The cost-effectiveness of sugammadex for the routine reversal of muscle relaxation produced by rocuronium or vecuronium in UK practice is uncertain. We performed a systematic review of randomized controlled trials of sugammadex compared with neostigmine/glycopyrrolate and an economic assessment of sugammadex for the reversal of moderate or profound neuromuscular block (NMB) produced by rocuronium or vecuronium. The economic assessment aimed to establish the reduction in recovery time and the ‘value of time saved’ which would be necessary for sugammadex to be potentially cost-effective compared with existing practice. Three trials indicated that sugammadex 2 mg kg−1 (4 mg kg−1) produces more rapid recovery from moderate (profound) NMB than neostigmine/glycopyrrolate. The economic assessment indicated that if the reductions in recovery time associated with sugammadex in the trials are replicated in routine practice, sugammadex would be cost-effective if those reductions are achieved in the operating theatre (assumed value of staff time, £4.44 per minute), but not if they are achieved in the recovery room (assumed value of staff time, £0.33 per minute). However, there is considerable uncertainty in these results. Sugammadex has the potential to be cost-effective compared with neostigmine/glycopyrrolate for the reversal of rocuronium-induced moderate or profound NMB, provided that the time savings observed in trials can be achieved and put to productive use in clinical practice. Further research is required to evaluate the effects of sugammadex on patient safety, predictability of recovery from NMB, patient outcomes, and efficient use of resources.
clinical trials; neuromuscular block, recovery; neuromuscular block, rocuronium
Sugammadex 16 mg kg−1 can be used for the immediate reversal of neuromuscular block 3 min after administration of rocuronium and could be used in place of succinylcholine for emergency intubation. We have systematically reviewed the efficacy and cost-effectiveness and made an economic assessment of sugammadex for immediate reversal. The economic assessment investigated whether sugammadex appears cost-effective under various assumptions about the value of any reduction in recovery time with sugammadex, the likelihood of a ‘can't intubate, can't ventilate’ (CICV) event, the age of the patient, and the length of the procedure. Three trials were included in the efficacy review. Sugammadex administered 3 or 5 min after rocuronium produced markedly faster recovery than placebo or spontaneous recovery from succinylcholine-induced block. No published economic evaluations were found. Our economic analyses showed that sugammadex appears more cost-effective, where the value of any reduction in recovery time is greater, where the reduction in mortality compared with succinylcholine is greater, and where the patient is younger, for lower probabilities of a CICV event and for long procedures which do not require profound block throughout. Because of the lack of evidence, the value of some parameters remains unknown, which makes it difficult to provide a definitive assessment of the cost-effectiveness of sugammadex in practice. The use of sugammadex in combination with high-dose rocuronium is efficacious. Further research is needed to clarify key parameters in the analysis and to allow a fuller economic assessment.
complications, intubation tracheal; neuromuscular block, recovery; neuromuscular block, rocuronium; neuromuscular block, succinylcholine
oxide (NO) is detectable in the exhaled breath, is involved in airway
defence and inflammation, and probably modulates bronchial smooth
muscle tone. Given the sensitivity of nitrogen oxides to local redox
conditions, we postulated that exposure to oxidant or antioxidant
compounds could alter concentrations of NO in the exhaled breath (eNO).
We assessed the effect of nitrogen dioxide (NO2) and
ascorbic acid exposure on eNO in healthy human subjects.
subjects were randomised to undergo a 20 minute single blind exposure
to NO2 (1.5 parts per million) or medical air in a
crossover fashion. Exhaled NO and pulmonary function were measured
before and for 3 hours after exposure. In a separate double blind
crossover study 20 healthy subjects received ascorbic acid 500 mg
twice daily or placebo for 2 weeks with a 6 week interim washout. Serum
ascorbic acid levels and eNO were measured before and after each
induced a decrease of 0.62 (95% CI 0.32 to 0.92) ppb in the mean
post-exposure eNO (p<0.01) with no change in forced expiratory volume
in 1 second (FEV1). Oral supplementation with ascorbic acid
increased the mean serum ascorbic acid concentration by 7.4(95% CI
5.1 to 9.7) µg/ml (63%) but did not alter eNO.
