Indian Injection Technique Study: Population Characteristics and Injection Practices

Indian BMI values are lower, in adults, adolescents, and children, compared to those in ROW (Table 4), reflecting the fact that Asians in general are at higher risk for T2DM at lower BMIs than most ethnicities in other regions of the world. Perhaps for this reason, we found that the mean TDD of insulin was lower in every category of Indian patient than in ROW (Table 4). Lower BMI values may also have contributed to the popularity of the shorter insulin needles, as Indian patients become aware of the risks of IM injections with the longer needles, especially in the presence of their lower BMI.

Syringe use continues to be common in India compared to ROW, but use of the shortest needles is very common in India regardless of whether pens or syringes are used. The 4- and 6-mm needles are the most popular lengths (Table 5). When we cross-matched these findings to injecting device we found that the 4-mm needle (shortest in the pen line) was the most commonly used by pen users and the 6-mm needle (shortest in syringes) was the most commonly used by syringe users. Hence the message of the superiority of the shortest needle seems to have been heeded amongst professionals and patients in India.

Comparison of previous worldwide ITQs show that needle length over the last 5–6 years has shifted dramatically, away from the 8 mm and towards the 4 and 5 mm. This follows a trend towards shorter needles that began 2 decades ago. But in the last 5–6 years, a sea-change has occurred with a much faster conversion to 4 mm than seen with other needle length changes. Currently just less than 30% of ROW patients use 4 and 8 mm, respectively [3, 4]. Just over 20% of ROW use the 5 and 6 mm, respectively. There is considerable variability, however, country to country worldwide, but it appears that India is now ahead of the curve. However we are still concerned that considerable percentages of Indian patients continue to use the 8-mm needle in high-risk sites (e.g., in the limbs, especially in males).

Recent studies indicate that skin thickness at insulin injection sites in a varied population of adults with diabetes differs minimally by patient characteristics, including BMI (e.g., obese patients have similar skin thickness as normal and thin patients) [16]. However the same study showed that fat thickness (SC space) varied widely from one individual to another on the basis of gender, BMI, and injection zone of the body. It highlighted the risk of IM injections and showed that they were lowest with 4-mm needles. A study recently published in India confirms these findings [17].

Table 6, adapted from another publication [18], shows the risk of IM injections as a function of needle length. The red circle identifies situations in which the IM risk is particularly high, i.e., injections with 6- and 8-mm needles in the limbs (arms and thighs). Comparative analysis of the worldwide ITQ data [3] revealed that the 4-mm needle was associated with lower BMI, fewer years on insulin, younger age, lower total daily doses (TDD) of insulin, more fingersticks/day, less hyperglycemia and hospitalization for hypoglycemia, less needle reuse, and less LH (all difference with p < 0.05 by multivariate analysis).

The 4-mm/32G pen needles were shown to provide equivalent glycemic control (HbA1c) to 8-mm/31G and 12.7-mm/29G pen needles in a large, prospective randomized controlled crossover study of obese patients taking large insulin doses, with two separate arms (4 vs 8 mm and 4 vs 12.7 mm) [19]. There was no increase in backflow or skin leakage with the 4-mm needles. Additionally patients reported less injection pain with the 4-mm needles. There is no evidence to date of additional leakage of insulin, LH, or pain nor of poorer diabetes control or other complications in patients using 4-, 5-, or 6-mm needles [19‐25].

Additional studies have recently been performed using the 4-mm needle with identical results. Miwa et al. [26] compared 4-mm/32G with 6-mm/32G needles and showed equivalent safety and efficacy results. The 4-mm needle was judged by Japanese patients to be less painful and easier to use. Nagai et al. [27] compared 4-mm/32G to 5-mm/33G (tapered) needles and found similar results. Hirose et al. [28] performed PK/PD studies which showed bioequivalent maximum concentration and area under the curve for the 4-mm/32G needle relative to the 6-mm/32G and 8-mm/31G needles. A PK/PD crossover study using the euglycemic clamp in both normal-weight and obese subjects, healthy adults showed equivalent insulin uptake and action for insulin lispro, injected one day with a 5-mm needle and another day with an 8-mm needle [29].

Birkebaek et al. [30] compared the 4-mm with the 6-mm pen needle in lean subjects, both children and adults, with diabetes. The 4-mm needle led to fewer IM injections with equivalent levels of leakage compared to the 6-mm needle. The probability of IM injection with the 6 mm vs the 4 mm was considerably higher when comparing percentages in adults and was dramatically higher in children and adolescents. Hirsch et al. [31] have shown equivalence between 4-, 5-, and 8-mm pen needles in regards to glucose control, with no difference between obese and non-obese subjects.

