This pilot study in a Malian district hospital reports the effect over a 40 minute period of two administrations of sublingual sugar in young children (< 5 years of age) with severe malaria and BGC below 60 mg/dl (3.3 mmol/l). This administration was compared with the standardised intravenous infusion of 10% glucose. Results were similar in both groups. Overall 71% of the SLS reached a BGC over 60 mg/dl within 40 minutes and 64% within 20 minutes. SLS resulted in a rapid correction of BGC; among nine children who really kept the sugar sublingually, all but one increased their BGC within 10 minutes of sublingual sugar administration with a mean gain of 44 mg/dl. These results suggest the efficacy of SLS for the rapid correction of hypoglycaemia, but also the need for more frequent and repeated administration as objectified by the 30% relapse rate at 40 minutes before the third administration of sugar. The number and interval of repeated sugar doses needed to obtain a steady BGC requires further study over a longer duration, and with more patients. The results of this study with children with BGC < 60 mg/dl give important information to allow a further study in children with more severe hypoglycaemia (e.g. < 40 mg/dl) and comatose children who stand to benefit more from such a treatment.
This study suggests that sublingual sugar is almost certainly better than no treatment because no significant gain in glycaemia was seen in patients in the IVG group before the intravenous infusion of glucose was started (and it would be unethical to include a no treatment arm in any study of hypoglycaemia in severe malaria). Therefore sublingual sugar can be recommended in situations where the gold standard treatment of intravenous glucose is not immediately available.
Hypoglycaemia is particularly common in children with falciparum malaria who are younger than three years of age [4, 17, 18]. This feature of severe malaria is associated with a three- to ten-fold increase in case fatality [3, 19, 23]. Correction of hypoglycaemia is an important therapeutic measure, although it is not clear whether this is sufficient to improve the prognosis.
When intravenous infusions are not feasible, because of lack of material or trained staff, which is the case in many rural health centres, no alternative has yet been developed. Oral absorption is delayed until the sugar reaches the duodenum  and may cause severe inhalation in prostrated or comatose children. The oral mucosa and the sublingual cavity offer a relatively unexplored alternative  though degradation of sucrose and a transport system of sucrose has been shown in the dorsal part of the tongue [11, 12]. The previous study conducted in Burkina Faso in children with low glycaemia confirmed that SLS was more rapidly absorbed than oral sugar . It also suggested the need for repeated administration and gave preliminary information on the interval doses for sugar administration. Further evaluation is needed to determine whether the interval can be decreased between administrations of sugar, which may enhance the efficacy of the SLS. Absorption appeared to be effective within the 10 first minutes in the present Malian study.
Compared to the previous study , the treatment failure and early failure rates were greater, but the CGmax was the same (46 mg/dl). This may be explained by the lower initial glycaemia of children in this study, their younger age and their more severe disease.
As in Burkina Faso SLS was well tolerated, painless and easy to use, no inhalation was reported. The feasibility was good with only one failure due to trismus. SLS appeared to be a child-friendly method.
Various definitions of hypoglycemic blood sugar levels for infants and children have been reported and remain controversial [20, 21]. For severe malaria a cut-off of 2.2 mmol/L (40 mg/dl) is widely used but other thresholds have also been used: 41, 48, and 54 mg/dl [4, 17, 22, 23]. The definition of standard paediatric reference texts was used in this study: the normal serum glucose concentration for children beyond the newborn period is greater than or equal to 60 mg/dl (3.3 mmol/L) [14, 15]. In fact, the 3.0 mmol/L (54 mg/dl) cut-off could have been used with very similar results, since five children had a BGC of 55 mg/dl and two had a BGC of 57 mg/dl, with an equal distribution between both groups.
Interestingly, with sublingual sugar, the correction of hypoglycaemia tended to occur faster than with intravenous glucose because there are inevitable delays in setting up the infusion, as it is often difficult to find a vein in a small, unconscious and shocked child. Four early failures at 20 minutes were observed due to delays in the IVG group.
