221
Thus, drugs with
long plasma half-life may cause extended hypotension with its attendant risk of acute neurological deterioration.3,4 To some extent this risk can be countered by use of intravenous sodium nitroprusside, a vasodilator with a short plasma half-life, and many clinicians use this agent when severe hypertension requires immediate control. It is particularly attractive in patients with concomitant pulmonary oedema. Over-zealous reduction of pressure can be quickly corrected by reducing the rate of delivery. Lately a
conventional oral medications have been tried sublingually in these circumstances-notably, nifedipine. Given sublingually, 10 mg nifedipine begins to act within three minutes, achieves the maximum fall within one hour, and is well tolerated,5 although a few patients experience vasodilator sideeffects such as headache, dizziness, flushing, and transient palpitations.6Early reports of profound hypotension in some patients could be ascribed, in part at least, to premature additional doses of oral some
nifedipine.7 Sublingual captopril, 25 mg, has also been reported to be effective in hypertensive emergencies, producing a pressure fall within 5 min and a useful hypotensive action for hours.8,9 Side-effects seem to be remarkably few.5,9 Obviously the big attraction of sublingual administration is that rapid reduction of blood pressure can be achieved without need for intravenous access. Angeli and co-workers5 have now compared captopril and nifedipine in hypertensive emergencies. In their randomised single-blind trial, 9 of 10 patients receiving sublingual captopril responded well, with a mean maximum fall of 55/29 mm Hg at 50 min, and the hypotensive effects lasted an average of four hours. In 6 of the 9 patients there were clear improvements in target organ damage within one hour. Dangerous
observed. Nifedipine was given hypotension to a further 10 patients, of whom 8 responded, the mean maximum fall at 50 min being 42/35 mm Hg. Again no severe hypotensive episodes were recorded and only 1 patient complained of headache and 2 of brief flushing. Whilst the onset of the hypotensive effects of nifedipine was more rapid than that of captopril (10 versus 20 min for diastolic pressure and 20 versus 30 min for systolic pressure), there were no statistically significant differences in the efficacy of the was not
drugs. Agents such as hydralazine, methyldopa, and reserpine have a poor record in hypertensive emergencies because of their unpredictable onset and duration of action; diazoxide has more consistent effects but severe hypotension is a recognised dangerous side-effect.10 Clearly, the immediate goal of two
treatment should be
a reduction in pressure that and continues gradually. Complete normalisation of pressure can be attempted later. Intravenous agents have not lost their place entirely: during or after surgery, or in hypertensive crisis plus myocardial infarction, or in the unconscious patient,
begins quickly
sodium nitroprusside is a valuable agent that allows sensitive titration against continuously monitored pressure. Other agents can be also used in this fashion: some physicians favour labetalol, and intravenous calcium channel blockers are also available. However, for many patients with severe hypertension sublingual drugs are now alternatives. Nifedipine and captopril are equally effective. With nifedipine the vasodilator side-effects are a minor drawback;5,6 with captopril there is the slight concern that a patient may have severe renal failure, bilateral renal artery stenoses, or stenosis in a single functioning kidneycircumstances in which such a drug is dangerous. In case of doubt, nifedipine will be the safer option. 1. Editorial. Severe symptomless hypertension. Lancet 1989; i: 1369-70. 2. Strandgaard S, Olesen J, Skinhof E, Lassen NA. Autoregulation of brain circulation in severe arterial circulation. Br Med J 1973; i: 507-10. 3. Graham DI. Ischaemic brain damage of cerebral perfusion type after treatment of severe hypertension. Br Med J 1975; iv: 739. 4. Ledingham JGG, Rajagopalan B. Cerebral complications in the treatment of accelerated hypertension. Q J Med 1979; 48: 25-41. 5. Angeli P, Chieza M, Caregaro L, et al. Comparison of sublingual catopril and nifedipine in immediate treatment of hypertensive emergencies. Arch Intern Med 1991; 151: 678-82. 6. Opie LH, Jennings A. Sublingual captopril versus nifedipine in hypertensive cases. Lancet 1985; ii: 555. 7. Wachter RM. Symptomatic hypotension induced by nifedipine in the acute treatment of severe hypertension. Arch Intern Med 1987; 147: 556-558. 8. Tschollar W, Belz GG. Sublingual captopril in hypertensive crisis. Lancet 1985; ii: 34-35. 9. Hauger-Klevene JH. Captopril in hypertensive crisis. Lancet 1985; ii: 732-33. 10. Weber MA. Immediate treatment of severe hypertension. Arch Intern Med 1989; 149: 2535-36.
Ozone: too much in the wrong
place In Britain, introduction of the Clean Air Act in 1956 after the disastrous London fog of December, 1952,1 led to a considerable reduction in concentrations of smoke and sulphur dioxide and a consequent improvement in the nation’s health.2However, the increased number and use of motor vehicles has
produced a new problem-photochemical pollution. Oxides of nitrogen (NOx) react in the presence of volatile organic compounds, in sunlight, to produce
(03), In temperate climates the risk of enhanced atmospheric levels of 03 is weather-dependent and ozone
largely limited to the summer months when anticyclonic conditions are ideal for photochemical reactions to proceed. In the UK, 03 and other pollutant gases are monitored at air sampling stations and the information is coordinated by the Department of Trade and Industry’s Warren Spring Laboratory. During the summer months ozone rarely exceeds 150 parts per billion (ppb), although in 1976 an hourly level of 258 ppb was recorded. Since 1987 the highest hourly average ozone concentration measured in the UK was 161 ppb at Lullington Heath on August 4, 1990. The duration of most periods with consecutive hours above ppb is 1-5 hours. Other characteristics
222
striking diurnal variation, peak levels occurring at approximately 1600 h, a pronounced decreasing gradient south to north and, perhaps unexpectedly, the highest concentration being some 30-50 miles are
from urban conurbations. Because nitric oxide reacts with ozone, 03 levels are lowest in busy streets in an atmosphere rich in primary pollutants. Most studies on the health effects of 03 have been conducted in chambers under controlled conditions, usually with healthy adults in an ambient ozone concentration of > 120 ppb5,6 and often with repeated moderate to severe exercise. Under such conditions dose-related changes in indices of lung function include a fall in the forced expiratory volume in 1 second (FEV1) and vital capacity, an increase in specific airways resistance, a rise in the respiratory frequency, and a fall in tidal volume.6Other changes include an increase in pulmonary permeability’ and a small increase (of the order of one doubling dose) in bronchial responsiveness to agents such as inhaled histamine.8There do not seem to be any categories of disease causing increased sensitivity to this pollutant gas, although patients with asthma and other forms of compromised airway function may find the effects especially troublesome. Athletic performance may also be affected at a competitive level.9 Several studies conducted in children attending summer camps in North America have confirmed a negative association between ambient 03 concentrations and measured lung function, giving a regression coefficient for FEV1 on 03 concentration of 0-4-0-8 ml/ppb.10,11 The mechanisms of ozone-induced impairment of lung function are only partly understood. About 40 % of 03 delivered to the human respiratory tract is taken up by the upper airways. Studies in rodents have shown that the epithelia of the terminal bronchioles and proximal alveolar ducts are the main sites of damage.12 The 03 molecule contains two unpaired electrons and can oxidise target molecules directly or generate free radicals with a capacity to abstract hydrogen from polyunsaturated fatty acids in cell membranes and surfactant to form lipid peroxides.l3 03 also attacks the sulphydryl group of glutathione and readily reacts with reducing compounds such as NADH and NADPH. The net result is damage to the respiratory epithelium with production of potent mediators of inflammation and the accumulation and activation of neutrophils that amplify the inflammatory response.14 The effects of a single exposure to 03 are reversible and last up to 48 h. Repeated exposure leads to adaptation. 15 In this issue (p 199), Molfino and colleagues report that exposure to an ozone concentration of 120 ppb for 60 minutes produced no detectable effects on baseline lung function, but increased airway responsiveness to inhaled allergen in atopic patients with asthma by 1 -5 doubling-dose dilutions. At far higher 03 concentrations exposure of guineapigs (500 ppb) and dogs (3000 ppb) has been shown to increase allergen responsiveness of the airways by a mechanism
thought to involve increased access of allergen to subepithelial mediator secreting cells.16,17 Other animal work has indicated that 03 exposure may also increase IgE sensitisation of the lower respiratory tract. In patients with allergic rhinitis, a 4 h exposure to 500 ppb 03produced a 20-fold increase in eosinophils and a 7-fold increase in neutrophils recovered by lavage,18 while a 2 h exposure of the lower airways to 400 ppb increased lavage levels of histamine, prostanoids, albumin, and neutrophils. 14 However, the effects of lower ambient concentrations of 03on these indices of airway inflammation are not known. Since high concentrations of atmospheric ozone often coincide with peak levels of aeroallergens, the observations of Molfino and colleagues are clearly
important. Awareness of detectable effects of this pollutant at a low atmospheric concentration should encourage more research not only on the basic mechanisms of 03-induced lung injury but also on interactions with other environmental pollutants.
