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Critical Care Medicine Mar 2004In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for severe sepsis and septic shock that... (Review)
Review
OBJECTIVE
In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for severe sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis.
DESIGN
The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee.
METHODS
We used a modified Delphi methodology for grading recommendations, built on a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade. Pediatric considerations were provided to contrast adult and pediatric management.
RESULTS
Key recommendations, listed by category and not by hierarchy, include early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition; appropriate diagnostic studies to ascertain causative organisms before starting antibiotics; early administration of broad-spectrum antibiotic therapy; reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate; a usual 7-10 days of antibiotic therapy guided by clinical response; source control with attention to the method that balances risks and benefits; equivalence of crystalloid and colloid resuscitation; aggressive fluid challenge to restore mean circulating filling pressure; vasopressor preference for norepinephrine and dopamine; cautious use of vasopressin pending further studies; avoiding low-dose dopamine administration for renal protection; consideration of dobutamine inotropic therapy in some clinical situations; avoidance of supranormal oxygen delivery as a goal of therapy; stress-dose steroid therapy for septic shock; use of recombinant activated protein C in patients with severe sepsis and high risk for death; with resolution of tissue hypoperfusion and in the absence of coronary artery disease or acute hemorrhage, targeting a hemoglobin of 7-9 g/dL; appropriate use of fresh frozen plasma and platelets; a low tidal volume and limitation of inspiratory plateau pressure strategy for acute lung injury and acute respiratory distress syndrome; application of a minimal amount of positive end-expiratory pressure in acute lung injury/acute respiratory distress syndrome; a semirecumbent bed position unless contraindicated; protocols for weaning and sedation/analgesia, using either intermittent bolus sedation or continuous infusion sedation with daily interruptions/lightening; avoidance of neuromuscular blockers, if at all possible; maintenance of blood glucose <150 mg/dL after initial stabilization; equivalence of continuous veno-veno hemofiltration and intermittent hemodialysis; lack of utility of bicarbonate use for pH > or =7.15; use of deep vein thrombosis/stress ulcer prophylaxis; and consideration of limitation of support where appropriate. Pediatric considerations included a more likely need for intubation due to low functional residual capacity; more difficult intravenous access; fluid resuscitation based on weight with 40-60 mL/kg or higher needed; decreased cardiac output and increased systemic vascular resistance as the most common hemodynamic profile; greater use of physical examination therapeutic end points; unsettled issue of high-dose steroids for therapy of septic shock; and greater risk of hypoglycemia with aggressive glucose control.
CONCLUSION
Evidence-based recommendations can be made regarding many aspects of the acute management of sepsis and septic shock that are hoped to translate into improved outcomes for the critically ill patient. The impact of these guidelines will be formally tested and guidelines updated annually and even more rapidly as some important new knowledge becomes as available.
Topics: Adult; Age Factors; Algorithms; Child; Evidence-Based Medicine; Humans; Sepsis; Shock, Septic
PubMed: 15090974
DOI: 10.1097/01.ccm.0000117317.18092.e4 -
Cureus Sep 2022Acute pancreatitis is one of the most common conditions with high rates of morbidity and mortality. Different scoring systems are used to gauge the severity of this... (Review)
Review
Acute pancreatitis is one of the most common conditions with high rates of morbidity and mortality. Different scoring systems are used to gauge the severity of this condition, which, in turn, estimates the complications and mortality rates. With the ever-evolving use of the acute-phase reactant protein, C-reactive protein (CRP), and an abundant circulating protein in plasma, albumin, in daily practice, this study aimed to assess the ratio of CRP and albumin for assessing the severity of acute pancreatitis. A systematic review of the literature was performed using the keywords CRP albumin ratio and acute pancreatitis in the PubMed and Cochrane databases. Studies reporting the use of the ratio of CRP and albumin in acute pancreatitis as well as the outcomes were included in this analysis. The quality of studies was assessed using the MINORS (methodological index for non-randomized studies) assessment tool. In our review, across these three studies, 956 patients with acute pancreatitis were identified and enrolled in studies that examined the relationship between the CRP/Albumin ratio and the severity of acute pancreatitis. Overall, a positive correlation was found between the CRP/albumin ratio at admission and the development of subsequent severe acute pancreatitis, increased hospital length of stay, and the higher rate of mortality in these studies.
