Tidal Volume Ventilation Research Articles

Fentanyl and neostigmine delivered to mouse prefrontal cortex differentially alter breathing

Opioids impair many functions modulated by the prefrontal cortex (PFC), including wakefulness, cognition, and breathing. In contrast, cholinergic activity in the PFC increases wakefulness. This study tested the hypothesis that microinjecting the opioid fentanyl and the acetylcholinesterase inhibitor neostigmine into the PFC of awake C57BL/6J male mice (n = 27) alters breathing. The lateral and medial PFC were unilaterally microinjected with saline (control) and fentanyl. The medial PFC received additional microinjections of neostigmine. The results show that fentanyl caused site-specific changes in breathing. Fentanyl delivered to the lateral PFC significantly decreased minute ventilation variability, whereas fentanyl delivered to the medial PFC significantly increased tidal volume and duty cycle. Neostigmine microinjected into the medial PFC significantly increased respiratory rate, tidal volume, and minute ventilation. A final series of experiments revealed that decreased minute ventilation caused by systemic fentanyl administration was mitigated by PFC microinjection of neostigmine.

High flow nasal cannula improves breathing efficiency and ventilatory ratio in COPD patients recovering from an exacerbation.

High flow nasal cannula (HFNC) may improve CO2 elimination by washing out CO2 from the upper airways. This study aimed at assessing the effect of HFNC on minute ventilation and ventilatory ratio (VR), a surrogate of dead space, in patients hospitalized for acute hypercapnic COPD exacerbation. Physiological study comparing HFNC at 40 L/min to low flow oxygen. Variations of tidal volume (VT) and minute ventilation between the two treatments were estimated from chest plethysmography. Respiratory rate (RR) and arterial blood gases were measured. Variations in VR were calculated. Data were compared using Wilcoxon tests. Recordings performed in 10 patients. Minute ventilation was reduced with HFNC by -16.2 [-30.9-0.4] % (p = 0.049). VT was not different but RR was lower during HFNC. PaCO2 was lower with HFNC compared to standard oxygen: 48.7 [46.4-58.1] vs 50.7 [48.4-57.5] mmHg (p = 0.020). VR decreased by -18.0 [-34.7 - -4.0] % (p = 0.020) with HFNC. In patients recovering from acute COPD exacerbation, the use of HFNC reduced RR, minute ventilation, PaCO2 and VR compared to standard oxygen. These changes are consistent with a decrease in physiologic dead space with HFNC.

S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats.

Endogenous and exogenously administered S-nitrosothiols modulate the activities of central and peripheral systems that control breathing. We have unpublished data showing that the deleterious effects of morphine on arterial blood-gas chemistry (i.e., pH, pCO2, pO2, and sO2) and Alveolar-arterial gradient (i.e., index of gas exchange) were markedly diminished in anesthetized Sprague Dawley rats that received a continuous intravenous infusion of the endogenous S-nitrosothiol, S-nitroso-L-cysteine. The present study extends these findings by showing that unanesthetized adult male Sprague Dawley rats receiving an intravenous infusion of S-nitroso-L-cysteine (100 or 200 nmol/kg/min) markedly diminished the ability of intravenous injections of the potent synthetic opioid, fentanyl (10, 25, and 50 μg/kg), to depress the frequency of breathing, tidal volume, and minute ventilation. Our study also found that the ability of intravenously injected fentanyl (10, 25, and 50 μg/kg) to disturb eupneic breathing, which was measured as a marked increase of the non-eupneic breathing index, was substantially reduced in unanesthetized rats receiving intravenous infusions of S-nitroso-L-cysteine (100 or 200 nmol/kg/min). In contrast, the deleterious effects of fentanyl (10, 25, and 50 μg/kg) on frequency of breathing, tidal volume, minute ventilation and non-eupneic breathing index were fully expressed in rats receiving continuous infusions (200 nmol/kg/min) of the parent amino acid, L-cysteine, or the D-isomer, namely, S-nitroso-D-cysteine. In addition, the antinociceptive actions of the above doses of fentanyl as monitored by the tail-flick latency assay, were enhanced by S-nitroso-L-cysteine, but not L-cysteine or S-nitroso-D-cysteine. Taken together, these findings add to existing knowledge that S-nitroso-L-cysteine stereoselectively modulates the detrimental effects of opioids on breathing, and opens the door for mechanistic studies designed to establish whether the pharmacological actions of S-nitroso-L-cysteine involve signaling processes that include 1) the activation of plasma membrane ion channels and receptors, 2) selective intracellular entry of S-nitroso-L-cysteine, and/or 3) S-nitrosylation events. Whether alterations in the bioavailability and bioactivity of endogenous S-nitroso-L-cysteine is a key factor in determining the potency/efficacy of fentanyl on breathing is an intriguing question.

Inhaled CO2 vs. Hypercapnia Obtained by Low Tidal Volume or Instrumental Dead Space in Unilateral Pulmonary Artery Ligation: Any Difference for Lung Protection?

