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The effects on resting ventilation of intravenous infusions of morphine or sameridine, a novel molecule with both local anesthetic and opioid properties.

UNLABELLED: Sameridine has both local anesthetic and partial mu-opioid receptor agonistic properties. The aim of this single-blinded, randomized, three-way cross-over study of 12 subjects was to investigate the effects on resting ventilation of two doses of sameridine: 0.15 mg/kg (S-Small) and 0.73 mg/kg (S-Large) compared with 0.10 mg/kg morphine. Each drug was infused IV over 20 min. Ventilation was measured by pneumotachography and in-line capnography, and sedation was rated by the subjects using a visual analog scale (VAS). Plasma was collected and analyzed for sameridine and morphine. At the end of drug infusion, minute ventilation (VE) and tidal volume (VT) were reduced in the S-Large group, and VE was reduced in the morphine group. End-tidal CO2 increased in both groups (P < 0.05), but respiratory rates remained unchanged. In the S-Small group, no ventilatory changes were recorded. In the S-Large group, the median sedation score was 6.8 cm with corresponding values in the morphine and S-Small groups of 3.3 and 2.5 cm, respectively. There was a relationship between the plasma concentration of sameridine and the depression of ventilation. We conclude that sameridine influences resting ventilation and that this effect is directly related to plasma concentrations of sameridine. From a ventilatory aspect, a clinical dose of sameridine with both local anesthetic and opioid properties seems safe. IMPLICATIONS: Sameridine, a molecule with both local anesthetic and analgesic properties, impaired resting ventilation after a large IV dose (0.73 mg/kg), more so than 0.10 mg/kg IV morphine. A clinical dose of sameridine (0.15 mg/kg) did not have any effects on ventilation.

Adult↗

Intravenous infusion of phenytoin relieves neuropathic pain: a randomized, double-blinded, placebo-controlled, crossover study.

UNLABELLED: Neuropathic pain responds inconsistently to opioids and nonsteroidal antiinflammatory drugs. However, oral anticonvulsants have a proven analgesic effect on neuropathic pain, but may not be practical in an acute flare-up. Phenytoin was the first oral anticonvulsant used as an analgesic for neuropathic pain. There have been few studies on the parenteral analgesic effect of this drug. In this randomized, double-blind, placebo-controlled, crossover study of 20 patients with acute flare-ups of neuropathic pain, we compared a 2-h placebo infusion with a 2-h infusion of 15 mg/kg phenytoin. Overall pain, shooting pain, burning pain, paresthesia, numbness, and sensitivity were measured using a 10-cm linear visual analog score. Numbness and sensitivity were reduced in the placebo group during infusion, but not in the 7 days after infusion. In the phenytoin group, there were significant reductions in burning pain (P < 0.05), shooting pain (P < 0.001), sensitivity (P < 0.001), numbness (P < 0.05), and overall pain (P < 0.005) during the infusion period. The reduction in overall pain persisted for 1 day, in sensitivity for 2 days, and in shooting pain for 4 days after infusion. We conclude that IV infusion of 15 mg/kg phenytoin has an analgesic effect in acute flare-ups of neuropathic pain and that this relief outlives both the infusion time and plasma half-life of phenytoin. IMPLICATIONS: Oral phenytoin can relieve neuropathic pain. The aim of this study was to examine the effect of IV phenytoin on neuropathic pain. The results indicate that IV phenytoin may be used to treat flare-ups of chronic neuropathic pain.

Adult↗

Mitral Doppler indices are superior to two-dimensional echocardiographic and hemodynamic variables in predicting responsiveness of cardiac output to a rapid intravenous infusion of colloid.

UNLABELLED: We hypothesized that mitral flow (MF) Doppler measurements could be used to predict cardiac output (CO) responsiveness to fluid challenge. Fourteen patients with normal systolic and diastolic function, scheduled for coronary artery bypass graft surgery, were evaluated as part of a pilot study in which preload was varied immediately before the beginning of cardiopulmonary bypass. A Validation group of 36 patients with different levels of systolic and diastolic function received a rapid infusion of 500 mL of 10% pentastarch. By use of transesophageal echocardiography, we measured left ventricular end-diastolic area, pulsed Doppler indices of the MF and pulmonary venous flow, and standard hemodynamic variables during acute volemic variations. A baseline measurement was first recorded, followed by measurements taken after a decrease (211 +/- 87 mL) and then an increase (176 +/- 149 mL) in preload (pilot study) and before and after 500 mL of pentastarch (validation study). In the pilot study, we found that a low velocity/time integral (VTI) E wave/A wave (E/A) ratio was associated with a larger increase in CO secondary to an increase in preload (r = 0.64, P < 0.05). Stepwise linear regression identified Doppler measurements of the mitral VTI E/A ratio as the most important variable to predict the increase in CO after fluid infusion. In the validation study, a mitral E/A ratio <1.26 before fluid infusion best predicted a 20% increase in stroke volume (receiver operating characteristic curve, 71%; P < 0.05), whereas no other hemodynamic or echocardiographic variable predicted preload responsiveness. We conclude that the MF Doppler filling pattern is an important factor to predict the increase in CO after intravascular fluid challenge in patients undergoing coronary artery bypass grafting. IMPLICATIONS: In the presence of low cardiac output, the clinician's ability to identify which patients are more likely to benefit from volume administration to improve hemodynamic status while avoiding fluid overload is important. The analysis of Doppler measurement of the mitral flow as an indirect indicator of the individual diastolic pressure/volume relationship may be useful to predict the intravascular volume responsiveness in patients undergoing coronary artery bypass graft surgery.

