Cardiovascular complications in head & neck microvascular flap reconstruction: A retrospective risk stratification and outcomes assessment

Accepted Manuscript Cardiovascular Complications in Head & Neck Microvascular Flap Reconstruction: A Retrospective Risk Stratification and Outcomes Assessment Naseem Ghazali, MBBS, BDS, MSc, DOHNS, FDSRCS, FRCS(OMFS), Steven Caldroney, DDS, MD, Donita Dyalram, DDS, MD, FACS, Joshua E. Lubek, DDS, MD, FACS PII:

S1010-5182(17)30341-4

DOI:

10.1016/j.jcms.2017.10.002

Reference:

YJCMS 2803

To appear in:

Journal of Cranio-Maxillo-Facial Surgery

Received Date: 12 May 2017 Revised Date:

2 October 2017

Accepted Date: 5 October 2017

Please cite this article as: Ghazali N, Caldroney S, Dyalram D, Lubek JE, Cardiovascular Complications in Head & Neck Microvascular Flap Reconstruction: A Retrospective Risk Stratification and Outcomes Assessment, Journal of Cranio-Maxillofacial Surgery (2017), doi: 10.1016/j.jcms.2017.10.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Title: Cardiovascular Complications in Head & Neck Microvascular Flap Reconstruction: A

RI PT

Retrospective Risk Stratification and Outcomes Assessment

Authors:

Naseem Ghazali, MBBS, BDS, MSc, DOHNS, FDSRCS, FRCS(OMFS)1 Steven Caldroney, DDS, MD1

SC

Donita Dyalram, DDS, MD, FACS1

Institution: 1

M AN U

Joshua E. Lubek, DDS, MD, FACS1

Department of Oral & Maxillofacial Surgery, University of Maryland, 650 West Baltimore Street, Baltimore, MD 21201.

TE D

Author for correspondence: Joshua E. Lubek MD, DDS, FACS

AC C

EP

Associate Professor & Fellowship Director Oral-Head & Neck Surgery/Microvascular Surgery Department of Oral & Maxillofacial Surgery University of Maryland 650 West Baltimore St. Rm 1215 Baltimore, MD, 21201 [email protected] tel# 410-706-6195 fax# 410-706-4199

Declaration:

This work was presented at the 23rd Congress of the European Association of CranioMaxillofacial Surgery, London. The authors have no financial disclosures Running Title: Cardiovascular Complications in Head & Neck Flaps

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Keywords: Head and Neck Reconstruction – Revised Cardiac Risk Index – Cardiac Complications

ACCEPTED MANUSCRIPT

Abstract

Background: To determine the incidence and predictors of cardiac complications (CC) in head & neck microvascular flap reconstruction. Methods: A series of 216 microvascular flaps performed between 2012 and 2015 were

RI PT

analyzed using the Revised Cardiac Risk Index (CRCI) and the Charlson comorbidity index (CCI). Multivariate regression analysis was undertaken for predictive factors of outcomes.

Results: Twenty patients developed CC (9.7%) with transient cardiac arrhythmia (6.5%) and

SC

myocardial infarction (2.8%) occurring most frequently. Univariate analyses demonstrated significant differences between the two groups in terms of their age, smoking status, occurrence

M AN U

of peripheral vascular disease, CCI, RCRI, length of hospitalization and duration of anesthesia. Multivariate analyses showed that RCRI (p<0.001) and amount of blood transfused (p=0.02) were independent predictors of CC.

Conclusions: Cardiac complications are uncommon in head and neck microvascular flap surgery. The RCRI is a useful screening tool for estimating cardiac complication risk and

EP

Introduction

TE D

improving patient and flap outcomes.

The risk of cardiac-related morbidity and mortality are concerning issues with head and neck

AC C

microvascular free tissue transfers. (Clark et al.,2007; Vandersteen et al.,2013) In a study based on the National Surgical Quality Improvement Program, NSQIP database of 2349 patients who underwent free flaps procedures over a 6-year period, the incidence of catastrophic medical outcomes was recorded at 5.2%, with cardiac-related events accounting for 11.9% of those events. (Grant et al.,2014)

The ability to identify and stratify patients at risk of perioperative cardiac events during microvascular free flap surgery may potentially facilitate risk management of such events

ACCEPTED MANUSCRIPT thereby reducing cardiac morbidity and improving patient outcomes. This is especially true in the current era of scrutinized health care economics (Jones et al.,2007), and is particularly relevant in a head and neck cancer subpopulation who often present with a higher cardiovascular comorbidity risk assessment secondary to factors such as; older age (i.e. ≥ 60 years), social habits (higher prevalence of alcohol and tobacco history), and various medical including

peripheral

vascular

disease,

hypertension,

hypercholesterolemia. (Chiang et al.,2002; Nouraei et al., 2007)

diabetes

and

RI PT

conditions

SC

Microvascular free tissue transfer during head and neck surgery often involves prolonged surgery and anesthesia (> 8 hours surgery time). Hemodynamic instability due to large volume

M AN U

fluid shifts from significant intraoperative blood loss and large intravenous volume replacement, can result in a cardiac demand ischemia especially in a patient population with pre-existing cardiac morbidities. (Nagele et al.,2011) Cardiac strain may be further increased with manipulation of the carotid sinus during neck dissection and carotid vasculature exposure for use in microvascular free tissue reconstruction. (Nouraei et al.,2011) Furthermore, the risk of

TE D

cardiac workload and possible myocardial infarction (MI) or heart failure during the perioperative period can be exacerbated by a hyperdynamic circulation, which is achieved through a combination of perioperative fluid management, use of vasoactive agents and

EP

antithrombotic agents for the specific management in the free flap reconstruction. (Brinkman et al.,2013) Significant postoperative inflammation and pain can also increase workload and stress

AC C

on the heart resulting in a cardiac-related complication. (Nouraei et al.,2007)

Despite advances in perioperative medical/surgical management, myocardial strain and injury may occur irrespective of preoperative optimization, close intraoperative monitoring and intensive medical management during the postoperative period. (Devereaux et al., 2005)

ACCEPTED MANUSCRIPT The aims of this study are (1) to determine the incidence, treatment and predictors of major cardiac complications in head and neck microvascular flap reconstruction, and (2) to determine the impact of major cardiac complications on flap outcomes and hospitalization.

