Cerebrovascular reactivity to hypercapnia in patients with migraine: A dual-echo arterial spin labeling MRI study.

OBJECTIVE: This study aimed to compare cerebrovascular reactivity between patients with migraine and controls using state-of-the-art magnetic resonance imaging (MRI) techniques. BACKGROUND: Migraine is associated with an increased risk of cerebrovascular disease, but the underlying mechanisms are still not fully understood. Impaired cerebrovascular reactivity has been proposed as a link. Previous studies have evaluated cerebrovascular reactivity with different methodologies and results are conflicting. METHODS: In this single-center, observational, case-control study, we included 31 interictal patients with migraine without aura (aged 19-66 years, 17 females) and 31 controls (aged 22-64 years, 18 females) with no history of vascular disease. Global and regional cerebrovascular reactivities were assessed with a dual-echo arterial spin labeling (ASL) 3.0 T MRI scan of the brain which measured the change in cerebral blood flow (CBF) and BOLD (blood oxygen level dependent) signal to inhalation of 5% carbon dioxide. RESULTS: When comparing patients with migraine to controls, cerebrovascular reactivity values were similar between the groups, including mean gray matter CBF-based cerebrovascular reactivity (3.2 ± 0.9 vs 3.4 ± 1% ΔCBF/mmHg CO2 ; p = 0.527), mean gray matter BOLD-based cerebrovascular reactivity (0.18 ± 0.04 vs 0.18 ± 0.04% ΔBOLD/mmHg CO2 ; p = 0.587), and mean white matter BOLD-based cerebrovascular reactivity (0.08 ± 0.03 vs 0.08 ± 0.02% ΔBOLD/mmHg CO2 ; p = 0.621).There was no association of cerebrovascular reactivity with monthly migraine days or migraine disease duration (all analyses p > 0.05). CONCLUSION: Cerebrovascular reactivity to carbon dioxide seems to be preserved in patients with migraine without aura.

Legal and ethical implications of defining an optimum means of achieving unconsciousness in assisted dying.

A decision by a society to sanction assisted dying in any form should logically go hand-in-hand with defining the acceptable method(s). Assisted dying is legal in several countries and we have reviewed the methods commonly used, contrasting these with an analysis of capital punishment in the USA. We expected that, since a common humane aim is to achieve unconsciousness at the point of death, which then occurs rapidly without pain or distress, there might be a single technique being used. However, the considerable heterogeneity in methods suggests that an optimum method of achieving unconsciousness remains undefined. In voluntary assisted dying (in some US states and European countries), the common method to induce unconsciousness appears to be self-administered barbiturate ingestion, with death resulting slowly from asphyxia due to cardiorespiratory depression. Physician-administered injections (a combination of general anaesthetic and neuromuscular blockade) are an option in Dutch guidelines. Hypoxic methods involving helium rebreathing have also been reported. The method of capital punishment (USA) resembles the Dutch injection technique, but specific drugs, doses and monitoring employed vary. However, for all these forms of assisted dying, there appears to be a relatively high incidence of vomiting (up to 10%), prolongation of death (up to 7 days), and re-awakening from coma (up to 4%), constituting failure of unconsciousness. This raises a concern that some deaths may be inhumane, and we have used lessons from the most recent studies of accidental awareness during anaesthesia to describe an optimal means that could better achieve unconsciousness. We found that the very act of defining an 'optimum' itself has important implications for ethics and the law.

Differential role of nitric oxide in the psychedelic symptoms induced by racemic ketamine and esketamine in human volunteers.

BACKGROUND: Animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) hypofunction and subsequent decline in intracellular nitric oxide (NO) are responsible for development of ketamine-induced psychedelic symptoms. To examine this mechanism in humans, we administered the NO donor sodium nitroprusside during infusion of racemic ketamine (RS-ketamine), containing equal amounts of S(+)- and R(-)-ketamine isomers, or esketamine, containing just the S(+)-isomer. METHODS: In this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0.5 µg kg-1 min-1 or placebo during administration of escalating doses of RS-ketamine (total dose 140 mg) or esketamine (70 mg). Drug high, internal and external perception, obtained using the Bowdle questionnaire, were scored over time on a visual analogue scale. The area-under-the-time-effect-curve (AUC) was calculated for each end-point. RESULTS: Sodium nitroprusside significantly reduced drug high AUC [mean (standard deviation); placebo 9070 (4630) vs sodium nitroprusside 7100 (3320), P=0.02], internal perception AUC [placebo 1310 (1250) vs nitroprusside 748 (786), P<0.01] and external perception AUC [placebo 4110 (2840) vs nitroprusside 2890 (2120), P=0.02] during RS-ketamine infusion, but was without effect on any of these measures during esketamine infusion. CONCLUSIONS: These data suggest that NO depletion plays a role in RS-ketamine-induced psychedelic symptoms in humans. The sodium nitroprusside effect was observed for R(-)- but not S(+)-isomer-induced psychedelic symptoms. Further studies are needed to corroborate our findings and assess whether higher sodium nitroprusside doses will reduce esketamine-induced psychedelic symptoms. CLINICAL TRIAL REGISTRATION: NTR 5359.

