Prolonged Periods Of Bed Rest Research Articles

Impact of Hindlimb Disuse on Sepsis-Induced Myopathy in Older Adult Mice

BACKGROUND: Sepsis, a life-threatening condition due to an overactive immune response, adversely affects multiple organ systems. Despite its significance of accounting for 40% of total body mass, the skeletal muscle system is considered the forgotten organ system affected by sepsis. In addition to the inflammatory aspects of sepsis, patients in the intensive care unit (ICU) frequently experience prolonged periods of bed rest, which can lead to muscle disuse-induced myopathy characterized by muscle atrophy, weakness, and impaired regenerative capacity. Despite the higher incidence of sepsis in bedridden older adults, most research on sepsis-induced myopathy primarily focuses on younger adults under conditions that do not mimic bed rest. In this study, we simulated the clinical conditions of older adult ICU patients by combining sepsis with hindlimb disuse. Our hypotheses were that the combination of sepsis, disuse, and aging would exacerbate muscle atrophy and weakness, while also reducing the number of regenerative stem cells in muscle tissue. Methods: To investigate the functional and morphological responses of skeletal muscle to sepsis, we conducted experiments on 78-week-old male wild-type C57Bl6 mice. They underwent either cecal ligation and puncture (CLP, n = 17) or Sham (n = 14) surgeries. Four days post-surgery, the animals were allocated to hindlimb suspension (HLS — CLP, n=9; Sham, n=10) or normal ambulation (NA — CLP, n=8; Sham, n=4) for seven days. Terminal experiments were conducted after hindlimb suspension or normal ambulation treatments. We assessed peak force production ex vivo in solei muscles, examined the cross-sectional area (CSA) of relevant hindlimb muscles using immunohistochemistry, and quantified the abundance of stem cells through immunohistochemistry (e.g., PAX7+ cells) in muscle sections. Additionally, we evaluated markers of senescence by measuring the protein abundance of p16 and p53 in hindlimb muscle homogenates. Results: CLP surgery resulted in 50% mortality rate (p<0.05). Percentage body mass loss was as follows: 5.3 ± 4.2 for Sham/NA group, 13.3 ± 5.2 for Sham/HLS group, 7.3 ± 4.4 for CLP/NA group, and 17.7 ± 5.5 for CLP/HLS group. Peak absolute force was significantly lower in Sham/HLS and CLP/HLS compared to Sham/NA (Sham/NA = 277±2.4, Sham/HLS = 189±28.4, CLP/NA = 264±23.0, CLP/HLS = 180±48.9 mN, p<0.05). Mice exposed to CLP/HLS displayed a higher cumulative fiber area at smaller fiber sizes (800 to 1000 μm2) (p<0.05), indicating muscle atrophy. CLP/NA caused a 9.8% reduction in solei muscle mass (p < 0.05), while CLP/HLS led to an additional 30% loss in solei mass (p<0.05). Furthermore, CLP/HLS significantly decreased the number of PAX7+ stem cells by 75% (p<0.05). Notably, p16 was significantly increased in response to CLP/HLS (p<0.05), while no changes were observed in p53 abundance. CONCLUSION: This study demonstrates the role of muscle disuse in exacerbating skeletal muscle functional and morphological abnormalities in older adult septic mice, emphasizing the critical contribution of disuse to the pathophysiology of sepsis-induced myopathy. NIH R21AG072011 to OL. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Early Mobilization of Patients on Extracorporeal Membrane Oxygenation: A Systematic Review.

Patients on extracorporeal membrane oxygenation (ECMO) often require prolonged periods of bed rest owing to the severity of their illness. Care is also required to maintain the position and integrity of the ECMO cannula. However, they experience a range of effects due to prolonged bed rest. This systematic review examined the possible effects of the early mobilization in patients on ECMO. The database PUBMED was searched by using appropriate keywords: "rehabilitation", "mobilization", "ECMO" and "extracorporeal membrane oxygenation". The selection criteria for the article search were the following: (a) studies published in the last five years, (b) descriptive studies, (c) randomized studies, (d) published in the English language and (e) studies in adults. A total of 259 studies were found, 8 of which were finally selected. Most of the studies showed that early intensive physical rehabilitation related to a decrease in in-hospital stay and a reduction in the duration of mechanical ventilation and doses of vasopressors. In addition, improvements in the functional status and rate of mortality were observed along with a reduction in health care costs. Exercise training should be a fundamental part of the management of patients on ECMO.

