A Case Report of Syndrome of Inappropriate Secretion ofAntidiuretic Hormone With Marked Edema Due to

Administration of Hypertonic Saline

Hiroto Maeda, Kazuhiko Tsuruya, Hideki Yotsueda, Masatomo Taniguchi,Masanori Tokumoto, Hideki Hirakata, and Mitsuo Iida

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University,Fukuoka, Japan

Abstract: A 61-year-old man had hyponatremia (serumNa112 mmol/L), which was associated with disturbance ofconsciousness. Therefore, administration of hypertonicsaline was commenced. Eventually he was diagnosed withthe syndrome of inappropriate secretion of antidiuretichormone (SIADH). Hypertonic saline was continued for45 days, and plasma Na concentration rose to 138 mmol/L.At that time we were consulted regarding further adminis-tration of hypertonic saline.At the time of the consultationmarked edema had developed affecting the whole body.The cardiothoracic ratio was increased and pleural effusionwas evident on the chest X-ray. Administration of hyper-tonic saline was discontinued to prevent further worseningof the edema. Furthermore, water restriction (500 mL/day)

was started. Body weight decreased by 4.3 kg in 7 days andthe edema was diminished. However, plasma Na concen-tration decreased to 117 mmol/L.At that stage, we neededto balance the treatment of hyponatremia to the increasedextracellular fluid volume (ECF).To normalize the ECF,wecarried out ultrafiltration (UF) three times. Resolution ofedema by using an extracorporeal UF method allowed thecontrol of plasma Na concentration. In this case increasedECF volume hindered the adjustment of plasma Na con-centration. The infusion of hypertonic saline is now usedcommonly by physicians. It is necessary to consider thepotential risks of such treatment. KeyWords:Hyponatre-mia, Olfactory neuroblastoma, Syndrome of inappropriatesecretion of antidiuretic hormone, Ultrafiltration.

Under normal conditions, antidiuretic hormone(ADH) provides fine adjustment of plasma Na con-centration based on plasma osmotic pressure. Thesyndrome of inappropriate secretion of ADH(SIADH) is characterized by non-physiologic releaseof ADH with resultant impairment of water excre-tion. Since the excretion of Na is normal in SIADH,the extracellular fluid (ECF) volume is normal oronly slightly increased. Therefore, patients withSIADH are typically euvolemic and free of periph-eral or pulmonary edema. Here, we report a patientof SIADH who developed marked edema, which wascaused by continuous administration of hypertonic

saline. Resolution of edema by using an extracorpo-real ultrafiltration (UF) method allowed the controlof plasma Na concentration. It is concluded thatincreased ECF volume hinders the adjustment ofplasma Na concentration.

CASE REPORT

A 61-year-old man noticed swelling of the rightcervical lymph node in the first 10 days of January2005, but did not seek medical consultation.However, he later visited the local hospital afterdeveloping nasal bleeding and nasal congestion on 28January. Lymph node biopsy was carried out and hewas diagnosed with malignant lymphoma. Becausethere was no hematologist in the hospital, he wasreferred to another hospital on 1 March 2005. Onadmission (2 March), he was noted to havehyponatremia (serum Na: 116 mmol/L), which

Received May 2006.Address correspondence and reprint requests to Dr Kazuhiko

Tsuruya, Department of Medicine and Clinical Science, GraduateSchool of Medical Sciences, Kyushu University, Maidashi 3-1-1,Higashi-ku, Fukuoka 812-8582, Japan. Email: tsuruya@intmed2.med.kyushu-u.ac.jp

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further deteriorated to 112 mmol/L on 5 March. Thelatter was associated with disturbance of conscious-ness.Administration of hypertonic saline (2.5%NaClat 600 mL/day) was commenced on the same day.Theconsciousness status improved with the rise in plasmaNa concentration, which was maintained between115 and 126 mmol/L thereafter. In summary, thepatient showed the following features: (i) hyponatre-mia and hypo-osmolality (plasma Na: 125 mmol/L,Posm: 258 mOsm/kgH2O); (ii) inappropriately highurinary osmolality (Uosm: 580 mOsm/kgH2O); (iii)high urinary Na concentration (209 mmol/L); (iv)normovolemia; and (v) normal renal, adrenal, andthyroid functions. Based on these findings, he wasdiagnosed with SIADH.Nasal cavity biopsy established the diagnosis as

olfactory neuroblastoma (ONB), not malignant lym-phoma.ONB was thought to be the cause of SIADH.He was considered not suitable for surgical treatmentbecause magnetic resonance imaging (MRI) showedintracranial infiltration of the ONB. Therefore, hewas transferred to our hospital for radiotherapy bythe otolaryngologist on 22 March.On admission, he was consciously alert.Height was

156.3 cm, body weight was 53.4 kg and blood pres-sure was 144/86 mm Hg. The right cheek and righteye were swollen and cervical lymph nodes were pal-pable.Laboratory findings are shown in Table 1.Totalprotein and serum albumin were slightly low; bloodurea nitrogen was markedly decreased, with persis-tence of hyponatremia. Renal function was normalwith a creatinine clearance of 114 mL/min/1.73 m2.

