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Morning Agenda Theoretical perspectives Kidney Anatomy & Physiology Acute Kidney Injury (AKI) Acute Blood Purification Transport Mechanisms Treatment Modalities Treatment Dose Practical Aquarius Overview Lining and Priming Recirculation Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Afternoon Agenda Theoretical Filtration Fraction Filtration Ratio Vascular Access Practical Programming Connection Alarms Troubleshooting Disconnection Safe Disposal Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

RENAL ANATOMY AND PHYSIOLOGY
Renal Anatomy and Physiology changed from previous Kidney Anatomy and Physiology. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Renal Anatomy and Physiology1
The kidneys are two bean shaped organs, located just below the inferior boundary of the rib cage. The right kidney is displaced slightly by the liver and thus sits12mm lower than the left kidney Each kidney can function independently of the other Each adult kidney weighs approx. 140g and is approx. 11cm long and 6cm wide1 The adult kidneys receive 1.2 litres of blood every minute equal to 20-25% of total cardiac output. That is 72 l/hr or 1728 litres per day Normal kidney function is measured in terms of glomerular filtration rate (GFR). Normal GFR is typically ml/min. An estimation of Glomerular Filtration Rate (eGFR) can be calculated based on patient’s creatinine level with adjustments made for age, gender and race 1Jones T Crash Course: Renal and Urinary Systems, 4th Edition (2015) Mosby Elsevier:London pg 1-15 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Components of the Kidney1
Each kidney consists of 3 components: Cortex contains 85% of the nephrons used to filter the blood continuously to maintain fluid balance Medulla contains 15% of the nephrons that filter the blood & concentrate urine Renal pelvis is the start of the collection system - containing the collecting tubules and the ureter Illustration for example only. 1 Jones T Crash Course: Renal and Urinary Systems, 4th Edition (2015) Mosby Elsevier:London pg 2-4 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Components of the Kidney
The kidney functions using three principles: Ultrafiltration Excretion Re-absorption Illustration for example only. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Components of the Kidney – Nephron1
Is the functional unit of the kidney – each kidney has about one million nephrons Each nephron contains a glomerulus, which functions as an individual filtering unit - ultrafiltration The nephron also contains tubules for secretion and absorption of substances 1Jones T Crash Course: Renal and Urinary Systems, 4th Edition (2015) Mosby Elsevier:London pg 3-4 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Components of the Kidney - Glomerulus
A group of cells with selective permeability - Ultrafiltration Selective permeability: only certain substances will cross the membrane is how the kidney regulates fluid and electrolyte balance Adult kidneys produce approx litres of filtrate per day – only litres is excreted as urine 2 The remaining litres are reabsorbed by the kidney 2 A tea filter is a good example of a semi-permeable membrane 2Kumar P Clark M Chapter 11 Renal disease in Clinical Medicine 6th Edition (2005) Elsevier Saunders : Edinburgh pg Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Functions of the Nephron 2
Glomerulus (Bowmans Capsule) Proximal Convoluted Tubule Loop of Henle Distal Convoluted Tubule Collecting Duct Filtration Reabsorbs: Sodium Glucose Potassium Amino Acids Bicarbonate Phosphate Urea Secretes: Hydrogen Foreign Substances Concentrates Urine (using a counter current system) Descending Loop: Water reabsorption – sodium diffuses in Ascending Loop: Sodium reabsorbed (using active transport) water is retained. Resorbs: Water Ammonia Resorbs / 2 Kumar P Clark M Chapter 11 Renal disease in Clinical Medicine 6th Edition (2005) Elsevier Saunders : Edinburgh pg Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Functions of the Kidney 1,2
Fluid balance ultrafiltration & reabsorption Electrolyte balance reabsorption & excretion Acid-base balance Excretion of drugs and by-products of metabolism nitrogen, urea, creatinine Synthesis of erythropoietin stimulates bone marrow to produce mature red blood cells Regulation of blood pressure through the secretion of renin Maintenance of calcium-phosphate balance through the activation of vitamin D production 1 Jones T Crash Course: Renal and Urinary Systems, 4th Edition (2015) Mosby Elsevier:London pg 6-7 2 Kumar P Clark M Chapter 11 Renal disease in Clinical Medicine 6th Edition (2005) Elsevier Saunders : Edinburgh pg Copyright © NIKKISO Co., LTD. All rights reserved.

Acute kidney injury (AKI)
Aquarius System Acute kidney injury (AKI) Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Acute Kidney Injury Results from the sudden loss of kidney function. AKI in the setting of critical care patients is defined as: “..an abrupt decline in glomerular filtration rate3” Waste products will start to accumulate in the blood AKI may be accompanied by metabolic, acid-base & electrolyte disturbances and fluid overload AKI may affect other organ systems and may require immediate treatment 3Jefferson JA, Schrier RW. Pathophysiology and Etiology of Acute Renal Failure. In: Comprehensive Clinical Nephrology. 3rd ed. Philadelphia, PA: Mosby Elsevier; 2007: Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

AKI Classification There are 3 types of AKI Classification1: Prerenal Postrenal Intrinsic renal 1 Jones T Crash Course: Renal and Urinary Systems, 4th Edition (2015) Mosby Elsevier : London pg 93 Copyright © 2015 NIKKISO Co., LTD. All rights reserved.

Prerenal Causes of AKI1 Usually results from decreased blood flow to the kidneys. The reduction in glomerular filtration enables the solutes in the blood to accumulate, without causing any structural damage to the kidney. Examples of situations leading to pre-renal failure may include: Dehydration (↓volume) Haemorrhage (↓ volume) Congestive heart failure (↓CO) Liver failure Shock NSAIDs and ACE inhibitors Pre renal 30-60% (think ‘p’ for pressure) Volume depletion Decreased circulating volume Reduced cardiac output Renal vascular disease 1 Jones T Crash Course: Renal and Urinary Systems, 4th Edition (2015) Mosby Elsevier : London pg 93 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Intrinsic Renal Causes of AKI1
Typically involves direct injury to the kidney itself. The most common cause is Acute Tubular Necrosis (ATN). Some causes of ATN are: Ischaemia; caused by any prerenal cause Drug toxicity and toxins; e.g. gentamicin, aciclovir, lipopolysaccharide in gram negative sepsis Acute interstitial nephritis; due to drugs, infections, hypercalcaemia Glomerular disease; acute glomerulonephritis Vascular disease; vasculitis, hypertension Intrinsic Renal 20-40% (think “I” for ischaemia) Ischaemia Glomerular infection Vascular Nephritis 1 Jones T Crash Course: Renal and Urinary Systems, 4th Edition (2015) Mosby Elsevier : London pg 93 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Postrenal causes of AKI1
In post-renal failure, the underlying cause occurs in both kidney or in a single functioning kidney. Causes for this may be related to: Tumour development Urinary tract obstruction Hypertrophic prostate Post renal 1 – 10% (think ‘O’ for obstruction) Obstruction Ureters Bladder Urethra 1 Jones T Crash Course: Renal and Urinary Systems, 4th Edition (2015) Mosby Elsevier : London pg 93 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

