- Email: [email protected]
STREPTOKINASE AND PULMONARY EMBOLISM
1039
weight-bearing exercises; but weight-bearing on the affected limb was normally prohibited until union was found radiographically. In order to avoid excessive periods in hospital, many of these patients were discharged home in weight-relieving callipers, which were normally discarded about 3 months after operation. Often this was not a popular method with the patients, but it was introduced to speed bed turnover; and very careful steps were taken to ensure that the callipers transferred the body-weight, as intended, to the tuber ischii. More recently we have allowed early weight-bearing in cases of transcervical fractures where satisfactory reduction of the fracture and its adequate fixation was achieved by SmithPetersen nailing. This has not apparently affected the results adversely; but it is probably not safe for subcapital fractures, and it would certainly not be expected to improve on the results achieved by delaying weightbearing until union is established. ANTICOAGULANT THERAPY
In late 1960
instituted prophylactic anticoagulant therapy, as recommended by Sevitt and Gallagher (1959), routinely in all patients over the age of 60 with these injuries, unless it was contraindicated by the patient’s history or condition. This has resulted in a very impressive fall in mortality from pulmonary embolism and in morbidity due to thromboembolism (Fagan 1964). This treatment has undoubtedly contributed to the maintenance of a low rate of postoperative mortality and morbidity in our Austin Moore series. Without pro,phylactic anticoagulant therapy, thromboembolic complications might have occurred in considerably more of these cases than of the Smith-Petersen nail series, because of the far longer period of bed rest imposed on the Austin Moore cases. we
Discussion
Moore inserted the first vitallium prosthesis in 1940, to replace the upper end of a femur that was the seat of a questionably malignant tumour; the operation was successful and the patient lived for about 2 years with 75% function of the hip and died of a heart-attack (Moore 1957). Moore maintained that for fractures of the neck of the femur perfect reduction, perfect fixation, and perfect postoperative protection must be ensured until union had occurred. He predicted poorer end-results with poor technique and said that " partially reduced fractures may unite, but there will be more or less aseptic necrosis of the femoral head ". Viability of the femoral head after fractures of the neck of the femur has been assessed by several methods including radioactive tracer techniques, arteriography, venography, needle aspiration biopsy of the femoral head (Price 1962), but Barnes (1962) suggested that " the prospects of finding a reliable method of determining the viability of the femoral head are poor ". He felt that " diagnosis of ischasmia of the capital fragment at an early stage would be invaluable in the study of non-union and segmental necrosis. But until we can be sure that it is impossible to achieve a satisfactory result when the capital fragment is ischaemic, we should hesitate to perform a primary replacement arthroplasty unless this is indicated for other reasons." Studies on the vascular supply of the femoral head have shown, however, that the lateral epiphyseal vessels supply the outer two-thirds of the head, and these are completely severed when the neck is displaced proximally; the inferior metaphyseal vessels are torn in all displaced fractures by lateral rotation of the distal fragment; and,
if the fracture is fairly accurately reduced but the nail traverses the upper and posterior quadrant of the neck, the vascular supply is very likely to be endangered (Trueta and Harrison 1953, Brodetti 1960, Claffey 1960). Prosthetic replacement takes no longer and involves little more bleeding than Smith-Petersen nailing; and the total duration of anxsthesia is usually much shorter. Moreover a radiographer need not attend at the operation, and repeated radiographs are not necessary. Conclusions A plea is here made for immediate primary replacement arthroplasty in displaced subcapital fractures of the femur. We believe that in these cases results of fixation with Smith-Petersen nails are poor. Prosthetic replacement is technically not difficult, involves little blood-loss, and normally takes not more than 45 minutes. In our hands there have been no unforeseen complications. The average postoperative stay in hospital has been 4 weeks only. Fit patients were easily rehabilitated. Nevertheless, in our view transcervical fractures are still best treated by even
Smith-Petersen nailing. We recommend routine administration of anticoagulants prophylactically to reduce postoperative mortality and morbidity from thromboembolic episodes. Among our own patients with a 5-year follow-up, there has been no suggestion of late complications. We agree with Moore
(1957)
that
"
when fractures of the femoral neck can be treated with satisresults by a method which preserves the natural head of the femur there is no reason for insertion of a prosthesis. When a better result can be obtained with artificial replacement of the head there is every justification for the use of a prosthesis." The Lancet, in a leading article (1964), has rightly remarked: "... the operation [prosthetic replacement] is a desirable alternative to reduction and fixation if it permits early movement and ambulation ... "
factory
It is a pleasure to thank Sister Marangou for nursing the majority of these patients and for statistical help; and many members of the orthopaedic staff for valuable assistance. REFERENCES
Addison, J. (1959) Proc. R. Soc. Med. 52, 908. Barnes, R. (1962) J. Bone Jt Surg. 44B, 760 Brodetti, A. (1960) ibid. 42B, 794. Claffey, T. J. (1960) ibid. p. 802. Fagan, D. G. (1964) Lancet, i, 846. Lancet (1964) i, 1261. Moore, A. T. (1957) J. Bone Jt Surg. 39A, 811. Price, E. R. (1962) ibid. 44B, 854. Sevitt, S., Gallagher, N. G. (1959) Lancet, ii, 981. Trueta, J., Harrison, M. H. M. (1953) J. Bone Jt Surg. 35B,
442.
STREPTOKINASE AND PULMONARY EMBOLISM N. L. BROWSE M.D. Brist., F.R.C.S. LECTURER IN SURGERY
D. C. O. JAMES M.D., B.Sc. Lond., B.Pharm. Wales BLOOD-TRANSFUSION OFFICER
Surgical Professorial Unit, and Blood-Transfusion Department, Westminster Hospital, London, S.W.1
From the
THE prevalence of deep-vein thrombosis or pulmonary embolism associated with surgery and protracted confinement to bed has not diminished in the past thirty years (Sevitt 1962). Since we do not understand how these conditions are caused, we can only prevent them by means of routine anticoagulant therapy. This is costly, often impracticable, and by no means always successful. In the established case the drug of choice is heparin, not only for its anticoagulant effect but also because it can be
1040 virtue of some ill-understood (possibly vasodilator or anti-serotinin) action. The discovery of methods of lysing blood-clots in vivo raised hopes of an effective way of treating thromboembolic disorders. Though there are many published reports of the use of these substances in peripheral venous and arterial thromboembolic disease, there are few reports of their use in pulmonary embolism. The experimental work of Hume (1961) and Cahill et al. (1963) did not simulate the conditions in man, for both groups used emboli made of fresh blood-clot and the method of assessing lysis was open to many errors. Clinical studies (Moser 1959, Sheffer and Israel 1959, Cliffton 1960, Sheffer et al. 1961) are also difficult to interpret because none of them provide objective data of the efficacy of the drugs used. We have investigated the effect of streptokinase (SK) on artificial pulmonary emboli in dogs and used it in four
life-saving by
Fig. 2-Thrombus
Experiment1 The emboli consisted of a mixture of 4-5 ml. fresh blood, 0-5 ml. thromboplastin, 0-5 ml. calcium gluconate, and 0-5 g. ’ Diodrast ’ (Allison et al. 1960). These substances, mixed together in a glass tube, produced a jelly-like clot 15 cm. long and 0-3 cm. in diameter, which was introduced into the right common iliac vein. In most cases it became fragmented and produced multiple emboli. Method of assessment.-Since the emboli were radio-opaque owing to the diodrast, their fate was followed by serial radiographs taken 1, 2, 3, 4, and 24 hours after embolisation. The changes in the size and density of the emboli were assessed. Treatment.-Emboli were inserted in 8 dogs. A four-hour intravenous infusion of 500 ml. physiological saline solution was given, during which the dogs were kept anaesthetised, and X-rays and blood-samples were taken hourly. At twenty-four hours further chest X-rays and blood-samples were obtained. The animals were then killed. These formed the control group. The same procedure was carried out in another 8 dogs with 2 megaunits of SK added to the infusion of 500 ml. physiological saline solution. These formed the test group. Blood changes.-There were no changes in the S.C.T., simplastin-time, whole-blood clotting-time, plasma-fibrinogen, and 50% lysis-time in the blood of the control group. The extent of the relevant mean changes in the blood of the test group (8 dogs) is shown in fig. 1. The infusion of SK lengthened simplastintime, the Lee and White clotting-time, and the S.C.T., which pointed to the presence of a major coagulation defect. Plasmafibrinogen was also significantly reduced (from 306 mg. per 100 ml. to 199 mg. per 100 ml.), whereas the magnitude of the fibrinolytic activity is clearly shown by the striking reduction of the 50% lysis-time. Before the infusion, diluted blood clotted with thrombin did not lyse spontaneously under six hours; two hours after the SK infusion was begun lysis occurred within three hours and thirty-six minutes, and at four hours lysis took only an hour and a half. Blood lipsmia was reduced in both control and test groups, and must therefore have been associated with the surgical manipulations. Its significance is not clear. Results.-There was no change at two hours in the control group; no significant change. at four hours; but 75% of the emboli had disappeared after twenty-four hours. In the test group there was slight loss of density and some disintegration of most emboli at two hours, and 75% of the emboli had disappeared at four hours. The emboli had completely disappeared in 4 animals at twenty-four hours, but no further change had taken place in the others.
