Nefopam for the prevention of postoperative pain: quantitative systematic review

Nefopam, a centrally acting analgesic, has been used in the surgical setting in many countries since the mid-1970s. However, clinical trials provide contflicting results for its analgesic potency. We performed a systematic search (multiple databases, bibliographies, any language, to January 2008) for randomized, placebo-controlled trials of nefopam for the prevention of postoperative pain. Data were combined using classic methods of meta-analyses and were expressed as weighted mean difference (WMD), relative risk (RR), and number needed to treat/harm (NNT/H) with 95% confidence interval (CI). Nine trials (847 adult patients, 359 received nefopam) were included. Nefopam (cumulative doses, 20-160 mg) was given orally or i.v., as single or multiple doses, or as a continuous infusion. Compared with placebo, cumulative 24 h morphine consumption was decreased with nefopam: WMD −13 mg (95% CI −17.9 to −8.15). Pain intensity at 24 h was also decreased: on a 100 mm visual analogue scale, WMD −11.5 mm (95% CI −15.1 to −7.85). The incidence of tachycardia was increased with nefopam (RR 3.12, 95% CI 1.11-8.79; NNH 7), as was the incidence of sweating (RR 4.92, 95% CI 2.0-12.1; NNH 13). There is limited evidence from the published literature that nefopam may be a useful non-opioid analgesic in surgical patients. The analgesic potency seems to be similar to non-steroidal anti-inflammatory drugs. However, dose responsiveness and adverse effect profile remain unclear, and the role of nefopam as part of multimodal analgesia needs to be established. Data in children are lackin

Benefit and risk of intrathecal morphine without local anaesthetic in patients undergoing major surgery: meta-analysis of randomized trials

Intrathecal morphine without local anaesthetic is often added to a general anaesthetic to prevent pain after major surgery. Quantification of benefit and harm and assessment of dose-response are needed. We performed a meta-analysis of randomized trials testing intrathecal morphine alone (without local anaesthetic) in adults undergoing major surgery under general anaesthesia. Twenty-seven studies (15 cardiac-thoracic, nine abdominal, and three spine surgery) were included; 645 patients received intrathecal morphine (dose-range, 100-4000 µg). Pain intensity at rest was decreased by 2 cm on the 10 cm visual analogue scale up to 4 h after operation and by about 1 cm at 12 and 24 h. Pain intensity on movement was decreased by 2 cm at 12 and 24 h. Opioid requirement was decreased intraoperatively, and up to 48 h after operation. Morphine-sparing at 24 h was significantly greater after abdominal surgery {weighted mean difference, −24.2 mg [95% confidence interval (CI) −29.5 to −19.0]}, compared with cardiac-thoracic surgery [−9.7 mg (95% CI −17.6 to −1.80)]. The incidence of respiratory depression was increased with intrathecal morphine [odds ratio (OR) 7.86 (95% CI 1.54-40.3)], as was the incidence of pruritus [OR 3.85 (95% CI 2.40-6.15)]. There was no evidence of linear dose-responsiveness for any of the beneficial or harmful outcomes. In conclusion, intrathecal morphine decreases pain intensity at rest and on movement up to 24 h after major surgery. Morphine-sparing is more pronounced after abdominal than after cardiac-thoracic surgery. Respiratory depression remains a major safety concer

Propofol 1% versus propofol 2% in children undergoing minor ENT surgery

Background. The induction characteristics of propofol 1% and 2% were compared in children undergoing ENT surgery, in a prospective, randomized, double‐blind study. Methods. One hundred and eight children received propofol 1% (n=55) or 2% (n=53) for induction and maintenance of anaesthesia. For induction, propofol 4mgkg-1 was injected at a constant rate (1200mlh-1), supplemented with alfentanil. Intubating conditions without the use of a neuromuscular blocking agent were scored. Results. Pain on injection occurred in 9% and 21% of patients after propofol 1% and 2%, respectively (P=0.09). Loss of consciousness was more rapid with propofol 2% compared with propofol 1% (47s vs 54s; P=0.02). Spontaneous movements during induction occurred in 22% and 34% (P=0.18), and intubating conditions were satisfactory in 87% and 96% (P=0.19) of children receiving propofol 1% or 2%, respectively. There were no differences between the two groups in respect of haemodynamic changes or adverse events. Conclusions. For the end‐points tested, propofol 1% and propofol 2% are similar for induction of anaesthesia in children undergoing minor ENT surgery. Br J Anaesth 2003: 90: 375-