How to Identify an AKI A series of tools have been developed in order to help nurses and clinicians identify an emerging AKI. These tools began with RIFLE in (2001), AKIN (2007) and KDIGO (2012) Table below adapted from Kristensen et al (2014) 4 Kristensen et al (2014) ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). European Heart Journal 35 (35) 2383–2431 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

RIFLE The AKIN and KDIGO tools both use a 3 stage process. The RIFLE classification uses 5 stages; Risk, Injury, Failure, Loss and End Stage Kidney Disease (ESKD)5. Ricci et al - The RIFLE criteria and mortality in acute kidney injury: A systematic review. Kidney International (2008) 73, 538–546 5 Ricci et al - The RIFLE criteria and mortality in acute kidney injury: A systematic review. Kidney International (2008) 73, 538–546 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Nephrotoxic Drugs6 Nephrotoxicity is the poisonous effect on the kidneys caused by toxic chemicals and medication Drug-induced AKI is common in critical illness and accounts for 15% to 25% of all cases of renal failure seen in this population6 The medications implicated in causing drug-induced AKI can be classified based on their mechanism of renal injury (eg: pre, intrinsic or post-renal) The mechanisms of toxicity are complex and, in many cases, affect more than one aspect of kidney function NSAIDs have been associated with AKI, and consideration should be given to either avoid their use or, when indicated, use with extreme caution Bentley, M.L., Corwin H.L., Dasta J. (2010) Identification and Prevention of Common Adverse Drug Events in the Intensive Care Unit. (Supplement in) Critical Care 38 S Ricci Z., Ronco C., (2008) The RIFLE criteria and mortality in acute kidney injury: a systematic review. Kidney International 7 (5) 6Bentley, M.L., Corwin H.L., Dasta J. (2010) Identification and Prevention of Common Adverse Drug Events in the Intensive Care Unit. (Supplement in) Critical Care 38 S Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Nephrotoxic Drugs – NSAIDS6
Volume contraction from any cause or other forms of pre-renal AKI (cirrhosis, congestive heart failure) will increase the incidence/severity of nephrotoxicity due to nonsteroidal anti-inflammatory drugs (NSAIDs). Due to a decrease in effective arterial flow the following conditions can predispose the patient to a NSAID-induced Nephrotoxicity; Congestive heart failure Hypotension Volume depletion 3rd spacing 6 Bentley, M.L., Corwin H.L., Dasta J. (2010) Identification and Prevention of Common Adverse Drug Events in the Intensive Care Unit. (Supplement in) Critical Care 38 S Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Nephrotoxic Drugs- ACE Inhibitors, others6
ACE inhibitors - commonly prescribed for hypertension, congestive heart failure and chronic kidney disease. Affect renal haemodynamics via a decrease in efferent arteriolar tone and intraglomerular capillary pressure The use of these drugs under normal circumstances when renal perfusion is adequate poses very little problem. However when these drugs are used in states of prerenal azotemia, renal artery stenosis or concomitantly with other drugs such as NSAIDs, renal failure may occur Other drugs – e.g. cyclosporine and tacrolimus can cause altered glomerular haemodynamic instability These belong to a class of commonly used immunosuppressant's for organ transplantation referred to as calcineurin inhibitors Calcineurin inhibitors are associated with early pre-renal oliguria due to vasoconstriction 6Bentley, M.L., Corwin H.L., Dasta J. (2010) Identification and Prevention of Common Adverse Drug Events in the Intensive Care Unit. (Supplement in) Critical Care 38 S Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Phases of Acute Kidney Injury
Oliguric phase • Low urine output (< 400 mL/24 hrs) • Possibly protein in the urine • Electrolyte imbalances • Metabolic acidosis Polyuric phase • Begins as UO ↑ • Has variable time frames, occurring as little as 24 hrs after the onset of renal failure • Associated with K+ and Na+ loss in the urine • Enhanced UO may not reflect restored function – can be result of ↑serum urea & creatinine (osmotic diuretic effect ) Recovery phase • May last several months after the onset of the AKI • During this time kidney function gradually returns to normal and proper urine concentrations & volumes are achieved Diagram for illustrative purposes only. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Management Goals for AKI7
Fluid balance Removal of waste products Haemodynamic stablisation Correction of electrolyte abnormalities Restoration of acid-base balance Nutritional support 7 Khilnani P Section 6 Fluids, Electrolytes and Renal Issues in Practical Approach to Pediatric Intensive Care 3rd Edition (2015) Jaypee: Jones T Crash Course: Renal and Urinary Systems, 4th Edition (2015) Mosby Elsevier : London pg 93 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Treatment options for AKI1,7
Acute Kidney Injury Information & Support Peritoneal Dialysis Pharmacological & Fluid Management Relieve Urological obstruction Continuous Renal Replacement therapy Monitoring Intermittent hemodialysis (IHD) Acute Kidney Injury 1Jones T Crash Course: Renal and Urinary Systems, 4th Edition (2015) Mosby Elsevier : London pg 93 7Khilnani P Section 6 Fluids, Electrolytes and Renal Issues in Practical Approach to Pediatric Intensive Care 3rd Edition (2015) Jaypee: Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Indications for commencing CRRT8
Renal Indications: Rapidly rising serum urea and creatinine or the development of uraemic complications Hyperkalaemia unresponsive to medical management Severe metabolic acidosis Diuretic resistant pulmonary oedema Oliguria or anuria Non Renal indications: Management of fluid balance e.g. in cardiac failure Clearing of ingested toxins Correction of electrolyte abnormalities Temperature control Removal of inflammatory mediators in sepsis 8 Rona A, Fumagalli R. (2009) Indications for Renal Replacement Therapy in the Critically Ill Patient. In: Critical Care Nephrology. 2nd ed. Philadelphia, PA: Saunders Elsevier; Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Some Indications for CRRT
Pre & Post Cardiac Surgery Haemodynamic Instability Shock Drug Overdose Sepsis – Lactate Acidosis Fluid Overload Illustration for example only. ARDS VAP Acute Multi-Organ Failure Trauma - Rhabdomylosis Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

