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Background: Patients discharged following admissions for acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) frequently require unplanned readmissions, increasing costs and morbidity for thousands of patients suffering from COPD. The Hospital Readmissions Reduction Program provided financial incentives to reduce 30-day readmissions for AE-COPD, but although risk factors for readmission are known, few evidence-based interventions achieve this goal. Members of the Mayo Clinic Care Network (MCCN) formed a collaborative to seek ways to reduce 30-day readmission for patients admitted with AE-COPD., Methods: Seventeen MCCN organizations participated in an improvement collaborative in 2016 and 2017. Mayo Clinic subject matter experts shared improvement webinars, protocols, and educational materials related to AE-COPD and delivered individualized coaching to facilitate improvement at each site over a six-month engagement. Among other recommended interventions, organizations worked to increase the proportion of COPD patients who had a standardized disease severity staging during admission, inhaler appropriateness evaluations, a COPD treatment action plan, and clinical contact at < 48 hours and 10 ± 4 days postdischarge., Results: Same-hospital readmission rates improved from 17.7% ± 3.6 to 14.5% ± 4.0 (weighted difference -4.38, p = 0.008, paired t-test). In addition, participating teams stated that the collaborative framework helped them develop strategies that improved patient care and organizational capacity for improvement in other domains., Conclusion: The collaborative framework, beginning with education delivered in person and via webinars, combined with telephonically delivered coaching and knowledge sharing, assisted most members to improve care. Fourteen of 17 participating sites experienced a reduced AE-COPD readmission rate., (Copyright © 2021 The Joint Commission. Published by Elsevier Inc. All rights reserved.)

Background: Cystic fibrosis patients are often adminstered tobramycin to treat pulmonary infections. Unfortunately, a common side effect is hearing loss, which can fluctuate. Ebselen has known anti-inflammatory properties and could reduce the incidence and severity of tobramycin-induced hearing loss., Methods: In vitro: neonatal cochlear cultures were treated with tobramycin or cotreated with tobramycin and ebselen for 3 days. In vivo: adult mice were injected with tobramycin or tobramycin and ebselen for 14 days. ABRs were collected in a repeated measures design until 56 days after treatments. ABR threshold shifts were analyzed and a novel cochleotoxic criteria applied to determine the incidence of ototoxicity. Cochlear immunohistology was analyzed for IHC and OHC loss., Results: Tobramycin leads to significant IHC and OHC loss in cochlear explant cultures. Ebselen co-treatment at 1:20 concentrations resulted in significant otoprotection. Tobramycin leads to significant ABR threshold shifts that are ameliorated by ebselen co-treatment. Hearing loss did not correlate with significant IHC or OHC loss., Conclusions: This mouse model of tobramycin-induced ototoxicity is clinically relevant in that it results in an incidence and severity of hearing loss recently documented in clinic. The in vitro experiments show that tobramycin kills hair cells and that ebselen co-treatment can attenuate this ototoxicity. The in vivo model shows tobramycin-induced hearing loss is ameliorated by ebselen co-treatment, but this is not explained by concomitant hair cell loss. These preclinical data support the testing of ebselen in CF patients receiving tobramycin treatment., Competing Interests: Declaration of Conpeting Interest The authors disclose that they are employed by Sound Pharmaceuticals and have stock ownership in the Company., (Copyright © 2020. Published by Elsevier B.V.)

