Effects of Propofol on H-reflex in Humans

After obtaining approval from the Institutional Review Board at Johannes Gutenberg University Hospital and written informed consent, 33 otherwise healthy patients in American Society of Anesthesiologists class I or II, scheduled for elective urologic, orthopedic, or transnasal surgery of nonfunctional pituitary tumors were chronologically divided into three groups. Group 1 consisted of 13 patients, and groups 2 and 3 consisted of 10 patients each. All patients were given 100 mg hydroxyzine orally 1 h before arriving at the operating room. No patient suffered from central or peripheral neurologic disorders.

After the patient arrived at the operating room, an intravenous infusion of normal saline was started, and the study equipment was attached. All patients received preoxygenation for 3 min by face mask before anesthesia induction was begun.

In group 1, an initial propofol dose of 2 mg/kg over 1 min was given, immediately followed by propofol as a continuous infusion at a rate of 10 mg · kg⁻¹· h⁻¹(167 μg · kg⁻¹· min⁻¹). Electrophysiologic measurements were taken at baseline (preanesthesia = T⁰), 3 min after induction (T¹), and 10 min after induction (T²). The effect-site propofol concentration was calculated later with the IVA-SIM program using a three-compartment model (Version 3.01; Zeneca, Plankstadt, Germany).

In groups 2 and 3, propofol was injected with an Alaris IVAC TCI pump (Alaris Medical Systems, Hampshire, United Kingdom), indicating an estimate for the concentration in the blood and brain compartment. The TCI pump was programmed with patient age, weight, and the desired blood level. Targeted blood levels of 6 μg/ml in group 2 and 9 μg/ml in group 3 were achieved after 1 min as the pump was programmed for a three-step induction with a 20-s pause after each step. Electrophysiologic measurements were taken at baseline (preanesthesia = T⁰) and 3 min after induction (T¹). To ensure sufficient equilibration between the blood and the effect site, the third measurement (T²) was taken 10 min after the estimated effect-site concentration, as indicated at the TCI pump’s display, corresponded to the preset blood target concentration of 6 or 9 μg/ml.

If spontaneous breathing ceased, controlled ventilation was initiated by a face mask to maintain an end-tidal carbon dioxide level of 33–40 mmHg (Capnomac Datex, Helsinki, Finland). Fraction of inspired oxygen was 1.0. No patient required supplementary propofol injections.

H-reflexes and M-responses were evoked by stimulating the tibial nerve in the popliteal fossa using cutaneous surface electrodes, and electromyographic activity was recorded over the soleus muscle by means of two surface electrodes placed 2–3 cm apart from each other. Records were taken using a Nicolet Viking II (Nicolet, Offenbach, Germany) with a rectangular stimulus lasting 1 ms and intensities varying from 0 to 20 mA to elicit a maximal H-reflex amplitude. After having established the intensity that gave rise to a baseline maximal H-reflex amplitude, a series of eight (H-reflex) or four (M-response) stimuli was elicited at each time point (H⁰, H¹, H²; M⁰, M¹, M²). H-reflexes were distinguished from M-responses by their late occurrence and their elicitation by less intense stimuli. All subsequent stimulations were undertaken at the same intensity that had given rise to a maximal amplitude. At least 30 s was allowed to pass before a subsequent stimulation was performed. M-responses were evoked by supramaximal stimulation. Repetition of stimulation was performed using identical stimulus intensities as at T⁰.

The signals were stored on the system’s hard disk. H- and M-amplitudes were measured offline from peak to peak, using the cursor of the electromyograph apparatus. Latencies were also determined by use of the system’s cursor. H/M ratios were calculated (H⁰/M⁰, H¹/M¹, H²/M²).

Data collection was achieved and stored with the electromyograph apparatus, and the average amplitude of a series was taken into account. Demographic data and group comparisons were performed by chi-square analysis. Amplitudes were compared by a one-way analysis of variance for repeated measurements. When data were not normally distributed, a Friedman repeated-measures analysis of variance on ranks was used. All pairwise multiple comparison procedures were conducted with a Tukey test. Values for parametric data are represented as mean ± SD, and for nonparametric data they are given as median (interquartile range). A P  value less than 0.05 was considered statistically significant. Statistical analyses were performed with an appropriate computer program (StatView 4.0, Abacus Concepts Inc., Berkeley, CA).