Esketamine counters opioid-induced respiratory depression.

BACKGROUND: Opioids can produce life-threatening respiratory depression. This study tested whether subanaesthetic doses of esketamine stimulate breathing in an established human model of opioid-induced respiratory depression. METHODS: In a study with a randomised, double blind, placebo controlled, crossover design, 12 healthy, young volunteers of either sex received a dose escalating infusion of esketamine (cumulative dose 40 mg infused in 1 h) on top of remifentanil-induced respiratory depression. A population pharmacokinetic-pharmacodynamic analysis was performed with sites of drug action at baseline ventilation, ventilatory CO2-chemosensitivity, or both. RESULTS: Remifentanil reduced isohypercapnic ventilation (end-tidal PCO2 6.5 kPa) by approximately 40% (from 20 to 12 litre min-1) in esketamine and placebo arms of the study, through an effect on baseline ventilation and ventilatory CO2 sensitivity. The reduction in ventilation was related to a remifentanil effect on ventilatory CO2 sensitivity (~39%) and on baseline ventilation (~61%). Esketamine increased breathing through an exclusive stimulatory effect on ventilatory CO2 sensitivity. The remifentanil concentration that reduced ventilatory CO2 sensitivity by 50% (C50) was doubled at an esketamine concentration of 127 (84-191) ng ml-1 [median (interquartile range)]; the esketamine effect was rapid and driven by plasma pharmacokinetics. Placebo had no systematic effect on opioid-induced respiratory depression. CONCLUSIONS: Esketamine effectively countered remifentanil-induced respiratory depression, an effect that was attributed to an increase in remifentanil-reduced ventilatory CO2 chemosensitivity.

Deep neuromuscular blockade improves surgical conditions during low-pressure pneumoperitoneum laparoscopic donor nephrectomy.

BACKGROUND: Evidence indicates that low-pressure pneumoperitoneum (PNP) reduces postoperative pain and analgesic consumption. A lower insufflation pressure may hamper visibility and working space. The aim of the study is to investigate whether deep neuromuscular blockade (NMB) improves surgical conditions during low-pressure PNP. METHODS: This study was a blinded randomized controlled multicenter trial. 34 kidney donors scheduled for laparoscopic donor nephrectomy randomly received low-pressure PNP (6 mmHg) with either deep (PTC 1-5) or moderate NMB (TOF 0-1). In case of insufficient surgical conditions, the insufflation pressure was increased stepwise. Surgical conditions were rated by the Leiden-Surgical Rating Scale (L-SRS) ranging from 1 (extremely poor) to 5 (optimal). RESULTS: Mean surgical conditions were significantly better for patients allocated to a deep NMB (SRS 4.5 versus 4.0; p < 0.01). The final insufflation pressure was 7.7 mmHg in patients with deep NMB as compared to 9.1 mmHg with moderate NMB (p = 0.19). The cumulative opiate consumption during the first 48 h was significantly lower in patients receiving deep NMB, while postoperative pain scores were similar. In four patients allocated to a moderate NMB, a significant intraoperative complication occurred, and in two of these patients a conversion to an open procedure was required. CONCLUSIONS: Our data show that deep NMB facilitates the use of low-pressure PNP during laparoscopic donor nephrectomy by improving the quality of the surgical field. The relatively high incidence of intraoperative complications indicates that the use of low pressure with moderate NMB may compromise safety during LDN. Clinicaltrials.gov identifier: NCT 02602964.

Anomalies in target-controlled infusion: an analysis after 20 years of clinical use.

