Sleep and meal-time misalignment alters functional connectivity: a pilot resting-state study.

Delayed sleep and meal times promote metabolic dysregulation and obesity. Altered coordination of sleeping and eating times may impact food-reward valuation and interoception in the brain, yet the independent and collective contributions of sleep and meal times are unknown. This randomized, in-patient crossover study experimentally manipulates sleep and meal times while preserving sleep duration (7.05±0.44 h for 5 nights). Resting-state functional magnetic resonance imaging scans (2 × 5-minute runs) were obtained for four participants (three males; 25.3±4.6 years), each completing all study phases (normal sleep/normal meal; late sleep/normal meal; normal sleep/late meal; and late sleep/late meal). Normal mealtimes were 1, 5, 11 and 12.5 h after awakening; late mealtimes were 4.5, 8.5, 14.5 and 16 h after awakening. Seed-based resting-state functional connectivity (RSFC) was computed for a priori regions-of-interest (seeds) and contrasted across conditions. Statistically significant (P<0.05, whole-brain corrected) regionally specific effects were found for multiple seeds. The strongest effects were linked to the amygdala: increased RSFC for late versus normal mealtimes (equivalent to skipping breakfast). A main effect of sleep and interaction with meal time were also observed. Preliminary findings support the feasibility of examining the effects of sleep and meal-time misalignment, independent of sleep duration, on RSFC in regions relevant to food reward and interoception.

Sleep restriction increases the neuronal response to unhealthy food in normal-weight individuals.

CONTEXT: Sleep restriction alters responses to food. However, the underlying neural mechanisms for this effect are not well understood. OBJECTIVE: The purpose of this study was to determine whether there is a neural system that is preferentially activated in response to unhealthy compared with healthy foods. PARTICIPANTS: Twenty-five normal-weight individuals, who normally slept 7-9 h per night, completed both phases of this randomized controlled study. INTERVENTION: Each participant was tested after a period of five nights of either 4 or 9 h in bed. Functional magnetic resonance imaging (fMRI) was performed in the fasted state, presenting healthy and unhealthy food stimuli and objects in a block design. Neuronal responses to unhealthy, relative to healthy food stimuli after each sleep period were assessed and compared. RESULTS: After a period of restricted sleep, viewing unhealthy foods led to greater activation in the superior and middle temporal gyri, middle and superior frontal gyri, left inferior parietal lobule, orbitofrontal cortex, and right insula compared with healthy foods. These same stimuli presented after a period of habitual sleep did not produce marked activity patterns specific to unhealthy foods. Further, food intake during restricted sleep increased in association with a relative decrease in brain oxygenation level-dependent (BOLD) activity observed in the right insula. CONCLUSION: This inverse relationship between insula activity and food intake and enhanced activation in brain reward and food-sensitive centers in response to unhealthy foods provides a model of neuronal mechanisms relating short sleep duration to obesity.

Postprandial thermogenesis and substrate oxidation are unaffected by sleep restriction.

BACKGROUND/OBJECTIVES: The extent to which alterations in energy expenditure (EE) in response to sleep restriction contribute to the short sleep-obesity relationship is not clearly defined. Short sleep may induce changes in resting metabolic rate (RMR), thermic effect of food (TEF) and postprandial substrate oxidation. SUBJECTS/METHODS: Ten females (age and body mass index: 22-43 years and 23.4-28 kg m(-2)) completed a randomized, crossover study assessing the effects of short (4 h per night) and habitual (8 h per night) sleep duration on fasting and postprandial RMR and respiratory quotient (RQ). Measurements were taken after three nights using whole-room indirect calorimetry. The TEF was assessed over a 6-h period following consumption of a high-fat liquid meal. RESULTS: Short versus habitual sleep did not affect RMR (1.01±0.05 and 0.97±0.04 kcal min(-1); P=0.23). Fasting RQ was significantly lower after short versus habitual sleep (0.84±0.01 and 0.88±0.01; P=0.028). Postprandial EE (short: 1.13±0.04 and habitual: 1.10±0.04, P=0.09) and RQ (short: 0.88±0.01 and habitual: 0.88±0.01, P=0.50) after the high-fat meal were not different between conditions. TEF was similar between conditions (0.24±0.02 kcal min(-1) in both; P=0.98), as was the ~6-h incremental area under the curve (1.16±0.10 and 1.17±0.09 kcal min(-1) × 356 min after short and habitual sleep, respectively; P=0.92). CONCLUSIONS: Current findings observed in non-obese healthy premenopausal women do not support the hypothesis that alterations in TEF and postprandial substrate oxidation are major contributors to the higher rate of obesity observed in short sleepers. In exploring a role of sleep duration on EE, research should focus on potential alterations in physical activity to explain the increased obesity risk in short sleepers.

