Intraoperative vasopressors in head and neck free flap reconstruction

Abstract

Introduction:

Historically, there were concerns vasopressors impair free flap outcomes, but recent studies suggest vasopressors are safe. Here we investigate this controversy by (1) evaluating vasopressors’ effect on head and neck free-flap survival and surgical complications, and (2) performing soft tissue and bony subset analysis.

Patients and methods:

Post hoc analysis was performed of a single-blinded, prospective, randomized clinical trial at a tertiary care academic medical center involving patients ≥18 years old undergoing head and neck free flap reconstruction over a 16-month period. Patients were excluded if factors prevented accurate FloTrac^™ use. Patients were randomized to traditional volume-based support, or goal-directed support including vasopressor use. Primary data was obtained by study personnel through intraoperative data recording and postoperative medical record review.

Results:

Forty-one and 38 patients were randomized to traditional and pressor-based algorithms, respectively. Flap survival was 95% (75/79). There was no significant difference between the pressor-based and traditional protocols’ flap failure (1/38 [3%] vs. 3/41 [7%], RR 0.36, 95% CI of RR 0.04–3.31, p = .63) or flap-related complications (12/38 [32%] vs. 18/41 [44%], RR 0.72, 95% CI 0.40–1.29, p = .36) Soft tissue flaps had surgical complication rates of 12/30 (40%) and 9/27 (33%) for traditional and pressor-based protocols, respectively. Bony flaps had surgical complication rates of 6/11 (55%), and 3/11 (27%) for traditional and pressor-based protocols, respectively.

Conclusions:

Intraoperative goal-directed vasopressor administration during head and neck free flap reconstruction does not appear to increase the rate of flap complications or failures.

1 |. INTRODUCTION

Free tissue transfer is commonly employed for reconstruction of post-ablative head and neck oncologic defects. Although the overall free flap success rate is >95%, the effect of intraoperative hemodynamic management remains an area of controversy (Harris, Goldstein, Hofer, & Gilbert, 2012; Kelly, Reynolds, Crantford, & Pestana, 2014; Monroe, Cannady, Ghanem, Swide, & Wax, 2011; Monroe, McClelland, Swide, & Wax, 2010; Motakef, Mountziaris, Ismail, Agag, & Patel, 2015a; Vyas & Wong, 2014). Fluid resuscitation has been preferred for hemodynamic support due to concerns about free flap ischemia from systemic vasopressors (Vyas & Wong, 2014). To avoid intraoperative vasopressor use, patients often receive significant amounts of intraoperative intravenous fluids (IVF). Excessive fluid administration can result in an altered microvascular environment and potentially contribute to free flap failure via hemodilution-induced hypercoagulability (Clark, McCluskey, Hall, et al., 2007; Martin, Bennett-Guerrero, Wakeling, et al., 2002; Namdar, Bartscher, Stollwerck, Mailander, & Lange, 2010; Ruttmann, James, & Finlayson, 2002).

The historical bias against vasopressor use in free flap reconstruction was based on animal models suggesting that intravenous vasopressor administration decreases blood flow to free musculocutaneous flaps (Banic, Krejci, Erni, Wheatley, & Sigurdsson, 1999; Benes et al., 2010; Sigurdsson & Thomson, 1995). Advances in technology now allow minimally invasive assessment of circulating blood volumes to prevent hypovolemic patients being treated with vasopressors. As centers have gained experience with the surgical and anesthetic management of head and neck free flap reconstruction, this belief has been challenged (Kelly et al., 2014; Monroe et al., 2011; Motakef et al., 2015a; Motakef, Mountziaris, Ismail, Agag, & Patel, 2015b; Swanson et al., 2015; Vyas & Wong, 2014). In fact, a recent review of vasopressor use and free flap outcomes in humans showed more than 80% of patients at one institution were administered vasopressors and the cohort receiving pressors had a lower rate of flap failure (Monroe et al., 2010). This is corroborated by growing literature suggesting that in high-volume free flap centers with specific vasopressor protocols that vasopressors have no significant impact on flap survival or postoperative complications (Hand, McSwain, McEvoy, et al., 2015; Harris et al., 2012; Kelly et al., 2014; Monroe et al., 2010).

