The Advantages and Disadvantages of Citrate Anticoagulation

Welcome to PICU Doc On Call, a podcast dedicated to current and aspiring intensivists. I am Pradip Kamat.

I am Rahul Damania, a current 3rd year pediatric critical care fellow.

I am Kate Phelps- a second year pediatric critical care medicine. We come to you from Children's Healthcare of Atlanta Emory University School of Medicine.

We are delighted to be joined by guest expert Dr Stephanie Jernigan Assistant Professor of Pediatric-Pediatric nephrology, Medical Director of the Pediatric Dialysis Program at Children’s Healthcare of Atlanta. She is the Chief of Medicine and Campus Medical Director at Children’s Healthcare of Atlanta, Egleston Campus. Her research interests include chronic kidney disease, and dialysis. She is on twitter @stephaniejern13

I will turn it over to Rahul to start with our patient case...

• A 3 year old previously healthy male presents with periorbital edema. Patient was initially seen by a pediatrician who prescribed anti-histamines for allergy. After no improvement in the eye swelling after a two week anti-histamine course, the patient was given a short course of steroids, which also did not improve his periorbital edema. The patient progressed to having abdominal distention and was prescribed miralax for constipation. Grandparents subsequently noticed worsening edema in his face, eyes, and feet. The patient subsequently had low urine output, low appetite and lack of energy patient was subsequently brought to an ED and labs were obtained. Grandparents denied any illness prior to presentation, fever, congestion, sore throat, cough, nausea, vomiting, gross hematuria, or diarrhea. In ED patient was noted to be hypertensive (Average systolic 135-highest 159mm HG), tachycardic (HR 130s-140s), breathing ~20-30 times per minute on RA with SpO2 92%. Admission weight was recorded at 16.5Kg. Physical exam showed periorbital edema, edema of ankles, there was mild abdominal distention (no tenderness and no hepatosplenomegaly), heart and lung exams were normal. There were no rashes on extremities.

Labs at the time of transfer to the PICU: WBC 10 (62% neutrophils, 26% lymphocytes) Hgb 7.2, Hct 21, Platelets 276. BMP: Na 142/K 8.4/Cl 102/HCO3 19/BUN 173/creatinine 5.8. Serum phosphorus was 10.5, Total Ca 6.4 (ionized Ca= 3.4), Mag 2.0, albumin 2.6, AST/ALT were normal. An urine analysis showed: 1015, ph 7.5, urine protein 300 and rest negative. Chest radiograph revealed small bilateral pleural effusions. After initial stabilization of his hyperkalemia-patient was admitted to the PICU. PTH intact 295 (range 8.5-22pg/mL). Respiratory viral panel including for SARS-COV-2 was negative. C3 and C4 were normal. A nephrotic syndrome/FSGS genetic panel was sent. A renal US showed: bilateral echogenic kidneys and ascites (small volume).

Pradip: Dr Phelps what are the salient features of the above case presented?

Kate Phelps: This patient has a subacute illness characterized by edema, anemia, and proteinuria. His labs show that he has severe acute kidney injury with significantly elevated BUN and Creatinine, hyperkalemia, hyperphosphatemia, and hypocalemia.

Rahul: Dr Jernigan welcome to PICU Doc on Call Podcast.

Thanks Kate, Rahul and Pradip for inviting me to your podcast. This is a such a great way to provide education and it is my pleasure to come today to speak about one of my favorite topics, pediatric dialysis. I have no financial disclosures or conflicts of interest and am ready to get started.

Rahul: Dr Jernigan as you get that call from the ED and then subsequently from the PCCM docs, as a nephrologists whats going on in your mind ?

When I get the call from the outside hospital my first job is to make sure the patient is safe and stable for transfer to a tertiary care center. This includes concern about airway, breathing and level of alertness. From a renal standpoint, I am worried about elevated blood pressure, electrolyte abnormalities, in this case primarily the hyperkalemia, and fluid overload, especially given the low oxygen saturation. It is important that children are transported to an appropriate center early, but still safely, to allow for diagnostic work up and intervention. This is particularly true in the case of renal replacement therapy which most community hospitals are reticent or unable to offer to our pediatric patients.

