Metformin in Gestational Diabetes: The Offspring Follow-Up (MiG TOFU)Body composition at 2 years of age ANET A. ROWAN, MBCHB MALCOLM BATTIN, MD that because of continued exposure to nu- LAINE C. RUSH, PHD TRECIA WOULDES, PHD trient excess in utero, the subcutaneous ICTOR OBOLONKIN, BSC WILLIAM M. HAGUE, MD fat stores become overloaded and, thus,the fetus develops leptin and insulin re-sistance and deposits excess nutrients as
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Vita.had.co.nzAuthor's personal copy Annals of Biomedical Engineering (Ó 2013)DOI: 10.1007/s10439-013-0780-z Design, Evaluation, and Dissemination of a Plastic Syringe Clip to Improve Dosing Accuracy of Liquid Medications GARRETT J. SPIEGEL,1 CINDY DINH,1 AMANDA GUTIERREZ,1 JULIA LUKOMNIK,1 BENJAMIN LU,1 KAMAL SHAH,1 TARA SLOUGH,1 PING TERESA YEH,1 YVETTE MIRABAL,1 LAUREN VESTEWIG GRAY,1 STEPHANIE MARTON,2 MICHELLE ADLER,2 GORDON E. SCHUTZE,2 HADLEY WICKHAM,3 MARIA ODEN,1 EBECCA RICHARDS-KORTUM 1Rice 360°: Institute for Global Health Technologies, Rice University, 6100 Main St., Houston, TX 77005, USA; 2Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; and 3Department of Statistics, Rice University, 6100 Main St., Houston, TX 77005, USA (Received 13 November 2012; accepted 15 February 2013) Associate Editor John Desjardins oversaw the review of this article.
Abstract—Pediatricians in Africa requested a tool to improve program in which students from all disciplines work caregiver dosing of liquid antiretroviral medication. We collaboratively to use the engineering design process to developed, evaluated and disseminated a clip to control the develop technological solutions to challenges of health amount of medication drawn into an oral syringe. In a and healthcare delivery in the developing world.
laboratory, a user tested clips of different lengths, corre-sponding to different volumes, by drawing water into a These challenges are identiﬁed by healthcare providers syringe with a clip. In Texas and Malawi, 149 adults working in low-resource settingsIn this paper, we attempted to measure Pepto-BismolTM using a syringe with describe the design, evaluation, and implementation of a clip, a syringe without a clip, and a dosing cup, in a a syringe clip, a student-designed technology devel- randomly assigned order. In the laboratory, the volume of oped through this process to help improve the accuracy liquid, ranging from 1 to 4.5 mL, drawn into the syringe wasalways within at least 5 lL of the intended dose. In Texas, of dosing liquid medication. The syringe clip ﬁts into 84% of doses were accurate within ±10%, vs. 63% using the the barrel of an oral dosing syringe to regulate the syringe alone, and 21% with the dosing cup. In Malawi, 98% amount of liquid drawn into the syringe according to of doses were accurate to within ±10%, vs. 90% using the dosage. The syringe clip was tested in community set- syringe alone, and 27% with the dosing cup. For target tings in Houston, Texas, and Kamangira, Malawi. The accuracy values within ±45% (±21%), a signiﬁcantly higherfraction of Houston (Kamangira) participants delivered an syringe clip, which has dual application in the devel- accurate dose using the syringe with the clip than with the oped and developing worlds, has been licensed to pri- syringe alone (p < 0.05). The clip enables a greater propor- tion of users to accurately measure liquid medication.
Swaziland's National Prevention of Mother to ChildTransmission (PMTCT) of HIV/AIDS program.
