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Endotoxin

Explore the Benefits & Solutions of Endotoxin Retention with IV In-line Filters

It is universally accepted by medical and pharmaceutical authorities world-wide that all devices and substances put into a patient's bloodstream must be free from endotoxin or 'pyrogen free', so regardless of the patient's status, they should be protected against exogenous endotoxin.

Summary

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The investigation of the function of endotoxin in the pathophysiology of sepsis has been studied since the 1800s, when endotoxin was first revealed as a gram-negative cell wall toxin responsible for lethal shock.1 Today, systemic gram-negative sepsis with endotoxin as the prime initiator remains one of the most severe conditions complicating the course of hospitalized subjects, mainly in critically ill patients in the intensive care unit (ICU).2,3

 

Chemical structure analysis has shown an endotoxin unit is consisting of a lipid A component and an O-Antigen component. The O-Antigen is made of polysaccharides and is associated with immunogenicity, while the lipid A portion of the endotoxin is the toxic component.4 The immune system's reaction to a lipid A component may lead to serious generalized inflammation, manifesting clinically as septic shock with multiple organ dysfunction, especially myocardial depression and renal impairment.5 In IV therapy gram-negative bacteria and associated endotoxin may get into the patient’s blood stream from an external source, such as contaminated equipment or fluids.6-13 Hospital cases of endotoxin in intravenous solutions leading to adverse reactions or even death have been investigated in the past.14-19

 

This is where our Posidyne® IV in-line filters come into play - retaining endotoxin and preventing it entering the patient’s bloodstream during IV therapy. Our validation testing over 96 hours confirmed that

 

  • Our ELD96 IV in-line filters (aged and unaged) retained > 99.9999 % of the endotoxin challenge produced from a 1 x 108 E. coli challenge in 0.9% saline with an effluent concentration of < 0.1 EU/mL* from an average challenge level of > 1 x 103 EU/cm2 (*limit of detection of the assay = 0.1 EU/mL).20
  • Our NEO96 IV in-line filters (aged and unaged) retained > 99.9999 % of the endotoxin challenge produced from a 1 x 108 E. coli challenge in 0.9% saline with an effluent concentration of < 0.1 EU/mL*  from an average challenge level of > 1 x 104 EU/cm2 (*limit of detection of the assay = 0.1 EU/mL).21

 

If a patient is already sick, with septic shock or other critical illness, will a few endotoxin units really make a difference?

 

Yes, studies have described the clinical effects of even small doses of endotoxin on humans.22,23

 

Your benefits with our Posidyne IV in-line filters

  • Retention of endotoxin up to 96 hours under clinically relevant conditions24-27
  • Reducing staff time & costs due to less IV filter-set changes28-30
  • Improvement of clinical outcomes32-36

 

We are the leading pioneer and have manufactured positively charged, membrane-based IV in-line filter products with a claim for the removal of bacteria and associated endotoxins for the health care community for over four decades.

 

References

What is endotoxin?

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In 1892, Richard Pfeiffer, a German physician and bacteriologist working together with Robert Koch at the Institute for Infectious Diseases at Berlin, coined the term “endotoxin” and described the concept that toxic bacteria were due to a factor released by lyzed bacteria. Through this research Richard Pfeiffer formulated the concept of “endotoxin as a poison which, during microbial life, is firmly bound to the bacterial cell and is only released postmortem to evolve a sickening effect.”

 

Today, an endotoxin is defined as a toxic heat-stable lipopolysaccharide substance present in the outer membrane of gram-negative bacteria that is released from the cell upon lysis.2 Hence an endotoxin is also known as a lipopolysaccharide or LPS. Contrary to gram-negative bacteria, gram-positive bacteria do not produce endotoxin since these bacteria do not have an outer cell membrane. Chemical structure analysis revealed that an endotoxin unit consists of 

  • fat (known as lipid A) and
  • carbohydrates (polysaccharides).

 

The lipid A portion of the endotoxin is the toxic component, while the O-Antigen is made of polysaccharides and is associated with immunogenicity.3

References

Hospital-associated infections and endotoxin producing Gram-negative bacteria

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Data between 2008 and 2018 showed that in American hospitals alone, the Centers for Disease Control (CDC) estimated that hospital-associated infections (HAIs) account for an estimated 1.7 million infections and 98,000 associated deaths each year.1,2 Almost one-third of all HAIs and 60% of HAIs in intensive care units are caused by gram-negative bacteria.3 Furthermore, gram-negative bacteria are among the most significant public health problems in the world due to the high resistance to antibiotics.4 Gram-negative infections include those caused by Klebsiella, Acinetobacter, Pseudomonas aeruginosa, and E. coli., as well as many other less common bacteria.4

 

References

Even small doses of endotoxin lead to clinical effects in humans

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The clinical consequences of endotoxin include1,2

 

  • fever, headache, chills
  • reduced heart function (cardiac contractility), causing tachycardia to try to keep the circulation going
  • intravascular coagulation, leading to vascular occlusion (blockage of circulation)
  • widening of the blood vessels (vasodilatation), causing a fall in blood pressure (hypotension)
  • damage to the lining of the blood vessels (increased endothelium permeability), causing leakage of fluid from the blood vessel into the surrounding tissue (oedema)
  • decreased oxygen transport to the tissues (decreased perfusion)
  • in the worst cases, the heart is unable to pump blood around the system, the blood pressure falls, large areas of circulation are not reached, especially in the organs that require a high throughput of blood, and the tissues don't get enough oxygen.