BackgroundUnilateral ligation of the pulmonary artery (UPAL) induces bilateral lung injury in pigs undergoing controlled mechanical ventilation. Possible mechanisms include redistribution of ventilation toward the non-ligated lung and hypoperfusion of the ligated lung. The addition of 5% CO2 to the inspiratory gas (FiCO2) prevents the injury, but it is not clear whether lung protection is a direct effect of CO2 inhalation or it is mediated by plasmatic hypercapnia. This study aims to compare the effects and mechanisms of FiCO2 vs. hypercapnia induced by low tidal volume ventilation or instrumental dead space.MethodsHealthy pigs underwent left UPAL and were allocated for 48 h to the following: Volume-controlled ventilation (VCV) with VT 10 ml/kg (injury, n = 6); VCV plus 5% FiCO2 (FiCO2, n = 7); VCV with VT 6 ml/kg (low VT, n = 6); VCV plus additional circuit dead space (instrumental VD, n = 6). Histological score, regional compliance, wet-to-dry ratio, and inflammatory infiltrate were assessed to evaluate lung injury at the end of the study. To investigate the mechanisms of protection, we quantified the redistribution of ventilation to the non-ligated lung, as the ratio between the percentage of tidal volume to the right and to the left lung (VTRIGHT/LEFT), and the hypoperfusion of the ligated lung as the percentage of blood flow reaching the left lung (PerfusionLEFT).ResultsIn the left ligated lung, injury was prevented only in the FiCO2 group, as indicated by lower histological score, higher regional compliance, lower wet-to-dry ratio and lower density of inflammatory cells compared to other groups. For the right lung, the histological score was lower both in the FiCO2 and in the low VT groups, but the other measures of injury showed lower intensity only in the FiCO2 group. VTRIGHT/LEFT was lower and PerfusionLEFT was higher in the FiCO2 group compared to other groups.ConclusionIn a model of UPAL, inhaled CO2 but not hypercapnia grants bilateral lung protection. Mechanisms of protection include reduced overdistension of the non-ligated and increased perfusion of the ligated lung.

Time-Controlled Adaptive Ventilation Does Not Induce Hemodynamic Impairment in a Swine ARDS Model.

BackgroundThe current standard of care during severe acute respiratory distress syndrome (ARDS) is based on low tidal volume (VT) ventilation, at 6 mL/kg of predicted body weight. The time-controlled adaptive ventilation (TCAV) is an alternative strategy, based on specific settings of the airway pressure release ventilation (APRV) mode. Briefly, TCAV reduces lung injury, including: (1) an improvement in alveolar recruitment and homogeneity; (2) reduction in alveolar and alveolar duct micro-strain and stress-risers. TCAV can result in higher intra-thoracic pressures and thus impair hemodynamics resulting from heart-lung interactions. The objective of our study was to compare hemodynamics between TCAV and conventional protective ventilation in a porcine ARDS model.MethodsIn 10 pigs (63–73 kg), lung injury was induced by repeated bronchial saline lavages followed by 2 h of injurious ventilation. The animals were then randomized into two groups: (1) Conventional protective ventilation with a VT of 6 mL/kg and PEEP adjusted to a plateau pressure set between 28 and 30 cmH2O; (2) TCAV group with P-high set between 27 and 29 cmH2O, P-low at 0 cmH2O, T-low adjusted to terminate at 75% of the expiratory flow peak, and T-high at 3–4 s, with I:E > 6:1.ResultsBoth lung elastance and PaO2:FiO2 were consistent with severe ARDS after 2 h of injurious mechanical ventilation. There was no significant difference in systemic arterial blood pressure, pulmonary blood pressure or cardiac output between Conventional protective ventilation and TCAV. Levels of total PEEP were significantly higher in the TCAV group (p < 0.05). Driving pressure and lung elastance were significantly lower in the TCAV group (p < 0.05).ConclusionNo hemodynamic adverse events were observed in the TCAV group compared as to the standard protective ventilation group in this swine ARDS model, and TCAV appeared to be beneficial to the respiratory system.

Intraoperative low tidal volume ventilation and the risk of ICD-10 coded delirium and the use for antipsychotic medications

BackgroundLow tidal volume (VT) ventilation and its associated increase in arterial carbon dioxide (PaCO2) may affect postoperative neurologic function. We aimed to test the hypothesis that intraoperative low VT ventilation affect the incidence of postoperative ICD-10 coded delirium and/or the need for antipsychotic medications.MethodsThis is a post-hoc analysis of a large randomized controlled trial evaluating low vs. conventional VT ventilation during major non-cardiothoracic, non-intracranial surgery. The primary outcome was the incidence of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay, and the absolute difference with its 95% confidence interval (CI) was calculated.ResultsWe studied 1206 patients (median age of 64 [55–72] years, 59.0% males, median ARISCAT of 26 [19–37], and 47.6% of ASA 3). ICD-10 coded delirium and /or antipsychotic medication use was diagnosed in 11.2% with similar incidence between low and conventional VT ventilation (11.1% vs. 11.3%; absolute difference, -0.24 [95%CI, -3.82 to 3.32]; p = 0.894). There was no interaction between allocation group and type of surgery.ConclusionIn adult patients undergoing major surgery, low VT ventilation was not associated with increased risk of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay.Trial registrationANZCTR Identifier: ACTRN12614000790640.

