Renal Replacement Therapy in ICU

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RENAL REPLACEMENT THERAPY IN ICU Dr Deepa C MD

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SEVERE ACUTE RENAL FAILURE (ARF)  dysregulation in the homeostasis of fluid, potassium, metabolic acids and waste products EXTRACORPOREAL BLOOD PURIFICATION TECHNIQUES  prevent life-threatening complications & improve homeostasis HEMODIALYSIS HEMOFILTRATION HEMODIAFILTRATION PERITONEAL DIALYSIS Continuous or Intermittent Fundamental principle ̶ removal of unwanted solutes and water through a semipermeable membrane

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MODERN CRITERIA FOR THE INITIATION OF RRT IN ICU Oliguria (urine output < 200 ml/12 h) Anuria (urine output: 0–50 ml/12 h) [Urea] > 35 mmol/l (> 98mg/dL) [Creatinine] > 400 mmol/l (> 4.5mg/dL) Uncompensated metabolic acidosis (pH < 7. 1) [K⁺] > 6.5 mmol/l or rapidly rising [Na⁺] < 110 and > 160 mmol/l Pulmonary oedema unresponsive to diuretics Temperature > 40°C Uraemic complications (encephalopathy/myopathy/ neuropathy/pericarditis) Overdose with a dialysable toxin (e.g. lithium)

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NEWER INDICATIONS FOR CRRT Cardiac failure Patients requiring a large amount of fluid, parenteral nutrition or blood products, but at risk of developing pulmonary edema or ARDS Hyperthermia (core temp> 39.5°C) or Hypothermia (core temp< 37°C)

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ESRD PATIENTS ON MAINTENANCE DIALYSIS

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Commonly accepted criteria for initiating ESRD patients on maintenance dialysis the presence of uremic symptoms the presence of hyperkalemia unresponsive to conservative measures persistent extracellular volume expansion despite diuretic therapy acidosis refractory to medical therapy a bleeding diathesis a creatinine clearance or estimated GFR < 10 mL/min /1.73 m²

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PRINCIPLES OF RRT WATER REMOVAL SOLUTE REMOVAL

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Through ULTRAFILTRATION Similar to glomerular filtration Requires a DRIVING PRESSURE to move fluid across a semipermeable membrane generating a TRANSMEMBRANE PRESSURE which is GREATER THAN ONCOTIC PRESSURE [as in hemofiltration ( HF ) or during intermittent hemodialysis ( IHD )] 2. increasing OSMOLARITY of the dialysate [as in peritoneal dialysis ( PD )] WATER REMOVAL

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SOLUTE REMOVAL DIFFUSION CONVECTION creating an electrochemical gradient across the membrane using a flow-past system with toxin-free dialysate IHD and PD creating a transmembrane pressure -driven ʽsolvent drag’ , where solute moves together with solvent across a porous membrane Ultrafiltrate is discarded and then replaced with toxin-free replacement fluid , as in HF

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SOLUTE TRANSPORT by DIFFUSION governed by J = DTA (dc/dx) Where J is the solute flux D is diffusion coefficient T is temperature of the solution A is membrane surface area dc is concn. grad. bw the two compartments dx is diffusion distance (thickness of the membrane) The RATE OF DIFFUSION of a given solute depends on • molecular weight • porosity of the membrane • blood flow rate • dialysate flow rate • degree of protein binding • conc. grad. across the memb.

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CLEARANCE by CONVECTION governed by where K is clearance Q𝒇 is ultrafiltration rate [x]UF is the solute concn in the ultrafiltrate [x]Pw is the solute concn in plasma water [x]UF/[x]Pw is called the sieving coefficient where Km is coefficient of permeability of the membrane TMP is transmembrane pressure Pb is hydrostatic pressure of blood Puf is hydrostatic pressue of UF component π is oncotic pressure of the blood

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HEMODIALYSIS HEMOFILTRATION HEMODIAFILTRATION DIALYSATE ULTRAFILTRATE ULTRAFILTRATE + DIALYSATE DIALYSIS FLUID TO PATIENT TO PATIENT REPLACEMENT FLUID REPLACEMENT FLUID TO PATIENT DIALYSIS FLUID

