Sandip Sinha1, Manjushree Ray2, Maitreyee Mukherjee3, Sajib Chatterjee4, Avijit Hazra5, Nabanita Das6
1Assistant Professor, 2Professor and Head, 3RMO cum clinical tutor, 5Associate Professor, 6PG student,
Department of Anaesthesiology, Institute of Post Graduate Medical Education and Research (IPGMER), 244, Acharya Jagadish Chandra Bose Road, Kolkata-700020.
4RMO cum clinical tutor, Department of General Surgery, NRSMCH, West Bengal (India)
Correspondence: Dr. Sandip Sinha, 16/D Rishi Bankim Street, P.O. Konnagar, Dist. Hooghly, West Bengal 712235 (India); Phone: 09831865165; e-mail: dr.sandipsinha72@yahoo.in
ABSTRACT
Aims and Objectives: To assess intubating conditions and haemodynamic changes in patients pre-treated with dopamine during rapid tracheal intubation using rocuronium and propofol.
Methodology: Forty adult patients of ASA I and II, aged 20–60 years, scheduled for elective as well as emergency surgery, were included in this prospective randomized open label group double blind study. In Group A patients injection dopamine infusion 3 μg/Kg/min and in Group B patients an equal volume of normal saline was infused over 15 minutes before administering general anesthesia using propofol 2 mg/Kg and rocuronium 0.6 mg/Kg . Laryngoscopy and tracheal intubation was attempted at 60 seconds, whereby anaesthesiologist assessed the intubating conditions.
Duration of laryngoscopy , Train of four ratio (TOF ratio) at 60 sec after rocuronium administration, time from disappearance of all four twitches on TOF count, intubation score at 60 seconds were recorded. Mean arterial pressure, pulse rate and oxygen saturation were recorded at different time points.
Results: Intubating conditions at 60 seconds were significantly better in Group A than in Group B patients. Haemodynamic parameters were not significantly altered in Group A. Time taken for intubation was significantly lower in Group A than in Group B.
Conclusion: Dopamine pretreatment improves intubating conditions after rocuronium injection without significantly altering haemodynamic parameters.
Keywords : Rapid sequence induction; Dopamine pre-treatment; Rocuronium; Propofol
Citations: Sinha S, Ray M, Mukherjee M, Chatterjee S, Hazra A, Das N. The effect of dopamine pre-treatment on intubating conditions and haemodynamics during rapid tracheal intubation using propofol and rocuronium. Anaesth Pain & Intensive Care 2012; 16(2): 152-156
INTRODUCTION
During the rapid sequence induction of general anaesthesia, the use of a muscle relaxant with a rapid onset time is crucial to reduce the risk of hypoxia and aspiration pneumonia. Although succinylcholine is an excellent choice for the purpose, its many potential complications has lead to the search for an alternative. In addition to the development of a new muscle relaxant for rapid tracheal intubation, efforts have been made to reduce the onset time of existing non depolarising muscle relaxant (NDMR).
To reduce the onset time, many studies were focussed on modifying haemodynamic factors such as the cardiac output, the circulation time and the muscle blood flow.1 Researchers have suggested that a NDMR may act more rapidly on the neuro-muscular (NM) junction through increased cardiac output and muscle blood flow, because the agent injected in the vein may reach to the NM junction more rapidly.2.
