Duloxetine in OsteoArthritis (DOA) study: effects of duloxetine on pain and function in end-stage hip and knee OA - a pragmatic enriched randomized controlled trial.

BACKGROUND: Some osteoarthritis (OA) patients experience inadequate pain relief from analgesics like acetaminophen and nonsteroidal anti-inflammatory drugs. This could be the result of experienced non-nociceptive centralized pain. Placebo-controlled randomized trials (RCT) have proven the effectiveness of duloxetine for OA and several chronic pain conditions where central sensitization (CS) is one of the key underlying pain mechanisms. OBJECTIVES: Assess the efficacy of an 8-week duloxetine treatment compared to usual care in end-stage knee and hip OA patients with a level of centralized pain. DESIGN: Pragmatic, enriched, open-label RCT. METHODS: Patients were randomized to duloxetine or to care-as-usual. Primary outcome was pain in the index joint, measured with the pain domain of the Knee injury and Osteoarthritis Outcome Score (KOOS) or the Hip disability and Osteoarthritis Outcome Score (HOOS). The intention-to-treat principle was used, with mixed-model repeated measures to analyze the effect. RESULTS: One hundred eleven patients were randomized. Nearly 44% felt much to very much better after duloxetine usage compared to 0% in the care-as-usual group (p < 0.001). The duloxetine group scored 11.3 points (95%CI: 5.8, 16.8) better on the pain domain of the KOOS/HOOS (p < 0.001). Knee patients improved significantly more than hip patients (18.7 [95%CI: 11.3, 26.1] versus 6.0 [95%CI: - 2.6, 14.5] points better). CONCLUSIONS: Adding duloxetine treatment seems to be beneficial for end-stage knee OA patients with neuropathic-like symptoms (at risk of CS). End stage Hip OA patients seem to be nonresponsive to duloxetine. TRIAL REGISTRATION: Dutch Trial Registry with number NTR 4744 (15/08/2014) and in the EudraCT database with number 2013-004313-41 .

Predictors of treatment success in children with difficult to treat atopic dermatitis using a personalized integrative multidisciplinary (PIM) treatment programme.

BACKGROUND: A 6-week personalized integrative multidisciplinary treatment programme (PIM) was developed for children with difficult to treat AD who appeared unresponsive to treatment according to current guidelines. OBJECTIVE: The aim of the present study was to identify clinical and psychosocial characteristics that predict long-term treatment success after PIM. METHODS: Treatment was considered successful when there was a 75% reduction on the Self-Administered Eczema Area and Severity Index and/or little impact of AD on daily life, measured with the Children's Dermatology Life Quality Index (score ≤ 6), 6 months after the end of PIM. PIM is a personalized, integrative, multidisciplinary treatment programme with clearly defined goals and strategies, addressing atopic, paediatric, mental health comorbidities and general well-being, for children and adolescents aged 8- to 18 years. Multivariate logistic regression models were constructed using a backward selection procedure. Questionnaires were used to assess psychosocial characteristics; clinical data was extracted from medical records. RESULTS: In total, 79 children/adolescents with difficult to treat AD completed PIM and long-term treatment results were available for 74 children/adolescents. The majority (77%) of children/adolescents demonstrated long-term treatment success with PIM. Predictors of long-term treatment success (adjusted ORs) included maternal disease acceptance OR (95% CI) 1.84 (1.15-2.94). A group (23%) of mostly females OR (95% CI) 0.10 (0.02-0.54) with multiple somatic complaints OR (95% CI) 0.88(0.80-0.97), from families where the mother has anxiety for the use of topical corticosteroids OR (95% CI) 0.62(0.40-0.94), is less likely to obtain long-term treatment success. CONCLUSION: Most children and adolescents with difficult to treat AD, seemingly unresponsive to conventional treatment according to current guidelines, are able to improve with PIM. Psychosocial and family but not clinical variables, predicted long-term treatment success after participating in PIM.

Effectiveness of alpine climate treatment for children with difficult to treat atopic dermatitis: Results of a pragmatic randomized controlled trial (DAVOS trial).