The head MRI showed direct tumor invasion fromthe right nasal cavity into the mandible, maxillarysinus, ethmoid bone, sphenoidal sinus, frontal sinusand frontal lobe (Fig. 1). Although hypertonic saline(2.5% NaCl at 600 mL/day) was continued to beadministered through the central vein catheter,plasma Na concentration was low at 116 mmol/L on25 March. Subsequently, a higher concentration ofsaline solution was infused and plasma Na concentra-tion rose to 138 mmol/L on 18 April (Fig. 2). Basedon the need to withdraw the central venous catheterdue to infection at the site of the catheter exit, theotolaryngologist consulted us on 18 April regardingfurther administration of hypertonic saline.At the time of the consultation, body weight had

increased by 3.4 kg since admission to our hospitaland marked edema had developed affecting thewhole body. The cardiothoracic ratio was increasedand pleural effusion was evident on the chest X-ray(Fig. 3).Administration of hypertonic saline was dis-continued to prevent further worsening of theedema. Furthermore, water restriction (500 mL/day)was started for treatment of hyponatremia from 19April. On 26 April, body weight decreased by 4.3 kg(from 56.7 to 52.4 kg) and the edema was diminished.However, plasma Na concentration decreased to117 mmol/L.Accordingly, we carefully recommencedthe administration of hypertonic saline (2.5% NaClat 600 mL/day) on 26April to prevent any increase inECF. However, plasma Na concentration did not risebut rather decreased to 115 mmol/L on 28 April, andthe patient developed consciousness disturbance.

TABLE 1. Laboratory data on admission

Peripheral blood Blood chemistry Immunology

WBC (35009000) 7380/uL Total protein (6.78.3) 6.3 g/dL CRP (

FIG. 2. Clinical course of urinaryNa, serum Na, antidiuretic hormone(ADH) and body weight. The extra-cellular fluid volume (ECF) wasincreased due to continuous hyper-tonic saline. We reasoned the diffi-culty of treatment of hyponatremiawas due to the increased ECFvolume and carried out ultrafiltra-tion (UF) three times. It allowed thecontrol of plasma Na concentrationto remain within the range of 128131 mmol/L.

3.2

Body weight

2.5% 3.8%

ADH4.0 2.8

3.0%UF

UFrosemide 40 mgNaCl 2.5%

Serum Na

Urinary Na

(kg)

(mmol/L) (mmol/L)

(pg/mL)

45

50

55

60

3/23 3/30 4/6 4/13 4/20 4/27 5/4 5/11 5/18 5/25

100

110

120

130

140

0

50

100

150

200

250

FIG. 3. Chest X-rays taken on (A)admission, and (B) at time of consul-tation. Note the appearance ofpleural fluid and increased cardio-thoracic ratio on B.

A B

FIG. 1. Magnetic resonance image(MRI) of the head. The MRI showstumor infiltration. (A) Note thespread of the tumor into the maxil-lary sinus, ethmoid bone, sphenoidalsinus and frontal sinus. (B) Cancerinvasion of the frontal lobe (arrow).

A B

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The control of hyponatremia was so difficult in thispatient that the plasma Na concentration haddecreased 24 mmol/L in 9 days. Although totalpatient intake had been almost controlled, urineoutput remained high (Fig. 4). Serum albumin wasgradually increased and it showed that ECF wasdecreased. It was likely that the more ECFdecreased, the more Na had decreased.At that stage,we reasoned the difficulty of treatment of hyponatre-mia was due to the increased ECF volume. To nor-malize the ECF, we carried out UF three timesbetween 30 April and 7 May. UF was carried out for10 h in total until systolic blood pressure decreased to

