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The Journal of Clinical Endocrinology & Metabolism 87(10):4564 – 4568 Copyright © 2002 by The Endocrine Society doi: 10.1210/jc.2002-020090

Baroregulation of Vasopressin Release in Adipsic Diabetes Insipidus D. SMITH, K. MCKENNA, K. MOORE, W. TORMEY, J. FINUCANE, J. PHILLIPS, P. BAYLIS, C. J. THOMPSON

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Departments of Endocrinology (D.S., K.Mc., K.Mo., W.T., J.F., C.J.T.) and Neurosurgery (J.P.), Beaumont Hospital, Dublin 9; and Department of Endocrinology (P.B.), Royal Victoria Infirmary, NE1 4LP Newcastle-upon-Tyne, United Kingdom Adipsic diabetes insipidus (ADI) occurs in association with a heterogenous group of conditions. We report vasopressin (AVP) responses to hypotension in nine patients with ADI and nine controls. Hypertonic saline infusion produced absent thirst (1.7 ⴞ 1.7 to 1.5 ⴞ 1.7 cm, P ⴝ 0.99) and AVP responses (0.3 ⴞ 0.1 to 0.4 ⴞ 0.1 pmol/liter, P ⴝ 0.99) in the ADI group, who also drank less than the control group (258 ⴞ 200 ml vs. 1544 ⴞ 306 ml, P < 0.001). Intravenous infusion of trimetaphan camsylate produced a fall in mean arterial pressure of 31.6% ⴞ 8.9% in patients and 29.4% ⴞ 6.1% in controls. Plasma AVP

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ENTRAL DIABETES INSIPIDUS (CDI) is characterized by hypotonic polyuria, secondary to vasopressin (AVP) deficiency, and thirst, secondary to elevation in plasma osmolality. Most patients with CDI have normal osmoregulated thirst appreciation (1), and they are able to replace urinary water losses with oral fluids, such that plasma osmolality is rarely much above the normal reference range as long as water supplies are adequate. Adipsic diabetes insipidus (ADI) is an unusual form of CDI (2), which has been reported in association with clipping of anterior communicating artery aneurysms (3–5), head injury (1), toluene exposure (6), and intracranial tumors (2) in which AVP deficiency is accompanied by absent or attenuated thirst sensation in response to elevations in plasma osmolality. The cooccurrence of AVP deficiency and adipsia suggests that the site of the lesion in ADI is the osmoreceptor cells in the anterior hypothalamus rather than the supraoptic and paraventricular nuclei, which synthesize AVP, or the posterior pituitary, from which AVP is released into the circulation. The osmoreceptors are postulated in man to be situated in the circumventricular organ of the anterior hypothalamus (7); in response to elevation of plasma osmolality, they stimulate AVP secretion and the sensation of thirst. Circumstantial evidence that the site of the lesion in ADI is the osmoreceptor region comes from individual case studies that report that despite absent thirst and AVP release in response to osmotic stimuli, patients respond to nonosmotic stimuli, such as hypotension and apomorphine-induced nausea, with normal secretion of AVP (5, 6, 8). This indicates that synthesis, storage, and release of AVP are normal in ADI and that AVP release can be provoked by stimuli that bypass the osmoreceptors, such as hypotension and emesis.

Abbreviations: ADI, Adipsic diabetes insipidus; AVP, vasopressin; CDI, central diabetes insipidus; MAP, mean arterial pressure.

concentrations rose from 1.4 ⴞ 0.8 to 340.3 ⴞ 497.4 pmol/liter (P < 0.001) in the control group. In three patients with craniopharyngioma, there was no rise in plasma AVP concentrations (0.3 ⴞ 0.1 to 0.3 ⴞ 0.1 pmol/liter, P ⴝ 0.96), but plasma AVP rose significantly in response to hypotension in the other six patients (0.4 ⴞ 0.2 to 204.5 ⴞ 223.2 pmol/liter, P < 0.001). We concluded that the AVP responses to hypotension in ADI are heterogenous and reflect the site of the lesion causing the diabetes insipidus. (J Clin Endocrinol Metab 87: 4564 – 4568, 2002)

Here, we report the results of a study of baroregulated AVP release in a large series of patients with well documented ADI. Patients and Methods Patients Nine patients with ADI (six males) and nine control volunteers (six males) were studied. The clinical characteristics of the patients and the controls are shown in Table 1. Patients were considered to have ADI on the basis of subnormal thirst and AVP responses to hypertonic saline infusion in the presence of hypotonic polyuria (24-h urine volume ⬎3 liters). All patients were tested for anterior pituitary hypofunction; ACTH and GH reserve were tested by either insulin hypoglycemia or glucagon testing, TSH deficiency by TRH test, and gonadotrophin deficiency by GnRH test. Three patients were on pituitary replacement therapy (glucocorticoids, T4, and sex steroids), and these medications were continued throughout the studies. None of the patients and none of the controls were on any other medication.

