Deneysel sepsis modelinde intravenöz hipokloröz asit (HOCL) uygulamasının etkileri
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Tarih
2021
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Yayıncı
Necmettin Erbakan Üniversitesi Sağlık Bilimleri Enstitüsü
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info:eu-repo/semantics/openAccess
Özet
Amaç: Deneysel sepsis modeli oluşturulan sıçanlarda intravenöz (İ.V) Hipokloröz asit (HOCl) uygulaması ile HOCl'nin geniş antimikrobiyal ve antiinflamatuvar etki mekanizmasının sepsis tedavisinde etkili olup olmadığını ve sepsis tedavisinde ilk defa İ.V. uygulanacak olan HOCl'nin böbrek fonksiyon testlerinin ve karaciğer enzimlerinin düzeylerini etkileyip-etkilemediğini araştırmayı amaçladık. Gereç ve Yöntem: Çalışmamızda ağırlıkları ortalama 220-250 gr. arasında değişen toplam 30 adet dişi Wistar-Albino cinsi sıçan kullanıldı ve denekler; 1. Grup: Sham Grubu (n:10), 2. Grup: Sepsis Grubu (n:10) ve 3. Grup: Sepsis + İ.V HOCl Grubu (n:10) olmak üzere toplam 3 gruba ayrıldı. Sepsis ve Sepsis + İ.V HOCl gruplarındaki deneklere Çekum Ligasyon ve Perforasyon (ÇLP) yöntemi ile deneysel sepsis modeli uygulandı. Sham grubundaki deneklere ise anestezi ve operatif işlem yapıldı fakat ÇLP modeli uygulanmadı. Sepsis + İ.V. HOCl grubuna tedavide 0,75 ml/kg/gün dozunda İ.V. HOCl verilirken, diğer gruplara aynı dozda İ.V serum fizyolojik verildi. Juguler ven kateterizasyonu yoluyla tüm deneklerden 0. (bazal), 24. ve 48. saatlerde kan numuneleri alınarak; böbrek fonksiyon testleri ve karaciğer enzimleri gibi biyokimyasal testlerin, C-Reaktif Protein (CRP) ve Prokalsitonin (PCT) gibi akut faz reaktanlarının, TNF-α (Tümör Nekrozis Faktör-alfa) ve IL-1 (İnterlökin-1) gibi proinflamatuvar sitokinlerin ve total beyaz küre (WBC) ve nötrofil (NEU) sayısı gibi hemogram (tam kan) parametrelerinin düzeyleri ölçüldü. Grupların ölçülen tüm bu sepsis parametreleri, ortalama ve standart sapma değerleri hesaplanarak tablolar haline getirildi. Gruplararası istatistiksel karşılaştırmalar tek yönlü varyans incelemesi (One-way ANOVA) ile yapıldı ve Post Hoc Test olarak Tukey HSD testi kullanıldı. p<0.05 değerleri istatistiksel olarak anlamlı kabul edildi. Tüm istatistiksel analizler için PRISM-5 programı kullanıldı. Bulgular: Sepsisteki inflamatuvar sürecin göstergesi olarak IL-1 ve TNF-α gibi proinflamatuvar sitokinlerin düzeyleri değerlendirildiğinde; Sepsis + İ.V HOCl (Grup-3) grubundaki 48. saat IL-1 ve TNF-α düzeyleri; Sepsis (Grup-2) grubuna göre istatistiksel olarak anlamlı şekilde düşük bulundu (p<0,01). Sepsisteki enfeksiyöz sürecin göstergesi olarak WBC ve NEU sayısı gibi hemogram (tam kan) parametrelerinin düzeyleri değerlendirildiğinde ise; Sepsis + İ.V HOCl (Grup-3) grubundaki 48. saat WBC ve NEU düzeyleri; Sepsis (Grup-2) grubuna göre istatistiksel olarak anlamlı şekilde düşük bulundu (sırasıyla p<0,01 ve p<0,05). Çalışmada ayrıca sepsisteki enfeksiyöz ve