Safety of the reuse of needles for subcutaneous insulin injection: A systematic review and meta-analysis

International Journal of Nursing Studies 60 (2016) 121–132

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International Journal of Nursing Studies journal homepage: www.elsevier.com/ijns

Review

Safety of the reuse of needles for subcutaneous insulin injection: A systematic review and meta-analysis Edurne Zabaleta-del-Olmo a,b,c,*, Bogdan Vlacho a, Lina Jodar-Ferna´ndez d, Ana-Marı´a Urpı´-Ferna´ndez e, Iris Lumillo-Gutie´rrez f, Josep Agudo-Ugena g, Rosa Morros-Pedro´s a,b, Concepcio´n Viola´n a,b a

Institut Universitari d’Investigacio´ en Atencio´ Prima`ria (IDIAP) Jordi Gol, Gran Via Corts Catalanes, 587 a`tic, 08007 Barcelona, Spain Universitat Auto`noma de Barcelona, Bellaterra, Cerdanyola del Valle`s, Spain Department of Nursing, Universitat de Girona, c/ Emili Grahit 77, 17071 Girona, Spain d Primary Health Care Centre Cornella` 2 (Sant Ildefons), Direccio´ d’Atencio´ Prima`ria Costa de Ponent, Institut Catala` de la Salut, Av. Repu´blica Argentina s/n (cantonada Av. de Sant Ildefons), 08940 Cornella` de Llobregat, Spain e Primary Health Care Centre Carles I, A`mbit d’Atencio´ Prima`ria Barcelona-Ciutat, Institut Catala` de la Salut, c. de la Marina, 168, 08018 Barcelona, Spain f Emergency Primary Care Centre El Castell, Consorci Castelldefels Agents de Salut (CASAP), c. Guillermo Marconi, 9 bxs, 08860 Castelldefels, Spain g Primary Health Care Centre La Mina, A`mbit d’Atencio´ Prima`ria Barcelona-Ciutat, Institut Catala` de la Salut, c. del Mar, s/n, 08930 Sant Adria` de Beso`s, Spain b c

A R T I C L E I N F O

A B S T R A C T

Article history: Received 13 January 2016 Received in revised form 30 March 2016 Accepted 20 April 2016

Objective: Many people with diabetes often reuse disposable needles for subcutaneous insulin injection. We aimed to identify, critically appraise and summarize the available evidence about the safety of this practice. Design: Systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Data sources: MEDLINE (via PubMed), CINALH (via EBSCO), SCOPUS, Web of Science, Cochrane Central Register of Controlled Trials and Open Grey were searched from their inception to December 2015, with no language restrictions. Review methods: Epidemiologic and experimental studies assessing adverse effects of reusing needles in people of any age or sex, with or without diabetes, were included. Two reviewers independently assessed the methodological quality of included studies using a multi-design tool. Results: In total, 25 studies were included. All studies had a high risk of bias and data from only nine studies could be pooled. Five studies showed no association between infection at site of injection and reuse of needles (risk difference = 0.00; 95% confidence interval = 0.12–0.11; P = 0.99); heterogeneity between these studies was substantial (I2 = 66%; P = 0.02). Five cross-sectional studies showed an association between lipohypertrophy and needle reuse (risk difference = 0.16, 95% confidence interval = 0.05–0.28, P = 0.006); there was strong evidence of heterogeneity between these studies (I2 = 87%; P < 0.001). Pooled data of two studies with no evidence of heterogeneity between them showed more perceived pain among reusers (risk difference = 0.24; 95%

Keywords: Equipment reuse Insulin Meta-analysis Needles Patient safety Systematic review

* Corresponding author at: Gran Via Corts Catalanes, 587 a`tic, 08007 Barcelona, Spain. Tel.: +34 934 824 105. E-mail addresses: [email protected] (E. Zabaleta-del-Olmo), [email protected] (B. Vlacho), [email protected] (L. Jodar-Ferna´ndez), [email protected] (A.-M. Urpı´-Ferna´ndez), [email protected] (I. Lumillo-Gutie´rrez), [email protected] (J. Agudo-Ugena), [email protected] (R. Morros-Pedro´s), [email protected] (C. Viola´n). http://dx.doi.org/10.1016/j.ijnurstu.2016.04.010 0020-7489/ß 2016 Elsevier Ltd. All rights reserved.

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confidence interval = 0.06–0.43; P = 0.006). Reusing a pen needle or disposable syringeneedle was not associated with worse glycaemic control. Conclusions: There is currently no clear scientific evidence to suggest for or against the reuse of needles for subcutaneous insulin injection. This practice is very common among people with diabetes; consequently, further research is necessary to establish its safety. ß 2016 Elsevier Ltd. All rights reserved.

