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S.I. UNITS
1231 GLUCAGON IN TREATMENT OF ACUTE PANCREATITIS
SIR,—Glucagon has been shown to suppress exocrine pancreatic secretion,l and Knight et al. have suggested
its use in the treatment of acute pancreatitis.2,33 To date there has been no controlled clinical trial to assess the value of this treatment, and initial impressions should be viewed with caution.44 We have planned a controlled double-blind trial of glucagon therapy in patients with acute pancreatitis. The first twenty patients were regarded as a separate pilot study from which it would be decided whether there was any justification in embarking on a prolonged study over several years, and also to make any necessary adjustments to the protocol. The 20 patients admitted to the trial all fulfilled the following criteria: (1) history and physical examination compatible with acute pancreatitis; (2) plain X-ray abdomen showing no evidence of other disease; and (3) serum-amylase concentration greater than 600 Pimstone units per ml.,6 at the time of admission to the trial. Patients received glucagon or an equal volume of 0-15 M sodium chloride placebo on a random double-blind regimen, 1 mg. as a bolus dose and then a constant intravenous infusion of 15 tLg. per kg. body-weight per hour for 6 hours and 10 ug. per kg. body-weight per hour for a further 18 hours. Their clinical management included nasogastric decompression, intravenous fluids, antibiotics, and analgesia. Anticholinergics and aprotonin were specifically withheld. Patients were closely monitored clinically and biochemically every 6 hours for the first 48 hours, and once daily thereafter while in hospital, and were then followed up after discharge for 3-12 months.
Of the twenty patients initially entering the trial, nine received glucagon and eleven placebo. On analysis of the results, three of the treated groups and two controls were discarded because their serum-amylase levels had fallen below 600 units per ml. between the first blood-sample taken in the casualty department and actual start of the trial. However, excluding these patients did not alter the conclusions drawn from the trial when the results were analysed. Two-thirds of the patients in each group had alcohol-induced pancreatitis. Serum-amylase levels were slightly but not significantly lower in the treated group at the start of the trial. A significant difference which favoured the treated group (p < 0-05) was noted by 18 hours and persisted for a further 12 hours. There was also a significant difference on the 4th and 5th days (see accompanying figure). Serumamylase returned to normal in a mean time of 66 hours in treated patients compared to 264 hours in controls (P < 0-05). Similarly, pain disappeared in 80 hours in the treated group, compared with a mean of 120 hours in the controls (p < 005). One patient in the control group died with
hsemorrhagic pancreatitis and ursemia 17 days The period of inpatient hospital stay, duration of ileus, and development of pancreatic mass or No adverse cyst was unaltered by glucagon therapy. reactions to glucagon were encountered. This preliminary study in man has shown a significant lowering of serum-amylase levels and shortened duration of pain in patients with acute pancreatitis receiving glucagon compared with controls receiving saline solution. Controlled studies performed in our laboratory on pigs with induced pancreatitis have shown a highly significant reduction in morbidity and mortality (P < 0-005) with glucagon treatment.6 However, it is calculated that a trial of some two hundred and fifty patients would be necessary acute
after admission.
1.
2. 3. 4. 5. 6.
Dyck, W. P., Rudick, J., Hoexter, B., Janowitz, H. D. Gastroenterology, 1969, 56, 531. Knight, M. J., Condon, J. R., Day, J. L. Lancet, 1972, i, 1097. Condon, J. R., Knight, M., Day, J. L. Br. J. Surg. 1973, 60, 59. Slade, A. J. Br. med. J. 1974, i, 200. Pimstone, N. R. Clin. Chem. 1964, 10, 891. Waterworth, M. W., Barbezat, G. O., Terblanche, J. S. Afr. J. Surg. 1973, 11, 111.
Serum-amylase levels in glucagon-treated
Significant
differences
are
starred.
group and controls.
Vertical lines show
s.s.Ht.
accurately assess the value of glucagon therapy in reducing mortality and morbidity in human pancreatitis. In the light of our controlled experimental and preliminary clinical data, we consider a prolonged clinical trial of glucagon therapy a justified prerequisite to settle the question of its value in the treatment of acute pancreatitis in man. Such a trial is being launched using a similar dose regimen to the one described above, but infusing the glucagon for 72 instead of 24 hours. to
University Department of Surgery and Groote Schuur Hospital, Cape Town. Gastrointestinal Clinic, Department of Medicine, University of Cape Town, and Groote Schuur Hospital, Observatory 7925, South Africa.
