Hypoventilation and Respiratory Muscle Dysfunction

Hypercapnic respiratory failure is conventionally defined as a state in which ventilation is insufficient to maintain an arterial tension of carbon dioxide (PaCO₂) of less than 45 mm Hg for the level of metabolic activity (measured by CO₂ production, ).¹ Under steady-state conditions, the relationship among PaCO₂, alveolar ventilation (), and is given by the equation:

in which K (usually stated as 0.863) is a constant that converts measurement of from standard conditions to body temperature conditions. The term represents the portion of minute ventilation () that reaches the terminal gas exchange units and is calculated as

where equals dead space ventilation. A reduction in may result from an inadequate or an increase in (resulting from an increase in true or a functional increase in secondary to lung regions with high ventilation-perfusion [] relationships).*

Hypercapnia is synonymous with alveolar hypoventilation for the patient’s level of carbon dioxide production. Alveolar hypoventilation can result from decreased neuromuscular capacity and increased respiratory load (Fig. 40.1).² Isolated impairments in gas exchange—i.e., conditions in which the alveolar-arterial O₂ gradient* is increased—usually do not cause hypercapnia.³ When gas exchange is impaired, however, the magnitude of neuromuscular derangements causing hypercapnia or the magnitude of increased respiratory loads causing hypercapnia is less than the corresponding derangements when gas exchange is normal. Conditions in which gas exchange contributes to hypercapnia are usually characterized by ventilation-perfusion inequality. When gas exchange is impaired total minute ventilation may actually be increased despite a concurrent decrease in alveolar ventilation.

Figure 40.1 Diagnostic approach to critically ill patient with hypercapnia. A-aDO₂, alveolar-arterial difference in partial pressure of oxygen; ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease.

Decreased Neuromuscular Capacity

Disease states that may result in decreased neuromuscular capacity and thus in alveolar hypoventilation include conditions characterized by decreased respiratory center output and by respiratory muscle weakness and respiratory muscle fatigue.

Decreased Respiratory Center Output

Isolated decreases in respiratory drive can produce ventilatory failure without distress. Potential causes include sedative overdose,¹ hypothyroidism,⁴ metabolic alkalosis,⁵ semistarvation,⁶ and central alveolar hypoventilation syndrome. The latter can be either idiopathic (i.e., primary alveolar hypoventilation, or Ondine’s curse) or secondary to neurologic lesions, such as trauma, infection (poliomyelitis), infarction, and obesity hypoventilation syndrome.⁴ In mechanically ventilated patients, decreases in respiratory drive are suspected when patients develop marked increases in PCO₂ despite relatively normal measurements of resistance and elastance and no apparent evidence of lower motor neuron disease.⁷ Whether sleep deprivation decreases respiratory drive remains controversial.^8,9

Respiratory Muscle Weakness

Detection of Respiratory Muscle Weakness in Critically Ill Patients

Measurements of airway pressure during maximal voluntary inspiratory efforts are used to evaluate global inspiratory muscle strength.¹⁰ In healthy subjects, maximum inspiratory airway pressure is usually more negative than −80 cm H₂O.¹⁰ In mechanically ventilated patients recovering from an episode or acute respiratory failure, maximum inspiratory airway pressure can range from less negative than −20 cm H₂O to about −100 cm H₂O.^7,11,12 Values of maximal airway pressure during voluntary maneuvers depend greatly on a level of motivation and comprehension of the maneuver (often not obtainable in critically ill patients).¹³ Not surprisingly, in patients requiring short-term mechanical ventilation, measurements of maximum inspiratory airway pressure commonly do not differentiate between weaning success and weaning failure patients.^12–14

In contrast to the voluntary nature of maximal voluntary inspiratory efforts, transdiaphragmatic pressures elicited by single stimulations of the phrenic nerves—or twitch pressure—are independent of patients’ motivation and eliminate the influence of the central nervous system.¹⁰ Activation can be achieved with either an electrical stimulator¹⁵ or a magnetic stimulator,¹⁵ though the latter is easier to use in mechanically ventilated patients (Fig. 40.2).^13,16,17

Figure 40.2 Recording of transdiaphragmatic twitch pressure. A, An esophageal balloon and a gastric balloon are passed through the nares. Magnetic stimulation of the phrenic nerves elicits diaphragmatic contraction. B, Continuous recordings of esophageal (Pes) and gastric pressures (Pga) and transdiaphragmatic pressure (Pdi)—calculated by subtracting Pes from Pga. Phrenic nerve stimulation (arrows) results in contraction of the diaphragm with consequent fall in intrathoracic pressure (negative defection of Pes) and rise in intra-abdominal pressure (positive deflection of Pga). These swings in pressure are responsible for the transdiaphragmatic twitch pressure. The smaller the transdiaphragmatic twitch pressure, the smaller the force generation capacity of the diaphragm.

