Abstract
Purpose: The concept of priming was introduced to facilitate a faster onset of nondepolarizing neuromuscular blocker for endotracheal intubation. Vecuronium is still very much in use for most chronic renal failure patients posted for renal transplantation. The aim of this study was to examine the pharmacodynamics of vecuronium without and with preceding different small doses. Methods: One hundred chronic renal failure patients were assigned into four groups according to the used vecuronium priming regimen. The first control group (V0-group), where no priming dose was given. The other three priming groups (V10- , V15- , and V20-groups), where 10%, 15%, and 20% of ED95 of vecuronium were administrated 5 min prior to the remaining intubating dose (2 × ED95) of vecuronium. Neuromuscular blockade was measured via acceleromyographic response of the ulnar nerve. Train-of-four (TOF) ratio was measured every minute during priming interval. Any unpleasant symptoms during precurarization were recorded. Lag time and onset time (from injection of intubating dose) were recorded. Endotracheal intubation condition was scored blindly. The duration and recovery times were also recorded. Results: The significant higher incidence of symptoms of paresis was encountered in V20-group in comparison with other two priming groups. TOF ratio started to decrease significantly at the first minute in V20-group, at the second minute in V15-group, and at the third minute in V10-group, till the fourth minute in the priming interval. Although TOF ratio was still above 0.90 in V10-group, it was below 0.80 in V20-group. Priming groups did not show significant intergroup difference in onset time. However, duration and recovery times were significantly longer in priming groups in comparison with V0-group without priming. Conclusion: Priming the chronic renal failure patients with 10% of ED95 vecuronium dose acquit the best pharmacodynamics with the fewest signs of muscle weakness. Larger vecuronium priming doses are unfavorable and convey no more clinical utility.
INTRODUCTION
In the anesthetic practice, muscle relaxation is used to serve two prime purposes: one to facilitate enclotracheal intubation and the other one provide good surgical relaxation. Orotracheal intubating conditions depend on patient anatomy, experience of the anesthesiologist and drugs administered.Citation1,2 The concern has led investigators to seek on the best drug for rapid endotracheal intubation. Shortening onset of action of nondepolarizing muscle relaxant to provide good intubating conditions has been achieved using the priming principle.Citation3
The priming principle was first introduced into clinical practice by Mehta and his associates and Schwarz and his colleagues.Citation4,5 They suggested that onset of neuromuscular block could be markedly accelerated if an intubating dose of relaxant was preceded by a small priming dose administered few minutes earlier. Schwarz and his associates suggested 30% of ED95, whereas Mehta and his colleagues proposed 25% of ED95.Citation4,5 The theory is based on the fact that a small dose of a nondepolarizing blocking drug, that would cause no unpleasant symptoms, could occupy a considerable portion of the postsynaptic nicotinic receptors. It was expected that the administration of a second dose of the same drug at the time of maximal effect of the small priming dose would increase the receptor occupancy to approximately 95%, which is necessary for complete block of neuromuscular transmission.Citation6
Sensitivity to vecuronium was assumed to be increased in patients with chronic renal failure due to down regulation of both the presynaptic and postsynaptic cholinergic receptors.Citation7,8 As studies describing the priming principle multiplied, no consensus regarding the correct priming dose or priming interval was achieved. However, many authors reported that the priming dose 20% of ED95, which is approximately 10% of intubating dose, was recommended.Citation9–11
It was postulated that the vecuronium priming dose could hasten the subsequent onset of its intubating dose administration. All the priming studies were conducted in healthy patients scheduled for elective surgery. To the best of our knowledge, there were no previous studies published to determine the proper priming dose of vecuronium in patients with chronic renal failure. So, this study was designed with different priming doses of vecuronium in chronic renal failure to determine the proper priming dose with the least misadventures that may endanger patient’s safety.
PATIENTS AND METHODS
Approval of this prospective randomized study was received from the medical and research ethical committee of Anesthesia Department, Mansoura University, Mansoura, Egypt. Written informed consent was obtained from all patients enrolled in the study after full explanation of the methods and the possible associated signs of mild muscle weakness. A total of one hundred end-stage chronic renal failure patients of both gender were recruited for the study. Preanesthetic medication was not used for the selected patients.