PubMed: 36262941
DOI: 10.7759/cureus.29243 -
Osteoarthritis and Cartilage May 2019This study was design to examine the diagnostic performance of cartilage oligomeric matrix protein (COMP), C-terminal cross-linking telopeptide of type II collagen... (Meta-Analysis)
Meta-Analysis
Cartilage oligomeric matrix protein, C-terminal cross-linking telopeptide of type II collagen, and matrix metalloproteinase-3 as biomarkers for knee and hip osteoarthritis (OA) diagnosis: a systematic review and meta-analysis.
OBJECTIVE
This study was design to examine the diagnostic performance of cartilage oligomeric matrix protein (COMP), C-terminal cross-linking telopeptide of type II collagen (CTX-II), and matrix metalloproteinase-3 (MMP-3) as biomarker for knee and hip OA.
METHODS
Systematic search on multiple databases was completed in January 2018 using certain keywords. COMP, CTX-II, MMP-3 levels in knee and hip OA patients and healthy individuals were collected and calculated. Differences between subgroups were expressed as standardized mean differences (SMD). Subgroup analyses were performed to compare COMP, CTX-II, and MMP-3 performance between measuring sources, genders, large and small sample size and diagnostic criteria for OA patients.
RESULTS
A moderate performance of COMP in distinguishing between knee (SMD: 0.68; 95% confidence intervals (CI): 0.43-0.93; P < 0.0001) or hip (SMD: 0.25; 95% CI, 0.10, 0.40; P = 0.0008) OA patients and controls were found. CTX-II showed a moderated standardised mean differences (SMD) of 0.48 (95% CI, 0.32, 0.64; P < 0.0001) in the detection of knee OA and a large SMD of 0.76 (95% CI, 0.09, 1.42; P = 0.03) in diagnosing hip OA. A small SMD of 0.32 (95% CI, -0.03, 0.67; P = 0.07) was found for MMP-3 performance and the results did not reach statistic significance. Progression study revealed potential effectiveness of serum COMP in predicting OA progression. Subgroup analysis showed that serum COMP and urinary CTX-II performed better in male than female. Study size and diagnostic criteria did not significantly influence the pooled SMD, but they might be the sources of heterogeneity among studies.
CONCLUSION
The overall results indicates that serum COMP and urinary CTX-II can distinguish between knee or hip OA patients and control subjects. Serum COMP is effective in predicting OA progression.Further researches with rigorous study design and a larger sample size are required to validate our findings.
Topics: Biomarkers; Cartilage Oligomeric Matrix Protein; Collagen Type II; Humans; Matrix Metalloproteinase 3; Osteoarthritis, Hip; Osteoarthritis, Knee; Peptide Fragments; Prognosis
PubMed: 30391538
DOI: 10.1016/j.joca.2018.10.009 -
The Cochrane Database of Systematic... Dec 2012Sepsis is a common and frequently fatal condition. Human recombinant activated protein C (APC) has been introduced to reduce the high risk of death associated with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Sepsis is a common and frequently fatal condition. Human recombinant activated protein C (APC) has been introduced to reduce the high risk of death associated with severe sepsis or septic shock. This systematic review is an update of a Cochrane review originally published in 2007.
OBJECTIVES
We assessed the benefits and harms of APC for patients with severe sepsis or septic shock.