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THREE ESSENTIAL COMPONENTS TO HEMODIALYSIS the dialyzer the composition and delivery of the dialysate the blood delivery system DIALYZER - plastic device with the facility to perfuse blood and dialysate compartments at very high flow rates

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The surface area of modern dialysis membranes in adult patients - 1.5–2.0 m 2 Hollow-fiber dialyzer – most commonly used Composed of bundles of capillary tubes through which blood circulates & dialysate travels on the outside of the fiber bundle

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Four categories of DIALYSIS MEMBRANES : cellulose substituted cellulose cellulosynthetic synthetic Synthetic membranes , such as polysulfone , polymethylmethacrylate , and polyacrylonitrile membranes, are more biocompatible Bioincompatibility is generally defined as the ability of the membrane to activate the complement cascade.

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Electrolytes Na 136–140 mEq /L Cl 99–110 mEq /L K 0–4.0 mEq /L Ca 2.5 mEq /L Mg 0.5–1.0 mEq /L Buffer Acetate 2.5 – 5 mEq /L HCO3 27–39 mEq /L Glucose 2.0 mEq /L COMPOSITION OF DIALYSATE FLUID

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extracorporeal circuit in the dialysis machine and the dialysis access Dialysis machine -- a blood pump, dialysis solution delivery system, and various safety monitors The fistula, graft, or catheter through which blood is obtained for hemodialysis is often referred to as a dialysis access . BLOOD DELIVERY SYSTEM

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extracorporeal circuit in the dialysis machine and the dialysis access Dialysis machine -- a blood pump, dialysis solution delivery system, and various safety monitors The fistula, graft, or catheter through which blood is obtained for hemodialysis is often referred to as a dialysis access . BLOOD DELIVERY SYSTEM

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DIALYSIS ACCESS

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GOALS OF DIALYSIS Efficiency of dialysis is determined by blood and dialysate flow through the dialyzer dialyzer characteristics (i.e., its efficiency in removing solute) The dose of dialysis, which is currently defined as a derivation of the fractional urea clearance during a single dialysis treatment, is further governed by patient size • residual kidney function dietary protein intake • degree of anabolism or catabolism presence of comorbid conditions

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Effficiency of renal replacement therapy = Kt/V where K is clearance in mL/min T is time of treatment in minutes V is volume of total body water in litres A large multicenter randomized clinical trial (the HEMO Study) failed to show a difference in mortality associated with a large difference in urea clearance Data are emerging that better uremic control may translate into better survival

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Current targets include a urea reduction ratio (the fractional reduction in blood urea nitrogen per hemodialysis session) of > 65–70% body water–indexed clearance x time product ( KT/V ) above 1.3 or 1.05 Urea levels between 10 and 20 mmol /L throughout the treatment period despite adequate nutrition suppport with a protein intake around 1.5g/kg/day CRRT at urea clearances of 35–45 L/day If intermittent therapy is used, daily and extended treatment such as SLEDD becomes desirable

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MODES OF RRT Intermittent Hemodialysis (IHD) Continuous RRT (CRRT) – SCUF, CVVHD, CVVHF, CVVHDF, CVVHFD, CPFA Slow low-efficiency daily dialysis(SLEDD) Peritoneal dialysis (PD) Plasmapheresis or plasma exchange CRRT and SLEDD offer many advantages over PD and conventional IHD (3–4 h/day, 3–4 times/week)

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There is a great deal of controversy as to which mode of RRT is ‘best’ in the ICU, due to the lack of randomised controlled trials comparing different techniques Techniques of RRT may be judged on the basis of the following criteria: haemodynamic side-effects ability to control fluid status biocompatibility risk of infection uraemic control avoidance of cerebral oedema ability to allow full nutritional support ability to control acidosis absence of specific side-effects cost