CRRT Therapy Goals9 Clean the blood - Waste removal from the blood by diffusion and convection Manage intravascular volume - Water removal by ultrafiltration 9Chaturvedi et al. Continuous Renal Replacement Therapy (2004) online ISSN ,P1; 4, Acessed at Copyright © NIKKISO Co., LTD. All rights reserved.

Defining the Therapy10 Early application of CRRT may prove to be beneficial to the patient CRRT is indicated for continuous solute removal in the critically ill patient CRRT allows for continuous, slow and isotonic fluid removal that results in better haemodynamic tolerance even in unstable patients with shock and severe fluid overload CRRT can be modified at any time day/night to meet the rapidly changing haemodynamic situation of critically ill patients CRRT therapy indications may be renal, non-renal, or a combination of both. It is the treatment of choice for the critically ill patient requiring renal support and/or fluid management 10Kellum J, Ronco C, Joannidis M (2012) An emerging consensus for AKI ICU Management 12 (1) 38-40 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Treatment modalities & Transport mechanisms
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Treatment Modalities CRRT includes several treatment modalities All of these modalities use veno-venous access via a central line The choice of therapy will depend on the needs of the patient, the preferences of the physician and the protocol within the ICU Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

CRRT Treatment Modalities
SCUF Slow Continuous Ultrafiltration CVVH Continuous Veno-Venous Haemofiltration Convective Therapy CVVHDF Continuous Veno-Venous HaemoDiaFiltration CVVHD Continuous Veno-Venous Haemodialysis Quick recap. Recap slide – remember scuf and cvvh are convective – we are physically pulling solutes out CVVH – Clearences in this mode are good for middle molecures good for septic mediators Diffusive – countercurrent passive movement – good for small molecule clearance ie high potassium. CVVHDF – bit of both but remember blocks easily - only convective continues. Ok that was the first bit – any questions? CVVHDF – when septic medicators block holes – loose diffusive aaspect Prismaflex only do citrate in CVVHDF Aquarius citrate CVVH Diffusive & Convective Therapy Diffusive Therapy Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Slow Continuous Ultrafiltration (SCUF)
Primary therapeutic goal: Safe management of fluid removal Primary indications: Fluid overload Principle used: Ultrafiltration (removal of water) Therapy characteristics: No dialysate solutions No substitution solutions Fluid removal only Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Transport Mechanism: Ultrafiltration
Is the movement of fluid through a semi-permeable membrane along a pressure gradient Graphics will become visible in presenter mode. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Slow Continuous Ultrafiltration (SCUF)
Graphics will become visible in presenter mode. Graphics will become visible in presenter mode. Copyright ©2016 NIKKISO Co., LTD. All rights reserved.

Continuous Veno-Venous Haemofiltration (CVVH)
Primary therapeutic goal: Solute removal and safe management of fluid volume Primary indications: Uremia, acid/base and/or electrolyte imbalances, fluid overload Principle used: Ultrafiltration (removal of water) Convection (clearance of solutes) Therapy characteristics: Requires substitution solution with a buffer to drive convection No dialysate solution Used to achieve solute removal (small, medium and large sized molecules) and fluid balance Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Transport Mechanism: Convection
Is the one-way movement of solutes through a semi-permeable membrane with a water flow. Sometimes referred to as ‘solvent drag.’ Graphics will become visible in presenter mode. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Continuous Veno-Venous Haemofiltration (CVVH)
Graphics will become visible in presenter mode. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Continuous Veno-Venous Haemodialysis (CVVHD)
Primary therapeutic goal: Solute removal and safe management of fluid volume Primary indications: Uremia, acid/base and/or electrolyte imbalances, fluid overload Principle used: Diffusion Therapy characteristics: Requires substitution solution with a buffer to aid the diffusive process No substitution solution Used to achieve solute removal (small and medium sized molecules) and fluid balance Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Transport Mechanism: Diffusion
Is the movement of solutes through a semi-permeable membrane from an area of higher concentration to an area of lower concentration Graphics will become visible in presenter mode. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Transport Mechanism: Diffusion
Solutes move from a higher concentration to a lower concentration In CRRT, diffusion occurs when blood flows on one side of the membrane, and dialysate solution flows counter-current on the other side The dialysate does not mix with the blood Efficient for removing small and medium molecules but not large molecules - molecular size and membrane type can affect clearances Diffusion occurs during haemodialysis Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

No Counter Current Principle 11
11Anaesthesia UK (2003) Acute renal failure and renal replacement therapy in the ICU - Accessed 10th August :10 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Counter current principle (Diffusion)12
Anaesthesia UK (2003) Acute renal failure and renal replacement therapy in the ICU Accessed 10th August :10 12Anaesthesia UK (2003) Acute renal failure and renal replacement therapy in the ICU - Accessed 10th August :10 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Continuous Veno-Venous Haemodialysis (CVVHD)

Continuous Veno-Venous Haemodiafiltration (CVVHDF)
Primary therapeutic goal: Solute removal and safe management of fluid volume Primary indications: Uremia, acid/base and/or electrolyte imbalances, fluid overload Principle used: Diffusion and Convection Therapy characteristics: Requires dialysate solution and substitution solution - both contain a buffer that drives the convection and diffusion processes Used to achieve solute removal (small, medium and large sized molecules) and fluid balance. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Continuous Veno-Venous Haemodiafiltration (CVVHDF)

