中田 孝明

Septic shock is the most severe form of sepsis. It is widely accepted that cytokines play pivotal roles in the pathophysiology of septic shock. We reported previously that continuous hemodiafiltration (CHDF) using a polymethylmethacrylate (PMMA) membrane hemofilter removed various cytokines from blood continuously and efficiently, mainly by adsorption to membrane matrix of the hemofilter. Furthermore, in April 2000, we introduced to clinical practice a rapid assay system that determines blood levels of IL (interleukin)-6 in approximately 30 min. This enabled us to routinely measure blood IL-6 as an index of cytokine cascade activation in critically ill patients for real-time clinical monitoring of hypercytokinemia. The aim of the present cohort study was to evaluate the clinical efficacy of PMMA-CHDF in septic shock, a typical condition associated with hypercytokinemia. Forty-three patients with septic shock were assessed by monitoring of blood IL-6 level with a rapid assay system and immediate initiation of critical care including PMMA-CHDF for cytokine removal. Following initiation of PMMA-CHDF, early improvement of hemodynamics was noted, as well as an increase in urine output. PMMA-CHDF treatment improved both hypercytokinemia (assessed by measurement of blood IL-6 level) and dysoxia (assessed by measurement of blood lactate level). The present findings suggest that cytokine-oriented critical care using PMMA-CHDF might be an effective strategy for the treatment of septic shock.

56歳、男性。胆石膵炎に対し加療受けるも改善せず当院紹介となった。厚生労働省の急性膵炎重症度スコアは転院時13点、CT gradeはVであった。胆石は自然排石していた。PMMA-CHDFやSDDを含む集中治療を開始したが、経過中septic shockに陥り、steroidの使用を余儀なくされた。さらに感染性膵壊死を合併し、第40病日にnecrosectomy+open peritoneal drainageを施行した。当初腹腔内は細菌感染が主であったが、その後真菌が検出されmicafungin sodiumの投与を開始した。しかしその後も感染が制御できず炎症反応高値が遷延し、血液培養からTrichosporon asahiiが検出された。抗真菌薬をfluconazoleへ変更し血液培養は陰性化したが、他の感染を制御できず第138病日に永眠された。近年新しい抗真菌薬の開発・使用に伴い、真菌のbreakthroughが問題となっている。本症例のように著しい免疫不全の状態にある重症患者では特に注意が必要である。(著者抄録)

近年、敗血症性ショックに対する循環管理法は凄まじい勢いで進歩しており、その治療成績も向上していると考えられる。しかしながら、敗血症性ショック症例の中には、通常の循環管理に反応せず、急激な経過をとり死亡する場合も存在する。このように激烈な経過をとる敗血症性ショックでは経皮的心肺補助(PCPS)による循環のサポートが必要と考えられるが、敗血症性ショックに対するPCPS治療は侵襲が大きく、一般的ではない。われわれはIABPやCHDFを併用することで、PCPS施行に伴う侵襲を最小限度とするよう配慮し、敗血症性ショックに対しても、適応があればPCPSを施行することにしている。幾つかの工夫を施せば敗血症性ショックにおいてもPCPS治療は、安全にかつ効果的に施行できるものと考えられる。(著者抄録)

クリティカルケア領域における肝不全の診断や肝機能の評価は、まず肝細胞機能を評価し、その上で肝機能を代謝合成能、排泄能、細網内皮系機能に分け、これらを総合的に判断して行う。肝細胞機能としては動脈血中ケトン体比(AKBR)やosmolality gap(OG)、血中乳酸値の測定がある。劇症肝不全患者においては、生存例でAKBRの有意な上昇が認められ肝機能評価法として有用と考えられた。OGは治療経過中に正常値域に収斂する傾向にあったが、OGの算出法や有用性に依然として議論があり、肝機能評価法として極めて有用とは言い難い。また、代謝合成能としてはprothrombin timeやhepaplastin test等の凝固因子活性測定が一般的である。排泄能としてはbilirubinやD/T比測定、ICG試験が一般的に行われている。細網内皮機能としては99m-Tc-phytate colloid scintigraphによりKupffer cell機能を評価できる。これらの指標を組み合わせることで、重症患者の肝機能評価を正しく行うことが可能である。(著者抄録)

