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Anesth Analg 1999;89:243
© 1999 International Anesthesia Research Society

REVIEW ARTICLE

The Effects of Residual Neuromuscular Blockade and Volatile Anesthetics on the Control of Ventilation

Lars I. Eriksson, MD, PhD

Department of Anesthesiology and Intensive Care, Karolinska Hospital and Institute, Stockholm, Sweden

Address correspondence and reprint requests to Lars I. Eriksson, MD, PhD, Department of Anesthesiology and Intensive Care, Karolinska Hospital and Institute, SE-171 76 Stockholm, Sweden. Address e-mail to alie{at}kir.ks.se


   Introduction
Top
 Introduction
Residual Neuromuscular Block and...
 Hypoxic Ventilatory Control
 Residual Effects of Volatile...
 Human Studies
 Animal Studies
 References
 
Among critical events in the immediate postoperative period, ventilatory depression, airway obstruction, and aspiration of gastric contents are the three most common life-threatening anesthesia-related complications (1). They account for more than two thirds of all critical events after an anesthetic procedure, and in most of these events the consequence for the patient is a risk of hypoxic injury (1,2). Residual effects of anesthetics play essential roles as underlying mechanisms of postoperative ventilatory failure and hypoxia. Impaired respiratory control may be caused by depression of central ventilatory control, by depression of peripheral sensory organs, such as the carotid body chemoreceptors, or by impaired control of the pharynx and the upper airways due to muscular weakness and dyscoordination with risk for airway obstruction and aspiration. In this review, new findings concerning ventilation and residual effects of neuromuscular blocking drugs and volatile inhaled anesthetics will be put in perspective.


   Residual Neuromuscular Block and Ventilation
Top
 Introduction
 Residual Neuromuscular Block and...
Hypoxic Ventilatory Control
 Residual Effects of Volatile...
 Human Studies
 Animal Studies
 References
 
Early fundamental knowledge about the effects of curare-like drugs on ventilation was discovered >150 yr ago. The British surgeon Brodie (3) showed in 1811 that lethal effects of curare in animals could be overcome, provided artificial ventilation was given. After application of curare to a small wound in his cat and by applying manual ventilation, he not only showed that the cat survived, but also described how the animal recovered gradually, starting with small respiratory efforts and continuing with gross muscle movements until the animal completely recovered after approximately 1 h. Although not concluded in this classical experiment, the author indirectly describes the different recovery pattern of respiratory and nonrespiratory muscles.

The different sensitivity to muscle relaxants among central and peripheral muscle groups has been studied extensively (4–8). In a series of human experiments under partial neuromuscular block, Gal and Smith (9) and Gal and Goldberg (10) characterized the resistance of respiratory muscles to muscle relaxants (the respiratory sparing effect) and the different sensitivity between peripheral skeletal muscles of the hand and the diaphragm. Residual neuromuscular paralysis only minimally affected tidal volumes and respiratory frequency during supine resting ventilation. Yet, resting minute ventilation was maintained at normocarbia despite considerable weakness of peripheral skeletal muscles of the hand (Fig. 1). During more intense neuromuscular block with a subsequent reduction of the tidal volume, a normal minute ventilation is maintained by an increased respiratory frequency. Hence, during resting ventilation in the presence of an incomplete neuromuscular block, normocarbia is usually well maintained but at the cost of an increased work of breathing. Moreover, the ventilatory response to carbon dioxide stimulation (hypercapnic ventilatory response [HCVR]) is well maintained in the partially paralyzed awake subject. Studies on neuromuscular blocking drugs with intermediate durationsof action have confirmed this lack of depression of minute ventilation and maintained HCVR during a partial neuromuscular block (11,12). These findings support the early observations made by Gal and Smith (9) and Gal and Goldberg (10) and demonstrate the relative resistance of central respiratory muscles, such as the diaphragm and intercostal muscles, making it possible for the partially paralyzed subject to maintain adequate minute ventilation, even during hypercapnic stimulation. More importantly, it also shows that ventilatory control during hypercarbia is unaffected, indicating that central respiratory neurons are uninfluenced by a partial neuromuscular block, which indirectly confirms the lack of blood-brain barrier transfer by these highly hydrophilic compounds (13).



