Is diaphragmatic dysfunction a major problem following mechanical ventilation?

12 Is Diaphragmatic Dysfunction a Major Problem Following Mechanical Ventilation? Ewan C. Goligher and Martin Dres

INTRODUCTION Critically ill patients are at high risk of developing acute generalized muscle injury and weakness. Injury and dysfunction of the respiratory muscles, especially the diaphragm, is of particular concern in mechanically ventilated patients because of the crucial role played by these muscles in enabling a patient to be liberated from mechanical ventilation. Mounting evidence suggests that diaphragmatic dysfunction developing during critical illness presents a serious obstacle to recovery. As yet there are no proven therapies for diaphragmatic dysfunction, but the field is evolving rapidly with a number of potential approaches to prevention and treatment on the horizon.

DEFINITION AND EPIDEMIOLOGY The diaphragm is a thin, dome-shaped muscular structure separating the thoracic and abdominal cavities. Under normal conditions, the diaphragm acts like a piston within a syringe, generating flow as its dome descends, enabling tidal breathing.1 The pressure generated across the dome between the thoracic and abdominal cavities is called the transdiaphragmatic pressure and is proportional to the tension developed within the muscle fibers.

Diagnostic Criteria Diaphragmatic dysfunction can be defined as a reduction in the force-generating capacity of the diaphragm. Several methods are available to detect the presence of diaphragmatic dysfunction in critically ill patients. Bilateral anterior magnetic phrenic stimulation (BAMPS) is regarded as the reference technique because it generates a consistent level of diaphragm activation independent of volitional effort.2,3 BAMPS elicits an isolated contraction (twitch) of the diaphragm to measure the change in transdiaphragmatic pressure or airway pressure.4 Using this method, diaphragmatic dysfunction is defined by a decrease in its capacity to generate a negative intrathoracic pressure, usually below 11 cm H2O.2 While BAMPS provides a rigorous assessment of the diaphragm function, it is only available in expert centers and requires costly equipment, which precludes its widespread use. 82

An alternative means of evaluating diaphragmatic function in the intensive care unit (ICU) is ultrasound. When the diaphragm contracts, it thickens, and this thickening can be quantified by directly visualizing the muscle on ultrasound.5 the motion (excursion) of the dome of the diaphragm during inspiration can also be visualized.6 To assess thickening, the diaphragm is examined on its zone of apposition to the rib cage. In this location, ultrasound can measure end-expiratory and peak-inspiratory diaphragm thickness. Diaphragmthickening fraction is computed as the fractional increase in diaphragm thickness during inspiration. Thickening fraction is tightly correlated with transdiaphragmatic pressure.7,8 Thickening fraction is also correlated with the twitch pressure generated by BAMPS (r 5 0.87), provided that patients trigger the ventilator. A thickening fraction below 30% is diagnostic for diaphragmatic dysfunction.9 Diaphragm excursion can be used to assess diaphragm function but only during nonassisted breathing; otherwise the downward displacement of the diaphragm may reflect passive insufflation of the chest by the ventilator. Diaphragm excursion #1 cm during resting unsupported breathing is diagnostic for diaphragmatic dysfunction.6 Respiratory muscle function can also be assessed by airway pressures generated during maximal inspiratory efforts against an occluded airway.10 Transient airway occlusion for up to 20 seconds can be used to enhance respiratory drive and ensure maximal volition in mechanically ventilated patients.11 Using this technique, respiratory muscle weakness is defined as maximal inspiratory pressure below 30–40 cm H2O, although expected values vary somewhat with age.10

Epidemiology Diaphragm weakness is strikingly common in mechanically ventilated patients. Diaphragmatic dysfunction is present in up to 63% of patients within 24 hours of ICU admission and intubation.12 Since the initial severity of diaphragm weakness upon ICU admission is associated with the number and magnitude of organ failures, this early diaphragm weakness might simply be a form of organ failure associated with critical illness.12 At the time of weaning, diaphragmatic dysfunction is present in between 63% and 80% of patients.13,14 Using diaphragm ultrasound, Kim et al. identified diaphragmatic dysfunction in 24/82 medical ICU patients (29%) undergoing

