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).
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.
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