Low-dose Continuous Infusion Research Articles

Thrombolytic Treatment of Simultaneous Pulmonary Embolism and Impending Paradoxical Embolism Through a Patent Foramen Ovale: A Different Thrombolytic Regimen

A 72 year-old woman was admitted with a one-week history of weakness, right limb pain and progressive breathlessness. Her blood pressure was 60/40 mmHg, ECG showed inverted T waves in the precordial leads and incomplete right bundle branch block (RBBB). Transthoracic echocardiography revealed a large serpentine mobile mass across the atrial septum and mitrale valve extending into the left ventricular cavity. The right ventricle was dilated and peak systolic tricuspid annular velocity (RV-Sm) was 6.5 cm/sn, indicate right ventricular systolic function was severely depressed. Transoesophageal echocardiography showed a large, mobile thrombus in the foramen ovale, extending into the left atrium and ventricle. As the patient was in a haemodynamically compromised condition, high dose rapid infusion of streptokinase was administered. However, the thrombus did not fully resolve with this intervention. Therefore, low dose continuous streptokinase infusion was administered for an additional 72 h resulting in full resolution of the lesion by the third day of therapy. The optimal management of impending paradoxical embolism remains unclear. Prolonged continuous thrombolytic infusion may be a option for patients who do not experience full resolution of high risk thrombi with conventional thrombolytic therapy.

The Optimal Dose of Prophylactic Intravenous Naloxone in Ameliorating Opioid-Induced Side Effects in Children Receiving Intravenous Patient-Controlled Analgesia Morphine for Moderate to Severe Pain

Opioid-induced side effects, such as pruritus, nausea, and vomiting are common and may be more debilitating than pain itself. A continuous low-dose naloxone infusion (0.25 μg/kg/h) ameliorates some of these side effects in many but not all patients without adversely affecting analgesia. We sought to determine the optimal dose of naloxone required to minimize opioid-induced side effects and to measure plasma morphine and naloxone levels in a dose escalation study. Fifty-nine pediatric patients (24 male/35 female; average age 14.2 ± 2.2 years) experiencing moderate to severe postoperative pain were started on IV patient-controlled analgesia morphine (basal infusion 20 μg/kg/h, demand dose 20 μg/kg, 5 doses/h) and a low-dose naloxone infusion (initial cohort: 0.05 μg/kg/h; subsequent cohorts: 0.10, 0.15, 0.25, 0.40, 0.65, 1, and 1.65 μg/kg/h). If 2 patients developed intolerable nausea, vomiting, or pruritus, the naloxone infusion was increased for subsequent patients. Dose/treatment success occurred when 10 patients had minimal side effects at a naloxone dose. Blood samples were obtained for measurement of plasma morphine and naloxone levels after initiation of the naloxone infusion, processed, stored, and measured by tandem mass spectrometry with electrospray positive ionization. The minimum naloxone dose at which patients were successfully treated with a <10% side effect/failure rate was 1 μg/kg/h; cohort size varied between 4 and 11 patients. Naloxone was more effective in preventing pruritus than nausea and vomiting. Concomitant use of supplemental medicines to treat opioid-induced side effects was required at all naloxone infusion rates. Plasma naloxone levels were below the level of assay quantification (0.1 ng/mL) for infusion rates ≤0.15 μg/kg/h. At rates >0.25 μg/kg/h, plasma levels increased linearly with increasing infusion rate. In each dose cohort, patients who failed therapy had comparable or higher plasma naloxone levels than those levels measured in patients who did not fail treatment. Plasma morphine levels ranged between 3.52 and 172 ng/mL, and >90% of levels ranged between 10.2 and 61.6 ng/mL. Plasma morphine levels were comparable between patients who failed therapy and those patients who achieved symptom control. Naloxone infusion rates ≥1 μg/kg/h significantly reduced, but did not eliminate, the incidence of opioid-induced side effects in postoperative pediatric patients receiving IV patient-controlled analgesia morphine. Patients who failed therapy generally had plasma naloxone and morphine levels that were comparable to those who had good symptom relief suggesting that success or failure to ameliorate opioid-induced side effects was unrelated to plasma levels.

