Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Canadian Institutes of Health Research. Background/Introduction Excessive epicardial adipose tissue (EAT) is associated with worse exercise capacity and is thought to play a role in the pathophysiology of heart failure with preserved ejection fraction. Few studies have explored the relationship between EAT, cardiorespiratory fitness in men and women without cardiovascular disease. Purpose To investigate the association between EAT, cardiorespiratory fitness, and physical activity levels in asymptomatic men and women of variable degree of adiposity. Methods A total of 239 participants (43% women) free from cardiovascular disease who underwent concurrent quantification of EAT volume assessed by cardiac magnetic resonance and a cardiopulmonary exercise testing (CPET) (VO2peak [ml/kg/min]) were studied. Physical activity levels/intensity were measured by questionnaire and using pedometer. Participants were categorized into low-EAT, moderate-EAT, and high-EAT groups on the basis of EAT volume. Results Mean age of participants was 49.8 ± 8.3 years, BMI 26.0 ± 3.7 kg/m2 (15% with obesity), waist circumference 89 ± 11 cm, visceral adipose tissue volume 91.3 ± 51.3 cm3, and EAT volume 9.8 ± 3.1 cm3. EAT volume decreased with increment in cardiorespiratory fitness in men and women of variable adiposity (p<0.05). Men and women with high-EAT had worse cardiometabolic profile (visceral adiposity, insulin resistance, high blood pressure, dysglycemia, atherogenic dyslipidemia), and lower cardiorespiratory fitness (VO2peak) than those with low-EAT (all p<0.05). Physical activity levels were comparable across EAT tertiles (p=NS). The association between EAT and cardiorespiratory fitness was no longer significant after controlling for visceral adiposity. Conclusions In men and women of variable degree of adiposity, excessive EAT accumulation is associated with visceral adiposity and worse cardiorespiratory fitness. Further longitudinal studies are needed to understand the interplay between EAT and cardiorespiratory fitness, and the development of obesity-related heart failure features.

BACKGROUND AND HYPOTHESISLow circulating levels of insulin-like growth-factor binding protein-2 (IGFBP-2) have been associated with increased adiposity and metabolic alterations such as insulin resistance, dyslipidemia, and non-alcoholic fatty liver disease in individuals with obesity. However, whether IGFBP-2 affects energy metabolism in the early stages of these disorders remains unclear. Herein, we hypothesized that plasma IGFBP-2 concentrations are inversely associated with early liver fat accumulation and alterations in lipid and glucose homeostasis in apparently healthy and asymptomatic men and women.METHODS333 middle-aged Caucasian men and women apparently healthy and without cardiovascular symptoms were enrolled for a cross-sectional cardiometabolic imaging study. Individuals with BMI ≥ 40 kg/m2, cardiovascular disease, dyslipidemia, hypertension, and diabetes were excluded. Fasting glucose and lipid profiles were measured and an oral glucose tolerance test was performed. Liver fat content was assessed by magnetic resonance spectroscopy. Volume of visceral adipose tissue (VAT) was evaluated by magnetic resonance imaging. Plasma IGFBP-2 levels were quantified by ELISA.RESULTSParticipants with low IGFBP-2 levels were characterized by a higher body fat mass (p<0.0001), insulin resistance (p<0.0001), higher plasma triglyceride (TG) (p<0.0001) and lower HDL-cholesterol levels (p<0.0001) in a sex-independent manner. IGFBP-2 levels were inversely correlated with liver fat fraction in both men (r=-0.36, p<0.0001) and women (r=-0.40, p<0.0001). IGFBP-2 concentrations were negatively associated with hepatic fat fraction independently of age and VAT in both men (R2=0.23, p=0.012) and women (R2=0.27, p=0.028).CONCLUSIONSOur findings show that even in asymptomatic, apparently healthy individuals, low IGFBP-2 levels are associated with a more deteriorated cardiometabolic risk profile and with a high hepatic fat content in a VAT-independent manner. However, IGFBP-2 does not appear to influence the established sexual dysmorphism observed for metabolic variables and hepatic fat fraction. Additional studies are required to better understand the relationships between IGFBP-2 and liver fat content.

