Physiopathological mechanisms of diaphragmatic dysfunction associated with mechanical ventilation | Revista Española de Anestesiología y Reanimación (English Edition)

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Approximately 34% of patients requiring MV present weaning problems.<a class="elsevierStyleCrossRef" href="#bib0265">3</a> Use of MV for more than 7 days increases mortality by 12.1%.<a class="elsevierStyleCrossRef" href="#bib0270">4</a> Estimates suggest that costs associated with VM will total around $64 billion by 2020.<a class="elsevierStyleCrossRef" href="#bib0260">2</a> Ventilator-induced diaphragmatic dysfunction (VIDD) has a major clinical impact, given its early appearance (in the first 12–24h of controlled ventilation) and incidence (approximately 64%).<a class="elsevierStyleCrossRef" href="#bib0275">5</a>The term VIDD was first coined in 2004 by Theodoros Vassilakopoulos and Basil J. Petrof, who defined it as the loss of diaphragmatic force-generating capacity that is specifically related to the use of mechanical ventilation.<a class="elsevierStyleCrossRef" href="#bib0280">6</a> Demoule et al., among others, demonstrated that MV causes progressive diaphragm dysfunction, particularly in patients with critical conditions such as septic shock.<a class="elsevierStyleCrossRef" href="#bib0275">5</a> Ventilator-induce lung injury is traditionally attributed to 4 mechanisms: barotrauma, volutrauma, atelectrauma and biotrauma.<a class="elsevierStyleCrossRef" href="#bib0285">7</a> Of these, biotrauma is the form of injury most closely associated with VIDD. It is important to know the pathophysiological mechanisms that can trigger multiorgan failure due to VIDD in order to create preventive strategies that can reduce the risk of complications. The aim of this article is to describe the pathophysiological mechanisms of biotrauma and how it causes diaphragmatic dysfunction through various pathways that converge in proteolysis or reduced synthesis of muscle proteins, which is a histological sign of atrophy.<a class="elsevierStyleCrossRef" href="#bib0290">8</a>MethodsWe conducted a non-systematic narrative review of the literature in: Clinical Key, Pubmed and Google Scholar. The search terms used were: “Diaphragmatic Dysfunction”, “Mechanical Ventilation”, “Biotrauma”, “Proteolysis” and “Surface electromyography”. Search terms were used individually and then connected using “AND” and “OR”. The final combinations used in the search were “Diaphragmatic Dysfunction” AND “Mechanical Ventilation” AND “Biotrauma” AND “Proteolysis” AND “Surface electromyography”, OR “Diaphragmatic Dysfunction” AND “Mechanically Ventilation” AND “Biotrauma” AND “Surface electromyography”, OR “Diaphragmatic Dysfunction” AND “Mechanical Ventilation” AND “Proteolysis” AND “Surface electromyography”, OR “Diaphragmatic Dysfunction” AND “Mechanical Ventilation” AND “Surface electromyography”, OR “Mechanic Ventilation” AND “Proteolysis” AND “Surface electromyography”, OR “Diaphragmatic Dysfunction” AND “Proteolysis”, OR “Mechanic Ventilation” AND “Biotrauma”. As of 16 October 2019, 101 articles had been retrieved from Pubmed, 4209 from Google Scholar and 130 articles from Clinical Key.We then reviewed the titles and abstracts, selecting those that were original articles and addressed topics such as the pathophysiology of diaphragmatic dysfunction due to MV, associated factors, and the molecular cascades involved in this complication. Only articles published less than 9 years ago were selected.The search was extended by consulting the references of the articles identified in the initial search, and by using the “similar articles” option in Pubmed. We finally selected 50 articles, 13 of which were published prior to 2010 and contained important findings that are still relevant or introduced new terminology. These manuscripts were independently examined by each author, and the review was written, edited and corrected once the most relevant concepts had been agreed.Histological changes of diaphragmatic musculatureBiotrauma is a type of lung injury promoted by a complex biological response that involves the activation of inflammatory cytokines.<a class="elsevierStyleCrossRef" href="#bib0295">9</a> The mechanisms driving these proteolysis systems are not fully understood, but they are known to be activated by increased oxidative stress or decreased blood flow.<a class="elsevierStyleCrossRef" href="#bib0300">10</a> This cascade can cause lesions in lung regions that do not show mechanical damage, and cause extrapulmonary lesions that lead to multi-organ failure.<a class="elsevierStyleCrossRef" href="#bib0305">11</a>The diaphragm is a striated muscle with certain physiological characteristics that make it more sensitive than other skeletal muscles to events that generate oxidative stress. It contains a predominance of type i (slow oxidative) fatigue resistant fibres with high blood flow and mitochondrial volume density and multiple phrenic motoneurons, combined with type iib and iix glycolytic fibres which, though highly fatigable, allow the diaphragm to generate the force needed to support breathing during exercise or vital capacity for short periods.<a class="elsevierStyleCrossRef" href="#bib0310">12</a>The formation and differentiation of diaphragm fibres is closely related to the known mechanisms of muscular atrophy.<a class="elsevierStyleCrossRefs" href="#bib0290">8,12</a> Differentiation can occur even before innervation, and in some neuromuscular junctions formation occurs after birth. Initially, before being innervated, they resemble type I slow-twitch fibres, and acetylcholine receptors are embedded in the sarcolemma, being highly sensitive to neurotransmitters.<a class="elsevierStyleCrossRef" href="#bib0315">13</a>The end plate is formed when the first nerve ending connects to a muscle fibre, giving rise to further muscle fibres and nerve connections. Acetylcholine receptors are grouped in the muscle end plate membrane to facilitate this process.<a class="elsevierStyleCrossRef" href="#bib0315">13</a> Innervation causes changes at the muscle fibre level, such as the synthesis of myosin isoforms, and directly affects the type of muscle fibre that will be formed (type i, ii or ii). Cells that are innervated by small motor neurons will give rise to slow-twitch muscle fibres (type i), and cells innervated by large motor units will give rise to fast-twitch muscle fibres (type ii). The diaphragm contains a predominance of small motor units, and therefore type i muscle fibres.<a class="elsevierStyleCrossRef" href="#bib0315">13</a> The characterization of muscle fibres and their association with innervation have been related to the release of Ca++ at the sarcoplasmic level. Small motor units generate low intensity action potentials with prolonged calcium release, stimulating nuclear receptors that give rise to mRNA, which is associated with protein synthesis for type i slow-twitch fibres; more abrupt Ca++ release at higher action potential frequencies would give rise to type ii fibres. This calcium is now thought to cross the nuclear membrane and generate transcriptional and post-transcriptional changes in these proteins.<a class="elsevierStyleCrossRef" href="#bib0320">14</a>In addition to the differences already described, some proteins are fibre-dependent, as is the case with sarcolemma calcium channels (SERCA), the 3 subunits of troponin, tropomyosin and protein C. Different SERCA types determine the relaxation speed of slow and fast fibres (SERCA 1 and SERCA 2 in fast and slow fibres, respectively). SERCA 1 has greater activity than SERCA 2, and therefore its Ca++ reuptake to the sarcoplasmic reticulum is faster; this allows the fibres to relax faster. Troponin and tropomyosin isoforms determine Ca++ dependence of muscle contraction; slow diaphragmatic fibres require lower calcium concentrations to contract, and this is largely due to the fact that the troponin C isoform only has 1 low affinity binding site for C++, whereas the fast fibre isoform has 2.<a class="elsevierStyleCrossRef" href="#bib0320">14</a>Molecular signalling sequences that contribute to the development of diaphragmatic muscular atrophyHistologically, VIDD is characterized by muscular atrophy and decreased protein synthesis, with a decrease in the length-tension relationship.