Introduction

Augmented renal clearance (ARC) may be defined as an altered state of circulation that leads to an increased clearance of renally eliminated solutes 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 develop a hyperdynamic cardiovascular circulatory pattern as a consequence of systemic inflammatory response. High cardiac output leads to increased perfusion in different organs, including the kidneys. In this way, increases in the glomerular filtration rate could ensue, with subsequent enhanced renal elimination of circulating solutes.

Augmented renal clearance (ARC)^[8] may significantly impact the successful application of many renally eliminated 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 been documented in sepsis^[10], ventilator associated pneumonia^[11], traumatic brain injury^[12], burns^[13], multi-trauma^[14] and post-operatively^[15]. Application of aggressive fluid resuscitation ^[25] and vasopressor support ^[26] further augments this process, leading to substantial changes in renal function. ARC in the critically ill is associated with some conditions, mostly trauma⁽⁴⁾ and burns.⁽⁵⁾ Nevertheless, its epidemiology, risk factors, and clinical characteristics have not been comprehensively investigated. Particularly, studies focused on general population patients are scarce.

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

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

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

Similar studies on objectively assessing inflammatory response in cancer surgery are lacking.

In addition, rapidly fluctuating renal hemodynamic, constantly changing volume status of the patient and the fact that concept of ARC is not frequently applied in calculating GFR can lead to inadequate dosing of drugs in this setting. This may result in sub therapeutic dosing of antibiotics delivered intra-operatively which may impact post-operative infections. Hence, it is imperative to 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 Point prevalence 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, there is no study to the best of

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

Detection of ARC

Based on the values of creatinine in the urine, measured creatinine clearance (Cr. Clr._m) would be estimated. Patients having Cr. Clr._m> 130ml/min/1.73 m² would be categorised to have ARC.

At the end of the surgery, an additional blood sample would be collected to measure serum creatinine values. This value would then be used to assess calculated creatinine clearance. This would help draw a comparison between measured and calculated creatinine clearance values. As most of drug administration in post-operative period is based on calculated creatinine clearance values.

Methodology

This study will be conducted in two phases

Phase 1 Pilot study:- To Establish Augmented renal clearance phenomenon.

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

Phase 1 Pilot Study.

This phase 1 of study would be a pilot clinical trial of 36 consecutive patients undergoing major thoraco-abdominal and orthopaedic surgeries.

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

Pre-operative Part of Study

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

Measured creatinine clearance will be calculated pre-operatively by collecting 12 hour urine sample of the patient upon admission of the patient to the ward. Patient will be provided container to empty urine and a 12 hour urine sample would be collected to measure pre-operative urine creatinine clearance. This sample would be sent for estimation of creatinine.

On the day of surgery

All patients will receive the treatment as a part of routine treatment protocol intra-operatively.

The induction and maintenance of anaesthesia and post-operative ICU management would be done routinely as per the decision of consultant OT and ICU anaesthetist respectively. We would collect blood samples (volume-3ml) just prior the surgery and at the time of closure for measuring serum creatinine (Cr_s).

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

Sample Size

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

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

Phase 2 Main Study

Phase 2 will be done to confirm Augmented Renal clearance and to study effect of ARC on antibiotics pharmacokinetics.

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

Pre-operative Part of Study

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

Measured creatinine clearance will be calculated pre-operatively by collecting 12 hour urine sample of the patient upon admission of the patient to the ward. Patient will be provided container to empty urine and a 12 hour urine sample would be collected to measure pre-operative urine creatinine clearance. This sample would be sent for estimation of creatinine.

On the day of surgery

All patients will receive the treatment as a part of routine treatment protocol intra-operatively.

The induction and maintenance of anaesthesia and post-operative ICU management would be done routinely as per the decision of consultant OT and ICU anaesthetist respectively. We would collect blood samples (volume – 3ml) just prior the surgery and for measuring serum creatinine (Cr_s). Also two samples each of 3 mL would be collected at the time of closure for measuring serum creatinine (Cr_s) and inflammatory biomarkers respectively. Urine would be collected preoperatively from a container provided to patient for urine collection and post operatively from an urometer after Foley’s catheter insertion intra-operatively.

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

Pharmacokinetic analysis-

For cefuroxime (half life -1hr), we will collect 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 the drug.

For cefoperazone-sulbactam ( half life- 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 2 hrs. After second dosage of antibiotic, samples will be collected at (t=0 mins) and then at  5 mins, 15 mins, 30 mins, 1 hr, 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, 2 hrs, 3 hrs and 4 hrs. After second dosage of antibiotic, samples will be collected at (t=0 mins) and then at  5 mins, 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 EDTA vacutainers stored in an icebox for transport to ACTREC. Samples would be stored at ACTREC in refrigerator at -20 ^o C temperature until analysis. Samples will be centrifuged at 3000rpm for 15 mins to separate plasma following which, estimation of cefuroxime, cefoperazone and amoxicillin levels will be done using LC-MS-MS technique.

The blood antibiotic levels would be used to estimate up to what duration intra-operatively MIC of antibiotic is maintained using standard bolus dosing protocol followed intra-operatively.

At the end of the surgery, an additional blood sample would be collected to measure serum creatinine values. This value would then be used to assess calculated creatinine clearance. This would help draw a comparison between measured and calculated creatinine clearance values. As most of drug administration in post-operative period is based on calculated creatinine clearance values.

Sample Size

Since this is a feasibility study, we shall assess 50 patients undergoing major surgery to detect the incidence of ARC.