All patients were scheduled for living-related renal transplantation at Mansoura urology and nephrology center. Dialysis was done last time routinely 48 h prior to surgery. At the time of preanesthetic evaluation, patients who had major cardiovascular, respiratory, hepatic, and neuromuscular diseases were excluded. Additionally, the possibility of difficult laryngoscopy (e.g., Mallampati class ≥3, short mandibular space, limited mobility of airway joints), diabetic patients, or those taken preoperative medications known or suspected to interact with neuromuscular blocking agents (e.g., antiepileptics, calcium-channel blockers, or amino-glycosides) were also excluded.
The patients were randomly allocated into four groups of 25 patients each. The randomization was carried out by a computer random generator number method according to the priming dose of vecuronium selected. Patients were assigned to three priming groups and one control (placebo) group. The three priming groups had received either in V10-group (10% of ED95 of vecuronium that equals to 5 μg/kg), in V15-group (15% of ED95 of vecuronium that equals to 7.5 μg/kg) or in V20-group (20% of ED95 of vecuronium that equals to 10 μg/kg). The priming dose in each group was administered 5 min prior to the intubation dose of vecuronium, which included 95 μg/kg, 92.5 μg/kg, and 90 μg/kg in three priming groups (V10, V15, and V20), respectively. The fourth control group (Vo-group), where a single bolus double ED95 of vecuronium (100 μg/Kg) was administered during induction of anesthesia without priming.
On arrival at the operating room, routine monitoring including five leads ECG, noninvasive arterial blood pressure, and pulse oximetry (Hewlett Packard Monitor, HP model 68S, Viridia CMS; Hewlett-Packard, Boeblingen, Germany) was done. Intravenous line was secured and Ringer’s acetate infusion was started slowly. Blood pressure cuff and intravenous line were placed in the arm devoid of arteriovenous shunt. A standardized anesthetic technique was applied in each group. Preemptive epidural analgesia was performed at the lateral decubitus position at L2–3 or L3–4 interspaces using a single bolus bupivacaine 0.25% with 2–2.5 mg morphine.
All patients were previously informed about the possible signs and symptoms of precurarization (e.g., diplopia, heavy eyelids, breathing discomfort, difficult in swallowing or difficult head lift). A blind investigator intermittently questioned every patient about these symptoms, and any symptom experienced by any patient was recorded. Neuromuscular function was assessed by preparing the skin of the contralateral arm (away from blood pressure cuff and intravenous line) and wrist using alcohol and by drying. The presence of arteriovenous shunt did not modify the monitoring of neuromuscular block.Citation12 Two surface electrodes for the ulnar nerve stimulation were placed at the wrist on the radial side of flexor carpi-ulnaris muscle and 3 cm proximal to the distal electrode. Electrodes were connected to the monitor (TOF-Watch SX®, Organon Ltd., Dublin, Ireland). The hand was immobilized with a tap leaving only the thumb free. The acceleration transducer was attached to the volar aspect of the thumb using the specific plastic fixation device designed for this purpose. The skin temperature probe was fixed with a tap to the thenar skin. Core temperature was continuously monitored from the nasopharynx. Both core temperature and skin temperature were maintained throughout the procedure at greater than 36°C and 32°C, respectively using forced air-warming device on the upper half of the body (Bair Hugger, model 505, Augustine Medical, Inc., Eden Prairie, MN, USA). All patients were preoxygenated with face mask (6 L/min) for at least 5 min. Fentanyl 1μg/kg was administered intravenously before start of the study.
After baseline monitoring had been established, the precise priming dose of vecuronium was calculated by insulin syringe (100 IU/mL) in the priming groups. The calculated dose was prepared in equal volume for each patient by an attending anesthesiologist who was not contributing to the evaluation and data collection. Neuromuscular monitoring was started after successful automatic calibration of the TOF-watch SX® monitor.Citation13 TOF-watch was programmed to deliver 30 mA single twitch impulses at 0.1 Hz and 200 ms duration. Continuous monitoring of neuromuscular function was performed using TOF stimuli (four stimuli at 2 Hz) at 15 s interval till the end of study. The prepared priming dose of vecuronium was administered based on double blind fashion. During the priming interval (5 min) in the priming groups, all patients were closely monitored for signs of discomfort, ptosis, or any respiratory problems. Train-of-four ratio was recorded at 1 min interval up to 5 min in order to determine the extent of neuromuscular block between the priming and intubation dose.
