- Email: [email protected]
SCREENING TEST FOR CHLOROQUINE RETINOPATHY
40
less disease-centred criterion of therapeutic success. Sickness absence from work, ability to continue housework, or other facility for specific activity may be of value. These factors would take account of the enormous power of human adaptability in adversity. We should also avoid the lesser degrees of " the operation was a success, but the patient died ". J. J. MCMULLAN. London, W.2.
some
internal massage should be used. Donald et al. have not measured cardiac output and coronary flow during internal cardiac massage, and they therefore have no reasons other than purely theoretical ones for assuming that it will be more effective than external massage. Furthermore their suggestion that internal massage may be less damaging to an already ailing myocardium is contrary to the established facts. Thoracic
METHOD OF ARTERIAL SAMPLING SIR,-The frequency with which single arterial samples
required from conscious patients for clinical or research purposes makes a simple, reliable, and painless
are
method of arterial puncture desirable. The usual technique of inserting a medium to large needle into the brachial or femoral arteries after infiltration of a local anxsthetic does not fulfil these requirements, being always uncomfortable, often painful, and sometimes difficult. The following technique has been found to be free from these objections:
Surgical Unit, Papworth Hospital, Cambridge.
B. B. MILSTEIN.
PLASMA-CORTICOTROPHIN SIR,-May I add two comments to the correspondence
about
plasma-corticotrophin estimations ?
Espiner1 suggested that venesection for large blood samples (always 500 ml.) causes pituitary secretion of corticotrophin during the collection period. Naturally, precautions to minimise the possible shock of this procedure were taken in my work, such as using subjects resting in bed to whom a simple prior explanation (and breakfast) was given. The blood was obtained, in the majority of cases, by very experienced The region around the radial artery at the wrist is infiltrated people, including a blood-transfusion officer for the normal with 1 % procaine using a fine no. 20 needle; the same needle subjects. While augmentation of blood-corticotrophin by is used to puncture the artery, and the sample syringe is then venepuncture cannot be ruled out, I think it arguable that, if attached in place of that containing the procaine and the sample venepuncture had a great quantitative effect in the hypertensive obtained. The needle is then withdrawn and the puncture site Cushing’s patients, it would have " blanketed " the variations compressed for 30 seconds. The freedom from discomfort, in blood-corticotrophin that I found between individual cases. haematomas, or inadvertent venepuncture, together with the I am at present using a method, to be published, involving ease of making the actual arterial ’puncture have made 50-100 ml. samples of blood, but this was introduced mainly to the collection of these samples a pleasanter matter for both save the patients parting with so much blood. As I mentioned the patient and the operator. previously, at present perhaps most information can be obtained by comparing corticotrophin values for pathological Department of Anæsthesia, Addenbrooke’s Hospital, BRYAN E. MARSHALL. plasmas with the same worker’s figures for normal plasma. Cambridge. It is a little difficult that the results of the sheep adrenal autotransplant work have been given before a full description HÆMODYNAMIC EFFECTS OF EXTERNAL of the assay has been published, and I look forward to reading CARDIAC COMPRESSION this in the Journal of Physiology. I still think it reasonable to SIR,-Professor Donald and his colleagues must be con- expect that a bioassay be based on an effect measured at its gratulated on their initiative in obtaining measurements peak (or over a short period containing its rise to and fall from of the hxmodynamic changes during external cardiac the maximum); that the test preparation causes its response at same time-interval after injection as the standard hormone; compression in man.1 Several interesting points arise from the and that the assay has a statistical design. their findings: 1. The venous pressure is not necessarily elevated to a very high level during the phase of cardiac compression. I have published an illustration of the consecutively recorded arterial and venous pressures during external cardiac compression in one patient. In this case the venous pressure was elevated only slightly during cardiac compression. Possibly, therefore, the technique of cardiac compression, or the condition of the heart, determines whether venous pressures are high. 2. Donald and his colleagues show that the cardiac output from external cardiac compression is only about half that during normal sinus rhythm. As they point out, the cardiac output was in any event low as a result of myocardial damage in their cases. It has always been apparent, however, from observation of skin pallor or cyanosis during cardiac massage, and subsequent flushing of the skin when the heart starts, that the cardiac output is abnormally low during cardiac massage. This has not prevented resuscitation of the heart or the return of normal cerebral function. Although Donald has produced some evidence that the coronary arteries were inadequately perfused during cardiac massage, no evidence has been adduced concerning the cerebral blood-flow. It seems likely that, as the cardiac output falls, the cerebral blood-flow will come to represent an increasing proportion of the total.
