868
inactivated poliovaccine in varying
amounts from 1954 through 1962. On June 30, 1961, new manufacturing regulations were established to free the Salk vaccine of SV40. Previous lots of Salk vaccine, however, were not withdrawn from the market. Such vaccine was permitted to be stored for one year and thereafter permitted a shelf life of six months.1 Ingested Sabin attenuated live poliovaccine was only first licensed and marketed in the USA following the new regulations of June 30, 1961, which called for poliovaccines to be free of SV40. An airline steward arriving from Europe is thought to have initiated the 1981 AIDS epidemic in the USA through homosexual spread. However, the earliest documented case of AIDS in the United States was retrospectively diagnosed in 1968.2
Child and Family, PO Box 508, Oak Park, Illinois 60303, USA
some HIV-seronegative individuals, we examined for the presence of tat sequences in peripheral-blood lymphocytes by PCR; the results were negative. Other workers7-9 have suggested that another, as yet undiscovered, agent could be implicated in the pathogenesis of KS. A. CASTRO Service of Internal Medicine, J. PEDREIRA Juan Hospital Canalejo, V. SORIANO 15006 La Coruña, Spain, Centre of Clinical Investigation, I. HEWLETT Instituto de Salud Carlos III, Madrid, B. JHOSI and Laboratory of Retrovirology, J. EPSTEIN Food and Drug Administration,
Bethesda, USA
J. GONZÁLEZ-LAHOZ
case definition for AIDS MMWR 1987; 36 (suppl 1): 3-15. 2. Afrasiabi R, Mitsuyasu R, Nishanian P, et al. Characterization of a distinct subgroup of high-risk persons with Kaposi’s sarcoma and good prognosis who present with normal T4 cell number and T4:T8 ratio and negative HTLV-III/LAV serologic test results. Am J Med 1986; 81: 969-73. 3. Friedman-Kien A, Satsman B, Cao Y, et al. Kaposi’s sarcoma in HIV-negative homosexual men. Lancet 1990; 335: 168-69. 4. Garcia-Muret MP, Sonano V, Pujol R, Hewlett I, Clotet B, Moragas J. AIDS and Kaposi’s sarcoma pre-1979 Lancet 1990; 335: 969-70. 5. Veyssier-Belot C, Couderc L, Desgranges C. Kaposi’s sarcoma and HTLV-I infection. Lancet 1990, 336: 575. Y 6. Ho D, Moudgil T, Robin H, Alam M, Wallace B, Mizrachi HIV-1 in a seronegative patient with visceral Kaposi’s sarcoma and hypogammaglobulinemia. Am J Med
1. CDC. Revision of the CDC surveillance
HERBERT RATNER
Shah, Kerti, Nathanson, Neal. Exposure to SV40: review and comment. Am J Epidemiol 1976; 103: 1-12. 2. Garry, Robert F, et al. Documentation of an AIDS virus infection in the United States in 1968. JAMA 1988; 260: 2085-67. 1.
Kaposi’s sarcoma and disseminated HIV-negative individual
tuberculosis in
1989; 86: 349-51. Tschaachler E, Zonzits E, et al. Endemic Kaposi’s sarcoma in seronegative persons: demonstration of retrovirus-like particles in cutaneous lesions. J Invest Dermatol 1990; 95: 371-81 8. Bowden F, McPhee D, Deacon N, et al. Antibodies to gp41 and nef in otherwise HIV-negative homosexual man with Kaposi’s sarcoma. Lancet 1991; 337: 1313-14. 9 Huang YQ, Li JJ, Rush MG, et al. HPV-16-related DNA sequences in Kaposi’s sarcoma. Lancet 1992, 339: 515-18. 7.