Materials and Laboratory Methods were taken by means of siliconed syringes and needles from 26 dogs weighing between 10 and 20 kg., and the blood was immediately cooled on ice. Except when blood was required for measuring fibrinolytic activity, e-aminocaproic acid was added to the anticoagulant solution to inhibit in-vitro- SK effect.
Blood-samples
Fig. l-Effect of streptokinase (compared with controls) on bloodcoagulation and other factors. 0 =Controls (no SK). X =Emboli formed in vitro. Experiment 1. 2 megaunits SK. Å. = Emboli formed in inferior vena cava. Experiment 2. 1 mega.
,
,
SK.
vena cava.
Fibrinolytic activity was measured according to the method of Billimoria et al. (1959). One-stage prothrombin-time, Lee and White clotting-time, and factor v assays were determined according to the method of.Biggs and Macfarlane (1962). A modified’ Stypven’ (Russel viper venom) clotting-time (s.c.T.) method was used (Maclagan et al. 1958). ’Simplastin ’-time was measured with 0-2 ml. of the reagent and 0-1 ml. of plasma. Lipsmia was measured in arbitrary turbidity units. Fibrinogen was estimated by means of an ammonium-sulphate precipitation technique (Parfentjev et al. 1953).
patients.
unit
removed from inferior
This experiment showed that SK accelerated the normal lysis of small multiple artificial pulmonary emboli (Allison et al. 1960) from twenty-four to four hours. But the method of assessment was crude and inaccurate, and the emboli were totally unlike emboli in man. With these objections in mind the following experiment was
performed. 2 The embolus.-To obtain emboli like those in the pulmonary
Experiment
1041 tree of patients who died on account of pulmonary emboli, thrombi were induced in vivo by the method of Sabiston et al. (1962). The abdominal vena cava was temporarily occluded and filled with 90% phenol for two minutes. It was then washed out, occluding clamps were removed, and the abdomen Seven to ten days later the abdomen was rewas closed. and thrombectomy was performed (fig. 2). Macroopened and microscopically the thrombi were exactly like the scopically of man. They were dabbed dry, weighed, emboli pulmonary and inserted into the vena cava with a special tube and plunger. None of these thrombi fragmented. Method of assessment.-The effect of the SK was assessed by weighing the embolus before insertion into the vena cava and twenty-four hours later, after it had been removed from the pulmonary artery at postmortem. Treatment.-In 5 dogs, a four-hour intravenous infusion of 500 ml. physiological saline solution was given, beginning immediately after embolisation. Serial blood-samples were taken. When the animals were killed twenty-four hours later, the embolus was removed from the pulmonary. artery and weighed. In another 5 dogs 1 megaunit of SK was added to the infusion of physiological saline solution. Blood-changes.-In the control group there were no significant changes in any of the blood-factors tested in the course of the experiment. The changes in the test group are shown in fig. 1. There was a distinct lengthening of the one-stage prothrombin, simplastin, and stypven clotting times. There was a slight lengthening of the Lee and White clotting-time, and some depression of both factor v and plasma-fibrinogen. The 50% fibrinolysis-time was very significantly reduced; hence blood which preoperatively did not lyse under six hours now lysed in two hours and forty-two minutes, two hours after the SK infusion was begun, and in forty-two minutes after four hours. Blood-samples taken at twenty-four hours showed a return to almost normal values. The effect on blood-coagulation factors was not so evident in this series because only 1 megaunit of SK was infused, as against 2 megaunits in the first experiment. Nevertheless, the reduction of the 50% fibrinolysis-time shows that this dose was adequate. Results.-Tableshows the change in weight of the five emboli of the control group. There was little change in either ,
TABLE I-WET WEIGHT OF PREFORMED PULMONARY EMBOLI BEFORE AND 24 HOURS AFTER EMBOLISATION
TABLE II-WET WEIGHT OF PERFORMED PULMONARY
EMBOLI, BEFORE AND 24 HOURS AFTER EMBOLISATION AND TREATMENT WITH STREPTOKINASE
THE FIRST PATIENT
A man, aged 56 years, under the care of Dr. C. J. Gavey, gave a two-year history of recurrent attacks of superficial and deepvein thrombosis of the right leg. He had been treated for nine months with long-term anticoagulants (phenindione), but these had been discontinued eighteen months before his
present admission. A month before admission the right leg became painful and more swollen, and the patient became breathless and had palpitations. Three days before admission the breathlessness began to increase until he collapsed and was admitted as an emergency. Both legs were swollen, the patient was very dyspnoeic, and he complained of severe central chest pain. On examination the jugular venous pressure was raised +5 cm.; the blood-pressure was 80/75 mm. Hg; there was bilateral ankle oedema, E.C.G. showed inversion of the T wave in leads VI, V2, and Vg. The clinical diagnosis was pulmonary embolism, and the patient was treated with heparin, oxygen, and vasopressors. The next day the hypotension had slightly improved but the remaining signs were unchanged. On the fourth day the patient’s condition deteriorated, despite the treatment with heparin, and there were signs of right ventricular strain on the E.C.G. and the jugular venous pressure was still raised. SK was given on the fifth, sixth, and seventh days in 3 eight-hour intravenous infusions of 2 megaunits each. Steroid cover was provided with prednisone (15 mg. daily) and 10,000 units of heparin was given intravenously between the infusions and for two days after treatment. In view of the patient’s long history of recurrent thrombosis, long-term anticoagulation with
phenindione was thought necessary. This patient and patient 2 were treated in 1961 when little guidance in SK therapy was available. Such large doses of SK are not now thought necessary, and, apart from the high initial dose (to counteract anti-SK antibody), a maintenance dose of about 70,000 units per hour seems to maintain a reasonably high level of fibrinolytic activity. Therapy was controlled by means of estimating the prothrombin-times (which in this patient remained at twenty-eight to thirty seconds during therapy), and fibrinogen-levels which averaged 100-150 mg. per 100 ml., although on occasion values of 50-60 mg. per 100 ml. were
(six-day) or old (ten-day) emboli. The mean loss of weight was 9-4%. In the test group (table n) there was considerable loss of weight, 23-86%. The mean weight loss was 62-6%, significantly different from the 9-4% of the control young
group.
