Long-term Intravenous Infusion Research Articles

Comparison of complications and indwelling time in midline catheters versus central venous catheters: A systematic review and meta-analysis.

Central venous catheters and midline catheters are commonly used as medium- to long-term intravenous infusion tools in clinical nursing. However, there is currently no reliable conclusion on whether there are differences in complications and indwelling time between these two types of catheters. To investigate whether there are differences in the incidence of complications and indwelling time between the use of midline catheters and central venous catheters as intravenous infusion tools. A systematic search was conducted across various databases including Web of Science, PubMed, Embase, Cochrane Library, CINAHL, Wanfang and China National Knowledge Infrastructure. The selection of studies and assessment of their quality was carried out independently by two reviewers. Meta-analysis was conducted using the RevMan 5.3 software. Heterogeneity was evaluated, one of the pooled analyses was performed using the random-effect model, while the others used the fixed-effect model. Mean differences or odds ratios with corresponding 95% confidence intervals were calculated. Ten studies (1,554 participants) met the inclusion criteria. Meta-analysis showed that there was a statistically significant difference in the complication rates [OR = 0.36, 95% CI (0.18, 0.70), p = 0.003], incidence of catheter-related thrombosis [OR = 0.28, 95% CI (0.11, 0.71), I2= 0%,p = 0.007], catheter-related infection[OR = 0.36, 95% CI (0.16, 0.78), I2= 27%, p = 0.007] and catheter blockage [OR = 0.21, 95% CI (0.09, 0.51), I2= 18%, p = 0.0005] between midline catheters group and central venous catheters group. There was a statistically significant difference in the catheter indwelling time between the two groups [MD = 0.9, 95% CI (0.33, 1.46), I2= 0%, p = 0.002]. There was no significant difference in other complications such as phlebitis, catheter dislodgement and leakage between the two groups. Midline catheter was superior to central venous catheter in terms of the overall complication rates and incidence of catheter-related thrombosis, catheter blockage, catheter-related infection and indwelling time.

In vivo intranasal delivery of coagulation factor IX: a proof-of-concept study

BackgroundHemophilia B (HB) is a bleeding disorder characterized by coagulation factor (F) IX (FIX) deficiency. The current standard-of-care for severe HB is prophylaxis with long-term repetitive intravenous (i.v.) infusions of recombinant FIX (rFIX) with standard half-life or extended half-life. Unmet needs remain regarding the development of non-invasive administration routes for coagulation factors. The aim of this study was to evaluate the effectiveness of intranasal delivery (IND) of rFIX and rFIX fused to Fc fragment (rFIX-Fc) in mice. MethodsDrops of rFIX and rFIX-Fc were deposited in the nostrils of wild-type, FcRn knock-out, FcRn humanized, and FIX knock-out mice. rFIX mucosal uptake was evaluated by measuring plasma FIX antigen and FIX activity (FIX:C) levels, and by performing histologic analysis of the nasal mucosa following IND. ResultsAfter IND, both rFIX and rFIX-Fc were equally delivered to the blood compartment, irrespective of the mouse strain studied, mostly through a passive mechanism of transportation across the mucosal barrier, independent of FcRn receptor. Both plasma FIX antigen and FIX:C activity levels increased following IND in FIX knock-out mice. ConclusionThis proof-of-concept study describes evidence supporting the nasal route as an alternative to FIX i.v. infusion for the treatment of HB.

Pharmacokinetics of dalteparin and nadroparin for thromboses in children with oncological diseases

