David Shimabukuro

Injury and repair in lung and airways.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common causes of morbidity and mortality in the intensive care unit. ALI/ARDS occurs as a result of systemic inflammation, usually triggered by a microorganism. Activation of leukocytes and release of proinflammatory mediators from multiple cellular sources result in both local and distant tissue injury. Tumor necrosis factor-alpha and interleukin-1 beta are the best characterized of the proinflammatory cytokines contributing to ALI/ARDS and subsequent fibrosis. The ultimate clinical course of ALI/ARDS often is determined by the ability of the injured lung to repopulate the alveolar epithelium with functional cells. Death may occur when fibrosis predominates the healing response, as it results in worsening lung compliance and oxygenation. The rodent bleomycin model of lung fibrosis allows the use of molecular tools to dissect the cellular and subcellular processes leading to fibrosis. The elements of this response may provide therapeutic targets for the prevention of this devastating complication of ALI/ARDS.

Effects of monoclonal anti-PcrV antibody on Pseudomonas aeruginosa-induced acute lung injury in a rat model

BackgroundThe effects of the murine monoclonal anti-PcrV antibody Mab166 on acute lung injury induced by Pseudomonas aeruginosa were analyzed in a rat model.MethodsLung injury was induced by the instillation of P. aeruginosa strain PA103 directly into the left lungs of anesthetized rats. One hour after the bacterial instillation, rabbit polyclonal anti-PcrV IgG, murine monoclonal anti-PcrV IgG Mab166 or Mab166 Fab-fragments were administered intratracheally directly into the lungs. The degree of alveolar epithelial injury, amount of lung edema, decrease in oxygenation and extent of lung inflammation by histology were evaluated as independent parameters of acute lung injury.ResultsThese parameters improved in rats that had received intratracheal instillation of either rabbit polyclonal anti-PcrV IgG, murine monoclonal anti-PcrV IgG Mab166 or Mab166 Fab-fragments in comparison with the control group.ConclusionMab166 and its Fab fragments have potential as adjuvant therapy for acute lung injury due to P. aeruginosa pneumonia.

Fresh and stored red blood cell transfusion equivalently induce subclinical pulmonary gas exchange deficit in normal humans.

BACKGROUND: Transfusion can cause severe acute lung injury, although most transfusions do not seem to induce complications. We tested the hypothesis that transfusion can cause mild pulmonary dysfunction that has not been noticed clinically and is not sufficiently severe to fit the definition of transfusion-related acute lung injury. METHODS: We studied 35 healthy, normal volunteers who donated 1 U of blood 4 weeks and another 3 weeks before 2 study days separated by 1 week. On study days, 2 U of blood were withdrawn while maintaining isovolemia, followed by transfusion with either the volunteers autologous fresh red blood cells (RBCs) removed 2 hours earlier or their autologous stored RBCs (random order). The following week, each volunteer was studied again, transfused with the RBCs of the other storage duration. The primary outcome variable was the change in alveolar to arterial difference in oxygen partial pressure (AaDO2) from before to 60 minutes after transfusion with fresh or older RBCs. RESULTS: Fresh RBCs and RBCs stored for 24.5 days equally (P = 0.85) caused an increase of AaDO2 (fresh: 2.8 mm Hg [95% confidence interval: 0.8–4.8; P = 0.007]; stored: 3.0 mm Hg [1.4–4.7; P = 0.0006]). Concentrations of all measured cytokines, except for interleukin-10 (P = 0.15), were less in stored leukoreduced (LR) than stored non-LR packed RBCs; however, vascular endothelial growth factor was the only measured in vivo cytokine that increased more after transfusion with LR than non-LR stored packed RBCs. Vascular endothelial growth factor was the only cytokine tested with in vivo concentrations that correlated with AaDO2. CONCLUSION: RBC transfusion causes subtle pulmonary dysfunction, as evidenced by impaired gas exchange for oxygen, supporting our hypothesis that lung impairment after transfusion includes a wide spectrum of physiologic derangements and may not require an existing state of altered physiology. These data do not support the hypothesis that transfusion of RBCs stored for >21 days is more injurious than that of fresh RBCs.

