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Intermittent Hemodialysis & Plasmapheresis Dr Chu Kwok Hong Renal Unit Princess Margaret Hospital
IHD in ICU
Dr Claudio Ronco
Intermittent Hemodialysis u The concept of ‘ARF’ and renal support u The practical issues of IHD u The evidence Who, when, which and how.
ARF and ICU u Increasingly common. u Sepsis as no. 1 cause of ARF; usually occurs in the context of MODS. u Increased mortality, varies from 3090%.
The Concept u To define ARF is very difficult u What is normal? u How acute is acute? u How much loss is considered significant? u In a recent questionnaire, 560 contributors reported >200 different definitions of ARF and ~90 different RRT initiation criteria.
The Concept 2 individuals with 100% renal masses may function at different GFR, e. g. subjects on a vegetarian diet may have a GFR of 45 ml/min whereas subjects with high protein intake may have a GFR of 140 ml/min.
The Concept u ‘no such thing as ARF…. only people who have malfunction of the kidney. ’ u Imperfect biomarkers u Unstable conditions u Unknown baseline…etc
The classification system includes separate criteria for creatinine and urine output. The criteria that leads to the worst classification should be used. Note that RIFLE-F is present even if the increase in SCrt is <3 fold so long as the new SCrt is 4. 0 mg/d. L (350 mcmol/L) in the setting of an acute increase of at least 0. 5 mg/d. L (44 mcmol/L). The designation RIFLE-FC should be used in this case to denote "acute-on-chronic" disease. Similarly when RIFLE-F classification is reached by urine output criteria, a designation of RIFLE-FO should be used to denote oliguria. The shape the figure denotes the fact that more patients (high sensitivity) will be included in the mild category, including some without actually having renal failure (less specificity). In contrast, at the bottom, the criteria are strict and therefore specific, but some patients will be missed. Reproduced with permission from: Bellomo, R, Ronco, C, Kellum, JA, et al. Acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: B 204. Copyright © 2004 Bio. Med Central Ltd.
AKIN criteria u Acute Kidney Injury Network. u Abrupt (within 48 hrs) absolute increase in S. Cr of > or = 0. 3 mg/dl (26. 4 mmo; /l) from baseline, a % increase in S. Cr of > or = 50%, or oliguria (<0. 5 ml/kg/hr) for > 6 hrs.
The messages u Early recognition. u Concept of acute kidney injury.
Indications for renal replacement therapy Traditionally, indications for RRT in the ICU were the same those for pts with CKD. u More aggressive nowadays aiming at improving outcomes. u Improving the overall condition of the pt, thus allowing time for otherapies directed at the pt’s comorbidities to work. u The concept of ‘Renal Support Therapy’. u
Indications for renal support A. E. I. O. U
When? The earlier the better? ? u No definition for ARF, making a specific BUN or S. Cr concen at which RRT should be started difficult to define.
The earlier the better Early initiation of RRT and the use of high ultrafiltration rates improved survival and the recovery of renal function Gettings LG et al Intensive Care Med 1999 Oudemans-van Straaten HM et al Intensive Care Med 1999 Nonrandomized and retrospective!
The earlier the better u CVVH when persistent oliguria for 24 hr; independent of BUN or S. Cr levels. u Improved 28 -day survival compared to a historical cohort. Piccinni P et al Intensive Care Med 2006
The earlier the better u Effects of different doses in CVVH on outcomes of ARF : a prospective randomized trial. Ronco C et al Lancet 2000 u Daily hemodialysis and the outcome of ARF. Schiffl H et al NEJM 2002
Starting very early ? ‘Prophylactic’ Prophylactic hemofiltration in the absence of evidence for renal injury has been shown to be ineffective in studies in trauma patients and in patients with septic shock without renal dysfunction. Bauer M et al Intensive Care Med 2001 Cole L et al Crit care Med 2002
Which u IHD vs CVVH u Survival benefit has not been demonstrated u Underlying disease, its severity and stage, the etiology of ARF, the clinical and hemodynamic status, the resources available and the costs all influence the choice of RRT u Patient-specific
Mechanism of transport Mainly by diffusion. u Two solutions separated by a semipermeable membrane with pores of different sizes. u Random molecular movement i. e. dependent on molecular weight. The smaller the faster and the higher the chance that it will collide with the membrane. u The molecular weight, the membrane surface area and the pore size. (membrane design) u The concentration gradient (blood and dialysate flow rates). u
The catheters Double-lumen or even triple-lumen catheters, noncuffed. u The femoral vein most easily accessible. u Less complications. More infections. u Patient discomfort. u Ready to use, no need for X-ray. u Most suitable in the hyperacute situation where dialysis is immediately required and the patient cannot lie flat because of breathlessness. u Should not be in place for >4 days. u
The catheters u The IJs. u Relatively easy procedure. L more difficult than the R and needs a longer line. u Preferably USS guided.
