YBÜ Hastalarında Sepsis ve ABY’de Kan Arıtma Tedavileri Prof Dr Serhan Tuğlular Marmara Üniversitesi Tıp Fakültesi Nefroloji Bilim Dalı

Sunum Planı YBÜ’de AKI’de Renal Replasman Tedavileri Zamanlama Seçenekler Doz Sepsis’de adjuvan tedavi yöntemi olarak RRT

AKIN AKI Klasifikasyon/Evreleme sistemi Evre 1 Evre 2 Evre 3 Sınıf/Evre Kr Kriteri İdrar kriteri AKIN Evre 1 Evre 2 Evre 3 >0.3 mg/dl veya Bazal x 1.5-2 Bazal x 2-3 Bazal x > 3 Kr>4mg/dl + en az akut 0.5mg/dl↑ RRT gereksinimi <0.5ml/kg/saat -6saat <0.5ml/kg/saat -12 saat <0.3 ml/kg/saat -24 saat veya anuri-12 saat

AKI Tedavisi/Yönetimi Destekleyici Sıvı elektrolit dengesi Ortalama Arter basıncının >60 mmHg Diğer sistem hastalıklarının tedavisi/önlenmesi The management of patients with acute renal failure or acute kidney injury (AKI) is principally supportive, with renal replacement therapy (RRT) indicated in patients with severe kidney injury. Multiple modalities of RRT are currently available. These include intermittent hemodialysis (IHD), continuous renal replacement therapies (CRRTs), and hybrid therapies, such as sustained low-efficiency dialysis (SLED). Despite these varied techniques, mortality in patients with ARF remains high, greater than 50 percent in severely ill patients Gereken Hastada RRT

RRT: Başlama Nedenleri ve Zamanlaması Refrakter Sıvı Yüklenmesi Hiperkalemi (K+ >6.5mEq/L ya da hızla ↑) Üremik komplikasyonlar (perikardit, ensefalopati , kanama v.b.) Metabolik asidoz (pH<7.1) Bazı alkol ve ilaç entoksikasyonları Mantar zehirlenmesi Ne zaman ? ERKEN

RRT ZAMANLAMASI: Neden Erken? > 1950 → ‘Profilaktik Diyaliz’ n/Erken Kriteri Hastane mortalitesi Erken vs geç Referans Posttravmatik ABY 100 / BUN < 60 mg/dl 20. 0 % vs 39.0% Intensive Care Med. 1999 Kardiyak cerrahi sonrası ABY 61/ İdrar çıkışı: <100ml/8 saat 23.5% vs 55.5% J Card Surg. 2004 64/İdrar çıkışı: <100ml/8 saat %22 vs %43 Eur J Cardiothorac Surg. 2004 YBÜ’de AKI 243/ BUN<76mg/dl RR 1.97 95% CI 1.21 to 3.2 Clin J Am Soc Nephrol. 2006 When introduced into clinical practice in the 1940s and early 1950s, RRT was used to principally treat the advanced symptoms of renal failure [2-4]. Although effective at reversing the metabolic complications of renal failure, dialysis did not clearly lower acute mortality [4]. Given the severity of illness and the lack of advanced critical care medicine during this period, patients acutely died of complications such as infection, bleeding, and other conditions. In the 1950s, the concept of prophylactic dialysis was introduced [4]. Studies published during the 1960s and 1970s suggested that improved outcomes were associated with the initiation of hemodialysis when the blood urea nitrogen (BUN) reached approximately 90 to 100 mg/dL, as compared to waiting until the BUN exceeded 150 to 200 mg/dL [5-9]. Although these studies have reported decreased mortality with earlier initiation of renal support, these results are somewhat suspect given many study design limitations. These include non-randomization of groups, probable differences in indications for initiation, and the lack of inclusion in the analysis of patients with AKI who did not receive RRT because they either recovered renal function or died.

Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial Bouman et al.Crit Care Med 2002

RRT ZAMANLAMASI: SONUÇ Aşikar üremik belirti ve bulgular gelişmeden RRT başlanmasını öneriyoruz Belirli bir renal hasar süresi ya da azotemi derecesi vermek olası/uygun değil Başkaca bir spesifik indikasyon yok ise BUN 80-100 mg/dl olduğunda RRT başlanıyor Bu sorunun yanıtı için yeterli güçte RKÇ gerekli Bu konuda kanıta dayalı veri elde edilmesi çok güç Despite this, we suggest the initiation of RRT prior to the development of overt symptoms and signs of renal failure due to AKI, such as advanced uremic symptoms (eg, encephalopathy and serositis). However, it is not possible to specify a specific duration of renal injury or level of azotemia at which RRT should be optimally initiated. In the absence of other specific indications, RRT is often initiated when the BUN reaches 80 to 100 mg/dL, although there is no consensus and practice patterns vary widely. The optimal timing for initiation of RRT in patients with AKI will require an adequately powered prospective randomized trial. Adequate design of such a trial is limited by the current inability to quickly prospectively identify patients with early AKI who will have protracted renal injury and eventually require RRT. For this reason, it is not possible to provide evidence-based criteria for the initiation of RRT in AKI. Similarly, although severity of volume overload at the time of initiation of RRT is associated with increasing mortality risk, current data do not demonstrate that initiating RRT at a specific threshold of fluid overload is associated with improved outcomes.

YBÜ’DE RENAL REPLASMAN TEDAVİSİ PD - Periton Diyalizi IHD- Intermittan Hemodiyaliz CRRT-Sürekli Renal Replasman Tedavisi SLED- Sustained Low Efficiency Dialysis (Sürekli düşük etkinlikli diyaliz) These novel techniques of renal substitution therapy have permitted a conceptual shift from renal ‘‘replacement’’ to renal ‘‘support’’ therapies (4), whereby the strategies to treat AKI have become an integral part of overall critically ill patient management, with ‘‘renal’’ and ‘‘nonrenal’’ applications such as sepsis and acute respiratory distress syndrome (ARDS).

Periton Diyalizi Basit ve ucuz Yeterince hızlı etkili değil Peritonit riski yüksek Pulmoner ve kardiyovasküler performansı mekanik olarak etkileyebilir Peritoneal dialysis has the advantage of being simple and cost effective. The major disadvantages of PD are – poor solute clearance, poor uremic control, risk of peritoneal infection and mechanical obstruction of pulmonary and cardiovascular performance.

Diyaliz/Diffüzyon Küçük moleküllerin temizlenmesi Two fundamental processes underlie continuous renal replacement therapy – diffusion and convection Diffusion / dialysis– the movement of solutes from a compartment in which they are in high concentration to one in which they are in lower concentration – along an electrochemical gradient. An electrolyte solution runs countercurrent to blood flowing on the other side of a semipermeable (small pore) filter. Small molecules such as urea move along the concentration gradient into the dialysate fluid. Larger molecules are poorly removed by this process. Solute removal is directly proportional to the dialysate flow rate. Küçük moleküllerin temizlenmesi

Konveksiyon/Ultrafiltrasyon solute is carried (in solution) a fluid across a semipermeable membrane in response to a transmembrane pressure gradient (a process known as solvent drag). This mimics what actually happens in the normal human kidney. The rate of ultrafiltration depends upon the porosity of the membrane and the hydrostatic pressure of the blood, which depends upon blood flow.  This is very effective in removal of fluid and middle-sized molecules, which are thought to cause uremia. Moreover, most of the cytokines involved in sepsis are “middle molecules”. Membranın gözenekliliği Kanın hidrostatik basıncı Sıvı ve orta boy moleküllerin temizlenmesi

İntermittan Hemodiyaliz En etkin temizleme yöntemi Büyük miktarlarda sıvı hızla uzaklaştırılabilit Elektrolit bozuklukları hızla düzeltilebilir Stabil olmayan hastalar için uygun olmayabilir: %20-30’unda hipotansiyon Disequlibrium sendromu YBÜ hastalarının bu değişimlere toleransı düşük Altta yatan AKI daha da kötüleşebilir Intermittent hemodialysis is the most efficient – large amounts of fluid can be removed and electrolyte abnormalities can be rapidly corrected. However, this is not suitable in unstable patients: 20-30% of patients with ARF who are being hemodialysed become hypotensive, with huge associated osmotic shifts – disequilibrium syndrome. Many ICU patients are intolerant of such shifts. Moreover it appears that the hemodynamic changes that occur during hemodialysis (hypotension) may worsen the pre-existing renal injury by increasing the ischemic insult.

