Time to Antibiotics (TTA) – Überlegungen der Arbeitsgruppe Fieber bei Granulozytopenie im Kindes- und Jugendalter (GPOH/DGPI) zu einer Neubewertung.

Zusammenfassung

Hintergrund Die geltende Leitlinie für kinderonkologische Patienten mit febriler Granulozytopenie (FN) von 2016 empfiehlt eine Time-to-Antibiotics (TTA)<60 min.

Methode Kritische Analyse verfügbarer Studien und Metaanalysen, Diskussion der Konsequenzen in der Arbeitsgruppe Fieber bei Granulozytopenie der Fachgesellschaften für pädiatrische Onkologie und Hämatologie und pädiatrische Infektiologie.

Ergebnisse Die verfügbaren Studien können keinen klinisch signifikanten Vorteil einer TTA<60 min für alle kinderonkologischen Patienten mit FN darstellen. Studien, die einen solchen Zusammenhang nahelegen, sind mit einem Triage Bias und anderen methodischen Limitationen behaftet und nutzen unterschiedliche TTA Definitionen. Hingegen ist eine TTA<60 min elementarer Bestandteil des Einstunden-Maßnahme-Bündels bei septischem Schock oder Sepsis mit Organdysfunktion.

Zusammenfassung Wenn alle kinderonkologischen Patienten mit neu aufgetretenem Fieber zeitnah durch gut ausgebildetes und trainiertes Fachpersonal eine strukturierte Anamnese und körperliche Untersuchung (inkl. Vitalzeichen) erhalten und unter der Voraussetzung, dass lokal eine Sepsis Triage und Management Bündel etabliert und implementiert wurde, ist eine TTA<3 h bei kinderonkologischen Patienten mit FN angemessen.

Abstract

Background The current German guidance from 2016 recommends a Time to Antibiotics (TTA) of<60 min in children and adolescents with febrile neutropenia (FN).

Methods Critical analysis of available studies and recent meta-analyses, and discussion of the practical consequences in the FN working group of the German Societies for Paediatric Oncology and Haematology and Paediatric Infectious Diseases.

ResultsThe available evidence does not support a clinically significant outcome benefit of a TTA<60 min in all paediatric patients with FN. Studies suggesting such a benefit are biased (mainly triage bias), use different TTA definitions and display further methodical limitations. In any case, a TTA<60 min remains an essential component of the 1st hour-bundle in paediatric cancer patients with septic shock or sepsis with organ dysfunction.

Conclusion Provided that all paediatric FN patients receive a structured medical history and physical examination (including vital signs) by experienced and trained medical personnel in a timely fashion, and provided that a sepsis triage and management bundle is established and implemented, a TTA lower than 3 hours is sufficient and reasonable in stable paediatric cancer patients with FN.