Sleep duration and disorders in pregnancy: implications for glucose metabolism and pregnancy outcomes.

Humans have an innate requirement for sleep that is intrinsically governed by circadian and endocrine systems. More recently, reduced sleep duration has gained significant attention for its possible contribution to metabolic dysfunction. Significant evidence suggests that reduced sleep duration may elevate the risk for impaired glucose functioning, insulin resistance and type 2 diabetes. However, to date, few studies have determined the implications of reduced sleep duration with regard to glucose control during pregnancy. With the high prevalence of overweight and obesity in women of reproductive age, the occurrence of gestational diabetes mellitus (GDM) is increasing. GDM results in elevated risk of maternal and fetal complications, as well as increased risk of type 2 diabetes postpartum. Infants born to women with GDM also carry a life-long risk of obesity and type 2 diabetes. The impact of reduced sleep on glucose management during pregnancy has not yet been fully assessed and a paucity of literature currently exits. Herein, we review the association between reduced sleep and impaired carbohydrate metabolism and propose how reduced sleep during pregnancy may result in further dysfunction of the carbohydrate axis. A particular focus will be given to sleep-disordered breathing, as well as GDM-complicated pregnancies. Putative mechanisms of action by which reduced sleep may adversely affect maternal and infant outcomes are also discussed. Finally, we will outline important research questions that need to be addressed.

Daytime Sleepiness Is Associated with Lower Cognitive Scores: The Look AHEAD Study.

Background: Daytime sleepiness is common in older adults and may result from poor nighttime sleep due to sleep disordered breathing, fragmented sleep, or other sleep disorders. Daytime sleepiness may be associated with cognition in older adults. Objectives: We investigated the association between self-reported daytime sleepiness and cognitive function in the Look AHEAD clinical trial. Design: Observational follow-up of a randomized clinical trial of an intensive lifestyle intervention. Setting: Clinic. Participants: Participants (n=1,778) aged 45-76 years at baseline with type 2 diabetes and overweight or obesity. Interventions: Participants were randomized to an intensive lifestyle intervention for weight loss or a control condition of diabetes support and education. Measurements: Participants provided self-reported levels of daytime sleepiness at baseline and years 12-13. Cognitive function was assessed with a neurocognitive battery at years 12-13 and 18-20. Results: Participants who reported having frequent daytime sleepiness (often or always) performed significantly worse than others on the cognitive composite (-0.35; p-value=0.014) after controlling for covariates. When stratified by intervention arm, participants assigned to the intensive lifestyle intervention who reported often/always having daytime sleepiness performed worse on Digit Symbol Coding (-0.63; p-value=0.05) and Trail Making Part-B (-0.56; p-value=0.02) after controlling for covariates. Statistical interactions revealed associations between daytime sleepiness and the following covariates: race and ethnicity, APOE ε4 carrier status, baseline history of cardiovascular disease, and depression. Conclusions: Daytime sleepiness over ~13 years predicted poorer cognitive performance in older individuals who, by virtue of having diabetes and overweight/obesity, are at high risk for sleep disorders and cognitive impairment.

Sleep-obesity relation: underlying mechanisms and consequences for treatment.

