The effect of phenylephrine on cerebral perfusion when used to treat anesthesia-induced hypotension: a systematic review protocol : JBI Evidence Synthesis

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SYSTEMATIC REVIEW PROTOCOLS

The effect of phenylephrine on cerebral perfusion when used to treat anesthesia-induced hypotension: a systematic review protocol

Larson, Sandra Louise; Anderson, Lori Rae; Thomson, J. Scott

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JBI Database of Systematic Reviews and Implementation Reports 16(6):p 1346-1353, June 2018. | DOI: 10.11124/JBISRIR-2017-003426
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Abstract

Introduction

While the etiology of perioperative cognitive dysfunction (POCD) in adults following surgery is likely multifactorial, cerebral hypoperfusion is a commonly proposed mechanism.1,2 Its incidence has been widely reported in adults 65 years and over undergoing major surgical procedures.3 However, due to the lack of a universally accepted definition of POCD and failure to consistently diagnose the phenomenon, its overall incidence remains uncertain. In addition, isolated cases of POCD have been reported in young, healthy adults undergoing orthopedic procedures in the sitting postion,4 and in middle-aged adults undergoing cardiac and noncardiac surgery.5 Across all of these adult groups, the severity of cognitive dysfunction ranges from mild memory, concentration and comprehension impairments to persistent vegetative states.3-5 This systematic review seeks to evaluate the effect of phenylephrine on cerebral blood flow. Phenylephrine is a medication routinely used in anesthesia practice to treat hypotension. There is increasing concern that phenylephrine has the potential to reduce cerebral perfusion despite its ability to restore mean arterial pressure to normal values.6

Cerebral blood flow is regulated through: i) end products of cerebral tissue metabolism (neurovascular coupling), ii) chemical stimuli (chemoregulation), iii) myogenic mechanisms (autoregulation), and iv) direct autonomic (neurovascular) mechanisms.7,8 Metabolic end products are largely H+, K+ and adenosine. Chemical stimuli are largely the result of respiratory acidosis or alkalosis, and hypoxemia. Myogenic mechanisms involve the direct detection of transmural blood pressure changes by vascular smooth muscle. Neurogenic mechanisms involve perivascular nerves that alter the diameter of intra- and extra-parenchymal cerebral arteries, arterioles and veins.7,8

In the adult population, while anesthetic agents directly affect cerebral metabolic rates and perfusion in dose-dependent and variable ways, their potential to cause persistent POCD is generally considered to be clinically insignificant, within commonly prescribed dosages, except in certain situations involving neurosurgical patients.9-11 Instead, most threats to cerebral perfusion tend to be caused by the anesthetist's management of the effects of the anesthetic and surgical procedure on the cardiac, pulmonary and vascular systems.12-15 Additional threats are posed by factors associated with surgery such as blood loss, and factors associated with a patient's baseline cardiopulmonary status such as an abnormally low left-ventricular ejection fraction. Collectively, these threats compromise cerebral perfusion because of alterations in cardiac index, vascular resistance, mean arterial pressure (MAP), oxygen content and/or tissue oxygen uptake. Finally, cerebral perfusion is directly threatened by certain surgical procedures such as carotid endarterectomy,16 cardiac surgery and procedures during which the patient is in the sitting position.4,17-19

Anesthesia management of cerebral perfusion necessitates that the anesthetist perceive (monitor) essential information related to cerebral perfusion, accurately diagnose cerebral hypoperfusion (comprehend monitoring data), and intervene (treatment strategy) in ways that support cerebral perfusion. In anesthesia practice, low to moderate risk patients presenting for low to moderate risk surgical procedures are typically monitored according to the basic standards-of-care defined by the American Association of Nurse Anesthetists or the American Society of Anesthesiologists. These standards require monitoring with non-invasive blood pressure, pulse oximetry, electrocardiogram, temperature and end tidal CO2.20,21 It is important to note that none of these basic monitors provide a direct assessment of cerebral perfusion. Instead, the provider must accurately comprehend the information provided by these monitors in combination with other situational cues to indirectly diagnose the adequacy of cerebral perfusion. This is in contrast to the types of monitors used for high-risk patients and/or high-risk surgical procedures that enable more reliable assessments and management of tissue perfusion generally, and cerebral perfusion specifically. For these patients, the basic standard-of-care monitoring is supplemented with advanced monitoring that often includes invasive blood pressure, arterial blood gas analysis, mixed venous oxygen saturation, cerebral oxygen saturation, cardiac index, stroke volume, stroke volume variation, and measures of systolic and diastolic ventricular function using transesophageal echocardiography. Among these monitors, cerebral oxygen saturation using near infrared spectroscopy is the most commonly employed measure of global oxygenation in the right and left cerebral hemisphere during cardiac surgery. Furthermore, intraoperative cerebral oxygen desaturation has been shown to predict early neurocognitive decline and longer hospital stay after cardiac surgery.22

