Çocuk yoğun bakım ünitesinde terapötik plazma değişiminin serum sitokin düzeylerine etkisinin değerlendirilmesi
Evaluation of the effect of therapeutic plasma exchange therapy on plasma cytokine levels in pediatric intensive care unit
Yazar: SELEN CEREN ÇAKMAK
Danışman: DOÇ. DR. SEHER ERDOĞAN
Sağlık Bilimleri Üniversitesi / İstanbul Ümraniye Eğitim ve Araştırma Hastanesi / Çocuk Sağlığı ve Hastalıkları Ana Bilim Dalı
Derece: Tıpta Uzmanlık, 2023
Konu: Çocuk Sağlığı ve Hastalıkları = Child Health and Diseases
Dizin: Plazmaferez = Plasmapheresis ; İnterleukin 6 = Interleukin 6

Özet:
Amaç: Terapotik plazma değişimi, uygun endikasyonlarda yapıldığında hayat kurtarıcı bir yöntemdir, erişkinlerde etkin ve güvenli bir şekilde kullanılsa da; pediatrik kullanımı damar yolu erişim kısıtlamaları, yan etkiler, düşük kan hacmi, işlem sırasındaki komplikasyonlar, hasta uyumu, teknik zorluklar ve evrensel kabul edilmiş endikasyonların eksik olması nedeniyle sınırlı kalmaktadır. Bununla birlikte, uygun endikasyonlarda uygulanmış TPD'nin çocuk hastalarda da güvenilir olduğuna dair deneyimler mevcut olup son dönemde birçok merkezin çocuk yoğun bakım ünitelerinde TDP uygulamasının arttığı gözlenmektedir.
Bu çalışmayı yapmaktaki amacımız, çeşitli nedenlerle terapotik plazma değişimi uygulanan kritik çocuk hastalarda prognozu belirleyen risk faktörlerini araştırmak ve terapotik plazma değişiminin TWEAK proteini ve IL-6 düzeylerine etkisinini araştırmaktır. 
Gereç ve Yöntem: Çalışma Çocuk yoğun bakım ünitesinde yatan hastalarda, prospektif ve tek merkezli olarak gerçekleştirildi. Mayıs 2022-Aralık 2022 tarihleri arasında TPD uygulanan 41 hasta çalışmaya dahil edildi. Hastaların demografik özellikleri, laboratuvar parametreleri, işlem öncesi ve sonrası TWEAK ,  IL-6 düzeyleri kaydedildi. IL-6 ve TWEAK çalışma kitleri için ödenek Sağlık Bilimleri Üniversitesi Bilimsel Araştırma Proje Birimi tarafından 2023/016 proje numarası ile desteklendi. 
Bulgular: Çalışma yaşları 2 ile 191 ay arasında değişen, %53.7'si erkek,  toplam 41 hasta ile gerçekleştirildi. Yaş ortalaması 91.07±67.74 ay, vücut ağırlığı ortalaması 28,46±20.09 kg, nabız ortalaması 111.41±34.33/dk, sistolik kan basıncı ortalaması 98.85±23.72 mmHg, solunum sayısı ortalaması ise 28.17±6.95/dk idi. ÇYBÜ yatış gün sayısı 3 ile 170 gün arasında değişmekte olup, ortalama 25.68±29.79 gündü. Hastaların yatış tanıları değerlendirildiğinde ilk sırada MIS-C hastalarının olduğu, bunu sırasıyla sepsis (%24.4), MAS/HLH (%22) ve nörolojik hastalıkların (%17.1)  izlediği görüldü. Hastaların PRISM skoru ortalaması 8,10±10,70 idi, TPD öncesi ve sonrası PELOD ve OFI skorlarında istatistiksel olarak anlamlı bir değişiklik