M. W. WATERWORTH.
G. O. BARBEZAT S. BANK.
S.I. UNITS
SIR,-While the suggestion by Dr Hall (May 18, p. 1006) to simplify the introduction of s.i. units is superficially attractive, it is not so easy as he implies. As a pilot scheme on selected wards, we have been using a method of reporting some tests in clinical chemistry very similar to the one he advocates,in addition to reporting actual values. It seems to be useful, and we hope shortly to be able to apply it to all our reports. However, this is made feasible only by using a computer. Since many tests are affected by age and sex amongst other factors, there may not be one but many standard deviations or means of values for the test. Laboratories without a computer would hardly welcome the considerable labour involved in recalculating their results in the way Dr Hall suggests. Clinicians might appreciate the magnitude of the problem if on all their patients they had
to
record
———
for such
s
simple
measurements as
body-weight, temperature, pulse-rate, and blood-pressure; they would, of course, make due allowance for the fact that m (.means of the values) and s (standard deviation of the distribution) are affected by age, build, posture, time of day, &c. The introduction of
S.I.
units may well
cause some con-
fusion, though reports from hospitals that have already taken the plunge suggest this may not be serious. After all, doctors
were
resilient
enough
to
cope with metrication of
1232
drugs. The justification for s.i. units arises from the need for uniformity of units in science generally (for example, there are now some seven methods of expressing pressure), and in the short term their use appears to offer no advantages to doctors. However, the increasingly scientific nature of much of medicine makes it imperative that doctors are able to communicate with workers in other branches of science. The use of s.i. units will remove one barrier to such interdisciplinary exchange of information; it is to be hoped that there will be some advantage in the long term to compensate for overburdened hippocampi now. Queen Elizabeth Medical Centre, Edgbaston, Birmingham B15 2TH.
A. M. BOLD.
CARBON MONOXIDE AND SMOKING SiR,—Dr Hickey and his collaborators (March 9, p. 409) suggest that two of our studies support the hypothesis that elevated levels of COHb in smokers are influenced significantly by individual constitutional variations that affect both smoking behaviour and efficiency of detoxification of CO and COHb. Their interpretation is, in my view, biologically inconsistent and potentially misleading. They interpret the persistence of carbon-monoxide levels in smokers who were asked not to smoke for 8 hours as compatible with a constitutional hypothesis rather than with smoking-causality hypothesis. Would they similarly levels a few hours after interpret elevated blood-alcohol " a drinking bout as due to constitutional variations or to drinking? The courts and forensic pathologists hold that drinking is the cause. It seems inconsistent to define smokers as " self-selected " and then assert that smoking behaviour is constitutionally determined. " Self-selected to me implies that there is a degree of capacity to choose whether or not to smoke. In support of the truism that smoking behaviour in the population is not randomly allocated, Hickey et al. mistakenly assume that smokers who report that they do not inhale deeply have elevated COHb levels due to some constitutional inefficiency of CO detoxification. That humans have COHb levels in proportion to inhaling carbon monoxide has been abundantly documented from, inter alia, consistency of experimental exposures and smoking exposures 1-3; the effects on the cardiovascular system also show such consistency. Although some variation in the rate of uptake and of respiratory excretion has been documented and the sources and magnitude of endogenous carbon monoxide are well understood, no constitutional inefficiency of CO detoxification is known to me. When dose-response relationships are well established for a drug, pollutant, or pesticide, it seems illogical to attribute the presence of varying levels of such agents in blood or excreta primarily to an unknown constitutional inefficiency of detoxification, and not to variations in dose, and interval since exposure. That cigarette smokers can differ in some non-random ways from non-smokers can be admitted without the necessity of assuming that all smoking-associated disease is caused by these non-specified differences. Concern with alleviating the huge burden of smokingassociated disease requires that the " constitutional hypotheses " be considered and relegated then to its "
but the smoking exposure " symptoms " are not. Physicians who themselves have stopped smoking or who have patients who have done so will not be misled, since they know that their treatment has been effective. Epidemiological Studies Laboratory, California Health Department, 2151 Berkeley Way, California, Berkeley, 94704.
