H.W.H. van Hees

Monitoring of the Respiratory Muscles in the Critically Ill

Evidence has accumulated that respiratory muscle dysfunction develops in critically ill patients and contributes to prolonged weaning from mechanical ventilation. Accordingly, it seems highly appropriate to monitor the respiratory muscles in these patients. Today, we are only at the beginning of routinely monitoring respiratory muscle function. Indeed, most clinicians do not evaluate respiratory muscle function in critically ill patients at all. In our opinion, however, practical issues and the absence of sound scientific data for clinical benefit should not discourage clinicians from having a closer look at respiratory muscle function in critically ill patients. This perspective discusses the latest developments in the field of respiratory muscle monitoring and possible implications of monitoring respiratory muscle function in critically ill patients.

The Calcium Sensitizer Levosimendan Improves Human Diaphragm Function

RATIONALE Acquired diaphragm muscle weakness is a key feature in several chronic conditions, including chronic obstructive pulmonary disease, congestive heart failure, and difficult weaning from mechanical ventilation. No drugs are available to improve respiratory muscle function in these patients. Recently, we have shown that the calcium sensitizer levosimendan enhances the force-generating capacity of isolated diaphragm fibers. OBJECTIVES To investigate the effects of the calcium sensitizer levosimendan on in vivo human diaphragm function. METHODS In a double-blind, randomized, crossover design, 30 healthy subjects performed two identical inspiratory loading tasks. After the first loading task, subjects received levosimendan (40 μg/kg bolus followed by 0.1/0.2 μg/kg/min continuous infusion) or placebo. Transdiaphragmatic pressure, diaphragm electrical activity, and their relationship (neuromechanical efficiency) were measured during loading. Magnetic phrenic nerve stimulation was performed before the first loading task and after bolus administration to assess twitch contractility. Center frequency of diaphragm electrical activity was evaluated to study the effects of levosimendan on muscle fiber conduction velocity. MEASUREMENTS AND MAIN RESULTS The placebo group showed a 9% (P=0.01) loss of twitch contractility after loaded breathing, whereas no loss in contractility was observed in the levosimendan group. Neuro-mechanical efficiency of the diaphragm during loading improved by 21% (P<0.05) in the levosimendan group. Baseline center frequency of diaphragm electrical activity was reduced after levosimendan administration (P<0.05). CONCLUSIONS The calcium sensitizer levosimendan improves neuromechanical efficiency and contractile function of the human diaphragm. Our findings suggest a new therapeutic approach to improve respiratory muscle function in patients with respiratory failure.

Levosimendan Enhances Force Generation of Diaphragm Muscle from Patients with Chronic Obstructive Pulmonary Disease

RATIONALE Levosimendan is clinically used to improve myocardial contractility by enhancing calcium sensitivity of force generation. The effects of levosimendan on skeletal muscle contractility are unknown. Patients with chronic obstructive pulmonary disease (COPD) suffer from diaphragm weakness, which is associated with decreased calcium sensitivity. OBJECTIVES To investigate the effects of levosimendan on contractility of diaphragm fibers from patients with COPD. METHODS Muscle fibers were isolated from diaphragm biopsies obtained from thoracotomized patients with and without COPD (both groups n = 5, 10 fibers per patient). Diaphragm fibers were skinned and activated with solutions containing incremental calcium concentrations and 10 microM levosimendan or vehicle (0.02% dimethyl sulfoxide). Developed force was measured at each step and force versus calcium concentration relationships were derived. Results were grouped per myosin heavy chain isoform, which was determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). MEASUREMENTS AND MAIN RESULTS At sub-maximal activation levosimendan improved force generation of COPD and non-COPD diaphragm fibers by approximately 25%, both in slow and fast fibers. Levosimendan increased calcium sensitivity of force generation (P < 0.01) in both slow and fast diaphragm fibers from patients with and without COPD, without affecting maximal force generation. CONCLUSIONS Levosimendan enhances force generating capacity of diaphragm fibers from patients with and without COPD patients by increasing calcium sensitivity of force generation. These results provide a strong rationale for testing the effect of calcium sensitizers on respiratory muscle dysfunction in patients with COPD.

Partial Neuromuscular Blockade during Partial Ventilatory Support in Sedated Patients with High Tidal Volumes

Rationale: Controlled mechanical ventilation is used to deliver lung‐protective ventilation in patients with acute respiratory distress syndrome. Despite recognized benefits, such as preserved diaphragm activity, partial support ventilation modes may be incompatible with lung‐protective ventilation due to high Vt and high transpulmonary pressure. As an alternative to high‐dose sedatives and controlled mechanical ventilation, pharmacologically induced neuromechanical uncoupling of the diaphragm should facilitate lung‐protective ventilation under partial support modes. Objectives: To investigate whether partial neuromuscular blockade can facilitate lung‐protective ventilation while maintaining diaphragm activity under partial ventilatory support. Methods: In a proof‐of‐concept study, we enrolled 10 patients with lung injury and a Vt greater than 8 ml/kg under pressure support ventilation (PSV) and under sedation. After baseline measurements, rocuronium administration was titrated to a target Vt of 6 ml/kg during neurally adjusted ventilatory assist (NAVA). Thereafter, patients were ventilated in PSV and NAVA under continuous rocuronium infusion for 2 hours. Respiratory parameters, hemodynamic parameters, and blood gas values were measured. Measurements and Main Results: Rocuronium titration resulted in significant declines of Vt (mean ± SEM, 9.3 ± 0.6 to 5.6 ± 0.2 ml/kg; P < 0.0001), transpulmonary pressure (26.7 ± 2.5 to 10.7 ± 1.2 cm H2O; P < 0.0001), and diaphragm electrical activity (17.4 ± 2.3 to 4.5 ± 0.7 &mgr;V; P < 0.0001), and could be maintained under continuous rocuronium infusion. During titration, pH decreased (7.42 ± 0.02 to 7.35 ± 0.02; P < 0.0001), and mean arterial blood pressure increased (84 ± 6 to 99 ± 6 mm Hg; P = 0.0004), as did heart rate (83 ± 7 to 93 ± 8 beats/min; P = 0.0004). Conclusions: Partial neuromuscular blockade facilitates lung‐protective ventilation during partial ventilatory support, while maintaining diaphragm activity, in sedated patients with lung injury.