<a class="elsevierStyleCrossRef" href="#bib0325">15</a> Muscular atrophy occurs when the number of muscle sarcomeres is reduced due to muscle inactivity, cachexia diseases (diabetes, cancer, cardiovascular disease, kidney disease, sepsis, starvation, among others), fasting and age-related atrophy or sarcopenia. This reduces the cross-sectional area of the muscle fibre, reducing its strength and power, and increasing insulin resistance and muscle fatigue.<a class="elsevierStyleCrossRef" href="#bib0325">15</a>The complex molecular mechanisms that activate the proteolytic systems triggering muscle atrophy are shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>. Previous studies have described the role of ubiquitin ligases and caspase-3, decreased activity of the insulin-like growth factor/phosphoinositide 3-kinase/protein kinase B (IGF/PI3/AKT) pathway, the activity of Forkhead box O (FOXO) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signalling.<a class="elsevierStyleCrossRef" href="#bib0330">16</a> The IGF/PI3K/AKT pathway participates in the synthesis of proteins involved in muscle hypertrophy.<a class="elsevierStyleCrossRef" href="#bib0335">17</a> Specifically, AKT maintains the integrity and size of muscle fibres. IGF type 1 (IGF-1) is a powerful stimulator of mitogenic and growth effects, and therefore favours the growth of myofibrils and helps strengthen muscles during intense physical exercise.<a class="elsevierStyleCrossRef" href="#bib0335">17</a> PI3K, meanwhile, regulates intracellular functions, such as apoptosis, cell differentiation, metabolism, and growth, among others.<a class="elsevierStyleCrossRef" href="#bib0340">18</a> At the muscular level, the p85 subunit of PI3K, through interaction with IGF with activation of pyruvate dehydrogenase kinase, results in AKT/PKB phosphorylation, which facilitates protein synthesis by activating kinase P70 S6 (p70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), thus regulating skeletal muscle hypertrophy.<a class="elsevierStyleCrossRefs" href="#bib0335">17,18</a> Reduction in the activity of this pathway has been associated with the development of muscle atrophy through activation of caspase 3, expression of atrophy genes such as ubiquitin ligase atrogin-1, and reduction in protein synthesis by stimulating the activation of the translation inhibitor 4E-BP1.<a class="elsevierStyleCrossRefs" href="#bib0335">17,18</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Loss of PI3K/AKT pathway activity also activates the FOXO transcription factor, specifically, overexpression of FOXO3a and stimulation of atrogin-1, along with the aforementioned proteolytic transcription factors (ubiquitin ligases), which determine the rapid development of atrophy.<a class="elsevierStyleCrossRef" href="#bib0340">18</a> In 2010 Hussain et al. conducted a study to identify the role of the FOXO transcription factor in the activation of the autophagy-lysosome pathway (ALP) in response to MV. They took muscle biopsies of the diaphragm from ventilated patients and found that induction of the ALP pathway and the ubiquitin proteasome system responsible for degrading proteins at the cytosolic, nuclear, and myofibrillar level were closely related to increased expression of autophagy-related genes (atrogin-1 and MURF1) and an increase in protein oxidation, increased expression and phosphorylation of the FOXO1 gene, and inhibition of AKT expression.<a class="elsevierStyleCrossRef" href="#bib0345">19</a>Another type of ubiquitin involved in this process is the muscle RING-finger-2 (MuRF2) ubiquitin ligase, which is released in periods of mechanical inactivity and inhibits transcription by exporting the serum response factor from the nucleus to the myoplasm. MuRF2 also triggers protein degradation by binding to ubiquitin, and is involved in the inhibition of the PI3K transmission cascade.<a class="elsevierStyleCrossRef" href="#bib0315">13</a> Muscle RING-finger protein-1 (MuRF1), on the other hand, increases in the first 24h after muscle inactivity. This ligase inhibits muscle proteins, including titin, myotilin, myosin heavy chain and troponin, for subsequent degradation.<a class="elsevierStyleCrossRefs" href="#bib0350">20,21</a> Another factor implicated in muscle apoptosis is caspase-3, an endoprotease that is activated by reactive oxygen species, and can degrade the actin–myosin complex, which in turn triggers ubiquitin-proteasome activity.<a class="elsevierStyleCrossRef" href="#bib0360">22</a>Finally, NF-κB signalling, which is involved in the regulation of atrophy, is activated by cytokine tumour necrosis factor alpha (TNF-α<a class="elsevierStyleCrossRef" href="#bib0355">21</a>). TNF-α is an inflammatory cytokine that is produced during disease-related muscle wasting, and plays an important role in the development of atrophy in these conditions, since it is a potent activator of this pathway and has a catabolic effect.<a class="elsevierStyleCrossRef" href="#bib0355">21</a> At high concentrations, TNF-α is responsible for degrading myoproteins and inhibiting muscle differentiation. The catabolic effect of this cytokine is determined by NF-κB and the activation of p38 mitogen-activated protein kinase (p38MAPK), which enhance the activity of the ubiquitin-proteasome pathway.<a class="elsevierStyleCrossRef" href="#bib0365">23</a> TNF-α also promotes nuclear translocation of p65, a component of the NF-κB family, which increases expression of MuRF1.<a class="elsevierStyleCrossRef" href="#bib0370">24</a> Increased levels of this cytokine also enhance expression of atrogin-1 in response to the activation of p38MAPK.<a class="elsevierStyleCrossRef" href="#bib0365">23</a>Pathophysiological description of factors associated with diaphragmatic dysfunctionA consensus conference held in 1999 between the American Thoracic Society, the European Society of Intensive Care Medicine and the Société de Réanimation de Langue Française concluded that mechanical ventilation can cause lung damage, including histological damage at the alveolar level, interstitial and alveolar oedema, alveolar haemorrhage, neutrophilic alveolitis, diffuse alveolar injury and hyaline membranes, with proliferation of type II pneumocytes. Experts found that as injury and duration of mechanical ventilation progress there is profound remodelling of lung structure manifested as fibroproliferation, cyst formation, and local emphysema.<a class="elsevierStyleCrossRef" href="#bib0375">25</a> Other deleterious effects found were changes in muscular strength, ventilatory mechanics and patient-ventilator asynchrony.<a class="elsevierStyleCrossRef" href="#bib0380">26</a><a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a> shows the factors that have been associated with diaphragmatic dysfunction, such as age, duration and type of ventilation, the nutritional and metabolic status of the patient, some comorbidities, and the use of various drugs.<a class="elsevierStyleCrossRefs" href="#bib0385">27,28</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>AgeSarcopenia is the term used to describe age-related loss of muscle mass and strength.<a class="elsevierStyleCrossRef" href="#bib0395">29</a> Between the ages of 40 and 70, 8% of muscle mass is lost for each decade; this increases to 15% per decade after the age of 70. In physiological ageing, approximately 20–30% of muscle mass is lost (between 0.5% and 1.0% per year).<a class="elsevierStyleCrossRef" href="#bib0390">28</a> One of the main characteristics of sarcopenia in the diaphragm muscle is selective atrophy and the loss of type ii x or ii b muscle fibres, which generate greater strength and are therefore more susceptible to injury.<a class="elsevierStyleCrossRef" href="#bib0400">30</a> This is accompanied by a 15% increase in the fatigue index and a 30% decrease in muscle strength.<a class="elsevierStyleCrossRef" href="#bib0405">31</a>Studies carried out to evaluate the effects of sarcopenia on diaphragm function have shown that maximum transdiaphragmatic pressure generated by the Mueller manoeuvre was 13% and 25% lower in individuals aged between 65 and 83.