Peri- and postoperative subcutaneous adipose tissue cefazolin determination using microdialysis in morbidly obese and non-obese patients

Morbid obesity prevalence is rising worldwide. As a consequence weight reducing
therapies such as bariatric surgeries including gastric banding, and -bypass
surgery and sleeve-gastrectomy are rising as well. Complications of these
interventions include, among others, surgical site infections (SSI), as obesity
itself is a risk factor for SSIs. In an earlier study in 20 obese patients
(POP-2 study, NCT01097148) 2 patients developed an SSI despite the fact that
unbound cefazolin concentrations were all above the minimal inhibitory
concentration (MIC90) of S. Aureus of this hospital until 2 hours after
surgery. Reduced perfusion of adipose tissue in obese patients, resulting in
subcutaneous cefazolin concentrations below MIC, could be a plausible
explanation for this controversy. To test this hypothesis, we aim to determine
cefazolin concentrations in subcutaneous adipose tissue and investigate the
relation to unbound and total cefazolin concentrations in morbidly obese
patients undergoing (bariatric) surgery.
Currently, there are no specific reports providing information on cefazolin
distribution in non-obese patients. Comparing the unbound cefazolin plasma and
cefazoline subcutaneous concentration in morbidly obese and non-obese will
provide insight on what factors are of influence on the distribution of
cefazolin (is it bodyweight, tissue perfusion, distribution of adipose tissue,
etc?). When factors of influence are identified, it will be possible to predict
the cefazoline subcutaneous concentrations from plasma cefazolin
concentrations. This way we will be able to adequately adjust standard
cefazoline doses for the specific patient that needs it. To accomplish this
important predictive step, we will determine unbound and total cefazolin
concentrations in plasma and subcutaneous adipose tissue in non-obese patients
as well. All observations will be used to construct a population
pharmacokinetic (PK) model and to define an adequate cefazolin dosing regimen
in the morbidly obese population.
Other complications of weight reducing surgery include deep vein thrombosis and
pulmonary embolism. In the earlier POP-2 study we determined anti-factor Xa
concentrations in response to subcutaneous administration of nadroparin in
morbidly obese patients and found a large variation in anti-factor Xa
concentrations over time. It is unknown whether this variation can be explained
by the variability in bodyweight, clearance and/or in subcutaneous resorption.
Therefore anti-factor Xa concentrations in non-obese patients are urgently
needed. Data of both morbidly obese and non-obese patients will allow
investigation into what extent the nadroparin pharmacokinetics and/or -dynamics
of these drugs are affected in morbidly obese patients, thereby reducing the
risk of deep venous thrombosis/pulmonary embolism and/or excessive bleeding
complications. Findings will be used to construct a population pharmacodynamic
(PD) model and to define an adequate nadroparin dosing regimen in the morbidly
obese population.

The primary objective of this study is to investigate target site penetration
of cefazolin in morbidly obese patients. Also, we aim to investigate whether
cefazolin plasma concentrations are predictive of subcutaneous (target)
cefazolin concentrations and what factors are of influence on the distribution
of cefazolin (tissue perfusion, bodyweight, distribution of adipose tissue;
etc.). For this reason, we will determine unbound and total cefazolin
concentrations in plasma and subcutaneous adipose tissue in non-obese patients
as well and we will compare the observations between morbidly obese and
non-obese patients. All observed cefazolin concentrations will be analyses
using nonlinear mixed effects modelling in order to develop a population PK
model.
Secondary objective of the study is to collect anti-factor Xa concentrations in
non-obese patients. Together with anti-factor Xa plasma concentrations obtained
in the POP-2 study and 3 additional samples in morbidly obese patients in the
current study, a population PD model will be constructed.
The influence of patient and procedure-related covariates on pharmacokinetic
and -dynamic parameters will be investigated. Finally, with these two models,
we aim to develop evidence-based dosing schedules for both nadroparin and
cefazoline in morbidly obese patients.

Prospective observational expolarory pilot study

Clinical microdialysis is a safe and reproducible technique for studying drug
distribution in patients. The burden of this study is minimal and consists of
the insertion of a microdialysis probe in the ride side of the patient's
abdomen 2 hours before until 2 hours post surgery. Insertion of the probe is
comparable to an intra-muscular injection.
For the non-obese patient group an arterial line will be placed for the purpose
of this study. We believe that the extra burden and risk associated with this
procedure is acceptable, as anesthesiologist in this hospital are highly
experienced in placing arterials lines (due to large scale open heart surgery
in the St. Antonius Hospital). Furthermore, as the arterial line will be placed
after induction of anaesthesia, the patient will not experience local pain due
to the placement of the arterial line involved.
A maximum amount of 50 millilitres of blood will be sampled from an indwelling
arterial line during and after surgery. The arterial line will be kept in place
approximately 2 hours longer than usual for the morbidly obese patients and 4
hours longer for the non-obese patients.
During surgery the cardiac output will be measured using two different
monitoring systems, the NICOM® (Cheetah Medical) and Vigileo (Edwards
Lifesciences). These non-invasive cardiac output measurements do not represent
additional burden of the patient.