American Journal of Respiratory and Critical Care Medicine

Respiratory drive, the intensity of the respiratory center’s output, determines the effort exerted in each breath. The increasing awareness of the adverse effects of both strong and weak respiratory efforts during mechanical ventilation on patient outcome brings attention to the respiratory drive of the critically ill patient. Critical illness can affect patients’ respiratory drive through multiple pathways, mainly operating through three feedback systems: cortical, metabolic, and chemical. The chemical feedback system, defined as the response of the respiratory center’s output to changes in arterial blood gases and pH, is one of the most important determinants of respiratory drive. The purpose of this state-of-the-art review is to describe the determinants of respiratory drive in critically ill patients, review the tools available to assess respiratory drive at the bedside, and discuss the implications of altered respiratory drive during mechanical ventilation. An analysis that relates arterial carbon dioxide levels with brain’s response to this stimulus will be presented, contrasting the brain’s responses to the patient’s ability to generate effective alveolar ventilation, both during unassisted breathing and with different modes of ventilatory assist. This analysis may facilitate comprehension of the pathophysiology of respiratory drive in critically ill patients. As we aim to avoid both over- and under-assistance with mechanical ventilation, considering the patients’ respiratory drive at the bedside may improve clinical assessment and management of the patient and the ventilator.

Respiratory Drive and the Ιnspiratory Flow–Generation Pathway

Determinants of Respiratory Drive

Chemical Feedback

 Chemical Feedback to Changes in PaCO2/pH

 Chemical Feedback to Changes in PaO2

Effects of Critical Illness on the Determinants of Respiratory Drive

 Dissociation between Respiratory Drive and Actual Ventilation

 Effects of Critical Illness on the Brain Curve, the Ventilation Curve, and the Metabolic Hyperbola

 Effects of Mechanical Ventilation

Measuring Respiratory Drive in Critically Ill Patients

 EAdi

 Transdiaphragmatic and Inspiratory Pressure Produced by All Inspiratory Muscles (Pdi and Pmus)

 Airway Occlusion Pressure

 Clinical Signs and Breathing Pattern

Clinical Implications

 Low Respiratory Drive

 High Respiratory Drive

Conclusions

Recent data indicate that during mechanical ventilation, both strong and weak respiratory efforts may adversely affect patient outcome through multiple pathways, such as patient–ventilator dyssynchrony, ventilation-induced lung injury (including patient self-inflicted lung injury [P-SILI]), diaphragmatic myotrauma, poor sleep quality, and cardiovascular compromise (16). It is important to recognize that the reason behind deleterious strong or weak respiratory efforts is a relatively high or low respiratory drive. In addition, the broad term “respiratory distress,” often described in critically ill patients as a reason for manipulating ventilation and sedation, implies high respiratory drive. It is therefore important for intensivists to recognize the determinants of respiratory drive in critically ill patients and, ideally, to assess the patient’s respiratory drive and effort when setting and managing mechanical assist. In this review, we summarize the physiological control of respiratory drive and its determinants and discuss the effects of critical illness and mechanical ventilation on respiratory drive. We then describe the methods available to evaluate respiratory drive at the bedside and discuss the clinical implications of altered respiratory drive in critically ill patients. We focus on an analysis that relates CO2 production and elimination with the brain’s response to this stimulus, contrasting this response to the patient’s ability to generate effective alveolar ventilation. This analysis aims to facilitate understanding of how different variables modify respiratory drive in critically ill patients and to support clinical assessment and decision making.

Breathing is centrally controlled by the respiratory center, comprising a complex network of interconnected neurons in the medulla and pons. The respiratory center receives rather constant (tonic) inputs from various sources that, through a complicated process, are translated into an output with an oscillatory pattern (710). This output can be functionally divided into rhythm- and pattern-generating signals and regulates the three phases of the respiratory cycle: inspiratory, postinspiratory, and expiratory (711). The system employs “gating” to modulate the inputs, meaning that the same tonic input may have a different effect on the respiratory center, depending on the phase of the respiratory cycle (12). For example, a given input (e.g., PaCO2) activates the respiratory center during inspiration but not during expiration (gate function) (Figure 1).