 

Due to the above, there may be progressive loss of function in the kidneys, lungs, heart, and brain, leading to multiple organ failure, which can be fatal.

 

Studies have described the effects of even small doses of endotoxin on humans. Experiments on healthy volunteers found adverse effects using 2-4 nanograms of endotoxin per kilogram body weight. This equates to 20-40 endotoxin units (EU) per kg. At this level, the subjects experienced fever, increased heart rate, headache, chills, aching limbs, and were found to have significantly decreased cardiac function, increased blood pressure, raised white cell count and inflammatory factors, increased gut permeability and activation of the coagulation system.3-10

References

Are there endotoxin limits for parenteral drug products?

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Yes, the endotoxin limit for a product is the endotoxin concentration that must not be met or exceeded to release the product for sale. For parenteral drugs the endotoxin limit equation given in the United States Pharmacopeia (USP) <85> is as follows:1,2

 

Endotoxin limit = K/M

 

K = 5 EU/kg of body weight for any parenteral route of administration other than intrathecal, which is the threshold pyrogenic dose of endotoxin per kg of body weight.

M = The maximum recommended bolus dose of drug per kg of body weight – when infused continuously M = the maximum total dose administered in a single hour period

 

Example

 

In essence based on a 70 kg patient the endotoxin limit would be 350 EU so for a 2 mL bolus the drug would need to have less than 175 EU/mL of solution and for 1 L of a drug given intravenously over 1 hour it would need to have less than 0.35 EU/mL of solution.

 

For a drug administered as a 2 mL bolus to a 10 kg patient it would need to have less than 25 EU/mL.

 

How is endotoxin tested in infusion solutions?

 

The Limulus amoebocyte lysate (LAL) test uses an extract of blood from the horseshoe crab, which clots rapidly in the presence of endotoxin. The LAL test has been widely used for ~30 years for the detection of endotoxin in the quality assurance of injectable drugs and medical devices.3

 

 

References

The risk: endotoxin production in intravenous solutions occurs within 24 hours

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Previous studies have shown that gram-negative bacteria can multiply and will shed endotoxin in intravenous solutions.1-3 Accidental infusion of nonsterile fluids contaminated with endotoxins may be rare, but hospital cases of endotoxin in intravenous solutions leading to adverse reactions or even death have been investigated.4-9

 

Our test: The accumulation of endotoxin in infusion solutions

 

We have previously monitored the concentration of E.coli and corresponding endotoxin levels over a 96-hour period when a 1 L container of 0.9 % Saline or 1 L of AKE 1100 with Xylit (Fresenius Kabi) was contaminated with 1 x 108 CFU of E.coli.

 

The table below shows the concentration of E.coli (CFU/mL) detected in the solutions at time 0 and following 96 hours storage at ambient temperature (internal data).While the endotoxin units / mL remains relatively constant over 96 hours in saline solution, endotoxin units / mL increased in the parenteral nutrition solution approximately

 

  • by a factor of 10 after 24 hours,
  • by a factor of 100 after 48 hours,
  • by a factor of 1,000 after 72 hours,
  • and by a factor > 1,000 after 96 hours (above the limit of the assay).

 

 

(A) Average total count (CFU/mL) at T(0h) & T(96h)
Time (h) 0 24 48 72 96
Mean number of bacteria in 0.9 % saline 9.14 x 103 N/A N/A N/A 1.62 x 102
Mean number of bacteria in AKE 1100 9.14 x 103 N/A N/A N/A 5.20 x 107
(B) Concentration of Endotoxin (EU/mL) over time
Time (h) 0 24 48 72 96
Endotoxin units in 0.9 % saline 1.54 1.54 1.22 2.2 0.91
Endotoxin units in AKE 1100 1.5 13.2 95.6 1.75 x 103 >5.00 x 103

 

 

References

The problem: The need to change IV in-line filters every 24 hours due to the risk of endotoxin

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Many solutions are administered for periods longer than 24 hours. Should a clinical practitioner be concerned that IV in-line filters are safe regarding endotoxin?

 

Yes. An in vitro study by Holmes et al simulated growth of bacteria during simulated infusion and investigated uncharged 0.22 µm IV in-line filters in respect to their retention capabilities of bacteria (R. agglomerans, S.marcescens, K. pneumoniae, and P. aeruginosa) and their associated endotoxin over a 72-hour period.1

 

The study showed that whilst the gram-negative bacteria proliferated in the solutions upstream of the IV in-line filters, none of the 0.22 µm IV in-line filters allowed the passage of the bacteria downstream over the 72-hour period. However, for all 4 of the gram-negative bacteria used endotoxin was detected downstream of the IV in-line filters between 24 and 48 hours and led to the conclusion that “to avoid this potential hazard of terminal filtration, in-line filter sets should be changed every 24 hours.”

