Cardiovascular Effects of Nondepolarizing Relaxants Employed for Pretreatment Prior Bruce P

Home , Gallamine triethiodide, Metocurine

Cardiovascular effects of nondepolarizing relaxants employed for pretreatment prior Bruce P. Kingsley Me, M. Sue Vaughan, vHt), Robert W~ Vaughan MD to succinylcholine

A pregnant woman with severe pre-eclampsia experi- Subparalyzing, pretreatment doses of nondepolar- enced a hypertensive crisis following a pretreatment dose izing muscle relaxants are widely employed in the (20 rag) of gallamine. That episode initiated a study to induction period to limit the adverse effects of determine the cardiovascular effects of non-depolarizing succinylcholine. These modest doses of nonde- muscle relaxants in 58 nonobese, ASA physical status polarizing muscle relaxants can limit changes in I and I1 adults. Subjects were assigned randomly to intragastric ~'z and intraocular pressures, 3 serum one of five treatment groups as follows: gallamine potassium, 4 creatine kinase, 5 the incidence of (0.29 mg-kg J), d-tuboeurarine (0~04 mg-kg t ), meto- postoperative myalgias,6 and the bradycardia asso- curine (0.014 mg.kg-J ), pancuronium (0.007 mg'kg-t ), ciated with a repeat dose of succinylcholine. 7'8 or normal saline (control). Baseline measurements of Although controversial and recently challenged, 9 systolic, diastolic, mean arterial pressure, heart rate "pretreatment" has become an accepted part of the (HR) and rate pressure product (calculated RPP) were rapid induction-intubation sequence for general recorded at one-minute intervals while electrocardio- anaesthesia, particularly for the patient with a full gram, lead H, was recorded continuously. Statistically stomach, ao significant increases occurred in HR at minutes 2, 3 and 4; RPP at minutes 3 and4; and per cent change in HR at Case Summary minutes 2, 3 and 4 foUowing gallamine pretreatment. The A 38-year-old primagravida at 30 weeks' gestation rise in RPP was predominately due to the elevation in required emergency Cesarean section for severe HR. These results suggest that even modest doses of pre-eclampsia complicated by progressive reduc- gallamine should be avoided in clinical situations where tion in platelet count. There was no history of lability el cardiovascular dynamics can be anticipated. previous anaesthetics, major illnesses, or adverse reactions to medications. The patient had been Key words taking alpha-methyl dopa and hydrochlorthiazide NEUROMUSCULAR BLOCKING DRUGS: d-tubo- for blood pressure control. Physical examination curarine, gallamine, metocurine, pancuronium, revealed: weight, 66kg; blood pressure, 220/110 suecinylcholine. ton'; pulse, 84 beats/minute; temperature, 37.0 ~ C orally; respiration, 16 per minute. The upper airway and the cardiopulmonary system were judged normal. Pitting edema (2+/4+) of the lower extremi- From the Department of Anesthesiology, Arizona ties and sustained ankle clonus were demonstrated. Health Sciences Center, Tucson, Arizona. Laboratory results were: haemoglobin 15.6 gm/dl, Address correspondence to: R.W. Vaughan ~, serum potassium 4.1 mEqtL, blood urea nitrogen Department of Anesthesiology, University of North 28 mg/dl, serum creatinine 1.3 mg/dl, and a normal Carolina School of Medicine, Chapel Hill, N.C. 27514. coagulation profile with the single exception of a

CAN ANAESTH SOC J 1984 / 31: I / pp13-19 14 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL

platelet count of 17,000/mm 3. No urine was obtain- ment doses have been presumed to be innocuous. able for analysis. However, their effects have not been examined The patient was placed in a quiet room with within a controlled experimental (control group, subdued lighting. Using local anaesthesia, a periph- randomization, double blinded) design. The impor- eral intravenous cannula was inserted, a loading tance of considering the cardiovascular effects of dose of magnesium sulfate (4 Gm) administered and these small doses was the subject of a recent a continuous infusion initiated. Using local anaes- editorial. ]2 To evaluate this question we performed thesia, a teflon 20 gauge 1J''e cannula was inserted a prospective, randomized, blinded clinical trial. into the left radial artery at the wrist and attached to a pressure transducer. Using the same technique, a Methods central venous cannula was inserted via the left Following protocol approval by the institutional anteeubital vein. Initial readings were a blood Human Subjects Committee, vebal and written pressure of220/110 tort and central venous pressure consent was obtained from 58 subjects on the (CVP) of -5 tort. Rapid hydration was begun until evening prior to operation, ASA physical status 1 the CVP approached normal levels. The patient was and I1 patients scheduled for elective surgical taken to the operating room where her blood procedures udder genera] anaesthesia were chosen pressure was controlled (160/80 ton-) with sodium for study. Subjects excluded from the clinical trial nitroprusside (1 Izg-kg-t.min-I). Subsequently were those who were obese (body mass index > anaesthetic induction was begun. After the patient 30kg/m2), ~3 allergic to iodine or bromide, or received oxygen by mask for five minutes, galla- receiving adrenergic blocking drugs. All patients mine (20rag) was given into the peripheral intra- were fasted after midnight and no patient received venous infusion. The pulse rate immediately in- overnight intravenous hydration. Both preoperative creased from 90 to 130 and the blood pressure medications and preoxygenation were withheld. increased from 160/95 to 230/115. This hyper- Patients were assigned, using a table of random tensive response was unchanged by increasing numbers, to one of five pretreatment groups as the nitroprusside infusion to approximately 4 ~,g. follows: gaUamine (0.29 mg'kg-~), d-tubocurarine kg-Lmin -l. Anaesthetic induction proceeded with (0.04 mg.kg- 1), metocurine (0.014 mg.kg- l), pan- sodium thiopentone (200 mg) while skeletal muscle curonium (0.007 mg'kg-l), or normal saline (con- relaxation was acomplished with succinylcholine trol). The total volume of the pretreatment agent (100rag). When the lash reflex was lost following was adjusted to one ml prior to injection. thiopental, cricoid pressure was applied and the Upon arrival in the operating room holding area, larynx was intubated with a cuffed endotracheal an intravenous cannula was placed and the patient tube. Following induction and intubation, the blood transported to the operating suite where blood pressure decreased to 200/90. Six minutes after pressure (BP), electrocardiogram (EKG), and chest induction of anaesthesia a viable infant was de- stethoscope monitors were applied. An automated livered, the placenta manually removed, and the oscillometric technique (Sentry) was employed to nitroprusside infusmn discontinued. The BP slowly measure systolic (SBP), diastolic (DBP), and heart decreased to 100/60. The remainder of the case was rate (HR) as well as calculate mean arterial pressure uneventful. The mother and child were followed for (MAP). Subsequent calculations included rate pres- 48 hours and no sequelae were observed. sure product (HR times SBP) and per cent change from baseline of HR and RPP. Lead I1 of the EKG Comment was recorded continuously. Tile cardiovascular and autonomic side effects of All cardiovascular measurements were recorded paralyzing doses of nondepolarizing neuromuscular by a knowledgeable, blinded clinical investigator blockers have been extensively examined. For (MSV). The same anaesthesiologist (RWV) admin- example, in anaesthetized patients, paralyzing istered all pretreatment drugs and induction agents. doses of gaUamine result in increases in heart rate The other investigator (BPK), blinded to patient and cardiac output secondary to the muscarinic variables and assigned pretreatment group, evalu- blocking, chronotropic actions of the drug. lj The ated all EKG recordings for presence and tinting of cardiovascular effects of these drugs in pretreat- dysrhythmias. Kingsley et al.: CARDIOVASCULAR EFFECTS OF PRETREATMENT RELAXANTS 15

TABLE I Descriptivecharacteristics of the sample by treatmentgroup" (mean • SE)

Gallarninef DTC MTC PCB NS

Number of patients 10 l 3 12 12 11 Age (yrs) 39+5 32---3 41 ---5 38-+'4 ,15• Weight (kg) 71• 59---3 63• 69---3 68---5 Height (cm) ]67--.5 162-+2 165• 168--.2 166+3

*p > 0.05 among groups. "tAbbreviatioes: DTC = d-tubocurarine, MTC = metocurine, PCB = pancuronium, NS = normal ~aline.

laryngoscopy. Measurement of cardiovascular vari- Blood Pressure ables at minute six concluded the study. Gallamine Results were analyzed using a one-way analysis 170- DTC MTC of variance and the TukeyrB multiple range test for 1604 PCB o 1504 ~---o Oonlrol ,,'" interpretation of differences among groups. In 3-- addition, Chi-square analysis was used to test differences among groups for incidence of dysrhyth- 120- mias. Statistical significance was set at p --< 0.05. 110- I00- Results o 90- Fifty-eight adult subjects, 12 males and 46 females,

...... were studied. Descriptive characteristics for the 70- total sample included (mean --- SE (range)): age, 39 - 2 years (19-84); weight, 66 +-- 2kg (41-127);