In healthy volunteers, magnetic stimulation elicits twitch pressures that average 31 to 39 cm H₂O.¹⁰ In patients with severe chronic obstructive pulmonary disease (COPD), twitch pressures average 19 to 20 cm H₂O.^18,19 The value of transdiaphragmatic twitch pressure in patients recovering from an episode of acute respiratory failure is about one third of that recorded in healthy subjects (Fig. 40.3).²⁰ This marked reduction in twitch pressure^16,17 indicates the presence of respiratory muscle weakness in most of these patients. Respiratory muscle weakness in critically ill patients can result from preexisting conditions or from new-onset conditions.

Figure 40.3 Transdiaphragmatic pressure in response to single stimulations (twitch stimulation) of the phrenic nerves recorded in ventilated patients recovering from acute respiratory failure. The boxed area represents the 95% confidence interval of values obtained in healthy subjects. The decreased transdiaphragmatic twitch pressure in patients indicates presence of diaphragmatic weakness. (From Laghi F: Ventilator-induced diaphragmatic dysfunction: Is there a dim light at the end of the tunnel? Crit Care Med 2011;39:903.)

Weakness Due to Preexisting Conditions

Neuromuscular diseases, malnutrition, endocrine disorders, and hyperinflation are some of the preexisting conditions that can cause respiratory muscle weakness. The existence of preexisting conditions can be recognized before the patient develops acute ventilatory failure, at the time the patient develops acute ventilatory failure, or when acute ventilatory failure is already established.4,21–24

Neuromuscular Disorders

The capacity of the respiratory muscles to generate tension can be decreased in certain disorders, such as stroke, amyotrophic lateral sclerosis, spinal cord injuries, poliomyelitis, Guillain-Barré syndrome, neuropathies due to massive intoxications of arsenic ²⁵ or thallium,²⁶ chronic inflammatory demyelinating polyneuropathy, axonopathy of acute intermittent porphyria, myasthenia gravis, acid maltase deficiency, and muscular dystrophies such as myotonic dystrophy (i.e., the most frequent adult form of muscular dystrophy).^4,27,28

Hypercapnic respiratory failure usually occurs when respiratory muscle strength falls to 39% of the predicted normal value.²⁹ However, Gibson and associates³⁰ described several patients with neuromuscular disease who had a normal partial pressure of CO₂ despite decreases in respiratory muscle strength to less than 20% of predicted. Conversely, some patients with only moderate respiratory muscle weakness displayed hypercapnia (Fig. 40.4).³⁰ In other words, reductions in muscle strength do not consistently predict alveolar hypoventilation in this setting.

Figure 40.4 Relationship between muscle strength and mixed venous partial pressure of CO₂ () in patients with respiratory muscle weakness. Respiratory muscle strength is the arithmetic sum of maximum static inspiratory and expiratory mouth pressures (Pmax = PImax + PEmax). The open circles are patients with myotonic dystrophy, and the closed circles are patients with a variety of nonmyotonic muscle diseases. As respiratory muscle weakness became more severe rose, although considerable variability was observed among patients. The regression lines were similar in the myotonic and nonmyotonic patients. (From Gibson GJ, Gilmartin JJ, Veale D, et al: Respiratory muscle function in neuromuscular disease. In Jones NL, Killian KJ [eds]: Breathlessness. The Campbell Symposium. Hamilton, Ontario, Boehringer-Ingelheim, 1992.)

