Noradrenaline-induced changes in cerebral blood flow in health, traumatic brain injury and critical illness: a systematic review with meta-analysis
1 Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN, USA
2 Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
3 Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
4 Department of Anesthesiology, Section of Neuroanesthesia, Aarhus University Hospital, Aarhus, Denmark
5 Indiana University School of Medicine, Indianapolis, IN, USA
6 Choate Rosemary Hall School, Wallingford, CT, USA
7 Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, USA
8 Departments of Anesthesiology and Pain Management, Neurological Surgery, Neurology, UT Southwestern Medical Center, Dallas, TX, USA
Summary
Background
Noradrenaline is a standard treatment for hypotension in acute care. The precise effects of noradrenaline on cerebral blood flow in health and disease remain unclear.
Methods
We systematically reviewed and synthesised data from studies examining changes in cerebral blood flow in healthy participants and patients with traumatic brain injury and critical illness.
Results
Twenty-eight eligible studies were included. In healthy subjects and patients without critical illness or traumatic brain injury, noradrenaline did not significantly change cerebral blood flow velocity (-1.7%, 95%CI -4.7–1.3%) despite a 24.1% (95%CI 19.4–28.7%) increase in mean arterial pressure. In patients with traumatic brain injury, noradrenaline significantly increased cerebral blood flow velocity (21.5%, 95%CI 11.0–32.0%), along with a 33.8% (95%CI 14.7–52.9%) increase in mean arterial pressure. In patients who were critically ill, noradrenaline significantly increased cerebral blood flow velocity (20.0%, 95%CI 9.7–30.3%), along with a 32.4% (95%CI 25.0–39.9%) increase in mean arterial pressure. Our analyses suggest intact cerebral autoregulation in healthy subjects and patients without critical illness or traumatic brain injury., and impaired cerebral autoregulation in patients with traumatic brain injury and who were critically ill. The extent of mean arterial pressure changes and the pre-treatment blood pressure levels may affect the magnitude of cerebral blood flow changes. Studies assessing cerebral blood flow using non-transcranial Doppler methods were inadequate and heterogeneous in enabling meaningful meta-analysis.
Conclusions
Noradrenaline significantly increases cerebral blood flow in humans with impaired, not intact, cerebral autoregulation, with the extent of changes related to the severity of functional impairment, the extent of mean arterial pressure changes and pre-treatment blood pressure levels.
Introduction
Hypotension is generally treated to address concerns regarding resultant organ hypoperfusion. Although a universally accepted definition of hypotension does not yet exist, brain perfusion is prioritised due to its high metabolic rate and lack of fuel storage, requiring a continuous supply of metabolic substrates and washing out of metabolic wastes via cerebral blood flow (CBF). Noradrenaline is one of the most commonly used vasopressors and is often a preferred choice for conditions including septic shock [1], traumatic brain injury [2], acute ischaemic stroke [3] and anaesthesia-related hypotension [4]. However, despite its widespread use, the effects of noradrenaline on CBF remain unresolved. One recent scoping review, primarily on animal studies, reported increases and decreases in CBF following noradrenaline administration [5]. Moreover, based on 13 human studies, the authors concluded that CBF in most patients remained relatively unchanged, with seven studies involving healthy brains and six studies involving traumatic brain injury [5]. These findings question contemporary practice if the effect of noradrenaline on CBF is either unpredictable or negligible. The review did not perform a meta-analysis, meta-regression or explore the factors modulating the noradrenaline-induced CBF changes. Our knowledge gap is echoed by a recent review that called the relationship between vasopressor therapy and the brain “the dark side of the moon” [6].
Our hypothesis regarding noradrenaline-induced changes in CBF in the human brain comprises three key aspects. First, we propose that changes in CBF are contingent on the patient population and functional status (i.e. intact or impaired) of cerebral autoregulation. Second, we posit that CBF changes are proportional to changes in blood pressure, especially in patients with impaired cerebral autoregulation. Third, we expect an association between the extent of CBF changes and the pre-treatment blood pressure level. Acknowledging the need to substantiate our hypotheses, we performed a systematic review with meta-analysis to assess noradrenaline-induced alterations in CBF in human subjects. We aimed to substantiate the above-elaborated hypotheses in human subjects stratified by brain conditions.
