Development of 8-h urine collections and an augmented renal clearance dosing program at an academic medical center

Ensuring appropriate dosing of medications is an essential practice of clinical pharmacists. Dose adjustments in the setting of decreased renal function are common but may also be warranted for patients with supraphysiologic or augmented renal clearance (ARC). Conventional estimates of creatinine clearance using only serum creatinine may not be accurate in the setting of ARC, thus a measured creatinine clearance using serum and urine creatinine measurements are preferred. We describe the development of an 8-h urine collection and ARC dosing program at a large academic medical center initiated by critical care and infectious disease pharmacists. Using a Plan – Do – Study – Act approach, we implemented and updated the 8-h collection program with the guidance of our clinical laboratories. Eight-hour urine collections are useful for patients with suspected ARC and for other scenarios where accurate dose adjustments are needed to minimize toxicity in the absence of therapeutic drug monitoring


| INTRODUCTION
2][3][4] It is thought that drugs with low protein binding, small molecular size, and predominate renal elimination, such as β-lactam antibiotics, have increased elimination in patients with ARC.While not a comprehensive list, drugs affected by high CrCl include edoxaban, levetiracetam, daptomycin, and linezolid. 1e new siderophore cephalosporin, cefiderocol, even has increased dosing recommendations for patients with a CrCl greater than 120 mL/min. 5Ultimately, underdosing of renally eliminated medications may have negative consequences on clinical outcomes.
ARC is best described in critically ill patients and is associated with trauma, sepsis, burn injury, pancreatitis, traumatic brain injury, subarachnoid hemorrhage, and surgery. 1,6Younger patients with low severity of illness and few or no comorbidities are more likely to develop ARC. 1,7While the term is relatively new, the concept of ARC has previously been described in pregnancy and in patients with burn injuries, which in part explains why these patients often need higher than normal dosing for some medications.In critically ill patients, the incidence of ARC ranges between 28% and 65% depending on the definition for ARC and patient population. 1,8Few studies have described the incidence outside of the intensive care unit.Declercq and colleagues reported ARC in approximately one third of floor surgical and trauma patients. 9While ARC is more common in those 50 years and younger, Lavelle and colleagues report an incidence of 11% in hospitalized elderly patients with a median age of 71 years. 10entifying patients with ARC is challenging, especially in the critically ill. 6,116][17][18][19][20] The Cockcroft-Gault equation continues to be used to estimate CrCl despite recommendations against its use by the National Kidney Foundation and the American Society of Nephrology. 21Major limitations include its development prior to standardized creatinine measurements and limited population diversity in the validation cohort. 22There is variability in the application of using these renal clearance estimates with body surface adjustment, and particularly in the elderly patient population where some clinicians may round serum creatinine up to 1 mg/dL, while others may use the actual lab result. 23Based on these limitations, two scoring systems were developed to identify risk of ARC, the ARC, and the Augmented Renal Clearance in Trauma Intensive Care (ARCTIC) scoring system. 24,25Both were created using data from trauma patients, and the ARC score weighted this patient population in the score. 23,24While these scores may be useful in trauma populations, they may underestimate risk of ARC in other populations. 26,27ven that historical equations and existing ARC risk scoring systems are not valid in all patient populations, Hobbs and colleagues recommended an 8-h urine creatinine collection in efforts to improve CrCl estimations. 1 The optimal collection time between 8-, 12-, and 24-h collections has not been established. 1Twenty-four-hour collection is common but the longer time for results and potential for increased collection error may limit its use. 1 The choice of an 8-h urine collection was suggested for a good balance of accuracy and feasibility as a 2-h urine collection may be inaccurate. 1 Unfortunately in many institutions, 8-h urine creatinine collections are not orderable.Since 2013, pharmacists have been credentialed and privileged for specific tasks including "ordering and adjusting laboratory tests related to monitoring medication therapy as necessary," and "monitoring and adjusting medications based on renal parameters." 29e critical care pharmacy team has engaged in formalized strategic planning since 2015.In early 2017, a team of six critical care pharmacists and two infectious diseases pharmacists developed an ad hoc committee to implement 8-h urine CrCl monitoring accompanied with a dosing guide for patients with ARC.The Plan-Do-Act-Study is a practical method for implementation and follow-up for quality improvement initiatives (Figure 1).

| PLAN
The committee initially met to discuss goals and a timeline for implementation.It was determined that the first step in the process was the development of an 8-h urine collection test allowing for the measurement of CrCl at our institution.At that time, the hospital and reference laboratory only offered 24-h urine collections for creatinine.

