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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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New formulations of artemisinin derivatives are now available for rectal administration. This development means that children too sick to take medication orally could be treated in the community, either as emergency pre-referral treatment (before transportation of the child to a health facility for higher-level treatment) or, if referral is not possible, as part of a complete treatment course given at home. Because the artemisinin drugs have an excellent safety profile and a wide therapeutic margin, rectal administration could be safely and effectively performed by individuals in the community (such as a village-health worker or the child’s mother) who have had little or no medical training. However, optimal strategies for deploying intrarectal artemisinin drugs at community level are yet to be determined. In particular, it is not clear to what extent this strategy is socially or culturally acceptable and feasible across the range of societies in which this intervention could be deployed. Information on existing attitudes to rectal administration in specific cultural contexts should help to inform the development of the most appropriate deployment strategies.
Of the artemisinin derivatives that can be given rectally, the most well-studied is artesunate, which is formulated as 50-mg or 200-mg suppositories (Plasmotrim Rectocaps®; Mepha Pharmaceuticals, Aesch-Basel, Switzerland).3–7 These are safe and at least as effective as conventional parenteral treatments for severe malaria when given at doses of approximately 10 mg/kg.3,6
In Papua New Guinea, malaria remains a major disease burden. Plasmodium falciparum predominates and is highly endemic throughout most coastal regions of the country. It is the second-leading cause of death nationwide, with most malaria-related deaths occurring in children less than five years of age.8 Challenges to malaria management in Papua New Guinea include parasite resistance to first-line non-artemisinin antimalarial drugs, poor primary health care infrastructure, and an at-risk population living predominantly in remote rural areas. The country’s large size relative to its small population and rugged terrain limit access to acute care services, and further reinforce the need for effective community-based health interventions. Artesunate suppositories have been shown to be well-tolerated, safe, and highly effective in hospitalized Melanesian children.4–6 However, although such hospital-based treatment appears well accepted, this may not apply when rectal artesunate is given outside in the community when the caregiver is the person administering the drug. The aim of this study was to examine the feasibility and acceptability of this form of malaria management in Papua New Guinea.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Mugil health center is operated by the local Catholic mission and is situated within the Sumkar district in Madang Province. Sumkar has a total population of 67,000, with Mugil health center covering a large catchment area of between 20,000 and 25,000 people. This includes patients from outside the district. Local P. falciparum transmission is hyperendemic and the health center treats up to 8,000 cases each year. Malaria is the second leading cause of morbidity in the district and the leading cause of death. The health center is easily accessible from the main highway and most patients travel long distances either by foot or by local public transport to reach it. The center is staffed by 11 people and sees an average of 30 new malaria cases per day.
The study was conducted during April 2004, May 2004, and February 2005 in Kunjingini and between March and April 2006 in Mugil as part of a larger study examining the operational feasibility of administering artesunate suppositories as treatment of P. falciparum in Papua New Guinea. The study was reviewed and approved by the Papua New Guinea Medical Research Advisory Committee (MRAC#02.05).
Preliminary formative research was initially conducted in six villages in the Wosera district during November 2003 to inform the design of a questionnaire for caregivers. Forty women with children less than five years of age were randomly selected from the PNGIMR demographic surveillance system and asked to participate in in-depth interviews with the chief investigator (RLH). An initial general enquiry into mothers’ perceptions and practices relating to childhood fevers was used to provide a context in which to investigate issues that may become important if artesunate suppositories were to be introduced in the area and to define the terminology to be used in the subsequent questionnaire. Questioning was open-ended and care was taken to ensure that questions about suppositories were placed in the context of other malaria treatment modalities, often by way of ranking exercises. For example, mothers were shown four different treatment modes for malaria (suppository, tablet, syrup, and syringe), asked to rank them in order of preference, strength and efficacy, potential for side effects, and preference for self-administration, and asked to give reasons for their preferences. Issues raised by mothers during the ranking exercises included lack of knowledge of suppositories, fear of side effects, uncertainties regarding self-administration, concern about older children physically resisting suppository administration, and concerns about the effectiveness of conventional treatments for malaria. These were incorporated into multiple-choice options in the questionnaire for caregivers along with responses relating to shame, embarrassment, and perceptions of efficacy and harmful effects of suppositories.