O-Antigen Serotypes and Type III Secretory Toxins in Clinical Isolates of Pseudomonas aeruginosa

ABSTRACT The association of O-antigen serotypes with type III secretory toxins was analyzed in 99 clinical isolates of Pseudomonas aeruginosa. Isolates secreting ExoU were frequently serotyped as O11, but none were serotype O1. Most of the isolates that were nontypeable for O antigen did not secrete type III secretory toxins.

Rescue Therapies for Acute Hypoxemic Respiratory Failure

The recent H1N1 epidemic has resulted in a large number of deaths, primarily from acute hypoxemic respiratory failure. We reviewed the current strategies to rescue patients with severe hypoxemia. Included in these strategies are high-frequency oscillatory ventilation, airway pressure release ventilation, inhaled vasodilators, and the use of extracorporeal life support. All of these strategies are targeted at improving oxygenation, but improved oxygenation alone has yet to be demonstrated to correlate with improved survival. The risks and benefits of these strategies, including cost-effectiveness data, are discussed.

Noisy mechanical ventilation: listen to the melody.

BIOLOGIC systems are characterized by variability, termed “noise,” rather than monotonous patterns. For example, two cells will have different chemical compositions, despite identical gene expression. The random nature of these fluctuations improves the fitness of both subcellular processes and organismal survival, when compared to deterministic systems. This phenomenon has been termed stochastic resonance, whereby noise added to a system improves the systems performance. Traditional volume-cycled mechanical ventilation is monotonous; if the diaphragm does not participate in facilitating mechanical ventilation, then disuse atrophy occurs rapidly. Using variability in breathing patterns during assisted spontaneous ventilation while improving lung function is not a completely new concept. It was probably first elucidated by Suki et al., in Nature in 1998. In their study, variation of pressure during mechanical ventilation led to an increase in oxygenation and was explained by stochastic resonance, where increasing the SD of noise can amplify a weak signal and eventually increase the output. How might noise improve oxygenation? Because of hysteresis, more lung volume is gained when noise increases inflation pressure than is lost when the noise reduces inflation pressure. Today, there are several programs on newer generation mechanical ventilators that allow for this type of variability (Bi-level and Airway Pressure Release Ventilation). However, there is no large-scale data showing patient mortality or morbidity benefits while using these newer modalities. In this issue of ANESTHESIOLOGY, Spieth and colleagues provide insight into novel spontaneous breathing modes of mechanical ventilation in acute lung injury (ALI). This study complements their previous work describing the importance of spontaneous breathing in acute lung injury. Using a porcine animal model, ALI was induced using surfactant depletion. When compared to more traditional modes of mechanical ventilation, noisy pressure support ventilation led to increased variability in respiratory pattern, resulting in improved ventilation/ perfusion matching, lower mean airway pressures, and improved oxygenation. In this study, Spieth et al. used spontaneously breathing anesthetized pigs and the concept of noisy pressure support ventilation. A target mean pressure support value was designated at the value needed to maintain a tidal volume of 6 ml/kg. From this value, variability of up to 45% over a normal distribution was introduced into the pressure support levels (no higher than 40 cm H2O) that resulted in tidal volume variability. Looking specifically at 7.5%, 15%, 30%, and 45% variability from the mean, they determined that at moderate levels (15–30%) there was improvement in the PaO2/FIO2 ratio with no significant impact on hemodynamics or comfort of breathing. Spieth and colleagues show that noisy pressure support ventilation in surfactant depleted ALI can improve oxygenation on a short-term basis. However, it has yet to be clearly illustrated that a quick improvement in this ratio can improve pulmonary function in the long run. In fact, there is no clear clinical evidence based on human trials that there is a significant improvement in patient mortality when the PaO2/FIO2 ratio is improved over a short period of time. The original ARDSNet low tidal volume versus traditional tidal volume multicenter study showed that patients who received larger tidal volumes had a statistically significant improvement in their PaO2/ FIO2 ratio, but ultimately showed substantially increased mortality. This potential epiphenomenon has also been shown with high frequency oscillatory ventilation in adults with the acute respiratory distress syndrome (ARDS), although these studies have not been nearly as large as the ARDSNet trial. Therefore, rapid improvement in pulmonary function in ARDS/ALI does not necessarily translate to improvements in overall morbidity or mortality. However, improving oxygenation through increased mean airway pressure may be detrimental, whereby in the case of noisy ventilation, oxygenation is improved without concomitant increases in airway pressure. Controlled mechanical ventilation is usually used in patients with ARDS and/or ALI. In most cases, to achieve ventilator synchrony, patients are administered sedatives and, less frequently, muscle relaxants. It is well accepted that patients on spontaneous breathing modes probably require less sedation. This sedation decrease alone can have significant beneficial effects on a patient’s hospital course (fewer ventilator days, decreased intensive care unit length of stay, less delirium, etc.). The majority of experimental models have examined the efficacy of noisy ventilation in the setting of ALI. What about the use of noisy ventilation in normal lungs? Could this technique protect the lungs from inflammaThis Editorial View accompanies the following article: Spieth PM, Carvalho AR, Güldner A, Pelosi P, Kirichuk O, Koch T, Gama de Abreu M: Effects of different levels of pressure support variability in experimental lung injury. ANESTHESIOLOGY 2009; 110:342–50.

