Bolus Treatment Research Articles

When enough is enough: how the decision was made to stop the FEAST trial: data and safety monitoring in an African trial of Fluid Expansion As Supportive Therapy (FEAST) for critically ill children

In resource-rich countries, bolus fluid expansion is routinely used for the treatment of poor perfusion and shock, but is less commonly used in many African settings. Controversial results from the recently completed FEAST (Fluid Expansion As Supportive Therapy) trial in African children have raised questions about the use of intravenous bolus fluid for the treatment of shock. Prior to the start of the trial, the Independent data monitoring committee (IDMC) developed stopping rules for the proof of benefit that bolus fluid resuscitation would bring. Although careful safety monitoring was put in place, there was less expectation that bolus fluid expansion would be harmful and differential stopping rules for harm were not formulated.In July 2010, two protocol amendments were agreed to increase the sample size from 2,880 to 3,600 children, and to increase bolus fluid administration. There was a non-significant trend against bolus treatment, but although the implications were discussed, the IDMC did not comment on the results, or on the amendments, in order to avoid inadvertent partial unblinding of the study.In January 2011, the trial was stopped for futility, as the combined intervention arms had significantly higher mortality (relative risk 1.46, 95% CI 1.13 to 1.90, P = 0.004) than the control arm. The stopping rule for proof of benefit was not achieved, and the IDMC stopped the trial with a lower level of significance (P = 0.01) due to futility and an increased risk of mortality from bolus fluid expansion in children enrolled in the trial. The basis for this decision was that the local standard of care was not to use bolus fluid for the care of children with shock in these African countries, and this was a different standard of care to that used in the UK. These decisions emphasize two important principles: firstly, the IDMC should avoid inadvertent unblinding of the trial by commenting on amendments, and secondly, when considering stopping a trial, the IDMC should be guided by the local standard of care rather than standards of care in other parts of the world.

Https://painphysicianjournal.com/current/pdf?article=MTgwMw%3D%3D&journal=71

Background: Current treatments for neuropathic pain are far from satisfactory. Considering the essential contribution of central immune factors to the pathogenesis of neuropathic pain, targeting inflammatory response is well accepted as an effective strategy for treating neuropathic pain. Triptolide has a long history in traditional Chinese medicine for treating inflammatory diseases and has been proven to inhibit cytokines released from glial cells. Objective: In the present study, we tested whether systemic treatment with triptolide could prevent or attenuate nocifensive behaviors associated with neuropathic pain. We further tried to explore the underlying mechanism of the potential anti-allodynia effect of triptolide. Study Design: A randomized, double blind, controlled animal trial. Methods: Triptolide was administered systemically in a rat model of neuropathic pain induced by spinal nerve ligation (SNL) in the single bolus and repeated treatment manners. In the single bolus treatment experiment, triptolide (30 μg/kg, 100 μg/kg, 300 μg/kg) or vehicle was given to SNL and sham-operated rats once on day 1 or on day 10 after surgery (n = 6 each). In the repeated treatment study, prophylactic treatment with triptolide (30 μg/kg, 100 μg/kg, 300 μg/kg) was given to rats during the period of day -3 (3 days prior to SNL) to day 7 (7 days post-SNL) inclusively (n = 6 each). Another set of SNL and sham rats on postoperative day 10 received treatment with triptolide (30 μg/kg, 100 μg/kg, 300 μg/kg) or vehicle during the period of days 11–20 inclusively (n = 6 each), to assess potential reversal of established pain behavior. Mechanical allodynia of the rats was tested with von Frey filaments. Astrocytic and microglial activation in the spinal dorsal horn was evaluated with immunofluorescent histochemistry. Phosphorylation of mitogen-activated protein kinases (MAPKs), and expression of inflammatory cytokines (interleukin-6, interleukin-1beta, monocyte chemotactic protein-1, and tumor necrosis factor-alpha) were examined with Western blot analysis and real-time reverse transcription polymerase chain reaction study. Results: A single bolus treatment with triptolide could neither prevent the induction nor reverse the maintenance of SNL-induced mechanical allodynia. However, repeated administration of triptolide dose-dependently inhibited neuropathic pain behavior in both preventative and interventional paradigms. Triptolide hampered SNL-induced activation of glial cells (astrocytes and microglia) in the spinal dorsal horn without influencing neurons. In addition, SNL-induced phosphorylation of MAPKs could be inhibited by triptolide. Furthermore, up-regulated expression of inflammatory cytokines in neuropathic pain states could be remarkably blocked by triptolide. Limitations: The direct target site (such as a specific receptor) of triptolide is still to be determined. In addition, triptolide could not completely block the SNL-induced mechanical allodynia. Conclusions: Our data suggest that triptolide may be a potential novel treatment for neuropathic pain through modulating immune response in the spinal dorsal horn. Key words: Triptolide, neuropathic pain, spinal dorsal horn, astrocyte, microglia, MAPK.

