Hvordan skapes ulike behandlingstradisjoner og hvor lette er de å endre? Håvard Ove Skjerven, PhD Overlege og forsker

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1 1 Hvordan skapes ulike behandlingstradisjoner og hvor lette er de å endre? Håvard Ove Skjerven, PhD Overlege og forsker

2 2 Påstander Behandlingstrender er selvforsterkende Ikke avhengig av ny evidens Vilje og motivasjon er sterkere til å iverksette ny behandling enn til å avslutte eksisterende Individnivå Gruppenivå

3 3 Agenda Eksempler på ulike behandlingstradisjoner, som endrer seg over tid Bronkiolitt fra årelating til high flow Pneumoni antibiotika eller ikke Diskutere strategier for å sørge for å Unngå overbehandling Innfase ny behandling I rett tid På riktig måte Til riktig gruppe

4 4 Courts definition 2 Age Tachypnoe + Dyspnoea + Wheezing + Chest recession + Cough + Rhonchi + Rales + Fever + Cyanosis <12 months (x) Nasal discharge (+) Red pharynx (+) 1. Hubble D, Osborn GR. Br Med J 1941; 1: Court SD. Postgrad Med J 1973; 49: The characteristic clinical picture is distressing and unforgettable: The head turning restlessly from side to side on the pillow, the dusky cyanosis of the lips and cheeks, the expression concentrated but unprotesting, the wildly distressed breathing, the relentless cough, and the final apathy. 1

5 5 Diagnosis Bronchitis, Capillary Etiology Disease burden Management Small tubes inflammation Air vesicles Always two-sided Rapid development Nothing can be more serious to a fat healthy child, than this capillary bronchitis Prevention 1. Swett JA. The Boston Medical and Surgical Journal 1846; 34:

6 6 Diagnosis Etiology Bronchitis, Capillary Bronchiolitis Infiltration and proliferation of the bronchiolar wall Disease burden Management Prevention Epithelium pushed to the centre of the lumen 1. Engel, Newns GH. Arch Dis Child 1940; 15:

7 7 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Disease burden Management Prevention Heycock JB, Noble TC. An epidemic of acute bronchiolitis in infancy. Br Med J 1956; 1:438-9.

8 8 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere Disease burden Management Prevention 1. Armstrong. The Lancet 1825; 3:

9 9 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere Influenza virus? Disease burden Management Prevention 1. Hubble D, Osborn GR. Br Med J 1941; 1:107-26

10 10 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere Influenza virus? Hemophilus Influenzae? Disease burden Management Prevention 1. Wood SH, Buddingh GJ, Abberger BF, Jr. Pediatrics 1954; 13: Wood Sell SH, Womack FC. Am J Dis Child 1960; 100: Wood Sell SH, Shapiro JL. Am J Dis Child 1960; 100:16-22.

11 11 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere Influenza virus? Hemophilus Influenzae? Disease burden Management Prevention

12 12 1. Blount RE et al. Proc Soc Exp Biol Med 1956; 92: Red Book Online Visual Library, Image 109_01. Available at:

13 13 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere Influenza virus? Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Management Prevention

14 14 RSV 80-90% of cases high load: more severe disease Coinfections Not associated with disease severity 1. Skjerven HO, Megremis A et al. J Infect Dis 2015.

15 15 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Management Prevention 1. Leinikki PO et al. J Infect Dis 1977; 136 Suppl:S Paton AW et al. J Clin Microbiol 1992; 30:901-4.

16 16 RSV specific global mortality: /year 1. Liu L et al. Lancet 2015; 385: Nair H. Lancet 2010; 375:

17 17 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Global infant mortality 48% inpatient mortality 6% inpatient mortality <1% inpatient mortality Management Prevention 1. Leinikki PO et al. J Infect Dis 1977; 136 Suppl:S Paton AW et al. J Clin Microbiol 1992; 30:901-4.

