Intraoperative ketamine for prevention of depressive symptoms after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial.

BACKGROUND: Ketamine is a general anaesthetic with anti-depressant effects at subanaesthetic doses. We hypothesised that intraoperative administration of ketamine would prevent or mitigate postoperative depressive symptoms in surgical patients. METHODS: We conducted an international, randomised clinical trial testing the effects of intraoperative administration of ketamine [0.5 mg kg-1 (Lo-K) or 1.0 mg kg-1 (Hi-K)] vs control [saline placebo (P)] in patients ≥60 yr old undergoing major surgery with general anaesthesia. We administered the Patient Health Questionnaire-8 before the operation, on postoperative day (POD) 3 (primary outcome), and on POD30 to assess depressive symptoms, a secondary outcome of the original trial. RESULTS: There was no significant difference on POD3 in the proportion of patients with symptoms suggestive of depression between the placebo [23/156 (14.7%)] and combined ketamine (Lo-K plus Hi-K) [61/349 (17.5%)] groups [difference = -2.7%; 95% confidence interval (CI), 5.0% to -9.4%; P=0.446]. Of the total cohort, 9.6% (64/670; 95% CI, 7.6-12.0%) had symptoms suggestive of depression before operation, which increased to 16.6% (84/505; 95% CI, 13.6-20.1%) on POD3, and decreased to 11.9% (47/395; 95% CI, 9.1-15.5%) on POD30. Of the patients with depressive symptoms on POD3 and POD30, 51% and 49%, respectively, had no prior history of depression or depressive symptoms. CONCLUSIONS: Major surgery is associated with new-onset symptoms suggestive of depression in patients ≥60 yr old. Intraoperative administration of subanaesthetic ketamine does not appear to prevent or improve depressive symptoms. CLINICAL TRIALS REGISTRATION: NCT01690988.

Protocol for the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) study: a pragmatic, randomised clinical trial.

INTRODUCTION: Postoperative delirium, arbitrarily defined as occurring within 5 days of surgery, affects up to 50% of patients older than 60 after a major operation. This geriatric syndrome is associated with longer intensive care unit and hospital stay, readmission, persistent cognitive deterioration and mortality. No effective preventive methods have been identified, but preliminary evidence suggests that EEG monitoring during general anaesthesia, by facilitating reduced anaesthetic exposure and EEG suppression, might decrease incident postoperative delirium. This study hypothesises that EEG-guidance of anaesthetic administration prevents postoperative delirium and downstream sequelae, including falls and decreased quality of life. METHODS AND ANALYSIS: This is a 1232 patient, block-randomised, double-blinded, comparative effectiveness trial. Patients older than 60, undergoing volatile agent-based general anaesthesia for major surgery, are eligible. Patients are randomised to 1 of 2 anaesthetic approaches. One group receives general anaesthesia with clinicians blinded to EEG monitoring. The other group receives EEG-guidance of anaesthetic agent administration. The outcomes of postoperative delirium (≤5 days), falls at 1 and 12 months and health-related quality of life at 1 and 12 months will be compared between groups. Postoperative delirium is assessed with the confusion assessment method, falls with ProFaNE consensus questions and quality of life with the Veteran's RAND 12-item Health Survey. The intention-to-treat principle will be followed for all analyses. Differences between groups will be presented with 95% CIs and will be considered statistically significant at a two-sided p<0.05. ETHICS AND DISSEMINATION: Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) is approved by the ethics board at Washington University. Recruitment began in January 2015. Dissemination plans include presentations at scientific conferences, scientific publications, internet-based educational materials and mass media. TRIAL REGISTRATION NUMBER: NCT02241655; Pre-results.

Association between intraoperative electroencephalographic suppression and postoperative mortality.

