Transvenous stimulation yields exposure-dependent protection from ventilator-induced diaphragm atrophy.

Mechanical ventilation (MV)-induced diaphragmatic atrophy can contribute to weaning difficulties. A temporary transvenous diaphragm neurostimulation (TTDN) device that elicits diaphragm contractions has previously been shown to mitigate atrophy during MV in a preclinical model; however, its effects on different myofiber types remain unknown. It is important to examine these effects, as each myofiber type plays a role in the range of diaphragmatic movements to ensure successful liberation from MV. Eighteen pigs were assigned to one of three ventilation conditions for 50 hours: MV-Only and TTDN contracting the diaphragm every other breath or every breath synchronously with MV (TTDN50% + MV and TTDN100% + MV, respectively). Six pigs were assigned to a never-ventilated, never-paced (NV-NP) group. Diaphragm biopsies were fiber-typed, and myofiber cross-sectional areas were measured and normalized to subject weight. There were effect differences based on TTDN exposure. The TTDN100% + MV group showed less atrophy in Type 2A and 2X myofibers than the TTDN50% + MV group, relative to the NV-NP group. The TTDN50% + MV animals showed less MV-induced atrophy in type 1 myofibers than TTDN100% + MV animals. Additionally, there were no significant differences in proportions of myofiber types between each condition. TTDN applied synchronously with MV for 50 hours mitigates MV-induced atrophy in all myofiber types, with no evidence of stimulation-induced myofiber-type shift. At this stimulation profile, enhanced protection for type 1 myofibers and type 2 myofibers was seen when diaphragm contractions occurred every other breath and every breath, respectively.NEW & NOTEWORTHY This research adds to our current understanding of applying temporary transvenous diaphragmatic neurostimulation (TTDN) synchronously with mechanical ventilation by examining its diaphragm-myofiber effects. We observed that using this therapy for 50 hours with mechanical ventilation not only mitigated ventilator-induced atrophy on all myofiber types with dose effects, it also did not invoke alterations in diaphragm myofiber type proportions. These findings suggest that applying TTDN with mechanical ventilation at different doses represents its broad spectrum use and viability as a diaphragm protective strategy.

Phrenic nerve stimulation mitigates hippocampal and brainstem inflammation in an ARDS model.

Rationale: In porcine healthy-lung and moderate acute respiratory distress syndrome (ARDS) models, groups that received phrenic nerve stimulation (PNS) with mechanical ventilation (MV) showed lower hippocampal apoptosis, and microglia and astrocyte percentages than MV alone. Objectives: Explore whether PNS in combination with MV for 12 h leads to differences in hippocampal and brainstem tissue concentrations of inflammatory and synaptic markers compared to MV-only animals. Methods: Compare tissue concentrations of inflammatory markers (IL-1α, IL-1ß, IL-6, IL-8, IL-10, IFN-γ, TNFα and GM-CSF), pre-synaptic markers (synapsin and synaptophysin) and post-synaptic markers (disc-large-homolog 4, N-methyl-D-aspartate receptors 2A and 2B) in the hippocampus and brainstem in three groups of mechanically ventilated pigs with injured lungs: MV only (MV), MV plus PNS every other breath (MV + PNS50%), and MV plus PNS every breath (MV + PNS100%). MV settings in volume control were tidal volume 8 ml/kg, and positive end-expiratory pressure 5 cmH2O. Moderate ARDS was achieved by infusing oleic acid into the pulmonary artery. Measurements and Main Results: Hippocampal concentrations of GM-CSF, N-methyl-D-aspartate receptor 2B, and synaptophysin were greater in the MV + PNS100% group compared to the MV group, p = 0.0199, p = 0.0175, and p = 0.0479, respectively. The MV + PNS100% group had lower brainstem concentrations of IL-1ß, and IL-8 than the MV group, p = 0.0194, and p = 0.0319, respectively; and greater brainstem concentrations of IFN-γ and N-methyl-D-aspartate receptor 2A than the MV group, p = 0.0329, and p = 0.0125, respectively. Conclusion: In a moderate-ARDS porcine model, MV is associated with hippocampal and brainstem inflammation, and phrenic nerve stimulation on every breath mitigates that inflammation.

