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Differential effects of phenylephrine and norepinephrine on peripheral tissue oxygenation during general anaesthesia

A randomised controlled trial

Poterman, Marieke; Vos, Jaap Jan; Vereecke, Hugo E.M.; Struys, Michel M.R.F.; Vanoverschelde, Henk; Scheeren, Thomas W.L.; Kalmar, Alain F.

European Journal of Anaesthesiology (EJA): August 2015 - Volume 32 - Issue 8 - p 571–580
doi: 10.1097/EJA.0000000000000247
Perioperative medicine: the cardiac patient

BACKGROUND Phenylephrine and norepinephrine are two vasopressors commonly used to counteract anaesthesia-induced hypotension. Their dissimilar working mechanisms may differentially affect the macro and microcirculation, and ultimately tissue oxygenation.

OBJECTIVES We investigated the differential effect of phenylephrine and norepinephrine on the heart rate (HR), stroke volume (SV), cardiac index (CI), cerebral tissue oxygenation (SctO2) and peripheral tissue oxygenation (SptO2), and rate-pressure product (RPP).

DESIGN A randomised controlled study.

SETTING Single-centre, University Medical Center Groningen, The Netherlands.

PATIENTS Sixty normovolaemic patients under balanced propofol/remifentanil anaesthesia.

INTERVENTIONS If the mean arterial pressure (MAP) dropped below 80% of the awake state value, phenylephrine (100 μg + 0.5 μg kg−1 min−1) or norepinephrine (10 μg + 0.05 μg kg−1 min−1) was administered in a randomised fashion.

MAIN OUTCOME MEASURES MAP, HR, SV, CI, SctO2, SptO2 and rate-pressure product (RPP) analysed from 30 s before drug administration until 240 s thereafter.

RESULTS Phenylephrine and norepinephrine caused an equivalent increase in MAP [Δ = 13 (8 to 22) and Δ = 13 (9 to 19) mmHg, respectively] and SV [Δ = 6 ± 6 and Δ = 5 ± 7 ml, respectively], combined with a significant equivalent decrease in HR (both Δ = −8 ± 6 bpm), CI (both Δ = −0.2 ± 0.3 l min−1 m−2) and SctO2 and an unchanged RPP (Δ = 345 ± 876 and Δ = 537 ± 1076 mmHg min−1). However, SptO2 was slightly but statistically significantly (P < 0.05) decreased after norepinephrine [Δ = −3 (−6 to 0)%] but not after phenylephrine administration [Δ = 0 (−1 to 1)%]. In both groups, SptO2 after vasopressor was still higher than the awake value.

CONCLUSION In normovolaemic patients under balanced propofol/remifentanil anaesthesia, phenylephrine and norepinephrine produced similar clinical effects when used to counteract anaesthesia-induced hypotension. After norepinephrine, a fall in peripheral tissue oxygenation was statistically significant, but its magnitude was not clinically relevant.

From the Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (MP, JJV, HEMV, TWLS, AFK, MMRFS), Department of Anesthesia, Ghent University (MMRFS), and Department of Anesthesia and Intensive Care Medicine, Maria Middelares Hospital, Ghent, Belgium (HV, AFK)

Correspondence to Marieke Poterman, MD, Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30 001, 9700 RB Groningen, The Netherlands Tel: +31 50 361 61 61; fax: +31 50 361 37 63; e-mail:

Published online 10 March 2015

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Arterial hypotension is commonly observed after in- duction of general anaesthesia, especially during the administration of a balanced combination of propofol and an opioid. The major mechanisms of hypotension are attributed to peripheral vasodilation and to a lesser extent to a decrease in cardiac contractility.1 When remifentanil is used, the incidence of bradycardia may be higher than with other opioids.2

Phenylephrine and norepinephrine are commonly used in clinical practice to counteract anaesthesia-induced hypotension. Phenylephrine is a pure α1 adrenoceptor agonist, predominantly resulting in vasoconstriction, whereas norepinephrine has both α1 and β1 adrenoceptor agonist properties, with additional positive inotropic and chronotropic effects.3,4 Although both agents are equally effective in restoring a desired blood pressure, their individual working mechanisms may have different consequences for the macro and microcirculation. Reports on the effects of equipressor doses of norepinephrine and phenylephrine on septic myocardial dysfunction and on microcirculatory blood flow in the gastrointestinal tract in sepsis have shown an increase in cardiac output (CO) and cardiac index (CI) in the norepinephrine group, whereas the phenylephrine group showed either a decreased or maintained CO and CI.5,6 Differences in the cardiovascular response may lead to different effects on tissue oxygenation.