<a class="elsevierStyleCrossRef" href="#bib0405">31</a> Other authors also showed that expulsive manoeuvres that require greater muscle strength, such as sneezing or coughing, are affected by muscle loss, and could underlie the increased susceptibility of older individuals to respiratory tract infections.<a class="elsevierStyleCrossRef" href="#bib0395">29</a> There is evidence that loss of strength in the respiratory muscles is accompanied by a 0.8–2.7cmH2O/year decrease in peak inspiratory pressure between the ages of 65 and 85.<a class="elsevierStyleCrossRef" href="#bib0410">32</a>Some authors have suggested that a process of muscle fibre remodelling occurs with age, in which fast-twitch myosin fibres are replaced by slow-twitch isoforms. This has been associated with changes in the discharge frequencies of action potentials and denervation in sarcopenic muscle fibres of the diaphragm muscle.<a class="elsevierStyleCrossRefs" href="#bib0395">29,30</a>Various factors are involved in the development of sarcopenia,<a class="elsevierStyleCrossRef" href="#bib0415">33</a> including alterations in protein synthesis and degradation, inflammation, hormonal alterations, and mitochondrial dysfunction. Most of these are related to an increase in oxidative stress,<a class="elsevierStyleCrossRef" href="#bib0415">33</a> which is consistent with the hypothesis that free radicals are involved in ageing, proposed by Denham Harman in 1956.<a class="elsevierStyleCrossRef" href="#bib0420">34</a> Regarding mitochondrial dysfunction and its association with ageing, studies have found mutations and reductions in mitochondrial DNA, signalling abnormalities in apoptosis pathways, decreased activity of the electron transport chain, and increased mitochondrial production of free radicals.<a class="elsevierStyleCrossRef" href="#bib0415">33</a> The mechanism behind all these alterations remains unclear, but peroxisome proliferator-activated receptor gamma coactivator 1-alpha is thought to play a key role in age-related reduction of mitochondriogenesis.<a class="elsevierStyleCrossRef" href="#bib0415">33</a> Interleukins (IL) involved in muscle dysfunction (IL-1, IL-6) also increase with age, together with TNF-α, which binds to sarcolemma receptors by stimulating free radical synthesis. NF-κB is also elevated, and chronic activation of this complex is one of the most important factors in the loss of muscle mass.<a class="elsevierStyleCrossRef" href="#bib0415">33</a>Reduced levels of anabolic hormones, particularly testosterone and oestrogen, have considerable effect on muscle mass.<a class="elsevierStyleCrossRef" href="#bib0425">35</a> Decreased testosterone levels are associated with loss of muscle mass and strength in both men and women; oestrogen deficiency in women during menopause has similar effects. A reduction in the IL-1 and IL-6-inhibitory action of these two hormones allows inflammatory interleukins to cause muscle damage.<a class="elsevierStyleCrossRefs" href="#bib0415">33,35</a>Duration and type of mechanical ventilationThe most widely used ventilation mode is assist-control (71.6%), followed by synchronized intermittent-mandatory ventilation with pressure support (6.5%).<a class="elsevierStyleCrossRef" href="#bib0430">36</a> The mode and duration of MV are decisive factors in the appearance of diaphragm dysfunction. MV can cause atrophy and diaphragm weakness if the pressure and flow administered are excessively high,<a class="elsevierStyleCrossRef" href="#bib0380">26</a> while studies have shown that in some patients disuse atrophy reduces diaphragmatic thickness by 6% per day on average.<a class="elsevierStyleCrossRef" href="#bib0435">37</a>Evidence indicates that calpain and proteasome activity increases, and with it diaphragm protein degradation, after 12h of assist-control MV.<a class="elsevierStyleCrossRef" href="#bib0360">22</a> Insulin-like growth factor type i (IFG-I) and myogenic differentiation protein 1 (MyoD) are involved in the regulation, production and transcription of contractile proteins.<a class="elsevierStyleCrossRef" href="#bib0440">38</a> After 18–24h of assist-control MV or diaphragm passivity, IFG-I and MyoD activity is reduced; oxidative stress and protease activity increases and diaphragm fibre cross-section decreases after 18h of assist-control VM.<a class="elsevierStyleCrossRef" href="#bib0440">38</a> The mechanism most closely associated with atrophy is increased proteolysis<a class="elsevierStyleCrossRef" href="#bib0345">19</a>; animal studies have also shown a decrease in protein synthesis, particularly myosin heavy chain protein synthesis.<a class="elsevierStyleCrossRef" href="#bib0445">39</a> Another problem associated with VM is the loss of electrical activity in the diaphragm.<a class="elsevierStyleCrossRef" href="#bib0450">40</a> This causes problems in the transcription of myogenic regulatory factors, which leads to changes in muscle fibre types.<a class="elsevierStyleCrossRef" href="#bib0450">40</a>Nutritional and metabolic statusEvidence has shown that between 30% and 60% of hospitalized patients are malnourished; this percentage is even higher in critically ill patients. Muscle loss is accelerated during anorexia, could even reach 1% per day.<a class="elsevierStyleCrossRef" href="#bib0390">28</a> Metabolic disturbances lead to higher energy expenditure, nutrient deficits, and decreased absorption or availability of these nutrients during illness.<a class="elsevierStyleCrossRef" href="#bib0455">41</a> Hypermetabolic states are associated with an increase in catabolic hormones (glucagon, adrenaline, and cortisol) and cytokines,<a class="elsevierStyleCrossRef" href="#bib0460">42</a> together with inhibition of anabolic hormones (insulin and testosterone). Prolonging the catabolic state reduces muscle mass, muscle strength and the immune response, increasing susceptibility to serious infections and failure of vital organs.<a class="elsevierStyleCrossRef" href="#bib0460">42</a>Hormonal imbalance has been closely associated with the appearance of hyperglycaemia of over 150mg/dl.<a class="elsevierStyleCrossRef" href="#bib0465">43</a> Hyperglycaemia due to insulin resistance is common in critically ill patients, even those with no history of diabetes mellitus, and is a negative prognosis factor in the short, medium, and long term.<a class="elsevierStyleCrossRef" href="#bib0470">44</a> Hyperglycaemia promotes the storage of lipids in the form of triglycerides and low-density lipoproteins.<a class="elsevierStyleCrossRef" href="#bib0470">44</a> Additionally, acute phase proteins associated with injury, inflammation or sepsis reduce plasma cholesterol due to a reduction in high-density lipoproteins, and worsen the metabolic status of these patients. Changes also occur in the protein and lipid composition of lipoproteins, increasing their atherogenic and inflammatory properties.<a class="elsevierStyleCrossRef" href="#bib0470">44</a> Less use of lipid substrates as an energy source triggers proteolysis, leading to loss of muscle mass, increased risk of infection, multi-organ failure and, in the worst case, death.<a class="elsevierStyleCrossRef" href="#bib0470">44</a>ComorbiditiesThe most frequent comorbidities in patients requiring MV are diabetes mellitus, sepsis, hypertension, and acute myocardial infarction. Other complications that may be present during ventilation are: acute respiratory distress syndrome, ventilator-associated pneumonia, sepsis, cardiogenic shock, acute kidney failure, liver failure, multifactorial coagulopathy, burns, respiratory acidosis, and metabolic acidosis.<a class="elsevierStyleCrossRefs" href="#bib0360">22,42,45</a> Several of these syndromes or pathologies can promote diaphragm dysfunction due to changes protein metabolism.<a class="elsevierStyleCrossRef" href="#bib0475">45</a> In sepsis, the systemic inflammatory response syndrome increases proinflammatory cytokines (TNF-α, IL-6, IL-1, IL-1 β), nitric oxide, and free radicals, which promote the activity of proteolytic pathways; therefore, inhibition of these pathways is expected to alter the course and progression of septic myopathy and could reduce the risk of muscle weakness.<a class="elsevierStyleCrossRef" href="#bib0480">46</a> IL-1 β reduces phosphorylation of eukaryotic translation initiation factor 4 gamma (eIF4G), altering the translation of sarcoplasmic and myofibrillar proteins in fast-twitch muscles.