Mean Dose Requirement Research Articles

COMPARATIVE STUDY OF RINGER’S LACTATE AND 6% HYDROXYETHYL STARCH AS PRELOADING FLUID FOR PREVENTION OF HYPOTENSION FOLLOWING SUBARACHNOID BLOCK

Background and Objective: To compare the efcacy of Ringer's lactate and 6% hydroxyethyl starch in reducing the incidence and severity of hypotension after subarachnoid block. Design: Prospective and randomized comparative study. Materials and methods: 100 patients in the age group of 20 to 60 years of ASA Grade I scheduled for elective lower abdominal and lower limb surgeries were randomly allocated into two groups. CRL-Group: received 20ml/kg of Ringer's lactate. COL-Group: received 10 ml/kg of HES 6%20 minutes prior to spinal anaesthesia. Pulse rate, systolic, diastolic and mean arterial blood pressure was recorded at an interval of every minute up to 5 minutes, every 5 minutes up to 60 minutes duration. Results: The incidence of hypotension was 86% in CRL-Group, and 6% in COL-Group, which was statistically signicant. The Mephentermine bolus requirements were less in COL-Group (3 of 50 patients) when compared to CRL-Group (43 of 50 patients). None of them have allergic reactions in COL-Group. Interpretation and Conclusion: It was observed from our study that 6% HES group reduces incidence of hypotension after subarachnoid block, thus requiring lesser mean dose requirements of Mephentermine when compared to Ringer's lactate group. 6% HES is effective and safer when compared with Ringer's lactate in preventing hypotension in patients undergoing surgeries under SAB. In conclusion we found that colloids when compared with crystalloids reduce the incidence of spinal anaesthesia induced hypotension.

Significance of CYP4F2 polymorphism on oral anticoagulation therapy with acenocoumarol in South Indian patients with mechanical heart valves

BackgroundThe coumarin group of oral anticoagulants has a narrow therapeutic range and wide inter-individual variability. Polymorphism of VKORC1 and CYP2C9 genes are the major genetic determinants of the drug-dose response. Our study aimed to investigate the role of CYP4F2 (1347 G > A) polymorphism on the acenocoumarol daily dose requirement, and its interaction with VKORC1 and CYP2C9 polymorphism. Methods301 Rheumatic Heart Disease (RHD) patients with mechanical cardiac valves were recruited. Genotyping for CYP4F2, VKORC1 and CYP2C9 was done by PCR-RFLP. CYP4F2 genotype distribution GG, GA and AA was 23.5%, 51.5% and 25% respectively. The mean daily dose requirement for variant homozygous patients (AA) was 0.46 folds more when compared to wild type (GG) (Adjusted OR 0.46; 0.21–0.99, p = .048). However, on combined genotype analysis of CYP4F2, VKORC1 and CYP2C9 there was no significant difference in mean dose requirement. ConclusionThe homozygous genotype (AA) of CYP4F2 gene was more prevalent in our study cohort. No significant association was found between CYP4F2 gene polymorphism and acenocoumarol mean dose requirement, both when analyzed individually and in combination with VKORC1 and CYP2C9 polymorphisms.

Effect of oral melatonin on patients' anxiety scores and dose requirement of propofol during bispectral index-guided induction of general anesthesia

Background: Management of preoperative anxiety in surgical patients is usually required for better perioperative hemodynamics and patient management. Various pharmacological and nonpharmacological entities have been used for the management of anxiety. The aim of this study was to analyze the effect of oral melatonin on patient anxiety scores and dose requirement of propofol using bispectral index (BIS)-guided induction of general anesthesia. Materials and Methods: Sixty patients of American Society of Anesthesiologists physical Status I and II between 18 and 45 years of age scheduled to undergo elective surgery of more than 30 min participated in this study. Patients were divided into control and melatonin groups, comprising 30 patients each. Group M patients received two melatonin tablets (3 mg each) and Group C patients received two placebo tablets 120 min before induction. Anxiety scores using visual analog scale-anxiety at baseline and 120 min, mean dose requirement of propofol, time to attain BIS value of 55 in seconds, and hemodynamic parameters were studied in-between the groups. Results: There were significant differences between two groups in anxiety scores 120 min after drug dosage (P = 0.0013) with Group M patients with reduced levels of anxiety, and mean requirement of propofol in Group C (104.67 ± 16.34 mg) was found to be statistically significantly higher than Group M (70.67 ± 16.39 mg), P Conclusion: 6 mg of melatonin 120 min before elective surgery can allay anxiety in patients along with reduced dose requirement for propofol for BIS-guided induction of general anesthesia without any adverse effects.