The debate within the anesthesia community as to what management strategy prevents cerebral hypoperfusion continues to be narrowly focused on MAP, and on the MAP threshold to treat anesthesia-induced hypotension (AIH). Anesthesia providers typically define AIH as a reduction in blood pressure of at least 20% from a patient's baseline MAP, or an absolute value of 60 mmHg or less, whichever is higher.23 Anesthesia-induced hypotension may occur at any time when anesthesia services are being provided, and may be the result of the anesthetic technique, the surgical procedure and/or the patient's preexisting condition(s). The anesthesia community's narrowly focused attention on MAP is the result of Lassen's sentinel research on cerebral autoregulation (CA), which found that cerebral perfusion is maintained within a range of MAPs.24 Lassen's research has been translated in anesthesia texts and in practice as: normal cerebral perfusion is maintained within a MAP range of 50 mm Hg and 150 mm Hg (assuming normal oxygen content is maintained).25 In addition, this rule of thumb has been modified in hypertensive populations: the CA curve may shift to the right in this population, therefore the MAP should be maintained within 20% of the patient's baseline.26

These longstanding beliefs governing CA are based on flawed research and inaccurate translation to practice, thereby creating significant gaps and errors in our understanding and alignment with evidence-based practice.27,28 In the seven studies that involved 11 samples of patients, which Lassen combined to create the CA curve, the studies failed to control for the potential myogenic and neurogenic influence of vasoactive drugs (used to induce hypotension and hypertension), and the chemical influence of changes in alveolar ventilation that accompany acute hypotension and hypertension. Most egregiously, group means for the low and high limits of the plateau portion of the CA curve have been incorrectly translated into clinical practice as every subject behaves like the mean, ignoring significant individual variability in the lower limits of CA. Findings have also been incorrectly generalized to all patients without regard for the gross disparities that often exist between the research conditions and clinical conditions. Finally, findings have been translated without regard for all three components of Poiseuille's Law, which states that flow (cardiac output) is a function of pressure over resistance (Q = P/R). Fortunately, piqued awareness that CA is poorly understood,29 and that considerable individual-to-individual variability in the lower limit of CA exists,27 is causing closer scrutiny of these practice patterns.

Two additional evidence-based practice challenges related to cerebral perfusion exist. The first relates to the significant gap in knowledge regarding neurogenic control of cerebral perfusion,7,30-33 and the second relates to the significant gap in knowledge regarding the effect of vasopressors on the cerebral vasculature. In a review of the nervous control of the cerebral vascular system, Sandor7 noted that neuroanatomists and neurochemists have scientifically established the presence of a highly complex cerebral neuroregulatory system, complete with perivascular nerve endings in the outer smooth muscle layer of extra cortical and intra cortical arteries, arterioles and veins, along with axon terminals and transmitters. However, inconsistent research findings of the effect of alpha-adrenergic stimulation on cerebral blood flow have resulted in the conclusion that neurogenic control is either: i) unimportant, or ii) negligible. Sandor7 challenges the conclusions of the scientific community that neurogenic control is insignificant, and offers a critique that the disparate findings are related to the fact that researchers: i) did not account for the heterogeneous density of sympathetic innervation across different regions of the brain, ii) inappropriately compared findings across different species, iii) failed to control for intraspecies development differences, and iv) failed to control for other confounding variables such as the degree to which the neurotransmitter can permeate the blood brain barrier. In addition, there is no universally accepted gold standard for how to measure cerebral perfusion, nor are there universal standards for the implementation of commonly employed measurement strategies.34

