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epinephrine manual injection

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epinephrine manual injectionThe images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit. The Creative Commons Public Domain Dedication waiver ( ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Abstract Background Intramuscular (IM) injection of epinephrine (adrenaline) at the mid-anterolateral (AL) thigh is the international standard therapy for acute anaphylaxis. Concerns exist regarding implications of epinephrine auto-injector needles not penetrating the muscle in patients with greater skin-to-muscle-distances (STMD). Methods This open-label, randomized, crossover study investigated pharmacokinetics and pharmacodynamics following injection of epinephrine in healthy volunteers. Individuals were stratified by maximally compressed STMD (low, 20 mm). Model-independent pharmacokinetic parameters and pharmacodynamics were assessed. Treatments were well tolerated. Conclusions Epinephrine delivery via EpiPen resulted in greater early systemic exposure to epinephrine vs IM syringe as assessed by epinephrine plasma levels. Delivery via EpiPen was consistent across participants with a wide range of STMD, even when the needle may not have penetrated the muscle. Trial registrations This trial was registered with the German Clinical Trials Register (DRKS-ID: DRKS00011263; secondary ID, EudraCT 2016-000104-29) on 23 March 2017. Other factors that may affect epinephrine delivery include the force and speed of delivery of epinephrine through the needle.http://futurestradingnepal.com/cmsimages/dnx5120-manual.xml

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The present study was performed to assess whether EpiPen can provide systemic delivery of epinephrine in healthy volunteers with a wide range of STMD compared with manual syringe injections of epinephrine with customized needle lengths to ensure IM injection. Methods Study design and inclusion criteria This exploratory study was an open-label, randomized, crossover study assessing pharmacokinetics (PK), pharmacodynamics (PD), and safety after epinephrine administration via EpiPen or IM syringe in people with a wide range of STMD. This study was designed using advice from the European Medicines Agency (EMA) Scientific Advice Working Party. This study was agreed upon as being exploratory in nature but was designed to utilize methodology recommended for bioequivalence studies. This study received Institutional Review Board approval, was conducted in accordance with the Declaration of Helsinki, and was registered as EudraCT 2016-000104-29. Anthropometric measurements, including STMD at the mid- and distal-AL thigh, were collected at screening. Skin-to-muscle distance was measured as the depth from the surface of the skin to the surface of the vastus lateralis muscle, which was measured with ultrasound imaging on the participant’s dominant side, under both minimum and maximum compression. Minimum compression was defined as the pressure induced by the weight of the ultrasound sensor with no additional pressure enforced other than what was required to ensure an adequate reading. Maximum compression was defined as the operator pressing the ultrasound sensor with maximum force against the femur bone and withdrawing only as needed to obtain a clear ultrasound image. Skin-to-muscle distances were measured in triplicate for both minimum and maximum levels of compression. The average STMD values at the mid-AL thigh under maximum compression were used for stratification into 3 sex-balanced groups, defined as low ( 20 mm) STMD.http://tornsif.com/dnx5120-service-manual.xml Written informed consent was obtained from all participants before screening. Study measurements The primary objective of this study was to estimate differences in epinephrine PK after administration of epinephrine 0.3 mg via EpiPen or IM syringe at the mid-AL thigh. As epinephrine is endogenous, saline administration via IM syringe was included as a control. For each study period, 6-mL blood samples were collected into EDTA vacutainer tubes at predefined time points before and after epinephrine administration. These parameters were calculated using noncompartmental techniques and compared across injection types (EpiPen vs IM syringe) and STMD groups. Pharmacodynamic parameters, including systolic blood pressure, diastolic blood pressure, and heart rate, were measured at predefined times before and after dosing. Participants were asked open-ended queries regarding the presence or absence of adverse events (AEs) every 8 to 12 h during their stay in the clinic. Correlations of PK and PD parameters with anthropometric measurements were assessed by Pearson r and Kendall tau. Anthropometric measurements were assessed during the screening period and included BMI; height; weight; STMD at mid- and distal-AL thigh; circumference of the thigh, hip, waist, and neck; and skin fold at the mid thigh, distal thigh, abdomen, and chest. Statistical analyses were performed on PK and PD parameters using crossover analysis of covariance with sequence, subject (sequence), period, treatment, STMD group, and sex as fixed effects and baseline values as continuous covariates for the first 3 periods. The 90 CIs were calculated for PK-pairwise treatment comparisons, and 95 CIs were calculated for both PK- and PD-pairwise treatment comparisons. Geometric mean ratios were used to compare PK parameters, and PD parameters were analyzed in a similar way for