Bruising—An Ignored Issue?

Introduction

According to Wikipedia,

A bruise, also known as a contusion, is a type of hematoma of tissue, the most common cause being capillaries damaged by trauma, causing localized bleeding that extravasates into the surrounding interstitial tissues. The bruise then remains visible until the blood is either absorbed by tissues or cleared by immune system action.

Bruises can arise for a number of different reasons. One common source of bruising (BR) involves the insertion of metal needles through the skin, which may disrupt blood vessels below the skin and can lead to bleeding. Depending on the extent of damage and subsequent bleeding, the extravasated blood may or may not be visible as BR at the skin surface. The outcome depends on several factors, such as the following:

• number of blood vessels at a given skin site;

• state of vasoactivity (constriction or dilation) at the site;

• size of blood vessels interrupted by the foreign object;

• amount of blood that is released and the depth of the bleeding;

• blood clotting properties as influenced by a patient’s genetics, disease, or drugs that may reduce clotting or exacerbate bleeding;

• age of patient (elderly patients have more fragile blood vessels); and

• BMI of the patient.

During the course of diabetes therapy, bruises may appear when a needle is used for measuring glucose (a diagnostic step) or administering insulin and other parenteral agents (a therapeutic step):

• utilization of lancing devices to collect a blood sample from fingertips for capillary blood glucose meters;

• insertion of needle-type glucose sensors of continuous glucose monitoring (CGM) systems through the skin into the subcutaneous tissue; and

• application of insulin or another agent into the subcutaneous tissue via a needle (attached to a syringe or pen) or a catheter (attached to an insulin infusion set [IIS]) used with insulin pumps.

Bruising can also occur when excessive pressure is applied to the skin and induces the rupture of blood vessels in the skin. For example, bruises may appear when a patient applies too much pressure on the syringe or insulin pen while administering insulin during diabetes therapy.

The fundamental question is whether bleeding (visible or not) infiltrated into the dermis or the subcutaneous space caused by the use of needle-based medical products is solely a cosmetic issue, or whether it may have an impact on diabetes management, such as through alteration of glucose measurement or insulin absorption. The answer to this question may depend on whether bruises occur in the skin or the subcutaneous tissue. In other words, is insulin absorption from a subcutaneous depot hampered or improved if bleeding occurs? In addition, does bleeding affect the accuracy of glucose measurements by CGM systems?

Most diabetologists would likely respond to this question by saying, “no, bruising is not of relevance for diabetes therapy.” If it were, then BR would have been observed and described early in diabetes therapy when needles had much larger diameters. However, it is noteworthy that experienced diabetologists have anecdotally observed that certain patients frequently show BR after their insulin injections. In many instances, diabetes care and education specialists may observe such “side effects” of diabetes therapy more often than the treating physician. Many patients are not included in clinical trials because of bleeding disorders from thrombocytopenia, anemia, vitamin K deficiency, and cirrhosis, or the need for anticoagulants for factor 5 deficiency, atrial fibrillation, and other thrombotic disorders. Age likely plays a role, that is, thinning of the skin and vascular walls with age can also contribute to the frequency of observed BR. One may wonder whether the manufacturers of different medical products have compiled data collected from patients or providers reporting pronounced BR associated with a given product.

Hopefully, the thoughts raised in this editorial about BR and whether—at least to a given extent—diabetes therapy-induced BR may have an impact on the performance of other technologies used for diabetes therapy will raise interest in and awareness of this topic. As discussed in previous Journal of Diabetes Science and Technology (JDST) publications, our knowledge of subcutaneous tissue is still limited.^1,2

What Do We Know About BR With Diabetes Therapy, and Is It Relevant?