Pulse Corticosteroid Therapy for Alopecia Areata: Long-Term Outcome after 10 Years

Background: Few data are available concerning the efficiency of pulse corticosteroids in alopecia areata (AA). Objective: Our purpose was to assess the long-term outcomes of patients treated with methylprednisolone bolus. Methods: This study included 60 patients treated between 1995 and 2000. The short-term outcomes were analyzed in 2000. The long-term assessment of 30 patients was performed in 2010 by phone questionnaire. Results: Significant hair regrowth was observed in 10/30 patients at 6 months after the bolus treatment. Half of the plurifocalis AA patients were responders at 6 months, but less than one quarter of alopecia totalis (AT) and alopecia universalis (AU) patients responded. Long-term outcomes were assessed after a mean duration of 12.3 years; 8/10 initial responders had mild or no disease, and 14/20 initial nonresponders had severe AA. Conclusions: This study confirmed the low efficiency, both short- and long-term, of this treatment for AT and AU.

Sustained Submicromolar H2O2 Levels Induce Hepcidin via Signal Transducer and Activator of Transcription 3 (STAT3)

The peptide hormone hepcidin regulates mammalian iron homeostasis by blocking ferroportin-mediated iron export from macrophages and the duodenum. During inflammation, hepcidin is strongly induced by interleukin 6, eventually leading to the anemia of chronic disease. Here we show that hepatoma cells and primary hepatocytes strongly up-regulate hepcidin when exposed to low concentrations of H(2)O(2) (0.3-6 μM), concentrations that are comparable with levels of H(2)O(2) released by inflammatory cells. In contrast, bolus treatment of H(2)O(2) has no effect at low concentrations and even suppresses hepcidin at concentrations of >50 μM. H(2)O(2) treatment synergistically stimulates hepcidin promoter activity in combination with recombinant interleukin-6 or bone morphogenetic protein-6 and in a manner that requires a functional STAT3-responsive element. The H(2)O(2)-mediated hepcidin induction requires STAT3 phosphorylation and is effectively blocked by siRNA-mediated STAT3 silencing, overexpression of SOCS3 (suppressor of cytokine signaling 3), and antioxidants such as N-acetylcysteine. Glycoprotein 130 (gp130) is required for H(2)O(2) responsiveness, and Janus kinase 1 (JAK1) is required for adequate basal signaling, whereas Janus kinase 2 (JAK2) is dispensable upstream of STAT3. Importantly, hepcidin levels are also increased by intracellular H(2)O(2) released from the respiratory chain in the presence of rotenone or antimycin A. Our results suggest a novel mechanism of hepcidin regulation by nanomolar levels of sustained H(2)O(2). Thus, similar to cytokines, H(2)O(2) provides an important regulatory link between inflammation and iron metabolism.

Life or Death Decisions in the Corpus Luteum

The corpus luteum (CL) is an ephemeral endocrine organ. During its lifespan, it undergoes a period of extremely rapid growth that involves hypertrophy, proliferation and differentiation of the steroidogenic cells, as well as extensive angiogenesis. The growth phase is followed by a period in which remodelling of the tissue ceases, but it engages in unparalleled production of steroids, resulting in extraordinarily high metabolic activity within the tissue. It is during this stage that a critical juncture occurs. In the non-fertile cycle, uterine release of prostaglandin (PG)F(2α) initiates a cascade of events that result in rapid loss of steroidogenesis and destruction of the luteal tissue. Alternatively, if a viable embryo is present, signals are produced that result in rescue of the CL. This review article summarizes the major concepts related to the fate of the CL, with particular focus on recent insights into the mechanisms associated with the ability of PGF(2α) to bring about complete luteolysis. It has become clear that the achievement of luteolysis depends on repeated exposure to PGF(2α) and involves coordinated actions of heterogeneous cell types within the CL. Together, these components of the process bring about not only the loss in progesterone production, but also the rapid demise of the structure itself.

