Effect of Continuous Venovenous

Hemofiltration Dose on Achievement of

Adequate Vancomycin Trough
Concentrations
Erin N. Frazee, Philip J. Kuper, Garrett E. Schramm, Scott L.
Larson, Kianoush B. Kashani, Douglas R. Osmon and

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Nelson Leung
Antimicrob. Agents Chemother. 2012, 56(12):6181. DOI:
10.1128/AAC.00459-12.
Published Ahead of Print 17 September 2012.

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Effect of Continuous Venovenous Hemofiltration Dose on
Achievement of Adequate Vancomycin Trough Concentrations
Erin N. Frazee,a Philip J. Kuper,a Garrett E. Schramm,a Scott L. Larson,a Kianoush B. Kashani,b,c Douglas R. Osmon,d and
Nelson Leungb
Hospital Pharmacy Services, Mayo Clinic, Rochester, Minnesota, USAa; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USAb; Division of

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Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USAc; and Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USAd

The vancomycin dose necessary for the achievement of target serum trough concentrations during continuous venovenous he-
mofiltration (CVVH) remains to be elucidated. This was a retrospective cohort study of critically ill adults at a tertiary medical
center on concurrent CVVH and vancomycin between 2006 and 2010 with a steady-state vancomycin trough concentration. The
87 included patients were grouped according to low (<30 ml/kg/h; n ⴝ 10) or high (>30 ml/kg/h; n ⴝ 77) CVVH hemofiltration
rate (HFR) for analysis. Vancomycin goal trough achievement occurred in only 32 (37%) patients. The primary endpoint of
trough attainment significantly differed between HFR subgroups: 90% versus 30% in low- and high-HFR individuals, respec-
tively (P < 0.001). Patients with subtherapeutic trough concentrations had a median (interquartile range) HFR of 40 ml/kg/h
(range, 37 to 47 ml/kg/h) compared to 36 ml/kg/h (range, 30 to 39 ml/kg/h) in those who achieved the trough goal. Irrespective of
goal trough, an inverse correlation existed between HFR and serum vancomycin concentration (r ⴝ ⴚ0.423; P < 0.001). In the
subgroup of 14 methicillin-resistant Staphylococcus aureus (MRSA) patients, trough achievement was similar to the aggregate
cohort (36%). Mortality at 28 days was unrelated to trough achievement in both the overall sample (P ⴝ 0.516) and in culture-
positive MRSA patients (P ⴝ 0.396). Critically ill patients undergoing CVVH therapy may experience clinically significant reduc-
tions in goal vancomycin troughs. The results of the present study justify prospective evaluations in this population to determine
the optimal vancomycin dosing strategy for attainment of goal trough concentrations.

S evere sepsis contributes to 10 to 20% of intensive care unit

(ICU) admissions and is associated with an estimated 30%
mortality rate (2, 24, 25). Sepsis-related sequelae precipitate
nearly 50% of all acute kidney injury cases, which often progress to
require renal replacement therapy (1, 3, 31). In a 2003 multicenter
practice survey, 86.2% of providers reported utilization of contin-
uous renal replacement therapy (CRRT) as one of their manage-
ment strategies for acute kidney injury (18). Provision of CRRT
accomplishes steady correction of metabolic abnormalities and
fluid balance without exacerbating unstable hemodynamics (17,
22). Use of continuous venovenous hemofiltration (CVVH), a
convective clearance CRRT modality, has become the preferred
modality likely due to the poor solute removal and arterial cannu-
lation complications associated with arteriovenous circuits (17,
18, 20, 28).
Hemofiltration rate impacts solute removal during CVVH (8).
Early CVVH literature demonstrated an improvement in mortal-
ity with hemofiltration rates of 35 to 45 ml/kg/h compared to rates
of 20 ml/kg/h (22). The conflicting results of subsequent studies
on the appropriate dose of CRRT have led to varied applications in
clinical practice (4, 6, 19). Despite this variability, it is clear that an
upward titration of hemofiltration rates occurred in the last de-
cade (4, 6, 19, 22, 26).
The importance of rate-dependent solute removal is magnified
when the solute is an essential pharmacotherapeutic intervention.
Evolution of hemofiltration rate practices may impact antimicro-
bial agent adequacy resulting in adverse clinical outcomes in the
septic patient (27). The Surviving Sepsis guideline recommenda-
tions stress not only activity of anti-infective agents against all
likely pathogens but also pharmacokinetic/pharmacodynamic
optimization to ensure maximal efficacy (10). Continuous veno-
venous hemofiltration is known to impact the clearance of van-
comycin, an antimicrobial often recommended for empirical
coverage in sepsis (5, 10, 12, 14, 23). Published literature on
vancomycin clearance during CVVH is limited to small sample
sizes, limited patient populations, and lower hemofiltration rates
than those currently used (5, 9, 12, 21). With the change in CVVH
practices, the adequacy of existing vancomycin dosing strategies
has not been investigated. The purpose of the present study was to
determine the success rate of an institutional vancomycin dosing
recommendation in achieving target trough concentrations in pa-
tients on CVVH. The investigators hypothesized that use of high
hemofiltration rates would portend failure to achieve goal troughs
more often than low hemofiltration rates.
MATERIALS AND METHODS
Subject identification and data collection. This retrospective cohort
study examined adult ICU patients at Mayo Clinic in Rochester, Minne-
sota, who received concurrent CVVH and vancomycin between January
2006 and December 2010. The institutional review board approved the
present study and waived the need for informed consent. An existing
CVVH database identified eligible patients who were then grouped ac-
cording to low (ⱕ30 ml/kg/h) or high (⬎30 ml/kg/h) hemofiltration rate
(6, 7, 19, 21, 22, 26, 28).
The study included adults aged ⱖ18 years who received 15 to 20 mg/kg
(actual body weight [ABW]) vancomycin as a single daily dose consistent
Received 8 March 2012 Returned for modification 18 August 2012
Accepted 5 September 2012
Published ahead of print 17 September 2012
Address correspondence to Erin N. Frazee, frazee.erin@mayo.edu.
Copyright © 2012, American Society for Microbiology. All Rights Reserved.
doi:10.1128/AAC.00459-12

