Paradoxical response to chest wall loading predicts a favorable mechanical response to reduction in tidal volume or PEEP.

BACKGROUND: Chest wall loading has been shown to paradoxically improve respiratory system compliance (CRS) in patients with moderate to severe acute respiratory distress syndrome (ARDS). The most likely, albeit unconfirmed, mechanism is relief of end-tidal overdistension in 'baby lungs' of low-capacity. The purpose of this study was to define how small changes of tidal volume (VT) and positive end-expiratory pressure (PEEP) affect CRS (and its associated airway pressures) in patients with ARDS who demonstrate a paradoxical response to chest wall loading. We hypothesized that small reductions of VT or PEEP would alleviate overdistension and favorably affect CRS and conversely, that small increases of VT or PEEP would worsen CRS. METHODS: Prospective, multi-center physiologic study of seventeen patients with moderate to severe ARDS who demonstrated paradoxical responses to chest wall loading. All patients received mechanical ventilation in volume control mode and were passively ventilated. Airway pressures were measured before and after decreasing/increasing VT by 1 ml/kg predicted body weight and decreasing/increasing PEEP by 2.5 cmH2O. RESULTS: Decreasing either VT or PEEP improved CRS in all patients. Driving pressure (DP) decreased by a mean of 4.9 cmH2O (supine) and by 4.3 cmH2O (prone) after decreasing VT, and by a mean of 2.9 cmH2O (supine) and 2.2 cmH2O (prone) after decreasing PEEP. CRS increased by a mean of 3.1 ml/cmH2O (supine) and by 2.5 ml/cmH2O (prone) after decreasing VT. CRS increased by a mean of 5.2 ml/cmH2O (supine) and 3.6 ml/cmH2O (prone) after decreasing PEEP (P < 0.01 for all). Small increments of either VT or PEEP worsened CRS in the majority of patients. CONCLUSION: Patients with a paradoxical response to chest wall loading demonstrate uniform improvement in both DP and CRS following a reduction in either VT or PEEP, findings in keeping with prior evidence suggesting its presence is a sign of end-tidal overdistension. The presence of 'paradox' should prompt re-evaluation of modifiable determinants of end-tidal overdistension, including VT, PEEP, and body position.

Paradoxical Positioning: Does "Head Up" Always Improve Mechanics and Lung Protection?

OBJECTIVES: Head-elevated body positioning, a default clinical practice, predictably increases end-expiratory transpulmonary pressure and aerated lung volume. In acute respiratory distress syndrome (ARDS), however, the net effect of such vertical inclination on tidal mechanics depends upon whether lung recruitment or overdistension predominates. We hypothesized that in moderate to severe ARDS, bed inclination toward vertical unloads the chest wall but adversely affects overall respiratory system compliance (C rs ). DESIGN: Prospective physiologic study. SETTING: Two medical ICUs in the United States. PATIENTS: Seventeen patients with ARDS, predominantly moderate to severe. INTERVENTION: Patients were ventilated passively by volume control. We measured airway pressures at baseline (noninclined) and following bed inclination toward vertical by an additional 15°. At baseline and following inclination, we manually loaded the chest wall to determine if C rs increased or paradoxically declined, suggestive of end-tidal overdistension. MEASUREMENTS AND MAIN RESULTS: Inclination resulted in a higher plateau pressure (supineΔ: 2.8 ± 3.3 cm H 2 O [ p = 0.01]; proneΔ: 3.3 ± 2.5 cm H 2 O [ p = 0.004]), higher driving pressure (supineΔ: 2.9 ± 3.3 cm H 2 O [ p = 0.01]; proneΔ: 3.3 ± 2.8 cm H 2 O [ p = 0.007]), and lower C rs (supine Δ: 3.4 ± 3.7 mL/cm H 2 O [ p = 0.01]; proneΔ: 3.1 ± 3.2 mL/cm H 2 O [ p = 0.02]). Following inclination, manual loading of the chest wall restored C rs and driving pressure to baseline (preinclination) values. CONCLUSIONS: In advanced ARDS, bed inclination toward vertical adversely affects C rs and therefore affects the numerical values for plateau and driving tidal pressures commonly targeted in lung protective strategies. These changes are fully reversed with manual loading of the chest wall, suggestive of end-tidal overdistension in the upright position. Body inclination should be considered a modifiable determinant of transpulmonary pressure and lung protection, directionally similar to tidal volume and positive end-expiratory pressure.

