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Raimondi L'iperbilirubinemia post-dimissione · 2009. 8. 20. · Francesco Raimondi, Teresa...
Transcript of Raimondi L'iperbilirubinemia post-dimissione · 2009. 8. 20. · Francesco Raimondi, Teresa...
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L’iperbilirubinemia
post-dimissioneFrancesco Raimondi.
Neonatologia, Dipartimento di Pediatria,Università “Federico II”di Napoli
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La bilirubina è…
un rifiuto costoso?
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La paura di ieri……
- 1904 Schmorl descriveil Kernicterus
MEN Rh
Prevenzione della MEN Rh
Exanguinotrasfusione
Fototerapia
Fine del
Problema?
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….arriva sino ad oggiParents of Infants and Children with Kernicterus
• USA Kernicterus
registry
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La bilirubina fa….male !!
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…ma in Italia esiste il Kernicterus ?
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Bilirubina ed intestino
Neonati a termine
iperbilirubinemici hanno
un’aumentata permeabilità
intestinale rispetto ai controlliIndrio el at Acta Pediatr 2007
La iperbilirubinemia moderata è
associata in neonati predisposti
a un aumento di rischio per
IPLVRaimondi F et al Acta Ped 2008
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Bilirubina e asmaAspberg et al Ped Allergy Immunol 2007
• 14.803 bambini ospedalizzati per asma bronchiale
• L’iperbilirubinemia/ fototerapia era significativamente associata al ricovero (OR=1.27)
• L’associazione era ancora più forte considerando i bambini ricoverati più di una volta (OR= 1.5)
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Bilirubina e diabete.1.
• Studio collaborativo europeo su 892 bambini diabetici e 2291 controlli
Dahlquist G et al Diabetes Care 1999
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Bilirubina e diabete.2.
• Swedish Childhood
Diabetes Registry :
7343 bambini
Fototerapia =OR 1.95
Dahlquist G et al Diabetes Care
2003
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• Discutere lo stato della malpractice negli USA
• Delineare i rischi di malpractice specifici della neonatologia
• Elencare i motivi più frequenti di contenzioso medico-legale in
neonatologia
• Identificare strategie di riduzione del rischio di contenzioso
Neoreviews January 2008
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• Elencare i motivi più frequenti di contenzioso medico-
legale in neonatologia
- Rianimazione neonatale /Danno neurologico
- Iperbilirubinemia
- Prevenzione del GBS
Neoreviews January 2008
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Iperbilirubinemia e…tribunali
• Not performing a screening evaluation
• Incomplete charting regarding jaundice
• Lack of recognition of high-risk condition
• Not measuring bilirubin
• Incomplete follow-up after discharge
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Qual è il compito del Pediatra ?
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Prevenire è meglio che curare ..
• Stima visiva
dell’ittero
• Bilirubina capillare
• Bilirubina
transcutanea
• Fattori di rischio
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La stima visiva dell’ittero.1.Arch Pediatr Adolesc Med 2000; 154: 391-394
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La stima visiva dell’ittero.2.
Gosset- Lancet 1960; 1: 87-88
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La stima visiva dell’ittero.3.
Madlon-Kay Pediatrics 1997; 100, e3
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La stima visiva dell’ittero.4.
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Prevenire l’iperbilirubinemia
La bilirubina sierica
• L’AAP ha emesso le linee
guida per il trattamento
del’iperbilirubinemia del
neonato con EG> 35
settimane
• L’outcome da prevenire è
però intrinsecamente
ambiguo
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Prevenire l’iperbilirubinemia neonatale
la misurazione transcutanea.1.
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Prevenire l’iperbilirubinemia neonatale
la misurazione transcutanea.2.
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MeasuringMeasuringMeasuringMeasuring TranscutaneousTranscutaneousTranscutaneousTranscutaneous Bilirubin: A Bilirubin: A Bilirubin: A Bilirubin: A
Comparative Comparative Comparative Comparative AnalysisAnalysisAnalysisAnalysis of Three of Three of Three of Three DevicesDevicesDevicesDevices
Francesco Raimondi, Teresa Ferrara, Silvia Lama, Maria Sellitto,
Letizia Capasso, Francesca Landolfo, Roberto Paludetto, Anna
Maria Spera and Mariangela De Rosa
Division of Neonatology, Università “Federico II” Napoli,
Naples, Italy
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Monitoring bilirubin levels is routine work in any Neonatology unit.