Study protocol Hypertonic saline infusion. To confirm the diagnosis of ADI and normal osmoregulation in the controls, patients and controls underwent intravenous hypertonic saline infusion. After an overnight fast, all subjects were admitted to the investigation unit. All subjects were requested to abstain from caffeine, nicotine, or alcohol for 12 h before study. Patients with ADI withheld treatment with AVP analogs for 24 h before study but were encouraged to drink water in excess of urine volumes to prevent dehydration before infusion of saline. Subjects voided urine and were rested recumbent. Indwelling cannulae were introduced into the veins of each antecubital fossa under lignocaine 1% local anesthesia, one for infusion of saline and the other for blood sampling. Two baseline blood samples separated by an interval of 15 min were withdrawn into chilled syringes and transferred into chilled lithium heparin tubes. Blood samples were centrifuged immediately at 4 C for 15 min at 2000 ⫻ g. The plasma supernatant was withdrawn and samples separated for immediate measurement of plasma osmolality and plasma sodium, and the remainder was stored in a ⫺70 C freezer for later measurement of plasma AVP. Hypertonic saline (855 mmol/liter) was then infused at a rate of 0.05 ml/kg䡠min for 2h. Blood was withdrawn at 30-min intervals until the end of the infusion. Thirst was measured at blood sampling times

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Smith et al. • Baroregulated AVP in ADI

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TABLE 1. Clinical details of patients Patient

Sex

Age

Etiology of ADI

Anterior pituitary dysfunction

Associated conditions

A B C D E F G H I Mean (SD) Control group

F M M M M M F F M

39 30 28 40 22 26 18 16 56 30.2 (13.1) 32.8 (11.4)

Surgery to ACAA Surgery to ACAA Surgery to ACAA Surgery to ACAA Head injury Toluene exposure Craniopharyngioma Craniopharyngioma Craniopharyngioma

No No No No No No ACTH, GH, TSH, LH, FSH ACTH, GH, TSH, LH, FSH ACTH, GH, TSH, LH, FSH

Nil Mild left hemiparesis Myoclonus, absence attacks, hypothermia Nil Nil Hypothermia, sleep apnea Obesity Obesity

ACAA, Anterior communicating artery aneurysm. using a visual analog scale. At the end of the infusion there was a 15-min equilibration period, following which subjects were allowed free access to tap water at room temperature. The volume of water drunk in 30 min was recorded. Trimetaphan infusion. To study baroregulated AVP secretion, subjects underwent iv infusion of trimethaphan camsylate, a ganglion-blocking drug that produces a rapidly reversible fall in arterial blood pressure. On the day of study, subjects were admitted to the investigation unit in a fasted state, having avoided caffeine, alcohol, and nicotine for 12 h. Patients with ADI had discontinued AVP analogs for 24 h before study. An iv infusion of trimetaphan, 250 mg in 50 ml 5% dextrose, was commenced at 0.5 mg/min. Blood pressure was measured at 5-min intervals using a Bosomat 11 automatic sphygmomanometer (Bosch & Sohn, Munich, Germany), and the infusion rate of trimetaphan was doubled every 15 min until a 20% fall in mean arterial pressure (MAP) had been achieved, after which the infusion was discontinued, and the subject was placed in a head-down position until blood pressure recovered. Blood samples were taken as above for measurement of plasma AVP, osmolality, and sodium at 5-min intervals.

Laboratory analyses Plasma osmolality was measured by the depression of freezing point method and plasma sodium by ion-selective electrode. Plasma AVP was measured by a sensitive and specific RIA after extraction from plasma by adsorption onto magnesium silicate (Florisil, U.S. Silica, Berkeley Springs, WV). The limit of detection of the assay is 0.3 pmol/liter, with intra- and interassay coefficients of variation of 9.7% and 15.3%, respectively (9).

Measurement of thirst Thirst was measured on a 10-cm long visual analog scale, which has been validated previously and found to be an accurate (10) and reproducible (11) reflection of thirst sensation.

Statistics MAP was calculated by adding one third of the pulse pressure to the diastolic blood pressure. Changes in parameters with time were calculated by one-way ANOVA and between groups by two-way ANOVA, using Statistical Package for Social Sciences (SPSS, Inc., Chicago, IL).

