Advanced organ support (ADVOS) in the critically ill: first clinical experience in patients with multiple organ failure

Frequency of multiple organ failure (MOF) is significantly increasing in critically ill patients within the last decades with a prevalence of more than 30% [1]. Despite significant progress in management, mortality in patients with advanced stages of MOF is still excessively high. Recent publications indicate that more than 60% of these patients did not survive their stay at the ICU [1, 2]. Liver failure is present in 20% of the ICU patients [1]. Acute kidney injury (AKI) occurs in > 50% of critically ill patients [3] and is more common in association with various forms of liver disease [4‐6]. AKI contributes significantly to increased morbidity and mortality in these patients [5, 7, 8]. Respiratory failure is present in up to 30 percent of patients with acute liver failure during their stay at the ICU [9, 10].

In recent years, extracorporeal support has become common place in the management of patients with liver failure [11]. These treatments are usually indicated as a bridge to recovery or transplantation in critically ill patients with various kinds of organ failure. Although conventional renal replacement modalities are commonly used during daily clinical practice in patients with liver failure, most published data are available for advanced dialysis devices like liver support systems [12‐14]. However, recommendations from professional societies note that using extracorporeal therapies in patients with liver failure is controversial and clinical practice is variable [15‐17].

As suggested by Bellomo and Ronco already in the 1990s, a device combining different forms of organ support might be feasible to improve patient outcome in patients with MOF [18]. This concept was further described by Ranieri et al. defining the term extracorporeal organ support (ECOS) to represent all forms of devices, encompassing kidney, respiratory, cardiac and liver support [19].

ADVanced Organ Support (ADVOS, ADVITOS GmbH, Munich, Germany) is a new albumin dialysis procedure (CE-Marking obtained on 2013) that can eliminate water-soluble and albumin-bound substances. Furthermore, it can correct acid–base abnormalities by an adjustable dialysate composition on an individual basis. ADVOS uses a novel system for dialysate recirculation where physicochemical changes (i.e., pH and temperature) are implemented. Apart from properties of a conventional dialysis device, this allows for (i) recycling albumin following a modification of the pH in the albumin circuit of the device resulting in a conformational change of albumin that contributes to toxin release and liberation of binding sites [20]; (ii) customization of dialysate acid–base composition (including pH) as the dialysate is formed via the on-line mixing of an acidic and an alkaline concentrate, which can be automatically formulated to the patients’ needs in order to control acid–base balance. Preclinical studies demonstrated high detoxification rates for protein-bound and water-soluble toxins. Removal of relevant amounts of CO₂ at blood flow rates typical for renal replacement therapies was shown in vitro [21‐23]. A clinical case series using a prototype of the system demonstrated the ability to remove water-soluble and albumin-bound substances [24]. Here, we report our first clinical experience with ADVOS in the management of critically ill patients with severe MOF.

This analysis included data from 34 patients with MOF receiving 102 treatment sessions with the ADVOS device. All patients were treated as clinically indicated at the Department of Intensive Care Medicine of the University Medical Center Hamburg-Eppendorf on-label of the intended use of the device, as indicated in the instructions for use of the manufacturer. Patients were treated between December 2014 and August 2016. Data were automatically prospectively documented in the electronic patient data management system (ICM, Dräger, Lübeck, Germany) and thereafter extracted retrospectively for statistical analysis. Patients were followed up for 90 days after ICU admission, until ICU discharge or until death, whichever occurs first. The study was approved by the local ethics committee (WF 046/15).

On admission, Simplified Acute Physiology Score II (SAPS II) [25], Sequential Organ Failure Assessment (SOFA) Score [26], infections, organ failure and need for vasopressor support, mechanical ventilation or renal replacement therapy (RRT), were documented. Daily data from routine laboratory conducted analysis were documented.

Diagnostic criteria for AKI, hypoxic liver injury (HLI), cardiogenic shock and septic shock have been previously described [4]. In detail, criteria for AKI were calculated according to the KDIGO clinical practice guideline for AKI based on serum creatinine and urinary output [27]. All patients had AKI stage 3 prior to initiation of ADVOS and suffered from different forms of liver failure (acute-on-chronic liver failure, primary and secondary acute liver failure) [27]. Acute-on-chronic liver failure (ACLF) is defined by presence of acute hepatic decompensation in combination with hepatic or extrahepatic organ failure (as defined by the CLIF-consortium and the CLIF-SOFA-score) [7]. Acute liver failure (ALF) is defined according to the recent definition of EASL practical clinical guidelines by INR > 1.5 and presence of hepatic encephalopathy [28]. Hypoxic liver injury (HLI) was defined according to well-established criteria: (a) setting of cardiac, circulatory or respiratory failure; (b) dramatic but transient elevation of aminotransferase levels to at least 20-fold the upper limit of normal; (c) exclusion of other putative causes of liver cell necrosis (viral or drug induced hepatitis) [7, 29, 30]. ARDS was defined according to the Berlin definition [31]. ADVOS was started in patients with severe metabolic derangement, anuria irresponsive to fluids, hyperkalemia and/or uremic complications, as previously published [4, 32, 33].

Severe metabolic acidemia was defined as pH less than 7.2, partial pressure of carbon dioxide (PaCO₂) ≤ 45 mmHg and sodium bicarbonate < 22 mmol/l according to previous publications [34, 35]. 28-day mortality, 90-day mortality and ICU mortality were assessed on site or by contacting the patient, respectively.

