Brett L. Houston

Association of Hydroxyethyl Starch Administration With Mortality and Acute Kidney Injury in Critically Ill Patients Requiring Volume Resuscitation: A Systematic Review and Meta-analysis

IMPORTANCE Hydroxyethyl starch is commonly used for volume resuscitation yet has been associated with serious adverse events, including acute kidney injury and death. Clinical trials of hydroxyethyl starch are conflicting. Moreover, multiple trials from one investigator have been retracted because of scientific misconduct. OBJECTIVES To evaluate the association of hydroxyethyl starch use with mortality and acute kidney injury. DATA SOURCES Randomized controlled trials from MEDLINE, EMBASE, CENTRAL, Global Health, HealthStar, Scopus, Web of Science, the International Clinical Trials Registry Platform (inception to October 2012), reference lists of relevant articles, and gray literature. STUDY SELECTION Two reviewers independently identified randomized controlled trials comparing hydroxyethyl starch with other resuscitation fluids in critically ill patients receiving acute volume resuscitation. DATA EXTRACTION Two reviewers independently extracted trial-level data including population characteristics, interventions, outcomes, and funding sources. Risk of bias was assessed using the risk of bias tool; the strength of evidence was adjudicated using the GRADE methodology. RESULTS We included 38 eligible trials comparing hydroxyethyl starch to crystalloids, albumin, or gelatin. The majority of trials were categorized as having an unclear risk or high risk of bias. For the 10,880 patients in studies contributing mortality data, the risk ratio (RR) for death among patients randomized to receive hydroxyethyl starch was 1.07 (95% CI, 1.00 to 1.14; I2, 0%; absolute risk [AR], 1.20%; 95% CI, -0.26% to 2.66%). This summary effect measure included results from 7 trials performed by an investigator whose subsequent research had been retracted because of scientific misconduct. When we excluded these 7 trials that involved 590 patients, hydroxyethyl starch was found to be associated with increased mortality among 10,290 patients (RR, 1.09; 95% CI, 1.02 to 1.17; I2, 0%; AR, 1.51%; 95% CI, 0.02% to 3.00%), increased renal failure among 8725 patients (RR, 1.27; 95% CI, 1.09 to 1.47; I2, 26%; AR, 5.45%; 95% CI, 0.44% to 10.47%), and increased use of renal replacement therapy among 9258 patients (RR, 1.32; 95% CI, 1.15 to 1.50; I2, 0%; AR, 3.12%; 95% CI, 0.47% to 5.78%). CONCLUSION AND RELEVANCE In critically ill patients requiring acute volume resuscitation, use of hydroxyethyl starch compared with other resuscitation solutions was not associated with a decrease in mortality. Moreover, after exclusion of 7 trials performed by an investigator whose research has been retracted because of scientific misconduct, hydroxyethyl starch was associated with a significant increased risk of mortality and acute kidney injury. Clinical use of hydroxyethyl starch for acute volume resuscitation is not warranted due to serious safety concerns.

Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis

Hereditary xerocytosis (HX, MIM 194380) is an autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. Copy number analyses, linkage studies, and exome sequencing were used to identify novel mutations affecting PIEZO1, encoded by the FAM38A gene, in 2 multigenerational HX kindreds. Segregation analyses confirmed transmission of the PIEZO1 mutations and cosegregation with the disease phenotype in all affected persons in both kindreds. All patients were heterozygous for FAM38A mutations, except for 3 patients predicted to be homozygous by clinical and physiologic studies who were also homozygous at the DNA level. The FAM38A mutations were both in residues highly conserved across species and within members of the Piezo family of proteins. PIEZO proteins are the recently identified pore-forming subunits of channels that mediate mechanotransduction in mammalian cells. FAM38A transcripts were identified in human erythroid cell mRNA, and discovery proteomics identified PIEZO1 peptides in human erythrocyte membranes. These findings, the first report of mutation in a mammalian mechanosensory transduction channel-associated with genetic disease, suggest that PIEZO proteins play an important role in maintaining erythrocyte volume homeostasis.