Treatment Modality Summary
Modes Principles Molecules Cleared Fluids Pumps In Use SCUF Slow Continuous UltraFiltration UltraFiltration Movement of fluid through a semi-permeable membrane along a pressure gradient. Nil No Fluid (for fluid removal only) Pre-dilution pump Post-dilution pump Filtrate Pump CVVH Continuous Veno-Venous Haemofiltration (can be pre or post dilution) Convection (active) One-way movement of solutes through a semi permeable membrane with a water flow – sometimes referred to as ‘solvent drag’. Small Medium Large Substitution fluid (pre/post) CVVHD Continuous Veno-Venous HaemoDialysis Diffusion (passive) Movement of solutes through a semi-permeable membrane from an area of high concentration to low concentration. Dialysate fluid Dialysate pump Filtrate pump CVVHDF Continuous Veno-Venous HaemoDiaFiltration Combined Mode: Convection Haemofiltration Active – convection Diffusion Haemodialysis Passive - diffusion Substitution / Replacement Fluid Dialysate Post dilution pump Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Molecular Weights13 Molecule Molecular Weight (Daltons) Potassium 28
Sodium 33 Urea 60 Creatinine 113 Aquamax Hemofilter Cut-Off 55 000 Albumin 68 000 Haemoglobin 64 000 Globulin Ashley et al. The Renal Drug Handbook, 2nd Ed. 2004, Medical Press, Abingdon, UK. ISBN: 13 Ashley et al. The Renal Drug Handbook, 2nd Ed. 2004, Medical Press, Abingdon, UK. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Sieving Coefficient 14 A sieving coefficient is the measure of how easily a substance passes from the blood compartment to the dialysate compartment in a haemofilter. A sieving coefficient of 1.0 means the solute is 100% filterable; i.e. in a haemofilter, the solute will equilibrate on both sides of . the membrane So… the returning blood and the effluent both have the same concentration (50:50) A sieving coefficient of 0 means the solute does not cross the membrane, e.g. albumin. Depends on the membrane, and sieving coefficients will vary depending on the pore size. 14Kellum J et al Continuous Renal Replacement Therapy (2010) Oxford : New York pg 27 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Copyright © 2016 NIKKISO Co., LTD. All rights reserved
Molecular weight15 Aquamax Hemofilter Cut-Off 55,000 da Ashley et al. The Renal Drug Handbook, 2nd Ed. 2004, Medical Press, Abingdon, UK. ISBN: 16 Ashley et all. The Renal Drug Handbook, 2nd Ed. 2004, Medical Press, Abingdon, UK. Copyright © 2016 NIKKISO Co., LTD. All rights reserved

Transport Mechanism: Adsorption
High levels of adsorption can cause some filters to clog and become ineffective Membrane type affects adsorption tendencies/effectiveness Adsorption may also affect the removal of some solutes (eg. β2 microglobulins) from the blood16 16Hasse M. A pilot study of high adsorption hemofiltration in human septic shock. The International Journal of Artificial Organs 30(2) Copyright © 2015 NIKKISO Co., LTD. All rights reserved.

Replacement Fluid – Accusol 35*
Is a bicarbonate based solution primarily intended for use in patients with hyperkalaemia Is a convenient, easy-to-use solution that is lactate-free, with a 100% bicarbonate buffer, providing all the necessary electrolytes Is available in ready-to-mix formulations with varying potassium concentrations Replacement fluid is known as ‘substitution’ fluid in haemofiltration and haemodiafiltration and as a ‘dialysis’ solution in haemodialysis and haemodiafiltration Potassium Content Description 0 mmol/litre Accusol 35 2 mmol/litre Accusol 35 Potassium 4 mmol/litre * Not available in all markets Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Accusol 35 Purifies blood of waste products - helping to correct acidity/alkalinity Supplied in a dual chambered non PVC bag The long seal separating the two chambers (bicarbonate and electrolytes) needs to be broken so the solution can mix thoroughly before use - once mixed, the solution is stable for 24 hours Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Accusol 35 Accusol 35 works closely with the body’s natural chemistry to maintain electrolyte balance during therapy and restore haemodynamic stability Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Treatment Dose/Renal Dose
Aquarius System Treatment Dose/Renal Dose Copyright ©2016 NIKKISO Co., LTD. All rights reserved.

Measurement of therapy dose
Therapy dose is a measure of the quantity of blood purification achieved The concept of clearance represents the volume of blood cleared of a given solute over time Commonly used solute markers to quantify clearance are serum urea and creatinine Best clinical practices combine clearance and dosing effectiveness using a weight-related dosage of therapy17 On Aquarius, therapy dose is defined by the total ultrafiltration rate and is expressed as millilitres (therapy amount) per kilogramme (patient weight) per hour (time) or ml/kg/hr 17 Prowle et al. Clinical review: Optimal dose of continuous renal replacement therapy in acute kidney injury Critical Care 2011, 15:207 Accessed at Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Guidelines: Intensive Care Society18
The ideal dose for CRRT is not known; however 35 ml/kg/h of ultrafiltrate production is recommended as a minimum for CVVH (post-dilution) and CVVHDF Pre dilution CRRT reduces solute clearance and an increase of 15% for ultrafiltration rates of 2L and up to 40% for rates of 4.5L or more should be considered The Intensive Care Society (ICS) (2009) Standards and Recommendations for the Provision of Renal Replacement Therapy on Intensive Care Units in the United Kingdom 10th August :10 18 The Intensive Care Society (2009) Standards and Recommendations for the Provision of Renal Replacement Therapy on Intensive Care Units in the United Kingdom 10th August :10 Copyright © 2016 NIKKISO Co., LTD. All rights reserved

Renal Association AKI Guideline 10.1-10.519
Guideline 10.1 – AKI: Renal Replacement Therapy Prescription “We recommend that the delivered dose of RRT (renal replacement therapy) should be assessed to ensure the adequacy of the prescription.” Guideline 10.2 – AKI: Renal Replacement Therapy Prescription “We recommend that the prescribed dose should be assessed at each session for IHD and daily for CRRT to account for any measured shortfalls in delivered dose.” Guideline 10.3 – AKI: Renal Replacement Therapy Prescription “We recommend that the patients with AKI and multi-organ failure treated by CRRT should receive treatment doses equivalent to post dilution ultrafiltration rates ≥ 25mls/kg/hr.” 19 The Renal Association (2011) CLINICAL PRACTICE GUIDELINES ACUTE KIDNEY INJURY Accessed 2nd July :23 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