Objective: evaluate the pharmacokinetics and pharmacodynamics of nadroparin and dalteparin in thrombosis that occurred in children with malignant neoplasms. Materials and methods: The results of 52 pharmacokinetic studies involving 34 patients with oncological diseases, whose treatment was complicated by venous thrombosis, were analyzed. The median age of patients was 14.5 (7–18) years. Depending on the daily dose and the type of heparin administered, the results of pharmacokinetic studies were divided into 6 groups. Dalteparin sodium: against the background of chemo-induced thrombocytopenia, subcutaneous administration of dalteparin at a dose of 51.0 (40.0–72.0) anti-Xa IU/kg every 12 hours – 6 observations; subcutaneous injection every 12 hours at a dose of 100.5 (91.0–141.0) anti-Xa IU/kg – 18 observations; long-term continuous intravenous infusion at a constant rate at a daily dose of 201.0 (180.0–265.0) anti-Xa IU/kg - 6 observations. Nadroparin calcium: 62.0 (53.0-71.0) anti-Xa IU/kg every 12 hours - 6 observations; 93.5 (80.0–117.0) anti-Xa IU/kg every 12 hours – 10 observations; subcutaneous injection at a dose of 203.0 (170.0–236.0) anti-Xa IU/kg once a day - 6 observations. Results: We confirmed that in the acute period of thrombosis in children, the most optimal way to administer low molecular weight heparin is intravenous infusion of dalteparin sodium at a constant rate. Subcutaneous injection of 50% of the daily dose of LMWH at intervals of 12 hours is preferable to a single injection of 100% of the daily dose every 24 hours. There were no significant advantages of nadroparin compared with dalteparin when using anticoagulants in comparable doses in case of venous thrombosis, which complicated the treatment of children with malignant neoplasms. Conclusion: Control over the adequacy of the dose of LMWH can be performed at any stage of treatment. The specific anti-Xa activity of nadroparin and dalteparin needs to be checked before the next subcutaneous injection and between 3 and 4 hours after administration. An increase in chronometric indicators of blood coagulation indirectly reflects the presence of an anticoagulant in the blood, but does not allow an objective assessment of the achievement of a therapeutic effect.

The Right Time for Certification

The Right Time for Certification

Peculiarities of Periodontal Pocket Microbiome in Patients with Generalized Periodontitis in the Post-COVID Period

The oral cavity, like the lungs, is often referred to as the «ecological niche of commensal, symbiotic, and pathogenic organisms», and the emigration and elimination of microbes between them are constant, ensuring a healthy distribution of saprophytic microorganisms that maintains organ, tissue, and immune homeostasis. The prolonged hospital stays due to COVID-19 complications, cross-infection, oxygenation therapy through the mask or incubation, and long-term intravenous infusions limit the patient’s ability to care about the oral cavity, regularly clean teeth, floss interdental, etc., which creates extremely favorable conditions for colonization by aerobic and anaerobic pathogens of the oral cavity and periodontal pockets and leads to the rapid progression of chronic generalized periodontitis in this category of patients in the future. The goal of the study was to assess the state of the microbiome of the periodontal pockets of dental patients in the post-covid period. Methods. The object of the study was 140 patients with generalized periodontitis of the I and II stages of development in the chronic course (GP), among which 80 patients had coronavirus disease in the closest past. The patients were randomized by age, sex, and stage of GP development. The diagnosis of periodontal disease was established according to the classifi cation by Danilevskyi. The bacteriological material for aerobic and facultative anaerobic microflora and yeast-like fungi was collected from periodontal pockets with a calibrated bacteriological loop and immediately seeded on blood agar. Results. Significant qualitative and quantitative changes in the nature of the oral microbiocenosis were observed in patients with GP after the recent coronavirus disease, compared with similar patients who did not suffer from COVID-19. We have noticed almost complete disappearance of bacteria that belong to the transient representatives of the oral microflora such as Neisseria, corynebacteria (diphtheria), micrococci, and lactobacilli. The main resident representatives of the oral microflora, i.e., α-hemolytic Streptococci of the mitis group, were found in all healthy individuals and patients of groups A and C, but in 30.0±4.58% of patients in group B, α-hemolytic streptococci in the contents of periodontal pockets are present in quantities not available for detection by the applied method (<2.7 lg CCU/mL). In terms of species, Streptococcus oralis and Streptococcus salivarius are more characteristic in gingival crevicular fluid in healthy individuals (93.8% of selected strains). In 68.4±3.32% of patients in group A, 64.0±3.43% of patients in group B, and 67.5±3.76% of patients in group C, the dominant species were Streptococcus gordonii and Streptococcus sanguinis (p<0.01), which increased pathogenic potential as they produce streptolysin-O, inhibit complement activation, bind to fibronectine, actively form biofilms on the surface of tooth enamel and gum epithelial surface, and can act as an initiator of adhesion of periodontal pathogens. The other representatives of the resident microflora of the oral cavity — Stomatococcus mucilaginosus and Veillonella parvula for the patients of group C are also found in periodontal pockets with a signifi cantly lower index of persistence and minimal population level. In the post-covid period, both the population level and the frequency of colonization of periodontal pockets by Staphylococci and β-hemolytic Streptococci decreases rapidly. For these patient groups, unlike for those that did not suff er from COVID-19, we did not find any case of colonization with Staphylococcus aureus, as well as β-hemolytic Streptococci and epidermal Staphylococcus were also absent. The most characteristic in the post-covid period is a decrease in the proportion of α-hemolytic Streptococci, an increase in the proportion of yeast-like fungi of Candida species, as well as the appearance of a significant number of gram-negative rod-shaped bacteria (Enterobacteria and Pseudomonads). In periodontal patients, the microbial count is approximately 2 orders of magnitude lower than in those with GP who did not suffer from COVID-19 (p<0.05). Conclusions. The overpassed coronavirus disease due to intensive antibiotic therapy leads to a marked decrease in the number of viable saprophytic microorganisms in the periodontal pockets of patients with GP. In the post-covid period for the patients with GP, there is a decrease in the level of colonization of periodontal pockets by species of resident oral microflora — α-hemolytic Streptococci, reduction of resident microorganism’s species, and almost complete disappearance of transient microfl ora. On the other hand, the frequency of colonization of periodontal pockets by fungi species, enterobacteria, and pseudomonads significantly increases. There are more expressed disorders in the periodontal pocket’s microbiome for the patients with a severe and complicated course of coronavirus disease, such as post-covid pulmonary fibrosis, which requires reconsideration of approaches to therapeutic and pharmacological treatment in this category of patients.