Background: For a number of years the laparoscopic adjustable gastric band has been one of the leading bariatric procedures with good short-term outcomes. However, inadequate weight loss, weight regain, and other band-related complications in the long term led to an increase in revisional Roux-en-Y gastric bypass (RYGB) procedures. Lengthening the biliopancreatic limb, a relatively simple and safe adjustment of the standard technique, could improve the results of the revisional procedure., Objectives: The aim of this randomized controlled trial was to evaluate the effect of a long biliopancreatic limb RYGB (LBP-GB) and standard RYGB (S-GB) as revisional procedure after laparoscopic adjustable gastric band., Setting: General hospital specialized in bariatric surgery METHODS: One hundred forty-six patients were randomized in 2 groups; 73 patients underwent an S-GB (alimentary/biliopancreatic limb 150/75 cm), and 73 patients underwent LBP-GB (alimentary/biliopancreatic limb 75/150). Weight loss, remission of co-morbidities, quality of life, and complications were assessed during a period of 4 years., Results: Baseline characteristics between the groups were comparable. At 48 months the follow-up rate was 95%. Mean total weight loss after 24 months was 27% for LBP-GB versus 22% S-GB (P = .015); mean total weight loss after 48 months was 23% and 18%, respectively (P = .036). No significant differences in other parameters were found between the groups., Conclusions: A LBP-GB as revisional procedure after a failing laparoscopic adjustable gastric band improves short- and long-term total weight loss compared with an S-GB. Together with future modifications this technically simple adjustment of the RYGB could significantly improve disappointing results after revisional surgery., (Copyright © 2018 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: After Roux-en-Y gastric bypass (RYGB), patients often develop a vitamin B-12 deficiency., Objective: Our objective was to investigate whether oral supplementation increases and normalizes low vitamin B-12 concentrations (vitamin B-12 > 200 pmol/L) in RYGB patients as compared to intramuscular injections., Design: A randomized controlled trial in RYGB patients with subnormal serum B-12 concentrations was performed. One group (IM B-12) received bimonthly intramuscular hydroxocobalamin injections (2000 µg as loading dose and 1000 µg at follow-up) for 6 mo. The second group (oral B-12) received daily doses of oral methylcobalamin (1000 µg). Serum vitamin B-12 was determined at baseline (T0) and at 2 (T1), 4 (T2), and 6 mo (T3) after start of treatment. Concentrations of the secondary markers methylmalonic acid (MMA) and homocysteine (Hcy) were measured at T0 and T3., Results: Fifty patients were included and randomized, 27 in IM B-12 and 23 in oral B-12. The median vitamin B-12 concentration at T0 was 175 pmol/L (range: 114-196 pmol/L) for IM B-12 and 167 pmol/L (range: 129-199 pmol/L) for oral B-12. Vitamin B-12 normalized in all individuals, and there was no significant difference in vitamin B-12 between the two groups. MMA and Hcy concentrations decreased significantly after 6 mo within each group (P < 0.001 and P < 0.001 for MMA and P = 0.03 and P = 0.045 for Hcy, respectively). There was no significant difference between the groups at 6 mo for both MMA and Hcy (P = 0.53 and P = 0.79)., Conclusion: The efficacy of oral vitamin B-12 supplementation was similar to that of hydroxocobalamin injections in the present study. Oral supplementation can be used as an alternative to hydroxocobalamin injections to treat RYGB patients with low values of serum vitamin B-12. This trial was registered at clinicaltrials.gov as NCT02270749.