Schlüsselwörter

Kinder mit Krebserkrankung - Fieber - Granulozytopenie - Time to Antibiotics

Key words

children with cancer - fever - neutropenia - time to antibiotics

• Literatur

• 1 Wösten-van Asperen RM, van Gestel JPJ, van Grotel M. et al. PICU mortality of children with cancer admitted to pediatric intensive care unit a systematic review and meta-analysis. Crit Rev Oncol Hematol 2019; 142: 153-163
• 2 Barking C, Masjosthusmann K, Rellensmann G. et al. Treatment of Children With Cancer and/or Hematopoietic Stem Cell Transplantation in the Intensive Care Unit: Experience at a Large European Pediatric Cancer Center. J Pediatr Hematol Oncol 2020; 42: e583-e588
• 3 Azevedo RT, Araujo OR, Petrilli AS. et al. Children with malignancies and septic shock – an attempt to understand the risk factors. J Pediatr (Rio J) 2023; 99: 127-132
• 4 Long E, Babl FE, Phillips N. et al. Prevalence and predictors of poor outcome in children with febrile neutropaenia presenting to the emergency department. Emergency medicine Australasia: EMA 2022; 34: 786-793
• 5 Sano H, Kobayashi R, Iguchi A. et al. Risk factors for sepsis-related death in children and adolescents with hematologic and malignant diseases. J Microbiol Immunol Infect 2017; 50: 232-238
• 6 Caballero M, Faura A, Margarit A. et al. Outcomes for paediatric acute leukaemia patients admitted to the paediatric intensive care unit. Eur J Pediatr 2022; 181: 1037-1045
• 7 Salstrom JL, Coughlin RL, Pool K. et al. Pediatric patients who receive antibiotics for fever and neutropenia in less than 60 min have decreased intensive care needs. Pediatr Blood Cancer 2015; 62: 807-815
• 8 Pakakasama S, Surayuthpreecha K, Pandee U. et al. Clinical practice guidelines for children with cancer presenting with fever to the emergency room. Pediatr Int 2011; 53: 902-905
• 9 Fletcher M, Hodgkiss H, Zhang S. et al. Prompt administration of antibiotics is associated with improved outcomes in febrile neutropenia in children with cancer. Pediatr Blood Cancer 2013; 60: 1299-1306
• 10 Corey AL, Snyder S. Antibiotics in 30 minutes or less for febrile neutropenic patients: a quality control measure in a new hospital. J Pediatr Oncol Nurs 2008; 25: 208-212
• 11 Deutsche Gesellschaft für pädiatrische Infektiologie (DGPI), Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH). Diagnostik und Therapie bei Kindern mit onkologischer Grunderkrankung, Fieber und Granulozytopenie (mit febriler Neutropenie) außerhalb der allogenen Stammzelltransplantation. Arbeitsgemeinschaft Wissenschaftlicher Fachgesellschaften (AWMF). 2016 Registernummer 048/14
• 12 Evans IVR, Phillips GS, Alpern ER. et al. Association Between the New York Sepsis Care Mandate and In-Hospital Mortality for Pediatric Sepsis. JAMA 2018; 320: 358-367
• 13 Weiss SL, Peters MJ, Alhazzani W. et al. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Intensive Care Med 2020; 46: 10-67
• 14 Weiss SL, Peters MJ, Alhazzani W. et al. Executive Summary: Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children. Pediatr Crit Care Med 2020; 21: 186-195
• 15 Scott HF, Kempe A, Deakyne Davies SJ. et al. Managing Diagnostic Uncertainty in Pediatric Sepsis Quality Improvement with a Two-Tiered Approach. Pediatr Qual Saf 2020; 5: e244
• 16 Eisenberg MA, Balamuth F. Pediatric sepsis screening in US hospitals. Pediatr Res 2022; 91: 351-358
• 17 Davis AL, Carcillo JA, Aneja RK. et al. The American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock: Executive Summary. Pediatr Crit Care Med 2017; 18: 884-890
• 18 Hoffmann F, Schmalhofer M, Lehner M. et al. Comparison of the AVPU Scale and the Pediatric GCS in Prehospital Setting. Prehospital emergency care 2016; 20: 493-498
• 19 Dieckmann RA, Brownstein D, Gausche-Hill M. The pediatric assessment triangle: a novel approach for the rapid evaluation of children. Pediatr Emerg Care 2010; 26: 312-315
• 20 Fernandez A, Ares MI, Garcia S. et al. The Validity of the Pediatric Assessment Triangle as the First Step in the Triage Process in a Pediatric Emergency Department. Pediatr Emerg Care 2017; 33: 234-238
• 21 Blythe R, Lister P, Seaton R. et al. Patient and economic impact of implementing a paediatric sepsis pathway in emergency departments in Queensland, Australia. Scientific reports 2022; 12: 10113
• 22 Harley A, Lister P, Gilholm P. et al. Queensland Pediatric Sepsis Breakthrough Collaborative: Multicenter Observational Study to Evaluate the Implementation of a Pediatric Sepsis Pathway Within the Emergency Department. Crit Care Explor 2021; 3: e0573
• 23 Larsen GY, Brilli R, Macias CG. et al. Development of a Quality Improvement Learning Collaborative to Improve Pediatric Sepsis Outcomes. Pediatrics 2021; 147: e20201434
• 24 Nijman RG, Jorgensen R, Levin M. et al. Management of Children With Fever at Risk for Pediatric Sepsis: A Prospective Study in Pediatric Emergency Care. Frontiers in pediatrics 2020; 8: 548154
• 25 Schlapbach LJ, Weiss SL, Wolf J. Reducing Collateral Damage From Mandates for Time to Antibiotics in Pediatric Sepsis-Primum Non Nocere. JAMA Pediatr 2019; 173: 409-410
