- Email: [email protected]
Timolol, carotid sinus hypersensitivity, and elderly patients
CORRESPONDENCE 3
4
5
Ellis SJ, Severe hyponatraemia: complications and treatment Q J Med 1995; 88: 905–09. Laureno R, Karp BI. Myelinolysis after correction of hyponatraemia. Ann Int Med 1997; 126: 57–62. Pradhan S, Jha R, Singh MN. Central pontine myelinolysis following ‘slow’ correction of hyponatraemia. Clin Neurol Neurosurg 1995; 97: 340–43.
Authors’ reply Sir—We appreciate James Kelly’s comments about our recommendations for the treatment of symptomatic chronic hyponatraemia. In view of the scarcity of studies that strictly compare water restriction versus hypertonic saline in the treatment of such patients, the guidelines we present are somewhat arbitrary. In highly susceptible patients there may not be a limit that is entirely safe. In fact in one study, neurological symptoms occurred even in those whose serum sodium was increased by 1 mmol–1 h-1. It should also be noted that osmotic demyelination can occur in alcoholics (such as the one described by Kelly) even in the absence of changes in serum tonicity. What deserves emphasis is that the presence of central nervous system symptoms indicates cerebral dysfunction, which calls for prompt correction. In a study to be presented at the forthcoming meetings of the American Society of Nephrology in a group of elderly, chronically hyponatraemic patients with symptoms, mortality was very high when water restriction only was used as a therapeutic intervention. Those patients whose serum sodium was more rapidly increased fared better.2 Therefore advocacy of a purely conservative approach seems to also carry risks. Clearly, the ideal approach that balances the risks of osmotic demyelination with those of cerebral oedema in every patient has not been fully defined. We feel that pending further data our recommendations aim at providing this balance. *Tomas Berl, Sumit Kumar Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA 1
2
Sterns RH. Severe symptomatic hyponatremia: treatment and outcome: a study of 64 cases. Ann Intern Med 1987; 107: 656–664. Ayus JC, Arieff AI. Morbidity and mortality from chronic symptomatic hyponatremia in elderly women. JASN (in press).
Sir—Sumit Kumar and Tomas Berl’s review 1 of sodium, apart from widening our knowledge on the
THE LANCET • Vol 352 • October 3, 1998
subject, helped us to re-evaluate one of our patients. A 10-year-old girl was admitted vomiting and with consciousness disturbances. She started vomiting at night about 12 h before she presented. There was no accompanying fever or diarrhoea. After the first episode she went to sleep. A few hours later she vomited several times again. Just before hospitalisation her carers observed tonic spasm of upper limbs and she lost consciousness. There was no eye or verbal contact although her eyes were open. On admission physical examination showed only disturbed consciousness with no other abnormal findings. Laboratory tests showed hyponatraemia (117 mmol/L) and metabolic acidosis. Cerebrospinal fluid was normal. Electroencephalography showed generalised theta and delta waves with frontotemporal region domination. Encephalitis, brain tumour, and epilepsy were taken into account. We regarded hyponatraemia to be secondary to vomiting. We decided to undertake computed tomography (CT) of the head to exclude brain tumour. We initiated therapy for encephalitis (dexamethasone, mannitol, acyclovir). We also treated hyponatraemia with intravenous infusions containing sodium. She improved rapidly. The next day we could communicate with her, serum sodium was 132 mmol/L, and her head CT scan was normal. We returned to the history of her illness. We found that 2 weeks before admission she had undergone an unconventional medical procedure targeted at the removal of an excess of cadmium. After the so-called therapy she was asked to drink an additional 1·5 L daily of boiled tap water. We thought that this intake might be the reason for her troubles. According to Kumar and Berl children are one of the groups of patients especially prone to develop neurological symptoms in the course of very low sodium. We believe that while drinking a huge extra amount of pure water she was slowly decreasing her serum sodium. In this situation hyponatraemia caused cerebral symptoms including vomiting. The child made a very good and quick recovery. Her state improved most rapidly after withdrawal of mannitol from the treatment; this also confirms our opinion. *Wojciech Ostoja-Chrzastowski, Piotr Albrecht Clinic of Child Gastroenterology and Nutrition, Medical University of Warsaw, 01-184 Warsaw, Poland 1
Kumar S, Berl T. Sodium. Lancet 1998; 352: 220–28.
