NEW INJECTION RECOMMENDATIONS FOR

PATIENTS WITH DIABETES

Anders Frid, Ruth Gaspar, Debbie Hicks, Larry Hirsch, Gillian Kreugel, Jutta Liersch,
Corinne Letondeur, Jean-Pierre Sauvanet, Nadia Tubiana-Rufi, Kenneth Strauss*

*All authors are members of the Scientific Advisory Board for the Third Injection
Technique Workshop in Athens (TITAN), September 11-13, 2009


Introduction

Patients with diabetes who inject insulin or other agents often get less than optimal
training on appropriate techniques. This is usually not the fault of the diabetes educator,
who often has years of experience and is highly dedicated. Best practice in injecting has
just not been a topic which has attracted a great deal of interest or serious study.
Injections were considered just shots and could be mastered in a few minutes of practice,
once the fear of needles was overcome. Millions of dollars were spent developing new
human insulins, new analogues and, most recently, new glucagon-like protein-1 agents
(GLP-1 or incretins) but precious little attention was spent on the way these drugs should
be delivered. Few suspected the truth: that injection methodology can be critically
important to the PK and PD effects of the drug

The authors are members of a dedicated group of practitioners and scientists who have
studied, published, issued recommendations on and taught best practice in injections for
many years. The First Insulin Injection Technique Workshop was organized in June,
1997 in Strasbourg, France (1). This workshop commissioned a Europe-wide survey in
order to understand current practice with a view to issuing best practice guidelines (2).
The first Insulin Injection Technique survey was performed from 1999-2000 and results
were shared at the Second Injection Technique Event (SITE) in Barcelona in 2000 (3),
followed by publication shortly thereafter (4). The injection issues and challenges raised
by the survey began to be addressed by focused health care professional efforts, including
the development of local and national injection guidelines.
1

Two northern European countries were the first to develop and publish guidelines of their
own. The Danish guidelines (5) were first published in 2002 and then updated in 2006 by
the Danish Nurses Organization under the title, Evidence-based Clinical Guidelines for
Injection of Insulin for Adults with Diabetes Mellitus. The document is available in both
Danish and English. The Dutch guidelines (6) were published in September 2008 by the
Association for Diabetes Care Professionals (EADV) under the title, Guideline: The
Administration of Insulin with the Insulin Pen. It is available in both Dutch and English.
Other injecting guidelines exist, both at a local and national level (e.g. from the American
Diabetes Association [7, 8]), but none are published as a separate, dedicated set like these
four (the first [1] and second workshops [2] and the Danish [5] and Dutch guidelines [6])
and none are as comprehensive.

This paper will present new injection recommendations built upon these previous sets.
We, however, seek to enlarge upon their scope, covering issues that were not addressed
or that have arisen subsequent to their publication. This set of new recommendations
reflects the work of a group of experts in injection technique (see list of authors and
Appendix 1) who met face-to-face periodically over an eighteen month period as well as
maintained continuous email contact. The work is based on their review and analysis of
all peer-reviewed studies and publications which bear on the subject of injections in
diabetes. Articles were searched using Pub Med, Medline and Cochrane Reviews. More
than three hundred were identified, of which nearly a hundred and sixty were felt relevant
enough to be sited.

These new recommendations take into account the arrival of a number of new insulin
analogues and GLP-1 agents for which no injection guidelines have yet been developed.
Since there continues to be a move to more intensive insulin regimens and an increasing
proportion of injections are being given by Type 2 patients, the role of General
Practitioners in the injection arena has been enhanced. However, few GPs are
experienced with the finer points of patient self-injection and few Type 2 patients get
intensive injection training. Newer needle lengths, such as the 5 and 6mm pen needles,
2
are gaining prominence (or dominance) in many countries, yet questions remain
regarding the appropriateness of their use in certain populations. The new
recommendations target unmet needs of these patient groups and the devices and agents
they use. On the horizon, according to certain publications, are even shorter needles (9).

Furthermore new subgroups of injectors are demanding recommendations targeted to
their own needs. This includes pediatric patients, obese patients and pregnant women.
Similarly, new and recent concerns, unaddressed by other sets of recommendations, have
arisen. These include how to treat and prevent lipohypertrophies, psychological aspects
of injection including needle fear and pain management, the safe disposal of used sharps
and the protection from needlestick injuries of downstream persons.

Finally, the new recommendations were informed by insights gained from the second
injection technique questionnaire survey. Over 8 months, from September 2008 to June
2009, 4352 insulin-injecting Type 1 and 2 diabetic patients from 171 centers in 16
countries participated in the survey, making it one of the largest multicenter studies of its
kind in diabetes. The results of this survey (still unpublished) were just coming available
when the new recommendations were being formulated.

In the light of these needs and using the guidance of recent publications and new data, the
team of experts proposes new recommendations on the following set of subjects.

The Role of the Health Care Professional
Psychological Challenges of Injections
Children
Adolescents
Adults
Therapeutic Education
Injection Site Care
Insulin Storage, Suspension and Insulin Pen Priming
Injecting Process
3
The Proper Use of Pens
The Proper Use of Syringes
Insulin analogues (rapid-acting)
Insulin analogues (slow-acting)
Human and Pre-mixed Insulins
GLP-1 agents
Needle Length
Children and Adolescents
Adults
Skin Folds
Lipohypertrophy
Background and Consequences
Prevention
Therapy and Follow Up
Rotation of Injection Sites
Bleeding and Bruising
Pregnancy
Intra-dermal Injections
Safety Needles
Disposal of injecting material

For the strength of recommendation we use the following scale:
A. Strongly recommended
B. Recommended
C. Unresolved issue.

For the scientific evidence we use this scale:
1. At least one randomized controlled study
2. At least one non-randomized (or non-controlled or epidemiologic) study
3. Consensus expert opinion based on extensive patient experience

4
Thus the letter will indicate the weight the recommendations should have in daily
practice and the grade will indicate the level of support it has in the medical literature.
Every one of the new recommendations will have both a letter and number following it
(e.g. A2). The most relevant publications bearing on the recommendation are also sited.

An initial draft of the New Recommendations was presented at the Third Injection
Technique workshop in AtheNs (TITAN) held in Athens, Greece from 10-13 September,
2009. During these three days 127 doctors, nurses, educators and psychologists, all
injection experts from 27 countries, engaged in intense discussion of these proposals (see
list of attendees in Appendix 1). The discussions continued after the meeting by
electronic means, leading to a complete revision of the initial guidelines and, eventually,
to the recommendations of this paper.

The New Injection Recommendations

Introduction

The assumption that animates this document is that proper injection technique is
absolutely essential to good diabetes management. It may be as important as the
choice and dose of injected agent, otherwise the latter will not act with optimal effect (10).
These recommendations apply to the vast majority of injecting patients, but there will
inevitably be individual exceptions for which these rules must be adjusted. Background
information and actionable advice sometimes overlap in the sections below. There are
currently three classes of injectable substances available for diabetes therapy: insulin,
GLP-1 agents and amylin agonists (11). The health care professional (especially the
diabetes educator) plays a crucial role in the optimal use of these agents.


