Increased creatinine clearance in polytrauma patients with normal serum creatinine: a retrospective observational study

Introduction The aim of this study, performed in an intensive care unit (ICU) population with a normal serum creatinine, was to estimate urinary creatinine clearance (CLCR) in a population of polytrauma patients (PT) through a comparison with a population of non trauma patients (NPT). Methods This was a retrospective, observational study in a medical and surgical ICU in a university hospital. A total of 284 patients were consecutively included. Two different groups were studied: PT (n = 144) and NPT (n = 140). Within the second week after admission to the ICU, renal function was assessed using serum creatinine, 24 h urinary CLCR . Results Among the 106 patients with a CLCR above 120 mL minute-1 1.73 m-2, 79 were PT and 27 NPT (P < 0.0001). Only 63 patients had a CLCR below 60 mL minute-1 1.73 m-2 with 15 PT and 48 NPT (P < 0.0001). Patients with CLCR greater than 120 mL minute-1. 1.73 m -2 were younger, had a lower SAPS II score and a higher male ratio as compared to those having CLCR lower than 120 mL minute-1. 1.73 m -2. Through a logistic regression analysis, age and trauma were the only factors independently correlated to CLCR. Conclusions In ICU patients with normal serum creatinine, CLCR, is higher in PT than in NPT. The measure of CLCR should be proposed as routine for PT patients in order to adjust dose regimen, especially for drugs with renal elimination.


Introduction
Early detection of renal dysfunction in intensive care unit (ICU) patients is important. Indeed, an increase of the glomerular filtration rate (GFR) was demonstrated in some ICU patients populations by using urinary creatinine clearance (CL CR ) as a surrogate marker, and many of the drugs used in ICU patients need dose adjustment as a function of GFR [1]. Despite a normal serum creatinine measurement, a substantial number of burn patients demonstrated an increase in GFR with the need for increasing doses of renal elimination drugs to maintain therapeutic concentrations [1,2]. A study of our group showed that 42% of burn patients had a creatinine clearance greater than 120 mL minute -1 1.73 m 2 [1]. Also, several studies performed in a general population of ICU patients suggested a poor correlation between serum creatinine concentration and GFR in polytrauma patients (PT) [3][4][5]. To the best of our knowledge, no study has specifically explored this population of PT patients.
The aim of this study, performed in a population of ICU patients with normal serum creatinine, was to estimate GFR, evaluated by measured CL CR , in a population of PT patients through a comparison with a population of non-trauma patients (NPT).

Patients
This observational study was conducted in the ICU of Toulouse University hospital during a five-year period (November 2002 to December 2007). The study was performed according to the Declaration of Helsinki. No change in our current clinical practice (measured creatinine clearance monitoring, at least once a week, is a part of the routine medical care of the patients) and no randomization was performed. As it was an observational retrospective study, in accordance with French law, neither approval of the ethics committee nor informed consent was required.
Ten days, on average, after admission in ICU, consecutive critically ill patients meeting the inclusion criteria were included. Inclusion criteria were: patients older than 18 years, with an arterial catheter, a urinary bladder catheter, a diuresis over 500 mL d -1 . All patients had a tracheal tube and were mechanically ventilated. Patients were hemodynamically stable presenting with a stable serum creatinine in a normal range (40 to 125 μmol L -1 ).
Patients were excluded from the study: if they were hemodynamically unstable or if they needed a high dose of catecholamine (norepinephrine > 1 mg h -1 ); if they were recovering from acute kidney injury (AKI) or developing AKI; if they received histamine-2-receptor antagonist due to its interference with tubular creatinine secretion [6]; and if they had a medical history of diabetes, of chronic hepatic disease, cirrhosis or ongoing liver dysfunction with hepatitis [7,8]. Patients treated with diuretics were also excluded.
Baseline characteristics of patients were recorded at enrolment in the study and the SAPS II was obtained at ICU admission. PT patients had an ISS (Injury Severity Score) > 16. SOFA (Sequential Organ Failure Assessment) score was obtained on the day the urine 24-hour measure was sampled [9][10][11].
Urine was sampled over 24 hours to measure urinary creatinine concentration. Serum creatinine was also measured during the urine collection period.

