VAKA 1 M.A. 3 yaşında, kız hasta

Transkript

1 VAKA 1 M.A. 3 yaşında, kız hasta tarihleri arasında sistemik JRA tanısı ile metotreksat+metil prednizolzon+siklosporin tedavisi başlanmış tarihinde tedaviye dirençli sistemik JRA düşünülerek pulse steroid 3 gün ve IVIg tedavisi verilmiş 1

2 VAKA tarihinde genel durumunda kötüleşme olması üzerine eğitim ve araştırma hastanesi ÇYBÜ ne hemofiltrasyon ve plazma değişimi yapılması için sevk edilmiş Kateter takılamayan hastada işlem gerçekleştirilememiş ve üç gün izlendikten sonra takip edildiği hastaneye geri gönderilmiş 2

3 VAKA tarihinde HLH-2004 kemoterapi protokolü (deksametazon+etoposid+siklosporin) başlanmış tarihinde genel durum bozulması ve solunum yetersizliği tanıları ile Bezmiâlem Üniversitesi Tıp Fakültesi ÇYBÜ ne sevk edildi. 3

4 VAKA 1 Genel durum orta, dispneik, taşipneik, ödemli KTA: 162/R, DSS: 40/R, TA: 70/38 mmhg, ateş 37.5 C Bilinç aşık, huzursuz Taşipneik, dispneik, yer yer krepitan raller duyulmakta, ekspiryum uzun Dinlemekle kalp sesleri derinden duyulmakta, S3 yok Batın distandü, hepatomegali yok, 3 cm splenomegali var 4

5 VAKA 1 Hb: 5.7 g/dl Hct: %17.8 Lökosit: 3300/mm 3 Trombosit: /mm 3 PT: 20 ıı aptt: 49 ıı INR: 1.67 Fibrinojen: 120 mg/dl Üre:64.2 mg/dl Ürik asit: 14.5 mg/dl Na: 137mEq/L Fosfor: 6.4 mg/dl Albumin: 2.8 g/l CRP:17.2 mg/dl (<0.5) Trigliserid: 352 mg/dl Ferritin: mcg/l Ekokardiyografi: Aort yetersizliği, mitral yetersizliği, minimal perikardiyal efüzyon 5

6 VAKA 1 Dolaşım yetersizliğinde olan hastaya noradrenalin başlandı Çekilen akciğer grafisinde bilateral infiltrasyonları olan hastaya NIV başlandı Makrofaj aktivasyon sendromu tanısı ile plazma değişimi+pulse steroid+il-1ra tedavileri başlandı. İlk TPE sonrası idrar çıkışının olmadığı gözlene hastada 6 TPE sonrasında hemofiltrasyon başlandı.

7 HYPERFERRITINEMIA IN THE CRITICALLY ILL CHILD WITH SECONDARY HLH, MAS, and SEPSIS INDUCED MODS: WHAT IS THE TREATMENT? D Demirkol, D Yıldızdas, B Bayrakcı, B Karapınar, T Kendirli, T Koroglu, O Dursun, N Atay, H Gedik, A Citak, M Karabocuoglu; Turkish Secondary HLH/MAS Critical Care Study Group, J Carcillo 7

8 Hemophagocytic Lymphohistiocytosis In 1987 the Writing Group of the Histiocyte Society recommended a division of the histiocytic disorders into three classes: Langerhans cell histiocytosis, non-langerhans cell histiocytosis, to which belongs hemophagocytic lymphohistiocytosis (HLH), and malignant histiocyte disorders. In 1997 revision of this classification termed those three groups as dendritic cell-related disorders, macrophage related disorders, and malignant disorders. HLH was among the macrophage-related disorders. Two forms of HLH were described: primary and secondary. Primary HLH is the prototype of hemophagocytic syndromes, can be familial or sporadic, and is often elicited by viral infections. Secondary HLH can be associated with infections, particularly viral infections, and malignant disorders. In 2007, International Histiocyte Society described new guidelines for the diagnosis of HLH. 8

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10 On Distinguishing Sepsis from MAS/SHLH.. An unfinished story Even with the published diagnostic criteria patients of all ages presenting with HLH will often have features consistent with sepsis. Many of the criteria listed in the revised diagnostic guidelines for HLH can be found in patients with sepsis or systemic inflammatory response syndrome Many HLH patients will progress to develop multi-organ dysfunction syndrome (MODS), which is also seen in patients with severe sepsis 10

11 The relevance of this overlap lies in the treatment and outcomes In the intermediate groups use of the cytotoxic HLH protocol may not be necessary in SHLH/MAS or may be deleterious in severe sepsis, MODS or MAS. 11

