MILESTONES IN NEPHROLOGY

CRUSH INJURIES WITH IMPAIRMENT OF RENAL FUNCTION

BY
E. G. L. BYWATERS, M.B., B.S., M.R.C.P.
Beit Memorial Fellow

AND

D. BEALL, Ph.D.Toronto
(From the Departments of Medicine and Pathology, British Postgraduate Medical School)

[WITH SPECIAL PLATE]

with comments by

ERIC G. L. BYWATERS AND JAMES P. KNOCHEL

Reprinted from Br. Med. I. 1: 427-432, 1941

Amongst air-raid casualties seen at this hospital have been four

AUTHOR COMMENT4RY
cases of crush injury of the limbs which, because of the gener-
al similarity of their clinical course, were thought to represent Eric G. L Bywaters
a specific and hitherto unreported syndrome, and one which has
been and will be seen elsewhere during the war. Such a condi-
Bucks, United Kingdom
tion may have been observed in civil practice, but we have been en this article was published in
unable to find any account of it in the literature. The cases are May 1941, Britain was alone
of interest on account of the problem propounded by both against the German Reich. Most of
pathogenesis and treatment. The picture presented by these four Europe had fallen to Hitler. London in
cases, and substantiated by others, is briefly as follows: particular was undergoing savage
The patient has been buried for several hours with pressure attack by the Luftwaffe. This involved chiefly the docks in
on a limb. On admission he looks in good condition except for East London and the city. Hammersmith Hospital was on
swelling of the limb, some local anaesthesia, and whealing. The the western fringes. We got a few bombs locally and fire-
haemoglobin, however, is raised, and a few hours later, despite bombs on the hospital. In the Medical Department during
vasoconstriction, made manifest by pallor, coldness, and sweat- the “phoney war,” we had already been studying, under the
ing, the blood pressure falls. This is restored to pre-shock level direction of John McMichael, the physiologic functions in
by (often multiple) transfusions of serum, plasma, or, occa- “shock” and were well prepared to deal with a few casual-
sionally, blood. Anxiety may now arise concerning the circula- ties. On September 16, 1940, two cases were admitted
tion in the injured limb, which may show diminution of arteri- (among others) and two later (which formed the basis of
al pulsation distally, accompanied by all the changes of incipi- this article) were characterized by limb edema and unex-
ent gangrene. Signs of renal damage soon appear, and progress pected death from renal failure. They were investigated
even though the crushed limb be amputated. The urinary out- extensively and this was bitterly attacked in public by the
put, initially small, owing perhaps to the severity of the shock, Professor of Surgery, who counted the number of investiga-
diminishes further. The urine contains albumin and many dark tions, including systolic and diastolic pressures, as two sep-
brown or black granular casts. These later decrease in number. arate ones. Elsewhere in London the casualties were so
The patient is alternately drowsy and anxiously aware of the numerous that proper study was seldom possible, and late
severity of his illness. Slight generalized oedema, thirst, and shock were transferred
cases to small local hospitals. Some
incessant vomiting develop, and the blood pressure often of these were recorded briefly in the British Medical
remains slightly raised. The blood urea and potassium, raised at Journal and Lancet concurrently. On December 30, 1940,
an early stage, become progressively higher, and death occurs the Medical Research Council (MRC) formed a committee
comparatively suddenly, frequently within a week. Necropsy of experts whose suggestions on nomenclature (especially),
reveals necrosis of muscle and, in the renal tubules, degenera- causation, and treatment varied widely. As may be seen,
tive changes and casts containing brown pigment. this first publication was prepared hurriedly, with rather
amateur diagrams. I did better later. Other later cases, most-
Case I ly single, were recorded in the same issue, but pathologists
A female aged 17 had been buried for nine hours with heavy
were hampered by lack of legal permission for autopsy
masonry lying across the left leg. On admission she showed slight
(relations not found).
bruises generally, and multiple superficial abrasions below the left
 Milestones Iii Neplirology

