Population study of pupillary unrest in ambient light.

INTRODUCTION: Pupillary unrest in ambient light (PUAL) describes the fluctuation of pupil diameter observed in normal, awake subjects under typical levels of indoor light. PUAL becomes low to absent in young healthy subjects during opioid intoxication. We sought to determine the age-related distribution of PUAL values in a random sample of ambulatory participants. METHODS: Subjects ≥18 years of age were recruited. All were identified by age range (18-29, 30-49, 50-69, and ≥70), and surveyed for diabetes, beta-blocker use, and prior 24-hour opioid use. Relationship between mean PUAL, age group, comorbidity and opioid use were examined by Kruskal Wallis test, and PUAL and was modeled using stepwise multilevel linear regression, including diabetes, beta blocker use, prior 24-hour opioid use, autonomic dysfunction, and pupil diameter as fixed effects and subject as random effect. RESULTS: Among 150 subjects, 17 reported diabetes, 12 reported beta-blocker use, 14 reported prior 24-hour opioid use, and 120 reported no comorbid conditions. PUAL declined in higher age categories (by 0.0307, P < 0.001), with diabetes (by 0.0481, P = 0.025), and with beta-blocker use (by 0.0616, P = 0.005). Opioid related PUAL decline was observed, but statistical significance varied by model. Among healthy subjects, no PUAL value fell within range indicating high likelihood of opioid toxicity based on previous data from healthy subjects undergoing opioid infusion. CONCLUSION: PUAL declined in higher age groups, diabetes and beta-blocker use, conditions associated with impaired autonomic function, and with opioid use but significance varied depending on the chosen model.

Effects of porcine somatotropin administration on the responses to dietary lysine and a near-ideal blend of amino acids on the amino acid composition of whole-body protein and amino acid accretion rate in growing pigs.

An experiment was conducted to assess the effects of porcine somatotropin (pST) on the responses to a near-ideal blend of AA on the AA composition of empty, whole-empty body (WEB) protein and WEB essential AA accretion rate in pigs from 22 to 60 kg BW. Forty Hampshire × Yorkshire gilts were individually penned and assigned to a 4 × 2 factorial arrangement of treatments consisting of four diets with and without pST injection. A fortified corn-soybean meal basal diet was formulated to contain 1.50% total Lys with Thr, Met, and Trp added to obtain a near-ideal blend of these AA relative to Lys. In three additional diets, Lys was reduced to 1.25%, 1.00%, and 0.75% by diluting the basal diet with cornstarch, cellulose, and sand such that the diets also contained the same ratios of AA. Pigs that received pST were administered a daily i.m. injection of 2 mg of pST. At 60 kg BW, the WEB (carcass, head, viscera, blood, nails, and hair) was ground and analyzed for proximate and AA composition. Administration of pST increased (P < 0.001) accretion rates of WEB protein and essential AA. Increasing dietary essential AA increased (quadratic, P < 0.03) accretion rate of WEB protein, His, Leu, Trp, and Val in pST-treated pigs, but not in untreated pigs. Lysine composition in the accreted WEB protein was not affected (P > 0.05) by dietary Lys. The efficiency of Lys utilization for WEB Lys accretion was linearly affected (P < 0.01) by dietary Lys. These results indicated that the dietary Lys needed to achieve maximum WEB Lys accretion is markedly increased by pST administration.

This study evaluated the effects of two factors, porcine somatotropin and graded levels of amino acids, on the total accumulation and the accretion rate of amino acids across a broad range of protein deposition rates in growing pigs. Treatments included 1) with or without a daily injection of porcine somatotropin and 2) graded levels of total dietary lysine from 0.75% to 1.50%. As expected, both the administration of porcine somatotropin and increased dietary lysine increased both the amount and the rate of amino acid accretion. However, the amount and rate of amino acid accretion from increased dietary amino acids were markedly greater in pigs treated with porcine somatotropin. Thus, the extent to which the genetic potential for protein deposition is achieved depends on both the anabolic capacity of the pig and the amino acid concentration of the diet provided.

Measurements of pupillary unrest using infrared pupillometry fail to detect changes in pain intensity in patients after surgery: a prospective observational study.

