Mark J. Rumbak

Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock

Summary Background Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40–70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor α (TNF α MAb) in the treatment of septic shock. Methods In a randomised, multicentre, double-blind, placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7·5 mg/kg TNFα MAb (n=949) or placebo (0·25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days. Findings 382 (40·3%) of 948 patients who received TNFα MAb and 398 (42·8%) of 930 who received placebo had died at 28 days (95% CI −0·02 to 0·07, p=0·27). We found no association between therapy with TNFα MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNFα MAb therapy. Coagulopathy but not other organ or system failures, was significantly decreased in the TNFα MAb group compared with placebo (day 7, p Interpretation We did not find an improvement in survival after septic shock with TNFα MAb. Therapy not solely dependent on TNFα blockade may be required to improve survival.

Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical trial. TLC C-53 ARDS Study Group

OBJECTIVE To evaluate the safety and efficacy of an intravenous liposomal dispersion of prostaglandin E1 as TLC C-53 in the treatment of patients with acute respiratory distress syndrome (ARDS). DESIGN Randomized, prospective, multicenter, double-blind, placebo-controlled, phase III clinical trial. SETTING Forty-seven community and university-affiliated hospitals in the United States. PATIENTS A total of 350 patients with ARDS were enrolled in this clinical trial. INTERVENTION Patients were prospectively randomized in a 1:1 ratio to receive either liposomal prostaglandin E1 or placebo. The study drug was infused intravenously for 60 mins every 6 hrs for 7 days starting with a dosage of 0.15 microg/kg/hr. The dose was increased every 12 hrs until the maximal dose (3.6 microg/kg/hr) was attained or intolerance to further increases developed. Patients received standard aggressive medical/surgical care during the infusion period. OUTCOME MEASURES The primary outcome measure was the time it took to wean the patient from the ventilator. Secondary end points included time to improvement of the PaO2/FIO2 ratio (defined as first PaO2/FIO2 > 300 mm Hg), day 28 mortality, ventilator dependence at day 8, changes in PaO2/FIO2, incidence of and time to development/resolution of organ failure other than ARDS. RESULTS A total of 348 patients could be evaluated for efficacy. The distribution of variables at baseline describing gender, lung injury scores, Acute Physiology and Chronic Health Evaluation II scores, PaO2/FIO2, pulmonary compliance, and time from onset of ARDS or from institution of mechanical ventilation to the first dose of study drug was similar among patients in the liposomal prostaglandin E1 (n = 177) and the placebo (n = 171) treatment arms. There was no significant difference in the number of days to the discontinuation of ventilation in the liposomal prostaglandin E1 group compared with the placebo group (median number of days to off mechanical ventilation, 16.9 in patients receiving liposomal prostaglandin E1 and 19.6 in those administered placebo; p = .94). Similarly, mortality at day 28 was not significantly different in the two groups (day 28 mortality, 57 of 176 (32%) in the liposomal prostaglandin E1 group and 50 of 170 (29%) in patients receiving placebo; p = .55). In contrast, treatment with liposomal prostaglandin E1 was associated with a significantly shorter time to reach a PaO2/FIO2 ratio of >300 mm Hg (median number of days to reaching a PaO2/FIO2 ratio >300 mm Hg: 9.8 days in the liposomal prostaglandin E1 group and 13.7 days in patients receiving the placebo; p = .02). Among the subgroups examined, time to off mechanical ventilation was significantly reduced in patients who received at least 85% of a full dose (i.e., > 45.9 microg/kg) of liposomal prostaglandin E1 (median number of days to discontinuation of ventilation, 10.3 in the liposomal prostaglandin E1 group and 16.3 days in patients receiving placebo; p = .05). The overall incidence of serious adverse events was not significantly different in the liposomal prostaglandin E1 (40%) or placebo-treated (37%) groups. Drug-related adverse events of all kinds were reported in 69% of the patients receiving liposomal prostaglandin E1 compared with 33% of the placebo group, with hypotension and hypoxia (occurring in 52% and 24% of the liposomal prostaglandin E1-treated patients, respectively, and 17% and 5% of the placebo-treated patients, respectively) being noted most frequently. CONCLUSIONS In the intent-to-treat population of patients with ARDS, treatment with liposomal prostaglandin E1 accelerated improvement in indexes of oxygenation but did not decrease the duration of mechanical ventilation and did not improve day 28 survival.