18 18 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Global infant mortality 48% inpatient mortality 6% inpatient mortality <1% inpatient mortality Hospitalization rate 1% -> 2.3% Management Prevention 1. Orstavik I et al.acta Paediatr Scand 1980; 69: Fjaerli HO et al. BMC Pediatr 2004; 4:25.

19 19 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Global infant mortality 48% inpatient mortality 6% inpatient mortality <1% inpatient mortality Skin inflammation Hospitalization rate 1% -> 2.3% Management Prevention 1. Armstrong. The Lancet 1825; 3:

20 20 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Global infant mortality 48% inpatient mortality 6% inpatient mortality <1% inpatient mortality Hospitalization rate 1% -> 2.3% Skin inflammation Recurrent wheeze Management Prevention 1. Heycock JB et al. Br Med J 1956; 1: Carlsen KH et al. Eur J Respir Dis 1987; 70:86-92.

21 21 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Global infant mortality 48% inpatient mortality 6% inpatient mortality <1% inpatient mortality Hospitalization rate 1% -> 2.3% Skin inflammation Recurrent wheeze Allergies Management Antiphlogistic therapy Prevention

22 22 Every 4 hours: 1 gr Ipecacuanha, 2gr Tragacanth If no improvement: 1-2 Leeches Blisters 1. Miller CM. The Lancet 1845; 46: Thomson J. The Lancet 1846; 47:434.

23 23 Every 2-3 hours Antimonial wine, 1dr Muriate of Morphia, 20min Tincture of Henbane, 20min Syrup of tolu, ½ ounce Water-andmilk

24 24 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Global infant mortality 48% inpatient mortality 6% inpatient mortality <1% inpatient mortality Hospitalization rate 1% -> 2.3% Skin inflammation Recurrent wheeze Allergies Management Antiphlogistic therapy Stimulants Vapor Antibiotics Oxygen Adrenaline Prevention

25 25 1. The infection Sulphapyridine Alkalis or nicotinic acid as anti-emetic 2. The Obstructive Dyspnoe Steam Adrenaline Atropine Bronchoscopic aspiration 3. The Cyanosis Oxygen 4. The Collapse Coramine (nicotinic acid diethylamide) Blood letting, if distended jugular vein Hubble D, Osborn GR. Br Med J 1941; 1:

26 26 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Global infant mortality 48% inpatient mortality 6% inpatient mortality <1% inpatient mortality Hospitalization rate 1% -> 2.3% Skin inflammation Recurrent wheeze Allergies Management Antiphlogistic therapy Stimulants Vapor Antibiotics Oxygen Adrenaline Primum non nocere Fluid & nutrtition support Mechanical ventilation Prevention 1. Wright FH, Beem MO. Pediatrics 1965; 35: Holdaway D. Pediatrics 1967; 39:924-8.

27 27 1. Fluid/nutrition support Nasogastric tube Intravenous 2. Oxygen support Nasal cannulae 3. Ventilatory support Non-invasive (CPAP/BIPAP) Invasive Ricci V et al.. BMJ 2015; 350:h Ralston SL et al. Pediatrics 2014; 134:e Parikh K Pediatrics 2014; 133:e1-7.

28 28 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Global infant mortality 48% inpatient mortality 6% inpatient mortality <1% inpatient mortality Hospitalization rate 1% -> 2.3% Skin inflammation Recurrent wheeze Allergies Management Prevention Antiphlogistic therapy Stimulants Vapor Antibiotics Oxygen Adrenaline Primum non nocere Fluid & nutrtition support Mechanical ventilation Corticosteroids Inhaled β-2-agonists and adrenaline

29 29 Asthma medications for acute bronchiolitis? Corticosteroids β-2-agonists Adrenaline 1. Encyclopædia Britannica, Inc., Wohl ME et al. Am Rev Respir Dis 1978; 118: Engel, Newns GH. Arch Dis Child 1940; 15: Epithelium pushed to the centre of the lumen

30 30 Corticosteroids Adrenaline β-2-agonists 1. Fernandes RM et al. Cochrane Database Syst Rev 2013; 6:CD Gadomski AM et al. Cochrane Database Syst Rev 2014; 6:CD Skjerven HO, Hunderi JO et al. N Engl J Med 2013; 368:

