Titan 2009

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 lsquojust shotsrsquo 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

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 (eg 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

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 lsquodownstreamrsquo 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

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

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

(eg 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

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

leakagebackflow 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

bull For the purpose of these recommendations childhood is defined as birth to

the onset of puberty

bull 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)

bull HCPs and parents fear hurting children and often transmit their own

anxieties

bull 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

bull Anticipatory fear is often worse than the actual experience of the injection

bull 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

bull 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

bull 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

bull 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

bull CBT include relaxation training guided imagery graded exposure active

behavioral rehearsal modeling and reinforcement incentive scheduling

(19) B2

Adolescents

bull For the purpose of these recommendations adolescence is defined as puberty

through 18 years of age

bull HCPs should recognize that many adolescents are reluctant to inject insulin

in front of peers

bull 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)

bull 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

bull 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

bull 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

bull Any steps which enhance their sense of control will have positive

consequences for the adolescent (eg flexible injection schedule for weekends

and holidays)

bull All patients but especially adolescents should be encouraged to express their

feelings about injecting particularly their frustrations and struggles

Adults

bull Very few adults have true needle phobia but many have anxiety about

injecting especially at the beginning of therapy (20 21)

bull Even experienced patients may view injections with a degree of regret and

loathing (22 23)

bull At the beginning of therapy the demonstration of a self-injection of saline by

the HCP can relieve patient anxiety

bull 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

bull 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)

bull Both the short-term and long-term advantages of good glucose management

should be emphasized (25)

bull 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)

bull HCPs should reflect on their own perceptions of insulin therapy and avoid

using any terms ndash even casually - which imply that such therapy is a sign of

failure a form of punishment or a threat (27 28)

bull Through culturally-appropriate metaphors pictures and stories HCPs

should show how insulin injections enhance both the duration and quality of

life (25)

bull In all age groups pen therapy may have psychological advantages over

syringe therapy (25 29)

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)

The HCP should spend time exploring patient (and other care-giversrsquo)

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

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 (eg hospital) (41) A1

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

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 (eg NPH and pre-mixed insulins) must be gently rolled

andor 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 lsquosee the insulin going inrsquo 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 leakagereflux 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

- 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

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)

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

bull There are regions of the world where significant numbers of patients still use

syringes as their primary injecting device

bull There is currently no syringe with a needle lt8mm in length due to

compatibility issues with certain insulin vial stoppers (67)

bull 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

bull There is no medical rationale to use syringes with detachable needles for

insulin injection

bull Permanently-attached needle syringes offer better dose accuracy and

reduced dead space allowing one to mix insulins if needed

bull In regions of the world where U40 insulin and U100 are still on the market

together (eg Asia Africa) careful attention must be paid to using the

appropriate syringe for each concentration

bull When drawing up insulin air equivalent to the dose needs to be drawn up

first and injected into the vial to facilitate insulin withdrawal

bull 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

bull Like pen needles syringes should preferably be used only once (3 5 6 17

43 44 59 60) A2

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

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

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 (Lantusreg)

or detemir (Levemirreg) 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

Soluble human insulins (Actrapidreg Humulinreg Regular) may have a slower

absorption profile than the rapid-acting analogs (Humalogreg Novologreg

Apidrareg)

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

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 (exeacutenatide Byettareg

liraglutide Victozareg) 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)

Needle Length The goal of injections with insulin GLP-1 agentsamylin 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 safetytolerability with

shorter-length needles (5 and 6 mm) as with 8mm and 127 mm needles The

decision as to needle length is an individual decision made conjointly by the patient

and hisher health care provider based on multiple factors including physical

pharmacologic and psychological (85 89) A1

Needle anxiety is common among younger patients and other care givers

especially at the beginning of therapy and should be carefully addressed (19)

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)

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

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 andor parents who inject should demonstrate their injection technique

to the HCP

Use of indwelling catheters and injection ports (eg Insuflonreg I-portreg) 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

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 127 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 gt 8 mm (99 116) B2

Lifting a skin fold andor 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 ge8 mm (110 115 117) A2

Needle length and general injecting technique should be evaluated every year for

patients with suboptimal glucose control

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

bull Skin folds are essential when the distance from skin surface to the muscle is

less than the length of the needle

bull Lifting a skin fold is an easy and effective means for ensuring SC injections

bull All patients should be taught the correct technique for lifting a skin fold from

the onset of insulin therapy

bull A proper skin fold is made with the thumb and index finger (possibly with

the addition of the middle finger)

bull Lifting the skin by using the whole hand risks lifting muscle with the SC

tissue and can lead to IM injections

bull Figure 4 shows correct (left) and incorrect (right) ways of performing the

skin fold (105) A2

bull The skin fold should not be squeezed so tightly that it causes skin blanching

or pain

bull 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

bull 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 lsquorubberyrsquo 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 lsquorubberyrsquo 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)

