Transcript RRT in Intoxications - Pediatric Continuous Renal Replacement

Renal Replacement Therapy for
Intoxications
Timothy E. Bunchman
Pediatric Nephrology & Transplantation
DeVos Children’s Hospital
Grand Rapids, MI
(thanks to Pat Brophy for his help and
some slides)
Before we get going remember

Looking at therapeutic medications or
intoxications there is an
 Absorption process
&
 An elimination/metabolism process
What is unique to Pediatric
Intoxications?
Vehicle in which the medication was
delivered
 Metabolism of drug
 Volume of distribution
 Variable size of the child

Vehicle in which drug was
administered
Oral liquid/mucosal absorption
 Rapid absorption fixed metabolism
 Short acting pill form
 Slower absorption, fix metabolism
 Long acting pill form
 Slowest absorption, fix metabolism

Drug absorption in a child
60
50
40
liquid
short acting pill
long acting pill
30
20
10
0
0
2
4
6
12
CSA metabolism varies with Age
700
600
500
adult
child
infant
400
300
200
100
0
0
2
4
8
12
24
Intoxications

2.2 million reported poisonings
(1998)
• 67% in pediatrics
• Approximately 0.05%
required extracorporeal
elimination
Developmental Changes in Physiologic Factors That Influence Drug Disposition in Infants,
Children, and Adolescents
Kearns, G. L. et. al. N Engl J Med 2003;349:1157-1167
PHARMOCOKINETIC COMPARTMENTS
ELIMINATION
I
N
P
U
T
Distribution
Re-distribution
kidney
blood
Peripheral
liver
GI Tract
Factors affecting clearance
Delivery of drug to hemofilter
Blood flow, volume of distribution
(Vd)
 Drugs unique ultrafiltration properties
Mol. Wt., Chemical structure, drugmembrane interaction, protein
binding
 Ultrafiltration rate

Protein binding
Golper TA et al, Int J Art Organs, 1985
A. Jör res 02/2 001

Extracorporeal Methods
• Peritoneal Dialysis
• Hemodialysis
• Hemofiltration
• Charcoal hemoperfusion
– No longer needed (historical
perspective)
• HD followed by HF

INDICATIONS





>48 hrs on vent
ARF
Impaired metabolism
high probability of
significant
morbidity/mortality
progressive clinical
deterioration

INDICATIONS
severe intoxication
with abnormal vital
signs
 complications of
coma
 prolonged coma
 intoxication with an
extractable drug


PERITONEAL DIALYSIS
 1st done in 1934 for 2 anuric patients after
sublimate poisoning (Balzs et al; Wien Klin Wschr 1934;47:851 )
 Allows diffusion of toxins across peritoneal
membrane from mesenteric capillaries into
dialysis solution within the peritoneal cavity
 limited use in poisoning (clears drugs with low
Mwt., Small Vd, minimal protein binding &
those that are water soluble)

alcohols, NaCl intoxications,
salicylates

HEMODIALYSIS
 optimal drug characteristics for removal:
 relative molecular mass < 500
 water soluble
 small Vd (< 1 L/Kg)
 minimal plasma protein binding
 single compartment kinetics
 low endogenous clearance (< 4ml/Kg/min)
– (Pond, SM - Med J Australia 1991;
154: 617-622)
Hemodialysis: Nl vs High Flux
Normal is a smaller pore size (12 Kda) and
dialysate runs at ~ 30 l/hr
 High flux is larger pore size (up to 50 Kda)
and runs dialysate at ~ 50 l/hr

Hemofiltration use for
intoxications (primary or tandem)
Hemofiltration allows for continuous
therapy at bedside 24 hrs a day
 Can be Convective (CVVH), Diffusive
(CVVHD), or combination (CVVHD)
 CVVHD does not add significantly to what
can be done with maximizing CVVH or
CVVHD alone

Filtration vs. Dialysis
A. Jör res 02/2 001
Filtration:
Clearance by
convection
Dialysis:
Clearance by
diffusion
Dependent
on UFR and
sieving
coefficient
Dependent
on
concentration
gradient
CAVH/CVVH:
Convective Clearance



CVVH/CAVH
Convective clearance
Replacement Solutions
 Physiologic sterile
solution that is either
infused pre filter or
post filter that
infused at a set rate
(Qr)
CAVHD/CVVHD
Diffusive Clearance