Keywords—Dosing error, Measuring devices, Medication Studies in the developed world show that inaccurate administration, Medication errors, Global health, Low- dosing of liquid medication, particularly in the home- resource settings.
setting, is a common occurrence. Liquid medicationsare commonly used in the pediatric population; onestudy reported that more than 80% of children have received liquid acetaminophen by 6 months of age.Most medications for children are administered by The Beyond Traditional Borders (BTB) initiative their parents or guardians, and a number of studies at Rice University is an undergraduate education show that 40–60% of parents make errors when givingmedications to their children., Dosing devices for oral medications include oral Address correspondence to Rebecca Richards-Kortum, Rice 360°: Institute for Global Health Technologies, Rice University, 6100 syringes, oral droppers, dosing spoons, and plastic Main St., Houston, TX 77005, USA. Electronic mail: rkortum@ medicine cups.Even when such calibrated delivery Ó 2013 Biomedical Engineering Society Author's personal copy SPIEGEL et al.
devices are used, they do not eliminate inaccurate the plunger can be pulled back, dictating the amount dosing. Recent studies in the developed world show of medication that can be drawn into the syringe.
that more than half of parents made errors in dosing Different lengths of the clip correspond to different with plastic dosing cups, primarily overdosin dosages of medication. The dosing clips are color- While several comparisons of dosage delivery devices coded by dosage; when prescribing liquid medication have demonstrated that oral syringes are superior to to be delivered with an oral syringe, a physician can other devices,one study found that a large prescribe the color of clip that corresponds with the proportion of caregivers could not measure the proper correct dosage. A pharmacist then includes this color amount of medication using either an oral dosing of clip with the syringe when dispensing medication to syringe or a dosing cup.In addition, small markings the patient. In this paper, we describe an assessment of on oral syringes can be difﬁcult to read by users with the accuracy of the dosing clip in a laboratory and limited visual acuity and can wash off after multiple community setting. We discuss efforts to disseminate uses. Studies in the developed world have shown that the technology in low-resource settings.
caregivers with low health literacy are at greatest riskfor inaccurate dosing.
Little is reported about caregiver dosing accuracy in MATERIALS AND METHODS the developing world. However, there are many studiesthat focus on adherence to antiretroviral medication Standard oral dosing syringes are designed to for HIV-positive patients in the developing world.
deliver variable doses of liquid medication. In order to Young HIV-positive children receiving treatment and deliver the proper dose, the user must identify mark- ings corresponding to the intended dose on the outside PMTCT of HIV/AIDS are often prescribed liquid of the syringe barrel and pull the plunger back until the antiretroviral medication, which is administered using liquid level in the barrel matches the correct marking.
an oral dosing syringe.Dosing regimens, especially We designed a plastic clip that can be inserted into a for HIV treatment, can be complex, requiring different standard oral dosing syringe to simplify the process of volumes for each drug and the continual increase of delivering an accurate dose of medication. Clips used the volume of the dose as the child grows.For for this study were made from ABS plastic using a caregivers who are unfamiliar with liquid measure- 3D-printer (SST 768, Dimension/Stratasys). Using this ments or who are elderly with poor visual acuity, low-volume method of manufacture, clips can be correct dosing can be a Bagenda et al.
produced for a materials cost of approximately $0.23 found that users of syrup formulations, particularly per clip. At current production levels, the clips cost elderly or illiterate caregivers, had difﬁculty measuring approximately $0.10 per clip. By comparison, when the precise dosing measurements using a calibrated syringe clips are mass produced, we anticipate that the price of and/or cup, and that adherence to syrups is lower than the clips will change to $0.02–$0.05 per clip. Syringes adherence to tablets. Some studies ﬁnd that caregivers can be purchased at a distributor discount of approx- in the developing world overestimate their children's imately $0.35 per syringe; thus, the clips cost about adherence to antiretroviral medication.Some phy- one-third the price of the syringe. Because treatment sicians in the developing world have noted that if oral regimens for antiretroviral medication often call for syringes are not available, patients use bottle tops, decreases in dosage over time, a combination of dif- spoons, medicine caps, and other improvised tools for ferent syringe sizes would be required. Including dosing,which may exacerbate inaccurate dosing.
syringes of all necessary sizes, rather than simply To address these concerns, in 2007, pediatricians including clips at diﬀerent lengths for a single syringe, prescribing liquid antiretroviral medication to HIV- positive children in Swaziland identiﬁed a need for a expenses required to make alternate lengths of clips is low-cost dosage delivery device for liquid drugs that signiﬁcantly lower than that required to build syringes could be preset by a health care professional and given of diﬀerent volumes, and in some cases, the dosages are to a caregiver to administer to a patient, regardless of unusual volumes. It is therefore more economical to the caregiver's visual acuity, manual dexterity, literacy, make many diﬀerent lengths of clips than to make or numeracy skills. To address this need, students ﬁrst many diﬀerent syringes.
