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Augmented Creatinine Clearance in Traumatic Brain Injury

Udy, Andrew BHB, MB ChB, PG Cert(AME), FCICM*,†; Boots, Robert MBBS, PhD, MMedSci, MHAIS, FRACP, FCICM*,†; Senthuran, Siva MBBS, BSc, FRCA, FCICM*,†; Stuart, Janine RN; Deans, Renae RN; Lassig-Smith, Melissa RN; Lipman, Jeffrey MBBCh, DA, FFA, FFA(Crit Care), FCICM, MD*,†

doi: 10.1213/ANE.0b013e3181f7107d
Neuroscience in Anesthesiology and Perioperative Medicine: Research Reports

BACKGROUND: Hypertonic saline and/or norepinephrine infusion are routinely used to achieve a desired cerebral perfusion pressure (CPP) in the management of traumatic brain injury (TBI). We hypothesized that creatinine clearances (CrCls) would be significantly augmented in this setting.

METHODS: This was an observational cohort study in TBI patients older than 16 years with normal serum creatinine concentrations, requiring maintenance of CPP. Eight-hour urinary CrCl collections were performed while on and off active management. Demographic data, use of vasoactive medications, fluid balance, feeding regimen, and hemodynamic variables were recorded throughout the study period. Augmented CrCl was defined as >150 mL/min/1.73 m2 in women and >160 mL/min/1.73 m2 in men.

RESULTS: Twenty patients were enrolled, and augmented clearances were demonstrated in 17 (85%). The mean maximum CrCl was 179 mL/min/1.73 m2 while receiving CPP therapy (95% confidence interval [CI], 159–198), returning to a mean of 111 mL/min/1.73 m2 (95% CI, 91–131; P < 0.001) when measured after discharge from the intensive care unit. The mean CrCl in the intensive care unit while not receiving CPP therapy was 150 mL/min/1.73 m2 (95% CI, 134–167; P = 0.03). The mean time to reach peak CrCl while receiving active treatment was 4.7 days (95% CI, 3.0–6.4). In a multivariate analysis, norepinephrine use, saline loading, mean arterial blood pressure, and central venous pressure were associated with augmented CrCl on the day of measurement.

CONCLUSIONS: Augmented CrCls are common in TBI patients receiving active management of CPP and persist even after discontinuation of such therapy. Further work is needed to clarify the impact of such clearances on renally excreted drugs in this setting.

Published ahead of print November 3, 2010 Supplemental Digital Content is available in the text.

From the *Burns, Trauma and Critical Care Research Centre, University of Queensland; and Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.

Study funding information is provided at the end of the article.

Address correspondence and reprint requests to Robert Boots, MBBS, PhD, MMedSci, MHAIS, FRACP, FCICM, Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Herston Rd., Herston, Queensland 4029, Australia. Address e-mail to

Accepted July 30, 2010

Published ahead of print November 3, 2010

Renal function is often assumed to be normal or reduced in the critically ill, and although inaccurate,1 serum creatinine concentrations are routinely used as an index of glomerular filtration in this setting. An increased serum creatinine concentration is interpreted as representing renal impairment and often triggers dose reduction for drugs that are renally eliminated. However, an increased glomerular filtration rate (GFR) arising as a consequence of the underlying disease or its treatment2 is rarely considered because of the insensitivity of serum creatinine to changes in GFR. As such, appropriate increases in drug dosing are rarely initiated.3

In the setting of traumatic brain injury (TBI), cytokine release from acute cerebral injury,4 the innate immune and inflammatory response to trauma,5 and aggressive fluid resuscitation may promote increased organ blood flow and enhanced excretory function. Despite its limitations, timed urinary creatinine clearance (CrCl) remains the most accurate and convenient method of evaluating GFR in the critically ill, and using this method, increased clearances have been demonstrated in burn patients,6,7 sepsis,8 after surgery,9 and on admission to the intensive care unit (ICU).10 In relation to TBI, previous studies have demonstrated high CrCls in patients receiving vasoactive medications,11,12 although this work did not control for confounders (such as the administration of mannitol13), that may influence GFR. Furthermore, there has been no previous report on the renal effects of hypertonic saline in this setting.

