Purpose
Prolonged mechanical ventilation (MV) is a major complication following cardiac surgery. We conducted a secondary analysis of the Transfusion Requirements in Cardiac Surgery (TRICTS) III ...trial to describe MV duration, identify factors associated with prolonged MV, and examine associations of prolonged MV with mortality and complications.
Methods
Four thousand, eight hundred and nine participants undergoing cardiac surgery at 71 hospitals worldwide were included. Prolonged MV was defined based on the Society of Thoracic Surgeons definition as MV lasting 24 hr or longer. Adjusted associations of patient and surgical factors with prolonged MV were examined using multivariable logistic regression. Associations of prolonged MV with complications were assessed using odds ratios, and adjusted associations between prolonged MV and mortality were evaluated using multinomial regression. Associations of shorter durations of MV with survival and complications were explored.
Results
Prolonged MV occurred in 15% (725/4,809) of participants. Prolonged MV was associated with surgical factors indicative of complexity, such as previous cardiac surgery, cardiopulmonary bypass duration, and separation attempts; and patient factors such as critical preoperative state, left ventricular impairment, renal failure, and pulmonary hypertension. Prolonged MV was associated with perioperative but not long-term complications. After risk adjustment, prolonged MV was associated with perioperative mortality; its association with long-term mortality among survivors was weaker. Shorter durations of MV were not associated with increased risk of mortality or complications.
Conclusion
In this substudy of the TRICS III trial, prolonged MV was common after cardiac surgery and was associated with patient and surgical risk factors. Although prolonged MV showed strong associations with perioperative complications and mortality, it was not associated with long-term complications and had weaker association with long-term mortality among survivors.
Study registration
www.ClinicalTrials.gov
(NCT02042898); registered 23 January 2014. This is a substudy of the Transfusion Requirements in Cardiac Surgery (TRICS) III trial.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Mobilization in the intensive care unit (ICU) has the potential to improve patient outcomes following acute stroke. The optimal duration and intensity of mobilization for patients with ...hemorrhagic or ischemic stroke in the ICU remain unclear.
Objective
To assess the effect of mobilization dose in the ICU on adverse discharge disposition in patients after stroke.
Design
This is an international, prospective, observational cohort study of critically ill stroke patients (November 2017–September 2019). Duration and intensity of mobilization was quantified daily by the mobilization quantification score (MQS).
Setting
Patients requiring ICU‐level care were enrolled within 48 hours of admission at four separate academic medical centers (two in Europe, two in the United States).
Participants
Participants included individuals (>18 years old) admitted to an ICU within 48 hours of ischemic or hemorrhagic stroke onset who were functionally independent at baseline.
Interventions
Not applicable.
Main Outcome Measure
The primary outcome was adverse discharge disposition.
Results
Of the patients screened, 163 were eligible for inclusion in the study. One patient was subsequently excluded due to insufficient data collection (n = 162). The dose of mobilization varied greatly between centers and patients, which could not be explained by patients' comorbidities or disease severity. High dose of mobilization (mean MQS > 7.3) was associated with a lower likelihood of adverse discharge (adjusted odds ratio, aOR: 0.14; 95% confidence interval CI: 0.06–0.31; p < .01).
Conclusion
The increased use of mobilization acutely in the ICU setting may improve patient outcomes.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A central component of septic shock treatment is the infusion of vasopressors, most commonly starting with norepinephrine. However, the optimal approach and practice patterns for initiating ...adjunctive vasopressors and corticosteroids are unknown.
To characterize practice pattern variation in the norepinephrine dose at which secondary vasopressors and adjunctive corticosteroids are initiated and to identify factors associated with a treatment strategy favoring secondary vasopressors compared with factors associated with a treatment strategy favoring adjunctive corticosteroids among patients with septic shock on norepinephrine.
We used a multicenter intensive care unit (ICU) database to identify patients with septic shock who were started on norepinephrine followed by an additional vasopressor or corticosteroids. We used multilevel models to determine the hospital risk-adjusted norepinephrine dose at which additional vasopressors and corticosteroids were started, the percentage of variation in the norepinephrine dose at the time of adjunctive treatment associated with the hospital of admission, and the factors associated with choosing an "additional-vasopressor-first" strategy versus a "corticosteroid-first" strategy.
