Corona crisis and the ICU patient: focus on particles (2023)

1. The location: lungs

One major threat during COVID-19 infection is that the lungs of ICU patients are under attack.

• First, in severe cases of a corona virus infection, the lungs are the hardest-hit organ (pneumonia-like symptoms, respiratory failure)¹⁵.
• Second, assuming an average intravenous solution administration of 5 L per ICU patient¹⁶, nearly 190 million L of intravenous fluid are administered annually alone in the US¹⁷.
• Given these data, ICU patients receive intravenously large numbers of particles of different sizes and origin, e.g. particles from drugs and particles from different parts of the infusion equipment^5,6,18. Eventually, particles may end up in the lungs¹⁹ and have been hypothesized to contribute to respiratory complications^12,13,14.

2. The problem: particles

a. Particles matter, no matter what size

No matter what size particles are, they have the potential to hurt the human body once they are in the circulatory system. The potential particle damage depends on a variety of parameters, such as size, shape, number and charge of the particles.

One septic shock animal study found that injecting intravenously tiny polystyrene particles with a diameter 6 μm after injection of lipopolysaccharides (LPS) led to a significantly lower survival rate compared to injection of LPS without particles²¹. The scientists also demonstrated a dose dependent effect: Higher numbers of infused particles led to high mortality rates and earlier death of the animals.

Furthermore, particles affect drug-induced toxicity (3): While treatments of mice with acetaminophen (APAP), 5-aminosalicylic acid (5-ASA) and tetracycline (TC) were non-lethal and did not result in severe toxicity, injections of the same drugs together with polystyrene particles with a diameter of 50nm led to synergistic enhanced toxicity. These results suggest interactions between pharmaceutical products and infused polystyrene particles²².

b. Particles correlate with functional disturbance in the microcirculation

Mortality of critically ill patients is driven by severity of the insult, comorbidities, appropriate treatment, and organ failure. Alterations of microcirculatory perfusion are associated with organ failure severity and mortality²⁷. Maintaining a patent and well-regulated microcirculation is a key therapeutic end point in resuscitated and intensive care patients²⁸.

Studies have shown that generic drugs may contain many more particles than the original product, in a size range relevant for impacting the microcirculation and contributing to a significant shut-down of tissue perfusion². The data from this animal study, mimicking the ICU patient, indicates that the presence of a large number of small particles correlates with functional disturbance in the microcirculation. Measurement of the Functional Capillary Density (FCD) following drug injection revealed marked differences between the generic drugs and the control.

An additional animal study showed that using generic antibiotics led to the loss of almost 50% of hamster capillary network that was already compromised by prior ischemia and reperfusion, a loss that may well “tip the balance from recovery to organ failure or even death”³. These deleterious effects of particle contaminants on the post-ischemic microcirculation were entirely prevented using 0.2 µm in-line filters. These findings suggest that particle contaminants may pose a major threat to critical tissue perfusion, with potentially enormous relevance for patients with prior microvascular compromise of vital organs (i. e. post trauma, major surgery, sepsis) and that this danger can be averted by the use of commercially available in-line filters.

c. Where do particles come from and how many are there?

In 2017 and 2019 the Parenteral Drug Association (PDA) hosted the European convention in Berlin “Particles in Parenteral Injection Solutions”. The objective of the convention was an exchange of information about foreign particles regarding the production and inspection of pharmaceuticals, as well as the assessment of potential health risks for patients and possible ways of eliminating these. Prof. Cornelia Keck from the Philipps University of Marburg presented the following^5,6:

• Roughly 50% of particles derive from drug products.
• Roughly 50% of particles derive from the infusion equipment such as the infusion set, tubes, syringes, valves and stoppers.
• The characterization of the particles revealed substances such as sulfur, silicone, silicone active mix, cellulose, rubber, starch, polypropylene, polyethylene, polyester, Titanium(IV)oxide (Rutile), polycarbonate, polystyrene and Heliogen Blue.

d. How many particles are infused into the ICU patient?

The numbers vary, depending on what size you measure. Rule of thumb - the smaller the size, the more there are.

