- Email: [email protected]
INHALED CORTICOSTEROIDS FOR RESPIRATORY DISTRESS?
1061 after the first mitozantrone injection no blasts were found in the CSF sample from the reservoir (see figure). The following day, CSF samples were taken from the reservoir and through a lumbar puncture and 2 mg mitozantrone was given through the reservoir. The reservoir sample was pale blue whilst the lumbar puncture sample was clear, indicating that the drug had not been circulated throughout the CSF. Also, no blasts were found in the reservoir sample, while the lumbar puncture sample contained 28 blasts/1. 3 days later, patency of the reservoir valve was checked by giving mitozantrone intrathecally by the lumbar route after taking a CSF sample and then sampling the CSF via the reservoir, which showed the characteristic blue colour indicating patency. The reservoir sample was free from blasts, while the lumbar puncture sample now showed only I blast/1. Unfortunately, the patient continued to deteriorate and became comatose and died in bone marrow remission and, probably, impending CNS remission. This is the second reported case in which mitozantrone has been given intrathecally with remarkable reduction in the number of blasts. Instillation of mitozantrone into an Ommaya reservoir may not result in even dissemination of the drug throughout the CSF, so that sampling of CSF taken only from the reservoir may give misleading results. There were no toxic side-effects from the intrathecal mitozantrone. We suggest that, in the presence of resistant CNS leukaemia, mitozantrone should be used as a third agent at an early stage. A. ZUIABLE
neurologically
J. MAITLAND A. NANDI H. M. CLINK R. L. POWLES
Leukaemia Unit, Royal Marsden Hospital, Sutton, Surrey SM2 5PT
INHALED CORTICOSTEROIDS FOR RESPIRATORY DISTRESS?
SIR,-Many
of
the
morphological changes
caused
by
experimental normobaric hyperoxia, such as interstitial oedema and endothelial cell damage, are similar to those seen in adult respiratory distress syndrome (ARDS).’t Our studies in normal and inflamed (by exposure to oxygen) lungs from guinea pigs, perfused in vitro through the trachea or the pulmonary artery, suggest that the population of cells which participates in the inflammatory process is located closer to the alveolar side of the lung and is therefore more accessible from the airways than from the circulation.2-4 Most of the causes of ARDS are of systemic and not pulmonary origin. It is reasonable to assume that pulmonary cells are normally protected by the integrity of the vascular endothelium against noxious stimuli from the circulation. Such cells would be exposed to challenge in ARDS as a consequence of endothelial damage which may occur either before or as a result of white cell and/or platelet activation. For the prevention of ARDS, these cells would be more accessible if drugs were delivered from the alveolar side. Furthermore, the earlier treatment begins in a potential ARDS patient the better the prognosis will be, since these cells would be protected in advance from stimuli reaching them from the circulation. Although there is controversy about the theoretical and experimental justification for massive corticosteroid therapy for ARDS, there is reasonable evidence of clinical benefit. 5-7 It is possible that such large doses are needed because, when given systemically, they are not penetrating sufficiently to the pulmonary site of action. Indeed, it has become clear that the vascular endothelium represents a barrier to the penetration of naturally occurring substances or drugs into the lungs. This is especially true for some of the steroids such as prednisone and
synthetic methylprednisolone. Corticosteroids
’
were successfully introduced in aerosols over a decade ago for the treatment of asthma and provide therapeutic benefit safely without systemic effects.9 This is probably because they are delivered in higher concentrations at their pulmonary site of action. If our hypothesis is correct, it is likely that better protection could be afforded in ARDS if corticosteroids were given early and by inhalation. Since in patients with severe ARDS areas of the lung which are vascularly occluded still remain ventilated,5
even when given at later stages, are likely to better tissue distribution in the lung. a concept could also be extended to infant respiratory syndrome (IRDS). Corticosteroids protect against the development of IRDS when given to the mother.10 The beneficial effect is reflected in the ability of the lungs to produce surfactant, an index of lung maturation and fetal viability. Conversely, corticosteroids do not have any beneficial effect when given systemically to the child after birth. 1Since surfactant is produced by the type II pneumocyte, which is located in the alveolus, it is likely that when corticosteroids are given to the mother they have access to such cells which are later functionally separated from the circulation by the vascular endothelial barrier. We suggest that the clinical efficacy of corticosteroids should be evaluated after administration by inhalation to patients with ARDS or IRDS since, by this route, the cells which may be responsible for the pathophysiological changes observed in these syndromes would be exposed to higher concentrations of the drugs.
inhaled achieve Such distress
steroids,
a
Therapeutic Research Division, Wellcome Research Laboratories, Beckenham, Kent BR3 3BS
GILBERTO DE NUCCI SALVADOR MONCADA
Jones R, Reid LM, Zapol WM, Tomashefski JF, Kirton OC, Kobayashi K. Pulmonary vascular pathology: Human and experimental studies. In: Acute respiratory failure. New York Marcel Dekker, 1985: 23-160. 2. Bakhle YS, Moncada S, de Nucci G, Salmon JA. Ovalbumin-induce release of eicosanoids from guinea-pig lungs perfused via the pulmonary artery and via the trachea. Br J Pharmacol (in press). 3. de Nucci G, Astbury P, Read N, Salmon JA, Moncada S. Release of eicosanoids from isolated lungs of guinea-pigs exposed to pure oxygen: Effect of dexamethasone. Unpublished. 4. Parente L, Fitzgerald M, de Nucci G, Moncada S. The release of lyso-PAF from guinea-pig lungs. Eur J Pharmacol 1985, 112: 281-84. 5. James PM. Treatment of shock lung. Am Surg 1975; 41: 451-56. 6. Du Toit HJ, Erasmus FR, MacFarlane CM, et al. Methylprednisolone and the adult respiratory distress syndrome. S Afr Med J 1984; 65: 1049-53. 7. Wilson JW. Treatment or prevention of pulmonary cellular damage with pharmacologic doses of corticosteroid. Surg Gynecol Obstet 1972; 134: 675-81. 8. Rebuck AS, Braude AC. Assessment of drug disposition in the lung. Drugs 1984; 28: 1.
544-53 9.
10.
Clark TJH, McAllister WAC. Corticosteroids. In: Clark TJH, Godfrey S, eds. Asthma. London: Chapman and Hall, 1983: 372-92. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972; 50: 515-25. M, Bauer CR, Colle E, Klein G, Taeusch HW, Stern L. A controlled trial of hydrocortisone therapy in infants with respiratory distress syndrome Pediatrics 1972; 50: 516-34.
11. Baden
HEPATITIS B VACCINATION AND IDIOPATHIC HAEMOCHROMATOSIS
SiR,-Degos et all have reported a very poor response to hepatitis (HBV) vaccine in patients with alcoholic cirrhosis. Vaccination was aimed at preventing hepatocellular carcinoma (HCC), Degos and colleagues having detected integration of the B virus
HBV genome in the liver of alcoholics with HCC.2 Patients with idiopathic haemochromatosis (IH) have cirrhosis of the liver too and the lifetime risk of HCC in such patients’ is 15% (in some of these HCC cases HBV-DNA integration in the genomic DNA of the liver cells has been found’). In 1983 we began a prospective study of HBV vaccination in patients with IH; in contrast to the situation in alcoholic cirrhosis the antibody response in IH seems satisfactory. Of 99 non-alcoholic IH patients entering the study 52 were vaccinated-ie, all those who consented and were negative for HBV markers (tested three times) and negative for HBV-DNA (tested once by hybridisation). 47 completed a course of vaccine (donated by the Pasteur Institute) consisting of three injections one month apart with a booster in the twelfth month. Antibody titres 1, 2,4,8, and 12 months after the first injection and 1 month after the booster were expressed as geometric means in mIU/ml,4 anti-HBs titration (Abbott RIA) being done by the same laboratory personnel who tested the three comparison populations. Responses were classified5 as good, low, and none 50, 10-49, <10 mIU/ml), permitting comparison of antibody titres in IH patients with those obtained in healthy people and in patients with uraemia on haemodialysis and with cirrhotic patients. Statistical analysis was by non-parametric tests (Spearman correlation and Kruskall and Wallis H test).
neurologically
J. MAITLAND A. NANDI H. M. CLINK R. L. POWLES
Leukaemia Unit, Royal Marsden Hospital, Sutton, Surrey SM2 5PT
INHALED CORTICOSTEROIDS FOR RESPIRATORY DISTRESS?
SIR,-Many
of
the
morphological changes
caused
by
experimental normobaric hyperoxia, such as interstitial oedema and endothelial cell damage, are similar to those seen in adult respiratory distress syndrome (ARDS).’t Our studies in normal and inflamed (by exposure to oxygen) lungs from guinea pigs, perfused in vitro through the trachea or the pulmonary artery, suggest that the population of cells which participates in the inflammatory process is located closer to the alveolar side of the lung and is therefore more accessible from the airways than from the circulation.2-4 Most of the causes of ARDS are of systemic and not pulmonary origin. It is reasonable to assume that pulmonary cells are normally protected by the integrity of the vascular endothelium against noxious stimuli from the circulation. Such cells would be exposed to challenge in ARDS as a consequence of endothelial damage which may occur either before or as a result of white cell and/or platelet activation. For the prevention of ARDS, these cells would be more accessible if drugs were delivered from the alveolar side. Furthermore, the earlier treatment begins in a potential ARDS patient the better the prognosis will be, since these cells would be protected in advance from stimuli reaching them from the circulation. Although there is controversy about the theoretical and experimental justification for massive corticosteroid therapy for ARDS, there is reasonable evidence of clinical benefit. 5-7 It is possible that such large doses are needed because, when given systemically, they are not penetrating sufficiently to the pulmonary site of action. Indeed, it has become clear that the vascular endothelium represents a barrier to the penetration of naturally occurring substances or drugs into the lungs. This is especially true for some of the steroids such as prednisone and
synthetic methylprednisolone. Corticosteroids
’
were successfully introduced in aerosols over a decade ago for the treatment of asthma and provide therapeutic benefit safely without systemic effects.9 This is probably because they are delivered in higher concentrations at their pulmonary site of action. If our hypothesis is correct, it is likely that better protection could be afforded in ARDS if corticosteroids were given early and by inhalation. Since in patients with severe ARDS areas of the lung which are vascularly occluded still remain ventilated,5
even when given at later stages, are likely to better tissue distribution in the lung. a concept could also be extended to infant respiratory syndrome (IRDS). Corticosteroids protect against the development of IRDS when given to the mother.10 The beneficial effect is reflected in the ability of the lungs to produce surfactant, an index of lung maturation and fetal viability. Conversely, corticosteroids do not have any beneficial effect when given systemically to the child after birth. 1Since surfactant is produced by the type II pneumocyte, which is located in the alveolus, it is likely that when corticosteroids are given to the mother they have access to such cells which are later functionally separated from the circulation by the vascular endothelial barrier. We suggest that the clinical efficacy of corticosteroids should be evaluated after administration by inhalation to patients with ARDS or IRDS since, by this route, the cells which may be responsible for the pathophysiological changes observed in these syndromes would be exposed to higher concentrations of the drugs.