Because the study aimed to assess attitudes and treatment preferences of caregivers with young children with malaria, it was believed that the best way to recruit a representative sample was to identify children coming to the health center with confirmed malaria and then interview the caregiver at the time they were offered treatment with artesunate suppositories. Participants were selected for the study if they came to the center with a child six months to seven years of age with confirmed uncomplicated P. falciparum malaria. Eligible caregivers were those coming sequentially over at least a two-week period, thus reflecting a realistic representation of health center attendees. Children with fever (axillary temperature > 37.5°C) or a history of fever were screened using a Paracheck® rapid test (Tulip Diagnostics, Mumbai, India) for P. falciparum malaria. Positive test results were confirmed by microscopy. Children with signs of severe malaria12 (including impaired conscious state, respiratory distress, severe anemia, fitting, prostration, or inability to tolerate oral medication) and children with signs of another infection or significant co-morbidity were excluded from the study. For eligible children with a confirmed diagnosis of P. falciparum, caregivers were informed of the study, offered suppository treatment for their child, and requested to answer a standard set of questions regardless of whether they declined or consented to suppository treatment. This included multiple-choice questions regarding preconceptions of effectiveness, harmful effects, and shame or embarrassment.
If the caregiver declined rectal therapy, the child received oral chloroquine and sulfadoxine-pyrimethamine in accordance with Papua New Guinea standard treatment guidelines.13 In this situation, additional multiple-choice questions were asked to determine the primary reason for the caregiver’s choice. If caregivers consented, children were treated with 10–15 mg/kg artesunate suppositories (Rectocaps®; Mepha Pharmaceuticals, Aesch-Basel, Switzerland) administered as a combination of one to two 50-mg or 200-mg suppositories. Suppositories were administered as a daily dose for three days, with a single dose of sulfadoxine-pyrimethamine administered on the final day of treatment. To ensure adequate clinical response, each child was assessed daily through a symptom questionnaire and a blood film for parasite density. The child was observed at the health center for one hour after suppository administration so that if he or she passed the suppository, the treatment could be re-administered. The first dose was administered by a health worker and caregivers were asked to administer the second and third dose under health worker supervision. On completion of treatment, a second questionnaire was administered to caregivers. This included multiple-choice questions to assess satisfaction with the treatment, including perceptions of efficacy, adverse effects, or other associated problems. At this time, caregivers were also asked whether they would prefer to administer suppositories or oral therapy as home-based treatment of their children.
Questionnaire responses and demographic and clinical data were recorded in an Excel® (Microsoft, Redmond, WA) spreadsheet. Some questionnaire responses were recorded as categorical data (e.g., disagree strongly, disagree, not sure, agree, and agree strongly). These responses were sometimes grouped and recoded as binary variables to facilitate data analysis. For instance, negative responses (e.g., very unsafe and not very safe) would be grouped together (unsafe). Key questionnaire outcomes included whether the caregiver accepted or refused to have their child be treated with suppositories at the time of presentation and initial interview, whether the caregiver was able to successfully self-administer suppositories on the second day of treatment, and whether the caregiver said he or she would prefer suppositories for either home or health-center treatment when questioned at the conclusion of the treatment course. Factors associated with these key questionnaire responses (the dependent variables) were ascertained by univariate analysis of a number of independent demographic (age and sex of child, relationship of caregiver to the child), sociological (educational and marital status), and clinical (temperature, respiratory rate, parasite density, and hemoglobin concentration at baseline) variables.
Data were analyzed with SPSS for Windows version 10.0 (SPSS Inc., Chicago, IL). Continuous variables were compared using Student’s t-test for comparison of means from two independent samples. Non-normally distributed data were compared using the Mann-Whitney U test. For binary variables, odds ratios were determined with 2 x 2 tables and P values were calculated using the Pearson chi-square test.
