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New Insulin Delivery Recommendations

      Abstract

      Many primary care professionals manage injection or infusion therapies in patients with diabetes. Few published guidelines have been available to help such professionals and their patients manage these therapies. Herein, we present new, practical, and comprehensive recommendations for diabetes injections and infusions. These recommendations were informed by a large international survey of current practice and were written and vetted by 183 diabetes experts from 54 countries at the Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop held in Rome, Italy, in 2015. Recommendations are organized around the themes of anatomy, physiology, pathology, psychology, and technology. Key among the recommendations are that the shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and, therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them; effective long-term therapy with insulin is critically dependent on addressing psychological hurdles upstream, even before insulin has been started; inappropriate disposal of used sharps poses a risk of infection with blood-borne pathogens; and mitigation is possible with proper training, effective disposal strategies, and the use of safety devices. Adherence to these new recommendations should lead to more effective therapies, improved outcomes, and lower costs for patients with diabetes.

      Abbreviations and Acronyms:

      BMI (body mass index), CSII (continuous subcutaneous insulin infusion), FIT (Forum for Injection Technique), FITTER (Forum for Injection Technique and Therapy: Expert Recommendations), GLP-1 (glucagon-like peptide-1), HCP (health care professional), IM (intramuscular), ITQ (Injection Technique Questionnaire), LH (lipohypertrophy), NPH (neutral protamine Hagedorn (also known as Insulin N)), NSI (needlestick injury), SC (subcutaneous), TITAN (Third Injection Technique workshop in AtheNs)
      Correct technique in insulin delivery is critical for optimal control of diabetes. This article reviews the most recent studies in the field and then offers new injection and infusion recommendations for insulin users. It is meant to complement and extend the injection recommendations published in 2010.
      • Frid A.
      • Hirsch L.
      • Gaspar R.
      • et al.
      New injection recommendations for patients with diabetes.
      These latest recommendations were based on the results of the fourth Injection Technique Questionnaire (ITQ) survey (published elsewhere in this issue). From February 2014 through June 2015, 13,289 insulin-injecting patients with diabetes from 42 countries participated in the ITQ survey, one of the largest multinational studies of its kind. A smaller Infusion Technique Questionnaire survey was undertaken concurrently with the ITQ in 356 patients using continuous subcutaneous insulin infusion (CSII) in four countries and informed the drafting of the new infusion recommendations.
      The ITQ survey results (for injection and infusion) and the initial draft of these recommendations were presented at the Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop held in Rome, Italy, on October 23 and 24, 2015, at which 183 physicians, nurses, educators, and allied health care professionals (HCPs) from 54 countries (see the list in Supplemental Appendix 1, available online at http://www.mayoclinicproceedings.org)

      Fitter4Diabetes website. http://www.fitter4diabetes.com. Accessed June 7, 2016.

      met to debate, revise, and adapt these proposals. FITTER was the fourth in a series of expert workshops that have issued recommendations on insulin delivery.
      • Frid A.
      • Hirsch L.
      • Gaspar R.
      • et al.
      New injection recommendations for patients with diabetes.
      • Strauss K.
      Insulin injection techniques: report from the 1st International Insulin Injection Technique Workshop, Strasbourg, France—June 1997.
      • Strauss K.
      • De Gols H.
      • Letondeur C.
      • Matyjaszczyk M.
      • Frid A.
      The second injection technique event (SITE), May 2000, Barcelona, Spain.
      • Costigliola V.
      • Frid A.
      • Letondeur C.
      • Strauss K.
      Needlestick injuries in European nurses in diabetes.

      Materials and Methods

      Publications were identified using Medline, EMBASE, PubMed, and Cochrane Controlled Trials. The search was focused on the period between January 2008 and December 2015, although we had at our disposal the medical literature going back to 1980. We used the terms subcutaneous injections, insulin, injection technique, insulin infusion, CSII sets, infusion sets, and glucagon-like peptide-1 receptor agonists (GLP-1). For those seeking other related terms, a glossary is also available as Supplemental Appendix 2 (available online at http://www.mayoclinicproceedings.org).

      Fitter4Diabetes website. http://www.fitter4diabetes.com. Accessed June 7, 2016.

      Of 368 articles found, 254 met the criteria for inclusion as outlined in the Cochrane Handbook for Systematic Reviews of Interventions.

      Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 (See especially chapter 8, Assessing Risk of Bias in Included Studies). http://handbook.cochrane.org. Accessed June 9, 2016.

      One of us (K.W.S.) drafted the initial version of the recommendations. This draft was then extensively revised during 12 monthly web conferences with a group of international experts in injection and infusion techniques (see authors). This new draft was then extensively revised by the 183 expert invitees to the FITTER meeting in Rome. After FITTER, additional revisions were made by FITTER attendees. The current version reflects the collective input of these diabetes experts from around the world and bears little resemblance to the earlier drafts.
      The panel used a previously established scale
      • Frid A.
      • Hirsch L.
      • Gaspar R.
      • et al.
      New injection recommendations for patients with diabetes.
      • Strauss K.
      • De Gols H.
      • Letondeur C.
      • Matyjaszczyk M.
      • Frid A.
      The second injection technique event (SITE), May 2000, Barcelona, Spain.
      • Guyatt G.
      • Gutterman D.
      • Baumann M.H.
      • et al.
      Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force.
      for the strength of each recommendation: A = strongly recommended, B = recommended, and C = unresolved issue. For grading the degree of scientific support for each recommendation, we used the following scale: 1 = at least 1 rigorously performed study that is peer reviewed and published (excludes observational studies); 2 = at least 1 observational, epidemiologic, or population-based published study; and 3 = expert consensus opinion informed by broad patient experience.
      This simplified version of the grading scales commonly used
      • Guyatt G.
      • Gutterman D.
      • Baumann M.H.
      • et al.
      Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force.
      was believed to be more appropriate for our field, where randomized, controlled outcome trials are rarely available but good-quality studies on the performance of devices do exist. Each recommendation is followed by a letter and number in bold (eg, A2). The letter indicates the importance that the recommendation should have in practice, and the number indicates its level of evidence in the medical literature. The most relevant publications bearing on a recommendation are also cited or summarized. Although these recommendations will be suitable for most patients, individual exceptions may occur for which the guidelines should be adapted.

      Anatomy

      Skin Thickness

      The skin is the first obstacle a needle must traverse when giving an injection or infusion. A variety of studies of adult skin at injection sites using various imaging techniques have all shown similar results: the skin varies in thickness from approximately 1.25 to 3.25 mm in 90% of individuals and averages approximately 2.0 to 2.5 mm. Studies have included both healthy volunteers and persons with diabetes, and their results are consistent across age groups, sexes, body mass indexes (BMIs), and geographic locations. Studies included four ethnic groups in the United States
      • Gibney M.
      • Arce C.
      • Byron K.
      • Hirsch L.
      Skin and subcutaneous adipose layer thickness in adults with diabetes at sites used for insulin injections: implications for needle length recommendations.
      ; Italian
      • Lo Presti D.
      • Ingegnosi C.
      • Strauss K.
      Skin and subcutaneous thickness at injecting sites in children with diabetes: ultrasound findings and recommendations for giving injection.
      and South African
      • Marran K.
      • Segal D.
      SKINNY—Skin thickness and Needles in the Young.
      children and adolescents with type 1 diabetes; and groups of Chinese,

      Wang W, Guo X, Shen G, et al. Skin and subcutaneous thickness at insulin injection sites in Chinese patients with diabetes: clinical implications [published June 8, 2016]. Diabetes Metab. http://dx.doi.org/10.1016/j.diabet.2016.04.010.

      Indian,
      • Jain S.M.
      • Pandey K.
      • Lahoti A.
      • Rao P.K.
      Evaluation of skin and subcutaneous tissue thickness at insulin injection sites in Indian, insulin naïve, type-2 diabetic adult population.
      Filipino,
      • Catambing I.
      • Villa M.
      Ultrasonographic measurement of skin and subcutaneous thickness at insulin injection sites among adult Filipinos with diabetes.
      and Korean adults
      • Sim K.H.
      • Hwang M.S.
      • Kim S.Y.
      • Lee H.M.
      • Chang J.Y.
      • Lee M.K.
      The appropriateness of the length of insulin needles based on determination of skin and subcutaneous fat thickness in the abdomen and upper arm in patients with type 2 diabetes.
      (most with type 2 diabetes). Details of these studies are summarized in Supplemental Figure 1
      • Gibney M.
      • Arce C.
      • Byron K.
      • Hirsch L.
      Skin and subcutaneous adipose layer thickness in adults with diabetes at sites used for insulin injections: implications for needle length recommendations.
      and Supplemental Tables 1-4 (available online at http://www.mayoclinicproceedings.org).
      • Lo Presti D.
      • Ingegnosi C.
      • Strauss K.
      Skin and subcutaneous thickness at injecting sites in children with diabetes: ultrasound findings and recommendations for giving injection.
      • Marran K.
      • Segal D.
      SKINNY—Skin thickness and Needles in the Young.

      Wang W, Guo X, Shen G, et al. Skin and subcutaneous thickness at insulin injection sites in Chinese patients with diabetes: clinical implications [published June 8, 2016]. Diabetes Metab. http://dx.doi.org/10.1016/j.diabet.2016.04.010.

      • Jain S.M.
      • Pandey K.
      • Lahoti A.
      • Rao P.K.
      Evaluation of skin and subcutaneous tissue thickness at insulin injection sites in Indian, insulin naïve, type-2 diabetic adult population.
      • Catambing I.
      • Villa M.
      Ultrasonographic measurement of skin and subcutaneous thickness at insulin injection sites among adult Filipinos with diabetes.
      • Sim K.H.
      • Hwang M.S.
      • Kim S.Y.
      • Lee H.M.
      • Chang J.Y.
      • Lee M.K.
      The appropriateness of the length of insulin needles based on determination of skin and subcutaneous fat thickness in the abdomen and upper arm in patients with type 2 diabetes.
      • Hirsch L.
      • Byron K.
      • Gibney M.
      Intramuscular risk at insulin injection sites: measurement of the distance from skin to muscle and rationale for shorter-length needles for subcutaneous insulin therapy.
      The skin is slightly less thick in children, but by puberty it increases to adult levels. However, these differences are small and are irrelevant for insulin injections and infusions. In both children and adults, even the shortest needles (4 mm) reliably traverse the skin and enter the subcutaneous (SC) fat.

      SC Thickness

      The distance from the surface of the skin to the muscle fascia (ie, the sum of skin and SC thickness) determines the potential for intramuscular (IM) injection. Compared with skin thickness, which is relatively constant, SC tissue thickness varies widely. Ultrasound measurements of skin and SC thickness at insulin injection sites in adult patients with diabetes have recently been published.

      Wang W, Guo X, Shen G, et al. Skin and subcutaneous thickness at insulin injection sites in Chinese patients with diabetes: clinical implications [published June 8, 2016]. Diabetes Metab. http://dx.doi.org/10.1016/j.diabet.2016.04.010.

      • Catambing I.
      • Villa M.
      Ultrasonographic measurement of skin and subcutaneous thickness at insulin injection sites among adult Filipinos with diabetes.
      See Supplemental Tables 1-4
      • Lo Presti D.
      • Ingegnosi C.
      • Strauss K.
      Skin and subcutaneous thickness at injecting sites in children with diabetes: ultrasound findings and recommendations for giving injection.
      • Marran K.
      • Segal D.
      SKINNY—Skin thickness and Needles in the Young.

      Wang W, Guo X, Shen G, et al. Skin and subcutaneous thickness at insulin injection sites in Chinese patients with diabetes: clinical implications [published June 8, 2016]. Diabetes Metab. http://dx.doi.org/10.1016/j.diabet.2016.04.010.