RI PT

Materials and Method

Study Design and Patient Population

This retrospective case study included 223 consecutive microvascular free flaps performed over

SC

a 3-year period (2012-2015) for reconstruction of head and neck defects performed by reconstructive surgeons in the Department of Oral and Maxillofacial Surgery at the University

M AN U

of Maryland Medical Center. Clinical data was obtained from a reconstructive database within the Department of Oral & Maxillofacial Surgery, University of Maryland. Patients with incomplete/absent surgical and/or anesthesia documentation (n=7) were excluded. This study was approved by the University of Maryland Institutional Review Board for Ethical Human

TE D

Research.

Patients planned for microvascular free tissue transfer surgery routinely undergo a full preoperative medical assessment through their medical physician. When there is significant

EP

cardiac history or when patients are already under the care of a cardiologist, additional consultation with the cardiologist for cardiac evaluation is undertaken. The findings of these

AC C

assessments are submitted to the University of Maryland Medical Center Preoperative Anesthesia Clinic to be reviewed by an anesthesiologist. With this arrangement, very few patients required further evaluation at the anesthesiologist’s request.

Covariates collected Body mass index (BMI) was determined as the body mass divided by the square of body height (kg/m2). Smoking status was determined using the following categories: current smokers, quit and non-smokers. Definitive diagnosis was based on the final surgical pathological report, and

ACCEPTED MANUSCRIPT classified into benign and malignant conditions. The type of flap undertaken for head and neck reconstruction was recorded as either bone-flap or soft tissue only flap. Regarding intraoperative data, the following data were obtained: length of general anesthetic (GA), administration of intravenous fluid and blood transfusion, vasopressor use, and estimated blood loss. In this study, ASA classification (American Society of Anesthesiologists’ Classification of

RI PT

Physical Status) was based on the preoperative assessment of patient condition obtained from the anesthesia record.

SC

Calculation of comorbidity & cardiac risk

Comorbidity refers to the other diseases, illnesses, or conditions that a patient with cancer has at

M AN U

the time of diagnosis and that may impact on treatment selection and outcome. (Piccirillo and Feinstein, 1996) The Charlson Comorbidity index (CCI) was used to calculate the overall comorbidity in this study. (Charlson et al.,1987) The ICD-10 (International Classification of Disease) diagnosis codes were used based on hospital administrative data. (Quan et al.,2005) Each comorbidity category is assigned an associated weight (from 1 to 6), based on the adjusted

TE D

risk of mortality or resource use. (TABLE 1) The impact of age is incorporated into the overall scoring by using an age-weighted scoring method, which starts at age 50 years onwards (from 0 to 3 points). The final summation of all the weights results in a single comorbidity score for a

EP

patient. The CCI score starts at zero (no comorbidities present), and a higher score indicates the

AC C

more likelihood of mortality, morbidity and/or higher resource use.

The Revised Cardiac Risk Index (RCRI) was used to estimate cardiovascular risk. (Lee et al.,1999) A cumulative score is calculated based on 6 risk categories, where 1 point is awarded when there is presentation with any history in the 6 risk categories is categorized into 4 classes (I-IV) where the risk of risk of a major cardiac event is estimated at 0.4%, 0.9%, 6.6% and 11%, respectively. The variables of the RCRI risk category were scored based on specific criteria and the coding used is shown in TABLE 2.

ACCEPTED MANUSCRIPT

End-point

The primary end-point in this study was the incidence of major cardiac complications from hospital admission to 30-days after hospital discharge. Cardiac complications (CC) were defined as cardiac death, MI, heart failure and cardiac arrhythmias. A diagnosis of MI was made based on ECG findings and a positive serum troponin-I levels. A clinical diagnosis of heart

RI PT

failure was confirmed with formal radiological or echocardiographic reports. Persistent cardiac arrhythmias were identified and diagnosed with ECG findings. Cardiac death was confirmed by death notification available in hospital records.

SC

The secondary endpoints were length of hospitalization, and the occurrence of major flap complications that occurred from time of surgery to hospital discharge. Length of

M AN U

hospitalization was considered from date of admission to date of discharge. Major flap complications were defined as complete failure, partial failure, or operative take-back for venous or arterial thrombosis.

TE D

Statistical analysis

Statistical analysis was performed using SPSS version 11 software. Analyses between groups for continuous variables were analyzed using the unpaired t-test, while categorical variables

EP

were analyzed using the Chi-square test. Ordinal variables (e.g. ASA score) were compared

AC C

between groups using the Mann-Whitney test.

Evaluation of possible predictors of CC was undertaken. Initial analyses compared the differences in the characteristics of patients with and without CC. In this analysis, continuous variables were analyzed using the unpaired t-test or the Mann-Whitney test. The Mann-Whitney test was also used for ordinal variables, whilst the Chi-square test was used for categorical variables. Multiple logistic regression analysis considered the joint association between the factors and the occurrence of complications. In addition, the association between length of hospitalization stay in those with and without major cardiac complications was evaluated using the Mann-Whitney test.