J. R. GOLDSMITH.
CELLULAR IMMUNE RESPONSIVENESS IN CIGARETTE SMOKERS SIR,-We should like to add to the observations of Dr Suciu-Foca and others (May 25, p. 1062) on the effects of smoking on lymphocyte function as measured by phytohaemagglutinin (P.H.A.) stimulation. We have studied the direct effect of smoking on lymphocyte response to P.H.A. in a group of 18 volunteer smokers. Subjects were asked to abstain from smoking for 12 hours and to have a standard breakfast of tea and toast (so as to minimise any effects of a recent and varying food intake on P.H.A. stimulation). Pre-smoking blood-samples were taken at 9.00 A.M.; the subject then smoked two cigarettes having a high tar and nicotine yield (’Richmond’ filter, 23 mg. tar per cigarette; 1-6 mg. nicotine per cigarette)in a 30-minute period. Further blood-samples were taken 15 minutes and 2 hours after completion of the smoking period. No further cigarettes were allowed until the completion of the study. The 45-minute interval COMPARISON
OF
P.H.A.-INDUCED
LYMPHOCYTE
STIMULATION
BEFORE AND AFTER SMOKING
"
appropriate place. In their final sentence Hickey et al. infer that the presumed constitutional " cause " of smoking is treatable, 1. Goldsmith, J. R., Landaw, S. A. Science, 1968, 162, 1352. 2. National Academy of Sciences-National Academy of Engineering. Effects of Chronic Exposure to low levels of Carbon Monoxide on Human Health, Behavior, and Performance. Washington, 1969. 3. Aronow, W. S., Isbell, M. W. Ann. intern. Med. 1973, 79, 392.
between the first and second bleeding was chosen because maximum plasma-nicotine levels are attained very soon after smoking,2and it was assumed that any facter that might affect lymphocyte function would also reach the circulation quickly. A group of 14 volunteer non-smokers were bled at the same time intervals as the smokers to determine the intrinsic variability of the test. P.H.A. stimulation studies were done, using three concentrations of purified P.H.A. (final concentrations of 0’3 g. per ml., 0-8 g. per ml., and 4-0 .g. per ml.) by a microculture method in McCoy’s 5A medium+15% fetal calf serum on Linbro 1S-FB-96 disposable plates (Biocult Ltd., Paisley). All cultures were done in triplicate. Saline was added to control wells in the same volume as P.H.A.
No alteration of P.H.A. stimulation that could be attributed to smoking was seen at any P.H.A. concentration (see table). Stimulations varied considerably over the 2!-hour period in some volunteers, but the fluctuation seen was similar in both groups of volunteers. The levels of stimulation were the same in both groups. The direct effects of nicotine on lymphocyte function were studied by adding nicotine to lymphocytes stimulated by 1. See Lancet, 1973, i, 874. 2. Isaac, P. F., Rand, M. J.
Nature, 1972, 236, 308.
SIR,—Glucagon has been shown to suppress exocrine pancreatic secretion,l and Knight et al. have suggested
its use in the treatment of acute pancreatitis.2,33 To date there has been no controlled clinical trial to assess the value of this treatment, and initial impressions should be viewed with caution.44 We have planned a controlled double-blind trial of glucagon therapy in patients with acute pancreatitis. The first twenty patients were regarded as a separate pilot study from which it would be decided whether there was any justification in embarking on a prolonged study over several years, and also to make any necessary adjustments to the protocol. The 20 patients admitted to the trial all fulfilled the following criteria: (1) history and physical examination compatible with acute pancreatitis; (2) plain X-ray abdomen showing no evidence of other disease; and (3) serum-amylase concentration greater than 600 Pimstone units per ml.,6 at the time of admission to the trial. Patients received glucagon or an equal volume of 0-15 M sodium chloride placebo on a random double-blind regimen, 1 mg. as a bolus dose and then a constant intravenous infusion of 15 tLg. per kg. body-weight per hour for 6 hours and 10 ug. per kg. body-weight per hour for a further 18 hours. Their clinical management included nasogastric decompression, intravenous fluids, antibiotics, and analgesia. Anticholinergics and aprotonin were specifically withheld. Patients were closely monitored clinically and biochemically every 6 hours for the first 48 hours, and once daily thereafter while in hospital, and were then followed up after discharge for 3-12 months.
Of the twenty patients initially entering the trial, nine received glucagon and eleven placebo. On analysis of the results, three of the treated groups and two controls were discarded because their serum-amylase levels had fallen below 600 units per ml. between the first blood-sample taken in the casualty department and actual start of the trial. However, excluding these patients did not alter the conclusions drawn from the trial when the results were analysed. Two-thirds of the patients in each group had alcohol-induced pancreatitis. Serum-amylase levels were slightly but not significantly lower in the treated group at the start of the trial. A significant difference which favoured the treated group (p < 0-05) was noted by 18 hours and persisted for a further 12 hours. There was also a significant difference on the 4th and 5th days (see accompanying figure). Serumamylase returned to normal in a mean time of 66 hours in treated patients compared to 264 hours in controls (P < 0-05). Similarly, pain disappeared in 80 hours in the treated group, compared with a mean of 120 hours in the controls (p < 005). One patient in the control group died with
hsemorrhagic pancreatitis and ursemia 17 days The period of inpatient hospital stay, duration of ileus, and development of pancreatic mass or No adverse cyst was unaltered by glucagon therapy. reactions to glucagon were encountered. This preliminary study in man has shown a significant lowering of serum-amylase levels and shortened duration of pain in patients with acute pancreatitis receiving glucagon compared with controls receiving saline solution. Controlled studies performed in our laboratory on pigs with induced pancreatitis have shown a highly significant reduction in morbidity and mortality (P < 0-005) with glucagon treatment.6 However, it is calculated that a trial of some two hundred and fifty patients would be necessary acute
after admission.
