Sublingual Sugar Administration As an Alternative to Intravenous Dextrose Administration to Correct Hypoglycemia Among Children in the Tropics
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Sublingual Sugar Administration as an Alternative to Intravenous Dextrose Administration to Correct Hypoglycemia Among Children in the Tropics Hubert Barennes, MD, MPH, PhD*; Innocent Valea, MPH*; Nicolas Nagot, MD, MPH*; Philippe Van de Perre, MD, PhD*‡; and Eric Pussard, PhD§ ABSTRACT. Background. Hypoglycemia is a common ABBREVIATIONS. OG, oral group; SG, sublingual group; IG, determining factor of poor prognosis for children with intravenous group; WG, water group; Cmax, blood glucose con- severe malaria in sub-Saharan Africa. Intravenous dex- centration gain; AUC, area under the concentration-time curve. trose administration is rarely available. Oral mucosal delivery may be an alternative to parenteral administra- tion. A randomized, clinical trial was performed in ypoglycemia aggravates many severe clini- Burkina Faso among moderately hypoglycemic children, cal conditions, including malnutrition, intox- comparing sublingual sugar administration with oral wa- Hications, and malaria, leading to higher mor- ter, oral sugar, and dextrose infusion administrations. bidity and mortality rates for affected children in Methods. Sixty-nine children with glucose concentra- sub-Saharan Africa. Hypoglycemia related to ma- tions of <0.8 g/L were assigned randomly to 1 of 4 meth- laria represents by far the best example, because it ods of administration, 1 with 3 different doses of sugar, contributes to a significant proportion of the 225 000 g of sugar; Ͻ 2.5 :(15 ؍ as follows: oral group (OG) (n yearly deaths among African children 5 years of ؍ sublingual group (SG) (n 27): 2.5 g of sugar under the age with malaria.1 Hypoglycemia is present for 10% tongue, with 3 treatment subgroups, ie, 0.1 g/kg, 0.15 to 20% of comatose children with cerebral malaria.2 8mL:(8 ؍ g/kg, and 0.2 g/kg; intravenous group (IG) (n -Reasons for the occurrence and severity of malaria .(11 ؍ of 30% dextrose in a single bolus; water group (n Eight children received sublingual sugar twice, ie, 0.1 associated hypoglycemia are multiple and still con- g/kg at baseline and 20 minutes later. Blood glucose troversial. Hypercatabolism, stress, inhibition of glu- concentrations were measured every 20 minutes for 80 coneogenesis, and anaerobic glycolysis have all been minutes. Treatment failures, peak glucose concentra- suspected.3–7 Quinine, a drug used frequently in the tions, times to glucose concentration normalization, and treatment of severe malaria in Africa, is also respon- kinetic profiles were evaluated. sible for hypoglycemia, because it is a powerful in- Results. No treatment failures were observed in the ducer of insulin secretion.8,9 For these reasons, an SG and IG, compared with 8 (53%) and 9 (81.8%) failures infusion of dextrose is strongly recommended for in the OG and water group, respectively. SG children severe malaria among children, as a complement to exhibited glucose kinetic profiles and bioavailabilities antimalarial drugs.2 However, infusion requires (77%, 99%, and 81% in the 3 SG groups) similar to those trained staff and equipment that often are not avail- of IG children. Bioavailabilities were 84% and 38% in the SG and OG, respectively. Children >7 years of age re- able in peripheral health care settings. Frequently quired repeated sublingual administrations to maintain this results in delays in adequate management of normoglycemia. severe malaria. Malaria-associated hypoglycemia, Conclusions. The sublingual administration of sugar and not the direct effects of malaria parasites, may be proved to be effective among moderately hypoglycemic an additional contributor to early deaths among co- children. It is a simple and promising method to control matose children before they reach a health center.10 hypoglycemia among children in both developing and Oral mucosal drug delivery is an alternative method developed countries. This pediatric practice should be of systemic drug delivery that offers several advan- investigated in more detail among children with severe tages over both injectable and enteral methods.11 malaria. Pediatrics 2005;116:e648–e653. URL: www. Because the sublingual mucosa is highly vascular- pediatrics.org/cgi/doi/10.1542/peds.2004-2218; hypoglyce- ized, drugs that are absorbed through the sublingual mia, tropics, sublingual, malaria. mucosa enter the systemic circulation directly, by- passing the gastrointestinal tract and metabolism in the liver. For some drugs, this results in a rapid onset From the *Centre Muraz, Bobo-Dioulasso, Burkina Faso; ‡Montpellier Uni- of action through a more comfortable and convenient versity Hospital Arnaud de Villeneuve, Laboratory of Bacteriology-Virol- delivery route than the