Efficacy of using tidal volume challenge to improve the reliability of pulse pressure variation reduced in low tidal volume ventilated critically ill patients with decreased respiratory system compliance

BackgroundThe prediction accuracy of pulse pressure variation (PPV) for fluid responsiveness was proposed to be unreliable in low tidal volume (Vt) ventilation. It was suggested that changes in PPV obtained by transiently increasing Vt to 8 ml/kg accurately predicted fluid responsiveness even in subjects receiving low Vt. We assessed whether the changes in PPV induced by a Vt challenge predicted fluid responsiveness in our critically ill subjects ventilated with low Vt 6 ml/kg.MethodsThis study is a prospective single-center study. PPV and other parameters were measured at a Vt of 6 mL/kg, 8 mL/kg, and after volume expansion. The prediction accuracy of PPV and other parameters for fluid responsiveness before and after tidal volume challenge was also analyzed using receiver operating characteristic (ROC) curves.ResultsThirty-one of the 76 subjects enrolled in the study were responders (41%). Respiratory system compliance of all subjects decreased significantly (26 ± 4.3). The PPV values were significantly higher in the responder group than the non-responder group before (8.8 ± 2.7 vs 6.8 ± 3.1) or after (13.0 ± 1.7 vs 8.5 ± 3.0) Vt challenge. In the receiver operating characteristic curve (ROC) analysis, PPV6 showed unsatisfactory predictive capability with an area under the curve (AUC) of 0.69 (95%CI, 0.57–0.79, p = 0.002) at a Vt of 6 mL/kg. PPV8 andΔPPV6–8 showed good predictive capability with an AUC of 0.90 (95% CI, 0.81–0.96, p < 0.001) and 0.90 (95% CI, 0.80–0.95, P < 0.001) respectively. The corresponding cutoff values were 11% for PPV8 and 2% for ΔPPV6–8.ConclusionsPPV shows a poor operative performance as a predictor of fluid responsiveness in critically ill subjects ventilated with a tidal volume of 6 mL/ kg. Vt challenge could improve the predictive accuracy of PPV to a good but not excellent extent when respiratory system compliance decreased significantly.

The efficacy of different alveolar recruitment maneuvers in holmium laser lithotripsy surgery under general anesthesia using a laryngeal mask

BackgroundAlveolar recruitment maneuvers (ARMs) is an important part of lung-protective ventilation strategies (LPVSs), but the optimal duration and interval Remain unclear.MethodsPatients:252 patients who underwent holmium laser lithotripsy surgery and meet inclusion criteria were included and randomized into three groups based on the duration and frequency of ARMs (Regular, one 30 s ARM (RARMs); Improved and intermittent, three 10s ARMs (IARMs); and Control (C), no ARMs).Interventions: Groups R and I received ARMs at 20 cmH2O pressures every 30 min. All patients received the same anesthesia and mechanical ventilation. Measurements:Outcomes included heart rate and mean arterial pressure changes during ARMs and postoperative pulmonary complications (PPCs) within the first 7 postoperative days.Main resultsIncidences of PPCs in groups R(7.1%) and I (5.0%)were slightly lower than those in group C (8.9%).This indicated the potential to reduce lung injury. Heart rate and mean arterial pressure fluctuations during ARMs were significantly higher in groups R and I than in group C (P < 0.01). The rate of blood pressure decrease was significantly higher in group R than in group I (P < 0.01).ConclusionsIARMs can reduce cycle fluctuations than RARMs in patients Undergoing holmium laser lithotripsy surgery with laryngeal mask general anesthesia. Low tidal volume ventilation and low PEEP combined with ARM did not significantly reduce the incidence of PPCs in healthy lung patients, but tended to reduce lung injury.Trial registrationThe study was registered on the Chinese Clinical Trial Registry.(ChiCTR2000030815,15/03/2020). This study was approved by the ethics committee of Chengdu Fifth People’s Hospital with approval number(2020–005(Study)-1).

