William D. Haire

Corticosteroids as adjunctive therapy for diffuse alveolar hemorrhage associated with bone marrow transplantation

BACKGROUND Diffuse alveolar hemorrhage is a frequent complication of treating malignancies with high-dose chemotherapy and bone marrow transplantation and is associated with very high mortality. This disorders association with pulmonary inflammation, its coincidence with marrow recovery, and the usefulness of corticosteroids for treating other pulmonary hemorrhage syndromes provided the rationale for this study. METHODS We retrospectively studied 65 episodes of diffuse alveolar hemorrhage that has occurred in 63 of 603 consecutively treated patients who had undergone high-dose chemotherapy with bone marrow transplantation. Patients were divided into three groups according to the therapy they had received for diffuse alveolar hemorrhage: supportive therapy alone (n = 12); low-dose corticosteroids (30 mg or less of methylprednisolone or its equivalent; n = 10); and high-dose corticosteroids (more than 30 mg methylprednisolone or its equivalent; n = 43). The primary outcome measures were overall survival and survival to hospital discharge, occurrence of respiratory failure requiring intubation, and development of infections subsequent to the diagnosis of diffuse alveolar hemorrhage. RESULTS Overall survival at the end of the follow-up period was significantly higher for the high-dose corticosteroid group compared with the supportive therapy group (P = 0.005); however, treatment with low-dose steroids did not increase survival over supportive therapy alone (P = 0.198). In addition, survival to discharge was significantly increased for the high-dose group compared with the other two groups combined (33% versus 9.1%, P = 0.038). Respiratory failure after the diagnosis of diffuse alveolar hemorrhage developed in only 12 of the 22 unintubated patients in the high-dose group compared with 9 of the 10 initially unintubated patients in the other two groups (P = 0.056). Although the incidence of infections was high (40%) subsequent to diffuse alveolar hemorrhage, neither high-dose nor low-dose corticosteroid treatment significantly increased the risk of infections (P > 0.4, all comparisons). CONCLUSIONS In this study, high-dose corticosteroid therapy for diffuse alveolar hemorrhage related to bone marrow transplantation was associated with improved total survival and survival to hospital discharge, and decreased development of respiratory failure in these patients. These results suggest the therapy is beneficial, and further prospective studies are warranted to verify the effectiveness of the treatment.

Hickman catheter-induced thoracic vein thrombosis. Frequency and long-term sequelae in patients receiving high-dose chemotherapy and marrow transplantation

One hundred sixty‐eight bone marrow transplant recipients and 49 patients who received high‐dose chemotherapy were evaluated for symptomatic thrombosis after Hickman catheter placement. The timing of thrombotic complications was different between these two groups, with the transplant group having a significantly lower thrombus‐free survival by 28 days after catheter placement. By 100 days after placement the thrombus‐free survival rates of the two groups were similar. The platelet count at time of catheter placement was significantly lower in the nontransplant group, and the thrombus‐free survival was longer in patients whose catheter was placed when their platelet count was less than 150,000, suggesting that thrombocytopenia delays thrombotic complications. Placement of two Hickman catheters resulted in a 12.9% thrombosis rate (21 of 162 patients) and was significantly more likely to be associated with thrombosis than placement of one catheter. Long‐term follow‐up evaluation of patients treated without successful fibrinolytic therapy showed no residual symptoms of venous obstruction. In those patients presenting with concomitant catheter obstruction resulting from thrombosis, low‐dose fibrinolytic therapy was successful in restoring catheter function 70% of the time. Placement of two Hickman catheters is associated with an inordinate incidence of thrombosis. Thrombocytopenia at the time of catheter placement may delay this complication. Thrombotic catheter obstruction can be treated successfully with low‐dose fibrinolytic therapy. Even without fibrinolytic therapy, catheter‐induced subclavian vein thrombosis rarely causes long‐term disability.

Are Clinical Signs Accurate Indicators of the Cause of Central Venous Catheter Occlusion

BACKGROUND Two hundred dysfunctional central venous catheters used for total parenteral nutrition and administration of cancer chemotherapy were radiographically examined in order to objectively identify thrombotic occlusions as the cause of catheter dysfunction. METHODS Outcomes of radiographic dye injections were compared with factors such as the inability to aspirate blood or to infuse fluids, catheter type, and duration of catheter placement. RESULTS Catheter type and duration of placement were not significant factors for predicting the type of dysfunction. Failure to withdraw blood was associated with 96% of the thrombosed catheters; this was also associated with 65% of the catheters with nonthrombotic dysfunctions. Once the cause of catheter occlusion was correctly identified, 90% of the catheters were restored to normal function. CONCLUSIONS Inability to withdraw blood from a catheter does not necessarily mean it is occluded by thrombus. Mechanical complications account for a significant portion of dysfunctional catheters.