The chief criticism of Donald’s article must be of the last paragraph in which it is suggested that, if cardiac massage is to be continued for more than a brief period, 1.
2.
MacKenzie, G. J., Taylor, S. H., McDonald, A. H., Donald, K. W. Lancet, 1964, i, 1342. Milstein, B. B. Cardiac Arrest and Resuscitation; fig. 14, p. 117. London, 1963.
Dr.
Division of Physiology and Endocrinology, Imperial Cancer Research Fund, Lincoln’s Inn Fields, London, W.C.2.
BERYL M. A. DAVIES.
SCREENING TEST FOR CHLOROQUINE RETINOPATHY
SIR,-Inoted with interest the article by Dr. Copeman and his colleagues.2 First I wish to congratulate the authors on their adaptation of the E.G.G. machine to do electro-oculography (E.O.G.) Unfortunately there are several points in their article with which I must disagree. First, the initials E.o.G. generally stand for electro-oculogram, and there is little reason for calling the test the extraoculogram. The authors’ statement, " Extraoculography is the only reliable method for detecting early retinopathy caused by chloroquine and related antimalarial drugs ", does not appear to be supported by any of the material they provide. Indeed, they mention the paper of Gouras and Gunkel3 which, far from supporting their statement, actually shows that the E.o.G. may be normal in patients with definite early retinopathy. My own experience 4 indicates that there is often visible evidence of chloroquine retinopathy preceding any notable change in the E.o.G. or the E.R.G. (electroretinogram). The early changes usually occur in the macular region and consist of the following: loss of foveal reflex, macular mottling-probably resulting in changes in the underlying pigment epithelium, and the so-called macular bull’s-eye ". Undoubtedly the E.o.G. is a useful "
1. 2. 3. 4.
Espiner, E. A. Lancet, 1964, i, 1327. Copeman, P. W. M., Cowell, T. K., Dallas, M. L. ibid p. 1369. Gouras, P., Gunkel, R. D. Arch. Ophthal. 1963, 70, 629. Henkind, P., Carr, R., Siegel, I. ibid. 1964, 71, 157.
41
adjunct in diagnosis, provided serial studies are made before and during synthetic antimalarial therapy. It is not, however, the only reliable method for detecting early chloroquine retinopathy. Finally, the incidence of retinopathy following chloroquine administration is not the oft-quoted ill-supported figure of 3%. The incidence appears to depend upon dosage and duration of therapy, and perhaps individual sensitivity. Thousands, perhaps millions, of people have taken and do take chloroquine and related drugs for the treatment and prevention of malaria, without any incidence of retinopathy. On the other hand patients taking chloroquine in high dosages for long periods (particularly for skin and connective-tissue disorders) have an incidence of retinopathy exceeding 3 % .5 Department of Pathology, Institute of Ophthalmology, Judd Street, London, W.C.1.
PAUL HENKIND
SIR, Two recent articles 6on the use of the electrooculogram (E.O.G.) in routine screening for chloroquine retinopathy call for comment. The technique, as originally described,8 is indeed simple, and requires little more than a commercial electrocardiograph. The use in the input stages of a short time constant7 which reduces the eye movements to " spikes " is convenient, but in the initial stages of an investigation may lead to spurious results, since baseline drifts, which give warning that the electrodes are moving as the eye rotates, are totally eliminated. If measurements are to be made from the traces with any degree of accuracy, the pen excursion must be sufficiently large for measurement errors to be negligible. Many simple electrocardiographs have pen systems which do not give large deflections without introducing considerable distortion. The actual quantitative results obtained depend very much on the illumination used, and of course the eye is sensitive to the colourtemperature of the source. For this reason we use fluorescent tubes. If tungsten photoflood lamps are employed, and the intensity is controlled with a variac, it would be wise to control the lamp current with a suitable meter. We have modified our apparatus by including a cheap tape-recorder which instructs the patient when to move his eyes. This means that the tester, once the patient has been prepared, is free to leave the test room, and perform other duties. We have not found it necessary to have flashing fixation lights: many patients prefer to adopt their own rhythm.