Serum creatinine measurement and calibration
Creatinine measurements were performed in the same laboratory of the University Hospital of Toulouse. Blood samples were obtained simultaneously with the CL CR measurement. A modified kinetic Jaffe colorimetric method was used with a COBAS MIRA (ABX Diagnostics, Montpellier, France) analyzer. A two-point calibration was applied in each assay.
Before measurement, ultrafiltration of plasma through a 20 kD cutoff membrane (MPS-1; Amicon, Beverly, MA, USA) was performed to discard chromogens that were linked to albumin-like bilirubinemia and other heavy proteins. In the absence of an international standard for creatinine assay, the linearity of the measurements was verified by using plasma samples from normal subjects in which increasing amounts of desiccated creatinine hydrochloride (MW 149.6; Sigma Chemicals, Perth, Australia) had been added. Linear regression analysis showed that the relationship between measured and expected creatinine concentrations was 1.0008 ± 0.006 (95% confidence interval, 0.997 to 1.020) and that the Y-intercept was 0.014 ± 0.013 (95% confidence interval, -0.013 to 0.041). Squared Spearman rank coefficient of correlation was 0.998. Internal quality controls showed a coefficient of variation of 2.3% during the period.

Results
Demographic and renal data are shown in Table 1. Two hundred, eighty-four patients were consecutively included in this observational study. The process of screening and inclusion in the study is shown in Figure 1 (flow chart).
The overall results show that serum creatinine was normal (73 ± 22 μmol L -1 ) and serum urea (8 ± 4 mmol L -1 ) was slightly higher than the normal limits, but with no difference between groups. One hundred, six patients had a CL CR above 120 mL minute -1 1.73 m -2 , including 79 PT and 27 NPT (P < 0.0001). Only 63 patients had a CL CR below 60 mL minute -1 1.73 m -2 with 15 PT and 48 NPT (P < 0.0001), whereas nine patients had a CL CR below 30 mL minute -1 1.73 m -2 , including two PT.
Most patients with increased CL CR (above 120 mL minute -1 1.73 m -2 ) were PT patients as shown in Table  2. On the opposite, most patients with decreased CL CR (below 60 mL minute -1 1.73 m -2 ) were NPT patients.
Patients with CL CR greater than 120 mL minute -1 1.73 m -2 were younger (40 ± 16 years vs 56 ± 18 years), had a lower SAPS II score (43 ± 14 vs 50 ± 15) and a higher male ratio as compared with patients presenting a CL CR lower than 120 mL minute. All factors presenting a statistical difference between hyperfiltration and hypofiltration subgroups ( Table 2) were analyzed. Through a logistic regression analysis, including goodness of fit of the model, age and trauma were the only factors independently correlated to CL CR (Table 3).

Discussion
The present results comparing a population of hemodynamic stable PT patients to a population of hemodynamic stable NPT patients with steady state serum creatinine concentration with a normal creatinine serum value demonstrate that (i) PT patients exhibit dramatic variations of their CrCl; (ii) CrCl is higher in PT patients than in NPT patients; (iii) Age and trauma are independently correlated factors to CL CR in our study and in these study conditions.
Considering serum creatinine values, no significant difference was found between PT and NPT groups despite the variations of CrCl. These data demonstrated that a wide range of measured CL CR variations exists and, therefore, confirm Hoste data obtained in critically ill patients with serum creatinine within normal range [16]. These authors demonstrated that "serum creatinine has a low sensitivity for detection of renal dysfunction". Our results also revealed some opposite trends between CrCl and creatinine measurements, as some patients had significantly lower values of serum creatinine for CL CR > 60 mL minute -1 1.73 m -2 than for CL CR < 60 mL minute -1 1.73 m -2 . These data underline the inaccuracy of serum creatinine values in estimating the renal function.
Fifty-five percent of PT patients, and only 19% of NPT patients presented a measured CL CR above 120 mL minute -1 1.73 m -2 . In addition, only 10% of PT patients vs 34% of NPT patients presented a measured CL CR below 60 mL minute -1 1.73 m -2 . In clinical practice, the diagnosis of increased CL CR as a surrogate marker of GFR is important and has largely been demonstrated in burn patients in the setting of antibiotics monitoring: ceftazidime, cefepime, vancomycin and amikacin [4,5,17,18]. In critically ill patients, high CL CR required high doses of drugs, which are eliminated by the kidneys to obtain therapeutic concentration. Recently we confirmed the need for CL CR monitoring in order to accurately monitor renal function and, therefore, to optimize the doses of antibiotics [4,19].
Our results demonstrate that age, gender, ideal body weight, severity index, trauma patients, and serum creatinine are factors for a CL CR above normal (> 120 mL minute -1 1.73 m -2 ), and for a moderate renal impairment (CL CR < 60 mL minute -1 1.73 m -2 ). Through a logistic regression analysis, only two factors (age and trauma patients) remained significantly correlated with a CL CR above normal and for a moderate renal impairment. In the current results, 12% of elderly patients (over 65 years) have a CL CR greater than 120 mL minute -1 1.73 m -2 . The impact of age on CL CR is well known and this parameter was, therefore, introduced in the formulas estimating CL CR (Cockcroft-Gault, Robert and simplified MDRD) [13][14][15]. The decrease in glomerular filtration, the involution of nephronic units and the reduction of the renal blood flow explain the high frequency of renal impairement in elderly patients. However, it should be kept in mind that glomerular ageing is correlated to age in only two-thirds of the patients, and this phenomenon accounts for the inaccuracy of the CL CR estimated by calculated formulae [20].
Current evidence suggests that PT (mainly, young patients without significant comorbidities) present with a CL CR increase. However, this phenomenon as received little attention in the literature, and dose modification are therefore rarely considered. The present results clearly demonstrate for the first time that trauma is a major factor for CL CR increase. Several factors may explain this increase in CL CR in PT patients. First, urinary creatinine excretion may be involved in such a phenomenon. A higher creatinine urinary excretion was observed in PT compared with NPT patients whereas serum creatinine was similar in both groups. However, the higher creatinine urinary excretion observed in PT patients was within a normal range. Serum protein variations may impact our results. However, all the patients had a serum protein value between 50 and 55 gL -1 . It is, therefore, very unlikely that serum protein variations interfere with the present results. Also, regarding hemodynamics, CL CR were studied and measured at a steady state in both groups (that is, distant from the admittance). It should be noted that our patients were hemodynamically stable at the time of data collection with no sign of dehydration. Although interference due to some cephalosporin has been described when the creatininemia was measured by using the Jaffe method [21]; no changes in this parameter were observed during the overall period of the study. Sepsis can also reduce creatinine production as described in mice [22]. Moreover, in critically-ill patients, a positive All data are expressed as ratio or mean ± SD. *The P-values correspond to comparison between subgroup with CL CR greater than 120 mL minute -1 1.73 m -2 versus subgroup with CL CR lower than 120 mL minute -1 1.73 m -2 .