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

Figure 6 The different lsquopinchrsquo 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

Additionally patients should be informed of the benefits of avoiding

lipohypertrophy less variability of blood glucose better control of HbA1c

fewer hypoglycemias and improved cosmeticaesthetic 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 lsquolipo modelrsquo (in which patients can feel typical lesions) may facilitate

this learning

Group sessions where patients share information about lipohypertrophy are

usually very helpful

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

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 (eg Diabetes Management software or written

diaries) can help patients directly lsquoseersquo the metabolic advantages of not

injecting into lipohypertrophy and thus will reinforce adherence (121) A2

Rotation of Injecting Sites

bull Many studies show that to safeguard normal tissue one must properly and

consistently rotate sites (46 133 134) A1

bull Patients should be taught an easy-to-follow rotation scheme from the onset of

injection therapy (135 136) A1

bull 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

bull 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

bull HCP should verify that the rotation scheme is being followed at each visit and

give help and advice where needed

bull Needles will on occasion hit a blood vessel on injection producing bleeding or

bruising (138)

bull Figure 9 shows the blood vessel distribution in the dermis and SC layers

bull 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

bull 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

The epidermal-dermal thickness ranges from ~12-30 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

bull Needlestick injuries are common among HCP with most studies showing

significant under-reporting for a variety of reasons (146)

bull Safety needles could effectively protect against such injuries and should be

recommended whenever there is a risk of a contaminated needle stick injury (eg

in hospital) (147) B1

bull Considerable education and training are needed to ensure that currently

available safety needles are used properly and effectively (147 148) A1

bull 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

bull 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

bull 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

bull 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

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 needlessyringes 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 (eg hospital) 2) to another Health Care provider

(eg laboratory pharmacist doctorrsquos office)

Under no circumstance should sharps material be disposed of into the normal

(public) trash or rubbish system

Potential adverse events to the patientsrsquo family (eg needlestick injuries to

children) as well as to service providers (eg 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

The first indication that analogues might behave differently from conventional insulins

came when Rave (69) confirmed that in IM injections of soluble (ldquoRegularrdquo) insulin the

metabolic activity peaks more rapidly than with SC administration but that the metabolic

effect of insulin Lispro (Humalogreg) 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 (Novologreg)

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

Owens (75) showed using radioactive glargine (Lantusreg) there were no significant

differences in its absorption amongst the three classic injection sites arm leg and

abdomen The T75 was 119 153 and 132 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 (Levemirreg) 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

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=0001) not rotating injection sites (p=0004) and

not changing the needle with each injection (p=0004)

Johansson (150) has shown that aspart (Novologreg NovoRapidreg) 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 127mm

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 127mm 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

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) ldquoInrsquoObeserdquo 126 of 130 enrolled insulin-taking obese (BMI ge 30 kgm2) 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 127mm 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 127-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 lt40 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 90deg in the thigh When using a 6-mm needle in such patients the authors

propose injecting in a skinfold with a 45deg angle

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 (lt8 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 ldquopinching uprdquo or switching their

injections to other (more fat-endowed) sites The compliance record on such behavioral

change is poor

The next question is lsquowhat length are you using nowrsquo If they are using a needle longer

than 8mm and there are no clinically-evident problems (eg 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

gt8mm long

All other patients are directed to use a needle lt8mm if they are children or adolescents or

le8mm if they are adults We believe this drive to shorter needles is in the patientsrsquo best

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 (127mm) at

all sites except the buttock but in most girls the distances were greater than 127mm

except over the calf In the abdomen the distance from skin to peritoneum was less than

127mm 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

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 Hocircpital Robert Debreacute 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=059) The pain of injection was

rated by the children to be significantly lower with the 5mm needle (12 plusmn11 vs 42plusmn26

on a 10-point scale p=0001) and there were fewer hypoglycemic events during the

period in which the 5mm needle was used (p=005) 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

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

Heinemann (30) gave ten healthy male volunteers 10 IU insulin lispro (Humalogreg) SC

on study day 1 and the same dose intradermally the next day Intradermal injections were

given via three different microneedles lengths 125 15 and 175 mm Results showed

that the relative bioavailability (147155 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 kgm2) 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 15mm in all subgroups considered it was between 18

and 27mm 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

Conclusion

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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2 Partanen TM A Rissanen Insulin injection practices Pract Diabetes Int 2000 17 252-254

3 Strauss K De Gols H Letondeur C Matyjaszczyk M Frid A The second injection technique event (SITE) May 2000 Barcelona Spain Pract Diab Int 2002 1917-21

4 Strauss K De Gols H Hannet I Partanen TM Frid A A pan-European epidemiologic study of insulin injection technique in patients with diabetes Pract Diab Int April 2002 Vol 1971-76