ACCEPTED MANUSCRIPT Results

216 microvascular flaps were considered in this study, with 52 benign (24%) and 164 malignant (76%) pathologies. The mean age of all subjects was 58.9 ± 13.3 years. As a group, cancer

RI PT

subjects were older (mean, 60.8 ± 11.2) than the benign subjects (mean, 52.9 ± 17.1). Subgroup analysis found significant differences between benign and cancer patients in terms of their age, smoking status, Charlson co-morbidity index (CCI), ASA classification, flap type (bone versus

SC

soft tissue) and length of general anesthesia. (TABLE 3)

M AN U

Cardiac Complications

From a total of 216 patients, 20 patients developed 21 CC (21/216; 9.7%). From these, MI occurred in 6 patients while in hospital (6/216, 2.7%). Cardiac mortality occurred in one patient (0.5%). This patient was one of the 6 patients who developed MI during hospitalization, but died after hospital discharge due to cardiac arrest, which occurred within 30-days of discharge.

TE D

Episodes of cardiac failure or in-patient cardiac mortality were not noted. Of the treatment given for perioperative MI, 2 required cardiac catheterization with/without stent placement, while 4 patients were managed only with standard medical intervention. Minor cardiac-related

EP

complications included 14 patients who developed atrial fibrillation (14/216, 6.5%). All cases of atrial fibrillation were transient and responded to strict fluid balance and/or medical

AC C

cardioversion.

Comparisons were made between patients who developed cardiac complications and those patients who did not develop cardiac events to help identify any risk contributing risk factors. There were statistically significant differences between the two groups in terms of their age, smoking status, occurrence of peripheral vascular disease (PVD), Charlson co-morbidity index, RCRI and length of general anesthesia. There was suggestion of a difference in the amount of blood transfusion (p=0.08), but this result was not statistically significant. (TABLE 4)

ACCEPTED MANUSCRIPT Subsequent statistical analysis considered the joint association between the risk factors and the occurrence of CC. A backwards selection procedure was used to retain only the significant variables in the final regression model. Multiple logistic regression analysis suggested that both RCRI and the amount of blood transfusion were statistically significant, suggesting that both

RI PT

were independent predictors of complications (TABLE 5). A higher RCRI, particularly Class III, was associated with an increased risk of CC. Patients with RCRI Class III were had odds of a CC that were 68 times greater than patients with RCRI Class I. A greater amount of blood

SC

transfusion was also associated with a higher risk of CC. Patients who received ≥ 4 units transfusion had odds of a CC that were 4 times higher than patients who did not receive blood

M AN U

transfusions. After adjusting for these two variables, there was no additional significant effect of age, smoking status, PVD, CCI and length of GA, each of which were found to be significant in the initial analysis.

Length of hospitalization

TE D

Data on length of hospitalization (LOH) was available for 216 patients, with missing data for 2 patients. Those patients with a major cardiac complication had a longer LOH. Median LOH was 12 days for those with CC, compared to 10 days for those with no complication. This difference

EP

was found to be statistically significant (p=0.02).

AC C

Flap-related complications

Flap complication occurred in 15/216 (6.9%). There were 18 episodes of flap take-back for exploration in 15 patients. The 18 flap take-back episodes were related to 15 anastomotic and 3 non-anastomotic problems. From the 15 episodes of anastomotic-related take–backs, 14 veinrelated and 1 artery-related problems were identified and rectified successfully in 11 cases. Exploration of 3 venous congested flaps revealed perfectly working anastomoses, and these were successfully managed with leech therapy. Therefore, the overall flap salvage rate was 14/18 (76%). Partial flap failure occurred in 3 cases (1.4%), while complete flap failure occurred in 1 case (0.5%) for a total overall flap success rate of 98.1% (212/216).

ACCEPTED MANUSCRIPT There were two cases where CC and major flap complication had occurred in the same patient. The first patient developed a non-ST elevation MI (NSTEMI) after the take-back procedure for venous congestion, for which the flap was successfully salvaged. The NSTEMI did not require cardiac catheterization. In the second case, the patient developed atrial fibrillation in the

RI PT

immediate postoperative period, and subsequently underwent a take-back procedure for venous congestion, for which the flap was also successfully salvaged. The atrial fibrillation responded

SC

to medical cardioversion. Due to the small numbers, statistical analysis was not undertaken.

M AN U

Discussion

There is ample published evidence on the surgical outcomes of head and neck free tissue transfer. Much less is known about the medical complications and their specific risk factors that occur in relation to head and neck free tissue transfer. (Grant et al.,2014; Pohlenz et al.,2013) This is particularly true when cardiac complications are considered. There are very few papers

TE D

that address this subject specifically, and these reports are based on outcomes obtained from individual medical centers where free flap surgery was predominantly undertaken for head and neck cancers. (TABLE 6) Only two series document the rate of events defined as CC in this

EP

study with an incidence of 7.3% and 16.3%, respectively. (Clark et al.,2007; Datema et

AC C

al.,2010) Our current study reports an overall incidence of 9.7%.

Mortality related to head and neck free flaps is considered very uncommon ≈ 1%. (Suh et al.,2004) In a large (n = 804) single institution study of head and neck free flaps over a 21-year period, deaths of patients hospitalized for head and neck free flaps (post-operative deaths inhospital before or after the 30th postoperative day without discharge) was reported to occur in 5.2% (42/804), of which four patients were confirmed cardiac-related deaths for an overall incidence of 0.5% (4/804). (Pohlenz et al.,2013) This incidence is similar to the authors’ current series of cardiac-related mortality of 0.5% (1/216).