The Renal Association (2011)20
Delivered dose of therapy should be assessed to ensure the adequacy of the prescription Prescribed dose of therapy should be assessed daily to account for any measured shortfalls in delivered dose Patients with Acute Kidney Injury and multi-organ failure treated by continuous renal replacement therapy should receive a: Delivered therapy dose equivalent to 25 ml/kg/hr Patients receiving pre dilution treatment with CVVH should receive a proportional upward adjustment to this dose The Renal Association (2011) CLINICAL PRACTICE GUIDELINES ACUTE KIDNEY INJURY Accessed 2nd July :23 20 The Renal Association (2011) CLINICAL PRACTICE GUIDELINES ACUTE KIDNEY INJURY Accessed 2nd July :23 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Prescribed vs Delivered Dose21
Prescription should exceed that calculated to be adequate because of the known gap 8ml/kg/hr less Prescribed dose of therapy should be assessed daily to account for any measured shortfalls in delivered dose Delivered dose of therapy should be assessed to ensure the adequacy of the prescription. A study by Vesconi et al (2009)18 showed that in actual practice the delivered therapy dose was on average 8ml/kg/hr less than the prescription We loose 8ml/kg/hr in a 35ml/kg/hr therapy. Clinicians typically choose to increase the amount of prescribed dose to compensate. This is why prescribed dose is a starting point from which we evaluate the effectiveness of the therapy by monitoring certain markers and their clearance. If happy we continue but if not we re-evaluate and prescribe according the individual patient needs. 21 Vesconi et al (2009) Delivered dose of renal replacement therapy and mortality in critically ill patients with acute kidney injury. Critical Care 13 (2) Copyright ©2016 NIKKISO Co., LTD. All rights reserved.

Where does that 8mls/kg/hr go?22
Why might we ‘lose’ significant amounts of therapy dose? Recirculation in the vascular access High filtration fractions Filter clogging and clotting Troubleshooting skills Changing of circuits Filter down time 22 Vesconi et al (2009) Delivered dose of renal replacement therapy and mortality in critically ill patients with acute kidney injury. Critical Care 13 (2);r57 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Clinical Evidence for Therapy Dose
Landmark studies suggest that increasing therapy dose improved survival23 Recent studies find no difference in survival between 25 and 40 ml/kg/hr therapy dose24,25 Higher therapy doses (40 ml/kg/hr) did not alter mortality in the subgroup of sepsis patients. How may clinicians use the evolving evidence base to choose an appropriate therapy dose? 23 Ronco et al Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial Lancet 2000; 355: 26–30 24 Bellomo et al Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients NEJM ;17 25 Palevsky et al Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury NEJM ;1 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Pedrini et al (2000)26: The comparison of mixed pre and postdilution compared to traditional infusion modes. Pedrini LA1, De Cristofaro V, Pagliari B, Samà F. (2000) Mixed predilution and postdilution online hemodiafiltration compared with the traditional infusion modes. Kidney Int Nov; 58 (5): What is clearly demonstrated is the difference in clearance of small molecules using solely pre or post dilution. What Pedrini also essentially demonstrated is that with the same ultrafiltrate rate, mixed dilution clearances were definitely higher than pre-dilution, but not significantly different to post-dilution with the smaller moelcule sizes. What this study did not demonstrate was any significant difference in clearance of middle-molecules. Urea Creatinine Phosphate 26 Pedrini et al. (2000) Mixed predilution and postdilution online hemodiafiltration compared with the traditional infusion modes. Kidney Int Nov; 58 (5): Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Predilution and Middle Molecule Clearances
Cole et al (2001)27 had preliminary experience with high volume haemofiltration in human septic shock 6 litre exchange Effects of predilution on clearance of Vancomycin (middle sized molecule) Bellomo R, Tipping P, Boyce N (1993) Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients. Crit Care Med 21:522–526 Which is why we turn to a study by Bellomo looking at clearance of Vancomycin (as it is a middle molecule). A total of 6 litres was exchanged per hour in CVVH with an increasing amount of the returning 6 litres replacement fluid being placed before the filter (pre-dilution). Unfortunately he couldn’t explain why clearance rose with 2 litres pre-dilution, putting this down to an anomaly. But what is very clear if pre-dilution is increased to more than a third of the total exchange, clearances significantly drop. Which could explain why Pedrini who had a 50/50 ratio noticed no significant difference in middle-molecule size. 27 Cole L et al High volume hemofiltration in human septic shock. (2001) Intensive Care Medicine 27(6) Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Aquarius- Renal Dose display
Renal Dose display (V6.02 and later) during treatment - patient weight can be entered and modified at any time At the start of treatment or after a programmed value change, the programmed renal dose is displayed for the first 2 min After 2 min. of uninterrupted therapy, the delivered renal dose is displayed based on the actual pump rates Look in RCA and new slides Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Filtration Ratio & Filtration Fraction
Aquarius System Filtration Ratio & Filtration Fraction Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Overview Blood is pumped through the filter fibres, the filtrate pump removes a proportion of the plasma water, leaving the blood concentrated As the blood becomes more concentrated within the filter fibres, it displays a greater tendency to clog and clot, reducing filter lifespan An understanding of this process is useful in providing optimal therapy Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Filtration Ratio Gives an indication of filtrate volume compared to the total volume of fluid through the filter Should be kept as low as practicable, ideally below 25%. Aquarius advisory message is displayed at 30%. Is not affected by the rate programmed on the pre-dilution pump. Is affected by blood pump speed and modality choice Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Filtration Fraction Gives an indication of haematocrit increases in the filter before the post -dilution solution replaces the filtrate removed Generally kept as low as practicable, ideally below 25%. No Aquarius message, as this parameter may be used to adjust therapy Is affected by the rate programmed on the pre-dilution pump and by the blood pump speed Is affected by modality choice Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

The effect of blood pump speed
Filtrate removed is a percentage of the total flow through the filter fibres Why is the total blood flow important? With a faster blood pump speed, the total flow is increased and effects of haemoconcentration are reduced Increasing blood flow gives a reduced filtration ratio which may slow filter clogging and extend filter lifespan Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Filtration Ratio and blood pump speed
Postdilution (l/h) Blood Pump Speed (mls/min)  60 (mins) = Filtration Ratio /1000 3l/h Exchange mls/min x 60 mins = 6 = 2 = 50% Filtration Ratio 3l/h Exchange mls/min x 60 mins = 12 = 4 = 25% Filtration Ratio 3l/hr Exchange mls/min x 60 mins = 18 = 6 = 17% Filtration Ratio What may happen in the filter fibres if low blood pump speeds are chosen? Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

The effect of Pre-dilution
Filtrate removed is a percentage of total flow through the filter fibres The proportion of predilution flow may be adjusted to optimise treatment With a greater proportion of predilution, the filtration fraction and effects of haemoconcentration are reduced An improved filtration fraction may slow filter clogging and extend filter lifespan Clinicans may also influence filtration fraction using Change Therapy Copyright © 2015 NIKKISO Co., LTD. All rights reserved.