Dextran Fractional Clearance Studies in Acute Dengue Infection

BackgroundAlthough increased capillary permeability is the major clinical feature associated with severe dengue infections the mechanisms underlying this phenomenon remain unclear. Dextran clearance methodology has been used to investigate the molecular sieving properties of the microvasculature in clinical situations associated with altered permeability, including during pregnancy and in various renal disorders. In order to better understand the characteristics of the vascular leak associated with dengue we undertook formal dextran clearance studies in Vietnamese dengue patients and healthy volunteers.Methodology/Principal FindingsWe carried out serial clearance studies in 15 young adult males with acute dengue and evidence of vascular leakage a) during the phase of maximal leakage and b) one and three months later, as well as in 16 healthy control subjects. Interestingly we found no difference in the clearance profiles of neutral dextran solutions among the dengue patients at any time-point or in comparison to the healthy volunteers.Conclusions/SignificanceThe surface glycocalyx layer, a fibre-matrix of proteoglycans, glycosaminoglycans, and plasma proteins, forms a complex with the underlying endothelial cells to regulate plasma volume within circumscribed limits. It is likely that during dengue infections loss of plasma proteins from this layer alters the permeability characteristics of the complex; physical and/or electrostatic interactions between the dextran molecules and the glycocalyx structure may temporarily restore normal function, rendering the technique unsuitable for assessing permeability in these patients. The implications for resuscitation of patients with dengue shock syndrome (DSS) are potentially important. It is possible that continuous low-dose infusions of dextran may help to stabilize the permeability barrier in patients with profound or refractory shock, reducing the need for repeated boluses, limiting the total colloid volume required. Formal clinical studies should help to assess this strategy as an alternative to conventional fluid resuscitation for severe DSS.

Clinical Experience with Low-Dose Continuous Infusion Furosemide in Acute Heart Failure: Assessment of Efficacy and Safety

Clinical Experience with Low-Dose Continuous Infusion Furosemide in Acute Heart Failure: Assessment of Efficacy and Safety

C-type natriuretic peptide does not attenuate the development of pulmonary hypertension caused by hypoxia and VEGF receptor blockade

Aims C-type natriuretic peptide (CNP) is a local regulator of vascular tone and remodeling in many vascular beds. However, the role of CNP in modulating pulmonary arterial hypertensive and vascular remodeling responses is unclear. The purpose of this study was to determine if CNP is capable of preventing the development of pulmonary hypertension (PH). Main methods We used animal models of PH caused by chronic hypoxia alone or in combination with the vascular endothelial growth factor (VEGF) receptor blocker SU5416. We measured pulmonary hemodynamics, right ventricular hypertrophy and vascular remodeling effects in response to a continuous infusion of low dose or high dose CNP or vehicle placebo. Key findings Right ventricular hypertrophy and a marked elevation in right ventricular systolic pressure (RVSP) were seen in both models of PH. Rats treated with the combination of SU5416 and chronic hypoxia also developed pulmonary endothelial hyperproliferative lesions. Continuous intravenous infusion of CNP at either dose did not attenuate the development of PH, right ventricular hypertrophy or vascular remodeling in either of the models of PH despite a three-fold increase in serum CNP levels. Significance CNP does not prevent the development of PH in the chronic hypoxia or SU5416 plus hypoxia models of pulmonary hypertension suggesting that CNP may not play an important modulatory role in human PH.