Methods
Our literature search strategy sought to identify all relevant research addressing changes in CBF resulting from the intravenous administration of noradrenaline in adult human subjects. We included studies involving human participants, whether volunteers or patients with or without critical illness and traumatic brain injury. However, we excluded studies conducted during caesarean sections or cardiopulmonary bypass surgeries, as these unique populations merit distinct and specialised reviews. We also excluded studies conducted in patients with haemodynamically significant carotid/cerebral arterial stenotic lesions and intracranial collateral flow activation because these conditions can affect middle cerebral artery flow, confounding transcranial Doppler (TCD) flow velocity assessments. The eligible intervention was the intravenous administration of noradrenaline, delivered as a bolus or infusion. We required that the studies report pre- and post-treatment blood pressure and CBF values or changes in these two variables. The study designs were prospective observational studies or randomised trials conducted in settings including research laboratories or hospitals. We considered reports published in any year or language.
We systematically searched databases including Ovid MEDLINE®, EMBASE and Web of Science from inception to 21 May 2023. The search was updated to check for additional articles in April 2024. The systematic literature search strategy was tailored to our objectives and the criteria for eligible studies (online Supporting Information Table S1). In addition to our primary database searches, we expanded our inquiry to PubMed and Google Scholar, employing keywords such as ‘noradrenaline’ and ‘cerebral blood flow’ in various combinations. Furthermore, we screened relevant reference lists to identify additional studies.
The records retrieved from the systematic search were exported into EndNote (Clarivate, Philadelphia, PA, USA). Semi-automated and manual screening were used to remove duplicates. Four reviewers (LM, YS, XZ and YA) independently screened the records to identify potentially eligible studies. They then independently assessed the eligibility of the candidate publications based on predefined criteria. In cases of discrepancies between reviewers, the lead author (LM) was consulted for resolution.
We extracted the relevant data from the eligible articles into a pre-designed data collection form. We classified study participants into different categories: healthy subjects; patients without critical illness or traumatic brain injury; patients with traumatic brain injury; and patients who were critically ill. Examples of critical illness included conditions such as hepatic encephalopathy in patients with fulminant hepatic failure requiring mechanical ventilation; acute bacterial meningitis necessitating mechanical ventilation; post-cardiac arrest status necessitating mechanical ventilation; large acute stroke necessitating intensive care unit admission; subarachnoid haemorrhage requiring surgical intervention; and severe sepsis or septic shock requiring mechanical ventilation.
Articles published before 2000 were ultimately eliminated from the primary analysis, as most of the identified studies were published since 2000. These newer studies, unlike older studies, used a consistent approach to CBF analysis. On editorial review, it was agreed that the older studies should be excluded in order to draw conclusions that were relevant to contemporary clinical practice.
Proportional changes were calculated to quantify the noradrenaline-induced changes in mean arterial pressure (MAP) and CBF by subtracting the pre-treatment value from the post-treatment value, dividing the result by the pre-treatment value and multiplying by 100. Our analysis predominantly relied on group mean values reported in the original studies, as most eligible studies presented their data in this aggregated format.
We conducted meta-analyses to examine the changes in MAP and CBF. These analyses were stratified by populations, as described above. Random-effects models were employed to estimate the pooled changes in MAP and CBF, along with their corresponding 95%CIs.
We tested three hypotheses regarding the factors that modulate noradrenaline-induced changes in CBF: the functional status of cerebral autoregulation; the magnitude of blood pressure change; and the pre-treatment blood pressure levels.
