Personalised perioperative dosing of ivabradine in noncardiac surgery: a single-centre, randomised, placebo-controlled, double-blind feasibility pilot trial.

BACKGROUND: Perioperative myocardial injury after noncardiac surgery is associated with postoperative mortality. Heart rate (HR) is an independent risk factor for perioperative myocardial injury. In this pilot trial we tested the feasibility of a randomised, placebo-controlled trial of personalised HR-targeted perioperative ivabradine. METHODS: This was a single-centre, randomised, placebo-controlled, double-blind, parallel group, feasibility pilot trial conducted at Geneva University Hospitals. We included patients ≥75 yr old or ≥45 yr old with cardiovascular risk factors planned for intermediate- or high-risk surgery. Patients were randomised to receive ivabradine (2.5, 5.0, or 7.5 mg) or placebo according to their HR, twice daily, from the morning of surgery until postoperative day 2. Primary outcomes were appropriate dosage and blinding success rates. RESULTS: Between October 2020 and January 2022, we randomised 78 patients (recruitment rate of 1.3 patients week-1). Some 439 of 444 study drug administrations were adequate (99% appropriate dosage rate). The blinding success rate was 100%. There were 137 (31%) administrations of Pill A (placebo in both groups for HR ≤70 beats min-1). Nine (11.5%) patients had a high-sensitive cardiac troponin T elevation ≥14 ng L-1 between any two measurements. The number of bradycardia episodes was eight in the placebo group and nine in the ivabradine group. CONCLUSIONS: This pilot study demonstrates the feasibility of, and provides guidance for, a future trial testing the efficacy of personalised perioperative ivabradine. Future studies should include patients at higher risk of cardiac complications. CLINICAL TRIAL REGISTRATION: NCT04436016.

Sonographic evaluation of the diaphragm in critically ill patients. Technique and clinical applications.

The use of ultrasonography has become increasingly popular in the everyday management of critically ill patients. It has been demonstrated to be a safe and handy bedside tool that allows rapid hemodynamic assessment and visualization of the thoracic, abdominal and major vessels structures. More recently, M-mode ultrasonography has been used in the assessment of diaphragm kinetics. Ultrasounds provide a simple, non-invasive method of quantifying diaphragmatic movement in a variety of normal and pathological conditions. Ultrasonography can assess the characteristics of diaphragmatic movement such as amplitude, force and velocity of contraction, special patterns of motion and changes in diaphragmatic thickness during inspiration. These sonographic diaphragmatic parameters can provide valuable information in the assessment and follow up of patients with diaphragmatic weakness or paralysis, in terms of patient-ventilator interactions during controlled or assisted modalities of mechanical ventilation, and can potentially help to understand post-operative pulmonary dysfunction or weaning failure from mechanical ventilation. This article reviews the technique and the clinical applications of ultrasonography in the evaluation of diaphragmatic function in ICU patients.

Diaphragm ultrasonography to estimate the work of breathing during non-invasive ventilation.

PURPOSE: Ultrasonography allows the direct observation of the diaphragm. Its thickness variation measured in the zone of apposition has been previously used to diagnose diaphragm paralysis. We assessed the feasibility and accuracy of this method to assess diaphragmatic function and its contribution to respiratory workload in critically ill patients under non-invasive ventilation. METHODS: This was a preliminary physiological study in the intensive care unit of a university hospital. Twelve patients requiring planned non-invasive ventilation after extubation were studied while spontaneously breathing and during non-invasive ventilation at three levels of pressure support (5, 10 and 15 cmH(2)O). Diaphragm thickness was measured in the zone of apposition during tidal ventilation and the thickening fraction (TF) was calculated as (thickness at inspiration - thickness at expiration)/thickness at expiration. Diaphragmatic pressure-time product per breath (PTP(di)) was measured from oesophageal and gastric pressure recordings. RESULTS: PTP(di) and TF both decreased as the level of pressure support increased. A significant correlation was found between PTP(di) and TF (ρ = 0.74, p < 0.001). The overall reproducibility of TF assessment was good but the coefficient of repeatability reached 18% for inter-observer reproducibility. CONCLUSIONS: Ultrasonographic assessment of the diaphragm TF is a non-invasive method that may prove useful in evaluating diaphragmatic function and its contribution to respiratory workload in intensive care unit patients.