Omeprazol produces changes in blood calcium, phosphorous and magnesium after food ingestion in horses

Omeprazol (OMPZ) is used to prevent gastric ulcer syndrome in athletic horses. The aim of this research was to characterize changes in blood [Ca++], [P‐] and [Mg++] in ulcer‐free horses after omeprazol treatment. A Latin square design, with four horses and four treatments (T1: control, T2: 4mg/kg PO bolus treatment, T3: 1mg/kg PO during 11 days and T4: 4mg/kg PO during 11 days) was used. Blood was collected during fasting and 0.5h through 7.0h after feeding. Data were analyzed by two‐way ANOVA. It was observed decrease in [P] between treatments (P<0.05) but not change in [Ca] or [Mg] (P>0.05). Similarly, only [P] showed a significant difference between the phases of blood collection (P<0.05). There were no interactions between the phases of blood collection and treatments (P>0.05). These results demonstrated that OMPZ, which reduces pH of stomach, changed absorption of dietary P, reducing the serum concentration (T1: ~3,4mg/mL; T2: ~3,6mg/mL; T3: ~2,6mg/mL; T4: ~3,2mg/mL). In conclusion, treatment with OMPZ lowered serum [P] but not [Ca] or [Mg] in healthy horses. Changes in blood mineral parameters are important in athletic horses, which are undergo intense bone adaptation in response to exercise.

Effect of Phenylephrine and Ephedrine Bolus Treatment on Cerebral Oxygenation in Anaesthetized Patients

Meng, L.*; Cannesson, M.*; Alexander, B.S.*; Yu, Z.†; Kain, Z.N.*; Cerussi, A.E.‡; Tromberg, B.J.‡; Mantulin, W.W.‡ Author Information

Effect of iodine, selenium and cobalt rumen boluses given to dry dairy cows on the immunoglobulin and thyroid hormone status of calves

The objective was to determine the effect of rumen boluses containing 6800 mg iodine, 1000 mg selenium and 1000 mg cobalt given to dry dairy cows on the efficiency of colostral immunoglobulin G (IgG) absorption in calves. Thirteen cows received the bolus approximately 58 days before calving. A further 12 cows received no bolus and were used as controls. The cows were housed as one group. Calves were prevented from suckling for the first 24 h of life, and were given three feeds of a fixed quantity of colostrum. At 24 h, the average plasma concentrations of IgG in the calves were 15.5 and 13.4 g/L for the control and bolus groups, respectively; these were not significantly different (P = 0.212). Bolus treatment was associated with higher levels of free and total tri-iodothyronine (T3) and thyroxine (T4) in the dams (all P < 0.001), although it had no effect on thyroid hormone levels in the calves. There were nevertheless positive and negative relationships between the efficiency with which colostral IgG was absorbed at 24 h and, respectively, total T3 at 24 h (P < 0.05) and total T4 at 1 h of age (P < 0.05). The underlying basis for these relationships remains to be established.

Efficacy against lung metastasis with a tumor-targeting mutant of Salmonella typhimurium in immunocompetent mice

Salmonella typhimurium double leu-arg auxotrophs have been shown to be highly effective as antitumor agents in nude mouse models of human metastatic cancer. In order to proceed to clinical development of the S. typhimurium double auxotroph, termed A1-R, it is necessary to evaluate antitumor efficacy in immunocompetent mice. In the present study, we have observed the efficacy of A1-R on the Lewis lung (LLC) carcinoma in vitro as well as in C57BL/6 (C57) immunocompetent mice. In vitro, A1-R treatment of LLC began to induce cell death within one hour. Various doses and schedules of A1-R were administered to C57 mice implanted with LLC, including bolus single intravenous injection; medium dose with weekly intravenous administration and metronomic treatment with small intravenous doses twice a week. Bolus treatment was toxic to the immunocompetent host, in contrast to nude mice. Lower-dose weekly doses and metronomic doses were well tolerated by the immunocompetent host. Weekly intravenous injection with 2 x 107 bacteria and twice a week intravenous injection with 107 bacteria significantly inhibited metastasis formation, while bolus injection was toxic. Intra-thoracic administration was carried out with 108 bacteria A1-R injected into Lewis lung-bearing C57 mice weekly for three weeks. Lung metastasis was significantly inhibited by intrathoracic bacterial administration, without toxicity. The results in this report, demonstrating the anti-metastatic efficacy of S. typhimurium A1-R in immunocompetent mice, indicate the clinical potential of bacterial therapy of cancer.