Although target-controlled infusion has been in use for more than two decades, its benefits are being obscured by anomalies in clinical practice caused by a number of important problems. These include: a variety of pharmacokinetic models available in open target-controlled infusion systems, which often confuse the user; the extrapolation of anthropomorphic data which provokes anomalous adjustments of dosing by such systems; and the uncertainty of regulatory requirements for the application of target-controlled infusion which causes uncontrolled exploitation of drugs and pharmacokinetic models in target-controlled infusion devices. Comparison of performance of pharmacokinetic models is complex and mostly inconclusive. However, a specific behaviour of a model in a target-controlled infusion system that is neither intended nor supported by scientific data can be considered an artefact or anomaly. Several of these anomalies can be identified in the current commercially available target-controlled infusion systems and are discussed in this review.

Pharmacokinetics and pharmacodynamics of sublingual sufentanil for postoperative pain management.

Achieving successful treatment of postoperative pain remains a challenge. Recently, a sufentanil sublingual tablet system has been developed for treatment of moderate-to-severe postoperative pain. The phenylpiperidine sufentanil is a potent analgesic that rapidly crosses the blood-brain barrier and selectively activates central µ-opioid receptors. The system makes use of a hand-held dispenser system, which contains forty 15-µg sufentanil sublingual micro-tablets. The patient can release one tablet at 20-min intervals using a unique radiofrequency adhesive tag, which is wrapped around the patient's thumb. In this review, the authors discuss the pharmacology of sublingual sufentanil with reference to its suitability in the treatment of postoperative pain, the current evidence for the sublingual sufentanil system in postoperative pain treatment, and advantages and limitations of the sublingual system. We conclude that sufentanil is suited for the transmucosal route due to its pharmacokinetic profile, including rapid onset, absence of active metabolites and low tissue accumulation. The efficacy and safety of the sufentanil sublingual tablet system has been shown in over 600 patients in a limited set of studies; further independent studies are required to determine the position of the system among other forms of postoperative pain treatment. We conclude that the sublingual sufentanil tablet system allows effective pain relief, and allows patients to control their own pain relief and early postoperative mobility.

An experimental study comparing the respiratory effects of tapentadol and oxycodone in healthy volunteers.

Background: There is a clinical need for potent opioids that produce little or no respiratory depression. In the current study we compared the respiratory effects of tapentadol, a mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and oxycodone, a selective mu-opioid receptor agonist. We hypothesize that tapentadol 100 mg has a lesser effect on the control of breathing than oxycodone 20 mg. Methods: Fifteen healthy volunteers were randomized to receive oral tapentadol (100 and 150 mg), oxycodone 20 mg or placebo immediate release tablets in a crossover double-blind randomized design. The main end-point of the study was the effect of treatment on the ventilatory response to hypercapnia and ventilation at an extrapolated end-tidal PCO2 of 7.3 kPa (55 mmHg, VE55); VE55 was assessed prior and for 6-h following drug intake. Results: All three treatments had typical opioid effects on the hypercapnic ventilatory response: a shift to the right coupled to a decrease of the response slope. Oxycodone 20 mg had a significantly larger respiratory depressant effect than tapentadol 100 mg (mean difference -5.0 L min-1, 95% confidence interval: -7.1 to -2.9 L min-1, P<0.01), but not larger than tapentadol 150 mg (oxycodone vs. tapentadol 150 mg: P>0.05). Conclusions: In this exploratory study we observed that both tapentadol and oxycodone produce respiratory depression. Tapentadol 100 mg but not 150 mg had a modest respiratory advantage over oxycodone 20 mg. Further studies are needed to explore how these results translate to the clinical setting.

Deep neuromuscular block to optimize surgical space conditions during laparoscopic surgery: a systematic review and meta-analysis.

