ECMO and Continuous Renal Replacement Therapy - PPAG

ECMO and ContinuousRenal ReplacementTherapyBrenda L. Dodson, Pharm.D.Learning Objectives• Describe the basic mechanics ofExtracorporeal MembraneOxygenation (ECMO)• Describe the basic mechanics ofContinuous Renal ReplacementTherapy (CRRT)• Discuss modification of drug therapybased on the effects ofextracorporeal circuitsWhat do I know? What do I needto know? How do I get there?• Overwhelming information• $10 dollar words• Paucity of reliable data• Difficult patient population• Don’t forget the basics• Balance benefits and risks• Good guesstimates• Keep it as simple as possible

ECMO - Basics• Extracorporeal Membrane Oxygenation• Break it down• Extracorporeal - Not in the body• Something to do with a membrane• Oxygenation occurs• Prolonged form bypass used to supportpatients with life-threatening potentiallyreversible respiratory or cardiac failureunresponsive to optimal conventionaltherapy• Introduced in 1975• ECCO 2 R, ECLS, ECLA, ECMOECMO - Neonates• Neonatal population• Has been used extensively• Treat severe respiratory failure• Meconium aspiration syndrome• Congenital diaphragmatic hernia• Persistent pulmonary hypertension• Respiratory distress syndrome• Sepsis• Now less often necessary due to advent ofinhaled nitric oxide therapy and Hi-FrequencyOscillatory Ventilation (Hi-FOV)• Success rate of ~80%ECMO - Pediatrics• Pediatric population• ~1990• ~55% survival for respiratory failure• ARDS• Viral/bacterial pneumonia• Sickle cell disease• Asthma• Other conditions• Severe sepsis• Near drowning• Pulmonary embolism• Pulmonary contusion• Severe, reversible myocardial dysfunction

ECMO• Purpose of ECMO• Provides carbon dioxide removal andoxygenation of venous blood• Replaces broken lungs• Both VA and VV• Can remove deoxygenated blood from thevenous system and return of oxygenatedblood into the arterial circulation• Replaces broken hearts• VA• Patients still intubated and on ventilatorysupport to prevent lung collapse• Minimize barotrauma and volutrauma fromhigh pressuresKinds of ECMO• Venovenous (VV) – Pulmonary• Venous (deoxygenated) blood removal fromright internal jugular (RIJ) vein and return ofoxygenated blood to (RIJ)• Venoarterial (VA) – Pulmonary and Cardiac• Venous (deoxygenated) blood removed fromRIJ or femoral vein and return of oxygenatedblood to right common carotid artery orfemoral artery, nonpulsatile flow• Bypasses heart and pulmonary circulation• Not 100% bypass…still allows some venous bloodto proceed through the normal heart/lungcirculatory patternECMO – What’s Happening?• What happens in the circuit• Tubing – carries blood• Collapsible reservoir/bladder• Captures air bubbles and clots, drug administration• Roller pump• Advances blood through the circuit to the oxygenator• Membrane Oxygenator (Silicone)• “Roll of paper towels”• “Artificial lung” for CO 2 removal and oxygenation of blood• Sweep gas to prevent excessive CO 2 removal and metabolicalkalosis• Heater• Prior to being returned to the body• In patients with renal dysfunction or fluid overload, ahemofiltration unit can also be added to the circuit

What do we know about drugson ECMO?• Few studies• Limited by small sample sizes, differencesin ECMO techniques and equipment, andcomplexity of patients with lack of uniformdiagnosis• Clinical judgment• Benefits versus risk• Toxicity profile• Monitoring capabilitiesHow do critically ill patientschange things?• Complex• Patient effects• Volume of Distribution• Fluid overload• Hypoalbuminemia• Renal function• Sometimes impaired or becomes impaired• Diuresis• Overall organ function• Hypoxia

How does ECMO changethings?• Complex• ECMO circuit effects• Adsorption• Saturable, depends on frequency of circuit changes• To tubing• To oxygenator• Volume of distribution• Blood product volume for initial prime and dailymaintenance of coagulation parameters• Administration of medications into circuit• Pre-, intra-, post- bladder locations• HemofiltrationDrug Loss in Circuit• Adsorption• Tubing•Albumin administration to circuitbefore blood prime helps to minimize• Oxygenator•Not well studied•Variable effects•Saturable•Depends on circuit change frequency