BACKGROUND: Alpine climate treatment has historically been used in Europe to treat atopic dermatitis (AD), but no randomized trials have been conducted to provide evidence for its effectiveness. OBJECTIVE: To investigate the long-term effectiveness of alpine climate treatment for children with difficult to treat AD. MATERIALS & METHODS: A pragmatic, open, randomized controlled trial was conducted. Children diagnosed with AD that was considered difficult to treat, aged between 8 and 18 years and willing to be treated in Switzerland were randomized to a six-week personalized integrative multidisciplinary treatment period in a clinical setting in the alpine climate (Switzerland) or an outpatient setting in moderate maritime climate (Netherlands). Study assessments were conducted at the Wilhelmina Children's Hospital; an electronic portal was used for the collection of questionnaire data. Primary outcomes were disease activity (SAEASI), quality of life (CDLQI) and catastrophizing thoughts (JUCKKI/JU) 6 months after intervention. Other assessments were immediately and 6 weeks after intervention. Subgroup analyses concerned asthma-related outcomes. Children were randomly assigned to either the intervention or control group using a covariate adaptive randomization method, taking age and asthma diagnosis into account. Children, parents and healthcare professionals involved in treatment were not blinded to group assignment. Data were analysed according to intention-to-treat with linear mixed-effects models for continuous outcomes. The trial is registered at Current Controlled Trials ISCRTN88136485. RESULTS: Between 14 September 2010 and 30 September 2014, 88 children were enrolled in the trial, 84 children were randomized (41 assigned to intervention, 43 to control) of whom 77 completed the intervention (38 of 41 (93%) intervention, 39 of 43 (91%) control) and 74 completed follow-up (38 of 41 (93%) intervention, 36 of 43 (84%) control). Six months after intervention there were no significant differences between the groups on disease activity (SAEASI mean difference -3.4 (95%CI -8.5 to 1.7)), quality of life (CDLQI mean difference -0.3 (95%CI -2.0 to 1.4)) and catastrophizing thoughts (JUCCKI/JU subscale mean difference -0.7 (95%CI -1.4 to -0.0)). Immediately and 6 weeks after intervention, disease activity and quality of life were significantly different in favour of alpine climate treatment. Mean differences on SAEASI were -10.1 (95%CI -14.5 to -5.8) and -8.4 (95%CI -12.2 to -4.6) and on CDLQI -1.9 (95%CI -3.3 to -0.5) and -1.5 (95%CI -2.8 to -0.3) immediately and 6 weeks after the intervention, respectively. There were no long-term differences on asthma-related outcomes. Five serious adverse events occurred during the study period, which were not thought to be related to the treatment. CONCLUSIONS & CLINICAL RELEVANCE: For children with difficult to treat AD, there was no additional long-term benefit of alpine climate treatment, in contrast to the short-term, compared to an outpatient treatment programme in moderate maritime climate, using a personalized integrative multidisciplinary treatment approach.

Trajectories in quality of life of patients with a fracture of the distal radius or ankle using latent class analysis.

PURPOSE: This prospective study aimed to identify the different trajectories of quality of life (QOL) in patients with distal radius fractures (DRF) and ankle fractures (AF). Secondly, it was examined if subgroups could be characterized by sociodemographic, clinical, and psychological variables. METHODS: Patients (n = 543) completed the World Health Organization Quality of Life assessment instrument-Bref (WHOQOL-Bref), the pain, coping, and cognitions questionnaire, NEO-five factor inventory (neuroticism and extraversion), and the state-trait anxiety inventory (short version) a few days after fracture (i.e., pre-injury QOL reported). The WHOQOL-Bref was also completed at three, six, and 12 months post-fracture. Latent class trajectory analysis (i.e., regression model) including the Step 3 method was performed in Latent Gold 5.0. RESULTS: The number of classes ranged from three to five for the WHOQOL-Bref facet and the four domains with a total variance explained ranging from 71.6 to 79.4%. Sex was only significant for physical and psychological QOL (p < 0.05), whereas age showed significance for overall, physical, psychological, and environmental QOL (p < 0.05). Type of treatment or fracture type was not significant (p > 0.05). Percentages of chronic comorbidities were 1.8 (i.e., social QOL) to 4.5 (i.e., physical QOL) higher in the lowest compared to the highest QOL classes. Trait anxiety, neuroticism, extraversion, pain catastrophizing, and internal pain locus of control were significantly different between QOL trajectories (p < 0.05). CONCLUSIONS: The importance of a biopsychosocial model in trauma care was confirmed. The different courses of QOL after fracture were defined by several sociodemographic and clinical variables as well as psychological characteristics. Based on the identified characteristics, patients at risk for lower QOL may be recognized earlier by health care providers offering opportunities for monitoring and intervention.