Central nervous system 5‐HT plays a role in ventilatory and arousal responses to hypoxia and hypercapnia in spinal cord injured mice

PurposeThe present investigation was designed to explore the impact of serotonin (5HT) on the arousal and ventilatory response to hypercapnia and hypoxia following spinal cord injury (SCI) in mice.MethodsTelemetry transmitters were surgically implanted in wild type mice (Tph2+/+) (n =7 for SCI, n=7 for Sham) and tryptophan hydroxylase 2 knockout mice (Tph2‐/‐) (n=6 for SCI, n=6 for Sham) to measure electroencephalography, electromyography (EMG) of the genioglossus (GG) muscle, core body temperature and gross motor activity. Following recovery, the Tph2+/+ and Tph2‐/‐ mice were placed in whole body plethysmographs and measures of the ventilatory and arousal response to hypoxia and hypercapnia during non‐rapid eye movement sleep were obtained. Following these measures, a C2 hemi‐section of the spinal cord was completed and the physiological measurements were repeated 4 and 21 days following SCI. The ventilatory data is presented as a fraction of baseline.ResultsThe breathing frequency, tidal volume, and minute ventilation response to hypercapnia was greater in Tph2+/+ compared to Tph2‐/‐ mice at 21 days post SCI (Breathing frequency: 1.37 ± 0.12 vs. 1.02 ± 0.10, p = 0.036, Tidal volume: 1.70 ± 0.21 vs. 0.91 ± 0.09, p = 0.002, Minute Ventilation: 2.87 ± 0.48 vs. 0.93 ± 0.12, p = 0.001). In addition, the tidal volume and minute ventilation response to hypoxia was greater in Tph2+/+ compared to Tph2‐/‐ mice at 21 days post SCI (Tidal Volume: 1.27 ± 0.09 vs. 0.94 ± 0.08, p = 0.009, Minute Ventilation: 1.45 ± 0.14 vs. 0.98 ± 0.09, p = 0.012). The arousal latency to hypercapnia was reduced in Tph2+/+ compared to Tph2‐/‐ mice at 4 days post SCI (16.22 ± 4.15 vs. 73.83 ± 15.78 s, p = 0.013). The number of arousals during exposure to hypercapnia was greater in Tph2+/+ compared to Tph2‐/‐ mice at 21 days post SCI (5.31 ± 0.50 vs. 3.40 ± 0.51, p = 0.021). The magnitude of the GG response to hypercapnia and hypoxia was greater in Tph2+/+ compared to Tph2‐/‐ mice at 21 days post SCI (Hypercapnia: 47.42 ± 10.17 vs. 0.73 ± 0.18, p = 0.012, Hypoxia: 43.82 ± 11.25 vs. 3.30 ± 1.65, p = 0.019). The fraction of episodes in which there was no EMG response to hypercapnia and hypoxia was lower in Tph2+/+ compared to Tph2‐/‐mice at 4 days post SCI (Hypercapnia: 0.43 ± 0.10 vs. 0.92 ± 0.08, p = 0.001 Hypoxia: 0.19 ± 0.12 vs. 0.85 ± 0.15, p = 0.008). The fraction of episodes in which there was no EMG response to hypercapnia was lower in Tph2+/+ compared to Tph2‐/‐ mice at 21 days post SCI (0.19 ± 0.06 vs. 0.79 ± 0.10, p = 0.001).ConclusionThe ventilatory, arousal and GG response to hypercapnia and hypoxia is greater in Tph2+/+ compared to Tph2‐/‐ mice following SCI. Our results suggest that deficiencies in serotonin have a role in regulating respiratory and arousal responses to hypercapnia and hypoxia following SCI.

A Model of Repeated Opioid Use Producing Tolerance to Opioid Induced Respiratory Depression

Repeated opioid users, such as those who suffer from opioid use disorder, are among the most vulnerable to overdose, overdose‐related death, and opioid‑related morbidities in breathing in the ongoing epidemic. Despite the significant progress made in defining the cellular and circuit basis by which opioid induced respiratory depression (OIRD) occurs, very little is known about the impact that repeated opioid use (ROU) has on the control of breathing. This ongoing work aims to define how ROU impacts the OIRD. We developed a mouse model of ROU that involved six consecutive days of fentanyl (0.7mg/kg via i.p. injection) administration. Breathing was measured via unrestrained whole‐body plethysmography prior to and immediately after fentanyl administration on Day 1 and Day 6. Prior to fentanyl administration, tidal volume (TV), respiratory rate (RR) and minute ventilation (Vmin) were similar on Day 1 and Day 6 (n= 7 mice). Peak depression of TV during fentanyl was similar on Day 1 and Day 6 (n=7, P=0.28); whereas, peak depression of RR (Day 1: 145.5±19.66­BPM vs. Day 6: 172.0 ± 18.89,P=0.005) and Vmin (Day 1: 142.0±30.23­microL•min‐1•g‐1 vs. Day 6: 210.1±21.96­microL•min‐1•g‐1, P=0.04) during fentanyl was greater on Day 1 (n= 6 of 7). Moreover, the change in body temperature during OIRD was not different between Day 1 and Day 6 (Day 1: 0.04±0.021oC vs. Day 6: 0.64 ± 0.021oC, P=0.62). Together these data suggest that tolerance to OIRD emerges following six days of ROU and does not involve significant changes in body temperature. The data from this ongoing study provides foundational knowledge to the impact of ROU on breathing and introduces a novel model of ROU that leads to tolerance to OIRD.

Low tidal volume ventilation is associated with mortality in COVID-19 patients-Insights from the PRoVENT-COVID study.