Timolol, carotid sinus hypersensitivity, and elderly patients Sir—F H J Wolfhagen and colleagues’ report (Aug 1, p 373)1 of severe nausea and vomiting with timolol eyedrops prompted us to analyse adverse effects associated with timolol eyedrops in an integrated unit for investigation of falls and syncope. In a district general hospital, three of 153 consecutive patients (ages 85, 89, and 87 years) presenting for investigation of falls and syncope were on timolol eye drops. All three complained of unexplained falls and two had dizziness and blackouts. Cardioinhibitory carotid sinus syndrome (CICSS) was shown in two of the patients and the third had vasodepressor carotid sinus syndrome (VDCSS) during carotid sinus massage. CICSS is diagnosed in syncopal patients when carotid sinus massage produces a period of asystole greater than 3 s.2 VDCSS is defined as a reduction in systolic blood pressure exceeding 50 mm Hg, independent of heart rate during carotid sinus massage.2 There is a spectrum of associated symptoms including nausea, dizziness, falls, and syncope. Of note, resting heart rate and blood pressure may be normal. In our three patients, timolol eyedrops were discontinued and a suitable alternative was begun after discussion with the ophthalmologists. Follow-up carotid sinus massage in the two patients with CICSH off timolol was negative and all reported complete resolution of symptoms. We are unaware of other reports of VDCSS as a side-effect of timolol eye drops. There has been one report of CICSS secondary to timolol.3 Other reported cardiovascular sideeffects of the drops include antrioventricular block, bradycardia, hypotension, and heart failure.4 Respiratory complications of ocular timolol include bronchospasm with reduced FEV1 (forced expiratory volume in 1 s) and reduced exercise tolerance.5 Other side-effects in association with timolol include confusion, lethargy, and depression and all are more commonly reported in the elderly than in young patients. Although Wolfhagen and colleagues suggest that the nausea and vomiting were due to gastrointestinal adverse effects of timolol, they did not include valuable clinical data including electrocardiograph, 24 h heart rate monitoring, and spirometry.
1147
CORRESPONDENCE
Ocular timolol is a non-cardioselective adrenoceptor antagonist of which variable amounts are absorbed by the nasal mucosa, producing unpredictable plasma concentrations. This variation in plasma concentrations is further affected by genetic subtype because oxidation of timolol shows genetic polymorphism of the debrisoquine type. Cardiopulmonary adverse effects of timolol remain the most common, and are usually reversible on its discontinuation. An alternative treatment for glaucoma should be selected in close liaison with ophthalmologists. *Riona Mulcahy, Liesl Allcock, Diarmuid O’Shea, *Care of the Elderly and General Medicine, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK; and North Tyneside General Hospital, Rakelane, North Shields 1
2
3
4
5
Wolfhagen FHJ, Van Neerven JAFM, Groen FC, Ouwendijk RJT. Severe nausea and vomiting with timolol eye drops. Lancet 1998; 352: 373. McIntosh SJ, Lawson J, Kenny RA. Clinical characteristics of vasodepressor, cardioinhibitory, and mixed carotid sinus syndrome in the elderly. Am J Med 1993; 95: 203–08. Kenny RA, Wynne HA, Daly AK, Davies AJ. Cardioinhibitory carotid sinus syncope induced by ocular administration of timolol. Card Eld 1995; 3: 301–02. Backlund M, Kirvela M, Lindgren L. Cardiac failure aggravated by timolol eyedrops: preoperative improvement by changing to pilocarpine. Acta Anaesthesia Scand 1996; 3: 379–81. Diggory P, Cassels-Brown A, Vail A, Abbey LM, Hillman JS. Avoiding unsuspected respiratory side effects of topical timolol cardioselective or sympathomimetic agents. Lancet 1995; 345: 1604–06.