Rocuronium is the currently preferred non-depolarizing agent used as an alternative to succinylcholine for rapid tracheal intubation.3 Recognizing the problem of prolonged duration of action with larger doses, attempts were made to decrease the dose of rocuronium without compromising on its onset time or intubating conditions.4 Thus the use of ephedrine during the induction of general anesthesia has been described to accelerate the onset of action of rocuronium and improve the intubating condition.5-8 . Dopamine has been shown to exhibit a graded pharmacological response, with a dose-dependent predominant activation of dopaminergic receptors, β-receptors and α-receptors. At doses <3 μg/kg/min, dopamine has been found to activate dopamine A1 receptors, which cause vasodilation of the renal arteries and other vascular beds, including mesenteric, coronary, and cerebral beds. In addition, there is stimulation of dopamine A2 receptors that leads to inhibition of norepinephrine release from sympathetic nerve endings.17 Activation of dopamine A1 and A2 receptors also results in a decline in systemic vascular resistance and an increase in renal blood flow. Dopamine infused at approximately 3 to 5 μg/kg/min activates β1- and β2-adrenergic receptors, conferring a positive inotropic effect that is responsible for the increase in cardiac output. This β-adrenergic receptor induced increase in cardiac output and tissue perfusion results in faster delivery of rocuronium to the neuromuscular junction of the laryngeal and diaphragmatic muscles which might shorten the onset of action of rocuronium and improve the intubating conditions. Also the introduction of rocuronium at the point when the cardiac output was increased by dopamine effectively reduced the onset time. In this study we have administered dopamine 15 minutes prior to induction of anesthesia and assessed the intubating condition one minute after administration of rocuronium bromide.
We conducted this study to find out the effect of dopamine infusion on intubating condition at 60 seconds following administration of rocuronium bromide (0.6 mg/kg) and the haemodynamic changes associated with induction of anesthesia and endotracheal intubation.
METHODOLOGY
This single centre, prospective randomized open label group double blind study was conducted at the Department of Anesthesiology at Institute of Post Graduate Medical Education and Research, Kolkata for 11 months.
Forty ASA grade I and II patients, aged 20-60 years, scheduled for elective and emergency surgical procedures were included in the study. Patients with hypertension, cardiovascular diseases, neuromuscular disorders, anticipated difficult airway, morbid obesity, increased risk of pulmonary aspiration, on drugs that influence NM blocking agents or those with known allergy to the drugs, as well as pregnant female patients were excluded.
The rate (%) of successful intubation at 1 minute was taken for the primary outcome measure for this study assuming this rate will be at the best 10% for the normal saline group (Group B) and at least 60% for the dopamine pre-treated group (Group A), it was calculated that 17 subjects will be required per group with order to detect this 50% difference with 90% power and 5% probability of type I error. Rounding at the required subject was kept at 20 persons per group.
Patients were randomized into two groups, Group A and Group B, each group containing 20 patients. Randomization was generated by the statistical software “Microsoft Excel XPTM (2003)”. Statistica version 6 [Tulsa, Oklahoma: StatSoft Inc., 2001] and MedCalc version 11.6 [Mariakerke, Belgium: MedCalc Software 11.6] was used to analyse the data. Comparison of numerical variables between Group A and Group B – was done by Student’s t test and Mann-Whitney U test was used to analyse the numerical variables. Repeated measures ANOVA with post-hoc Tukey’s test was used to see any change of haemodynamics within groups.
Written, informed consent was obtained from each patient prior to including him or her in the study. The anesthesiologist performing the laryngoscopy and endotracheal intubation and the anesthesiologist administering the drugs both were blinded to the group allocation.
All the patients were fasted for at least 8 hours for solid food and 3 hours for clear fluid. On arrival in the OR, standard monitoring devices such as five leads electrocardiogram (ECG), automated noninvasive arterial pressure by oscillometry, pulse oximetry and N-M monitors were instituted. Intravenous access was obtained and infusion of lactated Ringer was started at a rate of 2 ml/kg/hr. All the patients were premedicated with injection fentanyl 2µg/kg ten minutes before induction. Group A patients received 3 μg/kg/min of dopamine hydrochloride by syringe pump. Fifteen milligram dopamine was added to 50 ml normal saline. Thus each ml solution contained 0.3mg or 300 μg dopamine. This solution was infused at a rate of 0.01 ml/kg/min for 15 minutes. Group B patients received 0.01 ml/kg/min of normal saline for 15 minutes as a control group. Subsequently both Group A and Group B patients were administered general anaesthesia using propofol 2 mg/kg over 20 sec and rocuronium 0.6 mg/kg 10 seconds later.
