In recent years the risk of subcutaneous or intraosseous injection of epinephrine using EAIs has been widely discussed. This paper is based on data from three original publications [2,3,4]. Those three studies represents the most extensive investigation of the relationships between the distances from skin to muscle, and skin surface to the bone. Distances were determined by ultrasound at the mid anterolateral aspect of the thigh, the recommended area for intramuscular injection of epinephrine using EAIs .
The influence of thick clothing on the deposition of epinephrine has not been investigated previously. In this paper, we analysed the influence of thick clothing on skin to muscle distance and skin to bone distance vs. weight, the most commonly used parameter for dosing epinephrine. All winter clothing does not have the same thickness. We decided to use 3 mm and to estimate compressed winter clothing thickness based on caliper measurements. The result of thicker or less thick winter clothing can easily be calculated from the figures in this paper.
The true distance from skin to muscle and bone during the delivery of epinephrine with an EAI will vary with the pressure applied to release the needle of the EAI [2,3,4,5,6]. In previous studies, we identified that EAIs that require high pressure likely compress primarily muscle tissue, which reduces the distance from skin surface to the bone. We estimate that about 90% of the compression originates from compression of the muscle and not from compression of the subcutaneous tissue [2,3,4].
In a previous paper, we used the limits for acceptance of needle lengths from the manufacturers’ internal specifications, kindly supplied by the manufacturers . This data was also used in this communication. The risk of intraosseous/periosteal penetration was most pronounced using EpipenJr® in small children. The likelihood of subcutaneous injection was highest with the newly introduced Auvi-Q® 0.1 mg epinephrine EAI and in adult obese women . Our findings suggest that it is difficult to obtain reduced risk of both intraosseous/periosteal injection and subcutaneous injection using the same HPEAI. A rough estimate would be to calculate the minimum value of intraosseous/periosteal. Injection combined with the minimum number subcutaneous injection.
In this study, we found the highest risk for intraosseous/periosteal injection at 59 and 1% in children weighing less than 15 kg when using the longest needle of EpipenJr® that is accepted by the manufacturer. Thick clothing reduced the risk to 15 and 0%.
According to our data, the Auvi-Q® 0.1 mg has an estimated risk of bone injection in children less than 15 kg of 0%. However, this EAI has a marked increase in subcutaneous injection from 28 and 94% for naked skin to 100 and 99% if injected through winter clothing, Table 3. This illustrates the difficulty to design an EAI that has both a low risk of intraosseous/periosteal injection and subcutaneous injection.
In adults, winter clothing reduced the risk of intraosseous/periosteal injection from 16 and 3% using the longest needles of Epipen® and from 12 and 3% using Auvi-Q®. Emerade® had no risk of intraosseous/periosteal injection in adults.
On the other hand, using the shortest approved needles in adults, the risk of subcutaneous injection increased for Epipen® from 45% to 60%, for Auvi-Q® from 38 to 52% and for Emerade from 14 to 28%.
It would be desirable to have a longer needle length available in EAIs for the obese and overweight adults having the risk of subcutaneous injection. The risk for these patients must be better defined than by weight.
It may be possible to better characterize patients to identify those at risk for subcutaneous injection by Auvi-Q® 0.1 mg, intraosseous/periosteal injection using EpipenJr® and Auvi-Q 0.15 mg, and adults at risk of subcutaneous injection.
In general, winter clothing reduced the risk of intraosseous/periosteal injection in children and increased the risk of subcutaneous injection in adults and in children using Auvi-Q® 0.1 mg epinephrine EAIs.
In this series of studies [2,3,4], we used 8 lb or about 35 Newtons (N) as high pressure and applied a low pressure to mimic the required pressure to release the needle of HPEAIs and LPEAIs, respectively. The declared variation in pressure that is accepted by companies for release of new batches, applied to EAIs has been presented elsewhere . There are instruments that can apply a specified pressure to the ultrasound probe and such instruments should be used in all future trials and in the instruction to prescribing health care personnel [10, 11]. Furthermore, we propose the variation in needle length and the influence of thick clothes should be defined.
In future trials, we recommend the pressure applied to the ultrasound probe should be applied at the lowest and the highest pressure levels according to the specifications for each device.
Furthermore, the probe should have the same foot print as that of the specific EAI. This applies to both the EAIs available on the market at present as well as new brands or modifications of the presently available brands.
In our opinion, it is difficult to find a needle a length that would have no risk of intraosseous/periosteal injection and at the same time no risk of subcutaneous injection employing the present approach with the high pressure injection technique. Performing ultrasounds on individual patients could better estimate the risks in individual patients.
Recently, Duong et al. presented data on BMI versus skin to muscle distance and skin to bone distance without considering the age dependant successive increase of BMI . BMI-limits in childhood and adolescence must include evaluation using age dependent and puberty stage dependant limits for BMI using z-scores. This is a complex task and will be investigated in the future.
Based on our ultrasound estimations of the skin to bone distance and skin to muscle distance, some EAIs, currently available in Europe and North America, do not likely deliver epinephrine intramuscularly in a significant number of patients. When wearing thick clothes, the risk of subcutaneous injection in overweight and especially obese patients is increased, and the risk of intraosseous/periosteal injection in young children using HPEAIs is reduced. In children weighing less than 15 kg the new Auvi-Q® 0.1 mg EAI has no risk of intraosseous/periosteal injection but it has a 100% risk of subcutaneous injection wen injected through thick clothing. The only LPEAI, Emerade®, has a low risk of intraosseous injection, but a risk of subcutaneous injection in adult overweight/obese patients.
When developing and evaluating new EAIs and updating existing EAIs, it will be a challenge to balance the risk of subcutaneous injection and intraosseous/periosteal injection when considering the influence of thick winter clothing. There are some points that must be considered:
The variation of the length of the part of the needle exposed, i.e. the part of needle inserted in the thigh. The variation depends on the narrow or wide range of needle lengths approved in batches released for marketing. Every EAI of each brand can have a needle that is as long as the longest allowed by the batch release limits. The variation can be supervised and the range can be decreased by improved manufacturing processes. The needle length should be modified according to the pressures needed for needle release and injection.
The variation in pressure between EAIs of a specific brand allowed for batch release of that brand. We asked the manufacturers for this information who generously supplied this data . No-one has investigated the influence of variation of pressure on the EAIs.
A third parameter is the variation of clothing. We now have shown the potential influences that clothing has on the delivery of epinephrine.
Children and adolescents grow and humans of all ages vary in weight and configuration. Therefore the risk of subcutaneous and intraosseous/periosteal injection will also vary individually from time to time. The only proper solution is to perform ultra-sound determination of skin to bone distance and skin to muscle distance every time an EAI is prescribed.
The choice between increased risk for subcutaneous and intraosseous/periosteal injection, between the Scylla of intraosseous/periosteal injection or the Carybdis of subcutaneous injection, is depending on the other factors.
We believe that all of these papramerters must be taken into consideration in future studies.