This experiment -reproduced the conditions of pulmonary embolism in man. The emboli were old and partly organised, identical on microscopy with those found in man, and they remained whole and always impacted in the right or left branches of the pulmonary artery. The SK was given in a dose that produced changes in the blood similar to those sought in the treatment of human patients. We believe that this experiment proves conclusively that SK can lyse pulmonary emboli in man. Clinical Studies 4 patients with clinically proven pulmonary emboli have been treated with SK.
recorded.
The fifth day brought no improvement. On the sixth day the patient felt better, the blood-pressure returned to normal and the jugular venous pressure fell to zero. But the dyspnoea was worse, and the chest pain was unchanged. On the seventh day (last day of treatment) the dyspnoea began to improve. The next day there was no dyspnoea at rest and the chest pain was a little less. From this time on the patient recovered steadily. He has been kept on phenindione and is still well. THE SECOND PATIENT care of Dr. R. D. Tonkin, aged month before admission experienced a pleuritic pain in the lower left chest. It lasted a week and then almost disappeared. Three days before admission it became much more severe. On admission he was flushed but not dyspnoeic. Respiration-rate 25 per min., there was a pleural rub at the right base, and a chest X-ray revealed a confluent bronchopneumonia of the right middle and lower lobes. He was treated with antibiotics and physiotherapy, but nine days after admission he collapsed,
A
one
man
58 years, under the
1042 SK was infused over a thirty-hour period with steroid cover. The preliminary dose was calculated and therapy was controlled by estimations of the prothrombin-time, plasmafibrinogen, and thrombin-time as in the previous cases, but, in addition, various other tests including euglobulin lysis-time, plasminogen-levels, and fibrin plates were included. Of these further tests the euglobulin lysis-time probably gave the most useful information, and in this instance the patient’s normal euglobulin lysis-time of two and a half hours was reduced to fifteen to twenty minutes during therapy. The next day there was some clinical improvement, and the pleuritic pain and the dyspnoea were easier. There was further improvement in the next twenty-four hours, though crepitations and rhonchi appeared at the left base. Chest X-ray showed patchy shadows, some pleural reaction, and an enlarged pulmonary artery consistent with the diagnosis of pulmonary embolism. After three days of SK the patient was given heparin 10,000 units four-hourly. The next day he complained of a pain in the wound and inspection revealed a large haematoma. This was evacuated and a litre of blood was transfused. Twelve days after operation deep-vein thrombosis developed in the left calf (swelling.and tenderness) which was treated by means of raising the leg and bandaging. Eighteen days after operation the chest X-ray was normal.
unrecordable blood-pressure, severe dyspnoea, and cyanosis. He had no chest pain and no haemoptysis. It was noticed that his left leg had become swollen. Pulmonary embolism was diagnosed on clinical grounds, and he was given intravenous heparin. There was no improvement and he was taken to theatre with a view to embolectomy. By the time he arrived there was sufficient, though slight, improvement to contraindicate embolectomy and he was returned to the ward. There was no further improvement during the next few hours, and it was decided to give SK through a catheter passed from the antecubital fossa into the right atrium. 3 eight-hour infusions of 2 megaunits of SK were given on three consecutive days. Adequate evidence of fibrinolytic activity in the blood was obtained, and control of therapy was maintained as in the first patient. Prothrombin-time was usually twenty-two to twentyfour seconds during treatment and plasma-fibrinogen was reduced from an original level of 580 mg. per 100 ml. to 300-340 mg. per 100 ml. Although the thrombin clotting-times were apparently normal, the clots lysed spontaneously in twenty to thirty minutes, indicating effective fibrinolytic activity in the patient’s blood. During these three days the patient made a steady recovery. Chest X-rays after the acute episode confirmed the diagnosis. Unfortunately, he was not considered well enough for pulmonary angiography during the period when he had the indwelling right atrial catheter. He is now alive and well and has not had to consult his doctor for the past two years.
with
an
Discussion
There is no doubt that substances which activate the THE THIRD PATIENT normal fibrinolytic mechanisms can cause lysis of intraA man, aged 36 years, under the care of Mr. E. Stanley Lee, vascular thrombi. The most effective of these agents at was admitted for repair of bilateral recurrent inguinal hernia. present is streptokinase. In theory, pulmonary emboli He had had no deep-vein thrombosis or pulmonary emboli should be particularly susceptible to lysis; for they are soft after the previous operations, but the routine preoperative " red " thrombi in normal vessels through which blood chest X-ray showed some linear collapse of the right midzone. flows rapidly. Experimentally, in-vivo lysis of pulmonary The patient’s postoperative course was satisfactory until the twelfth day, when he suddenly became dyspnoeic, felt a pleuritic emboli has been detected by means of methods based on in the lower left and had a There small chest, pain haemoptysis. counting the radioactivity of labelled thrombi (Hume was no hypotension or evidence of a raised central venous 1961), on measurements of the pulmonary-artery pressure pressure. Chest X-ray showed linear collapse of the left base et al. 1963), on X-rays, and on weight changes of (Cahill consistent with the diagnosis of pulmonary embolism. It was the emboli themselves as already described. decided to treat the patient with SK. The clinical value of SK therapy is still unproven. The A preliminary blood-sample was taken to ascertain the anti4 cases reported here demonstrate that the drug is safe if streptokinase titre, baseline prothrombin-time, and plasmaused with care. Occasionally it causes hypotension, but it fibrinogen. Treatment consisted of a two-hour infusion of SK 750,000 units (as loading dose), followed by a further con- had no deleterious effect on the blood-pressure of patients tinuous infusion for twenty-eight hours at a concentration of 1 and 2, who were very ill. We give corticosteroids in the 70,000 units SK per hour. Further blood-samples were first twelve hours to subdue any pyrexial reaction, which obtained at 2, 4, 12, 24, and 30 hours. A 100 mg. dose of hydrois the most common complication. SK is safe when used cortisone was injected into the infusion at the beginning and within thirty-six hours of major non-vascular surgery. after twelve hours to minimise a possible pyrexial side reaction, A hsematoma developed in the wound of patient 4 when and the infusion was followed by heparin 10,000 units fourhe was put back on to heparin immediately after the SK hourly and phenindione. infusion. This problem does not arise if the heparin is Three hours after the infusion was begun the patient showed striking clinical improvement. The pain and dyspnoea sub- started two hours after stopping the SK. It is reassuring that bleeding due to excessive fibrisided, and he felt well. At the end of treatment he was symptomfree. An X-ray on the second day of treatment showed some nolytic activity can be controlled by an intravenous clearing of the left base, but one taken immediately after the injection of e-amino-caproic acid (’ Epsikapron ’), which cessation of treatment showed some collapse and consolidation specifically inhibits fibrinolytic activity in a few minutes. and a small pleural effusion. By the day of discharge (on the Adequate thrombolysis can be obtained with a loading twenty-first day) the chest X-ray was clear. dose twice the titrated initial dose (T.I.D.) and mainTHE FOURTH PATIENT tained with an infusion of 70,000 units of SK per hour A 48 under the care of Prof. H. man,
aged
Ellis,
years,
admitted for vagotomy and pyloroplasty and repair of incisional hernia. A previous laparotomy a year earlier had been uneventful. He was admitted for investigation, and was operated upon a week after being admitted. Three hours after the operation he complained of a severe pleuritic pain in the: lower left chest which was separate and different from the painl in his wound. His blood-pressure was 100/75 mm. Hg, and he: was extremely dyspnoeic. There was a pleural friction rub at the’ left base. A chest X-ray and E.C.G. were normal. Pulmonary embolism was diagnosed, but it was decided to wait twenty-four hours before beginning treatment. Thirty-six hours later the blood-pressure was still 100/75 mm. Hg, and the pleuritic pain1
was
:
was worse.