Multicentre validation of a sepsis prediction algorithm using only vital sign data in the emergency department, general ward and ICU

Objectives We validate a machine learning-based sepsis-prediction algorithm (InSight) for the detection and prediction of three sepsis-related gold standards, using only six vital signs. We evaluate robustness to missing data, customisation to site-specific data using transfer learning and generalisability to new settings. Design A machine-learning algorithm with gradient tree boosting. Features for prediction were created from combinations of six vital sign measurements and their changes over time. Setting A mixed-ward retrospective dataset from the University of California, San Francisco (UCSF) Medical Center (San Francisco, California, USA) as the primary source, an intensive care unit dataset from the Beth Israel Deaconess Medical Center (Boston, Massachusetts, USA) as a transfer-learning source and four additional institutions’ datasets to evaluate generalisability. Participants 684 443 total encounters, with 90 353 encounters from June 2011 to March 2016 at UCSF. Interventions None. Primary and secondary outcome measures Area under the receiver operating characteristic (AUROC) curve for detection and prediction of sepsis, severe sepsis and septic shock. Results For detection of sepsis and severe sepsis, InSight achieves an AUROC curve of 0.92 (95% CI 0.90 to 0.93) and 0.87 (95% CI 0.86 to 0.88), respectively. Four hours before onset, InSight predicts septic shock with an AUROC of 0.96 (95% CI 0.94 to 0.98) and severe sepsis with an AUROC of 0.85 (95% CI 0.79 to 0.91). Conclusions InSight outperforms existing sepsis scoring systems in identifying and predicting sepsis, severe sepsis and septic shock. This is the first sepsis screening system to exceed an AUROC of 0.90 using only vital sign inputs. InSight is robust to missing data, can be customised to novel hospital data using a small fraction of site data and retains strong discrimination across all institutions.

Effect of a machine learning-based severe sepsis prediction algorithm on patient survival and hospital length of stay: a randomised clinical trial