The present study was designed to investigate CrCls in a cohort of TBI patients receiving active therapy to maintain a cerebral perfusion pressure (CPP) of 60 mm Hg. Patients were excluded a priori if they had any antecedent cause for an altered GFR. The aim was to document the incidence and time course of augmented CrCls in this population.

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Our institution operates a 30-bed tertiary-level ICU that acts as a major referral center for neurosurgical trauma. Specialist intensive care physicians are supported by an active neurosurgical service, with expertise in intracranial pressure (ICP) monitoring and management of severe TBI. From January 2006 to May 2008, all admissions to the ICU were screened daily for TBI patients older than 16 years requiring hyperosmolar therapy using infusions of 3% saline or boluses of 20% saline (to maintain a serum sodium concentration between 145 and 155 mmol/L) and/or norepinephrine infusion for the maintenance of a CPP >60 mm Hg. Subjects were enrolled consecutively regardless of their need for neurosurgical intervention. The study protocol was approved by the institutional ethics committee and informed consent was obtained from the patient or their next of kin where appropriate. The funding source had no role in protocol development, patient recruitment, study analysis, interpretation, or the decision to submit for publication.

We excluded patients who were likely to have any antecedent cause for an altered GFR, such as pregnancy, preexisting renal disease or nephrectomy, serum urea or creatinine concentration outside the reference range, mannitol or radiographic contrast use 24 hours before commencing CrCl collection, current corticosteroid use, hyperthyroidism, cachexia (body mass index <18 kg/m2), crush injury, abnormal urine dipstick, patients not expected to survive >24 hours, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, positive findings on an abdomen computed tomography scan, laparotomy, or a retroperitoneal hematoma, intraabdominal hypertension, and amphotericin or other potential nephrotoxin administration during admission. The cohort thus consisted predominantly of young patients with isolated head injury.

Additional management was consistent with local practice and in line with the recommendations of the Brain Trauma Foundation.14 An increase in ICP to >20 mm Hg or a decrease in CPP <60 mm Hg for >10 minutes was managed in a stepwise manner as outlined in Table 1. ICP was monitored by means of a Codman™ intraparenchymal monitor (Codman & Shurtleff, Inc., Raynham, MA) (n = 13) or an external ventricular drain (n = 7). CPP was calculated as the difference between the mean arterial blood pressure and ICP (MAP − ICP).

Table 1

Table 1

All patients had an indwelling urinary catheter. Once-daily 8-hour CrCl collection (collected between midnight and 0800 hours) was commenced after active management of increased ICP was initiated. Creatinine estimation in urine and blood was determined by our central laboratory using a modified Jaffe assay, and CrCl results were corrected to a body surface area of 1.73 m2. Daily collections were ceased once active management of CPP was discontinued. A further measure (midnight to 0800 hours) was collected just before discharge from the ICU (off CPP therapy). If this value was still outside of the reference range, a further measure was obtained during ward-based care. During the ICU stay, note was made of daily fluid therapy, the need for and total daily dose of norepinephrine, ventilation strategy, arterial blood gases, and daily feeding regime. For the purpose of the study, augmented clearances were defined as a CrCl 10% more than the upper limits of normal (>160 mL/min/1.73 m2 for males and >150 mL/min/1.73 m2 for females).15

Based on previous work by Baumann et al.,16 a sample size of 12 patients was estimated to provide a power of 80% (α error 0.05) to demonstrate a 50% change in CrCl (i.e., an increase from 120 to 180 mL/min/1.73 m2 in a young male patient). This was considered the minimally significant difference to potentially impact drug clearance. We used the STATA 9™ software package (StataCorp LP, College Station, TX) to analyze the data. For principal analysis of the entire cohort, paired t tests (continuous data) and McNemar tests (categorical data) were used. Differences in subgroups were assessed using Kruskal-Wallis (continuous) and Fisher exact tests (categorical) for non-normally distributed data. The predictors of CrCl were examined using forward stepwise multiple analysis of covariance of repeated measures. A double-sided P value <0.05 was considered statistically significant.

