Dapagliflozin for Critically Ill Patients With Acute Organ Dysfunction: The DEFENDER Randomized Clinical Trial.

Importance: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve outcomes in patients with type 2 diabetes, heart failure, and chronic kidney disease, but their effect on outcomes of critically ill patients with organ failure is unknown. Objective: To determine whether the addition of dapagliflozin, an SGLT-2 inhibitor, to standard intensive care unit (ICU) care improves outcomes in a critically ill population with acute organ dysfunction. Design, Setting, and Participants: Multicenter, randomized, open-label, clinical trial conducted at 22 ICUs in Brazil. Participants with unplanned ICU admission and presenting with at least 1 organ dysfunction (respiratory, cardiovascular, or kidney) were enrolled between November 22, 2022, and August 30, 2023, with follow-up through September 27, 2023. Intervention: Participants were randomized to 10 mg of dapagliflozin (intervention, n = 248) plus standard care or to standard care alone (control, n = 259) for up to 14 days or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay through 28 days, analyzed using the win ratio method. Secondary outcomes included the individual components of the hierarchical outcome, duration of organ support-free days, ICU, and hospital stay, assessed using bayesian regression models. Results: Among 507 randomized participants (mean age, 63.9 [SD, 15] years; 46.9%, women), 39.6% had an ICU admission due to suspected infection. The median time from ICU admission to randomization was 1 day (IQR, 0-1). The win ratio for dapagliflozin for the primary outcome was 1.01 (95% CI, 0.90 to 1.13; P = .89). Among all secondary outcomes, the highest probability of benefit found was 0.90 for dapagliflozin regarding use of kidney replacement therapy among 27 patients (10.9%) in the dapagliflozin group vs 39 (15.1%) in the control group. Conclusion and Relevance: The addition of dapagliflozin to standard care for critically ill patients and acute organ dysfunction did not improve clinical outcomes; however, confidence intervals were wide and could not exclude relevant benefits or harms for dapagliflozin. Trial Registration: ClinicalTrials.gov Identifier: NCT05558098.

Evidence-Based Checklist to Delay Cardiac Arrest in Brain-Dead Potential Organ Donors: The DONORS Cluster Randomized Clinical Trial.

Importance: The effectiveness of goal-directed care to reduce loss of brain-dead potential donors to cardiac arrest is unclear. Objective: To evaluate the effectiveness of an evidence-based, goal-directed checklist in the clinical management of brain-dead potential donors in the intensive care unit (ICU). Design, Setting, and Participants: The Donation Network to Optimize Organ Recovery Study (DONORS) was an open-label, parallel-group cluster randomized clinical trial in Brazil. Enrollment and follow-up were conducted from June 20, 2017, to November 30, 2019. Hospital ICUs that reported 10 or more brain deaths in the previous 2 years were included. Consecutive brain-dead potential donors in the ICU aged 14 to 90 years with a condition consistent with brain death after the first clinical examination were enrolled. Participants were randomized to either the intervention group or the control group. The intention-to-treat data analysis was conducted from June 15 to August 30, 2020. Interventions: Hospital staff in the intervention group were instructed to administer to brain-dead potential donors in the intervention group an evidence-based checklist with 13 clinical goals and 14 corresponding actions to guide care, every 6 hours, from study enrollment to organ retrieval. The control group provided or received usual care. Main Outcomes and Measures: The primary outcome was loss of brain-dead potential donors to cardiac arrest at the individual level. A prespecified sensitivity analysis assessed the effect of adherence to the checklist in the intervention group. Results: Among the 1771 brain-dead potential donors screened in 63 hospitals, 1535 were included. These patients included 673 males (59.2%) and had a median (IQR) age of 51 (36.3-62.0) years. The main cause of brain injury was stroke (877 [57.1%]), followed by trauma (485 [31.6%]). Of the 63 hospitals, 31 (49.2%) were assigned to the intervention group (743 [48.4%] brain-dead potential donors) and 32 (50.8%) to the control group (792 [51.6%] brain-dead potential donors). Seventy potential donors (9.4%) at intervention hospitals and 117 (14.8%) at control hospitals met the primary outcome (risk ratio [RR], 0.70; 95% CI, 0.46-1.08; P = .11). The primary outcome rate was lower in those with adherence higher than 79.0% than in the control group (5.3% vs 14.8%; RR, 0.41; 95% CI, 0.22-0.78; P = .006). Conclusions and Relevance: This cluster randomized clinical trial was inconclusive in determining whether the overall use of an evidence-based, goal-directed checklist reduced brain-dead potential donor loss to cardiac arrest. The findings suggest that use of such a checklist has limited effectiveness without adherence to the actions recommended in this checklist. Trial Registration: ClinicalTrials.gov Identifier: NCT03179020.