PURPOSE: The pupil displays chaotic oscillations, also referred to as pupillary unrest in ambient light (PUAL). As pain has previously been shown to increase pupillary unrest, the quantitative assessment of PUAL has been considered a possible tool to identify and quantify pain. Nevertheless, PUAL is affected by various states, such as vigilance, cognitive load, or emotional arousal, independent of pain. Furthermore, systematically applied opioids are known to reduce PUAL, thus potentially limiting its usefulness to detect pain or changes in pain intensity. To test the hypothesis that PUAL can reliably identify changes in pain intensity in a clinical setting, we measured PUAL in patients experiencing substantial pain relief when regional anesthesia interventions were applied after surgery. METHODS: We conducted an observational study at an academic surgery centre following institutional review board approval. Eighteen patients with unsatisfactory pain control following surgery underwent regional anesthesia procedures to improve pain control. We used infrared pupillometry to assess pupillary unrest before and after the regional block. We then compared the changes in pupillary unrest with the changes in pain scores (numeric rating scale [NRS], range 0-10). RESULTS: Eighteen patients received epidural anesthesia (n = 14) or peripheral nerve blocks (n = 4), resulting in improvement of mean (standard deviation [SD]) NRS pain scores from 7.2 (1.7) to 1.9 (1.8) (difference in means, -2.2; 95% confidence interval [CI], -6.3 to -4.1; P < 0.001). Nevertheless, pupillary unrest did not change as pain decreased; the mean (SD) PUAL was 0.113 (0.062) before analgesia and 0.112 (0.068) after analgesia (difference in means, -0.001; 95% CI, -0.018 to 0.015; P = 0.88). CONCLUSION: In this prospective observational study, pupillometric measurements of pupillary unrest did not identify changes in pain intensity in a postoperative, predominantly opioid-exposed patient population. While the sample size was small, the use of measurements of pupillary unrest to detect and quantify pain has to be questioned.

RéSUMé: OBJECTIF: La pupille affiche des oscillations chaotiques, également appelées fluctuations du diamètre pupillaire (FDP). Comme il a déjà été démontré que la douleur augmente les troubles pupillaires, l'évaluation quantitative des FDP a été envisagée comme outil potentiel pour identifier et quantifier la douleur. Néanmoins, les FDP sont affectées par divers états, tels que la vigilance, la charge cognitive ou l'excitation émotionnelle, indépendamment de la douleur. De plus, nous savons que l'application systématique d'opioïdes réduit les FDP, ce qui limite potentiellement leur utilité pour détecter la douleur ou les changements d'intensité de la douleur. Pour tester l'hypothèse selon laquelle les FDP permettent d'identifier de manière fiable les changements dans l'intensité de la douleur dans un cadre clinique, nous avons mesuré les FDP chez les patient·es manifestant un soulagement substantiel de la douleur lorsque des interventions d'anesthésie régionale ont été appliquées après la chirurgie. MéTHODE: Nous avons mené une étude observationnelle dans un centre de chirurgie universitaire après avoir obtenu l'approbation du comité d'éthique indépendant. Dix-huit patient·es dont le contrôle de la douleur n'était pas satisfaisant à la suite d'une intervention chirurgicale ont bénéficié d'interventions d'anesthésie régionale pour améliorer le contrôle de la douleur. Nous avons utilisé la pupillométrie infrarouge pour évaluer les fluctuations du diamètre pupillaire avant et après le bloc régional. Nous avons ensuite comparé les changements dans les fluctuations pupillaires avec les changements dans les scores de douleur (échelle d'évaluation numérique [EVA], plage de 0 à 10). RéSULTATS: Dix-huit patient·es ont reçu une anesthésie péridurale (n = 14) ou des blocs nerveux périphériques (n = 4), ce qui a entraîné une amélioration des scores de douleur moyens (écart type [ET]) sur l'EVA de 7,2 (1,7) à 1,9 (1,8) (différence de moyennes, −2,2 ; intervalle de confiance [IC] à 95 %, −6,3 à −4,1; P < 0,001). Néanmoins, les fluctuations du diamètre pupillaire n'ont pas changé à mesure que la douleur diminuait; la moyenne (ET) des FDP était de 0,113 (0,062) avant l'analgésie et de 0,112 (0,068) après l'analgésie (différence de moyennes, −0,001; IC 95 %, −0,018 à 0,015; P = 0,88). CONCLUSION: Dans cette étude observationnelle prospective, les mesures pupillométriques des fluctuations du diamètre pupillaire n'ont pas permis d'identifier de changements dans l'intensité de la douleur dans une population de patient·es postopératoires, principalement exposé·es aux opioïdes. Bien que la taille de l'échantillon soit petite, l'utilisation de mesures des fluctuations du diamètre pupillaire pour détecter et quantifier la douleur doit être remise en question.

Effects of a second iron-dextran injection administered to piglets during lactation on differential gene expression in liver and duodenum at weaning.