have been conducting years, During who are screening patients taking a variety of 9 10 The antimalarial drugs. following summary may interest the E.o.G. for screening: those who wish to use the past tests for
two
we
(1) Patients with collagenoses who have not been treated with antimalarials have lower than normal E.O.G.S. Thus, while there is a statistically significant difference between treated and untreated patients, if healthy subjects are used to calibrate the apparatus, almost all patients will seem to give suspiciously low values. (2) Patients who are taking antimalarials have decreased E.O.G.s. This effect can be seen after as little as one month’s treatment.
(3) When therapy is discontinued the E.O.G. values rise toward normal. This explains the observation 11 that cases with mild retinopathy tested one year after discontinuation of the drug may have normal E.O.G.S. (4) The E.o.G. decreases when the collagenosis recrudesces. In view of these findings, and the statements in your
editorial,6 we believe it important to emphasise that one should perform serial E.o.G.s on each patient. If this is not done, the lower limit of the " safe " E.O.G. will have to be fixed so high that many patients will be thought, erroneously, to be at risk. Alternatively a patient with an 5. 6. 7. 8. 9. 10. 11.
Henkmd, P., Rothfield, N. F. New Engl. J. Med. 1963, 269, 433. Annotation, Lancet, 1964, i, 423. Copeman, P. W. M., Cowell, T. K., Dallas, N. L. ibid. p. 1369. Arden, G. B., Friedmann, A., Kolb, H. ibid. 1962, i, 1164. Kolb, H. M.Sc. thesis, Bristol, 1964. Arden, G. B., Kolb, H. Exp. Eye Res. (in the press). Gouras, P., Gunkel, R. D. Arch. Ophthal. 1963, 70, 629.
initially large
seem to be at the lower E.o.G. may at a time when a retinopathy is incipient.
only
limit of normal, Institute of
Ophthalmology, Judd Street,
London, W.C.1.
G. B. ARDEN HELGA KOLB.
LOW-MOLECULAR-WEIGHT DEXTRAN SIR,-In view of Mr. Matheson’s letter,! I should like to summarise the history of the evolution of low-molecular-
weight dextran (L.M.W.D.). Dr. Bjorn Ingleman, in Sweden, carried out the basic biochemistry and evolved a clinically sound dextran preparation to increase plasma-volume. Along with Grbnwall 2 he noticed that intravascular aggregations (LA.) decreased with fractions composed of decreasing molecular weights. Thorsen and Hint3 clarified this by using certain molecular-weight fractions to reverse the l.A. induced by means of high-molecular-weight fractions. Meanwhile Gelin4 had postulated that intravascular aggregation was the principal cause of the anaemia of injury. He established what most people would agree to be a causeand-effect relationship between LA. and diffuse necrotic lesions in parenchymatous organs. Several people, including Stalker,5 have confirmed this. Jong6 considers that this constitutes the counterproof to the basic work on LA. by Knisely.Few people in the field of micro-circulation would disagree with the findings of these workers. We all recognise the fundamental clinical contributions that Gelin has made using the conjunctival vessels as a means of monitoring LA., and also the clinical soundness
of his definition of shock as " any acute haemodynamic disturbance which causes such a degree of reduced capillary flow that tissue hypoxia of a degree leading to functional and/or morphological change occurs ". Red cells must pass, as he says, in single file, through true capillaries, to perfuse tissues adequately. If they aggregate out of circulation, as it were, they invariably do so by accumulating on the venous side of a capillary loop, in the venous component of the subpapillary plexus, or fail to pass the capillary at all, bypassing them in subpapillary anastomoses. All these areas can be seen clearly by patient examination of human nail-fold capillary networks. 8-12 The most characteristic clinical appearances of advanced
LA.