Safety and Efficacy of Low-Dose Continuous Infusion of Landiolol, an Ultra-Short-Acting β-blocker, in Cardiac Surgery

Introduction: Landiolol hydrochloride is an ultra‐short‐acting β‐blocker that is administered intravenously and has many advantages in cardiac surgery. This study was performed to examine the safety and efficacy of low‐dose landiolol continuous infusion in cardiac surgery.Methods and Results: Nineteen patients who underwent either aortic valve replacement or coronary artery bypass surgery received low‐dose continuous infusion of landiolol (2.8 ± 0.75 μg/kg/min. from the time of skin incision until the second postoperative day. Nineteen patients who did not receive landiolol served as controls. Heart rate, arterial pressure, cardiac index, and stroke volume were measured and the occurrence of supraventricular tachyarrythmia was monitored for one week after surgery. Landiolol decreased the heart rate without causing hemodynamic deterioration. The incidence of supraventricular tachyarrythmia was 32% and 47% in the landiolol and control groups, respectively (P = 0.50).Conclusions: Landiolol is effective for decreasing heart rate while maintaining other hemodynamic parameters. Our data did not show a clear prophylactic effect of landiolol on postoperative supraventricular tachyarrythmia.

Safety and Efficacy of Low-Dose Continuous Infusion of Landiolol, an Ultra-Short-Acting β-blocker, in Cardiac Surgery

Safety and Efficacy of Low-Dose Continuous Infusion of Landiolol, an Ultra-Short-Acting β-blocker, in Cardiac Surgery

Anti‐inflammatory effect of an insulin infusion in patients on maintenance haemodialysis: A randomized controlled pilot study

A pilot study to investigate the anti-inflammatory effect of insulin in patients on maintenance haemodialysis. Elevated concentrations of pro-inflammatory and oxidative mediators are thought to contribute to the increased cardiovascular risk in haemodialysis. Insulin has been demonstrated to have anti-inflammatory properties and a continuous low-dose insulin infusion in critically ill patients is associated with improved outcomes. The anti-inflammatory effects of insulin in haemodialysis have not been investigated. In a single-blind cross-over study, 11 stable, non-diabetic, haemodialysis patients received a continuous insulin infusion (Actrapid 2 IU/h) during a dialysis of 4 h or a conventional dialysis in random order. Normoglycaemia was maintained by a modified glucose dialysate and glucose infusion. Blood samples were collected at baseline, 1, 4, 6 and 24 h. C-reactive protein (CRP), tumour necrosis factor-α, interleukin-6, neopterin, vascular cell adhesion molecule 1, protein thiols, dityrosine and peroxides were measured. Insulin produced a significant reduction in median CRP over the immediate dialysis phase (confidence interval) by 6% (2-9% (95% CI), P=0.006) and an even greater decline at 24 h (19% (8-28%, 95% CI), P=0.001) compared with values of the conventional dialysis. No significant changes were observed in the other markers. Median glucose levels were comparable during both dialysis sessions. During haemodialysis, insulin may have a modest anti-inflammatory effect as evident by a reduction in CRP that appears to have a persistent effect over the next 24 h post dialysis. More studies are required to examine longer-term benefits as well as the potential role in more high-risk individuals.

Defibrotide Low-Dose Continuous Infusion After Allogeneic Stem Cell Transplantation as Prophylaxis for Veno-Occlusive Disease of the Liver.