Among 4,401 patients with septic shock on norepinephrine, 1,940 (44.0%) were started on adjuncts (1,357 received an additional-vasopressor-first strategy, and 583 received a corticosteroid-first strategy). The hospital risk-adjusted norepinephrine dose at which vasopressors were initiated ranged from 6.4 μg/min (95% confidence interval CI, 5.9-7.0 μg/min) to 92.6 μg/min (95% CI, 72.8-113.0 μg/min). The hospital risk-adjusted norepinephrine dose at which corticosteroids were initiated ranged from 3.0 μg/min (95% CI, 2.4-3.8 μg/min) to 32.7 μg/min (95% CI, 24.9-43.0 μg/min). Of the variation in the norepinephrine dose at which additional vasopressors were initiated, 25.1% (intraclass correlation coefficient 95% CI, 24.8-25.5%) was explained by the hospital site after adjusting for all hospital- and patient-level covariates. The hospital of admission was strongly associated with receiving an additional-vasopressor-first strategy over a corticosteroid-first strategy (median odds ratio, 3.28 95% CI, 2.81-3.83).
Practice patterns for adjunctive therapies to norepinephrine during septic shock are variable and are determined in large part by the hospital of admission. These results inform several future studies seeking to improve septic shock management.
Background
A substantial proportion of patients undergoing inpatient surgery each year is at risk for postoperative institutionalization and loss of independence. Reliable individualized preoperative ...prediction of adverse discharge can facilitate advanced care planning and shared decision making.
Methods
Using hospital registry data from previously home‐dwelling adults undergoing inpatient surgery, we retrospectively developed and externally validated a score predicting adverse discharge. Multivariable logistic regression analysis and bootstrapping were used to develop the score. Adverse discharge was defined as in‐hospital mortality or discharge to a skilled nursing facility. The model was subsequently externally validated in a cohort of patients from an independent hospital.
Results
In total, 106 164 patients in the development cohort and 92 962 patients in the validation cohort were included, of which 16 624 (15.7%) and 7717 (8.3%) patients experienced adverse discharge, respectively. The model was predictive of adverse discharge with an area under the receiver operating characteristic curve (AUC) of 0.87 (95% CI 0.87‐0.88) in the development cohort and an AUC of 0.86 (95% CI 0.86‐0.87) in the validation cohort.
Conclusion
Using preoperatively available data, we developed and validated a prediction instrument for adverse discharge following inpatient surgery. Reliable prediction of this patient centered outcome can facilitate individualized operative planning to maximize value of care.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Background: There is paucity of data regarding prevalence and key harms of non-medical cannabis use in surgical patients. We investigated whether cannabis use in patients undergoing surgery or ...interventional procedures patients was associated with a higher degree of post-procedural healthcare utilisation. Methods: 210,639 adults undergoing non-cardiac surgery between January 2008 and June 2020 at an academic healthcare network in Massachusetts, USA, were included. The primary exposure was use of cannabis, differentiated by reported ongoing non-medical use, self-identified during structured, preoperative nursing/physician interviews, or diagnosis of cannabis use disorder based on International Classification of Diseases, 9th/10th Revision, diagnostic codes. The main outcome measure was the requirement of advanced post-procedural healthcare utilisation (unplanned intensive care unit admission, hospital re-admission or non-home discharge). Findings: 16,211 patients (7.7%) were identified as cannabis users. The prevalence of cannabis use increased from 4.9% in 2008 to 14.3% by 2020 (p < 0.001). Patients who consumed cannabis had higher rates of psychiatric comorbidities (25.3 versus 16.8%; p < 0.001) and concomitant non-tobacco substance abuse (30.2 versus 7.0%; p < 0.001). Compared to non-users, patients with a diagnosis of cannabis use disorder had higher odds of requiring advanced post-procedural healthcare utilisation after adjusting for patient characteristics, concomitant substance use and socioeconomic factors (aOR adjusted odds ratio 1.16; 95% CI 1.02–1.32). By contrast, patients with ongoing non-medical cannabis use had lower odds of advanced post-procedural healthcare utilisation (aOR 0.87; 95% CI 0.81–0.92, compared to non-users). Interpretation: One in seven patients undergoing surgery or interventional procedures in 2020 reported cannabis consumption. Differential effects on post-procedural healthcare utilisation were observed between patients with non-medical cannabis use and cannabis use disorder. Funding: This work was supported by an unrestricted philantropic grant from Jeff and Judy Buzen to Maximilian S. Schaefer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There is paucity of data regarding prevalence and key harms of non-medical cannabis use in surgical patients. We investigated whether cannabis use in patients undergoing surgery or interventional ...procedures patients was associated with a higher degree of post-procedural healthcare utilisation.
210,639 adults undergoing non-cardiac surgery between January 2008 and June 2020 at an academic healthcare network in Massachusetts, USA, were included. The primary exposure was use of cannabis, differentiated by reported ongoing non-medical use, self-identified during structured, preoperative nursing/physician interviews, or diagnosis of cannabis use disorder based on International Classification of Diseases, 9th/10th Revision, diagnostic codes. The main outcome measure was the requirement of advanced post-procedural healthcare utilisation (unplanned intensive care unit admission, hospital re-admission or non-home discharge).