Ventilation strategies in obese patients undergoing surgery: a quantitative systematic review and meta-analysis†

Background Pathophysiological changes due to obesity may complicate mechanical ventilation during general anaesthesia. The ideal ventilation strategy is expected to optimize gas exchange and pulmonary mechanics and to reduce the risk of respiratory complications. Methods Systematic search (databases, bibliographies, to March 2012, all languages) was performed for randomized trials testing intraoperative ventilation strategies in obese patients (BMI ≥30 kg m−2), and reporting on gas exchange, pulmonary mechanics, or pulmonary complications. Meta-analyses were performed when data from at least three studies or 100 patients could be combined. Results Thirteen studies (505 obese surgical patients) reported on a variety of ventilation strategies: pressure- or volume-controlled ventilation (PCV, VCV), various tidal volumes, and different PEEP or recruitment manoeuvres (RM), and combinations thereof. Definitions and reporting of endpoints were inconsistent. In five trials (182 patients), RM added to PEEP compared with PEEP alone improved intraoperative ratio [weighted mean difference (WMD), 16.2 kPa; 95% confidence interval (CI), 8.0-24.4] and increased respiratory system compliance (WMD, 14 ml cm H2O−1; 95% CI, 8-20). Arterial pressure remained unchanged. In four trials (100 patients) comparing PCV with VCV, there was no difference in ratio, tidal volume, or arterial pressure. Comparison of further ventilation strategies or combination of other outcomes was not feasible. Data on postoperative complications were seldom reported. Conclusions The ideal intraoperative ventilation strategy in obese patients remains obscure. There is some evidence that RM added to PEEP compared with PEEP alone improves intraoperative oxygenation and compliance without adverse effects. There is no evidence of any difference between PCV and VC

Bispectral and spectral entropy indices at propofol-induced loss of consciousness in young and elderly patients

Background Bispectral (BIS) and state/response entropy (SE/RE) indices have been widely used to estimate depth of anaesthesia and sedation. In adults, independent of age, adequate and safe depth of anaesthesia for surgery is usually assumed when these indices are between 40 and 60. Since the EEG is changing with increasing age, we investigated the impact of advanced age on BIS, SE, and RE indices during induction. Methods BIS and SE/RE indices were recorded continuously in elderly (≥65 yr) and young (≤40 yr) surgical patients who received propofol until loss of consciousness (LOC) using stepwise increasing effect-site concentrations. LOC was defined as an observer assessment of alertness/sedation score <2, corresponding to the absence of response to mild prodding or shaking. Results We analysed 35 elderly [average age, 78 yr (range, 67-96)] and 34 young [35 (19-40)] patients. At LOC, all indices were significantly higher in elderly compared with young patients: BISLOC, median 70 (range, 58-91) vs 58 (40-70); SELOC, 71 (31-88) vs 55.5 (23-79); and RELOC, 79 (35-96) vs 59 (25-80) (P<0.001 for all comparisons). With all three monitors, only a minority of elderly patients lost consciousness within a 40-60 index range: two (5.7%) with BIS and RE each, and seven (20%) with SE. In young patients, the respective numbers were 20 (58.8%) for BIS, 13 (38.2%) for SE, and nine (26.5%) for RE. Conclusions In adults undergoing propofol induction, BIS, SE, and RE indices at LOC are significantly affected by ag

Altered outer hair cell mitochondrial and subsurface cisternae connectomics are candidate mechanisms for hearing loss in mice

Organelle crosstalk is vital for cellular functions. The propinquity of mitochondria, ER, and plasma membrane promote regulation of multiple functions, which include intracellular C