The Role of the Health Care Professional

5
Key tasks of the health care professional (HCP) are to teach patients (and
other care-givers) how to inject correctly and to address the many
psychological hurdles the patient may face when injecting, especially at the
initiation of such treatment. (12) A1
The HCP must have an understanding of the anatomy of injection sites in
order to help patients avoid intramuscular (IM) injections and to ensure that
injections are consistently made into the subcutaneous (SC) tissue, without
leakage/backflow or other complications. (13) A1
In addition the HCP must have knowledge of absorption profiles of the
various agents from different tissues. (14-16) A1

Psychological Challenges of Injections


Children

For the purpose of these recommendations, childhood is defined as birth to
the onset of puberty.
The anxiety most children face when starting insulin therapy often relates to
earlier experiences with immunizations as well as negative societal messages
regarding injections. (17)
HCPs and parents fear hurting children and often transmit their own
anxieties.
Parents who are well-prepared beforehand will transmit less anxiety; the
presence of a calm and reassuring parent is the most effective support for a
distressed child.
Anticipatory fear is often worse than the actual experience of the injection.
Fear of injection can also be significantly relieved by having the patient or
parent give a self-injection of saline or one unit of insulin early on after their
diagnosis of diabetes.
6
A HCP who smiles while giving an injection may be interpreted as one who
enjoys hurting the child. A neutral expression at that moment is preferred.
Children have a lower threshold for pain than adults and sometimes find
injecting uncomfortable. The HCP should ask about pain, since many young
patients will not bring it up spontaneously. (18) B2
Younger children may be helped by distraction techniques (as long as they
do not involve trickery) while older children respond better to cognitive
behavioral therapies (CBT). (19) B2
CBT include relaxation training, guided imagery, graded exposure, active
behavioral rehearsal / modeling and reinforcement / incentive scheduling.
(19) B2

Adolescents

For the purpose of these recommendations, adolescence is defined as puberty
through 18 years of age.
HCPs should recognize that many adolescents are reluctant to inject insulin
in front of peers.
There is a greater tendency among adolescents to skip injections, often
because of simple forgetfulness, although at other times this may be due to
peer pressure, rebellion, pain, etc. (17)
If skipping injections becomes habitual it may be due to the dangerous
practice, common in some young women, of under-dosing insulin as a means
of weight control.
This practice should be actively investigated whenever there is a discrepancy
between the doses advised or reported and blood glucose readings or when
one finds unexplained weight loss.
Adolescents should be reassured that no one manages diabetes perfectly all
the time and that occasional slip-ups, as long as they do not become habitual,
are not signs of failure.
7
Any steps which enhance their sense of control will have positive
consequences for the adolescent (e.g. flexible injection schedule for weekends
and holidays).
All patients, but especially adolescents, should be encouraged to express their
feelings about injecting, particularly their frustrations and struggles.

Adults

Very few adults have true needle phobia but many have anxiety about
injecting, especially at the beginning of therapy. (20, 21)
Even experienced patients may view injections with a degree of regret and
loathing. (22, 23)
At the beginning of therapy the demonstration of a self-injection of saline by
the HCP can relieve patient anxiety.
Fear of injection can also be significantly relieved by having the patient give
a self-injection of saline or one unit of insulin early on after their diagnosis of
diabetes.
As insulin itself is also a source of anxiety, the HCP should prepare all newly-
diagnosed patients with type 2 diabetes for possible future insulin therapy by
explaining the natural, progressive nature of the disease, stating that it
includes insulin therapy and making clear that insulin treatment is not a sign
of their failure. (24)
Both the short-term and long-term advantages of good glucose management
should be emphasized. (25)
Early on, finding the right combination of therapies leading to good glucose
management should be the goal, rather than minimizing the number of
agents used. (25, 26)
HCPs should reflect on their own perceptions of insulin therapy and avoid
using any terms even casually - which imply that such therapy is a sign of
failure, a form of punishment or a threat. (27, 28)
8
Through culturally-appropriate metaphors, pictures and stories, HCPs
should show how insulin injections enhance both the duration and quality of
life. (25)
In all age groups pen therapy may have psychological advantages over
syringe therapy. (25, 29)

Therapeutic Education

Decisions regarding injections should be made in a discussion context where
the patient is a partner and the HCP offers experience and advice. (30, 31)
A1
The HCP should spend time exploring patient (and other care-givers)
anxieties about the injecting process and insulin itself. (27, 32) A1
At the beginning of injection therapy (and at least every year thereafter) the
HCP should discuss, among other topics:
the injecting regimen
the choice and management of the devices used
choice, care and self-examination of injection sites
proper injection technique, including site rotation, injection angle,
and possible use of skin folds
optimal needle lengths
appropriate disposal options. (26, 27, 30, 32) A1

The HCP should ensure this information has been fully understood. (28) A1
A Quality Management Process should be put in place to ensure that correct
injection technique is practiced by the patient. Documentation is essential.
Current injection practice should be queried and observed, and injecting
sites examined and palpated, if possible at each visit, but at least every year
(especially in pediatrics). (30, 32) A1
9
Patients (and parents of children with diabetes) should be taught to inspect
and palpate their own injection sites in order to detect lipohypertrophy early
on. (33) A2
In group education there is evidence that HbA1c is lowered if the educator
has formal training as educator. (34) A2

Injection Site Care

Figure 1 shows the recommended injection sites. (35-39)


The sites should be inspected prior to injection. (5, 6) A1
Change sites if current one shows signs of lipohypertrophy, inflammation, or
infection. (40) A1
Injections should be given in a clean site using clean hands. (41) A2
Disinfection of the site is usually not required outside the hospital setting. (6,
42-44) B2
Disinfection may be appropriate when the site is found to be unclean or the
patient is in a setting where infections can be spread from the hands of the
injector (e.g. hospital) (41) A1
10
Injection through clothing has not been associated with adverse outcomes
but the fact that one cannot lift a skin fold or visualize the site when injecting
through clothing suggest that this is suboptimal practice. (45) C3

Insulin Storage, Suspension and Insulin Pen Priming

Store insulin in current use (pen, cartridge or vial) at room temperature (for
a maximum of one month after initial use, and within expiry date). Store
back up insulin bottles in an area of the refrigerator where freezing is
unlikely to occur. (46, 47) A1
Cloudy insulins (e.g. NPH and pre-mixed insulins) must be gently rolled
and/or tipped for 20 cycles until the crystals go back into suspension
(solution becomes milky white). (48-52) A1
Unlike syringe users, the pen user cannot see the insulin going in when
injecting. Obstruction of flow with pens is rare but, when it happens, can
have serious consequences. C3
Therefore it is recommended to prime pens (observing at least a drop at the
needle tip) before the injection to ensure there is unobstructed flow and to
clear needle dead space. Once flow is verified, the desired dose should be
dialed and the injection administered. (53, 54) B2

Injecting Process

Inject slowly and ensure that the plunger (syringe) or thumb button (pen)
has been fully depressed. (55) A1
When using a pen, wait another 10 seconds after dose delivery before
removing the needle in order to avoid leakage/reflux; this ensures full
delivery of the injected dose. (56) A1
Massaging the site before or after injection may speed up absorption and is
generally not recommended. (5, 6, 57) C3
Tips for making injections less painful include:
11
- Keeping insulin in use at room temperature or taking out the insulin
thirty minutes before injecting so that it attains room temperature,
since cold insulin can be more painful when injected; (17) B2
- If using alcohol, injecting only when the alcohol has dried out;
- Not injecting at hair roots;
- Using a new needle at each injection.