Volume of Distribution• ECMO requires the addition exogenous bloodproducts to prime the circuit• Increases circulating blood volume and overallvolume of distribution• Some cases more than doubles normal blood volume• Can have effects on the volume ofdistribution of medications• More significant in neonates than in pediatricand adolescent patients• Especially significant for drugs primarilydistributed in the central compartment• Low population V dCHB prime packs• Albumin• Shown to decrease drug adsorption• An electrolyte solution and Albumin are added tocircuit after the CO 2 prime and before the bloodproduct prime• Neonatal Pac• 500 mL CMV negative PRBCs

Heparin• Heparinization to prevent clotting of the circuit• ACT – activated clotting time• 180-200 seconds during ECMO (normal 90-100 seconds)• Goal can be lowered if patient is bleeding• Heparin clearance reported to be increasedduring ECMO• ?binding/inactivation to circuit• CHB: 30 units/kg IV x1, then begin ~10units/kg/hr and titrate as necessary +/-intermittent doses to keep ACT (Q1h checks)180-200 seconds• Maintenance of platelet count, fibrinogen, andclotting factors necessary, QOD head ultrasoundAminocaproic Acid• Antifibrinolytic used in patients at risk of IVH• Gestational age

Sedatives and Analgesics• Anesthetic doses given during cannulation• Maintenance Therapies• Opioids• Fentanyl – shown to have significant binding to circuit (~70%)• Morphine – also shown to bind to circuit, but to a lesser extent• CHB – morphine infusion started at 0.05 mg/kg/hr, titrated• Benzodiazepines• Lorazepam – can be used in intermittent doses• Midazolam – circuit binding• CHB – midazolam infusion started at 0.05 mg/kg/hr, titrated• Barbiturates: Pentobarbital 2-6 mg/kg IV Q2h PRN• Constant titration• Consider weaning as able and empirically decreasinginfusion rates when ECMO is discontinuedChemical Paralysis• Not routinely administered• Use of muscle relaxants is indicated under thefollowing circumstances• During conditioning or cycling• Acutely when patient movement interferes withvenous return• Particularly during VV ECMO• In the rare situation when excessive patientmovement threatens accidental decannulation.• Pancuronium 0.1-0.2 mg/kg IV• Cisatracurium 0.2 mg/kg IV• Continuous infusionsAntiepileptics• Fosphenytoin/Phenytoin• Typically difficult to achieve therapeutic levels inneonatal population• Not often used• Phenobarbital• Most commonly used• ECMO circuit shown to have significant effects -increased elimination• Begin with typical doses and adjust as necessary• Midazolam/Lorazepam on board

Cardiovascular• Vasoactive infusions routinely used• Titrate to effect• Dopamine• Epinephrine• Norepinephrine• Dobutamine• Milrinone• Consider access• ElectrolytesFEN• Replace electrolytes as necessary• Allows for optimal efficacy of diuretics• Correct metabolic acidosis• Tromethamine• Hypernatremia• Alternate to sodium bicarbonate in hypernatremia• Beware renal function• PN/enteral feeds• Intralipids are okay• NTE 2 g/kg/day to prevent accumulation and embolismin circuit.GI• Stress Ulcer Prophylaxis• Ranitidine• Studies suggest greater elimination onECMO• Typical dosing, most often added to PN• Renal function• Monitor gastric pH• Proton Pump Inhibitors• Pantoprazole, Omeprazole• Monitor gastric pH