Our first hypothesis examined the impact of cerebral autoregulation functional status on noradrenaline-induced changes in CBF. To investigate this, we categorised participants into three distinct groups: those with a healthy or relatively healthy brain; those with traumatic brain injury; and patients who were critically ill. We postulated that different populations would exhibit different cerebral autoregulatory capacities, which are associated with different changes in CBF. The functional status of cerebral autoregulation was assessed based on the data presented by the original studies and MAP-CBF association plots, utilising both pre- and post-noradrenaline treatment group mean values. These plots included trendlines and 95%CIs based on locally estimated scatterplot smoothing, weighted with sample size.
Our second hypothesis was that the extent of CBF changes depends on the extent of MAP changes. To explore this, we visually represented the relationship between noradrenaline-induced changes in MAP and CBF through bubble plots. These featured linear trendlines and 95%CIs, computed using random-effects meta-regression. We reported the coefficient of determination (R2), heterogeneity (I2), regression coefficient (slope) and the corresponding p values. R2 denotes the proportion of the total heterogeneity of CBF changes among studies explained by the MAP changes.
Our third hypothesis was that the noradrenaline-induced changes in CBF were associated with the pre-treatment blood pressure levels. We employed a ratio-based approach to mitigate the potential confounding effect of varying magnitudes of CBF changes. Specifically, we calculated the ratio of the CBF change to the MAP change in this analysis, with the changes in CBF and MAP calculated as the post-treatment value minus the pre-treatment value. We investigated this hypothesis using simple linear regression weighted with sample size. We did not perform meta-regression because the ratio variance cannot be reliably estimated.
Various methods for measuring CBF can yield non-interchangeable measurements. For example, TCD measures flow velocity in cm s-1, which differs from the mass flow measurements obtained using the Kety-Schmidt nitrous oxide method (expressed in ml 100 g-1 min-1) [7]. Therefore, our analysis considered different CBF measurement methods as a stratification factor. Nevertheless, previous research has shown a significant association between proportional changes derived from TCD-measured flow velocity and non-TCD-measured mass flow [8, 9].
To examine the inter-relationships among the proportional changes in CBF (y-axis) and MAP (x-axis), the pre-treatment blood pressure (z-axis) and the functional status of cerebral autoregulation (a binary variable, differentiated using colour-coded data points), we used three-dimensional bubble plots.
We performed all statistical analyses using R version 4.3.1 (R Studio, Vienna, Austria). Data pre-processing and analyses used these R packages: meta version 6.5-0; metafor version 4.4-0; ggplot2 version 3.4.2; multcomp version 1.4-25; dplyr version 1.1.2; mgcv version 1.8-42; tidymv version 3.4.2; and rgl version 1.2.1. Statistical significance was defined as p values < 0.05.
We assessed the risk of bias according to Cochrane guidance, i.e. risk of bias in uncontrolled before and after studies (including interrupted time series) [10]. We used the GRADE method to determine certainty in estimates.
Results
The systematic literature search yielded 1741 records. After removing 448 duplicates and six retracted records, we screened 1287. Among these, we identified 38 eligible records. We identified two additional eligible records through the search on PubMed and Google Scholar, along with the screening of the relevant reference lists (online Supporting Information Fig. S1) [11-50]. Of these 40 studies, 12 were published before, and 28 after, 2000.
The study characteristics of all eligible studies without publication year restriction are shown in online Supporting Information Table S2. In most cases, studies did not explicitly specify the bolus dose or infusion rate of noradrenaline administration; instead, they reported that noradrenaline administration was titrated to achieve the desired effect. Online Supporting Information Table S3 provides physiological measurements and the methods employed for CBF measurements.
There was a clear time dependence for measurement techniques, with TCD becoming predominant in the 1990s and beyond, thanks in part to the pioneering work by Aaslid in the 1980s [51]. Before this shift, the primary methods were based on nitrous oxide and xenon tracer (online Supporting Information Fig. S2). Of note, a recent study published in 2024 used phase-contrast magnetic resonance imaging for CBF assessment [50]. This review focused on the 28 studies published since 2000 (online Supporting Information Table S4). As described previously, the following reports were stratified by populations and CBF measurement methods.
