Saikosaponin D reverses epinephrine- and norepinephrine-induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signaling.

Intrahepatic cholangiocarcinoma (iCCA) is a highly fatal malignancy with rapidly increasing incidence and mortality worldwide. Currently, gemcitabine-based systemic chemotherapy is the main clinical therapeutic regimen; however, its efficacy is poor, and its mechanism has not been elucidated. In this study, we use a Seahorse Extracellular Flux analyser to measure glycolysis capacity (extracellular acidification rate, ECAR) and oxygen consumption rate (OCR). The glucose uptake or lactic acid content is detected, and the effects of saikosaponin D, an active compound derived from Bupleuri Radix (a traditional Chinese medicine for soothing the liver and relieving depression), on gemcitabine cytotoxicity in norepinephrine-stimulated iCCA cells are analysed. We find that adrenergic signaling plays a fundamental role in chronic stress-induced therapeutic resistance in iCCA. Norepinephrine (NE) and epinephrine (E) enhance the proliferation of iCCA cells and interfere with the response to gemcitabine through activation of the ß2-adrenergic receptor (ADRB2). Furthermore, we find that NE upregulates the expressions of several drug efflux-related genes (such as ABCG2 and MDR1) and promotes glycolysis in iCCA cells. In addition, saikosaponin D reverses the poor response of iCCA cells to gemcitabine by downregulating ADRB2 level. Furthermore, saikosaponin D inhibits drug efflux and glycolysis in iCCA cells by regulating the expressions of MDR1, ABCG2, HK2, and GLUT1. Collectively, saikosaponin D enhances the antitumor effect of gemcitabine by controlling glucose metabolism and drug efflux by inhibiting the ADRB2 signaling. Therefore, the combination of saikosaponin D and gemcitabine may be a potential therapeutic strategy for the treatment of iCCA.

Ameliorative effects of half-dose saffron and chamomile combination on Psycho-endocrinological changes in a diabetic murine model.

INTRODUCTION: Diabetes mellitus is a chronic metabolic disorder with an increasing prevalence worldwide. Reduction in blood insulin level alters brain function by inducing oxidative stress with changes in dopamine and norepinephrine neurotransmission, ultimately leading to neuropsychological symptoms. The efficacy of currently available psychotropic drugs is not satisfactory. Therefore, this study was conducted to explore the beneficial effects of a combination of the natural herbs, saffron and chamomile, in treating diabetes and its resultant neuropsychological effects using a rodent model of diabetes mellitus. METHOD: The rats were randomly divided in to eight groups (n = 10), healthy control (HC), diabetic control (DC) and six groups of diabetic rats treated with various concentrations and combinations of saffron and chamomile. Diabetic treatment groups individually received methanolic extract and water decoction of chamomile (30 mg/kg) and saffron (10mg/kg) and their combined half doses (saffron 5mg/kg and chamomile 15mg/kg) for two weeks. Open field test (OFT) and forced swim test (FST) were used to measure the anxiolytic and antidepressant effects of herbs, respectively. Finally, biochemical, and neurochemical estimations were made. RESULTS: The present study suggests the therapeutic effects of herbs especially in co-administrated decoction, against diabetes with improved antioxidant profile and enhanced levels of dopamine and norepinephrine. Anxiolytic and antidepressant effects were evident with improvements in the OFT and FST. Examination of the cortex of the diabetic group revealed cellular damage and tangle formation, which indicates advanced stages of dementia. CONCLUSION: This study shows that the use of a combination of saffron and chamomile improves diabetes control and reduces its related psychiatric effects.

Integrated Metabolomics and Network Pharmacology to Reveal the Mechanisms of Guizhi-Fuling Treatment for Myocardial Ischemia.

