Pure Alpha vs. Mixed Adrenergic Vasopressors Perioperative Outcomes in Autologous Free Flap Surgery: A Systematic Review and Meta-analysis

Pure Alpha vs. Mixed Adrenergic Vasopressors Perioperative Outcomes in Autologous Free Flap Surgery: A Systematic Review and Meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF book-review Pure Alpha vs. Mixed Adrenergic Vasopressors Perioperative Outcomes in Autologous Free Flap Surgery: A Systematic Review and Meta-analysis Mohammed Ehmidat, Ibrahim Etfeiheh, Raghad Abuzant, Abdulrahman Ahmed Albalasy, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7360899/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Autologous free-flap reconstruction has transformed reconstructive surgery, restoring form and function in complex head, neck, breast, and limb defects. Maintaining stable perfusion during surgery is essential, yet the choice of vasopressor remains controversial. Surgeons have long feared that α-adrenergic vasoconstriction might jeopardize microcirculation, despite increasing evidence to the contrary. Whether specific vasopressor classes differ in their impact on flap survival has remained uncertain. Methods We conducted a systematic review and meta-analysis following PRISMA guidelines (PROSPERO-registered). Eligible randomized controlled trials and observational cohort studies compared perioperative phenylephrine (pure α-agonist) with mixed α/β-agonists (norepinephrine or ephedrine) in adult free-flap surgery. Primary outcomes were flap failure and surgical revision for microvascular compromise; secondary outcomes included thrombosis. Pooled estimates were calculated using random-effects models. Results Nine studies (two RCTs, seven cohorts) comprising 7,181 patients and 8,626 flaps were included. Overall flap failure was low (3%), but norepinephrine was associated with higher failure (6%) compared to phenylephrine (2%) and ephedrine (2%). Surgical revision occurred in 12% overall, with norepinephrine again higher (15%) versus phenylephrine (2%). Thrombosis occurred in 7% overall, most frequently with norepinephrine (11%). Sensitivity analyses confirmed the robustness of these findings, though heterogeneity was high and publication bias could not be excluded. Conclusions In contemporary free-flap surgery, vasopressors are not uniformly harmful—but choice may matter. Phenylephrine and ephedrine were associated with fewer surgical revisions and thrombotic events compared to norepinephrine. While absolute differences in flap failure were small, the higher complication rates with norepinephrine warrant caution, and agent selection should be individualized. Further randomized trials are needed to refine hemodynamic management strategies in microvascular reconstruction. Autologous free-flap reconstruction Vasopressor Phenylephrine Norepinephrine Ephedrine Flap failure Microvascular surgery Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 1. Introduction Autologous microvascular free-flap reconstruction has become a cornerstone of modern surgery, enabling restoration of complex defects in the head and neck, breast and extremities. Its uptake has grown steadily and contemporary series report success rates exceeding 95% ( 1 ), underscoring its importance but also highlighting the imperative to prevent even rare failures. Maintaining reliable flap perfusion is critical during the perioperative period: hypotension may endanger arterial inflow, whereas excessive fluid administration can lead to oedema and venous congestion ( 2 ). To support blood pressure, anaesthetists often employ vasopressor agents; yet fears that α-adrenergic vasoconstriction could compromise microcirculatory perfusion have led many microsurgeons to discourage their use ( 1 ). Studies report vasopressor utilization in up to 85% of free flap procedures ( 3 ), determining whether different vasopressor classes influence outcomes represents a matter of significant clinical and public health relevance. The evidence on vasopressor use in free-flap surgery remains heterogeneous and incomplete regarding pharmacological specificity. Early experimental and clinical observations suggested that phenylephrine might reduce pedicle blood flow ( 1 ). Subsequent observational studies and meta-analyses began to challenge this paradigm. A large retrospective cohort of 5,671 cancer patients undergoing free flaps found that 85% received intraoperative vasopressors demonstrated no increase in pedicle compromise or flap failure, ( 3 ) A comprehensive meta-analysis of 6,321 patients reported no significant increase in flap failure when vasopressors were used ( 4 ) Recent primary studies provide more detailed but conflicting data regarding vasopressor class-specific effects. A randomized pilot trial in breast reconstruction patients revealed that norepinephrine preserved flap blood flow superior to phenylephrine without increasing complications ( 5 ) These emerging data suggest vasopressors may be safe when used judiciously, but the heterogeneity in agents and study designs precludes definitive conclusions regarding whether phenylephrine differs from norepinephrine or ephedrine in clinically meaningful ways. To address this critical knowledge gap, we will conduct a systematic review and meta-analysis to determine whether perioperative phenylephrine (a pure α-adrenergic agonist) differs from mixed α/β-adrenergic vasopressors (norepinephrine or ephedrine) in adult patients undergoing autologous free-flap reconstruction. Our primary outcomes will encompass total flap loss and the need for re-exploration for microvascular compromise; secondary outcomes will include thrombotic events. By focusing on vasopressor pharmacological class rather than the mere presence or absence of pressor therapy, this review aims to provide clinicians with definitive, evidence-based guidance for perioperative hemodynamic management. 2. Methods Study Design and Protocol Registration This systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol was registered prospectively in the PROSPERO database (CRD420251086419). Eligibility Criteria Participants Included studies involved adult patients undergoing autologous free flap surgery for any indication, including head and neck reconstruction, breast reconstruction, limb salvage, and other reconstructive procedures. Interventions and Comparators Intervention groups utilized phenylephrine as the primary vasopressor or for blood pressure support during the perioperative period. Comparator groups used mixed alpha/beta adrenergic agonists (norepinephrine and/or ephedrine) as the primary vasopressor or for blood pressure support during the perioperative period. Outcomes Eligible studies reported at least one comparative outcome between phenylephrine and mixed adrenergic agonist groups, including: Primary : Free flap failure, need for re-exploration for microvascular compromise. Secondary : Microvascular complications (e.g., thrombosis) and other clinically relevant complications as reported. Study Types Randomized controlled trials (RCTs), prospective cohort studies, retrospective cohort studies, and case-control studies that directly compared perioperative use of phenylephrine versus mixed adrenergic agonists in the specified population were included. Studies were excluded if they were case series, case reports, editorials, or reviews. Studies where vasopressors were used for other indications (such as solely for cardiac arrest management) were excluded unless data specific to the perioperative period in free flap patients was clearly separable. Conference abstracts (published or unpublished) were excluded. Language restriction: English only. Eligible studies were published from the inception of the database to the date the search was conducted. Information Sources and Search Strategy A comprehensive literature search was conducted in the following electronic databases: MEDLINE (PubMed), Web of Science, Scopus, and Google Scholar. Additional sources included reference lists of included studies and relevant reviews. The last search was conducted from inception to the final search date. Search Strategy Database-specific strategies were developed using a combination of MeSH terms and free-text keywords related to free flap surgery, microvascular reconstruction, vasopressors, and perioperative outcomes. The detailed PubMed search strategy can be found in supplementary file 1. Search strategies were tailored for each database and reviewed by the research team. All search results were imported for screening and de-duplication. Study Selection Records were pooled and duplicates removed. Titles and abstracts were independently screened by two reviewers based on the eligibility criteria. Full texts of potentially eligible studies were retrieved and independently assessed by two reviewers. Any discrepancies at either stage were resolved by discussion or consultation with a third reviewer. A PRISMA flow diagram was used to document the selection process. Data Extraction A standardized data extraction form was used. Data were independently extracted by two reviewers. Any discrepancies were resolved by discussion or consultation with a third reviewer. Extracted data included: Study Characteristics : Design, year, country, sample size, follow-up duration. Patient Demographics : Age, sex, comorbidities, surgical indication. Surgery Details : Type of free flap, recipient site, surgical approach. Vasopressor Details : Specific agent(s) used, dosing, timing of administration. Outcome Data : As listed in the outcomes section, including denominators and numerators for binary outcomes, means and standard deviations for continuous outcomes, and definitions used for outcomes including flap failure definition. When data were missing or unclear, study authors were contacted for clarification. Risk of Bias Assessment The risk of bias for included RCTs was assessed using the Cochrane Risk of Bias tool (RoB 2.0). The risk of bias for non-randomized studies was assessed using ROBINS-I (Risk Of Bias In Non-randomized Studies - of Interventions). Risk of bias assessment was performed independently by two reviewers, with discrepancies resolved by discussion or consultation with a third reviewer. Results