The catheters u The subclavian route. u Not recommended due to high rates of chronic venous obstruction (>30%). u Technically more demanding. u Site not compressible.
The catheters u Cuffed ‘permanent’ catheters with subcutaneous tunnel. u Should be considered if HD >2 -4 weeks. u Bedside procedures +/- fluroscopic guide. u e. g. Retrocath, Tesio catheter.
Acute HD prescription u HD session length Reduce 1 st HD treatment time especially if serum urea level is very high e. g. >40 mmol/L. The ‘disequilibrium’ syndrome. A 2 -hr session is recommended. Aim at URR of <40%. Subsequent session length can be gradually increased to a standard of 4 -5 hrs.
Acute HD prescription Dialysis freq and dose Freq should be tailored to clinical needs. ? better survival if performed daily versus every other day. Dose measurement difficult: -lack of guideline in ARF. -freq interruptions. -unstable conditions. If performed on every-other-day basis, should provide a single-pool Kt/V of at least 1. 2 -1. 3 per session, as recommended for chronic patients. u
Acute HD prescription Dialyzer Unsubstituted cellulose membrane not used. Activate complement and may delay renal recovery. High-flux membrane not necessary. Water permeability (Kuf) – most machines are equipped with UF controller. Urea clearance (K 0 A) – not recommended to use high-efficiency dialyzer. To avoid overdialysis. u
Acute HD prescription Dialysis solution The HCO 3 setting – monitor pre-dialysis bicarbonate levels. The Na setting: -rapid correction of hypo-Na can occur. Prudent to set Na level to no >15 -20 mmol/L above the plasma level in severe long -standing hypo-Na. -rapid correction of hyper-Na is equally dangerous. Water from the dialyzed, relatively hypo-Na blood enters cell, causing cerebral edema and exacerbating the disequilibrium syndrome. Set Na level close to that of the plasma (within 2 mmol/L). The calcium setting: 1. 25 -1. 75 mol (3. 0 -3. 5 m. Eq). Seldom uses low Ca bath since it may potentate hypotension and promoting arrhythmias. The dextrose level – septic patients, diabetics and patients on beta-blockers are at risk of intra-dialytic hypo-G. u
Acute HD prescription u Dialysis solution flow rates – usually set at 500 ml per min. u Dialysis solution temperature – 3537 C.
Dose measurement u Efficiency u Intensity u Frequency u Clinical efficacy
Dose measurement u Efficiency – K, the clearance u Intensity – t, time u Frequency u Clinical efficacy
Urea kinetic modeling u Urea reduction ratio: - pre- and post-HD urea ratio. u Kt/V: - a dimensionless index - indicates how much solute, usually urea, is removed in one single session - Kt/V = 1. 0 means 1 plasma volume of plasma is cleared of urea
Kt/V u Single pool Kt/V (sp. Kt/V) u Assumed urea distribution in a single homogenous compartment u By Daugirdas 2 nd generation equation u Problems of sequestrated compartments, urea generation during HD and UF volume, etc e. Kt/V
Kt/V in ARF Lack of a steady state u Distribution volume u High catabolism u Labile fluid volumes u RRF u ? use of ionic dialysance as a new parameter for quantification of dialysis efficiency in ARF
Disequilibrium syndrome u Definition: a set of systematic and neurologic symptoms often associated with characteristic electroencephalographic findings that can occur either during or following dialysis. u Manifestations: nausea, vomiting, restlessness, headache, seizures, obtundation and coma.