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  		Figure 1. Effects of increasing doses of d-tubocurarine on ventilatory responses during controlled hypercapnia. {image}E= minute ventilation; VT= tidal volume; f = respiratory frequency. From Gal and Smith (9) with permission from Anesthesiology.

 
Safe recovery from a neuromuscular block allowing tracheal extubation and institution of spontaneous breathing was facilitated by the introduction of neuromuscular monitoring techniques, i.e., after description of the train-of-four (TOF) nerve stimulus pattern (14). After spirometry of awake volunteers receiving bolus doses of d-tubocurarine (15), Ali et al. (14) concluded that a mechanical adductor pollicis muscle TOF ratio (T4/T1 twitch ratio) of 0.70 was associated with normal respiratory function. This conclusion was based on the assumption that sustained maximal inspiratory force and minute ventilation indicated safe recovery from a neuromuscular block (Fig. 2). Later, similar findings and conclusions were made for intermediate-duration drugs, such as vecuronium and atracurium (12). Pavlin et al. (16) demonstrated, however, that despite adequate recovery of the diaphragm, there may be considerable weakness of muscles involved in the maintenance of the airway. Recently, further information has been collected concerning pharyngeal function and protection of the airway in partially paralyzed subjects (17,18). Moreover, residual neuromuscular block is a risk factor for postoperative pulmonary complications (19). From this important study (19), it is clear that patient outcome can be changed by using neuromuscular blocking drugs with shorter durations of action instead of those with a long recovery time profile (e.g., pancuronium) and by avoiding residual neuromuscular block. After the administration of mivacurium in subparalyzing doses (18), awake, nonanesthetized subjects were not able to control the tongue and complained of diplopia, despite almost complete recovery of the adductor pollicis muscle TOF responses above a T4/T1 ratio of 0.90. In contrast, D'Honneur et al. (20), with a limited number of subjects (n = 6), could not demonstrate changes in upper airway resistance during resting ventilation or hypercapnia-induced hyperventilation at an adductor pollicis TOF ratio of approximately 0.50 (20). However, functional assessment of the pharynx using fluoroscopy-controlled solid-state manometry and simultaneous videoradiographical detection of aspiration revealed that recovery of neuromuscular function to allow spontaneous breathing with normal pharyngeal function requires a mechanical adductor pollicis TOF of <=0.90 (17,21,22). Moreover, there is a four- to five-fold increase in the incidence of misdirected swallowing and aspiration with an adductor pollicis TOF ratio of <0.90 in awake, nonanesthetized volunteers (22). Hence, a TOF ratio of 0.70 is not associated with normal vital muscle function of the pharynx and upper esophagus, and should not be used as an indication of safe recovery from a neuromuscular block. Normal vital muscle function requires that the adductor pollicis TOF ratio recover to <=0.90 (17,21,22).



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  		Figure 2. Correlation between the train-of-four ratio and respiratory measurements in awake human subjects partially paralyzed by d-tubocurarine. There is a significant change in inspiratory force when the train-of-four ratio decreases to <=60% and a significant change in vital capacity when the train-of-four ratio is <=70% or less. Data from Ali et al. (15) and figure reprinted with permission from Ali HH, Wilson RS, Savarese JJ, Kitz RJ. The effect of tubocuraine on indirect elicited train-of-four muscle responses and respiratory measurements in humans. Br J Anaesth 1975;47:570–4. (by permission of Oxford University Press).

 

   Hypoxic Ventilatory Control
Top
 Introduction
 Residual Neuromuscular Block and...
 Hypoxic Ventilatory Control
Residual Effects of Volatile...
 Human Studies
 Animal Studies
 References
 
The increase in ventilation during hypoxia is mainly governed by afferent neuronal input from peripheral chemoreceptors of the carotid bodies, and, to some extent, from those of the aortic arch (23). The peripheral chemoreceptors respond to both hypoxia and hypercapnia, the acute ventilatory response to hypoxia being solely dependent on activation of the peripheral chemoreceptors, whereas only 25% of the increase in ventilation during hypercarbia is due to the activity from peripheral chemoreceptor activity (23). The remainder of the increase in ventilation is due to activation of chemoreceptors within the central nervous system (CNS). Interestingly, the carotid body chemoreceptors contribute only minimally to the maintenance of normal resting ventilation but become an essential part in the acute hypoxic ventilatory response (HVR) as their firing activity increases dramatically during hypoxia, forming a curvilinear function with arterial oxygen tension (23–26). Notably, the carotid bodies are not located within the CNS and are therefore not protected by the blood-brain barrier from entrance of neuromuscular blocking drugs or other hydrophilic compounds. Several neurotransmittors are involved in the chemical transmission of the chemoreceptors, such as acetylcholine, dopamine, and substance P (27,28).

