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Desmopressin Toxicity Due to Prolonged Half-Life in 18 Patients With Nocturnal Enuresis
Desmopressin Toxicity Due to Prolonged Half-Life in 18 Patients With Nocturnal Enuresis Jo L. Dehoorne,* Ann M. Raes, Erik van Laecke, Piet Hoebeke and Johan G. Vande Walle From the Pediatric Nephrology and Urology Department, University Hospital Gent, Ghent, Belgium
Purpose: Desmopressin has been used extensively for primary nocturnal enuresis and it is associated with a low incidence of adverse effects. The only reported serious side effect is seizure or altered levels of consciousness resulting from water intoxication, which has been reported for the nasal spray. We describe 18 children with clinical symptoms of water intoxication due to the prolonged bioactivity of desmopressin nasal spray. Materials and Methods: We evaluated 18 patients with clinical suspicion of prolonged desmopressin bioactivity during treatment with intranasal desmopressin for primary nocturnal enuresis. The control group consisted of 50 children with primary nocturnal enuresis and proven nocturnal polyuria who were treated with the same desmopressin regimen. Results: All patients had prolonged maximal urinary concentration capacity and delayed restoration of daytime diluting capacity (p ⬍0.01). Of the patients 15 had the characteristic clinical symptoms of water intoxication with vomiting, headache, decreased consciousness and hyponatremia. We suspect that these symptoms are secondary to prolonged desmopressin bioactivity. Conclusions: Prolonged desmopressin bioactivity may increase the risk of water intoxication. Key Words: bladder, enuresis, deamino arginine vasopressin, toxicity, half-life
igh nocturnal production of a hypotonic urine is documented in PNE and it may be related to a low nocturnal plasma concentration of circulating AVP.1 Based on this rationale DDAVP has been used extensively for PNE with a response of up to 70%,1,2 leading to a major place in initial therapy.2,3 Despite its widespread use as therapy for PNE the incidence of reported adverse effects is low.4 – 6 The only reported serious side effects are seizures or altered levels of consciousness secondary to water intoxication and hyponatremia.7–9 However in the absence of polydipsia hyponatremia can theoretically not occur in a patient with PNE if DDAVP administration is correct and fluid restriction is maintained during the night, at least if the pharmacodynamic and kinetic properties of DDAVP in children are as expected. However, proper pharmacokinetic and dynamic studies with the DDAVP spray are lacking. In 1999 a patient treated with intranasal DDAVP presented with seizures and hyponatremia. Anamnesis revealed a delay of first morning voiding until late in the afternoon and there was no history of high fluid intake. After this observation we started prospectively documenting patients with possible clinical symptoms compatible with prolonged bioactivity of DDAVP and/or potential water intoxication.
PATIENTS AND METHODS
H
Patients Ten boys and 8 girls 6 to 15 years old with PNE, including 2 ⫻ 2 siblings, who had clinical suspicion of prolonged bioactivity of DDAVP and/or water intoxication were identified of a total of 2,043 consecutive patients at a tertiary university enuresis center in 1999 to 2004. Data on serum sodium, Uosm, the morning diuresis rate and clinical characteristics, such as convulsions, headache, consciousness and nausea, were collected (table 1). Plasma sodium was measured at the first visit at the outdoor clinic after the appearance of symptoms. In some patients DDAVP was withdrawn spontaneously by parents or after telephone advice, resulting in sodium levels that were not representative of the level at the time of symptoms. Patients were considered to have NP if nocturnal diuresis volume at the intake visit was higher than estimated bladder capacity for age, as calculated by the Koff formula, (age in years ⫹ 2) ⫻ 30 ml,10 and higher than their MBC. Bladder volume was estimated as MBC during water load and forced diuresis. The patient was asked to drink as much as possible, postpone voiding as long as possible and then measure the volume after micturition. The largest volume of at least 6 measurements was considered MBC. None of the patients had an organic urological or renal disease, diabetes insipidus, diabetes mellitus type 1, cardiopathy or ongoing use of drugs interfering with renal function. Not only daytime incontinence according to the International Children’s Continence Society definition, but also daytime symptoms, such as frequency, urgency, small bladder capacity for age, constipation and urinary tract history, were exclusion criteria to make the study group as homogeneous as possible.
Study received local ethics committee approval. * Correspondence and requests for reprints: Department of Pediatric Nephrology, University Hospital Gent, 5K6, De Pintelaan 185, 9000 Gent, Belgium (telephone: ⫹32 9 240 5089; FAX: ⫹32 9 240 2193; e-mail: [email protected]).
0022-5347/06/1762-0754/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
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TABLE 1. Study group characteristics No. Pts Overall Nausea Headache Abdominal pain Vomiting Decreased consciousness Low morning diuresis rate Seizures (mmol/l Na): Less than 135 Less than 132
18 14 15 7 3 2 18 3 9 7
Study group values were compared with those in a control group, consisting of 50 children 6 to 17 years old (median age 8.5) who were sex matched (22 girls and 38 boys) with PNE and proven nocturnal polyuria. These children were treated with the same desmopressin regimen but without clinical symptoms suggestive of water intoxication. Median body weight ⫾ SD in the control and patient groups was 32 ⫾ 7 and 28 ⫾ 7 kg, respectively. Patients and parents provided written consent for participation in the investigation after having been informed of the nature and purpose of the study. The study was approved by the local ethics committee. Testing was performed on an ambulatory basis except in the 3 children with seizures. Pharmacodynamic Test for Diluting/Concentrating Capacity Each subject received a standardized high daytime fluid of 1,600 to 1,800 ml/m2 divided throughout the day. No fluid intake was allowed after 6 p.m. or overnight. All children received a standard regimen of 20 g intranasal desmopressin ⫾ 1 hour before bedtime using a precompression spray pump that delivers an accurate dose of 10 g. The bladder was emptied at bedtime and no fluid intake was allowed overnight. The 24-hour urine collection started at bedtime, 1 hour after DDAVP administration. The children were requested to fractionally collect urine every 3 hours with documentation of volume and time correlating with DDAVP administration. During sleep patients were awakened by their parents every 3 hours. On each timed urine collection Uosm was measured. In some patients extra collections before DDAVP administration were available (see figure). Statistical Procedure Patients and controls were compared regarding the Uosm nycthemeral rhythm with the Mann-Whitney U test with significance considered at p ⬍0,01. All data are reported as the mean ⫾ 1 SD. RESULTS Table 1 lists characteristics of the study population at the first visit after the appearance of clinical symptoms. For all 18 children parents reported that they did not void after awakening and/or passed the first morning void at least more than 15 hours, some up to more than 18 hours, after DDAVP administration. Although 15 of 18 patients had characteristic clinical symptoms compatible with water intoxication, such as vomiting, decreased consciousness and
Mean individual Uosm in mOsm/kg vs mean control population reference frame ⫾ 1 SD in 3-hour urine collections in relation to time after DDAVP administration ⫾ 1 hour before sleeping. Asterisk indicates Mann-Whitney U test p ⬍0.01.
