the use of computers in clinical trials

Brit. J. Anaesth. (1967), 39, 311

THE USE OF COMPUTERS IN CLINICAL TRIALSBY

WILLIAM H. FORREST JR. AND J. WELDON BELLVILLEStanford University School of Medicine, Palo Alto, California, U.S.A.

The electronic computer has already affected ourdaily life and within the foreseeable future it willcompletely change the practice of anaesthesia,inasmuch as the techniques developed for clinicalresearch today will be demanded for routineclinical care tomorrow.

There are three forces that dictate this change:(1) rapid technological advances in the computertechniques; (2) better medical care afforded bythese advances; and (3) increased cost of patientcare in terms of man-hours per patient.

The digital computers that are presently avail-able operate at astronomical speeds (up to1,000,000 operations per second), they can storelarge volumes of readily retrievable data inexpen-sively and they can be used by many userssimultaneously (time sharing). Furthermore, it iseasier for the user to communicate with thesemachines now that user-oriented languages arebeing evolved. Major effort is now being expendedso that physicians will be able to communicatedirectly with the computer. These four factorsmake the computer an accessible, relatively inex-pensive, clinical and research tool for everyphysician.

There is, and rightfully so, scepticism as towhether the use of computers in the clinicalsetting will permit physicians to bring a higherlevel of medical care to the patient. Our experiencewith computers in clinical research suggests thatthey will.

During the last twenty years great strides havebeen made in understanding the pathophysiologyof disease and its rational treatment. Most of theseadvances have been accompanied by an increasedcost in terms of man-hours per patient. The useof computers offers a solution to this perplexingproblem. For example, while the number oflaboratory examinations performed on patients insome hospitals has more than doubled in the lastten years, computer techniques have been devel-oped to automate these processes and the savings

in cost plus the benefit of better care is passedalong to the patient.

This paper describes the application of com-puter techniques in several clinical studies. Specialforms and systems that were designed andmethods that were used in collecting and evalua-ting the data collected are discussed.

CLINICAL STUDIES USING COMPUTERS

Data collection.In clinical pharmacological studies of analgesics,

sedatives and anti-emetics in the Departmentof Anesthesia at Stanford University and theVeterans Administration, Palo Alto (VAPA), thecombined interest in methodologic problems inevaluating drugs and in problems of drug inter-action has led to the application of computertechniques to facilitate the collection, storage andevaluation of data from these studies (Forrest etal.j 1963). Forms were designed to facilitate:(1) uniform collection of data; (2) its easy trans-cription to a Hollerith system for storage; (3)assessment of data in many ways, first to error-check and second to analyze the data; and (4) useof this data for historical controls for futurestudies.

Figure 1 shows two analgesic forms used tocollect data. They are designed so that a trainednurse observer can complete them in triplicateduring her rounds. One copy of each form isrequired for each medication and there are well-defined areas for each observation to be recorded.After the forms are completed by the observer,the principal investiptor reviews and signs them,and one copy of each of these forms is kept in theinvestigator's file. The second copy is used topunch the data on to Hollerith cards for casereporting to the Food and Drug AdministrationSimilar forms have also been developed for usein our sedative and anti-emetic studies.

For each of our clinical studies, an intricatesystem of error-check programmes has been

Downloaded from https://academic.oup.com/bja/article-abstract/39/4/311/319629by gueston 09 April 2018

NATIONAL ANALGESIC STUDY DATA FORMFORM ONE - PART ONE

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NATIONAL ANALGESIC STUDY DATA FORMFORM TWO -- PART ONE

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FIG. 1National Analgesic Study data form used to collect data on analgesics in Veterans AdministrationCo-operative Analgesic studies. The forms are designed to allow direct transcription to Hollerith

cards.


THE USE OF COMPUTERS IN CLINICAL TRIALS 313

developed (Forrest, 1967), so that the data canbe error-checked as soon as it is received fromthe nurse observer and punched on the cards.Errors of commission and omission are detectedas illustrated in figure 2. The first column indicatesthe serial number of the card and the secondcolumn indicates the type of error. The thirdcolumn is one in which the error occurred, thenext column indicates what is coded in the columnand the last column shows what the proper entryshould be. A 9999 means that the computercannot tell the right answer from the data givenit. Figure 3 depicts a history of the patient, whoseobservations arc shown in figure 1. This outputis generated by a special programme* and isplaced in the patient's permanent record.