0 1 2 3 4 $ 6 and height, 165 --- 1.3 cm (147 201). There was no difference among the pretreatment groups with respect to age, weight, height (Table I), medication Time (minutes) history, allergies, or smoking history. Of the 35 patients requiring intubation, eight were intubated FIGURE I Systolic and diastolie blood pressurein pretreat- just prior to minute six and 27 were intubated after ment groups and control. No significantdifference occurred among groups at any time interval (p > 0.05). the study concluded. No significant difference occurred among the treatment groups with respect to those intubatcd between minutes five and six. Medication history revealed that 51 subjects re- Once baseline measurements of cardiovascular ceived no medication while seven were inter- variables (SBP, DBP, MAP, HR, continuous EKG mittently taking sedatives (3), diuretics (2), or recording) were completed, pretreatment drag or chemotherapeutic drugs (2). No significant differ- control (normal saline) was administered. Cardio- ences among groups in baseline cardiovascular vascular measurements were recorded at one min- variables were present. In addition, neither SBP nor ute intervals for six minutes. At 3.5 minutes after DBP differed significantly among groups at any pretreatment, induction commenced with sodium time interval (Figure 1). In contrast, the group given thinpentone (4mg.kg 1) and succinylcholine (1.5 gallamine pretreatment developed a significant in- mg.kg i) injected intravenously over a 20- to crease in HR at minutes two, three, and four (Figure 30-second interval. At minute five, ventilation was 2). Subsequent mask ventilation during light nitrous controlled by mask with 100 per cent oxygen. oxide-barbiturate anaesthesia resulted in persistent Following oxygenation, patients requiting an endo- increases in HR during the study period. In addi- tracheal tube were intubated while airway manage- tion, calculated RPP also was significantly elevated ment for other patients was by mask without in the gallamine group when compared with the 16 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL

Heart Rate Rate-Pressure Product (RPP) 18.000. ~. !!/c~mlne ,;, ,-'/,1~ ,'.--.--aGallamine 17.000 OTC .~ PCBMTC I c-.- "::Control 5.1 16.000 *p< 0.05Among Groups E • o 15,000 3- E "~ 1r

~ ~3,0g~ 80" .2y 12.008-

$l.gO0 70- 1O,0CO- 0

9QgO- N 0 ( Time (minules)

FIGURE 2 Heart rate (mean -+ SE) in pretreatmentgroups lime tminute~) and control. A significantincrease in rate occurredin the gal]amine group at minutestwo, thsec, and four (p < 0.05). FIGURE 3 Ratep[ezsum product (mean -+ SE) in pretreatmentgroups and control. A significantelevation occurred in the gallaminegroup at minutesthree and four (p < 0.05). other groups at minutes three and four following pretreatment nondepolarizer (Figure 3). When change in HR following pretreatment drugs was Discussion calculated as percent of baseline, patients receiving Undesirable tachycardia and arterial hypertension gallamine demonstrated a maximum change of 20 can occur in the operative patient following neuro- per cent that was significantly greater than all other muscular paralyzing doses of nondepolarizing groups at minutes two, three and four (Figure 4,). skeletal muscle relaxants. J4,15 Animal studies sug- Other treatment groups were not significantly dif- gest that the effects of tachycardia after administra- ferent from each other with respect to SBP, DBP, tion of gallamine result in part from release of MAP, RPP or HR. norepinephrine from cardiac adrenergic postgang- Dysrhythmias, after succinylcholine but prior to lionic nerve endings.16 Although other investiga- intubation, occurred in seven of 58 subjects (12. l tors conclude that heart rate and arterial pressure per cent: (Table II)). Rhythm disturbances were changes in cats given 1.2 mg'kg- 1 and 1.5 mg.kg- characterized as nodal (n = 1), premature atrial doses of gallamine are minimal, neuromuscular contractions greater than five per minute (n = 4), blocking agents which cause vagal blockade do not premature ventdcular contractions greater than five produce such a marked degree of tachycardin in per minute (n = 2), and atrial bigeminy (n = 1). cats, dogs, and monkeys as they do in man. It One patient experienced both premature atrial and appears that normal vagal tone is less in these ventricular contractions. Five subjects experienced animal species, t7 Descriptive studies in man further dysrhythmias prior to laryngoscopy, one after, and suggest partial blockade of muscarinic receptors in one dysrhythmia occurred at minute six in a vagally innervated cardiac muscle.iI As tachycar- nonintubated subject. There was significant differ- dia develops, cardiac output and blood pressure ence in EKG changes between patient groups. increase concomitant with mild decrease in sys- temic peripheral vascular resistance (SVR). ts Hy- Kinssley eta1.: CARDIOVA$CUL/kR EFFECTS OF PRETREATMENT RELAXANTS 17