Cortical processing in persistent vegetative state
Force on PVS3 has recommended that the term persistent vegetative state is not used. Rather, the term vegetative state should be used, and to add to this the duration: for instance vegetative state of 4 months’ duration. A patient in a vegetative state becomes permanently vegetative when the criteria of irreversibility are fulfilled. Second, the patient described by Menon et al was not in a vegetative state. This patient was able to recognise faces, for which visual fixation is required. Patients in a vegetative state do not fixate on a visual target. 3 The diagnosis of vegetative state should not be made when there is doubt about the presence of visual fixation.3 Third, this patient was unlikely to be in a vegetative state since this diagnosis is usually made in patients with head trauma or hypoxic ischaemic encephalopathy. The principal findings in these patients is extensive multifocal or diffuse laminar neuronal loss. The white matter disease acute disseminated encephalomyelitis, the diagnosis of the patient described by Menon and colleagues, is not mentioned in a list of the most common disorders that have been reported to cause a vegetative state.3 J F Meilof Department of Neurology H2-222, Academic Medical Centre, 1105 AZ Amsterdam, Netherlands (e-mail: [email protected]) 1
2
3
Menon DK, Owen AM, Williams EJ, et al. Cortical processing in persistent vegetative state. Lancet 1998; 352: 200. Jennett B, Plum F. Persistent vegetative state after brain damage: a syndrome in search of a name. Lancet 1972; i: 734–37. The Multi-Society Task Force on PVS. Medical aspects of the persistent vegetative state. N Engl J Med 1994; 330: 1499–508.
Authors’ reply Sir—D K Menon and colleagues’ report (July 18, p 200) 1 on cortical processing in persistent vegetative state could lead to confusion in the discussions on withholding or withdrawing treatment from patients in permanent vegetative state. For three reasons this report should not be considered in these discussions. First, these discussions deal with patients in the permanent vegetative state, which is different from the persistent vegetative state. Jennett and Plum2 defined persistent as sustained over time and permanent as irreversible. Persistent vegetative state is a diagnosis; permanent vegetative state is a prognosis. 3 To avoid confusion between the terms persistent and permanent the Multi-Society Task
1148
Sir—J F Meilof makes several important points about persistent vegetative state. We agree that it would be unwise to use our data as the basis for making decisions about withholding or withdrawing treatment in such patients, but point out that we did not make such a suggestion. We did state that it was “difficult to make judgments about awareness or consciousness on the basis of these results”. We did, however, imply that the data provided an insight into the level of cortical processing of visual stimuli in persistent vegetative state, and believe that carefully conducted activation studies in such patients will provide important information about its pathophysiology.
Such understanding may improve management. We do not disagree with Meilhof’s definitions of persistent and permanent vegetative state. Our patient was not in a permanent vegetative state, and we made no suggestion that this was the case. Although the Royal College of Physicians working group did suggest that the use of the phrase persistent vegetative state should be replaced by continuing vegetative state for patients who remained in this state after 4 weeks,1 this change in usage is by no means universally accepted. The Multi-Society Task Force on PVS in the USA which Meilhof cites (inappropriately) clearly endorses the use of the term persistent vegetative state: “We define persistent vegetative state as a vegetative state present one month after acute traumatic or nontraumatic or lasting for at least one month in patients with degenerative or metabolic disorders or developmental Further, the malformations”. 2 description of a vegetative state lasting beyond 1 month as persistent is one that remains in common use in publications from both sides of the Atlantic, including a recent review article in The Lancet.3 Contrary to Meilhof’s implication, we did not state that the patient showed sustained fixation on faces. In the original version of our report (as submitted) we specifically stated that “The subject exhibited no consistent behavioural responses that might have suggested awareness of image content during the study”. However, notwithstanding the responses in this particular patient, we would be less dogmatic than Meilhof about the importance of visual fixation in the differential diagnosis of prolonged unresponsiveness, since there seems to be real doubt about this issue.4 We dismiss Meilhof’s suggestion that failure to appear on a list of “the most common disorders that have been reported to cause a vegetative state” should invalidate this diagnosis in patients in whom the primary clinical diagnosis is that of acute disseminated encephalomyelitis. The diagnosis of a vegetative state is an operational one that depends on the residual neurophysiology and neurological deficit in a given patient, and is independent of the aetiology that results in the deficit. Both the citation quoted by Meilhof to support his claim,1 and other reports implicitly or explicitly make the point that “the vegetative state can result from any acute insult or chronic process which severely damages part or all of the
THE LANCET • Vol 352 • October 3, 1998
4
5
Ellis SJ, Severe hyponatraemia: complications and treatment Q J Med 1995; 88: 905–09. Laureno R, Karp BI. Myelinolysis after correction of hyponatraemia. Ann Int Med 1997; 126: 57–62. Pradhan S, Jha R, Singh MN. Central pontine myelinolysis following ‘slow’ correction of hyponatraemia. Clin Neurol Neurosurg 1995; 97: 340–43.