Comparison of Effectiveness of Sublingual and Vaginal Misoprostol for Second-Trimester Abortion.

The aim of this study was to compare the efficacy and safety of sublingual and vaginal misoprostol in second-trimester termination of pregnancy in 24 and 48h. This is a retrospective study of 240 pregnant women seeking termination in second trimester (13-18.5weeks), in which the patients are subdivided into two groups-first group received 400mcg of misoprostol sublingually (n = 120), and second group received 400mcg of misoprostol vaginally (n = 120) every 4h for a maximum of five doses. The course of misoprostol was repeated if the patient did not abort within 24h. The mean induction-to-abortion interval was shorter in sublingual group (10.28 ± 3.1h) versus 14.68 ± 4.2h in vaginal group in 24h (p = 0.0001), and 36.9 ± 4.4h in sublingual versus 29.7 ± 14 in vaginal group in 48h (p = 0.0933). Mean dose requirement for misoprostol by sublingual route was low as compared to vaginal misoprostol (1048 ± 301mg versus 1250 ± 375mg; p = 0.0001 in 24h and 1110 ± 833mg versus 1325 ± 536mg; p = 0.0231 in 48h). No significant difference was found in the success rate (both at 24 and 48h) and in side effects among the two comparison groups. Misoprostol as such by any route has been proven as an effective abortifacient in second trimester. Both sublingual and vaginal routes are effective for medical abortion. But shorter induction-to-abortion interval in sublingual route, less dose requirement and higher acceptability makes sublingual route as a better choice.

English

BACKGROUND: Spinal anesthesia is the more commonly administered procedure for pelvic, lower abdominal and lower limb procedures. Hypotension is the most common complication of spinal anesthesia. It is a common practice to give intravenous fluids, usually crystalloids, prior to centro neuraxial block in order to prevent hypotension and this is usually referred as preloading. AIMS: Compare the efficacy of preloading with crystalloid to that of colloids in reducing the incidence and severity of hypotension in spinal anesthesia for lower abdominal surgery and also to find out if hydroxyl ethyl starch (HES) is a better colloid than polygelatin. STUDY DESIGN: The study population included 150 patients belonging to either sex undergoing elective lower abdominal surgeries under spinal anesthesia. METHODS AND MATERIAL: One hundred and fifty ASA I and II patients posted for lower abdominal surgeries under spinal anesthesia were randomly allocated to receive either 10mL/Kg of HES (Group A), 10mL/Kg of polygelatin (Group B) or 10mL/Kg of Ringer's lactate solution as preloading solution. Heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) were recorded once in two minutes for the first ten minutes and once in five minutes for the next fifty minutes. The incidence of hypotension and the mean dose requirement of mephentermine were noted after spinal anesthesia. STATISTICAL METHODS: The analysis of variance to find the significance difference of pulse rate, SBP and MAP between the three groups of patients. The Post hoc test by Tukey to find the pair wise significance between the three groups. The Chi-square test to find the significance of proportions of mephentermine dose requirement between the three groups. RESULTS: The incidence of hypotension was 9 of 50 (18%) in Group A, 17 of 50 (34%) in Group B and 27 of 50 (54%) in group C. The mephentermine bolus requirements were also less in group A (9 times) when compared to group B (18times) and group C (32 times), which was statistically significant. INTERPRETATION AND CONCLUSION: HES reduced the incidence of hypotension after spinal anesthesia and required lesser mean dose requirements of mephentermine when compared to polygelatin and ringers lactate. It can be concluded from the present study that colloids offset hypotension and hypovolemia more effectively than crystalloids. Also it can be concluded that hydroxyethyl starch is a better

The effect of dexmedetomidine infusion on propofol requirement for maintenance of optimum depth of anaesthesia during elective spine surgery