Effect of phenylephrine and ephedrine bolus treatment on cerebral oxygenation in anaesthetized patients

Effect of phenylephrine and ephedrine bolus treatment on cerebral oxygenation in anaesthetized patients

Treatment duration (persistence) of basal insulin supported oral therapy (BOT) in Type-2 diabetic patients: comparison of insulin glargine with NPH insulin

To compare the persistence (treatment duration) of basal insulin supported oral therapy (BOT) using insulin glargine (GLA) or NPH insulin (NPH) in Type-2 diabetic patients. This retrospective cohort study reports results from an analysis of claims data from prescriptions for ambulatory patients within the German Statutory Health Insurance scheme. The study is based on claims data from more than 80% of German community pharmacies. Treatment duration until switching to a basal bolus treatment regimen (intensified conventional insulin therapy: ICT) was determined in insulin-naïve patients who began treatment with BOT using GLA or NPH between 01/2003 and 12/2006. A total of 97,998 patients (61,070 GLA and 36,928 NPH) were included. Within the observation period, 23.5% of GLA patients and 28.0% of NPH patients switched from BOT to ICT. The upper quartile of probability of continuation of therapy (the 75th percentile) was reached after 769 days in GLA patients and after 517 days in NPH patients. Therefore, the risk of switching to ICT was significantly higher with NPH compared to GLA: hazard ratios were 1.34 (99% CI: 1.29-1.38; unadjusted) and 1.22 (99% CI: 1.18-1.27) after adjustment for predefined covariates. Various sensitivity analyses using modified inclusion criteria and endpoint definitions were applied and these confirmed the initial results. Type-2 diabetic patients under BOT with GLA stayed significantly longer on the initial therapy before switching to ICT than patients on BOT using NPH.

Continuous infusion versus bolus injection of furosemide in pediatric patients after cardiac surgery: a meta-analysis of randomized studies

Introduction. Acute renal failure and fluid retention are common problems in pediatric patients after cardiac surgery. Furosemide, a loop diuretic drug, is frequently administered to increase urinary output. The aim of the present study was to compare efficacy and complications of continuous infusion of furosemide vs bolus injection among pediatric patients after cardiac surgery. Methods. A systematic review and meta-analysis was performed in compliance with The Cochrane Collaboration and the Quality of Reporting of Meta-Analysis (QUORUM) guidelines. The following inclusion criteria were employed for potentially relevant studies: a) random treatment allocation, b) comparison of furosemide bolus vs continuous infusion, c) surgical or intensive care pediatric patients. Non-parallel design randomized trials (e.g. cross-over), duplicate publications and non-human experimental studies were excluded. Results. Up to August 2008, only three studies were found, with 92 patients randomized (50 to continuous infusion and 42 to bolus treatment). Overall analysis showed that continuous infusion and bolus administration were equally effective in achieving the predefined urinary output, and were associated with a similar amount of administered furosemide (WMD=- 1.71 mg/kg/day (-5.20; +1.78), p for effect=0.34, p for heterogeneity<0.001, I2=99.0). However, in the continuous infu- sion group, patients had a significantly reduced urinary output (WMD=-0.48 ml/kg/day (-0.88; -0.08), p for effect=0.02, p for heterogeneity <0.70, I2=0%). Conclusions. Existing data comparing furosemide bolus injection with a continuous infusion are insufficient to confidently assess the best way to administer furosemide to pediatric patients after cardiac surgery. Larger studies are needed before any recommendations can be made.

Effect of phenylephrine and ephedrine bolus treatment on cerebral oxygenation in anaesthetized patients

How phenylephrine and ephedrine treatments affect global and regional haemodynamics is of major clinical relevance. Cerebral tissue oxygen saturation (Sct(O2) )-guided management may improve postoperative outcome. The physiological variables responsible for Sct(O2) changes induced by phenylephrine and ephedrine bolus treatment in anaesthetized patients need to be defined. A randomized two-treatment cross-over trial was conducted: one bolus dose of phenylephrine (100-200 µg) and one bolus dose of ephedrine (5-20 mg) were given to 29 ASA I-III patients anaesthetized with propofol and remifentanil. , mean arterial pressure (MAP), cardiac output (CO), and other physiological variables were recorded before and after treatments. The associations of changes were analysed using linear-mixed models. The CO decreased significantly after phenylephrine treatment [▵CO = -2.1 (1.4) litre min(-1), P<0.001], but was preserved after ephedrine treatment [▵CO = 0.5 (1.4) litre min(-1), P>0.05]. The was significantly decreased after phenylephrine treatment [▵ = -3.2 (3.0)%, P<0.01] but preserved after ephedrine treatment [▵ = 0.04 (1.9)%, P>0.05]. CO was identified to have the most significant association with (P<0.001). After taking CO into consideration, the other physiological variables, including MAP, were not significantly associated with (P>0.05). Associated with changes in CO, decreased after phenylephrine treatment, but remained unchanged after ephedrine treatment. The significant correlation between CO and implies a cause-effect relationship between global and regional haemodynamics.

