraham E
        • Controlled Mortality Trial of Platelet-Activating Factor Acetylhydrolase in Severe Sepsis Investigators
        • et al.
        Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial.
        Crit Care Med. 2004; 32: 332-341
        • Hotchkiss RS
        • Karl IE
        The pathophysiology and treatment of sepsis.
        N Engl JMed. 2003; 348: 138-150
        • Ranieri VM
        • Thompson BT
        • Barie PS
        • PROWESS-SHOCK Study Group
        • et al.
        Drotrecogin alfa (activated) in adults with septic shock.
        N Engl J Med. 2012; 366: 2055-2064
        • Opal SM
        • Laterre PF
        • Francois B
        • ACCESS Study Group
        • et al.
        Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial.
        JAMA. 2013; 309: 1154-1162
        • Bernard GR
        • Francois B
        • Mira JP
        • et al.
        Evaluating the efficacy and safety of two doses of the polyclonal anti-tumor necrosis factor-α fragment antibody AZD9773 in adult patients with severe sepsis and/or septic shock: randomized, double-blind, placebo-controlled phase IIb study.
        Crit Care Med. 2014; 42: 504-511
        • Vincent JL
        • Donadello K
        • Schmit X
        Biomarkers in the critically ill patient: C-reactive protein.
        Crit Care Clin. 2011; 27: 241-251
        • Que YA
        • Virgini V
        • Lozeron ED
        • et al.
        Low C-reactive protein values at admission predict mortality in patients with severe community-acquired pneumonia caused by Streptococcus pneumoniae that require intensive care management.
        Infection. 2015; 43: 193-199
        • Tang BM
        • Eslick GD
        • Craig JC
        • McLean AS
        Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis.
        Lancet Infect Dis. 2007; 7: 210-217
        • Keel M
        • Härter L
        • Reding T
        • et al.
        Pancreatic stone protein is highly increased during posttraumatic sepsis and activates neutrophil granulocytes.
        Crit Care Med. 2009; 37: 1642-1648
        • Schlapbach LJ
        • Graf R
        • Woerner A
        • et al.
        Pancreatic stone protein as a novel marker for neonatal sepsis.
        Intensive Care Med. 2013; 39: 754-763
        • Llewelyn MJ
        • Berger M
        • Gregory M
        • et al.
        Sepsis biomarkers in unselected patients on admission to intensive or high-dependency care.
        Crit Care. 2013; 17: R60
        • Klein HJ
        • Csordas A
        • Falk V
        • et al.
        Pancreatic stone protein predicts postoperative infection in cardiac surgery patients irrespective of cardiopulmonary bypass or surgical technique.
        PLoS ONE. 2015; 10: e0120276
        • Boeck L
        • Graf R
        • Eggimann P
        • et al.
        Pancreatic stone protein: a marker of organ failure and outcome in ventilator-associated pneumonia.
        Chest. 2011; 140: 925-932
        • Que YA
        • Delodder F
        • Guessous I
        • et al.
        Pancreatic stone protein as an early biomarker predicting mortality in a prospective cohort of patients with sepsis requiring ICU management.
        Crit Care. 2012; 16: R114
        • Gukasjan R
        • Raptis DA
        • Schulz HU
        • Halangk W
        • Graf R
        Pancreatic stone protein predicts outcome in patients with peritonitis in the ICU.
        Crit Care Med. 2013; 41: 1027-1036
        • Calandra T
        • Baumgartner JD
        • Grau GE
        • et al.
        Prognostic values of tumor necrosis factor/cachectin, interleukin-1, interferonalpha, and interferon-gamma in the serum of patients with septic shock. Swiss-Dutch J5 Immunoglobulin Study Group.
        J Infect Dis. 1990; 161: 982-987
        • Calandra T
        • Gerain J
        • Heumann D
        • Baumgartner JD
        • Glauser MP
        High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss-Dutch J5 Immunoglobulin Study Group.
        Am J Med. 1991; 91: 23-29
        • Pierrakos C
        • Vincent JL
        Sepsis biomarkers: a review.
        Crit Care. 2010; 14: R15
        • Levy MM
        • Fink MP
        • Marshall JC
        • SCCM/ESICM/ACCP/ATS/SIS
        • et al.
        2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.
        Crit Care Med. 2003; 31: 1250-1256
        • Garner JS
        • Jarvis WR
        • Emori TG
        • Horan TC
        • Hughes JM
        CDC definitions for nosocomial infections, 1988.