exposure causes a decrease in eNO, an effect which may be mediated
through changes in epithelial lining fluid redox state or through a
direct effect on epithelial cells. In contrast, ascorbic acid does not
appear to play a significant role in the metabolism of NO in the
epithelial lining fluid.
oxide (NO) is a product of the enzyme nitric oxide synthase (NOS) and
is found in normal and asthmatic human airways. The administration of
L-arginine results in an increase in airway NO production
in asthmatic subjects. This is thought to occur because
L-arginine is the substrate for NOS. However, studies in
the systemic vasculature suggest that other mechanisms may be responsible.
with steroid naive asthma each received 2.5 g L-arginine,
2.5 g D-arginine, and 2.0% saline by ultrasonic nebuliser on separate days in a randomised, single blind manner. Exhaled NO was
measured by chemiluminescence and spirometric tests were performed
before and for 3 hours after each administration. The mean
concentration of NO after exposure was calculated from the area under
D-arginine, and 2.0% saline induced a mean (95% CI)
maximal bronchoconstriction of 11.9% (-1.7 to 25.4), 10.0% (2.8 to
17.2), and 8.5% (-2.5 to 19.5) of the starting forced expiratory
volume in one second (FEV1), respectively. Exhaled NO
declined in proportion to the degree of bronchoconstriction (r=0.60, p<0.01). Bronchoconstriction and
the acute reduction in exhaled NO resolved within 15 minutes. The mean
post-exposure concentration of NO was 15.75 parts per billion (ppb)
after L-arginine, 15.16 ppb after D-arginine,
and 12.74 ppb after 2.0% saline. The mean (95% CI) difference
between L-arginine and placebo was 3.01(0.32 to 5.7) ppb,
between D-arginine and placebo 2.42 (0.10 to 4.74) ppb,
and between L- and D-arginine 0.59 (-1.56 to
decreased with acute bronchoconstriction and returned to baseline with
the resolution of bronchoconstriction. Exhaled NO increased following
the administration of both L-arginine and D-arginine. Since NOS is stereospecific, this finding
suggests that the increase in exhaled NO is not entirely mediated
through an increase in NOS enzyme activity. We suggest that arginine
may react in a non-stereospecific fashion with reactive oxygen species present in asthmatic airways.
smoking is associated with a number of common pulmonary diseases
including chronic airflow limitation and bronchial carcinoma. Lower
respiratory tract (LRT) nitric oxide (NO) concentrations are reduced in
habitual cigarette smokers between cigarettes, and although this
finding has been implicated in the pathogenesis of smoking related
disease, the underlying mechanisms are unclear. A study was undertaken
to determine the nature and time course for changes in LRT NO
concentrations following acute inhalation of cigarette smoke.
healthy habitual smokers were studied. The concentration of LRT NO in
exhaled breath before, one and ten minutes after smoking a single
cigarette was measured using chemiluminescence.
concentrations increased in all subjects from a mean (SE) of 2.6 (0.27)
to 4.8 (0.26) ppb (p<0.0001) at one minute, and at 10 minutes remained
significantly raised above the baseline level at 3.2 (0.25) ppb (p = 0.003). The mean (95% CI) increases in NO concentrations were 2.2 (1.7 to 2.7) and 0.6 (0.2 to 1.0) ppb, respectively.
findings were unexpected in both their direction and time course. They
suggest a novel mechanism for the handling of NO in the human lung. We
hypothesise that NO is trapped in the epithelial lining fluid (ELF) of
the normal human respiratory tract in bioequivalent forms such as
S-nitrosothiols or peroxynitrite and that this trapping mechanism is
sensitive to the redox state of the ELF. LRT NO concentrations will
thus increase with oxidant exposure and decline as pulmonary
antioxidant defence mechanisms take effect. These findings may have
implications for the pathogenesis and diagnosis of oxidant mediated
Smooth muscle tumors are uncommon lesions of the vulva and represent a variety of histologic types. When encountered, surgical treatment is guided by the malignant potential of the tumors. This article presents the case of a 45-year-old woman who underwent conservative excision of a 10-cm vulvar lesion consistent with benign epithelioid leiomyoma. This unusual case provides an opportunity to review the clinical and pathologic features of this uncommon variant of leiomyoma and to describe the recently suggested pathologic criteria for determining the malignant potential of smooth muscle tumors arising in the vulva. Knowledge of these criteria can guide the clinician in selecting the appropriate management.