PurposeLow tidal volume ventilation (LTVV) is associated with mortality in patients with acute respiratory distress syndrome. We investigated the association of LTVV with mortality in COVID-19 patients.MethodsSecondary analysis of a national observational study in COVID-19 patients in the first wave of the pandemic. We compared COVID-19 patients that received LTVV, defined as controlled ventilation with a median tidal volume ≤ 6 mL/kg predicted body weight over the first 4 calendar days of ventilation, with patients that did not receive LTVV. The primary endpoint was 28-day mortality. In addition, we identified factors associated with use of LTVV.ResultsOf 903 patients, 294 (32.5%) received LTVV. Disease severity scores and ARDS classification was not different between the two patient groups. The primary endpoint, 28-day mortality, was met in 68 out of 294 patients (23.1%) that received LTVV versus in 193 out of 609 patients (31.7%) that did not receive LTVV (P < 0.001). LTVV was independently associated with 28-day mortality (HR, 0.68 (0.45 to 0.95); P = 0.025). Age, height, the initial tidal volume and continuous muscle paralysis was independently associated with use of LTVV.ConclusionsIn this cohort of invasively ventilated COVID-19 patients, approximately a third of patients received LTVV. Use of LTVV was independently associated with reduced 28-day mortality. The initial tidal volume and continuous muscle paralysis were potentially modifiable factors associated with use of LTVV. These findings are important as they could help clinicians to recognize patients who are at risk of not receiving LTVV.

Acute intermittent hypercapnic-hypoxia elicits central neural respiratory motor plasticity in humans.

Acute intermittent hypoxia (AIH) elicits long-term facilitation (LTF) of respiration. Although LTF is observed when CO2 is elevated during AIH in awake humans, the influence of CO2 on corticospinal respiratory motor plasticity is unknown. Thus, we tested the hypotheses that acute intermittent hypercapnic-hypoxia (AIHH): (1) enhances cortico-phrenic neurotransmission (reflecting volitional respiratory control); and (2) elicits ventilatory LTF (reflecting automatic respiratory control). Eighteen healthy adults completed four study visits. Day 1 consisted of anthropometry and pulmonary function testing. On Days 2, 3 and 4, in a balanced alternating sequence, participants received: AIHH, poikilocapnic AIH, and normocapnic-normoxia (Sham). Protocols consisted of 15, 60s exposures with 90s normoxic intervals. Transcranial (TMS) and cervical (CMS) magnetic stimulation were used to induce diaphragmatic motor-evoked potentials and compound muscle action potentials, respectively. Respiratory drive was assessed via mouth occlusion pressure (P0.1 ), and minute ventilation measured at rest. Dependent variables were assessed at baseline and 30-60min after exposures. Increases in TMS-evoked diaphragm potential amplitudes were observed following AIHH vs. Sham (+28±41%, P=0.003), but not after AIH. No changes were observed in CMS-evoked diaphragm potential amplitudes. Mouth occlusion pressure also increased after AIHH (+21±34%, P=0.033), but not after AIH. Ventilatory LTF was not observed after any treatment. We demonstrate that AIHH elicits central neural mechanisms of respiratory motor plasticity and increases resting respiratory drive in awake humans. These findings may have important implications for neurorehabilitation after spinal cord injury and other neuromuscular disorders compromising breathing. KEY POINTS: The occurrence of respiratory long-term facilitation following acute exposure to intermittent hypoxia is believed to be dependent upon CO2 regulation - mechanisms governing the critical role of CO2 have seldom been explored. We tested the hypothesis that acute intermittent hypercapnic-hypoxia (AIHH) enhances cortico-phrenic neurotransmission in awake healthy humans. The amplitude of diaphragmatic motor-evoked potentials induced by transcranial magnetic stimulation was increased after AIHH, but not the amplitude of compound muscle action potentials evoked by cervical magnetic stimulation. Mouth occlusion pressure (P0.1 , an indicator of neural respiratory drive) was also increased after AIHH, but not tidal volume or minute ventilation. Thus, moderate AIHH elicits central neural mechanisms of respiratory motor plasticity, without measurable ventilatory long-term facilitation in awake humans.

Lung-Protective Ventilation Attenuates Mechanical Injury While Hypercapnia Attenuates Biological Injury in a Rat Model of Ventilator-Associated Lung Injury.