Background & Aims: Roux-en-Y gastric bypass (RYGB) is an effective treatment for obesity. However, it also leads to multiple nutritional deficiencies. Much is known about the short term prevalence, but hardly any long term data is available on deficiencies. The aim of this study was to assess the long term outcome of nutritional status after RYGB., Methods: We performed a retrospective analysis of prospectively collected data obtained from 51 morbidly obese patients who underwent a primary laparoscopic RYGB. Primary outcomes were iron, vitamin B12 and vitamin D deficiencies. Secondary outcomes were deficiencies of other vitamins and minerals and compliance of the patients to multivitamin use., Results: The mean follow-up was 81 ± 27 months. A total of 35%, 16% and 55% of the patients had deficiencies for iron, vitamin B12 and vitamin D respectively. Sixty-nine percent of patients used a (nonspecific) multivitamin supplement on a daily basis. Patients with multivitamin usage had a lower rate of iron deficiency (26% vs. 56%, p = 0.034), vitamin B12 (11% vs. 25%, p = 0.46) and vitamin D (46% vs. 75%, p = 0.07), compared to non-compliant patients., Conclusions: Nutritional deficiencies are common after a RYGB operation. Therefore, strict follow-up by a bariatric surgeon, endocrinologist or general practitioner is required, both short and long term., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Vitamin and mineral deficiencies are common after Roux-en-Y gastric bypass (RYGB) surgery. In particular, inadequate serum concentrations of ferritin and vitamin B12 have been found in 11% and 23% (respectively) of patients using a standard multivitamin supplement (sMVS) 1 year after RYGB., Objective: To evaluate the effectiveness and safety of Weight Loss Surgery (WLS) Forte® (a pharmaceutical-grade, optimized multivitamin supplement) compared with an sMVS and a control group (nonuser) 3 years after RYGB., Setting: General hospital specialized in bariatric surgery., Methods: A follow-up cohort study of a triple-blind randomized, controlled clinical trial., Results: At baseline 148 patients were enrolled (74 [50%] in the sMVS group and 74 [50%] in the WLS Forte group). After a mean follow-up of 36 months, 11 (7%) patients were lost to follow-up, of whom 2 were secondary to death. At the end of the study, 11 (17%) patients in the WLS Forte and 17 (24%) in the sMVS group stopped using a supplement. In addition, 64 (47%) patients were using WLS Forte and 45 (33%) patients a sMVS. Patient characteristics and follow-up length were comparable between the groups. Significantly more patients were diagnosed with anemia (16% versus 3% [P = .021]), a ferritin deficiency (14% versus 3% [P = .043]), and a zinc deficiency (8% versus 0% [P = .033]) in the sMVS group compared with WLS Forte. Five patients developed a vitamin B12 deficiency while using WLS Forte, versus 15 of sMVS users (P = .001). No adverse events occurred that were related to supplement use., Conclusion: At 3 years postoperative of RYGB, an optimized multivitamin supplement (WLS Forte) was more effective in reducing anemia and ferritin, vitamin B12, and zinc deficiencies compared with a standard supplement and control., (Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Reduced serum vitamin K levels are frequently observed after biliopancreatic diversion (BPD) and BPD with duodenal switch (BPD/DS). The criteria for treatment are not precisely defined., Objectives: To assess the effects of standardized vitamin K supplementation in patients who develop vitamin K deficiency after BPD or BPD/DS., Setting: Teaching hospital specializing in bariatric surgery., Methods: Serum vitamin K levels, clotting times, and vitamin K-dependent coagulation factors were measured after an overnight fast at baseline and then at 4 days and 1, 4, and 52 weeks after the start of vitamin K supplementation in 10 consecutive patients who had developed severe vitamin K deficiency after BPD or BPD/DS. Vitamin K was administered in a dose of 5 mg/d for 1 week, followed by a maintenance dose of 5 mg once a week., Results: At baseline, all patients had serum vitamin K1 levels below the limit of detection, but none reported symptoms of easy bleeding. Minor prolongation of the prothrombin time and minimal decreases of some coagulation factors were observed in a minority of patients. During the first week of vitamin K loading, median serum vitamin K1 levels rose into the high normal range. During maintenance treatment, median vitamin K1 levels settled in the low normal range., Conclusion: Vitamin K1 deficiency in patients with BPD or BPD/DS is not commonly associated with bleeding or clinically relevant decreases in coagulation factor activity. We hypothesize that vitamin K2 production in the large intestine is usually sufficient to compensate for vitamin K1 deficiency and to maintain total liver vitamin K stores within the range required for (near) normal coagulation factor production., (Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Since the introduction of total mesorectal surgery the outcome of rectal cancer patients has improved significantly. Involvement of the circumferential resection margin (CRM) is an important predictor of increased local recurrence, distant metastases and decreased overall survival. Abdomino perineal excision (APE) is associated with increased risk of CRM involvement. Aim of this study was to analyze reporting of CRM and to identify predictive factors for CRM involvement., Methods: A population-based dataset was used selecting 2153 patients diagnosed between 2008 and 2013 with primary rectal cancer undergoing surgery. Variation in CRM reporting was assessed and predictive factors for CRM involvement were calculated and used in multivariate analyses., Results: Large variation in CRM reporting was found between pathology departments, with missing cases varying from 6% to 30%. CRM reporting increased from 77% in 2008 to 90% in 2012 (p < 0.001). CRM involvement significantly decreased from 12% to 6% over the years (p < 0.001). In multivariate analysis type of operation, low anterior resection or APE, did not influence the risk of CRM involvement. Clinical T4-stage [odds ratio (OR) = 3.51; 95% confidence interval (CI) = 1.85-6.65) was associated with increased risk of CRM involvement, whereas neoadjuvant treatment (5 × 5 gray radiotherapy [OR 0.39; CI 0.25-0.62] or chemoradiation therapy [OR 0.30; CI 0.17-0.53]) were associated with significant decreased risk of CRM involvement., Conclusion: Although significant improvements are made during the last years there still is variation in reporting of CRM involvement in the Southern Netherlands. In multivariate analysis APE was no longer associated with increased risk of CRM involvement., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Subclinical hypothyroidism (SH), defined as a raised serum thyroid-stimulating hormone (TSH) with a normal free thyroxine (FT4), is occasionally observed in morbidly obese patients., Objectives: It is currently not known whether thyroid hormone treatment is indicated. The aim of the present study was to assess the changes in thyroid hormone levels in thyroxine-naïve patients with SH in response to weight loss induced by Roux-en-Y gastric bypass (RYGB)., Setting: General hospital specialized in bariatric surgery., Methods: Serum levels of TSH and FT4 were measured at baseline in 503 patients presenting for RYGB. In patients diagnosed with SH, these measurements were repeated 12 months postoperatively., Results: SH de novo was present in 71 out of 503 patients (14.1%). One-year follow-up was available in 61 out of 71 patients (86%). TSH level >10 mU/L was observed in 3 patients (.5%). RYGB induced a decrease in BMI from 47±8 kg/m(2) to 33±6 kg/m(2) at 12-month follow-up (P<.001), and this was associated with a decrease in TSH from 5.8±2.0 to 2.8±1.3 mU/L (P<.001) and a decrease in FT4 from 15.2±2.1 to 13.9±2.3 pmol/L (P<.001), respectively. SH completely resolved in 53 (87%) of the de novo cases., Conclusion: The prevalence of SH de novo is high in morbidly obese patients. After RYGB it resolves in about 90% of patients. This high degree of spontaneous recovery suggests that follow-up alone is sufficient in the majority of patients., (Copyright © 2015 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Laparoscopic sleeve gastrectomy (LSG) has gained popularity as a stand-alone procedure with good short-term results for weight loss. However, in the long-term, weight regain and other complications are reported. Demand for secondary surgery is rising, partly for these reasons., Objectives: To review the indications and effects of secondary surgery, biliopancreatic diversion with duodenal switch (BPD/DS) versus laparoscopic Roux-en-Y gastric bypass (LRYGB), after LSG., Methods: Data from all patients who underwent revision of LSG was retrospectively analyzed, concerning data on indications for secondary surgery, weight loss, and complications., Results: 43 Patients underwent secondary surgery after LSG; 25 BPD/DS and 18 LRYGB, respectively. Main indications for secondary surgery were inadequate weight loss (n = 17 [40%]) and weight regain (n = 8 [19%]). For these indications, the median excess weight loss was greater for BPD/DS (59% [range 15-113]) compared to LRYGB (23% [range -49-84]) (P = .008) after 34 months (range 14-79). In case of dysphagia or gastroesophageal reflux disease the complaints resolved after converting to LRYGB. BPD/DS patients were more likely to develop a short-term complication and vitamin deficiencies compared to LRYGB., Conclusions: Secondary surgery of LSG to BPD/DS or LRYGB is feasible with slightly more complications after BPD/DS. Conversion to LRYGB is preferred in cases of dysphagia or gastroesophageal reflux disease. In cases of weight regain or insufficient weight loss after LSG, patients had better weight loss with a BPD/DS; however, this procedure has the risk of complications, such as severe vitamin deficiencies., (Copyright © 2015 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to determine the change in cerebral blood flow and substrate metabolism in relation to electrocortical activity in the near-term ovine fetus with repeated umbilical cord occlusion of a severe degree., Study Design: Eight near-term fetal sheep were studied through a 2-hour control period, a 6-hour experimental period with repeated cord occlusion of 4 minutes' duration every 90 minutes, and a 16-hour recovery period. Regional cerebral blood flow was measured with the microsphere technique before, during, and after the first cord occlusion; blood flow in the superior sagittal sinus, the cerebral perfusion pressure, and the electrocortical activity were monitored continuously. Brachiocephalic arterial and sagittal venous blood were sampled at selected time points for blood gas and pH, oxygen content, and glucose and lactate levels., Results: Severe umbilical cord occlusion as studied resulted in profound hypoxemia with modest hypercapnia and acidemia, to a similar degree with each insult, but with a return to preocclusion values after occluder release. Glucose values also fell acutely with each cord occlusion by approximately 30% but showed an overall increase through the experimental period, from 0.80 to 1.44 mmol/L; lactate values showed an increase, from 1.21 to 6.10 mmol/L (both P 1 <.01). Fetal electrocortical activity was disrupted markedly, with an abrupt flattening of the electrocortical amplitude by 1.5 minutes of each cord occlusion on average and with an overall increase in indeterminate state activity during the experimental and through the recovery periods. Cerebral blood flow increased approximately 2.5- and 2.8-fold, as measured at 2 and 3.5 minutes during the first cord occlusion (both P <.01) and with the regional flow increase greater in the subcortex and brainstem. Cerebral extraction of oxygen fell toward zero, as measured at 2 minutes during the second and fourth occlusions (P <.05) with oxygen uptake no longer measurable; glucose extraction was now increased approximately 2-fold (P <.05), which indicates that anaerobic metabolism of glucose must be the predominant source of energy at this time. Superior sagittal sinus blood flow also increased in all animals, approximately 1.4- and 1.6-fold at 2 and 3.5 minutes of the first cord occlusion, but much less than the corresponding increase in arterial inflow; the increase was in response to subsequent occlusions was further reduced., Conclusion: Severe umbilical cord occlusion in the near-term ovine fetus results in a rapid decrease in the availability of oxygen to the brain. The low PO (2) gradient from blood to tissue rate limits for oxygen consumption by 2 minutes of insult (despite the marked increase in blood flow) and signals the shift to anaerobic metabolism, the suppression in electrocortical activity, and the probable shutdown of other energy-using processes.