During the inspiratory phase, the respiratory center’s output to the inspiratory muscles (electrical activity) gradually rises, eventually reaching a peak value. Thereafter, the postinspiratory phase begins, and this output subsides to the baseline value. Finally, the expiratory phase commences, during which there is no respiratory center activity at resting breathing in healthy individuals. The duration of these three phases, although the phases are not always discrete, determines the timing of the breath and thus breathing frequency, whereas the intensity of the output is referred to as “respiratory drive” (710, 1214). The distinction is important because respiratory drive may change without any changes in breath timing (i.e., frequency) and vice versa (15, 16). The respiratory center’s output during the inspiratory phase travels through the inspiratory flow–generation pathway (Figure 1): from the brainstem and upper cervical spine neurons to the nucleus of respiratory motoneurons, leading to activation and contraction of the inspiratory muscles, finally resulting in the generation of inspiratory flow (79, 1719).

In humans, because the intensity of the respiratory center’s output cannot be directly measured, respiratory drive is quantified using the average rate of increase of various indices of motor output that, under certain circumstances, reflect the respiratory center’s output to the inspiratory muscles (electrical activity). Indeed, in healthy humans, the respiratory drive determines the average rate of increase of 1) the electrical activity of respiratory motoneurons (mainly the phrenic nerve in quiet breathing); 2) the electrical activity of the diaphragm and, during strenuous breathing, of other inspiratory muscles; and 3) the transdiaphragmatic pressure, or pressure developed by all inspiratory muscles. Finally, the transdiaphragmatic pressure (Pdi) or pressure developed by all inspiratory muscles (Pmus) is translated into flow (V.) and volume (V) according to the equation of motion (Figure 1) (1921).

The main inputs to the respiratory center affecting the respiratory drive are the cortical and chemical feedback and the metabolic rate (7, 19, 20, 22). Reflex responses, such as the Hering-Breuer reflex, affect mainly the duration of the inspiratory and expiratory phases of the breath (19, 23, 24). Cortical inputs may override the automatic control of breathing (i.e., voluntary apnea) (25, 26). In critically ill patients, sensory and emotional stimuli such as pain and anxiety can significantly affect the respiratory drive (27, 28). Cortical inputs also mediate the effect of the wakefulness drive to breathe, as discussed below. Normally, in the absence of voluntary activity, the cerebral cortex exerts an inhibitory effect on the respiratory center and decreases its output (29). High respiratory drive is common in critically ill patients with brain injury involving the cerebral cortex and is associated with poor outcome (30, 31). Although metabolic rate plays a key role in modulating the respiratory drive during exercise, linking CO2 production and elimination, its role in critically ill patients is unclear (32, 33). The main determinant of respiratory drive in many critically ill patients (and the most studied) is the chemical feedback, which is the response of the respiratory center to changes in arterial blood gases and pH. Systemic inflammation and afferents from the lung and chest wall, through poorly described pathways, may also have a strong influence on the respiratory center and can increase respiratory drive for a given chemical stimulus (33, 34).

Chemical Feedback to Changes in PaCO2/pH

Changes in PaCO2 (and pH) are sensed by both peripheral and central chemoreceptors, the latter located at the retrotrapezoid nucleus on the ventrolateral surface of the medulla, and induce changes in the respiratory center’s output (79). At steady state, the arterial PaCO2 is determined by the intersection of two curves: the metabolic hyperbola and the PaCO2–ventilation response curve (Figure 2) (20). The metabolic hyperbola describes PaCO2 as a function of V.e (i.e., the change in PaCO2 obtained by a given change in V.e), based on the alveolar gas equation:

PaCO2=kV.COV.E(1VDVT).

The PaCO2–ventilation response curve describes V.e as a function of PaCO2 (i.e., the change in V.e induced by a change in PaCO2).

The normal response to hypercapnia (e.g., in case of increases in Vd, CO2 production, or inspired concentration of CO2) consists of a linear increase in ventilation in response to a rise in PaCO2 (9, 3537). The change in V.e per unit of increase in PaCO2 (Figure 2) varies widely in healthy individuals, having an average value of 2–3 L/min/mm Hg and a range of 0.6–8 L/min/mm Hg (19, 20, 35, 37). The normal response to hypocapnia (e.g., in case of excessive ventilation) depends on the wakefulness/sleep or sedation state. In awake individuals, below the eupneic PaCO2 level (the normal PaCO2 at rest), the slope of the curve deviates from linear, becoming almost horizontal at a minimum level of ventilation (Figure 2), which is maintained despite hypocapnia, a phenomenon known as “wakefulness drive to breathe” (22, 38). The wakefulness drive to breathe varies among healthy individuals and is affected by PaO2 and pH (19, 20, 37, 39). During sleep or sedation, the slope remains mostly linear, and, as a result, progressive hypocapnia leads to apnea (35, 3941). The PaCO2 level that causes apnea is referred to as “apneic threshold”; this level varies among healthy individuals and is also affected by PaO2 and pH (Figure 2).

