Restrictive fluid therapy and high-dose vitamin C in sepsis.
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ABSTRACT:
SUBMITTER: Plummer MP
PROVIDER: S-EPMC9341155 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
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Restrictive fluid therapy and high-dose vitamin C in sepsis.
Plummer Mark Philip MP Bellomo Rinaldo R
Nature reviews. Nephrology 20221001 10
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Project description:Sepsis is a condition with high morbidity and mortality. Prompt recognition and initiation of treatment is essential. Despite forming an integral part of sepsis management, fluid resuscitation may also lead to volume overload, which in turn is associated with increased mortality. The optimal fluid strategy in sepsis resuscitation is yet to be defined. Hyaluronan, an endogenous glycosaminoglycan with high affinity to water is an important constituent of the endothelial glycocalyx. We hypothesized that exogenously administered hyaluronan would counteract intravascular volume depletion and contribute to endothelial glycocalyx integrity in a fluid restrictive model of peritonitis. In a prospective, blinded model of porcine peritonitis sepsis, we randomized animals to intervention with hyaluronan (n = 8) or 0.9% saline (n = 8). The animals received an infusion of 0.1% hyaluronan 6 ml/kg/h, or the same volume of saline, during the first 2 h of peritonitis. Stroke volume variation and hemoconcentration were comparable in the two groups throughout the experiment. Cardiac output was higher in the intervention group during the infusion of hyaluronan (3.2 ± 0.5 l/min in intervention group vs 2.7 ± 0.2 l/min in the control group) (p = 0.039). The increase in lactate was more pronounced in the intervention group (3.2 ± 1.0 mmol/l in the intervention group and 1.7 ± 0.7 mmol/l in the control group) at the end of the experiment (p < 0.001). Concentrations of surrogate markers of glycocalyx damage; syndecan 1 (0.6 ± 0.2 ng/ml vs 0.5 ± 0.2 ng/ml, p = 0.292), heparan sulphate (1.23 ± 0.2 vs 1.4 ± 0.3 ng/ml, p = 0.211) and vascular adhesion protein 1 (7.0 ± 4.1 vs 8.2 ± 2.3 ng/ml, p = 0.492) were comparable in the two groups at the end of the experiment. In conclusion, hyaluronan did not counteract intravascular volume depletion in early peritonitis sepsis. However, this finding is hampered by the short observation period and a beneficial effect of HMW-HA in peritonitis sepsis cannot be discarded based on the results of the present study.
| S-EPMC10513979 | biostudies-literature
Project description:BackgroundIntravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited.MethodsIn an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed.ResultsA total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups.ConclusionsAmong patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.).
| S-EPMC10685906 | biostudies-literature
Project description:Sepsis is a common and life-threatening inflammatory response to severe infection treated with antibiotics and fluid resuscitation. Despite the central role of intravenous fluid in sepsis management, fundamental questions regarding which fluid and in what amount remain unanswered. Recent advances in understanding the physiologic response to fluid administration, and large clinical studies examining resuscitation strategies, fluid balance after resuscitation, colloid versus crystalloid solutions, and high- versus low-chloride crystalloids, inform the current approach to sepsis fluid management and suggest areas for future research.
| S-EPMC4884304 | biostudies-literature
Project description:Vitamins are essential micronutrients with key roles in many biological pathways relevant to sepsis. Some of these relevant biological mechanisms include antioxidant and anti-inflammatory effects, protein and hormone synthesis, energy generation, and regulation of gene transcription. Moreover, relative vitamin deficiencies in plasma are common during sepsis and vitamin therapy has been associated with improved outcomes in some adult and pediatric studies. High-dose intravenous vitamin C has been the vitamin therapy most extensively studied in adult patients with sepsis and septic shock. This includes three randomized control trials (RCTs) as monotherapy with a total of 219 patients showing significant reduction in organ dysfunction and lower mortality when compared to placebo, and five RCTs as a combination therapy with thiamine and hydrocortisone with a total of 1134 patients showing no difference in clinical outcomes. Likewise, the evidence for the role of other vitamins in sepsis remains mixed. In this narrative review, we present the preclinical, clinical, and safety evidence of the most studied vitamins in sepsis, including vitamin C, thiamine (i.e., vitamin B1), and vitamin D. We also present the relevant evidence of the other vitamins that have been studied in sepsis and critical illness in both children and adults, including vitamins A, B2, B6, B12, and E. IMPACT: Vitamins are key effectors in many biological processes relevant to sepsis. We present the preclinical, clinical, and safety evidence of the most studied vitamins in pediatric sepsis. Designing response-adaptive platform trials may help fill in knowledge gaps regarding vitamin use for critical illness and association with clinical outcomes.