SIR,-A 42-year-old man was seen in November, 1990, because he had two red-brown nodules on the left foot. Skin biopsy specimens showed atypical spindle cells arranged in fascicles, suggesting Kaposi’s sarcoma (KS). He was in a stable heterosexual relationship and denied other sexual partners. He had no history of drug misuse or blood product transfusion. He denied use of recreational nitrite inhalants, and had no history of opportunistic infections, lymphoreticular malignant disease, or use of immunosuppressive drugs. Nor had he visited the United States, the Caribbean, or Africa. His wife was HIV-seronegative. He had no other KS lesions. White cell count was 4009/ul and total lymphocyte count was 670/)il, wih 120/nl CD4 cells. CD4/CD8 ratio was 0-2. Total and differential immunoglobulin concentrations were normal. Other haematological and biochemical indices were all normal. Tests for antibody to cytomegalovirus, herpes simplex virus, Treponema pallidum, hepatitis B and C viruses, and toxoplasma were negative. No antibodies to HIV-1 or HIV-2 were demonstrable by repeated ELISA and western blot analysis in various serum samples obtained at that time. HIV antigenaemia was also repeatedly negative. Nine months later the patient returned with cough and dyspnoea. White cell count was 9300/1, total lymphocyte count 697/jI, CD4 cells 146/ul, and CD4/CD8 ratio 0-56. Chest radiography showed a bilateral interstitial infiltrate. Bronchoscopy was indicated, and bronchoalveolar lavage was negative for Pneurrwcystis carinii, bacteria, and fungal infection. Ziehl and Lowenstein analyses were also negative. Thoracotomy and lung biopsy were done, which disclosed multiple granulomas with positive results (Ziehl and Lowenstein) for Mycobacterium tuberculosis. At that time, a miliary pattern was seen overlying the previous interstitial infiltrate on the chest radiograph. In addition, ultrasonography showed hepatosplenomegaly, and he had a cholestatic biochemical pattern. Antituberculous drugs were started, and clinical symptoms and abnormal laboratory findings resolved. The patient continues to be in good health, and no new KS lesions have appeared. In January, 1992, he had 40/ul CD4 cells and remains HIV-seronegative. According to CDC criteria,’ this patient should have had a diagnosis of AIDS. Although more than 20 cases of KS have been reported among HIV-seronegative individuals judged at high-risk for HIV infection,2-4 we believe that this case is unique because the patient had a low CD4 cell count and at least one opportunistic infection. HTLV-I infection’ or hypogammaglobulinaemiabhave been reported in similar cases, but were excluded in our patient. In fact, HIV-1gag, tat, and env genomic sequences, and HTLV-1 tax sequences were investigated in DNA extracted from peripheral blood mononuclear cells, and results were repeatedly negative. Because it has been postulated that a replication defective HIV that can express TAT (a growth factor for KS cells) may cause KS in
Rappersberger K, HIV-1
Local anaesthesia to prevent post-laparoscopic shoulder pain SiR,—There is argument about the best way to present and analyse visual analogue pain scores. Should they be treated for what they are, ordinal data, to be described by median and intercentile range and analysed by non-parametric tests-or can they be regarded as interval data, and described and analysed using parametric descriptions and tests? Dr Narchi and colleagues’ paper (Dec 21/28, p 1569) on gynaecological laparoscopy illustrates the absurdity of describing pain scores parametrically unless they are distributed roughly normally. The scale used was the standard 10 cm one with a possible range of score of zero to 10. Table II presents mean and SD pain scores in four groups (control, saline, lignocaine, bupivacaine) at six time points. In these 24 sets of figures the mean is smaller than the SD in 17. In the most extreme example (lignocaine at time zero) the mean is 0-92 and the SD is 2 38. The scores are clearly not distributed normally, being skewed by the large number of zero scores. Table in shows that 22 of 35 patients given intraperitoneal local anaesthetic were pain-free. On the assumption that this proportion applies to the figures for lignocaine at time zero, 13 of the 20 patients will have had pain scores of zero, and to generate the mean (SD) presented would require that the other 7 observations contain one or two very high scores: for instance, scores of 0,5, 0,5, 0’5,1’5,2,4, and 9,5 plus 13 zeros have a of093 and SD of 2-25. set up four groups of patients and demonstrated nj significant differences between control and saline or between lignocaine and bupivacaine, they then combine the non-treated (control and saline) and treated (lignocaine and bupivacaine) groups for further comparison. (They do not say if this had been intended at the outset, though with smallish numbers and a large variability there must have been the risk of a type II error in the original comparisons.) The figure for these data exaggerates their findings by having its y-axis restricted to a range of 0-4, whereas many scores were more than 4. Curiously, the combined SDs on the graph are smaller than those in table ii for the original groupings--eg, at 8 h SDs measured from the graph are 1-67 (non-treatment) and 1 30 (treatment) while those in table u are 2 83 and 3-32 (control and saline) and 1 99 and 2-17 (lignocaine and bupivacaine). Probably the most important finding was that 22 of 35 patients given intraperitoneal local anaesthetic were pain-free compared mean