As previously noted, in anesthesia practice, cerebral oximetry is the most common method of monitoring cerebral perfusion in high-risk patients. This non-invasive technology uses near infrared wavelengths of light to assess regional oxygen saturation in the right and left frontal cortex.35 There is consensus among clinicians who frequently use cerebral oximetry monitoring that administration of phenylephrine is associated with declines in cerebral oximetry across a significant number of patients (personal communications). Phenylephrine is commonly accepted as the optimal method of managing MAP during high-risk carotid endarterectomy procedures.27 It is also administered on a daily basis via intravenous bolus dosages or continuous infusion by a vast number of anesthetists to manage AIH. Phenylephrine is an alpha-1 receptor agonist, affecting beta-receptors only at very high doses.36 The drug is thought to produce greater venoconstriction than vasoconstriction, thereby predominantly increasing venous return and preload. However, phenylephrine does increase arterial vascular resistance in the skin, muscles, and renal and mesenteric vascular beds, leading to increases in both systolic and diastolic blood pressure.37 This increase in blood pressure following the administration of phenylephrine is typically accompanied by a vagally-mediated baroreflex slowing of the heart rate. Phenylephrine's combined effects of increased preload, increased arterial vascular resistance and decreased heart rate may produce variable effects on cardiac output. While phenylephrine is likely a pulmonary artery vasoconstrictor,38 it has classically been credited with little direct effect on coronary or cerebral circulation, and phenylephrine has been described as not being able to cross the blood-brain barrier.39 More recently, some authors have postulated that the cerebral vasculature may have significant sympathetic innervation,40 and that phenylephrine may directly or indirectly, through a sympathetically mediated reflex,41 cause cerebrovascular constriction.

Research findings from a preliminary literature review investigating the effect of phenylephrine on cerebral hemodynamics in anesthetized patients in the sitting position showed that when phenylephrine was used to treat AIH, it consistently: i) decreased cerebral oxygen saturation despite a simultaneous increase in MAP; ii) consistently increased middle cerebral artery (MCA) blood flow velocity, which may indicate sympathetically mediated constriction of the MCA; and iii) frequently decreased cardiac output.6 Also reported was that hypocapnia enhanced the potential for phenylephrine to reduce cerebral blood volume.6 The authors of this protocol have done a preliminary search of Ovid MEDLINE, CINAHL, Embase, Google Scholar and PsycINFO, which has identified studies that meet the inclusion criteria.42-51 This same search found no evidence that a systematic review is in process or has been conducted.

In summary, while the etiology of POCD in adults following surgery is likely multifactorial, cerebral hypoperfusion is a commonly proposed mechanism.1,2 Research evidence and expert opinion are now emerging that suggest phenylephrine may adversely affect cerebral oxygen saturation and perfusion.42-51 The use of phenylephrine to treat AIH is a ubiquitous practice among anesthesia providers, despite the fact that it has never been shown to improve outcomes. Therefore, a systematic review of the effect of phenylephrine on cerebral perfusion, when used to treat AIH, has significant implications for anesthesia practice and is warranted.

Inclusion criteria

Participants

Studies in the systematic review will include human subjects who are 18 years or over undergoing elective surgical procedures involving sedation, regional or general anesthesia provided by a nurse anesthetist or anesthesiologist. Studies in which subjects are undergoing intracranial surgical procedures will be excluded from this review.

Intervention

Studies in the systematic review will include those that evaluate the effect of intravenous phenylephrine administered as a bolus or continuous infusion to treat AIH. Studies must use dosages consistent with typical anesthesia practice, which is 40–200ug per bolus, or 10–200ug/minute for continuous infusion.

Comparator

Comparators include placebo, ephedrine, normal saline, or other vasopressor agents such as epinephrine, norepinephrine or dopamine.

Outcomes

Outcomes for this systematic review include cerebral oxygen saturation or MCA blood flow velocity. Cerebral oxygen saturation must be measured using near infrared spectroscopy, and MCA blood flow velocity must be measured using transcranial doppler. Cardiac output, heart rate, MAP, length of stay, postoperative cognitive decline and mortality will be also be included as outcome variables, if available.