It is important to emphasize that, normally, the changes in ventilation are primarily achieved through changes in respiratory drive and Vt, whereas breathing frequency changes little over a wide range of PaCO2. Breathing frequency increases significantly when respiratory drive is increased severalfold above resting ventilation and, in the absence of wakefulness drive to breathe, decreases abruptly to zero when PaCO2 reaches the apneic threshold (2, 36, 38, 4245) (Figure 3). Nevertheless, in patients with severe Vt constraints due to respiratory muscle weakness or those with abnormal mechanics, even small increases in PaCO2 may elicit significant increases in breathing frequency (42, 46, 47). Finally, as increasing breathing frequency decreases the duration of inspiratory phase (42, 46, 47), respiratory drive increases (the same peak output is achieved in a shorter time).

Chemical Feedback to Changes in PaO2

The main chemoreceptors mediating the ventilatory response to hypoxemia are the carotid bodies, small clusters of oxygen-sensitive cells located at the carotid bifurcation (7, 48). Hypoxemia increases respiratory drive and thus V.e (49, 50), an effect that is modified by the PaCO2 and acid–base status. In healthy individuals, the respiratory drive changes minimally with mild hypoxemia (PaO2, 60–70 mm Hg), but at lower PaO2, it increases progressively with hypoxemia (48, 50). Although PaO2 is a relatively weaker modulator of respiratory drive than PaCO2, PaO2 may significantly affect the respiratory drive through changes of the ventilatory response to PaCO2 (37, 50, 51).

Dissociation between Respiratory Drive and Actual Ventilation

As discussed above, a change in respiratory drive normally translates into a change in ventilation through the inspiratory flow–generation pathway (Figure 1). The relationship between changes in respiratory drive and the resulting change in ventilation depends on the integrity of the inspiratory flow–generation pathway. In critically ill patients, this pathway is often compromised (impaired neuromuscular function, abnormal respiratory system mechanics) (Figure 1). Therefore, in critically ill patients, a change in respiratory drive does not usually result in the expected change in ventilation.

To better understand the dissociation between respiratory drive and the resulting ventilation, we introduce the terms “brain curve” and “ventilation curve.” The term brain curve refers to the V.e that would theoretically result in a response to PaCO2 changes if the inspiratory flow–generation pathway were intact (Figure 4A). In other words, the brain curve represents the ventilation desired by the brain at any PaCO2 level. The term ventilation curve refers to the actual changes in V.e in response to changes in PaCO2, as modified by any impairment in the inspiratory flow–generation pathway (Figure 4B). Accordingly, if the inspiratory flow–generation pathway is intact, the brain curve is identical to the ventilation curve; there is no dissociation, and at a given PaCO2, the desired ventilation is equal to actual ventilation.

When the inspiratory flow–generation pathway is impaired by critical illness, the brain and ventilation curves dissociate, and the resulting PaCO2 at a given level of respiratory drive is higher than the brain desires. This increased PaCO2 stimulates a further increase in respiratory drive according to the brain curve, and the resulting increase in ventilation is determined by the ventilation curve. Steady state is reached (i.e., no further increases in PaCO2 or V.e) at the intersection of the actual ventilation curve (not the brain curve) and the metabolic hyperbola (Figure 4B) (5255). It is considered that the difference between the actual ventilation (i.e., the ventilation curve) and the needs based on afferent signals (i.e., the brain curve) is a major contributor to dyspnea (56, 57). The reader should appreciate that these mathematically described curves and their relationships are simplified representations of experimental data, with the aim being to facilitate understanding of the effects of critical illness and mechanical ventilation on respiratory drive, and they cannot be directly applied to compute the ventilatory demands of a critically ill patient.

Effects of Critical Illness on the Brain Curve, the Ventilation Curve, and the Metabolic Hyperbola
Brain curve

The slope and position of the brain curve are considerably modified by PaO2 and pH (Figure 2 and Table 1); hypoxemia and metabolic acidosis shift the curve upward and left (i.e., increasing ventilatory response to CO2), whereas hyperoxemia and metabolic alkalosis shift the curve downward and right (i.e., decreasing ventilatory response to CO2) (35, 37, 51, 5860). Moreover, stimulation of lung and chest wall receptors due to various pathologies of the respiratory system may shift the brain curve to the left and increase its slope, whereas sedatives and opioids have the opposite effect (3335, 61, 62). Although these ventilatory responses to CO2 have not been evaluated specifically in critically ill patients, clinical data support these experimental observations (42, 46, 52, 63).