We approached the director of Automated Chemistry and Critical
Care Testing in the Department of Clinical Laboratories regarding the possibility of offering 8-h urine creatinine testing and shared existing literature on ARC and internal data from a research project comparing outcomes in patients suspected of having ARC who were treated with cefepime or piperacillin-tazobactam for serious infections due to Pseudomonas aeruginosa. 1,30After review of the data, the director agreed to move forward and an orderable test was created for the 8-h urine creatinine.Information needed to develop 8-h urine collection included: test name; units; reference range; critical values; source; measurable range; reportable range; specimen type; stability at room temperature; and outreach (nursing) notes.The test catalog information for creatinine from 24-h urine collections was modified with both 8-and 24-h having non-applicable critical values, or a value that would require communication to the bedside nurse.A webpage in the laboratory's online test catalog was also created listing the measuring range, reportable range (with dilutions), and outreach notes.The 8-h urine creatinine was subsequently presented and approved by the Clinical and Reference Laboratory.
The ARC committee then created resources to identify which patients may benefit from an 8-h urine collection and a guide for dosing in patients with ARC.The algorithm guiding an 8-h urine collection included risk factors for ARC, calculation of the ARC score, and assessment of serum creatinine (Figure 2).The dosing guide focused on drugs without routine therapeutic drug monitoring (TDM) at our institution, which included cefazolin, cefepime, daptomycin, enoxaparin, levetiracetam, linezolid, meropenem, and piperacillin/tazobactam (Table 1).At our institution, all maintenance doses of cefepime, meropenem, and piperacillin/tazobactam are administered as extended infusions.that were predicted to have high use of 8-h urine collection (e.g., surgical ICU) and was shared via staff email and meetings.Otherwise, education was provided by pharmacists.In June 2017, 8-h urine collections were made available for ordering in the EMR with a calculation prebuilt into the EMR for those with a detectable serum creatinine in the previous 24 h from an 8-h urine collection.The pharmacy resources were posted on the internal pharmacy website.With the implementation of the 8-h urine process, pharmacists with inpatient privileges were now also permitted to order 8-h urine collections and adjust medications based on 8-h urine CrCl.In the EMR, 8-h urine collections are reported with measured volume, urine creatinine concentration (mg/dL) with an 8-h interval, and CrCl based on last serum creatinine within 24 h of urine collection.

| STUDY
In October 2017, a simple audit was conducted of 8-h urine collections for the month of September to determine indication, how often ordered, and documentation in the EMR.The use of 8-h urine collections were at the discretion of individual pharmacists as they were not mandatory.There were 26 collections in 19 unique patients, and 80% were ICU patients at the time of collection.Half of all collections occurred in the surgical/trauma/burn ICU, with 15% each in a medical ICU or Neurological ICU.All collections were for medication-related dosing purposes with antimicrobials, most notably cefepime, being the primary reason for ordering.Over one third of patients had ARC including one patient with ARC 5 days after initial collection and one patient without ARC 10 days after initial collection.Less than half of 8-h collections had an associated note in the EMR.After the completion of the audit, the results were shared with key stakeholders.

| ACT
Based on the audit, a templated note was built to document both 8-h urine collections, CrCl measurement, and medication adjustment as appropriate.This was made available in December 2017.

| REPEAT PLAN-DO-STUDY-ACT
Part of continuous quality improvement is repeating the Plan-Do-Study-Act process as appropriate.For this project, this involved updating the dosing guide when new literature became available or new renally adjusted medications were added to the formulary.For this ongoing process, the committee lead would send out information via email and when consensus was reached within the committee, the lead would obtain approval from the appropriate committee(s) for the updated dosing guide with changes communicated to the Department of Pharmacy and key stakeholders.Within the first 6 months of use, there were some concerns raised in patients especially in the elderly, residents and have been published in peer-reviewed journals. 10,16In 2021, the dosing guide was updated and the algorithm for identifying at risk patients transitioned from the ARC score to the ARCTIC score based on internal data showing higher sensitivity and improved ease of use.The algorithm is the same as Figure 2 except using the ARCTIC sore with a cutoff of 7 or more.