were presented in tabular form and factored into data interpretation and sensitivity analysis. Data Synthesis and Statistical Analysis Qualitative Synthesis A narrative synthesis of the included studies was conducted, summarizing their characteristics, findings, and methodological quality. Quantitative Synthesis : If sufficient homogeneous data (in terms of population, intervention/comparison, and outcome measurement) were available for specific outcomes, a meta-analysis was performed. Binary Outcomes : Pooled risk ratios (RR) or odds ratios (OR) with 95% confidence intervals (CI) were calculated. Continuous Outcomes : Pooled mean differences (MD) or standardized mean differences (SMD) with 95% CI were calculated. Heterogeneity : Statistical heterogeneity was assessed using the Chi-squared test and quantified using the I² statistic. Model : If heterogeneity was low (I² < 50%), a fixed-effect model was used. If heterogeneity was moderate to high (I² ≥ 50%), a random-effects model was used. Potential sources of heterogeneity were explored through subgroup analysis or sensitivity analysis if appropriate. Analyses were conducted using appropriate statistical software. Funnel plots and Egger's test were used to assess publication bias if there were enough studies (typically > 10) contributing to a meta-analysis for a specific outcome. Subgroup Analysis Potential subgroups for analysis included type of free flap (head and neck vs. breast vs. limb), specific mixed agonist used (norepinephrine vs. ephedrine vs. combination), and study design (RCT vs. observational). Sensitivity Analysis Sensitivity analyses were conducted by excluding studies at high risk of bias and using alternative statistical models (fixed vs. random effects regardless of heterogeneity). Certainty of Evidence The overall certainty of evidence for key outcomes was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Ratings considered risk of bias, inconsistency, indirectness, imprecision, and publication bias. GRADE summary tables were generated to support conclusions. 3. Results 3.1. Study Characteristics In order to determine the Vasopressor Choice in Microsurgery: A Meta-Analysis of Flap Outcomes with Pure Alpha-Agonists versus Mixed Agents was conducted. 9 studies were included as follows; Two randomized clinical trials (RCTs) and seven observational cohort studies, which were conducted in United States, United Kingdom, Germany, Canada, South Korea, Finland and India, with a total of 7181 patients underwent different types of free flaps with a total of 8626 flaps were done with use of norepinephrine, ephedrine and phenylephrine as vasopressors for comparisons The characteristics of included studies are present in Table 1 . Table 1 , Characterstics of included studies: Author (Country, Year) Study Design Sample Size (Patients / Flaps) Mean Age (years) ± SD Mean BMI ± SD Surgical Site(s) Vasopressor(s) Compared Key Comorbidities Follow-up Fang (USA, 2017) Retrospective 4,888 / 5,671 54.7 ± 14.1 27.2 ± 7.1 Head & neck, breast, extremities Phenylephrine, ephedrine, CaCl₂ – – Geldern (Germany, 2018) Retrospective 425 / 437 – – Lower extremity gracilis or ALT flaps Norepinephrine DM (23.3%), HTN (32.7%) – Grill (Germany, 2019) Prospective 52 / – 61 ± 14.34 24.33 ± 4.59 Head & neck Noradrenaline, RBC transfusion – – Lee (South Korea, 2023) RCT (pilot) 20 / – 50 ± 8 25.1 ± 4.1 TRAM flap (breast) Norepinephrine vs phenylephrine DM (n = 5), HTN (n = 15) ~ 7 days Raittinen (Finland, 2016) RCT (unblinded) 25 / – 61 ± 13 – Head & neck Norepinephrine vs dopamine vs control DM (n = 8), HTN (n = 24), smokers (n = 44) ~ 3 days Rose (UK, 2016) Retrospective 123 / – – – Maxillofacial Norepinephrine vs metaraminol vs combination vs control – – Zhu (Canada, 2022) Retrospective 1,102 / 1,729 50.2 ± 7.7 28.5 ± 6.1 DIEP flaps Phenylephrine and/or ephedrine – ~ 30 days Gardner (USA, 2022) Retrospective 426 / 449 62 ± 11.4 – ALT, radial forearm, osteocutaneous – – ~ 5 days Rajan (India, 2019) Retrospective 120 / – 55.44 ± 14.16 – Radial forearm, ALT, LD myocutaneous, free fibula osteocutaneous Noradrenaline – – 3.2. Main Outcomes A) Overall Flap Failure Rate A total of 10 studies were included in the analysis of flap failure rate for all vasoconstrictors, encompassing a total of 7,732 procedures. The heterogeneity between the included research results was high (I² = 64.5%), so a random-effects model was used for the meta-analysis. The results showed that the overall flap failure rate was 3%, and this finding was statistically significant [Proportion = 0.03, 95% CI (0.02, 0.04)] Fig. 1 . The test for subgroup differences between vasoconstrictor types (Ephedrine, Norepinephrine, and Phenylephrine) was statistically significant (χ² = 12.16, df = 2, p = 0.0023), with the norepinephrine subgroup showing a higher failure rate [Proportion = 0.06, 95% CI (0.03, 0.08)] compared to ephedrine [Proportion = 0.02, 95% CI (0.01, 0.02)] and phenylephrine [Proportion = 0.02, 95% CI (0.00, 0.05)]. Figure 2 B) Overall Surgical Revision Rate A total of 9 studies were included in the analysis of surgical revision rate, covering a total of 502 procedures. The heterogeneity between the included research results was high (I² = 81.3%), so a random-effects model was used for the meta-analysis. The results showed that the overall surgical revision rate was 12%, and this was statistically significant [Proportion = 0.12, 95% CI (0.04, 0.19)] Fig. 3 . The test for subgroup differences between vasoconstrictor types (Norepinephrine and Phenylephrine) was statistically significant (χ² = 16.83, df = 1, p < 0.0001), indicating a significantly higher revision rate in the norepinephrine group [Proportion = 0.15, 95% CI (0.10, 0.21)] compared to the phenylephrine group [Proportion = 0.02, 95% CI (0.00, 0.06)] Fig. 4 . C) Overall Thrombosis Rate A total of 7 studies were included in the analysis of thrombosis rate for all vasoconstrictors, for a total of 7,206 procedures. The heterogeneity between the included research results was high (I² = 88.8%), necessitating the use of a random-effects model for the meta-analysis. The results showed that the overall thrombosis rate was 7%, and this was statistically significant [Proportion = 0.07, 95% CI (0.04, 0.11)] Fig. 5 . The test for subgroup differences between vasoconstrictor types (Ephedrine, Norepinephrine, and Phenylephrine) was statistically significant (χ² = 32.11, df = 2, p < 0.0001), with the norepinephrine group showing the highest rate of thrombosis [Proportion = 0.11, 95% CI (0.06, 0.16)] Fig. 6 . 3.3. Sensitivity Analysis & Publication Bias A) Sensitivity Analysis To evaluate the stability of the meta-analysis results, a leave-one-out sensitivity analysis was performed for each primary outcome. For the overall flap failure rate, removing individual studies did not significantly alter the pooled estimate, which ranged from 2.2–3.1%, demonstrating the robustness of the result (Fig. 7 ). Furthermore, a sensitivity analysis excluding the largest study (Fang et al. 2017) yielded a consistent flap failure rate of 3% [95% CI (0.02, 0.05)](Fig. 8 ). For the overall surgical revision rate, the leave-one-out analysis showed the pooled estimate remained stable, ranging from 9.9–14.0% (Fig. 9 ). Excluding the largest study (Geldern 2018) resulted in an overall revision rate of 10% [95% CI (0.03, 0.17)](Fig. 10 ), which was consistent with the primary analysis. Similarly, for the overall thrombosis rate, the leave-one-out analysis confirmed the stability of the findings, with the pooled estimate ranging from 5.6–9.0%.(Fig. 11 ) Excluding the largest study (Fang 2017) resulted in an overall thrombosis rate of 9% [95% CI (0.05, 0.13)](Fig. 12 )These analyses confirm that the results were not unduly influenced by any single study. B) Publication Bias Publication bias was assessed by visual inspection of funnel plots and by using Egger’s regression test. For the overall flap failure rate, the funnel plot appeared somewhat asymmetrical, and the Egger’s test was borderline for statistical significance [P = 0.062], suggesting a potential for publication bias (Fig. 13 ). For the overall surgical revision rate, the funnel plot was visually symmetrical, and the Egger’s test did not indicate the presence of significant publication bias [P = 0.619] (Fig. 14 ). For the overall thrombosis rate, the funnel plot appeared visually symmetrical, and this was supported by the Egger’s test, which was not statistically significant (Fig. 15 )[P = 0.897]. 4. Discussion Optimal maintenance of hemodynamic state perioperatively in patients undergoing free flap reconstruction determines the prognosis of the patient and the fate of the flap ( 6 , 7 ). Tissue damage, fluid loss and VD effect of anesthetics precipitate a state of low blood pressure with subsequent flap hypoperfusion. ( 8 ) Hemodynamic support in such conditions should be balanced to correct the hypoperfusion without precipitating edema, which is a common cause of flap failure. ( 9 ) Stemming from theoretical risk of vasospasm, the reconstructive surgeons held a tough perspective against use of vasopressors in free flap surgery ( 10 ). Old beliefs of the vasopressors being associated with increased rates of flap failure and microvascular complications have no supporting evidence, except some animal studies which report contradictory results. ( 11 ) (Grodeiro, 1997) ( 12 ) Recently, there was evidence from many studies that the use of vasopressors peri-operatively does not increase the risk of flap failure. ( 13 , 14 ) In answer to the question “Which vasopressor to use for hemodynamic support in patients undergoing free flap surgery?”; we systematically reviewed and quantitatively analyzed results from 9 studies which met our inclusion criteria. Two of the included studies were RCTs, and 7 were observational cohorts. The outcomes of interest to this study were overall flap failure, surgical revision rate, and thrombosis rate. The analysis reports overall flap failure rate to be as low as 3%, a rate close to that reported by another studies ( 15 ). There is no association between vasopressors administration and flap failure. For between group differences, the meta-analysis suggests a statistically