ACCEPTED MANUSCRIPT Myocardial infarction is the most commonly reported major CC in head and neck free flap studies. (Clark et al.,2007; Jones et al.,2007; Chiang et al.,2002; Nouraei et al.,2007; Nagele et al.,2011; Datema et al.,2010) The incidence of MI in these studies ranged from 1 to 32.1% (mean, 8.9%) due to inter-study differences in the definition used for MI. In our study, MI

RI PT

occurred in 2.7%. Even though the overall incidence of perioperative MI in head and neck microvascular free flaps is relatively low, the risk of mortality may potentially remain high from cardiac ischemia and dysfunction. Indeed, cardiac deaths were all related to MI in both the

SC

studies by Chiang et al. and Pohlenz et al., as well as in our study. (Chiang et al.,2002; Pohlenz et al.,2013) Furthermore, these deaths also occurred in those with a previous history of cardiac

M AN U

disease.

Heart failure was not identified in our cohort, but was reported in other studies at 5.4% and 13.3%, respectively. (Clark et al.,2007; Jones et al.,2007) Persistent cardiac arrhythmia was also not recorded in our study. Transient arrhythmias may be considered as a ‘minor’ CC in

TE D

contrast to the more significant arrhythmias (ie. ventricular fibrillation) with major CC. Atrial fibrillation was the most common cardiac arrhythmia recorded in our cohort (6.5%), which falls within the reported range of 2.2% and 9%. (Clark et al.,2007; Jones et al.,2007; Datema et

EP

al.,2010) The transient nature of postoperative arrhythmias in our cohort was largely due to fluid overload that occurs not infrequently during free flap surgery in predominantly elderly

AC C

patients (≥60 years, 11/14). (Brinkman et al.,2013)

It has been suggested that head and neck cancer patients undergoing resection and microvascular free flap reconstruction are more likely to develop CC peri-operatively due to older age, a higher prevalence of medical comorbidities, tobacco use and alcohol intake. In our cohort, those diagnosed with head and neck cancer accounted for 76% (164/216) and there were significant differences in patient characteristics compared with those who underwent microvascular free flap reconstruction for benign conditions (24%, 52/216). The malignant

MANUSCRIPT subgroup were older, had aACCEPTED higher proportion of tobacco smokers, demonstrated higher comorbidity scores, higher ASA grade and were more likely to receive a soft tissue free flap reconstruction, when compared with the cohort of patients with benign conditions. Nevertheless, having benign or malignant pathologies did not show an association with CC on univariate analysis suggesting that any subgroup differences noted initially did not ultimately

RI PT

translate into any statistically significant predictive association with CC.

A similar study of predictive factors of CC in head and neck microvascular free flaps, (Datema

SC

et al., 2010) provided direct comparison to our findings. Other than a comparable finding of higher RCRI score being an independent predictive factor for CC, they also reported two other

M AN U

predictive factors (i.e. higher ACE-27 grade and Age >70 years). (Clark et al., 2007) Our study found older age and comorbidity as measured by CCI to be significantly associated with CC but did not independently predict cardiac complications.

The RCRI was developed to help identify patients who are at risk of major cardiac

TE D

complications in non-cardiac surgery. (Lee et al.,1999) In head and neck surgery where a free flap is undertaken, higher RCRI scores were related to higher risk of major CC with a reported 12-fold higher risk for major CC, compared with those with RCRI Class I. (Datema et al.,2010)

EP

Our study found a similar finding although the odds in our study were higher over all, particularly in RCRI Class III, (68 times greater odds risk for RCRI III than patients with RCRI

AC C

Class I). Both these findings suggest that RCRI may be a useful screening tool in estimating the risk of CC preoperatively, particularly in asymptomatic, older patients who will undergo head and neck surgery with microvascular free flaps. (Simeoni et al.,2016) In this circumstance, a higher RCRI score may facilitate more systematic and judicious use of detailed cardiac assessments preoperatively. In addition, appropriate cardiac investigation of high-risk patients can assist in highlighting those who require closer perioperative monitoring, including management in intensive care units. (Mooney et al.,2016)

The amount of blood transfused intra-operatively was an independent predictor for CC, where

ACCEPTED MANUSCRIPT the risk of developing CC increased with the number of units transfused (CC with transfusion of 1-3 units, ≥ 4 units compared to those receiving no transfusion were 0.72- and 4-fold greater, respectively). This finding has not been reported before in similar studies of cardiac-related complications in head and neck free flaps. However, studies of intraoperative blood transfusion in microvascular free tissue transfer have documented a higher incidence of medical

RI PT

complications in those who received transfusions. (Kim et al.,2014) In a study by Puram et al., the authors reported that blood transfusion was associated with significant medical risks including; MI, congestive heart failure, arrhythmias, respiratory failure, pneumonia, and

SC

postoperative wound infections. (Puram et al.,2015) Intraoperative transfusion requirement suggests the possibility of cardiovascular instability having occurred and the subsequent

M AN U

triggering of systemic inflammatory response. Opportunities to preempt and modulate cardiovascular instability and myocardial stress by avoiding intraoperative transfusion and utilizing other methods may reduce the possibility of cardiac complications. This is particularly interesting as blood pressure, intraoperative heart rate variability and the degree of postoperative inflammatory response are predictive of the likelihood of postoperative myocardial injury in

TE D

head and neck free flaps. (Nouraei et al.,2007)

Comorbidity is associated with higher medical complications including CC in major head and

EP

neck surgery. (Clark et al.,2007) We found the specific comorbidity (i.e. PVD), and a higher composite comorbidity score measured by CCI, were significantly associated with CC but these

AC C

factors were not independent predictors for CC. It is possible that the choice of CCI instead of ACE-27 (Adult Comorbidity Evaluation-27) to measure comorbidity in our study may influence the findings of multivariate analysis, even though the CCI has been validated for use in head and neck surgery. In the series by Nagele et al. MI specific comorbidities such as preexisting renal insufficiency, coronary artery disease, PVD, hypertension and previous combined chemoradiotherapy were found to be independent predictive factors. (Nagele et al.,2011) These factors are considered in the calculation of both the CCI and ACE-27 co-morbidity scores.