Background:Maintenance of adequate depth of anaesthesia in spine surgery is vital to prevent awareness, to reduce stress response and possible autonomic instability frequently associated with spine surgery. Dexmedetomidine, a α2-adrenoceptor agonist with analgesic and sedative adjuvant property has been found to reduce dose requirement of multiple anaesthetic agents both for induction and during the maintenance of anaesthesia.Aim:The aim of this study is to observe the effect of dexmedetomidine, on the requirement of propofol for induction and maintenance of adequate depth of anaesthesia during spine surgery.Methods:It was a prospective, randomised, double-blinded, parallel group, placebo controlled and open-lebel study in tertiary care hospital. A total of 70 patients aged 20-60 years, American Society of Anaesthesiologists GradeI and II, scheduled for elective spine surgery were randomly allocated into two groups. Each patient of Group D (n=35) received an initial loading dose of dexmedetomidine at 1 μg/kg over 10 min, started 15 min before induction of anaesthesia followed by an infusion at a rate of 0.2 μg/kg/h. Patients of Group P (n=35) received the same volume of 0.9% normal saline solution as placebo. Requirement of propofol at induction and during maintenance was calculated maintaining bispectral index between 40 and 60. P<0.05 was considered to be statistically significant.Results:Mean requirement of propofol was found to be lessened by 48.08% and 61.87% for induction and maintenance of anaesthesia respectively while using dexmedetomidine.Conclusion:Administration of dexmedetomidine significantly reduces the requirement of propofol while maintaining desired depth of anaesthesia without any significant complication.

A prospective, open-label, observational clinical cohort study of the association between delayed renal allograft function, tacrolimus exposure, and CYP3A5 genotype in adult recipients

Background: Tacrolimus, a calcineurin inhibitor with a macrolide lactone structure, is currently used as a cornerstone immunosuppressive drug in solid organ transplantation. It is metabolized by hepatic and intestinal cytochrome P450 (CYP) 3A4/3A5 enzymes and is a substrate for P-glycoprotein (ABCB1). The disposition of tacrolimus might be influenced by severe renal allograft dysfunction (eg, in cases of delayed graft function [DGF]). New-onset diabetes after transplantation (NODAT) is a known adverse effect of tacrolimus therapy and has been associated with DGF. Objectives: The impact of DGF on tacrolimus C min and dose requirements was evaluated in renal transplant recipients in the first postoperative week. The effects of the CYP3A5*3 A6986G polymorphism on initial mean tacrolimus C min and dose requirements in the presence and absence of DGF were assessed. This study also tested the hypothesis that if DGF influences early tacrolimus exposure, this would lead to a higher risk for NODAT (defined as the need for glucose-lowering medication for an uninterrupted period of ≥26 weeks). Methods: This prospective, open-label, observational clinical cohort study enrolled renal allograft recipients aged ≥18 years. Tacrolimus was administered as an oral loading dose of 0.2 mg/kg/d and adjusted to achieve a target mean daily tacrolimus C min between 12 and 15 ng/mL. C min values and oral dose requirements in the first postoperative week were compared between patients with and without DGF. Patients were genotyped for the CYP3A4*1B -290A>G, CYP3A5*3 A6986G, ABCB1 Exon26 C3435T, ABCB1 Exon21 G2677T, and ABCB1 Exon21 G2677A single nucleotide polymorphisms. NODAT that occurred within the first 12 weeks after transplantation was confirmed using an oral glucose tolerance test. Results: A total of 304 patients were enrolled (184 men, 120 women; mean [SD] age, 52.9 [14.1] years). Through day 3 after transplantation, mean (SD) 12-hour tacrolimus C min values were significantly higher in recipients experiencing DGF despite identical loading doses of 0.2 mg/kg. Mean tacrolimus dose requirements were significantly lower in patients with DGF during the first week. After recovery of DGF, mean tacrolimus dose requirements were not significantly different between recipients with and without DGF. In homozygous CYP3A5*3 carriers (n = 252), mean (SD) tacrolimus dose requirements remained significantly lower during DGF, while in CYP3A5*1 carriers with DGF (n = 52), lower mean dose requirements were observed only after postoperative day 4. The proportion of patients in whom NODAT developed was significantly greater in patients with DGF and tacrolimus C min >15 ng/mL on the first day after transplantation (27.2%) compared with recipients who remained free of DGF and had Cmin ≤15 ng/mL on day 1 (6.5%) ( P = 0.016). On logistic regression analysis, greater recipient age (odds ratio [OR] = 1.044; 95% CI, 1.009–1.080), higher tacrolimus C min on day 1 (OR = 1.048; 95% CI, 1.017–1.080), and DGF (OR = 2.968; 95% CI, 1.107–7.959) were associated with an increased risk for NODAT. Conclusion: In this open-label, observational study, DGF was associated with higher initial mean tacrolimus Cmin values and lower daily dose requirements predominantly in CYP3A5 nonexpressers.