Having
869
with 10 of 30 in the non-treatment group, but the confidence limits difference are wide, and 15 of the 80 patients recruited were withdrawn. My conclusion from this paper is that intraperitoneal local anaesthesia could be a useful technique in this setting but that Narchi et al are premature in describing it as "efficient"-and mistaken in claiming it to be "non-invasive". on this
Department of Anaesthesia, University of Bristol and Southmead Hospital, Bristol BS10 5NB, UK
NEVILLE W. GOODMAN
Transcutaneous ultrasound measurement of flow in internal mammary artery SIR,-Our approach differs from that of Professor de Bono and colleagues (Feb 15, p 379). We studied patients serially, attempting transcutaneous imaging before and after surgery and making direct intraoperative free flow measurements. 35 patients admitted for elective cardiac surgery (29 males, 6 females; aged 43-72) underwent preoperative transcutaneous imaging of left and right internal mammary arteries with a 7-5 MHz colour flow duplex scanner. The left internal mammary artery was satisfactorily visualised in all patients (mean diameter 2-2 [SD 03] mm, peak systolic velocity 76-4 [23’4] cm/s) with a calculated mean flow of 43 (16-7) ml/min [range 21-90]). The right internal mammary artery was visualised satisfactorily in 32 patients (mean 2-4 [SD 04] mm, peak systolic velocity 72-7 [23’1] cm/s with a mean derived flow of 41 [16’7] ml/min [range 20-80]). Intraoperative free flow measurements were made in 15 patients before cardiopulmonary bypass with a measured mean flow of 69 ml/min (range 36-140). Intraoperative flows correlated poorly with calculated preoperative flows (r=0’l). Postoperative imaging of internal mammary artery to left anterior descending coronary artery grafts was attempted in 9 patients and satisfactory doppler frequency signals were obtained in 6. In only 2 patients was postoperative imaging of the graft adequate to allow diameter and hence the calculations of flow. There was a reduction in peak systolic frequency and increased peak diastolic frequency compared with preoperative measurements indicating predominantly diastolic graft flow. Our results therefore concur with those of de Bono et al in that ultrasonic imaging of the native internal mammary artery is almost always possible. After grafting, the flow patterns within the graft follow those of the coronary vasculature. In addition we have shown that intraoperative measurements of free flow are not predicted by preoperative measurements, probably because of the multifactorial influences on intraoperative flow (spasm and so on). Where our experience diverges from that of de Bono et al is in the postoperative imaging of internal mammary to coronary artery grafts. While we were able to obtain doppler signals from 6 out of 9 of these grafts, satisfactory imaging to allow accurate diameter measurements and hence derived flows was possible in only 2. We believe that this is consistent with the surgical principles of internal mammary harvesting which are to divide all its branches and mobilise the vessel to the level of the subclavian artery beyond the first intercostal space.’ Since the natural tendency of the graft is to fall away from the chest wall there are sound anatomical reasons why satisfactory transcutaneous postoperative imaging may not be possible in a substantial proportion of patients unless the original mobilisation is inadequate. de Bono et al acknowledge that 40% of grafts in their series could not be imaged and note the large potential for error in derived flow measurements in small-calibre vessels with dopper ultrasound techniques. It therefore seems to us more appropriate to conclude that it is unlikely to be either a valuable technique in clinical follow-up, given its lack of sensitivity in graft detection, or in serial studies of physiology or pharmacology, given the potential large errors inherent in derived flows in small-calibre vessels.
measurements
Department of Cardiac Surgery, University Hospital of Wales, Cardiff CF4 4XW, UK
ALAN J. BRYAN SION P. BARNARD
1 Green GE Use of internal thoracic artery for coronary artery
1989; 79: I-30-I-33.
grafting.
