Cephalad Movement of Morphine and Fentanyl in Humans after Intrathecal Injection

Background: Despite decades of use, controversy remains regarding the extent and time course of cephalad spread of opioids in cerebrospinal fluid (CSF) after intrathecal injection. The purpose of this study was to examine differences between two often used opioids, morphine and fentanyl, in distribution in the CSF after intrathecal injection.

Methods: Eight healthy volunteers received intrathecal injection of morphine (50 [mu]g) plus fentanyl (50 [mu]g) at a lower lumbar interspace. CSF was sampled through a needle in an upper lumbar interspace for 60-120 min. At the end of this time, a sample was taken from the lower lumbar needle, and both needles were withdrawn. CSF volume was determined by magnetic resonance imaging. Pharmacokinetic modeling was performed with NONMEM.

Results: Morphine and fentanyl peaked in CSF at the cephalad needle at similar times (41 +/- 13 min for fentanyl, 57 +/- 12 min for morphine). The ratio of morphine to fentanyl in CSF at the cephalad needle increased with time, surpassing 2:1 by 36 min and 4:1 by 103 min. CSF concentrations did not correlate with weight, height, or lumbosacral CSF volume. The concentrations of morphine and fentanyl at both sampling sites were well described by a simple pharmacokinetic model. The individual model parameters did not correlate with the distance between the needles, CSF volume, patient height, or patient weight.     

Gabapentin Activates Spinal Noradrenergic Activity in Rats and Humans and Reduces Hypersensitivity after Surgery

Background: Gabapentin has been reported to inhibit various acute and chronic pain conditions in animals and humans. Although the efficacy of gabapentin depends on the [alpha]2[delta] subunit of voltage-gated calcium channels, its analgesic mechanisms in vivo are still unknown. Here, the authors tested the role of spinal noradrenergic inhibition in gabapentin's analgesia for postoperative pain.

Methods: Gabapentin was administered orally and intracerebroventricularly to rats on the day after paw incision, and withdrawal threshold to paw pressure was measured. The authors also measured cerebrospinal fluid concentration of norepinephrine and postoperative morphine use after surgery in patients who received oral placebo or gabapentin.

Results: Both oral and intracerebroventricular gabapentin attenuated postoperative hypersensitivity in rats in a dose-dependent manner. This effect of gabapentin was blocked by intrathecal administration of the [alpha]2-adrenergic receptor antagonist idazoxan and the G protein-coupled inwardly rectifying potassium channel antagonist tertiapin-Q, but not by atropine. In humans, preoperative gabapentin, 1,200 mg, significantly increased norepinephrine concentration in cerebrospinal fluid and decreased morphine requirements.     

Factor Xa-activated whole blood clotting time (Xa-ACT) for bedside monitoring of dalteparin anticoagulation during haemodialysis.

BACKGROUND: Low molecular weight heparins (LMWH) like dalteparin are increasingly used for anticoagulation during haemodialysis (HD). The available laboratory tests for monitoring LMWH anticoagulation are time-consuming and expensive, and the suitability of the conventional activated clotting time (ACT) is controversial. A simple and cheap bedside test would be useful. METHODS: We studied the factor Xa-activated whole blood clotting time (Xa-ACT) in vitro and in vivo in nine patients undergoing chronic HD with i.v. dalteparin bolus anticoagulation and compared it with the conventional ACT. Plasma anti-factor Xa (antiXa) activity was determined with a chromogenic assay. Thrombin-antithrombin complexes were measured to detect coagulation activation. RESULTS: Xa-ACT and ACT were prolonged with rising dalteparin concentration. In vitro, both clotting times were strongly correlated with the antiXa levels (r = 0.94 and 0.89, respectively). Nevertheless, compared with the ACT, the Xa-ACT was considerably more sensitive to the LMWH in vitro (healthy blood: Xa-ACT 90 s/U vs ACT 26 s/U; uraemic blood: Xa-ACT 96 s/U vs ACT 31 s/U) as well as in vivo (Xa-ACT 81 s/U vs ACT 22 s/U) and reflected different intensities of anticoagulation. An initial dalteparin bolus of 80+/-11 U/kg body weight was able to prevent coagulation activation for up to 4 h of HD. CONCLUSION: For monitoring LMWH anticoagulation the Xa-ACT was superior to the conventional ACT in vitro as well as in vivo during HD. The Xa-ACT can be useful as a LMWH bedside test. The ACT was not sensitive enough to serve as a LMWH monitoring tool.     

Genetic predisposition for adult lactose intolerance and relation to diet, bone density, and bone fractures.

Evidence that genetic disposition for adult lactose intolerance significantly affects calcium intake, bone density, and fractures in postmenopausal women is presented. PCR-based genotyping of lactase gene polymorphisms may complement diagnostic procedures to identify persons at risk for both lactose malabsorption and osteoporosis. INTRODUCTION: Lactase deficiency is a common autosomal recessive condition resulting in decreased intestinal lactose degradation. A -13910 T/C dimorphism (LCT) near the lactase phlorizin hydrolase gene, reported to be strongly associated with adult lactase nonpersistence, may have an impact on calcium supply, bone density, and osteoporotic fractures in the elderly. MATERIALS AND METHODS: We determined LCT genotypes TT, TC, and CC in 258 postmenopausal women using a polymerase chain reaction-based assay. Genotypes were related to milk intolerance, nutritional calcium intake, intestinal calcium absorption, bone mineral density (BMD), and nonvertebral fractures. RESULTS: Twenty-four percent of all women were found to have CC genotypes and genetic lactase deficiency. Age-adjusted BMD at the hip in CC genotypes and at the spine in CC and TC genotypes was reduced by -7% to -11% depending on the site measured (p = 0.04). LCT(T/C-13910) polymorphisms alone accounted for 2-4% of BMD in a multiple regression model. Bone fracture incidence was significantly associated with CC genotypes (p = 0.001). Milk calcium intake was significantly lower (-55%, p = 0.004) and aversion to milk consumption was significantly higher (+166%, p = 0.01) in women with the CC genotype, but there were no differences in overall dietary calcium intake or in intestinal calcium absorption test values. CONCLUSION: The LCT(T/C-13910) polymorphism is associated with subjective milk intolerance, reduced milk calcium intake, and reduced BMD at the hip and the lumbar spine and may predispose to bone fractures. Genetic testing for lactase deficiency may complement indirect methods in the detection of individuals at risk for both lactose malabsorption and osteoporosis.     