Risk Factors of Catheter-Related Infection in Unplanned Extubation of Totally Implantable Venous-Accessportsin Tumor Patients.

Background Totally implantable intravenous ports (TIVAPs) are mostly used for long-term intravenous infusion therapy in cancer patients and can be left in the body for long periods of time for easy management, making them a simple and safe infusion device. Although the risks associated with long-term retention of fully implantable IV ports are less than those associated with other intravenous catheters, various complications may still occur at the time of implantation or during long-term use. Purpose To provide a scientific basis for clinical reduction of implantable intravenous port-associated infection complications by studying the risk factors for catheter-associated infection complications in patients applying implantable intravenous ports. Methods A retrospective study was conducted on oncology patients treated with TIVAP at our hospital between January 2017 and November 2021, with a review of patients who were unplanned for extubation. Their demographic data, underlying disease status, and surgery-related data were counted to summarize and analyze the complications and related influencing factors of implantation and postimplantation. Results A total of 70 individuals with a mean age of 56.49 ± 12.19 years were included in the study. Among them, 39 were male and 64 had the highest percentage of epithelial tumors, followed by tumors of the lymphopoiesis system and mesenchymal tumors with 4 and 2 cases, respectively. Forty-eight of these patients did not have their ports removed as planned due to the occurrence of catheter-related hematogenous infections. In univariate analysis, BMI and neutropenia were risk factors for catheter-associated infections. In the multivariate analysis, BMI (OR = 1.38, 95% CI: 1.07–1.78, p=0.013) was an independent risk factor for catheter-associated infections. Conclusions The overall complication rate of fully implanted intravenous ports was high, but most complications improved with symptomatic management, and no deaths due to port complications were identified. Infection was the most common complication, with catheter-associated bloodstream infection being the most common cause of unplanned port extraction. Patients with a higher BMI were at high risk of developing implantable IV port-associated infections, which may be an independent risk factor for implantable IV port-associated infections.

Evaluation of the in vitro Activity and in vivo Efficacy of Anidulafungin-Loaded Human Serum Albumin Nanoparticles Against Candida albicans.