inflamatuvar süreçlerin göstergesi olarak PCT ve CRP gibi akut faz reaktanlarının düzeyleri değerlendirildiğinde; Sepsis + İ.V HOCl (Grup-3) grubundaki 48. saat PCT düzeyi; Sepsis (Grup-2) grubuna göre istatistiksel olarak anlamlı şekilde düşük bulundu (p<0,01). Tüm grupların CRP değerleri saatlere göre birbirleriyle karşılaştırıldığında ise; Sepsis grubunun 48. saatteki CRP değerlerinde diğer gruplara göre rakamsal olarak artma varken; aradaki farkın istatistiksel olarak anlamlı olmadığı gözlendi (p>0,05). Sepsisteki böbrek disfonksiyonu göstergesi olarak üre, kreatinin gibi böbrek fonksiyon testlerinin düzeyleri değerlendirildiğinde; Sepsis + İ.V HOCl (Grup-3) grubundaki 48. saat üre düzeyi; Sepsis (Grup-2) grubuna göre istatistiksel olarak anlamlı şekilde düşük bulundu (p<0,01). Tüm grupların serum kreatinin değerleri saatlere göre birbirleriyle karşılaştırıldığında ise; Sepsis (Grup-2) grubundaki 0. saat kreatinin düzeyinin; Sham (Grup-1) ve Sepsis + İ.V HOCl (Grup-3) gruplarına göre istatistiksel olarak anlamlı şekilde azaldığı gözlendi (sırasıyla p<0,05 ve p<0,01). Sepsisteki karaciğer harabiyetinin göstergesi olarak AST, ALT, ALP ve GGT gibi karaciğer enzimlerinin düzeyleri değerlendirildiğinde, Sepsis (Grup-2) grubundaki 48. saat ALP düzeylerinin; Sham (Grup-1) ve Sepsis + İ.V HOCl (Grup-3) gruplarına göre istatistiksel olarak anlamlı şekilde yükseldiği (p<0,01) fakat ALT düzeylerinde anlamlı bir farklılık olmadığı gözlendi (p<0,05). Tüm grupların AST ve GGT değerleri saatlere göre birbirleriyle karşılaştırıldığında ise; Sepsis + İ.V HOCl grubunun (Grup-3) 0. saat AST değerlerinin; Sepsis grubuna (Grup-2) göre istatistiksel olarak anlamlı şekilde yükseldiği (p<0,05) ve Sepsis+İ.V HOCl (Grup-3) grubundaki 24. saat GGT düzeylerinin; Sham (Grup-1) grubuna göre istatistiksel olarak anlamlı şekilde yükseldiği bulundu (p<0,01). Sonuç: Çalışmada İ.V HOCl tedavisinin sepsisteki özellikle enfeksiyöz ve inflamatuvar süreçlerde seviyeleri yükselen PCT, TNF-α, IL-1, WBC ve nötrofil sayısı gibi sepsis parametrelerinin düzeylerini azaltarak antienfektif ve antiinflamatuvar özellikler için olumlu etkisi olduğu ve üre, kreatinin gibi böbrek fonksiyon testlerini olumsuz etkilemediği gözlenmiştir. Ayrıca yeni teknolojiler ile üretilmiş stabil ve fizyolojik bir antiseptik olan 200 ppm HOCl'nin literatürde ilk kez sepsis tedavisi için İ.V uygulandığında böbrek fonksiyonlarını olumsuz etkilemediği ancak özellikle ilk 24 saat içinde AST ve GGT gibi karaciğer enzimleri üzerinde yükselmeler yapabileceği tespit edilmiştir. Bu da bize karaciğer yapısı ve fonksiyonlarını koruma adına; ileride hem İ.V HOCl dozlaması ve metabolizması ile ilgili yeni farmakokinetik çalışmaların, hem de İ.V HOCl tedavisi sonrasında karaciğer ile ilgili sitotoksisite çalışmalarının yapılması gerektiğini düşündürmektedir. Bu yeni ve daha kapsamlı çalışmalar ışığında İ.V HOCl uygulamasının sepsis tedavisindeki yeri daha iyi anlaşılacaktır.
