Postgrad Med J: first published as 10.1136/pgmj.54.635.623 on 1 September 1978. Downloaded from Postgraduiate Medical Journal (September 1978) 54, 623-627. Demeclocycline in the treatment of the syndrome of inappropriate antidiuretic hormone release: with measurement of plasma ADH P. L. PADFIELD G. P. HODSMAN M.B., M.R.C.P. M.B., M.R.C.P. J. J. MORTON Ph.D. MRC Blood Pressure Unit anid Department ofMedicine, Western Infirmary, Glasgow GIl 6NT Summary fluid and electrolyte balance in a patient with A patient with the syndrome of inappropriate anti- SIADH following head injury and meningitis, diuretic hormone release (SIADH) following head together with serial measurements of plasma ADH. injury and meningitis was studied during treatment with demeclocycline, a drug known to produce a Case history reversible nephrogenic diabetes insipidus. No changes A 64-year-old male was admitted to hospital, were observed during six days of demeclocycline 4 days following a head injury, with a story of pro- 1200 mg/24 hr but urine output increased significantly, gressive confusion. A clinical diagnosis of menin- Protected by copyright. with the production of a dilute urine, when the dose gitis was confirmed by the finding of an increased was increased to 2400 mg/24 hr. The patient lost cell count in the cerebrospinal fluid with pneumo- weight, and all biochemical features of the syndrome cocci on direct film and grown on culture. He was were rapidly corrected despite an unchanged fluid started on penicillin and sulphadimidine and 12 days intake and despite the persistence of high plasma levels later was much improved. On admission his serum of ADH. The rise in serum sodium was accompanied sodium had been 139 mmol/l with a blood urea of by mild sodium retention, as measured by external 5-1 mmol/l and 12 days later 133 mmol/l and 29 balance and exchangeable sodium. mmol/l respectively. Skull radiology revealed an A complication of treatment was the development occipital fracture but chest X-rays were persistently of acute renal failure possibly induced by a nephro- normal. Seventeen days after admission he was dis- toxic effect of high circulating levels of demeclocyline. charged although his serum sodium at that time was On stopping demeclocyline renal function returned to 128 mmol/l. He was re-admitted one week later normal and, after some delay, SIADH returned, and grossly confused with no focal neurological signs. was still present 9 months after initial presentation. A repeat lumbar puncture was normal but his serum This confirms earlier reports of the efficacy of de- sodium had fallen to 112 mmol/l. On the day after http://pmj.bmj.com/ meclocycline in SIADH; but the authors advise admission, serum sodium was 108 mmol/l with a caution against increasing the dose above 1200 mg/ plasma osmolality of 219 mosmol/kg with a con- 24 hr. current urine osmolality of 473 mosmol/kg. Plasma ADH was elevated at 9 pg/ml (normal range 4-8 Introduction pg/ml); clearly inappropriate for the plasma Fluid restriction, the conventional therapy for the osmolality. Fluid restriction resulted in a rise of syndrome of inappropriate antidiuretic hormone serum sodium to 136 mmol/l with a parallel im- secretion (SIADH) (Bartter and Schwartz, 1967) can provement in clinical state. He was discharged from on October 1, 2021 by guest. be irksome and requires close supervision of fluid hospital with advice to restrict his fluid intake but intake. Both lithium carbonate (Singer, Rotenberg serum sodium fell again to 126 mmol/l. He was re- and Puschett, 1972) and demeclocycline (White admitted 3 months after his initial presentation for and Fetner, 1975; De Troyer and Demanet, 1975; assessment of the effects of demeclocycline. ^herrill et al., 1975; Cledes, Clavier and Kerbrat, 1976; Perks, Mohr and Liversedge, 1976) have been Special studies shown to be effective in the treatment of SIADH in The patient was admitted to a metabolic ward and a small number of patients. It has been possible to placed on a fixed normal intake of sodium (133 study, in detail, the effects of demeclocycline on mmol/24 hr) and potassium (53 mmol/24 hr). Fluid Requcsts for reprints to: Dr Paul L. Padfield, Western intake was arbitrarily fixed at 2000 ml/24 hr (a volume Infirmary, Glasgow, GIl 6NT. designed to ensure the presence of SIADH). During 0032-5473/78/0900-0623 $02.00 (© 1978 The Fellowship of Postgraduate Medicine Postgrad Med J: first published as 10.1136/pgmj.54.635.623 on 1 September 1978. Downloaded from 624 Case reports 160r cq 0 120 E E E 80 m 0 uC0 40 ._C O0 IlI vn) 0 C. 10 DC 2400 go i- DC 1200 J .4 Control llw mg/24 hr -1.4 mg/24hr Time (days) FIG. 1. Effect of demeclocycline (DC) on urinary sodium in the syndrome of inappropriate antidiuretic hormone release (SIADH). of demeclocycline were measured using gas-liquid chromatography (quoted antibacterial range 3-5 Plasma ' II/ 0 l±g/ml). ADH 0I'@0 (pg/mi) 6 2 ' Results of special studies Protected by copyright. 