Sensory interventions to relieve dyspnoea in critically ill mechanically ventilated patients.

BACKGROUND: In critically ill patients receiving mechanical ventilation, dyspnoea is frequent, severe and associated with an increased risk of neuropsychological sequelae. We evaluated the efficacy of sensory interventions targeting the brain rather than the respiratory system to relieve dyspnoea in mechanically ventilated patients. METHODS: Patients receiving mechanical ventilation for ≥48 h and reporting dyspnoea (unidimensional dyspnoea visual analogue scale (Dyspnoea-VAS)) first underwent increased pressure support and then, in random order, auditory stimulation (relaxing music versus pink noise) and air flux stimulation (facial versus lower limb). Treatment responses were assessed using Dyspnoea-VAS, the Multidimensional Dyspnea Profile and measures of the neural drive to breathe (airway occlusion pressure (P 0.1) and electromyography of inspiratory muscles). RESULTS: We included 46 patients (tracheotomy or intubation n=37; noninvasive ventilation n=9). Increasing pressure support decreased Dyspnoea-VAS by median 40 mm (p<0.001). Exposure to music decreased Dyspnoea-VAS compared with exposure to pink noise by median 40 mm (p<0.001). Exposure to facial air flux decreased Dyspnoea-VAS compared with limb air flux by median 30 mm (p<0.001). Increasing pressure support, but not music exposure and facial air flux, reduced P 0.1 by median 3.3 cmH2O (p<0.001). CONCLUSIONS: In mechanically ventilated patients, sensory interventions can modulate the processing of respiratory signals by the brain irrespective of the intensity of the neural drive to breathe. It should therefore be possible to alleviate dyspnoea without resorting to pharmacological interventions or having to infringe the constraints of mechanical ventilation lung protection strategies by increasing ventilatory support.

Comparison of hydroxychloroquine, lopinavir/ritonavir, and standard of care in critically ill patients with SARS-CoV-2 pneumonia: an opportunistic retrospective analysis.

BACKGROUND: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak is spreading worldwide. To date, no specific treatment has convincingly demonstrated its efficacy. Hydroxychloroquine and lopinavir/ritonavir have potential interest, but virological and clinical data are scarce, especially in critically ill patients. METHODS: The present report took the opportunity of compassionate use and successive drug shortages to compare the effects of two therapeutic options, lopinavir/ritonavir and hydroxychloroquine, as compared to standard of care only. The primary outcomes were treatment escalation (intubation, extra-corporeal membrane oxygenation support, or renal replacement therapy) after day 1 until day 28. Secondary outcomes included ventilator-free days at day 28, mortality at day 14 and day 28, treatment safety issues and changes in respiratory tracts, and plasma viral load (as estimated by cycle threshold value) between admission and day 7. RESULTS: Eighty patients were treated during a 4-week period and included in the analysis: 22 (28%) received standard of care only, 20 (25%) patients received lopinavir/ritonavir associated to standard of care, and 38 (47%) patients received hydroxychloroquine and standard of care. Baseline characteristics were well balanced between the 3 groups. Treatment escalation occurred in 9 (41%), 10 (50%), and 15 (39%) patients who received standard of care only, standard of care and lopinavir/ritonavir, and standard of care and hydroxychloroquine, respectively (p = 0.567). There was no significant difference between groups regarding the number of ventilator-free days at day 28 and mortality at day 14 and day 28. Finally, there was no significant change between groups in viral respiratory or plasma load between admission and day 7. CONCLUSION: In critically ill patients admitted for SARS-CoV-2-related pneumonia, no difference was found between hydroxychloroquine or lopinavir/ritonavir as compared to standard of care only on the proportion of patients who needed treatment escalation at day 28. Further randomized controlled trials are required to demonstrate whether these drugs may be useful in this context.

Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation from Mechanical Ventilation in Medical Intensive Care Unit Patients.

RATIONALE: Intensive care unit (ICU)- and mechanical ventilation (MV)-acquired limb muscle and diaphragm dysfunction may both be associated with longer length of stay and worse outcome. Whether they are two aspects of the same entity or have a different prevalence and prognostic impact remains unclear. OBJECTIVES: To quantify the prevalence and coexistence of these two forms of ICU-acquired weakness and their impact on outcome. METHODS: In patients undergoing a first spontaneous breathing trial after at least 24 hours of MV, diaphragm dysfunction was evaluated using twitch tracheal pressure in response to bilateral anterior magnetic phrenic nerve stimulation (a pressure <11 cm H2O defined dysfunction) and ultrasonography (thickening fraction [TFdi] and excursion). Limb muscle weakness was defined as a Medical Research Council (MRC) score less than 48. MEASUREMENTS AND MAIN RESULTS: Seventy-six patients were assessed at their first spontaneous breathing trial: 63% had diaphragm dysfunction, 34% had limb muscle weakness, and 21% had both. There was a significant but weak correlation between MRC score and twitch pressure (ρ = 0.26; P = 0.03) and TFdi (ρ = 0.28; P = 0.01), respectively. Low twitch pressure (odds ratio, 0.60; 95% confidence interval, 0.45-0.79; P < 0.001) and TFdi (odds ratio, 0.84; 95% confidence interval, 0.76-0.92; P < 0.001) were independently associated with weaning failure, but the MRC score was not. Diaphragm dysfunction was associated with higher ICU and hospital mortality, and limb muscle weakness was associated with longer duration of MV and hospital stay. CONCLUSIONS: Diaphragm dysfunction is twice as frequent as limb muscle weakness and has a direct negative impact on weaning outcome. The two types of muscle weakness have only limited overlap.