<a class="elsevierStyleCrossRef" href="#bib0485">47</a>Drugs and their association with diaphragmatic dysfunctionGlucocorticoids (GC) exacerbate metabolic abnormalities induced by acute critical illness, and at high doses generate neuromuscular disorders that produce peripheral and respiratory muscle dysfunction.<a class="elsevierStyleCrossRef" href="#bib0490">48</a>The use of GC is associated with muscular dysfunction due to the inhibition of anabolism and protein catabolism. Anabolism inhibition in turn inhibits protein synthesis by various mechanisms, including inhibition of amino acid transport in muscles and inhibition of the stimulatory action of insulin and IGF-1 on the phosphorylation of F4G-binding protein 1 and ribosomal protein kinase S6, which determine mRNA translation.<a class="elsevierStyleCrossRef" href="#bib0495">49</a> Myogenesis is also affected by the down-regulation of myogenin, an essential transcription factor in the differentiation of satellite cells into muscle fibres.<a class="elsevierStyleCrossRefs" href="#bib0490">48,49</a> Evidence has shown that intracellular mediators associated with muscle wasting, such as FOXO, GSK3β, C/EBPb, p300, REDD1 and ATF4, are elevated by excess GC, while the phosphorylation of S6K1 and 4E-BP1 is reduced.<a class="elsevierStyleCrossRefs" href="#bib0490">48,49</a>Another group of drugs responsible for stimulating atrophy due to inactivity and muscle disuse are neuromuscular blockers (NMB), which decrease cellular excitation, causing alterations in neurotransmission.<a class="elsevierStyleCrossRef" href="#bib0500">50</a> Long-term use of NMBs in conjunction with steroids and prolonged immobilization promotes muscle weakness and, in some cases, acute necrotizing myopathy. This type of myopathy has a long clinical course and disabling sequelae.<a class="elsevierStyleCrossRef" href="#bib0500">50</a>ConclusionsBiotrauma is an inflammatory reaction of the respiratory muscles. The main molecular pathways involved in this lesion are based on increased levels of ubiquitin ligases and caspase-3. These promote muscle atrophy and wasting due to activation of the ALP pathway, reduction of the IGF/PI3K/AKT pathway responsible for maintaining muscle integrity, FOXO overexpression, which promotes the rapid development of atrophy, and NF-kappa B signalling, which activates TNF-α. Proinflammatory cytokines such as TNF-α can translocate one of the components of NF-kB (p65) and activate p38MAPK. This process ultimately inhibits cell differentiation, myoprotein degradation, and increased expression of atrophic genes, such as MuRF1 and atrogin 1.Some conditions can hasten activation of these pathways; age, type and duration of MV, the patient's nutritional and metabolic status, the presence of comorbidities, particularly sepsis, and the use of drugs such as glucocorticoids and neuromuscular blockers. All these molecular alterations or conditions increase the risk of weaning failure, and this raises the need for further investigation into strategies that can reduce their impact on diaphragmatic dysfunction.FundingThis study has not received any funding.Conflicts of interestThe authors have no conflict of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres1330891" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1226237" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1330890" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1226236" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Histological changes of diaphragmatic musculature" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Molecular signalling sequences that contribute to the development of diaphragmatic muscular atrophy" ] 8 => array:3 [ "identificador" => "sec0025" "titulo" => "Pathophysiological description of factors associated with diaphragmatic dysfunction" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Age" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Duration and type of mechanical ventilation" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Nutritional and metabolic status" ] 3 => array:2 [ "identificador" => "sec0045" "titulo" => "Comorbidities" ] 4 => array:2 [ "identificador" => "sec0050" "titulo" => "Drugs and their association with diaphragmatic dysfunction" ] ] ] 9 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0060" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflicts of interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-07-22" "fechaAceptado" => "2019-12-16" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1226237" "palabras" => array:5 [ 0 => "Diaphragm dysfunction" 1 => "Mechanically ventilated" 2 => "Biotrauma" 3 => "Risk factors" 4 => "Proteolysis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1226236" "palabras" => array:5 [ 0 => "Ventilación mecánica" 1 => "Disfunción diafragmática" 2 => "Biotrauma" 3 => "Factores de riego" 4 => "Proteólisis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Ventilator-induced diaphragm dysfunction (VIDD) is the loss of diaphragmatic muscle strength related to of mechanical ventilation, noticed during the first day or 48h after initiating controlled mechanical ventilation. This alteration has been related to disruption on the insulin growth factor/phosphoinositol 3-kinase/kinase B protein pathway (IGF/PI3K/AKT), in addition to an overexpression of FOXO, expression of NF-kB signalling, increase function of muscular ubiquitin ligase and activation of caspasa-3. VIDD has a negative impact on quality of life, duration of mechanical ventilation, and hospitalization stance and cost. More studies are necessary to understated the process and impact of VIDD. This is a narrative review of non-systematic literature, aiming to explain the molecular pathways involved in VIDD." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La disfunción diafragmática inducida por ventilación mecánica (DDVI) es la pérdida de la fuerza diafragmática relacionada al uso de ventilación mecánica y se observa con frecuencia en las primeras 24 a 48 h de asistencia ventilatoria controlada. La evidencia reciente relaciona esa pérdida de función diafragmática con alteraciones de la vía del factor de crecimiento insulínico/fosfoinositol 3-cinasas/proteína cinasa B (IGF/PI3K/AKT), sobreexpresión de FOXO, señalización NF-kB, mayor función de ligasas de ubiquitina muscular y activación de la caspasa-3. La DDVI tiene un impacto negativo en los días de ventilación mecánica, la retirada de la asistencia ventilatoria, la calidad de vida y los costos hospitalarios. Es importante realizar nuevos estudios encaminados a mitigar la aparición o incidencia de esta lesión. Esta es una revisión narrativa de la literatura no sistemática, tiene por objetivo explicar con detalle las vías moleculares implicadas en el desarrollo de la disfunción diafragmática asociada al soporte ventilatorio." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Molina Peña ME, Sánchez CM, Rodríguez-Triviño CY. Mecanismos fisiopatológicos de la disfunción diafragmática asociada a ventilación mecánica. Rev Esp Anestesiol Reanim. 2020;67:195–203." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2005 "Ancho" => 2925 "Tamanyo" => 292783 ] ] "descripcion" => array:1 [ "en" => "Pathophysiological and molecular mechanisms involved in ventilator-induced diaphragmatic dysfunction." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1744 "Ancho" => 2925 "Tamanyo" => 252938 ] ] "descripcion" => array:1 [ "en" => "Clinical factors associated with ventilator-induced diaphragmatic dysfunction." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:50 [ 0 => array:3 [ "identificador" => "bib0255" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The epidemiology of mechanical ventilation use in the United States" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "H. 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Physiopathological mechanisms of diaphragmatic dysfunction associated with mechanical ventilation

Mecanismos fisiopatológicos de la disfunción diafragmática asociada a ventilación mecánica

M.E. Molina Peñaa,

Corresponding author

maria.molina@uninavarra.edu.co

Corresponding author.