Transcutaneous bilirubin (TcB) measurement is now considered a
harmless and reliable screening alternative to total serum bilirubin (TSB)
dosage. Manufacturers offer tools that differ for technology, user-
friendliness and costs.
To compare the performance of three
transcutaneous bilirubinometers versus the
spectrophotometric TSB quantitation.
Background
Aim
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Methods
From January 2008 to January 2009, bilirubin was determined in
inborn, at term or near term neonates born at our hospital using
traditional photometric determination (Ginevri, Rome, Italy) and,
within 30 minutes, TcB by Bilicheck (SpectRX, Norcross, GA),
BiliMed ( Medick, S.A.France) and JM-103 (Draeger Medical Systems,
Inc.,Telford, PA) in random order.
Phototherapy was an exclusion criterion. Measurements were
carried out on the neonate’s forehead as ordered by an
indipendent physician. The operator was blind with respect to
TSB determination.
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Results. Patients characteristics
• Neonates enrolled 283
• Non Caucasians 36
• Number of determinations 343
• Birth weight (gr) 3060 (1800-4750)
• Gestational age (wks) 35-41
• Mean TSB (mg/dl) 9.5 (15,8 – 0,7)
• Mean TcB (Bilicheck) 9.8 (17,2 – 0,4)
Mean TcB (BiliMed) 10.4(17,5 – 2,9)
• Mean TcB (JM-103) 9.8 (18,8 – 0,1)
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Results : Bland-Altman plots
0 5 10 15 20
6
4
2
0
-2
-4
-6
-8
AVERAGE of BbCap and BiliCheck
BbC
ap -
Bili
Che
ck
Mean
-0,2
-1.96 SD
-3,4
+1.96 SD
2,9
0 5 10 15 20
6
4
2
0
-2
-4
-6
-8
AVERAGE of BbCap and Bilimed
BbC
ap -
Bili
med
Mean
-0,8
-1.96 SD
-5,3
+1.96 SD
3,6
0 5 10 15 20
8
6
4
2
0
-2
-4
-6
-8
AVERAGE of BbCap and JM103
BbC
ap -
JM
103
Mean
0,5
-1.96 SD
-3,1
+1.96 SD
4,1
Bilicheck BiliMedJM-103
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Results : Receiver operator curves
TSB > 12 mg/dl
Bilicheck BiliMed JM-103
Sensitivity 74% 69.9% 65%
Specificity 86.5% 78.6% 90%
AUC 0.89 0.80 0.90
PPV 59% 46% 63%
NPV 92% 90% 90%
TSB > 14 mg/dl
Bilicheck BiliMed JM-103
Sensitivity 70% 5% 65%
Specificity 56% 88.7% 95%
AUC 0.94 0.75 0.92
PPV 29% 3% 43%
NPV 97% 94% 97%
0 20 40 60 80 100
100
80
60
40
20
0
100-Specificity
Sen
sitiv
ity
0 20 40 60 80 100
100
80
60
40
20
0
100-Specificity
Sen
sitiv
ity
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Results: Non-Caucasians (n=36)TSB > 12 mg/dl
Bilicheck BiliMed JM-103
Sensitivity 66.7% 44% 100%
Specificity 92.6% 88.9% 78%
AUC 0.86 0.75 0.85
TSB > 14 mg/dl
Bilicheck BiliMed JM-103
Sensitivity 66.7% 33.3% 100%
Specificity 100% 90.9% 82%
AUC 0.97 0.74 0.93
Linear regression
Bilicheck BiliMed JM-103
Pearson r 0.87 0.74 0.92
R2 0.77 0.55 0.85
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Conclusions
Bilicheck and JM-103 but not BiliMed are reliable
screening tools for moderate neonatal
hyperbilirubinemia especially when considering
non-Caucasian infants.
JM-103 is quicker than Bilicheck and does not
require disposables.
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Prevenire l’iperbilirubinemiala misurazione transcutanea.3.
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Prevenire l’iperbilirubinemia neonatale
la misurazione transcutanea.4.
• TcB e TSB sono due misure diverse !
• Diverse apparecchiature per TcB usano
differenti tecnologie
• Performance paragonabili ( Bilicheck e JM-103)
• Affidabilità limitata per alte TSB
• Misure ripetute (Bilicheck)
• Materiale di consumo (Bilicheck)
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• “ Before we had pulse oximetry we assessed the oxygen saturation of a newborn or of a child withasthma by eye, and we were often wrong.
Today it is difficult to imagine managing suchchildren without the benefits of pulse oximetry.