Lo Presti et al. [32] studied the skin and SC thickness at various injecting sites in children and adolescents with diabetes (ages 2–17) and concluded that the safest injecting alternative for all ages is the 4-mm needle. A 4-mm needle is long enough to penetrate the skin but sufficiently short to avoid reaching the muscle in the vast majority of children. However, all pediatric groups have values at the lower range of skin plus SC thickness which are below the threshold of 4 mm. These findings show that in very young patients injections may be IM when given perpendicularly without a skinfold, even with 4-mm needles.

Hofman et al. [33] have done similar studies using the 5-mm needle. They found that 5-mm needles gave equivalent glucose control to 8-mm ones in both children and adults, and no substantial back flow or leakage was seen from 5 mm compared to 8 mm in doses up to 60 IU. Children prefer the 5-mm to longer needles and generally have less pain with 5 mm. HbA1c improvements on the 5-mm needle are sometimes seen and are probably a result of fewer IM injections. Hirsch et al. [34] have shown equivalence between 4-, 5-, and 8-mm pen needles in regards to glucose control, with no difference between obese and non-obese subjects.

Strock et al. [35] performed a subgroup analysis of a large study comparing 4-mm/32G pen needles with 8-mm/31G and 12.7-mm/29G ones in obese subjects, among those taking relatively high doses of glargine (>40 IU). No significant differences in glucose control (as measured by HbA1c), number of hypo- or hyperglycemic events, or insulin leakage were seen in obese subjects (BMI ≥30 kg/m² [2]) amongst the three needle lengths. The 4-mm needle was judged to be less painful, easier to insert, easier to use, and less anxiety-provoking than the other two lengths (all at p < 0.05).

In a crossover trial involving obese adults with DM, Ignaut and Fu [36] compared the 5-mm to the 8-mm pen needle. They found minimal leakage overall with no difference between needle lengths, no difference by injection volume (20 and 60 IU compared), and no difference in bruising, bleeding, or pain between the needle lengths. They concluded that the 5-mm needle is acceptable for obese patients at low and high insulin volumes.

In a crossover trial involving obese adults (BMI ≥30 kg/m²) with DM, Kreugel et al. [37] compared the 5-mm to the 8-mm pen needle. No within-group changes were observed using three different integrated measures of glucose control: HbA1C, serum fructosamine, and 1,5-anhydroglucitol. Furthermore, there were no differences in hypoglycemic events, bruising, or pain. The authors concluded that the 5-mm needle may be used safely in obese patients. Several other authors [19, 31, 34] have shown equivalence between 4-, 5-, and 8-mm pen needles in regards to glucose control, with no difference between obese and non-obese subjects.

Despite the fact that India is ahead of the curve in using the shortest needles, there is a disturbingly high rate of needle reuse with both syringes and pens (Table 5). There are many possible reasons for this, including expense and convenience. Indian patients often have to pay for their needles and, when faced with tight expenses, they may choose to reuse them. It may also be possible that patients are unaware of the association between needle reuse and the presence of LH.

Vardar and Kizilci [38] identified, by logistic regression analysis, three independent risk factors for LH: duration of insulin use, with longer use associated with more LH (p = 0.001); site rotation, with a failure to rotate associated with higher LH risk (p = 0.004); changing needles, with needle reuse also associated with LH (p = 0.004). An earlier study [39] identified similar risk factors.

In a recent Spanish study, Blanco [40] showed a significant correlation between the presence of LH (in 52% of T2DM and 72% of T1DM) and the reuse of needles (p < 0.05), and a trend to greater frequency of LH with higher number of uses of the needle. The relationship was greatest when the needle was used more than five times. Of the patients in whom LH was found, 61% reported needle reuse. Of those who reused, 70% had LH (with the figure 84% in DM1). Of those who did not reuse, 57% had LH.

A similar observational study in four large Chinese cities reported an overall prevalence of LH of 53%. About 95% of patients reuse needles in China, and rates did not differ between those with and without LH. Patients with LH had increased BMI, took more injections daily, and reused their needles nearly twice as many times (all p < 0.001). By regression analysis, insulin dose/kg, BMI, and needle reuse frequency are significantly associated with LH (all p ≤ 0.02) [41].

As in India, the principal reasons patients in ROW reuse needles are convenience and cost [42]. The Indian guidelines [7] state clearly that “Healthcare professionals should create awareness in patients regarding the potential adverse effects of needle reuse, and discourage this practice” and admonish patients to “Never reuse needles, syringes or lancets as there is a high risk of transmission of blood-borne pathogens (HIV and hepatitis).”

A Russian study [43] showed that injection pain was greater with reuse, presumably from dulling of the needle tip. The authors cultured less bacteria from the tips of needles that had been used only once compared to reused needles, and they found inflammatory changes (skin redness) only at injection sites of patients who had reused needles. They did not report the occurrence of any skin or SC tissue infections, however. Similar observations have been reported by others for plastic insulin syringe use [44, 45].