Hyperinflation

Hyperinflation is a common preexisting problem in patients with obstructive lung diseases such as COPD,⁴ cystic fibrosis,³¹ bronchiolitis,³² and lymphangioleiomyomatosis.⁴ The severity of preexisting hyperinflation commonly worsens in patients experiencing an exacerbation of COPD.³³ Hyperinflation has a number of adverse effects on inspiratory muscle function: the inspiratory muscles operate at an unfavorable position of the length-tension relationship (Fig. 40.5);³⁴ flattening of the diaphragm decreases the size of the zone of apposition with the result that diaphragmatic contraction causes less effective rib cage expansion.⁴ Hyperinflation also has an adverse effect on the elastic recoil of the thoracic cage.⁴ This means that the inspiratory muscles must work not only against the elastic recoil of the lungs but also against that of the thoracic cage. The functional consequences of dynamic hyperinflation are probably the main mechanisms of ventilatory failure in patients with COPD.³⁵ Hyperinflation can also occur de novo in patients with pneumonia, chest trauma, and acute respiratory distress syndrome (ARDS).^33,36 Impairment of inspiratory muscle function is less likely in patients with ARDS than in patients with obstructive lung disease because patients with ARDS breathe at a low lung volume despite dynamic hyperinflation.^36,37

Figure 40.5 Twitch transdiaphragmatic pressure elicited by phrenic nerve stimulation (upper panels) and functional residual capacity (FRC) (lower panels) in a patient with severe emphysema before (left) and after (right) lung volume reduction surgery. The increase in transdiaphragmatic pressure after surgery was in part due to a decrease in the operating lung volume as demonstrated by the decrease in functional residual capacity. (Data from Laghi F, Jubran A, Topeli A, et al: Effect of lung volume reduction surgery on neuromechanical coupling of the diaphragm. Am J Respir Crit Care Med 1998;157:475.)

Malnutrition

Malnutrition is highly prevalent among critically ill patients requiring mechanical ventilation,38,39 and it is associated with poor prognosis.³⁹ Malnutrition decreases muscle mass and respiratory muscle strength both in humans^40,41 and in laboratory animals.^42–44 Likely mechanisms contributing to decrease in respiratory muscle mass include proteolysis of myofibrillar proteins by the ubiquitin-proteasome proteolytic system (Fig. 40.6) and apoptosis.^4,45 Apoptosis can be triggered by local and circulating tumor necrosis factor-α and by release of cytochrome c from the mitochondria.^46,47

Figure 40.6 Ubiquitin-proteasome degradation of contractile proteins. The first step in degradation of actin and myosin is activation of ubiquitin (Ub) by a first enzyme, E₁—a process requiring adenosine triphosphate (ATP). Activated ubiquitin interacts with a second enzyme, E₂, a carrier protein. Ub and E₂ join a third enzyme, E₃. E₃ transfers activated Ub to actin and myosin. The cycle is repeated until a chain of Ub is bound to the contractile proteins. The chain of Ub binds to one end of a proteasome complex in a process requiring ATP. The Ub chain is subsequently removed (allowing reuse of Ub), and actin and myosin are unfolded and pushed into the core of the proteasome. Multiple enzymes within the core degrade actin and myosin into small peptides. The peptides are extruded from the proteasome and degraded to amino acids by peptidases in the cytoplasm. The ubiquitin-proteasome system degrades myofibrillar proteins only after they have been cleaved and released by other proteolytic pathways—i.e., the ubiquitin-proteasome pathway cannot degrade intact myofibrillar proteins. (From Laghi F, Tobin MJ: Disorders of the respiratory muscles. Am J Respir Crit Care Med 2003;168:10-48.)

In patients with COPD, inspiratory muscle strength is about 30% less in poorly nourished patients than in well-nourished patients with equivalent airway obstruction.⁴⁸ Similarly, malnourished patients with anorexia nervosa can present with reduced inspiratory muscle strength to 35% to 50% predicted,⁴¹ impaired respiratory muscle endurance,⁴⁹ impaired hypercapnic ventilatory response,⁴⁹ and occasionally, with hypercapnia at rest.⁴¹ In malnourished patients, inspiratory weakness,^41,48,49 fatigability,⁴⁸ and dyspnea⁴⁸ are partially reversible with nutritional support. The process is slow and, in laboratory animals, can take months of refeeding for muscle mass to return to normal values.⁵⁰ To date, it remains unclear whether malnutrition by itself can cause sufficient respiratory muscle weakness to produce hypoventilation. It is more likely for malnutrition to be a contributory factor and not a sole cause of hypercapnic respiratory failure.