Myocardial ischemia is a cardio-physiological condition due to a decrease in blood perfusion to the heart, leading to reduced oxygen supply and abnormal myocardial energy metabolism. Guizhi-Fuling (GZFL) is effective in treating Myocardial ischemia. However, its mechanism of action is unclear and requires further exploration. We attempt to decipher the mechanisms behind GZFL treating Myocardial ischemia by integrating metabolomics and network pharmacology. In this study, myocardial metabolomic analysis was performed using GC/MS to identify the potential mechanism of action of GZFL during myocardial ischemia. Then, network pharmacology was utilized to analyze key pathways and construct a pathway-core target network. Molecular docking was incorporated to validate core targets within network pharmacological signaling pathways. Finally, western blots were utilized to verify core targets of metabolomics, network pharmacology integrated pathways, and key signaling targets. Thus, 22 critical biomarkers of GZFL for treating myocardial ischemia were identified. Most of these metabolites were restored using modulation after GZFL treatment. Based on the network pharmacology, 297 targets of GZFL in treating myocardial ischemia were identified. The further comprehensive analysis focused on three key targets, such as Tyrosine hydroxylase (TH), myeloperoxidase (MPO), and phosphatidylinositol 3-kinases (PIK3CA), and their related metabolites and pathways. Compared with the model group, the protein expression levels of TH, MPO and PIK3CA were reduced in GZFL. Therefore, the mechanism of GZFL for treating myocardial ischemia could inhibit myocardial inflammatory factors, reduce myocardial inflammation, and restore endothelial function while controlling norepinephrine release and uric acid concentration.

Intraarterial Nimodipine Versus Induced Hypertension for Delayed Cerebral Ischemia: A Modified Treatment Protocol.

BACKGROUND: Rescue treatment for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage can include induced hypertension (iHTN) and, in refractory cases, endovascular approaches, of which selective, continuous intraarterial nimodipine (IAN) is one variant. The combination of iHTN and IAN can dramatically increase vasopressor demand. In case of unsustainable doses, iHTN is often prioritized over IAN. However, evidence in this regard is largely lacking. We investigated the effects of a classical (iHTN+IAN) and modified (IANonly) treatment protocol for refractory DCI in an observational study. METHODS: Rescue treatment for DCI was initiated with iHTN (target >180 mm Hg systolic) and escalated to IAN in refractory cases. Until July 2018, both iHTN and IAN were offered in cases refractory to iHTN alone. After protocol modification, iHTN target was preemptively lowered to >120 mm Hg when IAN was initiated (IANonly). Primary outcome was noradrenaline demand. Secondary outcomes included noradrenaline-associated complications, brain tissue oxygenation, DCI-related infarction and favorable 6-month outcome (Glasgow Outcome Scale 4-5). RESULTS: N=29 and n=20 patients were treated according to the classical and modified protocol, respectively. Protocol modification resulted in a significant reduction of noradrenaline demand (iHTN+IAN 0.70±0.54 µg/kg per minute and IANonly 0.26±0.20 µg/kg per minute, P<0.0001) and minor complications (15.0% versus 48.3%, unadjusted odds ratio, 0.19 [95% CI, 0.05-0.79]; P<0.05) with comparable rates of major complications (20.0% versus 20.7%, odds ratio, 0.96 [0.23-3.95]; P=0.95). Incidence of DCI-related infarction (45.0% versus 41.1%, odds ratio, 1.16 [0.37-3.66]; P=0.80) and favorable clinical outcome (55.6% versus 40.0%, odds ratio, 1.88 [0.55-6.39]; P=0.32) were similar. Brain tissue oxygenation was significantly higher with IANonly (26.6±12.8, 39.6±15.4 mm Hg; P<0.01). CONCLUSIONS: Assuming the potential of iHTN to be exhausted in case of refractory hypoperfusion, additional IAN may serve as a last-resort measure to bridge hypoperfusion in the DCI phase. With close monitoring, preemptive lowering of pressure target after induction of IAN may be a safe alternative to alleviate total noradrenaline load and potentially reduce complication rate.

Hemodynamic response and clinical outcome following intravenous milrinone plus norepinephrine-based hyperdynamic hypertensive therapy in patients suffering secondary cerebral ischemia after aneurysmal subarachnoid hemorrhage.