A Rationale for Safe Ventilation with Inhalation Injury: An Editorial Review.

Lung injury from smoke inhalation manifests as airway and parenchymal damage, at times leading to the acute respiratory distress syndrome. From the beginning of this millennium, the approach to mechanical ventilation in the patient with ARDS was based on reduction of tidal volume to 6 milliliters/kilogram of ideal body weight, maintaining a ceiling of plateau pressure, and titration of driving pressure (plateau pressure minus PEEP). Beyond these broad constraints, there is little specification for the mechanics of ventilator settings, consideration of the metabolic impact of the disease process on the patient, or interaction of patient disease and ventilator settings. Various studies suggest that inhomogeneity of lung injury, which increases the risk of regional lung trauma from mechanical ventilation, may be found in the patient with smoke inhalation. We now appreciate that energy transfer principles may affect optimal ventilator management and come into play in damaged heterogenous lungs. Mechanical ventilation in the patient with inhalation injury should consider various factors. Self-injurious respiratory demand by the patient can be reduced using analgesia and sedation. Dynamic factors beginning with rate management can reduce the incidence of potentially damaging ventilation. Moreover, preclinical study is underway to examine the flow of gas based on the ventilator mode selected, which may also be a factor triggering regional lung injury.

Static and Dynamic Measurements of Compliance and Driving Pressure: A Pilot Study.

RATIONALE: Monitoring tidal cycle mechanics is key to lung protection. For this purpose, compliance and driving pressure of the respiratory system are often measured clinically using the plateau pressure, obtained after imposing an extended end-inspiratory pause, which allows for relaxation of the respiratory system and redistribution of inflation volume (method A). Alternative methods for estimating compliance and driving pressure utilize the measured pressure at the earliest instance of zero flow (method B), the inspiratory slope of the pressure-time tracing during inflation with constant flow (method C), and the expiratory time constant (method D). METHODS: Ten passive mechanically ventilated subjects, at a large tertiary referral center, underwent measurements of compliance and driving pressure using the four different methods. The inspiratory tidal volume, inspiratory to expiratory ratio, and positive end expiratory pressures were then adjusted from baseline and the measurements re-obtained. RESULTS: Method A yielded consistently higher compliance and lower driving pressure calculations compared to methods B and C. Methods B and C most closely approximated one another. Method D did not yield a consistent reliable pattern. CONCLUSION: Static measurements of compliance and driving pressure using the plateau pressure may underestimate the maximum pressure experienced by the most vulnerable lung units during dynamic inflation. Utilizing the pressure at zero flow as a static measurement, or the inspiratory slope as a dynamic measurement, may calculate a truer estimate of the maximum alveolar pressure that generates stress upon compromised lung units.

Reliable Estimates of Power Delivery During Mechanical Ventilation Utilizing Easily Obtained Bedside Parameters.

BACKGROUND: Ventilator-induced lung injury (VILI) requires repetitive transfer of energy from the ventilator to the compromised lung. To understand this phenomenon, 2 sets of equations have been developed to partition total inflation energy into harmless and hazardous components using an arbitrary level of alveolar pressure as a threshold beyond which further energy increments may become damaging. One set of equations uses premeasured resistance and compliance as inputs to predict the energy that would be delivered by typical ventilator settings, whereas the other equation set uses observed output values for end-inspiratory peak and plateau pressure of an already completed inflation. METHODS: Our aim for this study was to compare the relative accuracy of these equation sets against the performance of a physical one-compartment model of the respiratory system, programmed with information readily available at the bedside and ventilated using both constant and decelerating flow profiles. Accordingly, equations of each set were compared against the corresponding energy areas measured by digital planimetry of pressure-volume curves for 76 ventilator and patient parameter combinations and over 500 power calculations. RESULTS: With few exceptions, all equations strongly correlated with their corresponding measurements by planimetry. CONCLUSIONS: This validation of threshold-partitioned energy equations suggests their potential utility for implementing practical strategies for VILI avoidance.

