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Anesth Analg 2003;96:750-754
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Effect of Vecuronium Is Enhanced by a Large Rather than a Modest Dose of Gentamicin as Compared with No Preoperative Gentamicin

Zohar A. Dotan, MD*, Rene Hana, MD{dagger}, Daniel Simon, MD{dagger}, Daniel Geva, MD{ddagger}, Reuven A. Pfeffermann, MD{dagger}, and Tiberiu Ezri, MD§

*Department of Urology, Sheba Medical Center, Ramat Gan; Departments of {dagger}General Surgery and {ddagger}Anesthesia, Kaplan Medical Center, Rehovot; and §Department of Anesthesia, Wolfson Medical Center, Holon, Israel (Affiliated with *§Sackler School of Medicine, Tel Aviv and {dagger}{ddagger}Hadassah Medical School, Jerusalem, Israel)

Address correspondence to Tiberiu Ezri, MD, Department of Anesthesia, Wolfson Medical Center, Holon 58100, Israel. Address e-mail to tezri{at}netvision.net.il


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We compared the effect of two doses of gentamicin versus no gentamicin (NG) given before surgery on the neuromuscular relaxant effect of vecuronium. Seventy patients (intraabdominal procedures) were randomly allocated to receive preoperative large-dose (4 mg/kg) gentamicin (LD), a modest dose (1.2 mg/kg) of gentamicin (MD), or NG. No more than one dose of gentamicin was given before the vecuronium administration. Serum gentamicin levels, the time for 25% recovery of the first twitch in the train-of-four after a bolus of vecuronium, and the time from cessation of the vecuronium infusion to extubation of the trachea were estimated. Serum gentamicin levels were higher (P < 0.001) for LD than MD. The time for 25% recovery of the first twitch after the vecuronium bolus was slightly longer with LD than MD (P = 0.06) and longer in LD than NG (P = 0.001) (42.9 ± 23.6 min versus 36.2 ± 17 min and 27.4 ± 9 min, respectively). The time to extubation was similar with LD and MD and longer for LD than NG (P = 0.008) (34.7 ± 19.2 min versus 27.4 ± 19.3 min and 19.4 ± 10.1 min, respectively). The differences in these times were insignificant between MD and NG. Gentamicin administered as a LD rather than MD enhanced the neuromuscular blockade of vecuronium as compared with NG given before surgery.

IMPLICATIONS: We demonstrated that the neuromuscular relaxant effect of vecuronium is enhanced by a large (4 mg/kg) rather than a modest (1.2 mg/kg) dose of gentamicin as compared with no gentamicin given before surgery.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Aminoglycosides are often used for infection prophylaxis in surgical patients owing to their bactericidal effects and broad activity against Enterobacteriaceae (1). Their major limitations are adverse reactions such as nephrotoxicity, oto-vestibular toxicity, neurotoxicity, and drug interactions (1,2). The total daily dose of aminoglycosides is routinely administered in two to three equally divided aliquots in patients with normal renal function. However, a single daily dose proved to be at least as effective, with reduced nephrotoxicity (2,3). Numerous randomized trials have compared the single versus multiple daily doses of aminoglycosides in terms of treatment efficacy (3–7). The paralyzing effect of nondepolarizing muscle relaxants is prolonged by the aminoglycosides. This is caused by inhibition of calcium influx to the motor nerve terminals, which decreases the amount of acetylcholine released into the neuromuscular synapse (8). Traditionally, IV prophylaxis with gentamicin during colorectal surgery is given either as a single modest dose (MD; 80 mg or approximately 1.2 mg/kg in adults) before surgery (9) or in three doses (10) of 80 mg each, administered every 8 h during the day of surgery, with the first dose given before surgery. The administration of a single, daily large dose (LD; 4–4.5 mg/kg) of gentamicin given before surgery for antibiotic prophylaxis in colorectal surgery has also been reported (11).

