Therapeutic Apheresis in Critically Ill Patients: Indications, Modalities and Techniques, Clinical Results

General Aspects

Whenever TA comes into play, the underlying disease condition and the way apheresis may interfere with the ongoing disease should be given further consideration. This then may lead to the decision for a more or less selective procedure. Although TPE will lead to the unselective removal of all plasma components, the more advanced immunoadsorption (IA) techniques lead to a more selective removal of target molecules. On the other hand, TPE provides the chance of an isovolumetric replacement of the patient's plasma and intact plasma components, and this may exert beneficial effects for treated patients. Despite recent efforts to aim at several newer targets such as viruses and bacteria as well as chemokines, apheresis is used predominantly to target the antibody-mediated immune response and therefore is applied in a wide variety of autoimmune disorders.

Modulation of the Immune Response by Apheresis

As mentioned earlier, a higher selectivity has certain advantages but drawbacks with respect to its modulatory effect. Clearly, the removal of pathogenically relevant (auto)antibodies is one major aim of TA. This then affects not only the subsequent activation of complement and immune cells but also the neutralizing and opsonizing functions of immunoglobulins (Ig) and thereby downregulates the antibody-mediated immune response. Thereby the humoral as well as the cellular immune response is modulated. By the same mechanisms, TA also affects/compromises the patient's host defense. Although, for instance, plasma separation filters also induce complement activation, adsorptive surfaces seem to decrease complement activation in human plasma. All TA systems will, to a higher or lesser extent, modulate the humoral immune response, although only TPE may exert additional effects via the substitution of functional human plasma components. In turn this could inhibit but also drive the immune response under certain conditions such as a genetically dysregulated complement cascade. Effectiveness of TA in diseases without known pathophysiologically relevant autoantibodies (aab) suggests that TA does not modulate ongoing disease exclusively on the level of antibody removal but may be a signal that the precise pathophysiology, including potentially relevant aab, is still unknown. Clearly, TA has also modulatory effects on the chemokine levels. However, direct beneficial effects have not been identified and cannot be titrated.

Procedure-Related Considerations

Apart from pathophysiology, a number of treatment-specific considerations should be made before the initiation of treatment. Of course, the risk of the procedure, especially under ICU conditions, versus the potential benefit has to be weighed. This includes the patient's comorbidities, which may be influenced by the extracorporeal treatment. With respect to the ICU setting, especially TPE also will remove all pharmacologic compounds either solubilized in plasma or bound to albumin. For TPE, adequate substitution has to be performed during each treatment, whereas IA does not, or only to a very limited extent, interfere with or remove medications and/or albumin. The only exemptions are antibody therapies including intravenous immunoglobulins (IvIg).

Technical aspects include the use of either systemic (heparin) or regional (citrate) anticoagulation. Procedures with a longer duration frequently apply a combination of both. Although citrate will expose patients to a much lower risk for bleeding complications, it may be problematic in patients with reduced liver function and a lacking capacity to metabolize the infused citrate solution. The same problem may arise from substitution of larger volumes of human plasma, because plasma products contain a relevant amount of citrate. For TPE, volume substitution has to be adjusted to the specific needs of treated patients. Citrate solution will cause additional volume load in treated patients, whereas the effective removal of Ig by immunoadsorption will cause a reduction of colloid-osmotic pressure and a drift of fluid into the third space, which finally may harm respiratory-compromised patients.

With respect to the vascular access, the ICU setting and general management predisposes patients to the placement of central venous catheters. However, it is necessary to make a careful decision in this direction, because central catheters are a frequent cause of complications, inside and outside the ICU. Whenever technically feasible, peripheral venous access will be the better choice.

Frequently, specific therapeutic plans cannot, or only to a limited extent, be taken from existing literature. Nevertheless, a therapeutic strategy and readouts for treatment effectiveness, and thereby prolongation or interruption of TA, must be developed. This may relate to the removal of target molecules or the clinical course of disease. Clinically, a number of patients show a delayed improvement of symptoms, making such treatment decisions even more complicated.

Finally, all TA systems have to be placed close to the patient and require a defined amount of space in sometimes relatively narrow ICU settings. Therefore decisions about the placement of these systems in addition to the frequently already well-equipped ICU have to be made. On the other hand, logistic considerations also may drive the decision that patients should undergo apheresis in an ICU setting instead of under the standard fashion of care. This is another reason why nephrologists face a continuum with respect to the severity of disease that may be treated in critical care nephrology.

Therapeutic Plasma Exchange

The fundamental basis of TPE is the separation of patient's plasma from cellular blood components. For many years, this could be achieved only in extracorporeal circuits equipped with plasma filters, necessitating a relatively high and constant blood flow that could be provided only via central venous catheters or arteriovenous fistulas. The introduction of centrifugal plasma separation systems overcame this limitation, today enabling TPE procedures using peripheral venous access. Modern centrifugal systems provide high effectivity using a blood flow of approximately 50 to 80 mL/min and can adapt to changes in blood flow during treatment.

Because separated plasma will be discarded after treatment, isovolumetric substitution of iso-oncotic fluid is necessary to keep up the colloid-osmotic pressure. This can be achieved by using either a combination of human albumin and crystalloids or fresh frozen plasma from healthy donors. Both variants provide the risk for a number of adverse events, including hypotension and allergic reactions. As a major limitation, one TPE procedure can process/replace only a bit less than one time the complete plasma volume of the individual patient in a single session. On the other hand, the complete removal of plasma components may offer the advantage to target additional, disease-relevant pathogenetic (so-called pleiotropic) mechanisms such as altered chemokine signaling and circulating miRNAs. Table 190.1 summarizes potential risks and benefits arising from TPE.