Circulation
Lithium and pregnancy SIR,-Dr Jacobson and colleagues (Feb 29, p 530) conclude from their prospective study that "lithium is not an important human teratogen". The study does not necessarily support this optimistic view. Ebstein’s anomaly in the fetus of a lithium-treated mother strengthens the view’ that this very rare cardiac defect is associated with lithium treatment. Jacobson’s study lacked the statistical power to show whether the condition was truly more or less common in the offspring of exposed women than in controls. However, if the incidence in the general population is 1 in 20 000 births, the probability of finding 1 or more cases in 149 births is 0-007. Jacobson et al also found an increase in the rate of all congenital defects combined. The risk ratio in the lithium-exposed population was 12 and the 95% confidence interval ranged up to 6-7. Our review of lithium’s teratogenicity concluded that only a prospective trial can give a definitive answer.2 Jacobson and colleagues’ study is not the trial required and we would still recommend that, if possible, lithium should be withdrawn or avoided during the first trimester of pregnancy. West Midlands Poisons Unit, Dudley Road Hospital,
Birmingham B18 7QH, UK
R. E. FERNER
Northern Regional Drug and Therapeutics Centre, Wolfson Unit, Newcastle upon Tyne
J. M. SMITH
1. Weinstein MR, Goldfield MD. Cardiovascular malformanons with lithium use during
pregnancy. Am J Psychiatry 1975; 132: 529-31. 2. Femer RE, Smith JM. Disorders of the fetus and infant. In: Davies DM, ed. Oxford textbook of adverse drug reactions. 4th ed. Oxford: Oxford University Press, 1991: 62-98.
** This letter has been shown - end. L.
to
Dr
Koren, whose reply follows.
SIR,-We agree that the case of Ebstein’s anomaly supports a potential association between lithium and this defect. However, Dr Ferner and Dr Smith misinterpret the results for the overall malformation rate. One does not judge such a figure by the upper 95 % confidence limit but by whether the lower limit is below unity. Here the risk ratio was 1(95% CI 0-2-5-7). More importantly, we did not find increased risk for the more common cardiac malformation suggested previously. Ferner and Smith suggest that "if possible lithium should be withdrawn or avoided" but what does "if possible" mean? Everyone agrees that pregnant women should receive only drugs they need-but how can one tell for sure? In Motherisk we have witnessed such exercises that ended in suicide attempts. More importantly, even if Ebstein’s anomaly is a real association, severe cases can be detected during the second trimester. Ferner and Smith admit that a prospective study was needed but seem not to accept the one that refutes their 1991 recommendation. Motherisk Program, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8
Colorectal
cancer
and
GIDEON KOREN
dietary intervention
IR,—iipidemiotogical studies suggest a link between diet and the risk of colorectal cancer.1.2 Since this cancer is difficult to treat, more emphasis is being placed on dietary intervention. However, a word of caution is necessary. The dietary administration of supplementary calcium can suppress the proliferation of colonic cells;3 and this has generally been interpreted as a good thing. Some patients at risk of colorectal cancer are now being given high levels of calcium, and at the 5th International Symposium on Colorectal Cancer (Turin, Sept 24-26, 1991) there was a workshop devoted to chemoprevention at which several trials of calcium supplementation were discussed. The study showing in-vivo and in-vitro3 sensitivity of normal colonic epithelium to calcium also revealed that colorectal cancers are relatively resistant to the inhibitory effects of calcium compared with normal epithelium and that colorectal adenomas are resistant. This indicates that a reduced response to the inhibitory effects of calcium happens at an early