ACCEPTED MANUSCRIPT Longer hospitalization is associated and predicted by medical complications. (Jones et al.,2007) Longer hospitalization is reported in patients who develop CC compared to those who did not develop this complication. Patients with CC are likely to spend an extra 2-7 days on average in hospital compared to those who did not develop this complication. (Datema et al.,2010) In our study, the mean length of hospitalization was 12 days for those with a CC, compared to 10 days

RI PT

for those with no complication (p=0.02). Similarly, those who developed MI had significantly longer hospital stay (8.5 vs. 10.1 days; p=0.014) and they also a significantly longer length of stay in intensive care unit (3 vs. 4.5 days; p=0.001). Longer hospitalization, including intensive

M AN U

costs. (Jones et al.,2007; Nagele et al.,2011)

SC

care occupancy places higher demand on the healthcare system and an increase in healthcare

The association of flap complication simultaneous with CC occurred in two cases, both flaps were not compromised by the NSTEMI, which was managed with medical therapy only and the associated atrial fibrillation, responded to conservative treatment as well. The small sample size

TE D

did not allow for any statistical analysis or meaningful conclusion.

The 2007 and recently updated 2013 ACCF/AHA guidelines in the management of unstable angina and NSTEMI indicate that patients with documented high-risk of acute coronary

EP

syndrome should receive standard medical therapy and considerations for angiography (percutaneous coronary intervention, PCI) must be undertaken to improve cardiac ischemia.

AC C

(Anderson et al.,2012) The PCI strategy may involve a more aggressive early PCI undertaken within 24 hour of admission/diagnosis or an initial conservative strategy, where PCI is reserved for those with recurrent ischemia or demonstrating high-risk stress test despite medical therapy. Coronary artery bypass graft (CABG) may be appropriate when coronary artery anatomy indications are present. (Hillis et al.,2011)

Perioperative MI and its management present a challenge to microvascular free flap care and may compromise its outcomes. Potential flap failure can occur due to increased risk of

ACCEPTED MANUSCRIPT microvascular clot formation with post-MI hypotension. (Chiang et al.,2002; Khouri,1992) The microanastamosis may also be threatened by potential hemorrhage and hematoma in the neck that can follow ACCF/AHA recommended administration of triple antiplatelet therapy.24 This may be further jeopardized by a decision to undertake PCI early with the administration of highdoses of anticoagulants, particularly within the first 48-hours post-surgery. In our study, the 2

RI PT

patients who underwent cardiac catheterization did not require high-doses of anticoagulants as no actual arterial occlusion was noted, and no bleeding/hematoma post-PCI was observed. In the series by Chiang et al., one head and neck free flap patient underwent PCI and stent

SC

placement on postoperative day 8 but while the flap survived, the patient subsequently died of congestive cardiac failure at postoperative day 78. Revascularization with CABG (coronary

M AN U

artery bypass graft) is thought to carry the theoretical risk of hypotension on free flaps from the low-flow state induced with cardiopulmonary bypass during the procedure. The authors reported that there were no flap failures involving the 3 head and neck free flap patients who subsequently underwent CABG post MI. (Chiang et al.,2002)

TE D

In practice, ACCF/AHA guidelines adherence may vary and compromises to the ideal care outlined is the more likely scenario. The selection of triple antithrombotic therapy may be considered a matter of clinical judgment for an individual patient, based on the perceived

EP

balance between the patient's risk for recurrent ischemic events, expected duration of treatment, and patient risk for bleeding. (Hermosillo and Spinler,2008) Thus, some microvascular

AC C

surgeons may consider a less than ideal option of dual therapy rather than triple therapy to balance out the risk of flap loss secondary to bleeding and hematoma. In our cohort, all 6 patients who developed MI did not receive triple antithrombotic therapy, and all free flaps survived. In the single case of MI and 30-day cardiac mortality in our cohort, CABG was indicated following MI due to occlusion of previous coronary stents but this procedure was deferred due to concerns for postoperative median sternotomy wound infection from the presence of a fresh tracheostomy wound. It is unclear if this had an impact to the mortality outcome.

ACCEPTED MANUSCRIPT This study is limited by several factors. Despite availability to a flap database and extensive resources accessible for retrospective data extraction, incomplete data collection remains a possibility. While calculation of comorbidity and cardiac indices was undertaken by one individual to limit variances, estimation of ASA grades were undertaken by various

RI PT

anesthesiologists throughout the study period. Future investigations can include a comparison of the two common validated co-morbidity indices (CCI vs. ACE-27) and larger prospective cohorts. This study could be further strengthened with a prospective trial comparing patients

M AN U

morbidity scores (not examined in this retrospective study).

SC

whom were considered for flap reconstruction but excluded due to increased cardiac co-

Conclusions

Major cardiovascular complications are very uncommon in head and neck surgery involving microvascular free flaps (MI 2.7%, cardiac death 0.5%), with transient cardiac arrhythmia being

TE D

the most common occurrence. Factors that independently predicted cardiac complications in patients undergoing head and neck surgery involving microvascular free flaps included the cardiac risk index and the amount of intraoperative blood transfusion. Consequently, the cardiac

EP

risk index may be a useful screening tool for estimating cardiac complication risk, rationalizing cardiac investigation and in preplanning of intra-and postoperative care. Strategies to improve

AC C

intraoperative management particularly of fluid shifts may help reduce cardiac complications.

