Alterations in diaphragm EMG activity during opiate-induced respiratory depression

doi:10.1016/0034-5687(94)00119-K

Respiration Physiology

Volume 100, Issue 2, May 1995, Pages 107-117

Respiration Physiolo...

https://doi.org/10.1016/0034-5687(94)00119-K Get rights and content

Abstract

While opiate-induced increases in thoracic muscle tone may contribute to impaired ventilation during opiate anesthesia, the effects of high-dose opiates on diaphragm muscle activity have not been elucidated. The effects of the opiate agonist alfentanil (ALF, 500 μg/kg subcutaneously) on diaphragm (DIA) and intercostal (IC) electromyographic (EMG) activity in spontaneously ventilating adult rats were studied. EMG segments corresponding to inspiration and expiration were selected using an impedance plethysmographic respiratory waveform. Total EMG activity over a respiratory cycle was significantly greater in the DIA than in the IC. ALF produced a decrease in inspiratory and an increase in expiratory DIA EMG activity. These changes in diaphragm function following ALF were accompanied by significant respiratory depression. The effects of the alpha-2 agonist dexmedetomidine on ALF-induced changes in diaphragm and intercostal EMG activity were also examined. While dexmedetomidine alone had minimal effects on DIA activity, it significantly attenuated the ALF-induced increase in expiratory DIA EMG. The potential etiology and implications of these opiate-induced changes in diaphragm muscle function are discussed.