inactivated poliovaccine in varying
amounts from 1954 through 1962. On June 30, 1961, new manufacturing regulations were established to free the Salk vaccine of SV40. Previous lots of Salk vaccine, however, were not withdrawn from the market. Such vaccine was permitted to be stored for one year and thereafter permitted a shelf life of six months.1 Ingested Sabin attenuated live poliovaccine was only first licensed and marketed in the USA following the new regulations of June 30, 1961, which called for poliovaccines to be free of SV40. An airline steward arriving from Europe is thought to have initiated the 1981 AIDS epidemic in the USA through homosexual spread. However, the earliest documented case of AIDS in the United States was retrospectively diagnosed in 1968.2
Child and Family, PO Box 508, Oak Park, Illinois 60303, USA
some HIV-seronegative individuals, we examined for the presence of tat sequences in peripheral-blood lymphocytes by PCR; the results were negative. Other workers7-9 have suggested that another, as yet undiscovered, agent could be implicated in the pathogenesis of KS. A. CASTRO Service of Internal Medicine, J. PEDREIRA Juan Hospital Canalejo, V. SORIANO 15006 La Coruña, Spain, Centre of Clinical Investigation, I. HEWLETT Instituto de Salud Carlos III, Madrid, B. JHOSI and Laboratory of Retrovirology, J. EPSTEIN Food and Drug Administration,
Bethesda, USA
J. GONZÁLEZ-LAHOZ
case definition for AIDS MMWR 1987; 36 (suppl 1): 3-15. 2. Afrasiabi R, Mitsuyasu R, Nishanian P, et al. Characterization of a distinct subgroup of high-risk persons with Kaposi’s sarcoma and good prognosis who present with normal T4 cell number and T4:T8 ratio and negative HTLV-III/LAV serologic test results. Am J Med 1986; 81: 969-73. 3. Friedman-Kien A, Satsman B, Cao Y, et al. Kaposi’s sarcoma in HIV-negative homosexual men. Lancet 1990; 335: 168-69. 4. Garcia-Muret MP, Sonano V, Pujol R, Hewlett I, Clotet B, Moragas J. AIDS and Kaposi’s sarcoma pre-1979 Lancet 1990; 335: 969-70. 5. Veyssier-Belot C, Couderc L, Desgranges C. Kaposi’s sarcoma and HTLV-I infection. Lancet 1990, 336: 575. Y 6. Ho D, Moudgil T, Robin H, Alam M, Wallace B, Mizrachi HIV-1 in a seronegative patient with visceral Kaposi’s sarcoma and hypogammaglobulinemia. Am J Med
1. CDC. Revision of the CDC surveillance
HERBERT RATNER
Shah, Kerti, Nathanson, Neal. Exposure to SV40: review and comment. Am J Epidemiol 1976; 103: 1-12. 2. Garry, Robert F, et al. Documentation of an AIDS virus infection in the United States in 1968. JAMA 1988; 260: 2085-67. 1.
Kaposi’s sarcoma and disseminated HIV-negative individual
tuberculosis in
1989; 86: 349-51. Tschaachler E, Zonzits E, et al. Endemic Kaposi’s sarcoma in seronegative persons: demonstration of retrovirus-like particles in cutaneous lesions. J Invest Dermatol 1990; 95: 371-81 8. Bowden F, McPhee D, Deacon N, et al. Antibodies to gp41 and nef in otherwise HIV-negative homosexual man with Kaposi’s sarcoma. Lancet 1991; 337: 1313-14. 9 Huang YQ, Li JJ, Rush MG, et al. HPV-16-related DNA sequences in Kaposi’s sarcoma. Lancet 1992, 339: 515-18. 7.