Authors’ reply Sir—We appreciate James Kelly’s comments about our recommendations for the treatment of symptomatic chronic hyponatraemia. In view of the scarcity of studies that strictly compare water restriction versus hypertonic saline in the treatment of such patients, the guidelines we present are somewhat arbitrary. In highly susceptible patients there may not be a limit that is entirely safe. In fact in one study, neurological symptoms occurred even in those whose serum sodium was increased by 1 mmol–1 h-1. It should also be noted that osmotic demyelination can occur in alcoholics (such as the one described by Kelly) even in the absence of changes in serum tonicity. What deserves emphasis is that the presence of central nervous system symptoms indicates cerebral dysfunction, which calls for prompt correction. In a study to be presented at the forthcoming meetings of the American Society of Nephrology in a group of elderly, chronically hyponatraemic patients with symptoms, mortality was very high when water restriction only was used as a therapeutic intervention. Those patients whose serum sodium was more rapidly increased fared better.2 Therefore advocacy of a purely conservative approach seems to also carry risks. Clearly, the ideal approach that balances the risks of osmotic demyelination with those of cerebral oedema in every patient has not been fully defined. We feel that pending further data our recommendations aim at providing this balance. *Tomas Berl, Sumit Kumar Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA 1
2
Sterns RH. Severe symptomatic hyponatremia: treatment and outcome: a study of 64 cases. Ann Intern Med 1987; 107: 656–664. Ayus JC, Arieff AI. Morbidity and mortality from chronic symptomatic hyponatremia in elderly women. JASN (in press).
Sir—Sumit Kumar and Tomas Berl’s review 1 of sodium, apart from widening our knowledge on the
THE LANCET • Vol 352 • October 3, 1998
subject, helped us to re-evaluate one of our patients. A 10-year-old girl was admitted vomiting and with consciousness disturbances. She started vomiting at night about 12 h before she presented. There was no accompanying fever or diarrhoea. After the first episode she went to sleep. A few hours later she vomited several times again. Just before hospitalisation her carers observed tonic spasm of upper limbs and she lost consciousness. There was no eye or verbal contact although her eyes were open. On admission physical examination showed only disturbed consciousness with no other abnormal findings. Laboratory tests showed hyponatraemia (117 mmol/L) and metabolic acidosis. Cerebrospinal fluid was normal. Electroencephalography showed generalised theta and delta waves with frontotemporal region domination. Encephalitis, brain tumour, and epilepsy were taken into account. We regarded hyponatraemia to be secondary to vomiting. We decided to undertake computed tomography (CT) of the head to exclude brain tumour. We initiated therapy for encephalitis (dexamethasone, mannitol, acyclovir). We also treated hyponatraemia with intravenous infusions containing sodium. She improved rapidly. The next day we could communicate with her, serum sodium was 132 mmol/L, and her head CT scan was normal. We returned to the history of her illness. We found that 2 weeks before admission she had undergone an unconventional medical procedure targeted at the removal of an excess of cadmium. After the so-called therapy she was asked to drink an additional 1·5 L daily of boiled tap water. We thought that this intake might be the reason for her troubles. According to Kumar and Berl children are one of the groups of patients especially prone to develop neurological symptoms in the course of very low sodium. We believe that while drinking a huge extra amount of pure water she was slowly decreasing her serum sodium. In this situation hyponatraemia caused cerebral symptoms including vomiting. The child made a very good and quick recovery. Her state improved most rapidly after withdrawal of mannitol from the treatment; this also confirms our opinion. *Wojciech Ostoja-Chrzastowski, Piotr Albrecht Clinic of Child Gastroenterology and Nutrition, Medical University of Warsaw, 01-184 Warsaw, Poland 1
Kumar S, Berl T. Sodium. Lancet 1998; 352: 220–28.
