SummaryWe report the results of a double-blind, randomised trial of venous thrombosis (VT) prevention in 117 patients having elective hip replacement where low dose heparin alone (5,000 IU sodium heparin given subcutaneously [sc] 8 hourly until the seventh postoperative day) was compared with low dose heparin plus dihydroergotamine (DHE; 0.5 mg, given 8 hourly by sc injection). The trial end point consisted of VT discovered through bilateral ascending venography done routinely on the seventh postoperative day. VT developed in 34% of patients given heparin/DHE (95% confidence interval = 22% – 47%) compared with 24% in those given low dose heparin alone (95% confidence interval = 14% – 37%; p = 0.34), difference = 10% (95% confidence interval = –7% to +26%). Corresponding figures for the incidence of proximal (above-knee) thrombosis were 17% and 14% (95% confidence intervals = 8% – 29% and 6% – 25% respectively). These results are discussed in the context of a detailed overview of published evidence concerning VT prevention with heparin/DHE after hip replacement and we conclude it is unlikely that heparin/DHE is markedly superior to low dose heparin alone in this clinical setting.

The oxygen tension for half saturation (P50) was determined for venous blood in thirteen patients with the adult respiratory distress syndrome undergoing intensive therapy. The mean value for P50 was found to be significantly lower than the value found in ten normal control subjects (22.9 mmHg and 26.7 mmHg respectively; t = 3.03, P < 0.01). The extent of reduction in P50 was not related to serum phosphate level nor was it a predictor of short-term outcome. It is unlikely that the slight left-shifted oxygen-haemoglobin dissociation curve contributes in a major way to an oxygen delivery deficiency and its cause is unexplained.

Dihydro-ergotaraine (DHE) appears to be synergistic with small doses of hepari when used to prevent VT after general surgery. However, doubt remains whether DHEhas this effect in patients with elective hip replacement (THR). We have therefore compared the results of VT prophylaxis using sub-cutaneous (sc) low-dose heparinalone or sc heparin plus sc DHE in a double-blind, randomised, study of 126 patientshaving elective THR, 98 at centre (1)and 28 at centre (2). All received 5000 iu sodium heparin, hourly for 7 days, starting 2 hours before surgery at centre (1), or immediately after surgery at centre (2). Patients alsoreceived a separate 0.5 ml (0.5 mg) DHEorplacebo injection each time they receivedheparin. Patients had bilateral ascendingvenography on the 7th postoperativeday, and venograms were read before the treatment code was broken. These results do not support the presence of synergism between heparin and DHE in this situation.

Although sophisticated intensive care units have become universal in major public hospitals in Australia, this complex and expensive form of patient care is usually not available in independent private hospitals. Such a unit was recently established in a large private hospital which had expanded its facilities to encourage major surgery and its admission policies to include complex specialist medical problems. The unit's organisation included an appropriate physical area, comprehensive equipment, skilled nursing staff, resident medical staff, accredited medical specialists, and a common set of policies and protocols. In its first 12 months, the unit had 301 admissions, 82% of whom were surgical. Unit mortality was 3.3% and hospital mortality 6%. Patients were similar in age and sex distribution to those admitted to an intensive care unit in a public hospital but their numbers, type of illness, duration of admission and mortality differed. Despite the feasibility of establishing a sophisticated intensive care unit in a private hospital, there were potential problems related to staffing (especially insufficient numbers of trained nurses), funding (especially inadequacy of hospital and medical insurance and unavailability of many drugs on the Government's Schedule of Pharmaceutical Benefits) and relations with medical staff outside the unit.

