Anna Włudarczyk

Fluid Resuscitation in Sepsis: A Systematic Review and Network Meta-analysis

Resuscitation with crystalloids compared with colloids for critically ill patients has been evaluated in large randomized, controlled trials (16) and meta-analyses (713). One meta-analysis(10) including 74 trials reported no difference in mortality between critically ill patients resuscitated with crystalloids and albumin (relative risk [RR], 1.01 [95% CI, 0.93 to 1.10]), hydroxyethyl starch (HES) (RR, 1.10 [CI, 0.91 to 1.32]), gelatin (RR, 0.91 [CI, 0.49 to 1.72]), or dextran (RR, 1.24 [CI, 0.94 to 1.65]). Another meta-analysis (8) reported that resuscitation with an albumin-containing solution in patients with sepsis may decrease mortality compared with solutions containing no albumin (RR, 0.82 [CI, 0.67 to 1.00]). Recent evidence suggests that starches, compared with other fluids and regardless of molecular weight, may be associated with acute kidney injury in the general population of critically ill patients and in those with sepsis (5, 11, 1315). A recent large pragmatic trial comparing colloids (mostly starches) with crystalloids (mostly 0.9% sodium chloride) suggested a 90-day mortality benefit with colloids (RR, 0.92 [CI, 0.86 to 0.99]) (16). Crystalloids can be characterized on the basis of tonicity and electrolyte content. The presence of an organic anion (for example, lactate, acetate, or gluconate) and correspondingly lower chloride content that more closely resembles the composition of plasma suggest that a crystalloid is balanced (for example, Ringer lactate and acetate solutions) (17). The most commonly used crystalloid, normal saline (0.9% sodium chloride), is far from normal, with a pH much less than 7.0 and a supraphysiologic chloride content of 154 mmol/L (18, 19). Compared with a balanced crystalloid solution, normal saline predisposes patients to hyperchloremic metabolic acidosis, decreased renal blood flow to the glomerulus, and impaired smooth-muscle contractility (20). Investigators have not done randomized, controlled trials (RCTs) comparing balanced and unbalanced crystalloids. However, 1 large beforeafter study of critically ill patients showed that balanced versus unbalanced fluid solution was associated with a lower incidence of acute kidney injury (8.4% vs. 14%; P< 0.01) and renal replacement therapy (6.3% vs. 10%; P= 0.05) but no differences in hospital mortality (18). Colloids include natural compounds, such as albumin, and synthetic compounds of HES, gelatin, or dextran. Expansion of plasma volume increases in proportion to the osmotic or oncotic potential, and colloids theoretically require less volume than crystalloids to achieve equivalent hemodynamic effect (19). Limitations of colloids include development of acute kidney injury and coagulation disorders with starches (14) and albumin creates risk for exposure to blood products (19). Another important consideration is the biochemical properties of the crystalloid solution in which the colloid is dissolved. For example, the chloride concentrations in HES may vary between 154 mmol/L (Voluven, Fresenius Kabi) and 118 mmol/L (Tetraspan, B. Braun Medical) (21). Whether any of these fluid properties translate into a survival advantage remains unclear, particularly regarding the optimal fluid for resuscitation in patients with sepsis. Fluid resuscitation, in addition to antibiotics and source control, is a cornerstone of initial management of sepsis (22). However, fluid management in patients with sepsis varies widely in practice (16, 23, 24). Meta-analyses of fluid resuscitation have been limited by not focusing on patients with sepsis (7, 9, 10), not considering electrolyte composition (5, 8, 10, 11), considering only 2 or 3 categories of fluid (25), not including direct and indirect comparisons in the same model, and omission of recent large RCTs(35, 16). Therefore, we did a network meta-analysis (NMA) considering direct and indirect comparisons of all types of fluid resuscitation tested in RCTs in patients with severe sepsis and septic shock, focusing on the effect of these interventions on mortality. Methods Data Sources and Searches This review was done using a predefined protocol. Initially, we searched MEDLINE (1948 to December 2012), EMBASE (1980 to December 2012), ACP Journal Club (1991 to December 2012), the Cochrane Central Register of Controlled Trials, HealthSTAR, the Allied and Complementary Medicine Database, and CINAHL. We updated the MEDLINE and EMBASE searches in August 2013 and March 2014. We screened previously published meta-analyses for relevant citations. Supplement 1 presents the search terms used. Supplement 1. WinBUGS Code for NMA Six reviewers working in 3 pairs screened the titles and abstracts to determine potential eligibility, and entries identified by any reviewer proceeded to the full-text eligibility review. Pretested eligibility forms were used for full-text review, which was also done in duplicate. A third adjudicator helped to resolve disagreements through consensus. Study