Air Bubbles in Insulin Pumps: A Clinically Relevant Issue?

Introduction

Despite four decades of experience with insulin pumps, we still lack an understanding of any clinical impact that the formation of air bubbles may have on the underdelivery or overdelivery of insulin. The Food and Drug Administration (FDA) has recently expressed interest in this topic. This editorial will discuss some aspects of air bubble formation and its clinical impact (Table 1).

Table 1.

Factors that can Lead to the Formation of Air Bubbles in Conventional Insulin Pumps and Patch Pumps.

- Refilling insulin in the pump/insufficient priming - Degassing from cold insulin - Impact of the reservoir design/type of insulin used/excipients - Change in ambient temperature/air pressure (physical factors)

Formation of Air Bubbles When (Re-)filling Insulin in the Pump

When filling the insulin infusion line after changing the insulin reservoir in the pump, users ensure there are no air bubbles in the infusion line. If there are, then they must prime the infusion line to remove the bubbles to avoid interrupting insulin delivery when infusing the insulin with a low basal infusion rate or high infusion rates when applying a bolus.

Failure to observe and remove air bubbles may lead to hyperglycemia, especially in children or patients requiring low infusion rates. This is one reason that changing infusion sets and reservoirs is encouraged to occur in the morning rather than at bedtime. The reasons for these air bubbles can also be “dead space” in the reservoirs, connectors, and so on.

Formation of Air Bubbles by De-gassing From (Cold) Insulin

Another important source of air bubbles that might alter insulin dosing occurs when cold insulin is taken from a refrigerator and placed into the pump. Warming of the liquid in the pump causes outgassing and the formation of air bubbles. Although no air bubbles are visible at first when starting pump use, they appear later in the reservoir and subsequently in the infusion line when the insulin warms. The formation of air bubbles may alter insulin delivery. More insulin might be pushed into the subcutaneous tissue, depending on the backpressure in the tissue at the tip of the cannula (see below), or cause an interruption of insulin infusion. With a low basal infusion rate of 0.5 U/h and an air bubble of 10 cm in length (rule of thumb = 1-2 units of insulin), basal insulin infusion might be interrupted for up to 4 hours.

Train Patients to Warm Up the Insulin Before Refilling the Reservoir

One good measure to avoid such air bubbles—or make them visible early on—is that the insulin is allowed to warm to room temperature before using it. Patients should be well trained in doing so; however, they often ignore this advice in daily practice. An issue is that when a 10-mL insulin vial is warmed up for the withdrawal of 2 mL to fill the reservoir, the cool chain for the remaining insulin is broken.

Further outgassing might continue when the insulin warms further when the pump is in contact with the body. ¹ The insulin in the reservoirs has a temperature of about 30°C at normal ambient temperatures. To avoid this, patients might carry the reservoir in a pocket at their body for 30 to 60 minutes before changing it. If the insulin pump is carried around in a pocket, then the “new” insulin has the same temperature as the pump. How the reservoir is filled with the insulin after manufacturing, with or without an increase in pressure, may affect the amount of gas dissolved in this liquid. However, no information could be found on how the insulin is handled at the manufacturing site when placed into a reservoir. It would be of interest to know if this has an impact on degassing of air bubbles from the insulin or not.

A well-trained patient knows that the formation of air bubbles can take place and will perform a visual check of their insulin pump to make sure that the performance of the pump is not hampered by them. In case they show up, then he or she knows what to do, that is, how to remove them. If needed, then the patient will detach the pump from the infusion set.

Reservoir—Factors That Affect the Formation of Air Bubbles

Temperature differences between the insulin in the cartridge/reservoir and the external world during pump usage, exposing the insulin to changes in ambient temperature over time, and depending on wear conditions, such as proximity to skin/body or within a belt clip, might influence the degree of the outgassing. For example, walking in the summer sun and entering a room with air conditioning might significantly affect the insulin temperature in the reservoir. The outgassing of air from the insulin also depends on air pressure and may take place more easily when the user goes to higher altitudes, such as while in a plane.

