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ORIGINAL ARTICLE
Year : 2019  |  Volume : 56  |  Issue : 4  |  Page : 320-324
 

Higher incidence of syndrome of inappropriate antidiuretic hormone secretion during induction chemotherapy of acute lymphoblastic leukemia in indian children


1 Division of Paediatric Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
2 Department of Cancer Epidemiology and Biostatistics, Regional Cancer Centre, Thiruvananthapuram, Kerala, India

Date of Web Publication11-Oct-2019

Correspondence Address:
Priyakumari Thankamony
Division of Paediatric Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_737_18

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 » Abstract 


BACKGROUND: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a well-known adverse effect of vincristine (VCR). Literature suggests that Asians are predisposed to develop SIADH following VCR administration. However, data regarding the occurrence of SIADH in children with malignancy are limited. This study aims to analyze the incidence, clinical picture, risk factors, management, and outcome of SIADH during induction chemotherapy for pediatric acute lymphoblastic leukemia (ALL).
MATERIALS AND METHODS: A prospective study was conducted among the 166 newly diagnosed pediatric ALL patients who were treated at a tertiary cancer center in India between January 2015 and December 2015. Patients who developed hyponatremia during induction chemotherapy were further investigated for SIADH.
RESULTS: The incidence of SIADH was 10.8% (n = 18) with a mean sodium level of 125 mEq/L (114–129 mEq/L). In the preceding 2 weeks, 72% of episodes were associated with the administration of two (n = 6) or three (n = 7) doses of VCR. One child presented with seizures. All the patients were managed with fluid restriction and only two patients required sodium correction with 3% saline. Girls older than 10 years of age showed a marginally significant correlation to develop SIADH (P-value = 0.059).
CONCLUSION: We report a higher incidence of SIADH (10.8%) in Indian children, compared to that described in the literature, during induction chemotherapy for ALL. Regular monitoring of sodium levels during this period of chemotherapy is hence essential for the timely diagnosis and appropriate management of SIADH, which in turn will avert complications, including neurological symptoms secondary to SIADH.


Keywords: Acute lymphoblastic leukemia, pediatric, SIADH, vincristine


How to cite this article:
Seetharam S, Thankamony P, Gopakumar KG, Krishna K M. Higher incidence of syndrome of inappropriate antidiuretic hormone secretion during induction chemotherapy of acute lymphoblastic leukemia in indian children. Indian J Cancer 2019;56:320-4

How to cite this URL:
Seetharam S, Thankamony P, Gopakumar KG, Krishna K M. Higher incidence of syndrome of inappropriate antidiuretic hormone secretion during induction chemotherapy of acute lymphoblastic leukemia in indian children. Indian J Cancer [serial online] 2019 [cited 2019 Nov 21];56:320-4. Available from: http://www.indianjcancer.com/text.asp?2019/56/4/0/267603





 » Introduction Top


Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by excessive secretion of antidiuretic hormone (ADH) which increases the water resorption by the kidneys with a resultant euvolemic hyponatremia.

SIADH is a common cause of hyponatremia in oncology which may occur either as a paraneoplastic syndrome or may be induced by chemotherapy drugs.[1],[2],[3] Vincristine (VCR) is usually the cause of SIADH in a patient with acute lymphoblastic leukemia (ALL).[4],[5],[6] VCR is seen to produce a neurotoxic effect on the hypothalamic pituitary axis and alter the normal osmolality control of ADH secretion.[7] The risk of developing SIADH peaks 4–7 days after administration of the drug and this condition occurs most often during the induction chemotherapy where weekly VCR is given.[5],[6] Cyclophosphamide also causes SIADH by potentiating the effect of ADH on the kidneys and possibly by inducing ADH secretion.[8] Cisplatin may cause hyponatremia by stimulating ADH secretion leading to SIADH or by causing renal tubular damage leading to decreased sodium re absorption.[9]

Although SIADH is a common adverse effect of VCR, there are only limited reports about the incidence of this condition in pediatric patients with ALL, who are not routinely screened for SIADH during treatment.[5],[6],[10],[11],[12] Our study explores the occurrence of SIADH in children on induction chemotherapy for ALL.