SIR,-A 42-year-old man was seen in November, 1990, because he had two red-brown nodules on the left foot. Skin biopsy specimens showed atypical spindle cells arranged in fascicles, suggesting Kaposi’s sarcoma (KS). He was in a stable heterosexual relationship and denied other sexual partners. He had no history of drug misuse or blood product transfusion. He denied use of recreational nitrite inhalants, and had no history of opportunistic infections, lymphoreticular malignant disease, or use of immunosuppressive drugs. Nor had he visited the United States, the Caribbean, or Africa. His wife was HIV-seronegative. He had no other KS lesions. White cell count was 4009/ul and total lymphocyte count was 670/)il, wih 120/nl CD4 cells. CD4/CD8 ratio was 0-2. Total and differential immunoglobulin concentrations were normal. Other haematological and biochemical indices were all normal. Tests for antibody to cytomegalovirus, herpes simplex virus, Treponema pallidum, hepatitis B and C viruses, and toxoplasma were negative. No antibodies to HIV-1 or HIV-2 were demonstrable by repeated ELISA and western blot analysis in various serum samples obtained at that time. HIV antigenaemia was also repeatedly negative. Nine months later the patient returned with cough and dyspnoea. White cell count was 9300/1, total lymphocyte count 697/jI, CD4 cells 146/ul, and CD4/CD8 ratio 0-56. Chest radiography showed a bilateral interstitial infiltrate. Bronchoscopy was indicated, and bronchoalveolar lavage was negative for Pneurrwcystis carinii, bacteria, and fungal infection. Ziehl and Lowenstein analyses were also negative. Thoracotomy and lung biopsy were done, which disclosed multiple granulomas with positive results (Ziehl and Lowenstein) for Mycobacterium tuberculosis. At that time, a miliary pattern was seen overlying the previous interstitial infiltrate on the chest radiograph. In addition, ultrasonography showed hepatosplenomegaly, and he had a cholestatic biochemical pattern. Antituberculous drugs were started, and clinical symptoms and abnormal laboratory findings resolved. The patient continues to be in good health, and no new KS lesions have appeared. In January, 1992, he had 40/ul CD4 cells and remains HIV-seronegative. According to CDC criteria,’ this patient should have had a diagnosis of AIDS. Although more than 20 cases of KS have been reported among HIV-seronegative individuals judged at high-risk for HIV infection,2-4 we believe that this case is unique because the patient had a low CD4 cell count and at least one opportunistic infection. HTLV-I infection’ or hypogammaglobulinaemiabhave been reported in similar cases, but were excluded in our patient. In fact, HIV-1gag, tat, and env genomic sequences, and HTLV-1 tax sequences were investigated in DNA extracted from peripheral blood mononuclear cells, and results were repeatedly negative. Because it has been postulated that a replication defective HIV that can express TAT (a growth factor for KS cells) may cause KS in
Rappersberger K, HIV-1
Local anaesthesia to prevent post-laparoscopic shoulder pain SiR,—There is argument about the best way to present and analyse visual analogue pain scores. Should they be treated for what they are, ordinal data, to be described by median and intercentile range and analysed by non-parametric tests-or can they be regarded as interval data, and described and analysed using parametric descriptions and tests? Dr Narchi and colleagues’ paper (Dec 21/28, p 1569) on gynaecological laparoscopy illustrates the absurdity of describing pain scores parametrically unless they are distributed roughly normally. The scale used was the standard 10 cm one with a possible range of score of zero to 10. Table II presents mean and SD pain scores in four groups (control, saline, lignocaine, bupivacaine) at six time points. In these 24 sets of figures the mean is smaller than the SD in 17. In the most extreme example (lignocaine at time zero) the mean is 0-92 and the SD is 2 38. The scores are clearly not distributed normally, being skewed by the large number of zero scores. Table in shows that 22 of 35 patients given intraperitoneal local anaesthetic were pain-free. On the assumption that this proportion applies to the figures for lignocaine at time zero, 13 of the 20 patients will have had pain scores of zero, and to generate the mean (SD) presented would require that the other 7 observations contain one or two very high scores: for instance, scores of 0,5, 0,5, 0’5,1’5,2,4, and 9,5 plus 13 zeros have a of093 and SD of 2-25. set up four groups of patients and demonstrated nj significant differences between control and saline or between lignocaine and bupivacaine, they then combine the non-treated (control and saline) and treated (lignocaine and bupivacaine) groups for further comparison. (They do not say if this had been intended at the outset, though with smallish numbers and a large variability there must have been the risk of a type II error in the original comparisons.) The figure for these data exaggerates their findings by having its y-axis restricted to a range of 0-4, whereas many scores were more than 4. Curiously, the combined SDs on the graph are smaller than those in table ii for the original groupings--eg, at 8 h SDs measured from the graph are 1-67 (non-treatment) and 1 30 (treatment) while those in table u are 2 83 and 3-32 (control and saline) and 1 99 and 2-17 (lignocaine and bupivacaine). Probably the most important finding was that 22 of 35 patients given intraperitoneal local anaesthetic were pain-free compared mean
