micro particles contamination: innocent bystander or real threat ?

Micro Particles Contamination: Innocent Bystander or Real

Threat ?

Pediatric and Adolescent MedicineDept. of Pediatric Cardiology and Intensive Care MedicineProf. Dr. med. A. Wessel

Thomas Jack; MDDept. of Pediatric Cardiology and Intensive Care Medicine

IFAD Antwerpen 2012

Disclosure

Pall Corporation

B. Braun Melsungen AG


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] 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.


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 – 7Vogel Kahmann I. et al. Anaesthesist. 2003 52: 409 – 412Kähny-Simonius J. Schweiz Rundsch Med Prax. 1993; 82:1320-7

Pediatric and Adolescent MedicineDept. of Pediatric Cardiology and Intensive Care MedicinePD Dr. med. H. Bertram

Origin of particles2. 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: 699-700Lehr 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


Origin of particlesAggravating 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


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)

Electrone microscopy

Particles from a filter membrane after 72 hours use in a 17 yaer old girl after aortic valve replacemant.[1] In-line filtration prevents intravascular infusion of "knife blades" and

"spearheads" after open heart surgery. Brent B, Jack T, Sasse M; Eur Heart J. 2007 May; 28(10)

70%of the demonstarted particles were larger than a pulmonary capillary

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


Particulate contamination retained on filter membranes Dependence on complexity of infusion regimen

applied components via filter membrane

part

icle

load

/ cm

2

Jack and Brent et al.; Intensive Care Med. (2010)

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.

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

The use of in-line intravenous filters in sick newborn infants

Prospective, randomized clinical trial for the use of In-line filtration in critically ill childrenStudy 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 ratePediatric and Adolescent

MedicineDept. of Pediatric Cardiology and Intensive Care MedicineProf. Dr. med. A. Wessel

optio

nal

catech. 1following/change

catech. 2

catech. 3

following/change

following/change

AA CH Lipidoptional

syringe pumpoptional

syringe pump

CVP measurement

basic iv-solution

short infusion

bolus application

volumereplacement

optio

nal

Central venous catheter (3 lumen) for parenteral nutrition and catecholamine therapy

sedation

heparinization

Heparin

Propofol

jugulas veinright / left

subclavian veinright / left

femoral veinright / left

Clonidin

Midazolam

Fentanyl

Comprehensive view – Infusion setup Hannover Medical School


Prospective, randomized clinical trial for the use of In-line filtration in critically ill children


• 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

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

Significant reduction in incidence of SIRS in the filter group (123 non-filter group vs. 90 filter group; 95% CI, p<0.01)



Results: Hazard Ratios of primary Endpoints and Mortality


P=0,028

Length of stay on PICU

Length of mechanical j ventilation jjjj

Min

utes


* *

* * P<0,05

Organ dysfunctions (IPSCC 2005):

non-Filter

Filter

Boehne M & Jack T, et al. unpublished data, under review

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


Thank you for your attention


Members of the study groupMartin Boehne MDBernadette Brent MDMichael Sasse MDJohann WesselsMichaela AburaVerena QuartierMarkus BeckerDilek YilmazMeike Müller PhDKatharina Seewald PhDArmin Braun PhDArmin Wessel MD, PhD