| S-EPMC8325544 | biostudies-literature
Project description:Sepsis is the dysregulated immune response to severe infection that is common and lethal among critically ill patients. Fluid administration is a common treatment for hypotension and shock in early sepsis. Fluid therapy can also cause edema and organ dysfunction. Research on the best treatment strategies for sepsis has provided insights on the optimal timing, dose, and type of fluid to treat patients with sepsis. Initial research on early goal-directed therapy for sepsis included an initial bolus of 30 ml/kg of fluid, but more recent research has supported use of smaller volumes. After initial fluid resuscitation, minimizing additional fluid administration may be beneficial, but no single measure has been established as the best method to guide ongoing fluid management in sepsis. Dynamic measures of "fluid responsiveness" can predict which patients will experience an increase in cardiac output from a fluid bolus. Use of such a measure in clinical care remains limited by applicability to patient populations and uncertainty regarding the effect on clinical outcomes. Recent research informs the effect of fluid composition on outcomes for patients with sepsis. Current data support the use of balanced crystalloids, rather than saline, and the use of crystalloids, rather than semisynthetic colloids. The role for albumin administration in sepsis remains uncertain. Future research should focus on determining the optimal volume of fluid during sepsis resuscitation, the effectiveness of measures of "fluid responsiveness" in improving outcomes, the optimal composition of crystalloid solutions, the role of albumin, and the effects of "deresuscitation" after septic shock.
| S-EPMC9463107 | biostudies-literature
Project description:Sepsis is an extremely complex clinical syndrome, usually involving an excessive inflammatory response including an overshooting cytokine release that damages tissue and organs of the patient. Due to the severity of this condition, it is estimated that over 11 million people die from sepsis each year. Despite intensive research in the field, there is still no specific therapy for sepsis. Many sepsis patients show a marked deficiency of vitamin C. 9 out of 10 sepsis patients have a hypovitaminosis C, and every third patient even shows a clinical deficiency in the scurvy range. In addition, low vitamin C levels of intensive care sepsis patients correlate with a higher need for vasopressors, higher Sequential Organ Failure Assessment (SOFA) scores, and increased mortality. Based on this observation and the conducted clinical trials using vitamin C as sepsis therapy in intensive care patients, the aim of the present ex vivo study was to evaluate the effects of high-dose vitamin C alone and in a triple combination supplemented with vitamin B1 (thiamine) and hydrocortisone on the lipopolysaccharide (LPS)-induced cytokine response in peripheral blood mononuclear cells (PBMCs) from healthy human donors. We found that all corticosteroid combinations strongly reduced the cytokine response on RNA- and protein levels, while high-dose vitamin C alone significantly diminished the PBMC mediated secretion of the cytokines interleukin (IL)-10, IL-23, and monocyte chemo-attractant protein (MCP-1), which mediate the inflammatory response. However, vitamin C showed no enhancing effect on the secretion of further cytokines studied. This data provides important insights into the possible immunomodulatory function of vitamin C in an ex vivo setting of human PBMCs and the modulation of their cytokine profile in the context of sepsis. Since vitamin C is a vital micronutrient, the restoration of physiologically adequate concentrations should be integrated into routine sepsis therapy, and the therapeutic effects of supraphysiological concentrations of vitamin C in sepsis patients should be further investigated in clinical trials.
| S-EPMC8308809 | biostudies-literature
Project description:ObjectivesIt is unclear if a low- or high-volume IV fluid resuscitation strategy is better for patients with severe sepsis and septic shock.DesignProspective randomized controlled trial.SettingTwo adult acute care hospitals within a single academic system.PatientsPatients with severe sepsis and septic shock admitted from the emergency department to the ICU from November 2016 to February 2018.InterventionsPatients were randomly assigned to a restrictive IV fluid resuscitation strategy (≤ 60 mL/kg of IV fluid) or usual care for the first 72 hours of care.Measurements and main resultsWe enrolled 109 patients, of whom 55 were assigned to the restrictive resuscitation group and 54 to the usual care group. The restrictive group received significantly less resuscitative IV fluid than the usual care group (47.1 vs 61.1 mL/kg; p = 0.01) over 72 hours. By 30 days, there were 12 deaths (21.8%) in the restrictive group and 12 deaths (22.2%) in the usual care group (odds ratio, 1.02; 95% CI, 0.41-2.53). There were no differences between groups in the rate of new organ failure, hospital or ICU length of stay, or serious adverse events.ConclusionsThis pilot study demonstrates that a restrictive resuscitation strategy can successfully reduce the amount of IV fluid administered to patients with severe sepsis and septic shock compared with usual care. Although limited by the sample size, we observed no increase in mortality, organ failure, or adverse events. These findings further support that a restrictive IV fluid strategy should be explored in a larger multicenter trial.
