LE EVIDENZE SCIENTIFICHE PER LA TERAPIA LOCALE

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1 La bronchiolite : come riconoscerla per meglio curarla LE EVIDENZE SCIENTIFICHE PER LA TERAPIA LOCALE Maurizio Poloni U.O. Pediatria - RIMINI

2 RSV INFECTION- BRONCHIOLITIS Leading cause of hospitalization in infants - Up to 3% of all children in first year of life are hospitalized with bronchiolitis (18% of all hospitalizations in US) 10-12% need intensive care Virtually all children have been infected with RSV by the age of 2 years Previous infection does not transmit persistent immunity and reinfection is common and can recur in the same RSV season Of RSV infected infants 40% will develop a LRTI Wright Ped Pulmonol 2011 Glezen Am J Dis Child 1986

3 BURDEN OF RSV INFECTION IN ARGENTINA 2011 season Prospective study in 56,560 children < 2 years. 60% of respiratory infections in hospitalized children (n=1293) were due to RSV. Annual mortality rate for RSV was 7%. Life-threatening RSV infections are a heavy burden on infants in the developing world. Ferolla AJRCCM 2013

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6 DIAGNOSIS OF BRONCHIOLITIS UK, Australia USA (EU) Bronchiolitis Bronchiolitis EU (age < 12m) (age < 2 yrs) inspiratory crackles + wheezing Everard CurrOp 2006 wheezing Early onset Asthma???

7 Hig risk for RSV bronchiolitis in Late preterms and select infants affected by rare disorders; a dilemma of specific prevenction Prematurity and BPD Age less than 12 weeks Congenital cardiac illness Pediatrics 2006;118; Immunodeficiency Congenital pulmonary anomalies Chronic pulmonary Disease (CF, PCD ) Neuromuscolar Disease Down Syndrome Manzoni Early Human Dev 2012

8 Withholding therapy is much more difficult than giving it! NEJM 2007;357:402-4

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10 Impact of a bronchiolitis guideline on E.D. resource use and cost: a segmented time-series analysis Akenroye AT, Baskin MN, Samnaliev M, Stack AM Pediatrics Jan Novembre Aprile Bambini (1 12 mm) CONFRONTO CON IL PERIODO PRECEDENTE RX: - 23% Test per RSV: - 11% Salbutamolo: - 7% RISPARMIO TOTALE DOPO 2 AA : dollari

11 Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. (children from 1 through 23 months of age) Pediatrics 2014 Nov

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13 Clinical Questions Efficacy of pharmaceutical therapies for treatment of bronchiolitis Role of prophylaxis in prevention of bronchiolitis

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15 Efficacy of pharmaceutical therapies for treatment of bronchiolitis Management of Bronchiolitis When supplemental O2 is indicated?

16 Supplemental O2 is indicated when SatO2 falls persistently < 90% Infants with O2 saturation levels < 92% should receive supplemental oxygen by nasal cannulae or facemask

17 Supplemental O2 is indicated when SatO2 falls < 90% or < 92% Impact on the number of hospitalization!!! The routine measurement of O2 saturation may be responsible for the increased admission rates of the last years Smyth Lancet 2006

18 Supplemental O2 HOW TO OBTAIN A GOOD MEASUREMENT OF O2 SATURATION? proper probe and appropriate placement avoid movement stability of readings pulse amplitude vasoconstriction and hypothermia???

19 HOW TO OBTAIN A GOOD MEASUREMENT OF O2 SATURATION? Suctioning of the nares should be performed before to measure O2 saturation

20 O2 SATURATION IN INFANT S WITH BRONCHIOLITIS BEFORE AND AFTER SUCTIONING OF THE NARES 100 n = Sat O2 < 96% 88 PRE-NARES SUCTIONING POST-NARES SUCTIONING Measurement : pre and post 10 min.

21 INDICAZIONI AL RICOVERO - Sat O2 persistentemente < % - Entità del Distress respiratorio - Presenza di Apnea (5-10 % RSV, HRV) - Disidratazione (introduzione di liquidi nelle 24 ore precedenti < al 50 % dell abituale) - Presistenti fattori di rischio (prematurità, BPD, CHD, immunodeficienza, malformazione delle vie aeree, severo deficit neurologico, Fibrosi Cistica)

