Anaesthesia for several surgical procedures often involves a combination of specific challenges, such as no patient movement, deep analgesia, fast and reliable induction and reversal of anaesthesia, swift postoperative recovery and avoidance of postoperative nausea and vomiting (PONV). In particular types of surgery, for instance eye surgery, additional requirements must be met such as a stable intraocular pressure, because abrupt increase of intraocular pressure can lead to major complications like retinal haemorrhage and expulsion of intraocular contents when the eye is opened.1 Also in several types of ear–nose–throat surgery, surgical requirements include stable and controlled blood pressure (BP) independent of surgical stimuli, complete suppression of the cough reflex, fast postoperative recovery and minimal risk of PONV. To provide optimal surgical conditions safely and avoid particular complications, balanced general anaesthesia with a relatively high-analgesic contribution is often desired, a state that can be readily achieved by administering a combination of propofol and remifentanil.2,3 Although very effective in achieving this combination of desired effects, induction of this type of balanced anaesthesia often induces unwanted bradycardia and hypotension, raising concerns regarding haemodynamic stability and tissue oxygenation.4–6 To minimise these changes, haemodynamic monitoring and intraoperative interventions (e.g. administration of fluid, phenylephrine, norepinephrine and atropine) are often used. The preservation of adequate tissue perfusion is particularly critical in our increasingly ageing population, with the associated conditions such as diabetes mellitus, coronary and peripheral arterial disease and arterial hypertension. These conditions have negative effects on microvascular blood flow and tissue oxygenation.1,6 Remifentanil is known to have an explicitly strong suppressive effect on the heart rate (HR),7 which can be reversed by atropine,8 and such reversal may not only mitigate bradycardia and promote a desired increase in arterial BP, but also increases cardiac index (CI) and tissue oxygenation. It is possible that atropine could replace the common clinical practice of administering vasoactive medication such as phenylephrine or norepinephrine to maintain mean arterial pressure (MAP) levels, particularly as such vasoactive medication is often considered to induce negative effects on CI and tissue oxygenation.9
In a perioperative setting, impaired tissue oxygenation is often associated with postoperative complications.10 Even though the coherence between changes in macrohaemodynamics, microcirculation and tissue oxygenation is not readily predictable in the individual patient, optimising systemic haemodynamics and microcirculatory perfusion are known to improve postoperative outcomes and result in fewer complications.10,11 Hence, to maintain adequate tissue oxygenation, one should not merely rely on MAP but also focus on flow-based variables (e.g. CI).
Therefore, we hypothesised that, particularly in balanced anaesthesia with high-dose remifentanil, pre-emptive administration of atropine may moderate the haemodynamic effects of the induction of anaesthesia. More specifically, although a positive influence of atropine on HR was obviously anticipated, we wanted to quantify to what degree MAP and CI as well as cerebral tissue oxygenation (SctO2) and peripheral tissue oxygenation (SptO2) would be affected by a single administration of atropine just before induction of anaesthesia. Second, we wanted to evaluate the evolution of the HR and the changes in myocardial oxygen demand, calculated by the rate pressure product (RPP).12
The current study was approved by the Medical Ethical Committee of the University Medical Center Groningen (Ref: METc 2012/218), Groningen, The Netherlands (Chairperson Prof W.A. Kamps) on 13 September 2012 and registered with ClinicalTrials.gov (Ref: NCT01871922). All patients 18 years or older, who were scheduled for elective surgery under general total intravenous anaesthesia (TIVA) between 17 September 2012 and 30 January 2013, were assessed for eligibility for this interventional, prospective double-blind randomised controlled trial according to the CONSORT group statement (Fig. 1).13 Patients with a contra-indication for atropine administration were excluded. There was no selection based on sex, age, American Society of Anesthesiologists’ (ASA) physical status classification or ethnic background. After written informed consent, all patients included were randomised using a sealed envelope technique to the atropine or saline group. All measurements were performed before the start of the surgery.