SEARCH METHODS
We searched CENTRAL (The Cochrane Library 2012, Issue 6); MEDLINE (2010 to June 2012); EMBASE (2010 to June 2012); BIOSIS (1965 to June 2012); CINAHL (1982 to June 2012) and LILACS (1982 to June 2012). There was no language restriction.
SELECTION CRITERIA
We included randomized clinical trials assessing the effects of APC for severe sepsis or septic shock in adults and children. We excluded studies on neonates. We considered all-cause mortality at day 28 and at the end of study follow up, and hospital mortality as the primary outcomes.
DATA COLLECTION AND ANALYSIS
We independently performed trial selection, risk of bias assessment, and data extraction in duplicate. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We used a random-effects model.
MAIN RESULTS
We identified one new randomized clinical trial in this update which includes six randomized clinical trials involving 6781 participants in total, five randomized clinical trials in adult (N = 6307) and one randomized clinical trial in paediatric (N = 474) participants. All trials had high risk of bias and were sponsored by the pharmaceutical industry. APC compared with placebo did not significantly affect all-cause mortality at day 28 compared with placebo (780/3435 (22.7%) versus 767/3346 (22.9%); RR 1.00, 95% confidence interval (CI) 0.86 to 1.16; I(2) = 56%). APC did not significantly affect in-hospital mortality (393/1767 (22.2%) versus 379/1710 (22.1%); RR 1.01, 95% CI 0.87 to 1.16; I(2) = 20%). APC was associated with an increased risk of serious bleeding (113/3424 (3.3%) versus 74/3343 (2.2%); RR 1.45, 95% CI 1.08 to 1.94; I(2) = 0%). APC did not significantly affect serious adverse events (463/3334 (13.9%) versus 439/3302 (13.2%); RR 1.04, 95% CI 0.92 to 1.18; I(2) = 0%). Trial sequential analyses showed that more trials do not seem to be needed for reliable conclusions regarding these outcomes.
AUTHORS' CONCLUSIONS
This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. APC seems to be associated with a higher risk of bleeding. The drug company behind APC, Eli Lilly, has announced the discontinuation of all ongoing clinical trials using this drug for treating patients with severe sepsis or septic shock. APC should not be used for sepsis or septic shock outside randomized clinical trials.
Topics: Adult; Age Factors; Anti-Infective Agents; Cause of Death; Child; Drug Recalls; Early Termination of Clinical Trials; Hospital Mortality; Humans; Protein C; Randomized Controlled Trials as Topic; Recombinant Proteins; Sepsis; Shock, Septic
PubMed: 23235609
DOI: 10.1002/14651858.CD004388.pub6 -
Critical Care Medicine Aug 2002Given the efficacy and safety of recombinant human activated protein C (rhAPC) in the systemic inflammatory response syndrome, this study was designed to review the... (Clinical Trial)
Clinical Trial Randomized Controlled Trial Review
OBJECTIVES
Given the efficacy and safety of recombinant human activated protein C (rhAPC) in the systemic inflammatory response syndrome, this study was designed to review the evidence for a role for APC in the pathogenesis of preeclampsia. Preeclampsia is a proinflammatory and procoagulant state, and it is a pregnancy-specific condition that mimics the systemic inflammatory response syndrome. rhAPC reduces mortality in patients with systemic inflammatory response syndrome and could potentially have a role as disease-modifying therapy in preeclampsia. To determine which patients would be offered rhAPC, the literature pertaining to fetal/neonatal outcomes for preeclampsia remote from term, transplacental transport of protein C, and pregnancy experience with the compound were reviewed.
DATA SOURCES
MEDLINE, review papers, hand searches of relevant nonindexed journals, and the bibliographies of relevant textbooks and articles reviewed.
STUDY SELECTION
Randomized controlled trials were considered to provide the best quality of clinical data. Case-control series were considered over uncontrolled data. Some data were not available in the published literature (e.g., neonatal outcomes at various gestational ages and birthweights after a hypertensive pregnancy; and transplacental transfer of protein C), and these data were determined by us.
