This prospective study examined whether the length of the EAI needles are adequate for delivering epinephrine intramuscularly in pediatric patients at risk of anaphylaxis who weighed <15 kg. Importantly, although the Epipen® Jr and the Allerject® 0.15 mg are officially indicated for children between 15 and 30 kg in Canada, they are often prescribed in children <15 kg as there is no clinically available EAI that delivers a lower dose of epinephrine. Ultrasound measurements of the mid anterolateral thigh were performed with pressure application to simulate the pressure required to inject an auto-injector. Although we originally believed that a significant proportion of these children was at risk of receiving the auto-injector subcutaneously (rather than intramuscularly) due to obesity, we found that a significant proportion of these children were at risk of receiving the auto-injectors into the bone. Physicians should be aware of this potential risk.
Currently, there are no published clinical studies assessing whether the 12.7-mm length of the EAI needles are adequate for delivering epinephrine intramuscularly in pediatric patients weighing <15 kg at risk of anaphylaxis. All of our subjects had a STMDmax <12.7 mm, suggesting that none of these children were at risk of having the auto-injector administered into the subcutaneous space. Our findings contrast those reported by Stecher et al. who identified 12% of children weighing <30 kg that were at risk of receiving the EAI into the subcutaneous space. Age and BMI correlated with STMD in these children. It is important to note that this study enrolled children (1–12 years of age) presenting to the radiology or emergency departments of a tertiary-care hospital in a non-consecutive fashion. Subjects were not at risk of anaphylaxis, and ultrasounds with pressure and measurements to the femur were not completed. Almost half of the study population was Hispanic and children who weighed <15 kg were not analyzed separately. Our study, on the other hand, assessed primarily Caucasian children <15 kg who were at risk of anaphylaxis. Also, ultrasounds with pressure were performed to simulate how auto-injectors are given in the "real-life" setting.
Our study found that almost 30% of children < 15 kg had a STBDmax <12.7 mm and were therefore at risk of receiving epinephrine into the bone. Patients weighing <10 kg were at even greater risk since 60% of these subjects had a STBDmax <12.7 mm. We believe these findings are clinically important, particularly since there are currently no randomized controlled trials evaluating or comparing subcutaneous, intramuscular, periosteal, cortical, intraosseous or intravenous epinephrine administration in patients with anaphylaxis. However, the ethical considerations in completing studies of this nature may be prohibitive. In children with a history of anaphylaxis, epinephrine injected intramuscularly compared to subcutaneously has been shown to lead to higher serum epinephrine levels more rapidly[13, 14]. This more rapid peak in epinephrine levels has been the basis for recommending intramuscular epinephrine administration as the standard of care for anaphylaxis. Intravenous or intraosseous epinephrine is reserved for severe, life-threatening anaphylaxis with associated hypotension, airway swelling, severe bronchospasm or inadequate response to intramuscular epinephrine. Intravenous epinephrine should be given at a 1/100,000 strength at a maximum infusion rate of 10 mcg/min[1, 11, 15]. The Epipen® Jr and Allerject® 0.15 mg provide a total dose of epinephrine of 0.15 mg at 1/2,000 and 1/1,000 strengths respectively[9, 10]. These strengths are 50 and 100 times the concentration suggested for intraosseous infusion respectively. Importantly, there are no studies to confirm that the auto-injectors would penetrate through the femur of children. But we believe the auto-injector needle would penetrate the bone as supported by a case report of an adult female experiencing an accidental injection that went completely through the bone of a distal phalanx. Also, the thickness of the cortical bone of the femur has not been formally studied in young children. Animal studies confirm that intraosseous epinephrine administration leads to similar serum epinephrine levels as intravenous administration[17, 18]. Although the intravenous or intraosseous route of administration should be used in the appropriate clinical setting, there have been reports of severe side effects with intravenous epinephrine administration. For example, a 29-year-old woman had a myocardial infarction after receiving 0.1 mL of 1/10,000 intravenous epinephrine. Sullivan reported two patients who had ventricular tachycardia after receiving a 5-mL intravenous injection of 1/10,000 epinephrine. There is also a report of a 5-month-old child weighing 7 kg who presented with an allergic reaction to an emergency department and received 0.7 mL of 1/1,000 subcutaneous epinephrine twice and then 0.7 mL of 1/1,000 epinephrine intravenously. The infant had a cardiac arrest and could not be resuscitated. Although these reports involve cases where epinephrine was given at higher doses or concentrations than currently recommended, they illustrate the potential risks of intravenous and intraosseous epinephrine.
Children weighing <15 kg with a STBDmax <12.7 mm who are prescribed an EAI are at risk of injecting a more concentrated and higher-than-recommended dose of epinephrine into the intraosseous space. There are various strategies that might be considered to help the clinician to deal with this issue. Ideally, all children requiring an EAI should have a STBDmax measurement with ultrasound to identify those who may be at risk of intraosseous administration. In at-risk children, other forms of injectable epinephrine could be considered, such as the provision of separate syringes (with variable needle lengths) and vials of epinephrine. However, one study suggests that the parents of these children may not be able to draw up the proper doses of epinephrine reliably in a reasonable timeframe to manage anaphylaxis. Another strategy would be to instruct the child’s parent or care provider to squeeze the leg and muscle at the site of injection so that the EAI does not compress the muscle. In most patients, we believe this would lead to intramuscular injection. If using this strategy, persons injecting must be cautious not to inject the device into their own hand. Manufacturers should also consider developing auto-injectors with variable needle lengths (and doses) and/or devices that require less pressure for administration, as this would increase the likelihood of intramuscular injection. More thorough studies assessing the pharmacokinetics and pharmacodynamics of injecting epinephrine into the periosteum, cortical bone or intraosseous space are also required.
The main strengths of this study were that the patient cohort included children at risk of anaphylaxis who weighed <15 kg, the STBDmax was used as the primary variable, and ultrasound measurements were taken in the proper location for EAI application. The findings of this research reveal a potential shortcoming in our current approach to anaphylaxis.
One limitation of this study was that it was performed in only one clinic. It is possible that the findings may differ if utilizing a multicentre study design. Therefore, we suggest that a similar study be replicated in other centres. A second limitation was that one physician performed all of the ultrasound measurements in an unblinded fashion. Nonetheless, we feel the data collected were accurate since measurements were simple to perform and easily reproducible. The ultrasound machine included an easy-to-use tool to accurately determine the measurements for each variable assessed in our study. A third limitation is that the physician applied the maximum pressure to the thigh without using any method of formally quantifying the pressure applied with the ultrasound probe. We believe that, in many children, "real-life" use of the auto-injector may actually lead to more muscle compression and/or an increased risk of injecting into the bone than was noted in our study. This may occur because greater force may be applied by parents injecting the auto-injectors, the surface area of the currently available auto-injectors are less than that of the ultrasound probe and/or the device may be given in an area were muscle thickness is less than that in the mid anterolateral thigh. In future studies, we suggest that the pressures required to trigger the various types of auto-injectors be measured and that these pressures be applied for ultrasound measurements. The pressure required and the depth of muscle compression may vary for each device and, possibly, for each individual patient. A final limitation of this study is that the data were not analyzed to address other EAIs aside from the Epipen® Jr and the Allerject® 0.15 mg. The risk is likely similar for injection into the bone with the Epipen® Jr and the Allerject® 0.15 mg. But the surface area and pressure required to inject these devices may affect the depth of injection. These products as well as products that become available later should be compared in future studies.