Diuretics/Hemofiltration• Fluid overload is common problem• Furosemide• Higher doses secondary to loss in circuit• Up to 2 mg/kg IV Q8h• Infusions 0.05 – 0.2 mg/kg/hr• Chlorothiazide• Up to 20 mg/kg IV Q12h• Give 30 minutes before furosemide• Spironolactone• Hemofiltration• Ultrafiltration – convective removal of medicationspossible• Maintain urine outputInfectious Diseases• Broad-spectrum antibiotics• Prophylaxis and treatment• Gram negative coverage• Gram positive coverage• Listeria monocytogenes• Infectious complications• Cannulation process• Prolonged exposure to the catheters• Manipulation of the ECMO circuit• Immune function of the patient• Children’s Hospital Boston Neonatal ECMO• Ampicillin, Oxacillin, CefotaximeInfectious Diseases• Gentamicin• Most well studied drug• Studies indicate decreased clearance andincreased volume of distribution• 2.5 mg/kg IV Q18h suggested• Typically no change necessary – monitor peakand troughs and increase dose or extendinterval as appropriate• 35 weeks gestational age: 4 mg/kg IV Q24h• 1 month – 10 yo: 2.5 mg/kg IV Q8h• >10 yo: 2 mg/kg IV Q8h

• VancomycinInfectious Diseases• Studies indicate decreased clearance and increasedvolume of distribution• 15 mg/kg IV Q18h suggested• 15 mg/kg IV Q8-12h – monitor trough levels and adjust asappropriate• Meropenem, Fluconazole, Ambisome®,Piperacillin/Tazobactam, Clindamycin• Balance risks of underdosing with expectedtoxicities• PrioritizationECMO - Renal Function• Usually some evidence ofcompromise• Circulating vasoactive substancesmay be stimulated as blood passesthrough the oxygenator•Arachidonic acid metabolites andrenin•Causes reduction of renal blood flow• Aggressive diuretic therapy• Renal hypoxia prior to or duringECMOBasics - CRRT• What is CRRT?• Continuous Renal ReplacementTherapy• Any continuous mode ofextracorporeal solute or fluidremoval• Continuous hemofiltration was firstused in 1977 for diureticunresponsive fluid overload

What happened to.….• SCUF – Slow Continuous UltraFiltration• Convective removal, no replacement fluid• CAVH – Continuous ArterioVenous Hemofiltration• Convective removal, patient blood pressure determinesflow, 2 vessels, replacement fluid• CVVHD – Continuous VenoVenous HemoDialysis• Diffusive removal, pump driven, usually no replacementfluid, dialysate delivered countercurrent to blood• CVVH – Continuous VenoVenous Hemofiltration• Convective removal, pump driven, replacement fluid• CVVHDF – Continuous VenoVenousHemoDiaFiltration• Diffusive + Convective Removal, pump driven,replacement fluid, dialysate delivered countercurrent tobloodCRRT - Principles• Blood flows through a semipermeablemembrane driven either by patient bloodpressure (AV mode) or by a peristalticpump (VV mode)• Semipermeable membrane of the filter istypically synthetic and high-flux• Solute clearance can be achieved bydiffusion, convection, or a combinationDiffusion• Solutes such as urea, phosphate, and uremictoxins are driven by their electrochemicalgradient to move across the membrane into thesterile dialysate, which is runningcountercurrent to blood on the other side of themembrane capillaries• Different than IHD• CRRT – dialysate flow is slow• Typically 0.6 - 2 L/hr• IHD – dialysate flow is fast• Typically 500 mL/min or 30 L/hr

Convection (Hemofiltration)• Solute movement across the membrane is drivenby solvent drag• Solvent (plasma water) is pushed across themembrane by the filtrating pressure generatedby blood flow• Identical to glomerular ultrafiltration• High-flux membranes have permeability cutoff pointsof up to 30,000 daltons• Solvent takes all plasma water solutes• Combination becomes the effluent or ultrafiltrate (UF)from the filter which is discarded• UF – replaced with a fluid that contains thenecessary electrolytes and volume but none ofthe toxinsHemodiafiltration• Diffusion + convection• Improved clearance of large and smallmolecules• Removal of excess fluidReplacement Fluids• Replace fluid volume and electrolytes• Lactate-based and bicarbonate-basedsolutions• Normocarb HF solutions• Sodium 140 mEq/L• Magnesium 1.5 mEq/L• Chloride 116.5 mEq/L (25) vs. 106.5 mEq/L (35)• Bicarbonate 25 mEq/L (25) vs. 35 mEq/L (35)• Can add Potassium Chloride, PotassiumPhosphate

