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FURTHER OBSERVATIONS ON THE RESULTS OF SYMPATHECTOMY OF THE UPPER LIMB
770 FURTHER OBSERVATIONS ON
THE RESULTS OF SYMPATHECTOMY OF THE UPPER LIMB G. T. C. HAMILTON
H. BARCROFT M.A., M.D. Camb.
M.D. Belf.
LONDON AT ST.
DEMONSTRATOR PHYSIOLOGY IN THE
SENIOR
PROFESSOR OF PHYSIOLOGY IN THE UNIVERSITY OF
IN
QUEEN’S
THOMAS’S
UNIVERSITY OF BELFAST
HOSPITAL
PBEGANGMONic section of the sympathetic nerveto the arm (Smithwick 1940) is designed to leave a wide gap between the cut fibres. That sympathetic function can be regained, even to a small extent, seems at first sight difficult to believe ; yet there is good evidence that this is so (Simmons and Sheehan 1939, Haxton 1947, Barcroft and Hamilton 1948). The question is of such fundamental importance to the surgery of the sympathetic nervous system that we describe below some further evidence in favour of it. In our previous work (Barcroft and Hamilton 1948) vasomotor and sudomotor reflexes were completely absent in seventeen limbs tested 1-6 months after operation. Sixteen of these limbs have now been re-examined 1-11/2 years later, and the results compared with those
supply
The ratios of the sympathectomised limbs are arranged in two groups, 1-6 months after operation (the-- first test), and 1-11/2 years later, when the tests wererepeated. In each group the ratios are arranged in order of the length of time between the operation and the performance of the first test, those tested soonest after sympathectomy being on the left. As noted in the previous paper, all hands tested within six months of operation had heating ratios of about 1-i.e., indirect heating had no effect on the vessels of the hands. In contrast to this, many of the same hands, when tested a year or more later, had heating ratios considerably greater than 1-i.e., in these vasodilatation could once more be produced in the hands. Sudomotor Test The current differences of the same normal and sympathectomised hands are given vertically below theix heating ratios in the lower half of the figure. All the normal hands showed large current differences due to the low resistance of the moist test skin and the relatively larger resistance of the dry control skin. The results from the sympathectomised limbs are arranged in the same groups, 1-6 months after operation and 1-11/2 years later. All the hands tested within 6 months of operation had very small current differences. When retested many of these same hands showed quite large current differences. The figure shows conclusively that there was no evidence of any sympathetic nervous connexion between the brain and the hand for several months after sympathectomy. A year or more later, vasomotor and sudomotor reflexes were obtainable in many hands. This confirms the findings of Simmons and Sheehan (1939), Haxton (1947), and Barcroft and Hamilton (1948).
obtained earlier. Vasomotor Test.-Warming the feet elicits a reflex increase in blood-flow in the hands, the efferent limb of the reflex arc being from the vasomotor centre through sympathetic fibres. In the absence of sympathetic connexions to the limb heating of the feet does not alter the blood-flow. The details of the test were described in The results are expressed as the our previous paper. Blood-flow during heating. This ratio heating ratio is 3 Blood-flow before heating. in completely sympathecor more in normal hands ; tomised hands it is 1. Sudomotor Test.-The resistance to the passage of an electric current through the body is located almost entirely in the skin and is determined chiefly by the activity of the sweat glands. This activity depends on nervous excitation mediated through sympathetic fibres. In practice the test we used previously (Barcroft and Hamilton 1948) was simplified and was as follows. The feet - were heated to encourage free sweating. The currents which flowed through the pads of the thumb and middle and little fingers were measured in A, and the average of them was called the current difference. Normal hands have current differences of 20 A or more, since the skin is moist. In fully sympathectomised hands current differences are negligible, since the brain cannot elicit sweating. (The absence of any humoral mechanism for excitation of sweating is proved by the fact that ulnar-nerve block reduces the current through the little finger to less than 1 pA.)
Results of vasomotor and sudomotor tests obtained in sympathectomised hands.
It will be seen that clinical improvement persisted in all hands, though reflexes had reappeared in most. Therefore the new nerve path formed is probably functionally poorer than that present before sympathectomy.
RESULTS
Vasospastic Attacks.-All the sixteen limbs had operated on for frequent severe vasospastic attacks.
been The clinical condition at the time of the first and second tests was : No reèur1’ence. of attacks operation 14 1-6 months ’ 12 1-2 years Time after
..
Attacks less
disabling ..
..
23 4
. ..
..