Just before the administration of propofol, Train of four (TOF) ratio monitoring in response to ulnar nerve stimulation was begun using TOF-GUARD. Laryngoscopy and tracheal intubation was attempted by an expert anaesthesiologist (with at least 3 years of experience) who was blinded to the group allocation, with an appropriate sized Macintosh blade 60 sec after administration of rocuronium. The anaesthesiologist also assessed the intubating conditions as per the intubation scoring system of the Consensus Conference on Good Clinical Research Practice in Pharmacodynamic Studies of Neuromuscular Blocking Agents, Copenhagen Consensus.9 Oral tracheal tubes (7.0 and 8 mm, internal diameter) were used for female and male patients, respectively. The cuff was inflated with air until the disappearance of a palpable leak on positive pressure ventilation. In Group A patients dopamine infusion and in Group B patients normal saline infusion was stopped just after intubation.
Successful intubation was defined as a condition when each score of three components was more than 2 points. Failed intubation was defined if any component showed less than 2 points.
Table 1: Intubation scoring system according to Viby Mogensen 9
| Score | Vocal cord | Jaw relaxation | Coughing or bucking |
| 3 | Fully abducted | Fully relaxed | Nil |
| 2 | Slightly abducted | Slightly stiff | Slight |
| 1 | Partially abducted | Stiff | Moderate |
| 0 | Closed | Impossible to open | Severe |
Anaesthesia was maintained with oxygen 33%, nitrous oxide 66% and isoflurane 0.5-1% with positive pressure ventilation maintaining normocapnia.
Patient’s mean arterial pressure (as recorded by NIBP), heart rate (as displayed by the electrocardiogram monitor) and oxygen saturation were recorded prior to administration of the study drug (baseline), at 5 min, at 10 min after starting the drug infusion, just before and after intubation, and at 1min, 3min and 10min after intubation.
A 20% change in haemodynamic variables from the baseline value was regarded as significant and managed by the concerned anaesthesiologist at their discretion.
The duration of laryngoscopy (the time from the insertion of the laryngoscope blade into the patient’s mouth to its removal after successful intubation), TOF ratio (ulnar nerve stimulation; adductor pollicis response to supramaximal stimuli) at 60 sec after rocuronium administration using TOF-GUARD, time from the disappearance of all four twitches on TOF count, reaction of the patients to tracheal intubation and intubation score at 60 seconds were recorded.
RESULTS
Total forty patients were needed for the study. There were no statistical significant differences among the groups in terms of demographic data (p>0.05). Table 2 shows comparison of demographic and ASA Grade profile between the groups.
Table 2: Comparison of demographic profile between the groups
| Parameter | Group A
n=20 |
Group B
n=20 |
p value |
| Age (Years)
Mean±SD |
37.95±10.42 | 41.15±12.81 | 0.391 |
| Weight (Kg)
Mean±SD |
50.95±4.18 | 50.8±5.41 | 0.922 |
| ASA Grade
I II |
11 (55%) 9 (45%) |
13 (65%) 7 (35%) |
0.748 |
| Sex (M:F) | 12:8 (60:40%) | 10:10 (50:50%) | 0.751 |
Table 3 compares the haemodynamics between the groups at various time points. Baseline haemodynamics (Mean Arterial Pressure-MAP, Pulse Rate-PR) were comparable between the groups with no statistical significant differences.