When using standard haemodynamic monitoring consisting of noninvasive blood pressure, heart rate (HR) and rhythm and pulse oximetry, the subtle differences in the effects on the macro and microcirculation and on the tissue oxygenation remain undetected. The recent introduction of the Nexfin monitor allows a noninvasive measurement of advanced haemodynamic variables, such as beat-to-beat mean arterial pressure (MAP), stroke volume (SV), CI and systemic vascular resistance (SVR).7–9 In addition, on the basis of the Nexfin-derived MAP and HR, one can calculate a continuous rate-pressure product (RPP), which is a surrogate measure of cardiac oxygen consumption.10 Near-infrared spectroscopy (NIRS) permits noninvasive monitoring of tissue oxygenation in many clinical settings.11 The FORE-SIGHT and InSpectra devices can be employed to monitor the cerebral (SctO2) and the peripheral (SptO2) tissue oxygenation, respectively, in a continuous manner.12,13 Both tissue oxygen measurements are based on haemoglobin oxygen saturation. For an extended explanation of NIRS concepts and applications, we refer to recent review articles.11,14,15

Our impression was that norepinephrine was more effective than phenylephrine in improving advanced cardiovascular variables and tissue oxygenation. The aim of this study was to test the hypothesis that norepinephrine results in a signficantly different CI, SctO2, SptO2, and RPP than phenylephrine.

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Materials and methods

Ethical approval for this study (Reference: METc2011.261) was provided by the Ethical Committee of University Medical Centre Groningen, Groningen, The Netherlands on 12 December 2011. The trial was registered at (NCT01609491).

Patients aged at least 18 years and scheduled for elective surgery under general anaesthesia between 30 December 2011 and 16 March 2012 were assessed for eligibility for this interventional, prospective randomised controlled trial according to the CONSORT group statement (Fig. 1).16 Following written informed consent, all recruits were randomly assigned to either the phenylephrine or norepinephrine group by the sealed envelope technique.

Fig. 1

Fig. 1

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Anaesthetic management

No premedication was administered. Upon arrival in the operating theatre, a peripheral intravenous line was inserted in a large left forearm vein. The Nexfin monitor was connected and euvolaemia was pursued by administration of 500 ml of colloid (Voluven, Fresenius, Bad Homburg, Germany). Thereafter, awake state haemodynamic values were determined before induction of anaesthesia with a face mask held adjacent to the face and the FiO2 assumed to be 40 to 50%. After intubation and ventilation, additional fluid was administered if necessary until the pulse pressure variation was below 12%.17

Our target was to induce and maintain reproducible steady-state anaesthesia with a beneficial clinical profile, although with a moderate risk for relative hypotension. During the study period, maximal reproducibility of the anaesthetic pharmacological condition was pursued by using a target-controlled infusion (TCI) with a high remifentanil effect-site concentration (Ce) of 8 ng ml−1 (Minto model)18,19 and a corresponding propofol TCI Ce at 2.5 μg ml−1 (Schnider model)20 in order to remain within a clinically acceptable dosing range. This combined administration of remifentanil in high dose and propofol in low dose results in a tolerance of laryngoscopy in 95% of patients as predicted by a hierarchical interaction model.21,22 As such, this balanced anaesthesia should be considered ethically well tolerated and clinical acceptable. Cisatracurium (0.1 mg kg−1) was administered to facilitate tracheal intubation. Patients’ lungs were mechanically ventilated in the volume control mode (tidal volume: 8 ml kg−1) with an O2/air mixture (FiO2 0.4) and a positive end expiratory pressure of 5 cmH2O. The respiratory rate was adjusted to keep end-tidal carbon dioxide partial pressure (PeCO2) between 4.0 and 5.0 kPa.