Subjects with a healthy brain
Eight studies reported noradrenaline-induced CBF changes in healthy humans [11, 12, 21, 28, 31, 33, 39, 50]. One of these also investigated noradrenaline-induced CBF changes in patients with a critical illness [31]. Four studies investigated noradrenaline-induced changes in CBF in patients who did not have traumatic brain injury or a critical illness (or had recovered from such) [23, 30, 36, 45]. Three of these studies also investigated noradrenaline-induced CBF changes in patients who were critically ill [23, 30, 45]. We combined the data derived from healthy humans and patients without critical illness or traumatic brain injury, as none of these participants were determined to have impaired cerebral autoregulation in the original studies (online Supporting Information Table S4).
When considering only the data pairs with CBF assessed using TCD, noradrenaline treatment induced a MAP increase of 24.1% (95%CI 19.4–28.7%, Fig. 1a and Table 1), with a corresponding CBF change of -1.7% (95%CI -4.7–1.3%, Fig. 1b and Table 1). In contrast, when considering only the data pairs with CBF assessed using non-TCD methods, noradrenaline resulted in a MAP increase of 25.8% (95%CI 13.8–37.7%, online Supporting Information Fig. S3a), with a corresponding CBF change of -9.5% (95%CI -13.2% to -5.8%, online Supporting Information Fig. S3b). In this population, the MAP-CBF plot based on the data pairs with CBF assessed using TCD suggested intact cerebral autoregulation, as there was an evident plateau range starting with a lower MAP limit at approximately 88 mmHg (light blue area, Fig. 2a). The same plot based on data pairs with CBF assessed using non-TCD methods is shown in online Supporting Information Figure S4a. The proportional changes in MAP and CBF based on the data pairs with CBF assessed using TCD did not exhibit a significant association (R2 = 0, p = 0.41, Fig. 3a). There were insufficient data to make the same plot based on data pairs with CBF assessed using non-TCD methods. The ratio of the changes in CBF over MAP and the pre-treatment MAP were also not significantly associated (R2 = 0.02, p = 0.69, Fig. 4a). There were insufficient data to make the same plot based on data pairs with CBF assessed using non-TCD methods.
| Brain conditions and methods of CBF measurement | Proportional changes in MAP | Proportional changes in CBF | Cerebral autoregulation functional status† | Interpretation |
|---|---|---|---|---|
| Healthy brain | ||||
| TCD measurement | 24.1% (19.4–28.7%) | -1.7% (-4.7–1.3%) | Intact | Insignificant change in CBF when cerebral autoregulation intact |
| Non-TCD measurement | 25.8% (13.8–37.7%) | -9.5% (-13.2% to -5.8%) | Likely intact (insufficient data‡) | Significant decrease in CBF |
| Traumatic brain injury | ||||
| TCD measurement | 33.8% (14.7–52.9%) | 21.5% (11.0–32.0%) | Likely impaired (insufficient data‡) | Significant increase in CBF |
| Non-TCD measurement | 29.2% (27.1–31.3%) | -3.0% (-13.7–7.7%) | Likely intact (insufficient data‡) | Insignificant change in CBF |
| Critical illness | ||||
| TCD measurement | 32.4% (25.0–39.9%) | 20.0% (9.7–30.3) | Impaired | Significant increase in CBF when cerebral autoregulation impaired |
| Non-TCD measurement | 25.3% (11.8–38.9%) | 15.7% (1.25–30.1%) | Likely impaired (insufficient data‡) | Significant increase in CBF |
- TCD, transcranial Doppler.
- † Functional status of cerebral autoregulation was assessed based on the MAP-CBF association plots (Fig. 2 and online Supporting Information Fig. S4). The results of the assessment performed by the original studies are shown in online Supporting Information Table S4.