It is likely that TcB measurements will beconsidered similarly indispensable in the care of the jaundice newborn”
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Prevenire l’iperbilirubinemia
i fattori di rischio
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• Nello studio di Zimmerman et al, il 5% dei
bambini osservati a 48 ore avevano
diagnosi che sarebbero state perse ad
una dimissione precoce (24 ore)
• L’iperbilirubinemia era la diagnosi più
frequente
Early discharge after delivery. A study of safety and risk factors.
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Early hospital discharge of the healthy
term neonate: the Italian perspective
Petrone et al Minerva Pediatrica 2008
• Questionario a 136 punti nascita in Italia
• L’età media alla dimissione era 72 ore dopo il
parto spontaneo
• A 72 ore con una BT = 13 mg/dl si è dimessi ma
non ricontrollati nel 15% casi
• A 45 ore con una BT= 10 mg/dl si è dimessi (66%
centri) ma non ricontrollati nel 11.9% casi
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Conclusioni
• L’iperbilirubinemia è ancora un “tema
insidioso”
• Al Pediatra compete la prevenzione delle
conseguenze dell’iperbilirubinemia
• La TcB è il più significativo ed innovativo
strumento di prevenzione
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…..grazie a….
• Letizia Capasso
• Francesca Landolfo
• Maria Sellitto
• Pasquale Santoro
• Roberta Pisanti
• Mariangela De Rosa
• Annamaria Spera
• Teresa Ferrara
• Antonia Romano
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MeasuringMeasuringMeasuringMeasuring TranscutaneousTranscutaneousTranscutaneousTranscutaneous Bilirubin: A Bilirubin: A Bilirubin: A Bilirubin: A
Comparative Comparative Comparative Comparative AnalysisAnalysisAnalysisAnalysis of Three of Three of Three of Three DevicesDevicesDevicesDevices
Francesco Raimondi, Teresa Ferrara, Silvia Lama, Maria Sellitto,
Letizia Capasso, Francesca Landolfo, Roberto Paludetto, Anna
Maria Spera and Mariangela De Rosa
Division of Neonatology, Università “Federico II” Napoli,
Naples, Italy
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Monitoring bilirubin levels is routine work in any Neonatology unit.
Transcutaneous bilirubin (TcB) measurement is now considered a
harmless and reliable screening alternative to total serum bilirubin (TSB)
dosage. Manufacturers offer tools that differ for technology, user-
friendliness and costs.
To compare the performance of three
transcutaneous bilirubinometers versus the
spectrophotometric TSB quantitation.
Background
Aim
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Methods
From January 2008 to January 2009, bilirubin was determined in
inborn, at term or near term neonates born at our hospital using
traditional photometric determination (Ginevri, Rome, Italy) and,
within 30 minutes, TcB by Bilicheck (SpectRX, Norcross, GA),
BiliMed ( Medick, S.A.France) and JM-103 (Draeger Medical Systems,
Inc.,Telford, PA) in random order.
Phototherapy was an exclusion criterion. Measurements were
carried out on the neonate’s forehead as ordered by an
indipendent physician. The operator was blind with respect to
TSB determination.
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Results. Patients characteristics
• Neonates enrolled 283
• Non Caucasians 36
• Number of determinations 343
• Birth weight (gr) 3060 (1800-4750)
• Gestational age (wks) 35-41
• Mean TSB (mg/dl) 9.5 (15,8 – 0,7)
• Mean TcB (Bilicheck) 9.8 (17,2 – 0,4)
Mean TcB (BiliMed) 10.4(17,5 – 2,9)
• Mean TcB (JM-103) 9.8 (18,8 – 0,1)
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MeasuringMeasuringMeasuringMeasuring TranscutaneousTranscutaneousTranscutaneousTranscutaneous Bilirubin: A Bilirubin: A Bilirubin: A Bilirubin: A
Comparative Comparative Comparative Comparative AnalysisAnalysisAnalysisAnalysis of Three of Three of Three of Three DevicesDevicesDevicesDevices
Francesco Raimondi, Teresa Ferrara, Silvia Lama, Maria Sellitto,
Letizia Capasso, Francesca Landolfo, Roberto Paludetto, Anna
Maria Spera and Mariangela De Rosa
Division of Neonatology, Università “Federico II” Napoli,
Naples, Italy
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Monitoring bilirubin levels is routine work in any Neonatology unit.
Transcutaneous bilirubin (TcB) measurement is now considered a
harmless and reliable screening alternative to total serum bilirubin (TSB)
dosage. Manufacturers offer tools that differ for technology, user-
friendliness and costs.