Table 1. Conditions Affecting Position of the Brain and Ventilation Curves and Metabolic Hyperbola

 Upward/Left ShiftDownward/Right Shift
Brain curveMetabolic acidosisMetabolic alkalosis
HypoxemiaHyperoxemia
Interstitial lung edemaSedation
Brain pathology (cortical)Brain pathology (brainstem)
Ventilation curveMechanical ventilationUpper motor neuron disease
Partial or full recovery from disease that affects inspiratory–flow generation pathway (upward shift from disease state, toward normal)Diseases affecting nerve conduction (Guillain-Barré syndrome)
Diseases affecting neuromuscular junction (myasthenia gravis)
Respiratory muscle weakness/injury
Impaired diaphragm length–tension relationship
Increased airway resistance
Decreased respiratory system compliance
 Upward Shift: Increased Vd/Vt or Increased V.co2Downward Shift: Decreased Vd/Vt or Decreased V.co2
Metabolic hyperbolaLow Vt (Vd/Vt)High Vt (Vd/Vt)
Rapid shallow breathing (Vd/Vt)Sedation (V.co2)
Increased Vd: lung pathology (Vd/Vt)Hypothermia (V.co2)
Increased Vd: ventilator circuit (Vd/Vt)
Agitation/shivering (V.co2)
Fever (V.co2)
Strenuous breathing (V.co2)
Ventilation curve

The ventilation curve is affected by any impairment in the inspiratory flow–generation pathway (Figure 1 and Table 1). As a result, in critically ill patients during unassisted breathing, the ventilation curve is shifted to the right (to higher PaCO2), and its slope is decreased compared with the brain curve (Figure 4B). Because of this dissociation between the brain and ventilation curves, the ventilation curve and the metabolic hyperbola intersect at a higher PaCO2 than the one desired by the brain (Figure 4B).

Metabolic hyperbola

Several conditions common in critically ill patients can affect both components of the metabolic hyperbola equation, CO2 production and alveolar ventilation, and thus shift the metabolic hyperbola (Figure 5 and Table 1). Increased muscle activity, both voluntary (such as during exercise) and involuntary (such as during shivering, agitation, or tachypnea), can dramatically increase CO2 production (6467). The production of CO2 can also be affected, similarly to in healthy individuals, by the type and amount of nutrition administered (68, 69), body temperature (70), and sleep/wakefulness/sedation states (71, 72). Alveolar ventilation is determined by Vd/Vt and thus is affected by lung disease, hyperinflation, instrumental dead space, and breathing pattern (7376). For example, a rapid shallow breathing pattern would increase Vd/Vt and shift the metabolic hyperbola upward. Conversely, unloading the inspiratory muscles by mechanical ventilation would decrease CO2 production and increase Vt (thus decreasing Vd/Vt), shifting the metabolic hyperbola downward.

Effects of Mechanical Ventilation

When mechanical ventilation is used to assist breathing, the ventilation curve is determined not only by the respiratory drive, respiratory rate, and the inspiratory flow–generation pathway but also by the mode of support, settings, and patient–ventilator interactions (19, 20, 24, 45, 77). In contrast to unassisted breathing, in which the ventilation curve is always shifted downward from the brain curve (Figure 4), the ventilation curve can be shifted to either side of the brain curve by mechanical ventilation. That is because during mechanical ventilation, the total pressure applied to the respiratory system (Ptot) with each breath is the sum of Pmus and pressure provided by the ventilator (Pvent). According to the equation of motion, Ptot is dissipated to overcome respiratory system resistance (Rrs) and respiratory system elastance (Ers), determining the volume–time profile as follows:

Ptot=Pmus+Pvent=V.×Rrs+ΔV×Ers+Pee,

where Pee is elastic recoil pressure at the end of expiration (zero at passive FRC) and ΔV and V. are volume above end-expiratory lung volume and flow, respectively. The extent to which Pvent and Pmus contribute to Vt (and thus to ventilation) depends on several factors related to the patient and the ventilator (19, 77, 78).

The mode and settings of assisted ventilatory support exert a tremendous influence on the ventilation curve and thus on the resulting PaCO2 and respiratory drive (19, 77, 78). We focus on three main modes of assisted mechanical ventilation: 1) assist volume control (AVC; Vt is constant), 2) pressure support (PS; pressure is constant), and 3) proportional assist modes (proportional assist ventilation with load-adjustable gain factors and neurally adjusted ventilatory assist, in which neither pressure nor volume is constant but the patient’s effort drives airway pressure). These various modes modify the ventilation curve by adding the ventilator pressure (Pvent) to Pmus (Figure 6).