Objective: To determine the cardiovascular and metabolic responses to umbilical cord occlusion in the preterm ovine fetus and the impact of repetitive intermittent insults over a 4-day period., Methods: Repetitive umbilical cord occlusions (experimental group, n = 7; control group, n = 7) were performed daily (112-115 days' gestation, term = 147 days). Mean arterial pressure (MAP), fetal heart rate (FHR), and FHR variation were monitored, and arterial blood was sampled at predetermined intervals., Results: During umbilical cord occlusions, arterial oxygen pressure (PaO2) (approximately 17 mmHg) and glucose (approximately 0.3) millimoles per liter (mmol/L) fell and arterial carbon dioxide pressure (approximately 8 mmHg) rose (P < .01) to a similar extent on days 1 and 4. Umbilical cord occlusion produced a rise in lactate over the course of successive umbilical cord occlusions each day, the magnitude of which tended to be reduced by day 4 (0.3 +/- 0.1 versus 0.6 +/- 0.1 mmol/L). Control hour FHR and MAP were unaltered over the 4 days, but the delta (delta) FHR to delta PaO2 ratio during umbilical cord occlusions was less on day 4 than on day 1 (6.0 +/- 0.4 versus 10.9 +/- 1.5 beats per minute/mmHg; P < .01). During occlusion hours, high FHR variation episodes, as a measure of fetal activity, were reduced (14.6 +/- 1.5 versus 4.2 +/- 1.3 min/h; P < .01), whereas the reduction in short-term (7.4 +/- 0.7 to 5.8 +/- 0.6 milliseconds; P < .05) and long-term (34.9 +/- 2.7 to 30.0 +/- 0.6 milliseconds; P < .05) FHR variation reached significance only on day 4., Conclusion: The increase in lactate and reduced high-FHR variation episodes over successive umbilical cord occlusions may affect fetal growth and development. Furthermore, repeated umbilical cord occlusions over several days alter the preterm FHR response to subsequent stresses, suggesting an altered chemoreflex response.

