Rupesh Raina, MD
Akron Nephrology Associates, Inc

Rupesh Raina MD,FAAP and FACP
Consultant Nephrologist
Adult-Pediatric Kidney Disease/Hypertension
Department of Nephrology
Director of Medical Research
Akron General Medical Center Associate of Cleveland Clinic Foundation
&
Akron Children's Hospital, Cleveland Ohio.
Council Member for University Council of Deans
Northeast Ohio Medical University
Faculty Staff at Case Western Reserve University
School of Medicine Cleveland Ohio.
www.akronchildrens.org/giving

• Ranked a Best Children’s Hospital by
U.S. News & World Report
• 10 th largest children’s hospital in country*
• Magnet® Recognition for Nursing
Excellence
• Largest pediatric provider in NE Ohio
• 2 hospital campuses
• 23+ primary care locations
• 60+ specialty location
• 4,700+ employees
• 700+ medical staff
*
Source: 2013 Becker's Hospital Review www.akronchildrens.org/giving

Circuit Clotting in Chil
• Children's have smaller blood volume
• Higher relative surface area of the dialyzer
• Smaller lumen lines and small-bore vascular catheters
• All this potentially increasing contact activation of coagulation proteins, platelets, and inflammatory cells.
Hemodilaysis International 2003 www.akronchildrens.org/giving

• A survey of 54 intensive care units in 23 countries confirmed the overall safety of UFH in managing 1006
ICU patients requiring CRRT for AKI
-33% no anticoagulation
-42.9% UFH
-4.4% LMWH
-9% regional citrate
-6.1% nafamostat mesilate
• Incidence of bleeding was higher with LMWH compared to UFH, 11.4% vs. 2.3%, p < 0.0083

Demographic Characteristics of Pediatric Continuous Renal
Replacement Therapy: Report of the Prospective Registry
• Preference among ppCRRT Registry participants for diffusion-based modalities, with CVVHD and CVVHDF used in 78% of circuits
- CVVHD (48%)
- CVVHDF (30%)
- CVVH (21%),
- SCUF(1%).
• There was also a preference noted for citrate anticoagulation
56% of circuits had citrate anticoagulation
37% had heparin
7% had no anticoagulation
• Initial vascular access is overwhelmingly by femoral catheter (73%)
Clin J Am Soc Nephrol 2: 732 www.akronchildrens.org/giving

• Central to the coagulation cascade is the generation of thrombin (factor IIa)
– Thrombin generated from prothrombin by the action of activated factor X (Xa)
– Thrombin then acts on fibrinogen to generate fibrin clot www.akronchildrens.org/giving

Heparin enhances binding of antithrombin III to factor II & X
Large fragments : Anti IIa Activity
Small fragments : Anti Xa activity
Acts directly and taken up by RES
Metabolised by the liver
Metabolites are eliminated by the kidneys
Plasma half-life is approximately 90 minutes

Heparin
F
Thrombin
S
H
C
AT
Heparin binds to antithrombin and increases the rate of thrombin inactivation www.akronchildrens.org/giving

Differential inhibitory activity against factor Xa and IIa activity
Unfractionated Heparin
F
Thrombin (IIa)
S
H
C
AT
F
Thrombin (IIa)
S
H
C
LMWH
AT
By binding to AT, most UH and LMWH can inhibit Xa activity.
Fewer than half the chains of LMWH are of sufficient length to also bind factor IIa, therefore has decreased anti-IIa activity www.akronchildrens.org/giving

www.akronchildrens.org/giving

Heparin (24) Citrate (12)
Median age
Median circuit survival
Clotting incidence of bleeding
Total CRRT dose (sum of substitution, dialysis, citrate, and extraction flows) per kilogram
Metabolic complications
Platelet; 24hr 72 hrs
33 months
31.0 hours (IQR 15.5
–71.0)
76%
10.3%
59 mL/kg/hour hypophosphatemia
138.000 77.000
36 months
48 hours (IQR 31.0
–93.7)
18%
0%
69 mL/kg/hour
Hypochloremia and hypomagnesaemia
117.000 161.000
www.akronchildrens.org/giving

UFH
PROs
Half life 30 min to 3 hrs
Cons
UFH has an anti-Xa versus anti-IIa ratio of 1:1
Bioavailability 30%
LMWH
Pros anti-Xa effect of LMWHs is stronger than their anti-
IIa effect 3:1
Bioavailability 90%
Cons
Half Life 2-4 hrs
Effect more prolonged in renal failure
Possibility to antagonize by protamine -Each mg of protamine sulfate neutralizes approximately
85 – 110 IU of UFH.
Increased risk for bleeding 11%
Reduced risk of bleeding
2.4%
Possibility to antagonize only partial
Pharmokinetics individually unpredictable as it is negatively charged and bind to various protein
Linear pharmokinetics proportionality between anti-Xa plasma concentration and dose, stationary distribution volume and clearance processes
Price of LMWHs is fivefold the price of UFH
Moderate correlation with
UF heparin and aPTT
HIT 9-20.7%
Routine monitoring unnecessary
HIT 2.8-7.5%
Special assays to monitor anti-Xa activity www.akronchildrens.org/giving

Lack of correlation between heparin dose and standard clinical monitoring tests in treatment with unfractionated heparin in critically III children
 Determine correlations of aPTT, anti-Xa and UFH dose in children
 Single center prospective cohort study N=39 (median age 18 days)
 aPTT reflected anti-Xa activity less than 33% of the time and there was no relationship between aPTT and anti-Xa activity
(r 2 =0.22)
 The aPTT overestimated anti-Xa activity in 67% of cases and underestimated anti-Xa activity in 5%