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Thirty-six consecutive head-injured patients requiring active management of CPP were screened for enrollment during the study period. Twenty patients meeting the inclusion and exclusion criteria were subsequently included, and their baseline demographic data are presented in Table 2. Three patients died in the ICU while receiving CPP-based therapy and did not complete the study protocol. One patient did not complete a CrCl while “off CPP” therapy in the ICU, although a collection was obtained in the ward. Three patients failed to complete ward collections, 1 because the off-CPP measure was in the normal range, and 2 others because of early hospital discharge.

Table 2

Table 2

The average time spent in the ICU was 15 days (95% confidence interval [CI], 11–18) with a hospitalization of 38 days (95% CI, 21–54). The time to study entry averaged 2.3 days (95% CI, 1.7–2.8) and patients received on average 7.6 days of therapy for increased ICP (95% CI, 5.6–9.5). All patients received norepinephrine by infusion for management of CPP, and hypertonic saline was used in addition in 85% of patients (n = 17). Tables 3 and 4 summarize the CrCl results during active therapy and during ward care. Augmented CrCls were demonstrated in 17 patients (85%) during active management of CPP, although CrCl values varied daily. The mean maximum CrCl was 179 mL/min/1.73 m2 while receiving CPP therapy (95% CI, 159–198), returning to a mean CrCl of 111 mL/min/1.73 m2 (95% CI, 91–131; P < 0.001) when measured in the ward.

Table 3

Table 3

Table 4

Table 4

Comparison was made between those with extracranial trauma (n = 5) and the remainder of the cohort (n = 15) in terms of MAP (median 86 vs 88 mm Hg, P = 0.52), norepinephrine use (80% vs 73.3%, P = 1.00), CrCl (median 152 vs 133 mL/min/1.73 m2, P = 0.52), fluid balance (median 308 vs 458 mL, P = 0.82), central venous pressure (median 11 vs 11 mm Hg, P = 0.76) and ICP (median 15 vs 16 mm Hg, P = 0.93) during the first 24 hours of the study. There were no statistically significant differences identified in this subgroup.

The mean CrCl in the ICU while not receiving CPP maintenance therapy was 150 mL/min/1.73 m2 (95% CI, 134–167; P = 0.03). The mean difference between the peak and minimum CrCl while receiving active treatment was 66 mL/min/1.73 m2 (95% CI, 43–89) and the mean time to reach peak CrCl while receiving active treatment was 4.7 days (95% CI, 3.0–6.4). While receiving active therapy, the mean serum creatinine concentration when the CrCl was maximal was 57 μmol/L (95% CI, 50–64) as compared with 73 μmol/L (95% CI, 63–83; P = 0.02) at the time of the lowest CrCl. The mean serum creatinine during nonactive treatment was 68 μmol/L (95% CI, 62–74; P = 0.02) and during ward care was 65 μmol/L (95% CI, 58–72; P = 0.09).

Using a stepwise multiple analysis of covariance model, augmented CrCl was associated with MAP (Wilks Λ, 0.93; P = 0.0002), central venous pressure (Wilks Λ, 0.97; P = 0.02), amount of sodium infused as 0.9% saline (Wilks Λ, 0.91; P < 0.0001), amount of sodium infused as 3% saline (Wilks Λ, 0.98; P = 0.04), and use of norepinephrine (Wilks Λ, 0.97; P = 0.01) on the day of measurement (F = 9.33, P < 0.0001). Despite that protein intake (Wilks Λ, 0.97; P = 0.03) and ICP (Wilks Λ, 0.96; P = 0.008) were predictive of CrCl in univariate modeling, they were not independent predictors in the multivariate model. No relationship could be found between CrCl and 24-hour caloric intake (P = 0.21), positive end-expiratory pressure (P = 0.73), or 24-hour fluid balance (P = 0.26).