Puder et al. [46] tested the pain of needle reuse in 270 injections and found that pain intensity and unpleasantness do not increase with repeated injections using the same needles in people with diabetes (p = 0.1 and 0.96, respectively) and in volunteers (p = 0.63 and 0.92). The authors concluded that using pen needles up to five times does not lead to needle tip deformity and does not increase pain or unpleasantness. Furthermore, needle reuse could help save money for health care systems.

After sifting the pros and cons of the above studies, it appears that needle reuse, particularly reuse frequency, is associated with the development of LH.

The majority (56.8%) of Indian insulin users performed only 2 injections/day as opposed to ROW where 45% of patients performed at least 4 injections/day. This may reflect the fact that Indian injectors had been using insulin for only 5.5 years on average, while ROW injectors had been using it for on average 9.0 years (Table 3); or it may mean that intensive therapy with multiple daily injections (MDI) is still not common in India. The frequent use of premixes in India and the comparative lower use of analogues compared to ROW (Table 13) support the latter hypothesis.

Indian patients inject insulin in the thighs more often than patients in ROW and this is a site where IM injections are more risky (especially given the lower BMI of Indian patients). Arm use, however, is comparatively less common in India than in ROW, and use of the buttocks is exceedingly rare (Tables 8, 9).

Absorption characteristics change depending on the type of insulin given. Abdominal site subcutaneous (SQ) injection of soluble rapid-acting (“regular”) insulin results in 29% lower postprandial plasma glucose concentrations than thigh site injections [11, 47]. This effect is due to more rapid absorption from the abdomen. Furthermore, the use of inappropriate sites and techniques may modify insulin absorption parameters so that maximum glucose load does not match peak insulin effect. This can lead to unexpected hyperglycemia as well as a greater risk of nocturnal hypoglycemia. [48‐54]. Analogues can be given at any injection site with similar absorption and action (PK-PD), but human insulins (regular, NPH) vary a great deal—absorption is fastest from the abdomen and slowest from the buttocks.

Both human insulins and analogues have different absorption profiles when administered into muscle. In 1988 Frid et al. [55] showed that human soluble insulin was absorbed faster from muscle compared to fat tissue, especially when the muscles were exercised. Vaag et al. [56] showed the same for NPH insulins in 1990. Thow et al. [57] have shown that significantly higher amounts of infused glucose were required during a glucose clamp to maintain euglycemia from IM injections than from SC ones.

In contrast the rapid-acting insulin analogue lispro seems to have the same speed of absorption from fat tissue and resting muscle tissue [58]. There are no published studies for modern long-acting analogues, but clinical experience and a case report [59] make it probable that long-acting analogues are absorbed faster from muscle compared to fat tissue.

Hence IM injections, especially into working muscle, can distort absorption of possibly all of the insulins and thus decouple maximum glucose load from peak insulin activity. This can lead to poor glycemic control, including excessive glycemic variability. When this happens IM injections may lead to unexplained hypoglycemia according to a number of studies [55, 60, 61].

Patients may not be aware that they are injecting IM. Thow and Home [62] have shown that IM injections are no more painful than SC. It is likely that many patients have been unknowingly injecting IM for years—especially with the newer, thinner needles.

Hirsch et al. [63] have recently shown that BMI, gender, and body site are the most critical factors impacting SC fat thickness. Women have nearly 5 mm more fat than men given the same BMI. Hence, men are at much greater risk for IM injections than women (2–4 times). The lower the BMI is, the greater the IM risk is. Body site is critical. Injections in the thigh have 2- to 4-fold greater IM risk at any length needle than injections in the abdomen. Abdomen and thigh are, of course, the most common sites used.

There is a general paucity of studies regarding insulin absorption from deep or superficial parts of subcutaneous fat tissue. However Frid and Lindén [12] showed no difference in absorption of soluble human insulin from deep compared to superficial injection in patients with T1DM. A more recent study has also suggested that the depth of insulin injection (shallow versus deep SC tissue) does not affect the absorption of insulin [64].

More than a quarter of Indian patients report insulin dripping from the tip of their pen needle after injecting and one out of five report leakage of insulin from their injection sites (data not shown). Both these sources of insulin loss may be the result of not leaving the pen needle under the skin for the requisite time (a full 10 s). Only 12.5% of Indian patients do so (Table 10).

After pushing the thumb button completely in, patients should slowly count to ten before removing the needle in order to get the complete dose and to prevent leakage of insulin [21, 65‐69]. Counting higher than ten may be necessary for larger doses. Counting merely to five may be acceptable for low doses. Patients can find the ideal time for themselves by trial and error, using insulin leakage as a guide.