CRRT-Sürekli Renal Replasman Tedavisi Sürekli veno-venöz Hemofiltrasyon (CVVH) Yavaş sürekli UF (SCUF) Sürekli veno- venöz Hemodiyaliz (CVVHD) Sürekli veno- venöz Hemodiyafiltrasyon (CVVHDF)  CRRT represents a family of modalities that provide continuous support for severely ill patients with AKI. These include continuous hemofiltration, hemodialysis, and hemodiafiltration, which involve both convective and diffusive therapies. Although superior clearance of middle and larger molecular weight molecules are associated with convective therapies (hemofiltration) compared with diffusive therapies (hemodialysis), there are no studies clearly showing improved clinical outcomes compared with the type of solute transport.

CVVH Konvektif diyaliz UF↑ Replasman sıvısı Gerekli Orta boy moleküller İyi temizlenir: SİTOKİNLER continuous venovenous hemofiltration, a form of convective dialysis. The ultrafiltration rate is high,  and replacement electrolyte solution is required to maintain hemodynamic stability. This mode is also very effective for clearing mid sized molecules, such as inflammatory cytokines. It is hypothesized that removal of such mediators may play a role in improving outcome in sepsis. A very simple version of this is SCUF (click here) - slow continuous ultrafiltration, which is used for volume control in fluid overloaded patients. SCUF does not require the use of replacement fluid, and fluid removal is 300ml to 500ml per hour

SCUF CVVHF’nun daha da basit hali A very simple version of this is SCUF (click here) - slow continuous ultrafiltration, which is used for volume control in fluid overloaded patients. SCUF does not require the use of replacement fluid, and fluid removal is 300ml to 500ml per hour. CVVHF’nun daha da basit hali Hipervolemik hastalar için volüm kontrolü için kullanılır Replasman sıvısı yok 300-500mL/saat sıvı uzaklaştırılabilir

Daha çok küçük boy moleküller CVVHD Difüzyon/ diyaliz Replasman sıvısı Yok Daha çok küçük boy moleküller temizlenir Örn: üre continuous venous venous hemodialysis– which is continuous diffusive dialysis, the dialysate is driven in a direction countercurrent to the blood. This provides reasonably effective solute clearance, although mostly small molecules are removed.

Konveksiyon + diffüzyon CVVHDF YBÜ’nde en popüler Konveksiyon + diffüzyon Diyalizat + Replasman sıvısı gerekli Küçük ve Orta boy moleküller İyi temizlenir: continuous venous venous hemodiafiltration, which is the most popular method of dialysis in ICU, combines convective and diffusive dialysis. Both small and middle molecules are cleared, and both dialysate and replacement fluids are required. Most of these modes can remove up to 1 litre per hour of fluid. It is rare that this volume of fluid removal is required in intensive care (critically ill patients rarely tolerate any significant fluid removal).

Sürekli Tedavi İntermittan Diyaliz Kan akım hızı: 350-450 ml/dk Diyalizat Akımı 500-800 ml/dk Kan akım hızı: 100-200 ml/dk Diyalizat Akımı 1000-2000 ml/saat Conventional hemodialysis blood flow is 350-450 ml/min and dialysate flow is 500-800 ml/min. In continuous hemodialysis (CVVHD) blood flow is usually set at 100-200 ml/min, and dialysate flows at 1000-2000 ml/hr.