December 2012 Volume 56 Number 12 Antimicrobial Agents and Chemotherapy p. 6181– 6185 aac.asm.org 6181
Frazee et al.
with institutional recommendations (5, 12, 27). Goal vancomycin trough
concentrations were in accordance with Infectious Diseases Society of
America guideline recommendations, 10 to 15 mg/liter or 15 to 20 mg/
liter, based on suspected or documented source(s) of infection (23).
Trough concentrations were drawn no earlier than before the fourth con-
sistent vancomycin dose or the third if given a loading dose to assure
steady-state conditions (5, 11). Vancomycin concentration analysis uti-
lized an Olympus AU680 (Olympus America, Inc., Melville, NY) with the
Syva Emit 2000 vancomycin assay (Siemens Healthcare Diagnostics, Inc.,
Newark, DE). The assay has an analytical range between 5.0 and 50.0
mg/liter, and the between-run coefficient of variation was ⬍10%
throughout the analytical range. All CVVH treatments applied the Pris-
maflex System and the HF 1400 polyarylethersulfone filter (Gambro,
Stockholm, Sweden). Blood flow rate was standard at 200 ml/min and
anticoagulation achieved with sodium citrate. Prismasate (Gambro, Inc.,
Lakewood, CO) replaced the hemofiltration fluid, 50% prefilter and 50%
postfilter. The attending nephrologist prescribed an individualized hemo-
filtration rate for each patient. Excluded patients did not authorize their
medical chart for review, received ⬍85% of their prescribed hemofiltra-
tion rate, had CVVH held for more than eight consecutive hours during
vancomycin therapy, required group crossover due to hemofiltration rate
prescription changes, had a ⱖ0.5-ml/kg/h average urine output for six
consecutive hours during the study, or received concurrent extracorpo-
real membrane oxygenation (10, 19, 22, 30). Outcome analysis included
only the first ICU admission for each patient during the study time frame.
Demographic data (age, sex, ABW, ideal body weight, body mass in-
dex [BMI], baseline renal function, and comorbid conditions), severity of
illness scores (Acute Physiology and Chronic Health Evaluation II
[APACHE II], Sequential Organ Failure Assessment [SOFA]), and labo-
ratory parameters (serum albumin, blood urea nitrogen) were retrospec-
tively collected for each patient in the study. Other gathered data included
admitting diagnosis, primary ICU service, source of infection, renal pa-
rameters (daily CVVH hemofiltration rate, dialyzer used, fluid balance,
and urine output), weight-based vancomycin dose, and serum trough
concentration.
Endpoints. The primary outcome measured the success rate of van-
comycin goal trough achievement between low and high hemofiltration
rate groups. Secondary outcomes included trough concentrations in the
aggregate cohort, factors associated with hemofiltration rate prescription,
and 28-day all-cause mortality.
Data analysis. No formal sample size calculation was able to be per-
formed and all eligible patients who met inclusion/exclusion criteria were
analyzed. Descriptive data were summarized by medians with interquar-
tile ranges (IQR) and percentages. The chi-square test (or the Fisher exact
test as appropriate) studied categorical variables and the Wilcoxon rank
sum test analyzed continuous variables. The Spearman rank correlation
coefficient tested the association between two continuous variables.
Patient-specific characteristics were imputed in a multivariate least-
squares regression model to analyze factors associated with continuous