Disequilibrium syndrome u Etiology: controversial. u Related to acute increase in brain water content. When the plasma solute level is rapidly lowered during dialysis, water shifts from the relatively hypotonic plasma to the brain cells. u ? change in the CSF p. H.
Disequilibrium syndrome u Management: u Mild forms – symptomatic. To reduce BFR or early termination if syndrome suspected. Leg cramps can be relieved by hypertonic saline or glucose solutions. u Severe forms – stops HD. Supportive treatment e. g. , control of seizure, endotracheal intubation. Intravenous mannitol may help. Improves within 24 hrs.
Disequilibrium syndrome u Prevention is better than cure. u Avoid overly aggressive HD treatment. u Initial target URR 40%. u Avoid using low Na dialysis solution since it may aggravate cerebral edema.
Dialyzer reactions u Old term, ‘first-use’ syndrome. Occurs more often when new dialyzers are used. Similar reactions do occur with reused dialyzers. u Type A & B.
Dialyzer reactions Type A – the anaphylactic type. u Itching, cough, urticaria and watery eyes to cardiac arrest. u Usually in the first few mins; can be delayed for up to 30 mins or more. u Causes: ethylene oxide, AN 69 and ACEI, contaminated solution, reuse and heparin. u Stop HD and do not return the contained blood. u Anti-histamines, steroids and epinephrine. u
Dialyzer reactions u Nonspecific type B reactions. u Chest-back pain. 20 -40 mins after starting dialysis. u Less severe. u Unknown etiology. Complement activation? Biocompatibility? u HD can continue.
In summary, u Early recognition. u Renal Support Therapy. u Should not start late. u No survival benefit among different modalities – individualized.
Plasmapheresis (Therapeutic plasma exchange)
Therapeutic Apheresis u Extracorporeal procedure in removing abnormal blood cells and plasma constituents. u Plasmaphersis, leukaphersis, erythrocytapheresis and thrombocytapheresis. u Membrane or centrifugation.
Possible mechanisms Removal of abnormal circulating factors: - Ab e. g. anti-GBM disease - monoclonal protein e. g. Waldenstrom macroglobulinemia - circulating immune complexes e. g. SLE u Replenishment of specific plasma factor: - TTP u Other effects on immune system: - improvement in function of RE system - removal of inflammatory mediators - shift in Ab-to-antigen ratio, resulting in more soluble forms of immune complexes - stimulation of lymphocyte clones to enhance cytotoxic therapy u
Rationale for TPE u Relatively large molecules (MW>15000) so that it cannot be easily removed by less expensive techniques e. g. hemofiltration. u Long T 1/2 so that extracorporeal removal is much more rapid than endogenous clearance. u Acutely toxic substance so that rapid elimination is indicated.
The Principles u Use of concomitant immunosuppression: - reduction in plasma factors should be coupled with immunosuppressant to reduce the rate of re-synthesis. u Treat early. u Alternative treatment, if available, should be used first.
TPE prescription – theoretical considerations u What is being removed? - Ig. G vs Ig. M u What is the desired endpoint? - clinical improvement or a reduction in the plasma level of a specific measurable pathologic moiety
Pharmacokinetic considerations u 70 -kg patient with a plasma volume of 2800 ml. assume removal from a single compartment. PV exchanged 0. 5 Volume exchanged (ml) 1400 Removal ratio (%) 39 1. 0 2800 63 1. 5 4200 78 2. 0 5600 86 2. 5 7000 92 3. 0 8400 95
Pharmacokinetic considerations Reaccumulation -From lymphatic drainage -Endogenous synthesis u After 4 or 5 TPEs, the conc would be oscillating between 10% to 20 -25%. u
The regimen u Numbers of PV q X days for Y sessions. u Membrane vs centrifugal separator. u Anticoagulation. u Replacement solutions.