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a first spontaneous breathing trial.15 Using BAMPs at time of weaning, diaphragmatic dysfunction was present in 63% of nonselected ICU patients13 and in 80% of patients with critical illness polyneuropathy and polyneuropathy.14 Later in the course of ventilation, diaphragm weakness is nearly universal in mechanically ventilated patients. The severity of diaphragm weakness is directly correlated with the duration of ventilation.16,17 In several studies, average twitch transdiaphragmatic pressures ranged between 7 and 10 cm H2O, well below the lower limit of normal values in healthy subjects (28–30 cm H2O).4,18,19 In one study, 30% of patients had twitch transdiaphragmatic pressure below 5 cm H2O, consistent with nearly complete muscle paralysis.18 The very high prevalence of profound diaphragm weakness is particularly striking when one considers that these studies generally excluded patients with any antecedent history of neuromuscular disease. Within a given patient, diaphragmatic function varies considerably through time. A recent cohort study found that many patients with profound diaphragm weakness on admission exhibited substantial recovery, while others without diaphragm weakness at baseline developed significant weakness.20 The time-dependent variation in diaphragmatic function reflects the complex interplay of various waxing and waning pathophysiologic insults responsible for the development of muscle injury at weakness throughout the course of critical illness.

PATHOGENESIS A variety of factors contribute to the high prevalence of diaphragmatic dysfunction among mechanically ventilated patients (Fig. 12.1).

Sepsis Sepsis acutely impairs muscle function by several mechanisms. It interferes with systemic oxygen delivery and oxygen utilization (septic shock). Circulating inflammatory mediators directly impair the function of contractile proteins involved in the myofilament’s force-generating mechanism.21 Inflammatory cytokines also amplify nitric oxide production within muscle tissue by upregulating inducible nitric oxide synthase expression in specific tissues, including the diaphragm, leading to rapid impairment in muscle force generation.22 As sepsis resolves, diaphragmatic function may rapidly improve.20

Metabolic Factors Many metabolic derangements commonly associated with critical illness contribute to diaphragm weakness, including hypercapnia,23,24 hypokalemia, hypophosphatemia, malnutrition, and hypoxemia.25 Shock states also induce acute diaphragm weakness and fatigue by impairing oxygen delivery to the strenuously active respiratory muscles,26,27 despite the redirection of oxygen delivery away from vital organs to the diaphragm.28

Pharmacologic Exposures Sedative agents may directly injure the diaphragm or impair muscle function apart from causing muscle disuse (see below). For example, propofol causes acute diaphragm weakness in healthy subjects undergoing anesthesia29 and activates muscle proteolysis in experimental models.30 Corticosteroids are well-known to cause atrophy and myopathy with long-term administration by activating muscle proteolytic pathways.31 Their impact on the development of ICUacquired weakness and diaphragmatic dysfunction is less

Critical illness

Mechanical ventilation

Eccentric contractions

Excess loading

83

Disuse atrophy

Structural diaphragm injury

Sepsis

Electrolyte deficiencies

Diaphragmatic dysfunction

Sedatlon & neuromuscular blockade

Hypercapnla

Impaired contractile performance

Prolonged mechanical ventilation

Death or long-term disability

Fig. 12.1  ​Mechanisms of diaphragm injury and diaphragmatic dysfunction during critical illness.

Shock states

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certain, as recent studies do not bear out an association between corticosteroid exposure and ICU-acquired weakness32 or diaphragm atrophy.33