Dynamic displacement of normal and detached semicircular canal cupula

© 2009 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial License. The definitive version was published in JARO - Journal of the Association for Research in Otolaryngology 10 (2009): 497-509, doi:10.1007/s10162-009-0174-y.The dynamic displacement of the semicircular canal cupula and modulation of afferent nerve discharge were measured simultaneously in response to physiological stimuli in vivo. The adaptation time constant(s) of normal cupulae in response to step stimuli averaged 36 s, corresponding to a mechanical lower corner frequency for sinusoidal stimuli of 0.0044 Hz. For stimuli equivalent to 40–200 deg/s of angular head velocity, the displacement gain of the central region of the cupula averaged 53 nm per deg/s. Afferents adapted more rapidly than the cupula, demonstrating the presence of a relaxation process that contributes significantly to the neural representation of angular head motions by the discharge patterns of canal afferent neurons. We also investigated changes in time constants of the cupula and afferents following detachment of the cupula at its apex—mechanical detachment that occurs in response to excessive transcupular endolymph pressure. Detached cupulae exhibited sharply reduced adaptation time constants (300 ms–3 s, n = 3) and can be explained by endolymph flowing rapidly over the apex of the cupula. Partially detached cupulae reattached and normal afferent discharge patterns were recovered 5–7 h following detachment. This regeneration process may have relevance to the recovery of semicircular canal function following head trauma.Financial support was provided by the NIDCD R01 DC06685 (Rabbitt) and NASA GSRP 56000135 & NSF IGERT DGE- 9987616 (Breneman)

Development and organization of polarity-specific segregation of primary vestibular afferent fibers in mice

A striking feature of vestibular hair cells is the polarized arrangement of their stereocilia as the basis for their directional sensitivity. In mammals, each of the vestibular end organs is characterized by a distinct distribution of these polarized cells. We utilized the technique of post-fixation transganglionic neuronal tracing with fluorescent lipid soluble dyes in embryonic and postnatal mice to investigate whether these polarity characteristics correlate with the pattern of connections between the endorgans and their central targets; the vestibular nuclei and cerebellum. We found that the cerebellar and brainstem projections develop independently from each other and have a non-overlapping distribution of neurons and afferents from E11.5 on. In addition, we show that the vestibular fibers projecting to the cerebellum originate preferentially from the lateral half of the utricular macula and the medial half of the saccular macula. In contrast, the brainstem vestibular afferents originate primarily from the medial half of the utricular macula and the lateral half of the saccular macula. This indicates that the line of hair cell polarity reversal within the striola region segregates almost mutually exclusive central projections. A possible interpretation of this feature is that this macular organization provides an inhibitory side-loop through the cerebellum to produce synergistic tuning effects in the vestibular nuclei. The canal cristae project to the brainstem vestibular nuclei and cerebellum, but the projection to the vestibulocerebellum originates preferentially from the superior half of each of the cristae. The reason for this pattern is not clear, but it may compensate for unequal activation of crista hair cells or may be an evolutionary atavism reflecting a different polarity organization in ancestral vertebrate ears

Hes5 Expression in the Postnatal and Adult Mouse Inner Ear and the Drug-Damaged Cochlea

The Notch signaling pathway is known to have multiple roles during development of the inner ear. Notch signaling activates transcription of Hes5, a homologue of Drosophila hairy and enhancer of split, which encodes a basic helix-loop-helix transcriptional repressor. Previous studies have shown that Hes5 is expressed in the cochlea during embryonic development, and loss of Hes5 leads to overproduction of auditory and vestibular hair cells. However, due to technical limitations and inconsistency between previous reports, the precise spatial and temporal pattern of Hes5 expression in the postnatal and adult inner ear has remained unclear. In this study, we use Hes5-GFP transgenic mice and in situ hybridization to report the expression pattern of Hes5 in the inner ear. We find that Hes5 is expressed in the developing auditory epithelium of the cochlea beginning at embryonic day 14.5 (E14.5), becomes restricted to a particular subset of cochlear supporting cells, is downregulated in the postnatal cochlea, and is not present in adults. In the vestibular system, we detect Hes5 in developing supporting cells as early as E12.5 and find that Hes5 expression is maintained in some adult vestibular supporting cells. In order to determine the effect of hair cell damage on Notch signaling in the cochlea, we damaged cochlear hair cells of adult Hes5-GFP mice in vivo using injection of kanamycin and furosemide. Although outer hair cells were killed in treated animals and supporting cells were still present after damage, supporting cells did not upregulate Hes5-GFP in the damaged cochlea. Therefore, absence of Notch-Hes5 signaling in the normal and damaged adult cochlea is correlated with lack of regeneration potential, while its presence in the neonatal cochlea and adult vestibular epithelia is associated with greater capacity for plasticity or regeneration in these tissues; which suggests that this pathway may be involved in regulating regenerative potential