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Haemodynamic management

Haemodynamic management was based on MAP as measured by the Nexfin monitor. When haemodynamic support was necessary during the study period, that is when the MAP dropped below 80% of the awake state value,23,24 administration of a continuous infusion of phenylephrine or norepinephrine was started according to allocation. With the applied concentrations of phenylephrine (100 μg ml−1) and norepinephrine (10 μg ml−1), an equivalent effect on the MAP was expected from an equal infusion rate.25 Administration of the vasopressors began with a bolus of 1 ml, followed by a continuous infusion rate of 0.3 ml kg−1 h−1. A target MAP during infusion of vasopressor was between 80 and 100% of awake state value. Any adjustment to the infusion rate was in response to the MAP. The anaesthetist was blind to the drug allocation.

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Noninvasive haemodynamic monitoring

Before induction of anaesthesia, standard monitoring equipment was connected to the patient: ECG, pulse oximeter (SpO2) and noninvasive blood pressure monitor on the right upper arm.

The Nexfin monitor (Edwards Lifesciences, Irvine, USA) is an advanced haemodynamic monitoring device that uses a cuff manometer with a light absorption sensor. It was placed around the left middle finger. It continuously calculates the MAP, HR, SV, CI and SVR in a beat-to-beat manner.9,26,27 In addition to the continuous MAP and HR provided by the Nexfin monitor, the RPP was calculated offline as RPP = HR x MAP.

FORE-SIGHT Cerebral Oximeter (CASMED, Branford, USA) continuously provides the SctO2. The working principle is based on NIRS technology. Two sensors placed on the patients’ forehead emit near-infrared light in four specific wavelengths (690, 780, 805 and 850 nm), which is then partially absorbed and partially reflected to the sensors, based on the ratio of oxygenated to deoxygenated haemoglobin in the cerebral tissue.14

Several commercial NIRS monitors exist and research results may not be interchangeable. Some have reported weak correlation between INVOS SctO2 and jugular bulb saturation, but relative trend changes were similar.28 Also, substantial haemodilution may render SctO2 values less reliable.29 Because important limitations exist regarding the use of SctO2, fluid administration was restricted during our measurements and SctO2 and SptO2 changes were calculated relative to baseline values within each patient.

The InSpectra device (Hutchinson Technology, Hutchinson, USA) is also based on the NIRS technology, though with different wavelengths (600 and 800 nm). It measures the SptO2 with one probe on the left thenar eminence.11,13 Relative changes in SptO2 correlate significantly with oxygen delivery and perfusion deficits.30

Furthermore, when the ventilation settings are kept the same, a change in PeCO2 indicates a change in pulmonary blood flow and thus CO.31 Therefore, the evolution of the PeCO2 can be used as a surrogate for CI trends, independent of the CI measurement by the Nexfin monitor.

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Data registration and analysis

All standard data from the Philips MP70 anaesthesia monitor and all SctO2 data of the FORE-SIGHT Cerebral Oximeter were recorded continuously (sampling rate of 1 Hz) using data-logging software (RugLoop II; Demed Engineering, Temse, Belgium) on a computer. The SptO2 data of the InSpectra device and the haemodynamic data from the Nexfin monitor were recorded and saved in the internal storage of the devices and afterwards extracted as data files using appropriate software. Synchronisation markers of the InSpectra device and the Nexfin monitor and all important events, such as the start of administration of the vasopressor, were also recorded in the RugLoop II system.

The electronic data of all the devices were imported into Microsoft Excel 2010 (Microsoft, Redmond, USA) for synchronisation and analysis. After graphical representation, a visual inspection of the data plots was performed to correct obvious atypical values caused by artefacts. In addition, a 30-second running median with 15-second steps was calculated for all studied variables. The evolution of the absolute changes and absolute values was plotted from 30 s before the start of drug administration until the moment relative steady-state was achieved for all studied variables (Time = 240 s).