Patients did not receive premedication. On arrival in the operating theatre, a peripheral intravenous line was inserted in a large left forearm vein. Adequate preoxygenation was ensured with at least eight vital capacity breaths via a tightly fitting facemask. To compensate for the vasodilatory effects of induction of anaesthesia, an infusion of 500 ml colloid solution (Voluven 6%; Fresenius, Bad Homburg, Germany) was administered and completed before induction of anaesthesia. During the study period, maximal reproducibility of the induction of anaesthesia was pursued by using a target-controlled infusion with a propofol target effect-site concentration (Ce) of 2.5 μg ml−1 (Schnider model14) and a corresponding remifentanil Ce at 8 ng ml−1 (Minto model15,16). According to previous studies, this induction technique will result in tolerance of laryngoscopy in 95% of patients.3,17,18 The research assistant prepared identically labelled syringes containing either methylatropine (0.5 mg in 1 ml) or 0.9% saline (1 ml) and handed the appropriate syringe to the anaesthetist for administration at the start of induction of anaesthesia. The anaesthetist was thus blind to the drug. After the administration of cis-atracurium (0.1 mg kg−1) and endotracheal intubation, the patients’ lungs were mechanically ventilated using the volume control mode (tidal volume 8 ml kg−1) with an O2/air mixture [inspired oxygen fraction (FiO2) 0.4] and positive end-expiratory pressure of 5 cmH2O. The respiratory rate was adjusted to keep end-tidal carbon dioxide partial pressure between 4.5 and 5.5 kPa.
Noninvasive haemodynamic monitoring
Before induction of anaesthesia, standard monitoring equipment was connected to the patient: ECG, noninvasive BP monitoring on the right upper arm with pulse oximetry on a left finger (Philips IntelliVue MX800, Eindhoven, The Netherlands).
The Nexfin cuff manometer, currently known as the ClearSight system, with light absorption sensor (Edwards Lifesciences, Irvine, California, USA) was attached to the left middle finger to calculate the MAP, HR, stroke volume and CI continuously.19–21 In a subsequent offline analysis, the RPP was estimated by calculating as MAP multiplied by HR.
Two FORE-SIGHT Cerebral Oximeter (CASMED, Branford, Connecticut, USA) sensors were placed on the patient's forehead to record SctO2 continuously and bilaterally.22 An InSpectra (Hutchinson Technology, Hutchinson, Minnesota, USA) probe was positioned on the left thenar eminence to measure the SptO2.23 The working principle of both devices is based on NIRS technology: sensors positioned on the patient's skin use light in several device-specific wavelengths to assess the ratio of oxygenated and deoxygenated haemoglobin in the cerebral or peripheral tissue.24 Changes relative to baseline tissue oxygenation are significantly correlated with oxygen delivery and perfusion deficits.25
Data registration and analysis
All standard data from the anaesthesia monitors and all SctO2 data of the FORE-SIGHT Cerebral Oximeter were recorded continuously onto the hard drive of a computer (sampling rate of 1 Hz) utilising data-logging software (Rugloop II, Demed Engineering, Temse, Belgium). The SptO2 data of the InSpectra device and the haemodynamic variables from the Nexfin monitor were recorded and saved in the internal storage of these devices and later extracted as data files using appropriate software. Synchronisation markers of the InSpectra device and the Nexfin monitor and timestamps of all important events, such as the start of induction of anaesthesia and administration of atropine, were also recorded using the RugLoop II system (Demed Engineering, Temse, Belgium).
The electronic data from all the devices were imported into Microsoft Excel 2010 (Microsoft, Redmond, Washington, USA) for synchronisation and analysis. After graphical representation, obvious atypical values caused by artefacts were corrected during a visual inspection of the data plots. In addition, a 30-s running median with 15-s steps was calculated for all studied variables. For all study variables, the changes in the absolute values and also the changes relative to baseline were plotted from 1 min before induction of anaesthesia until a relative steady state was achieved at 10 min after induction: T0 = induction, T10 = 10 min after the start of induction. All measurements for the study were obtained before surgery commenced.
Sample size calculation was based on the CI, one of the primary endpoints.
We considered a mean difference in CI of 20% between both groups at T10 to be clinically relevant (estimated SD of 10% in both groups at T10 based on pilot measurements). To detect this difference with an alpha error of 0.05 and a power of 0.95, a total sample size of 46 was needed.26 An additional 12 patients were included in each group in anticipation of unsatisfactory data recordings, making a total of 60 patients (30 patients in each group).
