1000 0.05 to 0.2 micromicrocuries per g. of calcium. It is not surprising that the highest activity was in a child, since growing bone, compared with adult bone, takes up more bone-seeking isotopes. Samples of sheep bones contained 14 micromicrocuries per g. but in a few mountain pastures figures were up to ten times greater. So far as we know, the M.R.C. committee and the International Commission on Radiological Protection have no records of human damage attributable to strontium. In making their recommendations, there- fore, they have had to extrapolate from animal work and from the scanty records of human radium poison- ing. - The International Commission recommended that the body burden of radium should not exceed 0-1 microcuries for persons exposed to radiation at work ; and it is known that a large safety factor was not included in this figure. Easily recognised radio- graphic bone changes have been recorded in patients with body burdens of from 0-4 microcuries of radium upwards ; and radium produced a bone sarcoma in a person with a burden of 3-6 microcuries.3 These effects of radium usually appear after very long latent periods of ten or twenty years. Larger body burdens may, of course, be associated with different and earlier changes, as in the American dial painters 4 who had massive bone necroses, infections, and aplastic anaemia (these " aplastic anaemias " might today have been diagnosed as acute aleukaemic leukaemias). Though damage by ingested radium in man has been known for many years, there are as yet no data on the ultimate results of long-continued low-level activity from ingested radium in a " closed population "-i.e.. one which has been followed up to extinction. There is, therefore, no evidence about the possibility of premature ageing or chronic ill health in man as a result of irradiation. Such changes have been observed in animals, 5 It is hard to say how radium and strontium compare, but the biological effects in bone of alpha-particle emission from radium are probably greater than the beta-radiation from strontium- yttrium decay. In view of this difference the Inter- national Commission recommended a higher maximum permissible body burden for strontium than for radium -namely, 1-0 microcuries for those occupationally exposed. This corresponds to 1000 micromicrocuries of strontium per g. of calcium in the skeleton, which is about a thousand times greater than the most heavily contaminated bones yet examined. But the M.R.C. committee declare that " immediate considera- tion would be required if the concentration of radio- active strontium in bone showed signs of rising greatly beyond that corresponding to one hundredth of the maximum permissible occupational level." In other words, if it goes above 10 micromicrocuries per g. If, in fact, poisoning reaches that level it is likely to do so first in young people with growing bones. It is also reasonable to suppose that, apart from this age difference, the whole population would be equally affected. It seems that the fall-out of thermonuclear explosions is deposited at the rate of 10-20% per year, so that strontium would continue to find its way into bone for years after the " alarm level " had been 3. Looney, W. B., Hasterlik, R. J., Brues, A. M., Skirmont, E. Amer. J. Roentgenol. 1955, 73, 1006. See also Recommendations of the International Commission on Radiological Protection. Brit. J. Radiol. 1955, suppl. no. 6. 4. Martland, H. S. Proc. N.Y. Path. Soc. 1926, 26, 65 ; J. Amer. med. Ass. 1929, 92, 466, 552 ; Amer. J. Cancer, 1931, 15, 2435. 5. Blair, H. A. U.S. Atomic Energy Commission Report, 1953, p. 227 ; Ibid, 1954, p. 312. reached. No doubt this is one of the reasons for the guarded words which the M.R.C. committee use about the hazards of fall-out from test explosions. They say that the hazards from external radiation due to fall-out are so far negligible ; and no detectable increase in the incidence of ill effects is to be expected from internal radiation by radioactive strontium at its present level. But if the rate of firing, particularly of thermonuclear weapons, increases, harm may be done in a small proportion of the population. The report makes no estimate of how big an increase in the rate of firing would be required to produce the first detectable, and presumably gross, damage. This question of poisoning by strontium 90 is one on which the medical profession, like the M.R.C. committee, can only advise on the possible results of continued exposure. It is the committee’s view that, with proper safeguards, exposure from all sources in peace- time can be maintained at levels which can be accepted by the citizen " without undue concern either for himself or his offspring.’’ But unless the safeguards include the stopping of further thermonuclear tests, is this conclusion justified ? By the time we have gathered sufficient evidence to assess more accurately the danger of strontium-90 poisoning, it may be too late to prevent disastrous consequences. 1. Weiss, S., Parker, F. jun. Medicine, Baltimore, 1939, 18, 221. Pyelonephritis PYELONEPHRITIS is the commonest disease of the kidneys.l In some forms, such as " pyelitis " of children, its course is relatively benign; and acute attacks in the adult can readily be controlled, after identification of the causal organism, by appropriate treatment. Recurrent and chronic attacks, however, are very resistant to treatment. On p. 973 this week, Dr. JAN BROD points out that, while chronic pyelo- nephritis is the commonest cause of deaths from renal failure in Prague, two-thirds of the cases had escaped clinical recognition. In an attempt to improve this situation, Dr. BROD compared the clinical features of 132 cases of chronic pyelonephritis, 54 of chronic glomerulonephritis, and 16 of vascular nephrosclerosis ; and his inquiry throws welcome light on a confused subject. The well-known diagnostic points were not always as helpful as expected : pathogenic organisms were grown from the urine in 81 % of cases of chronic pyelonephritis, but also from 50% of cases of chronic glomerulonephritis. On the other hand, a large excess of white blood-cells was found in the urine of 76% of those with pyelonephritis, as opposed to only 14% in glomerulonephritis and vascular nephritis. Otherwise, the most helpful and easily determined abnormality was a long-continued loss of renal concentrating power, quite out of proportion to the degree of impairment of the glomerular filtration- rate. This disorder of the distal tubules included decreased ability to save base (Na), and there was a tendency towards dehydration, decreased alkali reserve, and acidosis. Another point of diagnostic importance was a striking difference in the function of the two kidneys in chronic pyelonephritis, as assessed by ureteric catheterisation, using the con- centrating index of endogenous creatinine(; ratio the difference was insignificant in normal kidneys and in those affected by chronic glomerulonephritis
0.05 to 0.2 micromicrocuries per g. of calcium. It isnot surprising that the highest activity was in a child,since growing bone, compared with adult bone, takesup more bone-seeking isotopes. Samples of sheepbones contained 14 micromicrocuries per g. but in a fewmountain pastures figures were up to ten times greater.
So far as we know, the M.R.C. committee and theInternational Commission on Radiological Protectionhave no records of human damage attributable tostrontium. In making their recommendations, there-fore, they have had to extrapolate from animal workand from the scanty records of human radium poison-ing. - The International Commission recommendedthat the body burden of radium should not exceed0-1 microcuries for persons exposed to radiation atwork ; and it is known that a large safety factor wasnot included in this figure. Easily recognised radio-graphic bone changes have been recorded in patientswith body burdens of from 0-4 microcuries of radiumupwards ; and radium produced a bone sarcoma in aperson with a burden of 3-6 microcuries.3 These effectsof radium usually appear after very long latent
periods of ten or twenty years. Larger body burdensmay, of course, be associated with different and earlier
changes, as in the American dial painters 4 who hadmassive bone necroses, infections, and aplastic anaemia(these " aplastic anaemias " might today have beendiagnosed as acute aleukaemic leukaemias). Thoughdamage by ingested radium in man has been knownfor many years, there are as yet no data on theultimate results of long-continued low-level activityfrom ingested radium in a
" closed population "-i.e..one which has been followed up to extinction. Thereis, therefore, no evidence about the possibility of
premature ageing or chronic ill health in man as aresult of irradiation. Such changes have been observedin animals, 5 It is hard to say how radium andstrontium compare, but the biological effects in boneof alpha-particle emission from radium are probablygreater than the beta-radiation from strontium-
yttrium decay. In view of this difference the Inter-national Commission recommended a higher maximumpermissible body burden for strontium than for radium-namely, 1-0 microcuries for those occupationallyexposed. This corresponds to 1000 micromicrocuriesof strontium per g. of calcium in the skeleton, whichis about a thousand times greater than the mostheavily contaminated bones yet examined. But theM.R.C. committee declare that " immediate considera-tion would be required if the concentration of radio-active strontium in bone showed signs of rising greatlybeyond that corresponding to one hundredth of themaximum permissible occupational level." In otherwords, if it goes above 10 micromicrocuries per g.
