A POPULATION PHARMACODYNAMIC APPROACH TO HEPARIN DOSING …
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Transcript A POPULATION PHARMACODYNAMIC APPROACH TO HEPARIN DOSING …
MINIMIZING THE IMPACT OF WATER-BORNE
BACTERIA ON HEMODIALYSIS PATIENTS
Richard A. Ward
University of Louisville
Hosted by Paul Webber
[email protected]
A Webber Training Teleclass
www.webbertraining.com
OVERVIEW
WHAT IS THE ROLE OF DIALYSIS FLUID (DIALYSATE) IN
HEMODIALYSIS?
WHY IS THE MICROBIOLOGICAL QUALITY OF THE
DIALYSIS FLUID IMPORTANT?
HOW CAN SAFE LEVELS OF MICROBIOLOGICAL
CONTAMINANTS BE ASSURED?
HEMODIALYSIS
REPLACES THE EXCRETORY
FUNCTIONS OF THE KIDNEY
BLOOD
REGULATES WATER BALANCE
REGULATES ELECTROLYTE
WASTE METABOLITES
C
(UREA, CREATININE, URIC ACID)
ELECTROLYTES
(POTASSIUM, PHOSPHATE)
BALANCE
P
ELIMINATES WASTE
WATER
PRODUCTS OF METABOLISM
DOES NOT REPLACE
ENDOCRINE AND METABOLIC
FUNCTIONS OF THE KIDNEY
C
HCO3-
DIALYSIS
FLUID
SEMIPERMEABLE
MEMBRANE
HEMODIALYSIS
ANTICOAGULATION
DIALYZER
BLOOD PUMP
DIALYSIS
FLUID
BLOOD ACCESS
BLOOD
TUBING
PREPARATION OF DIALYSIS FLUID
DIALYSIS
MACHINE
DIALYZER
DIALYSIS
FLUID
WATER
DRAIN
ACID CONCENTRATE
BICARBONATE CONCENTRATE
DIALYSIS FLUID PREPARATION
FIXED
HCO3(1.83 PARTS)
ACID
(1 PART)
DIALYSATE
HEATER
WATER
(34 PARTS)
CT
DYNAMIC
HCO3-
ACID
DIALYSATE
WATER
HEATER
CA
CT
3
6
0
l
/
w
k
1
4
l
/
w
k
G
I
T
R
A
C
T
U
R
I
N
A
R
Y
E
X
C
R
E
T
I
O
N
N
O
N
S
E
L
E
C
T
I
V
E
M
E
M
B
R
A
N
E
AAMI WATER QUALITY STANDARDS - RD62:2001
SUBSTANCES IN DIALYSATE
2
CALCIUM
4
MAGNESIUM
70
SODIUM
8
POTASSIUM
TOXIC SUBSTANCES (SDWA)
0.006
ANTIMONY
0.005
ARSENIC
0.0004
BERYLLIUM
0.1
BARIUM
0.001
CADMIUM
0.014
CHROMIUM
0.005
LEAD
0.0002
MERCURY
0.09
SELENIUM
0.005
SILVER
0.002
THALIUM
SUBSTANCES TOXIC IN DIALYSIS
0.01
ALUMINUM
0.10
CHLORAMINES
0.5
FREE CHLORINE
0.10
COPPER
0.20
FLUORIDE
NITRATE (as N)
SULFATE
ZINC
2.0
100
0.10
MICROBIOLOGICAL CONTAMINANTS
200
BACTERIA
50
ACTION LEVEL
2
ENDOTOXIN
1
ACTION LEVEL
CHEMICAL CONCENTRATIONS IN mg/L, BACTERIA CFU/ml, ENDOTOXIN EU/ml
WATER TREATMENT SYSTEM
REQUIRED FOR ALL DIALYSIS FACILITIES
MUST PRODUCE WATER OF APPROPRIATE QUALITY
FROM THE WORST CASE FEED WATER
MUST MEET THE PEAK DEMAND FOR WATER (SOME
EXCESS CAPACITY IS DESIRABLE)
SHOULD BE DESIGNED FOR EASE OF MAINTENANCE
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DIALYSIS FLUID QUALITY
AAMI RD52 - DIALYSATE FOR HEMODIALYSIS
LIMITS FOR CHEMICAL CONTAMINANTS
SAME AS FOR WATER (RD62:2001)
LIMITS FOR MICROBIOLOGICAL CONTAMINANTS
BACTERIA: 200 CFU/ml
ACTION LEVEL: 50 CFU/ml
ENDOTOXIN: 2 EU/ml
ACTION LEVEL: 1 EU/ml
DIALYSIS FLUID