Timolol, carotid sinus hypersensitivity, and elderly patients Sir—F H J Wolfhagen and colleagues’ report (Aug 1, p 373)1 of severe nausea and vomiting with timolol eyedrops prompted us to analyse adverse effects associated with timolol eyedrops in an integrated unit for investigation of falls and syncope. In a district general hospital, three of 153 consecutive patients (ages 85, 89, and 87 years) presenting for investigation of falls and syncope were on timolol eye drops. All three complained of unexplained falls and two had dizziness and blackouts. Cardioinhibitory carotid sinus syndrome (CICSS) was shown in two of the patients and the third had vasodepressor carotid sinus syndrome (VDCSS) during carotid sinus massage. CICSS is diagnosed in syncopal patients when carotid sinus massage produces a period of asystole greater than 3 s.2 VDCSS is defined as a reduction in systolic blood pressure exceeding 50 mm Hg, independent of heart rate during carotid sinus massage.2 There is a spectrum of associated symptoms including nausea, dizziness, falls, and syncope. Of note, resting heart rate and blood pressure may be normal. In our three patients, timolol eyedrops were discontinued and a suitable alternative was begun after discussion with the ophthalmologists. Follow-up carotid sinus massage in the two patients with CICSH off timolol was negative and all reported complete resolution of symptoms. We are unaware of other reports of VDCSS as a side-effect of timolol eye drops. There has been one report of CICSS secondary to timolol.3 Other reported cardiovascular sideeffects of the drops include antrioventricular block, bradycardia, hypotension, and heart failure.4 Respiratory complications of ocular timolol include bronchospasm with reduced FEV1 (forced expiratory volume in 1 s) and reduced exercise tolerance.5 Other side-effects in association with timolol include confusion, lethargy, and depression and all are more commonly reported in the elderly than in young patients. Although Wolfhagen and colleagues suggest that the nausea and vomiting were due to gastrointestinal adverse effects of timolol, they did not include valuable clinical data including electrocardiograph, 24 h heart rate monitoring, and spirometry.
1147
CORRESPONDENCE
Ocular timolol is a non-cardioselective adrenoceptor antagonist of which variable amounts are absorbed by the nasal mucosa, producing unpredictable plasma concentrations. This variation in plasma concentrations is further affected by genetic subtype because oxidation of timolol shows genetic polymorphism of the debrisoquine type. Cardiopulmonary adverse effects of timolol remain the most common, and are usually reversible on its discontinuation. An alternative treatment for glaucoma should be selected in close liaison with ophthalmologists. *Riona Mulcahy, Liesl Allcock, Diarmuid O’Shea, *Care of the Elderly and General Medicine, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK; and North Tyneside General Hospital, Rakelane, North Shields 1
2
3
4
5
Wolfhagen FHJ, Van Neerven JAFM, Groen FC, Ouwendijk RJT. Severe nausea and vomiting with timolol eye drops. Lancet 1998; 352: 373. McIntosh SJ, Lawson J, Kenny RA. Clinical characteristics of vasodepressor, cardioinhibitory, and mixed carotid sinus syndrome in the elderly. Am J Med 1993; 95: 203–08. Kenny RA, Wynne HA, Daly AK, Davies AJ. Cardioinhibitory carotid sinus syncope induced by ocular administration of timolol. Card Eld 1995; 3: 301–02. Backlund M, Kirvela M, Lindgren L. Cardiac failure aggravated by timolol eyedrops: preoperative improvement by changing to pilocarpine. Acta Anaesthesia Scand 1996; 3: 379–81. Diggory P, Cassels-Brown A, Vail A, Abbey LM, Hillman JS. Avoiding unsuspected respiratory side effects of topical timolol cardioselective or sympathomimetic agents. Lancet 1995; 345: 1604–06.