Recent decades have seen a significant increase in invasive fungal infections, resulting in unacceptably high mortality rates. Anidulafungin (AN) is the newest echinocandin and appears to have several advantages over existing antifungals. However, its poor water solubility and burdensome route of administration (i.e., repeated, long-term intravenous infusions) have limited its practical use. The objective of this study was to develop anidulafungin-loaded Human Serum Albumin (HSA) nanoparticles (NP) so as to increase both its solubility and antifungal efficacy. HSA was reduced using SDS and DTT, allowing liberation of free thiols to form the intermolecular disulfide network and nanoassembly. Reduced HSA was then added to MES buffer (0.1 M, pH 4.8) and magnetically stirred at 350 rpm and 25°C with AN (m/m 50:1) for 2 h to form nanoparticles (AN NP). We next performed routine antifungal susceptibility testing of Candida strains (n = 31) using Clinical and Laboratory Standards Institute (CLSI) methodologies. Finally, the in vivo efficacy of both AN and AN NP was investigated in a murine model of invasive infection by one of the most common fungal species—C. albicans. The results indicated that our carrier formulations successfully improved the water solubility of AN and encapsulated AN, with the latter having a particle size of 29 ± 1.5 nm with Polymer dispersity index (PDI) equaling 0.173 ± 0.039. In vitro AN NP testing revealed a stronger effect against Candida species (n = 31), with Minimum Inhibitory Concentration (MIC) values 4- to 32-fold lower than AN alone. In mice infected with Candida and having invasive candidiasis, we found that AN NP prolonged survival time (P < 0.005) and reduced fungal burden in kidneys compared to equivalent concentrations of free drug (P < 0.0001). In conclusion, the anidulafungin nanoparticles developed here have the potential to improve drug administration and therapeutic outcomes for individuals suffering from fungal diseases.

A prospective, randomized study assessing different modalities for flushing totally implanted vascular access device in children with malignancy.

The totally implanted vascular access device (TIVAD) is commonly used in patients with malignant tumors requiring chemotherapy or long-term intravenous infusion and those with difficulty placing peripheral venous catheters. It could also be used to draw blood in pediatric patients. Thus, how to maintain the patency and longevity of TIVAD is always emphasized. In this prospective study, TIVAD was randomly infused in patients under 18 years with three different concentrations of heparinized solutions: 10 mL with 100 U/mL heparin, 20 mL with 10 U/mL heparin, and 30 mL with 10 U/mL heparin. A total of 81 patients (46 males and 35 females) were enrolled in this study from August 2, 2013 to February 1, 2017. The mean age of those who received TIVAD implantation was 7.2 ± 5.3 years, and the mean duration of using TIVAD was 1027.6 ± 369.1 days. Patients without catheter occlusion events experienced significantly shorter hospitalizations, fewer admissions, and fewer punctures than those with catheter occlusion events (p < 0.05). The administration and frequency of blood transfusions, history of bacteremia, and medication history did not increase the risk of catheter occlusion, but puncture frequency increased this risk. In patients with catheter occlusion events (38/81, 46.9%), catheter patency was restored after instillation of urokinase solution. In this study, the risk of TIVAD catheter occlusion was only related to puncture frequency regardless of the heparin flush composition or patient characteristics. A high puncture frequency of TIVAD during the 3.5-year study period significantly increased the risk of catheter occlusion. Besides, flushing and locking solutions for TIVAD using heparin at 10 U/mL was effective as using heparin at 100 U/mL regardless of the flushing volume of 10, 20, or 30 mL.

Analysis on P Wave Morphology for PICC Placement Guided by Intracardiacelectrogram in Chinese Elderly Patients

Objective: PICC can effectively protect upper extremity veins. It can reduce repetitive puncture and the incidence of phlebitis, relieve the pain, and improve the quality of life for those with long-term intravenous infusion, repeated infusion of stimulant drugs and blood products, and poor peripheral superficial vein conditions etc.. Successful PICC tip positioning can effectively avoid catheter-related complications during clinical care. If the catheter tip is misplaced, it may cause malfunction and related complications, such as venous thrombosis, bacteremia, arrhythmia, and heart valve injury etc. To investigate the correlation and clinical significance of monitoring P-wave characteristics, especially the occurrence of double peaks for precise tip positioning of peripherally inserted central catheter (PICC) guided by intracardiacelectrogram (IEGM). Methods: Enrolled 116 PICC patients (age≥60, no heart diseases) in our hospital. Conducted retrospective analysis on patients’ medical records, PICC catheterization data, IEGM-guided positioning records and nursing records. Observed and recorded patients’ P-wave changes (peaked P wave, bi-directional P wave and double-peaked P wave) at different catheter tip positions by real-time IEGM, and then analyzed the case number and positioning accuracy. Used chest X-ray to determine whether the catheter tip had reached the ideal position, the tracheal carina to the cavo-atrial junction (CAJ). Results: Among 116 patients (63 males, 53 females), bidirectional P waves were detected in 112 of them (96.55%) in ECG Lead II; 63 with peaked P waves (53.3%); 49 with double-peaked P waves but no peaked P waves (42.2%), meaning bidirectional P waves were seen when fed in the catheter and returned to double peaks when the catheter was withdrawn; 4 with no significant changes (3.4%). Chest X-ray proved that 49 of 49 cases with double-peaked P waves reached the ideal catheterization position (100% in accuracy), and 43 of 69 cases with peaked P waves succeeded as well (68.2% in accuracy). Conclusions: Double-peaked P waves in IEGM-guided PICC positioning for elderly patients can be considered as an indicator of the catheter tip entering the CAJ and supplementary support of peaked P wave and bidirectional P wave guidance for catheterization.