Having
869
with 10 of 30 in the non-treatment group, but the confidence limits difference are wide, and 15 of the 80 patients recruited were withdrawn. My conclusion from this paper is that intraperitoneal local anaesthesia could be a useful technique in this setting but that Narchi et al are premature in describing it as "efficient"-and mistaken in claiming it to be "non-invasive". on this
Department of Anaesthesia, University of Bristol and Southmead Hospital, Bristol BS10 5NB, UK
NEVILLE W. GOODMAN
Transcutaneous ultrasound measurement of flow in internal mammary artery SIR,-Our approach differs from that of Professor de Bono and colleagues (Feb 15, p 379). We studied patients serially, attempting transcutaneous imaging before and after surgery and making direct intraoperative free flow measurements. 35 patients admitted for elective cardiac surgery (29 males, 6 females; aged 43-72) underwent preoperative transcutaneous imaging of left and right internal mammary arteries with a 7-5 MHz colour flow duplex scanner. The left internal mammary artery was satisfactorily visualised in all patients (mean diameter 2-2 [SD 03] mm, peak systolic velocity 76-4 [23’4] cm/s) with a calculated mean flow of 43 (16-7) ml/min [range 21-90]). The right internal mammary artery was visualised satisfactorily in 32 patients (mean 2-4 [SD 04] mm, peak systolic velocity 72-7 [23’1] cm/s with a mean derived flow of 41 [16’7] ml/min [range 20-80]). Intraoperative free flow measurements were made in 15 patients before cardiopulmonary bypass with a measured mean flow of 69 ml/min (range 36-140). Intraoperative flows correlated poorly with calculated preoperative flows (r=0’l). Postoperative imaging of internal mammary artery to left anterior descending coronary artery grafts was attempted in 9 patients and satisfactory doppler frequency signals were obtained in 6. In only 2 patients was postoperative imaging of the graft adequate to allow diameter and hence the calculations of flow. There was a reduction in peak systolic frequency and increased peak diastolic frequency compared with preoperative measurements indicating predominantly diastolic graft flow. Our results therefore concur with those of de Bono et al in that ultrasonic imaging of the native internal mammary artery is almost always possible. After grafting, the flow patterns within the graft follow those of the coronary vasculature. In addition we have shown that intraoperative measurements of free flow are not predicted by preoperative measurements, probably because of the multifactorial influences on intraoperative flow (spasm and so on). Where our experience diverges from that of de Bono et al is in the postoperative imaging of internal mammary to coronary artery grafts. While we were able to obtain doppler signals from 6 out of 9 of these grafts, satisfactory imaging to allow accurate diameter measurements and hence derived flows was possible in only 2. We believe that this is consistent with the surgical principles of internal mammary harvesting which are to divide all its branches and mobilise the vessel to the level of the subclavian artery beyond the first intercostal space.’ Since the natural tendency of the graft is to fall away from the chest wall there are sound anatomical reasons why satisfactory transcutaneous postoperative imaging may not be possible in a substantial proportion of patients unless the original mobilisation is inadequate. de Bono et al acknowledge that 40% of grafts in their series could not be imaged and note the large potential for error in derived flow measurements in small-calibre vessels with dopper ultrasound techniques. It therefore seems to us more appropriate to conclude that it is unlikely to be either a valuable technique in clinical follow-up, given its lack of sensitivity in graft detection, or in serial studies of physiology or pharmacology, given the potential large errors inherent in derived flows in small-calibre vessels.
measurements
Department of Cardiac Surgery, University Hospital of Wales, Cardiff CF4 4XW, UK
ALAN J. BRYAN SION P. BARNARD
1 Green GE Use of internal thoracic artery for coronary artery
1989; 79: I-30-I-33.
grafting.