Thus far, not much scientific attention has been focused on BR. To wit, a respective literature search provided few hits. However, a group of Italian researchers recently published a retrospective evaluation focused on insulin therapy using insulin pens. ³ Their evaluation provided insights into adverse events like BR: Within a multicenter cross-sectional study, 780 patients with diabetes were examined to determine the types of skin changes they exhibited at their typical insulin application sites. The evaluation focused on lipohypertrophy (LHT) and hemorrhage (BR) at these sites. The study was conducted at 16 appropriately trained diabetes centers, with a mean of 60 patients per center. The gender distribution of the patients was 50/50. The mean age of the patients was 62 years and other mean values included a body mass index (BMI) of 29 kg/m², an hemoglobin A1c (HbA1c) of 7.8%, and a daily insulin dose of 46 units at 3.7 injections per day. About 29% of the patients had type 1 diabetes. Data were collected on insulin dose, frequency of injections per day, type of needle used (length and thickness), frequency of needle reuse, temperature of applied insulin, distance between injection sites, frequency of unexplained hypoglycemia, blood glucose variability, and whether insulin was injected in areas of the skin with LHT. The frequency and characteristics of LHT were systematically studied, including the use of ultrasound. Bruising was also recorded by systematic inspection of injection sites.

Most patients used a needle length of 5 (30.6%) or 4 mm (28.5%) for insulin administration, and >50% of patients used a needle thickness of 31G. As many as 46.2% of patients had LHT. Bruising was observed in 33.2% of patients. Patients reported that BR had been observed at injection sites over long periods of time. Skin sites with LHT were used for injections 53.9% of the time. Patients preferred shorter needles for the following reasons:

• injection at these sites is painless (53%),

• they have seen other patients doing the same (21%), and

• they do it out of habit or carelessness (26%).

Bruising was observed only at injection sites while other skin sites were unaffected. Women and older patients were more likely to exhibit BR. Patients with BR were more likely to have type 2 diabetes and a higher BMI than those without BR. There were no differences in HbA1c levels among patients with or without BR, but the frequency of hypoglycemia and glucose variability was lower in patients with BR. One third of patients with BR were on anti-thrombotic therapy or had received anticoagulants.

This analysis raises several questions. One would expect that patients with a higher degree of glucose variability would express with BR rather than patients with lower glucose variability, that is, insulin absorption is more irregular depending on the amount of bleeding in the subcutaneous tissue. Conversely, lower glycemic variability would mean that insulin absorption is more consistent when BR has occurred. However, the study does not clearly make this distinction; are they referring to lower variability with BR versus LHT or lower glycemic variability versus nonbruised patients with LHT? In addition, the study is missing a true negative control, that is, the same patients adjusting their therapy while strenuously avoiding insulin injection into bruised and skin sites with LHT.

It would also be of interest to know more details about the medication therapy of the study participants, that is, was the proportion of patients on, for example, anti-thrombotic therapy comparable in both patient groups (the ones with BR and the ones without)? Was the use of acetylsalicylic acid also assessed? Future studies may benefit from the evaluation of such additional variables.

Lancing Devices

Among all the medical devices used in diabetes therapy by patients, lancing devices are the only tools used to purposely induce bleeding. Accordingly, users are aware that bruises may appear on the skin sites where lancing devices are deployed. Given the short distance that the needles are supposed to travel into the skin, these types of bruises may be produced by blood penetrating the different skin layers. It would be interesting to know whether the phlogistic property of blood is somehow involved in the cornification observed at the fingertips of patients who have performed fingerpricking in their therapy for many years.

CGM

In continuous glucose monitors, a glucose sensor is located at the tip of a thin plastic filament, which is then inserted into the subcutaneous tissue using a “needle.” Although the needle is immediately retracted after it guides the filament into the subcutaneous tissue, this insertion process inevitably induces bleeding to some extent. However, because the insertion sites are covered by the continuous glucose monitor’s plastic housing and an adhesive patch after application, preventing visual inspection of these sites, the superficial bleeding, and BR that occur at CGM sites are usually not observed. It is not easy for the user to “see” whether or not bleeding is induced, especially if the bleeding after insertion is not excessive. It is unknown (at least no publication could be found) whether the bleeding differs depending on the diameter of the needles used, the form of the needle tip, the needle coating, and so on. It is also unknown whether these factors have an impact on the risk of (substantial) bleeding. It would be interesting to determine whether shorter needles induce less bleeding, as observed in earlier studies on pen needles.