- ‡ Insufficient data means the number of data points for cerebral autoregulation plotting is <20.
Patients with traumatic brain injury
Nine studies investigated noradrenaline-induced CBF changes in patients with traumatic brain injury [13-15, 20, 29, 40-42, 48]. Eight of these studies reported that the patients' lungs were mechanically ventilated during the study. The functional status of cerebral autoregulation was determined to be impaired in the original studies, except for two studies having mixed functional statuses [13, 29] and one having hyper-reactive autoregulation (online Supporting Information Table S4) [14].
When considering only the data pairs with CBF assessed using TCD, noradrenaline resulted in a MAP increase of 33.8% (95%CI 14.7–52.9%, Fig. 1a and Table 1), with a corresponding CBF increase of 21.5% (95%CI 11.0–32.0%, Fig. 1b and Table 1). In contrast, when considering only the data pairs with CBF assessed using non-TCD methods, noradrenaline led to a MAP increase of 29.2% (95%CI 27.1–31.3%, online Supporting Information Fig. S3a), with a corresponding CBF change of -3.0% (95%CI -13.7–7.7%, online Supporting Information Fig. S3b).
Three studies performed in patients with traumatic brain injury require special attention [13, 14, 29]. One found that noradrenaline-induced MAP increase (26.0%) was associated with a decrease in CBF (-9.7%) [29]. However, this study also suggested that 10 of the 12 participants had intact cerebral autoregulation. The remaining two studies, conducted by the same group of researchers, also showed noradrenaline-induced MAP increases (27.4% and 28.7%) associated with significant CBF decreases (-20.1% and -40.9%); the authors again speculated that some or all of their patients had intact cerebral autoregulation [13, 14]. Notably, all three of these studies used non-TCD methods for CBF assessment, with one study using the Xe133 inhalation technique [29] and the other using xenon-computed tomography [13, 14].
The decreased CBF observed in these three studies [13, 14, 29] presents a sharp contrast to the remaining studies conducted in patients with traumatic brain injury and the studies conducted in patients who were critically ill, which consistently showed an increase in CBF, especially with measurements based on TCD. These divergent results remain to be reconciled but these three studies were included in the analysis. In this population, the MAP-CBF plot based on the data pairs with CBF assessed using TCD suggested likely impaired cerebral autoregulation, as there was no identifiable plateau range (Fig. 2b). We caution that the number of data points is limited. The same plot based on data pairs with CBF assessed using non-TCD methods is presented in online Supporting Information Figure S4b. The proportional changes in MAP and CBF based on the data pairs with CBF assessed using TCD did not exhibit a significant association (R2 = 0, p = 0.65, Fig. 3b). The same plot based on data pairs with CBF assessed using non-TCD methods was not constructed, to be consistent with the situations in other populations. The ratio of the changes in CBF over MAP and the pre-treatment MAP were also not significantly associated (R2 = 0.59, p = 0.13, Fig. 4b). The same plot based on data pairs with CBF assessed using non-TCD methods was not constructed, to be consistent with the situations in other populations.
Patients who were critically ill
Eleven studies reported noradrenaline-induced CBF changes in patients with a critical illness (excluding traumatic brain injury) [18, 23, 26, 27, 30-32, 37, 45, 47, 49]. Ten of these studies reported that the patients were mechanically ventilated during the study. All reported that cerebral autoregulation was impaired in their patients (online Supporting Information Table S4).