ß1-Adrenergic Inhibition Improves Cardiac and Vascular Function in Experimental Septic Shock.

OBJECTIVE: Preliminary experimental data suggest that selective ß1-blockers may improve ex vivo cardiac function in animal sepsis. Currently, the effects of esmolol on in vivo cardiac function and on vascular function are unknown. The present study was designed to examine the effects of the ß1-selective blocker esmolol on myocardial and vascular function in peritonitis-induced septic rats and to explore the inflammatory pathways involved in this process. DESIGN: Randomized animal study. SETTING: University research laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Four hours after cecal ligation and puncture, Wistar rats were randomly allocated to the following groups: control, esmolol, norepinephrine (started at 18 hr after the surgery), and esmolol (started at 4 hr after the surgery) + norepinephrine (started at 18 hr after the surgery). Assessment at 18 hours after surgery was focused on cardiac contractility and vascular ex vivo function. Cardiac and vascular protein expressions of nuclear factor κB and endothelial nitric oxide synthase/Akt/inducible nitric oxide synthase pathways were assessed by Western blotting. MEASUREMENTS AND MAIN RESULTS: When compared with sham-operated animals, cecal ligation and puncture animals developed hypotension, cardiac depression, and vascular hyporesponsiveness to vasopressor treatment. Esmolol infusion increased cardiac contractility and restored mesenteric vasoreactivity. This effect was associated with a decrease in nuclear factor κB activation, an increase in Akt and endothelial nitric oxide synthase phosphorylation, and a decrease in inducible nitric oxide synthase expression both at the cardiac and vessel level. Esmolol infusion was also associated with an up-regulation in α1-vascular adrenoreceptors. CONCLUSION: Adjunction of selective ß1-blockade to standard septic shock management enhances intrinsic cardiac contractility and vascular responsiveness to catecholamines. These protective cardiovascular effects are likely predominantly attributed to the anti-inflammatory effect of esmolol.

Dyspnea and the electromyographic activity of inspiratory muscles during weaning from mechanical ventilation.

RATIONALE: Dyspnea, a key symptom of acute respiratory failure, is not among the criteria for spontaneous breathing trial (SBT) failure. Here, we sought (1) to determine whether dyspnea is a reliable failure criterion for SBT failure; (2) to quantify the relationship between dyspnea and the respective electromyographic activity of the diaphragm (EMGdi), the parasternal (EMGpa) and the Alae nasi (EMGan). METHODS: Mechanically ventilated patients undergoing an SBT were included. Dyspnea intensity was measured by the Dyspnea-Visual Analogic Scale (Dyspnea-VAS) at the initiation and end of the SBT. During the 30-min SBT or until SBT failure, the EMGdi was continuously measured with a multi-electrode nasogastric catheter and the EMGan and EMGpa with surface electrodes. RESULTS: Thirty-one patients were included, SAPS 2 (median [interquartile range]) 53 (37‒74), mechanically ventilated for 6 (3‒10) days. Seventeen patients (45%) failed the SBT. The increase in Dyspnea-VAS along the SBT was higher in patients who failed (6 [4‒8] cm) than in those who passed (0 [0‒1] cm, p = 0.01). The area under the receiver operating characteristics curve for Dyspnea-VAS was 0.909 (0.786-1.032). The increase in Dyspnea-VAS was significantly correlated to the increase in EMGan (Rho = 0.42 [0.04‒0.70], p < 0.05), but not to the increase in EMGpa (Rho = - 0.121 [- 0.495 to - 0.290], p = 0.555) and EMGdi (Rho = - 0.26 [- 0.68 to 0.28], p = 0.289). CONCLUSION: Dyspnea is a reliable criterion of SBT failure, suggesting that Dyspnea-VAS could be used as a monitoring tool of the SBT. In addition, dyspnea seems to be more closely related to the electromyographic activity of the Alae nasi than of the diaphragm.

Specialized Weaning Unit in the Trajectory of SARS-CoV-2 ARDS: Influence of Limb Muscle Strength on Decannulation and Rehabilitation.