      • Jain S.M.
      • Pandey K.
      • Lahoti A.
      • Rao P.K.
      Evaluation of skin and subcutaneous tissue thickness at insulin injection sites in Indian, insulin naïve, type-2 diabetic adult population.
      • Catambing I.
      • Villa M.
      Ultrasonographic measurement of skin and subcutaneous thickness at insulin injection sites among adult Filipinos with diabetes.
      • Sim K.H.
      • Hwang M.S.
      • Kim S.Y.
      • Lee H.M.
      • Chang J.Y.
      • Lee M.K.
      The appropriateness of the length of insulin needles based on determination of skin and subcutaneous fat thickness in the abdomen and upper arm in patients with type 2 diabetes.
      • Hirsch L.
      • Byron K.
      • Gibney M.
      Intramuscular risk at insulin injection sites: measurement of the distance from skin to muscle and rationale for shorter-length needles for subcutaneous insulin therapy.
      for a summary of findings from the most important of these studies. Gibney et al
      • Gibney M.
      • Arce C.
      • Byron K.
      • Hirsch L.
      Skin and subcutaneous adipose layer thickness in adults with diabetes at sites used for insulin injections: implications for needle length recommendations.
      and Hirsch et al
      • Hirsch L.
      • Byron K.
      • Gibney M.
      Intramuscular risk at insulin injection sites: measurement of the distance from skin to muscle and rationale for shorter-length needles for subcutaneous insulin therapy.
      (separate reports on the same study) measured SC fat depth at single locations in the thigh, arm, abdomen, and buttock. Studies by Ludescher et al
      • Ludescher B.
      • Rommel M.
      • Willmer T.
      • Fritsche A.
      • Schick F.
      • Machann J.
      Subcutaneous adipose tissue thickness in adults: correlation with BMI and recommendations for pen needle lengths for subcutaneous self-injection.
      and Sim et al
      • Sim K.H.
      • Hwang M.S.
      • Kim S.Y.
      • Lee H.M.
      • Chang J.Y.
      • Lee M.K.
      The appropriateness of the length of insulin needles based on determination of skin and subcutaneous fat thickness in the abdomen and upper arm in patients with type 2 diabetes.
      (where 8-10 measurements were taken and averaged for each body site) largely confirmed the ultrasound study findings from a single site.
      Several rules of thumb have emerged from these studies: SC fat thickness increases in direct proportion to BMI; women, on average, have an approximately 5-mm greater SC fat thickness than men at the same BMI; and truncal sites (abdomen and buttocks) have thicker SC fat layers than limbs (thighs and arms) in the same individual. The most important outcome of these studies is that they inform us about the risk of IM injections. Intramuscular deposition of insulin leads to unpredictable (largely faster) absorption of insulin and destabilization of the blood glucose level. Intramuscular injections occur more frequently with longer needles, in slimmer and younger patients, males, and in those who use limbs rather than truncal sites for insulin delivery.
      Supplemental Tables 5-9
      • Gibney M.
      • Arce C.
      • Byron K.
      • Hirsch L.
      Skin and subcutaneous adipose layer thickness in adults with diabetes at sites used for insulin injections: implications for needle length recommendations.

      Wang W, Guo X, Shen G, et al. Skin and subcutaneous thickness at insulin injection sites in Chinese patients with diabetes: clinical implications [published June 8, 2016]. Diabetes Metab. http://dx.doi.org/10.1016/j.diabet.2016.04.010.

      • Sim K.H.
      • Hwang M.S.
      • Kim S.Y.
      • Lee H.M.
      • Chang J.Y.
      • Lee M.K.
      The appropriateness of the length of insulin needles based on determination of skin and subcutaneous fat thickness in the abdomen and upper arm in patients with type 2 diabetes.
      • Hirsch L.
      • Byron K.
      • Gibney M.
      Intramuscular risk at insulin injection sites: measurement of the distance from skin to muscle and rationale for shorter-length needles for subcutaneous insulin therapy.
      (available online at http://www.mayoclinicproceedings.org) provide estimates of the IM injection risk by site, needle length, and patient type. Different risk estimates in several studies reflect differing patient populations with a wide range of average BMIs.
      Children aged 0 to 2 years have higher BMIs and more SC tissue than preschool children. Preschool children (2-6 years old) are usually at the thinnest point in their lives, and both sexes usually have very little SC tissue. School-age children (7-13 years old) slowly gain SC tissue, but there are few sex differences until puberty. During puberty, young women gain considerably more SC tissue than young men owing to hormonal influences. See Supplemental Tables 1-4
      • Lo Presti D.
      • Ingegnosi C.
      • Strauss K.
      Skin and subcutaneous thickness at injecting sites in children with diabetes: ultrasound findings and recommendations for giving injection.
      • Marran K.
      • Segal D.
      SKINNY—Skin thickness and Needles in the Young.

      Wang W, Guo X, Shen G, et al. Skin and subcutaneous thickness at insulin injection sites in Chinese patients with diabetes: clinical implications [published June 8, 2016]. Diabetes Metab. http://dx.doi.org/10.1016/j.diabet.2016.04.010.

      • Jain S.M.
      • Pandey K.
      • Lahoti A.
      • Rao P.K.
      Evaluation of skin and subcutaneous tissue thickness at insulin injection sites in Indian, insulin naïve, type-2 diabetic adult population.
      • Catambing I.
      • Villa M.
      Ultrasonographic measurement of skin and subcutaneous thickness at insulin injection sites among adult Filipinos with diabetes.
      • Sim K.H.
      • Hwang M.S.
      • Kim S.Y.
      • Lee H.M.
      • Chang J.Y.
      • Lee M.K.
      The appropriateness of the length of insulin needles based on determination of skin and subcutaneous fat thickness in the abdomen and upper arm in patients with type 2 diabetes.
      • Hirsch L.
      • Byron K.
      • Gibney M.
      Intramuscular risk at insulin injection sites: measurement of the distance from skin to muscle and rationale for shorter-length needles for subcutaneous insulin therapy.
      for a summary of findings from the most important pediatric studies. See Supplemental Table 10
      • Lo Presti D.
      • Ingegnosi C.
      • Strauss K.
      Skin and subcutaneous thickness at injecting sites in children with diabetes: ultrasound findings and recommendations for giving injection.
      • Marran K.
      • Segal D.
      SKINNY—Skin thickness and Needles in the Young.
      (available online at http://www.mayoclinicproceedings.org) for estimates of IM risk in pediatric patients by site, needle length, and patient age.

      Physiology

      Risk of IM Injections

      Insulin absorption rates from IM injections differ according to the activity of the muscle. Muscle can be resting (eg, abdominal muscles in a recumbent person), active (abdominal muscles in a standing person), or exercising (abdominal muscles in a person doing sit-ups). Intramuscular-injected insulin is absorbed differently in resting, active, and exercising muscle, with the rate increasing as one progresses through the 3 stages.
      Human insulins and analogues have different absorption profiles when deposited into muscle. Intramuscular injections, especially into working muscle, can distort absorption and, thus, decouple maximum blood glucose levels from peak insulin activity. This can cause poor glycemic control, including excessive glycemic variability. Intramuscular injections can lead to frequent and unexplained hypoglycemia according to several studies.
      • Karges B.
      • Boehm B.O.
      • Karges W.
      Early hypoglycaemia after accidental intramuscular injection of insulin glargine.
      • Frid A.
      • Gunnarson R.
      • Guntner P.
      • Linde P.
      Effects of accidental intramuscular injection on insulin absorption in IDDM.
      • Spraul M.
      • Chantelau E.
      • Koumoulidou J.
      • Berger M.
      Subcutaneous or nonsubcutaneous injection of insulin.
      Patients may be unaware that they are injecting IM. Several clinical pointers can give clues as to whether the injection is IM or SC. Intramuscular injections can lead to a greater risk of bleeding, bruising, and pain. The pain may be described as stinging, and it worsens if the relevant muscle is contracted with the needle in situ. If a patient releases the syringe with the needle still under the skin, it may continue to stand upright if it is IM (whereas it topples over in SC injections).
      • Kalra S.
      • Yashdeep Y.
      Clinical applications of intramuscular insulin.
      Unexplained glycemic variability and episodes of hypoglycemia may suggest IM injection. At special risk are children, thin persons, and persons using longer needles or following improper technique.

      Needle Length

      The needle lengths that were once recommended for SC injection (for adults, ≥8 mm; for children, ≥6 mm) are now known to be too long because they increase the risk of IM injections without evidence of improved glucose control.
      • Sindelka G.
      • Heinemann L.
      • Berger M.
      • Frenck W.
      • Chantelau E.
      Effect of insulin concentration, subcutaneous fat thickness and skin temperature on subcutaneous insulin absorption in healthy subjects.
      • Becker D.
      Individualized insulin therapy in children and adolescents with type 1 diabetes.
      • Uzun S.
      • lnanc N.
      • Azal S.
      Determining optimal needle length for subcutaneous insulin injection.
      Shorter needles are much safer and are better tolerated and less painful. Hirsch et al
      • Hirsch L.
      • Klaff L.
      • Bailey T.
      • et al.
      Comparative glycemic control, safety and patient ratings for a new 4 mm × 32G insulin pen needle in adults with diabetes.
      compared a 4-mm pen needle with 5- and 8-mm needles in a large randomized controlled study. The 4-mm needle was shown to be safe and efficacious in adult patients of all sizes (ie, equivalent glucose control); skin leakage was equivalent and pain scores were improved with the 4-mm needle. Similar studies have been performed in various other groups,
      • Miwa T.
      • Itoh R.
      • Kobayashi T.
      • et al.
      Comparison of the effects of a new 32-gauge × 4-mm pen needle and a 32-gauge × 6-mm pen needle on glycemic control, safety, and patient ratings in Japanese adults with diabetes.
      • Nagai Y.
      • Ohshige T.
      • Arai K.
      • Kobayashi H.
      • Sada Y.
      • Ohmori S.
      Comparison between shorter straight and thinner microtapered insulin injection needles.
      • Hirose T.
      • Ogihara T.
      • Tozaka S.
      • Kanderian S.
      • Watada H.
      Identification and comparison of insulin pharmacokinetics injected with a new 4-mm needle vs 6- and 8-mm needles accounting for endogenous insulin and C-peptide secretion kinetics in non-diabetic adult males.
      including obese patients.
      • Bergenstal R.M.
      • Strock E.S.
      • Peremislov D.
      • et al.
      Safety and efficacy of insulin therapy delivered via a 4mm pen needle in obese patients with diabetes.
      All earlier studies on needle length
      • Kreugel G.
      • Keers J.C.
      • Jongbloed A.
      • Verweij-Gjaltema A.H.
      • Wolffenbuttel B.H.R.
      The influence of needle length on glycemic control and patient preference in obese diabetic patients.
      • Hirsch L.
      • Klaff L.
      • Bailey T.
      • et al.
      Comparative glycemic control, safety and patient ratings for a new 4 mm × 32G insulin pen needle in adults with diabetes.
      • Schwartz S.
      • Hassman D.
      • Shelmet J.
      • et al.
      A multicenter, open-label, randomized, two-period crossover trial comparing glycemic control, satisfaction, and preference achieved with a 31 gauge x 6mm needle versus a 29 gauge x 12.7mm needle in obese patients with diabetes mellitus.
      • Ross S.A.
      • Jamal R.
      • Leiter L.A.
      • et al.
      Evaluation of 8 mm insulin pen needles in people with type 1 and type 2 diabetes.
      • Tubiana-Rufi N.
      • Belarbi N.
      • Du Pasquier-Fediaevsky L.
      • et al.
      Short needles (8 mm) reduce the risk of intramuscular injections in children with type 1 diabetes.
      • Strauss K.
      • Hannet I.
      • McGonigle J.
      • et al.
      Ultra-short (5mm) insulin needles: trial results and clinical recommendations.
      • Kreugel G.
      • Keers J.C.
      • Kerstens M.N.
      • Wolffenbuttel B.H.
      Randomized trial on the influence of the length of two insulin pen needles on glycemic control and patient preference in obese patients with diabetes.
      • Iwanaga M.
      • Kamoi K.
      Patient perceptions of injection pain and anxiety: a comparison of NovoFine 32-gauge tip 6 mm and Micro Fine Plus 31-gauge 5 mm needles.
      • McKay M.
      • Compion G.
      • Lytzen L.
      A comparison of insulin injection needles on patients' perceptions of pain, handling, and acceptability: a randomized, open-label, crossover study in subjects with diabetes.
      have also shown similar glucose control (glycated hemoglobin, glycated albumin, or fructosamine) without increased leakage with the shorter-length needle. The shortest-length pen needle is 4 mm, but the shortest syringe needle today is 6 mm long (the syringe needle has to pass through the vial septum or stopper). Insulin pharmacokinetics/pharmacodynamics has been shown to be the same when injected into resting individuals using short and long needles.
      • Hirose T.
      • Ogihara T.
      • Tozaka S.
      • Kanderian S.
      • Watada H.
      Identification and comparison of insulin pharmacokinetics injected with a new 4-mm needle vs 6- and 8-mm needles accounting for endogenous insulin and C-peptide secretion kinetics in non-diabetic adult males.
      • Frid A.
      • Linde B.
      Intraregional differences in absorption of unmodified insulin from the abdominal wall.
      • de la Peña A.
      • Yeo K.P.
      • Linnebjerg H.
      • et al.
      Subcutaneous injection depth does not affect the pharmacokinetics or glucodynamics of insulin lispro in normal weight or healthy obese subjects.
      A summary of these needle length and insulin absorption studies is presented in Supplemental Appendix 3 (available online at http://www.mayoclinicproceedings.org).
      • Ross S.A.
      • Jamal R.
      • Leiter L.A.
      • et al.
      Evaluation of 8 mm insulin pen needles in people with type 1 and type 2 diabetes.
      • Iwanaga M.
      • Kamoi K.
      Patient perceptions of injection pain and anxiety: a comparison of NovoFine 32-gauge tip 6 mm and Micro Fine Plus 31-gauge 5 mm needles.
      • Birkebaek N.H.
      • Solvig J.
      • Hansen B.
      • Jorgensen C.
      • Smedegaard J.
      • Christiansen J.S.
      A 4-mm needle reduces the risk of intramuscular injections without increasing backflow to skin surface in lean diabetic children and adults.
      • Hofman P.L.
      • Derraik J.G.
      • Pinto T.E.
      • et al.
      Defining the ideal injection techniques when using 5-mm needles in children and adults.
      • Hofman P.L.
      • Lawton S.A.
      • Peart J.M.
      • et al.
      An angled insertion technique using 6-mm needles markedly reduces the risk of intramuscular injections in children and adolescents.
      • Jamal R.
      • Ross S.A.
      • Parkes J.L.
      • Pardo S.
      • Ginsberg B.H.
      Role of injection technique in use of insulin pens: prospective evaluation of a 31-gauge, 8mm insulin pen needle.
      • Kreugel G.
      • Beijer H.J.M.
      • Kerstens M.N.
      • ter Maaten J.C.
      • Sluiter W.J.
      • Boot B.S.
      Influence of needle size for SC insulin administration on metabolic control and patient acceptance.
      • Van Doorn L.G.
      • Alberda A.
      • Lytzen L.
      Insulin leakage and pain perception with NovoFine 6 mm and NovoFine 12 mm needle lengths in patients with type 1 or type 2 diabetes.

