The Effect of Fluid Resuscitation Timing in Early Sepsis Resuscitation.

PURPOSE: The dose and timing of early fluid resuscitation in sepsis remains a debated topic. The objective of this study is to evaluate the effect of fluid timing in early sepsis management on mortality and other clinical outcomes. METHODS: Single-center, retrospective cohort study of emergency-department-treated adults (>18 years, n = 1032) presenting with severe sepsis or septic shock. Logistic regression evaluating the impact of 30 mL/kg crystalloids timing and mortality-versus-time plot controlling for mortality in emergency department sepsis score, lactate, antibiotic timing, obesity, sex, systemic inflammatory response syndrome criteria, hypotension, and heart and renal failures. This study is a subanalysis of a previously published investigation. RESULTS: Mortality was 17.1% (n = 176) overall and 20.4% (n = 133 of 653) among those in septic shock. 30 mL/kg was given to 16.9%, 32.2%, 16.2%, 14.5%, and 20.3% of patients within ≤1, 1 ≤ 3, 3 ≤ 6, 6 ≤ 24, and not reached within 24 h, respectively. A 24-h plot of adjusted mortality versus time did not reach significance, but within the first 12 h, the linear function showed a per-hour mortality increase (odds ratio [OR] 1.29, 95% confidence interval [CI] 1.02-1.67) which peaks around 5h, although the quadratic function does not reach significance (P = .09). When compared to patients receiving 30 mL/kg within 1 h, increased mortality was observed when not reached within 24 h (OR 2.69, 95% CI 1.37-5.37) but no difference when receiving this volume between 1 and 3 (OR 1.11, 95% CI 0.62-2.01), 3 and 6 (OR 1.83, 95% CI 0.97-3.52), or 6 and 24 h (OR 1.51, 95% CI 0.75-3.06). Receiving 30 mL/kg between 1 and 3 versus <1 h increased the incidence of delayed hypotension (OR 1.83, 95% CI 1.23-2.72) but did not impact need for intubation, intensive care unit admission, or vasopressors. CONCLUSIONS: We observed weak evidence that supports that earlier is better for survival when reaching fluid goals of 30 mL/kg, but benefits may wane at later time points. These findings should be viewed as hypothesis generating.

Conducta actual frente la hemorragia digestiva alta: desde el diagnóstico al tratamiento / Current behavior against Upper Digestive Hemorrhage: from diagnosis to treatment

Resumen La hemorragia digestiva alta (HDA) es una emergencia médico-quirúrgica común que debe ser tratada precozmente por su alta morbimortalidad. Corresponde a sangrado del esófago, estómago o del duodeno proximal, y se divide en etiología no variceal y variceal. Dentro de las no variceales destaca la úlcera péptica como la más frecuente, siendo esta producida por un desbalance entre factores protectores y agresivos. Por otro lado, en las hemorragias variceales destacan las várices gastroduodenales, las cuales son consecuencia del aumento de la presión portal. La incidencia de la HDA a nivel mundial varía entre 37 a 172 casos por cada 100.000 habitantes por año y la mortalidad entre un 5 y un 14% según diferentes estudios. Lamentablemente, no existen cifras nacionales fidedignas de incidencia y prevalencia. El médico debe conocer bien la presentación clínica y la fisiopatología para ser asertivo en la sospecha, diagnóstico y manejo de esta patología. En cuanto al tratamiento, el enfrentamiento se divide en el manejo de urgencias y luego endoscópico, puesto que la resucitación temprana intensiva puede reducir la morbimortalidad en pacientes con HDA. A continuación se hará una revisión actualizada enfocada en los aspectos más relevantes del manejo de esta patología. Se obtuvieron los datos de Pubmed y Scielo, específicamente la búsqueda de artículos originales y de revisiones sistemáticas con las palabras "hemorragia digestiva alta", "úlcera péptica", "várices esofágicas" y otras relacionadas. Los criterios usados fueron artículos preferentemente menores a 5 años de publicación en revistas científicas de alto índice de impacto.

