Principali problemi tecnici e clinici

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1 Principali problemi tecnici e clinici Regione Veneto AULSS 8 Berica Dipartimento di Nefrologia, Dialisi e Trapianto Renale International Renal Research Institute Vicenza IRRIV Ospedale San Bortolo, Vicenza Associazione Amici del Rene di Vicenza onlus Zaccaria Ricci Dipartimento Medico Chirurgico di Cardiologia Pediatrica

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4 COMPLICANZE DURANTE CRRT CLINICHE Ipotensione Coagulazione Anemia Ipotermia Complicazioni correlate all accesso vascolare Diselettrolitemie Perdita di soluti TECNICHE Errori nella somm.ne della terapia Errori di bilancio Interfaccia macchinaoperatore Altre complicanze elettroniche

5 % of Hypotensive Episodes FREQUENZA DI IPOTENSIONE IN HD 100 Ronco et Al, Int J. Artif Organs, 3, , Ultrafiltration Rate ( ml/min/kg )

6 Pz di 70 Kg con AKI: necessità di bilancio fluidico 24 hour input 24 hour output Blood - plasma infusions Drugs and Medications Parenteral Nutrition Volume administration Urine output Intestinal fluid losses Insensible losses Other fluid losses Ultrafiltration required = 4000 ml Short Daily HD 3 hours 23 ml/min 0.4 ml/min/kg Ext.Daily HD 8 hours 8.3 ml/min 0.1 ml/min/kg CVVH 24 hours 2.5 ml/min 0.03 ml/min/kg

7 BLOOD VOLUME = Ultrafiltration - Refilling Transcellular water flux Osmolality Interstitium Intravascular Refilling Starling Forces Cardiovascular Conditions Vascular Space Blood Volume Extracorporeal Uf

8 Body Weight Variation (Kg) CVVH dhd dexthd +20 Blood Volume Variation (%) Mean Art. Press. (mmhg) Hours of observation

9 IHD SLED IUF CRRT Net UF (L/day) (ml/h) VA/NIH Acute Renal Failure Trial Network, NEJM 2008

10 BJA 2014 THE IMPORTANCE OF NET UF TRAJECTORY Rapid early fluid removal may be indicated in cardio-renal syndrome (A), but a slower removal may be required for haemodynamic tolerance after resolution of pulmonary oedema. Patients with single organ renal failure (B) may tolerate more rapid fluid removal than those with AKI complicating severe sepsis (C) or septic shock (D).

11 2018 HIRRT is a common phenomenon across RRT modalities utilized for the treatment of AKI: approximately 10 70% of IHD sessions, approximately 40 60% of SLED sessions, and up to 50% of CRRT sessions. Part of the variability in the frequency of HIRRT observed across studies is most likely attributable to variations in the definition of HIRRT being used, as well as other aspects of how and when different RRT modalities are applied.

12 2018 Only 5 RCTs and 4 observational studies assessed RRT-related interventions aimed at reducing HIRRT These studies were generally small, likely underpowered, and mostly of low quality. Overall, there is no definitive evidence to support the routine use of any particular RRTrelated intervention to limit HIRRT. Higher dialysate sodium or sodium modeling, lower dialysate temperature, and slower blood flow rates can be considered. The lack of a consistent definition for HIRRT presents an impediment for further study.

13 CAUSE DI SBILANCIO FLUIDICO DURANTE CRRT Fluid Imbalance Positive Negative Insufficient fluid removal Fluid Gain Absolute volume (Total Uf) Relative Volume (Uf rate)

14 Dimensions Heigth x Width x Weight Blood Management 80 cm x 50 cm x 13 Kg Blood flow rate 2 50 ml/min Blood flow rate resolution 1 ml/min Blood pressures range: Heparin administration (syringe 10 ml): Air detector (100 ml bubbles) Blood leakage detector Arterial pressure Venous pressure Test of extracorporeal circuit integrity by pressure Fluid management Continuous Flow rate Bolus -400, +100 mmhg -100, +400 mmhg 0 20 ml/h ml Ultrasound sensor Infrared sensor 200 mmhg Weight loss rate 0 5 ml/min Ultrafiltration (UF) rate ml/h UF rate supervision Gravimetric weight supervision accuracy Fluid management gravimetric control: max deviation from UF rate and scale control Fluid administration Infusion flow rate Gravimetric infusion supervision accuracy Automated priming at fixed blood flow rate 20% of blood flow rate 1 g 20 g ml/h 1 g 30 ml/min

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17 UF error ml/h small children neonates ecmo nonecmo N = 4 pts with AKI (2 neonates +2 children) 1 neonate and 1 child required pcrrt+ecmo 1 neonate a 1 child required pcrrt alone

18 ANEMIA Fiber clotting results in blood loss Blood loss from vascular access (example: arterial catheter in CAVH/ CAVH/ CAVHD) Mechanical hemolysis from shear stress/roller pumps on RBC in extracorporeal circuit IN CHILDREN, DEDICATED CIRCUITS WITH LOW PRIMING VOLUMES ARE MANDATORY

19 ANEMIA No study currently evaluated the incidence of hemolysis during CRRT and its clinical Betrus et al. impact Betrus, ATCVS 2007 not r at the peak perce with in LD refle possi obser tion more