Mechanical Ventilation By suppressing respiratory muscle effort, mechanical ventilation can induce a remarkably rapid disuse atrophy of the diaphragm. This phenomenon has been demonstrated repeatedly in a range of experimental models.34–37 Histologic studies in brain-dead organ donors and living mechanically ventilated patients have documented significant reductions in diaphragm myofiber cross-sectional area compared with that of other axial skeletal muscles.16,38–40 Using bedside ultrasound, several clinical studies have documented widespread progressive thinning of the diaphragm over several days of mechanical ventilation.33,41–43 The rate of thinning is directly related to the level of diaphragm contractile activity: patients with low or absent diaphragm contractility during mechanical ventilation exhibit significantly faster atrophy.33 On the other hand, changes in diaphragm thickness were minimal when diaphragm thickening fraction (a sonographic marker for contractile effort) was similar to that of healthy subjects breathing at rest. Diaphragm injury and diaphragmatic dysfunction may also result from insufficient ventilatory assistance. The work of breathing is often excessive in ventilated patients because of elevated respiratory load (compromised respiratory mechanics) and significantly increased respiratory drive (owing to a variety of chemoreceptive, mechanoreceptive, and cortical stimuli).44 If the respiratory muscles are not adequately unloaded by mechanical ventilation, acute diaphragm injury can result. Sepsis and systemic inflammation render the myofiber cell membrane (sarcolemma) more fragile and susceptible to injury from mechanical stress; sarcolemma rupture leads to muscle edema and inflammation.45 Eccentric loading of the diaphragm (diaphragm contractile efforts occurring while the muscle is lengthening rather than shortening) may be especially injurious.46 Eccentric diaphragm contractions may occur in the context of significant atelectasis, where the diaphragm contracts during expiration to maintain end-expiratory lung volume (“expiratory braking”),47 or during various forms of patient–ventilator dyssynchrony, where diaphragm contractions are mistimed and often occur during expiratory flow (ineffective triggering, reverse triggering).48,49

CLINICAL OUTCOMES The diaphragm muscle has a range of important physiologic functions—the generation of inspiratory flow, cough effectiveness, posture, and maintenance of hemodynamic function in the face of intravascular volume depletion.50–53 Axial skeletal muscle performance is limited in the event that diaphragmatic fatigue develops.54 Diaphragm weakness can therefore impair cardiopulmonary function, limit mobility, and seriously reduce the patient’s capacity to tolerate cardiopulmonary insults. In ventilated patients, diaphragmatic function is

a crucial determinant of weaning success.55 Diaphragmatic dysfunction is associated with a substantial increase in the risk of weaning failure.13,15,56 Patients with diaphragm weakness also require a significantly greater duration of weaning from mechanical ventilation and a prolonged ICU stay, and are at higher risk of death in the ICU or in hospital.13,15 Of note, at the time of the first trial of spontaneous breathing, diaphragm muscle weakness has a much greater impact on prognosis than limb muscle weakness (Fig. 12.2).13 Similarly, the development of diaphragm atrophy during mechanical ventilation portends a much greater risk of reintubation, tracheostomy, and prolonged ventilation (Fig. 12.3).57 This finding is important because it suggests that a potentially avoidable mechanism of injury, disuse atrophy from ventilator overassistance or oversedation, is responsible for prolonged ventilation and poor outcomes. Avoiding diaphragm atrophy may therefore prevent diaphragm weakness and the attendant poor outcomes. The impact of diaphragm weakness after critical illness extends beyond the initial period of respiratory failure. The risk of readmission to ICU or hospital is substantially increased in patients with diaphragm weakness, persisting 7 days after ICU discharge.58 Long-term outcomes are also probably significantly affected: patients with diaphragm weakness at ICU discharge are at significantly greater risk of death at 1 year after ICU discharge.59 Given that diaphragm weakness prolongs ICU admission, and ICU admission in turn consistently predicts long-term functional disability in ICU survivors, the development of diaphragm weakness probably contributes to poor long-term functional status and quality of life. Although diaphragmatic dysfunction and poor long-term outcomes have not yet been directly linked, available data suggest that impaired respiratory muscle strength may persist for months and years after ICU admission in some patients.32 Diaphragm weakness may account for the profound dyspnea experienced by some survivors of critical illness in the absence of any abnormality on pulmonary function testing.60

POTENTIAL THERAPIES As yet, there are no proven therapies for diaphragmatic dysfunction following mechanical ventilation. Several potential approaches to prevention and treatment are on the horizon based on a rapidly evolving understanding of the mechanisms responsible for diaphragmatic dysfunction (Fig. 12.4).