Upper gastrointestinal bleeding (UHD) is a common medical-surgical emergency that must be treated early due to its high morbidity and mortality. It corresponds to bleeding from the esophagus, stomach, or proximal duodenum, and is divided into non-variceal and variceal etiology. Among the non-variceal, the peptic ulcer stands out as the most frequent, being this produced by an imbalance between protective and aggressive factors. On the other hand, in variceal hemorrhages gastroduodenal varices stand out, are a consequence of increased portal pressure. The incidence of HDA worldwide varies between 37 to 172 cases per 100,000 inhabitants per year and mortality between 5 to 14% according to different studies. Unfortunately, there are no reliable national statistics of incidence and prevalence. The physician must have a good understanding of the clinical presentation and pathophysiology to be assertive in the suspicion, diagnosis, and management of this pathology. Regarding treatment, the confrontation is divided into emergency management and then endoscopic, because early intensive resuscitation can reduce morbidity and mortality in patients with UHD. This is an updated review which will be focused on the most relevant aspects of the management of this pathology. Data were obtained from Pubmed and Scielo, specifically searching for original articles and systematic reviews with the words "upper gastrointestinal bleeding", "peptic ulcer", "esophageal varices" and other related words. The criteria used were articles preferably less than 5 years old in scientific journals with a high impact index.

A lactate-targeted resuscitation strategy may be associated with higher mortality in patients with septic shock and normal capillary refill time: a post hoc analysis of the ANDROMEDA-SHOCK study.

BACKGROUND: Capillary refill time (CRT) may improve more rapidly than lactate in response to increments in systemic flow. Therefore, it can be assessed more frequently during septic shock (SS) resuscitation. Hyperlactatemia, in contrast, exhibits a slower recovery in SS survivors, probably explained by the delayed resolution of non-hypoperfusion-related sources. Thus, targeting lactate normalization may be associated with impaired outcomes. The ANDROMEDA-SHOCK trial compared CRT- versus lactate-targeted resuscitation in early SS. CRT-targeted resuscitation associated with lower mortality and organ dysfunction; mechanisms were not investigated. CRT was assessed every 30 min and lactate every 2 h during the 8-h intervention period, allowing a first comparison between groups at 2 h (T2). Our primary aim was to determine if SS patients evolving with normal CRT at T2 after randomization (T0) exhibited a higher mortality and organ dysfunction when allocated to the LT arm than when randomized to the CRT arm. Our secondary aim was to determine if those patients with normal CRT at T2 had received more therapeutic interventions when randomized to the LT arm. To address these issues, we performed a post hoc analysis of the ANDROMEDA-SHOCK dataset. RESULTS: Patients randomized to the lactate arm at T0, evolving with normal CRT at T2 exhibited significantly higher mortality than patients with normal CRT at T2 initially allocated to CRT (40 vs 23%, p = 0.009). These results replicated at T8 and T24. LT arm received significantly more resuscitative interventions (fluid boluses: 1000[500-2000] vs. 500[0-1500], p = 0.004; norepinephrine test in previously hypertensive patients: 43 (35) vs. 19 (19), p = 0.001; and inodilators: 16 (13) vs. 3 (3), p = 0.003). A multivariate logistic regression of patients with normal CRT at T2, including APACHE-II, baseline lactate, cumulative fluids administered since emergency admission, source of infection, and randomization group) confirmed that allocation to LT group was a statistically significant determinant of 28-day mortality (OR 3.3; 95%CI[1.5-7.1]); p = 0.003). CONCLUSIONS: Septic shock patients with normal CRT at baseline received more therapeutic interventions and presented more organ dysfunction when allocated to the lactate group. This could associate with worse outcomes.

Systematic assessment of fluid responsiveness during early septic shock resuscitation: secondary analysis of the ANDROMEDA-SHOCK trial.