intravenous and intramuscu- ogy, and University of Montpellier 1, Montpellier, France; and §Hoˆpital Kremlin Biceˆtre, Pharmacology Unit, Paris, France. lar routes. Moreover, administration is not painful Accepted for publication May 12, 2005. and has no risk of blood-borne pathogen transmis- doi:10.1542/peds.2004-2218 sion and no neurologic risk of sciatic nerve trauma, a No conflict of interest declared. frequent consequence of inappropriate intramuscu- Reprint requests to (H.B.) 1 Impasse Larrode´, 64200 Biarritz, France. E-mail: [email protected] lar injections among African children. PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Acad- In Burkina Faso, hospital management of severe emy of Pediatrics. malaria among children involves a loading dose of e648 PEDIATRICS Vol. 116Downloaded No. 5 November from www.aappublications.org/news 2005 www.pediatrics.org/cgi/doi/10.1542/peds.2004-2218 by guest on October 2, 2021 16 mg/kg quinine base delivered through slow infu- Eight children 10 to 12 years of age received 0.1 g/kg sugar at sion in 5% dextrose over 4 hours. This is equivalent baseline and again 20 minutes later, under the tongue. They were ϳ matched with 1 child of the same age, gender, and sugar dose who to delivering 2.5 g of dextrose to a 10-kg child in 1 was enrolled just before or just after. hour. Only 30% dextrose in 10-mL vials is available in hospitals and private pharmacies. In resource- Laboratory Methods poor settings, where frequently infusion is not avail- Before enrollment, 0.1 mL of blood was collected through finger able or is not operational, the sublingual administra- prick, with a Glucomatic lancet (Bayer Diagnostics, Leverkusen, tion of sugar could represent a noninvasive, painless, Germany), to confirm the baseline blood glucose level. After treat- and practical alternative treatment.12 It is also widely ment administration, this measurement was repeated every 20 minutes until a blood glucose level of Ն0.9 g/L (defined as nor- available, cheap, and user-friendly for home treat- moglycemia) was achieved. At least 4 measurements were per- ment that could be extended to all cases of hypogly- formed for each child within 80 minutes. Glucose was measured in cemia among children in the tropics, whatever the blood with a precision of 0.01 g/mL, by means of a Glucomatic level of care. mini-automate system (Bayer Diagnostics) based on glucose oxi- The most important advantage of the sublingual dase and glucose peroxidase. The reproducibility of this technique was 5.7% at a concentration of 1 g/L and 8.3% at 0.5 g/L. The route is its potential use among comatose children Glucomatic performance was quality-controlled in the Centre Mu- who are not able to swallow. The sublingual route raz laboratory with the biochemistry automate LabSysteme FP-140 was used occasionally by our team in Niger, with (LSI, Cergy Pontoise, France), before the beginning of the study good results (H. B. and M. A. Sani, MD, unpublished and after each series of 50 measurements. The mini-automate was also quality-controlled with the Glucomatic Esprit control solution data, 2000). As a first step in confirming this hypoth- after each 50 measurements. esis, we conducted the first clinical trial aimed at For all children, malaria parasite density was assessed on the evaluating whether early correction of hypoglyce- day preceding study enrollment, by counting asexual P falciparum parasites, relative to white blood cells, in thin films. The presence mia could be achieved with sublingual administra- Ͼ Ͼ tion of dextrose among moderately hypoglycemic of 1000 parasites per L and a body temperature of 37.5°C defined an acute episode of malaria. children, with or without malaria, in Burkina Faso. Study Outcomes and Definitions METHODS The treatment failure rate and early treatment failure rate were the primary outcomes. The treatment failure rate was defined as Study Design, Site, and Patients the proportion of children who did not reach glucose concentra- A randomized, open, clinical trial of oral, sublingual, and in- tions of Ն0.9 g/L during the study period. The early treatment travenous dextrose administration was launched in the Hamdal- failure rate was the proportion of children with no blood glucose laye Health Center, in Bobo-Dioulasso (500 000 inhabitants), dur- gain at 20 minutes. The maximal blood glucose concentration gain ing the high malaria transmission period (October to December (Cmax) was the difference between the peak glucose concentration 2002). Children 1 to 15 years of age who presented with moderate and the initial glucose concentration. Cmax and the time to obtain clinical symptoms were recruited among the 2 main pathologic normoglycemia were observed values. The area under the curve conditions observed in the health center outpatient department, ie, (AUC) of glucose concentrations (difference