BACKGROUND: Low bispectral index values frequently reflect EEG suppression and have been associated with postoperative mortality. This study investigated whether intraoperative EEG suppression was an independent predictor of 90 day postoperative mortality and explored risk factors for EEG suppression. METHODS: This observational study included 2662 adults enrolled in the B-Unaware or BAG-RECALL trials. A cohort was defined with >5 cumulative minutes of EEG suppression, and 1:2 propensity-matched to a non-suppressed cohort (≤5 min suppression). We evaluated the association between EEG suppression and mortality using multivariable logistic regression, and examined risk factors for EEG suppression using zero-inflated mixed effects analysis. RESULTS: Ninety day postoperative mortality was 3.9% overall, 6.3% in the suppressed cohort, and 3.0% in the non-suppressed cohort {odds ratio (OR) [95% confidence interval (CI)]=2.19 (1.48-3.26)}. After matching and multivariable adjustment, EEG suppression was not associated with mortality [OR (95% CI)=0.83 (0.55-1.25)]; however, the interaction between EEG suppression and mean arterial pressure (MAP) <55 mm Hg was [OR (95% CI)=2.96 (1.34-6.52)]. Risk factors for EEG suppression were older age, number of comorbidities, chronic obstructive pulmonary disease, and higher intraoperative doses of benzodiazepines, opioids, or volatile anaesthetics. EEG suppression was less likely in patients with cancer, preoperative alcohol, opioid or benzodiazepine consumption, and intraoperative nitrous oxide exposure. CONCLUSIONS: Although EEG suppression was associated with increasing anaesthetic administration and comorbidities, the hypothesis that intraoperative EEG suppression is a predictor of postoperative mortality was only supported if it was coincident with low MAP. CLINICAL TRIAL REGISTRATION: NCT00281489 and NCT00682825.

Impact of right-handedness on anaesthetic sensitivity, intra-operative awareness and postoperative mortality.

Anatomical, neurological and behavioural research has suggested differences between the brains of right- and non-right-handed individuals, including differences in brain structure, electroencephalogram patterns, explicit memory and sleep architecture. Some studies have also found decreased longevity in left-handed individuals. We therefore aimed to determine whether handedness independently affects the relationship between volatile anaesthetic concentration and the bispectral index, the incidence of definite or possible intra-operative awareness with explicit recall, or postoperative mortality. We studied 5585 patients in this secondary analysis of data collected in a multicentre clinical trial. There were 4992 (89.4%) right-handed and 593 (10.6%) non-right-handed patients. Handedness was not associated with (a) an alteration in anaesthetic sensitivity in terms of the relationship between the bispectral index and volatile anaesthetic concentration (estimated effect on the regression relationship -0.52 parallel shift; 95% CI -1.27 to 0.23, p = 0.17); (b) the incidence of intra-operative awareness with 26/4992 (0.52%) right-handed vs 1/593 (0.17%) non-right-handed (difference = 0.35%; 95% CI -0.45 to 0.63%; p = 0.35); or (c) postoperative mortality rates (90-day relative risk for non-right-handedness 1.19, 95% CI 0.76-1.86; p = 0.45). Thus, no change in anaesthetic management is indicated for non-right-handed patients.

Transthoracic echocardiography: impact on diagnosis and management in tertiary care intensive care units.

The purpose of this study was to evaluate the utility of transthoracic echocardiography (TTE) in an intensive care unit by determining its impact on diagnosis and management. Over a six-month time period, we performed a prospective observational study on all patients admitted to either the medical or the surgical intensive care unit. Structured interviews were conducted with referring physicians before and after the TTE to determine the referring physicians' pre-TTE diagnosis, reasons for requesting the TTE, and whether the TTE resulted in a change in diagnosis and/or management. A total of 135 TTE examinations were done in 126 patients. The referring physicians deemed that clinical information was inadequate to make a definitive diagnosis and management plan in 36/135 (27%) of the requests. In 99/135 (73%) studies, physicians indicated that there was probably sufficient clinical information to formulate a diagnosis and management plan, but ordered a TTE to corroborate their clinical findings. Overall, a change in diagnosis occurred in 39/135 (29%) of studies, and a change in management in 55/135 (41%) of studies. Diagnosis was changed in 19/99 (19%) studies with adequate clinical data, and in 20/36 (56%) studies with inadequate clinical data (P<0.001). Management was changed in 34/99 (34%) of studies with adequate clinical data and in 21/36 (58%) of studies with inadequate clinical data (P=0.017). Of the 62 management changes, 57/62 (92%) changes were minor, and 5/62 (8%) were major. In conclusion we have found that TTE frequently resulted in a change in the diagnosis and management.

Ethical and practical considerations of withdrawal of treatment in the intensive care unit.

