Phenylephrine is a rapid-onset vasoactive drug widely used to maintain mean arterial pressure (MAP) and tissue oxygen delivery to minimise perioperative morbidity and mortality.1–3 It is a direct α-adrenergic receptor agonist, predominantly α1, increasing arterial pressure, systemic vascular resistance, and thereby left ventricular (LV) afterload.4 However, an increase in LV afterload may decrease stroke volume (SV) and thus cardiac output (CO). Finally, α1-adrenergic receptor stimulation also decreases venous capacitance, which could in turn increase venous return, and SV.5 Magder et al.6 have suggested that these two mechanisms may be both concomitant and competitive. The resulting haemodynamic effect may depend on the position of the heart in relation to the Frank–Starling relationship, depicted by the Sarnoff curve.7 If the heart is on the steep part of the curve then phenylephrine could increase CO (preload dependency), whereas if it is on the plateau it could decrease CO (preload independency). This hypothesis is supported by a laboratory study showing that the effect of phenylephrine on CO depends on the preload dependency of the cardiovascular system.8 To the best of our knowledge, no data are available on the influence of preload dependency on the effect of phenylephrine on CO in anaesthetised patients. The aim of this study was to examine whether the effect of phenylephrine on CO differs according to preload dependency during surgery under general anaesthesia.
Ethical approval for this study (reference: A12-D20-volume12) was provided by the the local Ethics Committee (Comité de Protection des Personnes Nord Ouest III, Caen, France) on 12 May 2012. The trial was registered at ClinicalTrials.gov (NCT 01730820). This prospective observational study was performed between November 2012 and July 2013. The study was conducted in accordance with the STrengthening the Reporting of OBservational studies in Epidemiology statement concerning observational studies.9 Because data were collected during routine care of patients that conformed to standard procedures used in Caen University Hospital, written informed consent was waived.
Consecutive adults undergoing surgery requiring general anaesthesia with mechanical ventilation and advanced haemodynamic monitoring by oesophageal Doppler and arterial catheter were eligible for the study. They were included if hypotension, defined as systolic arterial pressure (SAP) less than 90 mmHg or MAP less than 60 mmHg, was treated with a bolus injection of phenylephrine on the decision of the attending physician and in accordance with the local protocol. Minors, adults under protection, patients with an oesophageal disease, arrhythmia,10 history of valvular heart disease, history of right ventricular heart failure or pulmonary artery hypertension,11 history of severe LV heart failure (known LV ejection fraction <30%),12 known intracardiac shunt, or receiving medical treatment with α-adrenergic blocking agents or prior injection of any vasopressor were not included. Patients were also excluded if they had a tidal volume less than 8 ml kg−1 of predicted weight,13 heart rate (HR) on respiratory rate ratio less than 3.6,14 known intra-abdominal hypertension,15 pulmonary compliance less than 30 ml cmH2O−1,16 spontaneous breathing10 or had undergone open lung surgery.17
All perioperative management took place in accordance with our institutional standards. After i.v. line placement and monitoring (IntelliVue MP70 Philips HealthCare, Amsterdam, The Netherlands) with continuous 5-lead electrocardiography, pulse oximetry, and bispectral index (BIS quatro sensor, Covidien, Dublin, Ireland), a radial intra-arterial catheter was placed (Leader-cath; VYGON, Ecouen, France) and connected to a pressure transducer zeroed at the intersection of the mid-axillary line and the fifth intercostal space. Arterial pressure and pulse pressure variation (PPV) were continuously displayed on the IntelliVue MP70 monitor. After induction, anaesthesia was maintained using target-controlled total i.v. anaesthesia with propofol and remifentanil, and muscle relaxation using atracurium. All the patients were intubated and ventilated (Aisys, Ge Healthcare, Little Chalfont, UK) with controlled ventilation mode (inspired oxygen fraction 40%, tidal volume: 8 ml kg−1, and respiratory rate between 10 and 15 min−1 according to the end tidal CO2). An oesophageal Doppler probe was inserted after tracheal intubation and connected to its monitor (CardioQ-ODM, Deltex Medical, UK). Cardiac index (CI), SV, peak velocity and corrected flow time (FTc) were averaged across 10 successive measurements. The systemic vascular resistance index (SVRI) was calculated using the following formula: SVRI = (MAP/CI) × 80.
The protocol began with the decision by the attending anaesthesiologist to administer an intravascular bolus of 50 to 150 μg of phenylephrine based on depth of hypotension according to the local protocol to treat the initial episode of peroperative hypotension as defined above. The duration of hypotension before treatment was left to the discretion of the attending physician. The following data were recorded both before phenylephrine administration and at peak effect on MAP: HR, SAP, MAP, diastolic arterial pressure (DAP), PPV, bispectral index, CI, SV, peak velocity, FTc. Data were recorded by a resident in anaesthesiology without responsibility for clinical care. All the data records were measured without surgical stimulation, between anaesthetic induction and the start of surgery.
The primary outcome was CO and the changes associated with administration of phenylephrine in preload-dependent and independent patients. Secondary outcomes were the changes in HR, SV, FTc, MAP, PPV and SVRI following phenylephrine in preload-dependent and independent patients.