Acknowledgement The authors would like to acknowledge Dr. Hether Khosa, and Mr. Taylor Duckworth, at the University of Maryland, for their contributions towards data collection for this study, and Mr.

ACCEPTED MANUSCRIPT Paul Bassett, medical statistician, for his assistance with statistical analysis undertaken for this

AC C

EP

TE D

M AN U

SC

RI PT

study.

ACCEPTED MANUSCRIPT References Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Jneid H, Ettinger SM, Ganiats TG, Philippides GJ, Jacobs AK, Halperin

RI PT

JL, Albert NM, Creager MA, DeMets D, Guyton RA, Kushner FG, Ohman EM, Stevenson W, Yancy CW. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation infarction:

a

report

of

the

American

College

of

Cardiology

SC

myocardial

Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll

M AN U

Cardiol 11:61:e179-347, 2013.

Brinkman JN, Derks LH, Klimek M, Mureau MA. Perioperative fluid management and use of vasoactive and antithrombotic agents in free flap surgery: a literature review and clinical

TE D

recommendations. J Reconstr Microsurg 29:357–66, 2013.

Buresly K, Eisenberg MJ, Zhang X, Pilote L. Bleeding complications associated with combinations of aspirin, thienopyridine derivatives, and warfarin in elderly patients

EP

following acute myocardial infarction. Arch Intern Med 165:784-9, 2005.

AC C

Chiang S, Cohen B, Blackwell K. Myocardial infarction after microvascular head and neck reconstruction. Laryngoscope 112:1849-52, 2002.

Charlson ME, Pompei P, Ales KL, Mackenzie CR. A new method of classifying prognostic co-morbidity in longitudinal studies: development and validation. J Chronic Dis 40:373–

383, 1987.

Clark JR, McCluskey SA, Hall F, Lipa J, Neligan P, Brown D, Irish J, Gullane P, Gilbert R.

ACCEPTED Predictors of morbidity following free flapMANUSCRIPT reconstruction for cancer of the head and neck. Head Neck 29:1090–101, 2007.

Datema FR, Poldermans D, Baatenburg de Jong RJ. Incidence and prediction of major

RI PT

cardiovascular complications in head and neck surgery. Head Neck 32:1485-93, 2010.

Devereaux PJ, Goldman L, Cook DJ, Gilbert K, Leslie K, Guyatt GH. Perioperative cardiac events in patients undergoing noncardiac surgery: a review of the magnitude of the problem,

SC

the pathophysiology of the events and methods to estimate and communicate risk. Can Med

M AN U

Assoc J 173:627–634, 2005.

Grant DW, Mlodinow A, Ver Halen JP, Kim JY. Catastrophic Outcomes in Free Tissue Transfer:

A

Six-Year

Review

doi:10.1155/2014/704206.

of

the

NSQIP

Database.

Plast

Surg

Int

TE D

Hermosillo AJ, Spinler SA. Aspirin, clopidogrel, and warfarin: is the combination appropriate and effective or inappropriate and too dangerous? Ann Pharmacother 42:790-

EP

805, 2008.

Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, Cigarroa JE, Disesa

AC C

VJ, Hiratzka LF, Hutter AM Jr, Jessen ME, Keeley EC, Lahey SJ, Lange RA, London MJ, Mack MJ, Patel MR, Puskas JD, Sabik JF, Selnes O, Shahian DM, Trost JC, Winniford MD. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 124:e652-735, 2011.

Jones NF, Jarrahy R, Song JI, Kaufman MR, Markowitz B. Postoperative medical complications--not microsurgical complications--negatively influence the morbidity,

ACCEPTED MANUSCRIPT mortality, and true costs after microsurgical reconstruction for head and neck cancer. Plast Reconstr Surg 119:2053-60, 2007.

Khouri RK. Avoiding free flap failure. Clin Plast Surg 19:773–781, 1992. Kim BD, Ver Halen JP, Mlodinow AS, Kim JY. Intraoperative transfusion of packed red

RI PT

blood cells in microvascular free tissue transfer patients: assessment of 30-day morbidity using the NSQIP dataset. J Reconstr Microsurg 30:103-14, 2014.

SC

Lee TH, Marcantonio ER, Mangione CM, Thomas EJ, Polanczyk CA, Cook EF, Sugarbaker DJ, Donaldson MC, Poss R, Ho KK, Ludwig LE, Pedan A, Goldman L.

M AN U

Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 100:1043–1049, 1999.

Mooney JF, Hillis GS, Lee VW, Halliwell R, Vicaretti M, Moncrieff C, Chow CK. Cardiac

TE D

assessment prior to non-cardiac surgery. Intern Med J 46:932-41, 2016.

Nagele P, Rao LK, Penta M, Kallogjeri D, Spitznagel EL, Cavallone LF, Nussenbaum B, Piccirillo JF. Postoperative myocardial injury after major head and neck cancer surgery.

EP

Head & Neck 33:1085, 2011.

AC C

Nouraei SAR, Al-Yaghchi C, Sandhu GS, Giussani DA, Doyle P, Clarke PM. Incidence and Significance of Myocardial Injury After Surgical Treatment of Head and Neck Cancer. Laryngoscope 117:1581, 2007.

Piccirillo JF, Feinstein AR. Clinical symptoms and comorbidity: significance for the prognostic classification of cancer. Cancer 77:834–842, 1996.