CRRT Avantajları Dezavantajları Hemodinamik stabilitesi olmayan hastalarda uygun Değişen koşullara uyum sağlayabilen volüm kontrolü Üremi, hiperfosfatemi ve hiperkalemi kontrolü Metabolik asidozun hızla düzeltilmesi Daha iyi beslenme desteği 24 saat mümkün, kullanımı komplike değil Beyin hasarı ya da KKY’de daha güvenli Sepsisde adjuvan etki Ülkemizde daha pahalı Antikoagülasyon gereği Kateter takılması ve infeksiyon riski Hattın ayrılması Hipotermi Ciddi hipokalemi ve hipofosfatemi Suitable for use in hemodynamically unstable patients. Precise volume control, which is immediately adaptable to changing circumstances. Very effective control of uremia, hypophosphatemia and hyperkalemia. Rapid control of metabolic acidosis Improved nutritional support (full protein diet). Available 24 hours a day with minimal training. Safer for patients with brain injuries and cardiovascular disorders (particularly diuretic resistant CCF). May have an effect as an adjuvant therapy in sepsis. Probable advantage in terms of renal recovery. Dezavantajları: Expense – probably the same as IHD. Anticoagulation – to prevent extracorporeal circuit from clotting. Complications of line insertion and sepsis. Risk of line disconnection. Hypothermia. Severe depletion of electrolytes – particularly K+ and PO4, where care is not taken.

Aralıklı Hemodiyaliz Avantajları Dezavantajları En etkin temizleme yöntemi Büyük miktarlarda sıvı hızla uzaklaştırılabilir. Elektrolit bozuklukları hızla düzeltilebilir Tanı ve tedavi girişimleri için arada zaman kalır Ciddi hiperkalemi için daha uygun Daha ucuz Teknik personel gerekir Hemodinamik kontrol biraz daha zor olabilir Sıvı kontrolü yeterli olmayabilir Metabolik kontrol yeterli olmayabilir Beslenme desteği yetersiz olabilir KİBAS’da uygun değil Sitokinleri uzaklaştırmaz Biyouyumlu membranlar kullanılmadığında kompleman aktivasyonu Altta yatan AKI daha da kötüleşebilir

MODS olan AKI hastalarında CVVHDF versus IHD : Çok Merkezli Randomize Çalışma In the HemoDiafe Study (a prospective multicenter French study), 360 patients with acute renal failure and multi-organ dysfunction syndrome were randomly assigned to intermittent hemodialysis or continuous venovenous hemodiafiltration [30]. The primary endpoint was survival at 60 days. Severity of illness was similar in both randomized groups, protocol adherence was good, both groups used the same dialysis membranes, and there was a low rate of cross-over from continuous to intermittent therapies (3.3 percent). At 60 days, survival was the same in both groups (32 and 33 percent in the intermittent and continuous groups, respectively). In addition, both therapies were associated with similar rates of hypotension, including the group of hemodynamically unstable patients. Hemodiafe Study Group Lancet 2006; 368: 379–85

ABY hastalarında sağkalım açısından 15 RCT , 1550 Hasta ABY hastalarında sağkalım açısından Renal fonksiyonun geri kazanılma beklentisi açısından , CRRT’nin üstünlüğü yok CRRT’de MAP anlamlı daha ↑ We identified 15 RCTs with 1550 patients comparing CRRT with IRRT. The key findings from our systematic review are: • CRRT offers no survival advantage over IRRT in patients with ARF • Patients surviving ARF who are managed with CRRT have a similar expectation of recovery of renal function as those treated with IRRT • CRRT is associated with a significantly higher MAP • CRRT is associated with a significantly increased risk of recurrent filter clotting compared to IRRT In patients who are haemodynamically stable, the RRT modality does not appear to influence important patient outcomes, and therefore the preference for CRRT over IRRT in such patients does not appear justified in the light of available evidence. CRRT was shown to achieve better haemodynamic parameters such as MAP. Future research should focus on factors such as the dose of dialysis and evaluation of newer promising hybrid technologies such as SLED. Triallists should follow the recommendations regarding clinical endpoints assessment in RCTs in ARF made by the Working Group of the Acute Dialysis Quality Initiative Working Group. Hemodinamik olarak stabil hastalarda seçilen RRT tipi hasta sağkalımını etkilemiyor The Cochrane Library, 2008, Issue 3