BACKGROUND: Patients with ARDS due to COVID-19 may require tracheostomy and transfer to a weaning center. To date, data on the outcome of these patients are scarce. The objectives of this study were to determine the factors associated with time to decannulation and limb-muscle strength recovery. METHODS: This was an observational retrospective study of subjects with COVID-19-related ARDS requiring tracheostomy after prolonged ventilation, who were subsequently transferred to a weaning center from April 4, 2020-May 30, 2020. RESULTS: Forty-three subjects were included. Median age (interquartile range) was 61 (48-66) y; 81% were men, and median body mass index (BMI) was 30 (26-35) kg/m2. Tracheostomy was performed after a median of 19 (12-27) d of mechanical ventilation, and the median ICU length of stay prior to transfer to the weaning center was 30 (21-46) d. On admission to the weaning center, the median Medical Research Council (MRC) score was 36 (27-44). Time to decannulation was 9 (7-18) d after admission to the weaning center. The only factor independently associated with early decannulation was the MRC score on admission to the weaning center (odds ratio 1.16 [95% CI 1.06-1.31], P = .005). Two factors were independently associated with MRC gain ≥ 10: BMI (odds ratio 0.88 [95% CI 0.76-0.99], P = .045) and MRC on admission (odds ratio 0.91 [95% CI 0.82-0.98], P = .03. Three months after admission to the weaning center, 40 subjects (93%) were weaned from mechanical ventilation and 36 (84%) had returned home. CONCLUSIONS: MRC score at weaning center admission predicted both early decannulation and limb-muscle strength recovery.

Diaphragm dysfunction, lung aeration loss and weaning-induced pulmonary oedema in difficult-to-wean patients.

BACKGROUND: Diaphragm dysfunction and weaning-induced pulmonary oedema are commonly involved during weaning failure, but their physiological interactions have been poorly reported. Our hypothesis was that diaphragm dysfunction is not particularly associated with weaning-induced pulmonary oedema. METHODS: It was a single-centre and physiological study conducted in patients who had failed a first spontaneous breathing trial and who underwent a second trial. The diaphragm function was evaluated by measuring the tracheal pressure generated in response to a bilateral magnetic phrenic nerves stimulations. Weaning-induced pulmonary oedema was diagnosed in case of failure of the spontaneous breathing trial if patients exhibited signs of plasma concentration or echocardiographic diagnosis of pulmonary artery occlusion pressure elevation. RESULTS: Fifty-three patients were included and 31/53 (58%) failed the spontaneous breathing trial, including 24/31 (77%) patients with weaning-induced pulmonary oedema. Diaphragm dysfunction was present in 33/53 (62%) patients. Diaphragm dysfunction or weaning-induced pulmonary oedema were present in 26/31 (84%) of the patients who failed the spontaneous breathing trial. Weaning-induced pulmonary oedema occurred in 20/33 (61%) patients with a diaphragm dysfunction and in 4/20 (20%) patients without (p = 0.005). CONCLUSION: Weaning-induced pulmonary oedema was three times more frequent in case of diaphragm dysfunction. Even in case of diaphragm dysfunction, physicians might be encouraged to investigate the presence of weaning-induced pulmonary oedema during weaning failure.

Clinical features and outcome of patients with primary central nervous system lymphoma admitted to the intensive care unit: a French national expert center experience.

INTRODUCTION: To describe the reasons for intensive care unit (ICU) admission and to evaluate the outcomes and prognostic factors of patients with primary central nervous system lymphoma (PCNSL) admitted to the ICU. PATIENTS AND METHODS: Retrospective observational cohort study of 101 PCNSL patients admitted to 3 ICUs over a two-decade period. RESULTS: Acute respiratory failure, mainly secondary to aspiration pneumonia and Pneumocystis jirovecii pneumonia, was the leading reason for ICU admission (33%). Aspiration pneumonia was more common in patients with brainstem tumor (67% vs. 0%, p < 0.001), whereas patients with intracranial hypertension were more frequently admitted for coma without seizures (61% vs. 9%, p = 0.004). Hospital and 6-month mortality were 47% and 53%, respectively. In multivariate analysis, admission for coma without seizures (OR 7.28), cancer progression (OR 3.47), mechanical ventilation (OR 6.58) and vasopressors (OR 4.07) were associated with higher 6-month mortality. Karnofsky performance status prior to ICU admission was independently associated with lower 6-month mortality (OR 0.96). DISCUSSION: Six-month survival of PCNSL patients admitted to the ICU appears to be relatively favorable (around 50%) and the presence of PCNSL alone is not a relevant criterion for ICU refusal. Predictive factors of mortality may help clinicians to make optimal triage decisions.

ICU-acquired weakness, diaphragm dysfunction and long-term outcomes of critically ill patients.

