- Email: [email protected]
ORAL CIMETIDINE IN SEVERE DUODENAL ULCERATION
4 TABLE
V-POST-CONCUSSION SYMPTOMS
AND POST-TRAUMATIC
AMNESIA IN PATIENTS WITH NO BLOOD-ALCOHOL
Numbers in
parentheses are percentages. d.f.=degrees of freedom.
Steadman and Graham’ reported that P.T.A. remains the best measure of severity when related to long-term results of the injury. While for severe head injuries amnesia may well be an accurate indicator of the severity of the trauma, it may not be as valuable in mild head injuries. It is certainly conceivable that each of the postconcussion symptoms is caused by injury to a specific area of brain tissue, and that amnesia also has a specific location. Symptoms and amnesia would then depend not only on the force of any shock-waves travelling through the brain, but their precise path. We tested this by dividing the head into a grid, and plotting the apparent area where major force had been applied. No positive correlalations with symptoms were found. This may have been due to the small numbers for any particular area. Also the presence of a wound or bruise did not by itself indicate the direction along which the force was travelling. A bruise in the same part of the forehead could be caused either by a blow causing backward thrust or one causing rotation. The lack of obvious correlation between P.T.A. and symptoms is also confirmed by the experience of cases with no complete amnesia and only a short period of feeling dazed, who none the less feel very nauseated, drowsy, and dizzy for two or three days. If such severe early symptoms can arise in cases with almost no amnesia, it is not surprising that some patients with symptoms continuing for six weeks and more also have very short amnesia. It is difficult to get enough information of the details of accidents to allow an accurate computation of the forces involved. Although most traffic accidents would appear to involve larger amounts of energy than falls from the same level, it was those patients who had had falls who had a higher symptom-rate. We cannot explain this. The higher symptom-rate in patients who blamed an employer or a large organisation appears to indicate a psychogehic or neurotic element in the cause of symptoms. It is a stronger indication than the absence of proof of organic factors-the usual grounds for a neurotic cause. Kay et al. reported a high correlation between middle-age, married status, social class iv, an industrial accident, a semi-skilled occupation, and a previous psychiatric history but gave no separate figures for industrial accidents. The marked difference in symptom-rates between men and women could possibly be due to different physical characteristics of the skull and brain in the two sexes, but is more likely to be due to differences in emotional and psychological sensitivity. Every post-concussion symptom is explicable on the basis of either organic injury or functional disorder. This is true both when treating patients and when attempting to give an opinion for medicolegal purposes.
While our results could be interpreted as an indication that some patients suffer from organic brain damage and others from post-traumatic neurosis, it seems probable that in many patients there is an interplay of both these elements. The main value of our study is the positive evidence it supplies. The neurotic element is indicated by the strong correlation between symptoms and motivation. Each of the correlations indicating an organic element would have been conclusive on its. own. The presence of four separate correlations appears to put the matter beyond all reasonable doubt. We thank Mrs McGovern and Mrs Armstrong for their help in foland for keeping all the basic documentation in order; the nurses and doctors of the accident and emergency department for cooperating in a research project despite very heavy day-to-day commitments ; Mrs J. J. Smith-Davidson and her staff for their help with data preparation; and the Department of Health and Social Services,
low-up visiting
Ireland, for a research grant. Requests for reprints should be addressed to W. H. R., Accident and Emergency Department, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA, Northern Ireland. Northern
REFERENCES 1. 2. 3. 4. 5.
Miller, H. Br. med. J. 1961, i, 919. Miller, H. Proc. R. Soc. Med. 1966, 59, 257. Taylor, A. R. Br. med. J. 1967, iii, 67. Gronwall, D., Wrightson, P. Lancet, 1974, ii, 605. Lidvall, H. F., Linderoth, B., Norton, B. Acta neurol.
scand.
1974, 50,
56. W. Br.
suppl. 6. 7. 8.
Lewin, med. J. 1968, i, 465. Steadman, J. G., Graham, J. G. Proc. R. Soc. Med. 1970, 63, 23. Kay, D. W. K., Kerr, T. A., Lassman, L. P. Lancet, 1971, ii, 1092.