In the 1930s the Belgian physiologist Heymans (29) showed that direct application of acetylcholine to the carotid body resulted in an instant and short-lasting episode of hyperventilation in the animal and a simultaneous reduction in heart rate (Fig. 3). Hence, the results show that acetylcholine is most likely involved in the transmission of afferent neuronal activity from the carotid bodies to the CNS. Although his results have been questioned by some investigators (30), further experiments have confirmed the importance of intact cholinergic function of the carotid bodies for chemoreceptor firing during hypoxia. Using anticholinergic drugs, Fitzgerald and Shirata (31) demonstrated in an in vitro study that the carotid body chemosensitivity, expressed as the increase in whole neuronal activity of the carotid body sinus nerve during hypoxia, was completely abolished after the administration of a mixture of nicotinic (d-tubocurarine) and muscarinic (atropine) anticholinergics. Moreover, nicotinic and muscarinic reactive sites are present on the chemoreceptor cell (glomus cell), causing the cell to hyperpolarize after administration of d-tubocurarine (32). Acetylcholine may not be the primary neurotransmitttor involved in the carotid body chemoreception, but it may play the role of a modulatory feedback mechanism. It seems more likely that substance P and dopamine are directly involved in chemical transmission of the carotid body chemoreceptors (33,34).



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  		Figure 3. A, Pneumogram of a dog under chloralose anesthesia. B, Systemic blood pressure and heart rate. Time in 3-s intervals. Acetylcholine (0.1 mg) was applied to the chemoreceptors of the glomus caroticum, which results in a marked reflex hyperpnea and bradycardia. From Heymans (29) with permission from Elsevier.

 
In 1992, the first report showing that a clinically used muscle relaxant (vecuronium) may depress the hypoxic ventilatory response in partially paralyzed human subjects appeared (35). The investigation was performed using a poikilocapnic ventilatory test procedure (35) and was later reconfirmed after similar findings using a normo-isocapnic ventilatory test procedure (36), as well as after the administration of other nondepolarizing muscle relaxants (11). At a mechanical adductor pollicis TOF ratio of 0.70, the hypoxic ventilatory response was reduced by approximately 30% in the awake volunteer after atracurium, vecuronium, and pancuronium (Fig. 4). Hence, the magnitude of HVR depression is the same regardless of whether the muscle relaxant is an aminosteroid or a bensylisoquinolinium compound. Furthermore, the depression is not different in compounds with muscarinic acetylcholine receptor affinity (pancuronium) compared to those with very low or no muscarinic acetylcholine receptor affinity (vecuronium and atracurium) (11,35,36). For all drugs, however, there is a considerable interindividual variation in the degree of depression of human hypoxic ventilatory responses. Some individuals may have a completely abolished response to hypoxia while others may only have a minimal depression (11). It is therefore difficult to predict the depression of HVR in a single subject.



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  		Figure 4. Hypoxic ventilatory responses (isocapnic HVR) before (control), during steady-state infusion of muscle relaxants (TOF 0.70), and after recovery (TOF > 0.90). Data presented are mean ± SD. TOF = train-of-four. ** = P < 0.01. Data from Eriksson (11) and figure reprinted with permission from Eriksson LL. Reduced hypoxic chemosensitivity in partially paralyzed man: a new property of muscle relaxants? Acta Anesthesiol Scand 1996; 40:520–3. © 1996 Munksgaard International Publishers Ltd., Copenhagen, Denmark.