Risk factors for ventilator-induced-lung injury develop three to five times faster after a single episode of lung injury.

Introduction: Mechanical ventilator breaths provided to deeply sedated patients have an abnormal volume distribution, encouraging alveolar collapse in dependent regions and promoting alveolar overdistention in non-dependent regions. Collapse and overdistention both start with the first breath and worsen over time, driving ventilator-induced lung injury (VILI). This is exacerbated when the lung is already injured or has increased heterogeneity. Our study investigated the impact of a single episode of lung injury on lung mechanics and the risk factors for ventilator-induced injury, compared with non-injured lungs. Methods: Two groups of pigs were sedated and ventilated using lung-protective volume-controlled mode at 8 mL/kg, positive end-expiratory pressure (PEEP) 5 cmH2O, with respiratory rate and FiO2 set to maintain normal blood gas values. Animals in one group were ventilated for 50 h (50-Hour MV group, n=10). Animals in the second group had lung injury induced using oleic acid and were ventilated for 12 h post-injury (LI MV group, n=6). Both groups were compared with a never-ventilated control group (NV, n=6). Lung mechanics and injury were measured using electrical impedance tomography, esophageal pressure monitoring and tissue histology. Results: End-expiratory lung-volume loss was greater in the 50-Hour MV group (P<0.05). Plateau pressure, driving pressure and lung injury score were higher in the LI MV group, (P<0.05). Conclusion: Risk factors for VILI developed three- to five-times faster in the group with injured lungs, demonstrating that a single lung-injury episode substantially increased the risk of VILI, compared with normal lungs, despite using a lung-protective mechanical ventilation protocol.

Negative-pressure-assisted ventilation lowers driving pressure and mechanical power in an ARDS model.

Increased lung heterogeneity from regional alveolar collapse drives ventilator-induced lung injury in patients with acute respiratory distress syndrome (ARDS). New methods of preventing this injury require study. Our study objective was to determine whether the combination of temporary transvenous diaphragm neurostimulation (TTDN) with standard-of-care volume-control mode ventilation changes lung mechanics, reducing ventilator-induced lung injury risk in a preclinical ARDS model. Moderate ARDS was induced using oleic acid administered into the pulmonary artery in pigs, which were ventilated for 12 h postinjury using volume-control mode at 8 mL/kg, positive end-expiratory pressure (PEEP) 5 cmH2O, with respiratory rate and [Formula: see text] set to achieve normal arterial blood gases. Two groups received TTDN, either every second breath [mechanical ventilation (MV) + TTDN50%, n = 6] or every breath (MV + TTDN100%, n = 6). A third group received volume-control ventilation only (MV, n = 6). At study-end, [Formula: see text]/[Formula: see text] was highest and alveolar-arterial oxygen (A-a) gradient was lowest for MV + TTDN100% (P < 0.05). MV + TTDN100% had the smallest end-expiratory lung volume loss and lowest extravascular lung water at study-end (P < 0.05). Static lung compliance was highest and transpulmonary driving pressure was lowest at baseline, postinjury, and study-end in MV + TTDN100% (P < 0.05). The total exposure to transpulmonary driving pressure, mechanical power, and mechanical work was the lowest in MV + TTDN100% (P < 0.05). Lung injury score and total inflammatory cytokine concentration in lung tissue were the lowest in MV + TTDN100% (P < 0.05). Volume-control ventilation plus transvenous diaphragm neurostimulation on every breath improved [Formula: see text]/[Formula: see text], A-a gradient, and alveolar homogeneity, as well as reduced driving pressure, mechanical power, and mechanical work, and resulted in lower lung injury scores and tissue cytokine concentrations in a preclinical ARDS model.NEW & NOTEWORTHY Combining temporary transvenous diaphragm neurostimulation with volume-control ventilation on every breath, called negative-pressure-assisted ventilation, improved gas exchange and alveolar homogeneity in a preclinical model of moderate ARDS. Transpulmonary driving pressure, mechanical power, and mechanical work reductions were observed and resulted in lower lung injury scores and tissue cytokine concentrations in the every-breath-neurostimulation group compared with volume-control ventilation only. Negative-pressure-assisted ventilation is an exciting new potential tool to reduce ventilator-induced lung injury in patients with ARDS.