What is already known about the topic?  Experts as well as manufacturers advise against the reuse of insulin needles.  Many people with diabetes often reuse disposable insulin needles.  Reusing needles could lead to major cost savings if safety were established. What this paper adds  There is no strong evidence to suggest for or against the reuse of insulin needles.  More high-quality research is needed to determine the risks of insulin needle reuse. 1. Introduction The advent of the disposable syringe-needle was a turning point in the method of administering insulin, which until then was injected by devices that must be sterilized after each use. These new disposable devices have generated controversies in the health sector with regard to their cost, appropriateness, and accuracy. One of the most controversial issues was the reuse of these devices (Bloom, 1985; Dudley Hart, 1988; Fawbush, 1984; Greenough et al., 1979). At present, in most developed countries over 80% of people with diabetes use insulin pens; in Russia and the United States of America (USA), a lower percentage of patients use these devices (67.8% and 43.7%, respectively), with the remainder continuing to use disposable syringe-needles (De Coninck et al., 2010). However, considerable controversy remains about the reuse of disposable devices, especially regarding needle reuse. Diabetes-related institutions, associations and experts as well as manufacturers advise against the reuse of needles for subcutaneous insulin injection, arguing a possible relationship with numerous health risks, including infection, cutaneous lipodystrophy, more painful punctures and loss of accuracy in insulin dose administration (American Diabetes Association, 2004; Deutschen Gesellschaft fur Krankenhaushygiene (DGKH), 2011; King, 2003; Loczenski, 2011). Furthermore, the international best practice document for insulin administration recommends not reusing needles due to its association with lipohypertrophy, although the same document mentions the lack of conclusive scientific evidence of the risks of reuse (Frid et al., 2010). However, many people with diabetes often reuse needles. An international study shows that users of disposable syringe-needle devices reuse needles an average of 3.3 times and users of insulin pen devices an average of 3.6 times, noting that 26.6% of users of insulin pens reuse needles more than five times (De Coninck et al., 2010).

These disagreements between expert recommendations and real-world practice have led to studies that call into question these recommendations and their rationale (Berger et al., 2004; Puder et al., 2005). If patient safety were established, reusing needles could lead to significant cost savings, estimated at about 100 million euros annually in Europe (Puder et al., 2005). Moreover, loss of manual dexterity is a common problem among people with diabetes (Yang et al., 2015), so the assembling and the disassembling of a needle device may present a difficulty. If assembly could be done, for example, every five administrations rather than each time, this barrier would be diminished. In this context and in view of the potential benefits and the possible harms of reusing needles for insulin administration, this systematic review aimed to identify, critically appraise and summarize the available scientific evidence on its safety. 2. Methods We performed a systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Moher et al., 2009). The review protocol is available in the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42013005161. 2.1. Eligibility criteria Studies were selected according to the following criteria. 2.1.1. Study designs We included epidemiologic (cross-sectional, cohort or case-control) and experimental studies. Case studies, case series and qualitative studies were excluded. 2.1.2. Participants and setting The target population consisted of people of any age or sex, with or without diabetes. We included all studies conducted in any setting (inpatients or outpatients) in which the injection was self-administered by the patient or was administered by a health care professional. 2.1.3. Exposure The exposure was the reuse of insulin pen needles and disposable insulin syringe-needles. 2.1.4. Outcomes We only included studies that analysed the association of reusing needles with any adverse effects, mainly signs of

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infection at injection site, lipodystrophy, sensation of pain and poorly controlled glucose level. 2.1.5. Language We included articles published in any language. 2.2. Information sources and search The literature search was conducted in MEDLINE (via PubMed), CINALH (via EBSCO), SCOPUS, Web of Science (WoS), Cochrane Central Register of Controlled Trials (CCRCT) and Open Grey. The databases were searched from their inception to December 2015, with no limit regarding original language of the publication. Reference lists of included publications were checked to identify other studies not found by the initial search. We also used special citation tracking databases (Google Scholar, SCOPUS and WoS) to identify additional articles and contacted study authors to obtain additional data as needed. The search terms employed were ‘‘insulin’’, ‘‘needle’’, ‘‘reuse’’, ‘‘reusing’’, ‘‘re-use’’, ‘‘recycling’’, ‘‘reusability’’, ‘‘repeated use’’, ‘‘multiple use’’ and ‘‘recurrent use’’. Search strategies were developed using controlled vocabulary and free-text terms and were reviewed and refined by the reviewers. Two of the reviewers (EZO and CVF) are health information specialists with systematic review experience. A draft MEDLINE (via PubMed) search strategy is included as Supplementary Data file 1. Supplementary Data file 1 related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j. ijnurstu.2016.04.010.

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and Black form used by the Agency for Healthcare Research and Quality (Deeks et al., 2003; Downs and Black, 1998; Kennelly, 2011). This tool allows the review of methodological quality of studies across the variety of study designs, including both observational and experimental studies. It has 30 items that cover the following domains: reporting (12 items), external validity (4 items), internal validity (13 items) and power (1 item). Each domain generates a score; the maximum total quality score is 31. Total scores greater than or equal to 20 were considered to indicate ‘‘good’’ quality studies, 15–19 ‘‘fair’’ and below 15 ‘‘poor’’ quality. Discrepancies were resolved by consensus or by the judgement of a third reviewer (RMP and CVF). 2.6. Synthesis of results The Cochrane Collaboration’s Review Manager software 5.3 was used to summarize the data. We carried out metaanalyses based on the data available. Outcomes observed were dichotomous and we calculated the risk difference, reporting all outcomes with 95% confidence intervals and overall effects weighted by Mantel–Haenszel methods using random effects models. Statistical heterogeneity was assessed by visual inspection of forest plots and by performing chi-square tests. We quantified the heterogeneity by the I2, which describes ‘‘the percentage of total variation across studies that is due to heterogeneity rather than chance’’ (Higgins et al., 2003). If the P-value was less than 0.10 and I2 exceeded 50%, we considered heterogeneity to be substantial. If the meta-analysis included at least 10 studies, we drew funnel plots to investigate the possibility of publication bias (Higgins and Green, 2011).