ORAL CIMETIDINE IN SEVERE
DUODENAL ULCERATION A Double-blind Controlled Trial I. MCKENZIE G. P. CREAN
G. R. GRAY I. S. SMITH
G. GILLESPIE
Department of Surgery, Victoria Infirmary, and Gastrointestinal Centre, Southern General Hospital, Glasgow
Summary
outpatients with active endoscopically proven duodenal ulceration,
40 adult
who would otherwise have merited elective ulcer surgery, entered a double-blind trial of either cimetidine (1 g/day) or placebo. After twenty-eight days, 17 of 20
(85%) patients receiving cimetidine showed ulcer healing, compared with 5 of 20 patients receiving placebo (P<0·0005). Patients receiving cimetidine had significantly more pain-free days and pain-free nights than those receiving placebo. There was good correlation between ulcer healing and symptomatic relief (p<0·0005). Introduction
-
THE histamine H2-receptor antagonist cimetidine suppresses meal-stimulated and nocturnal gastric-acid secretion in man’2 and so has potential use in the management of duodenal peptic ulceration. Work from Sweden3 has provided early indications of promise in this role, and it is hoped that this compound will be free from the marrow depression of its predecessor metiamide. So far, in studies with H2-receptor antagonists, there has been
5
uncertainty regarding correlation between relief of symptoms and ulcer healing as judged endoscopically. The aims of the present study, therefore, were to assess by a prospective controlled double-blind trial firstly the therapeutic efficacy of oral cimetidine (lg/day) in the treatment of severe duodenal ulceration in patients who would otherwise have been submitted to ulcer surgery, and secondly to assess the correlation, if any, between symptomatic relief and ulcer healing.
Patients and Methods 40 adult outpatients who had severe and prolonged ulcer and who had been referred for ulcer surgery were admitted to the trial within one week of endoscopic confirmation of their ulcers. All gave their informed consent. During the week before the trial began gastric acid and pepsin ressponse to intravenous insulin 0.2 u/kg was measured. Full clinical assessment was made of the patients before their entry to the trial and again at two and four weeks. At the end of the fourth week a second endoscopy was performed to assess ulcer healing. After this second endoscopy and twelve to twenty-four
dyspepsia
Fig. 2-Comparison of pain-free days in cimetidine and placebo patients. Comparison of patients with and without pain (x.2 test) shows significant
improvement in the cimetidine group
in every week of trial.
Results
Relief of Ulcer Symptoms Day pain (fig. 2).-Comparison of patients in the cimetidine and placebo groups with regard to the number of pain-free days experienced during each of the four weeks of the trial, shows that there were significantly more patients without any pain in the cimetidine group. Nocturnal more
pain (fig. 3.-Similarly, significantly patients on cimetidine were pain-free during all
four weeks of the trial.
Fig. I-Comparison of day pain and night pain in cimetidine and placebo patients in week before trial. Figs. 1-4: N.s.=Not significant; 0 =placebo, e=cimetidine.
hours after stopping all trial medication, a second insulin test was done. On entry to the trial patients were randomly allocated to treatment with identically prepared tablets containing either cimetidine (20 patients) or placebo (20 patients). Cimetidine was taken orally in three 200 mg doses after meals and a night dose of 400 mg just before retiring. Every patient was provided with a supply of unmarked supplementary antacid (’Rennies’) with instructions to use freely in the event of unsatisfactory pain relief by the trial medication. All other medication where possible was discontinued, in particular all other anti-ulcer medicaments were withdrawn. Throughout the study patients made use of personal diary cards to record attacks of day or nocturnal pain, the severity of the pain, and the extent to which they made use of the supplementary antacids. The cimetidine (C) and placebo (P) groups were comparable with regard to age (C=46 years±2-9 s.E.; P=39 years±3-4 s.E.), (C, M/F=16/4; P, M/F=18/2) and duration of ulcer disease (C=14 years±2-4 s.E.; P=10 years±l-3s.E.). Furthermore, there was no significant difference between the groups with respect to symptoms in the week before entry to the trial
(fig. 1).
Supplementary Antacid Consumption (fig. 4) Throughout the trial significantly fewer patients in the cimetidine group made use of supplementary antacids.
Fig. 3--Comparison of pain-free nights in cimetidine and placebo patients. Comparison of patients with and without pain (Z2 test) shows significant improvement in cimetidine group in every week of trial.