A Simulation of Warfarin Maintenance Dose Requirement Using a Pharmacogenetic Algorithm in an Ethnically Diverse Cohort

Patient demographics and variant alleles in the CYP2C9 and VKORC1 genes account for 50% of the population variability in warfarin maintenance doses. These variant alleles occur in varying frequencies between racial groups and contribute to differences in mean dose requirements between these groups. We used a pharmacogenetic simulation to estimate warfarin maintenance doses in an ethnically diverse cohort. In total, 366 individuals with coronary disease, of mixed South Pacific and European ethnicity, were genotyped for the CYP2C9*2 (rs1799853), *3 (rs1057910) and the VKORC1*2 haplotype, -1639 G>A, (rs9923231). The cohort contained New Zealand Europeans (n = 287), Mãori (n = 49), Pacific Islanders (n = 21) and Chinese subjects (n = 9). SNPs were genotyped using the Sequenom (CA, USA) mass spectrometer. Body surface area, age, smoking status and genotype were entered into a modified pharmacogenetic algorithm with a target international normalized ratio of 2.5. Bootstrap analysis using the @RISK software v5.0, (Palisade Co., NY, USA) was performed to simulate a population of 1000 for each ethnic group. Simulated warfarin doses were lower in Chinese subjects than New Zealand Europeans (Δ1.39 mg; 95% CI: 0.4-2.4; p = 0.006) owing to the high prevalence of the VKORC1*2 haplotype in Chinese subjects. Doses were higher in Pacific Islanders compared with New Zealand Europeans (Δ1.26 mg; 95% CI: 0.6-1.9; p = 0.0002) owing to the near absence of the CYP2C9 variant alleles. Simulated warfarin doses in Mãori patients were similar to those in European patients. This simulation study demonstrated differences in mean warfarin maintenance doses between ethnic groups in this cohort. Individualizing treatment regimens, using pharmacogenetics, may reduce ethnic disparities in treatment outcomes, particularly if differences can be appreciated at the genomic level.

Alfaxalone induction dose following administration of medetomidine and butorphanol in the dog

ObjectiveTo determine in dogs the effects of medetomidine and butorphanol, alone and in combination, on the induction dose of alfaxalone and to describe the induction and intubation conditions. Study designProspective, randomized, blinded clinical trial. AnimalsEighty-five client-owned dogs (ASA 1 or 2). MethodsSubjects were block randomized to treatment group according to temperament. The treatment groups were: medetomidine 4 μg kg−1 (M), butorphanol 0.1 mg kg−1 (B), or a combination of both (MB), all administered intramuscularly. After 30 minutes, a sedation score was assigned, and alfaxalone 0.5 mg kg−1 was administered intravenously over 60 seconds by an observer who was unaware of treatment group. Tracheal intubation conditions were assessed and, if tracheal intubation was not possible after 20 seconds, further boluses of 0.2 mg kg−1 were given every 20 seconds until intubation was achieved. Induction dose and adverse events (sneezing, twitching, paddling, excitement, apnoea and cyanosis) were recorded; induction quality and intubation conditions were scored and recorded. ResultsThe mean dose of alfaxalone required for induction was similar for groups M and B: 1.2 ± 0.4 mg kg−1. The mean dose requirement for group MB (0.8 ± 0.3 mg kg−1) was lower than groups M and B (p < 0.0001). Induction dose was not influenced by temperament or level of sedation. Induction and intubation scores did not differ between treatment groups. Adverse events were noted in 16 dogs; there was no association with treatment group, temperament or level of sedation. Conclusions and clinical relevanceMedetomidine and butorphanol administered in combination reduce the anaesthetic induction dose of alfaxalone compared to either agent alone. This difference should be taken into account when using this combination of drugs in a clinical setting.