Our episode today will be divided into a few broad categories: INDICATIONS/PRINCIPLES of KIDNEY REPLACEMENT, TECHNICAL ASPECTS of RRT, Anticoagulation, and a comparison of various types of RRT and their complications.

Let’s start with INDICATIONS/PRINCIPLES of KIDNEY REPLACEMENT

Kate Phelps: What are in general indications for renal replacement in pediatric patients?

Indications for renal replacement therapy are similar for acute vs chronic dialysis however differ in their urgency. As we know, our kidneys are important for waste product elimination, a primary measurement of this is blood urea nitrogen, acid base and electrolyte balance and of course maintaining fluid balance. When these functions fail acutely so as to be dangerous to a patient or when they are chronically inadequate despite medical management, then renal replacement is indicated. Acute indications tend to be significant uremia which can have consequences on multiple systems (CNS, heart, coagulation), symptomatic fluid overload (affecting breathing and cardiac function), and/or hyperkalemia and intractable acidosis not responsive to medical intervention. Medical management includes for fluid overload the use of diuretics and the use of bicarb in order to correct acidosis and shift potassium intracellularly. Additional therapy for hyperkalemia – membrane stabilization with calcium, further increase of uptake of potassium by cells with glucose, insulin and Beta agonists and elimination of potassium in the gut with ion exchange resin (kayexlate). Not related to the kidney directly, dialysis may also be needed in toxic overdose (salicylates and acetaminophen, lithium, metformin to name a few) or inborn errors of metabolism resulting in hyperammonemia.

This has led to the mnemonic AEIOU – acidosis, electrolytes, ingestions, overload and uremia.

Uremia with a BUN of greater than 100 and symptomatic or greater than 150 even without current symptoms are concerning and in most cases indication for dialysis.

Less acute indication but no less important is need for dialysis when treatment and caloric nutrition are impeded by fluid issues and dialysis allows for these to be maximized without regard the secondary consequences of fluid imbalance.

Of note, while creatinine gives us a stable measurement of glomerular filtration rate, it’s value is not in and of itself an indicator for renal replacement therapy.

🎯 Just to summarize, acidosis – metabolic acidosis with a pH <7.1; electrolyte refractory hyperkalemia with a serum potassium >6.5 mEq/L or rapidly rising potassium levels; Intoxications

 – use the mnemonic SLIME to remember the drugs and toxins that can be removed with dialysis: salicylates, lithium, isopropyl alcohol, methanol, ethylene glycol; Overload

 – volume overload refractory to diuresis; Uremia

 – elevated BUN with signs or symptoms of uremia, including pericarditis, neuropathy, uremic bleeding, or an otherwise unexplained decline in mental status

Rahul: Dr Jernigan what physical principles are used in dialysis and what are the properties of the substances we can dialyze?

Let’s start with the principles of dialysis. Important here is understanding the laws governing movement of molecules between solutions and across a semipermeable membrane.

First is diffusion which is movement of molecules from a solution of higher concentration to lower concentration. This is much like “tea” where tea in the bag diffuses out into the water based on a concentration gradient. In diffusion, equilibrium will eventually occur and all things equal diffusion will slow and then stop. Smaller molecules will diffuse faster than larger molecules so this modality does better with smaller molecules.

Next is convection. Convection is movement across the membrane due to a pressure gradient, sometimes called solute drag. This can be compared to the making of coffee where water passed through the coffee grounds “pulling” or “dragging” the coffee (flavor and caffeine thank goodness) with it. This can be a pressure gradient (CVVH) or an osmotic gradient (PD)Convective therapies are better for larger molecular weight substances but removes small molecules as well.

Hemofiltration is movement of fluid across the membrane due to a gradient.

I believe we will talk more specifically about the different types of dialysis later however in brief, Hemodialysis utilizes primarily diffusion with the blood flow rate and the dialyzer being the factors that increases or decreases clearance.

PD uses both diffusion and convection equally but is not the most common modality seen in the ICU setting.

CVVH (continuous veno-venous hemofiltration) in its classic form uses primarily convection but has different modes which also allows for convection , diffusion and a combination of both.