Objective: The aim of this study was to determine whether the broad antimicrobial and antiinflammatory action mechanism of HOCl is effective in the treatment of sepsis by intravenous (I.V) administration in rats in an experimental sepsis model, and to investigate whether the IV administration of HOCl for the first time in the treatment of sepsis affects the levels of kidney function tests and liver enzymes. Materials and Methods: In our study, a total of 30 female Wistar-Albino rats with an average weight of 220-250 g were used and the subjects were divided into three groups as Group 1: Sham Group (n:10), Group 2: Sepsis Group (n:10) and Group 3: Sepsis + IV HOCl Group (n:10). Experimental sepsis model was applied to the subjects in Sepsis and Sepsis + IV HOCl groups by Cecum Ligation and Perforation (CLP) method. The subjects in the Sham group underwent anesthesia and operative procedures, but the CLP model was not applied. In the treatment while 0.75 ml/kg/day I.V. HOCl was given to Sepsis + I.V. HOCl group, the other groups were given the same dose of IV saline. Blood samples were taken from all subjects at 0 (basal), 24 and 48 hours via jugular vein catheterization; biochemical tests such as kidney function tests and liver enzymes, acute phase reactants such as C-Reactive Protein (CRP) and Procalcitonin (PCT), proinflammatory cytokines such as TNF-α (Tumor Necrosis Factor-alpha) and IL-1 (Interleukin-1) and the levels of hemogram parameters such as total white blood cell (WBC) and neutrophil (NEU) counts were measured. Mean and standard deviation values of all these sepsis parameters measured in the groups were calculated and tabulated. Intergroup statistical comparisons were made with one-way analysis of variance test (One-way ANOVA) and Tukey HSD test was used as Post Hoc Test. p<0.05 values were considered statistically significant. The PRISM-5 program was used for all statistical analyses. Results: When the levels of proinflammatory cytokines such as IL-1 and TNF-α as an indicator of the inflammatory process in sepsis are evaluated; 48th hour IL-1 and TNF-α levels in the Sepsis + IV HOCl (Group-3) group were found to be statistically significantly lower than the Sepsis group (Group-2) (p<0.01). When the levels of hemogram parameters such as WBC and NEU counts as an indicator of the infectious process in sepsis are evaluated; 48th hour WBC and NEU levels in the Sepsis + IV HOCl (Group-3) group were found to be statistically significantly lower than the Sepsis group (Group-2) (p<0.01 and p<0.05, respectively). In the study, when the levels of acute phase reactants such as PCT and CRP as indicators of infectious and inflammatory processes in sepsis are evaluated; 48th hour PCT level in Sepsis + IV HOCl (Group-3) group was found to be statistically significantly lower than the Sepsis group (Group-2) (p<0.01). When the CRP values of all groups were compared with each other according to the hours; while there was a numerical increase in the CRP values of Sepsis group at the 48th hour compared to the other groups; it was observed that the difference was not statistically significant (p>0.05). When the levels of kidney function tests such as urea and creatinine as an indicator of kidney dysfunction in sepsis are evaluated; 48th hour urea level in Sepsis + IV HOCl (Group-3) group was found to be statistically significantly lower than the sepsis group (Group-2) (p<0.01). When the serum creatinine values of all groups were compared with each other according to the hours; 0th hour creatinine level in the Sepsis (Group-2) group was observed to decrease statistically significantly compared to Sham (Group-1) and Sepsis + IV HOCl (Group-3) groups (p<0.05 and p<0.01, respectively). When the levels of liver enzymes such as AST, ALT, ALP and GGT are evaluated as an indicator of liver damage in sepsis, 48th hour ALP levels in the Sepsis (Group-2) group was observed to increase statistically compared to Sham (Group-1) and