Pediatr Nephrol (2008) 23:13671370 DOI 10.

1007/s00467-008-0809-y

BRIEF REPORT

Use of conivaptan to allow aggressive hydration to prevent tumor lysis syndrome in a pediatric patient with large-cell lymphoma and SIADH
Pornpimol Rianthavorn & Joan P. Cain & Martin A. Turman

Received: 14 January 2008 / Revised: 27 February 2008 / Accepted: 27 February 2008 / Published online: 24 April 2008 # IPNA 2008

Abstract The available treatment options for hyponatremia secondary to SIADH are limited and not completely effective. Conivaptan is a vasopressin 1a and 2 receptor antagonist recently approved by the US Food and Drug Administration (FDA) for treating euvolemic and hypervolemic hyponatremia in adult patients. However, data on efficacy and safety of conivaptan in pediatrics are limited. We report a case of a 13year-old boy with extensively metastasized anaplastic largecell lymphoma. He also developed hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) prior to chemotherapy initiation. SIADH management in this case was complicated when fluid restriction was not safely attainable. Conivaptan played a significant role in this situation by allowing provision of a large amount of intravenous fluid prior to and during induction chemotherapy. It proved to be an important component in preventing uric acid nephropathy/tumor lysis syndrome. Conivaptan induced free-water clearance as indicated by increased urine output and decreased urine osmolality. The patient responded to conivaptan without any adverse effects. Keywords Conivaptan . Hyponatremia . SIADH . Tumor lysis syndrome

Introduction Hyponatremia is a common electrolyte disorder occurring in approximately 15% of hospitalized patients [1]. HypoP. Rianthavorn (*) : J. P. Cain : M. A. Turman Department of Pediatrics, University of Oklahoma Health Sciences Center, 940 NE 13th Street, 2B2309 Oklahoma City, OK, USA e-mail: pornpimol-rianthavorn@ouhsc.edu

natremia is most often caused by the nonosmotic release of vasopressin from various causes [1, 2]. The available treatment options for hyponatremia from inappropriate antidiuretic hormone (ADH) secretion are limited. They consist of fluid restriction, diuretics, or hypertonic solutions. These therapies are associated with significant adverse effects, and they are not entirely effective [3]. Hyponatremia, when not treated appropriately, may lead to significant morbidity and death [4, 5]. Vasopressin 2 (V2) receptor antagonists have recently been approved by the US Food and Drug Administration (FDA) for managing euvolemic and hypervolemic hyponatremia in adults. These medications are promising due to their direct action against the effect of ADH at the V2 receptor and thus effectively enhance electrolyte-free water excretion. They may simplify managing hyponatremia from inappropriate ADH secretion. However, data on the efficacy and safety of the V2 receptor antagonists in pediatrics are limited. We report a case of hyponatremia due to inappropriate ADH secretion in a child with newly diagnosed anaplastic large-cell lymphoma. The patient did not respond to conventional management for hyponatremia, including diuretics and hypertonic saline. Whereas rasburicase, the uric-acid-lowering agent, has become the mainstay of tumor lysis syndrome prophylaxis, it is important that it be given with aggressive hydration for full effectiveness. The administration of conivaptan, a V2 receptor antagonist, permitted large amount of IV fluid to be given. The patient responded nicely to conivaptan without any adverse effects.

Case report A 13-year-old white boy had a 3-month history of severe intermittent back pain that limited his ambulation and did

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not improve with naproxen. He experienced decreased energy and appetite loss and had lost 11 kg over the preceding month. He also developed several scattered soft tissue nodules, most prominent on his upper back and chest. Computed tomography of the abdomen showed a retroperitoneal mass that measured 6.97.3 cm and appeared to arise from the area of the iliacus/psoas musculature. Extensive adenopathy was seen in the chest, abdomen, and pelvis. Numerous soft-tissue nodules (24 cm in size) were also clearly seen on the imaging studies. Biopsy of one of those nodules showed anaplastic large-cell lymphoma. Despite extensive metastases to the soft-tissues and lymph nodes, bone marrow and spinal fluid were not involved, making this a stage III non-Hodgkins lymphoma according to the Murphy staging criteria. Serum sodium 2 days prior to admission was 132 mEq/l. Serum sodium upon admission was 133 mEq/l and subsequently decreased to 122 mEq/l. The oncology service made preparations for the initiation of induction chemotherapy with vincristine, prednisone, and doxorubicin as per Childrens Oncology Group protocol ANH L 0131. The patient was transferred to the pediatric intensive care unit, and the nephrology service was consulted for managing the hyponatremia in light of the pressing need for aggressive hydration. Physical examination revealed a well-developed child with a temperature of 39.2 C, pulse rate 80/min, respiratory rate 20/min, and blood pressure 125/71 mmHg. His height was 162 cm and his weight was 49.1 kg. He did not have orthostatic hypotension. He was pale, but his mucous membranes were moist. There were multiple subcutaneous nodules over the entire body ranging from 24 cm. Some were tender to palpation. His neurological examination was completely unremarkable. He had no edema. Laboratory studies revealed anemia (hemoglobin 10 g/dl) and hyponatremia (serum sodium 122 mEq/l). Other

