Hyponatraemic seizures resulting from inadequate post-operative fluid intake following a single dose of desmopressin

Zoltán Molnár1, Viktor Farkas1, László Nemes2, György S. Reusz1 and Attila J. Szabó1

1 First Department of Pediatrics, Semmelweis University, Budapest and 2 National Haemophilia Center, National Medical Center, Budapest, Hungary

Correspondence and offprint requests to: Zoltán Molnár, MD, PhD, First Department of Pediatrics, Semmelweis University, Budapest, Bókay János u. 53, H-1083 Budapest, Hungary. Email: zmolnar77{at}hotmail.com

Keywords: desmopressin; hyponatraemia; seizure



   Introduction
 Top
 Introduction
 Case
 Discussion
 References
 
1-Deamino-8-D-arginine vasopressin (desmopressin, DDAVP), a selective agonist of type 2 vasopressin receptors, has been widely used to treat enuresis. The early works of Manucci et al. have established that infusion of DDAVP elicits a rapid, transient rise in the levels of both plasma factor VIII (FVIII) and von Willebrand factor (vWF) [1]. This effect provides an approach to the treatment of mild haemophiliacs, and, according to recent guidelines, DDAVP is the treatment of choice in these patients prior to minor surgical procedures.

The administration of DDAVP is often accompanied by headache, facial flushing, a drop of blood pressure and a secondary increase in heart rate. Moreover, since free water reabsorption in renal collecting ducts is enhanced, water intoxication and dilutional hyponatraemia may result. Though this effect can be easily prevented by water restriction, the ignorance of medical personnel or the inadequate compliance of patients may lead to severe hyponatraemia and the neurological sequelae that accompany it. The control of fluid intake during DDAVP treatment is therefore of utmost importance.

Here we present the case of a 3.5-year-old girl with mild haemophilia A who received a single intravenous dose of DDAVP prior to adenotonsillectomy. Hypotonic fluid intake in the early post-operative period led to the patient rapidly developing hyponatraemia and its associated neurological symptoms. Correcting electrolyte abnormality with hypertonic saline stopped the recurrent convulsions, and the patient recovered without any residual neurological sequelae.



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
The father of the index patient suffered from severe haemophilia A; the medical history of the patient's mother was negative. According to the report of the comprehensive haemophilia care centre, the girl was a symptomatic carrier with a slightly reduced FVIII level (49 IU/dl). Though she was not tested genetically, the most plausible explanation for this symptomatic carrier state is non-random X chromosome inactivation (lyonization) in her liver cells. Aside from this, her medical history was unremarkable.

At the age of 3.5 years, she was considered a candidate for elective adenotonsillectomy because of chronic adenoid hypertrophy. To prevent perioperative haemorrhage, the patient received 250 mg of tranexamic acid (Exacyl, Sanofi-Chinoin) orally every 6 h and 0.3 µg/kg desmopressin (Octostim, Ferring) intravenously 30 min prior to the adenotonsillectomy. We found no history of any previous exposure to DDAVP. The patient's serum sodium (Na+) was not checked in the morning of surgery, but her serum concentration ([Na+]) was 139 mmol/l 6 days before the operation. The operation was performed under intratracheal narcosis without any notable complications. Bleeding was within the normal range during surgery, and no excessive haemorrhage was observed in the early post-operative period. She was allowed to take fluids ad libitum; her total intake was roughly 600 ml in the first 10 post-operative hours. Approximately 12 h after the surgery, the girl was awoken by a mild headache and nausea; she later also vomited. Then she had a generalized, tonic–clonic seizure of 3 min duration, which resolved spontaneously. As a result, she was transferred to our department for further evaluation and treatment. While being transferred, the patient received 300 ml of 5% dextrose in half isotonic saline intravenously.

At presentation in our department, the patient did not show any focal neurological signs. She still had headache; we also found her hard to arouse, but she withdrew from noxious stimuli. Her vital signs showed no significant deviations; her blood pressure was 110/70 mmHg and body weight 15.3 kg (based on her history, her body weight was 15.0 kg 12 h earlier). Serum glucose, calcium, magnesium and C-reactive protein were within normal limits; serum [Na+] was at 121 mmol/l. Serum osmolality was calculated to be 250 mosmol/l. At admission and in the first hour of hospitalization after transfer, the girl experienced more seizures and emesis. Having assumed that the observed neurological sequelae were due to acute hyponatraemia, we started to correct the electrolyte anomaly by infusing 3% NaCl solution, until the neurological symptoms disappeared (serum [Na+] was 129 mmol/l by that time). We also administered an intravenous bolus of ~1 mg/kg furosemide (Furon, Ratiopharm) at the beginning of our electrolyte therapy, to bring about a net water loss. The serum Na+ rose to 137, 135 and 137 mmol/l 8, 14 and 30 h after admission, respectively. Ophthalmological investigation did not reveal papillary oedema, and the girl's neurological examination was normal on the following days. Although a slight, generalized slowing of the background electroencephalographic (EEG) activity was observed on the first day, EEG records normalized within 10 days. The girl was doing well at her follow-up several weeks later and had no neurological abnormalities.