Objective: To evaluate the effect of genotypic differences and the blood interleukin-1 receptor antagonist (IL-1ra) / interleukin-1β (IL-1β) levels ratio within IL-1 gene cluster polymorphisms on the outcome. Methods: One hundred and ninety consecutive critically ill patients recruited on admission to the ICU, regardless of diagnosis, were studied. Interleukin-6 (IL-6) blood levels were measured daily with chemiluminescent enzyme immunoassay. IL-1β and IL-1ra blood levels at corresponding time when routinely measured IL-6 showed maximal values were measured retrospectively with enzyme amplified sensitivity immunoassay. Single nucleotide polymorphisms at position -511 and +3953 sites of the IL-1β (IL-1β-511^*C/T and IL1β+3953^*C/T) were identified with restriction fragment length polymorphism method. IL-1ra intron 2nd various number of tandem repeat polymorphism (IL-1RN^*1-5) was identified after polymerase chain reaction with gel electrophoresis. Results: IL-1RN^*1.1 homozygotes had significantly higher survival (P = 0.04) and higher blood IL-1ra/IL-1β ratio (P = 0.01) than the other genotypes in IL-1RN^*1-5. However, all those three polymorphisms (IL-1β-511^*C/T, IL-1β+3953^*C/T, and IL-1RN^*1-5) solely affect neither IL-1β nor IL-1ra blood levels in each. Conclusions: Non-IL-1RN^*1 alleles are associated with poor outcome and decrease in IL-1ra/IL-1β ratio causing overproduction of IL-6. Therefore, IL-1ra/IL-1β imbalance is considered to have induced the cytokine network collapse in those genetically high risk patients for hypercytokinemia.

Blood purification has been steadily improved in the field of critical care, supported by advances in related biomedical technologies as well as efforts to develop better operating procedures. As it has become clear that hypercytokinemia plays a key role in the pathophysiology of critical pathological conditions, use of various blood purification techniques to control hypercytokinemia has been investigated. Answers to questions concerning the optimal cytokine-removing device (dialyzer/hemofilter/adsorber) as well as operating procedures and conditions of such devices in particular clinical conditions have been obtained in the course Of Such investigations. The recent success in real-time monitoring of cytokine levels in clinical practice to assess the extent of cytokine network activation may improve the precision and efficacy of blood purification in the treatment of hypercytokinemia. In addition, the recently documented effects of genetic factors oil hypercytokinemia suggest that the introduction of tailor-made medicine considering the differences in genetic background among individual patients may improve the efficacy of blood purification as a countermeasure to hypercytokinemia. (c) 2006 Elsevier Ltd. All rights reserved.

The innate recognition of microbial components and subsequent activation of cytokine network are important in the pathophysiology of sepsis. Recently, functional gene polymorphisms in molecules associated with these responses were demonstrated. On the other hand, it has been claimed that there are ethnic differences in genetic polymorphisms. This study investigated toll-like receptor (TLR) 4, CD14, tumor necrosis factor (TNF)-alpha and -beta, and interleukin (IL)-10 gene polymorphisms in 197 Japanese critically ill patients and 214 healthy control subjects to evaluate the influence of these polymorphisms on clinical outcome. No Japanese participant carrying TLR4Asp299Gly or Thr399Ile was detected. No association of CD14-159C/T polymorphisms with genotype frequency or sepsis mortality was observed. Frequency of TNF-alpha-308 GA genotype was significantly higher in the sepsis group than in the control group and TNF-alpha-308GA and IL-10-592CC genotypes were related to poor outcome of sepsis. Ethnic differences in genetic variations are very important issues and the frequencies in this study differ from those previously reported in Caucasians. In conclusion, this study may indicate that TNF-alpha-308G/A and IL-10-592C/A polymorphisms involved in subsequent activation of cytokine network had a larger effect on clinical outcome in patients with sepsis than TLR4Asp299Gly, Thr399Ile, and CD14-159C/T polymorphisms associated with the initial host-microbial interaction. (c) 2005 Elsevier Inc. All rights reserved.

Background: The aim of the present study was to investigate whether tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6-related genotypic differences affect IL-6 blood levels m patients with systemic inflammatory response syndrome (SIRS) in an intensive care unit (ICU). Methods: Seven polymorphisms of TNF, IL-1, and IL-6-related polymorphisms were studied with an allele-specific polymerase chain reaction. One hundred and thirteen patients diagnosed with SIRS whose sequential organ failure assessment scores were ≥5 at the time when their daily measured IL-6 blood level peaked during the ICU stay (IL-6 max) were examined. IL-6 max, survival, and septic complications were compared between carriers and non-carriers of less frequent alleles, indicated as allele*2, in each polymorphism. Results: In single nucleotide polymorphism (SNP) at position -238 site of TNF-α (TNF-α- 238*G/A), IL-6-596*G/A, and IL-6-174*C/T, allele*2 frequencies were much lower in the Japanese than in the Caucasian population. IL-6 max was significantly higher in allele*2 carriers of IL-1β-511*C/T. Associations were found between susceptibility to septic shock and allele*2 carriage for both IL-1β-511*C/T and TNF-α-308*G/A, and also between poor prognosis and allele*2 carriage in both IL-1 receptor antagonist second intron various number of tandem repeats polymorphism (IL-1raRN*1-5) and TNF-α-308*G/A. IL-1β-511*C/T and IL-1raRN*1-5 were in linkage disequilibrium in this study population. Conclusions: Carriers of less frequent alleles in IL-1-related polymorphisms appear to have significant vulnerability to production of excessive IL-6 blood levels and to deterioration in septic shock. Copyright © 2005 by Lippincott Williams &amp Wilkins, Inc.

