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Anticoagulationin CRRT

Akash DeepDirector - PICU

King’s College Hospital London

ChairCritical Care Nephrology

European Society of Paediatric and Neonatal Intensive Care (ESPNIC)

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‘Circuit life’ – ?determinants(children)

‘circuit’ factors • (a) flow rate • (b) pre-dilution • (c) catheter size • (d) anticoagulation

‘patient’ factors • (a) primary condition • (b) INR • (c) platelet count • (d) haemoglobin • (e) venous access issues• (f) blood products use.

Overview• Why do we change filters? Is everything

related to clotted filters?• Why do filters/circuits clot?• Various Anticoagulants available – Actions,

advantages, disadvantages• Is there a single best anticoagulant?• Available evidence• Anticoagulation in special circumstances

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Reason for circuit change• Clotting• Manufacturer recommendation(72 hours)• access malfunction- kinking, bending, leakage,

inappropriately small size• machine malfunction• unrelated patient indication (e.g., needs CT scan)• CRRT discontinued

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Effects of circuit/filter clotting• Decreased efficacy of treatment -

(important in circumstances like in ALF)• Increased blood loss especially in

newborns• Increased costs • Propensity to increased haemodynamic

instability during re-connection• Staff dissatisfaction

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Factors related to premature Clotting• Patient related• Access related• Circuit related• Treatment related

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Where does thrombus form?• Any blood-artificial surface interface

o Hemofiltero Bubble trapo Vascath

• Areas of turbulence /Resistanceo Luer lock connections

/ 3 way stopcocks

Small vascath sizes and lower blood flows add to already existing challenges in paediatric population

• Seven ppCRRT centerso 138 patients/442 circuitso 3 centers: hepACG onlyo 2 centers: citACG onlyo 2 centers: switched from hepACG to citACG

• 18000 hours of CRRT, 442 CRRT circuits• HepACG = 230 circuits (52%)• CitACG= 158 circuits(36%)• NoACG = 54 circuits(12%)• Circuit survival censored for

o Scheduled changeo Unrelated patient issueo Death/withdrawal of supporto Regain renal function/switch to intermittent HD.

Circuitsfunctionalat60hrs– 69%withHep&Citrate;28%withnoACGLifethreateningbleedingcomplicationsattributabletoanticoagulationnotedintheheparinACGgroupbutwereabsentinthecitrateACGgroup.

Similar life spans with heparin and citrate but lesser bleeding complications with citrate

Mean circuit life- 41 hoursHeparin – 42 hoursCitrate – 44.7 hoursNo ACG- 27.2 hours

Ideal Anticoagulation• Readily available• Safe -Selectively active in the circuit – minimal effects on

patient hemostasis• Prolonged filter life ideally > 48 hours• Monitoring – Rapid and Simple• Rapidly reversible in case of complications• Uncomplicated ,easy to follow consistently delivered

protocols- Staff training• Cost Effective

Anticoagulants

• Saline Flushes• Heparin (UFH)• Low molecular weight heparin• Citrate regional anticoagulation• Prostacyclin• Nafamostat mesilate • Danaparoid• Hirudin/Lepirudin• Argatroban (thrombin inhibitor).

The elements of haemostasis

A newer model of the coagulation pathway

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Heparin• Most commonly used anticoagulant• Large experience • Short biological half-life• Availability of an efficient inhibitor• Possibility to monitor its effect with routine

laboratory tests – ACT.

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Heparin

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Heparin enhances binding of antithrombin III to factor II & X

Large fragments – Anti IIa ActivitySmall fragments : Anti Xa activityActs directly and taken up by RES

Metabolised by the liverMetabolites are eliminated by the kidneysPlasma half-life is approximately 90 mins

Heparins and LMWH

21Courtesy –Andrew Durward

Heparin Protocols• Heparin infusion prior to filter with post filter ACT

measurement and heparin adjustment based upon parameters

• Bolus with 10-20 units/kg – Not always• Infuse heparin at 10-20 units/kg/hr• Adjust post filter ACT 180-220 secs• Interval of checking is local standard and varies from

1-4 hr increments.• Personal practice – doses < 20 U/kg/hr – not very

efficacious

Heparin – Side Effects• Bleeding -10-50% ( Dose ACT adjusted)• Heparin Resistance ( AT reduced in sick

patients + increased AT degradation)• Heparin Induced Thrombocytopenia (HIT)

(<1 to 5%) The antibody–platelet factor 4–heparin complex subsequently binds to platelets, inducing platelet activation, aggregation and activation of the coagulation pathways.