Sixteen limbs,
Attacks as bad as before 0
0
Vasomotor Test The heating ratios of some normal hands and those of the sympathectomised ones are shown in the upper half of the accompanying figure. Heating produced vasodilatation in all normal hands, the blood-flows being increased at least threefold. ’
..
spastic attacks, operation. ,
SUMMARY
.
for frequent vasoexamined twice after
sympathectomised were
each
At the first examination, 1-6 months after operation, attacks had not recurred in 14 ; they had recurred but were less severe in 2 ; and vasomotor and sudomotor reflexes were absent in all the hands. At the second examination, 1-11/2 years later, attacks had not recurred in 12 ; they had recurred but were less severe in 4. Vasomotor and sudomotor reflexes, though absent in some limbs, had returned in many.
771 The
persistence
of the excellent clinical results in these
limbs, in spite of the reappearance of the reflexes in most, signifies that the new nerve path is functionally less efficient than that present before operation. Once more, we acknowledge our gratitude to Prof. J. R. Learmonth, Mr. P. Fitzgerald, and Mr. J. S. Loughridge for putting us in touch with their patients ; Mr. D. B. Smith
is therefore essential that the identity of substances under trial be not known by anybody until all the tests are completed.. As well as a control tablet and the substance being investigated, it is useful to include a substance of established reputation so that we can answer two questions : (1) does the substance work ? and (2) does it work any better than what we are using at
for technical assistance ; and the Medical Research Council for defraying expenses.
present ?
REFERENCES
saridone,
Barcroft, H., Hamilton, G. T. C. (1948) Lancet, i, 441. Haxton, H. A. (1947) Brit. J. Surg. 35, 69. Simmons, H. T., Sheehan, D. (1939) Ibid, 27, 234. Smithwick, R. H. (1940) Ann. Surg. 112, 1085.
A METHOD OF TESTING ANALGESICS
possible way of knowing which colour to which tablets. The key to the identity of the tablets was provided in a sealed envelope which was
There
RICHARD ASHER M.D. Lond., M.R.C.P. PHYSICIAN,
was
no
corresponded
CENTRAL MIDDLESEX HOSPITAL
EARLY in 1947 Messrs. Roche asked the Central Middlesex County Hospital to perform a clinical trial of their analgesic preparationSaridone.’ * This paper describes an attempt to judge the effectiveness of these tablets by as impartial and accurate a method as possible. It is notoriously difficult to assess the power of different analgesics. There are three main methods-animal experiments, experiments on human volunteers with artificially produced pain, and clinical trial on patients with naturally occurring pain. Animal experiments are useful in initial tests to select a substance for further trial, but they assess properties only remotely connected with the purpose of an analgesic. A patient wants a tablet that makes his pain better and not only one that stops a rat from twitching its tail away from a painfully hot lamp (a common laboratory test for analgesic properties is to measure the time taken before a rat moves its tail from an increasingly hot beam of light). Experiments on artificially p’i’oduced pain have disadvantages too. First, the subjects have not the same mental attitude to the pain as ordinary patients have. It is a pain of their own choosing, and so they suffer none of the anxiety, resentment, and irritability that usually attend naturally occurring pain. Their discomfortis somewhat modified too by the pleasure of feeling slightly heroic and by the curiosity of being
experimented
present trial three kinds of tablets were used: an inert tablet, and tab. codeine co. (N.W.F.), which is perhaps better known a ’Veganin.’ Messrs. Roche kindly made up these three substances in tablets of identical appearance, except that they were coloured red, white, and blue (not necessarily respectively). For the second halfof the experiment they supplied another set of tablets in which these colours, were changed round. In the
on.
kept locked in a drawer until after the whole trial was completed, when it was publicly opened by the chairman (Dr. Avery Jones) at a meeting of the clinical society of the Central Middlesex County Hospital. Messrs. Roche also printed for me a corresponding number of cards bearing on one side instructions, to the nurse and on the other side instructions to the patient. The instructions to the
nurse were as
follows :
These tablets are to be given for the relief of pain, not for sleeplessness without pain. Two tablets of the same colour are to be given. Only one pair of tablets may be tried by each patient. Please ’ hand this form to any patient who is given these tablets. Please complete this side of the form first and see that the patient fills in the other side properly. -
Name of Patient
...........
-
...............
Ward .............................................
Description of Pain and/or Diagnosis
................. ,
Colour of Tablets Supplied.........., (Different coloured tablets may not be given together.)
..........................
The instructions to the
patient
were as
follows :
You are asked to try these. tablets which are for easing pain. Please help us to judge them by filling in this form. Do not fill it up for at least two hours after taking the tablets. 1. Was the pain (a) Slightly eased ..............