variables. Survival rates were estimated and compared between subgroups
using the Kaplan-Meier method with the log-rank test. All analyses were
carried out using the JMP statistical software package (version 8; SAS
Institute, Inc., Cary, NC). A P value of ⬍0.05 was considered statistically
significant.
RESULTS
Patients. During the study period, 435 patients underwent evalu-
ation for eligibility (Fig. 1). The majority of the 348 excluded pa-
tients lacked an available steady-state trough concentration (n ⫽
277; 80%) or received vancomycin at a dose different from the
institutional recommendation (n ⫽ 38; 11%). The 87 included
patients had a median age of 62 years (IQR ⫽ 55 to 72 years) and
were 64% male. The sample was predominantly comprised of
mixed-surgical ICU (43%) and medical ICU (26%) patients with
critical illness reflected in APACHE II and SOFA scores of 25 (16
6182 aac.asm.org
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FIG 1 Study flow chart.
to 34) and 12 (7 to 15), respectively. Pulmonary (n ⫽ 44) and
intra-abdominal (n ⫽ 19) sources of infection occurred most
commonly. Few differences existed between groups at baseline
(Table 1). Hemofiltration rates were 27 ml/kg/h (24 to 30 ml/kg/h)
and 39 ml/kg/h (36 to 45 ml/kg/h) in the low (n ⫽ 10)- and high
(n ⫽ 77)-rate groups, respectively (P ⬍ 0.0001). The low-hemo-
filtration-rate group had a significantly higher BMI than high-
hemofiltration-rate patients (P ⬍ 0.001), and proportionally
more intra-abdominal infections occurred in low rate individuals
(P ⫽ 0.037). First vancomycin dose which met study definition
was administered on day ⫺0.1 (days ⫺0.5 to 1.6) from CVVH
initiation. Twenty-two patients (25%) received a loading dose, all
of which were in the high hemofiltration rate group. The loading
doses were 24.0 mg/kg (20.3 to 26.4 mg/kg).
Microbiologic confirmation of infection was present in 43
(49%) cases. Fourteen patients (16%) developed culture-positive
methicillin-resistant Staphylococcus aureus (MRSA) infections, of
which 7 (50%) experienced an MRSA bacteremia. The severity of
illness at ICU admission in this subgroup compared well to the
aggregate cohort with the median (IQR) APACHE II score of 25
(18 to 37) and SOFA score of 11 (7 to 13). The baseline BMI for
these patients was 28 kg/m2 (23 to 34 kg/m2), and they were pre-
scribed a hemofiltration rate of 41 ml/kg/h (37 to 49 ml/kg/h).
Endpoints. Trough concentrations were obtained a median
(IQR) of 3.0 (3.0 to 4.0) days after vancomycin therapy com-
menced. Overall, goal trough attainment occurred in 32 (37%) of
the patients. For the primary endpoint of trough achievement
according to hemofiltration rate subgroup, low-rate patients
achieved goal trough concentrations 90% of the time, while only
30% of high-hemofiltration-rate cases reached their goal (P ⬍
0.001). Patients with subtherapeutic trough concentrations had
hemofiltration rates of 40 ml/kg/h (37 to 47 ml/kg/h), in contrast
to hemofiltration rates of 36 ml/kg/h (30 to 39 ml/kg/h) in patients
who reached goal trough levels (P ⬍ 0.001). Irrespective of trough
goal, a significant inverse correlation exists between hemofiltra-
tion rate and vancomycin serum concentration (Fig. 2; P ⬍
0.001). Mortality at 28 days did not differ according to trough
achievement (Fig. 3; P ⫽ 0.516).
In the subgroup of 14 patients with a documented MRSA in-
fection, 2 (14%) patients were prescribed a ⱕ30-ml/kg/h hemo-
Antimicrobial Agents and Chemotherapy
 CVVH Dose and Vancomycin Trough Achievement