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Administration of opioids to humans exerts deleterious effects on the status of arterial blood gas chemistry by suppressing breathing and impairing gas-exchange in alveoli (Rybro et al., 1982; Cepeda et al., 2003; Chow et al., 2003; Cashman and Dolin, 2004; Taylor et al., 2005; Wang et al., 2005; Lötsch et al., 2006; Dahan et al., 2010). Opioids elicit effects in animals that impair arterial blood gas (ABG) chemistry via cardiopulmonary afferent- and centrally-induced decreases in breathing, enhanced rigidity of skeletal muscle in the chest-wall/abdomen, and increased resistance of the upper airway via collapse/closure of the larynx and vocal folds (Willette et al., 1982, 1983, 1987; Bennett et al., 1997; Niedhart et al., 1989; Campbell et al., 1995; Bowdle, 1998; Kaczyńska and Szereda-Przestaszewska, 2005; Dahan et al., 2010). Additionally, opioids have deleterious actions on ventilation-perfusion in the lungs (Ling et al., 1985; Szikszay et al., 1986; Copland et al., 1987; Hannon and Bossone, 1991; Shafford and Schadt, 2008; Henderson et al., 2014; Jenkins et al., 2021; Gaston et al., 2021), and depress activity of carotid body chemoreceptor afferents and their ability to (1) respond to environmental hypoxia and/or hypercapnia (McQueen and Ribeiro, 1980, 1981; Zimpfer et al., 1983; Kirby and McQueen, 1986; Mayer et al., 1989), and (2) diminish changes in ventilation during hypoxic and/or hypercapnic gas challenges (Zhang et al., 2009; May et al., 2013a; b).
We determined whether intravenous injections of the membrane-permeable ventilatory stimulants, D-cysteine ethyl ester (ethyl (2 S)− 2-amino-3-sulfanylpropanoate) (D-CYSee) and D-cystine dimethyl ester (methyl (2 S)− 2-amino-3-[[(2 S)− 2-amino-3-methoxy-3-oxopropyl]disulfanyl] propanoate) (D-CYSdime), could overcome the deleterious actions of intravenous morphine on arterial blood pH, pCO₂, pO₂ and sO₂, and Alveolar-arterial (A-a) gradient (i.e., the measure of exchange of gases in the lungs) in Sprague Dawley rats anesthetized with isoflurane. Injection of morphine (2 mg/kg, IV) caused pronounced reductions in pH, pO₂ and sO₂ accompanied by elevations in pCO₂_, all which are suggestive of diminished ventilation, and elevations in A-a gradient, which suggests a mismatch of ventilation-perfusion. Subsequent boluses of D-cysteine ethyl ester (2 ×100 μmol/kg, IV) or D-cystine dimethyl ester (2 ×50 μmol/kg, IV) rapidly reversed of the negative actions of morphine on pH, pCO₂, pO₂ and sO₂_, and A-a gradient. Similar injections of D-cysteine (2 ×100 μmol/kg, IV) were without effect, whereas injections of D-cystine (2 ×50 μmol/kg, IV) produced a modest reversal. Our data show that D-cysteine ethyl ester and D-cystine dimethyl ester readily overcome the deleterious effects of morphine on arterial blood gas (ABG) chemistry and A-a gradient by mechanisms that may depend upon their ability to rapidly enter cells. As a result of their known ability to enter the brain, lungs, muscles of the chest wall, and most likely the major peripheral chemoreceptors (i.e., carotid bodies), the effects of the thiolesters on changes in ABG chemistry and A-a gradient elicited by morphine likely involve central and peripheral mechanisms. We are employing target prediction methods to identify an array of in vitro and in vivo methods to test potential functional proteins by which D-CYSee and D-CYSdime modulate the effects of morphine on breathing.
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Citation Excerpt :
Both opioids and benzodiazepines induce upper airway obstruction by oropharyngeal muscle relaxation.36 Opioids also increase intercostal muscle rigidity, decreasing chest compliance.37 In response to upper airway obstruction and opioid-induced decrease in chest compliance, diaphragm contraction amplitude is not altered.37
The safety profile of buprenorphine has encouraged its widespread use. However, fatalities have been attributed to benzodiazepine/buprenorphine combinations, by poorly understood mechanisms of toxicity. Mechanistic hypotheses include (i) benzodiazepine-mediated increase in brain buprenorphine (pharmacokinetic hypothesis); (ii) benzodiazepine-mediated potentiation of buprenorphine interaction with opioid receptors (receptor hypothesis); and (iii) combined effects of buprenorphine and benzodiazepine on respiratory parameters (pharmacodynamic hypothesis).
We studied the neuro-respiratory effects of buprenorphine (30 mg kg⁻¹, i.p.), diazepam (20 mg kg⁻¹, s.c.), and diazepam/buprenorphine combination in rats using arterial blood gas analysis, plethysmography, and diaphragm electromyography. Pretreatments with various opioid and gamma-aminobutyric acid receptor antagonists were tested. Diazepam impact on brain ¹¹C-buprenorphine kinetics and binding to opioid receptors was studied using positron emission tomography imaging.