Suppose bleeding takes place in the subcutaneous tissue nearby the tip of the filament (which might not be visible on the skin!) where glucose measurement occurs. In this case, the bleeding induced by the CGM insertion process may have an impact on the accuracy of the glucose measurement and may be at least one reason for the “run-in phase” seen with all CGM systems during the first 24 hours after the glucose sensor’s insertion. This well-known phenomenon refers to a period of high variability in the accuracy of glucose measurement, showing a pronounced intrapatient and interpatient variability. Glucose variability may also be affected by the degree of bleeding in the individual situation. It would be interesting to see whether a reduction in the measurement error observed on day 1 (sometimes also on day 2) of a given glucose sensor’s total usage period can be achieved with a less traumatic insertion method. If this reduction is observed, then BR should be considered with high practical relevance.

Thus far, in most of the clinical studies performed with CGM systems that are already on the market or in clinical development, the issue of BR has not been systematically studied, documented, and reported. However, a recent prospective, multicenter, randomized study compared the performance of two different widely used CGM systems (G6 by Dexcom vs Libre by Abbott) in 269 adult patients with type 1 diabetes over a period of six months. The authors reported a significant difference in bleeding after sensor insertion; bleeding was reported to be more frequent with the real-time CGM (rtCGM) system than with the intermittently scanned CGM (isCGM) system. ⁴ However, as noted, how was the bleeding evaluated, and did it occur in the skin or the subcutaneous tissue? Nevertheless, this study raises an important question; does BR have a relevant impact on the performance of CGM systems?

When selecting patients for clinical studies with CGM systems, patients with clotting issues are usually excluded. Thus, issues like BR may show up more often than reported in clinical studies.

Insulin Administration

Although bruises in the skin (those that are well visible) may not affect insulin absorption, bruises in the subcutaneous tissue may have an impact. However, it is difficult to discern the compartmental location of BR.

Needles Used With Syringes and Pens

The extent to which needle insertion into the skin to administer insulin induces bleeding is unclear, as are the compartments that may be affected by any such bleeding. Although one may expect that a needle’s diameter and length would influence the degree of induced bleeding, no study data currently support this assumption.

IISs

The tip of the cannula of an IIS is inserted into the subcutaneous compartment to enable insulin infusion into a small depot over a few days. Bleeding may occur near the cannula infusion port either upon initial insertion or at a later time. Exercise or mild trauma at the infusion site may also cause bleeding. The presence of blood in the tissue is, in and of itself, phlogistic, and, depending on the degree of inflammation invoked by the presence of blood, there may be enhanced proteolytic digestion of insulin at the infusion site leading to reduced insulin absorption. It may also be conceivable that blood entering the cannula tip can result in a partial or total infusion set occlusion. Unfortunately, there is usually a substantial lag time before an insulin pump occlusion alarm triggers an alert for the user. Occlusions are commonly identified by either hyperglycemia that does not respond to correction boluses or by increasing ketonemia. The proximate cause of cannula occlusion is rarely known with certainty. However, infiltration of blood products (blood proteins, red blood cells, platelets, and white blood cells) into the cannula may contribute to this outcome. It would be interesting to see how often “bleeding” is identified as a reason for an IIS failure in the clinical studies performed using novel IISs that promise a usable life span of up to a week. Such studies often collect the used IISs for laboratory analysis after removal and thus offer a window into potential causes of IIS cannula failures. In the case of IIS failure, users are recommended to check the tip of the catheter and to replace their IIS if blood is visible. However, as discussed earlier, even if there is no visible BR at the insertion site in the skin, it is likely that BR has occurred in the subcutaneous tissue below. While a visible bruise is a cosmetic issue (which is nonetheless disturbing for patients), bruises in the subcutaneous tissue are of clinical relevance with respect to glucose control.

The Force With Which Syringes or Pens Are Inserted Into the Skin

Excessively high pressure applied to a small skin area can also induce BR. Many patients apply considerable force against the skin when using insulin pens. However, this potential issue does not garner much attention. Patients may apply excessive force to ensure that the short pen needle has been correctly inserted. Consequently, short needles may increase the risk of patients applying high pressure when using pens to administer insulin. One can imagine a wide range of applied forces during clinical use of pens with high intrasubject and intersubject variability. Another reason, less dependent on needle length, why patients may use excessive force when inserting needles could be that patients with limited eyesight or even a mild tremor have to do so to ensure that the needle remains in the skin over the whole injection period.