Bleeding is an important complication of heparin therapy. A number of low molecular weight heparin fractions produce less bleeding than standard heparin for an equivalent antithrombotic effect in experimental animals. Low molecular weight heparin fractions and fragments are produced by a number of different procedures but their relative effects on haemostasis and thrombosis have not been evaluated. We have compared the antithrombotic and haemorrhagic effects of two low molecular weight heparin fragments and of a heparinoid with porcine mucosa heparin and related these in vivo findings to the results of ex vivo tests of blood coagulation and in vitro tests of platelet function. Haemorrhage was assessed using a rabbit ear bleeding model. The antithrombotic effects were assessed by measuring inhibition of a tissue thromboplastin-induced jugular vein thrombus and by inhibition of fibrin and platelet accumulation in an arterial-venous shunt. The ex vivo anticoagulant effects were

The relative efficacy of sodium and calcium heparin in preventing venous thromboembolism and their relative side-effects were studied in 234 high-risk patients in a randomised, double-blind, placebo-controlled trial. The two heparin preparations were from the same batch and in the same concentration, and were given in a dose of 5000 U 12 hourly. Positive leg scans were found in 19% after placebo, 12% after sodium heparin and 8% after calcium heparin. Bruising at the injection site was more common after calcium heparin (66%) than after sodium heparin (53%) or placebo (38%). Pain at the injection site was also more common after calcium heparin (26%) than after sodium heparin (8%) or placebo (6%). Changes in the activated partial thromboplastin time were small and did not correlate with leg scan results or bruising. While there was a tendency for calcium heparin to be possibly more effective, it was followed by significantly more local haematoma and pain.

Herpes simplex virus (HSV) was found in the tracheobronchial secretions of 14 of 46 (30%) consecutive patients with the adult respiratory distress syndrome (ARDS). The HSV has not hitherto been associated with ARDS, and most previous reports of HSV in the lower respiratory tract have come from autopsy material. In the present study, the diagnosis during life was initially made by identification of the characteristic inclusion bodies of HSV in bronchial epithelial cells obtained from tracheobronchial aspiration. The presence of HSV in the lower respiratory tract was associated with the need for more prolonged respiratory support and an increased late mortality.

Relationships between 51Cr platelet survival and plasma concentrations of beta-thromboglobulin (betaTG) and platelet factor 4 (PF4) were analyzed in 91 studies of patients with coronary artery disease. betaTG was significantly correlated with platelet life-span, turnover, and the number of hits in the multiple hit model. PF4 was significantly correlated with life-span and turnover. The most significant relationship involving platelet-specific protein concentrations and life-span estimates was between betaTG and life-span estimated using the multiple hit model (r = -0.39, p less than 0.001). There was a high correlation between betaTG and PF4 (r = 0.62, p less than 0.001), and no improvement could be obtained by combining the measurements of the two proteins in any regression with life-span or turnover. The results indicate that the patients with the shortest platelet survival time in this group tended to have the highest plasma concentration of betaTG and PF4 and thus probably increased in vivo release of betaTG and PF4. They strengthen the claim that these platelet-specific proteins may be indicators of platelet involvement in disease.

In this study we have examined the influence of intravenous Escherichia coli endotoxin on the induction of endothelial injury and repair in the aorta and pulmonary artery of the dog, with special reference to areas of Evans blue dye uptake. The sequential changes were monitored by quantitation of the numbers of circulating endothelial cells in three vascular beds, by incorporation of [3H] thymidine by endothelial cell nuclei, and by light microscopy of silver nitrate-stained Häutchen preparations.

The response to a standard dose of heparin was studied in 20 patients with venous thromboembolism. The heparin regimen consisted of intravenous injection of 70 units per kg, followed after 90 minutes by a maintenance dose of 400 units per kg per 24 hours given by continuous infusion. Plasma heparin activity and the activated partial thromboplastin time (APTT) were measured at intervals to determine clearance of the initial injection and the response to maintenance dose. Large inter-individual variations were found in the anticoagulant effect and these were due in part to differences in heparin clearance and in part to differences in the APTT response to given amounts of heparin (heparin effect index). The heparin half-life was 63 +/- 15 minutes when plasma heparin activities were used for this calculation and 84 +/- 71.5 minutes when the APTT was used. These results are similar to values previously reported in normal volunteers. Four of the 20 patients had pulmonary embolism and in these heparin half-life was significantly shortened (P less than 0.005).

The mechanism and significance of elevated levels of serum fibrin degradation products (FDP) in pulmonary embolism were investigated experimentally. Dogs were embolized with autologous blood clot-incorporating canine 125I-fibrin and were infused with either saline, heparin, or streptokinase. Serial measurements were made of total FDP by hemagglutination inhibition assay and of radioactive FDP. After saline, the peak level of total FDP was 323 mug/ml, but radioactive FDP was only 8 mug/ml. After heparin, these values were 44 and 11 mug/ml, respectively, and after streptokinase, 415 and 20 mug/ml. The results suggest that under these experimental conditions the elevated levels of FDP in pulmonary embolism are derived mainly from lysis of fibrin deposited after embolization rather than from lysis of the original embolus. Heparin inhibits both fibrin deposition and elevation of FDP levels after embolism.

Treatment with the plasminogen activator streptokinase or urokinase has been shown to accelerate lysis of acute pulmonary emboli [23, 34, 39, 45, 46] and recent peripheral venous thrombi [5, 15, 16, 25, 37]. Although the clinical value of these effects has not been completely defined, it is likely that the rapid lysis of major pulmonary emboli benefits patients by relieving pulmonary artery hypertension in the acute phase of pulmonary embolism, particularly if there is limited cardiopulmonary reserve. Treatment may also reduce the degree of chronic residual pulmonary artery obstruction in patients who have a reduced ability to resolve pulmonary emboli. In addition, early complete lysis of deep leg vein thrombi has been shown to preserve function of venous valves [27, 35] and hence may prevent serious late postphlebitic disability. These probable consequences of fibrinolytic therapy have made it an attractive form of treatment in some patients with thromboembolic disease. The presently used dosage schedules for streptokinase and urokinase treatment were derived from the fundamental and applied investigations of Fletcher, Alkjaersig and Sherry [1, 9, 10] and the work of Verstraete and his associates [2, 47]. The use of these regimens has produced encouraging clinical results, but they have some possible disadvantages [24] and are not necessarily the most effective treatment schedules for producing thrombolysis. We have therefore evaluated another approach to achieving thrombolysis, the use of combinations of the anticoagulant drug, heparin, with various dosage schedules of the fibrinolytic agent, streptokinase.

At least 50% of patients who die of major pulmonary embolism have no clinical signs of venous thrombosis yet the vast majority of these have evidence of thrombosis at autopsy (Hume et al. 1970; Miller and Sutton 1970). It is likely that early detection and adequate anticoagulant t,reatment of these silent thrombi would greatly reduce the mortality from pulmonary embolism. A number of methods are available for the diagnosis of venous thrombosis. Some of these are of proven value, some are promising and some are still in an early stage of development.

Experimental pulmonary emboli can be difficult to identify with certainty and to quantitate with accuracy by currently available techniques. A new method is reported based on the incorporation of exactly known amounts of radioactive fibrinogen into blood clot before its embolization into the lungs of dogs. The emboli can then be identified by lung scanning and quantitated by counting the lungs. The new method has been found to correspond much more closely than pulmonary angiography to post-mortem observations.

Summary. When 125I‐fibrinogen scanning is used for the early detection of venous thrombosis, comparison with venography has shown a small percentage of abnormal scans associated with normal venograms. The mechanism of this discrepancy was investigated in an experimental model. Venous thrombosis was produced in 56 dogs using stasis and local thrombin. The data obtained from scanning and venography were validated by direct vein examination. 125I scanning agreed in 96% with venography when thrombus was present, but when thrombus lysed or embolized scans continued to read positive even though venograms were negative. Deliberate embolization of thrombi showed that these false positive scans continued for up to 48 hr owing to activity persisting in the vein wall. This was shown on histology to be related to fibrin deposition in the sub‐endothelial and adventitial layers with inflammatory changes.

Summary Hemorrhage from post-operative wounds in different organs and structures during thrombolytic therapy was investigated in relation to the time after surgical trauma and to the results of laboratory tests of coagulation and fibrinolysis. Streptokinase was given to rabbits at different times following the production of standardized wounds in different organs. Bleeding was frequent and severe when streptokinase was given between one and five days after surgery and was most marked from artery, followed in order by kidney, vein, liver, muscle, gut and skin. Bleeding appeared to be associated with the in vitro demonstration of an active systemic fibrinolytic state together with elevated levels of fibrin degradation products.