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GENERAL ARTICLES

The Effects on Hypercarbic Ventilatory Response of Sameridine Compared to Morphine and Placebo

Department of Anesthesiology and Intensive Care, Karolinska Hospital and Institute, Stockholm

Address correspondence and reprint requests to Åsa Österlund Modalen, MD, Department of Anesthesiology and Intensive Care, Karolinska Hospital and Institute, SE-171 76 Stockholm, Sweden.

	Abstract

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Sameridine, a novel molecule, has both local anesthetic and partial µ-opioid receptor properties. The aim of this single, blinded, randomized, four-way cross-over study was to investigate the hypercarbic ventilatory response (HCVR) in 12 healthy volunteers. A 20-min IV infusion of two doses of sameridine 0.15 mg/kg (S-Small) and 0.73 mg/kg (S-Large) were compared with 0.10 mg/kg of morphine and placebo. Ventilation was studied repeatedly for 2 h by pneumotachography and inline capnography. The hypercarbic ventilatory response was measured after addition of 4% CO₂ to inspired air until steady state. A visual analog scale followed sedation. After drug infusion there was a significant rightward shift (on average 4.5 mm Hg) of the ventilatory response curve (HCVR = &OV0312;E/ETCO₂) in the S-Large group. There were no changes of HCVR in the other groups. On a molar basis, the S-Large dose was 6.5 times the morphine dose, and such a dose would have been expected to cause a 12 mm Hg rightward shift. This discrepancy in effect is most likely a result of the partial µ-agonist effect of sameridine. Sedation was most pronounced after S-Large and morphine infusions. The authors concluded that a large IV dose of sameridine depressed the hypercarbic ventilatory response, whereas a smaller, clinical dose did not.

Implications: A novel molecule, sameridine, produces both a local anesthetic blockade and a partial µ-agonist action. In large doses, the ventilatory CO₂ response was depressed, which was not the case when the recommended clinical dose was used.

	Introduction

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Epidural and intrathecal injections of local anesthetics are widely used for surgical procedures and occasionally in combination with potent analgesics for advanced postoperative pain relief. These routes of opioid administration are, however, known to cause delayed respiratory depression, which dictates careful usage of these drugs (1).

There are few studies describing the effects of local anesthetics on ventilatory control in humans. Jorfeldt et al. (2) showed in 1968 that resting ventilation in humans was not affected by lidocaine, mepivacaine, or bupivacaine. In a more recent study, various local anesthetics did not alter ventilation stimulated by hypercarbia. Hypoxic ventilatory responses were, however, slightly stimulated by local anesthetics (3). Hence, as far as hypercarbic ventilatory responses and local anesthetics are concerned, there is a discrepancy in previous results.

A new, interesting molecule (N-ethyl-1-hexyl-N-methyl-4-phenyl-4-piperidine carboxamide hydrochloride), sameridine, with both local anesthetic and opioid properties has been developed. Sameridine acts as a partial µ-agonist in vitro(4).¹ Because sameridine has an opioid component, ventilatory depression may occur at rest. In preclinical studies, a dose-dependent respiratory depression was found in rats whereas no respiratory depressive effects were measured in dogs.² In patients subjected to arthroscopic knee joint surgery, sameridine was administered intrathecally in escalating doses (10–25 mg). In that study, respiratory rates (RRs) or peripheral oxygen saturation did not change (5).

In a previous study, we demonstrated that sameridine influenced resting ventilation in a dose-dependent fashion (6). The aim of this crossover investigation was to quantify the influences of IV sameridine infusions on resting ventilation and ventilatory CO₂ response (HCVR) in 12 healthy volunteers. Two doses of sameridine were used with IV morphine infusion for comparison. A placebo group served as a control.