We planned to include 20 patients in each group to detect a 10% variation in CO in the preload-dependent group (type I error = 5%, type II error = 10%). We therefore chose to conduct the study until 50 patients were recruited to take into account 20% of missing data. Data are expressed as mean (SD), or median (25th; 75th) for nonnormally distributed variables (Shapiro–Wilk test), or numbers (%), as appropriate. The patients were separated into two groups according to the PPV measured before phenylephrine administration: preload-dependent (PPV ≥ 13%) and preload-independent (PPV < 13%).18 Continuous variables were analysed with unpaired Student t and Mann–Whitney U tests according to their distribution, to compare preload-dependent and independent values. Absolute values and changes in haemodynamic variables after phenylephrine injection were compared using the paired Wilcoxon test. All the tests were two-tailed and a P value less than 0.05 was considered significant. Statistical analyses were performed using Microsoft Microsoft software name for Mac version 14.2.0 (Microsoft Corporation, Redmond, Washington, USA) and Addinsoft software name (Version 7.5.2, Addinsoft, New York, New York, USA).
The study flow chart is shown in Fig. 1. Fifty patients were included in the study. Twenty seven (54%) were preload-dependent and 23 (46%) were preload-independent according to the PPV measured before administration of phenylephrine. Personal characteristics between the two groups were similar (Table 1).
The PPV was 17% (15; 19) in the preload-dependent group and 8% (7; 11) in the preload-independent group (P < 0.0001). Table 2 shows that PPV validity criteria were as recommended. The BIS was unchanged for the whole cohort during the study period [before phenylephrine: 41 (12) ‘vs.’ after phenylephrine: 41 (13); P = 0.44].
Haemodynamic data before and after injection of phenylephrine for the entire cohort
The dose of phenylephrine administered was comparable between preload-dependent [1.5 (0.6) μg kg−1] and preload-independent groups [1.4 (0.4) μg kg−1; P = 0.279].
For the entire cohort, phenylephrine significantly increased systolic [83 (13) mmHg ‘vs.’ 113 (18) mmHg; P < 0.0001], diastolic [46 (8) mmHg ‘vs.’ 63 (13) mmHg; P < 0.0001], mean [58 (8) mmHg ‘vs.’ 79 (13) mmHg; P < 0.0001] arterial pressure and calculated SVRI [2010 (1338; 2481) dyn s cm−5 m−2 ‘vs.’ 2989 (2155; 3870) dyn s cm−5 m−2; P < 0.0001]. Phenylephrine significantly decreased HR [77 (18) min−1 ‘vs.’ 65 (17) min−1; P < 0.0001] and the CI [2.3 (1.8; 3.7) l min−1 m−2 to 1.9 (1.6; 2.9) l min−1 m−2; P < 0.0001].
Differences between preload-dependent and independent groups
Haemodynamic data before and after administration of phenylephrine in the preload-dependent and independent groups are given in Table 3. Before administration of phenylephrine, preload-dependent patients had a higher HR (P < 0.0001) and lower SAP (P < 0.0001). Individual arterial pressures before phenylephrine administration are shown in Fig. 2. Following phenylephrine, CI and SV decreased in the preload-independent group (P < 0.0001 for both) but not in the preload-dependent (P = 0.168 and P
= 0.191, respectively).
The increase in arterial pressure was similar between groups, whereas the increase in SVRI was greater in the preload-independent than the preload-dependent group (Table 4).
The phenylephrine-induced variations in CI are given in Table 4. SV did not change significantly in the preload-dependent, but decreased in the preload-independent group. At the same time there was no difference in HR variation between the groups (Table 4).
The FTc significantly increased in the preload-dependent but decreased in the preload-independent group. The phenylephrine-induced decrease in peak velocity was lower in the preload-dependent group (Table 4).
We have shown that the effect of phenylephrine on CI and SV is influenced by the preload-dependency state of the heart. In preload-independent patients, administration of phenylephrine decreased CI and SV, whereas in preload-dependent patients CI and SV remained unchanged. Also in preload-dependent patients, the increase in FTc and decrease in PPV suggest that phenylephrine increases cardiac preload, which may have helped maintain SV despite the phenylephrine-induced increase in cardiac afterload.