Ethical approval All control studies were performed with the permission of the local ethical committee. Hypertonic saline infusion and trimetaphan infusion studies are performed as part of the routine investigation of cases of suspected osmoreceptor dysfunction in both institutions after full explanation of potential risks and benefit to the patient.

Results Hypertonic saline infusion

Baseline plasma osmolality was higher in the ADI group than in controls (296.7 ⫹ 12.1 vs. 288.3 ⫾ 1.6 mOsm/kg,

mean ⫾ sd, P ⫽ 0.02). Infusion of saline led to a rise in plasma osmolality in both ADI (296.7 ⫾ 12.1 to 318 ⫾ 15.8 mOsm/kg, P ⫽ 0.0016) and controls (288.3 ⫾ 1.6 to 305.4 ⫾ 2.7, with plasma osmolality higher throughout the period of infusion in the ADI group (P ⬍ 0.001). The rise in plasma osmolality was caused by a rise in plasma sodium concentration (ADI, 142.1 ⫾ 5.7 to 152.8 ⫾ 6.6 mmol/liter, P ⬍ 0.001; controls 140.2 ⫾ 1.4 to 145.9 ⫾ 1.7 mmol/liter, P ⬍ 0.001); blood glucose remained unchanged in both ADI (4.3 ⫾ 0.4 to 4.3 ⫾ 0.5 mmol/liter, P ⫽ 0.87) and controls (4.1 ⫾ 0.2 to 4.1 ⫾ 0.2 mmol/liter, P ⫽ 0.92). The rise in plasma osmolality stimulated a rise in plasma AVP, from 0.7 ⫾ 0.4 to 5.6 ⫾ 2.1 pmol/liter, P ⬍ 0.001 in controls but did not produce a rise in plasma AVP in any of the ADI group (0.4 ⫾ 0.2 to 0.5 ⫾ 0.3 pmol/liter, P ⫽ 0.08), confirming complete cranial diabetes insipidus in each patient (Fig. 1). Thirst ratings rose in the control group, from 1.2 ⫾ 0.8 to 7.3 ⫾ 1.4 cm, P ⬍ 0.001), but there was no change in thirst ratings in the ADI group (1.7 ⫾ 1.7 to 1.5 ⫾ 1.7 cm, P ⫽ 0.99). The control group drank significantly more in the 30-min drinking period (1544 ⫾ 306 ml) than the ADI group (258 ⫾ 200 ml, P ⬍ 0.001). Baseline MAP was similar in the two groups, and there were similar rises throughout the infusion in ADI (88.4 ⫾ 10.0 to 97.1 ⫾ 9.7 mm Hg, P ⬍ 0.001) and controls (86.8 ⫾ 8.1 to 96.2 ⫾ 7.0 mm Hg, P ⬍ 0.001). Trimetaphan infusion

Infusion of trimetaphan in the control group produced a fall in MAP from 90.2 ⫾ 7.1 to 63.7 ⫾ 7.7 mm Hg (P ⬍ 0.001), a fall in MAP of 29.4% ⫾ 6.1%, with a rise in plasma AVP from 1.4 ⫾ 0.8 to 340.3 ⫾ 497.4 pmol/liter (P ⬍ 0.001). Plasma osmolality remained unchanged (287.6 ⫾ 1.4 to 288.4 ⫾ 0.8, P ⫽ 0.87). Infusion of trimetaphan in the patient group caused a fall in MAP from 91.8 ⫾ 7.5 to 62.7 ⫾ 9.9 mm Hg (P ⬍ 0.01), a percentage fall of 31.6% ⫾ 8.9%. Six of the ADI group (patients A–F) had rises in plasma AVP, which were comparable with those in the controls (0.4 ⫾ 0.2 to 204.5 ⫾ 223.2 pmol/ liter, P ⬍ 0.001). All six of these patients expressed the sensation of thirst when their MAP fell substantially. The three patients with ADI secondary to craniopharyngioma showed no rise in plasma AVP (0.3 ⫾ 0.1 to 0.3 ⫾ 0.1 pmol/liter, P ⫽ 0.96), despite similar falls in MAP to the other MAP patients (Fig. 2). None of the three patients with ADI secondary to craniopharyngioma developed thirst during

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Smith et al. • Baroregulated AVP in ADI

FIG. 1. Plasma osmolality, plasma AVP, and thirst responses to hypertonic saline infusion in patients with ADI (f) and controls (E). Results are expressed as mean with SD bars.

arterial hypotension. Plasma osmolality remained unchanged during the infusion period (294.4 ⫾ 3.1 to 296.8 ⫾ 3.4 mOsm/kg, P ⫽ 0.11). Discussion