This problem may also be due to the configuration of the plastic component that holds the needle. The needle is typically seated in a plastic hub that is topped by a relatively small plastic dome (“pen needle hub”). One manufacturer (Becton Dickinson) has recently redesigned this hub from a dome to a tip that looks more like a ring. ⁵ The new hub design aims to reduce the impact of variable injection techniques by dispersing insertion forces across a re-engineered, contoured, and expanded surface area. ⁵ The design of the hub enables a more comfortable insulin application with a full-length needle penetration regardless of application force. By applying pressure to a larger skin area, the redesigned pen needle hub aims to significantly reduce the risk of local bleeding. This redesign was motivated by studies in humans and animal models recording variations in injection depth associated with the variable force applied against the skin during injections.^5,6

LHT/Fibrosis and BR

Skin changes in patients with diabetes induced by repeated administration of insulin in the same skin areas are a well-known, adverse effect of insulin therapy.^7,8 It is well known that LHT is not only a cosmetic issue as insulin absorption from such subcutaneous tissue is markedly impaired in such tissue. ⁹ There is an ongoing discussion about which factors drive the development of LHT and it is worth considering that bleeding may contribute to this clinically relevant phenomenon. The data from Italy discussed above do suggest that BR is not related to insulin absorption; however, this should be studied more carefully in appropriately designed studies (see below).

Although BR was not associated with LHT in the study from Italy, the occurrence of BR is associated with many of the same factors that influence the occurrence of LHTs. One might speculate that extensive, consistent, or routine BR may contribute over the long term to LHT formation (ie, be causative). One may also wonder whether BR acts simply as a biomarker for potential LHT formation (eg, be indicative), or BR and LHT are both due to the same individual and human factors effects (associative but not causally related). If possible, this would be an interesting phenomenon to try and tease out.

Summary and Conclusions (or “How to Go Ahead . . .”)

• The fundamental question is, “How often does BR show up? Is it rare or not?” A clear definition of “significant” BR and its characteristics are needed. It is worth nothing that clinically experienced colleagues regard BR as a practically relevant topic.

• Performance of epidemiological studies with a focus on this phenomenon would help understand whether or not this is a commonly relevant side effect of diabetes therapy. If so, and BR appears in daily practice in various patient groups differentially, then does the phenomenon appear in children, the elderly, or the chronically ill to the same degree? Attention should also be paid if patients have a known blood clotting impairment or are on antiplatelet therapy.

• Performance of clinical-experimental studies with multiple applications of different “needles” in a limited number of patients at different skin sites would help understand how often visible bruises appear, as well as their related factors.

• Performance of specifically designed studies would help to evaluate the clinical relevance of BR on glucose measurement and insulin absorption. This would require inducing a certain amount of visible BR on the skin, delivering insulin into the area, and measuring blood glucose and insulin levels in a head-to-head comparison with skin areas without BR. Reproducibility of BR may be difficult. Such studies can also be performed by employing a glucose clamp study procedure.

• There appear to be many errors in the day-to-day practice of diabetes therapy. A practical action item can be paying more attention to the mechanisms and risks of BR through training in appropriately performing injections with an insulin pen. In addition, HCPs (including diabetes care and education specialists) should be trained to better identify and treat patient BR. If HCPs have patients with frequent occurrence of BR, then they should instruct patients on optimizing their insulin injection technique.

• For some patients, BR may also carry a psychological impact. These patients who experience BR may try to avoid actions that induce this unwanted side effect. For example, they may reduce the number of insulin injections, extend infusion sets or glucose sensors, or use the same insertion sites repeatedly. This can negatively impact their glucose control.

This editorial’s take-home message is that our current knowledge of BR is scarce and a closer look at this aspect of diabetes therapy should have merits. While it is difficult to state how pronounced the therapeutic consequences of BR are (they might be small), as long as our current understanding is limited, the issue of BR should be regarded as an open and important question.