Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients

Abstract

IntroductionImproved methods to optimize drug dosing in the critically ill are urgently needed. Traditional prescribing culture involves recognition of factors that mandate dose reduction (such as renal impairment), although optimizing drug exposure, through more frequent or augmented dosing, represents an evolving strategy. Elevated creatinine clearance (CLCR) has been associated with sub-therapeutic antibacterial concentrations in the critically ill, a concept termed augmented renal clearance (ARC). We aimed to determine the prevalence of ARC in a cohort of septic and traumatized critically ill patients, while also examining demographic, physiological and illness severity characteristics that may help identify this phenomenon.MethodsThis prospective observational study was performed in a 30-bed tertiary level, university affiliated, adult intensive care unit. Consecutive traumatized and septic critically ill patients, receiving antibacterial therapy, with a plasma creatinine concentration ≤110 μmol/L, were eligible for enrolment. Pulse contour analysis (Vigileo / Flo Trac® system, Edwards Lifesciences, Irvine, CA, USA), was used to provide continuous cardiac index (CI) assessment over a single six-hour dosing interval. Urinary CLCR measures were obtained concurrently.ResultsSeventy-one patients contributed data (sepsis n = 43, multi-trauma n = 28). Overall, 57.7% of the cohort manifested ARC, although there was a greater prevalence in trauma (85.7% versus 39.5%, P <0.001). In all patients, a weak correlation was noted between CI and CLCR (r = 0.346, P = 0.003). This was mostly driven by septic patients (r = 0.508, P = 0.001), as no correlation (r = -0.012, P = 0.951) was identified in trauma. Those manifesting ARC were younger (P <0.001), male (P = 0.012), with lower acute physiology and chronic health evaluation (APACHE) II (P= 0.008) and modified sequential organ failure assessment (SOFA) scores (P = 0.013), and higher cardiac indices (P = 0.013). In multivariate analysis, age ≤50 years, trauma, and a modified SOFA score ≤4, were identified as significant risk factors. These had greater utility in predicting ARC, compared with CI assessment alone.ConclusionsDiagnosis, illness severity and age, are likely to significantly influence renal drug elimination in the critically ill, and must be regularly considered in future study design and daily prescribing practice.See related commentary by De Waele and Carlier, http://ccforum.com/content/17/2/130

Using Population Pharmacokinetic Modeling and Monte Carlo Simulations To Determine whether Standard Doses of Piperacillin in Piperacillin-Tazobactam Regimens Are Adequate for the Management of Febrile Neutropenia

“…In the critically ill, for instance, clearance could be elevated (e.g., 17.1 liters [18]) or similar/slightly higher (e.g., 13.8 liters/h [15,16] and 14.0 Ϯ 7.1 liters [17]) or may even be reduced (e.g., 3.6 liters/h [19] and 5.6 Ϯ 3.2 liters/h [12]) compared to healthy volunteers (13). It could be particularly high in those patients with burns and trauma (20). For example, a pharmacokinetic model for burn patients predicts elevated clearance of 16 liters/h for patients when CL CR is 130 ml/min and 20 ml/min when CL CR is 160 ml/min (21).…”

Increased Creatinine Clearance in Acute Kidney Injury due to Heat Stroke

“…In septic AKI patients, renal function was reported not to decline as low as expected, which could lead to underestimation of glomerular filtration rate and insufficient drug dosing [10]. This phenomenon is termed aug- mented renal clearance in which renal function for solution clearance is elevated more than expected by visible laboratory data in critically ill patients [11,12]. Therefore, more sensitive biomarkers such as the measured creatinine clearance are needed.…”

Optimising the administration of antibiotics in critically ill patients

“…Increased β-lactam clearance in patients with sepsis, but without organ dysfunction, can lead to subtherapeutic levels for significant periods. [14][15][16][17] CLcr should be routinely measured if there is doubt about the GFR and evidence that an 8-hour collection may be just as accurate as a 24-hour one. A recent prospective, singlecentre observational study of patients with VAP treated with doripenem or imipenem demonstrated a greater mortality and lower cure with CLcr >150 mL/min.…”