Prevention Efforts to prevent diaphragm weakness are primarily focused on different mechanistic aspects of ventilator-induced diaphragmatic dysfunction. Because ventilator-induced diaphragmatic dysfunction primarily results from absent or insufficient inspiratory effort (disuse atrophy), adjusting mechanical ventilation and/or sedation to maintain a safe level of inspiratory effort may prevent disuse atrophy and diaphragm weakness. This

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Difficult weaning

Prolonged weaning

Hospital mortality

60%

Clinical outcome

50%

40%

30%

20%

10%

0% Diaphragm weakness

Limb muscle weakness

Diaphragm weakness

Limb muscle weakness

Diaphragm weakness

Limb muscle weakness

Limb and respiratory muscle function at first spontaneous breathing trial Present

Absent

Fig. 12.2  ​Diaphragm weakness is more strongly associated with prognosis than limb muscle weakness at the time of the first trial of spontaneous breathing.  (From Schreiber A, Bertoni M, Goligher EC. Avoiding respiratory and peripheral muscle injury during mechanical ventilation: diaphragm-protective ventilation and early mobilization. Crit Care Clin. 2018;34[3]:357-381. Based on data from Dres M, Dubé B-P, Mayaux J, et al. Coexistence and impact of limb muscle and diaphragm weakness at time of liberation from mechanical ventilation in medical intensive care unit patients. Am J Respir Crit Care Med. 2017;195[1]:57-66.)

Cumulative incidence of liberation or death

100%

80% Initial change in diaphragm thickness on or before day 7 of ventilation

* *

60%

40%

No change from baseline (n = 66) >10% decrease (n = 78) >10% increase (n = 47) Status at disconnection from ventilator Alive Dead

20%

0% 0

7 14 Duration of follow-up (days)

21

Fig. 12.3  Changes in diaphragm thickness are associated with delayed liberation from mechanical ventilation. In patients with early decreases or increases in thickness, the risk of remaining on mechanical ventilation at day 21 is approximately doubled.  (From Goligher EC, Dres M, Fan E, et al. Mechanical ventilation-induced diaphragm atrophy strongly impacts clinical outcomes. Am J Respir Crit Care Med. 2018;197[2]:204-213.)

85

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Non-ARDS and Noninfectious Respiratory Disorders

Mechanical ventilation

Critical illness

Prevention

Diaphragm-protective ventilation Phrenic nerve stimulation Pharmacologic therapies

Treatment

Reverse contributing factors Early mobilization Pharmacologic therapies Inspiratory muscle training

Diaphragmatic dysfunction

Clinical outcome Fig. 12.4  Approach to prevention and treatment of diaphragmatic dysfunction in mechanically ventilated patients. The benefits of preventive strategies remain unproven. Interventions highlighted in bold have at least moderate evidence in support of clinical benefit.

approach—referred to as diaphragm-protective ventilation— offers a promising potential means of preventing diaphragm weakness.61 In support of this concept, a recent study found that both insufficient and excessive levels of inspiratory effort were associated with prolonged ventilation, while an intermediate level of effort (similar to that of healthy subjects breathing at rest) was associated with a relatively shorter duration of ventilation.57 These data provide a potential therapeutic target. However, in view of competing concerns such as the need to prevent ventilator-induced lung injury by maintaining a protective tidal volume and the need to ensure that patients are adequately sedated to be calm and comfortable, it is unclear whether the benefits of diaphragm protection outweigh the potential harms of maintaining spontaneous breathing.62 It is also unclear whether it is possible to titrate ventilation and/or sedation to achieve the desired level of inspiratory effort, given the very high levels of respiratory drive in many conscious critically ill patients. An alternative approach to preventing disuse atrophy is phrenic nerve stimulation, which can activate the diaphragm while permitting ongoing deep sedation and controlled ventilation as indicated. In animal models, phrenic nerve stimulation prevents the development of diaphragm atrophy.63 In patients undergoing cardiac surgery, phrenic nerve stimulation maintains mitochondrial function and diaphragm muscle fiber force generation while mitigating autophagy and oxidative stress,64–66 all cardinal features of ventilator-induced diaphragmatic dysfunction. The benefits of this technique have yet to be explored in mechanically ventilated patients with respiratory failure; patient selection and stimulation dosing remain important areas of uncertainty. A variety of pharmacologic agents have been proposed for preventing diaphragm weakness based on a burgeoning understanding of the basic cellular mechanisms leading to diaphragmatic dysfunction. For example, a number of antioxidant agents or antiproteolytic agents have shown promise in preventing cellular derangements associated with