      How do I decide where to inject? Joslin Diabetes Center website. http://www.joslin.org/info/how_to_improve_the_insulin_injection_experience.html. Accessed June 8, 2016.

      • Strauss K.
      Insulin injection techniques.
      • Thow J.C.
      • Coulthard A.
      • Home P.D.
      Insulin injection site tissue depths and localization of a simulated insulin bolus using a novel air contrast ultrasonographic technique in insulin treated diabetic subjects.
      • Thow J.C.
      • Home P.D.
      Insulin injection technique: depth of injection is important.
      • Hildebrandt P.
      Skinfold thickness, local subcutaneous blood flow and insulin absorption in diabetic patients.
      • Vora J.P.
      • Peters J.R.
      • Burch A.
      • Owens D.R.
      Relationship between absorption of radiolabeled soluble insulin subcutaneous blood flow, and anthropometry.
      • Laurent A.
      • Mistretta F.
      • Bottigioli D.
      • et al.
      Echographic measurement of skin thickness in adults by high frequency ultrasound to assess the appropriate microneedle length for intradermal delivery of vaccines.
      • Lasagni C.
      • Seidenari S.
      Echographic assessment of age-dependent variations of skin thickness: a study on 162 subjects.
      • Swindle L.D.
      • Thomas S.G.
      • Freeman M.
      • Delaney P.M.
      View of normal human skin in vivo as observed using fluorescent fiber-optic confocal microscopic imaging.
      • Huzaira M.
      • Rius F.
      • Rajadhyaksha M.
      • Anderson R.R.
      • González S.
      Topographic variations in normal skin, as viewed by in vivo reflectance confocal microscopy.
      • Tan C.Y.
      • Statham B.
      • Marks R.
      • Payne P.A.
      Skin thickness measured by pulsed ultrasound: its reproducibility, validation and variability.

      Solvig J, Christiansen JS, Hansen B, Lytzen L. Localisation of potential insulin deposition in normal weight and obese patients with diabetes using Novofine 6 mm and Novofine 12 mm needles. Paper presented at: 5th Annual Conference of the Federation of European Nurses in Diabetes; September 14-15, 2000; Jerusalem, Israel.

      • Ignuat D.
      • Fu H.
      Comparison of insulin diluent leakage postinjection using two different needle lengths and injection volumes in obese patients with type 1 or type 2 diabetes mellitus.
      • Hirsch L.J.
      • Gibney M.A.
      • Albanese J.
      • et al.
      Comparative glycemic control, safety and patient ratings for a new 4 mm x 32G insulin pen needle in adults with diabetes.
      • Hirsch L.J.
      • Gibney M.A.
      • Li L.
      • Bérubé J.
      Glycemic control, reported pain and leakage with a 4 mm × 32 G pen needle in obese and non-obese adults with diabetes: a post hoc analysis.
      • Polak M.
      • Beregszaszi M.
      • Belarbi N.
      • et al.
      Subcutaneous or intra-muscular injections of insulin in children: are we injecting where we think we are?.
      • Vaag A.
      • Handberg A.
      • Lauritzen M.
      • et al.
      Variation in absorption of NPH insulin due to intramuscular injection.
      • Thow J.
      • Johnson A.
      • Fulcher G.
      • Home P.
      Different absorption of Isophane (NPH) Insulin from subcutaneous and intramuscular sites suggests a need to reassess recommended insulin injection technique.
      • Rave K.
      • Heise T.
      • Weyer C.
      • et al.
      Intramuscular versus subcutaneous injection of soluble and lispro insulins: comparison of metabolic effects in healthy subjects.
      • Alexander H.
      • Dugale A.
      Fascial planes with subcutaneous fat in humans.
      • Gasperoni C.
      • Salgarello M.
      Liposuction related to the anatomy of subcutaneous fat and superficial fascial system.
      • Johnson D.
      • Cormack G.C.
      • Abrahams P.H.
      • Dixon A.K.
      Computed tomographic observations on subcutaneous fat: implications for liposuction.
      • Markman B.
      • Barton J.F.
      Anatomy of the subcutaneous tissue of the trunk and lower extremity.
      • Kelley D.E.
      • Thaete F.L.
      • Troost F.
      • Huwe T.
      • Goodpaster B.H.
      Subdivisions of subcutaneous abdominal adipose tissue and insulin resistance.
      • de la Peña A.
      • Ma X.
      • Reddy S.
      • Ovalle F.
      • Bergenstal R.M.
      • Jackson J.A.
      Application of PK/PD modeling and simulation to dosing regimen optimization of high-dose human regular U-500 insulin.

      Recommendations

      • The 4-mm needle is long enough to traverse the skin and enter the SC tissue, with little risk of IM (or intradermal) injection. Therefore, it is considered the safest pen needle for adults and children regardless of age, sex, ethnicity, or BMI. A1
      • The 4-mm needle may be used safely and effectively in all obese patients. Although it is the needle of choice for these patients, a 5-mm needle may also be acceptable. A1
      • The 4-mm needle should be inserted perpendicular to the skin (at 90° to the skin surface), not at an angle, regardless of whether a skinfold is raised. A1
      • Very young children (≤6 years old) and very thin adults should use the 4-mm needle by lifting a skinfold and inserting the needle perpendicularly into it. Others may inject using the 4-mm needle without lifting a skinfold. A1
      • The safest currently available syringe needle for all patients is 6 mm in length. However, when any syringe needle is used in children (≥6 years old), adolescents, or slim to normal-weight adults (BMI of 19-25 [calculated as the weight in kilograms divided by the height in meters squared]), injections should always be given into a lifted skinfold. A1
      • Use of syringe needles in very young children (<6 years old) and extremely thin adults (BMI <19) is not recommended, even if they use a raised skinfold, because of the excessively high risk of IM injections. A1
      • Health care authorities and payers should be alerted to the risks associated with using syringe or pen needles 6 mm or longer in children. A2
      • Children still using the 5-mm pen needle should inject using a lifted skinfold. Children using pen needles 5 mm or longer should be switched to 4-mm pen needles if possible and if not should always use a lifted skinfold. A2
      • Injecting at a 45° angle using a 6-mm needle is an acceptable substitute for lifting a skinfold because the net penetration of a 45° injection using the 6-mm needle is approximately 4 mm.
        • Hofman P.L.
        • Lawton S.A.
        • Peart J.M.
        • et al.
        An angled insertion technique using 6mm needles markedly reduces the risk of IM injections in children and adolescents.
        A1
      • If arms are used for injections with needles 6 mm or longer, a skinfold must be lifted. This requires that the injection be given by a third party. A2
      • Avoid pushing the needle hub in so deeply that it indents the skin because this increases the risk of IM injections. B3
      • Patients with tremors or other disorders that make them unable to hold a 4-mm pen needle in place may need longer needles. B3
      • High-flow needles (with extra-thin walls) have been shown to be appropriate for all injecting patients. Their obstruction, bending, and breakage rates are the same as for conventional-quality needles (extremely low) and offer flow and ease-of-use advantages. A3

      Site Care

      The recommended injection and infusion sites are the abdomen, thigh, buttock, and upper arm.
      • Koivisto V.A.
      • Felig P.
      Alterations in insulin absorption and in blood glucose control associated with varying insulin injection sites in diabetic patients.
      • Annersten M.
      • Willman A.
      Performing subcutaneous injections: a literature review.
      • Vidal M.
      • Colungo C.
      • Jansà M.
      Actualización sobre técnicas y sistemas de administración de la insulina (I).
      • Fleming D.
      • Jacober S.J.
      • Vanderberg M.
      • Fitzgerald J.T.
      • Grunberger G.
      The safety of injecting insulin through clothing.
      • Bantle J.P.
      • Neal L.
      • Frankamp L.M.
      Effects of the anatomical region used for insulin injections on glycaemia in type 1 diabetes subjects.
      Suggested boundaries in these sites for insulin delivery are stated in the golden rules (see the Appendix).

      Recommendations

      • Patients should inspect the site before injection. Injections should be given into clean sites, only using clean hands.
        • Gorman K.C.
        Good hygiene versus alcohol swabs before insulin injections.
        Danish Nurses Organization
        Evidence-based Clinical Guidelines for Injection of Insulin for Adults with Diabetes Mellitus.
        Association for Diabetes Care Professionals (EADV)
        Guideline: The Administration of Insulin with the Insulin Pen.
        A2
      • If the site is found to be unclean it should be disinfected. Disinfection is also required in institutional settings such as hospitals and nursing homes. If alcohol is used, it must be allowed to dry completely before the injection is given.
        • McCarthy J.A.
        • Covarrubias B.
        • Sink P.
        Is the traditional alcohol wipe necessary before an insulin injection? dogma disputed.
        • Swahn Å
        Experiences from 94000 insulin injections given without skin swab.
        A2
      • Disinfection is usually not required when injections are given in noninstitutional settings such as homes, restaurants, and workplaces.
        • Le Floch J.P.
        • Herbreteau C.
        • Lange F.
        • Perlemuter L.
        Biologic material in needles and cartridges after insulin injection with a pen in diabetic patients.
        • Schuler G.
        • Pelz K.
        • Kerp L.
        Is the reuse of needles for insulin injection systems associated with a higher risk of cutaneous complications?.
        • Johansson U.
        • Amsberg S.
        • Hannerz L.
        • et al.
        Impaired absorption of insulin aspart from lipohypertrophic injection sites.
        • Ariza-Andraca C.R.
        • Altamirano-Bustamante E.
        • Frati-Munari A.C.
        • Altamirano-Bustamante P.
        • Graef-Sanchez A.
        Delayed insulin absorption due to subcutaneous edema.
        • Saez-de Ibarra L.
        • Gallego F.
        Factors related to lipohypertrophy in insulin-treated diabetic patients: role of educational intervention.
        A3
      • Patients should never inject into sites of lipohypertrophy (LH), inflammation, edema, ulceration, or infection.
        • Johansson U.
        • Amsberg S.
        • Hannerz L.
        • et al.
        Impaired absorption of insulin aspart from lipohypertrophic injection sites.
        • Ariza-Andraca C.R.
        • Altamirano-Bustamante E.
        • Frati-Munari A.C.
        • Altamirano-Bustamante P.
        • Graef-Sanchez A.
        Delayed insulin absorption due to subcutaneous edema.
        • Saez-de Ibarra L.
        • Gallego F.
        Factors related to lipohypertrophy in insulin-treated diabetic patients: role of educational intervention.
        • Young R.J.
        • Hannan W.J.
        • Frier B.M.
        • et al.
        Diabetic lipohypertrophy delays insulin absorption.
        • Chowdhury T.A.
        • Escudier V.
        Poor glycaemic control caused by insulin induced lipohypertrophy.
        • Overland J.
        • Molyneaux L.
        • Tewari S.
        • et al.
        Lipohypertrophy: does it matter in daily life? a study using a continuous glucose monitoring system.
        • Frid A.
        • Linden B.
        Computed Tomography of Injection Sites in Patients With Diabetes Mellitus: Injection and Absorption of Insulin.
        • Tandon N.
        • Kalra S.
        • Balhara Y.S.
        • et al.
        Forum for Injection Technique (FIT), India: the Indian recommendations 2.0, for best practice in Insulin Injection Technique, 2015.
        • Gentile S.
        • Agrusta M.
        • Guarino G.
        • et al.
        Metabolic consequences of incorrect insulin administration techniques in aging subjects with diabetes.
        A1
      • Patients should not inject through clothing because they cannot inspect the site beforehand or easily lift a skinfold.
        • McCarthy J.A.
        • Covarrubias B.
        • Sink P.
        Is the traditional alcohol wipe necessary before an insulin injection? dogma disputed.
        B2