 
Eriksson et al. (35) hypothesized that the underlying mechanism of this HVR depression was caused by an interaction with hypoxic chemosensitivity of the carotid bodies. In the anesthetized rabbit, it was later shown that injection of small doses of a muscle relaxants into the carotid body via a lingual artery catheter caused a dose-dependent depression of the phrenic nerve activity during systemic hypoxia (37). Wyon et al. (38) also showed in vivo that the firing frequencies of single isolated chemoreceptors in the carotid body were almost abolished by the systemic administration of vecuronium (Fig. 5). After vecuronium doses of 0.15 mg/kg body weight, the depressed chemoreceptor recovered spontaneously, and complete recovery was achieved after 90–120 min.



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  		Figure 5. The relationship between chemoreceptor activity and PaO2 in a single carotid body chemoreceptor after systemic administration of vecuronium to a rabbit. Original hyperbolic plot (chemoreceptor output = a + b(PaO2)-1. Chemoreceptor response curves during control and after the administration of 0.1 and 0.5 mg of vecuronium IV are presented. Data from Wyon et al. (38) and figure reprinted with permission from Anesthesiology.

 
Thus, there is evidence from both early in vitro experiments (27,29,31,32) and from recent human and animal studies (34–38) that nondepolarizing neuromuscular blocking drugs interfere with hypoxic ventilatory control. In anesthetic practice, this is a new and hitherto unknown property of these drugs. The mechanism behind this interaction seems to be a spontaneously reversible depression of carotid body chemoreceptor activity during hypoxia. Although a cholinergic receptor inhibition seems most likely, the exact nature of this interaction with the chemoreceptor remains to be clarified. In addition, it is not known whether this interaction can be reversed by the administration of an anticholinesterase drug.

The significance of this interference should be considered. Depressed hypoxic ventilatory responses during partial neuromuscular block has been described among awake and healthy volunteers to whom no other sedative or hypnotic drugs have been given. Obviously, the postoperative patient most likely has residual levels of other anesthetics, such as IV opioids, hypnotics and/or inhaled anesthetics. In the presence of a partial neuromuscular block, the postoperative patient may therefore have further depression of ventilation. In addition, when conducting animal experiments, the depression of chemoreceptor activity may have important implications for interpretation of previous experimental work in the field of carotid body chemoreceptor function. In many studies, muscle relaxants have been administered as intermittent bolus doses or continuous infusions as a part of the anesthetic procedure to keep the animal immobilized. The possibility that this anesthetic technique may have interfered with normal chemoreceptor function and thus, with the results of the experiment, should be kept in mind. Hence, these findings have implications not only for daily patient care, but also for experimental practice concerning ventilatory studies.


   Residual Effects of Volatile Anesthetics and Hypoxic Ventilatory Control
Top
 Introduction
 Residual Neuromuscular Block and...
 Hypoxic Ventilatory Control
 Residual Effects of Volatile...
Human Studies
 Animal Studies
 References
 
Volatile anesthetics are associated with a dose-dependent depression of minute ventilation, which is due to changes in both tidal volume and respiratory frequency. The reduced minute ventilation is caused by a reduction of tidal volumes that is relatively greater than the simultaneous increase in respiratory frequency (39,40). Thus, the alveolar minute ventilation is reduced, which is followed by an increase in arterial carbon dioxide tension. As a consequence, the ventilatory response and sensitivity to carbon dioxide are reduced (39,40).


   Human Studies
Top
 Introduction
 Residual Neuromuscular Block and...
 Hypoxic Ventilatory Control
 Residual Effects of Volatile...
 Human Studies
Animal Studies
 References
 
The effects on hypoxic ventilatory control by volatile inhaled anesthetics are controversial. Knill and Gelb (41), Knill et al. (42), and Gelb and Knill (43) presented a series of investigations that identified the effects of sedative and anesthetic concentrations of these drugs on hypoxic ventilatory control. Based on their findings, it was concluded that volatile inhaled in both anesthetic (41) and subanesthetic concentrations (42,43), caused a pronounced depression of peripheral hypoxic chemosensitivity. This has subsequently been the general opinion in anesthesia literature (44,45). A series of conflicting findings have been published in which different groups of researchers using somewhat different methodologies have found either a markedly depressed acute hypoxic ventilatory response during subanesthetic concentrations of inhaled anesthetics (46,47) or relatively well maintained hypoxic ventilatory responses (48–52). Hence, there is disagreement regarding the influence of small-dose inhaled anesthetics on the hypoxic chemosensitivity, that is, on the peripheral chemoreception.