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24 INDICAZIONI AL RICOVERO -Presistenti fattori di rischio (prematurità, BPD, CHD, immunodeficienza, malformazione delle vie aeree, severo deficit neurologico, Fibrosi Cistica) DA PRENDERE IN CONSIDERAZIONE Fattori sociali (distanza dall'ospedale, accesso ai mezzi di trasporto o di comunicazione, collaborazione dei genitori) Fattori ambientali (esposizione al fumo di sigaretta, dimora umida o fredda, abitazione affollata)

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27 TERAPIA DI SUPPORTO TE NO CT FFE IVE

28 NO TE FFE CT IVE TERAPIA FARMACOLOGICA

29 Hearly Hum Dev 2013

30 RCT n=96 4 ml of 3% hypertonic saline vs 0.9% every 6 hrs (+ albuterol or epinephrine as needed) 26% reduction in the length of hospitalization ($150 million annually) No adverse effects were observed Kuzik J Pediatrics 2007

31 Le soluzioni Saline Soluzione Fisiologica NaCl 0,9% (NS) Soluzione Ipertonica NaCl (HS) 1,5 % 3% 6-7%

32 Le soluzioni saline e l apparato respiratorio Modalità di Somministrazione L aerosol è una sospensione di particelle solide o liquide I vari tipi di device inalatori si differenziano tra loro per il diametro che imprimono alle particelle nebulizzate (DAMM: Diametro Aerodinamico Mediano di Massa) per le vie aeree superiori (device endonasali) DAMM > 10 micron vie aeree inferiori (device rino-orobuccali) DAMM < 5 micron

33 L apparato respiratorio

34 L epitelio dell apparato respiratorio

35 L epitelio dell apparato respiratorio Legenda: ML = strato mucoso ; PCL = liquido periciliare; ASL = liquido di superficie delle vie aeree; MCC = clearance mucociliare; ENaC = canale epiteliale del sodio; CaCC = canali del calcio; CFTR = Cistic Fibrosis Transmembrane Regulator Mandelberg A, Pediatric Pulmonol 2009

36 SOLUZIONE SALINA IPERTONICA PATOLOGIE COME FIBROSI CISTICA E BRONCHIOLITE PRESENTANO IL MEDESIMO APPROCCIO TERAPEUTICO.???

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38 Pediatric Pulmonol 2010

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40 Schematic representation of the antimicrobial, immunomodulatory and mucolytic properties of HS. 1.HS draws water into the dehydrated CF periciliary layer and improves mucus rheology and enhances mucociliary clearance. 2.IL-37, an antimicrobial protein is released by HS via disruption of the electrostatic interaction between IL37 and anionic glycosaminoglycans (GAGs). 3. HS liberates IL-8 from anionic matrices (GAGs) rendering the chemokine susceptible to proteolytic degradation by neutrophil elastase, thereby decreasing inflammation.

41 Conclusion: The positive effect of nebulised HS on mucociliary clearance is based on restoring the liquid layer lining the airways. Studies are now revealing that HS can also function by releasing essential antimicrobial and immune molecules from complexation with ionic matrices thus improving both antimicrobial efficiency and resolution of inflammation. These observations suggest that HS has beneficial therapeutic effects other than simply increasing mucociliary clearance and thus further investigations of the potential mechanisms of this currently available

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44 Wheezing prescolare Randomized, controlled, double-blind study 41 children (mean age months, range 1 6 years) presented with wheezing to the emergency department Randomized after 1 albuterol inhalation to receive either 4 ml of hypertonic saline 5% (HS) (n = 16) or 4 ml of normal saline (NS) (n = 25), both with 0.5 ml albuterol, twice every 20 minutes in the Emergency Department and 4 times a day thereafter if hospitalized

45 Wheezing prescolare

46 INDUCE BRONCOSPASMO?

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49 CONCLUSIONI 4 moderati eventi avversi (1%) durante la nebulizzazione - 1 broncospasmo L USO DI HS 3% E SICURO ANCHE SENZA SALBUTAMOLO Ralston Pediatrics tosse catarrale

50 Nebulized hypertonic saline (HS) solution for bronchiolitis in infants 11 trials involving 1090 infants with mild to moderate acute viral bronchiolitis 4 trials Current evidence suggests nebulised 3% saline: - reduces the length of hospital stay among infants hospitalised with non-severe acute viral bronchiolitis - improves the clinical severity score in both outpatient and inpatient populations. Zhang - Cochrane 2013 Jul

51 Nebulized hypertonic saline (HS) solution for bronchiolitis in infants 11 trials involving 1090 infants with mild to moderate acute viral bronchiolitis 4 trials Current evidence suggests nebulised 3% saline: - reduces the length of hospital stay among infants hospitalised with non-severe acute viral bronchiolitis - improves the clinical severity score in both outpatient and inpatient populations. Zhang - Cochrane 2013 Jul

