Respiratory deficits after C2 hemisection (C2Hx) have been well documented through single-sex investigations. Although ovarian sex hormones enable enhanced respiratory recovery observed in females 2 wk post-C2Hx, it remains unknown if sex impacts spontaneous respiratory recovery at chronic time points. We conducted a longitudinal study to provide a comprehensive sex-based characterization of respiratory neuromuscular recovery for 8 wk after C2Hx. We recorded ventilation and chronic diaphragm electromyography (EMG) output in awake, behaving animals, phrenic motor output in anesthetized animals, and performed diaphragm muscle histology in chronically injured male and female rodents. Our results show that females expressed a greater recovery of tidal volume and minute ventilation compared with males during subacute and chronic time points. Eupneic diaphragm EMG amplitude during wakefulness and phrenic motor amplitude are similar between sexes at all time points after injury. Our data also suggest that females have a greater reduction in ipsilateral diaphragm EMG amplitude during spontaneous deep breaths (e.g., sighs) compared with males. Finally, we show evidence for atrophy and remodeling of the fast, fatigable fibers ipsilateral to injury in females, but not in males. To our knowledge, the data presented here represent the first study to report sex-dependent differences in spontaneous respiratory recovery and diaphragm muscle morphology following chronic C2Hx. These data highlight the need to study both sexes to inform evidence-based therapeutic interventions in respiratory recovery after spinal cord injury (SCI).NEW & NOTEWORTHY In response to chronic C2 hemisection, female rodents display increased tidal volume during eupneic breathing compared with males. Females show a greater reduction in diaphragm electromyography (EMG) amplitude during spontaneous deep breaths (e.g., sighs) and atrophy and remodeling of fast, fatigable diaphragm fibers. Given that most rehabilitative interventions occur in the subacute to chronic stages of injury, these results highlight the importance of considering sex when developing and evaluating therapeutics after spinal cord injury.

Previous studies have concluded that breath intake patterns during speech emerge as a function of planning processes. Little work has tested for similar effects of respiratory recovery on these patterns. Moreover, previous work has relied on one-by-one elicitation of read sentences which incorporates a direct cue to upcoming length, allowing for anticipatory effects to emerge but prohibiting a test of preceding material on intakes. The current study investigated the relative influences of recovery and anticipatory factors on breath intakes in a connected speech task that better approximates spontaneous production. Participants (N = 6) were asked to recite a passage of 20 unrelated sentences from memory. Results revealed a significant effect of preceding utterance length on presence of breath intakes during pauses, but not of following utterance length. It is concluded that respiratory recovery drives breath intakes in connected speech.

Severe midcervical contusion injury causes profound deficits throughout the respiratory motor system that last from acute to chronic time points post-injury. We use chondroitinase ABC (ChABC) to digest chondroitin sulphate proteoglycans within the extracellular matrix (ECM) surrounding the respiratory system at both acute and chronic time points post-injury to explore whether augmentation of plasticity can recover normal motor function. We demonstrate that, regardless of time post-injury or treatment application, the lesion cavity remains consistent, showing little regeneration or neuroprotection within our model. Through electromyography (EMG) recordings of multiple inspiratory muscles, however, we show that application of the enzyme at chronic time points post-injury initiates the recovery of normal breathing in previously paralyzed respiratory muscles. This reduced the need for compensatory activity throughout the motor system. Application of ChABC at acute time points recovered only modest amounts of respiratory function. To further understand this effect, we assessed the anatomical mechanism of this recovery. Increased EMG activity in previously paralyzed muscles was brought about by activation of spared bulbospinal pathways through the site of injury and/or sprouting of spared serotonergic fibers from the contralateral side of the cord. Accordingly, we demonstrate that alterations to the ECM and augmentation of plasticity at chronic time points post-cervical contusion can cause functional recovery of the respiratory motor system and reveal mechanistic evidence of the pathways that govern this effect.

Decompressive laparotomy has been advised as potential treatment for abdominal compartment syndrome (ACS) when medical management fails; yet, the effect on parameters of organ function differs markedly in the published literature. In this study, we sought to investigate the effect of decompressive laparotomy on intra-abdominal pressure and organ function in critically ill adult and pediatric patients with ACS, specifically focusing on hemodynamic, respiratory, and kidney function and outcome.
A systematic review and meta-analysis of the literature was performed. Articles reporting data on intra-abdominal pressure (IAP), hemodynamic (mean arterial pressures [MAP], central venous pressure [CVP], cardiac index [CI], heart rate [HR], systemic vascular resistance index [SVRI] and/or pulmonary capillary wedge pressure [PCWP]), respiratory (positive end-expiratory pressure [PEEP], peak inspiratory pressure [PIP] and/or ratio of partial pressure arterial oxygen and fraction of inspired oxygen [P/F ratio]), and/or urinary output (UO) following decompressive laparotomy were analyzed.
A total of 15 articles were included; 3 included children only (aged 18 years or younger). Of the 286 patients who were included, 49.7% had primary ACS. The baseline mean IAP in adults decreased with an average of 18.2 ± 6.5 mmHg following decompression, from 31.7 ± 6.4 mmHg to 13.5 ± 3.0 mmHg. There was a decrease in HR (12.2 ± 9.5 beats/min; p = 0.04), CVP (4.6 ± 2.3 mmHg; p = 0.022), PCWP (5.8 ± 2.3 mmHg; p = 0.029), and PIP (10.1 ± 3.9 cmH2O; p < 0.001) and a mean increase in P/F ratio (70.4 ± 49.4; p < 0.001) and UO (95.3 ± 105.3 ml/h; p < 0.001). In children, there was a significant increase in MAP (20.0 ± 2.3 mmHg; p = 0.006), P/F ratio (238.2; p < 0.001), and UO (2.88 ± 0.64 ml/kg/h; p < 0.001) and a decrease in CVP (7 mmHg; p = 0.016) and PIP (9.9 cmH2O; p = 0.002). The overall mortality rate was 49.7% in adults and 60.8% in children following decompressive laparotomy.
Decompressive laparotomy resulted in a significantly lower IAP and had beneficial effects on hemodynamic, respiratory, and renal parameters. Mortality after decompressive laparotomy remains high in both adults and children.

