CRYOANALGESIA

932 In the present study twenty-four-hour urinary sodium determining hyporeninaemia in essential hypertension. The present findings are therefore consistent with the excretion did not help in defining patients with L.R.H. since basal sodium excretion (and intake) was too high hypothesis that hypertensive patients have impairment and therefore P.R.A. too low to differentiate a of renin secretion which becomes more apparent when a stimulation procedure is used. Because of this impairclearly subnormal group of P.R.A.s. It is clear from this, ment comparison with P.R.A. of normal subjects after stiand from Laragh’s nomograms20 that salt restriction is mulation yields a subgroup of patients with clearly suban essential prerequisite in the use of this approach. The of renin has normal values. Whilst there may be prognostic or levels after stimulation not distribution hitherto been analysed and our results indicate the therapeutic value in demonstration of such a group, the source of much of the confusion. Hypertensive patients dividing line is an arbitrary one. as a group have a significantly impaired renin response Requests for reprints should be addressed to J. D. S., Department to thiazide diuretics, when the percentage rise in renin of Medicme, General Hospital, Gwendolen Road, Leicester LE5 4PBB. level is examined. There is no single subgroup which REFERENCES shows an impaired proportionate rise in P.R.A. This find1. Brunner, H. R., Laragh, J. H., Baer, L., Newton, M. A., Goodwin, F J. ing is therefore consistent with the observations of PadKrakoff, L R., Bard, R. H., Buhler, F. R. New Engl. JMed 1972, 286, field et a1.3 and Thomas et al.4 who used frusemide sti441. mulation. On the other hand after stimulation a group 2. Buhler, F. R., Laragh, J. H., Baer, L., Vaughan, E D., Brunner, H. R. ibid 1972, 287, 1209. of patients exhibits P.R.A.s below those achieved by nor3. Padfield, P. L., Allison, M. E M., Brown, J. J., Lever, A. F., Luke, R G., mal subjects. These are the patients with initially low Robertson, C. C , Robertson, J. I S., Tree, M. Clin. Sci. molec. Med P.R.A. values (fig. 2) whose poor response to stimulation 1975, 49, 353. 4. Thomas, G. W., Ledingham, J. G. G , Beilin, L. J., Stott, A. N. ibid. (in the The subnormal stimulation values. identipost produces press) fication of L.R.H. depends therefore on whether propor5. Acheson, R. M. Int. J. Epidem. 1973, 2, 203 6 Sealey, J. E., Laragh, J. H., m Hypertension Manual (edited by J H tionate change in P.R.A. or absolute post-stimulation Laragh); p. 87. New York, 1974 P.R.A. is studied. In the latter case, a low renin subgroup 7 Brown, J. J., Davies, D. L., Lever, A. F., Robertson, J. I. S. Lancet, 1963, can be arbitrarily defined.1 19 22 This group can be misii, 278. 8. Ferriss, J. B , Brown, J. J., Fraser, R., Haywood, E., Davies, D. L, Kay, sed if untransformed P.R.A. values are analysed as the A. W., Lever. A. F , Robertson, J. I. S., Owen, K., Peart, W S Br med distribution of P.R.A. is skewed both in normal and J. 1975, ii, 135. 9. Christlieb, A. R. in Hypertension Manual (edited by J. H Laragh), p 405 hypertensive subjects.16 This skew was so pronounced in New York, 1974. was our data that the two standard deviation point % 10. Hauger-Klevene, J H., Brown, H., Zavaleta, J J clin. Endocr Metab 1972, 34, 625. below zero, so that no post-stimulation P.R.A. values for 11. Weidmann, P., De Myttenaere-Bursztein, S., Maxwell, M. H., De Lima, J hypertensives appeared to be significantly below those of Kidney Int. 1975, 8, 325. 