      Proper Use of Pens

      When patients use pens they usually cannot see the insulin going in as they can with a syringe. Obstruction of insulin flow with pens, although rare, can have serious consequences. When teaching patients proper pen use, HCPs should consult the instruction manual for the specific device being used.
      Several basic steps are important to follow with any pen injector, but few of these are known by (or taught to) patients. For example, it is important not to accidentally push the thumb button before the pen needle tip is inserted in the SC tissue. In fact, it is best not to touch the thumb button until the needle is completely inserted. Once the thumb button is pushed, patients should keep pressure on it until the needle is completely withdrawn from the body. If the button is released while the needle is still in the skin, body fluid and cells may be aspirated into the cartridge and contaminate it.
      • Asakura T.
      A step to prevent blood in the cartridge of an insulin pen.
      Another important step is to always push the button vertically (along the axis of the pen). Some patients, especially the frail or elderly, are unable to completely inject their total dose because they are pushing the button obliquely, eg, by pushing on its edge, generating excessive resistance along its glide path.
      • Asakura T.
      • Seino H.
      • Kageyama M.
      • Yohkoh N.
      Technical study of injection force of insulin injectors: at which angle to push the button.
      • Asakura T.
      Comparison of clinically relevant technical attributes of five insulin injection pens.

      Recommendations

      • Pens should be primed before injections to ensure free and unobstructed flow. Manufacturer's instructions should be followed. Priming entails seeing at least a drop of insulin at the tip of the needle. Once free flow is verified, the patient may dial the desired dose and inject.
        • Bohannon N.J.
        Insulin delivery using pen devices: simple-to-use tools may help young and old alike.
        • Dejgaard A.
        • Murmann C.
        Air bubbles in insulin pens.
        A3
      • Pens and their cartridges are for single-person use only and should never be shared among patients. Otherwise, biologic material from one person can be drawn into the cartridge and then injected into another person.
        • Le Floch J.P.
        • Herbreteau C.
        • Lange F.
        • Perlemuter L.
        Biologic material in needles and cartridges after insulin injection with a pen in diabetic patients.
        • Bärtsch U.
        • Comtesse C.
        • Wetekam B.
        Insulin pens for treatment of diabetes.
        A2
      • After use, needles should not be left attached to the pen but rather disposed of immediately. Otherwise, air or other contaminants can enter the cartridge or medication can leak out, both of which can distort dose accuracy.
        • Van Doorn L.G.
        • Alberda A.
        • Lytzen L.
        Insulin leakage and pain perception with NovoFine 6 mm and NovoFine 12 mm needle lengths in patients with type 1 or type 2 diabetes.
        • Ginsberg B.H.
        • Parkes J.L.
        • Sparacino C.
        The kinetics of insulin administration by insulin pens.
        • Annersten M.
        • Frid A.
        Insulin pens dribble from the tip of the needle after injection.
        • Chantelau E.
        • Heinemann L.
        • Ross D.
        Air bubbles in insulin pens.
        • Maljaars C.
        Sharp study needles for single use.
        A2
      • Pen needles should be used only once. They are no longer sterile after use.
        • Strauss K.
        Insulin injection techniques: report from the 1st International Insulin Injection Technique Workshop, Strasbourg, France—June 1997.
        • Strauss K.
        • De Gols H.
        • Letondeur C.
        • Matyjaszczyk M.
        • Frid A.
        The second injection technique event (SITE), May 2000, Barcelona, Spain.
        • Schuler G.
        • Pelz K.
        • Kerp L.
        Is the reuse of needles for insulin injection systems associated with a higher risk of cutaneous complications?.
        • Johansson U.
        • Amsberg S.
        • Hannerz L.
        • et al.
        Impaired absorption of insulin aspart from lipohypertrophic injection sites.
        • Chowdhury T.A.
        • Escudier V.
        Poor glycaemic control caused by insulin induced lipohypertrophy.
        • Maljaars C.
        Sharp study needles for single use.
        • Chantelau E.
        • Lee D.M.
        • Hemmann D.M.
        • Zipfel U.
        • Echterhoff S.
        What makes insulin injections painful?.
        • Torrance T.
        An unexpected hazard of insulin injection.
        A2
      • The thumb button should be touched only after the pen needle is fully inserted. After that, the button should be pressed along the axis of the pen, not at an angle.
        • Ginsberg B.H.
        • Parkes J.L.
        • Sparacino C.
        The kinetics of insulin administration by insulin pens.
        A2
      • After the thumb button is completely pushed in, patients should count slowly to 10 and then withdraw the needle from the skin. This is necessary to prevent medication leakage and to get the full dose.
        • Van Doorn L.G.
        • Alberda A.
        • Lytzen L.
        Insulin leakage and pain perception with NovoFine 6 mm and NovoFine 12 mm needle lengths in patients with type 1 or type 2 diabetes.
        • Torrance T.
        An unexpected hazard of insulin injection.
        • King L.
        Subcutaneous insulin injection technique.
        • Rissler J.
        • Jørgensen C.
        • Rye Hansen M.
        • Hansen N.A.
        Evaluation of the injection force dynamics of a modified prefilled insulin pen.
        • Broadway C.A.
        Prevention of insulin leakage after subcutaneous injection.
        A1
      • Some patients may need to count past 10, especially when giving higher doses. Counting only to 5 may be acceptable for lower doses. Patients may find the right time for themselves by trial and error, using leakage or dribbling of insulin as a guide. A3
      • Pressure should be maintained on the thumb button until the needle is withdrawn from the skin to prevent aspiration of patient tissue into the cartridge.
        • Annersten M.
        • Frid A.
        Insulin pens dribble from the tip of the needle after injection.
        A2

      Proper Use of Syringes

      Although insulin pens continue to grow in popularity, there are still many regions of the world where syringes are used extensively. Each syringe has scale markings appropriate for only one concentration of insulin, and mismatches of syringes to insulin can lead to serious underdosing or overdosing. In some countries, both U-40 and U-100 insulin may be on the market together. In others, concentrations varying from U-100 to U-500 may be simultaneously available. Patients should avoid using syringes with detachable needles because permanently attached needle syringes deliver better dose accuracy, have far less dead space, and allow the mixing of insulins if needed. Currently, there are no syringes with needles less than 6 mm in length because of incompatibility with some vial stoppers.
      • Caffrey R.M.
      Diabetes under control: are all syringes created equal?.

      Recommendations

      • Syringe users should ensure that their device is appropriate for the concentration of insulin they are using. A3
      • When drawing up insulin from a vial, the user should first draw air into the syringe at a dose equal to (or slightly greater than) the dose of insulin to be given. This air is then injected into the vial to facilitate withdrawal of insulin. A3
      • If air bubbles are found in the syringe, tap on the barrel to bring them to the surface. They may then be removed by pushing the plunger up. A3
      • With syringes, unlike pens, the needle does not need to be left under the skin for a count of 10 after the plunger has been fully depressed.
        • Torrance T.
        An unexpected hazard of insulin injection.
        • King L.
        Subcutaneous insulin injection technique.
        • Ter Braak E.W.
        • Woodworth J.R.
        • Bianchi R.
        • et al.
        Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin.
        A3
      • Syringe needles should be used only once. They are no longer sterile after use.
        • Strauss K.
        Insulin injection techniques: report from the 1st International Insulin Injection Technique Workshop, Strasbourg, France—June 1997.
        • Strauss K.
        • De Gols H.
        • Letondeur C.
        • Matyjaszczyk M.
        • Frid A.
        The second injection technique event (SITE), May 2000, Barcelona, Spain.
        • Schuler G.
        • Pelz K.
        • Kerp L.
        Is the reuse of needles for insulin injection systems associated with a higher risk of cutaneous complications?.
        • Johansson U.
        • Amsberg S.
        • Hannerz L.
        • et al.
        Impaired absorption of insulin aspart from lipohypertrophic injection sites.
        • Chowdhury T.A.
        • Escudier V.
        Poor glycaemic control caused by insulin induced lipohypertrophy.
        • Caffrey R.M.
        Diabetes under control: are all syringes created equal?.
        • Frid A.
        Fat thickness and insulin administration: what do we know?.
        • Lippert W.C.
        • Wall E.J.
        Optimal intramuscular needle-penetration depth.
        A2

      Insulin Analogues and Other Injectables (GLP-1 Receptor Agonists)

      Few studies address proper injection technique with these newer agents. Earlier studies suggested that absorption rates of rapid-acting analogues are similar between fat tissue and resting muscle; absorption from working muscle was not tested.
      • Frid A.
      Fat thickness and insulin administration: what do we know?.
      • Lippert W.C.
      • Wall E.J.
      Optimal intramuscular needle-penetration depth.

      Recommendations

      • Rapid-acting analogues can be given at any of the injection sites. Rates of absorption have not been shown to be site specific.
        • Mudaliar S.R.
        • Lindberg F.A.
        • Joyce M.
        • et al.
        Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects.
        • Guerci B.
        • Sauvanet J.P.
        Subcutaneous insulin: pharmacokinetic variability and glycemic variability.
        • Owens D.R.
        • Coates P.A.
        • Luzio S.D.
        • Tinbergen J.P.
        • Kurzhals R.
        Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites.
        A2
      • Intramuscluar injection of rapid-acting insulin analogues should be avoided if possible.
        • Calara F.
        • Taylor K.
        • Han J.
        • et al.
        A randomized, open-label, crossover study examining the effect of injection site on bioavailability of exenatide (synthetic exendin-4).
        A2
      • Similarly, long-acting analogues may also be given at any of the injection sites. However, IM injection should be scrupulously avoided because it can lead to profound hypoglycemia.
        • Owens D.R.
        • Coates P.A.
        • Luzio S.D.
        • Tinbergen J.P.
        • Kurzhals R.
        Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites.
        • Frid A.
        • Östman J.
        • Linde B.
        Hypoglycemia risk during exercise after intramuscular injection of insulin in thigh in IDDM.
        B2
      • Pending further studies, patients using noninsulin injectable therapies (such as GLP-1 receptor agonists) should follow the established recommendations for insulin injections (regarding needle length, site selection, and rotation).
        • Rissler J.
        • Jørgensen C.
        • Rye Hansen M.
        • Hansen N.A.
        Evaluation of the injection force dynamics of a modified prefilled insulin pen.
        • Calara F.
        • Taylor K.
        • Han J.
        • et al.
        A randomized, open-label, crossover study examining the effect of injection site on bioavailability of exenatide (synthetic exendin-4).
        A2

      Human Insulins

      Regular insulin (also known as soluble human insulin) has a slower absorption rate than rapid-acting analogues. Neutral protamine Hagedorn (NPH) insulin and other older long-acting insulins have absorption peaks that can lead to hypoglycemia, especially when given in larger doses.