Muscle strength, aerobic capacity, and exercise tolerance are impaired in left ventricular assist devices recipients: A pilot study.

Background: Left ventricular assist devices (LVAD) are increasingly being used as a therapy for advanced heart failure, both as a bridge to heart transplant and, given the rapid advances in the LVAD’s functionality and safety, and constant lack in availability of donor organs, as long-term destination therapy. With the diffusion of such therapy, it is crucial to assess patients’ muscle strength, aerobic capacity and exercise tolerance, to improve their functional capacity. Methods: 38 LVAD recipients (33 men and five women) were included. Exercise testing including a maximal cardiopulmonary exercise test (CPET), handgrip, isometric and isokinetic strength testing of knee and ankle flexion/extension, and Romberg balance test in three conditions (eyes open, eyes closed, double task). Given the small and heterogeneous final sample size, a mostly descriptive statistical approach was chosen. Results: 12 participants were classified as “Obese” (BMI>29.9). The most common comorbidities were type II diabetes and chronic kidney disease. Only 12 participants were able to successfully complete all the assessments. CPET and isokinetic strength trials were the least tolerated tests, and the handgrip test the best tolerated. Mean VO2 peak was 12.38 ± 3.43 ml/kg/min, with 15 participants below 50% of predicted VO2 max, of which 6 below 30% VO2max. Mean handgrip strength was 30.05 ± 10.61 Kg; 25 participants were below the 25° percentile of their population’s normative reference values for handgrip strength, 10 of which were below the 5° percentile. Issues with the management of the external pack of the LVAD and its influence on the test limited the validity of the balance tests data, therefore, no solid conclusions could be drawn from them. VO2 peak did not correlate with handgrip strength or with any of the lower limb strength measures. Conclusion: LVAD recipients show greatly reduced functional capacity and tolerance to exercise and exercise testing, with low overall strength levels. As strength variables appear to be independent from VO2 peak, different lower limbs strength tests should be explored to find a tolerable alternative in this population, which is subjected to muscle wasting due to old age, reduced tissue perfusion, side effects from the pharmacological therapies, and prolonged periods of bedrest.

Analysis of mobility level of COVID-19 patients undergoing mechanical ventilation support: A single center, retrospective cohort study.

Severe coronavirus disease 2019 (COVID-19) patients frequently require mechanical ventilation (MV) and undergo prolonged periods of bed rest with restriction of activities during the intensive care unit (ICU) stay. Our aim was to address the degree of mobilization in critically ill patients with COVID-19 undergoing to MV support. Retrospective single-center cohort study. We analyzed patients' mobility level, through the Perme ICU Mobility Score (Perme Score) of COVID-19 patients admitted to the ICU. The Perme Mobility Index (PMI) was calculated [PMI = ΔPerme Score (ICU discharge-ICU admission)/ICU length of stay], and patients were categorized as "improved" (PMI > 0) or "not improved" (PMI ≤ 0). Comparisons were performed with stratification according to the use of MV support. From February 2020, to February 2021, 1,297 patients with COVID-19 were admitted to the ICU and assessed for eligibility. Out of those, 949 patients were included in the study [524 (55.2%) were classified as "improved" and 425 (44.8%) as "not improved"], and 396 (41.7%) received MV during ICU stay. The overall rate of patients out of bed and able to walk ≥ 30 meters at ICU discharge were, respectively, 526 (63.3%) and 170 (20.5%). After adjusting for confounders, independent predictors of improvement of mobility level were frailty (OR: 0.52; 95% CI: 0.29-0.94; p = 0.03); SAPS III Score (OR: 0.75; 95% CI: 0.57-0.99; p = 0.04); SOFA Score (OR: 0.58; 95% CI: 0.43-0.78; p < 0.001); use of MV after the first hour of ICU admission (OR: 0.41; 95% CI: 0.17-0.99; p = 0.04); tracheostomy (OR: 0.54; 95% CI: 0.30-0.95; p = 0.03); use of extracorporeal membrane oxygenation (OR: 0.21; 95% CI: 0.05-0.8; p = 0.03); neuromuscular blockade (OR: 0.53; 95% CI: 0.3-0.95; p = 0.03); a higher Perme Score at admission (OR: 0.35; 95% CI: 0.28-0.43; p < 0.001); palliative care (OR: 0.05; 95% CI: 0.01-0.16; p < 0.001); and a longer ICU stay (OR: 0.79; 95% CI: 0.61-0.97; p = 0.04) were associated with a lower chance of mobility improvement, while non-invasive ventilation within the first hour of ICU admission and after the first hour of ICU admission (OR: 2.45; 95% CI: 1.59-3.81; p < 0.001) and (OR: 2.25; 95% CI: 1.56-3.26; p < 0.001), respectively; and vasopressor use (OR: 2.39; 95% CI: 1.07-5.5; p = 0.03) were associated with a higher chance of mobility improvement. The use of MV reduced mobility status in less than half of critically ill COVID-19 patients.