Metastasizing, Luciferase Transduced MAT‑Lu Rat Prostate Cancer Models: Follow up of Bolus and Metronomic Therapy with Doxorubicin as Model Drug

The most fatal outcomes of prostate carcinoma (PCa) result from hormone-refractory variants of the tumor, especially from metastatic spread rather than from primary tumor burden. The goal of the study was to establish and apply rat MAT-Lu prostate cancer tumor models for improved non-invasive live follow up of tumor growth and metastasis by in vivo bioluminescence. We established luciferase transduced MAT-Lu rat PCa cells and studied tumor growth and metastatic processes in an ectopic as well as orthotopic setting. An intravenous bolus treatment with doxorubicin was used to demonstrate the basic applicability of in vivo imaging to follow up therapeutic intervention in these models. In vitro analysis of tissue homogenates confirmed major metastatic spread of subcutaneous tumors into the lung. Our sensitive method, however, for the first time detects metastasis also in lymph node (11/24), spleen (3/24), kidney (4/24), liver (5/24), and bone tissue (femur or spinal cord - 5/20 and 12/20, respectively). Preliminary data of orthotopic implantation (three animals) showed metastatic invasion to investigated organs in all animals but with varying preference (e.g., to lymph nodes). Intravenous bolus treatment of MAT-Lu PCa with doxorubicin reduced subcutaneous tumor growth by about 50% and the number of animals affected by metastatic lesions in lymph nodes (0/4), lung (3/6) or lumbar spine (0/2), as determined by in vivo imaging and in vitro analysis. Additionally, the possible applicability of the luciferase transduced MAT-Lu model(s) to study basic principles of metronomic therapies via jugular vein catheter, using newly established active microport pumping systems, is presented.

Role of Luteinizing Hormone in Changes in Concentrations of Progesterone and Luteal Blood Flow During the Hours of a Simulated Pulse of 13,14-Dihydro-15-Keto-Prostaglandin F2alpha (PGFM) in Heifers

A bolus treatment (e.g., 25 mg) of prostaglandin F(2alpha) (PGF) in the study of luteolysis in cattle results in dubious interpretations. Therefore, in experiment 1 of the present study, a 13,14-dihydro-15-keto-PGF (PGFM) pulse was simulated by incremental intrauterine (IU) infusion of PGF for 2.7 h on Day 14 postovulation. Concentrations of PGFM during the first hour of infusion and at the maximum were not different between simulated (n = 7) and spontaneous (n = 7) pulses. In experiment 2, four groups (n = 6 per group) were treated at Minute 0 (beginning of infusion) as follows: saline (infused IU), PGF (infused IU), acyline/saline, and acyline/PGF. Two hours before Minute 0, each heifer was given flunixin meglumine to inhibit endogenous PGF secretion, and heifers in the acyline/saline and acyline/PGF groups were given acyline to inhibit luteinizing hormone (LH). Plasma progesterone concentrations were similar among groups during Minutes 0 to 60, with no indication of an initial transient progesterone increase in the two PGF groups. Progesterone began to decrease in the PGF groups at Minute 60 and to rebound at Minute 135 after the PGFM peak at Minute 120. The rebound was complete in association with an increase in LH in the PGF group, but it was not complete when LH was inhibited in the acyline/PGF group. Luteal blood flow increased during PGF infusion in the two PGF groups and remained elevated for approximately 2 h after the PGFM peak in the PGF group but not in the acyline/PGF group. Novel findings were that an initial transient increase in progesterone did not occur with the simulated PGFM pulse and that LH stimulated a progesterone rebound and maintained the elevated luteal blood flow after the PGFM peak.