The effect of a LD of aminoglycoside administered before surgery on the degree of neuromuscular blockade produced by neuromuscular relaxants has not been investigated.

The aim of our study was to investigate the effect of different doses of gentamicin treatment (a LD versus a MD) as compared with no gentamicin (NG) given before surgery on the degree of neuromuscular blockade produced by vecuronium (V).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Our IRB approved the study, and informed consent was obtained from each patient. In a prospective, randomized, double-blinded study, 90 patients undergoing elective abdominal surgery were equally allocated to the following three treatment groups: Group 1, scheduled for colorectal surgery and treated with a single, daily LD (4 mg/kg) of gentamicin before surgery (LD group); Group 2, undergoing colorectal surgery and treated with a single MD (1.2 mg/kg) of gentamicin before surgery (MD group); and Group 3, NG before surgery (NG group) scheduled for noncolorectal intraabdominal surgery (cholecystectomy or gastrectomy), which is also the control group. After randomization, 20 patients were excluded from the study because of omission by mistake of the preoperative antibiotics (two cases), a delay in administration of the preoperative antibiotic (seven cases), patients arriving too late to the hospital on the day of surgery (six cases), patients not NPO for 8 h before surgery (three cases), and patients who subsequently refused to take part in the study (two cases). The final participation consisted of 28 patients in the LD group, 20 patients in the MD group, and 22 patients in the NG group. Excluded from the study were patients with known allergies to aminoglycosides, a serum creatinine >=2 mg/dL, pregnant patients, those younger than 18 yr of age, patients with clinical hearing loss or vestibular disease, those treated with calcium channel blockers, magnesium, or steroids, and patients suffering from neuromuscular disease.

Patients undergoing colorectal surgery received IV gentamicin, ampicillin (500 mg tid), and metronidazole (500 mg tid). Patients for noncolorectal abdominal surgery were treated with a single dose of IV cefonicid (1000 mg). The gentamicin dose was randomly selected before surgery either as a LD or a MD. Patients in the LD group received their full daily dose of gentamicin as a single preoperative dose, whereas in the MD group, the daily dose was divided into 3 equal doses of 60–80 mg (depending on the patient’s weight), and the drug was given every 8 h. Only the first dose was given before surgery, and the study was completed before the second dose was due. The antibiotic treatment was administered approximately 60 min before the induction of anesthesia. The anesthesiologist was blinded as to the type of antibiotic regimen administered before surgery. The total gentamicin dose was adapted to the preoperative creatinine clearance and calculated with the Cockroft and Gault equation (12). Blood was sampled for serum levels of gentamicin at the induction of anesthesia and after stopping the infusion of V. The antibiotic treatment was continued for at least 24 h after surgery.

Anesthesia was induced in a rapid sequence manner because of the concern of possible delay in bowel emptying in the patients suffering from intestinal tumors. Thiopental (3 mg/kg), fentanyl (1 µg/kg), and succinylcholine (1 mg/kg) were administered, followed by repeat doses of fentanyl, isoflurane 0.5–1 minimal alveolar anesthetic concentration, and a mixture of N2O in O2 (60%:40%). Usual monitoring was used. The degree of neuromuscular blockade was assessed at the ulnar nerve with the accelerographic method (TOF-Guard Acceleromyograph, Organon Teknika BV, Boxtel, The Netherlands). Skin temperatures at the nerve stimulation site were recorded every 10 min. The patient’s core temperature was controlled with fluid warmers and a Bair-Hugger (Augustine Medical, Eden Prairie, MN) air warmer device. After administration of thiopental, the nerve stimulator was switched on to maximal current output to ensure that a supramaximal stimulus was applied. Train-of-four (TOF) stimulations were applied every 60 s.