Short sleep duration has been associated with obesity in numerous epidemiological studies. However, such association studies cannot establish evidence of causality. Clinical intervention studies, on the other hand, can provide information on a causal effect of sleep duration on markers of weight gain: energy intake and energy expenditure. Herein is an overview of the science related to the impact of sleep restriction, in the context of clinical intervention studies, on energy intake, energy expenditure and body weight. Additionally, studies that evaluate the impact of sleep restriction on weight loss and the impact of sleep extension on appetite are discussed. Information to date suggests that weight management is hindered when attempted in the context of sleep restriction, and the public should be made aware of the negative consequences of sleep restriction for weight regulation.

A sipometer for measuring motivation to consume and reward value of foods and beverages in humans: Description and proof of principle.

New methods, derived from animal work, for measuring food reward value (i.e. reinforcing value of food), and motivation (i.e. strength of desire) to consume, in humans are described and validated. A sipping device (sipometer) was developed that permits access to a liquid food or beverage on two reward schedules: continuous reinforcement (CR) and progressively increasing time spent exerting pressure on a straw (PR-schedule). In addition, a pictorial scale showing a cup, from which the 'amount wanted' could be marked was used to pre-test potential consumption. Intake, time spent sipping, breakpoint, and pressure exerted were the main dependent variables measured. Three pilot experiments were conducted. In Experiment 1, participants (n=8) consumed yogurt shakes after a 1-h or 21-h food deprivation period on both schedules. In Experiment 2, participants (n=8) sham-consumed (i.e. spit out) sweet and non-sweet beverages, utilizing both schedules. In Experiment 3, sham-consuming sweet and non-sweet beverages on both schedules and working for shake on the PR schedule were repeated, after three nights of either habitual sleep or short sleep duration (n=7) in a crossover design. In Experiment 1, participants sipped longer after 21-h vs. 1-h of food deprivation (13±3.0 vs. 8.0±2.1s; p=0.04), on the PR schedule. In Experiment 2, sham-intake (p=0.01) and sipping time (p=0.04) were greater for sweet than non-sweet beverages on the PR schedule and a similar, though not conventionally significant, effect was observed for exerted pressure (p=0.09). In both Experiment 2 and Experiment 3 after habitual sleep, on the PR schedule, cumulative pressure difference between sweet and non-sweet beverage increased with difference in amount wanted in the taste test. In contrast, after short sleep participants were less willing to work for sweet taste as their wanting increased, suggesting that sleep deprivation raises desire, but lowers behavioral output. Taken together these results demonstrate that the sipometer and associated ratings are reliable and useful measures of motivation to consume and reward value in humans. Participants were more motivated to obtain access to sweet beverages, especially when these were better liked than to obtain access to non-sweet beverages.

Lifestyle behaviours and components of energy balance as independent predictors of ghrelin and adiponectin in young non-obese women.

AIM: Dysregulation of the normal levels of ghrelin, leptin and adiponectin in young non-obese subjects could promote food intake, diabetes and cardiovascular disease in later stages of life. Little information is available on how plasmatic concentrations of these hormones may be influenced by eating habits and/or components of energy balance in a young population, which if known, could facilitate their voluntary regulation. METHODS: In this cross-sectional study we examined the predictors of fasting plasma ghrelin, adiponectin and leptin in a population of well-characterized young non-obese women (N = 63). Energy intake was assessed by 24-hour dietary recall, resting metabolic rate (RMR) by indirect calorimetry, physical activity energy expenditure (PAEE) by tri-axial accelerometer, physical fitness by VO(2 peak), and eating behaviors by self administrated questionnaire. RESULTS: Lower RMR and higher HDL-cholesterol were independent predictors of higher plasma ghrelin explaining 17.6% of its variation even after correcting for BMI. Higher total or central fat mass was the only predictor of higher plasma leptin, and no other variable added any power to the prediction equation. Finally, higher energy intake and waist circumference and lower PAEE predicted lower plasma adiponectin in young non-obese women, explaining 43% of the variation in its concentrations even after correcting for total or central fat mass. CONCLUSION: Components of the energy balance (ie: energy intake and/or expenditure) influence adiponectin and ghrelin circulating levels. That is, higher energy intake and lower physical activity independently predict lower adiponectin concentrations, whereas lower resting metabolic rate independently predicts higher ghrelin levels in young non-obese women. Prospective studies are needed to examine whether circulating concentrations of ghrelin and adiponectin can be voluntarily regulated by lifestyle interventions.

