Intravenous Anaesthetics Affect Phrenic Nerve Activity
D Ma, JG Whitwam
Department of Anaesthetics
and Intensive Care, Imperial College School of Medicine,
Hammersmith Hospital, London
W12 OHS
The inspiratory–expiratory “clock” for automatic ventilation is located in neurons in the medulla. It is influenced by blood gas tensions and CSF pH directly or indirectly via peripheral and central chemoreceptors, pulmonary receptors, baroreceptors and pain or nociceptive stimuli (1). Efferent phrenic nerve activity (PNA) provides a monitor of a final common pathway from cervical cord (C 3, 4 and 5) motorneurons innervating the diaphragm. For behavioural activity, e.g. speech, there is a direct voluntary override corticospinal pathway.
Traditionally, tidal volume and minute ventilation have been used to assess the output of the respiratory control system. However, previous studies have shown that they are not entirely satisfactory because the mechanical properties of the airways, lungs and even the chest wall may change (2). Furthermore, the system used for studying respiration is usually a closed loop and the changes in minute ventilation may reflect a change, for example, in carbon dioxide concentrations. Thus, the net direct effects of drugs on central respiratory control cannot be achieved by such conventional methods. One satisfactory solution, for example, in studies of the effect of drugs on central control, is to record the electrical activity in a respiratory muscle or an efferent nerve as a measure of respiratory neuronal output. The discharge of the diaphragmatic electromyogram (3) or phrenic nerve correlate well with tidal volume (4) and muscle force output (5). However, when a subject or an experimental animal was paralysed and artificially ventilated, PNA only indicates the output of the central respiratory control system.
The phrenic nerve is readily identifiable and multi-fiber efferent PNA is easy to record and integrate for comparison. Whereas PNA comprises bursts of activity in phase of inspiration during spontaneous breathing, during positive pressure ventilation its activity is still in phase with the respiratory cycle but bursts of activity start during expiration and are terminated by stretch receptors responding to inflation of the lungs. It responds to changes in baroreceptor activity and is inhibited by hypertension and increase during hypotension. Preoxygenation with a PaO2 > 170 mmHg, i.e. above peripheral chemoreceptor threshold, reduces PNA and increase the incidence and duration of apnoea during intravenous induction of anaesthesia (6).
PNA and intravenous
anaesthetics
Apnoea commonly occurs during the intravenous induction of anaesthesia with thiopentone, methohexitone or propofol (6,7). However, although benzodiaepines (BZDs) depress respiration (8), their effects may vary (9). This phenomenon could be explained by acute ‘tolerance’ to their effects, for example, on PNA (10). One mechanism of such tolerance is due to the formation of metabolites which block BZD receptors (11). All m opioids cause a dose-dependent depression of respiration, primarily through a direct action on the brainstem (12). Although the respiratory depression induced by BZDs, propofol and opioids could be due to a reduced responsiveness to hypercarbia and hypoxia mediated by chemoreceptors, our work comfirms direct central depression of PNA (10,13). PNA is much more sensitive to the depressant effect of opioids than nociceptive reflexes (13,14).
Pharmacodynamic anaesthetic drug interactions have been summarised (15). Briefly, midazolam and fentanyl have synergistic hypnotic and respiratory depressant effects which is also true for the combined depressant effect of midazolam and remifentanil on respiration. The degree of ventilatory depression during the induction of anaesthesia with propofol is increased by opioid premedication (16). We have observed the effects of propofol, midazolam, fentanyl and remifentanil, alone and in combination, in a normothemic rabbit model using chloralose for background anaesthesia with a PaO2 around 200 mmHg and a normal PaCO2. The comparative endpoints were heart rate (HR), mean arterial pressure (MAP) and directly recorded PNA. Dose response curves were observed and the mean ED50s were compared. All four drugs acted synergistically on PNA, but their combined effects on HR and MAP were less than expected (10,13).
These results could be explained, at least in part, by pharmacokinetic interactions. For example, fentanyl reduces the pulmonary uptake of propofol to increase its blood concentrations (17,18). Also alfentanil increases the blood levels of propofol and vice versa, due to interaction with hepatic P450 enzymes (19,20). There is also a study showing that systemic clearance of midazolam was decreased by 30% and its elimination half-time was prolonged by 50% by fentanyl (21).
In conclusion, intravenous anaesthetics, e.g. propofol, midazolam and opioids, have synergistic interactions on consciousness and respiration. They are used for co-induction of anaesthesia and during sedation for diagnostic and therapeutic procedures. Unplanned anaesthesia and severe respiratory depression during sedation for procedures away from conventional operating theatres without the presence of anaesthetically trained physicians are extremely dangerous (15).
1. Blessing WW. The lower barinstem and bodily homeostasis. Oxford: Oxford Uni. Press, 1997;pp101-164
2. Cherniack RM, Snidal DP. J Clin Invest 1965;35:1286-90.
3. Katz RL, Fink BR, Ngai SH. Proceedings Soc Exp Bio and Med 1962;110:792-4.
4. Lourenco RV, Cherniack NS, Malm JR, Fishman AP. J App Physiol 1966:21:527-53.
5. Eldridge FL. J App Physiol 1975:39:567-74.
6. Whitwam JG. Br J Anaesth 1962:34:729-732.
7. Goodman NW, Black AM, Carter JA. Br J Anaesth 1987:59:1497-503.
8. Alexnder CM, Gross JB. Anesth and Analg 1988:67:377-82.
9. Bailey PL, Andriano KP, Goldman M, Stanley TH, Pace NL. Anesthesiology 1986:64:460-5.
10. Ma D, Sapsed-Byrne SM, Chakrabarti MK, Whitwam JG. Acta Anaesthesiol Scand 1998;42:670-7.
11. Al-khudhairi D, Askitopoulou H, Whitwam JG. Br J Anaesth 1982:54:953-8.
12. Santiago TV, Edelman NH. J App Physio 1985;59:1675-85.
13. Ma D, Chakrabarti MK, Whitwam JG. Anesthesiology 1999;
14. Niv D, Whitwam JG. Neuropharmacology 1983;22:703-9.
15. Whitwam JG, Ma D. Pharmacology. In: Principles and Practice of Sedation. 2nd Ed. Eds Whitwam JG and McCloy RE. Oxford:Blackwell Science. 1998;pp8-53.
16. Taylor MB, Grounds RM, Mulrooney PD, Morgan M. Anaesthesia 1986:41:816-20.
17. Cockshott ID, Briggs LP, Douglas EJ, White M. Br J Anaesth 1987;59:1103-10.
18. Matot I, Neely CF, Katz RY, Neufeld GR. Anesthesiology 1993;78:1157-65.
19. Pavlin DJ, Coda B, Shen DD, Tschanz J, NguyenQ, Schaffer R, Donaldson D, Jacobson RC, Chapman CR. Anesthesiology 1996;84:23-37.
20. Janicki PK, James MF, Erskine WA. Br J Anaesth 1992;68:311-2.
21. Hase I, Oda Y, Tanaka K, Mizutani K, Nakamoto T, Asada A. Br J Anaesth 1997;79:740-3.