Diaphragm muscle fiber function and structure in humans with hemidiaphragm paralysis

Recent studies proposed that mechanical inactivity of the human diaphragm during mechanical ventilation rapidly causes diaphragm atrophy and weakness. However, conclusive evidence for the notion that diaphragm weakness is a direct consequence of mechanical inactivity is lacking. To study the effect of hemidiaphragm paralysis on diaphragm muscle fiber function and structure in humans, biopsies were obtained from the paralyzed hemidiaphragm in eight patients with hemidiaphragm paralysis. All patients had unilateral paralysis of known duration, caused by en bloc resection of the phrenic nerve with a tumor. Furthermore, diaphragm biopsies were obtained from three control subjects. The contractile performance of demembranated muscle fibers was determined, as well as fiber ultrastructure and morphology. Finally, expression of E3 ligases and proteasome activity was determined to evaluate activation of the ubiquitin-proteasome pathway. The force-generating capacity, as well as myofibrillar ultrastructure, of diaphragm muscle fibers was preserved up to 8 wk of paralysis. The cross-sectional area of slow fibers was reduced after 2 wk of paralysis; that of fast fibers was preserved up to 8 wk. The expression of the E3 ligases MAFbx and MuRF-1 and proteasome activity was not significantly upregulated in diaphragm fibers following paralysis, not even after 72 and 88 wk of paralysis, at which time marked atrophy of slow and fast diaphragm fibers had occurred. Diaphragm muscle fiber atrophy and weakness following hemidiaphragm paralysis develops slowly and takes months to occur.

EFFECTS OF EXPERIMENTAL HUMAN ENDOTOXEMIA ON DIAPHRAGM FUNCTION

Introduction: Systemic inflammation is a well-known risk factor for respiratory muscle weakness. Studies using animal models of inflammation have shown that endotoxin administration induces diaphragm dysfunction. However, the effects of in vivo endotoxin administration on diaphragm function in humans have not been studied. Our aim was to evaluate diaphragm function in a model of systemic inflammation in healthy subjects. Methods: Two groups of 12 male volunteers received an intravenous bolus of 2 ng/kg of Escherichia coli lipopolysaccharide (LPS) and were monitored until 8 h after LPS administration. In the first group, the twitch transdiaphragmatic pressure (Pditw) and compound muscle action potential of the diaphragm (CMAPdi) were measured. In addition, plasma levels of cytokines, heart rate, and arterial blood pressure were measured. In the second group, catecholamines as well as respiratory rate and blood gas values were measured. Diaphragm ultrasonography was performed in four subjects with severe shivering. Results: Lipopolysaccharide administration resulted in flulike symptoms, hemodynamic alterations, and increased plasma levels of cytokines. The Pditw increased after LPS administration from 31.2 ± 2.0 cmH2O (baseline) to 38.8 ± 2.0 cmH2O (t = 1 h) and 35.4 ± 2.0 cmH2O (t = 1.5 h). There was no correlation between cytokine plasma levels and the Pditw. We found a trend toward a gradual decrease in the CMAPdi from 0.78 ± 0.07 mV (baseline) to 0.58 ± 0.05 mV (t = 2 h). Respiratory rate increased after LPS administration from 16.8 ± 0.5 breaths/min (baseline) to 20.3 ± 0.6 breaths/min (t = 4 h), with a resulting decrease in PaCO2 of 0.5 ± 0.1 kPa. Plasma levels of epinephrine peaked at t = 1.5 h, with an increase of 1.3 ± 0.3 nmol/L from baseline. Rapid diaphragm contractions consistent with shivering were observed. Conclusions: This study shows that, in contrast to diaphragm dysfunction observed in animal models of inflammation, in vivo diaphragm contractility is augmented in the early phase after low-dose endotoxin administration in humans.

The effect of metabolic alkalosis on the ventilatory response in healthy subjects

BACKGROUND Patients with acute respiratory failure may develop respiratory acidosis. Metabolic compensation by bicarbonate production or retention results in posthypercapnic alkalosis with an increased arterial bicarbonate concentration. The hypothesis of this study was that elevated plasma bicarbonate levels decrease respiratory drive and minute ventilation. METHODS In an intervention study in 10 healthy subjects the ventilatory response using a hypercapnic ventilatory response (HCVR) test was assessed, before and after administration of high dose sodium bicarbonate. Total dose of sodiumbicarbonate was 1000 ml 8.4% in 3 days. RESULTS Plasma bicarbonate increased from 25.2 ± 2.2 to 29.2 ± 1.9 mmol/L. With increasing inspiratory CO2 pressure during the HCVR test, RR, Vt, Pdi, EAdi and VE increased. The clinical ratio ΔVE/ΔPetCO2 remained unchanged, but Pdi, EAdi and VE were significantly lower after bicarbonate administration for similar levels of inspired CO2. CONCLUSION This study demonstrates that in healthy subjects metabolic alkalosis decreases the neural respiratory drive and minute ventilation, as a response to inspiratory CO2.