It is also unclear whether vasopressors have different effects on outcomes of bony versus soft tissue free flap reconstruction. In contrast to soft tissue free flaps, bony free flaps typically involve longer procedures with increased flap ischemia time and often depend on blood supply from periosteal perforators that may develop a relatively higher degree of tissue ischemia in response to upstream vasopressor administration, as demonstrated in animal studies (Driessens & Vanhoutte, 1979; Tran & Geral, 1978).

This ongoing controversy has led to the present investigation involving a secondary analysis of our institution’s prospective randomized controlled trial. The objectives of this secondary analysis are to (1) evaluate the effect of a goal-directed pressor-based intraoperative protocol on head and neck flap failure and complications relative to a traditional fluid resuscitation protocol and (2) report rates of flap failure and complications following an intraoperative vasopressor regimen among bony and soft tissue free flaps.

2 |. PATIENTS AND METHODS

Institutional review board approval was obtained for a prospective, randomized controlled trial at this tertiary care academic medical center, and the trial was registered with clinicaltrials.gov (NCT02186938). Informed consent was obtained from all patients who participated in the study, and privacy rights were observed. The initial study evaluated the effect of a goal-directed intraoperative vasopressor versus fluid resuscitation protocol on intensive care unit length of stay (Hand, Stoll, McEvoy, et al., 2016). The present study represents a secondary analysis of the prior study. Patients and surgeons were blinded to randomization, although anesthesia providers were aware of the randomization assignment so they could implement the appropriate protocol. In addition, a retrospective chart review was performed involving all free flap patients who were not enrolled in the study during the study period, evaluating any differences in baseline clinical characteristics between enrolled and non-enrolled patients (Supplemental Table I).

Enrollment and disposition are displayed in Figure 1. One hundred seventy consecutive adult patients undergoing free flap reconstruction of the head and neck were recruited for study enrollment and 79 were included in final analysis with an intended 1:1 allocation ratio. Exclusion criteria included patients with factors preventing accurate arterial waveform analysis with either arterial line monitoring or the FloTrac^™ sensor (Edwards Lifesciences Corporation, Irvine, CA). The FloTrac^™ sensor is a validated medical device that analyzes the arterial pressure waveform to calculate stroke volume variation (SVV), serving as a proxy measure of intravascular volume status. This provides an objective measure to guide management of intraoperative hypotension with fluid versus pressor-based therapy (Sigurdsson & Thomson, 1995). The Flotrac^™ sensor is a commonly used device in operating rooms and intensive care units—over 2.6 million patients have been monitored with it in over 80 countries and it has been referenced in 190+ studies. Exclusion criteria included weight less than 55 kg or greater than 140 kilograms, patients with sustained intraoperative dysrhythmias including atrial fibrillation and atrial flutter, patients with documented NYHA class III–IV heart failure or ejection fraction less than 30 %, and patients with pulmonary disease preventing administration of goal tidal volumes without excessive inspiratory pressures.

FIGURE 1.

Enrollment and disposition of patients assessed for eligibility. Reported according to the consolidated standards of reporting trails

Patients meeting inclusion criteria were randomized using a random numerical identifier generated by study staff to undergo traditional arterial monitoring with an algorithm emphasizing volume-based hemodynamic support (traditional group), versus FloTrac^™ (Edwards Lifesciences) arterial waveform analysis directed hemodynamic management with an algorithm emphasizing goal-directed use of vasopressors (pressor-based group).