Data analysis.The bioassay programmes are designed to

accept only error-free data (Laska and Gormley,1967). Once the input data is free of errors, aseries of programmes are run, first to decode themedication and second to analyze the data. Inthese analgesic studies, the major analysis is abiologic assay which can be done on subsectionsof our population such as contributing hospitalsand/or patients who complete medications andthose who do not. Analysis of variance on 3-, 4-or 5-point assays are calculated, and relativepotencies with a range of fiducial limit are estima-ted. Data are then pooled over the populationand finally over the hospitals for relative potencyestimates. Effects such as order, hospital andpatient can be analyzed. Other programmes dotransformations or graph confidence curves (Bell-ville and Forrest, 1967). Figure 4 shows thefiducial limits computed by an IBM 360-50machine and printed out on a 2741 terminal.Thus, in postoperative patients it is possible toevaluate new analgesics and sedatives and tostudy drug interactions, as well as to gathervaluable information on drugs already marketedwhich, in general, have a paucity of informationfrom well-designed clinical studies.

Recently a subcommittee on the National Halo-thane Study of the Committee on Anesthesia,National Academy of Sciences—National Research

• Developed by Dr. Eugene Laska, Director, ComputerDepartment, Research Facility, Rockland State Hos-pital, Orangeburg, New York.

Council (1966) collected retrospective data fromover 950,000 general anaesthetics to evaluate thepossible relationship of halothane to postanaes-thesia massive hepatic necrosis. By using specialforms and computer techniques, analyses of deathrates were made and massive hepatic necrosisrates were determined. The attempt to analyzethe large volume of collected data has developednew methods of analysis which have been neededfor some time, but which were not producedpreviously because of limitations of technicalequipment. High-speed computers and experien-ced advisers set the stage for extensive manipula-tion of data from the halothane study which wouldpreviously have been impossible.

While the present forms are designed for easeof transcription and decoding into Hollerithstorage, one relies on optical scanning devices tomake direct transcription into the computer areality and an even more accurate way of storingthe data. The present limitations of optical scan-ning are such that the input is somewhat fixed,but it is possible to design forms with directinput. This will reduce the errors of transcriptionand increase the overall efficiency. The importanceof this device in clinical research in anaesthesiacan best be demonstrated by realizing that it ispossible to design anaesthesia forms that will beread directly into the computer. The wealth ofclinical material now available for retrospectiveand prospective studies can only be utilized andappreciated by using advanced computer tech-niques. The opportunities for clinical pharma-cologic research for the anaesthetist in theoperating and recovery rooms will be unlimited,and the use of computers will broaden our abilityto study and evaluate newer agents and tech-niques, as well as agents that are presently in use.While the use of optical scanners is practical atthe present time, it is interesting to speculateon what will be available in the near future interms of computer usage for the anaesthetist inresearch.

Other computer usages.New input-output devices are being developed

which will allow the physician to enter datadirectly into the computer from the patient'sbedside or operating table. Displayed on a scopeface in the patient's room or the operating room


PALO ALTO VA HOSPITAL 05 STUDY 09 ' 38 ROUNDS ERRORCHECK FORM I 8-65

SERIAL NUMBER TYPE OF ERROR -

901 NONCONSECUTIVE SERIAL NUMBER912 INCOMPLETE OBSERVATIONS9*7 TOTAL RAW SCORE975 INCOMPLETE OBSERVATIONS993 INCOMPLETE OBSERVATIONS

THERE MERE 23 INCOMPLETE ROUNDS

COLUMNS RECORDED CORRECTED

SUMMARY OF ERRORSERROR

INCOMPLETE OBSERVATIONSTOTAL RAH SCORENONCONSECUTIVE SERIAL NUMBER

71-101

62-6311

NUMBER OF OCCURRENCES

311

9010

9999I1II

FIG. 2Sample output of error-checkprogramme for Form I (fig. 1).The serial number of the in-correct card is Listed first,followed by the description ofthe column containing theerror. The incorrectly recordedvalue is next, followed by thecorrected value.

