Submit manuscript...
Journal of
eISSN: 2373-6437

Anesthesia & Critical Care: Open Access

Mini Review Volume 13 Issue 1

Augmented renal clearance in the intensive care units: concepts to considerate in drug dosing

Luisa M. Charco-Roca

Specialist in Anesthesiology and Intensive Care, University Hospital of Albacete, Spain

Correspondence: Luisa M. Charco-Roca, Specialist in Anesthesiology and Intensive Care, University Hospital of Albacete, Anesthesiology and Intensive Care Section, C/ Hermanos Falcó s/n. 02008 Albacete, Spain, Tel + 34 636667599

Received: January 21, 2021 | Published: January 29, 2021

Citation: Charco-Roca LM. Augmented renal clearance in the intensive care units: concepts to considerate in drug dosing. J Anesth Crit Care Open Access. 2021;13(1):1‒3. DOI: 10.15406/jaccoa.2021.13.00461

Download PDF

Abstract

Augmented renal clearance (ARC) is a manifestation of renal function that can be seen in patients admitted to the Intensive Care Unit. Its exact prevalence is unknown and it is detected by way of an urinary measurement of creatine. ARC is defined as a creatinine clearance greater than 130 ml / min / 1.72 m2. Pathological mechanisms are not clearly defined and are probably multifactorial. For patients with confirmed ARC, dosing modifications of all renally purified medicinal products should be taken into account. The use of conventional doses can lead to the failure of the therapy with worse results for the patient and a higher economic cost for the healthcare system. Future research will determine dosages in ARC cases and the use of drug plasma concentration measurements will help us to individualize treatments.

Keywords: augmented renal clearance; critically; enhanced kidney function; intensive care

Introduction

Renal function has a very important influence on the pharmacokinetics of many drugs used in intensive care units (ICU). Dose adjustment of renal elimination drugs is guided by the varying degrees of glomerular function that constitute the spectrum of acute renal failure. But do we know how to administer doses of drugs for increased renal clearance (ARC)? Do we routinely measure renal function in patients with normal creatinine?

ARC has been observed in critically ill patients.1,2 It had not been studied until less than 20 years ago. Nevertheless, little attention is currently paid to this phenomenon. Either as a result of a general lack of research or solid evidence, little have questions concerning the dosage adjustment in this clinical situation been addressed. Increased renal drug clearance can have significant consequences for clinical outcomes. Therapy failures compromise the lives of critical patients (e.g. with suboptimate antimicrobial dosages). Studying the pharmacological aspects in the context of ARC should be a priority for future research. The purpose of this brief review is to provide an up-to-date summary of available evidence regarding ARC in the Intensive Care Unit (ICU). As such, a primary search was carried out on pubmed and additional bibliographical references were revised when deemed relevant.

Prevalence of arc and risk factors

Daily monitoring of renal function in the critical patient is a common practice. Therefore, identifying kidney damage or ARC is easier than in other care contexts. The ARC identification method is complicated because having access to a good glomerular function lab r marking outside the research environment is a challenge. To diagnose ARC we need an accurate determination of the glomerular filtration rate (GFR). Urinary measurement of creatinine clearance (8 to 24 h of urine collection) is the most common practice for guiding GFR outside the scope of clinical studies.3 ARC has been defined using creatinine clearance but the cut-off point varies between published studies, preventing accurate identification of prevalence in the ICU. It has been reported that the prevalence of ARC in the ICU is around 14 to 80%, so we can say that it is a common phenomenon and that its implications may be clinically relevant for drug treatments.4 In addition, within this definition there are nuances: it is not clear in the studies whether more requirements are needed than the single cut-off point of 130 ml/min/1.73m2. Perhaps considering the stability of these measurements over time and through repeated treatments might be relevant.

Furthermore, one could relate the degree and stage of ARC in parallel with the categories used to describe renal failure as mild, moderate and severe. This taxonomy may shed light on other, as of yet un considered variables in the research. The true onset and duration of ARC is unknown. Its appearance consistently coincides with acute aggression to the body either by infection, trauma or surgical intervention. We find factors that are associated with ARC such as young age (<50 years), males, with antecedent trauma and low values on the severity scales at admission such as the sequential assessment score of organic insufficiency (SOFA),6 Simplified Acute Physiology Score (SAPS) II5 or Acute Physiology and Chronic Health Assessment (APACHE II). Age is the only risk factor repeated in several epidemiological studies. In studies in the paediatric patient, febrile neutropenia was identified as an independent risk factor of ARC in this critical patient subpopulation.7

From research in ICU, interesting scales have been proposed that try to predict whether or not patients will develop ARC. The ARC scoring system.6 uses age, SOFA scales, and the presence of trauma to identify arc probability. Subsequently, based on these studies, Barletta et al. developed ARCTIC8 focused on patients admitted to ICU following severe trauma (Table 1).