Adult↗

The pharmacokinetics and tolerability of an intravenous infusion of the new hydroxyethyl starch 130/0.4 (6%, 500 mL) in mild-to-severe renal impairment.

UNLABELLED: Hydroxyethyl starches (HES) are almost exclusively excreted glomerularly, in part after hydrolysis by amylase. HES 130/0.4 (Voluven; Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany) was developed to improve pharmacokinetics whereas preserving the efficacy of volume effect. We studied the dependency of pharmacokinetics of HES 130/0.4 on renal function. Nineteen volunteers with stable, non-anuric renal dysfunction, ranging from almost normal creatinine clearance (CL(cr)) to severe renal impairment (mean CL(cr): 50.6 mL. min(-1). 1.73 m(-2)), were given a single infusion of 500 mL 6% HES 130/0.4 over 30 min. HES plasma concentrations were determined until 72 h, urinary excretion until 72-96 h. CL(cr) had been obtained at least twice before and twice after dosing. Standard pharmacokinetic calculations and regression analysis were performed. Area under the time concentration curve (AUC(0-inf)) clearly depended on renal function comparing subjects with CL(cr) < 50 with those with CL(cr) > or =50 (ratio 1.73). Peak concentration (C(max), 4.34 mg/mL) as well as terminal half-life (16.1 h, model independent) were not affected by renal impairment. At CL(cr) > or =30, 59% of the drug could be retrieved in urine, versus 51% at CL(cr) 15-<30. The mean molecular weight of HES in plasma was 62,704 d at 30 min, showing lower values with increased renal impairment (P = 0.04). Pre-dose amylase concentrations inversely correlated with baseline CL(cr). Residual HES plasma concentrations after 24 h were small in all subjects (< or =0.6 mg/mL). We conclude that HES 130/0.4 (500 mL 6%) can be safely administered to patients even with severe renal impairment, as long as urine flow is preserved, without plasma accumulation. IMPLICATIONS: Dependency of the pharmacokinetics of hydroxyethyl starch 130/0.4 on renal function was studied. The area under the time concentration curve increased moderately with more severe renal dysfunction; however, small plasma concentrations were observed after 24 h. Terminal half-life and peak concentration remained unaffected by renal impairment.

Amylases↗

Regression of atherosclerosis by the intravenous infusion of specific biochemical nutrient substrates in animals and humans.

Preliminary studies in 400 New Zealand albino rabbits produced a reliable animal model of nutrient-induced atherosclerosis that simulated that observed in humans. Atherosclerosis was then induced in an additional 1600 rabbits in sets of 40 animals each, maintaining plasma cholesterol concentrations between 1000 and 2000 mg/dL for 6-20 weeks. In each set, 10 control rabbits were killed to document baseline atherosclerosis, and the other 30 rabbits were assigned randomly to one of three groups of 10 rabbits. Groups of 10 rabbits were either continued on the atherogenic diet (group I), given standard laboratory rabbit pellets (group II), or infused continuously with specially formulated anticholesterol solutions via central venous catheters (group III) for 6 weeks. At autopsy, atherosclerotic lesions consistently involved 85-95% of the aorta in group I. In group II, atherosclerosis was comparable with the baseline control group with no regression. In group III, regression of atherosclerosis by 90-95% was consistently documented. Correlations between plasma amino acids and plasma cholesterol concentrations were established in four humans with severe atherosclerosis to maximize the cholesterol reduction capacity of the amino acid formulation. Infusion of the modified total parenteral nutrition solution induced prompt reduction in plasma cholesterol levels by 40-60% regardless of the initial level and was accompanied by evidence of regression of atherosclerosis after a 90-day infusion therapy period.

Adult↗

Effects of intravenously infused pituitary adenylate cyclase-activating polypeptide on arginine vasopressin and oxytocin secretion in man.