5 Danish Nurses Organization Evidence-based Clinical Guidelines for Injection of Insulin for Adults with Diabetes Mellitus 2nd edition December 2006 Access via wwwdsrdk

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9 Birkebaek N Solvig J Hansen B Jorgensen C Smedegaard J Christiansen J A 4mm needle reduces the risk of intramuscular injections without increasing backflow to skin surface in lean diabetic children and adults Diabetes Care 2008 Sep22(9) e65

10 De Meijer PHEM Lutterman JA van Lier HJJ vanacutet Laar A The variability of the absorption of subcutaneously injected insulin effect on injection technique and relation with brittleness Diabetic Medicine 1990 7 499-505

11 Baron AD Kim D Weyer C Novel peptides under development for the treatment of type 1 and type 2 diabetes mellitus Curr Drug Targets Immune Endocr Metabol Disord 2002 263-82

12 Frid A Gunnarsson R Guumlntner P Linde B Effects of accidental intramuskulaeligr injection on insulin absorption in IDDM Diabetes Care 1988 11 41-45

13 Vaag A Damgaard Pedersen K Lauritzen M Hildebrandt P Beck-Nielsen H Intramuscular versus subcutaneous injection of unmodified insulin consequences for blood glukose control in patients with type 1 diabetes mellitus Diabetic Medicine 1990a 7 335-342

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15 Johansson U Amsberg S Hannerz L Wredling R Adamson U Arnqvist HJ amp P Lins (2005) Impaired Absorption of insulin Aspart from Lipohypertrophic Injection Sites Diabetes Care Vol 28 No 8 2025-2027

16 Frid A amp B Linde (1993) Clinically important differences in insulin absorption from the abdomen in IDDM Diabetes Research and Clinical Practice Vol 21 No 2-3 137-141

17 Chantelau E Lee DM Hemmann DM Zipfel U Echterhoff S What makes insulin injections painful British Medical Journal 1991 303 26-27

18 Eldholm S Karlegaumlrd M Poster report Swedish Medical Society 2001 19 Cocoman A Barron C Administering subcutaneous injections to children what

does the evidence say Journal of Children and Young Peoplersquos Nursing 2008 Feb 2 84-89

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21 Polonsky WH Fisher L Guzman S Villa-Caballero L Edelman SV Psychological insulin resistance in patients with type 2 diabetes the scope of the problem Diabetes Care 2005 Oct28(10)2543-5

22 Martinez L Consoli SM Monnier L Simon D Wong O Yomtov B Gueacuteron B Benmedjahed K Guillemin I Arnould B Studying the Hurdles of Insulin Prescription (SHIP) development scoring and initial validation of a new self-administered questionnaire Health Qual Life Outcomes 2007553 httpwwwpubmedcentralnihgovpicrenderfcgiartid=2042975ampblobtype=pdf

23 Cefalu WT Mathieu C Davidson J Freemantle N Gough S Canovatchel W OPTIMIZE Coalition Patients perceptions of subcutaneous insulin in the OPTIMIZE study a multicenter follow-up study Diabetes Technol Ther 20081025-38

24 Meece J Dispelling myths and removing barriers about insulin in type 2 diabetes The Diabetes Educator 2006 329S-18S

25 Davis SN Renda SM Psychological insulin resistance overcoming barriers to starting insulin therapy Diabetes Educ 2006 Jun32 Suppl 4146S-152S

26 Davidson M No need for the needle (at first) Diabetes Care 2008312070-2071 27 Reach G Patient non-adherence and healthcare-provider inertia are clinical

myopia Diabetes Metab 200834 382-385 28 Genev NM Flack JR Hoskins PL et al Diabetes education whose priorities are

met Diabetic Medicine 1992 9 475-479 29 Klonoff DC (2001) The pen is mightier than the needle (and syringe) Diabetes

Technol Ther 3(4)bull631-3 30 Heinemann L Hompesch M Kapitza C Harvey NG Ginsberg BH Pettis RJ

Intra-dermal insulin lispro application with a new microneedle delivery system led to a substantially more rapid insulin absorption than subcutaneous injection Diabetologia (2006) 49[Suppll]l-755 abstract 1014

31 DiMatteo RM DiNicola DD Achieving patient compliance The psychology of medical practitioneracutes role Pergamon Press Inc New York Oxford 1982

32 Joy SV Clinical pearls and strategies to optimize patient outcomes Diabetes Educ 2008 May-Jun34 Suppl 354S-59S

33 Seyoum B amp J Abdulkadir (1996) Systematic inspection of insulin injection sites for local complications related to incorrect injection technique Trop Doct Vol 26 No 4 159-161

34 Loveman E Frampton G Clegg A The clinical effectiveness of diabetes education models for type 2 diabetes Health Technology Assessment 2008 12 1-36

