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Kishimoto2015 PDF
cerebrospinal fluid. Diagnosis of infection was based on a hyponatremia. Parenteral fluid volume and sodium con-
positive culture or a combination of clinical, serological, centration were also not associated the onset of hypona-
and radiologic findings. tremia. Among 80 patients with hyponatremia, 49 (44%)
experienced symptomatic hyponatremia. The most com-
Data Collection mon symptom among the patients with hyponatremia was
The baseline characteristics of the patients including nausea and vomiting (55%). Seizure and altered mental
demographic information (sex, age, weight, height, and status were observed in 1 (0.9%) and 3 patients (3%),
performance status [PS]), clinical information (diagnosis, respectively. The median duration of hyponatremia was 8
treatment history, and comorbidity), and serum bio- days (range, 2 to 35 d). Treatment for symptomatic hypo-
chemical values, were collected. The PS of the patients was natremia (water restriction and/or 3% hypertonic saline)
assessed using the Eastern Cooperative Group PS scale.12 was required in 11 of 111 (11%) patients, and in 12 of 472
Serum sodium values were prospectively monitored closely (3%) cycles. Neurological sequelae were seen in 2 of 111
during treatment. Clinical records were reviewed retro- (2%) patients, and in 2 of 472 (0.4%) cycles: resting tremor
spectively to identify hyponatremia. in one patient and altered mental status in another patient.
Statistical Analysis Risk Factor Analysis for Developing
Univariate analysis was performed by Mann Whitney Hyponatremia
U test and unpaired t test for quantitative variables, and w2 Table 2 presents the characteristics of chemotherapy
test and Fisher exact test for qualitative variables. Risk cycles with overall hyponatremia and moderate to severe
factors for overall hyponatremia and moderate to severe hyponatremia episodes. In univariate analysis, the risk of
hyponatremia were identified through chemotherapy cycle– hyponatremia was significantly increased in patients with
based analysis. The most discriminative cut-off points for higher PS score (P = 0.001), total parenteral nutrition (TPN)
the variables were determined by univariate analysis. (P < 0.001), first or second chemotherapy cycle (P < 0.001),
Potential risk factors with P values of <0.15 on univariate past history of SCT (P = 0.040), renal injury (P < 0.001), CNS
analysis were included in a stepwise logistic regression disease (P = 0.020), and infection (P = 0.022). Other risk fac-
model to identify the risk factors. In the multivariate tors for hyponatremia included administration of carboplatin
logistic regression model, significant variables were identi- (P = 0.001), daunorubicin (P < 0.001), dexamethasone
fied by a backward stepwise procedure. For all models, the (P = 0.001), ifosfamide (P = 0.012), irinotecan (P = 0.032),
number of covariates examined was determined by the L-asparaginase (P < 0.001), pirarubicin (P = 0.015), pre-
number of outcome events with 10 events required for 1 dnisolone (P < 0.001), and vincristine (P < 0.001). Neither
covariate.13 Multicollinearity was examined using an initial serum sodium level nor the volume of parenteral fluid
explanatory variable correlation matrix. Odds ratios (ORs) was shown to be a significant predictor for hyponatremia. The
and 95% confidence intervals (CIs) were calculated for mean sodium concentration of parenteral fluid was higher in
predictors retained in the final models. A P value of <0.05 cycles with than without hyponatremia (55 vs. 50 mmol/L,
was considered statistically significant; all tests were 2- P = 0.002), and in cycles with than without moderate to
tailed. All statistical analyses were conducted using Dr severe hyponatremia (60 vs. 51 mmol/L, P < 0.001). Renal
SPSS II for Windows (release 11.0.1J; SPSS Japan, Tokyo, injury (P < 0.001), and administration of cyclophosphamide
Japan). (P = 0.007), dexamethasone (P = 0.001), and vincristine
(P < 0.001) were strongly associated with moderate to severe
RESULTS hyponatremia. The administration of daunorubicin, L-aspar-
aginase, or prednisolone was excluded from the multivariate
Incidence of Hyponatremia analysis because a strong correlation was observed between
The baseline characteristics of the patients are shown their administration and the administration of vincristine.