Coagulation biomarkers and coronavirus disease 2019 phenotyping: a prospective cohort study.

BACKGROUND: Because severe acute respiratory syndrome coronarivus 2 (SARS-CoV-2) leads to severe conditions and thrombus formation, evaluation of the coagulation markers is important in determining the prognosis and phenotyping of patients with COVID-19. METHODS: In a prospective study that included 213 COVID-19 patients admitted to the intensive care unit (ICU) the levels of antithrombin, C-reactive protein (CRP); factors XI, XII, XIII; prothrombin and D-dimer were measured. Spearman's correlation coefficient was used to assess the pairwise correlations between the biomarkers. Hierarchical and non-hierarchical cluster analysis was performed using the levels of biomarkers to identify patients´ phenotypes. Multivariate binary regression was used to determine the association of the patient´s outcome with clinical variables and biomarker levels. RESULTS: The levels of factors XI and XIII were significantly higher in patients with less severe COVID-19, while factor XIII and antithrombin levels were significantly associated with mortality. These coagulation biomarkers were associated with the in-hospital survival of COVID-19 patients over and above the core clinical factors on admission. Hierarchical cluster analysis showed a cluster between factor XIII and antithrombin, and this hierarchical cluster was extended to CRP in the next step. Furthermore, a non-hierarchical K-means cluster analysis was performed, and two phenotypes were identified based on the CRP and antithrombin levels independently of clinical variables and were associated with mortality. CONCLUSION: Coagulation biomarkers were associated with in-hospital survival of COVID-19 patients. Lower levels of factors XI, XII and XIII and prothrombin were associated with disease severity, while higher levels of both CRP and antithrombin clustered with worse prognosis. These results suggest the role of coagulation abnormalities in the development of COVID-19 and open the perspective of identifying subgroups of patients who would benefit more from interventions focused on regulating coagulation.

Attributable mortality due to nosocomial sepsis in Brazilian hospitals: a case-control study.

BACKGROUND: Nosocomial sepsis is a major healthcare issue, but there are few data on estimates of its attributable mortality. We aimed to estimate attributable mortality fraction (AF) due to nosocomial sepsis. METHODS: Matched 1:1 case-control study in 37 hospitals in Brazil. Hospitalized patients in participating hospitals were included. Cases were hospital non-survivors and controls were hospital survivors, which were matched by admission type and date of discharge. Exposure was defined as occurrence of nosocomial sepsis, defined as antibiotic prescription plus presence of organ dysfunction attributed to sepsis without an alternative reason for organ failure; alternative definitions were explored. Main outcome measurement was nosocomial sepsis-attributable fractions, estimated using inversed-weight probabilities methods using generalized mixed model considering time-dependency of sepsis occurrence. RESULTS: 3588 patients from 37 hospitals were included. Mean age was 63 years and 48.8% were female at birth. 470 sepsis episodes occurred in 388 patients (311 in cases and 77 in control group), with pneumonia being the most common source of infection (44.3%). Average AF for sepsis mortality was 0.076 (95% CI 0.068-0.084) for medical admissions; 0.043 (95% CI 0.032-0.055) for elective surgical admissions; and 0.036 (95% CI 0.017-0.055) for emergency surgeries. In a time-dependent analysis, AF for sepsis rose linearly for medical admissions, reaching close to 0.12 on day 28; AF plateaued earlier for other admission types (0.04 for elective surgery and 0.07 for urgent surgery). Alternative sepsis definitions yield different estimates. CONCLUSION: The impact of nosocomial sepsis on outcome is more pronounced in medical admissions and tends to increase over time. The results, however, are sensitive to sepsis definitions.

Antivirals for adult patients hospitalised with SARS-CoV-2 infection: a randomised, phase II/III, multicentre, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn trial.