All measurements for the study were performed before surgery commenced.

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Statistical analysis

As we did not have pilot data on tissue oxygenation, we based the sample size calculation on one of the other primary endpoints, CI. We considered a mean difference in CI of 10% between the phenylephrine and norepinephrine group to be clinically relevant (estimated SD of 10% in both groups). 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.32 Taking into account possible dropouts, we rounded this up to 60 patients (30 patients in each group).

Statistical analysis was performed using SPSS version 19 (IBM Inc., Chicago, Illinois, USA). Categorical variables are given as number of patients and analysed with the χ2 test and 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 (25th to 75th percentiles) for nonparametric data. Differences between groups were tested on absolute values before induction of anaesthesia and before and after administration of the vasopressors and on absolute changes from baseline induced by the two agents. To compare continuous variables of the different groups, the unpaired t-test and the Mann–Whitney U test were used, for parametric and nonparametric variables, respectively. The paired t-test and Wilcoxon signed rank test were utilised to compare the values of the parametric and nonparametric haemodynamic variables from the same group before (start: Time = 0 s) and after (steady-state moment: Time = 240 s) administration of the vasopressor. To analyse the relationship between the haemodynamic variables, we used Pearson's correlation. Two-tailed tests were performed and statistical significance was defined as a P value less than 0.05 (after Bonferroni correction for multiple comparisons) in all cases.

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A total of 60 patients were enrolled and subsequently assigned to the phenylephrine or norepinephrine group (Fig. 1). Three patients were excluded because of technical difficulties with the data recording (n = 2) or because they did not require haemodynamic support (n = 1) leaving 29 in the phenylephrine group and 28 in the norepinephrine group for analysis. Characteristics of the analysed patients in the two groups are summarised in Table 1. There were no significant between-group differences. Vasopressor administration was started 505 (295 to 627) s after induction of anaesthesia. All reported data were recorded before incision. The course of the haemodynamic variables is shown in Figs. 2 and 3 and Table 2. All data were synchronised at the moment of vasopressor administration.

Table 1

Table 1

Fig. 2

Fig. 2

Fig. 3

Fig. 3

Table 2

Table 2

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Haemodynamic response to phenylephrine or norepinephrine administration

Median (25th to 75th percentiles) dosages of phenylephrine and norepinephrine were 0.49 (0.47 to 0.62) and 0.05 (0.05 to 0.09) μg kg−1 min−1 respectively. Compared with baseline, both phenylephrine and norepinephrine increased MAP [Δ = 13 (8 to 22) and Δ = 13 (9 to 19) mmHg, respectively] and SV (Δ = 6 ± 6 and Δ = 5 ± 7 ml, respectively) significantly, while they induced a significant decrease in HR (both Δ = −8 ± 6 bpm) and CI (both Δ = −0.2 ± 0.3 l min−1 m−2) and maintained RPP (Δ = 345 ± 876 and Δ = 537 ± 1076 mmHg min−1, respectively). During the course of the procedure, SpO2 did not significantly vary [from 100 (99 to 100) at awake to 100 (99 to 100) at baseline and 100 (99 to 100)% after initiation of vasopressors]. SctO2 values significantly decreased in both groups [Δ = −4 (−7 to −2) and Δ = −4 (−5 to −1)%, respectively]. However, SptO2 only decreased in the norepinephrine group [Δ = −3 (−6 to 0)%], although it remained constant in the phenylephrine group [Δ = 0 (−1 to 1)%]. In both groups, SptO2 after vasopressor was still higher than the awake value.

Except for the significant difference in ΔSptO2 (P = 0.003), there were no significant differences in the values of the studied variables between the two vasopressor groups, at the awake state, baseline and the 240 s after assessments, nor in absolute changes. The SVR changed significantly from awake 1362 ± 405 to 1297 ± 344 dynes s cm−5 at baseline and ultimately to 1661 ± 391 dynes s cm−5 after administration of vasopressors.

