Exploring Alternate Targets for Respiratory Resuscitation in Patients With Sepsis and Septic Shock

Richardson L., Graham J.

Abstract In 1991, sepsis was first defined by the Society of Critical Care Medicine as the systemic inflammatory response syndrome, in the presence of infection. Systemic inflammatory response syndrome is an adaptive host response to infection, as well as to other insults like trauma and stress. Research pertaining to sepsis was guided by this adaptive definition for 25 years. After established guidelines for sepsis management were challenged in 2014, sepsis was redefined in 2016 as a dysregulated host response to infection. However, there still remains no consensus on which immunologic or metabolic mechanisms have become dysregulated. We sought to examine sepsis literature published after the 2016 consensus definition and compare it to the original systemic inflammatory response syndrome paradigm proposed in 1991. The purpose of this intensive analysis was to recommend a new sepsis archetype, with consideration to dysregulated immunologic and metabolic mechanisms that have recently been identified in sepsis. Nurses and other clinicians must shift their thought paradigm toward an evidence-based dysregulated model, in order to improve on sepsis recognition and management.

Yadav R.K., Gurung S., Karki S., Lama S., Tamang S., Poudel M.

Introduction and importance: While incidents are rare elsewhere, paraquat herbicide poisoning is a serious medical issue in some parts of Asia. It can cause the failure of various organs, including the heart, kidneys, liver, adrenal glands, central nervous system, muscles, and spleen. Due to its inherent toxicity and lack of available therapies, paraquat has a very high case fatality rate. Case presentation: The authors discuss a case of a 15-year-old female with an alleged history of paraquat ingestion who presented with complaints of vomiting, abdominal pain, and loose stools. Initially, she had gastrointestinal symptoms, but she developed renal failure and respiratory symptoms and died of multiple organ failure. Clinical discussion: Acute gastrointestinal tract necrosis and multiorgan failure are the initial effects of paraquat intake, and among those who survive the immediate post-ingestion interval, the lung is the target organ for poisoning. Ingestion of large amounts of liquid concentrates results in fulminant organ failure: pulmonary edema, cardiac, renal, and hepatic failure, and convulsions. The course of treatment can range from supportive care alone to various integration of immune modulation, antioxidant therapy, hemoperfusion, and hemodialysis. Conclusion: Patients presenting to the emergency department with an alleged history of ingestion of paraquat poisoning should be admitted even if they have mild symptoms initially. There is no specific antidote available. Early renal failure, along with progressive pulmonary fibrosis, can lead to death.

Hollenbeak C.S., Henning D.J., Geeting G.K., Ledeboer N.A., Faruqi I.A., Pierce C.G., Thomas C.B., O’Neal H.R.

OBJECTIVES: Sepsis causes 270,000 deaths and costs $38 billion annually in the United States. Most cases of sepsis present in the emergency department (ED), where rapid diagnosis remains challenging. The IntelliSep Index (ISI) is a novel diagnostic test that analyzes characteristics of WBC structure and provides a reliable early signal for sepsis. This study performs a cost-consequence analysis of the ISI relative to procalcitonin for early sepsis diagnosis in the ED. PERSPECTIVE: U.S. healthcare system. SETTING: Community hospital ED. METHODS: A decision tree analysis was performed comparing ISI with procalcitonin. Model parameters included prevalence of sepsis, sensitivity and specificity of diagnostic tests (both ISI and procalcitonin), costs of hospitalization, and mortality rate stratified by diagnostic test result. Mortality and prevalence of sepsis were estimated from best available literature. Costs were estimated based on an analysis of a large, national discharge dataset, and adjusted to 2018 U.S. dollars. Outcomes included expected costs and survival. RESULTS: Assuming a confirmed sepsis prevalence of 16.9% (adjudicated to Sepsis-3), the ISI strategy had an expected cost per patient of $3,849 and expected survival rate of 95.08%, whereas the procalcitonin strategy had an expected cost of $4,656 per patient and an expected survival of 94.98%. ISI was both less costly and more effective than procalcitonin, primarily because of fewer false-negative results. These results were robust in sensitivity analyses. CONCLUSIONS: ISI was both less costly and more effective in preventing mortality than procalcitonin, primarily because of fewer false-negative results. The ISI may provide health systems with a higher-value diagnostic test in ED sepsis evaluation. Additional work is needed to validate these results in clinical practice.

Piva S., Bertoni M., Gitti N., Rasulo F.A., Latronico N.

Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, is a leading cause of hospital and ICU admission. The central and peripheral nervous system may be the first organ system to show signs of dysfunction, leading to clinical manifestations such as sepsis-associated encephalopathy (SAE) with delirium or coma and ICU-acquired weakness (ICUAW). In the current review, we want to highlight developing insights into the epidemiology, diagnosis, prognosis, and treatment of patients with SAE and ICUAW.The diagnosis of neurological complications of sepsis remains clinical, although the use of electroencephalography and electromyography can support the diagnosis, especially in noncollaborative patients, and can help in defining disease severity. Moreover, recent studies suggest new insights into the long-term effects associated with SAE and ICUAW, highlighting the need for effective prevention and treatment.In this manuscript, we provide an overview of recent insights and developments in the prevention, diagnosis, and treatment of patients with SAE and ICUAW.

Andrés C.M., Pérez de la Lastra J.M., Juan C.A., Plou F.J., Pérez-Lebeña E.

This review examines the role of reactive species RS (of oxygen ROS, nitrogen RNS and halogen RHS) on innate immunity. The importance of these species in innate immunity was first recognized in phagocytes that underwent a “respiratory burst” after activation. The anion superoxide •O2− and hydrogen peroxide H2O2 are detrimental to the microbial population. NADPH oxidase NOx, as an •O2− producer is essential for microbial destruction, and patients lacking this functional oxidase are more susceptible to microbial infections. Reactive nitrogen species RNS (the most important are nitric oxide radical -•NO, peroxynitrite ONOO— and its derivatives), are also harmful to microorganisms, including bacteria, viruses, and parasites. Hypochlorous acid HOCl and hypothiocyanous acid HOSCN synthesized through the enzyme myeloperoxidase MPO, which catalyzes the reaction between H2O2 and Cl− or SCN−, are important inorganic bactericidal molecules, effective against a wide range of microbes. This review also discusses the role of antimicrobial peptides AMPs and their induction of ROS. In summary, reactive species RS are the heart of the innate immune system, and they are necessary for microbial lysis in infections that can affect mammals throughout their lives.

See W.Z., Naidu R., Tang K.S.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the cardinal features of tremor, bradykinesia, rigidity, and postural instability, in addition to other non-motor symptoms. Pathologically, PD is attributed to the loss of dopaminergic neurons in the substantia nigra pars compacta, with the hallmark of the presence of intracellular protein aggregates of α-synuclein in the form of Lewy bodies. The pathogenesis of PD is still yet to be fully elucidated due to the multifactorial nature of the disease. However, a myriad of studies has indicated several intracellular events in triggering apoptotic neuronal cell death in PD. These include oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, alteration in dopamine catabolism, inactivation of tyrosine hydroxylase, and decreased levels of neurotrophic factors. Laboratory studies using the herbicide paraquat in different in vitro and in vivo models have demonstrated the induction of many PD pathological features. The selective neurotoxicity induced by paraquat has brought a new dawn in our perspectives about the pathophysiology of PD. Epidemiological data have suggested an increased risk of developing PD in the human population exposed to paraquat for a long term. This model has opened new frontiers in the quest for new therapeutic targets for PD. The purpose of this review is to synthesize the relationship between the exposure of paraquat and the pathogenesis of PD in in vitro and in vivo models.

Nishimoto K., Umegaki T., Ohira S., Soeda T., Anada N., Uba T., Shoji T., Kusunoki M., Nakajima Y., Kamibayashi T.

Background. Septic patients often require mechanical ventilation due to respiratory dysfunction, and effective ventilatory strategies can improve survival. The effects of the combination of permissive hypoxia and hyperoxia avoidance for managing mechanically ventilated patients are unknown. This study examines these effects on outcomes in mechanically ventilated septic patients. Methods. In a retrospective before-and-after study, we examined adult septic patients (aged ≥18 years) requiring mechanical ventilation at a university hospital. On April 1, 2017, our mechanical ventilation policy changed from a conventional oxygenation target (SpO2: ≥96%) to more conservative targets with permissive hypoxia (SpO2: 88-92% or PaO2: 60 mmHg) and hyperoxia avoidance (reduced oxygenation for Pa O 2 > 110   mmHg ). Patients were divided into a prechange group (April 2015 to March 2017; n = 83 ) and a postchange group (April 2017 to March 2019; n = 130 ). Data were extracted from clinical records and insurance claims. Using a multiple logistic regression model, we examined the association of the postchange group (permissive hypoxia and hyperoxia avoidance) with intensive care unit (ICU) mortality after adjusting for variables such as Sequential Organ Failure Assessment (SOFA) score and PaO2/FiO2 ratios. Results. The postchange group did not have significantly lower adjusted ICU mortality (0.67, 0.33-1.43; P = 0.31 ) relative to the prechange group. However, there were significant intergroup differences in mechanical ventilation duration (prechange: 11.0 days, postchange: 7.0 days; P = 0.01 ) and ICU stay (prechange: 11.0 days, postchange: 9.0 days; P = 0.02 ). Conclusions. Permissive hypoxia and hyperoxia avoidance had no significant association with reduced ICU mortality in mechanically ventilated septic patients. However, this approach was significantly associated with shorter mechanical ventilation duration and ICU stay, which can improve patient turnover and ventilator access.