	Methods

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Our Ethical Committee of Human Research approved the study protocol, and all volunteers gave their written informed consent before inclusion. Six healthy males and six healthy females between 20–50 yr of age were studied on 4 different occasions. They fasted for 4 to 8 h before the drug administration. All subjects refrained from alcohol 24 h before the study and from coffee and tea from 10 PM the evening before the study. All volunteers were nonsmokers, had normal body mass index, and were screened by medical history, physical examination and electrocardiography. They were also informed about the breathing equipment and were offered to test it.

In this prospective, randomized, single-blinded, and four-way crossover investigation, the same subjects were investigated four times with at least 7-day intervals. Examinations were performed at the same time of the day for each individual, either at 8 am or at 1 PM. Hence, subjects that started their first investigation in the afternoon continued with afternoon investigations. A cannula was placed into a cubital vein. The subjects rested in a comfortable bed with a 15° head-up tilt and were not allowed to leave the bed during the first 2.5 h of the study. The ran-domly chosen test drug given was either 0.15 mg/ kg body weight of sameridine (S-Small), 0.73 mg/kg body weight of sameridine (S-Large), 0.1 mg/kg body weight of morphine, or 100 mL of physiological saline (placebo). The drugs were infused, in a volume of 100 mL, during 20 min by using an infusion pump. Ventilatory recordings and programming of the pump were performed by two different persons. A 12-lead electrocardiogram and noninvasive blood pressures were recorded before the drug administration and thereafter at 20, 60, and 120 min.

Ventilation was recorded with the subjects breathing air through a tightly fitted transparent face mask (Gibeck, Gibeck-Dryden; Stockholm, Sweden) positioned over the nose and mouth throughout the investigation. The subjects were allowed an initial resting period of approximately 20–30 min for adjustment. An inline infrared capnometer and a pneumotachograph (Fleisch #0.2^TM; linear for flows up to 2.4 L/s; Siemens Elena, Solna, Sweden) were placed in the dead space of the circuit. The dead space volume of the system was 70 mL as measured by water displacement. Inspiratory and expiratory resistances of the measuring apparatus were 2 cm H₂O L^-1 s^-1. Minute ventilation (&OV0312;E) was measured by integration of the flow signal from the pneumotachograph. Flow (V), tidal volume (VT), and inline end-tidal CO₂ tension (ETCO₂) were recorded on an inkjet recorder. These signals were also stored in a computer. Inspired and expired concentrations of oxygen were continuously recorded by a Datex Ultima S^TM device (Datex, Stockholm, Sweden), that also measured arterial oxygen saturation by finger pulse oxymetry (SpO₂). Ventilation volumes were presented at body temperature and pressure saturated (BTPS). The capnometer was calibrated with certified gases before each experiment. Calibration of the pneumotachograph was performed before and after each experiment, using a high precision syringe (Model 5530^TM; Hans Rudolph Inc., Kansas City, MO). At each study occasion the ventilatory variables recorded were: &OV0312;E, L/min, VT, mL, RR (breaths/min), times for inspiration (TI, s) and expiration (s), mean inspiratory flow (VT/TI, mL/s), and the respiratory duty cycle (s). Ventilatory variables were measured 5 min before the start of infusion and repeated at 20, 60, and 120 min.

Hypercarbic ventilatory responses (HCVR) were measured after adding 4% CO₂ to inspired air during 5–6 min periods. Steady state was reached after 3 min of CO₂ provocation and ventilatory measurements were then performed during 2 min of steady-state breathing. HCVR was defined according to the expression: HCVR (L/min/mm Hg) = &OV0312;E/ETCO₂.

The degree of sedation was assessed by a 100 mm visual analog scale (VAS), where the subject scaled the VAS-ruler from 0 (awake, not tired) to 100 (asleep).

The analyses were based on within-subject differences by using nonparametric procedures. Comparisons were made by pairwise sign tests corrected for multiplicity (i.e., corrected for the three possible pairs) according to Bonferroni-Holm. P < 0.05 was used for statistical significance. Ventilatory variables and sedation data are presented as median (range or quartiles).