In 1994, two editorials (53,54) addressed this controversy and stated independently that the conflicting results of human experiments by Knill and Gelb (41), Knill et al. (42), Gelb and Knill (43), Dahan et al. (46), and van den Elsen et al. (47) to those of Temp et al. (48,49) and Sjögren et al. (50,51) most likely were due to different states of consciousness (eyes open versus eyes closed, awake, versus asleep) or methodological differences (e.g., hypercapnia versus normocapnia versus poikilocapnia). Moreover, minor variations in terminology added to the disagreement among research groups. For instance, in the studies by Dahan et al. (46), van den Elsen et al. (47), and others (55), the method focused on effects on the "peripheral chemoreflex loop," rather than the peripheral chemoreceptor per se, which is any effect arising in the event chain from the carotid body chemoreceptor, via the afferent sinus nerve/glossopharyngeal nerve, into the respiratory integrator located in the brainstem. This imaginary functional structure is determined by mathematical modeling; that is, the dynamic acute hypoxic response is divided into a fast component (the peripheral response) and a slow component (the central response). Any effect found by this modeling in the peripheral response was attributed to the peripheral chemoreceptors. The term "reflex loop" illustrates that the technique does not directly measure the function of the peripheral chemoreceptor but rather indirectly measures the noncentral contribution to hypoxic ventilation. The technique has been validated in cats (56). As mentioned above, there is a consensus that volatile anesthetics have a dose-dependent depressant effect on the CNS (39,40), including respiratory neurons within the brainstem (57–59). Therefore, it must be expected that all inhaled anesthetics have a dose-dependent depressant effect on the ventilatory control during both hypoxia and hypercapnia, even if some key components in the oxygen sensing system may be intact.

There are limitations to how close an investigator can come to the peripheral oxygen sensor as long as human studies are evaluated. Most studies have been performed in human volunteers or patients in whom minute ventilation and changes in minute ventilation have been used to indirectly estimate effects of inhaled anesthetics on hypoxic ventilatory control, sometimes with advanced mathematical modeling (see above). The experimental conditions have also varied. Some studies have used hypercapnia with resting ventilation >10 L/min during recording of isocapnic hypoxic ventilatory responses (41–43,46,47), whereas others have used normocapnia or poikilocapnia for the same procedure with resting ventilation <10 L/min (50–52). Because of the profound interaction between inhaled anesthetics and central carbon dioxide chemosensitivity, the various methods cannot be expected to yield similar results. This is illustrated by the study of Dahan et al. (60) during desflurane anesthesia in which a ventilatory depression was found during hypercapnic isocapnia whereas no depression was found during normocapnic isocapnia. In other studies in which the consciousness of the subjects varied, similar interpretational problems have occurred (53,54). If the varying methods and their results are being compared, it is clear that the state of consciousness and/or level of carbon dioxide tension have a pronounced influence on whether a depression of the hypoxic ventilatory control during subanesthetic levels of inhaled anesthetics has been found. Finally, it should be remembered that, normally, patients respond to hypoxia with a poikilocapnic ventilatory response. Hence, in reviewing human studies, the acute hypoxic ventilatory response is depressed but still present during inhaled anesthesia, the magnitude of the depression being dose-dependent.

Robotham (53) and Goodman (54) also raise the question of whether the depression of ventilation during hypoxia is of clinical importance. Although Robotham (53) stated that even at 0.1 minimum alveolar anesthetic concentration there may be a clinically important depression, Goodman argued that this depression is of limited importance because patients in the recovery room most likely have CO2 levels sufficient to drive ventilation. Instead, he believes that the major risk during recovery from anesthesia is from obstruction of the airway, not from ventilatory depression. However, the possible interaction between inhaled anesthetics and other anesthetic drugs, such as hypnotics (e.g., bensodiazepines) and opioids, must be considered when discussing the clinical importance of ventilatory depression in the recovery room. Hence, any depression of ventilation by a single anesthetic drug should be regarded as unwanted in the recovery room.