(and probably irreversible shock) in man are cyanotic nailbeds; pale pressure-points which persist when the finger is withdrawn ; a marbled and blotchy skin which, in the lower extremities, resembles a major vessel crisis, with elements common to both complete arterial block and complete venous block, but in which the arterial pulses are present and the inferior vena cava is patent; a critically ill patient made worse by pressor agents, with eventually complete circulatory collapse and no convincing cause for this evident at necropsy. Demis,13 incidentally, using cinemicrophotography of nail-fold capillaries, clearly demonstrated distension of this venous component of a capillary loop by the topical application of pressor agents, and the resultant aggregation of cells.) This, then, is the prime condition in which L.M.w.D. appears clinically to have such dramatic effects, and the patient’s progress can be monitored at a capillary level by microscopy of the conjunctival vessels those of the gums, tongue, toes, or nail-fold. The advantage of the nail-fold is simplicity. Understanding of the mechanism by which L.M.W.D. acts
or
depends 1. 2. 3. 4.
on
two
W. A.
essentials-on
understanding viscosity
in
Matheson, Lancet, 1964, i, 1274. Gronwall, A., Ingleman, B. Acta physiol. scand. 1945, 9, 1. Thorsen, G., Hint, H. Acta chir. scand. 1950, suppl. 154. Gelin, L. E. ibid. 1956, suppl. 210. 5. Stalker, A. L. Bibl. anat. 1964, 4, 108. 6. Long, D. M. Proceedings of Conference on the Evaluation of L.M.W.D.; p. 26. National Research Council, U.S.A. 1963. 7. Knisely, M. H., Elliot, T. S., Bloch, E. H. Arch. Surg. 1945, 51, 220. 8. Bosley, P. G. H. J., Gibson, W. C., Griffiths, R. S. J. nerv. ment. Dis. 1956, 123, 219. 9. Bosley, P. G. H. J. Bibl. anat. 1961, 1, 229. 10. Bosley, P. G. H. J., Gibson, W. C. ibid. 1964, 4, 595. 11. Bosley, P. G. H. J. J. Anat., Lond. 1964, 97, 632. 12. Bosley, P. G. H. J. Israel J. exp. Med. 1964, 11, 133. 13. Demis, D. J., Zimmer, J. G. ibid. p. 142.
less disease-centred criterion of therapeutic success. Sickness absence from work, ability to continue housework, or other facility for specific activity may be of value. These factors would take account of the enormous power of human adaptability in adversity. We should also avoid the lesser degrees of " the operation was a success, but the patient died ". J. J. MCMULLAN. London, W.2.
some
internal massage should be used. Donald et al. have not measured cardiac output and coronary flow during internal cardiac massage, and they therefore have no reasons other than purely theoretical ones for assuming that it will be more effective than external massage. Furthermore their suggestion that internal massage may be less damaging to an already ailing myocardium is contrary to the established facts. Thoracic
METHOD OF ARTERIAL SAMPLING SIR,-The frequency with which single arterial samples
required from conscious patients for clinical or research purposes makes a simple, reliable, and painless
are
method of arterial puncture desirable. The usual technique of inserting a medium to large needle into the brachial or femoral arteries after infiltration of a local anxsthetic does not fulfil these requirements, being always uncomfortable, often painful, and sometimes difficult. The following technique has been found to be free from these objections:
Surgical Unit, Papworth Hospital, Cambridge.
B. B. MILSTEIN.
PLASMA-CORTICOTROPHIN SIR,-May I add two comments to the correspondence
about
plasma-corticotrophin estimations ?