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CONTINUOUS RENAL REPLACEMENT THERAPY ADVANTAGES continuous control of fluid status haemodynamic stability control of acid–base status ability to provide protein-rich nutrition while achieving uraemic control control of electrolyte balance, including phosphate and calcium balance prevention of swings in intracerebral water minimal risk of infection high level of biocompatibility

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CVVH – CONTINUOUS VENOVENOUS HEMOFILTRATION convective blood purification through high permeablility membrane UF rate controlled UF replaced by replacement flui d Qb = 50 – 200 ml/min Qf = 8 – 25 ml/min K = 12 - 36 L/24h CVVHD – CONTINUOUS VENOVENOUS HEMODIALYSIS diffusive blood purification through low permeability dialyzer dialysate solution in countercurrent flow no replacement fluid used small molecule clearance only Qb = 50 – 200 ml/min Qf = 2 -4 ml/min Qd = 10 -20 ml/min K= 14 – 36 L/24h

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CVVHDF - CONTINUOUS VENOVENOUS HEMODIAFILTRATION countercurrent dialysate blood flow High permeability membrane utilized – small and middle molecules removed Qb = 50 - 200 ml/min Qf = 8 – 12 ml/min Qd = 10 – 20 ml/min K = 20 - 40 L/24 h CVVHFD – CONTINUOUS HIGH FLUX DIALYSIS diffusive and convective blood purification through a high permeability membrane back diffusion occurs in membrane accessory pump to control UF replacement fluid not required due to fine regulation of filtration & backfiltration Qb = 50 -200 ml/min Qf = 2-8 ml/min Qd = 50 -200 ml/min k = 40 - 60 L/24 h

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SCUF – SLOW CONTINUOUS ULTRAFILTRATION technique used for fluid control only convective mechanism UF rate controlled No replacement fluid used Qb = 50 -100 ml/min CPFA – CONTINUOUS PLASMAFILTRATION ADSORPTION high permeability plasmafilter filters fluid plasma allowing it to pass through a bed of adsorbent material (carbon or resins) fluid balance maintained can be coupled with CVVH or CVVHD or CVVHDF Qb = 50 -200 ml/min Pf = 20 -30 ml/min

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The optimal dose (expressed as effective effluent /kg / hr ) of CRRT remains unknown Typical dose - approximately 25 ml/kg/hour Continuous circuit anticoagulation Increased risk of bleeding CIRCUIT ANTICOAGULATION DURING CRRT Activation of the coagulation cascade and clotting of the filter and circuit Anticoagulants - to delay clotting and achieve acceptable operational lives (approximately 24 hours) for the circuit

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STRATEGIES FOR CIRCUIT ANTICOAGULATION DURING CONTINUOUS RENAL REPLACEMENT THERAPY No anticoagulation Low-dose prefilter heparin (< 500 IU/h) Medium-dose prefilter heparin (500–1000 IU/h) Full heparinisation Regional anticoagulation ( prefilter heparin and postfilter protamine, usually at a 100 IU:1 mg ratio) Regional citrate anticoagulation ( prefilter citrate and postfilter calcium – special calcium-free dialysate needed) Low-molecular-weight heparin Prostacyclin Heparinoids Serine proteinase inhibitors ( nafamostat mesylate )

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In 10–20% of patients anticoagulation is best avoided because of endogenous coagulopathy or recent surgery Adequate filter life - blood flow is kept at about 200 ml/min and vascular access is reliable. Many circuits clot for mechanical reasons • inadequate access • kinking of catheter • unreliable blood low from double-lumen catheter depending on patient position Responding to frequent filter clotting by simply increasing anticoagulation without making the correct aetiological diagnosis (checking catheter flow and position, taking a history surrounding the episode of clotting, identifying the site of clotting) is often futile and exposes the patient to unnecessary risk.