Endocrine Disturbances

Endocrine disturbances such as hypothyroidism,⁵¹ hyperthyroidism,^47,52–54 and acromegaly⁵⁵ can adversely affect respiratory muscle function. Proteolysis of myofibrillar proteins by the ubiquitin-proteasome proteolytic system⁴⁵ (see Fig. 40.6) is probably responsible for respiratory muscle catabolism and weakness of hyperthyroidism.⁴⁷ This mechanism is implicated in muscle wasting associated with acidosis, renal failure, denervation, cancer, diabetes, acquired immunodeficiency syndrome (AIDS), trauma, and burns.⁴⁵ In contrast to other endocrine disturbances, respiratory muscle weakness is unusual in patients with Cushing syndrome.⁵⁶

Weakness Due to New-Onset Conditions

New-onset respiratory muscle weakness in critically ill patients may result from conditions that are unique to these patients. These conditions include ventilator-associated respiratory muscle dysfunction, sepsis-associated myopathy, and intensive care unit (ICU)-acquired paresis. New-onset respiratory muscle weakness can also result from conditions that are not unique to critically ill patients, including acid-base disorders, electrolyte disturbances, decreased oxygen delivery, and certain medications. Respiratory muscle weakness due to conditions that are unique to critically ill patients are often associated with alterations in respiratory muscle structure, although the others are not necessarily associated with alterations in muscle structure. Recovery from respiratory muscle weakness (if it occurs at all) is slow when the weakness is caused by alterations in muscle structure. In contrast, recovery of respiratory muscle weakness in conditions that are not necessarily associated with alterations in muscle structure is usually quick once the underlying triggering factor has been corrected.

Ventilator-Associated Respiratory Muscle Dysfunction

Since the late 1980s, several groups have studied the effect of mechanical ventilation on the muscles of laboratory animals.⁵⁷ A seminal study by Anzueto and colleagues⁵⁸ showed that 11 days of controlled mechanical ventilation (CMV) together with neuromuscular blocking agents produced a 46% decrease in respiratory muscle strength (Fig. 40.7). Subsequent studies have revealed that complete cessation of diaphragmatic activity with CMV—alone⁵⁹ or in combination with neuromuscular blocking agents⁶⁰—results in atrophy and injury of diaphragmatic fibers (Fig. 40.8). Muscle fibers generate less force in response to stimulation, not simply because of their decreased bulk but even when normalized for cross-sectional area.⁵⁷ The decrease in diaphragmatic force ranges from 20% to more than 50%. The alterations in muscle function occur rapidly, within 12 hours of instituting mechanical ventilation,⁶¹ and they appear to increase as ventilator duration is prolonged.^62,63

Figure 40.7 Transdiaphragmatic pressure (Pdi) response to phrenic nerve stimulation before (solid line) and after 11 days (dashed line) of mechanical ventilation. That the Pdi recorded after 11 days of mechanical ventilation shows a decreased response to all stimulation frequencies is suggestive of ventilator-associated diaphragmatic dysfunction (Modified from Anzueto A, Peters JI, Tobin MJ, et al: Effects of prolonged controlled mechanical ventilation on diaphragmatic function in healthy adult baboons. Crit Care Med 1997;25:1187.)

Figure 40.8 Electron microscopy of the diaphragm (longitudinal section) of a rabbit under control conditions (A, specimen processed with 1100-mOsm fixative) and after 3 days of controlled mechanical ventilation (B, specimen processed with 500-mOsm fixative). The control rabbit has an intact ultrastructure. The mechanically ventilated rabbit shows several areas of disrupted myofibrils (short thick arrows), the mitochondria are swollen (long thick arrow) and have abnormal cristae, and the intermyofibril space contains lipid droplets (long thin arrow), indicating decreased lipid uptake by the mitochondria. (From Laghi F, Tobin MJ: Disorders of the respiratory muscles. Am J Respir Crit Care Med 2003;168:10-48. Electron micrographs provided by Dr. Catherine S. H. Sassoon, Long Beach VA Hospital and University of California, Irvine, CA.)