Types of studies

This review will consider both experimental and quasi-experimental study designs including randomized controlled trials, non-randomized controlled trials, before and after studies, and interrupted time-series studies.

Only studies published in English will be included. Only studies published since 1999 will be included, as this time period correlates with the advent of cerebral oximetry technology in anesthesia practice using monitoring technology that is similar to today's devices.52

Methods

Search strategy

The search strategy aimed to find both published and unpublished studies. An initial limited search of Ovid MEDLINE(R) and the Trip Database was undertaken using the following search terms: phenylephrine, vasoconstrictor agents, cerebral oxygen saturation, cerebral perfusion, cerebral blood flow, cerebral circulation, cerebral vascular circulation, cerebral autoregulation, cerebral desaturation event, cerebral ischemia, beach chair position, sitting position and patient positioning. Subsequently, an analysis of the text words contained in the title and abstract, and of the index terms used to describe the articles was undertaken to expand the list of search terms. This information was used to inform the development of a search strategy, which was tailored for each information source. An example is appended in Appendix I. The reference lists of all studies selected for critical appraisal were screened for additional studies.

Information sources

The databases to be searched will include: Ovid MEDLINE(R), Trip Database, Embase, CINAHL and PsycINFO.

The trial registers to be searched will include: ClinicalTrials.gov.

The search for unpublished studies will include: Google Scholar, MedNar, Grey Literature Report, and ProQuest Dissertations and Theses.

Study selection

Following the search, all identified citations will be collated and uploaded into a Word document and duplicates removed. Titles and abstracts will then be screened by two independent reviewers for assessment against the inclusion criteria for the review. Studies that meet the inclusion criteria will be retrieved in full and their details imported into Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information (JBI SUMARI). The full text of selected studies will be retrieved and assessed in detail against the inclusion criteria. Full text studies that do not meet the inclusion criteria will be excluded and reasons for exclusion will be provided in an appendix in the final systematic review report. Included studies will undergo a process of critical appraisal. The results of the search will be reported in full in the final report and presented in a PRISMA flow diagram. Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer.

Assessment of methodological quality

Selected studies will be critically appraised by two independent reviewers at the study level for methodological quality in the review using the standardized critical appraisal instruments from the Joanna Briggs Institute for either randomized controlled trials or quasi experimental studies.53 Any disagreements that arise will be resolved through discussion, or with a third reviewer.

Following critical appraisal, studies that do not meet a certain quality threshold will be excluded. The decision to exclude will be based on the inability to meet one or more of the indicators on the appraisal instrument.

Data extraction

Data will be extracted from papers included in the review using the standardized data extraction tool available in JBI SUMARI by two independent reviewers.53 The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. Authors of papers will be contacted to request missing or additional data where required.

Data synthesis

Papers will, where possible be pooled in statistical meta-analysis using JBI SUMARI. Effect sizes will be expressed as either odds ratios (for dichotomous data), and weighted (or standardized) mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard chi-square and I square tests. Tufunaru et al.54 will guide the reviewers’ choice of model (random or fixed effects) and method for meta-analysis.

Subgroup analyses will be conducted where there is sufficient data to investigate the effect of other treatment strategies included in the various research designs, separate from phenylephrine. Sensitivity analyses will be conducted to test decisions made regarding whether confounding variables contributed to the effect. Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.

A funnel plot will be generated to assess publication bias if there are 10 or more studies included in a meta-analysis. Statistical tests for funnel plot asymmetry (Egger test, Begg test, Harbord test) will be performed, where appropriate.

Assessing confidence

A Summary of Findings table will be created using GRADEPro GDT software.55,56 The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for grading the quality of evidence will be followed. The summary table will present the following information where appropriate: absolute risks for treatment and control, estimates of relative risk, and a ranking of the quality of the evidence, based on study limitations (risk of bias), indirectness, inconsistency, imprecision and publication bias.

Appendix I: Search strategy

MEDLINE: search undertaken on July 27, 2017

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Keywords:

Cerebral autoregulation; cerebral ischemia; cerebral oxygen saturation; cerebrovascular circulation; transcranial Doppler

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