If, in fact, poisoning reaches that level it is likelyto do so first in young people with growing bones.It is also reasonable to suppose that, apart from thisage difference, the whole population would be equallyaffected. It seems that the fall-out of thermonuclear
explosions is deposited at the rate of 10-20% per year,so that strontium would continue to find its way intobone for years after the " alarm level " had been
3. Looney, W. B., Hasterlik, R. J., Brues, A. M., Skirmont, E.Amer. J. Roentgenol. 1955, 73, 1006. See also Recommendationsof the International Commission on Radiological Protection.Brit. J. Radiol. 1955, suppl. no. 6.
4. Martland, H. S. Proc. N.Y. Path. Soc. 1926, 26, 65 ; J. Amer.med. Ass. 1929, 92, 466, 552 ; Amer. J. Cancer, 1931, 15, 2435.
5. Blair, H. A. U.S. Atomic Energy Commission Report, 1953,p. 227 ; Ibid, 1954, p. 312.
reached. No doubt this is one of the reasons for the
guarded words which the M.R.C. committee use
about the hazards of fall-out from test explosions.They say that the hazards from external radiationdue to fall-out are so far negligible ; and no detectableincrease in the incidence of ill effects is to be expectedfrom internal radiation by radioactive strontium atits present level. But if the rate of firing, particularlyof thermonuclear weapons, increases, harm may bedone in a small proportion of the population. The
report makes no estimate of how big an increase inthe rate of firing would be required to produce thefirst detectable, and presumably gross, damage. Thisquestion of poisoning by strontium 90 is one on whichthe medical profession, like the M.R.C. committee,can only advise on the possible results of continuedexposure. It is the committee’s view that, with
proper safeguards, exposure from all sources in peace-time can be maintained at levels which can be acceptedby the citizen " without undue concern either forhimself or his offspring.’’ But unless the safeguardsinclude the stopping of further thermonuclear tests,is this conclusion justified ? By the time we havegathered sufficient evidence to assess more accuratelythe danger of strontium-90 poisoning, it may be toolate to prevent disastrous consequences.
PyelonephritisPYELONEPHRITIS is the commonest disease of the
kidneys.l In some forms, such as "
pyelitis " ofchildren, its course is relatively benign; and acuteattacks in the adult can readily be controlled, afteridentification of the causal organism, by appropriatetreatment. Recurrent and chronic attacks, however,are very resistant to treatment. On p. 973 this week,Dr. JAN BROD points out that, while chronic pyelo-nephritis is the commonest cause of deaths from renalfailure in Prague, two-thirds of the cases had escapedclinical recognition. In an attempt to improve thissituation, Dr. BROD compared the clinical featuresof 132 cases of chronic pyelonephritis, 54 of chronicglomerulonephritis, and 16 of vascular nephrosclerosis ;and his inquiry throws welcome light on a confusedsubject. The well-known diagnostic points were notalways as helpful as expected : pathogenic organismswere grown from the urine in 81 % of cases of chronicpyelonephritis, but also from 50% of cases of chronicglomerulonephritis. On the other hand, a largeexcess of white blood-cells was found in the urine of76% of those with pyelonephritis, as opposed to
only 14% in glomerulonephritis and vascular nephritis.Otherwise, the most helpful and easily determinedabnormality was a long-continued loss of renalconcentrating power, quite out of proportion to thedegree of impairment of the glomerular filtration-rate. This disorder of the distal tubules includeddecreased ability to save base (Na), and there wasa tendency towards dehydration, decreased alkalireserve, and acidosis. Another point of diagnosticimportance was a striking difference in the functionof the two kidneys in chronic pyelonephritis, asassessed by ureteric catheterisation, using the con-
centrating index of endogenous creatinine(; ratiothe difference was insignificant in normal kidneysand in those affected by chronic glomerulonephritis
or vascular nephrosclerosis. X-ray examination,and especially serial examination, in chronic pyelo-nephritis, often showed differences in size and densityof renal shadows and in spread and evacuation ofcontrast medium. Consideration of these points wouldundoubtedly help towards more widespread recognitionof the condition. -
The clinical picture has been correlated with the com-mon pathological finding of irregular superficial depres-sions associated with wedge-shaped scars through thekidney parenchyma 1-6-a type of lesion sometimesascribed to ischsemia 7 or developmental dysplasia.8 9The possible relation of these scars, and thereforeof pyelonephritis and the resulting vascular changes,to a type of hypertension 1 3 5 10 is of the first import-ance. Experimental evidence now provokes furtherthought on this subject. DE NAVASQUEZ 11 12 foundthat when gram-negative bacilli were injected intra-venously into animals with normal kidneys, the
organisms did not leave the blood-vessels but passedthrough the organ harmlessly and never appeared inthe urine. But when coagulase-positive Staphylococcusaureus was injected, pyelonephritis followed and renalscarring developed with the same features as thehuman disease : localisation of the organisms waspresumably due to diffusion of coagulase from theplasma to produce coagulative necrosis in the surround-ing tissues, thus enabling the organisms to multiplyin a presuppurative phase before the phagocytescould reach them. In animals which had surviveda staphylococcal infection and had presumed scars(later confirmed), intravenous injection of gram-negative bacilli of the coliform group invariably pro-duced an acute pyelonephritis which was fatal withintwo weeks. The kidneys s showed asymmetricalcontraction, with coarse stellate scars resulting inan intrarenal hydronephrosis. In addition to theseold scars, there were linear abscesses in theirimmediate vicinity, the purulent exudate beingconfined to the distended tubules ; and the pelvisshowed patchy inflammation. It seemed that theintrarenal hydronephrosis resulting from the firstinfection had slowed the blood-stream sufficientlyfor the second infecting organisms to multiply andproduce suppurative lesions. This was furtherevidence that, in kidneys without mechanical defects,infarctions, or atheroma, these stellate scars
were the result of haematogenous pyelonephritis.DE NAVASQUEZ pointed out that the primarystaphylococcal infection in the rabbit, with appro-priate dosage of organisms, was self-limiting and leftno clinical evidence, but it enabled the gram-negativebacilli to settle out in the kidney when they wouldnot otherwise have done so. But we must not concludefrom these animal experiments that in man a
previous infection must be staphylococcal before acoliform infection can take hold. Moreover, the
way in which these animals were infected (20-1002. Gibson, A. G. Lancet, 1928, ii, 903.3. Longcope, W. T., Winkenwerder, W. L. Bull. Johns Hopk.
Hosp. 1933, 53, 255.4. Platt, R., Davson, J. Quart. J. Med. 1950, 19, 33.5. Pickering, G. W., Heptinstall, R. H. Ibid, 1953, 22, 1.6. Enticknap, J. B., Joiner, C. L. Brit. med. J. 1953, i, 1016.7. Gaskell, J. F. J. Path. Bact. 1911-12, 16, 287.8. Ask-Upmark, E. Acta Path. microbiol. scand. 1929, 6, 383.9. Marshall, A. G. J. Path. Bact. 1956, 71, 95.
10. Goldring, W., Chasis, H. Hypertension and HypertensiveDiseases. New York and London, 1944.
11. De Navasquez, S. J. Path. Bact. 1950, 62, 429.12. De Navasquez, S. Ibid, 1956, 71, 27.
million bacilli were injected into an ear vein) isartificial and gives no clue to the method of infectionin man. The secondary infection in the rabbit led todeath from progressive ursemia and anuria, but, asDE NAVASQUEZ explained, this is because’the rabbit’skidney is monopyramidal, and obstruction at the
single papilla by a small lesion can affect all the
collecting tubules, whereas the multilobular humankidney has a much greater margin of safety.The development of these scars was also examined
by HEPTINSTALL and GORRILL,13 who injected Staph.aureus into rabbits, some of which were kept alivewith penicillin. They then examined the kidneys atintervals up to four months. Again, the naked-eyeand microscopic appearances were very similar tothe scars attributed to pyelonephritis in man.
