Darell E. Heiselman

Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial

Thrombolysis of acute pulmonary embolism can be accomplished more rapidly and safely with 100 mg of recombinant human tissue-type plasminogen activator (rt-PA) (Activase) than with a conventional dose of urokinase (Abbokinase) given as a 4,400-U/kg bolus dose, followed by 4,400 U/kg per h for 24 h. To determine the effects of a more concentrated urokinase dose administered over a shorter time course, this trial enrolled 90 patients with baseline perfusion lung scans and angiographically documented pulmonary embolism. They were randomized to receive either 100 mg/2 h of rt-PA or a novel dosing regimen of urokinase: 3 million U/2 h with the initial 1 million U given as a bolus injection over 10 min. Both drugs were delivered through a peripheral vein. To assess efficacy after initiation of therapy, repeat pulmonary angiograms at 2 h were performed in 87 patients and then graded in a blinded manner by a panel of six investigators. Of the 42 patients allocated to rt-PA therapy, 79% showed angiographic improvement at 2 h, compared with 67% of the 45 patients randomized to urokinase therapy (95% confidence interval for the difference in these proportions [rt-PA minus urokinase] is -6.6% to 30.4%; p = 0.11). The mean change in perfusion lung scans between baseline and 24 h was similar for both treatments. Three patients (two treated with rt-PA and one with urokinase) had an intracranial hemorrhage, which was fatal in one. The results indicate that a 2-h regimen of rt-PA and a new dosing regimen of urokinase exhibit similar efficacy and safety for treatment of acute pulmonary embolism.

The clinical evaluation committee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): role, methodology, and results.

ObjectiveIn the multinational PROWESS trial, drotrecogin alfa (activated) significantly reduced mortality rate in patients with severe sepsis compared with placebo. The use of large multiple-center trials can potentially complicate interpretation of results in severe sepsis populations because of variability in medical attitudes and practices and the frequency of confounding events such as protocol violations. The objective of this study was to perform a blinded, critical, integrated review of data from the 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial using a Clinical Evaluation Committee. DesignBlinded, critical, integrated review of data. SettingParticipating sites. PatientsThe 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial. InterventionsWe performed analyses of the optimal cohort, defined as patients who had full compliance with the protocol, had evidence of an infection, and received adequate anti-infective therapy. We also performed other analyses, including significant underlying disorders, life support measures, and causes of death. Measurements and Main ResultsThe optimal cohort of 81.4% of the intention-to-treat population [drotrecogin alfa (activated), n = 695; placebo, n = 680] had similar baseline severity of illness between the two groups, a similar pharmacodynamic effect, and a relative risk of death estimate consistent with that observed in the overall PROWESS trial (0.83, 95% confidence interval 0.69–0.99 vs. 0.806, 95% confidence interval 0.69–0.94). A beneficial effect of drotrecogin alfa (activated) similarly was observed in patients with significant underlying disorders (0.73, 95% confidence interval 0.57–0.93) who were more severely ill and had a higher percentage of patients forgoing life-sustaining therapy. In contrast with the original investigator determinations, a benefit associated with drotrecogin alfa (activated) treatment in urinary tract infection adjudicated by the Clinical Evaluation Committee was observed. ConclusionsThe survival benefit associated with drotrecogin alfa (activated) use was consistent with the results of the overall trial regardless of whether patients met criteria of the optimal cohort or had a significant underlying disorder.

Obesity Does Not Alter the Pharmacokinetics of Drotrecogin Alfa (Activated) in Severe Sepsis

BACKGROUND: Drotrecogin alfa (activated) [DrotAA] is approved for the reduction of mortality in adults with severe sepsis (sepsis with acute organ dysfunction) and high risk of death. Patients whose actual body weight was >135 kg were excluded from the Phase III PROWESS trial. OBJECTIVE: To compare exposure to DrotAA in patients with severe sepsis weighing >135 kg with those weighing ⩽135 kg in an open-label, Phase IV trial, and quantify the elimination half-life (t1/2) of DrotAA in these patients. METHODS: PROWESS inclusion/exclusion criteria were used, except that patients >135 kg were enrolled. Blood samples were collected for steady-state plasma concentration (Css) analysis of activated protein C once each day and for t1/2 analysis after infusion. Weight-normalized clearance (Clp) and t1/2 estimates for DrotAA were calculated and compared between weight groups. RESULTS: Patient weight range was 59–227 kg. There were 32 patients ⩽135 kg and 20 patients >135 kg enrolled. Median Clp was 0.45 L/h/kg (interquartile range [IQR] 0.37–0.54) for patients ⩽135 kg and 0.42 L/h/kg (IQR 0.33–0.54) for patients >135 kg (p = 0.692). Median estimates of Css were 51.9 ng/mL (IQR 43.4–62.0) and 56.5 ng/mL (IQR 44.9–71.1; p = 0.570). In patients ⩽135 kg, DrotAA had a median t1/2 of 16.7 minutes (IQR 13.9–20.0) compared with 16.0 minutes (IQR 12.9–19.8) in patients >135 kg (p = 0.767), for a composite median t1/2 of 16.3 minutes (IQR 14.2–18.8). CONCLUSIONS: There is no statistically significant difference in Css concentrations or t1/2 of DrotAA between patients weighing ⩽135 kg and >135 kg. DrotAA should be dosed by actual body weight.