knee. The leg was swollen and sensation was impaired at the ankle,
Meanwhile, the intensity of the Blitz diminished and we
where all power and movement were lost. Other limbs appeared
undamaged. The skin was pallid and clammy: the blood pressure was
were able to look for previously published records. As
85/70 mm Hg. The clinical course is shown on Chart I. Recalcified described by McMichael and Bywaters in a more leisurely
plasma-saline (Clegg and Dible, 1940) (subsequently referred to as postwar historical study (1), we found quite a number of
“serum”), followed by 5% glucose-saline, brought the blood pressure such case records in the German literature of the First World
from 60 mm. Hg, where it had remained for one and a half hours, to War, detailed also in their official Handbook of the World
160 mm. Hg. Urine was passed containing neither albumin nor blood. War 1922, as well as cases seen by Minami after the
By 7 p.m. the haemoglobin concentration had fallen. Blisters Messina earthquake of 1909. He suggested myglobin but
were forming on the left knee, where there was a joint effusion. Less was not able to investigate. No references were found in six
oedema of the leg was not present than on admission; measurements
English books or in articles on war surgery between 1918
were made of leg circumference, of leg volume (by a tape method),*
onward, and there was no later recognition.
and of pulsation by means of an oscillometer. During the next twen-
Meanwhile, using rabbits with a tourniquet applied to the
ty-four hours the volume and circumference of the leg decreased.
However, the oscillometer readings, after a deceptive rise towards legs under anesthesia, we established that myoglobin and
normal, fell to the low initial level, even though during this period acid urine were the important nephrotoxic factors.
the left leg had been bandaged and elevated to 50 degrees on a Before the later onslaught (1944-1945), we took over the
Thomas splint for two hours. The second specimen of urine still laboratory of Ronald Grant, run by the MRC Shock Unit in
showed neither albumin nor blood. Newcastle, and established that industrial traumatic uremia,
By 6 p.m. the next day the left leg was cold below the knee and so often discussed earlier, was due mainly to traumatic mus-
blue, and amputation was proposed. This was done under vinesthene dc necrosis, as in crush syndrome. Erasmus Barlow and
and gas-and-oxygen. Citrated stored blood (Group 0) was given dur- Ludwig Wittgenstein had remained with us there. The latter
ing and after operation, restoring the blood pressure, which had tem-
was uncommunicative but cut beautiful lung sections.
porarily fallen, to the pre-operative level. Urines collected after this
Erasmus Barlow was indefatigable, an expert clinician, and
showed albumin and gave a positive benzidine reaction; hyaline, gran-
prepared most accurate diagrams. On average, autopsies of
ular, and what appeared to be red cell casts were noticed, besides free
red corpuscles. such industrial victims took us about 6 hours each, as well
During the next five days the patient continued drowsy and apa- as histologic and quantitative biochemical analysis of each
thetic, from which state she was easily roused by the slightest stimu- damaged muscle and its opposite undamaged pair (per-
lus to become anxious and apprehensive, without, however, any loss of formed by J. K. Stead). The sheer bulk of all this material
precluded detailed publication in the scientific and medical
journals; however, it may be seen in the protocols, tables,
photographs, and descriptions stored in the Wellcome
Historical Museum. The amount of muscle damage proved
to be the major cause of posttraumatic uremia. The worst
cases had suffered a fracture of the pelvis. This was because
of the large number of muscle attachments thereon.
These studies all arose from that original 1941 publica-
tion. Later into the War, the Americans had few facilities for
their rapid advances, but full details of their findings in
“Shock, Kidney and Crush Syndrome” are given in the offi-
cial medical history ofthe War (2). There were no references
to World War I cases.
None of the four patients that were originally described
in 1941 survived, but others detailed in the same issue
recovered (5 of 13). Today, the outlook is much better as a
result of (1) early diagnosis and treatment; and (2) immedi-
ate hydration with lactate or bicarbonate solution, preferably
before release. This prevents precipitation of myoglobin and
its conversion to acid hematin. This is now standard prac-
tice. Minor degrees of muscle damage may show no kidney
damage clinically, but examination of the urine may show
CHART 1.-CASE I. myoglobin (detected after its conversion to metmyoglobin
and carbon monoxide to show better the specific bands).
* Worked out in conjunction with D. K. Hill. An inextensible tape of In those War days, however, it was thought important to
width (w) is wound round the limb without overlapping. The length of tape
promulgate this early alkaline rehydration. The MRC set up
(L), thus enclosing a certain volume (V) by a number of turns (n). is given by
a team led by an eminent surgeon, Sir James Walton, to visit
the formula:
immediately such bombed areas loaded with infusion bot-
L=VY tles, bicarbonate, a primitive hand spectroscope, and
syringes, etc. We answered urgent calls from the Ministry of
where k is a constant dependent on the shape of the leg. In Case I direct mea-
surement of volume by water displacement gave k a value of 0.90.
324 Journal of the American Society of Nephrologv

mental clarity. The output of urine became very small, despite a fluid
intake by mouth of between 1.5 and 2.5 litres daily; vomiting contin-
Home Security and went out, often in the middle of the
ued (between 50 and 250 c.cm. daily). Normal saline (1 litre), 30% night, driven by valiant women auxiliaries into the darkness,
saline (100 c.cm.), and 5% glucose-saline, followed later by caffeine only to find when we got to, e.g., Norwich, that all of the
benzoate (140 mg), 85 c.cm. of four-time-normal reconstituted dried victims were well and safely in bed, as were the doctors, a
serum (obtained from the Medical Research Council serum-drying totally noneffective enterprise. The second major advance in
unit), with, in addition, pitressin 1/100,000, were given intravenously, treatment was introduced by Kolif in 1944 (dialysis for kid-
and hot bottles were applied to the loins. Despite these measures, ney shutdown) but was too late for our wartime crush syn-
directed towards restarting urine flow, the patient, whose blood pres- drome cases. Lower nephron nephrosis, however, was now
sure was maintained at 130/70, suddenly collapsed at 12:13 p.m. on
recognized to be the result of muscle necrosis also in vari-
the eighth day and died in three minutes. A systolic murmur at the
ous conditions such as barbiturate, carbon monoxide poi-
apex and dropped beats had been noticed for forty-eight hours before
soning, and more recently in the earthquake disasters of the
death, and an electrocardiogram taken forty-eight hours before death
showed merely low voltage. A second, sixteen hours later, showed
postwar years when the difficulties have been due mainly to
widening of ORS, higher voltage, increase in Q3 and inversion of T3. late access and, in general, logistical problems. Thus, strict-
Biochemical findings are listed in Tables I and II. Necropsy was per- ly clinical and treatment problems have been solved, but
formed two and a half hours after death. others remain (3).

1. Cope Z: Crush syndrome. In: Medical History of the Second World

War, Surgery, Chapter 9, 1953, pp 673-688
TABLE 1.-Biochemical Findings in Case I: Blood
2. Surgery in World War!: PhysiologicalEffects ofWounds, Washington,
DC, 1952
.

a#{252}
.
--
Plasma Proteins
, .
E
3. Better OS: History of the crush
Messina, Sicily 1909 to Spitak,
syndrome:
Armenia
From the earthquakes
1988. Am J Nephml
of
17:
392-394, 1997
Urea ; . .