2.3. Study selection 3. Results Records of the database searches were merged and duplicates removed. Two reviewers (EZO and RMP) independently screened titles and abstracts. Full text of potentially relevant articles were retrieved and judged for eligibility independently by two reviewers (LJF, AUF, ILG and JAU). Disagreements were resolved by consensus with a third reviewer (EZO, RMP and CVF). Reasons for excluding studies were recorded. Reviewers were not blinded to study authors or their affiliations or to the journal titles. 2.4. Data collection process A data extraction form was developed to collect data on citation details, study design, setting, sample size, participant characteristics, details on exposure and adverse effects, statistical methods used and results. This form was pre-piloted. All data were extracted in duplicate (by LJF, AUF, ILG and JAU) and discrepancies were resolved by discussion involving all review authors. Reviewers used the American Dietetic Association algorithm to classify study designs (American Dietetic Association, 2005). 2.5. Risk of bias in individual studies Two review authors (EZO and BV) independently assessed the methodological quality of included studies using a checklist based on a modified version of the Downs

Our literature search and study selection process (PRISMA flow diagram, Fig. 1) identified 113 records, of which 53 were duplicates. Initial screening excluded 13 records. The remaining 47 full-text articles were assessed for eligibility. Twenty-five articles were excluded (reasons listed in Supplementary Data file 2), 22 articles met the inclusion criteria and three additional articles were identified by reference lists or citation tracking. In total, 25 studies were included in this review. Supplementary Data file 2 related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j. ijnurstu.2016.04.010. 3.1. Study characteristics The review included 11 cross-sectional studies (Angamo et al., 2013; Blanco et al., 2013; Castro and Grossi, 2007; De Coninck et al., 2010; Ji and Lou, 2014; Poteet et al., 1987; Schmeisl and Drobinski, 2009; Strathclyde Diabetic Group, 1983; Strauss et al., 2002; van Munster et al., 2014; Vardar and Kizilci, 2007), nine non-randomized trials (Aziz, 1984; Chlup et al., 1990; Collins et al., 1983; Hodge et al., 1980; Islam and Ali, 1990; Oli et al., 1982; Puder et al., 2005; Stepanas et al., 1982; Thomas et al., 1989), two randomized controlled trials (RCTs) (Crouch et al., 1979; Misnikova et al., 2011), one

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Records identified through database searching (n =113) MEDLINE n =37 CINALH n= 16 SCOPUS n = 46 WoS n =12 CCRCT n = 2 Open Grey n = 0

Records after duplicates removed (n = 60)

Records screened (n = 60)

Full-text articles excluded (n=25)

Records excluded (n = 13)

Full-text articles assessed for eligibility (n = 47) Additional records identified through reference lists or citation tracking (n = 3) Studies included in qualitative synthesis (n = 25)

Studies included in quantitative synthesis (metaanalyses) (n = 9)

Fig. 1. Details of literature search and study selection. PRISMA flow diagram.

prospective cohort study (Panamonta et al., 1989) and two observational studies combined with non-randomized trials (Bosquet et al., 1986; Schuler et al., 1992). Twelve studies were carried out in Europe (Blanco et al., 2013; Bosquet et al., 1986; Chlup et al., 1990; Collins et al., 1983; Misnikova et al., 2011; Puder et al., 2005; Schmeisl and Drobinski, 2009; Schuler et al., 1992; Strathclyde Diabetic Group, 1983; Strauss et al., 2002; van Munster et al., 2014; Vardar and Kizilci, 2007), five in USA (Aziz, 1984; Crouch et al., 1979; Hodge et al., 1980; Poteet et al., 1987; Thomas et al., 1989), three in Asia (Islam and Ali, 1990; Ji and Lou, 2014; Panamonta et al., 1989), two in Africa (Angamo et al., 2013; Oli et al., 1982), one in Brazil (Castro and Grossi, 2007), one in Australia (Stepanas et al., 1982) and one was a multicontinent study (De Coninck et al., 2010). The main characteristics of each study are shown in Table 1. 3.2. Risk of bias within studies 3.2.1. Observational studies There was a lack of information about sample selection in observational studies, such as how potential participants were identified or approached, the response rate, and about differences between those who agreed and declined to participate. Data about the insulin

injection technique used by participants were retrieved using face-to-face interviews (Angamo et al., 2013; Ji and Lou, 2014; Strathclyde Diabetic Group, 1983; Strauss et al., 2002; van Munster et al., 2014; Vardar and Kizilci, 2007) and self-administered questionnaires (De Coninck et al., 2010; Schmeisl and Drobinski, 2009); six studies did not differentiate between these two methods (Blanco et al., 2013; Bosquet et al., 1986; Castro and Grossi, 2007; Poteet et al., 1987; Schuler et al., 1992; Strauss et al., 2002). Three studies (Blanco et al., 2013; De Coninck et al., 2010; Strauss et al., 2002) used the same questionnaire. Only two studies performed a multivariate analysis (Angamo et al., 2013; Vardar and Kizilci, 2007). In two studies, skin changes at injection sites were self-reported (Castro and Grossi, 2007; Poteet et al., 1987). 3.2.2. Experimental studies The RCTs included (Crouch et al., 1979; Misnikova et al., 2011) do not describe the methods used to generate and to conceal the allocation sequence in sufficient detail. Baseline demographic and clinical characteristics for randomized groups are imbalanced (Misnikova et al., 2011) or not described (Crouch et al., 1979). Study participants were blinded in three trials (Misnikova et al., 2011; Puder et al., 2005; Schuler et al.,