| INSTITUTIONAL EXPERIENCE
The development of an 8-h urine creatinine collection for measurement of CrCl at our institution was relatively easy as 24-h urine collections for a variety of tests were already routinely performed.
Working with leadership within the Department of Clinical Laboratories, we were able to develop and add an 8-h urine creatinine test for measurement of CrCl by modifying the existing 24-urine collection order.We also built a calculation for CrCl in for those patients with detectable serum creatinine and reported it automatically in the EMR.
While there is no consensus for the cutoff point of ARC, it should be thought of as a continuum similar to renal insufficiency.Those with mild renal insufficiency may need different dosing than those with severe renal insufficiency or end stage renal disease.We have found that this might be true in those with ARC also. 31Only in the last year has β-lactam TDM been available as a send out laboratory at our institution.Prior to availability of β-lactam TDM, there have been some cases in patients with P. aeruginosa bacteremia and a measured CrCl > 180 mL/min who did not clear the bacteremia while receiving cefepime 2 g every 8 h.In these cases, cefepime was increased to 2 g every 6 h with successful clearance of bacteremia and no toxicity noted.Similarly, there have also been cases in patients with P. aeruginosa pneumonia and a measured CrCl > 180 mL/min that only defervesced when cefepime was increased to 2 g every 6 h. 31 Recently, we have also used 8-h urine collections in the rare instance where more than 12 g a day of ampicillin/sulbactam was being used for multiple drug resistant Acinetobacter baumannii infections to determine if TDM was warranted for toxicity concerns.Limitations include that an 8-h urine collection is not easily obtained in all patients.Currently, our institution does not routinely use other renal biomarkers such as Cystatin-C.For patients with a Foley catheter, collection by nursing is relatively easy; however, in patients with other catheters, such as a condom catheter or a female external catheter, there is the potential for spillage, which would limit interpretation of the results.The 8-h collection may also be inappropriate for some surgical patients, such as those with an ileal conduit.
Finally, diuretics may affect the results of an 8-h urine CrCl, and discussion about fluid management and diuresis plans should occur with the team and bedside nurse prior to ordering the test.For other patients without a urine collection device, it is more difficult as patient's urine collection may not be as accurate.For these reasons, 8-h urine collections occur mostly in ICU patients.Initially, there were concerns with discordance between 8-h urine measurements and Cockcroft-Gault estimates and potential differences in drug dosing. We 4 | DO After the critical care and infectious diseases pharmacy teams agreed to the algorithm and dosing protocol, key stakeholders were engaged.The algorithm and dosing protocol were presented to the multiprofessional Critical Care Clinical Quality Management Committee, the Antimicrobial Stewardship Program, and the Pharmacy and Therapeutics Committee for approval.After committee approval, a Department of Pharmacy continuing education session was presented by a pharmacy resident.The 1-h session highlighted the pathophysiology, incidence of ARC, urine collection ordering process, associated dosing protocols, and observed discordance with the Cockcroft-Gault equation.This education occurred before implementation of 8-h urine collection availability in the electronic medical record (EMR).Nurses routinely perform 24-h urine collection at our institution, so nurse education focused on units Plan Do Act Study • IdenƟfy team members • Develop commiƩee goals/Ɵmeline • Review literature • Brainstorm acƟviƟes • Work with laboratory to create 8-hour urine collecƟon for creaƟnine clearance • Develop dosing protocols for those with augmented renal • Present to key stakeholder groups • Get Pharmacy & TherapeuƟcs commiƩee approval • Educate pharmacy/nursing staffs • Implement 8-hour urine • Audit process • Develop templated notes for electronic medical record • Update dosing protocol for new medicaƟons and data published • Conduct research projects F I G U R E 1 PLAN-DO-STUDY-ACT.F I G U R E 2 Augmented renal clearance (ARC) identification and drug dosing algorithm.Scr = serum creatinine.

where 8 -
h urine collections measured CrCls did not correlate with Cockcroft-Gault estimates.As part of the Department of Pharmacy Residency Program, two residency research projects were vetted and approved for the 2018-2019 residency class: (1) Discordance of renal drug dosing comparing 8-h urine collected and estimated using Cockcroft-Gault equation, and (2) correlation of 8-h urine collection and Cockcroft-Gault equation in elderly hospitalized patients.Both projects were conducted by postgraduate Year 1 (PGY-1) pharmacy

Increasingly, 8 -
h urine collections are used to adjust pharmacotherapy in patients without ARC.Because 8-h urine collections have a relatively quick turnaround time, we use them to doseadjust any renally eliminated drugs to help either maximize efficacy or minimize toxicity.While relatively uncommon, 8-h collections are useful to guide dosing for patients on the antiarrhythmics dofetilide and sotatol.In 2022, almost 300 patients had at least one 8-h urine collection, and half were receiving cefepime.Currently, we are developing institution guidelines for β-lactam TDM, and in some cases, 8-h urine collection will be used for to help adjust therapy prior to levels being sent out.The benefit of urine collection compared with measured CrCl is that it assesses not only urine volume but urinary creatinine concentrations.Typically, the day shift clinical pharmacist independently orders 8-h urine collections as part of the privileging process (Figure3).Most often, the results are not available for 10-12 h, so evening and night shift pharmacists will independently make adjustments as appropriate.Kidney function especially in the critically ill patient is dynamic.The frequency of obtaining 8-h urine collections is left at discretion of the clinical pharmacist based on changes in serum creatinine, duration of therapy, and clinical changes in patients.
The critical care pharmacy team participates in a broad range of clinical, educational, research, and administrative activities including development of institutional policies and clinical practice guidelines.
Drug dosing considerations in patients with ARC.Note: ARC = augmented renal clearance defined as creatinine clearance ≥ mL/min unless otherwise noted.
conducted pharmacy resident research projects that helped answer these concerns and helped staff become more comfortable with 8-h urine results.Interpretations should proceed with caution when recorded volumes in 8-h urine do not match what is documented in nursing notes.Process for ordering, modification, and documenting 8-h urine collections.identify patients with ARC and more accurately assess renal function in high-risk populations.Using the Plan-Do-Study-Act model provides a practical method for continuous quality improvement to modify and update dosing strategies.
9 | CONCLUSIONWorking with the Department of Clinical Laboratories, we successfully implemented 8-h urine collections to measure CrCl to help