Model development to study strategies of younger and older adults getting up from the floor.

BACKGROUND: Long lies after a fall remain a public health challenge. Many successful fall prevention programmes have been developed but only few of them include recovery strategies after a fall. Once better understood, such movement strategies could be implemented into training interventions. AIMS: A model of motion sequences describing successful movement strategies for rising from the floor in different age groups was developed. Possible risk factors for poor rising performance such as flexibility and muscle power were evaluated. METHODS: Fourteen younger subjects between 20 and 50 years of age and 10 healthy older subjects (60+ years) were included. Movement strategies and key components of different rising sequences were determined from video analyses. The temporal parameters of transfers and number of components within the motion sequences were calculated. Possible explanatory variables for differences in rising performance were assessed (leg extension power, flexibility of the knee- and hip joints). RESULTS: Seven different components were identified for the lie-to-stand-walk transfer, labelled as lying, initiation, positioning, supporting, elevation, or stabilisation component followed by standing and/or walking. Median time to rise was significantly longer in older subjects (older 5.7s vs. younger 3.7s; p < 0.001), and leg extension power (left p = 0.002, right p = 0.013) and knee flexibility (left p = 0.019, right p = 0.025) were significantly lower. The number of components for rising was correlated with hip flexibility (r = 0.514) and maximal power (r = 0.582). The time to rise was correlated with minimal goniometric knee angle of the less flexible leg (r = 0.527) and maximal leg extension power (r = 0.725). CONCLUSIONS: A motion sequence model containing seven different components identified by individual key-frames could be established. Age-related differences in rising strategies and performance were identified.

Fall detection with body-worn sensors : a systematic review.

BACKGROUND AND AIMS: Falls among older people remain a major public health challenge. Body-worn sensors are needed to improve the understanding of the underlying mechanisms and kinematics of falls. The aim of this systematic review is to assemble, extract and critically discuss the information available in published studies, as well as the characteristics of these investigations (fall documentation and technical characteristics). METHODS: The searching of publically accessible electronic literature databases for articles on fall detection with body-worn sensors identified a collection of 96 records (33 journal articles, 60 conference proceedings and 3 project reports) published between 1998 and 2012. These publications were analysed by two independent expert reviewers. Information was extracted into a custom-built data form and processed using SPSS (SPSS Inc., Chicago, IL, USA). RESULTS: The main findings were the lack of agreement between the methodology and documentation protocols (study, fall reporting and technical characteristics) used in the studies, as well as a substantial lack of real-world fall recordings. A methodological pitfall identified in most articles was the lack of an established fall definition. The types of sensors and their technical specifications varied considerably between studies. CONCLUSION: Limited methodological agreement between sensor-based fall detection studies using body-worn sensors was identified. Published evidence-based support for commercially available fall detection devices is still lacking. A worldwide research group consensus is needed to address fundamental issues such as incident verification, the establishment of guidelines for fall reporting and the development of a common fall definition.

Development of a standard fall data format for signals from body-worn sensors : the FARSEEING consensus.

Objective measurement of real-world fall events by using body-worn sensor devices can improve the understanding of falls in older people and enable new technology to prevent, predict, and automatically recognize falls. However, these events are rare and hence challenging to capture. The FARSEEING (FAll Repository for the design of Smart and sElf-adapaive Environments prolonging INdependent livinG) consortium and associated partners strongly argue that a sufficient dataset of real-world falls can only be acquired through a collaboration of many research groups. Therefore, the major aim of the FARSEEING project is to build a meta-database of real-world falls. To establish this meta-database, standardization of data is necessary to make it possible to combine different sources for analysis and to guarantee data quality. A consensus process was started in January 2012 to propose a standard fall data format, involving 40 experts from different countries and different disciplines working in the field of fall recording and fall prevention. During a web-based Delphi process, possible variables to describe participants, falls, and fall signals were collected and rated by the experts. The summarized results were presented and finally discussed during a workshop at the 20th Conference of the International Society of Posture and Gait Research 2012, in Trondheim, Norway. The consensus includes recommendations for a fall definition, fall reporting (including fall reporting frequency, and fall reporting variables), a minimum clinical dataset, a sensor configuration, and variables to describe the signal characteristics.