TABLEII Dysrhythrnias- 7/58 = 12.5%(Type: Nodal = 1, PACs = 4, PVCs = 2)

Groups

GaUamlne DTC* MTC PCB NS

Cardiac rhythm'~ Abnormal 1:~ 3 0 0 3 Normal 9 10 12 12 8

*Abbreviations: DTC = d-tubocurarine, MTC = metocurine, PCB = pancuronium, NS - normal saline. l"p > 0.05 among groups. :~Number of dysrhythmias.

penension following gallamine relaxation may be related to increased endogenous cardiac stores of norepinephrine or failure of the moderating de- He~lrt Rate Gallamine crease in SVR. 40 : ~ DTC Several studies have described tachycardia in MTC / FCB operative patients after gallamine dosages of 0.5- c- - - <3 Conlrol p~ 0.05 AI~U[Ig Grou@s 1.0 mg.kg I and 0.3 mg-kg I ts.ls However, study T -"S.E. design limitations do not allow cause-effect deter- minations. For example, Viby-Mogensen et al. in a ' comparative study in adults described the effect of a ~EC second dose of suxamethonium after preinduction (three minutes before induction) administration Em ~E of atropine, gallamine or an intravenous com- bination. 18 All patients in the four treatment groups received ?remedication with diazepam (0.1 mg'kg -I) one hour before induction. A control 10 group (i.e., no treatment) was absent. A cause (gallamine) - effect (tachycardia) relationship could not be established. Factors further limiting interpretation of results included potential interac- tion of preanaesthetic medications with muscle relaxants, unblinded observations, and potential confounding variables (i.e., patient anxiety, face mask preoxygenation, manipulation of upper air- Time (minutes) way). Diazepam serves to illustrate the latter problem with confounding variables and the neces- FIGURE 4 Per cent change in heart rate (mean - SE) in sity to control each. For example, it is well accepted prctreatment groups and control. A significantly greater per that diazepam absorption following an intramuscu- cent change occurred in the gallamine group a~ minutes two, lar dose is dependent on site of injection, the thn~c, and four (p < 0.05). patient's body habitus, per cent body fat, and keneties of drugs distribution. Uniform absorption, distribution, and biotransformation cannot be as- don were eliminated to avoid confounding the sumed. Our study design was experimental and recorded cardiovascular effects after pretreatmcnt prospective in nature utilizing random assignment drug administration. Further, treatment groups with a random numbers table. Extraneous variables were compared to control (normal saline) while such as preoperative medication and preoxygena- employing double blinded observers strengthened 18 CANAD1AN ANAESTHETISTS' SOCIETY JOURNAL the research design. A cause-effect relationship can choline following trauma. JAMA 1969; 210: 490-3. now be concluded and clinical care altered. 5 Tammisto T, Leikkonen P, Airaksinen M. The Dysrhythmias (Table II) were evident in a certma inhibitory effect of d-tubecurarine on the increase of per cent of study patients, EKG changes occurred serum creatine-kinase activity produced by inter- after pretreatment and succinylcholine administra- mittent sur,amethonium administration during halo- tion but before laryngoscopy and intubation. No thane anaesthesia. Acta Anesthesiol Stand 1967; I 1: patient experienced serious or continuous nodal 333-40. changes, premature atrial contractions, or prema- 6 Lamoreaux LF, Urback KF. Incidence and preven- atre ventrieular contractions requiring therapy. tion of muscle pain following the administration No significant increase in systolic or diastolic of succinylcholine. Anesthesiology 1960; 21: blood pressures occurred among study groups. This 394-6. contrasts with the hypertensive crisis experienced 7 Stoelting RK, Peterson C Adverse effects of in- by our case study patient. However, that patient creased sueeinylcholine dose following d-tubo- manifested pre-eclampsia with apparent constricted curarine pretreatment. Anesth Analg 1975; 54: blood volume and concomitant labile cardiovas- 282-8. cular dynamics. Patients in the research groups 8 Stoe#ing RK, Peterson C. Heart-rate slowing and were not p~e-ectamptic hypertensives, and met the junctional rhythm foUowing intravenous succinyl- criteria for ASA I or II classification. choline with and without intramuscular atropine Finally, significant changes occurring after min- preanesthetic medication. Anesth Analg 1975; 54: ute 3.5 in our study are undoubtedly due to 705-9. interactive effects of sodium thiopentone and 9 Brodsky JB. Why routinely pretreat? Anesthesiol- :suecinytcholine. The effects of nondepolarizing ogy 1982; 56: 488-9. relaxants would likely be masked at minute four by 10 Giesecke AH. Anesthesia. New York: Churchill sUch confounding, interactive effects. In conclu- Livingstone, 1981. sion, oer controlled, clinical trial demonstrated a 11 Eisele JH. Marta JA, Hamilton SD. Quantitative statistically significant increase in heart rate and aspects of the chronotropic and neuromu~ular RPP following even a small pretreatment dose effects of gallamine in anesthetized man. Anes- (0.29mg-kg ') of gallamine when contrasted to thesiology 1971 ; 35: 630-3. other nondepolarizing relaxants and control. The 12 Modell 2H. Survey of Anesthesiology 1982; 26: cardiovascular effects of gallamine appear to occur 262. even in these minimal doses, suggesting that the 13 Bray GA, Jordan HA. Sims EAH. Evaluation of drag is unsuitable for use in patients with an the obese patient. 1. An algorithm. JAIvIA 1971 ; increased or fix,ed SVR, such as an individual with 235: 1487-91. pre-e~hmpsia. 14 Doughty AG. Wylie WD. An assessment of flaxedil (gallamine triethiodide, B.P.). Proc Royal Soc References IVied 1951; 4.4: 375-86. I Mffler RD, Way WL. lnhibitionof succinyleholine- 15 Kennedy BR, Furman JV. Cardiovascular effects induced increased intragastric pressure by nonde- of gallamme triethiodide in man. Br J Anaesth 1968; polarizing muscle relaxants and lidocaine. Anes- 40: 773-9. thesiology 1971; 34: 185-8. 16 Brown BR, CromRJ. The sympathonfimetic effect 2 Muravchick S. Burke# L, Gotd MI. Succinyl- of gallamine on the heart. J Pharmacol Exp Ther choline-indnced facieulations and intragastric 1970; 172: 266-73. pressure during induction of anesthesia. Anes- 17 HughesR, ChappleDJ. Effects of non-depolarizing 'thesiology 1981; 55: 180-3. neuromuscular blocking agents on peripheral 3 Mzller RD, Way WL, Hbdwy RF. Inhibition of autonomic mechanisms in cats. Br J Anaesth 1976; su0c'iayleholine-indueed inla'aocular pressure by non- ~-8: 59-67. depolarizing muscle relaxants. Anesthesiology t8 Viby-Mogensen J, Wisborg K, Sorensen O. Cardiac 1968; 29: 123-6. effects of atropine and gallamine in patients receiv- .4 BirchAA, Mitchell GD, Playford GA, Long CA. ing suxamethionittm. BrJ Anaesth 1980; 52:1137- Cha~ges in serum potassium response to saecinyl- 42. Kingsley etal.: CARDIOVASCULAR EFFECTS OF PRETKEATMENT RELAXANT,~ 19i