• 26 Schlapbach LJ, Kissoon N. Defining Pediatric Sepsis. JAMA Pediatr 2018; 172: 312-314
• 27 Bosk A, Groll AH, Hufnagel M. et al Leitlinie Sepsis bei Kindern jenseits der Neonatalperiode. Arbeitsgemeinschaft Wissenschaftlicher Fachgesellschaften (AWMF). 2016 Registernummer 024-05
• 28 Sasse M, Seidemann K. Sepsis bei Kindern. Monatsschr Kinderheilkd 2018; 166: 41-47
• 29 Singer M, Deutschman CS, Seymour CW. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315: 801-810
• 30 Massaud-Ribeiro L, Silami P, Lima-Setta F. et al. Pediatric Sepsis Research: Where Are We and Where Are We Going?. Frontiers in pediatrics 2022; 10: 829119
• 31 Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005; 6: 2-8
• 32 Fitzgerald JC, Ross ME, Thomas NJ. et al. Association of early hypotension in pediatric sepsis with development of new or persistent acute kidney injury. Pediatr Nephrol 2021; 36: 451-461
• 33 Emmel M, Hoffmann F, Dohna-Schwake C. et al. Schock im Kindesalter – viele Ursachen und schwierig zu erkennen. Definition und Besonderheiten im Kindesalter. Monatsschr Kinderheilkd 2020; 168: 118-129
• 34 Balamuth F, Scott HF, Weiss SL. et al. Validation of the Pediatric Sequential Organ Failure Assessment Score and Evaluation of Third International Consensus Definitions for Sepsis and Septic Shock Definitions in the Pediatric Emergency Department. JAMA Pediatr 2022; 176: 672-678
• 35 Weiss SL, Balamuth F, Hensley J. et al. The Epidemiology of Hospital Death Following Pediatric Severe Sepsis: When, Why, and How Children With Sepsis Die. Pediatr Crit Care Med 2017; 18: 823-830
• 36 Fausser JL, Tavenard A, Rialland F. et al. Should We Pay Attention to the Delay Before Admission to a Pediatric Intensive Care Unit for Children With Cancer? Impact on 1-Month Mortality. A Report From the French Children’s Oncology Study Group, GOCE. J Pediatr Hematol Oncol 2017; 39: e244-e248
• 37 Larsen GY, Mecham N, Greenberg R. An emergency department septic shock protocol and care guideline for children initiated at triage. Pediatrics 2011; 127: e1585-e1592
• 38 Balamuth F, Weiss SL, Fitzgerald JC. et al. Protocolized Treatment Is Associated With Decreased Organ Dysfunction in Pediatric Severe Sepsis. Pediatr Crit Care Med 2016; 17: 817-822
• 39 Sankar J, Garg M, Ghimire JJ. et al. Delayed Administration of Antibiotics Beyond the First Hour of Recognition Is Associated with Increased Mortality Rates in Children with Sepsis/Severe Sepsis and Septic Shock. J Pediatr 2021; 233: 183-190.e183
• 40 Stella P, Haines E, Aphinyanaphongs Y. Prediction of Resuscitation for Pediatric Sepsis from Data Available at Triage. AMIA Annual Symposium proceedings/AMIA Symposium AMIA Symposium 2021; 2021: 1129-1138
• 41 Gerber N, Vella A, Racine-Brzostek S. et al. Rapid Absolute Neutrophil Count Testing Guides Targeted Antimicrobial Therapy in Febrile Pediatric Oncology Patients. Pediatr Emerg Care 2022; 38: e743-e745
• 42 Koenig C, Morgan J, Ammann RA. et al. Protocol for a systematic review of time to antibiotics (TTA) in patients with fever and neutropenia during chemotherapy for cancer (FN) and interventions aiming to reduce TTA. Systematic reviews 2019; 8: 82
• 43 Koenig C, Schneider C, Morgan JE. et al. Association of time to antibiotics and clinical outcomes in patients with fever and neutropenia during chemotherapy for cancer: a systematic review. Support Care Cancer 2020; 28: 1369-1383
• 44 Koenig C, Schneider C, Morgan JE. et al. Interventions aiming to reduce time to antibiotics (TTA) in patients with fever and neutropenia during chemotherapy for cancer (FN), a systematic review. Support Care Cancer 2020; 28: 2369-2380
• 45 Koenig C, Kuehni CE, Bodmer N. et al. Time to antibiotics is unrelated to outcome in pediatric patients with fever in neutropenia presenting without severe disease during chemotherapy for cancer. Scientific reports 2022; 12: 14028
• 46 Koenig C, Bodmer N, Agyeman PKA. et al. 39·0°C versus 38·5°C ear temperature as fever limit in children with neutropenia undergoing chemotherapy for cancer: a multicentre, cluster-randomised, multiple-crossover, non-inferiority trial. The Lancet Child & adolescent health 2020; 4: 495-502
• 47 Dessie AS, Lanning M, Nichols T. et al. Patient Outcomes With Febrile Neutropenia Based on Time to Antibiotics in the Emergency Department. Pediatr Emerg Care 2022; 38: e259-e263
• 48 Fananapazir N, Dandoy C, Byczkowski T. et al. Study of Delayed Antibiotic in Pediatric Febrile Immunocompromised Patients and Adverse Events. Hospital pediatrics 2019; 9: 379-386
• 49 Dandoy CE, Hariharan S, Weiss B. et al. Sustained reductions in time to antibiotic delivery in febrile immunocompromised children: results of a quality improvement collaborative. BMJ Qual Saf 2016; 25: 100-109
• 50 De la Maza V, Simian D, Castro M. et al. Administration Time for the First Dose of Antimicrobials in Episodes of Fever and Neutropenia in Children With Cancer. Pediatr Infect Dis J 2015; 34: 1069-1073