To understand the effect of ventilator-delivered pressure on the ventilation curve, we need first to describe the relationships between peak Pmus per breath (Pmuspeak) and the resulting Vt or V.e under different modes of ventilation (Figures E1 and E2 in the online supplement). These relationships are qualitatively similar to the PaCO2–Vt and PaCO2V.e relationships because Pmuspeak increases linearly with increasing PaCO2 (Figure 6).

Unassisted breathing

During unassisted breathing, with constant respiratory system mechanics and at given inspiratory duration and end-expiratory lung volume, the Pmuspeak–Vt relationship is linear, and its slope depends mainly on mechanics (Figure E1) (41, 46). Obviously, at a given respiratory rate, the PmuspeakV.e relationship is also linear, but its slope depends both on respiratory system mechanics and on respiratory rate.

AVC and PS

With AVC, the slope of the Pmuspeak–Vt relationship is always zero because the set Vt is essentially independent of the patient’s effort (horizontal line, constant Vt) (41, 46). This also entails that the ventilator-delivered pressure actually decreases with increasing Pmuspeak; in other words, the ventilator, to keep Vt at the preset level, reduces assistance as patient respiratory effort increases. Of note, both the Vt and the peak flow set by the clinician during AVC have an enormous impact on respiratory drive and thus on Pmuspeak (79). During PS, a constant pressure is applied to the respiratory system after triggering, regardless of Pmuspeak, resulting in a parallel upward shift of the unassisted breathing line without affecting its slope (Figure E1) (41, 46). With both AVC and PS, changing the level of assist (Vt or PS level) does not affect the slope, but it causes a parallel upward or downward shift of the curve (41, 46). It is important to note that Vt may be substantial even at very low Pmuspeak (i.e., the patient relaxes all inspiratory muscles immediately after triggering), depending on the level of assist (41, 46). With AVC, this Vt is preset, whereas with PS, this Vt is referred to as “minimum Vt” and depends on the ventilator settings (the level of PS, rising time, and the flow-cycling threshold) and respiratory system mechanics (mainly Ers) (41, 46).

With both modes, at constant respiratory rate, the Pmuspeak–Vt relationship results in qualitatively similar PmuspeakV.e and thus PaCO2V.e relationships (Figures 6 and E2). If respiratory rate changes to a new constant value under AVC, the slope of the PmuspeakV.e curve will remain zero, and its position will be shifted upward (with increasing respiratory rate) or downward (with decreasing respiratory rate), whereas under PS, both the slope and position of the PmuspeakV.e curve will be modified (Figures E2A and E2B). Under AVC at high respiratory drive, the slope of PmuspeakV.e and PaCO2V.e relationships may deviate from zero (increase), owing to a progressive increase of patient respiratory rate, a common response pattern when Vt is constrained (42, 46, 47, 77) (Figures 6A and E4A). With PS, because respiratory rate changes little, particularly when the respiratory drive is not very high (2), changes in drive often have a minimal influence on the slope of the ventilation curve.

Proportional assist modes

The effect of proportional assist modes on the Pmuspeak–Vt relationship is fundamentally different: proportional ventilation effectively amplifies respiratory effort, increasing the slope of the Pmuspeak–Vt relationship (41, 46). The magnitude of this increase depends on the level of assist (Figures 6 and E1). Unlike AVC and PS, under proportional assist modes, relaxation of inspiratory muscles immediately after triggering terminates the pressure delivered by the ventilator. In this case, even at very high assist, Vt will be zero or close to zero.

As with AVC and PS, with proportional modes (as with AVC and PS), at constant respiratory rate, the Pmuspeak–Vt relationship results in qualitatively similar PmuspeakV.e and thus PaCO2V.e relationships (Figures 6 and E2). However, with proportional modes, changes in respiratory rate modify the slope of the PmuspeakV.e curve, but minimum ventilation is always close to zero (41, 80, 81) (Figure E2C). A more detailed description of the effects of varying levels of assist on respiratory drive with each mode is presented in the online supplement (Figures E3–E6).

The actual PaCO2 is determined by the intersection between the new ventilation curve (obtained by the patient’s respiratory drive interacting with mechanical ventilatory support) and the metabolic hyperbola. In contrast to unassisted breathing, under mechanical ventilation, this PaCO2 may in fact be lower than the one the brain desires, resulting in a decrease in respiratory drive. The respiratory drive is in either case determined by the ventilatory demand at the resulting PaCO2 defined by the brain curve, which, as discussed above, is modified by several other factors. Therefore, mechanical ventilation decreases respiratory drive indirectly by lowering PaCO2 (24, 45, 82). However, in conscious patients, when unloading of inspiratory muscles by mechanical assist results in relief of distress, this may also decrease respiratory drive through cortical inputs (28).

