40 Years of Continuous Renal Replacement Therapy

R. Bellomo, J. A. Kellum, G. La Manna, C. Ronco

• Publisher: S. Karger
• Year: 2018
• ISBN:
  9783318063073
• Topic: Medicina
• Subtopic: Nefrologia

Continuous renal replacement therapies (CRRT) started off as an alternative to hemo- or peritoneal dialysis. Today's machines and techniques are the result of 4 decades of developments, studies, and practices which can be divided into 4 distinct stages: exploration and development; birth of a new specialty called critical care nephrology; design of specific new devices and machines; and interaction among various specialists to adapt extracorporeal therapies for multiple organ support and sepsis. This book features contributions from prominent CRRT experts from around the world. It is an important tool for educating a new generation of nephrologists and intensivists. At the same time, it provides the most advanced CRRT users with the latest technological information, the most updated clinical evidence, and the personal opinion of key leaders who contributed to the last 40 years of history in the field.

Bellomo R, Kellum JA, La Manna G, Ronco C (eds): 40 Years of Continuous Renal Replacement Therapy.
Contrib Nephrol. Basel, Karger, 2018, vol 194, pp 155–169 (DOI: 10.1159/000485634)

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From Continuous Renal Replacement Therapies to Multiple Organ Support Therapy

Zaccaria Ricci^a · Stefano Romagnoli^{b, c} · Claudio Ronco^{d, e} · Gaetano La Manna^f

^aDepartment of Cardiology and Cardiac Surgery, Pediatric Cardiac Intensive Care Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, ^bDepartment of Health Science, Section of Anesthesiology and Intensive Care, University of Florence, and ^cDepartment of Anesthesia and Intensive Care, Azienda Ospedaliero-Universitaria Careggi, Florence, ^dDepartment of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, and ^eInternational Renal Research Institute, San Bortolo Hospital, Vicenza, and ^fDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES) – Nephrology, Dialysis and Transplantation Unit, St. Orsola Hospital, University of Bologna, Bologna, Italy

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Abstract

The incidence of the multiple organ dysfunction syndrome (MODS) is rapidly increasing in intensive care units (ICU). It usually combines with sepsis and is the most frequent cause of death in the ICU patients. The nature of the ICU patients has changed in the last years. It includes a variety of patients with severe cases due to major surgical interventions, trauma, hemodynamic instability, sepsis, and so on but also older people than previous times. All these situations can easily lead to MODS. In the prior years, the only available and efficient therapy was renal replacement therapy (RRT) for treating acute renal failure, but the development of technology also gives us devices to support the other systems. The adequacy of any artificial organ support is evaluated by how closely it mimics the flexibility and efficacy of the organ systems it seeks to substitute or support. In a sequence of events, such as that created by sepsis and MODS, all these criteria should be applied at the same time but for different organs and different tasks. RRT and especially continuous renal replacement therapies (CRRT) allowed extracorporeal treatment in critically ill patients with hyper catabolism and fluid overload with excellent hemodynamic stability. New techniques in CRRT as high volume hemofiltration have been applied in septic patients with very promising results. In the light of these observations, a new thought arises: Can extracorporeal blood purification have a positive impact on different organ systems? A possible answer might come from the simple observation that all organs share one aspect in common: contact with blood. All extracorporeal therapies also have one aspect in common: treatment of blood. Based on these observations and knowledge of the molecular biology of sepsis, a “humoral” theory of MODS makes pathophysiological sense and its consequence triggers the need to consider extracorporeal therapies as multiple organ support therapies and not just as single organ support.

© 2018 S. Karger AG, Basel

Introduction

Continuous renal replacement therapies (CRRT) have been developed 40 years ago and continued to evolve with progressive improvement of devices and techniques. The case mix however has changed significantly. Severity of illness at intensive care unit (ICU) admission has dramatically increased and acute kidney injury (AKI) is often complicated by multiple organ failure (MOF) with the simultaneous dysfunction of 2 or more organs. This has profoundly modified the approach of extracorporeal therapies and the design of blood purification techniques. Today, extracorporeal treatments aim at supporting different organs (kidneys, liver, lungs, heart, and septic blood) in critically ill patients in the ICU. Together with the evolution of continuous dialysis treatments, in recent years, a multiple organ support therapy (MOST) has been conceived, although it has often been delivered by adoptive equipment rather than a unified platform. Often, new therapies were added to the existing circuit as a “Christmas tree like system” (i.e., CRRT on extracorporeal membrane oxygenation or molecular adsorbent recycling system [MARS] on CRRT, etc.). New developments and the future of MOST foresee the application of specifically dedicated integrated multipurpose advanced platforms for the support of MOF patients. A comprehensive extracorporeal blood purification treatment will therefore be made possible by such new platforms in case of multiple organ dysfunctions beyond renal failure.

