Dataset Information

Inhibition of central activation of the diaphragm: a mechanism of weaning failure.

ABSTRACT: During a T-tube trial following disconnection of mechanical ventilation, patients failing the trial do not develop contractile diaphragmatic fatigue despite increases in inspiratory pressure output. Studies in volunteers, patients, and animals raise the possibility of spinal and supraspinal reflex mechanisms that inhibit central-neural output under loaded conditions. We hypothesized that diaphragmatic recruitment is submaximal at the end of a failed weaning trial despite concurrent respiratory distress. Tidal transdiaphragmatic pressure (?Pdi) and electrical activity (?EAdi) were recorded with esophago-gastric catheters during a T-tube trial in 20 critically ill patients. During the T-tube trial, ?EAdi was greater in weaning failure patients than in weaning success patients (P = 0.049). Despite increases in ?Pdi, from 18.1?±?2.5 to 25.9?±?3.7 cm H2O (P < 0.001), rate of transdiaphragmatic pressure development (from 22.6?±?3.1 to 37.8?±?6.7 cm H2O/s; P < 0.0004), and concurrent respiratory distress, ?EAdi at the end of a failed T-tube trial was half of maximum, signifying inhibition of central neural output to the diaphragm. The increase in ?Pdi in the weaning failure group, while ?EAdi remained constant, indicates unexpected improvement in diaphragmatic neuromuscular coupling (from 46.7?±?6.5 to 57.8?±?8.4 cm H2O/%; P = 0.006). Redistribution of neural output to the respiratory muscles characterized by a progressive increase in rib cage and accessory muscle contribution to tidal breathing and expiratory muscle recruitment contributed to enhanced coupling. In conclusion, diaphragmatic recruitment is submaximal at the end of a failed weaning trial despite concurrent respiratory distress. This finding signifies that reflex inhibition of central neural output to the diaphragm contributes to weaning failure.NEW & NOTEWORTHY Research into pathophysiology of failure to wean from mechanical ventilation has excluded several factors, including contractile fatigue, but the precise mechanism remains unknown. We recorded transdiaphragmatic pressure and diaphragmatic electrical activity in patients undergoing a T-tube trial. Diaphragmatic recruitment was submaximal at the end of a failed trial despite concurrent respiratory distress, signifying that inhibition of central neural output to the diaphragm is an important mechanism of weaning failure.

SUBMITTER: Laghi F

PROVIDER: S-EPMC7473953 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inhibition of central activation of the diaphragm: a mechanism of weaning failure.

Laghi Franco F Shaikh Hameeda H Littleton Stephen W SW Morales Daniel D Jubran Amal A Tobin Martin J MJ

Journal of applied physiology (Bethesda, Md. : 1985) 20200716 2

During a T-tube trial following disconnection of mechanical ventilation, patients failing the trial do not develop contractile diaphragmatic fatigue despite increases in inspiratory pressure output. Studies in volunteers, patients, and animals raise the possibility of spinal and supraspinal reflex mechanisms that inhibit central-neural output under loaded conditions. We hypothesized that diaphragmatic recruitment is submaximal at the end of a failed weaning trial despite concurrent respiratory d ...[more]

