Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes. METHODS: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors' cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete. FINDINGS: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo. INTERPRETATION: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults. FUNDING: National Institutes of Health and the US Department of Veterans Affairs.

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness.

BACKGROUND: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .).

Ventilatory Management of the Noninjured Lung.

This article reviews aspects of mechanical ventilation in patients without lung injury, patients in the perioperative period, and those with neurologic injury or disease including spinal cord injury. Specific emphasis is placed on ventilator strategies, including timing and indications for tracheostomy. Lung protective ventilation, using low tidal volumes and modest levels of positive end-expiratory pressure, should be the default consideration in all patients requiring mechanical ventilatory support. The exception may be the patient with high cervical spinal cord injuries who requires mechanical ventilatory support. There is no consensus on the timing of tracheostomy in patients with neurologic diseases.

The impact of hospital-wide use of a tapered-cuff endotracheal tube on the incidence of ventilator-associated pneumonia.

BACKGROUND: Aspiration of colonized oropharyngeal secretions is a major factor in the pathogenesis of ventilator-associated pneumonia (VAP). A tapered-cuff endotracheal tube (ETT) has been demonstrated to reduce aspiration around the cuff. Whether these properties are efficacious in reducing VAP is not known. METHODS: This 2-period, investigator-initiated observational study was designed to assess the efficacy of a tapered-cuff ETT to reduce the VAP rate. All intubated, mechanically ventilated patients over the age of 18 were included. During the baseline period a standard, barrel-shaped-cuff ETT (Mallinckrodt Hi-Lo) was used. All ETTs throughout the hospital were then replaced with a tapered-cuff ETT (TaperGuard). The primary outcome variable was the incidence of VAP per 1,000 ventilator days. RESULTS: We included 2,849 subjects, encompassing 15,250 ventilator days. The mean ± SD monthly VAP rate was 3.29 ± 1.79/1,000 ventilator days in the standard-cuff group and 2.77 ± 2.00/1,000 ventilator days in the tapered-cuff group (P = .65). While adherence to the VAP prevention bundle was high throughout the study, bundle adherence was significantly higher during the standard-cuff period (96.5 ± 2.7%) than in the tapered-cuff period (90.3 ± 3.5%, P = .01). CONCLUSIONS: In the setting of a VAP rate very near the average of ICUs in the United States, and where there was high adherence to a VAP prevention bundle, the use of a tapered-cuff ETT was not associated with a reduction in the VAP rate.

Variability in central venous pressure measurements and the potential impact on fluid management.

In the intensive care unit (ICU) of our tertiary care university medical center, central venous pressure (CVP) measurements derived from bedside monitors differ considerably from measurements by trained intensivists using paper tracings. To quantify these differences, printed CVP tracings and concurrent respiratory waveforms were collected from 100 consecutive critically ill patients along with the corresponding monitor-displayed CVP. Four blinded intensivists interpreted the tracings. The mean difference between the intensivists and the monitor was -0.26 mmHg (95% confidence interval, +7.19 to -7.71 mmHg). Seventy-six percent of the paired measurements were within 2 mmHg, whereas 7% differed by more than 5 mmHg. To determine the potential clinical impact of these differences, we used the original Surviving Sepsis Campaign Guidelines for fluid administration based upon the measurement of CVP. For individual physicians, protocol-driven fluid management strategy would have differed in 19.2% to 25.3% of cases, dependent upon which measured value was chosen. Although protocol-driven strategies to direct fluid infusion therapy may improve outcomes, these interventions in a specific patient are dependent upon the method by which the CVP is measured.

Nosocomial pneumonia risk and stress ulcer prophylaxis: a comparison of pantoprazole vs ranitidine in cardiothoracic surgery patients.