In contrast to diazepam and buprenorphine alone, diazepam/buprenorphine induced early-onset sedation (P<0.05) and respiratory depression (P<0.001). Diazepam did not alter ¹¹C-buprenorphine brain kinetics or binding to opioid receptors. Diazepam/buprenorphine-induced effects on inspiratory time were additive, driven by buprenorphine (P<0.0001) and were blocked by naloxonazine (P<0.01). Diazepam/buprenorphine-induced effects on expiratory time were non-additive (P<0.001), different from buprenorphine-induced effects (P<0.05) and were blocked by flumazenil (P<0.01). Diazepam/buprenorphine-induced effects on tidal volume were non-additive (P<0.01), different from diazepam- (P<0.05) and buprenorphine-induced effects (P<0.0001) and were blocked by naloxonazine (P<0.05) and flumazenil (P<0.05). Compared with buprenorphine, diazepam/buprenorphine decreased diaphragm contraction amplitude (P<0.01).
Pharmacodynamic parameters and antagonist pretreatments indicate that diazepam/buprenorphine-induced respiratory depression results from a pharmacodynamic interaction between both drugs on ventilatory parameters.
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Citation Excerpt :
Henderson et al. [34] found that pretreatment with the peripherally restricted μ-OR antagonist, naloxone methiodide, diminished, but did not abolish the actions of fentanyl on ventilatory parameters and gas-exchange in the lungs of rats. As such, the actions of fentanyl most likely involve peripheral (e.g., carotid bodies), central structures free of an effective blood-brain barrier (e.g., area postrema), and brain structures within the barrier such as the nucleus tractus solitarius (NTS), Kölliker-Fuse nucleus and pre-Bötzinger complex [7,9,34,48,74]. Nitric oxide (NO), and a multitude of nitrosyl factors, including S-nitrosothiols (SNOs), circulating in the blood [1,14,20,21], the carotid bodies [21,53,60,77] and brain nuclei, such as the NTS [29,43,58,70–72,75], ventral and dorsal respiratory groups, nucleus retrofacialis of the pre-Bötzinger complex [41], nucleus raphe magnus [57], rostral ventrolateral medulla [13], medial pontine reticular formation [40], locus coeruleus [18,19], and pontine respiratory group [42], play key roles in the regulation of breathing.
There is an urgent need to understand the intracellular mechanisms by which synthetic opioids, such as fentanyl, depress breathing. We used L-NAME (N^G-nitro-L-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor, to provide evidence for a role of nitric oxide (NO) and nitrosyl factors, including S-nitrosothiols, in fentanyl-induced suppression of breathing in rats. We measured breathing parameters using unrestrained plethysmography to record the changes produced by bolus administration of fentanyl (25 μg/kg, IV) in male Sprague Dawley rats that were pretreated with vehicle (saline), L-NAME (50 μmol/kg, IV) or the inactive D-isomer, D-NAME (50 μmol/kg, IV), 15 min previously. L-NAME produced a series of ventilatory changes that included (i) sustained elevations in breathing frequency, due to the reductions in the durations of inspiration and expiration, (ii) sustained elevations in minute ventilation, accompanied by minimal changes in tidal volume, and (iii) increases in inspiratory drive and expiratory drive, and peak inspiratory flow and peak expiratory flow. Subsequent administration of fentanyl in rats pretreated with vehicle produced negative effects on breathing, including decreases in frequency, tidal volume and therefore minute ventilation. Fentanyl elicited markedly different responses in rats that were pretreated with L-NAME, and conclusively, the negative effects of fentanyl were augmented by the NOS inhibitor. D-NAME did not alter ventilatory parameters or modulate the effects of fentanyl on breathing. Our study fully characterized the effects of L-NAME on ventilation in rats and is the first to suggest a potential role of nitrosyl factors in the ventilatory responses to fentanyl. Our data shows that nitrosyl factors reduce the expression of fentanyl-induced changes in ventilation.
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Increased chest wall muscle tone has been suggested to cause impaired ventilation and reduced tidal volume during administration of fentanyl and related compounds (Burns et al., 2016; Comstock et al., 1981; Çoruh et al., 2013). This muscle rigidity is due to opioid receptor activation in the dopaminergic and adrenergic systems (Campbell et al., 1995; Genç et al., 1983; Jerussi et al., 1987). In our experiments, fentanyl decreases amplitude (fictive tidal volume) of phrenic motor output in the absence of chest wall rigidity due to the paralyzed nature of the preparation.