BACKGROUND: Fluid boluses are administered to septic shock patients with the purpose of increasing cardiac output as a means to restore tissue perfusion. Unfortunately, fluid therapy has a narrow therapeutic index, and therefore, several approaches to increase safety have been proposed. Fluid responsiveness (FR) assessment might predict which patients will effectively increase cardiac output after a fluid bolus (FR+), thus preventing potentially harmful fluid administration in non-fluid responsive (FR-) patients. However, there are scarce data on the impact of assessing FR on major outcomes. The recent ANDROMEDA-SHOCK trial included systematic per-protocol assessment of FR. We performed a post hoc analysis of the study dataset with the aim of exploring the relationship between FR status at baseline, attainment of specific targets, and clinically relevant outcomes. METHODS: ANDROMEDA-SHOCK compared the effect of peripheral perfusion- vs. lactate-targeted resuscitation on 28-day mortality. FR was assessed before each fluid bolus and periodically thereafter. FR+ and FR- subgroups, independent of the original randomization, were compared for fluid administration, achievement of resuscitation targets, vasoactive agents use, and major outcomes such as organ dysfunction and support, length of stay, and 28-day mortality. RESULTS: FR could be determined in 348 patients at baseline. Two hundred and forty-two patients (70%) were categorized as fluid responders. Both groups achieved comparable successful resuscitation targets, although non-fluid responders received less resuscitation fluids (0 [0-500] vs. 1500 [1000-2500] mL; p 0.0001), exhibited less positive fluid balances, but received more vasopressor testing. No difference in clinically relevant outcomes between FR+ and FR- patients was found, including 24-h SOFA score (9 [5-12] vs. 8 [5-11], p = 0.4), need for MV (78% vs. 72%, p = 0.16), need for RRT (18% vs. 21%, p = 0.7), ICU-LOS (6 [3-11] vs. 6 [3-16] days, p = 0.2), and 28-day mortality (40% vs. 36%, p = 0.5). Only thirteen patients remained fluid responsive along the intervention period. CONCLUSIONS: Systematic assessment allowed determination of fluid responsiveness status in more than 80% of patients with early septic shock. Fluid boluses could be stopped in non-fluid responsive patients without any negative impact on clinical relevant outcomes. Our results suggest that fluid resuscitation might be safely guided by FR assessment in septic shock patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03078712. Registered retrospectively on March 13, 2017.

Lactated Ringer' Solution may be Superior to Saline-Based 6% Hydroxyethyl Starch 130/0.4 for Early Resuscitation within 12 hours from Hemorrhagic Shock.

Purpose: To compare the effects of fluid resuscitation with lactated Ringer's solution (LR) and saline-based 6% hydroxyethyl starch 130/0.4 (HES) on the inflammatory response and oxidative stress in the small intestine as well as on bacterial translocation to the liver. Methods: Sprague-Dawley rats were subjected to blood pressure-controlled hemorrhagic shock and then resuscitated with LR or HES. At 1, 3, 6, 12, and 24 hr after resuscitation, liver tissues were collected to count the bacterial colonies, and small intestines were harvested to analyze the levels of inflammatory (TNF-α and HO-1) and oxidative stress (MPO) mediators as well as the intestinal injury by immunohistochemistry, colorimetry and hematoxylin & eosin staining, respectively. Results: The expression level of TNF-α in the LR group was stable from 1 to 6 hr but decreased at 12 hr and then abruptly increased at 24 hr. The expression level of TNF-α in the LR group was significantly lower than that in the HES group, especially during the first 12 hr post-fluid infusion. MPO activity decreased to its lowest level at 3 hr but increased from 6 to 12 hr, with no difference at 24 hr between the two groups. Although a decreasing tendency was observed from 6 hr, HO-1 expression levels remained higher in the LR group than in the HES group at 12 and 24 hr, particularly at 12 hr. During the initial 12 hr, the LR group exhibited significantly lower colony-forming units in the liver tissues than the HES group. Chiu's score in the intestine decreased regardless of which resuscitative fluids were used. Conclusions: During early resuscitation (within 12 hr), LR may be superior to HES in reducing intestinal injuries by suppressing inflammatory and oxidative mediators.

Perfluorocarbon NVX-108 increased cerebral oxygen tension after traumatic brain injury in rats.