Espiner1 suggested that venesection for large blood samples (always 500 ml.) causes pituitary secretion of corticotrophin during the collection period. Naturally, precautions to minimise the possible shock of this procedure were taken in my work, such as using subjects resting in bed to whom a simple prior explanation (and breakfast) was given. The blood was obtained, in the majority of cases, by very experienced The region around the radial artery at the wrist is infiltrated people, including a blood-transfusion officer for the normal with 1 % procaine using a fine no. 20 needle; the same needle subjects. While augmentation of blood-corticotrophin by is used to puncture the artery, and the sample syringe is then venepuncture cannot be ruled out, I think it arguable that, if attached in place of that containing the procaine and the sample venepuncture had a great quantitative effect in the hypertensive obtained. The needle is then withdrawn and the puncture site Cushing’s patients, it would have " blanketed " the variations compressed for 30 seconds. The freedom from discomfort, in blood-corticotrophin that I found between individual cases. haematomas, or inadvertent venepuncture, together with the I am at present using a method, to be published, involving ease of making the actual arterial ’puncture have made 50-100 ml. samples of blood, but this was introduced mainly to the collection of these samples a pleasanter matter for both save the patients parting with so much blood. As I mentioned the patient and the operator. previously, at present perhaps most information can be obtained by comparing corticotrophin values for pathological Department of Anæsthesia, Addenbrooke’s Hospital, BRYAN E. MARSHALL. plasmas with the same worker’s figures for normal plasma. Cambridge. It is a little difficult that the results of the sheep adrenal autotransplant work have been given before a full description HÆMODYNAMIC EFFECTS OF EXTERNAL of the assay has been published, and I look forward to reading CARDIAC COMPRESSION this in the Journal of Physiology. I still think it reasonable to SIR,-Professor Donald and his colleagues must be con- expect that a bioassay be based on an effect measured at its gratulated on their initiative in obtaining measurements peak (or over a short period containing its rise to and fall from of the hxmodynamic changes during external cardiac the maximum); that the test preparation causes its response at same time-interval after injection as the standard hormone; compression in man.1 Several interesting points arise from the and that the assay has a statistical design. their findings: 1. The venous pressure is not necessarily elevated to a very high level during the phase of cardiac compression. I have published an illustration of the consecutively recorded arterial and venous pressures during external cardiac compression in one patient. In this case the venous pressure was elevated only slightly during cardiac compression. Possibly, therefore, the technique of cardiac compression, or the condition of the heart, determines whether venous pressures are high. 2. Donald and his colleagues show that the cardiac output from external cardiac compression is only about half that during normal sinus rhythm. As they point out, the cardiac output was in any event low as a result of myocardial damage in their cases. It has always been apparent, however, from observation of skin pallor or cyanosis during cardiac massage, and subsequent flushing of the skin when the heart starts, that the cardiac output is abnormally low during cardiac massage. This has not prevented resuscitation of the heart or the return of normal cerebral function. Although Donald has produced some evidence that the coronary arteries were inadequately perfused during cardiac massage, no evidence has been adduced concerning the cerebral blood-flow. It seems likely that, as the cardiac output falls, the cerebral blood-flow will come to represent an increasing proportion of the total.
The chief criticism of Donald’s article must be of the last paragraph in which it is suggested that, if cardiac massage is to be continued for more than a brief period, 1.
2.
MacKenzie, G. J., Taylor, S. H., McDonald, A. H., Donald, K. W. Lancet, 1964, i, 1342. Milstein, B. B. Cardiac Arrest and Resuscitation; fig. 14, p. 117. London, 1963.
Dr.
Division of Physiology and Endocrinology, Imperial Cancer Research Fund, Lincoln’s Inn Fields, London, W.C.2.
BERYL M. A. DAVIES.
SCREENING TEST FOR CHLOROQUINE RETINOPATHY
SIR,-Inoted with interest the article by Dr. Copeman and his colleagues.2 First I wish to congratulate the authors on their adaptation of the E.G.G. machine to do electro-oculography (E.O.G.) Unfortunately there are several points in their article with which I must disagree. First, the initials E.o.G. generally stand for electro-oculogram, and there is little reason for calling the test the extraoculogram. The authors’ statement, " Extraoculography is the only reliable method for detecting early retinopathy caused by chloroquine and related antimalarial drugs ", does not appear to be supported by any of the material they provide. Indeed, they mention the paper of Gouras and Gunkel3 which, far from supporting their statement, actually shows that the E.o.G. may be normal in patients with definite early retinopathy. My own experience 4 indicates that there is often visible evidence of chloroquine retinopathy preceding any notable change in the E.o.G. or the E.R.G. (electroretinogram). The early changes usually occur in the macular region and consist of the following: loss of foveal reflex, macular mottling-probably resulting in changes in the underlying pigment epithelium, and the so-called macular bull’s-eye ". Undoubtedly the E.o.G. is a useful "
1. 2. 3. 4.