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RESULTS |
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details the characteristics of the children and their caregivers. The clinical features in the children were consistent with uncomplicated malaria in Papua New Guinea. Seventy percent of caregivers identified themselves as the child’s mother and 24% as the father. A slightly higher number of male caregivers came to Mugil (31% at Mugil and 16% at Kunjingini). The remaining 6% were a close female relative such as an aunt or grandmother. Pooling of results from the two sites, which had similar epidemiologic characteristics and disease burdens, allowed us to extend the spectrum of caregivers questioned so that the results might be more generalizable to the national situation.
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. Although 41% had heard of suppositories, only 29% had personal experience with their use in their own or another child. The most common concerns related to perceptions that suppositories would not dissolve and be absorbed (44%) and the practical difficulties of administering to a reluctant child (47%). A smaller number were concerned that administration would cause pain (37%) or interfere with the child defecating normally (37%).
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Factors associated with caregiver refusal, either their own circumstance or the child’s condition, are summarized in Table 3. Caregivers coming to the Kunjingini field site were more likely to refuse treatment than those coming to the Mugil field site (odds ratio [OR] = 2.97, 95% confidence interval [CI] = 1.28–6.96), P = 0.005). Other factors associated with refusal included never having attended school (OR = 2.25, 95% CI = 0.98–5.18, P = 0.035), having had no initial prior knowledge of suppositories (OR = 2.81, 95% CI = 1.5–6.99, P = 0.012), no prior experience with their use (OR = 3.07, 95% CI = 1.08–9.15, P = 0.019), and having one or more deceased children (OR = 2.19, 95% CI = 0.93–5.16, P = 0.049). Mothers were more likely to refuse than were fathers, but this was not statistically significant (OR = 2.38, 95% CI = 0.82–7.22, P = 0.078). There was no significant difference in refusal rates according to the age of the care-giver, the age or sex of the child, or any clinical indicators of severity (including temperature, hemoglobin, respiratory rate, or parasite density).
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Mothers were much more likely to agree to, and successfully administer, suppositories than were fathers (OR = 4.72, 95% CI = 1.55–14.7, P = 0.002). Clinical variables (fever and parasitemia), educational or marital status, and prior knowledge or experience of suppository use were not significantly associated with successful administration.
Clinical response. Three children did not attend for one or more follow-up visits to the health center. One child developed signs of complicated malaria by the second day (impaired conscious state), was withdrawn from the study, and was given rescue treatment with intramuscular quinine. Another child completed three days of artesunate therapy, but the child’s conditions began to deteriorate on the second day, with worsening conscious state, vomiting, convulsions, focal neurologic signs, and neck stiffness, despite having cleared parasites from the blood film at 24 hours. A diagnosis of meningo-encephalitis was made and the child was treated with parenteral chloramphenicol. The child died five days later.
Overall, 88 children had a fully supervised three-day course of artesunate suppositories and a dose of sulfadoxine-pyrimethamine on the final day. Apart from the child with early treatment failure and the child who developed meningo-encephalitis, clinical response was adequate over the 48 hours of follow-up in all other children. Twenty-four hours after the beginning of treatment, 94% were afebrile and the mean reduction in parasite density from baseline was 99.3%. Of the evaluable patients, 28 (34%) had a negative blood slide by the second day (roughly 24 hours after first dose) and an additional 43 (52%) had a negative blood slide two days later (48 hours). Twelve (14%) had not cleared parasites by the third day (> 2 days). In all but two of these, parasitemia at 48 hours was low (< 200 parasites/µL). Two patients had parasitemias of 2,000/µL and 2,400/µL at the third day (48 hours) but both had had high initial baseline parasitemias (145,000/µL and 145,140/µL).
Satisfaction after treatment course.
After completion of the treatment course, caregivers were re-interviewed to determine their satisfaction with the treatment. The responses are summarized in Table 4. Almost all reported that the treatment was effective (99%) and safe (96%). The most common problems cited were the child struggling and resisting administration (56%) and wanting to defecate immediately after administration (26%). Perceived benefits included more rapid action (92%) and greater efficacy than other antimalarial treatments (91%). A substantial proportion (48%) reported that the route of administration was advantageous because it was an alternative to oral administration, which they found to be difficult in their own children. Only 8% regarded treatment as unhygienic.