Sepsis + IV HOCl (Group-3) groups (p<0.01), but there was no significant difference in ALT levels (p<0.05). When the AST and GGT values of all groups are compared with each other according to the hours; 0th hour AST values of Sepsis + IV HOCl group (Group-3) were found to be statistically significantly higher than Sepsis group (Group-2) (p<0.05) and 24th hour GGT levels in the Sepsis+IV HOCl (Group-3) group were found to be statistically significantly higher than Sham (Group-1) group (p<0.01). Conclusion: In this study, IV HOCl treatment had a beneficial effect on antiinfective and antiinflammatory properties by reducing the levels of sepsis parameters such as PCT, TNF-α, IL-1, WBC and neutrophil count, whose levels increase especially in infectious and inflammatory processes in sepsis, and it was observed that IV HOCl treatment did not adversely affect the kidney function tests such as urea and creatinine. In addition, it has been determined that 200 ppm HOCl, a stable and physiological antiseptic produced by new technologies, does not adversely affect kidney functions when administered IV for the treatment of sepsis for the first time in the literatüre, but it may increase liver enzymes such as AST and GGT, especially in the first 24 hours. This situation suggests that new pharmacokinetic studies on IV HOCl dosing and metabolism, as well as liver cytotoxicity studies after IV HOCl treatment should be performed in the future in order to protect the liver structure and functions. In the light of these new and more comprehensive studies, the place of IV HOCl administration in the treatment of sepsis will be better understood.
Objective: The aim of this study was to determine whether the broad antimicrobial and antiinflammatory action mechanism of HOCl is effective in the treatment of sepsis by intravenous (I.V) administration in rats in an experimental sepsis model, and to investigate whether the IV administration of HOCl for the first time in the treatment of sepsis affects the levels of kidney function tests and liver enzymes. Materials and Methods: In our study, a total of 30 female Wistar-Albino rats with an average weight of 220-250 g were used and the subjects were divided into three groups as Group 1: Sham Group (n:10), Group 2: Sepsis Group (n:10) and Group 3: Sepsis + IV HOCl Group (n:10). Experimental sepsis model was applied to the subjects in Sepsis and Sepsis + IV HOCl groups by Cecum Ligation and Perforation (CLP) method. The subjects in the Sham group underwent anesthesia and operative procedures, but the CLP model was not applied. In the treatment while 0.75 ml/kg/day I.V. HOCl was given to Sepsis + I.V. HOCl group, the other groups were given the same dose of IV saline. Blood samples were taken from all subjects at 0 (basal), 24 and 48 hours via jugular vein catheterization; biochemical tests such as kidney function tests and liver enzymes, acute phase reactants such as C-Reactive Protein (CRP) and Procalcitonin (PCT), proinflammatory cytokines such as TNF-α (Tumor Necrosis Factor-alpha) and IL-1 (Interleukin-1) and the levels of hemogram parameters such as total white blood cell (WBC) and neutrophil (NEU) counts were measured. Mean and standard deviation values of all these sepsis parameters measured in the groups were calculated and tabulated. Intergroup statistical comparisons were made with one-way analysis of variance test (One-way ANOVA) and Tukey HSD test was used as Post Hoc Test. p<0.05 values were considered statistically significant. The PRISM-5 program was used for all statistical analyses. Results: When the levels of proinflammatory cytokines such as IL-1 and TNF-α as an indicator of the inflammatory process in sepsis are evaluated; 48th hour IL-1 and TNF-α levels in the Sepsis + IV HOCl (Group-3) group were found to be statistically significantly lower than the Sepsis group (Group-2) (p<0.01). When the levels of hemogram parameters such as WBC and NEU counts as an indicator