1410

reports,3-6 however, including some suggesting increased fertilisation rates4,5 though cleavage and implantation were impaired;’ miscarriage rates were also increased, and eventual birth rates reduced 5,6 though generally lower than ours. We defined fertilisation in terms of cleaving embryos, which may explain some discrepancy between reports of fertilisation and cleavage rates. Our findings strongly emphasise the need to advise infertile couples to stop smoking, especially if they are having complex treatment such as IVF. How quickly the benefit of stopping may be gained has yet to be investigated. D. J. ROWLANDS A. MCDERMOTT M. G. R. HULL

University of Bristol IVF Unit, St Michael’s Hospital, Bristol BS2 8EG, UK

MGR, Eddowes HA, Fahy U, et al. Expectations of assisted conception for infertility. BMJ 1992; 304: 1465. 2. Elenenbogen A, Lipitz S, Mashiach S, Dor J, Levran D, Ben-Rafael Z. The effect of smoking on the outcome of in-vitro fertilisation-embryo transfer. Hum Reprod 1991; 3: 242. 3. Trapp M, Kemeter P, Feichtinger W. Smoking and in-vitro fertilisation. Hum Reprod 1986; 1: 357. 4. Hughes EG, YoungLai EV, Ward SM. Cigarette smoking and outcomes of in-vitro fertilization and embryo transfer: a prospective cohort study. Hum Reprod 1992; 7: 1. Hull

may also contribute to the pathogenesis of this abnormal healing process. SP antagonists may have a role in the treatment of

hypertrophic scars. RAFT Department of Research in Plastic Surgery, Mount Vernon Hospital, Northwood, Middlesex, UK

Department of Anatomy and Developmental Biology, University College, London WC1

Ondansetron and chest

KL, Bree TM, Hennessey JF. The effect of patient smoking habit on the outcome of IVF and GIFT treatment. Aust NZ J Obstet Gynaecol 1990; 30: 340. 6. Pattinson HA, Taylor PJ, Pattinson MH. The effect of cigarette smoking on ovarian function and early pregnancy outcome of in vitro fertilisation. Fertil Steril 1991; 55: 780.

Painful hypertrophic

scarring and neuropeptides

scar

hypertrophy

often

complicates injury

or

surgery to the skin. The lumpy, erythematous scar is confined to the area of injury, unlike true keloid scar which extends beyond the original wound. In practice, this distinction is often blurred and the aetiology is not known in either case.’ Painful itching commonly accompanies hypertrophic scar and is frequently the predominant clinical complaint, contrasting with the insensitivity of mature non-hypertrophic scars. However, the neurological aspects of hypertrophic scar tissue have received little attention, although the scar tissue may hamper regenerating nerves.2 Specimens of painful hypertrophic scar (n = 9), insensitive non-hypertrophic flat scar (5), and control scar (3) were obtained from eight women (aged 23-56) and three men (23-59). The specimens were studied histologically and immunohistochemically for vasoactive intestinal polypeptide, neuropeptide Y, calcitonin gene-related peptide (CGRP), substance P (SP), somatostatin (SOM), met-enkephalin, leu-enkephalin, and dopamine P-hydroxylase (DBH). Normal skin contained all the neuropeptides except for SOM and DBH immunoreactive nerves. In patients with flat nonhypertrophic scar, neuropeptides and DBH-containing nerves were absent. In patients with hypertrophic scars, neuropeptide and DBH-containing nerves were seen at a higher density than in controls. Only immunoreactive nerves penetrated the densely packed collagen matrix, oriented in the direction of fibroblasts. SP and CGRP were found at the base of the epidermis in the hypertrophic scar but not in the non-hypertrophic scar or the

control skin. SP and CGRP

RAHIMA CROWE D. ANGUS MCGROUTHER GEOFFREY BURNSTOCK

1. Rockwell WB, Cohen IK, Erlich HP. Keloids and hypertrophic scars: a comprehensive review. Plast Reconstr Surg 1989; 84: 827-37. 2. Waris T. Reinnervation of free skin autografts m the rat. Scund J Plast Reconstr Surg 1978; 12: 85-93 3. Foreman JC, Jordan CC, Dehme P, Renner H. Structure-activity relanonships for substance P-related peptides that cause wheal and flare reactions in human skin. J Physiol 1983; 335: 449-65. 4. Nilsson J, von Euler AM, Dalsgaard C-J. Stimulation of connective tissue cell growth by substance P and substance K. Nature 1985; 315: 61-63. 5. Linares HA. Proteoglycan-lymphocyte association in the development of hypertrophic scars. Burns 1990; 16: 21-24.