Background: Repurposed drugs for treatment of new onset disease may be an effective therapeutic shortcut. We aimed to evaluate the efficacy of repurposed antivirals compared to placebo in lowering SARS-CoV2 viral load of COVID-19 patients. Methods: REVOLUTIOn is a randomised, parallel, blinded, multistage, superiority and placebo controlled randomised trial conducted in 35 centres in Brazil. We include patients aged 18 years or older admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, symptoms onset 9 days or less and SpO2 94% or lower at room air were eligible. All participants were randomly allocated to receive either atazanavir, daclatasvir or sofosbuvir/daclatasvir or placebo for 10 days. The primary outcome was the decay rate (slope) of the SARS-CoV-2 viral load logarithm assessed in the modified intention to-treat population. This trial was registered with ClinicalTrials.gov, number NCT04468087. Findings: Between February 09, 2021, and August 04, 2021, 255 participants were enrolled and randomly assigned to atazanavir (n = 64), daclatasvir (n = 66), sofosbuvir/daclatasvir (n = 67) or placebo (n = 58). Compared to placebo group, the change from baseline to day 10 in log viral load was not significantly different for any of the treatment groups (0.05 [95% CI, -0.03 to 0.12], -0.02 [95% CI, -0.09 to 0.06], and -0.03 [95% CI, -0.11 to 0.04] for atazanavir, daclatasvir and sofosbuvir/daclatasvir groups respectively). There was no significant difference in the occurrence of serious adverse events between treatment groups. Interpretation: No significant reduction in viral load was observed from the use of atazanavir, daclatasvir or sofosbuvir/daclatasvir compared to placebo in hospitalised COVID-19 patients who need oxygen support with symptoms onset 9 days or less. Funding: Ministério da Ciência, Tecnologia e Inovação (MCTI) - Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ); Cia Latino-Americana de Medicamentos (Clamed); Cia Industrial H. Carlos Schneider (Ciser); Hospital Research Foundation Incorporation, Australia, HCor São Paulo; Blanver Farmoquímica; Instituto de Tecnologia em Fármacos (Farmanguinhos) da Fundação Oswaldo Cruz (Fiocruz); Coordenação Geral de Planejamento Estratégico (Cogeplan)/Fiocruz; and Fundação de apoio a Fiocruz (Fiotec, VPGDI-054-FIO-20-2-13).

Avaliação do impacto do tempo de espera para admissão em Unidade de Terapia Intensiva no desfecho clínico do paciente crítico / Assessment of the impact of waiting time until admission in the Intensive Care Unit on the clinical outcome of critical patients

RESUMO: Este estudo tem por base a premissa de que com um maior número de leitos de Unidade de Terapia Intensiva (UTI) disponíveis o tempo de espera para admissão em UTI é menor, o que resulta no melhor desfecho clínico, justifi-cando, portanto, a importância do presente estudo. Objetivo: Avaliar se o tempo de espera no Departamento de Emergência até a admissão em UTI tem influência no desfecho clínico do paciente crítico. Metodologia: Estudo ob-servacional, retrospectivo, do tipo antes e depois, realizado em um hospital público do município de Joinville/SC no ano de 2019. Foram incluídos os dados referentes aos pacientes adultos admitidos na UTI com até 72 horas de es-pera no Departamento de Emergência desde a chegada ao hospital. Comparou-se o último trimestre de 2017 (fase 1), período durante o qual havia 14 leitos de UTI no hospital, e último trimestre de 2018 (fase 2), período durante o qual havia 30 leitos de UTI. Resultados: Analisaram-se 173 prontuários elegíveis de 2017 e 2018. Houve diferen-ça estatisticamente significativa no tempo decorrido na emergência até a admissão em UTI entre 2017 e 2018 (me-diana de 22 vs. 15; p=0,0002). A diferença estatística também foi relevante para a mortalidade em até 24 horas após a admissão em UTI, comparando-se os dois anos em questão (9,61% vs. 2,47%; p=0,04). Não houve diferen-ça estatística significante na mortalidade hospitalar entre 2017 e 2018 (34,6% vs. 35,5%; p=0,57). Também não houve diferença estatisticamente relevante entre os demais parâmetros analisados. Conclusão: Comparando-se 2017 a 2018, percebeu-se que o tempo de espera pelo leito de UTI diminuiu, bem como a mortalidade em até 24h da admissão intensiva. No entanto, isto não se refletiu na mortalidade hospitalar. (AU)

ABSTRACT: The premise that underpins this study is that the more Intensive Care Unit (ICU) beds available, the shorter the waiting time for ICU admission, resulting in better clinical outcomes, which justifies the relevance of this study. Objective: Assess if the waiting time in the Emergency Room until ICU admission influences on the clinical outcome of critical patients. Methods: An observational longitudinal retrospective study performed in a public hospital in Joinville/SC in 2019. This study analyzed data from patients admitted to the ICU with up to 72h of waiting time in the Emergency Room. It compares Q4'2017 (phase 1), when there were 14 ICU beds in the hospital vs. Q4'2018 (phase 2), when there were 30 ICU beds. Results: 173 medical records were analyzed in 2017-2018. There was a statistically significant difference in the time for ICU admission between 2017 and 2018 (median 22h vs. 15h; p=0.0002). There was also a statistically significant difference for mortality rates up to 24h of admission (9.61% vs. 2.47%; p=0.04). There was no statistically significant difference for hospital mortality rates (34.6% vs. 35.5%; p=0.57). There was also no statistically significant difference between the other parameters analyzed. Conclusion:Comparing 2017 and 2018, waiting time for an ICU bed was shorter in 2018, and the mortality rates up to 24 hours of ICU admission were lower. However, waiting time in the Emergency Room until ICU admission did not show as-sociation with hospital mortality rates. (AU)

The Effect of Reconnection to Mechanical Ventilation for 1 Hour After Spontaneous Breathing Trial on Reintubation Among Patients Ventilated for More Than 12 Hours: A Randomized Clinical Trial.