Objective: Protein synthesis is significantly decreased in the near-term ovine fetus in response to induced hypoxemia of several hours' duration. We therefore sought to determine the extent to which DNA synthesis rates as an index of tissue mitotic activity are also affected by similarly induced compromises in fetal oxygenation., Methods: Fetal sheep were studied at 0.75 of gestation during a normoxic control period and an 8-hour experimental period of either sustained hypoxemia induced by lowering maternal inspired oxygen concentration of 11-8% (hypoxia group, n = 7) or continued exposure to room air (control group, n = 5). To estimate DNA synthesis rate, [3H]-thymidine (1 mCi/kg) was injected intravenously into each fetus at the beginning of the experimental period., Results: Sustained hypoxemia with a reduction in fetal arterial O2 content from (mean +/- standard error of the mean) 4.3 +/- 0.1 to 1.5 +/- 0.1 mmol/L by the end of study resulted in a variable degree of fetal acidemia, 7.26 +/- 0.03 (range from 7.41 to 7.10), which was entirely metabolic in nature., Conclusion: The DNA synthesis rates of most tissues were not significantly changed by the 8 hours of sustained hypoxemia, suggesting that restrictions in protein synthesis in response to fetal hypoxia are initially due to a differential effect on nonmitotic synthetic processes at this stage of development. However, selective decreases in the DNA synthesis rates of the hippocampus (approximately 50%, P < .01), adrenals (approximately 48%, P < .05), and left and right myocardial ventricles (approximately 42% and 27%, respectively, P = .08) were evident which may reflect altered mitotic activity in response to tissue related changes in energy expenditure.