DEFINITIONS OF MICROBIOLOGICAL QUALITY
Bacteria (cfu/ml)
Endotoxin (EU/ml)
AAMI Recommended
Practice
ERA-EDTA Best Practice
Guidelines
Ultrapure
200
2
100
0.25
0.1
<0.03
Sterile
10-6
<0.03
SEPTICEMIA AND PYROGENIC REACTIONS
BACTERIA
DO NOT CROSS DIALYZER MEMBRANES
MAY INFECT BLOOD COMPARTMENT DURING
PROCESSING OF DIALYZER FOR REUSE
CAN CAUSE SEPSIS CHARACTERIZED BY WATERBORNE ORGANISMS
ENDOTOXIN
FRAGMENTS MAY CROSS DIALYZER MEMBRANES
MAY CONTAMINATE BLOOD COMPARTMENT DURING
PROCESSING OF DIALYZER FOR REUSE
CAUSE PYROGENIC REACTIONS CHARACTERIZED BY
SHAKING CHILLS, FEVER AND HYPOTENSION
PYROGENIC REACTION RATE (%)
INTRADIALYTIC PYROGENIC REACTIONS
30
20
10
0
1 - 100
100 - 10000
> 10000
DIALYSATE BACTERIA (CFU/ml)
Favero MS et al. Trans Am Soc Artif Int Organs 20:175-183, 1974
PREVALENCE OF PYROGENIC REACTIONS
FREQUENCY OF PYROGENIC
REACTIONS (% Centers)
25
20
15
10
1982 1984 1986 1988 1990 1992 1994 1996 1998
YEAR
Centers for Disease Control, 2000
NUMBER OF CENTERS (%)
INFLUENCE OF DIALYSIS PRACTICES ON
PYROGENIC REACTIONS
30
No
Yes
*
*
*
20
10
0
DIALYZER REUSE
Tokars JI et al. ASAIO J 40:1020-1031, 1994
HIGH-FLUX
BICARBONATE
DIALYZER REUSE: OUTBREAKS OF SEPTICEMIA
AND PYROGENIC REACTIONS
INCORRECT GERMICIDE CONCENTRATION
5/10
INAPPROPRIATE GERMICIDE
2/10
USE OF TAP WATER TO CLEAN OR RINSE DIALYZERS
3/10
USE OF MULTIPLE GERMICIDES
1/10
USE OF WATER NOT MEETING AAMI STANDARDS
10/10
Arduino MJ et al. Dial Transplant 22:652-656, 1993
CHRONIC INFLAMMATION
CYTOKINE-INDUCING SUBSTANCES (ENDOTOXIN
FRAGMENTS, PEPTIDOGLYCANS, MURAMYL
DIPEPTIDES, EXOTOXINS)
CROSS LOW- AND HIGH-FLUX MEMBRANES
STIMULATE MONONUCLEAR CELL CYTOKINE PRODUCTION
ARE ASSOCIATED WITH INCREASED LEVELS OF ACUTE PHASE
PROTEINS (C-REACTIVE PROTEIN)
PRODUCE A MICROINFLAMMATORY STATE THAT MAY PLAY A
ROLE IN b2-MICROGLOBULIN AMYLOIDOISIS,
ATHEROSCLEROSIS, AND MALNUTRITION
PENTOSIDINE (nM)
2000
35
ULTRAPURE
ULTRAPURE
1800
1600
1400
30
1200
1000
25
0
3
TIME (months)
Furuya R, et al. Blood Purif 23:311-316, 2005
6
0
3
TIME (months)
6
b2-MICROGLOBULIN (mg/L)
EFFECT OF WATER QUALITY ON INFLAMMATION
AND b2-MICROGLOBULIN
RISK OF DEVELOPING DIALYSIS-ASSOCIATED
AMYLOIDOSIS WITH CONTAMINATED DIALYSIS FLUID
ODDS RATIO (95% CI)
b2-MICROGLOBULIN AMYLOIDOSIS
3.308 (1.45 – 6.35) p = 0.031
BONE CYSTS
1.85 (1.00 – 3.42) p = 0.047
CARPAL TUNNEL SYNDROME
2.86 (1.35 – 6.07) p = 0.006
ARTHROPATHY
9.04 (2.06 – 39.6) p = 0.004
N = 89
10 YEAR FOLLOW-UP
Schiffl H et al. Nephrol Dial Transplant 15:840-845, 2000
CONTAMINATED DIALYSIS FLUID: 550 CFU/ml
STANDARD DIALYSIS FLUID: 65 CFU/ml
