Vigilance Leading Parameter In Opioidrelated Respiratory Depression

Besides a direct action of opioids on the sensitivity of the respiratory center to changes of arterial pO2 and pCO2, also centrally-induced sedative effects very likely influence respiration. Such sedative effects can be derived with the aid of the electroencephalogram where clinically different potent opioids qualitatively induce

t. "i: i t i i _

to

Control t-

\ \ i \

*

Naltrindol 40 NTB 40ng'kg-1

i f i

Naltrindol 80 MTB 80p.g-kg'1

i A

I 1

\ 4

Naltrindol 160 NTB leopg-kg-1

1

\ *

Table II-9. Affinity data (displacement constants in nmol/L, where a high concentration reflects low binding, and vice versa) of various opioid ligands with the three main opioid receptor sites p, k and 8 in brain homogenates. Note the high affinity of sufentanil to the S-subsite. Adapted from [11]

Opioid

3H-D-Ala2-Met-

3H-D-Ala2-D-

3H-Ethyl-

Phe4-Gly-ol2-

Leu5-Enkephalin

ketocycla-zocine

Enkephalin

(8)

00

M

Morphine

1.8 ± 0.26

90 ± 16

317 ± 68

Pethidine

385 ± 51

4345±1183

5140±789

Pentazocine

7.0 ± 1.8

106 ± 10

22.2 ± 4.1

Fentanyl

7.0 ± 0.83

151 ± 21

470 ± 68

Sufentanil

1.58 ± 0.38

23.4 ± 7.2

124 ± 11

a different in the EEG pattern. Since such EEG changes are dose-related, one is able to derive a dose-relationship. At the same time such EEG-changes reflect the bioavailability of centrally active agents acting on nervous structures of the CNS, depicting the effect-concentration site [62, 63]. Thus, following intravenous administration of an agent, it is not the plasma concentration, which is responsible for a centrally induced effect. More importantly, it is the actual concentration of the opioid at the receptor site, which is affected significantly by issues such as distribution of an agent, its lipophilicity, or the present brain perfusion.

Therefore vigilance changes can be considered as important aspects in an opioid-related respiratory impairment being derived in two relevant experiments:

1. Wakefulness by itself already is a fact resulting in sufficient respiration. This could be demonstrated nicely in volunteers where hyperventilation and the resultant hypocapnia resulted in a rhythmic respiratory pattern. If however, the same volunteers were asleep or in anesthesia, hypocapnia was followed by apnea [64].

2. In the animal laryngeal stimulation during anesthesia resulted in apnae, without, however, initiating a cough reflex. Being awake, a cough reflex without apnae was induced following laryngeal stimulation [65].

3. There is a close exponential correlation of the physiologic regulatory mechanism affecting respiration. This had been demonstrated after sufentanil application in the canine, whereby increasing dosages of a selective antagonist not only <-

Figure 11-38. Dose-related reversal of sufentanil-induced hypercarbia and hypoxia with the two selective S-antagonists naltrindol (NTI) and naltribene (NTB) respectively, in the canine. Due to the higher lipophilicity of naltribene being able to pass through the blood-brain barrier, there is a superior reversal effect. In spite of increasing doses of the antagonist there is a blockade of response to the electrically induced evoked potential, which is only reversed by the highly specific p-antagonist cyprodime. Adapted from [60]

reversed the depressed respiratory drive but at the same time induced an increase of power in the high frequency beta band (13-30 Hz) of the EEG (Figure II-39), reflecting increase in vigilance [66]. 4. Clinically such sedative related respiratory depression can also be derived in patients, when cumulative dosages of an opioid reach a point where the respiratory center "forgets" to respond adequately by initiating deep breaths (oublie respiratoire). This is seen in classical neuroleptanalgsia where the patient's vigilance can be increased to a point by external stimuli (e.g. pain, auditory stimuli) resulting in the initiation of an inspiratory effort [67].

From all these data it can be derived that the simultaneous binding of opioid within the activating reticular system (ARS) in the brain stem, vigilance is depressed, which secondarily affects the response of the respiratory center following hypercapnia. At such instances the overall mesencephalic reticular control mechanism is no longer able to adequately respond to a stimulus and only with an increase in vigilance there is an accelerated reactivity, being able to sufficiently respond to an increase in arterial pCO2. Since the reticular mechanism is coupled with reticulo-cortical afferences, such changes can be derived from cortical changes in the EEG. Such a "forgotten" reaction to sufficiently respond to a given stimulus [65] is also seen in the clinical environment when a benzodiazepine is given on-top of an opioid resulting in a further deterioration of respiratory drive. This is because a benzodiazepine depresses the reaction of the ARS, and the concomittant reduction in vigilance results in a lessened reaction to external stimuli, producing a clinically relevant suppression of respiration.

j

--

— Uont

rof awa

-

c Full : reversal

/

160 p

g 'kg'

■J» . LM !

*40 |jg ■ kg 1

y

!

'"Sufentanil 20 uq • kq 1

y = 2.3962 e-2* 10*(3.5797 e-2x) \7-

0.963

/

>0 60 70 80 90 100 110 Pa02(mm Hg)

Figure 11-39. Close linear correlation between increase in desynchronisation (beta activation) of cortical activities and rise in arterial pO2 in the canine following sufentanil and the dose-related reversal by an antagonist. Adapted from [66]

Figure 11-39. Close linear correlation between increase in desynchronisation (beta activation) of cortical activities and rise in arterial pO2 in the canine following sufentanil and the dose-related reversal by an antagonist. Adapted from [66]

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