Intracycle power and ventilation mode as potential contributors to ventilator-induced lung injury.

BACKGROUND: High rates of inflation energy delivery coupled with transpulmonary tidal pressures of sufficient magnitude may augment the risk of damage to vulnerable, stress-focused units within a mechanically heterogeneous lung. Apart from flow amplitude, the clinician-selected flow waveform, a relatively neglected dimension of inflation power, may distribute inflation energy of each inflation cycle non-uniformly among alveoli with different mechanical properties over the domains of time and space. In this initial step in modeling intracycle power distribution, our primary objective was to develop a mathematical model of global intracycle inflation power that uses clinician-measurable inputs to allow comparisons of instantaneous ICP profiles among the flow modes commonly encountered in clinical practice: constant, linearly decelerating, exponentially decelerating (pressure control), and spontaneous (sinusoidal). METHODS: We first tested the predictions of our mathematical model of passive inflation with the actual physical performance of a mechanical ventilator-lung system that simulated ventilation to three types of patients: normal, severe ARDS, and severe airflow obstruction. After verification, model predictions were then generated for 5000 'virtual ARDS patients'. Holding constant the tidal volume and inflation time between modes, the validated model then varied the flow profile and quantitated the resulting intensity and timing of potentially damaging 'elastic' energy and intracycle power (pressure-flow product) developed in response to random combinations of machine settings and severity levels for ARDS. RESULTS: Our modeling indicates that while the varied flow patterns ultimately deliver similar total amounts of alveolar energy during each breath, they differ profoundly regarding the potentially damaging pattern with which that energy distributes over time during inflation. Pressure control imposed relatively high maximal intracycle power. CONCLUSIONS: Flow amplitude and waveform may be relatively neglected and modifiable determinants of VILI risk when ventilating ARDS.

Lethal hyperammonemia in a CAR-T cell recipient due to Ureaplasma pneumonia: a case report of a unique severe complication.

We report the first incidence of Ureaplasma infection causing lethal hyperammonemia in a chimeric receptor antigen T cell (CAR-T) recipient. A 53-year-old woman, after receiving CAR-T therapy, suffered sepsis and encephalopathy. She was found to have hyperammonemia up to 643 µmol/L. Imaging revealed lung consolidations and bronchoalveolar lavage PCR was positive for U. parvum Workup excluded liver failure and metabolic abnormalities. Antibiotics, lactulose, dextrose, arginine, levocarnitine, sodium phenylbutyrate and dialysis were used. Despite these, the patient suffered persistent elevations in ammonia, status epilepticus and cerebral oedema. Early recognition of this rare infection in susceptible populations is needed. CAR-T patients are at risk due to their immunocompromised state and may have amplified harm due to the impact of CAR-T therapy on astrocytes. An early aggressive multimodality approach is needed given the high mortality rates. These include antimicrobials, possibly with double coverage for Ureaplasma Additionally, concurrent ammonia-suppressing and ammonia-eliminating treatments are necessary.

Early (<4 Weeks) Versus Standard (≥ 4 Weeks) Endoscopically Centered Step-Up Interventions for Necrotizing Pancreatitis.

