Prevalence of DNA of regular occupants in vehicles.

People will deposit, redistribute and remove biological traces when they interact with their environment. Understanding the dynamics of trace DNA is crucial to assess both the optimal sampling strategy to recover traces and the relevance of DNA evidence in the context of a case. This paper addresses the prevalence of DNA of drivers, passengers, and unknown individuals in vehicles. Five vehicles with a regular driver only, and five vehicles with a regular driver and regular passenger have each been sampled at twenty locations. Based on the findings, we propose a sampling strategy for investigative purposes as well as for evaluative purposes when evaluating the findings given scenarios that propose the person-of-interest as either the driver or passenger in a vehicle.

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.

[Handovers during anaesthetic care can be further improved]. / Anesthesiologische overdracht op de OK kan nog beter.

In 2005, the Dutch Society of Anaesthesiologists showed that handovers during anaesthetic care increase complication and mortality rates, an observation that has recently been confirmed by a Canadian study. In contrast to surgical care, handovers in anaesthetic care are quite common for various reasons including end of shift, tiredness after night duty, and activities outside the operating centre. The quality of handovers could be improved by training on an anaesthesia simulator, with emphasis on communication, reduction of information loss and using checklists.

[Inhalational or intravenous anesthesia?]. / Algehele anesthesie: inhaleren of injecteren?

The debate continues whether there is a difference in patient outcome following inhalational versus intravenous anesthesia. A recent meta-analysis showed improved outcome following inhalational anesthesia in patients undergoing cardiac surgery but not in patients undergoing non-cardiac procedures. In this article we discuss the meta-analysis and its caveats, taking into account additional comparative studies. Our overall conclusion is that it is too early to definitively claim that one anesthesia technique results in a better outcome than the other.

Non-invasive continuous arterial pressure and pulse pressure variation measured with Nexfin(®) in patients following major upper abdominal surgery: a comparative study.

We compared the accuracy and precision of the non-invasive Nexfin(®) device for determining systolic, diastolic, mean arterial pressure and pulse pressure variation, with arterial blood pressure values measured from a radial artery catheter in 19 patients following upper abdominal surgery. Measurements were taken at baseline and following fluid loading. Pooled data results of the arterial blood pressures showed no difference between the two measurement modalities. Bland-Altman analysis of pulse pressure variation showed significant differences between values obtained from the radial artery catheter and Nexfin finger cuff technology (mean (SD) 1.49 (2.09)%, p < 0.001, coefficient of variation 24%, limits of agreement -2.71% to 5.69%). The effect of volume expansion on pulse pressure variation was identical between methods (concordance correlation coefficient 0.848). We consider the Nexfin monitor system to be acceptable for use in patients after major upper abdominal surgery without major cardiovascular compromise or haemodynamic support.

The effect of propofol on haemodynamics: cardiac output, venous return, mean systemic filling pressure, and vascular resistances.

BACKGROUND: Although arterial hypotension occurs frequently with propofol use in humans, its effects on intravascular volume and vascular capacitance are uncertain. We hypothesized that propofol decreases vascular capacitance and therefore decreases stressed volume. METHODS: Cardiac output (CO) was measured using Modelflow(®) in 17 adult subjects after upper abdominal surgery. Mean systemic filling pressure (MSFP) and vascular resistances were calculated using venous return curves constructed by measuring steady-state arterial and venous pressures and CO during inspiratory hold manoeuvres at increasing plateau pressures. Measurements were performed at three incremental levels of targeted blood propofol concentrations. RESULTS: Mean blood propofol concentrations for the three targeted levels were 3.0, 4.5, and 6.5 µg ml(-1). Mean arterial pressure, central venous pressure, MSFP, venous return pressure, Rv, systemic arterial resistance, and resistance of the systemic circulation decreased, stroke volume variation increased, and CO was not significantly different as propofol concentration increased. CONCLUSIONS: An increase in propofol concentration within the therapeutic range causes a decrease in vascular stressed volume without a change in CO. The absence of an effect of propofol on CO can be explained by the balance between the decrease in effective, or stressed, volume (as determined by MSFP), the decrease in resistance for venous return, and slightly improved heart function. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register: NTR2486.

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.

A randomized controlled trial and novel mathematical analysis of the analgesic effect of oxycodone versus paracetamol orodispersible tablets.

BACKGROUND: For effective treatment of acute pain, a rapid onset of action is important. Here we quantify the antinociceptive profile of an orodispersible oxycodone tablet (OOT) in a randomized, double-blind, active comparator (paracetamol orodispersible tablet, POT), crossover study design in a population of healthy volunteers. METHODS: Twelve female volunteers were randomized to receive 20 mg OOT and 500 mg POT sublingually on two occasions. The electrical pain threshold (EPTh), electrical pain tolerance (EPTol) and pressure pain threshold (PPT) were obtained at regular intervals for 5 h. Time-response data were analysed with a longitudinal pharmacodynamic model characterized by rate constants for analgesia onset (kON ), offset (kOFF ), potency parameter (EFF) and validated with a bootstrap analysis. Values are the median (95% CI) as derived from the bootstrap analysis. RESULTS: OOT produced a rapid increase in response values. For electrical pain analgesia onset, t½kON , 44 (25-67) versus analgesia offset, t½kOFF , 156 (63-552) min, p < 0.01. For pressure pain, t½kON equalled t½kOFF : 30 (16-48) min. OOT was most potent on EPTol: EFF 0.95 (0.39-1.71), p < 0.01, with similar potencies on EPTh, 0.43 (0.19-0.87) and PPT, 0.40 (0.21-0.67). Paracetamol displayed 14% of the analgesic efficacy of oxycodone. CONCLUSIONS: The analgesic effect of orodispersible oxycodone was successfully quantified using a mathematical model of analgesia evolution. This method allows quantification of a variety of responses times from sparse data sets. Response times as defined by a 30% increase in response thresholds varied significantly among end points: EPTol 15 min, PPTh 18 min and EPTh 41 min.

