Objective:To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008.Design:A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at ke

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.

To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008. A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7–9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a Pao
 2/Fio
 2 ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a Pao
 2/Fi
 o
 2 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5–10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven “absolute”’ adrenal insufficiency (2C). Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.

/pdf/surviving-sepsis-campaign-international-guidelines-for-229kg8suph.pdf

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012

Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury

Secret History: Return of the Black Death Channel 4, 7-8pm In 1348 the Black Death swept through London, killing people within days of the appearance of their first symptoms. Exactly how many died, and why, has long been a mystery. This Secret History documentary follows experts as they pick through the evidence and reveal why the plague killed on such a scale. And they ask, what might be coming next?

Medscape

118: major bleeding in medical-surgical critically ill patients is associated with increased use of blood products, longer hospital stay and higher mortality

Challenges of population-based colorectal cancer screening and the importance of time-trend analysis when evaluating system change.

The American Thoracic Society recently released a thoughtful and forward-thinking statement outlining a research agenda for precision medicine in sepsis and acute respiratory distress syndrome (ARDS). The statement draws attention to the problem of highly variable treatment responsiveness in these heterogeneous syndromes and proposes a range of promising solutions to address this problem, with a focus on enhanced molecular phenotyping and novel trial designs (1). This approach is predicated on an overarching hypothesis that the molecular contents of biospecimens contain the key to unlocking patient heterogeneity for precision-guided therapy for sepsis and ARDS. Although this hypothesis is very attractive and will undoubtedly yield exciting discoveries and therapies in the future, we suggest that the focus on molecular measurements is too narrow and overlooks critical readouts of systems biology, yielding an incomplete data set for precision medicine. We contend that physiology remains an important and feasible means to understand and predict heterogeneity of treatment effect. It has a proven record of success and can be used in real time to monitor and tailor treatment. The concept of precision medicine can carry multiple meanings. Applied to individual patients, it connotes the tailoring of treatments to some optimal dose or setting according to a patient’s individual characteristics. Physiology, including the information obtained from laboratory tests (e.g., blood gases), vital signs and hemodynamics (e.g., blood pressure), point-of-care ultrasound, and echocardiography, is routinely used to this end in the ICU (e.g., titration of ventilator settings, vasopressors, and inotropes). This tailoring relies on the individual patient’s physiological response, (often) in real time to the specific intervention, and how that intervention interacts with the patient’s host response to the particular insult (e.g., infection or trauma). The tailoring is also dependent on some understanding of the relationship between physiological parameters and the benefit or harm of the therapy, an understanding often derived from experimental physiology (e.g., plateau pressure and the risk of barotrauma). Applied to populations of patients, precision medicine connotes the selection of subgroups of patients for treatment on the basis of characteristics that suggest a higher probability of benefit. In discussions of this type of precision, increasing attention has focused on treatment responsiveness defined by molecular biological phenotypes (2), but here we also contend that physiology has an important role to play. For example, phenotypes based on molecular biomarkers may predict whether a broadly “liberal” or “conservative” fluid strategy is more likely to be of benefit in ARDS (3), but it is targeting fluid therapy to physiological parameters such as change in capillary refill time that may result in lower mortality and faster resolution of organ dysfunction in patients with septic shock (4). As a discipline studying the mechanisms of living organisms, physiology aims to assess and understand the integrated function of organ systems. There is compelling evidence that systematic assessment of whole-organ function can be used to identify treatment-responsive subpopulations across a range of interventions in ARDS and sepsis. Distinct clinical phenotypes of ARDS have been detected using physiological markers as well as molecular characteristics (5). Physiological parameters can predict not only prognosis but also treatment effect and can do so dynamically over time. For example, higher positive end-expiratory pressure probably benefits only patients with significant potential for lung recruitment as measured by lung mechanics and imaging (6). Dead space and respiratory system elastance identify patients with a greater clinical response to extracorporeal CO2 removal (7). Respiratory system elastance appears to identify patients who will (and who will not) benefit from lowering VT from 10–12 ml/kg to 4–8 ml/kg (8). Physiological markers of fluid responsiveness may be useful to determine whether patients are likely to benefit from further volume resuscitation (9, 10). Clinical physiology remains relevant and relatively easy to implement at the bedside to identify patients who are potentially more or less likely to benefit from a specific therapy. Of course, as with molecular markers, trials are required to confirm clinically relevant treatment benefits in subsets of patients defined by these physiological markers. Only those physiological characteristics that reflect the mechanisms that drive injury and outcomes will be relevant to personalizing care. Many physiological markers do not predict the relative benefit or harm of treatment, even those that usefully stratify the risk of death. For example, the benefit of lung-protective ventilation is unrelated to the severity of hypoxemia, as lung-protective ventilation in any given patient may be associated with worsened oxygenation but improved mortality (11), and the effect of lowering VT onmortality is independent of the severity of hypoxemia (8). In contrast, elastance and driving pressure, which reflect mechanistically relevant lung stress and strain, provide more appropriate targets for personalizing VT (8). The uses of physiology and physiological responsiveness for precision medicine in a prospective trial design have already been described (6, 7). The recent multiplatform trial of therapeutic anticoagulation with heparin in coronavirus disease (COVID-19) provides an instructive example of using both physiology and biomarkers in trial design for precision medicine (12). At the outset, the investigators hypothesized that treatment effect may vary according to both the patient’s physiological state (severely ill, requiring ICU-level organ support, vs. moderately ill, not requiring organ support) and by baseline D-dimer (a biomarker hypothesized to reflect hypercoagulation from COVID-19). Implementing some of This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).

https://doi.org/10.1164/rccm.202202-0230ed

Physiology Is Vital to Precision Medicine in Acute Respiratory Distress Syndrome and Sepsis

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9801169

“ISTH guidelines for antithrombotic treatment in COVID‐19”: Reply

Septic shock is associated with a mortality of 20–40%. The white blood cell count (WBC) at hospital admission correlates with prognosis in septic shock. Here, we explore whether the trajectory of WBC after admission provides further information about outcomes. We aimed to identify groups of patients with different WBC trajectories and the association of WBC trajectory with mortality. We included adult patients with septic shock in two academic intensive care units (ICU) in Winnipeg, MB, Canada between 2006 and 2012. We used group-based trajectory analysis to group patients according to their WBC patterns over the first seven days in the ICU. Our primary analysis was the association of WBC trajectory group on 30-day mortality using multivariable Cox proportional hazards regression. We included 917 patients with septic shock. The final model identified seven distinct WBC trajectories. The rising WBC trajectory was independently associated with increased mortality (hazard ratio, 3.41; 95% confidence interval, 1.86 to 6.26; P < 0.001) compared with the stable WBC trajectory. In patients with septic shock, distinct and clinically relevant groups can be identified by analyzing WBC trajectories. A rising WBC trajectory was associated with higher mortality. 

/pdf/white-blood-cell-count-trajectory-and-mortality-in-septic-uh2uee29.pdf

Ryan Zarychanski

Papers

118: major bleeding in medical-surgical critically ill patients is associated with increased use of blood products, longer hospital stay and higher mortality

Challenges of population-based colorectal cancer screening and the importance of time-trend analysis when evaluating system change.

Physiology Is Vital to Precision Medicine in Acute Respiratory Distress Syndrome and Sepsis

“ISTH guidelines for antithrombotic treatment in COVID‐19”: Reply

White blood cell count trajectory and mortality in septic shock: a historical cohort study