The Proper Use of Pens

Injecting pens and cartridges must be used individually, for a single patient,
and should never be shared between patients due to the risk of biological
material being drawn into the cartridge. (42, 58) A2
Pen needles should preferably be used only once. (3, 5, 6, 17, 43, 44, 59, 60)
A2
Needles should be disposed of immediately instead of being left attached to
the pen. This prevents the entry of air or other contaminants into the
cartridge as well as the leakage of medication out. (56, 61-64) A1
After pushing the thumb button in completely, patients should count slowly
to 10 before withdrawing the needle in order to get the full dose and prevent
the leakage of medication. (48, 55, 56, 63, 65) A1
Counting past 10 may be necessary for higher doses. (66) B3

The Proper Use of Syringes

There are regions of the world where significant numbers of patients still use
syringes as their primary injecting device.
There is currently no syringe with a needle <8mm in length, due to
compatibility issues with certain insulin vial stoppers. (67)
Unlike pens, there is no evidence suggesting that the syringe needle must be
left under the skin for 10 seconds after the plunger has been depressed. (55,
56, 66) B2
12
There is no medical rationale to use syringes with detachable needles for
insulin injection.
Permanently-attached needle syringes offer better dose accuracy and
reduced dead space, allowing one to mix insulins if needed.
In regions of the world where U40 insulin and U100 are still on the market
together (e.g. Asia, Africa) careful attention must be paid to using the
appropriate syringe for each concentration.
When drawing up insulin, air equivalent to the dose needs to be drawn up
first and injected into the vial to facilitate insulin withdrawal.
If air bubbles are seen in the syringe, tap the barrel to bring them to the
surface and then remove the bubbles by pushing up the plunger.
Like pen needles, syringes should preferably be used only once. (3, 5, 6, 17,
43, 44, 59, 60) A2


Insulin analogues (rapid-acting)

Rapid-acting insulin analogues may be given at any of the injection sites as
absorption rates do not appear to be site-specific. (68-72) B2
Rapid-acting analogues should not be given IM although studies have shown
that absorption rates are similar from fat tissue and resting muscle.
Absortpion from working muscle has, however, not been studied. (70, 73) C3
Giving injections several minutes before meals may help ensure that
analogue activity is better coupled with glucose absorption. (74) B2

Insulin analogues (slow-acting)

Pending further studies, patients may inject slow-acting insulin analogues in
any of the usual injecting sites. (75) B2
IM injections of long-acting analogues must be avoided due to the risk of
severe hypoglycemia. (76) A1
13
Absorption profiles of detemir may be dose-dependent, with larger doses
sometimes having rounded peaks. In such cases splitting of doses into two
injections may be appropriate. (77) B2
A threshold for splitting doses is not universally established but it is usually
accepted to be between 40-50 IU. (5, 6, 65) C3
Patients engaging in athletic activities after injection of glargine (Lantus)
or detemir (Levemir) should be warned against possible risk of early
hypoglycemia followed by blood sugar elevation due to quicker insulin
absorption and action. (78) B2

Human and Pre-mixed insulins

Human insulins are considered to include Regular and NPH insulin.
IM injection of NPH must be avoided since serious hypoglycemia can result.
(79) A1
NPH insulin will be more slowly absorbed when injected into the thigh or
buttocks. These sites are preferred when using NPH as the basal insulin. (35,
80) A1
NPH has pharmacologic peaks which can lead to hypoglycemia, especially
when injected in large doses.
As with slow-acting analogues, splitting of large doses into two injections
may be appropriate. (77, 81, 82) B2
A threshold for splitting doses is not universally established but it is usually
accepted to be between 40-50 IU. (5, 6, 63) C3
Soluble human insulins (Actrapid, Humulin Regular) may have a slower
absorption profile than the rapid-acting analogs (Humalog, Novolog,
Apidra)
The most rapid absorption of soluble human insulins is in the abdomen
which should be the preferred site. (16, 36, 38, 83-85) A1
The absorption of soluble human insulins in the elderly can be slow and these
insulins should not be used when a rapid effect is needed. (14, 86) B2
14
Pre-mixed insulins are advised to be given in the abdomen in the morning
and in thigh or buttock in the evening due to the risk of nocturnal
hypoglycemia if NPH insulin is absorbed too fast in the evening. (80, 81) A1

GLP-1 agents

Pending further studies, injections of GLP-1 agents (exnatide, Byetta

;
liraglutide, Victoza

) should be given using the recommendations already

established for insulin injections with regards to needle length and site
rotation. (61) A2
GLP-1 agents may be given at any of the injection sites as the
pharmacokinetics do not appear to be site-specific. (87) A1
Needles used to inject GLP-1 agents should preferably be used only once. (61)
A2

Needle Length

The goal of injections with insulin/ GLP-1 agents/amylin agonist is to reliably
deliver the medication into the SC space, without leakage and with minimal pain or
discomfort. Choosing an appropriate needle length is critical to accomplishing this
goal. Several studies have confirmed equal efficacy and safety/tolerability, with
shorter-length needles (5 and 6 mm), as with 8mm and 12.7 mm needles. The
decision as to needle length is an individual decision made conjointly by the patient
and his/her health care provider based on multiple factors, including physical,
pharmacologic and psychological. (85, 89) A1


Children and Adolescents

15
Needle anxiety is common among younger patients and other care givers,
especially at the beginning of therapy, and should be carefully addressed. (19)
A1
Appropriate needle length is critical in children and adolescents to avoid IM
injections, which can be painful, worsen diabetes management, contribute to
high glucose variability and, at times, provoke serious hypoglycemia. (73, 90, 91)
A1
SC tissue patterns are virtually the same in both sexes until puberty, after which
girls gain relatively more adipose mass than boys. Hence boys may be at a
higher long-term risk of IM injections. (73, 90, 92) A1
The increasing prevalence of obesity in children is an additional parameter to
take into account. (93) A1
Children and adolescents should use a 5 or 6 mm needle and should lift a skin
fold with each injection. (9, 70, 73, 90, 92, 94-97) A1
Further studies need to be performed with 4 mm needles before any
recommendations can be made regarding this length. (9) C3
There is evidence that injections at 45 degrees with the 6 mm needle is effective.
(94) A1
There is no medical reason for recommending needles longer than 6 mm for
children and adolescents. (98) C3
If children only have an 8 mm needle available (as is currently the case with
syringe users), they should lift a skin fold. Other options are to use needle
shorteners (where available) or use the buttocks in lean children or adolescents.
(90, 98, 99) A1
With a lifted skin fold the needle may penetrate at a 90 degree angle to the plane
of the skin surface at the point of injection but still be at a 45 degree angle to the
plane of the limb or abdominal surface. See Figure 2:

16

Avoid compressing or indenting the skin during the injection, as the needle may
penetrate deeper than intended and go into muscle.
Injections with 5 or 6mm needles should be performed at 90 degrees to the skin
surface and those with 8mm, at 45 degrees.
Arms should be used for injections only if a skin fold has been lifted.
It is not recommended that arms be used by patients who self-inject since lifting
a skin fold and injecting at the same time is not feasible.
Patients and/or parents who inject should demonstrate their injection technique
to the HCP.
Use of indwelling catheters and injection ports (e.g. Insuflon

, I-port

) at the
beginning of therapy can help reduce injection pain and this may improve
adherence to multiple daily insulin regimens. (100-104) A1


Adults

The thickness of SC tissue varies by gender, body site and BMI of the patient,
whereas the thickness of the skin varies minimally. Figure 3 summarizes some
observations on SC thickness in men and women, showing that SC fat tissue
may be thin in commonly used injection sites. Means are in bold numbers and
ranges in parenthesis. (39, 105-109) A1

17

Finding the appropriate needle length for each individual patient is critical to
ensuring SC injections and avoiding IM injections. (13) A1
5 and 6 mm needles may be used by any patient including obese ones; they will
provide equivalent glycemic control compared to 8 mm and 12.7 mm needles. (9,
63, 110, 112, 113) A1
There is no evidence to date of significant leakage of insulin, increased pain,
worsened diabetes management or other complications when using shorter (5-6
mm) needles. (9, 63, 110, 114) A1
Patients should be made aware that there are longer needle lengths available but
initial therapy should begin with the shorter lengths. (115) B2
Injections with shorter needles can be performed in adults at 90 degrees to the
skin surface. (9, 63, 110, 112, 113) A1
There is no medical reason for recommending needles > 8 mm. (99, 116) B2
Lifting a skin fold and/or injecting at a 45-degree angle are especially important
in slim or normal weight patients and in those injecting into the limbs or into
slim abdomens, particularly when using needles 8 mm. (110, 115, 117) A2
Needle length and general injecting technique should be evaluated every year for
patients with suboptimal glucose control.
18
Current needle lengths in infusion sets for Continuous Subcutaneous Insulin
Infusion (CCSI) vary from 6-9 mm (generally used at 90 degrees) to 13 or 17 mm
(generally used at 45 degrees).