saptanmadı (p<0.05), ancak TPD sonrası VIS skoru TPD öncesine göre anlamlı olarak daha yüksekti (p=0.028). Hastaların 21'inin (%51.2) altta yatan hastalıkları vardı, 16'sı (%39) sepsis kliniğine sahipken, 15'i (%36,6)  NIV/IMV desteği almaktaydı. Hastaların sağkalım oranı %68,3 olarak saptandı. Uygulanan TPD seans sayısı ortalama 5,71±3,21 idi. IL-6 düzeyi TPD sonrasında, TPD öncesine göre anlamlı olarak daha yüksekti (p:0.006; p<0.05). TWEAK protein düzeyinde, TPD sonrasında öncesine göre istatistiksel olarak anlamlı bir azalma saptandı (p:0.030; p<0.05). TPD işleminden sonra ALT, AST, üre, kreatin, ferritin, D-dimer, prokalsitonin, INR ve WBC düzeylerinde  istatistiksel olarak anlamlı bir azalma saptandı. Yaş, cinsiyet ile TPD öncesi IL-6 ve TWEAK protein düzeyleri arasında istatistiksel olarak anlamlı bir farklılık bulunmadı (p>0.05). Yatış tanıları, sepsis varlığı, NIV/IMV desteği ve kan ürünü ihtiyacı açısından hasta gruplarının TPD öncesi ve sonrası IL-6 ve TWEAK protein düzeyleri karşılaştırıldı, istatistiksel olarak anlamlı bir farklılık saptanmadı (p>0.05). TPD öncesi IL-6 düzeyi ile NIV-MV gün sayısı ve ferritin düzeyi arasında pozitif yönlü, orta düzeyde ve istatistiksel olarak anlamlı bir ilişki bulundu (p<0.05). TPD öncesi TWEAK protein düzeyi ile organ yetmezlik sayısı, OFİ  ve D-Dimer düzeyi arasında pozitif yönlü, orta düzeyde ve istatistiksel olarak anlamlı bir ilişki saptandı (p<0.05). TPD uygulamasından sonra saptanan IL-6 ve TWEAK  fark düzeyi ile ÇYBÜ gün sayısı, organ yetmezlik sayısı, prognoz, TPD öncesi ve sonrası VIS, PELOD ve OFI skorları arasında istatistiksel olarak anlamlı bir ilişki saptanmadı (p>0.05). Prognoza göre hastaların yaşı, cinsiyeti, ÇYBÜ yatış gün sayıları, WBC, hemoglobin, hematokrit, serum IL-6 ve TWEAK, üre, kreatinin, düzeyleri arasında istatistiksel olarak anlamlı bir farklılık yoktu (p>0.05). Kaybedilen hastaların organ yetmezlik sayısı, PRİSM, PELOD, OFİ ve VİS skorları,  sağ kalanlara göre istatistiksel olarak anlamlı düzeyde daha yüksekti (p<0.05). Prognoza göre TPD öncesi ALT, AST, CRP, prokalsitonin, INR düzeyleri arasında istatistiksel olarak anlamlı bir farklılık bulunmazken (p>0.05); kaybedilen hastaların TPD sonrası ALT, AST, CRP, prokalsitonin ve INR düzeyleri, sağ kalanlardan daha yüksekti (p:0.034, p:0.001, p:0.001; p<0.05). Kaybedilen hastaların TPD öncesi ve sonrası trombosit düzeyleri, sağ olanlardan istatistiksel olarak anlamlı düzeyde düşüktü (p:0.039; p:0.001; p<0.05), laktat düzeyleri ise daha yüksekti (p:0.025; p:0.001; p<0.05). Kaybedilen hastalarda NIV/MV ile solunum desteği, inotrop ilaç ihtiyacı ve sepsis oranı sağ kalanlara göre anlamlı olarak daha yüksekti (p:0.001; p<0.05).