Statistical analyses were performed in SPSS version 22 (IBM Inc., Chicago, Illinois, USA). Categorical variables are given as number of patients and are analysed with the Chi-square test or the Fisher's exact test. Normality of continuous variables was assessed by the Kolmogorov–Smirnov test. Continuous data are expressed as mean ± SD for parametric data or as median [inter-quartile range (IQR)] for nonparametric data. Differences within the groups were calculated on the absolute numerical values at the induction of anaesthesia (T0) and at steady state anaesthesia (T10). We denoted the numerical difference between T0 and T10 as Δ. Differences between groups were calculated on the absolute numerical values at T0, at steady state anaesthesia T10 and of the numerical values of Δ. To compare continuous variables between the different groups, the unpaired Student t test was used for parametric variables and the Mann–Whitney U test for nonparametric variables. Comparison of the haemodynamic variables within the same group at T0 and T10 was performed using a paired t test and Wilcoxon signed rank test as appropriate. All tests were two-tailed, and statistical significance was defined as P less than 0.05 in all cases.
Sixty patients were included in this double-blind, randomised controlled trial and were randomly assigned to the atropine or saline group (Fig. 1). Nine patients were excluded after registration: technical difficulties with data recording (n = 6), problems with data synchronisation (n = 1) and patients being treated with β-blocking medication (n = 2). Thus, the analyses were based on 25 patients in the atropine group and 26 patients in the saline group. Patients’ characteristics in the two groups are shown in Table 1. Most patients were of middle age, ASA I-II, with normal weight, height and BMI, were not on medications that could have interfered with the trial medication and were scheduled for elective eye surgery. The changes in the variables under investigation are shown in Figs. 2 and 3 and Table 2. Because the actual SDs of the differences between T0 and T10 (Δ) in both groups in our study were notably higher than 10%, an additional post-hoc analysis was performed on the basis of the actual data: observed CI Δ was −0.4 ± 0.7 l min−1 m−2 in the atropine groups (n = 25) and −0.9 ± 0.6 l min−1 m−2 in the placebo (n = 26) group. With an alpha error of 0.05, this indicates a power of 0.85 to detect a 20% difference in CI Δ between the two groups.
Significant decreases of MAP, HR and CI were observed after induction of anaesthesia in the saline group (Fig. 2). In the atropine group, this decrease was significantly attenuated, compared with the saline group: ΔMAP after 10 min was −24 (−40 to −21) and −37 mmHg (−41 to −31) (P = 0.021), respectively; ΔHR was 0 ± 13 and −19 ± 11 bpm (P < 0.01), respectively, and ΔCI was −0.4 ± 0.7 and −0.9 ± 0.6 l min−1 m−2 (P < 0.01), respectively (Table 2). Maximum HR [median (IQR; range)] at 1.5 min after induction of anaesthesia was 102 bpm (86 to 116; 53 to 138) in the atropine group and 85 bpm (76 to 95; 38 to 115) in the saline group. In addition, the reduction in the RPP was significantly smaller in the atropine group compared with the saline group: median (IQR) ΔRPP was −3241 (−5015 to −613) and −5712 mmHg min-1 (−6715 to −3917) (P < 0.01), respectively. Induction of anaesthesia resulted in a significant increase in SctO2 and SptO2, but between-groups comparison showed no significant differences of these variables (Fig. 3 and Table 2).
The major finding in this prospective double-blind randomised controlled trial was that during induction of a balanced general TIVA with propofol and high-dose remifentanil, the addition of atropine preserves haemodynamic stability without increasing the myocardial oxygen demand above the awake state level (T0).
Induction of anaesthesia with propofol and remifentanil in a dose sufficient manner to tolerate laryngoscopy17,18 is known to induce significant bradycardia and hypotension in a majority of patients.5 This combination of hypnotic and analgesic, with its particularly favourable pharmacokinetic profile, has many advantages in several clinical circumstances: the high level of antinociception, in synergism with a low concentration of propofol provides excellent analgesic and hypnotic conditions and complete akinesia during surgery.3 Simultaneously, the combination also prevents intraoperative or postoperative events that predispose to increases in intraocular pressure or pharyngeal reflexes and allows timely extubation and fast cognitive recovery.3 However, this combination of remifentanil and propofol may significantly jeopardise haemodynamic homeostasis. Compared with other opiates, remifentanil has a known explicitly strong suppressive effect on the HR.27 Remifentanil provokes dose-dependent depressor effects on both sinus and atrioventricular (AV) node function, manifested by a significant prolongation of sinus node recovery time, sinoatrial conduction time and Wenckebach cycle length, and inhibits both intra-atrial conduction and sinus node automaticity.7 A transoesophageal pacing electrophysiological investigation demonstrated that in 17.5% of patients, remifentanil administration was always accompanied by a transient depression of sinoatrial automaticity and a reduction of AV conductive reserve; atropine promptly normalised the electrophysiological parameters.8 These authors concluded that the remifentanil-associated hypokinetic cardiac effects are exclusively vagally mediated.8 As such, although the positive chronotropic effects of atropine have been well documented, the increasing use of TIVA and this particular effect of remifentanil on the chronicity warrant this evaluation on the potential favourable effects in these clinical conditions.