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53 EDITORIALE.Dalla nostra lettura della revisione Cochrane, che ora dovrà essere aggiornata, e quella degli studi di Florin e Wu, pensiamo comunque che non sia il caso di introdurre l uso routinario nei reparti di emergenza della soluzione salina ipertonica, la quale potrebbe comunque giocare un ruolo importante nei bambini ricoverati per bronchiolite... Jama Pediatr. Published online May 26, 2014

54 The effect of 3% and 6% HS in Viral Bronchiolitis : a RCT Teunissen, ERJ Ottobre 2014.Except for a possible effect of nebulised hypertonic saline, no evidence-based therapy is available...efficacy of nebulised 3% and 6% hypertonic saline compared with 0.9% hypertonic saline in children hospitalised with viral bronchiolitis.. Salbutamol was added to counteract possible bronchial constriction PRIMARY ENDPOINT : length of hospital stay Secondary outcomes : need for supplemental oxygen and tube feeding N = 292 (median age 3.4 months / moderate-to-severe viral bronchiolitis) RESULTS The median length of hospital stay did not differ between the groups The need for supplemental oxygen or tube feeding did not differ significantly Adverse effects were similar in the three groups.

55 UPDATE 2014 NO nei reparti di pronto soccorso HS SI in caso di ricovero ospedaliero

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57 Bronchodilators for bronchiolitis Gadomski AM, Brower M Cochrane Database Syst Rev 2010 Epinephrine for bronchiolitis Hartling L, Bialy LM, et Al. Cochrane Database Syst Rev 2011

58 Bronchodilators SHOULD NOT be used routinely in the management of bronchiolitis - overall, 1 in 4 may have a transient improvement in clinical score - no impact in the overall course of the illness: some improvement in shortterm outcomes (clinical score ) no effects on admission rates and lenght of hospital stay A carefully monitored trial of α-adrenergic or βadrenergic is an option

59 CINCINNATI CHILDREN S HOSPITAL MEDICAL CENTER Evidence based care guideline for management of bronchiolitis in infants 1 year of age or less with a first time episode, (2010) AMERICAN ACADEMY OF PAEDIATRICS Diagnosis and management of bronchiolitis (2006)

60 Update 2014 Uso di una dose di broncodilatatore non modifica il decorso della malattia NON RACCOMANDATA

61 Update 2014 Uso di una dose di broncodilatatore non modifica il decorso della malattia NON RACCOMANDATA

62 Which bronchodilator? Epinephrine may be the preferred bronchodilator for this trial in emergency department (0.25 mg/kg/dose) Epinephrine has demonstrated slightly better clinical effect than albuterol possibily related to the α effect of the medication

63 EPINEPHRINE FOR BRONCHIOLITIS Hartling L, Bialy LM, Vandermeer B, Tjosvold L, Johnson DW, Plint AC, Klassen TP, Patel H, Fernandes RM Cochrane Database Syst Rev 2011 Riduzione della necessità di ricovero in ED NON riduzione dei tempi di degenza nei b. ricoverati

64 The largest one meta-analysis on bronchiolitis 48 studies and 5000 patients Adrenaline reduced admission on day 1 in the outpatientemergency setting BUT no effect for inpatients! BMJ 2011;342:d1714

65 Skjerven HO, Hunderi JO, Brügmann-Pieper SK, Brun AC, Engen H, Eskedal L, Haavaldsen M, Kvenshagen B, Lunde J, Rolfsjord LB, Siva C, Vikin T, Mowinckel P, Carlsen KH, Lødrup Carlsen KC June 13, 2013

66 404 infants (mean age 4.2 m.) admitted to a pediatric department inhaled adrenaline vs. saline 0,9% (on-demand vs fixed-schedule) Primary outcome: lenght of hospital stay In the treatment of acute bronchiolitis, inhaled racemic adrenaline is NOT more effective than inhaled saline!!! Skjerven NEJM 2013 June 13

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68 Nebulised Adrenaline at home? Because of the lack of studies and potential adverse effects nebulised adrenaline is NOT recommended in the home setting

69 Efficacy of pharmaceutical therapies for treatment of bronchiolitis Corticosteroids are NOT recommended for the treatment of acute bronchiolitis 60% hospitalized children with brochiolitis receive corticosteroids sistemic corticosteroids - no benefits were found in length of stay, clinical score or outcomes (Cochrane 2010) inhaled corticosteroids - no benefits in the course of acute disease inhaled corticosteroids - no benefits in the prevention of post bronchiolitic wheeze (Cochrane 2011)

