948
changes. Installation of such machines in theatres would encourage frequent intraoperative sodium sampling to become routine and, together with volumetric irrigation fluid balance, would keep patient risk to a minimum. Department of Chemical Pathology, Beaumont Hospital,
W. P. TORMEY
Dublin 9, Ireland 1. Watkins-Pitchford
JM, Payne SR, Rennie CD, Riddle PR. Hyponatraemia during practical prevention. Br J Urol 1984; 56: 676-78.
transurethral resection: its
Compatibility of clozapine and chloroquine SiR,—Dr Gerson and colleagues (July 27, p 262) draw attention to possible clozapine incompatibilities. Some fatal interactions between the dibenzepine neuroleptic clozapine and antiypretics/analgesics have led to much caution and safeguards in the use of this drug. Because of restrictions on use, data on the compatibility of clozapine with other drugs are not readily available. With respect to possible interactions of clozapine and antimalarial agents, no information could be gained from the producer or from toxicological centres or institutions monitoring drug interactions on a large scale. A male caucasian patient, now aged 30 years, was first admitted in 1977 for psychiatric hospital care and was diagnosed as having schizoaffective psychosis. Since 1977 he has been on clozapine, after severe extrapyramidal symptoms developed with conventional neuroleptics. Since then he has had three more admissions to hospital despite clozapine maintenance and additional antidepressive therapy. Otherwise the patient has been active, completing various qualifications and doing well in his job. However, a slight residual syndrome remains. Clozapine had always been tolerated well, with doses ranging between 12.5 and 275 mg daily, with normal white blood cell (WBC) and platelet counts and hepatic function. On recovery from the last phase of his illness in 1988 the patient resumed work and planned to visit Brazil. Because antimalarial prophylaxis was indicated, he was told about the possibility of a drug interation. He decided to undertake this trip (from Dec 8, 1988, to Jan 7, 1989) but on his own volition reduced polyvalent antimalarial therapy to diphosphate of chloroquine only. He was advised to have weekly blood counts while taking chloroquine in Brazil, but he did so only once. The combination of the two drugs was well tolerated. Even after close questioning the patient reported no adverse reactions. Baseline and controls showed
an
average WBC count of 7-23
x
10/1
and
platelets 201-6 x 109/1 between Feb 2, 1988, and May 24, 1989 (7 blood counts). Between Dec 1, 1988, and Jan 2, 1989, chloroquine intake was 23g, the daily clozapine dose being 25 mg. In this one patient, control testing and follow-up showed that the two compounds potentially noxious to bone-marrow function were well tolerated. Although the clozapine dose was fairly low, the continuous administration of the drug since 1977 is an additional factor to be taken into account--doses in that period ranged from 12-5 to 275 mg daily. Psychiatry Department I, Landes-Nervenkrankenhaus Valduna, A-6830 Rankweil, Austria
PETER KONIG A. KÜNZ
Pesticide intoxication and chronic CNS effects SIR,-Dr Rosenstock and colleagues’ (July 27, p 223) statement, "We conclude that even single episodes of clinically significant organophosphate intoxication are associated with a persistent decline in neuropsychological functioning", should be accepted with caution. Their study included only 36 patients, with a question about single or multiple poisons (eg, solvent exposure). The case/control ratio was 1/1 instead of 1/2 or 1/3. Furthermore, both cases and controls had episodes of pesticide intoxication without medical attention or admission to hospital. The statistical significance of the results is uncertain. In the statistical analysis, the role of the point estimate, the confidence interval (CI), and the p-value should all be taken into account. Is there really an importance of a lower CI limit of 06 with a point estimate of only 1 5, as in the visual memory test, or a lower
CI limit of - 2with a point estimate of 32, as in the motor reaction time? Such lower limits indicate no significance and inconclusive results. The difficulty of interpreting these types of results has been pointed out by others,l as have the drawbacks of neurobehavioural testing procedures in this type of study. If one recognises these difficulties, Rosenstock and colleagues’ conclusion is risky. Their results may point out a tendency to have neuropsychological problems after organophosphate intoxication, but the data certainly are not compelling. One might as easily conclude that the difference between the cases and controls is the fact of admission to hospital and possible adverse consequences of treatment (atropine without pralidoxime), since the controls were defmed as occupationally exposed to pesticides with episodes of pesticide intoxication but no hospital admission. Department of Family Medicine, Agromedicine Program, Medical University of South Carolina, Charleston, South Carolina 29407, USA
STANLEY H. SCHUMAN
Department of Agricultural Chemistry, Oregon State University, Corvallis, Oregon
SHELDON L. WAGNER
1. Braitman LE. Confidence intervals assess both clinical significance and statistical significance. Ann Intern Med 1991, 114: 515-17 2. Matarazzo JD Psychological assessment versus psychological testing. Am Psychol
1990, 45: 999-1017.