So for best clearance molecules are smaller <10000 Daltons have high water solubility and small volume of distribution and low protein binding (most are greater than 10K Dalton, albumin is 66K Dalton)

To summarize, dialysis systems operate either via diffusion (i.e movement of molecules across a semipermeable membrane using a concentration gradient OR via convection where solutes move across a semipermeable membrane using a pressure gradient. In some modalities ultrafiltration occurs due to an osmotic pressure gradient. Lets transition to the next portion of our podcast which will cover vascular access & anticoagulation

VASCULAR ACCESS

Rahul: Dr Jernigan before we go into each modality, should we discuss the access required for RRT in the PICU?

Before we can begin dialysis we need access to the vasculature (HD and CRRT) and the peritoneal cavity (PD). Vascular access can be placed by you, our ICU colleagues, as well as interventional radiologists and surgeons. In general, we need a large gage vascular catheter. The smallest catheter utilized is 8 gage up to 14 gage. It is best placed in the internal jugular. The subclavian (the location of old) has been changed as complications during placement and vessel stenosis are problematic. This is especially true if future need of arteriovenous fistulas. If there is urgency of placement and especially in larger individuals (greater than 28 BMI) then femoral access may be needed but this has a higher infection risk and we worry about future vascular access for renal transplantation.

While old terminology included vas cath (temporary) and permcath (longer term), we have a system move to terminology that better describes the type of catheter placed. This includes single vs double lumen, low flow vs high flow, tunneled and cuffed (permanent) vs non tunneled. For dialysis we require double lumen and high flow. For long term, the catheter is tunneled and cuffed to allow for lesser infection and movement risk.

Peritoneal catheters are placed by surgeons. These are silicone or polyurethane and in best practice are double cuffed. The first cuff is placed under the skin and then the catheter is tunneled with the second cuff in the rectus muscle. The catheter then enters the peritoneal cavity where the coiled tip is placed in the pericolic gutter or pelvis. While they can be used urgently, the preference is to allow them to sit and heal for two weeks to avoid leakage and infection. The exception is in infants where this is the best option for many situations due to patient size.

ANTICOAGULATION

Kate: Dr Jernigan can you shed some light on the type of anticoagulation required during RRT?

Any time blood is circulated outside the body, it is at risk for clotting which leads to blood loss. For this reason, anticoagulation is required.

This original anticoagulation for blood dialysis is heparin and this is still the mainstay in hemodialysis. This is given as a bolus and thin continuous infusion until some point before discontinuation of dialysis as this is systemic anticoagulation (turned off sooner for fistula’s due to bleeding) Monitoring is through ACT’s however standard dosing is fairly well established and act’s used less often and not in the chronic unit. Starting bolus 20-50 units/kg and infusion of 10-30 units/kg/hr over remaining time.

Side effects are HIT (heparin induced thrombocytopenia) and bleeding risk due to systemic anticoagulation.

Citrate: This is used as regional anticoagulation meaning it only anticoagulates the circuit and not the patient. Citrate binds to calcium in the circuit and prevents activation of both coagulation cascades and platelet aggregation. The majority of the calcium–citrate complex is moves across the membrane by diffusion during dialysis and is lost in the ultrafiltrate. A systemic calcium infusion is necessary post filter to replace the calcium lost with citrate. Any calcium–citrate complex is not filtered and returns to the patient has a very short half life and is metabolized to bicarb by the liver, kidney and skeletal muscle. This citrate is titrated to blood flow to maintain low iCa in the circuit. The Calcium infusion is adjusted to keep iCa normal in the patient.

There are several advantages to citrate. First and foremost is the regional anticoagulation and less systemic bleeding, especially for those at high risk. It can be used in patients with HIT and in some patients, the additional bicarb from the citrate metabolism is helpful. The disadvantages are that in some patients the additional bicarb is not helpful and there can be other metabolic complications related to acid/base and calcium loss. In addition, with citrate there are the more complex protocols for the varying infusion rates and frequent calcium measurements. Citrate is relatively contraindicated in patient with hepatic failure and inborn errors of metabolism related to mitochondrial disorders.