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Augmented renal elimination of circulating solute is being increasingly described in subsets of critically ill patients.2 This phenomenon is likely to manifest as a consequence of the underlying disease process or the therapeutic interventions provided, resulting in augmented renal blood flow (RBF) and GFR in this setting. As such, our study is the first to demonstrate that during active management of CPP (using hypertonic saline and norepinephrine infusion), markedly augmented CrCls are common. In addition, even after ceasing CPP therapy in the ICU, these patients continued to manifest higher clearances than those recorded in the ward (mean CrCl off CPP = 150 mL/min/1.73 m2 vs 111 mL/min/1.73 m2 in the ward).

The implication of these findings is important, and prescribers should be cognizant of the potential influence on drug clearance in this population. For example, using the maximum CrCls recorded in our study, and a previously published pharmacokinetic model of vancomycin administration in the ICU,17 doses as high as 6000 mg per day would be required to achieve the desired pharmacokinetic targets for a fully susceptible strain of Staphylococcus aureus. As such, although specific changes in drug prescription cannot be recommended, TBI may be one patient group in whom therapeutic drug monitoring should be considered early, to optimize drug exposure.

Accurate assessment of renal function in the critically ill is a complex task, and usually focuses on identifying renal dysfunction, particularly in the setting of an elevated serum creatinine concentration and oliguria. However, our study reinforces the hypothesis that apparently “normal” serum creatinine concentrations may be associated with supranormal filtration rates, particularly in young patients, without preexisting comorbidity. Furthermore, CrCls can vary considerably in the same patient over time, and because “normal” serum creatinine concentrations are largely insensitive, an estimate of GFR should be considered regularly by the clinician in this setting.

Brown et al.9 investigated CrCls in a cohort of critically ill postoperative patients, and in the subgroup with trauma, illustrated a marked increase between day 2 and 7 postoperatively. A peak of 190 mL/min/1.73 m2 was recorded on the fourth postoperative day,9 which compares favorably to our study. Recently, Fuster-Lluch et al.10 have reported an incidence of “glomerular hyperfiltration” (defined as a CrCl >120 mL/min/1.73 m2) of 17.9% on the first morning of admission to the ICU. Specifically, the cohort identified with augmented clearances were primarily either postoperative or multitrauma patients, who were younger, with lower acute physiology and chronic health evaluation (APACHE) II scores, higher diastolic blood pressures, and higher urine outputs.10

Albanese et al.11 investigated the effects of IV norepinephrine in 12 patients with isolated head injury compared with a separate cohort with septic shock. Although this trial was not designed specifically to examine clearances in the head-injured population, as observed by Vincent et al.,18 mean CrCls before the institution of norepinephrine therapy were already increased (165 mL/min/1.73 m2) and remained so over the 24 hours of infusion (150 mL/min/1.73 m2). Importantly, this study did not control for factors known to influence GFR, only examined the effects of norepinephrine over a single 24-hour period, and there were no control values obtained from outside of the ICU environment.11

Benmalek et al.12 reported similar results in 20 head-injured patients in a study in which low-dose dopamine was added to norepinephrine to maintain CPP. Although the focus of this study was on the renal effects of dopamine infusion, mean CrCl values were still increased (>150 mL/min/1.73 m2) with either norepinephrine alone or the combination of agents. No measures off vasoactive medications were obtained.12 Our study significantly extends this prior work, in that multiple measures were obtained while patients received active management of CPP, and patients were selected so as to limit potential confounders.

The mechanisms underpinning this phenomenon in this population deserve consideration. A major determinant of glomerular filtration is RBF, which is in turn a function of cardiac output (CO). As such, an increase in CO has been correlated with an increase in CrCl,9 despite significant autoregulation over a range of perfusion pressures.19 Animal data have confirmed that this can occur in the setting of experimental sepsis,20 although we did not measure CO in our study group. The impact of norepinephrine on RBF is also not clearly established. Although experimental animal data demonstrate that norepinephrine acts to increase RBF,21,22 Albanese et al.11 were unable to demonstrate any significant increase in CrCl with the addition of this agent. Similarly, we have documented elevated clearances both on and off active CPP therapy, although we did identify norepinephrine use as being independently associated with augmented CrCl in a multivariate model.