Plasticity In GABAergic Neurotransmission In The Nucleus Tractus Solitarii After Cardiovascular Deconditioning

People exposed to prolonged periods of bed rest are susceptible to cardiovascular deconditioning (CVD), which is associated with orthostatic intolerance and autonomic imbalance. Hindlimb unloading (HU) in rats induces CVD analogous to that seen in bedridden individuals. The effects of HU are likely related to plasticity within the neuronal network processing cardiovascular afferent information. The nucleus tractus solitarii (nTS) is the first integrative central region for autonomic modulation. GABA and Glutamate are the major inhibitory and excitatory neurotransmitters within this nucleus. This study investigated the mechanisms by which HU affects GABA synaptic processing within the nTS. We hypothesized that HU increases GABA synaptic activity in the nTS and alters the regulation of cross-talk between GABA and glutamate at this region. Stainless wire rings were placed in the tail of male Sprague-Dawley rats (3 weeks old). After one week of recovery the rings were connected to a suspension apparatus and rats were suspended at an angle of 30–35° for two weeks with free access to food and water. Control animals were maintained in normal postural conditions. After the HU protocol, coronal brainstem slices were generated and whole-cell patch clamp was performed to evaluate synaptic neurotransmission and electrophysiological properties of nTS neurons. Compared to control rats, HU had no significant effects on spontaneous inhibitory postsynaptic currents (sIPSCs) but increased the amplitude of IPSCs evoked by nTS stimulation (nTS-IPSC). GABAA receptor antagonists (Gabazine 20µM and Bicuculline 20µM) depolarized membrane potential in HU but not in controls. Moreover, Gabazine increased spontaneous excitatory postsynaptic currents (sEPSC) in control, indicating an increase in network activity, but had no effect in HU. The results indicate that HU increases GABAergic signaling and alters the cross-talk regulation between GABA and Glutamate neurotransmission in the nTS, which may contribute to impaired autonomic and cardiovascular control.

Early rehabilitation during extracorporeal membrane oxygenation has minimal impact on physiological parameters: A pilot randomised controlled trial

BackgroundPatients on extracorporeal membrane oxygenation (ECMO) often require prolonged periods of bed rest owing to their severity of illness along with the care required to maintain the position and integrity of the ECMO cannula. Many patients on ECMO receive passive exercises, and rehabilitation is often delayed owing to medical instability, with a high proportion of patients demonstrating severe muscle weakness. The physiological effects of an intensive rehabilitation program started early after ECMO commencement remain unknown. ObjectivesThe primary objective of this study was to describe the respiratory and haemodynamic effects of early intensive rehabilitation compared with standard care physiotherapy over a 7-d period in patients requiring ECMO. MethodsThis was a physiological substudy of a multicentre randomised controlled trial conducted in one tertiary referral hospital. Consecutive adult patients undergoing ECMO were recruited. Respiratory and haemodynamic parameters, along with ECMO settings, were recorded 30 min before and after each session and continuously during the session. In addition, the minimum and maximum values for these parameters were recorded outside of the rehabilitation or standard care sessions for each 24-h period over the 7 d. The number of minutes of exercise per session was recorded. ResultsFifteen patients (mean age = 51.5 ± standard deviation of 14.3 y, 80% men) received ECMO. There was no difference between the groups for any of the respiratory, haemodynamic, or ECMO parameters. The minimum and maximum values for each parameter were recorded outside of the rehabilitation or standard care sessions. The intensive rehabilitation group (n = 7) spent more time exercising per session than the standard care group (n = 8) (mean = 28.7 versus 4.2 min, p < 0.0001). Three patients (43%) in the intensive rehabilitation group versus none in the standard care group mobilised out of bed during ECMO. ConclusionsIn summary, early intensive rehabilitation of patients on ECMO had minimal effect on physiological parameters.