Cortical processing in persistent vegetative state
Force on PVS3 has recommended that the term persistent vegetative state is not used. Rather, the term vegetative state should be used, and to add to this the duration: for instance vegetative state of 4 months’ duration. A patient in a vegetative state becomes permanently vegetative when the criteria of irreversibility are fulfilled. Second, the patient described by Menon et al was not in a vegetative state. This patient was able to recognise faces, for which visual fixation is required. Patients in a vegetative state do not fixate on a visual target. 3 The diagnosis of vegetative state should not be made when there is doubt about the presence of visual fixation.3 Third, this patient was unlikely to be in a vegetative state since this diagnosis is usually made in patients with head trauma or hypoxic ischaemic encephalopathy. The principal findings in these patients is extensive multifocal or diffuse laminar neuronal loss. The white matter disease acute disseminated encephalomyelitis, the diagnosis of the patient described by Menon and colleagues, is not mentioned in a list of the most common disorders that have been reported to cause a vegetative state.3 J F Meilof Department of Neurology H2-222, Academic Medical Centre, 1105 AZ Amsterdam, Netherlands (e-mail: [email protected]) 1
2
3
Menon DK, Owen AM, Williams EJ, et al. Cortical processing in persistent vegetative state. Lancet 1998; 352: 200. Jennett B, Plum F. Persistent vegetative state after brain damage: a syndrome in search of a name. Lancet 1972; i: 734–37. The Multi-Society Task Force on PVS. Medical aspects of the persistent vegetative state. N Engl J Med 1994; 330: 1499–508.
Authors’ reply Sir—D K Menon and colleagues’ report (July 18, p 200) 1 on cortical processing in persistent vegetative state could lead to confusion in the discussions on withholding or withdrawing treatment from patients in permanent vegetative state. For three reasons this report should not be considered in these discussions. First, these discussions deal with patients in the permanent vegetative state, which is different from the persistent vegetative state. Jennett and Plum2 defined persistent as sustained over time and permanent as irreversible. Persistent vegetative state is a diagnosis; permanent vegetative state is a prognosis. 3 To avoid confusion between the terms persistent and permanent the Multi-Society Task
1148
Sir—J F Meilof makes several important points about persistent vegetative state. We agree that it would be unwise to use our data as the basis for making decisions about withholding or withdrawing treatment in such patients, but point out that we did not make such a suggestion. We did state that it was “difficult to make judgments about awareness or consciousness on the basis of these results”. We did, however, imply that the data provided an insight into the level of cortical processing of visual stimuli in persistent vegetative state, and believe that carefully conducted activation studies in such patients will provide important information about its pathophysiology.
Such understanding may improve management. We do not disagree with Meilhof’s definitions of persistent and permanent vegetative state. Our patient was not in a permanent vegetative state, and we made no suggestion that this was the case. Although the Royal College of Physicians working group did suggest that the use of the phrase persistent vegetative state should be replaced by continuing vegetative state for patients who remained in this state after 4 weeks,1 this change in usage is by no means universally accepted. The Multi-Society Task Force on PVS in the USA which Meilhof cites (inappropriately) clearly endorses the use of the term persistent vegetative state: “We define persistent vegetative state as a vegetative state present one month after acute traumatic or nontraumatic or lasting for at least one month in patients with degenerative or metabolic disorders or developmental Further, the malformations”. 2 description of a vegetative state lasting beyond 1 month as persistent is one that remains in common use in publications from both sides of the Atlantic, including a recent review article in The Lancet.3 Contrary to Meilhof’s implication, we did not state that the patient showed sustained fixation on faces. In the original version of our report (as submitted) we specifically stated that “The subject exhibited no consistent behavioural responses that might have suggested awareness of image content during the study”. However, notwithstanding the responses in this particular patient, we would be less dogmatic than Meilhof about the importance of visual fixation in the differential diagnosis of prolonged unresponsiveness, since there seems to be real doubt about this issue.4 We dismiss Meilhof’s suggestion that failure to appear on a list of “the most common disorders that have been reported to cause a vegetative state” should invalidate this diagnosis in patients in whom the primary clinical diagnosis is that of acute disseminated encephalomyelitis. The diagnosis of a vegetative state is an operational one that depends on the residual neurophysiology and neurological deficit in a given patient, and is independent of the aetiology that results in the deficit. Both the citation quoted by Meilhof to support his claim,1 and other reports implicitly or explicitly make the point that “the vegetative state can result from any acute insult or chronic process which severely damages part or all of the
THE LANCET • Vol 352 • October 3, 1998