Prothrombotic abnormalities in inflammatory bowel disease

Inflammatory bowel disease (IBD) is known to be associated with a thrombotic tendency, which is often attributed to thrombocytosis, elevated fibrinogen, or decreased antithrombin III. We prospectively studied eight patients with IBD, seven of whom had little or no disease activity, to determine if they had any laboratory abnormality known to be associated with an increased risk of thrombosis. Abnormalities in fibrinolysis were noted in five patients: four with high plasminogen activator inhibitor levels and one with poor release of tissue plasminogen activator following venous occlusion. Circulating immune complexes were present in the sera of five patients. Fibrinogen was mildly elevated in one patient, and two patients had mild thrombocytosis. Decreased levels of antithrombin III, protein C, or protein S were not observed. There appears to be a high incidence of abnormalities in fibrinolysis in inactive IBD, which may contribute to the high frequency of thrombosis seen in IBD. The presence of circulating immune complexes may contribute to vascular injury and thrombosis.

Utility of duplex ultrasound in the diagnosis of asymptomatic catheter-induced subclavian vein thrombosis.

Asymptomatic thrombosis of the subclavian vein is common after placement of indwelling catheters. The sequelae of these thrombi are not known. Investigation is hampered by the requirement for venography for diagnosis; consequently, a noninvasive method of diagnosis would be welcome in this context. We have studied prospectively 32 subclavian catheters to determine the usefulness of duplex ultrasound in diagnosing asymptomatic thrombosis. Sixteen arm venograms were normal and all gave normal duplex scans. No false‐positive scans were obtained. Eleven venograms demonstrated nonocclusive mural thrombi. Only three of these were seen with duplex ultrasound. Five totally occlusive thrombi were seen on venography, of which only two were detected with duplex sonography. The three thrombi not found with duplex ultrasound were short proximal venous occlusions. The insensitivity of this technique to asymptomatic subclavian thrombi limits its usefulness as a screening tool.

Obstructed central venous catheters: Restoring function with a 12‐hour infusion of low‐dose urokinase

Thrombotic obstruction frequently prohibits infusion through or withdrawal of blood from central venous catheters and can occur in conjunction with symptomatic thrombosis of the subclavian vein. Thirty catheters were radiographically proved to be obstructed by thrombus and had not responded to at least one instillation of 5000 units of urokinase. All catheters were treated with a 12‐hour infusion of urokinase at the rate of 40,000 units/hour. the obstructing thrombus was either eliminated or reduced in size in all instances and full function was restored in all but one catheter. No bleeding complications were seen. Six patients with obstructed catheters also had symptoms of subclavian vein thrombosis. All patients with symptoms of subclavian vein obstruction became asymptomatic on anticoagulant therapy even though no attempt at dissolving the thrombus obstructing the subclavian vein was made. A 12‐hour infusion of low doses of urokinase can safely salvage function of obstructed catheters that otherwise may require replacement. Patients with concomitant subclavian vein thrombosis become asymptomatic on anticoagulant therapy without need to dissolve the obstructing thrombus.

Thrombosed Central Venous Catheters: Restoring Function With 6-Hour Urokinase Infusion After Failure of Bolus Urokinase

Nineteen central venous catheters with radiographically proven thrombotic occlusion failed to have function restored with a mean of 1.6 5000-unit boluses of urokinase per catheter. Catheters then underwent a 6-hour infusion of urokinase at 40,000 units per hour followed by repeat contrast injection and evaluation of function. Reduction in thrombus size occurred in all but one patient. Catheter function was restored in 15 patients. In two patients, thrombus dissolved but catheters remained occluded because of tip malposition. In the remaining two patients, catheter function was restored with an additional 6-hour infusion. No adverse reactions to the infusion were seen. After infusion catheters continued to function normally for a mean of 36.2 days. Five catheters rethrombosed, two of which responded to urokinase bolus instillation. Thrombosed catheters failing standard intracatheter bolus urokinase are generally salvaged with a 6-hour infusion of low-dose urokinase.

