This document summarizes a study on the effects of particulate contamination during intravenous therapy. The study found that in-line filters can significantly reduce complications in critically ill children. A randomized controlled trial assigned 807 pediatric intensive care patients to either a control non-filter group or an intervention filter group. The filter group showed a significant reduction in overall complication rates, systemic inflammatory response syndrome, organ dysfunction, length of stay, and mortality compared to the non-filter group. The results demonstrate that in-line filtration can effectively reduce harmful particulate contamination and its associated adverse effects during intravenous therapy in critically ill children.

1. Micro Particles Contamination:
Innocent Bystander or Real
Threat ?
Pediatric and Adolescent Medicine
Dept. of Pediatric Cardiology and Intensive Care Medicine
Prof. Dr. med. A. Wessel
Thomas Jack; MD
Dept. of Pediatric Cardiology
and Intensive Care Medicine
IFAD Antwerpen 2012

2. Disclosure
Pall Corporation
B. Braun Melsungen AG
Pediatric and Adolescent Medicine
Dept. of Pediatric Cardiology and Intensive Care Medicine
Prof. Dr. med. A. Wessel

3. Background:
Particles and intravenous therapy
• Particulate contamination during intravenous therapy has been
described for many years [1].
• In an intensive care setting it has been estimated that up to one
million particles per patient per day may be infused [2]
Different effects are proven [3,4,5]:
• Embolisation
• Thrombogenic effects
• Immunomodulation
• Impairment of microcirculation
[1][1] Garvan JM & Gunner BW. The harmful effects of particles in intravenous fluids. Med. J. Austr. 1964. 41 (2):1-6.Garvan JM & Gunner BW. The harmful effects of particles in intravenous fluids. Med. J. Austr. 1964. 41 (2):1-6.
[2] Mehrkens HH. Klin Anasthesiol Intensivther. 1977 (14):106-13.
[3] Walpot H. Anaesthesist.1989 Nov;38(11):617-21.
[4] Puntis JW. Arch Dis Child. 1992 Dec;67(12):1475-7.
[5] Lehr HA. Am J Respir Crit Care Med. 2002 Feb 15;165(4):514-20.
Pediatric and Adolescent Medicine
Dept. of Pediatric Cardiology and Intensive Care Medicine
Prof. Dr. med. A. Wessel

4. Origin of particles
1. Drug incompatibility reactions
– Account for 20% of all medication errors and up to 90% of
administration errors
– Impair efficacy of administered drugs or increase risk of
side effects, even formation of toxic compounds
– on ICU, coinfusion of two drugs is uncertain in up to 45%
of instances in which the compatibility of drug combination
is unknown
Taxis K, Barber N. Eur J Clin Pharmacol. 2004; 59: 815 – 7
Vogel Kahmann I. et al. Anaesthesist. 2003 52: 409 – 412
Kähny-Simonius J. Schweiz Rundsch Med Prax. 1993; 82:1320-7
Pediatric and Adolescent Medicine
Dept. of Pediatric Cardiology and Intensive Care Medicine
PD Dr. med. H. Bertram

5. Origin of particles
2. Incomplete reconstitution of drugs or particles
inherent to drug formulation
– Generic formulations of antibiotics have been found to be
heavily contaminated with particles
– Parenteral nutrition admixtures: enlarged lipid droplets arise from
emulsion instability and calcium phosphate precipitates occur
3. Arise from components of the infusion system (e.g.
three way taps, roller pumps a.o.)
Sendo T. et al. J Clin Pharmacy and Therapeutics. 2001; 26: 87 – 91 Driscoll DF et al. Clinical Nutrition. 2005; 24: 699-700
Lehr H.-A. et al. Am J Respir Crit Care Med. 2002; 165: 514–520 Driscoll DF et al Clinical Nutrition. 2006; 25(5): 842-50
Pediatric and Adolescent Medicine
Dept. of Pediatric Cardiology and Intensive Care Medicine
PD Dr. med. H. Bertram

6. Origin of particles
Aggravating factors for particle formation
• Quantity of administered drugs and complexity of
infusion regimen [1,2]
• Lack of available intravenous lines [3]
• Lack of incompatibility information for administered drugs
or their formulation [3]
[1] Jack & Brent et al. Intensive Care Med (2010) 36:707–711
[2] Mehrkens HH. Klin Anasthesiol Intensivther. 1977 (14):106-13.
[3] Schroder F. Infusionsther Transfusionsmed 1994; 21: 52-58
Pediatric and Adolescent Medicine
Dept. of Pediatric Cardiology and Intensive Care Medicine
PD Dr. med. H. Bertram