Educational and long-term therapeutic intervention in the ED: Effect on outcomes in adult indigent minority asthmatics

Minorities have increased morbidity and mortality rates resulting from asthma. The segment of minorities that is socioeconomically depressed often uses the emergency department (ED) as their primary site of medical care. For these reasons, we provided major long-term therapeutic intervention as well as intensive education in the ED for indigent adult African American asthmatics. We intervened in the cases of 30 patients who were frequent visitors to the ED over the previous 2 years. The intervention consisted of 1 hour of education in the ED before discharge regarding the prevention of asthma, the importance of decreasing inflammation as a means of improving asthma control, self-monitoring with a peak flow meter, and a demonstration of correct inhalation technique with metered-dose inhalers and a spacer device. Further, the intervention included management consistent with recent NIH Guidelines, stressing inhaled corticosteroids. After the intervention in the ED, patients were scheduled for follow-up asthma clinic visits. Outcome measures were ED visits and hospitalizations for 1 year after the ED intervention. Using the same inclusion/exclusion criteria, a retrospective control group of 22 patients for the same time period was compared with the intervention group. Before our intervention, the mean number of ED visits per patient for the previous 2 years was 4.4 +/- 2.7, and after the intervention, 2.6 +/- 2.6 (P < .01). The control group did not show a difference in the number of ED visits (3.4 +/- 2.6 before and 3.5 +/- 2.7 after, P = .96). After the intervention, the mean number of hospitalizations decreased significantly in the study group (P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Significant Tracheal Obstruction Causing Failure to Wean in Patients Requiring Prolonged Mechanical Ventilation: A Forgotten Complication of Long-term Mechanical Ventilation

INTRODUCTION Modern low-pressure, high-volume cuffed tracheotomy tubes have been shown to decrease tracheal injury. However, injury still occurs in patients requiring prolonged mechanical ventilation and prevents weaning, delays decannulation, prolongs hospitalization, and may totally obstruct the airway. We describe 37 patients, including the first reported case of failure to wean due to tracheal obstruction. METHODS Over a 3-year period, from September 1994 to August 1997, the hospital records of 37 patients requiring prolonged mechanical ventilation (> 4 weeks) and found to have tracheal obstruction were reviewed retrospectively. They were a subgroup of 756 patients admitted to hospitals during the same period. The average endotracheal/tracheostomy cannulation time was 3 weeks/12 weeks (range 2 to 4 weeks/8 to 14 weeks). Average age was 76 years (range, 34 to 81). Underlying diseases included COPD, postcoronary artery bypass graft surgery, postpneumonectomy, severe pneumonia, acute lung injury, and ischemic heart disease. RESULTS All 37 patients who initially failed to wean had difficulty in breathing and developed intermittent high peak airway pressures either early or during the weaning process or just on being ventilated. The insertion of a longer tracheal tube bypassed the obstruction, reestablished the airway, decreased peak airway pressures, and allowed the patient to breathe more easily. The obstruction was confirmed on bronchoscopy. Treatment consisted of either placement of a longer tracheal tube (34 of 37 patients) or placement of a tracheal stent. All but two of the patients (5.4%) were able to be weaned within a week. The two patients who still failed to be weaned were subsequently diagnosed as having amyotrophic lateral sclerosis. CONCLUSION Tracheal obstruction in patients requiring prolonged mechanical ventilation prevented weaning. Reestablishment of the airway with a longer tracheal tube or tracheal stent allowed most of the patients to be weaned.

Significant reduction in methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia associated with the institution of a prevention protocol.