The role of nitric oxide in basal vasomotor tone and stimulated endothelium-dependent dilations in the coronary arteries in chronically instrumented awake dogs was studied by examining the consequences of inhibiting endogenous nitric oxide formation with the specific inhibitor of nitric oxide formation, NG-monomethyl-L-arginine (L-NMMA). In four awake dogs, coronary dimension crystals were chronically implanted on the circumflex artery for the measurement of epicardial coronary diameter, and Doppler flow probes were implanted for quantitation of phasic coronary blood flow (vasomotion of distal regulatory resistance vessels). Basal epicardial coronary diameter, acetylcholine-stimulated endothelium-dependent dilation, and flow-induced endothelium-dependent dilation of the epicardial arteries and phasic blood flow were recorded before, and after 5, 15, 50, and 120 mg/kg of L-NMMA. L-NMMA induced a dose-related increase in basal epicardial coronary vasomotor tone. There was an accompanying increase in aortic pressure and a decrease in heart rate. At doses greater than or equal to 50 mg/kg, rest phasic coronary blood flow was also decreased. Left ventricular end-diastolic pressure and contractility were not significantly changed. In contrast, the flow-induced or acetylcholine-stimulated endothelium-dependent responses were attenuated only after infusion of the highest does of L-NMMA (120 mg/kg). The changes in the basal vasomotor tone and acetylcholine-stimulated endothelium-dependent responses returned towards the control states in the presence of L-arginine (660 mg/kg). These data support the view that nitric oxide plays a significant role in modulating basal vasomotion and endothelial-dependent dilation stimulated by acetylcholine or increase in blood flow in epicardial coronary arteries and also influence the regulation of coronary blood flow during physiologic conditions.
Trichomonas vaginalis infection (TVI) was found by examination of Pap smears in 25% of 3,005 unselected urban black women being screened for cancer of the cervix and vagina. The incidence was 22% in the group under 29 years of age; 69% in those between 30 and 59; and 9% in those over 60. Women who had had a hysterectomy had 16% lower incidence of TVI than did the controls. Class 1 reports (atypia, metaplasia, hyperplasia) were obtained in 10% of the entire group. Cytologic changes were present in 19% of the women with TVI. Women who had had hysterectomy had a 40% less chance of having a class 1 report compared with controls. Class 1 reports occurred 2.7 times more frequently in TVI than in uninfected controls.
A highly significant, but unanswered, question in the pathogenesis of psoriasis relates to how normal appearing and diseased skin can coexist, undergo spontaneous flares and remissions, and yet appear to be genetically acquired. A plausible explanation for these disparate observations is that there is a basic defect in epidermal proliferation of skin of subjects with psoriasis and that disease expression is governed by other host factors. To address this question, we compared epidermal proliferation of skin involved and uninvolved with psoriasis with normal skin before and after transplantation to congenitally athymic (nude) mice, a biologic milieu free of humoral factors unique to the donor host. Results demonstrated that (a) before transplant, synthesis of DNA by the epidermal cells from skin uninvolved and involved with psoriasis is significantly higher than normal, 1.6 and 3.6 times, respectively; (b) 6 wk after transplantation, synthesis of DNA by epidermal cells is unchanged for normal skin, increased for uninvolved skin, and decreased for involved skin. These increases and decreases are of such a magnitude that at 6 wk the number of epidermal cells synthesizing DNA per 1,000 basal cells is identical, and is 2.2 times that of normal skin. When removed from the milieu of the afflicted host, skin involved and uninvolved with psoriasis appear equally "diseased." These data support the notion that there is aberrant epidermal proliferation in skin of patients with psoriasis and that host factors appear to play a role both in the expression and nonexpression of this disease.