Intrapulmonary percussive ventilation superimposed on spontaneous breathing: a physiological study in patients at risk for extubation failure.

PURPOSE: Intrapulmonary percussive ventilation (IPV) is a high-frequency ventilation modality that can be superimposed on spontaneous breathing. IPV may diminish respiratory muscle loading and help to mobilize secretions. The aim of this prospective study was to assess the short-term effects of IPV in patients at high risk for extubation failure who were receiving preventive non-invasive ventilation (NIV) after extubation. METHODS: Respiratory rate, work of breathing, and gas exchange were evaluated in 17 extubated patients during 20 min of IPV and 20 min of NIV delivered via a facial mask, separated by periods of spontaneous breathing. The pressure-support level during NIV was adjusted until tidal volume reached 6-8 ml/kg and positive end-expiratory pressure (PEEP) 4-5 cmH(2)O. For IPV, the pressurisation frequency was set at 250 cycles/min and driving pressure at 1.2 bar. The pressure-time product of the diaphragm (PTPdi/min) was measured using an oesophageal and gastric double-balloon catheter. RESULTS: Transdiaphragmatic pressure and PTPdi/min improved significantly (p < 0.01), from a median [25th-75th percentiles] of 264 [190-300] to 192 [152-221] cmH(2)O s/min with IPV and from 273 [212-397] to 176 [120-216] cmH(2)O s/min with NIV. Respiratory rate decreased significantly from 23 [19-27] to 22 [17-24] breaths/min for IPV and from 25 [19-28] to 20 [18-22] breaths/min for NIV (p < 0.01). Mean PaCO(2) decreased after NIV (from 46 [42-48] to 41 [36-42] mmHg, p < 0.01) but not after IPV. There was no noticeable effect on oxygenation. CONCLUSIONS: IPV is an interesting alternative to NIV in patients at risk for post-extubation respiratory failure. Both NIV and IPV diminished the respiratory rate and work of breathing, but IPV was less effective in improving alveolar ventilation.

Weaning difficult-to-wean chronic obstructive pulmonary disease patients: a pilot study comparing initial hemodynamic effects of levosimendan and dobutamine.

PURPOSE: To compare the short-term hemodynamic effects of levosimendan and dobutamine in chronic obstructive pulmonary disease (COPD) patients experiencing weaning difficulties in relation with increased left ventricular filling pressure. MATERIALS AND METHODS: This prospective, sequential, pilot study included 10 COPD patients experiencing weaning difficulties in relation with increased left ventricular filling pressure ascertained by an increase >10 mm Hg of pulmonary artery occlusion pressure (PAOP) at the shift from mechanical to spontaneous breathing (SB). Patients received 1 h infusion of 7 µg/kg per minute of dobutamine, followed by 24-hour infusion of 0.2 µg/kg per minute levosimendan. Hemodynamic variables were measured under MV and 15 to 30 minutes after SB at baseline, at the end of dobutamine infusion, at a washout period, and after levosimendan infusion. RESULTS: At baseline, the shift from mechanical ventilation to spontaneous ventilation was associated with a significant increase in PAOP from a median of 15 (interquartile range [IQR], 6) to 29 (9) mm Hg. Both drugs reduced significantly the level of PAOP increase at SB, but levosimendan had a greater effect than dobutamine [median PAOP increase (IQR): 5 (2) vs 9 (4) mm Hg, respectively; P < .01]. CONCLUSIONS: Both drugs reduced the magnitude of PAOP increase at SB in difficult-to-wean COPD patients. PAOP increase was reduced to a greater extent by levosimendan.

