Blood purification with a cytokine adsorber for the elimination of myoglobin in critically ill patients with severe rhabdomyolysis

Rhabdomyolysis describes the disintegration of skeletal muscles, leading to the release of muscle components into the blood [1]. The most common cause is traumatic damage of the muscles, for example in patients after multiple traumas [2]. However, the clinical picture can also occur as part of severe sepsis and due to drug side effects [3]. Ultimately, many intensive care unit (ICU) patients are affected. In addition to electrolyte disorders caused by cell decay, there is also an accumulation of creatine kinase (CK) and myoglobin in the blood [4]. Even though there are no uniform diagnostic criteria, rhabdomyolysis is typically referred to when the CK is > 5 times the upper normal [5].

After muscle damage, CK reaches its maximum value in the blood after about 24 h and is then inactivated by oxidation in the blood independently of liver and kidney function [6]. Persistent muscle damage can further increase serum CK levels. Myoglobin reaches its maximum value in the blood within about 12 h after muscle damage and is rapidly eliminated by the kidneys. The half-life is about 3 h, if kidney function is unrestricted and muscle damage is not persistent [7]. However, an accumulation of large amounts of myoglobin might have nephrotoxic effects although a clear mechanism about the renal toxicity is still not clear. Thus, renal vasoconstriction, the formation of intratubular casts and direct toxic effect of myoglobin on the tubule cells might lead to acute kidney injury (AKI) and the clinical picture of the “crush kidney” [8].

A frequently used conservative treatment option in preventing AKI is the alkalization of the urine, but no randomized controlled study showed its benefits so far. However, renal replacement therapy (RRT) is necessary in many ICU patients due to ongoing AKI [9]. Although the amount of CK defines rhabdomyolysis, its elimination is of secondary importance due to the absence of toxicity [10]. In contrast, myoglobin can cause persistent and potentially permanent damage of the tubular epithelial cells in the kidney and its elimination from the blood might be an approach to avoid AKI [8]. The problem is that myoglobin, with a molecular weight of approximately 17 kDa, is only poorly removed by many standard dialysis membrane used in critically ill patients with the need of RRT [8, 11]. The surface area of the dialyzers is often between 1 and 2 m² and the sieving coefficient for myoglobin mostly between 0.2 and 0.4.

One solution for a better myoglobin removal is the use of high cut-off (HCO) dialyzers. Heyne et al. [12] described this approach in a case series with an effective removal of myoglobin. Furthermore, Weidhase et al. [13] recently published the results of a randomized trial, where a higher myoglobin clearance can be seen in patients treated with HCO dialyzers in contrast to the typically used high-flux dialyzers. Both had the same surface area of 1.8 m² and myoglobin clearance was about 8–10 ml/min for HCO dialyzers and 2–3 ml/min for high-flux dialyzers. Another method is plasmapheresis, where a successful myoglobin elimination had also been described [14]. A new approach is the use of the cytokine adsorbed Cytosorb® (CS) (CytoSorbents Europe, Berlin, Germany), which is primarily intended for the elimination of cytokines in hyperinflammatory conditions [15]. It has a surface area of about 45.000 m² and hydrophobic molecules up to a size of approximately 55 kDa can be eliminated. The product has a CE mark for the elimination of myoglobin since 2019. Based on its molecular weight of 80 kDa, an elimination of CK cannot be assumed.

Although in vitro data showed the elimination of myoglobin by CS [16], there is a lack of clinical studies in the literature, except of two case reports. [17, 18]. Due to the lack of data describing the effects of CS in patients with rhabdomyolysis, a retrospective data analysis was investigated in critically ill patients with severe rhabdomyolysis and CS therapy. Within the scope of clinical practice, CS was used at two anesthesiological ICUs at the LMU hospital in Munich in patients with severe rhabdomyolysis and the need of RRT. To evaluate the clinical experience in a structured way and to gain first results on the in-vivo efficacy of CS in critically ill patients with rhabdomyolysis, a retrospective data analysis was performed.

To the best of the authors' knowledge, this is the first analysis of the effectiveness of the cytokine adsorber Cytosorb® integrated into a continuous high-flux dialysis system for myoglobin elimination in critically ill patients with severe rhabdomyolysis, apart from case reports. With 43 patients, the study represents the largest population in which blood purification was used for myoglobin elimination. A SAPS II of 80 points was indicative for the severity of disease of the study population. A median myoglobin level of > 25,000 ng/ml before the start of CS therapy underlines the massive rhabdomyolysis. Although all conservative therapeutic options should be exhausted to avoid a crush kidney [9, 19], acute renal failure can usually not be avoided, especially at such high myoglobin concentrations.

Since extracorporeal myoglobin elimination is only insufficiently possible with high-flux dialysis (small surface area and low sieving coefficient), several special elimination procedures are available. As all patients had an anuric renal failure, the authors do not assume a relevant endogenous myoglobin elimination in the study population. The median myoglobin clearance of a similar high-flux filter was recently described by Weidhase et al. [13] with approximately 2–3 ml/min. However, a new alternative for myoglobin elimination might be CS, whose integration into an, for example, existing high-flux dialysis system is quick and easy. Even though there is regular approval for the usage of CS in patients with rhabdomyolysis in the European Union, there is a general lack of clinical studies [16]. It is important to know which molecules can theoretically be eliminated by CS based on their molecular size. The cutoff value of CS based on manufacturer’s specifications is about 55 kDa. Therefore, the elimination of myoglobin with a molecular size of 17 kDa is possible [20], whereas CK with a size of about 80 kDa cannot be eliminated [21]. With this assumption, the elimination of CK by CS described by Dilken et al. [18] must be critically questioned and is most likely based on the endogenous decay and not on removal by CS. This was also clearly stated by Daum et al. [22], who referred directly to the case report presented by Dilken et al.