The traditional algorithm used maintenance and bolus infusions of PlasmaLyte to maintain a mean arterial pressure (MAP) of ≥70 or within 20% of baseline MAP. If a patient’s preoperative serum albumin <3.0 g/dl, they were repleted with 25% IV albumin based on a calculated total dose ([2.5 g/dl – actual albumin concentration] × kg × .8) = grams of albumin to administer. Blood transfusions were administered for hemoglobin <6.5 g/dl or pulse >100 or >33% increase from baseline pulse and lactate >2 mmol/L, suggestive of a physiological demonstration of tissue ischemia. Fresh frozen plasma (FFP) and/or platelets were administered based on surgical bleeding and coagulation tests in accordance with best practices.

For the pressor-based algorithm, if a patient was hypotensive (MAP <70 mmHg or MAP less than 20% of baseline preoperative blood pressure) SVV would be evaluated. If SVV >13%, a 250 ml IVF challenge would be given and MAP would be re-assessed in 10 min. If the patient were still hypotensive and SVV was still >13% after 10 min, a repeat IVF challenge would be given up to 1,500 ml. If SVV was <13%, then cardiac index (CI) would be evaluated. If CI <3.0 L/min/m² (normal CI is 2.6–4.2 L/min/m²) an inotrope epinephrine infusion would be added (glycopyrrolate was used in addition if pulse <60), and the MAP would be re-evaluated in 10 min. If CI >3.0 L/min/m², systemic vascular resistance (SVR) would be evaluated. If SVR >800 dyne/s/cm⁵ (normal SVR is 800–1,200), MAP would be reassessed in 10 min. If SVR <800 dyne/s/cm⁵ a phenylephrine infusion was begun (initiated at 20 mcg/kg/min and titrated to effect, max 120 mcg/kg/min) and MAP would be re-evaluated in 10 min. For patients that were not hypotensive on initial assessment the CI would be evaluated. If CI >3.0 then MAP would be reassessed in 10 min. If CI <3.0 a dobutamine drip would be added and MAP would be reassessed in 10 min.

Postoperative care was determined based on departmental standardized procedures and individualized therapies dictated by patient-specific factors. Notably all patients received sequential compression devices, aspirin 81 mg daily, and weight-based subcutaneous enoxaparin for thromboprophylaxis. If enoxaparin was contraindicated due to renal insufficiency, then weight-based subcutaneous heparin was used. Implantable Doppler wires were placed intraoperatively and the patients underwent flap monitoring by nurses every 1 hr and by physicians every 4 hr for the first 48 hr after surgery. Following this, flaps were monitored every 2 hr by nurses and every 12 hr by physicians.

The primary outcome of the study was a composite measure of flap failure or flap-related complications including intraoperative anastomotic failure/vessel thrombosis, venous congestion, hematoma, and fistula within 30 days of surgery. Medical complications were also recorded and categorized as renal, cardiac, and pulmonary. Outcomes were compared between pressor-based versus traditional groups, and an exploratory analysis was performed of subsets receiving bony and soft tissue reconstructions.

Associations between treatment group and categorical variables were examined using chi-square tests or Fisher’s exact test when appropriate. Associations between patient flap group and all continuous outcomes were examined using a Student’s t-test for normally distributed data and a Wilcoxon rank-sum test for non-normally distributed data. All tests were two-tailed. Relative risk (RR) for categorical outcomes and mean or median difference for continuous outcomes and respective 95% confidence intervals (CI) were estimated from the results of the univariate analysis. Median differences with 95% confidence interval in total IVF administration between treatment groups were estimated using the Hodges-Lehmann approach. Statistical analyses were conducted using SAS 9.4 (SAS Institute, Cary, NC) with statistical significance defined as a p-value <.05.

A sample size calculation was performed for the prior study evaluating the effect of these protocols on intensive care unit length of stay (Hand et al., 2016). A posthoc power analysis was conducted to estimate the power to detect the observed differences in flap complication rate between the two treatment arms. A sample size of 41 subjects in the traditional arm and 38 in the pressor-based arm with the composite endpoint of flap complication or failure rates of 44 and 32%, respectively provides only 18% power to detect this difference. The present study is underpowered to detect changes in surgical complications or free flap failures and thus serves as preliminary evidence.