When considering only the data pairs with CBF assessed using TCD, noradrenaline caused a MAP increase of 32.4% (95%CI 25.0–39.9%, Fig. 1a and Table 1), corresponding to a CBF increase of 20.0% (95%CI 9.7–30.3%, Fig. 1b and Table 1). Only one study reported data with CBF assessed using non-TCD methods, in which noradrenaline led to a MAP increase of 25.3% (95%CI 11.8–38.9%, online Supporting Information Fig. S3a), corresponding to a CBF increase of 15.7% (95%CI 1.3–30.1%, online Supporting Information Fig. S3b). In this population, the MAP-CBF plot based on the data pairs with CBF assessed using TCD suggested impaired cerebral autoregulation, as the trendline sloped throughout (Fig. 2c). The same plot based on data pairs with CBF assessed using non-TCD methods is presented in online Supporting Information Figure S4c. The proportional changes in MAP and CBF based on the data pairs with CBF assessed using TCD exhibited a significant association (R2 = 0.43, p = 0.03, Fig. 3c). There were insufficient data to make the same plot based on data pairs with CBF assessed using non-TCD methods. The ratio of the changes in CBF over MAP and the pre-treatment MAP were not significantly associated (R2 = 0.27, p = 0.10, Fig. 4c). There were insufficient data to make the same plot based on data pairs with CBF assessed using non-TCD methods.
The results of analyses based on all eligible studies without publication year restriction are presented in online Supporting Information Figures S5–S10.
Of the 40 studies, nine provided subject-level data, seven involved healthy subjects and patients without critical illness or traumatic brain injury [16, 17, 19, 22, 34, 35, 38] and two involved subjects who were critically ill [18, 26]. The seven studies involving healthy subjects and patients without critical illness or traumatic brain injury used non-TCD methods for CBF assessment, while the two studies conducted in patients who were critically ill used TCD for CBF assessments. The results of the relevant analyses are presented in online Supporting Information Figure S11.
The 3D plot showed distinct trajectories of changes in CBF considering factors of the magnitude of changes in MAP, pre-treatment blood pressure and subject populations (online Supporting Information Video S1).
The studies included in our systematic review were typical interventional physiological studies, meaning their risk of bias cannot be assessed using the well-established criteria for randomised trials. Most eligible studies did not have comparator groups. Our systematic review focused on treatment effects by comparing pre-treatment and post-treatment measurements. Nonetheless, studies based on self-control could introduce bias from confounding factors. Participant selection criteria in most of the included studies were vague, consistent with ‘convenience samples’. Clinical indications for noradrenaline infusion may have influenced patient selection. Bias can also stem from varied measurement methods. Missing data could affect the results, especially when unreported exclusions occur. Although it was challenging to assess the risk of bias in the included studies, we rank the body of evidence as having an overall moderate risk of bias.
We exercise caution and rate the certainty of evidence as moderate based on the following reasoning. The eligible studies had relatively small sample sizes (median 10; range 3–42), even for observational physiological studies. Determining whether the combined number of participants across different patient populations reached the optimal information size was challenging due to the non-randomised nature of these studies. Therefore, trial sequential analysis could not be applied to ascertain this. Heterogeneity was observed in noradrenaline-induced CBF changes among patients who were critically ill with CBF measured using TCD (I2 = 72%, Fig. 1b). This observed heterogeneity could be attributed in part to various factors such as varying functional status of cerebral autoregulation, varying extents of noradrenaline-induced MAP increases and pre-treatment blood pressure variations. In contrast, noradrenaline-induced changes in CBF did not exhibit heterogeneity in healthy subjects and patients without critical illness or traumatic brain injury combined (I2 = 0%, Fig. 1b) and in patients with traumatic brain injury (I2 = 0%, Fig. 1b). Most studies published since the 1990s utilised TCD, which is considered an indirect method for measuring CBF. However, its reliability in tracking CBF changes has been shown. Our assessment of publication bias using funnel plots did not suggest significant publication bias (online Supporting Information Figure S12). Additionally, we searched ClinicalTrials.gov to gain insights into potential bias related to unpublished studies and identified only three ongoing eligible studies (online Supporting Information Table S5). However, given the non-randomised study design, the majority, if not all, of the eligible studies were likely not registered.