6
All
symptom-free when subsequent endosevidence of ulceration. All symptom-free patients from the short-term trial together with patients symptom-free after "open" cimetidine, have entered a double-blind prospective maintenance trial with a single nightly dose of cimetidine (400 mg) or placebo. So far 60 patients have entered this trial and, to date, 10 patients have suffered early relapse of ulcer dyspepsia at 27 days (±5.9 s.E.). All have shown reappearance of duodenal ulceration at endoscopy; on decoding all were found to be on placebo. 2 other patients have relapsed after discontinuing their trial medication, having been symptom-free for eighty-seven and thirty-five days, respectively. Ulcer symptoms had recurred within seven days and endoscopic ulceration was confirmed. On decoding their trial medication was found to have been cimetidine.
days).
were
copy showed
no
Correlation between Ulcer Healing and Symptom
Relief
22
Pig. 4--Comparison of use made by cimetidine and placebo patients of supplementary antacids during trial. Comparison of those taking some antacids with those not taking any (X2 test) shows significantly fewer cimetidine patients used supplementary antacids.
Recovery of Vagally Mediated Acid and Pepsin Secretion after Cimetidine Cimetidine inhibits gastric-acid secretory response to insulin hypoglÿcaemia.4 The accompanying table shows
Ulcer Healing All 20 patients in the cimetidine group completed the protocol up to the second endoscopy at four weeks. 17 (85%) showed no evidence of ulcer at twenty-eight days and all were free from ulcer symptoms. Of the remaining 3 patients who showed some evidence of persisting ulceration, 2 were completely symptom-free. 5 of the 20 patients on placebo had healed their ulcers at four weeks and none of these patients had ulcer symptoms. However, 13 patients (65%) on placebo showed clear evidence of persisting unchanged duodenal ulceration on endoscopy at twenty-eight days and all but one had severe persisting ulcer dyspepsia. 2 patients on placebo who refused endoscopy had severe continuing dyspeptic symptoms. Fate of Patients after Short-term Trial and Maintenance Trial
Progress
on
patients on placebo with persistent ulceration twenty-eight days were asked to continue their medication but, unknown to them, cimetidine (Ig/day) was substituted for placebo. Endoscopic and laboratory assessments were repeated over a further twenty-eight day period. All rapidly became symptom-free with no evidence of ulceration at endoscopy. Since the completion of this trial a number of other patients with endoscopically confirmed severe duodenal ulceration have been studied while receiving cimetidine lg/day for twenty-eight days (in 2 patients for forty-two All 13
at
patients (5 placebo, 17 cimetidine) who became symptom-free during the acute four-week trial had no evidence of ulcer at the second endoscopy. On the other hand, 12 of the 13 patients who received placebo had persisting ulceration and continued to have severe dyspeptic symptoms. The remaining patient was symptom-free. 2 patients receiving cimetidine, were asymptomatic at four weeks but had some evidence of persisting ulceration on endoscopy. In this study, therefore, there is good correlation between relief of ulcer symptoms and endoscopic ulcer healing (X2=22.88, P<0.0005).
COMPARISON OF PRE AND POST TRIAL GASTRIC ACID AND PEPSIN
RESPONSES TO
0.2
UlCg INTRAVENOUS
INSULIN
Pepsin was measured by the method of Piper.7 that after twelve to twenty-four hours without cimetidine at the end of the four-week trial, no significant differences in the acid or pepsin responses to insulin were found compared to the pre-trial values. This rapid recovery of secretory response to insulin after discontinuing cimetidine accords with early experience in the maintenance trial where almost all relapses so far observed have occurred within one month of discontinuing cimetidine.
Discussion The results of this
study clearly
demonstrate the abi-
7
of cimetidine (lg/day) to control symptoms of patients with longstanding duodenal ulcer dyspepsia who would otherwise have undergone elective ulcer surgery. In 85% of patients receiving cimetidine, ulcer healing as judged endoscopically was achieved within four weeks. Although there were 3 patients who received cimetidine and still showed evidence of persisting ulceration after four weeks, 2 of these were symptom-free. The work of Bodemar and Walan3 suggests that in some patients progress to complete healing occurs between three and six weeks after starting the drug. It is conceivable, therefore, that a more prolonged course of treatment may further increase the healing-rate. There has been uncertainty concerning the relationship between ulcer symptoms and the presence of an ulcer. Firm evidence has been lacking despite two controlled trials using metiamideland one similar study using cimetidine.3 The results of the present double-blind controlled trial show good correlation between the presence or absence of peptic ulcer and
lity
symptomatic status. While the use of supplementary standard antacids was permitted during this trial, our results make it clear that such additional antacids themselves had little influence the pattern of symptom relief. The rapid recovery of vagally mediated acid and pepsin secretion after discontinuation of cimetidine therapy suggests no fundamental change in parietal-cell sensitivity as a result of exposure to the compound over four weeks. The early relapse of some patients often within a few days of randomisation to maintenance placebo in our current maintenance trial may bear some relationship to this rapid recovery of pre-trial gastric secretory status. The results of similar double-blind controlled gastric secretory responses to various stimulants following longer periods at different dose schedules of cimetidine are awaited. There has been no clinical or laboratory evidence of toxicity in the four-week trial and none so far in our maintenance trial (400 mg at night). Nevertheless, we await the conclusions not only of this longer-term prospective trial, but reports of other workers using different dose regimens to assess the long-term efficacy and safety of this histamine H2-receptor antagonist. on
We thank Mr R. G. MacLeod, Mr H. Reid, Mr J. McArthur, Mr G. D. Smellie, Mr A. J. Mack, and Mr C. McArdle for referring their patients to us; the ward and theatre nursing staff at the Victoria Infirmary, Glasgow for their help throughout this trial; the Medical Illustration Department, Victoria Infirmary for providing the figures; and Miss Lesley Gilmour for preparing the manuscript. The research department of Smith, Kline and French Laboratories, Welwyn Garden City, Hertfordshire kindly provided the materials for these studies.