BACKGROUND: The resting of the respiratory musculature after undergoing the spontaneous breathing trial (SBT) to prevent extubation failures in critically ill patients needs to be studied further. RESEARCH QUESTION: Is the reconnection to mechanical ventilation (MV) for 1 h after a successful SBT able to reduce the risk of reintubation? STUDY DESIGN AND METHODS: Randomized clinical trial conducted in four ICUs between August 2018 and July 2019. Candidates for tracheal extubation who met all screening criteria for weaning were included. After achieving success in the SBT using a T-tube, the patients were randomized to the following groups: direct extubation (DE) or extubation after reconnection to MV for 1 h (R1h). The primary outcome was reintubation within 48 h. RESULTS: Among the 336 patients studied (women, 41.1%; median age, 59 years [interquartile range, 45-70 years]), 12.9% (22/171) in the R1h group required reintubation within 48 h vs 18.2% (30/165) in the DE group (risk difference, 5.3 [95% CI, -2.49 to 13.12]; P = .18). No differences were found in mortality, length of ICU or hospital stay, causes of reintubation, or signs of extubation failure. A prespecified exploratory analysis showed that among the 233 patients (69.3%) who were ventilated for more than 72 h, the incidence of reintubation was 12.7% (15/118) in the R1h group compared with 22.6% (26/115) observed in the DE group (P = .04). INTERPRETATION: Reconnection to MV after a successful SBT, compared with DE, did not result in a statistically significant reduction in the risk of reintubation in mechanically ventilated patients. Subgroup exploratory findings suggest that the strategy may benefit patients who were ventilated for more than 72 h, which should be confirmed in further studies. TRIAL REGISTRY: Brazilian Clinical Trials Registry; No.: RBR-3x8nxn; URL: www.ensaiosclinicos.gov.br.

Predictive Accuracy of the Quick Sepsis-related Organ Failure Assessment Score in Brazil. A Prospective Multicenter Study.

Rationale: Although proposed as a clinical prompt to sepsis based on predictive validity for mortality, the Quick Sepsis-related Organ Failure Assessment (qSOFA) score is often used as a screening tool, which requires high sensitivity.Objectives: To assess the predictive accuracy of qSOFA for mortality in Brazil, focusing on sensitivity.Methods: We prospectively collected data from two cohorts of emergency department and ward patients. Cohort 1 included patients with suspected infection but without organ dysfunction or sepsis (22 hospitals: 3 public and 19 private). Cohort 2 included patients with sepsis (54 hospitals: 24 public and 28 private). The primary outcome was in-hospital mortality. The predictive accuracy of qSOFA was examined considering only the worst values before the suspicion of infection or sepsis.Measurements and Main Results: Cohort 1 contained 5,460 patients (mortality rate, 14.0%; 95% confidence interval [CI], 13.1-15.0), among whom 78.3% had a qSOFA score less than or equal to 1 (mortality rate, 8.3%; 95% CI, 7.5-9.1). The sensitivity of a qSOFA score greater than or equal to 2 for predicting mortality was 53.9% and the 95% CI was 50.3 to 57.5. The sensitivity was higher for a qSOFA greater than or equal to 1 (84.9%; 95% CI, 82.1-87.3), a qSOFA score greater than or equal to 1 or lactate greater than 2 mmol/L (91.3%; 95% CI, 89.0-93.2), and systemic inflammatory response syndrome plus organ dysfunction (68.7%; 95% CI, 65.2-71.9). Cohort 2 contained 4,711 patients, among whom 62.3% had a qSOFA score less than or equal to 1 (mortality rate, 17.3%; 95% CI, 15.9-18.7), whereas in public hospitals the mortality rate was 39.3% (95% CI, 35.5-43.3).Conclusions: A qSOFA score greater than or equal to 2 has low sensitivity for predicting death in patients with suspected infection in a developing country. Using a qSOFA score greater than or equal to 2 as a screening tool for sepsis may miss patients who ultimately die. Using a qSOFA score greater than or equal to 1 or adding lactate to a qSOFA score greater than or equal to 1 may improve sensitivity.Clinical trial registered with www.clinicaltrials.gov (NCT03158493).

Management of donation after brain death (DBD) in the ICU: the potential donor is identified, what's next?