PeCO2 values were unchanged 240 s after phenylephrine and norepinephrine administration [Δ = 0.1 (−0.2 to 0.1) and Δ = 0.0 (−0.1 to 0.3) kPa, respectively].

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Association between changes in SctO2 or SptO2 and changes in other haemodynamic variables

Except for the positive correlation between decreases in CI and SctO2 in the phenylephrine group, there was no significant relationship between the changes in MAP or CI and the changes in SctO2 or SptO2 after administration of phenylephrine or norepinephrine (Fig. 4). Pearson correlation coefficients (r) between SctO2 or SptO2 and all other investigated haemodynamic variables are summarised in Table 3.

Fig. 4

Fig. 4

Table 3

Table 3

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We have demonstrated that both phenylephrine and norepinephrine at the given dose produce an equivalent increase in MAP, while simultaneously decreasing HR, CI and SctO2. Although norepinephrine and phenylephrine have different adrenoceptor activity, we failed to find a statistically significant difference between either the effects on the MAP, CI or SctO2, or on the incidence of bradycardia in both groups. There was a small and clinically insignificant decrease in SptO2 in the norepinephrine group compared with the phenylephrine group, wherein values were maintained.

Regarding the clinical use of phenylephrine and norepinephrine, we observed a similar increase in MAP. Reports on the effects of phenylephrine and norepinephrine on CI are controversial and are thought to be related to preload dependency.33,34 As normovolaemia was achieved before the induction of anaesthesia in our study, we consider that the patients’ hearts were relatively preload independent. Therefore, the initial decrease in CI seen after administration of both phenylephrine and norepinephrine is in concordance with previous reports and results from the induced bradycardia in response to the administered vasopressors.

Figure 2 shows that after a fast increase in MAP with a simultaneous decrease in HR, and an unchanging SV, there is a second phase when the HR is stabilising with a steadily increasing SV, and as a result a partly recovering CI. This can most reliably be explained by the effect of the vasopressors on the capacitance vessels, resulting in a centralisation of venous blood, increasing venous return and ultimately stroke volume.33 This should arguably generate an increase in global tissue perfusion. However, because normovolaemia was aimed for prior to administration of the vasopressors, the heart was on the more horizontal part of the Frank–Starling curve, with the result that these effects were small. Despite the different pharmacological profiles of phenylephrine (a pure α1 adrenoceptor agonist) and norepinephrine (an α1 and β1 adrenoceptor agonist), no major differences between the two vasoconstrictors were observed in this setting.

The cost of achieving a rise in blood pressure after phenylephrine or norepinephrine in normovolaemia patients is almost always a decrease in SctO2, as shown here and in previous studies.35–37 It is often postulated that the cerebral vasculature lacks α1 adrenoceptors so that the general vasoconstriction induced by α1 agonists does not cause cerebral hypoperfusion.38 We found that after both phenylephrine and norepinephrine administration, there was a fall in SctO2, but much less so in SptO2. One way to explain this would be by the existence of cerebral α1 adrenoceptors.

The changes we observed in tissue oxygenation are based on absolute changes of SptO2 and SctO2, which provide very stable signals during stable physiological conditions. Therefore, we consider it unlikely that these observations are a result of measurement error alone. As SctO2 levels after the vasopressor administration only fell to those of the awake state value or slightly below it, it is probable that despite falling, cerebral oxygenation would have remained within acceptable physiological limits.

Changes in SctO2 are thought to be an acceptable surrogate of changes in cerebral blood flow when the arterial blood oxygenation and tissue oxygen consumption are kept constant.39 Because there was no sign of desaturation and no haemorrhage during the procedures, we assume the arterial blood oxygenation to be constant, and this was reflected in constant SpO2 levels. As patients in this study were under general anaesthesia with constant effect-site concentrations of propofol and remifentanil, cerebral metabolism and oxygen consumption by the tissues were also considered to be constant. Therefore, we assume that the changes in tissue oxygenation (on both sides) reliably reflect changes in regional blood flow.