Proposal for a multiphase fall model based on real-world fall recordings with body-fixed sensors.

Falls are by far the leading cause of fractures and accidents in the home environment. The current Cochrane reviews and other systematic reviews report on more than 200 intervention studies about fall prevention. A recent meta-analysis has summarized the most important risk factors of accidental falls. However, falls and fall-related injuries remain a major challenge. One novel approach to recognize, analyze, and work better toward preventing falls could be the differentiation of the fall event into separate phases. This might aid in reconsidering ways to design preventive efforts and diagnostic approaches. From a conceptual point of view, falls can be separated into a pre-fall phase, a falling phase, an impact phase, a resting phase, and a recovery phase. Patient and external observers are often unable to give detailed comments concerning these phases. With new technological developments, it is now at least partly possible to examine the phases of falls separately and to generate new hypotheses.The article describes the practicality and the limitations of this approach using body-fixed sensor technology. The features of the different phases are outlined with selected real-world fall signals.

A protocol for periprosthetic joint infections from the Northern Infection Network for Joint Arthroplasty (NINJA) in the Netherlands.

Periprosthetic joint infection (PJI) is a devastating complication of joint arthroplasty surgery. Treatment success depends on accurate diagnostics, adequate surgical experience and interdisciplinary consultation between orthopedic surgeons, plastic surgeons, infectious disease specialists and medical microbiologists. For this purpose, we initiated the Northern Infection Network for Joint Arthroplasty (NINJA) in the Netherlands in 2014. The establishment of a mutual diagnostic and treatment protocol for PJI in our region has enabled mutual understanding, has supported agreement on how to treat specific patients, and has led to clarity for smaller hospitals in our region for when to refer patients without jeopardizing important initial treatment locally. Furthermore, a mutual PJI patient database has enabled the improvement of our protocol, based on medicine-based evidence from our scientific data. In this paper we describe our NINJA protocol.Level of evidence: III.

Do dual tasks have an added value over single tasks for balance assessment in fall prevention programs? A mini-review.

BACKGROUND: The Prevention of Falls Network Europe (ProFaNE) aims to bring together European researchers and clinicians to focus on the development of effective falls prevention programs for older people. One of the objectives is to identify suitable balance assessment tools. Assessment procedures that combine a balance task with a cognitive task may be relevant since part of all falls occurs during dual-task performance of walking or other balance activities. OBJECTIVE: To evaluate whether dual-task balance assessments are more sensitive than single balance tasks in predicting falls and detecting changes in balance performance after fall interventions. METHODS: A systematic literature search was performed in the databases PubMed, EMBASE, CINAHL, AMED, PsycINFO and Cochrane. Articles were selected according to the following inclusion criteria: (1) population: older adults (mean age > or =65 years), (2) assessment tool: dual task combining gait or other balance task with a cognitive task, (3) design: prospective or retrospective data collection of falls, or intervention study. Analysis of papers focused on measures of predictive ability or sensitivity-to-change for both tasks during dual-task performance as well as for the single balance and cognitive task. RESULTS: Out of 114 dual-task studies in older people, 19 articles matched the inclusion criteria. Fourteen studies had sample sizes of 60 subjects or less; the studied populations, task combinations as well as other methodological aspects varied. None of the articles reported the same statistical measures for both tasks during dual-task performance as well as single balance and cognitive task. In two studies with prospective data collection of falls, higher odds ratios were found for the dual compared to the single balance task. CONCLUSIONS: Upon the available literature, conclusions for an added value of dual balance tasks for fall prediction or assessing fall intervention effects cannot be made due to incomplete comparisons of single and dual balance tasks. Nevertheless, two studies do provide an indication that dual balance tasks may have added value for fall prediction.

Distance to achieve steady state walking speed in frail elderly persons.