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INTERMITTENT HAEMODIALYSIS Uses high dialysate flows (300–400 ml/min) Generates dialysate by mixing purified water and concentrate Treatment is applied for short periods of time (3–4 hours), usually every 2 nd day Volume has to be removed over a short period of time  hypotension Repeated hypotensive episodes may delay renal recovery Solute removal is episodic - inferior uraemic control and acid-base control Limited fluid and uraemic control imposes unnecessary limitations on nutritional support DISADVANTAGES

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Rapid solute shifts increase brain water content and raise intracranial pressure membrane bioincompatibility Standard low-flux dialysing membranes -- trigger the activation of several inflammatory pathways, when compared to high-flux synthetic membranes (also used for continuous HF)  proinflammatory effect contributes to further renal damage  delays recovery or even affects mortality Biocompatible membranes ( polysulfone ) are now preferred

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New approaches (so-called ‘hybrid techniques’) such as SLEDD. These techniques seek to adapt IHD to the clinical circumstances and thereby increase its tolerance and its clearances.

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CVVH Versus Daily Hemodialysis Body weight Bicarbonate MAP BUN

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COMPLICATIONS DURING HEMODIALYSIS Hypotension Muscle cramps Anaphylactoid reactions to the dialyzer Cardiovascular diseases Infections

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the most common acute complication of hemodialysis , particularly among diabetics excessive ultrafiltration with inadequate compensatory vascular filling impaired vasoactive or autonomic responses osmolar shifts overzealous use of antihypertensive agents reduced cardiac reserve high output cardiac failure in patients with arteriovenous fistulae and grafts due to shunting of blood through the dialysis access the vasodilatory and cardiodepressive effects of acetate buffer in dialysate HYPOTENSION

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Management of hypotension during dialysis discontinuing ultrafiltration administration of 100–250 mL of isotonic saline or 10 mL of 23% saturated hypertonic saline administration of salt-poor albumin Hypotension during dialysis can be prevented by careful evaluation of the dry weight and ultrafiltration modeling , such that more fluid is removed at the beginning rather than the end of the dialysis procedure performance of sequential ultrafiltration followed by dialysis use of midodrine , a selective α 1-adrenergic pressor agent cooling of the dialysate during dialysis treatment avoiding heavy meals during dialysis

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Changes in muscle perfusion because of excessively aggressive volume removal, particularly below the estimated dry weight Use of low-sodium–containing dialysate Prevention of cramps by reducing volume removal during dialysis ultrafiltration modeling sodium modeling MUSCLE CRAMPS

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Lower dialysate sodium concentrations are associated with a higher frequency of hypotension, cramping, nausea, vomiting, fatigue, and dizziness. In patients who frequently develop hypotension during their dialysis run, "sodium modeling" to counterbalance urea-related osmolar gradients is often used When sodium modeling, the dialysate sodium concentration is gradually lowered from the range of 145–155 meq/L to isotonic concentrations (140 meq/L) near the end of the dialysis treatment, typically declining either in steps or in a linear or exponential fashion.

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ANAPHYLACTOID REACTIONS TO THE DIALYZER Dialyzer reactions - two types - A and B TYPE A REACTIONS  IgE -mediated immediate hypersensitivity reaction to ethylene oxide used in the sterilization of new dialyzers. typically occurs soon after the initiation of a treatment (within the first few minutes) and can progress to full-blown anaphylaxis if the therapy is not promptly discontinued. Treatment with steroids or epinephrine may be needed if symptoms are severe

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TYPE B REACTION  results from complement activation and cytokine release Consists of a symptom complex of nonspecific chest and back pain Symptoms typically occur several minutes into the dialysis run Typically resolve over time with continued dialysis Most frequently with the bioincompatible cellulosic-containing membranes INFECTIONS Hepatitis C & B BSI CRI

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CARDIOVASCULAR DISEASES constitute the major causes of death in patients with ESRD Shared risk factors (e.g., DM) Chronic inflammation Dystrophic vascular calcification Hyperhomocysteinemia Massive changes in extracellular volume (especially with high interdialytic weight gains) Inadequate treatment of hypertension, dyslipidemia , anemia Alterations in cardiovascular dynamics during the dialysis

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PERITONEAL DIALYSIS 1.5–3 L of a dextrose-containing solution is infused into the peritoneal cavity and allowed to dwell for a set period of time, usually 2–4 h A combination of convective clearance and diffusive clearance the clearance of solutes and water depends on the balance between the movement of solute and water into the peritoneal cavity versus absorption from the peritoneal cavity The rate of diffusion diminishes with time and eventually stops when equilibration between plasma and dialysate is reached.