After 5 min from injection of the priming dose, anesthesia was induced with thiopental 2.5% in a dose 3–5 mg/kg and the calculated intubation dose of vecuronium in each group was administered intravenously. The lungs were ventilated using a face mask with oxygen (Fio2 = 1.0). After injection of intubation dose, neuromuscular monitoring was continued to record the response to TOF stimulation every 15 s. Laryngoscopy was started by an experienced anesthesiologist who was not aware of the priming dose of vecuronium, or the purpose of the study. Laryngoscopy was accomplished when twitch height 1 Hz depression <80% or disappearance of the fourth response to TOF stimulation. If first twitch of TOF was less than 20%, or less than four responses were detected, only the number of TOF twitches (TOF count) was displayed. Endotracheal intubation was done when TOF count = 0 or 1. Intubation conditions were scored as described by Cooper and his associates.Citation14 Criteria used in grading intubation conditions are outlined in .
Table 1. Intubation condition score.Citation14
After injection of vecuronium intubating dose, the lag time (duration of unchanged neuromuscular transmission) and the onset time (time from vecuronium injection until maximum twitch depression or zero response to TOF stimulation) were recorded. After intubation, mechanical ventilation with a mixture of air, oxygen (Fio2 = 0.35) and isoflurane at end-tidal concentration (0.8–1.2%) was adjusted to help minimal changes in hemodynamics. Tidal volume and respiratory rate were adjusted to keep end-tidal Co2 tension around 30–35 mmHg. Any hemodynamics changes were recorded during the priming interval. The duration time of intubating dose of vecuronium (time from onset to 10% twitch height 1 Hz recovery) and recovery index (time interval from 25% to 75% twitch height 1 Hz recovery) were recorded in all patients. Any adverse events (e.g., unusual or unexpected clinical signs) that manifested itself or worsened during the study period were recorded. Any concurrent medications were also recorded. All results were complied, compared, and analyzed statistically.
STATISTICAL ANALYSIS
The statistical program SPSS 10.0 was used for analysis. Normality was tested using Kolmogorov–Smirnov test. The different groups were compared with one-way analysis of variance (ANOVA), followed by the Tukey-B multiple comparisons if normally distributed, and using the Kruskal–Wallis test followed by the Mann–Whitney U-test with Finner’s modifications of Bonferroni’s correction if not normally distributed. Qualitative data were analyzed using the χ2 test. Power analysis was not performed; rather sample size was based on estimated enrollment over a 36-month period. A post hoc power analysis showed that the study had 82% power to show any difference in the onset of action of vecuronium between the different studied groups at p-value < 0.05.
RESULTS
This prospective randomized study was carried out on 100 chronic renal failure patients scheduled for renal transplantation. All patients underwent hemodialysis 48 h before surgery to keep preoperative serum potassium level below 5.0 mEq/L. Demographic characteristics of the studied groups were comparable with respect of age, weight, height, and gender distribution. Also, Mallampati class was nearly similar in the studied four groups. Preoperative laboratory investigations did not show any significant difference among the studied groups ().
Table 2. Patient demographic and preoperative laboratory characteristics of the studied groups.
shows no patient in V10-group voluntarily complained of any intolerable symptoms of paralysis during the priming interval. However, when the patients were asked about the presence of symptoms of precurarization, two patients only in V10-group had complained of heavy eye lids and diplopia. On the contrary, 20% and 44% of patients in V15- and V20-groups, respectively experienced different signs of precurarization before induction of anesthesia. Although difficulty in swallowing was present in 8% and 28% of patients, difficulty in breathing was present in 4% and 20% of patients in V15- and V20-groups, respectively. Patients in both V15- and V20-groups were presented with significant higher incidence of unpleasant symptoms of vecuronium priming than V10-group, being of higher significant incidence in V20-group. Arterial oxygen saturation was significantly lower in both V15- and V20-groups than the other two groups Voluntary hyperventilation and oxygen mask helped in minimizing the sense of breathing difficulty in those patients.
Table 3. Patients in whom symptoms and signs of paralysis were observed after vecuronium priming interval (5 min) in the studied groups.
