Correction to: Noninvasive Intracranial Pressure Assessment in Acute Liver Failure.

The authors note that the number 14 was inadvertently omitted from the formula listed on page 5 of the article. It currently reads.

Noninvasive Intracranial Pressure Assessment in Acute Liver Failure.

BACKGROUND: Elevated intracranial pressure (ICP) is an important cause of death following acute liver failure (ALF). While invasive ICP monitoring (IICPM) is most accurate, the presence of coagulopathy increases bleeding risk in ALF. Our objective was to evaluate the accuracy of three noninvasive ultrasound-based measures for the detection of concurrent ICP elevation in ALF-optic nerve sheath diameter (ONSD) using optic nerve ultrasound (ONUS); middle cerebral artery pulsatility index (PI) on transcranial Doppler (TCD); and ICP calculated from TCD flow velocities (ICPtcd) using the estimated cerebral perfusion pressure (CPPe) technique. METHODS: In this retrospective study, consecutive ALF patients admitted over a 6-year period who underwent IICPM as well as measurement of ONSD, TCD-PI or ICPtcd were included. ONSD was measured offline by a blinded investigator from deidentified videos. The ability of highest ONSD, TCD-PI, and ICPtcd to detect concurrent invasive ICP > 20 mmHg was assessed using receiver operating characteristic (ROC) curves. The ROC area under the curve (AUC) was calculated with 95% confidence interval (95% CI) and evaluated against the null hypothesis of AUC = 0.5. Noninvasive measures were also evaluated as predictors of in-hospital death. RESULTS: Forty-one ALF patients were admitted during the study period. In total, 27 (66%) underwent IICPM, of these, 23 underwent ONUS and 21 underwent TCD. Eleven out of 23 (48%) patients died (two from intracranial hypertension). Results of ROC analysis for detection of concurrent ICP > 20 mmHg were as follows: ONSD AUC = 0.59 (95% CI 0.37-0.79, p = 0.54); TCD-PI AUC = 0.55 (95% CI 0.34-0.75, p = 0.70); and ICPtcd AUC = 0.90 (0.72-0.98, p < 0.0001). None of the noninvasive measures were significant predictors of death. CONCLUSIONS: In patients with ALF, neither ONSD nor TCD-PI reliably detected concurrent ICP elevation on invasive monitoring. Estimation of ICP (ICPtcd) using the TCD CPPe technique was associated with concurrent ICP elevation. Additional studies of TCD CPPe in larger numbers of ALF patients may prove worthwhile.

Protocol based invasive intracranial pressure monitoring in acute liver failure: feasibility, safety and impact on management.

BACKGROUND: Acute liver failure (ALF) may result in elevated intracranial pressure (ICP). While invasive ICP monitoring (IICPM) may have a role in ALF management, these patients are typically coagulopathic and at risk for intracranial hemorrhage (ICH). Contemporary ICP monitoring techniques and coagulopathy reversal strategies may be associated with a lower risk of hemorrhage. Our objective was to evaluate the safety, feasibility, impact on clinical management and outcomes associated with protocol-directed use of IICPM in ALF. METHODS: Adult patients admitted between June 2011 and October 2016, with ALF and grade-4 encephalopathy with a reasonable likelihood of survival, were eligible for IICPM. The coagulopathy reversal protocol included administration of recombinant Factor VIIa (rFVIIa) and desmopressin, a goal platelet count >50,000/mm3 and fibrinogen >100 mg/dL. Monitor insertion was performed within an hour of the rFVIIa dose. Only intraparenchymal monitors were used. Computed tomography of the brain was performed prior to and within 24 hours of monitor placement. Outcomes of interest included ICH, sustained intracranial hypertension, therapeutic intensity level (TIL) for ICP management, mortality and functional outcome on the Glasgow Outcome Scale (GOS) at discharge and 6 months. RESULTS: A total of 24/37 patients (65%) with ALF underwent IICPM. The most common reason for exclusion was encephalopathy grade <4. Four patients underwent liver transplantation. There was one asymptomatic ICH following IICPM, in a patient who had an excellent outcome. Sustained intracranial hypertension occurred in 13/24 monitored patients (54%), 5/24 (21%) required extreme measures (TIL-4) for ICP control, which were successful in 4 patients: 12/24 patients (50%) died but only 4 deaths (17%) were attributed to intracranial hypertension. Six of the 8 survivors with 6-month follow up had good functional outcome (GOS >3). CONCLUSIONS: Protocol-directed use of IICPM in ALF is feasible, associated with a low incidence of serious complications and has a significant impact on clinical management.