35 Bantle JP Neal L Frankamp LM Effects of the anatomical region used for insulin injections on glycaemia in type 1 diabetes subjects Diabetes Care 1993 16 1592-1597

36 Frid A Lindeacuten B Intraregional differences in the absorption of unmodified insulin from the abdominal wall Diabetic Medicine 1992 9 236-239

37 Koivisto VA Felig P Alterations in insulin absorption and in blood glukose control associated with varying insulin injection sites in diabetic patients Annals of Internal Medicine 1980 92 59-61

38 Annersten M Willman A Performing subcutaneous injections a literature review Worldviews on Evidence-Based Nursing 2005 2122-130

39 Vidal M Colungo C Jansagrave M Actualizacioacuten sobre teacutecnicas y sistemas de administracioacuten de la insulina (I) [Update on insulin administration techniques and devices (I)] Av Diabetol 2008 24175-190

40 Ariza-Andraca CR Altamirano-Bustamante E Frati-Munari AC Altamirano-Bustamante P amp A Graef-Sanchez (1991) Delayed insulin absorption due to subcutaneous edema Archivos de Investigacioacuten Medica Vol 22 No 2 229-233

41 Gorman KC Good hygiene versus alcohol swabs before insulin injections (Letter) Diabetes Care 1993 16 960-961

42 Le Floch JP Herbreteau C Lange F Perlemuter L Biologic material in needles and cartridges after insulin injection with a pen in diabetic patients Diabetes Care 1998 211502-1504

43 McCarthy JA Covarrubias B Sink P Is the traditional alcohol wipe necessary before an insulin injection Dogma disputed (Letter) Diabetes Care 1993 16 402

44 Schuler G Pelz K Kerp L Is the reuse of needles for insulin injection systems associated with a higher risk of cutaneous complications Diabetes Research and Clinical Practice 1992 16 209-212

45 Fleming D Jacober SJ Vanderberg M Fitzgerald JT Grunberger G The safety of injecting insulin through clothing Diabetes Care 1997 20 244-247

46 Ahern J amp ML Mazur (2001) Site rotation Diabetes Forecast Vol 54 No 4 66-68

47 Perriello G Torlone E Di Santo S Fanelli C De Feo P Santusanio F Brunetti P amp GB Bolli (1988) Effect of storage temperature on pharmacokinetics and pharmadynamics of insulinmixtures injected subcutaneously in subjects with type 1 (insulin-dependent) diabetes mellitus Diabetologia Vol 31 No 11 811 -815

48 King L Subcutaneous insulin injection technique Nurs Stand 2003 May 7-1317(34)45-52

49 Jehle PM Micheler C Jehle DR Breitig D Boehm BO Inadequate suspension of neutral protamine Hagendorn (NPH) insulin in pens The Lancet 1999 354 1604-1607

50 Brown A Steel JM Duncan C Duncun A amp AM McBain (2004) An assessment of the adequacy of suspension of insulin in pen injectors Diabet Med Vol 21 No 6 604-608

51 Nath C (2002) Mixing insulin shake rattle or roll Nursing Vol 32 No 5 10 52 Springs MH (1999) Shake rattle or rollrdquoChallenging traditional insulin

injection practicesrdquo American Journal of Nursing Vol 99 No 7 14 53 Bohannon NJ (1999) Insulin delivery using pen devices Simple-to-use tools may

help young and old alike Postgraduate Medicine Vol 106 No 5 57-58 54 Dejgaard A amp CMurmann (1989) Air bubbles in insulin pens The Lancet Vol

334 No 8667 871 55 Ginsberg BH Parkes JL amp C Sparacino (1994) The kinetics of insulin

administration by insulin pens Horm Metab Researchrsquo Vol 26 No 12584-587 56 Annersten M Frid A Insulin pens dribble from the tip of the needle after

injection Practical Diabetes International 2000 17 109-111

57 Ezzo J Donner T Nickols D amp M Cox (2001) Is Massage Useful in the Management of Diabetes A Systematic Review Diabetes Spectrum Vol 14 218-224

58 Baumlrtsch U Comtesse C Wetekam B Insulin pens for treatment of diabetes (article in German) Ther Umsch 2006 Jun63(6)398-404

59 Maljaars C (2002) Scherpe studie naalden voor eenmalig gebruik [Sharp study needles for single use] Diabetes and Levery Vol 4 No 3 36-37

60 Torrance T (2002) An unexpected hazard of insulin injection Practical Diabetes International Vol 19 No 2 63

61 Byetta Pen User Manual Eli Lilly and Company 2007 62 Baumlrtsch U Comtesse C Wetekam B Insulin pens for treatment of diabetes

(article in German) Ther Umsch 2006 Jun63(6)398-404 63 Jamal R Ross SA Parkes JL Pardo S Ginsberg BH Role of injection technique

in use of insulin pens prospective evaluation of a 31-gauge 8mm insulin pen needle Endocr Pract 1999 Sep-Oct5(5)245-50