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Table 1 Characteristics of included studies. Authors, year, country, study design

Sample, source, age: mean (SD) or median (range), % male

Exposure/intervention

Outcomes

Results

Ji and Lou, 2014, China, cross-sectional

380 type 2 diabetes patients, ambulatory care, 54.6 (8.7) years, 50%

Self-reported needle reuse: – mean number of pen needle uses, 9.19 (SD, 9.30). – 64.5% of participants used a pen needle between 4 and 16 times and 26.8% used it more than 10 times.

– HbA1c recorded in patients’ health records within 3 months. – Lipohypertrophy, bleeding or bruising observed at injection sites by a nurse.

van Munster et al., 2014, The Netherlands, crosssectional

69 children with type 1 diabetes using multiple daily injections, ambulatory care, 15.0 (4.0) years, 55.1%

Self-reported needle reuse.

Angamo et al., 2013, Ethiopia, crosssectional

284 patients with insulin-treated diabetes, diabetes clinic, 40 (16–92) years, 58.5%

Blanco et al., 2013, Spain, cross-sectional

430 people with insulintreated diabetes, primary care and specialty centres, 49 (22.8) years, 51.4%

Repeated use defined as self-reported reuse of disposable syringeneedle more than three injections per needle. Self-reported reuse of needles at least once.

Lipohypertrophy, lipoatrophy and erythema observed at injection sites by experienced paediatric diabetes nurse practitioners. Poor glycaemic control drawn from patient database.

– Significant relationship between needle reuse and lipohypertrophy (r = 0.426, P < 0.001 and chi-square = 8.478, P = 0.004). – Not associated with worse HbA1c (P = 0.480) or bleeding and bruising at the injection sites (P = 0.188). No statistically significant associations were observed.

Misnikova et al., 2011, Russia, randomized controlled trial

45 patients with diabetes type 1 and 2, hospital based, 48 years, 37.8%

Three groups of 15 patients: – 1st group used needles only once (control group). – 2nd group used a needle for 4 days. – 3rd group used a needle for 7 days.

Pain after injection and the presence of any local reaction at the site of injection.

De Coninck et al., 2010, 14 European countries, China and USA, crosssectional

4352 people with insulintreated diabetes, specialist diabetes clinics, community care centres and general practice centres, 48.4 (20.1) years, 49.4%.

– Lipodystrophy and bruising observed at injection sites by a nurse. – Self-reported pain. – HbA1c.

Schmeisl and Drobinski, 2009, Germany, crosssectional

500 insulin-dependent diabetics on intensified conventional insulin therapy, specialist diabetes clinic, 47.7 years, 51.2%

Self-reported reuse of needles – For the users of disposable syringeneedle, the mean number of reported uses per needle was 3.2 (SD, 3.2). – For the users of pen devices, the mean was 3.6 (SD, 3.4). Self-reported reuse of needles.

Lipodystrophy observed at injection sites by a nurse.

Lipodystrophy observed at injection sites.

Reusing disposable syringe-needle not found to be predictor of poor glycaemic control. – Significant relationship between needle reuse and lipohypertrophy (P < 0.05). – Trend towards greater frequency of lipohypertrophy the more times the needle was reused. – On day 1 the degree of pain did not differ statistically between the experimental groups. – On day 4 pain intensity was significantly higher in the 2nd group than in 1st group (P = 0.045). – On day 7 pain was significantly higher in the 3rd group than in the 1st group. – Hyperemic foci were detected only in the 2nd and 3rd groups (13.3% and 26.6%, respectively). – There was a modest but significant relationship between pen needle reuse and lipohypertrophy. – It was not associated with worsening HbA1c, increased pain or the presence of bruising at the injection sites. Using the same needle more than once increases the risk of lipohypertrophy.

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Table 1 (Continued ) Authors, year, country, study design

Sample, source, age: mean (SD) or median (range), % male

Exposure/intervention

Outcomes

Results

Castro and Grossi, 2007, Brazil, cross-sectional

199 diabetic children and adolescents divided in two groups: 153 reusers and 46 non-reusers, ambulatory care, 11.3 (4.5) and 9.1 (4.5) years respectively, 34.7%.

Disposable syringes were reused from one to 19 times.

Nodules, lipodystrophy, pain, bruising, hyperaemia.

Vardar and Kizilci, 2007, Turkey, cross-sectional

215 diabetic people, adult endocrinology polyclinics, 59.6 years, 36.3%. 15 people with insulintreated diabetes, ambulatory care, 23–78 years old Four blinded nondiabetic volunteers.

Self-reported reuse of needles.

Lipohypertrophy observed at injection sites.

People with diabetes used insulin pen needles one to four times (10 injections per person) and non-diabetic volunteers, one to five times with two different needles (30 injections per person).

Pain intensity and unpleasantness measured by a visual analogue scale.