Dose reduction of epoetin-alpha in the prevention of chemotherapy-induced anaemia

Anaemia during chemotherapy is often left untreated. Erythropoiesis-stimulating agents are frequently used to treat overt anaemia. Their prophylactic use, however, remains controversial and raises concerns about cost-effectiveness. Therefore, we assessed the efficacy of a dose-reduction schedule in anaemia prophylaxis. The study included patients with untreated solid tumours about to receive platinum-based chemotherapy and had haemoglobin (Hb) levels ≥11 g/dL. Epoetin-α was administered at a dose level of 3 × 10,000 U weekly as soon as Hb descended to < 13 g/dL. Dose reductions to 3 × 4,000 U and 3 × 2,000 U weekly were planned in 4-week intervals if Hb stabilised in the range of 11-13 g/dL. Upon ascending to ≥13 g/dL, epoetin was discontinued. Iron supplements of 100 mg intravenous doses were given weekly. Of 37 patients who enrolled, 33 could be evaluated. Their median Hb level was 13.7 (10.9-16.2) g/dL at baseline and descended to 11.0 (7.4-13.8) g/dL by the end of chemotherapy. Anaemia (Hb < 10 g/dL) was prevented in 24 patients (73%). The mean dose requirement for epoetin-α was 3 × 5,866 U per week per patient, representing a dose reduction of 41%. Treatment failed in nine patients (27%), in part due to epoetin-α resistance in four (12%) and blood transfusion in three (9%) patients. Dose reduction was as effective as fixed doses in anaemia prophylaxis but reduced the amount of prescribed epoetin substantially.

Effectiveness and safety of recombinant human erythropoietin beta in maintaining common haemoglobin targets in routine clinical practice in Europe: the GAIN study

ABSTRACTObjective: The Gain effectiveness in Anaemia treatment wIth NeoRecormon (epoetin beta) study (GAIN) evaluated the effectiveness and safety of recombinant human erythropoietin beta in correcting and/or maintaining common haemoglobin (Hb) targets in routine clinical practice in Europe.* NeoRecormon is a registered trade name of F. Hoffmann-La Roche, Basel, SwitzerlandResearch design and methods: European 18-month observational, prospective clinical practice study across 217 centres from 13 countries. During a 3-month retrospective period, patients received any erythropoiesis stimulating agent (ESA). For the subsequent 18-month study phase, patients receiving intravenous (IV) epoetin beta or any other ESA were recommended to be switched to subcutaneous (SC) epoetin beta. Presence of anti-erythropoietin antibodies (AEAB) and related outcomes was investigated before and during the study.Clinical trial registration: ClinicalTrials.gov number: NCT00551603.Main outcome measures: Correction and maintenance of Hb levels within recommended target range and mean dose requirement to correct and maintain target Hb levels.Results: A total of 4264 patients on haemodialysis received an ESA for treatment of renal anaemia. During the study period, the number of patients who maintained Hb levels in the recommended target range of 10–12 g/dL increased from 57% to 62%. Administration of SC epoetin beta resulted in a 24% lower mean dose requirement to maintain target Hb levels compared to IV administration (p < 0.001). Considerable differences were observed between countries in the study. No patients developed pure red cell aplasia associated with AEAB during observation.Conclusion: This observational study suggests that haemodialysis patients who are receiving any ESA via SC or IV administration for treatment of their renal anaemia can be safely and effectively switched to SC epoetin beta to achieve or maintain the currently recommended Hb targets. SC required a lower dose than IV administration to maintain similar efficacy, thereby potentially lowering the drug costs.Trial registration: ClinicalTrials.gov identifier: NCT00551603.

Endotoxin Adsorption Therapy for Septic Shock Using Polymyxin B‐Immobilized Fibers (PMX): Evaluation by High‐sensitivity Endotoxin Assay and Measurement of the Cytokine Production Capacity

Because of its low sensitivity, the conventional measurement method for endotoxin (ET) is not the most appropriate for monitoring the effect of ET adsorption therapy. Thus, the efficacy of ET adsorption therapy was investigated using a newly developed high-sensitivity ET assay method. The changes in the cytokine production capacity of whole blood were also examined. We treated 24 peritonitis patients who had developed postoperative septic shock with ET adsorption therapy using a column of polymyxin B-immobilized fibers (PMX) and their serum ET levels were measured using the high-sensitivity ET assay based on the kinetic turbidimetric Limulus assay. In addition, the changes in the tumor necrosis factor-(TNF-alpha) production capacity of whole blood following lipopolysaccharide (LPS) stimulation and clinical outcome in the study patients were also examined. The 28-day mortality rate was 12%. PMX-direct hemoperfusion (PMX-DHP) was associated with elevation of the mean arterial pressure and urine output, reduction in the mean dose requirement of vasopressor agents, and recovery from the shock state in all the patients. The PaO2/FIO2 ratio also showed significant improvement. Using the high-sensitivity ET assay, ET was detected in the blood of 20 out of the 24 patients (80%) before the PMX-DHP, and a significant reduction in the ET level was noted after the PMX-DHP. The TNF-alpha production capacity of whole blood, which was found to be lower in the septic shock patients than in healthy subjects, was significantly increased after PMX-DHP. Elimination of ET by PMX-DHP in septic shock patients was confirmed by the high-sensitivity ET assay. PMX-DHP is thus considered to be a useful adjuvant therapeutic technique in the treatment of septic shock. Also, PMX-DHP might alleviate the immunosuppression associated with severe sepsis.