This is the largest series of patients with ADI published to date. The diagnosis was confirmed in each case by the demonstration of absent thirst and AVP responses to osmotic stimulation by the acute elevation of plasma sodium concentration. Acute arterial hypotension causes a reduction in the tonic inhibition of AVP secretion exerted by stretching of the baroreceptors; this leads to a rise in plasma AVP concentrations, which is independent of the hypothalamic osmoreceptors that control physiological release of the hormone. The results of trimetaphan infusion show two distinct patterns of AVP response to arterial hypotension, depending on the etiology of the ADI. None of the patients who had a craniopharyngioma responded to hypotension with a rise in

plasma AVP concentration. In contrast, all of the patients with surgical clipping of bleeding anterior communicating artery aneurysms showed normal rises in plasma AVP concentration in responses to hypotension, as did the two patients with head injury and toluene exposure. There have been a number of case reports that have shown that clipping of anterior communicating artery aneurysms following rupture causing subarachnoid hemorrhage is associated with cranial diabetes insipidus associated with absent thirst (3–5). It has also been shown in one such patient, that nonosmotic stimuli to AVP secretion, such as hypotension and apomorphine-induced nausea, can produce very large rises in plasma AVP concentrations, well in excess of the plasma concentrations needed to effect maximum antidiuresis (5). We have confirmed these findings in all four of the patients whom we studied, and our data clearly imply that in these patients, although there is inability to perceive elevations in plasma osmolality and respond with appropri-

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Smith et al. • Baroregulated AVP in ADI

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FIG. 2. Graph of log plasma AVP against percentage fall in mean arterial in patients with ADI (A–I). The range of responses in the normal controls is shown in the shaded area.

ate secretion of AVP and thirst, there is an intact mechanism for secretion of AVP by nonosmotic pathways. This would confirm the suggestions that clipping of anterior communicating artery aneurysms can produce selective lesions of the osmoreceptors (4). The organum vasculosum laminae terminalis, the site of the putative osmoreceptor (7), derives its vascular supply from small perforating branches of the anterior cerebral and anterior communicating arteries (12), and it is therefore likely that clipping of the hemorrhaging anterior communicating artery aneurysms compromises the blood supply to the osmoreceptor cells. The localized nature of the lesion produced is also reflected in the lack of anterior pituitary dysfunction in these patients (Table 1). Although clipping of anterior communicating artery aneurysm following subarachnoid hemorrhage was the most common cause of ADI in our series, it remains a very rare complication of aneurysm surgery. Diabetes insipidus was reported in 0.4% of a large series of 1000 cases of subarachnoid hemorrhage (13), and in a review of 104 patients with CDI, only one case occurred after rupture of a cerebral aneurysm (14). Of the four cases that we have reported in this series, one each followed neurosurgery in the two units represented by the authors and two were referrals for workup from another center, so our own relatively large number represents the experience of three large neurosurgery centers. However, the cases reported in the literature of ADI reflect our own experience, in that the most common cause in the literature is clipping of an anterior communicating artery aneurysm (3–5, 14). Particular care must be given, therefore, to water balance following this particular surgical procedure. It is possible also that the patient with ADI secondary to head injury sustained damage to the vascular supply (patient E, Table 1). Computerized tomography of the brain was normal in this patient as was anterior pituitary function. Head injury is commonly associated with diabetes insipidus, even in the absence of skull fracture or loss of consciousness (15), but adipsia is rare. The nature of the head injury in this man was mild suggesting that a trivial contusion may have damaged the delicate blood supply to the osmoreceptors.

The patient with toluene exposure (patient F, Table 1) also had normal brain imaging but had more widespread evidence of hypothalamic damage clinically, with sleep apnea, hypothermia, and hypothalamic fits. The patients with craniopharyngioma did not secrete AVP in response to hypotension, nor did they express the sensation of thirst when their blood pressure dropped. These patients had evidence on dynamic testing of panhypopituitarism, indicating that surgery to their tumors had left more widespread damage to pituitary function. The absent AVP response to both osmotic and hypotensive stimuli in these patients also suggests damage of the posterior pituitary, which is the final common pathway for AVP secretion, and possibly also the supraoptic and paraventricular nuclei. The absent thirst responses to hypertonic saline suggests damage also to the osmoreceptors. The size of the lesion in the craniopharyngioma patients is therefore more marked than in the other patients with ADI. In one case described in the literature with ADI caused by a pinealoma, the patient had panhypopituitarism in addition to diabetes insipidus and adipsia, although the results of AVP response to nonosmotic stimuli were not reported (2). It seems, however, that when ADI occurs secondary to intracranial tumors, the pattern of endocrine dysfunction is different, with the likelihood of anterior pituitary dysfunction and absent baroregulated AVP release. The failure of the craniopharyngioma patients to secrete AVP in response to hypotension or hypovolemia may increase the likelihood of hospital admission with hypernatremia. Two of our three craniopharyngioma patients have been admitted with symptoms directly attributable to severe hypernatremic dehydration. In contrast, we have not encountered clinical problems with hypovolemic dehydration sufficient to precipitate emergency admission in the other patients in our series. It is possible that baroregulated AVP release, in response to volume depletion or hypotension, exerts an antidiuretic effect that attenuates dehydration in the ADI owing to causes other than craniopharyngioma. In practical terms, the management of patients remains the same, irrespective of the etiology of ADI, with regular des-