1. 2.
Ministry of Health. Mortality and morbidity during the London fog of December 1952. London: HM Stationery Office, 1954. Reid DD. The beginnings of bronchitis. Proc R Soc Med 1969; 62:
311-16. 3. Bower JS,
et
al. Ozone in the UK:
a
review of
1989/1990
data from
monitoring sites by Warren Spring Laboratory. Report No. LR 793. Stevenage: Warren Spring Laboratory, 1990. 4. Department of Health Advisory Group on the Medical Aspects of Air Pollution Episodes. Ozone. London: HM Stationery Office (in press). 5. Hazucha MJ. Relationship between ozone exposure and pulmonary function changes. J Appl Physiol 1987; 62: 1671-80. 6. Horstman DH, Folinsbee LJ, Ives PJ, Abdul-Salaam S, McDonnell WF. Ozone concentration and pulmonary response relationships for 6·6 hour exposures with 5 hours of moderate exercise to 0·08,0·10, and 0·12 ppm. Am Rev Respir Dis 1990; 142: 1158-63. 7. Kerl HR, Vincent LM, Kowalsky RJ, et al. Ozone exposure increases respiratory epithelial permeability in humans. Am Rev Respir Dis 1987; 135: 1124-28. 8. Holtzmann MJ, Cunningham JH, Sheller JR, Irsigler GB, Vadel JA, Bushey H. Effect of ozone on bronchial reactivity in atopic and non-atopic subjects. Am Rev Respir Dis 1979; 120: 1059-67. 9. Schelegle ES, Adams WC. Reduced exercise time in competitive simulations consequent to low level ozone exposure. Med J Sports Exerc 1986; 18: 408. 10. Spektor DM, Lipmann M, Lioy PJ, et al. Effects of ambient ozone on respiratory function in active, normal children. Am Rev Respir Dis 1988; 137: 313-20. 11. Higgins ITT, D’Arcy JB, Gibbons DI, Avol EL, Gross KB Effect of exposures to ambient ozone on ventilatory lung function in children. Am Rev Resp Dis 1990; 141: 1136-46. 12. Barry BE, Mercer RR, Miller FJ, Crapo JD. Effect of inhalation of 0·25 ppm ozone on the terminal bronchioles of juvenile and adult rats. Exp Lung Resp 1988; 14: 225-45. 13. Mustafa MG. Biochemical basis of ozone toxicity. Free Rad Biol Med 1990; 9: 2455 14. Devlin RB, McDonnell WF, Mann R, et al. Exposure of humans to ambient levels of ozone for 6·6 hours causes cellular and biochemical changes in the lung. Am J Respir Cell Mol Biol 1991; 4: 72-81. 15. Howarth JM, Gliner JA, Folinsbee LJ. Adaptation to ozone, duration of effect. Am Rev Respir Dis 1981; 123: 496-99. 16. Matsumura Y. The effects of ozone, nitrogen dioxide and sulphur dioxide on the experimentally induced respiratory disorder in guinea pigs. 1. The effect of sensitisation with albumen through the airway. Am Rev Respir Dis 1970; 102: 438-43. 17. Yanai M, Ohrai T, Aikawa T, et al. Ozone increases susceptibility to antigen inhalation in allergic dogs. J Appl Physiol 1990; 68: 2267-73. 18. Bascom R, Naclerio RM, Fitzgerald TK, Kagey-Sobotka A, Proud D. Effect of ozone inhalation on the response to nasal challenge with antigen in allergic subjects. Am Rev Respir Dis 1990; 142: 594-601.