 » Materials and Methods Top


Patients

A total of 166 pediatric patients (up to 14 years), with newly diagnosed ALL who were treated according to the institutional chemotherapy protocol (a modified BFM ALL 95 protocol) between January 2015 and December 2015, at a tertiary cancer care center in India were included. The induction protocol is detailed in [Figure 1].
Figure 1: ALL induction chemotherapy protocol

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Data collection

The study was initiated after availing permission from the Institutional Review Board of the institute and informed consent was obtained from all individual participants included in the study. Clinical data concerning patient details, diagnosis, baseline count and biochemistry, general condition at diagnosis, as well as complications at presentation or during the course of induction phase of chemotherapy were recorded on a structured proforma. Renal function tests and serum electrolyte levels were checked at least once a week during induction and more frequently if the patient was symptomatic.

Definitions

Hyponatremia was defined as a serum sodium level ≤130 mEq/L on at least two consecutive days. Further investigations were done in patients with hyponatremia and included urine sodium, urine osmolality, and serum osmolality, where serum osmolality is calculated as: Serum osmolality = [2 × (Na)] + (BUN/2.8) + (glucose/18).

SIADH was diagnosed in patients with serum sodium ≤130 mEq/L, urine sodium >30 mEq/L, and with urine osmolality greater than serum osmolality.

Statistical analysis

Categorical data were summarized using frequency and percentages and continuous data with mean and standard deviation. The association between categorical variables was investigated by a Chi-square test or Fisher's exact test. P value below 0.05 was considered significant.


 » Results Top


Incidence and causes of hyponatremia

Of the 166 children with newly diagnosed ALL, the mean age was 5.2 years (range 2–13) and included 90 boys and 76 girls, with a male/female ratio of 1.2:1. A total of 29 patients (17.4%) were detected to have hyponatremia, of which 18 (10.8%) were attributed to SIADH. Therefore, SIADH accounted for 62% of the hyponatremic episodes during pediatric ALL induction. Other causes of hyponatremia included severe sepsis in five patients and hyper-hydration with one-fourth dextrose normal saline for the management of tumor lysis syndrome in three patients. One patient had hypothyroidism and another had pseudo-hyponatremia associated with elevated blood sugars. The remaining two patients with hyponatremia did not fulfil the criteria for SIADH [Figure 2]. Hormonal assessment was not attempted as all the patients in the study group were given prednisolone at 60 mg/m2 or equivalent steroid during the entire duration of induction chemotherapy, which rules out the possibility of cortisol or aldosterone insufficiency during that duration. None of the patients developed hyponatremia during tapering of steroids. The demographic characteristics of the patients with SIADH are presented in [Table 1]. The mean age of the group of patients with SIADH was 6.7 years (range 2–12 years).
Figure 2: Etiology of hyponatremia in the study population

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Table 1: Comparison of demographic characteristics of the study group versus the patients with SIADH

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Biochemical parameters in patients with SIADH

The biochemical parameters of patients with SIADH are discussed in [Table 2]. The patients in the SIADH group had a mean sodium of 125 mEq/L (range 114–129 mEq/L), mean urine sodium of 144 mEq/L (range 31–300 mEq/L), mean urine osmolality of 387 mOsm/L (range 261–808 mOsm/L), and mean serum osmolality of 269 mOsm/L (range 252–291 mOsm/L).
Table 2: Clinical features and biochemical parameters of patients with SIADH

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Clinical features at diagnosis of SIADH

Symptomatic patients (nine out of 18) presented with abdominal pain associated with VCR-induced constipation (n = 4), fatigue and irritability (n = 3), seizures (n = 1), and headache (n = 1) [Table 2]. None of the patients demonstrated other complications of VCR like peripheral neuropathy. The patient with seizures had a sodium level of 114 mEq/L along with hypertension. He was treated with 3% saline for sodium correction as well as with anti-hypertensives. The patient who presented with severe headache and hyponatremia was evaluated with a CT scan of the brain, which revealed a sagittal sinus thrombosis that was managed with thrombolytics. The remaining 50% of the patients (nine out of 18) were asymptomatic without any manifestations of hyponatremia, and SIADH was either detected incidentally or was discovered during investigations for a febrile episode.