To compare the performance of three
transcutaneous bilirubinometers versus the
spectrophotometric TSB quantitation.
Background
Aim
![Page 50: Raimondi L'iperbilirubinemia post-dimissione · 2009. 8. 20. · Francesco Raimondi, Teresa Ferrara, Silvia Lama, Maria Sellitto, Letizia Capasso, Francesca Landolfo, Roberto Paludetto,](https://reader036.fdocuments.us/reader036/viewer/2022070218/6126a8f34d8534621a277fe3/html5/thumbnails/50.jpg)
Methods
From January 2008 to January 2009, bilirubin was determined in
inborn, at term or near term neonates born at our hospital using
traditional photometric determination (Ginevri, Rome, Italy) and,
within 30 minutes, TcB by Bilicheck (SpectRX, Norcross, GA),
BiliMed ( Medick, S.A.France) and JM-103 (Draeger Medical Systems,
Inc.,Telford, PA) in random order.
Phototherapy was an exclusion criterion. Measurements were
carried out on the neonate’s forehead as ordered by an
indipendent physician. The operator was blind with respect to
TSB determination.
![Page 51: Raimondi L'iperbilirubinemia post-dimissione · 2009. 8. 20. · Francesco Raimondi, Teresa Ferrara, Silvia Lama, Maria Sellitto, Letizia Capasso, Francesca Landolfo, Roberto Paludetto,](https://reader036.fdocuments.us/reader036/viewer/2022070218/6126a8f34d8534621a277fe3/html5/thumbnails/51.jpg)
Results. Patients characteristics
• Neonates enrolled 283
• Non Caucasians 36
• Number of determinations 343
• Birth weight (gr) 3060 (1800-4750)
• Gestational age (wks) 35-41
• Mean TSB (mg/dl) 9.5 (15,8 – 0,7)
• Mean TcB (Bilicheck) 9.8 (17,2 – 0,4)
Mean TcB (BiliMed) 10.4(17,5 – 2,9)
• Mean TcB (JM-103) 9.8 (18,8 – 0,1)
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Results : Bland-Altman plots
0 5 10 15 20
6
4
2
0
-2
-4
-6
-8
AVERAGE of BbCap and BiliCheck
BbC
ap -
Bili
Che
ck
Mean
-0,2
-1.96 SD
-3,4
+1.96 SD
2,9
0 5 10 15 20
6
4
2
0
-2
-4
-6
-8
AVERAGE of BbCap and Bilimed
BbC
ap -
Bili
med
Mean
-0,8
-1.96 SD
-5,3
+1.96 SD
3,6
0 5 10 15 20
8
6
4
2
0
-2
-4
-6
-8
AVERAGE of BbCap and JM103
BbC
ap -
JM
103
Mean
0,5
-1.96 SD
-3,1
+1.96 SD
4,1
Bilicheck BiliMedJM-103
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Results : Receiver operator curves
TSB > 12 mg/dl
Bilicheck BiliMed JM-103
Sensitivity 74% 69.9% 65%
Specificity 86.5% 78.6% 90%
AUC 0.89 0.80 0.90
PPV 59% 46% 63%
NPV 92% 90% 90%
TSB > 14 mg/dl
Bilicheck BiliMed JM-103
Sensitivity 70% 5% 65%
Specificity 56% 88.7% 95%
AUC 0.94 0.75 0.92
PPV 29% 3% 43%
NPV 97% 94% 97%
0 20 40 60 80 100
100
80
60
40
20
0
100-Specificity
Sen
sitiv
ity
0 20 40 60 80 100
100
80
60
40
20
0
100-Specificity
Sen
sitiv
ity
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Results: Non-Caucasians (n=36)TSB > 12 mg/dl
Bilicheck BiliMed JM-103
Sensitivity 66.7% 44% 100%
Specificity 92.6% 88.9% 78%
AUC 0.86 0.75 0.85
TSB > 14 mg/dl
Bilicheck BiliMed JM-103
Sensitivity 66.7% 33.3% 100%
Specificity 100% 90.9% 82%
AUC 0.97 0.74 0.93
Linear regression
Bilicheck BiliMed JM-103
Pearson r 0.87 0.74 0.92
R2 0.77 0.55 0.85
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Conclusions
Bilicheck and JM-103 but not BiliMed are reliable
screening tools for moderate neonatal
hyperbilirubinemia especially when considering
non-Caucasian infants.
JM-103 is quicker than Bilicheck and does not
require disposables.
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La bilirubina fa… bene?
