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DANGERS OF INTRAVENOUS FAT INFUSIONS
967
requirements during the daylight hours. This would reduce the incidence of thrombophlebitis and seprohcl’ ticæmia, preserve peripheral veins so that they could be re-used after a few days central vein catheterisation would therefore be less frequently necessary, and allow the patient an undisturbed intravenous
night’s sleep. 1 Jasmin Avenue,
Chapel Park,
Westerhope, Newcastle upon Tyne NE5
1TL
CHRISTINE COLLIN JACK COLLIN
DANGERS OF INTRAVENOUS FAT INFUSIONS
SIR,—Your editorials’and subsequent correspondence of intravenous fat emulsions. The standard text on side-effects of drugs3 states that "acute reactions are rare", although an earlier volume4 mentioned hypotension and, occasionally, hypertension. Two major cerebral disasters during ’Intralipid’ infusions have been seen. A 22-year-old female with severe Crohn’s disease was being treated in 1970 with corticosteroids and was fed intravenously: this included intralipid. Occasional high blood-pressures were recorded, culminating at 240/170 mm Hg in the early morning of June 3. The blood-pressure was normal later that morning but by mid-day she complained of headache; she then had focal and generalised convulsions which were treated by infusions of mannitol and diazepam. That evening she was stuporose and had a stiff neck, but there were no other neurological signs. There were further major convulsions during the night and she lapsed into coma. A small retinal haemorrhage and petechix on the arms were noted. Electroencephalography showed severe generalised abnormalities. After 4 days consciousness returned, but she remained confused and dysmnesic for 2-3 weeks. It then emerged that she had cortical blindness. In the third week there was some vision in the right upper quadrant of the visual fields. During the next 6 years the Crohn’s disease remitted; however, she can only lead a sheltered existence in her parent’s house. She has no vision in the lower left quadrant but she can count fingers in the rest of the fie!ds, She can read N6 slowly and complains of inability to recognise faces (prosopagnosia): people are recognised by their voices. There have been no major convulsions, but she has daily minor parietal attacks in which she feels enormous and scared. During the attack she misjudges distances but can talk. The t.E.G, remains diffusely abnormal. The acute clinical illness resembled hypertensive encephalopathy.1 The retinal and skin haemorrhages could have resulted from asphyxia in the convulsions or from fat emboli. A 76-year-old man had a resection of the oesophagus for extensive carcinoma on Aug. 25, 1975. The anastomosis leaked, fluid collected in the mediastinum, and he was fed parenterally. On the tenth postoperative day, when he was receiving an infusion of intralipid, he suddenly stopped speaking to his family and became quadriplegic. There was no concomitant change in his pulse or blood-pressure, and he did not lose consciousness. On neurological examination 24 h later he had an almost complete motor aphasia. He seemed to understand but was apraxic. Cranial nerves were normal, but he had spastic weakness of all limbs. An E.E.G. was normal. 1 month later he spoke single words. The left side remained paralysed but he had limited use of a spastic right arm,and leg. He died on Nov. 21,1975. At necropsy the operation site was sound but there ’tas macroscopic tumour in one lymph-node, and acute pyelonephritis. There was no ischaemic damage of the myocardium have favoured the
Northern General Hospital, Edinburgh EH5 2DQ
E. H.
JELLINEK
use
°
1 Lancet, 1975, ii, 263. 2 ibid. 1976, i, 1059. 3 Dukes, M N G Meyler’s Side Effects of Drugs, vol VIII, p. 570. Amsterdam, 1975 4 Meyl er. L, Herxheimer, A Side Effects of Drugs, vol. VI, p. 511. Amsterdam, 1968 5 Jellinek, E H , Painter, M., Prineas, J., Ross Russell, R. Q Jl Med 1964,
33, 239
the coronaries were atheromatous. The great vessels of the neck were patent. Neuropathological study (Dr A. F. J. Maloney) revealed minimal atheroma of arteries and extensive cortical infarction in the distribution of both anterior cerebral arteries, right more than left, compatible with a duration of 2 or 3 months. There was a focal infarct of similar age in the watershed area on the convexity of the occipital lobe. Microscopy confirmed extensive healing infarcts: "the arteries in relation to the infarcts are all relatively normal and no thrombi are seen". Dr Maloney commented that the cause of the infarction was unknown, but the absence of myocardial infarction, and the experience of the first case, seem to incriminate the infusion ofintralipid.
