Augmented Renal Clearance in patients undergoing cancer surgery and its impact on pharmacokinetics of administered antibiotics.

Introduction

Augmented renal clearance (ARC) may be defined as an alteredstate of circulation that leads to an increased clearance of renally eliminatedsolutes with CrCl ≥ 130 mL/min/1.73 m2. The physiology behind ARC is not well understood.Recent studies have shown critically ill patients to frequently developa hyperdynamic cardiovascular circulatory pattern as a consequence of systemicinflammatory response. High cardiac output leads to increased perfusion indifferent organs, including the kidneys. In this way, increases in theglomerular filtration rate could ensue, with subsequent enhanced renalelimination of circulating solutes.

Augmented renal clearance (ARC)[8]may significantly impact the successful application of many renallyeliminated agents by promoting sub-therapeutic drug exposure [8,9].Although specific data concerning drug CL in critical illness remains sparse,elevated urinary creatinine clearance (CLCR), as a marker of ARC, has beendocumented in sepsis[10], ventilator associated pneumonia[11],traumatic brain injury[12], burns[13], multi-trauma[14]and post-operatively[15]. Application of aggressive fluidresuscitation [25] and vasopressor support [26] furtheraugments this process, leading to substantial changes in renal function. ARC inthe critically ill is associated with some conditions, mostly trauma(4)and burns.(5) Nevertheless, its epidemiology, risk factors, andclinical characteristics have not been comprehensively investigated.Particularly, studies focused on general population patients are scarce.

Surgical stress is part of the systemic reactionto surgical injury which encompasses a wide range of endocrinological,immunological and haematological effects. There is activation of sympatheticnervous system and endocrine stress response. The inflammatory response relatedto surgery both surgical and anesthesia induced lead to release of cytokineswhich mediate and maintain the inflammatory response to tissue injury known asacute phase response. This inflammatory and sympatheticresponse that could produce similar effects as seen in ICU admitted patients. Astudy by Lin Mt et al assessed the impact of surgery on local and systemicresponses of cytokines and adhesion molecules by measuring the levels ofinflammatory markers prior to surgery and on post-operative days 1, 3 and 7.The authors demonstrated that circulating IL-6 and P-selectin increased aftersurgery while circulating ICAM-1 and E-selectin diminished post- surgery.(27)

Veenhof A. et al studied the surgical Stress Response andpostoperative immune function in patients undergoing laparoscopy vs open surgeryusing IL-6 levels to predict the inflammatory response.(28)

Another study by Baigrie et al examined patients before, duringand after major surgery, exploring the association between plasma cytokine levelsnamely IL-1b,IL-6,TNF-a andIFN-^, theclinical course and CRP response. They observed that the systemic IL-I beta andIL-6 response to surgical trauma increased with the severity of the surgicalinsult and an early, exaggerated IL-6 response was associated with thesubsequent clinical development of major complications (29).

Similar studies on objectively assessing inflammatory response incancer surgery are lacking.

In addition, rapidly fluctuating renal hemodynamic, constantlychanging volume status of the patient and the fact that concept of ARC is notfrequently applied in calculating GFR can lead to inadequate dosing of drugs inthis setting. This may result in sub therapeutic dosing of antibiotics deliveredintra-operatively which may impact post-operative infections. Hence, it is imperativeto identify if there is ARC in patients undergoing surgery and if so, to modify the dose of commonly used antibiotics intra-operatively.

Apart from one study, currently underway, ARC PPS (Augmented renal clearance Pointprevalence study) that is studying the prevalence of augmented renal clearance(i.e. a measured 8-hour urinary creatinine clearance >= 120 ml/min/1.73m²)in an adult non-critically ill abdominal and trauma surgery population, thereis no study to the best of

 our knowledge that has attempted to document ARC in non-critically illpatients going cancer surgery.