Requests for reprints should be addressed to G. G., Infirmary, Glasgow G42 9TY.
Division of Sur-
gery, Victoria
NEUROLOGICAL AND PSYCHOMETRIC STUDIES IN CHILDREN SURVIVING FRESHWATER IMMERSION ACCIDENTS
JOHN PEARN Department of Child Health, University of Queensland, Royal Children’s Hospital, Herston, Brisbane, Queensland, Australia 4029
A study of the neurological and intellectual sequelæ of childhood near-drowning is reported. Results are from a total population study, without selection, of all freshwater immersion accidents in which consciousness was lost in the water. Such accidents affected 56 children in the city of Brisbane and environs over the period 1971-75. 54 of these children have been re-examined medically and psychometrically. Over 95% of children who survived such accidents were neurologically normal. The median I.Q. of survivors was 110 (range 90 to 137), which is higher than that of the general population. There is a suggestion that visualmotor (performance) skills are particularly vulnerable to freshwater immersion hypoxia. In 20% of survivors subscale disparities between verbal and performance skills exceeded 15 I.Q. points. No correlation between the post-immersion I.Q. and either estimated immersion-time or water temperature was demonstrated in this study. No long-term emotional or personality disorders were encountered. Uncommon gross clinical sequelæ of prolonged immersion in fresh water included spastic quadriplegia and gross mental retardation. All children in this study were apparently dead at the moment of rescue; despite this, the prognosis of near-drowning in childhood is excellent.
Summary
Introduction THERE are numerous anecdotal single-case reports of survival after childhood near-drowning.’ Almost all recount an excellent outcome reportedly free from neurological sequelae. Both adult2 and childhood3 4 series of post-immersion survivors have been reported in which the outcome was excellent,S 6 according to parents and discharge case-notes. In the reported series the survivors were not re-examined neurologically or with formal psychometric tests.3-5 In practice, therapy and management decisions about a near-drowned child require a knowledge of the relative chance that a child will be normal intellectually and neurologically if he survives; and of the details of residual neurological and psychological sequelae that might result if life is saved. For this purpose most reported series are of limited use, for two reasons. First, only selected cases tend to be reported, and unless a total population study is undertaken, the true incidence of sequelae, or lack of them, may be hidden; and until recently the survival-rate itself from freshwater near-drowning had not been accurately estimated.6-8 Secondly, because of the complex pathophysiology of mammalian drowning and near-drowning,9-13 salt-water and freshwater cases should not be grouped together. There is good evidence that survival (albeit a crude index of pathophysiology) is significantly higher after sea-water than freshwater immersion, provided the water is not extremely cold. It is quite possible that indices other than survival itself (such as neurological
neurological
REFERENCES
1.
Pounder, R. E., Williams, J. G., Russell, R. C. G., Milton-Thompson, G. J., Misiewicz, J. J. Gut, 1976, 17, 161. 2. Henn, R. M., Isenberg, J. I., Maxwell, V., Sturdevant, R. A. L. New Engl. J. Med. 1975, 293, 371. 3. Bodemar G., Walan, A. Lancet, 1976, ii, 161. 4. Carter, D. C., Logan, R., Forrest, J. A. H., Ansell, I., Heading, R. C., Shearman, D. J. C. Br. J. Surg. 1975, 62, 664. 5. Multicentre Trial (U.K.) Lancet, 1975, ii, 779. 6. Pounder, R. E., Williams, J. G., Milton-Thompson, G. J., Misiewicz, J. J. Br. med. J. 1975, ii p. 307. 7. Piper, D. W. Gastroenterology, 1960, 38, 616.