Nasointestinal tube placement with a pH sensor feeding tube

Radiographic confirmation of enteral feeding tube placement is a common practice representing considerable expense and causing delay in the initiation of enteral nutrition therapy. We evaluated an enteral feeding tube with a pH sensor, which allows immediate verification of the location of the tube by assessment of the pH upon insertion. Insertion pHs were obtained for 24 intensive care unit patients requiring feeding tube placement. Placement was verified radiographically and compared with expected location on the basis of the pH profile. The radiograph and the insertion pH profile were in agreement in 87.5% (21 of 24) of the cases. Concomitant use of histamine blockers did not affect the ability of the pH sensor to detect placement accurately (Fishers Exact Test, p 5.71) Use of these pH measurements eliminates the need for radiographic documentation of placement, provides a savings for the patient, and may be beneficial in promoting enteral feedings in critically ill patients.

Management of patients with severe sepsis, treated by drotrecogin alfa (activated)

A number of management issues confront the clinician treating a critically ill patient with drotrecogin alfa (activated) (Xigris; Eli Lilly and Company, Indianapolis, IN), a compound documented to significantly reduce the risk of 28-day all-cause mortality in patients with severe sepsis. The management issues that will be discussed include differentiating drug effect from the hemostatic changes of sepsis, prevention and management of bleeding during drotrecogin alfa (activated) infusion, treatment considerations in the patient with thrombocytopenia or disseminated intravascular coagulation, thromboprophylaxis in drug-treated patients, and the use of drotrecogin alfa (activated) in patients requiring renal replacement therapy. Proper adherence to principles described in this article can facilitate patient management and reduce the risk of bleeding.

Electrode Displacement from a Multipurpose Swan‐Ganz Catheter

. A patient is described in whom a multipurpose pulmonary artery catheter had been placed. Upon removal of the catheter, it was noted that the electrodes had become detached from the lead. A new method is described for insertion and removal of the catheter which will prevent this complication.

Treatment of Urokinase-Related Anaphylactoid Reaction with Intravenous Famotidine

OBJECTIVE: We describe our experience with an anaphylactoid reaction to urokinase and the treatment used. We also discuss the use of histamine H1- and H2-blockers in combination for the treatment of allergic anaphylactoid reactions. DESIGN: Case report. SETTING: Hospital. PARTICIPANTS: Observation of a patient who had a pulmonary embolism. INTERVENTION: During the use of urokinase, in treatment of a pulmonary embolism, the patient developed an anaphylactoid reaction that did not respond to diphenhydramine or hydrocortisone. Famotidine was administered. RESULTS: Abatement of urticaria and normalization of vital signs were obtained soon after famotidine was given. Completion of thrombolysis took place. CONCLUSIONS: Further investigation of the use of H1- and H2-blocking agents in the presence of anaphylactoid reactions to thrombolytic agents should be performed. Consideration of intravenous famotidine for the treatment of anaphylactoid-type reactions to urokinase is suggested.

Hemodynamic Status during Famotidine Infusion

Histamine H2 antagonists, which reduce gastric acid secretion, are often used in the intensive care setting for the prophylaxis of stress ulcers. This double-blind, placebo-controlled study evaluated hemodynamic parameters in 11 stable, critically ill patients receiving famotidine. Repeated-measures ANOVA demonstrated that famotidine had no significant effect on baseline hemodynamic measurements and that there was no significant difference in hemodynamic values following the famotidine infusion as compared with NaCl 0.9% placebo (p>0.05).

Fatal intrapartum pulmonary embolus during tocolysis

Intrapartum pulmonary embolus, especially in association with hypercapnea, is an extremely dangerous situation requiring immediate detection and aggressive management. The predisposing factors of obesity and bed rest must be assessed, with strong consideration given to the use of prophylactic heparin.

Hemodynamic status during famotidine infusion

Histamine H2 antagonists, which reduce gastric acid secretion, are often used in the intensive care setting for the prophylaxis of stress ulcers. This double-blind, placebo-controlled study evaluated hemodynamic parameters in 11 stable, critically ill patients receiving famotidine. Repeated-measures ANOVA demonstrated that famotidine had no significant effect on baseline hemodynamic measurements and that there was no significant difference in hemodynamic values following the famotidine infusion as compared with NaCl 0.9% placebo (p greater than 0.05).