| S-EPMC6579683 | biostudies-literature
Project description:Sepsis survivors present long-term cognitive deficits. The present study was to investigate the effect of early administration of high-dose vitamin C on cognitive function in septic rats and explore its possible cerebral protective mechanism. Rat sepsis models were established by cecal ligation and puncture (CLP). Ten days after surgery, the Morris water maze test was performed to evaluate the behavior and cognitive function. Histopathologic changes in the hippocampus were evaluated by nissl staining. The inflammatory cytokines, activities of antioxidant enzymes (superoxide dismutase or SOD) and oxidative products (malondialdehyde or MDA) in the serum and hippocampus were tested 24 h after surgery. The activity of matrix metalloproteinase-9 (MMP-9) and expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) in the hippocampus were measured 24 h after surgery. Compared with the sham group in the Morris water maze test, the escape latency of sepsis rats was significantly (P = 0.001) prolonged in the navigation test, whereas the frequency to cross the platform and the time spent in the target quadrant were significantly (P = 0.003) reduced. High-dose vitamin C significantly decreased the escape latency (P = 0.01), but increased the time spent in the target quadrant (P = 0.04) and the frequency to cross the platform (P = 0.19). In the CLP+ saline group, the pyramidal neurons were reduced and distributed sparsely and disorderly, the levels of inflammatory cytokines of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 in the serum and hippocampus were significantly increased (P = 0.000), the blood brain barrier (BBB) permeability in the hippocampus was significantly (P = 0.000) increased, the activities of SOD in the serum and hippocampus were significantly (P = 0.000 and P = 0.03, respectively) diminished while the levels of MDA in the serum and hippocampus were significantly (P = 0.007) increased. High-dose vitamin C mitigated hippocampus histopathologic changes, reduced systemic inflammation and neuroinflammation, attenuated BBB disruption, inhibited oxidative stress in brain tissue, and up-regulated the expression of nuclear and total Nrf2 and HO-1. High-dose vitamin C significantly (P < 0.05) decreased the levels of tumor necrosis factor- (TNF)-α, interleukin-6 (IL-6), MDA in the serum and hippocampus, and the activity of MMP-9 in the hippocampus, but significantly (P < 0.05) increased the levels of SOD, the anti-inflammatory cytokine (IL-10) in the serum and hippocampus, and nuclear and total Nrf2, and HO-1 in the hippocampus. In conclusion, high-dose vitamin C can improve cognition impairment in septic rats, and the possible protective mechanism may be related to inhibition of inflammatory factors, alleviation of oxidative stress, and activation of the Nrf2/HO-1 pathway.
| S-EPMC8282649 | biostudies-literature
Project description:ObjectiveRestrictive fluid therapy is recommended in thoracoscopic lobectomy to reduce postoperative pulmonary complications, but it may contribute to hypovolemia. Goal-directed fluid therapy (GDFT) regulates fluid infusion to an amount required to avoid dehydration. We compared the effects of GDFT versus restrictive fluid therapy on postoperative complications after thoracoscopic lobectomy.MethodsIn total, 124 patients who underwent thoracoscopic lobectomy were randomized into the GDFT group (group G, n = 62) or restrictive fluid therapy group (group R, n = 62). The fluid volume and postoperative complications within 30 days of surgery were recorded.ResultsThe total fluid volume in groups G and R was 1332 ± 364 and 1178 ± 278 mL, respectively. Group R received a smaller colloid fluid volume (523 ± 120 vs. 686 ± 180 mL), had a smaller urine output (448 ± 98 vs. 491 ± 101 mL), and received more norepinephrine (120 ± 66 vs. 4 ± 18 µg) than group G. However, there were no significant differences in postoperative pulmonary complications, acute kidney injury, length of hospital stay, or in-hospital mortality between the two groups.ConclusionRestrictive fluid therapy performs similarly to GDFT in thoracoscopic lobectomy but is a simpler fluid strategy than GDFT.Trial registration: This study has been registered at the Chinese Clinical Trial Registry (ChiCTR2100051339) (http://www.chictr.org.cn/index.aspx).
| S-EPMC8728787 | biostudies-literature
Project description:BackgroundIntravenous vitamin C therapy has been associated with reduced mortality in patients with sepsis. Of potential concern with this therapy are falsely elevated point-of-care (POC) blood glucose values vs laboratory analyzed (LA) readings. The purpose of this study was to compare POC and LA blood glucose measurements in patients receiving intravenous vitamin C therapy.MethodsAll adults (≥18 years old) admitted from January 2017 to December 2018 who received at least two doses of intravenous vitamin C and had at least one paired blood glucose collection were eligible for inclusion. The primary endpoint was the accuracy in paired blood glucose values determined using the International Organization for Standardization (ISO) 15197:2013 criteria. Paired values were assessed for clinical impact using the Parkes consensus error grid analysis. A subgroup analysis was conducted to determine the impact of impaired renal function on outcomes.ResultsFourteen patients were included for analysis with 46 paired blood glucose levels. Compliance with ISO15197:2013 criteria was met in 34 (73.9%) paired values, which did not meet the minimum criteria for accuracy. Subgroup analysis showed that the paired values from patients with impaired renal function did not meet the minimum requirements for compliance, while those from patients without impaired renal function did. The Parkes error grid showed that the variation in POC measurements likely had minimal clinical impact.ConclusionsOur study suggests that most patients receiving vitamin C for sepsis may still be monitored at POC with the glucose meter used in our study with minimal clinical impact.
| S-EPMC8256056 | biostudies-literature