V-POST-CONCUSSION SYMPTOMS
AND POST-TRAUMATIC
AMNESIA IN PATIENTS WITH NO BLOOD-ALCOHOL
Numbers in
parentheses are percentages. d.f.=degrees of freedom.
Steadman and Graham’ reported that P.T.A. remains the best measure of severity when related to long-term results of the injury. While for severe head injuries amnesia may well be an accurate indicator of the severity of the trauma, it may not be as valuable in mild head injuries. It is certainly conceivable that each of the postconcussion symptoms is caused by injury to a specific area of brain tissue, and that amnesia also has a specific location. Symptoms and amnesia would then depend not only on the force of any shock-waves travelling through the brain, but their precise path. We tested this by dividing the head into a grid, and plotting the apparent area where major force had been applied. No positive correlalations with symptoms were found. This may have been due to the small numbers for any particular area. Also the presence of a wound or bruise did not by itself indicate the direction along which the force was travelling. A bruise in the same part of the forehead could be caused either by a blow causing backward thrust or one causing rotation. The lack of obvious correlation between P.T.A. and symptoms is also confirmed by the experience of cases with no complete amnesia and only a short period of feeling dazed, who none the less feel very nauseated, drowsy, and dizzy for two or three days. If such severe early symptoms can arise in cases with almost no amnesia, it is not surprising that some patients with symptoms continuing for six weeks and more also have very short amnesia. It is difficult to get enough information of the details of accidents to allow an accurate computation of the forces involved. Although most traffic accidents would appear to involve larger amounts of energy than falls from the same level, it was those patients who had had falls who had a higher symptom-rate. We cannot explain this. The higher symptom-rate in patients who blamed an employer or a large organisation appears to indicate a psychogehic or neurotic element in the cause of symptoms. It is a stronger indication than the absence of proof of organic factors-the usual grounds for a neurotic cause. Kay et al. reported a high correlation between middle-age, married status, social class iv, an industrial accident, a semi-skilled occupation, and a previous psychiatric history but gave no separate figures for industrial accidents. The marked difference in symptom-rates between men and women could possibly be due to different physical characteristics of the skull and brain in the two sexes, but is more likely to be due to differences in emotional and psychological sensitivity. Every post-concussion symptom is explicable on the basis of either organic injury or functional disorder. This is true both when treating patients and when attempting to give an opinion for medicolegal purposes.
While our results could be interpreted as an indication that some patients suffer from organic brain damage and others from post-traumatic neurosis, it seems probable that in many patients there is an interplay of both these elements. The main value of our study is the positive evidence it supplies. The neurotic element is indicated by the strong correlation between symptoms and motivation. Each of the correlations indicating an organic element would have been conclusive on its. own. The presence of four separate correlations appears to put the matter beyond all reasonable doubt. We thank Mrs McGovern and Mrs Armstrong for their help in foland for keeping all the basic documentation in order; the nurses and doctors of the accident and emergency department for cooperating in a research project despite very heavy day-to-day commitments ; Mrs J. J. Smith-Davidson and her staff for their help with data preparation; and the Department of Health and Social Services,
low-up visiting
Ireland, for a research grant. Requests for reprints should be addressed to W. H. R., Accident and Emergency Department, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA, Northern Ireland. Northern
REFERENCES 1. 2. 3. 4. 5.
Miller, H. Br. med. J. 1961, i, 919. Miller, H. Proc. R. Soc. Med. 1966, 59, 257. Taylor, A. R. Br. med. J. 1967, iii, 67. Gronwall, D., Wrightson, P. Lancet, 1974, ii, 605. Lidvall, H. F., Linderoth, B., Norton, B. Acta neurol.
scand.
1974, 50,
56. W. Br.
suppl. 6. 7. 8.
Lewin, med. J. 1968, i, 465. Steadman, J. G., Graham, J. G. Proc. R. Soc. Med. 1970, 63, 23. Kay, D. W. K., Kerr, T. A., Lassman, L. P. Lancet, 1971, ii, 1092.