Background and Objective: Lung-protective mechanical ventilation is known to attenuate ventilator-associated lung injury (VALI), but often at the expense of hypoventilation and hypercapnia. It remains unclear whether the main mechanism by which VALI is attenuated is a product of limiting mechanical forces to the lung during ventilation, or a direct biological effect of hypercapnia. Methods: Acute lung injury (ALI) was induced in 60 anesthetized rats by the instillation of 1.25 M HCl into the lungs via tracheostomy. Ten rats each were randomly assigned to one of six experimental groups and ventilated for 4 h with: 1) Conventional HighV E Normocapnia (high VT, high minute ventilation, normocapnia), 2) Conventional Normocapnia (high VT, normocapnia), 3) Protective Normocapnia (VT 8 ml/kg, high RR), 4) Conventional iCO 2 Hypercapnia (high VT, low RR, inhaled CO2), 5) Protective iCO 2 Hypercapnia (VT 8 ml/kg, high RR, added CO2), 6) Protective endogenous Hypercapnia (VT 8 ml/kg, low RR). Blood gasses, broncho-alveolar lavage fluid (BALF), and tissue specimens were collected and analyzed for histologic and biologic lung injury assessment. Results: Mild ALI was achieved in all groups characterized by a decreased mean PaO2/FiO2 ratio from 428 to 242 mmHg (p < 0.05), and an increased mean elastance from 2.46 to 4.32 cmH2O/L (p < 0.0001). There were no differences in gas exchange among groups. Wet-to-dry ratios and formation of hyaline membranes were significantly lower in low VT groups compared to conventional tidal volumes. Hypercapnia reduced diffuse alveolar damage and IL-6 levels in the BALF, which was also true when CO2 was added to conventional VT. In low VT groups, hypercapnia did not induce any further protective effect except increasing pulmonary IL-10 in the BALF. No differences in lung injury were observed when hypercapnia was induced by adding CO2 or decreasing minute ventilation, although permissive hypercapnia decreased the pH significantly and decreased liver histologic injury. Conclusion: Our findings suggest that low tidal volume ventilation likely attenuates VALI by limiting mechanical damage to the lung, while hypercapnia attenuates VALI by limiting pro-inflammatory and biochemical mechanisms of injury. When combined, both lung-protective ventilation and hypercapnia have the potential to exert an synergistic effect for the prevention of VALI.

Surfactant Treatment Shows Higher Correlation Between Ventilator and EIT Tidal Volumes in an RDS Animal Model.

Neonatal respiratory distress syndrome (RDS) is a condition of pulmonary surfactant insufficiency in the premature newborn. As such, artificial pulmonary surfactant administration is a key treatment. Despite continued improvement in the clinical outcomes of RDS, there are currently no established bedside tools to monitor whether pulmonary surfactant is effectively instilled throughout the lungs. Electrical impedance tomography (EIT) is an emerging technique in which physiological functions are monitored on the basis of temporal changes in conductivity of different tissues in the body. In this preliminary study, we aimed to assess how EIT tidal volumes correlate with ventilator tidal volumes in an RDS animal model, namely untreated, surfactant-treated, and normal control rabbit pups. Tidal volumes were measured simultaneously on an EIT system and a mechanical ventilator and compared at different peak inspiratory pressures. The linear correlation between tidal volumes measured by EIT and by ventilator had an R 2 of 0.71, 0.76 and 0.86 in the untreated, surfactant-treated, and normal control groups, respectively. Bland–Altman analysis showed a good correlation between the measurements obtained with these two modalities. The intraclass correlation coefficients (ICC) between ventilator tidal volume and EIT tidal volume were 0.83, 0.87, and 0.93 (all p < 0.001) in the untreated, surfactant-treated, and normal control groups, respectively, indicating that the higher ICC value, the better inflated status of the lung. In conclusion, we demonstrated that EIT tidal volume correlated with ventilator tidal volume. ICC was higher in the surfactant treated group.

Mechanical Ventilation Practices and Low Tidal Volume Ventilation in Air Medical Transport Patients: The AIR-VENT Study.

The management of mechanical ventilation critically impacts outcome for patients with acute respiratory failure. Ventilator settings in the early post-intubation period may be especially influential on outcome. Low tidal volume ventilation in the prehospital setting has been shown to impact the provision of low tidal volume after admission and influence outcome. However, there is an overall paucity of data on mechanical ventilation for air medical transport patients. The objectives of this study were to characterize air medical transport ventilation practices and assess variables associated with nonprotective ventilation. This was a multi-center, nationwide (approximately 130 bases) retrospective cohort study conducted on consecutive, adult mechanically ventilated air medical transport patients treated in the prehospital environment. Descriptive statistics were used to assess the cohort; the chi-square test compared categorical variables, and continuous variables were compared using independent samples t test or Mann-Whitney U test. To assess for predictors of nonprotective ventilation, a multivariable logistic regression model was constructed to adjust for potentially confounding variables. Low tidal volume ventilation was defined as a tidal volume of ≤ 8 mL/kg predicted body weight (PBW). A total of 68,365 subjects were studied. Height was documented in only 4,186 (6.1%) subjects. Significantly higher tidal volume/PBW (8.6 [8.3-9.2] mL vs 6.5 [6.1-7.0] mL) and plateau pressure (20.0 [16.5-25.0] cm H2O vs 18.0 [15.0-22.0] cm H2O) were seen in the nonpro-tective ventilation group (P < .001 for both). According to sex, females received higher tidal volume/PBW compared to males (7.4 [6.6-8.0] mL vs 6.4 [6.0-6.8] mL, P < .001) and composed 75% of those subjects with nonprotective ventilation compared to 25% male, P < .001. After multivariable logistic regression, female sex was an independent predictor of nonprotective ventilation (adjusted odds ratio 6.79 [95% CI 5.47-8.43], P < .001). The overwhelming majority of air medical transport subjects had tidal volume set empirically, which may be exposing patients to nonprotective ventilator settings. Given a lack of PBW assessments, the frequency of low tidal volume use remains unknown. Performance improvement initiatives aimed at indexing tidal volume to PBW are easy targets to improve the delivery of mechanical ventilation in the prehospital arena, especially for females.