in Table 1. All patients received hypotonic intravenous Similarly, administration of dexamethasone was excluded due
fluids at the initiation of the chemotherapy cycle for sup- to its correlation with cyclophosphamide. Multivariate analysis
portive treatment. The mean and SD of parenteral fluid identified age 10 to 18 years (OR = 3.24, 95% CI, 2.07-5.07),
volume were 74 and 31 mL/kg/d, respectively (Table 2). TPN (OR = 8.15, 95% CI, 2.17-30.5), first or second chemo-
Hyponatremia was observed in 80 of 111 (72%) patients. therapy cycle (OR = 1.74, 95% CI, 1.12-2.70), administration
Of these 80 patients, 35 patients (32%) developed hypo- of carboplatin (OR = 6.51, 95% CI, 2.43-17.5), and admin-
natremia in >2 cycles. The median age was significantly istration of vincristine (OR = 3.56, 95% CI, 2.25-5.63) as
higher in patients with than without hyponatremia (11 vs. independent risk factors for overall hyponatremia. Renal injury
2 y, P < 0.001), and in patients with than without moderate (OR = 5.38, 95% CI, 2.15-13.5), administration of ifosfamide
to severe hyponatremia (12 vs. 5 y, P = 0.001). In the che- (OR = 8.03, 95% CI, 1.83-35.2), and administration of vin-
motherapy cycle–based analysis, hyponatremia was cristine (OR = 5.90, 95% CI, 2.24-15.5) were also identified as
observed in 138 of 472 (29%) cycles: mild hyponatremia in independent risk factors for moderate to severe hyponatremia
108 cycles (23%); moderate hyponatremia in 26 cycles (Table 3). The magnitude of correlations among the variables
(6%); and severe hyponatremia in 4 cycles (1%). Hypona- was also assessed, and there was no evidence of multi-
tremia at the initiation of the chemotherapy cycle was collinearity.
observed in 7 of 472 (1%) cycles, all of which were mild
hyponatremia. The median onset of hyponatremia occurred
8 days (range, 1 to 34 d) after the initiation of chemo- DISCUSSION
therapy. In 69 of 138 (50%) cycles with hyponatremia, In the present study, the risk of hyponatremia during
patients developed hyponatremia within the first week of chemotherapy was significantly dependent on the clinical
the chemotherapy. There was no significant relation conditions of patients, such as age, PS, past history, and
between severity of hyponatremia and the timing of comorbidities, as well as on the chemotherapeutic agents.
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J Pediatr Hematol Oncol Volume 00, Number 00, ’’ 2015 Analysis of Risk Factors for Hyponatremia
TABLE 1. Baseline Characteristics of the Total Population and the Subgroups With Hyponatremia and With Moderate to Severe
Hyponatremia
Baseline Characteristics Total (n = 111) Hyponatremia (n = 80) P* Moderate to Severe Hyponatremia (n = 24) Pw
Age (median [range]) (y) 7 (0-18) 11 (0-18) < 0.001 12 (2-18) 0.001
Male/female 59/52 43/37 0.840 12/12 0.727
Treatment history (n [%])
Chemotherapy 18 (16) 15 (19) 0.245 5 (21) 0.535
SCT 8 (7) 7 (9) 0.439 3 (13) 0.367
Surgery 23 (21) 18 (23) 0.457 6 (25) 0.576
Comorbidity (n [%])
Renal injury 13 (12) 12 (15) 0.106 6 (25) 0.033
CNS disease 9 (8) 7 (9) 1.0 3 (13) 0.403
Infection 5 (5) 5 (6) 0.319 1 (4) 1.0
Diagnosis (n [%])
Hematological malignancy 87 (78) 62 (78) 0.718 19 (79) 0.916
ALL 50 (45) 37 (46) 14 (58)
AML 24 (22) 14 (18) 1 (4)
NHL 9 (8) 8 (10) 3 (13)
Other 4 (4) 3 (4) 0.316 1 (4) 0.101
Solid tumor 24 (22) 18 (23) 0.718 5 (21) 0.916
Neuroblastoma 8 (7) 7 (9) 2 (8)
Hepatoblastoma 5 (5) 4 (5) 1 (4)
Other 11 (10) 7 (9) 0.475 2 (8) 0.936
Disease status (n [%])
Newly diagnosed 93 (84) 65 (81) 19 (79)
Relapsed 18 (16) 15 (19) 0.245 5 (21) 0.535
*P value for comparison of hyponatremia versus none.
wP value for comparison of moderate to severe hyponatremia versus none.
ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; CNS, central nervous system; NHL, non-Hodgkin lymphoma; SCT, stem cell
transplantation.