16,211 patients (7.7%) were identified as cannabis users. The prevalence of cannabis use increased from 4.9% in 2008 to 14.3% by 2020 (p < 0.001). Patients who consumed cannabis had higher rates of psychiatric comorbidities (25.3 versus 16.8%; p < 0.001) and concomitant non-tobacco substance abuse (30.2 versus 7.0%; p < 0.001). Compared to non-users, patients with a diagnosis of cannabis use disorder had higher odds of requiring advanced post-procedural healthcare utilisation after adjusting for patient characteristics, concomitant substance use and socioeconomic factors (aOR adjusted odds ratio 1.16; 95% CI 1.02–1.32). By contrast, patients with ongoing non-medical cannabis use had lower odds of advanced post-procedural healthcare utilisation (aOR 0.87; 95% CI 0.81–0.92, compared to non-users).
One in seven patients undergoing surgery or interventional procedures in 2020 reported cannabis consumption. Differential effects on post-procedural healthcare utilisation were observed between patients with non-medical cannabis use and cannabis use disorder.
This work was supported by an unrestricted philantropic grant from Jeff and Judy Buzen to Maximilian S. Schaefer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Juvenile myelomonocytic leukemia (JMML) is considered to be one of the most difficult to treat and deadliest diseases of early childhood. The pathogenesis of JMML involves deregulated cytokine signal ...transduction, especially a selective hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Current treatment modalities do not provide significant long-term disease control. We describe an experimental model system in which the effect of targeted agents can be studied in the context of GM-CSF mediated growth and survival of JMML cells.
Bone marrow and peripheral mononuclear cells from JMML patients were enriched by immunoaffinity chromatography and grown in the presence of GM-CSF. Purity of these cells was confirmed by FACS and their absolute dependence on GM-CSF for growth and survival was assessed. A direct role for GM-CSF was confirmed by the addition of neutralizing antibodies. Molecular techniques showed the lack of excess GM-CSF secretion by these cells that proved receptor hypersensitivity as the principal driving force behind the excessive proliferation. To understand the signaling pathways involved in this process, we constructed a capture antibody array with antibodies to critical signaling molecules. GM-CSF treated and control lysates were incubated with the arrays and the expression and phosphorylation of the signaling molecules were detected by anti p-tyr, p-Ser and p-Thr antibodies. Blots were then quantified by an automated image analysis program. Results showed consistent activation of a group of signaling molecules mediated by the addition of GM-CSF. These include IRS-1, FAK, IkappaB and LIFR. Using this assay system we then looked at the effects of a number of novel therapeutic agents to inhibit the growth and specifically interfere with the GM-CSF mediated signaling cascade. These novel therapeutic agents and targeted kinase inhibitors such as 17-AAG, DMAG, arsenic trioxide, rebeccamycin, AMN-107, and Prima-1. (IC50: 0.1, 0.01. 0.5, 0.1, 0 and 10, uM respectively). These agents were studied in combination to identify agents that exhibit synergistic and additive properties. Significant additive effects were seen with certain combinations, notably in combination with Hsp90 inhibitors.
We describe an effective experimental model to identify the players and pathways involved in the abnormal growth properties of JMML. We discuss in detail the implications of these findings in the development of potential anti JMML therapies in the future.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Heat shock protein 90 (Hsp90) safeguards the structural integrity and function of many of the key growth regulatory proteins found in malignant cells. Consequently, among the new generation targeted ...therapeutics, heat shock protein inhibitors have the unique property of being able to target an expansive array of divergent molecular mechanisms involved in cancer growth and metastasis. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) is one such agent that has been shown to bind to Hsp90 and thus reduce the stability and activity of many key growth regulatory molecules and pathways. A number of recent clinical trials have investigated the maximum tolerated dose, toxicity and pharmacokinetic profiles of 17-AAG in pediatric patients with recurrent tumors. In this study, we describe the effects of 17-AAG against a panel of neuroblastoma (NB) cell lines with respect to cytotoxicity, target modulation and inhibition of vascular endothelial growth factor (VEGF) expression. 17-AAG was found to inhibit the growth of all NB cell lines tested, though effective inhibitory concentrations varied among cell lines. 17-AAG also suppressed the expression of VEGF. The cytotoxic effect of 17-AAG on tumor cells was diminished when co-cultured with bone marrow stromal cells suggesting a potential role for the microenvironment in tumor drug interactions. Findings from target modulation analysis as well as drug combination assays provide a frame-work to formulate effective protocols for the treatment of NB.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