Intraoperative positive end-expiratory pressure and postoperative pulmonary complications: a patient-level meta-analysis of three randomised clinical trials

BackgroundHigh intraoperative PEEP with recruitment manoeuvres may improve perioperative outcomes. We re-examined this question by conducting a patient-level meta-analysis of three clinical trials in adult patients at increased risk for postoperative pulmonary complications who underwent non-cardiothoracic and non-neurological surgery. MethodsThe three trials enrolled patients at 128 hospitals in 24 countries from February 2011 to February 2018. All patients received volume-controlled ventilation with low tidal volume. Analyses were performed using one-stage, two-level, mixed modelling (site as a random effect; trial as a fixed effect). The primary outcome was a composite of postoperative pulmonary complications within the first week, analysed using mixed-effect logistic regression. Pre-specified subgroup analyses of nine patient characteristics and seven procedure and care-delivery characteristics were also performed. ResultsComplete datasets were available for 1913 participants ventilated with high PEEP and recruitment manoeuvres, compared with 1924 participants who received low PEEP. The primary outcome occurred in 562/1913 (29.4%) participants randomised to high PEEP, compared with 620/1924 (32.2%) participants randomised to low PEEP (unadjusted odds ratio [OR]=0.87; 95% confidence interval [95% CI], 0.75–1.01; P=0.06). Higher PEEP resulted in 87/1913 (4.5%) participants requiring interventions for desaturation, compared with 216/1924 (11.2%) participants randomised to low PEEP (OR=0.34; 95% CI, 0.26–0.45). Intraoperative hypotension was associated more frequently (784/1913 [41.0%]) with high PEEP, compared with low PEEP (579/1924 [30.1%]; OR=1.87; 95% CI, 1.60–2.17). ConclusionsHigh PEEP combined with recruitment manoeuvres during low tidal volume ventilation in patients undergoing major surgery did not reduce postoperative pulmonary complications. Clinical trial registrationNCT03937375 (Clinicaltrials.gov).

Diaphragmatic Activity and Respiratory Function Following C3 or C6 Unilateral Spinal Cord Contusion in Mice.

Simple SummaryTetraplegia is one of the most devastating conditions that an individual can sustain and affects more than 2.5 million people worldwide. Tetraplegia not only affects mobility but also impacts spontaneous breathing such that survivors can be rendered ventilator dependent and have increased mortality. Although no treatment can restore respiratory function after tetraplegia, there is a need for more exploratory studies defining therapeutic approaches to ameliorate respiratory decline in tetraplegia. Here, we studied two models of tetraplegia mimicking human forms of injury, using spinal cord contusion in mice, either above the third cervical metameric segment (C3 model) or below the sixth cervical metameric segment (C6 model) innervation of the phrenic nerves. These nerves are responsible for contraction of the diaphragm, the main inspiratory muscle. Using measurements of spontaneous breathing and muscle activity of the diaphragm, we found reduced diaphragmatic activity in both models, but only the C3 model led to reduced spontaneous breathing similar to what is seen in humans with tetraplegia. Moreover, we found a decline in basal contractility of the diaphragm in the C3 model only. We conclude that the C3 model is an appropriate model to explore interventions aimed at restoring breathing following tetraplegia.The majority of spinal cord injuries (SCIs) are cervical (cSCI), leading to a marked reduction in respiratory capacity. We aimed to investigate the effect of hemicontusion models of cSCI on both diaphragm activity and respiratory function to serve as preclinical models of cervical SCI. Since phrenic motoneuron pools are located at the C3–C5 spinal level, we investigated two models of preclinical cSCI mimicking human forms of injury, namely, one above (C3 hemicontusion—C3HC) and one below phrenic motoneuron pools (C6HC) in wild-type swiss OF-1 mice, and we compared their effects on respiratory function using whole-body plethysmography and on diaphragm activity using electromyography (EMG). At 7 days post-surgery, both C3HC and C6HC damaged spinal cord integrity above the lesion level, suggesting that C6HC potentially alters C5 motoneurons. Although both models led to decreased diaphragmatic EMG activity in the injured hemidiaphragm compared to the intact one (−46% and −26% in C3HC and C6HC, respectively, both p = 0.02), only C3HC led to a significant reduction in tidal volume and minute ventilation compared to sham surgery (−25% and −20% vs. baseline). Moreover, changes in EMG amplitude between respiratory bursts were observed post-C3HC, reflecting a change in phrenic motoneuronal excitability. Hence, C3HC and C6HC models induced alteration in respiratory function proportionally to injury level, and the C3HC model is a more appropriate model for interventional studies aiming to restore respiratory function in cSCI.