significant increase in flap failure with nor-adrenaline [Proportion = 0.06, 95% CI (0.03, 0.08)] compared to phenylephrine [Proportion = 0.02, 95% CI (0.01, 0.02)] and ephedrine [Proportion = 0.02, 95% CI (0.00, 0.05)]. Such difference was not detected by the individual Lee study ( 5 ), maybe due to small sample size. Although statistically significant, this result is prone to publication bias, clinical significance of such differences should be assessed and studied further, taking into consideration the low incidence of overall flap failure. Moreover, the analysis reports surgical revision rate of 12% and overall thrombosis rate of 7%, nor-adrenaline was associated with statistically significant increase in thrombosis and surgical revision compared to phenylephrine. These results are worth attention because of the higher incidence of these complications relative to flap failure, However, these complications are not independent. Arterial thrombosis is a known cause of flap failure; for proper choice of hemodynamic agent, clinical significance of such difference and other hemodynamic effects of the used agents should be considered together with the patient condition. Collectively, Nor-adrenaline is associated with more surgical complications than phenylephrine. While previous studies debated the safety of vasopressors in free flap surgery ( 15 ), this is – up to our knowledge- the first robust pooled estimate of their comparative effects on flap failure and complications, and the first to include clinical trials, which make its conclusion applicable for clinical practice. As for all meta-analyses, the most considerable limitation was the included studies, given the very small number of clinical trials addressing this question; we included 2 clinical trials, and 7 observational studies, whose quality was assessed using ROB criteria. The heterogeneity between the research results included was high for all outcomes as evident by the high I2 and non-overlapping confidence intervals on forest ploy and wide spread of effect size, necessitating the use of random effects model. To address possible publication bias, funnel plots were examined for results of the three outcomes, funnel plot appeared asymmetrical for overall flap failure, egger’s test for it was statistically insignificant. For overall surgical revision and overall thrombosis rate the funnel plots were apparently symmetrical, consistent with egger’s test of no statistical significance [P = 0.619] and [P = 0.897] respectively. To address the possibility of biased results from the large effect of single study results, we questioned robustness of results using two sensitivity analyses. For each outcome the meta-analysis was recalculated with each study removed once and then recalculated excluding the single largest study. in both analyses, results were comparable to the original analysis. In conclusion, because of paucity of research on this topic, this analysis has small number of included studies, they are heterogenous, and there is considerable risk of publication bias for the results of subgroup analysis on overall flap failure rates. Given the paucity of clinical trials on this area, one considerable limitation was the presence of many variables that can’t be controlled by our study, including the timing of vasopressor administration, preoperative, post operative, or intraoperative. The type of surgery and flap, comorbidities, fluid protocol, and the add medications. All these factors may have profound effects on outcome that couldn’t be measured by this analysis, it is an area of further research. 5. Conclusion Vasopressors are not the universal threat to free-flap survival they were once believed to be. In our analysis, phenylephrine and ephedrine were linked to fewer revisions and thrombotic events than norepinephrine, though absolute differences in flap failure were small. These findings suggest that agent choice matters and should be tailored to the patient’s condition and flap characteristics. More high-quality trials are needed to guide truly evidence-based vasopressor use in microsurgery. Declarations Ethics approval and consent to participate: Not applicable in our study Competing interests: The authors declare that there are no competing interests regarding the publication of this paper. Funding: No external funding was received. Author Contribution Mohammed Ehmidat 1st, MD – Principal investigator; conceived and designed the study; led the project; participated in database search, study selection, data extraction, statistical interpretation, and drafting/revising the manuscript.Ibrahim Etfeiheh, MD – Led data analysis and statistical synthesis; contributed to interpretation of results and critical revision of the manuscript.Raghad Abuzant, MD – Contributed to literature search, study screening, data extraction, and drafting of manuscript sections.Abdulrahman Ahmed Albalasy, MD – Participated in study screening, quality assessment, manuscript writing, and critical revision for important intellectual content.Jamal Ahmad, MD – Contributed to data extraction, results synthesis, and manuscript revision for intellectual content.Engy Amgad Nasr Tolis, MD – Participated in literature review, data collection, and editing of manuscript drafts.Waheed Qaisi, MD – Assisted in methodological planning, interpretation of findings, and manuscript review.Abdeljalil El Hilali, MD – Contributed to data verification, literature review, and proofreading for accuracy.Amr Elzahy, MD – Assisted with preparation of figures/tables, supplementary material, and manuscript formatting.Soffar Mohamed M., MD – Senior mentor; provided supervision throughout the project; offered expert guidance on study design, interpretation, and final manuscript approval.All authors meet the ICMJE criteria for authorship: each made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data; drafted or critically revised the work; approved the final version; and agree to be accountable for all aspects of the work. Acknowledgments: None Data Availability Data is provided within the manuscript or supplementary information files References Naik AN, Freeman T, Li MM, Marshall S, Tamaki A, Ozer E, et al. The use of vasopressor agents in free tissue transfer for head and neck reconstruction: current trends and review of the literature. Front Pharmacol. 2020 Aug 28;11:1248. Dooley BJ, Karassawa Zanoni D, Mcgill MR, Awad MI, Shah JP, Wong RJ, et al. Intraoperative and postanesthesia care unit fluid administration as risk factors for postoperative complications in patients with head and neck cancer undergoing free tissue transfer. Head Neck. 2020 Jan;42(1):14–24. Fang L, Liu J, Yu C, Hanasono MM, Zheng G, Yu P. Intraoperative use of vasopressors does not increase the risk of free flap compromise and failure in cancer patients. Ann Surg. 2018 Aug;268(2):379–84. Knackstedt R, Gatherwright J, Gurunluoglu R. A literature review and meta-analysis of outcomes in microsurgical reconstruction using vasopressors. Microsurgery. 2019 Mar;39(3):267–75. Lee S, Ju J-W, Yoon S, Lee H-J, Ha JH, Hong KY, et al. Norepinephrine preserved flap blood flow compared to phenylephrine in free transverse rectus abdominis myocutaneous flap breast reconstruction surgery: A randomized pilot study. J Plast Reconstr Aesthet Surg. 2023 Aug;83:438–47. Chen C, Nguyen M-D, Bar-Meir E, Hess PA, Lin S, Tobias AM, et al. Effects of vasopressor administration on the outcomes of microsurgical breast reconstruction. Ann Plast Surg. 2010 Jul;65(1):28–31. Haughey BH, Wilson E, Kluwe L, Piccirillo J, Fredrickson J, Sessions D, et al. Free flap reconstruction of the head and neck: analysis of 241 cases. Otolaryngol Head Neck Surg. 2001 Jul;125(1):10–7. Raittinen L, Kääriäinen MT, Lopez JF, Pukander J, Laranne J. The effect of norepinephrine and dopamine on radial forearm flap partial tissue oxygen pressure and microdialysate metabolite measurements: A randomized controlled trial. Plast Reconstr Surg. 2016 Jun;137(6):1016e–23e. Scholz A, Pugh S, Fardy M, Shafik M, Hall JE. The effect of dobutamine on blood flow of free tissue transfer flaps during head and neck reconstructive surgery*. Anaesthesia. 2009 Oct;64(10):1089–93. Girod DA, Tsue TT, Shnayder Y. Free Tissue Transfer. Cummings Otolaryngology - Head and Neck Surgery. Elsevier; 2010. p. 1080–99. Godden DR, Little R, Weston A, Greenstein A, Woodwards RT. Catecholamine sensitivity in the rat femoral artery after microvascular anastomosis. Microsurgery. 2000;20(5):217–20. Cordeiro PG, Santamaria E, Hu QY, Heerdt P. Effects of vasoactive medications on the blood flow of island musculocutaneous flaps in swine. Ann Plast Surg. 1997 Nov;39(5):524–31. Chan JYW, Chow VLY, Liu LHL. 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Table 1 Table 1, Characterstics of included studies: Author (Country, Year) Study Design Sample Size (Patients / Flaps) Mean Age (years) ± SD Mean BMI ± SD Surgical Site(s) Vasopressor(s) Compared Key Comorbidities Follow-up Fang (USA, 2017) Retrospective 4,888 / 5,671 54.7 ± 14.1 27.2 ± 7.1 Head & neck, breast, extremities Phenylephrine, ephedrine, CaCl₂ – – Geldern (Germany, 2018) Retrospective 425 / 437 – – Lower extremity gracilis or ALT flaps Norepinephrine DM (23.3%), HTN (32.7%) – Grill (Germany, 2019) Prospective 52 / – 61 ± 14.34 24.33 ± 4.59 Head & neck Noradrenaline, RBC transfusion – – Lee (South Korea, 2023) RCT (pilot) 20 / – 50 ± 8 25.1 ± 4.1 TRAM flap (breast) Norepinephrine vs phenylephrine DM (n=5), HTN (n=15) ~7 days Raittinen (Finland, 2016) RCT (unblinded) 25 / – 61 ± 13 – Head & neck Norepinephrine vs dopamine vs control DM (n=8), HTN (n=24), smokers (n=44) ~3 days Rose (UK, 2016) Retrospective 123 / – – – Maxillofacial Norepinephrine vs metaraminol vs combination vs control – – Zhu (Canada, 2022) Retrospective 1,102 / 1,729 50.2 ± 7.7 28.5 ± 6.1 DIEP flaps Phenylephrine and/or ephedrine – ~30 days Gardner (USA, 2022) Retrospective 426 / 449 62 ± 11.4 – ALT, radial forearm, osteocutaneous – – ~5 days Rajan (India, 2019) Retrospective 120 / – 55.44 ± 14.16 – Radial forearm, ALT, LD myocutaneous, free fibula osteocutaneous Noradrenaline – – Additional Declarations No competing interests reported. 