Cardiorespiratory failure in rat induced by severe inspiratory resistive loading

Abstract

Simpson JA, Iscoe S. Cardiorespiratory failure in rat induced by severe inspiratory resistive loading. J Appl Physiol 102: [1556][1557][1558][1559][1560][1561][1562][1563][1564] 2007. First published December 7, 2006; doi:10.1152/japplphysiol.00785.2006.-The mechanisms underlying acute respiratory failure induced by respiratory loads are unclear. We hypothesized that, in contrast to a moderate inspiratory resistive load, a severe one would elicit central respiratory failure (decreased respiratory drive) before diaphragmatic injury and fatigue. We also wished to elucidate the factors that predict endurance time and peak tracheal pressure generation. Anesthetized rats breathed air against a severe load (ϳ75% of the peak tracheal pressure generated during a 30-s occlusion) until pump failure (fall in tracheal pressure to half; mean 38 min). Hypercapnia and hypoxemia developed rapidly (ϳ4 min), coincident with diaphragmatic fatigue (decreased ratio of transdiaphragmatic pressure to peak integrated phrenic activity) and the detection in blood of the fast isoform of skeletal troponin I (muscle injury). At ϳ23 min, respiratory frequency and then blood pressure fell, followed immediately by secondary diaphragmatic fatigue. Blood taken after termination of loading contained cardiac troponin T (myocardial injury). Contrary to our hypothesis, diaphragmatic fatigue and injury occurred early in loading before central failure, evident only as a change in the timing but not the drive component of the central respiratory pattern generator.Stepwise multiple regression analysis selected changes in mean arterial pressure and arterial PCO 2 during loading as the principal contributing factors in load endurance time, and changes in mean arterial pressure as the principal contributing factor in peak tracheal pressure generation. In conclusion, the temporal development of respiratory failure is not stereotyped but depends on load magnitude; moreover respiratory loads induce cardiorespiratory, not just respiratory, failure. diaphragm; fatigue; heart; injury; troponin WHEN THE RESPIRATORY MUSCLES are subjected to contractile demands that exceed their energy supply, respiratory pump failure (inadequate pressure generation) eventually occurs (e.g., 35). Pump failure can result from central failure (inadequate output from the respiratory central pattern generator; sometimes referred to as central fatigue) (50), peripheral fatigue (35) (neurotransmission failure, decreased contractile function; 9), or some combination. Central failure is denoted by a decrease in central neural output despite adequate chemical drive, peripheral fatigue by a reduction in force-generating capacity that is reversible by rest (35), and neurotransmission failure by impaired transmission of the action potential across the neuromuscular junction. All have been implicated in respiratory pump failure, but there is no consensus about either their relative contributions or the sequence in which they occur. Even with similar protocols in healthy human subjects (27,33) o...

Pulmonary delivery of dry powders to rats: Tolerability limits of an intra-tracheal administration model

“…Cardiovascular failure secondary to expiratory load has previously been reported in a spontaneously breathing anesthetized rat model (Simpson et al, 2009). Our observations are consistent with the cardio-respiratory consequences of respiratory load, as previously described (Simpson and Iscoe, 2007;Simpson et al, 2009), which could be a plausible explanation.…”

“…The high rate of respiratory failure observed during powder administration could thus be secondary to a resistive respiratory load generated by proximal aerosol deposition. In an anesthetized rat model with inspiratory resistive load (75% of the peak tracheal pressure developed during a prior 30-s occlusion), bradypnea was observed seconds after the obstruction; respiratory pump failure occurred in all rats when the inspiratory resistive load was maintained, and most of the rats died within 5 min (Simpson and Iscoe, 2007). The mechanism responsible for the bradypnea was unclear but may have been part of a central reflex mechanism designed to reduce diaphragmatic activity, thereby avoiding fatigue and pump failure.…”

MAPKs and NF-κB differentially regulate cytokine expression in the diaphragm in response to resistive breathing: the role of oxidative stress

“…Most studies in the literature have used a high inspiratory load, demonstrating a time-to-task failure that ranged from few minutes to 1 h maximum (2,47). However, recent studies have shown that IRB with a moderate load differs from that with a high load (21,42,43,51,55,56). Specifically, compared with the rapid development of diaphragmatic fatigue that led to pump failure observed with high inspiratory loads (42), a moderate load can be sustained for a long time, tracheal pressure does remain constant during the course of IRB, and hypercapnia development precedes that of diaphragmatic fatigue that is a late event (43).…”

Repeated inspiratory occlusions acutely impair myocardial function in rats

“…Moreover, in the same preparation (e.g. anaesthesia and species), during severe continuous inspiratory resistive loading, HR progressively increases from an average of 380 to ∼470 beats per minute (Simpson & Iscoe, 2007). In the present study, HR between occlusions remained steady at ∼400 beats per minute during 3 h of occlusions, indicating an unexploited reserve of 100 beats per minute.…”