AbstractAbstract 3483Defibrotide (DF) has been shown to be effective in the treatment and prophylaxis of the veno-occlusive disease (VOD) of the liver, a relatively common complication after allogeneic stem cell transplant (SCT). We report our experience in 46 consecutive adult patients (pts). The pts (mean age 41 yrs, range 16–66) were affected by leukemia (22), lymphoma (15), multiple myeloma (4), myelodisplasia (2), solid tumor (2), Fanconi anemia (1). Risk factors for VOD were: resistant disease 9, previous transplant 8, B virus hepatitis 6, liver metastases 1, lymphoma of the liver 1, increased transaminases before conditioning 7. All were transplanted from their HLA-identical siblings; the conditioning regimen was reduced in 17, while it was conventional in 29. All the pts received a combination of drugs as conditioning regimen, 23 of them received Busulfan and 8 of them oral Busulfan. 15 received bone marrow and 31 peripheral blood as source of stem cells. None was T-cell depleted; the GVHD prophylaxis regimen was: CsA alone or combined with MTX 45, FK506+MTX 1. For VOD prophylaxis no heparin was administered, while DF was given at the dose of 10 mg/Kg in continuous iv infusion starting on day +1 until day +21 after the SCT. DF was very well tolerated and no hemorrhagic complications were seen. Blood coagulation significant alterations were: prolonged PT (4/46), prolonged aPTT (3/46), elevated fibrinogen (24/46), (never over 800 mg/dl), low level (less than 50%) of ATIII and/or protein C and or protein S (2/46). By using the VOD Baltimore criteria, only 1 case of VOD was observed on day +29 in a patient who died at day +36 with VOD, aspergillosis and CMV pneumonia. The bilirubin was more than 2 times the normal value in 26/46; US-scan of the liver and Doppler, performed in 16 pts with a possible sign of VOD, was positive only in the patient who died for VOD. We documented 32 infectious complications (16 FUO, 9 gram positive bacteremias, 3 pneumonia and 4 invasive aspergillosis). We documented acute GVHD in 14 pts (12 grade I-II and 2 grade III). Five pts died between +36 and +100 but none for VOD (3 for progression of their disease and 2 for aspergillosis). Our laboratory data demonstrated modest alterations of the coagulative parameters, low consumption of coagulative factors and reduced fibrinolysis. Since in this at risk transplanted population only 1 VOD has been observed, DF low-dose continuous infusion, without heparin, seems able to play a relevant role in the VOD prophylaxis. On considering the favourable results by us and others, the absence of toxicity and the low cost of the drug, we intend to continue this experience with DF as VOD prophylaxis, even if we foretell a large randomized study to find better indications. Disclosures:No relevant conflicts of interest to declare.

Continuous low-dose fructose infusion does not reverse glucagon-mediated decrease in hepatic glucose utilization

An adaptation to continuous total parenteral nutrition (TPN; 75% of nonprotein calories as glucose) is the liver becomes a major consumer of glucose with lactate release as a by-product. The liver is able to further increase liver glucose uptake when a small dose of fructose is acutely infused via the portal system. Glucagon, commonly elevated during inflammatory stress, is a potent inhibitor of glucose uptake by the liver during TPN. The aim was to determine if continuous fructose infusion could overcome the glucagon-mediated decrease in hepatic glucose uptake. Studies were performed in conscious, insulin-treated, chronically catheterized, pancreatectomized dogs that adapted to TPN for 33 hours. They were then assigned to 1 of 4 groups: TPN (C), TPN + fructose (4.4 μmol kg −1 min −1; F), TPN + glucagon (0.2 pmol kg −1 min −1; GGN), or TPN + fructose and glucagon (F + GGN) for an additional 63 hours (33-96 hours). Insulin, fructose, and glucagon were infused into the portal vein. During that period, all animals received a fixed insulin infusion of 0.4 mU·kg −1·min −1 (33-96 hours); and the glucose infusion rates were adjusted to maintain euglycemia (6.6 mmol/L). Continuous fructose infusion was unable to further enhance net hepatic glucose uptake (in micromoles per kilogram per minute) (31.1 ± 2.8 vs 36.1 ± 5.0; C vs F), nor was it able to overcome glucagon-mediated decrease in net hepatic glucose uptake (10.0 ± 4.4 vs 12.2 ± 3.9; GGN vs F + GGN). In summary, continuous fructose infusion cannot augment liver glucose uptake during TPN; nor can it overcome the inhibitory effects of glucagon.