CHDF施行808例を対象に,血液浄化器膜素材の種類や膜面積,操作条件と小・中・大分子量物質のclearance(CL),filter life(FL)との関係について検討した.その結果,中・大分子量物質においては血流量や透析液流量,濾液流量を増加させてもCLはそれほど増大しないが膜面積を大きくすると増大することが明らかになった.小分子量物質ついては以下のことが判明した.濾液流量+透析液流量を増加させればCLは増大する.血流量や膜面積を大きくしてもCLはそれほど増大しない.膜素材によるCL差はほとんどない.濾液流量を大きくするとFLは短縮する.膜面積を大きくするとFLは延びる.膜素材によってFLは異なる

腎不全非合併急性呼吸促進症候群(ARDS)11症例へPMMA膜hemofilerを用いた持続的血液濾過透析(PMMA-CHDF)を行い,その有効性について検討した.PMMA-CHDF施行により,血漿膠質浸透圧は上昇せず,cumulative water balanceもnegative balanceにはならなかった.インターロイキン-6血中濃度は通常の管理では有意な低下は認められなかったが,PMMA-CHDF施行により初めて低下した.顆粒球エラスターゼ血中濃度もPMMA-CHDF3日間施行により有意に低下した.また,PMMA-CHDF3日間施行後,呼気終末陽圧呼吸を変化させずにRespiratory Indexの著明な改善を認めることが可能であった.PMMA-CHDFは血中からのmediator除去,肺間質の浮腫除去を介し,通常の呼吸・水分管理では改善しない腎不全非合併ARDS症例の呼吸状態を改善させることが可能であり,ARDSに対する新たな治療法になると考えられた

Background/Aims: Infection control is of key importance especially in the application of long-term continuous hemodiafiltration (CHDF) involving invasive vascular catheterization to critically ill patients. We investigated hemodialysis catheter-related infections in long-term CHDF. Methods: We examined catheter infections in 54 patients who were admitted to the intensive care unit and underwent CHDF for 2 weeks or longer. Results: With a total of 155 catheters (1,071 catheter days) studied, catheter colonization and catheter-related bloodstream infection were noted with an incidence rate of 4.8 and 2.7 per 1,000 catheter days, respectively. No difference in catheter colonization rate was observed depending on the catheterization sites or duration of catheterization. Infections were identified in 39 patients (72%) and blood culture positivity was noted in 25 patients (46%). Conclusions: Since the majority of cases requiring long-term CHDF are complicated with a variety of infections, it is difficult to control infections associated with hemodialysis catheters separately from infections of other types. Systemic infection control should serve as a strategy finally leading to successful control of catheter-related infection. Copyright (C) 2004 S. Karger AG, Basel.

外科重症感染症の治療においては,感染のコントロールと共に,続発する多臓器不全の予防及び治療が救命のために不可欠である.著者等は最近,IL-6血中濃度迅速測定システムを導入し,real timeに高サイトカイン血症を診断し,その対策を講じることが可能となった.その結果,敗血症性ショック症例に対して,早期よりサイトカイン除去を目的としたPMMA-CHDFを施行することが可能となり,ショック離脱率,救命率の改善が認められた.又,TNF-α308A/Gの遺伝子多型を解析したところ,IL-6異常高値例では特定のgenotypeが高頻度に認められ,これらの症例は予後不良であることが判明した

The aim of our study was to examine renal replacement therapies (RRT) that have been used for acute renal failure (ARF) in our intensive care unit (ICU) patients and to compare their outcomes. Sixteen patients who underwent intermittent hemodialysis (IHD), 14 patients who underwent continuous hemofiltration (CHF) in combination with IHD (CHF + IHD), and 38 patients who underwent continuous hemodiafiltration (CHDF) were evaluated. Regarding the effects of blood purification on hemodynamics and renal function, the percentage increase in blood pressure and percent rapid increase in urinary output were the greatest in the CHDF group. The hourly urinary output after the start of initial blood purification increased only in the CHDF group. The survival rate was significantly higher in the CHDF group. These results suggest that CHDF should be the first-line therapy for patients with ARF and that we are moving in the right direction regarding the application of RRT to treat ARF in ICU patients.