Overall, critical illness is associated with variable changes in the metabolic hyperbola and a dissociation between the brain curve and the ventilation curve (Table 1). At steady state, the PaCO2 derives from the intersection of the metabolic hyperbola and the ventilation curve, both of which are altered by critical illness and mechanical ventilation. The patient’s respiratory drive is determined by the ventilation desired by the brain for this PaCO2 (Figure 4B).

As stated above, because the intensity of the respiratory center’s output cannot be directly measured, respiratory drive is quantified either by various indices of motor output or by the mean inspiratory flow (20, 83). The indices of motor output include the change in electrical activity of the diaphragm (EAdi), Pdi, Pmus during inspiration, and the change in airway pressure observed during the inspiratory effort against occluded airways. When estimating the respiratory drive of critically ill patients, it is important to recognize that the presence of a disease that affects the inspiratory flow–generation pathway at or before the anatomical site of measurement (closer to the respiratory center) always leads to underestimation of the respiratory drive. Despite the limitations posed by critical illness, indices of respiratory drive may provide the physician information for the changes of respiratory drive over time or in response to changes in ventilator settings. The methods available at the bedside to evaluate respiratory drive are described below, together with their limitations. In everyday practice, selecting which method to use in the individual patient depends not only on the limitations of each method but also on the availability of the equipment required for measurement acquisition and the complexity of the clinical condition.

EAdi

EAdi can be recorded using surface electrodes or via an esophageal catheter (81, 84, 85). It is, anatomically, the closest measurement to brain output that can be obtained at the bedside. The change in EAdi is linearly correlated with the increase in ventilation stimulated by CO2 rebreathing in healthy volunteers (86). In patients with acute respiratory distress syndrome, EAdi increased with decreasing rates of extracorporeal CO2 removal (87). Moreover, in mechanically ventilated patients, changes in Pdi and Pmuspeak were shown to follow changes in EAdi in response to changes in levels of PS and neurally adjusted ventilatory assist, respectively (88). It should be noted, though, that the EAdi signal does not have normal values. Thus, it can be used as a trend to monitor changes in the same patient (8789). Finally, EAdi does not evaluate the recruitment of accessory respiratory muscles (90).

Transdiaphragmatic and Inspiratory Pressure Produced by All Inspiratory Muscles (Pdi and Pmus)

EAdi is translated into Pdi, which is measured using esophageal and gastric pressure sensors. As stated above, the average rate of increase of transdiaphragmatic pressure (dPdi/dt) quantifies respiratory drive if the pathway between the respiratory center and the diaphragm pressure output is intact. Therefore, prerequisites include not only normal neural transmission but also normal muscle pressure generation for a given neural stimulation. During quiet breathing, dPdi/dt values of about 5 cm H2O/s are observed in healthy adults (91). As with all indices of respiratory drive, high dPdi/dt indicates high respiratory drive. Conversely, normal or low dPdi/dt values do not necessarily entail normal or low drive, unless intact neuromuscular function can be confirmed. Normalizing dPdi/dt for the maximum Pdi takes into account abnormalities of inspiratory–flow generation pathway (19), but the latter can only be obtained in fully alert and cooperating patients.

In critically ill patients, diaphragmatic indices of respiratory drive may underestimate the true drive, particularly if it is high, owing to the contribution of accessory inspiratory muscles to inspiratory pressure. Calculating the Pmus using the Campbell diagram may overcome this error (82, 92), but this method is cumbersome, relies on several assumptions, and is not suitable for everyday clinical practice.

Airway Occlusion Pressure

Airway occlusion pressure (P0.1) is the drop in Paw at the first 100 milliseconds of an inspiratory effort against an occluded airway. The rationale to use it as an indicator of drive is that P0.1 increases proportionally to a rise in PaCO2 (21, 93) and during the short occlusion, 1) Paw follows muscle pressure; 2) there is no significant behavioral or unconscious reaction; and 3) because no significant volume is displaced, abnormal respiratory mechanics do not affect the measurement. In healthy adults breathing at rest, P0.1 ranges between 0.5 and 1.5 cm H2O. In mechanically ventilated patients, values above 3.5 cm H2O have been associated with elevated respiratory muscle effort (esophageal pressure–time product >200 cm H2O·s/min) and indicate high drive (94).