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3","display":"","copyAsset":false,"role":"figure","size":123658,"visible":true,"origin":"","legend":"\u003cp\u003eOverall Surgical Revision Rate − All Vasoconstrictors\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/99a326087500abb93f7ad1f9.jpg"},{"id":93007695,"identity":"abd882fa-fd42-4c00-92c6-d236a6c22a00","added_by":"auto","created_at":"2025-10-08 06:55:15","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":169557,"visible":true,"origin":"","legend":"\u003cp\u003eOverall Surgical Revision Rate by Vasoconstrictor Type\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/5f37f59a411bc7b113e37ec6.jpg"},{"id":93007690,"identity":"ebae5d09-47d9-4fa2-99a1-8a56d657ab0e","added_by":"auto","created_at":"2025-10-08 06:55:15","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":103032,"visible":true,"origin":"","legend":"\u003cp\u003eOverall Thrombosis Rate − All Vasoconstrictors\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/52b11875a842a4e0878c0096.jpg"},{"id":93006513,"identity":"c5637e28-c9b8-4786-b920-05f5d8854a39","added_by":"auto","created_at":"2025-10-08 06:47:15","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":157653,"visible":true,"origin":"","legend":"\u003cp\u003eOverall Thrombosis Rate by Vasoconstrictor Type\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/c1c20e11dbb4e2c2407148a7.jpg"},{"id":93006510,"identity":"9c2ba348-59a7-452a-9ac7-80ef44ccb970","added_by":"auto","created_at":"2025-10-08 06:47:15","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":125001,"visible":true,"origin":"","legend":"\u003cp\u003eLeave−One−Out Analysis of Overall Flap Failure Rate − All Vasoconstrictors (0.5 Continuity Correction for Zero Events)\u003c/p\u003e","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/dd2e92cf7664fe9f795eb8c0.jpg"},{"id":93006537,"identity":"eab4369f-879a-4326-b802-dba56c04f548","added_by":"auto","created_at":"2025-10-08 06:47:16","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":127416,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity Analysis: Excluding largest study (Fang et al 2017 (Ephedrine))\u003c/p\u003e","description":"","filename":"8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/f1544d718dec8149d3969070.jpg"},{"id":93007697,"identity":"763f843e-d39b-4df3-bdbe-fcc03a259d7d","added_by":"auto","created_at":"2025-10-08 06:55:16","extension":"jpg","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":121819,"visible":true,"origin":"","legend":"\u003cp\u003eLeave−One−Out Analysis of Overall Surgical Revision Rate − All Vasoconstrictors (0.5 Continuity Correction for Zero Events)\u003c/p\u003e","description":"","filename":"9.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/9d90734339ceebff14f09d11.jpg"},{"id":93007708,"identity":"c5ed4745-d1b2-4e2c-9223-ef8b6963929c","added_by":"auto","created_at":"2025-10-08 06:55:17","extension":"jpg","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":141441,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity Analysis: Excluding largest study (Geldern 2018 (Norepinephrine))\u003c/p\u003e","description":"","filename":"10.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/2f38e07681a86ae84d93e03b.jpg"},{"id":93006528,"identity":"b635e45f-66bc-4f84-9ad5-daa967063fa8","added_by":"auto","created_at":"2025-10-08 06:47:16","extension":"jpg","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":97645,"visible":true,"origin":"","legend":"\u003cp\u003eLeave−One−Out Analysis of Overall Thrombosis Rate − All Vasoconstrictors (0.5 Continuity Correction for Zero Events)\u003c/p\u003e","description":"","filename":"11.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/93e1f3c6ef55a3eac1cc26f8.jpg"},{"id":93006543,"identity":"525249d1-b721-4b1a-9e81-db01e82b4677","added_by":"auto","created_at":"2025-10-08 06:47:16","extension":"jpg","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":129047,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity Analysis: Excluding largest study (Fang et al 2017 (Ephedrine))\u003c/p\u003e","description":"","filename":"12.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/8442740fece722b6cf2009a9.jpg"},{"id":93006516,"identity":"af6bc89a-a0ac-420f-946a-c3b98c70581d","added_by":"auto","created_at":"2025-10-08 06:47:15","extension":"jpg","order_by":13,"title":"Figure 13","display":"","copyAsset":false,"role":"figure","size":466410,"visible":true,"origin":"","legend":"\u003cp\u003eEnhanced Funnel Plot of Overall Flap Failure Rate Studies\u003c/p\u003e","description":"","filename":"13.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/a992db7d1533ee0cc0f52def.jpg"},{"id":93006533,"identity":"30a18173-63fd-4c73-8fda-737ecc1b5952","added_by":"auto","created_at":"2025-10-08 06:47:16","extension":"jpg","order_by":14,"title":"Figure 14","display":"","copyAsset":false,"role":"figure","size":448745,"visible":true,"origin":"","legend":"\u003cp\u003eEnhanced Funnel Plot of Overall Surgical Revision Rate Studies\u003c/p\u003e","description":"","filename":"14.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/b41e2eebe2392f714b3464bd.jpg"},{"id":93006556,"identity":"51518fff-0285-4c56-bdec-4255beedba00","added_by":"auto","created_at":"2025-10-08 06:47:17","extension":"jpg","order_by":15,"title":"Figure 15","display":"","copyAsset":false,"role":"figure","size":468308,"visible":true,"origin":"","legend":"\u003cp\u003eEnhanced Funnel Plot of Overall Thrombosis Rate Studies\u003c/p\u003e","description":"","filename":"15.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/c7a22c84088fd8023233f7c5.jpg"},{"id":104727240,"identity":"85c7150e-df8e-462a-9605-f66e31115c11","added_by":"auto","created_at":"2026-03-16 13:43:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4086019,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/e382326b-4777-4fd8-9989-d0d9e3bf9736.pdf"},{"id":93006504,"identity":"a40ce27e-25f2-4831-9e43-eecf7a85717d","added_by":"auto","created_at":"2025-10-08 06:47:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14855,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-7360899/v1/a50f7c32401acf7c3f501d91.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pure Alpha vs. Mixed Adrenergic Vasopressors Perioperative Outcomes in Autologous Free Flap Surgery: A Systematic Review and Meta-analysis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAutologous microvascular free-flap reconstruction has become a cornerstone of modern surgery, enabling restoration of complex defects in the head and neck, breast and extremities. Its uptake has grown steadily and contemporary series report success rates exceeding 95% (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), underscoring its importance but also highlighting the imperative to prevent even rare failures. Maintaining reliable flap perfusion is critical during the perioperative period: hypotension may endanger arterial inflow, whereas excessive fluid administration can lead to oedema and venous congestion (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eTo support blood pressure, anaesthetists often employ vasopressor agents; yet fears that α-adrenergic vasoconstriction could compromise microcirculatory perfusion have led many microsurgeons to discourage their use (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Studies report vasopressor utilization in up to 85% of free flap procedures (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), determining whether different vasopressor classes influence outcomes represents a matter of significant clinical and public health relevance.\u003c/p\u003e\u003cp\u003eThe evidence on vasopressor use in free-flap surgery remains heterogeneous and incomplete regarding pharmacological specificity. Early experimental and clinical observations suggested that phenylephrine might reduce pedicle blood flow (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Subsequent observational studies and meta-analyses began to challenge this paradigm. A large retrospective cohort of 5,671 cancer patients undergoing free flaps found that 85% received intraoperative vasopressors demonstrated no increase in pedicle compromise or flap failure, (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) A comprehensive meta-analysis of 6,321 patients reported no significant increase in flap failure when vasopressors were used (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eRecent primary studies provide more detailed but conflicting data regarding vasopressor class-specific effects. A randomized pilot trial in breast reconstruction patients revealed that norepinephrine preserved flap blood flow superior to phenylephrine without increasing complications (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) These emerging data suggest vasopressors may be safe when used judiciously, but the heterogeneity in agents and study designs precludes definitive conclusions regarding whether phenylephrine differs from norepinephrine or ephedrine in clinically meaningful ways.\u003c/p\u003e\u003cp\u003eTo address this critical knowledge gap, we will conduct a systematic review and meta-analysis to determine whether perioperative phenylephrine (a pure α-adrenergic agonist) differs from mixed α/β-adrenergic vasopressors (norepinephrine or ephedrine) in adult patients undergoing autologous free-flap reconstruction. Our primary outcomes will encompass total flap loss and the need for re-exploration for microvascular compromise; secondary outcomes will include thrombotic events. By focusing on vasopressor pharmacological class rather than the mere presence or absence of pressor therapy, this review aims to provide clinicians with definitive, evidence-based guidance for perioperative hemodynamic management.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003e\u003cb\u003eStudy Design and Protocol Registration\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol was registered prospectively in the PROSPERO database (CRD420251086419).\u003c/p\u003e\u003cp\u003e\u003cb\u003eEligibility Criteria\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eParticipants\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIncluded studies involved adult patients undergoing autologous free flap surgery for any indication, including head and neck reconstruction, breast reconstruction, limb salvage, and other reconstructive procedures.\u003c/p\u003e\u003cp\u003e\u003cb\u003eInterventions and Comparators\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIntervention groups utilized phenylephrine as the primary vasopressor or for blood pressure support during the perioperative period. Comparator groups used mixed alpha/beta adrenergic agonists (norepinephrine and/or ephedrine) as the primary vasopressor or for blood pressure support during the perioperative period.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eEligible studies reported at least one comparative outcome between phenylephrine and mixed adrenergic agonist groups, including:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003ePrimary\u003c/b\u003e: Free flap failure, need for re-exploration for microvascular compromise.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eSecondary\u003c/b\u003e: Microvascular complications (e.g., thrombosis) and other clinically relevant complications as reported.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy Types\u003c/b\u003e\u003c/p\u003e\u003cp\u003eRandomized controlled trials (RCTs), prospective cohort studies, retrospective cohort studies, and case-control studies that directly compared perioperative use of phenylephrine versus mixed adrenergic agonists in the specified population were included. Studies were excluded if they were case series, case reports, editorials, or reviews. Studies where vasopressors were used for other indications (such as solely for cardiac arrest management) were excluded unless data specific to the perioperative period in free flap patients was clearly separable. Conference abstracts (published or unpublished) were excluded. Language restriction: English only. Eligible studies were published from the inception of the database to the date the search was conducted.\u003c/p\u003e\u003cp\u003e\u003cb\u003eInformation Sources and Search Strategy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA comprehensive literature search was conducted in the following electronic databases: MEDLINE (PubMed), Web of Science, Scopus, and Google Scholar. Additional sources included reference lists of included studies and relevant reviews. The last search was conducted from inception to the final search date.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSearch Strategy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDatabase-specific strategies were developed using a combination of MeSH terms and free-text keywords related to free flap surgery, microvascular reconstruction, vasopressors, and perioperative outcomes. The detailed \u003cb\u003ePubMed\u003c/b\u003e search strategy can be found in supplementary file 1.\u003c/p\u003e\u003cp\u003eSearch strategies were tailored for each database and reviewed by the research team. All search results were imported for screening and de-duplication.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy Selection\u003c/b\u003e\u003c/p\u003e\u003cp\u003eRecords were pooled and duplicates removed. Titles and abstracts were independently screened by two reviewers based on the eligibility criteria. Full texts of potentially eligible studies were retrieved and independently assessed by two reviewers. Any discrepancies at either stage were resolved by discussion or consultation with a third reviewer. A PRISMA flow diagram was used to document the selection process.\u003c/p\u003e\u003cp\u003e\u003cb\u003eData Extraction\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA standardized data extraction form was used. Data were independently extracted by two reviewers. Any discrepancies were resolved by discussion or consultation with a third reviewer. Extracted data included: \u003cb\u003eStudy Characteristics\u003c/b\u003e: Design, year, country, sample size, follow-up duration. \u003cb\u003ePatient Demographics\u003c/b\u003e: Age, sex, comorbidities, surgical indication. \u003cb\u003eSurgery Details\u003c/b\u003e: Type of free flap, recipient site, surgical approach. \u003cb\u003eVasopressor Details\u003c/b\u003e: Specific agent(s) used, dosing, timing of administration. \u003cb\u003eOutcome Data\u003c/b\u003e: As listed in the outcomes section, including denominators and numerators for binary outcomes, means and standard deviations for continuous outcomes, and definitions used for outcomes including flap failure definition. When data were missing or unclear, study authors were contacted for clarification.\u003c/p\u003e\u003cp\u003e\u003cb\u003eRisk of Bias Assessment\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe risk of bias for included RCTs was assessed using the Cochrane Risk of Bias tool (RoB 2.0). The risk of bias for non-randomized studies was assessed using ROBINS-I (Risk Of Bias In Non-randomized Studies - of Interventions). Risk of bias assessment was performed independently by two reviewers, with discrepancies resolved by discussion or consultation with a third reviewer. Results were presented in tabular form and factored into data interpretation and sensitivity analysis.\u003c/p\u003e\u003cp\u003e\u003cb\u003eData Synthesis and Statistical Analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eQualitative Synthesis\u003c/strong\u003e\u003cp\u003eA narrative synthesis of the included studies was conducted, summarizing their characteristics, findings, and methodological quality.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eQuantitative Synthesis\u003c/b\u003e: If sufficient homogeneous data (in terms of population, intervention/comparison, and outcome measurement) were available for specific outcomes, a meta-analysis was performed. \u003cb\u003eBinary Outcomes\u003c/b\u003e: Pooled risk ratios (RR) or odds ratios (OR) with 95% confidence intervals (CI) were calculated. \u003cb\u003eContinuous Outcomes\u003c/b\u003e: Pooled mean differences (MD) or standardized mean differences (SMD) with 95% CI were calculated. \u003cb\u003eHeterogeneity\u003c/b\u003e: Statistical heterogeneity was assessed using the Chi-squared test and quantified using the I\u0026sup2; statistic. \u003cb\u003eModel\u003c/b\u003e: If heterogeneity was low (I\u0026sup2; \u0026lt; 50%), a fixed-effect model was used. If heterogeneity was moderate to high (I\u0026sup2; \u0026ge; 50%), a random-effects model was used.\u003c/p\u003e\u003cp\u003ePotential sources of heterogeneity were explored through subgroup analysis or sensitivity analysis if appropriate. Analyses were conducted using appropriate statistical software. Funnel plots and Egger's test were used to assess publication bias if there were enough studies (typically\u0026thinsp;\u0026gt;\u0026thinsp;10) contributing to a meta-analysis for a specific outcome.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSubgroup Analysis\u003c/strong\u003e\u003cp\u003ePotential subgroups for analysis included type of free flap (head and neck vs. breast vs. limb), specific mixed agonist used (norepinephrine vs. ephedrine vs. combination), and study design (RCT vs. observational).\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSensitivity Analysis\u003c/strong\u003e\u003cp\u003eSensitivity analyses were conducted by excluding studies at high risk of bias and using alternative statistical models (fixed vs. random effects regardless of heterogeneity).\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eCertainty of Evidence\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe overall certainty of evidence for key outcomes was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Ratings considered risk of bias, inconsistency, indirectness, imprecision, and publication bias. GRADE summary tables were generated to support conclusions.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Study Characteristics\u003c/h2\u003e\u003cp\u003eIn order to determine the Vasopressor Choice in Microsurgery: A Meta-Analysis of Flap Outcomes with Pure Alpha-Agonists versus Mixed Agents was conducted. 9 studies were included as follows; Two randomized clinical trials (RCTs) and seven observational cohort studies, which were conducted in United States, United Kingdom, Germany, Canada, South Korea, Finland and India, with a total of 7181 patients underwent different types of free flaps with a total of 8626 flaps were done with use of norepinephrine, ephedrine and phenylephrine as vasopressors for comparisons\u003c/p\u003e\u003cp\u003eThe characteristics of included studies are present in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e, Characterstics of included studies:\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAuthor (Country, Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStudy Design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSample Size (Patients / Flaps)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMean Age (years)\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMean BMI\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSurgical Site(s)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eVasopressor(s) Compared\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eKey Comorbidities\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFollow-up\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFang (USA, 2017)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRetrospective\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4,888 / 5,671\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e54.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e27.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHead \u0026amp; neck, breast, extremities\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePhenylephrine, ephedrine, CaCl₂\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGeldern (Germany, 2018)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRetrospective\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e425 / 437\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLower extremity gracilis or ALT flaps\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNorepinephrine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDM (23.3%), HTN (32.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrill (Germany, 2019)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eProspective\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e52 / \u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e61\u0026thinsp;\u0026plusmn;\u0026thinsp;14.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24.33\u0026thinsp;\u0026plusmn;\u0026thinsp;4.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHead \u0026amp; neck\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNoradrenaline, RBC transfusion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLee (South Korea, 2023)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRCT (pilot)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 / \u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e50\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e25.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTRAM flap (breast)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNorepinephrine vs phenylephrine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDM (n\u0026thinsp;=\u0026thinsp;5), HTN (n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e~\u0026thinsp;7 days\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRaittinen (Finland, 2016)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRCT (unblinded)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25 / \u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e61\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHead \u0026amp; neck\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNorepinephrine vs dopamine vs control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDM (n\u0026thinsp;=\u0026thinsp;8), HTN (n\u0026thinsp;=\u0026thinsp;24), smokers (n\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e~\u0026thinsp;3 days\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRose (UK, 2016)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRetrospective\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e123 / \u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMaxillofacial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNorepinephrine vs metaraminol vs combination vs control\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZhu (Canada, 2022)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRetrospective\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1,102 / 1,729\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e50.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e28.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDIEP flaps\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePhenylephrine and/or ephedrine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e~\u0026thinsp;30 days\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGardner (USA, 2022)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRetrospective\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e426 / 449\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e62\u0026thinsp;\u0026plusmn;\u0026thinsp;11.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eALT, radial forearm, osteocutaneous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e~\u0026thinsp;5 days\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRajan (India, 2019)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRetrospective\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e120 / \u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e55.44\u0026thinsp;\u0026plusmn;\u0026thinsp;14.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eRadial forearm, ALT, LD myocutaneous, free fibula osteocutaneous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNoradrenaline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e3.2. Main Outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA) Overall Flap Failure Rate\u003c/p\u003e\u003cp\u003eA total of 10 studies were included in the analysis of flap failure rate for all vasoconstrictors, encompassing a total of 7,732 procedures. The heterogeneity between the included research results was high (I\u0026sup2; = 64.5%), so a random-effects model was used for the meta-analysis. The results showed that the overall flap failure rate was 3%, and this finding was statistically significant [Proportion\u0026thinsp;=\u0026thinsp;0.03, 95% CI (0.02, 0.04)] Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The test for subgroup differences between vasoconstrictor types (Ephedrine, Norepinephrine, and Phenylephrine) was statistically significant (χ\u0026sup2; = 12.16, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.0023), with the norepinephrine subgroup showing a higher failure rate [Proportion\u0026thinsp;=\u0026thinsp;0.06, 95% CI (0.03, 0.08)] compared to ephedrine [Proportion\u0026thinsp;=\u0026thinsp;0.02, 95% CI (0.01, 0.02)] and phenylephrine [Proportion\u0026thinsp;=\u0026thinsp;0.02, 95% CI (0.00, 0.05)]. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003c/p\u003e\u003cp\u003eB) Overall Surgical Revision Rate\u003c/p\u003e\u003cp\u003eA total of 9 studies were included in the analysis of surgical revision rate, covering a total of 502 procedures. The heterogeneity between the included research results was high (I\u0026sup2; = 81.3%), so a random-effects model was used for the meta-analysis. The results showed that the overall surgical revision rate was 12%, and this was statistically significant [Proportion\u0026thinsp;=\u0026thinsp;0.12, 95% CI (0.04, 0.19)] Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The test for subgroup differences between vasoconstrictor types (Norepinephrine and Phenylephrine) was statistically significant (χ\u0026sup2; = 16.83, df\u0026thinsp;=\u0026thinsp;1, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), indicating a significantly higher revision rate in the norepinephrine group [Proportion\u0026thinsp;=\u0026thinsp;0.15, 95% CI (0.10, 0.21)] compared to the phenylephrine group [Proportion\u0026thinsp;=\u0026thinsp;0.02, 95% CI (0.00, 0.06)] Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eC) Overall Thrombosis Rate\u003c/p\u003e\u003cp\u003eA total of 7 studies were included in the analysis of thrombosis rate for all vasoconstrictors, for a total of 7,206 procedures. The heterogeneity between the included research results was high (I\u0026sup2; = 88.8%), necessitating the use of a random-effects model for the meta-analysis. The results showed that the overall thrombosis rate was 7%, and this was statistically significant [Proportion\u0026thinsp;=\u0026thinsp;0.07, 95% CI (0.04, 0.11)] Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. The test for subgroup differences between vasoconstrictor types (Ephedrine, Norepinephrine, and Phenylephrine) was statistically significant (χ\u0026sup2; = 32.11, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), with the norepinephrine group showing the highest rate of thrombosis [Proportion\u0026thinsp;=\u0026thinsp;0.11, 95% CI (0.06, 0.16)] Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cb\u003e3.3. Sensitivity Analysis \u0026amp; Publication Bias\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eA) Sensitivity Analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo evaluate the stability of the meta-analysis results, a leave-one-out sensitivity analysis was performed for each primary outcome. For the overall flap failure rate, removing individual studies did not significantly alter the pooled estimate, which ranged from 2.2\u0026ndash;3.1%, demonstrating the robustness of the result (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). Furthermore, a sensitivity analysis excluding the largest study (Fang et al. 2017) yielded a consistent flap failure rate of 3% [95% CI (0.02, 0.05)](Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e). For the overall surgical revision rate, the leave-one-out analysis showed the pooled estimate remained stable, ranging from 9.9\u0026ndash;14.0% (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e). Excluding the largest study (Geldern 2018) resulted in an overall revision rate of 10% [95% CI (0.03, 0.17)](Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e10\u003c/span\u003e), which was consistent with the primary analysis. Similarly, for the overall thrombosis rate, the leave-one-out analysis confirmed the stability of the findings, with the pooled estimate ranging from 5.6\u0026ndash;9.0%.(Fig.\u0026nbsp;\u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e11\u003c/span\u003e) Excluding the largest study (Fang 2017) resulted in an overall thrombosis rate of 9% [95% CI (0.05, 0.13)](Fig.\u0026nbsp;\u003cspan refid=\"Fig12\" class=\"InternalRef\"\u003e12\u003c/span\u003e)These analyses confirm that the results were not unduly influenced by any single study.\u003c/p\u003e\u003cp\u003e\u003cb\u003eB) Publication Bias\u003c/b\u003e\u003c/p\u003e\u003cp\u003ePublication bias was assessed by visual inspection of funnel plots and by using Egger\u0026rsquo;s regression test. For the overall flap failure rate, the funnel plot appeared somewhat asymmetrical, and the Egger\u0026rsquo;s test was borderline for statistical significance [P\u0026thinsp;=\u0026thinsp;0.062], suggesting a potential for publication bias (Fig.\u0026nbsp;\u003cspan refid=\"Fig13\" class=\"InternalRef\"\u003e13\u003c/span\u003e). For the overall surgical revision rate, the funnel plot was visually symmetrical, and the Egger\u0026rsquo;s test did not indicate the presence of significant publication bias [P\u0026thinsp;=\u0026thinsp;0.619] (Fig.\u0026nbsp;\u003cspan refid=\"Fig14\" class=\"InternalRef\"\u003e14\u003c/span\u003e). For the overall thrombosis rate, the funnel plot appeared visually symmetrical, and this was supported by the Egger\u0026rsquo;s test, which was not statistically significant (Fig.\u0026nbsp;\u003cspan refid=\"Fig15\" class=\"InternalRef\"\u003e15\u003c/span\u003e)[P\u0026thinsp;=\u0026thinsp;0.897].\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eOptimal maintenance of hemodynamic state perioperatively in patients undergoing free flap reconstruction determines the prognosis of the patient and the fate of the flap (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Tissue damage, fluid loss and VD effect of anesthetics precipitate a state of low blood pressure with subsequent flap hypoperfusion. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) Hemodynamic support in such conditions should be balanced to correct the hypoperfusion without precipitating edema, which is a common cause of flap failure. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) Stemming from theoretical risk of vasospasm, the reconstructive surgeons held a tough perspective against use of vasopressors in free flap surgery (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Old beliefs of the vasopressors being associated with increased rates of flap failure and microvascular complications have no supporting evidence, except some animal studies which report contradictory results. (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) (Grodeiro, 1997) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) Recently, there was evidence from many studies that the use of vasopressors peri-operatively does not increase the risk of flap failure. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eIn answer to the question \u0026ldquo;Which vasopressor to use for hemodynamic support in patients undergoing free flap surgery?\u0026rdquo;; we systematically reviewed and quantitatively analyzed results from 9 studies which met our inclusion criteria. Two of the included studies were RCTs, and 7 were observational cohorts. The outcomes of interest to this study were overall flap failure, surgical revision rate, and thrombosis rate.\u003c/p\u003e\u003cp\u003eThe analysis reports overall flap failure rate to be as low as 3%, a rate close to that reported by another studies (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). There is no association between vasopressors administration and flap failure. For between group differences, the meta-analysis suggests a statistically significant increase in flap failure with nor-adrenaline [Proportion\u0026thinsp;=\u0026thinsp;0.06, 95% CI (0.03, 0.08)] compared to phenylephrine [Proportion\u0026thinsp;=\u0026thinsp;0.02, 95% CI (0.01, 0.02)] and ephedrine [Proportion\u0026thinsp;=\u0026thinsp;0.02, 95% CI (0.00, 0.05)]. Such difference was not detected by the individual Lee study (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), maybe due to small sample size. Although statistically significant, this result is prone to publication bias, clinical significance of such differences should be assessed and studied further, taking into consideration the low incidence of overall flap failure. Moreover, the analysis reports surgical revision rate of 12% and overall thrombosis rate of 7%, nor-adrenaline was associated with statistically significant increase in thrombosis and surgical revision compared to phenylephrine. These results are worth attention because of the higher incidence of these complications relative to flap failure, However, these complications are not independent. Arterial thrombosis is a known cause of flap failure; for proper choice of hemodynamic agent, clinical significance of such difference and other hemodynamic effects of the used agents should be considered together with the patient condition. Collectively, Nor-adrenaline is associated with more surgical complications than phenylephrine.\u003c/p\u003e\u003cp\u003eWhile previous studies debated the safety of vasopressors in free flap surgery (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), this is \u0026ndash; up to our knowledge- the first robust pooled estimate of their comparative effects on flap failure and complications, and the first to include clinical trials, which make its conclusion applicable for clinical practice. As for all meta-analyses, the most considerable limitation was the included studies, given the very small number of clinical trials addressing this question; we included 2 clinical trials, and 7 observational studies, whose quality was assessed using ROB criteria. The heterogeneity between the research results included was high for all outcomes as evident by the high I2 and non-overlapping confidence intervals on forest ploy and wide spread of effect size, necessitating the use of random effects model. To address possible publication bias, funnel plots were examined for results of the three outcomes, funnel plot appeared asymmetrical for overall flap failure, egger\u0026rsquo;s test for it was statistically insignificant. For overall surgical revision and overall thrombosis rate the funnel plots were apparently symmetrical, consistent with egger\u0026rsquo;s test of no statistical significance [P\u0026thinsp;=\u0026thinsp;0.619] and [P\u0026thinsp;=\u0026thinsp;0.897] respectively. To address the possibility of biased results from the large effect of single study results, we questioned robustness of results using two sensitivity analyses. For each outcome the meta-analysis was recalculated with each study removed once and then recalculated excluding the single largest study. in both analyses, results were comparable to the original analysis. In conclusion, because of paucity of research on this topic, this analysis has small number of included studies, they are heterogenous, and there is considerable risk of publication bias for the results of subgroup analysis on overall flap failure rates.\u003c/p\u003e\u003cp\u003eGiven the paucity of clinical trials on this area, one considerable limitation was the presence of many variables that can\u0026rsquo;t be controlled by our study, including the timing of vasopressor administration, preoperative, post operative, or intraoperative. The type of surgery and flap, comorbidities, fluid protocol, and the add medications. All these factors may have profound effects on outcome that couldn\u0026rsquo;t be measured by this analysis, it is an area of further research.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eVasopressors are not the universal threat to free-flap survival they were once believed to be. In our analysis, phenylephrine and ephedrine were linked to fewer revisions and thrombotic events than norepinephrine, though absolute differences in flap failure were small. These findings suggest that agent choice matters and should be tailored to the patient\u0026rsquo;s condition and flap characteristics. More high-quality trials are needed to guide truly evidence-based vasopressor use in microsurgery.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003cp\u003eNot applicable in our study\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eCompeting interests:\u003c/h2\u003e\u003cp\u003eThe authors declare that there are no competing interests regarding the publication of this paper.\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eNo external funding was received.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMohammed Ehmidat 1st, MD \u0026ndash; Principal investigator; conceived and designed the study; led the project; participated in database search, study selection, data extraction, statistical interpretation, and drafting/revising the manuscript.Ibrahim Etfeiheh, MD \u0026ndash; Led data analysis and statistical synthesis; contributed to interpretation of results and critical revision of the manuscript.Raghad Abuzant, MD \u0026ndash; Contributed to literature search, study screening, data extraction, and drafting of manuscript sections.Abdulrahman Ahmed Albalasy, MD \u0026ndash; Participated in study screening, quality assessment, manuscript writing, and critical revision for important intellectual content.Jamal Ahmad, MD \u0026ndash; Contributed to data extraction, results synthesis, and manuscript revision for intellectual content.Engy Amgad Nasr Tolis, MD \u0026ndash; Participated in literature review, data collection, and editing of manuscript drafts.Waheed Qaisi, MD \u0026ndash; Assisted in methodological planning, interpretation of findings, and manuscript review.Abdeljalil El Hilali, MD \u0026ndash; Contributed to data verification, literature review, and proofreading for accuracy.Amr Elzahy, MD \u0026ndash; Assisted with preparation of figures/tables, supplementary material, and manuscript formatting.Soffar Mohamed M., MD \u0026ndash; Senior mentor; provided supervision throughout the project; offered expert guidance on study design, interpretation, and final manuscript approval.All authors meet the ICMJE criteria for authorship: each made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data; drafted or critically revised the work; approved the final version; and agree to be accountable for all aspects of the work.\u003c/p\u003e\u003ch2\u003eAcknowledgments:\u003c/h2\u003e\u003cp\u003eNone\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData is provided within the manuscript or supplementary information files\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNaik AN, Freeman T, Li MM, Marshall S, Tamaki A, Ozer E, et al. The use of vasopressor agents in free tissue transfer for head and neck reconstruction: current trends and review of the literature. Front Pharmacol. 2020 Aug 28;11:1248.\u003c/li\u003e\n\u003cli\u003eDooley BJ, Karassawa Zanoni D, Mcgill MR, Awad MI, Shah JP, Wong RJ, et al. Intraoperative and postanesthesia care unit fluid administration as risk factors for postoperative complications in patients with head and neck cancer undergoing free tissue transfer. Head Neck. 2020 Jan;42(1):14\u0026ndash;24.\u003c/li\u003e\n\u003cli\u003eFang L, Liu J, Yu C, Hanasono MM, Zheng G, Yu P. Intraoperative use of vasopressors does not increase the risk of free flap compromise and failure in cancer patients. Ann Surg. 2018 Aug;268(2):379\u0026ndash;84.\u003c/li\u003e\n\u003cli\u003eKnackstedt R, Gatherwright J, Gurunluoglu R. A literature review and meta-analysis of outcomes in microsurgical reconstruction using vasopressors. Microsurgery. 2019 Mar;39(3):267\u0026ndash;75.\u003c/li\u003e\n\u003cli\u003eLee S, Ju J-W, Yoon S, Lee H-J, Ha JH, Hong KY, et al. Norepinephrine preserved flap blood flow compared to phenylephrine in free transverse rectus abdominis myocutaneous flap breast reconstruction surgery: A randomized pilot study. J Plast Reconstr Aesthet Surg. 2023 Aug;83:438\u0026ndash;47.\u003c/li\u003e\n\u003cli\u003eChen C, Nguyen M-D, Bar-Meir E, Hess PA, Lin S, Tobias AM, et al. Effects of vasopressor administration on the outcomes of microsurgical breast reconstruction. Ann Plast Surg. 2010 Jul;65(1):28\u0026ndash;31.\u003c/li\u003e\n\u003cli\u003eHaughey BH, Wilson E, Kluwe L, Piccirillo J, Fredrickson J, Sessions D, et al. Free flap reconstruction of the head and neck: analysis of 241 cases. Otolaryngol Head Neck Surg. 2001 Jul;125(1):10\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eRaittinen L, K\u0026auml;\u0026auml;ri\u0026auml;inen MT, Lopez JF, Pukander J, Laranne J. The effect of norepinephrine and dopamine on radial forearm flap partial tissue oxygen pressure and microdialysate metabolite measurements: A randomized controlled trial. Plast Reconstr Surg. 2016 Jun;137(6):1016e\u0026ndash;23e.\u003c/li\u003e\n\u003cli\u003eScholz A, Pugh S, Fardy M, Shafik M, Hall JE. The effect of dobutamine on blood flow of free tissue transfer flaps during head and neck reconstructive surgery*. Anaesthesia. 2009 Oct;64(10):1089\u0026ndash;93.\u003c/li\u003e\n\u003cli\u003eGirod DA, Tsue TT, Shnayder Y. Free Tissue Transfer. Cummings Otolaryngology - Head and Neck Surgery. Elsevier; 2010. p. 1080\u0026ndash;99.\u003c/li\u003e\n\u003cli\u003eGodden DR, Little R, Weston A, Greenstein A, Woodwards RT. Catecholamine sensitivity in the rat femoral artery after microvascular anastomosis. Microsurgery. 2000;20(5):217\u0026ndash;20.\u003c/li\u003e\n\u003cli\u003eCordeiro PG, Santamaria E, Hu QY, Heerdt P. Effects of vasoactive medications on the blood flow of island musculocutaneous flaps in swine. Ann Plast Surg. 1997 Nov;39(5):524\u0026ndash;31.\u003c/li\u003e\n\u003cli\u003eChan JYW, Chow VLY, Liu LHL. Safety of intra-operative vasopressor in free jejunal flap reconstruction. Microsurgery. 2013 Jul;33(5):358\u0026ndash;61.\u003c/li\u003e\n\u003cli\u003eSwanson EW, Cheng H-T, Susarla SM, Yalanis GC, Lough DM, Johnson O, et al. Intraoperative use of vasopressors is safe in head and neck free tissue transfer. J Reconstr Microsurg. 2016 Feb;32(2):87\u0026ndash;93.\u003c/li\u003e\n\u003cli\u003eGoh CSL, Ng MJM, Song DH, Ooi ASH. Perioperative Vasopressor Use in Free Flap Surgery: A Systematic Review and Meta-Analysis. J Reconstr Microsurg. 2019 Sep;35(7):529\u0026ndash;40.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1, Characterstics of included studies:\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"853\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAuthor (Country, Year)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy Design\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample Size (Patients / Flaps)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean Age (years) \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean BMI \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurgical Site(s)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVasopressor(s) Compared\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKey Comorbidities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eFang (USA, 2017)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e4,888 / 5,671\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e54.7 \u0026plusmn; 14.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e27.2 \u0026plusmn; 7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eHead \u0026amp; neck, breast, extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003ePhenylephrine, ephedrine, CaCl₂\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eGeldern (Germany, 2018)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e425 / 437\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eLower extremity gracilis or ALT flaps\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eNorepinephrine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003eDM (23.3%), HTN (32.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eGrill (Germany, 2019)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eProspective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e52 / \u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e61 \u0026plusmn; 14.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e24.33 \u0026plusmn; 4.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eHead \u0026amp; neck\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eNoradrenaline, RBC transfusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eLee (South Korea, 2023)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eRCT (pilot)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e20 / \u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e50 \u0026plusmn; 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e25.1 \u0026plusmn; 4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eTRAM flap (breast)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eNorepinephrine vs phenylephrine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003eDM (n=5), HTN (n=15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e~7 days\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eRaittinen (Finland, 2016)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eRCT (unblinded)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e25 / \u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e61 \u0026plusmn; 13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eHead \u0026amp; neck\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eNorepinephrine vs dopamine vs control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003eDM (n=8), HTN (n=24), smokers (n=44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e~3 days\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eRose (UK, 2016)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e123 / \u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eMaxillofacial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eNorepinephrine vs metaraminol vs combination vs control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eZhu (Canada, 2022)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e1,102 / 1,729\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e50.2 \u0026plusmn; 7.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e28.5 \u0026plusmn; 6.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eDIEP flaps\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003ePhenylephrine and/or ephedrine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e~30 days\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eGardner (USA, 2022)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e426 / 449\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e62 \u0026plusmn; 11.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eALT, radial forearm, osteocutaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e~5 days\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eRajan (India, 2019)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e120 / \u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e55.44 \u0026plusmn; 14.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eRadial forearm, ALT, LD myocutaneous, free fibula osteocutaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eNoradrenaline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Autologous free-flap reconstruction, Vasopressor, Phenylephrine, Norepinephrine, Ephedrine, Flap failure, Microvascular surgery","lastPublishedDoi":"10.21203/rs.3.rs-7360899/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7360899/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAutologous free-flap reconstruction has transformed reconstructive surgery, restoring form and function in complex head, neck, breast, and limb defects. Maintaining stable perfusion during surgery is essential, yet the choice of vasopressor remains controversial. Surgeons have long feared that α-adrenergic vasoconstriction might jeopardize microcirculation, despite increasing evidence to the contrary. Whether specific vasopressor classes differ in their impact on flap survival has remained uncertain.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a systematic review and meta-analysis following PRISMA guidelines (PROSPERO-registered). Eligible randomized controlled trials and observational cohort studies compared perioperative phenylephrine (pure α-agonist) with mixed α/β-agonists (norepinephrine or ephedrine) in adult free-flap surgery. Primary outcomes were flap failure and surgical revision for microvascular compromise; secondary outcomes included thrombosis. Pooled estimates were calculated using random-effects models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eNine studies (two RCTs, seven cohorts) comprising 7,181 patients and 8,626 flaps were included. Overall flap failure was low (3%), but norepinephrine was associated with higher failure (6%) compared to phenylephrine (2%) and ephedrine (2%). Surgical revision occurred in 12% overall, with norepinephrine again higher (15%) versus phenylephrine (2%). Thrombosis occurred in 7% overall, most frequently with norepinephrine (11%). Sensitivity analyses confirmed the robustness of these findings, though heterogeneity was high and publication bias could not be excluded.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eIn contemporary free-flap surgery, vasopressors are not uniformly harmful\u0026mdash;but choice may matter. Phenylephrine and ephedrine were associated with fewer surgical revisions and thrombotic events compared to norepinephrine. While absolute differences in flap failure were small, the higher complication rates with norepinephrine warrant caution, and agent selection should be individualized. Further randomized trials are needed to refine hemodynamic management strategies in microvascular reconstruction.\u003c/p\u003e","manuscriptTitle":"Pure Alpha vs. Mixed Adrenergic Vasopressors Perioperative Outcomes in Autologous Free Flap Surgery: A Systematic Review and Meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-08 06:47:08","doi":"10.21203/rs.3.rs-7360899/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8a860bef-2a15-4648-aa50-0f7c9a5c1a82","owner":[],"postedDate":"October 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-16T13:42:02+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-08 06:47:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7360899","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7360899","identity":"rs-7360899","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}