SLED- Sustained Low Efficiency Dialysis (Sürekli düşük etkinlikli diyaliz) CRRT ile aynı tedavi amaçlarına sahip IHD gibi aralıklı tedavi olanağı sağlıyor Yavaş diyalizle başlanır: Qb=150ml/dk Qd=100-300 ml/dk UF hızı= max:350 ml/saat In conclusion, the question of superiority of a modality for renal support may be artificial. In routine clinical practice, as designed by the Vinsonneau protocol, a change from one approach to another seems reasonable when clinical status changes (e.g., from CRRT to IHD when hemodynamics improve or patient is extubated and vice versa), even if this common sense approach has never been scientifically validated. Randomizing patients to receive one therapy or the other regardless of the conditions may yield results that are difficult to generalize to clinical practice. About 10 yrs ago, a similar passionate debate on ventilation weaning strategies (pressure support ventilation vs. T-piece spontaneous ventilation vs. continuous pressure airway pressure vs. synchronized intermittent mandatory ventilation) was ongoing.

Intensive Care Med 33:1563–1570, 2007

Ciddi metabolik asidoz Amaç Hemodinami Tercih edilen RRT Sıvı Çekilmesi Stabil Stabil değil Aralıklı izole UF Yavaş sürekli UF Üre klirensi IHD CRRT Ciddi hiperkalemi Stabil / stabil değil Ciddi metabolik asidoz Ciddi Hiperfosfatemi Stabil/stabil değil

AKI (+) YBÜ Hastası – en az 1 böbrek dışı organ tutulumu veya sepsis Primer sonlanım noktası – 60 günde tüm nedenli ölüm We randomly assigned critically ill patients with acute kidney injury and failure of at least one nonrenal organ or sepsis to receive intensive or less intensive renal-replacement therapy. The primary end point was death from any cause by day 60. In both study groups, hemodynamically stable patients underwent intermittent hemodialysis, and hemodynamically unstable patients underwent continuous venovenous hemodiafiltration or sustained low-efficiency dialysis. Patients receiving the intensive treatment strategy underwent intermittent hemodialysis and sustained low-efficiency dialysis six times per week and continuous venovenous hemodiafiltration at 35 ml per kilogram of body weight per hour; for patients receiving the less-intensive treatment strategy, the corresponding treatments were provided thrice weekly and at 20 ml per kilogram per hour. Results Baseline characteristics of the 1124 patients in the two groups were similar. The rate of death from any cause by day 60 was 53.6% with intensive therapy and 51.5% with less-intensive therapy (odds ratio, 1.09; 95% confidence interval, 0.86 to 1.40; P = 0.47). There was no significant difference between the two groups in the duration of renal replacement therapy or the rate of recovery of kidney function or nonrenal organ failure. Hypotension during intermittent dialysis occurred in more patients randomly assigned to receive intensive therapy, although the frequency of hemodialysis sessions complicated by hypotension was similar in the two groups. Conclusions Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.) Yoğun RRT Az Yoğun RRT Hemodinamik stabil→ IHD Hemodinamik stabil olmayan → CVVHD/SLED

NEJM 2008 :359; 7-20

Ağır Septik Şoktaki Hastalar Aşırı sistemik pro-inflamatuvar ve anti-inflamatuvar medyatör salınımı Yaygın endotelyal hasar Multi organ disfonksiyonu (MOD) ve bozulmuş hücresel immunolojik yanıt For patients with severe sepsis or septic shock, there is an overwhelming systemic overflow of pro-inflammatory and anti-inflammatory mediators, leading to generalised endothelial damage, multiple organ dysfunction and altered cellular immunological responsiveness. The removal of sepsis pro-inflammatory and antiinflammatory mediators may help in the treatment of severe sepsis. Cytokines levels in sepsis were found to be lowered only with HVHF (~45ml/kg/h) but not conventional continuous veno-venous haemofiltration (CVVH) (17ml/kg/h).14 Early animal studies and small scale human trials provided good data on improving the haemodynamic status and survival with HVHF. In the Ronco study published in the Lancet in 2000, although there was no overall survival difference between the two groups with 35 and 45 ml/kg/h doses, a significant survival difference was detected between these groups in a subgroup analysis for patients with sepsis.11 pro-inflamatuvar ve anti-inflamatuvar medyatörlerin uzaklaştırılması yararlı olabilir mi?