Introduction Several methods have been developed to electronically monitor patients for severe sepsis, but few provide predictive capabilities to enable early intervention; furthermore, no severe sepsis prediction systems have been previously validated in a randomised study. We tested the use of a machine learning-based severe sepsis prediction system for reductions in average length of stay and in-hospital mortality rate. Methods We conducted a randomised controlled clinical trial at two medical-surgical intensive care units at the University of California, San Francisco Medical Center, evaluating the primary outcome of average length of stay, and secondary outcome of in-hospital mortality rate from December 2016 to February 2017. Adult patients (18+) admitted to participating units were eligible for this factorial, open-label study. Enrolled patients were assigned to a trial arm by a random allocation sequence. In the control group, only the current severe sepsis detector was used; in the experimental group, the machine learning algorithm (MLA) was also used. On receiving an alert, the care team evaluated the patient and initiated the severe sepsis bundle, if appropriate. Although participants were randomly assigned to a trial arm, group assignments were automatically revealed for any patients who received MLA alerts. Results Outcomes from 75 patients in the control and 67 patients in the experimental group were analysed. Average length of stay decreased from 13.0 days in the control to 10.3 days in the experimental group (p=0.042). In-hospital mortality decreased by 12.4 percentage points when using the MLA (p=0.018), a relative reduction of 58.0%. No adverse events were reported during this trial. Conclusion The MLA was associated with improved patient outcomes. This is the first randomised controlled trial of a sepsis surveillance system to demonstrate statistically significant differences in length of stay and in-hospital mortality. Trial registration NCT03015454.

Relationship Between a Sepsis Intervention Bundle and In-hospital Mortality Among Hospitalized Patients: A Retrospective Analysis of Real-world Data

BACKGROUND: Sepsis is a systemic response to infection that can lead to tissue damage, organ failure, and death. Efforts have been made to develop evidence-based intervention bundles to identify and manage sepsis early in the course of the disease to decrease sepsis-related morbidity and mortality. We evaluated the relationship between a minimally invasive sepsis intervention bundle and in-hospital mortality using robust methods for observational data. METHODS: We performed a retrospective cohort study at the University of California, San Francisco, Medical Center among adult patients discharged between January 1, 2012, and December 31, 2014, and who received a diagnosis of severe sepsis/septic shock (SS/SS). Sepsis intervention bundle elements included measurement of blood lactate; drawing of blood cultures before starting antibiotics; initiation of broad spectrum antibiotics within 3 hours of sepsis presentation in the emergency department or 1 hour of presentation on an inpatient unit; administration of intravenous fluid bolus if the patient was hypotensive or had a lactate level >4 mmol/L; and starting intravenous vasopressors if the patient remained hypotensive after fluid bolus administration. Poisson regression for a binary outcome variable was used to estimate an adjusted incidence-rate ratio (IRR) comparing mortality in groups defined by bundle compliance measured as a binary predictor, and to estimate an adjusted number needed to treat (NNT). RESULTS: Complete bundle compliance was associated with a 31% lower risk of mortality (adjusted IRR, 0.69, 95% confidence interval [CI], 0.53–0.91), adjusting for SS/SS presentation in the emergency department, SS/SS present on admission (POA), age, admission severity of illness and risk of mortality, Medicaid/Medicare payor status, immunocompromised host status, and congestive heart failure POA. The adjusted NNT to save one life was 15 (CI, 8–69). Other factors independently associated with mortality included SS/SS POA (adjusted IRR, 0.55; CI, 0.32–0.92) and increased age (adjusted IRR, 1.13 per 10-year increase in age; CI, 1.03–1.24). CONCLUSIONS: The University of California, San Francisco, sepsis bundle was associated with a decreased risk of in-hospital mortality across hospital units after robust control for confounders and risk adjustment. The adjusted NNT provides a reasonable and achievable goal to observe measureable improvements in outcomes for patients diagnosed with SS/SS.

Respiratory Complications and Management of Mechanical Ventilation in Cervical Spine Injury

It is estimated that the annual incidence of spinal cord injury in the United States is 12 000 new cases per year. Victims of spinal cord injury are prone to developing respiratory complications such as atelectasis, pneumonia, and ventilatory failure secondary to physiologic derangements resulting from spinal shock and paralysis. Respiratory complications are the leading cause of death in those who survive the initial injury. The goal in ventilator management of spinal cord injury patients in the intensive care unit setting is to prevent these complications and optimize patients for early transfer to a spinal cord rehabilitation facility. To minimize atelectasis, current guidelines recommend the use of very high tidal volumes (15 mL/kg) or setting high tidal volumes (10 mL/kg) in addition to using positive end-expiratory pressure. In this article, the authors discuss the pulmonary complications that affect the mortality of these patients and review the evidence behind the current high tidal volume ventila...