Low-dose continuous infusion of landiolol can reduce adrenergic response during tracheal intubation in elderly patients with cardiovascular disease

The objective of this study was to examine the effects of low-dose infusion of landiolol on hemodynamics during tracheal intubation in elderly patients with cardiovascular disease. The study population consisted of 30 patients with American Society of Anesthesiologists physical status II and III, aged 65-77years, who were scheduled to undergo elective surgery under general anesthesia. Patients were randomly divided into two groups (n=15 each): a control group, receiving normal saline, and a landiolol group, receiving landiolol at 30μg/kg/min. After oxygenation, 1μg/kg of fentanyl was injected intravenously, followed by continuous infusion of normal saline or landiolol for 5min. General anesthesia was induced and maintained with target-controlled infusion of propofol at a blood concentration of 4μg/ml and tracheal intubation was performed 3min after vecuronium injection. Heart rate, blood pressure, and bispectral index were measured before and after tracheal intubation. Results showed that low-dose continuous infusion of landiolol is an effective and relatively safe method of preventing an intubation-induced adrenergic response in elderly patients with cardiovascular disease.

Low-dose continuous infusion 5-fluorouracil combined with weekly leucovorin, nab-paclitaxel, oxaliplatin, and bevacizumab for patients with advanced pancreatic cancer: A pilot study.

e14545 Background: Gemcitabine based chemotherapy has become the standard of care for first-line treatment of patients with advanced pancreatic cancer. However, median survival remains disappointing. Continuous infusion 5-fluorouracil (5 FU), calcium leucovorin plus paclitaxel and oxaliplatin has shown activity in patients with pancreatic cancer. As a protracted low dose infusion, 5FU is antiangiogenic and potentiates bevacizumab as observed in the treatment of colon cancer. When combined with bevacizumab, nab-paclitaxel is also synergetic because of its antiangiogenic properties. We administered low doses of continuous cytotoxic chemotherapy with conventional anti-VEGF therapy for patients with advanced pancreatic cancer. Methods: Since July of 2008 we treated 28 patients with 5 FU (180 mg/m2/d) as a continuous infusion on days 1-15 via ambulatory chemotherapy pump into a surgically placed central venous line. Calcium leucovorin (20 mg/m2) IVP, nab-paclitaxel (100 mg/m2) IV as a 30 minute infusion and ox...

The effect of low-dose heparin on maintaining peripherally inserted percutaneous central venous catheters in neonates

To evaluate the effect of low-dose heparin on duration of peripherally inserted percutaneous central venous catheter (PCVC) patency and catheter occlusion. Our research was a prospective, randomized, controlled, double-blind clinical study including 246 eligible neonates with PCVCs. It was conducted at the neonatal intensive care unit (NICU) of Diyarbakir Children's Hospital between 1 February 2007 and 31 October 2008. In the heparin group (n=118), the total parenteral nutrition (TPN) solutions contained heparin, which was infused at a rate of 0.5 IU kg⁻¹ h⁻¹ . The no-heparin group (n=121) received TPN fluids without heparin. In the heparin group, the duration of catheter patency was longer than that of the no-heparin group reaching a statistically significant difference (12.4 ± 4.5 vs 9.7 ± 4.0, P<0.0001). In the heparin group, the proportion of patients completing the TPN therapy successfully was higher than in the no-heparin group (P=0.0001; relative risk (RR): 3.32 (95% confidence interval (CI): 1.92 to 5.73)) also demonstrating a statistically significant difference. The rate of catheter occlusion among infants in the heparin group was smaller (P=0.0001; RR: 3.44 (95% CI: 1.92 to 6.44)). There were no statistically significant differences between the two groups in the incidence of other catheter-related problems. The length of the occluded catheter outside the skin, TPN infusion rate and catheter duration time were found to be the factors associated with catheter occlusion. Heparin prevented catheter occlusion with a mechanism unrelated to these factors. In neonates with PCVCs, low-dose continuous infusion of heparin (0.5 IU kg ⁻¹h⁻¹ within TPN fluids is an effective measure in terms of reducing catheter occlusion, allowing successful completion of the therapy, without increasing adverse effects. Furthermore, this effect of heparin may occur independently via occlusion-related factors that we evaluated in the study.