consistency.https://www.becompta.be/emploi/carrier-infinity-control-user-manual Likewise, if the 90 CI for the relative mean fell completely outside the 80 to 125 range, interventions were not considered to be bioequivalent. For correlation between anthropometric measurements and epinephrine PK parameters, Pearson r and Kendall tau correlation coefficient were assessed and tested for significance. For measuring changes in PD parameters (i.e., heart rate and systolic and diastolic blood pressure), changes relative to median baseline values were assessed using analysis of covariance with a significance level of P Results Baseline demographics Healthy participants were included in the study, with a target enrollment of 36 participants. Only 5 male participants met the inclusion criteria for the high-STMD group within the study timeline; therefore, 35 participants were included. Baseline demographics (age, weight, height, STMD) are presented in Table 1. Average BMI values and weight tended to be higher in groups with greater STMD. Other baseline variables (i.e., age, gender, height) were well balanced between groups, though females in each STMD group tended to be older than their male counterparts, particularly in the low-STMD group. Epinephrine also reached maximum concentrations more rapidly via EpiPen vs IM syringe, as evidenced by a shorter median t peak (20 vs 50 min, respectively). Error bars are the standard error of the mean. It was also investigated whether administration via EpiPen at an alternate injection site (the distal-AL thigh) for the moderate- and high-STMD groups would lead to an increase in systemic exposure to epinephrine because of an increased likelihood for IM injection. Although each group had a different range of STMD, epinephrine exposure after administration via EpiPen at the mid-AL thigh was similar across all 3 STMD groups (Fig. 2 a; Table 2 ). Females tended to have greater C peak values than males within STMD groups after administration via EpiPen.https://www.kroatien-croliday.de/images/comprehensive-trail-making-test-examiner-manual.pdf Post hoc analyses revealed no significant differences between STMD groups in partial AUC values at 6, 15, or 30 min after administration via EpiPen at the mid-AL thigh, reflecting a similar time course across a wide range of STMD. Mean plasma concentrations over time were also similar across STMD groups for IM syringe (Fig. 2 b) and for moderate- and high-STMD groups receiving EpiPen at the distal-AL thigh (Fig. 2 c). Open in a separate window Fig. 2 Epinephrine plasma concentrations stratified by STMD group for different injection types and locations. Mean epinephrine plasma concentrations in participants with low ( 20 mm) STMD after epinephrine administration with (a) EpiPen at the mid-AL thigh, (b) IM syringe at the mid-AL thigh, or (c) EpiPen at the distal-AL thigh. The low-STMD group did not receive epinephrine administration via EpiPen at the distal-AL thigh because of safety considerations. Open in a separate window Fig. 3 Epinephrine plasma concentrations stratified by injection type and location for low, moderate, and high STMD. AL anterolateral, EpiPen EpiPen Auto-Injector, IM intramuscular, STMD skin-to-muscle distance Pharmacodynamics Heart rate and blood pressure measurements were similar between STMD groups for each treatment, although these data were highly variable. Administration of epinephrine by either EpiPen or IM syringe led to significantly elevated heart rates within 5 min of injection in the overall population. These results were generally consistent across STMD groups. Heart rates were significantly elevated compared with median baseline heart rates for all 3 active treatments. In general, systolic blood pressure profiles demonstrated limited changes from baseline, and most of these changes were insignificant and did not appear to be similar to changes observed in epinephrine plasma levels (Fig. 4 b). The profiles in diastolic blood pressure after injections were inversely similar to trends in epinephrine levels, though these trends were less pronounced than with heart rate measures (Fig. 4 c). Significant changes in diastolic blood pressure were observed 5 min after EpiPen administration at the mid- and distal-AL thigh and 10 min after IM syringe injection. These trends in diastolic blood pressure changes were similar across STMD groups. Open in a separate window Fig. 4 Pharmacodynamic measurements after administration of epinephrine or saline via different injection types and locations. Asterisks reflect significant changes ( P AL anterolateral, EpiPen EpiPen Auto-Injector, IM intramuscular Anthropometric measurements and PK parameters To further investigate whether epinephrine exposure was influenced by participant characteristics, the correlations between anthropometric measurements and PK parameters were assessed using Pearson r and Kendall tau for EpiPen at the mid-AL thigh. Anthropometric measurements assessed included BMI; height; weight; STMD at mid- and distal-AL thigh; circumference of the thigh, hip, waist, and neck; and skin fold at the mid thigh, distal thigh, abdomen, and chest. Twenty-four participants experienced a total of 73 AEs (Table 3 ). All AEs were mild to moderate in severity and no serious AEs were reported. This study demonstrated that epinephrine administration with EpiPen resulted in higher peak plasma levels of epinephrine and more rapid systemic delivery during the first 30 min postinjection compared with manual IM syringe injections with individualized needle lengths selected to reach the muscle layer. Moreover, systemic epinephrine