Six female littermate piglets were used in an experiment to evaluate the mRNA expression in tissues from piglets given one or two 1 mL injections of iron dextran (200 mg Fe/mL). All piglets in the litter were administered the first 1 mL injection < 24 h after birth. On day 7, piglets were paired by weight (mean body weight = 1.72 ±â€…0.13 kg) and one piglet from each pair was randomly selected as control (CON) and the other received a second injection (+Fe). At weaning on day 22, each piglet was anesthetized, and samples of liver and duodenum were taken from the anesthetized piglets and preserved until mRNA extraction. differential gene expression data were analyzed with a fold change cutoff (FC) of |1.2| P < 0.05. Pathway analysis was conducted with Z-score cutoff of P < 0.05. In the duodenum 435 genes were significantly changed with a FC ≥ |1.2| P < 0.05. In the duodenum, Claudin 1 and Claudin 2 were inversely affected by + Fe. Claudin 1 (CLDN1) plays a key role in cell-to-cell adhesion in the epithelial cell sheets and was upregulated (FC = 4.48, P = 0.0423). Claudin 2 (CLDN2) is expressed in cation leaky epithelia, especially during disease or inflammation and was downregulated (FC = -1.41, P = 0.0097). In the liver, 362 genes were expressed with a FC ≥ |1.2| P < 0.05. The gene most affected by a second dose of 200 mg Fe was hepcidin antimicrobial peptide (HAMP) with a FC of 40.8. HAMP is a liver-produced hormone that is the main circulating regulator of Fe absorption and distribution across tissues. It also controls the major flows of Fe into plasma by promoting endocytosis and degradation of ferroportin (SLC4A1). This leads to the retention of Fe in Fe-exporting cells and decreased flow of Fe into plasma. Gene expression related to metabolic pathway changes in the duodenum and liver provides evidence for the improved feed conversion and growth rates in piglets given two iron injections preweaning with contemporary pigs in a companion study. In the duodenum, there is a downregulation of gene clusters associated with gluconeogenesis (P < 0.05). Concurrently, there was a decrease in the mRNA expression of genes for enzymes required for urea production in the liver (P < 0.05). These observations suggest that there may be less need for gluconeogenesis, and possibly less urea production from deaminated amino acids. The genomic and pathway analyses provided empirical evidence linking gene expression with phenotypic observations of piglet health and growth improvements.

Iron deficiency anemia (IDA) in neonatal piglets is a problem that occurs unless there is intervention with exogenous iron. The most common method to prevent IDA is with an iron injection within 48 h of birth. However, the iron from the first injection will only support normal iron status in the piglets for ~4 kg of growth. As a result, with faster-growing piglets and larger litters, many piglets weaned today are iron deficient which results in slower growth and poor immunity. Pigs never fully recover nor grow at the same rate as those that have sufficient iron status. The aim of this study was to evaluate the effects of one or two injections of iron dextran on the differences in gene expression and metabolic pathway changes in the small intestine and liver of nursing piglets. At weaning, samples of liver and duodenum underwent genome-wide RNA sequencing. The data obtained were statistically analyzed to determine which genes and metabolic pathways were affected. There were 362 and 435 genes significantly changed in the liver and duodenum, respectively, due to a second dose of iron dextran on day 7 after birth.

Overcoming Obstacles: The Legacy of Fidel Pagés, Founder of the Epidural, 100 Years After His Passing.

Fidel Pagés, a Spanish surgeon, tragically died in 1923 at the age of 37, just 2 years after his publication "Anestesia Metamérica," the first description of human thoracolumbar epidural anesthesia. In the intervening 100 years, epidural anesthesia has faced countless obstacles, starting with the dissemination of his initial report, which was not widely read nor appreciated at the time. However, the merits of the technique have fueled innovations to meet these challenges over the years. Even today, while epidural anesthesia is widely embraced, particularly in obstetric and chronic pain medicine, the pressures of the operating room for efficiency and a low tolerance for failure, pose modern-day challenges. Here, we revisit Pagés' original report and highlight the key innovations that have allowed for the evolution of this essential anesthesia technique.

A second iron injection administered to piglets during lactation improves hemoglobin concentration, growth performance, and carcass characteristics at slaughter.

An experiment was conducted to evaluate the effects of a second injection of iron dextran administered on days 6 to 8 of age. A total of 144 crossbred pigs (equal barrows and gilts; initial age 6 to 8 d; initial body weight [BW] = 2.86 ± 0.01 kg) were assigned to either the control (CON) or an added-injection treatment (+Fe). Pigs were paired by sex and BW within a litter and randomly assigned to the iron treatment within each pair. All pigs had received an initial intramuscular (IM) injection of iron dextran (200 mg Fe) <24 h after birth. Pigs assigned to the +Fe treatment received a second IM injection of iron dextran (200 mg Fe) on days 6 to 8. All pigs were weaned at 22 to 25 d, housed 6 pigs/pen, and received a common corn-soybean meal diet. BW and feed disappearance were recorded every 2 wk. Hemoglobin (Hb) concentrations were measured at birth, initiation of experiment (days 6 to 8), weaning, and the end of the nursery and end of the study. At the end of the study, 1 pig/pen (n = 12 pigs/treatment), closest to the pen mean was selected and slaughtered for carcass characteristic measures. The individual pig served as the experimental unit for BW, Hb, average daily gain (ADG), and carcass characteristic data whereas the pen served as the experimental unit for average daily feed intake, and gain/feed ratio data. The +Fe pigs had a greater Hb at weaning (13.1 vs. 10.7 g/dL, respectively; P < 0.01) and end of the nursery (12.1 vs. 11.7 g/dL, respectively; P = 0.01) compared to CON pigs. During the finisher period, +Fe pigs had a greater ADG (0.94 vs. 0.91 kg, respectively; P = 0.05) compared to CON pigs. Overall, pigs receiving the second iron injection had an ~4% increase in ADG (P = 0.04) from weaning to the end of study. The cumulative improvement in ADG from weaning to the end of study observed for +Fe group resulted in +Fe pigs having a heavier BW at the end of the study (~3 kg; P = 0.04). Following slaughter, +Fe pigs had ~7.2% heavier trimmed loin (P = 0.04) compared to the CON pigs. In conclusion, administering a second iron injection resulted in greater Hb at weaning and the end of the nursery as well as improved growth performance from weaning to the end of study weight and increased carcass weight at slaughter.