To the best of our knowledge, this study is the first to have been reported to cause hyponatremia.18–21 Most of the
describe the risk factors for hyponatremia during chemo- previous literature consists of case reports or small case
therapy. The present study showed that hyponatremia series, however, and the precise incidence of hyponatremia
during chemotherapy was common in children with cancer. induced by these agents remains unknown. We actually
We previously reported the incidence of the syndrome of confirmed that these drugs were significant risk factors for
inappropriate secretion of antidiuretic hormone (SIADH) hyponatremia during chemotherapy. A previous study
as 40% in 140 pediatric patients who underwent SCT.14 reported an estimated rate of hyponatremia and/or SIADH
The high incidence of hyponatremia in our studies seems to of 1.3/100,000 vincristine-treated patients,19 which is clearly
be similar to that reported in a previous study of 63 children lower than the present result. This marked difference may
who received chemotherapy or SCT.15 Comparisons of be attributed to the difference in regimens and patient
hyponatremia incidence are difficult, however, because populations between the studies.
there have been considerable differences in the definitions of Besides chemotherapy agents, age, PS, need for TPN,
hyponatremia among the previous studies.3–5,7,14,15 It past history, and comorbidities were also found to be
should be noted, that although about one half of patients important factors in the development of hyponatremia during
with hyponatremia were asymptomatic in the present study, chemotherapy. We revealed that adolescents are at higher risk
several patients developed severe neurological symptoms of hyponatremia during chemotherapy. An increased inci-
and sequelae. In the present study, all patients received dence of some chemotherapy-related toxicities in older ado-
hypotonic intravenous fluids, and a lower sodium concen- lescents was reported in patients with acute lymphoblastic
tration of parenteral fluid was not shown to be a risk factor leukemia,22,23 suggesting that they are more susceptible to
for hyponatremia. It has been suggested, however, that use treatment-related toxicity than younger children. Supple-
of hypotonic fluids itself may be a potential risk factor for mental nutrition and infection have been reported as risk
hospital-acquired hyponatremia.5–7 We considered that our factors for hyponatremia in children undergoing surgery for
results did not support the routine use of parenteral fluid intracranial tumors.9 We identified renal injury as one of the
with lower sodium concentration in children with cancer most important risk factors for developing hyponatremia,
because there was no comparison between isotonic and especially for moderate to severe hyponatremia. Renal injury
hypotonic fluids in the present study. Moreover, recent is common in patients with cancer,24 and its cause is multi-
clinical evidence suggests that isotonic parenteral main- factorial, including nephrotoxic agents, cancer infiltration,
tenance fluids offer more effective prophylaxis against extrarenal obstruction, and infection.25 Renal salt wasting
hyponatremia than hypotonic fluids in hospitalized chil- syndrome induced by cisplatin has been described in previous
dren.16,17 The optimal fluid therapy should be established reports.20 In the present study, hyponatremia was also
for children with cancer, who have a greater risk of observed in patients with renal injury from causes other than
hyponatremia.7 cisplatin. The present results suggest that renal injury, as well
Several drugs used in chemotherapy, such as vinka as SIADH, the definition of which includes normal renal
alkaloids, platinum compounds, and alkylating agents, function,26 plays a critical role in the etiology of hyponatremia
