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 are not.
Complications include PD non function (poor flow) due to adhesions, fibrin sheaths, constipation or wrapping of catheter in omentum or bowels. Other complications include hernias, hydrothorax or pneumoperitoneum. From an infectious standpoint exit site and tunnel infections can occur but most concerning is infected peritoneal fluid, peritonitis, which is treated with intraperitoneal and or iv antibiotics. Fungal prophylaxis while on antibiotics for any reason is critical as fungal peritonitis is a major cause of catheter loss.
Dr Phelps: What about hemodialysis ?
As we mentioned, hemodialysis uses primarily the principle of diffusion to remove waste with counter current blood and dialysate. The rate limiting factor is blood flow and this is relative to patient and catheter size. The advantage of hemodialysis is fast removal of waste and water. It is an excellent method to quickly treat hyperkalemia and fluid overload. It has also been shown to be the most efficient method to remove dialyzable drugs due to overdose and ammonia in inborn errors of metabolism or liver failure though CVVH techniques are gaining ground. These rapid fluid and electrolyte shifts, however, can make HD a problematic modality for patients with hemodynamic instability or poor cardiac function. If used in patients presenting with severe uremia, caution must be taken to lower blood urea slowly as to not cause disequilibrium syndrome from osmotic shift in the central nervous system and secondary cerebral edema. HD does require specialized equipment and trained personnel which may cause delays in getting started.
HD is generally done only three times a week or occasionally every other day in the acute setting, so this does require fluid limitations between sessions. In small babies, less than about 7.5 kg, blood primes must be used due to extracorporeal circuit volumes and this causes significant blood and therefor antigen exposure. As HD removes unwanted drugs, it also removes those of routine use and adjustments need to be made. Blood infections are the primary infectious complication.
To summarize, lets go into the disequilibrium syndrome: Rapid lowering of urea levels that were markedly elevated prior to dialysis especially in patients with prolonged elevations may result in neurologic symptoms such as headache, seizures, and altered mental status. The disequilibrium syndrome is due to the solutes in the brain which leads to cerebral cell swelling due to osmotic fluid shifts. Mannitol is the preferred therapy. It can also be mitigated by shortening the dialysis session, decreasing blood flow and allowing the slow decrease in BUN.
Rahul: Dr Jernigan what about Continuous Veno-venous Hemofiltration (CVVH)?
CVVH is the most common dialysis modality used in the pediatric intensive care unit. It is often incorporated into the staffing of an ICU and this can be initiated quickly. As a continuous therapy, it is slower and gentler than HD in it’s fluid and electrolyte removal and thus better for less hemodynamically stable patients. Blood flows of 30-100ml/min as compared to 80-300ml/min with HD. This also allows for slower and more controlled lowering of urea when needed. As it is continuous, it allows for consistent fluid administration, including nutrition, medications and blood products.
Traditional CVVH relies on convection for solute removal with pre filter substitution fluid providing the hydrostatic pressure gradient. CVVH has the ability to remove larger molecules and this may include inflammatory cytokines. The substitution fluid, duosol, is near physiologic with sodium, potassium, magnesium, chloride and bicarbonate as either 25 or 32. It does not contain calcium or glucose, but these are in the fluids required for citrate anticoagulation so if utilizing heparin need to be aware of this difference. Calculations are made and entered into the CVVH equipment to allow for net accrual, net neutral or net removal of fluid as it relates to effluent and substitution fluid.
If additional clearance is needed with CVVH, counter current duosol being used as a dialysate can be added – CVVHDF (continuous veno venous hemodiafiltration . This adds diffusive clearance. While comparative studies are still lacking, this modality is beginning to rival HD for drug and ammonia removal when toxic.
COMPLICATIONS OF RENAL REPLACEMENT
Pradip**: Dr Jernigan what are some of the complications of RRT in the PICU**
Catheter complications with infection, kinking (especially as many of these catheters are placed acutely and thus not tunneled)
Circuit complications: The tubing is large volume so <15 kg often needs a blood prime. We are thankful for the newer HF20 filter. Blood leakage, blood clotting given the slower flow, air embolism but thankfully the equipment has multiple bells and whistles to monitor for and alarm if these occur.
Hemodynamic instability and electrolyte shifts are possible but much less common than with HD.
Timing and intensity of RRT
Rahul: Dr Jernigan When should we initiate RRT in the PICU and would you start for the patient in our case presented today.