70 Immunohistochemistry of lungs on day 7 after infection RSV Normal Neutrophils infiltration Huck et al Respir Research 2007

71 600 children (2-12 months) - first episode of bronchiolitis: 20 emergency departments Excluded children with previous wheeze episodes Dexamethasone os 1mg/kg vs placebo Outcomes: - Hospital admission after 4 hr of observation - Clinical Score - Length of hospital stay (LOS) Corneli et al NEJM 2007;357:331

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73 GLUCOCORTICOIDS FOR ACUTE VIRAL BRONCHIOLITIS IN INFANTS AND YOUNG CHILDREN RCTs comparing systemic or inhaled steroids versus placebo in children with bronchiolitis under 24 months. 17 trials participants Current evidence does not support a clinically effect of systemic or inhaled steroids on admissions or length of hospitalisation Cochrane Database Syst Rev Jun

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75 Withholding therapy is much more difficult than giving it! NEJM 2007;357:402-4

76 Gupta et al. Indian Pediatr 2008 Boogaard Chest 2007 Kneyber Pediatr Pulm 2008 Bisgaard AJRCCM 2008

77 PEDIATRICS AAP GUIDE-LINE UPDATE 2014 AAP : non raccomandata dose di prova con broncodilatatore (albuterolo o salbutamolo) EBM : broncodilatatori ininfluenti sul decorso della bronchiolite (qualità evidenza: B, forte raccomandazione) S.Ralston (American Academy of Pediatrics Subcommittee on Bronchiolitis) Commento - Bmj Ottobre le linee guida non ti dicono cosa fare nel caso del singolo paziente (= base condivisa evidence-based) La grande maggioranza dei pazienti con bronchiolite non beneficia di broncodilatatori, questo non significa che il paziente occasionale non potrebbe trarne benefici

78 PEDIATRICS AAP GUIDE-LINE UPDATE Uso a breve termine di SOLUZIONE SALINA IPERTONICA non impatto clinico EBM : una, due, o tre dosi in D.E. non incide sul rischio di ospedalizzazione (maggioranza degli studi, numero consistente) Ralston : Commento - Bmj Ottobre 2014 NB non si può ignorare la Revisione Cochrane del 2013 durata Ricovero = -1 giorno QUINDI HS utile nella bronchiolite se somministrata IN MODO COSTANTE per un PERIODO RELATIVAMENTE PROLUNGATO

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80 Some final thoughts.. Several aspects of bronchiolitis management are still debated Beta-agonists and steroids (systemic and inhaled) are not recommended for routine use Hypertonic saline may provide significant benefit but.

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86 Adults (n=88) experimentally infected with wild-type RSV A nasal spray of RNA-interference (ALN-RSV01) or saline placebo was administered for 3 days after RSV inoculation. Acquisition of infection lower (p<0.007) in ALN-RSV01 treated RNA-i is a natural mechanism regulating protein expression DeVincenzo PNAS 2010

87 Plint AC, Johnson DW, Patel H, Wiebe N, Correll R, Brant R, Mitton C, Gouin S, Bhatt M, Joubert G, Black KJ, Turner T, Whitehouse S, Klassen TP: Pediatric emergency research canada (PERC) epinephrine and dexamethasone in children with bronchiolitis. N Engl J Med 2009, 360(20):

88 Nebulized Hypertonic Saline for Bronchiolitis A Randomized Clinical Trial 1,2 Susan Wu, MD ; Chris Baker, MD3; Michael E. Lang, MD, MPH4; Sheree M. Schrager, PhD, MS5; Fasha F. Liley, MD6,7; Carmel Papa, MS-HCA3; Valerie Mira, MPH1,2; Ara Balkian, MD, MBA1,2; Wilbert H. Mason, MD, MPH8,9 JULY 2014 To compare the effect of nebulized 3% hypertonic saline vs 0.9% normal saline on admis Patients received 4 ml of 3% sodium chloride (hypertonic saline [HS group]) or 0.9% sodium chloride (normal saline [NS group]) inhaled as many as 3 times in the ED.sion rate and length of stay in infants with bronchiolitis. Those admitted received the assigned medication every 8 hours until discharge. All treatment solutions were premedicated with albuterol sulfate. Main Outcomes and Measures Hospital admission rate, length of stay for admitted patients, and Respiratory Distress Assessment Instrument score. A total of 197 patients were enrolled in the NS group and 211 in the HS group. Mean (SD) length of stay for hospitalized patients was 3.92 (5.24) days for the NS group and 3.16 (2.11) days for the HS group (P =.24). The Respiratory Distress Assessment Instrument score decreased after treatment in both groups; however, we found no significant difference between groups (P =.35). Conclusions and Relevance Hypertonic saline given to children with bronchiolitis in the ED decreases hospital admissions. We can detect no significant difference in Respiratory Distress Assessment Instrument score or length of stay between the HS and NS groups.