Table 3: Haemodynamic profile
| Time | Mean Arterial Pressure (mmHg) | Pulse rate (beats per minute) | ||||
| Group A (mean±SD) | Group B (mean±SD) | p-value between groups | Group A (mean±SD) | Group B (mean±SD) | p-value between groups | |
| Before infusion | 73.17±6.70 | 71.16±9.25 | 0.511 | 73.36±6.17 | 72.9±14.62 | 0.801 |
| 5 min after infusion | 74.30±5.22 | 71.65±9.32 | 0.463 | 76.11±5.26 | 74.45±5.47 | 0.713 |
| 10 min after infusion | 77.21±6.46 | 73.35±9.99 | 0.121 | 78.20±5.16 | 74.23±5.53 | 0.110 |
| before intubation | 78.33±6.05 | 73.08±6.86 | 0.078 | 82.15±4.52 | 74.10±8.78 | 0.004 |
| 1 min after intubation | 81.15±8.55 | 85.35 ±12.57 | 0.093 | 85.55±7.05 | 87.10±5.26 | 0.529 |
| 3 min after intubation | 78.65 ±10.95 | 81.21±7.72 | 0.351 | 78.54±4.43 | 82.00±3.58 | 0.135 |
| 10 min after intubation | 74.63±6.74 | 75.6±5.08 | 0.764 | 74.10±5.52 | 76.32±6.45 | 0.519 |
| p-value within group | < 0.001 | 0.003 | 0.001 | <0.001 | ||
*p-value within group comes from repeated measures
Just before intubation, there was a significant increase in PR in Group A (82.15) when compared with Group B (74.10) (p<0.05). Apart from this, haemodynamics (MAP, PR) were comparable between the groups with no statistical significant differences at various time points.
SpO2 values were comparable among the groups at different time points.
Within group comparison of MAP and PR showed significant differences across time both in Group A and in Group B (Table 3) but within group comparison of SpO2 did not reveal any significant differences across time.
The duration of laryngoscopy is significantly lower in Group A (13.9±2.29 sec.) than in Group B (23.3±4.40 sec.) (p<0.05).
Mean TOF count at 60 sec in Group A is 64.25±7.30 and in Group B is 81.25±6.66. (p<0.05).
TOF disappearance time in Group A is 169.65±7.22 and in Group B is 226.05±29.97 (p<0.05).
Intubation score at 60 seconds is significantly higher in Group A (8±0.64) than in Group B (4±0.99) (p<0.05).
Table 4: Onset and quality of neuromuscular block
| Onset and quality of block | Group A
(mean±SD) |
Group B
(mean±SD) |
p-value |
| Intubation score at 60 seconds | 8±0.64 | 4±0.99 | 0.000 |
| TOF ratio at 60 seconds | 64.25±7.30 | 81.25±6.66 | |
| TOF disappearance time(seconds) | 169.65±7.22 | 226.05±29.97 | |
| Duration of laryngoscopy (seconds) | 13.90±2.29 | 23.30±4.40 |
DISCUSSION
Recognizing the problem of prolonged duration of action with larger doses (1 mg/kg), attempts were made to decrease the dose of rocuronium(0.6 mg/kg) without compromising on its onset time or intubating conditions. Thus, pre-treatment with dopamine infusion (3 μg/kg/min) during the induction of general anaesthesia was found to accelerate the onset of action of rocuronium and improve the intubating condition. However, there were no clinically significant differences in mean arterial pressures and heart rates among the groups during the first 10 minutes after intubation. Rocuronium used in the lower dose of 0.6 mg/Kg for rapid tracheal intubation is known to provide suboptimal intubating conditions in 20–25% of patients.10 This could be as a result of a decrease in cardiac output caused by the induction agent resulting in slower onset of action at the laryngeal muscles and the diaphragm.
The onset time of a neuromuscular blocking agent is partly determined by the speed with which the drug reaches the neuromuscular junction, a factor that appears to be proportional to cardiac output and muscle blood flow. Studies using induction agents that maintain cardiac output and arterial pressure (i.e. etomidate and ketamine) have suggested that the use of these drugs was associated with faster onset of action and better intubating conditions with rocuronium.11,12 Ephedrine, by stimulating the β-adrenergic recepter, increases the cardiac output and tissue perfusion, which results in faster delivery of rocuronium to the neuromuscular junction of the laryngeal and diaphragmatic muscles which might shorten the onset of action of rocuronium and improve the intubating conditions.3,13,14. As an indirect evidence, Han et al14 reported that the introduction of rocuronium at the point when the cardiac output was increased by ephedrine effectively reduced the onset time. In addition, another study using esmolol, which is a β1-adrenergic antagonist, reported that the onset time of rocuronium was delayed when esmolol was introduced before the settlement of rocuronium. These studies support the fact that the effect of a β-adrenergic receptor agonist oriented by the ephedrine served a significant role in accelerating the onset time.13,15. On the basis of this hypothesis, pre- treatment with dopamine during propofol induction was found to improve the intubating conditions with rocuronium 0.6 mg/ Kg.