PURPOSE: To discuss the medical, ethical and legal basis of decisions to discontinue life-support therapy in the adult intensive care unit (ICU), and to provide practical guidelines for the discontinuation of life support therapy. SOURCE: Relevant articles were retrieved through Medline (1991-present; terms: ethics, life support discontinuation, double effect, beneficence, non-maleficence). Other sources include legal references, and personal files. PRINCIPAL FINDINGS: Understanding the legal and ethical principles of autonomy, beneficence, non-maleficence and double effect are crucial when withdrawing life support therapy. The law respects a competent patient's right to direct his/her healthcare but does not uphold his/her right to demand futile care. Surrogate decision makers can be used when the patient is incompetent, provided they are acting in the patient's best interest. Euthanasia is illegal and the distinction between discontinuation of therapy and euthanasia is legally clear. Skillful administration of palliative therapy cannot be construed as euthanasia when the aforementioned ethical principals are respected. The various practical methods of discontinuing therapy are discussed. Every ICU should develop its own guidelines and a checklist to help caregivers during this difficult time. Caregivers must anticipate the mechanism of death and direct interventions at the symptoms that are likely to cause discomfort. Drugs and dosages must be individualized, and depend on the underlying disease, anticipated mechanism of death, and the patient's pharmacological history. When prescribing a drug, the intention should be clear. CONCLUSIONS: Appropriate discontinuation of therapy in the ICU allows patients a dignified and comfortable death.

The influence of collateral flow on the antegrade and retrograde distribution of cardioplegia in patients with an occluded right coronary artery.

BACKGROUND: The predictive value of electrocardiography (ECG) and coronary angiography for cardioplegia distribution in patients with an occluded right coronary artery was evaluated. METHODS: Coronary angiograms and ECGs were evaluated in 15 patients with right coronary artery occlusion. Prediction of antegrade cardioplegia distribution was based on ECG evidence of infarction and coronary collateral flow determined from the angiogram. Antegrade and retrograde delivery of cardioplegia was directly assessed in all patients by myocardial contrast echocardiography. Intraoperative transesophageal echocardiographic images of the right ventricular free wall, the apex, and the intraventricular septum were recorded while 4 ml of Albunex (Mallinckrodt Medical, St. Louis, MO) was injected into antegrade and retrograde cardioplegic catheters during cardioplegia delivery. The observed (myocardial contrast echocardiography) cardioplegia distribution was compared to the predicted cardioplegia distribution. Sensitivity, specificity, positive predictive values, and negative predictive values were calculated. RESULTS: Eighty seven of 90 (97%) segments were analyzed. Angiography and ECG poorly predicted incomplete cardioplegia distribution. Electrocardiography was a better predictor of inadequate cardioplegia distribution to the right ventricle than was angiography. The negative predicted values of cardioplegia distribution ranged from 20 to 50% for the septum and right ventricle, respectively, with ECG criteria and from 0 to 33% for the septum and apex, respectively, with angiographic criteria. Antegrade cardioplegia delivery was distributed to the right ventricle in 31% of patients, despite 100% occlusion of the right coronary artery; whereas retrograde cardioplegia delivery to the right ventricle occurred 20% of the time. CONCLUSIONS: In the presence of 100% right coronary artery occlusion, retrograde cardioplegia delivery is not often observed and antegrade delivery of cardioplegia to the right ventricle is not easily predicted. The preoperative angiography and ECG are not predictive of coronary collateral circulation and therefore not predictive of cardioplegia distribution to the right ventricle.

Ischaemic preconditioning: mechanisms and potential clinical applications.

PURPOSE: Brief ischaemic episodes, followed by periods of reperfusion, increase the resistance to further ischaemic damage. This response is called "ischaemic preconditioning." By reviewing the molecular basis and fundamental principals of ischaemic preconditioning, this paper will enable the anaesthetic and critical care practitioner to understand this developing therapeutic modality. SOURCE: Articles were obtained from a Medline review (1960-1997; search terms: ischaemia, reperfusion injury, preconditioning, ischaemic preconditioning, cardiac protection). Other sources include review articles, textbooks, hand-searches (Index Medicus), and personal files. PRINCIPLE FINDING: Ischaemic preconditioning is a powerful protective mechanism against ischaemic injury that has been shown to occur in a variety of organ systems, including the heart, brain, spinal cord, retina, liver, lung and skeletal muscle. Ischaemic preconditioning has both immediate and delayed protective effects, the importance of which varies between species and organ systems. While the exact mechanisms of both protective components are yet to be clearly defined, ischaemic preconditioning is a multifactorial process requiring the interaction of numerous signals, second messengers and effector mechanisms. Stimuli other than ischaemia, such as hypoxic perfusion, tachycardia and pharmacological agents, including isoflurane, have preconditioning-like effects. Currently ischaemic preconditioning is used during minimally invasive cardiac surgery without cardiopulmonary bypass to protect the myocardium against ischaemic injury during the anastomosis. CONCLUSION: Ischaemic preconditioning is a powerful protective mechanism against ischaemic injury in many organ systems. Future clinical applications will depend on the clarification of the underlying biochemical mechanisms, the development of pharmacological methods to induce preconditioning, and controlled trials in humans showing improved outcomes.