BACKGROUND: Stress ulcer prophylaxis (SUP) using ranitidine, a histamine H2 receptor antagonist, has been associated with an increased risk of ventilator-associated pneumonia. The proton pump inhibitor (PPI) pantoprazole is also commonly used for SUP. PPI use has been linked to an increased risk of community-acquired pneumonia. The objective of this study was to determine whether SUP with pantoprazole increases pneumonia risk compared with ranitidine in critically ill patients. METHODS: The cardiothoracic surgery database at our institution was used to identify retrospectively all patients who had received SUP with pantoprazole or ranitidine, without crossover between agents. From January 1, 2004, to March 31, 2007, 887 patients were identified, with 53 patients excluded (pantoprazole, 30 patients; ranitidine, 23 patients). Our analysis compared the incidence of nosocomial pneumonia in 377 patients who received pantoprazole with 457 patients who received ranitidine. RESULTS: Nosocomial pneumonia developed in 35 of the 377 patients (9.3%) who received pantoprazole, compared with 7 of the 457 patients (1.5%) who received ranitidine (odds ratio [OR], 6.6; 95% confidence interval [CI], 2.9 to 14.9). Twenty-three covariates were used to estimate the probability of receiving pantoprazole as measured by propensity score (C-index, 0.77). Using this score, pantoprazole and ranitidine patients were stratified according to their probability of receiving pantoprazole. After propensity adjusted, multivariable logistic regression, pantoprazole treatment was found to be an independent risk factor for nosocomial pneumonia (OR, 2.7; 95% CI, 1.1 to 6.7; p = 0.034). CONCLUSION: The use of pantoprazole for SUP was associated with a higher risk of nosocomial pneumonia compared with ranitidine. This relationship warrants further study in a randomized controlled trial.

Regulation of arachidonate remodeling enzymes impacts eosinophil survival during allergic asthma.

Although the role of arachidonic acid (AA) metabolism to eicosanoids has been well established in allergy and asthma, recent studies in neoplastic cells have revealed that AA remodeling through phospholipids impacts cell survival. This study tests the hypothesis that regulation of AA/phospholipid-remodeling enzymes, cytosolic phospholipase A(2) alpha(cPLA(2)-alpha, gIValphaPLA(2)) and CoA-independent transacylase (CoA-IT), provides a mechanism for altered eosinophil survival during allergic asthma. In vitro incubation of human eosinophils (from donors without asthma) with IL-5 markedly increased cell survival, induced gIValphaPLA(2) phosphorylation, and increased both gIValphaPLA(2) and CoA-IT activity. Furthermore, treatment of eosinophils with nonselective (ET18-O-CH(3)) and selective (SK&F 98625) inhibitors of CoA-IT triggered apoptosis, measured by changes in morphology, membrane phosphatidylserine exposure, and caspase activation, completely reversing IL-5-induced eosinophil survival. To determine if similar activation occurs in vivo, human blood eosinophils were isolated from either normal individuals at baseline or from subjects with mild asthma, at both baseline and 24 hours after inhaled allergen challenge. Allergen challenge of subjects with allergic asthma induced a marked increase in cPLA(2) phosphorylation, augmented gIValphaPLA(2) activity, and increased CoA-IT activity. These findings indicate that both in vitro and in vivo challenge of eosinophils activated gIValphaPLA(2) and CoA-IT, which may play a key role in enhanced eosinophil survival.

Using local microbiologic data to develop institution-specific guidelines for the treatment of hospital-acquired pneumonia.

BACKGROUND: While current guidelines recommend consideration of local microbiologic data when selecting empiric treatment for hospital-acquired pneumonia (HAP), few specifics of how to do this have been offered. METHODS: We conducted a retrospective analysis of HAP pathogens in 111 consecutive patients who acquired HAP during July to December 2004 and had a corresponding positive culture finding for a bacterial pathogen. These data were used to develop institution-specific guidelines. RESULTS: The most common bacteria identified were Staphylococcus aureus, Acinetobacter baumannii, and Pseudomonas aeruginosa, which were associated with 38%, 25%, and 19% of pneumonias, respectively. Susceptibility of Gram-negative bacteria to piperacillin-tazobactam and cefepime was 80% and 81%, respectively. The isolation of organisms resistant to piperacillin-tazobactam or cefepime was significantly more frequent in patients who had been hospitalized > or = 10 days. Of Gram-negative isolates resistant to piperacillin-tazobactam or cefepime, ciprofloxacin was active against < 10%, while amikacin was active against > 80%. New treatment guidelines were developed that divided the American Thoracic Society/Infectious Diseases Society of America "late onset/risk of multidrug-resistant pathogens" group of patients into two subcategories: "early-late" pneumonias (< 10 days of hospitalization) and "late-late" pneumonias (> or = 10 days of hospitalization). Guideline-directed treatment regimens would be predicted to provide adequate initial therapy for > 90% of late-onset pneumonias at our institution. CONCLUSIONS: Current guidelines suggest adding either an aminoglycoside or a fluoroquinolone to beta-lactam therapy for empiric Gram-negative coverage. However, in our institution, adding ciprofloxacin would not appreciably enhance the likelihood of providing initial appropriate antibiotic coverage. This underscores the importance of employing a systematic analysis of local data when developing treatment guidelines.