Objectives: Our purpose was to determine the effect of magnesium sulfate infusion on nonlabor uterine contractures and corticotropin-induced preterm uterine contractions in pregnant sheep., Study Design: Fetal and maternal vascular catheters and uterine electromyographic electrodes were surgically placed in 15 pregnant sheep between 118 and 125 days' gestation. After 3 to 5 days of recovery, magnesium sulfate was infused into 7 ewes with a 0.11 gm/kg bolus over 20 minutes, followed by 0.08 gm/kg/hr. In 8 animals labor was induced with use of an intrafetal corticotropin infusion, after which 4 ewes received magnesium sulfate and 4 received saline solution. Continuous recordings of uterine electromyographic activity, amniotic pressure, fetal heart rate, blood pressure, and tracheal pressure were made. Maternal and fetal magnesium, calcium, albumin concentrations, and blood gases were determined before and during the infusion., Results: Maternal magnesium concentrations increased from an average of 0.94 +/- 0.03 mmol/L to 2.73 +/- 0.1 mmol/L at the end of the bolus, remaining elevated (2.44 +/- 0.17 mmol/L) for 8 hours. Fetal magnesium concentrations (0.89 +/- 0.03 mmol/L before the bolus) did not change with the maternal infusion. In ewes not in labor, uterine contractures occurred 3.7 +/- 0.7 times per 2 hours before and did not change significantly with the infusion of magnesium sulfate. During corticotropin-induced preterm labor uterine contractions were present 13 +/- 3.2 times per hour before infusions and were unchanged by infusion of magnesium sulfate to the ewes., Conclusions: Magnesium sulfate infusion in pregnant sheep has no effect on either nonlabor uterine contractures or on corticotropin-induced preterm uterine contractions.

Objective: The purpose of this study was to determine the cerebral, circulatory, and metabolic responses of the ovine fetus near term to umbilical cord compression with variable-type fetal heart rate decelerations., Study Design: Nine fetal sheep, at 0.9 of gestation, were studied before, during, and after umbilical cord occlusion for 1-minute and again after repetitive 1-minute cord occlusions every 5 minutes for 1 hour, with resultant fetal heart rate decelerations of approximately 90 beats/min. Brachiocephalic arterial and sagittal venous blood was analyzed for oxygen content, blood gases and pH, glucose, and lactate. Cerebral and upper body blood flow was measured with the microsphere technique., Results: Umbilical cord occlusion with moderate to severe variable-type fetal heart rate deceleration resulted in an immediate drop in arterial PO2 by approximately 7 torr, an increase in PCO2 by approximately 9 torr, and a small but significant increase in lactate levels. Cerebral oxidative metabolism was well maintained but required an increase in fractional oxygen extraction because the variable change in cerebral blood flow was insufficient to maintain oxygen delivery. A redistribution of upper body blood flow was evident, with that to the bran and heart variably maintained or increased whereas that to muscle tissue was markedly decreased. Repetitive umbilical cord occlusion over 1 hour resulted in a significant drop in fetal arterial pH, with the acidemia mixed as PCO2 increased approximately 6 torr, whereas lactate levels increased almost fourfold., Conclusion: Although cerebral oxidative metabolism appears to be well maintained during moderate to severe variable-type fetal heart rate decelerations with umbilical cord occlusion, the need to increase fractional oxygen extraction and the redistribution of blood flow from carcass tissues may contribute to an accumulation of lactic acid both within the brain and systemically when such an insult occurs repeatedly.

Objective: The purpose of this study was to establish a continuous measure of cerebral blood flow in the ovine fetus with a transit time flow probe., Methods: Seven chronically catheterized fetal sheep were studied near term with placement of a 3R Transonic flow probe on the external carotid artery, just proximal to the internal maxillary artery. Blood flow changes were induced by altering maternal inspired oxygen and carbon dioxide concentrations, with cerebral and extracerebral blood flows also determined by the microsphere technique., Results: Although absolute carotid and cerebral blood flow values were only modestly related under the present study conditions (r = 0.60, P < .05), both the percent change and the actual change in carotid arterial blood flow showed a strong linear correlation with that for cerebral blood flow (r = 0.84, P < .01, and r = 0.72, P < .02) but less so with that for extracerebral blood flow (r = 0.44 and r = 0.28)., Conclusion: Measurements of carotid blood flow as studied with a transit time flow probe and induced blood gas changes can provide for a continuous assessment of changes in blood flow to the ovine fetal brain.