Effects Of 10-days Bed-rest On Nitric Oxide Metabolites And Microvascular Function Assessed By Near-infrared Spectroscopy

PURPOSE: Prolonged periods of bed-rest (BR), experimental simulation of microgravity, greatly affect oxidative metabolism by acting at several levels of the O2 pathway. Short duration (10 days) of horizontal BR negatively affects in-vivo functional biomarkers related to skeletal muscle oxidative metabolism without affecting mitochondrial respiration ex-vivo. The impairment of muscle oxidative metabolism can partially derive from reduced O2 delivery, altered peripheral O2 diffusion and a mismatch between O2 delivery and O2 consumption, likely related to an altered nitric oxide signaling. Aim of this study was to evaluate the effects of 10 days of BR on microvascular reactivity indexes determined at skeletal muscle level by near infrared spectroscopy and nitric oxide metabolites. METHODS: Measurements were carried out on 10 recreationally active young males (age 23 ± 5 years [mean±SD]) before (PRE) and after (POST) 10 days of horizontal BR. Pulmonary O2 uptake (V̇O2) and other respiratory, cardiovascular and skeletal muscle variables were determined during an incremental exercise on a cycle ergometer. Microvascular endothelial function was assessed during vascular occlusion test (VOT) by evaluating the slope of re-oxygenation rate (SLOPE 2) and the area under the curve (AUC) over the baseline of 5min reperfusion phase of delta[oxy(Hb+Mb)] signal obtained from vastus lateralis muscle. Plasma nitrite concentration was determined by chemiluminescence. RESULTS: Peak V̇O2 was lower in POST (41.5±6.5 ml.kg-1.min-1) vs. PRE (44.5±7.4, P<0.01). SLOPE 2 was significantly slower in POST (5.3±0.8 %.s-1) compared to PRE (6.4±0.7, P<0.01). AUC was significantly reduced in POST (11025±2145 %.s) compared to PRE (13094±1940, P<0.01). Plasma nitrite concentration diminished from PRE (85.4±35.0 nM) to POST (65.5±45.6, P<0.01). CONCLUSIONS: These preliminary data suggest that after 10 days of horizontal BR whole-body impairment of oxidative metabolism during exercise is associated with reduced level of nitrite and an altered microvascular endothelial function. Further analyses of systemic functional variables as well as biochemical data obtained during the bed-rest campaign, and not yet analysed, will help us to define sites of limitation to muscle oxidative metabolism along the O2 pathway.

The Role of Enhanced Cognition to Counteract Detrimental Effects of Prolonged Bed Rest: Current Evidence and Perspectives.

Prolonged periods of physical inactivity or bed rest can lead to a significant decline of functional and cognitive functions. Different kinds of countermeasures (e.g., centrifugation, nutritional, and aerobic interventions) have been developed to attempt to mitigate negative effects related to bed rest confinement. The aim of this report is to provide an overview of the current evidence related to the effectiveness of computerized cognitive training (CCT) intervention during a period of complete physical inactivity in older adults. CCT, using a virtual maze navigation task, appears to be effective and has long-lasting benefits (up to 1.5 years after the study). Moreover, enhanced cognition (executive control) reduces decline in the ability to perform complex motor-cognitive dual-tasks after prolonged period of bed rest. It has been demonstrated that CCT administration in older adults also prevents bed rest stress-related physiological changes [these groups showed minimal changes in vascular function and an unchanged level of brain-derived neurotrophic factor (BDNF)] while control subjects showed decreased peripheral vascularization and increased plasma level of the neurotrophin BDNF during a 14-day bed rest. In addition, the effects of CCT are evident also from the brain electrocortical findings: CCT group revealed a decreased power in lower delta and theta bands while significant increases in the same EEG spectral bands power were found in control subjects. If we consider an increase of power in delta band as a marker of cortical aging, then the lack of shift of EEG power to lower band indicates a preventive role of CCT on the cortical level during physiological deconditioning induced by 2-week bed rest immobilization. However, replication on a larger sample is required to confirm the observed findings. Applications derived from these findings could be appropriate for implementation of hospital treatment for bed ridden patients as well as for fall prevention programs.

