Jean Francois Pittet

The perioperative surgical home: How anesthesiology can collaboratively achieve and leverage the triple aim in health care

ORIGINS AND PARTICIPANTS OF THE PERIOPERATIVE SURGICAL HOMEGuiding Principles of the Triple Aim and the Patient-Centered Medical HomeBy 2019, an estimated 19.3% of the United States gross domestic product will be devoted to health care.1 Health care delivery and payment systems in the United States

Regulation of apoptotic and inflammatory cell signaling in cerebral ischemia - the complex roles of Heat Shock Protein 70

Although heat shock proteins have been studied for decades, new intracellular and extracellular functions in a variety of diseases continue to be discovered. Heat shock proteins function within networks of interacting proteins; they can alter cellular physiology rapidly in response to stress without requiring new protein synthesis. This review focuses on the heat shock protein 70 family and considers especially the functions of the inducible member, heat shock protein 72, in the setting of cerebral ischemia. In general, inhibiting apoptotic signaling at multiple points and up-regulating survival signaling, heat shock protein 70 has a net prosurvival effect. Heat shock protein 70 has both antiinflammatory and proinflammatory effects depending on the cell type, context, and intracellular or extracellular location. Intracellular effects are often antiinflammatory with inhibition of nuclear factor-&kgr;B signaling. Extracellular effects can lead to inflammatory cytokine production or induction of regulatory immune cells and reduced inflammation.

The Perioperative Surgical Home: how can it make the case so everyone wins?

BackgroundVaried and fragmented care plans undertaken by different practitioners currently expose surgical patients to lapses in expected care, increase the chance for operational mistakes and accidents, and often result in unnecessary care. The Perioperative Surgical Home has thus been proposed by the American Society of Anesthesiologists and other stakeholders as an innovative, patient-centered, surgical continuity of care model that incorporates shared decision making. Topics central to the debate about an anesthesiology-based Perioperative Surgical Home include: holding the gains made in anesthesia-related patient safety; impacting surgical morbidity and mortality, including failure-to-rescue; achieving healthcare outcome metrics; assimilating comparative effectiveness research into the model; establishing necessary audit and data collection; a comparison with the hospitalist model of perioperative care; the perspective of the surgeon; the benefits of the Perioperative Surgical Home to the specialty of anesthesiology; and its associated healthcare economic advantages.DiscussionImproving surgical morbidity and mortality mandates a more comprehensive and integrated approach to the management of surgical patients. In their expanded capacity as the surgical patient’s “perioperativist,” anesthesiologists can play a key role in compliance with broader set of process measures, thus becoming a more vital and valuable provider from the patient, administrator, and payer perspective. The robust perioperative databases created within the Perioperative Surgical Home present new opportunities for health services and population-level research. The Perioperative Surgical Home is not intended to replace the surgeon’s patient care responsibility, but rather leverage the abilities of the entire perioperative care team in the service of the patient. To achieve this goal, it will be necessary to expand the core knowledge, skills, and experience of anesthesiologists. Anesthesiologists will need to view becoming perioperative physicians as an expansion of the specialty, rather than an abdication of their traditional intraoperative role. The Perioperative Surgical Home will need to create strategic added value for a health system and payers. This added value will strengthen the position of anesthesiologists as they navigate and negotiate in the face of finite, if not decreasing fiscal resources.SummaryBroadening the anesthesiologist’s scope of practice via the Perioperative Surgical Home may promote standardization and improve clinical outcomes and decrease resource utilization by providing greater patient-centered continuity of care throughout the preoperative, intraoperative, and postoperative periods.

HMGB1 promotes neutrophil extracellular trap formation through interactions with Toll-like receptor 4

Although neutrophil extracellular traps (NETs) form to prevent dissemination of pathogenic microorganisms, excessive release of DNA and DNA-associated proteins can also perpetuate sterile inflammation. In this study, we found that the danger-associated molecular pattern protein high-mobility group box 1 (HMGB1) can induce NET formation. NET formation was found after exposure of wild-type and receptor for advanced glycation end products-deficient neutrophil to HMGB1, whereas deficiency of Toll-like receptor (TLR)4 diminished the ability of neutrophils to produce NETs. Incubation of neutrophils with HMGB1 significantly increased the amount of DNA and histone 3 released as well as intracellular histone 3 citrullination, a signaling event that precedes chromatin decondensation. In vivo, neutrophils isolated from bronchoalveolar lavages of mice exposed to LPS and HMGB1 showed consistently greater ability to produce NETs compared with pulmonary neutrophils from mice that received LPS alone. In contrast, mice treated with LPS and neutralizing antibody to HMGB1 had decreased amounts of the inflammatory cytokines TNF-α and macrophage inflammatory protein 2, as well as of free DNA and histone 3 in bronchoalveolar lavage fluids. Airway neutrophils from LPS-exposed mice that had been treated with anti-HMGB1 antibodies showed decreased citrullination of histone 3. These results demonstrate that interactions between HMGB1 and TLR4 enhance the formation of NETs and provide a novel mechanism through which HMGB1 may contribute to the severity of neutrophil-associated inflammatory conditions.