ON AUG.1*,1966 AT U 3 0 HOURS, PATIENT NO.*2I3, A POST-OP NON-AMBULATORYPATIENT, HAS OBSERVED AND GIVEN MEDICATION AS PART OF ANALGESIC STUDY NO.2»-PRINCIPAL INVESTIGATOR DR. H.H.FORREST,JR., AT VETERANS ADMINISTRATION HOS-PITAL, PALO ALTO, CALIFORNIA.

THE PATIENT IS MALE, kl YEARS OLD, WITH A HEIGHT OF 167 CM. ANO WEIGHTOF 70 KG. THE PAIN, PREDOMINANTLY IN THE BACK, HAS DESCRIBED AS RADIATINGSHOOTING. NO ANALGESIC HAD BEEN ADMINISTERED FOR 6 HOURS PRIOR TO THE INITIALOBSERVATION AT WHICH TIME THE PATIENT COMPLAINED OF MODERATE PAIN. I MG OFMORPHINE HERE THEN ADMINISTERED I.M. AND OBSERVATIONS WERE MADE AT INTERVALSOF 60 MINUTES. THE FOLLOWING ARE GRAPHS OF PAIN INTENSITIES AND RELIEFSREPORTED BY THE PATIENT.

FIG. 3A computer generated historytaken from Form I and II andshown in figure 1.

1NTENS1TY

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MODERATE X

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X X X X

1 2 3 * 5 6

OBSERVATION

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APART FROM THE STUDY DRUG, THE PATIENT HAS BEEN ON SEDATIVE MEDICATION.THE PATIENTS HISTORY OF PREVIOUS DRUGS INCLUOES SEDATIVES AND NARCOTICANALGESICS IN LARGE AMOUNTS FOR SHORT PERIODS. THERE IS NO HISTORY OF ALLERGY.PRE-DRUG AFFECT WAS NORMAL AND THERE HAS BEEN NO ALLERGIC REACTION TO THESTUDY DRUG. SIDE EFFECTS NOTED WERE MODERATE SLEEPINESS, SLIGHT VERTIGO,AND SLIGHT DEPRESSION.

•/ BIOASSAY CONFIDENCE CURVE PROGRAM/*•/ COMPUTES CONFIDENCE CURVES FOR 3, », OR 5 POINT PARALLEL LINE ASSAY/*•/ REFERENCE STATISTICAL METHOD IN BIOLOGICAL ASSAY, CHAS. GRIFFIN 4 CO/*•/ RESPIRATORY ASSAY OF MORPHINE AND PENTAZOCINE, 12-01-66/*

DOSE MEAN

10.0 3.2820.0 "1.25%0.e 7.005.0 3.5910.0 5.57

SLOPE- 6.259

RH0- 2.563 1/RHO- 0.390

SQRT OF MEAN SQUARE- t.211LAMBDA- 0 . 6 7 3

FIG. 4Computer printout showingoutput from a programmewhich calculates relativepotencies of analgesics as wellas confidence limits.

CONFIDENCE

99.997.595.090.0ao.o60.050.030.010.0

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0.901O.tll0.3200.22*0.13S0.0590.0370.0120.001

UPPER LIMIT

211.7675.61lift.81*t.2793.7653.2753.1132.1652.659

LOWER LIMIT

0.0**1.0171.227.l.*511.6921.9S22.0952.288i.*71

I/UPPER LIMIT

0.0*00.1710.2050.23k0.2660.3050.3210.3*90.376

1/LOWER LIMIT

22.6390.98k0.1150.6190.5910.505O.*770.1.37o.tos



will be any part of the chart. A light pen can beused to enter patient's data on the face of thescope and thus directly into the computer memory.In addition, the computer can be programmed toprompt the anaesthetist for necessary data tocomplete an observation or group of observationsnecessary to make a decision or computation. Sucha system requires large computers with extensivestorage capacities

For many clinical pharmacologic studies, whereinput data flows in slowly, the 2741 terminal(fig. 5) will be used to enter data into computermemory daily. At appropriate intervals the datawill be analyzed by programmes stored in thecomputer memory and the results will be listedby the 2741 terminal (15 characters per second)in the laboratory. Thus data can be fed indirectly from the clinical areas in which they arebeing gathered. A myriad of biostatistical andspecial programmes stored in memory may be

called upon to perform any manipulation desiredupon the data. Data gathered in clinical studiessince 1955 have been stored in memory so thatcomparisons of interest on any clinical pharmaco-logic problem relating to these medications maybeaccomplished.