Effect of switching from subcutaneous to intravenous administration of epoetin-α in haemodialysis patients: Results from a Swedish multicentre survey

In 2002, many haemodialysis patients were switched from subcutaneous (s.c.) to intravenous (i.v.) administration of epoetin-alpha following reports of antibody formation and development of pure red-cell aplasia in patients treated via the s.c. route. We evaluated the possible effect of this change in the route of administration on haemoglobin (Hb) levels and epoetin-alpha requirements. This retrospective survey involved 223 haemodialysis patients from 25 Swedish centres. Variables were recorded before and after a mean period of 213 days (range 89-297 days) after the change in the route of administration. The mean epoetin-alpha do had to be increased from 159+/-104 to 185+/-122 U/kg/week (p<0.0001) to maintain a constant Hb level (121+/-12 vs 120+/-11 g/l). Plasma ferritin, albumin, C-reactive protein, iron, iron transferrin saturation and body mass index remained constant. The relative increase in epoetin-alpha dose was negatively correlated with the s.c. dose prior to the switch (R=-0.3; p<0.0001), with the most pronounced dose increases occurring in patients who received a low s.c. dose. A switch from s.c. to i.v. administration of epoetin-alpha in haemodialysis patients was accompanied by an increase in the mean dose requirement of 15%. This increase may be less pronounced in patients receiving high s.c. doses prior to the switch.

Non-opioid analgesics: other: Long-term intrathecal ziconotide effectiveness in chronic malignant and nonmalignant pain

The objective of this study was to evaluate the effectiveness of long-term intrathecal (IT) ziconotide (PRIALTTM) therapy in patients with chronic, intractable pain. This phase III, open-label, multicenter extension study included patients with malignant or nonmalignant chronic pain. Patients had demonstrated analgesic response to ziconotide in previous placebo-controlled trials. Patients were maintained on their optimal dose, established in previous trials, for 30 days. Thereafter, dosage adjustments were not to exceed a twofold increase per 12-hour period. Patients indicated level of pain on the Visual Analog Scale of Pain Intensity (VASPI) (0 mm, no pain to 100 mm, worst pain possible). Ziconotide effectiveness was assessed at monthly intervals and at discontinuation from the study via mean percent change from baseline (defined as initial pre-treatment VASPI score from previous trials). A total of 145 patients received ziconotide and had at least 1 efficacy assessment during treatment. Mean patient age was 55 years (range, 24-85 years). Mean ziconotide dosage was 0.6 mcg/h or 14.4 mcg/d (range, 0.05-6.67 mcg/h) at study initiation and 0.5 mcg/h or 12 mcg/d (range, 0.03-6.67 mcg/h) at study termination. By Week 4, mean percentage change in VASPI was statistically significant in 139 evaluable patients (mean change, 37.2%, P<0.0001). This statistically significant improvement in level of pain was maintained through Month 12 in 31 evaluable patients (mean change, 45.8%, P<0.0001) and the last available observation for 144 evaluable patients (mean change, 36.9%, P<0.0001). Mean ziconotide dosage at Month 12 among the 31 evaluable patients was 0.6 mcg/h or 14.4 mcg/d (range, 0-3 mcg/h). Patients treated with IT ziconotide showed significant improvement from baseline at all monthly assessments from Week 4 through Month 12 of treatment. Stable mean dose requirements in conjunction with sustained VASPI reductions suggest the potential for long-term analgesic benefit.

Carfentanil citrate used as an oral anesthetic agent for brown bears (Ursus arctos).