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La bilirubina fa… bene?.2.
• 11 studi riuniti in meta-analisi dimostrano una
relazione inversa tra concentrazioni di bilirubina
e grado di aterosclerosi
• 1 microm/L di bilirubina in più corrisponde ad
una diminuzione del 6.5% di malattia
cardiovascolare
Novotny e Vitek – Exp Biol Med 2003
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La bilirubina fa… bene?.3.
Bilirubina come terapia
• Combatte gli effetti
dell’ischemiaAm J Physiol 2002
• Migliora la fibrosi
polmonare da
bleomicinaAm J Resp Crit Care Med 2002
• Protegge il fegato
trapiantatoHepatology 2003Sedlak TW, Snyder SH
Pediatrics 2004
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La bilirubina fa ….bene !!!
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La bilirubina… fa male?
….fa bene ??
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Bilirubina ed intestino
La bilirubina libera aumenta
la permeabilità
dell’epitelio intestinale
L’effetto è legato al
potenziale redox della
molecola
Raimondi F , Crivaro V, Capasso L et al
Pediatric Research 2006
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Iperbilirubinemia del neonato ELBWOh, Tyson, Fanaroff et al Pediatrics Oct. 2003
• Studio retrospettivo su 2575 neonati ELBW
• Il picco di bilirubinaè associato con:- morte od handicap di sviluppo neurologico (OR= 1.068)- indice di sviluppo psicomotorio <70 (OR= 1.057)- handicap uditivo (OR= 1.138)
Dati ottenuti dopo normalizzazione per sesso, età ed istruzione materna, steroidi prenatali, terapia con surfattante, IVH> gr 3, CLD, NEC, steroidi postnatali
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Iperbilirubinemia e ritardo del linguaggio
Amin et al Pediatrics 2009
• Studio retrospettivo caso-controllo
• 102 ex pretermine VLBW seguiti per 3 anni
• Outcome = ritardo del linguaggio
• Analisi dei picchi di bilirubinae del numero di giorni con BT>8 mg/dl
• Nessuna differenza tra casi e controlli
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26 ±2.026 ±1.9EG
777 ±134777 ±134PN
Conservativa
n=984
Aggressiva
n=990
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• Nessuna differenza significativa per:
Morte
Danno neurologico severo
Irradiazione 15-40 W/cm2 ?!
Un imprecisato numero di neonati
facevano fototerapia on-off
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La bilirubina di domani
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Raimondi et al. It J Pediatrics 2004
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Bilirubina e barriera emato-
encefalica del pretermine
• La permeabilitàdell’endotelio vascolare è regolata da TJ identiche a quelle epiteliali.
• La bilirubina influenza la permeabilità dell’ENDOtelio?
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Ancora bilirubina ed intestino
• Valutare se l’ azione “permeabilizzante” della bilirubina favorisce la traslocazione di batteri o di prodotti batterici e dunque la sepsi
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Esposizione alla bilirubina nel VLBW:
un problema di metodo ?!
• Neonati VLBW con
diagnosi di microbiologica
di sepsi “late-onset”
• Controlli appaiati per PN,
EG, età post-natale
• Calcolo dell’esposizione
alla bilirubina come AUC
nella settimana
precedente alla
emocoltura positiva
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Esposizione alla bilirubina e sepsi
F. Raimondi et al. dati non pubblicati
0
1
2
3
4
5E
spos
izio
ne b
iliru
bina
(un
ità a
rbitr
arie
)
X Title
Sepsis
Control
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Studio funzionale dei PMN del pretermine VLBW
•
metabolismo ossidativo • Indotto da:
– a) peptide chemiotattico fMLP– b) batteri opsonizzati, ma non
marcati – c) PMA ( legante della chinasi
proteica C),
Viene determinato valutando la % di
granulociti che in seguito ai vari
stimoli producono H202
trasformante il substrato
fluorogenico DHR 123 in R123 e
l’IMF legata alla quantità di R123
per cellula.
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Risposta ad E.coli del neutrofilo del
neonato VLBW
A B C0
500
1000
1500
2000
2500
3000
3500In
tens
ità d
i flu
ores
cenz
a
X Ti tle
BT> 8mg/dl BT<8 mg/dl
F. Raimondi et al. Dati non pubblicati
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Conclusioni
• Ieri abbiamo debellato l’encefalopatia bilirubinica (?)
• Oggi stiamo imparando che l’iperbilirubinemia può causare
danni ad organi diversi dal SNC
• Domani……..…………..l’eterna sfida
continua………