There were no differences in demographic data between the three groups (table 1). No relevant changes of blood pressure (> 30% of baseline) were observed throughout the study period, nor was there any single recording of a mean arterial blood pressure less than 55 mmHg. In all groups, every patient had lost eyelash reflexes at T¹and T².

H-reflex amplitudes for the three patient groups at baseline and at different calculated effect-site concentrations at T²are shown in figure 1.

In group 1, there was a decrease of H-reflex amplitudes and the H/M ratio after induction with propofol. The effect on H-reflex had disappeared 10 min later as there was no effect when H⁰measurements were compared with H²values. Depression of the H/M ratio still persisted at T²(table 2). The calculated effect-site propofol concentration 10 min after induction with 2 mg/kg propofol over 1 min and consecutive infusion of 10 mg · kg⁻¹· h⁻¹at T²was 1.9 ± 0.2 μg/ml.

No difference was detected in group 2 (6 μg/ml propofol;table 3). However, one patient in group 2 showed complete loss of the H-reflex, whereas another showed a marked reduction of the H-reflex amplitude.

In group 3 (9 μg/ml propofol;table 4), propofol depressed amplitudes of H-reflexes. A multiple comparison analysis in this group revealed H-reflex amplitudes diminished at T²versus  T⁰amplitudes (H⁰vs.  H²;P < 0.01), and T²-amplitudes were lower than T¹values (H¹vs.  H²;P < 0.01). Values for the H/M ratio differed from T⁰to T².

The percentage of patients showing any signs of movement during the entire study period was 62% in group 1, 40% in group 2, and 0% in group 3 (P = 0.009, group 3 vs.  group 1). H-reflex latencies remained unchanged throughout the study period in all groups. In no case did latencies exceed 35 ms.

The results of our study demonstrate a concentration-dependent effect of propofol on spinal cord motoneuron excitability as measured by H-reflexes and the H/M ratio. No effect on axonal conduction or neuromuscular transmission could be detected, as the M-response remained unchanged throughout the experiment.

Previous studies of motoneuron excitability using H-reflexes or F-waves during general anesthesia found significant depression after administration of halothane, 17enflurane, 12isoflurane, 3,4,18desflurane, 5or nitrous oxide. 18–21Only two studies in humans have assessed the effect of intravenous anesthetics on H-reflexes. 13,14H-reflex amplitudes were found to be increased after administration of ketamine 13and etomidate. 14These two intravenous anesthetics are supposed to exert their effects at different receptor sites, ketamine on N -methyl-D-aspartate–type glutamate receptors 22and etomidate, at least in part, on γ-aminobutyric acid^Areceptors. 23 

Depression of α-motoneuron excitability by volatile anesthetic agents has led to the conclusion that this effect would contribute to immobility during anesthesia and surgery. 3,4Several researchers have exclusively studies F-waves 3or both F-waves and H-reflexes, 4as H-reflexes are affected by afferent terminals or interneurons, whereas F-waves can be considered as a pure indicator of motoneuron excitability. Those studying the effects of general anesthetics on H-reflexes found a 50% depression of H-reflex amplitudes from baseline values at relatively low isoflurane concentrations (0.6 minimum alveolar concentration). Further increase in isoflurane had no significant effect on the amplitudes. When nitrous oxide was added at concentrations between 30% and 70% and isoflurane was reduced simultaneously to maintain 1 minimum alveolar concentration, H-reflex amplitudes decreased further to 34% of baseline at 30% nitric oxide. Further increase in nitric oxide, while isoflurane was reduced again, left amplitudes unchanged. 4In our opinion, this would point to a drug-dependent effect in volatile anesthetics on motoneuron excitability. In contrast, and as our results show, the effect of the intravenous anesthetic agent propofol on motoneuron excitability appears to be concentration-dependent.

Loss of consciousness with propofol anesthesia occurs at blood concentrations of 3.5–5 μg/ml. 24Plasma concentrations of 10.0 and 17.4 μg/ml propofol prevented movement in 50% of patients on skin incision and during intubation, respectively. 24In our study, 62% of patients in group 1 and 40% in group 2 showed spontaneous movements, whereas this was the case in none of the patients in the group with 9 μg/ml of targeted propofol blood and estimated effect-site concentration (P = 0.009). As H-reflexes in group 3 showed a significant depression compared with baseline recordings, this immobility during pure propofol anesthesia could possibly be caused by an effect of propofol on spinal motoneuron excitability. Whether this immobility is caused by supraspinal action or is directly related to α-motoneuron depression remains to be clarified in a separate study.