The study aimed to evaluate the effects of a second iron dextran injection administered to piglets before weaning on hemoglobin concentration (Hb), growth performance, and carcass measures. Treatments included: a single iron injection administered within 24 h after birth (CON) and two iron injections (+Fe), one administered within 24 h after birth followed by a second iron injection administered 6 to 8 d after birth. Administering a second iron injection before weaning resulted in increased Hb at weaning and the end of the nursery period. Furthermore, pigs receiving a second iron injection had a greater average daily gain from weaning to final market weight which resulted in a final bodyweight difference of ~3 kg. The increased slaughter weight observed for pigs receiving a second iron injection was associated with an increase in trimmed loin yield. In the current study, providing a second iron injection before weaning was a practical method to improve weaning Hb in early life and resulted in a faster overall growth from weaning to the end of the study.

Effects of multiple vitamin E levels and two fat sources in diets for swine fed to heavy slaughter weight of 150 kg: I. Growth performance, lean growth, organ size, carcass characteristics, primal cuts, and pork quality.

The study objective was to evaluate the effect of two fat source and graded levels of vitamin E (VE) supplementation on growth performance, carcass characteristics, and meat quality of pigs at heavy slaughter weight (150 kg). A total of 48 individually-fed pigs (24 barrows, 24 gilts; 28.44  ±â€…2.69 kg) were blocked by sex and weight and randomly assigned to eight dietary treatments in a 2 × 4 factorial arrangement. Fat treatments were 5% tallow (TW) and distiller's corn-oil (DCO) in the diets. The VE treatments included four levels of α-tocopheryl-acetate (11, 40, 100, and 200 ppm). Growth performance, carcass traits, organ weight, primal cuts, and pork quality were measured. Increasing dietary VE supplementation levels linearly increased overall Average daily gain (ADG) and average daily feed intake (P < 0.05), with an interaction between fat sources and VE supplementation levels on cumulative ADG (P < 0.05) during phases 1 and 3 (28 to 100 kg) and 1 to 4 (28 to125 kg) wherein ADG in the pigs fed the DCO diet, but not the TW diet, increased with increasing dietary VE supplementation level. A similar interaction was observed in 24 h pH and picnic shoulder (P < 0.05). No notable effect of fat source was observed in growth performance. With increasing dietary VE supplementation levels, there were quadratic responses in pork pH at 45 min and 24 h postmortem with the highest value in 40 and 100 ppm of VE levels while TBARS values on day 7 postmortem decreased linearly (P < 0.05). Compared with the TW diet, the DCO diet resulted in greater TBARS values during 7 postmortem (P < 0.05; day 5, P = 0.09). These results demonstrated that increasing dietary VE supplementation level could enhance growth rate and feed intake and reduce lipid peroxidation of pork whereas the diet containing DCO as a fat source could negatively affect pork shelf-life and carcass characteristics and that increasing VE supplementation level had no notable interaction with fat sources for carcass characteristics.

Effects of multiple vitamin E levels and two fat sources in diets for swine fed to heavy slaughter weight of 150 kg: II. Tissue fatty acid profile, vitamin E concentrations, immune capacity, and antioxidant capacity of plasma and tissue.

The study objective was to evaluate the effect of two fat sources and graded levels of vitamin E (VE) supplementation on tissue fatty acid profile, VE concentrations, immune capacity, and antioxidant capacity of plasma and tissues of pigs at heavy slaughter weight (150 kg). A total of 48 individually-fed pigs (24 barrows, 24 gilts; 28.44 ±â€…2.69 kg) were randomly assigned to eight dietary treatments in a 2 × 4 factorial arrangement. The two fat treatments were either 5% tallow (TW) or 5% distiller's corn-oil (DCO). The VE treatments included four levels of α-tocopheryl-acetate (11, 40, 100, and 200 ppm). Compared to pigs fed the DCO diet, pigs fed the TW diet had greater SFA (C14, C16, and C18; P < 0.05) and MUFAs (C14:1, C16:1, C18:1, and C20:1; P < 0.05), lower PUFA (C18:2n-6, C18:3n-3, C20:2, C20:3, and C20:4; P < 0.05) and iodine value in the backfat and belly fat. Increasing dietary VE supplementation level increased α- and total tocopherol concentrations in plasma (linear and quadratic, P < 0.05), liver, and loin muscle (linear, P < 0.06), superoxide dismutase activity (quadratic, P < 0.05), but decreased γ-tocopherol concentrations in liver (linear, P = 0.06), plasma, and loin muscle (quadratic, P < 0.07), and decreased liver glutathione disulfide (GSSG; linear, P = 0.07) and malondialdehyde (MDA) content (quadratic, P < 0.05). There was an interaction between fat sources and dietary VE supplementation level on the concentration of α-tocopherol in the loin muscle (P < 0.05) wherein a greater increase was observed in the TW treatment than the DCO treatment with the increasing dietary VE supplementation level. In conclusion, dietary FA composition in TW and DCO affected the composition of most FA in backfat, belly fat, and liver while increasing VE supplementation level did not significantly alter the FA profile in these tissues. Increasing dietary VE supplementation level increased tocopherol concentrations in plasma, liver and loin muscle, and improved antioxidant capacity while tocopherol concentrations in plasma, liver and loin muscle in the TW treatment increased more than they did in the DCO treatment.