designed a mechanical, metered dosing pump for liquid Figure a shows a photo of the clip, which consists medications.After receiving feedback on the design of two segments: a distal straight segment which is from physicians in the United States, Botswana, inserted into the barrel of the syringe, and a proximal Malawi, and a second team of students C-shaped segment which clips over the neck of the designed a simple syringe clip that can be inserted into syringe and holds the clip in place. To use the clip, a a standard oral dosing syringe to limit the distance that physician, pharmacist, nurse, health educator, or Author's personal copy Plastic Syringe Clip to Improve Dosing Accuracy caretaker inserts it into the barrel of the syringe and The performance of the clips was then compared to rotates the clip in order to secure it to the lip of the standard oral dosing syringes and cups in community barrel. The distal tip of the clip limits the extent to settings in Houston, Texas, and Kamangira, Malawi. The which the plunger can be pulled back. Therefore, the study was reviewed and approved by the Institutional length of the distal segment of the clip determines the Review Board at Rice University. In Houston, 89 adults dosage; clips can be color coded to indicate dose attending a health fair at a YMCA were recruited to participate in the study; all participants gave written The accuracy of the dosage of medication that could informed consent. Participants completed an anonymous be delivered using the clips was tested ﬁrst in a labo- questionnaire to collect demographic information, ratory setting. Eight lengths of clips, representing eight including age and highest level of completed education. In intended doses ranging from 1.0 to 4.5 mL in 0.5 mL Malawi, village elders recruited 60 interested adults to increments, were tested by a single user. For each participate; 49 had never measured liquid medication intended dose, four clips were tested. In the test, the before. Due to comparatively low literacy levels, all par- same clip was inserted into three diﬀerent oral syringes, ticipants gave informed consent and answered selected and water was drawn into each syringe three times, for survey questions verbally in the local language of Chi- a total of nine trials per clip, or 36 trials per dose. The chewa. For each participant, an investigator or translator weight of water drawn into the syringe for each trial read identical instructions and demonstrated proper was measured using a balance. The volume of the measurement of a 2.5 mL dose of liquid using each of the delivered dose was then calculated using the known three dosing methods: a standard 5 mL oral dosing syr- density of water.
inge with a clip, a standard 5 mL oral dosing syringewithout a clip, and a standard oral dosing cup. InHouston, a standard 15 mL commercially availableliquid medication dosing cup was used, and in Malawi, astandard 10 mL dosing cup was used, reﬂecting the cur-rent stock of the local hospital. The 2.5 mL dose wasselected because it is a mid-range dose for the 5 mL oraldosing syringe and within range for pediatric dosing.
After watching the demonstration, participants were thenasked to measure a 2.5 mL dose of Pepto-BismolTM usingthe three dosing methods; the order in which participantscompleted the three tasks was randomly assigned. Pepto-BismolTM was used due to its higher viscosity to simulatemedications such as Kaletra, a standard antiretroviralmedication for children in developing countries. Theamount of liquid was weighed and recorded for all dosingmethods; the volume of the delivered dose was calculatedusing the density of the liquid.
Table compares the intended dose and the dose delivered using the clips in a laboratory setting. Usingthe dosing clips, the volume of water drawn into thesyringe was within 5 lL of the intended dose for alldoses tested. This ﬁnding held across all combinationsof clips and syringes.
Eighty-nine participants from Houston and 60 (a) The process of inserting the dosing clip into a standard oral dosing syringe. (1) The plunger is pulled back; participants from Kamangira were recruited to par- (2) the clip is placed alongside the plunger; (3) the plunger ticipate in the study in the community setting; partic- and clip are pushed into the syringe barrel until the C-shaped ipants ranged in age from 18 years old to >70 years upper segment of the clip reaches the lip of the barrel; (4) theclip is rotated to lock the clip into place. With the clip in place, old (Fig. ). Table shows the average, SD, range of the syringe plunger can only be pulled back until it reaches the dose of Pepto-BismolTM for each dosing method in the distal tip of the clip. (b) The length of the distal segment of each participant group. On average, the dose delivered the clip determines the dose which can be delivered; clips arecolor coded and labeled according to dose.
using the oral dosing syringe, either with or without a Author's personal copy SPIEGEL et al.
dosing clip, was closest to the intended dose. The use of A v2 test with correction for cells with fewer than the dosing clip was associated with least variation in ﬁve entries was used to assess whether differences in delivered dose, as assessed both by the SD and the range the fraction of participants achieving the target accu- of the delivered dose. When using the syringe with a racy (in terms of % error) were statistically signi; dosing clip, no participants delivered a dose greater than results are shown in Figs. a and b. Differences in 2.55 mL. In contrast, when using the syringe alone, accuracy associated with the dosing cup were statisti- some participants delivered a dose of almost double the cally signiﬁcant at all accuracy thresholds. For target intended dose (4.66 mL). For both study populations, accuracy values less than or equal to ±45%, a signif- the average dose delivered using the dosing cup was icantly higher fraction of Houston participants could furthest from the intended dose. The dosing cup was deliver an accurate dose using the syringe with the clip associated with the greatest variation in delivered dose than using the syringe alone (p < 0.05); for target for both groups, with some participants delivering more accuracy values of less than or equal to ±21% a sig- than ﬁve times the intended dose (14.16 mL).
niﬁcantly higher fraction of the Kamangira partici- Figure shows a cumulative frequency plot indi- pants delivered an accurate dose using the syringe with cating the fraction of Houston participants who the clip compared to the syringe alone (p < 0.05).
delivered a volume of Pepto-BismolTM less than or The target accuracy for our clip is the set dose of ±10%, equal to the dose indicated. The dotted line shows the consistent with other studies of dosing accuracy, which expected step-function result if all participants had ranged from ±4 to 20%.We evaluated the per- delivered the correct dose of 2.50 mL. Figure shows centage of participants who prepared a dose within these a similar cumulative frequency plot for the Kamangira limits (Fig. ). Using the dosing clip resulted in 84% of population. Results for both groups indicate that doses doses in the target range of 2.5 mL ± 10% for the delivered with the dosing clip are most similar to the Houston participant group. Within this same group, only ideal result.
63% drew the target dose with the oral syringe alone and21% met this target with the dosing cup. In addition, with The average dose (61 SD) delivered using dosing the dosing clip in place, the maximum volume of Pepto- clips vs. intended dose measured in a laboratory setting.
BismolTM that any participant measured was 2.50 mL, Intended dose (mL) Measured dose (mL) indicating that the dosing clip did not allow more than theintended liquid to be drawn into the syringe. In contrast, using the dosing syringe alone, more than 10% of partic- ipants drew more than 2.5 mL into the syringe, with a maximum of 4.66 mL. In the Kamangira study group, using the dosing clip resulted in 98% of doses in the target range of 2.5 mL ± 10%. Within this same group, 90% drew the target dosage of Pepto-BismolTM using the oral syringe alone; only 27% met this target with the dosing cup The number of participants by age range (in years).
Author's personal copy Plastic Syringe Clip to Improve Dosing Accuracy Average (61 SD) and range of doses of Pepto-BismolTM for each dosing method measured in a community setting.
Pepto-BismolTM2.5 mL target dose Average dose (mL) Average dose (mL) Syringe with clip SyringeSyringe with Clip Cumulative Count (%)
Syringe with Clip Cumulative Count (%)
The cumulative count (as a percentage of the total) of the (a) Houston and (b) Kamangira participants' measured doses of Pepto-BismolTM. For each delivery method, the graph shows the percentage of participants delivering a volume less than orequal to the dose indicated. The dotted curve labeled ‘Intended Dose' represents an ideal population response where the entirepopulation delivers a dose of 2.5 mL.
(Fig. ). With the dosing clip in place, the maximum vol- antiretroviral medication, the ramiﬁcations of inaccu- ume of Pepto-BismolTM that any participant in this sub- rate dosing of liquid medications could be even more group measured was 2.55 mL. However, when using the serious. For HIV-positive and exposed patients, con- dosing syringe alone, 35% of participants drew more than sistently excellent adherence to drug regimens is 2.5 mL into the syringe, with a maximum dose of 2.82 mL.
required for viral suppression, the prevention ofresistance, disease progression, and andeffective prophylaxis. This is a special concern in the PMTCT of HIV/AIDS, as children are provided semi-daily doses of liquid antiretrovirals for an extended Misdosing liquid medications has potentially serious period of time. In 2010, the World Health Organiza- consequences. For prescription medications, such as tion presented new guidelines for PMTCT which state
Author's personal copy SPIEGEL et al.
a 5 mL syringe found that lower educational attainmentwas associated with dosing errors for these devicesIn addition, studies focused on antiretroviral adherence for Comparison of syringe children in the developing world have identiﬁed as bar- with and without clip riers to adherence poor socio-economic circumstances Comparison of 3 dosing methods and low literacy.Mills et al.reported that two barriers to antiretroviral adherence reported by adult understanding the treatment instructions and compli- cated regimens. Mahas a relatively low literacyrate (74% of adults can read). 98% of middle school students in Malawi fail to demonstrate skills beyond Error as % of 2.5 mL Intended Dose of Pepto-Bismol
basic numThese conditions may impose addi-tional limitations upon health literacy and decreasecaregivers' ability to adhere to accurate dosing.
Additionally, accidental overdoses in the developed Comparison of syringe world have been attributed, in part, to markings on with and without clip dosage devices that are misleading or incompatible with labeled dosing directions.A recent study showed that 74% of 200 top-selling pediatric oral liquid over-the-counter medications were packaged with measuring devices; 98.6% of these products hadinconsistencies between the medication's dosing direc- tions and markings on the dosage delivery device.Toaddress the lack of standardized measuring devices and labeling directions, the US Food and Drug Adminis- tration issued voluntary industry guidelines regardingdosage delivery devices for over-the-counter liquid Error as % of 2.5 mL Intended Dose of Pepto-Bismol
drug products in late 200FDA recommendations p value for comparison of dosing accuracy (in state that over-the-counter drugs should include a terms of % error) of all three methods (solid line) and syringe dosage delivery device, dosage delivery devices should without clip vs. syringe alone (dashed line) with Pepto-BismolTM for (a) Houston and (b) Kamangira. At all target be clearly calibrated and consistent with the product's accuracy values, the dosing cup was significantly less accu- directions, and dosage devices should include only rate than the syringe with or without the clip. For target necessary markings and not be substantially bigger accuracy values less than or equal to 645%, a significantlyhigher fraction of Houston participants could deliver an than the largest intended dose. In addition, the FDA accurate dose using the syringe with the clip than using the recommends that usability studies be performed to syringe alone; for target accuracy values less than or equal to conﬁrm accurate use by consumer 621% a significantly higher fraction of the Kamangira partic-ipants delivered an accurate dose using the syringe with the There is surprisingly little information available clip compared to the syringe alone.
about eﬀective strategies to reduce dosing errors. Yinet al.demonstrates that pictogram-based instructionsheets could reduce medication dosing errors. In 83 that all infants born to HIV-positive women should families randomized to receive standard counseling or receive nevirapine (NVP) or zidovudine (AZT) for a pictogram-based intervention, the fraction observed 4–6 weeks. If the mother is not on antiretroviral ther- to draw up more than 20% above or below the pre- apy and is breastfeeding, exposed infants should receive scribed dose dropped from 47.8% with standard NVP until 1 week after exposure to breastfeeding cea- counseling to 5.4% with pictogram-based intervention.
ses. Non-breastfeeding exposed infants should receive McMahon et showed that marking an oral dosing NVP or sd-NVP and AZT for 4–6 weeks.
syringe with a line at the correct dose and demon- Most studies of inaccurate caregiver dosing have been strating its proper use increased the number of patients performed in developed world settings. These studies receiving the correct dose. In this study, 90 families have found that inaccurate dosing occurs for a number were randomized to one of three groups: the ﬁrst of reasons. Caregivers who have low health literacy are received a prescription for liquid medication and ver- at greatest risk for inaccurate dosing.One study in bal dosing directions; the second received the pre- India that examined the dosing accuracy of parents scription, an oral dosing syringe, and a demonstration; using an etched dosing cup, 1 mL medicine dropper, and and the third received the prescription, an oral dosing Author's personal copy Plastic Syringe Clip to Improve Dosing Accuracy The percentage of participants who delivered a Pepto-BismolTM dose of 2.5 mL 6 10% with each dosing method (*p < 0.05).
syringe marked at the correct dose, and a demonstra- interventions to improve dosing accuracy. Using a tion. Only 11% of caregivers in the ﬁrst group were similar deﬁnition of correct dose as McMahon et al., observed to draw up the correct dose (±4%) at a fol- we found that 21% more participants in Houston and low up visit, while 83 and 100% of caregivers drew up 8% more in Malawi could deliver the correct dose of the correct dose in the second and third groups, Pepto-BismolTM using a dosing syringe with a dosing respectively. Moreover, Frush et showed that col- clip compared to using an oral dosing syringe alone.
or-coding regions of the dosing syringe to match There are limitations to our study. We did not test directions for dosing improved accuracy. Here 101 the dosing clips in settings where a caregiver is dosing caregivers visiting a pediatric emergency room were medication for a child or with repeated use. While we randomized to two groups, and asked to demonstrate have not undertaken an exhaustive study of how the dosing oral over-the-counter medication using either clip responds to washing, removal, or reinstallation, we conventional dosing instructions or the color-coded have removed and reinstalled the clips hundreds of method. The average deviation from the recommended times in the laboratory. The clips have not broken, nor dosage was 25.8% in the group receiving conventional is accuracy aﬀected. Breakage with removal and rein- dosing directions, compared to 1.7% for the group stallation has also not been noted as a problem in receiving color-coded directions.
Swaziland, where more than 200,000 clips have been The purpose of this study was to evaluate a new distributed over the course of 18 months.
dosing clip to improve dosing accuracy with an oral Our sample size was not large enough to permit dosing syringe. We found that the simple addition of a subanalysis based on age in each population. Further, dosing clip to a standard oral dosing syringe increases the populations in each location are not especially well substantially the fraction of participants who can matched, largely due to the demographic diﬀerences deliver the correct dose of liquid medication; however, between the Americans and the Malawians; the median the clip appears to underdose patients on average. The age of the participants in the United States is use of the dosing clips increased both the accuracy and 35.3 years old, while in Malawi the median age of the precision of dosing liquid medications in both the participants is 17.3 years old. The clips were designed Houston and the Kamangira populations. Surpris- to ﬁt 5.0 mL oral dosing syringes manufactured by ingly, the Malawian population measured liquid Becton–Dickinson and were thus tested with these medication more accurately than the Houston study syringes only; however, the clips could be adjusted to group despite comparatively lower levels of literacy ﬁt oral dosing syringes with larger or smaller maximum and numeracy. This may be attributed to diﬀerent volumes, or from other manufacturers. The clips are cultural norms; the Malawian participants were incompatible with syringes that have solid plunger noticeably eager to impress researchers who were rods. The clips are labeled to indicate the syringes they guests in their village. Participants followed the verbal are intended to be used with.
instructions as closely as possible. The impact of the In summer 2010, undergraduates in the BTB ini- dosing clip in this study is consistent with other tiative traveled to Swaziland as international interns.
Author's personal copy SPIEGEL et al.
They were given the task of demonstrating the syringe 2Bagenda, A., L. Barlow-Mosha, D. Bagenda, R. Sakwa, clips to clinicians to gather feedback on the design.
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The Journal of Emergency Medicine, Vol. 45, No. 2, pp. e31–e34, 2013 Copyright Ó 2013 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter DIGOXIN TOXICITY WITH NORMAL DIGOXIN AND SERUM POTASSIUM LEVELS: BEWARE OF MAGNESIUM, THE HIDDEN MALEFACTOR Mamatha Punjee Raja Rao, MBBSPrashanth Panduranga, MRCP,† Kadhim Sulaiman, FRCPI,† and