Optimal timing for the start of vasopressors (VP) in septic shock has not been widely studied since it is assumed that fluids must be administered in advance. We sought to evaluate whether a very ...early start of VP, even without completing the initial fluid loading, might impact clinical outcomes in septic shock.
A total of 337 patients with sepsis requiring VP support for at least 6 h were initially selected from a prospectively collected database in a 90-bed mixed-ICU during a 24-month period. They were classified into very-early (VE-VPs) or delayed vasopressor start (D-VPs) categories according to whether norepinephrine was initiated or not within/before the next hour of the first resuscitative fluid load. Then, VE-VPs (n = 93) patients were 1:1 propensity matched to D-VPs (n = 93) based on age; source of admission (emergency room, general wards, intensive care unit); chronic and acute comorbidities; and lactate, heart rate, systolic, and diastolic pressure at vasopressor start. A risk-adjusted Cox proportional hazard model was fitted to assess the association between VE-VPs and day 28 mortality. Finally, a sensitivity analysis was performed also including those patients requiring VP support for less than 6 h.
Patients subjected to VE-VPs received significantly less resuscitation fluids at vasopressor starting (00-510 vs. 1500650-2300 mL, p < 0.001) and during the first 8 h of resuscitation (1100500-1900 vs. 26001600-3800 mL, p < 0.001), with no significant increase in acute renal failure and/or renal replacement therapy requirements. VE-VPs was related with significant lower net fluid balances 8 and 24 h after VPs. VE-VPs was also associated with a significant reduction in the risk of death compared to D-VPs (HR 0.31, CI95% 0.17-0.57, p < 0.001) at day 28. Such association was maintained after including patients receiving vasopressors for < 6 h.
A very early start of vasopressor support seems to be safe, might limit the amount of fluids to resuscitate septic shock, and could lead to better clinical outcomes.
Background
Loss of vascular tone is a key pathophysiological feature of septic shock. Combination of gradual diastolic hypotension and tachycardia could reflect more serious vasodilatory conditions. ...We sought to evaluate the relationships between heart rate (HR) to diastolic arterial pressure (DAP) ratios and clinical outcomes during early phases of septic shock.
Methods
Diastolic shock index (DSI) was defined as the ratio between HR and DAP. DSI calculated just before starting vasopressors (Pre-VPs/DSI) in a preliminary cohort of 337 patients with septic shock (January 2015 to February 2017) and at vasopressor start (VPs/DSI) in 424 patients with septic shock included in a recent randomized controlled trial (ANDROMEDA-SHOCK; March 2017 to April 2018) was partitioned into five quantiles to estimate the relative risks (RR) of death with respect to the mean risk of each population (assumed to be 1). Matched HR and DAP subsamples were created to evaluate the effect of the individual components of the DSI on RRs. In addition, time-course of DSI and interaction between DSI and vasopressor dose (DSI*NE.dose) were compared between survivors and non-survivors from both populations, while ROC curves were used to identify variables predicting mortality. Finally, as exploratory observation, effect of early start of vasopressors was evaluated at each Pre-VPs/DSI quintile from the preliminary cohort.
Results
Risk of death progressively increased at gradual increments of Pre-VPs/DSI or VPs/DSI (One-way ANOVA,
p
< 0.001). Progressive DAP decrease or HR increase was associated with higher mortality risks only when DSI concomitantly increased. Areas under the ROC curve for Pre-VPs/DSI, SOFA and initial lactate were similar, while mean arterial pressure and systolic shock index showed poor performances to predict mortality. Time-course of DSI and DSI*NE.dose was significantly higher in non-survivors from both populations (repeated-measures ANOVA,
p
< 0.001). Very early start of vasopressors exhibited an apparent benefit at higher Pre-VPs/DSI quintile.
Conclusions
DSI at pre-vasopressor and vasopressor start points might represent a very early identifier of patients at high risk of death. Isolated DAP or HR values do not clearly identify such risk. Usefulness of DSI to trigger or to direct therapeutic interventions in early resuscitation of septic shock need to be addressed in future studies.
To investigate the effects of immediate start of norepinephrine versus initial fluid loading followed by norepinephrine on macro hemodynamics, regional splanchnic and intestinal microcirculatory ...flows in endotoxic shock.
Animal experimental study.
University translational research laboratory.
Fifteen Landrace pigs.
Shock was induced by escalating dose of lipopolysaccharide. Animals were allocated to immediate start of norepinephrine (i-NE) ( n = 6) versus mandatory 1-hour fluid loading (30 mL/kg) followed by norepinephrine (i-FL) ( n = 6). Once mean arterial pressure greater than or equal to 75 mm Hg was, respectively, achieved, successive mini-fluid boluses of 4 mL/kg of Ringer Lactate were given whenever: a) arterial lactate greater than 2.0 mmol/L or decrease less than 10% per 30 min and b) fluid responsiveness was judged to be positive. Three additional animals were used as controls (Sham) ( n = 3). Time × group interactions were evaluated by repeated-measures analysis of variance.