Standardized ileal digestibility of amino acids differs among sources of bakery meal when fed to growing pigs.

A multistate experiment involving universities in IL, IN, KY, and MN was conducted as a part of the research efforts by the North-Central Coordinating Committee-42 on swine nutrition. The null hypothesis that there are no differences in the standardized ileal digestibility (SID) of amino acids (AA) among different sources of bakery meal was tested. Eleven sources of bakery meal were procured from swine-producing states in the United States and each source was included in one diet as the sole source of AA. A N-free diet was prepared as well. Diets were prepared in one batch and divided into four sub-batches that were subsequently distributed to the four participating universities. At each university, diets were fed to 12 pigs that had a T- cannula installed in the distal ileum. Pigs were allotted to incomplete Latin square designs with 12 pigs and 4, 5, or 6 periods for a total of 21 replicate pigs per diet. Each period lasted 7 d with ileal digesta being collected from the cannulas on days 6 and 7. Samples were analyzed for AA and the SID of each AA was calculated. Results indicated that there were differences (P < 0.001) in the SID of all AA except Pro among the 11 sources of bakery meal. The differences in SID of AA observed in this experiment were greater than what is usually observed among sources of the same ingredient, indicating that there is more variability among sources of bakery meal than among different sources of other ingredients. This is likely a consequence of different raw materials being used in the production of different sources of bakery meal. Regardless of source of bakery meal, the AA with the least SID was Lys indicating that some of the raw materials in the product streams used to generate the bakery meals may have been overheated. Additionally, the Lys:crude protein ratio in each source of bakery meal was not a good predictor of the SID of Lys, which likely reflects the different raw materials being included in the different meals. In conclusion, the SID of AA varies among different sources of bakery meal and the SID of Lys is less than the SID of all other indispensable AA.

Eleven sources of bakery meal were used in a regional experiment to determine digestibility of amino acids. Diets containing each source of bakery meal were prepared at one university and distributed to three other universities. Diets were fed to pigs that had a cannula installed in the distal ileum and ileal digesta were collected from pigs for 2 d following 5 d of adaptation. Results indicated that there is considerable variation in the digestibility of all amino acids among sources of bakery meal, which is likely a reflection of differences in raw material use among different producers of bakery meal. Results also demonstrated that the digestibility of Lys is less than the digestibility of all other amino acids, indicating that some of the raw materials used in the production of bakery meal may have been heat damaged. It may, therefore, be necessary to add additional Lys to diets containing bakery meal.

Brimonidine eye drops reveal diminished sympathetic pupillary tone in comatose patients with brain injury.

BACKGROUND: There is an urgent need for easy-to-perform bedside measures to detect residual consciousness in clinically unresponsive patients with acute brain injury. Interestingly, the sympathetic control of pupil size is thought to be lost in states of unconsciousness. We therefore hypothesized that administration of brimonidine (an alpha-2-adrenergic agonist) eye drops into one eye should produce a pharmacologic Horner's syndrome if the clinically unresponsive patient is conscious, but not if the patient is unconscious. Here, in a first step to explore this hypothesis, we investigated the potential of brimonidine eye drops to distinguish preserved sympathetic pupillary function in awake volunteers from impairment of sympathetic tone in patients in a coma. METHODS: We enrolled comatose patients admitted for acute brain injury to one of the intensive care units (ICU) of a tertiary referral center, in whom EEG and/or neuroimaging for all practical purposes had ruled out residual consciousness. Exclusion criteria were deep sedation, medications with known drug interactions with brimonidine, and a history of eye disease. Age- and sex-matched healthy and awake volunteers served as controls. We measured pupils of both eyes, under scotopic conditions, at baseline and five times 5-120 min after administering brimonidine into the right eye, using automated pupillometry. Primary outcomes were miosis and anisocoria at the individual and group levels. RESULTS: We included 15 comatose ICU patients (seven women, mean age 59 ± 13.8 years) and 15 controls (seven women, mean age 55 ± 16.3 years). At 30 min, miosis and anisocoria were seen in all 15 controls (mean difference between the brimonidine-treated pupil and the control pupil: - 1.31 mm, 95% CI [- 1.51; - 1.11], p < 0.001), but in none (p < 0.001) of the 15 ICU patients (mean difference: 0.09 mm, 95% CI [- 0.12;0.30], p > 0.99). This effect was unchanged after 120 min and remained robust in sensitivity analyses correcting for baseline pupil size, age, and room illuminance. CONCLUSION: In this proof-of-principle study, brimonidine eye drops produced anisocoria in awake volunteers but not in comatose patients with brain injury. This suggests that automated pupillometry after administration of brimonidine can distinguish between the extremes of the spectrum of consciousness (i.e., fully conscious vs. deeply comatose). A larger study testing the "intermediate zone" of disorders of consciousness in the ICU seems warranted.