Continuous Low-Dose Infusion of Human Atrial Natriuretic Peptide in Patients With Left Ventricular Dysfunction Undergoing Coronary Artery Bypass Grafting: The NU-HIT (Nihon University working group study of low-dose Human ANP Infusion Therapy during cardiac surgery) for Left Ventricular Dysfunction

Continuous low-dose infusion of human atrial natriuretic peptide (hANP) in patients undergoing cardiac surgery on cardiopulmonary bypass (CPB) inhibits the renin-angiotensin-aldosterone system and compensates for the adverse effects of CPB. We examined the influence of hANP infusion on cardiac and renal function in patients with left ventricular dysfunction undergoing coronary artery bypass grafting (CABG). The subjects were 133 patients who underwent CABG and had a pre-operative ejection fraction < or =35%. They were randomized to receive 0.02 microg/kg/min of hANP from the initiation of CPB (hANP group) or placebo (saline) infusion. Early post-operative mortality did not show a significant difference between the 2 groups, but perioperative complications were significantly less frequent in the hANP group (p = 0.015). Long-term all-cause mortality showed no difference, but the cardiac death-free rate at 5 or 8 years post-operatively was 98.5% in the hANP group and 85.5% in the placebo group (p = 0.0285). Post-operative ejection fraction was significantly larger and the post-operative brain natriuretic peptide level was significantly lower in the hANP group. Serum creatinine was significantly lower in the hANP group than the placebo group at 1 month, 6 months, and 1 year post-operatively, whereas the estimated glomerular filtration rate was significantly higher in the hANP group at these times. In patients with left ventricular dysfunction undergoing CABG, hANP showed renal- and cardio-protective effects and reduced post-operative complications. It also improved the long-term prognosis. We suggest that hANP should be considered as part of perioperative management of patients with cardiac dysfunction undergoing cardiac surgery. (NU-HIT trial for LVD; UMIN000001652).

Improved Outcomes Using Tacrolimus/Sirolimus for Graft-versus-Host Disease Prophylaxis with a Reduced-Intensity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplant as treatment of Myelofibrosis

Allogeneic hematopoietic cell transplantation (HCT) using reduced-intensity conditioning (RIC) regimens is a potentially curative treatment for patients (patients) with myelofibrosis (MF), as we and others have reported. Nonrelapse mortality (NRM) from graft-versus-host disease (GVHD) and other complications has limited the success of this approach. As part of an ongoing prospective research study at City of Hope, a combination of tacrolimus/sirolimus +/- methotrexate (MTX) for GVHD prophylaxis has become the standard treatment for our allogeneic HCT patients. In this report, we present results for 23 consecutive patients, including extended follow up for 9 patients previously reported who received cyclosporine (CsA)/mycophenolate moffetil (MMF)+/-MTX, and the current series of 14 patients who received tacrolimus/sirolimus+/-MTX, and evaluate the impact of the GVHD prophylaxis regimen on the outcomes. Median follow-up for alive patients was 29.0 months (9.5-97.0). The estimated 2-year overall survival (OS) for the CsA/MMF cohort was 55.6% (confidence interval 36.0, 71.3), and for the tacrolimus/sirolimus cohort it was 92.9% (63.3, 98.8) (P=.047). The probability of grade III or IV acute GVHD (aGVHD) was 60% for the CsA/MMF patients, and 10% for the tacrolimus/sirolimus group (P=.0102). No significant differences were seen for grade II to IV aGVHD in the 2 groups. We conclude that the combination of tacrolimus/sirolimus+/-MTX for GVHD prophylaxis in the setting of RIC HCT for MF appears to reduce the incidence of severe aGVHD and NRM, and leads to improved OS compared to CSA/MMF+/-MTX.

