Indications and management of mechanical fluid removal in critical illness.

BACKGROUND: The Acute Dialysis Quality Initiative (ADQI) dedicated its Twelfth Consensus Conference (2013) to all aspects of fluid therapy, including the management of fluid overload (FO). The aim of the working subgroup 'Mechanical fluid removal' was to review the indications, prescription, and management of mechanical fluid removal within the broad context of fluid management of critically ill patients. METHODS: The working group developed a list of preliminary questions and objectives and performed a modified Delphi analysis of the existing literature. Relevant studies were identified through a literature search using the MEDLINE database and bibliographies of relevant research and review articles. RESULTS: After review of the existing literature, the group agreed the following consensus statements: (i) in critically ill patients with FO and with failure of or inadequate response to pharmacological therapy, mechanical fluid removal should be considered as a therapy to optimize fluid balance. (ii) When using mechanical fluid removal or management, targets for rate of fluid removal and net fluid removal should be based upon the overall fluid balance of the patient and also physiological variables, individualized, and reassessed frequently. (iii) More research on the role and practice of mechanical fluid removal in critically ill patients not meeting fluid balance goals (including in children) is necessary. CONCLUSION: Mechanical fluid removal should be considered as a therapy for FO, but more research is necessary to determine its exact role and clinical application.

Outcomes for hepatorenal syndrome and acute kidney injury in patients undergoing liver transplantation: a single-center experience.

Acute kidney injury occurs commonly among patients with advanced liver disease. These patients may undergo liver transplantation with subsequent improvement in hepatic function. However, the renal outcomes of these patients after liver transplantation has only occasionally been reported. Knowledge of these outcomes would be useful to identify patients who may benefit from combined liver-renal transplantation. We retrospectively analyzed 29 patients who subsequently went on to have a liver transplantation. Seventeen of cases could be ascribed to hepatorenal syndrome (HRS) and 12 cases to ATN. Four patients with non-HRS and 12 patients with HRS required hemodialysis prior to transplantation. The duration of kidney injury prior to transplantation was 7.75 +/- 7.53 weeks in the HRS group and 5.09 +/- 4.47 weeks in the ATN group (P = NS). Demographic variables between patients with HRS and ATN were similar with the exception of a higher prevalence of diabetes among the ATN group (P < .05). At 3 months post-liver transplantation, 66% of patients with non-HRS and 77% of those surviving patients with HRS showed serum creatinine values less than 1.5 mg/dL. No patients remained on chronic hemodialysis at 3 months post-liver transplantation. The outcome of kidney dysfunction and more specifically, HRS, among those patients surviving to liver transplantation was excellent with subsequent resolution in the majority of patients. Determination of prognostic factors for renal outcome will require multicenter prospective trials, which would be useful to determine which patients benefit from combined liver-renal transplantation.

Measuring risk in end-stage renal disease: is N-terminal pro brain natriuretic peptide a useful marker?

Natriuretic peptides are important in the maintenance of body volume homeostasis. There has been interest in utilizing the levels of these peptides to diagnose and prognosticate cardiovascular disease. In end-stage renal disease, the diagnostic utility of these peptides is limited. Madsen et al. report that levels of N-terminal pro brain natriuretic peptide (NT-proBNP) levels offer important information on the risk of mortality in patients undergoing hemodialysis.

Risk factors for symptomatic hyponatraemia: the role of pre-existing asymptomatic hyponatraemia.

BACKGROUND: Hyponatraemia is associated with substantial morbidity and mortality. Identification of the risk factors associated with the development of symptomatic hyponatraemia is important in determining preventive strategies. METHODS: A retrospective analysis of the risks factors associated with the development of severe, symptomatic hyponatraemia requiring hospital admission over the past 3 years at our institution was carried out. RESULTS: Forty-seven patients (26 women, 21 men) with a hospital admission serum sodium <134 mmol/L were identified. Of these patients, 31 (65.9%) had associated changes in the mental status that improved with the treatment of the hyponatraemia suggesting causality. The average admission sodium level of this cohort was 118.8 mmol/L. Symptomatic hyponatraemia was associated with volume depletion (32.6%), congestive heart failure (26%), syndrome of inappropriate antidiuretic hormone (26%), thiazide diuretic use (26%) and selective serotonin re-uptake inhibitor use (26%). In 21.7% of cases, the cause was multifactorial (congestive heart failure, syndrome of inappropriate antidiuretic hormone or medication use with volume depletion). In 11% of cases, patients were taking both thiazide diuretics and serotonin re-uptake inhibitors. Most importantly, 70.9% of all patients admitted with symptomatic hyponatraemia had pre-existing hyponatraemia that was untreated and believed to be asymptomatic (P < 0.05). This was the most common risk factor identified. We next investigated the prevalence of presumed asymptomatic hyponatraemia in the outpatient setting. Out of 27 496 patients analysed, 14% had serum sodium levels less than or equal to 134 mEq/L and 4% had values less than 130 mEq/L. CONCLUSION: Pre-existing asymptomatic hyponatraemia is a common finding and is associated with a high risk for the development of worsening hyponatraemia with altered mental status.