An answer to that question was given by Prof. Cornelia Keck at the European convention in Berlin on the topic of “Particles in Parenteral Injection Solutions”. In her experiment in cooperation with the Medical University of Hanover, a clinical PICU infusion scenario was set up in the laboratory. Instead of PICU patients, glass vials collected the infusion solutions which were infused for 72 hours. 69 billion submicron particles (< 1 µm) over a period of 3 days were counted^5,6.

In 2012 Ernst and colleagues from the Fraunhofer Institute for Manufacturing Engineering and Automation IPA in Germany investigated 14 drug products in respect to their particle load. The particle count for the various drugs differed from 420,000 particles per ml drug up to 110 million particles per ml drug (particles with a size > 0.05 µm)⁴.

The authors of a study of real-life multidrug IV therapy protocols on a NICU (neonatal ICU) found that despite the absence of visible particles in the IV tubing, patients are infused with up to 85,000 particles per day (particles > 1 µm). Moreover, the study revealed that very large particles of about 60 μm were infused to infants. Further, the combined infusion of several drugs – standard for almost all ICU patients – causes a significant increase in particulate matter⁷.

Perez and colleagues demonstrated in 2018 that PICU (pediatric ICU) patients are infused with up to 416,974 particles per day (particles > 1 µm)⁸.

Adult ICU patients may receive up to 8256 particles over the 6-h infusion (particles > 1 µm). The largest particles found had the size of 341 µm. In comparison: a small blood vessels in the microcirculatory system has a dimeter of roughly 8 µm⁹.

Another study found that patients can receive up to 900,000 particles per day during hospitalization. The choice of drug concentration and/or the type of infusion set may reduce this¹⁰.

3. The solution: in-line filters

Reduction of particles

• In-line filters reduced the sub-micron particle load from 69 billion to 2 billion for a 3-day infusion regime, corresponding to a particle reduction of 97%^5,6.
• In-line filters led to a significant reduction in overall particulate matter, from 416,974 to 7,551 particles. This correlates to a reduction rate of 98.2%⁸.
• In-line filters have been demonstrated to reduce the particle count of a specific drug from 110 million particles per ml drug to 371,000 particles per ml drug (particles with a size > 0.05 µm). This correlates to a reduction rate of 99.7%⁴.

Potential clinical benefits

• The deleterious effects of particle contaminants on the post-ischemic microcirculation were entirely prevented by the use of 0.2 µm in-line filters³.
• An adult ICU study with 3215 patients concluded that in-line filtration with finer 0.2 µm and 1.2 μm filters (vs. control group with 5 µm filter) may be associated with less organ dysfunction and less inflammation in critically ill adult patients, since respiratory dysfunction, pneumonia and sepsis were significantly reduced¹⁴.
• A pediatric study on 800 critically ill children showed a significant reduction in the overall complication rate (40.9 vs. 30.9%) in the filter group, a significantly lower incidence of SIRS (systemic inflammatory response syndrome) as well as a significant reduction of the length of stay in the PICU and duration of mechanical ventilation¹³.
• A separate analysis of the pediatric study showed that in-line filtration reduced the incidence rates of respiratory, renal and hematologic dysfunction vs. controls without in-line filtration¹².

These last two studies were instrumental in bringing about a change in recommendations from national and international guidelines^23,24,25.

The Infusion Nursing Society (INS) in the Infusion Therapy Standards of Practice (2016) states: “Consider fluid and medication filtration in critically ill patients; filter use was associated with a significant reduction in overall complications for patients in pediatric intensive care units, including a significant reduction in systemic inflammatory response syndrome (SIRS); a 0.2-micron filter was used for crystalline solutions and a 1.2-micron filter was used for lipid-containing admixtures”²³.

Summary

Particles do not only potentially come from infusion equipment, but also through the given drugs. Particles of all sizes may cause a variety of problems for the ICU patient including emboli, triggering of inflammatory responses, respiratory distress, potential interruption of the microcirculation, hematological, renal or systemic complications. In-line filters can retain particles^4,5,6,8. Clinical studies suggest the clinical benefit of in-line filters^12,13,14.

National and international guideline makers have started to react to the latest scientific and clinical outcomes of particle and in-line filter studies and implement these findings in their respective recommendations in favor of in-line filtration in critical ill patients^23,24,25.

Intravenous in-line filters are a suitable and easy to use solution for everyday use and may be particularly relevant during the COVID-19 pandemic crisis.