Skin Folds

Skin folds are essential when the distance from skin surface to the muscle is
less than the length of the needle.
Lifting a skin fold is an easy and effective means for ensuring SC injections.
All patients should be taught the correct technique for lifting a skin fold from
the onset of insulin therapy.
A proper skin fold is made with the thumb and index finger (possibly with
the addition of the middle finger).
Lifting the skin by using the whole hand risks lifting muscle with the SC
tissue and can lead to IM injections.
Figure 4 shows correct (left) and incorrect (right) ways of performing the
skin fold. (105) A2

The skin fold should not be squeezed so tightly that it causes skin blanching
or pain.
19
Lifting a skin fold in the abdomen and thigh is relatively easy (except in very
obese tense abdomens), but it is more difficult to do in the buttocks (where it
is rarely needed) and is virtually impossible (for patients who self-inject) to
perform properly in the arm.
The optimal sequence should be: 1) make skin fold; 2) inject insulin slowly;
3) leave the needle in the skin for 10 seconds (when injecting with a pen); 4)
withdraw needle from the skin; 5) release skin fold; 6) dispose of used needle
safely.

Lipohypertrophy

Diagnosis and Consequences

Lipohypertrophy is a thickened, rubbery lesion that appears in the SC
tissue of injecting sites in up to half of patients who inject insulin. In some
patients the lesions can be hard or scar-like. (118, 119) A1
Detection of lipohypertrophy requires both visualization and palpation of
injecting sites, as some lesions can be more easily felt than seen. (33) A1
Making two ink marks at opposite edges of the lipohypertrophy (at the
junctions between normal and rubbery tissue) will allow the lesion to be
measured, recorded, and followed long-term.
If visible, the lipohypertrophy can also be photographed for the same
purpose (see Figure 5).
Figure 5 illustrates visible lipohypertrophy in a woman who had injected in
the same two locations below the umbilicus for twelve years. Figure 6
illustrates the detection of palpable lipohypertrophy by comparing a fold of
normal skin (arrow tips close together) with lipohypertrophic tissue (arrow
tips spread apart). Normal skin can be pinched tightly together, while
lipohypertrophic lesions cannot. (120)

20

Figure 5: Two visible lipohypertrophic lesions below the umbilicus; many lesions
are smaller than these.


Figure 6: The different pinch characteristics of normal (left) versus
lipohypertrophic (right) tissue.


Both pen and syringe devices (and all needle lengths and gauges) have been
associated with lipohypertrophy as well as insulin pump cannulae (when
repeatedly inserted into the same location).
Patients should not inject into areas of lipohypertrophy since insulin
absorption can be delayed or made erratic, potentially worsening diabetes
management. (15, 121-123) A1
Injections into lipohypertrophy may also worsen the hypertrophy.
21
Additionally patients should be informed of the benefits of avoiding
lipohypertrophy: less variability of blood glucose, better control of HbA1c,
fewer hypoglycemias and improved cosmetic/aesthetic outcome.

Prevention

No randomized, prospective studies have been published establishing
causative factors in lipohypertrophy. (124)
Published observations support an association between the presence of
lipohypertrophy and the use of older, less pure insulin formulations, failure
to rotate sites, using small injecting zones, repeatedly injecting into the same
location and reusing needles. (3, 44, 121, 125) A1
Sites should be inspected by the HCP at every visit, especially if
lipohypertrophy is already present. At a minimum each site should be
inspected annually (preferably at each visit in pediatric patients). (33) A2
Patients should be taught to inspect their own sites and should be given
training in how to detect lipohypertrophy. (33, 126) A2
Use of a lipo model (in which patients can feel typical lesions) may facilitate
this learning.
Group sessions where patients share information about lipohypertrophy are
usually very helpful.

Therapy and Follow Up

The best current therapeutic strategies for lipohypertrophy include use of
purified human insulins, rotation of injection sites with each injection, using
larger injecting zones and non-reuse of needles. (125, 127-130) A2
Injections should be avoided in hypertrophic areas until the abnormal tissue
returns to normal (which can take months to years). (131, 132) A2
22
Switching injections from lipohypertrophic to normal tissue usually requires
a readjustment of the dose of insulin injected. The amount of change varies
from one individual to another and should be guided by frequent blood
glucose measurements. (121, 132) A2
Use of monitoring tools (e.g. Diabetes Management software or written
diaries) can help patients directly see the metabolic advantages of not
injecting into lipohypertrophy and thus will reinforce adherence. (121) A2

Rotation of Injecting Sites

Many studies show that to safeguard normal tissue one must properly and
consistently rotate sites. (46, 133, 134) A1
Patients should be taught an easy-to-follow rotation scheme from the onset of
injection therapy. (135, 136) A1
One scheme with proven effectiveness involves dividing the injection site into
quadrants (or halves when using the thighs or buttocks), using one quadrant per
week and moving always clockwise, as shown by figures below. (137)






Figure 7: Abdominal rotation pattern by quadrants

Figure 8: Thigh and Buttocks rotational pattern by halves
23
Injections within any quadrant or half should be spaced at least 1cm from each
other in order to avoid repeat tissue trauma. Pump cannulae should be placed
at least 3cm away from previous sites.
HCP should verify that the rotation scheme is being followed at each visit and
give help and advice where needed.

Bleeding and Bruising

Needles will on occasion hit a blood vessel on injection, producing bleeding or
bruising. (138)
Figure 9 shows the blood vessel distribution in the dermis and SC layers.




Changing the needle length or other injecting parameters does not appear to
alter the frequency of bleeding or bruising, (138) although one study (139)
does suggest that these may be less frequent with the 5 mm needle.
24
Bleeding or bruising does not appear to have adverse clinical consequences
for the absorption of insulin or for overall diabetes management.

Pregnancy

More studies are needed to clarify injecting issues in pregnancy. In the absence of
these studies it seems reasonable to recommend that:
Pregnant women with diabetes (of any type) who continue to inject into the
abdomen should give all injections using a raised skin fold. (140) B2
Use of routine fetal ultrasonography presents the HCP with an opportunity of
assessing SC abdominal fat and of making data-based recommendations
regarding injections. (140) B2
Avoid using abdominal sites around the umbilicus during the last trimester. C3
Injections into abdominal flanks may still be used with a raised skin fold. C3

Intra-dermal Injections

The epidermal-dermal thickness ranges from ~1.2-3.0 mm at all the usual
injecting sites, therefore the proper use of 5 and 6 mm needles does not risk
accidentally injecting into the dermis. (141-145) A2
In the future, the intra-dermal space may be a target for injections but until
further study is done its use is not recommended. (30) C3

Safety Needles

Needlestick injuries are common among HCP with most studies showing
significant under-reporting for a variety of reasons. (146)
Safety needles could effectively protect against such injuries and should be
recommended whenever there is a risk of a contaminated needle stick injury (e.g.
in hospital). (147) B1
25
Considerable education and training are needed to ensure that currently
available safety needles are used properly and effectively. (147, 148) A1
Safety features of these needles should be made as intuitive as possible and their
mechanisms should be incorporated automatically into the routine use of the
device.
When insulin is administered in the hospital, through-and-through needle stick
injury is the more common mechanism of injury. This is particularly a risk
when HCPs give injections into a lifted skin fold on the arm.
Since most safety mechanisms would not protect against such injuries, the use of
shorter needles without a skin fold may be more appropriate in adults until
other safety mechanisms are available.
If needle length is such that IM injury would be a risk, using a 45 degree angle
approach (rather than a skin fold) may be a safer approach.