delivery was observed across individuals with varying STMD, including those with an STMD greater than the EpiPen needle length. However, the mechanisms underlying this ability are unclear. An alternative explanation may be that SC absorption of epinephrine is sufficient to drive systemic delivery. Of note, the median t peak in participants with high STMD receiving EpiPen at the mid-AL thigh was 30 min, which was numerically higher than the median t peak observed for the low- and moderate-STMD groups (9 and 15 min, respectively). However, the median t peak in the high-STMD group was even longer (50 min) after manual IM syringe injection with individualized needle lengths selected to reach the muscle layer. Similarly, partial AUC analyses revealed much greater systemic exposure to epinephrine in the high-STMD group during the first 30 min postinjection compared with manual IM syringe injections. These data suggest that EpiPen injection at the mid-AL thigh remains a preferred approach in patients with high STMD, even if the peak exposure to epinephrine is delayed in these patients compared with patients with lower STMD. Both studies reported an initial peak in epinephrine plasma concentrations after IM syringe injection at approximately 5 to 10 min after injection followed by a later, higher peak at approximately 50 min after injection. Ultimately, it is the opinion of the authors that the similarity of PK results between the current study and the recent Duvauchelle et al.Reliable delivery of epinephrine via EpiPen across participants was also supported by changes in heart rate observed in this study, with EpiPen administration leading to significant elevations in heart rate within 5 min postinjection. Unexpectedly, statistically significant reductions from baseline in systolic and diastolic blood pressure were observed at some time points after epinephrine injection; however, the magnitude of these changes were low and unlikely to be clinically relevant, as significant reductions were also observed with saline. The mechanism underlying such reductions is unclear but could be attributed to a general vasovagal response. The authors concluded that a few epinephrine auto-injectors, including EpiPen, had an elevated risk of SC injection in some adults and children with higher STMD on the basis of semiquantitative grading. However, these conclusions were based on ultrasound or computed tomography measurements, needle lengths, and an estimated needle length threshold needed to reach the muscle layer, and no epinephrine injections or PK measurements were made in these studies. Though our study did not directly address the conclusions of these studies that epinephrine may be deposited subcutaneously with EpiPen, the systemic epinephrine delivery observed in our study should help address the implications of these concerns previously raised that EpiPen needle length is insufficient to drive systemic exposure to epinephrine. These results suggest that the design of EpiPen is sufficient for use across a broad clinical population. The ability of EpiPen to consistently deliver systemic epinephrine is further supported by the lack of strong correlations between PK parameters and anthropometric measurements, though interpretation of these correlations may be limited by the small sample size. There are several limitations to this study. First, the sample size was somewhat small because of the exploratory nature of the study, which may limit the interpretability of statistical differences between groups, particularly given the variability in PK and PD measurements. However, the size was considered minimally adequate for assessing bioequivalence within groups. Second, this study was a single-center study, so the generalizability of these results to other geographic regions is unclear; however, we feel the distribution of BMI in this study was appropriate for the concerns this study was designed to address (i.e., previous concerns that EpiPen may be insufficient to provide systemic epinephrine delivery in individuals with high STMD). Third, although this study demonstrated rapid absorption kinetics of epinephrine after EpiPen administration vs IM syringe across different STMD groups, this study was conducted in healthy participants. Fourth, the IM syringe needles used for this study were selected on the basis of needle length, rather than needle gauge, to ensure IM delivery. Because of a finite number of commercially available needles, some participants, particularly in the low-STMD group, received IM syringe injections with needles that had a higher gauge than that used for EpiPen (22 gauge). The use of higher-gauge needles may have increased the resistance to injection, which in turn may have affected the force of injection and subsequent epinephrine PK measurements for the IM syringe group. However, the needle gauges used in the high-STMD group were the same gauge as that used for EpiPen (22 gauge) for 10 of 11 participants, so differences in needle gauge were unlikely to affect the findings in the key population of concern for this study, particularly given the consistent findings across STMD groups. Finally, this study did not use ultrasound imaging or radiolabeled injectate to assess localization of the epinephrine boluses in the muscle after epinephrine administration, so the ability of different injection methods to deliver IM epinephrine was assessed indirectly by systemic PK measurements. Despite these limitations, the broad inclusion criteria and randomized, crossover design of this study enabled investigation of