Outcomes of hospitalized hematologic oncology patients receiving rapid response system activation for acute deterioration.

BACKGROUND: Patients with hematologic malignancies who are admitted to hospital are at increased risk of deterioration and death. Rapid response systems (RRSs) respond to hospitalized patients who clinically deteriorate. We sought to describe the characteristics and outcomes of hematologic oncology inpatients requiring rapid response system (RRS) activation, and to determine the prognostic accuracy of the SIRS and qSOFA criteria for in-hospital mortality of hematologic oncology patients with suspected infection. METHODS: We used registry data from two hospitals within The Ottawa Hospital network, between 2012 and 2016. Consecutive hematologic oncology inpatients who experienced activation of the RRS were included in the study. Data was gathered at the time of RRS activation and assessment. The primary outcome was in-hospital mortality. Logistical regression was used to evaluate for predictors of in-hospital mortality. RESULTS: We included 401 patients during the study period. In-hospital mortality for all included patients was 41.9% (168 patients), and 145 patients (45%) were admitted to ICU following RRS activation. Among patients with suspected infection at the time of RRS activation, Systemic Inflammatory Response Syndrome (SIRS) criteria had a sensitivity of 86.9% (95% CI 80.9-91.6) and a specificity of 38.2% (95% CI 31.9-44.8) for predicting in-hospital mortality, while Quick Sequential Organ Failure Assessment (qSOFA) criteria had a sensitivity of 61.9% (95% CI 54.1-69.3) and a specificity of 91.4% (95% CI 87.1-94.7). Factors associated with increased in-hospital mortality included transfer to ICU after RRS activation (adjusted odds ratio [OR] 3.56, 95% CI 2.12-5.97) and a higher number of RRS activations (OR 2.45, 95% CI 1.63-3.69). Factors associated with improved survival included active malignancy treatment at the time of RRS activation (OR 0.54, 95% CI 0.34-0.86) and longer hospital length of stay (OR 0.78, 95% CI 0.70-0.87). CONCLUSIONS: Hematologic oncology inpatients requiring RRS activation have high rates of subsequent ICU admission and mortality. ICU admission and higher number of RRS activations are associated with increased risk of death, while active cancer treatment and longer hospital stay are associated with lower risk of mortality. Clinicians should consider these factors in risk-stratifying these patients during RRS assessment.

Mitochondrial NLRP3 protein induces reactive oxygen species to promote Smad protein signaling and fibrosis independent from the inflammasome.

Nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) is a pattern recognition receptor that is implicated in the pathogenesis of inflammation and chronic diseases. Although much is known regarding the NLRP3 inflammasome that regulates proinflammatory cytokine production in innate immune cells, the role of NLRP3 in non-professional immune cells is unclear. Here we report that NLRP3 is expressed in cardiac fibroblasts and increased during TGFß stimulation. NLRP3-deficient cardiac fibroblasts displayed impaired differentiation and R-Smad activation in response to TGFß. Only the central nucleotide binding domain of NLRP3 was required to augment R-Smad signaling because the N-terminal Pyrin or C-terminal leucine-rich repeat domains were dispensable. Interestingly, NLRP3 regulation of myofibroblast differentiation proceeded independently from the inflammasome, IL-1ß/IL-18, or caspase 1. Instead, mitochondrially localized NLRP3 potentiated reactive oxygen species to augment R-Smad activation. In vivo, NLRP3-deficient mice were protected against angiotensin II-induced cardiac fibrosis with preserved cardiac architecture and reduced collagen 1. Together, these results support a distinct role for NLRP3 in non-professional immune cells independent from the inflammasome to regulate differential aspects of wound healing and chronic disease.

Heat shock protein 27 in the pathogenesis of COVID-19 and non-COVID acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a common cause of hypoxemic respiratory failure in intensive care units that has increased dramatically as a result of the COVID-19 pandemic. In both COVID-19 and non-COVID ARDS, the pathogenesis of lung injury involves local (pulmonary) and systemic inflammation, leading to impaired gas exchange, requirement for mechanical ventilation, and a high risk of mortality. Heat shock protein 27 (HSP27) is a chaperone protein expressed in times of cell stress with roles in modulation of systemic inflammation via the NF-κB pathway. Given its important role as a modulator of inflammation, we sought to investigate the role of HSP27 and its associated auto-antibodies in ARDS caused by both SARS-CoV-2 and non-COVID etiologies. A total of 68 patients admitted to the intensive care unit with ARDS requiring mechanical ventilation were enrolled in a prospective, observational study that included 22 non-COVID-19 and 46 COVID-19 patients. Blood plasma levels of HSP27, anti-HSP27 auto-antibody (AAB), and cytokine profiles were measured on days 1 and 3 of ICU admission along with clinical outcome measures. Patients with COVID-19 ARDS displayed significantly higher levels of HSP27 in plasma, and a higher ratio of HSP27:AAB on both day 1 and day 3 of ICU admission. In patients with COVID-19, higher levels of circulating HSP27 and HSP27:AAB ratio were associated with a more severe systemic inflammatory response and adverse clinical outcomes including more severe hypoxemic respiratory failure. These findings implicate HSP27 as a marker of advanced pathogenesis of disease contributing to the dysregulated systemic inflammation and worse clinical outcomes in COVID-19 ARDS, and therefore may represent a potential therapeutic target.