Neuromuscular block (NMB) is frequently used in abdominal surgery to improve surgical conditions by relaxation of the abdominal wall and prevention of sudden muscle contractions. The evidence supporting routine use of deep NMB is still under debate. We aimed to provide evidence for the superiority of routine use of deep NMB during laparoscopic surgery. We performed a systematic review and meta-analysis of studies comparing the influence of deep vs moderate NMB during laparoscopic procedures on surgical space conditions and clinical outcomes. Trials were identified from Medline, Embase, and Central databases from inception to December 2016. We included randomized trials, crossover studies, and cohort studies. Our search yielded 12 studies on the effect of deep NMB on the surgical space conditions. Deep NMB during laparoscopic surgeries improves the surgical space conditions when compared with moderate NMB, with a mean difference of 0.65 (95% confidence interval (CI): 0.47-0.83) on a scale of 1-5, and it facilitates the use of low-pressure pneumoperitoneum. Furthermore, deep NMB reduces postoperative pain scores in the postanaesthesia care unit, with a mean difference of - 0.52 (95% CI: -0.71 to - 0.32). Deep NMB improves surgical space conditions during laparoscopic surgery and reduces postoperative pain scores in the postanaesthesia care unit. Whether this leads to fewer intraoperative complications, an improved quality of recovery, or both after laparoscopic surgery should be pursued in future studies. The review methodology was specified in advance and registered at Prospero on July 27, 2016, registration number CRD42016042144.

Venlafaxine and oxycodone effects on human spinal and supraspinal pain processing: a randomized cross-over trial.

Severe pain is often treated with opioids. Antidepressants that inhibit serotonin and norepinephrine reuptake (SNRI) have also shown a pain relieving effect, but for both SNRI and opioids, the specific mode of action in humans remains vague. This study investigated how oxycodone and venlafaxine affect spinal and supraspinal pain processing. Twenty volunteers were included in this randomized cross-over study comparing 5-day treatment with venlafaxine, oxycodone and placebo. As a proxy of the spinal pain transmission, the nociceptive withdrawal reflex (NWR) to electrical stimulation on the sole of the foot was recorded at the tibialis anterior muscle before and after 5 days of treatment. For the supraspinal activity, 61-channel electroencephalogram evoked potentials (EPs) to the electrical stimulations were simultaneously recorded. Areas under curve (AUCs) of the EMG signals were analyzed. Latencies and AUCs were computed for the major EP peaks and brain source analysis was done. The NWR was decreased in venlafaxine arm (P = 0.02), but the EP parameters did not change. Oxycodone increased the AUC of the EP response (P = 0.04). Oxycodone also shifted the cingulate activity anteriorly in the mid-cingulate-operculum network (P < 0.01), and the cingulate activity was increased while the operculum activity was decreased (P = 0.02). Venlafaxine exerts its effects on the modulation of spinal nociceptive transmission, which may reflect changes in balance between descending inhibition and descending facilitation. Oxycodone, on the other hand, exerts its effects at the cortical level. This study sheds light on how opioids and SNRI drugs modify the human central nervous system and where their effects dominate.

Erythropoietin to reduce allogeneic red blood cell transfusion in patients undergoing total hip or knee arthroplasty.

BACKGROUND AND OBJECTIVES: To determine the value of erythropoietin in reducing allogeneic transfusions, it is important to assess the effects, safety and costs for individual indications. Previous studies neither compared the effects of erythropoietin between total hip and total knee arthroplasty, nor evaluated the safety or costs. We performed a meta-analysis to assess the effects of erythropoietin in total hip and knee arthroplasty separately. Safety and costs were evaluated as secondary outcomes. MATERIALS AND METHODS: A systematic literature search was performed to identify randomized controlled trials evaluating the effect of erythropoietin in total hip and knee arthroplasty until April 2014. Study data were extracted using standardized forms and pooled using a random-effects model. Strength of the evidence was evaluated using Cochrane's Collaboration's tool for risk of bias assessment. RESULTS: Seven studies were included (2439 patients). Erythropoietin significantly reduced exposure to allogeneic transfusion in both hip (RR 0·45; 95%CI 0·33-0·61) and knee (RR 0·38; 95%CI 0·27-0·53) arthroplasty, without differences between indications (P = 0·44). Mean number of transfused red blood cell units was significantly decreased in erythropoietin-treated patients (mean difference -0·57; 95%CI -0·86 to -0·29)(unable to split). No differences in thromboembolic or adverse events were found. Only one study evaluated costs, so that no pooled cost-effectiveness estimates could be given. CONCLUSION: Erythropoietin is effective in both hip and knee arthroplasty and can be considered as safe. However, the decision to use erythropoietin on a routine base should be balanced against its costs, which may be relatively high.

Influence of variations in arterial PCO2 on surgical conditions during laparoscopic retroperitoneal surgery.