After succinylcholine, time was allowed for the first twitch response to fully recover and settle at 100%. Then, with the first twitch established as control, a bolus dose of V (0.1 mg/kg) was administered, followed by a continuous infusion (0.5–2 µg · kg-1 · min-1). The continuous infusion of V was started with 25% recovery of the first twitch response in the TOF stimulation after the bolus dose of V. Throughout surgery, the infusion rate of V was aimed at maintaining a <25% height of the first twitch response in the TOF. The V infusion was stopped at the beginning of closure of the abdominal fascia. Reversal of muscle relaxation was performed with neostigmine (50 µg/kg) if at least 2 twitches in the TOF stimulation had recovered. The isoflurane was discontinued 5 min before the administration of neostigmine. The patient’s trachea was extubated with a TOF ratio >=0.8 if the patient was awake and able to lift their head and push their tongue forward for at least 5 s. The trachea was extubated on the operating table. Each patient remained on the operating table for up to 20 min after the end of surgery so the trachea could be extubated before transporting the patient to the recovery room. Those patients who did not meet the extubation criteria during this period, those with hypothermia <35°C, and those with central respiratory depression were transported intubated and ventilated to the recovery room. The following variables were assessed: serum levels of gentamicin at the time of the induction of anesthesia and at cessation of V infusion, the time taken to the disappearance of the twitch response after succinylcholine (T1), time to first evidence of the first twitch return after succinylcholine (T2), the time required for 25% recovery of the first twitch response in the TOF stimulation after the bolus dose of V (T3), and the time from cessation of the V infusion to extubation of the trachea (T4). The time from the administration of V to achieving a TOF ratio >=80 was also recorded, along with the total dose of V infused (µg · kg-1 · min-1), whether extubation of the trachea was not performed on the operating table because of residual muscle relaxation, the need for reintubation in the recovery room, and core temperatures at the end of surgery.

Randomization was performed with the closed-envelope method. For comparison of ordinal variables among the three groups, we used the {chi}2 analysis. For the continuous variables, we used the t-test and the one-way analysis of variance method for comparison of two or three groups, respectively. Variability is expressed as mean ± SD for quantitative data. Posttests were applied as required. A P <= 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
There were no differences among the groups with regard to sex, age, weight, duration of surgery (128 ± 44 min for LD, 136 ± 38 min for MD, and 116 ± 28 min for NG), the ASA risk score, and skin temperatures at the neuromuscular blockade monitoring site. Mean age was 67 ± 8 and 66 ± 16 yr old for LD and MD groups, respectively. Mean age of the NG group was 53 ± 16 yr old (P < 0.005).

The mean serum gentamicin levels (Table 1) were significantly higher for the LD group (P < 0.001) as compared with the MD group, both during the induction of anesthesia and at the end of surgery. Upon the cessation of V infusion, the mean serum levels of gentamicin were less than the recommended therapeutic levels (2–10 ng/mL) in the MD group. Gentamicin treatment was stopped 24 h after surgery in 15 (53%) LD patients and in 12 (60%) MD patients (P = 0.83).


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  		Table 1. Serum Levels of Gentamicin
 
There were no statistically significant differences among groups with regard to T1 and T2 (Table 2). The time allowed for the first twitch response to fully recover and settle at 100% to establish the control first twitch before the administration of the V bolus was similar among the three groups (9.2 ± 1.2 min in LD, 9 ± 1.6 min in MD, and 8.9 ± 1.8 min in NG). The time required for 25% recovery of the first twitch response in the TOF stimulation after the bolus of V (T3) was slightly longer in the LD group than MD group (P = 0.06) and longer in LD as compared with the NG group (P = 0.001). The difference in T3 was not significant between the MD group and the NG group (P = 0.1). The time to extubation (T4) was similar in the LD and MD (P = 0.12) groups and longer in LD group versus the NG group (P = 0.008). No difference was found between the MD group and the NG group (P = 0.26). The duration of V-induced blockade was similar in all age groups. The LD patients required less V than the MD and NG patients (Table 2; P = 0.05). Four patients in the LD group and three in the MD group were not tracheally extubated before the transfer to the recovery room because of residual muscle relaxation (P = 0.77). In these cases, the muscle relaxation was not reversed because only one single twitch was present in the TOF. All were subsequently reversed and extubated within 30 min after arrival in the recovery room. None of the patients in the NG group remained intubated after surgery because of prolonged muscle relaxation. The times between neostigmine administration to attaining a TOF ratio of >=0.8 were 3 ± 0.5 min in MD, 2.5 ± 0.8 min in LD, and 2.1 ± 0.6 min in NG (no significant difference).