An analysis of methodologies that can be used to validate if a perioperative surgical home improves the patient-centeredness, evidence-based practice, quality, safety, and value of patient care.

Approximately 80 million inpatient and outpatient surgeries are performed annually in the United States. Widely variable and fragmented perioperative care exposes these surgical patients to lapses in expected standard of care, increases the chance for operational mistakes and accidents, results in unnecessary and potentially detrimental care, needlessly drives up costs, and adversely affects the patient healthcare experience. The American Society of Anesthesiologists and other stakeholders have proposed a more comprehensive model of perioperative care, the Perioperative Surgical Home (PSH), to improve current care of surgical patients and to meet the future demands of increased volume, quality standards, and patient-centered care. To justify implementation of this new healthcare delivery model to surgical colleagues, administrators, and patients and maintain the integrity of evidenced-based practice, the nascent PSH model must be rigorously evaluated. This special article proposes comparative effectiveness research aims or objectives and an optimal study design for the novel PSH model.

Protein C and acute inflammation: a clinical and biological perspective

The protein C system plays an active role in modulating severe systemic inflammatory processes such as sepsis, trauma, and acute respiratory distress syndrome (ARDS) via its anticoagulant and anti-inflammatory properties. Plasma levels of activated protein C (aPC) are lower than normal in acute inflammation in humans, except early after severe trauma when high plasma levels of aPC may play a mechanistic role in the development of posttraumatic coagulopathy. Thus, following positive results of preclinical studies, a clinical trial (PROWESS) with high continuous doses of recombinant human aPC given for 4 days demonstrated a survival benefit in patients with severe sepsis. This result was not confirmed by subsequent clinical trials, including the recently published PROWESS-SHOCK trial in patients with septic shock and a phase II trial with patients with nonseptic ARDS. A possible explanation for the major difference in outcome between PROWESS and PROWESS-SHOCK trials is that lung-protective ventilation was used for the patients included in the recent PROWESS-SHOCK, but not in the original PROWESS trial. Since up to 75% of sepsis originates from the lung, aPC treatment may not have added enough to the beneficial effect of lung-protective ventilation to show lower mortality. Thus whether aPC will continue to be used to modulate the acute inflammatory response in humans remains uncertain. Because recombinant human aPC has been withdrawn from the market, a better understanding of the complex interactions between coagulation and inflammation is needed before considering the development of new drugs that modulate both coagulation and acute inflammation in humans.

Protein Kinase C-α and Arginase I Mediate Pneumolysin-Induced Pulmonary Endothelial Hyperpermeability

Antibiotics-induced release of the pore-forming virulence factor pneumolysin (PLY) in patients with pneumococcal pneumonia results in its presence days after lungs are sterile and is a major factor responsible for the induction of permeability edema. Here we sought to identify major mechanisms mediating PLY-induced endothelial dysfunction. We evaluated PLY-induced endothelial hyperpermeability in human lung microvascular endothelial cells (HL-MVECs) and human lung pulmonary artery endothelial cells in vitro and in mice instilled intratracheally with PLY. PLY increases permeability in endothelial monolayers by reducing stable and dynamic microtubule content and modulating VE-cadherin expression. These events, dependent upon an increased calcium influx, are preceded by protein kinase C (PKC)-α activation, perturbation of the RhoA/Rac1 balance, and an increase in myosin light chain phosphorylation. At later time points, PLY treatment increases the expression and activity of arginase in HL-MVECs. Arginase inhibition abrogates and suppresses PLY-induced endothelial barrier dysfunction by restoring NO generation. Consequently, a specific PKC-α inhibitor and the TNF-derived tonoplast intrinsic protein peptide, which blunts PLY-induced PKC-α activation, are able to prevent activation of arginase in HL-MVECs and to reduce PLY-induced endothelial hyperpermeability in mice. Arginase I (AI)(+/-)/arginase II (AII)(-/-) C57BL/6 mice, displaying a significantly reduced arginase I expression in the lungs, are significantly less sensitive to PLY-induced capillary leak than their wild-type or AI(+/+)/AII(-/-) counterparts, indicating an important role for arginase I in PLY-induced endothelial hyperpermeability. These results identify PKC-α and arginase I as potential upstream and downstream therapeutic targets in PLY-induced pulmonary endothelial dysfunction.