Arthrodese des unteren Sprunggelenks

Pain in or symptomatic destruction of any number of the joints of the hindfoot can have several causes. As well as primary osteoarthritis, these include secondary arthrotic changes following fractures (especially of the talus and/or calcaneus), muscular and/or tenoligamentous instability (e.g., rupture of the posterior tibialis tendon, poliomyelitis, Charcot-Marie-Tooth disease), spastic and flaccid paresis of the lower leg and foot, late stages of various inflammatory arthritides (rheumatoid arthritis, seronegative spondarthritis, collagenoses), and neuropathic diseases with impaired depth perception (Charcot disease of the foot in diabetes mellitis, for example). As a general policy, only joints that are causing symptoms, are clearly arthritic, or are involved in a fixed foot deformity should be fused, so that as much of the residual hindfoot motion as possible is preserved. This helps to restrict future osteoarthritis in adjacent joints. The use of screws rather than staples seems to increase the fusion rates because this technique allows compression on the fusion.     

Adverse reactions to non-ionic contrast media with special regard to high-risk patients

Non-ionic contrast media (CM) are proven to be significantly safer than the high osmolar ionic contrast media (HOCM). Nevertheless deaths are reported after administration of non-ionic agents. The aim of the study was to investigate the rate of adverse reactions to non-ionic CM with special regard to high-risk patients and the effects of premedication with H1-and H2-receptor antagonists.In a prospective study conducted over about 2 years 12 995 examinations with intravenous or intra-arterial non-ionic CM were evaluated. Premedication with H1-and H2-antagonists was used in 1276 high-risk patients with known adverse reaction to CM, history of allergy or severe cardiac or pulmonary disease. 229 patients received no premedication inspite of known risk factors. In total, there were 143 (1.10%) adverse reactions (mild in 0.58%, moderate in 0.41% and severe in 0.05%). In high-risk patients there were adverse reactions in 4.37% without and in 1.57% with premedication. There were no severe adverse reactions in the high-risk patients after premedication. The age of the patient, CM dosage and CM concentration were not shown to be risk factors in the present study. In conclusion, the additional premedication with H1- and H2-antagonists could be an effective agent to reduce the risk of mild and moderate adverse reactions and to avoid severe adverse reactions in high-risk patients. Correspondence to: U. Fink     

Treatment of post-traumatic limb shortening]

The physiological phenomenon of changes in callus formation during distraction was first described by Codivilla at the beginning of this century. Having investigated and proved the influence of tension stress on callus formation, Ilizarov used this as a method to treat limb shortening and deformities. Because of his remarkable results we introduced this method in our hospital in 1990, using the original Ilizarov ring fixator. From November 1990 to December 1991, we used this technique in 10 cases of combined post-traumatic bone shortening with deformity (the tibia was affected in six patients, the femur in three and the forearm in one). The mean shortening was 3.1 cm, the mean varus or valgus deformity 9.5 degrees, the mean anteflexion or recurvation 8.3 degrees, and the mean rotation deformity 8.5 degrees. Distraction/correction lasted between 8 and 55 days (mean: 37 days). Fixation was necessary for between 60 and 339 days. If corticotomy was performed in the diaphyseal bone, fixation lasted almost twice as long (11.33 days/mm lengthening) as in the metaphyseal area (6.55 days/mm lengthening). There were 14 complications, most of which were considered minor. The latter included pin infections (4), wire breaking (1) and restricted range of motion of the knee or ankle (5). Among the major complications were two nerve irritations, which recovered spontaneously, and two pin-induced local bone infections, which required surgical intervention. Achievement of the goals of treatment-complete correction of shortening and deformity-was not affected by these complications.     

Health promotion and disease prevention in HMOs: a survey of newly established IPAs in New York City

Independent Practice Associations (IPAs) are the fastest growing segment of the Health Maintenance Organization (HMO) industry, but little is known about their provision of health promotion and disease prevention to subscribers. To examine the extent to which IPA policies encourage health promotion and disease prevention, we interviewed medical directors and other senior administrators of six newly developing IPA-HMOs in New York City. We also reviewed promotional literature to assess how extensively health promotion and disease prevention were marketed to the potential subscriber. Although medical protocols for preventive screening exist in most IPAs, compliance with guidelines is left largely to the individual physician's judgment for implementation. IPA respondents suggested that their physician panels are oriented toward prevention, but there is uncertain evidence in this regard, and incentive payments could discourage referrals for screening. Health education programs are sporadic. Health promotion and disease prevention do not appear to be a high priority among six newly established IPAs in New York City. We recommend several steps that would encourage IPA-HMOs to increase their health promotion activities.