Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial.

This research by Fujii and other was first published in JAMA during January 2020
Importance:  It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock.
Objective:  To determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock.
Design, Setting, and Participants:  Multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019.
Interventions: Patients were randomized to the intervention group (n = 109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n = 107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days.
Main Outcomes and Measures:  The primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were pre-specified, including 90-day mortality.
Results:  Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years [SD, 15.0]; 133 men [63%]). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was -0.6 hours (95% CI, -8.3 to 7.2 hours; P = .83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported.
Conclusions and Relevance:  In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone.
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From a pressure-guided to a perfusion-centered resuscitation strategy in septic shock: Critical literature review and illustrative case

This research by Gazmuri and Anez de Gomez was published online in the Journal of Critical Care during January 2020.
Purpose:  To support a paradigm shift in the management of septic shock from pressure-guided to perfusion-centered, expected to improve outcome while reducing adverse effects from vasopressor therapy and aggressive fluid resuscitation.
Material and methods:  Critical review of the literature cited in support of vasopressor use to achieve a predefined mean arterial pressure (MAP) of 65 mmHg and review of pertinent clinical trials and studies enabling deeper understanding of the hemodynamic pathophysiology supportive of a perfusion-centered approach, accompanied by an illustrative case.
Results:  Review of the literature cited by the Surviving Sepsis Campaign revealed lack of controlled clinical trials supporting outcome benefits from vasopressors. Additional literature review revealed adverse effects associated with vasopressors and worsened outcome in some studies. Vasopressors increase MAP primarily by peripheral vasoconstriction and in occasions by a modest increase in cardiac output when using norepinephrine. Thus, achieving the recommended MAP of 65 mmHg using vasopressors should not be presumed indicative that organ perfusion has been restored. It may instead create a false sense of hemodynamic stability hampering shock resolution.
Conclusions:  We propose focusing the hemodynamic management of septic shock on reversing organ hypoperfusion instead of attaining a predefined MAP target as the key strategy for improving outcome.
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Delayed vasopressor initiation is associated with increased mortality in patients with septic shock

This research by Hidalgo and others was first published online in the Journal of Critical Care during November 2019.
Purpose:  Mortality rate for septic shock, despite advancements in knowledge and treatment, remains high. Treatment includes administration of broad-spectrum antibiotics and stabilization of the mean arterial pressure (MAP) with intravenous fluid resuscitation. Fluid-refractory shock warrants vasopressor initiation. There is a paucity of evidence regarding the timing of vasopressor initiation and its effect on patient outcomes.
Materials and methods:  This retrospective, single-centered, cohort study included patients with septic shock from January 2017 to July 2017. Time from initial hypotension to vasopressor initiation was measured for each patient. The primary outcome was 30-day mortality.
Results:  Of 530 patients screened,119 patients were included. There were no differences in baseline patient characteristics. Thirty-day mortality was higher in patients who received vasopressors after 6 h (51.1% vs 25%, p < .01). Patients who received vasopressors within the first 6 h had more vasopressor-free hours at 72 h (34.5 h vs 13.1, p = .03) and shorter time to MAP of 65 mmHg (1.5 h vs 3.0, p < .01).
Conclusion:  Vasopressor initiation after 6 h from shock recognition is associated with a significant increase in 30-day mortality. Vasopressor administration within 6 h was associated with shorter time to achievement of MAP goals and higher vasopressor-free hours within the first 72 h.
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Gender differences in mortality and quality of life after septic shock: A post-hoc analysis of the ARISE study

This article by Luethi and others was published online in the Journal of Critical Care during November 2019.
Purpose:  To assess the impact of gender and pre-menopausal state on short- and long-term outcomes in patients with septic shock.
Material and methods:  Cohort study of the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial, an international randomized controlled trial comparing early goal-directed therapy (EGDT) to usual care in patients with early septic shock, conducted between October 2008 and April 2014. The primary exposure in this analysis was legal gender and the secondary exposure was pre-menopausal state defined by chronological age (≤ 50 years).
Results:  641 (40.3%) of all 1591 ARISE trial participants in the intention-to-treat population were females and overall, 337 (21.2%) (146 females) patients were 50 years of age or younger. After risk-adjustment, we could not identify any survival benefit for female patients at day 90 in the younger (≤50 years) (adjusted Odds Ratio (aOR): 0.91 (0.46–1.89), p = .85) nor in the older (>50 years) age-group (aOR: 1.10 (0.81–1.49), p = .56). Similarly, there was no gender-difference in ICU, hospital, 1-year mortality nor quality of life measures.
Conclusions:  This post-hoc analysis of a large multi-center trial in early septic shock has shown no short- or long-term survival effect for women overall as well as in the pre-menopausal age-group.
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Fluid resuscitation in patients with end-stage renal disease on hemodialysis presenting with severe sepsis or septic shock: A case control study