Effects of strict prolonged bed rest on cardiorespiratory fitness: systematic review and meta-analysis.

The aim of this systematic review and meta-analysis [International Prospective Register of Systematic Reviews (PROSPERO) CRD42017055619] was to assess the effects of strict prolonged bed rest (without countermeasures) on maximal oxygen uptake (V̇o2max) and to explore sources of variation therein. Since 1949, 80 studies with a total of 949 participants (>90% men) have been published with data on strict bed rest and V̇o2max The studies were conducted mainly in young participants [median age (interquartile range) 24.5 (22.4-34.0) yr]. The duration of bed rest ranged from 1 to 90 days. V̇o2max declined linearly across bed rest duration. No statistical difference in the decline among studies reporting V̇o2max as l/min (-0.3% per day) compared with studies reporting V̇o2max normalized to body weight (ml·kg-1·min-1; -0.43% per day) was observed. Although both total body weight and lean body mass declined in response to bed rest, we did not see any associations with the decline in V̇o2max However, 15-26% of the variation in the decline in V̇o2max was explained by the pre-bed-rest V̇o2max levels, independent of the duration of bed rest (i.e., higher pre-bed-rest V̇o2max levels were associated with larger declines in V̇o2max). Furthermore, the systematic review revealed a gap in the knowledge about the cardiovascular response to extreme physical inactivity, particularly in older subjects and women of any age group. In addition to its relevance to spaceflight, this lack of data has significant translational implications because younger women sometimes undergo prolonged periods of bed rest associated with the complications of pregnancy and the incidence of hospitalization including prolonged periods of bed rest increases with age.NEW & NOTEWORTHY Large interindividual responses of maximal oxygen uptake (V̇o2max) to aerobic exercise training exist. However, less is known about the variability in the response of V̇o2max to prolonged bed rest. This systematic review and meta-analysis showed that pre-bed-rest V̇o2max values were inversely associated with the change in V̇o2max independent of the duration of bed rest. Moreover, we identified a large knowledge gap about the causes of decline in V̇o2max, particularly in postmenopausal women, which may have clinical implications.

Exercise is delayed in critically ill patients: a five year observational study in an Australian tertiary intensive care unit

Duration of bed rest among critically ill patients in ICU has been associated with development of persistent weakness that can last for more than five years. Commencing early exercise interventions in ICU is likely to reduce critically ill patients’ physical dysfunction. However, critically ill patients often experience prolonged periods of bed rest and inactivity.

A mobility program for an inpatient acute care medical unit.

For many patients, hospitalization brings prolonged periods of bed rest, which are associated with such adverse health outcomes as increased length of stay, increased risk of falls, functional decline, and extended-care facility placement. Most studies of progressive or early mobility protocols designed to minimize these adverse effects have been geared toward specific patient populations and conducted by multidisciplinary teams in either ICUs or surgical units. Very few mobility programs have been developed for and implemented on acute care medical units. This evidence-based quality improvement project describes how a mobility program, devised for and put to use on a general medical unit in a large Midwestern academic health care system, improved patient outcomes.

The physiological response of skin tissues to alternating support pressures in able-bodied subjects

Prolonged mechanical loading can lead to breakdown of skin and underlying tissues which can, in turn, develop into a pressure ulcer. The benefits of pressure relief and/or redistribution to minimise risk have been well documented and these strategies can be provided by employing support mattresses in which internal air pressures can be alternated to minimise the risk of pressure ulcers in patients during prolonged periods of bed-rest. The paper describes the performance of a prototype alternating pressure air mattress (APAM), in terms of its ability to maintain skin viability in a group of healthy volunteers lying in a supine position. In particular, the mattress includes a sacral section supported with alternating low pressure (ALP), with values adjusted to subject morphology, using an in-built pressure sensor. The mattress was supported at four different head of bed (HOB) angles ranging from 0 to 60°. Internal mattress pressures and transcutaneous gas (TcPO2/TcPCO2) tensions at the sacrum and a control site, the scapula, were monitored. Interface pressures were also measured. The sensor was found to be sensitive to the BMI values of the 12 healthy volunteers. In the majority of test conditions the internal support produced sacral TcPO2 values, which either remained similar to those at the scapula or fluctuated at levels providing adequate viability. However in a few cases, associated with a raised HOB angle (≥45°), there was compromise to the skin viability at the sacrum, as reflected in depressed TcPO2 levels associated with an elevation of TcPCO2 levels above the normal range. In all cases, interface pressures at the sacrum rarely exceeded 60mmHg. Although such studies need to be extended to involve bed-bound individuals, the results offer the potential for the development of intelligent APAM systems, whose characteristics can be adjusted to an individual morphology. Such preventive strategies to maintain skin viability at loaded sites will be designed for subjects deemed to be at high risk of developing pressure ulcers.