Phytosterols in nonfat and low-fat beverages have no impact on the LDL size phenotype.

OBJECTIVE: To examine the impact of nonfat and low-fat phytosterol-enriched beverages on low-density lipoprotein (LDL) electrophoretic characteristics. DESIGN: Double-blind, randomized, crossover, placebo-controlled dietary trial. SETTING: Diets were prepared and consumed at the Mary Emily Clinical Nutrition Research Unit of McGill University. Analyses were performed at the Institute on Nutraceuticals and Functional Foods of Laval University. SUBJECTS AND INTERVENTION: In total, 15 moderately hypercholesterolemic persons consumed each of three experimental diets that each comprised a different beverage: nonfat placebo (NF control), nonfat with phytosterols (NFPS) or low-fat with phytosterols (LFPS). Participants consumed three beverages daily at meal time for a total of 1.8 g of phytosterols per day. Nondenaturing 2-16% polyacrylamide gradient gel electrophoreses were used to characterize LDL size characteristics. RESULTS: The NFPS and LFPS beverage induced no significant changes in several features of the LDL size phenotype compared to the control diet. CONCLUSION: The consumption of phytosterol-supplemented nonfat and low-fat beverages is not associated with clinically meaningful changes in the LDL particle size phenotype.

Consumption of fermented and nonfermented dairy products: effects on cholesterol concentrations and metabolism.

The objective of this article was to review existing literature concerning the effects and mechanisms of action of fermented dairy products on serum cholesterol concentrations. Although not without exception, existing evidence from animal and human studies suggests a moderate cholesterol-lowering action of fermented dairy products. Mechanistically, fermented milk has been shown to cause an increase in human gut bacterial content. These bacteria, once resident in the large intestine, are believed to ferment food-derived indigestible carbohydrates. Such fermentation causes increased production of short-chain fatty acids, which decreases circulatory cholesterol concentrations either by inhibiting hepatic cholesterol synthesis or by redistributing cholesterol from plasma to the liver. Furthermore, increased bacterial activity in the large intestine results in enhanced bile acid deconjugation. Deconjugated bile acids are not well absorbed by the gut mucosa and are excreted. Consequently, cholesterol, being a precursor of bile acids, is utilized to a greater extent for de novo bile acid synthesis. These actions combined are proposed as contributing mechanisms to the association of fermented milk consumption with decreased circulating cholesterol concentrations.

New bioimpedance analysis system: improved phenotyping with whole-body analysis.

OBJECTIVE: Bioimpedance analysis (BIA) is a potential field and clinical method for evaluating skeletal muscle mass (SM) and %fat. A new BIA system has 8-(two on each hand and foot) rather than 4-contact electrodes allowing for rapid 'whole-body' and regional body composition evaluation. DESIGN: This study evaluated the 50 kHz BC-418 8-contact electrode and TBF-310 4-contact electrode foot-foot BIA systems (Tanita Corp., Tokyo, Japan). SUBJECTS: There were 40 subject evaluations in males (n=20) and females (n=20) ranging in age from 6 to 64 y. BIA was evaluated in each subject and compared to reference lean soft-tissue (LST) and %fat estimates in the appendages and remainder (trunk+head) provided by dual-energy X-ray absorptiometry (DXA). Appendicular LST (ALST) estimates from both BIA and DXA were used to derive total body SM mass. RESULTS: The highest correlation between total body LST by DXA and impedance index (Ht(2)/Z) by BC-418 was for the foot-hand segments (r=0.986; left side only) compared to the arm (r=0.970-0.979) and leg segments (r=0.942-0.957)(all P<0.001). The within- and between-day coefficient of variation for %fat and ALST evaluated in five subjects was <1% and approximately 1-3.7%, respectively. The correlations between 8-electrode predicted and DXA appendicular (arms, legs, total) and trunk+head LST were strong and highly significant (all r> or =0.95, P<0.001) and group means did not differ across methods. Skeletal muscle mass calculated (Kim equation) from total ALST by DXA (X+/-s.d.)(23.7+/-9.7 kg) was not significantly different and highly correlated with BC-418 estimates (25.2+/-9.6 kg; r=0.96, P<0.001). There was a good correlation between total body %fat by 8-electrode BIA vs DXA (r=0.87, P<0.001) that exceeded the corresponding association with 4-electrode BIA (r=0.82, P<0.001). Group mean segmental %fat estimates from BC-418 did not differ significantly from corresponding DXA estimates. No between-method bias was detected in the whole body, ALST, and skeletal muscle analyses. CONCLUSIONS: The new 8-electrode BIA system offers an important new opportunity of evaluating SM in research and clinical settings. The additional electrodes of the new BIA system also improve the association with DXA %fat estimates over those provided by the conventional foot-foot BIA.

Teenage pregnancy: a reconsideration.

Teenage pregnancies may be diminishing, but the same cannot be said about the risks for abnormal pregnancy and pregnancy outcome in this group. This study sought to examine rates (by mother's age at time of birth) for a number of variables indicative of pregnancy and birth problems. Specifically, the charts of 1,681 babies, born at a regional mid-northern Ontario Labour and Delivery Unit between 1987 and 1988, were examined. Results suggest that this group of teenaged mothers continue to demonstrate a higher rate of substance, tobacco and dietary abuse during pregnancy than older aged mothers. Further, more babies born to these particular teenaged mothers received low APGAR scores, 5 minutes after birth, than babies born to other aged mothers. The same group (teenaged mothers) gave birth to pre-term babies more often, and had a higher rate of congenital abnormality than did other aged mothers.

PIP: Despite the declining incidence of teen pregnancy, attention should not be diverted from the comparatively greater risk of problem pregnancies and births among the young. Drawing from charts of 1681 babies born at a regional hospital in Ontario, Canada, over the period 1987-88, this study explores the differential risks of abnormal pregnancy and pregnancy outcome among mothers aged 15-19, 20-34, and those 35 years and older. Factors considered include the presence of a congenital abnormality in babies, gestation duration, birth weight, baby's APGAR score, maternal history of substance or dietary abuse, maternal history of patent or prescribed medication use, and maternal history of medical or surgical problems during pregnancy, parity, and gravidity. Teen mothers demonstrated higher rates of substance, tobacco, and dietary abuse during pregnancy than older mothers. Likewise, babies born to teens received comparatively lower APGAR scores 5 minutes after birth, were more likely to be preterm, and had a higher rate of congenital abnormality.

Qualitative and quantitative effects of ACTH, piromen, cytoxan and isobutyl-2-cyanoacrylate treatments following spinal cord transection in rats.

Adult, male, Long-Evans hooded rats were subjected to a spinal cord transection in the mid-thoracic region. Following surgery, animals were divided into groups for treatments with ACTH, Piromen, isobutyl-2-cyanoacrylate and Cytoxan. Animals were sacrificed at varying intervals from 7-180 days. Horizontal sections of the lesion site were stained with the Bodian silver and Gomori trichrome techniques and numbers of nerve fibers counted within the lesion. Statistical analysis of the quantitative data indicated that Piromen and Cytoxan, respectively, were significantly more effective than the other treatments in promoting regeneration of nerve fibers into the scar. Microcysts appeared adjacent to the lesion in all animals early in the postoperative period and coalesced to form large cavitations which continued to enlarge throughout the postoperative period. Although nerve fibers appeared to traverse the lesion, no return of function was observed.

Predictors of psychological distress in family caregivers of persons with psychiatric disabilities.

The purpose of the study was to determine the relationships of primary and secondary stressors, and informal and formal supports, to psychological distress in 154 family caregivers of persons with psychiatric disabilities. All caregivers were members of self-help groups located in the Province of Quebec in Canada. Psychological distress was significantly lower among older caregivers, those working full time, and those experiencing lower objective and subjective burdens. Contrary to the hypotheses, caregivers who perceived more support from friends and had more contacts with their relatives' primary mental health providers experienced a higher level of psychological distress.

[Collective kitchens: the way to promote mental health]. / Les cuisines collectives: une voie vers la promotion de la santé mentale.

Collective kitchens represent a relatively new social and community practice in the province of Quebec. They provide support that goes far beyond the food they supply, affecting the participants' life conditions and personal development. This qualitative study aimed to evaluate the effects that collective kitchens have on participants. We carried out semistructured interviews with a stratified sample of 25 people between the ages of 20 and 60, a majority of whom were single parents. These 20 women and 5 men were involved in 13 different groups for an average of 1 to 2 years. The results showed that the main reasons for participating in these groups were economic, nutritional, and psychosocial in nature. Prominent among the psychosocial reasons was a desire to overcome a feeling of isolation, which a majority of respondents perceived as one of the most disturbing features of their lives before they were involved in the collective kitchens. We identified 3 types of factors that influence the effects of the respondents' participation in collective kitchens: (a) factors related to the internal dynamics of each collective kitchen (their modes of functioning and organizational structure), (b) factors related to the personal situation of the participants and (c) factors related to the use of other services or to the participants' social involvement. The various effects differ not only in character (psychosocial, economic, nutritional, etc.) but also in the time they appeared in the participation process and in their direct or indirect links with participation in collective kitchens. It would be interesting in future research to evaluate whether the benefits of participation in collective kitchens identified in this study have a long-term impact on the lives of the people in these groups.

{Social support and the help offered by mothers to their psychologically troubled sons or daughters}. / L&apaide que des femmes offrent à leur fils ou à leur fille présentant des troubles psychotiques et le rseau de soutien de ces femmes.

We describe in this paper the everyday support mothers give to their adult sons or daughters suffering from psychotic disorders. We also describe the support these women receive from their social network regarding specific needs related to their children's disorders. Ninety-nine women, representing all socioeconomic groups, were interviewed. They were recruited through hospitals and self-help groups. The results of this study highlight the fact that participants give a substantial amount of support to their children, that they have considerable concern for their children's well-being, and that members of their family are their main source of emotional and practical support, and of advice. Mental health professionals give primarily informational support to respondents, in part through community-based agencies. The respondents who belong to self-help groups have significantly more needs related to their children's disorders and have more concern for their children's well-being than do the other respondents.

[Mothers of psychotic patients and their difficulties with the health care system]. / Les difficultées perçues par des mères de personnes atteintes de troubles psychotiques face au système de soins professionnels.

This article describes the difficulties perceived by mothers of people suffering from psychotic problems when coping with the healthcare system. The 99 interviewees were recruited through mutual help groups and hospitals. In addition to feeling left to themselves to care for their child, their main grievances relate to the fact that their child does not have access to workforce integration resources, that therapeutic follow-up (non-drug related) is inadequate and that they do not receive updates on the state of health of their child. Mothers belonging to mutual help groups are significantly more upset about the difficulties they encounter when coping with the healthcare system, in comparison to mothers who do not belong to such groups. In light of comments by experts and the interviewees, the authors make suggestions designed to improve existing services, as well as collaboration between healthcare teams and the families concerned.

Impact of medium and long chain triglycerides consumption on appetite and food intake in overweight men.