64 Chantelau E Heinemann L amp D Ross (1989) Air Bubbles in insulin pens Lancet Vol 334 No 8659 387-388

65 Rissler J Joslashrgensen C Rye Hansen M Hansen NA Evaluation of the injection force dynamics of a modified prefilled insulin pen Expert Opin Pharmacother 2008 Sep9(13)2217-22

66 Broadway CA (1991) Prevention of insulin leakage after subcutaneous injection Diabetes Educator Vol 17 No 2 90

67 Caffrey RM (2003) Diabetes under Control Are all Syringes created equal American Journal of Nursing Vol 103 No 6 46-49

68 Mudaliar SR Lindberg FA Joyce M Beerdsen P Strange P Lin A Henry RR 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 Diabetes Care 1999 Sep22(9)1501-6

69 Rave K Heise T Weyer C Herrnberger J Bender R Hirschberger S Heinemann L Intramuscular versus subcutaneous injection of soluble and lispro insulin comparison of metabolic effects in healthy subjects Diabet Med 1998 Sep15(9)747-51

70 Frid A Fat thickness and insulin administration what do we know Infusystems International 2006 5 17-19

71 Guerci B Sauvanet J-P Subcutaneous insulin pharmacokinetic variability and glycemic variability Diabetes Metab 2005314S7-4S24

72 Braak ter EW Woodworth JR Bianchi R Cermele B Erkelens DW Thijssen JH amp D Kurtz (1996) Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin Diabetes Care Vol 19 No 12 1437-1440

73 Lippert WC Wall EJ Optimal intramuscular needle-penetration depth Pediatrics 2008 122 e556-e563

74 Rassam AG Zeise TM Burge MR Schade DS Optimal Administration of Lispro Insulin in Hyperglycemic Type 1 Diabetes Diabetes Care 1999 Jan22(1)133-6

75 Owens DR Coates PA Luzio SD Tinbergen JP 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 Diabetes Care 2000 Jun23(6)813-9

76 Karges B Boehm BO Karges W Early hypoglycaemia after accidental intramuscular injection of insulin glargine Diabetic Medicine 2005221444-45

77 Broadway C Prevention of insulin leakage after subcutaneous injection The Diabetes Educator 1991 Mar-Apr17(2)90

78 Frid A Oumlstman J Linde B Hypoglycemia risk during exercise after intramuscular injection of insulin in thigh in IDDM Diabetes Care 1990 13 473-477

79 Vaag A Handberg Aa Laritzen M et al Variation in absorption of NPH insulin due to intramuscular injection Diabetes Care 1990b 13 74-76

80 Henriksen JE Vaag A Hansen IR Lauritzen M Djurhuus MS Beck-Nielsen H Absorption of NPH (isophane) insulin in resting diabetic patients evidence for subcutaneous injection in the thigh as preferred site Diabetic Medicine 1991 8 453-457

81 Koslashlendorf K Bojsen J Deckert T Clinical factors influencing the absorption of 125 I-NPH insulin in diabetic patients Hormone Metabolisme Research 1983 15 274-278

82 Chen JVV Christiansen JS amp T Lauritzen (2003) Limitation to subcutaneous insulin administration in type 1 diabetes Diabetes obesity and metabolism Vol 5 No 4 223-233

83 Zehrer C Hansen R Bantle J Reducing blood glukose variability by use of abdominal insulin injection sites Diabetes Educator 1985 16 474-477

84 Henriksen JE Djurhuus MS Vaag A Thye-Ronn P Knudsen D Hother-Nielsen 0 amp H Beck-Nielsen (1993) Impact of injection sites for soluble insulin on glycaemic control in type 1 (insulin-dependent) diabetic patients treated with a multiple insulin injection regimen Diabetologia Vol 36 No 8 752-758

85 Sindelka G Heinemann L Berger M FrenckW amp E Chantelau (1994) Effect of insulin concentration subcutaneous fat thickness and skin temperature on subcutaneous insulin absorption in healthy subjects Diabetologia Vol 37 No 4 377-340

86 Clauson PG Linde B Absorption of rapid-acting insulin in obese and nonobese NIDDM patients Diabetes Care 1995 Jul18(7)986-91

87 Calara F Taylor K Han J Zabala E Carr EM Wintle M Fineman M A randomized open-label crossover study examining the effect of injection site on bioavailability of exenatide (synthetic exendin-4) Clin Ther 2005 Feb27(2)210-5

88 Becker D (1998) Individualized insulin therapy in children and adolescente with type 1 diabetes Acta Paediatr Suppi Vol 425 20-24

89 Uzun S lnanc N amp Azal (2001) Determining optima) needle length for subcutaneous insulin injection Journal of Diabetes Nursing Vol 5 No 3 83-87