E z
E
. .-
=,, E
c - .2 .c
E < L i <

mg. mg. mg. gm. gm. gm. gm. mg. GUEST COMMENTARY
Date Time per per per per per per per per
lOt) lOt) 100 lOt) 100 lOt) 100 c.cm. lOt)
c.cm. cern. c.cm. cern. c.cm. cern. c.cm. cern.
James P. Knochel

Dec. 5 2 p.m. 148 - 584 6.9 4.0 2.8 0.1 50 30 Presbyterian Hospital of Dallas,
‘. 7 10:40a.m. 286 - 498 - - - - 42 - University ofTexas Southwestern
‘. 8
1 1 am. 305 7.3 6152 6.2 - - - 40 3i Medical Center, Dallas, Texas
‘. 10 2:30p.m. 268 - 575 33
“ 11 12:20 p.m.’ 320 7.7 496 6.6 3.7 2.7 0.2 - 34 en Dr. Tisher and his Editorial
I At death.
Board established the criteria for
2 Received 1.0(M) cern. of saline. the “Milestones in Nephrology” series,
3 Uric acid 10.8 mg.. creatininc 2 mg.. plasma sodium 307 mg.
4 Serum calcium 9.1 mg.
the classic by Eric Bywaters and Devon Beall, published in
1941 (1), is a prototype. In this article, Bywaters, the astute
clinician, characterized the relationship between ischemic
TABLE 11.-Biochemical Findings in Case I: Urine necrosis of skeletal muscle and acute renal failure that we
now identify as the crush syndrome.
.-? Bywaters made his observations during the battle of
I .
Britain. The attack on Britain began in July 1940 after the
;g
evacuation from Dunkirk. When Britain refused Hitler’s
mg. mg. gm. Bcnzidine demands to surrender, the Germans responded by bombing
Date Time per Reaction DC1X)SIt
per per
British airfields and ship docks in preparation for an inva-
cern. 1(K) lOt) 1(X)
cern. cern. cern. sion. Because several bombs had fallen errantly on London,
on August 25th Churchill ordered
Force to the Royal Air
I I 2 noon 96 (( - ()4() Negative
Dec.4 I
51) 1) ..
bomb Berlin. In retaliation, began
Goering’s Luftwaffe
I 9p.m. - -

,. 6 I 10.30 am. 332 (o - 27(1 Positive

Hyaltne. red cell, bombing London on September 7, 1940. Many British citi-
and granular
t 5 p.m. 22 35() - 361) zens were killed or injured. The injuries consumed all avail-

-
casts
able hospital beds in London. Four patients were of particu-
,. 7 7.3(( am. (9) 5(X) 561)
.. 8 Pus cells lar interest. Each had been buried in debris for several hours.
1 1 am. 5() 1(5K) 514 52()
.. 9 10 am. 30 9(5) - 4)9) ‘ bacteria
When freed, they appeared unscathed, had normal blood
9 am. 38 9(X) 57)) 52)) pressure, and, as a result, were transferred from the site of
5.55 p.m. 4.5 - 72)) 44(1 the bombing to the Hammersmith Hospital for observation.
.. 1(1 6.45 p.m. 14.2 - 65(1 44(1 Shortly after arrival, they became hypotensive, collapsed,
8 p.m. 4.8 - 77(1 44()
and appeared to have hypovolemic shock with pallor, cold-
9 p.m. 3.4 - 75(1 41(1
10 p.m. 2.2 - 74(1 42(1
ness, thirst, and sweating. None of these patients showed
.. I I 9.15 am. 38 - 77(1 42(1
 Milestones in Nephrology 325

SUMMARY OF POST-MORTEM RECORD BY DR. THOMAS BELT have been great reabsorption in the tubules, resulting in a scanty con-
The point of major interest was the condition of the kidneys. They centrated urine. Some of them were surrounded and invaded by leuco-
were large, weighing 210 and 230 grammes respectively, rather dark cytes, and, in the lower reaches of the straight tubules, leucocytes were
red and firm, quite smooth of surface, having tense capsules due to sometimes the predominant constituent. Here and there a cast-filled
swelling of the cortices. The cut edges everted; the cut surfaces were tubule was undergoing disintegration and was surrounded by inflam-
wet and glassy owing to oozing of serous fluid. Parts of cortex mid- matory cells. Stains for iron were negative. Fatty changes were
way between renal pyramids were blanched by a zonal ischaemia. absent. The glomeruli showed no obvious structural changes, though
There was no evidence of ascending infection. The bladder was slight- the frequent presence of albuminous material in Bowman’s capsule
ly reddened, and contained a few drops of very thick cloudy urine. suggests that they had not escaped injury. The glomerular tufts con-
Subcutaneous and retroperitoncal tissues oozed serous fluid when cut, tamed relatively little blood, but the vessels of the medullary parts
indicating a slight generalized oedema. Marked cyanosis was evident were greatly engorged.
in the internal parts, but the skin was pale. Other organs and tissues Other Tissues-Thyroid: Signs of commencing activity with
presented no striking change. increased height of cells and many mitoses. Liver: cloudy swelling
Microscopical Examination-Kidney: The main change was to be but no necrosis. Adrenal: patchy loss of cortical lipoid. Heart: vac-
found in the tubules. The convoluted tubules and the loops of Henle uolation of neuromuscular fibres (bundle of His). Muscles of right
were severely damaged. The cytoplasm of the lining epithelium was leg: not abnormal.
swollen, frayed, granular, and vacuolated. Individual cells here and The amputated leg showed haemorrhage in the popliteal fossa
there were devitalized and desquamated, while those that remained around the artery, extending along the intermuscular fascial planes.
attached showed fairly frequent mitotic figures. The cast-off cells in There was no oedema beneath the deep fascia, hut slight sttperficial
various stages of disintegration merged in the lumina with loose col- oedema with punetate haemorrhage was present over the pressure areas
lections of eosinophilic debris. In the loops of Henle and the collect- in the skin. There was a haemarthrosis of the knee-joint, with cracks in
ing tubules there were numerous casts of dense eosinophilic material, the patella and tihial cartilages, extending down across the bone of the
most of which had a brownish colour, as though lightly stained with tibial condyle. Sections of artery showed no lesion; sections of muscle
bile or blood pigment. These casts seemed to be all of the same sub- (which macroscopically looked normal) revealed a few fibres (1%)
stance, though their morphological appearance varied a good deal, undergoing necrosis, with loss of striation and staining power.
depending upon the degree of condensation they had undergone. Some
looked not unlike collections of disintegrating erythrocytes; others Case II
simulated shreds of fibrin or beaded ribbon, while still others were A female aged 45 had been crushed under a collapsed building for
condensed into solid hyaline cylinders. They seemed to he compound- six hours. On admission there was a large scalp wound and lacerations
ed of dead epithelial cells, inspissated albumin, and perhaps hyaline and bruises of both legs, on which debris had been pressing. Both
material exuding from the lining of the tubules. One could identify an calves were extremely hard, swollen, and tense. The blood pressure
occasional erythrocyte within the tubules, but, so far as could be deter- was 130/98, and, despite considerable bleeding from the scalp, the
mined by histological means, the majority of the casts were not red haemoglobin amounted to 92%; the pulse was 130. (See Chart II.)
cell casts, though some of their colour might have been due to haemo- Measurements were taken of leg volume. Pulsation (oscillometer) was
globin. They were probably not of a specific type, as similar casts are decreased in both legs. The scalp wound was sutured under gas-and-
to be seen in acute nephritis and other conditions where there seems to oxygen and ether.

