that the effective doses required to produce 50, 90 and 95 ... patients constituted the control group. ..... 2 Savege DS, Sleigh T, Carlyle I. The emergence of.
491
D.R. Bevan MB MRCP FFARCS, F. Donati PH D MD, H. Gyasi MB FFARCS, A. Williams Ma FFARCS
Vecuronium in renal failure
route of excretion in animals. ~ In addition, vecuronium undergoes spontaneous deacetylation to hydroxy metabolites 2 which have minimal neuromuscular blocking effects. 3 These alternative mechanisms probably explain why the duration of action of equipotent doses o f vecuronium in normal subjects is only one-third that of pancuronium. 4 Its action should be altered little by renal dysfunction ahhrough the available evidence is scanty. In rats, clamping of the renal arteries did not alter significantly the depth or duration of vecuronium blockade. S In man, renal failure is associated with only small increases in the duration of neuromuscular block and recovery rate 6 as a result of statislically insignificant alterations in the pharmacokinetic behaviour of vecuronium in renal failure. 7 However, these observations are based upon small patient populations and there is no information of the potency, cumulative tendency, or reversibility Key words NEUROMUSCULARRELAXANTS:vecuronium; RENAL of vecuronium in renal failure in man. The present study was designed to compare the FAILURE: anaesthesia. potency, duration of action, cumulative tendency of repeated doses and the reversibility of vecuronium in patients with normal renal function and with All non-depolarizing neuromuscular blocking drugs those in end-stage renal failure. are ionized quaternary ammonium compounds and, because they are water soluble, are excreted in the Methods urine. Consequently, their duration of action is The protocol was approved by the hospital Ethics prolonged in renal failure unless they are metabo- Committee. After informed consent had been oblized rapidly. The degree to which renal impairment tained, 45 adult surgical patients were studied. influences their duration of action depends on the Twenty-one of the patients had normal renal funcpresence of alternative routes of excretion. Vecuro- tion, were ASA physical status class I-i1, were nium is a monoquaternary analogue of pancuro- without known or suspected neuromuscular disnium which has been released recently for clinical ease, and were not taking medication known to use in the United States, Although the kidney is an interfere with neuromuscular transmission. These important site o f clearance, the liver is the major patients constituted the control group. Twenty four patients were in end-stage renal failure undergoing a variety o f surgical procedures; renal transplantation (7), dialysis access (13), transplant nephrectomy From the Departments of Anaesthesia, Royal Victoria (2), parathyroidectomy (1) and laparotomy (1). Hospital & McGill University, Montreal, Quebec. Patients in both groups received premedication Address' correspondence to: Dr. D.R Bevan, with a narcotic and atropine intramuscularly apDepartment of Anaesthesia, Royal Victoria Hospital, proximately 60 rain before surgery. Anaesthesia 687 Pine Avenue West, Montreal, Que., H3A lA1.
Neuromuscular blockade during surgery was provided with vecuronium in 24 adult patients in end-stage renal failure and in 21 normal patients who xert.'ed as contror$ Dose response curves were conslructed which showed that the effective doses required to produce 50, 90 and 95 per cent neuromuscular blockade in patients w#h tonal ]ailure were 27.5, 43 and 491zg'kg t respectively. Tirese were not significantly different from the doses o.[31, 49 and 57 r 1 tn the normal patients. Repeated small doses ofO. 01 tug'k g - I had a signifietmtly longer duration of action and were associated with some cumuhttion in the renal failure group. Recovery from the block occurred rapidly after neostigmine, was no different in re~a? failure and was not associated with recurarization. It is concluded that, when given to sMuects in renal jailure, vecaronium offers advantages over established agents such as shorter duration of action and easy reversibility.