The design of the reservoir—where air bubbles appear before they enter the infusion line—might affect the number and size of air bubbles entering the line. If reservoir design is essential, could air bubbles be removed using some “anti-bubble technology,” such as air traps that remove air bubbles? Modern insulin infusion sets that are designed for a longer wear-time have a filter at the entrance of the set that might prevent air bubbles from entering the set. ²

From a practical point of view, it might be recommended that users carry their pump so that the reservoir outlet does not point upward but attach it to the body or clothes to minimize air bubbles entering the infusion line. However, one wonders how many patients would pay attention to this in reality. Once air bubbles form, their movement is probably influenced by the pump’s location, that is, if the pump itself is “fixed” above or below the infusion site.

Is there any relation between air bubbles and insulin aggregation within the infusion cannula? It is known that the hydrophobic air-water interface of air bubbles or an air–water–catheter-surface triple interface promotes protein unfolding and thereby denaturation. This may enhance the aggregation of insulin molecules in general. This topic was widely discussed in the early days of implantable insulin pumps that are all the time at body temperature. However, probably because of the relatively limited usage of this type of insulin pump, this topic has not been discussed much lately. Nevertheless, it might be one of the many interacting factors causing infusion set occlusion.

Are Air Bubbles a Topic for Pumps With an Infusion Set Only? What About Patch Pumps?

Is switching from a “conventional” insulin pump (= one with a visible infusion set) to a pump with no visible infusion set (patch pump) of help? Patch pumps are not immune from developing air bubbles, such as having similar reservoir filling steps. Even though not visible to the naked eye, at what point in the cannula’s length does its inner diameter become its smallest? Could points with the smallest inner diameter in insulin’s path generate turbulence and aggregation or greater impact on insulin flow? Nevertheless, the inner diameter in the different tubing/connections in a patch pump might be smaller than that in conventional insulin pumps. With most patch pumps, the user has no way of knowing that air bubbles are present, and this has happened, except that these might explain why they experience low or high glucose levels.

Some patch pumps have windows above the cannula’s insertion site that, in principle, enables the detection of insulin leakage. However, bubbles would rarely be visible in a pod’s short cannula even when the cannula is visible due to the minimal transfer time from the patch pump’s reservoir through the cannula to the skin. In contrast with conventional insulin pumps, where the user can prime out air but preserve the infusion site, troubleshooting a patch pump can only occur if the user can see air bubbles within a clear reservoir visible to the user. Only if air bubbles might stay in the reservoir or stick at corners or connections between different parts in the fluid paths toward the cannula would they not influence insulin delivery.

Depending on where the way from the insulin reservoir to the cannula an air bubble shows up, this might have a different impact. Also, the orientation of the pump on the site where it is attached to the body might have an impact on where a given air bubble is moving to.

Statements in Social Media/Guidelines About the Relevance of Air Bubbles

An analysis of reports on social media showed that bubbles are discussed by insulin pump users (eg, https://www.diabetesdaily.com/forum/threads/air-bubbles-in-tube.89716/); however, it is known that such anecdotal reports have to be interpreted with great care. Also, insulin pump manufacturers provide recommendations on how to remove air bubbles (eg, Medtronic: https://www.medtronicdiabetes.com/customer-support/device-settings-and-features/sd512-712/filling-your-reservoir; Roche Diabetes Care: https://accu-chek.academy/en/handbook/46036/view/46896.558971; Tandem: https://support.tandemdiabetes.com/hc/en-us/articles/4409162924695-What-should-I-do-if-I-see-air-bubbles-in-my-tubing-t-slim-X2-insulin-pump-). Information about how to handle air bubbles is also given in guidelines for pump users also (eg, https://www.diabetesnet.com/bubbles/; https://www.diabetes.co.uk/insulin-pumps/insulin-pump-problems.html).

Clinical Relevance of Air Bubbles

Air bubbles can not only delay insulin delivery but also displace insulin in the infusion line when they form (push the insulin ahead), and lead to unintended (slow) insulin delivery, at least not at the time point when the infusion was intended. My interest in this topic was generated by a clinically active colleague who reported such an observation. The size of the air bubbles might have an impact, that is, small bubbles that do not block insulin flow might differ in their importance from that of large bubbles; however, how do we define small versus large? Nevertheless, one can assume that small bubbles are less of an issue, that is, systematic destruction of large bubbles might be an option to avoid issues with air bubbles or at least minimize them, although no such process is currently used.