Contrary to our hypothesis, SptO2 values were unaffected by the phenylephrine while after norepinephrine they fell, but by a clinically insignificant amount. Despite falling, SptO2 still remained higher than it was in the awake state. The lack of effects of phenylephrine on the SptO2 values is surprising, as it raises blood pressure mainly by a vasoconstriction-induced increase in peri- pheral vascular resistance, interfering with the balance between oxygen delivery and oxygen consumption. This might be expected to induce a decrease in SptO2. The methodology of our study does not allow us to provide a clear physiological explanation for this finding.

In the present clinical setting, the observed differences are probably of little clinical relevance, and both vasoconstrictors could be considered equally benign, despite their different pharmacological profiles, particularly as the baseline value was already increased compared with awake state values.

Although CI and MAP fairly reflect average macro-haemodynamics or possibly macrohaemodynamic changes, significant differences between particular organ systems may occur, potentially with significant clinical effects. Organ systems that are more sensitive to α-effects will react more strongly to vasoconstrictors, and as a result, asymetric haemodynamic effects are to be expected. Laser doppler flowmetry on the splanchnic mucosa in postcardiac surgery patients revealed a more pronounced splanchnic vasoconstriction after phenylephrine than after an equipotent dose of norepinephrine.40 It is important that all clinicians are aware of the distinction between changes in macroheamodynamics and changes in individual organ systems.

One of the study limitations is that both phenylephrine and norepinephrine can reduce skin blood flow possibly creating artefacts in the measurement of SctO2 and SptO2.41,42 Studies examining cerebral oxygenation using NIRS should quantify skin blood flow for an optimal interpretation of the data.43 One argument against this is that when norepinephrine is given in a dose similar to our study to treat postspinal hypotension, it does not impair skin perfusion, already increased by postspinal vasodilation.44 Also, a reported decrease in SctO2 in response to vasopressor administration was matched with a simultaneous fall in jugular venous bulb oxygen saturation.45 Our data provide further evidence, showing a much more pronounced decrease in SctO2 than SptO2, which suggests that these differences are not solely explained by differences in skin perfusion. However, it must be accepted that when a measurable decrease in SctO2 occurs in response to vasopressor administration, this may, to an unknown degree, be induced by changes in skin blood flow. This means that it is not possible to reach a definite conclusion regarding the cerebral effects of vasopressor administration.

Another limitation of the study is the use of the Nexfin monitor to record the haemodynamic changes. This new technology still needs additional validation to establish its limits of accuracy and precision. Initial studies conducted in the setting of anaesthesia and intensive care were based on small sample sizes and reported contrasting results.46,47 Without an accepted validation, its performance is in question for different clinical settings and physiopathological states. The Nexfin monitor derives CI from auto-calibrated pulse contour analysis of the pressure waveform. Every CI monitoring device has an intrinsic variability for which an inter-device error up to 30% is generally allowed.48 The accuracy of CI calculation by the Nexfin is generally believed to be within this limit. Noninvasive technology is subject to a certain amount of unavoidable inaccuracy. To keep this to a minimum instead of absolute CI values, we used absolute changes, which are thought to be more accurate.47 The administration of vasopressors itself might have some influence on accuracy, but the modest changes in SVR observed following administration of moderate doses of vasopressor suggests that the reliability of the Nexfin is largely unaffected.47 This is supported by the evolution of PeCO2, which is described as a noninvasive measure of pulmonary blood flow and therefore CI.30 The graphical representation of PeCO2 demonstrates the same trend as that of CI for the same ventilation settings, providing some validation for the Nexfin and its CI derivation.

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In normovolaemic patients under balanced propofol/remifentanil anaesthesia, no clinically relevant different effects between phenylephrine and norepinephrine on advanced haemodynamics or tissue oxygenation were observed when used to counteract anaesthesia-induced hypotension. After norepinephrine, a fall in peripheral tissue oxygenation was statistically significant, but its magnitude was not clinically relevant.

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Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: this work was solely supported by departmental and institutional funding.

Conflicts of interest: none.

Presentation: preliminary data of this study were presented as a poster presentation at the American Society of Anesthesiologists (ASA) annual meeting, October 2012, Washington, USA.

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