P0.1 is easily obtained in the ICU because it is an automated measurement available on the majority of modern ventilators (95), but some issues need to be considered to properly interpret P0.1 in critically ill patients. First, P0.1 could underestimate respiratory drive in very severe muscle weakness because of impairment in the inspiratory flow–generation pathway. In moderate to severe weakness, however, P0.1 still increases reliably with increasing PaCO2, implying that the initial part of muscle contraction is relatively spared (54). Second, intrinsic positive end-expiratory pressure (PEEPi) can introduce a bias resulting from a phase lag between the change in Pmus and the change in Paw during an occlusion. Nevertheless, P0.1 was shown to be a reasonable estimate of drive in intubated patients with PEEPi (96). Third, the decrease in Paw at the beginning of a breath can result from relaxation of the expiratory muscles, and the accuracy of P0.1 as a measure of drive in this condition is unknown (93). Fourth, the initial shape of the Pmus–time curve may be influenced by increased resistance, exercise, or positive pressure ventilation, giving rise to some noise in the measurement (19, 97, 98). Fifth, breath-to-breath variability of P0.1 is significant, and the clinical measurement of P0.1 should be taken from an average of three or four measurements (99). Notwithstanding these potential pitfalls, P0.1 may provide indications of changes in drive.

Clinical Signs and Breathing Pattern

Clinical signs of dyspnea and respiratory distress, whenever present, are good indicators of high drive because dyspnea is directly linked to high drive (100, 101). A rapid shallow breathing pattern, the use of accessory inspiratory muscles, activation of expiratory muscles, tachycardia, hypertension, and diaphoresis have been associated with high respiratory drive (76, 101). Obviously, in patients with severe neuromuscular disease or cervical spine injury, clinical signs of dyspnea may be blunted because patients may not be able to recruit expiratory muscles or accessory inspiratory muscles, even in the presence of high respiratory drive.

Importantly, although it is generally accepted that tachypnea is an indicator of high drive and bradypnea is an indicator of low drive, respiratory rate is a highly insensitive sign of increasing respiratory drive (2, 102). Even under normal conditions, respiratory rate has a rather large variability between and within individuals. Moreover, respiratory rate changes little with changes in respiratory drive or ventilator support until drive increases by more than three- to fourfold of resting value (2, 36, 38, 4245).

Although respiratory drive may not be easily measured in the critically ill patient, and although thresholds defining injurious high or low drive have not been defined, the clinical conditions associated with alterations in brain and ventilation curves are easily recognized in everyday practice. Assessment of respiratory drive may help to direct management of the patient and the ventilator.

Low Respiratory Drive

A low respiratory drive implies that the respiratory center demands a relatively low V.e at the current PaCO2. This occurs when the brain curve is shifted downward and to the right and/or when the intersection between the ventilation curve and the metabolic hyperbola is at lower PaCO2 than the PaCO2 desired by the respiratory center. The most common conditions associated with a downward shift of the brain curve in critically ill patients are sedation and metabolic alkalosis (6062). In the presence of these conditions, the physician should expect that the patient’s brain would be satisfied with a V.e resulting in a higher-than-normal PaCO2. It is important to recognize that a PaCO2 that is lower than the PaCO2 desired by the brain occurs only as a result of mechanical ventilation (i.e., overassistance), because all disease processes decrease ventilation output for a given respiratory center output.

Potential adverse consequences of low respiratory drive include weak inspiratory efforts resulting in disuse diaphragm atrophy (6, 103), patient–ventilator dyssynchronies (20, 104), and sleep disruption (20, 41). It is not uncommon that the decrease in respiratory drive is such that patients with conventional modes of support (volume or pressure) relax the diaphragm immediately after triggering (Figures E1, E2A, and E2B). When the patient is sedated or asleep and the delivered V.e, as determined by the ventilator settings, results in a PaCO2 level that reaches the apneic threshold, respiratory drive will hover around zero, and the patient will exhibit apneas and periodic breathing during assisted modes such as PS (Figures 6A, 6B, E4D, and E5D) (105). Apneas cause sleep fragmentation, which has been associated with neurocognitive dysfunction, delirium, and autonomic nervous system dysfunction (105). The presence of apneas may affect ventilator management because patients developing apneas are often placed for safety in controlled modes of ventilation, thus unnecessarily prolonging weaning. Weak inspiratory efforts may result in diaphragmatic myotrauma, also prolonging weaning and ICU stay (3, 4, 6, 89, 103, 106). Weak inspiratory efforts caused by low drive could also be falsely diagnosed as muscle weakness and mislead the clinical assessment.