The present study reports the feasibility and safety of ADVOS to eliminate water-soluble and protein-bound substances and to significantly support the correction of severe acid–base abnormalities in critically ill patients suffering from MOF.

The principle of the ADVOS therapy is based on a recirculating customizable albumin dialysate. The recycling of the dialysate by physicochemical methods has several consequences. First, since no further albumin addition is needed, treatments can be performed up to 24 h with 200 ml of 20% albumin and low blood flow rates (in our study: 100 ml/min, IQR: 100-150 ml/min), which might facilitate a detoxification of all compartments and an adequate ultrafiltration [41‐43]. Second, the modification of pH within the ADVOS multi circuit (Fig. 1) contributes to the release of protein-bound toxins from albumin and its corresponding convective filtration in addition to filtration of water-soluble substances. Furthermore, the possibility to set a customized dialysate pH and with it, modify the acid–base composition of the dialysate permits acid–base control depending on the needs of the patient.

We observed an improvement of hemodynamic parameters like vasopressor dosage and degree of respiratory support like driving pressure during ADVOS therapy. Vasopressors were needed in 74% of the patients before ADVOS treatment. We want to emphasize that these findings are associations which still lack proof of causality. Future studies should clarify whether the reduction of norepinephrine during ADVOS (Table 4 and Additional file 1: Table S3) might be the consequence of improvement and normalization of severe acidemia and if elimination of vasodilatory substances might play an additional role as demonstrated in previous studies [44, 45]. Furthermore, ADVOS significantly reduced water-soluble substances like creatinine, BUN and ammonia. The degree of elimination of these substances was concentration dependent. A reduction of creatinine and BUN could be expected as with other dialysis procedures. Future studies should assess the impact of ADVOS on clinical improvement of hepatic encephalopathy, as shown by other albumin dialysis devices such as MARS [46].

In patients treated with ADVOS, a significant reduction of serum bilirubin was observed (Tables 2, 4). Bilirubin is not only a marker of liver disease. New onset of jaundice is well known to contribute to new onset of acute kidney injury and increased rates of infection as demonstrated in a prospective clinical study [47]. An increase of bilirubin 5 times above the upper limit of normal was identified as an independent risk factor for the development of cholemic nephropathy in clinical and autopsy studies [48‐50]. In this study, 53% of the patients ended with bilirubin levels < 6 mg/dl. The degree of bilirubin detoxification by ADVOS is quite comparable to other available albumin dialysis [12, 13, 24].

Interestingly, due to the acid–base composition change achieved when a high dialysate pH was set in treatment of acidosis, the ADVOS procedure supported normalization of systemic blood pH with low blood flow rates (100–200 ml/min) within 6 h, even in cases that were refractory to conventional renal replacement therapies [51]. Furthermore, a correlation between dialysate pH set and pCO₂ reduction of up to 40 mmHg (− 23 mmHg, IQR: − 37, − 7) between the inlet and the outlet of the dialyzer could be observed. In blood, CO₂ is mainly converted to HCO₃⁻ and H⁺. A high dialysate pH allows a concentration gradient for H⁺ between blood and dialysate. Moreover, the dialysate contains bicarbonate levels around 20–24 mmol/l, which allows a further gradient for HCO₃⁻. Consequently, a reduction in pCO₂ through the removal of HCO₃⁻ and the compensation of acidosis can be achieved with ADVOS. This can further be explained in terms of a quantitative Stewart approach, based on strong ion difference changes. This is only possible due to an increased buffering capacity of the dialysate thanks to albumin, as this can protonate its imidazole side chain [52, 53], allowing an adequate dialysate acid–base composition adjustment at each set dialysate pH. This pCO₂ reduction together with the regulation of metabolic acid–base balance was responsible for an improvement of acidosis, as already shown in vitro. We observed a significant reduction of driving pressure during ADVOS treatment in patients with ARDS. We want to emphasize once again that these findings are only associations which still lack proof of causality. Future studies should assess the clinical impact of this alteration in a larger cohort of patients and aim at the proof of causality [54].

A lower mortality rate than expected could be observed in our cohort of patients with advanced stages of MOF treated with ADVOS. Recently, mortality rates > 80% were reported in critically ill patients with SOFA-scores ≥ 17 [55]. In contrast, 28- and 90-day mortality rates in our cohort (with a median SOFA score of 17) were 50% and 62%, respectively. However, this difference can be at least in part be explained by the fact that not all patients in our cohort suffered from sepsis. Moreover, treatment with ADVOS was safe. The number of adverse events were comparable to other studies assessing conventional renal replacement systems in critically ill patients as illustrated in Additional file 1: Table S7 [33, 56].

There are several limitations of our study. First, this is a single-center study with a rather small number of patients. However, it is the first study investigating the ADVOS device in patients with severe MOF. Second, we report data of a non-homogeneous population with AKI and ALF or ACLF with high SOFA score. Therefore, results of this study might not be applicable to other group of patients with single-organ disorders or better prognosis. In this regard, small pilot studies in specific populations that could benefit from this therapy followed by a larger randomized controlled trial are needed for a more detailed assessment of ADVOS.

Our results demonstrate that the ADVOS device can eliminate water-soluble and protein-bound substances significantly by a new physicochemical method. Furthermore, the device interacts significantly in severe acid–base abnormalities. Future studies should assess its impact in patients with multiple organ failure where a combination of kidney failure and/or liver failure and/or lung failure is present.