, C.M. Sáncheza, C.Y. Rodríguez-Triviñob,c

a Semillero de Fisiología Práctica aplicada, Grupo Navarra Medicina, Departamento de Ciencias Fisiológicas, Facultad de Ciencias de la Salud, Fundación Universitaria Navarra-UNINAVARRA, Neiva, Huila, Colombia

b Grupo Navarra Medicina, Departamento de Ciencias Fisiológicas, Facultad de Ciencias de la Salud, Fundación Universitaria Navarra-UNINAVARRA, Neiva, Huila, Colombia

c Grupo Cuidar, Facultad de Ciencias de la Salud, Universidad Surcolombiana, Neiva, Huila, Colombia

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Mechanical ventilation &#40;MV&#41; contributes to the survival of almost 60&#37; of patients who require it for more than 12<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">1</span></a> The use of MV increased by 56&#37; between 1997 and 2011&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">2</span></a> Despite its benefits&#44; MV can directly cause pulmonary and systemic complications&#46; Approximately 34&#37; of patients requiring MV present weaning problems&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">3</span></a> Use of MV for more than 7 days increases mortality by 12&#46;1&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">4</span></a> Estimates suggest that costs associated with VM will total around &#36;64 billion by 2020&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">2</span></a> Ventilator-induced diaphragmatic dysfunction &#40;VIDD&#41; has a major clinical impact&#44; given its early appearance &#40;in the first 12&#8211;24<span class="elsevierStyleHsp" style=""></span>h of controlled ventilation&#41; and incidence &#40;approximately 64&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The term VIDD was first coined in 2004 by Theodoros Vassilakopoulos and Basil J&#46; Petrof&#44; who defined it as the loss of diaphragmatic force-generating capacity that is specifically related to the use of mechanical ventilation&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">6</span></a> Demoule et al&#46;&#44; among others&#44; demonstrated that MV causes progressive diaphragm dysfunction&#44; particularly in patients with critical conditions such as septic shock&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">5</span></a> Ventilator-induce lung injury is traditionally attributed to 4 mechanisms&#58; barotrauma&#44; volutrauma&#44; atelectrauma and biotrauma&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a> Of these&#44; biotrauma is the form of injury most closely associated with VIDD&#46; It is important to know the pathophysiological mechanisms that can trigger multiorgan failure due to VIDD in order to create preventive strategies that can reduce the risk of complications&#46; The aim of this article is to describe the pathophysiological mechanisms of biotrauma and how it causes diaphragmatic dysfunction through various pathways that converge in proteolysis or reduced synthesis of muscle proteins&#44; which is a histological sign of atrophy&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methods</span><p id="par0015" class="elsevierStylePara elsevierViewall">We conducted a non-systematic narrative review of the literature in&#58; Clinical Key&#44; Pubmed and Google Scholar&#46; The search terms used were&#58; &#8220;Diaphragmatic Dysfunction&#8221;&#44; &#8220;Mechanical Ventilation&#8221;&#44; &#8220;Biotrauma&#8221;&#44; &#8220;Proteolysis&#8221; and &#8220;Surface electromyography&#8221;&#46; Search terms were used individually and then connected using &#8220;AND&#8221; and &#8220;OR&#8221;&#46; The final combinations used in the search were &#8220;Diaphragmatic Dysfunction&#8221; AND &#8220;Mechanical Ventilation&#8221; AND &#8220;Biotrauma&#8221; AND &#8220;Proteolysis&#8221; AND &#8220;Surface electromyography&#8221;&#44; OR &#8220;Diaphragmatic Dysfunction&#8221; AND &#8220;Mechanically Ventilation&#8221; AND &#8220;Biotrauma&#8221; AND &#8220;Surface electromyography&#8221;&#44; OR &#8220;Diaphragmatic Dysfunction&#8221; AND &#8220;Mechanical Ventilation&#8221; AND &#8220;Proteolysis&#8221; AND &#8220;Surface electromyography&#8221;&#44; OR &#8220;Diaphragmatic Dysfunction&#8221; AND &#8220;Mechanical Ventilation&#8221; AND &#8220;Surface electromyography&#8221;&#44; OR &#8220;Mechanic Ventilation&#8221; AND &#8220;Proteolysis&#8221; AND &#8220;Surface electromyography&#8221;&#44; OR &#8220;Diaphragmatic Dysfunction&#8221; AND &#8220;Proteolysis&#8221;&#44; OR &#8220;Mechanic Ventilation&#8221; AND &#8220;Biotrauma&#8221;&#46; As of 16 October 2019&#44; 101 articles had been retrieved from Pubmed&#44; 4209 from Google Scholar and 130 articles from Clinical Key&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">We then reviewed the titles and abstracts&#44; selecting those that were original articles and addressed topics such as the pathophysiology of diaphragmatic dysfunction due to MV&#44; associated factors&#44; and the molecular cascades involved in this complication&#46; Only articles published less than 9 years ago were selected&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The search was extended by consulting the references of the articles identified in the initial search&#44; and by using the &#8220;similar articles&#8221; option in Pubmed&#46; We finally selected 50 articles&#44; 13 of which were published prior to 2010 and contained important findings that are still relevant or introduced new terminology&#46; These manuscripts were independently examined by each author&#44; and the review was written&#44; edited and corrected once the most relevant concepts had been agreed&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Histological changes of diaphragmatic musculature</span><p id="par0030" class="elsevierStylePara elsevierViewall">Biotrauma is a type of lung injury promoted by a complex biological response that involves the activation of inflammatory cytokines&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">9</span></a> The mechanisms driving these proteolysis systems are not fully understood&#44; but they are known to be activated by increased oxidative stress or decreased blood flow&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">10</span></a> This cascade can cause lesions in lung regions that do not show mechanical damage&#44; and cause extrapulmonary lesions that lead to multi-organ failure&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">11</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The diaphragm is a striated muscle with certain physiological characteristics that make it more sensitive than other skeletal muscles to events that generate oxidative stress&#46; It contains a predominance of type <span class="elsevierStyleSmallCaps">i</span> &#40;slow oxidative&#41; fatigue resistant fibres with high blood flow and mitochondrial volume density and multiple phrenic motoneurons&#44; combined with type <span class="elsevierStyleSmallCaps">ii</span>b and <span class="elsevierStyleSmallCaps">ii</span>x glycolytic fibres which&#44; though highly fatigable&#44; allow the diaphragm to generate the force needed to support breathing during exercise or vital capacity for short periods&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">12</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The formation and differentiation of diaphragm fibres is closely related to the known mechanisms of muscular atrophy&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">8&#44;12</span></a> Differentiation can occur even before innervation&#44; and in some neuromuscular junctions formation occurs after birth&#46; Initially&#44; before being innervated&#44; they resemble type <span class="elsevierStyleSmallCaps">I</span> slow-twitch fibres&#44; and acetylcholine receptors are embedded in the sarcolemma&#44; being highly sensitive to neurotransmitters&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">13</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The end plate is formed when the first nerve ending connects to a muscle fibre&#44; giving rise to further muscle fibres and nerve connections&#46; Acetylcholine receptors are grouped in the muscle end plate membrane to facilitate this process&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">13</span></a> Innervation causes changes at the muscle fibre level&#44; such as the synthesis of myosin isoforms&#44; and directly affects the type of muscle fibre that will be formed &#40;type <span class="elsevierStyleSmallCaps">i</span>&#44; <span class="elsevierStyleSmallCaps">ii</span> or <span class="elsevierStyleSmallCaps">ii</span>&#41;&#46; Cells that are innervated by small motor neurons will give rise to slow-twitch muscle fibres &#40;type <span class="elsevierStyleSmallCaps">i</span>&#41;&#44; and cells innervated by large motor units will give rise to fast-twitch muscle fibres &#40;type <span class="elsevierStyleSmallCaps">ii</span>&#41;&#46; The diaphragm contains a predominance of small motor units&#44; and therefore type <span class="elsevierStyleSmallCaps">i</span> muscle fibres&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">13</span></a> The characterization of muscle fibres and their association with innervation have been related to the release of Ca<span class="elsevierStyleSup">&#43;&#43;</span> at the sarcoplasmic level&#46; Small motor units generate low intensity action potentials with prolonged calcium release&#44; stimulating nuclear receptors that give rise to mRNA&#44; which is associated with protein synthesis for type <span