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TOXIC REACTIONS AFTER INTRAVENOUS IRON
77
Circumferential incision.—Here, the diaphragm is divided close to its attachment to the chest wall. The full periphery may be divided and the left leaf turned upwards hinged on its pericardial attachment. This gives an excellent exposure of the upper abdomen, but the resuture is tedious, and it is doubtful if the repair would resist a much raised intra-abdominal tension following on the development of intestinal atony. Parapericardial incision.—The incision is made close to the pericardial attachment medial to the posterior division of the nerve, running from the main phrenic This nerve trunk posteriorly towards the cesophagus. incision may be of value in exposing the upper surface of the left lobe of the liver, but it is of limited application. Left paracrural incision.—The incision runs from the posterior attachment of the diaphragm, 3/4 inch lateral to the oesophageal hiatus, directly forwards to the central tendon of the diaphragm. This incision is just lateral to the fibres of the left crus. This gives a good exposure of the fundus of the stomach and is adequate for exploration of the immediate upper abdomen and for the various manipulations and subdiaphragmatic suturing necessary in the reduction of a hiatus hernia. It has been successfully used in many cases now.
over 420 of the patients, and in the remainder the information was obtained from the doctor giving the
injections. General Reactions
Character The most
injections
prominent features of the reactions after
were :
(1) Flushing and dizziness, followed by sweating, pallor, unconsciousness, fall of blood-pressure, and tachycardia (or
rarely bradycardia). (2) Dyspnoea, cyanosis, and constricting pain in the chest. (3) Vomiting, diarrhoea, and abdominal pains which, if severe, might be accompanied by rigidity resembling a perforated ulcer, except that the gut sounds remained audible. (4) Generalised aching pains of varying severity in the back, loins, limbs, head, and eyes. (5) High temperature and rigors.
A few patients had reactions with features confined to of these groups, but most had features from two or more groups with the emphasis on one. Cardiovascular and respiratory symptoms were acute and early, but other symptoms were more delayed and prolonged. With 100 mg. doses, most reactions were seen during the injection or within thirty minutes of its completion, a minority being delayed for up to three hours ; they lasted from about a half to three hours, but occasionally usually Summary for twenty-four hours. A given patient always had a The distribution of the left phrenic nerve in the similar reaction. All reactions subsided completely and diaphragm follows two distinct patterns. In two-thirds no permanent effects were noted. 7 patients received there is a single major arcade from which multiple fibres Over courses totalling 2000-4000 mg. without ill effect. arise, and in one-third there are multiple minor arcades of intravenous saccharated iron oxide 10,000 injections providing the same distribution. have been given in this hospital without fatality. Patients Three incisions in the diaphragm are suggested which with reactions were treated with rest, occasionally with avoid all major branches of the nerve. The left parasedatives including morphia, and intravenous norcrural incision appears to have considerable practical use. adrenaline if vasomotor collapse persisted. We wish to thank Miss Barbara Duckworth for the illustrawe are grateful to Prof. Charles Wells for his advice and help.
tions, and
REFERENCES Cavalie. M. (1898) J. Anat., Paris, 34, 642. Collis, L., Satchwell, L. M., Abrams. L. D. (1954) Felix, W. (1922) Dtsch. Z. Chir. 171, 283. Schlaepfer, K. (1926) Anat. Rec. 32, 143. Strauss, L. H. (1933) Z. ges. exp. Med. 86, 244.
Thorax, 9, 22.
TOXIC REACTIONS AFTER INTRAVENOUS IRON IAN P. Ross Lond., M.R.C.P.
M.D. LATELY MEDICAL
REGISTRAR,
THE
LONDON HOSPITAL
Toxic reactions after intravenous saccharated iron oxide are well known, but it has not yet been possible to predict in which patients they will arise. Certain factors predispose to them, and recognition of these will enable some reactions to be avoided. In 1947 Nissim described the low incidence of toxic effects of intravenous saccharated iron oxide, and its effectiveness in treating iron-deficiency anaemias was later established. The necessary injections are, however, timeconsuming, sometimes difficult to give, and occasionally associated with alarming reactions. Nissim (1954) reviewed reports of these reactions, and added his own experience in 28 patients. It was hard to assess the predisposing factors because observations were based on small series of patients given variable doses and different preparations of saccharated iron oxide. I have therefore tried to discover which patients are liable to reactions by
studying large group treated with the
a —’ Ferrivenin
same
preparation
’-in a standard dose. This investigation is based on 802 treated patients whose anaemias were mostly associated with pregnancy, the puerperium, menorrhagia, gastro-intestinal haemorrhage, rheumatoid arthritis, ulcerative colitis, and chronic nephritis. I saw
one
Incidence 779 patients were treated with standard 100-mg. doses of intravenous saccharated iron oxide ; most patients received a smaller initial dose of 25 or 50 mg., all subsequent doses being 100 mg. A total of 4818 injections was given. 58 (7.5%) of these patients had at least one toxic reaction (table i). In 28 the reactions were minor and treatment was continued, but in 30 the reactions were so severe that treatment was abandoned. The relation between the number of injections given and the onset of reactions was variable. 13 reacted to the first dose, 18 to the second, 22 to the third to fifth doses, 1 to the seventh and 1 to the eighth ; 3 others had reactions to the first dose of a second course of injections. Patients having a minor reaction often received subsequent full doses without ill effect. 23 patients received large intravenous infusions of saccharated iron oxide (500-600 mg. in a pint of 5% dextrose) and 10 (43%) of these had reactions (table i). TABLE I-INCIDENCE OF REACTIONS IN RELATION TO DOSE
These were similar in character to those following a dose of 100 mg., but more severe, prolonged, and alarming. They began during the infusion or up to six hours later, and took up to forty-eight hours to subside. Predisposing Factors The incidence and character of reactions are influenced by several factors. The incidence varies with the cause of the anaemia (table II). Reactions are least common in the anaemias associated with pregnancy, the puerperium, menorrhagia, and gastro-intestinal haemorrhage, and commonest in the anaemias associated with chronic infection, rheumatoid arthritis, ulcerative colitis, and
78 TABLE
OF REACTIONS IN RELATION CAUSE OF THE ANEMIA
II-INCIDENCE
TO
THE
nephritis. In the latter two conditions reactions twice as common in those patients with abnormalities of the plasma-proteins-either a low serum-albumin or an elevated serum-globulin. 3 patients with chronic bronchitis and emphysema, 2 out of 6 with mitral stenosis, and 1 with a severe kyphoscoliosis all developed similar respiratory distress after intravenous saccharated iron oxide. During the injection, or within five minutes of it, acute and alarming dyspnoea developed, with cyanosis and constricting pain in the chest which persisted for from fifteen minutes to about three hours. In 1 old lady with chronic bronchitis and emphysema, the reaction precipitated a relapse of congestive heart-failure. Similar reactions were not seen in chronic
were
other
patients.
Backache, loin pain, and vomiting
were particularly prominent in patients with renal disease and after massive infusions. Reactions seemed more frequent in the frail and elderly, though nothing was seen comparable to the sudden death of a man aged 69, reported by Barritt and Swain in 1953. Pregnant women were particularly prone to syncopal reactions. 38 of the patients who had reactions were closely questioned : they gave no history of asthma, urticaria, or sensitivity rashes.
Discussion
These observations suggest that reactions to intrasaccharated iron oxide are related to such factors as dosage, the presence of pulmonary vascular disease, and the cause of the anaemia. Though the significance of the first of these is recognised and the second suspected, the third has not previously been recorded. Consideration of these points should enable some reactions to be avoided. Dosage has an important influence on the incidence of reactions. With a dose of 100 mg. the incidence of reactions was 7-5%, but with a dose of 500 mg. the incidence was 43%. Ramsey (1950) also recorded a high incidence of reactions after large doses. ’It should be emphasised that it is the amount in a single injection that is important : with 100 mg. doses, there is no evidence to suggest that the incidence of reactions rises with the increase in the number of injections. Most reactions arise from the first 5 injections, and patients have received 2000-4000 mg. in divided doses without ill effect. The incidence of reactions is so high after massive infusions that they should not be given. The association of reactions with lung disease has not Reactions with acute been sufficiently emphasised. respiratory distress have been observed in mitral stenosis, chronic bronchitis and emphysema, and severe kyphoscoliosis, and Librach (1953) reported similar reactions in a patient with pulmonary tuberculosis. Although respiratory symptoms have occasionally been noted in other patients, they have never been severe or prominent. This particular type of reaction resembles the clinical picture of pulmonary embolism, and there is experimental evidence to suggest that this is the mechanism. Nissim and Robson (1949) have shown in mice that the injection of saccharated iron oxide is associated with
venous
precipitation of iron particles particularly in the lung capillaries. It seems reasonable therefore to suggest that this occurs in man, and that symptoms arise particularly when the pulmonary capillary bed is damaged as happens in all the diseases mentioned. The clinical and experi. mental evidence suggests that greater care should be exercised in giving this substance to patients with dis. orders of the pulmomary capillary bed; doses must be smaller than usual (i.e., 25-50 mg.), and given particu. larly slowly. The loin pain noted after massive infusions and in patients with nephritis may similarly be due to renal emboli, for Ellis (1956) has shown, in rabbits given intravenous saccharated iron oxide, that iron precipitathe
tion causes renal damage. Fewest reactions were seen in patients with pure iron-deficient anæmias—e.g., in pregnancy and the puerperium, and from chronic blood-loss (table II). Reactions were more common when iron-deficiency was accom-
panied by fever, toxaemia, or metabolic disturbances. This is further supported by the increased liability to reactions when the plasma-proteins were abnormal, as also happened in a case reported by Librach (1953). The objection could be raised that some of these patients should not have received intravenous iron therapy. When, however, an element of iron-deficiency has been established as judged by the appearance of the red cells, the colour-index, and the mean corpuscular haemoglobin concentration, this form of treatment has seemed justified after the failure of oral iron. It is noted that reactions are more common in those patients whose anaemias respond poorly to this type of treatment. Avoiding these reactions depends chiefly on correct selection of patients ; iron deficiency must be clearly established. When there is chronic infection or nephritis, the injections should be of the order of 25-50 mg., and if these doses are tolerated, then the 100 mg. dose may be given. With the higher incidence of reactions in these anaemias and the variable response, alternative methods of treatment require more careful consideration. The cause of reactions remains uncertain, but allergy and iron precipitation have been considered most likely. In this series the absence of an allergic background, and the absence of rashes, urticaria, and simple bronchospasm, suggest that allergy is not an important ætiological factor, though it may have been in earlier preparations containing impurities, particularly in the sucrose. Iron precipitation is the likely explanation for some early and most of the delayed reactions, but there remain reactions, particularly early ones, in which the aetiology is obscure. Nissim (1954) classified reactions into early and late, but with so much variation and overlap of symptoms this seems an oversimplification, and such a distinction should not be used for suggesting that early and late reactions have completely different aetiologies. It seems that with the standard 100 mg. dose, about 5% of patients will continue to have reactions in spite of careful selection and slow injections. Reducing the dose is unsatisfactory from a practical aspect, since the number of injections needed is then increased. There is thus still a need for a less toxic iron preparation for parenteral use. The newer intramuscular iron (’Imferon’) is perhaps an advance, but even this may result in toxic reactions (Ross 1955). Since intravenous saccharated iron oxide and intramuscular iron have been thought equally effective in the treatment of iron-deficiency anaemias (Cope et al. 1956) the assessment of their relative toxicity becomes particularly important.
Summary 802 anaemic patients treated with intravenous saccharated iron oxide were observed for toxic reactions. The reactions were related to the cardiovascular, respiratory, and gastro-intestinal systems and were accompanied by pains and fever. The overall incidence was 75% with
79 100 mg. doses and 43% with 500 mg. doses. Acute respiratory distress was seen only in patients with chronic lung disease and mitral stenosis. Reactions were least common (5%) in pure iron-deficiency anaemias, but when there was fever, toxaemia, or metabolic disturbance, the incidence increased to 24%. It is concluded that, with careful selection and the standard 100 mg. dose, the incidence of reactions will remain about 5% ; hence the necessity for less toxic parenteral iron preparations. I wish to thank Dr. Wallace Brigden and Dr. Adam Turnbull for their help, and those members of the staff of this hospital whose patients I have been permitted to see. REFERENCES
Barritt, D. W., Swain, G. C. (1953) Brit. med. J. i, 379. Cope, E., Gillhespy, R. O., Richardson, R. W. (1956) Ibid, ii, 638. Ellis, J. T. (1956) J. exp. Med. 103, 127. Librach, I. M. (1953) Brit. med. J. i, 21. Nissim, J. A. (1947) Lancet, ii, 49. (1954) Brit. med. J. i, 352. Robson, J. M. (1949) Lancet, i, 686. Ramsey, A. S. (1950) Brit. med. J. i, 1109. Ross, I. P. (1955) Lancet, i, 51. —
—
Preliminary Communication
infra-red analysis revealed a ’spectrum identical with that of &Dgr; 1—4-androstadiene-3-11-17-trione and b.. 1-4-
androstadiene-11-&bgr;-ol-3-17-dione respectively. Our results prove that 17-ketosteroid formation is only a minor pathway of prednisone and prednisolone metabolism, and offer additional evidence for the absence of tetrahydro-derivatives. The two 17-ketosteroids identified were present in only minor quantities (corresponding to less than 05% of the administered dose), suggesting again that the enzymatic systems converting the corticoids to 17-ketosteroids are largely inhibited by the presence of the dienone group. The urinary metabolites of prednisone and prednisolone so far known represent only a small proportion of the administered dose, and we are still ignorant of what happens to the bulk of the administered dose.
The very low transformation of A 1-corticoids to 17-ketosteroids enables us to study the depression of the adrenal cortex by determining urinary 17-ketosteroids before and during prednisone treatment. This may be of value in the study of Cushing’s syndrome for differentiation between adrenal hyperplasia and tumour. Medical Clinic, State University,
A. VERMEULEN M.D. Ghent
Ghent, Belgium
17-KETOSTEROIDS AFTER PREDNISONE AND PREDNISOLONE THE metabolism of A-corticoids is still incompletely known. So far, we know that reduction of the A ring is not a main pathway of metabolism, because in all metabolites so far identified the dienone grouping was preserved.12 Oxidation of the side-chain to the corresponding 17-ketosteroid generally follows the reduction of the A ring, so it is to be expected that 17-ketosteroid formation will be only a minor pathway of prednisone and prednisolone metabolism. To date, 17-ketosteroid excretion after administration of prednisone and prednisolone has not been thoroughly studied. The matter is complicated by the fact that these substances do not comof 17-ketopletely suppress the endogenous formation steroids. Slaunwhite and Sandberg 3 found very low 17-ketosteroid excretion during prednisone treatment. Recently wehave had the opportunity to study the 17-ketosteroid excretion pattern in patients who had undergone bilateral ovariectomy and adrenalectomy on account of metastatising breast carcinoma. The patients were given prednisolone 80 mg. daily and the collected urines were extracted with benzene for 17-ketosteroid determination by the usual method. The dried extract was purified by girardisation. Total 17-ketosteroids were determined by the method of Holtorff-Koch on a suitable aliquot. The remainder of the extract was to subjected gradient elution chromatography on alumina. Less than 2% of the prednisolone administered could be recovered as 17-ketosteroid. The chromatogram showed two main peaks of dinitrobenzene-reacting material. The fractions corresponding to each peak were pooled and evaporated to dryness. An aliquot of each residue was subjected to paper-chromatography in the systems toluol/cyclohexane (1/3) propyleneglycol, and heptane/propyleneglycol. The chromatograms revealed a steroid whose mobility was similar to that of &Dgr;1-adrenosterone and &Dgr;1—4-adrostadiene-
11- &bgr;-ol-3-17 -dione respectively, showing ultraviolet absorption (254 mu source) without sodafluorescence and with positive dinitrobenzene reaction. Recrystallisation of the residues from acetone and petroleum ether yielded colourless crystals whose meltingpoints were respectively 195-196 and 183-185°C. Finally, Gray, C. H., Green, M. A. S., Holness, N. J., Lunnon, J. B J. Endocrin. 1956, 14, 146. 2. Vermeulen, A. Acta endocr., Copenhagen, 1956, 23, 113. 3. Slaunwhite, W. R., Sandberg, A. A. J. clin. Endocrin. Metabol. 1957, 17, 395. 1.
New Inventions OUTPATIENT TREATMENT OF THE FRACTURED FEMORAL SHAFT IN CHILDREN
in lbadan will improve when the new opens; but at present beds are so scarce that children cannot be treated as inpatients unless they present some very serious pædiatric problem, and they have to be discharged as soon as possible. The child with a fractured femur blocked a bed for 3-6 weeks, and often he was discharged in very unsatis" factory 11/2-bip spicas as soon as there was any radiological callus. Wedecided therefore to try a portable hed for gallows traction, a.s used (Dr. Ra,lnh Hendrickse
CONDITIONS
teaching hospital
"
told me) in a South African hospital. A prototype was made by the hospital maintenance staff from ‘ Dexian ’ light angled-steel (fig. 1) the measurements being: Bed frame.. Gallows standard
Legs
27 27
x
x
....
18 in. 18 in. 9 in.
Other models were made to suit individual patients. For example : For a child a month old: 18 x 9 in. Bed frame.. 18 x 9 in. Gallows .... For children of 6-10 years : Bed frame.. 30 x 18 in. Gallows.... 30 x 18 in.
The bed-frame
was
com-
of stretcher canvas, secured to the frame by standard In practice cord lacing. the dexian crosspiece was placed lower on the legs so that the buttocks could at no time touch metal. The patient’s legs are suspended from the gallows by skin-traction
pleted by
a
piece
Circumferential incision.—Here, the diaphragm is divided close to its attachment to the chest wall. The full periphery may be divided and the left leaf turned upwards hinged on its pericardial attachment. This gives an excellent exposure of the upper abdomen, but the resuture is tedious, and it is doubtful if the repair would resist a much raised intra-abdominal tension following on the development of intestinal atony. Parapericardial incision.—The incision is made close to the pericardial attachment medial to the posterior division of the nerve, running from the main phrenic This nerve trunk posteriorly towards the cesophagus. incision may be of value in exposing the upper surface of the left lobe of the liver, but it is of limited application. Left paracrural incision.—The incision runs from the posterior attachment of the diaphragm, 3/4 inch lateral to the oesophageal hiatus, directly forwards to the central tendon of the diaphragm. This incision is just lateral to the fibres of the left crus. This gives a good exposure of the fundus of the stomach and is adequate for exploration of the immediate upper abdomen and for the various manipulations and subdiaphragmatic suturing necessary in the reduction of a hiatus hernia. It has been successfully used in many cases now.
over 420 of the patients, and in the remainder the information was obtained from the doctor giving the
injections. General Reactions
Character The most
injections
prominent features of the reactions after
were :
(1) Flushing and dizziness, followed by sweating, pallor, unconsciousness, fall of blood-pressure, and tachycardia (or
rarely bradycardia). (2) Dyspnoea, cyanosis, and constricting pain in the chest. (3) Vomiting, diarrhoea, and abdominal pains which, if severe, might be accompanied by rigidity resembling a perforated ulcer, except that the gut sounds remained audible. (4) Generalised aching pains of varying severity in the back, loins, limbs, head, and eyes. (5) High temperature and rigors.
A few patients had reactions with features confined to of these groups, but most had features from two or more groups with the emphasis on one. Cardiovascular and respiratory symptoms were acute and early, but other symptoms were more delayed and prolonged. With 100 mg. doses, most reactions were seen during the injection or within thirty minutes of its completion, a minority being delayed for up to three hours ; they lasted from about a half to three hours, but occasionally usually Summary for twenty-four hours. A given patient always had a The distribution of the left phrenic nerve in the similar reaction. All reactions subsided completely and diaphragm follows two distinct patterns. In two-thirds no permanent effects were noted. 7 patients received there is a single major arcade from which multiple fibres Over courses totalling 2000-4000 mg. without ill effect. arise, and in one-third there are multiple minor arcades of intravenous saccharated iron oxide 10,000 injections providing the same distribution. have been given in this hospital without fatality. Patients Three incisions in the diaphragm are suggested which with reactions were treated with rest, occasionally with avoid all major branches of the nerve. The left parasedatives including morphia, and intravenous norcrural incision appears to have considerable practical use. adrenaline if vasomotor collapse persisted. We wish to thank Miss Barbara Duckworth for the illustrawe are grateful to Prof. Charles Wells for his advice and help.
tions, and
REFERENCES Cavalie. M. (1898) J. Anat., Paris, 34, 642. Collis, L., Satchwell, L. M., Abrams. L. D. (1954) Felix, W. (1922) Dtsch. Z. Chir. 171, 283. Schlaepfer, K. (1926) Anat. Rec. 32, 143. Strauss, L. H. (1933) Z. ges. exp. Med. 86, 244.
Thorax, 9, 22.
TOXIC REACTIONS AFTER INTRAVENOUS IRON IAN P. Ross Lond., M.R.C.P.