The patient presented today has hyperkalemia, severe elevation of BUN, oliguria and fluid overload. Fluid restriction would worsen his uremia and fluid administration to challenge his UOP and uremia runs the great risk of worsening his pulmonary status. I would initiate CVVH for this patient to acutely lower potassium, slowly lower BUN as well as remove and control his fluid status.
The timing of RRT depends on the urgency of the electrolyte imbalance and fluid status as well as symptomatology (refractory acidosis, hyperkalemia, pulmonary edema). I am of the opinion of starting earlier to not allow fluid overload if patients have diminishing UOP in a setting where this is unlikely to improve quickly. Studies in certain pediatric populations have shown worsened outcomes when fluid overload is present. Earlier starts often allow for adequate nutrition which is also important for recovery. While RRT imitation timing may still be an educated assessment (hate to say guess) in some patients, we are in some now able to follow NGAL as a marker of renal damage and likelihood of worsening renal function.
So far, we have talked about some important complications — infection, mechanical issues, hemorrhage, and hemodynamic instability. A good clinical pearl is to make sure you are re-evaluating your patient on the onset of CRRT & placing in your differential complications of CRRT especially if the patient decompensates.
RECOVERY OF KIDNEY FUNCTION AND CESSATION OF THERAPY
Kate: Dr Jernigan how do we know when to stop CVVH in the PICU ?
In general, we discontinue RRT when renal recovery is such that the patient can maintain a fluid and electrolyte milieu with medical intervention but without dialysis. Many times we have some idea of the likelihood of this occurring based on the etiology that got them to renal injury but not always. Cessation of RRT almost certainly requires the return of some urine out put. If we are running at a net 0 or net negative balance this is less likely to occur so we will often do a trial of net positive balance or stopping dialysis for a period of time particularly if time for a circuit change or clotting of the circuit. Medical management that can replace CRRT includes the use of diuretics if effective, fluid restrictions and dietary modifications and medications such bicarb and calcium.
It is important to realize that if we run the risk of further adding to renal injury if we overly diuresis patients on CVVH. I feel this is more an issue of overly aggressive fluid removal as opposed to early initiation which may even allow for less aggressive removal as patients not allowed to become so fluid overload. That said we are often balancing the need to improve cardiac and respiratory status to which fluid overload is problematic.
As we have learned today that initiation of RRT in critically -ill pediatric patients in the PICU can result in complications that need to be recognized and managed early. Renal replacement in the ICU requires a multidisciplinary team approach that is facilitated by a pediatric nephrologist in conjunction with intensivists and skilled nursing staff.
Dr. Jernigan we greatly appreciate your expertise on renal replacement therapies in the PICU.
This concludes our episode today on Providing Kidney Support in the PICU. We hope you found value in this podcast. We welcome you to share your feedback & place a review on our podcast. PICU Doc on Call is co-hosted by me Pradip Kamat and my co-hosts Dr Kate Phelps and Dr. Rahul Damania.
Stay tuned for our next episode! Thank you
References:
Gaudry S, Palevsky PM, Dreyfuss D. Extracorporeal Kidney-Replacement Therapy for Acute Kidney Injury. N Engl J Med. 2022 Mar 10;386(10):964-975. doi: 10.1056/NEJMra2104090. PMID: 35263520.
Stanski NL, Fuhrman D, Basu RK. Controversies in paediatric acute kidney injury and continuous renal replacement therapy: can paediatric care lead the way to precision acute kidney injury medicine? Curr Opin Crit Care. 2021 Dec 1;27(6):604-610. doi: 10.1097/MCC.0000000000000888. PMID: 34561357.
Tolwani A. Continuous renal-replacement therapy for acute kidney injury. N Engl J Med. 2012 Dec 27;367(26):2505-14. doi: 10.1056/NEJMct1206045. PMID: 23268665.
Sanderson KR, Harshman LA. Renal replacement therapies for infants and children in the ICU. Curr Opin Pediatr. 2020 Jun;32(3):360-366. doi: 10.1097/MOP.0000000000000894. PMID: 32332327; PMCID: PMC7310588.
John JC, Taha S, Bunchman TE. Basics of continuous renal replacement therapy in pediatrics. Kidney Res Clin Pract. 2019 Dec 31;38(4):455-461. doi: 10.23876/j.krcp.19.060. PMID: 31661760; PMCID: PMC6913589.