BACKGROUND: Medium chain triglycerides (MCT) enhance thermogenesis and may reduce food intake relative to long chain triglycerides (LCT). The goal of this study was to establish the effects of MCT on appetite and food intake and determine whether differences were due to differences in hormone concentrations. METHODS: Two randomized, crossover studies were conducted in which overweight men consumed 20 g of MCT or corn oil (LCT) at breakfast. Blood samples were obtained over 3 h. In Study 1 (n=10), an ad lib lunch was served after 3 h. In Study 2 (n=7), a preload containing 10 g of test oil was given at 3 h and lunch was served 1 h later. Linear mixed model analyses were performed to determine the effects of MCT and LCT oil on change in hormones and metabolites from fasting, adjusting for body weight. Correlations were computed between differences in hormones just before the test meals and differences in intakes after the two oils for Study 1 only. RESULTS: Food intake at the lunch test meal after the MCT preload (Study 2) was (mean±s.e.m.) 532±389 kcal vs 804±486 kcal after LCT (P<0.05). MCT consumption resulted in a lower rise in triglycerides (P=0.014) and glucose (P=0.066) and a higher rise in peptide YY (PYY, P=0.017) and leptin (P=0.036) compared with LCT (combined data). Correlations between differences in hormone levels (glucagon-like peptide (GLP-1), PYY) and differences in food intake were in the opposite direction to expectations. CONCLUSIONS: MCT consumption reduced food intake acutely but this does not seem to be mediated by changes in GLP-1, PYY and insulin.

Treatment for calcium channel blocker poisoning: a systematic review.

CONTEXT: Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion. OBJECTIVE: To evaluate the reported effects of treatments for calcium channel blocker poisoning. The primary outcomes of interest were mortality and hemodynamic parameters. The secondary outcomes included length of stay in hospital, length of stay in intensive care unit, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations. METHODS: Medline/Ovid, PubMed, EMBASE, Cochrane Library, TOXLINE, International pharmaceutical abstracts, Google Scholar, and the gray literature up to December 31, 2013 were searched without time restriction to identify all types of studies that examined effects of various treatments for calcium channel blocker poisoning for the outcomes of interest. The search strategy included the following Keywords: [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected studies and a group of reviewers abstracted all relevant data using a pilot-tested form. A second group analyzed the risk of bias and overall quality using the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist and the Thomas tool for observational studies, the Institute of Health Economics tool for Quality of Case Series, the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines, and the modified NRCNA (National Research Council for the National Academies) list for animal studies. Qualitative synthesis was used to summarize the evidence. Of 15,577 citations identified in the initial search, 216 were selected for analysis, including 117 case reports. The kappa on the quality analysis tools was greater than 0.80 for all study types. RESULTS: The only observational study in humans examined high-dose insulin and extracorporeal life support. The risk of bias across studies was high for all interventions and moderate to high for extracorporeal life support. High-dose insulin. High-dose insulin (bolus of 1 unit/kg followed by an infusion of 0.5-2.0 units/kg/h) was associated with improved hemodynamic parameters and lower mortality, at the risks of hypoglycemia and hypokalemia (low quality of evidence). Extracorporeal life support. Extracorporeal life support was associated with improved survival in patients with severe shock or cardiac arrest at the cost of limb ischemia, thrombosis, and bleeding (low quality of evidence). Calcium, dopamine, and norepinephrine. These agents improved hemodynamic parameters and survival without documented severe side effects (very low quality of evidence). 4-Aminopyridine. Use of 4-aminopyridine was associated with improved hemodynamic parameters and survival in animal studies, at the risk of seizures. Lipid emulsion therapy. Lipid emulsion was associated with improved hemodynamic parameters and survival in animal models of intravenous verapamil poisoning, but not in models of oral verapamil poisoning. Other studies. Studies on decontamination, atropine, glucagon, pacemakers, levosimendan, and plasma exchange reported variable results, and the methodologies used limit their interpretation. No trial was documented in humans poisoned with calcium channel blockers for Bay K8644, CGP 28932, digoxin, cyclodextrin, liposomes, bicarbonate, carnitine, fructose 1,6-diphosphate, PK 11195, or triiodothyronine. Case reports were only found for charcoal hemoperfusion, dialysis, intra-aortic balloon pump, Impella device and methylene blue. CONCLUSIONS: The treatment for calcium channel blocker poisoning is supported by low-quality evidence drawn from a heterogeneous and heavily biased literature. High-dose insulin and extracorporeal life support were the interventions supported by the strongest evidence, although the evidence is of low quality.