Perioperative anesthesia

Background. Ensuring adequate analgesia is a prerequisite for rapid recovery after surgery. Improving the management of acute pain is important to ensure the safe and effective analgesia needed for early mobilization and for avoidance of organ dysfunction due to inadequate analgesia. For this purpose, multimodal analgesia (MMA) is used. It includes opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAID), paracetamol or metamizole, local anesthetics and ancillary drugs.&#x0D; Objective. To describe modern views on perioperative analgesia.&#x0D; Materials and methods. Analysis of literature data on this issue.&#x0D; Results and discussion. MMA involves an opioid-preserving approach (reducing the dose of opioids without reducing the quality of analgesia), procedure and patient specificity. The postoperative recovery improvement program includes several items, three of which have been associated with a reduction in treatment duration, namely, multimodal prevention of postoperative nausea and vomiting, perioperative NSAID use, and post-operative opioid protocol. The combined use of NSAID and paracetamol provides a better result than the use of each of these drugs alone. At the correct dose, paracetamol (Infulgan, “Yuria-Pharm”) is an effective non-opioid analgesic for the treatment of acute pain with minimal side effects for a long time. Pre- and intraoperative administration of paracetamol is recommended in a number of guidelines. Intravenous administration of local anesthetics is an another important component of MMA. The 2016 Cochrane review showed that long-term intravenous perioperative infusion of lidocaine significantly reduced the postoperative need for opioids. However, the meta-analysis of 10 randomized controlled trials found that perioperative intravenous lidocaine did not differ from placebo in post-operative pain assessed with the help of a visual analog scale and in opioid requirements (Rollins K.E., 2020). Similar results have been obtained in other studies in recent years. Inclusion of nefopam in MMA can reduce the dose of opioids. The use of nefopam, paracetamol and deksketoprofen makes it possible to dramatically reduce the use of morphine. Neither pain nor postoperative recovery can be adequately controlled with a single treatment due to the multifactorial nature of the problem. It is recommended to use MMA, but there are no recommendations for optimal combinations of analgesics for specific procedures. Administration of paracetamol and NSAID in combination with the use of regional techniques is a golden standard of MMA.&#x0D; Conclusions. 1. After the surgery, the patient should be adequately anesthetized. 2. To achieve optimal, preferably non-opioid, analgesia, it is recommended to use MMA. 3. NSAID, paracetamol, nefopam and regional techniques are the important components of MMA.

Maturation of midazolam clearance in critically ill children with severe bronchiolitis: A population pharmacokinetic analysis

PurposeThe aim of the present study was to develop a population pharmacokinetic model of midazolam, and to evaluate the influence of maturation process and other variability factors in critically ill children with severe acute bronchiolitis, who received a long-term intravenous infusion of midazolam. MethodsIn the study were included 49 critically ill children of both genders (from 0 to 130 weeks of age) with severe acute bronchiolitis hospitalised in intensive care units. Nonlinear mixed effects modelling approach was applied for data analyses and simulations. ResultsThe final model is a two-compartment model that includes the effects of body weight using allometric scaling with fixed exponents and maturation of clearance. For a typical subject, scaled to the adult body weight of 70 kg, population pharmacokinetic values were estimated at 8.52 L/h for clearance (when maturation function was 1), 25.5 L/h for intercompartmental clearance, and 5.71 L and 39.8 L for the volume of the central and peripheral compartment, respectively. Based on the final model, maturation reaches 50% of the adult clearance in 45.9 weeks of postmenstrual age. The influence of gender, ABCB1 genotype and biochemical parameters on midazolam clearance was not detected. Results of simulations indicate the need for reduced dosing in certain groups of patients in order to maintain plasma concentrations of midazolam within recommended values. ConclusionsThe developed population pharmacokinetic model can contribute to the dosing optimisation of midazolam, especially in critically ill children as it includes the influence of size and maturation of clearance, which are important parameters for achieving the desired plasma concentrations of midazolam.