Pohlenz P, Klatt J, Schmelzle R, Li L. The importance of in-hospital mortality for patients

ACCEPTED MANUSCRIPT requiring free tissue transfer for head and neck oncology. Br J Oral Maxillofac Surg 51:508-13, 2013.

Puram SV, Yarlagadda BB, Sethi R, Muralidhar V, Chambers KJ, Emerick KS, Rocco JW, Lin DT, Deschler DG. Transfusion in head and neck free flap patients: practice patterns and

RI PT

a comparative analysis by flap type. Otolaryngol Head Neck Surg 152:449-57, 2015.

Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC, Saunders LD, Beck CA,

SC

Feasby TE, Ghali WA. Coding algorithms for defining comorbidities in ICD-9-CM and

M AN U

ICD-10 administrative data. Med Care 43:1130-1139, 2005.

Simeoni R, Breitenstein K, Eßer D, Guntinas-Lichius O. Cardiac comorbidity in head and neck cancer patients and its influence on cancer treatment selection and mortality: a prospective cohort study. Eur Arch Otorhinolaryngol 273:2765-72, 2016.

TE D

Suh JD, Sercarz JA, Abemayor E, Calcaterra TC, rawnsley JD, Alam D, Blackwell KE. Analysis of outcome and complications in 400 cases of microvascular head and neck

EP

reconstruction. Arch Otolaryngol Head Neck Surg 30:962–6, 2004.

Vandersteen C, Dassonville O, Chamorey E, Poissonnet G, Nao EE, Pierre CS, Leyssale A,

AC C

Peyrade F, Falewee MN, Sudaka A, Haudebourg J, Demard F, Santini J, Bozec A. Impact of patient comorbidities on head and neck microvascular reconstruction. A report on 423 cases. Eur Arch Otorhinolaryngol 270:1741-6, 2013.

ACCEPTED MANUSCRIPT Table 1: Charlson Comorbidity Index coding used [Charlson ME et al, 1987] Point Score

Condition

1 Point

Myocardial Infarction

RI PT

Congestive Heart Failure

Peripheral Vascular Disease

Dementia

M AN U

Cerebrovascular Disease

SC

Pulmonary Disease/COPD/Asthma

Connective Tissue Disease Peptic Ulcer Disease

Chronic Liver Disease Diabetes mellitus Hemiplegia

TE D

2 Points

Moderate to Severe Kidney Disease Diabetes Mellitus with End Organ Damage

EP

Solid Tumor Leukemia

AC C

Lymphoma

3 Points

Moderate to Severe Liver Disease

6 Points

Malignant Tumor Metastasis AIDS

COPD, chronic obstructive pulmonary disease; AIDS, acquired immune deficiency syndrome

MANUSCRIPT Table 2: Revised cardiac riskACCEPTED index coding used [Lee et al, 1999; Datema et al, 2010]

High-risk surgery

Conditions

Definitions used for coding

Head & Neck

‘surgery with an intermediate to high risk’

Surgery History of ischemic heart

Myocardial infarction

Preoperative ECG showed signs of an old MI.

History of congestive

RI PT

disease (IHD)

History of MI

Angina pectoris

Presence of typical chest pain complaints.

Heart failure

Presence of dyspnea during exercise or dyspnea in rest with physical evidence of signs of heart failure.

SC

heart failure

Preoperative echocardiography findings. Stroke and/or

History of TIA or cerebrovascular ischemia or

cerebrovascular event

transient ischemic

haemorrhage.

attack (TIA)

Diabetes mellitus

Preoperative treatment

Current/previous user of insulin or oral

medication.

Preoperative creatinine

TE D

with insulin

Renal impairment

EP

>2mg/dL

M AN U

History of

Fasting blood glucose levels, >7.0 mmol/L. Random blood glucose levels, >11.0 mmol/L. Preoperative serum creatinine level, >160 mmol/L or 2.0 mg/dL.

AC C

Patients with a history of bypass surgery or angioplasty were not coded when typical angina pectoris cardiac complaints were absent.

ACCEPTED MANUSCRIPT Table 3: Subgroup comparison between benign and malignant pathology

Benign (n=52)

Cancer (n=164)

P-value

Age

58.9 ± 13.3

52.9 ± 17.1

60.8 ± 11.2

<0.001

Weight (kg)

77.4 ± 20.0

78.1 ± 17.1

77.4 ± 20.0

0.83

Non-smoker Quit Current smoker

108 (50%) 60 (28%) 48 (22%)

38 (71%) 7 (13%) 8 (15%)

71 (43%) 53 (32%) 40 (24%)

0.002

No diabetes Diabetes

181 (84%) 35 (16%)

43 (83%) 9 (17%)

138 (84%) 26 (16%)

0.80

No PVD PVD

198 (92%) 16 (8%)

50 (96%) 2 (4%)

4.5 ± 2.0

3.9 ± 2.5

172 (80%) 36 (17%) 8 (4%)

ASA 1 ASA 2 ASA 3 ASA 4

9 (4%) 70 (32%) 133 (62%) 4 (2%)

Bone flap (*) Soft tissue flap

116 (54%) 100 (46%)

Length of GA(hours) No vasopressors Vasopressors

148 (90%) 16 (10%)

0.18

4.7 ± 1.8

0.01

44 (85%) 7 (13%) 1 (2%)

128 (78%) 29 (18%) 7 (4%)

0.54

8 (15%) 19 (37%) 24 (46%) 1 (2%)

1 (0.6%) 51 (31%) 109 (66%) 3 (2%)

0.002

44 (85%) 8 (15%)

72 (44%) 92 (56%)

<0.001

13.3 ± 2.7

12.6 ± 2.1

13.5 ± 2.8

0.04

43 (20%) 173 (80%)