DATA EXTRACTION
Data were extracted by systematic review onto data collection sheets. Because of the quality of the data, this review is primarily qualitative.
DATA SYNTHESIS
APC levels fall during normal gestation, returning to normal values by 6 wks postpartum. Limited data suggest that early onset preeclampsia is a state of further, and inappropriate, reduction in APC. Preeclampsia resembles systemic inflammatory response syndrome in this regard. After hypertensive pregnancies, neonates have a 50% chance of intact survival if delivered after 27 + 0 wks of gestation with a birthweight of >600 g. It would seem ethical to offer women with preeclampsia with <50% chance of intact perinatal survival novel and potentially disease-modifying therapy such as rhAPC, especially as there is no transplacental transfer of protein C. Limited evidence would support the use of rhAPC in women with severe postpartum preeclampsia.
CONCLUSIONS
Sufficient data exist to support the use of rhAPC in phase II clinical studies for women with either early onset preeclampsia or severe or deteriorating postpartum disease.
Topics: Case-Control Studies; Clinical Trials, Phase II as Topic; Female; Humans; MEDLINE; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Protein C; Severity of Illness Index; Women's Health
PubMed: 12163810
DOI: 10.1097/00003246-200208000-00035 -
Thrombosis Journal 2018The pathophysiological mechanisms of acute coagulopathy of trauma-shock (ACOTS) are reported to include activated protein C-mediated suppression of thrombin generation... (Review)
Review
BACKGROUND
The pathophysiological mechanisms of acute coagulopathy of trauma-shock (ACOTS) are reported to include activated protein C-mediated suppression of thrombin generation via the proteolytic inactivation of activated Factor V (FVa) and FVIIIa; an increased fibrinolysis via neutralization of plasminogen activator inhibitor-1 (PAI-1) by activated protein C. The aims of this study are to review the evidences for the role of activated protein C in thrombin generation and fibrinolysis and to validate the diagnosis of ACOTS based on the activated protein C dynamics.
METHODS
We conducted systematic literature search (2007-2017) using PubMed, the Cochrane Database of Systematic Reviews (CDSR), and the Cochrane Central Register of Controlled Trials (CENTRAL). Clinical studies on trauma that measured activated protein C or the circulating levels of activated protein C-related coagulation and fibrinolysis markers were included in our study.
RESULTS
Out of 7613 studies, 17 clinical studies met the inclusion criteria. The levels of activated protein C in ACOTS were inconsistently decreased, showed no change, or were increased in comparison to the control groups. Irrespective of the activated protein C levels, thrombin generation was always preserved or highly elevated. There was no report on the activated protein C-mediated neutralization of PAI-1 with increased fibrinolysis. No included studies used unified diagnostic criteria to diagnose ACOTS and those studies also used different terms to refer to the condition known as ACOTS.
CONCLUSIONS
None of the studies showed direct cause and effect relationships between activated protein C and the suppression of coagulation and increased fibrinolysis. No definitive diagnostic criteria or unified terminology have been established for ACOTS based on the activated protein C dynamics.
PubMed: 29946227
DOI: 10.1186/s12959-018-0167-3 -
Blood Mar 2012The endothelial protein C receptor (EPCR) limits thrombus formation by enhancing activation of the protein C anticoagulant pathway, and therefore may play a role in the... (Meta-Analysis)
Meta-Analysis Review
The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies.