POTS versus deconditioning: the same or different?

The 2007 Streeten Lecture focused on the idea that physical deconditioning plays a key role in the symptomology and pathophysiology of POTS. Parallels were drawn between the physiological responses to orthostatic stress seen in POTS patients and the physiological responses seen in "normal" humans after prolonged periods of bedrest, deconditioning, or space flight. Additionally, the idea that endurance exercise training might ameliorate some of these symptoms was also advanced. Finally, potential parallels between POTS, chronic fatigue syndrome, and fibromyalgia were also drawn and the potential role of exercise training as a "therapeutic intervention" in all three conditions was raised. The conceptual model for the lecture was that after some "initiating event" chronic deconditioning plays a significant role in the pathophysiology of these conditions, and these physiological changes in conjunction with "somatic hypervigilence" explain many of the complaints that this diverse group of patients have. Additionally, the idea that systematic endurance exercise training might be helpful was advanced, and data supportive of this idea was reviewed. The main conclusion is that the medical community must retain their empathy for patients with unusual conditions but at the same time send a firm but empowering message about physical activity. As always, we must also ask what do the ideas about physical activity and inactivity and the conditions mentioned above not explain?

A Mobility Protocol for Critically Ill Adults

Although the complications of immobility are well-described in the literature, critically ill patients are often subjected to prolonged periods of bed rest. Nurses, by virtue of their expertise in preventing iatrogenic complications, are in an ideal position to prevent the adverse outcomes associated with immobility. This article describes how nurses can use a mobility protocol to increase the activity of critically ill patients in a timely manner that may prevent the infirmity and suffering that is caused by unnecessarily long periods of bed rest.

Venous Tone after Cardiovascular Deconditioning in Intact and Autonomic Blocked Conscious Rats

Prolonged periods of bed rest and spaceflight result in tachycardia and increased prevalence of orthostatic intolerance, effects that are mimicked by hindlimb unloading (HU) in rats. Regulation of venous function is important for compensation to orthostatic stress; however, the effects of HU on the venous system remain unclear. We hypothesized that 14 days of HU would result in a decrease in venous tone. Male SD (300–400 g) control (n=4) and HU (n=6) rats were instrumented with a femoral venous and arterial catheter and a balloon tipped catheter in the right jugular vein advanced to the right atrium. After recovery (2–5 days) conscious animals were subjected to 4 balloon inflations (0.2–0.3 ml saline for 5–7 seconds once every 10–15 minutes). Mean circulatory filling pressure (MCFP) was calculated from the plateau levels of mean arterial pressure (MAP) and central venous pressure during balloon occlusion. Under baseline conditions, heart rate was increased in HU rats (Con: 346 ± 6 vs HU: 405 ± 7 bpm), while MAP and MCFP were similar in control and HU rats (MAP: 111 ± 6 vs 119 ± 3 mmHg; MCFP: 7.6 ± 0.6 vs 7.5 ± 0.3 mmHg). Some of the rats were ganglionic blocked (hexamethonium, 30 mg/kg and atropine, 0.1 mg/kg) and MCFP was evaluated. MAP and MCFP were reduced in both groups after autonomic blockade. However, MCFP was still similar in control (6.2 ± 0.2 (n=2)) and HU (5.2 ± 0.6 (n=6)) rats. These preliminary data suggest that venous tone under control conditions and after autonomic blockade is unchanged after 14 days of hindlimb unloading. (HL55306)