TOF ratio started to decrease significantly by the end of first minute priming in V20-group, at the second minute in V15-group and at the third minute in V10-group. The decrease in TOF ratio was significantly continued till the fourth minute during vecuronium priming interval. No further decrease in TOF ratio was achieved at fifth minute. However, TOF ratio, just before the administration of intubating dose, was significantly lower in V20-group than in other vecuronium priming groups. In V10-group, TOF ratio remained above 0.92 with no respiratory complaints. On the contrary, five patients in V20-group experienced breathing discomfort, the corresponding TOF ratio measured before induction of anesthesia were 0.76, 0.73, 0.74, 0.72, and 0.75, respectively. Only one patient in V15-group complained of respiratory difficulty with the corresponding TOF ratio 0.76 before induction of anesthesia ().
Table 4. Train-of-four ratio during the vecuronium priming interval (5 min) after priming dose administration in patients of the studied groups.
Endotracheal intubation was successfully carried out in all patients of the study. No patients were classified as fair or poor score. Intubation conditions were comparable in the three priming groups. Significant high percentage of patients in the priming groups were scored as excellent (9–8) and presented as 92%, 96%, and 96% in V10, V15, and V20-groups, respectively. However, two patients in V10-group and one patient in both V15 and V20-groups were scored good [7–6] because of vocal cord movement and mild cough after intubation. All patients in the three priming groups were intubated at nearly 75 s after injection of vecuronium intubating dose. In Vo-group, intubation was performed after nearly 3.5 min and the intubation was scored excellent in only 72% of patients ( and ).
Table 5. The intubation score achieved after injection of vecuronium intubating dose in patients of the studied groups.
Table 6. Lag time, onset time, duration and recovery times of intubating dose of vecuronium in patients of the studied groups.
The lag time which represents the time of no change in neuromuscular transmission after injection of intubating vecuronium dose was significantly delayed in Vo-group in comparison with other three priming groups. However, lag time was significantly shorter in V20-group in comparison with V10-group. The onset time was significantly shorter in all priming groups and approximately one-third to that of control Vo-group. Additionally, the duration and recovery times were significantly longer in the priming groups in comparison with control V0-group. All the previous times were comparable in V10 and V15 groups ().
Hemodynamics during the peri-priming time did not show any significant intergroup difference and were within the normal physiological range. Only two patients in Vo-group and three patients in each priming groups were in need of ephedrine (5 mg once) before induction of anesthesia. No one in the four studied groups was presented with any other worse signs that need to interrupt the priming time and to induce general anesthesia early.
DISCUSSION
Administration of a subparalyzing 10% of ED95 of vecuronium, 4 min prior to its intubating dose, could hasten the onset time to less than 75 s. Meanwhile, higher vecuronium priming doses were associated with higher symptoms and signs of precurarization with no additional pharmacodynamic advantages. The other positive finding of this study was the significant prolonged duration and recovery times in all vecuronium priming groups more than in the group without priming.
The time interval between the administration of neuromuscular blocking drugs used to facilitate tracheal intubation and the tracheal intubation itself is important because it is considered to be the most dangerous phase of the whole procedure of anesthesia.Citation15,16 The current study has shown that priming technique was statistically and clinically accepted in shortening onset of action of vecuronium when compared to non-priming technique. Similar observations were reported by many other authors using priming dose with different neuromuscular blockers.Citation17–19
Priming action mechanism could be explained by the wide safety margin in neuromuscular transmission. Approximately, 75% of nicotinic receptors have to be occupied for any neuromuscular function change as evaluated by acceleromyography.Citation20 If a low nondepolarizing neuromuscular blocker dose is given and occupies a small portion of 75% of nicotinic receptors, the second high dose will provide shorter onset.Citation21
In this study, the lag time was significantly shortened in the priming groups. The buffered diffusion theory (the biophase model), as described by Hull, may play a role in the explanation of latency of onset, an idea that was later reinforced by Feldman.Citation22,23 This theory proposed that nonfunctional receptors are found in a biophase zone close to the neuromuscular junction and have high affinity for nondepolarizing muscle relaxant. They have to be occupied before postsynaptic acetylcholine receptors binding to establish an eventual neuromuscular block.Citation24 During the priming interval, the initial subparalyzing dose had to undergo a slow diffusion process through the capillary membrane, then to occupy a large number of receptors in the biophase zone. After a few minutes, the eventual large dose of relaxant can directly bind to the postsynaptic cholinergic receptors and thus could hasten the onset of paralysis. This theory helps to clarify the effectiveness of precurarization being independent of drug plasma concentration. However, the site of this biophase and the actual receptor legends still need to be laboratory investigated.Citation25