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  		Table 2. Times of Action of the Muscle Relaxants and the Mean Total Dose of Vecuronium Infused
 
None of the patients had a core temperature less than 35°C. Among the groups, the differences in core temperature at the end of surgery were insignificant.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The advantages of an administration of aminoglycosides as single rather than multiple divided doses include increased efficacy and lower cost of treatment along with better control of drug preparation and administration (1,2) and increased mean peak serum concentrations (5,6). Also, the single, LD administration is associated with a decreased risk of nephrotoxicity (2,4,6,8,9). Aminoglycosides enhance the neuromuscular relaxants’ activity by decreasing the availability of calcium at the presynaptic membrane and, thus, by reducing the amount of acetylcholine released into the synaptic cleft (13,14). Another, presumably postsynaptic mechanism may be a diminished sensitivity of the postsynaptic membrane to acetylcholine (15).

We investigated the effect of a single, LD daily versus a MD of gentamicin given before surgery or NG at all on the neuromuscular function of patients undergoing elective intraabdominal surgery. We found that the rate of extubation of the trachea at the end of surgery and reintubation in the recovery room were similar in the two gentamicin groups. All the patients were tracheally extubated at the end of surgery in the NG group. Patients in the NG group were significantly younger. The difference in age between the gentamicin groups and NG group may seem confounding. Nevertheless, Rupp et al. (16) have shown that in healthy 70- to 84-year-old patients, the pharmacokinetics and pharmacodynamics of V were similar to that of their younger counterparts. Furthermore, with normal renal function, a single daily dose of gentamicin (17) elicited similar pharmacokinetics and toxicity in both young and elderly patients. Therefore, we believe that age difference did not invalidate the comparisons of control with the gentamicin groups. A significant difference was noted between the LD (but not MD) and NG groups in the readiness for extubation of the trachea after cessation of the continuous vecuronium infusion. The LD patients required less vecuronium than MD and NG and a longer time than NG to meet extubation criteria. We could not demonstrate any significant effect of the LD gentamicin regimen on the depolarizing blockade produced by succinylcholine.

Similar to reported data (5,6), the serum levels of gentamicin at the beginning and at the end of surgery were significantly increased in the LD versus MD group. The higher serum levels of gentamicin in the LD group (as opposite to MD) may explain the potentiation of V in that group of patients as compared with the control patients. Several authors reported a prolongation of neuromuscular blockade produced by the muscle relaxants [among them V (18)] after the administration of aminoglycosides either IV, orally, intraperitoneally, or after wound irrigation (19,20). In an animal study (21), the effect of aminoglycosides on neuromuscular blockade was marginal, whereas another report revealed a significant delay in the recovery after atracurium, when the animals were pretreated with gentamicin (22).

The duration of clinical activity of V was significantly prolonged by the previous administration of aminoglycosides in both healthy patients (23) and in renal transplant patients (24). However, in all the above studies, gentamicin was administered in three daily MDs. Interestingly, as opposed to these data, the standard MDs used in our patients did not prolong the effect of V. This might be explained by the low level of serum gentamicin that was measured in this group of patients.

The LD of gentamicin significantly prolonged the effect of V as compared with the patients who did not receive preoperative gentamicin. No study has investigated the effect of a single, daily LD of gentamicin administered before surgery on the neuromuscular blocking effect of V or other nondepolarizing muscle relaxants. A clinical study of intensive care unit patients who were not receiving muscle relaxants has failed to demonstrate significant clinical differences with regard to the neuromuscular blocking effect of a single dose versus the tid dosing of aminoglycosides (25). This trial was performed on a small group of patients, and the depth of neuromuscular blockade was assessed by measurements of maximal negative inspiratory pressures rather than using more sensitive monitoring.