This study aims to determine the length of the gait initiation phase before achieving steady state walking in frail older people. Based on body fixed sensors, habitual walking was analysed in 116 community-dwelling older persons (mean age 83.1 years, 84% women). The start of steady state walking was identified using an algorithm taking into account speeds from consecutive strides. On average, participants reached a walking speed of 0.66 m/s after an acceleration phase of 1.43 m (89% after 2.47 m). When spatio-temporal variables were calculated from 4, 6, 8, 10, or 20 consecutive stride cycles after achieving steady state, similar values were observed for mean gait speed and stride length. The variability of these factors differed depending on the number of gait cycles. Assessments of steady state gait in frail elderly people should therefore exclude the first 2.5m of walking. If gait variability is to be assessed, it is recommended that more than 20 stride cycles be used.

[A 65-year-old patient with an odontoid fracture caused by 'headbanging']. / Een 65-jarige patiënte met een densfractuur veroorzaakt door 'headbangen'.

A 65-year-old woman who habitually made flexion-extension movements with her cervical vertebral column (so-called 'headbanging') was seen with complaints of the neck. X-rays of the neck revealed an odontoid fracture. Bone densitometry revealed lowered bone mineral density (osteopenia). The diagnosis was odontoid fracture due to headbanging, in the presence of osteopenia. Patient recovered after treatment with a neck collar worn for 6 months.

Blood volume and body fluid compartments in lambs with aortopulmonary left-to-right shunts.

A left-to-right shunt is accompanied by an increased plasma and blood volume. Since this is likely realized through renin/aldosterone-mediated salt and water retention, other body fluid compartments may be changed too. Therefore, we studied blood volume and body fluid compartments by a single-injection, triple-indicator dilution technique in nine 8-wk-old lambs with an aortopulmonary left-to-right shunt (55 +/- 3% of left ventricular output; mean +/- SEM) and in 11 control lambs, 2.5 wk after surgery. Systemic blood flow was maintained at the same level as in control lambs, but the aortic pressure of the shunt lambs was lower. Blood volume in shunt lambs was larger than in control lambs (110 +/- 6 vs. 84 +/- 7 ml/kg, P < 0.001) through an increase in plasma volume, which correlated significantly with the magnitude of the left-to-right shunt (r = 0.81, P < 0.01). Red blood cell volume was equal to that of control lambs. Evidence was obtained that the increase in plasma volume was induced by a transient increase in renin (8.0 +/- 2.2 vs. 1.6 +/- 0.2 nmol.l-1.h-1; P < 0.02) and aldosterone (0.51 +/- 0.14 vs. 0.24 +/- 0.09 nmol/liter) concentrations. Interstitial water volume, however, was not significantly different from that in control lambs. The amount of intravascular protein was significantly higher than in control lambs (5.0 +/- 0.3 vs. 3.5 +/- 0.2 g/kg body mass, P < 0.001). There were no significant differences in intracellular and total body water volumes between the two groups. We conclude that the increased amount of intravascular protein confines the fluid retained by the kidneys to the vascular compartment.

Effects of short and prolonged transcutaneous vagus nerve stimulation on heart rate variability in healthy subjects.

The vagus nerve is strategically located in the body, and has multiple homeostatic and health-promoting effects. Low vagal activity predicts onset and progression of diseases. These are the reasons to activate this nerve. This study examined the effects of transcutaneous vagus nerve stimulation (t-VNS) on a main index of vagal activity, namely heart rate variability (HRV). In Study 1, we compared short (10min) left versus right ear t-VNS versus sham (no stimulation) in a within-subjects experimental design. Results revealed significant increases in only one HRV parameter (standard deviation of the RR intervals (SDNN)) following right-ear t-VNS. Study 2 examined the prolonged effects of t-VNS (1h) in the right ear. Compared to baseline, right-t-VNS significantly increased the LF and LF/HF components of HRV, and SDNN in women, but not in men. These results show limited effects of t-VNS on HRV, and are discussed in light of neuroanatomical and statistical considerations and future directions are proposed.

Duloxetine in OsteoArthritis (DOA) study: study protocol of a pragmatic open-label randomised controlled trial assessing the effect of preoperative pain treatment on postoperative outcome after total hip or knee arthroplasty.

