in neonates and small infants , early diagnosis of central diabetes insipidus ( cdi ) and treatment with desmopressin in low doses ( avoiding severe hypo- or hypernatremia ) are important to prevent associated high morbidity and mortality in this particular age group . we described pharmacokinetic and pharmacodynamic results of the use of recently launched oral desmopressin lyophilisate ( minirin melt ) in two infants with cdi , diagnosed at the age of 12 and 62 days , respectively . we observed that a starting dose of 60 g of minirin melt in the first case resulted in a pharmacokinetic profile largely exceeding the reference frame observed in children with nocturnal enuresis , while a dose of 15 g in the second case resulted in acceptable concentrations . after initial dose adjustments , administration of sublingual lyophilisate resulted in rather stable serum sodium concentrations . using minirin melt in infants with cdi appears to be effective , easy to use and well tolerated . central diabetes insipidus ( cdi ) is very rare in ( premature ) neonates and infants ( 1 ) . etiological factors are idiopathic , asphyxia , cerebral infections ( usually meningitis , encephalitis or ventriculitis ) , congenital anomalies of all types ( holoprosencephaly , septo - optic dysplasia , encephalocoele ) and rarely intraventricular hemorrhage ( 2 , 3 ) . treatment in neonates and infants differs slightly because their diet contains a proportionally larger quantity of water . careful and precise administration of small doses of synthetic analogue of vasopressin , desmopressin ( ddavp ) is warranted to prevent potential severe side effects as hyponatremia and convulsions secondary to water intoxication ( 4 ) . however , there is no appropriate infant formulation available allowing titration and individualization of treatment at low doses . clinicians have experimented with subcutaneous administration of desmopressin and dilution of commercially available nasal solution , but there is a high variability in absorption of these formulations and stability studies are lacking . some authors suggest that aiming at an un - physiological steady state with a higher plasma osmolality level , might be preferable to unstable plasma osmolality shifts during intranasal administration of desmopressin . desmopressin oral lyophilisate ( minirin melt ) has been launched in 2005 , mainly for the treatment of enuresis nocturna . it is a wafer - like formulation , which dissolves instantly in the mouth with no need for water . its bioavailability is approximately 60% greater than tablets and retains similar levels of efficacy and safety at lower dosing levels than the tablet . we reported our experience with oral lyophilisate form ( minirin melt ) in two very young infants with central diabetes insipidus . case one was a preterm male infant , born by spontaneous vaginal delivery after a pregnancy of 28 weeks and 3 days with a weight of 1220 grams and length of 38.6 cm . at 12 days of age , enterococcus meningitis / ventriculitis was diagnosed , which was managed with intravenous antibiotics and supportive management . a few days later , he developed hypernatremia ( 160 mmol / l ) and polyuria ( 13 ml / kg / h ) with normal glycaemia . adequate hydration was performed to normalize the sodium levels , but during an episode of catheter sepsis with staphylococcus aureus , serum sodium concentrations remained high ( 164 mmol / l ) with a serum osmolality of 320 mosm / kg and polyuria with a urine osmolality of 60 mosm / kg . central diabetes insipidus was confirmed by administration of 60 g minirin melt , which lowered the serum osmolality from 298 mosm / kg to 259 mosm / kg . urine osmolality increased from 113 to 430 mosm / kg within three hours of administration and persisted above 400 mosm / kg for 24 hours . at different time points , the concentration - time curve of a dose of 60 g at the age of 20 days and a body weight of 1300 grams showed very high ddavp concentration levels , persisting for more than 24 hours , demonstrating that even in critical ill children , bioavailability of melt formulation is largely maintained ( figure 1 ) . on treatment with minirin melt , serum and urine electrolytes and osmolality were monitored closely , in addition to weight and urine output . high variability in urine output and body weight necessitated initially several dose adjustments ( by 15 g ) . at discharge , after 125 days , minirin melt 60 g was given daily , together with a normal fluid intake . the parents were taught to monitor body weight daily and to allow a short time of diuresis . this regimen resulted in stable random sodium concentrations , around 140 to 150 mmol / l . psychomotor development was severely delayed , and seizures and bilateral blindness were present . at the age of 12 months , mri showed absence of bright spot , confirming the permanency of diabetes insipidus . at the age of 2.5 years , diabetes insipidus was managed with minirin melt , 60 g daily and combined oral and gastric feeding . the second neonate was a girl , born at term by spontaneous vaginal delivery with a birth weight of 2700 grams and length of 47 cm . her mother , a 16-year old teenager , denied any use of medication or ( illegal ) drugs during pregnancy . at birth , mild dysmorphic features were noticed , including asymmetry of the skull and ptosis of the right eye lid ( due to n. oculomotorius paralysis ) . brain mri revealed bilateral subdural hygroma , schizencephaly with polymicrogyria and midline abnormalities ( absent septum pellucidum , agenesis of the corpus callosum , hypoplastic optic nerves and chiasm , and absence of normal posterior pituitary bright spot ) . on day 60 , she was admitted to hospital for neurosurgical intervention with subdural peritoneal shunting . laboratory investigations on day 1 after the operation showed hypernatremia ( 168 mmol / l ) with a serum osmolality of 322 mosm / kg and a urine osmolality of 100 mosm / kg . careful reviewing of the history revealed that the infant was very hungry and irritable since shortly after birth , with very frequent soaked diapers and drinking more than 230 ml / kg / day of formula . normalization of urine output and osmolality after iv administration of ddavp confirmed the diagnosis of central diabetes insipidus . urine osmolality increased within three hours and remained above 400 mosm / kg for the next 12 hours . pharmacokinetic data are represented in figure 1 . at the age of 12 months , she was well managed with minirin melt 45 g daily . no episode of hypo or extreme hypernatremia occurred and a normal weight