**3. Adjunctive therapies**

The mainstay of etiological treatment in septic shock remains source control and the administration of anti-infective agents. Especially with regard to the latter, dosing issues are extremely important. Finally, there is also some emerging literature, unfortunately mainly anecdotal, on the use of immunoadsorptive strategies.

#### **3.1. Source control**

Resection or drainage of an infectious inoculum is important. Due the necessity of anticoagulating ECMO treated patients, this is not without risk of bleeding during or after (at restart of anticoagulation) the procedure. However, as mentioned in previous sections of this chapter, performing surgical procedures in ECMO patients is feasible [22, 23].

#### **3.2. Dosing of anti-infective agents**

In the last decade, the interest in pharmacodynamics and therapeutic drug monitoring (especially for antibiotics) has grown tremendously. With regard to prescribing antibiotics, several reports have dealt with therapeutic drug monitoring in ICU patients in the absence [35] or in the presence [36] of concomitant use of renal replacement therapy.

However, there are no clear guidelines for dosing antibiotics in ECMO-treated patients. Therefore, the interest on the matter increased in the latest years and several publications investigated this topic [37–39], mainly in the class of beta-lactam antibiotics.

In ECMO patients, the volume of distribution increases tremendously, but clearance is usually lower than controls [37]. Although pharmacokinetic variability is high, decreased meropenem clearance usually compensates for ECMO and critical illness-related increases in the volume of distribution. With standard 1 g IV dosing 8-hourly, target concentrations of >2 mg/L are usually met, but an increase in dose may be appropriate in patients with elevated creatinine clearance or when higher concentrations are needed for less susceptible microorganisms.

The use of continuous infusions of carbapenems might be useful in this regard [38]. In a pediatric ECMO case, a bolus of 40 mg/kg meropenem followed by a continuous infusion of 200 mg/kg/day resulted in target attainment of 100% for serum and lung concentrations above the MIC.

Also, other beta-lactam antibiotics [39] were investigated. For piperacillin/tazobactam insufficient concentrations were more frequent than with meropenem therapy in the treatment of *Pseudomonas aeruginosa* infections.

Also while prescribing antifungal agents, caution is warranted for subtherapeutic exposure. In pediatric ECMO case [40], insufficient plasma levels were measured despite the administration of normal to high doses of caspofungin.

#### **3.3. Immunoadsorption**

Finally, a Taiwanese group [34] recently published their retrospective single center review of 55 pediatric septic shock patients. In this cohort, overall survival to discharge was 31%. However, 25 patients were immunocompromised, in whom mortality was 75%. Mean ECMO duration was 9 days (range, 0–103) with a duration in survivors that doubled the one in nonsurvivors (14 vs. 7 days, p = 0.09). In 17 of them, causal pathogens could be identified of which 7 were bacterial and 1 was an invasive fungal infection. In the previously healthy kids, in 18

The mainstay of etiological treatment in septic shock remains source control and the administration of anti-infective agents. Especially with regard to the latter, dosing issues are extremely important. Finally, there is also some emerging literature, unfortunately mainly anecdotal, on

Resection or drainage of an infectious inoculum is important. Due the necessity of anticoagulating ECMO treated patients, this is not without risk of bleeding during or after (at restart of anticoagulation) the procedure. However, as mentioned in previous sections of this chapter,

In the last decade, the interest in pharmacodynamics and therapeutic drug monitoring (especially for antibiotics) has grown tremendously. With regard to prescribing antibiotics, several reports have dealt with therapeutic drug monitoring in ICU patients in the absence [35] or in

However, there are no clear guidelines for dosing antibiotics in ECMO-treated patients. Therefore, the interest on the matter increased in the latest years and several publications

In ECMO patients, the volume of distribution increases tremendously, but clearance is usually lower than controls [37]. Although pharmacokinetic variability is high, decreased meropenem clearance usually compensates for ECMO and critical illness-related increases in the volume of distribution. With standard 1 g IV dosing 8-hourly, target concentrations of >2 mg/L are usually met, but an increase in dose may be appropriate in patients with elevated creatinine clearance or when higher concentrations are needed for less susceptible

The use of continuous infusions of carbapenems might be useful in this regard [38]. In a pediatric ECMO case, a bolus of 40 mg/kg meropenem followed by a continuous infusion of 200 mg/kg/day resulted in target attainment of 100% for serum and lung concentrations above

performing surgical procedures in ECMO patients is feasible [22, 23].

the presence [36] of concomitant use of renal replacement therapy.

investigated this topic [37–39], mainly in the class of beta-lactam antibiotics.

cases with an identified pathogen 10 were bacteremic (mainly pneumococcal).

**3. Adjunctive therapies**

126 Advances in Extra-corporeal Perfusion Therapies

**3.1. Source control**

microorganisms.

the MIC.

the use of immunoadsorptive strategies.

**3.2. Dosing of anti-infective agents**

In the last decade, several publications report on the use of cytokine adsorption techniques [41–46]. In several case reports [41–43], the Cytosorb hemoadsorption column (Linc Medical, Leicestershire, United Kingdom) was installed either in the ECMO circuit or in the CRRT circuit in order to stabilize septic shock patients more rapidly and to improve their outcome. Cytosorb removes the proinflammatory cytokines and has been shown to reduce vasopressor doses and serum inflammatory markers in septic patients. A similar device is the polymethylmethacrylate membrane hemofilter is also available for clinical use and a report on its use has been published [46]. Although promising, the addition of these immunabsorption techniques is costly and still under investigation.