An example of printed output from the 2741is shown in figure 4. This programme was exe-cuted in 32 seconds and data were entered froma 2741 remote terminal located in a research officeseveral miles from the computer but connectedvia telephone lines. The result represents an iter-ative solution of Feilers Theorem for calculatingfiducial limits on a relative potency estimate, asdescribed by Finney (1964). Computationally, itis a trivial mathematical problem, because of theability of the computer to repeat the same cal-culations many times so rapidly; whereas with adesk calculator such procedures are very time-consuming.

FIG. 52741 remote terminal used to communicate with IBM 360-50 computer. Dataand programmes may be entered directly from this terminal and printout data

received from the computer. (See printout shown in figures 2, 3, and 4)


316 BRITISH JOURNAL OF ANAESTHESIA

The lack of large digital computers andslow turn-around caused by manual handlingof input and output present problems that arenow being solved by employing large centralizedcomputers in conjunction with smaller digital oranalogue computers located in the investigator'slaboratory.

One such machine is the IBM 360-50 digitalcomputer. Its main memory size is 250,000 words(8 million bits) and it has a backup storage of3,200 million bits. The configuration of some ofthe major parts of this system is shown in figure6. The items shown above the dashed lines arelocated in our laboratories. Thus, the analoguecomputer (Ease 2132) is coupled to the 360-50facility through the IBM 1800 process controlcomputer which performs the necessary analogue-to-digital and digital-to-analogue conversion.

Em2132

POP-I2741

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C M I K I I H

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310-50

- — l u dfuck—

2540Card Piuk-hi ' i r

1403-2l in Prill.i

CilCoi) Pltllir

FIG. 6Computer equipment in the Stanford Anesthesia Lab-oratory, shown above the dotted line, linked withlarger equipment in the Medical Center, shown below

the dotted line.

Stroke volume or any other physiologic variablecomputed on-line by the Ease 2132 analoguecomputer can be entered directly into the IBM360-50 for statistical analysis of the entire experi-ment (calculation of regression curves or doseeffect curves) as described by Smith, Fleischliand Carbascio (1966). Thus data for statisticalanalysis obtained from a paper strip chart recorderis obsolete, since data from the complete experi-ment can now be entered into the computer andthe complete analysis printed out. The PDP-8digital computer with its limited memory (8,000bits) can communicate with the 360-50 throughthe 1800 process controller. This, in essence,permits access to essentially an infinite memory,

and greatly extends the utility of the small digitalcomputer. Another method of communication isvia a 2741 keyboard. In addition, some instru-ments (scintillation counters) will be linkeddirectly to the 360-50 via the 1800.

ANALOGUE COMPUTERS

Although much of this article refers to batchprocessing of clinical data by computers andimplies a digital computer, there are many areasof clinical investigation, such as that of Bellvilleand Hara (1966), where an analogue computermay find significant application. The analoguecomputer represents the variables of a problemby easily generated or controlled physical quan-tities, usually electrical voltages. A digital com-puter, on the other hand, deals with discretequantities such as notches on a toothed wheel(e.g., desk calculator) or electrical pulses (e.g.,electrical digital computer). For instance, in theevaluation of bronchodilators, where one wishesto evaluate the effects of an agent such as iso-prenaline on the mechanics of ventilation, Fletcherand Bellville (1966) have shown that it is possibleto compute pulmonary compliance, resistance,work, power of breathing on a breath-to-breathbasis while the subject is breathing. Similarly, thesame type of computer system may be used toevaluate mechanical performance of respirators.

Figure 7 shows the analogue computer locatedin our anaesthesia laboratories. This has beenused in many clinical studies in humans to com-pute physiological parameters "on-line", i.e.,while the data is being transduced. With theadvent of monolithic integrated circuits, it is tobe expected that small special-purpose analoguecomputers can be built into the anaesthesiamachine so that a continuous read-out of variablesof interest, such as pulmonary blood flow, carbondioxide excretion and pulmonary compliance,might be available.