89 Nebulized Hypertonic Saline for Bronchiolitis in the Emergency DepartmentA Randomized Clinical Trial Todd A. Florin, MD, MSCE1,2; Kathy N. Shaw, MD, MSCE3,4; Marlena Kittick, MPH3; Stephen Yakscoe, BA3; Joseph J. Zorc, MD, MSCE3,4 July 2014 Objective To determine whether nebulized 3% HS compared with normal saline (NS) improves respiratory distress in infants with bronchiolitis not responding to standard treatments in the emergency department. Interventions Patients were randomized to receive either nebulized 3% HS (HS group) or NS (NS group). Main Outcomes and Measures The primary outcome was change in respiratory distress at 1 hour after the intervention, as measured by the Respiratory Assessment Change Score (a decrease indicates improvement). Secondary outcomes included vital signs, oxygen saturation, hospitalization, physician clinical impression, parental assessment, and adverse events. Results The 31 patients enrolled in each treatment arm had similar baseline demographic and clinical characteristics. At 1 hour after the intervention, the HS group demonstrated significantly less improvement in the median Respiratory Assessment Change Score compared with the NS group There were no significant differences in heart rate, oxygen saturation, hospitalization rate, or other outcomes. Conclusions and Relevance Infants with bronchiolitis and persistent respiratory distress after standard treatment in the emergency department had less improvement after receiving 3% HS compared with those who received NS. Based on these results and the existing evidence, administration of a single dose of 3% HS does not appear to be indicated to treat bronchiolitis in the acute care setting.

90 Per i pediatri in cerca di risposte sul modo migliore curare i loro pazienti nulla può essere più frustrante di due studi clinici controllati (RCT) con risultati contraddittori scrivono in un editoriale su JAMA Pediatrics due ricercatori canadesi - Sim Grewal, dell Università dell Alberta e Terry Klassen, dell Università di Winnipeg - a proposito di due studi clinici di recente pubblicati. Nel primo, di Todd Florin e colleghi, 62 pazienti con bronchiolite e distress respiratorio persistente sono stati randomizzati a ricevere soluzione fisiologica o soluzione ipertonica al 3%: a un ora dall intervento le condizioni respiratorie del gruppo trattato con l ipertonica erano migliorate meno rispetto ai pazienti curati con soluzione salina. Nel secondo studio, svolto da Suzan Wu e colleghi, 408 bambini con bronchiolite sono stati randomizzati a ricevere ipertonica o fisiologica in un reparto di emergenza. Gli autori hanno riscontrato un tasso di ricovero nel gruppo ipertonica inferiore al gruppo fisiologica, senza peraltro che emergessero differenze significative tra i due gruppi nella durata del ricovero o nelle condizioni respiratorie. «Valutare l'efficacia della soluzione salina ipertonica nel trattamento della bronchiolite non è facile, e una limitazioni più significative nei dati pubblicati finora è la casistica limitata» sottolineano i due autori, ricordando che l ultima revisione sistematica sul ruolo della salina ipertonica nel trattamento della bronchiolite è la Cochrane del 2013, da cui emerge che probabilmente l ipertonica non serve ai pazienti trattati nei reparti di emergenza ma può essere utile nel ridurre la degenza in ospedale. «I due studi appena pubblicati, apparentemente contraddittori e potenziale fonte di confusione, per svolgere appieno il loro ruolo di ricerca sull argomento dovranno essere incorporati in una revisione sistematica aggiornata per vedere se i risultati globali cambieranno» aggiungono Grewal e Klassen. E concludono: «Dalla nostra lettura della revisione Cochrane, che ora dovrà essere aggiornata, e quella degli studi di Florin e Wu, pensiamo comunque che non sia il caso di introdurre l uso routinario nei reparti di emergenza della soluzione salina ipertonica, la quale potrebbe comunque giocare un ruolo importante nei bambini ricoverati per bronchiolite». Jama Pediatr. Published online May 26, 2014

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