High Respiratory Drive

A high respiratory drive implies that the respiratory center demands a relatively high V.e (1). This occurs when the intersection between the ventilation curve and the metabolic hyperbola is at PaCO2 that is higher than the PaCO2 desired by the brain (Figure 4). The deviation between actual and desired PaCO2 will become larger if the brain curve is shifted left and/or has increased slope, a common scenario with metabolic acidosis and hypoxemia but also with various pathologies that stimulate respiratory system receptors (lung and chest wall) or brain damage (30, 33, 34).

A high respiratory drive may be associated with a rapid shallow breathing pattern and agitation (76, 101, 107) that increase both Vd/Vt and CO2 production and move the metabolic hyperbola upward, further increasing ventilatory demand and respiratory drive. Such a breathing pattern may be the result of constraints to Vt increase due to impaired respiratory muscle output or abnormal mechanics, as commonly observed in patients in whom a weaning trial fails (20, 47, 76, 108). Moreover, when the excessive effort is perceived by the patient, high respiratory drive causes dyspnea and respiratory distress (57, 100). The inability to generate high inspiratory effort in patients with high respiratory drive may also contribute to respiratory distress and dyspnea (56, 109).

High respiratory drive leading to strong inspiratory efforts can promote patient–ventilator dyssynchrony (20, 77) and increase oxygen cost of breathing (67) while concomitantly increasing lung-distending pressures, thus potentially placing patients at risk for P-SILI and inspiratory muscle damage (5, 110, 111). Although there is no direct evidence in humans that links strong inspiratory efforts to P-SILI and inspiratory muscle damage, experimental studies and indirect data in critically ill patients indicate that both matters should be of concern for the management of these patients (1, 111114). Strong inspiratory efforts in pressure-regulated modes can result in the delivery of high Vt. In volume-regulated modes, strong efforts can result in double triggering, increasing Vt, or increased regional stress in dependent areas, even without an increase in Vt (114). Also, with proportional modes, high respiratory drive may override the protective mechanisms of control of breathing, particularly when respiratory system compliance is low (<30 cm H2O/L) (112), and lead to lung injury (102, 115).

The ability of critically ill patients to increase Pmus in response to increased respiratory drive is often limited. Healthy individuals can sustain indefinitely an increase in Pmus up to 50–60% of maximum inspiratory muscle pressure (Pmax) in each breath, although with further increases in load, contractile fatigue ensues and endurance time decreases progressively (116). Maintaining a very high fraction of Pmax per breath may result, as a terminal event, in a decrease of respiratory drive to the point of central apnea/fatigue (117, 118). Endurance time is also affected by the duty cycle; it decreases with increasing respiratory duty cycle (119). Because Pmax is markedly reduced for a variety of reasons in the majority of critically ill patients (19, 120), the level of respiratory drive that results in an unsustainable Pmus may be considerably decreased; a Pmus of 10 cm H2O represents an insignificant load in a patient with near-normal Pmax (100 cm H2O), but it may be unsustainable in a patient with a Pmax of 20 cm H2O. Thus, the patient with high respiratory drive and muscle weakness, unable to increase ventilation when needed, would develop dyspnea, respiratory distress, rapid shallow breathing, dyssynchrony, and gas exchange abnormalities (20, 107, 108, 121).

Critical illness affects the patient’s respiratory drive through multiple mechanisms. The presence of high respiratory drive may induce injurious strenuous breathing and dyspnea, whereas low respiratory drive may lead to weak inspiratory efforts and apneas. Considering the determinants of a patient’s respiratory drive at the bedside may facilitate a better understanding and management of the patient and the ventilator, potentially avoiding some of the complications associated with high and low respiratory drive.

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Correspondence and requests for reprints should be addressed to Dimitris Georgopoulos, M.D., PhD., Department of Intensive Care Medicine, University Hospital of Heraklion, School of Medicine, University of Crete, Voutes, 71110, Heraklion, Crete, Greece. E-mail: .

*These authors contributed equally to this work.

L.B. is Deputy Editor of AJRCCM. His participation complies with American Thoracic Society requirements for recusal from review and decisions for authored works.

Author Contributions: L.B. and D.G. contributed to the conception of this work. K.V., E.A., E.C.G., I.T., and D.G. drafted and reviewed the manuscript. All authors critically revised the manuscript for intellectually important content and gave final approval of the version to be submitted.

This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.

Originally Published in Press as DOI: 10.1164/rccm.201903-0596SO on August 22, 2019

Author disclosures are available with the text of this article at www.atsjournals.org.

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