Circulation
Lithium and pregnancy SIR,-Dr Jacobson and colleagues (Feb 29, p 530) conclude from their prospective study that "lithium is not an important human teratogen". The study does not necessarily support this optimistic view. Ebstein’s anomaly in the fetus of a lithium-treated mother strengthens the view’ that this very rare cardiac defect is associated with lithium treatment. Jacobson’s study lacked the statistical power to show whether the condition was truly more or less common in the offspring of exposed women than in controls. However, if the incidence in the general population is 1 in 20 000 births, the probability of finding 1 or more cases in 149 births is 0-007. Jacobson et al also found an increase in the rate of all congenital defects combined. The risk ratio in the lithium-exposed population was 12 and the 95% confidence interval ranged up to 6-7. Our review of lithium’s teratogenicity concluded that only a prospective trial can give a definitive answer.2 Jacobson and colleagues’ study is not the trial required and we would still recommend that, if possible, lithium should be withdrawn or avoided during the first trimester of pregnancy. West Midlands Poisons Unit, Dudley Road Hospital,
Birmingham B18 7QH, UK
R. E. FERNER
Northern Regional Drug and Therapeutics Centre, Wolfson Unit, Newcastle upon Tyne
J. M. SMITH
1. Weinstein MR, Goldfield MD. Cardiovascular malformanons with lithium use during
pregnancy. Am J Psychiatry 1975; 132: 529-31. 2. Femer RE, Smith JM. Disorders of the fetus and infant. In: Davies DM, ed. Oxford textbook of adverse drug reactions. 4th ed. Oxford: Oxford University Press, 1991: 62-98.
** This letter has been shown - end. L.
to
Dr
Koren, whose reply follows.
SIR,-We agree that the case of Ebstein’s anomaly supports a potential association between lithium and this defect. However, Dr Ferner and Dr Smith misinterpret the results for the overall malformation rate. One does not judge such a figure by the upper 95 % confidence limit but by whether the lower limit is below unity. Here the risk ratio was 1(95% CI 0-2-5-7). More importantly, we did not find increased risk for the more common cardiac malformation suggested previously. Ferner and Smith suggest that "if possible lithium should be withdrawn or avoided" but what does "if possible" mean? Everyone agrees that pregnant women should receive only drugs they need-but how can one tell for sure? In Motherisk we have witnessed such exercises that ended in suicide attempts. More importantly, even if Ebstein’s anomaly is a real association, severe cases can be detected during the second trimester. Ferner and Smith admit that a prospective study was needed but seem not to accept the one that refutes their 1991 recommendation. Motherisk Program, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8
Colorectal
cancer
and
GIDEON KOREN
dietary intervention
IR,—iipidemiotogical studies suggest a link between diet and the risk of colorectal cancer.1.2 Since this cancer is difficult to treat, more emphasis is being placed on dietary intervention. However, a word of caution is necessary. The dietary administration of supplementary calcium can suppress the proliferation of colonic cells;3 and this has generally been interpreted as a good thing. Some patients at risk of colorectal cancer are now being given high levels of calcium, and at the 5th International Symposium on Colorectal Cancer (Turin, Sept 24-26, 1991) there was a workshop devoted to chemoprevention at which several trials of calcium supplementation were discussed. The study showing in-vivo and in-vitro3 sensitivity of normal colonic epithelium to calcium also revealed that colorectal cancers are relatively resistant to the inhibitory effects of calcium compared with normal epithelium and that colorectal adenomas are resistant. This indicates that a reduced response to the inhibitory effects of calcium happens at an early