Disposal of injecting material

Every country has its own regulations regarding the discarding and disposal of
contaminated biologic waste. Both HCPs and patients should be aware of these
regulations. (48) A3
Legal and societal consequences of non-adherence should be reviewed.
Proper disposal should be taught to patients from the beginning of injection
therapy and reinforced throughout. (149) A2
Where available, a needle clipping device should be used. It can be carried in
the patient kit and used multiple times before discarding.
Options for discarding a used needle, in order of preference, are: 1) in a
container especially made for used needles/syringes; 2) if not available, into
another puncture-proof container such as a plastic bottle.
Options for final disposal of the container, in order of preference, are to take it:
1) to a Health Care facility (e.g. hospital); 2) to another Health Care provider
(e.g. laboratory, pharmacist, doctors office).
26
Under no circumstance should sharps material be disposed of into the normal
(public) trash or rubbish system.
Potential adverse events to the patients family (e.g. needlestick injuries to
children) as well as to service providers (e.g. rubbish collectors and cleaners)
should be explained.
All stakeholders (patients, HCPs, pharmacists, community officials and
manufacturers) bear a responsibility (both professional and financial) in
ensuring proper disposal of used sharps.

Discussion

In this paper we have attempted to update and extend the injecting recommendations
already available for patients with diabetes. In Appendix 2 we provide selected verbatim
extracts from four previous sets of guidelines. The new recommendations cover many
new areas for which no previous recommendations were available: insulin analogues
(rapid- and slow-acting), GLP-1 injectables, pregnancy, intra-dermal injections and safety
needles. We have given more detailed recommendations on topics which, though
addressed earlier, still lacked specificity: lipohypertrophy, pediatrics, pens, disposal of
injecting material and education. And we have tried to simplify the rules for choosing an
appropriate length of needle for the patient.

We have not included an extensive review of the literature within each section of the new
recommendations. They are meant for use by primary care HCPs and are to be read by
patients and their families themselves. Hence we felt reference numbers, grading systems
and literature exposes would be distracting. Nevertheless, we do feel it is appropriate
here to engage with selected publications which were seminal to the recommendations.

Insulin analogues (rapid-acting)

27
The first indication that analogues might behave differently from conventional insulins
came when Rave (69) confirmed that in IM injections of soluble (Regular) insulin the
metabolic activity peaks more rapidly than with SC administration but that the metabolic
effect of insulin Lispro (Humalog) was similar with either route. The time-action
profile of IM-injected soluble insulin thus lies somewhere between that of SC soluble
insulin and insulin Lispro.

In a euglycemic clamp study Mudaliar (68) showed that with injected Aspart (Novolog),
a fast-acting analog of human insulin, the maximum glucose infusion rate was greater and
occurred at an earlier time than regular insulin regardless of the injection site.
Importantly, the absorption of Aspart was just as fast from the thigh as it was from the
abdomen.

Insulin analogues (slow-acting)

Owens (75) showed, using radioactive glargine (Lantus), there were no significant
differences in its absorption amongst the three classic injection sites: arm, leg, and
abdomen. The T
75%
was 11.9, 15.3, and 13.2 hours for arm, leg, and abdomen,
respectively. There were also no differences in residual radioactivity at 24 h. His study
however only involved twelve healthy subjects and a difference might have been seen
had the sample been larger.

Detemir (Levemir) also appears to have different absorption characteristics than other
conventional slow-acting insulins. Reports from the manufacturer suggest that
absorption of detemir may be higher when administered in the abdomen or deltoid than in
the thigh, but more studies are needed..

Lipohypertrophy

De Villiers (129) showed that lipohypertrophy had an overall prevalence rate of 52% in
their pediatric center and was related to patients injecting the same site day after day.
28
The study also found that lipohypertrophy affects the rate of absorption of the insulin.
Their paper recommends that sites should be palpated and not just visually examined.
Patients also need to be educated so that they can avoid lipohypertrophy and re-educated
whenever the problem has already occurred

Vardar and Kizilci (128) found that the risk factors for lipohypertrophy included the
length of time insulin had been used (p=0.001), not rotating injection sites (p=0.004) and
not changing the needle with each injection (p=0.004).

Johansson (150) has shown that aspart (Novolog, NovoRapid

) has 25% lower

maximum concentrations when injected into lipohypertrophic lesions.

More recently, Overland (151) used continuous glucose monitoring for 72 hours to assess
pharmacokinetics and pharmacodynamics following injection of insulin specifically into
lipohypertrophic or normal areas, in eight type 1 patients. They found no significant
differences in both insulin levels and blood glucose, in this randomized, cross-over study,
and concluded that the effects of lipos on insulin absorption and action were small,
compared to the larger variability of insulin uptake with SC injection. These results are
somewhat surprising and warrant further evaluation.

Insulin Needle Length

In a series of 91 normal-weight diabetic patients undergoing computer tomography
scanning, Frid and Linde (152) have shown that the median distance from the skin to the
muscle fascia in the upper lateral quadrant of the thigh (a key insulin injection site) is
7mm in men and 14mm in women. In 91% of the men and 48% of the women, a 12.7mm
needle enters the muscle in this area if the injection is performed perpendicular to the
skin without lifting a skinfold. Twenty-eight percent of the women and 44% of the men
have less than 12.7mm of subcutanous fat lateral to the umbilicus, the area of maximal fat
in the abdomen. Moreover, the fat cushion tapers rapidly when moving further laterally,
29
even in obese individuals, making the flanks an area of greater potential for intra-
muscular insulin injections due to thin SC layers.

In 2006, after a decade of clinical use of shorter needles Frid (70) concluded that 5 and 6
mm needles may very well be our standard needles, especially since leakage of insulin
does not appear to be a problem. He also stated that the rule of injecting into a pinched
skinfold applies also to these needles. Similarly in 2007 Kreugel (139) showed that 5mm
needles are associated with unchanged HbA1C levels, unchanged hypo events and
reduced discomfort for patients compared with 8 or 12mm needles, although this study
was weakened by a relatively high rate of patient drop-out. In their more recent study
(114), InObese, 126 of 130 enrolled insulin-taking obese (BMI 30 kg/m
2
)

diabetic
patients completed a two-period cross-over trial comparing 5mm and 8 mm needles.
HbA1c levels did not differ between the two periods, and there were little, if any
differences in patient-reported bleeding, bruising, leakage, and pain. A slightly higher
proportion of patients preferred the shorter, 5 mm needle.

In 2004, Schwartz (153) published that 31 G x 6mm vs 29 G x 12.7mm gave comparable
HbA1c values, double-blind pain and leakage scores and equal convenience and ease of
use. Patients however preferred the 6mm needle. In 2007, Hofman et al showed that 8-
and 12.7-mm needle lengths used in children result in an unacceptably high rate of IM
injections. He proved that an angled 6-mm needle results in very consistent deposition in
SC fat.