headache, the parents of 3 patients reported only mild complaints, that is the children were acting slightly differently after the decreased morning diuresis rate was identified. None of the patients had a history of ingesting large amounts of fluids before bedtime or during the night. Seven patients had significantly decreased plasma sodium of less than 132 mmol/l but only 2 of the 3 with seizures had severe hyponatremia (119 and 123 mmol/l, respectively). The third patient underwent no blood sampling at the time of convulsions. In 5 patients with symptoms DDAVP had already been withdrawn more than 24 hours previously by parents before the blood sample was taken, which might have caused underestimation of the incidence of hyponatremia in this group. All 18 patients had significantly increased Uosm in the urine collection 13 to 16 hour after DDAVP administration (1.021 ⫾ 60 vs 765 ⫾ 87 mOsm/l, respectively, p ⬍0.01, see figure and table 2). Mean Uosm remained significantly increased in the urine collection 16 to 19 hours after DDAVP administration (901 ⫾ 81 and 679 ⫾ 129 mOsm/l, respectively, p ⬍0.01, see figure and table 2). At 22 to 25 hours Uosm was significantly lower compared to that in the control population (398 ⫾ 122 vs 723 ⫾ 149 mOsm/l, p ⬍0.01, see figure).
TABLE 2. Uosm of timed 3-hour urine collections vs time after dDAVP administration Time After dDAVP (hrs) No. pts 1–4 4–7 7–10 10–13 13–16 16–19 19–22 22–25 p ⬍0.01.
Mean Osmolality ⫾ 1 SD (mOsm/l) Pts
Controls
18 929 ⫾ 65 1,027 ⫾ 66 1,061 ⫾ 82 1,030 ⫾ 50 1,021 ⫾ 60* 901 ⫾ 81* 690 ⫾ 128 398 ⫾ 122*
50 970 ⫾ 75 1,020 ⫾ 65 990 ⫾ 45 960 ⫾ 65 765 ⫾ 87 679 ⫾ 129 793 ⫾ 150 723 ⫾ 149
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DISCUSSION Treatment with DDAVP has improved quality of life in thousands of children and adults with nocturnal enuresis. It is generally regarded as a safe drug and adverse effects due to treatment with DDAVP are uncommon.4 – 6 The only serious side effect is seizure or altered levels of consciousness due to water intoxication. This has only been reported in children treated with intranasal or intravenous desmopressin. Often excess fluid intake is identified as a contributing factor. We describe 18 children treated with intranasal DDAVP for PNE who had clinical suspicion of DDAVP toxicity, in whom we documented prolonged DDAVP bioactivity, identified as delayed recovery of diluting capacity. All 18 patients had a prolonged excretion time of hyperosmolar urine, suggesting an increased half-life of the drug or at least of its bioactivity even at the rather low dose of 20 g. DDAVP is a synthetic analogue of the naturally occurring antidiuretic hormone AVP. As with antidiuretic hormone, the antidiuretic effect of DDAVP is due to activation of the V2 receptor of the adenyl cyclase system in the renal collecting tubule. This activation leads to insertion of aquaporins in the cell membrane, resulting in increased reabsorption of free water. Due to its prolonged and extensive antidiuretic effect and decreased vasopressor activity11 DDAVP became the drug of choice central diabetes insipidus.12 Since its therapeutic potential in nocturnal enuresis was proved in 1978, DDAVP has been used in many countries.13 However, there is only limited information on the pharmacodynamic response to DDAVP in children with PNE, especially for the spray. Doses are derived from adult pharmacodynamic studies and clinical anti-enuretic trials in children, thereby neglecting proper studies of the antidiuretic effect in children. To our knowledge no proper dose-response studies or pharmacokinetic/dynamic studies have been performed with the nasal spray. The plasma half-life of desmopressin has been estimated to be between 1 and 2 hours, whereas the antidiuretic effect has a total duration of 7 to 10 hours.14 Based on these values we would expect Uosm to remain increased (⫾ greater than 850 mOsm/l) and accordingly urine volume to remain low up to 10 hours following DDAVP administration. The bioavailability of the intranasal DDAVP is low (⫾ 3%) but still better than that of the tablets (⫾ 0.25%). However, it remains unpredictable. The statement that the duration of action is 7 to 10 hours indicates only that maximal concentrating capacity is maintained for 7 to 10 hours but it does not mean that maximal diluting capacity is restored immediately after those 7 to 10 hours. The study results in our patient group could not be attributable to an increase in the dose or to nocturnal fluid intake because all studied patients received a classic low dose of 20 g and nocturnal fluid restriction. All patients had a good antidiuretic effect (Uosm greater than 850 mOsm/l) up to 16 hours after DDAVP administration and only 2 attained an Uosm of less than 850 mOsm/l in the urine collection 16 to 19 hours after DDAVP administration, clearly indicating deficient diluting capacity. Because of the relatively high daytime fluid intake secondary to the centerdependent strategy of 1,500 ml/m2 fluid divided throughout the day, we can exclude relative dehydration as the cause of the apparently prolonged bioactivity. Patient Uosm in the urine collection 22 to 25 hours after DDAVP administration