Diaphragm Neurostimulation Mitigates Ventilation-Associated Brain Injury in a Preclinical Acute Respiratory Distress Syndrome Model.

In a porcine healthy lung model, temporary transvenous diaphragm neurostimulation (TTDN) for 50 hours mitigated hippocampal apoptosis and inflammation associated with mechanical ventilation (MV). HYPOTHESIS: Explore whether TTDN in combination with MV for 12 hours mitigates hippocampal apoptosis and inflammation in an acute respiratory distress syndrome (ARDS) preclinical model. METHODS AND MODELS: Compare hippocampal apoptosis, inflammatory markers, and serum markers of neurologic injury between never ventilated subjects and three groups of mechanically ventilated subjects with injured lungs: MV only (LI-MV), MV plus TTDN every other breath, and MV plus TTDN every breath. MV settings in volume control were tidal volume 8 mL/kg and positive end-expiratory pressure 5 cm H2O. Lung injury, equivalent to moderate ARDS, was achieved by infusing oleic acid into the pulmonary artery. RESULTS: Hippocampal apoptosis, microglia, and reactive-astrocyte percentages were similar between the TTDN-every-breath and never ventilated groups. The LI-MV group had a higher percentage of these measures than all other groups (p < 0.05). Transpulmonary driving pressure at study end was lower in the TTDN-every-breath group than in the LI-MV group; systemic inflammation and lung injury scores were not significantly different. The TTDN-every-breath group had considerably lower serum concentration of homovanillic acid (cerebral dopamine production surrogate) at study end than the LI-MV group (p < 0.05). Heart rate variability declined in the LI-MV group and increased in both TTDN groups (p < 0.05). INTERPRETATIONS AND CONCLUSIONS: In a moderate-ARDS porcine model, MV is associated with hippocampal apoptosis and inflammation, and TTDN mitigates that hippocampal apoptosis and inflammation.

Transvenous Diaphragm Neurostimulation Mitigates Ventilation-associated Brain Injury.

Rationale: Mechanical ventilation (MV) is associated with hippocampal apoptosis and inflammation, and it is important to study strategies to mitigate them. Objectives: To explore whether temporary transvenous diaphragm neurostimulation (TTDN) in association with MV mitigates hippocampal apoptosis and inflammation after 50 hours of MV. Methods: Normal-lung porcine study comparing apoptotic index, inflammatory markers, and neurological-damage serum markers between never-ventilated subjects, subjects undergoing 50 hours of MV plus either TTDN every other breath or every breath, and subjects undergoing 50 hours of MV (MV group). MV settings in volume control were Vt of 8 ml/kg, and positive end-expiratory pressure of 5 cm H2O. Measurements and Main Results: Apoptotic indices, microglia percentages, and reactive astrocyte percentages were greater in the MV group in comparison with the other groups (P < 0.05). Transpulmonary pressure at baseline and at study end were both lower in the group receiving TTDN every breath, but lung injury scores and systemic inflammatory markers were not different between the groups. Serum concentrations of four neurological-damage markers were lower in the group receiving TTDN every breath than in the MV group (P < 0.05). Heart rate variability declined significantly in the MV group and increased significantly in both TTDN groups over the course of the experiments. Conclusions: Our study found that mechanical ventilation is associated with hippocampal apoptosis and inflammation, independent of lung injury and systemic inflammation. Also, in a porcine model, TTDN results in neuroprotection after 50 hours, and the degree of neuroprotection increases with greater exposure to TTDN.