In this study, atropine completely prevented the occurrence of bradycardia, with a fully preserved HR 10 min after the induction of anaesthesia, compared with a significantly decreased HR in the saline group at this time. Although there was a short period of increased HR with atropine, this was within acceptable limits and lasted only 1 to 2 min. The increase in HR is not entirely attributable to atropine as it coincided with endotracheal intubation. Most importantly, both the MAP and CI were preserved significantly better in the atropine group compared with the control group.
Induction of general anaesthesia is known to induce general vasodilation. Together with an increased FiO2, this resulted in a significant increase in the measured SctO2 and SptO2 despite a distinct decrease in MAP and CI, in both the atropine and saline groups.
The principal objection against the administration of atropine is an unwanted increase in HR in some patients, such as patients with advanced coronary artery disease, cardiomyopathy or aortic valve stenosis. As for any drug, atropine should be administered only after due consideration of potential patient morbidity and after exclusion of contra-indications or administered only after the onset of relative bradycardia. Alternatively, glycopyrrolate could be considered as an alternative muscarinic antagonist, although this drug requires to be investigated in further research. Nevertheless, despite increases in HR, the RPP (a measure of the stress placed on the cardiac muscle and an indication of the myocardial oxygen demand12) decreased in both groups, albeit less so in the atropine group. This indicates that cardiac oxygen demand has decreased in both groups.
One limitation of the study is the fixed dose of 500 μg atropine for all patients. This may partly explain some of the inter-individual variations observed in the cardiovascular effects induced by atropine. Second, the Nexfin monitor was used to record the haemodynamic changes. As this device derives CI from auto-calibrated pulse contour analysis of the noninvasively recorded pressure waveform, there is a certain amount of unavoidable inaccuracy. Although there are conflicting reports on the limits of agreement of the Nexfin monitor with reference methods, we reduced the possible influence of measurement bias to a minimum: instead of using absolute CI values, we used absolute changes to baseline CI values, which are thought to be more appropriate for this kind of analysis.28–30
Induction and maintenance of balanced propofol/high-dose remifentanil anaesthesia induces a significant decrease in HR, MAP and CI. Administration of atropine immediately before induction of anaesthesia can significantly reduce these negative haemodynamic effects.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: none.
Conflicts of interest: TWLS has received honoraria for consulting from Edwards Lifesciences, the former owner of the Nexfin Technology. MMRFS and his department received grants and funding from The Medicines Company (Parsippany, New Jersey, USA), Masimo (Irvine, California, USA), Fresenius (Bad Homburg, Germany), Acacia Design (Maastricht, The Netherlands), Medtronic (Dublin, Ireland) and honoraria from The Medicines Company (Parsippany, New Jersey, USA), Masimo (Irvine, California, USA), Fresenius (Bad Homburg, Germany), Baxter (Deerfield, Illinois, USA), Medtronic (Dublin, Ireland) and Demed Medical (Temse, Belgium). In addition, MMRFS is an editorial board member to the British Journal of Anaesthesia and a senior editor to Anesthesia & Analgesia.
Presentation: preliminary data for this study were presented as a poster presentation at the European Society of Anaesthesiology (ESA) Euroanaesthesia, June 2013, Barcelona.
1. McGoldrick KE, Gayer SI. Barash PG, Cullen BF, Stoelting RK, et al. Anesthesia for ophthalmologic surgery. Clinical anesthesia
. Philadelphia: Lippincott Williams & Wilkins; 2013. 1373–1399.