TABLE 1 Baseline patient characteristics and demographic dataa pared to patients receiving high hemofiltration rates. Increases
HFR ⱕ 30 ml/kg/h HFR ⬎ 30 ml/kg/h in hemofiltration rates regardless of vancomycin goal range sig-
Characteristic (n ⫽ 10) (n ⫽ 77) P nificantly correlated with reductions in trough concentrations.
Age (yr) 68 (59–71) 62 (54–74) 0.55 Similar to the aggregate cohort, in the subset of patients with cul-
No. (%) of male patients 5 (50) 51 (66) 0.32 ture-positive MRSA infections, the majority of patients in the
Score high-hemofiltration-rate group demonstrated subtherapeutic
APACHE II 26 (20–34) 25 (16–35) 0.99 trough concentrations. Hemofiltration rate prescribing practices
SOFA 13 (6–16) 12 (7–15) 0.70 varied among providers and factors shown to be independently
Body mass index (kg/m2) 42 (31–55) 27 (24–32) ⬍0.001 associated with the prescribed rate (in ml/kg/h) included ABW,
Change in body wt (kg)b 1.2 (⫺3.9–5.1) 3.1 (0–9.4) 0.35 sex, BMI, and baseline serum creatinine.

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Net fluid balance (liters)b 9.6 (⫺0.5–17.0) 10.3 (3.3–19.0) 0.59 These findings are clinically relevant due to the paucity of avail-
No. (%) of ICU patients 0.29
able vancomycin pharmacokinetic data during CVVH. Joy et al.
Medical ICU 3 (30) 20 (26)
Surgical ICU 6 (60) 31 (40)
characterized the clearance of vancomycin during CVVH in eight
Other ICU 1 (10) 26 (34) non-critically ill end-stage renal disease patients. Each patient re-
No. (%) of patients with 1.00 ceived a 500-mg dose and CVVH clearance of vancomycin de-
admitting diagnosis pended on hemofiltration rates when assessed at 500 and 1,000
Nonoperative 5 (50) 41 (53) ml/h (12). Boereboom et al. described vancomycin clearance dur-
Operative 5 (50) 36 (47) ing CVVH in two cases of septic shock and multiple organ dys-
No. (%) of patients with 9 (90) 69 (90) 1.00 function syndrome. Determination of vancomycin pharmacoki-
sepsis netics occurred after a single dose in one individual and on the
No. (%) of patients with sixth day of therapy in the other study subject. Apparent volumes
various infection
of distribution (Vd) were 0.66 and 0.52 liter/kg, respectively, and
sourcesc
Respiratory 4 (40) 40 (52) 0.52
the terminal half-lives were 15.4 and 20.3 h for vancomycin. The
Intra-abdominal 5 (50) 14 (18) 0.037 CVVH clearance of vancomycin was 1,400 ml/h at a hemofiltra-
Bacteremia 3 (30) 19 (25) 0.71 tion rate of 1,500 ml/h (19 and 20 ml/kg/h) in the two patients (5).
Cardiovascular 0 (0) 4 (5) 1.00 New evidence tested these findings in seven patients given a single
Musculoskeletal 0 (0) 5 (6) 1.00 12.5- to 20-mg/kg vancomycin dose during CVVH at hemofiltra-
Other/unknown 1 (10) 18 (23) 0.68 tion rates of 800 to 1,200 ml/h (9). The calculated sieving coeffi-
Vancomycin dose (mg/kg) 16.9 (14.8–20.0) 16.3 (15.3–19.7) 0.76 cient of 0.71 ⫾ 0.13 approximated existing literature (0.70 ⫾ 0.15
No. (%) of patients with 0.28 to 0.89 ⫾ 0.03) (5, 9, 12). Chaijamorn et al. identified vancomycin
target trough CVVH clearance of 730 ml/h, a rate lower than that documented
10–15 mg/liter 5 (50) 23 (30)
in prior studies, and 50% of total clearance attributable to nonre-
15–20 mg/liter 5 (50) 54 (70)
a
nal mechanisms, similar to the findings of Macias and coworkers
Abbreviations: HFR, hemofiltration rate; APACHE, Acute Physiology and Chronic
(9, 15). A possible reason for the difference in the CVVH clearance
Health Evaluation; SOFA, Sequential Organ Failure Assessment; ICU, intensive care
unit. Values expressed as medians (interquartile ranges) unless noted otherwise in of vancomycin between studies may pertain to differences in the
column 1. applied hemofiltration rates. Also, existing literature varies in the
b
From ICU admission to trough concentration. distribution of predilution and postdilution replacement fluid ad-
c
Some total percentages may equal ⬎100 due to a patient having multiple infectious ministration, which is known to influence CVVH clearance of
sources.
vancomycin (29). The present study elaborates on the unique at-
tributes of critically ill patients exposed to concurrent vancomycin
and CVVH. Distinct similarities exist with prior literature, partic-
filtration rate, whereas 12 (86%) received ⬎30 ml/kg/h. Nine ularly with respect to dialyzer selection and blood flow rate. In
MRSA patients (64%) had subtherapeutic trough concentrations. addition, we document similarly poor trough achievement at 37%
Both low-hemofiltration-rate patients were within goal range,
whereas 9 (75%) high-hemofiltration-rate patients manifested
subtherapeutic troughs (P ⫽ 0.110). Similar to the aggregate sam-
ple, no difference in 28-day mortality was noted between trough
achievers and nonachievers (P ⫽ 0.396).
Nephrologists individualized CVVH hemofiltration rate pre-
scriptions for each patient and variability in prescribing practices
existed among practitioners. Hemofiltration rates in the aggregate
cohort ranged from 12 to 87 ml/kg/h. The prescribed hemofiltra-
tion rate (in ml/kg/h) was independently associated with ABW
(P ⬍ 0.001), sex (P ⫽ 0.002), BMI (P ⫽ 0.006), and baseline serum
creatinine (P ⫽ 0.03) in a multivariate analysis.