*** This letter has been shown to Dr Rosenstock and her colleagues, whose reply follows.-ED. L. Sj[R,—Dr Schuman and Dr Wagner raise concerns about our study design and conclusions. We are confused by their comments about statistical significance, including sample size and matching ratios. While a priori attention to components of calculating study power is very important, these considerations are irrelevant when, as in our study, results indicate consistent, statistically significant differences. Had we claimed clinical significance on the basis of non-statistically significant trends, or had we claimed no effect, with our admittedly small sample size, then study power would be an
important question. We agree with Schuman and Wagner that the point estimate, the confidence interval (CI), and the p-value are important in consideration of statistical significance. To this list we add consistency of fmdings. As we indicate, although worse performance was observed among the previously poisoned cohort for all neuropsychological outcomes, it was significantly worse (p < 001; 95 % CI of point estimate excluding zero) for only 9 of 14 subtests. For example, we do not claim that differences in motor reaction time differ (95% CI = - 2-0, 66) but in the same table we denote significant differences in visual memory (the point estimate is 1-7 and not 1-5, as Schuman and Wagner state, CI=0’6, 2-5). Whether the roughly 25% worse performance on this latter test is clinically significant, however, is an important issue and was not addressed by our study design. We did observe a more than 10% difference between cohort mean values in 12 of 14 subtests studied, and a more than 20% difference in 7 of these subtests. We encourage further study to answer remaining important questions about the effects of specific pesticides, the contribution of chronic versus acute overexposures, and the clinical significance in individuals of altered neuropsychological functioning. With respect to effects of therapy, there is no evidence that atropine, when given appropriately to reverse cholinesterase inhibition of acute organophosphate poisoning, is associated with acute or chronic central-nervous-system disturbance. Even if it were, atropine remains the mainstay of treatment and is potentially life-saving. Pralidoxime is also an indicated concomitant treatment, but it is expensive and not readily available in most developing countries. The effects of atropine are not only unlikely to have contributed to our fmdings, but any attempts to untangle this treatment from the poisoning would probably prove not only impossible but also unsound. We too believe that the results of any one epidemiological study should be interpreted with caution. We find increasing evidence-experimental, clinical, and epidemiological-of the risk for chronic
neurological sequelae after substantial organophosphate pesticide
changes. Installation of such machines in theatres would encourage frequent intraoperative sodium sampling to become routine and, together with volumetric irrigation fluid balance, would keep patient risk to a minimum. Department of Chemical Pathology, Beaumont Hospital,
W. P. TORMEY
Dublin 9, Ireland 1. Watkins-Pitchford
JM, Payne SR, Rennie CD, Riddle PR. Hyponatraemia during practical prevention. Br J Urol 1984; 56: 676-78.
transurethral resection: its
Compatibility of clozapine and chloroquine SiR,—Dr Gerson and colleagues (July 27, p 262) draw attention to possible clozapine incompatibilities. Some fatal interactions between the dibenzepine neuroleptic clozapine and antiypretics/analgesics have led to much caution and safeguards in the use of this drug. Because of restrictions on use, data on the compatibility of clozapine with other drugs are not readily available. With respect to possible interactions of clozapine and antimalarial agents, no information could be gained from the producer or from toxicological centres or institutions monitoring drug interactions on a large scale. A male caucasian patient, now aged 30 years, was first admitted in 1977 for psychiatric hospital care and was diagnosed as having schizoaffective psychosis. Since 1977 he has been on clozapine, after severe extrapyramidal symptoms developed with conventional neuroleptics. Since then he has had three more admissions to hospital despite clozapine maintenance and additional antidepressive therapy. Otherwise the patient has been active, completing various qualifications and doing well in his job. However, a slight residual syndrome remains. Clozapine had always been tolerated well, with doses ranging between 12.5 and 275 mg daily, with normal white blood cell (WBC) and platelet counts and hepatic function. On recovery from the last phase of his illness in 1988 the patient resumed work and planned to visit Brazil. Because antimalarial prophylaxis was indicated, he was told about the possibility of a drug interation. He decided to undertake this trip (from Dec 8, 1988, to Jan 7, 1989) but on his own volition reduced polyvalent antimalarial therapy to diphosphate of chloroquine only. He was advised to have weekly blood counts while taking chloroquine in Brazil, but he did so only once. The combination of the two drugs was well tolerated. Even after close questioning the patient reported no adverse reactions. Baseline and controls showed
an
average WBC count of 7-23
x
10/1
and