though
COTRIMOXAZOLE AND FOLATE METABOLISM was developed as an antimicrobial antifol structure and the fact that it was because of its agent "found to antagonise competively folic and folinic acids in the growth of Lactobacillus casei".1 Thus, it is startling to see Dr Bateson and his colleagues (Aug. 14, p. 339) present evidence to "suggest" that trimethoprim interferes with the growth of L. casei. At the very least, the authors should have cited a previous publication2showing inhibition of the L. caseiserumfolate assay at the same serum-trimethoprim concentrations as they observed. If the authors had read the reference they cited3 to claim that there was a controversy about whether L. casei serumfolate falls on trimethoprim therapy, they would have seen that the reason the folate levels did not fall in that study was that a mutant strain of L. casei was used, which had been developed by the inventors of trimethoprim to be resistant to that drug. Thus, there was no controversy for them to solve in the first place. Although it may be helpful to the supplier of the commercial radiofolate-assay kit they worked with for them to claim that "radiofolate assay values correlate very well with the microbiological ones", their own data contradict that claim. The statistical method used to calculate p values for correlation coefficients essentially tests whether the slope of the regression line is significantly different from zero-i.e., the probability tested is whether sera with increasing microbiological-assay values are likely to have increasing radioassay values. It does not test whether the latter reliably duplicated the former, and the values shown (r=0-69-0-76) suggest that they did not. Reliable duplication in a similar number of samples results in correlation coefficients much closer to unity; the correlation coefficient observed during comparison of the microbiological and radioisotopic folate assays developed in this laboratory was 0.96.4 The claim that folic acid is more reliable labelled with 125I than with tritium is unsupported. 125I-Iabelled folate may be more convenient because it eliminates the need for liquid scintillation counting, but there is no published evidence that its label is more reliable than that of 3H-folate. Finally, much of their discussion is aimed at claiming that trimethoprim does not interfere with folate metabolism in man. This is not supported by the published data they failed 5 to cite, which has been reviewed elsewhere.
SIR,—Trimethoprim
Hematology and Nutrition Laboratory, Bronx Veterans Administration Hospital, and Columbia University College of Physicians and Surgeons, Bronx, N.Y 10468, U.S.A.
NEVILLE COLMAN VICTOR HERBERT
1. Rolo, I. M in Pharmacological Basis of Therapeutics (edited by L. A. Goodman and A Gilman); p. 1055. New York, 1975. 2. Asbjornsen, G. Acta path. microbiol scand. sect. B, 1974, 82, 371. 3. Khan, S B., Fern, A S., Brodsky, I. Clin. Pharmac. Ther 1968, 9, 550 4. Longo, D. L , Herbert, V. J. Lab clin. Med. 1976, 87, 138. 5. Herbert, V. J. infect. Dis. 1973, 128 (suppl.), s601.
requirements during the daylight hours. This would reduce the incidence of thrombophlebitis and seprohcl’ ticæmia, preserve peripheral veins so that they could be re-used after a few days central vein catheterisation would therefore be less frequently necessary, and allow the patient an undisturbed intravenous
night’s sleep. 1 Jasmin Avenue,
Chapel Park,
Westerhope, Newcastle upon Tyne NE5
1TL
CHRISTINE COLLIN JACK COLLIN
DANGERS OF INTRAVENOUS FAT INFUSIONS
SIR,—Your editorials’and subsequent correspondence of intravenous fat emulsions. The standard text on side-effects of drugs3 states that "acute reactions are rare", although an earlier volume4 mentioned hypotension and, occasionally, hypertension. Two major cerebral disasters during ’Intralipid’ infusions have been seen. A 22-year-old female with severe Crohn’s disease was being treated in 1970 with corticosteroids and was fed intravenously: this included intralipid. Occasional high blood-pressures were recorded, culminating at 240/170 mm Hg in the early morning of June 3. The blood-pressure was normal later that morning but by mid-day she complained of headache; she then had focal and generalised convulsions which were treated by infusions of mannitol and diazepam. That evening she was stuporose and had a stiff neck, but there were no other neurological signs. There were further major convulsions during the night and she lapsed into coma. A small retinal haemorrhage and petechix on the arms were noted. Electroencephalography showed severe generalised abnormalities. After 4 days consciousness returned, but she remained confused and dysmnesic for 2-3 weeks. It then emerged that she had cortical blindness. In the third week there was some vision in the right upper quadrant of the visual fields. During the next 6 years the Crohn’s disease remitted; however, she can only lead a sheltered existence in her parent’s house. She has no vision in the lower left quadrant but she can count fingers in the rest of the fie!ds, She can read N6 slowly and complains of inability to recognise faces (prosopagnosia): people are recognised by their voices. There have been no major convulsions, but she has daily minor parietal attacks in which she feels enormous and scared. During the attack she misjudges distances but can talk. The t.E.G, remains diffusely abnormal. The acute clinical illness resembled hypertensive encephalopathy.1 The retinal and skin haemorrhages could have resulted from asphyxia in the convulsions or from fat emboli. A 76-year-old man had a resection of the oesophagus for extensive carcinoma on Aug. 25, 1975. The anastomosis leaked, fluid collected in the mediastinum, and he was fed parenterally. On the tenth postoperative day, when he was receiving an infusion of intralipid, he suddenly stopped speaking to his family and became quadriplegic. There was no concomitant change in his pulse or blood-pressure, and he did not lose consciousness. On neurological examination 24 h later he had an almost complete motor aphasia. He seemed to understand but was apraxic. Cranial nerves were normal, but he had spastic weakness of all limbs. An E.E.G. was normal. 1 month later he spoke single words. The left side remained paralysed but he had limited use of a spastic right arm,and leg. He died on Nov. 21,1975. At necropsy the operation site was sound but there ’tas macroscopic tumour in one lymph-node, and acute pyelonephritis. There was no ischaemic damage of the myocardium have favoured the