Strauss et al., 2002, Belgium, France, Germany, Italy, Spain, Sweden and United Kingdom, crosssectional

1002 insulin-injecting type 1 and 2 diabetic patients, specialist diabetes clinics, community care centres and general practice centres, 46.9 (18.4) years, 49.2%.

Reuse of disposable needles. 59.1% of patients reuse more than once. The mean number of reported uses per needle was 3.3 (SD, 3.1).

– Observed anomalies at injection sites (insulin reflux, bruising, lipoatrophy, lipohypertrophy, inflammation, induration, scarring). – Glucose control: latest HbA1c.

Schuler et al., 1992, Germany, (a) retrospective observational study (b) non-randomized trial

20 people with insulintreated diabetes and usual reusers of needles, ambulatory care, 35 (18–74) years.

Chlup et al., 1990, Czech Republic, nonrandomized trial

100 people with insulintreated diabetes with diabetes, hospital based.

(a) Self-reported frequency of needle reuse. (b) Insulin pen needles were reused from one to 12 times. Reuse of disposable needles from four to 200 injections (average 41) for one to 12 weeks.

Islam and Ali, 1990, Bangladesh, nonrandomized trial

92 people with insulintreated diabetes, hospital based, 52 (14) years, 72.8%. 11 people with insulintreated diabetes, hospital based, 5–13 years old, 36.4%. 56 diabetic patients who reused syringes and needles, ambulatory care, 54 (13) years, 30%.

(a) Self-reported complications associated with the injection. (b) Signs of local infection reported or recognized by a medical doctor. Clinical signs of infections and other skin changes at sites of injections, examination by medical check-up. Swelling, redness and tenderness observed at sites of injections.

– Frequency of nodules (P = 0.224) and lipohypertrophy (P = 0.70) was similar in both groups. – There was no significant difference between the groups (frequency of pain, bruising, hyperaemia and lipoatrophy < 3 in both groups). Using the same needle more than once increases the risk of lipohypertrophy. – 270 injections were performed with 123 needles. – There were no local complications at the injection sites. – Reusing insulin pen needles did not increase either sensation of pain or unpleasantness. – There is a strong tendency for patients who reuse needles to have more lipohypertrophic lesions (P = 0.067). – Patients who use pens and reuse needles have a higher risk of having lipohypertrophy (P = 0.058). – There is a 31% increased risk of lipohypertrophy if one reuses. No signs of local infection were reported or observed.

Puder et al., 2005, Switzerland, nonrandomized trial

Panamonta et al., 1989, Thailand, prospective cohort study Thomas et al., 1989, USA, non-randomized trial

Reuse of disposable needles from three to 10 days. Reuse of disposable needles for more than three days, study period was one month. Reuse of insulin syringe units seven times or less (mean 6.6 times), average follow-up was 8.3 months.

In rare cases slight redness not exceeding 4 mm2.

No signs were observed.

Swelling, redness and tenderness observed at sites of injections.

No signs were observed.

Pain and clinical signs of infections and other skin changes at sites of injections.

– No patient had an infection at injection site. – Redness in three of 56 patients. – Pain in two of 56 patients. – Itching in two of 56 patients.

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Table 1 (Continued ) Authors, year, country, study design

Sample, source, age: mean (SD) or median (range), % male

Exposure/intervention

Outcomes

Results

Poteet et al., 1987, USA, cross-sectional

166 insulin-dependent diabetics, ambulatory care, between 22 and 77 years.

Self-reported clinical signs of infections and other skin changes at sites of injections.

Four (5.4%) reusers reported redness at the injection site compared to 13 (14.1%) nonreusers.

Bosquet et al., 1986, France, (a) cross-sectional (b) non-randomized trial

(a) 120 insulindependent diabetics, hospital based and ambulatory care, (b) 37 insulin-dependent diabetics, hospital based.

Disposable insulin syringes were reused from one to 20 times. Of the 74 who reused their syringes, 90.5% reused them 2–4 times. (a) Self-reported reuse of disposable units, from 2 to 16 times for a few days to 4 weeks. (b) Reuse of disposable syringe-needle for three consecutive times.

Pain and clinical signs of infections and other skin changes at sites of injections.

Aziz, 1984, USA, nonrandomized trial

14 children with diabetes type 1, ambulatory care, 7–18 years old, 28.6%

Clinical signs of infections and other skin changes at sites of injections.

Strathclyde Diabetic Group, 1983, United Kingdom, crosssectional Collins et al., 1983, Northern Ireland, nonrandomized trial

153 insulin-dependent diabetics who reuse disposable equipment.

Reuse of disposable needles from one to 16 times (average 6.3) for 11–444 days (mean 94 days). Reuse of disposable syringe-needle.

(a) Two people reported pain from the third injection and one person had an abdominal abscess. (b) Signs of infection were not observed and minor local incidents (pain, pruritus) were rare and unrelated to the reuse of equipment. Only one instance of local redness lasting one day was reported.

Stepanas et al., 1982, Australia, nonrandomized trial

17 insulin-dependent diabetics, hospital based, 10–67 years, 29%.

Oli et al., 1982, Nigeria, non-randomized trial

21 insulin-dependent diabetics.

Hodge et al., 1980, USA, non-randomized trial

14 insulin-dependent adult diabetics, 36–70 years.