Ultrasonographic diagnostic criterion for severe diaphragmatic dysfunction after cardiac surgery.

BACKGROUND: Severe diaphragmatic dysfunction can prolong mechanical ventilation after cardiac surgery. An ultrasonographic criterion for diagnosing severe diaphragmatic dysfunction defined by a reference technique such as transdiaphragmatic pressure measurements has never been determined. METHODS: Twenty-eight patients requiring mechanical ventilation > 7 days postoperatively were studied. Esophageal and gastric pressures were measured to calculate transdiaphragmatic pressure during maximal inspiratory effort and the Gilbert index, which evaluates the diaphragm contribution to respiratory pressure swings during quiet ventilation. Ultrasonography allowed measuring right and left hemidiaphragmatic excursions during maximal inspiratory effort. Best E is the greatest positive value from either hemidiaphragm. Twenty cardiac surgery patients with uncomplicated postoperative course were also evaluated with ultrasonography preoperatively and postoperatively. Measurements were performed in semirecumbent position. RESULTS: Transdiaphragmatic pressure during maximal inspiratory effort was below normal value in 27 of the 28 patients receiving prolonged mechanical ventilation (median, 39 cm H(2)O; interquartile range [IQR] 28 cm H(2)O). Eight patients had Gilbert indexes 0 (30 mm; IQR, 10 mm; vs 19 mm; IQR, 7 mm, respectively; p = 0.001). Best E < 25 mm had a positive likelihood ratio of 6.7 (95% confidence interval [CI], 2.4 to 19) and a negative likelihood ratio of 0 (95% CI, 0 to 1.1) for having a Gilbert index

Effects of norepinephrine on static and dynamic preload indicators in experimental hemorrhagic shock.

OBJECTIVE: To investigate the effect of norepinephrine on static (right atrial pressure, pulmonary artery occlusion pressure ) and dynamic (pulse pressure variation and arterial systolic pressure variation) preload indicators in experimental hemorrhagic shock. DESIGN: Prospective controlled experimental study. SETTING: Animal research laboratory. SUBJECTS: Six anesthetized and mechanically ventilated dogs. INTERVENTIONS: Dogs were instrumented for measurement of arterial blood pressure, pulmonary artery catheter derived variables including right atrial pressure, pulmonary artery occlusion pressure, and cardiac output. Simultaneously, pulse pressure variation and systolic pressure variation were calculated. Pulse pressure variation is the difference between the maximal and the minimal value of pulse pressure divided by the mean of the two values and is expressed as a percentage. Systolic pressure variation is the difference between the maximal and the minimal systolic pressure and is expressed as an absolute value. After baseline measurements, hemorrhagic shock was induced by a stepwise cumulative blood withdrawal of 35 mL.kg of body weight. A second set of hemodynamic measurement was made 30 mins after bleeding. The third set was made 30 mins later under norepinephrine. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure and cardiac output decreased after hemorrhage (p < .05), whereas right atrial pressure and pulmonary artery occlusion pressure remained unchanged. Baseline pulse pressure variation and systolic pressure variation increased significantly with hemorrhage, from 12% (9%) to 28% (11.5%) (p < .001) and from 12.5 (6.5) to 21 (8.2) mm Hg (p < .05), respectively. Norepinephrine induced a significant increase of cardiac output and a significant decrease of pulse pressure variation and systolic pressure variation but did not significantly change right atrial pressure or pulmonary artery occlusion pressure values. Stroke volume was correlated to pulse pressure variation and systolic pressure variation but was not correlated to right atrial pressure or pulmonary artery occlusion pressure. CONCLUSION: Our study confirms the superiority of dynamic variables (pulse pressure variation and systolic pressure variation) over static ones (right atrial pressure and pulmonary artery occlusion pressure) in assessing cardiac preload changes in hemorrhagic shock. However, norepinephrine could significantly reduce the value of these dynamic variables and mask a true intravascular volume deficit possibly by shifting blood from unstressed to stressed volume.