• CRRTCRRT vs. IHD• Volume control is continuous and adaptable• Prevent/treat volume overload without inducing acute volumedepletion• Prevent IHD-associated surge in intracranial pressure• Benefits in cardiac disease and renal dysfunction due todecreased volume overload, improved urine output,decreased LEDV• Appropriate fluid resuscitation, administration ofblood products, and nutrition• Rapid improvement and control of metabolic acidosis• More rapid and reliable control of serum electrolytes• Uremic control is superior• Frequency of dialysis• Dose of IHD can be increased, although cannot ever reachthe levels obtained in CRRTOther Considerations• Continuous anticoagulation therapy• Heparin vs. Citrate• Electrolyte Replenishment• Phosphorus• Calcium• CostPharmacokinetics - Basics• Total body clearance (TBC)• Sum of clearances from different sites in thebody• Hepatic, renal, other metabolic pathways,extracorporeal• If renal clearance is normally

Factors DeterminingExtracorporeal Removal• Protein binding• Free circulating fraction of drug is available for removalby extracorporeal means• pH, heparin therapy, hyperbilirubinemia, relativeconcentration of drug and protein, uremia, other drugs• Volume of distribution• Indirectly proportional to free drug in vascularcompartment• IHD vs. CRRT• IHD - drugs with large V d and high clearance during high-fluxIHD will have a rapid decrease in plasma level of freecirculating drug, but only a small amount of the body’s drugcontent is removed• Plasma concentration will be restored between IHD sessions• CRRT - less acute changes in plasma concentration because ofcontinuous redistribution of drugFactors DeterminingExtracorporeal Removal• Molecular weight• Most drugs have molecular weight 1500 daltons (vancomycin 1448 daltons)• Conventional dialysis membranes clear molecules

Adjustments• Critically ill patients at risk for overdoseand drug accumulation, but also at risk forunder dosing which may be lifethreatening• How to Adjust?• D = D N (Cl ANUR + Q E x C E /C P /Cl N• Cl CRRT = f u x (Q UF + Q D x Kd rel )• D E = D N x [P x + f u x (Q UF + Q D x Kd rel )/Cl N ]• Cl CRtot = Cl CRren + Cl CRfiltYeah, Right!• Use published references• CAVH – often recommendation is to usedosage adjustments for creatinine clearanceof 10-50 mL/min/1.73 m 2• Therapeutic drug monitoring wheneverpossible to direct therapy• Clinical effect• Risk vs. benefit• Expected toxicity• Best guessReferences• Mols G, Loop T, Geiger K, Farthmann E, Benzing A. Extracorporeal membrane oxygenation: aten-year experience. Am J Surg. 2000;180:144–154• Kellum J, Mehta R, Angus D, Palevsky P, Ronco C. The first international consensus conferenceon continuous renal replacement therapy. Kidney International 2002;62:1855-63• Petroni K, Cohen N. Continuous Renal Replacement Therapy: Anesthetic Implications. AnesthAnalg 2002;94:1288–97• Ronco C, Bellomo R, Ricci Z. Continuous renal replacement therapy in critically ill patients.Nephrol Dial Transplant 2001;16 Supp 5:67-72• Ronco C, Bellomo R, Kellum J. Continuous Renal Replacement Therapy: Opinions andEvidence. Advances in Renal Replacement Therapy 2002;9(4):229-44.• Goldstein S. Overview of Pediatric Renal Replacement Therapy in Acute Renal Failure. ArtificialOrgans 2003;27(9):781–785• Buck M. Pharmacokinetic Changes During Extracorporeal Membrane Oxygenation Implicationsfor Drug Therapy of Neonates. Clin Pharmacokinet 2003;42(5):403-17.• Bugge J. Pharmacokinetics and drug dosing adjustments during continuous venovenoushemofiltration or hemodiafiltration in critically ill patients. Acta Anaesthesiol Scand 2001;45:929–34.• Wilson B. Extracorporeal and Intracorporeal Techniques for the treatment of severe respiratoryfailure. Respiratory Care 1996;41:306-17.• Dalton H. Extracorporeal life support in the new millenium: forging ahead or fading out? New Horiz1999;7:414-32• Children’s Hospital Boston Neonatal ECMO Clinical Practice Guideline