inhaled achieve Such distress
steroids,
a
Therapeutic Research Division, Wellcome Research Laboratories, Beckenham, Kent BR3 3BS
GILBERTO DE NUCCI SALVADOR MONCADA
Jones R, Reid LM, Zapol WM, Tomashefski JF, Kirton OC, Kobayashi K. Pulmonary vascular pathology: Human and experimental studies. In: Acute respiratory failure. New York Marcel Dekker, 1985: 23-160. 2. Bakhle YS, Moncada S, de Nucci G, Salmon JA. Ovalbumin-induce release of eicosanoids from guinea-pig lungs perfused via the pulmonary artery and via the trachea. Br J Pharmacol (in press). 3. de Nucci G, Astbury P, Read N, Salmon JA, Moncada S. Release of eicosanoids from isolated lungs of guinea-pigs exposed to pure oxygen: Effect of dexamethasone. Unpublished. 4. Parente L, Fitzgerald M, de Nucci G, Moncada S. The release of lyso-PAF from guinea-pig lungs. Eur J Pharmacol 1985, 112: 281-84. 5. James PM. Treatment of shock lung. Am Surg 1975; 41: 451-56. 6. Du Toit HJ, Erasmus FR, MacFarlane CM, et al. Methylprednisolone and the adult respiratory distress syndrome. S Afr Med J 1984; 65: 1049-53. 7. Wilson JW. Treatment or prevention of pulmonary cellular damage with pharmacologic doses of corticosteroid. Surg Gynecol Obstet 1972; 134: 675-81. 8. Rebuck AS, Braude AC. Assessment of drug disposition in the lung. Drugs 1984; 28: 1.
544-53 9.
10.
Clark TJH, McAllister WAC. Corticosteroids. In: Clark TJH, Godfrey S, eds. Asthma. London: Chapman and Hall, 1983: 372-92. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972; 50: 515-25. M, Bauer CR, Colle E, Klein G, Taeusch HW, Stern L. A controlled trial of hydrocortisone therapy in infants with respiratory distress syndrome Pediatrics 1972; 50: 516-34.
11. Baden
HEPATITIS B VACCINATION AND IDIOPATHIC HAEMOCHROMATOSIS
SiR,-Degos et all have reported a very poor response to hepatitis (HBV) vaccine in patients with alcoholic cirrhosis. Vaccination was aimed at preventing hepatocellular carcinoma (HCC), Degos and colleagues having detected integration of the B virus
HBV genome in the liver of alcoholics with HCC.2 Patients with idiopathic haemochromatosis (IH) have cirrhosis of the liver too and the lifetime risk of HCC in such patients’ is 15% (in some of these HCC cases HBV-DNA integration in the genomic DNA of the liver cells has been found’). In 1983 we began a prospective study of HBV vaccination in patients with IH; in contrast to the situation in alcoholic cirrhosis the antibody response in IH seems satisfactory. Of 99 non-alcoholic IH patients entering the study 52 were vaccinated-ie, all those who consented and were negative for HBV markers (tested three times) and negative for HBV-DNA (tested once by hybridisation). 47 completed a course of vaccine (donated by the Pasteur Institute) consisting of three injections one month apart with a booster in the twelfth month. Antibody titres 1, 2,4,8, and 12 months after the first injection and 1 month after the booster were expressed as geometric means in mIU/ml,4 anti-HBs titration (Abbott RIA) being done by the same laboratory personnel who tested the three comparison populations. Responses were classified5 as good, low, and none 50, 10-49, <10 mIU/ml), permitting comparison of antibody titres in IH patients with those obtained in healthy people and in patients with uraemia on haemodialysis and with cirrhotic patients. Statistical analysis was by non-parametric tests (Spearman correlation and Kruskall and Wallis H test).