Pneumothorax After Transbronchial Biopsy in Pulmonary Fibrosis: Lessons from the Multicenter COMET Trial.

PURPOSE: Some patients with diffuse interstitial lung disease (ILD) undergo bronchoscopy with transbronchial biopsy (TBB) as part of their diagnostic evaluation. It is unclear what the incidence and risk factors for pneumothorax (PTX) following TBB are in this patient population. METHODS: Ninety-seven subjects with pulmonary fibrosis who underwent a research bronchoscopy with TBB as part of the multicenter correlating outcomes with biochemical markers to estimate time-progression in idiopathic pulmonary fibrosis (COMET) trial were retrospectively reviewed. We compared subjects who developed a PTX during research bronchoscopy with TBB versus those who did not. RESULTS: Seven patients (7.2%) experienced a PTX during research bronchoscopy with TBB. Subjects who experienced PTX during TBB had significantly lower DLCO percent predicted (29 ± 8 vs. 45 ± 15, P = 0.006) and had lower resting room air saturation of peripheral oxygen (SPO2) on 6-min walk testing (91 ± 10 vs. 95 ± 3, P = 0.02). No differences between groups were found with respect to age, gender, race, BMI, HRCT characteristics, or the number of transbronchial biopsies performed. CONCLUSION: The incidence of PTX following research bronchoscopy with TBB in patients with pulmonary fibrosis was found to be 7.2% in this study. Patients who developed a pneumothorax had greater impairments in gas exchange at baseline evidenced by a lower DLCO  % predicted and a lower resting room air SPO2 compared with subjects without PTX as a complication.

The Michigan Appropriateness Guide for Intravenous Catheters (MAGIC): Results From a Multispecialty Panel Using the RAND/UCLA Appropriateness Method.

Use of peripherally inserted central catheters (PICCs) has grown substantially in recent years. Increasing use has led to the realization that PICCs are associated with important complications, including thrombosis and infection. Moreover, some PICCs may not be placed for clinically valid reasons. Defining appropriate indications for insertion, maintenance, and care of PICCs is thus important for patient safety. An international panel was convened that applied the RAND/UCLA Appropriateness Method to develop criteria for use of PICCs. After systematic reviews of the literature, scenarios related to PICC use, care, and maintenance were developed according to patient population (for example, general hospitalized, critically ill, cancer, kidney disease), indication for insertion (infusion of peripherally compatible infusates vs. vesicants), and duration of use (≤5 days, 6 to 14 days, 15 to 30 days, or ≥31 days). Within each scenario, appropriateness of PICC use was compared with that of other venous access devices. After review of 665 scenarios, 253 (38%) were rated as appropriate, 124 (19%) as neutral/uncertain, and 288 (43%) as inappropriate. For peripherally compatible infusions, PICC use was rated as inappropriate when the proposed duration of use was 5 or fewer days. Midline catheters and ultrasonography-guided peripheral intravenous catheters were preferred to PICCs for use between 6 and 14 days. In critically ill patients, nontunneled central venous catheters were preferred over PICCs when 14 or fewer days of use were likely. In patients with cancer, PICCs were rated as appropriate for irritant or vesicant infusion, regardless of duration. The panel of experts used a validated method to develop appropriate indications for PICC use across patient populations. These criteria can be used to improve care, inform quality improvement efforts, and advance the safety of medical patients.

The vitronectin-binding function of PAI-1 exacerbates lung fibrosis in mice.

Plasminogen activator inhibitor-1 (PAI-1) is increased in the lungs of patients with pulmonary fibrosis, and animal studies have shown that experimental manipulations of PAI-1 levels directly influence the extent of scarring that follows lung injury. PAI-1 has 2 known properties that could potentiate fibrosis, namely an antiprotease activity that inhibits the generation of plasmin, and a vitronectin-binding function that interferes with cell adhesion to this extracellular matrix protein. To determine the relative importance of each PAI-1 function in lung fibrogenesis, we administered mutant PAI-1 proteins that possessed either intact antiprotease or vitronectin-binding activity to bleomycin-injured mice genetically deficient in PAI-1. We found that the vitronectin-binding capacity of PAI-1 was the primary determinant required for its ability to exacerbate lung scarring induced by intratracheal bleomycin administration. The critical role of the vitronectin-binding function of PAI-1 in fibrosis was confirmed in the bleomycin model using mice genetically modified to express the mutant PAI-1 proteins. We conclude that the vitronectin-binding function of PAI-1 is necessary and sufficient in its ability to exacerbate fibrotic processes in the lung.