Extracorporeal Blood Purification in Sepsis

Although mortality related to sepsis has significantly decreased throughout the last decade, it still represents a major challenge for healthcare systems from a clinical and economical point of view [1, 2]. The broad heterogeneity of clinical presentations and the complex interplay of host proinflammatory and anti-inflammatory processes are among the principal obstacles for further reduction in sepsis-related morbidity and mortality. Since the imbalance between hyper-inflammation and immunosuppression is supposed to be a key factor in determining outcomes, during the last years, most research on sepsis was focused in reestablishing equilibrium in the cytokine (CK)-mediated inflammation by clearing them from the blood with CRRT-based techniques [3].

High Volume Hemofiltration

It has been speculated that CRRT “pushed” to a dose higher than usual (>45 mL/kg/h; high volume hemofiltration [HVHF]) may play a role in blood purification by clearing the bloodstream from CKs in septic patients. Animal models of severe sepsis demonstrated a beneficial effect of HVHF on hemodynamics, proportional to the intensity of ultrafiltration [4] and based on this hypothesis, different protocols have been developed and tested [5]. A Cochrane analysis published in 2013, including randomized controlled trials and quasi-randomized trials, which compared HVHF to standard dialysis in adult ICU patients, concluded that the evidence was still insufficient to recommend it in septic critically ill patients [6]. A systematic review and meta-analysis of studies performed between 1966 and 2013 was recently published [7]. The analysis included four randomized controlled trials (470 participants) that compared HVHF (effluent rate >50 mL/kg/h) and standard hemofiltration (HF) in patients with sepsis and septic shock. Pooled analysis for 28-day mortality did not show any difference between HVHF and HF, kidney recovery, improvement in hemodynamics, or reduction in ICU or hospital length-of-stay. In addition, significant side effects, including hypophosphatemia and hypokalemia, were more common in the HVHF-group. Based on current literature, HVHF cannot be recommended for routine use in sepsis and septic AKI. Moreover, side effects should be carefully monitored when more intense doses in CRRT are applied to septic and nonseptic patients.

Polymixin B Hemoperfusion

High levels of endotoxin activity, a basic component on the outer membrane of gram-negative bacteria, have been associated with worse clinical outcomes [8]. Polymixin B hemoperfusion (PMX-HP) is a technique based on the high affinity of endotoxin for Polymixin B that, during an extracorporeal HP treatment, remains bound to filter. In 2009, a multicenter randomized control study [9] showed, in 64 patients with severe sepsis or septic shock, that PMX-HP added to conventional therapy significantly improved hemodynamics and organ dysfunction and reduced 28-day mortality. More recently, in a larger multicenter randomized control study including 232 patients with septic shock (119 vs 113 controls), PMX-HP did not confirm the previous findings [10]: no difference in 28-day mortality was found in the study group vs. controls. On the other hand, a recent retrospective analysis from an ongoing study (EUPHAS2; PMX-HP in abdominal vs. non-abdominal sepsis) showed that the SOFA score significantly decreased 72-h after PMX-HP (p < 0.001), the 28-day mortality was 35 vs. 49% in non-abdominal septic patients, and in-hospital mortality was 44% in abdominal sepsis vs. 55% in the others [11]. Based on the current evidence, PMX-HP efficacy is currently being questioned and new data are absolutely necessary to clarify its role in abdominal and nonabdominal septic patients.

High Cutoff Membranes

Due to the role of the humoral mediators of the immune system in the pathogenesis of sepsis, many attempts have been made to remove the CKs from the bloodstream [12]. High cutoff (HCO) membranes have pore diameters (>0.01 μm) that allow molecules up to 60 kDa to pass [13]. A review, including 23 publications on HCO-HF, showed that a reduction in inflammatory and anti-inflammatory CKs (interleukins [IL]-4, IL-6, IL-1ra, IL-8, IL-10, IL-12, tumor necrosis factor-α) was common in all the studies [13]. Moreover, CKs removal was associated with significant improvement in hemodynamics, oxygenation, and organ dysfunction [13]. A 16-ICU multicenter observational study, designed to evaluate changes in inflammatory biomarkers and tissue oxygenation/perfusion indexes in septic ICU patients with AKI during HCO-continuous veno-venous hemodialysis, has been recently concluded and preliminary results released [14]. A significant improvement in organ function has been demonstrated, but mortality reduction was not obtained. Before drawing definitive conclusions on HCO-HF in sepsis, some considerations are mandatory: first, current literature is biased due to the lack of a standardized definition and classification of HCO dialysis membranes leading to comparison among different studies [13, 15]; second, heterogeneity of clinical picture of septic patients may require a strict patient selection; third, it has still not been established as to which mediators should be removed and which should not during different phases of sepsis [16] and finally, technology that i...