(b) Completely relieved ? (c) Not changed at all ? Put a cross against one of these answers. 2. How soon after taking the tablets did
...............
U
1 n .,-nn - . h-
you
get any benefit ?z
3. Did you notice any other effects from the tablet ?
If
so
write
them here.................................................. Clinical 1’rials The danger of clinical trials is that a perfectly conI EXPERIMENT trolled test is so hard to arrange. Also, the more elaborate Two hundred pairs of tablets from the first set were the arrangements, the less closely do the conditions of distributed to the wards with the same number of cards, normal bedside the tablet resemble administration. taking and an explanation of the experiment was given to the For any fair trial a control inert tablet should be given, nurses. They were asked to give the tablets to patients but if the identity of the tablet is known to the doctor two whom they would normally have given aspirin or tests or to the nurses the the tablets, giving supervising codeine tablets, but not to patients with severe pain their own attitude may much influence the attitude of the patients and so corrupt the results. Consciously or needing morphine. They were not told that any of the tablets were inert, but most of them guessed that at a a substance she knows to nurse unconsciously giving least one colour of the three kinds would be inactive. be inert may convey her distrust of the tablet to the or word. The They were only told one deliberate lie-that different patient by manner, gesture, way people wards were being given different sets of tablets. I did can be unconsciously influenced by a word is well shown " by the results of an American bureau of salesmanship not want rumours, such as blue are the duds," to spread from ward to ward ; so I left them believing that what who found that when a salesman said " Ice-cream, sir ? Large" he sold over 50% more large ice-creams than was blue in one ward might be white in another. Further I feared that tablets might be lent by one ward to when he said It Ice-cream, sir Large or small ? another, which would muddle results if different sets * Saridone, according to the makers, is an effective and balanced were used (and this actually happened). It was interesting combination of analgesics, rapid in action and free from disto hear the different reputations of the various colours. agreeable effects. It is recommended for headache, toothache, The formula is : rheumatism, &c. In one ward the sister told me " am sure the white have 150 mg. Isopropyl antipyrine .. Phenacetin .. 250 mg. nothing in them ; so I only give them to patients I don’t 50 mg. ’ Persedon’ think have really got a pain." In an adjacent ward the 50 mg. Caffeine .... sister swore by the blue and restricted their use to the 600 mg. Weight of tablet .... "
"
I
....
THE RESULTS OF SYMPATHECTOMY OF THE UPPER LIMB G. T. C. HAMILTON
H. BARCROFT M.A., M.D. Camb.
M.D. Belf.
LONDON AT ST.
DEMONSTRATOR PHYSIOLOGY IN THE
SENIOR
PROFESSOR OF PHYSIOLOGY IN THE UNIVERSITY OF
IN
QUEEN’S
THOMAS’S
UNIVERSITY OF BELFAST
HOSPITAL
PBEGANGMONic section of the sympathetic nerveto the arm (Smithwick 1940) is designed to leave a wide gap between the cut fibres. That sympathetic function can be regained, even to a small extent, seems at first sight difficult to believe ; yet there is good evidence that this is so (Simmons and Sheehan 1939, Haxton 1947, Barcroft and Hamilton 1948). The question is of such fundamental importance to the surgery of the sympathetic nervous system that we describe below some further evidence in favour of it. In our previous work (Barcroft and Hamilton 1948) vasomotor and sudomotor reflexes were completely absent in seventeen limbs tested 1-6 months after operation. Sixteen of these limbs have now been re-examined 1-11/2 years later, and the results compared with those
supply
The ratios of the sympathectomised limbs are arranged in two groups, 1-6 months after operation (the-- first test), and 1-11/2 years later, when the tests wererepeated. In each group the ratios are arranged in order of the length of time between the operation and the performance of the first test, those tested soonest after sympathectomy being on the left. As noted in the previous paper, all hands tested within six months of operation had heating ratios of about 1-i.e., indirect heating had no effect on the vessels of the hands. In contrast to this, many of the same hands, when tested a year or more later, had heating ratios considerably greater than 1-i.e., in these vasodilatation could once more be produced in the hands. Sudomotor Test The current differences of the same normal and sympathectomised hands are given vertically below theix heating ratios in the lower half of the figure. All the normal hands showed large current differences due to the low resistance of the moist test skin and the relatively larger resistance of the dry control skin. The results from the sympathectomised limbs are arranged in the same groups, 1-6 months after operation and 1-11/2 years later. All the hands tested within 6 months of operation had very small current differences. When retested many of these same hands showed quite large current differences. The figure shows conclusively that there was no evidence of any sympathetic nervous connexion between the brain and the hand for several months after sympathectomy. A year or more later, vasomotor and sudomotor reflexes were obtainable in many hands. This confirms the findings of Simmons and Sheehan (1939), Haxton (1947), and Barcroft and Hamilton (1948).