-
intravenously. The first 2 patients were given daily eight-hour infusions. This was because we were not sure that we could control the lytic effect and because it enabled us to perform frequent serial testing. We now test the blood one hour and two hours after treatment is begun, and then daily during a constant infusion of 70,000 units per hour. All patients showed a striking clinical improvement. It is impossible to say what caused this improvement. Similar results are seen with patients treated with heparin, or without any treatment at all, but two of our patients (1 and 2) were being treated with anticoagulants without
1043 success
before their therapy. Other workers have claimed
"WHITE LIVER " DISEASE
results, but there is still no report which presents angiographic proof of thrombolysis in human cases. Our 4 patients are alive and well, and patient 2 who had similar
had recurrent emboli before treatment has had none since. We would evaluate SK in the treatment of pulmonary embolism thus: 1. The extremely ill, near to death patient should be treated initially with heparin, since there is ample evidence that this drug is sometimes lifesaving by virtue of some action separate from its anticoagulant effect. 2. All other patients, and those who do not respond after six to twelve hours of heparin, should be treated with SK; for it is logical to attempt to lyse the clot as soon as possible in order to relieve the strain on the heart and to reduce the likelihood of long-lasting pulmonary hypertension. After treatment with SK the patient should receive anticoagulants until the risk of further thrombosis has passed. 3. The contraindications that apply to anticoagulants also apply to SK. In particular, SK should not be given to patients with the following disorders : haemorrhagic diathesis, hypofibrinogenxmia, peptic ulcer, or other potential bleeding sites. 4. The diagnosis of pulmonary embolism is often difficult and SK should be used only when there is strong evidence to support the diagnosis. The trend in the past two years has been to increase the number of tests thought necessary to control fibrinolytic therapy. Although these increase the safety for the patient and our understanding of the drug, they naturally make it more difficult for smaller hospitals to embark on fibrinolytic therapy as an alternative to routine
anticoagulation. We believe that,
before this promising therapy can gain in smaller hospitals, a determined attempt must be made by some competent authority to define the minimum of tests compatible with the safety of the patient and adequate control of SK therapy. Considerable experience of this form of treatment exists already not only in America, Scandinavia, and other parts of Europe, but also in various centres in the United Kingdom, and it should now be possible to define basic tests, which could be carried out in most routine pathology laboratories. The need for adequate laboratory supervision is as great as in treatment with anticoagulants. the necessary
momentum
Summary
.
In laboratory animals a four-hour infusion of streptokinase lysed 60-70% of an artificially induced pulmonary embolus identical histologically with that in man. In 4 patients treated with streptokinase there was striking clinical improvement in all, previous anticoagulation having failed to improve 2 of them. Streptokinase is recommended as the treatment of choice in all cases, except the moribund, in whom heparin should first be tried. We are very grateful to Dr. C. J. Gavey, Mr. E. Stanley Lee, Dr. R. D. Tonkin, and Prof. H. Ellis for permission to discuss their cases; to Miss B. Littlehales and Mrs. C. Dowsett for technical help; to Miss J. Brayley for secretarial assistance; and to the department of photography and illustration, Westminster Medical School, for the
illustrations. We should also like to thank Kabi Pharmaceuticals Ltd., London, for generous supplies of the streptokinase (’ Kabikinase ’) used in the animal experiments and fibrinolytic therapy of the patients and also for their product ’Epsikapron ’ (e-amino-caproic acid).
J. M.
H. L. UTIAN M.B. W’srand, M.R.C.P.E., D.C.H.
M.B.
WAGNER
M.B. W’srand, M.R.C.P.
R. J. S. SICHEL Cape Town, M.C.Path., D.C.H., D.C.P.
From the Transvaal Memorial Hospital for Johannesburg, South Africa
Children,
SINCE 1955 we have encountered a very striking and characteristic syndrome which usually affects infants and consists of: (1) hypoglycaemia of sudden onset with consequent coma and convulsions and death in most cases; (2) metabolic acidosis (often accompanied by uraemia and hypematrxmia); and (3) extensive fatty change in the liver. No cause has been found for the disease, but in most patients the illness began with an upper-respiratory-tract infection; hence we believe that infection may play a part in its origin. We have never obtained a history of poisoning, and all the patients have been well-cared-for, well-nourished white children; mal-
nutrition, therefore,
seems a most
unlikely contributing
All the children were quite well before the onset of the disease and showed no signs of pre-existing metabolic or endocrine disorders. 14 children with this disease were seen at this hospital, which serves a white population. 13 were aged between four and fifteen months, and 1 was thirteen years old. 8 were male and 6 female; 11 died, and necropsies were performed on all of these. 2 of the 3 children who survived have been followed up-1 for five years; both show evidence of diffuse organic cerebral injury, and 1 is severely retarded mentally. We describe here three cause.
representative cases Case-records Case 1 A five-month-old male infant had been ill for six days with a respiratory-tract infection. On the night before admission he had lost consciousness. He was well nourished, unconscious, and apyrexial, and had deep noisy respiration. The liver was 2 cm. enlarged. Blood-sugar was 16 mg. per 100 ml. the cerebrospinal fluid C.S.F.) was normal, except for a sugar content of 27 mg. per 100 ml., blood-urea 50 mg. per 100 ml., serumsodium 140 mEq. per litre, serum-potassium 5-4 mEq. per litre, serum-chloride 105 mEq. per litre, and CO2 content 15 mEq. per litre. Liver biopsy revealed extensive fatty change with very scanty glycogen. Blood-count showed 16,200 white cells per c.mm. with a neutrophilia. Despite vigorous therapy with intravenous sugar and electrolyte, insulin, glucagon, adrenaline, steroids and antibiotics, recurrent massive spasmodic convulsions supervened and the infant died some thirty hours after admission. Necropsy revealed a grossly fatty liver and partial collapse of the right lung, confirmed on microscopy. No virus was grown from any of the organs cultured. Case 2 A seven-month old female infant had been
vomiting for
two
MR. BROWSE, DR. JAMES: REFERENCES Allison, P. R., Dunnill, M. S., Marshall, R. (1960) Thorax, 15, 273. Biggs, R., Macfarlane, R. G. (1962) Human Blood Coagulation and
Disorders.
Its
Oxford.
D. C. O., Maclagan, N. F. (1959) Lancet, ii, 471. Cahill, J. M., Byrne, J. J., White, R. L. (1963) Surg. Obstet. Gynec. 116, 486. Cliffton, E. E. (1960) Amer.J. Cardiol. 6, 476 Hume, M. (1961) New Engl.J. Med. 264, 471. Maclagan, N. F., Billimoria, J. D., Curtis, C. (1958) Lancet, ii, 865. Moser, K. M. (1959) Angiology, 10, 319. Parfentjev, I. A., Johnston, M. L., Cliffton, E. E. (1953) Arch. Biochem. 46, 470. Sabiston, D. C., Marshall, R., Dunnill, M. S., Allison, P. R. (1962) Surgery, 52, 9. Sevitt, S. (1962) Amer. J. Med. 33, 703. Sheffer, A. L., Israel, H. L. (1959) Angiology, 10, 292. Lisker, S., Nemir, P. (1961) ibid. 12, 165.