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C/tart 11.-Case II.

326 Journal of the American Society of Nephrology

Two hours later haemoconcentration developed and the blood pres-

signs of external or internal blood loss. Their hematocrit 1ev-
sure fell. Repeated infusions of “serum,” plasma, and saline restored
the blood pressure to 1 15 mm. Hg; then, following a transfusion of cit-
els became elevated, reflecting plasma trapping in injured
rated stored blood, to the abnormally high level of 160 mm. Hg. With muscle. As their blood pressure fell, edema and pressure
the rise in blood pressure the volumes of both legs increased, and the blisters appeared in the crushed limbs. Transiently, the tirine
oscillometric readings fell. Dark smoky urine was obtained by catheter showed pigmented casts. Despite reversal of shock and
next day, showing albumin and red cell and hyaline casts. maintenance of an adequate blood pressure by infusions of
A 2 p.m. she was vomiting and had oedema of the face, eyelids, saline, reconstituted serum or blood, the patients became
and arms as well as the legs. Venous blood showed raised urea (1 15 oliguric, progressively azotemic, hyperphosphatemic,
mg.), plasma chloride (801 mg. as NaC1), and serum potassium (28
hypocalcemic, and hyperkalemic, and died of uremia within
mg.), and a lowered CO2-combining power (41 c.cm. per 100 c.cm.).
1 week. After the appearance of oliguria, the urine no longer
Pulsation had returned in the right leg but not yet in the left. The chlo-
showed a positive test for heme pigment. Postmortem exam-
ride content of the body was therefore reduced (by sweating, purga-
ination showed necrotic muscle in the crushed extremities
tion, and replacement of gastric juice by sodium bicarbonate) and the
oedema disappeared, except from the legs. During the next three days and changes in the kidney essentially identical to those
her condition remained the same: the blood pressure reached as high described earlier in patients who died after hemoglobinuria
as 168/104, and, while the plasma chloride and alkali reserve fell, from unmatched blood transfusions. Bywaters became sus-
urea, phosphates, and potassium steadily rose. Urinary output was picious at this point that myoglobin (called myohemoglobin
very low (50 c.cm. daily) in spite of a daily intake of between 1 and then) was the culprit underlying the acute renal failure. As
2 litres. The urine became blood-free but infected (catheterization), opposed to findings in patients with hemolysis, myoglobin
and showed a low chloride concentration. was detected in the urine but not in the blood. This was
On the sixth day at 1 1 :15 p.m. the patient became distressed, cold, explained by observations made in the early part of the cen-
and wet with sweat: a systolic murmur was heard at the apex and the
tury (2,3) that when muscle pigment was infused intra-
blood pressure fell to 106/85. An electrocardiogram taken before this
venously, it never caused evident discoloration of serum but
(at 7 p.m.) showed bundle-branch block. The pulse suddenly fell to 70
was rapidly excreted. In contrast, infusions of a hemoglobin
(previously steady at 100) and showed dropped beats. She died at
12:10 am. on the seventh day. Biochemical findings are shown in solution promptly lead to brownish or reddish discoloration
Tables III and IV. of the serum before any of the pigment appeared in the
urine. Later, it was shown that there was no effective bind-
ing protein for myoglobin in serum (4). On the other hand,
hemoglobin was bound tightly to a circulating protein,
TABLE 111.-Biochemical Findings in Case II: Blood
which resulted in discoloration of plasma, and when a con-
E centration of 123 mg/dl was exceeded, then hemoglobin
.a
Urea
Plasma
norg. P
: !
Plasma
Protein
Alkalt
Reserve
appeared in the urine. That the urine was always intensely
acidic in those patients who developed acute renal failure
Date Time mg. mg. gm. gm. gm.
had been recognized in 1925 when it was shown that hemo-
per tOt) per 100 per 1(10 per 1(5) per lOt) c.cm.
cern. cern. cern. cern. cern. globin readily precipitated in an acid pH (5). Accordingly,
Bywaters proposed the following scenario to explain this
Dec.
,,
..
5
6
7
2p.m.
11 am.
11a.m. 214
115
156
-