 

On the downside, changing IV in-line filter every 24 hour leads to substantial cost, staff time and set manipulations with associated risks of bacterial contamination.2-7 Extending the usage time of the IV in-line administration set with an endotoxin-retentive filter can lead to substantial cost and time savings and potentially minimizes the risk of bacterial contamination due to less manipulation of the IV lines.8

 

 

References

The solution: Expanding the use of IV in-line filters up to 96 hours

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It would be reasonable to expect that any IV in-line filter intended for use for more than 24 hours in an infusion line would be validated, to show that it retains endotoxin in infusion lines. Several studies have evaluated the endotoxin-retention properties of 0.2 µm filters during simulated clinical infusions. Those studies demonstrated that, distinct differences exist in the ability to retain endotoxins under those test conditions.1-4

 

We have manufactured positively charged, membrane-based intravenous filter products with a claim for the removal of bacteria and associated endotoxins up to 96 hours for the health care community for over four decades.

 

The endotoxin aggregate shed from the cell is a particle with a high negative charge. It is possible to retain these aggregates by the incorporation of a positive charge, at an appropriate density and configuration, in the filter membrane. The addition of a positive charge does not automatically guarantee reliable endotoxin retention and extensive testing is necessary.

 

Endotoxin contains exposed phosphate groups. Generally, at pH values above pH 2, these phosphate groups are strongly negatively charged.  IV solutions have a pH value above this and our positively charged IV in-line filter therefore provide the opportunity for the removal of the negatively charged endotoxins. 

 

References

The proof: our IV in-line Posidyne filters retain inadvertent endotoxins up to 96 hours

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Several publications over the last 40 years have shown that our IV in-line filters with Posidyne membrane retain endotoxin in both clinical and laboratory settings.1-7

 

In addition, our scientific laboratory services (SLS) have tested our IV in-line filters containing Posidyne membrane with E. coli, a clinically relevant organisms, that can result in endotoxin generation.

 

Our ELD96 and NEO96 Posidyne IV in-line filters are air eliminating filters with a 0.2 µm Posidyne membrane for up to 96 hours use, with any administration set, for removal of inadvertent particulate debris, microbial contaminants and their associated endotoxins and entrained air which may be found in solutions intended for intravenous or subcutaneous administration.

 

Evaluation of endotoxin retention efficiency of our ELD96 IV filters with 0.2 µm Posidyne® membrane over a 96-hour period.

 

Our ELD96 Posidyne IV in-line filters (aged and unaged) retained > 99.9999 % of the endotoxin challenge produced from the 1 x 108 E. coli challenge with an effluent concentration of < 0.1 EU/mL from an average challenge level of > 1 x 103 EU/cm2.

 

Evaluation of endotoxin retention efficiency of our NEO96 Posidyne IV filters with 0.2 µm Posidyne® membrane over a 96-hour period.

 

Our NEO96 Posidyne IV in-line filters (aged and unaged) retained > 99.9999 % of the endotoxin challenge produced from the 1 x 108 E. coli challenge with an effluent concentration of < 0.1 EU/mL from an average challenge level of > 1 x 104 EU/cm2.

 

References

Benefits of our IV Posidyne in-line filters

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Endotoxin can get into an ICU patient’s blood stream from gram-negative bacteria trapped on a non-positive charged IV filter or from an external source, such as contaminated equipment or IV fluids.

 

Increase the IV in-line filter duration from 24 hours to 96 hours

 

Only IV filters that retain endotoxin can safely be used for more than 24 hours. Studies have shown that our Posidyne IV-inline filters retain endotoxin under clinically relevant conditions.1-4 By increasing the time of IV in-line filter up to 96 hours, ICU staff are reducing the chance of potential contaminations.

 

Benefits for your ICU patients

 

Several studies have described the clinical effects of even small doses of endotoxin on humans.5 But if a patient is already sick, with septic shock or other critical illness, will a few endotoxin units really make a difference?

 

It is universally accepted by medical and pharmaceutical authorities world-wide that all devices and substances put into a patient's bloodstream must be free from endotoxin or 'pyrogen free', so regardless of the patient's status, they should be protected against exogenous endotoxin. Patients with coagulation disorders, inflammation or cardiac dysfunction would not benefit from additional endotoxin and it could represent an additional burden.

 

Cost savings for your hospital

 

Substantial cost and time savings can be achieved with the use of 0.2 µm endotoxin-retaining IV in-line filters because the IV in-line filters and administration sets could be extended up to 96 h. Recent studies have reported the extent of these savings.6-10

 

 

References

Our IV Filtration Team is Here to Help You

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Our highly skilled technical experts in our “Scientific Laboratory Services” (SLS) are here to support you and offer advice on optimal intravenous filtration and infusion solutions or to perform drug compatibility studies.

 

Our Clinical Specialists support customers who wish to implement Pall intravenous, breathing and gas filtration devices. They implement and evaluate our products in hospitals at the patient’s bedside and advise on any problems that might arise.

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