BACKGROUND Functional brain imaging offers a way to investigate how general anaesthetics impair consciousness. However, functional imaging changes may result from drug effects unrelated to hypnosis. Establishing a causal link with loss of consciousness is thus difficult. METHODS To identify changes of neuronal activity functionally linked to the level of consciousness, physostigmine was used to restore consciousness without changing the anaesthetic concentration in 11 subjects anaesthetized with propofol. Eight subjects (responders) regained consciousness after physostigmine and three did not (non-responders). Positron emission tomography was used to measure regional cerebral blood flow (rCBF); during baseline (awake), after anaesthesia-induced loss of consciousness, after physostigmine administration, and recovery. In addition to subtraction analyses, we used conjunction analysis in the responders to identify changes common to the baseline-anaesthesia and physostigmine-anaesthesia contrasts. RESULTS Complete data were available for seven subjects (four responders and three non-responders). The analyses revealed that unconsciousness was associated with rCBF decreases in the thalamus and precuneus. Restoration of consciousness by physostigmine was associated with rCBF increases in these same structures, with the strongest effect in the thalamus. CONCLUSIONS The results provide strong evidence that reductions in rCBF in the thalamus and precuneus are functionally related to propofol-induced unconsciousness independently of any non-specific effects of propofol. These observations confirm that the thalamus and precuneus are key elements to understand how general anaesthetics cause unconsciousness and how patients wake up from anaesthesia. Furthermore, they are consistent with the notion that anaesthetic-induced unconsciousness is associated with reduced cholinergic activation.

BACKGROUND:Surgery for intracranial aneurysm often results in postoperative neurologic deficits. We conducted a randomized trial at 30 centers to determine whether intraoperative cooling during open craniotomy would improve the outcome among patients with acute aneurysmal subarachnoid hemorrhage. METHODS:A total of 1001 patients with a preoperative World Federation of Neurological Surgeons score of I, II, or III ("good-grade patients"), who had had a subarachnoid hemorrhage no more than 14 days before planned surgical aneurysm clipping, were randomly assigned to intraoperative hypothermia (target temperature, 33 degrees C, with the use of surface cooling techniques) or normothermia (target temperature, 36.5 degrees C). Patients were followed closely postoperatively and examined approximately 90 days after surgery, at which time a Glasgow Outcome Score was assigned. RESULTS:There were no significant differences between the group assigned to intraoperative hypothermia and the group assigned to normothermia in the duration of stay in the intensive care unit, the total length of hospitalization, the rates of death at follow-up (6 percent in both groups), or the destination at discharge (home or another hospital, among surviving patients). At the final follow-up, 329 of 499 patients in the hypothermia group had a Glasgow Outcome Score of 1 (good outcome), as compared with 314 of 501 patients in the normothermia group (66 percent vs. 63 percent; odds ratio, 1.14; 95 percent confidence interval, 0.88 to 1.48; P=0.32). Postoperative bacteremia was more common in the hypothermia group than in the normothermia group (5 percent vs. 3 percent, P=0.05). CONCLUSIONS:Intraoperative hypothermia did not improve the neurologic outcome after craniotomy among good-grade patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND:Physostigmine, a centrally acting anticholinesterase, antagonizes the hypnotic effect of propofol, as shown by the return of consciousness (response to commands) or wakefulness (spontaneous eye-opening without response to commands) and by recovery of auditory evoked potentials (40 Hz auditory steady-state response (ASSR)) and the bispectral index (BIS). We measured the effects of physostigmine on the hypnotic effect of inhaled volatile anaesthetics, using sevoflurane as the representative agent.METHODS:Eight healthy volunteers received sevoflurane adjusted to produce loss of consciousness. Physostigmine (plus glycopyrrolate) was given while the end-tidal concentration of sevoflurane was kept constant.RESULTS:Loss of consciousness was accompanied by a significant (P<0.02) decrease in ASSR amplitude (to 21% of awake value) and BIS (to 70% of awake value). Five subjects had return of consciousness or wakefulness after physostigmine. The others showed no behavioural change. Physostigmine caused a significant increase of the mean ASSR amplitude from 0.11 (SD 0.04) to 0.17 (0.06) microV (P<0.05). The BIS also increased, from 66 (12) to 74 (12), but the difference was not significant.CONCLUSIONS:Physostigmine can antagonize, at least partially, the hypnotic effect of sevoflurane and changes in arousal after physostigmine are shown by ASSR measurements. However, the antagonism is not as clear or reliable as with propofol.