The practical considerations of managing negative pressure pulmonary edema for anesthesiologists – literature review

IntroductionNegative pressure pulmonary edema (NPPE) is an uncommon perioperative complication with a potentially fatal outcome. It is most predominant in young healthy men undergoing surgical procedures under general anesthesia. Due to its rare occurrence and uncharacteristic clinical presentation, it poses a potential diagnostic pitfall.AimThe purpose of this article is to present clinical characteristics and management of NPPE.Material and methodsThis paper is based on the available literature and the authors’ experience.Results and discussionClinical presentation of NPPE is uncharacteristic and includes i.e. agitation, tachypnea, tachycardia, cyanosis and pink frothy sputum. Postponed extubation after general anesthesia is believed to be optimal in order to prevent NPPE as it minimizes asynchrony of muscle function reversal and probability of laryngospasm. Differential diagnosis includes and is not limited to pulmonary edema, aspiration pneumonia, anaphylaxis, septic shock, pulmonary embolism or exacerbation of bronchial asthma. Management of NPPE is symptomatic and focuses on symptomatic treatment and maintaining an open airway passage. Endotracheal intubation with low tidal volume ventilation of 6 mL/kg of ideal body weight with a plateau pressure of less than 30 cm H&lt;sub&gt;2&lt;/sub&gt;O and high positive end-expiratory pressure (PEEP) may improve patients outcomes.ConclusionsIt is crucial for anesthesiologists to familiarize themselves with this phenomenon for early recognition and proper therapeutic decisions. It should be emphasized that under the highest risk of developing NPPE are young male patients and the most common cause is post-extubation laryngospasm.

Ventilating the blast lung: Exploring ventilation strategies in primary blast lung injury

Introduction Primary blast lung injury (PBLI) is the most common and fatal of all primary blast injuries. The majority of those with PBLI will require early intubation and mechanical ventilation, and thus, ventilation strategy forms a crucial part of any management plan. Methods: A comprehensive, but not systematic, PubMed and Google Scholar database search identified articles that contribute to our current understanding of ventilation strategies in PBLI for a narrative educational review. Results A PBLI ventilation strategy must strive to minimise all four of ventilator-associated lung injury (VALI), volutrauma, barotrauma and biotrauma. The three main ventilation strategies available are conventional low tidal volume (LTV) ventilation, airway pressure release ventilation (APRV) and high frequency oscillatory ventilation (HFOV). Conventional LTV ventilation together with a variable positive end-expiratory pressure (PEEP) and permissive hypercapnia has demonstrated reduced inflammation and mortality with a greater number of ventilator-free days. APRV has the potential to reduce dynamic strain, PaO2/FiO2 ratios, levels of applied mechanical power and extravascular lung water while encouraging spontaneous breathing. HFOV is able to effectively avoid VALI while curbing inflammation and histological lung injury, though not necessarily mortality. Conclusions: Presently, PBLI should largely be managed with conventional LTV ventilation alongside a variable PEEP and permissive hypercapnia with APRV and HFOV reserved as rescue strategies for where conventional LTV ventilation fails. Clinicians should additionally consider supplementing their strategy with adjunctive therapies such as prone positioning, inhaled nitric oxide and extracorporeal membrane oxygenation that may further reduce mortality and combat severe respiratory and/or cardiac failure.

Mechanical Ventilation in Pediatric and Neonatal Patients.

Pediatric acute respiratory distress syndrome (PARDS) remains a significant cause of morbidity and mortality, with mortality rates as high as 50% in children with severe PARDS. Despite this, pediatric lung injury and mechanical ventilation has been poorly studied, with the majority of investigations being observational or retrospective and with only a few randomized controlled trials to guide intensivists. The most recent and universally accepted guidelines for pediatric lung injury are based on consensus opinion rather than objective data. Therefore, most neonatal and pediatric mechanical ventilation practices have been arbitrarily adapted from adult protocols, neglecting the differences in lung pathophysiology, response to injury, and co-morbidities among the three groups. Low tidal volume ventilation has been generally accepted for pediatric patients, even in the absence of supporting evidence. No target tidal volume range has consistently been associated with outcomes, and compliance with delivering specific tidal volume ranges has been poor. Similarly, optimal PEEP has not been well-studied, with a general acceptance of higher levels of FiO2 and less aggressive PEEP titration as compared with adults. Other modes of ventilation including airway pressure release ventilation and high frequency ventilation have not been studied in a systematic fashion and there is too little evidence to recommend supporting or refraining from their use. There have been no consistent outcomes among studies in determining optimal modes or methods of setting them. In this review, the studies performed to date on mechanical ventilation strategies in neonatal and pediatric populations will be analyzed. There may not be a single optimal mechanical ventilation approach, where the best method may simply be one that allows for a personalized approach with settings adapted to the individual patient and disease pathophysiology. The challenges and barriers to conducting well-powered and robust multi-institutional studies will also be addressed, as well as reconsidering outcome measures and study design.