11.1
SOt
572
513 -
-
7.1 28
-

-
41
40
40
syndrome.
.. 8’
1030a.m. 270 9.2 513 6.9 - 34

.. I 11 am. 314 12.9 464 - 32 30 1. Crushing or limb entrapment for at least two and one-half
9 ‘i at death 640 - - - 34 30 hours causes irreversible ischemic muscle necrosis.
. Uric acid to mg.. creatinine 2 mg.. and serum sodium 29(1 mg.
2. Upon rescue, blood flow to the ischemic limb is reestab-
lished, allowing perfused plasma to become entrapped in
damaged tissue, resulting in edema, hemoconcentration,
TABLE IV.-Biochemical Findings in Case II: Urine and clinical shock.
3. Some of the plasma perfusing the necrotic muscle reap-
..‘

. .z pears in the venous drainage, along with other protein

: L) components, allowing large quantities of myoglobin,
mg. mg. gm. potassium, and phosphorus to enter the venous plasma.
Date Time per per per Deposit
c.cm. tOt) 100 tOt)
4. The myoglobin released into plasma is readily filtered by
c.cm. c.cm. c.cm. the glomerulus, which transiently appears in the urine as
6 am. 92 400 - 111) Positive D a r k a n d benzidine-positive material and pigmented casts. Volume
Dec. 5 .. smoky. Many
5.15 p.m. 134 - - ISo
blood casts.
depletion, along with release of acid components from
Some red cells, injured muscle, causes a low urine pH. The low urine pH
few granular
casts causes myoglobin to form a gel, which obstructs the dis-
., 6 1 7.30 am. 25 401) - 240 ‘ Red cells. Red tal nephron resulting in oliguria.
1 5 p.m. 2() 3(X) - 180 cell casts. Pus
cells
5. Potassium disrupts cardiac rhythm and calcium precipi-
,.
..
7
(I
530a.m. 21 160 - 180 ‘ .
tates in injured muscle, causing a potentially lethal corn-
1 1.30 am. 15 400 520 240 .. an
P(#{149}g
1 It) am. 16 900 - 32(1 Few red cells
bination of hypocalcemia and hyperkalemia.
., 9
t at death 16 801) 671) 240
 Milestones in Nephrology 327

SUMMARY OF POST-MORTEM RECORD BY DR. THOMAS BELT

Necropsy twelve hours after death: Calf muscles on both sides

showed widespread necrosis. They were blanched and swollen as if
parboiled, and mottled with haemorrhagic areas. The vessels of the
legs were apparently undamaged. The kidneys were relatively large
(weighing 190 and 170 grammes), smooth, tense, and dark red. There
was no pyelitis. The bladder mucosa was slightly reddened; the liver
was swollen (1,830 grammes); and the lungs were slightly oedema-
tous (500 grammes each).
Microscopical Examination.-Kidney changes were very much
like those in Case I. There were perhaps more leucocytes in the
tubules, and these occasionally extended right up into the cortex. The
liver showed cloudy swelling but no necrosis. Muscle displayed wide-
spread necrosis, chiefly coagulative but becoming liquefactive in
small foci. There was much patchy haemorrhage and polymorph reac-
tion in disintegrating areas, but no bacteria. Some small vessels in the
section showed necrosis of the wall. The pancreas had a few patches
of fat necrosis, and the adrenal gland showed patchy loss of cortical
lipoid. Other tissues appeared normal.

Case III
A male aged 34 was pinned down by beams across shoulders,
arms, and thighs for twelve hours. On admission he was pale and
shocked, with great swelling of both arms and thighs, and skin-wheal-
ing at pressure sites. There was occasional vomiting (about 120 cern.
daily). The blood pressure could not be taken on account of the
swelling. 1,900 c.cm. of “serum” was given intravenous over ninety
minutes, reducing the haemoglobin from 160 to 112%. (See Chart
III.) Next day the left arm appeared greatly swollen, and the hand
blue, cold, and pulseless. An incision was therefore made from mid-
arm to below the elbow, relieving the tension beneath the deep fascia
so that the brachial artery again began to pulsate. This was followed
by a transfusion of 460 cern. of blood (Group 0). Urine was passed-
specific gravity 1015-containing albumin and blood but no casts. On
the third day the left hand was warm but still devoid of sensation and
power: there was oedema of both thighs, but a radiograph showed that

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C/tart 111-Case III, iicluding biochemical data.