Overdoses caused by the opioid agonist fentanyl have increased exponentially in recent years. Identifying mechanisms to counter progression to fatal respiratory apnea during opioid overdose is desirable, but difficult to study in vivo. The pontine Kölliker-Fuse/Parabrachial complex (KF/PB) provides respiratory drive and contains opioid-sensitive neurons. The contribution of the KF/PB complex to fentanyl-induced apnea was investigated using the in situ arterially perfused preparation of rat. Systemic application of fentanyl resulted in concentration-dependent respiratory disturbances. At low concentrations, respiratory rate slowed and subsequently transitioned to an apneustic-like, 2-phase pattern. Higher concentrations caused prolonged apnea, interrupted by occasional apneustic-like bursts. Application of CTAP, a selective mu opioid receptor antagonist, directly into the KF/PB complex reversed and prevented fentanyl-induced apnea by increasing the frequency of apneustic-like bursting. These results demonstrate that countering opioid effects in the KF/PB complex is sufficient to restore phasic respiratory output at a rate similar to pre-fentanyl conditions, which could be beneficial in opioid overdose.
Effects of Anesthetics, Operative Pharmacotherapy, and Recovery from Anesthesia
2018, Neurocritical Care Management of the Neurosurgical Patient
L-Cysteine ethyl ester reverses the deleterious effects of morphine on, arterial blood-gas chemistry in tracheotomized rats
2013, Respiratory Physiology and Neurobiology
Citation Excerpt :
Systemically administered opioids disturb arterial blood–gas chemistry in humans by direct suppression of minute ventilation (Cepeda et al., 2003; Cashman and Dolin, 2004; Taylor et al., 2005; Lötsch et al., 2006) and by negative affects on ventilation–perfusion in the lungs (Rybro et al., 1982; Chow et al., 2003; Wang et al., 2005). Systemic opioids also depress ventilation in animals by mechanisms, including central- (Campbell et al., 1995) and vagal afferent-mediated (Kaczyńska and Szereda-Przestaszewska, 2005) depression of ventilatory drive; skeletal muscle rigidity in the chest-wall and abdomen (Niedhart et al., 1989; Bowdle, 1998); increases in pulmonary airway resistance (Willette et al., 1983); and increases in upper airway resistance via closure of the larynx (Willette et al., 1982, 1987; Bennett et al., 1997). Moreover, agonist-induced activation of central and peripheral opioid receptors blunt the hypoxic ventilatory response (see Zhang et al., 2009), and opioids such morphine and fentanyl inhibit carotid body chemoafferent activity and depress the responses of these afferents to hypoxic and hypercapnic challenges (McQueen and Ribeiro, 1980, 1981; Zimpfer et al., 1983; Kirby and McQueen, 1986; Mayer et al., 1989).
This study determined whether the membrane-permeable ventilatory stimulant, l-cysteine ethylester (l-CYSee), reversed the deleterious actions of morphine on arterial blood–gas chemistry in isoflurane-anesthetized rats. Morphine (2 mg/kg, i.v.) elicited sustained decreases in arterial blood pH, pO₂ and sO₂, and increases in pCO₂ (all responses indicative of hypoventilation) and alveolar–arterial gradient (indicative of ventilation–perfusion mismatch). Injections of l-CYSee (100 μmol/kg, i.v.) reversed the effects of morphine in tracheotomized rats but were minimally active in non-tracheotomized rats. l-cysteine or l-serine ethylester (100 μmol/kg, i.v.) were without effect. It is evident that l-CYSee can reverse the negative effects of morphine on arterial blood–gas chemistry and alveolar–arterial gradient but that this positive activity is negated by increases in upper-airway resistance. Since l-cysteine and l-serine ethylester were ineffective, it is evident that cell penetrability and the sulfur moiety of l-CYSee are essential for activity. Due to its ready penetrability into the lungs, chest wall muscle and brain, the effects of l-CYSee on morphine-induced changes in arterial blood–gas chemistry are likely to involve both central and peripheral sites of action.

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¹: Present Address: Dept. of Pharmacology, University of Michigan, Ann Arbor, MI. USA.

²: Present Address: Pacific Science and Engineering, San Diego, CA, USA.

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Alterations in diaphragm EMG activity during opiate-induced respiratory depression

Abstract

Respir. Physiology.

Neurosci. Lett.

Neurosci. Lett.

Brain Res.

Physiol. Behav.

Anesthetic induction with fentanyl

Anesth. Analg.

Central effects of an alpha 2-adrenergic antagonist on fetal lambs: a possible mechanism for hypoxic apnea

J. Dev. Physiol.

Ventilatory effects of dexmedetomidine in humans

Anesthesiology.

Physiology of alfentanil-induced rigidity

Anesthesiology

Respiratory muscle responses to changes in chemoreceptor drive in infants

J. Appl. Physiol.

A procedure for chronic recording of diaphragmatic electromyographic activity

Brain Res. Bull.

Chest wall mechanics in dogs with acute diaphragm paralysis

J. Appl. Physiol.

Activation of the parasternal intercostals during breathing efforts in humans subjects

J. Appl. Physiol.