diaphragm inactivity.67–69,70 However, none of these therapies have undergone clinical testing. While awaiting the confirmation of effective preventive strategies, clinicians can reasonably aim to ensure a comfortable and safe level of inspiratory effort in their ventilated patients by attending to patient effort levels and minimizing exposure to unnecessary sedation or neuromuscular blockade.

Treatment Diaphragmatic function will improve as the factors that contribute to muscle weakness are addressed. Effective treatment of sepsis and avoidance of immobility are paramount. Pharmacologic agents, including levosimendan and methylxanthines such as theophylline, can improve diaphragmatic function but their role remains undefined in critically ill patients given potential adverse effects.71,72 Early mobilization may recruit the diaphragm even as it recruits limb muscles for rehabilitation.73 Specific inspiratory muscle training (IMT) can be accomplished by a variety of techniques designed to load the inspiratory muscles and diaphragm.74 Two basic forms of IMT may be distinguished: flow-resistive loading and threshold loading. The former applies a resistance to inspiratory flow; the resistive pressure (the load) is therefore somewhat dependent on the patient’s effort levels. Threshold loading involves the application of a specific pressure load that must be overcome in order to generate inspiratory flow. These methods of loading can be achieved at the bedside by attaching simple devices designed for this purpose to the airway. The magnitude and timing of the load can be titrated according to the patient’s tolerance. A recent systematic review of IMT techniques reported 28 studies in the literature.75 The available evidence suggests that IMT can improve both inspiratory and expiratory muscle function. IMT was also associated with a shorter duration of ventilation and ICU stay, but further trials are awaited to definitively confirm this finding.

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AUTHORS’ RECOMMENDATIONS • Diaphragmatic dysfunction (DD) is extremely common in mechanically ventilated patients, occurring in two-thirds of patients within 24 hours, and directly contributes to poor clinical outcomes in critical illness. • DD can be defined as a reduction in the force-generating capacity of the diaphragm: a decrease in its capacity to generate a negative intrathoracic pressure, usually below 11 cm H2O. • DD can be diagnosed using ultrasound at the level of the rib cage—to assess diaphragmatic thickness on inspiration and expiration. A thickening fraction below 30% is diagnostic. • Epidemiologic factors for DD include sepsis, metabolic derangements, drugs (sedatives, neuromuscular blockers and, possibly, corticosteroids), mechanical ventilation, and inadequate ventilatory support. • DD significantly contributes to weaning failure, prolonged mechanical ventilation, and readmission to ICU, and is associated with increased 1-year mortality. • Preventive strategies for DD include avoidance of critical illness, by treating and source controlling sepsis early, avoidance of oversedation, “diaphragm-protective ventilation,” phrenic nerve stimulation, and metabolic support. • Therapeutic approaches to DD include early mobilization and inspiratory muscle training (flow resistive and threshold loading).

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e1 Abstract: Diaphragmatic dysfunction is highly prevalent among mechanically ventilated patients. The diaphragm is vulnerable to a range of insults associated with critical illness and mechanical ventilation, including sepsis, metabolic derangements, pharmacologic exposures, disuse atrophy, and load-induced injury. Patients who develop diaphragm weakness during mechanical ventilation are at high risk of poor short-term and long-term clinical outcomes. Diaphragm

weakness may be diagnosed by ultrasound and other techniques. Efforts to prevent diaphragm weakness are primarily focused on optimizing mechanical ventilation. Treatments include correction of reversible factors, early mobilization, and inspiratory muscle training. Keywords: diaphragm weakness, mechanical ventilation, clinical outcomes, sepsis, ultrasound