OBJECTIVES: Current guidelines for necrotizing pancreatitis (NP) recommend delay in drainage ± necrosectomy until 4 or more weeks after initial presentation to allow collections to wall off. However, evidence of infection with clinical deterioration despite maximum support may mandate earlier (<4 weeks) intervention. There are concerns, but scant data regarding risk of complications and outcomes with early endoscopic intervention. Our aim was to compare the results of an endoscopic centered step-up approach to NP when initiated before versus 4 or more weeks. METHODS: All patients undergoing intervention for NP were managed using an endoscopically centered step-up approach, with transluminal drainage whenever feasible, ±necrosectomy, and/or percutaneous catheter drainage as needed, with surgery only for failures. Interventions were categorized as early or standard based on timing of intervention (<4 weeks or ≥ 4 weeks from onset of pancreatitis). Demographic data, indications and timing for interventions, number and type of intervention, mortality and morbidity (length of stay in hospital and ICU) and complications were compared. RESULTS: Of 305 patients with collections associated with NP, 193 (63%) (median age-52 years) required intervention, performed by a step-up approach. Of the 193 patients, 76 patients underwent early and 117 patients standard intervention. 144 (75%) interventions included endoscopic drainage ± necrosectomy. As compared with standard intervention, early intervention was more often performed for infection (91% vs. 39%, p < 0.05), more associated with acute kidney injury (43% vs. 32%, p = 0.09), respiratory failure (41% vs. 22%, p = 0.005), and shock (13% vs. 4%, p < 0.05). Organ failure improved significantly after intervention in both groups. There was a significant difference in mortality (13% vs. 4%, p = 0.02) and need for rescue open necrosectomy (7% vs. 1%, p = 0.03) between groups. Patients undergoing early intervention had increased median hospital (37 days vs. 26 days, p = 0.01) and ICU stay (median 2.5 days vs. 0 days, p = 0.001). There was no difference in complications. CONCLUSIONS: When using an endoscopically centered step-up strategy in necrotizing pancreatitis, early (<4 weeks) interventions were more often performed for infection and organ failure, with no increase in complications, similar improvement in organ failure, slightly increased need for surgery, and relatively low mortality. Early endoscopic drainage ± necrosectomy should be considered when there is a strong indication for intervention.

The Rare Complication and Diagnostic Challenges of Pulmonary Eosinophilia in Graft versus Host Disease Patients after Hematopoietic Stem Cell Transplantation.

PURPOSE: Chronic graft versus host disease (cGvHD) is a common complication of hematopoietic stem cell transplantation (HSCT). Eosinophilic lung disease is a rare poorly understood complication in HSCT patients with cGvHD. These patients present similarly to those with Acute Eosinophilic Pneumonia (AEP). The purpose of this study is to better elucidate the presentation and potential treatment of this phenomenon. METHODS: We reviewed over 170 bronchoscopies in post-HSCT patients with respiratory symptoms. Of these, four patients, whose course was complicated by cGvHD, presented with respiratory symptoms, diffuse ground-glass opacities (GGO) on chest computerized tomography (CT), bronchoalveolar lavage (BAL) eosinophilia, and no evidence of infection. The clinical course of these patients was reviewed. RESULTS: Despite clinical presentation similar to AEP, not all patients had > 25% eosinophils on BAL, one criterion for AEP, however all improved with steroids. Steroid initiation was often delayed in favor of empiric antibiotics despite negative infectious workup. Several patients had recurrent episodes. Regarding possible associations, we examined but found no link between particular demographics, reason for HSCT, chemotherapy, immunosuppressants, or peripheral eosinophil count and pulmonary eosinophilia in these patients. GGO present on initial CT imaging became chronic in several of these patients. CONCLUSION: We propose that in post-HSCT patients with GvHD presenting with respiratory symptoms, GGO on CT, BAL eosinophilia of > 10%, and negative respiratory cultures, an autoimmune eosinophilic process may be occurring. Earlier recognition and initiation of corticosteroids in these patients may improve their outcomes as an autoimmune diagnosis was often delayed in favor of antibiotics.

Severe polyserositis induced by the 13-valent pneumococcal conjugate vaccine: a case report.

BACKGROUND: The United States Advisory Committee on Immunization Practices recommends administration of the 13-valent pneumococcal conjugate vaccine in series with the 23-valent pneumococcal polysaccharide vaccine for prevention of pneumonia in the elderly. Reports of autoimmune or auto-inflammatory diseases as a result of pneumococcal vaccination, especially pneumococcal conjugate vaccine, are extremely rare. CASE PRESENTATION: We present a case of severe serositis in a 75-year-old Caucasian woman complicated by pericardial and pleural effusions in the setting of recent 13-valent pneumococcal conjugate vaccine vaccination and no other obvious etiology. Our patient required steroid treatment, thoracentesis, chest tube, and pericardial window and subsequently recovered to her baseline. CONCLUSIONS: To the best of our knowledge, no such reaction to the 13-valent pneumococcal conjugate vaccine has previously been documented. Although the benefits of vaccination outweigh the risks, knowledge of this potential side effect can help clinicians in diagnosis and treatment of similar patients.