      Recommendations

      • It is preferable that NPH (when given alone) be injected at bedtime rather than earlier in the evening to reduce the risk of nocturnal hypoglycemia. A1
      • Intramuscular injections of NPH and other long-acting insulins must be strictly avoided because of the risk of serious hypoglycemia (Anders H. Frid, MD, oral communication, October 24, 2015).
        • Karges B.
        • Boehm B.O.
        • Karges W.
        Early hypoglycaemia after accidental intramuscular injection of insulin glargine.
        • Frid A.
        • Östman J.
        • Linde B.
        Hypoglycemia risk during exercise after intramuscular injection of insulin in thigh in IDDM.
        A2
      • The preferred site for regular (soluble human) insulin is the abdomen because absorption of this insulin is fastest there.
        • Sindelka G.
        • Heinemann L.
        • Berger M.
        • Frenck W.
        • Chantelau E.
        Effect of insulin concentration, subcutaneous fat thickness and skin temperature on subcutaneous insulin absorption in healthy subjects.
        • Frid A.
        • Linde B.
        Intraregional differences in absorption of unmodified insulin from the abdominal wall.
        • Frid A.
        • Linden B.
        Clinically important differences in insulin absorption from the abdomen in IDDM.
        • Zehrer C.
        • Hansen R.
        • Bantle J.
        Reducing blood glucose variability by use of abdominal insulin injection sites.
        • Henriksen J.E.
        • Djurhuus M.S.
        • Vaag A.
        • et al.
        Impact of injection sites for soluble insulin on glycaemic control in type 1 (insulin-dependent) diabetic patients treated with a multiple insulin injection regimen.
        A1
      • The regular/NPH insulin mix should be given in the abdomen to increase the speed of absorption of the short-acting insulin to cover postprandial glycemic excursions.
        • Frid A.
        • Gunnarson R.
        • Guntner P.
        • Linde P.
        Effects of accidental intramuscular injection on insulin absorption in IDDM.
        A1
      • If there is a risk of nocturnal hypoglycemia, NPH and NPH-containing insulin mixes given in the evening should be injected into the buttock or thigh because these sites have slower absorption rates for NPH insulin.
        Association for Diabetes Care Professionals (EADV)
        Guideline: The Administration of Insulin with the Insulin Pen.
        • Henriksen J.E.
        • Vaag A.
        • Hansen I.R.
        • Lauritzen M.
        • Djurhuus M.S.
        • Beck-Nielsen H.
        Absorption of NPH (isophane) insulin in resting diabetic patients: evidence for subcutaneous injection in the thigh as preferred site.
        • Kølendorf K.
        • Bojsen J.
        • Deckert T.
        Clinical factors influencing the absorption of 125 I-NPH insulin in diabetic patients.
        A1

      Lifting a Skinfold

      Lifting a skinfold is required when the distance from the skin surface to the muscle is less than or equal to the needle length. Lifting a skinfold in the abdomen nearly doubles the skin-to-muscle distance. In the thigh, it is sometimes difficult to lift a skinfold, and the mean increase in skin-to-muscle distance may be only 20%. In thin patients, thigh skinfolds may actually decrease the distance to muscle fascia—the exact opposite of what is desired.
      • Hofman P.L.
      • Lawton S.A.
      • Peart J.M.
      • et al.
      An angled insertion technique using 6-mm needles markedly reduces the risk of intramuscular injections in children and adolescents.
      Lifting a skinfold is rarely needed in the buttocks because of the abundance of SC tissue there. When performed in the arm, skinfolds must be lifted by someone other than the patient.

      Recommendations

      • A correct fold is made by lifting the skin with the thumb and index finger (possibly adding the middle finger). If the skin is lifted using the whole hand, muscle may be lifted as well as SC tissue, which can lead to IM injections.

        What is the best injection technique? Joslin Diabetes Center website. http://www.joslin.org/info/how_to_improve_the_insulin_injection_experience.html. Accessed June 8, 2016.

        A3
      • Skinfolds should be lifted gently and not squeezed so tightly as to cause blanching or pain. A3
      • The optimal sequence when injecting into a skinfold is as follows: (1) gently lift a skinfold, (2) inject the insulin slowly at a 90° angle to the surface of the skinfold, (3) let the needle remain in the skin for a count of 10 after the plunger is depressed (when using a pen), (4) withdraw the needle from the skin at the same angle it was inserted, (5) release the skinfold, and (6) dispose of the used needle safely. A3

      Cloudy Insulin Resuspension

      Several studies have shown that cloudy insulins are often inadequately resuspended.
      • Ter Braak E.W.
      • Woodworth J.R.
      • Bianchi R.
      • et al.
      Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin.
      • Jehle P.M.
      • Micheler C.
      • Jehle D.R.
      • Breitig D.
      • Boehm B.O.
      Inadequate suspension of neutral protamine Hagendorn (NPH) insulin in pens.
      • Brown A.
      • Steel J.M.
      • Duncan C.
      • Duncun A.
      • McBain A.M.
      An assessment of the adequacy of suspension of insulin in pen injectors.
      • Nath C.
      Mixing insulin: shake, rattle, or roll?.
      • Springs M.H.
      Shake, rattle, or roll?.
      Crystals of insulin must be mechanically agitated so that they go back into solution before injection, but many patients do not know how to do this or do it inappropriately. Inadequate resuspension can lead to varying concentrations of insulin and unpredictable clinical responses. A summary of key studies on insulin resuspension can be found in Supplemental Appendix 4 (available online at http://www.mayoclinicproceedings.org).
      • Jehle P.M.
      • Micheler C.
      • Jehle D.R.
      • Breitig D.
      • Boehm B.O.
      Inadequate suspension of neutral protamine Hagendorn (NPH) insulin in pens.
      • Brown A.
      • Steel J.M.
      • Duncan C.
      • Duncun A.
      • McBain A.M.
      An assessment of the adequacy of suspension of insulin in pen injectors.
      • Nath C.
      Mixing insulin: shake, rattle, or roll?.
      • Springs M.H.
      Shake, rattle, or roll?.
      • Kaiser P.
      • Maxeiner S.
      • Weise A.
      • et al.
      Assessment of the mixing efficiency of neutral protamine Hagedorn cartridges.
      • Kawasaki E.
      • Asakura T.
      • Karasawa H.
      • Yohkoh N.
      Examination of the suspensibility of insulin suspensions in clinical use.

      Recommendations

      • Gently roll and tip cloudy insulins (eg, NPH and premixed insulins) until the crystals are resuspended (the solution becomes milk white).
        • Ter Braak E.W.
        • Woodworth J.R.
        • Bianchi R.
        • et al.
        Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin.
        • Jehle P.M.
        • Micheler C.
        • Jehle D.R.
        • Breitig D.
        • Boehm B.O.
        Inadequate suspension of neutral protamine Hagendorn (NPH) insulin in pens.
        • Brown A.
        • Steel J.M.
        • Duncan C.
        • Duncun A.
        • McBain A.M.
        An assessment of the adequacy of suspension of insulin in pen injectors.
        • Nath C.
        Mixing insulin: shake, rattle, or roll?.
        • Springs M.H.
        Shake, rattle, or roll?.
        • Kaiser P.
        • Maxeiner S.
        • Weise A.
        • et al.
        Assessment of the mixing efficiency of neutral protamine Hagedorn cartridges.
        • Kawasaki E.
        • Asakura T.
        • Karasawa H.
        • Yohkoh N.
        Examination of the suspensibility of insulin suspensions in clinical use.
        A2
      • Tipping involves one full up-down motion of the pen or vial, and rolling is a full rotation cycle between the palms. One evidence-based method involves rolling the insulin cartridge horizontally between the palms 10 times for 5 seconds, then tipping 10 times for 10 seconds at room temperature.
        • Kawasaki E.
        • Asakura T.
        • Karasawa H.
        • Yohkoh N.
        Examination of the suspensibility of insulin suspensions in clinical use.
        A2
      • Visually confirm that the resuspended insulin is sufficiently mixed after each rolling and tipping, and repeat the procedure if crystal mass remains in the cartridge. A2
      • Vigorous shaking should be avoided because this produces bubbles that will affect accurate dosing. Avoid exposing insulin to direct heat, light, or excessive agitation. A2
      • Store unopened insulin in a refrigerator in which there is no risk of freezing. A2
      • After initial use (in pen, cartridge, or vial), insulin should be stored at ambient temperature (15°-30°C or 59°-86°F) for up to 30 days or according to the manufacturer's recommendations and within expiration dates. Premixed insulin pens and some of the newer insulins may vary in storage guidelines, so patients should check the manufacturer's recommendations.
        • Kawasaki E.
        • Asakura T.
        • Karasawa H.
        • Yohkoh N.
        Examination of the suspensibility of insulin suspensions in clinical use.
        • Ahern J.
        • Mazur M.L.
        Site rotation.
        • Perriello G.
        • Torlone E.
        • Di Santo S.
        • et al.
        Effect of storage temperature on pharmacokinetics and pharmacodynamics of insulin mixtures injected subcutaneously in subjects with type 1 (insulin-dependent) diabetes mellitus.
        A2
      • If room temperatures exceed 30°C (86°F), then insulin in current use should be stored in a refrigerator. It should be allowed to warm up before injection. Insulin can be warmed by rolling it between the palms. A2

      Pregnancy

      Studies are still lacking on the optimal injecting technique during pregnancy, but the following recommendations are considered reasonable.

      Recommendations

      • When fetal ultrasound is performed, SC fat patterns in the mother may be assessed at the same time and recommendations given to her regarding safe zones for injections.

        Engström L, Jinnerot H, Jonasson E. Thickness of subcutaneous fat tissue where pregnant diabetics inject their insulin: an ultrasound study. Poster presented at: 17th International Diabetes Federation Congress; November 5-10, 2000; Mexico City, Mexico.

        B2
      • The abdomen is generally a safe site for insulin administration during pregnancy. Given the thinning of abdominal fat from uterine expansion, pregnant women with diabetes (of any type) should use a 4-mm pen needle. B2
      • First trimester: Women should be reassured that no change in insulin site or technique is needed. B2
      • Second trimester: Insulin can be injected over the entire abdomen as long as properly raised skinfolds are used. Lateral aspects of the abdomen can be used to inject insulin when no skinfold is raised. B2
      • Third trimester: Injections can be given into the lateral abdomen as long as they are made into properly raised skinfolds. Apprehensive patients may use the thigh, upper arm, or buttock instead of the abdomen. B2

      Role of the HCP

      Currently there are 3 classes of injectable therapies for diabetes: insulin, GLP-1 receptor agonists, and amylin analogues.
      • Hofman P.L.
      • Derraik J.G.
      • Pinto T.E.
      • et al.
      Defining the ideal injection techniques when using 5-mm needles in children and adults.
      • De Meijer P.H.E.M.
      • Lutterman J.A.
      • van Lier H.J.J.
      • van't Laar A.
      The variability of the absorption of subcutaneously injected insulin: effect of injection technique and relation with brittleness.
      • Baron A.D.
      • Kim D.
      • Weyer C.
      Novel peptides under development for the treatment of type 1 and type 2 diabetes mellitus.
      Of these, only insulin is in common use for CSII. Despite more than 90 years of use, insulin injections and infusions are often performed incorrectly, with adverse clinical consequences for patients and additional costs for payers. Often, even simple rules are not taught or followed. The HCP has a crucial role in the proper use of these therapies. Proper technique is essential to achieve optimal diabetes control, reduce variability, and achieve desired outcomes.
      • Frid A.
      • Gunnarson R.
      • Guntner P.
      • Linde P.
      Effects of accidental intramuscular injection on insulin absorption in IDDM.
      • Ariza-Andraca C.R.
      • Altamirano-Bustamante E.
      • Frati-Munari A.C.
      • Altamirano-Bustamante P.
      • Graef-Sanchez A.
      Delayed insulin absorption due to subcutaneous edema.
      • Zehrer C.
      • Hansen R.
      • Bantle J.
      Reducing blood glucose variability by use of abdominal insulin injection sites.
      • Vaag A.
      • Damgaard Pedersen K.
      • Lauritzen M.
      • Hildebrandt P.
      • Beck-Nielsen H.
      Intramuscular versus subcutaneous injection of unmodified insulin: consequences for blood glucose control in patients with type 1 diabetes mellitus.
      • Hildebrandt P.
      Subcutaneous absorption of insulin in insulin-dependent diabetic patients: influences of species, physico-chemical properties of insulin and physiological factors.
      • Joy S.V.
      Clinical pearls and strategies to optimize patient outcomes.
      Often the most important determinant of patients' injection technique is the knowledge and commitment of their HCP.