Objective: The purpose of this study was to determine the effect of sustained hypoxia with resulting metabolic acidosis on cerebral metabolism in the preterm ovine fetus., Study Design: Twelve fetal sheep were studied at 0.75 of gestation during a normoxic control period, after 1 and 8 hours of sustained hypoxemia, and again after a 1-hour recovery period. Cerebral arteriovenous differences were analyzed for oxygen content, blood gases and pH, glucose, and lactate. Cerebral blood flow was measured with the microsphere technique., Results: Induced hypoxemia resulted in a variable degree of fetal acidemia that was entirely metabolic. Although cerebral oxidative metabolism was well maintained throughout the study, cerebral glucose consumption was variably increased when measured after 1 hour of sustained hypoxemia, with a subsequent decrease after 1 hour of recovery. Although lactate was neither consumed nor produced during the control period, by 8 hours of hypoxic study a significant efflux of lactate from the brain was evident, which continued into the recovery period., Conclusion: Sustained hypoxemia results in an increase in the anaerobic metabolism of glucose by the preterm fetal brain independent of any change in cerebral oxidative metabolism, which may give rise to an accumulation of lactic acid and contribute to neurologic impairment.

Objective: Our objective was to determine the effect of a prolonged and graded reduction in fetal arterial oxygen saturation on electrocortical activity and associated biophysical variables., Study Design: Fourteen unanesthetized fetal sheep were studied between 126 and 135 days' gestation with continuous monitoring of electrocortical and electroocular activity and breathing movements, during a 24-hour control period, and subsequently during 4 days of prolonged and graded hypoxemia induced by progressively lowering the maternal inspired oxygen concentration., Results: Graded reduction in fetal arterial oxygen saturation resulted in little change in arterial pH until close to 30% when metabolic acidemia was apparent. The incidence of low-voltage electrocortical activity, electroocular activity, and breathing movements were marginally decreased with hypoxemia alone; however, a significant decrease was not apparent until associated with the onset of fetal acidemia., Conclusion: Hypoxemia of a chronic nature must approach the level at which acidemia becomes apparent before a marked change in fetal behavioral activity is noted.

Experiments were conducted in 11 chronically catheterized pregnant sheep to determine the distribution of blood flow within the fetus during prolonged (48 hours) hypoxemia secondary to the restriction of uterine blood flow. Uterine blood flow was mechanically restricted with a polytetrafluoroethylene vascular clamp placed around the maternal common internal iliac artery such that mean (+/- SEM) fetal arterial oxygen tension decreased from 23.4 +/- 1.9 to 17.3 +/- 0.8 mm Hg at 1 hour of hypoxemia and remained low for 48 hours. There was an initial increase in fetal arterial carbon dioxide pressure from 48.5 +/- 0.9 mm Hg during the control period to 56.2 +/- 2.3 mm Hg at 1 hour; this parameter subsequently returned to control values, whereas base excess showed a transient decrease. Fetal cerebral, myocardial, and adrenal blood flows were significantly increased at 1, 24, and 48 hours of hypoxemia. In contrast, there was no change in nuchal muscle or renal blood flows with hypoxemia of this magnitude. Cotyledonary blood flow increased transiently by 38% at 1 hour of hypoxemia, but was not changed from control at 24 and 48 hours. These experiments demonstrate that the sheep fetus is able to maintain the normal protective circulatory adjustments seen with acute hypoxemia for up to 48 hours in the absence of progressive metabolic acidemia.

Although the changes in circulating concentrations of adrenocorticotropic hormone, cortisol, and progesterone are well established for the fetal and neonatal lamb, there is little information on these hormones in the immediate perinatal period. We have examined the relationship between these hormones and systemic blood gas tensions and substrate concentrations in the perinatal period. Measurements were made in arterial blood of seven unanesthetized fetal sheep at 138 to 141 days' gestation during low- and high-voltage electrocortical activity. After cesarean delivery each newborn lamb was studied again at 2, 5, and 10 minutes and at 2 and 24 hours while awake. There was no correlation between fetal or maternal adrenocorticotropic hormone, cortisol, or progesterone and fetal electrocortical activity. Within 2 to 5 minutes of delivery there was a dramatic increase in neonatal immunoreactive adrenocorticotropic hormone concentrations associated with an increase in plasma cortisol. Neonatal Pao2 rose progressively, but a mixed respiratory and metabolic acidosis was evident during the first 10 minutes after delivery. This was partially corrected by 2 hours of neonatal life and was fully corrected by 24 hours of life. We conclude that rapid responsiveness of the fetal pituitary-adrenal axis occurs in response to birth in the absence of active labor, and we suggest that this may have survival value for the preterm fetus.

