[New Approaches in Perioperative Algesimetry]. / Neue Ansätze in der perioperativen Algesimetrie.

The measurement of anaesthetic depth and muscle relaxation have been routine procedures during general anaesthesia for years. Quantification of intraoperative nociception, on the other hand, is still largely impossible. Various methods have been tested and commercialised for more than 10 years. However, a real breakthrough has not yet been achieved and the routine application of all methods available so far is not without problems. This article explains methodological similarities, but also points to specific aspects of various commercial solutions for perioperative algesimetry.

Nociception level index: do intra-operative values allow the prediction of acute postoperative pain?

Nociception Level Index (NOL) guided analgesia has previously been found to correlate with noxious stimuli during surgery. It was aim of this study to investigate the relationship between intra-operative NOL and acute postoperative pain. After IRB approval, 80 patients scheduled for non-emergency surgery were enrolled. NOL data were recorded from induction of anaesthesia until the end of surgery. After admission to the postoperative acute care unit (PACU), pain scores (numeric rating scale [NRS, 0-10] were obtained 5-minutely for 15 min. NOL data of 74 patients were analyzed. Receiver-operating curve (ROC) analysis identified the NOL reaction to the knife to skin incision (median NOL within 60 s post knife to skin) vs. the median NOL during surgery vs. NOL at the end of surgery to have the highest correlation coefficient (ρ = 0.3; P = 0.01) as well as the highest area under the ROC curve (AUC 0.68; P = 0.01) for the prediction of moderate-severe pain in PACU. A NOL > 20 after skin incision predicted moderate-severe postoperative pain with the highest combined sensitivity (73%) and specificity (58%). A NOL < 10 after skin incision excluded moderate-severe pain in PACU with a negative predictive value of 83%. The NOL reaction to skin incision, but not NOL during surgery appears to allow the exclusion and, to a lesser degree the prediction of moderate-severe pain in PACU. The results may also strengthen the manufacturers recommendation of an intraoperative NOL range of 10-25.Australian New Zealand Clinical Trials Registry: ACTRN12619001596190.

Reversal of residual neuromuscular block with neostigmine or sugammadex and postoperative pulmonary complications: a prospective, randomised, double-blind trial in high-risk older patients.

BACKGROUND: Residual neuromuscular block is associated with an increased risk of postoperative pulmonary complications in retrospective studies. The aim of our study was to investigate prospectively the incidence of postoperative pulmonary complications after reversal with either sugammadex (SUG) or neostigmine (NEO) in high-risk older patients. METHODS: We randomly allocated 180 older patients with significant morbidity (ASA physical status 3) ≥75 yr old to reversal of rocuronium with either SUG or NEO. Adverse events in the recovery room and pulmonary complications (defined by a 5-point [0-4; 0=best to 4=worst] outcome score) on postoperative Days 1, 3, and 7 were compared between groups. RESULTS: Data from 168 patients aged 80 (4) yr were analysed; SUG vs NEO resulted in a reduced probability (0.052 vs 0.122) of increased pulmonary outcome score (impaired outcome) on postoperative Day 7, but not on Days 1 and 3. More patients in the NEO group were diagnosed with radiographically confirmed pneumonia (9.6% vs 2.4%; P=0.046). The NEO group showed a non-significant trend towards longer hospital length of stay across all individual centres (combined 9 vs 7.5 days), with a significant difference in Malaysia (6 vs 4 days; P=0.011). CONCLUSIONS: Reversal of rocuronium neuromuscular block with SUG resulted in a small, but possibly clinically relevant improvement in pulmonary outcome in a select cohort of high-risk older patients. CLINICAL TRIAL REGISTRATION: ACTRN12614000108617.

Predicting acute postoperative pain by the Qnox score at the end of surgery: a prospective observational study.

BACKGROUND: The QNox score (Quantium Medical S.L., distributed by Fresenius Kabi) has recently been introduced as a tool to quantify intraoperative analgesia. Being based on the analysis of electroencephalographic data, QNox is distinctly different to other methods of nociception monitoring that rely almost entirely on the assessment of sympathetic activity. However, there are currently no published data to validate use of QNox in a clinical setting. We investigated the value of pre-arousal QNox data at the end of surgery for prediction of acute postoperative pain in the PACU. METHODS: A total of 150 patients scheduled for non-emergency surgery under sevoflurane-opioid general anaesthesia were included in the study. At the end of surgery but before patient arousal, QNox was measured minutely for 5 min. After admission to the recovery room, pain scores (numeric rating scale [NRS], 0-10) were obtained 5 minutely for 15 min. RESULTS: Data from 144 patients were analysed. QNox before arousal showed no correlation (ρ=0.057) with acute postoperative pain in the PACU. Furthermore, the score was found to have no value for the prediction of acute postoperative pain (area under the receiver operating curve, 0.501; 95% confidence interval, 0.406-0.597). CONCLUSION: QNox at the end of surgery before arousal showed no association with and allowed no prediction of acute pain in the PACU. CLINICAL TRIAL REGISTRATION: ACTRN12618001662257.