 

Criteria

Interpretation

 

ARC Scoring System

Age 50 or younger x 6 sts

7–10 points: high ARC risk

Sensitivity 100%

 

Trauma s 3 sts

 

Specificity 71%

 

SOFA score ≤4 x 1 st

   

ARCTIC Scoring System

SCr< 62 μmol/L s 3 sts

>6 points: high ARC risk

Sensitivity 84%

 

Male sex s 2 sts

 

Specificity 68%

 

Age <56 years ? 4 sts

   
 

Age: 56–75 years x 3 sts

   

Table 1 ARC risk scoring systems (6.8). Abbreviations: ARC - increased renal clearance; ARCTIC - increased renal clearance in intensive trauma care (ARCTIC); SOFA, sequential evaluation score for organic insufficiency; SCr, serum creatinine concentration; pt s dot; sts dots

Pathophysiologyof ARC

ARC has been reported to affect many components of nephron physiology when studied using endogenous markers; glomerular hyperfiltration, renal tubular anion secretion and tubular reabsorption.9 A hyperdynamic response to an aggression of the body, with the effects of inflammatory mediators secreted acutely and in large quantities, are involved in the appearance of the ARC phenomenon. Some authors even proposed a hyperdynamic state model10 that would explain how from a number of factors resulting from critical disease are combined. Systemic inflammatory response syndrome (SIRS) results in an increase in inflammatory mediators that generate increased cardiac output and decreased peripheral vascular resistance. Both combine to produce a hyperdynamic state that results in increased renal blood flow, which by glomerular changes is followed by glomerular hyperfiltration that manifests itself as ARC.

Not only do these factors alone explain the physiopathology of ARC. In the ICU, patients receive aggressive fluid therapy, transfusion of blood products, vasoactive drugs... Clinical situations that contribute to increased cardiac output by generating hyperdynamic status.

Although these studies propose valid circumstances to explain pathophyology, the exact mechanism that leads to ARC remains uncertain and only by having more   evidence can we clarify why it does not manifest itself in all patients, and why it develops to varying degrees.

Pharmacokinetics and ARC

Knowledge of pharmacokinetics is of great importance when administering pharmacological guidelines. Critical patients have an altered and often very changing pharmacokinetics even in less than 24 hours of disease,11 so actively evaluating the optimal dose should be a daily task.

The clinical implications of ARC are more obviously related to conventional dose under dosing. Standard doses of medicinal products that are eliminated renally are not considered valid and only adjustments guided by plasma concentration monitoring will be as indicated.

The implications of under dosing an ICU patient can be very important for your clinical outcomes. Renally clarified drugs have a direct correlation between renal clearance and creatinine clearance. Improved drug clearance will result in shorter drug half-life, lower maximum drug concentration, and lower concentration curved area (AUC).

For example, antibiotics such as aminoglycosides, vancomycin and beta-lalactamics require dose adjustment. Also levetiracetam, widely used to treat or prevent comic seizures in patients with head trauma is eliminated by 95% renally.

In a survey of physicians questioning their attitudes towards antibiotic prescribing and renal function assessment in ICU septic patients, only 15% responded that they would consider modifying the antimicrobial dosing regimen in patients with ARC.12

To optimize our proper treatment in the critical patient it is necessary to insist on the individualization of treatments and the close monitoring of plasma concentrations, both to avoid toxicities and to ensure effectiveness.

Conclusion

ARC is a phenomenon present in the ICU and causes a significant impact on clinical outcomes and its consequence is underdosing. Knowledge of critical patient-dependent risk factors and the use of prediction tools such as proposed scales can help doctors make dose adjustment decisions and more actively monitor kidney function. More research is needed to be able to establish robust dosing adjustment recommendations in arc patients and with varying grades of ARC. Therapeutic monitoring of serum concentrations of the drug is recommended whenever available.

References

  1. Udy AA, Putt MT, Boots RJ, et al. ARC—Augmented renal clearance. Curr Pharm Biotechnol. 2011;12:2020–2029.
  2. Udy AA, Roberts, JA, Boots RJ, et al. Augmented renal clearance: Implications for antibacterial dosing in the critically ill. Clin Pharmacokinet. 2010;49:1–16.        
  3. Carlier M, Dumoulin A, Janssen A, et al. Comparison of different equations to assess glomerular filtration in critically ill patients. Intensive Care Med. 2015;41:427–435.  
  4. Mahmoud SH, Shen C. Augmented Renal Clearance in Critical Illness: An Important Consideration in Drug Dosing. Pharmaceutics. 2017;9:36;doi:10.3390.
  5. Minville, V, Asehnoune K, Ruiz S, et al. Increased creatinine clearance in polytrauma patients with normal serum creatinine: A retrospective observational study. Crit Care (Lond. Engl.) 2011;15:R49.    
  6. Udy AA, Roberts JA, Shorr AF, et al. Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: Identifying at-risk patients. Crit Care (Lond. Engl.) 2013;17:R35.          
  7. Hirai K, Ihara S, Kinae A, et al. Augmented renal clearance in pediatric patients with febrile neutropenia associated with vancomycin clearance. Ther Drug Monit. 2016;38:393–397.
  8. Barletta JF, Mangram AJ, Byrne M, et al. Identifying augmented renal clearance in trauma patients: Validation of the augmented renal clearance in trauma intensive care (arctic) scoring system. J. Trauma Acute Care Surg. 2017;82:665–671.
  9. Udy AA, Jarrett P, Stuart J, Lassig Smith, et al. Determining the mechanisms underlying augmented renal drug clearance in the critically ill: Use of exogenous marker compounds. Cri Care. 2014;18:657.         
  10. Sime FB, Udy AA, Roberts JA. Augmented renal clearance in critically ill patients: Etiology, definition and implications for beta-lactam dose optimization. Curr Opin Pharmacol. 2015;24:1–6.
  11. Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current β- lactam antibiotic doses sufficient for critically ill patients? Clin  Infect Dis. 2019;58(8):1072–1083.
  12. Dunnin, J, Robert, J. Assessment of renal function in dosing antibiotics in septic patients: A survey of current practice within critical care units in England. Anaesthesia. 2015;70;21.
Creative Commons Attribution License

©2021 Charco-Roca. This is an open access article distributed under the terms of the, which permits unrestricted use, distribution, and build upon your work non-commercially.