The endothelial protein C receptor (EPCR) limits thrombus formation by enhancing activation of the protein C anticoagulant pathway, and therefore may play a role in the etiology of thrombotic disorders. The rs867186 single-nucleotide polymorphism in the PROCR gene (g.6936A > G, c.4600A > G), resulting in a serine-to-glycine substitution at codon 219, has been associated with reduced activation of the protein C pathway, although its association with thrombosis risk remains unclear. The present study is a highly comprehensive systematic review and meta-analysis, including unpublished genome-wide association study results, conducted to evaluate the evidence for an association between rs867186 and 2 common thrombotic outcomes, venous thromboembolism (VTE) and myocardial infarction (MI), which are hypothesized to share some etiologic pathways. MEDLINE, EMBASE, and HuGE Navigator were searched through July 2011 to identify relevant epidemiologic studies, and data were summarized using random-effects meta-analysis. Twelve candidate genes and 13 genome-wide association studies were analyzed (11 VTE and 14 MI, including 37,415 cases and 84,406 noncases). Under the additive genetic model, the odds of VTE increased by a factor of 1.22 (95% confidence interval, 1.11-1.33, P < .001) for every additional copy of the G allele. No evidence for association with MI was observed.
Topics: Amino Acid Substitution; Antigens, CD; Databases, Factual; Endothelial Protein C Receptor; Genome-Wide Association Study; Humans; Myocardial Infarction; Polymorphism, Single Nucleotide; Receptors, Cell Surface; Risk Assessment; Thrombosis; Venous Thromboembolism
PubMed: 22251481
DOI: 10.1182/blood-2011-10-383448 -
Human Reproduction (Oxford, England) Apr 2021Is there an association between hereditary thrombophilia in pregnant women and risk of recurrent pregnancy loss (RPL)? (Meta-Analysis)
Meta-Analysis
STUDY QUESTION
Is there an association between hereditary thrombophilia in pregnant women and risk of recurrent pregnancy loss (RPL)?
SUMMARY ANSWER
Pregnant women with hereditary thrombophilia have an increased risk of RPL, especially for pregnant women with the G1691A mutation of the factor V Leiden (FVL) gene, the G20210A mutation of the prothrombin gene (PGM), and deficiency of protein S (PS).
WHAT IS KNOWN ALREADY
Prior studies have suggested that pregnant women with hereditary thrombophilia have a higher risk of RPL, however, the results are inconsistent; furthermore, a complete overview is missing. This lack of information is an obstacle to the risk assessment of RPL in pregnant women with hereditary thrombophilia. A comprehensive meta-analysis on the relation between hereditary thrombophilia and the risk of RPL is needed.
STUDY DESIGN, SIZE, DURATION
A systematic review and meta-analysis was performed using observational studies published in English before 1 April 2020 to evaluate the relation between hereditary thrombophilia and risk of RPL.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Relevant studies were identified from PubMed, Web of Science, and EMBASE searches and complemented with perusal of bibliographies of retrieved articles. The exposure of interest was hereditary thrombophilia, including FVL mutation, PGM, deficiency of antithrombin (AT), deficiency of protein C (PC), and deficiency of PS. The overall risk estimates were pooled using random effects models. Subgroup and sensitivity analyses were carried out to explore possible sources of heterogeneity and assess the robustness of the results.
MAIN RESULTS AND THE ROLE OF CHANCE
A total of 89 studies involving 30 254 individuals were included. Results showed that women with FVL mutation (odds ratio (OR): 2.44, 95% CI: 1.96-3.03), PGM (OR: 2.08, 95% CI: 1.61-2.68), or deficiency of PS (OR: 3.45, 95% CI: 1.15-10.35) had higher risks of developing RPL. Compared with the reference group, there was no observed relation between a deficiency in AT or PC and RPL (all P > 0.05). Heterogeneity in the risk estimates of RPL was partially explained by geographic region, definitions of RPL, types of RPL, and controlled confounders. Sensitivity analyses validated the robustness of the findings.
LIMITATIONS, REASONS FOR CAUTION
Only 39 of the included studies controlled for one or more confounders, and the heterogeneity across all included studies was high. Based on the data available, we cannot determine whether this association is confounded by other potential risk factors of RPL.
WIDER IMPLICATIONS OF THE FINDINGS
This systematic review and meta-analysis show a possible association between hereditary thrombophilia and an increased risk of RPL, suggesting that testing for hereditary thrombophilia should be considered in individuals with RPL.