12 (23%) 40 (77%)

31 (19%) 133 (81%)

0.51

EP

TE D

RCRI I RCRI II RCRI III

SC

Charlson Comorbidity Index

RI PT

All subjects (n=216)

M AN U

Variable

AC C

Summary statistics are mean ± standard deviation, or number (percentage) (*) Includes one patient with both bone and soft tissue flap PVD peripheral vascular disease RCRI revised cardiac risk index ASA American Society of Anesthesiologist risk stratification ASA 1, normal healthy patient; ASA 2, patient with mild systemic disease; ASA3, patient with severe systemic disease; ASA 4, patients with a life-threatening systemic disease GA general anesthesia

ACCEPTED MANUSCRIPT Table 4: Patients showing cardiac complications versus no complication

Cardiac complications (n=20)

P-value

Age

58.1 ± 13.4

65.5 ± 9.4

0.01

Benign Cancer

49 (25%) 148 (75%)

3 (18%) 17 (82%)

0.61

Non-smoker Quit Current smoker

103 (53%) 54 (27%) 39 (20%)

5 (27%) 6 (32%) 9 (41%)

No diabetes Diabetes

164 (85%) 30 (15%)

17 (77%) 5 (23%)

No PVD PVD

182 (93%) 12 (7%)

16 (80%) 4 (20%)

4.4 ± 2.0

5.5 ± 2.0

0.04

0.37

SC

Charlson CI

RI PT

No complication (n=194)

M AN U

Variable

0.02

0.02

164 (85%) 30 (15%) 2 (1%)

ASA 1 ASA 2 ASA 3 ASA 4

9 (4%) 66 (34%) 117 (61%) 4 (2%)

Bone flap (*) Soft flap

108 (55%) 88 (45%)

8 (40%) 12 (60%)

0.26

Length of GA

13.1 ± 2.6

14.5 ± 3.4

0.02

No vasopressors Vasopressors

41 (21%) 153 (79%)

2 (9%) 20 (91%)

0.26

Intra-op IV fluid (mL/kg/hr)

7.4 ± 2.6

6.8 ± 2.0

0.33

0 [0, 2]

2 [0, 4]

0.08

575 [400, 850]

525 [400, 1100]

0.85

EP

AC C

Volume blood transfusion

Estimated blood loss

8 (40%) 6 (30%) 6 (30%)

<0.001

0 (0%) 4 (20%) 16 (80%) 0 (0%)

0.18

TE D

RCRI I RCRI II RCRI III

(*) Includes one patient with both bone and soft flap PVD,peripheral vascular disease; Charlson CI, comorbidity index; RCRI, revised cardiac risk index; ASA, American Society of Anesthesiology risk stratification; GA, general anesthesia

ACCEPTED MANUSCRIPT Table 5: Multiple logistic regression analysis of predictors of major cardiac complications Category

Odds Ratio (95% CI)

P-value

RCRI

I II III

1 3.67 (1.22, 11.1) 68.0 (11.1, 419)

<0.001

Blood transfusion

0 units 1-3 units 4+ units

1 0.72 (0.20, 2.57) 4.10 (1.20, 13.9)

0.03

AC C

EP

TE D

M AN U

SC

RI PT

Variable

ACCEPTED MANUSCRIPT

Table 6: Reported series major cardiac complications related to free flap surgery in head and neck (HN) surgery. Overall CC rate

120/378 (31.7%)

24/120 (20%)

0

Cardiac death 1 (0.5%)

Ghazali et al.

216

Nagele et al. [2011]

378

Mixed HN cancer and benign conditions HN cancer

Datema et al. [2010]

135

HNSCC

135/135 (100%)

23/135 (16.3%)

0

Clark et al. [2007]

185

HN cancer

185/185 (100%)

20/185 (10.8%)

0

Nouraei et al. [2007]

65

UADSCC

28/65 (43%)

9/28 (32.1%)

Chiang et al. [2002]

193

n/a

193/193 (100%)

7/193 (3.6%)

Jones et al. [2007]

100

HN cancer, and ORN

100/100 (100%)

Analysis of predictive factors of cardiac outcomes Cardiac outcome Predictors of cardiac outcome measured CC Higher RCRI score Higher units of blood transfused

0

0

MI, elevated postoperative Troponin I levels

Preexisting renal insufficiency Coronary artery disease PVD Hypertension Previous combined CRT

4 (3%)

18 (13.3%)

VF, 1 (0.7%)

Major CC

6 (2.8%)

10 (5.4%)

AF, 4 (2.2%)

n/a

n/a

9/28 (32.1%)

0

0

Myocardial injury, Elevated Troponin assay at postop day 3

Blood pressure level Intraoperative heart rate variability Degree of postoperative inflammatory response

2 (1%)

7 (3.6%)

0

0

n/a

n/a

0

1 (1%) Mean, 8.9%

0

0

n/a

n/a

0

EP

AC C 10/100 (10%)

24/120 (20%)

TE D

21/216 (9.7%)

Cardiac Complications (CC) MI Heart Cardiac failure arrhythmia 6 0 AF, 14 (2.7%) (6.5%)

RI PT

Free flap surgery undertaken 216/216 (100%)

SC

Pathology

M AN U

n

Higher RCRI score Higher ACE-27 grade Age >70 years

Mean, 9.4%

Abbreviations: SCC, squamous cell carcinoma;UAD, upper aerodigestive tract; PVD, peripheral vascular disease; RCRI, Revised Cardiac Risk Index; CRT, chemoradiotherapy; n/a, not available; CC, cardiac complication; MI, myocardial infarction