In 2008, Birkebaek (9) showed that in lean patients using doses <40 IU, a 4-mm needle
reduces the risk of IM injections without increasing the amount of leakage of insulin to
the skin surface. He concluded that most patients can inject with a 4-mm needle without
a pinch-up at 90 in the thigh. When using a 6-mm needle in such patients, the authors
propose injecting in a skinfold with a 45 angle.

30
In Appendix 2 we include two tables already published on needle length. (5, 6) Why
have we felt the need to introduce our own recommendations in this regard? Are not the
Dutch and Danish versions (Tables 1, 2) sufficiently clear and comprehensive?

Our recommendations and the two tables are in substantial agreement. However, we
believe our approach is an even simpler and more clinically-useful approach. Unlike the
Dutch and Danish versions we have eliminated both the BMI and injection angle
components. The BMI may not be known at the time of the visit; it may change during
the course of therapy; and it can be misleading, as in patients with android obesity. The
injection angle is rarely a perfect 45 or 90 degrees and may change according to the
injection site the patient uses, the use or not of a pinch-up and the visual perception of the
patient or observer.

Instead of using these imperfect measures, we first divide patients into their most
straightforward and self-evident groups: children, adolescents and adults. Next we ask if
they are in the habit of raising a skin fold or not, regardless of the injection site. If the
answer is no we direct the patient onto shorter (<8 mm) needles. This is the only means
of protection from IM injections in those recalcitrant to skin folds. We do not try to
change behavior either in terms of starting them on pinching up or switching their
injections to other (more fat-endowed) sites. The compliance record on such behavioral
change is poor.

The next question is what length are you using now? If they are using a needle longer
than 8mm and there are no clinically-evident problems (e.g. unexplained glucose
instability, a history of IM injections) then we have no objection to continuing on that
needle length except that we encourage them to adopt a skin fold for added safety. Still,
for patients starting on insulin we see no clinical reason for recommending a needle
>8mm long.

All other patients are directed to use a needle <8mm if they are children or adolescents or
8mm if they are adults. We believe this drive to shorter needles is in the patients best
31
interest and has not been shown to come at any clinical price. We also believe that
raising a skin fold should become a habit used by most if not all patients. It is a cost-
effective (free!) guarantee against IM injections. Hence we encourage its use even with
shorter needles, since some very thin people and children have very little SC fat in
commonly-used injecting sites. However this is not as evidence-based as other
recommendations in our paper, and most patients are able to inject safely with shorter
needles without raising a skin fold.

Despite the fact that some experimentation and study of 4mm needles has begun, we did
not think that there was enough published data as yet to make clear recommendations
regarding its usage. Initial studies have not shown any adverse events related to their use.
It is clear that the greatest trial and publishing experience with shorter needles has been
with the 5mm needle. However many, if not most, of the conclusions about the 5mm can
be extrapolated to the 4 and 6mm needles. Manufacturing variances with the short
needles now on the market mean that a significant number of injections already made
with these needles are at depths less than 5mm. There is now conclusive evidence that
these shorter needles have been proven safe and efficacious, provide numerous improved
clinical outcomes and achieve higher patient preference.

Pediatrics

Smith (154) measured the distance from skin to muscle fascia in children and adolescents,
using ultrasonography, at injection sites on the outer arm, anterior and lateral thigh,
abdomen, buttock and calf. Distances were greater in girls (n = 15) than in boys (n = 17).
In most boys the distances were less than the length of the standard needle (12.7mm) at
all sites except the buttock, but in most girls, the distances were greater than 12.7mm
except over the calf. In the abdomen, the distance from skin to peritoneum was less than
12.7mm in 14 of the 17 boys but only in one of the 15 girls. The measurements in the
abdomen were done where fat tissue depth is the greatest, near the umbilicus. Their
findings raise serious concerns over the risk of intra-muscular and even intra-peritoneal
32
injections in certain pediatric populations. In these and perhaps other populations,
needles which are shorter than those previously provided to the market are clearly needed.

The first study of the 5mm needle in children compared it, using a non-pinched approach,
to the 8mm pen needle using a pinch-up (the recommended technique with this needle).
(96) Fifteen normal-weight children and adolescents (7 to 17 years old) with Type 1
diabetes seen in the out-patient service of Hpital Robert Debr in Paris used, in a
randomized study, either the 30 Gauge 8mm pen needle with a pinch-up or the 31 Gauge
5mm pen needle, also with a pinch up for 60 days. At the end of this period they were
crossed over to the other needle for another 60 days. HbA1c levels were measured at
baseline, cross over point and study termination. Hypoglycemic events, bleeding at
puncture site, leakage of insulin, pain of injection and patient satisfaction were also
assessed.

There were no significant changes in HbA1c levels (p=0.59). The pain of injection was
rated by the children to be significantly lower with the 5mm needle (1.2 1.1 vs. 4.22.6
on a 10-point scale, p=0.001) and there were fewer hypoglycemic events during the
period in which the 5mm needle was used (p=0.05). There were no differences in
leakage or bleeding at the injection site. The children clearly preferred the 5mm over the
8mm on subsequent questioning.

This study (96) did not image the injection site with ultrasound; therefore the frequency
of intra-dermal injection is unknown. However, the fact that HbA1c levels remained
unchanged suggests that intra-dermal deposition of insulin, if it occurred, had no effect
from a clinical perspective. The improvement in hypoglycemic events may have been a
chance observation, or could have been a result of fewer intra-muscular injections; the
pain and preference advantages of the 5mm needle may have positive effects on well-
being and compliance in pediatric populations.

GLP-1 agents

33
In a recent study, Calara (87) has shown that in Type 2 patients, SC administration of
exenatide into the abdomen, arm, or thigh resulted in comparable bioavailability. It thus
appears that patients treated with exenatide have the option of rotating injection sites
from the arm to the abdomen or to the thigh. More work is clearly needed to elucidate
the optimal injection techniques with GLP-1 agents.

Intra-dermal Injections

Heinemann (30) gave ten healthy male volunteers 10 IU insulin lispro (Humalog) SC
on study day 1 and the same dose intradermally the next day. Intradermal injections were
given via three different microneedles lengths: 1.25, 1.5 and 1.75 mm. Results showed
that the relative bioavailability (147,155, 150%) and effect on glucose disposition (142,
137, 124%) of intradermal Lispro were higher than with SC. There were significant
reductions in the time to Cmax and other pharmacokinetic indices with ID vs SC
injection of Lispro.

In a study of men versus women, Caucasians vs. Asians vs. Africans and across a range
of ages (18-70 yrs) and BMI values (18-30 kg/m
2
) Laurent (141) showed that skin
thickness varies less across these parameters than between different body sites. While
skin at the thigh was very close to 1.5mm in all subgroups considered, it was between 1.8
and 2.7mm at the other three body sites (deltoid, suprascapular, waist).

Several hypothetical concerns have been raised with regard to intra-dermal insulin
administration. Such practices could lead to increased reflux and loss of insulin from the
puncture site due to proximity of the depot to the skin surface or increased immune
response to insulin due to lymphocyte and other immune cell surveillance of the dermis.
However these concerns remain purely speculative at this point and further study is called
for.

Conclusion

34
Using shorter needles and lifting a skin fold give patients significant benefits without side
effects. We encourage more study on the optimal injection techniques for GLP-1
mimetic agents and strongly advise insulin makers to include a study of appropriate
injection technique in their Phase 2 and 3 trials of any new analogues planned for launch.
In dozens of papers on the new analogues, no data were provided on where and how they
should be injected. This does not provide optimal service to patients and their care givers.

We encourage more and better studies in pediatric, obese and pregnant subjects. We also
look forward to the day when we understand the etiology of lipohypertrophy and can
identify at-risk patients before they develop it. Only then can we adopt the appropriate
preventative strategies.