3 |. RESULTS

3.1 |. Demographics and clinical characteristics

Demographics are displayed in Table 1. Forty-one patients were randomized to the traditional volume-based hemodynamic support algorithm while 38 patients received the goal-directed pressor-based algorithm. Mean age (SD) of participants in each group was 60.8 (10) and 56.8(15) years, respectively. Participants had similar prior treatment histories with 14/38 (37%) and 13/41 (32%) having received prior definitive radiation or definitive surgery. No differences were identified in preoperative BMI, history of hypertension, coronary artery disease, peripheral vascular disease, smoking history, preoperative hemoglobin, ASA classification, intraoperative estimated blood loss, intraoperative transfusions, defect type, flap type, or surgical duration. There was a greater proportion of non-Caucasian patients in the traditional group 11/41 (27%) compared to the pressor-based group (1/38, 3%).

TABLE 1.

Clinical characteristics of 79 patients randomized to a traditional volume-based or a goal-directed pressor-based hemodynamic protocol during head and neck free flap reconstruction

Clinical characteristic	Pressor-baseda N = 38	Traditionala N = 41	P b
Gender, n (%)			.94
Male	29 (76%)	31 (76%)
Female	9 (24%)	10 (24%)
Age, mean ± SD	60.8 ± 10	56.8 ± 15	.15
Race, n (%)			.004
Caucasian	37 (97%)	30 (73%)
African American/other	1 (3%)	11 (27%)c
BMI, mean ± SD	25.2 ± 5	25.9 ± 6	.58
HTN, CAD, or PVD, n (%)	27 (71%)	22 (54%)	.11
Smoking history, n (%)	29 (76%)	31 (76%)	.94
Total prior definitive treatment, n (%)	14 (37%)	13 (32%)	.64
Prior surgery, n (%)	10 (26%)	4 (10%)	.07
Prior XRT/CXRT, n (%)	7 (18%)	11 (27%)	.43
ASA classification, n (%)			.62
2	7 (18%)	7 (17%)
3	31 (82%)	33 (80%)
4	0 (0%)	1 (3%)
Preoperative hemoglobin, mean ± SD	12.3 ± 2.1	11.5 ± 1.9	.12
EBL, mL, median (IQR)	300 (175–600)	400 (250–500)	.23
Intraoperative units pRBC, mean ± SD	0.4 ± 0.8	0.5 ± 1.0	.63
Defect type, n (%)			.95
Oral cavity	18 (47%)	22 (54%)
Laryngopharyngeal	6 (16%)	7 (17%)
Oropharyngeal	5 (13%)	5 (12%)
Cutaneous	7 (18%)	5 (12%)
Midface	2 (5%)	2 (5%)
Flap type, n (%)			.63
Fasciocutaneous scapula	2 (5%)	2 (5%)
Osteocutaneous scapula	6 (16%)	8 (20%)
Osteocutaneous fibula	6 (16%)	7 (17%)
Fasciocutaneous radial forearm	11 (29%)	8 (20%)
Anterolateral thigh	12 (32%)	10 (24%)
Latissimus	1 (3%)	3 (7%)
Fasciocutaneous ulnar	0 (0%)	3 (7%)
Surgery duration (H:M), mean ± SD	10:57 ± 2:42	10:55 ± 2:44	.96
Intraoperative IVF(mL), median (IQR)	5,624 (3,910–7,750)	5,900 (4,200–8,340)	.54d
ICU length of stay, mean days ± SD	1.6 ± 1.6	2.6 ±2.7	.05

Abbreviations: BMI, body mass index; CAD, coronary artery disease; EBL, estimated blood loss in mL; HTN, hypertension; IVF, intravenous fluid; PVD, peripheral vascular disease; SD, standard deviation.

^aCharacteristics denoted by n, (%) unless otherwise noted.

^bChi square, Fisher’s exact, and Student’s t-test analysis performed as appropriate.

^cThis includes one South Asian Indian.

^dMedian difference (Hodges–Lehmann 95% confidence interval) in intraoperative fluid administration (ml) for traditional versus pressor-based groups was −349.5 (−1,293 to 765).