was significantly lower than in the control population, suggestive of a correction mechanism (see figure and table 2). These data clearly suggest that the half-life of DDAVP may differ significantly among individuals. Interindividual differences based on receptor sensitivity is another possible explanation.15 To prove this suggestion we should in theory repeat the test after a water load, resulting in maximal diluting capacity and, thereby, suppressing endogenous vasopressin secretion to a maximum and correlate with plasma DDAVP. However, since our patients already had a history of clinical symptoms of water intoxication and documented prolonged bioactivity, it was hardly defensible to put them at risk for a new period of potential water intoxication. To submit patients to 1-day repeat exposure was defensible because as long as fluid intake does not lead to a positive fluid balance of greater than 1 l/24 hours, a decrease in plasma serum sodium of more than 5 mmol/l is not a risk. Several mechanisms can explain such prolonged bioactivity and/or the apparent clinical symptoms of water intoxication in our study group. Nasal absorption of DDAVP has a low bioavailability but relative high variability. Whether children have higher absorption is not known, but it is well known that children have different pharmacodynamic characteristics than adults. Because multiple groups have reported low but not absent secretion of plasma AVP in patients with enuresis and nocturnal polyuria, the effect of the pharmacological action of DDAVP in addition to naturally occurring AVP might increase the V2 agonist effect and the risk of water intoxication in some patients.1,16 Other groups speculated that V2 receptors in the kidneys of children on chronic DDAVP treatment can be up-regulated and, therefore, they are more sensitive to the action of DDAVP.17 Since higher doses of DDAVP prolong the duration of its pharmacological action and may subsequently increase the risk of water intoxication,18 it is possible that some patients were not therapy compliant. Some investigators suggested that the ingestion of larger than prescribed amounts of DDAVP might be more common than is appreciated.5 It is possible that patients who are not completely dry on the prescribed dose might increase the dose in an attempt to improve efficacy. As mentioned, excess fluid intake is often identified as a factor contributing to water intoxication in patients treated with DDAVP. Evening fluid restriction is a common practice in most children with nocturnal enuresis. Consequently most patients treated with DDAVP do not ingest large amounts of fluid during the evening. In all of our patients evening and overnight fluid intake was strongly restricted but high daytime fluid intake was rather promoted as part of a systematic urotherapy protocol. This high daytime fluid intake divided over the day may definitely have had a role in the rather high incidence of water intoxication symptoms in this single center study. Rather than advising a decrease in fluid intake before bedtime in all patients, we advise documenting diuresis volume during the morning hours, definitely before increasing the nasal dose to more than 20 g. In cases of prolonged DDAVP action the diuresis rate during the morning is low. The weakness of this observational study is that it lacks epidemiological background. Although we describe 18 patients, which is not a small number, we have no idea about the true incidence of these water intoxication symptoms in patients treated with DDAVP. This is because patients were
DESMOPRESSIN TOXICITY DUE TO PROLONGED HALF-LIFE recruited in a tertiary center, while treatment with DDAVP is often already started at primary and/or secondary centers. Additionally, we cannot document having identified all potential index patients, nor did we perform the testing in all DDAVP treated patients. The documented patient characteristics are poorly standardized because they were retrieved from the clinical history and not prospectively documented in a diary (table 1). If we had wanted to do this prospectively, we would have had to continue DDAVP treatment, which was ethically not defensible. Blood sodium was measured at the outpatient clinic at the time of suspicion of clinical symptoms and/or after discontinuing the drug. We are convinced that this weakness in the study design on the epidemiological side and on the documentation of clinical symptoms in index patients does not undermine the importance of this study. That is, in comparison with that generally described in the literature, in a highly select study population all index patients had prolonged bioactivity of DDAVP spray even at daily doses of 20 g.
4.
5.
6.
7.
8.
9.
10. 11.
CONCLUSIONS Although DDAVP is generally regarded as a safe drug, prolonged DDAVP bioavailability may increase the risk of water intoxication when high fluid intake is promoted during the day. In children pharmacokinetic and pharmacodynamic data are often limited, thereby causing the impression that drugs are safe. These data clearly demonstrate that the half-life of a drug may differ significantly among individuals. Therefore, it is recommended that when DDAVP is administered in the evening, parents should observe if children have a normal diuresis volume in the morning. The fact that this was documented in 2 ⫻ 2 siblings may indicate some genetic predisposition. Treatment with DDAVP should only be prescribed in compliant families with specific instructions regarding the risk associated with excess fluid ingestion. Patients should be specifically instructed not to ingest larger doses than prescribed. For a drug with such a high prescription rate in children full pharmacodynamic and kinetic data, and dose-response studies are necessary to identify patients at risk for side effects.
Abbreviations and Acronyms AVP DDAVP MBC PNE Uosm
⫽ ⫽ ⫽ ⫽ ⫽
arginine vasopressin desmopressin maximal bladder capacity primary nocturnal enuresis urine osmolality
REFERENCES 1.
Nørgaard, J. P., Pedersen, E. B. and Djurhuus, J. C.: Diurnal anti-diuretic-hormone levels in enuretics. J Urol, 134: 1029, 1985 2. Moffatt, M. E., Harlos, S., Kirshen, A. J. and Burd, L.: Desmopressin acetate and nocturnal enuresis: how much do we know? Pediatrics, 92: 420, 1993 3. Hjalmas, K., Arnold, T., Bower, W., Caione, P., Chiozza, L. M. and von Gontard, A.: Nocturnal enuresis: an international evidence based management strategy. J Urol, 171: 2545, 2004
12.
13.
14.
15. 16.
17.
18.