Objective monitoring of nociception: a review of current commercial solutions.

Nociception, in contrast to pain, is not a subjective feeling, but the physiological encoding and processing of nociceptive stimuli. However, monitoring nociception remains a challenge in attempts to lower the incidence of acute postoperative pain and the move towards a more automated approach to analgesia and anaesthesia. To date, several commercialised devices promise a more accurate reflection of nociception than the traditionally used vital signs, blood pressure and heart rate. This narrative review presents an overview of existing technologies and commercially available devices, and offers a perspective for future research. Although firm conclusions about individual methods may be premature, none currently appears to offer a sufficiently broad applicability. Furthermore, there is currently no firm evidence for any clinically relevant influence of such devices on patient outcome. However, the available monitors have significantly aided the understanding of underlying mechanisms and identification of potential pitfalls.

Cheaper drugs and techniques to fulfill chief executive officer perspectives - any choices?

PURPOSE OF REVIEW: Against the background of increasing healthcare costs and diminishing budgets, this review aims to present clinicians with ethically viable options to overcome budgetary restraints when seeking to introduce novel products. RECENT FINDINGS: Healthcare administrators and primary healthcare providers are not unlikely to have different opinions when discussing the introduction of novel products. However, rather than taking a 'no' for an answer, doctors may be able to argue for a change - even if this may seem to come at a higher cost. The recent introduction of the reversal agent sugammadex may provide a timely example for the possibility of success 'against all financial odds'. SUMMARY: Health professionals have the responsibility to deliver high-quality care while acknowledging the financial budget constraints. However, evidence (vs. perception) for outcome benefits of novel drugs or devices should stimulate a robust desire for their timely introduction. Demonstrating actual benefits understandable to administrators, seeking alliances with other medical specialties or patient groups, as well as negotiations with the healthcare industry may all represent viable options. Simply waiting for patents to expire should remain a measure of last resort.

Retrospective investigation of postoperative outcome after reversal of residual neuromuscular blockade: sugammadex, neostigmine or no reversal.

BACKGROUND: Postoperative residual neuromuscular blockade (RNMB) is associated with significant morbidity. OBJECTIVE: The aim of this retrospective data analysis was to investigate the influence of the method of RNMB reversal on postoperative outcome. SETTING: Tertiary teaching hospital in Western Australia. PATIENTS: With Ethics Committee approval, data from 1444 patients who received at least one dose of a non-depolarising muscle relaxant intraoperatively during 2011 were analysed. MAIN OUTCOME MEASURES: Endpoints included unwanted events in the postanaesthesia care unit (PACU); symptoms of pulmonary complications within 7 postoperative days (0 to 100 outcome score based on 'temperature >38°C', 'leucocyte count >11 × 10 l', 'physical examination consistent with pneumonia' and 'shortness of breath'); PACU turnover time; and length of hospital stay. RESULTS: Data from 1444 patients (722 sugammadex, 212 neostigmine and 510 no-reversal) were analysed. The incidence of postoperative nausea and vomiting (PONV) in PACU was higher in neostigmine-reversed than sugammadex-reversed patients (21.5 vs. 13.6%; P <0.05). No differences were found regarding other PACU incidents, length of PACU stay or hospital stay. Pulmonary outcome deteriorated significantly (outcome score increased) with age and American Society of Anesthesiologists (ASA) physical status. This was observed particularly in ASA 3/4 patients more than 60 years of age in neostigmine-reversed or non-reversed patients, but almost no detrimental effect of age on pulmonary outcome was found in the sugammadex group (P <0.05). CONCLUSION: RNMB reversal with sugammadex was associated with the lowest rate of PONV and may reduce the risk of pulmonary complications in elderly ASA 3/4 patients. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12612000087853.

The influence of age and sex on the relationship between heart rate variability, haemodynamic variables and subjective measures of acute post-operative pain.