Carfentanil citrate was given orally to five adult brown bears (Ursus arctos) on 14 separate occasions during the winter and summer to determine effective anesthetic dosages and how season may alter these dosages. Lower blood urea nitrogen:creatinine ratios, depressed appetite, and decreased activity levels in the winter versus summer were reflective of different metabolic states, even though bears were not hibernating in the winter. Doses of carfentanil citrate between 6.0 and 15.2 microg/kg were mixed with 5-10 ml of honey, which the bears licked voluntarily from a spoon. During each anesthetization, respiratory and heart rates, hemoglobin saturation, temperature, electrocardiogram, blood gas values, and level of consciousness were monitored and utilized to determine effective dosages. Mean (+/- SE) dose requirements in the winter were 7.6 +/- 0.4 microg/kg, whereas a greater mean dose of 12.7 +/- 0.5 microg/kg was required in the summer (P < 0.05). After ingestion began, sternal recumbency occurred in an average of 7.5 min (range: 4-11 min), and full restraint and safe handling was achieved in 21 min (range: 8-40 min). At the end of each procedure, naltrexone was given as the reversal agent at a ratio of 100 mg naltrexone per 1 mg carfentanil, with 25% of the dose given i.v. or i.m. and 75% given s.c. Mean reversal time was 6 min after injection of naltrexone (range: 4-9 min). Rapid induction and recovery times and ease of oral administration make carfentanil citrate an effective anesthetic agent for use in brown bears. However, hypoventilation and respiratory acidosis were noted in all bears, and oxygen insufflation is recommended.

Comparison of the Soluble Basal Insulin Analog Insulin Detemir With NPH Insulin

Insulin detemir (NN304) is a soluble basal insulin analog developed to cover basal insulin requirements. This trial aimed to compare the blood glucose-lowering effect of insulin detemir with that of NPH insulin (NPH) and to evaluate the two treatments with regard to intrasubject variation of fasting blood glucose, incidence of hypoglycemia, dose requirements, and safety. This multicenter open randomized crossover trial in 59 type 1 diabetic subjects comprised a 2-week run-in period on a basal-bolus regimen with NPH insulin once daily, followed by two 6-week periods of optimized basal-bolus therapy with either once-daily insulin detemir or NPH insulin. The area under the curve, in the time interval 23:00-8:00, derived from 24-h serum glucose profiles, was not statistically significantly different for the two treatment periods (insulin detemir:NPH ratio 89.2:83.5, P = 0.59). The intrasubject variation in fasting blood glucose during the last 4 days of treatment was lower for insulin detemir compared with NPH (P < 0.001). Mean dose requirements of insulin detemir were 2.35 times higher (95% CI 2.22-2.48) compared with NPH. During the last week of treatment, fewer subjects experienced hypoglycemic episodes on insulin detemir (60%) compared with NPH treatment (77%) (P = 0.049). Insulin detemir was as effective as NPH in maintaining glycemic control when administered at a higher molar dose. The results indicate that insulin detemir may provide more predictable fasting blood glucose with lower intrasubject variation and reduced risk of hypoglycemia compared with NPH.

Leg elevation and wrapping in the prevention of hypotension following spinal anaesthesia for elective Caesarean section

Ninety-seven parturients undergoing elective Caesarean section were allocated randomly to have their legs elevated to approximately 30 degrees on pillows or elevated and wrapped with elasticated Esmarch bandages or neither (controls) following spinal anaesthesia. All patients received intravenous crystalloid (20 ml.kg-1 over 20 min) prior to spinal injection and were placed in the left lateral tilt position. Significant hypotension was treated with intravenous ephedrine in 5 mg bolus doses. Leg wrapping resulted in a significant reduction in the incidence of postspinal hypotension in comparison to the control group (18% compared to 53%, p = 0.004). This represents a five-fold reduction in the likelihood of postspinal hypotension (odds ratio 5.3, 95% CI 1.7-16.3). Leg elevation alone did not significantly reduce the incidence of hypotension (39%). There was no significant difference in the time of onset of hypotension between the groups. For those patients requiring ephedrine, there was no significant difference in mean dose requirements between the groups. The use of leg compression immediately postspinal provides a simple means of reducing the accompanying hypotension and should be used more widely.

Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid cancer.