Billimoria, J. D., Drysdale, J., James,
—
weight-bearing exercises; but weight-bearing on the affected limb was normally prohibited until union was found radiographically. In order to avoid excessive periods in hospital, many of these patients were discharged home in weight-relieving callipers, which were normally discarded about 3 months after operation. Often this was not a popular method with the patients, but it was introduced to speed bed turnover; and very careful steps were taken to ensure that the callipers transferred the body-weight, as intended, to the tuber ischii. More recently we have allowed early weight-bearing in cases of transcervical fractures where satisfactory reduction of the fracture and its adequate fixation was achieved by SmithPetersen nailing. This has not apparently affected the results adversely; but it is probably not safe for subcapital fractures, and it would certainly not be expected to improve on the results achieved by delaying weightbearing until union is established. ANTICOAGULANT THERAPY
In late 1960
instituted prophylactic anticoagulant therapy, as recommended by Sevitt and Gallagher (1959), routinely in all patients over the age of 60 with these injuries, unless it was contraindicated by the patient’s history or condition. This has resulted in a very impressive fall in mortality from pulmonary embolism and in morbidity due to thromboembolism (Fagan 1964). This treatment has undoubtedly contributed to the maintenance of a low rate of postoperative mortality and morbidity in our Austin Moore series. Without pro,phylactic anticoagulant therapy, thromboembolic complications might have occurred in considerably more of these cases than of the Smith-Petersen nail series, because of the far longer period of bed rest imposed on the Austin Moore cases. we
Discussion
Moore inserted the first vitallium prosthesis in 1940, to replace the upper end of a femur that was the seat of a questionably malignant tumour; the operation was successful and the patient lived for about 2 years with 75% function of the hip and died of a heart-attack (Moore 1957). Moore maintained that for fractures of the neck of the femur perfect reduction, perfect fixation, and perfect postoperative protection must be ensured until union had occurred. He predicted poorer end-results with poor technique and said that " partially reduced fractures may unite, but there will be more or less aseptic necrosis of the femoral head ". Viability of the femoral head after fractures of the neck of the femur has been assessed by several methods including radioactive tracer techniques, arteriography, venography, needle aspiration biopsy of the femoral head (Price 1962), but Barnes (1962) suggested that " the prospects of finding a reliable method of determining the viability of the femoral head are poor ". He felt that " diagnosis of ischasmia of the capital fragment at an early stage would be invaluable in the study of non-union and segmental necrosis. But until we can be sure that it is impossible to achieve a satisfactory result when the capital fragment is ischaemic, we should hesitate to perform a primary replacement arthroplasty unless this is indicated for other reasons." Studies on the vascular supply of the femoral head have shown, however, that the lateral epiphyseal vessels supply the outer two-thirds of the head, and these are completely severed when the neck is displaced proximally; the inferior metaphyseal vessels are torn in all displaced fractures by lateral rotation of the distal fragment; and,
if the fracture is fairly accurately reduced but the nail traverses the upper and posterior quadrant of the neck, the vascular supply is very likely to be endangered (Trueta and Harrison 1953, Brodetti 1960, Claffey 1960). Prosthetic replacement takes no longer and involves little more bleeding than Smith-Petersen nailing; and the total duration of anxsthesia is usually much shorter. Moreover a radiographer need not attend at the operation, and repeated radiographs are not necessary. Conclusions A plea is here made for immediate primary replacement arthroplasty in displaced subcapital fractures of the femur. We believe that in these cases results of fixation with Smith-Petersen nails are poor. Prosthetic replacement is technically not difficult, involves little blood-loss, and normally takes not more than 45 minutes. In our hands there have been no unforeseen complications. The average postoperative stay in hospital has been 4 weeks only. Fit patients were easily rehabilitated. Nevertheless, in our view transcervical fractures are still best treated by even
Smith-Petersen nailing. We recommend routine administration of anticoagulants prophylactically to reduce postoperative mortality and morbidity from thromboembolic episodes. Among our own patients with a 5-year follow-up, there has been no suggestion of late complications. We agree with Moore
(1957)
that
"
when fractures of the femoral neck can be treated with satisresults by a method which preserves the natural head of the femur there is no reason for insertion of a prosthesis. When a better result can be obtained with artificial replacement of the head there is every justification for the use of a prosthesis." The Lancet, in a leading article (1964), has rightly remarked: "... the operation [prosthetic replacement] is a desirable alternative to reduction and fixation if it permits early movement and ambulation ... "
factory
It is a pleasure to thank Sister Marangou for nursing the majority of these patients and for statistical help; and many members of the orthopaedic staff for valuable assistance. REFERENCES
Addison, J. (1959) Proc. R. Soc. Med. 52, 908. Barnes, R. (1962) J. Bone Jt Surg. 44B, 760 Brodetti, A. (1960) ibid. 42B, 794. Claffey, T. J. (1960) ibid. p. 802. Fagan, D. G. (1964) Lancet, i, 846. Lancet (1964) i, 1261. Moore, A. T. (1957) J. Bone Jt Surg. 39A, 811. Price, E. R. (1962) ibid. 44B, 854. Sevitt, S., Gallagher, N. G. (1959) Lancet, ii, 981. Trueta, J., Harrison, M. H. M. (1953) J. Bone Jt Surg. 35B,
442.
STREPTOKINASE AND PULMONARY EMBOLISM N. L. BROWSE M.D. Brist., F.R.C.S. LECTURER IN SURGERY
D. C. O. JAMES M.D., B.Sc. Lond., B.Pharm. Wales BLOOD-TRANSFUSION OFFICER
Surgical Professorial Unit, and Blood-Transfusion Department, Westminster Hospital, London, S.W.1
From the
THE prevalence of deep-vein thrombosis or pulmonary embolism associated with surgery and protracted confinement to bed has not diminished in the past thirty years (Sevitt 1962). Since we do not understand how these conditions are caused, we can only prevent them by means of routine anticoagulant therapy. This is costly, often impracticable, and by no means always successful. In the established case the drug of choice is heparin, not only for its anticoagulant effect but also because it can be
1040 virtue of some ill-understood (possibly vasodilator or anti-serotinin) action. The discovery of methods of lysing blood-clots in vivo raised hopes of an effective way of treating thromboembolic disorders. Though there are many published reports of the use of these substances in peripheral venous and arterial thromboembolic disease, there are few reports of their use in pulmonary embolism. The experimental work of Hume (1961) and Cahill et al. (1963) did not simulate the conditions in man, for both groups used emboli made of fresh blood-clot and the method of assessing lysis was open to many errors. Clinical studies (Moser 1959, Sheffer and Israel 1959, Cliffton 1960, Sheffer et al. 1961) are also difficult to interpret because none of them provide objective data of the efficacy of the drugs used. We have investigated the effect of streptokinase (SK) on artificial pulmonary emboli in dogs and used it in four
life-saving by
Fig. 2-Thrombus
Experiment1 The emboli consisted of a mixture of 4-5 ml. fresh blood, 0-5 ml. thromboplastin, 0-5 ml. calcium gluconate, and 0-5 g. ’ Diodrast ’ (Allison et al. 1960). These substances, mixed together in a glass tube, produced a jelly-like clot 15 cm. long and 0-3 cm. in diameter, which was introduced into the right common iliac vein. In most cases it became fragmented and produced multiple emboli. Method of assessment.-Since the emboli were radio-opaque owing to the diodrast, their fate was followed by serial radiographs taken 1, 2, 3, 4, and 24 hours after embolisation. The changes in the size and density of the emboli were assessed. Treatment.-Emboli were inserted in 8 dogs. A four-hour intravenous infusion of 500 ml. physiological saline solution was given, during which the dogs were kept anaesthetised, and X-rays and blood-samples were taken hourly. At twenty-four hours further chest X-rays and blood-samples were obtained. The animals were then killed. These formed the control group. The same procedure was carried out in another 8 dogs with 2 megaunits of SK added to the infusion of 500 ml. physiological saline solution. These formed the test group. Blood changes.-There were no changes in the S.C.T., simplastin-time, whole-blood clotting-time, plasma-fibrinogen, and 50% lysis-time in the blood of the control group. The extent of the relevant mean changes in the blood of the test group (8 dogs) is shown in fig. 1. The infusion of SK lengthened simplastintime, the Lee and White clotting-time, and the S.C.T., which pointed to the presence of a major coagulation defect. Plasmafibrinogen was also significantly reduced (from 306 mg. per 100 ml. to 199 mg. per 100 ml.), whereas the magnitude of the fibrinolytic activity is clearly shown by the striking reduction of the 50% lysis-time. Before the infusion, diluted blood clotted with thrombin did not lyse spontaneously under six hours; two hours after the SK infusion was begun lysis occurred within three hours and thirty-six minutes, and at four hours lysis took only an hour and a half. Blood lipsmia was reduced in both control and test groups, and must therefore have been associated with the surgical manipulations. Its significance is not clear. Results.-There was no change at two hours in the control group; no significant change. at four hours; but 75% of the emboli had disappeared after twenty-four hours. In the test group there was slight loss of density and some disintegration of most emboli at two hours, and 75% of the emboli had disappeared at four hours. The emboli had completely disappeared in 4 animals at twenty-four hours, but no further change had taken place in the others.