chemistries were potassium 4.5 mEq/l, chloride 89 mEq/l, bicarbonate 24 mEq/l, albumin 2.1 g/dl, calcium 7.7 mg/dl, ionized calcium 1.1 mmol/l, and uric acid 3.3 mg/dl. Serum blood urea nitrogen (BUN) and creatinine were 7 and 0.5 mg/dl, respectively. Serum osmolality was 260 mOsm/l. Urinalysis showed a specific gravity of 1.025, pH 5.0, trace protein, negative nitrite, and negative leukocyte esterase. Urine electrolytes showed sodium 27 mEq/l, potassium 122 mEq/l, chloride 179 mEq/l, creatinine 154 mg/dl, and osmolality 843 mOsm/l. The diagnosis of syndrome of inappropriate antidiuretic hormone secretion (SIADH) was entertained; 3% sodium chloride (NaCl) 3 ml/kg was given. Fluids were restricted to 25% of maintenance, and IV furosemide was begun at 50 mg IV every 12 h. Repeat sodium was 121 mEq/l, 18 h later despite three boluses of 3 ml/kg of 3% NaCl. Aggressive hydration was essential to allow induction chemotherapy. Due to failure of conventional treatment, 10 mg conivaptan (half of the recommended loading dose for adults) was given to correct serum sodium to allow safe fluid hydration during induction. After the loading dose, conivaptan was provided as an infusion at 10 mg/day (half of the recommended continuous infusion dose for adults, which is 20 mg over 24 h and may be titrated up to 40 mg daily) [6]. After the first 6 h, serum sodium was not rising as expected. Conivaptan infusion was then increased to 30 mg/day. At the end of the first 24 h, the effective water clearance (EWC) was 322 ml, and serum sodium increased to 129 mEq/l. EWC was calculated as follows: EWC=V[1-(UNa+UK/SNa+SK)] [7]. Conivaptan dose was then titrated to 20 mg/day. Normal saline at 3 l/m2 was started. EWC during the next 24 h was 4,283 ml, and serum sodium was increased to 138 mEq/l. (Fig. 1 and Table 1) The patient responded very well to conivaptan. Serum osmolality increased (Fig. 2), and urine osmolality decreased (Fig. 1). We were able to start fluid hydration at 3 l/m2

Fig. 1 Serum sodium and urine osmolality at different hours after conivaptan administration

S Na 150

U Osm 1000 800 600 400 200 0

S Na (m Eq/l)

140 130 120 110 100

0 60 12 24 36 48 72 84 96 10 8 12 0 13 8

hours

U Osm (m osm/Kg)

30 mg/day

5 mg/day Conivaptan 20 mg/day 10 mg load 2 Normal saline 3 l/m started then 10 mg/day

10 mg/day

Stop conivaptan infusion

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Table 1 Serum sodium (S Na) and potassium (S K) (mEq/l), urine sodium (U Na) and potassium (U K) (mEq/l), daily intake and output (ml), effective water clearance (EWC) (ml), and body weight (kg) Hour 0 6 24 48 72 96 S Na 124 121 129 138 138 141 SK 4.7 4.3 3.6 3.7 3.8 U Na 28 100 12 111 162 UK 118 17 13 12 31 3,361 6,169 7,512 5,336 2,630 5,201 6,313 6,345 322 4,283 833 2,112 Intake Output EWC Body weight 49.1 54.3 54.6 56.0 56.2

with normal saline and standard dose of induction chemotherapy 24 h after conivaptan was started. The conivaptan dose was gradually decreased based on serum sodium and was discontinued over a 4-day period. The patient tolerated the medication well and did not report any side effects, including headache, insomnia, nausea, vomiting, diarrhea, or constipation. However, he reported increased sense of thirst and dry mouth. He did not develop any infusion-site reactions such as phlebitis, which has been reported to be the most common adverse reaction (52.5% with 40 mg/day administration of conivaptan) [6].