12. Swales, J. D. Lancet, 1975, i, 75. normal subjects. Thus the low renin group could not be 13. Melby, J. C., Dale, S. L., Wilson, T. E. Circulation Res. 1971, 28, suppl identified if standard deviations were calculated on unII, 143. transformed data. 14. Dunn, M. J., Tannen, R. L., Kidney Int. 1974, 5, 317 15. Kaplan, N. M. J. Am med Ass. 1975, 231, 167 The demonstration of L.R.H. is therefore a function of 16. Padfield, P. L , Beevers, D. G., Brown, J J., Davies, D. L., Lever, A F., the type of analysis performed upon the data. There is Robertson, J. I. S., Schalekamp, M. A. D., Tree, M. Lancet, 1975, ii, 548. 17. Crane, M. G , Harris, J. J., Johns, V. J. Am. J. Med 1972, 52, 457. no evidence from the present work that the subgroup 18. Channick, B. J., Adlin, E. V , Marks, A. D. Archs intern Med 1969, 123, has a discrete identity. Basal P.R.A. values show no evi131. 19. Drayer, J. I M , Kloppenberg, P. W. C., Benraad, T J. Clin. Sci. molec dence of bimodality, although there is a slight skew with Med 1975, 48, 91. a tail to the right in the distribution of the square root 20 Kuchel, O., Fishman, L. M., Liddle, G. W., Michelakis, A. Ann. intern Med of the P.R.A. value. This is not necessarily in conflict 1967, 67, 791. 21. Brunner, H. R., Sealey, J. E., Laragh, J. H. Circulation Res 1973, 32, with a previous study where low P.R.A. was normally disSuppl. I, 199. tributed in hypertensive patients.16 Our series is based 22. Wallach, L., Nyarai, I., Dawson, K. G. Ann. intern. Med. 1975, 82, 27 23. Thurston, H., Swales, J D Q. Jl. Med. (in the press). upon hospital-referred patients and patients with high renin hypertension may therefore be over represented since there will be a bias in favour of severity. Community-based studies on the other hand may tend to under estimate more severely hypertensive patients who CRYOANALGESIA would have been removed by treatment. In the present A NEW APPROACH TO PAIN RELIEF study patients with accelerated hypertension (i.e., those with grade ill or grade iv fundal changes) who generally J. D. W. BARNARD† J. W. LLOYD* show high renin levels have been omitted. If they are inGLYNN* C. J. cluded the tail to the right becomes much more pronounced.23 Pain Relief Unit, Abingdon Hospital, Abingdon, Oxfordshire There is a much wider scatter of P.R.A. values after stimulation but again no evidence of a separate low Summary Cryotherapy has been clinically applied renin group. Patients with low P.R.A. values after stimuto relieve pain using a new cryosurgical lation showed no difference in blood-pressure or in hisprobe to block peripheral nerve function to achieve analtory of previous treatment although they were signifigesia. Sixty-four patients with intractable pain were cantly older than the other patients (see accompanying treated with cryoanalgesia. Fifty-two obtained relief of table). The slope of the regression of P.R.A. upon age is pain for a median duration of 11 days and a range of however, too shallow for age to be a major factor in this up to 224 days. group. The relationship between age and P.R.A. in normal subjects was much less impressive suggesting that *Also at Nuffield Department of Anæsthetics, Radcliffe Infirmary, Oxford age and high blood-pressure may act synergistically in †Present address. Department of Oral Surgery, Radcliffe Infirmary, Oxford

933 DETAILS OF

Introduction

64

PATIENTS WITH PAIN TREATED BY CRYOANALGESIA

INTEREST in the effect of cold on living tissues has increased considerably in the past twenty years as a result of the development of apparatus for the controlled maintenance

of

extreme

low

temperature.’

Previous studies

have evaluated the role of cryosurgery in surgical specialties, including its use in neurosurgery to achieve local destruction of brain tissue.23 The use of cryotherapy in the treatment of glossopharyngeal neuralgia

Brainy but the clinical application of cryotherapy to produce local blocking of peripheral nerves has not been developed. Experimental work on animals has shown that a second degree type of nerve injury follows freeing. 56 A return to normal function can be expected 8 with minimal inflammatory reaction and subsequent scarring.9 10 The reversible blocking of peripheral nerves has been achieved by the use of local anxsthetic solutions, but even long-acting preparations are generally not effective for more than 12 hYFor prolonged analgesia, neurolytic agents such as alcohol and phenol are employed. The use of these agents on peripheral nerves is disappointing, as incomplete destruction of the nerve often causes a painful neuritis. We postulate that the blocking of peripheral nerves by the application of a cryoprobe offers advantages over these techniques.

was

described by

Patients and Methods

Apparatus The Spembly-Lloyd nerve blocking unit incorporates a cryosurgical system which is coupled to a nerve stimulator for accurate positioning of the probe. A chromel-constantan thermocouple is fitted to the tip of the probe to monitor the temperature. The probe has a stem 100 mm in length and is constructed from 15 gauge stainless-steel hypodermic tube with an 18° short, sharp, bevelled point. An electrical connection is made to the tip of the probe from the nerve stimulator, and all other parts of the probe are insulated from the patient and operator by ’Teflon’ (polytetrafluoroethylene) coating (see

accompanying figure). The probe is connected by 6 ft (about 180 cm) of flexible tubing to a console which has a gas pressure regulator switch,

stimulator socket, and dials to record probe-tip temperature. The refrigerant used is nitrous oxide and at an operating pressure of 600 p.s.i. a minimum temperature of -60°C can be achieved rapidly within the iceball generated at the probe tip. An injection of local anxsthetic solution is given at a preious visit so that the effects can be assessed by the patient and operator. The access ability of the nerve dictates the method of application of the cryoprobe. a nerve

gas pressure and

Closed Application The skin is anaesthetised with local anxsthetic and a SISE introducer is used to create a track through the tissues, ’ .rough which the probe is inserted. Using the stimulator,

maximum response with minimum current indicates that the tip is lying adjacent to the target tissue. A cryolesion is then produced, confirmed by the temperature. As the iceball cannot be visualised, temperature monitoring is the only check on probe function.

Open Application Under local or general anaæsthesia the nerve is exposed surgically and the cryoprobe is applied under direct vision. Freeze-thaw

Cycle

It has been shown that

repeated freeze-thaw cycles are likely increase the destructive effect. 12 Two freeze-thaw cycles are therefore carried out. Each freeze is timed for 2 min from the establishment of a steady low temperature of around -60°C. After each freeze the temperature returns to above 0°C before refreezing or withdrawal of the probe. Sixty-four patients with pain from different causes were treated to

with

cryoanalgesia (see accompanying table).

Results The median duration of pain relief obtained was days, with a range of up to 224 days. The duration pain relief was taken as the number of days from cryoanalgesia to the last communication with the patient when he stated he was pain free. A pain-free period of less than 24 h was recorded as "no relief : twelve patients obtained no relief. With the exception of the patients treated at thoracotomy, all had received previous therapy which was unsuccessful. Intercostal pain.- Twelve patients were treated by closed application of the cryoprobe to the intercostal nerves, using the conventional techniques for this nerve block. The median duration of pain relief was 14 days, and a range of up to 147 days was achieved. Two patients obtained no relief. Five patients had open application of the cryoprobe at thoracotomy. All these patients were analgesic over the treated area on discharge 10 days later. Low back pain.-Seventeen patients with low back pain, in which the sciatic distribution of pain was predominant, were treated with closed application via the sacral hiatus or the relevant sacral foramina. The median duration of pain relief achieved was 10 days with a range of up to 49 days. Five patients obtained no relief. Facial pain.—Six patients with facial neuralgia (five infraorbital and one mental) were treated by open application. All patients obtained pain relief with a range of up to 112 days and a median of 21 days. Cancer.-Nine patients with cancer were treated with closed application. Four patients had intercostal blocks and in the remaining five the probe was inserted through the sacral hiatus as with a conventional caudal block.

11 of

934 blocks all transmission. This may be of importance in situations where motor function needs to be preserved. Cryoanalgesia is a simple technique which appears to have a place in the management of acute pain. Its role in the relief of chronic pain is being further evaluated,

The median duration of pain relief achieved was 14 days, with a range of up to 120 days; one patient obtained no relief. Fifteen patients with pain of unknown aetiology were treated by cryotherapy applied to the affected nerve or directly into painful foci. The median duration of pain relief achieved was 10 days with a range of up to 224 days. Four patients obtained no relief.

The cryoprobe has been developed in conjunction with Sponbh & Co. of Andover. We are grateful for their encouragement and support in this project.

Discussion

Requests for reprints should be addressed to J. W. L., Pain Relief Unit, Abingdon Hospital, Abingdon, Oxfordshire.

an effective reversible nerve median duration of 11 days. This has particular significance in the postoperative period as demonstrated with thoracotomy when no additional

Cryoanalgesia produces

block with

REFERENCES

a

postoperative analgesia

was

required. Occasionally pain

relief lasted for many months despite earlier recovery of motor and sensory function. The reasons for this are not known, but may be related to the breakdown of the cycle of pain. No patients have developed neuralgia subsequent to treatment. The application of the cryoprobe to a peripheral nerve