BACKGROUND: Intensive care unit (ICU)-acquired weakness and diaphragm dysfunction are frequent conditions, both associated with poor prognosis in critically ill patients. While it is well established that ICU-acquired weakness severely impairs long-term prognosis, the association of diaphragm dysfunction with this outcome has never been reported. This study investigated whether diaphragm dysfunction is associated with negative long-term outcomes and whether the coexistence of diaphragm dysfunction and ICU-acquired weakness has a particular association with 2-year survival and health-related quality of life (HRQOL). METHODS: This study is an ancillary study derived from an observational cohort study. Patients under mechanical ventilation were enrolled at the time of their first spontaneous breathing trial. Diaphragm dysfunction was defined by tracheal pressure generated by phrenic nerve stimulation < 11 cmH2O and ICU-acquired weakness was defined by Medical Research Council (MRC) score < 48. HRQOL was evaluated with the SF-36 questionnaire. RESULTS: Sixty-nine of the 76 patients enrolled in the original study were included in the survival analysis and 40 were interviewed. Overall 2-year survival was 67% (46/69): 64% (29/45) in patients with diaphragm dysfunction, 71% (17/24) in patients without diaphragm dysfunction, 46% (11/24) in patients with ICU-acquired weakness and 76% (34/45) in patients without ICU-acquired weakness. Patients with concomitant diaphragm dysfunction and ICU-acquired weakness had a poorer outcome with a 2-year survival rate of 36% (5/14) compared to patients without diaphragm function and ICU-acquired weakness [79% (11/14) (p < 0.01)]. Health-related quality of life was not influenced by the presence of ICU-acquired weakness, diaphragm dysfunction or their coexistence. CONCLUSIONS: ICU-acquired weakness but not diaphragm dysfunction was associated with a poor 2-year survival of critically ill patients.

Survival of amyotrophic lateral sclerosis patients after admission to the intensive care unit for acute respiratory failure: an observational cohort study.

PURPOSE: Amyotrophic lateral sclerosis (ALS) entails a risk of acute respiratory failure (ARF). The decision to admit such patients to the intensive care unit (ICU) is difficult given the inexorable prognosis of ALS. To fuel this discussion, this study describes the ICU and post-ICU survival of ALS-related ARF. MATERIAL AND METHODS: Retrospective cohort analysis over 10 years (university hospital setting, ALS reference center). RESULTS: Of 90 patients (66 men, median age: 67 [IQR 59-71], median interval since ALS diagnosis: 26.5 months [14-53], ALSFRS-R: 19 [12-30], bulbar signs 73%), 48 were managed by noninvasive ventilation (NIV) only, 7 were already tracheotomized upon admission, 12 were tracheotomized during the ICU stay (advance care planning project), 18 were already intubated before admission, 5 received oxygen and physiotherapy only. Median ICU stay was 4 days [2-9] with 20% mortality. Median hospital stay was 10 days [5-22] with 33% mortality. The 3-month and one year mortality wer 46% and 71%. Hospital mortality was higher in patients with more severe respiratory acidosis and higher simplified acute physiology scores on admission. CONCLUSIONS: The prognosis of ALS-related ARF requiring ICU admission resembles that of ARF complicating other conditions with high short-term mortality (e.g. lung cancer).

Corrective effect of diaphragm pacing on the decrease in cardiac output induced by positive pressure mechanical ventilation in anesthetized sheep.

Positive pressure ventilation (PPV) is a fundamental life support measure, but it decreases cardiac output (CO). Diaphragmatic contractions produce negative intrathoracic and positive abdominal pressures, promoting splanchnic venous return. We hypothesized that: 1) diaphragm pacing alone could produce adequate ventilation without decreasing CO; 2) diaphragm pacing on top of PPV could improve CO. Of 11 anesthetized and mechanically ventilated ewes (39.6±5.9kg), 3 were discarded from analysis because of hemodynamic instability during the experiment, and 8 retained for analysis. Phrenic stimulation electrodes were inserted in the diaphragm (implanted phrenic nerve stimulation, iPS). CO was measured by the thermodilution technique (pulmonary artery catheter). CO during end-expiratory apnea served as reference. Median CO was 9.77 [6.25-11.25] lmin-1 during end-expiratory apnea, 8.25 [5.06-9.25] lmin-1 during "PPV" (-15%) (p<0.05), 9.19 [5.60-10.19] lmin-1 during "PPV-iPS" (NS vs apnea) and 9.37 [6.12-10.48] lmin-1 during "iPS" (NS vs. apnea). iPS-driven ventilation was comparable to its PPV counterpart (median 92% [74-97], NS). Diaphragm pacing alone can produce adequate ventilation without reducing CO. Superimposed onto PPV, diaphragm pacing can reduce the PPV-induced decrease in CO.