Mechanical ventilation may also harm the respiratory muscles of patients. In 1988, Knisely and coworkers ⁶⁴ reported that the cross-sectional area of diaphragmatic fibers in infants who had died after receiving mechanical ventilation for 12 or more days was much smaller than that in infants who had received mechanical ventilation for 7 days or less (Fig. 40.9). Fibers taken from extradiaphragmatic muscles were similar in the two groups. Twenty years later, Levine and associates⁶⁵ obtained biopsies of the diaphragm from 14 brain-dead organ donors who were maintained on CMV for 18 to 69 hours. They also obtained intraoperative biopsies of the diaphragms of eight control patients who had received CMV for 2 to 3 hours. Histologic measurements revealed marked diaphragmatic atrophy in the brain-dead patients. Compared with the control group, the mean cross-sectional areas of muscle fibers were decreased by more than 50%. A number of these results have been corroborated by Jaber and colleagues⁶³ and Hermans and coworkers,⁶⁶ who also reported a progressive decrease in diaphragmatic contractility of mechanically ventilated patients. The decrease in contractility correlated with the duration of ventilator support (Fig. 40.10).^63,66

Figure 40.9 Photomicrographs of transverse sections of diaphragm from an infant ventilated from birth until death at day 47 (A) and from an infant ventilated from birth until accidental death at day 3 (B). Prolonged mechanical ventilation was associated with reduction in myofiber cross-sectional area. (The yellow arrow indicates a developing myofiber also known as Wohlfart myofiber.) (Modified from Knisely AS, Leal SM, Singer DB: Abnormalities of diaphragmatic muscle in neonates with ventilated lungs. J Pediatr 1988;113:1074.)

Figure 40.10 Twitch airway pressure elicited by magnetic stimulation of the phrenic nerves in six patients who received mechanical ventilation (MV) for 30 minutes (short-term MV; open bar) and in six patients who received MV for about 6 days (long-term MV; solid bars). On day 1 twitch airway pressure was already less in the long-term than in the short-term MV group. In addition, long-term MV was associated with a progressive decrease in twitch pressure over time—mean reduction of 32 ± 6% after 6 days of MV. H, number of hours of mechanical ventilation; D, number of days of mechanical ventilation. (From Jaber, Petrof BJ, Jung B, et al: Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans. Am J Respir Crit Care Med 2011;183:364-371.)

Biochemical and gene-expression studies in animals and humans 65,67 suggest that oxidative stress is probably one of the most proximal mechanisms in the biochemical cascade that leads to ventilator-induced muscle injury.⁶⁸ Oxidative stress decreases contractility by causing protein oxidation and by promoting protein catabolism⁶⁸—including up-regulation of the autophagy-lysosome pathway.⁶⁹ The synergism between ventilator-induced muscle injury and oxidative stress has caused investigators to explore whether early administration of antioxidants might minimize muscle injury.^70–72 In a study of more than 200 critically ill patients—80% of whom required acute ventilator support—duration of mechanical ventilation was nearly 3 days shorter in those who completed a 10-day antioxidant supplementation protocol (vitamin E and vitamin C) than in those who completed a 10-day course of placebo.⁷³ Similar results have been reported in critically ill surgical patients requiring mechanical ventilation.⁷⁴ Whether the decrease in duration of mechanical ventilation was, at least in part, due to the potential positive effects of antioxidants on the respiratory muscles remains to be demonstrated. Of concern, however, was the report that administration of the antioxidant N-acetylcysteine (NAC) to critically ill patients with severe sepsis worsened sepsis-induced organ failure.⁷⁵

In animal models, ventilator settings can affect the extent of ventilator-associated respiratory muscle dysfunction.76–79 In rabbits, assist-control mechanical ventilation causes a nonsignificant decrease in diaphragm muscle contractility, which contrasts with the 48% decrease recorded with CMV.⁷⁶ Similar results have been obtained when comparing CMV to adaptive support ventilation in piglets⁷⁸ or when comparing CMV to pressure support in rats⁷⁹ or CMV to intermittent spontaneous breathing again in rats.⁷⁷ These observations raise the important question of whether maintenance of partial diaphragmatic activity or intermittent loading of the diaphragm could prevent the harm done to diaphragmatic function by mechanical ventilation.⁸⁰

Considering that decrease in protein synthesis probably contributes to ventilator-associated respiratory muscle dysfunction,81,82 it would seem biologically plausible that administration of anabolic factors—such as growth hormone—might be of benefit in ventilated patients. Unfortunately, when growth hormone has been administered to patients requiring prolonged mechanical ventilation, duration of mechanical ventilation was not decreased, nor was muscle strength increased.⁸³ Of concern was the report that recombinant growth hormone can increase the mortality rate of critically ill patients.⁸⁴ An even more fundamental point in regard to ventilator-associated respiratory muscle dysfunction has been raised recently by the preliminary data of Hooijman and associates.⁸⁵ These investigators measured the contractile properties of single diaphragmatic fibers obtained from nine brain-dead organ donors who had received CMV for 30 to 84 hours (case subjects) and from nine patients undergoing surgery for localized lung cancer (control subjects). In this preliminary study no difference was noted between the muscle fibers of the two groups of patients with respect to maximum force per unit area, calcium sensitivity of contractile force, and rate constant of redevelopment of force (Ktr). How to reconcile the preliminary results of Hooijman and associates⁸⁵ with previous data obtained on muscle strips from animal models and by phrenic nerve stimulation in patients remains to be determined.