   Animal Studies
Top
 Introduction
 Residual Neuromuscular Block and...
 Hypoxic Ventilatory Control
 Residual Effects of Volatile...
 Human Studies
 Animal Studies
References
 
When focusing the question on whether there is a direct depressant effect by inhaled anesthetics on the chemoreceptor, animal studies have yielded data that are more uniform than human data, because similar findings have been described in various species and among various researchers (61–64). Van Dissel et al. (62) and Gaudy et al. (63) did not find any evidence of a depressant effect by inhaled anesthetics on the peripheral chemoreceptor. The hypothesis was also tested by Koh and Severinghaus (61) in the spontaneously breathing goat during halothane anesthesia. They found an increase in minute ventilation during hypoxic challenge that was minimally reduced at 0.5% (end-tidal) halothane anesthesia compared with awake control response and a further dose-dependent reduction during deeper halothane anesthesia (1.2% end-tidal halothane). Interestingly, similar findings have been shown by Sollevi and Lindahl (52) in humans during subanesthetic and anesthetic levels of isoflurane. Hence, these findings in two different species (Fig. 6) speak against conclusions made by Knill and Gelb (41), Knill et al. (42), Gelb and Knill (43), and others (46,47,55) about peripheral chemosensitivity and show that there is a hypoxic ventilatory response present even at anesthetic levels of inhaled anesthetics. Furthermore, similar findings were reported by Stuth et al. (59) who demonstrated a phrenic nerve response to hypoxia in the anesthetized dog (Fig. 7). Although the overall phrenic nerve activity was markedly depressed during hypoxia, the relationship between resting activity and the activity during hypoxia was unchanged during deep halothane anesthesia. In addition, chemoreceptor denervation caused an abolished ventilatory response to hypoxia, which confirmed that the recorded hypoxic ventilatory response during anesthesia originated from the carotid body chemoreceptors (Fig. 8). Hence, it is clear that the peripheral chemoreceptors were activated by hypoxia during inhaled anesthesia.



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  		Figure 6. Lack of species differences between isocapnic hypoxic ventilatory responses during halothane and isoflurane anesthesia in an animal model and in humans. Data redrawn from Koh and Severinghaus (61) and from Sollevi and Lindahl (52). There was an increase in ventilation during isocapnic hypoxia that is of the same magnitude in goats and humans, comparing control ventilation with hypoxic challenges during subanesthetic levels of inhaled anesthesia (halothane 0.5% and isoflurane 0.2%), which indicates that the peripheral chemoreception is intact. Moreover, the the dose-dependent reduction in hypoxic ventilatory responses during inhaled anesthesia (halothane and isoflurane > 1.0%) is comparable in these two. Data shown with permission from Koh SO, Severinghaus JW. Effect of halothane on hypoxic and hypercapnic ventilatory responses of goats. Br J Anaesth 1990;65:713–7. (by permission of Oxford University Press) and Sollevi A, Lindahl SGE. Hypoxic and hypercapnic ventilatory responses during isoflurane sedation and anaesthesia in women. Acta Anaesthesiol Scand 1995;39:931–8. © 1995 Munksgaard International Publishers Ltd., Copenhagen, Denmark.

 


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  		Figure 7. Effect of halothane concentration on peak phrenic nerve activity (PPA) during hyperoxic hypercapnic control states (solid bars) and for corresponding hypoxic runs (hatched bars). All PPA values were normalized to the hyperoxic control PPA at 1 minimum alveolar concentration (MAC). asterisks = significant increase due to hypoxia compared with respective hyperoxic control. *** P < 0.001. §Significant halothane dose-dependent difference for the hyperoxic hypercapnic control compared with the 1-MAC dose, §§§ = P < 0.001. From Stuth et al. (59) and figure reprinted with permission from Anesthesiology.

 


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  		Figure 8. Phrenic nerve responses (PNG) to acute isocapnic hypoxia before (top) and after carotid body chemoreceptor denervation during 1 minimum alveolar concentration (MAC) halothane anesthesia (middle) during hypoxic challenge (O2% airway concentration, bottom). The increase in phrenic nerve during hypoxia (60–120 s) was abolished, which indicates that the observed response is mediated by the carotid body chemoreceptors. Note the absence of any centrally mediated depressant effect of hypoxia in the denervated animal. From Stuth et al. (59) and with permission from Anesthesiology.