obtained earlier. Vasomotor Test.-Warming the feet elicits a reflex increase in blood-flow in the hands, the efferent limb of the reflex arc being from the vasomotor centre through sympathetic fibres. In the absence of sympathetic connexions to the limb heating of the feet does not alter the blood-flow. The details of the test were described in The results are expressed as the our previous paper. Blood-flow during heating. This ratio heating ratio is 3 Blood-flow before heating. in completely sympathecor more in normal hands ; tomised hands it is 1. Sudomotor Test.-The resistance to the passage of an electric current through the body is located almost entirely in the skin and is determined chiefly by the activity of the sweat glands. This activity depends on nervous excitation mediated through sympathetic fibres. In practice the test we used previously (Barcroft and Hamilton 1948) was simplified and was as follows. The feet - were heated to encourage free sweating. The currents which flowed through the pads of the thumb and middle and little fingers were measured in A, and the average of them was called the current difference. Normal hands have current differences of 20 A or more, since the skin is moist. In fully sympathectomised hands current differences are negligible, since the brain cannot elicit sweating. (The absence of any humoral mechanism for excitation of sweating is proved by the fact that ulnar-nerve block reduces the current through the little finger to less than 1 pA.)
Results of vasomotor and sudomotor tests obtained in sympathectomised hands.
It will be seen that clinical improvement persisted in all hands, though reflexes had reappeared in most. Therefore the new nerve path formed is probably functionally poorer than that present before sympathectomy.
RESULTS
Vasospastic Attacks.-All the sixteen limbs had operated on for frequent severe vasospastic attacks.
been The clinical condition at the time of the first and second tests was : No reèur1’ence. of attacks operation 14 1-6 months ’ 12 1-2 years Time after
..
Attacks less
disabling ..
..
23 4
. ..
..
Sixteen limbs,
Attacks as bad as before 0
0
Vasomotor Test The heating ratios of some normal hands and those of the sympathectomised ones are shown in the upper half of the accompanying figure. Heating produced vasodilatation in all normal hands, the blood-flows being increased at least threefold. ’
..
spastic attacks, operation. ,
SUMMARY
.
for frequent vasoexamined twice after
sympathectomised were
each
At the first examination, 1-6 months after operation, attacks had not recurred in 14 ; they had recurred but were less severe in 2 ; and vasomotor and sudomotor reflexes were absent in all the hands. At the second examination, 1-11/2 years later, attacks had not recurred in 12 ; they had recurred but were less severe in 4. Vasomotor and sudomotor reflexes, though absent in some limbs, had returned in many.
771 The
persistence
of the excellent clinical results in these
limbs, in spite of the reappearance of the reflexes in most, signifies that the new nerve path is functionally less efficient than that present before operation. Once more, we acknowledge our gratitude to Prof. J. R. Learmonth, Mr. P. Fitzgerald, and Mr. J. S. Loughridge for putting us in touch with their patients ; Mr. D. B. Smith
is therefore essential that the identity of substances under trial be not known by anybody until all the tests are completed.. As well as a control tablet and the substance being investigated, it is useful to include a substance of established reputation so that we can answer two questions : (1) does the substance work ? and (2) does it work any better than what we are using at
for technical assistance ; and the Medical Research Council for defraying expenses.
present ?
REFERENCES
saridone,
Barcroft, H., Hamilton, G. T. C. (1948) Lancet, i, 441. Haxton, H. A. (1947) Brit. J. Surg. 35, 69. Simmons, H. T., Sheehan, D. (1939) Ibid, 27, 234. Smithwick, R. H. (1940) Ann. Surg. 112, 1085.