90 Birkebaek NH Johansen A Solvig J Cutissubcutis thickness at insulin injection sites and localization of simulated insulin boluses in children with type 1 diabetes mellitus need for individualization of injection technique Diabetic Medicine 1998 15 965-971

91 Smith CP Sargent MA Wilson BP Price DA (1991) Subcutaneous or intramuscular insulin injections Archives of disease in childhood Vol 66 No 7 879-882

92 Tafeit E Moumlller R Jurimae T Sudi K Wallner SJ Subcutaneous adipose tissue topography (SAT-Top) development in children and young adults Coll Antropol 2007 Jun31(2)395-402

93 Haines L Chong Wan K Lynn R Barrett T Shield J Rising Incidence of Type 2 Diabetes in Children in the UK Diabetes Care 2007 30 1097-1101

94 Hofman PL Lawton SA Peart JM Holt JA Jefferies CA Robinson E Cutfield WS An angled insertion technique using 6mm needles markedly reduces the risk of IM injections in children and adolescents Diabet Med 2007 Dec24(12)1400-5

95 Polak M Beregszaszi M Belarbi N Benali K Hassan M Czernichow P Tubiana-Rufi N Subcutaneous or intramuscular injections of insulin in children Are we injecting where we think we are Diabetes Care 1996 Dec 19(12) 1434-1436

96 Strauss K Hannet I McGonigle J Parkes JL Ginsberg B Jamal R Frid A Ultra-short (5mm) insulin needles trial results and clinical recommendations Practical Diabetes Oct 1999 16(7) 218-222

97 Tubiana-Rufi N Belarbi N Du Pasquier-Fediaevsky L Polak M Kakou B Leridon L Hassan M Czernichow P Short needles (8 mm) reduce the risk of intramuscular injections in children with type 1 diabetes Diabetes Care 1999 Oct22(10)1621-5

98 Chiarelli F Severi F Damacco F Vanelli M Lytzen L Coronel G Insulin leakage and pain perception in IDDM children and adolescents where the injections are performed with NovoFine 6 mm needles and NovoFine 8 mm needles Abstract presented at FEND Jerusalem Israel 2000

99 Ross SA Jamal R Leiter LA Josse RG Parkes JL Qu S Kerestan SP Ginsberg BH Evaluation of 8 mm insulin pen needles in people with type 1 and type 2 diabetes Practical Diabetes International 1999 16 145-148

100Hanas R Ludvigsson J Experience of pain from insulin injections and needlephobia in young patients with IDDM Practical Diabetes International 1997 1495-99

101Hanas SR Carlsson S Frid A Ludvigsson J Unchanged insulin absorption after 4 daysacuteuse of subcutaneous indwelling catheters for insulin injections Diabetes Care 1997 20 487-490

102Zambanini A Newson RB Maisey M Feher MD Injection related anxiety in insulin-treated diabetes Diabetes Res Clin Pract 199946239-46

103Hanas R Adolfsson P Elfvin-Akesson K Hammaren L Ilvered R Jansson I Johansson C Kroon M Lindgren J Lindh A Ludvigsson J Sigstrom L Wilk A Aman J Indwelling catheters used from the onset of diabetes decrease injection pain and pre-injection anxiety J Pediatr 2002140315-20

104Burdick P Cooper S Horner B Cobry E McFann K Chase HP Use of a subcutaneous injection port to improve glycemic control in children with type 1 diabetes Pediatr Diabetes 200910116-9

105Strauss K Insulin injection techniques Practical Diabetes International 1998 15 181-184

106Thow JC Coulthard A Home PD Insulin injection site tissue depths and localization of a simulated insulin bolus using a novel air contrast ultrasonographic technique in insulin treated diabetic subjects Diabetic Medicine 1992 9 915-920

107Thow JC Home PD Insulin injection technique depth of injection is important BMJ 301 3-4 1990

108Hildebrandt P (1991) Skinfold thickness local subcutaneous blood flow and insulin absorption in diabetic patients Acta Physiol Scand Suppl Vol 603 41-45

109Vora JP Peters JR Burch A amp DR Owens (1992) Relationship between Absorption of Radiolabeled Soluble Insulin Subcutaneous Blood Flow and Anthropometry Diabetes Care Vol 15 No 11 1484-1493

110Kreugel G Beijer HJM Kerstens MN ter Maaten JC Sluiter WJ Boot BS Influence of needle size for SC insulin administration on metabolic control and patient acceptance European Diabetes Nursing 2007 4 1-5

111Solvig J Christiansen JS Hansen B Lytzen L 2000 Localisation of potential insulin deposition in normal weight and obese patients with diabetes using Novofine 6 mm and Novofine 12 mm needles Abstract FEND Jerusalem Israel 2000

112Van Doorn LG 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 Diabetic Medicine 1998 1 suppl 1 S50