Recently small general-purpose digital com-puters have become readily available. The firstto be designed specifically for biological investiga-tion was the LINC designed by Wes dark atMassachusetts Institute of Technology. Theseinstruments are limited in terms of ability to storeprogrammes and data but are relatively inexpen-sive, so that they are practical in the investigator'slaboratory.



FIG. 7General purpose analogue computer with associated XY plotter, oscilloscope, tape recorder andstrip chart recorder used for readout. Programmes are stored on wired patch boards shown in

background.

MONITORING BY COMPUTERS

The PDP-8 in our laboratories is used princi-pally to study new computer techniques in a clini-cal research project to monitor the e.c.g. on-line(Caceres, 1963; Toole, von der Groeben andSpivack, 1963). We expect to have displayed ona "scope" in the operating room the patient'spre-operative e.c.g. and his present e.c.g., todetermine whether there have been significantchanges with regard to the e.c.g. wave contour. Ahistogram display of the last 300 hean beats canbe used to visualize heart rate and arrhythmias,this histogram being continuously updated.

In figure 8 is shown part of the equipmentemployed in this research project. The PDP-8digital computer is connected via cables to theoutput of the e.c.g. amplifiers in the operatingroom. A patient can be continuously monitoredand a "redundancy dump" can be employed toprevent saturation of computer memory withrepetitive unchanged e.c.g.'s. This dumpingtechnique, adapted from that used to monitorastronauts, means that the e.c.g. is sampled ata relatively low sampling rate and, if the valuefalls within limits established for that patient, theinformation is not stored. However, if it fallsoutside these limits, sampling occurs every milli-



second and the entire e.c.g. is stored in memoryof a large IBM 360-50 computer.

The computer is programmed to make adiagnosis based on extensive research carried outby Dr. von der Groeben (1967) on over 800 nor-mal individuals, as well as over 500 patients withheart disease (Forsythe, von der Groeben andToole, 1962). An orthogonal vector-cardiogramsystem is used and the space the normal vectortraverses is statistically defined. If the vectormoves outside the normal space, depending onwhich cluster it traverses, various types of abnor-malities may be diagnosed. Studies have shownthat the diagnostic accuracy of the e.c.g. is 54per cent if visual inspection is used. Preliminarystudies indicate that this will be greatly improvedif computer techniques are employed.

Now anaesthetists use e.c.g. monitoringalmost exclusively to detect arrhythmias. Normallymanv ST segment changes go unnoticed while

changes in QT interval during blood transfusioncannot be carefully monitored. These parametersand others will be monitored constantly anddisplayed for the anaesthetist almost instan-taneously.

The on-line monitoring of the e.c.g. is envis-aged as one of the first steps in computer-administration of anaesthesia by the anaesthetist.Monitoring of other important parameters willfollow as suitable transducers become available.The volumes and concentrations of each gasinhaled and exhaled may be monitored. By em-ploying the Fick principle, the computer couldbe used to provide an estimate of pulmonaryblood flow, and the work and power of breathingcould easily be computed. These computers willbe programmed initially to call departures fromthe established norm to the anaesthetist'sattention and thus we may come into an era ofcomputer-assisted anaesthesia. It is evident that

FIG. 8PDP-8 digital computer with associated oscilloscope digitized display and CalComp Plotter. Thiscomputer communicates with the operating room suite and also with the large IBM 360-50

computer.



once this goal is achieved, sensing can be carriedout rapidly, and with greater vigilance andreliability than by any human operator. There willbe a phase beyond this that will depend on ourcomplete understanding of all the decisions wemake during the day-to-day administration of ananaesthetic. Once the body of knowledge normallyemployed by an anaesthetist is defined, acomputer with adequate sensors can easily performthe motor tasks and improve on the humancapacities for administering anaesthesia.

CONCLUSIONS

From the foregoing, it is dear that the questionis not whether computer controlled anaesthesiawill ever be a reality, but when it will be a reality.There will be a time when the reality will nolonger be delayed by technological considerations.With the advent of time-sharing of computers,financial considerations will no longer be deter-ring factors. The shortage of anaesthetists willhasten it.