7. Electron microscopy of used in-line filters
• 20 Filters of different patients were examined
after 72 hours use on our PICU
• Average number of particles found on the
surface of the membrane was 542/cm2.
• More than 20% of the examined filters
showed signs of beginning blockage by
particles retaintion
Jack and Brent et al.; Intensive Care Med. (2010)

8. Electrone microscopy
Particles from a filter membrane after 72 hours use in a 17Particles from a filter membrane after 72 hours use in a 17
yaer old girl after aortic valve replacemant.yaer old girl after aortic valve replacemant.
[1][1] In-line filtration prevents intravascular infusion of "knife blades" and "spearheads" after open heartIn-line filtration prevents intravascular infusion of "knife blades" and "spearheads" after open heart
surgery. Brent B, Jack T, Sasse M;surgery. Brent B, Jack T, Sasse M; Eur Heart J. 2007 May; 28(10)Eur Heart J. 2007 May; 28(10)
70%of the demonstarted70%of the demonstarted
particles were larger thanparticles were larger than
a pulmonary capillarya pulmonary capillary

9. Particulate contamination retained on filter membranes
Precipitation leads to blockage
Parenteral nutrition with high
osmolarity, 5ml/h, analysis of filter
membrane after 72 hours in use

10. Pediatric and Adolescent Medicine
Dept. of Pediatric Cardiology and Intensive Care
Medicine
Prof. Dr. med. A. Wessel
Particulate contamination retained on filter membranes
Dependence on complexity of infusion regimen
0
500
1000
1500
2000
0 1 2 3 4 5 6 7
applied components via filter membrane
particleload/cm2
Jack and Brent et al.; Intensive Care Med. (2010)

11. Clinical Data about the influence of intravenous
particles
Deleterious effects of particles on microperfusion in
different organ systems after ischemia and reperfusion
(Lehr et al. 2002 and 2008; Walpot et al. 1989)
Reduction of thrombophlebitis after elimination of particles
with infusion filters (Falchuk et al. 1985; Chee und Tan
2002)
 Increase of typical neonatal complications like
inflammation, sepsis and enterocolitis (van Lingen et al.
2004)
•Chee S& Tan W (2002: Reducing Infusion Phlebitis in Singapore Hospitals Using Extended Life End-Line Filters. Journal of Infusion Nursing Vol
25, No 2:95-104.
•Falchuk KH, Peterson l, McNeil BJ (1985): Microparticulate-induces Phlebitis. Ist prevention by in-line filtration. NEJM, Jan 10; 312(2):78-82
•Van Lingen RA, Baerts W, Marquering ACM, Ruijs GJHM (2004): The use of in-line filtration in sick newborn infants. Acta paedirtica 93; 1-5
•Lehr HA, Br unner J, Rangoonwala R, Kirkpatrick CJ (2002) Particulate Matter Contamination of Intravenous Antibiotics Aggravates Loss of
Functional Capillary Density in Postischemic Striated Muscle. Am. J. Resp. Crit. Care Med Volume 165. Number 4. February: 514-520.
•Walpot H, Franke RP, Burchard WG, Agternkamp, Mueller FG, Mittermayer Ch, Kalff G (1989) Particulate contamination of infusion solutions
and drug additives during long-trem intensiv care (Part 2-Animal model). Anaesthesist 38: 617-621.

12. van Lingen RA, Baerts W, Marquering ACM, Ruijs GJHM:van Lingen RA, Baerts W, Marquering ACM, Ruijs GJHM:
The use ofThe use of in-line intravenous filters in sick newborn infantsintravenous filters in sick newborn infants
Acta Paediatr. 2004 93; 1-5.Acta Paediatr. 2004 93; 1-5.
The use of in-line intravenous filters in sickThe use of in-line intravenous filters in sick
newborn infantsnewborn infants