BACKGROUND: Although deep neuromuscular block (post-tetanic-count 1-2 twitches) improves surgical conditions during laparoscopic retroperitoneal surgery compared with standard block (train-of-four 1-2 twitches), the quality of surgical conditions varies widely, often related to diaphragmatic contractions. Hypocapnia may improve surgical conditions. Therefore we studied the effect of changes in arterial carbon dioxide concentrations on surgical conditions in patients undergoing laparoscopic surgery under general anaesthesia and deep neuromuscular block. METHODS: Forty patients undergoing elective laparoscopic surgery for prostatectomy or nephrectomy received propofol/remifentanil anaesthesia and deep neuromuscular block with rocuronium. Patients were randomized to surgery under hypocapnic or hypercapnic conditions. During surgery, the surgical conditions were evaluated using the 5-point Leiden-Surgical Rating Scale (L-SRS) ranging from 1 (extremely poor conditions) to 5 (optimal conditions) by the surgeon, who was blinded to group. RESULTS: Mean (sd) arterial carbon dioxide concentrations were 4.5 (0.6) [range: 3.8-5.6] kPa under hypocapnic and 6.9 (0.6) [6.1-8.1] kPa under hypercapnic conditions. The L-SRS did not differ between groups: 4.84 (0.4) [4-5] in hypocapnia and 4.77 (0.4) [3.9-5] in hypercapnia. Ninety-nine percent of ratings were good or excellent irrespective of treatment. CONCLUSIONS: Deep neuromuscular block provides good to optimal surgical conditions in laparoscopic retroperitoneal urological surgery, independent of the level of arterial [Formula: see text]. CLINICAL TRIAL REGISTRATION: NCT01968447.

Effect of subanaesthetic ketamine on plasma and saliva cortisol secretion.

BACKGROUND: The commonality between chronic conditions that are treated with low-dose ketamine, such as specific chronic pain conditions, depression, and post-traumatic stress disorder, can be found in relation to the stress system, particularly the hypothalamus-pituitary-adrenal axis. In this study we assess the effect of ketamine on the stress system by measuring plasma and saliva cortisol production during and following exposure to low-dose ketamine. METHODS: In a double-blind, randomized, placebo-controlled study, the influence of subanaesthetic ketamine (0.29 mg kg(-1) h(-1) for 1 h, followed by 0.57 mg kg(-1) h(-1) for another hour) was studied with repeated plasma and saliva cortisol samples in 12 healthy male volunteers. A pharmacokinetic-pharmacodynamic model was used to describe the circadian rhythm-dependent ketamine-induced production of cortisol. RESULTS: The endogenous mean baseline cortisol production was 7.9 (SE 1.5) nM min(-1). Consistent with the circadian rhythm, cortisol production decayed by 1.25 nM min(-1) h(-1). Ketamine doubled the cortisol production at a concentration of 165 (SE 35) ng ml(-1). The salivary cortisol concentration closely mirrored the plasma concentration and was exponentially related to the plasma concentration with, at 100 ng ml(-1) ketamine, a saliva:plasma ratio of 0.036 (se 0.006). CONCLUSIONS: Ketamine has an appreciable effect on cortisol production. This may impact on critical physiological and psychological functions. CLINICAL TRIAL REGISTRATION: This study was registered in the Dutch Trial Register under number NTR2717 at www.trialregister.nl.

Evaluation of surgical conditions during laparoscopic surgery in patients with moderate vs deep neuromuscular block.

BACKGROUND: The routine use of neuromuscular blocking agents reduces the occurrence of unacceptable surgical conditions. In some surgeries, such as retroperitoneal laparoscopies, deep neuromuscular block (NMB) may further improve surgical conditions compared with moderate NMB. In this study, the effect of deep NMB on surgical conditions was assessed. METHODS: Twenty-four patients undergoing elective laparoscopic surgery for prostatectomy or nephrectomy were randomized to receive moderate NMB (train-of-four 1-2) using the combination of atracurium/mivacurium, or deep NMB (post-tetanic count 1-2) using high-dose rocuronium. After surgery, NMB was antagonized with neostigmine (moderate NMB), or sugammadex (deep NMB). During all surgeries, one surgeon scored the quality of surgical conditions using a five-point surgical rating scale (SRS) ranging from 1 (extremely poor conditions) to 5 (optimal conditions). Video images were obtained and 12 anaesthetists rated a random selection of images. RESULTS: Mean (standard deviation) SRS was 4.0 (0.4) during moderate and 4.7 (0.4) during deep NMB (P<0.001). Moderate block resulted in 18% of scores at the low end of the scale (Scores 1-3); deep block resulted in 99% of scores at the high end of the scale (Scores 4 and 5). Cardiorespiratory conditions were similar during and after surgery in both groups. Between anaesthetists and surgeon, there was poor agreement between scores of individual images (average κ statistic 0.05). CONCLUSIONS: Application of the five-point SRS showed that deep NMB results in an improved quality of surgical conditions compared with moderate block in retroperitoneal laparoscopies, without compromise to the patients' peri- and postoperative cardiorespiratory conditions. Trial registration The study was registered at clinicaltrials.gov under number NCT01361149.

Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy.

BACKGROUND: Tapentadol is an analgesic agent for treatment of acute and chronic pain that activates the µ-opioid receptor combined with inhibition of neuronal norepinephrine reuptake. Both mechanisms are implicated in activation of descending inhibitory pain pathways. In this study, we investigated the influence of tapentadol on conditioned pain modulation (CPM, an experimental measure of endogenous pain inhibition that gates incoming pain signals as a consequence of a preceding tonic painful stimulus) and offset analgesia (OA, a test in which a disproportionally large amount of analgesia becomes apparent upon a slight decrease in noxious heat stimulation). METHODS: Twenty-four patients with diabetic polyneuropathy (DPN) were randomized to receive daily treatment with tapentadol sustained-release (SR) [average daily dose 433 (31) mg] or placebo for 4 weeks. CPM and OA were measured before and on the last day of treatment. RESULTS: Before treatment, none of the patients had significant CPM or OA responses. At week 4 of treatment, CPM was significantly activated by tapentadol SR and coincided with significant analgesic responses. CPM increased from 9.1 (5.4)% (baseline) to 14.3 (7.2)% (placebo) and 24.2 (7.7)% (tapentadol SR, P<0.001 vs placebo); relief of DPN pain was also greater in patients treated with tapentadol than placebo (P=0.028). Neither placebo nor tapentadol SR treatment had an effect on the magnitude of the OA responses (P=0.78). CONCLUSIONS: Tapentadol's analgesic effect in chronic pain patients with DPN is dependent on activation of descending inhibitory pain pathways as observed by CPM responses. CLINICAL TRIAL REGISTRATION: The study was registered at trialregister.nl under number NTR2716.

Perception of patient safety differs by clinical area and discipline.

BACKGROUND: Current thinking about patient safety emphasizes the relationship between organizational factors, that is, latent risk factors (LRFs) and patient safety. This study explores the influence of the operating theatre (OT), intensive care unit (ICU), and disciplines on ratings of LRFs. If we have an understanding of the contribution made by these factors, we can identify significant points from which we can promote a safe environment. METHODS: Staff in four university hospitals were sent a survey relating to the state of LRFs, which included communication, planning and coordination, design, maintenance, equipment, teamwork, team instructions, housekeeping, situational awareness, hierarchy, and procedures. RESULTS: The ICU staff had more favourable perceptions of training, communication, team instruction, and hierarchy. The OT staff had more favourable perceptions of technical LRFs. We found three profiles for disciplines: (i) anaesthetists and intensivists had more favourable perceptions of technical LRFs than surgeons and nurses. (ii) Anaesthetists, anaesthesia nurse-technicians, and recovery nurses had a poorer perception of non-technical skills. (iii) Anaesthesia nurse-technicians and recovery nurses had less favourable perceptions of procedures, housekeeping, and situational awareness than anaesthetists and intensivists. CONCLUSIONS: As healthcare focuses its safety efforts towards system issues rather than towards the individual provider of care, attention has turned to organizational factors, known as LRFs. Understanding how LRFs affect safety should enable us to design more effective measures that will improve overall safety. Strategies for improving patient safety should be tailored specifically for various clinical areas and disciplines.

High-inspired oxygen concentration further impairs opioid-induced respiratory depression.