3.2 |. Goal-directed pressor-based versus traditional protocol

As expected, patients in the pressor-based algorithm were more likely to receive intraoperative vasopressors than those in the traditional algorithm (87% vs. 20%, RR 4.32 [95% CI 2.28–8.16]) (Table 2). Interestingly there was no difference in intraoperative IVF administration between those who received the pressor-based algorithm compared to those who received the traditional algorithm (median 5,624 vs. 5,900 ml, 95% CI of difference −349.5 [−1,293 to 765]).

TABLE 2.

Free flap failures and complications associated with traditional volume-based versus goal-directed pressor-based intraoperative hemodynamic protocol for head and neck reconstruction

Outcomea	Pressor-based n = 38	Traditional n = 41	Relative risk	95% CI	P
Intraoperative Pressors, n (%)	32 (84%)	8 (20%)	4.32	2.28–8.16	<.0001
Flap failure, n (%)	1 (3%)	3 (7%)	0.36	0.04–3.31	.63
Flap-related complication, n (%)a	12 (32%)	18 (44%)	0.72	0.40–1.29	.36
Any medical complication, n (%)	1 (3%)	8 (20%)	0.13	0.02–1.03	.03
Renal	1 (3%)	1 (2%)	1.08	0.07–16.65	1.00
Cardiac	0 (0%)	4 (10%)	0.12	0.01–2.15	.12b
Pulmonary	0 (0%)	5 (12%)	0.10	0.01–1.71	.06b

^aPatients who had a flap failure were included in the group of flap-related complications.

^bContinuity correction applied.

The overall free flap survival rate was 95% (75/79). Three of the four flap failures (75%) were associated with venous congestion. There was not a significant difference between the pressor-based and traditional protocol in terms of flap failure (1/38 [3%] vs. 3/41 [7%], RR 0.36, 95% CI of RR 0.04–3.31) or any flap-related complications (12/38 [32%] vs. 18/41 [44%], RR 0.72, 95% CI 0.40–1.29) (Table 2).

The pressor-based group experienced fewer medical complications than the than the traditional protocol (1/38 [3%] vs. 8/41 [20%]), RR 4.32, 95% CI 0.02–1.03) (Table 2). There were no pulmonary or cardiac complications among 38 pressor protocol patients, but among the traditional protocol patients there were 4/41 (10%) and 5/41(12%) cardiac and pulmonary complications, respectively.

3.3 |. Flap failure or surgical complication rates by flap type and flap type within treatment group

Twenty-eight percent (22/79) of patients received bony reconstruction and 72% (57/79) received soft tissue flap reconstruction. Fifty percent (11/22) of patients with bony tissue reconstruction and 47% (27/57) of patients with soft tissue reconstruction were randomized to the pressor-based treatment arm. Flap complications or failure occurred in 41% (9/22) of patients with bony construction compared to 37% (21/57) among patients with soft tissue reconstruction (Table 3). Among patients in the traditional arm, 55% (6/11) of patients with bony reconstruction and 40% (12/30) with soft tissue reconstruction experienced flap complications or failure. Among patients in the pressor-based arm, 27% (3/11) of patients with bony reconstruction and 33% (9/27) with soft tissue reconstruction experienced flap complications or failure. Given the limited sample size, formal hypothesis testing was determined to be inappropriate for comparison of these groups. Demographics and clinical characteristics are provided in Supplemental Tables II and III.

TABLE 3.