PMID: 32673161

Similar Datasets

Project description:Weaning is the process of successfully liberating the patient from mechanical ventilation. The majority of patients will separate from the ventilator after a successful spontaneous breathing trial (SBT).1 In a minority of patients, weaning can be challenging and prolonged. Finding the cause of weaning difficulty is crucial to minimize the rates of extubation failure and prolonged ventilation. Diaphragm dysfunction (DD) has been described as a separate entity responsible for weaning failure with an incidence of 23–80%. It has also been associated with difficult weaning, prolonged intensive care unit (ICU) stay and mechanical ventilation, and increased ICU and hospital mortality.2 Sepsis, shock, and ventilator induced diaphragm dysfunction are important risk factors of DD. Diaphragm dysfunction has several mechanisms. Disuse atrophy and microstructural changes of the diaphragm have been described as the two cardinal pathophysiologic features. Establishing the diagnosis of DD can be complex in critically ill patients. Bilateral anterior magnetic phrenic stimulation is widely considered as the gold standard but is only available in large research centers with limited availability. Ultrasonography of the diaphragm is a promising tool given its wide availability, affordability, and non-invasive nature. Ultrasound is operator dependent, however and it does not provide continuous monitoring capabilities. The diaphragm thickening fraction (DTF) can be calculated from measuring the end-expiratory and end-inspiratory diaphragm thickness at the bedside. It correlates well with transdiaphragmatic pressure.3 Electromyography of the diaphragm may overcome the limitation of ultrasound by offering a continuous assessment of the diaphragmatic electrical activity, but it requires the placement of a specialized nasogastric tube. Management of DD is better approached by implementing a preventive and a curative strategy. From animal studies, allowing for spontaneous breathing on mechanical ventilation may prevent the problem. The degree of the recommended patient effort and ventilator assistance to achieve optimal balance between diaphragmatic loading and unloading are yet to be defined. Monitoring DTF while finding the optimal ventilator support level can be useful in this context. Another modality to prevent DD is diaphragm pacing applied through a transvenous phrenic nerve pacing system. Animal studies in pigs showed that this modality resulted in less diaphragm atrophy when pacing was synchronized with ventilation.4 There is an ongoing study to assess the role of diaphragm pacing to recondition and strengthen the diaphragm in difficult to wean mechanically ventilated patients (Clinicaltrials.gov NCT03107949). Once diaphragm dysfunction is established, no specific treatments exist at this time. Other causes of weaning failure like cardiac dysfunction have to be excluded and treated. Improving respiratory load and respiratory muscle weakness imbalance is also crucial. While it appears to improve inspiratory muscle strength parameters, inspiratory muscle training has not consistently shown improvements in weaning success.5 Levosemindan showed some benefit in improving diaphragm contractility and efficiency in healthy volunteers but was later found to increase likelihood of weaning failure in septic patients. Anabolic steroids were not found to be effective in treating diaphragm dysfunction in several studies. More evidence is needed before recommending non-invasive ventilation post-extubation in all DD patients.

Project description:BackgroundLung and diaphragm ultrasound methods have recently been introduced to predict the outcome of weaning from mechanical ventilation (MV). The aim of this study is to assess the reliability and accuracy of these techniques for predicting successful weaning in critically ill adults.MethodsWe conducted two studies: a cross-sectional interobserver agreement study between two sonographers and a prospective cohort study to assess the accuracy of lung and diaphragm ultrasound for predicting weaning and extubation outcome. For the interobserver agreement study, we included 50 general critical care patients who were consecutively admitted to the ICU. For the predictive accuracy study, we included consecutively 69 patients on MV who were ready for weaning. We assessed interobserver agreement of ultrasound measurements, using the weighted kappa coefficient for LUSm score (modified lung ultrasound score) and the intraclass correlation coefficient (ICC) and Bland-Altman method for TI (diaphragm thickening index). We assessed the predictive value of LUSm and TI in weaning outcome by plotting the corresponding ROC curves.ResultsWe found adequate interobserver agreement for both LUSm (weighted kappa 0.95) and TI (ICC 0.78, difference according to Bland-Altman analysis?±?12.5%). LUSm showed good-moderate discriminative power for successful weaning and extubation (area under the ROC curve (AUC) for successful weaning 0.80, and sensitivity and specificity at optimal cut-off point 0.76 and 0.73, respectively; AUC for successful extubation 0.78, and optimal sensitivity and specificity 0.76 and 0.47, respectively. TI was more sensitive but less specific for predicting successful weaning (AUC 0.71, optimal sensitivity and specificity 0.93 and 0.48) and successful extubation (AUC 0.76, optimal sensitivity and specificity 0.93 and 0.58). The area under the ROC curve for predicting weaning success was 0.83 for both ultrasound measurements together.ConclusionsInterobserver agreement was excellent for LUSm and moderate-good for TI. A low TI value or high LUSm value indicates high risk of weaning failure.