Blinatumomab for the treatment of acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a potentially fatal disease that involves clonal expansion of early lymphoid progenitor cells. Much of drug development for ALL treatment involves targeting antigens of the clonal cell surface. Blinatumomab belongs to an emerging class of anti-cancer therapeutics referred to as bispecific T-cell engaging antibodies. The Food and Drug Administration approved its use in relapsed or refractory adult Philadelphia chromosome-negative B-cell precursor ALL in December of 2014. Blinatumomab contains both an anti-CD3 and anti-CD19 arm, allowing for the juxtaposition of CD3+ T-cells to malignant CD19+ B-cells, thereby resulting in granzyme- and perforin-mediated B-cell apoptosis. Preclinical studies suggest that blinatumomab's efficacy is related to the effector-to-target ratio and to the difference between its affinity for CD19 and CD3. Preclinical and early phase clinical studies have allowed for the characterization of the pharmacokinetics of blinatumomab, including the determination of its short half-life. The metabolic pathway has not been fully characterized but is thought to be similar to that of other antibodies. Phase I and II studies led to the identification of an ideal stepwise dose, involving long-term continuous intravenous infusion (CIVI), to optimize its efficacy and reduce the risk of certain toxicities. A high remission rate and duration were noted among a relapsed/refractory population of patients. The results of clinical trials have identified cytokine release syndrome and neurotoxicity, among others, as serious drug-related toxicities, leading to the institution of a Risk Evaluation and Mitigation Strategy. Blinatumomab represents a significant addition to the treatment options for ALL, but it is not without its limitations, of which are its short-half life, necessitating long-term CIVI, and the eventual emergence of CD19-negative clones. Continual development of the agent involves assessing its role in the frontline setting and in combination with chemotherapy.

Continuous terbutaline infusion in severe asthma in adults: a retrospective study of long-term efficacy and safety

Background: Long-term subcutaneous or intravenous infusion of terbutaline has been used to stabilize asthma in patients enduring frequent hospital admissions due to severe asthma despite maximum therapy. However, this treatment is not supported by significant body of evidence. Aim: To study long-term efficacy and safety of using continuous infusions of terbutaline in unstable severe asthma. Methods: The available medical records of all patients received terbutaline infusions at a severe asthma unit between 1982 and 2008 were retrospectively studied. We retrieved data on treatment indication, asthma subtype, patient demographics, pre-treatment terbutaline trial outcome, duration of treatment, effect on lung function, hospital admissions, oral corticosteroids (OCSs) requirement, safety and side effects. Results: Forty-two patients with adequate medical information were studied (31 females, mean age 43.6 years, 88% had type 1 brittle asthma and 12% had other severe asthma). This group of patients had a mean body mass index of 30.8 kg/m2, mean oral prednisolone or equivalent of 26.6 mg and mean predicted FEV1 of 66.8%. The mean treatment duration was 86.7 months (range 7–216). Long-term continuous terbutaline infusion significantly reduced hospital admissions (mean pre-treatment = 6.7 (95% CI 0.96–12.4) per annum, and mean annualized on-treatment admission = 3.3 (95% CI 0.63–6.9, p = 0.045). We observed overall reduction in OCSs use in 59% of patients with available data, but there was no significant change in lung function. Side effects related to terbutaline or the method of its infusion were common and some were serious especially when central venous access device were used. Conclusion: Continuous terbutaline infusion could be a treatment option for severe unstable asthma and may reduce hospital admissions. However, the treatment was associated with significant side effects and its use should be limited to centers possessing necessary expertise.

The haemophilia certification system in Canada.