As previously reported, phenylephrine increased arterial pressure and SVRI, but decreased CI,19,20 gaining rapid control of arterial hypotension in anaesthetised patients. However, the global effect of phenylephrine on CO may result from the increase in venous return because α1-adrenergic receptor stimulation also decreases venous capacitance.6
Effect of phenylephrine on cardiac index
In a laboratory study, the effect phenylephrine on CO was shown to depend on the position of the heart in the Frank–Starling relationship; CO increased if the heart operated on the steep portion of the relationship (preload dependency), but decreased if it operated on its plateau (preload independency).8 In anaesthetised patients monitored with oesophageal Doppler, phenylephrine administration was shown to decrease CO in contrast to ephedrine.21,22 However, these studies did not examine patient preload dependency. Following cardiac surgery, the effect of norepinephrine on CO has been shown to depend on mean systemic filling pressure.23 However, norepinephrine exerts α- and β-adrenergic receptor stimulation, and vascular dysfunction as observed following cardiopulmonary bypass for cardiac surgery could be a confounding factor.24,25 The present study showed that phenylephrine decreased CI in preload-independent patients, whereas CI remained unchanged in preload-dependent patients. In preload-independent patients, CI and SV variations were above the oesophageal Doppler precision threshold, which is estimated at 8%, whereas in preload-dependent patients, slight CI and SV variations were below this threshold.26
In preload-independent patients, there were decreases in HR, SV, FTc and peak velocity.27,28 Taking the increase in SVRI into account, these data suggested that a phenylephrine-induced increase in cardiac afterload was the main cause of the decrease in SV and CI. In contrast, in preload-dependent patients, our data showed an increase in FTc and a decrease in PPV suggesting that phenylephrine increased cardiac preload.29–32
Interestingly, in anaesthetised hypovolaemic pigs, a bolus of phenylephrine increased inferior vena cava blood flow and decreased PPV.8 The CO measured by a pulmonary arterial catheter, reflecting right ventricular CO, increased, suggesting the recruitment of blood volume from the splanchnic reservoir. Furthermore, the authors also showed that PPV and SV variation could predict the phenylephrine-induced increase in SV.
Finally, in intensive care patients, it has been shown that norepinephrine decreases preload dependency evaluated by the increase in CO following a passive leg raising test.33,34 However, norepinephrine also increased HR and myocardial contractility through β1-adrenergic receptor stimulation; both should have increased CO. Furthermore, following cardiac surgery, an increase in continuous i.v. administration of norepinephrine raised systemic filling pressure and CO in preload-dependent patients according to SV variation.23
In preload-dependent patients, for whom the ventricles operate on the steep part of the Sarnoff curve, phenylephrine increases preload by increasing venous return. This was indicated by increased FTc and decreased PPV, thereby increasing contractility and stabilising SV in spite of increased SVRI and LV afterload.30
In preload-independent patients, for whom the ventricles operate on the plateau part of the Sarnoff curve, the action of phenylephrine on preload and venous return does not produce a further increase in contractility, and therefore SV is decreased because of the increase in SVRI and LV afterload. Figures 3 and 4 show the effects of phenyleprhine on venous return and SV curves in preload-dependent and preload-independent patients.
In clinical practice, phenylephrine is used to control hypotension during anaesthesia, maintaining adequate tissue oxygen delivery for oxygen consumption and preventing perioperative morbidity and mortality.2,3 Previous studies have reported that phenylephrine decreases CI,19,20 ventricular performance and ventriculo-arterial coupling in hypokinetic and hypotensive experimental septic shock.35 The present study showed a critical phenylephrine-induced decrease in CI in preload-independent patients which could impair regional oxygen delivery. In contrast, phenylephrine did not decrease CO in preload-dependent patients. Altogether, these data suggest that anaesthesiologists should evaluate preload dependecy before phenylephrine administration because the effect on CI is strikingly different.
Our study has limitations. First, preload dependency was defined by PPV at least 13% which has been recognised as a good predictor of fluid responsiveness,18 and is used to help anaesthesiologists optimise perioperative fluid administration.30 Although the main validity criteria were checked, we did not measure intra-abdominal pressure, nor assess right heart failure or pulmonary artery hypertension, which we assume to be rare.11,15
Second, the groups were not identical in terms of arterial pressure before phenylephrine administration, with the preload-dependent group ‘more hypotensive’ in terms of SAP but not in terms of MAP and DAP. Third, we estimated CO with an oesophageal Doppler based on descending aortic blood flow velocity and an aortic diameter estimated from a nomogram.25,26 Although the estimation of aortic diameter can reduce the accuracy of oesophageal Doppler used to detect CO changes, it has been suggested that the oesophageal Doppler remains the most reliable beat-to-beat CO monitoring tool if vasopressors are administered.20
Fourth, following phenylephrine administration, it was no longer possible to confirm the fluid responsiveness of patients in the preload-dependent group because phenylephrine had modified filling pressure and vascular tone.5 Fifth, the main goal of haemodynamic optimisation is to improve oxygen delivery. Phenylephrine injection decreased cerebral tissue oxygen saturation with a significant correlation with CO, suggesting a causal relationship between global and regional haemodynamics.22 We found that the effect of phenylephrine on CI depended on the heart's preload dependency and we did not provide evidence that the decrease in CI in preload-independent patients was deleterious to systemic or regional oxygenation. Further studies are needed to evaluate the impact of preload dependency on the effects of phenylephrine on tissue microcirculatory oxygenation.36,37
In conclusion, in anaesthetised patients, the effects of phenylephrine on CO depend on the preload-dependent state of the heart, with a fall in CI in the event of preload independency, mainly with an afterload effect, and CI stability in the event of preload dependency, presumably through an increase in venous return.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: this work was supported by the Department of Anaesthesiology and Critical Care, University Hospital of Caen, Caen, France.
Conflicts of interest: none.
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