Uridine triacetate for prevention of 5FU toxicity due to dihydropyrimidine dehydrogenase (DPD) deficiency.

e19560 Background: Dihydropyrimidine dehydrogenase (DPD) catalyzes degradation of 5-fluorouracil (5FU). Patients with complete or partial DPD deficiency (0.1 and 3% of the population, respectively) can experience severe or lethal toxicities to 5FU, and impaired clearance may underlie many of the 1300 US 5FU toxicity deaths each year. Uridine triacetate prevents or diminishes toxicities when orally administered after 5FU overexposure, and has been used successfully as an investigational antidote in >50 patients following accidental overdoses. Methods: A colorectal cancer patient experienced Grade 3 and 4 GI and hematologic toxicities after a 96 hour infusion of 1000 mg/m2 5FU and was found to be DPD deficient (double mutation). The patient subsequently tolerated 50 and 100 mg 5FU bolus treatments in a modified FOLFOX regimen. However, during the second cycle, this DPD-deficient patient inadvertently received 1000 mg 5FU in 1 minute. Life-threatening toxicity was expected. Treatment with uridine triacetate (10 g q6h for 20 total doses) began within 8 hours. Results: In marked contrast to his first exposure to 5FU, the patient experienced no mucositis or additional cytopenia. Preclinical and mechanistic data predicted and support this observation. In a mouse model of DPD deficiency using ethynyluracil (2 mg/kg i.p.), a standard therapeutic 5FU dose of 100 mg/kg i.p. was lethal. Treatment with oral uridine triacetate (2 g/kg t.i.d. x 5 d) starting 2, 24 or 72 hours after 5FU resulted in 100%, 80% or 70% survival, respectively. Conclusions: Timely treatment with uridine triacetate appeared to prevent severe 5FU toxicity in a DPD-deficient patient and reduced mortality in DPD-inhibited mice receiving 5FU. Uridine triacetate has been shown previously to protect patients (and mice) from 5FU toxicities following 5FU overdose. Therefore, DPD-deficient patients who have received 5FU should also benefit from uridine triacetate treatment if the overexposure is identified soon enough after 5FU dosing. Therapeutic monitoring of 5FU during or after infusions would permit rapid detection of 5FU overexposure due to DPD-deficiency or other clearance defects, enabling the use of uridine triacetate as a potential antidote.

Toll-like Receptor Signaling during Myocardial Ischemia

Acute myocardial infarction and myocardial ischemia are leading causes of short- and long-term morbidity and mortality in the perioperative period. In part, this relates to the fact that treatment options for a myocardial infarction in surgical patients are extremely limited. For example, anti-coagulation or treatment with highly effective inhibitors of platelet aggregation may not be an option due to the risk for bleeding from the operative site. Therefore, it is not surprising that the search for new pharmacologic approaches to treat myocardial ischemia or to render the myocardium more resistant to limited oxygen availability is an area of intense investigation for perioperative scientists.1-4 In fact, the introduction of intraoperative beta-blockers for cardio-protection from ischemia was one of the most significant alterations in anesthesia practice during the past fifteen years. In line with the search for novel therapeutic approaches to render the myocardium more resistant to ischemia, a very exciting research study by Wang et al. from the research laboratory of Dr. Wei Chao from the Anesthesia Center for Critical Care Research of the Massachusetts General Hospital in Boston provides new insight into signaling pathways involving toll-like receptor (TLR)-elicited cardio-protection from ischemia.1

Continuous infusion versus bolus injection of furosemide in critically ill patients.A systematic review and meta-analysis

Introduction. Fluid overload and a positive fluid balance are common in the intensive care unit (ICU). Furosemide is frequently administered to increase urine output. A bolus injection is the traditional mode of administration, but many concerns have been raised about possible intravascular volume fluctuations, toxicity and enhanced tolerance. Furosemide related adverse effects can be enhanced in critically ill patients. Continuous infusion should allow better hemodynamic stability, less side effects and an easier achievement of the desired diuretic effect. We performed a systematic review and meta-analysis to compare the effects and complications of continuous furosemide infusion with those of bolus injections in critically ill patients in the ICU. Methods. Studies were searched in PubMed (updated January 2009). Backward snowballing of included papers was performed. International experts were contacted for further studies. The inclusion criteria were: random allocation to treatment, comparison of furosemide bolus vs continuous infusion, performed in surgical or intensive care patients. The exclusion criteria were: non-parallel design randomized trials, duplicate publications, non-human experimental studies, no outcome data. Results. Four eligible randomized clinical trials were identified, including 129 patients (64 to continuous infusion and 65 to bolus treatment). Continuous perfusion was not associated with a significant reduction in risk of mortality as compared to bolus injection Conclusions. Furosemide in continuous perfusion was not associated with a significant reduction in risk of hospital mortality as compared to bolus administration in critically ill patients in ICU, but existing data are insufficient to confidently assess the best way to administer furosemide . Applying a protocol to drive furosemide therapy could be more relevant than the chosen mode of administration.