Inherited bleeding disorders are caused by the deficiency or dysfunction of plasma proteins required for the development of a physiological hemostatic process1,2. Von Willebrand disease (vWD), haemophilia A and haemophilia B are the most common inherited disorders of hemostasis. In their severe forms, these disorders are life-threatening. However advanced treatment modalities have enabled even severely affected patients to reach the same life expectancy of the general male population at least in high-income countries3,4. Indeed, after the dramatic events of widespread blood-borne virus transmission in the 1970s–1980s in haemophilic patients, leading to a 35-to-40-year reduction in life expectancy in Canadian patients5, there has been a strong drive towards continuous improvement, primarily in the safety of replacement therapy6. There is now a very high degree of safety from risk of blood borne transmission of pathogens as evidenced by the absence of reported transmission of blood-borne viruses in persons with haemophilia since the late 1980s to date7. The safety of current replacement therapies was recently confirmed by a prospective surveillance program ongoing since 2008 and based on regular monitoring of 22,242 European patients (European Haemophilia Safety Surveillance System; www.euhass.org). Regular factor prophylaxis as a therapeutic regimen has been proven effective in preventing haemophilic arthropathy8. Even in the presence of neutralizing antibodies (inhibitors) directed against the deficient clotting factor, particularly in haemophilia A, bleeding can usually be treated successfully using activated variants of coagulation factors9. Moreover, immune tolerance induction (ITI), based on the long-term intravenous infusion of large doses of FVIII, eradicates inhibitors in as many as two-thirds of patients10. Therefore, improving quality of life has become the primary objective of care in developed countries; thus multiple modalities (psychosocial support, physiotherapy, integration into community life, etc), not just the infusion of the deficient factor, are made available to the patient and his family, to allow them to fully experience good health.

Effect of Shorter Term of Intravenous Infusion for Reduction of Catheter-Related Bloodstream Infection After Gastrectomy

After gastrectomy, a longer period of intravenous alimentation is required than for other digestive surgeries, portending a higher risk of catheter-related bloodstream infection (CRBSI). From assessment of CRBSI occurring between 2004 and 2007 (preintervention group), the duration of intravenous infusion between 2008 and 2010 (postintervention group) was changed to shorter-term (6-day) infusion. To verify the effect of changes in injection schedule on the incidence of CRBSI, the occurrence of CRBSI was studied comparatively among preintervention and postintervention cases, excluding cases requiring intravenous infusion preoperatively, and cases requiring long-term intravenous infusion postoperatively due to postoperative complications. The rate of CRBSI in the postintervention group (0%; 0 of 298) was significantly lower than that in the preintervention group (1.7%; 8 of 477; P = 0.026). There was no significant difference between preintervention and postintervention groups in postoperative complications. Six-day infusion decreased the incidence of CRBSI after gastrectomy significantly, without increasing postoperative complications.

Reversal of cerebral vasospasm via intravenous sodium nitrite after subarachnoid hemorrhage in primates

Subarachnoid hemorrhage (SAH)-induced vasospasm is a significant underlying cause of aneurysm rupture-related morbidity and death. While long-term intravenous infusion of sodium nitrite (NaNO(2)) can prevent cerebral vasospasm after SAH, it is not known if the intravenous administration of this compound can reverse established SAH-induced vasospasm. To determine if the intravenous infusion of NaNO(2) can reverse established vasospasm, the authors infused primates with the compound after SAH-induced vasospasm was established. Subarachnoid hemorrhage-induced vasospasm was created in 14 cynomolgus macaques via subarachnoid implantation of a 5-ml blood clot. On Day 7 after clot implantation, animals were randomized to either control (saline infusion, 5 monkeys) or treatment groups (intravenous NaNO(2) infusion at 300 μg/kg/hr for 3 hours [7 monkeys] or 8 hours [2 monkeys]). Arteriographic vessel diameter was blindly analyzed to determine the degree of vasospasm before, during, and after treatment. Nitric oxide metabolites (nitrite, nitrate, and S-nitrosothiols) were measured in whole blood and CSF. Moderate-to-severe vasospasm was present in all animals before treatment (control, 36.2% ± 8.8% [mean ± SD]; treatment, 45.5% ± 12.5%; p = 0.9). While saline infusion did not reduce vasospasm, NaNO(2) infusion significantly reduced the degree of vasospasm (26.9% ± 7.6%; p = 0.008). Reversal of the vasospasm lasted more than 2 hours after cessation of the infusion and could be maintained with a prolonged infusion. Nitrite (peak value, 3.7 ± 2.1 μmol/L), nitrate (18.2 ± 5.3 μmol/L), and S-nitrosothiols (33.4 ± 11.4 nmol/L) increased significantly in whole blood, and nitrite increased significantly in CSF. These findings indicate that the intravenous infusion of NaNO(2) can reverse SAH-induced vasospasm in primates. Further, these findings indicate that a similar treatment paradigm could be useful in reversing cerebral vasospasm after aneurysmal SAH.