Exploratory subset analysis of pressor-based versus traditional protocol in bony and soft tissue reconstruction for head and neck defects

Outcome	Pressor-based	Traditional	Relative risk	95% CI
Bony flap cohort a	n = 11	n = 11
Intraoperative pressors, n (%)	9 (82%)	3 (27%)	3.00	1.10–8.20
Flap failure, n (%)	0 (0%)	1 (9%)	0.33b	0.02–7.39b
Flap-related complication, n (%)c	3 (27%)	6 (55%)	0.50	0.17–1.51
Medical complication, n (%)	0 (0%)	3 (27%)	0.14	0.01–2.48
Renal	0 (0%)	0 (0%)	1.00	0.02–46.41
Cardiac	0 (0%)	1 (9%)	0.33	0.02–7.39
Pulmonary	0 (0%)	2 (18%)	0.20	0.01–3.74
Soft tissue flap cohort d	n = 27	n = 30
Intraoperative pressors, n (%)	23 (85%)	5 (17%)	5.11	2.26–11.60
Flap failure, n (%)	1 (4%)	2 (7%)	0.56	0.05–5.79
Flap-related complication, n (%)c	9 (33%)	12 (40%)	0.83	0.41–1.66
Medical complication, n (%)	1 (4%)	5 (17%)	0.22	0.03–1.78
Renal	1 (4%)	1 (3%)	1.11	0.07–16.91
Cardiac	0 (0%)	3 (10%)	0.16	0.01–2.93
Pulmonary	0 (0%)	3 (10%)	0.16	0.01–2.93

^aMedian difference (Hodges–Lehmann 95% confidence interval) in intraoperative fluid administration (ml) for traditional versus pressor-based groups was −208 (−3,750 to 2,397).

^bContinuity correction applied.

^cPatients who had a flap failure were included in the group of flap-related complications.

^dMedian difference (Hodges–Lehmann 95% confidence interval) in intraoperative fluid administration (ml) for traditional versus pressor-based groups was −600 (−1,847 to 500).

4 |. DISCUSSION

In the present study, we sought to answer the question, “Is an algorithm emphasizing goal-directed use of vasopressors associated with more flap-related complications than a traditional hemodynamic support strategy emphasizing fluid administration?” To assess this we conducted a secondary analysis of a prospective, randomized study examining the effect of an intraoperative vasopressor-based algorithm versus a traditional volume-based algorithm on free flap reconstruction of the head and neck, with a secondary subset analysis reporting rates of complications for bony and soft-tissue reconstructions. Our findings that a pressor-based algorithm was not associated with more complications is in line with previous studies showing that vasopressors use did not significantly affect surgical morbidity or free flap survival (Harris et al., 2012; Monroe et al., 2010).

The hemodynamic parameters for optimal free flap outcomes have yet to be determined. Some degree of hemodilution has been thought to minimize the risk for vessel thrombosis, although extensive hemodilution has also been associated with a procoagulative state leading to venous thrombosis, especially with crystalloids (Martin et al., 2002; Namdar et al., 2010; Ruttmann et al., 2002). In head and neck free flap reconstruction excess intraoperative IV fluid administration has been associated with increased flap failure rates, potentially due to local interstitial edema diminishing flow either at the pedicle or in the flap microcirculation (Eley, Young, & Watt-Smith, 2012; Sigurdsson & Thomson, 1995).

Given the concerns about the adverse effects of excess intraoperative IV fluid administration, there is interest in exploring the safety of alternative methods of maintaining intraoperative perfusion pressure. The primary finding of our study was that a goal-directed protocol utilizing vasopressors did not lead to an increase in flap failures or flap specific complications, although we are underpowered to detect all but large differences. In fact, contrary to the historical opinion that vasopressor use contributes to free flap death through vascular compromise, we even observed a slightly lower rate of flap complications among the group that received pressors. The variability of the types of free flaps utilized in this study enhances its generalizability to the field of head and neck free flap reconstruction as a whole. Overall these results are consistent with multiple other clinical studies examining pressors in head and neck reconstruction (Chao, Taylor, Rahmati, & Rohde, 2014; Harris et al., 2012; Kelly et al., 2014; Monroe et al., 2010; Monroe et al., 2011), as well as larger studies evaluating the effect of vasopressors in free flap reconstruction of the breast, head and neck, extremities, and trunk (Table 4; Chan, Chow, & Liu, 2013; Chen et al., 2010; Fang et al., 2018; Knackstedt, Gatherwright, & Gurunluoglu, 2019; Nelson et al., 2017). The study by Nelson et al. (2017) observed retrospectively that within 682 patients undergoing 1,039 flaps for breast reconstruction there was no increase in intraoperative thrombotic events (arterial or venous) or flap loss associated with vasopressor administration, but they did have a higher rate of minor complications (wound healing issues, seroma, infection, partial flap loss, and fat necrosis): 53% in the vasopressor group and 43% in those who did not receive vasopressors. Fang et al. (2018) observed that in retrospective review of 5,671 free flap cases in 4888 patients where 85% of cases had intraoperative vasopressors, after propensity score matching analysis there was no increased risk of pedicle compromise (3.2 vs. 4.7%) or flap failure (1.6 vs. 2.4%) rates with vasopressor use.