1. Amoils, S. P. Archs Ophthal. N.Y , 1965, 78, 201. 2. Hankinson, J. Practical Cryosurgery; p. 100. London, 1965. 3. Richardson, A. Br. J Hosp. Med. 14, 39. 4. Brain, D. J. Practical Cryosurgery; p. 69. London, 1975. 5 Sunderland, S Nerves and Nerve Injuries; Edinburgh, 1968. 6. Whittaker, D. W. PH.D. thesis, University of Wales, 1973. 7. Beazley, R. M., Bagley, D. H., Ketcham, A. S. J. surg. Res. 1974, 16, 231 8. Lenz, H. Minn. Med. 1974, 65, 3647. 9. Carter, D. C., Lee, P. W. R., Gill, W., Johnston, R. J. Jl R Coll Surg Edinb. 1972, 17, 1. 10. Poswillo, D. E. Br J. oral Surg. 1971, 9, 1. 11. Watt, M. J., Akhtar, M., Atkinson, R. S. Anæsthesia, 1970, 25, 24. 12. Gill, W., Frazer, J., Carter, D. C. Nature, 1968, 219, 410.

Preliminary Communication INFANT BOTULISM IDENTIFICATION OF CLOSTRIDIUM BOTULINUM AND ITS TOXINS IN FÆCES

THADDEUS F. MIDURA

STEPHEN S. ARNON

Microbial Diseases Laboratory and Infectious Disease Section California State Department of Health, Berkeley, California 94704, U.S.A.

Clostridium botulinum and its toxin identified in the fæces of four infants, aged 6 to 13 weeks, who had symptoms consistent with botulism. Two cases had type-A toxin and two cases had type-B toxin present in their fæces. No toxin was detectable in sera. C. botulinum and toxin could be recovered from fæces more than 8 weeks after admission to hospital. All four cases occurred within a 6-month period. The source of the toxin in these infants may have been in-vivo production from ingested organisms.

Summary

were

INTRODUCTION

BOTULISM is currently regarded as an illness which results chiefly from ingestion of preformed toxin produced by Clostridium botulinum.’ This gram-positive, anaerobic, spore-forming bacterium has 7 serotypes (A-G). Occasionally a wound infection with C. botulinum leads to in-vivo toxin production and illness.2 Infants too young to eat foods which may contain toxin have generally been thought to be safe from this disease. For example, of the six hundred and three cases of botulism reported during the 77 years that such records have been kept in California (1899-1976), no case of this disease has occurred in a child younger than 1 year.3 We now report the unexpected identification of C. botulinum and its toxin in the faeces of four infants, aged 6 to 13 weeks, who had symptoms compatible with botulism.

METHODS

Case identification.-The first fæcal specimen contaming C. botulinum and toxin from an affected infant came to our attention when the attending physicians submitted it to the California State Department of Health laboratory for botulism testing. When another infant with similar symptoms was referred to the same hospital, the physicians again submitted a faecal specimen, this time to confirm their clinical diagnosis of botulism. The clinical findings in these two infants will be

reported elsewhere.4 of the initial cases was confirmed by of us (S.S.A.) contacted the physicians who referred the other two cases. Epidemiology.-We interviewed the patients’ families, visited their homes, and collected samples of food items which the infants had eaten. We also collected garden soil samples at the homes, stool samples from other family members, and, if the infant had been breast-fed, samples of breast-milk. We reviewed hospital records and interviewed attending obstetncians and paediatricians. As controls, we sought to obtain stools from well infants matched for age, neighbourhood of residence, and diet (breast-milk or prepared formula). We were able to find six such infants. Since honey was fed to two of the infants, we purchased honey from different suppliers at a local Northern California supermarket. Laboratory.—Fæcal specimens were examined by anærobic and special enrichment techniques.6 Food and faecal specimens were also examined by the use of fluorescent antibody reagents prepared against C. botulinum organisms.’ The mouse neutralisation assay was used to test for the presence of toxin in faeces and serum.Identification of C. botulinum from fxcesor food was confirmed by isolating a pure culture of the organism and verifying toxin production by means of the mouse Once the

laboratory

diagnosis

tests,

one

neutralisation assay.

Fisher’s exact test was used to determine the probabilitive that the observed association between illness and the presence of C. botulinum in faeces of cases occurred by chance alone, CASE-REPORTS

Each infant had been well from birth until

onset

of

constipation, poor feeding, and diminished sucking and crying ability. Each had cranial-nerve palsy, loss of head control, and neck, limb or respiratory muscle weakness. One infant experienced several episodes of respiraton arrest before and during hospital stay. No infar.;