Normosang ® (human hemin) Acute attacks of Hepatic Porphyria

Wilzin ® (Zinc acetate dihydrate) Wilson's disease

Cystadane ® (Betaine) Adjunctive treatment of Homocystinuria

Carbaglu ® (carglumic acid) Hyperammonemia due to NAGS deficiency or Organic Acidemias

Pedea ® (i/v Ibuprofen ) Open Ductus Arteriosus

Vedrop ® (Tocofersolan) Vitamin E deficiency - Chronic Cholestasis

Cystagon ® (Cystamine) Nephropathic Cystinosis

Orphan Europe

medicines

Patent Ductus Arteriosus

In 2010, the Swedish government asked Socialstyrelsen (the Social welfare board) to develop guidelines for the treatment and care of extremely premature children born before pregnancy week 28 .

The guidelines are now public. Please observe that they are still preliminary.

All data presented in this slide kit are from these guidelines unless otherwise stated.

http://www.socialstyrelsen.se/Lists/Artikelkatalog/Attachments/19209/2013-10-6.pdf

Expert group PDA

• Mikael Norman, Astrid Lindgrens Barnsjukhus, Karolinska universitetssjukhuset, Stockholm

• Anna-Karin Edstedt Bonamy, Sachsska Barn- och Ungdomssjukhuset, Södersjukhuset, Stockholm

• Per Winberg, Astrid Lindgrens Barnsjukhus, Karolinska universitetssjukhuset, Stockholm

• Stellan Håkansson, Barn och ungdomsmedicinska kliniken, Norrlands universitetssjukhus, Umeå

• David Ley, Skånes universitetssjukhus, Lund • Ola Hafström, Sahlgrenska Universitetssjukhuset, Göteborg

Diagnosis of PDA

• Ductus width > 1,5 mm

• Enlargement of left atrium. A LA/Ao ratio >1,5 indicates a significant shunt and a ratio >2 indicates a substantial shunt.

• Low or reversed diastolic blood flow in the descending aorta, mesenteric vessels or brain vessels (strong indicator).

• Diastolic forward flow in the pulmonary artery branches. An end diastolic velocity larger than 0,2 meters/second indicates a significant PDA and a velocity in excess of 0,5 meters/second indicates a significant shunt.

• A ductus examination usually includes an assessment of left ventricular size. For extremely preterm children, there are currently no reliable standard materials.

Treatment of PDA

• Treatment should be considered when eccocardiographic criteria and clinical symptoms indicate a significant PDA.

• Pharmaceutical treatment is first line treatment.

• Surgical treatment should be considered in case of pharmaceutical treatment failure, ductus relapse or when pharmaceutical treatment is contra indicated.

• Fluid restriction (maximum120–160 ml/kilo/24hours) has some obsevational study support and can be considered.

• Loop diuretica and blood transfusions are not recommended.

• Approximately 60% of all extremely premature babies receive treatment.

Pharmaceutical treatment

• Treatment with IV ibuprofen is recommended as first line treatment in haemodynamically significant PDA in children up to 14 days after birth.

• Indomethacin and IV ibuprofen are rated as equal in terms of effect.

• Due to a more favourable safety profile IV ibuprofen is recommended as drug of choice.

Risk factors

Risk factors in pharmaceutical treatment•Lower risk of NEC in patients treated with IV ibuprofen versus indomethacin has been reported.

•Lower risk of oliguria and renal damage in patients treated with IV ibuprofen versus indomethacin has been reported.

•Postnatal treatment with steroids in combination with indomethacin has shown to increase the incidense of NEC and intestinal perforation.

•There is no evidence supporting the fear that IV ibuprofen would cause an increased risk of BPD.

Ibuprofen approaches

• The most studied dosage in treatment with IV ibuprofen is 10mg/kg as initial dose followed by 5mg/kg/day during the next two days.

• Clearence of ibuprofen increases relatively fast with the age of the patient and higher dosages may then be more effective.

• Enteral ibuprofen treatment has been reported with an increased risk of gastrointestinal bleeding.

10mg – 5mg – 5mg

Patients born before week 26

• Most studies comparing indomethacin and iv ibuprofen are with patients born > week 26.

• The efficacy of ibuprofen in patients born before week 26 is less documented.

• As a result, indomethacin may still be an option for patients born before week 26.

Remarks

These guidelines and treatment recommendations are still preliminary.

Please be aware of possible changes in the final guidelines from the Swedish Social welfare board (Socialstyrelsen).

The full report is 72 pages and therefore more in depth.