SIADH such as drugs and pulmonary diseases werealso not obvious, we concluded that ONB causedSIADH.SIADH is characterized by non-physiologic release

of ADH, resulting in impaired water excretion withnormal sodium excretion.Renal water reabsorption isenhanced due to persistentADH activity, resulting indilution (hyponatremia and hypo-osmolality) andexpansion of body fluids. However, edema does notoccur under such circumstances because the volumereceptors are activated, leading to appropriateincrease in urinary Na and water excretion, which areprobably mediated by the renin-angiotensin system,atrial natriuretic peptide, and activation of sympa-thetic nerves.The ensuing volume expansion activatessecondary natriureticmechanisms,resulting inNa andwater loss (9).Therefore, water retention and Na lossdonot occur,andplasmaNa concentrations donot fallwhen water intake is restricted. However, plasma Naconcentration fell rapidly in spite of the restriction ofwater intake in our patient. The ECF volume tendedto be normalized and renal water reabsorption con-tinued to enhance due to persistent ADH activity.Therefore, even when water intake was restricted,urinaryNa excretion remained high and the control ofplasma Na concentration was incomplete.The correc-tion of the excess ECF volume by UF decreasedurinary Na excretion (Fig. 2), and it is likely thatplasma Na concentration became easier to control.Following repeated courses of UF, the plasma Naconcentration could be controlled only by waterrestriction.Based on this finding, it is thought that thedifficulty in the treatment of hyponatremia was due tothe excess of ECF volume.Increased ECF volume is thought to be solely due

to hypertonic saline for the following reasons: (i)cardiac and hepatic functions were normal, and (ii)the lack of venous or lymph duct obstruction by thetumor in radiologic images.In this case we started water restriction only; as

a result, plasma Na concentration decreased to115 mmol/L. The patient developed consciousnessdisturbance, and we therefore carried out UF toeliminate the increased ECF volume in haste.However, hyponatremia of SIADH is best correctedby giving loop diuretic and by replacing sodium lost

in the urine by a quantitative replacement in the formof a hypertonic saline infusion (10).Therefore if furo-semide was used earlier, it is likely that UF couldhave been avoided. Furthermore if no hypertonicsaline was administered, the edema would not occurand plasma Na concentration could be controlled bywater restriction only.In summary, we report a patient who developed

marked edema in association with SIADH. Thecontrol of plasma Na concentration was difficult dueto increased ECF volume. Finally, an adjustment ofECF volume by using UF method allowed easiercontrol of plasma Na concentration. The infusion ofhypertonic saline only is now used commonly by phy-sicians. Therefore, it is necessary to consider thepotential risks of such treatment.

REFERENCES

1. Miura K, Mineta H, Yokota N et al. Olfactory neuroblastomawith epithelial and endocrine differentiation transformed intoganglioneuroma after chemoradiotherapy. Pathol Int 2001;51:9427.

2. Myers SL, Hardy DA, Wiebe CB et al. Olfactory neuroblas-toma invading the oral cavity in a patient with inappropriateantidiuretic hormone secretion. Oral Surg Oral Med OralPathol 1994;77:64550.

3. Ahwal MA, Jha N, Nabholtz JM et al. Olfactory neuro-blastoma: report of a case associated with inappropriate anti-diuretic hormone secretion. J Otolaryngol 1994;23:4379.

4. Cullen MJ, Cusack DA, OBrian DS et al. Neuroblastoma ofarginine vasopressin by an olfactory neuroblastoma causingreversible syndrome of antidiuresis. Am J Med 1986;81:91116.

5. Osterman J, Calhoun A, Dunham M et al. Chronic syndromeof inappropriate antidiuretic hormone secretion and hyperten-sion in a patient with olfactory neuroblastoma. Evidence ofectopic production of arginine vasopressin by the tumor.ArchIntern Med 1986;146:17315.

6. Srigley JR,Dayal VS,Gregor RT et al. Hyponatremia second-ary to olfactory neuroblastoma. Arch Otolaryngol 1983;109:55962.

7. Singh W,Ramage C, Best P et al. Nasal neuroblastoma secret-ing vasopressin. A case report. Cancer 1980;45:9616.

8. Pope TL, Morris JL, Cail WS et al. Esthesioneuroblastomapresenting as an intracranial mass. South Med J 1980;73:6435.

9. Verbalis JG. Pathogenesis of hyponatremia in an experimentalmodel of the syndrome of inappropriate antidiuresis. Am JPhysiol 1994;267:R161725.

10. Decaux G, Waterlot Y, Genette F et al. Treatment of the syn-drome of inappropriate secretion of antidiuretic hormone withfurosemide. N Engl J Med 1981;304:32930.

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