Materials and Laboratory Methods were taken by means of siliconed syringes and needles from 26 dogs weighing between 10 and 20 kg., and the blood was immediately cooled on ice. Except when blood was required for measuring fibrinolytic activity, e-aminocaproic acid was added to the anticoagulant solution to inhibit in-vitro- SK effect.
Blood-samples
Fig. l-Effect of streptokinase (compared with controls) on bloodcoagulation and other factors. 0 =Controls (no SK). X =Emboli formed in vitro. Experiment 1. 2 megaunits SK. Å. = Emboli formed in inferior vena cava. Experiment 2. 1 mega.
,
,
SK.
vena cava.
Fibrinolytic activity was measured according to the method of Billimoria et al. (1959). One-stage prothrombin-time, Lee and White clotting-time, and factor v assays were determined according to the method of.Biggs and Macfarlane (1962). A modified’ Stypven’ (Russel viper venom) clotting-time (s.c.T.) method was used (Maclagan et al. 1958). ’Simplastin ’-time was measured with 0-2 ml. of the reagent and 0-1 ml. of plasma. Lipsmia was measured in arbitrary turbidity units. Fibrinogen was estimated by means of an ammonium-sulphate precipitation technique (Parfentjev et al. 1953).
patients.
unit
removed from inferior
This experiment showed that SK accelerated the normal lysis of small multiple artificial pulmonary emboli (Allison et al. 1960) from twenty-four to four hours. But the method of assessment was crude and inaccurate, and the emboli were totally unlike emboli in man. With these objections in mind the following experiment was
performed. 2 The embolus.-To obtain emboli like those in the pulmonary
Experiment
1041 tree of patients who died on account of pulmonary emboli, thrombi were induced in vivo by the method of Sabiston et al. (1962). The abdominal vena cava was temporarily occluded and filled with 90% phenol for two minutes. It was then washed out, occluding clamps were removed, and the abdomen Seven to ten days later the abdomen was rewas closed. and thrombectomy was performed (fig. 2). Macroopened and microscopically the thrombi were exactly like the scopically of man. They were dabbed dry, weighed, emboli pulmonary and inserted into the vena cava with a special tube and plunger. None of these thrombi fragmented. Method of assessment.-The effect of the SK was assessed by weighing the embolus before insertion into the vena cava and twenty-four hours later, after it had been removed from the pulmonary artery at postmortem. Treatment.-In 5 dogs, a four-hour intravenous infusion of 500 ml. physiological saline solution was given, beginning immediately after embolisation. Serial blood-samples were taken. When the animals were killed twenty-four hours later, the embolus was removed from the pulmonary. artery and weighed. In another 5 dogs 1 megaunit of SK was added to the infusion of physiological saline solution. Blood-changes.-In the control group there were no significant changes in any of the blood-factors tested in the course of the experiment. The changes in the test group are shown in fig. 1. There was a distinct lengthening of the one-stage prothrombin, simplastin, and stypven clotting times. There was a slight lengthening of the Lee and White clotting-time, and some depression of both factor v and plasma-fibrinogen. The 50% fibrinolysis-time was very significantly reduced; hence blood which preoperatively did not lyse under six hours now lysed in two hours and forty-two minutes, two hours after the SK infusion was begun, and in forty-two minutes after four hours. Blood-samples taken at twenty-four hours showed a return to almost normal values. The effect on blood-coagulation factors was not so evident in this series because only 1 megaunit of SK was infused, as against 2 megaunits in the first experiment. Nevertheless, the reduction of the 50% fibrinolysis-time shows that this dose was adequate. Results.-Tableshows the change in weight of the five emboli of the control group. There was little change in either ,
TABLE I-WET WEIGHT OF PREFORMED PULMONARY EMBOLI BEFORE AND 24 HOURS AFTER EMBOLISATION
TABLE II-WET WEIGHT OF PERFORMED PULMONARY
EMBOLI, BEFORE AND 24 HOURS AFTER EMBOLISATION AND TREATMENT WITH STREPTOKINASE
THE FIRST PATIENT
A man, aged 56 years, under the care of Dr. C. J. Gavey, gave a two-year history of recurrent attacks of superficial and deepvein thrombosis of the right leg. He had been treated for nine months with long-term anticoagulants (phenindione), but these had been discontinued eighteen months before his
present admission. A month before admission the right leg became painful and more swollen, and the patient became breathless and had palpitations. Three days before admission the breathlessness began to increase until he collapsed and was admitted as an emergency. Both legs were swollen, the patient was very dyspnoeic, and he complained of severe central chest pain. On examination the jugular venous pressure was raised +5 cm.; the blood-pressure was 80/75 mm. Hg; there was bilateral ankle oedema, E.C.G. showed inversion of the T wave in leads VI, V2, and Vg. The clinical diagnosis was pulmonary embolism, and the patient was treated with heparin, oxygen, and vasopressors. The next day the hypotension had slightly improved but the remaining signs were unchanged. On the fourth day the patient’s condition deteriorated, despite the treatment with heparin, and there were signs of right ventricular strain on the E.C.G. and the jugular venous pressure was still raised. SK was given on the fifth, sixth, and seventh days in 3 eight-hour intravenous infusions of 2 megaunits each. Steroid cover was provided with prednisone (15 mg. daily) and 10,000 units of heparin was given intravenously between the infusions and for two days after treatment. In view of the patient’s long history of recurrent thrombosis, long-term anticoagulation with
phenindione was thought necessary. This patient and patient 2 were treated in 1961 when little guidance in SK therapy was available. Such large doses of SK are not now thought necessary, and, apart from the high initial dose (to counteract anti-SK antibody), a maintenance dose of about 70,000 units per hour seems to maintain a reasonably high level of fibrinolytic activity. Therapy was controlled by means of estimating the prothrombin-times (which in this patient remained at twenty-eight to thirty seconds during therapy), and fibrinogen-levels which averaged 100-150 mg. per 100 ml., although on occasion values of 50-60 mg. per 100 ml. were
(six-day) or old (ten-day) emboli. The mean loss of weight was 9-4%. In the test group (table n) there was considerable loss of weight, 23-86%. The mean weight loss was 62-6%, significantly different from the 9-4% of the control young
group.