Lower doses of rFVIIa therapy are safe and effective for surgical interventions in patients with severe FXI deficiency and inhibitors

Severe FXI deficiency is a rare injury-related bleeding disorder. In patients with FXI inhibitors, surgeries may be treated using recombinant activated factor VII; however, treatment safety is a major concern and the best dosing regimen as well as mode of administration is still to be defined. We describe four patients with severe factor XI deficiency and inhibitors to FXI, undergoing eight (four major) surgical procedures treated with continuous infusion of rFVIIa. Following acute MI that evolved after surgery of our first patient, all other patients were treated with low-dose bolus rFVIIa followed by low-dose continuous infusion of rFVIIa. Haemostasis was successfully achieved and no further thrombotic complications occurred. To support our clinical results ex-vivo thromboelastography studies were performed, demonstrating the differences of clot formation and lysis between patients with FXI deficiency and healthy controls and suggesting that low-dose rFVIIa corrects coagulation similarly to high-dose rFVIIa in FXI deficiency. Recombinant FVIIa at low doses may effectively induce haemostasis and seems to be a safe treatment mode in patients with FXI deficiency and inhibitors undergoing surgeries.

Unfractioned heparin for treatment of sepsis: A randomized clinical trial (The HETRASE Study)*

The primary aims of this study were to determine the effects of heparin on length of stay and change from baseline multiple organ dysfunction (MOD) score. Secondary objectives were to estimate the effects of heparin on 28-day all-cause mortality, and to determine the possible effect modification on 28-day all-cause mortality, in subgroups defined by site of infection and baseline values of Acute Physiology and Chronic Health Evaluation II score, MOD score, and d-dimer. Randomized, double-masked, placebo-controlled, single-center clinical trial, testing low dose continuous infusion of unfractioned heparin (UFH) as complementary treatment for sepsis. Five hundred fifty bed University Hospital and referral center in Medellín, Columbia. Three hundred nineteen patients admitted at the emergency room with signs indicative of sepsis. Patients were randomly assigned to receive placebo or UFH (500 units/hour for 7 days). The median length of stay in patients discharged alive in the placebo group was 12.5 days (interquartile range = 8-20), and 12 days (interquartile range = 8-19.5) in the heparin group (p = 0.976). The MOD score improved equally in the two treatments arms with an average decline of 0.13 and 0.11 per day for the placebo and heparin groups (p = 0.240), respectively. The overall 28-day mortality was 16% in the placebo group and 14% in the heparin group (p = 0.652). Subgroup analyses did not show any statistically significant reduction in 28-day mortality with UFH. There was only one serious adverse event on a patient who received heparin but it was fully resolved without complications. Our findings suggested that UFH may be a feasible and safe intervention in sepsis. However, this study was not able to demonstrate a beneficial effect on the chosen primary outcomes or in the 28-day mortality rate.

Continuous intraventricular infusion of erythropoietin exerts neuroprotective/rescue effects upon Parkinson's disease model of rats with enhanced neurogenesis

Parkinson's disease (PD) is characterized by degeneration of nigrostriatal dopaminergic neuronal systems. Several therapeutic tools for PD include medication using l-DOPA and surgeries such as deep brain stimulation are established. However, the therapies are considered as symptomatic therapy, but not basic remedy for PD and a new regenerative therapy would be desired to explore. In this study, the neuroprotective/rescue effects of erythropoietin (EPO), a well known hematopoietic hormone, on dopaminergic neurons were explored with neurogeneic potencies of EPO. EPO (100 IU/day) was continuously administered with micro-osmotic pump for a week to PD model of rats induced by intrastriatal 6-hydroxydopamine (6-OHDA) injection with subsequent behavioral and immunohistochemical investigations. The number of amphetamine-induced rotations of EPO-treated rats significantly decreased, compared to the control rats. The preservation of dopaminergic neurons of EPO-treated rats were confirmed by tyrosine hydroxylase staining and Fluoro-Gold staining. The number of bromodeoxyuridine (BrdU)/polysialic acid-neural cell adhesion molecule (PSA-NCAM) double positive cells in the subventricular zone of EPO-treated rats significantly increased with migratory potencies to the damaged striatum, compared to the control rats. Furthermore, TUNEL staining and phosphorylated Akt staining revealed that the neuroprotective/rescue effects of EPO might be mediated by anti-apoptotic effects through the increase of phosphorylated Akt. These results suggest that continuous low dose infusion of EPO exerts neuroprotective/rescue effects with neurogeneic potentials. EPO might be a strong tool for PD therapy, although the further experiments should be added.