#
The P-values correspond to comparaison between subgroup with CL CR greater than 60 mL minute -1 1.73 m -2 versus subgroup with CL CR lower than 60 mL minute -1 1.73 m -2 . §The P-values correspond to comparison between less than 60 mL minute -1 1.73 m -2 more than 120 mL minute -1 1.73 m -2 . a NPT = non-polytrauma patients. b PT = polytrauma patients. fluid balance may lead to underestimation of the severity of AKI and delay the recognition of a 50% relative increase in sCr [23]. Finally, it should be hypothesized that humoral and inflammatory mechanisms encountered after severe trauma [24] or burn [1] are involved in the observed CL CR increase. The present study encountered some limitations. Increased CL CR is related with enhanced renal elimination of circulating drugs. However, describing this phenomenon in terms of current available measures of the GFR at the bedside is still debated. In our study, the GFR was estimated by measured creatinine clearance on a 24hour urine collection. However, the gold standard for GFR assessment is the measure of inuline clearance [25] but the cost and complexity of this tool limits its application in routine. Another limitation is the lack of consensus regarding the upper limit of normal GFR. However, increasing data support the concept of increased GFR in PT patients, and several reports demonstrated subtherapeutic concentrations of drugs in PT patients [5,26]. Also, a cross-sectional single 24-hr measure of CL CR at 10 days in relatively stable patients was performed but fast modifications of kidney function may occur and there is a need for a continuous re-evaluation. Finally, some other factors may influence our results. In particular, fluid status, cardiac output may be significantly altered from baseline. However, whatever the causes of these alterations, the ATLS (Advanced Trauma Life support) principles are applied in our institution regarding resuscitation of PT patients. We, therefore, believe that the current results are broadly representative of the population of PT patients. It could be argued that the external validity of this single-center study may be limited. However, our findings may be relevant to the vast majority of level I trauma centers, provided that ATLS principles are applied in these institutions.

Conclusions
In hemodynamic ICU stable patients with steady state serum creatinine concentration, CL CR , which is a surrogate marker of GFR, is higher in polytrauma patients than in other critically ill patients. In ICU patients, the drug monitoring must take into account the glomerular filtration rate. The measure of CL CR should be routinely proposed for PT patients in order to adjust dose regimen, especially for drugs with renal elimination (betalactams, ceftazidime, cefepime, piperacillin, vancomycin, aminoglycosides, and so on).

Key messages
• In ICU patients with normal serum creatinine, CL CR , is higher in trauma than in non-trauma patients.
• The measure of CL CR should be proposed in routine for ICU patients in order to adjust dose regimen, especially for drugs with renal elimination.
• Age and trauma were the only factors independently correlated to CL CR .
• Glomerular filtration rate should be measured in ICU patient to detect renal filtration abnormalities.
• Serum creatinine is not a good marker for renal function estimation.