EFFECT OF IMPROVED WATER QUALITY ON
ANEMIA CORRECTION
rHuEPO DOSE (u/kg/week)
200
Hct = 0.32
> 0.15 EU/ml
< 0.007 EU/ml
NO DIFFERENCE IN EPO DOSE
- FILTER
+ FILTER
150
14
12
100
10
50
HEMOGLOBIN (g/dL)
Hct = 0.30
Mean ± SEM n = 27
0
8
-3
-2
-1
0
1
2
3
4
5
3 MONTHS PRE
6 MONTHS POST
MONTH
Matsuhashi N and Yoshioka T. Nephron 92:601-604, 2002
Rahmati MA et al. Int J Artif Organs 27:723-727, 2004
POTENTIAL ADVANTAGES OF WATER AND DIALYSIS
FLUID OF HIGH MICROBIOLOGICAL PURITY
LESS INFLAMMATORY STIMULUS
REDUCED INCIDENCE OF b2MICROGLOBULIN AMYLOID DISEASE
IMPROVED RESPONSIVENESS TO
ERYTHROPOIETIN
IMPROVED NUTRITIONAL STATUS
BETTER PRESERVATION OF RESIDUAL
RENAL FUNCTION
Tubing from a dialysis machine with > 106 CFU/ml
P. aeruginosa, Enterobacter cloacae and Candida parapsilosis
Carr J. Hospital Infections Program, CDCP
BIOMASS FROM DIALYSIS MACHINE TUBING
CFU/cm2
TOTAL
BACTERIA/cm2
WATER PATH
23
1.4 x 105
BICARBONATE PATH
17
1.54 x 105
DIALYSIS FLUID
PATH
12
3.2 x 105
0
0
TUBING FROM
DIALYSIS FLUID
N=3
Adapted from Man N-K et al. Artif Organs 22:596-600, 1998
STRATEGIES FOR BACTERIAL CONTROL
SYSTEM DESIGN
SYSTEM OPERATION
DISINFECTION
DESIGN TO LIMIT BACTERIAL PROLIFERATION
USE A DISTRIBUTION LOOP
AVOID STAGNANT FLOW
INCLUDE BACTERIAL CONTROL DEVICES
NO DEAD ENDS, PRESSURIZING TANKS, OR MULTIPLE BRANCHES
SIZE PIPES TO MAINTAIN VELOCITY > 3 ft/sec
ULTRAFILTERS
ON-LINE HOT WATER DISINFECTION
IF A STORAGE TANK IS USED
MINIMUM SIZE NEEDED TO ENSURE TURN-OVER OF WATER
TIGHT-FITTING LID WITH A HYDROPHOBIC 0.2 mm FILTER AIR VENT
CONICAL BOTTOM WITH DRAIN AT LOWEST POINT
ADEQUATE DISINFECTION MECHANISM
DISINFECTION
DISINFECTION SCHEDULES SHOULD BE DESIGNED TO PREVENT,
NOT ELIMINATE, CONTAMINATION WITH BACTERIA AND BIOFILM.
DISINFECTION SHOULD INCLUDE THE WATER STORAGE AND
DISTRIBUTION SYSTEM, CONCENTRATE PREPARATION AND
DISTRIBUTION SYSTEM, AND THE PROPORTIONING SYSTEM.
MONITORING WITH CULTURES AND ENDOTOXIN LEVELS IS
INTENDED TO VERIFY THE ADEQUACY OF DISINFECTION, NOT
INDICATE WHEN DISINFECTION IS NEEDED.
MONITORING FOR COMPLIANCE WITH AAMI
STANDARDS
CULTURING CONDITIONS
TECHNIQUE
MEMBRANE FILTER, SPREAD PLATE
MEDIUM
TRYPTIC SOY AGAR OR EQUIVALENT
TEMPERATURE
35 - 37°C
TIME
48 hours
ENDOTOXIN MEASUREMENT
TECHNIQUE
LIMULUS AMEBOCYTE LYSATE ASSAY
SAMPLE COLLECTION
SAMPLE PORTS SHOULD PROVIDE DIRECT ACCESS TO
THE FLUID OF INTEREST
FLUSH THE SAMPLE PORT FOR AT LEAST 30 sec
BEFORE COLLECTING THE SAMPLE
DO NOT DISINFECT THE SAMPLE PORT
COLLECT THE SAMPLES DIRECTLY INTO A STERILE
ENDOTOXIN-FREE CONTAINER
ASSAY SAMPLES WITHIN 30 min OR STORE AT 5C
FOR UP TO 24 hours.