The results of our study were similar to the findings of the earlier studies using ephedrine.3 Dopamine has been shown to exhibit a graded pharmacological response, with a dose-dependent predominant activation of dopaminergic receptors, β-receptors, and α-receptors.16,17 Generally, at doses <3 μg/Kg/min, dopamine has been found to activate dopamine A1 receptors, which cause vasodilation of the renal arteries and other vascular beds, including mesenteric, coronary, and cerebral beds. In addition, there is stimulation of dopamine A2 receptors that leads to inhibition of norepinephrine release from sympathetic nerve endings.17 Activation of dopamine A1 and A2 receptors also results in a decline in systemic vascular resistance and an increase in renal blood flow. Dopamine infused at approximately 3 to 5 μg/Kg/min activates β1– and β2-adrenergic receptors, conferring a positive inotropic effect that is responsible for the increase in cardiac output and tissueµ perfusion, which results in faster delivery of rocuronium to the neuromuscular junction of the laryngeal and diaphragmatic muscles which in turn results in shortening of the onset of action of rocuronium and thereby improves the intubating conditions. At a dose >5 μg/Kg/min, dopamine has been reported to exert clinically relevant activation of α1- and α2-adrenergic receptors, which results in arterial vasoconstriction. Thus, dopamine in the greater dosages (>5μg/Kg/min) produce vasoconstriction of blood vessels supplying laryngeal muscles, thus limiting the access of the relaxant to its site of action.
In our study we included patients scheduled for both elective and emergency surgical procedures. Rapid sequence intubation was needed in emergency surgical patients with full stomach. To remove the bias, we adopted similar technique and sequence in all of the patients.
The findings of neuromuscular monitoring in our study support the hypothesis that the dopamine pre-treatment improves the intubating conditions by shortening the onset of action of rocuronium. The times for disappearance of all four twitches on TOF count and the TOF ratio at the end of 60 seconds of rocuronium injection were significantly higher in Group B than in Group A. The lack of agreement between the blockade characteristics at the laryngeal muscles and the adductor pollicis is well demonstrated in the literature. 18 – 21. However, as the site of monitoring was the same in all four groups, the results can still be compared for the difference in onset of neuromuscular block. Heart rate increased in all the dopamine pre-treated patients in our study. This is similar to the findings of the earlier studies using ephedrine.5,6.Thus,caution needs to be exercised in the subset of patients in whom dopamine-induced tachycardia might be detrimental (e.g. patients with ischaemic heart disease). In such cases the risk of tachycardia has to be weighed carefully against the benefit of improved intubating conditions. There was no clinically significant difference in mean arterial pressure and heart rate among the groups during the first 10 min after intubation (considering 20% change as clinically significant). Thus, prophylactic dopamine pre-treatment only attenuates, but does not completely abolish the decrease in arterial pressure associated with induction of anesthesia using fentanyl and propofol. This is similar to the findings of the earlier studies using ephedrine.5
CONCLUSION
We conclude that pre-treatment with dopamine 3 μg/Kg/min for 15 minutes improves the intubating conditions during rapid tracheal intubation using propofol and rocuronium, without significantly altering haemodynamic parameters.
ACKNOWLEDGEMENTS: None
REFERENCES
1. Donati F. Onset of action of relaxants. Can J Anaesth 1988; 35 Suppl 1:S52-8.
2. Young Ju Won, Yang-Sik Shin, Ki-Young Lee, and Woon Young Cho The effect of phenylephrine on the onset time of rocuronium Korean J Anesthesiol 2010 October 59(4): 244-248
3. Gopalakrishna MD, Krishna HM, Shenoy UK. The effect of ephedrine on intubating conditions and haemodynamics during rapid tracheal intubation using propofol and rocuronium. Br J Anaesth 2007; 99(2): 191-4.