358. 5. Harrison

SIR,--Cutaneous

NICHOLAS PARKHOUSE

are released by nociceptive sensory nerves and mediate neurogenic inflammation.3 The increased density of these neuropeptides in the hypertrophic tissue suggests penetration of the scar by regenerating nociceptive nerves. Prolonged low threshold activity in these nerves may result in hyperaesthesia, spontaneous painful itching, erythema, and other features of inflammation, including perivascular lymphocytic infiltration.4 Furthermore, SP stimulates the proliferation of human skin fibroblasts in vitro and is inhibited by the specific SP agonist, spantide.5 Our results indicate that hypertrophic scars differ from nonhypertrophic scars in the degree to which they are penetrated by nerve fibres, especially nociceptive nerves. Low threshold activity of these nerves may not only be responsible for painful itching but

pain

SIR,-Dr Ballard and colleagues (Oct 31, p 1107) report the development of chest pain in five elderly patients (four of whom had an established history of ischaemic heart disease) receiving ondansetron and chemotherapy for the treatment of advanced cancer. Included in this report are two further patients who experienced other cardiac events. After reviewing these cases we believe that the cases offer no proof that ondansetron is causally related to the events described. A thorough review of Glaxo’s experience with ondansetron in over 14 000 patients in clinical trials and the spontaneously reported adverse events from over 4 million patient-treatments worldwide show no evidence of a causal relation between ondansetron and episodes of chest pain and cardiac abnormalities. Thus these events almost certainly result from the effects of the patient’s cancer, the effects of chemotherapy, or underlying cardiac disease. Ballard and colleagues note that angina is mentioned in the product information for ondansetron in the USA but not in the UK. It is not unusual for the content of the product information to vary from country to country depending on regulatory practice. In this case, in view of there being rare reports of angina, the US Food and Drug Administration, while recognising that there is no evidence of a cause-effect relation, requested that reference to angina be made in the US product information. Because there is no evidence of a causal relation between ondansetron and angina it has not been included in the product information for most other countries, including the UK. Glaxo Research Institute, Research Triangle Park, North Carolina, USA

JAMES B. D. PALMER

International Medical Affairs, Glaxo Group Research, Stockley Park West,

Uxbridge UB11 1BT, UK

YVONNE L. GREENSTREET

Visual loss associated with

bromocriptine

SIR,-We have observed transient visual loss in a patient treated bromocriptine. This otherwise healthy 73-year-old woman

with

presented with a 4 year history of progressive visual loss, which had been diagnosed as glaucoma. Visual field examination revealed a temporal field defect in the right eye and a three quadrant loss in the left, with sparing of the inferior nasal field. Magnetic resonance imaging revealed a large pituitary tumour with suprasellar extension and compression of the optic chiasm. In the face of progressive visual loss, the patient was started on bromocriptine while awaiting results of a complete endocrinological evaluation. Within 2 h after the initial dose of 2-5 mg, the patient noted light-headedness and dizziness, which prompted her to sit. Within minutes, while fully awake and conversant, she had rapid onset of

1411

total visual loss. The patient was placed supine by her spouse, which resulted in a slow return of vision to baseline over the ensuing hours. Bromocriptine was immediately discontinued, and she was admitted for resection of a non-functioning pituitary tumour via the transphenoidal route 2 days later without complication. and release by patients have intolerable side-effects to even small doses, bromocriptine is well:tolerated by most, and has proven effective in almost 15 years of widespread use in the treatment of prolactinomas.The drug also decreases tumour size and improves visual function in patients with prolactin-secreting macroadenomas, in which surgical cure rates are low’ (only 49% of patients with tumours > 1 cm among our first 1000 patients achieved chemical cure [ < 20 ng/ml prolactin postoperatively]). Thus our practice is to place all patients with large or invasive pituitary tumours with endocrinologically documented prolactin secretion on a trial of bromocriptine, with All solid monitoring of clinical status and radiographic tumours should primary prolactin-secreting respond to the medication by reduction in tumour size and by reduction in prolactin. The aim is to produce normal prolactin concentrations, because prolonged hyperprolactinaemia may be associated with osteoporosis.5 The most common side-effects with bromocriptine are nausea and orthostatic hypotension, which often occur at onset of treatment. Thus medication is usually started in small doses.6,7 The most likely cause of our patient’s transient visual loss was postural hypotension with resultant decrease in perfusion pressure to a compromised visual system, which underlines the need for close observation during the initial phase of treatment in such patients.

Bromocriptine

suppresses

prolactin production

stimulation of dopamine receptors. Although

some

appearance.

Department of Neurological Surgery, University of Southern California School of Medicine, Los Angeles, California 90033, USA

WILLIAM T. COULDWELL MARTIN H. WEISS

1. Vance ML, Evans WS, Thomer MO. Bromocriptine Ann Intern Med 1984; 100: 78-91. 2. Landolt AM. Surgical treatment of pituitary prolactinomas: postoperative prolactin and fertility in seventy patients. Fertil Steril 1981, 35: 620-25. 3. Weiss MH, Wycoff RR, Yadley R, Gott P, Feldon S. Bromocriptine treatment of

prolactin-secreting tumours: surgical implications. Neurosurgery 1983; 12: 640-42. Surgical results for pituitary adenomas: results of an international survey. In: Black PMcL, Zervas NT, Ridgeway EC, eds. Secretory tumors of the pituitary gland New York: Raven, 1984. 377-85. Klibanski A, Biller BMK, Rosenthal DI, Schoenfeld DA, Saxe V. Effects of prolactin and estrogen deficiency in amenorrheic bone loss. J Glin Endocrinol Metab 1988; 67:

4. Zervas NT

5

124-30. 6. Parkes D. Bromocriptine. N Engl J Med 1979; 301: 873-78. 7. Vance ML, Thomer MO. Prolactinomas. Endocrinol Metab Clin North Am 1987; 16: 731-51.