Northern General Hospital, Edinburgh EH5 2DQ
E. H.
JELLINEK
use
°
1 Lancet, 1975, ii, 263. 2 ibid. 1976, i, 1059. 3 Dukes, M N G Meyler’s Side Effects of Drugs, vol VIII, p. 570. Amsterdam, 1975 4 Meyl er. L, Herxheimer, A Side Effects of Drugs, vol. VI, p. 511. Amsterdam, 1968 5 Jellinek, E H , Painter, M., Prineas, J., Ross Russell, R. Q Jl Med 1964,
33, 239
the coronaries were atheromatous. The great vessels of the neck were patent. Neuropathological study (Dr A. F. J. Maloney) revealed minimal atheroma of arteries and extensive cortical infarction in the distribution of both anterior cerebral arteries, right more than left, compatible with a duration of 2 or 3 months. There was a focal infarct of similar age in the watershed area on the convexity of the occipital lobe. Microscopy confirmed extensive healing infarcts: "the arteries in relation to the infarcts are all relatively normal and no thrombi are seen". Dr Maloney commented that the cause of the infarction was unknown, but the absence of myocardial infarction, and the experience of the first case, seem to incriminate the infusion ofintralipid.
though
COTRIMOXAZOLE AND FOLATE METABOLISM was developed as an antimicrobial antifol structure and the fact that it was because of its agent "found to antagonise competively folic and folinic acids in the growth of Lactobacillus casei".1 Thus, it is startling to see Dr Bateson and his colleagues (Aug. 14, p. 339) present evidence to "suggest" that trimethoprim interferes with the growth of L. casei. At the very least, the authors should have cited a previous publication2showing inhibition of the L. caseiserumfolate assay at the same serum-trimethoprim concentrations as they observed. If the authors had read the reference they cited3 to claim that there was a controversy about whether L. casei serumfolate falls on trimethoprim therapy, they would have seen that the reason the folate levels did not fall in that study was that a mutant strain of L. casei was used, which had been developed by the inventors of trimethoprim to be resistant to that drug. Thus, there was no controversy for them to solve in the first place. Although it may be helpful to the supplier of the commercial radiofolate-assay kit they worked with for them to claim that "radiofolate assay values correlate very well with the microbiological ones", their own data contradict that claim. The statistical method used to calculate p values for correlation coefficients essentially tests whether the slope of the regression line is significantly different from zero-i.e., the probability tested is whether sera with increasing microbiological-assay values are likely to have increasing radioassay values. It does not test whether the latter reliably duplicated the former, and the values shown (r=0-69-0-76) suggest that they did not. Reliable duplication in a similar number of samples results in correlation coefficients much closer to unity; the correlation coefficient observed during comparison of the microbiological and radioisotopic folate assays developed in this laboratory was 0.96.4 The claim that folic acid is more reliable labelled with 125I than with tritium is unsupported. 125I-Iabelled folate may be more convenient because it eliminates the need for liquid scintillation counting, but there is no published evidence that its label is more reliable than that of 3H-folate. Finally, much of their discussion is aimed at claiming that trimethoprim does not interfere with folate metabolism in man. This is not supported by the published data they failed 5 to cite, which has been reviewed elsewhere.
SIR,—Trimethoprim
Hematology and Nutrition Laboratory, Bronx Veterans Administration Hospital, and Columbia University College of Physicians and Surgeons, Bronx, N.Y 10468, U.S.A.
NEVILLE COLMAN VICTOR HERBERT
1. Rolo, I. M in Pharmacological Basis of Therapeutics (edited by L. A. Goodman and A Gilman); p. 1055. New York, 1975. 2. Asbjornsen, G. Acta path. microbiol scand. sect. B, 1974, 82, 371. 3. Khan, S B., Fern, A S., Brodsky, I. Clin. Pharmac. Ther 1968, 9, 550 4. Longo, D. L , Herbert, V. J. Lab clin. Med. 1976, 87, 138. 5. Herbert, V. J. infect. Dis. 1973, 128 (suppl.), s601.