Diaphragm neurostimulation during mechanical ventilation reduces atelectasis and transpulmonary plateau pressure, preserving lung homogeneity and [Formula: see text]/[Formula: see text].

Tidal volume delivered by mechanical ventilation to a sedated patient is distributed in a nonphysiological pattern, causing atelectasis (underinflation) and overdistension (overinflation). Activation of the diaphragm during controlled mechanical ventilation in these sedated patients may provide a method to reduce atelectasis and alveolar inhomogeneity, protecting the lungs from ventilator-induced lung injury while also protecting the diaphragm by preventing ventilator-induced diaphragm dysfunction. We studied the hypothesis that diaphragm contractions elicited by transvenous phrenic nerve stimulation, delivered in synchrony with volume-control ventilation, would reduce atelectasis and lung inhomogeneity in a healthy, normal lung pig model. Twenty-five large pigs were ventilated for 50 h with lung-protective volume-control ventilation combined with synchronous transvenous phrenic-nerve neurostimulation on every breath, or every second breath. This was compared to lung-protective ventilation alone. Lung mechanics and ventilation pressures were measured using esophageal pressure manometry and electrical impedance tomography. Alveolar homogeneity was measured using alveolar chord length of preserved lung tissue. Lung injury was measured using inflammatory cytokine concentration in bronchoalveolar lavage fluid and serum. We found that diaphragm neurostimulation on every breath preserved [Formula: see text]/[Formula: see text] and significantly reduced the loss of end-expiratory lung volume after 50 h of mechanical ventilation. Neurostimulation on every breath reduced plateau and driving pressures, improved both static and dynamic compliance and resulted in less alveolar inhomogeneity. These findings support that temporary transvenous diaphragm neurostimulation during volume-controlled, lung-protective ventilation may offer a potential method to provide both lung- and diaphragm-protective ventilation.NEW & NOTEWORTHY Temporary transvenous diaphragm neurostimulation has been shown to mitigate diaphragm atrophy in a preclinical model. This study contributes to this work by demonstrating that diaphragm neurostimulation can also offer lung protection from ventilator injury, providing a potential solution to the dilemma of lung- versus diaphragm-protective ventilation. Our findings show that neurostimulation on every breath preserved [Formula: see text]/[Formula: see text], end-expiratory lung volume, alveolar homogeneity, and required lower pressures than lung-protective ventilation over 50 h in healthy pigs.

Systematic review of cognitive impairment and brain insult after mechanical ventilation.

We conducted a systematic review following the PRISMA protocol primarily to identify publications that assessed any links between mechanical ventilation (MV) and either cognitive impairment or brain insult, independent of underlying medical conditions. Secondary objectives were to identify possible gaps in the literature that can be used to inform future studies and move toward a better understanding of this complex problem. The preclinical literature suggests that MV is associated with neuroinflammation, cognitive impairment, and brain insult, reporting higher neuroinflammatory markers, greater evidence of brain injury markers, and lower cognitive scores in subjects that were ventilated longer, compared to those ventilated less, and to never-ventilated subjects. The clinical literature suggests an association between MV and delirium, and that delirium in mechanically ventilated patients may be associated with greater likelihood of long-term cognitive impairment; our systematic review found no clinical study that demonstrated a causal link between MV, cognitive dysfunction, and brain insult. More studies should be designed to investigate ventilation-induced brain injury pathways as well as any causative linkage between MV, cognitive impairment, and brain insult.

Brain injury after 50 h of lung-protective mechanical ventilation in a preclinical model.