BACKGROUND AND OBJECTIVE: Both skin conductance and surgical stress index have been proposed as useful means of assessing pain. Both methods are based on the assessment of the sympathovagal balance, which, according to reports, is influenced by age and sex, and currently neither of the assessments take these factors into account. The aim of this study was to determine the relationship between age, sex, magnitude of acute post-operative pain and haemodynamic and autonomic changes. METHODS: Two hundred twenty patients were asked to quantify their level of pain on a numeric rating scale (NRS) at different time points in the recovery room. Simultaneously, the following measures of heart rate variability were analysed: total power, low frequency, high frequency, low-to-high frequency ratio and ultra-short entropy. Additionally, SBP, heart rate and respiration rate were recorded. RESULTS: A total of 1098 NRS readings were obtained from 220 participants (123 men, 97 women, aged 40 ± 15 years). For heart rate variability, the low-to-high frequency ratio was significantly higher [mean (SE): 7.7 (0.56) vs. 6.7 (0.47); P < 0.05] and the ultra-short entropy significantly lower [mean (SE): 46.2 (0.8) vs. 47.2 (0.8); P < 0.05] for NRS 5-10 vs. NRS 0-4. Age correlated negatively with blood pressure and heart rate, and all measures of heart rate variability, except the low-to-high frequency ratio. Low-to-high frequency ratio and blood pressure were higher in men. CONCLUSION: Acute pain influences the sympathovagal balance. This response is significantly influenced by age and sex.

Skin conductance for monitoring of acute pain in adult postoperative patients: influence of electrode surface area and sampling time.

Aim of this prospective randomized study was to determine the influence of the electrode surface area and sampling time on the accuracy of the number of fluctuations in skin conductance per second to distinguish different states of acute pain. These methodological issues have been previously suggested as an explanation for contradictory data related to the accuracy of the skin conductance monitor. A total of 541 pain ratings on a numeric rating scale (0-10) were obtained from 120 adult postoperative patients. The number of fluctuations in skin conductance per second was recorded using two different electrode types (surface area 254 vs. 474 mm(2)) and sampling times (7.5 vs. 30 s). A longer sampling time did result in higher values for the number of fluctuations in skin conductance per second, though without improving its accuracy to distinguish different states of pain. However, the latter was found improved when the smaller surface area electrodes were used. A combination of small surface area electrodes and a 30 s sampling time resulted in the highest area under the curve in the receiver operating curve analysis of the method to identify states of moderate to severe pain (numeric rating scale > 3): 0.68 vs. e.g. 0.55 [data from all patients combined]). We conclude that the type of electrodes used but only to a lesser degree the sampling time influence the accuracy of the number of fluctuations in skin conductance per second to identify states of moderate or severe postoperative pain.

Deep neuromuscular paralysis during hip arthroscopic surgery: influence on perineal tissue pressures and hip joint width.

Pudendal nerve injuries are not an uncommon side effect of patient positioning on a traction table, and muscle relaxation has been suggested to mitigate this risk by reducing pressure on the perineum. A total of 40 patients scheduled for hip arthroscopic surgery under general anaesthesia were recruited. After induction of anaesthesia, pressures on the perineum were measured in 20 subjects by means of an ultra-thin pressure sensor mat wrapped around the perineal post. Perineal pressures were assessed after the induction of anaesthesia, after leg traction and after deep muscle relaxation. In 22 subjects, the hip joint width was measured radiographically at the same time points. Pressures on the perineum were high after traction (median maximum pressure 2540 g cm-2). Neuromuscular paralysis reduced perineal pressures only minimally, but significantly (-5 g cm-2; P = 0.007). Traction increased hip joint width significantly [mean 66 (12)%; P = 0.001) and muscle relaxation further increased joint width by a mean of 3.2 (0-20)% (P = 0.001). Muscle relaxation was more beneficial for male patients (joint width increase 6.8% versus 2.8%; P = 0.04), as well as patients in whom traction alone did not achieve sufficient joint width. Muscle relaxation reduced the perineal pressure during hip arthroscopic surgery by only a negligible amount. With regard to joint space, relaxation may be of highest benefit in male patients and/or patients in whom traction alone produces only a relatively small increase in joint width (trial registration: ANZCTR 12617000191392).

Monitoring electrical skin conductance: a tool for the assessment of postoperative pain in children?