Guided transfer of critically ill patients: where patients are transferred can be an informed choice.

PURPOSE OF REVIEW: Given increasingly scarce healthcare resources and highly differentiated hospitals, with growing demand for critical care, interhospital transfer is an essential part of the care of many patients. The purpose of this review is to examine the extent to which hospital quality is considered when transferring critically ill patients, and to examine the potential benefits to patients of a strategy that incorporates objective quality data into referral patterns. RECENT FINDINGS: Interhospital transfer of critically ill patients is now common and safe. Although extensive research has focused on which patients should be transferred and when they should be transferred, recent study has focused on where patients should be transferred. Yet, the choice of destination hospital is rarely recognized as a therapeutic choice with implications for patient outcomes. The recent public release of high-quality, risk-adjusted and reliability-adjusted outcome data for most hospitals now offers physicians an informed basis on which to choose to which destination hospital a patient should be transferred. A strategy of 'guided transfer' that integrates public quality information into critical care transfer decisions is now feasible. SUMMARY: Although hospitals often transfer patients, there may be substantial room for improvement in transfer patterns. Guiding transfers on the basis of objective quality information may offer substantial benefits to patients, and could be incorporated into quality improvement initiatives.

Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis.

RATIONALE: Ineffective repair of a damaged alveolar epithelium has been postulated to cause pulmonary fibrosis. In support of this theory, epithelial cell abnormalities, including hyperplasia, apoptosis, and persistent denudation of the alveolar basement membrane, are found in the lungs of humans with idiopathic pulmonary fibrosis and in animal models of fibrotic lung disease. Furthermore, mutations in genes that affect regenerative capacity or that cause injury/apoptosis of type II alveolar epithelial cells have been identified in familial forms of pulmonary fibrosis. Although these findings are compelling, there are no studies that demonstrate a direct role for the alveolar epithelium or, more specifically, type II cells in the scarring process. OBJECTIVES: To determine if a targeted injury to type II cells would result in pulmonary fibrosis. METHODS: A transgenic mouse was generated to express the human diphtheria toxin receptor on type II alveolar epithelial cells. Diphtheria toxin was administered to these animals to specifically target the type II epithelium for injury. Lung fibrosis was assessed by histology and hydroxyproline measurement. MEASUREMENTS AND MAIN RESULTS: Transgenic mice treated with diphtheria toxin developed an approximately twofold increase in their lung hydroxyproline content on Days 21 and 28 after diphtheria toxin treatment. The fibrosis developed in conjunction with type II cell injury. Histological evaluation revealed diffuse collagen deposition with patchy areas of more confluent scarring and associated alveolar contraction. CONCLUSIONS: The development of lung fibrosis in the setting of type II cell injury in our model provides evidence for a causal link between the epithelial defects seen in idiopathic pulmonary fibrosis and the corresponding areas of scarring.

Pneumocystis jirovecii Pneumonia-Associated Acute Respiratory Distress Syndrome Complicated by Pneumomediastinum and Pneumopericardium in a Non-Human Immunodeficiency Virus-Infected Patient.

Pneumocystis jirovecii pneumonia is widely known as a life-threatening opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS). However, with the widespread use of highly active antiretroviral therapy (HAART) and effective anti-Pneumocystis antimicrobial prophylaxis, this entity has declined substantially in patients with human immunodeficiency virus (HIV) infection. Interestingly, the incidence of Pneumocystis jirovecii pneumonia has been increasing among patients without HIV infection, mainly as a consequence of the expanding use of chemotherapy and other immunosuppressive agents. Nevertheless, Pneumocystis jirovecii pneumonia remains an important cause of HIV- and non-HIV-related catastrophic complications. Pneumomediastinum and pneumopericardium are extremely uncommon events in patients with Pneumocystis jirovecii pneumonia. In this report, we described a unique case of Pneumocystis jirovecii pneumonia-associated acute respiratory distress syndrome (ARDS), complicated by pneumomediastinum and pneumopericardium in a non-HIV infected patient.

Interobserver Reliability of the Berlin ARDS Definition and Strategies to Improve the Reliability of ARDS Diagnosis.