Overview ‘Good’ Vascular access is required to perform all CRRT therapies Central venous catheters provide rapid and easy vascular access permitting immediate use The most common catheter now in use is the large-bore, double-lumen catheter A practical understanding of vascular access contributes to optimal delivery of CRRT therapies Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Insertion Sites – Choices28
Most popular sites for insertion are seen here although final decision is made by the clinician Internal Jugular Subclavian Femoral 28 Crosswell, J et al. Vascular access site influences circuit life in continuous renal replacement therapy. Crit Care Resusc Jun;16(2):127-30 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Considerations of Vascular Access
Diameter, length and types of catheters Type: Silicone Material features29 have lower thrombogenicity and better flexibility. Biocompatible and kink resistance Conform to vessel anatomy, therefore reduce risk of trauma Diameter and blood flow: 11 Fr ml/min blood flow 13.5 Fr ml/min blood flow Recirculation: can be up to 20% -especially if femoral access is less than 20 cm Avoid reverse AV connection 29 Parenti JJ, Catheter dysfunction and dialysis performance according to vascular access among 736 critically ill adults requiring renal replacement therapy: a randomized controlled study. Crit Care Med Apr;38(4): Accessed Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Patient Preparation Pre Insertion: Patient body status Coagulation and Intravascular filling Mobility influences Presence of other central lines Influences on catheter choice Clinician choice Availability of ultrasound guidance Post Insertion: Assessment of catheter patency Connection techniques Special circumstances Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Catheter Characteristics
Ease of insertion - to avoid vessel trauma Good flow profile - to optimise blood flow Kink resistant - to avoid access pressure problems Biocompatible - to reduce complication risks Guide wire exchange - to optimise therapy Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Side-by-Side Polyurethane Catheters

Coaxial Polyurethane Catheters
Clinical review: Patency of the circuit in continuous renal replacement therapy Michael Joannidis1 and Heleen M Oudemans-van Straaten2 Atlas of Hemofiltration – Bellomo, Baldwin, Ronco, Golper Continuous Renal Replacement Therapy – Kellum, Bellomo, Ronco Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Triple Lumen Catheters

Reversing the Lines30 30 Lewington et al. Acute Kidney Injury. Renal Association guidelines: Guideline 8.1 – AKI: Vascular access for RRT. Guideline 8.2, Page 45 Para 3 ‘Rationale for ’ lines 7-9 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Vascular Access Vascular Access is continuously tested during CRRT treatment Practical understanding about vascular access is necessary for optimal treatment Consider troubleshooting choices Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Vascular Access Troubleshooting
Starting blood flow Gradual increase Optimising blood flow rates Starting treatment Using Aquarius History Using Recirculation Troubleshooting choices Reference: IFU Version 6.02 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Inadequacies in vascular access may limit delivered therapy
Access is KING Vascular Access is continuously tested during CRRT treatment Catheter site, size, type and patient preparation should be considered Practical understanding about vascular access is necessary for optimal treatment Inadequacies in vascular access may limit delivered therapy Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Choices of Anticoagulation
Unfractioned Heparin Regional Heparinisation Regional Citrate Low Molecular Weight Heparin (LMWH) Adjunctive anticoagulation methods Picture taken from Module 1. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Introduction to Anticoagulation
In CRRT, the anticoagulation can be a challenge for physicians. The target is to limit the risk of circuit coagulation and at the same time to limit the Hemorrhage risk for the patient. The coagulation activation is due to: Exogenous causes - extracorporeal circuit i.e. lines and the filter that is in contact with the blood If no anticoagulation is used the thrombosis is inescapable with the following factors: Renal dose reduction Blood loss and loss of the coagulation factors Increase of the workload and the cost of the therapy Slides copied from Dalila’s RCA presentation July 2014. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Anticoagulation32 Systemic Regional La Prostacycline antiagrégant plaquettaire mais également vasodilatateur, protéine produit naturellement par endothélium vasculaire – prescription hypercoagulabilité du filtre Role of prostacyclin (epoprostenol) as anticoagulant in continuous renal replacement therapies: efficacy, security and cost analysis : J Nephrol. 2006 Sep-Oct;19(5): Gainza FJ et al L’Hirudine petite protéine aux propriétés anticoagulantes sécrétée par les glandes salivaires des sangsues – la lipéridudine est la forme recombinante de hirudine, la lipéirudine est réservée en 2ème intention aux TIH (thrombopénie induite) avec manifestations thromboemboliques. Conférences d'actualisation 2000, p La Protamine est principalement utilisé pour inverser les effets anticoagulants de l’héparine, c’est un cation qui que se lie à l’héparine pour formé une paire d’ion stable, ce complexe ionique sera ensuite retiré par le système réticulo-endothélial. Mais inversement, l'excès de protamine peut potentiellement augmenter les saignements dans le cas d'une thrombocytopénie sévère ou faible facteur VIII. The anticoagulant effect of protamine sulfate is attenuated in the presence of platelets or elevated factor VIII concentrations. - Bolliger D et al - Anesth Analg Sep;111(3): doi: /ANE.0b013e3181e9ed15. Epub 2010 Aug 4. Citrate 32 Joannidis, M and Oudemans-van Straaten, H. Clinical review: Patency of the circuit in continuous renal replacement therapy. Critical Care (2007), 11:218 (doi: /cc5937) Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