We do not pretend that this is the final version of injecting guidelines. We would be
disappointed if these recommendations were not revised and updated in a few short years
based on new studies and pertinent observations.

Duality of interest:

All authors are members of the Scientific Advisory Board (SAB) for the Third Injection Technique
Workshop in Athens (TITAN). TITAN and this Injection Technique Survey were sponsored by BD, a
manufacturer of injecting devices, and SAB members received an honorarium from BD for their
participation on the SAB; KS, LH and CL are employees of BD.

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muscular insulin injections. Archives of Disease in Childhood, 66:879-882, 1991.

44
Appendix 1: Attendees at TITAN

FAMILY NAME FIRST NAME COUNTRY
Amaya Baro Mara Luisa Spain
Annersten Gershater Magdalena Sweden
Bailey Tim USA
Barcos Isabelle France
Barron Carol Ireland
Basi Manraj UK
Berard Lori Canada
Brunnberg-Sundmark Mia Nordic
Burmiston Sheila UK
Busata-Drayton Isabelle UK
Caron Rudi Belgium
Celik Selda Turkey
Cetin Lydia Germany
Cheng, RN BSN Winnie MW Hong Kong
Chernikova Natalia Russia
Childs Belinda USA
Chobert-Bakouline Marine France
Christopoulou Martha Greece
Ciani Tania Italy
Cocoman Angela Ireland
Cureu Birgit Germany
Cypress Marjorie USA
Davidson Jamie USA
De Coninck Carina Belgium
Deml Angelika Germany
Dimo Lucile France
Disoteo Olga Eugenia Italy
Dones Gianluigi Italy
Drobinski Evelyn Germany
Dupuy Olivier France
Empacher Gudrun Germany
Engdal Larsen Mona Denmark
Engstrom Lars Sweden
Faber - Wildeboer Anita Netherlands
Finn Eileen USA
Frid Anders Sweden
Gabbay Robert USA
Gallego Rosa Mara Portugal
Gaspar La Fuente Ruth Spain
Gedikli Hikmet Turkey
Gibney Michael USA
45
Giely-Eloi Corinne France
Gil-Zorzo Esther Spain
Gonzalez Amparo USA
Gonzlez Bueso Carmen Spain
Grieco Gabreilla Italy
Gu Min-Jeong South Korea
Guo Xiaohui China
Guzman Susan USA
Hanas Ragnar Sweden
Hrm-Rodriquez Sari Finland
Hellenkamp Annegret Germany
Hensbergen Jacoba Fijtje Netherlands
Hicks Debbie UK
Hirsch Laurence USA
Hu Renming China
Jain Sunil M. India
King Laila UK
Kirketerp-Nielsen Grete Denmark
Kirkland Fiona UK
Kizilci Sevgi Turkey
Kreugel Gillian Netherlands
Kyne-Grzebalski Deirdre UK
Lamkanfi Farida Belgium
Langill Ed Canada
Laurent Philippe France
Le Floch Jean-Pierre France
Letondeur Corinne France
Losurdo Francesco Italy
Doukas
Loukas Greece
Lozano del Hoyo Mara Luisa Spain
Marjeta Anne Finland
Marleix Daniel France
Matter Dominique France
Mayorov Alexander Russia
Millet Thierry France
Mkrtumyan Ashot Russia
Navailles Marie Christine France
Nerantzi Afroditi Greece
Nhlen Ulrich Germany
Ochotta Isabella Germany
Osterbrink Brigitte Germany
Pasaporte Francis Philippines
Pastori Silvana Italy
Penalba Martnez Mara Teresa Spain
Pizzolato Pia USA
46
Pledger Julia UK
Riis Mette Denmark
Robert Jean-Jacques France
Rodriguez Jose-Juan Spain
Roggemans Marie-Paule Belgium
Rhrig Brbel Germany
Sachon Claude France
Saltiel-Berzin Rita USA
Sauvanet Jean-Pierre France
Schinz-Schweizer Regula Switzerland
Schmeisl Gerhard-W. Germany
Schulze Gabriele Germany
Sellar Carol UK
Sghaier Rida France
Shanchev Andrey Russia
Shera A. Samad Parkistan
Simonen Ritva Finland
Slover Robert USA
Snel Yvonne Netherlands
Sokolowska Urszula Russia
Harbuwuno Dante Saksono Indonesia
Starkman Harold USA
Strauss Ken Belgium
Sundaram Annamalai India
Svarrer Jakobsen Marianne Denmark
Svetic Cisic Rosana Croatia
Swenson Kris USA
Tharby Linda USA
Thymelli Ioanna Greece
Tomioka Miwako Japan
Tubiana-Rufi Nadia France
Tuttle Ryan USA
Vquez Jimnez Mara del Mar Spain
Vieillescazes Pierre France
Vorstermans Mia
Netherlands
Weber Siegfried Germany
Webster Amanda UK
Wisher Ann Maria UK
Wulff Pedersen Malene Denmark
Yan Wang Yvonne China
Yu Neng-Chun Taiwan


47
Appendix 2: Key Extracts from Previously Published Guidelines

Previously published guidelines are either in full agreement with or are otherwise complementary to the
above recommendations. We will quote selected passages from these guidelines in order to reinforce the
recommendations as well as to round off any uncovered themes. We will not include here a complete
literature review of the supporting documents for these guidelines. The reader is referred to the extensive
bibliography attached to each set as well as the excellent summaries of key studies found therein.

Target tissue for injected insulin

First Workshop: For everyday use in most patients, subcutaneous rather than intramuscular,
intraperitoneal or intradermal injection of insulin is preferred.
Danish Guidelines: The subcutaneous adipose tissue on the thigh is recommended as the preferred
injection site for intermediate-acting insulin (e.g. Insulatard, Humulin NPH and Insuman basal) and slow-
acting insulin analogues (e.g. Levemir and Lantus). For peoplewho cannot use the thighthe hip can be
used instead.
Dutch Guidelines: Insulin should be administered into the subcutaneous fatty tissue. Do not massage
the skin after the injection.

Optimal injection site for specific insulins

First Workshop: NPH, lente and ultra-lente when given anytime alone or when given in the afternoon
or evening in combination with fast-acting insulin should be injected into the thigh or buttocks to achieve
longest and most stable activity. Rapid-acting insulin (regular and LysPro) when given anytime alone or
when given in the morning in combination with NPH (or lente or ultra-lente) should be given in the
abdomen for fastest action.
Danish Guidelines: The abdomen isthe preferred injection site for rapid-acting insulin and insulin
analogues. The injection areas should be within approximately 12 cm on both sides of the navel and
approximately 4 cm below the navel, because the subcutaneous adipose tissue is much thinner further away
from the navel. It is also easy to lift a skin fold in these areas.
Dutch Guidelines: The fastest absorption of insulin takes place in the abdomen, followed by the upper
arms, the thighs and the buttocks. The abdomen is the preferred site for the administration of insulin when
rapid action is desired, such as the mealtime dose of insulin. The buttocks are the preferred site for the
administration of insulin when slow action is required.
48

Injections into the Arm

Danish Guidelines: The upper arm is not recommended as an injection site for insulin, because there
is often only minimal distance from skin to muscle.
Dutch Guidelines: The upper arm is not a recommended injection site because of the heightened risk
of intramuscular injection.