HEPTINSTALL and GORRILL then produced a unilateralpyelonephritis with a coliform organism by temporaryocclusion of one ureter 14 15-a procedure whichlocalised the infection to the affected kidney whilethe other remained normal. After three days theureter was released and, either then or at periodsup to four months, the normal kidney was removed.In this group of animals, the blood-pressure wasmeasured at least twice weekly. It was found thatthere was no elevation of blood-pressure with a
unilateral infection when the opposite kidney wasintact ; and even when it was removed, the blood-pressure rose only when there was considerablescarring in the affected kidney. In the scarred areasin all kidneys infected for over forty days, arteriesand arterioles seemed to have increased in numbers,merely because of the disappearance of tubules.The only structural change in the vessels was anincreased cellularity of the media in the older infections,and nothing significant was found in animals withhigh blood-pressure. It may well be that the designof the experiment did not allow the high pressure tocontinue long enough for changes to develop. Thus,in the animals, a rise in blood-pressure was due, notto vascular changes, but to extensive scarring ina remaining single kidney.
Patients with chronic pyelonephritis do not
necessarily develop hypertension. Of LONGCOPE’S 16patients with chronic pyelonephritis, those withouthypertension had normal vessels and some withsevere hypertension had vessels with slight changes.WEiss and PARKER formed a more definite viewfrom their cases of chronic pyelonephritis ; mild
proliferative vascular changes were associated withnormal blood-pressure, and severe changes were almostalways associated with severe hypertension. On theother hand, GoLDRING and CHASIS 10 found evidencethat pyelonephritis did not cause hypertension ;for hypertension was not more frequent in their
patients with pyelonephritis than in those without.From their study of 11 kidneys removed for hyper-tension and found to show scars of chronic pyelo-nephritis, PiCKERiNG and HEPTINSTALL 5 concludedthat the renal lesion was sometimes the cause of the
hypertension, but the evidence regarding the separateresponsibility of the pyelonephritis and the vascularchanges was too conflicting for either to be held
13. Heptinstall, R. H., Gorrill, R. H. Ibid, 1955, 69, 191.14. Lepper, E. H. Ibid, 1921, 24, 192.15. Mallory, G. K., Crane, A. R., Edwards, J. E. Arch. Path. 1940,
30, 330.16. Longcope, W. T. Ann. intern. Med. 1937, 11, 149.
responsible. Dr. BROD’S findings are that hyper-tension develops with increasing frequency as the
pyelonephritis progresses, to the same degree as inchronic glomerulonephritis, though four times moreoften than in chronic cholecystitis (taken as a controlfor other chronic infections) ; his biopsy studiesrebut the idea of a vascular cause, since vascularlesions were absent in 5 patients with grave hyper-tension. Malignant hypertension developed at anearlier age in pyelonephritis with hypertension thanin essential hypertension, but only when the renaldisease was far advanced. His results are in line withthe experimental findings in suggesting that the onsetof hypertension is determined by the lack of sufficienthealthy renal tissue (or the presence of sufficientdiseased renal tissue). Whatever the ultimate answerto these unsettled questions may be, all cases of
pyelonephritis must be treated seriously and everyresource must be used to eradicate the infection as
completely as possible at the earliest opportunity.
1. Selye, H. J. Pharmocol. 1941, 73, 127.2. Selye, H. Endocrinology, 1942, 30, 437.3. Laubach, G. D., P’an, S. Y., Rudel, H. W. Science, 1955, 122, 78.4. P’an, S. Y., Gardocki, J. E., Hutcheon, D. E., Rudel, H., Kodet,
M. J., Laubach, G. D. J. Pharmacol. 1955, 115, 432.5. Howland, W. S., Boyan, C. P., Kuo-Chen Wang. Anesthesiology,
1956, 17, 1.6. Murphy, F. J., Guadagni, N. P., Debon, F. J. Amer. med. Ass.
1955, 158, 1412.7. Taylor, N., Shearer, W. M. Brit. J. Anœsth. 1956, 28, 67.
Steroids in AnæsthesiaSOME years ago SELYE 1 2 demonstrated in rats the
anaesthetic properties of 75 steroids with variousstructures. He noted that some compounds werepotent anaesthetics but had little hormonal activity.Subsequently, hydroxydione (21-hydroxy pregnane-3,20-dione sodium succinate), a water-soluble steroid,was shown experimentally to have a wide margin ofsafety and to be a likely drug for clinical use.3 Indeed,work on various animals indicated that it has a
therapeutic index considerably greater than thatof thiopentone 4 ; hydroxydione has no hormonalactivity, 5 Under the name of Viadril,’ it was firstdescribed in use as a clinical intravenous anaestheticlast year. 6 Although it is not a barbiturate, it lendsitself to comparison with thiopentone, and other
thiobarbiturates, because of its similar effects andmethod of administration. The early reports sug-gested that it had some advantages over these drugsboth in its ability to produce greater relaxationwithout correspondingly increased medullary depres-sion and in its seemingly specific action on thereflexes of the respiratory tract. But some later
findings have been less encouraging, and the dis-
advantages of the new anaesthetic have becomemore apparent.On another page this week Dr. GALLEY and Dr.