Sonuç: Çalışma elde edilen veriler sonucunda TPD uygulanan hastalarda yüksek serum TWEAK düzeyinin daha yüksek organ yetmezliği sayısı, daha yüksek OFI skoru ve D-dimer düzeyi ile;  yüksek serum IL-6 düzeyinin ise daha uzun NIV/MV gün sayısı, daha yüksek ferritin düzeyi ile ilişkili olduğunu saptadık. TPD işleminden sonra TWEAK protein düzeyinde belirgin bir azalma varken, IL-6 düzeyinde ise azalmanın olmadığını belirledik. Ne TPD öncesi ve sonrası IL-6 ve TWEAK düzeyleri, ne de uygulama ile ortaya çıkan fark ile hastaların prognozu arasında bir ilişki saptanmadı. Serum IL-6 ve TWEAK proteininin hastalığın şiddetini ve inflamasyonun düzeyini belirlemede belirteç olarak kullanılabileceğini ancak hastanın prognozunu öngörmede yetersiz olduğunu düşünmekteyiz. 

Anahtar Kelimeler: Çocuk Yoğun Bakım Ünitesi, TWEAK, IL-6, Terapötik Plazma Değişimi

Abstract:
Objective: In our study, we evaluated and compared the demographic, clinical and laboratory data of patients who underwent Therapeutic Plasma Exchange (TPE) in our pediatric intensive care unit between May 2022 and December 2022 and tried to determine the risk factors affecting the prognosis of the patients. The results obtained were aimed to evaluate whether TPD is a safe and effective method and its effect on prognosis in pediatric patients with a disease picture caused by the accumulation of substances such as autoantibodies, monoclonal immunoglobulins, lipids, immunocomplexes and toxins.

Materials and Methods: This prospective, single-center study was approved by the Clinical Research Ethics Committee of Health Sciences University (SBU), Istanbul Ümraniye Training and Research Hospital. Forty-one patients aged between 1 month and 18 years who underwent TPD between May 2022 and December 2022 were included in the study. Data were obtained from the electronic files of the patients. Complete blood counts, biochemical tests, coagulation parameters, blood gases, CRP, procalcitonin, IL-6, TWEAK (TNF-like weak inducer of apoptosis), etc. of the patients hospitalized in the pediatric intensive care unit; protocol number, age, gender, body weight, comorbid conditions, PRISM score, PELOD score, OFI score, procedure details, replacement fluid, number of sessions, anticoagulant use, additional treatments, presence of infection, duration of hospitalization, mechanical ventilator and inotropic drug requirements were recorded. Patients were categorized according to the ASFA 2019 guideline, which includes evidence-based indications for TPE.