Diagnosis and treatment of ventilator-associated pneumonia.

Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in the ICU. Patients who acquire VAP have higher mortality rates and longer ICU and hospital stays. Because there are other potential causes of fever, leukocytosis, and pulmonary infiltrates, clinical diagnostic criteria are overly sensitive in the diagnosis of VAP. Employing quantitative cultures of bronchopulmonary secretions in the diagnostic algorithm leads to less antibiotic use and probably to lower mortality. With respect to microbiologic diagnosis, it is not clear that the use of a particular sampling method (bronchoscopic or nonbronchoscopic), when quantitatively cultured, is associated with better outcomes. Delayed administration of adequate antibiotic therapy is linked to an increased mortality rate. Hence, the focus of initial antibiotic therapy should be to rapidly provide antibiotic coverage for all likely pathogens and to then narrow or focus the antibiotic spectrum based on the results of quantitative cultures. Eight days of antibiotic therapy appears equivalent to 15 days of therapy except when treating nonlactose-fermenting Gram-negative organisms. In this latter situation, longer treatment durations appear to reduce the risk of recrudescence after discontinuation of antibiotic therapy. A guideline-based approach using the local hospital or ICU antibiogram can increase the likelihood that adequate initial antibiotic therapy is used and reduce the overall use of antibiotics and the associated selection pressure for multidrug-resistant organisms.

Prospective comparison of bronchoalveolar lavage and quantitative deep tracheal aspirate in the diagnosis of ventilator associated pneumonia.

BACKGROUND: Ventilator associated pneumonia (VAP) is common in trauma patients, and accurate diagnosis of VAP may improve survival. With the risk of development of bacterial resistance, we also strive to minimize the use of unnecessary antibiotics. Recent studies suggest that quantitative deep endotracheal aspirate (QDEA) is adequate in VAP diagnosis. We currently use bronchoalveolar lavage (BAL) diagnosis. The purpose of this study was to examine the accuracy of QDEA as compared with BAL in diagnosing VAP in trauma patients. METHODS: We prospectively compared the results of BAL and QDEA in intubated patients suspected of having VAP during an 8-month period. Indication for BAL was pulmonary infiltrate, systemic inflammatory response syndrome, and C-reactive protein >17 mg/dL at > or =48 hours after admission. Study patients underwent QDEA immediately before BAL, and quantitative cultures were compared for both specimens. The techniques differ in that QDEA involves the direct culture of sputum suctioned from the distal trachea, whereas BAL involves lavage of the bronchoalveolar tree with sterile saline, which is then cultured. VAP was diagnosed on BAL if > or =10(5) cfu/mL was present on culture. The ability of QDEA to diagnose pneumonia was examined at cutoffs of > or =10(5) cfu/mL and > or =10(4) cfu/mL, as compared with BAL at > or =10(5). RESULTS: Sixty-one patients underwent BAL during this period, and 39 of these underwent both BAL and QDEA for the study. Of the 39 studied patients between March 16, 2002, and November 4, 2002, 20 (51%) were found to have VAP by BAL (> or =10(5) cfu/mL). Using this cutoff for QDEA, 18 of 20 (90%) would have been correctly diagnosed. Using > or =10 cfu/mL for QDEA, the rate of correct diagnosis would increase to 19 of 20 (95%). However, of the 19 who did not have pneumonia according to BAL, 6 (31%) would have been incorrectly diagnosed with VAP using the QDEA cutoff of > or =10(5) cfu/mL. A QDEA cutoff of > or =10 (4) cfu/mL would result in the even higher false-positive rate of 8 of 19 patients (42%). CONCLUSION: Whereas most patients with pneumonia by BAL would have been diagnosed by QDEA, use of QDEA in treatment decisions would have led to needless antibiotic administration in 31% of VAP-negative patients at a cutoff of > or =10(5) cfu/mL and 42% at > or =10(4) cfu/mL. The use of QDEA in VAP diagnosis is limited because of the rate of over-diagnosis. With the increasing problems associated with excess antibiotic use, we believe these results support the use of BAL over QDEA in the diagnosis of VAP in the ventilated trauma patient.

Impact of a soluble phospholipase A2 inhibitor on inhaled allergen challenge in subjects with asthma.