Discussion
Our systematic review, based on 28 studies published since 2000, offers valuable insights into the effects of intravenous noradrenaline administration on CBF in healthy and injured brains. Noradrenaline exerts differing impacts on CBF among different populations. In healthy subjects and patients without critical illness or traumatic brain injury, noradrenaline treatment did not significantly change CBF velocity despite an almost 24% increase in MAP. In patients with traumatic brain injury, regardless of an approximate 34% increase in MAP, noradrenaline exerted significant increases (approximately 22%) in CBF velocity. In patients who were critically ill, despite an almost 32% increase in MAP, noradrenaline exerted significant increases (approximately 20%) in CBF velocity. These patterns of change appear to depend on the functional status of cerebral autoregulation; noradrenaline exerts insignificant effects on CBF when cerebral autoregulation is intact and results in significant increases in CBF when cerebral autoregulation is impaired (Table 1). These conclusions are based on the data with CBF assessed using TCD. We caution against drawing conclusions based on the data with CBF assessed using non-TCD methods as the data points are insufficient (comparing Fig. 1 with online Supporting Information Fig. S3).
Our findings underscore the importance of contextualising noradrenaline-induced CBF changes within the framework of cerebral autoregulation. The functional status of cerebral autoregulation was not only revealed by the original studies (online Supporting Information Table S4) but also suggested by our MAP-CBF association plots (Fig. 2): healthy subjects and patients without critical illness or traumatic brain injury had intact cerebral autoregulation, while patients with traumatic brain injury or who were critically ill had impaired cerebral autoregulation.
The magnitude of noradrenaline-induced changes in CBF may also be influenced by the extent of MAP changes (Fig. 3) and pre-treatment blood pressure levels (Fig. 4). No significant association was found between the proportional changes in MAP and CBF in healthy subjects and patients without critical illness or traumatic brain injury (Fig. 3a). This lack of association could be due to MAP values being within the 60–120 mmHg range, where CBF is typically maintained by cerebral autoregulation (Fig. 2a). Similarly, in patients with traumatic brain injury, a significant association between the proportional changes in MAP and CBF was not observed, potentially due to insufficient data (Fig. 3b). These considerations are also pertinent to analysing the relationship between the ratio of the changes in CBF over MAP and the pre-treatment MAP (Fig. 4a and b).
Conceptually, the factors influencing the noradrenaline-induced changes in CBF are illustrated in Fig. 5. First, the functional status of cerebral autoregulation matters. For instance, in cases where the autoregulatory plateau exhibits a prominent positive slope (indicating absent or minimal cerebral autoregulation), the administration of noradrenaline is anticipated to lead to a more significant change in CBF compared with instances where the change occurs on a flat plateau (Fig. 5a). Second, the extent of the MAP change may matter, as a greater magnitude of blood pressure change is associated with a more pronounced alteration in CBF, especially when it occurs over a sloped autoregulatory range (Fig. 5b). Third, the pre-treatment blood pressure may matter, as noradrenaline is expected to induce a more substantial increase in CBF if the pre-treatment blood pressure is below the lower limit of autoregulation compared with situations where the pre-treatment blood pressure is above the lower limit (Fig. 5c).
Our findings do offer clinical insights, particularly in the context of managing hypotension [52, 53]. We showed that the effectiveness of noradrenaline treatment in increasing CBF depends on the patient population (likely related to the functional status of cerebral autoregulation), magnitude of the increase in MAP and pre-treatment blood pressure. It is essential to note that our review deals only with physiological and not neurocognitive or other consequences of noradrenaline treatment. Moreover, our study does not provide specific guidance on treatment goals or when to initiate treatment, which should be resolved via outcomes research.