class="elsevierStyleSmallCaps">i</span> slow-twitch fibres&#59; more abrupt Ca<span class="elsevierStyleSup">&#43;&#43;</span> release at higher action potential frequencies would give rise to type <span class="elsevierStyleSmallCaps">ii</span> fibres&#46; This calcium is now thought to cross the nuclear membrane and generate transcriptional and post-transcriptional changes in these proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">14</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In addition to the differences already described&#44; some proteins are fibre-dependent&#44; as is the case with sarcolemma calcium channels &#40;SERCA&#41;&#44; the 3 subunits of troponin&#44; tropomyosin and protein C&#46; Different SERCA types determine the relaxation speed of slow and fast fibres &#40;SERCA 1 and SERCA 2 in fast and slow fibres&#44; respectively&#41;&#46; SERCA 1 has greater activity than SERCA 2&#44; and therefore its Ca<span class="elsevierStyleSup">&#43;&#43;</span> reuptake to the sarcoplasmic reticulum is faster&#59; this allows the fibres to relax faster&#46; Troponin and tropomyosin isoforms determine Ca<span class="elsevierStyleSup">&#43;&#43;</span> dependence of muscle contraction&#59; slow diaphragmatic fibres require lower calcium concentrations to contract&#44; and this is largely due to the fact that the troponin C isoform only has 1 low affinity binding site for C<span class="elsevierStyleSup">&#43;&#43;</span>&#44; whereas the fast fibre isoform has 2&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Molecular signalling sequences that contribute to the development of diaphragmatic muscular atrophy</span><p id="par0055" class="elsevierStylePara elsevierViewall">Histologically&#44; VIDD is characterized by muscular atrophy and decreased protein synthesis&#44; with a decrease in the length-tension relationship&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">15</span></a> Muscular atrophy occurs when the number of muscle sarcomeres is reduced due to muscle inactivity&#44; cachexia diseases &#40;diabetes&#44; cancer&#44; cardiovascular disease&#44; kidney disease&#44; sepsis&#44; starvation&#44; among others&#41;&#44; fasting and age-related atrophy or sarcopenia&#46; This reduces the cross-sectional area of the muscle fibre&#44; reducing its strength and power&#44; and increasing insulin resistance and muscle fatigue&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">15</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The complex molecular mechanisms that activate the proteolytic systems triggering muscle atrophy are shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46; Previous studies have described the role of ubiquitin ligases and caspase-3&#44; decreased activity of the insulin-like growth factor&#47;phosphoinositide 3-kinase&#47;protein kinase B &#40;IGF&#47;PI3&#47;AKT&#41; pathway&#44; the activity of Forkhead box O &#40;FOXO&#41; and nuclear factor kappa-light-chain-enhancer of activated B cells &#40;NF-kB&#41; signalling&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">16</span></a> The IGF&#47;PI3K&#47;AKT pathway participates in the synthesis of proteins involved in muscle hypertrophy&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">17</span></a> Specifically&#44; AKT maintains the integrity and size of muscle fibres&#46; IGF type 1 &#40;IGF-1&#41; is a powerful stimulator of mitogenic and growth effects&#44; and therefore favours the growth of myofibrils and helps strengthen muscles during intense physical exercise&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">17</span></a> PI3K&#44; meanwhile&#44; regulates intracellular functions&#44; such as apoptosis&#44; cell differentiation&#44; metabolism&#44; and growth&#44; among others&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">18</span></a> At the muscular level&#44; the p85 subunit of PI3K&#44; through interaction with IGF with activation of pyruvate dehydrogenase kinase&#44; results in AKT&#47;PKB phosphorylation&#44; which facilitates protein synthesis by activating kinase P70 S6 &#40;p70S6K&#41; and eukaryotic translation initiation factor 4E-binding protein 1 &#40;4E-BP1&#41;&#44; thus regulating skeletal muscle hypertrophy&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">17&#44;18</span></a> Reduction in the activity of this pathway has been associated with the development of muscle atrophy through activation of caspase 3&#44; expression of atrophy genes such as ubiquitin ligase atrogin-1&#44; and reduction in protein synthesis by stimulating the activation of the translation inhibitor 4E-BP1&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">17&#44;18</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Loss of PI3K&#47;AKT pathway activity also activates the FOXO transcription factor&#44; specifically&#44; overexpression of FOXO3a and stimulation of atrogin-1&#44; along with the aforementioned proteolytic transcription factors &#40;ubiquitin ligases&#41;&#44; which determine the rapid development of atrophy&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">18</span></a> In 2010 Hussain et al&#46; conducted a study to identify the role of the FOXO transcription factor in the activation of the autophagy-lysosome pathway &#40;ALP&#41; in response to MV&#46; They took muscle biopsies of the diaphragm from ventilated patients and found that induction of the ALP pathway and the ubiquitin proteasome system responsible for degrading proteins at the cytosolic&#44; nuclear&#44; and myofibrillar level were closely related to increased expression of autophagy-related genes &#40;atrogin-1 and MURF1&#41; and an increase in protein oxidation&#44; increased expression and phosphorylation of the FOXO1 gene&#44; and inhibition of AKT expression&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">19</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Another type of ubiquitin involved in this process is the muscle RING-finger-2 &#40;MuRF2&#41; ubiquitin ligase&#44; which is released in periods of mechanical inactivity and inhibits transcription by exporting the serum response factor from the nucleus to the myoplasm&#46; MuRF2 also triggers protein degradation by binding to ubiquitin&#44; and is involved in the inhibition of the PI3K transmission cascade&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">13</span></a> Muscle RING-finger protein-1 &#40;MuRF1&#41;&#44; on the other hand&#44; increases in the first 24<span class="elsevierStyleHsp" style=""></span>h after muscle inactivity&#46; This ligase inhibits muscle proteins&#44; including titin&#44; myotilin&#44; myosin heavy chain and troponin&#44; for subsequent degradation&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">20&#44;21</span></a> Another factor implicated in muscle apoptosis is caspase-3&#44; an endoprotease that is activated by reactive oxygen species&#44; and can degrade the actin&#8211;myosin complex&#44; which in turn triggers ubiquitin-proteasome activity&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">22</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Finally&#44; NF-&#954;B signalling&#44; which is involved in the regulation of atrophy&#44; is activated by cytokine tumour necrosis factor alpha &#40;TNF-&#945;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">21</span></a>&#41;&#46; TNF-&#945; is an inflammatory cytokine that is produced during disease-related muscle wasting&#44; and plays an important role in the development of atrophy in these conditions&#44; since it is a potent activator of this pathway and has a catabolic effect&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">21</span></a> At high concentrations&#44; TNF-&#945; is responsible for degrading myoproteins and inhibiting muscle differentiation&#46; The catabolic effect of this cytokine is determined by NF-&#954;B and the activation of p38 mitogen-activated protein kinase &#40;p38MAPK&#41;&#44; which enhance the activity of the ubiquitin-proteasome pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">23</span></a> TNF-&#945; also promotes nuclear translocation of p65&#44; a component of the NF-&#954;B family&#44; which increases expression of MuRF1&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">24</span></a> Increased levels of this cytokine also enhance expression of atrogin-1 in response to the activation of p38MAPK&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Pathophysiological description of factors associated with diaphragmatic dysfunction</span><p id="par0080" class="elsevierStylePara elsevierViewall">A consensus conference held in 1999 between the American Thoracic Society&#44; the European Society of Intensive Care Medicine and the Soci&#233;t&#233; de R&#233;animation de Langue Fran&#231;aise concluded that mechanical ventilation can cause lung damage&#44; including histological damage at the alveolar level&#44; interstitial and alveolar oedema&#44; alveolar haemorrhage&#44; neutrophilic alveolitis&#44; diffuse alveolar injury and hyaline membranes&#44; with proliferation of type <span class="elsevierStyleSmallCaps">II</span> pneumocytes&#46; Experts found that as injury and duration of mechanical ventilation progress there is profound remodelling of lung structure manifested as fibroproliferation&#44; cyst formation&#44; and local emphysema&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">25</span></a> Other deleterious effects found were changes in muscular strength&#44; ventilatory mechanics and patient-ventilator asynchrony&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">26</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a> shows