Roonts describe their experiences with hydroxydione ;and pharmacological and other clinical investigationshave lately been reported elsewhere.5 7 From the
start, it was realised that hydroxydione was an
irritant, and in one series venous thrombosis followedin 15 out of 70 patients who received dilutions as lowas 0-5% given as part of a freely running infusion.Dr. GALLEY and Dr. RooMs find that 2.5 g. dissolvedin a 540 ml. bottle of saline solution gives no trouble.These dilutions, however, necessitate the use of largevolumes of fluid to get even a small quantity of thedrug into the patient-a cumbersome method of induc-
ing anaesthesia. More concentrated solutions cause
pain (unless injected very slowly) and, commonly,thromboses. With the dilute solutions, loss of con-sciousness is slow, very closely resembling the onsetof natural sleep but depending on the concentration,rate of injection, and state of the patient. Drowsinessmay take as long as five minutes to appear, and sleepa further five minutes. The full anaesthetic effect isoften not attained until fifteen or twenty-five minutesafter the initial injection. A slightly quicker resultcan be achieved by speeding up the rate of injection,but hypotension may result. Experimental work oncats 7 suggests that the hypotension is caused byinhibition of the vasoconstrictor centres in the brain,coupled with a direct vasodilator action on the peri-pheral vessels themselves. But hydroxydione also
depresses the ventricular muscle, though not so muchnor for so long as an equivalent dose of thiopentone.Dr. GALLEY and Dr. RooMs have observed hypo-tension, even in young patients, and an increasedpulse-rate irrespective of a fall in blood-pressure.Respiration is seldom greatly influenced, butthe volume may be reduced slightly and the rateincreased. Apnoea, such as is often caused by thio-pentone, is very unusual. Investigation of the dura-tion of action suggests that 1 g. lasts for about twoand a half hours, 8
There is little evidence that hydroxydione is an
analgesic, and, under apparently deep anesthesia withhydroxydione alone, sensory stimulation producesimmediate reflex activity. This response is verysimilar to the reaction of patients under thiobar-biturates, such as thiopentone ; and indeed electro-
encephalography has failed to show any differencebetween hydroxydione and these ultra-short-actingdrugs.5 9 These facts are substantially in favour ofits classification as a hypnotic rather than as an
analgesic. On the other hand, all reports haveremarked on its selective depression of laryngeal andpharyngeal reflexes, without medullary depression.This action is the opposite of what may be expectedunder barbiturate anaesthesia, when many reflexes inthis area are often exaggerated, and it is a bigadvantage for some operations. A further differenceseems to be the remarkable sense of well-being andlack of fatigue during the first twenty-four hours afteroperation in patients anaesthetised with hvdroxvdione.
It is too early to assess the value of steroids inanaesthesia. Despite the valuable evidence given byDr. GALLEY and Dr. ROOMS, many ansesthetists willnot yet be convinced that hydroxydione has much tooffer that cannot already be achieved with fewer
disadvantages by existing drugs. Unless the anaes-thetist takes the chance of venous thrombosis andhypotension by giving a more concentrated or morerapid injection, induction takes too long for all butmajor operations. Moreover the selective depressionof respiratory-tract reflexes, when continued into thepostoperative stage, may well increase the ever-
present dangers of this period. Nevertheless the
investigation of hydroxydione has opened up possi-bilities in a new line of anaesthesia which may wellculminate in valuable additions to those drugs whichhave stood the test of time.
8. Harbord, R. P., Wild, W. N. Proc. R. Soc. Med. 1956 (to bepublished).
9. Bellville, J. W., Howland, W. S., Boyan, C. P. Brit. J. Anœsth.1956, 28, 50.