BACKGROUND: Hypoxia is a critical secondary injury mechanism in traumatic brain injury (TBI), and early intervention to alleviate post-TBI hypoxia may be beneficial. NVX-108, a dodecafluoropentane perfluorocarbon, was screened for its ability to increase brain tissue oxygen tension (PbtO2) when administered soon after TBI. METHODS: Ketamine-acepromazine anesthetized rats ventilated with 40% oxygen underwent moderate controlled cortical impact (CCI)-TBI at time 0 (T0). Rats received either no treatment (NON, n=8) or 0.5 ml/kg intravenous (IV) NVX-108 (NVX, n=9) at T15 (15 min after TBI) and T75. RESULTS: Baseline cortical PbtO2 was 28±3 mm Hg and CCI-TBI resulted in a 46±6% reduction in PbtO2 at T15 (P<0.001). Significant differences in time-group interactions (P=0.013) were found when comparing either absolute or percentage change of PbtO2 to post-injury (mixed-model ANOVA) suggesting that administration of NVX-108 increased PbtO2 above injury levels while it remained depressed in the NON group. Specifically in the NVX group, PbtO2 increased to a peak 143% of T15 (P=0.02) 60 min after completion of NVX-108 injection (T135). Systemic blood pressure was not different between the groups. CONCLUSION: NVX-108 caused an increase in PbtO2 following CCI-TBI in rats and should be evaluated further as a possible immediate treatment for TBI.

Effects of terlipressin on patients with sepsis via improving tissue blood flow.

Terlipressin (TP), an analog of arginine vasopressin, was reported beneficial in sepsis patients when combined use with norepinephrine (NE), but the undetermined action, mechanism, and safety limited it to become the first-line vasopressor for sepsis patients. With 32 septic shock patients, we investigated the effects of a small dose of TP (1.3 µg/kg/h) on hemodynamic, tissue blood flow, vital organ function, acid-base balance, and coagulation function to systemically know the beneficial effect and side effects of TP on septic shock. The results showed that as compared with the single use of NE group (17 patients), a small dose of TP (1.3 µg/kg/h) in combination with NE continuous infusion, except for decreasing the mortality and NE requirement, could better improve and stabilize the hemodynamics, improve the tissue blood flow, increase the blood oxygen saturation and urine volume, and decrease the lactate level and complication rate (47% versus 82.3% in NE group). Meanwhile, TP + NE did not induce blood bilirubin increase and platelet count decrease and hyponatremia that vasopressin has. The results show that low dose of TP continuous infusion can help NE achieve the good resuscitation effect by improving tissue blood flow, stabilizing hemodynamics, and protecting organ function in septic shock patients while did not induce the side effects that high dose or bonus of TP or vasopressin induced. Low dose of TP may be recommended as the first-line vasopressor for refractory hypotension after severe sepsis or septic shock.

Hypertonic solution does not decrease mortality from traumatic hemorrhagic shock: a systematic review and Meta-analysis based on randomized control trials / 中华急诊医学杂志

Objective To evaluate systematically whether administration of hypertonic saline transfusion affects clinical outcomes with compared to standard fluid in the early stage of resuscitation for traumatic shock patients.Methods Seven English and Chinese routine biology and medicine databases were searched for randomized controlled trials (RCTs) published from January 2002 to August 2012,and established inclusion and exclusion criteria to evaluate these RCTs.The quality assessment was based on the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 and Jadad' s score scale.RevMan 5.0 statistical software was used for meta-analysis.Results After evaluated 211 related literatures,five RCTs met all the inclusion criteria and were enrolled for meta-analysis.The meta-a nalysis demonstrated that early hypertonic transfusion did not decrease short-term (first 48 hours after admission) mortality (RR =1.04,P =0.74); nor did it decrease later-term (7day to 3month after injury) mortality (RR =0.97,P =0.72).It also did not decrease the total volume of fluid and blood transfusion required during the first day (P =0.38).Similarly,it did not affect the incidents of infections (RR =1.04,P =0.70),the length of stay in ICU (P =0.2) and total length of stay in the hospital.Conclusions Compared to standard fluid,there was no advantage on mortality and hospital infection by using hypertonic supplement transfusion in the early stage of resuscitation for traumatic shock patients.Hypertonic transfusion did not have any significant effect on the volume of total fluid and blood transfusion required the first day,and no trend of reduction for the length of ICU and hospital stay.Further well-designed randomized controlled trials are needed to demonstrate the cost effectiveness of hypertonic transfusion to traumatic shock patients while in ICU.