M.D. LATELY MEDICAL
REGISTRAR,
THE
LONDON HOSPITAL
Toxic reactions after intravenous saccharated iron oxide are well known, but it has not yet been possible to predict in which patients they will arise. Certain factors predispose to them, and recognition of these will enable some reactions to be avoided. In 1947 Nissim described the low incidence of toxic effects of intravenous saccharated iron oxide, and its effectiveness in treating iron-deficiency anaemias was later established. The necessary injections are, however, timeconsuming, sometimes difficult to give, and occasionally associated with alarming reactions. Nissim (1954) reviewed reports of these reactions, and added his own experience in 28 patients. It was hard to assess the predisposing factors because observations were based on small series of patients given variable doses and different preparations of saccharated iron oxide. I have therefore tried to discover which patients are liable to reactions by
studying large group treated with the
a —’ Ferrivenin
same
preparation
’-in a standard dose. This investigation is based on 802 treated patients whose anaemias were mostly associated with pregnancy, the puerperium, menorrhagia, gastro-intestinal haemorrhage, rheumatoid arthritis, ulcerative colitis, and chronic nephritis. I saw
one
Incidence 779 patients were treated with standard 100-mg. doses of intravenous saccharated iron oxide ; most patients received a smaller initial dose of 25 or 50 mg., all subsequent doses being 100 mg. A total of 4818 injections was given. 58 (7.5%) of these patients had at least one toxic reaction (table i). In 28 the reactions were minor and treatment was continued, but in 30 the reactions were so severe that treatment was abandoned. The relation between the number of injections given and the onset of reactions was variable. 13 reacted to the first dose, 18 to the second, 22 to the third to fifth doses, 1 to the seventh and 1 to the eighth ; 3 others had reactions to the first dose of a second course of injections. Patients having a minor reaction often received subsequent full doses without ill effect. 23 patients received large intravenous infusions of saccharated iron oxide (500-600 mg. in a pint of 5% dextrose) and 10 (43%) of these had reactions (table i). TABLE I-INCIDENCE OF REACTIONS IN RELATION TO DOSE
These were similar in character to those following a dose of 100 mg., but more severe, prolonged, and alarming. They began during the infusion or up to six hours later, and took up to forty-eight hours to subside. Predisposing Factors The incidence and character of reactions are influenced by several factors. The incidence varies with the cause of the anaemia (table II). Reactions are least common in the anaemias associated with pregnancy, the puerperium, menorrhagia, and gastro-intestinal haemorrhage, and commonest in the anaemias associated with chronic infection, rheumatoid arthritis, ulcerative colitis, and
78 TABLE
OF REACTIONS IN RELATION CAUSE OF THE ANEMIA
II-INCIDENCE
TO
THE
nephritis. In the latter two conditions reactions twice as common in those patients with abnormalities of the plasma-proteins-either a low serum-albumin or an elevated serum-globulin. 3 patients with chronic bronchitis and emphysema, 2 out of 6 with mitral stenosis, and 1 with a severe kyphoscoliosis all developed similar respiratory distress after intravenous saccharated iron oxide. During the injection, or within five minutes of it, acute and alarming dyspnoea developed, with cyanosis and constricting pain in the chest which persisted for from fifteen minutes to about three hours. In 1 old lady with chronic bronchitis and emphysema, the reaction precipitated a relapse of congestive heart-failure. Similar reactions were not seen in chronic
were
other
patients.
Backache, loin pain, and vomiting
were particularly prominent in patients with renal disease and after massive infusions. Reactions seemed more frequent in the frail and elderly, though nothing was seen comparable to the sudden death of a man aged 69, reported by Barritt and Swain in 1953. Pregnant women were particularly prone to syncopal reactions. 38 of the patients who had reactions were closely questioned : they gave no history of asthma, urticaria, or sensitivity rashes.
Discussion
These observations suggest that reactions to intrasaccharated iron oxide are related to such factors as dosage, the presence of pulmonary vascular disease, and the cause of the anaemia. Though the significance of the first of these is recognised and the second suspected, the third has not previously been recorded. Consideration of these points should enable some reactions to be avoided. Dosage has an important influence on the incidence of reactions. With a dose of 100 mg. the incidence of reactions was 7-5%, but with a dose of 500 mg. the incidence was 43%. Ramsey (1950) also recorded a high incidence of reactions after large doses. ’It should be emphasised that it is the amount in a single injection that is important : with 100 mg. doses, there is no evidence to suggest that the incidence of reactions rises with the increase in the number of injections. Most reactions arise from the first 5 injections, and patients have received 2000-4000 mg. in divided doses without ill effect. The incidence of reactions is so high after massive infusions that they should not be given. The association of reactions with lung disease has not Reactions with acute been sufficiently emphasised. respiratory distress have been observed in mitral stenosis, chronic bronchitis and emphysema, and severe kyphoscoliosis, and Librach (1953) reported similar reactions in a patient with pulmonary tuberculosis. Although respiratory symptoms have occasionally been noted in other patients, they have never been severe or prominent. This particular type of reaction resembles the clinical picture of pulmonary embolism, and there is experimental evidence to suggest that this is the mechanism. Nissim and Robson (1949) have shown in mice that the injection of saccharated iron oxide is associated with