ORAL CIMETIDINE IN SEVERE
DUODENAL ULCERATION A Double-blind Controlled Trial I. MCKENZIE G. P. CREAN
G. R. GRAY I. S. SMITH
G. GILLESPIE
Department of Surgery, Victoria Infirmary, and Gastrointestinal Centre, Southern General Hospital, Glasgow
Summary
outpatients with active endoscopically proven duodenal ulceration,
40 adult
who would otherwise have merited elective ulcer surgery, entered a double-blind trial of either cimetidine (1 g/day) or placebo. After twenty-eight days, 17 of 20
(85%) patients receiving cimetidine showed ulcer healing, compared with 5 of 20 patients receiving placebo (P<0·0005). Patients receiving cimetidine had significantly more pain-free days and pain-free nights than those receiving placebo. There was good correlation between ulcer healing and symptomatic relief (p<0·0005). Introduction
-
THE histamine H2-receptor antagonist cimetidine suppresses meal-stimulated and nocturnal gastric-acid secretion in man’2 and so has potential use in the management of duodenal peptic ulceration. Work from Sweden3 has provided early indications of promise in this role, and it is hoped that this compound will be free from the marrow depression of its predecessor metiamide. So far, in studies with H2-receptor antagonists, there has been
5
uncertainty regarding correlation between relief of symptoms and ulcer healing as judged endoscopically. The aims of the present study, therefore, were to assess by a prospective controlled double-blind trial firstly the therapeutic efficacy of oral cimetidine (lg/day) in the treatment of severe duodenal ulceration in patients who would otherwise have been submitted to ulcer surgery, and secondly to assess the correlation, if any, between symptomatic relief and ulcer healing.
Patients and Methods 40 adult outpatients who had severe and prolonged ulcer and who had been referred for ulcer surgery were admitted to the trial within one week of endoscopic confirmation of their ulcers. All gave their informed consent. During the week before the trial began gastric acid and pepsin ressponse to intravenous insulin 0.2 u/kg was measured. Full clinical assessment was made of the patients before their entry to the trial and again at two and four weeks. At the end of the fourth week a second endoscopy was performed to assess ulcer healing. After this second endoscopy and twelve to twenty-four
dyspepsia
Fig. 2-Comparison of pain-free days in cimetidine and placebo patients. Comparison of patients with and without pain (x.2 test) shows significant
improvement in the cimetidine group
in every week of trial.
Results
Relief of Ulcer Symptoms Day pain (fig. 2).-Comparison of patients in the cimetidine and placebo groups with regard to the number of pain-free days experienced during each of the four weeks of the trial, shows that there were significantly more patients without any pain in the cimetidine group. Nocturnal more
pain (fig. 3.-Similarly, significantly patients on cimetidine were pain-free during all
four weeks of the trial.
Fig. I-Comparison of day pain and night pain in cimetidine and placebo patients in week before trial. Figs. 1-4: N.s.=Not significant; 0 =placebo, e=cimetidine.
hours after stopping all trial medication, a second insulin test was done. On entry to the trial patients were randomly allocated to treatment with identically prepared tablets containing either cimetidine (20 patients) or placebo (20 patients). Cimetidine was taken orally in three 200 mg doses after meals and a night dose of 400 mg just before retiring. Every patient was provided with a supply of unmarked supplementary antacid (’Rennies’) with instructions to use freely in the event of unsatisfactory pain relief by the trial medication. All other medication where possible was discontinued, in particular all other anti-ulcer medicaments were withdrawn. Throughout the study patients made use of personal diary cards to record attacks of day or nocturnal pain, the severity of the pain, and the extent to which they made use of the supplementary antacids. The cimetidine (C) and placebo (P) groups were comparable with regard to age (C=46 years±2-9 s.E.; P=39 years±3-4 s.E.), (C, M/F=16/4; P, M/F=18/2) and duration of ulcer disease (C=14 years±2-4 s.E.; P=10 years±l-3s.E.). Furthermore, there was no significant difference between the groups with respect to symptoms in the week before entry to the trial
(fig. 1).
Supplementary Antacid Consumption (fig. 4) Throughout the trial significantly fewer patients in the cimetidine group made use of supplementary antacids.
Fig. 3--Comparison of pain-free nights in cimetidine and placebo patients. Comparison of patients with and without pain (Z2 test) shows significant improvement in cimetidine group in every week of trial.
6
All
symptom-free when subsequent endosevidence of ulceration. All symptom-free patients from the short-term trial together with patients symptom-free after "open" cimetidine, have entered a double-blind prospective maintenance trial with a single nightly dose of cimetidine (400 mg) or placebo. So far 60 patients have entered this trial and, to date, 10 patients have suffered early relapse of ulcer dyspepsia at 27 days (±5.9 s.E.). All have shown reappearance of duodenal ulceration at endoscopy; on decoding all were found to be on placebo. 2 other patients have relapsed after discontinuing their trial medication, having been symptom-free for eighty-seven and thirty-five days, respectively. Ulcer symptoms had recurred within seven days and endoscopic ulceration was confirmed. On decoding their trial medication was found to have been cimetidine.
days).
were
copy showed
no
Correlation between Ulcer Healing and Symptom
Relief
22
Pig. 4--Comparison of use made by cimetidine and placebo patients of supplementary antacids during trial. Comparison of those taking some antacids with those not taking any (X2 test) shows significantly fewer cimetidine patients used supplementary antacids.