The possible roles of secretory phospholipases A2 (sPLA2) in asthma include the release of arachidonic acid from cellular membranes, generation of lysophospholipids, sPLA2-mediated activation of cPLA2 with increased leukotriene production, and surfactant degradation. LY333013 is a potent inhibitor of sPLA2. This study examined the impact of two doses of LY333013 vs. placebo on allergen-induced bronchoconstriction following inhaled allergen challenge in atopic asthmatics. Fifty subjects were randomly assigned to treatment, and 40 subjects completed the study. A double-blind, placebo-controlled, random order, crossover study design was used. LY333013 had no impact on the primary outcome variables of the areas under the FEV1 response curve early (0-3 hours) (AUC(early)) and late (3-8 hours) (AUC(Iate)) following inhaled allergen challenge. No significant drug-related adverse effects were observed. The response to inhaled allergen challenge was reproducible and confirms the utility of this technique as a model in which to screen compounds for further testing in asthmatic patients.

Surfactant phospholipid changes after antigen challenge: a role for phosphatidylglycerol in dysfunction.

In asthma, inflammation-mediated surfactant dysfunction contributes to increased airway resistance, but the mechanisms for dysfunction are not understood. To test mechanisms that alter surfactant function, atopic asthmatics underwent endobronchial antigen challenge and bronchoalveolar lavage (BAL). BAL fluids were sequentially separated into cells, surfactant, and supernatant, and multiple end points were analyzed. Each end point's unique relationship to surfactant dysfunction was determined. Our results demonstrate that minimum surface tension (gamma(min)) of surfactant after antigen challenge was significantly increased with a spectrum of responses that included dysfunction in 6 of 13 asthmatics. Antigen challenge significantly altered the partitioning of surfactant phospholipid measured as a decreased ratio of large surfactant aggregates (LA) to small surfactant aggregates (SA), LA/SA ratio. Phosphatidylglycerol (PG) was significantly reduced in the LA of the dysfunctional asthmatic BALs. There was a corresponding significant increase in the ratio of phosphatidylcholine to PG, which strongly correlated with both increased gamma(min) and decreased LA/SA. Altered surfactant phospholipid properties correlated with surfactant dysfunction as well or better than either increased eosinophils or protein. Secretory phospholipase activity, measured in vitro, increased after antigen challenge and may explain the decrease in surfactant PG. In summary, alteration of phospholipids, particularly depletion of PG, in the LA of surfactant may be an important mechanism in asthma-associated surfactant dysfunction.

Quinine-induced disseminated intravascular coagulation: case report and review of the literature.

OBJECTIVE: To describe the clinical course of quinine-induced disseminated intravascular coagulation (DIC) and review all previous cases reported in the medical literature. DESIGN: Case report/literature review. SETTING: University teaching hospital medical ICU. PATIENTS: One patient in whom thrombocytopenia, coagulopathy, intravascular hemolysis, DIC, and acute renal failure temporally followed the ingestion of quinine. DATA SOURCES: We conducted a computerized free-text MEDLINE database search from 1969 to 2000 using the keywords quinine and thrombocytopenia, quinine and hemolytic-uremic syndrome, and quinine and disseminated intravascular coagulation. STUDY SELECTION: All reported cases and reviews of quinine-induced thrombocytopenia, hemolytic-uremic syndrome (HUS), and DIC were reviewed. DIC was distinguished from quinine-induced thrombocytopenia or quinine-induced HUS based on the presence of abnormal clotting times, elevated fibrin degradation products, and/or elevated D-dimer levels. DATA SYNTHESIS: Fifteen previous patients were found to meet the criteria for DIC temporally related to the recent ingestion of quinine. The clinical course and laboratory abnormalities documented for each case are reviewed. CONCLUSIONS: Quinine-induced DIC is a distinct clinical entity, which may present as unexplained thrombocytopenia, coagulopathy, or renal failure. In susceptible patients, the immune response to quinine may result in the production of not only anti-platelet antibodies but also antibodies against leukocytes, erythrocytes, and endothelial cells. Furthermore, the varying patterns and specificities of antibody production in an individual patient may result in a spectrum of clinical disease from mild, transient thrombocytopenia to overt intravascular hemolysis, renal failure, coagulopathy, and DIC. Early recognition of quinine-induced DIC is paramount, as this diagnosis affords a better prognosis than other adult forms of HUS or DIC.