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When caregivers were asked what would be their preferred mode of administration for their child if it was administered by health workers at a health center, 52% preferred suppository treatment, 13% preferred oral treatment, and 16% preferred injectable treatment. The sole factor associated with a preference for suppositories over other modes of administration was whether the caregiver believed that their child was still sick at day 2 (48 hours) (OR = 0, 95% CI = 0–0.7, P = 0.003).
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DISCUSSION |
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The present study involved relatively small numbers of subjects and was limited to two cultural groups in Papua New Guinea. Caution should therefore be exercised in generalizing its findings to other countries, or even to the many other cultural groups within Papau New Guinea. It was notable that the acceptance rate in this study was significantly higher at the Mugil site than at the Kunjingini site. As well as cultural and social differences, the community’s prior experience of and relationship to the health care system may also lead to important differences in the attitudes studied in this research. For instance, there is little access to medicines through an informal sector in Papua New Guinea, which make it very different from the situation in much of Asia and Africa. Furthermore, the population at the Kunjingini site has had a longstanding relationship with the PNGIMR, which may have significantly influenced perceptions of treatment of malaria. The degree of prior exposure of the population to rectal administration of other medicines (such as paracetamol at the Kunjingini site) is also clearly important. The face-to-face nature of the interview process may also have biased the results towards more positive responses than had they been conducted in an anonymous fashion. Nonetheless, some of the results bear great similarity to other experiences with suppository use.18
The present questionnaire responses indicate a relatively low level of existing familiarity with rectal administration. However, prior knowledge or experience with rectal administration was strongly associated with more positive attitudes to this form of treatment. Caregivers with prior experience of rectal administration were at least three times as likely to accept suppository treatment for their child. Experience with rectal administration in Papua New Guinea probably relates predominantly to paracetamol suppositories (although diazepam may also be given rectally to children with convulsions). Paracetamol is more rapidly absorbed when given rectally rather than orally, which indicates that suppositories may cause an earlier reduction in fever. It is possible that this may have contributed to positive perceptions of the efficacy of suppositories more generally among caregivers. Similarly artesunate, given its intrinsic potency, is likely to result in a more rapid killing of parasites and resolution of fever and other clinical signs than would occur with conventional anti-malarial drugs, regardless of route of administration.3 Although this study did not assess definitive cure using the standard World Health Organization 28-day test, the early clinical response was excellent. In particular, rapid parasite clearance and resolution of fever occurred in almost all patients. This appeared to be recognized by caregivers in this study, of whom 92% claimed the treatment worked more rapidly than other malaria medicine. Widespread deployment of suppositories in this population would seem likely to reinforce positive perceptions of rectal administration, as familiarity and experience with their rapid onset of action increased.
In the present setting, parental shame and embarrassment do not appear major impediments to the implementation of suppositories as standard treatment of malaria. In contrast, caregivers appeared to be more concerned with the more practical aspects of treatment such as whether the suppository would be well absorbed or cause side effects, their ability to administer the suppository properly themselves, and difficulties caused by the child struggling or defecating.
A moderate proportion of caregivers in this study refused treatment and the reasons for their refusal are instructive. As well as a lack of prior knowledge or experience of rectal administration, poor educational status was a significant association. Caregivers who had never been to school were twice as likely to refuse suppositories as those with some schooling. Caregivers most commonly cited lack of spousal approval as well as concerns about safety and the practical challenges of administering to a reluctant child as reasons for refusal. These issues should therefore be addressed in health education activities accompanying deployment. The most important group for health education messages to reach, the poorly educated and illiterate, would also be the most difficult to reach effectively. The issue of spousal approval was important and in this context the final decision making appears to rest with the father despite mothers having a primary role in accessing health care for their child. The higher rate of acceptance at Mugil might have also been attributable to the higher number of male caregivers, which our data show to be a predictor of compliance. Health education activities in this context should clearly target fathers as well as mothers.
