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TRANSIENT AMAUROSIS IN PATIENT WITH PITUITARY MACROADENOMA AFTER INTRAVENOUS GONADOTROPIN AND THYROTROPIN RELEASING HORMONES
95 TRANSIENT AMAUROSIS IN PATIENT WITH PITUITARY MACROADENOMA AFTER INTRAVENOUS GONADOTROPIN AND THYROTROPIN RELEASING HORMONES
SIR,-No serious side-effects have been described after rapid intravenous bolus injections of synthetic gonadotropin (GnRH) and thyrotropin (TRH) releasing hormones. However, the following case-history suggests that transient amaurosis is a
possible, although infrequent, complication. A 48-year-old man was admitted in March, 1980 with a 5 month history of loss of libido, impotence, and decreasing vision. Plain X-ray of the skull revealed a gross sellar enlargement (type III2). The visual acuity was 10/10 in the right eye and 6/10 in the left; visual fields revealed a temporal defect in the left eye. On fundus examination the left disk appeared pale. Serum prolactin, cortisol at 0800 and at 1200 hours, growth hormone, luteinising and follicle stimulating hormones, and thyroxine were normal. The pituitary reserve of thyrotropin, gonadotropins, and prolactin was evaluated using as a stimulus the simultaneous intravenous administration of 100 pg of synthetic GnRH (’Relisorm’; Serono) dissolved in 2 ml of saline and 200 g of synthetic TRH (’Relefact’; Hoechst) dissolved in 1 ml of saline. After overnight fast a forearm venous cannula was inserted at 0900 hours and used for rapid injection of GnRH and TRH at time 0 and for blood sampling at -15,0,10,20,30,45,60, and 120 min. The cannula was kept patent with a slow saline infusion. 20 min after GnRH and TRH injection the patient suddenly complained of a shooting frontal headache and of a decrease of visual acuity, which rapidly progressed to a complete amaurosis in both eyes. Amaurosis and headache lasted 2 h, then quickly subsided. On examination, the fundus in both eyes appeared unchanged. In the afternoon of the same day we did left carotid angiography and a cisternography which showed a pituitary macroadenoma with suprasellar extension. Computerised tomography showed a uniform density of the tumour mass. The patient was operated on via the frontal route and a pituitary macroadenoma compressing the optic nerves and chiasma was removed; the tissue was uniformly soft without sign of recent haemorrhage or necrosis. After surgery, visual field and visual acuity in the left eye improved. One year later, the pituitary function was reassessed and GnRH-TRH test was
repeated but no adverse reaction was observed. A. CIMINO R. CORSINI E. RADAELI A. BOLLATI G. GIUSTINA
Department of Internal Medicine, University of Milan, Brescia; and Division
of Neurosurgery,
Spedali Civili,
Brescia, Italy
N-ACETYLCYSTEINE PROTECTION AGAINST HALOTHANE HEPATOTOXICITY: EXPERIMENTS IN RATS
SIR,-The potential hepatotoxic effect of halothane is
a real incidence of anicteric "hepatitis" estimated to be as high as 1 in 7000-10 000. Reproducible models of halothane induced liver damage have been developed in rodents,4-6 and the toxicity has been attributed to a reactive reductive metabolite of halothane.5 This metabolite is normally dealt with by
clinical
problem
with
an
1 Hall
R, Besser GM. Thyrotrophin-releasing hormone diagnostic and therapeutic applications. In Motta M, et al, eds. Hypothalamic hormones. London Academic Press, 1975, 299-302. 2. Vezina JL, Maltais R La selle turcique dans l’acromégalie: Etude radiologique. Neurochirurgie 1973; 19 (suppl 2). 35-56. 3 Dundee JW Problems of multiple inhalation anaesthetics BrJ Anaesth 1981, 53: 4
5 6
7
63S-67S Sipes IG, Brown BR An animal model of hepatotoxicity associated with halothane anesthesia Anesthesiology 1976; 45: 622-28. McLain GE, Sipes IG, Brown BR. An animal model of halothane hepatoxicity: Roles of enzyme induction and hypoxia. Anesthesiology 1979; 51: 321-26. Wood M, Berman ML, Harbison RD, Hoyle P, Phythyon JM, Wood AJJ. Halothane induced hepatic necrosis in tri iodothyronine-pretreated rats. Anesthesiology 1980; 52: 470-76 Cousins MJ, Gourlay GK, Sharp JH, Adams JF, Hall P, O’Brien P, Haynes WD. Halothane hepatitis. Lancer 1978; ii: 1197
conjugation with glutathione, a scavenger of electrophilic compounds, and is excreted in the urine as the acetylcysteine derivative (mercapturate).7 This mode of detoxification is similar to the handling of paracetamol (acetaminophen), the toxicity of which can be prevented by the administration of the sulphydryl compound N-acetylcysteine (NAC), in animalsand in man.9 We have found a protective effect of pretreatment with NAC on halothane induced liver damage, using the thyrotoxic rat model of Wood et al.6 Male Sprague-Dawley rats (75-150 g) were treated for 6 days with triiodothyronine (T3) in 5% ’Tween 80’ in water 10 mg/kg orally. Their weight gain was 7±2 (SEM) g compared with 26±1g (n=8) for control animals given 5% tween 80 in water (p<0 0I).On the seventh day the animals were placed in a ’Plexiglass’ chamber and exposed to halothane 1% in air at a flow rate of 101/min. Half of the thyrotoxic rats (n= 18) were given NAC (’Parvolex’; Duncan Flockhart) orally in a dose of 600 mg/kg 30 min before and immediately before receiving halothane.