      Recommendations

      • Key tasks of the HCP include helping patients (and caregivers) overcome the psychological obstacles related to injecting or infusing, especially at the initiation of treatment, and then teaching them how to perform the procedure correctly. A2
      • The HCP must understand the anatomy and physiology of insulin delivery sites so that IM injections/infusions, LH, leakage, and other complications are avoided. A2
      • The HCP must understand the pharmacokinetics of the therapeutic agents and the absorption profiles of the various delivery sites. A2

      Therapeutic Education

      Decisions regarding insulin therapy should be made jointly by the HCP and the patient (and caregivers).
      • Joy S.V.
      Clinical pearls and strategies to optimize patient outcomes.
      Not all patients receive appropriate education about injections/infusions, and not all essential topics are covered.
      • Strauss K.
      • De Gols H.
      • Hannet I.
      • Partanen T.M.
      • Frid A.
      A pan-European epidemiologic study of insulin injection technique in patients with diabetes.
      • Martinez L.
      • Consoli S.M.
      • Monnier L.
      • et al.
      Studying the Hurdles of Insulin Prescription (SHIP): development, scoring and initial validation of a new self-administered questionnaire.
      • Cefalu W.T.
      • Mathieu C.
      • Davidson J.
      • Freemantle N.
      • Gough S.
      • Canovatchel W.
      Patients' perceptions of subcutaneous insulin in the OPTIMIZE study: a multicenter follow-up study.
      Education in a group setting may lead to better adherence and lower glycated hemoglobin values if the HCP has training as an educator.
      • Seyoum B.
      • Abdulkadir J.
      Systematic inspection of insulin injection sites for local complications related to incorrect injection technique.
      A summary of studies on therapeutic education for insulin delivery can be found in Supplemental Appendix 5 (available online at http://www.mayoclinicproceedings.org).
      • Grassi G.
      • Scuntero P.
      • Trepiccioni R.
      • et al.
      Optimizing insulin injection technique and its effect on blood glucose control.
      • Mujika-Zabaleta A.
      • Forbes A.
      • While A.
      • et al.
      Relationship between diabetes knowledge, glycaemic control and quality of life: pilot study.

      Recommendations

      • Explore anxieties about insulin and the injecting/infusing process.
        • Strauss K.
        • De Gols H.
        • Hannet I.
        • Partanen T.M.
        • Frid A.
        A pan-European epidemiologic study of insulin injection technique in patients with diabetes.
        • Reach G.
        Patient non-adherence and healthcare-provider inertia are clinical myopia.
        A3
      • Discuss each of the essential topics (see the next recommendation) at initiation of therapy and at least once a year thereafter. Make sure that information is delivered verbally and in writing and has been fully understood.
        • Genev N.M.
        • Flack J.R.
        • Hoskins P.L.
        • et al.
        Diabetes education: whose priorities are met?.
        A3
      • Essential topics include the injecting/infusing regimen; the choice and management of the devices used; the choice, care, and self-examination of injection sites; proper injection techniques (timing, site rotation, injection angle, skinfolds, insulin storage, resuspension of cloudy insulin, etc); injection complications and how to avoid them; optimal needle lengths; safe disposal of used sharps; and psychological hurdles and aids to overcome them.
        • Joy S.V.
        Clinical pearls and strategies to optimize patient outcomes.
        • Strauss K.
        • De Gols H.
        • Hannet I.
        • Partanen T.M.
        • Frid A.
        A pan-European epidemiologic study of insulin injection technique in patients with diabetes.
        • Grassi G.
        • Scuntero P.
        • Trepiccioni R.
        • et al.
        Optimizing insulin injection technique and its effect on blood glucose control.
        • Genev N.M.
        • Flack J.R.
        • Hoskins P.L.
        • et al.
        Diabetes education: whose priorities are met?.
        • Davidson M.
        No need for the needle (at first).
        • Klonoff D.C.
        The pen is mightier than the needle (and syringe).
        • Pettis R.J.
        • Ginsberg B.
        • Hirsch L.
        • et al.
        Intradermal microneedle delivery of insulin lispro achieves faster insulin absorption and insulin action than subcutaneous injection.
        A1
      • Instructions should be given in verbal and written form, and adherence should be checked. To confirm adherence to prescriptions, ask to see the needles, insulin, and other devices from the latest batch received from the pharmacy. A3
      • Assess each injection/infusion site visually and by palpation, if possible, at each visit but at minimum once a year.
        • Strauss K.
        • De Gols H.
        • Hannet I.
        • Partanen T.M.
        • Frid A.
        A pan-European epidemiologic study of insulin injection technique in patients with diabetes.
        • Grassi G.
        • Scuntero P.
        • Trepiccioni R.
        • et al.
        Optimizing insulin injection technique and its effect on blood glucose control.
        • Heinemann L.
        • Hompesch M.
        • Kapitza C.
        • Harvey N.G.
        • Ginsberg B.H.
        • Pettis R.J.
        Intra-dermal insulin lispro application with a new microneedle delivery system led to a substantially more rapid insulin absorption than subcutaneous injection.
        A3

      Pathology

      Lipohypertrophy

      Lipodystrophy is a disorder of fat tissue. There are 2 main types of lipodystrophy: lipoatrophy, which is loss of adipocytes that clinically manifests as indenting and cratering, and LH, which is enlargement of adipocytes that manifests as swelling or induration of fat tissue.

      MedlinePlus website. https://www.nlm.nih.gov/medlineplus. Accessed July 1, 2016.

      An even rarer type of lipodystrophy is amyloidosis,
      • Nagase T.
      • Katsura Y.
      • Iwaki Y.
      • et al.
      The insulin ball.
      • Okamura S.
      • Hayashino Y.
      • Kore-Eda S.
      • Tsujii S.
      Localized amyloidosis at the site of repeated insulin injection in a patient with type 2 diabetes.
      • Nagase T.
      • Iwaya K.
      • Iwaki Y.
      • et al.
      Insulin-derived amyloidosis and poor glycemic control: a case series.
      • Swift B.
      • Hawkins P.N.
      • Richards C.
      • Gregory R.
      Examination of insulin injection sites: an unexpected finding of localized amyloidosis.
      for which a biopsy and pathologic diagnosis are usually necessary. Insulin injected into amyloid deposits may have substantially impaired absorption. Usually, LH regresses after stopping insulin injections into the lesions, whereas localized amyloidosis does not. Distinguishing these lesions is clinically important.
      Lipohypertrophy is common, although studies vary on the exact frequency. A Spanish study
      • Blanco M.
      • Hernández M.T.
      • Strauss K.W.
      • Amaya M.
      Prevalence and risk factors of lipohypertrophy in insulin-injecting patients with diabetes.
      found LH in nearly two-thirds of injecting patients (64.4%) (type 1 diabetes, 72.3% vs type 2 diabetes, 53.4%). An Italian study
      • Grassi G.
      • Scuntero P.
      • Trepiccioni R.
      • et al.
      Optimizing insulin injection technique and its effect on blood glucose control.
      found the prevalence to be 48.7%, and in a Chinese study
      • Sun Z.
      • Li Q.
      • Ji L.
      • et al.
      Lipohypertrophy: prevalence, risk factors, clinical characteristics, and economic burden of insulin-requiring patients in China.
      it was 53.1%. The absorption of insulin injected into LH lesions may be erratic and unpredictable, which can lead to hyperglycemia, unexpected hypoglycemia, or increased glucose variability.
      • Famulla S.
      • Hövelmann U.
      • Fischer A.
      • et al.
      Insulin injection into lipohypertrophic tissue: blunted and more variable insulin absorption and action, and impaired postprandial glucose control.
      • Hovelmann U.
      • Famulla S.
      • Hermanski L.
      • et al.
      Insulin injection into regions with lipohypertrophy (LHT) worsens postprandial (PP) blood glucose (BG) versus injections into normal adipose tissue (NAT).
      Conversely, patients who switch from injecting into LH lesions to normal tissue are at risk for hypoglycemia unless they lower their doses. A summary of additional studies in LH and pointers for optimizing the physical examination for LH are presented in Supplemental Appendix 6 (available online at http://www.mayoclinicproceedings.org) (Irl B. Hirsch, MD, oral communication, October 24, 2015).
      • Chowdhury T.A.
      • Escudier V.
      Poor glycaemic control caused by insulin induced lipohypertrophy.

      Ji L, Li Q, Wei G. Lipohypertrophy: prevalence, risk factors and clinical characteristics of insulin-requiring patients in China. Paper presented at: 50th Annual Meeting of the European Association for the Study of Diabetes (EASD); September 15-19, 2014; Vienna, Austria.

      • Conwell L.S.
      • Pope E.
      • Artiles A.M.
      • Mohanta A.
      • Daneman A.
      • Daneman D.
      Dermatological complications of continuous subcutaneous insulin infusion in children and adolescents.
      • Pickup J.
      • Yemane N.
      • Brackenridge A.
      • Pender S.
      Nonmetabolic complications of continuous subcutaneous insulin infusion: a patient survey.
      • Vardar B.
      • Kizilci S.
      Incidence of lipohypertrophy in diabetic patients and a study of influencing factors.
      • Raile K.
      • Noelle V.
      • Landgraf R.
      • Schwarz H.P.
      Insulin antibodies are associated with lipoatrophy but also with lipohypertrophy in children and adolescents with type 1 diabetes.
      • Fujikura J.
      • Fujimoto M.
      • Yasue S.
      • et al.
      Insulin-induced lipohypertrophy: report of a case with histopathology.
      • Fernqvist-Forbes E.
      • Linde B.
      Insulin absorption, glucose homeostasis, and lipolysis in IDDM during mental stress.
      • Franzen I.
      • Ludvigsson J.
      Specific instructions gave reduction of lipomas and improved metabolic control in diabetic children.

      Li Q, Ji L, Sun Z, et al. Lipohypertrophy (LH) prevalence varies widely between Chinese cities: need for consistent LH diagnostic methods. Paper presented at: 75th Scientific Sessions of the American Diabetes Association; June 5-9, 2015; Boston, MA.

      Famulla S, Hövelmann U, Fischer A, et al. Lipohypertrophy (LHT) leads to blunted, more variable insulin absorption and action in patients with type 1 diabetes (T1DM). Paper presented at: 75th Scientific Sessions of the American Diabetes Association; June 5-9, 2015; Boston, MA.

      Hovelmann U, Famulla S, Hermanski L, et al. Insulin injection into regions with lipohypertrophy (LHT) worsens postprandial (PP) blood glucose (BG) versus injections into normal adipose tissue (NAT). Paper presented at: 75th Scientific Sessions of the American Diabetes Association; June 5-9, 2015; Boston, MA.

      • Heinemann L.
      • Hirsch L.
      • Hovorka R.
      Lipohypertrophy and the artificial pancreas: is this an issue?.
      • Del Olmo M.I.
      • Campos V.
      • Abellán P.
      • Merino-Torres J.F.
      • Piñón F.
      A case of lipoatrophy with insulin detemir.
      • Arranz A.
      • Andia V.
      • López-Guzmán A.
      A case of lipoatrophy with Lispro insulin without insulin pump therapy.
      • Breznik V.
      • Kokol R.
      • Luzar B.
      • Miljković J.
      Insulin-induced localized lipoatrophy.
      • Swelheim H.T.
      • Westerlaken C.
      • van Pinxteren-Nagler E.
      • Bocca G.
      Lipoatrophy in a girl with type 1 diabetes: beneficial effects of treatment with a glucocorticoid added to an insulin analog.
      • Babiker A.
      • Datta V.
      Lipoatrophy with insulin analogues in type I diabetes.
      • Holstein A.
      • Stege H.
      • Kovacs P.
      Lipoatrophy associated with the use of insulin analogues: a new case associated with the use of insulin glargine and review of the literature.
      Lipoatrophy studies are also summarized at this site.