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Absorption of solutes and water from the peritoneal cavity occurs across the peritoneal membrane into the peritoneal capillary circulation and via peritoneal lymphatics into the lymphatic circulation The rate of peritoneal solute transport varies from patient to patient and may be altered by the presence of infection (peritonitis) drugs physical factors such as position and exercise Lactate is the preferred buffer in peritoneal dialysis solutions

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The most common additives to peritoneal dialysis solutions heparin to prevent obstruction of the dialysis catheter lumen with fibrin antibiotics during an episode of acute peritonitis. insulin may also be added in patients with diabetes mellitus. COMPOSITION OF A COMMERCIALLY AVAILABLE PERITONEAL DIALYSATE Sodium 132mEq/L Potassium 0mEq/L Chloride 96mEq/L Calcium 3.5mEq/L Magnesium 0.5mEq/L D, L-Lactate 40mEq/L Glucose 1.5, 2.5, 4.25g/dL Osmolality 346, 396, 485 pH 5.2

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FORMS OF PERITONEAL DIALYSIS continuous ambulatory peritoneal dialysis (CAPD) continuous cyclic peritoneal dialysis (CCPD) combination of both

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Patients on peritoneal dialysis do well when they retain residual kidney function. The rates of technique failure increase with years on dialysis and have been correlated with loss of residual function to a greater extent than loss of peritoneal membrane capacity. A nonabsorbable carbohydrate ( ICODEXTRIN ) has been introduced as an alternative osmotic agent. Studies have demonstrated more efficient ultrafiltration with icodextrin than with dextrose-containing solutions. Icodextrin is typically used as the "last fill" for patients on CCPD or for the longest dwell in patients on CAPD.

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Peritonitis catheter-associated nonperitonitis infections weight gain unpredictable hyperglycemia fluid leaks protein loss and other metabolic disturbances interference with diaphragm function residual uremia (especially among patients with no residual kidney function) Peritoneal membrane failure COMPLICATIONS DURING PERITONEAL DIALYSIS

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Break in sterile technique during one or more of the exchange procedures Peritonitis is usually defined by an elevated peritoneal fluid leukocyte count (100/mm 3 , of which at least 50% are polymorphonuclear neutrophils) The clinical presentation typically consists of pain and cloudy dialysate, often with fever and other constitutional symptoms The most common culprit organisms are gram-positive cocci, including Staphylococcus PERITONITIS

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Gram-negative rod infections are less common Intraperitoneal or oral antibiotics, depending on the organism Peritonitis idue to hydrophilic gram negative rods (e.g., Pseudomonas sp.) or yeast, antimicrobial therapy is usually not sufficient, and catheter removal is required to ensure complete eradication of infection Nonperitonitis catheter-associated infections (often termed tunnel infections )  local antibiotic or silver nitrate administration; severe  parenteral antibiotic therapy and catheter removal

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Hypoproteinemia - albumin and other proteins can be lost across the peritoneal membrane Obligates a higher dietary protein intake in order to maintain nitrogen balance Hyperglycemia and weight gain Type ii diabetes mellitus, are prone to other complications of insulin resistance, including hypertriglyceridemia METABOLIC COMPLICATIONS On the positive side, the continuous nature of peritoneal dialysis usually allows for a more liberal diet, due to continuous removal of potassium and phosphorus—two major dietary components whose accumulation can be hazardous in ESRD