The success of any donation process requires that potential brain-dead donors (PBDD) are detected and referred early to professionals responsible for their evaluation and conversion to actual donors. The intensivist plays a crucial role in organ donation. However, identification and referral of PBDDs may be suboptimal in the critical care environment. Factors influencing lower rates of detection and referral include the lack of specific training and the need to provide concomitant urgent care to other critically ill patients. Excellent communication between the ICU staff and the procurement organization is necessary to ensure the optimization of both the number and quality of organs transplanted. The organ donation process has been improved over the last two decades with the involvement and commitment of many healthcare professionals. Clinical protocols have been developed and implemented to better organize the multidisciplinary approach to organ donation. In this manuscript, we aim to highlight the main steps of organ donation, taking into account the following: early identification and evaluation of the PBDD with the use of checklists; donor management, including clinical maintenance of the PBDD with high-quality intensive care to prevent graft failure in recipients and strategies for optimizing donated organs by simplified care standards, clinical guidelines and alert tools; the key role of the intensivist in the donation process with the interaction between ICU professionals and transplant coordinators, nurse protocol managers, and communication skills training; and a final remark on the importance of the development of research with further insight into brain death pathophysiology and reversible organ damage.

Comorbidities Might Condition the Recovery of Quality of Life in Survivors of Sepsis.

PURPOSE:: To assess how preexisting disabling comorbidities (DC) affect the recovery rate of quality of life (QOL) over time in sepsis survivors. METHODS:: A prospective study was conducted on sepsis survivors who answered the 36-Item Short Form Health Survey (SF-36) 7 days after discharge from the intensive care unit. Subsequent interviews were held at 3, 6, and 12 months. The results of the physical component score (PCS) and mental component score (MCS) of the SF-36 were evaluated. Patients were divided into 2 groups to compare patients with DC (DC group) and without DC (no-DC group). Quantile regression was used to model changes in PCS and MCS between different time points. RESULTS:: Seventy-nine sepsis survivors were enrolled. After controlling for baseline age and QOL, the QOL scores were lower among patients with DC than in no-DC patients. The QOL of DC group got worse when compared to no-DC group. Recovery rate of PCS and MCS was higher in the DC group than in the no-DC group (PCS: 20.51 vs 16.96, P < .01; MCS: 19.24 vs 9.66, P < .01). Their baseline QOL was recovered only by 6 months after the sepsis episode. CONCLUSION:: Quality-of-life impairment and its recovery rhythm in patients with sepsis appear to be conditioned by coexisting DC.

Positive impact of a clinical goal-directed protocol on reducing cardiac arrests during potential brain-dead donor maintenance.

BACKGROUND: The disproportion between the large organ demand and the low number of transplantations performed represents a serious public health problem worldwide. Reducing the loss of transplantable organs from deceased potential donors as a function of cardiac arrest (CA) may contribute to an increase in organ donations. Our purpose was to test the hypothesis that a goal-directed protocol to guide the management of deceased donors may reduce the losses of potential brain-dead donors (PBDDs) due to CA. METHODS: The quality improvement project included 27 hospitals that reported deceased donors prospectively to the Transplant Center of the State of Santa Catarina, Brazil. All deceased donors reported prospectively between May 2012 and April 2014 were analyzed. Hospitals were encouraged to use the VIP approach checklist during the management of PBDDs. The checklist was composed of the following goals: protocol duration 12-24 hours, temperature > 35 °C, mean arterial pressure ≥ 65 mmHg, diuresis 1-4 ml/kg/h, corticosteroids, vasopressin, tidal volume 6-8 ml/kg, positive end-expiratory pressure 8-10 cmH2O, sodium < 150 mEq/L, and glycemia < 180 mg/dl. A logistic regression model was used to identify predictors of CA. RESULTS: There were 726 PBDD notifications, of which 324 (44.6) were actual donors, 141 (19.4 %) CAs, 226 (31.1 %) family refusals, and 35 (4.8 %) contraindications. Factors associated with CA reduction included use of the checklist (odds ratio (OR) 0.43, p < 0.001), maintenance performed inside the ICU (OR 0.49, p = 0.013), and vasopressin administration (OR 0.56, p = 0.04). More than three interventions had association with less CAs (OR 0.19, p < 0.001). After 24 months, CAs decreased from 27.3 % to 14.6 % (p = 0.002), reaching 12.1 % in the following two 4-month periods (p < 0.001). Simultaneous increases in organ recovered per donor and in actual donors were observed. CONCLUSIONS: A quality improvement program based on education and the use of a goal checklist for the management of potential donors inside the ICU is strongly associated with a decrease in donor losses and an increase in organs recovered per donor.

Exercise training prevents skeletal muscle damage in an experimental sepsis model.