Assistant Professordermot@u.washington.eduProfessorClinical Nurse SpecialistDepartment of Anesthesiology and Multidisciplinary Pain CenterUniversity of WashingtonSeattle, Washington 98195–6540To the Editor:—We refer to the recent study by Choinière et al., 1which contrasted the efficacy and costs of patient-controlled analgesia (PCA) with regularly administered intramuscular (IM) opioid therapy. The conclusion that PCA is more costly and does not have clinical advantages for pain management after hysterectomy deserves comment. The limitations of on-demand nurse-administered IM opioid therapy as a method of controlling postoperative pain are well recognized. 2PCA was introduced into clinical practice in the early 1980s as a means of overcoming these limitations. Personal control, rapid onset of pain relief, and timely effective analgesic therapy at the bedside are important aspects of PCA use. 3The technique adjusts for interpatient and intrapatient variations in opioid requirements. Today, many consider PCA therapy the “gold standard” of parenteral opioid administration for the control of postoperative pain. Consequently, alternative techniques of opioid administration must at least demonstrate comparative efficacy to PCA use. In our experience, a large majority of patients who have had a chance to compare IM injections and PCA prefer the latter. Unfortunately, patients in this study received only one form of treatment. Allowing patients to compare both techniques by a crossover design might have shown higher satisfaction with PCA. Furthermore, many patients report significant discomfort from repeated IM injections in the buttock area. 4Patients administered IM opioids in this study received at least 12 injections. Of interest, patients who received scheduled IM morphine required significantly more morphine in a 48-h period (132 ± 37 vs. 93 ± 50 mg;P < 0.0001) to obtain equivalent pain relief, significantly more rescue doses (30%vs. 0%), and significantly more morphine dose adjustments (63%vs. 15%;P < 0.0001). Given that both patient groups had similar outcomes in terms of analgesic efficacy, it should be noted that the IM patients received more morphine, required more rescue doses and dose adjustments, and consumed more nursing time than the PCA patients. This is perhaps a testament to the individualization, ease of administration, and overall success of PCA therapy. Although pain scores were equal in both groups, pain on movement was not measured during the first 24 h of this study. If it had been, a difference between the two techniques might have been observed. The assessment of efficacy of an analgesic technique should also include a measure of convenience of that technique to both patient and staff. The authors failed to comment on the ease of applicability of the IM regimen and on how successful the nursing staff was with regard to administering drug on time and dealing with apparently frequent problems of inadequate pain control in the IM group, particularly during the first 24 h postoperatively. In the somewhat artificial environment of a study, it may be possible to administer timely and appropriate IM injections. However, previous clinical experience indicates that this is a major issue in providing adequate postoperative pain relief and results in significant patient dissatisfaction. 5Nurse-administered IM opioid injections require adequate staffing levels to minimize delay between request and injection. In this climate of ever-shrinking health care dollars, we question whether there are sufficient numbers of nursing staff to follow this proposed IM protocol. Indeed, in many hospitals in the United States, the move seems to be toward providing higher numbers of less-skilled workers (medical assistants and licensed practical nurses rather than registered nurses) to care for patients in the postoperative setting. The burden imposed on the nursing staff in determining the success of such an IM regimen is not defined in this study. The saying “if it isn't broken don't fix it” may well apply to this study. IM injection of opioids has had its day and failed. Let us not return to the dark days of postoperative pain management without just cause or reason.