Discussion Tumor lysis syndrome is a well-known hazard at the time of chemotherapy initiation in patients with leukemia or lymphoma. Rasburicase, the uric-acid-reducing agent that became available in the mid-1990s, has done much to simplify hyperuricemia treatment in these patients. However, it remains crucial to include aggressive hydration as part of the management strategy to prevent complications from phosphate and other cell-lysis products. This is problematic and potentially life threatening in a patient with SIADH, such as the one we describe.
Fig. 2 Serum osmolality at different hours after conivaptan given

Arginine vasopressin (AVP) plays a key role in salt and water balance. Increased AVP levels trigger free-water absorption in the kidneys, resulting in hyponatremia [8]. Thus, the recommended management for SIADH includes fluid restriction and increased free-water clearance. This sometimes can be problematic if aggressive hydration is required, as in our patient who needed fluid to prevent tumor lysis syndrome. V2 receptor antagonists play a significant role in this situation by promoting electrolytesparing water excretion. Conivaptan is a nonpeptide antagonist of AVP V1a and V2 receptors. Three oral agents, lixivaptan, tolvaptan, and satavaptan, are selective V2 receptor blockers. However, only conivaptan is available in the United States [9]. By blocking V2 receptors in the renal collecting duct, these agents promote aquaresis without excreting more sodium in the urine. A double-blind, placebo-controlled, randomized multicenter study of the efficacy of conivaptan was reported by Zeltser et al. This study involved 84 adult patients with euvolemic or hypervolemic hyponatremia. Fluid was restricted to less than 2 l/day in all patients. Each patient received a loading dose of conivaptan 20 mg IV followed by a 20 mg continuous infusion administered over 24 h, with the dose titrated up to 40 mg daily if serum sodium did not rise at the desired rate. Patients who received

S Osm

S Osm (m osm/Kg)

310 300 290 280 270 260 250

hours
0 12 48 36 24 60 72 84 96 8 0 12
30 mg/day 10 mg/day 5 mg/day Stop conivaptan infusion

Conivaptan 10 mg load then 10 mg/day

20 mg/day Normal saline 3 l/m2 started

10

13

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conivaptan showed a significant increase of serum sodium compared with the placebo group: 6.5 mEq/l vs. + 1.5 mEq/l. The increase in serum sodium can be attributable to increased effective water clearance. In the conivaptan group, the effective water clearance was 3.8 l by day 4 compared with only 1.3 l in the control group. The most common adverse reactions reported from this study were infusion-site reactions [7]. Conivaptan should either be administered through large veins or the infusion site should be changed every 24 h to minimize potential vascular irritation [6]. Conivaptan is mainly metabolized by the liver cytochrome P450 isoenzyme CYP3A4. It is also a potent inhibitor of CYP3A4. Drugs inhibiting the P450 system can increase conivaptan levels. Similarly, conivaptan can increase serum levels of medications metabolized via the P450 system [9]. Although formal pharmacodynamics of chemotherapy agents was not performed in our study, the patient did not have excessive or unexpected side effects from the standard-dose chemotherapy. Approximately 1% of the IV dose was excreted in urine as intact conivaptan over the first 24 h after dosing. One should apply extra caution when administering conivaptan to patients with impaired hepatic or renal function [9]. Data on efficacy and safety of conivaptan in children are limited. Nevertheless, conivaptan played a key role in our patient when fluid restriction was not safely attainable. Conivaptan was started after the conventional treatment failed to correct serum sodium to a safe range and to allow provision of a large amount of fluid to avoid tumor lysis syndrome in this patient with a high tumor load. As this was a child, we used half of the recommended adult dosage. The recommended dosage for pediatrics is not yet available. With conivaptan, urine osmolality dropped and urine volume increased with infusion, indicating success in clearing free water. By frequent monitoring of serum sodium, the rate of sodium correction was controlled by titrating the conivaptan dose. The dose had to be increased when a large amount of fluid was given, resulting in a

suboptimal increase in serum sodium. When aggressive hydration was stopped, conivaptan was so effective in increasing the serum sodium level that the dose then had to be titrated down to prevent too rapid a correction of serum sodium. Serum sodium increased by 5 mEq/l in the first 24 h and by a total of 14 mEq/l over 48 h (from 124 to 138 mEq/l). Our patient tolerated the medication well without any reported side effects. This ability to rapidly adjust the rate of free-water clearance in a complex patient such as this demonstrates the superb clinical usefulness of V2 receptor blockers. This report supports the use of this drug in pediatrics, but a controlled trial and pharmacokinetics study in children is needed before use can be routine. This report also describes a unique use of this drug to allow aggressive hydration to prevent tumor lysis syndrome in a cancer patient with SIADH.

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