The liquid chromatographic determination of N-alkylated analogues of dopamine is described. The retention of these compounds, ranging from dopamine to N,N-dibutyl-dopamine, was studied on four bonded-phase columns, of which Nucleosil 5 C18 was chosen for routine use. The compounds were detected by a rotating disc amperometric detector. Samples of rat brain and serum were taken through a clean-up step on small Sephadex G-10 columns from which the dopamine analogues eluted in the same fraction as dopamine. The overall recovery was 70--90% from brain tissue and 60--70% from serum or plasma. The limit of detection for the catechol-containing compounds in tissue was 40--100 pg, for O-methylated ones 100--200 pg. The method is applied to the determination of dopamine analogues in rat brain after peripheral administration.

Regional blood flow distribution was studied with a radioactive-labeled microsphere technique in 11 unanesthetized fetal sheep (139 to 143 days' gestation). After cesarean delivery each neonatal lamb was studied at 2 and 24 hours of age. Blood flow to the cerebral hemispheres and adrenal glands decreased progressively after birth and correlated inversely with the postnatal rise in arterial oxygen content (r = -0.77, p less than 0.001 and r = -0.52, p less than 0.01, respectively). Blood flow to the gastrointestinal tract and kidneys changed little despite the known increase in blood flow from the late fetal to the early neonatal period. Skeletal muscle and brown fat blood flow were both increased when measured at 2 hours after birth, with an even greater increase in their respective oxygen deliveries presumably reflecting their increased metabolic activity with thermogenesis at this time. Variable blood flow changes are thus evident over the immediate perinatal period. In some cases these changes reflect birth-related changes in either blood gases or functional activity whereas in others the changes simply reflect a continuum from the late fetal to the early neonatal period.

Ethanol (2 gm/kg of maternal body weight administered in four equal doses of 0.5 gm/kg over 5 hours) was infused intravenously into nine chronically prepared pregnant ewes between 124 and 137 days' gestation. The data demonstrated a dose-response relationship between fetal arterial ethanol concentrations and the incidence of fetal breathing movements. Suppression of normal fetal electrocortical activity occurred at a low ethanol concentration and returned to control values at a time of very high arterial ethanol concentrations. This experimental model of a binge drinking episode further supports the hypothesis that ethanol suppresses fetal breathing movements by a direct central mechanism rather than indirectly by alteration of electrocortical activity.

Most experimental interest has focused on the electrophysiologic mechanisms which may underlie sudden death. The purpose of the present study was to develop a model in the dog where ischemia would produce not just ventricular fibrillation but also histologic abnormalities similar to those previously reported in sudden death in humans. First, the collateral blood flow to a portion of the ventricle was surgically abolished and then the arterial blood supply to this region was interrupted for 15 minutes after which nutrient flow was restored for 30 minutes. If the animal survived, this cycle was repeated up to seven times. Thirty-six animals were studied: 15 controls (Group A) survived an average of 1.75 +/- 0.8 cycles (mean +/- SD); 11 others (Group B) received a loading dose of sodium verapamil and survived 3.7 +/- 1.8 cycles while 10 (Group C) received a continuous infusion as well as the loading dose of sodium verapamil and survived 4.4 +/- 2.6 cycles--the difference between each group being significant (p less than 0.05). Four animals in Group C survived all 7 cycles; out of the other 32, 27 fibrillated just after reperfusion and the rest during ischemia. Histological examination revealed small foci of contraction band necrosis widely interspersed amongst large areas of morphologically normal tissue. The beneficial effect of verapamil and the histologic findings suggest cellular calcium overload may be important in the genesis of the fatal arrhythmias produced by reperfusion.

Cerebral oxidative metabolism and cotylendonary blood flow were measured in 10 unanesthetized fetal sheep (127 to 132 days' gestation) during a control period, after the first, third, and fourth infusions of four doses of 0.5 gm of ethanol per kilogram of maternal body weight infused into the ewe during 5 hours, and 24 hours after ethanol infusion. Preductal arterial and sagittal vein blood samples were analyzed for oxygen content, blood gases, pH, and ethanol. Cerebral and cotylendonary blood flow were measured with a radioactive microsphere technique. Fetal blood gases and pH changed little with the ethanol infusions, although PaO2 and oxygen content decreased 24 hours after ethanol infusion. Cotylendonary blood flow, which was decreased after the third and fourth ethanol infusions, did not account for these delayed hypoxemic changes. Similarly, cerebral oxidative metabolism was decreased when measured after each of the ethanol infusions, with no dose response or tolerance evident. This noted fall in fetal cerebral oxidative metabolism appears to be a direct depressant effect that was maximal at rather low fetal ethanol levels, which, if prolonged, might well affect cerebral growth and development. Recovery of cerebral metabolic function appeared complete by 24 hours. However, relative fetal hypoxemia was evident at this time, the mechanism of which remains to be determined.