This research by Rajdev and colleagues was first published in October 2019 in the online edition of Journal of Critical Care.
Due to the potential risk of volume overload, physicians are hesitant to aggressively fluid-resuscitate septic patients with end-stage renal disease (ESRD) on hemodialysis (HD). Primary objective: To calculate the percentage of ESRD patients on HD (Case) who received ≥30 mL/Kg fluid resuscitation within the first 6 h compared to non-ESRD patients (Control) that presented with severe sepsis (SeS) or septic shock (SS). Secondary objectives: Effect of fluid resuscitation on intubation rate, need for urgent dialysis, hospital length of stay (LOS), intensive care unit (ICU) admission and LOS, need for vasopressors, and hospital mortality. Medical records of 715 patients with sepsis, SeS, SS, and ESRD were reviewed. We identified 104 Case and 111 Control patients. In the Case group, 23% of patients received ≥30 mL/Kg fluids compared to 60% in the Control group (p < 0.001). There was no significant difference in mortality, need for urgent dialysis, intubation rates, ICU LOS, or hospital LOS between the two groups. Subgroup analysis between ESRD patients who received ≥30 mL/Kg (N = 80) vs those who received <30 mL/Kg (N = 24) showed no significant difference in any of the secondary outcomes. Compliance with 30 mL/Kg fluids was low for all patients but significantly lower for ESRD patients. Aggressive fluid resuscitation appears to be safe in ESRD patients.
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Cost-effectiveness of second-line vasopressors for the treatment of septic shock

This article by Lam and associates was first published online in the Journal of Critical Care during October 2019.
Purpose:  To determine the cost-effectiveness of escalating doses of norepinephrine or norepinephrine plus the adjunctive use of vasopressin or angiotensin II as a second-line vasopressor for septic shock.
Materials and methods:  Decision tree analysis was performed to compare costs and outcomes associated with norepinephrine monotherapy or the two adjunctive second-line vasopressors. Short- and long-term outcomes modeled included ICU survival and lifetime quality-adjusted-life-years (QALY) gained. Costs were modeled from a payer’s perspective, with a willingness-to-pay threshold set at $100,000/unit gained. One-way (tornado diagrams) and probabilistic sensitivity analyses were performed.
Results:  Adjunctive vasopressin was the most cost-effective therapy, and dominated both norepinephrine monotherapy and adjunctive angiotensin II by producing higher ICU survival at less cost. For the lifetime horizon, while norepinephrine monotherapy was least expensive, adjunctive vasopressin was the most cost-effective with an incremental cost-effectiveness ratio of $19,762 / QALY gained. Although adjunctive angiotensin II produced more QALYs compared to norepinephrine monotherapy, it was dominated in the long-term evaluation by second-line vasopressin. Sensitivity analyses demonstrated model robustness and medication costs were not significant drivers of model results.
Conclusions:  Vasopressin is the most cost-effective second-line vasopressor in both the short- and long-term evaluations. Vasopressor price is a minor contributor to overall cost.
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Machine learning for prediction of septic shock at initial triage in emergency department

This research by Joonghee and colleagues was first published online in the Journal of Critical Care during October 2019.
Background:  We hypothesized utilizing machine learning (ML) algorithms for screening septic shock in ED would provide better accuracy than qSOFA or MEWS.
Methods:  The study population was adult (≥20 years) patients visiting ED for suspected infection. Target event was septic shock within 24 h after arrival. Demographics, vital signs, level of consciousness, chief complaints (CC) and initial blood test results were used as predictors. CC were embedded into 16-dimensional vector space using singular value decomposition. Six base learners including support vector machine, gradient-boosting machine, random forest, multivariate adaptive regression splines and least absolute shrinkage and selection operator and ridge regression and their ensembles were tested. We also trained and tested MLP networks with various setting.
Results:  A total of 49,560 patients were included and 4817 (9.7%) had septic shock within 24 h. All ML classifiers significantly outperformed qSOFA score, MEWS and their age-sex adjusted versions with their AUROC ranging from 0.883 to 0.929. The ensembles of the base classifiers showed the best performance and addition of CC embedding was associated with statistically significant increases in performance.
Conclusions:  ML classifiers significantly outperforms clinical scores in screening septic shock at ED triage.
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