Patient Safety During Anesthesia: 100 Years of Progress Documented in Anesthesia & Analgesia.

Anesthesiology has evolved to be a leader in addressing patient safety. Our specialty has overcome serious morbidities including explosions, fires, organ toxicity, fatal arrhythmias, and hypoxic brain damage. Anesthesia safety has been significantly improved due to modern drug development, technical advances, and a strong leadership willing to apply human factors and systems' research strategies, but patient safety concerns remain at the forefront as we strive to improve patient care even further. This year marks the centennial year since the publication of the first issue of Anesthesia & Analgesia. Today, the International Anesthesia Research Society (IARS) and Anesthesia & Analgesia continue to advance the boundaries of patient safety by disseminating practice standards, serving as a forum for novel ideas, and supporting research advancements. This review will discuss several topics published in Anesthesia & Analgesia that exemplify steady changes leading to the safe practices that we rely on currently as well as other IARS activities that have advocated and elevated patient safety within the specialty.

Metformin Prevents Key Mechanisms of Obesity-Related Complications in Visceral White Adipose Tissue of Obese Pregnant Mice.

With the gaining prevalence of obesity, related risks during pregnancy are rising. Inflammation and oxidative stress are considered key mechanisms arising in white adipose tissue (WAT) sparking obesity-associated complications and diseases. The established anti-diabetic drug metformin reduces both on a systemic level, but only little is known about such effects on WAT. Because inhibiting these mechanisms in WAT might prevent obesity-related adverse effects, we investigated metformin treatment during pregnancy using a mouse model of diet-induced maternal obesity. After mating, obese mice were randomised to metformin administration. On gestational day G15.5, phenotypic data were collected and perigonadal WAT (pgWAT) morphology and proteome were examined. Metformin treatment reduced weight gain and visceral fat accumulation. We detected downregulation of perilipin-1 as a correlate and observed indications of recovering respiratory capacity and adipocyte metabolism under metformin treatment. By regulating four newly discovered potential adipokines (alpha-1 antitrypsin, Apoa4, Lrg1 and Selenbp1), metformin could mediate anti-diabetic, anti-inflammatory and oxidative stress-modulating effects on local and systemic levels. Our study provides an insight into obesity-specific proteome alterations and shows novel modulating effects of metformin in pgWAT of obese dams. Accordingly, metformin therapy appears suitable to prevent some of obesity's key mechanisms in WAT.

Effects of dietary vitamin E and fat supplementation in growing-finishing swine fed to a heavy slaughter weight of 150 kg: II. Tissue fatty acid profile, vitamin E concentrations, and antioxidant capacity of plasma and tissue.

The study aimed to assess the effects of vitamin E (VE) supplementation and fat source on fatty acid (FA) composition, VE concentrations, and antioxidant capacity in plasma and tissues of pigs fed to a heavy slaughter weight (150 kg). A total of 64 pigs (32 barrows, 32 gilts; 28.41 ±â€…0.83 kg) were blocked by sex and weight, and randomly assigned to one of eight dietary treatments (n = 8 per treatment) in a 4 × 2 factorial arrangement. Fat sources included corn starch (CS), 5% tallow (TW), 5% distiller's corn oil (DCO), and 5% coconut oil (CN); VE supplementation levels were 11 and 200 ppm. Five-phase diets were formulated to meet requirement estimates of NRC (2012) and fed to pigs for each period of 25 kg from 25 to 150 kg. Increasing VE supplementation level increased C16:1 (P < 0.05) content but decreased C20:0 (P < 0.05) content in backfat and belly fat, while in liver, it increased C17:0 (P < 0.05) but decreased C18:0 (P < 0.05). Compared to the pigs fed the CS diet, the pigs fed the CN diet had greater (P < 0.05) content of total saturated FA, the pigs fed the DCO diet had greater (P < 0.05) content of total polyunsaturated FA content and iodine value, and the pigs fed the TW diet had greater (P < 0.05) content of total monounsaturated FA in backfat, belly fat, and liver. Plasma VE concentrations increased linearly (P < 0.05) with increasing length of feeding but faster (P < 0.05) in the pigs fed the CN and TW diets compared with the CS and DCO diets within the 200 ppm VE level; the pigs fed the DCO diet had the highest plasma VE concentrations (P < 0.05) from Phase 2 to Phase 5 within the 11 ppm VE level. The VE concentrations in liver and loin muscle (P < 0.05) increased with increasing dietary VE level from 11 to 200 ppm, but it was not affected by dietary fat source. There was no effect of VE supplementation and fat source on antioxidant capacity in plasma and liver except that pigs fed the DCO diet had greater liver SOD activity (P < 0.05) than the pigs fed the CN diet. In conclusion, dietary VE supplementation did not affect FA profile in backfat, belly fat, and liver consistently, while dietary FA composition with different fat sources affected much of the FA profile in backfat, belly fat, and liver. The higher level of VE supplementation increased liver and muscle VE concentrations and dietary fat sources affected plasma VE concentrations differently (P < 0.05), wherein the TW and CN diets increased the VE absorption greater than the DCO diet.