Espiner, E. A. Lancet, 1964, i, 1327. Copeman, P. W. M., Cowell, T. K., Dallas, M. L. ibid p. 1369. Gouras, P., Gunkel, R. D. Arch. Ophthal. 1963, 70, 629. Henkind, P., Carr, R., Siegel, I. ibid. 1964, 71, 157.
41
adjunct in diagnosis, provided serial studies are made before and during synthetic antimalarial therapy. It is not, however, the only reliable method for detecting early chloroquine retinopathy. Finally, the incidence of retinopathy following chloroquine administration is not the oft-quoted ill-supported figure of 3%. The incidence appears to depend upon dosage and duration of therapy, and perhaps individual sensitivity. Thousands, perhaps millions, of people have taken and do take chloroquine and related drugs for the treatment and prevention of malaria, without any incidence of retinopathy. On the other hand patients taking chloroquine in high dosages for long periods (particularly for skin and connective-tissue disorders) have an incidence of retinopathy exceeding 3 % .5 Department of Pathology, Institute of Ophthalmology, Judd Street, London, W.C.1.
PAUL HENKIND
SIR, Two recent articles 6on the use of the electrooculogram (E.O.G.) in routine screening for chloroquine retinopathy call for comment. The technique, as originally described,8 is indeed simple, and requires little more than a commercial electrocardiograph. The use in the input stages of a short time constant7 which reduces the eye movements to " spikes " is convenient, but in the initial stages of an investigation may lead to spurious results, since baseline drifts, which give warning that the electrodes are moving as the eye rotates, are totally eliminated. If measurements are to be made from the traces with any degree of accuracy, the pen excursion must be sufficiently large for measurement errors to be negligible. Many simple electrocardiographs have pen systems which do not give large deflections without introducing considerable distortion. The actual quantitative results obtained depend very much on the illumination used, and of course the eye is sensitive to the colourtemperature of the source. For this reason we use fluorescent tubes. If tungsten photoflood lamps are employed, and the intensity is controlled with a variac, it would be wise to control the lamp current with a suitable meter. We have modified our apparatus by including a cheap tape-recorder which instructs the patient when to move his eyes. This means that the tester, once the patient has been prepared, is free to leave the test room, and perform other duties. We have not found it necessary to have flashing fixation lights: many patients prefer to adopt their own rhythm.
have been conducting years, During who are screening patients taking a variety of 9 10 The antimalarial drugs. following summary may interest the E.o.G. for screening: those who wish to use the past tests for
two
we
(1) Patients with collagenoses who have not been treated with antimalarials have lower than normal E.O.G.S. Thus, while there is a statistically significant difference between treated and untreated patients, if healthy subjects are used to calibrate the apparatus, almost all patients will seem to give suspiciously low values. (2) Patients who are taking antimalarials have decreased E.O.G.s. This effect can be seen after as little as one month’s treatment.
(3) When therapy is discontinued the E.O.G. values rise toward normal. This explains the observation 11 that cases with mild retinopathy tested one year after discontinuation of the drug may have normal E.O.G.S. (4) The E.o.G. decreases when the collagenosis recrudesces. In view of these findings, and the statements in your
editorial,6 we believe it important to emphasise that one should perform serial E.o.G.s on each patient. If this is not done, the lower limit of the " safe " E.O.G. will have to be fixed so high that many patients will be thought, erroneously, to be at risk. Alternatively a patient with an 5. 6. 7. 8. 9. 10. 11.
Henkmd, P., Rothfield, N. F. New Engl. J. Med. 1963, 269, 433. Annotation, Lancet, 1964, i, 423. Copeman, P. W. M., Cowell, T. K., Dallas, N. L. ibid. p. 1369. Arden, G. B., Friedmann, A., Kolb, H. ibid. 1962, i, 1164. Kolb, H. M.Sc. thesis, Bristol, 1964. Arden, G. B., Kolb, H. Exp. Eye Res. (in the press). Gouras, P., Gunkel, R. D. Arch. Ophthal. 1963, 70, 629.
initially large
seem to be at the lower E.o.G. may at a time when a retinopathy is incipient.
only
limit of normal, Institute of
Ophthalmology, Judd Street,
London, W.C.1.
G. B. ARDEN HELGA KOLB.
LOW-MOLECULAR-WEIGHT DEXTRAN SIR,-In view of Mr. Matheson’s letter,! I should like to summarise the history of the evolution of low-molecular-
weight dextran (L.M.W.D.). Dr. Bjorn Ingleman, in Sweden, carried out the basic biochemistry and evolved a clinically sound dextran preparation to increase plasma-volume. Along with Grbnwall 2 he noticed that intravascular aggregations (LA.) decreased with fractions composed of decreasing molecular weights. Thorsen and Hint3 clarified this by using certain molecular-weight fractions to reverse the l.A. induced by means of high-molecular-weight fractions. Meanwhile Gelin4 had postulated that intravascular aggregation was the principal cause of the anaemia of injury. He established what most people would agree to be a causeand-effect relationship between LA. and diffuse necrotic lesions in parenchymatous organs. Several people, including Stalker,5 have confirmed this. Jong6 considers that this constitutes the counterproof to the basic work on LA. by Knisely.Few people in the field of micro-circulation would disagree with the findings of these workers. We all recognise the fundamental clinical contributions that Gelin has made using the conjunctival vessels as a means of monitoring LA., and also the clinical soundness
of his definition of shock as " any acute haemodynamic disturbance which causes such a degree of reduced capillary flow that tissue hypoxia of a degree leading to functional and/or morphological change occurs ". Red cells must pass, as he says, in single file, through true capillaries, to perfuse tissues adequately. If they aggregate out of circulation, as it were, they invariably do so by accumulating on the venous side of a capillary loop, in the venous component of the subpapillary plexus, or fail to pass the capillary at all, bypassing them in subpapillary anastomoses. All these areas can be seen clearly by patient examination of human nail-fold capillary networks. 8-12 The most characteristic clinical appearances of advanced
LA.
(and probably irreversible shock) in man are cyanotic nailbeds; pale pressure-points which persist when the finger is withdrawn ; a marbled and blotchy skin which, in the lower extremities, resembles a major vessel crisis, with elements common to both complete arterial block and complete venous block, but in which the arterial pulses are present and the inferior vena cava is patent; a critically ill patient made worse by pressor agents, with eventually complete circulatory collapse and no convincing cause for this evident at necropsy. Demis,13 incidentally, using cinemicrophotography of nail-fold capillaries, clearly demonstrated distension of this venous component of a capillary loop by the topical application of pressor agents, and the resultant aggregation of cells.) This, then, is the prime condition in which L.M.w.D. appears clinically to have such dramatic effects, and the patient’s progress can be monitored at a capillary level by microscopy of the conjunctival vessels those of the gums, tongue, toes, or nail-fold. The advantage of the nail-fold is simplicity. Understanding of the mechanism by which L.M.W.D. acts
or
depends 1. 2. 3. 4.
on
two
W. A.
essentials-on
understanding viscosity
in
Matheson, Lancet, 1964, i, 1274. Gronwall, A., Ingleman, B. Acta physiol. scand. 1945, 9, 1. Thorsen, G., Hint, H. Acta chir. scand. 1950, suppl. 154. Gelin, L. E. ibid. 1956, suppl. 210. 5. Stalker, A. L. Bibl. anat. 1964, 4, 108. 6. Long, D. M. Proceedings of Conference on the Evaluation of L.M.W.D.; p. 26. National Research Council, U.S.A. 1963. 7. Knisely, M. H., Elliot, T. S., Bloch, E. H. Arch. Surg. 1945, 51, 220. 8. Bosley, P. G. H. J., Gibson, W. C., Griffiths, R. S. J. nerv. ment. Dis. 1956, 123, 219. 9. Bosley, P. G. H. J. Bibl. anat. 1961, 1, 229. 10. Bosley, P. G. H. J., Gibson, W. C. ibid. 1964, 4, 595. 11. Bosley, P. G. H. J. J. Anat., Lond. 1964, 97, 632. 12. Bosley, P. G. H. J. Israel J. exp. Med. 1964, 11, 133. 13. Demis, D. J., Zimmer, J. G. ibid. p. 142.