CAN ANAESTH s a c I 1984 / 31:5 / pp491-6
CANADIAN ANAESTHETISTS' SOCIETY JOURNAL
492 was induced with thiopcntonc, 3-5 tug'ks-=, and maintained with nitrous oxide, 50-70 per cent, in oxygen and supplemented with halothane (0.5-1 per cent inspired). The tracheas of all patients were intubated and the lungs ventilated to maintain an end-tidal PCO_~of 32-35 mmHg (Hewlett Packard capnometer). Neuromtlscular transmission was measured, after induction or anaesthesia until the end of surgery, using train-of-four stimulation accor to the method of Aliet al.S The ulnar nerve was stimulated supramaximally at the elbow with subcutaneous needle electrodes. Four square wave impulses of 0.2 ms duration and 2 Hz frequency were administered every 12 seconds using a Grass .q4g stimulator and SIU5 isolation unit. The hand and forearm were immobilized in a splint. The force of contraction of the adductor pollicis muscle was measured with a Grass FTI0 force displacement transducer and the response recorded on a Grass Polygraph pen and ink recorder. The skin temperature over the thumb was monitored and maintained above 320 C. Alter stabilization of muscle twitch had been obtained, vceuronium was injected as a single bolus of one of 11 doses between 10 and 60 ~g'kg -~ . At least two patients received each dose which was chosen by random allocation. Twitch depression was measured after it had reached a stable level and these data points were used to construct a doseresponse curve using Iog-probit paper. 9 Additional doses, 10-20 ~g'kg ~l , of vecuronium were given to produce twitch depression of at least 95 percent. Neuromuscular blockade was maintained during surgery with repeated boluses of l0 btg'kg- t given whenever the force of the first stimulus of the train returned to ten per cent of control. Towards the end of surgery the neuromuscular block was antagonized with atropine, 1.2 ms-70 kg- ~, and neostigmine, 2.5 mg' 70 kg- ~. Monitoring of neuromuscu!at transmission continued until the train of four ratio (T4/TI), defined as the force of contraction of
9
9 NORMAL
~=,tll=,*0,,,,c.RENALFAILURE O OOllo
~ 9 90z
O
uJ r"l
Normal Renal failure
F
21 24
13 12
8 12
o
.Y
9
30
40
60
5030-
i-o
io3
I
m
~
1-
10
20
VECURONIUM (N9/Kgt FIGURE 1 Sillgle dose, veetJroniu~n Io=O-probit doge rcspon,se curves in normal and renal Failure patients. Data points for 0 antl Ilgl lYercent block were excluded floE1 ctmslru~tlon of
regressionlines. the fourth twitch in each train divided by the force of contraction of the first, exceeded 0.7. Then the patients were extubated and returned to the recovery room where neuromuscular activity was assessed by the usual clinical criteria which included adequacy of respiration, hand grip and head lift. Regression lines for dose response curves were constructed by the method of least squares excluding points of O and 100 per cent block. The curves in the normal and renal failure patients were compared graphically as a log-probit plot and analyzed for parallelism and potency. Mean values arc presented with the standard error of the mean as the index
Se.~ M
.g~'
.." ~,#r
70~
TABLE I Demographicdata
n
IIOO~//
99-
Age yrs
Wt kg
Duralio/~ rain
50.6+3.0 45.1 ---3.2
67.1-+2.1 65.5-+3.1
109.0--.17.6 89.3--- 14.9
]~s
TABLE
493
et E//'.: VECURONIUM IN RENAL FAILURE
[1
Normal Renal failure p
TABLE Ill
Lahoratol 3, data
Hb g.dt -~
Net mmol.I -j
K mmol.I -I
Ca mtnol.t - t
BUN mg,dl ' j
Cr mg.dl -~
Albumen g.d[ t
Protein g.dl
t4.1--0.3 8.9-+0.4 < 0.0001
141,0=0.6 136,7+-1.0 < 0.001
4.2-+0.1 4.7 -+ 0.2 < 005
9.4--0.1 9,1 -+0,2 NS
13,4-+1.0 834+7.2 < 0.0001
0.96-+0.04 11.5-+0.9 < 0 0001
4,l = 0.08 3.7--.0.1 < 0.0l
6.9-+0.1 6,4.-+0.[ < 01.15
Pharmaec, dynalnie data
Potency
Daration of O.OI mg.kg -I
T4tT1 n#nutes after neos#gmine
Normal Renal failure
ED .50 (#g kg -t)
El) ~0 (#g-kg I)
ED 95 (#g.kg-l)
Ist dose (rain]
lOth ,'lose (rain)
5
I0
31 27 5
49 43
57 49
7.7---0.8 9.0 -+ 0,8
8.3-'-0.6 13.8 -+ 2,0
0.44 9 0.05 0.54 - 0.03
0.67-+0.04 0.69 -+ 0.03
of dispersion. Probabilities were calculated from Student's t test, and ehi-square analysis and the null hypothesis rejected when p < 0.05. Results There were no significant differences in the sex ratios (X2), ages, weights or severity and duration of surgery between the two groups (Table [). ltowever, there were significant differences in the laboratory data (Table it). In parlicular, haemoglobin concentration was lower and blood urea and serum creatinine concentrations were increased in the renal failure group. The Iog-probit dose response curves for the two groups are shown in Figure 1. The curves were parallel and not sigs different [rom each other. Doses which produced 50, 90 and 95 per cent were obtained by interpolation and are recorded in Table III. The durations of action of"top-up" doses of 0.01 mg'kg - t are shown in Figure 2 and Table 111. In those patients who received more than ten doses of veeuronium there was a progressive, significant increase in the duration of action in the renal failure group of approximately 50 per cent over two hours. This cumulation was not seen in the patients with normal renal function. Mean duration of action of "ton-up" doses was gre.ater in the renal failure group ( 12.0 --- 1.4) than i n the con trol group (7.3 -+ 0.7; p < 0.05) (Figure 2). After antagonism of the block with neostigmine,
recovery occurred rapidly and at a similar rate in both groups (Table lll). All patients were extubated at the end of surgery and no problems with ventilation were seen postoperatively. Discussion Until recently the choice of non-depolarizing neuromuscular blocking drugs to provide muscle relaxation for prolonged operations in patients with renal failure has been limited. Alterations in the pharma-
15-
: ............9 ......
l
LI__I
.~ l o w
z 12, 7-ci B-
o
I
1
I
I
I
I
J
~
I
2 3 4 5 6 7 B NUMBER OF DOSES OF VECURONIUM
I
9
I
10
FIGURE 2 Durations of action of repeated small doses of vecuronium (0.01 mg'kg- ~) in patients receiving ten or mc~re "top-ups." Significant differences between the mean values of the two groups are shown. * = p