Risk factors of SIADH

VCR administration preceded 72% of SIADH episodes with two (n = 6) or three (n = 7) doses of VCR being given the preceding 2 weeks. Although a male predominance was noted with a male/female ratio of 2:1, there was no significant correlation between the incidence of SIADH and gender (P-value = 0.262) [Table 1]. As 50% of the patients with SIADH were ≤5 years of age, we attempted to discover a significant correlation with age. However, analysis revealed a P value of 0.266, which was not significant. A marginally significant correlation was noted in girls older than 10 years of age (P-value = 0.059).

Management and outcome of SIADH

All the patients were managed with fluid restriction and only two patients required sodium correction with 3% saline. One patient had presented with seizures and the other had intermittent diarrhea due to which fluid restriction could not be maintained. The mean duration of hyponatremia was 2 days symptomatic patients had complete recovery, including neurological recovery within 2 days. Each patient had only a single episode of hyponatremia during the induction chemotherapy and further chemotherapy could be continued in all the patients without any dose modification of VCR or recurrence of SIADH. There was no mortality due to SIADH in this group of patients.


 » Discussion Top


SIADH is known to account for approximately one-third of all cases of hyponatremia in hospitalized patients.[13] SIADH was first reported by Schwartz et al. in 1957. They described two patients with bronchogenic carcinoma who developed hyponatremia accompanied by continued urinary sodium loss.[14] The clinical features of the syndrome have shown little change in the past 70 years.[3] The criteria for SIADH include:[6] (i) hyponatremia with low plasma osmolality; (ii) sustained renal excretion of sodium (urine sodium concentration usually above 30 mEq/L), (iii) euvolemia, (iv) osmolality of the urine greater than that appropriate for the associated plasma osmolality, (v) normal renal and adrenal status, (vi) improvement in both hyponatremia and renal loss of sodium by fluid restriction.

Physiologically, any increase in the plasma osmolality is detected by the osmoreceptors in the anterior hypothalamus, which induces ADH release by the posterior pituitary.[15] ADH release may also occur with a fall in blood volume or pressure which is detected by baroreceptors in the carotid sinus. ADH then acts on the V2 receptor in the renal collecting duct to increase the water reabsorption and reduce the plasma osmolality to normal levels. This drop in plasma osmolality reduces ADH release by a negative feedback mechanism.[16]

However, in SIADH, the ADH release persists despite low plasma osmolality. This condition may be caused by ectopic production of ADH by tumor cells or by a variety of other conditions, including central nervous system disorders (e.g., inflammatory or demyelinating diseases, subarachnoid hemorrhage, head trauma), lung disorders (e.g., tuberculosis, pneumonia, acute respiratory failure, positive-pressure ventilation), and certain drugs.[17]

Fine et al. were the first to describe hyponatremia and excessive renal sodium loss associated with VCR therapy in a 11-month-old child who was treated for a rhabdomyosarcoma involving the spermatic cord.[18] Hammond et al. retrospectively studied the occurrence of hyponatremia and/or SIADH among patients treated with VCR and estimated the reporting rate at 1.3/100,000 treated patients.[19] Information regarding race was available in 39 patients in their study and 35 of them were of Asian origin. They concluded that Asians may be at increased risk for developing SIADH during treatment with VCR and advised that physicians caring for Asian patients in oncology should be aware of this predisposition. In our study on 166 Indian children with ALL, the incidence of SIADH was found to be much higher at 10.8%.