Fondaparinux: A new antithrombotic agent

Background: Venous thrombosis is usually triggered by a low-flow state, as in prolonged periods of bed rest after hip or knee surgery. Antithrombotic agents are the drugs of choice in such circumstances. The new factor Xa inhibitor fondaparinux has been approved by the US Food and Drug Administration for the prevention of venous thromboembolism in patients undergoing hip fracture surgery, hip replacement surgery, or knee replacement surgery. Objective: The aim of this article was to review the clinical pharmacology of fondaparinux and summarize the data from available clinical trials of this agent. Methods: The terms fondaparinux, SR90107A/ORG31540, and factor Xa were used to search MEDLINE and Current Contents/Clinical Medicine for English-language studies in humans published between 1996 and May 2002. Unpublished data were provided by the manufacturer of fondaparinux, and additional information was obtained from abstracts presented at the 2001 congress of the International Society on Thrombosis and Haemostasis in Paris. Results: Fondaparinux is a synthetic pentasaccharide that selectively binds to antithrombin III, inducing a conformational change that increases anti-factor Xa activity. Phase III studies to date have reported that fondaparinux had greater efficacy compared with enoxaparin in terms of prevention of venous thromboembolism after hip or knee replacement surgery. Preliminary studies have suggested that this agent may have efficacy in the treatment of deep vein thrombosis, as well as in the management of acute coronary syndromes. However, 1 study reported a significant increase in the risk of major bleeding with fondaparinux compared with enoxaparin (2.1% vs 0.2%, respectively; P = 0.006), and another reported a significant increase in the risk of minor bleeding (4.1% vs 2.1%; P = 0.02). Conclusions: Fondaparinux has shown efficacy in the prevention of venous thromboembolism in patients undergoing hip or knee replacement surgery. Large-scale clinical trials of its potential efficacy in deep vein thrombosis and acute coronary syndromes are ongoing. Use of fondaparinux may be associated with an increased bleeding risk, and patients should be assessed individually to ensure that the possible benefits outweigh the risks. Routine use of fondaparinux as a replacement for low-molecular-weight heparin is not recommended at this time.

Regulation of sympathetic nervous system function after cardiovascular deconditioning.

Humans subjected to prolonged periods of bed rest or microgravity undergo deconditioning of the cardiovascular system, characterized by resting tachycardia, reduced exercise capability, and a predisposition for orthostatic intolerance. These changes in cardiovascular function are likely due to a combination of factors, including changes in control of body fluid balance or cardiac alterations resulting in inadequate maintenance of stroke volume, altered arterial or venous vascular function, reduced activation of cardiovascular hormones, and diminished autonomic reflex function. There is evidence indicating a role for each of these mechanisms. Diminished reflex activation of the sympathetic nervous system and subsequent vasoconstriction appear to play an important role. Studies utilizing the hindlimb-unloaded (HU) rat, an animal model of deconditioning, evaluated the potential role of altered arterial baroreflex control of the sympathetic nervous system. These studies indicate that HU results in blunted baroreflex-mediated activation of both renal and lumbar sympathetic nerve activity in response to a hypotensive stimulus. HU rats are less able to maintain arterial pressure during hemorrhage, suggesting that diminished ability to increase sympathetic activity has functional consequences for the animal. Reflex control of vasopressin secretion appears to be enhanced following HU. Blunted baroreflex-mediated sympathoexcitation appears to involve altered central nervous system function. Baroreceptor afferent activity in response to changes in arterial pressure is unaltered in HU rats. However, increases in efferent sympathetic nerve activity for a given decrease in afferent input are blunted after HU. This altered central nervous system processing of baroreceptor inputs appears to involve an effect at the rostral ventrolateral medulla (RVLM). Specifically, it appears that tonic GABAA-mediated inhibition of the RVLM is enhanced after HU. Augmented inhibition apparently arises from sources other than the caudal ventrolateral medulla. If similar alterations in control of the sympathetic nervous system occur in humans in response to cardiovascular deconditioning, it is likely that they play an important role in the observed tendency for orthostatic intolerance. Combined with potential changes in vascular function, cardiac function, and hypovolemia, the predisposition for orthostatic intolerance following cardiovascular deconditioning would be markedly enhanced by blunted ability to reflexly activate the sympathetic nervous system.