How does Heparin work?33 Acts on multiple sites to inhibit reactions that lead to the clotting of blood and the formation of fibrin clots Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin Heparin prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor Bleeding time is usually unaffected by heparin Clotting time is prolonged by full therapeutic doses of heparin Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots 33 Oudemans-van Straaten, H et al. "Clinical review: anticoagulation for continuous renal replacement therapy–heparin or citrate." Critical Care 15.1 (2011): 202. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Advantages & Disadvantages - Heparin
Easy to administer and monitor Low cost of drug34 Short half life, Heparin can be antagonized Disadvantages: Results in systemic anticoagulation and potential risk of bleeding35 Heparin induced thrombocytopenia (HIT) around 1% to 5% in patients given heparin for 5 days leading to increased risk of central venous thrombosis within the catheter36 24 Regional Citrate Versus Heparin Anticoagulation for Continuous Renal Replacement Therapy: A Meta-Analysis of Randomized Controlled Trials Mei-Yi Wu, MD Am J Kidney Dis. 2012; 25 Regional citrate anticoagulation in continuous venovenous hemofiltration in critically ill patients with a high risk of bleeding Runolfur Palsson and John L Niles Kidney International (1999) 55, 1991–1997; doi: /j 26 Heparin-induced thrombocytopenia during renal replacement therapy Andrew DAVENPORT Center for Nephrology, The Royal Free Hospital, Pond Street, London, United Kingdom Hemodialysis International 2004; 8: 34 Mei- Yi Regional Citrate Versus Heparin Anticoagulation for Continuous Renal Replacement Therapy: A Meta-Analysis of Randomized Controlled Trials Am J Kidney Dis. 2012; 35 Palsson et al. Regional citrate anticoagulation in continuous venovenous hemofiltration in critically ill patients with a high risk of bleeding. Kidney International (1999) 55, 1991–1997; doi: /j 36 Heparin-induced thrombocytopenia during renal replacement therapy Andrew DAVENPORT Center for Nephrology, The Royal Free Hospital, Pond Street, London, United Kingdom Hemodialysis International 2004; 8: Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

How does Low Molecular Weight Heparin (LMWH) work?37
Are derived from UFH, e.g. Enoxaparin Have a reduced ability to catalyze inactivation of thrombin because the smaller fragments cannot bind to thrombin but retain their ability to inactivate factor Xa. Are smaller pieces of the heparin molecule that inhibit clotting factor Xa more than factor IIa (thrombin) Bind to antithrombin III; however, low-molecular-weight heparin inhibits thrombin to a lesser degree, and Factor Xa to a greater degree, than standard heparin Low-molecular-weight heparin binds less strongly to protein Interacts less with platelets 37 Oudemans-van Straaten, H et al. "Clinical review: anticoagulation for continuous renal replacement therapy–heparin or citrate." Critical Care 15.1 (2011): 202. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Advantages & Disadvantages related to the use of Low Molecular Weight Heparin38,39 Advantages Simple to use (Unique injection) HIT risk reduced in comparison with Heparin Reduced checking of INR and APPT Disadvantages Longer half life than Heparin No antagonist drug 38 Kellum J Bellomo R Ronco C Continuous Renal Replacement Therapy pg136 Oxford:New york 39 Joannidis M, Oudemans-van Straaten H. Clinical review: Patency of the circuit in continuous renal replacement therapy. Critical Care. 2007;11(4):218. Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

How does Prostacyclin (e.g. Flolan) work?
Prostacyclin, a naturally occurring prostaglandin synthesized from arachidonic acid It is a potent vasodilator with antiplatelet effects, i.e. inhibiting platelet aggregation40 40 Hall N, Fox A Renal replacement therapies in critical care Continuing Education in Anaesthesia, Critical Care and Pain (2006) 6(5) Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Advantages and Disadvantages related to the use of Prostacyclin41
Inhibition of the platelets aggregation >2H Few hemorrhage accident In association with Heparin or LMWH increase the circuit lifespan Disadvantages / Side Effects: Hypotension (less than 3 min, up to 15mmHg) Intracranial hypertension Impossible to antagonize Expensive (X3 the cost of a treatment) 41 Hall N, Fox A Renal replacement therapies in critical care Continuing Education in Anaesthesia, Critical Care and Pain (2006) 6(5) Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

How does Regional Citrate Anticoagulation (RCA) work?42
Citrate is added to the extracorporeal circuit pre-filter It chelates (binds) with ionized Calcium (free Calcium) in the filter by forming Ca-Citrate complexes, thus removing Ca needed in coagulation cascade - anticoagulant effect A percentage of these complexes are removed in the filter, some pass on to the systemic circulation Ca gets infused post-filter to restore iCa Ca-Citrate complexes are metabolized in the liver, muscle & kidney (Krebs cycle; aerobic) releasing Ca & forming Bicarbonate (1:3), buffer effect Anticoagulant effect is limited to the filter 42 Joannidis, M and Oudemans-van Straaten, H. Clinical review: Patency of the circuit in continuous renal replacement therapy. Critical Care (2007), 11:218 (doi: /cc5937 Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

How does Citrate work? ACD-A (Citrate Solution) Citrate binds Calcium in the blood circuit. ACD-A chelates (binds to) calcium creating calcium citrate. Once they are bound together there is not enough free calcium available to continue the activation of the clotting cascade. Remember Factor 9a needed Factor 8, phospholipid and calcium to enable Factor 10 and continue the cascade through. Think cake. Calcium is your flour if you don’t have flour your cake wont be a cake. You need all ingredients to react with each other to make the cake – clot! Citrate is both an anticoagulant and a buffer, and for this reason it can be difficult to use and understand. Sodium citrate, administered before the filter, chelates calcium. The associated regional hypocalcemia in the filter inhibits the generation of thrombin. Citrate is partially removed by filtration or dialysis [36], and the remaining amount is rapidly metabolized in the citric acid (Krebs) cycle – especially in the liver, muscle and renal cortex - while the chelated calcium is released and the lost calcium is replaced. Systemic coagulation is unaffected. For anticoagulation, the citrate dose is adjusted to blood flow to attain an ionized calcium concentration <0.4 mmol/l in the filter; the lower the calcium concentration, the higher the degree of anticoagulation. Some protocols use a fixed dose of citrate in relation to blood flow according to an algorithm, and target such doses at about 3 mmol citrate/l blood flow [37]. Other protocols measure postfilter ionized calcium and adjust the citrate dose, which complicates the intervention but optimizes anticoagulation. Reported derangements include metabolic alkalosis and acidosis, hypernatremia and hyponatremia, and hypocalcemia. They are detected with proper monitoring and the local protocol should describe how to adjust flows under different conditions to prevent such problems. Illustration for example only. Citrate binds to calcium forming calcium citrate complexes. These inhibit the coagulation pathway Copyright ©2016 NIKKISO Co., LTD. All rights reserved.