20 UNA POTENZIALE INDICAZIONE PER LE MEMBRANE AD ALTO CUT OFF Hulko et al, Scient Rep 2015

21 IPOTERMIA Extracorporeal radiant heat exchange Administration of large volumes of unwarmed substitution fluid may result in cooling of patient hypothermia Heat loss of 750 kcal day, thereby increasing the patient s daily energy requirements and need for a warming blanket

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23 ALTERAZIONI ELETTROLITICHE Hypophosphatemia (especially with high dose therapies May be associated with prolonged weaning (??Weakening of respiratory muscles) Hypokalemia Hypocalcemia (when using regional citrate anticoagulation) Hypercalcemia (with prolonged use of 3.5 Ca solutions) Hyperglycemia with use of PD solutions Human error (using the wrong solution)

24 PERDITA DI AMINOACIDI Dialysate/ ultrafiltrate protein losses as high as 1.3 g/l with CRRT outputs of up to 50 L/day = protein losses up to 65 g/day Mean dialysate/ultrafiltrate protein concentration = 4 mg/dl (Biuret method) Protein losses were higher during convection based CVVH than CVVHDF Amount of protein loss also dependent on serum protein concentration Not yet well-studied with high volume CRRT (HVHF, PHVHF)

25 PERDITA DI AMINOACIDI In standard clinical practice, CRRT overdose is a potential detrimental side effect of pediatric CRRT Amino acid clearances ranged from 2.8 to 51.1 ml/min per 1.73 m2. CVVHD losses corresponded to 20% of intake.

26 Farmaci: proprietà che determinano l entità della rimozione con le terapie sostitutive Legame proteico Volume di distribuzione (Vd) Peso molecolare (PM) Idrosolubilità e carica elettrica Volume e conformazione della molecola

27 Proprietà dei farmaci: volume di distribuzione (Vd) I farmaci ad alto legame tissutale sono caratterizzati da un Vd elevato (amfotericina B: 4 L/Kg) Per i farmaci con Vd elevato (>2 L/Kg) la quantità relativa di farmaco presente nel plasma è modesta rispetto agli altri compartimenti: Vd 1 L/Kg Cl EXTRACORPOREA significativa Vd > 2 L/Kg Cl EXTRACORPOREA irrilevante

28 Proprietà dei farmaci: Peso Molecolare (PM) La maggior parte dei farmaci di comune impiego nel paziente critico hanno un PM 500 Da Vancomicina: PM = 1448 Da Le membrane di impiego comune in CRRT, sono caratterizzate da elevata porosità e permeabilità idraulica e non costituiscono una barriera al trasporto convettivo/diffusivo della frazione libera di farmaci a PM anche superiore a 1500 Da

29 Quali sono le caratteristiche ideali per la dializzabilità di un farmaco? ridotto legame proteico (> frazione libera del farmaco) basso peso molecolare (< 1500 Daltons) ridotto volume di distribuzione (<1 L/Kg) idrosolubilità

30 Parametri farmacocinetici, SC e rimozione farmaci in CVVH Farmaco Escrez. Renale Fraz. libera (%) Vd (L Kg -1 ) PM (Da) SC Rimozione RRT Amikacina 95% >95% S Amfotericina B 5-10% 10% N Cefepime 85% 84% S Ceftazidime 60-85% 83% S Ceftriaxone 30-65% 10% << altri betalattamici Ciprofloxacina 50-70% 60-80% S Fluconazolo 70% 88% particolarmente Gentamicina 95% >95% S Imipenem/Cilast / 60% 79-87% / 56% 0.22 / / /0.7 5 S Meropenem 65% 98% S Piperacillina/ Tazobactam / 65% 70% / 78% 0.25 / / S (Piperacillina > Tazob.) Teicoplanina 40-60% 10-40% modesta Vancomicina % 50-90% S

31 Cl CRRT /CTC (%) 100 Cl. extracorporea vs Cl. Totale Corporea Valori osservati in CRRT con antibiotici diversi 80 76% 60 51% 54% 25% CVVHDF 3 L/h 20% CVVH L/h 21% CVVH 2.5 L/h CVVH 2 L/h CVVHDF 2.5 L/h Vancomicina Linezolid Ciprofloxacina Fluconazolo Ceftazidime DelDot, 2004 Meyer, 2005 Wallis, 2001 Bergner, 2006 Mariat, 2006 SA SC SC SC SA

32 2015

33 CCM 0212 Wide variability in trough concentrations: 6.7-fold for meropenem, 3.8-fold for piperacillin, 10.5-fold for tazobactam, 1.9-fold for vancomycin, and 3.9-fold for ciprofloxacin. Overall, 15% of dosing intervals did not meet predetermined minimum therapeutic target concentrations, 40% did not achieve the higher target concentration, and, during 10% of dosing intervals, antibiotic concentrations were excessive.

34 CC 2015

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36 The dialysate saturation coefficient was and the extracorporeal clearance (with a diffusive dose of 35 ml/kg/h) ranged from L/h. Total linezolid clearance was between 1.7 L/h and 6.3 L/h. Two of three patients did not reach the optimal PK/PD target of 85 even when using an MIC of 2.0 mg/l.

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40 CONCLUSIONI Le complicanze durante terapie continue sono frequenti ma RARAMENTE possono raggiungere elevati livelli di gravità! Non tutto ciò che viene depurato dalla CRRT risulta effettivamente benefico La prevenzione è la soluzione: conoscenza profonda e monitoraggio accurato della tecnica, procedure mediche e infermieristiche standardizzate e specificamente protocollate.