No relationship between heparin dose and either aPTT (r 2 =0.12) or anti-Xa activity
(r 2 =0.03)

• In the absence of coagulopathy (patient’s ACT < 150 seconds), a heparin bolus of 25-50 units/kg
(maximum 2000 units) should be administered prior to the onset of CRRT
• Recheck ACT and repeat heparin bolus (maximum x
2) if necessary to achieve ACT > 180 seconds
• Plasma anti-Xa activity can be used to assess the anticoagulation effect of either unfractionated heparin
(UFH) or low molecular weight heparin (LMWH), but it is not a rapid turnaround test and is unsuitable for routine use in the dialysis unit
RAINBOW BABIES & CHILDREN'S HOSPITAL CRRT PROTOCOL www.akronchildrens.org/giving

Heparin infusion should be ordered as follows in a 20-ml syringe:
20,000 units in 18 ml NS (1000 units/ml)
2,000 units in 18 ml NS (100 units/ml)
200 units in 20 ml NS (10 units/ml)
Patients > 60 kg
Patients 10 - 60 kg
Patients < 10 kg
• The heparin drip flow rate can be set from 0 to 5.0 ml/hr, in 0.5ml increments
• When ACT >180 seconds, initiate CRRT and begin continuous infusion of heparin at 10 units/kg/hour via the PRISMAFLEX circuit
RAINBOW BABIES & CHILDREN'S HOSPITAL CRRT PROTOCOL www.akronchildrens.org/giving

• ACTs should be monitored from the venous side of the filter q 30 minutes until in range x 2, then q hr. If in range x 2 hrs without change in heparin dose, check ACTs q 2 hours
• With each circuit change, and when platelets or blood are administered to the patient, and after any changes to heparin drip, obtain ACT q 30 minutes until stable
RAINBOW BABIES & CHILDREN'S HOSPITAL CRRT PROTOCOL www.akronchildrens.org/giving

Modify heparin administration as follows, to maintain ACT within goal range of 180-220:
ACT
< 160
160-180
(seconds)
180-220
220-260
> 260
Action
Heparin bolus 10 units/kg via circuit
Increase heparin drip by 20%
Heparin bolus 5 units/kg via circuit
Increase heparin drip by 10%
No action
Decrease heparin drip by 10%
Decrease heparin drip by 20%
RAINBOW BABIES & CHILDREN'S HOSPITAL CRRT PROTOCOL www.akronchildrens.org/giving

Assess the patient for evidence of bleeding:
–Q 4h neurological checks for evidence of intracranial bleeding, or more frequently per the ICU standard.
–All stools and body fluid output will be tested for gross or occult blood.
–Other areas of potential bleeding such line and drain insertion sites; endotracheal tube and mouth/nose will also be checked for evidence of bleeding q 4h.
–The Hb and Hct will be monitored as ordered for signs of significant bleeding.
RAINBOW BABIES & CHILDREN'S HOSPITAL CRRT PROTOCOL www.akronchildrens.org/giving

Crit Care. 2010; 14(3): 419 www.akronchildrens.org/giving

Courtesy Dr. Akashdeep www.akronchildrens.org/giving

• AT concentrations are often reduced as a result of consumption due to activation of coagulation and as a result of proteolytic degradation by granulocyte-derived elastase
• Heparin avidly binds to apoptotic and necrotic cells and signal phagocytotic clearance (LMW is less avidly bound)
• Heparin-binding proteins are released from endothelial stores as a acute-phase reactants such as platelet factor 4, histidine-rich glycoprotein, vitronectin, fibronectin and lipopolysaccharide-binding protein, all of which increase in sepsis and other forms of inflammation
Thromb Haemost www.akronchildrens.org/giving

Critical Care 2011, 15:202 www.akronchildrens.org/giving

• Osteoporosis -Proven for continuous use (e.g., DVT treatment in pregnancy) in non-CKD patient; unknown if intermittent use for hemodialysis aggravates the other causes of ESRD bone disease
• Hyperlipidemia Heparin (UFH and LMWH) releases and depletes endothelium-bound lipoprotein lipase causing hypertriglyceridemia
• Aldosterone suppression Promotesmodest interdialytic rise in serum potassium concentration, UFH > LMWH
• Allergic reaction Immediate hypersensitivity (Type I) to heparin can be confused with other systemic reactions (e.g., to dialyzer)
• Heparin-induced thrombocytopenia (HIT) Antibody-mediated
(Type II) reaction leading to platelet activation with arterial and venous thrombos www.akronchildrens.org/giving

• Occurs in up to 10%-Bovine (5.9%) vs porcine (1% or less)
• Platelet-activating IgG antibody directed at a platelet factor 4heparin complex.
• When heparin is withdrawn, platelet counts typically recover to baseline within 2 weeks
• Venous thromboembolism predominates over arterial events in a
4:1 ratio (Am J Med.1996; 101(5):502 –507)
• In Survey of N= 10546 maintenance HD patient in the UK, the prevalence of HIT was 0.26 per 100 patients and only 17% of these had complications related to the disorder (NDT. 2007;
22(6):1680 –1684) www.akronchildrens.org/giving

Br J Haematol.2003; 121(4):535 www.akronchildrens.org/giving

• The recommended danaparoid dosing schedule for
CRRT was a loading i.v. bolus of 2250 U, followed by
400 U/h x4h, then 300 U/h × 4h and finally a maintenance infusion rate of 150-200 U/h for as long as necessary.
• However, dose adaptation was possible for patients with initial circuit/systemic clotting problems or increased bleeding risk at least until the problem was overcome
Pediatric Critical Care Medicine: