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Pharmacokinetics of continuous intravenous infusion of methadone in the early post-burn period.

The pharmacokinetics of methadone were studied in 14 patients with acute, severe burns and receiving an intravenous infusion of methadone to control their pain. Serum methadone concentrations were measured by gas chromatography on 5 mL arterial blood samples obtained at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0 and 24 hours after the start of infusion. Albumin and Alpha-1-Acid glycoprotein (AAG) were measured by radial immunodiffusion. Serum methadone concentration-time data were fit with the appropriate sum of exponentials equation using iterative nonlinear regression analysis. All serum methadone concentration-time data were best described by a monoexponential equation. Estimates of Vd (180 +/- 62 L) were not significantly different from those predicted for Vc from body weight using literature values (156 +/- 41). Estimates of Vd were, however, significantly lower than those predicted for Vz using literature values (282 +/- 74) (P less than 0.001). In addition, CL values (53.0 +/- 19.3 L/h) were significantly higher than those predicted from body weight using literature values (9.2 +/- 2.3 L/h) (P less than 0.001). These changes resulted in estimates of the elimination half-life for methadone of 2.6 +/- 1.1 h. Methadone protein binding was independent of both albumin and AAG concentration. Multiple regression demonstrated that the significant predictors of CL in the early post burn injury period were serum albumin, days post injury and age. The coefficient of determination (r2) for this model was 0.8190. In summary, methadone CL is markedly elevated while the Vc is essentially unchanged during the early post burn injury period.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Platinum distribution in malignant glioma following intraoperative intravenous infusion of carboplatin.

The objective of this paper was to determine the time course and extent of platinum uptake into human malignant glioma tissue. An intraoperative, intravenous infusion of carboplatin was given to nine patients (seven glioblastoma and two anaplastic glioma) undergoing tumour excision. Carboplatin dosage was calculated individually to achieve a target systemic free carboplatin exposure. Tumour and peritumoural tissue was harvested at timed intervals following carboplatin administration. Plasma and tumour platinum concentrations were measured by graphite furnace flameless atomic absorption spectrophotometry. Histological examination was also performed on a piece of each tissue sample. The mean carboplatin dose administered was 783, SEM 56 mg (range 485-903). Plasma pharmacokinetics showed a typical elimination curve. The mean peak plasma platinum concentration was 44, SEM 5 micrograms/ml (range 27-74). The mean total elemental plasma platinum area under the curve (AUC) was 9.0, SEM 1.4 mg/ml/min. Platinum was detected in 61 tumour samples, the mean peak concentration being 13 SEM 2 micrograms/g (range 5-21). Platinum was also detected in peritumoural brain and necrotic tumour. No correlation was apparent between the degree of necrosis in each tumour specimen and tumour platinum concentration. Platinum concentrations achieved in tumour were similar to levels that would be cytotoxic for glioma cells in vitro. The results of this study have implications for future studies using capillary permeability modifying agents as adjuncts to brain tumour chemotherapy.

Adult↗

The effect of devices used to reduce the risk of blood spillage or needlestick injury on the flow of intravenous infusion systems.

We evaluated the effect of two devices used to reduce needlestick injury and blood spillage on the flow of saline, polygeline and blood through intravenous infusion equipment and their effects on methods of increasing flow. The devices studied all reduced flow compared with control. The reductions were less for the reflux valve (< or = 9%) and greater for the anaesthesia extension set (< or = 59%), with little further reduction in flow when both were used in series (< or = 60%). Reductions in flow increased with increasing viscosity of the fluid infused, being greatest with blood. The flow reduction produced by the reflux valve was more than compensated by increasing pressure or increasing to the next larger cannula size. The flow reduction produced by the anaesthesia extension was compensated by increasing pressure but not by increasing cannula size.

Blood↗

[The effects of nitroglycerin on refractory congestive heart failure by intravenous infusion].

Noninvasive hemodynamic and clinical studies were carried out in 24 patients with congestive heart failure refractory to digitalis, diuretics and vasodilators. Nitroglycerin was given by intravenous infusion for 5-7 days. The results showed that the symptoms, signs and hemodynamic parameters were markedly improved. The overall clinical effective rate was 96% and no serious side effect was noted.

Adult↗

Experimental studies on fluid pathophysiology in small intestinal obstruction in the rat. IV. Effects of intraluminal hyperosmolality and simultaneous intravenous infusions on mucosal micromorphology.