STUDY FUNDING/COMPETING INTEREST(S)
The study was funded by the Hunan Provincial Key Research and Development Program (Grant number: 2018SK2062) and National Natural Science Foundation Program (Grant number: 81973137). There are no conflicts of interest.
REGISTRATION NUMBER
N/A.
Topics: Abortion, Habitual; Female; Humans; Mutation; Odds Ratio; Pregnancy; Risk Factors; Thrombophilia
PubMed: 33575779
DOI: 10.1093/humrep/deab010 -
Proteomics. Clinical Applications Sep 2017Computed tomography (CT) scan is the mainstay for diagnosis of stroke; but the facility of CT scan is not easily available. A blood-based biomarker approach is required... (Review)
Review
Computed tomography (CT) scan is the mainstay for diagnosis of stroke; but the facility of CT scan is not easily available. A blood-based biomarker approach is required to distinguish ischemic stroke (IS) from hemorrhagic stroke (HS) in pre-hospital settings.To conduct a systematic review of diagnostic utility of blood biomarkers for differential diagnosis of stroke.A comprehensive literature search was carried out till March 7, 2017 in PubMed, Cochrane, Medline, OVID, and Google Scholar databases. Methodological quality of each study was assessed using the modified Quality Assessment of Diagnostic Accuracy Studies questionnaire.Eighteen studies were identified relevant to our systematic review. Ten single biomarkers and seven panels of different biomarkers were identified which showed potential for differentiating IS and HS. Activated Protein C- Protein C Inhibitor Complex (APC-PCI) (sensitivity-96%), Glial Fibrillary Acidic Protein (GFAP) (specificity-100%) and a panel of APC-PCI & GFAP (sensitivity- 71%) and Retinol Binding Protein 4 (RBP4) & GFAP (specificity- 100%) were found to have high sensitivity and specificity for differentiating the two stroke types.Our systematic review does not recommend the use of any blood biomarker for clinical purposes yet based on the studies conducted till date.
Topics: Biomarkers; Blood Proteins; Diagnosis, Differential; Humans; Stroke
PubMed: 28452132
DOI: 10.1002/prca.201700007 -
Respiratory Care Jul 2010Activated protein C reduces 28-day mortality in patients with severe sepsis, but its anticoagulant properties entail a risk of bleeding. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Activated protein C reduces 28-day mortality in patients with severe sepsis, but its anticoagulant properties entail a risk of bleeding.
OBJECTIVE
The aim of this systematic review was to evaluate the prevalence of serious bleeding events in patients receiving activated protein C.
METHODS
We searched the MEDLINE and EMBASE databases for studies that described the prevalence of serious bleeding events and intracranial hemorrhage in patients receiving activated protein C. We calculated the bleeding rates by calculating proportions and 95% CIs for each study, and then pooled the data to derive a pooled proportion and 95% CI.
RESULTS
Our search yielded 17 studies, which included 10,679 patients. The occurrence of serious bleeding events in patients receiving activated protein C ranged from 0.5% to 9.6%, and the pooled prevalence was 3.3% (95% CI 2.4-4.4%) by the random effects model. The occurrence of intracranial hemorrhage ranged from 0% to 1.4%, and the pooled prevalence was 0.44% (95% CI 0.31-0.6%). Sensitivity analysis showed a higher prevalence of bleeding in the observational studies than in the randomized controlled trials. There was substantial clinical and statistical heterogeneity, but no evidence of publication bias.
CONCLUSIONS
Activated protein C is associated with significant risk of bleeding, so strict inclusion and exclusion criteria should be set prior to administering activated protein C.
Topics: Chi-Square Distribution; Confidence Intervals; Hemorrhage; Humans; Intracranial Hemorrhages; Prevalence; Protein C; Research Design; Risk Factors
PubMed: 20587103
DOI: No ID Found