Forman H.J., Zhang H.

Masterson C., Horie S., McCarthy S.D., Gonzalez H., Byrnes D., Brady J., Fandiño J., Laffey J.G., O'Toole D.

Carbon dioxide (CO2) has long been considered, at best, a waste by-product of metabolism, and at worst, a toxic molecule with serious health consequences if physiological concentration is dysregulated. However, clinical observations have revealed that ‘permissive’ hypercapnia, the deliberate allowance of respiratory produced CO2to remain in the patient, can have anti-inflammatory effects that may be beneficial in certain circumstances. In parallel, studies at the cell level have demonstrated the profound effect of CO2on multiple diverse signalling pathways, be it the effect from CO2itself specifically or from the associated acidosis it generates. At the whole organism level, it now appears likely that there are many biological sensing systems designed to respond to CO2concentration and tailor respiratory and other responses to atmospheric or local levels. Animal models have been widely employed to study the changes in CO2levels in various disease states and also to what extent permissive or even directly delivered CO2can affect patient outcome. These findings have been advanced to the bedside at the same time that further clinical observations have been elucidated at the cell and animal level. Here we present a synopsis of the current understanding of how CO2affects mammalian biological systems, with a particular emphasis on inflammatory pathways and diseases such as lung specific or systemic sepsis. We also explore some future directions and possibilities, such as direct control of blood CO2levels, that could lead to improved clinical care in the future.

Loots F.J., Smulders D., Giesen P., Hopstaken R.M., Smits M.

Signs of the systemic inflammatory response syndrome (SIRS) - fever (or hypothermia), tachycardia and tachypnoea - are used in the hospital setting to identify patients with possible sepsis.To determine how frequently abnormalities in the vital signs of SIRS are present in adult out-of-hours (OOH) primary care patients with suspected infections and assess the association with acute hospital referral.We conducted a cross-sectional study at the OOH GP cooperative in Nijmegen, the Netherlands, between August and October 2015. GPs were instructed to record the body temperature, heart rate and respiratory rate of all patients with suspected acute infections. Vital signs of SIRS, other relevant signs and symptoms, and referral state were extracted from the electronic registration system of the OOH GP cooperative retrospectively. Logistic regression analysis was used to evaluate the association between clinical signs and hospital referral.A total of 558 patients with suspected infections were included. At least two SIRS vital signs were abnormal in 35/409 (8.6%) of the clinic consultations and 60/149 (40.3%) of the home visits. Referral rate increased from 13% when no SIRS vital sign was abnormal to 68% when all three SIRS vital signs were abnormal. Independent associations for referral were found for decreased oxygen saturation, hypotension and rapid illness progression, but not for individual SIRS vital signs.Although patients with abnormal vital signs of SIRS were referred more often, decreased oxygen saturation, hypotension and rapid illness progression seem to be most important for GPs to guide further management.

Cavaillon J., Singer M., Skirecki T.

Rudd K.E., Johnson S.C., Agesa K.M., Shackelford K.A., Tsoi D., Kievlan D.R., Colombara D.V., Ikuta K.S., Kissoon N., Finfer S., Fleischmann-Struzek C., Machado F.R., Reinhart K.K., Rowan K., Seymour C.W., et. al.

Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017.We used multiple cause-of-death data from 109 million individual death records to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990-2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. We used data for 8·7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates.In 2017, an estimated 48·9 million (95% uncertainty interval [UI] 38·9-62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1-12·0) sepsis-related deaths were reported, representing 19·7% (18·2-21·4) of all global deaths. Age-standardised sepsis incidence fell by 37·0% (95% UI 11·8-54·5) and mortality decreased by 52·8% (47·7-57·5) from 1990 to 2017. Sepsis incidence and mortality varied substantially across regions, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia, and southeast Asia.Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high health-related burden in sub-Saharan Africa.The Bill & Melinda Gates Foundation, the National Institutes of Health, the University of Pittsburgh, the British Columbia Children's Hospital Foundation, the Wellcome Trust, and the Fleming Fund.

Liu T., Zhang L., Joo D., Sun S.

The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation. In addition, NF-κB plays a critical role in regulating the survival, activation and differentiation of innate immune cells and inflammatory T cells. Consequently, deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-κB inhibition.

Gul F., Arslantas M.K., Cinel I., Kumar A.

Smallwood C.D., Walsh B.K.