Reuse of disposable needle for three consecutive days, average follow-up was 20.4 weeks.

Crouch et al., 1979, USA, randomized controlled trial

32 insulin-dependent adult diabetics (14 used glass syringes with daily new needles and 18 reused plastic disposable needle-syringe units), hospital based,

Reuse of disposable plastic syringe-needle for 5 consecutive days.

53 insulin-dependent diabetics, hospital based, 15–75 years old, 56.6%.

Reuse of disposable syringe-needle for 7 days, replaced when it became blunt. Reuse of disposable syringe-needle from one to 80 days (mean 12.2 days per syringe). Reuse of disposable needle from 3 to 9 days for 6 months.

1992); measures to blind those evaluating outcomes are not described for any of the included studies. Only two studies report losses to follow-up (Schuler et al., 1992; Thomas et al., 1989). In non-randomized trials, study participants were receiving antibiotic treatment (Islam and Ali, 1990) and only one trial included non-diabetic participants (Puder et al., 2005). 3.2.3. All studies Adverse effects at insulin administration sites were measured by a trained or experienced healthcare professional in most of the studies, but there is a lack of information about the reliability and validity of the examination criteria. Furthermore, only a few studies

Self-reported clinical signs of infections at injections sites (redness, swelling or both). Irritation or infection observed at sites of injections. Irritation, swelling, redness or soreness at injection sites. Clinical signs of infections and other skin changes at sites of injections. Clinical signs of infections and other skin changes at sites of injections.

Evidence of inflammation and/or induration at sites of injections.

One person reported signs of infections at injection site. No patient had evidence of injection-site irritation or infection. No signs related to erythema or local reactions were reported or observed. No signs related to erythema or local reactions were observed. No signs related to erythema or local reactions were reported by any patient or observed by the investigators. Four patients presented slight erythema (one of plastic group and three of glass group).

used available tools to improve the comparability, objectivity and reliability of this measurement (Angamo et al., 2013), blinded the examiners (Blanco et al., 2013), or reported the potential study limitation of not having assessed adverse effects other than at injection sites (Schmeisl and Drobinski, 2009). Moreover, a formal power calculation was rarely conducted. Table 2 shows the scores on each domain for all studies. 3.3. Results of studies 3.3.1. Infection or clinical signs of infection at injection sites Twenty-one studies reported infection outcomes or clinical signs of infection at injection sites.

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Table 2 Risk of bias of studies included. Authors, year, study design

Score on each domain

Methodologicalquality

External validity (4 items)

Internal validity/Bias (7 items)

Internal validity/ confounding (6 items)

Power (1 item)

6

1

0

1

0

8

Poor

9

2

0

2

0

13

Poor

8

2

4

2

0

16

Fair

6

2

0

1

0

9

Poor

6

2

1

2

0

11

Poor

2

2

0

1

0

5

Poor

9

2

1

2

0

14

Poor

5

0

1

1

0

7

Poor

10

1

5

2

0

16

4

0

2

0

0

6

Poor

7

0

0

1

0

8

Poor

9

0

0

1

0

14

Poor

4

0

0

1

0

5

Poor

3

1

0

0

0

4

Poor

7

0

1

0

0

8

Poor

8

0

1

1

0

10

Poor

3

1

0

0

0

4

Poor

4

0

1

0

0

5

Poor

3

0

0

0

0

3

Poor

5

0

0

0

0

5

Poor

1

0

0

0

0

1

Poor

3

0

1

0

0

4

Poor

2

0

0

0

0

2

Poor

5

0

0

1

0

6

Poor

4

1

0

1

0

5

Poor

Reporting (12 items)

Ji and Lou, 2014, crosssectional van Munster et al., 2014, cross-sectional Angamo et al., 2013, cross-sectional Blanco et al., 2013, cross-sectional Misnikova et al., 2011, randomized controlled trial De Coninck et al., 2010, cross-sectional Schmeisl and Drobinski, 2009, cross-sectional Castro and Grossi, 2007, cross-sectional survey Vardar and Kizilci, 2007, Turkey, cross-sectional Puder et al., 2005, non-randomized trial Strauss et al., 2002, cross-sectional Schuler et al., 1992, retrospective observational study and non-randomized trial Chlup et al., 1990, non-randomized trial Islam and Ali, 1990, non-randomized trial Panamonta et al., 1989, prospective cohort study Thomas et al., 1989, non-randomized trial Poteet et al., 1987, cross-sectional Bosquet et al., 1986, cross-sectional and non-randomized trial Aziz, 1984, nonrandomized trial Strathclyde Diabetic Group, 1983, cross-sectional Collins et al., 1983, non-randomized trial Stepanas et al., 1982, non-randomized trial Oli et al., 1982, non-randomized trial Hodge et al., 1980, non-randomized trial Crouch et al., 1979, randomized controlled trial

Sum of all domain scores (30 items)

Eight observational studies (Castro and Grossi, 2007; De Coninck et al., 2010; Islam and Ali, 1990; Ji and Lou, 2014; Panamonta et al., 1989; Poteet et al., 1987; Schuler et al., 1992; van Munster et al., 2014) found no association between infection and reusing needles. Six non-randomized

Fair

trials reported no signs of local infection (Collins et al., 1983; Hodge et al., 1980; Oli et al., 1982; Puder et al., 2005; Schuler et al., 1992; Stepanas et al., 1982) and one RCT did not find statistically significant differences between reusers and non-reusers (Crouch et al., 1979).