2. Hogue CW, Bowdle TA, O’Leary C, et al. A multicenter evaluation of total intravenous anesthesia with remifentanil and propofol for elective inpatient surgery. Anesth Analg
3. Vos JJ, Poterman M, Hannivoort LN, et al. Hemodynamics and tissue oxygenation during balanced anesthesia with a high antinociceptive contribution: an observational study. Perioper Med
4. Beers R, Camporesi E. Remifentanil update: clinical science and utility. CNS Drugs
5. Elliott P, O’Hare R, Bill KM, et al. Severe cardiovascular depression with remifentanil. Anesth Analg
6. Poterman M, Vos JJ, Vereecke HE, et al. Differential effects of phenylephrine and norepinephrine on peripheral tissue oxygenation during general anaesthesia: a randomised controlled trial. Eur J Anaesthesiol
7. Fujii K, Iranami H, Nakamura Y, et al. High-dose remifentanil suppresses sinoatrial conduction and sinus node automaticity in pediatric patients under propofol-based anesthesia. Anesth Analg
8. Fattorini F, Romano R, Ciccaglioni A, et al. Effects of remifentanil on human heart electrical system. A transesophageal pacing electrophysiological study. Minerva Anestesiol
9. Thiele RH, Nemergut EC, Lynch C. The physiologic implications of isolated alpha(1) adrenergic stimulation. Anesth Analg
10. Jhanji S, Lee C, Watson D, et al. Microvascular flow and tissue oxygenation after major abdominal surgery: association with postoperative complications. Intensive Care Med
11. Tassoudis V, Vretzakis G, Petsiti A, et al. Impact of intraoperative hypotension on hospital stay in major abdominal surgery. J Anesth
12. Fletcher GF, Balady GJ, Amsterdam EA, et al. Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association. Circulation
13. Schulz KF, Altman DG, Moher D. CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ
14. Schnider TW, Minto CF, Shafer SL, et al. The influence of age on propofol pharmacodynamics. Anesthesiology
15. Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology
16. Minto CF, Schnider TW, Shafer SL. Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. Anesthesiology
17. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology
18. Bouillon TW. Schüttler J, Schwilden H. Hypnotic and opioid anesthetic drug interaction on the CNS, focus on response surface modelling. Modern anesthetics. Handbook of experimental pharmacology
. Berlin: Springer; 2008. 471–487.
19. Vos JJ, Poterman M, Mooyaart EA, et al. Comparison of continuous noninvasive finger arterial pressure monitoring with conventional intermittent automated arm arterial pressure measurement in patients under general anaesthesia. Br J Anaesth
20. Martina JR, Westerhof BE, van Goudoever J, et al. Noninvasive continuous arterial blood pressure monitoring with Nexfin®
21. Broch O, Renner J, Gruenewald M, et al. A comparison of the Nexfin®
and transcardiopulmonary thermodilution to estimate cardiac output during coronary artery surgery. Anaesthesia
22. Murkin JM, Arango M. Near-infrared spectroscopy as an index of brain and tissue oxygenation. Br J Anaesth
23. Santora RJ, Moore FA. Monitoring trauma and intensive care unit resuscitation with tissue hemoglobin oxygen saturation. Crit Care
24. Scheeren TWL, Schober P, Schwarte LA. Monitoring tissue oxygenation by near infrared spectroscopy (NIRS): background and current applications. J Clin Monit Comput
25. Putnam B, Bricker S, Fedorka P, et al. The correlation of near-infrared spectroscopy with changes in oxygen delivery in a controlled model of altered perfusion. Am Surg
26. Faul F, Erdfelder E, Buchner A, et al. Statistical power analyses using G*Power 3.1: Tests for correlation and regression analyses. Behav Res Methods
27. Del Blanco Narciso BB, Jimeno Fernandez C, Almendral Garrote J, et al. Effects of remifentanil on the cardiac conduction system. Our experience in the study of remifentanil electrophysiological properties. Curr Pharm Des
28. Fischer MO, Avram R, Cârjaliu I, et al. Noninvasive continuous arterial pressure and cardiac index monitoring with Nexfin after cardiac surgery. Br J Anaesth
29. Critchley LA, Lee A, Ho AM. A critical review of the ability of continuous cardiac output monitors to measure trends in cardiac output. Anesth Analg
30. Saugel B, Wagner JY, Scheeren TW. Cardiac output monitoring: less invasiveness, less accuracy? J Clin Monit Comput