1.
2. 3. 4. 5. 6.
Dyck, W. P., Rudick, J., Hoexter, B., Janowitz, H. D. Gastroenterology, 1969, 56, 531. Knight, M. J., Condon, J. R., Day, J. L. Lancet, 1972, i, 1097. Condon, J. R., Knight, M., Day, J. L. Br. J. Surg. 1973, 60, 59. Slade, A. J. Br. med. J. 1974, i, 200. Pimstone, N. R. Clin. Chem. 1964, 10, 891. Waterworth, M. W., Barbezat, G. O., Terblanche, J. S. Afr. J. Surg. 1973, 11, 111.
Serum-amylase levels in glucagon-treated
Significant
differences
are
starred.
group and controls.
Vertical lines show
s.s.Ht.
accurately assess the value of glucagon therapy in reducing mortality and morbidity in human pancreatitis. In the light of our controlled experimental and preliminary clinical data, we consider a prolonged clinical trial of glucagon therapy a justified prerequisite to settle the question of its value in the treatment of acute pancreatitis in man. Such a trial is being launched using a similar dose regimen to the one described above, but infusing the glucagon for 72 instead of 24 hours. to
University Department of Surgery and Groote Schuur Hospital, Cape Town. Gastrointestinal Clinic, Department of Medicine, University of Cape Town, and Groote Schuur Hospital, Observatory 7925, South Africa.
M. W. WATERWORTH.
G. O. BARBEZAT S. BANK.
S.I. UNITS
SIR,-While the suggestion by Dr Hall (May 18, p. 1006) to simplify the introduction of s.i. units is superficially attractive, it is not so easy as he implies. As a pilot scheme on selected wards, we have been using a method of reporting some tests in clinical chemistry very similar to the one he advocates,in addition to reporting actual values. It seems to be useful, and we hope shortly to be able to apply it to all our reports. However, this is made feasible only by using a computer. Since many tests are affected by age and sex amongst other factors, there may not be one but many standard deviations or means of values for the test. Laboratories without a computer would hardly welcome the considerable labour involved in recalculating their results in the way Dr Hall suggests. Clinicians might appreciate the magnitude of the problem if on all their patients they had
to
record
———
for such
s
simple
measurements as
body-weight, temperature, pulse-rate, and blood-pressure; they would, of course, make due allowance for the fact that m (.means of the values) and s (standard deviation of the distribution) are affected by age, build, posture, time of day, &c. The introduction of
S.I.
units may well
cause some con-
fusion, though reports from hospitals that have already taken the plunge suggest this may not be serious. After all, doctors
were
resilient
enough
to
cope with metrication of
1232
drugs. The justification for s.i. units arises from the need for uniformity of units in science generally (for example, there are now some seven methods of expressing pressure), and in the short term their use appears to offer no advantages to doctors. However, the increasingly scientific nature of much of medicine makes it imperative that doctors are able to communicate with workers in other branches of science. The use of s.i. units will remove one barrier to such interdisciplinary exchange of information; it is to be hoped that there will be some advantage in the long term to compensate for overburdened hippocampi now. Queen Elizabeth Medical Centre, Edgbaston, Birmingham B15 2TH.