 
Finally, the effect of volatile inhaled anesthetics on carotid body chemoreceptors has been directly measured in various species. In 1968, Biscoe and Millar (64) showed that halothane did not depress the chemoreceptor activity during hypoxia (i.e., at PaO2 <80 mm Hg) as recorded from the whole sinus nerve preparation. Davies et al. (65) investigated chemoreceptor activities in the rat and found a moderate depression during anesthetic levels, whereas Ponte and Sadler (66) investigated several inhaled anesthetics and their direct effects on the chemoreceptor function during normocapnic hypoxic challenges in both cat and rabbit using a single chemoreceptor preparation. They found a minor chemoreceptor depression PaO2 > 40 mm Hg whereas no depression was found at PaO2 < 40 mm Hg. Interestingly, these experiments included the administration of a continuous infusion of nondepolarizing neuromuscular blocking drugs to keep the animals immobilized. In the rabbit, Joensen et al. (67) investigated the effects of 1.0% isoflurane on chemoreceptor activities during hypoxia at either hypocapnia, normocapnia, or hypercapnia, without the administration of a muscle relaxant. The chemoreceptor activity was unchanged during isoflurane anesthesia, regardless of the underlying arterial carbon dioxide tension (Fig. 9). Thus, over the years, similar findings has been obtained from a variety of species (goat, dog, rabbit, cat, and rat), and there is no reason to believe that it should be different in humans (54). Hence, the chemosensitivity of the carotid body chemoreceptor seems not to be influenced by volatile inhaled anesthetics. The depression of HVR during anesthesia must therefore originate within the CNS.



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  		Figure 9. The carotid body chemoreceptor activity (rabbit) during control state without isoflurane and during administration of 1.0% (end-tidal) isoflurane at normocapnia (PaCO2 37.5 mm Hg). Note the lack of depression of the chemoreceptor activity during isoflurane anesthesia. Data from Joensen et al. (67) and with permission from Joensen, Eriksson LI, Lindahl SGE et al. The effect of isoflurane on peripheral chemoreceptor sensitivity to varying PO2 and PCO2 [abstract]. Acta Anaesthesiol Scand 1997;32:152. © 1997 Munksgaard International Publishers Ltd., Copenhagen, Denmark.

 
In summary, residual effects of neuromuscular blocking drugs and inhaled anesthetics interfere with ventilatory control in the postoperative states by different mechanisms. Subparalyzing doses of neuromuscular blocking drugs rarely affect resting minute ventilation because a reduction in respiratory tidal volumes is counteracted by an increase in respiratory rate due to maintained carbon dioxide sensitivity. In contrast, the hypoxic ventilatory control is depressed due to an interaction with the carotid body chemoreceptors, most likely dependent on an interaction with cholinergic neurotransmission of the carotid bodies. At an adductor pollicis TOF ratio of <0.90, the pharyngeal function is impaired, resulting in a four- to fivefold increase in the risk of aspiration.

Inhaled anesthetics, however, cause a dose-dependent reduction of resting ventilation and minute ventilation during hypercarbia and hypoxia due to a general depression of central neuronal control, including the respiratory neurons of the brainstem. The hypoxic chemosensitivity of the carotid body chemoreceptors, however, are minimally affected by inhaled anesthetics, even at anesthetic levels of the vapor.

Residual neuromuscular block causes impaired regulation of ventilation during hypoxia and impaired pharyngeal function and airway protection, and it is a risk factor for the development of postoperative pulmonary complications. To assure normal vital muscle function and normal ventilatory regulation, an adductor pollicis TOF ratio of 0.90 should ideally be achieved before a patient is allowed to breath spontaneously after tracheal extubation. This can only be reliably detected using objective monitoring techinques of neuromuscular function, such as accelometry or electromyography. Inhaled halogenated anesthetics depress ventilation at anesthetic and subanesthetic levels. The carotid body chemoreceptor function is, however, well maintained at subanesthetic end-tidal concentrations of volatile inhaled anesthetics.


   References
Top
 Introduction
 Residual Neuromuscular Block and...
 Hypoxic Ventilatory Control
 Residual Effects of Volatile...
 Human Studies
 Animal Studies
 References
 

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Accepted for publication April 8, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press