As in many West African hospitals, intra-osseous infusions are not available to avoid this delay. This should be an important improvement at the district level in the future if the necessary equipment, hygienic conditions and trained staff are available.
In this study results for IVG were artificially good, because all the equipment was made immediately available at the point of need, and free-of-charge. The normal situation in the hospital is that the patient's parents are given a prescription for the bag of intravenous glucose, the intravenous catheter, the administration set and any other necessary medications. They must then go and purchase this from the pharmacy, and bring it back to the ward before treatment can commence. This can introduce severe delays if the parent has to go and find or borrow the money, or if the pharmacy is out-of-stock of one or more items, which is not an infrequent occurrence. The advantage of sublingual sugar is that it is virtually free, immediately available, and does not require a prescription or a pharmacy. Furthermore, it is also available everywhere, including peripheral health centres and villages, where intravenous glucose is not available.
This study may have important implications for the clinical management of malaria in children with a potential risk of hypoglycaemia in the field. SLS could be used as a preventive intervention at home, but also at the health centre. In fact, use of SLS was rapidly adopted by the community in Sikasso region before and during referral of children. A community-based study could evaluate the impact of such a recommendation on the prevalence of hypoglycaemia and mortality of children admitted to hospital.
This study was performed in the field conditions of a busy West African paediatric ward, during the malaria season, which explains some of its limitations (the small sample size and the incomplete data for some patients).
In the SLS group, the number of comatose children was small and lower than in the IVG group (table 1). Most children had other features of severe malaria with respiratory distress, prostration and convulsions. Children in coma are the most likely to benefit from SLS administration and these preliminary results need to be confirmed in a larger scale study of comatose children.
The sublingual sugar administration has two main limitations. Firstly, at least 29% of the children swallowed the sugar rather than keeping it under the tongue (particularly children in a less severe state and hence able to swallow). The oral route has a slower absorption in the duodenum and is slower to normalize glycaemia . Early swallowing may remain undetected by busy staff who have to be trained to detect this. When sugar is swallowed before 10 minutes, another SLS administration should be recommended. The non-responsive child on SLS may have swallowed the sugar undetected by the team. He received an infusion after 40 minutes so it is impossible to know whether he had delayed oral absorption. Secondly, the small volume of the sublingual cavity limits the SLS dose available and may restrict SLS to young children. Children were below five years of age and the SLS doses were satisfactory. However, this is the age group at greatest risk of severe malaria in Africa. The initial mean single SLS dose was 0.25 g/kg (95%CI: 0.20–1.28), which is below the recommended dose (0.5 g/kg). This implies the need to frequently repeat the SLS doses , in order to avoid relapses.
The limited duration time of the study only allowed evaluation of two administrations of sugar (i.e 5–6 g), but 3 or 4 administrations would be needed to obtain a steady BGC. Relapses at 40 minutes were observed after a rapid initial increase of BGC and BGC should be monitored until it remains stable  – or, when monitoring is impossible, SLS administration should be repeated every 10–20 minutes (e.g. during the transport to hospital). More studies with older children are necessary to see whether the SLS route is also adequate for older ages and how doses need to be adapted.
The aetiology of hypoglycaemia was presumed to be malaria and the duration of illness prior to the admission. However, the study did not enquire about other causes of hypoglycaemia and it is not known whether some traditional antimalarials may cause hypoglycaemia.
Although the sample size is small, the results indicate sufficient safety and efficacy to justify the use of sublingual sugar at the community level and to justify a further larger trial. Intravenous treatment is often considered the gold standard. It may give a false sense of security when monitoring is not correct, which is often the case in remote settings. One infusion was blocked at 15 minutes and the child's BGC quickly dropped to a very low level.
In hospital, SLS can be recommended when infusions are not immediately available (or until they are put in place) or when a transfusion is urgently needed. In the case of parallel blood transfusions (patients with anaemia and hypoglycaemia), SLS carries a lower risk of fluid overload than IVG, and as such might be useful even in well resourced settings.