Pinching up a Skin fold

First Workshop: Pinching up the skin is one method that has been documented by CT scan and
ultrasonography to increase the chance of subcutaneous injection. If one performs a pinch up it should be
made with 2 fingers (thumb and index). The fold should be maintained throughout the injection, and 5-10
seconds afterwards, before removing the needle. Pinching up should used by all when injecting into the
thigh or arm, when using needles longer than 8mm and when the patient is a child or slim adult.
Danish Guidelines: Normal-weight individuals are recommended to inject into a lifted skin fold. If
the patient is used to a 12-mm needle, and for whatever reason it is decided that he or she should continue
with a 12-mm needle, injection should always be into a lifted skin fold at an angle of 45 degrees due to the
risk of intramuscular injection.
Dutch Guidelines: When using 5-6 mm pen needles, the pen needle can be inserted vertically and
without skin fold. When using >8mm pen needles a skin fold should preferably be lifted before the pen
needle is inserted. There is no effect on the diabetes regulation of injecting a skin fold with a longer pen
needle compared with injecting vertically with a shorter pen needle.

Prevention and Treatment of Lipodystrophy

Second Workshop: Strategies in clinical practice include extensive use of rotation grids to ensure a
clear separation of injections, the use of videotapes to teach patients how to avoid lipodystrophy and the
signing of an agreement with patients to ensure serious follow through.
Danish Guidelines: Ensure that the new injection site is at least three centimeters from the previous
injection site.
Dutch Guidelines: It is important to rotate within the same body part in order to prevent
lipodystrophyeach injection must be at least 1 cm away from the previous site. An individual rotation
plan can help the patient to follow the advice about rotation.
49

NPH insulin re-suspension in pens

Second Workshop: Vials and cartridges should be rolled and tipped 10-20 cycles. Store pens
containing NPH currently being used at room temperature, rather than in the refrigerator, as re-suspension
is easier at higher temperatures.
Dutch Guidelines: Mix cloudy insulin thoroughly until a consistent white emulsion appears by
swinging back and forth at least 10 times. When there are less than 12 IU of cloudy insulin use a new pen
(cartridge).

Education regarding Insulin Injection Techniques

Second Workshop: HCPs should demonstrate injections on themselves when teaching patients.
HCPs should be tested as to their ability to find and correctly identify lipohypertrophy. The Internet and
other tele-medicine tools should be used.

Use of Imaging Technologies

Second Workshop: Ultrasound should be considered a tool for assessing selected patients fat
thickness in key injection areas both at the beginning of insulin therapy and when major body habitus
changes have taken place. MRI should be used to assess the performance of the shorter needles proposed
for the market as well as the effects of ID injections and of jet injectors.

Intra-muscular Injection Risks

Dutch Guidelines: Insulin must not be administered too deeply, i.e. intramuscularly. (This can lead
to)less well predictable action and possibly also the risk of hypoglycaemias.

Intra-dermal Injection Risks

50
Danish Guidelines: Intracutaneous injection may give rise to greater insulin leakage due to the short
distance to the surface of the skin and perhaps more pain due to direct nerve stimulation.
Dutch Guidelines: Insulin must preferably not be administered too shallowly, i.e. not into the
epidermis or the dermis. (This)can lead to leakage and consequent under-dosing and skin damage.

Same insulin, same site

Danish Guidelines: Insulin injections should be performed at the same time every day and within the
same anatomic area to ensure uniform insulin absorption. Rotation within the same anatomical area
reduces variations in blood glucose levels.

Inspection of Injection Sites by HCP

Dutch Guidelines: the skin should be checked at least once per year. When skin damage is found to
be present this check must be done more frequently and the patient must be instructed about and given
advice on other injection sites, the importance of systematic rotation, the importance of once-only use of
pen needles and the chance of a possible reduction in the need for insulin.

Maximum one-time doses

Danish Guidelines: When you need to administer more than 40 IU of insulin at a time, the dose is
divided into two injections.
Dutch Guidelines: split the dose whengreater than 50 IU insulin. A larger dose of insulin slows
the insulin absorption and the subcutaneous administration of a volume above 50 IU gives more pain and
leakage.

Dwell time of needle

Danish Guidelines: Inject the insulin and release the skin fold at the same time as drawing the needle
halfway out. Count to at least 10 (equivalent to 10 seconds) before withdrawing the needle completely.
Dutch Guidelines: The pen needle should preferably be left in the skin for 10 seconds or longer after
the administration of insulin to minimize any leakage of insulin.

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Needle Reuse

Danish Guidelines: The needles are disposable and it is therefore recommended that they be used only
once.
Dutch Guidelines: Pen needles must be use only once except when the dose of insulin has to be split
into two or more portions. Pen needles are manufactured for once-only use, become blunter on re-use
which can result in the injection becoming more painful and the skin becoming damaged faster. The
benefits of re-use, such as lower costs and the possible ease of use for patients are also described in the
literature. In the literature no opinion has been offered about a responsible frequency of re-use of the pen
needle. The chance of infections does not seem to be affected by re-use. After weighing up the advantages
and disadvantages the work group advised once-only use of pen needles.

Pen needles left on Pens

Danish Guidelines: It is recommended that needles always be removed immediately after the injection
when using NPH insulin or mixtures containing NPH insulin. This is done to avoid leakage of solvent
(fluid) through the needle, which can gradually cause the concentration of insulin in the remaining mixture
to increase.
Dutch Guidelines: Remove pen needle from the insulin pen immediately after the injection. Reasons
for doing so are mainly to prevent leakage of insulin from the pen cartridge and to prevent air entering the
pen cartridge.

Priming Pens

Danish Guidelines: (The pens function should be) checked. This is done by allowing a drop of
insulin to appear at the tip of the needle (follow the guidelines for the various pen systems). If no insulin
appears at the tip of the needle, repeat the procedure.
Dutch Guidelines: Before each injection 2 IU air shot of insulin (should be made) with the pen needle
directed upwardsrepeat this until insulin comes out of the pen needle.

Cleaning before Injection

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Danish Guidelines: Swab the skin with spirit before injecting the needle subcutaneously. Swabbing of
the skin prior to injection in hospital is recommended. It is recommended that at hospitals the membrane
on the insulin pen be swabbed before inserting the needle.
Dutch Guidelines: The skin must be clean and dry before an injection. The disinfection of the skin in
not necessarythe risk of infections is not reduced by doing so. This applies to both the patient in the
home setting as well as for patients in a different setting.

Disposal of Sharps

Danish Guidelines: Remove the needle and place it in an unbreakable sharps bin.

Needle length (see Tables 1 and 2 for specific Danish and Dutch Recommendations)

Dutch Guidelines: The desired length of the pen needle should preferably be individually defined in
children and adults. For children and adults who are not overweight (BMI<25) a short pen needle (8 mm)
can be used. The preference of the patient is for the shortest length of pen needles. In generaluse a pen
needle 8 mm for all children and adults. It even seems desirable to advise the use of 5-6 mm pen needles.
These are preferred by the patient and seem to have no negative effect on the diabetes regulation or leakage
of the injection site.

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Table 1: Danish Needle Length Recommendations

Patient type
Needle
length
Injection Angle Skin fold
6mm 90 degrees lifted
Normal weight
(BMI <25)
8mm 45 degrees lifted
without lifted skin
fold in abdomen 6mm

90 degrees

lifted skin fold in
thigh
8mm 90 degrees lifted
Above average
weight
(BMI >25)

12mm 45 degrees lifted


Table 2: Dutch Needle Length Recommendations

Target
group
Needle length
Insertion of
pen needle
Injection technique
Children 5-6 mm vertical With or without skin fold
5-6 mm vertical With or without skin fold
BMI <25
8 mm oblique With skin fold
5-6 mm vertical
Abdomen without skin fold, leg with
skin fold
8 mm vertical With skin fold
Adults
BMI >25
12 mm oblique With skin fold