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Hjälmas, K., Hanson, E., Hellstorm, A. L., Kruse, S. and Sillen, U.: Long-term treatment with desmopressin in children with primary monosymptomatic nocturnal enuresis: an open multicentre study. Swedish Enuresis Trial (SWEET) group. Br J Urol, 82: 704, 1998 Hjälmas, K. and Bengtsson, B.: Efficacy, safety and dosing of desmopressin for nocturnal enuresis in Europe. Clin Pediatr (Spec Ed), p. 19, 1993 Van Kerrebroeck, P. E.: Experience with the long-term use of desmopressin for nocturnal enuresis in children and adolescents. BJU Int, 89: 420, 2002 Beach, P.S., Beach, R.A. and Smith, L. R.: Hyponatremic seizures in a child treated with desmopressin to control enuresis. Clin Pediatr, 9: 566, 1993 Shindel, A., Tobin, G. and Klutke, C.: Hyponatremia associated with desmopressin for the treatment of nocturnal polyuria. Urology, 60: 344, 2002 Robson, W. L. and Leung, A. K.: Side effects and complications of treatment with desmopressin for enuresis. J Natl Med Assoc, 86: 775, 1994 Koff, S. A.: Estimating bladder capacity in children. Urology, 21: 248, 1983 Andersson, K. E., Bengtsson, B. and Paulsen, O.: Desamino-8D-arginine vasopressin (DDAVP): pharmacology and clinical use. Drugs Today, 24: 509, 1988 Becker, D. J. and Foley, T. P., Jr.: 1-Deamino-8D-arginine vasopressin the treatment of central diabetes insipidus in childhood. J Pediatr, 92: 1011, 1978 Birkásova, M., Birkás, O., Flynn, M. J. and Cort, J. H.: Desmopressin in the management of nocturnal enuresis in children: a double blind study. Pediatrics, 62: 970, 1978 Fjellestad-Paulsen, A., Hoglund, P., Lundin, S. and Paulsen, O.: Pharmacokinetics of 1-desamino-8-D-arginine vasopressin after various routes of administration in healthy volunteers. Clin Endocrinol (Oxf), 38: 177, 1993 Terho, P.: Desmopressin in nocturnal enuresis. J Urol, 145: 818, 1991 Robson, W. L., Nørgaard, J. P. and Leung, A. K.: Hyponatremia in patients with nocturnal enuresis treated with DDAVP. Eur J Pediatr, 155: 959, 1996 Kallio, J., Rautava, P. and Huupponen, R.: Severe hyponatremia caused by intranasal desmopressin for nocturnal enuresis. Acta Paediatr, 82: 881, 1993 Harris, A. S., Nilsson, I. M., Wagner, Z. G. and Alkner, U.: Intranasal administration of peptides: nasal deposition, biological response, and absorption of desmopressin. J Pharmacol Sci, 75: 1085, 1986
EDITORIAL COMMENTS Desmopressin acetate or DDAVP has become the mainstay of pharmacological treatment for PNE. Initially touted as a medication with a good safety profile, DDAVP has come under increased scrutiny. Several hundred articles on DDAVP have been published in the last 15 years and it is hardly surprising that certain dangerous side effects, specifically water intoxication and hyponatremia, have come to light. The literature on DDAVP was reviewed recently.1 The message from this report and the current article is clear: clinician, be aware! Intranasal administered DDAVP can in some patients cause significant and possibly life threatening hyponatremic hypervolemia, of which the symptoms are nausea, vomiting, headaches, altered states of consciousness and possibly seizures. The current article may not mirror the clinical picture since personally I have not encountered any such cases but then again was I paying close enough attention? These authors shed an interesting light on the
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pharmacology of DDAVP and suggest that its antidiuretic effects may last much longer than originally thought (reference 15 in article). The bottom line is that water intoxication can occur in the face of DDAVP therapy in the setting of excess water intake. Clearly this can be prevented by proper parental and patient education. However, a number of questions linger. Does the route of administration (oral vs intranasal) alter the risk? Should all patients on DDAVP have morning serum electrolytes checked and urine osmolarity evaluated? Does the dose of DDAVP influence the degree of hyponatemic hypervolemia? While this study does not give us a clear incidence of the problem, nor does it answer some of these questions, clinicians must take note and ensure that fluid restriction is enforced during DDAVP therapy. In fact, a protocol for dose and screening would be helpful. In the current medicolegal environment it may also behoove the clinician to document morning serum electrolytes and urine osmolarity in children on DDAVP, especially those younger than 10 years. These authors present a clinically relevant study. However, further study is clearly needed to ascertain the true extent of the problem, and whether oral DDAVP can also lead to water intoxication and at what dose. Marc Cendron Department of Pediatric Urology Childrens’ Hospital Boston Boston, Massachusetts 1.
hours following 20 g DDAVP nasal spray suggests the need for explicit fluid instructions to families and for a screening mechanism to identify patients at risk.1 Evening fluid restriction is clearly important and should continue to be routinely recommended. Fluid restriction during the subsequent day is likely neither a practical nor a desirable alternative in most children. Screening treated patients by history to decide whether they void on awakening or later in the morning is a noninvasive method that might identify some of those at risk but measuring serum sodium is the surest method to clarify whether water intoxication is a concern. First morning serum sodium determined at least 10 hours and up to 16 hours after the administration of DDAVP nasal spray should be considered as a screening test. Thumfart et al reported that the risk of water intoxication is particularly high at the beginning of therapy, and so the test should be performed within the first 2 weeks.2 If serum sodium is less than 135 mg/dl, DDAVP should be discontinued, the dose should be decreased or fluid intake should be further restricted. The blood test should be repeated after any change in dose. The duration of action and the risk of water intoxication is presumably increased at a larger dose. Any child who develops headache, nausea, or any neurological symptom while on DDAVP nasal spray should be advised to discontinue the medication and to promptly attend with a physician.
Thumfart, J., Roehr, C.-C., Kapelari, K., Querfeld, U., Eggert, P. and Muller, D.: Desmopressin associated symptomatic hyponatremic hypervolemia in children. Are there predictive factors? J Urol, 174: 294, 2005
The incidence of symptomatic water intoxication in children with nocturnal enuresis treated with DDAVP nasal spray is likely appreciably higher than we recognize. The 1% to 2% incidence of headache reported as an adverse event in children treated with DDAVP nasal spray might well represent unrecognized episodes of water intoxication (reference 9 in article). The incidence of asymptomatic water intoxication is likely even higher. The report of these authors that 18 patients with symptomatic water intoxication could not dilute urine for up to 19
Wm. Lane M. Robson Department of Paediatrics Tamam Hospital Calgary, Alberta Canada 1.
2.