Recovery of Vagally Mediated Acid and Pepsin Secretion after Cimetidine Cimetidine inhibits gastric-acid secretory response to insulin hypoglÿcaemia.4 The accompanying table shows
Ulcer Healing All 20 patients in the cimetidine group completed the protocol up to the second endoscopy at four weeks. 17 (85%) showed no evidence of ulcer at twenty-eight days and all were free from ulcer symptoms. Of the remaining 3 patients who showed some evidence of persisting ulceration, 2 were completely symptom-free. 5 of the 20 patients on placebo had healed their ulcers at four weeks and none of these patients had ulcer symptoms. However, 13 patients (65%) on placebo showed clear evidence of persisting unchanged duodenal ulceration on endoscopy at twenty-eight days and all but one had severe persisting ulcer dyspepsia. 2 patients on placebo who refused endoscopy had severe continuing dyspeptic symptoms. Fate of Patients after Short-term Trial and Maintenance Trial
Progress
on
patients on placebo with persistent ulceration twenty-eight days were asked to continue their medication but, unknown to them, cimetidine (Ig/day) was substituted for placebo. Endoscopic and laboratory assessments were repeated over a further twenty-eight day period. All rapidly became symptom-free with no evidence of ulceration at endoscopy. Since the completion of this trial a number of other patients with endoscopically confirmed severe duodenal ulceration have been studied while receiving cimetidine lg/day for twenty-eight days (in 2 patients for forty-two All 13
at
patients (5 placebo, 17 cimetidine) who became symptom-free during the acute four-week trial had no evidence of ulcer at the second endoscopy. On the other hand, 12 of the 13 patients who received placebo had persisting ulceration and continued to have severe dyspeptic symptoms. The remaining patient was symptom-free. 2 patients receiving cimetidine, were asymptomatic at four weeks but had some evidence of persisting ulceration on endoscopy. In this study, therefore, there is good correlation between relief of ulcer symptoms and endoscopic ulcer healing (X2=22.88, P<0.0005).
COMPARISON OF PRE AND POST TRIAL GASTRIC ACID AND PEPSIN
RESPONSES TO
0.2
UlCg INTRAVENOUS
INSULIN
Pepsin was measured by the method of Piper.7 that after twelve to twenty-four hours without cimetidine at the end of the four-week trial, no significant differences in the acid or pepsin responses to insulin were found compared to the pre-trial values. This rapid recovery of secretory response to insulin after discontinuing cimetidine accords with early experience in the maintenance trial where almost all relapses so far observed have occurred within one month of discontinuing cimetidine.
Discussion The results of this
study clearly
demonstrate the abi-
7
of cimetidine (lg/day) to control symptoms of patients with longstanding duodenal ulcer dyspepsia who would otherwise have undergone elective ulcer surgery. In 85% of patients receiving cimetidine, ulcer healing as judged endoscopically was achieved within four weeks. Although there were 3 patients who received cimetidine and still showed evidence of persisting ulceration after four weeks, 2 of these were symptom-free. The work of Bodemar and Walan3 suggests that in some patients progress to complete healing occurs between three and six weeks after starting the drug. It is conceivable, therefore, that a more prolonged course of treatment may further increase the healing-rate. There has been uncertainty concerning the relationship between ulcer symptoms and the presence of an ulcer. Firm evidence has been lacking despite two controlled trials using metiamideland one similar study using cimetidine.3 The results of the present double-blind controlled trial show good correlation between the presence or absence of peptic ulcer and
lity
symptomatic status. While the use of supplementary standard antacids was permitted during this trial, our results make it clear that such additional antacids themselves had little influence the pattern of symptom relief. The rapid recovery of vagally mediated acid and pepsin secretion after discontinuation of cimetidine therapy suggests no fundamental change in parietal-cell sensitivity as a result of exposure to the compound over four weeks. The early relapse of some patients often within a few days of randomisation to maintenance placebo in our current maintenance trial may bear some relationship to this rapid recovery of pre-trial gastric secretory status. The results of similar double-blind controlled gastric secretory responses to various stimulants following longer periods at different dose schedules of cimetidine are awaited. There has been no clinical or laboratory evidence of toxicity in the four-week trial and none so far in our maintenance trial (400 mg at night). Nevertheless, we await the conclusions not only of this longer-term prospective trial, but reports of other workers using different dose regimens to assess the long-term efficacy and safety of this histamine H2-receptor antagonist. on
We thank Mr R. G. MacLeod, Mr H. Reid, Mr J. McArthur, Mr G. D. Smellie, Mr A. J. Mack, and Mr C. McArdle for referring their patients to us; the ward and theatre nursing staff at the Victoria Infirmary, Glasgow for their help throughout this trial; the Medical Illustration Department, Victoria Infirmary for providing the figures; and Miss Lesley Gilmour for preparing the manuscript. The research department of Smith, Kline and French Laboratories, Welwyn Garden City, Hertfordshire kindly provided the materials for these studies.