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Kishimoto et al J Pediatr Hematol Oncol Volume 00, Number 00, ’’ 2015
TABLE 2. Characteristics of the Total Population and the Subgroups With Hyponatremia and With Moderate to Severe Hyponatremia:
Chemotherapy Cycle–based Comparison
Characteristic at the Initiation of the Total Hyponatremia Moderate to Severe Hyponatremia
Chemotherapy Cycle (n = 472) (n = 138) P* (n = 30) Pw
Age (median [range]) (y) 7 (0-18) 11 (0-18) < 0.001 13 (2-18) < 0.001
Male (n [%]) 242 (51) 72 (52) 0.801 13 (43) 0.369
PS score 2-4 (n [%]) 48 (10) 24 (17) 0.001 5 (17) 0.214
TPN (n [%]) 16 (3) 12 (9) < 0.001 2 (7) 0.270
No. chemotherapy cycle (n [%])
1-2 210 (44) 73 (53) 17 (57)
Z3 262 (56) 65 (47) 0.018 13 (43) 0.166
Serum sodium (mean ± SD) (mmol/L) 140 ± 3 139 ± 4 0.228 140 ± 3 0.477
Past history (n [%])
SCT 39 (8) 17 (12) 0.040 4 (13) 0.297
Surgery 116 (25) 42 (30) 0.057 10 (33) 0.250
Comorbidity (n [%])
Renal injury 34 (7) 23 (17) < 0.001 9 (30) < 0.001
CNS disease 29 (6) 14 (10) 0.020 4 (13) 0.103
Infection 24 (5) 12 (9) 0.022 3 (10) 0.190
Diagnosis (n [%])
Hematological malignancy 357 (76) 98 (71) 0.133 21 (70) 0.457
ALL 217 (46) 58 (42) 15 (50)
AML 92 (19) 22 (16) 1 (3)
NHL 38 (8) 13 (9) 3 (10)
Other 10 (2) 5 (4) 0.255 2 (7) 0.044
Solid tumor 115 (24) 40 (29) 0.133 9 (30) 0.457
Neuroblastoma 39 (8) 11 (8) 4 (13)
Hepatoblastoma 26 (6) 10 (7) 2 (7)
Other 50 (11) 19 (14) 0.569 3 (10) 0.759
Disease status (n)
Newly diagnosed 407 (86) 113 (82) 23 (77)
Relapsed 65 (14) 25 (18) 0.078 7 (23) 0.164
Chemotherapy agent (n [%])
Actinomycin D 19 (4) 8 (6) 0.208 0 (0) 0.624
Bleomycin 11 (2) 4 (3) 0.738 0 (0) 1.0
Carboplatin 23 (5) 14 (10) 0.001 1 (3) 1.0
Cisplatin 65 (14) 19 (14) 0.999 7 (23) 0.164
Cyclophosphamide 204 (43) 66 (48) 0.194 20 (67) 0.007
Cytarabine 209 (44) 44 (32) < 0.001 6 (20) 0.006
Daunorubicin 59 (13) 35 (25) < 0.001 11 (37) < 0.001
Dexamethasone 108 (23) 45 (33) 0.001 14 (47) 0.001
Doxorubicin 16 (3) 6 (4) 0.576 2 (7) 0.270
Etoposide 147 (31) 42 (30) 0.831 6 (20) 0.173
Fludarabine 8 (2) 2 (1) 1.0 0 (0) 1.0
Idarubicin 36 (8) 9 (7) 0.561 2 (7) 1.0
Ifosfamide 18 (4) 10 (7) 0.012 3 (10) 0.099
Irinotecan 14 (3) 8 (6) 0.032 0 (0) 1.0
L-asparaginase 117 (25) 52 (38) < 0.001 15 (50) 0.001
Mercaptopurine 36 (8) 7 (5) 0.179 2 (7) 1.0
Methotrexate 68 (14) 10 (7) 0.004 3 (10) 0.600
Mitoxantrone 46 (10) 17 (12) 0.226 2 (7) 0.756
Nelarabine 16 (3) 2 (1) 0.169 0 (0) 0.614
Pirarubicin 162 (34) 36 (26) 0.015 10 (33) 0.906
Prednisolone 99 (21) 45 (33) < 0.001 11 (37) 0.029
Rituximab 5 (1) 1 (1) 1.0 0 (0) 1.0
Vincristine 190 (40) 77 (56) < 0.001 23 (73) < 0.001
Vindesine 4 (1) 1 (1) 1.0 1 (3) 0.232
Parenteral fluid
Volume (mean ± SD) (mL/kg/d) 74 ± 31 74 ± 28 0.849 80 ± 33 0.321
Sodium concentration (mean ± SD) 52 ± 15 55 ± 15 0.002 60 ± 12 < 0.001
(mmol/L)
*P value for comparison of hyponatremia versus none.
wP value for comparison of moderate to severe hyponatremia versus none.
ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; CNS, central nervous system; NHL, non-Hodgkin lymphoma; PS, per-
formance status; SCT, stem cell transplantation; TPN, total parenteral nutrition.
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J Pediatr Hematol Oncol Volume 00, Number 00, ’’ 2015 Analysis of Risk Factors for Hyponatremia
in patients with cancer. Taken together, these findings suggest 7. Carandang F, Anglemyer A, Longhurst CA, et al. Association
that there are at least 2 possible mechanisms of hyponatremia between maintenance fluid tonicity and hospital-acquired
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The present study had several inherent limitations. The 8. Castillo JJ, Vincent M, Justice E. Diagnosis and management
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