14I Fluid balance (Fig. 1) During the initial run-in period, urine output was urea u / 3 Plasmao BloodBmmol/oo demeclocycline fairly constant and averaged 1333 ml/24 hr. The 0 6 A mean early morning urine osmolality was 603 2pI 4 (mmol/l) mosmol/kg. During the first day of demeclocycline Urine 600 /"-O' * therapy urine output increased to 2200 ml although osmololity 400 0 the osmolality was not measured. Thereafter, urine (mosmol/kg) F a mean - output fell, giving daily output of 1590 ml Plsa 290 - 0I 270 during the 6 days ofthe lower dose ofdemeclocycline. osmonality 0_0 (mosmol/kg) 25 0 0* mean T ~~~0-0 The early morning urine osmolality during 140 O_- SrmSeu this period was 600 mosmol/kg. On increasing the 130 - Nao - (mmol/l) 120 0e400-- dose of demeclocycline to 2400 mg/24 hr a diuresis 74 - occurred with a daily urine output averaging 2363 ml (osmolality 266 mosmol/kg). As fluid intake and Weight0 70 (kg) -0- ambient temperature were constant, this represents http://pmj.bmj.com/ 66 6 12 18 a true fluid loss and was accompanied by a dramatic DC 1200 DC 2400 *-Control4--Conlral 4mg/24 hr 4mg/24 hr fall in weight (Fig. 2). FIG. 2. The effects of demeclocycline (DC) in the syndrome of inappropriate antidiuretic hormone release Sodium balance (Fig. 2 and 3) (SIADH). Serum sodium remained low during the run-in period and during the first 6 days of demeclocycline an run-in of 6 measure- treatment. serum initial period days, serial Thereafter sodium and plasma on October 1, 2021 by guest. ments were made of weight, serum electrolytes osmolality rose rapidly to normal (Fig. 2). During (routine automated analysis), fluid and electrolyte the run-in period exchangeable sodium was 2860 balance, exchangeable sodium and potassium mmol and exchangeable potassium 2846 mmol. At (Davies and Robertson, 1973) and urine and plasma the end of the study exchangeable sodium had in- osmolality by freezing point depression (Advanced creased to 2957 mmol and potassium had remained Osmometer). Plasma ADH was measured by radio- unchanged at 2848 mmol. Urine samples for elec- immunoassay (Morton, Padfield and Forsling, 1975). trolyte measurement were lost during the first The patient then received demeclocycline (Leder- 3 days of the study but the net balance during the mycin9) 300 mg six-hourly for 6 days followed by remaining 3 days of the run-in period and the first 600 mg six-hourly for a further 6 days. Changes in 6 days of demeclocycline therapy was constant, the above measurements were noted. Plasma levels averaging an apparent positive balance of 53 and Postgrad Med J: first published as 10.1136/pgmj.54.635.623 on 1 September 1978. Downloaded from Case reports 625 3200r- 2400k E 1600k wE .50E 800- 0 6 12 18 DC 1200 DC *-CotroOt XI-w- 2400-b rg/24hr -t*mg/24 hr Time (days) FIG. 3. The effect of demeclocycline (DC) on urine output in the syndrome of inappropriate antidiuretic hormone release (SIADH). Protected by copyright. 51 mmol/24 hr respectively. During the last 6 days nine clearance increased to 98 ml/min. Serum sodium of the study there was initially sodium retention so remained above 135 mmol/l for approximately two that the average positive balance was 68 mmol/24 hr: months and then gradually fell over a period of a net increase of 16 mmol/day over the earlier three months to stabilize at about 126 mmol/l with periods. This represents a total gain of 96 mmol a plasma osmolality of 260 mosmol/kg and urine over the 6-day period (tallying well with exchange- osmolality of 570 mosmol/kg. Despite this, he has able sodium). There was no significant change in remained well with no complaints and chest X-ray either serum potassium or external potassium has been repeatedly negative. His migration abroad balance. has precluded further study. Antidiuretic hormone Discussion With the exception of one value of 3-6 pg/ml on the SIADH in this man was related to head injury first day of demeclocycline therapy ADH levels and subsequent meningitis and this seems the likely remained high throughout the study (Fig. 2) with a aetiology (Bartter and Schwartz, 1967). The duration probable slight increase at the end of the study. of the syndrome is rather long, however, and the http://pmj.bmj.com/ possibility of an occult neoplasm must continually be Renal function borne in mind. Fluid restriction proved difficult and During the phase of acute diuresis, renal function another form of treatment was clearly desirable.