Results: The study was performed with a total of 41 patients, 53.7% of whom were male, aged between 2 and 191 months. Mean age was 91.07±67.74 months, mean body weight was 28.46±20.09 kg, mean pulse rate was 111.41±34.33/min, mean systolic blood pressure was 98.85±23.72 mmHg, and mean respiratory rate was 28.17±6.95/min. The number of days of PICU hospitalization ranged between 3 and 170 days, with a mean of 25.68±29.79 days. When the hospitalization diagnoses of the patients were evaluated, it was observed that MIS-C patients were the primary diagnosis, followed by sepsis (24.4%), MAS/HLH (22%), and neurological diseases (17.1%). The mean PRISM score of the patients was 8.10±10.70. There was no statistically significant change in PELOD and OFI scores before and after TPD (p<0.05), but the VIS score after TPD was significantly higher than before TPD (p=0.028). There was no statistically significant change in VIS score after TPD compared to before TPD (p>0.05).  Out of 41 patients, 21 (51.2%) had underlying diseases, comprising 38.1% rheumatologic disease, 23.8% cardiac disease, 23.8% neurologic disease, and 14.3% other diseases. While 16 (39%) had sepsis clinic, 15 (36.6%) were receiving NIV/IMV support, 90.2% required blood product transfusion and 48.8% required inotropic drugs. The survival rate was 68.3%. The mean number of TPD sessions was 5.71±3.21. Fresh frozen plasma was used as replacement fluid during TPD in 90.2% (n=37), fresh frozen plasma and albumin in 4.9% (n=2), and albumin in 4.9% (n=2). There were no complications of plasmapheresis in 90.2% (n=37) of the patients, while one patient developed plasmapheresis filter obstruction and two developed allergic skin rash during the procedure. IL-6 level was significantly higher after TPD than before TPD (p:0.006; p<0.05). A statistically significant decrease was observed in the TWEAK protein level after TPE compared to before TPE (p:0.030; p<0.05). ALT level also significantly decreased after TPE compared to before TPE (p:0.001; p<0.05). The decrease in AST level after TPE compared to pre-TPE AST level was statistically significant (p:0.002; p<0.05). The levels of urea and creatinine showed a statistically significant decrease after TPE compared to pre-TPE levels (p:0.011 and p:0.009, respectively). On the other hand, a statistically significant increase was observed in the serum calcium level after TPE compared to before TPE (p:0.001; p<0.05). There was also a significant decrease in the levels of ferritin, D-dimer, procalcitonin, and WBC (leukocyte) after TPE (p:0.038; p:0.001, p:0.040 and p:0.029, respectively). Similarly, there was a statistically significant decrease in INR level after TPE (p:0.005; p<0.05). No significant difference was found in other laboratory parameters before and after TPE (p>0.05).
There was no statistically significant difference between the age and IL-6 and TWEAK protein levels before TPE (p>0.05). The same was true for the comparison of IL-6 and TWEAK protein levels between male and female patients (p>0.05). Additionally, there was no statistically significant difference in IL-6 and TWEAK protein levels before and after TPE between hospitalization diagnoses (p>0.05). Moreover, no statistically significant difference was found when comparing IL-6 and TWEAK protein levels of the patient groups before and after TPE based on the presence of sepsis, NIV/IMV support, and the need for blood products (p>0.05).
A positive, moderate (50.4%) and statistically significant relationship was found between IL-6 level before TPE and the number of days of NIV-MV (p:0.009; p<0.05). Similarly, a positive, moderate (37%) and statistically significant correlation were observed between IL-6 level and ferritin level before TPE (p:0.017; p<0.05). However, no statistically significant correlation was found between IL-6 level before TPE and other parameters (p>0.05).
A positive, moderate (31.3%) and statistically significant association was found between TWEAK protein level before TPE and the number of organ failure (p:0.046; p<0.05). Additionally, there was a positive, moderate (32.8%) and statistically significant association between pre-TPE TWEAK protein level and OFI (p:0.036; p<0.05). Furthermore, a positive, moderate (34.8%) and statistically significant relationship were observed between TWEAK level and D-Dimer level before TPE (p:0.026; p<0.05). However, no statistically significant correlation was found between TWEAK level and other parameters before TPE (p>0.05).
There was no statistically significant correlation between the difference level of IL-6 and TWEAK after TPE and the number of PICU days, number of organ failure, VIS, PELOD, and OFI scores before and after TPE (p>0.05). Similarly, no statistically significant difference was found between IL-6 and TWEAK protein difference and prognosis after TPE (p>0.05).
There was no statistically significant difference between the age, gender, number of days of PICU hospitalization, WBC, hemoglobin, hematocrit, serum IL-6 and TWEAK, urea, creatinine levels of the patients according to prognosis (p>0.05).
The number of organ failure, PRISM, PELOD, OFI, and VIS scores of the deceased patients were statistically significantly higher than those of the survivors (p<0.05). Conversely, while there was no statistically significant difference between ALT, AST, CRP, procalcitonin, and INR levels before TPE according to prognosis (p>0.05), ALT, AST, CRP, procalcitonin, and INR levels after TPE were higher in patients who died compared to survivors (p:0.034, p:0.001, p:0.001; p<0.05). Additionally, while there was no statistically significant difference between total protein levels before TPE according to prognosis (p>0.05), total protein levels of the deceased patients after TPE were lower than those of the survivors (p:0.001; p<0.05). Platelet levels of the deceased patients before and after TPE were statistically significantly lower (p:0.039; p:0.001; p<0.05), and lactate levels were higher (p:0.025; p:0.001; p<0.05) than those of the survivors. Moreover, respiratory support with NIV/MV, the need for inotropic drugs, and sepsis rate were significantly higher in deceased patients than in survivors (p:0.001; p<0.05).
Conclusion: In our study, serum IL-6 and TWEAK levels of survivors and enrolled patients before and after TPE were compared and no significant difference was observed between the two groups. The number of organ failure, PRISM, PELOD, OFI and VIS scores of the lost patients were higher than those of the survivors. Similarly, ALT, AST, PCT and INR levels were higher and platelet counts were lower before and after TPE in the lost patients compared to the survivors. There was also a positive correlation between baseline TWEAK level and number of organ failure, OFI score and D-dimer level. TWEAK level was 2946 mg/dL before TPE and 2712 mg/dL after TPE, and this difference was statistically significant (p:0.030). However, we did not detect a decrease in IL-6 level before and after TPE. The data obtained at the end of the study showed that high serum TWEAK level was associated with higher number of organ failure, higher OFI score and D-dimer level, while high serum IL-6 level was associated with longer NIV/MV days and higher ferritin level in patients who underwent TPE. After TPE, there was a significant decrease in TWEAK protein level, while IL-6 level did not decrease. Neither the IL-6 and TWEAK levels before and after TPE, nor the difference between TPE and the prognosis of the patients were correlated. We think that serum IL-6 and TWEAK protein can be used as markers to determine the severity of the disease and the level of inflammation, but they are insufficient to predict the prognosis of the patient. 

Keywords: Pediatric Intensive Care Unit, IL-6, Therapeutic Plasma Exchange, TWEAK