Safety and Feasibility of Long-term Intravenous Sodium Nitrite Infusion in Healthy Volunteers

BackgroundInfusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion.MethodologyHealthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate.Twelve subjects (5 males, 7 females; mean age, 38.8±9.2 years (range, 21–56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 µg/kg/hr; maximal dose of 533.8 µg/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed.FindingsThe maximal tolerated dose for intravenous infusion of sodium nitrite was 267 µg/kg/hr. Dose limiting toxicity occurred at 446 µg/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood.ConclusionSodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension.Clinical Trial Registration Information http://www.clinicaltrials.gov; NCT00103025

Ketamine for the treatment of chronic non-cancer pain

Importance of the field: Worldwide the number of patients affected by chronic pain is growing and conventional treatment is often insufficient. Recently the importance of the N-methyl-d-aspartate receptor (NMDAR) in the mechanisms and maintenance of chronic pain was established. Ketamine (introduced in the 1960s as an anesthetic) is the most studied NMDAR antagonist in the treatment of various chronic pain syndromes.Areas covered in this review: The pharmacology, safety and toxicology of ketamine are discussed. Further, electronic databases were scanned for prospective, randomized controlled trials that assessed ketamine's analgesic effect in patients with chronic pain. The focus of this review is on trials published after 2008 that applied long-term intravenous infusions.What the reader will gain: While most studies on intravenous ketamine show acute analgesic effects, three recent trials on long-term ketamine treatment (days to weeks) demonstrate the effectiveness of ketamine in causing long-term (months) relief of chronic pain. Despite these positive results, further studies are needed on safety/toxicity issues. Other administration modes are less effective in causing long-term pain relief.Take home message: There is now evidence form a limited number of studies that pain relief lasting for months is observed after long-term intravenous ketamine infusion, suggesting a modulatory effect of ketamine in the process of chronic pain, possibly via blockade of upregulated NMDAR.

サルを用いたWhole-Body Plethysmography による呼吸・循環器機能測定への静脈内持続投与の導入

サルを用いたWhole-Body Plethysmography による呼吸・循環器機能測定への静脈内持続投与の導入

Prognosis of Pulmonary Arterial Hypertension

The study of rare diseases is limited by just that, their infrequency. Pulmonary arterial hypertension (PAH), for example, has a prevalence of 15 cases per million.1 Although there has been an explosion in knowledge of and therapies for this life-threatening disease over the past decade, most of our insight is based on small studies. The first therapy that was approved by the Food and Drug Administration in 1995, intravenous epoprostenol, was based on the results of an 81-patient trial.2 The most recently approved therapy, inhaled treprostinil, in 2009, was based on the results of a 235-patient trial.3 Similarly, our understanding of the natural history of this disease is based on small observational series. Articles see pp 156 and 164 To further our comprehension of rare diseases, we often turn to “registries,” constructed as multicenter cohorts of patients who have the disease with longitudinal follow-up. Despite the inherent limitations of their observational and uncontrolled nature, which also represent strengths, these cohorts are useful to describe and compare patient characteristics, practice patterns, and outcomes. Observations from such registries can generate hypotheses that subsequently form the basis of further studies. Lastly, such cohorts facilitate the study of the prognostic profile of the disease via the derivation and validation of clinical prediction tools. In this issue of Circulation , data from the 2 of the most important present-day registries in PAH give us the opportunity to better understand the prognosis of PAH, its determinants, and outcomes in the current treatment era. Humbert and colleagues4 share data from the French National Registry, in which 354 consecutive idiopathic, heritable, and anorexigen-associated patients with PAH were enrolled from October 2002 to October 2003. They report 1-, 2-, and 3-year survival rates of 82.9%, 67.1%, and 58.2%, respectively. Sadly, despite the many advances in …