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.

Cardiospecific sevoflurane treatment quenches inflammation but does not attenuate myocardial cell damage markers: a proof-of-concept study in patients undergoing mitral valve repair.

BACKGROUND: Inflammation is considered a key mediator of complications after cardiac surgery. Sevoflurane has been shown to quench inflammation and to provide cardioprotection in preclinical studies. Clinical studies using sevoflurane confirm this effect on inflammation but do not consistently show clinical benefits. This paradox may indicate that the contribution of inflammation to postoperative sequalae is less than commonly thought or that systemic doses are too low in their local concentration. To test the latter, we evaluated the effects of intramyocardial sevoflurane delivery. METHODS: Selective myocardial sevoflurane delivery was performed during aortic cross-clamping in patients undergoing valve surgery (n=11). Results were compared with a control group not receiving sevoflurane (n=10). A reference group (n=5) was added to evaluate the effects of systemic sevoflurane delivery. Paired arterial and myocardial venous blood samples were collected at various time points post-reperfusion. Inflammatory mediators and myocardial cell damage were studied. RESULTS: Intramyocardial delivery was superior to systemic delivery in attenuation of interleukin-6 and interleukin-8 (-44% and -25%, respectively; both P=0.001). Myocardial and systemic sevoflurane delivery effectively suppressed surgery-related inflammatory responses including postoperative C-reactive protein levels when compared with controls [63 (47-99) (P=0.01) and 58 (56-81) (P=0.04) compared with 107 (79-144) mg litre(-1)]. Sevoflurane treatment did not reduce postoperative troponin T, creatine kinase, and creatine kinase-MB values. CONCLUSIONS: This proof-of-concept study suggests that intramyocardial delivery compared with the systemic delivery of sevoflurane more strongly attenuates the systemic inflammatory response after cardiopulmonary bypass without reducing postoperative markers of myocardial cell damage. CLINICAL TRIAL REGISTRATION: Nederlands Trial Register NTR2089.

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.

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.

Upper thoracic epidural anaesthesia: effects of age on neural blockade and cardiovascular parameters.

BACKGROUND: Segmental dose reduction with increasing age after thoracic epidural anaesthesia (TEA) has been documented. We hypothesised that after a fixed loading dose of ropivacaine at the T3-T4 level, increasing age would result in more extended analgesic spread. In addition, other aspects of neural blockade and haemodynamic changes were studied. METHODS: Thirty-five lung surgery patients were included in three age groups. Thirty-one patients received an epidural catheter at the T3-T4 interspace followed by an injection of 8-ml ropivacaine 0.75%. Analgesia was assessed with pinprick and temperature discrimination. Motor block was tested using the Bromage and epidural scoring scale for arm movements score. An arterial line was inserted for invasive measurement of blood pressure, cardiac index (CI) and stroke volume (SV). RESULTS: There was no influence of age on quality of TEA except for the caudal border of analgesia being somewhat lower in the middle and older age group compared with the young age group. Heart rate (6.0 ± 5.9, P < 0.001), mean arterial pressure (16.1 ± 15.6, P < 0.001), CI (0.55 ± 0.49, P < 0.001) and SV (9.6 ± 14.6, P = 0.001) decreased after TEA for the total group. Maximal reduction in heart rate after TEA was more extensive in the young age group compared with the other age groups. There was no effect of age on other cardiovascular parameters. CONCLUSION: We were unable to demonstrate an effect of age on the maximal number of spinal segments blocked after TEA; however, the caudad spread of analgesia increased with advancing age. In addition, reduction of heart rate was greater in the youngest group.

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.

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.

Validation of a novel respiratory rate monitor based on exhaled humidity.

BACKGROUND: Postoperative monitoring of ventilation is largely restricted to the measurement of haemoglobin-oxygen saturation and respiratory rate (RR) derived from the ECG. measurement is inadequate when used with supplemental oxygen and ECG-derived RR is subject to artifacts. A new monitor measures RR by quantifying the humidity of exhaled air (respiR8(®)). METHODS: The accuracy of the system was tested using a breathing simulator. In healthy volunteers, the respiR8(®) monitor was compared with two other methods of measuring RR: capnometry and counting of thoracic breathing movements. The ability of the monitor to track changes in RR resulting from the infusion of 2.5 µg kg(-1) fentanyl was assessed and compared with RR measured from a validated flow measurement system. The RR in 50 postoperative patients measured with the respiR8(®) was compared with that derived from the ECG. RR values were compared by population-based Bland-Altman analyses. RESULTS: The respiR8(®) monitor was accurate in the range required in clinical practice. There was a close agreement between RR from respiR8(®), capnometry, and manual counting of respiratory movements without bias (limits of agreement ±1 bpm). The respiR8(®) monitor was well able to accurately track RR changes from fentanyl. In postoperative patients, RR from respiR8(®) and ECG had a bias of 1.7 (5.7) bpm due to greater RR values observed from the ECG due to artifacts. CONCLUSIONS: The respiR8(®) gives an accurate measurement of RR and is useful in postoperative care.