TABLE 4.

Pertinent studies examining applications of vasopressors in microsurgery cases, listed in order of number of flaps analyzed

Authors	Study type	Area reconstructed	Flaps analyzed, n	Flaps receiving pressors, n (%)	Pressor flap failures, n (%)	No pressor flap failures, n (%)
Fang et al. (2018)	Retrospective	Alla	5,671	4,816 (85%)	74 (2%)	23 (3%)
Nelson et al. (2017)	Retrospective	Breast	1,033	735 (71%)	12 (2%)	3 (1%)
Chen et al. (2010)	Retrospective	Breast	258	140 (54%)	1 (1%)	5 (4%)
Monroe et al. (2010)	Retrospective	Alla	169	139 (82%)	4 (3%)	2 (7%)
Monroe et al. (2011)	Prospective	H&Nb	169	90 (53%)	4 (4%)	2 (3%)
Chan et al. (2013)	Retrospective	H&Nb	110	81 (74%)	4 (5%)	2 (7%)
Kelly et al. (2014)	Retrospective	Alla	47	25 (53%)	1 (4%)	2 (9%)
Raittinen et al. (2016)	Prospective	H&Nb	26	17 (65%)	0 (0%)	0 (0%)
Eley et al. (2012)	Prospective	H&Nb	24	24 (100%)	0 (0%)	—
Suominen et al. (2004)	Prospective	Breast	19	13 (68%)	0 (0%)	0 (0%)

^aThis included head and neck, breast, trunk, and extremities.

^bHead and neck.

Despite this reassuring overall data concerning pressors in free flap reconstruction, there remains questions about the safety of specific pressors and the timing of pressor administration. Within the pressor-based group we did notice a general trend toward use of vasopressors after induction of anesthesia, but there was even a high level of pressor administration later in the case with 24/38 (58%) patients in the pressor group receiving pressors during the time of microvascular anastomosis and afterward. This is important to consider since the study by Retrouvey et al. (2020) provided evidence that the administration of ephedrine after tourniquet deflation for digital reimplantation and revascularization procedures was associated with digit failure. In the present study, 1 flap failure occurred in the 24 patients (4%) receiving pressors during microvascular anastomosis, while there were no flap failures occurring in the 14 patients not receiving pressors during the microvascular anastomosis. Of particular note, phenylephrine was the pressor used during the microvascular anastomosis of the case of the flap failure that occurred in the pressor group. As the meta-analysis by Knackstedt et al. (2019) describes, many surgeons recommend against phenylephrine use during microsurgical reconstruction if a vasopressor is required. Similarly, Retrouvey et al. (2020) observed a trend toward increased odds of digit failure in patients who had received phenylephrine intraoperatively during their digit reimplantation/revascularization. Given the small sample size of the present study and its low rate of flap failures, it is difficult to draw conclusions about the effect of pressor administration—and specifically epinephrine—during microvascular anastomosis. It is reassuring that there was not a glaring difference in these outcomes—especially considering that 24 patients in the pressor group received epinephrine intraoperatively and there was only 1 associated flap failure—but it merits investigation in future large scale prospective studies.