328 Journal of the American Society of Nephrology

there was no bony lesion. The patient continued to vomit about 100
c.cm. daily; 6 litres of 5% glucose-saline had been given intravenous- article published in 1942 (7), he showed that tourniquet
ly over this and the previous day. There was some incontinence of compression of the limbs of a rabbit for a period of 4 to 6
urine, of which, however, 655 c.cm. was collected. On the fourth day, hours could reproduce at least part of the human crush syn-
despite a fluid intake of 1,340 c.cm., 590 c.cm. of urine was passed, drome. Thus, upon release of the tourniquet, the muscles
still containing albumin. At 5 p.m. the temperature rose suddenly to became progressively swollen, and as hemoconcentration
103.4#{176},
and there was some redness around the site of the intravenous progressed, the blood pressure fell. Although increased
puncture. Sulphapyridine by mouth was started. On the fifth day vom- amounts of creatine, phosphorus, and potassium appeared in
iting, dyspnoea, and slight generalized oedema occurred, with crepita-
the urine as a consequence of muscle necrosis, benzidine
tions at both bases and a pleuro-pericardial friction rub. A radiograph
tests for pigment were uniformly negative, and acute renal
revealed slight basal congestion only: an electrocardiogram showed
failure did not occur. Before those experiments, it was unap-
right axis deviation; the blood pressure was abnormally high
(170-180 mm. Hg), and, despite a urinary output of 990 c.cm. in the
preciated that rabbit muscle contains no myoglobin. At this
day (on an intake of 1,230 c.cm.), the blood urea was 260 mg., the point, Bywaters realized that he had selected the wrong
total plasma protein 8.0 grammes, and the plasma chlorides (as NaCI) experimental model. On the other hand, he also realized that
500 mg. per 100 c.cm. failure to reproduce acute renal failure indirectly suggested
During the sixth day the blood pressure fell progressively without that myoglobin plays a critical role. To pursue this idea, new
further concentration. At 8 p.m. the patient had become delirious and experiments were designed in light of a study published in
disorientated, and the pulse rapid. The skin became cold, wet, and 1911 (8) showing that intravenously infused hemoglobin
cyanosed. Coarse crepitations were heard at both bases; there was caused anuria in the rabbit if the animal were pre-fed with
incontinence of urine, of which 530 cern. was collected, showing
an acid ash diet but not an alkaline ash diet. First, myoglo-
albumin and numerous red cells but no casts in the deposit. Oxygen
bin was prepared from normal skeletal muscle of patients
was given. The fluid intake was 1,860 c.cm. The blood urea was 326
who had died in auto accidents by perfusing the muscle until
mg., the total plasma proteins 4.8 grammes, and the plasma chlorides
(as NaCl) 500 mg per 100 c.cm.
it was free of hemoglobin and then extracting the myoglobin
Death occurred on the seventh day, 160 minutes before death the by elution according to the method described in 1932 (9).
blood urea was 345 mg., the total plasma proteins 6.1 grammes, the Infusing this preparation into rabbits showed conclusively
plasma chlorides (as NaCl) 461 mg., and the serum potassium 33 that myoglobin caused renal failure, provided the rabbits
mg. per 100 c.cm. were fed an acidifying diet or, alternatively, a diet contain-
ing ammonium chloride, and excreted a urine with a pH
SUMMARY OF POSTMORTEM RECORD BY DR. THOMAS BELT
below 6. In contrast, renal failure did not develop after injec-
Necropsy showed staphylococcal pyaemia due to thrombophlebitis
tion of the same myoglobin solution in animals consuming
of saphenous veins. There was extensive crushing of leg muscles.
a normal diet elaborating a urine pH above 6. The kidneys
Microscopically, tubular changes in the kidneys resembled those of
of the rabbits with acute renal failure appeared almost iden-
Cases I and II. There were numerous casts of similar character, but the
picture was somewhat complicated by the presence of a few small tical to those of patients expiring from the crush syndrome.
pyaemic abscesses. He showed further that in animals fed an acid ash diet, the
pigment appeared in the urine as insoluble casts. On the
Case IV other hand, the pigment was rapidly excreted in solution in
A male aged 16 was buried under a collapsed house for eight hours, the animals elaborating a urine of higher pH. Based on these
the left thigh being pinned down by a heavy load of masonry. On experimental studies, it clearly appeared that acute renal
admission the systolic blood pressure was 140 mm. Hg, and superfi- failure in the crush syndrome requires the presence of myo-
cial abrasions were present on the left thigh, later becoming whealed. globin and a urine of low pH (10).
On getting out of bed that afternoon he fainted. At 8 p.m. he suddenly On the basis of Bywaters’ observations, the events having
collapsed; the haemoglobin had risen to 140% and the blood pressure changed from Luftwaffe bombing to unpredictable attacks
had fallen to 40 mm. Hg; the pulse rate was 108 per minute. Venous
by V-i bombs (doodle bugs) and V-2 missiles, a recommen-
blood showed plasma protein to be 9.1 grammes and chlorides (as
dation was circulated (1 1) by the Medical Research Council
NaCl) 545 mg. per 100 c.cm. He was given normal saline, and then
that fluids to alkalinize the urine should be given to patients
“serum” intravenously, which, as may be seen from Chart IV, brought
the blood pressure to 96 mm. Hg, and the haemoglobin down to 85%;
even before rescue from collapsed buildings or entrapment.
plasma protein was 7.9 grammes and chlorides (as NaC1) 705 mg per For this purpose, if oral intake were possible, he recom-
100 c.cm. This was immediately followed by serum, which effective- mended administration of 1 pint of water containing 1 tea-
ly lowered the haemoglobin and raised the blood pressure to a corn- spoon of sodium bicarbonate per hour. Alternatively, in
paratively high level. Next day further serum was given. On the third patients who could not ingest fluids, hydration and alkalin-
day the condition of the left foot, which had caused considerable anx- ization could be rapidly achieved by the intravenous route,
iety, was worse: extensive oedema of the thigh had apparently cut off administering 1.87% sodium lactate together with glucose
the circulation to the left foot, which was cold and pulseless. Under and saline. He recommended that urinary alkalinization
gas-and-oxygen and ether anaesthesia, incision was made into the left should be continued as long as pigment is found in the urine
thigh to relieve pressure on the vessels: a feeble pulse was temporari-
(1 1,12). A similar procedure has been recommended by
ly restored in the posterior tibial artery. Tissue fluid from the thigh
other authors since that time (13,14).
contained 1 .9 grammes of protein per 100 c.cm. Five hours after the
operation the patient suddenly collapsed: although the haemoglobin
In his review published in 1990 (12), Bywaters was con-
remained at 105%, the blood pressure fell to 30 mm. Hg. After giving cerned that neither American nor British military histories of
oxygen by B.L.B. mask the pressure rose to 130/82. This restoration
 Milestones in Nephrology 329

Fig. 1.-Photomicrograph of renal collecting tubules from medulla, stained haematoxylin and eosin,
showing, above, ribbon-like pigmented cast, and, below, similar cast invaded by polymorphs and surround-
ed by desquamated epithelial cells. X 300.