Respiratory complications in patients with spinal cord injury (SCI) are common and have a negative impact on the quality of patients\' lives. Systemic administration of drugs that improve respiratory function often cause deleterious side effects. The present study examines the applicability of a novel nanotechnology-based drug delivery system, which induces recovery of diaphragm function after SCI in the adult rat model. We developed a protein-coupled nanoconjugate to selectively deliver by transsynaptic transport small therapeutic amounts of an A1 adenosine receptor antagonist to the respiratory centers. A single administration of the nanoconjugate restored 75% of the respiratory drive at 0.1% of the systemic therapeutic drug dose. The reduction of the systemic dose may obviate the side effects. The recovery lasted for 4 weeks (the longest period studied). These findings have translational implications for patients with respiratory dysfunction after SCI.
CONCLUSIONS: The leading causes of death in humans following SCI are respiratory complications secondary to paralysis of respiratory muscles. Systemic administration of methylxantines improves respiratory function but also leads to the development of deleterious side effects due to actions of the drug on nonrespiratory sites. The importance of the present study lies in the novel drug delivery approach that uses nanotechnology to selectively deliver recovery-inducing drugs to the respiratory centers exclusively. This strategy allows for a reduction in the therapeutic drug dose, which may reduce harmful side effects and markedly improve the quality of life for SCI patients.

Hemisection of the spinal cord at C2 eliminates ipsilateral descending drive to the phrenic nucleus and causes hemidiaphragmatic paralysis in rats. Phrenic nerve (PhN) or diaphragmatic activity ipsilateral to hemisection can occasionally be induced acutely following hemisection by respiratory stressors (i.e., hypercapnia, asphyxia, contralateral phrenicotomy) and becomes spontaneously active days-to-weeks later. These investigations, however, are potentially confounded by the use of anesthesia, which may suppress spontaneously-active crossed phrenic pathways. Experiments were performed on vecuronium-paralyzed, unanesthetized, decerebrate adult male rats and whole PhN activity recorded continuously before, during, and after high cervical hemisection at the C1 spinal level. Crossed phrenic activity recovered spontaneously over minutes-to-hours with maximal recovery of 11.8 ± 3.1% (m ± SE) in the PhN ipsilateral to hemisection. Additionally, there was a significant increase in PhN activity contralateral to hemisection of 221.0 ± 4 0.4% (m ± SE); since animals were artificially-ventilated, these changes likely represent an increase in central respiratory drive. These results underscore the state-dependence of crossed bulbophrenic projections and suggest that unanesthetized models may be more sensitive in detecting acute recovery of respiratory output following spinal cord injury (SCI). Additionally, our results may suggest an important role for a group of C1-C2 neurons exhibiting respiratory-related activity, spared by the higher level of hemisection. These units may function as relays of polysynaptic bulbophrenic pathways and/or provide excitatory drive to phrenic motoneurons. Our findings provide a new model for investigating acute respiratory recovery following cervical SCI, the high C1-hemisected unanesthetized decerebrate rat and suggest a centrally-mediated increase in central respiratory drive in response to high cervical SCI.

Rat fetal spinal cord (FSC) tissue, naturally enriched with interneuronal progenitors, was introduced into high cervical, hemi-resection (Hx) lesions. Electrophysiological analyses were conducted to determine if such grafts exhibit physiologically-patterned neuronal activity and if stimuli which increase respiratory motor output also alter donor neuron bursting. Three months following transplantation, the bursting activity of FSC neurons and the contralateral phrenic nerve were recorded in anesthetized rats during a normoxic baseline period and brief respiratory challenges. Spontaneous neuronal activity was detected in 80% of the FSC transplants, and autocorrelation of action potential spikes revealed distinct correlogram peaks in 87% of neurons. At baseline, the average discharge frequency of graft neurons was 13.0 ± 1.7 Hz, and discharge frequency increased during a hypoxic respiratory challenge (p<0.001). Parallel studies in unanesthetized rats showed that FSC tissue recipients had larger inspiratory tidal volumes during brief hypoxic exposures (p<0.05 vs. C2Hx rats). Anatomical connectivity was explored in additional graft recipients by injecting a transsynaptic retrograde viral tracer (pseudorabies virus, PRV) directly into matured transplants. Neuronal labeling occurred throughout graft tissues and also in the host spinal cord and brainstem nuclei, including those associated with respiratory control. These results underscore the neuroplastic potential of host-graft interactions and training approaches to enhance functional integration within targeted spinal circuitry.