The study evaluated vitamin E (VE) supplementation and fat source on fatty acid (FA) composition and VE concentrations in pigs. Three fat sources with distinctive fatty acid profiles were used; VE levels were 11 (the requirement estimate) and 200 (a high level to assure any responses could be seen) ppm. Increasing VE affected very few FA in tissues. Compared with the control pigs, pigs fed the coconut oil diet had greater content of saturated FA, pigs fed the distiller's corn oil diet had greater content of polyunsaturated FA content, and pigs fed the tallow diet had greater content of monounsaturated FA in tissues. Plasma VE increased with increasing length of feeding but faster in pigs fed the coconut oil and tallow diets compared with the control and distiller's corn oil diets when the 200 ppm VE level was fed; pigs fed the distiller's corn oil diet had the highest plasma VE concentrations when the 11 ppm VE level was fed. In conclusion, dietary VE did not affect FA profile in backfat, belly fat, and liver consistently, while different dietary fat sources affected much of the FA profile in tissues. The higher level of VE, as expected, increased liver and muscle VE concentrations.

Effects of dietary vitamin E and fat supplementation in growing-finishing swine fed to a heavy slaughter weight of 150 kg: I. Growth performance, lean growth, organ size, carcass characteristics, primal cuts, and pork quality.

The study aimed to assess the effect of vitamin E (VE) supplementation and fat source on growth performance, lean growth, organ size, carcass characteristics, and pork quality of pigs at a heavy slaughter weight of 150 kg. A total of 64 pigs (32 barrows and 32 gilts; 28.41 ± 0.83 kg) were blocked by sex and body weight, and randomly assigned to one of eight dietary treatments (n = 8 per treatment) in a 4 × 2 factorial arrangement with main effects of fat source (corn starch [CS; no fat added], 5% tallow [TW], 5% distiller's corn oil [DCO], and 5% coconut oil [CN]) and VE supplementation level (11 and 200 ppm). Five-phase diets were formulated to meet requirement estimates of NRC and fed to pigs with each period of 25 kg from 25 to 150 kg. Increasing dietary VE supplementation from 11 to 200 ppm tended to increase average daily gain (ADG) in phase 5 (P = 0.08), and gain to feed ratio (G/F) in phase 4 (P = 0.06) and phase 5 (P = 0.06) resulting in increased G/F in the overall period (P = 0.10). Compared with the pigs fed the CS diet in the overall period, the pigs fed DCO diets had greater ADG (P < 0.05), the pigs fed the TW and CN diets had lower average daily feed intake (P < 0.05), and the pigs fed the fat-added diets had greater G/F (P < 0.05). Belly firmness was greatest in the pigs fed the CN diet and lowest in those fed the DCO diet (P < 0.05). Increasing dietary VE level from 11 to 200 ppm increased absolute and relative liver weight, absolute ham yield (P < 0.05), and tended to increase the relative yield of picnic shoulder (P = 0.07) and ham (P = 0.06) and the pigs fed the corn oil diet tended to have greater belly yield (P = 0.08) than the other fat treatments. Increasing dietary VE level increased 45-min pH and ΔpH at slaughter but decreased a* value, chroma (P < 0.10), and belly depth (P < 0.05). However, no effects of VE supplementation and fat source were observed on the other carcass traits and meat quality measurements. In conclusion, increasing dietary VE level from 11 to 200 ppm slightly increased growth rate and feed efficiency in the late finishing periods, and the addition of fat increased feed efficiency and backfat thickness, decreased lean content, and altered belly firmness. While there were some effects of VE supplementation and fat source observed on organ weight, primal cuts, carcass traits, and meat quality, there was no strong evidence that VE supplementation and fat source materially affected these measurements except for belly firmness.

The study aimed to assess the effect of vitamin E (VE) supplementation and fat source on growth performance, carcass characteristics, and pork quality of pigs slaughtered at 150 kg. Fat sources included corn starch (no fat added), or 5% tallow, distiller's corn oil (DCO), or coconut oil (CN); VE supplementation levels were 11 and 200 ppm. Increasing dietary VE from 11 to 200 ppm tended to increase the efficiency of conversion of feed to body weight gain for the overall study period. The pigs fed the DCO diet had greater backfat depth at slaughter. Belly (from which bacon is made) firmness was greatest in the pigs fed the CN diet and lowest in those fed the DCO diet. In conclusion, increasing dietary VE levels from 11 to 200 ppm slightly increased growth rate and feed efficiency, and the addition of fat increased feed efficiency and backfat thickness, decreased lean muscle content, and altered belly firmness. While there were some effects of VE supplementation and fat source, there was no strong evidence that VE supplementation and fat source materially affected these measurements except for belly firmness.