the factors that have been associated with diaphragmatic dysfunction&#44; such as age&#44; duration and type of ventilation&#44; the nutritional and metabolic status of the patient&#44; some comorbidities&#44; and the use of various drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">27&#44;28</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Age</span><p id="par0090" class="elsevierStylePara elsevierViewall">Sarcopenia is the term used to describe age-related loss of muscle mass and strength&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">29</span></a> Between the ages of 40 and 70&#44; 8&#37; of muscle mass is lost for each decade&#59; this increases to 15&#37; per decade after the age of 70&#46; In physiological ageing&#44; approximately 20&#8211;30&#37; of muscle mass is lost &#40;between 0&#46;5&#37; and 1&#46;0&#37; per year&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">28</span></a> One of the main characteristics of sarcopenia in the diaphragm muscle is selective atrophy and the loss of type <span class="elsevierStyleSmallCaps">ii</span> x or <span class="elsevierStyleSmallCaps">ii</span> b muscle fibres&#44; which generate greater strength and are therefore more susceptible to injury&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">30</span></a> This is accompanied by a 15&#37; increase in the fatigue index and a 30&#37; decrease in muscle strength&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">31</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Studies carried out to evaluate the effects of sarcopenia on diaphragm function have shown that maximum transdiaphragmatic pressure generated by the Mueller manoeuvre was 13&#37; and 25&#37; lower in individuals aged between 65 and 83&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">31</span></a> Other authors also showed that expulsive manoeuvres that require greater muscle strength&#44; such as sneezing or coughing&#44; are affected by muscle loss&#44; and could underlie the increased susceptibility of older individuals to respiratory tract infections&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">29</span></a> There is evidence that loss of strength in the respiratory muscles is accompanied by a 0&#46;8&#8211;2&#46;7<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O&#47;year decrease in peak inspiratory pressure between the ages of 65 and 85&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">32</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Some authors have suggested that a process of muscle fibre remodelling occurs with age&#44; in which fast-twitch myosin fibres are replaced by slow-twitch isoforms&#46; This has been associated with changes in the discharge frequencies of action potentials and denervation in sarcopenic muscle fibres of the diaphragm muscle&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">29&#44;30</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Various factors are involved in the development of sarcopenia&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">33</span></a> including alterations in protein synthesis and degradation&#44; inflammation&#44; hormonal alterations&#44; and mitochondrial dysfunction&#46; Most of these are related to an increase in oxidative stress&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">33</span></a> which is consistent with the hypothesis that free radicals are involved in ageing&#44; proposed by Denham Harman in 1956&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">34</span></a> Regarding mitochondrial dysfunction and its association with ageing&#44; studies have found mutations and reductions in mitochondrial DNA&#44; signalling abnormalities in apoptosis pathways&#44; decreased activity of the electron transport chain&#44; and increased mitochondrial production of free radicals&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">33</span></a> The mechanism behind all these alterations remains unclear&#44; but peroxisome proliferator-activated receptor gamma coactivator 1-alpha is thought to play a key role in age-related reduction of mitochondriogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">33</span></a> Interleukins &#40;IL&#41; involved in muscle dysfunction &#40;IL-1&#44; IL-6&#41; also increase with age&#44; together with TNF-&#945;&#44; which binds to sarcolemma receptors by stimulating free radical synthesis&#46; NF-&#954;B is also elevated&#44; and chronic activation of this complex is one of the most important factors in the loss of muscle mass&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">33</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Reduced levels of anabolic hormones&#44; particularly testosterone and oestrogen&#44; have considerable effect on muscle mass&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">35</span></a> Decreased testosterone levels are associated with loss of muscle mass and strength in both men and women&#59; oestrogen deficiency in women during menopause has similar effects&#46; A reduction in the IL-1 and IL-6-inhibitory action of these two hormones allows inflammatory interleukins to cause muscle damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">33&#44;35</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Duration and type of mechanical ventilation</span><p id="par0115" class="elsevierStylePara elsevierViewall">The most widely used ventilation mode is assist-control &#40;71&#46;6&#37;&#41;&#44; followed by synchronized intermittent-mandatory ventilation with pressure support &#40;6&#46;5&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">36</span></a> The mode and duration of MV are decisive factors in the appearance of diaphragm dysfunction&#46; MV can cause atrophy and diaphragm weakness if the pressure and flow administered are excessively high&#44;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">26</span></a> while studies have shown that in some patients disuse atrophy reduces diaphragmatic thickness by 6&#37; per day on average&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">37</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Evidence indicates that calpain and proteasome activity increases&#44; and with it diaphragm protein degradation&#44; after 12<span class="elsevierStyleHsp" style=""></span>h of assist-control MV&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">22</span></a> Insulin-like growth factor type <span class="elsevierStyleSmallCaps">i</span> &#40;IFG-I&#41; and myogenic differentiation protein 1 &#40;MyoD&#41; are involved in the regulation&#44; production and transcription of contractile proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">38</span></a> After 18&#8211;24<span class="elsevierStyleHsp" style=""></span>h of assist-control MV or diaphragm passivity&#44; IFG-I and MyoD activity is reduced&#59; oxidative stress and protease activity increases and diaphragm fibre cross-section decreases after 18<span class="elsevierStyleHsp" style=""></span>h of assist-control VM&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">38</span></a> The mechanism most closely associated with atrophy is increased proteolysis<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">19</span></a>&#59; animal studies have also shown a decrease in protein synthesis&#44; particularly myosin heavy chain protein synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">39</span></a> Another problem associated with VM is the loss of electrical activity in the diaphragm&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">40</span></a> This causes problems in the transcription of myogenic regulatory factors&#44; which leads to changes in muscle fibre types&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">40</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Nutritional and metabolic status</span><p id="par0125" class="elsevierStylePara elsevierViewall">Evidence has shown that between 30&#37; and 60&#37; of hospitalized patients are malnourished&#59; this percentage is even higher in critically ill patients&#46; Muscle loss is accelerated during anorexia&#44; could even reach 1&#37; per day&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">28</span></a> Metabolic disturbances lead to higher energy expenditure&#44; nutrient deficits&#44; and decreased absorption or availability of these nutrients during illness&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">41</span></a> Hypermetabolic states are associated with an increase in catabolic hormones &#40;glucagon&#44; adrenaline&#44; and cortisol&#41; and cytokines&#44;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">42</span></a> together with inhibition of anabolic hormones &#40;insulin and testosterone&#41;&#46; Prolonging the catabolic state reduces muscle mass&#44; muscle strength and the immune response&#44; increasing susceptibility to serious infections and failure of vital organs&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">42</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Hormonal imbalance has been closely associated with the appearance of hyperglycaemia of over 150<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">43</span></a> Hyperglycaemia due to insulin resistance is common in critically ill patients&#44; even those with no history of diabetes mellitus&#44; and is a negative prognosis factor in the short&#44; medium&#44; and long term&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">44</span></a> Hyperglycaemia