PURPOSE: Intravenous and intra-arterial milrinone as a rescue measure for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has been adopted by several groups, but so far, evidence for the clinical benefit is unclear and effect on brain perfusion is unknown. The aim of the actual analysis was to define cerebral hemodynamic effects and outcome of intravenous milrinone plus norepinephrine supplemented by intra-arterial nimodipine as a rescue strategy for DCI following aneurysmal SAH. METHODS: Of 176 patients with aneurysmal SAH treated at our neurosurgical department between April 2016 and March 2021, 98 suffered from DCI and were submitted to rescue therapy. For the current analysis, characteristics of these patients and clinical response to rescue therapy were correlated with hemodynamic parameters, as assessed by CT angiography (CTA) and perfusion CT. Time to peak (TTP) delay in the ischemic focus and the volume with a TTP delay of more than 4 s (T4 volume) were used as hemodynamic parameters. RESULTS: The median delay to neurological deterioration following SAH was 5 days. Perfusion CT at that time showed median T4 volumes of 40 cc and mean focal TTP delays of 2.5 ± 2.1 s in these patients. Following rescue therapy, median T4 volume decreased to 10 cc and mean focal TTP delay to 1.7 ± 1.9 s. Seventeen patients (17% of patients with DCI) underwent additional intra-arterial spasmolysis using nimodipine. Visible resolution of macroscopic vasospasm on CTA was observed in 43% patients with DCI and verified vasospasm on CTA, including those managed with additional intra-arterial spasmolysis. Initial WFNS grade, occurrence of secondary infarction, ischemic volumes and TTP delays at the time of decline, the time to clinical decline, and the necessity for additional intra-arterial spasmolysis were identified as the most important features determining neurological outcome at 6 months. CONCLUSION: The current analysis shows that cerebral perfusion in the setting of secondary cerebral ischemia following SAH is measurably improved by milrinone and norepinephrine-based hyperdynamic therapy. A long-term clinical benefit by the addition of milrinone appears likely. Separation of the direct effect of milrinone from the effect of induced hypertension is not possible based on the present dataset.

Comparison of norepinephrine, dopamine and dobutamine combined with enteral nutrition in the treatment of elderly patients harboring sepsis.

The present study was performed in order to investigate the safety and efficacy of different vasoactive drugs combined with enteral nutrition in terms of treating elderly patients with sepsis. A total of 75 elderly patients with sepsis treated with enteral nutrition in our hospital were randomly divided into three groups: group A (n = 25), group B (n = 25) and group C (n = 25). The three groups were treated with dopamine, dobutamine and norepinephrine respectively. One week after treatment, the therapeutic effects of the three groups were compared, the vascular elastic indexes, hemodynamic indexes and levels of inflammatory factors of the three groups were measured. After treatment, the clinical effective rate of group C was evidently higher than that of group A and group B. The vascular elasticity coefficient and stiffness coefficient in group C were significantly lower than those in group A and group B, and the arterial compliance in group C was significantly higher than that in group A and group B (P < 0.05). The levels of MAP and PVRI in group C were significantly higher than those in group A and B, and the levels of CI, CVP and HR in group C were significantly lower than those in group A and group B (P < 0.05). Norepinephrine elicited greater effects in terms of improving hemodynamic indexes, vascular elasticity and reducing the level of inflammatory factors compared with dopamine and dobutamine in elderly patients harboring sepsis.

Differences in effect of early enteral nutrition on mortality among ventilated adults with shock requiring low-, medium-, and high-dose noradrenaline: A propensity-matched analysis.