Choice of crystalloid fluid in the treatment of hyperglycemic emergencies: a systematic review protocol.

BACKGROUND: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are life-threatening complications of diabetes mellitus which require prompt treatment with large volume crystalloid fluid administration. A variety of crystalloid fluids is currently available for use and differs in their composition and ion concentrations. While there are potential pros and cons for different crystalloid fluids, it remains unknown if any particular fluid confers a clinical outcome benefit over others in the treatment of hyperglycemic emergencies. METHODS: A systematic search of MEDLINE, Embase, and the Cochrane Library of Systematic Reviews will be conducted to identify eligible studies, which will include observational and interventional studies involving adult and pediatric patients admitted to the hospital with either DKA or HHS. The interventions will include intravenous treatment with 0.9% saline versus other buffered (Ringer's lactate, Hartmann's, etc.), and non-buffered (0.45% saline) crystalloid fluids. The primary outcome is mortality at the latest follow-up time point. Secondary outcomes will include mortality at specific time points, length of hospital stay, development of acute kidney injury, requirement for renal replacement therapy, altered level of consciousness, and the time to normalization of several serum biochemical parameters. Where appropriate, meta-analyses will be performed for the outcomes and conducted separately for adult and pediatric patient populations. DISCUSSION: DKA and HHS are dangerous complications of diabetes mellitus and account for significant morbidity and mortality. Given the importance of crystalloid fluid administration in the management of these conditions, a systematic synthesis of the existing evidence base will identify potential evidence gaps and may help guide future clinical practice.

Incorporating Laboratory Values Into a Machine Learning Model Improves In-Hospital Mortality Predictions After Rapid Response Team Call.

OBJECTIVES: Machine learning models have been used to predict mortality among patients requiring rapid response team activation. The goal of our study was to assess the impact of adding laboratory values into the model. DESIGN: A gradient boosted decision tree model was derived and internally validated to predict a primary outcome of in-hospital mortality. The base model was then augmented with laboratory values. SETTING: Two tertiary care hospitals within The Ottawa Hospital network. PATIENTS: Inpatients over the age of 18 years who experienced a rapid response team activation between January 1, 2015, and May 31, 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 2,061 rapid response team activations occurred during the study period. The in-hospital mortality rate was 29.4%. Patients who died were older (median age, 72 vs 68 yr; p < 0.001), had a longer length of stay (length of stay) prior to rapid response team activation (4 vs 2 d; p < 0.001), and more often had respiratory distress (31% vs 22%; p < 0.001). Our base model without laboratory values performed with an area under the receiver operating curve of 0.71 (95% CI, 0.71-0.72). When the base model was augmented with laboratory values, the area under the receiver operating curve improved to 0.77 (95% CI, 0.77-0.78). Important mortality predictors in the base model were age, estimated ratio of Pao2 to Fio2 (calculated using oxygen saturation and estimated Fio2), length of stay prior to rapid response team activation, and systolic blood pressure. CONCLUSIONS: Machine learning models can identify rapid response team patients at a high risk of mortality and potentially supplement clinical decision making. Incorporating laboratory values into model development significantly improved predictive performance in this study.

A Unique Case of Metformin-Associated Lactic Acidosis.

Metformin-associated lactic acidosis [MALA] is a potentially fatal condition characterized by an elevation in serum lactate in patients with metformin exposure. An 82-year-old man with no prior renal history was brought to hospital after being found by his family in a confused state. He had a history of type 2 diabetes mellitus, and his medications included regular metformin. On arrival to our hospital he was conscious but confused and noted recent decreased oral intake. Initial investigations revealed severe acidemia (pH <6.75, undetectable bicarbonate), with elevated serum lactate, urea, creatinine, and hyperkalemia. He was treated with intravenous dextrose, crystalloids, and bicarbonate and underwent urgent hemodialysis. The patient responded well to supportive therapies and achieved full renal recovery one week after admission. He was discharged feeling well, with a new antihyperglycemic medication regimen. This case highlights the potential for life-threatening acidemia in cases of MALA. The case is further unique in that the patient was conscious and responded to questions on arrival, despite the serious metabolic disturbance, and recovered completely. From a safety standpoint, health care providers should advise and educate their patients about discontinuing metformin and other potentially harmful medications in the context of acute illness with volume contraction.