OBJECTIVE: Oxidative stress plays an important role in skeletal muscle damage in sepsis. Aerobic exercise can decrease oxidative stress and enhance antioxidant defenses. Therefore, it was hypothesized that aerobic exercise training before a sepsis stimulus could attenuate skeletal muscle damage by modulating oxidative stress. Thus, the aim of this study was to evaluate the effects of aerobic physical preconditioning on the different mechanisms that are involved in sepsis-induced myopathy. METHODS: Male Wistar rats were randomly assigned to either the untrained or trained group. The exercise training protocol consisted of an eight-week treadmill program. After the training protocol, the animals from both groups were randomly assigned to either a sham group or a cecal ligation and perforation surgery group. Thus, the groups were as follows: sham, cecal ligation and perforation, sham trained, and cecal ligation and perforation trained. Five days after surgery, the animals were euthanized and their soleus and plantaris muscles were harvested. Fiber cross-sectional area, creatine kinase, thiobarbituric acid reactive species, carbonyl, catalase and superoxide dismutase activities were measured. RESULTS: The fiber cross-sectional area was smaller, and the creatine kinase, thiobarbituric acid reactive species and carbonyl levels were higher in both muscles in the cecal ligation and perforation group than in the sham and cecal ligation and perforation trained groups. The muscle superoxide dismutase activity was higher in the cecal ligation and perforation trained group than in the sham and cecal ligation and perforation groups. The muscle catalase activity was lower in the cecal ligation and perforation group than in the sham group. CONCLUSION: In summary, aerobic physical preconditioning prevents atrophy, lipid peroxidation and protein oxidation and improves superoxide dismutase activity in the skeletal muscles of septic rats.

Exercise training prevents skeletal muscle damage in an experimental sepsis model

OBJECTIVE: Oxidative stress plays an important role in skeletal muscle damage in sepsis. Aerobic exercise can decrease oxidative stress and enhance antioxidant defenses. Therefore, it was hypothesized that aerobic exercise training before a sepsis stimulus could attenuate skeletal muscle damage by modulating oxidative stress. Thus, the aim of this study was to evaluate the effects of aerobic physical preconditioning on the different mechanisms that are involved in sepsis-induced myopathy. METHODS: Male Wistar rats were randomly assigned to either the untrained or trained group. The exercise training protocol consisted of an eight-week treadmill program. After the training protocol, the animals from both groups were randomly assigned to either a sham group or a cecal ligation and perforation surgery group. Thus, the groups were as follows: sham, cecal ligation and perforation, sham trained, and cecal ligation and perforation trained. Five days after surgery, the animals were euthanized and their soleus and plantaris muscles were harvested. Fiber cross-sectional area, creatine kinase, thiobarbituric acid reactive species, carbonyl, catalase and superoxide dismutase activities were measured. RESULTS: The fiber cross-sectional area was smaller, and the creatine kinase, thiobarbituric acid reactive species and carbonyl levels were higher in both muscles in the cecal ligation and perforation group than in the sham and cecal ligation and perforation trained groups. The muscle superoxide dismutase activity was higher in the cecal ligation and perforation trained group than in the sham and cecal ligation and perforation groups. The muscle catalase activity was lower in the cecal ligation and perforation group than in the sham group. CONCLUSION: In summary, aerobic physical preconditioning prevents atrophy, lipid peroxidation and protein oxidation and improves superoxide dismutase activity in the skeletal muscles of septic rats.

Reduced mortality after the implementation of a protocol for the early detection of severe sepsis.

OBJECTIVE: We evaluate the impact that implementing an in-hospital protocol for the early detection of sepsis risk has on mortality from severe sepsis/septic shock. METHODS: This was a prospective cohort study conducted in 2 phases at 2 general hospitals in Brazil. In phase I, patients with severe sepsis/septic shock were identified and treated in accordance with the Surviving Sepsis Campaign guidelines. Over the subsequent 12 months (phase II), patients with severe sepsis/septic shock were identified by means of active surveillance for signs of sepsis risk (SSR). We compared the 2 cohorts in terms of demographic variables, the time required for the identification of at least 2 SSRs, compliance with sepsis bundles (6- and 24-hour), and mortality rates. RESULTS: We identified 217 patients with severe sepsis/septic shock (102 during phase I and 115 during phase II). There were significant differences between phases I and II in terms of the time required for the identification of at least 2 SSRs (34 ± 48 vs 11 ± 17 hours; P < .001) and in terms of in-hospital mortality (61.7% vs 38.2%; P < .001). CONCLUSION: The early detection of sepsis promoted early treatment, reducing in-hospital mortality from severe sepsis/septic shock.

Vasodilation increases pulse pressure variation, mimicking hypovolemic status in rabbits.