BACKGROUND & AIMS: Despite extensive research on early enteral nutrition (EEN), it remains unclear whether EEN is effective for patients with shock requiring vasopressors. This study aimed to compare outcomes between EEN and late enteral nutrition (LEN) in ventilated patients with shock requiring low-, medium-, or high-dose noradrenaline. METHODS: Using a national inpatient database in Japan, we identified ventilated patients admitted to intensive care units who had shock requiring catecholamines (noradrenaline or dobutamine) from July 2010 to March 2016. We defined patients who started enteral nutrition within 2 days after starting mechanical ventilation as EEN group and the others as LEN group. Propensity score matching was performed between patients undergoing EEN and LEN in each of the low- (<0.1 µg/kg/min), medium- (0.1-0.3 µg/kg/min), and high-dose (≥0.3 µg/kg/min) noradrenaline groups. RESULTS: We identified 52,563 eligible patients during the 69-month study period, including 38,488, 11,042, and 3033 patients in the low-, medium-, and high-dose noradrenaline groups, respectively. One-to-two propensity score matching created 5,969, 2,162, and 477 one-to-two matched pairs in the low-, medium-, and high-dose noradrenaline groups, respectively. The 28-day mortality rate was significantly lower in the EEN than LEN group in the low-dose noradrenaline group (risk difference, -2.9%; 95% confidence interval [CI], -4.5% to -1.3%) and in the medium-dose noradrenaline group (risk difference, -6.8%; 95% CI, -9.6% to -4.0%). In the high-dose noradrenaline group, 28-day mortality did not differ significantly between the EEN and LEN groups (absolute risk difference, -1.4%; 95% CI, -7.4%-4.7%). CONCLUSIONS: Although the size of the subgroup requiring high-dose noradrenaline may have been too small to demonstrate a significant difference, the results suggest that EEN was associated with a reduction in mortality in ventilated adults treated with low- or medium-dose noradrenaline but not in those requiring high-dose noradrenaline.

Dexmedetomidine reduces norepinephrine requirements and preserves renal oxygenation and function in ovine septic acute kidney injury.

Norepinephrine exacerbates renal medullary hypoxia in experimental septic acute kidney injury. Here we examined whether dexmedetomidine, an α2-adrenergic agonist, can restore vasopressor responsiveness, decrease the requirement for norepinephrine and attenuate medullary hypoxia in ovine gram-negative sepsis. Sheep were instrumented with pulmonary and renal artery flow probes, and laser Doppler and oxygen-sensing probes in the renal cortex and medulla. Conscious sheep received an infusion of live Escherichia coli for 30 hours. Eight sheep in each group were randomized to receive norepinephrine, norepinephrine with dexmedetomidine, dexmedetomidine alone or saline vehicle, from 24-30 hours of sepsis. Sepsis significantly reduced the average mean arterial pressure (84 to 67 mmHg), average renal medullary perfusion (1250 to 730 perfusion units), average medullary tissue pO2 (40 to 21 mmHg) and creatinine clearance (2.50 to 0.78 mL/Kg/min). Norepinephrine restored baseline mean arterial pressure (to 83 mmHg) but worsened medullary hypoperfusion (to 330 perfusion units) and medullary hypoxia (to 9 mmHg). Dexmedetomidine (0.5 µg/kg/h) co-administration significantly reduced the norepinephrine dose (0.8 to 0.4 µg/kg/min) required to restore baseline mean arterial pressure, attenuated medullary hypoperfusion (to 606 perfusion units), decreased medullary tissue hypoxia (to 29 mmHg), and progressively increased creatinine clearance (to 1.8 mL/Kg/min). Compared with vehicle time-control, dexmedetomidine given alone significantly prevented the temporal reduction in mean arterial pressure, but had no significant effects on medullary perfusion and oxygenation or creatinine clearance. Thus, in experimental septic acute kidney injury, dexmedetomidine reduced norepinephrine requirements, attenuated its adverse effects on the renal medulla, and maintained renal function.

Pharmacologic Agents for the Treatment of Vasodilatory Shock.