The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis.

Objective:To evaluate the efficacy and safety of heparin in patients with sepsis, septic shock, or disseminated intravascular coagulation associated with infection. Design:Systematic review and metaanalysis. Data Sources:Randomized controlled trials from MEDLINE, EMBASE, CENTRAL, Global Health, Scopus, Web of Science, the International Clinical Trials Registry Platform (inception to April 2014), conference proceedings, and reference lists of relevant articles. Study Selection and Data Extraction:Two reviewers independently identified and extracted trial-level data from randomized trials investigating unfractionated or low molecular heparin administered to patients with sepsis, severe sepsis, septic shock, or disseminated intravascular coagulation associated with infection. Internal validity was assessed in duplicate using the Risk of Bias tool. The strength of evidence was assessed in duplicate using Grading of Recommendations Assessment, Development, and Evaluation methodology. Our primary outcome was mortality. Safety outcomes included hemorrhage, transfusion, and thrombocytopenia. Measurements and Main Results:We included nine trials enrolling 2,637 patients. Eight trials were of unclear risk of bias and one was classified as having low risk of bias. In trials comparing heparin to placebo or usual care, the risk ratio for death associated with heparin was 0.88 (95% CI, 0.77–1.00; I2 = 0%; 2,477 patients; six trials; moderate strength of evidence). In trials comparing heparin to other anticoagulants, the risk ratio for death was 1.30 (95% CI, 0.78–2.18; I2 = 0%; 160 patients; three trials; low strength of evidence). In trials comparing heparin to placebo or usual care, major hemorrhage was not statistically significantly increased (risk ratio, 0.79; 95% CI, 0.53–1.17; I2 = 0%; 2,392 patients; three trials). In one small trial of heparin compared with other anticoagulants, the risk of major hemorrhage was significantly increased (2.14; 95% CI, 1.07–4.30; 48 patients). Important secondary and safety outcomes, including minor bleeding, were sparsely reported. Conclusions:Heparin in patients with sepsis, septic shock, and disseminated intravascular coagulation associated with infection may be associated with decreased mortality; however, the overall impact remains uncertain. Safety outcomes have been underreported and require further study. Increased major bleeding with heparin administration cannot be excluded. Large rigorous randomized trials are needed to evaluate more carefully the efficacy and safety of heparin in patients with sepsis, severe sepsis, and septic shock.

Refinement of the hereditary xerocytosis locus on chromosome 16q in a large Canadian kindred

The hereditary stomatocytoses are a group of heterogeneous conditions associated with chronic red cell hemolysis for which the causative genetic mutations are not known. We investigated 137 members of a large Canadian kindred with phenotypic findings consistent with hereditary xerocytosis, one of the most common stomatocytosis syndromes. The objectives of this study were to characterize the clinical hallmarks of the hemolytic process, and to define the chromosomal region carrying the disease locus. The mode of inheritance was autosomal dominant. Affected family members had a well-compensated hemolysis, associated with an elevated MCHC, decreased osmotic fragility, decreased haptoglobin, and indirect hyperbilirubinemia. Cholelithiasis and progressive iron loading were common, despite normal hemoglobin levels. Quantitative erythrocyte morphologic evaluation revealed increased schistocytes, target cells, reticulocytes, and eccentrocytes in affected individuals; stomatocytes were not increased. Genetic linkage analysis confirmed the localization of the disease phenotype to chromosome 16q, and refined the candidate region to 16q24.2-16qter, a 2.4 million base pair interval containing 51 known or predicted genes.

Severe Rh alloimmunization and hemolytic disease of the fetus managed with plasmapheresis, intravenous immunoglobulin and intrauterine transfusion: A case report.