12 FHL- absent NK/CTL function- no cell mediated immunity or activated immune cell death MAS-Decreased T reg cells and NK function so undamped inflammation but no immune supression SEPSIS/SHLH-Prominent T H 2 phenotype with reduced NK activity and macrophage TNF response immune supression 12

13 Index Case Five years and six months old male, ALL+varicella infection He was admitted to PICU because of mucosal bleeding and organ dysfunction. PRISM-III score was 18 and had four organ involvements He had 8 cm hepatomegaly, melena and hematochesia occuring approximately eight times a day Required massive RBC transfusions - 11 units of red blood cell - on the first day 13

14 Index Case Hb 4.8 g/l, platelet 19000/mm 3, leucocyte 13500/mm 3 PT 35 sec, aptt 47 sec, fibrinogen 93 mg/dl AST 6534 IU/L, ALT 2362 IU/L, LDH IU/L Triglyceride 474 mg/dl, Ferritin > cg/ml Bone marrow showed hemophagocytic cells TPE was performed eleven times until multiple organ dysfunctions resolved Bleeding stopped after third TPE sessions Survived 14

15 Hypothesis Patients with hyperferritinemia associated sepsis/mods/secondary HLH/MAS can be successfully treated with a less immunosuppressant approach than is recommended for primary HLH. 15

16 Methods Observational cohort study 8 centers participated to the study A standardized study form developed together by all participating pediatric intensive care centers and was filled for each patient by responsible pediatric intensivits from each center The study was approved by the Ethics Committee of the Istanbul Faculty of Medicine, Ref. No. 2011/

17 Multi-center Turkish Pediatric Intensive Care Study Therapy for Reactive HLH without use of the HLH protocol Patients meeting 5/8 criteria for MAS/HLH (not thought to have primary HLH because of absent family history or effected sibling) will be given IVIG, solumedrol, plasma exchange. Our initial experience with hyperferritinemia and MODS included 34 patients. Eight were diagnosed as primary HLH and 3 did not meet the criterias and excluded from the study. 17

18 Patient characteristics at baseline 18

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21 The diagnosis and precipitating factors 65% (n=15) of the patients were classified as secondary HLH. The precipitating factors were viral and non viral infections in 93% (n=14) of the patients. Thirty five percent of the patients (n=8) were classified as MAS The precipitating factors were drugs in three and infection in one patients. 21

22 The treatment protocols and survival Protocol 1: TPE+ iv methyl prednisolone (n=8) Protocol 2: TPE+ IVIg (n=9) Protocol 3: iv dexamethasone + iv cyclosporine and/or etoposide + IVIg treatement failure TPE (n=4) Protocol 4: iv dexamethasone + IVIg treatment failure TPE (n=2) 22

23 The treatment protocols and survival In all the centers TPE was performed if the patient had hyperferritinemia and more than two organ dysfunctions and continued until organ dysfunctions resolved, ferritin levels decreased and platelet count increased to / mm 3. Therapeutic plasma exchange was performed median 5 (1-18) times, the dose median 1.5 estimated TPV and 78 ml/kg (60-80). 23

24 Ferritin Platelet LDH

25 The treatment protocols and survival The overall mortality was %13 (n=3). Mortality was 50% (2/4) and 50% (1/2) in the patients were treated with chemotherapy based treatment protocols and dexamethasone group -protocol 3 and 4- respectively. There was no mortality in TPE and IVIg or methly prednisolone treated group 25

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27 Survivors vs Non-survivors 27

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29 Survivors vs Non-survivors In the multiple regression analysis, survival was taken as dependent variable and gender, ferritin level and treatment protocols were taken as independent variables. Regression analysis revealed that survival was best explained by treatment protocol (R=0.65, β=0.65, p=0.001, 95% CI ) 29

30 TPE &chemotherapy or dexa vs TPE& methyl prednisolone or IVIg 30

31 TPE &chemotherapy or dexa vs TPE& methyl prednisolone or IVIg We also evaluated which factors were different between TPE and methyl prednisolone or IVIg treated group and TPE and chemotherapy or dexamethasone treated group 31

32 TPE &chemotherapy or dexa vs TPE& methyl prednisolone or IVIg 32

33 TPE &chemotherapy or dexa vs TPE& methyl prednisolone or IVIg There was statistically significant difference between treatment protocols regarding gender, ALT, PT, aptt levels (p<0.1). In the multiple regression analysis, controlling for gender, ALT, PT and aptt level and treatment protocol, regression analysis still revealed that there was significant association between treatment protocol and survival (R=0.65, β=0.65, p=0.002, 95% CI ). 33