In order to establish possible stimulatory effects of increasing plasma concentrations of pituitary adenylate cyclase-activating polypeptide (PACAP) on arginine vasopressin (AVP) and/or oxytocin (OT) secretion, successively increasing doses of PACAP-38 (2, 4 and 8 pmol kg min-1; each dose for 20 min) were infused in seven normal men. Plasma AVP and OT levels were measured before infusion and every 20 min, just before increasing the infusion dose of PACAP. During tests, PACAP infusion did not produce untoward side effects or changes in blood osmolality and/or pressure. Plasma OT levels did not change during PACAP infusion. Plasma AVP concentrations were not modified by infusion of the lowest dose of PACAP, whereas they were significantly increased in a dose-response fashion when higher amounts of PACAP were given. These findings demonstrate for the first time in humans that the systemic administration of PACAP exerts stimulatory effects on AVP, but not OT secretion.

Adult↗

Phase I trial of recombinant macrophage colony-stimulating factor by rapid intravenous infusion in patients with cancer.

Fourteen patients were entered into a phase I dose-escalation trial of macrophage colony-stimulating factor (M-CSF). M-CSF was administered to inpatients by rapid 15 min i.v. infusion every 8 h x 5 days, repeated after a 9-day rest. Dose levels evaluated were 20, 40, 80, 330, and 1,100 micrograms/m2. Monitoring of patients every 4 h included vital signs, daily complete blood count (CBC), and serum chemistries (SGOT, creatinine, and bilirubin) while receiving M-CSF. No clinical or laboratory evidence of toxicity was seen. The average serum t1/2 varied with dose level. At 330 and 1,100 micrograms/m2, the serum t1/2 was 25 and 84 min, respectively, implying a saturable mechanism of clearance. After 5 days of treatment, the t1/2 decreased by twofold, consistent with enhancement of the saturable mechanism. Monocyte cytotoxicity against the A375 melanoma cell line was evaluated pretreatment and day 5 of each cycle. No consistent enhancement of monocyte cytotoxicity was seen. No effect on peripheral blood monocyte number was seen until the 1,100 micrograms/m2 dose level. At this dose level, the mean monocyte number on day 5 was increased compared to baseline (1,300 mm3 vs. 300/mm3). Clinical activity was seen in two patients with previously progressive leiomyosarcoma metastatic to the liver. A partial response (PR) lasting 7 months occurred at the 330 micrograms/m2 dose level while a patient treated at 1,100 micrograms/m2 has had stable disease for 20+ months. The maximum tolerated dose (MTD) of M-CSF was not determined. Based on clinical responses, a phase II trial is warranted in patients with metastatic soft tissue sarcoma.

Antineoplastic Agents↗

Intravenous infusions of nitroprusside, dobutamine, and nitroglycerin are compatible.

It is now customary practice to couple separately metered infusions via a manifold to a common catheter that enters the patient. Nitroprusside, however, is considered incompatible with all other medications. Critically ill patients who require multiple infusions of vasoactive and inotropic medications would benefit if physicians had additional information regarding compatibility of nitroprusside with other commonly used infusions. Utilizing high-performance liquid chromatography, the authors investigated the physical and chemical compatibility of nitroprusside, dobutamine, and nitroglycerin in solutions of 5% dextrose or 0.9% NaCl at clinically relevant concentrations. All drugs were present within the guidelines of the U.S. Pharmacopeia (+/- 10%) over 24 h in NaCl, but nitroglycerin degraded over 24 h when the three drugs were mixed in dextrose. We recommend diluting these medicines in NaCl when mixtures of them would exist for greater than 4 h.

Dobutamine↗

Pharmacokinetics of midazolam administered by continuous intravenous infusion to intensive care patients.

OBJECTIVE: To determine the pharmacokinetics of continuously infused midazolam in patients during intensive care. DESIGN: Descriptive trial. SETTING: General ICU in a Swiss hospital. SUBJECTS: Eight critically ill patients requiring mechanical ventilation. INTERVENTIONS: To achieve an appropriate level of long-term sedation, the rate of iv infusion of midazolam in ICU patients was adjusted individually to between 6 and 15 mg/hr. Blood samples were taken during and after the continuous infusion of midazolam. MEASUREMENTS: Measurements included plasma concentration time profiles of midazolam and pharmacokinetic parameters, such as elimination half-life, clearance, and volume of distribution. RESULTS: The elimination half-life was prolonged (mean 5.4 vs. 2.3 hrs) and the volume of distribution was larger (3.1 vs. 0.9 L/kg) in patients vs. healthy volunteers. The clearance did not differ between groups (6.3 vs. 4.9 mL/min/kg in patients vs. volunteers, respectively). CONCLUSIONS: The increased volume of distribution in our critically ill patients is the major determinant for the observed slower elimination of midazolam. It is unlikely that the hepatic metabolism of midazolam was impaired in these patients.

Adult↗