Leucine-regulated self-association of leucine-responsive regulatory protein (Lrp) from Escherichia coli.

Lrp is a global regulatory protein in Escherichia coli that activates expression of more than a dozen operons and represses expression of another dozen. For some operons, exogenous leucine reduces the extent of Lrp action, for others it potentiates the effect of Lrp, and for yet other operons it has no effect. In an effort to understand how leucine affects Lrp-mediated expression, we examined Lrp self-association and the effect of leucine on self-association using light scattering, chemical cross-linking, and analytical ultracentrifugation. The following results were obtained. (i) Lrp self-associates to a hexadecamer and octamer with the predominant species being hexadecamer at microM concentrations. (ii) Lrp undergoes a leucine-induced dissociation of hexadecamer to octamer. (iii) A mutant Lrp lacking 11 amino acid residues at the C terminus does not form higher-order oligomers, suggesting that the C terminus is involved in subunit association. (iv) At nM concentrations, Lrp dissociates to a dimer. It is proposed that leucine regulates the equilibrium between Lrp oligomers and thus Lrp occupancy of sites within different operons, leading to diverse regulatory patterns.

Pseudohypertension in a patient with diffuse scleroderma.

Pseudohypertension is the artifactual elevation of blood pressure that occurs secondary to noncompressible blood vessels. It has been described in patients with uremia, diabetes mellitus, and severe atherosclerosis. If unrecognized, the condition may lead to inappropriate and potentially harmful therapy. We report a case of pseudohypertension in a 65-year-old man with diffuse scleroderma. His blood pressure as assessed by conventional sphygmomanometry was at least 240/135 to 145 mm Hg. Intra-arterial blood pressure was found to be 107/52 mm Hg. The severe rise in blood pressure as measured by sphygmomanometry led to the concern of scleroderma renal crisis and potentially harmful therapy. Intra-arterial pressure monitoring confirmed the presence of pseudohypertension, however. This is the first reported case of pseudohypertension in a patient with diffuse scleroderma.

Renovascular hypertension: can we identify a population at high risk?

Renovascular hypertension is a common cause of secondary hypertension. However, diagnostic tests are limited by lack of sensitivity and specificity, cost, or invasiveness. Selecting patients with hypertension for evaluation of renal artery stenosis can be challenging. This review focuses on the sensitivity and specificity of commonly used screening tests for renal artery stenosis and on the clinical variables that are most likely to distinguish patients with renal artery stenosis from patients with other causes of their hypertension. This approach allows for the rational screening of patients at high and moderate risk for renal artery disease.

Inhibiting protein-protein interactions: a model for antagonist design.

Protein-protein interactions (PPI) are a ubiquitous mode of transmitting signals in cells and tissues. We are testing a stepwise, generic, structure-driven approach for finding low molecular weight inhibitors of protein-protein interactions. The approach requires development of a high-affinity, single chain antibody directed specifically against the interaction surface of one of the proteins to obtain structural information on the interface. To this end, we developed a single chain antibody (sc1E3) against hIL-1beta that exhibited the equivalent affinity of the soluble IL-1 receptor type I (sIL-1R) for hIL-1beta and competitively blocked the sIL-1R from binding to the cytokine. The antibody proved to be more specific for hIL-1beta than the sIL-1R in that it failed to bind to either murine IL-1beta or human/murine IL-1alpha proteins. Additionally, failure of sc1E3 to bind to several hIL-1beta mutant proteins, altered at receptor site B, indicated that the antibody interacted preferentially with this site. This, coupled with other surface plasmon resonance and isothermal titration calorimetry measurements, shows that sc1E3 can achieve comparable affinity of binding hIL-1beta as the receptor through interactions at a smaller interface. This stable single chain antibody based heterodimer has simplified the complexity of the IL-1/IL-1R PPI system and will facilitate the design of the low molecular weight inhibitors of this interaction.

Identification, characterization, and crystal structure of the Omega class glutathione transferases.