OBJECTIVE To determine whether the institution of a methicillin-resistant Staphylococcus aureus prevention protocol was associated with a decrease in methicillin-resistant S. aureus ventilator-associated pneumonia in long-term, acute care ventilator patients. DESIGN A retrospective chart review comparing the number of episodes of clinical pneumonia per patient ventilator day in the 12 months preceding and 24 months following the introduction of the protocol. SETTING University affiliated, long-term, acute care ventilator hospital. PATIENTS Long-term, acute care ventilated patients who presented with clinical pneumonia. INTERVENTIONS Addition of a methicillin-resistant S. aureus prevention protocol. In addition to universal precautions, the protocol consisted of mupirocin 2% ointment applied to the anterior nares, and whole body washing with chlorhexidine. All patients were given mupirocin and chlorhexidine twice weekly. Patients were cohorted in the same room if they were, or had been, infected or colonized with methicillin-resistant S. aureus in any anatomical location or at any time. This procedure replaced strict isolation of methicillin-resistant S. aureus-infected or colonized individuals. MEASUREMENTS AND MAIN RESULTS Clinical pneumonia was diagnosed when a patient developed fever, bronchorrhea, increased white blood cell count, methicillin-resistant S. aureus isolated from the tracheal aspirate, and new or increasing infiltrate on chest roentgenograph. During the 12 months preceding the protocol, there were 0.2% episodes of methicillin-resistant S. aureus ventilator-associated pneumonia per ventilated patient day compared with 0.026% in the 24 months after the protocol (p < .001). The relative and absolute risk reductions associated with the introduction of the protocol were 87% and 6, respectively. CONCLUSIONS The period following the institution of the protocol showed a significant reduction in episodes of clinical pneumonia compared with the 12-month period preceding the use of the protocol (p < .001). Thus, we conclude that the introduction of this protocol is associated with a significant decrease in methicillin-resistant S. aureus ventilator-associated pneumonia.

Clinical Investigations in Critical CareSignificant Tracheal Obstruction Causing Failure to Wean in Patients Requiring Prolonged Mechanical Ventilation: A Forgotten Complication of Long-term Mechanical Ventilation

INTRODUCTION Modern low-pressure, high-volume cuffed tracheotomy tubes have been shown to decrease tracheal injury. However, injury still occurs in patients requiring prolonged mechanical ventilation and prevents weaning, delays decannulation, prolongs hospitalization, and may totally obstruct the airway. We describe 37 patients, including the first reported case of failure to wean due to tracheal obstruction. METHODS Over a 3-year period, from September 1994 to August 1997, the hospital records of 37 patients requiring prolonged mechanical ventilation (> 4 weeks) and found to have tracheal obstruction were reviewed retrospectively. They were a subgroup of 756 patients admitted to hospitals during the same period. The average endotracheal/tracheostomy cannulation time was 3 weeks/12 weeks (range 2 to 4 weeks/8 to 14 weeks). Average age was 76 years (range, 34 to 81). Underlying diseases included COPD, postcoronary artery bypass graft surgery, postpneumonectomy, severe pneumonia, acute lung injury, and ischemic heart disease. RESULTS All 37 patients who initially failed to wean had difficulty in breathing and developed intermittent high peak airway pressures either early or during the weaning process or just on being ventilated. The insertion of a longer tracheal tube bypassed the obstruction, reestablished the airway, decreased peak airway pressures, and allowed the patient to breathe more easily. The obstruction was confirmed on bronchoscopy. Treatment consisted of either placement of a longer tracheal tube (34 of 37 patients) or placement of a tracheal stent. All but two of the patients (5.4%) were able to be weaned within a week. The two patients who still failed to be weaned were subsequently diagnosed as having amyotrophic lateral sclerosis. CONCLUSION Tracheal obstruction in patients requiring prolonged mechanical ventilation prevented weaning. Reestablishment of the airway with a longer tracheal tube or tracheal stent allowed most of the patients to be weaned.

Topical treatment of life threatening haemoptysis from aspergillomas.

BACKGROUND: The efficacy of topical treatment of 12 episodes of severe life threatening haemoptysis from a pulmonary aspergilloma in 11 patients is reviewed. METHODS: A retrospective review was performed on five white and six African-American patients of mean age 49 years. The underlying diseases were bronchiectasis, sarcoidosis, tuberculosis, or histoplasmosis. The patients were prospectively considered poor surgical risks because they had a forced expiratory volume in one second (FEV1) of < 50% predicted and an arterial oxygen tension (PaO2) of < 7.95 kPa breathing room air. As surgical intervention was not possible, local intracavitary instillation of sodium or potassium iodide was performed. Two patients were previously treated with amphotericin B. In one patient sodium iodide alone was used and in the remaining eight potassium iodide alone was instilled. The transcricothyroid approach was used in six patients and the percutaneous approach in five. RESULTS: Haemoptysis ceased within 72 hours in all patients after the instillation of sodium or potassium iodide. There was no morbidity or mortality, and side effects included slight irritation on instillation of the iodide solution and occasional cough which was easily controlled. All patients were alive at least one year later. CONCLUSION: Intracavitary treatment is a viable option in the poor risk patient with life threatening haemoptysis from an aspergilloma.

