RUI VEIGA1; DALILA VEIGA1; NUNO PRÍNCIPE1; DANIEL MOURA2

1 INTENSIVE CARE DEPARTMENT, HOSPITAL S. JOÃO

2 DEPARTMENT OF PHARMACOLOGY AND THERAPEUTICS, FACULTY OF MEDICINE, UNIVERSITY OF PORTO

MARCH 2012

ANTIBIOTIC DOSING AND ECMO

The prolonged use of extracorporeal membrane oxygenation (ECMO) in the pediatric and adult populations has become increasingly commonplace over the past decades.

The renewed interest in this technique was triggered by the CESAR Trial and the recent 2009 H1N1 Flu pandemic.

ECMO Circuit

PK Issues

IS THERE ANY PHARMACOKINETIC CHANGE DURING ECMO?

There has been relative paucity of studies on the effects of ECMO on drug metabolism and elimination.

PK Issues

ECMO can increase the apparent Volume of Distribution:

1. by the dilutional effect of priming and ongoing I.V. fluid requirements.

2. by possible plasma protein denaturation passing through membrane oxygenator

lower serum protein concentration

PK Issues

Decreased drug binding and increasing free concentration of the drug with resulting redistribution to the tissues.

Thérapie 2011 Septembre-Octobre; 66 (5): 405–412

PK Issues

3. Significant uptake of drugs occur in the ECMO circuit, especially for lipophilic drugs, resulting in an increased Vd.

PK Issues

This effect may change over time as these binding sites become saturated.

PK Issues

PK Issues

Generally drugs are cleared as a result of processes happening mostly in the liver and kidneys.

Clearance is intimately related to the amount of drug presented to these organs, i.e., the blood flow to each organ; the Vd; and the bound/unbound fractions of the drug.

PK Issues

Drug Clearance can be affected by the degree to which ECMO impacts bound or unbound drug levels.

ECMO can result in altered end organ perfusion, most prominently by a lack of pulsatility in venoarterial ECMO, thus diminishing clearance of drugs.

PK issues

Overall, drugs have an increased Vd and decreased clearance, while on ECMO, resulting in prolonged half-life.

PK Issues

Thérapie 2011 Septembre-Octobre; 66 (5): 405–412

PK issues

There are, yet, reports where no drugs PK change is found on patients in ECMO.

Vancomycin review

Objective:

To evaluate the relation between vancomycin clearance with ECMO Blood Flow and Glomerular Filtration Rate (GFR).

Vancomycin review

Methods:

Reviewed 14 adult critically ill patients in whom vancomycin was administered while on veno-venous ECMO.

Vancomycin was administered as continuous perfusion. Serum level aim was 20-25 μg/ml. Total daily dose and serum levels were collected every 24 hours.

Medium daily ECMO flow was registered and GFR was calculated on a daily basis.

Steady-state clearance of vancomycin was calculated and its relation to ECMO blood flow and glomerular filtration rate was evaluated.

Vancomycin review

Vertical axis:

Vancomycin

clearance (L/h)

Horizontal axis:

Glomerular

filtration rate

(L/h)

Pearson r: 0.49

P< 0.001

Results:

Vancomycin review

CL Vanco & ECMOCL Vanco & ECMOCL Vanco & ECMO

Vertical axis:

Vancomycin

clearance (L/h)

Horizontal axis:

ECMO blood

flow (L/min)

Pearson r: -0.1

P: n.s.

Results:

Vancomycin review

Evolution of

vancomycin clearance,

ECMO blood flow and

glomerular filtration

rate of one patient over

time (days)

Vancomycin review

Our review showed a strong positive correlation of vancomycin clearance and GFR.

ECMO blood flow had no significant correlation with vancomycin clearance.

No vancomycin dosage adjustment seems necessary for different ECMO blood flow.

Conclusions

ECMO induces PK changes on drugs, namely augmentation of Vd and diminished CL that, with diminished organ perfusion, results in an elevation of their half-life.

The mechanisms that lead to differences in the plasma level concentrations of drugs are complex and probably in relation with interaction with ECMO circuit constituents.

Prediction of antibiotic dosage is difficult and further therapeutic studies are necessary.

Thank You