This experiment -reproduced the conditions of pulmonary embolism in man. The emboli were old and partly organised, identical on microscopy with those found in man, and they remained whole and always impacted in the right or left branches of the pulmonary artery. The SK was given in a dose that produced changes in the blood similar to those sought in the treatment of human patients. We believe that this experiment proves conclusively that SK can lyse pulmonary emboli in man. Clinical Studies 4 patients with clinically proven pulmonary emboli have been treated with SK.
recorded.
The fifth day brought no improvement. On the sixth day the patient felt better, the blood-pressure returned to normal and the jugular venous pressure fell to zero. But the dyspnoea was worse, and the chest pain was unchanged. On the seventh day (last day of treatment) the dyspnoea began to improve. The next day there was no dyspnoea at rest and the chest pain was a little less. From this time on the patient recovered steadily. He has been kept on phenindione and is still well. THE SECOND PATIENT care of Dr. R. D. Tonkin, aged month before admission experienced a pleuritic pain in the lower left chest. It lasted a week and then almost disappeared. Three days before admission it became much more severe. On admission he was flushed but not dyspnoeic. Respiration-rate 25 per min., there was a pleural rub at the right base, and a chest X-ray revealed a confluent bronchopneumonia of the right middle and lower lobes. He was treated with antibiotics and physiotherapy, but nine days after admission he collapsed,
A
one
man
58 years, under the
1042 SK was infused over a thirty-hour period with steroid cover. The preliminary dose was calculated and therapy was controlled by estimations of the prothrombin-time, plasmafibrinogen, and thrombin-time as in the previous cases, but, in addition, various other tests including euglobulin lysis-time, plasminogen-levels, and fibrin plates were included. Of these further tests the euglobulin lysis-time probably gave the most useful information, and in this instance the patient’s normal euglobulin lysis-time of two and a half hours was reduced to fifteen to twenty minutes during therapy. The next day there was some clinical improvement, and the pleuritic pain and the dyspnoea were easier. There was further improvement in the next twenty-four hours, though crepitations and rhonchi appeared at the left base. Chest X-ray showed patchy shadows, some pleural reaction, and an enlarged pulmonary artery consistent with the diagnosis of pulmonary embolism. After three days of SK the patient was given heparin 10,000 units four-hourly. The next day he complained of a pain in the wound and inspection revealed a large haematoma. This was evacuated and a litre of blood was transfused. Twelve days after operation deep-vein thrombosis developed in the left calf (swelling.and tenderness) which was treated by means of raising the leg and bandaging. Eighteen days after operation the chest X-ray was normal.
unrecordable blood-pressure, severe dyspnoea, and cyanosis. He had no chest pain and no haemoptysis. It was noticed that his left leg had become swollen. Pulmonary embolism was diagnosed on clinical grounds, and he was given intravenous heparin. There was no improvement and he was taken to theatre with a view to embolectomy. By the time he arrived there was sufficient, though slight, improvement to contraindicate embolectomy and he was returned to the ward. There was no further improvement during the next few hours, and it was decided to give SK through a catheter passed from the antecubital fossa into the right atrium. 3 eight-hour infusions of 2 megaunits of SK were given on three consecutive days. Adequate evidence of fibrinolytic activity in the blood was obtained, and control of therapy was maintained as in the first patient. Prothrombin-time was usually twenty-two to twentyfour seconds during treatment and plasma-fibrinogen was reduced from an original level of 580 mg. per 100 ml. to 300-340 mg. per 100 ml. Although the thrombin clotting-times were apparently normal, the clots lysed spontaneously in twenty to thirty minutes, indicating effective fibrinolytic activity in the patient’s blood. During these three days the patient made a steady recovery. Chest X-rays after the acute episode confirmed the diagnosis. Unfortunately, he was not considered well enough for pulmonary angiography during the period when he had the indwelling right atrial catheter. He is now alive and well and has not had to consult his doctor for the past two years.
with
an
Discussion
There is no doubt that substances which activate the THE THIRD PATIENT normal fibrinolytic mechanisms can cause lysis of intraA man, aged 36 years, under the care of Mr. E. Stanley Lee, vascular thrombi. The most effective of these agents at was admitted for repair of bilateral recurrent inguinal hernia. present is streptokinase. In theory, pulmonary emboli He had had no deep-vein thrombosis or pulmonary emboli should be particularly susceptible to lysis; for they are soft after the previous operations, but the routine preoperative " red " thrombi in normal vessels through which blood chest X-ray showed some linear collapse of the right midzone. flows rapidly. Experimentally, in-vivo lysis of pulmonary The patient’s postoperative course was satisfactory until the twelfth day, when he suddenly became dyspnoeic, felt a pleuritic emboli has been detected by means of methods based on in the lower left and had a There small chest, pain haemoptysis. counting the radioactivity of labelled thrombi (Hume was no hypotension or evidence of a raised central venous 1961), on measurements of the pulmonary-artery pressure pressure. Chest X-ray showed linear collapse of the left base et al. 1963), on X-rays, and on weight changes of (Cahill consistent with the diagnosis of pulmonary embolism. It was the emboli themselves as already described. decided to treat the patient with SK. The clinical value of SK therapy is still unproven. The A preliminary blood-sample was taken to ascertain the anti4 cases reported here demonstrate that the drug is safe if streptokinase titre, baseline prothrombin-time, and plasmaused with care. Occasionally it causes hypotension, but it fibrinogen. Treatment consisted of a two-hour infusion of SK 750,000 units (as loading dose), followed by a further con- had no deleterious effect on the blood-pressure of patients tinuous infusion for twenty-eight hours at a concentration of 1 and 2, who were very ill. We give corticosteroids in the 70,000 units SK per hour. Further blood-samples were first twelve hours to subdue any pyrexial reaction, which obtained at 2, 4, 12, 24, and 30 hours. A 100 mg. dose of hydrois the most common complication. SK is safe when used cortisone was injected into the infusion at the beginning and within thirty-six hours of major non-vascular surgery. after twelve hours to minimise a possible pyrexial side reaction, A hsematoma developed in the wound of patient 4 when and the infusion was followed by heparin 10,000 units fourhe was put back on to heparin immediately after the SK hourly and phenindione. infusion. This problem does not arise if the heparin is Three hours after the infusion was begun the patient showed striking clinical improvement. The pain and dyspnoea sub- started two hours after stopping the SK. It is reassuring that bleeding due to excessive fibrisided, and he felt well. At the end of treatment he was symptomfree. An X-ray on the second day of treatment showed some nolytic activity can be controlled by an intravenous clearing of the left base, but one taken immediately after the injection of e-amino-caproic acid (’ Epsikapron ’), which cessation of treatment showed some collapse and consolidation specifically inhibits fibrinolytic activity in a few minutes. and a small pleural effusion. By the day of discharge (on the Adequate thrombolysis can be obtained with a loading twenty-first day) the chest X-ray was clear. dose twice the titrated initial dose (T.I.D.) and mainTHE FOURTH PATIENT tained with an infusion of 70,000 units of SK per hour A 48 under the care of Prof. H. man,
aged
Ellis,
years,
admitted for vagotomy and pyloroplasty and repair of incisional hernia. A previous laparotomy a year earlier had been uneventful. He was admitted for investigation, and was operated upon a week after being admitted. Three hours after the operation he complained of a severe pleuritic pain in the: lower left chest which was separate and different from the painl in his wound. His blood-pressure was 100/75 mm. Hg, and he: was extremely dyspnoeic. There was a pleural friction rub at the’ left base. A chest X-ray and E.C.G. were normal. Pulmonary embolism was diagnosed, but it was decided to wait twenty-four hours before beginning treatment. Thirty-six hours later the blood-pressure was still 100/75 mm. Hg, and the pleuritic pain1
was
:
was worse.
-
intravenously. The first 2 patients were given daily eight-hour infusions. This was because we were not sure that we could control the lytic effect and because it enabled us to perform frequent serial testing. We now test the blood one hour and two hours after treatment is begun, and then daily during a constant infusion of 70,000 units per hour. All patients showed a striking clinical improvement. It is impossible to say what caused this improvement. Similar results are seen with patients treated with heparin, or without any treatment at all, but two of our patients (1 and 2) were being treated with anticoagulants without
1043 success
before their therapy. Other workers have claimed
"WHITE LIVER " DISEASE
results, but there is still no report which presents angiographic proof of thrombolysis in human cases. Our 4 patients are alive and well, and patient 2 who had similar
had recurrent emboli before treatment has had none since. We would evaluate SK in the treatment of pulmonary embolism thus: 1. The extremely ill, near to death patient should be treated initially with heparin, since there is ample evidence that this drug is sometimes lifesaving by virtue of some action separate from its anticoagulant effect. 2. All other patients, and those who do not respond after six to twelve hours of heparin, should be treated with SK; for it is logical to attempt to lyse the clot as soon as possible in order to relieve the strain on the heart and to reduce the likelihood of long-lasting pulmonary hypertension. After treatment with SK the patient should receive anticoagulants until the risk of further thrombosis has passed. 3. The contraindications that apply to anticoagulants also apply to SK. In particular, SK should not be given to patients with the following disorders : haemorrhagic diathesis, hypofibrinogenxmia, peptic ulcer, or other potential bleeding sites. 4. The diagnosis of pulmonary embolism is often difficult and SK should be used only when there is strong evidence to support the diagnosis. The trend in the past two years has been to increase the number of tests thought necessary to control fibrinolytic therapy. Although these increase the safety for the patient and our understanding of the drug, they naturally make it more difficult for smaller hospitals to embark on fibrinolytic therapy as an alternative to routine
anticoagulation. We believe that,
before this promising therapy can gain in smaller hospitals, a determined attempt must be made by some competent authority to define the minimum of tests compatible with the safety of the patient and adequate control of SK therapy. Considerable experience of this form of treatment exists already not only in America, Scandinavia, and other parts of Europe, but also in various centres in the United Kingdom, and it should now be possible to define basic tests, which could be carried out in most routine pathology laboratories. The need for adequate laboratory supervision is as great as in treatment with anticoagulants. the necessary
momentum
Summary
.
In laboratory animals a four-hour infusion of streptokinase lysed 60-70% of an artificially induced pulmonary embolus identical histologically with that in man. In 4 patients treated with streptokinase there was striking clinical improvement in all, previous anticoagulation having failed to improve 2 of them. Streptokinase is recommended as the treatment of choice in all cases, except the moribund, in whom heparin should first be tried. We are very grateful to Dr. C. J. Gavey, Mr. E. Stanley Lee, Dr. R. D. Tonkin, and Prof. H. Ellis for permission to discuss their cases; to Miss B. Littlehales and Mrs. C. Dowsett for technical help; to Miss J. Brayley for secretarial assistance; and to the department of photography and illustration, Westminster Medical School, for the
illustrations. We should also like to thank Kabi Pharmaceuticals Ltd., London, for generous supplies of the streptokinase (’ Kabikinase ’) used in the animal experiments and fibrinolytic therapy of the patients and also for their product ’Epsikapron ’ (e-amino-caproic acid).
J. M.
H. L. UTIAN M.B. W’srand, M.R.C.P.E., D.C.H.
M.B.
WAGNER
M.B. W’srand, M.R.C.P.
R. J. S. SICHEL Cape Town, M.C.Path., D.C.H., D.C.P.
From the Transvaal Memorial Hospital for Johannesburg, South Africa
Children,
SINCE 1955 we have encountered a very striking and characteristic syndrome which usually affects infants and consists of: (1) hypoglycaemia of sudden onset with consequent coma and convulsions and death in most cases; (2) metabolic acidosis (often accompanied by uraemia and hypematrxmia); and (3) extensive fatty change in the liver. No cause has been found for the disease, but in most patients the illness began with an upper-respiratory-tract infection; hence we believe that infection may play a part in its origin. We have never obtained a history of poisoning, and all the patients have been well-cared-for, well-nourished white children; mal-
nutrition, therefore,
seems a most
unlikely contributing
All the children were quite well before the onset of the disease and showed no signs of pre-existing metabolic or endocrine disorders. 14 children with this disease were seen at this hospital, which serves a white population. 13 were aged between four and fifteen months, and 1 was thirteen years old. 8 were male and 6 female; 11 died, and necropsies were performed on all of these. 2 of the 3 children who survived have been followed up-1 for five years; both show evidence of diffuse organic cerebral injury, and 1 is severely retarded mentally. We describe here three cause.
representative cases Case-records Case 1 A five-month-old male infant had been ill for six days with a respiratory-tract infection. On the night before admission he had lost consciousness. He was well nourished, unconscious, and apyrexial, and had deep noisy respiration. The liver was 2 cm. enlarged. Blood-sugar was 16 mg. per 100 ml. the cerebrospinal fluid C.S.F.) was normal, except for a sugar content of 27 mg. per 100 ml., blood-urea 50 mg. per 100 ml., serumsodium 140 mEq. per litre, serum-potassium 5-4 mEq. per litre, serum-chloride 105 mEq. per litre, and CO2 content 15 mEq. per litre. Liver biopsy revealed extensive fatty change with very scanty glycogen. Blood-count showed 16,200 white cells per c.mm. with a neutrophilia. Despite vigorous therapy with intravenous sugar and electrolyte, insulin, glucagon, adrenaline, steroids and antibiotics, recurrent massive spasmodic convulsions supervened and the infant died some thirty hours after admission. Necropsy revealed a grossly fatty liver and partial collapse of the right lung, confirmed on microscopy. No virus was grown from any of the organs cultured. Case 2 A seven-month old female infant had been
vomiting for
two
MR. BROWSE, DR. JAMES: REFERENCES Allison, P. R., Dunnill, M. S., Marshall, R. (1960) Thorax, 15, 273. Biggs, R., Macfarlane, R. G. (1962) Human Blood Coagulation and
Disorders.
Its
Oxford.
D. C. O., Maclagan, N. F. (1959) Lancet, ii, 471. Cahill, J. M., Byrne, J. J., White, R. L. (1963) Surg. Obstet. Gynec. 116, 486. Cliffton, E. E. (1960) Amer.J. Cardiol. 6, 476 Hume, M. (1961) New Engl.J. Med. 264, 471. Maclagan, N. F., Billimoria, J. D., Curtis, C. (1958) Lancet, ii, 865. Moser, K. M. (1959) Angiology, 10, 319. Parfentjev, I. A., Johnston, M. L., Cliffton, E. E. (1953) Arch. Biochem. 46, 470. Sabiston, D. C., Marshall, R., Dunnill, M. S., Allison, P. R. (1962) Surgery, 52, 9. Sevitt, S. (1962) Amer. J. Med. 33, 703. Sheffer, A. L., Israel, H. L. (1959) Angiology, 10, 292. Lisker, S., Nemir, P. (1961) ibid. 12, 165.
Billimoria, J. D., Drysdale, J., James,
—