promotes the storage of lipids in the form of triglycerides and low-density lipoproteins&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">44</span></a> Additionally&#44; acute phase proteins associated with injury&#44; inflammation or sepsis reduce plasma cholesterol due to a reduction in high-density lipoproteins&#44; and worsen the metabolic status of these patients&#46; Changes also occur in the protein and lipid composition of lipoproteins&#44; increasing their atherogenic and inflammatory properties&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">44</span></a> Less use of lipid substrates as an energy source triggers proteolysis&#44; leading to loss of muscle mass&#44; increased risk of infection&#44; multi-organ failure and&#44; in the worst case&#44; death&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">44</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Comorbidities</span><p id="par0135" class="elsevierStylePara elsevierViewall">The most frequent comorbidities in patients requiring MV are diabetes mellitus&#44; sepsis&#44; hypertension&#44; and acute myocardial infarction&#46; Other complications that may be present during ventilation are&#58; acute respiratory distress syndrome&#44; ventilator-associated pneumonia&#44; sepsis&#44; cardiogenic shock&#44; acute kidney failure&#44; liver failure&#44; multifactorial coagulopathy&#44; burns&#44; respiratory acidosis&#44; and metabolic acidosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">22&#44;42&#44;45</span></a> Several of these syndromes or pathologies can promote diaphragm dysfunction due to changes protein metabolism&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">45</span></a> In sepsis&#44; the systemic inflammatory response syndrome increases proinflammatory cytokines &#40;TNF-&#945;&#44; IL-6&#44; IL-1&#44; IL-1 &#946;&#41;&#44; nitric oxide&#44; and free radicals&#44; which promote the activity of proteolytic pathways&#59; therefore&#44; inhibition of these pathways is expected to alter the course and progression of septic myopathy and could reduce the risk of muscle weakness&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">46</span></a> IL-1 &#946; reduces phosphorylation of eukaryotic translation initiation factor 4 gamma &#40;eIF4G&#41;&#44; altering the translation of sarcoplasmic and myofibrillar proteins in fast-twitch muscles&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">47</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Drugs and their association with diaphragmatic dysfunction</span><p id="par0140" class="elsevierStylePara elsevierViewall">Glucocorticoids &#40;GC&#41; exacerbate metabolic abnormalities induced by acute critical illness&#44; and at high doses generate neuromuscular disorders that produce peripheral and respiratory muscle dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">48</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The use of GC is associated with muscular dysfunction due to the inhibition of anabolism and protein catabolism&#46; Anabolism inhibition in turn inhibits protein synthesis by various mechanisms&#44; including inhibition of amino acid transport in muscles and inhibition of the stimulatory action of insulin and IGF-1 on the phosphorylation of F4G-binding protein 1 and ribosomal protein kinase S6&#44; which determine mRNA translation&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">49</span></a> Myogenesis is also affected by the down-regulation of myogenin&#44; an essential transcription factor in the differentiation of satellite cells into muscle fibres&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">48&#44;49</span></a> Evidence has shown that intracellular mediators associated with muscle wasting&#44; such as FOXO&#44; GSK3&#946;&#44; C&#47;EBPb&#44; p300&#44; REDD1 and ATF4&#44; are elevated by excess GC&#44; while the phosphorylation of S6K1 and 4E-BP1 is reduced&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">48&#44;49</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Another group of drugs responsible for stimulating atrophy due to inactivity and muscle disuse are neuromuscular blockers &#40;NMB&#41;&#44; which decrease cellular excitation&#44; causing alterations in neurotransmission&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">50</span></a> Long-term use of NMBs in conjunction with steroids and prolonged immobilization promotes muscle weakness and&#44; in some cases&#44; acute necrotizing myopathy&#46; This type of myopathy has a long clinical course and disabling sequelae&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">50</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conclusions</span><p id="par0155" class="elsevierStylePara elsevierViewall">Biotrauma is an inflammatory reaction of the respiratory muscles&#46; The main molecular pathways involved in this lesion are based on increased levels of ubiquitin ligases and caspase-3&#46; These promote muscle atrophy and wasting due to activation of the ALP pathway&#44; reduction of the IGF&#47;PI3K&#47;AKT pathway responsible for maintaining muscle integrity&#44; FOXO overexpression&#44; which promotes the rapid development of atrophy&#44; and NF-kappa B signalling&#44; which activates TNF-&#945;&#46; Proinflammatory cytokines such as TNF-&#945; can translocate one of the components of NF-kB &#40;p65&#41; and activate p38MAPK&#46; This process ultimately inhibits cell differentiation&#44; myoprotein degradation&#44; and increased expression of atrophic genes&#44; such as MuRF1 and atrogin 1&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Some conditions can hasten activation of these pathways&#59; age&#44; type and duration of MV&#44; the patient&#39;s nutritional and metabolic status&#44; the presence of comorbidities&#44; particularly sepsis&#44; and the use of drugs such as glucocorticoids and neuromuscular blockers&#46; All these molecular alterations or conditions increase the risk of weaning failure&#44; and this raises the need for further investigation into strategies that can reduce their impact on diaphragmatic dysfunction&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Funding</span><p id="par0165" class="elsevierStylePara elsevierViewall">This study has not received any funding&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflicts of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare&#46;</p></span></span>"
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          "titulo" => "Histological changes of diaphragmatic musculature"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Ventilator-induced diaphragm dysfunction &#40;VIDD&#41; is the loss of diaphragmatic muscle strength related to of mechanical ventilation&#44; noticed during the first day or 48<span class="elsevierStyleHsp" style=""></span>h after initiating controlled mechanical ventilation&#46; This alteration has been related to disruption on the insulin growth factor&#47;phosphoinositol 3-kinase&#47;kinase B protein pathway &#40;IGF&#47;PI3K&#47;AKT&#41;&#44; in addition to an overexpression of FOXO&#44; expression of NF-kB signalling&#44; increase function of muscular ubiquitin ligase and activation of caspasa-3&#46; VIDD has a negative impact on quality of life&#44; duration of mechanical ventilation&#44; and hospitalization stance and cost&#46; More studies are necessary to understated the process and impact of VIDD&#46; This is a narrative review of non-systematic literature&#44; aiming to explain the molecular pathways involved in VIDD&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La disfunci&#243;n diafragm&#225;tica inducida por ventilaci&#243;n mec&#225;nica &#40;DDVI&#41; es la p&#233;rdida de la fuerza diafragm&#225;tica relacionada al uso de ventilaci&#243;n mec&#225;nica y se observa con frecuencia en las primeras 24 a 48 h de asistencia ventilatoria controlada&#46; La evidencia reciente relaciona esa p&#233;rdida de funci&#243;n diafragm&#225;tica con alteraciones de la v&#237;a del factor de crecimiento insul&#237;nico&#47;fosfoinositol 3-cinasas&#47;prote&#237;na cinasa B &#40;IGF&#47;PI3K&#47;AKT&#41;&#44; sobreexpresi&#243;n de FOXO&#44; se&#241;alizaci&#243;n NF-kB&#44; mayor funci&#243;n de ligasas de ubiquitina muscular y activaci&#243;n de la caspasa-3&#46; La DDVI tiene un impacto negativo en los d&#237;as de ventilaci&#243;n mec&#225;nica&#44; la retirada de la asistencia ventilatoria&#44; la calidad de vida y los costos hospitalarios&#46; Es importante realizar nuevos estudios encaminados a mitigar la aparici&#243;n o incidencia de esta lesi&#243;n&#46; Esta es una revisi&#243;n narrativa de la literatura no sistem&#225;tica&#44; tiene por objetivo explicar con detalle las v&#237;as moleculares implicadas en el desarrollo de la disfunci&#243;n diafragm&#225;tica asociada al soporte ventilatorio&#46;</p></span>"
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Molina Pe&#241;a ME&#44; S&#225;nchez CM&#44; Rodr&#237;guez-Trivi&#241;o CY&#46; Mecanismos fisiopatol&#243;gicos de la disfunci&#243;n diafragm&#225;tica asociada a ventilaci&#243;n mec&#225;nica&#46; Rev Esp Anestesiol Reanim&#46; 2020&#59;67&#58;195&#8211;203&#46;</p>"
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                        0 => array:2 [
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                        0 => array:2 [
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Article information

ISSN: 23411929
Original language: English

DOI:10.1016/j.redare.2019.12.003

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