113Clauson PGamp B Linde B(1995) Absorption of rapid-acting insulin in obese and nonobese NIIDM patients Diabetes Care Vol 18 No 7986-991

114Kreugel G Keers JC Jongbloed A Verweij-Gjaltema AH Wolffenbuttel BHR The influence of needle length on glycemic control and patient preference in obese diabetic patients Diabetes 200958(Suppl 1)

115Schwartz S Hassman D Shelmet J Sievers R Weinstein R Liang J Lyness W 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 127mm needle in obese patients with diabetes mellitus Clin Ther 2004 Oct26(10)1663-78

116Frid A Lindeacuten B CT scanning of injections sites in 24 diabetic patients after injection of contrast medium using 8 mm needles (Abstract) Diabetes 1996 45 suppl 2 A444

117Frid A Lindeacuten B Where do lean diabetics inject their insulin A study using computed tomography British Medical Journal 1986 292 1638

118Thow JC AB Johnson SMarsden RTaylor PD Home Morphology of palpably abnormal injection sites and effects on absorption of isophane (NPH) insulin Diabetic Medicine 1990 7 795-799

119Richardson T amp D Kerr (2003) Skin-related complications of insulin therapy epidemiology and emerging management strategies American J Clinical Dermatol Vol 4 No 10 661-667

120Photographs courtesy of Lourdes Saez-de Ibarra and Ruth Gaspar Diabetes Nurses and Specialist Educators of La Paz Hospital Madrid Spain

121Saez-de Ibarra L Gallego F Factors related to lipohypertrophy in insulin-treated diabetic patients role of educational intervention Practical Diabetes International 1998 15 9-11

122Young RJ Hannan WJ Frier BM Steel JM et al Diabetic lipohypertrophy delays insulin absorption Diabetes Care 1984 7 479-480

123Chowdhury TA amp V Escudier (2003) Poor glycaemic control caused by insulin induced lipohypertrophy BritishMedical Journal Vol 327 383-384

124Overland J Molyneaux L Tewari S et al Lipohypertrophy Does it matter in daily life A study using a continuous glucose monitoring system Diabetes Obes Metab 200911460-3

125Nielsen BB Musaeus L Gaeligde P Steno Diabetes Center Copenhagen Denmark Attention to injection technique is associated with a lower frequency of lipohypertrophy in insulin treated type 2 diabetic patients Abstract EASD Barcelona Spain 1998

126Teft G (2002) Lipohypertrophy patient awareness and implications for practice Journal of Diabetes Nursing Vol 6 No 1 20-23

127Ampudia-Blasco J Girbes J Carmena R A case of lipoatrophy with insulin glargine Diabetes Care 28 2005 2983

128Vardar B Kizilci S Incidence of lipohypertrophy in diabetic patients and a study of influencing factors Diabetes Res Clin Pract 2007 Aug77(2)231-6

129De Villiers FP Lipohypertrophy - a complication of insulin injections S Afr Med J 2005 Nov95(11)858-9

130Hauner H Stockamp B Haastert B Prevalence of lipohypertrophy in insulin-treated diabetic patients and predisposing factors Exp Clin Endocrinol Diabetes 1996104(2)106-10

131Hambridge K The management of lipohypertrophy in diabetes care Br J Nurs 200716520-524

132Jansagrave M Colungo C Vidal M Actualizacioacuten sobre teacutecnicas y sistemas de administracioacuten de la insulina (II) [Update on insulin administration techniques and devices (II)] Av Diabetol 2008 24255-269

133Bantle JP Weber MS Rao SM Chattopadhyay MK amp RP Robertson (1990) Rotation of the anatomic regions used for insulin injections day-to-day variability of plasma glucose in type 1 diabetic subjects JAMA Vol 263 No 13 1802-1806

134Davis ED amp P Chesnaky (1992) Site rotationtaking insulin Diabetes Forecast Vol 45 No 3 54-56

135Lumber T (2004) Tips for site rotation When it comes to insulin where you inject is just as important as how much and when Diabetes Forecast Vol 57 No 7 68-70

136Thatcher G (1985) Insulin injections The case against random rotation American Journal of Nursing Vol 85 No 6 690-692

137Diagrams courtesy of Lourdes Saez-de Ibarra and Ruth Gaspar Diabetes Nurses and Specialist Educators of La Paz Hospital Madrid Spain

138Kahara T Kawara S Shimizu A Hisada A Noto Y amp H Kida (2004) Subcutaneous hematoma due to frequent insulin injections in a single site Intern Med Vol 43 No 2 148-149

139Kreugel G Beter HJM Kerstens MN Maaten ter JC Sluiter WJ amp BS Boot (2007) Influence of needle size on metabolic control and patient acceptance European Diabetes Nursing Vol 4 No 2 51-55