A median relative reduction rate of 29% is a great success, especially with persistent rhabdomyolysis. Ongoing rhabdomyolysis might be the reason, why the effect of CS is often difficult to detect in laboratory measurements. However, correlation analysis revealed that there was a significant correlation between the CK and myoglobin values, and regression analysis showed that the change in CK during CS was the only factor that influenced myoglobin levels. Therefore, the two variables seem comparable, even though the flooding time and half-life of the substances are different [23].

Due to organ-independent degradation, there should be a relevant reduction of CK during CS application, assuming an expired rhabdomyolysis. In contrast, if the CK continues to increase, there might be an ongoing rhabdomyolysis. Therefore, two groups were formed based on this assumption. In conclusion, a significant reduction of myoglobin (median relative reduction: 38%) was detected in patients with decreasing CK (group 1). Since all patients had an anuric renal failure, renal elimination of myoglobin cannot be assumed and, in the authors' view, the reduction of myoglobin was largely due to the use of CS and not due to the high-flux dialyzer. The elimination rate was comparable to a study in pigs, where a myoglobin elimination of 41% by CS was described [24]. However, it should be noted that degradation pathways with spleen and liver have been rarely described [25].

Although no significant change in myoglobin was observed in patients with increasing CK (group 2), the elimination was evident from the substantial increase of CK during CS application (median relative increase of 78%), while there was a median decrease of 4% for myoglobin. Without CS therapy, a rapid increase in myoglobin, equivalent to the previously unidirectional change in CK and myoglobin, would be expected in those patients as well. Although the absence of an increase did not prove that CS therapy was successful, this must be supposed from the authors’ perspective.

As one-third of our patients needed support with ECMO-therapy, which potentially influences the performance of CS, a subgroup analysis was performed. Neither a more pronounced hemolysis, nor higher myoglobin levels before treatment or a significant difference in the relative myoglobin reduction can be seen. Although our population is not generally applicable to all other ICU patients, we conclude that ECMO therapy might not have relevant impact on CS elimination performance.

No clinical studies that examine the evidence of CS in the context of rhabdomyolysis are available. It further remains unclear whether and how much myoglobin elimination leads to less kidney damage and faster completion of dialysis. In this context, our study can provide the foundation for future prospective projects. Overall, other blood purification systems can also be used for the elimination of myoglobin [12, 26‐29]. The advantages of CS compared to, for example, plasmaphereses are that albumin, with a molecular size of 66–67 kDa, is not absorbed and that it can be easily and temporarily integrated into an existing dialysis system. Ultimately, all procedures lack both individual studies and comparative studies questioning the clinical relevance of myoglobin elimination. Therefore, a final evaluation according to the best procedure is not possible.

In summary, myoglobin removal with the cytokine adsorber CS integrated into a high-flux dialyzer can be recommended for clinical routine due to its existing CE mark, ease of use and absence of side effects. Even though an advantage in patient outcome has not yet been confirmed, extracorporeal elimination seems to be useful especially in cases of high myoglobin levels and existing AKI. Therefore, potentially permanent damage of the renal tubules cells caused by the accumulation of myoglobin could be prevented [30]. Nevertheless, prospective studies are lacking in which the myoglobin clearance of CS can be accurately determined by a dense blood collection scheme and, for example, simultaneous measurements at the adorber’s in—and outlet, to determine cross-adsorber clearance.

Finally, this study has several limitations. First, it was a retrospective, single-center data analysis, whereby laboratory parameters were collected in clinical routine. Although the time of blood collection and the duration of treatment with CS were electronically documented, a slight deviation was still possible. Second, there was no control group, so the course of myoglobin without CS could not be assessed and elimination outside the kidneys may have played a minor role. In this context, a statement on the difference in patients’ outcome with and without CS treatment is not possible. Third, CK was measured using a kinetic test, so the CK value included all isoforms. Last, statements about the myoglobin clearance and saturation kinetics of the CS absorber are not possible due to the relatively sparse blood sampling scheme. Moreover, small amounts of myoglobin can also be eliminated by the high-flux dialysis and the elimination was therefore a combination of CS therapy and high-flux dialysis.

Blood purification with Cytosorb® integrated into a high-flux dialyzer may be a useful tool for the elimination of myoglobin in critically ill patients with rhabdomyolysis. Myoglobin elimination could avert permanent kidney damage by avoiding its deposition in the kidney. A measurable effect might be obscured during sustained rhabdomyolysis, seen in patients with a rising CK during treatment. Thus, in-vivo pre- and post-adsorber measurements would be useful for investigating the elimination rate and elimination kinetic of myoglobin during CS treatment. Prospective randomized trials would, furthermore, be useful to examine the clinical benefits in terms of recovery of kidney function and patient outcome.