We conclude that gentamicin administered as a LD rather than a single MD enhanced the neuromuscular blockade produced by V as compared with NG given before surgery.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Begg EJ, Barclay ML. Aminoglycosides: 50 years on. Br J Clin Pharmacol 1995; 39: 597–603.[Web of Science][Medline]
  2. Prins JM, Buller HR, Kuijper EJ, et al. Once versus thrice daily gentamicin in patients with serious infections. Lancet 1993; 341: 335–9.[Web of Science][Medline]
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  5. Thureen PJ, Reiter PD, Gresores A, et al. Once versus twice daily gentamicin dosing in neonates >=34 weeks’ gestation: cost-effectiveness analyses. Pediatrics 1999; 103: 594–8.[Abstract/Free Full Text]
  6. Maller R, Ahrne H, Eilard T, et al. Efficacy and safety of amikacin in systemic infections when given as a single daily dose or in two divided doses. J Antimicrob Chemother 1991; 27: 121–8.
  7. Gilbert DN, Lee BL, Dworkin RJ, et al. A randomized comparison of the safety and efficacy of once-daily gentamicin or thrice-daily gentamicin in combination with ticarcillin clavulanate. Am J Med 1998; 105: 182–91.[Web of Science][Medline]
  8. Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996; 312: 338–45.[Abstract/Free Full Text]
  9. Jewesson P, Chow A, Wai A, et al. A double-blind, randomized study of three antimicrobial regimens in the prevention of infections after elective colorectal surgery. Diagn Microbiol Infect Dis 1997; 29: 155–65.[Web of Science][Medline]
  10. Rodolico G, Puleo S, Blandino G, et al. Colorectal surgery: short-term prophylaxis with clindamycin plus aztreonam or gentamicin. Rev Infect Dis 1991; 13: S612–5.
  11. Zelenitsky SA, Silverman RE, Duckworth H, Harding GK. A prospective, randomized, double-blind study of single high dose versus multiple standard dose gentamicin both in combination with metronidazole for colorectal surgical prophylaxis. J Hosp Infect 2000; 46: 135–40.[Web of Science][Medline]
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  16. Rupp SM, Castagnoli KP, Fisher DM, Miller RD. Pancuronium and vecuronium pharmacokinetics and pharmacodynamics in younger and elderly adults. Anesthesiology 1987; 67: 45–9.[Web of Science][Medline]
  17. Nicolau DP, Freeman CD, Belliveau PP, et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995; 39: 650–5.[Abstract]
  18. Kronenfeld MA, Thomas SJ, Turndorf H. Recurrence of neuromuscular blockade after reversal of vecuronium in a patient receiving polymyxin/amikacin sternal irrigation. Anesthesiology 1986; 65: 93–4.[Web of Science][Medline]
  19. Gilbert TB, Jacobs SC, Quaddoura AA. Deafness and prolonged neuromuscular blockade following single-dose peritoneal neomycin irrigation. Can J Anaesth 1998; 45: 568–70.[Web of Science][Medline]
  20. Jedeikin R, Dolgunski E, Kaplan R, Hoffman S. Prolongation of neuromuscular blocking effect of vecuronium by antibiotics. Anaesthesia 1987; 42: 858–60.[Web of Science][Medline]
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  25. Wong J, Brown G. Does once daily dosing of aminoglycosides affect neuromuscular function? J Clin Pharm Ther 1996; 21: 407–11.[Web of Science][Medline]
Accepted for publication November 19, 2002.





This Article
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Right arrow Articles by Dotan, Z. A.
Right arrow Articles by Ezri, T.
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Right arrow Pharmacology

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press