platelets 201-6 x 109/1 between Feb 2, 1988, and May 24, 1989 (7 blood counts). Between Dec 1, 1988, and Jan 2, 1989, chloroquine intake was 23g, the daily clozapine dose being 25 mg. In this one patient, control testing and follow-up showed that the two compounds potentially noxious to bone-marrow function were well tolerated. Although the clozapine dose was fairly low, the continuous administration of the drug since 1977 is an additional factor to be taken into account--doses in that period ranged from 12-5 to 275 mg daily. Psychiatry Department I, Landes-Nervenkrankenhaus Valduna, A-6830 Rankweil, Austria
PETER KONIG A. KÜNZ
Pesticide intoxication and chronic CNS effects SIR,-Dr Rosenstock and colleagues’ (July 27, p 223) statement, "We conclude that even single episodes of clinically significant organophosphate intoxication are associated with a persistent decline in neuropsychological functioning", should be accepted with caution. Their study included only 36 patients, with a question about single or multiple poisons (eg, solvent exposure). The case/control ratio was 1/1 instead of 1/2 or 1/3. Furthermore, both cases and controls had episodes of pesticide intoxication without medical attention or admission to hospital. The statistical significance of the results is uncertain. In the statistical analysis, the role of the point estimate, the confidence interval (CI), and the p-value should all be taken into account. Is there really an importance of a lower CI limit of 06 with a point estimate of only 1 5, as in the visual memory test, or a lower
CI limit of - 2with a point estimate of 32, as in the motor reaction time? Such lower limits indicate no significance and inconclusive results. The difficulty of interpreting these types of results has been pointed out by others,l as have the drawbacks of neurobehavioural testing procedures in this type of study. If one recognises these difficulties, Rosenstock and colleagues’ conclusion is risky. Their results may point out a tendency to have neuropsychological problems after organophosphate intoxication, but the data certainly are not compelling. One might as easily conclude that the difference between the cases and controls is the fact of admission to hospital and possible adverse consequences of treatment (atropine without pralidoxime), since the controls were defmed as occupationally exposed to pesticides with episodes of pesticide intoxication but no hospital admission. Department of Family Medicine, Agromedicine Program, Medical University of South Carolina, Charleston, South Carolina 29407, USA
STANLEY H. SCHUMAN
Department of Agricultural Chemistry, Oregon State University, Corvallis, Oregon
SHELDON L. WAGNER
1. Braitman LE. Confidence intervals assess both clinical significance and statistical significance. Ann Intern Med 1991, 114: 515-17 2. Matarazzo JD Psychological assessment versus psychological testing. Am Psychol
1990, 45: 999-1017.
*** This letter has been shown to Dr Rosenstock and her colleagues, whose reply follows.-ED. L. Sj[R,—Dr Schuman and Dr Wagner raise concerns about our study design and conclusions. We are confused by their comments about statistical significance, including sample size and matching ratios. While a priori attention to components of calculating study power is very important, these considerations are irrelevant when, as in our study, results indicate consistent, statistically significant differences. Had we claimed clinical significance on the basis of non-statistically significant trends, or had we claimed no effect, with our admittedly small sample size, then study power would be an
important question. We agree with Schuman and Wagner that the point estimate, the confidence interval (CI), and the p-value are important in consideration of statistical significance. To this list we add consistency of fmdings. As we indicate, although worse performance was observed among the previously poisoned cohort for all neuropsychological outcomes, it was significantly worse (p < 001; 95 % CI of point estimate excluding zero) for only 9 of 14 subtests. For example, we do not claim that differences in motor reaction time differ (95% CI = - 2-0, 66) but in the same table we denote significant differences in visual memory (the point estimate is 1-7 and not 1-5, as Schuman and Wagner state, CI=0’6, 2-5). Whether the roughly 25% worse performance on this latter test is clinically significant, however, is an important issue and was not addressed by our study design. We did observe a more than 10% difference between cohort mean values in 12 of 14 subtests studied, and a more than 20% difference in 7 of these subtests. We encourage further study to answer remaining important questions about the effects of specific pesticides, the contribution of chronic versus acute overexposures, and the clinical significance in individuals of altered neuropsychological functioning. With respect to effects of therapy, there is no evidence that atropine, when given appropriately to reverse cholinesterase inhibition of acute organophosphate poisoning, is associated with acute or chronic central-nervous-system disturbance. Even if it were, atropine remains the mainstay of treatment and is potentially life-saving. Pralidoxime is also an indicated concomitant treatment, but it is expensive and not readily available in most developing countries. The effects of atropine are not only unlikely to have contributed to our fmdings, but any attempts to untangle this treatment from the poisoning would probably prove not only impossible but also unsound. We too believe that the results of any one epidemiological study should be interpreted with caution. We find increasing evidence-experimental, clinical, and epidemiological-of the risk for chronic
neurological sequelae after substantial organophosphate pesticide