4. Magorian T, Flannery KB, Miller RD. Comparison of rocuronium succinylcholine and vecuronium for rapid sequence induction of anesthesia in adult patients. Anesthesiology 1993; 79: 913–8
5 Hernan RM, Aljandro GG, Gonzalez Jorge A. The effect of ephedrine on the onset time of rocuronium. Anesth Analg 1997; 85: 437-40
6. Tan CH, Onisong MK, Chiu WKY. The influence of induction technique on intubating conditions 1 minute after rocuronium administration: a comparison of propofol-ephedrine combination and propofol. Anesthesia2002; 57: 223–6
7. Belyamani L, Azendour H, Elhassouni A, Zidouh S, Atmani M, Kamili ND. Effect of ephedrine on the intubation conditions using rocuronium versus succinylcholine. Ann Fr Anesth Reanim 2008; 27: 292-6.
8. Leykin Y, Pellis T, Lucca M, Gullo A. Effects of ephedrine on intubating conditions following priming with rocuronium. Acta Anaesthesiol Scand 2005; 49: 792-7.
9. Viby-Mogensen J, Engbaek J, Eriksson LI, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996; 40: 59–74.
10. Sparr HJ, Giesinger H, Ulmer M, Hollenstein Z, Luger TJ. Influence of induction technique on intubating conditions after rocuronium in adults: comparison with rapid sequence induction using thiopentone and suxamethonium. Br J Anaesth 1996; 77: 339–42
11. Baraka AS, Sayyid SS, Assaf BA. Thiopental–rocuronium versus ketamine in parturients undergoing caesarean section. Anesth Analg 1997; 84: 1104–7
12. Fuchs-Buder T, Sparr HJ, Zweigenfu T. Thiopental or etomidate for rapid sequence induction with rocuronium. Br J Anaesth 1998; 80: 504–6
13. Ezri T, Szmuk P, Warters RD, Gebhard RE, Pivalizza EG, Katz J. Changes in onset time of rocuronium in patients pretreated with ephedrine and esmolol—the role of cardiac output. Acta Anaesthesiol Scand 2003; 47: 1067–72
14. Han DW, Chun DH, Kweon TD, Shin YS. Significance of the injection timing of ephedrine to reduce the onset time of rocuronium. Anesthesia2008; 63: 856-60.
15. Szmuk P, Ezri T, Chelly JE, Katz J. The onset time of rocuronium is slowed by esmolol and accelerated by ephedrine. Anesth Analg 2000; 90: 1217-9.
16. Lee MR. Dopamine and the kidney: ten years on. Clin Sci. 1993; 84: 357–375.
17. Goldberg LI, Rajfer SI. Dopamine receptors: applications in clinical cardiology. Circulation. 1985; 72: 245–248.
18. Pansard JL, Chauvin M, Lebrault C, Gauneau P, Duvaldestin P. Effect of an intubating dose of succinylcholine and atracurium on the diaphragm and adductor pollicis muscle in humans. Anesthesiology 1987; 67: 326–30
19. Cantineau JP, Porte F, d’Honneur G, Duvaldestin P. Neuromuscular effects of rocuronium on the diaphragm and adductor pollicis muscles in anesthetized patients. Anesthesiology 1994; 81: 585–90
20. Meistelman C, Plaud B, Donati F. Rocuronium (Org 9426) neuromuscular blockade at the adductor muscles of the larynx and adductor pollicis in humans. Can J Anaesth 1992; 39: 665–9
21. Plaud B, Proost JH, Wierda MKH, Barre J, Debaene B, Meistelman C. The pharmacokinetic and pharmacodynamics ofrocuronium at the vocal cords and the adductor pollicis in humans. Clin Pharmacol Ther 1995; 58: 185–91