R6sum~ Une femme enceinte souffrant de pr~-~ctamps~e s~vire a pr#sent~ une crise hypertensive ~ la suite d'un pr~-traite- ment d la galamine (20 rag). Cet incident est a la source de ce travail qui a ~tudi~ les effets cardio-vasculaires des myo-r~solutifs non d~polarfsants employ~s pour prdvenir les douleurs causdes par la sueeinyleholine. Nous avons ~tudi~ 58 adulres non-obdses; d'dtat physique I et 2 de I' A .S.A . Chaque sujet a (t# assign~ au hasard dun de cinq groupes diffdrents: galarnine 0.29 mg.kg -t, d(tuboc~ ratine 0.04 mg.kg -t, m~thocurine 0.014 mg.kg -1, pan- duronium O.O07mg,kg -Iet sotut~s salins pour une groupe contr$le. Les mesures de contrMe" pressfon systolique, diasto- lique et rnoyenne, la fr~quence cardiaque et produrt fr~quence]pressioa ont #t~ enregistr~s d une minute d' intervalle alors que l' (lectrocardiogramme en ddriva- tion dtait inscrit de Jason continue. Dans le groupe recevant de la galamine, on a observ~ des augmentation~ statistiquement significatives de la fr~quence cardiaque d deax, trois et quatre minutes, du RTP d trois et quatre minutes; de m~me le changement de la frdquence cardiaque demeurait statistiquement significatif lorsqu'ex- prim# en pourcentage de changement a ux minutes deur~ trois et quatre. L' (l~vation du RPT dtait en pattie due d l' augmentation de la frdquence. Ces rdsultats suggdrent que Yon devrait s'abstenir d~ la galamine m~me tJ dose modeste darts les situations cliniques o~ on soup~onne unr inatabilit~ cardio- vasculaire.