Tracheostomy tube occlusion protocol predicts significant tracheal obstruction to air flow in patients requiring prolonged mechanical ventilation

OBJECTIVE This study was undertaken to test the hypothesis that a tracheal tube occlusion protocol predicts clinically important obstruction to air flow in patients requiring prolonged mechanical ventilation, making routine bronchoscopy unnecessary. DESIGN A prospective evaluation of 75 patients who were clinically ready to be decannulated. All patients underwent the tracheal tube occlusion protocol followed by bronchoscopy. SETTING Three hospitals affiliated with a college of medicine. PATIENTS Over a 24-month period, 52 males and 23 females were enrolled in the study. Mean age was 55 yrs (range 25 to 85). Mean endotracheal/tracheostomy time was 2.4/8.9 wks (range 1 to 4/5 to 14). All patients were mechanically ventilated for at least 4 wks and were successfully weaned from the mechanical ventilator for at least 48 hrs. During spontaneous breathing, these data were observed: minute ventilation of < 10 L/min; resting respiratory rate of < 18 breaths/min; and arterial oxygen saturation of > 90% on 40% oxygen tracheal collar mask. The tracheal tube occlusion protocol consisted of deflating the cuff on the fenestrated tracheal tube and occluding the tube. INTERVENTIONS Patients who developed respiratory distress when the tracheal tube was occluded were deemed to have failed the protocol. At bronchoscopy, the patients were asked to cough and hyperventilate in an attempt to forcibly reduce the cross-sectional area of the trachea. A sustained, subjectively assessed decrease of > or = 50% of the effective cross-sectional area of the trachea was considered to be an indication for intervention. MEASUREMENTS AND MAIN RESULTS Sixty-three (84%) of 75 patients tolerated the tracheal tube occlusion protocol. Twelve (16%) of 75 patients developed signs of respiratory distress and showed decreased oxygen saturation values necessitating uncapping of the tracheal tube. All patients had some degree of tracheal injury. However, those patients who failed to tolerate the tracheal tube occlusion protocol had clinically important tracheal obstruction to air flow. CONCLUSION A tracheal tube occlusion protocol can predict clinically important obstruction to air flow after prolonged mechanical ventilation.

Insertion of intracranial pressure monitors in fulminant hepatic failure patients: early experience using recombinant factor VII.

BACKGROUNDCerebral edema contributes to the high morbidity and mortality of fulminant hepatic failure (FHF). OBJECTIVEWe report the results of our early experience with insertion of intraparenchymal intracranial pressure (ICP) monitors in these highly coagulopathic patients. METHODSEleven consecutive patients with FHF met the criteria for invasive ICP monitoring. Recombinant activated factor VII (rFVIIa) was administered at an average dose of 3 mg intravenous bolus (average, 36.7 μg/kg). We inserted the intraparenchymal ICP monitor within 15 minutes to 2 hours after rFVIIa administration, without waiting for the repeat coagulation results. Postprocedure computed tomographic scans of the brain were obtained in all patients. RESULTSNo hemorrhagic complications were detected on the immediate postprocedure computed tomographic scans. There were no thrombotic complications in this group of patients. CONCLUSIONIn this group of patients with FHF, placement of an ICP monitor without hemorrhagic or thrombotic complications was feasible after administration of rFVIIa. This is a report of our early experience, and caution is advised. Further collaborative randomized studies are needed to prove the efficacy, optimal dosing, and cost effectiveness of rFVIIa for the placement of ICP monitors in this group of patients.

Reducing Emergency Department Visits and Hospitalizations in African American and Hispanic Patients with Asthma: A 15-Year Review

Minority populations in the United States continue to experience a disproportionate share of emergency department (ED) visits and hospitalizations due to asthma. This review examines programs that have attempted to reduce these acute care visits in African American and Hispanic patients. We performed a PubMed search of the English literature for studies published from March 1990 to March 2005, aimed at reducing ED visits and hospitalizations in patients with asthma. Decreased acute care visits in African American and Hispanic patients with asthma have been demonstrated in several studies over the past 15 years, including collaboration by physicians, nurses, and clinical pharmacists in achieving this goal. These studies have shown that reduced acute care visits are associated with optimal drug therapy per national guidelines, concurrent with patient education, environmental control, and objective monitoring of this inflammatory airway disease. Early intensive patient education was a key feature of these successful programs. Written action plans, including early use of oral corticosteroids at home, and rapport with patients are other key components of programs that have resulted in a decrease in ED visits and hospitalizations.