BACKGROUND: Failure to reliably diagnose ARDS may be a major driver of negative clinical trials and underrecognition and treatment in clinical practice. We sought to examine the interobserver reliability of the Berlin ARDS definition and examine strategies for improving the reliability of ARDS diagnosis. METHODS: Two hundred five patients with hypoxic respiratory failure from four ICUs were reviewed independently by three clinicians, who evaluated whether patients had ARDS, the diagnostic confidence of the reviewers, whether patients met individual ARDS criteria, and the time when criteria were met. RESULTS: Interobserver reliability of an ARDS diagnosis was "moderate" (kappa = 0.50; 95% CI, 0.40-0.59). Sixty-seven percent of diagnostic disagreements between clinicians reviewing the same patient was explained by differences in how chest imaging studies were interpreted, with other ARDS criteria contributing less (identification of ARDS risk factor, 15%; cardiac edema/volume overload exclusion, 7%). Combining the independent reviews of three clinicians can increase reliability to "substantial" (kappa = 0.75; 95% CI, 0.68-0.80). When a clinician diagnosed ARDS with "high confidence," all other clinicians agreed with the diagnosis in 72% of reviews. There was close agreement between clinicians about the time when a patient met all ARDS criteria if ARDS developed within the first 48 hours of hospitalization (median difference, 5 hours). CONCLUSIONS: The reliability of the Berlin ARDS definition is moderate, driven primarily by differences in chest imaging interpretation. Combining independent reviews by multiple clinicians or improving methods to identify bilateral infiltrates on chest imaging are important strategies for improving the reliability of ARDS diagnosis.

The application and diagnostic utility of immunocytochemistry on direct smears in the diagnosis of pulmonary adenocarcinoma and squamous cell carcinoma.

The importance of subclassifying pulmonary nonsmall cell carcinoma (NSCLC) in cytologic material is becoming increasingly paramount. Occasionally, cell blocks traditionally used for ancillary studies are sparsely cellular or acellular. Hence, we investigated the diagnostic utility of immunocytochemistry for Napsin-A, TTF-1, and p63 on direct smears of NSCLC. Immunohistochemistry for Napsin-A was initially tested on a tissue microarray (TMA) composed of pulmonary adenocarcinoma. Subsequently, in 25 cases, immunocytochemistry for Napsin-A, TTF-1, and p63 was performed on cytologic direct smears. Smears were prepared from tumor cells scraped from lung resection specimens (n = 10), endobronchial ultrasound-guided transbronchial fine-needle aspirates (n = 13), and pelleted cell material from pleural effusions (n = 2). Immunohistochemistry utilizing the TMA revealed Napsin-A positivity in 73% of pulmonary ADCs. Next, immunocytochemistry on direct cytologic smears demonstrated a Napsin-A(+)/TTF-1(+) immunophenotype in 15 of 18 adenocarcinomas; p63 was completely negative (n = 12) or only focally positive (n = 3) in these 15 adenocarcinomas. The remaining three adenocarcinomas were negative for all three markers. All six squamous cell carcinomas were Napsin-A(-)/TTF-1(-) and diffusely p63(+). In conclusion, direct smears represent a feasible and robust source of cellular material for immunocytochemical studies to diagnose pulmonary ADC and SQC. Our method allows the cytologist to confirm on site that material for diagnostic immunocytochemistry is present thereby serving as a safeguard in instances where the cell block is of insufficient cellularity.

The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice.

Plasminogen activation to plasmin protects from lung fibrosis, but the mechanism underlying this antifibrotic effect remains unclear. We found that mice lacking plasminogen activation inhibitor-1 (PAI-1), which are protected from bleomycin-induced pulmonary fibrosis, exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin E2 (PGE2). Plasminogen activation upregulated PGE2 synthesis in alveolar epithelial cells, lung fibroblasts, and lung fibrocytes from saline- and bleomycin-treated mice, as well as in normal fetal and adult primary human lung fibroblasts. This response was exaggerated in cells from Pai1-/- mice. Although enhanced PGE2 formation required the generation of plasmin, it was independent of proteinase-activated receptor 1 (PAR-1) and instead reflected proteolytic activation and release of HGF with subsequent induction of COX-2. That the HGF/COX-2/PGE2 axis mediates in vivo protection from fibrosis in Pai1-/- mice was demonstrated by experiments showing that a selective inhibitor of the HGF receptor c-Met increased lung collagen to WT levels while reducing COX-2 protein and PGE2 levels. Of clinical interest, fibroblasts from patients with idiopathic pulmonary fibrosis were found to be defective in their ability to induce COX-2 and, therefore, unable to upregulate PGE2 synthesis in response to plasmin or HGF. These studies demonstrate crosstalk between plasminogen activation and PGE2 generation in the lung and provide a mechanism for the well-known antifibrotic actions of the fibrinolytic pathway.