INTRODUCTION: Residual pain is a major factor in patient dissatisfaction following total hip arthroplasty or total knee arthroplasty (THA/TKA). The proportion of patients with unfavourable long-term residual pain is high, ranging from 7% to 34%. There are studies indicating that a preoperative degree of central sensitisation (CS) is associated with poorer postoperative outcomes and residual pain. It is thus hypothesised that preoperative treatment of CS could enhance postoperative outcomes. Duloxetine has been shown to be effective for several chronic pain syndromes, including knee osteoarthritis (OA), in which CS is most likely one of the underlying pain mechanisms. This study aims to evaluate the postoperative effects of preoperative screening and targeted duloxetine treatment of CS on residual pain compared with care-as-usual. METHODS AND ANALYSIS: This multicentre, pragmatic, prospective, open-label, randomised controlled trial includes patients with idiopathic hip/knee OA who are on a waiting list for primary THA/TKA. Patients at risk for CS will be randomly allocated to the preoperative duloxetine treatment programme group or the care-as-usual control group. The primary end point is the degree of postoperative pain 6 months after THA/TKA. Secondary end points at multiple time points up to 12 months postoperatively are: pain, neuropathic pain-like symptoms, (pain) sensitisation, pain catastrophising, joint-associated problems, physical activity, health-related quality of life, depressive and anxiety symptoms, and perceived improvement. Data will be analysed on an intention-to-treat basis. ETHICS AND DISSEMINATION: The study is approved by the local Medical Ethics Committee (METc 2014/087) and will be conducted according to the principles of the Declaration of Helsinki (64th, 2013) and the Good Clinical Practice standard (GCP), and in compliance with the Medical Research Involving Human Subjects Act (WMO). TRIAL REGISTRATION NUMBER: 2013-004313-41; Pre-results.

Reliability of the Q Force; a mobile instrument for measuring isometric quadriceps muscle strength.

BACKGROUND: The ability to generate muscle strength is a pre-requisite for all human movement. Decreased quadriceps muscle strength is frequently observed in older adults and is associated with a decreased performance and activity limitations. To quantify the quadriceps muscle strength and to monitor changes over time, instruments and procedures with a sufficient reliability are needed. The Q Force is an innovative mobile muscle strength measurement instrument suitable to measure in various degrees of extension. Measurements between 110 and 130° extension present the highest values and the most significant increase after training. The objective of this study is to determine the test-retest reliability of muscle strength measurements by the Q Force in older adults in 110° extension. METHODS: Forty-one healthy older adults, 13 males and 28 females were included in the study. Mean (SD) age was 81.9 (4.89) years. Isometric muscle strength of the Quadriceps muscle was assessed with the Q Force at 110° of knee extension. Participants were measured at two sessions with a three to eight day interval between sessions. To determine relative reliability, the intraclass correlation coefficient (ICC) was calculated. To determine absolute reliability, Bland and Altman Limits of Agreement (LOA) were calculated and t-tests were performed. RESULTS: Relative reliability of the Q Force is good to excellent as all ICC coefficients are higher than 0.75. Generally a large 95 % LOA, reflecting only moderate absolute reliability, is found as exemplified for the peak torque left leg of -18.6 N to 33.8 N and the right leg of -9.2 N to 26.4 N was between 15.7 and 23.6 Newton representing 25.2 % to 39.9 % of the size of the mean. Small systematic differences in mean were found between measurement session 1 and 2. CONCLUSION: The present study shows that the Q Force has excellent relative test-retest reliability, but limited absolute test-retest reliability. Since the Q Force is relatively cheap and mobile it is suitable for application in various clinical settings, however, its capability to detect changes in muscle force over time is limited but comparable to existing instruments.

Myocardial lactate metabolism in fetal and newborn lambs.