      Recommendations

      • Sites should be examined by the HCP for LH at least once a year, or more frequently if LH is already present. It is often easier to palpate LH than to see it. Use of a lubricating gel facilitates palpation.
        • Strauss K.
        • De Gols H.
        • Hannet I.
        • Partanen T.M.
        • Frid A.
        A pan-European epidemiologic study of insulin injection technique in patients with diabetes.
        • Teft G.
        Lipohypertrophy: patient awareness and implications for practice. (Clinical Audit).
        A2
      • The physical examination for LH is ideally performed with the patient lying down and disrobed to the underwear. But in circumstances that preclude this, examination of the patient sitting, standing, or partially clothed is acceptable. A3
      • Teach patients to inspect their own sites, and give training in site rotation, proper injection technique, and detection and prevention of LH. A2
      • After obtaining patient consent, make 2 ink marks at the extreme edges of LH with a single-use skin-safe marker. This will allow the LH to be measured for future assessment. If visible, the lesions could also be photographed. A2
      • Patients should be encouraged to avoid injecting into areas of LH until the next examination by an HCP. Use of larger injection zones, correct injection site rotation, and non-reuse of needles should be recommended.
        • Hambridge K.
        The management of lipohypertrophy in diabetes care.
        • Jansà M.
        • Colungo C.
        • Vidal M.
        Actualización sobre técnicas y sistemas de administración de la insulina (II).
        A2
      • Switching injections away from LH and to normal tissue often requires a decrease in the dose of insulin injected. The amount of decrease varies from one individual to another and should be guided by blood glucose measurements. Reductions often exceed 20% of their original dose.
        • Young R.J.
        • Hannan W.J.
        • Frier B.M.
        • et al.
        Diabetic lipohypertrophy delays insulin absorption.
        A1

      Rotation of Injection Sites

      A variety of studies have shown that the best way to safeguard normal tissue is to consistently and properly rotate injection sites.
      • Bantle J.P.
      • Weber M.S.
      • Rao S.M.
      • Chattopadhyay M.K.
      • Robertson R.P.
      Rotation of the anatomic regions used for insulin injections and day-to-day variability of plasma glucose in type 1 diabetic subjects.
      • Davis E.D.
      • Chesnaky P.
      Site rotation… taking insulin.
      Injection can be rotated from one body region to another (abdomen to thigh, to buttock, to arm), but note that absorption characteristics change depending on the type of insulin given. Analogues may be given at any injection site with similar uptake and action (pharmacokinetics/pharmacodynamics), but human insulins (regular, NPH) vary substantially, with absorption being fastest from the abdomen and slowest from the buttocks. Correct rotation involves spacing injections a least 1 cm (approximately the width of an adult finger) apart even within an injection zone. Additional study summaries on rotation are presented in Supplemental Appendix 7 (available online at http://www.mayoclinicproceedings.org).

      Fitter4Diabetes website. http://www.fitter4diabetes.com. Accessed June 7, 2016.

      Recommendations

      • Injections should be systematically rotated to avoid LH. This means injecting at least 1 cm (or approximately the width of an adult finger) from previous injections, a vital procedure that requires careful planning and attention. A2
      • Patients should be given an easy-to-follow rotation scheme from the beginning of injection/infusion therapy. The HCP should review the site rotation scheme with the patient at least once a year.
        • Davis E.D.
        • Chesnaky P.
        Site rotation… taking insulin.
        • Lumber T.
        Tips for site rotation: when it comes to insulin, where you inject is just as important as how much and when.
        • Thatcher G.
        Insulin injections: the case against random rotation.

        Nielsen BB, Musaeus L, Gæde P. Attention to injection technique is associated with a lower frequency of lipohypertrophy in insulin treated type 2 diabetic patients. Paper presented at: 34th Annual Meeting of the European Association for the Study of Diabetes (EASD); September 8-12, 1998; Barcelona, Spain.

        • Ampudia-Blasco J.
        • Girbes J.
        • Carmena R.
        A case of lipoatrophy with insulin glargine.
        • De Villiers F.P.
        Lipohypertrophy: a complication of insulin injections.
        • Hauner H.
        • Stockamp B.
        • Haastert B.
        Prevalence of lipohypertrophy in insulin-treated diabetic patients and predisposing factors.
        A2
      • One evidence-based scheme involves dividing injection sites into quadrants (or halves when using the thighs or buttocks), using one quadrant per week, and rotating quadrant to quadrant in a consistent direction (eg, clockwise) (scheme courtesy of Lourdes Saez-de Ibarra and Ruth Gaspar, diabetes nurses and specialist educators at La Paz Hospital, Madrid, Spain). A3

      Needle Reuse

      Many insulin injectors find it burdensome to carry extra needles when away from home. They also are reluctant to carry containers to dispose of used needles. Sometimes patients have to pay a portion or the entire cost of their needles, and some decide that it is not worth it to buy a new needle for each injection. Others find that the injections from reused needles are not noticeably more painful, as long as they do not reuse excessively. Finally, some patients believe that disposing of a needle after 1 use is ecologically wasteful because the metal and plastic must be incinerated.
      However, official labeling on needles requires both single-use and sterility symbols. Labeling is linked to responsibility so that when HCPs advise against the official labeling they assume the responsibility for adverse outcomes. Published injection technique recommendations have usually opposed needle reuse,
      • Schuler G.
      • Pelz K.
      • Kerp L.
      Is the reuse of needles for insulin injection systems associated with a higher risk of cutaneous complications?.
      • Gentile S.
      • Agrusta M.
      • Guarino G.
      • et al.
      Metabolic consequences of incorrect insulin administration techniques in aging subjects with diabetes.
      • De Coninck C.
      • Frid A.
      • Gaspar R.
      • et al.
      Results and analysis of the 2008-2009 Insulin Injection Technique Questionnaire survey.
      for the reasons reviewed in studies summarized in Supplemental Appendix 8 (available online at http://www.mayoclinicproceedings.org),
      • Hirsch L.
      • Ji L.
      • Sun Z.
      • et al.
      Lipohypertrophy: prevalence, risk factors and clinical characteristics of insulin-requiring patients in China.
      • Misnikova I.
      • Dreval A.
      • Gubkina V.
      • Rusanova E.
      The risk of repeated use of insulin pen needles in patients with diabetes mellitus.
      • Thomas D.R.
      • Fischer R.G.
      • Nicholas W.C.
      • Beghe C.
      • Hatten K.W.
      • Thomas J.N.
      Disposable insulin syringe reuse and aseptic practices in diabetic patients.
      • Puder J.
      • Atar M.
      • Muller B.
      • Pavan M.
      • Keller U.
      Using insulin pen needles up to five times does not affect needle tip shape nor increase pain intensity.
      but they stop short of declaring it seriously harmful to the patient.
      It seems that needle reuse, particularly reuse frequency, is associated with the development of LH. Local skin or SC tissue infections, injection pain, and unpleasantness have not been clearly associated with limited needle reuse (until needle blunting occurs). The lack of infectious complications may be attributed to the antimicrobial preservatives in insulin preparations.

      Recommendations

      • There is an association between needle reuse and LH, although a causal relationship has not been proved. There is also an association between reuse and injection pain or bleeding. Patients should be made aware of these associations. A2
      • Reusing insulin needles is not an optimal injection practice, and patients should be discouraged from doing so. Elsewhere in these recommendations it is stated that pen needles (and syringe needles) should be used only once. They are no longer sterile after use.
        • Strauss K.
        Insulin injection techniques: report from the 1st International Insulin Injection Technique Workshop, Strasbourg, France—June 1997.
        • Strauss K.
        • De Gols H.
        • Letondeur C.
        • Matyjaszczyk M.
        • Frid A.
        The second injection technique event (SITE), May 2000, Barcelona, Spain.
        • Schuler G.
        • Pelz K.
        • Kerp L.
        Is the reuse of needles for insulin injection systems associated with a higher risk of cutaneous complications?.
        • Johansson U.
        • Amsberg S.
        • Hannerz L.
        • et al.
        Impaired absorption of insulin aspart from lipohypertrophic injection sites.
        • Chowdhury T.A.
        • Escudier V.
        Poor glycaemic control caused by insulin induced lipohypertrophy.
        • Caffrey R.M.
        Diabetes under control: are all syringes created equal?.
        • Ter Braak E.W.
        • Woodworth J.R.
        • Bianchi R.
        • et al.
        Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin.
        • Frid A.
        Fat thickness and insulin administration: what do we know?.
        A2
      • However, patients who reuse needles should not be subjected to alarming claims of excessive morbidity from this practice. A3

      Bleeding and Bruising

      Needles will occasionally hit a blood vessel or a capillary bed, producing local bruising or bleeding.
      • Kahara T.
      • Kawara S.
      • Shimizu A.
      • Hisada A.
      • Noto Y.
      • Kida H.
      Subcutaneous hematoma due to frequent insulin injections in a single site.
      Today's needles are of much smaller diameter than they once were, and the amount of blood loss is usually inconsequential. Applying pressure to the site for 5 to 10 seconds should stop the bleeding. Varying the needle length does not alter the frequency of bleeding or bruising.

      Recommendations

      • Patients should be reassured that local bruising and bleeding do not adversely affect clinical outcomes or the absorption of insulin. A2
      • If bleeding and bruising are frequent or excessive, the injection technique should be carefully assessed as well as the presence of a coagulopathy or the use of anticoagulant or antiplatelet agents. A3

      Leakage of Insulin

      There are 3 types of leakage. Leaking from the pen is due to a poor seal between the needle and the cartridge in the pen. Dripping from the needle (while it is on the pen) can occur when the plunger is not held down correctly or the needle is taken out of the skin too soon. Reflux or backflow out of the injection site can happen when the needle is taken out too soon or for some other reason (obese patient). Additional studies on leakage are summarized in Supplemental Appendix 9 (available online at http://www.mayoclinicproceedings.org).
      • Heise T.
      • Nosek L.
      • Dellweg S.
      • et al.
      Impact of injection speed and volume on perceived pain during subcutaneous injections into the abdomen and thigh: a single-centre, randomized controlled trial.
      • Wittmann A.
      • Köver J.
      • Kralj N.
      • et al.
      Insulin leakage value in relation to pen needle length and administered dose after subcutaneous injection.
      Data on innovations in needle geometry are available in Supplemental Appendix 10 (available online at http://www.mayoclinicproceedings.org).
      • Bossi A.C.
      • Ansah E.O.
      Bent needles: another problem in glycaemic control.
      • Siegmund T.
      • Blankenfeld H.
      • Schumm-Draeger P.M.
      Comparison of usability and patient preference for insulin pen needles produced with different production techniques: “thin-wall” needles compared to “regular-wall” needles: an open-label study.
      • Aronson R.
      • Gibney M.A.
      • Oza K.
      • Bérubé J.
      • Kassler-Taub K.
      • Hirsch L.
      Insulin pen needles: effects of extra-thin wall needle technology on preference, confidence, and other patient ratings.

      Recommendations: Leakage at Cartridge and Pen Needle Connection

      • Ensure that the pen needle is ISO-certified compatible with the insulin pen. A3
      • Position the pen needle along the axis of the pen before screwing or snapping it on. A3
      • Pierce straight through the septum of the cartridge. A3

      Recommendations: Dripping From the Needle

      • Use needles that have a wider inner diameter and improved insulin flow (eg, extra-thin-walled needles).
        • Aronson R.
        The role of comfort and discomfort in insulin therapy.
        • Anderson G.
        • Meyer D.
        • Herrman C.E.
        • et al.
        Tolerability and safety of novel half milliliter formulation of glatiramer acetate for subcutaneous injection: an open-label, multicenter, randomized comparative study.
        A1
      • Count to 10 after the plunger is fully depressed before removing the needle from the skin to allow time for expulsive forces to be transmitted through all pen parts to the insulin column in the cartridge. A2
      • By trial and error, patients may learn how long they need to hold the button down and the needle under the skin to avoid dripping from the needle tip or backflow out of the skin. This may be less than 10 seconds. A2
      • Larger doses may be split to reduce the volume of insulin. A2

      Recommendations: Skin Leakage

      • Use needles with thin-wall or extra-thin-wall technology. A1
      • Count to 10 after the plunger is fully depressed before removing the needle from the skin. This allows enough time for the injected medication to spread out through the tissue planes and to cause the tissue to expand and stretch. A2
      • A small amount of skin leakage (a little pearl of liquid at the injection site) can be ignored. It is almost always clinically insignificant. A1
      • For patients who report frequent skin leakage, direct observation of their self-injection is important for detecting possible technique-related issues that can be modified. A2