Fig. 2.-Photomicrograph of renal tubule from boundary zone, stained haematoxylin and eosin, showing necro-
sis of wall and commencing reactive changes. X 280.
330 Journal of the American Society of Nephrology

World War I mentioned the “crush syndrome.” He noted that

crush injury with muscle destruction and acute renal failure
was originally described in 1909 in casualties of the
Messina earthquake (15). There were other reports from the
“German Handbook on Medical Studies in World War I”
(16) and in soldiers wounded in 1916 (17). One author sug-
gested in 1923 that myoglobin was the nephropathic agent
(18). Bywaters goes on to say that “history, it is frequently
said, teaches us that man does not learn from history.
Although it may be true that the military machine begins
war prepared for the previous one, the medical machine in
1939 was not as fully prepared for even a previous war as it
might have been had it consulted its opponent’s publica-
tions.” In this line of thought, it is interesting that despite
World War II and the Korean conflict, military publications
from the United States were inconsistent. Thus, “TB Med
#252/AFP 160-5-16 entitled “Acute Renal Failure” (19) fails
to mention the crush syndrome or the possible role that
C/tart !V-Case IV (adtnitted nine hours before the beginning ofihis chart myoglobin could play in the development of acute renal fail-
wit/i a blood pressure of 140 ,nm. Hg). ure. In contrast, a handbook published in 1958 for the mili-
tar)’ by a committee of physicians under the direction of
Brig. Gen. Sam F. Seeley provides detailed recommenda-
of blood pressure was, however, only temporary, and the patient died
tions for urinary alkalinization in patients with the crush
three hours afterwards. During the last two days there was much vom-
syndrome (20).
iting and the abdomen was extremely tense. The urinary output was
very low throughout.
A recent review (21) has summarized the enormous quanti-
Necropsy, by Dr. Keith Simpson, forty-eight hours after death,
ty of work that has been performed to elucidate the precise
showed crushed and oedematous muscles of the thigh, with interstitial mechanisms underlying the crush syndrome, and especially the
haemorrhages. There was no bony lesion, no injection, and no gross pathophysiology of myoglobin nephrotoxicity. Nonetheless, in
change in other organs. clinical terms, we have added very little since World War II in
On microscopical examination (Dr. Thomas Belt) the muscle terms of identifying and managing patients with the crush syn-
showed patchy necrosis, and infiltration with polymorphs. The kidney drome. We owe Bywaters a great deal of respect and admira-
and other organs were not thus examined. tion for his pioneering work on this disorder (21).

Discussion 1. Bywaters LOL, Beall D: Crush injuries with impairment of renal

function. Br MedJ 1: 427-432, 1941
THE RENAL LESION 2. Camus J, Pagniez P: Hemoglobinurie d’origine musculaire. Compte
RendAcad Sci 135: 325, 1902
This consists structurally of severe degenerative changes in
3. Camus J, Pagniez P: Hemoglobinurie musclaire. Compte RendAcad
the proximal convoluted tubules and, in the more distal part of Sci 135: 1010, 1902
the nephron, brown pigmented casts of a colour, in unstained 4. Lathem W: The binding of myoglobin by plasma protein. J Exp Med
preparations, similar to that of blood corpuscles. There are 111: 65-75, 1960
5. Baker SL, Dodds EC: Obstruction of the renal tubules during the
reactive changes round the casts and desquamated epithelium excretion of hemoglobin. BrJ Exp Pathol 6: 247, 1925
in the medulla (Figs. 1 and 2 on Plate). The matrix of the casts 6. International Society of Nephrology: Excerpt from International
is thought, on histological grounds, to be composed not of red Society of Nephrology Legacy Interview of Eric Bywaters by J.
Stewart Cameron, 1996, with permission
corpuscles but of desquamated epithelial cells. The pigment 7. Bywaters EGL, Popjak 0: Experimental crushing injury: Peripheral
might therefore be accounted for either by excretion into the vascular collapse and other effects of muscle necrosis in the rabbit.
lumen from the blood stream of haemoglobin, myohaemoglo- Surg Gynecol Obstet 75: 612-627, 1942
8. Yorke W, Nauss RW: Ann Trap Med 5:287, 1911
bin, or bile pigment, or possibly by the extrusion into the lumen 9. Theorell H: Kristallinisches Myogtobin. V. Die Sauersstoff-
of cells already pigmented. bindungskurve des Myoglobins. Biochem Z 268: 73, 1934
10. Bywaters EGL, Stead JK: The production of renal failure following
Changes very similar to these are described following mis-
injection of solutions containing myoglobin. Q J Exp Physiol 33:
matched transfusion (Witts, 1929; Goldring and Graef, 136; 53-70, 1944
Baker, 1937). There is the same absence of changes in 11. Bywaters EUL: Ischaemic muscle necrosis (“Crush Syndrome”). Br
glomeruli, and similar changes in the convoluted tubules, in the MedBull3: 107-110, 1945
12. Bywaters EGL: 50 years on: the crush syndrome. Br Med J 301:
interstitial tissue, and in the straight tubules. The casts are not 1412-1415, 1990
composed of red cells, but sometimes there are spherical bod- 13. Eneas iF; Schoenfeld PF, Humphreys MH: The effect of infusion of
ies resembling them. Baird and Dunn (1933) and others have
mannitol-sodium bicarbonate on the clinical course of myoglobinuria.
Arch Intern Med 139: 801-805, 1979
noted similar casts containing “haemoglobin” in eclampsia. 14. Rozt D, Taitelman U, Michaelson M, Bar-Joseph G, Burtzstein S,
The effect on function of blockage by casts is obscure: if this Better OS: Prevention of acute renal faIlure in traumatic rhabdomyol-
were the only lesion, what urine was secreted (through unob- ysis. Arch Intern Med 144: 277-280, 1984