Our patient's medical history, laboratory data and fast response to treatment all indicate that she suffered from water intoxication. Her severe neurological symptoms were the consequence of cerebral oedema resulting from DDAVP-associated dilutional hyponatraemia.



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
Information in the current literature suggests that mild, asymptomatic hyponatraemia should be considered a common side effect of DDAVP treatment [2,3]. A symptomatic form is much less frequent, though numerous papers report such cases. Hyponatraemia causes headache, nausea, vomiting and slightly altered mental status, which may turn into seizures, dramatically altered mental status and coma, as cerebral oedema progresses. These symptoms, signs and neurological sequelae are mainly associated with and follow chronic use or, at least, repeated doses of DDAVP [4]. Few papers report cases like ours, in which severe neurological symptoms were due to only a single dose of desmopressin [3,5–7]. Excess fluid intake, young age, overdosage and the potentiating effect of other drugs have all been identified as factors contributing to DDAVP-associated hyponatraemia [4]. In our case, the intake of hypotonic fluid seemed to underlie the development of hyponatraemia; and the occurrence of neurological symptoms was most probably the consequence of the rapid decrease of serum [Na+] and the delayed adaptation of neurons to the lowered extracellular tonicity. In addition, children are also known to be at a higher risk of hyponatraemic encephalopathy, because the brain-to-skull ratio in children is greater than in adults, providing less room for brain expansion [9].

Given the neurological symptoms of our patient, we administered hypertonic saline, although rapid and exaggerated correction of hyponatraemia is known to be associated with osmotic demyelination of the pontine area, especially in patients with chronic hyponatraemia. Factors such as a hypoxic event during hyponatraemia, the presence of severe liver disease and the correction of plasma [Na+] by a rate >25 mmol/l in 48 h or creating hypernatraemia during correction may also increase the risk of myelinolysis [9]. In view of the absence of these predisposing factors, and considering that the child was without any neurological abnormalities at her follow-up 3 weeks later, we chose not to do a brain magnetic resonance imaging (MRI) examination to exclude myelinolysis.

In summary, our case highlights the importance of fluid restriction and regular checking of serum [Na+] when intravenous DDAVP is used, especially in children. Since even a single dose of the drug may induce symptomatic hyponatraemia within 12 h, serum [Na+] and urine output must be checked every 6 h for the first 24 h after administering DDAVP, as suggested by Sutor [8]. Taking this information into account will help to prevent this serious adverse effect of DDAVP, and will provide additional safety and effectiveness in its clinical use.



   Acknowledgments
 
This work was supported by grants from OTKA (T 046155) and DAAD (2005–2006 13).

Conflict of interest statement. None declared.



   References
 Top
 Introduction
 Case
 Discussion
 References
 

  1. Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. 1-Deamino-8-D-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands' diseases. Lancet 1977; 1: 869–872[ISI][Medline]
  2. Weatherall M. The risk of hyponatremia in older adults using desmopressin for nocturia: a systematic review and meta-analysis. Neurourol Urodyn 2004; 23: 302–305[CrossRef][ISI][Medline]
  3. Allen GC, Armfield DR, Bontempo FA, Kingsley LA, Goldstein NA, Post JC. Adenotonsillectomy in children with von Willebrand disease. Arch Otolaryngol Head Neck Surg 1999; 125: 547–551[Abstract/Free Full Text]
  4. Robson WL, Norgaard JP, Leung AK. Hyponatremia in patients with nocturnal enuresis treated with DDAVP. Eur J Pediatr 1996; 155: 959–962[ISI][Medline]
  5. Garcia EB, Ruitenberg A, Madretsma GS, Hintzen RQ. Hyponatraemic coma induced by desmopressin and ibuprofen in a woman with von Willebrand's disease. Haemophilia 2003; 9: 232–234[CrossRef][ISI][Medline]
  6. Neuhaus TJ, von der Heiden-Ranz M. Hyponatraemia and cerebral convulsion after a single dose of intranasal DDAVP. Pediatr Nephrol 1997; 11: 527[ISI][Medline]
  7. Shepherd LL, Hutchinson RJ, Worden EK, Koopmann CF, Coran A. Hyponatremia and seizures after intravenous administration of desmopressin acetate for surgical hemostasis. J Pediatr 1989; 114: 470–472[ISI][Medline]
  8. Sutor AH. DDAVP is not a panacea for children with bleeding disorders. Br J Haematol 2000; 108: 217–227[CrossRef][ISI][Medline]
  9. Moritz ML, Ayus JC. The pathophysiology and treatment of hyponatraemic encephalopathy: an update. Nephrol Dial Transplant 2003; 18: 2486–2491[Free Full Text]
Received for publication: 6. 1.05
Accepted in revised form: 17. 3.05





This Article
Extract
Full Text (PDF)
All Versions of this Article:
20/10/2265    most recent
gfh960v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Molnár, Z.
Articles by Szabó, A. J.
PubMed
PubMed Citation
Articles by Molnár, Z.
Articles by Szabó, A. J.