The role of the vasculature in regulating venous return and cardiac output: historical and graphical approach.

PURPOSE: To review the physiology of cardiac output regulation by the peripheral vasculature. This will enable the clinician to understand and manage the complex circulatory changes in various forms of shock, and in other common altered circulatory states encountered in anaesthetic practice. SOURCE: Articles were obtained from a Medline review (1966 to present; search terms: shock, venous return, cardiac output) and a hand search (Index Medicus). Other sources include review articles, personal files, and textbooks. PRINCIPAL FINDINGS: At steady state, cardiac output is equal to venous return (VR). Venous return depends on mean systemic pressure (PMS), which is the pressure in the peripheral vasculature driving blood flow to the heart, right atrial pressure (PRA), and the resistance to venous return (RV). When considering VR, PRA is the downstream pressure to VR, and not simply an indirect measure of the volume status. The pressure gradient for VR is, therefore, PMS-PRA, and in a system obeying Ohm's Law, [formula: see text] Shock and other altered circulatory states cause changes in both VR and cardiac function. The circulation can be conveniently described by a venous return and a cardiac output curve. By drawing these curves for each clinical situation, a clear understanding of the altered circulatory state is obtained, and treatment options can be clearly defined. CONCLUSION: The peripheral circulation controls cardiac output in many clinical conditions. Manipulation of the peripheral circulation is as important to the successful treatment of shock and other altered circulatory states, as is the manipulation of cardiac output.

Protection of the hypoxic myocardium by the bispyridine derivatives AWD 122-14 and milrinone: studies on isolated, working right rabbit hearts.

Isolated rabbit hearts were perfused via the aortic root with Muralt solution at a constant perfusion pressure of 52 mm Hg ("preload"). After passing the coronary system, the right ventricle pumps the perfusion medium against an "afterload" of 5.15 +/- 1.3 mm Hg through the arteria pulmonalis with a spontaneous heart rate of 131 +/- 11 beats/min. In this model, the right ventricle works under "physiological" conditions. The model was characterized by applying the parameters of Döring et al. The following parameters of this model were measured: RVPsyst. + diast., Qpulm., MVO2, HR, dp/dtmax, dp/dtmin. By applying the method of Neely et al. the external pressure work (w), the efficiency (e) and the coronary resistance (R) were calculated. After a short period of hypoxia of 5 min (the pO2 in the perfusion medium was decreased from 530 mm Hg to 160 mm Hg), the ventricle functions are reversibly depressed, and restored partially under reperfusion (15 min) of the myocardium in dependence of the hypoxia and reperfusion lesions. The application of 3 x 10(-6) mol/l of the two bispyridine derivatives AWD 122-14 and milrinone into the perfusion medium during the total experimental time protected the myocardium partially against the hypoxia and reperfusion lesions. This protecting activity can be shown in a better preserve and recovery of the ventricle functions (pulmonalis flow, external pressure work, efficiency). The application of 5 x 10(-8) mol/l nifedipine, a known protective substance, showed a lower activity in this model compared with the activity of the bispyridines.(ABSTRACT TRUNCATED AT 250 WORDS)

Deferoxamine (Desferal) improves the content of oxygen in myocardial tissues during recovery after hypoxia in isolated rabbit heart.

On isolated working right heart from rabbit tissue oxygen content as an indicator of function of oxygen transport and storage was observed by moderate hypoxia, hypoxia with deferoxamine (1) and iron infusion. In addition water content of myocardium as an indicator of metabolic damage was evaluated and the copper depletion was established. During the recovery the results presented a beneficial effect on the content of tissue oxygen which is due to 1. But the copper depletion was not changed. Possible connections are discussed.

[The occurrence of Heinz bodies in the erythrocytes of persons exposed to low dose radiation during work]. / Das Vorkommen von Heinz-Körpern in den Erythrozyten von im niederen Dosisbereich strahlenexponiert arbeitenden Personen

274 persons were examined by the provocation test of Heinz's bodies according to BEUTLER. 168 of them were working under x-rays exposure. No correlation could be identified between the dosage and the presence of Heinz's bodies in the lower range of the dosage related to the annual x-rays load and the integrated total exposure.