Perhaps the clinical relevance differs between children (with low basal infusion rates) and adults (with higher infusion rates); systematic evaluations in this respect are missing. At least, the studies referred to below describe the clinical relevance of air bubbles in kids and adolescents. ³ A correlation between the number of air bubbles and the age of the study participants was observed. Also, patients with high insulin sensitivity might respond more rapidly to interruptions in insulin flow. Depending on the type of insulin used (rapid-acting insulin analogs vs ultra-rapid acting insulin analogs), the clinical outcome of air bubbles might differ as well. It might also be that the structure of the insulin molecule or the excipients added to maintain insulin integrity, and its structure, and prevent fibrillation contribute to or protect against the formation of air bubbles.

The degree to which an unintentional insulin dose is applied by air bubbles that are formed probably also depends on how high the backpressure in the tissue is (tissue resistance pressure [TRP]). ⁴ The pressure which is building up in the infusion set/reservoir has an impact on the size of the air bubbles, which are much more compressible than the insulin fluid. The interaction between TRP, basal rate/bolus, and air bubbles is probably complex but might be of clinical relevance in patients with low insulin requirements (see above). The TRP might vary in case the user is physically active, an increase in blood flow in the subcutaneous tissue might increase this. Studies with rapid changes in ambient air pressure (eg, during flights) that generated a lot of interest—they suggested that insulin is administered induced in such situations—are probably misleading, due to the missing backpressure.^5,6

What amount of insulin (some units?) is administered unintentionally by air bubble formation in the practice of insulin pump therapy and whether this has clinical relevance is not clear. One can also ask the question: what is the maximal amount of air bubbles that can form in a reservoir containing 200 U insulin? One guess is, when the insulin was handled appropriately before filling the reservoir, the maximal number/size of air bubbles formed will represent not more than 1 unit of insulin per 100 U insulin when a change in ambient air pressure takes place. ⁵

Around the tip of the cannula in the subcutaneous tissue, an insulin “depot” might exist; which probably dampens interruptions in insulin flow to a certain extent. However, our knowledge about the size of this depot (which will depend on a large number of factors) is quite limited, as it is about insulin absorption in general. ⁷

Publications About Air Bubbles

It appears as if only a few clinical studies have addressed this question. If one enters a respective search term in PubMed (“air bubbles insulin pumps”), this leads to a limited number of articles:

• One study was conducted to evaluate how frequently air bubbles occur in insulin pump infusion lines and identify the factors that lead to clinically relevant air bubbles. ³ For this purpose, the authors recruited 53 children and adolescents with diabetes and visually observed their infusion sets. The length of all observed air bubbles was measured and converted to time without insulin delivery at the lowest basal rate. Forty-five air bubbles were found (ie, in approximately >70% of all patients), with five patients having air bubbles that resulted in a time without insulin delivery of >60 minutes. The length of the air bubbles varied <0.5 to 312.0 mm, with a mean of 14.5 mm (SD = 27.9 mm), corresponding to an amount of insulin displaced of <0.01 to 3.92 U (mean = 0.27 U, SD = 0.66 U). The length of air bubbles was inversely correlated with time since infusion set change (P < .001) and directly correlated with patient age (P = .049). That more air bubbles were observed shortly after the infusion set was changed is thought to be related to the temperature of the insulin used. More air bubbles were observed in older adults with diabetes and attributed to the technique used to fill the insulin reservoir and infusion line.

• Another study examined the mechanisms that contribute to the formation of air bubbles, such as temperature changes, changes in atmospheric pressure, and vibration. ⁸ Five Animas 2020 pumps with 2 mL reservoirs and Inset II infusion systems, five Medtronic Paradigm pumps with 1.8 mL reservoirs and Quickset, and three Roche Accu-chek pumps with 3.15 mL reservoirs were used. The insulin pumps were subjected to a temperature change of 4°C to 37°C, elevated to an altitude of 300 m, and subjected to violent vibration. Bubble formation was observed with temperature and atmospheric pressure changes but not with vibration.