The effects of equimolar infusions of 0.9% and 3% saline have also been studied in an animal model by Wan et al.23 Although they clearly augmented systemic hemodynamics, neither infusion affected RBF or renal conductance despite a significant increase in urine output and CrCl. The authors conclude that the dilutional effect of the administered fluid on plasma protein concentration is likely to have reduced plasma oncotic pressure, promoting enhanced glomerular filtration.23 In our analysis, the administration of both 0.9% and 3% saline was associated with augmented CrCl on the day of measurement, suggesting that a similar mechanism may be contributory in this setting.

Previous investigators have also demonstrated that the GFR increases after the ingestion of a protein meal24 or infusion of amino acids.25 This ability of the kidneys to respond to an increased protein load has been termed the “renal reserve,”26 and implies that the human kidney is not working at full capacity under basal conditions. In our cohort, there was no difference in protein intake between maximum and minimum recorded CrCls while receiving active therapy (Table 4), nor was this variable predictive of CrCl in the multivariate model. Finally, brain injury itself may be a significant contributor to this process and could explain why clearances remained significantly increased even off CPP-guided therapy. Although our data suggest an important effect of vasopressor infusion and saline loading on CrCls, further detailed work is needed to separate these effects from the expected changes in hemodynamic variables. As such, we cannot clearly specify an effect of CPP therapy alone, although this was not the primary aim of our study.

In this study, we used 8-hour urine collections for CrCl with a serum creatinine concentration obtained in the middle of this period. Such determinations have been found to be within 20% of a 24-hour collection and suitable for clinical practice.16 An 8-hour collection was also a more suitable time period for the effects of CPP management and improved the likelihood of a complete collection. Although measured urinary CrCl remains the most widely used and pragmatic clinical surrogate for GFR, it must be recognized that it will tend to overestimate the true value, particularly at lower filtration rates.27 In this respect, although the limitations of using CrCl must be acknowledged, its use is underscored by a significant body of literature correlating CrCl with renal drug elimination,2 particularly in a trauma setting.28

Our study was limited to a cohort of young patients with normal renal function and as such should be extrapolated with care to other patient populations. Significantly, some of the cohort (n = 5) had extracranial injuries, the treatment of which may have also promoted enhanced clearances,9 although we were unable to identify any significant differences in hemodynamic variables during the first 24 hours of the study between this subgroup, and the remainder of the study patients. In addition, sepsis may have complicated the course of some patients, although this was not considered in the analysis. Our definition of augmented CrCl is also new to the literature, but because prior categorization systems of “hyperfiltration” have not been validated,29 a conservative definition was generated to describe truly elevated clearances in this setting. In addition, the term “glomerular hyperfiltration” is more specific to nephrology, and may not represent the process occurring in the critically ill.

In conclusion, we have demonstrated a frequent incidence (85%) of augmented CrCl in a select group of young head-injured patients needing active maintenance of CPP. This has potentially important ramifications for renally excreted drugs, and may mean that standard dosing regimes are inadequate. These data should alert the clinician to this possibility, with a view to implementing therapeutic drug monitoring if subtherapeutic dosing is considered. Further research is urgently needed to better understand this phenomenon, in addition to the impact on dosing schedules.

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Supported by a special purpose grant awarded to Dr. Siva Senthuran from the Royal Brisbane and Women's Hospital Research Foundation. Dr. Andrew Udy was supported by a Clinical Research Skills Development grant from Queensland Health. The funding source had no role in protocol development, patient recruitment, study analysis, interpretation, or the decision to submit for publication. Professor Lipman is a consultant to AstraZeneca and Janssen-Cilag, and has received an honoraria from AstraZeneca, Janssen-Cilag, and Wyeth Australia. AstraZeneca provides an annual donation to the Burns, Trauma and Critical Care Research Center, University of Queensland.

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AU helped analyze the data and write the manuscript, and is the author responsible for archiving the study files. RB and JL helped design the study, analyze the data, and write the manuscript. SS helped design and conduct the study and write the manuscript. JS, RD, and MLS helped conduct the study. All the authors have seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

© 2010 International Anesthesia Research Society