The effects of variations in dose and method of administration on glucagon like peptide-2 activity in the rat

Glucagon-like peptide-2 (GLP-2) is a potent, intestinal-specific trophic hormone. However, the relationship between the dose and timing of GLP-2 administration and these trophic effects is not clear. We investigated the effects of variations in the dose and timing of GLP-2 administration on its intestinal trophic activity. A rodent model of total parenteral nutrition (TPN) mucosal atrophy was used, examining intestinal morphology in the adult male rat after 5 days. Groups were: controls, maintained with TPN alone and GLP-2 treated groups (high dose; 240 μg/kg/day, low dose; 24 μg/kg/day) given by continuous or intermittent (over 1 h, twice daily) intravenous infusion. Body weight and total small bowel length were significantly increased in the high dose, continuous infusion group. Both high dose infusion methods increased total small bowel weight, villus height, crypt depth, and total mucosal surface area. Both high dose infusion and low dose intermittent infusion routes increased crypt cell proliferation ( P < 0.05 for all comparisons). Both high dose routes gave nearly equivalent exposures; low dose continuous infusion gave higher exposure but intermittent low dose infusion resulted in an increase in crypt proliferation; neither low dose method resulted in morphologic changes. There were no differences in transporter protein expression or apoptosis rates. High dose continuous infusion appears to maximally induce intestinal growth, and also increases weight gain, while high dose GLP-2 intermittent infusion results in similar morphologic effects. A threshold level for the induction of proliferative and morphologic effects was seen in the low dose groups. These observations may be relevant for planning therapeutic trials.

Vasopressin vs. terlipressinin the treatmentof cardiovascular failure in sepsis

Arginine vasopressin (AVP) and terlipressin (TP) are increasingly used as adjunct vasopressors in the treatment of septic shock. Despite important pharmacological differences between the two drugs (e.g., receptor selectivity, effective half-life) the use of either substance is determined mainly by local availability and institutional inventory. We briefly describe the pathophysiology and pharmacology of septic shock relevant to the treatment with vasopressin analogues. In addition, differences in pharmacokinetics and pharmacodynamics between AVP and TP are discussed. The current literature suggests that neither AVP nor TP should be administered in high doses in patients with septic shock. Furthermore, increasing evidence indicates that early administration of vasopressin analogues may improve outcome as compared to a last-resort treatment. Low-dose infusion of AVP (0.6-2.4 U/h) has been demonstrated to be a safe adjunct in the management of septic shock. The V2 agonistic effects of AVP may exert favorable effects on hepatosplanchnic, renal, pulmonary, and coronary perfusion. However, the higher V1 receptor selectivity of TP may prove more potent in restoring arterial blood pressure and avoiding rebound hypotension, while carrying the risk of sustained global and regional vasoconstriction after bolus injection. Evidence from experimental studies and initial clinical reports suggests that continuous low-dose infusion of TP may stabilize hemodynamics in septic shock with reduced side effects. However, randomized, controlled trials are necessary to determine the role of bolus or continuous infusion of TP in the treatment of septic shock before this approach can be recommended for routine clinical use.