Thus, the administration of anaesthesia maywell be the first practice of medicine to be auto-mated. Will anaesthetists as a specialty disappear?Perhaps, in the narrow sense of the word, theywill, but a new physician will emerge. The prac-tice of anaesthesia as we know it will changeradically. Technical personnel will perform themechanical functions; the administration of drugsand control of physiological parameters will beautomated and a team of physicians will super-vise the entire procedure, and make the physi-cianly decisions.

It is highly likely that in this role the anaes-thetist will continue to be involved in thebroader practice of medicine rather than confininghis practice solely to the operating room. Inten-sive care units will be replaced by acute medicalcare units to offer, in addition to specialized nurs-ing care, continuous specialized medical care. Therequirements for moment-to-moment care of

coronary patients will require the same type ofautomated computer control as will be availableto patients during anaesthesia. Therefore, it islogical to assume that the anaesthetists ofthe future will be actually practising acute medi-cine and will be less concerned with the per-formance of technical aspects of the specialty asit is now practised.

REFERENCES

BeUvUle, J. W., and Forrest, W. H. (1967). Clinicalevaluation of analgesics. Methodology employed ina co-operative study. Clin. Pharmacol, exp. Ther.(submitted for publication).Hara, H. H. (1966). Use of analogue computers

in anesthetic research. Anesthesiology, 27, 70.Caceres, C A. (1963). Electrocardiographic analysis by

a computer system. Arch, intern. Med. (.Chicago),111, 196.

Finney, J. J. (1964). Statistical Method in BiologicalAssay, ch. 4. New York: Haffner.

Fletcher, G., and Bellville, J. W. (1966). On-line com-putation of pulmonary compliance and work ofbreathing. J. appl. Physiol., 21, 1321.

Forrest, W. H. (1967). Data management in the veter-ans administration co-operative analgesic study.Clin. Pharmacol, exp. Ther. (submitted for publi-cation).Bellville, J. W., Seed, J. C , Houde, R. W., Wallen-

stein, S. L., Sunshine, A., and Laska, E. (1963).A uniform method for collecting and processinganalgesic data. Psychopharm. Bull, 2, 1.

Forsythe, G. E., von der Groeben, J., and Toole, T. G.(1962). Vectocardiographic diagnosis with the aidof Algol. Communications A.C.M., 5, 118.

Laska, E., and Gormley, M. (1967). A bioassay com-puter programme for analgesic clinical trials. Clin.Pharmacol, exp. Ther. (submitted for publication).

National Halothane Study (1966). J. Amer. med. Ass.,197, 775.

Smith, N. T., Fleischli, G. J., and Garbascio, A. N.(1965). Estimation of stroke volume by analoguecomputer solution of the Starr ballistic formula.Proc. 1st World Cong. Ballistocard. Cardiovasc.Dynamics, Amsterdam, pp. 123-130. Basel/NewYork: Karges.

Toole, J. G., von der Groeben, J., and Spivack, A.(1963). The periodic abnormalities of the tempero-spatial QRS vector in isolated right ventricularoverwork. Amer. Heart J., 65, 77.

Von der Groeben, J. (1967). Decision rules in vectorelectrocardiography. Circulation (in press).


Brit. J. Anaesth. (1967), 39, 320

THE VALUE OF AN ORGANIZED ANAESTHETIC RECORDING SYSTEMIN CLINICAL TRIALS

BY

MICHAEL ROSEN AND WILLIAM W. MUSHINDepartment of Anaesthetics, Welsh National School of Medicine, Cardiff

The contribution that an already functioningorganized recording system can make to a clinicaltrial does not appear to be widely recognized.Such a system is often regarded as of doubtfulvalue in anaesthetic practice and, in particular,unsuitable for clinical trials and investigations; itis said that the special information accumulatedduring a trial is rarely applicable to routine re-cords. Our own experience does not support theseviews. We have found that an organized system ofrecords in the hospital can assist the clinician atevery stage of a trial of a new drug or treatment.

At the initiation of a clinical trial an existingorganized anaesthetic record system provides abackground of information and knowledge aboutthe hospital population, which may direct an in-vestigator to those groups of patients for whomthe treatment under trial is likely to be of mostbenefit. The records can also provide informationabout the usage and effects of other similar drugsin the same hospital. For instance, a knowledgeof the nature and the incidence of complicationsassociated with similar drugs already in use wouldprove invaluable when investigating a new one.