Vasodilatory shock is a life-threatening syndrome in critically ill patients and is characterized by severe hypotension and resultant tissue hypoperfusion. This shock state requires the use of vasopressor agents to restore adequate vascular tone. Norepinephrine is still recommended as first-line vasopressor in the management of critically ill patients suffering from severe vasodilation. In the recent time, catecholaminergic vasopressor drugs have been associated with possible side effects at higher dosages. This so-called catecholamine toxicity has focused on alternative noncatecholaminergic vasopressors or the use of moderate doses of multiple vasopressors with complementary mechanisms of action. Besides vasopressin and terlipressin, angiotensin II may be a promising drug for the management of vasodilatory shock. In addition, adjunctive drugs, such as hydrocortisone, methylene blue or ascorbic acid can be added to conventional vasopressor therapy. The objective of this review is to give an overview of the current available vasopressor agents used in vasodilatory shock. A thorough search of PubMed was conducted in order to identify the majority of studies related to the subject. Data on the outcome of several drugs and future perspective of possible management strategies for the therapy of vasodilatory shock are discussed.

Differences in the response to periarterial nerve stimulation or exogenous noradrenaline infusion in the mesenteric vascular bed with the intestinal tract harvested from commonly used rat models of hypertension.

Many hypertensive animal models have been developed and used to elucidate the pathophysiology of hypertension and to develop antihypertensive drugs. Among them, the spontaneous hypertensive rat (SHR), deoxycorticosterone acetate (DOCA)-treated and high salt intake rat (DOCA-salt), and high sodium-fed Dahl salt-sensitive rat (HS) models are commonly used. Multiple studies have been conducted, however, elevation in blood pressure in these models due to the reactivity of adrenergic vasoconstriction has not been well characterized in a centralized experiment. In this study, the pressor responses to periarterial nerve stimulation (PNS) or exogenous noradrenaline (NA) infusion were measured in the isolated mesenteric vascular bed with the intestinal tract to investigate the reactivity of mesenteric adrenergic vasoconstriction. The systemic arterial blood pressure of the hypertensive rat models was uniformly elevated compared with their respective controls. However, the changes in perfusion pressure in the mesenteric vascular bed in response to PNS and exogenous NA infusion were quite different depending on the model. The pressor responses to PNS in SHRs and Dahl S HS rats were significantly higher, and those in DOCA-salt rats were significantly lower than those in the controls. The pressor responses to exogenous NA infusion in SHRs were significantly higher, and those in Dahl S HS rats were significantly lower than those in their respective controls. No difference was observed in the pressor responses to the exogenous NA between the DOCA-salt and sham groups. These results demonstrate that the reactivity of adrenergic vasoconstriction is different for each type of experimental hypertensive model rat.

Successful treatment of repeated hematemesis secondary to postsclerotherapy esophageal ulcer in a cirrhotic patient: A case report.

Esophageal variceal bleeding is a common lethal complication of cirrhosis. Endoscopic injection sclerotherapy (EIS) is one of the major endoscopic approaches for treating esophageal variceal bleeding. However, complications may occur after EIS, which mainly include retrosternal discomfort/pain, dysphagia, re-bleeding, esophageal ulcer, esophageal strictures, and esophageal perforation, etc. In this article, we reported a 36-year-old male who developed esophageal ulcer related bleeding after EIS. Currently, there is no consensus on the treatment strategy for esophageal ulcer-related bleeding after EIS. In the present case, the following treatment strategy may be effective for ulcer related bleeding. The first step is to inhibit gastric acid secretion and reduce portal pressure by intravenous infusion of esomeprazole and somatostatin, respectively. The second is local hemostasis by oral norepinephrine and lyophilizing thrombin powder. The third is to protect digestive tract mucosa by oral Kangfuxin Ye and aluminum phosphate.

Vitamin C for Vasoplegia After Cardiopulmonary Bypass: A Case Series.