Thus, drugs with
long plasma half-life may cause extended hypotension with its attendant risk of acute neurological deterioration.3,4 To some extent this risk can be countered by use of intravenous sodium nitroprusside, a vasodilator with a short plasma half-life, and many clinicians use this agent when severe hypertension requires immediate control. It is particularly attractive in patients with concomitant pulmonary oedema. Over-zealous reduction of pressure can be quickly corrected by reducing the rate of delivery. Lately a
conventional oral medications have been tried sublingually in these circumstances-notably, nifedipine. Given sublingually, 10 mg nifedipine begins to act within three minutes, achieves the maximum fall within one hour, and is well tolerated,5 although a few patients experience vasodilator sideeffects such as headache, dizziness, flushing, and transient palpitations.6Early reports of profound hypotension in some patients could be ascribed, in part at least, to premature additional doses of oral some
nifedipine.7 Sublingual captopril, 25 mg, has also been reported to be effective in hypertensive emergencies, producing a pressure fall within 5 min and a useful hypotensive action for hours.8,9 Side-effects seem to be remarkably few.5,9 Obviously the big attraction of sublingual administration is that rapid reduction of blood pressure can be achieved without need for intravenous access. Angeli and co-workers5 have now compared captopril and nifedipine in hypertensive emergencies. In their randomised single-blind trial, 9 of 10 patients receiving sublingual captopril responded well, with a mean maximum fall of 55/29 mm Hg at 50 min, and the hypotensive effects lasted an average of four hours. In 6 of the 9 patients there were clear improvements in target organ damage within one hour. Dangerous
observed. Nifedipine was given hypotension to a further 10 patients, of whom 8 responded, the mean maximum fall at 50 min being 42/35 mm Hg. Again no severe hypotensive episodes were recorded and only 1 patient complained of headache and 2 of brief flushing. Whilst the onset of the hypotensive effects of nifedipine was more rapid than that of captopril (10 versus 20 min for diastolic pressure and 20 versus 30 min for systolic pressure), there were no statistically significant differences in the efficacy of the was not
drugs. Agents such as hydralazine, methyldopa, and reserpine have a poor record in hypertensive emergencies because of their unpredictable onset and duration of action; diazoxide has more consistent effects but severe hypotension is a recognised dangerous side-effect.10 Clearly, the immediate goal of two
treatment should be
a reduction in pressure that and continues gradually. Complete normalisation of pressure can be attempted later. Intravenous agents have not lost their place entirely: during or after surgery, or in hypertensive crisis plus myocardial infarction, or in the unconscious patient,
begins quickly
sodium nitroprusside is a valuable agent that allows sensitive titration against continuously monitored pressure. Other agents can be also used in this fashion: some physicians favour labetalol, and intravenous calcium channel blockers are also available. However, for many patients with severe hypertension sublingual drugs are now alternatives. Nifedipine and captopril are equally effective. With nifedipine the vasodilator side-effects are a minor drawback;5,6 with captopril there is the slight concern that a patient may have severe renal failure, bilateral renal artery stenoses, or stenosis in a single functioning kidneycircumstances in which such a drug is dangerous. In case of doubt, nifedipine will be the safer option. 1. Editorial. Severe symptomless hypertension. Lancet 1989; i: 1369-70. 2. Strandgaard S, Olesen J, Skinhof E, Lassen NA. Autoregulation of brain circulation in severe arterial circulation. Br Med J 1973; i: 507-10. 3. Graham DI. Ischaemic brain damage of cerebral perfusion type after treatment of severe hypertension. Br Med J 1975; iv: 739. 4. Ledingham JGG, Rajagopalan B. Cerebral complications in the treatment of accelerated hypertension. Q J Med 1979; 48: 25-41. 5. Angeli P, Chieza M, Caregaro L, et al. Comparison of sublingual catopril and nifedipine in immediate treatment of hypertensive emergencies. Arch Intern Med 1991; 151: 678-82. 6. Opie LH, Jennings A. Sublingual captopril versus nifedipine in hypertensive cases. Lancet 1985; ii: 555. 7. Wachter RM. Symptomatic hypotension induced by nifedipine in the acute treatment of severe hypertension. Arch Intern Med 1987; 147: 556-558. 8. Tschollar W, Belz GG. Sublingual captopril in hypertensive crisis. Lancet 1985; ii: 34-35. 9. Hauger-Klevene JH. Captopril in hypertensive crisis. Lancet 1985; ii: 732-33. 10. Weber MA. Immediate treatment of severe hypertension. Arch Intern Med 1989; 149: 2535-36.