Data about the prevalence of air bubbles are also mentioned in two other pump surveys.^9,10 A prevalence of 16% is reported in one survey and 46% in the other. Issues with such data are that the documentation of the rate of air bubble formation/size of air bubbles depends critically on the skills of the person making the assessment. It is difficult to standardize such surveys, which might be the reason why the reported outcome differs so much.

Air Bubbles Are Also of Relevance for AID Systems

The formation of air bubbles is not a complication of insulin pump therapy only, but can also have relevance for systems for automate insulin delivery (AID), as most of these rely on insulin pumps. One wonders how well patients are trained in such aspects when being introduced to AID systems, given the large number of aspects that the user should be trained in a short period, especially when they participate in a short technical training session by the manufacturer of the AID system only and not in an extensive therapeutically oriented training program. Patients might tend to rely more or less completely on this novel technological solution that handles most aspects of the daily life of patients with diabetes very well. In case air bubbles induce an interruption of insulin delivery, the algorithm might increase the infusion rate to counterbalance an increase in glucose levels.

Physical Factors That Have an Impact on Insulin Pumps

It is always interesting to see how many different factors can influence “successful” diabetes therapy and what all needs to be considered or how little we know about their relevance in practical insulin therapy. Physical factors, such as air pressure, air temperature, and electromagnetic fields interact with diabetes medical devices. Situations arise, particularly in occupational settings and during medical examinations, where the functional safety of continuous glucose monitoring (CGM) systems or insulin pumps can no longer be safely guaranteed. A recent review on this topic considers the various situations where this may have clinical relevance. ⁴

Position of the FDA

It is of interest to note that the FDA has approached manufacturers of insulin pumps and patch pumps and asked them about air bubbles. In their guidance documents, the FDA does not highlight the importance of air bubbles in detail; however, a statement in the “special controls for ACE pumps” says that design verification and validation must include the following:

Validation testing results demonstrating the ability of the pump to detect relevant hazards associated with drug delivery and the route of administration (e.g., occlusions, the air in the line, etc.) within a clinically relevant timeframe across the range of programmable drug delivery rates and volumes. Hazard detection must be appropriate for the intended use of the device and testing must validate appropriate performance under the conditions of use for the device. (https://www.fda.gov/news-events/press-announcements/fda-authorizes-first-interoperable-insulin-pump-intended-allow-patients-customize-treatment-through).

So, “air in line” is regarded as a relevant hazard and the manufacturer has to make sure, that air bubbles are detected and also eliminated. Probably the performance of well-designed clinical trials would be a good idea to back up clinical suspicions and advice.

Summary

My main problem is that currently, it is unclear whether air bubbles in insulin pumps present a real clinical problem or not? This editorial lists some of the possible or theoretical problems and influences on air bubble formation, but with almost no evidence base for any of them: Six unanswered questions relevant to the topic of this editorial are listed in Table 2.

Table 2.

Six Unanswered Questions Concerning Air Bubbles in Insulin Pumps.

- What is their impact on glucose control in everyday practice? - Does the design of the insulin reservoir matter in the formation of air bubbles? - Is an infusion set filter necessary? - Size of air bubbles: which size is of relevance? - How much does pump position affect air bubbles and glycemic control? - How does tissue resistance pressure interact with air bubble formation?

In summary, are additional remedies needed, or are air bubbles in insulin pumps a minor issue that is rarely a clinical problem, and is this the reason why air bubbles have not been discussed much before and hardly investigated at all? However, with such issues, you have to ask yourself, is it “rarely a clinical problem” because we simply just have accepted this, or has it become “minor” or “well-known” because of acceptance rather than because it is not a clinical issue. If undetected, then it could be an issue (high blood glucose values). Finally, if patients are not well-educated, then this could be a clinical issue. Highlighting bubbles when training patients in insulin pump use, especially in situations in which air bubbles could occur and how to remove them from the system, is definitively a good approach.