geometric mean (horizontal bar) values of AST activity in serum from control and NAC pretreated T3 thyrotoxic rats immediately after 2 h exposure to 1% halothane.
Individual and
After 2 h exposure
to
halothane the
rats
were
killed.
Hepatotoxicity was assessed by serum aspartate aminotransferase (AST) activities (Boehringer Mannheim). The ranges of values were: euthyroid 44-87 U/l; thyrotoxic, NAC treated 641-684 VII (n= 18); and thyrotoxic NAC untreated 687-820 U/1. The difference between NAC pretreated and control thyrotoxic rats was significant (p<0 01); Mann-Whitney U test. The relevance of the thyrotoxic rodent model to halothane. hepatotoxicity in man is uncertain. The prime factor in rendering thyrotoxic rats susceptible to halothane hepatotoxicity appears to be the depletion of hepatic glutathione levels,whereas obesity and recent exposure to halothane seem relevant in man.’ Despite these 3 uncertainties this investigation supports the suggestion by Dundee that administration of aminoacids to man might be of value in the prophylaxis of halo than "hepatitis". Dr L. J. Fish, of Duncan Flockhart and Co. Ltd., financial assistance.
Department of Pharmacology, Materia Medica and Therapeutics, University of Manchester, Manchester M 13 9PT
8. 9.
kindly supplied NAC and
NIALL P. KEANEY GILLIAN COCKING
Piperno E, Berssenbruegge DA. Reversal of experimental paracetamol toxicosis with N-acetylcysteine. Lancet 1976; ii: 738-39 Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT. Treatment of paracetamol (acetaminophen) poisoning with N-acetyl-cysteine. Lancet 1977; ii: 432-35.
study of liver enzyme and other changes following repeat administration of halothane and enflurane. Br J Anaesth 1979; 51: 1113-17.
10 Fee JPH, and others. A prospective
SIR,-No serious side-effects have been described after rapid intravenous bolus injections of synthetic gonadotropin (GnRH) and thyrotropin (TRH) releasing hormones. However, the following case-history suggests that transient amaurosis is a
possible, although infrequent, complication. A 48-year-old man was admitted in March, 1980 with a 5 month history of loss of libido, impotence, and decreasing vision. Plain X-ray of the skull revealed a gross sellar enlargement (type III2). The visual acuity was 10/10 in the right eye and 6/10 in the left; visual fields revealed a temporal defect in the left eye. On fundus examination the left disk appeared pale. Serum prolactin, cortisol at 0800 and at 1200 hours, growth hormone, luteinising and follicle stimulating hormones, and thyroxine were normal. The pituitary reserve of thyrotropin, gonadotropins, and prolactin was evaluated using as a stimulus the simultaneous intravenous administration of 100 pg of synthetic GnRH (’Relisorm’; Serono) dissolved in 2 ml of saline and 200 g of synthetic TRH (’Relefact’; Hoechst) dissolved in 1 ml of saline. After overnight fast a forearm venous cannula was inserted at 0900 hours and used for rapid injection of GnRH and TRH at time 0 and for blood sampling at -15,0,10,20,30,45,60, and 120 min. The cannula was kept patent with a slow saline infusion. 20 min after GnRH and TRH injection the patient suddenly complained of a shooting frontal headache and of a decrease of visual acuity, which rapidly progressed to a complete amaurosis in both eyes. Amaurosis and headache lasted 2 h, then quickly subsided. On examination, the fundus in both eyes appeared unchanged. In the afternoon of the same day we did left carotid angiography and a cisternography which showed a pituitary macroadenoma with suprasellar extension. Computerised tomography showed a uniform density of the tumour mass. The patient was operated on via the frontal route and a pituitary macroadenoma compressing the optic nerves and chiasma was removed; the tissue was uniformly soft without sign of recent haemorrhage or necrosis. After surgery, visual field and visual acuity in the left eye improved. One year later, the pituitary function was reassessed and GnRH-TRH test was
repeated but no adverse reaction was observed. A. CIMINO R. CORSINI E. RADAELI A. BOLLATI G. GIUSTINA
Department of Internal Medicine, University of Milan, Brescia; and Division
of Neurosurgery,
Spedali Civili,
Brescia, Italy