Flolan: Epoprostenol, a naturally occurring prostaglandin with potent vasodilatory activity and inhibitory activity of platelet aggregation and thrombus generation which is it’s mechanism to prevent clotting. For this reason it is avoided in patients with thrombocytopenia and should be used with caution in patients with hypotension. It has a short half-life and like other anticoagulants for CVVH is a continuous infusion of 2-8 ng/kg/min. Monitoring is simple and in addition to the above is circuit longevity.

🎯 Summary time — citrate binds calcium, be careful in patients with liver failure. With Flolan, watch for thrombocytopenia.

MEMBRANE

Pradip: Dr Jernigan what are the types of dialyzers used during RRT?

Hemodialysis dialyzers are primarily made of synthetic material. (polysulfone , poly mix) Synthetic membranes have less complement activation and systemic “allergic” reaction. They are made of multiple hollow semi permeable membrane fibers through which blood is flows with dialysate moving counter current outside the fibers. The effectiveness of the dialyzer is based on the thinness of the material and the number and size of the pores. There is a large surface area which in HD should approximate the patients BSA.

For prismaflex/CVVH we use two synthetic catheters the HF 20 and the HF1000 which are determined by patient size and clearance capability. HF 20 allows CRRT more safely on the small child weighing 8-20 kg.The volume of the dialyzer and tubing is important as in there is limit to the volume of blood that can be in the extracorporeal circuit. This is less than 10% of estimated blood volume and if more needs a blood prime. Keeping in mind that the extracorporeal tubing is also part of this calculation.

Although vascular access for dialysis in the PICU is easily attained by the intensivists, we have to be cautious about infants < 1 year of age. Due to fluid overload, platelet dysfunction (from uremia) etc., these are best done by the surgeon or interventional colleagues in a controlled setting. Pediatric Intensivists should be well versed with anti-coagulation choices during RRT.

RENAL REPLACEMENT MODALITIES

Dr. Phelps: Dr Jernigan what are modalities of renal replacement therapies typically used in children?

In children we can used peritoneal dialysis, hemodialysis, and continuous veno-venous hemofiltration (CVVH), CVVHD, or CVVHDF.

Rahul: Dr. Jernigan Lets start with peritoneal dialysis

After placement of the catheter, Peritoneal dialysis takes advantage of the large surface area of the peritoneal lining, a semi permeable bidirectional membrane to do dialysis by diffusion and convection.

PD is perfomed by instilling fluid, dianeal, into the peritoneal cavity which is then allowed to dwell for a prescribed amount of time (allowing solute movement via diffusion) and then drained. This is repeated for a prescribed number of cycles or time. Dianeal contains calcium, magnesium, sodium chloride and sodium lactate as a buffer. The variable in dianeal is dextrose which creates the osmolarity to allow for fluid removal and secondary solute drag (convection). The dextrose concentrations include 1.5%, 2.5% and 4.25% with higher dextrose pulling more fluid. As the peritoneal membrane is bidirectional, equilibration will occur so the fine art is to find the right dwell time to remove waste and fluid and drain before equilibration happens. Volumes range from 10-40 ml/kg and dialysis improves with increased volume and thus more membrane exposure to dianeal and by increasing time on dialysis.

In general PD is well tolerated and is the best dialysis for young babies with catheters being able to be placed in children weighing as little as 1.8 to 2kg without needing blood exposure as in hemodialysis. While inpatient, PD can be done with a manual exchange set for very small volumes and once appropriate volumes obtained transitioned to an automated cycler.

In addition to its advantage in the smallest patients, other advantages of PD include less need for specialized equipment and highly trained extracorporeal personnel. It does not require vascular access or anticoagulation. Electrolyte shifts are gentle and slow. In the outpatient world, PD is done at home and daily so has advantages to quality of life. Concerns include that waste and fluid removal are variable and may not be acute or aggressive enough for some ill children (fluid overload or hyperkalemia) and PD is not great acute therapy due to concerns for leakage with a fresh catheter. Instilling fluid into the abdomen may impinge on respiratory excursion could be an issue for some patients and as this modality does rely on adequate blood pressure to perfuse the peritoneum, it hypotension present, if may be less effective. Recent or impending abdominal surgery or gastroschisis /omphalocele are contraindications however VP shunts, ostomies and Eagle Barret...