Project description:In aging Fischer 344 rats, phrenic motor neuron loss, neuromuscular junction abnormalities, and diaphragm muscle (DIAm) sarcopenia are present by 24 mo of age, with larger fast-twitch fatigue-intermediate (type FInt) and fast-twitch fatigable (type FF) motor units particularly vulnerable. We hypothesize that in old rats, DIAm neuromuscular transmission deficits are specific to type FInt and/or FF units. In phrenic nerve/DIAm preparations from rats at 6 and 24 mo of age, the phrenic nerve was supramaximally stimulated at 10, 40, or 75 Hz. Every 15 s, the DIAm was directly stimulated, and the difference in forces evoked by nerve and muscle stimulation was used to estimate neuromuscular transmission failure. Neuromuscular transmission failure in the DIAm was observed at each stimulation frequency. In the initial stimulus trains, the forces evoked by phrenic nerve stimulation at 40 and 75 Hz were significantly less than those evoked by direct muscle stimulation, and this difference was markedly greater in 24-mo-old rats. During repetitive nerve stimulation, neuromuscular transmission failure at 40 and 75 Hz worsened to a greater extent in 24-mo-old rats compared with younger animals. Because type IIx and/or IIb DIAm fibers (type FInt and/or FF motor units) display greater susceptibility to neuromuscular transmission failure at higher frequencies of stimulation, these data suggest that the age-related loss of larger phrenic motor neurons impacts nerve conduction to muscle at higher frequencies and may contribute to DIAm sarcopenia in old rats. NEW & NOTEWORTHY Diaphragm muscle (DIAm) sarcopenia, phrenic motor neuron loss, and perturbations of neuromuscular junctions (NMJs) are well described in aged rodents and selectively affect FInt and FF motor units. Less attention has been paid to the motor unit-specific aspects of nerve-muscle conduction. In old rats, increased neuromuscular transmission failure occurred at stimulation frequencies where FInt and FF motor units exhibit conduction failures, along with decreased apposition of pre- and postsynaptic domains of DIAm NMJs of these units.

Project description:BackgroundNo effective drugs for the treatment of sepsis-induced diaphragm dysfunction are currently available. Therefore, it is particularly important to clarify the molecular regulatory mechanism of this condition and subsequently implement effective treatment and prevention of sepsis-induced diaphragm dysfunction.MethodsA mouse model of diaphragm dysfunction was established via injection of lipopolysaccharide (LPS). An RNA-sequencing (RNA-seq) technique was used to detect the differentially expressed genes (DEGs) in the diaphragms of mice. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed for functional analysis of DEGs. The protein-protein interaction network obtained from the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) website was imported into Cytoscape, the key molecular regulatory network was constructed with CytoNCA, the ClueGo plugin was further used to analyze the core regulatory pathways of key molecular, and finally, the iRegulon plugin was used to the identify key transcription factors.ResultsThe genes upregulated after LPS treatment were involved in biological processes and pathways related to immune response; the genes downregulated after LPS treatment were mainly correlated with the muscle contraction. The expressions of several inflammation-related genes were upregulated after LPS treatment, of which tumor necrosis factor (Tnf), interleukin (Il)-1β, and Il-6 assumed a core regulatory role in the network; meanwhile, the downregulated key genes included Col1a1, Uqcrfs1, Sdhb, and ATP5a1, among others. These key regulatory factors participated in the activation of Toll-like receptor (TLR) signaling pathway, nuclear factor (NF)-κB signaling pathway, and TNF signaling pathway as well as the inhibition of oxidative phosphorylation pathway, cardiac muscle contraction pathway, and citrate cycle pathway. Finally, RelA, IRF1, and STAT3, were identified as the key regulators in the early stage of diaphragmatic inflammatory response.ConclusionsSepsis-induced diaphragm dysfunction in mice is closely correlated with the activation of TLR signaling pathway, NF-κB signaling pathway, and TNF signaling pathway and the inhibition of oxidative phosphorylation pathway, cardiac muscle contraction pathway, and citrate cycle pathway. Our findings provide insight into the molecular mechanism of sepsis-induced diaphragm dysfunction in mice and provide a promising new strategy for targeted treatment of diaphragm dysfunction.

Dataset Information

Inhibition of central activation of the diaphragm: a mechanism of weaning failure.

Publications

Inhibition of central activation of the diaphragm: a mechanism of weaning failure.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets