The burden of perioperative hypertension/hypotension: A systematic review

Study objective Our goal is to review the outcomes of acute hypertensive/hypotensive episodes from articles published in the past 10 years that assessed the short- and long-term impact of acute hypertensive/hypotensive episodes in the perioperative setting. Methods We conducted a systematic peer review based upon PROSPERO and Cochrane Handbook protocols. The following study characteristics were collected: study type, author, year, population, sample size, their definition of acute hypertension, hypotension or other measures, and outcomes (probabilities, odds ratio, hazard ratio, and relative risk) and the p-values; and they were classified according to the type of surgery (cardiac and non-cardiac). Results A total of 3,680 articles were identified, and 66 articles fulfilled the criteria for data extraction. For the perioperative setting, the number of articles varies by outcome: 20 mortality, 16 renal outcomes, 6 stroke, 7 delirium and 34 other outcomes. Hypotension was reported to be associated with mortality (OR 1.02–20.826) as well as changes from the patient’s baseline blood pressure (BP) (OR 1.02–1.36); hypotension also had a role in the development of acute kidney injury (AKI) (OR 1.03–14.11). Postsurgical delirium was found in relation with BP lability (OR 1.018–1.038) and intra- and postsurgical hypotension (OR 1.05–1.22), and hypertension (OR 1.44–2.34). Increased OR (37.67) of intracranial hemorrhage was associated to postsurgical systolic BP >130 mmHg. There was a wide range of additional diverse outcomes related to hypo-, hypertension and BP lability. Conclusions The perioperative management of BP influences short- and long-term effects of surgical procedures in cardiac and non-cardiac interventions; these findings support the burden of BP fluctuations in this setting.

Introduction Perioperative blood pressure (BP) variability, hypertension (HTN) and hypotension (HPT) have all been associated with hemodynamic instability and poor clinical outcomes [1]. Optimal pharmacologic control of BP requires intravenous (IV) agents that are easy to prepare and administer and that have rapid onset and offset of action that allows a predictable effect and easy dose-titration to properly fine-tune the BP of the patient, among other requirements [1].
Treatment choices for acute HTN depend on several factors in addition to BP measurement. These include evidence of end-organ damage (e.g., cerebral, cardiac, vascular, renal) presence of comorbidities (e.g., aortic dissection, acute myocardial infarction (AMI), bleeding) and ability to ingest and absorb oral medicines [2]. Examples of such clinical circumstances include perioperative HTN, in which rapid control of BP is essential to limit or prevent endorgan injury.
Both HTN and HPT in perioperative settings or acute HTN may result in a high economic burden for healthcare systems [3][4][5] due to perioperative complications requiring prolonged hospitalization.
Even though there are several international reference guidelines that account for the importance of management of perioperative BP [6][7][8], at present there are no universally accepted preoperative BP thresholds, as BP targets need to consider patient baseline BP, surgery type, and risk of short-term complications [9]. Furthermore, there is a clear gap in the knowledge of short-and long-term implications of acute hypo-and hypertensive perioperative episodes. Thus, a comprehensive, systematic review would have important and broad implications, particularly due to anecdotal evidence that suggests substantial underutilization of antihypertensive agents by clinical area.
The objective of this research is to systematically review the available evidence on critical outcomes potentially associated with hypertensive/hypotensive episodes (e.g., mortality, stroke, AMI, acute kidney injury (AKI), and others) in the perioperative setting for cardiac and non-cardiac surgeries, and to compare these findings to serve as a guide for clinical decision making, health policy and future research.

Study design
A systematic review of the literature was conducted in order to identify studies that analyzed the implications of HTN and HPT in the perioperative setting. The study design was formulated based upon PROSPERO and Cochrane Handbook protocols (Fig 1 and S1 Checklist and S1 File). The research protocol was registered in Open Science Framework (https://osf.io/ vgjmu). assessed the full text of 137 articles. After this screening, we identified 66 articles for data extraction. This process is illustrated in the PRISMA diagram (Fig 2). Of these articles, 1 (1.5%) was graded as a moderate-high quality, 39 (59.1%) as moderate, and 26 (39.4%) as low quality (S1 Table).
The study characteristics are shown in Table 1. Sample sizes ranged from 33 to 368,222 patients, with different population types and surgeries. Studies varied greatly in their definition of HTN/HPT. Article results were then grouped by cardiac or non-cardiac surgery, and outcome: mortality, stroke, kidney function, delirium, myocardial injury/AMI, and other outcomes associated with HPT, HTN, or other measures such as control of intraoperative mean arterial pressure (MAP) or variability within the surgery. The parameters were primarily OR, but we also found associations, HR, and RR. For the perioperative setting, the number of articles varies by outcome: 20 mortality, 16 renal outcomes, 6 stroke, 7 delirium, and 34 other outcomes. Since one study may include more than one outcome, the total sum of the reported outcomes may exceed the total number of studies.

Mortality
Twenty articles reporting mortality outcomes in relation to perioperative HPT, HTN, and other measures were retrieved from the search.
Hypotension as a risk factor. Ten articles had results for mortality associated with HPT ( Table 2). There were two articles focused on cardiac surgery and what these authors demonstrated was that values such as the duration of min excursion of BP <95 mmHg were associated with increased odds (1.03) for 30-day mortality [15], and that MAP below 55 mmHg for

HPT/HTN
Association between preoperative pulse pressure and perioperative myocardial injury: an international observational cohort study of patients undergoing non-cardiac surgery [11] Abbott et al.

Non-cardiac surgery 15,057 HTN
A prospective international multicentre cohort study of intraoperative heart rate and systolic blood pressure and myocardial injury after noncardiac surgery: results of the VISION study [12] Abbott et al. 2018 Non-cardiac surgery 16,079 HPT/HTN Associations of intraoperative radial arterial systolic, diastolic, mean, and pulse pressures with myocardial and acute kidney injury after noncardiac surgery [13] Ahuja et al. 2020 Non-cardiac surgery 164,514 HPT Modifiable, postoperative risk factors for delayed discharge following total knee arthroplasty: the influence of hypotension and opioid use [14] Anastasio et al. 2020 Total knee arthroplasty 1,033 HPT Intraoperative systolic blood pressure variability predicts 30-day mortality in aortocoronary bypass surgery patients [15] Aronson et al. 2010 Aortocoronary bypass graft surgery 7,504 HPT/HTN Does perioperative systolic blood pressure variability predict mortality after cardiac surgery? an exploratory analysis of the ECLIPSE trials [16] Aronson et al. 2011 Cardiac surgery 1,512 BP variability Association between intraoperative low blood pressure and development of surgical site infection after colorectal surgery a retrospective cohort study [17] Babazade et al. 2016 Colorectal surgery 2,521 HPT High postoperative blood pressure after cardiac surgery is associated with acute kidney injury and death [18] Balzer et al.

Cardiac surgery 5,225 HTN
Hypotension during hip fracture surgery and postoperative morbidity [19] Beecham et al. 2020 Hip fracture surgery 52 HPT Intraoperative hypotension and perioperative ischemic stroke after general surgery a nested case-control study [20] Bijker et al. 2012 Non-cardiac and nonneurosurgery

48,241 HPT
Can routine perioperative haemodynamic parameters predict postoperative morbidity after major surgery? [21] Bonnet et al. 2020 Non-cardiac surgery 50 HPT Association of intraoperative blood pressure instability with adverse outcomes after liver transplantation [22] DeMaria et al. 2013 Orthotopic liver transplantation 827 HTN Intraoperative hypotension is associated with adverse clinical outcomes after noncardiac surgery [23] Gregory Intraoperative blood pressure variability predicts postoperative mortality in non-cardiac surgery-a prospective observational cohort study [71] Wiorek and Krzych. more than 10 minutes postsurgery or between 55-64 mmHg intraoperative or postsurgery are also associated with increased odds of death [55]. What was mainly seen in non-cardiac surgeries was that perioperative HPT entailed a higher risk of mortality, with increased odds of 30-day mortality of 1.81 when systolic blood pressure (SBP) was below 100 mmHg, as reported by Abbott et al. [12] Other authors also reported increased risk for 30-day mortality with diverse OR such as 1.79 for patients with intraoperative MAP <55 mmHg for more than 20 minutes [67] or 20.826 for intraoperative MAP below 40 mmHg for more than 5 minutes when comparing this patient group with patients with intraoperative BP levels between 60-109 mmHg [47]. The incidence of mortality was reported to be statistically significant for those patients with MAP below 67 mmHg versus above 67.3 mmHg (p<0.001) [65]. Some authors also reported an association between the duration of HPT (measured both as the MAP or SBP) and a higher risk of mortality [47,67]. In addition, an association between the threshold and the increased odds for 30-day and 90-day mortality has been recently demonstrated: the lower the MAP the higher the odds, as reported by Gregory et al. [23]. Hypertension as a risk factor. Ten articles studied mortality in patients with perioperative HTN (Table 3). Four articles investigated the outcomes of cardiac surgery and all but one found statistically significant associations, for example for every 0.10 increase in the coefficient of variation of the SBP an increase in the odds of death of 150% was reported by Jinadasa et al. [31], and postoperative HTN (SBP >130 mmHg) was found to be related to higher in-hospital mortality rates [18]. Other authors reported increased odds of 1.03 per minutes above 135 mmHg per BP excursion [15]. One of the articles reported non-statistical significance for the influence of HTN on mortality; the study analyzed the increase of 1 mmHg in SBP [45]. Regarding the non-cardiac surgeries, while some of the studies found an association of HTN and reduced odds of mortality [12,35], a recent article found increased odds of long-term mortality associated with the maximum SBP in days 2 (OR 1.28) and 3 (OR 1.30) after surgery [44]. One study associated preoperative SBP above 120 mmHg with increased mortality HR in cancer patients [74]. Zheng et al. showed that the incidence of in-hospital death was higher in those patients with BP >130 mmHg 24h after the intervention (16.70%, p-value 0.001) [76].
Blood pressure variability. Five articles studied intraoperative BP variability (Table 4) and what was mostly demonstrated was that changes from the baseline of each patient were associated with higher mortality outcomes. Within cardiac surgeries, Aronson et al. [16] reported 30-day mortality related to the extent of SBP excursions intraoperatively (outside the range 75-135 mmHg), and pre-and postoperatively (outside the range 85-145 mmHg); another study found that MAP below the limit of autoregulation was also associated with increased odds of mortality in patients undergoing coronary artery bypass grafting and/or valve surgery [51]. The same results were reported for patients undergoing non-cardiac surgery by Mascha et al. [42], who found that cumulative time of MAP less than 80, 70, 60, 55, and 50 mmHg were associated with higher odds of 30-day mortality. Small changes, 1% of variability in both DBP and SBP were also related to postoperative mortality [71]. Finally, the control of MAP during surgery between the limits 65-110 mmHg was reported to reduce the risk of mortality [72].

Renal outcomes
Sixteen articles investigated the influence of perioperative HPT and HTN in renal outcomes such as AKI or renal failure. Hypotension as a risk factor. Thirteen articles reported an association between perioperative HPT and increased risk of developing AKI or other adverse renal outcomes (Table 5). There were two works investigating these outcomes in cardiac surgery and it was seen that an area under the curve (AUC) below the optimal BP as well as MAP below 65 mmHg were associated with increased odds of developing AKI and requiring de novo renal replacement therapy, respectively. For de novo renal replacement therapy higher odds were reported with lower values of MAP [27,49]. In non-cardiac surgeries an increase of 1.51 odds was associated with a 10% decrease in MAP [46], while other authors demonstrated a cumulative effect of HPT over    [50]. And the intraoperative control of MAP in the range 80-95 mmHg could reduce postoperative AKI in elderly hypertensive patients (n = 678) after major abdominal surgery according to Wu et al. being the incidence (SD) of 31% (13.5%) in patients with a MAP between 65-79 mmHg; 13% (6.3%) in patients with MAP between 80-95 mmHg, and 27% (12.9%) in patients with MAP between 96-110 mmHg, p-value = 0.033 [72].

Stroke
Six of the retrieved articles investigated the relationship between HPT, HTN, and control of MAP during surgery and stroke.
Hypotension as a risk factor. Four articles that studied the relationship between intraoperative HPT and stroke were identified ( Table 6) and none of their results found a statistically significant difference in the influence of perioperative HPT on stroke. The approaches included absolute SBP below 100, 90, 80, and 70 mmHg; relative decreases of 10, 20, 30, and 40% from baseline; and MAP below 70, 65, and 60 mmHg [20,29].
Hypertension as a risk factor. Zheng et al. [76] investigated the influence of baseline and 24h after intervention SBP on the incidence of stroke in 173 patients undergoing carotid angioplasty stenting (CAS). Baseline SBP was not found to be statistically associated with stroke incidence being the incidence 0% in those patients with baseline SBP <120 mmHg, 7.90% for SBP 120-130 mmHg, and 4.10% for SBP >130 mmHg; p-value: 0.41. Post-intervention SBP increases incidence, increasing proportionally with higher levels of SBP, but no statistical significance was found; 3.50% incidence in patients with 24h post-CAS SBP <120 mmHg, 7.50% for 24h post-CAS SBP 120-130 mmHg, and 11.10% in 24h post-CAS SBP >130 mmHg; p-value = 0.174.

Delirium
There were seven articles reporting results for the association of perioperative HPT, HTN and postsurgical delirium.
Hypotension as a risk factor. Studies investigating the effect of perioperative HPT on delirium (n = 5) ( Table 7) found that what might be related to the development of postsurgical delirium is BP fluctuation or variance, the so-called lability, and no absolute or relative values of HPT themselves both in cardiac and non-cardiac surgical patients [26]. In those articles studying cardiac surgeries, influence of HPT over delirium was demonstrated [28,69]. Additionally, other authors studying non-cardiac interventions, reported increased HR for delirium in those patients with intraoperative and postoperative HPT (during intensive care unit (ICU) stay) [41] and increased OR of delirium for decreases of intraoperative MAP in ranges below 75 mmHg [23]. The study by Hirsch et al. [26] reported increased OR for the prediction of the number of days of delirium, both with MAP (OR 1.038, 95% CI 1.010-1.067, p-value = 0.008) and SBP (OR 1.018 95% CI 1.005-1.030, p-value = 0.004) variance as measured by mmHg 2 per 10 units decrease. Another study found no statistically significant results for the association of HPT with postoperative delirium in elderly patients undergoing non-cardiac surgery [34]. Hypertension as a risk factor. Two different studies demonstrated the implication of intraoperative HTN for postsurgical delirium. (Table 8) Hori et al. [28] found a statistically significant association of the AUC above the optimal MAP (as measured in mmHg x h) during cardiac surgery and the development of delirium on postoperative day 2, and the other reported increased odds (2.34) for delirium when suffering an increase of 10 mmHg in mean surgery mean arterial pressure (msMAP) when msMAP was equal or above 80 mmHg during trauma surgery [68].

Cardiovascular and cerebrovascular outcomes
There were 18 articles reporting results for the association of HPT and HTN with cardiovascular and cerebrovascular adverse outcomes such as AMI, myocardial injury after non-cardiac surgery (MINS), and others.
Hypotension as a risk factor. HPT association with cardiovascular and cerebrovascular outcomes was investigated in 15 articles ( Table 9). One of them reported results from patients undergoing cardiac surgery. The work by Sposato et al. [61] described the new onset of atrial fibrillation associated with intraoperative SBP below 80 mmHg for 15 minutes or more with increased odds of 9.6 in cardiac surgery. The rest of the articles referred to non-cardiac surgery; some of them studied HPT in relation to various cardiac outcomes and found a statistically significant association between SBP <100 mmHg and myocardial injury, increasing with an OR of 1.21 [12], this relation of HPT was also seen when the decrease in SBP is more than 50% relative to baseline values for more than 5 minutes, with OR of 4.4 for myocardial damage [24]. Other studies such as that of Roshanov et al. [56] reported that not just the intraoperative HPT is relevant for the development of cardiovascular events (SBP <90 mmHg for more than 10 minutes, OR 2.43) but also postoperative HPT (SBP <90 mmHg for more than 10 minutes, OR 2.17); there was also evidence showing that in addition to the postoperative MAP, the time under different thresholds also has an influence on the development of AMI [39]. Additionally it has been published that time under MAP also has an influence on myocardial outcomes, as demonstrated by Salmasi et al. [58], odds for MINS (AMI after non-cardiac surgery) MAP <65 mmHg during 13-28 minutes were 1.34, while odds for MAP <65 mmHg during more than 28 minutes were 1.60; influence was also seen for MAP <50 mmHg, in this category just one minutes below 50 mmHg was found to be statistically significant associated with the development of MINS. As well as Salmasi et al., van Lier et al. [65] saw that there was a statistically significant relationship between the levels of HPT and the incidence of AMI, with the

Author
Year Sample size

Definition of hypotension Result � P-value Event
Hallqvist et al. [24] 2016 300 Decrease in SBP more than 50% relative to baseline for more than 5 min 4 relationship being inversely proportional. Walsh et al. [67] also found that a longer time below <55 mmHg had an impact on the greater odds for both myocardial injury and cardiac complication. Gregory et al. reported statistically significant increased odds for developing MACCE (composite measure of all-cause mortality, AMI, or acute ischemic stroke) by any measure of MAP under any threshold considered, they also found increased odds for AMI [23]. Hypertension as a risk factor. Studies investigating the relationship between HTN and cardiac or cerebrovascular outcomes in non-cardiac surgery were also retrieved from our search (n = 5) (Table 10). Abbott et al. [12] described a statistically significant association between SBP above 160 mmHg and myocardial injury and AMI, which had been found to not be associated in a previous study [11]. Outcomes such as silent brain ischemia were found to be statistically significant related to a 20% increase of baseline SBP during carotid endarterectomy [57]. Further evidence regarding the influence of postoperative HTN has been described by Zheng et al. [76], who reported increased incidence of intracranial hemorrhage and

Other outcomes
In total, 16 articles were retrieved reporting other types of outcomes associated with perioperative HPT or HTN. Hypotension as a risk factor. Nine of them investigated perioperative HPT and other relevant outcomes such as myocardial injury or surgical site infection (Table 11). Other studies such as that of Roshanov et al. [56] reported hypotensive events in postoperative days 0 and 1 was also found to be associated with increased length of hospital stay (OR 1.305, p = 0.0239) [14,21]; and sepsis/systemic inflammatory response syndrome [23]. Other outcomes that were investigated were: surgical site infection, that was found to be not statistically significant in relation to MAP <55 mmHg and SBP <80 mmHg, but odds of 1.08 were found in association with minimum postoperative MAP, per 5 mmHg decrease by Yilmaz et al. [73]; or flap loss that was associated with MAP <60 mmHg for more than 20 episodes and per each episode the odds were 1.22 [33]. Increased risk of poor discharge outcomes (defined as death, discharge to a nursing facility, or discharge to hospice care) were reported by Sheffy et al. [60] for those patients with perioperative SBP <90 mmHg or <110 mmHg undergoing trauma surgery. Tassoudis et al. [64] described increased odds for hospital stay, complications, and duration of complications related to intraoperative MAP below 60 mmHg or MAP below 70 mmHg and MAP decrease above 30% from baseline values. Emergence agitation was associated with SBP <90 mmHg intraoperatively (OR 1.636, p = 0.025) in patients undergoing thoracoscopic lung surgery [32]. Hypertension as a risk factor. There were eight studies investigating the relationship between HTN and various outcomes that were retrieved from our search (Table 12). Other outcomes have been associated with HTN as well: hematoma [48], emergence agitation [32], and anastomotic leakage [53]. Postoperative HTN was reported to have a negative impact on functional independence of patients undergoing mechanical thrombectomy, especially for those patients with maximum SBP in postoperative day (POD) 3 [44]. There were two articles on cardiac surgical patients and one of the studies found statistically significant increased odds for the length of hospital stay due to HTN [18].
Blood pressure variation and control of mean arterial pressure. In non-cardiac surgeries, variation in BP (Table 13) has been reported to be correlated with adverse outcomes, such as primary graft non-function, ICU ventilator for more than 3 days, sepsis, prothrombin (PT) >16, poor early graft function and re-transplant, however, no data was available for these outcomes [22]. Additionally, an absolute fractional change of 10% in MAP was described as being protective against primary graft non-function [22]. Moreover, a work studying the influence of control of intraoperative MAP showed that the control of MAP between the range 80-95 mmHg had a protective action against hospital-acquired pneumonia, admission to the ICU and length of stay in ICU [72]. Lastly, the study by Zevallos et al. [75] analyzed the mean differences between intraprocedural SBP, DBP, and MAP, comparing cases and controls of patients developing contrast-induced neurotoxicity after neurointerventional procedures, and found statistically significant differences in all of them and concluded that HTN might have a role in increasing blood-brain barrier permeability, allowing the leak of the contrast.

Discussion
The main finding of this work is the existence of evidence supporting the burden of BP excursions in patients undergoing cardiac and non-cardiac surgeries that entail higher risks for negative outcomes after surgery. This review includes a wide range of surgical procedures and addresses several surgical outcomes that could be related to organ damage. There is also evidence that perioperative BP management is important for graft survival, flap loss, and length of hospital stay [18,22,33]. What can be highlighted from the results is that it is not just acute HPT or acute HTN that play a role in the development of adverse post-surgical outcomes but also the variation or lability in the values of BP from the patients' baseline. It is important to characterize each patient's baseline BP values and assess the intrapatient variability; this approach might have more clinically relevant results than establishing standard thresholds for all the patients [71,77]. A few studies also incorporated time spent outside of the determined acceptable BP range as a critical factor [3,46], as adverse outcomes seem to be related to the time the patient spends above or below the optimal ranges: the longer the time, the higher the risk [46,55,58,62,63,67]. Regarding longterm outcomes, it seems that no differential long-term effects are expected in the absence of short-term effects, however, further evidence would be needed in order to confirm this hypothesis due to the difficulty of tracing long-term consequences back to the surgery. Nonetheless, a need for the intensification of periopertive medicine has been reported due to the emergence of long-term consequences of postoperative complications; there is an opportunity for the improvement of follow-up, rehabilitation programs, and the fine-tuning of medical management [78].
What has also been seen is that within cardiac surgery all outcomes are significantly associated with BP excursions. Even though this might be expected, there is also evidence for the relationship of HPT and HTN with negative outcomes such as AKI, stroke, discharge to a nursing facility or hospice care, or even death, in non-critically ill trauma surgeries [60] and other type of surgeries.
We highlight the associated risks, especially for severe HPT and HTN [12,46,74]. AMI and myocardial injury were also significant events that have been researched extensively, as HPT and HTN have been associated with the risk of both [11,12,24,59,66,67]. Both HPT and HTN have also both been described as influencing the risk of stroke in patients undergoing non-cardiac surgeries.
More research needs to be done in order to determine the best strategies to deal with these morbidities in addition to developing new therapeutic strategies to better utilize current medications. Furthermore, a recent meta-analysis assessing the effect of vasoactive drugs (dobutamine, ephedrine, norepinephrine, nitroglycerine, theodrenaline/cafedrine, dopamine, dopexamine, colloids, phenylephrine, inotropes, nitrates, adrenaline) in the perioperative setting has concluded that these drugs might reduce postoperative complications and length of hospital stay in adults having major abdominal surgery [79]. It is clear that the opportunity loss of these agents controlling BP excursions in perioperative settings could be lower or partially compensated by the minimization of health resources that would be required to manage related complications. In this regard a few articles have provided some preliminary insights. Aronson et al. analyzed the impact of IV antihypertensive treatment for the management of perioperative BP during cardiac surgery and found that there was an association with shorter time to extubation and shorter ICU stays [80]. For some authors, anesthetic drugs and opioids can be used to control HTN [81][82][83]. However, their use can imply an increased risk of HPT and for this reason IV BP lowering drugs ideally should be used to control acute HTN episodes [59,67,84]. From a pharmacodynamic perspective, it would be reasonable to opt for a strategy that uses a specific type of therapy for each desired pharmacological effect for comprehensive intraprocedural patient management, to optimize their perioperative clinical evolution. Therefore, an opioid (e.g., remifentanil) would be the best option for managing acute pain, while keeping the level of anesthesia achieved separated from pain relief with the use of a hypnotic agent (e.g., propofol) and resorting to an IV antihypertensive that allows rapid, controlled, and predictable reductions in BP within a desired range. This evidence supports the view that new anti-hypertensive and vasoactive agents with favorable pharmacodynamic and pharmacokinetic properties might have a role in many clinical areas and thus, it would be pertinent to further investigate their role to guarantee the fine-tuning of BP and an individualized therapy for patients.
For the management of acute HPT there are also many therapeutic alternatives as described in a recent publication [85]. Fluid administration is a non-pharmacological approach intended to increase stroke volume and cardiac output but other options are also available within the pharmacological armamentarium, such as vasopressors and positive inotropic agents including ephedrine, phenylephrine; additional options are vasopressin and terlipressin, norepinephrine, epinephrine, and other less used agents, angiotensin II, vitamin C, hydroxicobalamin, dopamine, dobutamine, or milrinone. Recommended pharmacological treatments in case of acute HPT in the operating room are epinephrine or phenylephrine in case of mild HPT, and epinephrine in case of significant or refractory HPT [86].
Another study by Aronson et al. examined BP variability and demonstrated that by controlling BP during cardiac surgery, patients spent less time on mechanical ventilation and in the hospital, therefore avoiding the associated adverse outcomes and economic costs [5]. Getsios et al. took an in-depth look at clevidipine and found that it provided higher cost savings than other IV antihypertensives [4]. Keuffel et al. used Monte Carlo simulations to determine the association between intraoperative HPT and hospital expenditures, and concluded that limiting HPT during non-cardiac surgery will have an impact on hospital cost reductions, which may be highly relevant for resource allocation decisions [3]. This literature research also provides a basis for further research and potential economic models of reducing complications related to HPT and HTN.

Limitations
Although the methodology applied in this research meets international guidelines in the field, a few limitations should be noted. Firstly, in the absence of international guidelines on perioperative HPT and HTN definition (BP thresholds), articles vary greatly in how they define HTN and HPT. This could lead to issues when trying to compare results across studies and prevents performing a meta-analysis in order to assess the effect based on the published evidence due to the heterogeneity among studies. Also, there may be a publication bias that impedes the dissemination of negative findings.
Secondly, these sixty-six articles contain a wealth of evidence on the burden of acute HPT and HTN; however, the evidence remains uneven and difficult to synthesize due to differences in statistical presentation and target population.
Finally, any assessment of the burden is also complicated by the fact that the frequency of the long-term outcomes of acute HPT and HTN may be consequences of their short-term effects (e.g., stroke, AKI, hemorrhage, atrial fibrillation, and others.).

Conclusion
This review presents the available evidence on the burden of acute HPT and HTN across perioperative settings, and what seems to be clear is that HPT, HTN, and even fluctuations in BP from the patient's baseline, entail a high burden for patients undergoing diverse types of surgeries. This suggests the potential benefit from improved management of BP in terms of shortand long-term effects of surgical procedures in patient outcomes.