Sepsis-Associated Myopathy

Sepsis, a common occurrence in critically ill patients, can produce ventilatory failure by causing respiratory muscle dysfunction and increased metabolic demands.⁸⁶ Septic animals develop failure of neuromuscular transmission (due to increased sarcolemmal electric potential)^87–89 and failure of excitation-contraction coupling.^86,90 Mechanisms responsible for failure of excitation-contraction coupling include the cytotoxic effect of nitric oxide and its metabolites, free radicals, ubiquitin-proteasome proteolysis, and possibly, decrease in nicotinic acetylcholine receptors.^91,92 Local dysregulation of the circulation and Krebs cycle may also contribute.⁸⁶

Nitric oxide, a free radical that has a negative inotropic effect in the heart and skeletal muscle, is produced in large amounts during sepsis by a nitric oxide synthase inducible by lipopolysaccharide and several cytokines (Fig. 40.11).⁹³ Increased expression of inducible nitric oxide synthase in the diaphragm during sepsis is associated with morphologic evidence of widespread damage to the myofiber membrane, or sarcolemma (Fig. 40.12).⁸⁸ Diaphragmatic contractions enhance this sepsis-induced sarcolemmal injury,⁹⁴ while early mechanical ventilation decreases sarcolemmal injury and the associated diaphragmatic dysfunction.⁹⁵ The beneficial effects of resting the diaphragm with the use of mechanical ventilation are not coupled with a decrease in oxidative stress or with a decrease in the expression of inducible nitric oxide synthase in the muscle.⁹⁵ These observations suggest the existence of a detrimental interaction of two independent stressors (oxidative and biomechanical stresses) on the sarcolemma during sepsis.⁹⁵

Figure 40.11 A, A sample of gastrocnemius muscle obtained from an adult Sprague-Dawley rat injected 12 hours earlier with Escherichia coli endotoxin (20 mg/kg). The section was stained with an antibody to inducible nitric oxide synthase. Positive staining (brown coloration, arrows) is evident inside the fibers. B, A sample of gastrocnemius muscle obtained from a rat injected 12 hours earlier with normal saline. No positive staining is evident. (From Laghi F, Tobin MJ: Disorders of the respiratory muscles. Am J Respir Crit Care Med 2003;168:10-48. Photomicrographs provided by Dr. Sabah N. Hussain, Royal Victoria Hospital, Montreal, Canada.)

Figure 40.12 A, A strip of diaphragm obtained from a C57BL/6 mouse injected 12 hours earlier with normal saline. The strip was stimulated for 3 minutes (50 Hz, 300-ms duration) and then immersed for 90 minutes in Krebs solution containing a fluorescent probe, Procion orange 14 (0.15, wt/vol). B, A strip of diaphragm obtained from a C57BL/6 mouse injected 12 hours earlier with Escherichia coli endotoxin (20 mg/kg). Stimulation and staining were conducted as described in A. Sarcolemmal damage, indicated by yellow staining, was increased by endotoxin. (From Laghi F, Tobin MJ: Disorders of the respiratory muscles. Am J Respir Crit Care Med 2003;168:10-48. Photomicrographs provided by Dr. Sabah N. Hussain, Royal Victoria Hospital, Montreal, Canada.)

To determine whether the inducible nitric oxide synthase pathway contributes to impaired skeletal muscle contractility in humans, Lanone and coworkers ⁹⁶ obtained samples of the rectus abdominis in 16 septic patients and 21 control subjects. The muscles of the patients had lower contractile force, and increases in inducible nitric oxide synthase expression (mRNA and protein) and activity. Immunohistochemical studies revealed the generation of peroxynitrite (a highly reactive oxidant formed by the reaction of nitric oxide with superoxide anion). Exposure of control muscles to the amount of peroxynitrite found in patients caused an irreversible decrease in force generation. These data suggest that sepsis decreases muscle force through the production of nitric oxide and its toxic byproducts.