We have compared the dose of levothyroxine (L-T4) required to suppress serum TSH to given levels in two clinical groups: 1) 44 patients with thyroid cancer whose thyroid glands had been ablated by surgical thyroidectomy and 131I treatment, and 2) 113 patients with thyroidal failure due either to spontaneous primary hypothyroidism (31 patients) or after 131I treatment for Graves' hyperthyroidism (82 patients). The dose of L-T4 needed to attain serum TSH levels in the euthyroid range (0.5-6.2 microU/mL) was significantly greater (P less than 0.01) in patients with thyroid cancer (2.11 micrograms/kg.day) than in the patients with primary hypothyroidism associated with nonmalignant disease (1.63 micrograms/kg.day). Similarly, patients with thyroid cancer required a higher dose of L-T4 to suppress serum TSH to a given subnormal level. These findings suggest that the secretion of hormone from residual thyroid tissue in patients who have not been subjected to near-total thyroid ablation contributes substantially to the circulating levels of serum T4 and T3. We, therefore, infer that residual thyroidal secretion in the patients with hypothyroidism due to benign causes is relatively independent of TSH stimulation. Further subdivision of patients with benign hypothyroidism revealed that patients with Graves' who developed hypothyroidism after 131I treatment showed a lower mean dose requirement than patients with spontaneous hypothyroidism. This raises the possibility that continued secretion of thyroid-stimulating immunoglobulin in such patients might account for the lower dose requirement in the combined group with hypothyroidism. Our studies also have allowed us to make serial observations in 4 patients with thyroid cancer who exhibited elevated levels of serum thyroglobulin. In this limited series, maximal suppression of serum thyroglobulin was produced by doses of L-T4, which reduced circulating TSH to 0.4 mU/L.

Chronic Alcohol Intake Does Not Change Thiopental Anesthetic Requirement, Pharmacokinetics, or Pharmacodynamics

The anesthetic requirements of chronic alcoholics for induction of anesthesia with thiopental were investigated using an electroencephalographic (EEG) measure of thiopental's CNS drug effect and pharmacodynamic modeling to relate thiopental serum concentrations to drug effect. Eleven patients with a history of excessive alcohol intake were studied from an inpatient alcohol rehabilitation program and compared with nine control patients or volunteers who were social drinkers. The alcoholic population had consumed ethanol 9-17 days prior to the study. They had no evidence of acute intoxication or acute withdrawal at the time of the study. Five of the 11 alcoholic patients were restudied after 1 month of abstinence from alcohol consumption. Each study consisted of a thiopental infusion until EEG burst suppression (1-3 s of isoelectric signal) was achieved. Timed arterial and then venous blood samples were obtained for measurement of thiopental serum concentrations for up to 36 h. Pharmacokinetic differences between groups were analyzed using a three-compartment model. Power spectral analysis of the EEG allowed determination of spectral edge frequency. An inhibitory sigmoid Emax pharmacodynamic model combined with an effect compartment was used to analyze concentration-response relationships and to provide an estimate of brain sensitivity to thiopental in the study populations. The thiopental anesthetic dose requirement using the EEG was not different between alcoholics and nonalcoholics. The mean dose requirement (+/- SD) of alcoholics was 823 +/- 246 mg and the mean dose requirement of nonalcoholics was 733 +/- 218 mg. There were no differences in thiopental pharmacokinetic and pharmacodynamic parameters between alcoholics and nonalcoholics.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of a scheme for establishing and maintaining dosage of theophylline in ambulatory patients with chronic asthma

To assess the utility of a dose-titration scheme for determining maintenance theophylline requirements, dose requirements and stability of serum concentrations were examined using 3537 serum determinations from 1073 patients with chronic asthma during a 5-year period. When the dosing scheme was followed, 78% of initial serum concentrations were within the target range of 10 to 20 micrograms/ml; the mean number of measurements to attain this range was 1.3. Among 404 of these patients prospectively questioned, adverse effects were not present in all 41 whose initial serum concentration was less than 10 micrograms/ml, occurred in eight of 296 patients when serum concentrations were between 10 and 20 micrograms/ml, and were present in 21 of 67 when concentrations were greater than 20 micrograms/ml. After final dose adjustment, mean dose requirements among those who attained serum concentrations of 10 to 20 micrograms/ml averaged 22 mg/kg/day in 1- to 9-year-old children, 20 mg/kg/day in 9- to 12-year-old children, 18 mg/kg/day in 12- to 16 year-old children, and 13 mg/kg/day in the 94 patients older than 16 years of age. Repeat serum concentrations after 3 months to 2 years showed 66% remaining within the 10 to 20 micrograms/ml range and another 15% between 7.5 and 10 micrograms/ml; 9% were greater than 20 micrograms/ml, and none greater than 30 micrograms/ml. Thus the dosing scheme produces serum concentrations in the usual therapeutic range with a minimum of samples and few side effects; most patients maintained acceptably stable blood levels.