31 31 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Global infant mortality 48% inpatient mortality 6% inpatient mortality <1% inpatient mortality Hospitalization rate 1% -> 2.3% Skin inflammation Recurrent wheeze Allergies Management Antiphlogistic therapy Stimulants Vapor Antibiotics Oxygen Adrenaline Primum non nocere Fluid & nutrtition support Mechanical ventilation Corticosteroids Ribavirin Inhaled β-2-agonists and adrenaline Prevention 1. Hall CB. N Engl J Med 1983; 308: Reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections. American Academy of Pediatrics Committee on Infectious Diseases. Pediatrics 1996; 97:

32 32 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Global infant mortality 48% inpatient mortality 6% inpatient mortality <1% inpatient mortality Hospitalization rate 1% -> 2.3% Skin inflammation Recurrent wheeze Allergies Management Antiphlogistic therapy Stimulants Vapor Antibiotics Oxygen Adrenaline Primum non nocere Fluid & nutrtition support Mechanical ventilation Corticosteroids Ribavirin Inhaled β-2-agonists and adrenaline Hypertonic saline Prevention

33 Zhang L et al. Cochrane Database Syst Rev 2013; 7:CD Everard ML et al. Thorax 2014; 69:

34 34 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Global infant mortality 48% inpatient mortality 6% inpatient mortality <1% inpatient mortality Hospitalization rate 1% -> 2.3% Skin inflammation Recurrent wheeze Allergies Management Antiphlogistic therapy Stimulants Vapor Antibiotics Oxygen Adrenaline Primum non nocere Fluid & nutrtition support Mechanical ventilation Corticosteroids Ribavirin Inhaled β-2-agonists and adrenaline Hypertonic saline Prevention Vaccine 1. Kim HW. 1969; 89:

35 35 Drugs in the pipeline Vaccines 4 in phase 2 6 in phase 1 Maternal and infant Antivirals 7 in phase 2 4 in phase Saso A et al. The Lancet Infectious Diseases Mazur NI et al. Lancet Respir Med 2015; 3:

36 36 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Global infant mortality 48% inpatient mortality 6% inpatient mortality <1% inpatient mortality Hospitalization rate 1% -> 2.3% Skin inflammation Recurrent wheeze Allergies Management Antiphlogistic therapy Stimulants Vapor Antibiotics Oxygen Adrenaline Primum non nocere Fluid & nutrtition support Mechanical ventilation Corticosteroids Ribavirin Inhaled β-2-agonists and adrenaline Hypertonic saline Prevention Vaccine Palivizumab 1. Pediatrics 1998; 102:531-7.

37 37 Diagnosis Bronchitis, Capillary Bronchiolitis = Bronchopneumonia? Etiology Athmosphere PCR Influenza virus? Virus diagnostic techniques improves Hemophilus Influenzae? = Respiratory Syncytial Virus Disease burden Global infant mortality 48% inpatient mortality 6% inpatient mortality <1% inpatient mortality Hospitalization rate 2.3% Skin inflammation Recurrent wheeze Allergies Atopic diseases Management Antiphlogistic therapy Stimulants Vapor Antibiotics Oxygen Adrenaline Primum non nocere Fluid & nutrtition support Mechanical ventilation Corticosteroids Ribavirin Inhaled β-2-agonists and adrenaline Hypertonic saline Prevention Vaccine Palivizumab

38 38 Less is more treatment overuse Antibiotics ->resistance Pneumonia definition overlaps acute bronchiolitis Bronchodilators & steroids Presumption of effect in subgroups Hospitalization Resource demanding Skjerven HO et al. Lancet Respir Med 2015; 3: Rapid viral detection Pneumonia antibiotic trials Trials designed for subgroup analyses Home supportive therapy? Better triage tools Clinical registration, biochemistry, viral diagnostics and parental assessment

39 39 What have we learned from the past? New therapeutic options Ensure relevant effect Trials before general use Primum non nocere

40 Case 2.5 år gammel jente med hoste, t 38.3, rhinorrae Moderat nedsatt allmenntilstand, RF 40, lette inndragninger CRP 75, leukocytter 17 Rtg thorax: perihilære, peribronkiale fortetninger Diagnose? Antibiotika?