Development of Ulnar Neuropathy Not Limited to Perioperative Setting. Warner et al. (page 613)

In an attempt to determine the underlying causes of ulnar neuropathy, Warner et al. previously described 7 of 1502 prospectively studied surgical patients who reported onset of symptoms 2–7 days after their procedures. In the current issue, the team describes two patients from a prospective study of ulnar neuropathy in patients admitted to the hospital for nonsurgical conditions. Ulnar neuropathy was defined as current symptoms of paresthesia in the ulnar distribution, signs of abnormal two-point discrimination in the volar surface of the distal fifth digit, or weakness of the first dorsal interosseous and abductor digiti minimi muscles. Patients with current symptoms or preexisting ulnar neuropathy were excluded from the study.A specially trained research assistant performed a standardized daily baseline neurologic assessment of the upper extremities in all study participants while they were in the hospital. Those discharged before 7 days were interviewed by phone using a standardized questionnaire. Two of the study’s 986 patients had ulnar neuropathy. Patient 1 was a 55-yr-old man with a 6-month history of recurrent disseminated aspergillosis who was admitted for intravenous antifungal therapy, who experienced intermittent tingling in the fourth and fifth digits of his right hand on the third hospital day. By the fifth day, tingling had become constant and was accompanied by a burning dysesthesia when his elbow was flexed greater than 90°. His symptoms improved gradually and completely resolved over the next 6 months. Patient 2 was a 67-yr-old man with severe bronchiectasis admitted for treatment of recurrent Pseudomonas pneumonia with intravenous antibiotics and respiratory therapy, in whom developed tingling and aching in the fourth and fifth digits of his left hand on the fourth hospital day. By the sixth day, he also had symptoms in his right hand, which resolved within 2 weeks. Symptoms in his left hand, however, persisted for 8 months.The authors posit that factors common to medical and postoperative patients may contribute to the development of ulnar neuropathy. Specifically, male gender and prolonged periods of bed rest in the supine position seem to increase risk. When lying in a hospital bed, patients tend to bend their elbows and rest their hands on the upper abdomen or chest, thus increasing pressure on the ulnar nerve. Anatomic differences at the elbow, i.e. , larger tubercle of the coronoid process and less fatty tissue over the medial aspect, may explain why this condition is more likely to develop in men than in women.

Critical hemoglobin-oxygenation and PO2 of the skin

Prolonged mechanical loading can lead to breakdown of skin and underlying tissues which can, in turn, develop into a pressure ulcer. The benefits of pressure relief and/or redistribution to minimise risk have been well documented and these strategies can be provided by employing support mattresses in which internal air pressures can be alternated to minimise the risk of pressure ulcers in patients during prolonged periods of bed-rest. The paper describes the performance of a prototype alternating pressure air mattress (APAM), in terms of its ability to maintain skin viability in a group of healthy volunteers lying in a supine position. In particular, the mattress includes a sacral section supported with alternating low pressure (ALP), with values adjusted to subject morphology, using an in-built pressure sensor. The mattress was supported at four different head of bed (HOB) angles ranging from 0 to 60°. Internal mattress pressures and transcutaneous gas (TcPO2/TcPCO2) tensions at the sacrum and a control site, the scapula, were monitored. Interface pressures were also measured. The sensor was found to be sensitive to the BMI values of the 12 healthy volunteers. In the majority of test conditions the internal support produced sacral TcPO2 values, which either remained similar to those at the scapula or fluctuated at levels providing adequate viability. However in a few cases, associated with a raised HOB angle (≥45°), there was compromise to the skin viability at the sacrum, as reflected in depressed TcPO2 levels associated with an elevation of TcPCO2 levels above the normal range. In all cases, interface pressures at the sacrum rarely exceeded 60 mmHg. Although such studies need to be extended to involve bed-bound individuals, the results offer the potential for the development of intelligent APAM systems, whose characteristics can be adjusted to an individual morphology. Such preventive strategies to maintain skin viability at loaded sites will be designed for subjects deemed to be at high risk of developing pressure ulcers.

A 50-Year-Old Woman With Disabling Spinal Stenosis

Dr Delbanco: Miss W is a 50-year-old woman who has a long history of low back pain. Divorced, she lives in an apartment by herself and works as a medical technician in a community-based doctor's office. She is insured through a large not-for-profit managed care organization. At 4 years of age, Miss W fell off a horse, but she did not have subsequent problems until 18 years of age when she experienced low back pain. Since then, she has had intermittent pain and multiple therapeutic recommendations from chiropractors, orthopedists, and a neurosurgeon in addition to her primary care doctor. At times, she has been on prolonged periods of bed rest and has had to miss work. Approximately 8 years ago, Miss W developed symptoms of fibromyalgia with generalized pain focused on her knees, bunions, elbows, wrists, shoulders, and pelvic region. She has been treated with multiple nonsteroidal anti-inflammatory agents (NSAIDs),