Pupillary unrest, opioid intensity, and the impact of environmental stimulation on respiratory depression.

Opioid-induced respiratory depression (OIRD) confers significant morbidity, but its onset can be challenging to recognize. Pain or stimulation effects of conversation may mask or attenuate common clinical manifestations of OIRD. We asked whether pupillary unrest could provide an objective signal of opioid exposure, and whether this signal would be independent from the confounding influence of extrinsic stimulation. We conducted a cross-over trial of healthy volunteers using identical remifentanil infusions separated by a washout period; in both, pupillary unrest in ambient light (PUAL) was measured at 2.5-min intervals. During one infusion, investigators continuously engaged the subject in conversation, while in the other, a quiet environment was maintained; measures of respiratory depression were compared under each condition. We tested PUAL's relationship to estimated opioid concentration under quiet conditions, measured PUAL's discrimination of lower versus higher opioid exposure using receiver operating characteristic (ROC) analysis, and assessed the effect of stimulation on PUAL versus opioid using mixed effects regression. Respiratory depression occurred more frequently under quiet conditions (p < 0.0001). Under both conditions, PUAL declined significantly over the course of the remifentanil infusion and rose during recovery (p < 0.0001). PUAL showed excellent discrimination in distinguishing higher versus absent-moderate opioid exposure (AUROC = 0.957 [0.929 to 0.985]), but was unaffected by interactive versus quiet conditions (mean difference, interactive - quiet = - 0.007, 95% CI - 0.016 to 0.002). PUAL is a consistent indicator of opioid effect, and distinguishes higher opioid concentrations independently of the stimulating effects of conversational interaction. Under equivalent opioid exposure, conversational interaction delayed the onset and minimized the severity of OIRD.Clinical trial registration: NCT04301895.

Semimechanistic models to relate noxious stimulation, movement, and pupillary dilation responses in the presence of opioids.

Intraoperative targeting of the analgesic effect still lacks an optimal solution. Opioids are currently the main drug used to achieve antinociception, and although underdosing can lead to an increased stress response, overdose can also lead to undesirable adverse effects. To better understand how to achieve the optimal analgesic effect of opioids, we studied the influence of remifentanil on the pupillary reflex dilation (PRD) and its relationship with the reflex movement response to a standardized noxious stimulus. The main objective was to generate population pharmacodynamic models relating remifentanil predicted concentrations to movement and to pupillary dilation during general anesthesia. A total of 78 patients undergoing gynecological surgery under general anesthesia were recruited for the study. PRD and movement response to a tetanic stimulus were measured multiple times before and after surgery. We used nonlinear mixed effects modeling to generate a population pharmacodynamic model to describe both the time profiles of PRD and movement responses to noxious stimulation. Our model demonstrated that movement and PRD are equally depressed by remifentanil. Using the developed model, we changed the intensity of stimulation and simulated remifentanil predicted concentrations maximizing the probability of absence of movement response. An estimated effect site concentration of 2 ng/ml of remifentanil was found to inhibit movement to a tetanic stimulation with a probability of 81%.

Detection of opioid effect with pupillometry.

BACKGROUND: Opioids produce pupillary constriction but their impact on pupillary unrest and the dynamic parameters of the pupillary light reflex have not been characterized. Given the increasing use of portable pupillometers for care of critically ill patients, it is important to distinguish between opioid effects on the pupil versus those that have been reported to arise from traumatic and ischemic brain insults. We undertook this study to determine which pupillary responses are most profoundly and consistently affected by a progressive infusion of remifentanil. METHODS: We studied the effect of remifentanil on the pupil using two portable infrared pupillometers in 18 volunteers. One pupillometer measured pupillary unrest in ambient light (PUAL) and the other pupillometer measured neurological pupillary index (NPi), constriction velocity (CV), pupil diameter (PD), latency, and % reflex (% reflex) following a transient light flash. Remifentanil was administered at predetermined weight-adjusted rates to raise opioid effect site concentration up to a range known to produce respiratory depression and oxyhemoglobin desaturation, based on a previously published pharmacokinetic model. RESULTS: PUAL was ablated by remifentanil, declining 94 ± 6% from baseline at the time of maximum drug effect. Other pupillary measurements decreased 50-65% from baseline. NPi was unchanged. At the time of oxyhemoglobin desaturation, deviations in PD, CV, and % reflex were widely scattered, whereas PUAL consistently approached zero. CONCLUSION: PUAL is a highly specific indicator of central opioid effect. As a non-invasive measure, it may provide useful data to clinicians who prescribe opioids.