of the infectious process in sepsis are evaluated; 48th hour WBC and NEU levels in the Sepsis + IV HOCl (Group-3) group were found to be statistically significantly lower than the Sepsis group (Group-2) (p<0.01 and p<0.05, respectively). In the study, when the levels of acute phase reactants such as PCT and CRP as indicators of infectious and inflammatory processes in sepsis are evaluated; 48th hour PCT level in Sepsis + IV HOCl (Group-3) group was found to be statistically significantly lower than the Sepsis group (Group-2) (p<0.01). When the CRP values of all groups were compared with each other according to the hours; while there was a numerical increase in the CRP values of Sepsis group at the 48th hour compared to the other groups; it was observed that the difference was not statistically significant (p>0.05). When the levels of kidney function tests such as urea and creatinine as an indicator of kidney dysfunction in sepsis are evaluated; 48th hour urea level in Sepsis + IV HOCl (Group-3) group was found to be statistically significantly lower than the sepsis group (Group-2) (p<0.01). When the serum creatinine values of all groups were compared with each other according to the hours; 0th hour creatinine level in the Sepsis (Group-2) group was observed to decrease statistically significantly compared to Sham (Group-1) and Sepsis + IV HOCl (Group-3) groups (p<0.05 and p<0.01, respectively). When the levels of liver enzymes such as AST, ALT, ALP and GGT are evaluated as an indicator of liver damage in sepsis, 48th hour ALP levels in the Sepsis (Group-2) group was observed to increase statistically compared to Sham (Group-1) and Sepsis + IV HOCl (Group-3) groups (p<0.01), but there was no significant difference in ALT levels (p<0.05). When the AST and GGT values of all groups are compared with each other according to the hours; 0th hour AST values of Sepsis + IV HOCl group (Group-3) were found to be statistically significantly higher than Sepsis group (Group-2) (p<0.05) and 24th hour GGT levels in the Sepsis+IV HOCl (Group-3) group were found to be statistically significantly higher than Sham (Group-1) group (p<0.01). Conclusion: In this study, IV HOCl treatment had a beneficial effect on antiinfective and antiinflammatory properties by reducing the levels of sepsis parameters such as PCT, TNF-α, IL-1, WBC and neutrophil count, whose levels increase especially in infectious and inflammatory processes in sepsis, and it was observed that IV HOCl treatment did not adversely affect the kidney function tests such as urea and creatinine. In addition, it has been determined that 200 ppm HOCl, a stable and physiological antiseptic produced by new technologies, does not adversely affect kidney functions when administered IV for the treatment of sepsis for the first time in the literatüre, but it may increase liver enzymes such as AST and GGT, especially in the first 24 hours. This situation suggests that new pharmacokinetic studies on IV HOCl dosing and metabolism, as well as liver cytotoxicity studies after IV HOCl treatment should be performed in the future in order to protect the liver structure and functions. In the light of these new and more comprehensive studies, the place of IV HOCl administration in the treatment of sepsis will be better understood.
Açıklama
Doktora Tezi
Anahtar Kelimeler
Antiinflamatuvar Etki, Antimikrobiyal Etki, ÇLP (Çekum Ligasyon ve Perforasyon) Modeli, Deneysel Sepsis Modeli, İntravenöz (İ.V.) Hipokloröz Asit (HOCl) Uygulaması, Antiinflammatory and Antimicrobial Effect, Experimental Sepsis Model (CLP), IV HOCl
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WoS Q Değeri
Scopus Q Değeri
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Künye
Öztoprak, E. (2021). Deneysel sepsis modelinde intravenöz hipokloröz asit (HOCL) uygulamasının etkileri. (Yayımlanmamış doktora tezi). Necmettin Erbakan Üniversitesi Sağlık Bilimleri Enstitüsü, Tıbbi Farmakoloji Anabilim Dalı, Konya.