• Unpredictable and complex pharmacokinetics of UFH

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LMWH

Advantages DisadvantagesHigher anti Xa activityMore predictable pharmacokinetics-hence more reliable anticoagulant response Reduced risk of bleedingLess risk of HIT

No quick antidoteEffect more prolonged in renal failureSpecial assays to monitor anti-Xa activityIncreased costNo difference in filter life

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Daltaparin,enoxaprin,and nadroparin

Heparin- Summary• Most commonly used• Easy to use, monitor• No evidence on dose• Systemic side-effects• Contraindicated in bleeding patients

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Sites of Action of Citrate

CONTACT PHASEXII activation

XI IX

TISSUE FACTOR TF:VIIa

THROMBIN

fibrinogen

prothrombin

Xa

Va VIIIa Ca++

platelets

CLOT

monocytes / platelets /

macrophages

FIBRINOLYSIS ACTIVATIONFIBRINOLYSIS INHIBITION

NATURAL ANTICOAGULANTS

(APC, ATIII)

X

Phospholipid surface

Ca+

+Ca+

+Ca+

+Ca+

+Ca+

+Ca+

+

CITRATE

Citrate

Citrate: A Regional Anticoagulant

¯Ca++

¯Ca++

¯Ca++

CaCl

Normal Ca++

• Clotting is a calcium dependent mechanism, removal of calcium from the blood will inhibit clotting

• Adding citrate to blood will bind the free calcium (ionized) calcium in the blood thus inhibiting clotting

Calcium is returned to the patient independent of the dual lumen HF access or can be infused via the 3rd

lumen of the triple lumen access

(1.5 x BFR)

Citrate: Technical Considerations

• Measure patient and system iCa in 2 hours then at 6 hr increments

• Pre-filter infusion of Citrate– Aim for system iCa of 0.3-0.4 mmol/l

• Adjust for levels• Systemic calcium infusion

– Aim for patient iCa of 1.1-1.3 mmol/l• Adjust for levels

Advantages of citrate anticoagulation

• Zero effect upon patient bleeding • Monitor with ionized calcium assay- ACT nor

PTT is needed• Various programs report less clotted circuits =

less disposable cost and less overtime nursing hours

• Bedside surveys demonstrate less work of machinery allowing more attention to patient

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Citrate: Problems• Metabolic alkalosis

– Metabolized in liver / other tissues• Electrolyte disorders

– Hypernatremia– Hypocalcemia– Hypomagnesemia

• Cardiac toxicity– Neonatal hearts

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Prisma ionized Ca++ (mmol/L) Citrate Infusion Adjustment

> 20 kg < 20 kg < 0.35 ↓ rate by 10

ml/hr ↓ rate by 5 ml/hr

0.35 – 0.5 (Optimum Range) No adjustment 0.5 – 0.6 ↑ rate by 10

ml/hr ↑ rate by 5 ml/hr

> 0.6 ↑ rate by 20 ml/hr

↑ rate by 10 ml/hr

NOTIFY MD IF CITRATE INFUSION RATE > 200 ml/hr !

Titrate the Calcium infusion according to the calcium sliding scale below :

Patient ionized Ca++ (mmol/L) Calcium Infusion Adjustment > 20 kg < 20 kg

> 1.3 ↓ rate by 10 ml/hr

↓ rate by 5 ml/hr

1.1-1.3 (Optimum Range) No adjustment 0.9-1.1 ↑ rate by 10

ml/hr ↑ rate by 5 ml/hr

< 0.9 ↑ rate by 20 ml/hr

↑ rate by 10 ml/hr

NOTIFY MD IF Calcium INFUSION RATE > 200 ml/hr !

Titrate the Citrate infusion according to the citrate sliding scale below :

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• Seen with rising total calcium with dropping patient ionized calcium

• Essentially delivery of citrate exceeds hepatic metabolism and CRRT clearance

• Metabolic acidosis with an enlarged anion gap

• A serum total to ionic calcium ratio of ≥ 2.5 is assumed to be a critical threshold for the prediction of citrate accumulation

Decrease or stop citrate for 3-4 hrs then restart at 70% of prior rate or Increase D or FRF rate to enhance clearance

CITRATE LOCK

Citrate Anticoagulation• Well-designed and flexible protocol • Adjusted to the local preferences of modality and dose• Results of ionized calcium measurement should be

available 24 hours a day (Keep circuit [Ca++] levels around .30 for best results)

• Training of staff – understand monitoring and side effect profile

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Citrate versus Heparin

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• Safe and easy to be used• Better circuit life with RCA• Better 28-day hospital survival

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Heparin – 21 hoursCitrate – 45.2 hours

Actually administered effluent dose as compared to prescribed dose:85% heparin vs 92% with citrate

RBC units with Heparin – 6.5RBC unis with citrate -3

Heparin – 3723 hoursCitrate – 4530 hours

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RBC requirement – 0.17 with RCAvs 0.36 with heparin per circuit

Final Decision – Citrate vs Heparin• Local familiarity with protocol, patient population• Heparin common as vast experience, easy to monitor, good circuit life• Problems – Systemic anticoagulation, bleeding

(sometimes life-threatening), HIT, resistance• Citrate – comparable filter life, no risk of bleeding

Why is citrate not the standard of care ?v Physician’s perception- use of citrate complex, v Citrate module not in every machinev Metabolic complications with regular monitoring, metabolism in

liver disease complexv Huge training resourcev Cost• In UK – Heparin is the most commonly used ACG for ease of use.