34 Conclusion In patients who do not have primary HLH use of the cytotoxic HLH protocol may not be necessary in SHLH/MAS or may be deleterious in severe sepsis, MODS or MAS. Therapeutic plasma exchange therapy may be a useful therapeutic tool in the pediatric field for the treatment of critically ill SHLH/MAS patients with MODS. 34

35 VAKA 1 İlk TPE sonrası idrar çıkarmayan hastada 12 saat boyunca hemofiltrasyon yapılarak 1000 cc sıvı çekildi İntraabdominal basıncı azalan dolaşımı düzelen hastada yeterli diürez sağlandı ve hemofiltrasyon sonlandırıldı 24 saat NIV uygulanan hastanın solunum yetersizliği bulguları düzeldi ve maske ile oksijen tedavisine geçildi ve vazoaktif ilaç kesildi Beşinci TPE sonrası hasta enteral serbest beslenir hale geldi 35

36 VAKA Ferritin: mcg/l Ferritin: mcg/l Ferritin: mcg/l Ferritin: 1360 mcg/l 36

37 VAKA 2 M.K. Erkek, 6 aylık Yatış tarihi: Üç gündür kusma ishal yakınması olan hasta eğitim ve araştırma hastanesine götürülmüş Dolaşım yetersizliğinde olan hastanın bakılan tetkiklerinde metabolik asidoz, üre, kreatinin ve sodyum yüksekliği olması üzerine Bezmiâlem Vakıf Üniversitesi ÇYBÜ ne sevk edildi. 37

38 VAKA 2 Entübe, KDZ > 3 sn, KTA: 190/R, TA: 90/75 mmhg, DSS: 60 Göz küreleri çökük, mukozalar kuru, ön fontanel 2x2 cm çökük, alacalı ekstremiteler Turgor Dispne yok, solunum sesleri doğal Kalp sesleri derinden duyulmakta, S 3 yok Hepatosplenomegali yok 38

39 VAKA 2 Hb: 9.8 g/dl Htc: %27.5 Lökosit: /mm 3 Trombosit: /mm 3 PT: 41.6 ıı aptt: 83 ıı INR: 3.36 CRP: mg/dl (<0.5) Glukoz: 52 mg/dl Üre: 188 mg/dl Kreatinin: 1.28 mg/dl Na: 163 meq/l Fosfor: 9.8 mg/dl Potasyum: 3.8 meq/l Kalsiyum: 5.3 mg/dl ALT: 67 U/L AST: 25.9 U/L LDH: 1819 U/L 39

40 VAKA 2 ph: 6.93, pco2: 58, HCO3: 12, BD: -20 Hastaya 80 cc/kg SF 20 cc/kg TDP 15 cc/kg eritrosit süspansiyonu ilk altı saat içinde uygulandı Adrenalin infüzyonu başlandı Sefotaksim başlandı 40 Konvülziyon geçirdi, difenilhidantoin başlandı

41 VAKA 2 Hb: 9.9 g/dl Htc: %28.9 Lökosit: /mm 3 Trombosit: /mm 3 PT: 24 ıı aptt: 46 ıı INR: 1.95 Glukoz: 87mg/dL Üre: 164mg/dL Kreatinin: 1.32 mg/dl Na: 158mEq/L Fosfor: 9 mg/dl Potasyum: 3.2 meq/l Kalsiyum: 5.71 mg/dl ALT: 305 U/L AST: 98 U/L 41

42 VAKA 2 Batın USG: normal Ekokardiyografi: normal Periferik yayma: Çok sayıda şistosit 42

43 VAKA 2 Tanı: TAMOF Beş organ yetersizliği var Kardiyovasküler, renal, hepatik, nörolojik, hematolojik Ardışık olarak TPE ve hemofiltrasyon yapıldı Hemofiltrasyon ve TPE dört gün boyunca uygulandı Organ yetersizlikleri geriledi 43

44 VAKA 2 Hb: 8.4 g/dl Htc: %25.8 Lökosit: /mm 3 Trombosit: /mm 3 CRP: 6.6 mg/dl Glukoz: 99mg/dL Üre: 42mg/dL Kreatinin: 0.55 mg/dl Na: 141mEq/L Fosfor: 2.5 mg/dl Potasyum: 3.6 meq/l Kalsiyum: 8.8 mg/dl ALT: 78 U/L AST: 112U/L LDH: 825 U/L 44