BACKGROUND: Monitoring changes in electrical skin conductance has been described as a potentially useful tool for the detection of acute pain in adults. The aim of this study was to test the method in pediatric patients. METHODS: A total of 180 postoperative pediatric patients aged 1-16 yr were included in this prospective, blinded observational study. After arrival in the recovery unit, pain was assessed by standard clinical pain assessment tools (1-3 yr: Face Legs Activity Cry Consolability Scale, 4-7 yr: Revised Faces Scale, 8-16 yr: Visual Analogue Scale) at various time points during their stay in the recovery room. The number of fluctuations in skin conductance per second (NFSC) was recorded simultaneously. RESULTS: Data from 165 children were used for statistical analysis, and 15 patients were excluded. The area under the Receiver Operating Characteristic curve for predicting moderate to severe pain from NFSC was 0.82 (95% confidence interval 0.79-0.85). Over all age groups, an NFSC cutoff value of 0.13 was found to distinguish between no or mild versus moderate or severe pain with a sensitivity of 90% and a specificity of 64% (positive predictive value 35%, negative predictive value 97%). CONCLUSIONS: NFSC accurately predicted the absence of moderate to severe pain in postoperative pediatric patients. The measurement of NFSC may therefore provide an additional tool for pain assessment in this group of patients. However, more research is needed to prospectively investigate the observations made in this study and to determine the clinical applicability of the method.

Vitamin E supplementation and hepatic drug metabolism in humans.

Meta-analyses studies suggest that high-dose vitamin E may be associated with increased mortality in some populations. Vitamin E may increase the production of CYP3A4 in the liver, and this could lead to an increase in drug metabolism, potentially lowering the efficacy of therapeutic drugs. We hypothesized that upregulation of CYP3A4 by alpha-tocopherol (alpha-TOH) would decrease the plasma concentration of the CYP3A4 substrate midazolam. Baseline metabolism of midazolam (1 mg intravenously) was determined in 12 healthy subjects before randomization into 2 groups of 6 to receive either RRR-alpha-TOH (750 IU/d) or placebo for 3 weeks. At completion, subjects were given an additional 1 mg intravenous bolus of midazolam. Plasma midazolam, 1-hydroxy-midazolam, and urinary alpha-TOH metabolite excretion were measured using gas chromatography mass spectrometry. Serum alpha-TOH was measured using high performance liquid chromatography with electrochemical detection. Serum alpha-TOH increased by 100% (P = 0.002) and urinary alpha-TOH metabolite excretion increased 20-fold in the treatment group versus placebo (P = 0.001). There was no effect on the area under time curve of midazolam in subjects taking alpha-TOH compared with placebo. These findings do not support the hypothesis that alpha-TOH supplementation interferes with hepatic CYP3A4-mediated drug metabolism.

The effects of neostigmine and glycopyrrolate on skin conductance as a measure of pain.

BACKGROUND AND OBJECTIVE: The number of fluctuations in skin conductance per second has been shown to correlate with postoperative pain. In this context, the effects of cholinesterase inhibitors and anticholinergic drugs used for the reversal of muscle relaxants were investigated. METHODS: Muscle relaxant effects were reversed in 30 patients with neostigmine and glycopyrrolate. No reversal agents were given to 30 controls. Patients' level of pain was quantified using a numeric rating scale (0-10) at several time points in the recovery room. The number of fluctuations in skin conductance per second was measured simultaneously. RESULTS: The number of fluctuations in skin conductance per second was significantly higher in patients with no and severe pain in the control compared with the reversal group (no pain 0.19 vs. 0.12; severe pain 0.40 vs. 0.19). The number of fluctuations in skin conductance per second was less sensitive to identify time points with moderate/severe pain in the reversal group. CONCLUSION: Skin conductance-based assessment of pain is affected by reversal agents.

Effects of clonidine and midazolam premedication on bispectral index and recovery after elective surgery.

BACKGROUND AND OBJECTIVES: Alpha-2 agonists offer useful effects that make these drugs an interesting alternative for pharmacological premedication. METHODS: In a randomized, double-blind study, effects of clonidine (150 microg orally), midazolam (7.5 mg orally) and placebo administered 60-90 min prior to estimated anaesthesia induction time were investigated in 60 healthy ASA I or II patients. All patients received dipotassiumchlorazepate the evening before surgery. At predefined time points, effects of premedication on bispectral index, sedation score and visual analogue scales for anxiety and pain, cognitive function and stress hormones were determined. RESULTS: Administration of low-dose clonidine was associated with slightly lower bispectral index scores than a standard dose of midazolam or placebo. There were no significant differences in sedation score, visual analogue scale for anxiety and pain and cognitive function between treatment regimens. Clonidine, but not midazolam, reduced anaesthetic requirements for induction of anaesthesia and prevented an increase in heart rate as well as an increase in adrenocorticotropic hormone plasma levels during the preoperative period (P < 0.05 vs. placebo). Clonidine administration did not delay postoperative recovery. CONCLUSION: Clonidine augmented haemodynamic stability and partially blunted stress responses as determined by adrenocorticotropic hormone plasma levels. In addition, clonidine did not delay postoperative recovery. Therefore, surrogate parameters indicate that preanaesthetic medication with clonidine may be superior to midazolam in healthy individuals. Further studies have to confirm these results with regard to outcome parameters.