venous
precipitation of iron particles particularly in the lung capillaries. It seems reasonable therefore to suggest that this occurs in man, and that symptoms arise particularly when the pulmonary capillary bed is damaged as happens in all the diseases mentioned. The clinical and experi. mental evidence suggests that greater care should be exercised in giving this substance to patients with dis. orders of the pulmomary capillary bed; doses must be smaller than usual (i.e., 25-50 mg.), and given particu. larly slowly. The loin pain noted after massive infusions and in patients with nephritis may similarly be due to renal emboli, for Ellis (1956) has shown, in rabbits given intravenous saccharated iron oxide, that iron precipitathe
tion causes renal damage. Fewest reactions were seen in patients with pure iron-deficient anæmias—e.g., in pregnancy and the puerperium, and from chronic blood-loss (table II). Reactions were more common when iron-deficiency was accom-
panied by fever, toxaemia, or metabolic disturbances. This is further supported by the increased liability to reactions when the plasma-proteins were abnormal, as also happened in a case reported by Librach (1953). The objection could be raised that some of these patients should not have received intravenous iron therapy. When, however, an element of iron-deficiency has been established as judged by the appearance of the red cells, the colour-index, and the mean corpuscular haemoglobin concentration, this form of treatment has seemed justified after the failure of oral iron. It is noted that reactions are more common in those patients whose anaemias respond poorly to this type of treatment. Avoiding these reactions depends chiefly on correct selection of patients ; iron deficiency must be clearly established. When there is chronic infection or nephritis, the injections should be of the order of 25-50 mg., and if these doses are tolerated, then the 100 mg. dose may be given. With the higher incidence of reactions in these anaemias and the variable response, alternative methods of treatment require more careful consideration. The cause of reactions remains uncertain, but allergy and iron precipitation have been considered most likely. In this series the absence of an allergic background, and the absence of rashes, urticaria, and simple bronchospasm, suggest that allergy is not an important ætiological factor, though it may have been in earlier preparations containing impurities, particularly in the sucrose. Iron precipitation is the likely explanation for some early and most of the delayed reactions, but there remain reactions, particularly early ones, in which the aetiology is obscure. Nissim (1954) classified reactions into early and late, but with so much variation and overlap of symptoms this seems an oversimplification, and such a distinction should not be used for suggesting that early and late reactions have completely different aetiologies. It seems that with the standard 100 mg. dose, about 5% of patients will continue to have reactions in spite of careful selection and slow injections. Reducing the dose is unsatisfactory from a practical aspect, since the number of injections needed is then increased. There is thus still a need for a less toxic iron preparation for parenteral use. The newer intramuscular iron (’Imferon’) is perhaps an advance, but even this may result in toxic reactions (Ross 1955). Since intravenous saccharated iron oxide and intramuscular iron have been thought equally effective in the treatment of iron-deficiency anaemias (Cope et al. 1956) the assessment of their relative toxicity becomes particularly important.
Summary 802 anaemic patients treated with intravenous saccharated iron oxide were observed for toxic reactions. The reactions were related to the cardiovascular, respiratory, and gastro-intestinal systems and were accompanied by pains and fever. The overall incidence was 75% with
79 100 mg. doses and 43% with 500 mg. doses. Acute respiratory distress was seen only in patients with chronic lung disease and mitral stenosis. Reactions were least common (5%) in pure iron-deficiency anaemias, but when there was fever, toxaemia, or metabolic disturbance, the incidence increased to 24%. It is concluded that, with careful selection and the standard 100 mg. dose, the incidence of reactions will remain about 5% ; hence the necessity for less toxic parenteral iron preparations. I wish to thank Dr. Wallace Brigden and Dr. Adam Turnbull for their help, and those members of the staff of this hospital whose patients I have been permitted to see. REFERENCES
Barritt, D. W., Swain, G. C. (1953) Brit. med. J. i, 379. Cope, E., Gillhespy, R. O., Richardson, R. W. (1956) Ibid, ii, 638. Ellis, J. T. (1956) J. exp. Med. 103, 127. Librach, I. M. (1953) Brit. med. J. i, 21. Nissim, J. A. (1947) Lancet, ii, 49. (1954) Brit. med. J. i, 352. Robson, J. M. (1949) Lancet, i, 686. Ramsey, A. S. (1950) Brit. med. J. i, 1109. Ross, I. P. (1955) Lancet, i, 51. —
—
Preliminary Communication
infra-red analysis revealed a ’spectrum identical with that of &Dgr; 1—4-androstadiene-3-11-17-trione and b.. 1-4-
androstadiene-11-&bgr;-ol-3-17-dione respectively. Our results prove that 17-ketosteroid formation is only a minor pathway of prednisone and prednisolone metabolism, and offer additional evidence for the absence of tetrahydro-derivatives. The two 17-ketosteroids identified were present in only minor quantities (corresponding to less than 05% of the administered dose), suggesting again that the enzymatic systems converting the corticoids to 17-ketosteroids are largely inhibited by the presence of the dienone group. The urinary metabolites of prednisone and prednisolone so far known represent only a small proportion of the administered dose, and we are still ignorant of what happens to the bulk of the administered dose.