Detectionof ARC

Based on the values of creatinine inthe urine, measured creatinine clearance (Cr. Clr.m) would beestimated. Patients having Cr. Clr.m> 130ml/min/1.73 m2would be categorised to have ARC.

At the end of the surgery, an additional bloodsample would be collected to measure serum creatinine values. This value wouldthen be used to assess calculated creatinine clearance. This would help draw acomparison between measured and calculated creatinine clearance values. As mostof drug administration in post-operative period is based on calculatedcreatinine clearance values.

Methodology

This study will be conducted in two phases

Phase 1 Pilot study:- To EstablishAugmented renal clearance phenomenon.

Phase 2 Main study:- To confirmARC and to study effect of ARC on antibiotics pharmacokinetics.

Phase1 Pilot Study.

Thisphase 1 of study would be a pilot clinical trial of 36 consecutive patientsundergoing major thoraco-abdominal and orthopaedic surgeries.

Priorto the start of the main study, a pilot study and will be done to establish ifARC does exist in patients undergoing major surgeries.  Only after pilot study proves the presence ofAugmented Renal Clearance in more than 10 % patients, phase 2 of the study willbe started.

Pre-operative Part of Study

All patients who are admitted forabove mentioned surgeries have baseline renal functions already performed.Based on the most recent creatinine values, creatinine clearance would becalculated using Cockcroft-Gault formulae. Patients with calculated GFR < 90ml/min/1.73m2 would be excluded from the study.

Measured creatinine clearance will becalculated pre-operatively by collecting 12 hour urine sample of the patientupon admission of the patient to the ward. Patient will be provided containerto empty urine and a 12 hour urine sample would be collected to measurepre-operative urine creatinine clearance. This sample would be sent forestimation of creatinine.

Onthe day of surgery

All patientswill receive the treatment as a part of routine treatment protocolintra-operatively.

Theinduction and maintenance of anaesthesia and post-operative ICU managementwould be done routinely as per the decision of consultant OT and ICU anaesthetistrespectively. We would collect blood samples (volume-3ml) just prior thesurgery and at the time of closure for measuring serum creatinine (Crs).

All patients undergoing majorsurgeries have an Arterial catheter line and Foley’s catheter insertion as aroutine protocol prior to starting the surgery. Blood will be collected frompatient’s arterial line and patient will not be pricked intra-operatively forblood sampling. Intra-operatively foleys catheter is inserted in these patientsas a routine procedure. After discarding initial urine sample collected inurobag just after foley insertion, rest of the urine will be collected at theend of the surgery and will be used for estimation of urine creatinine levels(Cru).

SampleSize

1.       Augmentedrenal clearance prevalence was 30% and 35% in 103 abdominal and 129 traumasurgery patients, respectively. (Augmented renal clearance in non–criticallyill abdominal and trauma surgery patients is an underestimated phenomenon.Declercq Peter, Nijs Stefaan, DʼHoore André. s.l. : Journal of Trauma andAcute Care Surgery, 2016, Vol. 80.)

Considering the 30% prevalence prevalence of ARCin major abdominal and trauma surgeries and precision of 15% a total samplesize 36 is required to confirm the ARC phenomenon.

Phase 2 Main Study

Phase 2 willbe done to confirm Augmented Renal clearance and to study effect of ARC onantibiotics pharmacokinetics.

This phase 2 of study would be aclinical trial of 50 consecutive patients undergoing major thoraco-abdominaland orthopaedic surgeries. After confirming the effect of surgical stress onrenal clearance and defining presence of the Augmented renal clearance inpatient undergoing major thoraco-abdominal and orthopaedic surgeries phase 2will study the effect of ARC on antibiotic blood level. For studying thepharmacokinetics of antibiotics following extra samples will be collected alongwith the urine and blood sample as mentioned in phase1.

Pre-operative Part of Study

Anevening blood sample (3 mL) would be extracted from all the patient in plainvacutainer in the ward. This sample would be stored in a cold container andsent to ACTREC the next day for estimation of levels of cytokines IL1b, IL-6,TNF – alpha, IFN-^ andthe CRP levels to detect extent of inflammatory response.