A. M. BOLD.
CARBON MONOXIDE AND SMOKING SiR,—Dr Hickey and his collaborators (March 9, p. 409) suggest that two of our studies support the hypothesis that elevated levels of COHb in smokers are influenced significantly by individual constitutional variations that affect both smoking behaviour and efficiency of detoxification of CO and COHb. Their interpretation is, in my view, biologically inconsistent and potentially misleading. They interpret the persistence of carbon-monoxide levels in smokers who were asked not to smoke for 8 hours as compatible with a constitutional hypothesis rather than with smoking-causality hypothesis. Would they similarly levels a few hours after interpret elevated blood-alcohol " a drinking bout as due to constitutional variations or to drinking? The courts and forensic pathologists hold that drinking is the cause. It seems inconsistent to define smokers as " self-selected " and then assert that smoking behaviour is constitutionally determined. " Self-selected to me implies that there is a degree of capacity to choose whether or not to smoke. In support of the truism that smoking behaviour in the population is not randomly allocated, Hickey et al. mistakenly assume that smokers who report that they do not inhale deeply have elevated COHb levels due to some constitutional inefficiency of CO detoxification. That humans have COHb levels in proportion to inhaling carbon monoxide has been abundantly documented from, inter alia, consistency of experimental exposures and smoking exposures 1-3; the effects on the cardiovascular system also show such consistency. Although some variation in the rate of uptake and of respiratory excretion has been documented and the sources and magnitude of endogenous carbon monoxide are well understood, no constitutional inefficiency of CO detoxification is known to me. When dose-response relationships are well established for a drug, pollutant, or pesticide, it seems illogical to attribute the presence of varying levels of such agents in blood or excreta primarily to an unknown constitutional inefficiency of detoxification, and not to variations in dose, and interval since exposure. That cigarette smokers can differ in some non-random ways from non-smokers can be admitted without the necessity of assuming that all smoking-associated disease is caused by these non-specified differences. Concern with alleviating the huge burden of smokingassociated disease requires that the " constitutional hypotheses " be considered and relegated then to its "
but the smoking exposure " symptoms " are not. Physicians who themselves have stopped smoking or who have patients who have done so will not be misled, since they know that their treatment has been effective. Epidemiological Studies Laboratory, California Health Department, 2151 Berkeley Way, California, Berkeley, 94704.
J. R. GOLDSMITH.
CELLULAR IMMUNE RESPONSIVENESS IN CIGARETTE SMOKERS SIR,-We should like to add to the observations of Dr Suciu-Foca and others (May 25, p. 1062) on the effects of smoking on lymphocyte function as measured by phytohaemagglutinin (P.H.A.) stimulation. We have studied the direct effect of smoking on lymphocyte response to P.H.A. in a group of 18 volunteer smokers. Subjects were asked to abstain from smoking for 12 hours and to have a standard breakfast of tea and toast (so as to minimise any effects of a recent and varying food intake on P.H.A. stimulation). Pre-smoking blood-samples were taken at 9.00 A.M.; the subject then smoked two cigarettes having a high tar and nicotine yield (’Richmond’ filter, 23 mg. tar per cigarette; 1-6 mg. nicotine per cigarette)in a 30-minute period. Further blood-samples were taken 15 minutes and 2 hours after completion of the smoking period. No further cigarettes were allowed until the completion of the study. The 45-minute interval COMPARISON
OF
P.H.A.-INDUCED
LYMPHOCYTE
STIMULATION
BEFORE AND AFTER SMOKING
"
appropriate place. In their final sentence Hickey et al. infer that the presumed constitutional " cause " of smoking is treatable, 1. Goldsmith, J. R., Landaw, S. A. Science, 1968, 162, 1352. 2. National Academy of Sciences-National Academy of Engineering. Effects of Chronic Exposure to low levels of Carbon Monoxide on Human Health, Behavior, and Performance. Washington, 1969. 3. Aronow, W. S., Isbell, M. W. Ann. intern. Med. 1973, 79, 392.
between the first and second bleeding was chosen because maximum plasma-nicotine levels are attained very soon after smoking,2and it was assumed that any facter that might affect lymphocyte function would also reach the circulation quickly. A group of 14 volunteer non-smokers were bled at the same time intervals as the smokers to determine the intrinsic variability of the test. P.H.A. stimulation studies were done, using three concentrations of purified P.H.A. (final concentrations of 0’3 g. per ml., 0-8 g. per ml., and 4-0 .g. per ml.) by a microculture method in McCoy’s 5A medium+15% fetal calf serum on Linbro 1S-FB-96 disposable plates (Biocult Ltd., Paisley). All cultures were done in triplicate. Saline was added to control wells in the same volume as P.H.A.
No alteration of P.H.A. stimulation that could be attributed to smoking was seen at any P.H.A. concentration (see table). Stimulations varied considerably over the 2!-hour period in some volunteers, but the fluctuation seen was similar in both groups of volunteers. The levels of stimulation were the same in both groups. The direct effects of nicotine on lymphocyte function were studied by adding nicotine to lymphocytes stimulated by 1. See Lancet, 1973, i, 874. 2. Isaac, P. F., Rand, M. J.
Nature, 1972, 236, 308.