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mopressin, fixed fluid intake, daily weighing, and regular clinical review of crucial importance (2). In summary, therefore, we have shown that the pattern of baroregulated AVP release is heterogenous in ADI. Patients with isolated osmoreceptor defects are able to secrete AVP in response to hypotension, but the lesion in craniopharyngioma patients is more extensive, such that baroregulated AVP release is impaired. Acknowledgments All AVP assays were carried out in the laboratories of Prof. Baylis in Newcastle-upon-Tyne, United Kingdom. The data from two patients (C and F) have been previously published as individual case reports (5, 6). Received January 25, 2002. Accepted June 14, 2002. Address all correspondence and requests for reprints to: Dr. C. Thompson, Beaumont Private Clinic, Beaumont Hospital, Dublin 9, Republic of Ireland. E-mail: [email protected].

References 1. Thompson CJ, Baylis PH 1987 Thirst in diabetes insipidus: clinical relevance of quantitative assessment. Q J Med 65:853– 862 2. Ball SG, Vaidja B, Baylis PH 1997 Hypothalamic adipsic syndrome: diagnosis and management. Clin Endocrinol 47:405– 409

Smith et al. • Baroregulated AVP in ADI

3. Baylis PH, Robertson GL 1980 Plasma vasopressin response to hypertonic saline infusion to assess posterior pituitary function. J R Soc Med 73:255–260 4. McIver B, Connacher A, Whittle I, Baylis PH, Thompson CJ 1991 Adipsic hypothalamic diabetes insipidus after clipping of anterior communicating artery aneurysm. BMJ 303:1465–1468 5. Pearce S, Argent N, Baylis PH 1991 Chronic hypernatraemia due to impaired osmoregulated thirst and vasopressin secretion. Acta Endocrinol 125:234 –239 6. Teelucksingh S, Steers CR, Thompson CJ, Seckl JR, Douglas NJ, Edwards CRW 1991 Hypothalamic syndrome and central sleep apnoea associated with toluene exposure. Q J Med 78:185–190 7. Thrasher TN 1985 Circumventricular organs, thirst and vasopressin secretion. In: Schrier RW, ed. Vasopressin. New York: Raven Press; 311–318 8. Schaff-Blass E, Robertson GL, Rosenfield RL 1983 Chronic hypernatraemia from a congenital defect in osmoregulation of thirst and vasopressin. J Paediatr 102:703–708 9. Rooke P, Baylis PH 1982 A new sensitive radioimmunoassay for plasma arginine vasopressin. J Immunoassay 3:115–131 10. Thompson CJ, Bland J, Burd J, Baylis PH 1986 The osmotic thresholds for thirst and vasopressin release are similar in healthy man. Clin Sci 71:651– 656 11. Thompson CJ, Selby P, Baylis PH 1991 Reproducibility of osmotic and nonosmotic tests of vasopressin secretion in man. Am J Physiol 260:R533–R539 12. Perlmutter D, Rhoton AL 1976 Microsurgical anatomy of the anterior cerebralanterior communicating-recurrent artery complex. J Neurosurg 45:259 –271 13. Doczi T, Bende J, Huszka A, Kiss J 1981 Syndrome of inappropriate secretion of antidiuretic hormone after subarachnoid haemorrhage. Neurosurgery 9:394 –397 14. Moses AM 1984 Clinical and laboratory features of central and nephrogenic diabetes insipidus and primary polydipsia. In: Reichlin S, ed. The neurohypophysis. New York: Plenum Publishing; 115–138 15. Bohnen N, Twijnstra A, Jolles J 1993 Water metabolism and postconcussional symptoms 5 weeks after mild head injury. Eur Neurol 33:77–79

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