Severe HyperhomocysteinemiaHomocystinuria

Forms of Hyperhomocysteinemia

Homocystinuria is characterized by a Severe Hyperhomocysteinemia (accumulation of homocysteine in blood) with homocysteine excretion in the urine

CClinical featureslinical features

Symptoms affect mainly four organ systems:• Eye• Skeletal• Central Nervous system• Vascular system

Classic homocystinuria is accompanied by an abundance and variety of clinical and pathological abnormalities

17

Classic Homocystinuria- CBS deficiency

Clinical features

Early onset (usually occurs during the first year of life ) severe development delay , severe neurological signs, recurrent apnoe,

microcephaly and convulsions

Late onset (childhood, adolescence, or adulthood ) mental regression, ataxia common psychiatric disorders of the schizophrenic type that may be linked to

cerebrovascular accidents

Homocystinuria due to MTHFR deficiency and functional MS deficiency is a metabolic disorder characterized by severe neurological manifestations

Homocystinuria- MTHFR deficiency and functional MS deficiency

10. Schiff M, Blom HJ, Treatment of inherited homocystinurias. Neuropediatrics 2012; 43:295-304.11. Carillo- Carrasco n, Chandler RJ, Venditti CP. Combined methylmalonic acidemia and homocystinemia, cblC type. 1. Clinical presentations, diagnosis un management. J Inherit Metab Dis 2012; 35:91-102.12. Garcia- Jimenez MC, Baldellou A. Homocystinurias, a great stranger? Keys for the primary care diagnosis. Acta Pediatr Esp 2009;67:535-41.

When to suspect Homocystinuria?Foetuses and Neonates

12. Garcia- Jimenez MC, Baldellou A. Homocystinurias, a great stranger? Keys for the primary care diagnosis. Acta Pediatr Esp 2009;67:535-41.

Diagnosis

Hyperammonemias

Definition of hyperammonaemia

Hyperammonaemia is defined as plasma ammonia concentrations above the normal range1

• Ammonia levels can be >1000 µmol/L in affected individuals2

Normal plasma ammonia

concentrations (µMol/L) 1

Newborns 50159

Infants and children

2448

Adult female 1148

Adult male 1555

1. Häberle (2011) Eur J Pediatr 170:21–34; 2. Brusilow & Horwich (2001) McGraw-Hill: New York. p 1909

Ammonia production and elimination

High level of ammonia in the blood is not good for the body- it is toxic, especially for the brain

The excess of ammonia in the blood needs to be eliminated

Ammonia production in the body

Ammonia is produced as a result of breaking down or metabolizing proteins

The Failure of Urea Cycle

Enzyme deficiency(eg NAGS deficiency)

Failure of urea cycle

HYPERAMMONAEMIA

Enzyme toxic inhibition

(eg NAGS inhibition during OAs)

UCD, urea cycle disorder; NAGS, N-acetylglutamate synthase; OA, organic acidaemia

Clinical symptoms of hyperammonaemiaAcute hyperammmonaemia Chronic hyperammmonaemia

Lethargy Protein aversion

Somnolence Headaches and migraines

Coma Ataxia

Vomiting (metabolic alcalosis) Confusion, lethargy, dizziness

Seizures Hyperactive, aggressive, irritable behaviour

Cerebral oedema Cognitive deficits

Liver failure Abdominal pain and vomiting

Multi-organ failure Failure to thrive

Postpartum psychosis Seizures

Peripheral circulatory failure Stroke-like episodes

Häberle (2011) Eur J Pediatr 170:21–34

Chronic cholestasis and treatment of vitamin E deficiency

Intrahepatic cholestatic syndromes

Diseases causing chronic cholestasis

Biliary atresia

Alagille’s syndrome

Non-syndromatic paucity of

intrahepatic bile ducts

Perez-Atayde. In: Pediatric gastrointestinal disease – pathophysiology, diagnosis, management. Mosby 1996;1543–1553

Heterogeneous group of cholestatic disorders

Nutritional support for children with chronic cholestasisNutritional

element Daily requirement Products/source Means of administration Comments/monitoring

Vitamin A<10 kg 5000 IU

>10 kg 10,000 IUIM – 50,000 IU

Ketovite liquid and tabs, Abidec Oral

IM supplement only in severe refractory deficiency

serum retinol/RBP ≥0.8

Vitamin D 25-CHD: 2–5 µg/kgIM – 30,000 IU 1–3 monthly

Ketovite liquid and tabs, Abidec have calciferol

400 IU/dayIM calciferol

Oral/IM

Supplementation with oral products containing calciferol may suffice

Refractory cases may require 25–OHD or IM preps

25–OHD serum levels >20 ng/mL

Vitamin ETPGS* 25 IU/kg

IM 10 mg/kg (max 200 mg) every 3 weeks

TPGS* Orphan Europe Others include Ketovite

liquid and tabs, Abiden, Ephynal

Oral

Vitamin E/total lipids ≥0.6 mg/gVitamin E <30 µg/mL

Look for reflexes

Vitamin K

2 mg/day weekly5 mg: 5–10 kg10 mg >10 kg

IM – 5–10 mg every 2 weeks

Konakion MMMicellar formulation of

menadiolPhytomenadione

OralIM

Prothrombin timePIVKA II <3 ng/mL

Water soluble vitamins Twice RDA Children’s multivitamins, Ketovite liquid and tabs Oral Supplement as needed

Minerals•Calcium•Selenium•Zinc•Phosphate

25–100 mg/kg1–2 µg/kg1 mg/kg

25–50 mg/kg

Oral Supplement as needed

Baker et al. Pediatr Transplant 2007;11;8:825–834 IM, intramuscular; RDA, recommended daily allowance;PIVKA II, descarboxyprothrombin

Reproduced from Baker A et al. Guidelines for nutritional care for infants with cholestatic liver disease before liver transplantation. Pediatr Transplant 2007;11:825–834, with permission from John Wiley & Sons Inc

Ingrida LurinaPh: +371 29 337 903E-mail: ilurina@orphan-europe.com