Production of nitric oxide in sepsis may be protective and not solely deleterious.94,97–99 In mice deficient in inducible⁹⁷ or constitutive (neuronal) nitric oxide synthase,⁹⁴ endotoxin caused a greater decline in diaphragmatic contractility than in nondeficient mice. This finding contrasts with the observation that nitric oxide synthase inhibitors prevent muscle dysfunction in septic rats.^88,93,100 Although the results may be species-dependent,⁹⁴ the data underscore that nitric oxide has both antioxidant and pro-oxidant actions.¹⁰¹

In addition to nitric oxide and its derivatives, several other oxygen-derived free radicals (superoxide anion, hydroxyl radicals, hydrogen peroxide) contribute to the decreased contractility of the diaphragm in sepsis.99,102–104 This increased expression of oxygen-derived free radicals in sepsis is accompanied with enhanced activity of the antioxidant enzyme superoxide dismutase¹⁰² and with increased expression of the heme oxygenase-1 pathway.¹⁰⁴ The heme oxygenase-1 pathway is a powerful cellular system that protects against oxidative stress and contractile fatigue during sepsis.¹⁰⁴ Administration of an inhibitor (zinc protoporphyrin IX) or an inducer (hemin) of heme oxygenase activity respectively enhances or reduces the oxidative stress and contractile failure of the diaphragm in a rat model of sepsis.¹⁰⁴ In septic rats, decreased diaphragmatic contractility can also be improved by the administration of specific scavengers of superoxide ions, hydrogen peroxide, and hydroxyl radicals.¹⁰²

Intensive Care Unit–Acquired Paresis

While cared for in the ICU, critically ill patients can develop muscle weakness and, occasionally, paralysis. Some of these patients have evidence for axonal degeneration and denervation atrophy (Fig. 40.13).⁴ This constellation of findings is known as critical illness polyneuropathy (Table 40.1).¹⁰⁵ Cytokines¹⁰⁶ and low-molecular-weight neurotoxins¹⁰⁷ released during episodes of sepsis or when patients develop multiple organ failure are thought to be responsible for this axonal degeneration. Critical illness polyneuropathy has been considered one of the manifestations of multiple organ failure syndrome. Sepsis and multiple organ failure, though, are not essential prerequisites for the development of critical illness polyneuropathy.^108,109 Tight control of hyperglycemia may reduce the risk of polyneuropathy and the duration of mechanical ventilation.¹¹⁰

Table 40.1

Examples of Electromyography (EMG) Findings in Respiratory Muscle Weakness

Examples of injuries and deficits: axonal injury, critical illness polyneuropathy; myelin injury, Guillain-Barré syndrome; neuromuscular conduction defect, myasthenia, prolonged neuromuscular blockade; myopathy, critical illness myopathy.

Although features of myopathy can be recorded by electromyographic studies, electromyography cannot always distinguish critical illness myopathy from critical illness polyneuropathy, and muscle biopsy may be needed.

^*Elicited by motor nerve stimulation.

^†Decreased in Lambert-Eaton syndrome.

^‡Elicited by sensory nerve stimulation.

^§Spontaneous muscle depolarization (caused by denervation) is detected by presence of fibrillation potentials and positive sharp waves.

^¶Repetitive nerve stimulation is performed to exclude neuromuscular transmission defects such as prolonged neuromuscular paralysis.

From Laghi F, Tobin MJ: Disorders of the respiratory muscles. Am J Respir Crit Care Med 2003;168:10.

Figure 40.13 Transverse section of a peripheral motor nerve (deep peroneal nerve, A) and of a skeletal muscle (intercostal, B) in patients who developed profound weakness following a prolonged hospital course characterized by sepsis, multiple organ failure syndrome, and inability to wean from mechanical ventilation. A, The long thin dark structures seen in the left panel are myelin sheaths that contain axons. The axons are degenerating and dying. Following death, they disintegrate. The myelin surrounding the disintegrating axons collapses around the axonal debris to form ovoids of myelin—seen better on the lateral portions of the left micrograph. B, Amid muscle fibers that are normal in size and shape there are atrophic ones that appear small and that have developed contours with acute angles. These findings are consistent with denervation atrophy secondary to axonal degeneration, so-called critical illness polyneuropathy. (From Zochodne DW, Bolton CF, Wells GA, et al: Critical illness polyneuropathy. A complication of sepsis and multiple organ failure. Brain 1987;110:819.)