Rh alloimmunization remains a potentially devastating complication of pregnancy, with fetal anemia causing hydrops and intrauterine death. Intrauterine transfusion is the standard treatment, but is particularly dangerous before 20 weeks gestation. When the need for intrauterine transfusion is anticipated early in pregnancy, immune-modulating therapies such as plasmapheresis and IVIG have been used to delay transfusion to a later gestational age. We report a 35-year-old G5P1 Rh(D)-negative woman with severe Rh alloimmunization managed successfully with sequential plasmapheresis, intravenous immune globulin and intrauterine transfusion. The optimal plasmapheresis treatment protocol and incremental benefit of IVIG remains unknown.

Extracorporeal photopheresis in solid organ transplant–associated acute graft-versus-host disease

Extracorporeal photopheresis (ECP) culls pathogenic T lymphocytes, be these the clones of cutaneous T‐cell lymphoma, or mediators of chronic graft‐versus‐host disease (GVHD) after allogeneic bone marrow transplantation (BMT‐GVHD). Whether or not ECP may have an effect in the rarer instances of solid organ transplantation–associated GVHD (SOT‐GVHD) is unclear. Mortality rates in SOT‐GVHD rival those of transfusion‐associated GVHD, with fatalities preceded by pancytopenia and peripheral blood chimerism (PBC) levels exceeding 20%. ECP has been described in two SOT‐GVHD cases to date, with one surviving.

Coronary artery bypass surgery in a patient with Haemophilia A: a case report

laboratory because of improved precision, specificity and speed of assay [3]. However, it is important that laboratories recognize the limitations of their assay of choice including the interference from a number of substance including icterus, lipaemia and certain antibodies. The Siemens and Werfen VWF:Ag both use polyclonal rabbit anti-human VWF antibodies. The BC VWF:RCo, Werfen VWF:RCo and manual assay do not contain any antibodies whereas mouse monoclonal antibodies are present in the Innovance VWF Ac and Werfen VWF Act reagents. The chemiluminescent VWF:RCo does contains mouse monoclonal antibodies but includes a blocking agent for HAMA up to 1 lg mL . The Werfen VWF Act assay also contains a blocking agent against HAMA, but it is likely that the level in our patient swamps this agent. Acquired Von Willebrand Syndrome with a bleeding diathesis is a rare disorder [8], however, AVWS in the absence of bleeding appears to be more prevalent, particularly in patients secondary to lymphoor myelo-proliferative or cardiovascular diseases [9]. At present it is unknown how many humans develop anti-animal antibodies that interfere with assays employed in coagulation laboratories. The results presented in this report clearly demonstrate that some automated VWF activity assays may misdiagnose patients with AVWS and VWD. When using these VWF activity assays, which do not include ristocetin and platelets, in the initial diagnosis of acquired haemophilia and VWS, it is imperative that a VWF antigen should be tested at the same time. Where a discrepancy between a low VWF:Ag and higher VWF activity is found then an alternative, ristocetin-based assay, should be performed to exclude an erroneously high result and monitor subsequent replacement therapy.

Efficacy of iron supplementation on fatigue and physical capacity in non-anaemic iron-deficient adults: a systematic review of randomised controlled trials