N-ACETYLCYSTEINE PROTECTION AGAINST HALOTHANE HEPATOTOXICITY: EXPERIMENTS IN RATS
SIR,-The potential hepatotoxic effect of halothane is
a real incidence of anicteric "hepatitis" estimated to be as high as 1 in 7000-10 000. Reproducible models of halothane induced liver damage have been developed in rodents,4-6 and the toxicity has been attributed to a reactive reductive metabolite of halothane.5 This metabolite is normally dealt with by
clinical
problem
with
an
1 Hall
R, Besser GM. Thyrotrophin-releasing hormone diagnostic and therapeutic applications. In Motta M, et al, eds. Hypothalamic hormones. London Academic Press, 1975, 299-302. 2. Vezina JL, Maltais R La selle turcique dans l’acromégalie: Etude radiologique. Neurochirurgie 1973; 19 (suppl 2). 35-56. 3 Dundee JW Problems of multiple inhalation anaesthetics BrJ Anaesth 1981, 53: 4
5 6
7
63S-67S Sipes IG, Brown BR An animal model of hepatotoxicity associated with halothane anesthesia Anesthesiology 1976; 45: 622-28. McLain GE, Sipes IG, Brown BR. An animal model of halothane hepatoxicity: Roles of enzyme induction and hypoxia. Anesthesiology 1979; 51: 321-26. Wood M, Berman ML, Harbison RD, Hoyle P, Phythyon JM, Wood AJJ. Halothane induced hepatic necrosis in tri iodothyronine-pretreated rats. Anesthesiology 1980; 52: 470-76 Cousins MJ, Gourlay GK, Sharp JH, Adams JF, Hall P, O’Brien P, Haynes WD. Halothane hepatitis. Lancer 1978; ii: 1197
conjugation with glutathione, a scavenger of electrophilic compounds, and is excreted in the urine as the acetylcysteine derivative (mercapturate).7 This mode of detoxification is similar to the handling of paracetamol (acetaminophen), the toxicity of which can be prevented by the administration of the sulphydryl compound N-acetylcysteine (NAC), in animalsand in man.9 We have found a protective effect of pretreatment with NAC on halothane induced liver damage, using the thyrotoxic rat model of Wood et al.6 Male Sprague-Dawley rats (75-150 g) were treated for 6 days with triiodothyronine (T3) in 5% ’Tween 80’ in water 10 mg/kg orally. Their weight gain was 7±2 (SEM) g compared with 26±1g (n=8) for control animals given 5% tween 80 in water (p<0 0I).On the seventh day the animals were placed in a ’Plexiglass’ chamber and exposed to halothane 1% in air at a flow rate of 101/min. Half of the thyrotoxic rats (n= 18) were given NAC (’Parvolex’; Duncan Flockhart) orally in a dose of 600 mg/kg 30 min before and immediately before receiving halothane.
geometric mean (horizontal bar) values of AST activity in serum from control and NAC pretreated T3 thyrotoxic rats immediately after 2 h exposure to 1% halothane.
Individual and
After 2 h exposure
to
halothane the
rats
were
killed.
Hepatotoxicity was assessed by serum aspartate aminotransferase (AST) activities (Boehringer Mannheim). The ranges of values were: euthyroid 44-87 U/l; thyrotoxic, NAC treated 641-684 VII (n= 18); and thyrotoxic NAC untreated 687-820 U/1. The difference between NAC pretreated and control thyrotoxic rats was significant (p<0 01); Mann-Whitney U test. The relevance of the thyrotoxic rodent model to halothane. hepatotoxicity in man is uncertain. The prime factor in rendering thyrotoxic rats susceptible to halothane hepatotoxicity appears to be the depletion of hepatic glutathione levels,whereas obesity and recent exposure to halothane seem relevant in man.’ Despite these 3 uncertainties this investigation supports the suggestion by Dundee that administration of aminoacids to man might be of value in the prophylaxis of halo than "hepatitis". Dr L. J. Fish, of Duncan Flockhart and Co. Ltd., financial assistance.
Department of Pharmacology, Materia Medica and Therapeutics, University of Manchester, Manchester M 13 9PT
8. 9.
kindly supplied NAC and
NIALL P. KEANEY GILLIAN COCKING
Piperno E, Berssenbruegge DA. Reversal of experimental paracetamol toxicosis with N-acetylcysteine. Lancet 1976; ii: 738-39 Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT. Treatment of paracetamol (acetaminophen) poisoning with N-acetyl-cysteine. Lancet 1977; ii: 432-35.
study of liver enzyme and other changes following repeat administration of halothane and enflurane. Br J Anaesth 1979; 51: 1113-17.
10 Fee JPH, and others. A prospective