Effects of muscle relaxants on ischaemia damage in skeletal muscle.

Muscle ischaemia is frequently induced intraoperatively by i.e. a surgical tourniquet or during the re-grafting phase of a free muscle transplant. The resulting muscle cell damage may impact on postoperative recovery. Neuromuscular paralysis may mitigate the effects of ischaemia. After ethics approval, 25 male Sprague-Dawley rats were anaesthetized and randomly assigned to 1 of 4 groups: Sham operation, treatment with normal saline, treatment with rocuronium (muscle relaxant) 0.6 or 1 mg kg-1, respectively. In the non-sham groups, ischaemia of one hind leg was achieved by ligation of the femoral vessels. Muscle biopsies were taken at 30 and 90 min, respectively. Cell damage was assessed in the biopsies via the expression of dystrophin, free calcium, as well as the assessment of cell viability. Pre-ischaemia muscle relaxation led to a reduction in ischaemia-induced muscle cell damage when measured by the expression of dystrophin, cell viability and the expression of free calcium even after 90 min of ischaemia (i.e. ratio control/ischaemic site for dystrophin expression after saline 0.58 ± 0.12 vs. after 1 mg/kg rocuronium 1.08 ± 0.29; P < 0.05). Muscle relaxation decreased the degree of ischaemia-induced muscle cell damage. The results may have significant clinical implications.

Bronchial mucus transport velocity in patients receiving propofol and remifentanil versus sevoflurane and remifentanil anesthesia.

Volatile anesthetics reduce ciliary beat frequency in vitro. It has been reported that impaired bronchial mucus transport velocity (BTV) is associated with significantly increased pulmonary complications. In this study, we sought to determine in vivo differences in BTV, comparing patients having total IV anesthesia (TIVA) with propofol and remifentanil to anesthesia with sevoflurane and remifentanil. Twenty-two patients scheduled for elective general surgery were randomized to one of two groups: TIVA (propofol/remifentanil) or SEVO (sevoflurane/remifentanil). Thirty minutes after tracheal intubation, BTV was assessed by fiberoptic observation of the movement of methylene blue dye applied to the dorsal surface of the right main bronchus. BTV was significantly reduced in the SEVO group compared with the TIVA group (mean, 1.5 +/- 0.7 [0-2.3] versus 4.8 +/- 2.1 [2.3-8.8] mm/min; P < 0.0001). Anesthesia with sevoflurane may lead to significantly impaired bronchociliary clearance in comparison to TIVA. This could have implications for perioperative pulmonary complications, in particular in patients at risk for pulmonary complications.

Current Trends in Neuromuscular Blockade, Management, and Monitoring amongst Singaporean Anaesthetists.

Introduction. This survey aimed to investigate the attitudes/practice pertaining the use, management, and monitoring of neuromuscular blockade amongst Singaporean anaesthetists. Methods. All specialist accredited anaesthetists registered with the Singapore Medical Council were invited to complete an anonymous online survey. Results. The response rate was 39.5%. Neuromuscular monitoring (NM) was used routinely by only 13.1% despite the widespread availability of monitors. 82% stated residual NMB (RNMB) was a significant risk factor for patient outcome, but only 24% believed NMB monitoring should be compulsory in all paralyzed patients. 63.6% of anaesthetists estimated the risk of RNMB in their own institutions to be <5%. 63.1% always gave reversal. Neostigmine was predominantly used (85.1%), with 28.2% using sugammadex at least sometimes, citing unavailability and high costs. However, 83.8% believed in sugammadex's benefits for patients' safety and >50% said such benefits may be able to offset the associated costs. Conclusions. There is a significant need for reeducation about RNMB, studies on local RNMB incidences, and strengthening of current monitoring practices and guidelines. Strategies are discussed. As NM monitors appear widely available and reversal of NMB standard practice, it is hopeful that Singaporean anaesthetists will change and strive for evidence-based best clinical practice to enhance patient safety.