        Am J Infect Control. 1988; 16: 128-140
        • Calandra T
        • Cohen J
        • International Sepsis Forum Definition of Infection in the ICU Consensus Conference
        The international sepsis forum consensus conference on definitions of infection in the intensive care unit.
        Crit Care Med. 2005; 33: 1538-1548
        • DeLong ER
        • DeLong DM
        • Clarke-Pearson DL
        Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.
        Biometrics. 1988; 44: 837-845
        • Efron B
        How biased is the apparent error rate of a prediction rule?.
        J Am Stat Assoc. 1986; 81: 461-470
        • Sing T
        • Sander O
        • Beerenwinkel N
        • Lengauer T
        ROCR: visualizing classifier performance in R.
        Bioinformatics. 2005; 21: 3940-3941
        • Wood SN
        Fast stable restricted maximum likelihood and marginal likelihood estimation of semiparametric generalized linear models.
        J R Stat Soc Series B Stat Methodol. 2011; 73: 3-36
        • Robin X
        • Turck N
        • Hainard A
        • et al.
        pROC: an open-source package for R and S+ to analyze and compare ROC curves.
        BMC Bioinformatics. 2011; 12: 77
        • Wickham H
        ggplot2: Elegant Graphics for Data Analysis. Springer, New York, NY2009
        • Bouadma L
        • Luyt CE
        • Tubach F
        • PRORATA trial group
        • et al.
        Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial.
        Lancet. 2010; 375: 463-474
        • Wacker C
        • Prkno A
        • Brunkhorst FM
        • Schlattmann P
        Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis.
        Lancet Infect Dis. 2013; 13: 426-435
        • Vincent JL
        • Opal SM
        • Marshall JC
        Ten reasons why we should NOT use severity scores as entry criteria for clinical trials or in our treatment decisions.
        Crit Care Med. 2010; 38: 283-287
        • Shapiro NI
        • Trzeciak S
        • Hollander JE
        • et al.
        A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis.
        Crit Care Med. 2009; 37: 96-104
        • Giamarellos-Bourboulis EJ
        • Norrby-Teglund A
        • Mylona V
        • et al.
        Risk assessment in sepsis: a new prognostication rule by APACHE II score and serum soluble urokinase plasminogen activator receptor.
        Crit Care. 2012; 16: R149
        • Suberviola B
        • Castellanos-Ortega A
        • Ruiz Ruiz A
        • Lopez-Hoyos M
        • Santibañez M
        Hospital mortality prognostication in sepsis using the new biomarkers suPAR and proADM in a single determination on ICU admission.
        Intensive Care Med. 2013; 39: 1945-1952
      1. Alan M, Grolimund E, Kutz A, et al; the ProHOSP study group. Clinical risk scores and blood biomarkers as predictors of long-term outcome in patients with community-acquired pneumonia: a 6-year prospective follow-up study [published online ahead of print December 19, 2014]. J Intern Med. doi:https://doi.org/10.1111/joim.12341.

        • Angus DC
        • Linde-Zwirble WT
        • Lidicker J
        • Clermont G
        • Carcillo J
        • Pinsky MR
        Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.
        Crit Care Med. 2001; 29: 1303-1310
        • Angus DC
        • van der Poll T
        Severe sepsis and septic shock.
        N Engl J Med. 2013; 369: 840-851
        • Cruz DN
        • Antonelli M
        • Fumagalli R
        • et al.
        Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial.
        JAMA. 2009; 301: 2445-2452
        • Lu Q
        • Rouby JJ
        • Laterre PF
        • et al.
        Pharmacokinetics and safety of panobacumab: specific adjunctive immunotherapy in critical patients with nosocomial Pseudomonas aeruginosa O11 pneumonia..
        JAntimicrob Chemother. 2011; 66: 1110-1116
        • Bein T
        • Weber-Carstens S
        • Goldmann A
        • et al.
        Lower tidal volume strategy (′3 ml/kg) combined with extracorporeal CO2 removal versus ‘conventional’ protective ventilation (6 ml/kg) in severe ARDS: the prospective randomized Xtravent-study.
        Intensive Care Med. 2013; 39: 847-856
        • Calfee CS
        • Pugin J
        The search for diagnostic markers in sepsis: many miles yet to go.
        Am J Respir Crit Care Med. 2012; 186: 2-4
      2. Lascco announces a licensing agreement with Abbott for development and commercialization of pancreatic stone protein biomarker. Lajaunias Science Company website.
        (Accessed May 10, 2015)