OBJECTIVE: To test the hypothesis that pulse pressure respiratory variation (PPV) amplification, observed in hypovolemia, can also be observed during sodium nitroprusside (SNP)-induced vasodilation. INTRODUCTION: PPV is largely used for early identification of cardiac responsiveness, especially when hypovolemia is suspected. PPV results from respiratory variation in transpulmonary blood flow and reflects the left ventricular preload variations during respiratory cycles. Any factor that decreases left ventricular preload can be associated with PPV amplification, as seen in hypovolemia. METHODS: Ten anesthetized and mechanically ventilated rabbits underwent progressive hypotension by either controlled hemorrhage (Group 1) or intravenous SNP infusion (Group 2). Animals in Group 1 (n = 5) had graded hemorrhage induced at 10% steps until 50% of the total volume was bled. Mean arterial pressure (MAP) steps were registered and assumed as pressure targets to be reached in Group 2. Group 2 (n = 5) was subjected to a progressive SNP infusion to reach similar pressure targets as those defined in Group 1. Heart rate (HR), systolic pressure variation (SPV) and PPV were measured at each MAP step, and the values were compared between the groups. RESULTS: SPV and PPV were similar between the experimental models in all steps (p > 0.16). SPV increased earlier in Group 2. CONCLUSION: Both pharmacologic vasodilation and graded hemorrhage induced PPV amplification similar to that observed in hypovolemia, reinforcing the idea that amplified arterial pressure variation does not necessarily represent hypovolemic status but rather potential cardiovascular responsiveness to fluid infusion.

Vasodilation increases pulse pressure variation, mimicking hypovolemic status in rabbits

OBJECTIVE: To test the hypothesis that pulse pressure respiratory variation (PPV) amplification, observed in hypovolemia, can also be observed during sodium nitroprusside (SNP)-induced vasodilation. INTRODUCTION: PPV is largely used for early identification of cardiac responsiveness, especially when hypovolemia is suspected. PPV results from respiratory variation in transpulmonary blood flow and reflects the left ventricular preload variations during respiratory cycles. Any factor that decreases left ventricular preload can be associated with PPV amplification, as seen in hypovolemia. METHODS: Ten anesthetized and mechanically ventilated rabbits underwent progressive hypotension by either controlled hemorrhage (Group 1) or intravenous SNP infusion (Group 2). Animals in Group 1 (n = 5) had graded hemorrhage induced at 10 percent steps until 50 percent of the total volume was bled. Mean arterial pressure (MAP) steps were registered and assumed as pressure targets to be reached in Group 2. Group 2 (n = 5) was subjected to a progressive SNP infusion to reach similar pressure targets as those defined in Group 1. Heart rate (HR), systolic pressure variation (SPV) and PPV were measured at each MAP step, and the values were compared between the groups. RESULTS: SPV and PPV were similar between the experimental models in all steps (p > 0.16). SPV increased earlier in Group 2. CONCLUSION: Both pharmacologic vasodilation and graded hemorrhage induced PPV amplification similar to that observed in hypovolemia, reinforcing the idea that amplified arterial pressure variation does not necessarily represent hypovolemic status but rather potential cardiovascular responsiveness to fluid infusion.

A randomized controlled trial comparing a computer-assisted insulin infusion protocol with a strict and a conventional protocol for glucose control in critically ill patients.

PURPOSE: The objective of this study is to evaluate blood glucose (BG) control efficacy and safety of 3 insulin protocols in medical intensive care unit (MICU) patients. METHODS: This was a multicenter randomized controlled trial involving 167 MICU patients with at least one BG measurement >or=150 mg/dL and one or more of the following: mechanical ventilation, systemic inflammatory response syndrome, trauma, or burns. The interventions were computer-assisted insulin protocol (CAIP), with insulin infusion maintaining BG between 100 and 130 mg/dL; Leuven protocol, with insulin maintaining BG between 80 and 110 mg/dL; or conventional treatment-subcutaneous insulin if glucose >150 mg/dL. The main efficacy outcome was the mean of patients' median BG, and the safety outcome was the incidence of hypoglycemia (

Pulse oximetry wave variation as a noninvasive tool to assess volume status in cardiac surgery.

OBJECTIVE: To compare variations of plethysmographic wave amplitude (DeltaPpleth) and to determine the percent difference between inspiratory and expiratory pulse pressure (DeltaPp) cutoff values for volume responsiveness in a homogenous population of postoperative cardiac surgery patients. INTRODUCTION: Intra-thoracic pressure variations interfere with stroke volume variation. Pulse pressure variations through arterial lines during mechanical ventilation have been recommended for the estimation of fluid responsiveness. Pulse oximetry may offer a non-invasive plethysmographic method to evaluate pulse pressure; this may be useful for guiding fluid replacement. METHODS: Controlled, prospective study in cardiac surgery patients under controlled ventilation. Simultaneous digital recordings of arterial pressure and plethysmographic waves were performed. DeltaPp, systolic pressure (DeltaPs), DPpleth, and systolic component (DeltaSpleth) were calculated. A DPp > or = 13% identified fluid-responsive patients. Volume expansion was performed in responsive subjects. Systolic and amplitude components of pressure and plethysmographic waves were compared. RESULTS: In 50 measurements from 43 patients, DeltaPp was correlated with (Ppleth (r=0.90, p<0.001), (Ps (r=0.90, p<0.001), and (Spleth (r=0.73, p<0.001). An aArea under ROC curve (AUC) identified the fluid responsiveness thresholds: (Ppleth of 11% (AUC = 0.95+/-0.04), (Ps of 8% (AUC=0.93+/-0.05), and (Spleth of 32% (AUC=0.82+/-0.07). A (Ppleth value > or = 11% predicted (Pp > or = 13% with 100% specificity and 91% sensitivity. Volume expansion, performed in 20 patients, changed (Pp, (Ppleth, (Ps and (Spleth significantly (p<0.008). CONCLUSIONS: DeltaPpleth is well correlated with DPp and constitutes a simple and non-invasive method for assessing fluid responsiveness in patients following cardiac surgery.