	Results

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The sedative effect, after 20 min of infusion, in the S-Large group (VAS, sedation score 6.8 ± 2.1) ( Fig. 1) was similar to the morphine group (sedation score 5.5 ± 2.1, P = not significant [NS]). Placebo and S-Small groups had sedative scores of the same magnitude that were both less than in the S-Large and morphine groups (Fig. 1, P < 0.05). There were no signs of hypoxia throughout the investigation. Arterial blood pressure and heart rate showed only small fluctuations during the study period in all four groups. Most adverse events were noted in the S-Large group. They were nausea (n = 4), headache (n = 1), and pruritus (n = 1). In the morphine group, one subject reported headache and fatigue.

View larger version (16K): [in this window] [in a new window]   Figure 1. Median values of visual analog scale (VAS) scores for sedation after a 20-min IV infusion of sameridine (0.73 mg/kg), sameridine (0.15 mg/kg), morphine 0.10 mg/kg and placebo during 120 min in 12 healthy subjects in a cross-over study. Time 0 = start of infusion. For SDs at 20 min, please see the text.

There was no influence on ventilatory CO₂ stimulation in the S-Small and placebo groups (Table 1, Fig. 2). In the S-Large group, &OV0312;E increased during CO₂ challenge by on average 5.4 L/min in the control situation and by, on average, 3.6 L/min after 20 min infusion (P < 0.01). ETCO₂ tensions increased during CO₂ breathing from 39.0 mm Hg to 45.8 mm Hg before infusion and from 43.5 to 49.1 after 20 min of sameridine infusion. The average HCVR was decreased by 36% at the end of infusion in the S-Large group (P < 0.05) (Table 2) and the average displacement of the line was 4 mm Hg (Fig. 2). Thereafter the CO₂ response slowly recovered over time although the change at 120 min was still statistically significant (Fig. 2).

View larger version (23K): [in this window] [in a new window]   Figure 2. Median Hypercarbic Ventilatory Responses (HCVR’s) in the four different groups S-small, S-Large, Morphine, and Placebo. Slopes of the HCVR are presented before (-10 min), after 20 min of infusion of test solution (20 min), and after 60 and 120 min after the infusion start of the test solution.

	Discussion

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The most important finding in this study was that a large dose of sameridine, 0.73 mg/kg, depressed the ventilatory CO₂ response, which was not the case for the smaller more clinically relevant dose, 0.15 mg/kg, in the morphine group or for the placebo group. Because sameridine is a novel molecule with combined local anesthetic and opioid properties, the question arises whether the depressed CO₂ response was caused by one of these properties alone or both in combination?

Opinions regarding ventilatory effects of local anesthetics have not been consistent (2,3,7,8,10). Most of these investigations state that ventilation is unaffected by ordinary local anesthetics, such as lidocaine, mepivacaine, and bupivacaine. Two studies reveal an enhanced HCVR by these local anesthetics (8,9); this was not supported by Johnson and Löfström in 1991 (3). They stated that lidocaine did not alter HCVR, although Gross et al. (8,10) demonstrated a transient ventilatory depression after a bolus injection of lidocaine. Gross et al. also stated that a lidocaine infusion increased rather than decreased HCVR. Hence, ventilatory depression by amide local anesthetics appears unlikely. On the contrary, it seems as if these local anesthetics may stimulate ventilation. The local anesthetic properties of sameridine are similar to bupivacaine in clinical studies.³ Because sameridine’s local anesthetic action is similar to classic local anesthetics, it is unlikely that the depressed HCVR found by us was caused by local anesthetic action of the sameridine molecule.