Dehoorne, J. L., Raes, A. M., van Laecke, E., Hoebeke, P. and Vande Walle, J. G.: Desmopressin toxicity due to prolonged half-life in 18 patients with nocturnal enuresis. J Urol, 176: 754, 2006 Thumfart, J., Roehr, C. C., Kapelari, K., Quesfeld, U., Eggert P. and Muller, D.: Desmopressin associated symptomatic hyponatremic hypervolemia in children. Are there predictive factors? J Urol, 174: 294, 2005
Purpose: Desmopressin has been used extensively for primary nocturnal enuresis and it is associated with a low incidence of adverse effects. The only reported serious side effect is seizure or altered levels of consciousness resulting from water intoxication, which has been reported for the nasal spray. We describe 18 children with clinical symptoms of water intoxication due to the prolonged bioactivity of desmopressin nasal spray. Materials and Methods: We evaluated 18 patients with clinical suspicion of prolonged desmopressin bioactivity during treatment with intranasal desmopressin for primary nocturnal enuresis. The control group consisted of 50 children with primary nocturnal enuresis and proven nocturnal polyuria who were treated with the same desmopressin regimen. Results: All patients had prolonged maximal urinary concentration capacity and delayed restoration of daytime diluting capacity (p ⬍0.01). Of the patients 15 had the characteristic clinical symptoms of water intoxication with vomiting, headache, decreased consciousness and hyponatremia. We suspect that these symptoms are secondary to prolonged desmopressin bioactivity. Conclusions: Prolonged desmopressin bioactivity may increase the risk of water intoxication. Key Words: bladder, enuresis, deamino arginine vasopressin, toxicity, half-life
igh nocturnal production of a hypotonic urine is documented in PNE and it may be related to a low nocturnal plasma concentration of circulating AVP.1 Based on this rationale DDAVP has been used extensively for PNE with a response of up to 70%,1,2 leading to a major place in initial therapy.2,3 Despite its widespread use as therapy for PNE the incidence of reported adverse effects is low.4 – 6 The only reported serious side effects are seizures or altered levels of consciousness secondary to water intoxication and hyponatremia.7–9 However in the absence of polydipsia hyponatremia can theoretically not occur in a patient with PNE if DDAVP administration is correct and fluid restriction is maintained during the night, at least if the pharmacodynamic and kinetic properties of DDAVP in children are as expected. However, proper pharmacokinetic and dynamic studies with the DDAVP spray are lacking. In 1999 a patient treated with intranasal DDAVP presented with seizures and hyponatremia. Anamnesis revealed a delay of first morning voiding until late in the afternoon and there was no history of high fluid intake. After this observation we started prospectively documenting patients with possible clinical symptoms compatible with prolonged bioactivity of DDAVP and/or potential water intoxication.
PATIENTS AND METHODS
H
Patients Ten boys and 8 girls 6 to 15 years old with PNE, including 2 ⫻ 2 siblings, who had clinical suspicion of prolonged bioactivity of DDAVP and/or water intoxication were identified of a total of 2,043 consecutive patients at a tertiary university enuresis center in 1999 to 2004. Data on serum sodium, Uosm, the morning diuresis rate and clinical characteristics, such as convulsions, headache, consciousness and nausea, were collected (table 1). Plasma sodium was measured at the first visit at the outdoor clinic after the appearance of symptoms. In some patients DDAVP was withdrawn spontaneously by parents or after telephone advice, resulting in sodium levels that were not representative of the level at the time of symptoms. Patients were considered to have NP if nocturnal diuresis volume at the intake visit was higher than estimated bladder capacity for age, as calculated by the Koff formula, (age in years ⫹ 2) ⫻ 30 ml,10 and higher than their MBC. Bladder volume was estimated as MBC during water load and forced diuresis. The patient was asked to drink as much as possible, postpone voiding as long as possible and then measure the volume after micturition. The largest volume of at least 6 measurements was considered MBC. None of the patients had an organic urological or renal disease, diabetes insipidus, diabetes mellitus type 1, cardiopathy or ongoing use of drugs interfering with renal function. Not only daytime incontinence according to the International Children’s Continence Society definition, but also daytime symptoms, such as frequency, urgency, small bladder capacity for age, constipation and urinary tract history, were exclusion criteria to make the study group as homogeneous as possible.
Study received local ethics committee approval. * Correspondence and requests for reprints: Department of Pediatric Nephrology, University Hospital Gent, 5K6, De Pintelaan 185, 9000 Gent, Belgium (telephone: ⫹32 9 240 5089; FAX: ⫹32 9 240 2193; e-mail: [email protected]).
0022-5347/06/1762-0754/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
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Vol. 176, 754-758, August 2006 Printed in U.S.A. DOI:10.1016/S0022-5347(06)00299-0
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TABLE 1. Study group characteristics No. Pts Overall Nausea Headache Abdominal pain Vomiting Decreased consciousness Low morning diuresis rate Seizures (mmol/l Na): Less than 135 Less than 132
18 14 15 7 3 2 18 3 9 7
Study group values were compared with those in a control group, consisting of 50 children 6 to 17 years old (median age 8.5) who were sex matched (22 girls and 38 boys) with PNE and proven nocturnal polyuria. These children were treated with the same desmopressin regimen but without clinical symptoms suggestive of water intoxication. Median body weight ⫾ SD in the control and patient groups was 32 ⫾ 7 and 28 ⫾ 7 kg, respectively. Patients and parents provided written consent for participation in the investigation after having been informed of the nature and purpose of the study. The study was approved by the local ethics committee. Testing was performed on an ambulatory basis except in the 3 children with seizures. Pharmacodynamic Test for Diluting/Concentrating Capacity Each subject received a standardized high daytime fluid of 1,600 to 1,800 ml/m2 divided throughout the day. No fluid intake was allowed after 6 p.m. or overnight. All children received a standard regimen of 20 g intranasal desmopressin ⫾ 1 hour before bedtime using a precompression spray pump that delivers an accurate dose of 10 g. The bladder was emptied at bedtime and no fluid intake was allowed overnight. The 24-hour urine collection started at bedtime, 1 hour after DDAVP administration. The children were requested to fractionally collect urine every 3 hours with documentation of volume and time correlating with DDAVP administration. During sleep patients were awakened by their parents every 3 hours. On each timed urine collection Uosm was measured. In some patients extra collections before DDAVP administration were available (see figure). Statistical Procedure Patients and controls were compared regarding the Uosm nycthemeral rhythm with the Mann-Whitney U test with significance considered at p ⬍0,01. All data are reported as the mean ⫾ 1 SD. RESULTS Table 1 lists characteristics of the study population at the first visit after the appearance of clinical symptoms. For all 18 children parents reported that they did not void after awakening and/or passed the first morning void at least more than 15 hours, some up to more than 18 hours, after DDAVP administration. Although 15 of 18 patients had characteristic clinical symptoms compatible with water intoxication, such as vomiting, decreased consciousness and
Mean individual Uosm in mOsm/kg vs mean control population reference frame ⫾ 1 SD in 3-hour urine collections in relation to time after DDAVP administration ⫾ 1 hour before sleeping. Asterisk indicates Mann-Whitney U test p ⬍0.01.