A hyperosmolal glucose solution was introduced into a loop of small intestine of specified length and position while intravenous infusions of varying osmolality were given at the same time. The hyperosmolal solution in the lumen caused damage primarily to the tips of the villi where sloughing of the epithelial cells was frequently seen. These defects were repaired by an increase in surface coverage by neighboring epithelial cells, which thus were reduced in height. A varying degree of edema was generally seen in the epithelial cells. The severity of these lesions was modified by intravenous infusions in inverse relationship to the osmolality of the infusions. Thus the defence mounted by the intestinal mucosa against the hyperosmolal solution in the lumen was impaired by the infusion of hypo-osmolal solutions and improved by hyperosmolal solutions. In the latter cases the mucosa maintained a practically normal histological picture.

Animals↗

A comparison of field techniques used to pressure-infuse intravenous fluids.

Application of pressure infusion bags may increase intravenous (IV) flow rates three-fold. Commercially available pressure infusers, manual squeezing of the IV fluid bag, inflating a blood pressure (BP) cuff around the bag, and kneeling on the bag have been used by prehospital personnel attempting to augment fluid infusion rates. To test the efficacy of each these methods, seven experienced paramedics were asked to employ each method in two trials using a 1-liter bag of saline through a 14-gauge, 5.7cm catheter and a standard administration set. Gravity flow from 80 cm served as the control. Pressure infusers generated flow rates of 257+/-54 ml/min and 296+/-53 ml/min when inflated to 300 mmHg and maximum pressure respectively. This rate was 2-2.5 times that of gravity flow (123+/-2 ml/min) and significantly greater than those rates obtained by any other method (p less than .0005). Manually squeezing the bag also was significantly better than was gravity flow with flow rates of 184+/-46 ml/min and 173+/-40 ml/min achieved by each of two different squeezing methods (p less than .01). Neither blood pressure (BP) cuff application and inflation (135+/-28 ml/min) nor kneeling on the bag (125+/-36 ml/min) was better than gravity alone. These results indicate that pressure infusers should be used to the exclusion of other field methods of supplying infusion pressure. If pressure infusers are not available, manually squeezing the bag is the only alternative acceptable in the field.

Efficiency↗

Sorption of chlormethiazole by intravenous infusion giving sets.

The sorption of chlormethiazole by intravenous infusion giving sets was investigated. Average recoveries of chlormethiazole following 500 ml infusions were 78.5%, 82.2% and 71.2% for the IVAC Volume Infusion Set, Travenol Code AHC 2890 Blood Administration Set and the McGaw Metriset, respectively. The effluent concentration-time profile using set up procedures and infusion rates similar to those used clinically were followed. When compared to solutions flowing at an infusion rate of 75 and 150 ml/h, loss of chlormethiazole from solutions standing static in the infusion sets was higher while that of solutions flowing at a high rate of 999 ml/h was lower. The clinical and pharmacokinetic significance of these phenomena are discussed.

Adsorption↗

Ventilatory response to CO2 inhalation and intravenous infusion of hypercapnic blood.

The ventilatory responses to intravenous infusion of hypercapnic blood (equilibrated with 80% CO2: 20% O2) and inhaled CO2 (1.5-2.0% CO2) have been compared in anaesthetized rabbits. A control infusion of blood equilibrated with 4% CO2: 21% O2 produced no change in V, PaCO2 or PaO2. The ventilatory response to a given rise in PaCO2, deltaV - (delta PaCO2)-1, was greater during infusion of hypercapnic blood (69 +/- 33 ml-min-1-mm Hg-1, mean +/- SD) than during CO2 inhalation (28 +/- 16 ml-min-1-min Hg-1, P less than 0.01). There was no difference between the rates at which the final levels of ventilation were reached during inhalation of CO2 or infusion of hypercapnic blood. It is suggested that the difference between the responses may be accounted for by differences in the pattern of PaCO2 oscillations in the two situations.

Animals↗

Impairment of flow in routine gravity-fed intravenous infusions to surgical patients.

1. Gravity-fed intravenous infusions were studied in patients by using continuous flow recording and a new resistance-measuring method. 2. A common, though preventable, cause of reduced flow was the gradual deformation of the plastic tubing under the regulator clamp. 3. In many cases there was some constriction of the cannulated vein and in a few this constriction was severe enough to seriously impair the infusion. The severity of the constriction varied periodically. 4. There was no evidence of troble due to a generally raised pressure in the arm veins nor was clotting in the cannula a serious problem. 5. A simple test is described which may be found useful clinically for assessing the difficult infusion.