Cardiac vasoplegia remains a significant contributor of morbidity and mortality in cardiac surgery patients after cardiopulmonary bypass. Effective therapeutic options for vasopressor-refractory vasoplegia are limited. We report 3 patients in whom we administered high-dose intravenous ascorbic acid (vitamin C), a cofactor for endogenous catecholamine synthesis, to treat vasoplegia refractory to epinephrine, vasopressin, and norepinephrine after surgery requiring cardiopulmonary bypass. Reductions in vasopressor requirements were observed in all 3 patients, and, in 2 patients, norepinephrine was completely discontinued within 24 hours. Ascorbic acid is a novel potential therapeutic option for cardiac vasoplegia that warrants rigorous prospective studies.

Bizarre and scary ECG in yew leaves poisoning: Report of successful treatment.

Yew leaves poisoning is a rare life-threatening intoxication, whose diagnosis can be difficult. Initial symptoms are nausea, vomiting, abdominal pain, dizziness, tachycardia, muscle weakness, confusion, beginning within 1 hr from ingestion and followed by bradycardia, ventricular arrhythmias, ventricular fibrillation, severe hypotension, and death. Taxine-derived alkaloids are responsible for the toxicity of the yew leaves, blocking sodium and calcium channels, and causing conduction abnormalities. Because of lack of a specific antidote and limited efficacy of common antiarrhythmic drugs, prompt diagnosis, detoxification measures, and immediate hemodynamic support (also with transvenous cardiac stimulation) are essential.

Isolated limb perfusion with cytostatic drug leakage. / Perfusión aislada de extremidad inferior con fuga de quimioterapéutico.

Isolated limb perfusion is the treatment of stage III melanoma with in-transit metastasis. This technique allows the administration of cytostatics at an effective concentration and temperature, which could not be administered systemically because of their toxicity. The toxicity due to leakage of the chemotherapy agent from the limb into the systemic circulation is the most serious short-term complication, and is manifested by a systemic inflammatory response syndrome in the immediate post-intervention period. Early detection of this complication and its peri-operative management requires a multidisciplinary approach, in which the anaesthesiologist plays a key role. A case of isolated lower limb perfusion is reported in which the procedure had to be interrupted due to the passage of tumour necrosis factor into the systemic circulation, with severe intra-operative haemodynamic repercussions.

Haemodynamic changes during hyperthermic intra-thoracic chemotherapy for pseudomyxoma peritonei.

PURPOSE: Hyperthermic intra-thoracic chemotherapy (HITOC) combined with cytoreductive surgery (CRS) is a novel approach in the management of pseuodmyxoma peritonei with thoracic extension. The haemodynamic effects of hyperthermic chemotherapy present an anaesthetic challenge. Here, we describe the haemodynamic changes seen during HITOC. MATERIALS AND METHODS: A retrospective case note review of adult patients undergoing CRS with HITOC from 2009 to 2016. Intra-operative haemodynamics were measured using the LIDCOrapidTM brand of invasive cardiac output (CO) monitor. Intravenous fluids, vasopressor requirements and urine output (UO) were recorded. RESULTS: Four patients were included in the study. Mean heart rate (HR) peaked at 20 min following commencement of HITOC. The difference between HR at time 0 and at peak was minimal. There was minimal change in CO, and stroke volume variation (SVV) remained stable. Vasopressor dose was minimally changed throughout surgery. Average UO during HITOC was 142.5 ± 109.6 mls at 60 min. Mean fluid requirements during HITOC was 586.2 ± 441.2 mls. No significant change occurred in pH or base excess (BE). CONCLUSIONS: Significant haemodynamic instability including cardiac asystole has been reported during HITOC. The application of hyperthermic agents to the thorax results in vasodilatation, cardiac warming and compression of mediastinal vessels. Measurement of haemodynamic variables allowed careful titration of intravenous fluid therapy to CO and stroke volume, allowing for haemodynamic stability. This has not been described elsewhere.

Early treatment with intravenous lipid emulsion in a potentially lethal hydroxychloroquine intoxication.