Borker et al. studied all the episodes of hyponatremia in pediatric patients with ALL diagnosed from December 1991 to October 2002 at St Jude Children's Research Hospital.[10] A total of 605 patients were studied, and of them, 68 patients were reported to have had 79 episodes of SIADH, while 96% of episodes were associated with the administration of one (n = 29) or two (n = 43) doses of VCR in the preceding 2 weeks. The mean lowest sodium in this study was 128.3 mEq/L (121–130 mEq/L), which is higher than the mean sodium level of 125 mEq/L in our study. The lowest recorded sodium level in our study group was 114 mEq/L. The mean duration of hyponatremia in the St Jude study was 1.9 days, which was similar to our results where the mean duration was 2 days. Patients in our study group presented with lower sodium levels than that reported at St Jude. This may be explained by a difference in the frequency of monitoring of biochemistry levels. In asymptomatic patients we would limit testing to once a week and therefore, may miss early detection of hyponatremia. It is difficult to directly compare our results with that reported by Borker et al. as they have included all the episodes of hyponatremia during the entire duration of ALL chemotherapy, while we have restricted the study period exclusively to the duration of ALL induction chemotherapy, which is usually 1 month.

Janczar et al. retrospectively analyzed the incidence, risk factors, associations, and outcomes of severe hyponatremia (defined as sodium levels below 130 mmol/L on at least two of three consecutive days) in children with ALL.[11] This single-center study from Poland which included 84 children reported 11.9% (n = 10) incidence of severe hyponatremia during the entire ALL chemotherapy schedule. The mean sodium level in this study group was 125 mEq/L (121–129 mEq/L). Only four hyponatremic episodes occurred during induction chemotherapy and serum osmolality was tested in only three of these patients. The rest were detected during reinduction and maintenance chemotherapy. Seven out of ten episodes of hyponatremia were seen to follow VCR administration. Although hyponatremia was attributed to “suspected” SIADH in five out of the total of ten patients, renal sodium excretion was tested only in two cases. The other three patients were suspected to have SIADH as they had hyponatremia and serum osmolality below 280 mOsm/kg. Therefore, the incidence of “suspected” SIADH reported by Janczar et al. is 5.9%, while our study result is significantly higher at 10.8%. The incidence of proven SIADH during ALL induction therapy in their study was only 3.6% (3/84). [Table 3] compares the few pediatric studies on the incidence of SIADH during chemotherapy for ALL.
Table 3: Comparison of pediatric studies on SIADH during chemotherapy for ALL

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The first line of treatment in asymptomatic SIADH is fluid restriction.[1],[20] It causes a negative fluid balance that will increase the serum sodium concentration. Therefore, the daily water intake must be lowered below the water losses (urine, stool, skin, and respiratory tract).[21] However, the discomfort associated with fluid restriction often leads to poor compliance.[22] If the patient develops symptoms such as hallucination, somnolence, or vomiting, hypertonic saline may be used.[23] Although any infused saline will eventually be excreted in SIADH, the kidney is unable to generate urinary sodium concentrations as high as seen in 3% saline (>400 mEq/L) and hence 3% saline will improve hyponatremia, but only temporarily.[14],[21] All the patients in our study were managed with fluid restriction and only two of them required sodium correction with 3% saline.


 » Conclusion Top


We observed a higher incidence of SIADH (10.8%) during pediatric ALL induction chemotherapy than previously reported in the literature, suggesting that Indian children may be more predisposed to develop SIADH due to VCR therapy. Differentiating SIADH from other causes of hyponatremia is crucial in the management decision. Fluid restriction along with 3% saline when indicated will help in the appropriate management of hyponatremia due to SIADH in these children. Neurological problems during ALL induction, such as seizures and confusion may be multifactorial, including SIADH. Neurological symptoms secondary to SIADH can also be averted with regular monitoring of sodium levels and appropriate therapeutic interventions based on that.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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2.
List AF, Hainsworth JD, Davis BW, Hande KR, Greco FA, Johnson DH. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in small-cell lung cancer. J Clin Oncol 1986;4:1191-8.  Back to cited text no. 2
    