Initial approach to the hyponatremic patient

Hyponatremia with cerebral symptoms is a medical emergency in which treatment delay may prove fatal. However, controversy prevails over which treatment is the best. This paper presents a practical and unified approach based on a literature study of the physiology of plasma [Na(+) ], the brain's response and clinical and experimental studies. Experimental and clinical studies were thoroughly reviewed. The literature was identified through MESH and free text search in the databases PubMed, Embase and Cochrane, and references in the literature. Cerebral water homeostasis is pivotal in hyponatremia. Prompt, repeated boluses of 2 ml/kg 3% saline constitute a rational treatment of symptomatic hyponatremia. After the initial correction, concern is mainly with avoiding overcorrection and osmotic demyelination. Plasma [Na(+)] is determined by the external balances of water and cations. The water balance must therefore be carefully monitored to counter the dramatic increase in plasma [Na(+)] that may result from brisk diuresis. Definitive treatment of hyponatremia should be directed toward its etiology. This can be challenging and the clinical application of traditional classifications based on hydration is difficult. Therefore, a practical approach is proposed based on the mechanisms of impaired urine dilution. The conflict between previously opposing standpoints is gradually giving way to an emerging consensus: Prompt bolus treatment of symptomatic hyponatremia with hypertonic saline. After the initial treatment, overcorrection must be avoided. Definitive treatment should be directed toward the nature of the underlying disorder. An approach based on the mechanism governing the impaired urine dilution has been proposed.

The effect of zinc oxide and elemental zinc boluses on the concentrations of Zn in serum and faeces, and on providing protection from natural Pithomyces chartarum challenge in calves

AIM: To investigate the efficacy of intra-ruminal Zn boluses as aids in providing protection from natural Pithomyces chartarum challenge in calves. METHODS: Sixty-two calves (mean weight 187 (SEM 3.25) kg) were divided into three groups. Commencing on Day 0, they received either a proprietary bolus containing 83% ZnO (ZnO group), a prototype Zn bolus containing 88% elemental Zn (Zn group), or remained untreated (Control group). Concentrations of Znin serum and faeces were measured weekly between Days 6 and 34, activities of gamma-glutamyl transferase (GGT)in serum on Days -8, 20, 34 and 41, and faecal spore counts between Days 13 and 41. RESULTS: Between Days 6 and 34, mean concentrations of Zn in serum increased in both Zn treatment groups compared with Controls (p<0.001), but were lower in Zn than ZnO animals between Days 6 and 28 (p=0.05). Concentrations of Zn in faeces were increased in both groups following treatment with Zn. Mean concentrations of Zn in faeces in ZnO animals was higher than Zn animals on Days 13 and 20 (p<0.001), but decreased by Day 34, whereas for Zn animals they were still elevated on Day 34. Faecal spore counts were 354,000 and 183,000 on Days 13 and 20, respectively, 610,500 on Day 28, and 115,500 spores/g on Day 34. There were no clinical signs of facial eczema, but based on the activities of GGT on Day 41, 17/20 (85%) Controls were moderately or severely affected (GGT >250 IU/L) compared with 1/21 (5%) ZnO and 3/21 (14%) Zn animals. Mean activities of GGT on Day 41 for ZnO and Zn animals were not different (35 (95% CI=23-54) and 54 (95% CI=32-92) IU/L, respectively; p=0.18), but were below those of the Controls (502 (95% CI 296, 850) IU/L), confirming efficacy of both bolus treatments. In both ZnO and Zn animals, there was no significant relationship between concentration of Zn in serum and activity of GGT, but in Zn animals there was a significant relationship between the concentration of Zn in faeces and activity of GGT 21 days later. The regression equation y=2.136- 0.002197x (where y is log10GGT activity, and x the concentration of Zn in faeces) provided an estimate of the threshold level of concentration of Zn in faeces. CONCLUSION: The study confirmed efficacy of elemental Zn boluses in providing protection from natural P. chartarum challenge in young cattle.