Selection We selected parallel-group RCTs, including factorial designs, but excluded quasi-randomized and crossover trials. We excluded all studies published by Dr. Joachim Boldt because of suspected lack of integrity (26, 27). We did not apply restrictions on language or publication date. We included studies that involved adult (aged 16 years) critically ill patients with severe sepsis or septic shock as defined by the investigators and who required fluid resuscitation (defined as the administration of a bolus of intravenous fluid exceeding the amount required for maintenance or replacement fluids). We included studies with mixed critically ill populations whenever separate data for patients with sepsis were available. We excluded studies in which most patients had the systemic inflammatory response syndrome secondary to other causes (such as burn, pancreatitis, and trauma) without a clear sepsis subgroup and those focusing on patients after elective surgery. Interventions studied included any fluid or fluid strategy used for resuscitation compared with another fluid or fluid strategy. We excluded studies in which the primary goal was to assess short-term hemodynamic response. Our outcome was 90-day mortality or, if not available, 30-day, intensive care unit, or hospital mortality, whichever was longest. Data Extraction Pairs from the same 6 reviewers abstracted data in duplicate. Another clinician reviewed disagreements, and consensus was reached by discussion. We contacted authors of primary publications for missing or unclear information. Risk of Bias Independently and in duplicate, reviewers assessed risk of bias using a modified version of the Cochrane Collaboration assessment tool (28, 29). We judged each included study as having low, probably low, probably high, or high risk of bias for randomization-sequence generation, randomization concealment, blinding, incomplete data, selective reporting, and free of other bias (including intention-to-treat analysis). The overall rating of risk of bias for each study was the lowest rating for any of the criteria (Appendix Table). Appendix Table. Risk of Bias, by Study Data Synthesis and Analysis Our analysis classified fluids as crystalloids (divided into balanced and unbalanced solutions) and colloids (divided into albumin, gelatin, and low- and high-molecular-weight HES [threshold molecular weight, 150000 kDa]). We considered fluid balanced if it contained an anion of a weak acid (buffer) and its chloride content was correspondingly less than in 0.9% sodium chloride (21). The relevant analyses were a 4-node NMA (crystalloids vs. albumin vs. HES vs. gelatin), a 6-node NMA (crystalloids vs. albumin vs. HES vs. gelatin, with crystalloids divided into balanced or unbalanced and HES divided into low or high molecular weight), and a conventional direct frequentist fixed-effects meta-analytic comparison of crystalloids versus colloids. To calculate direct estimates of treatment effect for each pair of treatments in the 4- and 6-node networks, we did a frequentist fixed-effects meta-analysis. We reported the results as odds ratios (ORs) and corresponding 95% CIs. We evaluated heterogeneity by estimating the variance between studies (chi-square test and I 2 statistic) (30, 31). Using a Bayesian framework, we did 4- and 6-node fixed-effects NMAs for each treatment. We reported the results as ORs and corresponding 95% credibility intervals (CrIs), which are the Bayesian analogue of 95% CIs(32). The ORs reported are relative effects of compared fluids. The models are based on 80000 iterations with a burn-in of 40000 and a thin of 10. We used a random seed and vague priors. We assessed nonconvergence on the basis of BrooksGelmanRubin plots (33). We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess confidence in estimates of effect (quality of evidence) associated with specific comparisons, including estimates from direct, indirect, and final NMAs (Supplement 2) (34). Our confidence assessment addressed risk of bias, incoherence, imprecision, inconsistency, indirectness, and publication bias. Supplement 2. GRADE Confidence Explanations for All Point Estimates The starting point for confidence in direct and indirect estimates was high. However, indirect estimates were potentially rated down for intransitivity (that is, differences in patients, co-interventions, or settings that could lead to effect modification and thus a misleading comparison of fluid management strategies). We inferred confidence in indirect estimates by examining the connecting loops associated with the particular comparison. The confidence rating chosen was the lowest of the direct estimates contributing to the indirect comparison. For example, consider a comparison of A versus B that is informed by comparisons of A versus C and B versus C. If A versus C was rated as high confidence and B versus C as moderate confidence, the overall indirect confidence rating was ini

Altered preoperative coagulation and fibrinolysis are associated with myocardial injury after non-cardiac surgery.