headache, the parents of 3 patients reported only mild complaints, that is the children were acting slightly differently after the decreased morning diuresis rate was identified. None of the patients had a history of ingesting large amounts of fluids before bedtime or during the night. Seven patients had significantly decreased plasma sodium of less than 132 mmol/l but only 2 of the 3 with seizures had severe hyponatremia (119 and 123 mmol/l, respectively). The third patient underwent no blood sampling at the time of convulsions. In 5 patients with symptoms DDAVP had already been withdrawn more than 24 hours previously by parents before the blood sample was taken, which might have caused underestimation of the incidence of hyponatremia in this group. All 18 patients had significantly increased Uosm in the urine collection 13 to 16 hour after DDAVP administration (1.021 ⫾ 60 vs 765 ⫾ 87 mOsm/l, respectively, p ⬍0.01, see figure and table 2). Mean Uosm remained significantly increased in the urine collection 16 to 19 hours after DDAVP administration (901 ⫾ 81 and 679 ⫾ 129 mOsm/l, respectively, p ⬍0.01, see figure and table 2). At 22 to 25 hours Uosm was significantly lower compared to that in the control population (398 ⫾ 122 vs 723 ⫾ 149 mOsm/l, p ⬍0.01, see figure).
TABLE 2. Uosm of timed 3-hour urine collections vs time after dDAVP administration Time After dDAVP (hrs) No. pts 1–4 4–7 7–10 10–13 13–16 16–19 19–22 22–25 p ⬍0.01.
Mean Osmolality ⫾ 1 SD (mOsm/l) Pts
Controls
18 929 ⫾ 65 1,027 ⫾ 66 1,061 ⫾ 82 1,030 ⫾ 50 1,021 ⫾ 60* 901 ⫾ 81* 690 ⫾ 128 398 ⫾ 122*
50 970 ⫾ 75 1,020 ⫾ 65 990 ⫾ 45 960 ⫾ 65 765 ⫾ 87 679 ⫾ 129 793 ⫾ 150 723 ⫾ 149
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DISCUSSION Treatment with DDAVP has improved quality of life in thousands of children and adults with nocturnal enuresis. It is generally regarded as a safe drug and adverse effects due to treatment with DDAVP are uncommon.4 – 6 The only serious side effect is seizure or altered levels of consciousness due to water intoxication. This has only been reported in children treated with intranasal or intravenous desmopressin. Often excess fluid intake is identified as a contributing factor. We describe 18 children treated with intranasal DDAVP for PNE who had clinical suspicion of DDAVP toxicity, in whom we documented prolonged DDAVP bioactivity, identified as delayed recovery of diluting capacity. All 18 patients had a prolonged excretion time of hyperosmolar urine, suggesting an increased half-life of the drug or at least of its bioactivity even at the rather low dose of 20 g. DDAVP is a synthetic analogue of the naturally occurring antidiuretic hormone AVP. As with antidiuretic hormone, the antidiuretic effect of DDAVP is due to activation of the V2 receptor of the adenyl cyclase system in the renal collecting tubule. This activation leads to insertion of aquaporins in the cell membrane, resulting in increased reabsorption of free water. Due to its prolonged and extensive antidiuretic effect and decreased vasopressor activity11 DDAVP became the drug of choice central diabetes insipidus.12 Since its therapeutic potential in nocturnal enuresis was proved in 1978, DDAVP has been used in many countries.13 However, there is only limited information on the pharmacodynamic response to DDAVP in children with PNE, especially for the spray. Doses are derived from adult pharmacodynamic studies and clinical anti-enuretic trials in children, thereby neglecting proper studies of the antidiuretic effect in children. To our knowledge no proper dose-response studies or pharmacokinetic/dynamic studies have been performed with the nasal spray. The plasma half-life of desmopressin has been estimated to be between 1 and 2 hours, whereas the antidiuretic effect has a total duration of 7 to 10 hours.14 Based on these values we would expect Uosm to remain increased (⫾ greater than 850 mOsm/l) and accordingly urine volume to remain low up to 10 hours following DDAVP administration. The bioavailability of the intranasal DDAVP is low (⫾ 3%) but still better than that of the tablets (⫾ 0.25%). However, it remains unpredictable. The statement that the duration of action is 7 to 10 hours indicates only that maximal concentrating capacity is maintained for 7 to 10 hours but it does not mean that maximal diluting capacity is restored immediately after those 7 to 10 hours. The study results in our patient group could not be attributable to an increase in the dose or to nocturnal fluid intake because all studied patients received a classic low dose of 20 g and nocturnal fluid restriction. All patients had a good antidiuretic effect (Uosm greater than 850 mOsm/l) up to 16 hours after DDAVP administration and only 2 attained an Uosm of less than 850 mOsm/l in the urine collection 16 to 19 hours after DDAVP administration, clearly indicating deficient diluting capacity. Because of the relatively high daytime fluid intake secondary to the centerdependent strategy of 1,500 ml/m2 fluid divided throughout the day, we can exclude relative dehydration as the cause of the apparently prolonged bioactivity. Patient Uosm in the urine collection 22 to 25 hours after DDAVP administration