The records give information about the num-bers of patients in particular categories who areavailable for study, and this may enable answersto be given at the time to such important ques-tions as: "How long will this investigation take?";"How many cholycystectomies are there eachmonth between the ages of 35-65?"; "How manyvaricose vein operations are there each month inmales?" The answers may greatly influence whichgroups are included in a clinical trial.

The adequacy of control and of randomizationprocedures can only be determined by consideringthe comparability of groups of patients in respectof details such as the extent of pre-operative com-plications, e.g. diseases of the respiratory, renal,cardiovascular and central nervous systems, thenature of any premedication, the site and duration

of operation, the type of anaesthesia, and manyother details about the operation and the anaes-thetic. These points cannot easily be checkedunless there exists a body of data easily availablefrom an organized recording system. Many other-wise excellently devised clinical trials havefoundered because of inadequate informationabout the hospital population samples which werestudied, or because there was some important dif-ference between the control and the study groups.

During a trial, a properly designed anaestheticrecord contains not only all the usual details ofgeneral information, but in addition thoseitems of particular interest that are important inthe trial. Any recording and sorting system islimited to a certain number of facts, even thoughthe introduction of computers will make it pos-sible to include many more than was previouslypossible. In any particular investigation, therefore,there may be aspects of the problem which areeither not included in the standard record or,more commonly, are not graded in a suitableform. It is, therefore, particularly important tosee that the record is designed initially so thatextra items can be easily added. The Cardiffrecord (Mushin et al., 1954) was planned withthis in mind, and additional information whichcan be coded, and therefore sorted, can easily beadded.

The presence of an already functioning anaes-thetic record system in a hospital provides severalother advantages. Every anaesthetist comes toregard the completion of the record as a part ofnormal routine and the institution of a trial doesnot meet with any resistance to recording. Thereexists in fact a climate of opinion in which co-operation is readily forthcoming. There is also,and most important of all perhaps, a mechanismfor handling records. The processes of collection,coding, sorting, and reporting, call for an organi-zation and for skills which may be difficult to


THE VALUE OF AN ORGANIZED ANAESTHETIC RECORDING SYSTEM 321

bring into being just for a planned trial. Further-more, the experience gained in the routine hand-ling and interpretation of data contributes to thedetachment and cynicism necessary when judgingthe value of records involved in a trial.

The record system must be made as foolproofand complete as possible. We do this by makingas many processes as are practicable dependent onthe clerical staffs of the Records and StatisticalDepartments. The record starts in the ward andtravels with the patient to the operating theatre.From there it is collected and the theatreregister is checked to ensure that a record hasbeen completed for every patient who stays in thehospital at least one night. The record is thentransmitted to the anaesthetist who completesthe postoperative details. Finally the record goesto the Statistical Department for coding. Manynon-clinical details are recorded by the clericalstaff, saving the doctor both time and effort. Theseinclude the patient's name, address, age, sex, hos-pital number, anaesthetic record code number,ward, name of surgeon, date of admission, andsuch postoperative factual details as the durationof stay in hospital, and the date of death. A post-mortem report, if available, is appended. In addi-tion the clerk, by gentle reminders, encouragesthe anaesthetists to complete any inadvertentomissions from their records.

An established record system also overcomesother difficulties which those who have set upclinical trials in hospitals without a system willrecognize. Complicated records for a clinical trialare not usually kept well in a large-scale trial.They are therefore necessarily made as simple aspossible, containing questions requiring a crudetype of YES/NO answer. A high level of recordingis unlikely to be carried on for long periods, and aclinical trial, which encompasses many people,however keen, making precise detailed records,usually has to be confined to a reasonably shortperiod; the longer such a trial goes on the morelikely are inaccuracies to enter unless the trial isvery simple.

Routine experience with an organized recordsystem has taught us which items in an anaes-thetic record are of high or reasonable credibilityand which ones ought to be regarded with sus-picion. For instance, postoperative complication

rates are of doubtful reliability, and if they areimportant in an investigation special attentionshould be given to them. This nearly alwaysmeans that a specially delegated investigator mustfollow up the patients. On the other hand, mortal-ity figures and the duration of stay in hospital arefactual. The latter in particular gives a very use-ful indication of a complicated recovery.