Background Many studies have shown the efficacy of patient-controlled analgesia (PCA). However, it is not clear whether PCA has clinical or economic benefits in addition to efficient analgesia. The current study was designed to evaluate these issues by comparing PCA with regularly administered intramuscular injections of opioids after hysterectomy. Methods This prospective study included 126 patients who underwent abdominal hysterectomy and were randomly assigned to receive PCA or regularly timed intramuscular injections of morphine during a period of 48 h. Doses were adjusted to provide satisfactory analgesia in both treatment groups. Pain at rest and with movement, functional recovery, drug side effects, and patient satisfaction were measured using rating scales and questionnaires. The costs of PCA and intramuscular therapy were calculated based on personnel time and drug and material requirements. Results Comparable analgesia was observed with the two treatment methods, with no significant differences in the incidence of side effects or patient satisfaction. The medication dosage had to be adjusted significantly more frequently in the intramuscular group than in the PCA patients. The PCA did not favor a faster recuperation time compared with intramuscular therapy in terms of times to ambulation, resumption of liquid and solid diet, passage of bowel gas, or hospital discharge. The results of the economic evaluation, which used a cost-minimization model and sensitivity analyses, showed that PCA was more costly than regular intramuscular injections despite the fact that no costs for the pump were included in the analyses. Cost differences in nursing time favoring PCA were offset by drug and material costs associated with this type of treatment. Conclusions Compared with regularly scheduled intramuscular dosing, PCA is more costly and does not have clinical advantages for pain management after hysterectomy. Because of the comparable outcomes, the general use of PCA in similar patients should be questioned.

We studied diaphragmatic and abdominal muscle activity immediately and 16 h after laparoscopic cholecystectomy (LAPC). Tidal volumes (VT), partitioning of VT between the rib cage and the abdomen, and esophageal, gastric, and transdiaphragmatic pressures were recorded for 5 min every 15 min up to 90 min after the end of anesthesia in 10 young patients submitted to an elective LAPC. All had chest radiographs in full inspiration and expiration as well as lung function tests (LFTs) before and 16 h after surgery. In 5 of the 10 patients, thoracoabdominal patterns of breathing were also measured before both LFTs. After LAPC, VT did not change. There was no significant shift from abdominal to thoracic respiration. No paradoxical respiration developed. Functional residual capacity (FRC) and residual volume (RV) remained normal. However, all measures of LFTs requiring maximum inspiratory effort decreased up to 20%. Tonic and phasic activity of the abdominal muscle appeared early in the recovery period and disappeared after 75 min. The diaphragm adjusted to this additional load so that VT remained constant. These results indicate that diaphragm function is intact during quiet breathing after LAPC, but slightly reduced when maximum effort is needed. However, this represents a net gain over the changes previously described after classic ''open'' cholecystectomy (OC).

We measured the tidal volumes (Vt) delivered by two anesthesia ventilators (the Narkomed® 2B and the Ohmeda 7800) to a model lung at frequencies of 60 breaths/min and 99–100 breaths/min under two conditions of compliance and resistance designed to mimic mild and severe adult respiratory distress syndrome (ARDS) (mild ARDS = S1 and severe ARDS = S2). The Vt produced were measured with a pneumo-tachometer at the ventilator outflow and distal to the anesthesia circuit. With the Narkomed® 2B, the Vt measured at the entrance to the model lung decreased from 216 mL to 129 mL in S1′ and from 152 mL to 88 mL in S2 as the ventilatory frequency increased from 60 to 99 breaths/min. With the Ohmeda 7800, the Vt decreased from 213 mL to 118 mL in S1′ and from 134 mL to 73 mL in S2 when the frequency was changed from 60 to 100 breaths/min. Since the delivered Vt are similar to those previously reported to maintain adequate ventilation at these rates using standard high-frequency ventilation (HFV), it may be possible to use these newer anesthesia ventilators for this purpose.