Measured creatinine clearance will becalculated pre-operatively by collecting 12 hour urine sample of the patientupon admission of the patient to the ward. Patient will be provided containerto empty urine and a 12 hour urine sample would be collected to measurepre-operative urine creatinine clearance. This sample would be sent forestimation of creatinine.

 On the day of surgery

Allpatients will receive the treatment as a part of routine treatment protocolintra-operatively.

The induction and maintenance ofanaesthesia and post-operative ICU management would be done routinely as perthe decision of consultant OT and ICU anaesthetist respectively. We wouldcollect blood samples (volume – 3ml) just prior the surgery and for measuringserum creatinine (Crs). Also two samples each of 3 mL would becollected at the time of closure for measuring serum creatinine (Crs)and inflammatory biomarkers respectively. Urine would be collectedpreoperatively from a container provided to patient for urine collection and postoperatively from an urometer after Foley’s catheter insertionintra-operatively.

All patients, as a part of routineprotocol receive antibiotics prior to the incision intra-operatively. Theseantibiotics depend on unit protocol. Most commonly used antibiotic in thoracicand orthopaedic surgeries is Cefuroxime, gastrointestinal surgeries is Cefoperazoneand sulbactam and gynaecological surgeries is Amoxicillin and clavulanic acid.These antibiotics as a part of routine protocol are repeated intra-operativelyafter 4 hours.

Pharmacokineticanalysis-

For cefuroxime (half life -1hr), we willcollect samples at (t=0 mins) and then at 3 mins, 10 mins, 30 mins, 1 hr, 2 hrs, 3 hrs .After second dosage of antibiotic, samples will be collected at  (t=0 mins) and then at  3 mins, 10 mins, 30 mins, 1 hr, 2 hrs , 3 hrs,4 hrs , 5 hrs and 6 hrs to capture the entire pharmacokinetic profile of thedrug.

For cefoperazone-sulbactam ( halflife- 1.6 hrs), we will collect samples at (t=0 mins) and then at  5 mins, 15 mins, 30 mins, 1 hr, 1.5 hrs and 2hrs. After second dosage of antibiotic, samples will be collected at (t=0 mins)and then at  5 mins, 15 mins, 30 mins, 1hr, 1.5 hrs, 2 hrs , 4 hrs, 6 hrs, 8 hrs and 12 hrs.

For amoxicillin and clavulanic acid,we will collect samples at (t=0 mins) and then at  5 mins, 15 mins, 30 mins, 1 hr, 1.5 hrs, 2hrs, 3 hrs and 4 hrs. After second dosage of antibiotic, samples will becollected at (t=0 mins) and then at  5mins, 15 mins, 30 mins, 1 hr, 1.5 hrs, 2 hrs ,3 hrs, 4 hrs, 8 hrs, and 10 hrs.

The samples will be collected in EDTAvacutainers stored in an icebox for transport to ACTREC. Samples would bestored at ACTREC in refrigerator at -20 o C temperature untilanalysis. Samples will be centrifuged at 3000rpm for 15 mins to separate plasmafollowing which, estimation of cefuroxime, cefoperazone and amoxicillin levelswill be done using LC-MS-MS technique.

The blood antibiotic levels would beused to estimate up to what duration intra-operatively MIC of antibiotic ismaintained using standard bolus dosing protocol followed intra-operatively.

At the end of the surgery, an additional bloodsample would be collected to measure serum creatinine values. This value wouldthen be used to assess calculated creatinine clearance. This would help draw acomparison between measured and calculated creatinine clearance values. As mostof drug administration in post-operative period is based on calculatedcreatinine clearance values.

Sample Size

Sincethis is a feasibility study, we shall assess 50 patients undergoing majorsurgery to detect the incidence of ARC.