Mechanical ventilation is the cornerstone of the Intensive Care Unit. However, it has been associated with many negative consequences. Recently, ventilator-induced brain injury has been reported in rodents under injurious ventilation settings. Our group wanted to explore the extent of brain injury after 50 h of mechanical ventilation, sedation and physical immobility, quantifying hippocampal apoptosis and inflammation, in a normal-lung porcine study. After 50 h of lung-protective mechanical ventilation, sedation and immobility, greater levels of hippocampal apoptosis and neuroinflammation were clearly observed in the mechanically ventilated group, in comparison to a never-ventilated group. Markers in the serum for astrocyte damage and neuronal damage were also higher in the mechanically ventilated group. Therefore, our study demonstrated that considerable hippocampal insult can be observed after 50 h of lung-protective mechanical ventilation, sedation and physical immobility.

A Pilot Study on an Interprofessional Course Involving Pharmacy and Dental Students in a Dental Clinic.

Objective. To assess the effect of a dental clinical rotation program involving pharmacy students and dental students. Methods. An interprofessional education (IPE) course was offered as an elective to second-year pharmacy students and required for third-year dental students. The course included two in-class sessions, one online lecture, and five clinic sessions. Program evaluation analyses included a comparison of participating versus nonparticipating students on a knowledge survey of pharmacotherapy and IPE, and a descriptive analysis of IPE course evaluation results. Results. Among pharmacy students, mean scores were significantly higher for participants than nonparticipants on the 31-item pharmacy knowledge component of the survey. On the eight-item IPE component of the survey, scores were significantly higher for participants than for nonparticipants, both among pharmacy students and among dental students. Awareness and attitudes about IPE were generally high among course participants. Conclusion. An IPE course that integrates second-year pharmacy students with third-year dental students in the dental clinic to provide medication history, education, and identification of potential drug-related problems improved pharmacy students' knowledge of pharmacotherapy related to or associated with dental conditions and improved pharmacy and dental students' knowledge and attitudes about IPE.

Mitigation of Ventilator-induced Diaphragm Atrophy by Transvenous Phrenic Nerve Stimulation.

RATIONALE: Ventilator-induced diaphragm dysfunction is a significant contributor to weaning difficulty in ventilated critically ill patients. It has been hypothesized that electrically pacing the diaphragm during mechanical ventilation could reduce diaphragm dysfunction. OBJECTIVES: We tested a novel, central line catheter-based, transvenous phrenic nerve pacing therapy for protecting the diaphragm in sedated and ventilated pigs. METHODS: Eighteen Yorkshire pigs were studied. Six pigs were sedated and mechanically ventilated for 2.5 days with pacing on alternate breaths at intensities that reduced the ventilator pressure-time product by 20-30%. Six matched subjects were similarly sedated and ventilated but were not paced. Six pigs served as never-ventilated, never-paced control animals. MEASUREMENTS AND MAIN RESULTS: Cumulative duration of pacing therapy ranged from 19.7 to 35.7 hours. Diaphragm thickness assessed by ultrasound and normalized to initial value showed a significant decline in ventilated-not paced but not in ventilated-paced subjects (0.84 [interquartile range (IQR), 0.78-0.89] vs. 1.10 [IQR, 1.02-1.24]; P = 0.001). Compared with control animals (24.6 µm2/kg; IQR, 21.6-26.0), median myofiber cross-sectional areas normalized to weight and sarcomere length were significantly smaller in the ventilated-not paced (17.9 µm2/kg; IQR, 15.3-23.7; P = 0.005) but not in the ventilated-paced group (24.9 µm2/kg; IQR, 16.6-27.3; P = 0.351). After 60 hours of mechanical ventilation all six ventilated-paced subjects tolerated 8 minutes of intense phrenic stimulation, whereas three of six ventilated-not paced subjects did not (P = 0.055). There was a nonsignificant decrease in diaphragm tetanic force production over the experiment in the ventilated-paced and ventilated-not paced groups. CONCLUSIONS: These results suggest that early transvenous phrenic nerve pacing may mitigate ventilator-induced diaphragm dysfunction.