Hypotension was significantly shorter in i-NE group (7.5 min 5.5-22.0 min vs 49.3 min 29.5-60.0 min; p < 0.001). Regional mesenteric and microcirculatory flows at jejunal mucosa and serosa were significantly higher in i-NE group at 4 and 6 hours after initiation of therapy ( p = 0.011, p = 0.032, and p = 0.017, respectively). Misdistribution of intestinal microcirculatory blood flow at the onset of shock was significantly reversed in i-NE group ( p < 0.001), which agreed with dynamic changes in mesenteric-lactate levels ( p = 0.01) and venous-to-arterial carbon dioxide differences ( p = 0.001). Animals allocated to i-NE showed significantly higher global end-diastolic volumes ( p = 0.015) and required significantly less resuscitation fluids ( p < 0.001) and lower doses of norepinephrine ( p = 0.001) at the end of the experiment. Pulmonary vascular permeability and extravascular lung water indexes were significantly lower in i-NE group ( p = 0.021 and p = 0.004, respectively).
In endotoxemic shock, immediate start of norepinephrine significantly improved regional splanchnic and intestinal microcirculatory flows when compared with mandatory fixed-dose fluid loading preceding norepinephrine. Immediate norepinephrine strategy was related with less resuscitation fluids and lower vasopressor doses at the end of the experiment.
Septic shock involves a complex interaction between abnormal vasodilation, relative and/or absolute hypovolemia, myocardial dysfunction, and altered blood flow distribution to the tissues. Fluid ...administration, vasopressor support and inotropes, represent fundamental pieces of quantitative resuscitation protocols directed to assist the restoration of impaired tissue perfusion during septic shock. Indeed, current recommendations on sepsis management include the use of inotropes in the case of myocardial dysfunction, as suggested by a low cardiac output, increased filling pressures, or persisting signals of tissue hypoperfusion despite an adequate correction of intravascular volume and mean arterial pressure by fluid administration and vasopressor support. Evidence supporting the use of inotropes in sepsis and septic shock is mainly based on physiological studies. Most of them suggest a beneficial effect of inotropes on macro hemodynamics especially when sepsis coexists with myocardial dysfunction; others, however, have demonstrated variable results on regional splanchnic circulation, while others suggest favorable effects on microvascular distribution independently of its impact on cardiac output. Conversely, impact of inodilators on clinical outcomes in this context has been more controversial. Use of dobutamine has not been consistently related with more favorable clinical results, while systematic administration of levosimendan in sepsis do not prevent the development of multiorgan dysfunction, even in patients with evidence of myocardial dysfunction. Nevertheless, a recent metanalysis of clinical studies suggests that cardiovascular support regimens based on inodilators in sepsis and septic shock could provide some beneficial effect on mortality, while other one corroborated such effect on mortality specially in patients with proved lower cardiac output. Thus, using or not inotropes during sepsis and septic shock remains as controversy matter that deserves more research efforts.
The effect of high-flow oxygen therapy vs conventional oxygen therapy has not been established in the setting of severe COVID-19.
To determine the effect of high-flow oxygen therapy through a nasal ...cannula compared with conventional oxygen therapy on need for endotracheal intubation and clinical recovery in severe COVID-19.
Randomized, open-label clinical trial conducted in emergency and intensive care units in 3 hospitals in Colombia. A total of 220 adults with respiratory distress and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of less than 200 due to COVID-19 were randomized from August 2020 to January 2021, with last follow-up on February 10, 2021.
Patients were randomly assigned to receive high-flow oxygen through a nasal cannula (n = 109) or conventional oxygen therapy (n = 111).
The co-primary outcomes were need for intubation and time to clinical recovery until day 28 as assessed by a 7-category ordinal scale (range, 1-7, with higher scores indicating a worse condition). Effects of treatments were calculated with a Cox proportional hazards model adjusted for hypoxemia severity, age, and comorbidities.
Among 220 randomized patients, 199 were included in the analysis (median age, 60 years; n = 65 women 32.7%). Intubation occurred in 34 (34.3%) randomized to high-flow oxygen therapy and in 51 (51.0%) randomized to conventional oxygen therapy (hazard ratio, 0.62; 95% CI, 0.39-0.96; P = .03). The median time to clinical recovery within 28 days was 11 (IQR, 9-14) days in patients randomized to high-flow oxygen therapy vs 14 (IQR, 11-19) days in those randomized to conventional oxygen therapy (hazard ratio, 1.39; 95% CI, 1.00-1.92; P = .047). Suspected bacterial pneumonia occurred in 13 patients (13.1%) randomized to high-flow oxygen and in 17 (17.0%) of those randomized to conventional oxygen therapy, while bacteremia was detected in 7 (7.1%) vs 11 (11.0%), respectively.
Among patients with severe COVID-19, use of high-flow oxygen through a nasal cannula significantly decreased need for mechanical ventilation support and time to clinical recovery compared with conventional low-flow oxygen therapy.
ClinicalTrials.gov Identifier: NCT04609462.