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CitrateHeparin

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• A lipid molecule-eicosanoid

• Epoprostenol – synthetic derivative

• Platelet aggregation and adhesion inhibitor (PGI2)

• Heparin sparing effect• Reversibly inhibits platelet

function by diminishing the expression of platelet fibrinogen receptors and P-selectin

• Reduces heterotypic platelet-leukocyte aggregation.

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Monitoring• No complex monitoring required• Clinical – Bleeding, hypotension• Platelet aggregation tests – Costly,

time consuming• Thromboelastography (TEG) -

useful

Kinetics :• Half life – 42 seconds• Vasodilator effect at 20 ng/kg/minute• Platelet effect at 2-8 ng/kg/minute -½

life 2 hours• Limited clinical experience• Flolan – epoprostenol sodium

Evidence for use of Prostacyclin• None out there especially in Paediatrics• Dose ???• Route -?• Indications -?• Most work carried out in patients where

there is contraindication to heparin/citrate

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Guideline PICU KCH

Start 4 ng/kg/min(range 4-8 ng/kg/min)

Monitor circuit Life

8ng/kg/minmax

<48 h

Infusion:

12 mcg/kg of EPO

in 0.9% NaCl to make a total of 50 ml

1ml/h = 4ng/kg/min

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Why I feel prostacyclin is safe and effective

• Regional Anticoagulationo No systemic anticoagulation effect

• Can be used in patients with coagulopathy• Prolongs Filter Life• Suits my patient population• Protocol easy to use and follow with no complex

monitoring required• Minimal side effects

Cost factor – the biggest factor ???

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Summary • Heparin and citrate anticoagulation most

commonly used methods• Heparin: bleeding risk• Citrate: alkalosis, citrate lock• Evidence favours the use of citrate ( not

universally used)• Prostacyclin a good alternative in patients with

liver disease / bleeding diathesis ( Cost implications)

Anticoagulation in Special Circumstances• Anticoagulation in CRRT in liver patients - is it

different ? – Can citrate be used as liver which metabolises citrate is not functional OR can heparin be used to deranged clotting in ALF?

• ECMO• TPE • MARS/SPAD• Neonatal Population

Ward round details• Any problems with circuit/filter ?• No. of circuit/filter changed last 24 hours• TMP, predilution• Access pressure• Look closely at access- size, leakage, bending/kinking• Anticoagulation – dose, ACT, bleeding from any site• Persistently low ACT - ?AT deficiency ( FFP/Cryo) OR

add prostacyclin to low dose heparin

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Conclusion

• No perfect choice for anticoagulation exists• Choice of anticoagulation is best decided locally• Think of patient’s disease process, access issues, blood

product use• For the benefit of the bedside staff who do the work come

to consensus and use just one protocol• Having the “protocol” changed per whim of the physician

does not add to the care of the child but subtracts due to additional confusion and work at bedside.

First International Conference of Pediatric Critical Care Nephrology -August 2020

Queen Elizabeth Centre II, London

Conference Chairmen: Akash Deep - King’s College Hospital, LondonStuart Goldstein- Cincinnati Children’s Hospital

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9 783319 902807

ISBN 978-3-319-90280-7

Critical Care Medicine

Th is book represents an invaluable resource for professionals for the diagnosis and treatment of acute kidney injury (AKI) in children and how to select and deliver the appropriate form of renal replacement therapy (RRT). Experts from all over the globe have come together to share their wide experience in the fi eld of Critical Care Nephrology in children.

Paediatric critical care nephrology is a complex and highly specialised fi eld, presenting challenges and management strategies that are oft en quite distinct from those seen in adult practice. Th erefore, it is high time to address all the topics in the fi eld of critical care nephrology in children in a unique book which is the fi rst of its kind. Th is book covers the basics as well as advances in the fi eld of Critical Care Nephrology. Each chapter is dedicated to practical aspects of a particular topic elucidating various management decision points. Each chapter is also accompanied with algorithms, fi gures and protocols in tabulated format. Information on how to manage specifi c conditions are contextualized with relevant background anatomy, physiology and biochemistry and practical examples. At the end of the chapter, there are key learning points.

Paediatricians, nephrologists and paediatric intensivists, as well as paediatric critical care and nephrology nurses in all countries will fi nd this book an invaluable reference text.

Akash Deep · Stuart Goldstein EditorsCritical Care Nephrology and Renal Replacement Therapy in Children

Deep · Goldstein Eds.

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Critical Care Nephrology and Renal Replacem

ent Therapy in Children

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Akash DeepStuart GoldsteinEditors

Critical Care Nephrology and Renal Replacement Therapy in Children