It was notable that clinical indicators of severity were not associated with refusal or acceptance. Although this study was restricted to children with uncomplicated malaria, it suggests that caregivers will be happy for this treatment to be given to the most important group, children with more severe illness and a consequently increased risk of complications and death.
A variety of strategies might be used to deploy suppositories either at primary health care, village, or household level. Among these are the possibility that caregivers are provided with suppositories to either initiate treatment of their sick child or at least to administer some of the doses themselves. Seventy percent of caregivers who participated agreed to attempt to self-administer suppositories of whom most (94%) were able to do so on their first attempt. This is encouraging for the possibility of future deployment of suppositories at a household level and shows that, even without any medical training, suppositories are easy to use. However, it was notable that fathers were much more reluctant to administer suppositories. Any household deployment strategy in PNG should aim to have mothers administer suppositories in this context.
Satisfaction with suppository treatment, when assessed after administration of a three-day treatment course, was generally very good with most rating the treatment safe and rapidly effective and few raising concerns about hygiene. The most common problems experienced were the practical difficulties of forcibly administering treatment to a struggling child. However, almost half the caregivers also indicated that they found it easier to administer suppositories than oral medicine. Oral administration of antimalarial drugs can be difficult in very young children and probably contributes to the poor compliance with even short-course therapy in this group.19 This may explain why, in other settings, suppositories have proved more popular than oral formulations among both caregivers and health workers for the treatment of malaria in young children (Christophel E, World Health Organization, unpublished data). Although rectal administration may improve compliance, it might also lead to excessive and inappropriate use of suppositories beyond their suggested indications and therefore increase the theoretical risk of artemisinin parasite resistance. Nevertheless, in terms of future deployment strategies for suppositories in Papua New Guinea, it was reassuring that most caregivers said they would rather treat with suppositories in preference to other routes of administration whether given at home by themselves or in the health center by a health worker.
This study has demonstrated that in Papaua New Guinea overall acceptability of rectal administration is relatively high, at least in the areas surrounding the two study sites. It has also indicated that acceptance is closely linked with familiarity and therefore should improve as use becomes more widespread. However, deployment will be more effective if accompanied by appropriate health education directed at caregivers like those who expressed concerns in the present study. Key messages could stress that rectal administration is generally very safe and well tolerated; it does not interfere with normal defecation; and although children may struggle when the suppository is inserted, this may also apply when antimalarial drugs are given by mouth. Education messages should be delivered in a manner suitable for the illiterate rural poor and should be directed at fathers as well as mothers. Because suppositories may be easier to administer than oral medication in young children, excessive and inappropriate use could result. Although there should be careful consideration of the possibility and implications of this use, community-based interventions using artemisinin-derived suppositories are likely to be feasible in Papua New Guinea if combined with appropriate health education activities.
Received August 23, 2006. Accepted for publication November 23, 2006.
Acknowledgments: We thank the caregivers of the children for their participation in this study and the staff of the PNGIMR branches in Maprik and Madang and the clinics in Mugil and Kunjingini for assistance and support.
Financial support: This study was supported by the World Heath Organization Roll Back Malaria program, the Australian National Health and Medical Research Council, the Royal Australasian College of Physicians, and the Australian Agency for Overseas Development.
* Address correspondence to Rachael L. Hinton, Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, Papua New Guinea. E-mail: rachael.hinton{at}pngimr.org.pg 
Authors’ addresses: Rachael L. Hinton, Alma Auwun, Grace Pongua, and Olive Oa, Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, Papua New Guinea, Telephone: 675-732-1280, Fax: 675-732-1998, E-mail: rachael.hinton{at}pngimr.org.pg. Timothy M. E. Davis and Harin Karunajeewa, School of Medicine and Pharmacology, University of Western Australia, Perth 6009, Western Australia, Australia, Telephone: 61-8-9431-3229, Fax: 61-8-9431-2977. John C. Reeder, Burnet Institute for Medical Research and Public Health, Melbourne, Victoria 3001, Austalia, Telephone: 61-3-8506-2320, Fax: 61-3-9282-2144, E-mail: jreeder{at}burnet.edu.au.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