Opioids are well known respiratory depressants (11). This depression is central and is linked to opioid agonist effects on the µ-receptor. In the absence of ventilatory effects of local anesthetics, the resting ventilation and HCVRs of sameridine are likely caused by its partial µ-agonist properties. HCVR was reduced by a mean of 36% in the S-Large group, whereas no HCVR depression was found after 0.10 mg/kg of morphine or the S-Small dose. These results indicate that there is a dose-dependency of sameridine. Second, the S-Large dose had a more potent respiratory depressant action than morphine in the dosages used. On a molar basis, the S-Large dose was 6.5 times the morphine dose and 5 times the S-Small dose. Therefore, the modest HCVR depression caused by the S-Large dose probably reflects the partial µ-agonistic action of the drug because a dose of morphine six times larger most likely would have resulted in a severely depressed HCVR. Keats (12) found that cumulative morphine doses (10 mg IV at 40-minute intervals) shifted the ventilatory CO₂ response curve to the right and changed the slope of the curve at larger doses of approximately 0.6 mg/kg. In a 60 kg individual, he found that the initial dose of 10 mg morphine, equivalent to 0.16 mg/kg, displaced the CO₂ curve by 4.5 mm Hg, which corresponds to the 4 mm Hg displacement found in the current investigation after the S-Large dose. When Keats used a dose of 0.6 mg/kg during a 160-minute period, the displacement was 12 mm Hg. A similar dose of sameridine on a molar basis would have one-third the effect.⁴ Keats also presented changes of slopes (HCVR) at larger doses and stated, in one subject, that an approximate morphine dose of 0.6 mg/kg IV depressed HCVR by 80% (as compared with the 36% found in the current study). This illustrates the magnitude of the difference between quantitative ventilatory depressions using complete and partial µ-agonistic drugs at approximately equivalent molar dosages.

It is also of interest to find out if the local anesthetic property of the molecule had a stimulatory effect on ventilation, as suggested in some previous studies (3,8), thereby offsetting the µ effect on respiration. The pattern of ventilatory depression did, however, not allow any conclusions about these matters. There was a decreased inspiratory drive, as indicate by &OV0312;E, in the S-Large group despite an unchanged or reduced respiratory duty cycle, indicating a shorter rather than a longer duration of inspiration. Hence the ventilatory depression was a more because of a reduced motor activity (VTs) than of a slower respiratory timing. This is of interest with regard to the classical opinion that holds that opioid respiratory depression is caused by reduced RRs rather than by VTs. This pattern of ventilatory response does not, however, speak against µ-agonistic effects because morphine has also been described to depress VTs (11).

In conclusion, this new substance, sameridine, with combined effects of local anesthetic and partial µ-opioid agonistic properties, reduced the ventilatory response to hypercarbia when used in a large dose (0.73 mg/kg). A smaller, clinical dose (0.15 mg/kg) did not depress the HCVRs, which was also true for 0.10 mg/kg morphine and for placebo.

	Acknowledgments

 
We are most grateful to the excellent technical contribution from Anette Ebberyd and Ringvor Hägglöf, Department of Anesthesiology and Intensive Care, Karolinska Hospital. Thanks also to Pär Karlsson, MSc, Astra Pain Control AB, for statistical evaluation. This study was supported by grants from Astra Pain Control AB Sweden and the Swedish Medical Research Council.

	Footnotes

 
¹ AskA-L, Alari L, Torsvik C. Local anesthetic and analgesic effect of sameridine in mice and inhibition of 3H-naloone binding in guinea pig brain. Abstract D473, 11^th World Congress of Anesthesiology, Sydney, Australia, 1996.

² Ericson A-C, Forsberg T. Central nervous system and cardiovascular effects of sameridine after IV injection in rats and dogs. Abstract P490, 11^th World Congress of Anesthesiology, Sydney, Australia, 1996.

³ Muldoon T., Personne M., Belfrage M. et al. Anesthesia for total hip replacement: the use of intrathecal sameridine. Abstract A0.265. 11^th World Congress of Anaesthesiologists, Sydney, Australia, 1996.

⁴ Gustavsson LL, Vallin H, Sjövall J, Westerling P. A drug combining local anesthetic and opioid (sameridine) first time administration in man. Abstract P523, 11^th World Congress of Anesthesiology, Sydney, Australia, 1996.

	References

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