multiple epinephrine administration methods across different demographics that included individuals with a compressed STMD greater than the length of the EpiPen needle. Conclusions Epinephrine delivery with EpiPen may result in higher peak exposures and greater early exposure to systemic epinephrine compared with an IM syringe. Additionally, epinephrine administration via EpiPen may provide consistent systemic epinephrine delivery regardless of participants’ STMD. These findings may be confirmed with additional randomized prospective studies. Supplementary information Writing and editorial assistance were provided under the direction of the authors by Nathan Rodeberg, PhD, and Jenna Lewis, MA, ELS, MedThink SciCom, with financial support from Mylan Inc, Canonsburg, PA. DTN contributed to the conception of the study, the design of the study, the interpretation of data, and critically revising the manuscript for important intellectual content. RR contributed to the conception of the study, the design of the study, the acquisition of data, the interpretation of data, drafting the manuscript, and critically revising the manuscript for important intellectual content. AM contributed to the interpretation of data, drafting the manuscript, and critically revising the manuscript for important intellectual content. GDT contributed to the interpretation of data and drafting the manuscript. TL contributed to the design of the study, the analysis of data, the interpretation of data, and critically revising the manuscript for important intellectual content. HL contributed to the design of the study, the analysis of data, the interpretation of data, and critically revising the manuscript for important intellectual content. KB contributed to the acquisition of data, the analysis of data, the interpretation of data, drafting the manuscript, and critically revising the manuscript for important intellectual content. M Wickman contributed to the interpretation of data and critically revising the manuscript for important intellectual content. All authors read and approved the final manuscript. Funding This study was supported by Mylan Inc, Canonsburg, PA. Availability of data and materials The data generated and analyzed in this study are not publicly available because of the commercially sensitive nature of the research. Ethics approval and consent to participate Written informed consent was obtained from all participants before screening. Consent for publication Not applicable. GDT has received honoraria from Mylan Inc. RR, TL, HL, and KB are employees of and may own stock in Mylan Inc. M Wickman has no competing interests. Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Members of the joint task force, practice parameter workgroup. Emergency department diagnosis and treatment of anaphylaxis: a practice parameter. World allergy organization guidelines for the assessment and management of anaphylaxis. Comparison of drug delivery with autoinjector versus manual prefilled syringe and between three different autoinjector devices administered in pig thigh. Auto-injector needle length may be inadequate to deliver epinephrine intramuscularly in women with confirmed food allergy. Study on requirements of bioequivalence for registration of pharmaceutical products in USA, Europe and Canada. World Health Organization. 2017.. Accessed 5 Mar 2020. 10. Duvauchelle T, Robert P, Donazzolo Y, Loyau S, Orlandini B, Lehert P, et al. Bioavailability and cardiovascular effects of adrenaline administered by Anapen autoinjector in healthy volunteers. Fergeson JE, Patel SS, Lockey RF. Acute asthma, prognosis, and treatment. Diacono D, Pumphrey RS, Sharma V, Arkwright PD. The deep fascia of the thigh forms an impenetrable barrier to fluid injected subcutaneously by autoinjectors. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. Dreborg S, Tsai G, Kim H. Implications of variation of epinephrine auto-injector needle length. Dreborg S, Wen X, Kim L, Tsai G, Nevis I, Potts R, et al. Do epinephrine auto-injectors have an unsuitable needle length in children and adolescents at risk for anaphylaxis from food allergy. Song TT, Nelson MR, Chang JH, Engler RJ, Chowdhury BA. Adequacy of the epinephrine autoinjector needle length in delivering epinephrine to the intramuscular tissues. United Kingdom (UK) Resuscitation Council. Emergency treatment of anaphylactic reactions: guidelines for healthcare providers. 2008.. Accessed 5 Mar 2020. 20. Song TT, Lieberman P. Epinephrine auto-injector needle length: what is the ideal length. Epi-Kits with epinephrine are ONLY sold to individuals who are at least 18 years of age, have a valid driver's license, and have a valid prescription. If administering manually, it is recommended to not attempt to administer through clothing. Explore now. Education Overview Mayo Clinic College of Medicine and Science Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic Alix School of Medicine Mayo Clinic School of Continuous Professional Development Mayo Clinic School of Graduate Medical Education Mayo Clinic School of Health Sciences Alumni Center Visit Our Schools Educators at Mayo Clinic train tomorrow’s leaders to deliver compassionate, high-value, safe patient care. Choose a degree. For Medical Professionals Overview Provider Relations Referring Physician Portal AskMayoExpert Video Center Publications Continuing Medical Education Mayo Clinic Laboratories Professional Services Explore Mayo Clinic's many resources and see jobs available for medical professionals.Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. It is given through a needle placed into one of your veins. Also, tell your doctor if you or your caregiver has severe arthritis of the hands. If you have any questions about this, check with your doctor. Do not inject this medicine into a vein, into the muscle of your buttocks, or into your fingers, toes, hands, or feet. To do so, may increase the chance of having serious side effects. Read and follow these instructions carefully. Read it again each time you refill your prescription in case there is new information. Ask your doctor or pharmacist if you have any questions. This contains the correct dose of medicine your doctor has prescribed. This is to avoid an accidental injection. Do not flip the blue safety release off using the thumb or by pulling it sideways, or by bending and twisting it. This signals that the injection has started. The autoinjector needs to stay in place for a minimum of 3 seconds following activation. If more than 2 injections are needed for 1 reaction, however, those should be given only under medical supervision. It should be clear and colorless. Do not use this medicine if the liquid has changed its color (pinkish or brown in color), has become cloudy, or if there are particles in it. Throw away the autoinjector, prefilled syringe, or vial after you have used it. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine. You may repeat the injection every 5 to 10 minutes as needed.The dose is 0.01 mg per kg of body weight injected under the skin or into the muscle of your thigh. You may repeat the injection every 5 to 10 minutes as needed. However, the dose is usually not more than 0.3 mg per injection. Do not store the medicine in the refrigerator or freezer, or into your vehicle's glove box. However, this tube or case is not waterproof. If you accidentally drop it, check for damage or leakage. Do not throw it away in the trash bin. All rights reserved. Information is for End User's use only and may not be sold, redistributed or otherwise used for commercial purposes. Advertising revenue supports our not-for-profit mission. All rights reserved. However, some times you may need to know how to administer an epinephrine injection from an ampule or vial. Examples could be if the patient has a biphasic reaction, or if an auto-injector is not available at that moment. For hands-on practice, we recommend Wallcur’s Practi-Vial products as well as their puncture pad to practice drawing up and administering an injection with sterile water instead of using live drugs. When suggestions are available use up and down arrows to review and ENTER to select. Continue typing to refine. The auto injectors are indicated in the emergency treatment of allergic reactions (anaphylaxis) to insect stings or bites, foods, drugs and other allergens as well as idiopathic or exercise induced anaphylaxis. Such reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhoea and abdominal cramps, involuntary voiding, wheezing, dyspnoea due to laryngeal spasm, pruritus, rashes, urticaria or angioedema. Adrenaline effectively reverses the symptoms of rhinitis, urticaria, bronchospasm and hypotension because it is a pharmacological antagonist to the effects of the chemical mediators on smooth muscles, blood vessels and other tissues. Adrenaline is recommended as the initial and primary therapeutic agent in the treatment of anaphylaxis by every recognised authority in allergy, and its appropriate use in these circumstances is widely documented in medical literature. However, the prescribing physician has the option of prescribing more or less than these amounts based on careful assessment of each individual patient and recognising the life-threatening nature of reactions for which this is being prescribed. See detailed instructions for use, point 6.6 Adrenaline should only be prescribed to those patients, and elderly individuals if the potential benefit justifies the potential risk. In patients with Parkinson's disease, adrenaline may be associated with a transient worsening of Parkinson's symptoms such as rigidity and tremor. Anginal pain may be induced by adrenaline in patients with coronary insufficiency. If there is an accidental injection into these areas, advise the patient to go immediately to the nearest emergency room or hospital casualty department for treatment. The auto injector should be discarded if discoloured or contains a precipitate.Patients should be advised NOT to inject into the buttock. Large doses or accidental intravenous injection of adrenaline may result in cerebral haemorrhage due to sharp rise in blood pressure. Directions for proper use of the auto injectors must be followed in order to avoid intravenous injection. Rapidly acting vasodilators can counteract the marked pressor-effects of adrenaline. The alternatives to using adrenaline in a life-threatening situation may not be satisfactory. The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations. The effects of adrenaline may be potentiated by tricyclic antidepressants and mono amine oxidase inhibitors (MAO-inhibitors) and catechol-O-methyl transferase inhibitors (COMT-inhibitors), thyroid hormones, theophylline, oxytocin, parasympatholytics, certain antihistamines (diphenhydramine, chlorpheniramine), levodopa and alcohol. If prolonged hypotension follows such measures, it may be necessary to administer another pressor drug, such as levarterenol. It may be necessary for diabetic patients receiving adrenaline to increase their dosage of insulin or oral hypoglycaemic drugs. No clinical trials were performed in conjunction with this application.