In the analysis of data, an established routineand automatic apparatus for sorting and tabulationare invaluable. It is agonizingly slow and frustrat-ing to sort and cross-sort by hand even a com-paratively small number of records. An existingsystem for accurately coding and sorting recordsmay even encourage clinical research since it easesthis problem. Clerical errors are comparativelyrare from an experienced coding clerk. Neverthe-less the coding procedures should be scannedregularly.

Finally, the difficulty of achieving a nearlycomplete follow-up of patients who are includedin a trial can hardly be exaggerated. Omissionscast many doubts about validity. From the know-ledge which an established records system givesof the whole hospital population it is usually pos-sible to find out whether those omitted arerepresentative of the population studied, orwhether they form a special group.

In determining the value of a drug in clinicalpractice it is necessary as well to know the inci-dence of adverse reactions. This is clearly diffi-cult, unless some form of routine record is avail-able on which such reactions can be charted and,much more important, collated. The recognitionand recording of adverse reactions is dependenton how hard the investigator looks for them. Anatmosphere in which routine recording is en-couraged is bound to help. The interpretation ofwhether the appearance of some pathological con-dition is an adverse reaction related to a particulartreatment depends almost entirely on what theprevalence of this condition is in the communityand of the association between it and similartreatments. This was well illustrated in the caseof the alleged association between halothane andliver damage. After halothane had been intro-duced, reports of liver damage following its useappeared in the medical press. The associationwas taken by many as proved and clinical practice



was greatly affected by them. No relationship bet-ween liver damage and halothane could be estab-lished from animal experimental studies but theclinical reports alleging this association continuedto appear. Whether this was a true associationor not could only be determined by knowing theactual prevalence of liver damage following alltypes of surgery and anaesthesia in a surgicalpopulation. In one investigation the authors couldonly get for large hospitals an "estimated" num-ber of halothane anaesthetics and an "estimated"number of other anaesthetics. These "estimates"from hospitals which did not have routine estab-lished anaesthetic recording systems were value-less. More precise information was required. TheCardiff Record System enabled these facts to beelicited, and it transpired that any liver damagedue to halothane was no more common than withother anaesthetics (Mushin et al., 1964). If equallyadequate records had been kept in five or tenother large hospitals it would be possible to beeven more sure.

We hope that the importance and value ofroutine organized anaesthetic recording systemswill yet be universally recognized. If clinical trials

of anaesthetic drugs are to be extended they maywell come to be considered essential.

CONCLUSION

The value of an organized recording system in aclinical trial is not widely recognized. It can helpin selection of patients—those suitable and thosewho may benefit, in proper randomization, andin checking whether any omissions are random orsystematic. A properly designed routine recordis easily adapted to the special requirements of aclinical trial. An already functioning recordingsystem encourages research by easing the prob-lems, otherwise present, when analyzing andsorting records. The experience gained fromroutine records makes the investigator wary ofbeing too easily satisfied with information whichcannot be corroborated.

REFERENCES

Mushin, W. W., Rendell-Baker, L., Lewis-Faning, E.,and Morgan, J. H. (1954). The Cardiff anaestheticrecord system. Brit. J. Anaesth., 26, 298.

Rosen, M., Bowen, D. T., and Campbell, H.(1964). Halothane and liver dysfunctions: a retro-

spective study. Brit med. J., 2, 329.

THE FORTY-SIXTH SOUTH AFRICAN MEDICAL CONGRESSof the Medical Association of South Africa

will take place at

83 Medical Centre, Field Street, Durban

on JULY 17-22, 1967

Subjects likely to be of interest to anaesthetists include:

A Plenary session on Medical Responsibility.A Sub-Plenary session on Shock.Combined Sectional Meetings on the Management of Chest Injuries,

Cardiac Surgery, Special problems in Missionary Medicine.

Dr. C. Sliom is Honorary Secretary of the Scientific Section on Anaesthetics.Full information can be obtained from the Organizing Secretaries, 83, Medical Centre,

Field Street, Durban, Natal, South Africa.


the use of computers in clinical trials

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