41 WHO Guidelines 41

42 Fig 1 Algorithm for assessment and management of community acquired pneumonia (CAP). Iram J Haq et al. BMJ 2017;356:bmj.j by British Medical Journal Publishing Group

43 Amerikanske retningslinjer Gir ingen klar algoritme Erklærer at «Antimicrobial therapy is not routinely required for preschool-aged children with CAP, because viral pathogens are responsible for the great majority of clinical disease.», men gir ingen verktøy for å klargjøre dette Sier tvert imot, som de britiske retningslinjene, at rtg og blodprøver ikke er til å stole på. 45% av bronkiolittbarn får antibiotika. (Studie med barn, Christakis et.al., Pediatrics 2005) Bronkiolittstudien: 4,5% a.b. for pneumoni Bradley, J. S., C. L. Byington, S. S. Shah, B. Alverson, E. R. Carter, C. Harrison, S. L. Kaplan, S. E. Mace, G. H. McCracken, Jr., M. R. Moore, S. D. St Peter, J. A. Stockwell, J. T. Swanson, S. Pediatric Infectious Diseases and A. the Infectious Diseases Society of (2011). "The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America." Clin Infect Dis 53(7): e25-76.

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48 Norsk praksis hvor sikre er vi? Gradvis mer restriktiv CRP 130? 180? 220? Oksygenbehov, intensivbehandling Infiltrater, rtg Praksis endrer seg stadig, også siste 5-10 år Kunnskapsbasert?

49 Ubesvart spørsmål Er antibiotika nyttig ved nedre luftveisinfeksjon ( pneumoni ) hos førskolebarn, som ikke har klare holdepunkter for en bakteriell infeksjon? Kliniske kriterier (WHO, UK, USA) Cochrane review 2013: 29 studier sammenlignet ulike a.b., ingen placebo Fant ingen forskjell mellom f.ek.s amoxycillin p.o. og i.v. penicillin/ampicillin

50 NAPiC 9 sykehus: Tromsø, Bodø, Trondheim, Ålesund, Bergen, Stavanger, Ullevål, Østfold, AHUS N= I hver randomiseringsgruppe Alder mnd Inklusjon i ca 2.5 år Intervensjon i 7 dager: Amoxicillin 75mg/kg 24t /3 doser Placebo Daglig oppfølging de første 7 dagene og frem til 2 dager symptomfri / evt. til 21 dager etter inklusjon.

51 51 Nye behandlingsrutiner Behandlingsmåte introduseres Teoretisk fornuftig Lovende pilot-/mindre studier Brer deretter om seg Ny legemidler: streng regulering Alternativ anvendelse av eksisterende medikament (adrenalin inhalasjoner, steroider) Medisinsk teknisk utstyr (high flow) Også skifte mot mindre bruk

52 52 Angrepspunkter for forskning Store ulikheter i klinisk praksis og retningslinjer mellom Enkeltleger Nivåer av helsetjeneste Ulike spesialiteter Sykehus Land/regioner Manglende relevante studier Hånd i hånd med overnevnte

53 53 Timing Forskning Ved signifikant ulikhet Helst før behandling er så utbredt at det er vanskelig å utfordre etablert praksis Point of no return? Introduksjon av ny behandling VENT til de gode studiene er gjennomført

54 54 Forutsetninger for fornuftig implementering Observasjonell klinisk forskning Beskrivelse av behandlingspraksis Identifisere avvik fra retningslinjer Utprøvende klinisk forskning Strukturer (forskningsposter, forskningsstøtteavdelinger) Forankring i kliniske avdelinger Ledelse Ansatte; holdninger Prioritering av fordypningstid o.l. Samarbeid med legemiddelindustrien