We reviewed all adult patients (≥18 years old) who received CIV, either as monotherapy or combined with other antibiotics, in our multidisciplinary surgical ICU between January 2013 and January 2015. Patients were identified using the pharmacy informatics system. We included all adult patients who had a body mass index (BMI) ≥35 kg/m2, and had measurement of serum vancomycin concentrations 24 hours after treatment. Patients who had previously received vancomycin within 48 hours prior to the start of the continuous infusion (CI) were excluded. The protocol was approved by the Partners Institutional Review Board, which waived the need for informed consent because of the retrospective nature of the study.
Demographic data (age, sex, total body weight (TBW), ideal body weight (IBW), adjusted body weight (ABW), height, BMI, creatinine clearance upon vancomycin initiation (CrCL), severity of illness score (acute physiology and chronic health evaluation (APACHE) II) calculated at the time of ICU admission, and laboratory parameters were retrospectively collected for each patient in the study. ABW was calculated as follows:
$$ \mathrm{A}\mathrm{B}\mathrm{W} = 0.4\ \left(\mathrm{T}\mathrm{B}\mathrm{W}\ \hbox{--}\ \mathrm{I}\mathrm{B}\mathrm{W}\right) + \mathrm{I}\mathrm{B}\mathrm{W}. $$
TBW was estimated and measured by the nurse using the patient’s bed scale on the day of vancomycin therapy. Other gathered data included use of continuous venovenous hemofiltration (CVVH), CVVH hemofiltration rate, use of vasopressors or mechanical ventilation, vancomycin dose, and serum vancomycin concentration. Nephrotoxicity was defined as an increase in serum creatinine (SCr) by 0.5 mg/dL or at least a 50 % increase from baseline over two consecutive SCr values for patients not requiring CVVH.
CI vancomycin clearance (CLvanc) was calculated using the following equation:
$$ \frac{\mathrm{Dose}\ \left(\mathrm{mg}/\mathrm{hr}\right)}{\mathrm{Serum}\ \mathrm{concentration}\ \left(\mathrm{mg}/\mathrm{L}\right)}=\mathrm{CLvanc}\ \left(\mathrm{L}/\mathrm{hr}\right) $$
Area under the concentration curve 24 hr (AUC24) was calculated as follows:
$$ \mathrm{serum}\ \mathrm{vancomycin}\ \mathrm{concentration}\ \left(\frac{\mathrm{mg}}{\mathrm{L}}\right)*24\mathrm{hr} $$
Daily vancomycin dose (mg) needed to obtain a target concentration of 20 mg/L while on CI:
$$ \mathrm{target}\ \mathrm{concentration}\kern0.5em 20\ \left(\frac{\mathrm{mg}}{\mathrm{L}}\right)*\mathrm{CLvanc}\ \left(\frac{\mathrm{L}}{\mathrm{hr}}\right)*24\mathrm{hr} $$
The 24-hour urine creatinine clearance (CrCL) was calculated using the following formula:
$$ \mathrm{CrCL}\ \left(\frac{\mathrm{ml}}{ \min}\right)=\frac{\left(\mathrm{Urine}\ \mathrm{output},\ \mathrm{ml}\right)*\left(\mathrm{Urinary}\ \mathrm{creatinine},\frac{\mathrm{mg}}{\mathrm{dL}}\right)}{\left(\mathrm{serum}\ \mathrm{creatinine},\frac{\mathrm{mg}}{\mathrm{dL}}\right)*\left(\mathrm{Time}\ \mathrm{of}\ \mathrm{urine}\ \mathrm{collection},\ \mathrm{minutes}\right)} $$
All CVVH treatments applied the CAR-505 filter with a polyethersulfone membrane with a 1.6 m2 membrane surface area in conjunction with the NxStage System One dialysis machine. Vancomycin concentration analysis utilized a Syva Emit 2000 vancomycin assay (Siemens Healthcare Diagnostics, Inc. Newark, DE, USA). The assay has an analytical range between 5.0 and 50.0 mcg/ml, and the between-run coefficient of variation was <10 % throughout the analytical range.
Vancomycin treatment and measurements
In our surgical ICU, the use of CIV is at the discretion of the treating ICU physician and at a loading dose of 25–30 mg/kg, followed by maintenance doses adjusted based on CrCL or CVVH. Calculated CrCL was estimated using the Cockcroft-Gault (CG) equation using ABW. To account for a falsely elevated CrCL estimate in patients >65 years of age in whom low SCr values may indicate reduced muscle mass, SCr values <0.8 mg/dL were adjusted up to 0.8 mg/dL. CG CrCL was used in the dosing nomogram because 24-hour urine creatinine cannot provide immediate results and rapid administration of antibiotic is often essential. Of note, 24-hour urine creatinine is not performed daily in the study center, instead it is collected on the first day of CIV therapy. The daily maintenance dose starts at 2000 mg for CG CrCL of 60 ml/minute; increases in CG CrCL of 10 ml/minute requires an increase in maintenance dose of 250 mg vancomycin. The maximum maintenance dose is started at 4250 mg. For patients who receive concomitant CVVH, the initial vancomycin dose is 1500 mg daily.
Doses were not changed during the first 24 hours of therapy; afterwards, the daily regimen was adapted using a specific approach: if serum vancomycin concentration was <15 mg/L, an additional dose of 500 to 1000 mg was given as a bolus followed by an increased total daily dose proportional to the goal serum concentration. If the concentration was >25 mg/L, the CIV was discontinued for 4 to 6 hours and resumed with the daily dose reduced proportionally. Serum vancomycin concentrations were determined every 24 hours until two serum concentrations were within target range (15–25 mg/L). If CVVH was stopped due to a clotted circuit, the CIV was stopped and the infusion resumes once CVVH was restarted.
Matched controls
Using an institutional database of all ICU patients who received CIV during the same period, obese ICU patients (BMI >35 kg/m2) were matched with non-obese ICU patients (BMI <30 kg/m2) according to three criteria: (1) renal function (either the same 24-hour urine CrCL with a range of eligibility for matching of 25 ml/minute, or if on CVVH, the same CVVH intensity with a range of eligibility for matching of 10 ml/kg/minute); (2) age (range of eligibility for matching of 15 years); and (3) APACHE II score at admission (range of eligibility for matching of 10).
Endpoints
The primary outcome was the weight-based daily maintenance dose requirement to achieve vancomycin concentration of 20 mg/L at 24 hours. Secondary outcomes were achievement of a therapeutic level by 24 hours, CLvanc/IBW, CLvanc/ABW, CLvanc/TBW, and AUC24. Therapeutic levels were defined as a range of 15 to 25 mg/L to achieve an adequate AUC [11, 12].
Statistical analysis
Distributions of quantitative outcomes were summarized by the mean with standard deviation and were compared using the Mann-Whitney U test. Categorical outcomes were summarized by counts and proportions and compared using the Chi-square test (or the Fisher’s exact test as appropriate). Linear regression was used to identify the correlation between CLvanc and CrCL. All analyses were performed using STATA Data Analysis and Statistical Software (version 13; StatCorp LP, College Station, TX, USA). A p value <0.05 was considered statistically significant.