Objective Iron supplementation in iron-deficiency anaemia is standard practice, but the benefits of iron supplementation in iron-deficient non-anaemic (IDNA) individuals remains controversial. Our objective is to identify the effects of iron therapy on fatigue and physical capacity in IDNA adults. Design Systematic review and meta-analysis of randomised controlled trials (RCTs). Setting Primary care. Participants Adults (≥18 years) who were iron deficient but non-anaemic. Interventions Oral, intramuscular or intravenous iron supplementation; all therapy doses, frequencies and durations were included. Comparators Placebo or active therapy. Results We identified RCTs in Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health, SportDiscus and CAB Abstracts from inception to 31 October 2016. We searched the WHO’s International Clinical Trials Registry Platform for relevant ongoing trials and performed forward searches of included trials and relevant reviews in Web of Science. We assessed internal validity of included trials using the Cochrane Risk of Bias tool and the external validity using the Grading of Recommendations Assessment, Development and Evaluation methodology. From 11 580 citations, we included 18 unique trials and 2 companion papers enrolling 1170 patients. Using a Mantel-Haenszel random-effects model, iron supplementation was associated with reduced self-reported fatigue (standardised mean difference (SMD) −0.38; 95% CI −0.52 to −0.23; I2 0%; 4 trials; 714 participants) but was not associated with differences in objective measures of physical capacity, including maximal oxygen consumption (SMD 0.11; 95% CI −0.15 to 0.37; I2 0%; 9 trials; 235 participants) and timed methods of exercise testing. Iron supplementation significantly increased serum haemoglobin concentration (MD 4.01 g/L; 95% CI 1.22 to 6.81; I2 48%; 12 trials; 298 participants) and serum ferritin (MD 9.23 µmol/L; 95% CI 6.48 to 11.97; I2 58%; 14 trials; 616 participants). Conclusion In IDNA adults, iron supplementation is associated with reduced subjective measures of fatigue but not with objective improvements in physical capacity. Given the global prevalence of both iron deficiency and fatigue, patients and practitioners could consider consumption of iron-rich foods or iron supplementation to improve symptoms of fatigue in the absence of documented anaemia. PROSPERO registration number CRD42014007085.

Spontaneous migration of an implanted central venous access device into the ipsilateral jugular vein

A 46-year-old man with sickle cell disease was assessed in our outpatient clinic for right neck pain. To facilitate venous access for manual exchange transfusions and iron chelation therapy, a central venous access device had been inserted into his right internal jugular vein by an interventional

Levonorgestrel-releasing intrauterine device for symptomatic endometriosis following surgery: a Cochrane review

Objectives The aim of this study was to determine whether postoperative levonorgestrel-releasing intrauterine device (LNG-IUD) insertion in women with endometriosis improves pain and reduces symptoms compared with no treatment, placebo, or systemic therapy. Data source The following databases were searched from inception to June 2012: Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials, MEDLINE, PsycINFO, CINAHL, and the World Health Organization International Clinical Trials Registry Platform. EMBASE was searched from 2010 to June 2012. The citation lists of relevant publications, review articles, abstracts of scientific meetings, and included studies were also searched. Study selection Randomized trials comparing women who underwent LNG-IUD insertion with those who received no treatment, a placebo, or systemic therapy after surgical treatment for endometriosis within the preceding 3 months were included. Data extraction Two review authors independently selected studies for inclusion and extracted data to allow for an intention-to-treat analysis. For dichotomous data, the risk ratio (RR) and 95% confidence interval (CI) were calculated using the Mantel–Haenszel random-effects method. For continuous data, the mean difference (MD) and 95% CI were calculated using the inverse variance random-effects method. Results A total of three randomized-controlled trials were included. In two trials, there was a statistically significant reduction in the recurrence of painful menstruation in the LNG-IUD group compared with expectant management (RR 0.22, 95% CI 0.08–0.60, 95 women, I2 0%, moderate strength of evidence). The proportion of women who were satisfied with their treatment was also higher in the LNG-IUD group but did not reach statistical significance (RR 1.21, 95% CI 0.80–1.82, 95 women, I2 0%). The number of women reporting a change in their menstruation was significantly higher in the LNG-IUD group (RR 37.80, 95% CI 5.40–264.60, 95 women, I2 0%); however, the number of women who failed to complete the allocated treatment did not differ between the groups (RR 0.66, 95% CI 0.08–5.25, I2 43%). In one trial, women receiving LNG-IUD achieved slightly lower pain scores compared with women receiving gonadotropin-releasing hormone (GnRH) agonists (MD −0.16, 95% CI −2.02 to 1.70, 40 women), but this did not reach statistical significance. Conclusion There is limited but consistent evidence showing that postoperative LNG-IUD use reduces the recurrence of painful menstruation in women with endometriosis. Further well-designed randomized-controlled trials are needed to confirm these findings.