was significantly lower than in the control population, suggestive of a correction mechanism (see figure and table 2). These data clearly suggest that the half-life of DDAVP may differ significantly among individuals. Interindividual differences based on receptor sensitivity is another possible explanation.15 To prove this suggestion we should in theory repeat the test after a water load, resulting in maximal diluting capacity and, thereby, suppressing endogenous vasopressin secretion to a maximum and correlate with plasma DDAVP. However, since our patients already had a history of clinical symptoms of water intoxication and documented prolonged bioactivity, it was hardly defensible to put them at risk for a new period of potential water intoxication. To submit patients to 1-day repeat exposure was defensible because as long as fluid intake does not lead to a positive fluid balance of greater than 1 l/24 hours, a decrease in plasma serum sodium of more than 5 mmol/l is not a risk. Several mechanisms can explain such prolonged bioactivity and/or the apparent clinical symptoms of water intoxication in our study group. Nasal absorption of DDAVP has a low bioavailability but relative high variability. Whether children have higher absorption is not known, but it is well known that children have different pharmacodynamic characteristics than adults. Because multiple groups have reported low but not absent secretion of plasma AVP in patients with enuresis and nocturnal polyuria, the effect of the pharmacological action of DDAVP in addition to naturally occurring AVP might increase the V2 agonist effect and the risk of water intoxication in some patients.1,16 Other groups speculated that V2 receptors in the kidneys of children on chronic DDAVP treatment can be up-regulated and, therefore, they are more sensitive to the action of DDAVP.17 Since higher doses of DDAVP prolong the duration of its pharmacological action and may subsequently increase the risk of water intoxication,18 it is possible that some patients were not therapy compliant. Some investigators suggested that the ingestion of larger than prescribed amounts of DDAVP might be more common than is appreciated.5 It is possible that patients who are not completely dry on the prescribed dose might increase the dose in an attempt to improve efficacy. As mentioned, excess fluid intake is often identified as a factor contributing to water intoxication in patients treated with DDAVP. Evening fluid restriction is a common practice in most children with nocturnal enuresis. Consequently most patients treated with DDAVP do not ingest large amounts of fluid during the evening. In all of our patients evening and overnight fluid intake was strongly restricted but high daytime fluid intake was rather promoted as part of a systematic urotherapy protocol. This high daytime fluid intake divided over the day may definitely have had a role in the rather high incidence of water intoxication symptoms in this single center study. Rather than advising a decrease in fluid intake before bedtime in all patients, we advise documenting diuresis volume during the morning hours, definitely before increasing the nasal dose to more than 20 g. In cases of prolonged DDAVP action the diuresis rate during the morning is low. The weakness of this observational study is that it lacks epidemiological background. Although we describe 18 patients, which is not a small number, we have no idea about the true incidence of these water intoxication symptoms in patients treated with DDAVP. This is because patients were
DESMOPRESSIN TOXICITY DUE TO PROLONGED HALF-LIFE recruited in a tertiary center, while treatment with DDAVP is often already started at primary and/or secondary centers. Additionally, we cannot document having identified all potential index patients, nor did we perform the testing in all DDAVP treated patients. The documented patient characteristics are poorly standardized because they were retrieved from the clinical history and not prospectively documented in a diary (table 1). If we had wanted to do this prospectively, we would have had to continue DDAVP treatment, which was ethically not defensible. Blood sodium was measured at the outpatient clinic at the time of suspicion of clinical symptoms and/or after discontinuing the drug. We are convinced that this weakness in the study design on the epidemiological side and on the documentation of clinical symptoms in index patients does not undermine the importance of this study. That is, in comparison with that generally described in the literature, in a highly select study population all index patients had prolonged bioactivity of DDAVP spray even at daily doses of 20 g.
4.
5.
6.
7.
8.
9.
10. 11.
CONCLUSIONS Although DDAVP is generally regarded as a safe drug, prolonged DDAVP bioavailability may increase the risk of water intoxication when high fluid intake is promoted during the day. In children pharmacokinetic and pharmacodynamic data are often limited, thereby causing the impression that drugs are safe. These data clearly demonstrate that the half-life of a drug may differ significantly among individuals. Therefore, it is recommended that when DDAVP is administered in the evening, parents should observe if children have a normal diuresis volume in the morning. The fact that this was documented in 2 ⫻ 2 siblings may indicate some genetic predisposition. Treatment with DDAVP should only be prescribed in compliant families with specific instructions regarding the risk associated with excess fluid ingestion. Patients should be specifically instructed not to ingest larger doses than prescribed. For a drug with such a high prescription rate in children full pharmacodynamic and kinetic data, and dose-response studies are necessary to identify patients at risk for side effects.
Abbreviations and Acronyms AVP DDAVP MBC PNE Uosm
⫽ ⫽ ⫽ ⫽ ⫽
arginine vasopressin desmopressin maximal bladder capacity primary nocturnal enuresis urine osmolality
REFERENCES 1.
Nørgaard, J. P., Pedersen, E. B. and Djurhuus, J. C.: Diurnal anti-diuretic-hormone levels in enuretics. J Urol, 134: 1029, 1985 2. Moffatt, M. E., Harlos, S., Kirshen, A. J. and Burd, L.: Desmopressin acetate and nocturnal enuresis: how much do we know? Pediatrics, 92: 420, 1993 3. Hjalmas, K., Arnold, T., Bower, W., Caione, P., Chiozza, L. M. and von Gontard, A.: Nocturnal enuresis: an international evidence based management strategy. J Urol, 171: 2545, 2004
12.
13.
14.
15. 16.
17.
18.