Merely increasing blood pressure or cerebral perfusion pressure does not necessarily translate to improved brain perfusion and tissue oxygen delivery. Recent evidence suggests that vasopressor drugs may be associated with reduced microcirculatory brain perfusion and impaired tissue oxygen delivery during anaesthesia, even when reaching recommended blood pressure targets [54, 55]. One recent study performed in mice showed marked cerebral microvascular constriction, intravascular haemoglobin desaturation and a paradoxical increase in brain tissue oxygen levels following intravenous epinephrine administration [56]. A recent study showed a noradrenaline-induced 10% decrease in CBF assessed using phase-contrast magnetic resonance imaging in the face of a 20% increase in MAP, suggesting an inability of cerebral autoregulation to precisely maintain CBF in the face of the noradrenaline-induced increase in blood pressure [50]. Different vasopressors appear to have differing impacts on cerebral macro- and microcirculation, tissue oxygen delivery and cardiac output [54, 55, 57, 58]. Collectively, emerging evidence suggests that vasopressor drugs acting on both α- and β-adrenoceptors, such as noradrenaline, may have the potential to enhance blood flow to the brain, non-cerebral organs and tissue oxygen delivery compared with pure α-adrenergic agonists such as phenylephrine [59].
The impact of noradrenaline on cerebral circulation may be influenced by blood–brain barrier integrity [60]. Experimental studies support these findings, indicating that the impact of noradrenaline on CBF depends on blood–brain barrier status: little effect or a slight reduction when it is intact, but an increase in cerebral metabolic rate of oxygen and CBF when disrupted [61, 62].
In patients with septic shock, studies have shown an association between noradrenaline and decreased all-cause mortality and a lower risk of cardiac arrhythmias [1, 63, 64]. However, the effect of noradrenaline on brain outcomes, especially in patients with sepsis-associated encephalopathy, remains unclear [6]. Neurological complications, such as ischaemic stroke and cerebral bleeding, have been reported in septic patients with sepsis treated with vasopressors, including noradrenaline [65]. The relationship between these complications and noradrenaline treatment requires further investigation.
In cases of severe traumatic brain injury, recent retrospective cohort studies have suggested an increased risk of in-hospital mortality associated with noradrenaline compared with phenylephrine [66]. The available high-quality evidence supporting the use of noradrenaline in traumatic brain injury is limited [67]. Addressing these knowledge gaps should be a priority for future research efforts.
Our analysis has limitations. The studies that met our selection criteria are observational physiological studies characterised by small sample sizes and lacking comparators, which may reduce statistical power and increase variance. The relatively homogeneous increase in MAP (approximately 30%) induced by noradrenaline treatment across different studies does not give us a range of changes needed to understand the dose–response relationship. The insignificant findings in the association analysis between proportional changes in CBF and MAP echo this perspective. The three hypotheses we developed and tested should be considered post hoc, and the meta-regression results should be regarded as hypotheses-generating rather than providing definitive conclusions. The diverse non-TCD methods used for CBF assessment led to significant cross-study variations, which may affect the reliability of the conclusions. Ultimately, these studies will need to be repeated when a continuous quantitative, non-invasive CBF monitor is developed.
Noradrenaline, a vasopressor widely used to elevate blood pressure, has varying effects on CBF depending on the clinical context. In patients who are critically ill, including traumatic brain injury, the administration of noradrenaline results in a pressure-passive increase in CBF. In contrast, CBF remains relatively stable in healthy subjects and patients without critical illness or traumatic brain injury following noradrenaline treatment. These conclusions were primarily based on studies in which CBF was assessed using TCD instead of non-Doppler methods. Our review underscores the importance of understanding noradrenaline-induced CBF changes within the cerebral autoregulation framework. Several factors, including the functional status of cerebral autoregulation, magnitude of the increase in MAP and pre-treatment blood pressure, can influence the noradrenaline-induced CBF change. In patients who are critically ill with impaired cerebral autoregulation, maintaining precise control of blood pressure within a range that prevents cerebral hypoperfusion or hyperperfusion is of utmost importance. Outcomes research is warranted to define this critical blood pressure range for individual patients.
Acknowledgements
This systematic review was registered with PROSPERO (CRD42023428500). The original data are available via request to the corresponding author. No statistical code is available. Mads Rasmussen was funded by the Health Research Foundation of Central Denmark Region, Denmark. Other authors declared no external funding or competing interests.