The recommended propofol induction dose is 1.0–2.5 mg/kg, followed by an infusion of propofol 100–200 μg · kg⁻¹· min⁻¹. 25This corresponds to the dose used in group 1 of our study. Although only a relatively weak stimulus such as artificial ventilation by face mask was given during the study period, a majority of patients in this group showed spontaneous movements, but no eyelash reflex was observed. Because H-reflex amplitudes did not show prolonged depression, we assume that spinal motoneuron excitability is not persistently depressed when recommended clinical doses of propofol are given. On the other hand, 3 ng/ml of blood fentanyl reportedly decreases propofol requirements by approximately 50%. 24We did not measure the association of propofol and fentanyl on its effect on H-reflexes, but our results possibly indicate that immobility during propofol anesthesia in recommended doses is not caused by a specific propofol action on motoneuron excitability, but rather by a synergistic effect of all drugs used. When propofol is the single anesthetic agent, very high blood levels are required to prevent motor responses. Turtle et al.  26found that a propofol infusion of 350 μg · kg⁻¹· min⁻¹prevented 95% of adults from moving in response to surgical stimulation when used together with nitrous oxide.

It is unclear why the injection of 2 mg/kg pro-pofol over 1 min, followed by a propofol infusion of 10 mg · kg⁻¹· h⁻¹, diminished H-reflexes at T¹versus  baseline while there was no such reduction in group 2 or 3. The most likely explanation is probably very high transient propofol levels from the induction dose that were not reached when propofol was given via  the TCI pump. Kalkman et al.  27found that a single 2-mg/kg dose of propofol affected descending motor pathways in humans as it depressed evoked motor responses to transcranial stimulation. In that study, depression of motor evoked responses after administration of propofol even persisted for a much longer period than the effects on consciousness and was still detectable after 10 min, a time point when H-reflexes in our study no longer showed a difference compared with baseline. Motor evoked responses in the study by Kalkman et al.  were also depressed for a 30-min period after midazolam 0.05 mg/kg, a dosage that produced only sedation but not loss of consciousness. In contrast, the concentration used in our study group 3 (9 μg/ml propofol) is sufficient as the sole agent to produce anesthesia in almost every patient. Therefore, it is conceivable that motor evoked response to transcranial stimulation is a very sensitive method of measuring motoneuron excitability, whereas H-reflex is more insensitive and perhaps could have some relation to the depth of surgical anesthesia. Therefore, measurements of H-reflexes would seem more appropriate for monitoring or predicting motor responses during anesthesia than motor evoked responses. However, this would be subject to further study.

Several studies have shown that there is significant potentiation of neuromuscular blocking agents by inhalational anesthetics but not by propofol. 28–30Higher doses of muscle relaxants were required to provide adequate muscle paralysis when anesthesia was maintained with a continuous infusion of propofol as when anesthesia was maintained with inhalational halogenated agents. 29The lack of motoneuron excitability depression by propofol in recommended doses in contrast to inhalational anesthetics could explain these differences.

In patients with spasticity associated with cerebral palsy, H-reflex monitoring has been proposed for identifying rootlets to be sectioned during selective posterior rhizotomy. 31According to the results of this and the aforementioned studies, this monitoring technique can only be applied when the anesthetic drugs used exert no or minimal influence on electrophysiologic parameters. We therefore recommend avoiding the use of volatile anesthetics as well as the use of propofol at high dosages. However, the best anesthesia technique for this type of procedures still remains to be determined.

In summary, this study showed a concentration-dependent effect of propofol on spinal motoneuron circuit excitability as measured by H-reflexes and the H/M ratio. Recommended propofol doses for induction and maintenance only had a transient effect on the H-reflex and were no longer demonstrable after 10 min of propofol anesthesia. Propofol does not decrease axonal conduction or transmission at the neuromuscular junction, as M-responses remained unchanged. Immobility during propofol anesthesia at blood target and effect-site concentrations up to 6 μg/ml does not seem to be caused by a depression of spinal motoneuron circuit excitability.

The authors thank the operating room personnel involved in patient care during the study period and Karl-Heinz Schicketanz, M.D., Institüt für medizinische Statistik und Datenverarbeitung, Johannes Gutenberg-Universität, Mainz, Germany, for statistical advice.