We study the kinetics of eosinophils during the development of the cellular infiltrate surrounding the nurse cell of Trichinella spiralis (T. spiralis) in experimentally infected mice. Male CD1 mice ...were experimentally infected with 50 viable muscle larvae of the MSUS/MEX/91/CM-91 T. spiralis strain. Tongues and diaphragms were obtained daily from days 13 to 39 post infection. Diaphragms were compressed and subjected to Giemsa stain. Tongues were histologically sectioned and stained with erythrosine B or hematoxylin and eosin. The cellular infiltrate and the nurse cell-larva complex were detected by optical microscopy since day 16 post infection. The size of the larva increased exponentially during the course of the infection. The kinetics of eosinophils showed a multimodal trend, with a bimodal predominance. The maximum peaks were reached on days 21 and 27 post infection. The results of this study demonstrate that eosinophils occur abundantly in two transcendent moments of the T. spiralis life cycle: first, when the stage 1 larva invades the myocyte and second when the nurse cell-larva complex has been fully developed. These results help one to understand the immunobiology of T. spiralis, highlighting the importance of eosinophils in the survival of the larva in skeletal muscle. Further studies are needed to characterize the cell populations that comprise the cellular infiltrate during the development of the mother cell.
•A RBD-based synthetic peptide was shown safe when injected to mice and hamsters.•The vaccine candidate elicited antibodies that sustained for up to 2 months in mice.•Neutralizing antibodies and ...antigen-specific CD4 + CD8 + -IFNγ responses were detected.
The rapid spread of COVID-19 on all continents and the mortality induced by SARS-CoV-2 virus, the cause of the pandemic coronavirus disease 2019 (COVID-19) has motivated an unprecedented effort for vaccine development. Inactivated viruses as well as vaccines focused on the partial or total sequence of the Spike protein using different novel platforms such us RNA, DNA, proteins, and non-replicating viral vectors have been developed. The high global need for vaccines, now and in the future, and the emergence of new variants of concern still requires development of accessible vaccines that can be adapted according to the most prevalent variants in the respective regions.
Here, we describe the immunogenic properties of a group of theoretically predicted RBD peptides to be used as the first step towards the development of an effective, safe and low-cost epitope-focused vaccine. One of the tested peptides named P5, proved to be safe and immunogenic. Subcutaneous administration of the peptide, formulated with alumina, induced high levels of specific IgG antibodies in mice and hamsters, as well as an increase of IFN-γ expression by CD8+ T cells in C57 and BALB/c mice upon in vitro stimulation with P5. Neutralizing titers of anti-P5 antibodies, however, were disappointingly low, a deficiency that we will attempt to resolve by the inclusion of additional immunogenic epitopes to P5. The safety and immunogenicity data reported in this study support the use of this peptide as a starting point for the design of an epitope restricted vaccine.
Current literature shows the association of post-intubation hypotension and increased odds of mortality in critically ill non-trauma and trauma populations. However, there is a lack of research on ...potential interventions that can prevent or ameliorate the consequences of endotracheal intubation and thus improve the prognosis of trauma patients with post-intubation hypotension. This review paper hypothesizes that the deployment of REBOA among trauma patients with PIH, by its physiologic effects, will reduce the odds of mortality in this population. The objective of this paper is to review the current literature on REBOA and post-intubation hypotension, and, furthermore, to provide a rational hypothesis on the potential role of REBOA in severely injured patients with post-intubation hypotension.
Introducción: El presente artículo aborda la temática sobre el nivel de conocimiento y prevención del dengue en las madres de vaso de leche ubicado en la provincia de Chepén, enfermedad que apareció ...como consecuencia tras el paso del ciclón Yaku por la costa norte del Perú. Objetivo: Determinar la relación entre el nivel de conocimiento y medidas preventivas respecto al dengue, a su vez evaluar el nivel de conocimiento sobre el dengue y las medidas preventivas. Metodología: Estudio de enfoque cuantitativo, descriptivo correlacional de corte transeccional; para ello se aplicaron encuestas a madres integrantes del programa vaso de leche en la provincia de Chepén, se usó un muestreo aleatorio simple obteniendo una muestra óptima de 110 personas. la técnica de recolección de datos fue la encuesta y su instrumento el cuestionario a una escala de likert los cuales fueron confiables según la estadística Alfa de Cronbach de 83% Resultados: El nivel de conocimiento sobre la enfermedad y medidas preventivas de la misma. Tienen un “alto” nivel de conocimiento acerca del dengue, lo que representa el 9.09%, así mismo en 52 de ellos cuentan con un nivel de conocimiento “bajo” quienes representan el 47.27%, por último 48 de ellos tienen un nivel conocimiento “medio o regular” representando el 43.64%. Así mismo, para medidas preventivas se tiene nivel “alto” de prevención del dengue, con 1.82%, con un nivel de medidas de prevención “medio” con un 38.18%, por último, un nivel “bajo” a un 60%. Conclusión: la investigación sostiene la evidencia significativa sobre la relación moderada y directa existente entre el nivel de conocimiento y las medidas preventivas sobre el dengue
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