The very low transformation of A 1-corticoids to 17-ketosteroids enables us to study the depression of the adrenal cortex by determining urinary 17-ketosteroids before and during prednisone treatment. This may be of value in the study of Cushing’s syndrome for differentiation between adrenal hyperplasia and tumour. Medical Clinic, State University,
A. VERMEULEN M.D. Ghent
Ghent, Belgium
17-KETOSTEROIDS AFTER PREDNISONE AND PREDNISOLONE THE metabolism of A-corticoids is still incompletely known. So far, we know that reduction of the A ring is not a main pathway of metabolism, because in all metabolites so far identified the dienone grouping was preserved.12 Oxidation of the side-chain to the corresponding 17-ketosteroid generally follows the reduction of the A ring, so it is to be expected that 17-ketosteroid formation will be only a minor pathway of prednisone and prednisolone metabolism. To date, 17-ketosteroid excretion after administration of prednisone and prednisolone has not been thoroughly studied. The matter is complicated by the fact that these substances do not comof 17-ketopletely suppress the endogenous formation steroids. Slaunwhite and Sandberg 3 found very low 17-ketosteroid excretion during prednisone treatment. Recently wehave had the opportunity to study the 17-ketosteroid excretion pattern in patients who had undergone bilateral ovariectomy and adrenalectomy on account of metastatising breast carcinoma. The patients were given prednisolone 80 mg. daily and the collected urines were extracted with benzene for 17-ketosteroid determination by the usual method. The dried extract was purified by girardisation. Total 17-ketosteroids were determined by the method of Holtorff-Koch on a suitable aliquot. The remainder of the extract was to subjected gradient elution chromatography on alumina. Less than 2% of the prednisolone administered could be recovered as 17-ketosteroid. The chromatogram showed two main peaks of dinitrobenzene-reacting material. The fractions corresponding to each peak were pooled and evaporated to dryness. An aliquot of each residue was subjected to paper-chromatography in the systems toluol/cyclohexane (1/3) propyleneglycol, and heptane/propyleneglycol. The chromatograms revealed a steroid whose mobility was similar to that of &Dgr;1-adrenosterone and &Dgr;1—4-adrostadiene-
11- &bgr;-ol-3-17 -dione respectively, showing ultraviolet absorption (254 mu source) without sodafluorescence and with positive dinitrobenzene reaction. Recrystallisation of the residues from acetone and petroleum ether yielded colourless crystals whose meltingpoints were respectively 195-196 and 183-185°C. Finally, Gray, C. H., Green, M. A. S., Holness, N. J., Lunnon, J. B J. Endocrin. 1956, 14, 146. 2. Vermeulen, A. Acta endocr., Copenhagen, 1956, 23, 113. 3. Slaunwhite, W. R., Sandberg, A. A. J. clin. Endocrin. Metabol. 1957, 17, 395. 1.
New Inventions OUTPATIENT TREATMENT OF THE FRACTURED FEMORAL SHAFT IN CHILDREN
in lbadan will improve when the new opens; but at present beds are so scarce that children cannot be treated as inpatients unless they present some very serious pædiatric problem, and they have to be discharged as soon as possible. The child with a fractured femur blocked a bed for 3-6 weeks, and often he was discharged in very unsatis" factory 11/2-bip spicas as soon as there was any radiological callus. Wedecided therefore to try a portable hed for gallows traction, a.s used (Dr. Ra,lnh Hendrickse
CONDITIONS
teaching hospital
"
told me) in a South African hospital. A prototype was made by the hospital maintenance staff from ‘ Dexian ’ light angled-steel (fig. 1) the measurements being: Bed frame.. Gallows standard
Legs
27 27
x
x
....
18 in. 18 in. 9 in.
Other models were made to suit individual patients. For example : For a child a month old: 18 x 9 in. Bed frame.. 18 x 9 in. Gallows .... For children of 6-10 years : Bed frame.. 30 x 18 in. Gallows.... 30 x 18 in.
The bed-frame
was
com-
of stretcher canvas, secured to the frame by standard In practice cord lacing. the dexian crosspiece was placed lower on the legs so that the buttocks could at no time touch metal. The patient’s legs are suspended from the gallows by skin-traction
pleted by
a
piece