Arm↗

Behaviour of standard gravity-fed administration sets used for intravenous infusion.

The major factor influencing drip rate during intravenous infusion using a standard administration set is the variation in the venous pressure of the patient. Creep in the plastic material, though present, is shown to be unimportant. For steady and accurate infusion it is necessary to provide the ordinary gravity-fed administration set with some form of servo-control mechanism.

Gravitation↗

Hyposensitivity of peripheral alpha-adrenoceptors in respirator-dependent amyotrophic lateral sclerosis assessed by intravenous norepinephrine infusion.

Intravenous norepinephrine infusion test was performed in eight patients with amyotrophic lateral sclerosis (ALS) supported by respirators and nine control subjects, to examine alpha-adrenoceptor function of peripheral resistant blood vessels. Baseline plasma norepinephrine concentrations in ALS patients were significantly higher than those in control subjects, indicating basal sympathetic hyperactivity (normal 218.2 +/- 59.7 pg/ml; ALS 450.0 +/- 288.4 pg/ml). The stimulus-response curves in the patients were similar to those in control subjects, and there were no significant differences between mean gains of the stimulus-response curves in both groups (normal 18.7 +/- 5.5; ALS 15.2 +/- 11.2). However, three ALS patients, two of whom had circulatory fluctuation and sympathetic hyperactivity, revealed lower gain levels than the mean minus 2 SD in control subjects (4.7, 1.1 and 3.7). This indicates hyposensitivity or down-regulation of the alpha-adrenoceptor function of peripheral blood vessels in these ALS patients. For early detection of sympathetic hyperactivity and prediction of circulatory collapse, it would be useful to measure the plasma norepinephrine concentration and the gain of the norepinephrine infusion curve in respirator-dependent ALS patients.

Aged↗

Phase I study of Datelliptium chloride, hydrochloride given by 24-h continuous intravenous infusion.

Datelliptium chloride, hydrochloride (SR 95 156B, NSC 626718X, DHE) was studied in a phase I trial of escalating doses given on a single 24-h continuous intravenous infusion schedule. Doses were escalated from 40 to 500 mg/m2 in 19 patients who received a total of 24 courses. Courses were repeated after a minimal interval of 3 weeks. Local venous toxicity occurred at low doses (less than or equal to 100 mg/m2) and was circumvented by the use of a central venous access for higher doses. Other clinical adverse events occurred (greater than or equal to 330 mg/m2), including moderate nausea and vomiting, mild diarrhea, dry mouth, neuropsychiatric manifestations, and fatigue. All of these side effects were reversible and none was dose-limiting. The dose-limiting toxicity was related to hepatic laboratory-test abnormalities in the form of reversible elevations of levels of serum bilirubin and liver enzymes at doses of greater than or equal to 330 mg/m2. The maximum tolerated dose for this schedule is 500 mg/m2. Hematologic toxicity was minimal and non-dose-limiting. Neither drug-related deaths nor objective complete or partial responses were observed. However, a minor response and a long-term disease stabilization were obtained.

Adult↗

Effect of intravenous infusion of an alpha-adrenergic blocking agent on the haemodynamic changes in human masseter muscle induced by cold pressor stimulation.

This study evaluated the effect of intravenous infusion of a non-selective alpha-adrenergic blocking agent on masseter muscle haemodynamics induced by 4 degrees C cold pressor stimulation (CPS) of the right foot and ankle, which reportedly evokes a rapidly increasing sympathetic nerve activity in human skeletal muscle. Nine healthy non-smoking males (mean age 23.7+/-2.1 year) with no history of chronic muscle pain or migraine participated. The haemoglobin (Hb) concentration in the right masseter was continuously recorded by non-invasive, near-infrared spectroscopy. Heart rate and blood pressure were also recorded. The experiment involved the following sequence: (1) a placebo (physiological saline) with a CPS trial; (2) a 30-sec maximal voluntary clenching (MVC)-only trial; and (3) an alpha-adrenergic blocking agent with a CPS trial. The saline and drug trials each involved continuous recording for 1 min before, 2 min during and 5 min after the CPS. Physiological saline (20 ml) or phentolamine mesylate (20 ml) were infused at the rate of 2 ml/min. This infusion was begun 15 min before baseline recording and participants were not aware which solution (saline or phentolamine) was being infused. For the MVC trial, each participant performed a 30-sec MVC of his jaw-closing muscles followed by a 15-min rest between each trial. The individual Hb data were adjusted so that the baseline at the beginning of the experiment was equal to zero and all data were normalized as a percentage of the individual's highest absolute Hb change seen after the MVC. The mean baseline Hb concentrations 1 min before CPS were significantly higher in the alpha-blocker trial (83.6%) than in the placebo saline trial (P < 0.001). The change in mean Hb concentration from baseline during CPS in the alpha-blocker trial was significantly less than in the placebo trial (P = 0.006). Mean heart rate before CPS was also significantly higher in the alpha-blocker trial (85.2 beats/min) than in the placebo trial (69.6 beats/min) (P < 0.001). There were no significant differences in the mean systolic and diastolic blood pressures between the placebo and alpha-blocker trials in any time period. The results suggest that non-selective alpha-adrenoceptor blockade increases the blood volume in the masseter muscle. This change might be due to a combination of peripheral vasodilation and an increase in cardiac output.