Coagulopathy after severe pediatric trauma

ABSTRACT Trauma remains the leading cause of morbidity and mortality in the United States among children aged 1 to 21 years. The most common cause of lethality in pediatric trauma is traumatic brain injury. Early coagulopathy has been commonly observed after severe trauma and is usually associated with severe hemorrhage and/or traumatic brain injury. In contrast to adult patients, massive bleeding is less common after pediatric trauma. The classical drivers of trauma-induced coagulopathy include hypothermia, acidosis, hemodilution, and consumption of coagulation factors secondary to local activation of the coagulation system after severe traumatic injury. Furthermore, there is also recent evidence for a distinct mechanism of trauma-induced coagulopathy that involves the activation of the anticoagulant protein C pathway. Whether this new mechanism of posttraumatic coagulopathy plays a role in children is still unknown. The goal of this review is to summarize the current knowledge on the incidence and potential mechanisms of coagulopathy after pediatric trauma and the role of rapid diagnostic tests for early identification of coagulopathy. Finally, we discuss different options for treating coagulopathy after severe pediatric trauma.

A novel tumor necrosis factor–mediated mechanism of direct epithelial sodium channel activation

RATIONALE Alveolar liquid clearance is regulated by Na(+) uptake through the apically expressed epithelial sodium channel (ENaC) and basolaterally localized Na(+)-K(+)-ATPase in type II alveolar epithelial cells. Dysfunction of these Na(+) transporters during pulmonary inflammation can contribute to pulmonary edema. OBJECTIVES In this study, we sought to determine the precise mechanism by which the TIP peptide, mimicking the lectin-like domain of tumor necrosis factor (TNF), stimulates Na(+) uptake in a homologous cell system in the presence or absence of the bacterial toxin pneumolysin (PLY). METHODS We used a combined biochemical, electrophysiological, and molecular biological in vitro approach and assessed the physiological relevance of the lectin-like domain of TNF in alveolar liquid clearance in vivo by generating triple-mutant TNF knock-in mice that express a mutant TNF with deficient Na(+) uptake stimulatory activity. MEASUREMENTS AND MAIN RESULTS TIP peptide directly activates ENaC, but not the Na(+)-K(+)-ATPase, upon binding to the carboxy-terminal domain of the α subunit of the channel. In the presence of PLY, a mediator of pneumococcal-induced pulmonary edema, this binding stabilizes the ENaC-PIP2-MARCKS complex, which is necessary for the open probability conformation of the channel and preserves ENaC-α protein expression, by means of blunting the protein kinase C-α pathway. Triple-mutant TNF knock-in mice are more prone than wild-type mice to develop edema with low-dose intratracheal PLY, correlating with reduced pulmonary ENaC-α subunit expression. CONCLUSIONS These results demonstrate a novel TNF-mediated mechanism of direct ENaC activation and indicate a physiological role for the lectin-like domain of TNF in the resolution of alveolar edema during inflammation.

The glycocalyx and Trauma: A Review

ABSTRACT In the United States trauma is the leading cause of mortality among those under the age of 45, claiming approximately 192,000 lives each year. Significant personal disability, lost productivity, and long-term healthcare needs are common and contribute 580 billion dollars in economic impact each year. Improving resuscitation strategies and the early acute care of trauma patients has the potential to reduce the pathological sequelae of combined exuberant inflammation and immune suppression that can co-exist, or occur temporally, and adversely affect outcomes. The endothelial and epithelial glycocalyx has emerged as an important participant in both inflammation and immunomodulation. Constituents of the glycocalyx have been used as biomarkers of injury severity and have the potential to be target(s) for therapeutic interventions aimed at immune modulation. In this review, we provide a contemporary understanding of the physiologic structure and function of the glycocalyx and its role in traumatic injury with a particular emphasis on lung injury.