Erythropoietin production and pH iK,—ivicLauoiic

acluusis

may

oe unuerenumaLeu m

cuinnouLmg

defective erythropoietin production, mainly in chronic renal failure. We have assayed serum immunoreactive erythropoietin in three consecutive patients with diabetes mellitus who were admitted for correction of severe ketoacidosis. Samples for arterial blood gas analyses and erythropoietin measurements were taken before and on the first day after treatment with sodium bicarbonate, electrolytes, and insulin. Patient 1 was a 34-year-old woman with type I diabetes mellitus and chronic renal failure (pH 7-09, base excess - 22 mmol/l, haemoglobin 8-4 g/dl, creatinine 650 umol/1). Patient 2 was an 80-year-old man with type IIdiabetes mellitus (pH 6’92, base excess - 29 mmol/1, haemoglobin 11-7 g/dl, creatinine 251 jmiol/1). Patient 3 was a 53-year-old man with type II diabetes mellitus (pH 712, base excess - 22 mmol/1, haemoglobin 12-3 g/dl, creatinine 217 lunol/1). Serum erythropoietin increased in all three patients within a day of treatment and the pH became normal (figure). This erythropoietin increase was not attributable to change in haemoglobin concentration or arterial p02. pH concentration affected erythropoietin production despite uraemia in patient 1. Plasma erythropoietin may increase in patients with chronic renal failure during hypoxaemial or after a switch from haemodialysis to chronic ambulatory peritoneal dialysis,2 which indicates that the capacity to produce erythropoietin is not necessarily abolished in uraemia. Laboratory studies in man and animals have shown that to

arterial

pH

Serum erythropoietin in patients 1-3 with diabetes mellitus before and on day after pH correction.

Epo

=

erythropoietin

erythropoietin response to anaemia, hypoxaemia, or cobalt is suppressed in acidosis and enhanced in alkalosis when induced artificially.3 Based on our measurements in patients with diabetes mellitus, we propose that pH changes exert a significant influence on plasma erythropoietin in human disease. the

treatment

Department of Internal Medicine, Medical University of Lubeck, Lubeck, Germany

P. M. ROB

Department of Physiology, University of Bonn, 5300 Bonn 1, Germany

J. FANDREY W. JELKMANN

1. Chandra M, McVicar M, Clemons G, Mossey RT, Wilkes BM. Role of erythropoietin m the reversal of anemia of renal failure with continuous ambulatory peritoneal dialysis. Nephron 1987; 46: 312-15. 2. Chandra M, Clemons GK, McVicar MI. Relation of serum erythropoietin levels to renal excretory function: evidence for lowered set point for erythropoietin production in chronic renal failure. J Pediatr 1988; 113: 1015-21. 3. Jelkmann W. Erythropoietin: structure, control of production, and function. Physiol Rev 1992; 72: 449-89.

Living-related liver transplantation in fulminant hepatic failure SIR,-Fulminant hepatic failure (FHF) is an indication for liver transplantation. However, no guarantee can be given that a donor will be available when required, and death while waiting for a transplant is not uncommon. As outlined by Dr Takas (Nov 7, p 1164) there are obstacles to defining brain death and organ transplantation in Japan. Therefore FHF is treated by plasmapheresis. When a cadaveric donor is not available, livingrelated donor liver transplantation is an alternative. We report a case of FHF thus treated. A 15-year-old boy of 48 kg developed influenza-like symptoms on July 20,1992, and took medicines which had been prescribed for his mother by a family doctor. On Aug 2, he became jaundiced. Serological examination excluded infection with hepatitis A, B, or C viruses, cytomegalovirus, Epstein-Barr virus, adenovirus, and Coxsackie virus. A drug lymphocyte-stimulation test was positive for diclofenac (index 346%). Interferon-Qt, glucagon/insulin infusion, prostaglandin E1, and acetylcysteinel were started but were not effective. On Aug 14, hepatic encephalopathy developed, and plasmapheresis was started (3200 ml, 14 times). However, there was no improvement; the patient’s encephalopathy worsened and considerable liver contraction was observed. On August 21, the patient was referred to Shinshu University for the possibility of a transplant. As there were no contraindicating factors, a transplant from his father was planned. 500 ml of the patient’s fresh-frozen plasma was stored and computed tomography (CT), magnetic resonance imaging, and coeliac arteriography were done. The total volume of the father’s liver according to CT was 1192 cm3, the left lobe