Audible Coronary Artery Stenosis.

OBJECTIVE: Hemodynamically significant coronary artery stenoses generate turbulent blood flow patterns that manifest as intracoronary murmurs. This study aims to evaluate the performance of modern acoustic detection of these murmurs by acoustic signals captured from patients undergoing gold standard comparative coronary angiography. METHODS: We prospectively studied 156 patients undergoing elective coronary angiography, excluding those with acute coronary syndrome, prior chest surgery, or significant valvular disease. Acoustic signals were captured before arterial access. Angiographic degree of stenosis in each coronary artery was graded blinded to clinical and acoustic data. Acoustic data were analyzed blinded to clinical and angiographic data, categorizing subjects as "normal," "diseased," or "inconclusive." Of 156 patients examined, 123 generated analyzable data. RESULTS: Angiographically significant stenosis (≥50%) prevalence was 52% (18%, 23%, 11% with 1-, 2-, 3-vessel disease, respectively). Acoustic detection sensitivity and specificity for stenosis ≥50% in any vessel were 0.70 and 0.80, respectively (negative predictive value, 0.71; positive predictive value, 0.79). Acoustic detection optimally identified stenosis ≥50% with an area under the curve of 0.75. For stenosis ≥50% in major vessels only (left main, proximal-mid left anterior descending, proximal-mid circumflex, proximal-mid right coronary), prevalence was 46%; sensitivity and specificity were 0.72 and 0.76, respectively (negative predictive value, 0.76; positive predictive value, 0.72; area under the curve, 0.76). CONCLUSIONS: Acoustic signal patterns and modern analysis techniques may be used to identify intracoronary murmurs generated by hemodynamically significant coronary artery stenoses in all major vessels. Further investigation is warranted to compare the clinical performance of this modality with current noninvasive approaches that evaluate patients at risk for atherosclerotic and obstructive coronary artery disease.

Noninvasive quantification of ascorbate and glutathione concentration in the elderly human brain.

In this study, ascorbate (Asc) and glutathione (GSH) concentrations were quantified noninvasively using double-edited (1)H MRS at 4 T in the occipital cortex of healthy young [age (mean ± standard deviation) = 20.4 ± 1.4 years] and elderly (age = 76.6 ± 6.1 years) human subjects. Elderly subjects had a lower GSH concentration than younger subjects (p < 0.05). The Asc concentration was not significantly associated with age. Furthermore, the lactate (Lac) concentration was higher in elderly than young subjects. Lower GSH and higher Lac concentrations are indications of defective protection against oxidative damage and impaired mitochondrial respiration. The extent to which the observed concentration differences could be associated with physiological differences and methodological artifacts is discussed. In conclusion, GSH and Asc concentrations were compared noninvasively for the first time in young vs elderly subjects.

Hexapeptide libraries for enhanced protein PTM identification and relative abundance profiling in whole human saliva.

Dynamic range compression (DRC) by hexapeptide libraries increases MS/MS-based identification of lower-abundance proteins in complex mixtures. However, two unanswered questions impede fully realizing DRC's potential in shotgun proteomics. First, does DRC enhance identification of post-translationally modified proteins? Second, can DRC be incorporated into a workflow enabling relative protein abundance profiling? We sought to answer both questions analyzing human whole saliva. Addressing question one, we coupled DRC with covalent glycopeptide enrichment and MS/MS. With DRC we identified ∼2 times more N-linked glycoproteins and their glycosylation sites than without DRC, dramatically increasing the known salivary glycoprotein catalog. Addressing question two, we compared differentially stable isotope-labeled saliva samples pooled from healthy and metastatic breast cancer women using a multidimensional peptide fractionation-based workflow, analyzing in parallel one sample portion with DRC and one portion without. Our workflow categorizes proteins with higher absolute abundance, whose relative abundance ratios are altered by DRC, from proteins of lower absolute abundance detected only after DRC. Within each of these salivary protein categories, we identified novel abundance changes putatively associated with breast cancer, demonstrating feasibility and benefits of DRC for relative abundance profiling. Collectively, our results bring us closer to realizing the full potential of DRC for proteomic studies.