Adrenergic alpha-Antagonists↗

Water and solute dynamics after intravenous infusion of new irrigating fluids in the rabbit.

We used 25 rabbits to study blood chemistry, urinary flow and solute excretion for 2 h during and after intravenous infusion of 50, 75 and 100 ml/kg of 4 solutions that have recently been introduced in Sweden for irrigation during transurethral operations. Infusion of mannitol 3% + ethanol 1% and sorbitol 2% + mannitol 1% were followed by a higher urinary flow and excretion of sodium and other solutes than after glycine 1.5% + ethanol 1%, glycine 1.0% + ethanol 1%, and normal saline (control). The volume of urine and the total solute excretion, but not the sodium and potassium excretion, increased with the infused volume. The urea and creatinine clearances increased in proportion to the urinary flow. Using a mathematical model, we found a volume-dependent increase in the ratio of extracellular to intracellular accumulation of water, although the average ratio was the highest for glycine 1.5% + ethanol 1% (mean 0.78) and the lowest for mannitol 3% + ethanol 1% (mean 0.60). We conclude that there are marked differences between recently introduced irrigating fluids with respect to diuretic effects and the distribution in the body.

Animals↗

5-Fluorouracil (5-FU) continuous intravenous infusion compared with bolus administration. Final results of a randomised trial in metastatic colorectal cancer.

The aim of this Phase III, balanced randomised trial was to compare continuous intravenous infusion (CVI) of 5-FU with bolus (B) administration for metastatic colorectal cancer (CRC). One hundred and fifty-five non-pretreated patients were randomised to receive CVI 5-FU at a dose of 750 mg/m2/day (d), 7 d every 21 d (n = 77), or bolus 5-FU 500 mg/m2/d x 5 d every 28 d (n = 78). Incremental dose escalation at 50 mg per step was recommended in the absence of toxicity. All the patients had measurable metastatic disease (M), particularly, liver and a good performance status (WHO grade 0-1). Dose intensity was significantly higher in CVI than in the bolus group: 1369 mg/m2/week versus 558 mg/m2/week (P = 0.0001). Grade II-IV stomatitis was more frequent in the CVI group (31% versus 9%; P < 0.0001) as was hand and foot syndrome (14% versus 3%; P < 0.001). Diarrhoea (22% versus 12%) and grade III granulocytopenia (2% versus 6%) were comparable. Responses were more frequent in the CVI (26%) than in the bolus group (13%) (P < 0.04); progression-free survival was higher for the CVI group (P = 0.04), but there was no statistical difference in overall survival (median: 10 months (m) compared to 9 m), and 1 year survival (SD) 42% (6%) versus 40% (6%). In the multivariate analysis, survival was better for patients with a good PS, well-differentiated adenocarcinomas and a primary tumour without serosal extension. In conclusion, with a higher dose intensity, CVI 5-FU improved tumour control, but not overall survival.

Antimetabolites, Antineoplastic↗

Histamine lipolysis I: changes in the free fatty acid levels of dog plasma after intravenous infusion of histamine.

The effects of histamine (Hi) and related compounds on free fatty acid (FFA) levels and % changes in FFA composition of dog plasma were studied after intravenous infusion. Hi at doses of 2-10 micrograms/kg while affecting no changes in the cardiovascular system elicited a dose-related increase in FFA levels in plasma, as did epinephrine. Though all of the FFA concentrations in plasma were increased by Hi infusion, % change of each FFA in the composition did not correspond to that of plasma concentration; % increases in palmitoleic acid, linolenic acid and linoleic acid were remarkable, while stearic acid (18:0) was lowest. The increase in arachidonic acid was not marked, but a dose-related increase was observed after Hi infusion. The H2-agonist 4-methylHi produced an increase in FFA levels, whereas the H1-agonist 2-methylHi was not effective. 4-MethylHi increased all of the plasma FFA levels and the relative changes were similar to those caused by Hi. The effect induced by Hi was blocked by the H2-antagonists cimetidine and ranitidine. Pretreatment with aminophylline potentiated the Hi effect, indicating that Hi lipolysis may be intimately related to cyclic AMP.