13. Prospective, randomized clinical trial for the use of
In-line filtration in critically ill children
Study design
• Prior to the study: Optimization of infusion regimen to prevent
precipitation and incompatibilities of drugs and solutions
• Randomization of pediatric intensive care patients to either
control or interventional group
• Interventional group receiving in-line infusion filters throughout
complete infusion therapy (all solutions and medications),
open label
• Primary endpoints: Reduction in incidence of severe defined
complications (SIRS, sepsis organ failure, mortality and
thrombosis), study was powered (80%) for a reduction in the
overall complication rate
Pediatric and Adolescent Medicine
Dept. of Pediatric Cardiology and Intensive Care Medicine
Prof. Dr. med. A. Wessel

14. optional
catech. 1
following/change
catech. 2
catech. 3
following/change
following/change
AA CH Lipid
optional
syringe pump
optional
syringe pump
CVP measurement
basic iv-solution
short infusion
bolus application
volume
replacement
optional
Central venous catheter (3 lumen) for parenteral nutrition and catecholamine therapy
sedation
heparinization
Heparin
Propofol
jugulas vein
right / left
subclavian vein
right / left
femoral vein
right / left
Clonidin
Midazolam
Fentanyl
Comprehensive view – Infusion setup Hannover Medical School
Pediatric and Adolescent Medicine
Dept. of Pediatric Cardiology and Intensive Care Medicine
Prof. Dr. med. A. Wessel

15. Prospective, randomized clinical trial for the use of
In-line filtration in critically ill children
Pediatric and Adolescent Medicine
Dept. of Pediatric Cardiology and Intensive Care Medicine
Prof. Dr. med. A. Wessel
• Gaussian distribution of
patients to both groups
(406 non-filter vs.
401 filter)
•No differences in PIM II
score, median age,
weight or gender
distribution
•Heterogeneous
background of disease
with no significant
differences in filter vs.
control group
0
20
40
60
80
100
120
140
160
180
others
cardiac
disease
hem
atology/oncology
kidney
disease
gastroenterology
pulm
onary
disease
pediatric
surgery
traum
a
patients
neurosurgery
numberofpatients
non-filter group
filter group

16. Primary outcome: Complication ratio and Mortality: Filter vs non-Filter group
(n= 807)p=0,003
p=0,093
Jack T & Boehne M, et al. Intensive Care Med (2012) 38:1008–1016

17. Significant reduction in incidence of SIRS in the filter group
(123 non-filter group vs. 90 filter group; 95% CI, p<0.01)
Pediatric and Adolescent Medicine
Dept. of Pediatric Cardiology and Intensive Care Medicine
PD Dr. med. H. Bertram
Jack T & Boehne M, et al. Intensive Care Med (2012) 38:1008–1016

18. Results: Hazard Ratios of primary Endpoints and Mortality
Jack T & Boehne M, et al. Intensive Care Med (2012) 38:1008–1016

19. P=0,028
Length of stay
on PICU
Length of mechanical j
ventilation jjjj
Minutes

20. 60 59
2
26
40
34
38
3
20
24
18
54
0
10
20
30
40
50
60
70
cardiovascular
dysfunction
respiratory
dysfunction
neural
dysfunction
liver dysfunction renal dysfunction hematologic
dysfunction
patients
*
*
* * P<0,05
Organ dysfunctions (IPSCC 2005):
non-Filter
Filter
Boehne M & Jack T, et al. unpublished data, under review

21. Summary
• Particulate contamination of infusion solutions are not a
threat, but represent an additional risk for intensive care
patients
• Particles seem to influence immune reaction
• SIRS, Length of stay and length of MV was significantly
reduced in the interventional group by the use of in-line
filtration
• Therefore ifiltration offers a new therapeutic option to reduce
complications on ICU
• Ongoing analyses focus on subgroups and economic aspects
of filter use
Pediatric and Adolescent Medicine
Dept. of Pediatric Cardiology and Intensive Care Medicine
Prof. Dr. med. A. Wessel

22. Thank you for your attention
Pediatric and Adolescent Medicine
Dept. of Pediatric Cardiology and Intensive Care Medicine
Prof. Dr. med. A. Wessel
Members of the
study group
Martin Boehne MD
Bernadette Brent MD
Michael Sasse MD
Johann Wessels
Michaela Abura
Verena Quartier
Markus Becker
Dilek Yilmaz
Meike Müller PhD
Katharina Seewald PhD
Armin Braun PhD
Armin Wessel MD, PhD