The incidence of cytoplasmic metachromasia has been studied in cultures of skin fibroblasts derived from 6 cases of the syndrome of supravalvular aortic stenosis, characteristic facies, and mental retardation which in many instances represents the late normocalcaemic stage of the severe form of infantile hypercalcaemia. The percentage of metachromatic cells (mean positivity 7.3%) was significantly higher than in control cultures. The addition of vitamin D2 and calcium to culture media caused a highly significant increase in metachromatic cells (mean positivity in supplemented media 16.1%) compared with a lesser increase in controls. These findings strengthen previous suggestions that there is a genetically determined hypersensitivity to vitamin D in some cases of the syndrome. A multifactorial aetiology is proposed, dependent on a variable genetic susceptibility of fetal connective tissues to a non-physiological effect of D vitamins and a variable level of maternal vitamin D nutrition.
The development of the highly sensitive cytochemical bioassay for ACTH has permitted the measurement of plasma ACTH levels during the insulin hypoglycaemia test (I.H.T.) in patients treated with corticosteroids and corticotrophin. The ACTH, corticosteroid, and growth hormone (GH) responses in the I.H.T. were measured in three groups of 12 rheumatoid arthritis patients. One group was receiving long-term corticotrophin treatment, the second was undergoing long-term corticosteroid treatment, and the third had never received systemic hormone therapy. The increments in plasma ACTH, corticosteroids, and GH were diminished in the corticosteroid-treated group, as were increments in plasma GH and ACTH in the corticotrophin-treated group; but in this group the corticosteroid increment was normal. Examination of the area under the curve of the ACTH response showed that the total amount of ACTH secreted was normal though the rate of secretion was reduced. In the corticosteroid-treated group both rate and total secretion were diminished.
Oligonucleotide sequences based on the amino acid sequence of the putative testis determining gene ZFY have been used to isolate a 1.3 Kb Hind III Y genomic DNA fragment CMPXY1 and three human testis cDNA sequences (CMPXY2, CMPXY3 and CMPXY4). These sequences detect at least four potential exons on the Y (Y1, Y3, Y4 and Y5), three on the X (X1, X2 and X3) and three of autosomal origin (A1, A2 and A3) as determined by comparing the fragments detected by different clones. Analysis with subfragments of CMPXY4 shows that Y3 is unique to the Y and that Y4 and X1 are homologous. Y5 and X3 are detected by the same subfragment of CMPXY4. This is also the case for Y1, X2, A1, A2 and A3. Thus these exons may contain further regions of homology between the X, Y and an autosomal locus. The X-linked sequences all lie in Xp21.2-Xp22.1 and studies with XX males have placed the Y-linked sequences in distal Yp adjacent to the Y-autosomal homologous sequence GMGY3. We have confirmed these localizations by in situ hybridization with CMPXY4 and have shown additionally that the autosomal sequences of both the CMPXY4 sequence and GMGY3 map to 9p22-9pter. Restriction analysis demonstrates that CMPXY1/XY2/XY3 differ in sequence from CMPXY4 at three restriction enzyme sites, thus suggesting that they are transcribed from different but closely related genes and that CMPXY4 must be either X-linked or autosomal in origin. This indicates that more than one of the loci containing ZFY-related sequences are transcribed and potentially fulfil functionally distinct roles in the human sex determining pathway. Northern blot analysis of human foetal testis RNA has shown that three low abundance transcripts of 5, 6 and 8 Kb can be detected by ZFY-related DNA sequences.
We have determined the exon structure of the mouse tyrosinase-related protein-1 (TRP-1) gene. The gene is only 15kb in length, but contains seven introns, in contrast to the tyrosinase gene which is almost 100kb long with only four introns. Only two introns are located in homologous positions in both genes. Intron I of TRP-1 has three alternative 5' splice sites clustered within 21bp, which all splice to the same 3' site. Intron V has a very unusual 5' splice site, which has the dinucleotide GC rather than the conventional GT. We show that as little as 370bp of 5'-flanking DNA is sufficient to direct cell-specific expression of the chloramphenicol acetyl transferase gene. The flanking DNA of TRP-1, unlike tyrosinase, does not contain a TATA box or a CCAAT box. Both mouse genes, however, share an 11bp sequence, also found in human tyrosinase, which we suggest may be a melanocyte-specific promoter element.