BACKGROUND: Hyperoxaemia depresses the output of peripheral and central chemoreceptors. Patients treated with opioids often receive supplemental oxygen to avert possible decreases in oxygen saturation (Sp(O2)).We examined the effect of a single dose of remifentanil in healthy volunteers inhaling room air vs air enriched with 50% oxygen. METHODS: Twenty healthy volunteers received i.v. 50 mg remifentanil (infused over 60 s) at anormoxic (N) or hyperoxic (FI(O2) 0.5, H) background on separate occasions. Minute ventilation (Vi), respiratory rate (RR), end-tidal PC(O2), and Sp(O2) were collected on a breath to-breath basis. The occurrence of apnoea was recorded. RESULTS: During normoxia, remifentanil decreased Vi from 7.4 (1.3) [mean (SD)] to 2.2 (1.2) litre min 21 (P,0.01), and during hyperoxia from 7.9 (1.0) to 1.2 (1.2) litre min 21 (P,0.01; H vs N: P,0.001). RR decreased from 13.1 (2.9) to 6.1 (2.8) bpm during N (P,0.01) and from 13.2 (3.0) to 3.6 (4.0) bpm during H (P,0.01; H vs N: P,0.01). During normoxia, Sp(O2) decreased from 98.4 (1.5) to 88.6 (6.7)% (P,0.01), while during hyperoxia, Sp(O2) changed from 99.7 (0.7) to 98.7 (1.0)% (P,0.001). Apnoea developed in two subjects during normoxia and 10 during hyperoxia. CONCLUSIONS: Respiratory depression from remifentanil is more pronounced in hyperoxia than normoxia as determined from minute ventilation, end-tidal PC(O2), and RR. During hyperoxia, respiratory depression may be masked when measuring Sp(O2) as pulse oximetry remains in normal values during the first minutes of respiratory depression.

Influence of ketamine and morphine on descending pain modulation in chronic pain patients: a randomized placebo-controlled cross-over proof-of-concept study.

BACKGROUND: Descending inhibition of pain, part of the endogenous pain modulation system, is important for normal pain processing. Dysfunction is associated with various chronic pain states. Here, the effect of ketamine and morphine on descending inhibition is examined using the conditioned pain modulation (CPM) paradigm in chronic neuropathic pain patients. METHODS: CPM responses were obtained in 10 adult neuropathic pain subjects (two men/eight women). All subjects had peripheral neuropathy as defined by abnormal quantitative sensory testing. The effects of S(+)-ketamine (0.57 mg kg(-1) h(-1) for 1 h) and morphine (0.065 mg kg(-1) h(-1) for 1 h) were tested in a randomized, placebo-controlled double-blind study. CPM was measured at baseline and 100 min after the start of treatment and was induced by immersion of the leg into a cold-water bath. The test stimulus was a 30 s static thermal stimulus to the skin of the forearm. RESULTS: Without treatment, no CPM was detectable. Treatment with ketamine, morphine, and placebo produced CPM responses of 40.2 (10.9)%, 28.5 (7.0)%, and 22.1 (12.0)%, respectively (for all treatments, CPM effect P<0.05), with no statistical difference in the magnitude of CPM among treatments. The magnitude of CPM correlated positively with the magnitude and duration of spontaneous pain relief. CONCLUSIONS: The observed treatment effects in chronic pain patients suggest a role for CPM engagement in analgesic efficacy of ketamine, morphine, and placebo treatment.

Opioid-induced respiratory depression in paediatrics: a review of case reports.

Opioids remain the cornerstone of modern-day pain treatment, also in the paediatric population. Opioid treatment is potentially life-threatening, although there are no numbers available on the incidence of opioid-induced respiratory depression (OIRD) in paediatrics. To get an indication of specific patterns in the development/causes of OIRD, we searched PubMed (May 2012) for all available case reports on OIRD in paediatrics, including patients 12 yr of age or younger who developed OIRD from an opioid given to them for a medical indication or due to transfer of an opioid from their mother in the perinatal setting, requiring naloxone, tracheal intubation, and/or resuscitation. Twenty-seven cases are described in 24 reports; of which, seven cases were fatal. In eight cases, OIRD was due to an iatrogenic overdose. Three distinct patterns in the remaining data set specifically related to OIRD include: (i) morphine administration in patients with renal impairment, causing accumulation of the active metabolite of morphine; (ii) codeine use in patients with CYP2D6 gene polymorphism associated with the ultra-rapid metabolizer phenotype, causing enhanced production of the morphine; and (iii) opioid use in patients after adenotonsillectomy for recurrent tonsillitis and/or obstructive sleep apnoea, where OIRD may be related to hypoxia-induced enhancement of OIRD. Despite the restrictions of this approach, our analysis does yield an important insight in the development of OIRD, with specific risk factors clearly present in the data.