CVVHD/CAVHD
Diffusive clearance
Dialysate
 Physiologic sterile
solution that is infused
countercurrent to the
blood flow rate (Qd)
Sieving Coefficients
Solute (MW)
Convective Coefficient Diffusion Coefficient
Urea (60)
1.01 ± 0.05
1.01 ± 0.07
Creatinine (113)
1.00 ± 0.09
1.01 ± 0.06
Uric Acid (168)
1.01 ± 0.04
0.97 ± 0.04*
Vancomycin (1448)
0.84 ± 0.10
0.74 ± 0.04**
Cytokines (large)
*P<0.05 **P<0.01
adsorbed
minimal clearance
Dialysis Dose
10
9
8
7
6
5
4
3
2
1
0
35ml/kg
EDD
CRRT
20ml/kg
7
6
5
4
3
2
PD
0.3
0.5
0.7
0.9
1.1
1.3
No. of Days/week
Weekly stdKt/V
45ml/kg
1.5
eKt/V each dialysis
Adapted from Gotch et al. Kidney Int 2000;58:S3-18
So for any clearance moment to
moment
High (flux) efficiency HD > standard HD >
CVVH > CVVHD > PD
 Thought process of acute RRT needs to
ensure that pt does not become
hypophosphatemic, hypokalemic, etc
 Electrolyte components can be added to
the dialysate “bath”


Intoxicants amenable to Hemodialysis
 alcohols
 ethylene glycol
 Methanol
• (beware that one does not clear the rescue
drug)
 vancomycin (high flux)
 Highly protein bound seizure drugs
 lithium
 salicylates
A good Friday night
Teens deciding that beer was to expensive
so they went for anti-freeze instead
 Had metabolic acidosis and osmolar gap
 Before use of (fomepizol) treated with IV
alcohol and dialysis (may clear rescue drug)
 Alcohols are in general small molecular wt
poorly protein bound

Ethylene Glycol Intoxication
Rx with (std) Hemodialysis
900
800
700
600
500
Pt 1
Pt 2
400
300
200
100
0
0
2
4
Duration of Rx (hrs)
6
A bad Friday night
If a little vancomycin is good a lot is better
 Historically thought to be poorly dialyzable
but with High efficient membrane clears
easily
 Senario is in children with reduction in GFR
dosed based upon nl GFR
 Has a 2 compartment distribution

Vancomycin clearance
High efficiency dialysis membrane
250
Rx
Rx
Rx
200
Rebound
Rebound
150
Pt 1
Pt 2
100
50
0
0
3
12
15
Time of therapy
27
30
A fun Friday night
Highly protein bound anti-seizure meds
thought to be only cleared by CHP
 CHP is where one removes blood from the
pt, filters thru a charcoal filter, goes to a
dialysate membrane back to the pt
 Problem with CHP, large extracorporeal
circuit, cold, hypocalcemic, coagulopathic..
 essentially “they get ugly”

High flux hemodialysis for
Tegretol Intoxication
HD Rx
35
2 compartment
rebound
30
Mic/ml
25
20
CBZ level
(nl < 12;
76%
protein
bound))
15
10
5
0
0
5
10
15
20
25
30
Hrs from time of ingestion
35
40
Tandem therapies:
prevention of the rebound
If one has a rapid generation rate or a large
volume of distribution consider tandem
therapies
 HD for rapid removal followed by HF for
prevention of the rebound

micromoles/l
NH4
HD Rx of Hyperammonemia
(Gregory et al, Vol. 5,abst. 55P,1994: )
2000
1800
1600
1400
1200
1000
800
600
400
200
0
NH4 rebound with reinstitution of HD
0
1
2
3
4
5
6 10 11 12 13 17 18 19 20
Time
(Hrs)
HD to CRRT
(prevention of the rebound)
1200
1000
micromoles/L
NH4
800
Transition from HD to CVVHD
600
400
200
0
0
1
2
3
4
5
Time
(Hrs)
10
11
17
Tandem Therapies
HD to HF
CVVHD following HD for Lithium poisoning
L 6
i
HD started
5
CVVHD started
m 4
E
q 3
/
2
L
Pt #1
Pt #2
Li Therapeutic range
0.5-1.5 mEq/L
CT-190 (HD)
Multiflo-60
both patients
BFR-pt #1 200 ml/min
HD & CVVHD
-pt # 2 325 ml/min
HD & 200 ml/min
CVVHD
PO4 Based dialysate at
2L/1.73m2/hr
1
0
Hours
24
12
6
5
0
Summary
RRT can be an adjunct to normal
elimination of drug or a substitution of drug
removal (with concomitant ARF)
 RRT therapies are safe
 RRT machines are “pediatric friendly”
 HF HD > HF > CVVH > CVVHD
 No role for PD

Summary
Tandem therapies allow for rapid and
sustaining removal of drugs with prevention
of rebound…
 Vascular access already in place
 Early consideration of RRT

Conclusion
……..if you can measure it,
we can clear it…