structed tubules) should be of normal composition. The urine

 Milestones in Nephrology 331

resembled, however, more a glomerular filtrate; there was no

significant concentration of urea (hence no selective absorption
of water), and in Case I there was failure to reabsorb chloride
when the blood level was below 500 mg. per 100 c.cm. Case II
showed some degree of chloride reabsorption. There thus
appears to be dysfunction of the convoluted tubules. Whether
partial blockage or blockage of a few tubules-cf. the kidney
after mismatched transfusion, in multiple myeloma (Forbus et
a!., 1935; Holman, 1939), and in calcification affecting the
pyramids (Albright et al., 1940)-can so raise the intrarenal
pressure as to interfere with tubular function as well as with
glomerular filtration is not known. It has recently been sug-
gested (Navasquez, 1940) that the degree of tubular blockage is
not sufficient to account for the symptoms associated with
“transfusion kidney.” The hypertension in Cases II and III, and
also noted in the case reported elsewhere in this issue (Mayon-
White and Solandt, p. 433), may be allied to other types of pri-
atively insoluble material in the tubules both in man (e.g., sul-
mary “renal hypertension.”
phapyridine calculi) and experimentally (e.g., haemoglobin,
It is possible that minor degrees of this renal damage may
Yorke and Nauss, 191 1). Another possible cause for anuria in air-
occur, since at least one patient with crushed limbs has been
raid casualties receiving sulphapyridine is the formation of cal-
observed to recover completely (R. V. Christie, personal com-
culi at the uretero-vesical junction (Sadusk et al., 1940). None of
munication) with a raised blood urea and low urea clearance. In
these seemed to be of primary significance in the cases cited.
a similar case of muscle crush seen elsewhere (Beall, Belsey,
The part played by transfusion fluids (three of these patients
Bywaters, and Miles, unpublished data) there was a definite received Group 0 blood as well as plasma and “serum”) must
tendency towards recovery of renal function, shown by the
be considered, inasmuch as the pathological changes resemble
increasing resorption of both water and chloride. Certain cases
closely those of the “transfusion kidney.” There was no cvi-
of post-operative anuria may prove to fall into this category, but
dence clinically of a transfusion reaction, although such symp-
the majority of them appear to be associated mainly with
toms as rigor, chill, backache, and jaundice. Plasma samples
decreased blood volume and blood pressure, since restoration
taken at seventeen and a half and forty hours after transfusion
of blood volume to normal improves the renal output.
showed no increased colour. Further, although in Case I, before
In Case I fibroblast increase and tubular dilatation were blood transfusion, haematuria and albuminuria were absent, the
much more prominent than in the other cases. The latter may in
high blood urea and low urinary output suggested impairment
part be related to the strong therapeutic stimulation, as caffeine
of renal function. The case reported by Mayon-White and
raises the glomerular capillary pressure, with a resultant
Solandt in this issue (p. 433), and six other cases of which we
increase in filtrate (Verney and Winton, 1930).
have heard, received no blood, but plasma or reconstituted
serum only. Perhaps, however, the most potent argument
Aetiology of the Syndrome against these being due merely to transfusion reactions is that
no such condition has occurred in any of 25 shocked and
Muscle necrosis is the one aetiological factor common to
these cases and to those observed elsewhere. It was of limited
injured patients without severe muscle crush treated in this hos-
pital by blood or “serum” transfusion.
extent in Case I, although comparison with the degree of
necrosis in the other cases is difficult, since the leg was
removed thirty-six hours after admission. It would seem of Treatment
some significance that, in spite of amputation in this case, the The treatment of this condition so far has been by trial and
time interval between injury and death was of the same order error. It has been directed primarily to restoring urinary output
as in the others. by means of heat to the loins, by saline dilution of plasma pro-
It is known that when muscle is injured its permeability tein (thus increasing the glomerular filtering force), by increas-
increases and intracellular ions such as potassium leave it ing blood volume with serum and hence blood pressure (thus
rapidly (Horton, 1930). This may be related to the early increasing the glomerular capillary pressure), and by the use of
increase noted in serum potassium. An evaluation of the rela- diuretics such as caffeine. Decapsulation should perhaps be
tive importance of muscle injury, renal insufficiency, and pos- tried, as it has been shown to reduce the intrarenal pressure
sibly adrenal cortical deficiency in the composition of this bio- (Winton, 1937). In transfusion kidney this has been done twice
chemical picture must await the accumulation of further data. with successful results (Bancroft, 1925; Younge, 1936).
Oliguria in shocked patients may be due to dehydration, The effect of adrenal cortical extract in this condition should
sweating, and the fall in blood pressure (since a pressure below also be observed, in view of the raised potassium. The devel-
75 mm. Hg is insufficient to produce urine in the absence of cir- opment of electrocardiographic changes in Case I was not asso-
culating diuretic substances-Winton, 1937). The fall in blood ciated, however, with any significant alteration in serum potas-
pressure lasted for one and one and a half hours only in Cases I sium (cf. Thomson, 1939). In Case II the changes were similar
and II. Such oliguria certainly facilitates the precipitation of rel- to those seen in many patients a few minutes before death
332 Journal of the American Society of Nephrology

(Wood, personal communication). However, it is unknown ipation in this study-in particular to Prof. Dible and Dr. Thomas Belt,
whether changes in the heart muscle manifest electrocardio- and to Dr. J. Clegg, who supplied the serum. Our thanks are also due
graphically were concerned in the striking terminal collapse. to the Chief Medical Officer of the London County Council for per-

Prevention by early amputation was thought adequate in mission to publish this report.

Case I; it is evident that thirty-six hours was not early enough.

Whether there exists an alternative to immediate amputation we REFERENCES

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J. H. (1940).
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experimentally are already in progress at this institution. Clegg, J. W., and Dible, J. H. (1940). Lancet, 2, 294.
Forbus, W. D., Perlzweig, W. A., Parfentjev, I. A., and Burwell, J. C. (1935).
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Holman, R. L. (1939). Arch. Pat/tot., 27, 748.
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