140Engstroumlm L Jinnerot H Jonasson E Thickness of Subcutaneous Fat Tissue Where Pregnant Diabetics Inject Their Insulin - An Ultrasound Study Poster at IDF 17th World Diabetes Congress Mexico City Published as abstract in Diabetes Research and Clinical Practice Suppl 1 2000

141Laurent A Mistretta F Bottigioli D Dahel K Goujon C Nicolas JF Hennino A Laurent PE Echographic measurement of skin thickness in adults by high frequency ultrasound to assess the appropriate microneedle length for intradermal delivery of vaccines Vaccine 2007 Aug 2125(34)6423-30

142Lasagni C Seidenari S Echographic assessment of age-dependent variations of skin thickness Skin Research and Technology 1995 1 81-85

143Swindle LD Thomas SG Freeman M Delaney PM View of Normal Human Skin In Vivo as Observed Using Fluorescent Fiber-Optic Confocal Microscopic Imaging Journal of Investigative Dermatology (2003) 121 706ndash712

144Huzaira M Rius F Rajadhyaksha M Anderson RR Gonzaacutelez S Topographic Variations in Normal Skin as Viewed by In Vivo Reflectance Confocal Microscopy Journal of Investigative Dermatology (2001) 116 846ndash852

145Tan CY Statham B Marks R Payne PA Skin thickness measured by pulsed ultrasound its reproducibility validation and variability Br J Dermatol 1982 Jun106(6)657-67

146Smith DR Leggat PA Needlestick and sharps injuries among nursing students J Adv Nurs 2005 Sep51(5)449-55

147Adams D Elliott TS Impact of safety needle devices on occupationally acquired needlestick injuries a four-year prospective study J Hosp Infect 2006 Sep64(1)50-5

148Workman RGN (2000) Safe injection techniques Primary Health Care Vol 10 No 6 43 50

149Bain A Graham A How do patients dispose of syringes Practical Diabetes International 1998 15 19-21

150Johansson UB Impaired absorption of insulin aspart from lipohypertrophic injection sites Diabetes Care 2005 Aug28(8)2025-7

152Frid A Linde B Computed tomography of injection sites in patients with diabetes mellitus In Injection and Absorption of Insulin Thesis Stockholm 1992

154Smith C P Sargent M A Wilson B P M Price D A Subcutaneous or intra-muscular insulin injections Archives of Disease in Childhood 66879-882 1991

Appendix 1 Attendees at TITAN

FAMILY NAME FIRST NAME COUNTRY

Amaya Baro Mariacutea 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

Dimeacuteo 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 Mariacutea Portugal

Gaspar La Fuente Ruth Spain

Gedikli Hikmet Turkey

Gibney Michael USA

Giely-Eloi Corinne France

Gil-Zorzo Esther Spain

Gonzalez Amparo USA

Gonzaacutelez Bueso Carmen Spain

Grieco Gabreilla Italy

Gu Min-Jeong South Korea

Guo Xiaohui China

Guzman Susan USA

Hanas Ragnar Sweden

Haumlrmauml-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 Mariacutea 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

Nuumlhlen Ulrich Germany

Ochotta Isabella Germany

Osterbrink Brigitte Germany

Pasaporte Francis Philippines

Pastori Silvana Italy

Penalba Martiacutenez Mariacutea Teresa Spain

Pizzolato Pia USA

Pledger Julia UK

Riis Mette Denmark

Robert Jean-Jacques France

Rodriguez Jose-Juan Spain

Roggemans Marie-Paule Belgium

Roumlhrig Baumlrbel 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

Vaacutequez Jimeacutenez Mariacutea 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

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 (eg Insulatard Humulin NPH and Insuman basal) and slow-

acting insulin analogues (eg Levemir and Lantus) For peoplehellipwho cannot use the thighhellipthe 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 ishellipthe 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

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 gt8mm 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

lipodystrophyhellipeach 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

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 HCPrsquos should demonstrate injections on themselves when teaching patients

HCPrsquos 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 patientsrsquo 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 ie intramuscularly (This can lead

to)hellipless well predictable action and possibly also the risk of hypoglycaemias

Intra-dermal Injection Risks

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 ie not into the

epidermis or the dermis (This)hellipcan 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 hellipthe 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 hellipsplit the dose whenhellipgreater 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

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 penrsquos 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 upwardshelliprepeat this until insulin comes out of the pen needle

Cleaning before Injection

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 necessaryhellipthe 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 (BMIlt25) a short pen needle (le8 mm)

can be used The preference of the patient is for the shortest length of pen needles In generalhellipuse a pen

needle le8 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

Table 1 Danish Needle Length Recommendations

Patient type Needle length Injection Angle Skin fold

6mm 90 degrees lifted Normal weight (BMI lt25) 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 gt25)

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 lt25

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 gt25