Estimation of plasma volume u 35 -40 ml/kg u Kalpan’s simplified equation : [0. 065 x weight (kg)] x (1 – Hct)
Advantages Disadvantages Membrane apheresis -fast and efficient -no citrate requirements -can be adapted for cascade filtration -limited by sieving coefficient -no cytapheresis -high BFR, central access -requires heparin Centrifugal devices -cytapheresis -no heparin requirement -more efficient removal of all plasma components -expensive -requires citrate -loss of platelets
Anticoagulation Heparin -50 U/kg loading followed by continuous infusion of 1000 U per hr. monitor ACT 1. 5 -2. 0 x normal. u Citrate -hypo-Ca; return of citrated blood close to SA node can cause life-threatening arrhythmias. Femoral route may be preferred with short-term use. -patient with liver disease may have impaired ability to metabolize citrate. u
Replacement solutions u 5% albumin, albumin-saline or FFP. u With albumin-saline combination, albumin should not be < 50% of the total volume. An appropriate combination would be 60 -80% colloid and 20 -40% crystalloid.
Solution Adv Disadv Albumin -no viral transmission -room temp -allergic reactions rare -no blood gp concern -depletes inflammation mediators -expensive -no coagulation factors -no Igs FFP -coagulation factors -Igs -’beneficial’ factors -complement -viral transmission -allergic reactions -hemolytic reactions -must be thawed -ABO-compatible -citrate load
Some specific issues u u u Prevention of low i. Ca with citrate: -oral tabs of 500 -mg Ca. CO 3 q 30 mins -continuous infusion of Ca gluconate 10% in a proportion of 10 ml per L of return fluid. Depletion of coagulation factors: -unlikely with 1 or 2 sessions. -if PT or a. PTT is prolonged to 1. 5 x at 3 rd or subsequent exchanges, choose 2 -3 U of FFP as part of the replacement solution. Depletion of Igs: -if a severe infection occurs, a single infusion of IVIG (100 -400 mg/kg) will restore the Ig levels to normal
Drug removal by plasmapheresis: an evidence-based review Pharmacotherapy 2007; 27(11): 1529 -1549
Drug removal by plasmapheresis: an evidence-based review Pharmacotherapy 2007; 27(11): 1529 -1549 Administer drug after TPE!
Indications for emergency TPE Anti-GBM disease u Symptomatic hyperviscosity syndrome u TTP/HUS u Pre-op for pts with high factor VIII inhibitor levels u Guillain-Barre synd with resp insufficiency u MG with resp compromise u Acute poisoning with certain mushrooms or with other strongly protein-bound poisons e. g. paraquat u
Anti-GBM disease u For renal indication, only when S. Cr is still low and before the onset of oliguria. u Initial high vol and freq exchanges so as to rapidly decrease the Ab titre e. g. 2 PVs daily for 7 days, followed by e. g. alternate day schedule. u Duration dictated by clinical status and anti-GBM titres.
TTP/HUS u Daily TPE until normalization of plt counts. u 1. 0 -1. 5 PVs for 1 st 3 treatments followed by 1 PV exchange thereafter. u Replace with 50 -100% FFP. u Relapse may occur within a few days of stopping the treatment.
Guillain-Barre syndrome u IVIG equally effective. u 1. 0 -1. 5 PVs 2 -3 times per week. For mild cases, 2 exchanges may suffice. u 5% albumin as replacement.