However, it should be stated that while we did not obviously observe ill effects with intraoperative vasopressor use, there were no obvious ill effects with traditional volume-based hemodynamic support. In fact, the vasopressor group averaged about the same amount of overall fluid administered during surgery. So the evidence suggests that either method may be acceptable based on the evidence presented. However, it should be noted that our finding that medical complications appeared to be slightly more frequent in the traditional protocol compared to the pressor-based protocol merits further investigation and should be included as a safety endpoint in future trials. In a larger retrospective study with 682 patients undergoing breast reconstruction, there was no difference in medical complications when comparing patients that did versus did not receive pressors (Nelson et al., 2017).

Our finding of 38% of patients experiencing a surgical complication after undergoing free flap reconstruction for head and neck cancer reflects the high rate of revision/previously treated cases presenting to our institution and is in accordance with other reports. Clark et al. (2007) reported a similar overall complication rate of 37% in 185 patients undergoing free flap reconstruction of head and neck defects. In their study, it is not directly reported whether vasopressors were utilized, but it appears that volume replacement with crystalloids and colloids was the primary source of hemodynamic support. Monroe et al. (2011) in their retrospective review of 169 patients undergoing head and neck cancer reconstruction that included vasopressor utilization in 72% of cases at the discretion of the anesthesiologist reported a nonmedical complication rate of 32%. Their findings agree with the present study, reporting a similar flap failure rate of 4.4% (4/90) among those exposed to intraoperative vasopressors versus 2.5% (2/79) among those not exposed to vasopressors.

Because bony and soft tissue free flaps have fundamentally different vascular physiology, it is also of interest to know whether the effect of intraoperative vasopressors is different for each of these flap subtypes. Soft tissue flaps depend on a period of angiogenesis after which the main vascular pedicle is not the sole supply to the tissue. In contrast, bony flaps depend on a low-pressure system of blood flow through the periosteum and bone marrow that may be more dependent on the vascular tone of the supplying arterioles (Laroche, 2002; Travlos, 2006).

The exploratory analysis examining the effect of a pressor-based algorithm for soft tissue and osseous free flaps found similar rates of complications or survival. This study provides preliminary information that even though bony and soft tissue free flaps have different anatomic methods of perfusion, the use of intraoperative goal-directed vasopressor-based algorithm does not appear to have different effects on the rates of flap failure or complications. The sample sizes for comparison were small for each type of reconstruction and underpowered to detect clinically meaningful differences, so these results should be interpreted with caution. Nevertheless, this is important information as the use of intraoperative vasopressors in flap reconstruction continues to expand, and should be explored in a larger analysis (Kelly et al., 2014; Monroe et al., 2010, 2011; Motakef et al., 2015a, 2015b; Swanson et al., 2015; Vyas & Wong, 2014).

This study possesses several limitations. While it is strengthened by the data being obtained in a randomized, prospective manner—which has been utilized in relatively few investigations (Eley et al., 2012; Monroe et al., 2011; Raittinen, Kääriäinen, Lopez, Pukander, & Laranne, 2016; Suominen et al., 2004)—it was not initially aimed at comparing rates of flap failure or complication. Thus, the retrospective nature of this secondary analysis will affect data analysis and interpretation. It also did not directly assess the perfusion of each free flap and instead relied on clinical outcomes related to complications and flap survival. Although challenging, objective measurement of perfusion may be useful in future studies. Generalizability is limited by our sample size, lack of racial diversity, and single-institution study design. The study is also underpowered to detect small differences in complications or flap failure rates and therefore serves as preliminary evidence requiring confirmation in a prospective multi-institutional study with greater statistical power.

5 |. CONCLUSIONS

This study provides evidence that goal-directed intraoperative vasopressor administration does not appear to increase the rate of free flap surgical complications or failures relative to a traditional volume-based algorithm. We also provide an exploratory subset analysis reporting that the effect of the vasopressor-based algorithm did not have differential effects on flap failure or complications in bony versus soft tissue free flaps. It is important to note that this study does not support the use of vasopressors without guideline-directed use. Further investigation is needed to fully elucidate the factors contributing to free flap complications and to develop optimal hemodynamic protocols.