DISCUSSION
In this retrospective cohort analysis of CVVH patients, vancomy-
cin goal trough concentration achievement occurred significantly FIG 2 Vancomycin serum trough concentrations compared to hemofiltration
more often in individuals receiving low hemofiltration rates com- rate in the aggregate cohort.

December 2012 Volume 56 Number 12 aac.asm.org 6183

Frazee et al.
FIG 3 Kaplan-Meier survival curve for trough achievers versus nonachievers.
compared to recently released literature on this topic (30 to 50%)
(21, 33). The current analysis included a heterogeneous group of
critically ill individuals exposed to a consistent weight-based dos-
ing strategy with serum trough concentrations drawn under
steady-state conditions. Also, hemofiltration rates were generally
higher than in previous studies, and predilution consistently com-
prised 50% of replacement fluid administration.
Several studies note that increased doses of CRRT are not as-
sociated with improvement in patient outcomes (4, 6, 19, 32). The
mechanism by which this treatment modality fails to provide ben-
efit has yet to be fully understood. It is well known that early
appropriate antibiotics are essential to the management of indi-
viduals with severe sepsis or septic shock and that delays in therapy
are associated with dramatic increases in mortality (13). The ap-
propriateness of antimicrobials encompasses not only the spec-
trum of activity but also the adequacy of dosing with pharmaco-
kinetic and pharmacodynamic optimization (10, 16). Given the
present findings, it is possible that the absence of benefit associ-
ated with increasing hemofiltration rates during CRRT may be, in
part, attributable to a reduced ability to achieve therapeutic goals
for antimicrobials; however, further research is necessary to inves-
tigate this hypothesis.
Several important limitations exist for this type of study. The
retrospective nature limits the ability to perform formal pharma-
cokinetic modeling and establish causality. A potential selection
bias exists due to the large portion of patients excluded for the
absence of an available trough concentration. Although the strict
study definition for trough concentrations led to reductions in the
sample size, it facilitated assessment of concentrations under
steady-state conditions which strengthens the analysis. Patient
size, sex, and baseline serum creatinine were found to be indepen-
dently associated with prescribed hemofiltration rate. To our
knowledge, this is the first time patient-specific factors that may
influence dose prescribing practices have been characterized (28).
Unfortunately, the only way to minimize confounding factors
such as these would be to perform a randomized controlled trial
that prospectively accounts for these attributes among hemofiltra-
tion rate dose groups. Vancomycin dose variability existed; how-
ever, the relative contribution of this factor to the outcome is likely
minimal given the lack of a significant difference between groups
at baseline. Finally, the external validity of the results may be af-
6184 aac.asm.org
fected by the utilization of different CRRT modalities and institu-
tional CVVH practices, including, but not limited to, hemofiltra-
tion rate prescription patterns, blood flow rate, and dialyzer
selection.
These study results suggest that critically ill patients exposed to
current CVVH hemofiltration rates during vancomycin therapy
may experience a significant reduction in the ability to achieve
goal trough concentrations. Prospective studies are necessary in
critically ill patients exposed to CVVH to determine the optimal
vancomycin dosing strategy for the attainment of goal trough con-
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centrations.
ACKNOWLEDGMENTS
Support for this project was provided by NIH/NCRR CTSA grant number
UL1 RR024150. Its contents are solely the responsibility of the authors
and do not necessarily represent the official views of the NIH.
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