gain was observed . , diabetes insipidus was managed with minirin melt , 45 g daily and gastric feeding . to the best of our knowledge , this is the first report regarding the use of minirin melt for the treatment of central diabetes insipidus in very young infants . a starting dose of 15 g appeared safe at this young age and a maintenance dose of 30 to 60 g daily was effective in the first two years of life . infants consume almost all their calories in liquid form . to eliminate a large amount of dietary water , urine osmolality is typically low ( 100 - 150 mosm / l ) and urine output is high ( 5 ml / kg / h ) . because of this obligatory high urine output , infants are prone to water intoxication if fixed antidiuresis is achieved by desmopressin treatment . additionally , the exact volume of urine output is difficult to assess in young children , and infants are unable to both access fluids and articulate thirst to care providers . moreover , many of these infants present with severe congenital or acquired neurological problems , leading to an impairment of their thirst mechanism . two apparently contradictory treatment options have been proposed for young infants and very small children . either low solute diet combined with thiazide diuretics or the use of vasopressin analogue , desmopressin ( 5 ) . low renal solute load formula reduces obligatory urinary water losses and the use of thiazide diuretics results in sodium loss , subsequent decrease of circulating volume and increase in vasoactive hormones , leading to maximal proximal sodium and water reabsorption . this approach is only acceptable if hypernatremia is mild and does not coincide with neurological symptoms or failure to thrive . desmopressin was introduced for the treatment of cdi first in 1972 ( 6 ) and has been commercially available for many years as an intranasal solution ( 1972 ) , an injectable solution for intravenous , subcutaneous or intramuscular use ( 1981 ) , a nasal spray ( 1986 ) and oral solid tablet ( 1987 ) ( 7 ) . given high and fixed dosage of nasal spray , intranasal solution is more appropriate to treat cdi in young children . a major disadvantage of intranasal solution is that the absorption is highly variable and often a dilution has to be administered , making weekly preparations necessary ( 8) . large individual variations in absorption of ddavp following oral administration have also been observed in children with cdi , and swallowing whole tablets remains difficult for infants and young children . therefore , subcutaneous ddavp acetate ( 4 microgram / ml ) is often used in infants because of the possibility of precise administration and consistent dosing , but long - term use of subcutaneous injections is inconvenient ( 9 ) . due to variable absorption with the above mentioned formulations , it has been difficult to avoid potentially life threatening episodes of hyponatremia and fast changes of sodium levels , especially in infants . hyponatremia results from water retention caused by drugs potent antidiuretic effect and simultaneous intake of fluids . infants and young children are vulnerable for water intoxication and cerebral oedema , because their brain has a limited capacity to adapt with hyponatremia . this leads to a higher morbidity and mortality due to symptomatic hyponatremia in young children compared to adults ( 10 ) . we decided to treat our two young infants with sublingual desmopressin ( minirin melt ) because of its ease of administration ( the tablet was cut by a sterile stitch cutter and placed sublingually using small tweezers ) and our previous experience with high day - to - day variability of the nasal solution in infants . oral lyophilisate formulation is well tolerated , with the same type of adverse events as reported for desmopressin tablets . pharmacological studies demonstrated that sublingual route results in a more stable absorption compared to intranasal or oral route . additionally , oral lyophilisate has a higher bioavailability compared to tablet , allowing lower dosing ( 11 ) . in the absence of pharmacokinetic data of oral lyophilisate in neonates , we observed that 60 g melt in the first case resulted in a pharmacokinetic profile that largely exceeds ( 4x ) the reference frame from osterberg of 240 g for children ( 6 - 12 years ) with nocturnal enuresis . this is against the indication of nocturnal enuresis , in which only a 12-hour coverage is required . therefore , we started with a small dose of 15 g desmopressin in the second case , which resulted in a pk profile compatible to the reference frame . these results suggest that bioavailability characteristics are largely maintained . despite the fact that we had to cut the tablet minirin melt was administered to both infants with careful monitoring of the balance between liquid intake and output . both infants were managed with one to two daily dosing on long - term . in both infants , no episodes of hyponatremia or severe hypernatremia were reported during their first two years of life and they gained weight properly . in our experience of two cases , sublingual administration of desmopressin lyophilisate together with close follow - up of serum sodium and parent education about the risk of excessive fluid intake was successful and more convenient than intranasal ddavp therapy . we recommend a starting dose of 15 g in neonates and young infants and an upward titration depending on the effect . however , more studies are required to confirm the possible use of minirin melt as the first line therapy in young small infants .
introduction : in neonates and small infants , early diagnosis of central diabetes insipidus ( cdi ) and treatment with desmopressin in low doses ( avoiding severe hypo- or hypernatremia ) are important to prevent associated high morbidity and mortality in this particular age group.case presentation : we described pharmacokinetic and pharmacodynamic results of the use of recently launched oral desmopressin lyophilisate ( minirin melt ) in two infants with cdi , diagnosed at the age of 12 and 62 days , respectively . 
 we observed that a starting dose of 60 g of minirin melt in the first case resulted in a pharmacokinetic profile largely exceeding the reference frame observed in children with nocturnal enuresis , while a dose of 15 g in the second case resulted in acceptable concentrations . 
 after initial dose adjustments , administration of sublingual lyophilisate resulted in rather stable serum sodium concentrations.conclusions:using minirin melt in infants with cdi appears to be effective , easy to use and well tolerated .