A new class of glutathione transferases has been discovered by analysis of the expressed sequence tag data base and sequence alignment. Glutathione S-transferases (GSTs) of the new class, named Omega, exist in several mammalian species and Caenorhabditis elegans. In humans, GSTO 1-1 is expressed in most tissues and exhibits glutathione-dependent thiol transferase and dehydroascorbate reductase activities characteristic of the glutaredoxins. The structure of GSTO 1-1 has been determined at 2.0-A resolution and has a characteristic GST fold (Protein Data Bank entry code ). The Omega class GSTs exhibit an unusual N-terminal extension that abuts the C terminus to form a novel structural unit. Unlike other mammalian GSTs, GSTO 1-1 appears to have an active site cysteine that can form a disulfide bond with glutathione.

Electrocardiography in the patient with the Wolff-Parkinson-White syndrome: diagnostic and initial therapeutic issues.

The Wolff-Parkinson-White syndrome (WPW), estimated to occur in approximately 0.1% to 3% of the general population, is a form of ventricular preexcitation involving an accessory conduction pathway. The definition of WPW relies on the following electrocardiographic features: (1) a PR interval less than 0.12 seconds (2) with a slurring of the initial segment of the QRS complex, known as a delta wave, (3) a QRS complex widening with a total duration greater than 0.12 seconds, and (4) secondary repolarization changes reflected in ST segment-T wave changes that are generally directed opposite (discordant) to the major delta wave and QRS complex changes. The accessory pathway bypasses the atrioventricular (AV) node, creating a direct electrical connection between the atria and ventricles. The majority of patients with preexcitation syndromes remain asymptomatic throughout their lives. When symptoms do occur they are usually secondary to tachyarrhythmias; the importance of recognizing this syndrome is that these patients may be at risk to develop a variety of supraventricular tachyarrhythmias which cause disabling symptoms and, in the extreme, sudden cardiac death. The tachyarrhythmias encountered in the WPW patient include paroxysmal supraventricular tachycardia (both the narrow QRS and wide QRS complex varieties), atrial fibrillation, atrial flutter, and ventricular fibrillation. Diagnostic and urgent, initial therapeutic issues based on initial electrocardiographic information are presented via 5 illustrative cases.

The electrocardiographic diagnosis of acute myocardial infarction in patients with ventricular paced rhythms.

The electrocardiographic diagnosis of ischemic heart disease is more difficult in the setting of ventricular-paced rhythms (VPR). ST segment/T wave configurations are changed by the altered intraventricular conduction associated with ventricular pacing. The anticipated, or expected, morphology in patients with VPR is one of QRS complex-ST segment/T wave discordance. An awareness of the anticipated ST segment morphologies of VPR is mandatory for the emergency physician. This knowledge is not dependent on additional diagnostic testing, medical records, or expertise in pacemaker function. Two cases are presented in which an analysis of the electrocardiogram in the setting of VPR assisted the treating physicians in establishing the correct diagnosis of acute myocardial infarction and arranging for urgent revascularization.

The ECG diagnosis of acute myocardial infarction in the presence of left bundle branch block.

The electrocardiographic diagnosis of ischemic heart disease is made more difficult in the setting of confounding patterns, including left bundle branch block (LBBB). The electrocardiographic detection of abnormalities arising from acute ischemic cardiac disease in this setting is possible in certain cases, contrary to popular medical opinion. Several strategies are available to assist in the correct interpretation of the electrocardiogram (ECG) with LBBB and potential acute ischemia, including: (1) a knowledge of the anticipated ST segment-T wave morphologies of LBBB and, consequently, the ability to recognize ischemic changes; (2) the performance of serial ECGs demonstrating dynamic change; and (3) a comparison to previous ECGs. The first strategy, an awareness of the anticipated ST segment morphologies of LBBB, is the most important and not dependent on additional diagnostic testing or past medical records.

Oct-3 and mammalian development: correction of discussion.

The title of the 5 June report on page 1445 by R. C. deL. Milton et al. should have been "Total chemical synthesis of a D-enzyme: The enantiomers of HIV-1 protease show reciprocal chiral substrate specificity." Figure 3 in the same report (p. 1447) was inadvertently printed upside down. The labels "L-HIV protease" and "D-HIV protease" were therefore under the wrong illustrations. The correct figure is printed below. [See figure in the PDF file]

Immunochemical techniques in biological monitoring.