Pulse oximetry wave variation as a noninvasive tool to assess volume status in cardiac surgery

OBJECTIVE: To compare variations of plethysmographic wave amplitude (ÃPpleth) and to determine the percent difference between inspiratory and expiratory pulse pressure (ÃPp) cutoff values for volume responsiveness in a homogenous population of postoperative cardiac surgery patients. INTRODUCTION: Intra-thoracic pressure variations interfere with stroke volume variation. Pulse pressure variations through arterial lines during mechanical ventilation have been recommended for the estimation of fluid responsiveness. Pulse oximetry may offer a non-invasive plethysmographic method to evaluate pulse pressure; this may be useful for guiding fluid replacement. METHODS: Controlled, prospective study in cardiac surgery patients under controlled ventilation. Simultaneous digital recordings of arterial pressure and plethysmographic waves were performed. ÃPp, systolic pressure (ÃPs), DPpleth, and systolic component (ÃSpleth) were calculated. A DPp > 13 percent identified fluid-responsive patients. Volume expansion was performed in responsive subjects. Systolic and amplitude components of pressure and plethysmographic waves were compared. RESULTS: In 50 measurements from 43 patients, ÃPp was correlated with (Ppleth (r=0.90, p<0.001), (Ps (r=0.90, p<0.001), and (Spleth (r=0.73, p<0.001). An aArea under ROC curve (AUC) identified the fluid responsiveness thresholds: (Ppleth of 11 percent (AUC = 0.95±0.04), (Ps of 8 percent (AUC=0.93±0.05), and (Spleth of 32 percent (AUC=0.82±0.07). A (Ppleth value > 11 percent predicted (Pp > 13 percent with 100 percent specificity and 91 percent sensitivity. Volume expansion, performed in 20 patients, changed (Pp, (Ppleth, (Ps and (Spleth significantly (p<0.008). CONCLUSIONS: ÃPpleth is well correlated with DPp and constitutes a simple and non-invasive method for assessing fluid responsiveness in patients following cardiac surgery.

Variation in amplitude of central venous pressure curve induced by respiration is a useful tool to reveal fluid responsiveness in postcardiac surgery patients.

We tested the hypothesis that the dynamic evaluation of central venous pressure (CVP) amplitude could be a reliable predictor of fluid responsiveness in patients under mechanical ventilation, similar to the variation of arterial pulse pressure (DeltaPp). Thirty postcardiac surgery patients, under mechanical ventilation, were evaluated. The percentual difference between inspiratory (Ppins) and expiratory pulse pressure (Ppins) was so calculated: DeltaPp (%) = 100 x (Ppins - Ppexp)/[(Ppins + Ppexp)/2]. The respiratory variation of CVP curves amplitude were calculated by determining the percentual difference between inspiratory (CVPpins) and expiratory (CVPpexp) variation using vena cava "pressure" collapsibility index according the following formula: Cvci (%) = [(CVPpexp - CVPpins)/CVPpexp] x 100. There was a correlation between DeltaPp and Cvci (Pearson correlation coefficient, r = 0.45). Receiver operating characteristic curves showed that the Cvci value more than or equal to 5% predicted DeltaPp more than or equal to 13% with 91% specificity, 89% sensitivity, and AUC of 0.90. Therefore, Cvci presented a good agreement with DeltaPp (kappa = 0.76) to identify potential fluid responders (patients with DeltaPp > or =13%). In 9 potential fluid responders, both DeltaPp and Cvci significantly decreased from 18% +/- 8% to 8% +/- 6% (P < 0.004) and 23% +/- 15% to 7% +/- 6% (P < 0.004), respectively, after fluid replacement. Our findings suggest that vena cava "pressure" collapsibility index can be used as a marker of fluid responsiveness in postcardiac surgery patients under mechanical ventilation, such as arterial pulse pressure respiratory variation.