      Psychology

      Beginning insulin therapy can be fraught with psychological hurdles, regardless of the age of the patient. Foremost among these is the fear of pain. Insulin injections are usually not painful, except in the event that the needle hits a nerve ending, which is quite infrequent. Nevertheless, some patients are quite sensitive to sensations described as painful. Patient awareness of injection discomfort has been studied extensively and is related to 3 key factors: needle length, needle diameter, and injection context. Injection context includes the environment (eg, noise and the presence of other people), the appearance of the needle, and the anxieties of the HCP and the family. The more apprehension the latter display, the greater the pain and anxiety felt by the patient.
      • Brady K.A.
      • Avner J.R.
      • Khine H.
      Perception and attitude of providers towards pain and anxiety associated with pediatric vaccine injection.
      • Diamond S.
      • Matok I.
      Pharmacists' anticipated pain compared to experienced pain associated with insulin pen injection and fingertip.
      This reverse transference places a large responsibility on caregivers to assess their own attitudes toward injection pain. Some patients note discomfort when injecting insulins that have a low pH. This seems, anecdotally, to be reported more commonly in children. Other studies on the psychology of insulin delivery are summarized in Supplemental Appendix 11 (available online at http://www.mayoclinicproceedings.org).
      • Jorgensen J.T.
      • Romsing J.
      • Rasmussen M.
      • Moller-Sonnergaard J.
      • Vang L.
      • Musaeus L.
      Pain assessment of subcutaneous injections.
      • Egekvist H.
      • Bjerring P.
      • Arendt-Nielson L.
      Pain and mechanical injury to human skin following needle insertions.
      • Arendt-Nielsen L.
      • Egekvist H.
      • Bjerring P.
      Pain following controlled cutaneous insertion of needles with different diameters.
      • Hirsch L.
      • Gibney M.
      • Berube J.
      • Manocchio J.
      The impact of a modified needle tip geometry on penetration force as well as acceptability, preference and perceived pain in subjects with diabetes.
      • Rubin R.R.
      • Peyrot M.
      • Kruger D.F.
      • Travis L.B.
      Barriers to insulin injection therapy: patient and health care provider perspectives.
      • Lee D.M.
      How painful is intensive insulin therapy?.
      • Rubino A.
      • McQuay L.J.
      • Gough S.C.
      • et al.
      Delayed initiation of subcutaneous insulin therapy after failure of oral glucose-lowering agents in patients with type 2 diabetes: a population-based analysis in the UK.
      • Karter A.J.
      • Subramanian U.
      • Saha C.
      • et al.
      Barriers to insulin initiation: the translating research into action for diabetes insulin starts project.
      • Fu A.
      • Qiu Y.
      • Radican L.
      Impact of fear of insulin or fear of injection on treatment outcomes of patients with diabetes.
      • Goebel-Fabbri A.E.
      • Fikkan J.
      • Franko D.L.
      • et al.
      Insulin restriction and associated morbidity and mortality in women with type 1 diabetes.
      • Bienvenu O.J.
      • Eaton W.W.
      The epidemiology of blood-injection: injury phobia.
      • Larkin M.E.
      • Capasso V.A.
      • Chen C.
      • et al.
      Measuring psychological insulin resistance: barriers to insulin use.
      • Zambanini A.
      • Newson R.B.
      • Maisey M.
      • et al.
      Injection related anxiety in insulin-treated diabetes.
      • Mollema E.D.
      • Snoek F.J.
      • Heine R.J.
      Assessment of perceived barriers in self-care of insulin-requiring diabetic patients.
      • Mollema E.D.
      • Snoek F.J.
      • Ader H.J.
      • et al.
      Insulin-treated diabetes patients with fear of self-injecting or fear of self-testing: psychological comorbidity and general well-being.
      • Jenkins N.
      • Hallowell N.
      • Farmer A.J.
      • Holman R.R.
      • Lawton J.
      Initiating insulin as part of the Treating To Target in Type 2 Diabetes (4-T) trial: an interview study of patients' and health professionals' experiences.
      • Cocoman A.
      • Barron C.
      Administering subcutaneous injections to children: what does the evidence say?.
      • Karlegärd M.
      • Eldholm S.
      • Lindblad B.
      • Sigström L.
      Stickrädsla hos barn och ungdomar med diabetes (Fear of injection in children and adolescents with diabetes).
      • Polonsky W.H.
      • Jackson R.
      What's so tough about taking insulin? addressing the problem of psychological insulin resistance in type 2 diabetes.
      • Polonsky W.H.
      • Fisher L.
      • Guzman S.
      • Villa-Caballero L.
      • Edelman S.V.
      Psychological insulin resistance in patients with type 2 diabetes: the scope of the problem.
      • Meece J.
      Dispelling myths and removing barriers about insulin in type 2 diabetes.
      • Davis S.N.
      • Renda S.M.
      Psychological insulin resistance: overcoming barriers to starting insulin therapy.

      Recommendations

      Emotional and Psychosocial Issues

      • Show empathy by addressing the patients' emotional concerns first. The HCP should explore worries and barriers to treatment and acknowledge that anxiety is normal when beginning any new medication, especially injection therapy. A2
      • All patients, but especially adolescents, should be encouraged to express their feelings about injecting/infusing, particularly their anger, frustration, or other struggles. A3
      • Patients of all ages should be reassured that this is a learning process and that the health care team is there to help along the way. The message is, “You are not alone, we are here to help you; we will practice together until you are comfortable giving yourself an injection.” A3
      • With all patients, it is important to explain that insulin is not a punishment or a failure. Insulin is the best treatment we have for managing blood glucose levels. For patients with type 1 diabetes it is the primary treatment, and for patients with type 2 diabetes it is often an adjunct to oral therapy to improve blood glucose control. For patients with type 2 diabetes it is important that they understand the natural progression of the disease and that insulin therapy is a part of the logical progression in its management (Paul Hofman, MD, oral communication, October 24, 2015).
        • Genev N.M.
        • Flack J.R.
        • Hoskins P.L.
        • et al.
        Diabetes education: whose priorities are met?.
        • Davidson M.
        No need for the needle (at first).
        • Meece J.
        Dispelling myths and removing barriers about insulin in type 2 diabetes.
        • Davis S.N.
        • Renda S.M.
        Psychological insulin resistance: overcoming barriers to starting insulin therapy.
        • Pergallo-Dittko V.
        Rethinking subcutaneous injection technique.
        A3
      • Patients should understand that improving blood glucose control will make them feel better. Many patients report an overall improvement in their health and well-being when taking insulin. The message is, “You will not be urinating as frequently and should sleep better. You will have more energy and improved vision. Managing blood glucose with insulin will also help prevent long-term complications.”
        • Davidson M.
        No need for the needle (at first).
        • Hanas R.
        • Ludvigsson J.
        Experience of pain from insulin injections and needle phobia in young patients with IDDM.
        A3
      • Patients, especially adolescents, should be given as much control as possible in designing their regimen to fit their lifestyle. This could include basal bolus therapy, carbohydrate counting, and using insulin pens and insulin pumps. A3

      Strategies for Reducing Fear, Pain, and Anxiety

      • Include caregivers and family members in the planning and education of the patient, and tailor the therapeutic regimen to the individual needs of the patient. A3
      • Have a compassionate and straightforward approach when teaching injection technique. Demonstrate the injection technique to the patient. Have the patient follow along and then demonstrate correct technique back to the educator or HCP. A3
      • Consider using devices that hide the needle in case of anxiety provoked by seeing sharps. Also consider using vibration, cold temperature, or pressure to “distract” the nerves (gate control theory) from the perception of pain. A3
      • Children have a lower threshold for pain. The HCP should ask about pain (Paul Hofman, MD, oral communication, October 24, 2015).
        • Meece J.
        Dispelling myths and removing barriers about insulin in type 2 diabetes.
        For young children, consider distraction techniques or play therapy (such as injecting a soft toy [stuffed animal or doll]). Older children often respond better to cognitive behavioral therapies,
        • Pergallo-Dittko V.
        Rethinking subcutaneous injection technique.
        such as guided imagery, relaxation training, active behavioral rehearsal, graded exposure, modeling, positive reinforcement, and incentive scheduling. A2
      • Fear and anxiety may be substantially reduced by having the parent and child give themselves a dry injection. Often they are surprised and relieved at how painless the injection is. A2
      • Use of injection ports at the commencement of therapy may help reduce anxiety and fear of injections and its associated pain.
        • Hanas R.
        • Ludvigsson J.
        Experience of pain from insulin injections and needle phobia in young patients with IDDM.
        • Hanas S.R.
        • Carlsson S.
        • Frid A.
        • Ludvigsson J.
        Unchanged insulin absorption after 4 days' use of subcutaneous indwelling catheters for insulin injections.
        • Hanas R.
        • Adolfsson P.
        • Elfvin-Akesson K.
        • et al.
        Indwelling catheters used from the onset of diabetes decrease injection pain and pre-injection anxiety.
        • Burdick P.
        • Cooper S.
        • Horner B.
        • Cobry E.
        • McFann K.
        • Chase H.P.
        Use of a subcutaneous injection port to improve glycemic control in children with type 1 diabetes.
        B1
      • Insulin pens with very short needles may be more acceptable to patients than the syringe and vial. This should be discussed with the patient and family when teaching injection therapy. The 4-mm pen needle is reported by patients to be less painful than longer needles.
        • Bohannon N.J.
        Insulin delivery using pen devices: simple-to-use tools may help young and old alike.
        • Chantelau E.
        • Lee D.M.
        • Hemmann D.M.
        • Zipfel U.
        • Echterhoff S.
        What makes insulin injections painful?.
        • Klonoff D.C.
        The pen is mightier than the needle (and syringe).
        • Hanas R.
        • Ludvigsson J.
        Experience of pain from insulin injections and needle phobia in young patients with IDDM.
        A2
      • Patients who occasionally experience sharp pain on injection should be reassured that the needle may have touched a nerve ending, which happens randomly and will not cause any damage. If pain persists the HCP should see the patient and evaluate the injection technique. A3
      • Keep insulin at room temperature for a more comfortable injection. Injecting insulin while it is still cold often produces more pain. A3
      • If bleeding or bruising occur, reassure the patient that these do not affect the absorption of insulin or overall diabetes control. If bruising continues or hematomas develop, observe the injection technique and suggest improvements (eg, better rotation of injection sites). A3

      Tips for Injection Education

      • Demonstrate proper injection technique to the patient and family. Then have the patient and family demonstrate proper technique back to the HCP. A3
      • Ensure that the skin is clean and dry before injecting. Patients usually do not need to use a disinfectant on the skin, but if they do, they should allow it to dry completely before injecting. A3
      • Use needles of shorter length (4 mm or the shortest available) and smaller diameter (highest gauge number), and the tip with the lowest penetration force to minimize pain. Use a sterile, new needle with each injection. A1
      • Insert the needle through the skin in a smooth but not jabbing movement. Pain fibers are in the skin, and going through the skin too slowly or too forcefully may increase the pain. A1
      • Inject the insulin slowly, ensuring that the plunger (on the syringe) or thumb button (on the pen) has been fully depressed and all the insulin has been injected. With pens, the patient should count to 10 after the button has been depressed before withdrawing the needle to get the complete dose. A3
      • The HCP should teach the importance of rotation and create a rotation pattern with the patient when initiating injection therapy. The message should be: “Insulin will not be well-absorbed if it is always injected into the same area. It is important to move injections at least half an inch (1 cm) away from the previous injection and to use all injection sites on the body (back of the arms, buttocks, thighs, and abdomen).” A1
      • If the same injection site is used repeatedly it may become lumpy, firm, and enlarged. The insulin will not work correctly if injected into these areas. A1
      • If pain is experienced when injecting large volumes of insulin the dose may need to be divided into 2 injections of smaller volume or the concentration of insulin may need to be increased. A3

      Technology

      1 Person/1 Pen

      Sometimes macroscopic blood regurgitation into a cartridge is observed. Should the cartridges be used by another patient, this could result in the transmission of blood-borne diseases such as human immunodeficiency virus or hepatitis. More concerning is microscopic blood because the risk exists but there is no visible clue. Even one injection with an insulin pen can contaminate the insulin cartridge with biologic, possibly infectious, material. If the same cartridge is used to inject another patient, transmission of this material could occur, even if a new needle is used. The implication is clear: there should never be sharing of insulin pen cartridges between patients. Additional studies on this risk are summarized in Supplemental Appendix 12 (available online at http://www.mayoclinicproceedings.org).
      • Sonoki K.
      • Yoshinari M.
      • Iwase M.
      • et al.
      Regurgitation of blood into insulin cartridges in the pen-like injectors.
      • Shikata T.
      • Karasawa T.
      • Abe K.
      • et al.
      Hepatitis B e antigen and infectivity of hepatitis B virus.
      • Scioli D.
      • Pizzella T.
      • Vollaro L.
      • Nardiello S.
      • De Feo L.
      The action of VIRKON No Foam on the hepatitis B virus.