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Two cross-sectional studies and three non-randomized trials reported infection or clinical signs of infection in rare cases (Aziz, 1984; Bosquet et al., 1986; Chlup et al., 1990; Strathclyde Diabetic Group, 1983; Thomas et al., 1989). One RCT observed hyperaemic foci only in reusers (Misnikova et al., 2011). Five studies could be included in a meta-analysis (Bosquet et al., 1986; Crouch et al., 1979; Misnikova et al., 2011; Poteet et al., 1987; van Munster et al., 2014). The pooled data (Fig. 2) showed no significant difference between needle reusers and non-reusers (risk difference = 0.00, 95% confidence interval = 0.12– 0.11, P = 0.99). Heterogeneity between studies was substantial (I2 = 66%; chi-square = 11.68, df = 4; P = 0.02). 3.3.2. Lipodystrophy The relationship between needle reuse and lipodystrophy was examined in eight cross-sectional studies (Blanco et al., 2013; Castro and Grossi, 2007; De Coninck et al., 2010; Ji and Lou, 2014; Schmeisl and Drobinski, 2009; Strauss et al., 2002; van Munster et al., 2014; Vardar and Kizilci, 2007). Six of these studies found a positive association between lipohypertrophy and reusing (Blanco et al., 2013; De Coninck et al., 2010; Ji and Lou, 2014; Schmeisl and Drobinski, 2009; Strauss et al., 2002; Vardar and Kizilci, 2007) and two (Castro and Grossi, 2007; van Munster et al., 2014) found no association. Two studies that assessed lipoatrophy did not find an association with reusing needles (Castro and Grossi, 2007; van Munster et al., 2014). Lipohypertrophy data were available for five studies (Blanco et al., 2013; De Coninck et al., 2010; Schmeisl and Drobinski, 2009; van Munster et al., 2014; Vardar and Kizilci, 2007). In the pooled analysis (Fig. 3), lipohypertrophy was

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associated with needle reuse (risk difference = 0.16, 95% confidence interval = 0.05–0.28, P = 0.006), with strong evidence of heterogeneity (I2 = 87%; chi-square = 31.46, df = 4; P < 0.001). 3.3.3. Pain Six studies reported outcomes related to pain. Two cross-sectional studies (Castro and Grossi, 2007; De Coninck et al., 2010; Puder et al., 2005) and a nonrandomized trial (Castro and Grossi, 2007; De Coninck et al., 2010; Puder et al., 2005) found no association between reusing needles and pain at the injection site. In the cross-sectional study carried out by Bosquet et al. (1986), two of the 10 reusers perceived pain from the third injection and in the trial published in the same article, 10 of 37 reusers experienced pain and pruritus at the injection site. Results of a RCT showed that using needles only once causes less pain than reused needles (Misnikova et al., 2011). Finally, a non-randomized trial reported pain in two of 56 reusers (Thomas et al., 1989). Two studies could be included in a meta-analysis (Bosquet et al., 1986; Misnikova et al., 2011). Pooled data (Fig. 4) showed that pain was more often perceived among reusers (risk difference = 0.24, 95% confidence interval = 0.06–0.43, P = 0.006). There was no evidence of heterogeneity between studies (I2 = 0%). 3.3.4. Glycaemic control Three cross-sectional studies analysed the relationship between needle reuse and glycaemic control (Angamo et al., 2013; De Coninck et al., 2010; Ji and Lou, 2014). Reusing a pen needle or disposable syringe-needle was not associated with worse glycaemic control in any of these studies.

Fig. 2. Infections or clinical signs of infection at sites of injection in needle reusers compared to non-reusers, risk difference and 95% confidence interval (CI).

Fig. 3. Lipohypertrophy in needle reusers compared to non-reusers, risk difference and 95% confidence interval (CI).

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Fig. 4. Pain reported by needle reusers compared to non-reusers, risk difference and 95% confidence interval (CI).

3.4. Risk of bias across studies We did not draw a funnel plot to explore the possibility of publication bias because the meta-analyses included fewer than 10 studies. 4. Discussion To our knowledge, this is the first systematic review on the topic of the reuse of needles for subcutaneous insulin injection. The 25 studies included provide limited evidence to suggest for or against the reuse of pen needles or disposable syringe-needles. Infection or clinical signs of infection at injection sites were the most studied adverse effect, but reusing needles was not associated with local infection. Pooled data also showed that these signs were statistically similar between reusers and non-reusers. However, only five of 21 studies that analysed this result could be included in the metaanalysis and these studies were shown to be heterogeneous (Fig. 2). Moreover, the majority of the studies were cross-sectional and prospective studies that differed on the number of times a needle was reused as well as the conditions and type of reused material. Therefore, the available evidence is not conclusive to establish a causal relationship between reuse of needles and infection at the injection site. Lipodystrophy is the second most studied side effect, analysed in eight of the 25 studies identified; however, these studies were cross-sectional and showed inconsistent results. Only one study (Vardar and Kizilci, 2007) included multivariate analysis. The meta-analysis carried out with five of these studies showed a statistically significant association between the presence of lipohypertrophy and reuse of needles; however, these studies were highly heterogeneous, making the available evidence inconclusive. Three cross-sectional studies and three trials assessed the relationship between reusing needles and pain associated with the injection. Only one of these studies (Misnikova et al., 2011) showed a statistically significant association between increased perception of pain and the reuse of needles. The two studies that could be pooled into the meta-analysis were homogeneous and showed that people who reuse needles feel more pain at the injection site than whose do not reuse. However, it was impossible to incorporate the results of all the selected studies, so the data from the meta-analysis cannot be used to draw sound conclusions. Glycaemic control was the least evaluated result. Only three cross-sectional studies evaluated the effect of reusing needles and glycaemia; they found no association.