Ozone: too much in the wrong
place In Britain, introduction of the Clean Air Act in 1956 after the disastrous London fog of December, 1952,1 led to a considerable reduction in concentrations of smoke and sulphur dioxide and a consequent improvement in the nation’s health.2However, the increased number and use of motor vehicles has
produced a new problem-photochemical pollution. Oxides of nitrogen (NOx) react in the presence of volatile organic compounds, in sunlight, to produce
(03), In temperate climates the risk of enhanced atmospheric levels of 03 is weather-dependent and ozone
largely limited to the summer months when anticyclonic conditions are ideal for photochemical reactions to proceed. In the UK, 03 and other pollutant gases are monitored at air sampling stations and the information is coordinated by the Department of Trade and Industry’s Warren Spring Laboratory. During the summer months ozone rarely exceeds 150 parts per billion (ppb), although in 1976 an hourly level of 258 ppb was recorded. Since 1987 the highest hourly average ozone concentration measured in the UK was 161 ppb at Lullington Heath on August 4, 1990. The duration of most periods with consecutive hours above ppb is 1-5 hours. Other characteristics
222
striking diurnal variation, peak levels occurring at approximately 1600 h, a pronounced decreasing gradient south to north and, perhaps unexpectedly, the highest concentration being some 30-50 miles are
from urban conurbations. Because nitric oxide reacts with ozone, 03 levels are lowest in busy streets in an atmosphere rich in primary pollutants. Most studies on the health effects of 03 have been conducted in chambers under controlled conditions, usually with healthy adults in an ambient ozone concentration of > 120 ppb5,6 and often with repeated moderate to severe exercise. Under such conditions dose-related changes in indices of lung function include a fall in the forced expiratory volume in 1 second (FEV1) and vital capacity, an increase in specific airways resistance, a rise in the respiratory frequency, and a fall in tidal volume.6Other changes include an increase in pulmonary permeability’ and a small increase (of the order of one doubling dose) in bronchial responsiveness to agents such as inhaled histamine.8There do not seem to be any categories of disease causing increased sensitivity to this pollutant gas, although patients with asthma and other forms of compromised airway function may find the effects especially troublesome. Athletic performance may also be affected at a competitive level.9 Several studies conducted in children attending summer camps in North America have confirmed a negative association between ambient 03 concentrations and measured lung function, giving a regression coefficient for FEV1 on 03 concentration of 0-4-0-8 ml/ppb.10,11 The mechanisms of ozone-induced impairment of lung function are only partly understood. About 40 % of 03 delivered to the human respiratory tract is taken up by the upper airways. Studies in rodents have shown that the epithelia of the terminal bronchioles and proximal alveolar ducts are the main sites of damage.12 The 03 molecule contains two unpaired electrons and can oxidise target molecules directly or generate free radicals with a capacity to abstract hydrogen from polyunsaturated fatty acids in cell membranes and surfactant to form lipid peroxides.l3 03 also attacks the sulphydryl group of glutathione and readily reacts with reducing compounds such as NADH and NADPH. The net result is damage to the respiratory epithelium with production of potent mediators of inflammation and the accumulation and activation of neutrophils that amplify the inflammatory response.14 The effects of a single exposure to 03 are reversible and last up to 48 h. Repeated exposure leads to adaptation. 15 In this issue (p 199), Molfino and colleagues report that exposure to an ozone concentration of 120 ppb for 60 minutes produced no detectable effects on baseline lung function, but increased airway responsiveness to inhaled allergen in atopic patients with asthma by 1 -5 doubling-dose dilutions. At far higher 03 concentrations exposure of guineapigs (500 ppb) and dogs (3000 ppb) has been shown to increase allergen responsiveness of the airways by a mechanism
thought to involve increased access of allergen to subepithelial mediator secreting cells.16,17 Other animal work has indicated that 03 exposure may also increase IgE sensitisation of the lower respiratory tract. In patients with allergic rhinitis, a 4 h exposure to 500 ppb 03produced a 20-fold increase in eosinophils and a 7-fold increase in neutrophils recovered by lavage,18 while a 2 h exposure of the lower airways to 400 ppb increased lavage levels of histamine, prostanoids, albumin, and neutrophils. 14 However, the effects of lower ambient concentrations of 03on these indices of airway inflammation are not known. Since high concentrations of atmospheric ozone often coincide with peak levels of aeroallergens, the observations of Molfino and colleagues are clearly
important. Awareness of detectable effects of this pollutant at a low atmospheric concentration should encourage more research not only on the basic mechanisms of 03-induced lung injury but also on interactions with other environmental pollutants.