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Effects of reducing the lactate and glucose content of PD solutions on the peritoneum. Is the future GLAD? Raymond T. Krediet, Machteld M. Zweers, Roos van Westrhenen, Agnes Zegwaard and Dirk G. Stru ijk Division of Nephrology, Department of Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands NDT Plus (2008) 1 [Suppl 4]: iv56–iv62 doi: 10.1093/ndtplus/sfn126 Long-term peritoneal dialysis (PD) may lead to functional and morphologic changes in the peritoneal membrane, probably because of the continuous exposure to conventional dialysis solutions. The morphologic changes include neoangiogenesis and fibrosis . High lactate concentrations contributed to the glucose-induced neoangiogenesis by pseudohypoxia. Glucose degradation products were probably more important in the induction of peritoneal fibrosis. The promising results of a combination of amino acids, glycerol and glucose, each in a low concentration, buffered with either pyruvate or bicarbonate/lactate, include minimal peritoneal damage, even after long-term exposure to PD fluid. The combination of glycerol, amino acids and dextrose, dissolved in a bicarbonate/lactate buffer (GLAD) , may be an option for a new generation of dialysis fluids.

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DRUG DOSAGE DURING DIALYTIC THERAPY DRUG CRRT IHD Aminoglycosides Normal dose q 36 h 50% normal dose q 48 h – 2/3 redose after IHD Cefotaxime or ceftazidime 1 g q 8–12 h 1 g q 12–24 h after IHD Imipenem 500 mg q 8 h 250 mg q 8 h and after IHD Meropenem 500 mg q 8 h 250 mg q 8 h and after IHD Metronidazole 500 mg q 8 h 250 mg q 8 h and after IHD Amoxicillin 500 mg q 8 h 500 mg daily and after IHD Vancomycin 1 g q 24 h 1 g q 96–120 h Piperacillin 3–4 g q 6 h 3–4 g q 8 h and after IHD Ciprofloxacin 200 mg q 12 h 200 mg q 24 h and after IHD Fluconazole 200 mg q 24 h 200 mg q 48 h and after IHD Acyclovir 3.5 mg/kg q 24 h 2.5 mg/kg/day and after IHD Amphotericin B Normal dose Normal dose Liposomal amphotericin Normal dose Normal dose Ceftriaxone Normal dose Normal dose Milrinone Titrate to effect Titrate to effect Catecholamines Titrate to effect Titrate to effect Ampicillin 500 mg q 8-hourly 500 mg daily and after IHD

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OTHER BLOOD PURIFICATION TECHNIQUES HAEMOPERFUSION A charcoal cartridge is perfused with blood instead of a dialysis membrane In some cases an ion exchange resin ( amberlite ) is used Charcoal microcapsules effectively remove molecules of 300–500 D MW, including some lipid-soluble and protein-bound substances Heparinisation is necessary to prevent clotting.

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Attention must also be paid to changes in intravascular volume at the start of therapy because of the large priming volume of the cartridge (260 ml). Glucose absorption is significant and monitoring of blood glucose is necessary to avoid hypoglycaemia . Thrombocytopeni a is common, and can be marked Useful in patients with life-threatening theophylline overdose

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PLASMAPHERESIS OR PLASMA EXCHANGE Plasma is removed from the patient and exchanged with fresh frozen plasma (FFP) and a mixture of colloid and crystalloid solutions A plasmafilter (a filter that allows the passage of molecules up to 500 kd ) instead of a haemofilter is inserted in the CVVH circuit, and the filtrate (plasma) is discarded Replacement ( postfilter )  a 50/50 combination of FFP and albumin.

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Principles of centrifugation and filtration Effective treatment for Thrombotic thrombocytopenic purpura Guillain – Barre ´ syndrome Cryoglobulinaemia , Myasthenia gravis Goodpasture’s syndrome Its role in the treatment of sepsis remains uncertain

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BLOOD PURIFICATION TECHNOLOGY OUTSIDE ARF Blood purification may provide a clinically significant benefit in patients with severe sepsis/septic shock by removing circulating ‘mediators’. Plasmapheresis, high-volume HF, very-high-volume HF, coupled plasma filtration adsorption and large-pore HF MARS (Molecular Adsorption Recirculating System ), an albumin-based dialysis has shown benefits in patients with elevated intracranial pressure and/or acute-on-chronic liver failure

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