Risk factors for mortality in patients admitted to intensive care units with pneumonia.

BACKGROUND: Despite the high mortality in patients with pneumonia admitted to an ICU, data on risk factors for death remain limited. METHODS: In this secondary analysis of PROTECT (Prophylaxis for Thromboembolism in Critical Care Trial), we focused on the patients admitted to ICU with a primary diagnosis of pneumonia. The primary outcome for this study was 90-day hospital mortality and the secondary outcome was 90-day ICU mortality. Cox regression model was conducted to examine the relationship between baseline and time-dependent variables and hospital and ICU mortality. RESULTS: Six hundred sixty seven patients admitted with pneumonia (43.8 % females) were included in our analysis, with a mean age of 60.7 years and mean APACHE II score of 21.3. During follow-up, 111 patients (16.6 %) died in ICU and in total, 149 (22.3 %) died in hospital. Multivariable analysis demonstrated significant independent risk factors for hospital mortality including male sex (hazard ratio (HR) = 1.5, 95 % confidence interval (CI): 1.1 - 2.2, p-value = 0.021), higher APACHE II score (HR = 1.2, 95 % CI: 1.1 - 1.4, p-value < 0.001 for per-5 point increase), chronic heart failure (HR = 2.9, 95 % CI: 1.6 - 5.4, p-value = 0.001), and dialysis (time-dependent effect: HR = 2.7, 95 % CI: 1.3 - 5.7, p-value = 0.008). Higher APACHE II score (HR = 1.2, 95 % CI: 1.1 - 1.4, p-value = 0.002 for per-5 point increase) and chronic heart failure (HR = 2.6, 95 % CI: 1.3 - 5.0, p-value = 0.004) were significantly related to risk of death in the ICU. CONCLUSION: In this study using data from a multicenter thromboprophylaxis trial, we found that male sex, higher APACHE II score on admission, chronic heart failure, and dialysis were independently associated with risk of hospital mortality in patients admitted to ICU with pneumonia. While high illness severity score, presence of a serious comorbidity (heart failure) and need for an advanced life support (dialysis) are not unexpected risk factors of mortality, male sex might necessitate further exploration. More studies are warranted to clarify the effect of these risk factors on survival in critically ill patients admitted to ICU with pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00182143 .

Moral distress in intensive care unit professionals is associated with profession, age, and years of experience.

PURPOSE: To determine which demographic characteristics are associated with moral distress in intensive care unit (ICU) professionals. METHODS: We distributed a self-administered, validated survey to measure moral distress to all clinical personnel in 13 ICUs in British Columbia, Canada. Each respondent to the survey also reported their age, sex, and years of experience in the ICU where they were working. We used multivariate, hierarchical regression to analyze relationships between demographic characteristics and moral distress scores, and to analyze the relationship between moral distress and tendency to leave the workplace. RESULTS: Response rates to the surveys were the following: nurses--428/870 (49%); other health professionals (not nurses or physicians)--211/452 (47%); physicians--30/68 (44%). Nurses and other health professionals had higher moral distress scores than physicians. Highest ranked items associated with moral distress were related to cost constraints and end-of-life controversies. Multivariate analyses showed that age is inversely associated with moral distress, but only in other health professionals (rate ratio [95% confidence interval]: -7.3 [-13.4, -1.2]); years of experience is directly associated with moral distress, but only in nurses (rate ratio (95% confidence interval):10.8 [2.6, 18.9]). The moral distress score is directly related to the tendency to leave the ICU job, in both the past and present, but only for nurses and other non-physician health professionals. CONCLUSION: Moral distress is higher in ICU nurses and other non-physician professionals than in physicians, is lower with older age for other non-physician professionals but greater with more years of experience in nurses, and is associated with tendency to leave the job.