Normal saline versus heparin flush for maintaining central venous catheter patency during apheresis collection of peripheral blood stem cells (PBSC)

Thrombotic occlusion is frequently a complication of central venous catheters (CVCs). The original designers and producers of CVCs recommended heparin flush regimens to prevent thrombosis and maintain patency. This has become standard practice although no studies have demonstrated a relationship between heparin flushing and reduction of catheter thrombosis. Many consider the routine use of heparin flushing innocuous. However, serious complications including drug interactions and heparin induced thrombocytopenia and thrombosis syndrome (HITS) have been reported in association with heparin flushing. Numerous studies comparing heparin to saline flushing in peripheral devices suggest equal rates of thrombotic occlusions. The purpose of this study was to examine the incidence of thrombotic occlusions in CVCs using heparin compared to saline flushing. The study involved 78 cancer patients undergoing apheresis collection for peripheral blood stem cells; 29 received saline flushes and 49 received heparin (100 U/ml of saline) flushes. Study endpoints included slow apheresis flow rate (< 50 ml/min), urokinase use for thrombolysis, and radiographic evidence of catheter thrombosis. No significant differences were found for any endpoint between the two groups. These findings suggest saline may be as effective as heparin for maintaining patency of CVCs.

Recombinant urokinase for restoration of patency in occluded central venous access devices A double-blind, placebo-controlled trial

The interval occlusion of central venous access devices (CVADs) remains a significant clinical problem, often requiring re-intervention for catheter exchange or replacement. The purpose of this Phase 3, multi-center, double-blinded study was to test the hypothesis that instillation of recombinant urokinase (r-UK) 5000 IU/ml is superior to placebo in restoring total catheter patency to an unselected cohort of occluded CVADs. After obtaining informed consent, adult and pediatric patients with occluded, non-hemodialysis CVADs of any duration or type were randomized (2 : 1) to receive either r-UK 5000 IU/ml or placebo instilled into all occluded lumens of their catheter. Catheter function was assessed at 5, 15 and 30 min after the first instillation. If the catheter remained occluded after 30 min, a second dose was instilled with repeat assessments at 5, 15 and 30 min. The primary efficacy variable was the restoration of catheter function to all treated lumens (i.e., total catheter patency) after one or two instillations. Catheters that were not successfully recanalized after two instillations were allowed to receive up to two instillations of open-label r-UK administered in the same manner. The primary safety variable was the occurrence of hemorrhagic and non-hemorrhagic events within 72 hr after instillation. A total of 180 patients were enrolled at 43 sites in the United States and Canada. Most patients were adults, although 20% were </=18 years of age. CVAD types included totally implanted subcutaneous ports (45%), PICC lines (26%), non-tunneled percutaneous catheters (18%), and tunneled percutaneous catheters (10%). All CVADs were occluded by virtue of their inability to withdraw blood (withdrawal occlusion). Additionally, 32% of catheters were completely dysfunctional as blood could not be withdrawn and fluids could not be infused (total occlusion). Analysis of the results showed that r-UK was significantly better than placebo in restoring catheter function (54% versus 30%, p = 0.002). There were no major hemorrhagic events within 72 hr after up to four r-UK instillations, and the incidence of non-hemorrhagic events was similar among the r-UK and placebo groups. In conclusion, r-UK is superior to placebo in restoring total catheter patency to occluded CVADs. In patients with occluded CVADs, intra-catheter thrombolysis can restore patency and may obviate the need for catheter replacement.

Increased platelet transfusion requirement is associated with multiple organ dysfunctions in patients undergoing hematopoietic stem cell transplantation

Organ dysfunction following hematopoietic stem cell transplantation (HSCT) may be a manifestation of a systemic inflammatory response. We speculate that part of the platelet transfusion requirement in HSCT patients results from this systemic inflammatory response, and increased transfusion requirement would be associated with, or precede, organ dysfunction. We studied 199 adults undergoing autologous (n = 173) or allogeneic (n = 26) HSCT. Patients with CNS (P = 0.008) or pulmonary (P = 0.002) dysfunction, or with VOD (P = 0.05) received a higher mean number of platelet transfusions per week than patients who did not have these dysfunctions. Furthermore, a higher number of platelet transfusions during any 1 week period was significantly associated with development of pulmonary (P = 0.0002) or renal (P < 0.0001) dysfunction in the following week. this predictive value was strongest early in the hsct course, but remained significant over all 4 weeks. in multivariate analysis the number of platelet transfusions during the previous week was independently predictive for development of pulmonary dysfunction in week 2 (P = 0.01) and week 3 (P = 0.055). We believe that occurrence of increased platelet transfusion requirement prior to onset of dysfunction is consistent with the concept that an antecedent inflammatory response results in both platelet consumption and various organ dysfunctions. Increased platelet transfusion requirement may act as an early marker of subsequent organ dysfunction. Additionally, there may be a direct role of platelets in the development and progression of organ dysfunction in HSCT patients.