BACKGROUND: Around birth, myocardial substrate supply changes from carbohydrates before birth to primarily fatty acids after birth. Parallel to these changes, the myocardium is expected to switch from the use of primarily lactate before birth to fatty acids thereafter. However, myocardial lactate uptake and oxidation around birth has not been measured in vivo. METHODS AND RESULTS: We measured myocardial lactate uptake, oxidation, and release with infusion of [1-13C]lactate and myocardial flux of fatty acids and glucose in chronically instrumented fetal and newborn (1 to 15 days) lambs. Myocardial lactate oxidation was the same in newborn (81.7+/-14.7 micromol. min-1. 100 g-1, n=11) as in fetal lambs (60.7+/-26.7 micromol. min-1. 100 g-1, n=7). Lactate uptake was also the same in newborn as in fetal lambs. Lactate uptake was higher than lactate flux, indicating lactate release simultaneously with uptake. In the newborn lambs, lactate uptake declined with age. Lactate uptake was strongly related to lactate supply, whereas lactate oxidation was not. The supply of fatty acids or glucose did not interfere with lactate uptake, but the flux of fatty acids was inversely related to lactate oxidation. CONCLUSIONS: We show that lactate is an important energy source for the myocardium before birth as well as in the first 2 weeks after birth in lambs. We also show that there is release of lactate by the myocardium simultaneously with uptake of lactate. Furthermore, we show that lactate oxidation may be attenuated by fatty acids but not by glucose, probably at the level of pyruvate dehydrogenase.

Perinatal changes in myocardial metabolism in lambs.

BACKGROUND: Lactate accounts for a third of myocardial oxygen consumption before and in the first 2 weeks after birth. It is unknown how the remainder of myocardial oxygen is consumed. Glucose is thought to be important before birth, whereas long-chain fatty acids (LC-FA) are the prime substrate for the adult. However, the ability of the myocardium of the newborn to use LC-FA has been doubted. METHODS AND RESULTS: We measured the myocardial metabolism of glucose and LC-FA with [U-(13)C]glucose and [1-(13)C]palmitate in chronically instrumented fetal and newborn lambs. In fetal lambs, myocardial oxidation of glucose was high and that of LC-FA was low. Glucose and LC-FA accounted for 48+/-4% and 2+/-2% of myocardial oxygen consumption, respectively. In newborn lambs, oxidation of glucose decreased, whereas oxidation of LC-FA increased. Glucose and LC-FA accounted for 12+/-3% and 83+/-19% of myocardial oxygen consumption. To test whether near-term fetal lambs could use LC-FA, we increased the supply of LC-FA with a fat infusion. In fetal lambs during fat infusion, the oxidation of LC-FA increased 15-fold. Although the oxidation of LC-FA was still lower than in newborn lambs, the contribution to myocardial oxygen consumption (70+/-13%) was the same as in newborn lambs. CONCLUSIONS: These data show that glucose and lactate account for the majority of myocardial oxygen consumption in fetal lambs, whereas in newborn lambs, LC-FA and lactate account for the majority of myocardial oxygen consumption. Moreover, we showed that the fetal myocardium can use LC-FA as an energy substrate.

Comparative effects of isoproterenol and dopamine on myocardial oxygen consumption, blood flow distribution and total body oxygen consumption in conscious lambs with and without an aortopulmonary left to right shunt.

OBJECTIVES: We sought to study the effects of catecholamines on myocardial oxygen consumption (VO2), regional blood flows and total body VO2 in lambs with circulatory congestion. BACKGROUND: Catecholamines are often used to support cardiovascular function in children with circulatory congestion because they increase contractility as well as heart rate. However, these changes increase myocardial oxygen demand and thus can lead to a mismatch between myocardial oxygen supply and demand. Catecholamines can also change regional blood flows and VO2 unfavorably. METHODS: We infused isoproterenol (0.1 microg/kg body weight per min) and dopamine (10 microg/kg per min) and measured myocardial and total body VO2 and regional blood flows in chronically instrumented 7-week old lambs with and without a left to right shunt. RESULTS: Isoproterenol increased myocardial VO2, parallel to the increase in heart rate. However, myocardial blood flow and, consequently, oxygen supply also increased. This increase outweighed the increase in myocardial VO2, so that myocardial oxygen extraction decreased. Isoproterenol did not change blood flow distribution. Isoproterenol increased total body VO2; however, systemic oxygen supply increased even more, so that oxygen extraction decreased and mixed venous oxygen saturation increased. In contrast, dopamine had no or little effect on myocardial VO2 or blood flow distribution. CONCLUSIONS: We conclude that the catecholamines isoproterenol and dopamine do not lead to a mismatch between myocardial oxygen supply and demand, nor do they change blood flow distribution unfavorably in 7-week old lambs with a left to right shunt. We demonstrated that isoproterenol is superior to dopamine, because it shifts the balance between oxygen supply and consumption toward supply so that systemic oxygen extraction reserve increases.