Background. Myocardial injury after non‐cardiac surgery (MINS), a complication with unclear pathogenesis, occurs within the first 30 days after surgery and worsens prognosis. Hypercoagulability induced by surgery might contribute to plaque rupture, with subsequent thrombosis and myocardial injury. This study assessed haemostatic markers before surgery and evaluated their association with MINS. Methods. This is a substudy of VISION, a prospective cohort study of perioperative cardiovascular events. Of 475 consecutive vascular surgery patients, 47 (9.9%) developed MINS, defined as postoperative high‐sensitivity troponin ≥50 ng litre‐1, with ≥20% elevation from the preoperative concentration. The control group consisted of 84 non‐MINS patients matched for patient characteristics and co‐morbidities. The following preoperative markers of hypercoagulability and fibrinolysis were measured: antithrombin, factor VIII activity, von Willebrand factor concentration and activity, fibrinogen, D‐dimer, plasmin‐antiplasmin complex, and tissue plasminogen activator. Moreover, C‐reactive protein and CD40L concentrations were measured to assess inflammatory activity. Results. Patients with MINS compared with the non‐MINS group had a significantly higher concentration of factor VIII (186 vs 155%, P=0.006), von Willebrand factor activity (223 vs 160%, P<0.001), von Willebrand factor concentration (317 vs 237%, P=0.02), concentrations of fibrinogen (5.6 vs 4.2 g litre‐1, P=0.03), D‐dimer (1680.0 vs 1090.0 ng ml‐1, P=0.04), plasmin‐antiplasmin complex (747 vs 512 ng ml‐1, P=0.002) and C‐reactive protein (10 vs 4.5 mg litre‐1, P=0.02) but not antithrombin (95 vs 94%, P=0.89), tissue plasminogen activator (11 vs 9.7 ng ml‐1, P=0.06) and CD40L (8790 vs 8580 pg ml‐1, P=0.73). Conclusions. Preoperative elevation of blood markers of hypercoagulability in patients undergoing vascular surgery is associated with a higher risk of MINS. Clinical trial registration. NCT00512109.

Patients with small-vessel vasculitides have the highest mortality among systemic autoimmune diseases patients treated in intensive care unit: A retrospective study with 5-year follow-up

Purpose: Systemic autoimmune diseases are a heterogeneous group of disorders associated with dysfunction of multiple organs and unpredictable course. Complicated management and treatment become even more challenging when patients require critical care. This study aims to compare outcomes of small‐vessel vasculitides (SVV) and other systemic autoimmune diseases (SAD) patients admitted to the intensive care unit (ICU). Materials and methods: Retrospective, observational study conducted in the ICU of Allergy and Immunology Department at the University Hospital in Krakow, Poland, between years 2001–2014, with 5‐years follow‐up and no lost to follow‐up patients. Results: 74 patients with autoimmune diseases were enrolled in the study ‐ 23 with SVV and 51 with SAD. Patients in the SVV group achieved higher scores in APACHE II and III SAPS II and SOFA at ICU admission. The SVV patients required renal replacement techniques, blood products transfusion and immunosuppressive treatment more often. SVV patients had higher ICU mortality (60.9% vs. 35.3%, p = .04), however after discharge from ICU, in long term follow‐up (1 year and 5 years) mortality was similar in both studied groups. Conclusions: Among systemic autoimmune diseases small vessel vasculitides appear to be associated with the highest ICU mortality, higher requirement for advanced procedures and aggressive immunosuppressive therapy.

Neurological manifestations in ANCA-associated vasculitis - assessment and treatment

Antineutrophil cytoplasmic antibodies associated vasculitis (AAV) is an entity that encompasses three systemic autoimmune diseases: granulomatosis with polyangitis (GPA; formerly Wegener’s granulomatosis), microscopic polyangitis (MPA) and eosinophilic granulomatosis with polyangitis (EGPA; formerly Churg–Strauss syndrome) [1]. Their main common features are necrotizing inflammation of medium to small vessels and association with antineutrophil cytoplasmic antibodies (ANCA) production. AAV is rare with incidence ranging from 15 to 25/1 million in the general population [2]. It has a systemic course which means, the disease can affect virtually any organ. Although, the involvement of respiratory tract and kidneys remain hallmarks of the disease, the neurological manifestations are not rare, and if present, they may help in establishing the diagnosis and impose changes to the treatment regimen.