Reasons For Prolongation Of Opioidrelated Respiratory Depression In Patients

In general prolongation of respiratory depression after opioid administration has to be expected when the following agents are coadministered:

1. All agents that inhibit the biotransformation of opioids such as contraceptives, anti-tumor agents, anti-arrhythmics, antidepressants, systemically administered antimycotics, neuroleptic drugs, and volatile anesthetics [68, 69, 70, 71, 72]. By inhibition of conjugation of glucoronide and oxidative dealkylation, the necessary metabolic pathways for degradation and termination of activity of most agents, a prolongation of action has to be expected.

2. All agents, which are able to displace the opioid from protein binding within the plasma, resulting in a higher portion of the pharmacologically active agent. Preparations such as cumarine derivatives, and phenylbutazone, which when coadminstered are prone to result in a prolongation of effects [73, 74, 75, 76].

3. In addition, hypoproteinemia and acidosis of the blood, both of which result in lesser protein binding, cause a higher concentration of non-bound opioid in the blood plasma. Such increase in plasma concentration now is able to bind to the receptor site with an increase of efficacy and a longer duration of action [77].

Following opioid-based anesthesia, several factors cause an overhang of opioid action, which may even result in a "re-morphinisation" and the re-occurrence of respiratory impairment:

1. The excessive intramuscular premedication with an opioid, which may act like a depot.

2. The premedication with a long-acting benzodiazepine, which is able to induce a reduction in vigilance lasting into the postoperative period.

3. The uncritical intraoperative use of high concentrations of a volatile anesthetic, which results in a lesser biodegradation of the opioid.

4. The intraoperative administration of fractional doses of an opioid, which results in an accumulation. Due to the fact that a portion of each dose of an intravenously administered opioid is also taken up by peripheral sites (e.g. fatty tissue, musculature, skin, internal organs) there is an accumulation of the agent, which act like a depot. From there the drug later diffuses into the blood-stream, resulting in a prolongation of effects (Figure II-40).

5. An insufficient loading dose of the opioid, which may result in the necessity of re-administration of small amounts of the drug intraoperatively with consequent peripheral accumulation.

6. Long-term intravenous administration of an opioid by drip, resulting in the increase of the agent in the peripheral compartment with later recirculation into the blood stream.

7. The combination of opioids with different half-lifes, which may result in an unforeseen potentiation of effects.

8. Uncritical administration of bicarbonate resulting in alkalosis of the blood, which induces a faster release of the opioid from the peripheral compartment.

Figure 11-40. Schematic drawing of repetitive administration of fractional doses of fentanyl (a). Contrary to one high loading dose (b), there is an accumulation of the opioid in the peripheral compartment resulting in a prolongation of effects into the postoperative period. Adapted from [67]

9. A non-corrected hypovolemia, which coincides with lesser protein binding of the agent and a higher portion of the free active compound.

10. Uncritical use of a selective antagonist such as naloxone, not considering that its half-life is shorter than the agonist, resulting in a later reoccurrence of respiratory impairment.

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