In other patients, rather than axonopathy, there is evidence of isolated myopathy (i.e., critical illness myopathy).⁴ Patients developing isolated myopathy often have been treated with steroids and neuromuscular blocking agents (e.g., patients with status asthmaticus).⁴ Muscle biopsies demonstrate a general decrease in myofibrillar protein content and a selective loss of thick filaments (myosin) within type I and type II fibers (Table 40.2 and Fig. 40.14). Animal models of critical illness myopathy suggest that medical denervation with paralytic agents cause an up-regulation of glucocorticoid receptors in the muscle.¹¹¹ If the animal subsequently receives high-dose corticosteroids, it will develop depletion of thick myosin filaments.¹¹¹ Although a decrease in thick-filament proteins may be important for prolonged weakness,¹¹² this decrease is probably not the cause of the acute paralysis,¹¹³ particularly in patients with compound motor action potentials of low amplitude.¹¹⁴ Impaired muscle membrane excitability is probably more important during the acute stage.^113,115

Table 40.2

Characteristics of Types of Muscle Fibers

A single myosin heavy chain isoform typically is expressed within an adult skeletal muscle fiber. Fibers classified as type I, IIa, IIx, or IIb express myosin heavy chain isoform I (or slow), IIa, IIx, or IIb, respectively. Type IIx fibers have been reported in peripheral muscles of humans and animals and in the diaphragm of animals. Type IIx fibers have not been reported in the human diaphragm. More than one myosin heavy chain isoform is expressed in a few fibers (about 14% of adult rat diaphragm coexpresses myosin heavy chain isoforms IIb and IIx, and less than 1% coexpresses myosin heavy chain isoforms I and IIa).²²⁶ Whereas the velocity of muscle contraction depends primarily on the myosin heavy chain isoform, the velocity of muscle relaxation is mainly determined by troponin C calcium binding and release and by calcium reuptake by the sarcoendoplasmic reticulum calcium-adenosine triphosphatase (SERCA). Several SERCA isoenzymes have been identified: SERCA 1 is expressed in type II fibers (fast calcium reuptake), and SERCA 2a is expressed in type I fibers (slow calcium reuptake).²²⁷ The density of pumping sites largely accounts for different rates of calcium uptake in fast- and slow-twitch muscle fibers.²²⁷ Despite this separation of tasks, velocity of contraction and velocity of relaxation tend to parallel each other: type II fibers contract and relax with a greater velocity than type I fibers. Slower velocity of relaxation allows fusion of repetitive twitches at lower frequencies of stimulation than with fast relaxations. Impairment of SERCA activity has been implicated in the development of fatigue and in disease states including heart failure and corticosteroid myopathy.

^*Amount of work performed per unit of adenosine triphosphate (ATP) consumed.

From Laghi F, Tobin MJ: Disorders of the respiratory muscles. Am J Respir Crit Care Med 2003;168:10.

Figure 40.14 Electron micrographs of normal skeletal muscle (right panel) and skeletal muscle from a patient who received steroids and the neuromuscular blocking agent vecuronium during a hospitalization with status asthmaticus followed by flaccid quadriplegia. Compared with the normal structure, the patient developed extensive loss of thick (myosin) myofilaments and relative preservation of thin (actin) filaments. Muscle strength returned to normal 2 months after discontinuation of vecuronium. M, M-line formed by myosin filaments and M-line proteins; Z, Z-disk formed by a lattice of filaments that join the actin filaments of one sarcomere with the actin filaments of the adjacent sarcomere. (From Eisenberg BR: Can electron microscopy distinguish fiber types? In Bradley WG, Gardner-Medwin D, Walton JN [eds]: Recent Advances in Myology. Amsterdam, Excerpta Medica, 1975; and from Danon MJ, Carpenter S: Myopathy with thick filament (myosin) loss following prolonged paralysis with vecuronium during steroid treatment. Muscle Nerve 1991;14:1131.)

In the last few years it has become increasingly apparent that critical illness neuropathy and myopathy often coexist.106,109,115–118 It has become common to refer to patients who become weak while in the ICU as a result of acquired neuropathy or myopathy (not associated with a known disorder) as simply having ICU-acquired paresis.^115,116,118 In patients with ICU-acquired paresis duration of weaning from mechanical ventilation can be two to seven times longer than in patients without ICU-acquired paresis.¹¹⁹