Given the lack of solid scientific evidence, some experts express no objections to a patient’s reuse of his or her own needles within a limited time period (Nussbaum, 2005); however, most best-practice guidelines recommend against any reuse because of the possible adverse effects (Frid et al., 2010; Hutin et al., 2003; Saltiel-Berzin et al., 2012). Nonetheless, many of these adverse effects can be explained by other factors, such as the duration of insulin therapy, type of insulin, characteristics of the needles, injection technique used, or appropriate rotation of injection sites (Al Ajlouni et al., 2015; Hauner et al., 1996; Præstmark et al., 2016). With respect to the last two factors, it is important to emphasize that 21% of people with diabetes report using the same insulin injection site for an entire day or even various days, and 32% admit to having no systematic approach for selection of an injection site (De Coninck et al., 2010). On the other hand, some studies have raised the possibility of adverse effects from frequently changing the needle in reusable insulin pens, arguing that this can increase the risk of introducing pieces from the rubber stopper into the insulin cartridge (Puder et al., 2005). In one study, 73% of insulin cartridges were found to contain rubber pieces that could be injected into the subcutaneous tissue (Asakura et al., 2001). These conflicting reports clearly illustrate the urgent need for further research to establish the safety of reusing needles for subcutaneous insulin injection. 4.1. Limitations We conducted a comprehensive literature search with no language limits. Additionally, we checked the reference lists and turned to citation tracking to identify many relevant articles. We also contacted the authors of the included studies for any additional information needed. However, we could only pool data from nine studies. Studies included in this systematic review have a high risk of bias. The methodological quality of 23 studies was considered ‘‘poor’’. Only two cross-sectional studies were rated as ‘‘fair’’ and no studies were classified as having ‘‘good’’ methodological quality. Most of the studies included fewer than 100 participants (Aziz, 1984; Bosquet et al., 1986; Collins et al., 1983; Crouch et al., 1979; Hodge et al., 1980; Misnikova et al., 2011; Oli et al., 1982; Panamonta et al., 1989; Schuler et al., 1992; Stepanas et al., 1982; Thomas et al., 1989; van Munster et al., 2014). On the other hand, the applicability of the results is limited because about half of studies were carried out in the 80s and 90s and the settings and study population were very heterogeneous.

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4.2. Implications for practice and research Most people with diabetes reuse needles, mainly for economic reasons and convenience. Currently, best practice guidelines for insulin injection recommend using a new needle for each injection (Frid et al., 2010). These same guidelines emphasize the need for prospective research, which could produce sound evidence about the safety of reusing needles. Furthermore, clinical practice guides of recognized prestige and editorial independence do not address the issue of the reuse of needles. They merely establish guidelines on the length of the needles and recommend those that are less expensive (National Institute for Health and Care Excellence (NICE), 2015). Reusing needles can significantly increase cost savings for people with diabetes and for healthcare systems (Puder et al., 2005), but solid scientific evidence to support its safety is essential before a recommendation in this respect can be made. Prospective studies are needed, preferably RCTs involving enough participants to maximize statistical power and with a sufficiently long follow-up to display all possible associated adverse effects. It is also necessary to minimize potential information or classification biases by using appropriate participant selection methods to ensure the validity of results. Finally, studies are needed that isolate the confounding effect of other variables or exposure related to type of insulin or adverse effects of reuse of needles, such as rotation of the injection site.

5. Conclusions No clear scientific evidence is currently available to recommend for or against the reuse of needles for subcutaneous insulin injection. This practice is very common among people with diabetes; consequently, further research is necessary to establish its safety. Acknowledgements The authors wish to thank staff of the Documentation ˜ ezCentre of Institut Catala` de la Salut, Manuel Lupia´n Rodrı´guez and Elena Bilbao-Ventura, for their support to retrieve the full articles. We also appreciate the review of the English text by Elaine Lilly, PhD, and the support for dissemination of our study results awarded by Institut Universitari d’Investigacio´ en Atencio´ Prima`ria (IDIAP) Jordi Gol. Conflict of interest: None declared. Funding: None declared. References Al Ajlouni, M., Abujbara, M., Batieha, A., Ajlouni, K., 2015. Prevalence of lipohypertrophy and associated risk factors in insulin-treated patients with type 2 diabetes mellitus. Int. J. Endocrinol. Metab. 13, e20776, http://dx.doi.org/10.5812/ijem.20776. American Diabetes Association, 2004. Insulin administration. Diabetes Care 27, 106S–107S, http://dx.doi.org/10.2337/diacare.27.2007.S106. American Dietetic Association, 2005. ADA Evidence Analysis Manual. American Dietetic Association, Chicago.

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