757
Hjälmas, K., Hanson, E., Hellstorm, A. L., Kruse, S. and Sillen, U.: Long-term treatment with desmopressin in children with primary monosymptomatic nocturnal enuresis: an open multicentre study. Swedish Enuresis Trial (SWEET) group. Br J Urol, 82: 704, 1998 Hjälmas, K. and Bengtsson, B.: Efficacy, safety and dosing of desmopressin for nocturnal enuresis in Europe. Clin Pediatr (Spec Ed), p. 19, 1993 Van Kerrebroeck, P. E.: Experience with the long-term use of desmopressin for nocturnal enuresis in children and adolescents. BJU Int, 89: 420, 2002 Beach, P.S., Beach, R.A. and Smith, L. R.: Hyponatremic seizures in a child treated with desmopressin to control enuresis. Clin Pediatr, 9: 566, 1993 Shindel, A., Tobin, G. and Klutke, C.: Hyponatremia associated with desmopressin for the treatment of nocturnal polyuria. Urology, 60: 344, 2002 Robson, W. L. and Leung, A. K.: Side effects and complications of treatment with desmopressin for enuresis. J Natl Med Assoc, 86: 775, 1994 Koff, S. A.: Estimating bladder capacity in children. Urology, 21: 248, 1983 Andersson, K. E., Bengtsson, B. and Paulsen, O.: Desamino-8D-arginine vasopressin (DDAVP): pharmacology and clinical use. Drugs Today, 24: 509, 1988 Becker, D. J. and Foley, T. P., Jr.: 1-Deamino-8D-arginine vasopressin the treatment of central diabetes insipidus in childhood. J Pediatr, 92: 1011, 1978 Birkásova, M., Birkás, O., Flynn, M. J. and Cort, J. H.: Desmopressin in the management of nocturnal enuresis in children: a double blind study. Pediatrics, 62: 970, 1978 Fjellestad-Paulsen, A., Hoglund, P., Lundin, S. and Paulsen, O.: Pharmacokinetics of 1-desamino-8-D-arginine vasopressin after various routes of administration in healthy volunteers. Clin Endocrinol (Oxf), 38: 177, 1993 Terho, P.: Desmopressin in nocturnal enuresis. J Urol, 145: 818, 1991 Robson, W. L., Nørgaard, J. P. and Leung, A. K.: Hyponatremia in patients with nocturnal enuresis treated with DDAVP. Eur J Pediatr, 155: 959, 1996 Kallio, J., Rautava, P. and Huupponen, R.: Severe hyponatremia caused by intranasal desmopressin for nocturnal enuresis. Acta Paediatr, 82: 881, 1993 Harris, A. S., Nilsson, I. M., Wagner, Z. G. and Alkner, U.: Intranasal administration of peptides: nasal deposition, biological response, and absorption of desmopressin. J Pharmacol Sci, 75: 1085, 1986
EDITORIAL COMMENTS Desmopressin acetate or DDAVP has become the mainstay of pharmacological treatment for PNE. Initially touted as a medication with a good safety profile, DDAVP has come under increased scrutiny. Several hundred articles on DDAVP have been published in the last 15 years and it is hardly surprising that certain dangerous side effects, specifically water intoxication and hyponatremia, have come to light. The literature on DDAVP was reviewed recently.1 The message from this report and the current article is clear: clinician, be aware! Intranasal administered DDAVP can in some patients cause significant and possibly life threatening hyponatremic hypervolemia, of which the symptoms are nausea, vomiting, headaches, altered states of consciousness and possibly seizures. The current article may not mirror the clinical picture since personally I have not encountered any such cases but then again was I paying close enough attention? These authors shed an interesting light on the
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pharmacology of DDAVP and suggest that its antidiuretic effects may last much longer than originally thought (reference 15 in article). The bottom line is that water intoxication can occur in the face of DDAVP therapy in the setting of excess water intake. Clearly this can be prevented by proper parental and patient education. However, a number of questions linger. Does the route of administration (oral vs intranasal) alter the risk? Should all patients on DDAVP have morning serum electrolytes checked and urine osmolarity evaluated? Does the dose of DDAVP influence the degree of hyponatemic hypervolemia? While this study does not give us a clear incidence of the problem, nor does it answer some of these questions, clinicians must take note and ensure that fluid restriction is enforced during DDAVP therapy. In fact, a protocol for dose and screening would be helpful. In the current medicolegal environment it may also behoove the clinician to document morning serum electrolytes and urine osmolarity in children on DDAVP, especially those younger than 10 years. These authors present a clinically relevant study. However, further study is clearly needed to ascertain the true extent of the problem, and whether oral DDAVP can also lead to water intoxication and at what dose. Marc Cendron Department of Pediatric Urology Childrens’ Hospital Boston Boston, Massachusetts 1.
hours following 20 g DDAVP nasal spray suggests the need for explicit fluid instructions to families and for a screening mechanism to identify patients at risk.1 Evening fluid restriction is clearly important and should continue to be routinely recommended. Fluid restriction during the subsequent day is likely neither a practical nor a desirable alternative in most children. Screening treated patients by history to decide whether they void on awakening or later in the morning is a noninvasive method that might identify some of those at risk but measuring serum sodium is the surest method to clarify whether water intoxication is a concern. First morning serum sodium determined at least 10 hours and up to 16 hours after the administration of DDAVP nasal spray should be considered as a screening test. Thumfart et al reported that the risk of water intoxication is particularly high at the beginning of therapy, and so the test should be performed within the first 2 weeks.2 If serum sodium is less than 135 mg/dl, DDAVP should be discontinued, the dose should be decreased or fluid intake should be further restricted. The blood test should be repeated after any change in dose. The duration of action and the risk of water intoxication is presumably increased at a larger dose. Any child who develops headache, nausea, or any neurological symptom while on DDAVP nasal spray should be advised to discontinue the medication and to promptly attend with a physician.
Thumfart, J., Roehr, C.-C., Kapelari, K., Querfeld, U., Eggert, P. and Muller, D.: Desmopressin associated symptomatic hyponatremic hypervolemia in children. Are there predictive factors? J Urol, 174: 294, 2005
The incidence of symptomatic water intoxication in children with nocturnal enuresis treated with DDAVP nasal spray is likely appreciably higher than we recognize. The 1% to 2% incidence of headache reported as an adverse event in children treated with DDAVP nasal spray might well represent unrecognized episodes of water intoxication (reference 9 in article). The incidence of asymptomatic water intoxication is likely even higher. The report of these authors that 18 patients with symptomatic water intoxication could not dilute urine for up to 19
Wm. Lane M. Robson Department of Paediatrics Tamam Hospital Calgary, Alberta Canada 1.
2.
Dehoorne, J. L., Raes, A. M., van Laecke, E., Hoebeke, P. and Vande Walle, J. G.: Desmopressin toxicity due to prolonged half-life in 18 patients with nocturnal enuresis. J Urol, 176: 754, 2006 Thumfart, J., Roehr, C. C., Kapelari, K., Quesfeld, U., Eggert P. and Muller, D.: Desmopressin associated symptomatic hyponatremic hypervolemia in children. Are there predictive factors? J Urol, 174: 294, 2005