Pens and cartridges should never be shared between patients because of the risk that biological material from one patient could be drawn into the cartridge and then injected into a subsequent person [70, 71]. Pen needles should be disposed of right after use instead of being left attached. This prevents the entry of air into the cartridge as well as the leakage of insulin. Leakage can affect dose accuracy [21, 67, 71‐73]. Pen needles should be used only once [44, 74‐80].

India is one of the regions of the world where numbers of patients continue to use syringes as their primary device. In India where pens are used for many home injections, syringes are still used predominantly in hospitals. Often hospital insulin syringes are reused, i.e., a patient is assigned a syringe which is used to give all his/her insulin injections during the hospitalization. This increases the risk of blood-borne pathogen transmission since HCPs usually give these injections, recapping the needle between them. Needlestick injuries occur, and the most frequent provoking event is needle recapping.

Whether in the hospital or at home, there is no rationale for using syringes with detachable needles for injecting insulin. Permanently attached needle syringes provide better dose accuracy, reduced cannula diameters, and smaller dead space. They also allow patients to mix insulins if needed. Currently there are no syringes with a needle less than 6 mm in length because of incompatibility with some vial stoppers [81].

A major educational challenge for Indian patients using cloudy insulins (NPH alone or in premixes) is to tip or roll their vial or pen a sufficient number of times for the insulin to go completely back into solution. Failure to do this can lead to uneven concentrations of insulin which can provoke hyper- or hypoglycemia. Only 0.5% of Indian users of such insulins were compliant with the recommendation to tip or roll 20 times.

German studies [65, 82‐85] have revealed the extent of inadequate suspension of cloudy insulins. Some longer-acting insulins have a predetermined ratio of either crystalline insulin and rapid-acting soluble insulin or crystalline insulin and solvent. The crystalline element must be resuspended before each injection; however, patients may not know how best to do this. We believe this is the case in India. Inadequate resuspension of NPH insulin before pen injection is common among Indian patients treated with insulin.

Jehle et al. [86] showed that NPH resuspension was only achieved after mixing (tipping or rolling) 20 times immediately before injection. Patients, however, find this procedure annoying. The authors found that fewer than one in ten did it. Brown et al. [87] found similar results and concluded that significant inappropriate dosing resulted from inadequate resuspension.

Kaiser et al. [88] found that the amount of mixing needed to resuspend NPH varies according to manufacturer. Cartridges with the heaviest and highest number (three) of “bullets” inside took less mixing. However cartridges have only one or two lighter glass “bullets” inside and these take much more effort to resuspend. If resuspension is not done properly doses of NPH are well below what is anticipated by the patient. Kaiser et al. found that all cartridges performed well when used according to the instructions for use, i.e., when mixed 20 times.

Indian patients were asked where they stored their insulin before opening it and nearly nine out of ten reported doing so in the refrigerator. After opening it, three out of four Indian patients continued to store it in the fridge, probably reflecting the fact that ambient temperatures in India are often over 30°. However only 63.3% of those storing insulin in the fridge let it warm up to room temperature before injecting it (a possible cause of injection pain).

Pinching up the skin is a method that has been shown by computerized tomography (CT) scan and ultrasonography to increase the chance of subcutaneous injection. Nevertheless, even a pinch-up may not protect children from intramuscular injections if they use 8-mm needles (which are the shortest currently available in syringes). Polak et al. [89] have shown, however, that a lifted skinfold does not always eliminate the risk of an IM injection, especially in younger thinner children and when using these longer needles. Intramuscular injection occurred more frequently in boys and correlated with lower percentile of BMI and shorter distances from skin surface to muscle fascia, with or without a skinfold. A second study [90] found that the use of 8-mm needles in 50 thin to normal children, all of whom used a pinch-up, significantly reduced but by no means eliminated the risk of intramuscular injections. Thus needles even shorter than 8 mm must be used in children, which calls into question the use of syringes in this population.

We observed whether Indian patients lifted a skinfold and, if so, whether it was lifted correctly and released appropriately. In India more than three-quarters of patients lift a skinfold and, of these, three-quarters do it correctly. However, fewer than half of Indian patients release the fold appropriately (Table 12). Figure 2 shows correct (left) and incorrect (right) ways of performing the skinfold [47].

Management of used sharps in India is a major challenge according to our study. There are comparatively higher percentages of children and housekeepers exposed to used sharps in India than in ROW (Table 16). Many patients do not have proper access to sharps containers or have other risk factors that could lead to blood-borne pathogen spread (Table 17). Far too many used sharps go into the rubbish in India, either with a cap on or without (Tables 18, 19).

India has its own regulations regarding the disposal of contaminated biologic waste. Of note in this study is the fact that more than 60% of used sharps go into the rubbish, with nearly 12% not even having the minimum protection of a cap. These “naked needles” pose an imminent threat to anyone who comes near the rubbish, e.g., family members, house cleaners, rubbish collectors, or those operating incinerators or frequenting dumps.