Immunoassays are analytical methods that detect interactions between antibodies and antigens. Immunoassays were used originally to detect large biological molecules. The new generation of these antibody-based assays can detect small synthetic compounds. As a result, immunoassays are being developed specifically for biomarkers of exposure and effect to environmentally prevalent chemicals. Immunochemical detection of parent compounds in blood and tissues, metabolites in excreta, and adducts with DNA and protein have been successfully performed by several investigators. Although there is great potential for use of immunoassays in biological monitoring studies, the limitations of these analyses must be fully understood to prevent improper evaluation of the acquired data. This review will cover some of the background material necessary to understand how an antibody-based assay is developed. The differences between polyclonal and monoclonal antibody-based assays and the importance of antibody class, affinity, specificity, and cross-reactivity must be considered in both study design and data analysis.

Chromosomal location of the octamer transcription factors, Otf-1, Otf-2, and Otf-3, defines multiple Otf-3-related sequences dispersed in the mouse genome.

Chromosomal locations have been assigned for the octamer transcription factor, Otf, gene family (previously named the octamer-binding protein, Oct, gene family) using an interspecific backcross of [(C57BL/6J x Mus spretus)F1 x C57BL/6J] mice and the BXH recombinant inbred strains. Molecular probes for Otf-1 and Otf-2 recognized single loci on mouse chromosomes 1 and 7, respectively, whereas probes for Otf-3 recognized a minimum of eight independently segregating loci (designated Otf-3a through Otf-3h). Members of the Otf-3 family mapped to mouse chromosomes 1, 2, 3, 6, 14, 17, and the X chromosome, indicating that the Otf family has become widely dispersed during evolution. Several Otf loci mapped near developmental mutations, raising the possibility that these mutations result from defects in Otf family members.

Oct-3 is a maternal factor required for the first mouse embryonic division.

Oct-3 is a POU domain transcription factor that binds the octamer DNA motif and is present in mouse oocytes before and after fertilization. When fertilized oocytes were injected with antisense Oct-3 oligonucleotides or double-stranded DNA containing the octamer motif, embryonic DNA synthesis was inhibited and the embryos were arrested at the one-cell stage. In vitro synthesized Oct-3 mRNA rescued the developmental block induced by antisense Oct-3 oligonucleotide. We conclude that maternally inherited Oct-3 is required for DNA replication and division of the one-cell embryo.

A POU-domain transcription factor in early stem cells and germ cells of the mammalian embryo.

The murine oct-3 gene encodes a transcription factor containing a POU-specific domain and a homeodomain. In marked contrast to other homeodomain-encoding genes, oct-3 is expressed in the totipotent and pluripotent stem cells of the pregastrulation embryo and is down-regulated during differentiation to endoderm and mesoderm, suggesting that it has a role in early development. The oct-3 gene is also expressed in primordial germ cells and in the female germ line.

Metabolism and excretion of gallium arsenide and arsenic oxides by hamsters following intratracheal instillation.

The increasing use of gallium arsenide (GaAs) in the electronics industry has produced the need for pharmacokinetic and toxicologic data on GaAs. The disposition in male Syrian golden hamsters (n = 4) following intratracheal instillation of GaAs (mean volume diameter 5.8 micron), arsenic (III) oxide (arsenite), and arsenic (V) oxide (arsenate) at a dose of 5 mg/kg body weight was examined. Blood, kidney, liver, and lung samples were collected at 1, 2, and 4 days after administration. Excreta were collected daily. Urinary metabolite profiles were determined after separation on a mixed anion-cation-exchange column. Total As content was analyzed by direct hydride flame atomic absorption spectrophotometry after digestion. Arsenic blood levels after GaAs, arsenite, and arsenate administration were 0.185 +/- 0.041, 0.596 +/- 0.117, and 0.310 +/- 0.045 ppm, respectively, after Day 1. Arsenic blood levels after GaAs administration increased to 0.279 +/- 0.021 ppm on Day 2 indicating continued absorption while levels decreased for the arsenite and arsenate groups. At Day 1 the liver contained 0.565 +/- 0.036, 2.62 +/- 0.26, and 0.579 +/- 0.144% of the arsenic dose of GaAs, arsenite, and arsenate, respectively. The arsenite and arsenate were rapidly excreted in the urine with almost half the dose appearing after 4 days; in contrast, only about 5% of the GaAs was found at the corresponding time. Total recoveries, as arsenic equivalents, for the three compounds were between 75 and 80%. Ratios of the two major urinary metabolites (dimethylarsinic acid/total inorganic As species) were 1.41, 1.71, and 0.983 for GaAs, arsenite, and arsenate, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)