Requests for reprints should be addressed to G. G., Infirmary, Glasgow G42 9TY.
Division of Sur-
gery, Victoria
NEUROLOGICAL AND PSYCHOMETRIC STUDIES IN CHILDREN SURVIVING FRESHWATER IMMERSION ACCIDENTS
JOHN PEARN Department of Child Health, University of Queensland, Royal Children’s Hospital, Herston, Brisbane, Queensland, Australia 4029
A study of the neurological and intellectual sequelæ of childhood near-drowning is reported. Results are from a total population study, without selection, of all freshwater immersion accidents in which consciousness was lost in the water. Such accidents affected 56 children in the city of Brisbane and environs over the period 1971-75. 54 of these children have been re-examined medically and psychometrically. Over 95% of children who survived such accidents were neurologically normal. The median I.Q. of survivors was 110 (range 90 to 137), which is higher than that of the general population. There is a suggestion that visualmotor (performance) skills are particularly vulnerable to freshwater immersion hypoxia. In 20% of survivors subscale disparities between verbal and performance skills exceeded 15 I.Q. points. No correlation between the post-immersion I.Q. and either estimated immersion-time or water temperature was demonstrated in this study. No long-term emotional or personality disorders were encountered. Uncommon gross clinical sequelæ of prolonged immersion in fresh water included spastic quadriplegia and gross mental retardation. All children in this study were apparently dead at the moment of rescue; despite this, the prognosis of near-drowning in childhood is excellent.
Summary
Introduction THERE are numerous anecdotal single-case reports of survival after childhood near-drowning.’ Almost all recount an excellent outcome reportedly free from neurological sequelae. Both adult2 and childhood3 4 series of post-immersion survivors have been reported in which the outcome was excellent,S 6 according to parents and discharge case-notes. In the reported series the survivors were not re-examined neurologically or with formal psychometric tests.3-5 In practice, therapy and management decisions about a near-drowned child require a knowledge of the relative chance that a child will be normal intellectually and neurologically if he survives; and of the details of residual neurological and psychological sequelae that might result if life is saved. For this purpose most reported series are of limited use, for two reasons. First, only selected cases tend to be reported, and unless a total population study is undertaken, the true incidence of sequelae, or lack of them, may be hidden; and until recently the survival-rate itself from freshwater near-drowning had not been accurately estimated.6-8 Secondly, because of the complex pathophysiology of mammalian drowning and near-drowning,9-13 salt-water and freshwater cases should not be grouped together. There is good evidence that survival (albeit a crude index of pathophysiology) is significantly higher after sea-water than freshwater immersion, provided the water is not extremely cold. It is quite possible that indices other than survival itself (such as neurological
neurological
REFERENCES
1.
Pounder, R. E., Williams, J. G., Russell, R. C. G., Milton-Thompson, G. J., Misiewicz, J. J. Gut, 1976, 17, 161. 2. Henn, R. M., Isenberg, J. I., Maxwell, V., Sturdevant, R. A. L. New Engl. J. Med. 1975, 293, 371. 3. Bodemar G., Walan, A. Lancet, 1976, ii, 161. 4. Carter, D. C., Logan, R., Forrest, J. A. H., Ansell, I., Heading, R. C., Shearman, D. J. C. Br. J. Surg. 1975, 62, 664. 5. Multicentre Trial (U.K.) Lancet, 1975, ii, 779. 6. Pounder, R. E., Williams, J. G., Milton-Thompson, G. J., Misiewicz, J. J. Br. med. J. 1975, ii p. 307. 7. Piper, D. W. Gastroenterology, 1960, 38, 616.