1. 2.
Ministry of Health. Mortality and morbidity during the London fog of December 1952. London: HM Stationery Office, 1954. Reid DD. The beginnings of bronchitis. Proc R Soc Med 1969; 62:
311-16. 3. Bower JS,
et
al. Ozone in the UK:
a
review of
1989/1990
data from
monitoring sites by Warren Spring Laboratory. Report No. LR 793. Stevenage: Warren Spring Laboratory, 1990. 4. Department of Health Advisory Group on the Medical Aspects of Air Pollution Episodes. Ozone. London: HM Stationery Office (in press). 5. Hazucha MJ. Relationship between ozone exposure and pulmonary function changes. J Appl Physiol 1987; 62: 1671-80. 6. Horstman DH, Folinsbee LJ, Ives PJ, Abdul-Salaam S, McDonnell WF. Ozone concentration and pulmonary response relationships for 6·6 hour exposures with 5 hours of moderate exercise to 0·08,0·10, and 0·12 ppm. Am Rev Respir Dis 1990; 142: 1158-63. 7. Kerl HR, Vincent LM, Kowalsky RJ, et al. Ozone exposure increases respiratory epithelial permeability in humans. Am Rev Respir Dis 1987; 135: 1124-28. 8. Holtzmann MJ, Cunningham JH, Sheller JR, Irsigler GB, Vadel JA, Bushey H. Effect of ozone on bronchial reactivity in atopic and non-atopic subjects. Am Rev Respir Dis 1979; 120: 1059-67. 9. Schelegle ES, Adams WC. Reduced exercise time in competitive simulations consequent to low level ozone exposure. Med J Sports Exerc 1986; 18: 408. 10. Spektor DM, Lipmann M, Lioy PJ, et al. Effects of ambient ozone on respiratory function in active, normal children. Am Rev Respir Dis 1988; 137: 313-20. 11. Higgins ITT, D’Arcy JB, Gibbons DI, Avol EL, Gross KB Effect of exposures to ambient ozone on ventilatory lung function in children. Am Rev Resp Dis 1990; 141: 1136-46. 12. Barry BE, Mercer RR, Miller FJ, Crapo JD. Effect of inhalation of 0·25 ppm ozone on the terminal bronchioles of juvenile and adult rats. Exp Lung Resp 1988; 14: 225-45. 13. Mustafa MG. Biochemical basis of ozone toxicity. Free Rad Biol Med 1990; 9: 2455 14. Devlin RB, McDonnell WF, Mann R, et al. Exposure of humans to ambient levels of ozone for 6·6 hours causes cellular and biochemical changes in the lung. Am J Respir Cell Mol Biol 1991; 4: 72-81. 15. Howarth JM, Gliner JA, Folinsbee LJ. Adaptation to ozone, duration of effect. Am Rev Respir Dis 1981; 123: 496-99. 16. Matsumura Y. The effects of ozone, nitrogen dioxide and sulphur dioxide on the experimentally induced respiratory disorder in guinea pigs. 1. The effect of sensitisation with albumen through the airway. Am Rev Respir Dis 1970; 102: 438-43. 17. Yanai M, Ohrai T, Aikawa T, et al. Ozone increases susceptibility to antigen inhalation in allergic dogs. J Appl Physiol 1990; 68: 2267-73. 18. Bascom R, Naclerio RM, Fitzgerald TK, Kagey-Sobotka A, Proud D. Effect of ozone inhalation on the response to nasal challenge with antigen in allergic subjects. Am Rev Respir Dis 1990; 142: 594-601.