IVOIRE : hIgh VOlume in Intensive caRE High Volume: Experimental ultra filtration : High volume : 70 ml/kg/h Conventional volume : Ultra filtration : 35 ml/kg/h A large randomised trial is going on to confirm this unsettled dosing issue in RRT for patients with sepsis. The IVOIRE study (hIgh VOlume in Intensive care)15 in Europe will study the use of standard volume (35 mL/kg/h) against HVHF (70 mL/kg/h) in ARF patients with septic shock. It aims to enroll 460 patients to detect a 15% absolute risk reduction in 30-day mortality

Sepsisde Kan Arıtma Tedavileri Yüksek volümlü hemofiltrasyon Hemoadsoprsiyon Eşleştirilmiş plazma filtrasyon adsorpsiyonu Yüksek eşikli membran kullanımı Sepsis is one of the main causes of death in critically ill patients. The pathophysiology of sepsis is complex and not completely understood. The proinflammatory and anti-inflammatory response leads to cell and organ dysfunction and, in many cases, death. Thus, the goal of the intervention is to restore the homeostasis of circulating mediators rather than to inhibit selectively the proinflammatory or anti-inflammatory mediators. Blood purification has been reported to remove a wide array of inflammatory mediators. The effects are broad-spectrum and auto-regulating. Blood purification has also been demonstrated to restore immune function through improving antigen-presenting capability, adjusting leukocyte recruitment, oxidative burst and phagocytosis, and improving leukocyte responsiveness. A great deal of work has to be done in order to find and optimize the best extracorporeal blood purification therapy for sepsis. New devices specifically target the pathophysiological mechanisms involved in these conditions. High-volume hemofiltration, hemoadsorption, coupled plasma filtration adsorption, and high cutoff membrane are now being tested in septic patients. Preliminary data indicate the feasibility of these modified techniques in sepsis. Their impact on patient prognosis, however, still needs proof by large randomized clinical trials. Finally, the emerging paradigm of sepsis-induced immune suppression provides additional rationale for the development of extracorporeal blood purification therapy for sepsis. RKÇ gereksinimi var

SONUÇ YBÜ’deki hastalarda RRT tedavisine çok geç kalmadan başlanmalı : geçten ise erken! RRT yöntemleri arasında fark yok Daha yoğun veya daha az arasında fark yok IHD: haftada 3 gün ve tedavi başına %60 klirens ya da Kt/V >1.2 CRRT: Effluent akım hızının en az 25mL/kg/saat olması We recommend that intermittent hemodialysis be provided on a three-times per week schedule (alternate days) with monitoring of the delivered dose of dialysis to ensure delivery of a Kt/V of at least 1.2 per treatment (Grade 1B). We recommend that CRRT be provided with a delivered effluent flow rate (sum of hemofiltration rate and dialysate flow rate) of at least 20 mL/kg per hour (Grade 1B). In order to ensure delivery of this flow rate, we prescribe an effluent flow rate of at least 25 mL/kg per hour.

Biyouyumlu membranlar tercih edilmeli ama kanıta dayalı değil Sepsisde sitokin uzaklaştırma yöntemleri ile ilgili çalışma gereksinimi var. We recommend that intermittent hemodialysis be provided on a three-times per week schedule (alternate days) with monitoring of the delivered dose of dialysis to ensure delivery of a Kt/V of at least 1.2 per treatment (Grade 1B). We recommend that CRRT be provided with a delivered effluent flow rate (sum of hemofiltration rate and dialysate flow rate) of at least 20 mL/kg per hour (Grade 1B). In order to ensure delivery of this flow rate, we prescribe an effluent flow rate of at least 25 mL/kg per hour.

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