Kidney Disease Improving Global Outcomes (KDIGO)
A 2012 publication “based upon the best information available…designed to provide information and assist decision-making43”. For patients without an increased bleeding risk or impaired coagulation and not already receiving effective systemic anticoagulation, we suggest “ : For anticoagulation in CRRT, we suggest using regional citrate anticoagulation rather than heparin in patients who do not have contraindications for citrate. (2B)44” “The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined.45” Skim over, read out point 3 KDIGO – AKI Clinical Practice Guideline Reference 1 page 4 para 1 verbatim below: “SECTION I: USE OF THE CLINICAL PRACTICE GUIDELINE This Clinical Practice Guideline document is based upon the best information available as of February It is designed to provide information and assist decision-making. It is not intended to define a standard of care, and should not be construed as one, nor should it be interpreted as prescribing an exclusive course of management. Variations in practice will inevitably and appropriately occur when clinicians take into account the needs of individual patients, available resources, and limitations unique to an institution or type of practice. Every health-care professional making use of these recommendations is responsible for evaluating the appropriateness of applying them in the setting of any particular clinical situation. The recommendations for research contained within this document are general and do not imply a specific protocol.” Reference 2 Page 13 Section 5 “Dialysis interventions for Treatment of AKI” “5.3.2: For patients without an increased bleeding risk or impaired coagulation and not already receiving effective systemic anticoagulation, we suggest the following: : For anticoagulation in intermittent RRT, we recommend using either unfractionated or low-molecularweight heparin, rather than other anticoagulants. (1C) : For anticoagulation in CRRT, we suggest using regional citrate anticoagulation rather than heparin in patients who do not have contraindications for citrate. (2B) : For anticoagulation during CRRT in patients who have contraindications for citrate, we suggest using either unfractionated or low-molecular-weight heparin, rather than other anticoagulants. (2C)” Reference 3 Page 7 ‘Nomenclature and Descrition for rating Guideline Reccommendations’: “Grade* Patients Clinicians Policy Level 1 ‘‘We recommend’’ Patients: Most people in your situation would want the recommended course of action and only a small proportion would not. Clinicians: Most patients should receive the recommended course of action. Policy: The recommendation can be evaluated as a candidate for developing a policy or a performance measure. Level 2 ‘‘We suggest’’ Patients: The majority of people in your situation would want the recommended course of action, but many would not. Clinicians: Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with her or his values and preferences. Policy: The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined.” 43, 44, 45 KDIGO Clinical Practice Guideline for Acute Kidney Injury Kidney International Supplements Vol 2 Issue 1. Copyright ©2016 NIKKISO Co., LTD. All rights reserved.

What does the body do with Citrate?
Citrate is converted into citric acid. Citric acid = Bicarbonate ++ Yielding/resulting in the release of bicarbonate Also metabolised in the Krebs cycle in the liver, skeletal muscle and renal cortex. Or metabolised into glucose Excreted. What happens to the citrate in the body? Process of citrate converted into citric acid results in a relesaes on bicarb WHAT DO YOU THINK WILL HAPPEN TO GASES? What sort of solution do we use? Lots of bicarb floating about. Crap liver, malnourished and renal cortex 3rd strike and youre out you cant metabolised. But it still might be worth a go. Could go from 3 hours to 12 hours. Also metabolised into glucose. Is this a 50/50 split? If it cant metabolise in liver skeletal and cortex can it do it glucose? Do diabetic pts metabolise it easier or more effectively? , does a head injury or cooled pt with less glucose free around find it more difficult? Keeping this into a circle for the moment. No evidence with %s but there is annectodal evidence to suggest that some % of citrate is metabolised into glucose but no hard numbers. So its just another reason to keep a close eye on glucose levels Diagram for illustrative purposes only THINK! Copyright ©2016 NIKKISO Co., LTD. All rights reserved.

Advantages related to Citrate46,47
Citrate is recommended in patients who require CRRT but are at high risk of bleeding (only the extracorporeal circuit is anticoagulated) Monitoring can be easily performed by monitoring ionised calcium levels which most ICUs have on site to tightly control infusion rates Can be performed in combination with standard CRRT equipment 27 Citrate anticoagulation for continuous venovenous hemofiltration: Heleen M. Oudemans-van Straaten Crit Care Med 2009 Vol. 37, No. 2 28 Regional Citrate Versus Heparin Anticoagulation for Continuous Renal Replacement Therapy: A Meta-Analysis of Randomized Controlled Trials Mei-Yi Wu, MD Am J Kidney Dis. 2012; 46 Oudemans-van Straaten, H: Citrate anticoagulation for continuous venovenous hemofiltration: Crit Care Med 2009 Vol. 37, No. 2 47 Mei-Yi, W: Regional Citrate Versus Heparin Anticoagulation for Continuous Renal Replacement Therapy: A Meta-Analysis of Randomized Controlled Trials: Am J Kidney Dis. 2012; Copyright © 2016 NIKKISO Co., LTD. All rights reserved.

Copyright ©2015 NIKKISO Co., LTD. All rights reserved.
AQUARIUS system NIKKISO Europe GmbH Desbrocksriede 1 30855 Langenhagen Germany ACCUSOL solution Nikkiso Belgium bvba Industriepark 6 3300 Tienen Belgium AQUAMAX hemofilter Nikkiso Belgium bvba Industriepark 6 3300 Tienen Belgium AQUALINE tubing Haemotronic Via Carreri, 16 41037 Mirandola Italy CITRASETRCA Assembled by Haemotronic Via Carreri, 16 41037 Mirandola Italy ACCUSOL, AQUALINE, AQUAMAX and AQUARIUS are trademarks of Nikkiso Co Ltd. Copyright All rights reserved. Copyright ©2015 NIKKISO Co., LTD. All rights reserved.

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