A METHOD OF TESTING ANALGESICS
possible way of knowing which colour to which tablets. The key to the identity of the tablets was provided in a sealed envelope which was
There
RICHARD ASHER M.D. Lond., M.R.C.P. PHYSICIAN,
was
no
corresponded
CENTRAL MIDDLESEX HOSPITAL
EARLY in 1947 Messrs. Roche asked the Central Middlesex County Hospital to perform a clinical trial of their analgesic preparationSaridone.’ * This paper describes an attempt to judge the effectiveness of these tablets by as impartial and accurate a method as possible. It is notoriously difficult to assess the power of different analgesics. There are three main methods-animal experiments, experiments on human volunteers with artificially produced pain, and clinical trial on patients with naturally occurring pain. Animal experiments are useful in initial tests to select a substance for further trial, but they assess properties only remotely connected with the purpose of an analgesic. A patient wants a tablet that makes his pain better and not only one that stops a rat from twitching its tail away from a painfully hot lamp (a common laboratory test for analgesic properties is to measure the time taken before a rat moves its tail from an increasingly hot beam of light). Experiments on artificially p’i’oduced pain have disadvantages too. First, the subjects have not the same mental attitude to the pain as ordinary patients have. It is a pain of their own choosing, and so they suffer none of the anxiety, resentment, and irritability that usually attend naturally occurring pain. Their discomfortis somewhat modified too by the pleasure of feeling slightly heroic and by the curiosity of being
experimented
present trial three kinds of tablets were used: an inert tablet, and tab. codeine co. (N.W.F.), which is perhaps better known a ’Veganin.’ Messrs. Roche kindly made up these three substances in tablets of identical appearance, except that they were coloured red, white, and blue (not necessarily respectively). For the second halfof the experiment they supplied another set of tablets in which these colours, were changed round. In the
on.
kept locked in a drawer until after the whole trial was completed, when it was publicly opened by the chairman (Dr. Avery Jones) at a meeting of the clinical society of the Central Middlesex County Hospital. Messrs. Roche also printed for me a corresponding number of cards bearing on one side instructions, to the nurse and on the other side instructions to the patient. The instructions to the
nurse were as
follows :
These tablets are to be given for the relief of pain, not for sleeplessness without pain. Two tablets of the same colour are to be given. Only one pair of tablets may be tried by each patient. Please ’ hand this form to any patient who is given these tablets. Please complete this side of the form first and see that the patient fills in the other side properly. -
Name of Patient
...........
-
...............
Ward .............................................
Description of Pain and/or Diagnosis
................. ,
Colour of Tablets Supplied.........., (Different coloured tablets may not be given together.)
..........................
The instructions to the
patient
were as
follows :
You are asked to try these. tablets which are for easing pain. Please help us to judge them by filling in this form. Do not fill it up for at least two hours after taking the tablets. 1. Was the pain (a) Slightly eased ..............
(b) Completely relieved ? (c) Not changed at all ? Put a cross against one of these answers. 2. How soon after taking the tablets did
...............
U
1 n .,-nn - . h-
you
get any benefit ?z
3. Did you notice any other effects from the tablet ?
If
so
write
them here.................................................. Clinical 1’rials The danger of clinical trials is that a perfectly conI EXPERIMENT trolled test is so hard to arrange. Also, the more elaborate Two hundred pairs of tablets from the first set were the arrangements, the less closely do the conditions of distributed to the wards with the same number of cards, normal bedside the tablet resemble administration. taking and an explanation of the experiment was given to the For any fair trial a control inert tablet should be given, nurses. They were asked to give the tablets to patients but if the identity of the tablet is known to the doctor two whom they would normally have given aspirin or tests or to the nurses the the tablets, giving supervising codeine tablets, but not to patients with severe pain their own attitude may much influence the attitude of the patients and so corrupt the results. Consciously or needing morphine. They were not told that any of the tablets were inert, but most of them guessed that at a a substance she knows to nurse unconsciously giving least one colour of the three kinds would be inactive. be inert may convey her distrust of the tablet to the or word. The They were only told one deliberate lie-that different patient by manner, gesture, way people wards were being given different sets of tablets. I did can be unconsciously influenced by a word is well shown " by the results of an American bureau of salesmanship not want rumours, such as blue are the duds," to spread from ward to ward ; so I left them believing that what who found that when a salesman said " Ice-cream, sir ? Large" he sold over 50% more large ice-creams than was blue in one ward might be white in another. Further I feared that tablets might be lent by one ward to when he said It Ice-cream, sir Large or small ? another, which would muddle results if different sets * Saridone, according to the makers, is an effective and balanced were used (and this actually happened). It was interesting combination of analgesics, rapid in action and free from disto hear the different reputations of the various colours. agreeable effects. It is recommended for headache, toothache, The formula is : rheumatism, &c. In one ward the sister told me " am sure the white have 150 mg. Isopropyl antipyrine .. Phenacetin .. 250 mg. nothing in them ; so I only give them to patients I don’t 50 mg. ’ Persedon’ think have really got a pain." In an adjacent ward the 50 mg. Caffeine .... sister swore by the blue and restricted their use to the 600 mg. Weight of tablet .... "
"
I
....