Sepsis and MODS Extremely complex nature of inflammatory response in sepsis. u Unlikely a single agent (e. g. anticytokine Rx) would work. u Ronco proposed that ‘…unspecific removal of soluble mediators, be they pro or antiinflammatory, without completely eliminating their effect, may be the most logical and adequate approach to a complex and long-running process such as sepsis. ’ u
Sepsis and MODS u Observational studies showed no effect of exchange or plasmafiltration on cardiovascular parameters or mortality. Ataman K et al Intensive Care Med 2002 Reeves JH et al Crit Care Med 1999 u One RCT demonstrated a 20. 5% reduction in the 28 -day all-cause mortality among patients with severe sepsis or septic shock treated with 1 or 2 daily plasma exchanges compared to untreated control. Busund R et al Intensive Care Med 2002
American Association of Blood Banks indications for therapeutic hemapheresis-I Category I - Standard and acceptable therapy Category II - Generally accepted in a supportive role Plasmapheresis Acute & chron. inflamm. demyelinating polyradiculoneuropathy Cold agglutinin disease ABO-mismatched marrow transplant (recipient) Demyelinating polyneuropathy with Ig. G and Ig. A Anti-GBM antibody disease (Goodpasture's syndrome) Guillain-Barré syndrome Phytanic acid storage disease Familial hypercholesterolemia (selective adsorption) Thrombotic thrombocytopenic purpura Myasthenia gravis Posttransfusion purpura Cytapheresis Leukemia with hyperleukocytosis syndrome Sickle cell diseases (also see Category III) Thrombocytosis, symptomatic ABO mismatched marrow transplant (RBC, marrow) Polycythemia vera (phlebotomy) Cutaneous T-cell lymphoma (photopheresis) Coagulation factor inhibitors Lambert-Eaton myasthenia syndrome Acute CNS inflammatory demyelinating disease Cryoglobulinemia with or without polyneuropathy Rapidly progressive glomerulonephritis Myeloma paraproteins or hyperviscosity syndrome Acute renal failure due to myeloma kidney Familial hypercholesterolemia Sydenham's chorea Pediatric autoimmune neuropsychiatric disorders Polyneuropathy with Ig. M (with or without Waldenstrom's) Cytapheresis Rheumatoid arthritis (lymphoplasmapheresis) Polycythemia vera (erythrocytapheresis) Plasma perfusion (adsorption columns) Rheumatoid arthritis Hyperlipidemia Idiopathic thrombocytopenic purpura
Category III - Not clearly indicated (cont. ) Category III - Not clearly indicated Plasmapheresis apeutic hemapheresis-II Aplastic anemia or pure RBC Systemic lupus erythematosus Raynaud's phenomenon Relapsing or progressive multiple sclerosis Scleroderma or progressive systemic sclerosis Thyroid storm Autoimmune hemolytic anemia Hemolytic uremic syndrome Renal transplant sensitization Recurrent focal glomerulosclerosis Cytapheresis Multiple sclerosis ( lymphocytapheresis ) Organ transplant rejection Progressive systemic sclerosis Cutaneous T-cell lymphoma (leukaphersis) Sickle cell disease (prophylactic, pregnancy ) (prophylactic, pregnancy Malaria, babesiosis (RBC) Plasma perfusion (adsorption columns) Platelet alloimmunization and refractoriness Paraneoplastic neurologic syndromes Demyelinating polyneuropathy with Ig. G & Ig. A Polyneuropathy with Ig. M (with or without Waldenstrom's) Category IV - Demonstrated to have a lack of efficac Heart transplant rejection (includes photopheresis) Plasmapheresis Acute hepatic failure AIDS Drug overdose or poisoning Amyotrophic lateral sclerosis Vasculitis Chronic ITP Hemolytic disease of the newborn Lupus nephritis Inclusion body myositis Psoriasis Platelet alloimmunization and refractoriness Renal transplant rejection Paraneoplastic neurologic syndromes Rheumatoid arthritis Multiple myeloma with polyneuropathy or POEMS syndrome Schizophrenia Polymyositis or dermatomyositis Rasmussen's encephalitis Stiff man syndrome Systemic (AL) amyloidosis Cytapheresis Leukemia without hyperleukocytosis Inclusion body myositis Hypereosinophilia Polymyositis/dermatomyositis
In real life… u In the America, >50% were performed for neurologic conditions e. g. Guillain-Barre synd, MG. u In 1997, 5 most common indications in Canada were: 1) TTP (39%) 2) MG (14%) 3) CIDP (14%) 4) Waldenstrom macroglobulinemia (7%) 5) Guillain-Barre synd (6%)
PD in the Rx of ARF
The advantages Widely available u Easy to perform u Less labor intensive u Disequilibrium synd is not precipitated u Hemodynamically stable and can remove large amt of fluid in a continuous manner u No arterial or venous puncture u No anticoagulation u Extra caloric supplementation as glucose is absorbed u
Indications u Hemodynamically unstable pts. u Bleeding diathesis or active bleeding. u Difficulty in obtaining vascular access. u Removal of high MW toxins (>10 k. D). u Hypothermia or hyperthermia. u Heart failure refractory to medical Rx.
The evidence against PD!? u. A prospective study on 70 Vietnam ARF patients either due to malaria or sepsis. u Marked increased risk of death in the PD group u Mortality rate for CVVH group was unusually low u PD solutions were made in-house