Aminophylline↗

A single intravenous infusion of apoptotic cells, an alternative cell-based therapy approach facilitating hematopoietic cell engraftment, did not induce autoimmunity.

Previously, we reported that intravenous infusion of apoptotic leukocytes facilitated bone marrow (BM) engraftment across major histocompatibility barriers. This cell-based therapeutic approach is of great interest for stem cell therapy across histocompatibility barriers. Autoimmunity associated with apoptotic cell administration may, however, limit the use of this approach. Indeed, autoantigens are concentrated on the surface of apoptotic cells, and defective clearance of apoptotic bodies is associated with the occurrence of systemic autoimmune disease. In consequence, we assessed the autoimmune responses raised against ubiquitous double-stranded DNA (dsDNA) and cardiolipin autoantigens following a single intravenous infusion of apoptotic cells simultaneously to allogeneic BM administration. No difference was observed between levels of natural circulating immunoglobulin M (IgM) (anti-dsDNA and anti-cardiolipin) autoantibodies found in mice receiving allogeneic BM alone and those found in mice receiving apoptotic cells also. Pathogenic IgG autoantibody titers after apoptotic cell infusion were 9- to 200-fold lower than autoantibody titers found in lupus-prone mice and not different from titers detected in BM grafted mice. Kinetic analysis of autoantibodies after transplantation did not demonstrate any immunization against tested autoantigens after apoptotic cell infusion. Finally, neither immune complex deposition nor specific lesions were observed in the renal glomeruli of mice infused with apoptotic cells 9 months post-BM transplantation. Overall, these results show no specific toxicity of a single infusion of apoptotic cells administrated simultaneously to BM and may also shed light on factors influencing the immunogenic properties of apoptotic cells.

Animals↗

Efficacy and safety of sustained (48 hour) intravenous infusions of milrinone in patients with severe congestive heart failure: a multicenter study.

Milrinone is a new bipyridine inotrope that has shown promise in initial clinical testing when administered intravenously or orally. The present multicenter study was designed to evaluate the clinical effectiveness and safety of sustained (48 hour) intravenous infusions of different doses of milrinone, as would be used clinically, in a controlled fashion using invasive hemodynamic monitoring. Entry was limited to adult patients with chronic heart failure of functional class III or IV, with a cardiac index less than or equal to 2.5 liters/min per m2 or a pulmonary capillary wedge pressure greater than or equal to 15 mm Hg, or both. After stable baseline hemodynamic recordings were obtained, milrinone was given as loading (microgram/kg per 10 min) and maintenance infusions (microgram/kg per min) to 189 patients in one of four loading/maintenance dosage regimens: 37.5/0.375 (low dose, n = 26), 50/0.50 (intermediate dose, n = 95), 75/0.75 (high dose, n = 15) and 50/0.25 (lowest dose, n = 53). The lowest dose was shown to be ineffective for maintenance therapy. Effective individual patient responses were defined as greater than or equal to 20% increase in cardiac index or decrease in pulmonary capillary wedge pressure, or both. During early therapy (less than or equal to 3 hour), 99% of patients showed an effective maximal response, and 90% an effective mean response. An effective mean response was observed during days 1 and 2 in 80% of patients, with a positive dose-response trend (69% response, low dose; 80%, intermediate dose; 93%, high dose; day 1). Each loading regimen was effective, with maximal mean response occurring at 15 minutes. Cardiac index initially increased by an average of 24 to 42% for all patients in the three groups, whereas pulmonary capillary wedge pressure decreased by 24 to 33%. Initial decreases in systemic vascular resistance averaged 15 to 31%. Initial changes in heart rate (+4 to +13%) and mean arterial pressure (-2 to -13%) were modest. Significant mean hemodynamic responses were maintained over the 48 hours. Increases in cardiac index for days 1 and 2 averaged 38 and 39% for those completing constant low dose drug, 34 and 37% for intermediate dose and 73 and 44% for high dose. Decreases in pulmonary capillary wedge pressure for all patients averaged 18 to 32% on days 1 and 2, with little dose response. Heart rate changes were modest and variable, averaging -9 to 9%.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