The priming principle has been criticized because of symptoms of muscle weakness that the patient may experience before induction of anesthesia.Citation26 It was of higher incidence with higher priming doses more than 10% of ED95 in this study. It can be hypothesized that acute rise in plasma level of neuromuscular blocker after priming probably affected the small sensitive muscles earlier than the relatively resistance diaphragm.Citation27 It can be presented with many symptoms like diplopia, blurring of vision, and difficulty in eye opening (ocular muscle), difficulty in swallowing (glossal muscle), and difficulty in breathing (geniohyoid muscle) in supine position.Citation28,29 Geniohyoid muscle acts as upper airway dilator during inspiration by displacing the hyoid bone anteriorly. Its early paresis will lead to increase in upper airway resistance, especially in supine position and breathing difficulty.Citation29,30 Voluntary hyperventilation and oxygen mask helped in allying any incidence of desaturation and sense of breathing difficulty. Moreover, it has been reported that unpleasant effects of priming dose were short-lasting and rather improved at the peak time of monitored effect of the priming dose at adductor pollicis.Citation31
Agoston et al.Citation32 and Gergis et al.Citation33 had observed that good intubating conditions were present when 40–60% and 70% of twitch inhibition of adductor pollicis muscle was obtained. In this study, 95% or greater twitch height inhibition at intubation time was seen in all patients and provided good to excellent intubation conditions in the majority of patients. This study has demonstrated that using 10% of ED95 was efficient as 20% of ED95 of vecuronium as priming dose for chronic renal failure. The onset time could be significantly reduced to nearly one-third of the control group with no significant difference between the three used priming doses. Kopman and his associates had suggested that with priming technique, when using different muscle relaxants, the priming interval should be at least 6 min to allow the drug to reach its full effect prior to the final intubating dose.Citation34 The reason for this interval is that the time required for a given dose of muscle relaxant to reach its peak effect is independent of its initial dose. In this study, maximum TOF depression after priming, which was assumed to occur simultaneously with maximum receptor occupancy, was observed at the fourth minute in the priming groups. This finding was duplicated well with that reported by Toboada et al.Citation3 and Huemer et al.Citation35 who found that 4 min interval was optimal after different priming interval. On the contrary, Saitoh and his associates reported that 16 min interval was effective than 4 min vecuronium priming time to short the onset by 40 s.Citation30
Depression in swallowing reflex after atracurium and vecuronium priming was demonstrated in one study, but the corresponding T1% and TOF ratio were not measured.Citation28 Impairment of pulmonary function was demonstrated in other studies when using 20% of ED95 vecuronium with reduction in forced expiratory volume in 1 s (FEV1) and forced vital capacity.Citation36,37 Aziz et al.Citation26 observed that after vecuronium priming in elderly patients, pulmonary dysfunction with corresponding TOF ratio was 0.79. Congruently, the symptoms of muscle weakness in this study were higher incidence with the corresponding TOF ratio around 0.79 and 0.85 with the use of 20% and 15% of ED95 of vecuronium as priming dose, respectively. Symptomatic neuromuscular blockade can be present when TOF ratio become lower than 0.90. So the current study attested that vecuronium priming at a dose higher than 10% of ED95 is not recommended as priming dose in chronic renal failure patient.
The most striking pharmacodynamic finding of this study is the prolongation of the duration of action of vecuronium, especially in the priming groups. These results bear little relevance with the reports of Beauvoir and his associates.Citation38 In the current study, the prolonged duration of vecuronium was speculated to be due to delayed elimination of the drug. Changes in serum potassium and calcium were excluded because of their normal basal values. However, increased sensitivity to vecuronium and hypermagnesemia in chronic renal failure were proposed as other explanations.Citation7,8 Serum magnesium estimation was not available at the time of study. So the definite reason for prolonged duration in vecuronium priming groups is still not clear and need to be further investigated.
Priming technique was an attractive principle, because it seemed to fill a real clinical need. From the previous results, it was concluded that the pharmacodynamics of vecuronium in chronic renal failure has several application findings. The used different vecuronium priming doses had comparable shorter onset together with longer duration times than induction without priming. Also this clinical study emphasized that vecuronium priming dose more than 10% of ED95 for more than 4 min did not convey any clinical advantages and may jeopardize the patient’s safety. The interindividual variability in chronic renal failure mandates careful observation and obligates the neuromuscular monitoring during the priming time.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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