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Sørensen JB, Andersen MK, Hansen HH. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in malignant disease. J Intern Med 1995;238:97-110.  Back to cited text no. 3
    
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Cutting HO. Inappropriate secretion of antidiuretic hormone secondary to vincristine therapy. Am J Med 1971;51:269-71.  Back to cited text no. 4
    
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Howard SC, Pui C-H. Endocrine complications in pediatric patients with acute lymphoblastic leukemia. Blood Rev 2002;16:225-43.  Back to cited text no. 5
    
6.
Stuart MJ, Cuaso C, Miller M, Oski FA. Syndrome of recurrent increased secretion of antidiuretic hormone following multiple doses of vincristine. Blood 1975;45:315-20.  Back to cited text no. 6
    
7.
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Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis 2008;52:144-53.  Back to cited text no. 8
    
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Hamdi T, Latta S, Jallad B, Kheir F, Alhosaini MN, Patel A. Cisplatin-induced renal salt wasting syndrome. South Med J 2010;103:793-9.  Back to cited text no. 9
    
10.
Borker AS, Hutchins S, Grant R, Hijiya N, Sandlund JT, Metzger ML et al. Syndrome of inappropriate secretion of anti-diuretic hormone in children with acute lymphoblastic leukemia. Blood 2006;108:4474.  Back to cited text no. 10
    
11.
Janczar S, Zalewska-Szewczyk B, Mlynarski W. Severe hyponatremia in a single-center series of 84 homogenously treated children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2017;39:e54-8.  Back to cited text no. 11
    
12.
Kishimoto K, Kobayashi R, Sano H, Suzuki D, Yasuda K, Kobayashi K. Analysis of risk factors for hyponatremia during or following chemotherapy in children with cancer: A hospital-based, retrospective cohort study. J Pediatr Hematol Oncol 2016;38:443-8.  Back to cited text no. 12
    
13.
Anderson RJ, Chung HM, Kluge R, Schrier RW. Hyponatremia: A prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med 1985;102:164-8.  Back to cited text no. 13
    
14.
Schwartz WB, Bennett W, Curelop S, Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 1957;23:529-42.  Back to cited text no. 14
    
15.
Kinzie BJ. Management of the syndrome of inappropriate secretion of antidiuretic hormone. Clin Pharm 1987;6:625-33.  Back to cited text no. 15
    
16.
Baylis PH. Regulation of vasopressin secretion. Baillieres Clin Endocrinol Metab 1989;3:313-30.  Back to cited text no. 16
    
17.
Castillo JJ, Vincent M, Justice E. Diagnosis and management of hyponatremia in cancer patients. Oncologist 2012;17:756-65.  Back to cited text no. 17
    
18.
Fine RN, Clarke RR, Shore NA. Hyponatremia and vincristine therapy. Syndrome possibly resulting from inappropriate antidiuretic hormone secretion. Am J Dis Child 1966;112:256-9.  Back to cited text no. 18
    
19.
Hammond IW, Ferguson JA, Kwong K, Muniz E, Delisle F. Hyponatremia and syndrome of inappropriate anti-diuretic hormone reported with the use of Vincristine®: An over-representation of Asians? Pharmacoepidemiol Drug Saf 2002;11:229-34.  Back to cited text no. 19
    
20.
Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:1581-9.  Back to cited text no. 20
    
21.
Gross P. Clinical management of SIADH. Ther Adv Endocrinol Metab 2012;3:61-73.  Back to cited text no. 21
    
22.
Baylis PH. The syndrome of inappropriate antidiuretic hormone secretion. Int J Biochem Cell Biol 2003;35:1495-9.  Back to cited text no. 22
    
23.
Berl T, Quittnat-Pelletier F, Verbalis JG, Schrier RW, Bichet DG, Ouyang J, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 2010;21:705-12.  Back to cited text no. 23
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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