ALTERNATIVES TO SPREAD-PLATE CULTURES
CALIBRATED LOOP
– STANDARD TECHNIQUE IN CLINICAL LABORATORIES
– SAMPLE VOLUME IS TOO SMALL FOR REQUIRED SENSITIVITY
– SPECIFICALLY PROHIBITED FOR DIALYSIS APPLICATIONS
PADDLES
– CONVENIENT FOR ON-SITE TESTING
– REQUIRE A MAGNIFIER AND LIGHT-SOURCE FOR ACCURATE
ENUMERATION OF COLONIES
– MAY GIVE AN APPARENT FALSE NEGATIVE WITH HEAVILY
CONTAMINATED SAMPLES
MEMBRANE FILTRATION
– VERY SENSITIVE
– REQUIRES FILTRATION SYSTEM AND LARGE SAMPLE VOLUMES
EFFECT OF CULTURE CONDITIONS ON COLONY
COUNT IN DIALYSATE
BACTERIA (log CFU/ml)
4
3
2
1
0
BLOOD AGAR
37°C
TSA
37°C
Ledebo I, Nystrand R. Artif Organs 23:37-43, 1999
TGEA
37°C
TGEA
20°C
NO MAN’S LINE
EFFECTS OF CLEANING AND DISINFECTION ON
BIOFILM
Silicone rubber tubing allowed to develop biofilm by
exposure to dialysate (187 CFU/ml, 1.8 EU/ml).
Biofilm averaged 15 mm thickness,
covered 96% of
surface, and contained 1.7 x 109 CFU/ml
(Pseudomonas sp.).
Tubing was cleaned with 3% citric acid at 20°c for 5
minutes before disinfection for 40 minutes.
Marion-Ferey K, et al. J Hosp Infect 53:64-71, 2003
EFFECTS OF CLEANING AND DISINFECTION ON
BIOFILM
CLEANING
DISINFECTION
BIOFILM (%)
THICKNESS COVERAGE
RESIDUAL
CFU/cm2
EU/cm2
-
BLEACH (0.3%, 20°C)
50
58
22
354
CITRIC ACID
BLEACH (0.3%, 20°C)
60
65
<1
22
-
ACTRIL (3%, 20°C)
19
15
8.6 x 103
470
CITRIC ACID
ACTRIL (3%, 20°C)
54
68
2.1 x 103
70
-
CITRIC ACID (3%, 90°C)
0
7
3.6 x 105
2618
-
WATER (90°C)
0
7
9.1 x 104
1400
67-100
98
18
27
CITRIC ACID
BLEACH (3% 20°C)
Marion-Ferey K, et al. J Hosp Infect 53:64-71, 2003
EFFECT OF ACID CLEANING ON DISINFECTION
ENDOTOXIN (EU/mL)
1500
1000
120
80
40
0
BLEACH
PERACETIC ACID
HEAT
PRE DISINFECTION
POST DISINFECTION
24 h POST DISINFECTION
Cappelli G et al. Nephrol Dial Transplant 18:2105-2111, 2003
CITRIC ACID + HEAT
EFFECT OF CLEANING WITH ENZYMES AND
DETERGENT ON BIOFILM
60
50
PRONETRON (ENZYME/DETERGENT)
PERACETIC ACID
CITRIC ACID (85°C)
10
5
0
BACTERIA
2
CFU/cm
ENDOTOXIN
2
EU/cm
6
COVERAGE
%
2
UNTREATED TUBING:10 CFU/cm AND 4000 EU/cm
Marion K, et al. Blood Purif 23:339-348, 2005
2
USE OF SEQUENTIAL ULTRAFILTRATION TO
PREPARE ULTRAPURE DIALYSATE
SUMMARY
Hemodialysis patients are highly sensitive to contaminants in
the water used for dialysis fluid and dialyzer reprocessing.
In addition to the risk of septicemia and pyrogenic reactions,
microbiological contaminants may contribute to many
problems common in hemodialysis patients, including b2microglobulin amyloidosis, anemia, and malnutrition.
Avoiding complications from microbiological contaminants
requires a well designed water purification and distribution
system, a rigorous disinfection schedule, and constant
attention to water quality.
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