This case report describes the possible benefit of intravenous lipid emulsion in two patients surviving a severe intoxication with hydroxychloroquine in a dose that was previously considered to be lethal. The first case involves a 25-year-old female who ingested 17.5 grams of hydroxychloroquine, approximately one hour before presentation. An ECG showed QRS widening and the lab results showed hypokalaemia. She became unconscious, and developed hypotension and eventually apnoea. After intubation, supportive care consisted of norepinephrine and supplementation of potassium. Moreover, sodium bicarbonate and intravenous lipid emulsion were started to prevent cardiac toxicity. After these interventions, haemodynamic stability was established within a few hours. Although cardiomyopathy was confirmed, the patient recovered after two weeks. The second case concerns a 25-year-old male who took 5 grams of hydroxychloroquine. At presentation, two hours after intake, he showed QTc prolongation and hypokalaemia. The patient was treated with the usual supportive care and, although presentation to hospital was later, with intravenous lipid emulsion. Also this patient recovered. In conclusion, these cases show the benefit of supplemental intravenous lipid emulsion to prevent cardiac toxicity after a severe intoxication with hydroxychloroquine.

Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock?

Severe systemic inflammatory response to infection results in severe sepsis and septic shock, which are the leading causes of death in critically ill patients. Septic shock is characterised by refractory hypotension and is typically managed by fluid resuscitation and administration of catecholamine vasopressors such as norepinephrine. Vasopressin can also be administered to raise mean arterial pressure or decrease the norepinephrine dose. Endogenous norepinephrine and vasopressin are synthesised by the copper-containing enzymes dopamine ß-hydroxylase and peptidylglycine α-amidating monooxygenase, respectively. Both of these enzymes require ascorbate as a cofactor for optimal activity. Patients with severe sepsis present with hypovitaminosis C, and pre-clinical and clinical studies have indicated that administration of high-dose ascorbate decreases the levels of pro-inflammatory biomarkers, attenuates organ dysfunction and improves haemodynamic parameters. It is conceivable that administration of ascorbate to septic patients with hypovitaminosis C could improve endogenous vasopressor synthesis and thus ameliorate the requirement for exogenously administered vasopressors. Ascorbate-dependent vasopressor synthesis represents a currently underexplored biochemical mechanism by which ascorbate could act as an adjuvant therapy for severe sepsis and septic shock.

Complex regional pain syndrome: diagnosis and treatment.

This article discusses the diagnostic criteria, clinical course, and complications of complex regional pain syndrome. Multidisciplinary treatment including physical and occupational therapy, psychological evaluation and treatment, pharmacologic management, and more aggressive options including sympathetic blocks, sympathectomy, and spinal cord stimulation are also reviewed.

Small doses of arginine vasopressin in combination with norepinephrine "buy" time for definitive treatment for uncontrolled hemorrhagic shock in rats.

Implementation of fluid resuscitation and blood transfusion are greatly limited in prehospital or evacuation settings after severe trauma or war wounds. With uncontrolled hemorrhagic shock rats, we investigated if arginine vasopressin (AVP) in combination with norepinephrine (NE) is independent (or slightly dependent) of fluid resuscitation and can "buy" time for the subsequently definitive treatment of traumatic hemorrhagic shock in the present study. The results showed that AVP (0.4 U/kg) alone or with NE (3 µg/kg) with one-eighth and one-fourth volumes of total blood volume of lactated Ringer's infusion significantly increased and maintained the mean arterial pressure. Among all groups, 0.4 U/kg of AVP + NE (3 µg/kg) with one-eighth volume of lactated Ringer's infusion had the best effect: it significantly increased and maintained hemodynamics and prolonged the survival time. This early treatment strategy significantly improved the effects of subsequently definitive treatments (after bleeding controlled): it increased the subsequent survival, improved the hemodynamic parameters, improved the cardiac function, and increased the tissue blood flow and oxygen delivery. These results suggested that early application of small doses of AVP (0.4 U/kg) + NE before bleeding control can "buy" time for the definitive treatment of uncontrolled hemorrhagic shock, which may be an effective measure for the early treatment of traumatic hemorrhagic shock.