Dosing of drugs in the critically ill can be challenging due to multiple factors such as changes in organ function, multiple comorbidities and other clinical interventions which can change the pharmacokinetics of a drug significantly. While most clinicians are vigilant to dose reduce drugs when there is impaired organ function (e.g. acute kidney injury), less consideration is given to the opposite end of the spectrum – that is, augmented renal clearance (ARC).
What is ARC and how does it happen?
ARC is a state of increased kidney function that results in accelerated clearance of drugs. If no dosage adjustments occur, this may lead to sub-therapeutic levels of medications and subsequent therapy failure. Though there are no standardised cut off points for ARC, generally, it is defined as an increased creatinine clearance (CrCl) of greater than 130mL/min/1.73m2.
Although specific literature on ARC remains sparse, ARC has been documented in patients with sepsis, ventilator-associated pneumonia, traumatic brain injury, burns, multi-trauma and post-operatively. The incidence of ARC in the general ICU population is approximately 56% but has been reported to range from 30% in patients after abdominal surgery, to as high as 100% of patients with subarachnoid haemorrhage.
The pathophysiology behind ARC is complicated, and its onset tends to coincide with an acute insult to the body. Simplified, ARC is a hyperdynamic state of renal clearance in which changes to vascular permeability and increased blood flow secondary to elevated body temperature and cardiac output lead to an increase in kidney perfusion and subsequent increases in CrCl. However, there are a number of other factors which are thought to also contribute to ARC including insult to the brain (which may affect cerebral autoregulation of blood pressure, for example) and changes in nephron physiology (e.g. renal tubular reabsorption). Additionally, clinical interventions such as fluid resuscitation and the use of vasoactive drugs further augment this process.
In general, patients exhibiting ARC tend to be younger (<50 years old), of male gender, have a recent history of trauma, and have lower critical illness severity scores e.g. APACHE II (acute physiology and chronic health evaluation) score or SOFA (sequential organ failure assessment) score. However, young age appears to be the only risk factor that consistently predicts ARC.
Two main methods of identifying patients at risk of ARC have been suggested. The first method is the ARC scoring system which was developed by Udy et al. This method scores a patient based on the risk factors of age, presence of trauma, and SOFA score. The second method to identify ARC was developed by Barletta et al. which eliminated the need to complete a SOFA score. This was called the ARCTIC (augmented renal clearance in trauma intensive care) scoring system. While the ARC scoring system demonstrated greater sensitivity and specificity than the ARCTIC scoring system, the ARCTIC scoring system allows for earlier recognition of ARC in the ICU setting. The scoring systems are shown in Table 1.
Table 1. Comparison of ARC scoring systems
|ARC Scoring System||ARCTIC Scoring System|
|Age < 50 years
SOFA score < 4
Age <56 years
Age: 56-75 years
|Interpretation||0-6 points = low ARC risk
7-10 points = high ARC risk
|<6 points = low ARC risk
>6 points = high ARC risk
SCr = serum creatinine concentration; SOFA = sequential organ failure assessment score
Identification of ARC
When it comes to actually identifying whether a patient has ARC, calculating a patient’s glomerular filtration rate (GFR) via inulin clearance is regarded as the gold standard. However, routine monitoring using this method is labour intensive and often not practical. When various mathematical estimates were compared (e.g. Cockcroft Gault equation, the modification of diet in renal diseases formulae, and the chronic kidney disease-epidemiology equation), the Cockcroft Gault equation appeared to be the best method to estimate creatinine clearance in the ARC population.
Duration of ARC
The duration of ARC varies significantly, with some patients exhibiting transient ARC lasting for less than 24 hours, whilst other studies have reported ARC lasting for weeks. As such, continuous monitoring of a patient’s renal function is warranted to appropriately dose-modify renally cleared drugs.
Management and Drug dosing in ARC
In renally cleared drugs, the presence of ARC can lead to enhanced drug clearance – that is, a shorter drug half-life (t½), lower maximum drug concentration (Cmax), and lower area under the concentration curve (AUC). This makes dosing of drugs in ARC challenging, especially for those drugs which do not have measurable endpoints, e.g. antimicrobials. Low levels of antimicrobials can be difficult to detect, as you cannot immediately measure patient response as you might for other drugs, such as sedatives. However, therapy failure with an antimicrobial, especially in settings such as septic shock, can have significant effects on morbidity and mortality. A study which looked at antimicrobial use in patients with ARC found that there was a significant increase in the rate of antibiotic therapeutic failure in patients with ARC (27.3% vs 12.9%), with four patients in the ARC arm developing antibiotic resistance, as opposed to just one patient in the non-ARC group.
For patients with confirmed ARC, dose adjustments should be considered for all renally cleared medications. However, dosing of drugs in ARC is complicated, as drug monographs do not acknowledge the need for alterations to drug dosing regimens in ARC, and there is scant literature on the adjustment of drug dosages in the ARC population. Where possible, therapeutic drug monitoring (TDM) should be utilised to adjust dosages. For medications where TDM is not available, the use of the highest approved dose or most frequent administration could be considered with close clinical monitoring. For example, a suggested dosing for meropenem in an adult with ARC is 2g IV eight-hourly. Changing to alternative medications which are not renally cleared should also always be considered.
The following algorithm has been proposed as a guide for clinicians in managing patients presenting with ARC:
- Find out if 8 to 24-hour urinary measurement of creatinine clearance is readily available
- If yes, does the patient have ARC? If so, go to step 5.
- If no, consider risk factors and the need for measured creatinine clearance
- Assess if the patient has risk factors associated with ARC
- Younger age (<50 years old)?
- Male gender?
- Reason for admission (e.g. traumatic brain injury, subarachnoid haemorrhage, severe infection or sepsis)
- Hemodynamically stable?
- No history of impaired renal function?
- Serum creatinine within normal reference range?
- Is the patient at high ARC risk as per the ARC scoring system?
- Obtain 8 to 24 hour measured creatinine clearance
- Is the patient on renally eliminated medications affected by ARC?
- Is there delayed or insufficient clinical response?
- Do surrogate markers of disease indicate delayed or insufficient clinical response?
- Increase drug dosing or shorten administration regimen
- Consider therapeutic drug monitoring (TDM)
- Consider highest recommended dose or shortest administration regimen
- Consider alternative medications which are not eliminated renally
- Reassess for risk or presence of ARC daily
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- Claus BO, Hoste EA, Colpaert K, Robays H, Decruyenaere J, De Waele JJ. Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy. J Crit Care. 2013; 28(5):695-700. Doi10.1016/j.jcrc.2013.03.003.
- Mahmoud SH, Shen C. Augmented renal clearance in critical illness: an important consideration in drug dosing. Pharmaceutics. 2017; 9(3): 36.
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- Udy AA, Roberts JA, Shorr AF, Boots RJ, Lipman J. Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients. Critical Care. 2013, 17(1): R35.