Postoperative myocardial injury after major head and neck cancer surgery

Background/objective: This narrative review aims to assess the causes and evaluate the scientific evidence concerning the increased risk of postoperative myocardial infarction (PMI) in patients undergoing major head and neck surgery. Method: A comprehensive review of literature was conducted and findings from clinical trials, meta-analysis as well as observational studies were incorporated to explore the risk factors associated with PMI after a major head and neck surgery. Preoperative risk factors, appropriate diagnostic plans, biomarkers, risk stratification strategies, and treatment options were also assessed. Result: The review highlights that patients undergoing head and neck surgery are at a significant risk of developing PMI primarily due to surgical trauma, anesthesia, and the extensive nature of head and neck surgeries. However, pre-existing conditions like renal insufficiency, cerebrovascular diseases, and diabetes may also exacerbate this risk. Moreover, ECG and regular observation of troponin has proven to be successful in detecting PMI, which can be easily masked due to its ambiguous symptoms in postoperative patients that are receiving pain reducing medications. Once diagnosed, PMI is treated with standard medication for myocardial infarction, however, more emphasis has been put on its timely diagnosis through routine troponin testing. Conclusion: Head and neck cancers are prevalent in developing nations such as Pakistan where the use of tobacco is widespread. As a result of such aggressive cancer, patients may undergo surgery, which places them at a risk of developing PMI. This can be avoided through routine troponin testing which still requires further research on localized patient population considering the physiologic differences.


Introduction
Head and neck cancer is rapidly becoming a major cause of morbidity and mortality in the world.More than half a million new cases of head and neck cancer are diagnosed each year and are attributed to a number of risk factors [1] .These include alcohol use, long-term smoking and tobacco abuse-which is specifically rampant in South Asia.The presence of human papillomavirus alongside squamous cell carcinoma has also been predictive of cancer [2] .It is important to note that cancer screening and diagnosis in developing countries is often delayed due to low-resources and various barriers to healthcare as a result of which patients present with a developed, aggressive cancerous mass that most-often requires surgery.
These surgeries may present with postoperative complications amongst which, myocardial injury (MI) has been a great cause of concern.

Background/context
Head and neck surgeries are extensive, both in terms of precision and time.These surgeries consist of complicated high-risk procedures that may cause MI.
Cancer surgeries can last for more than 8 h and require multiple fluid administrations, which present as inflammation after the surgery.The provision of anesthesia and surgical trauma leads to the release of cortisol, catecholamines, and inflammatory cytokines which adds on to the existing inflammation.Tachycardia and hypertension both increase the oxygen requirements of the myocardial tissue and will raise the chances of ischemic damage [3] .Whereas bradycardia may lead to decreased coronary perfusion and therefore mismatched oxygen supply and demand.A hypercoagulable state after the surgery along with all of these factors can lead towards MI.
Postoperative MI can be classified into two types based on the cause of myocardial ischemia.Type I ischemia is caused by inflammation and hypercoagulability that leads to the rupture of a plaque and therefore acute coronary thrombosis.Type II on the other hand is caused by a decreased oxygen supply due to hypotension, hypertension, or tachycardia [4] .
MI or myocardial infarction is objectively defined as the death of cardiac myocytes caused by an imbalance in perfusion which leads to ischemia [5] .Clinically, MI ensues a combination of signs and symptoms that include chest, jaw, or epigastric discomfort.This is often not localized and may be accompanied with other symptoms such as dyspnea and syncope which makes it harder to diagnose this condition purely on observational basis [6] .Important and immediate symptoms like chest pain are also difficult to detect in some cases due to the provision of pain medication following most surgeries.Studies suggest that only 14% of patients suffer from chest pain while 53% display clinical signs and symptoms before experiencing postoperative myocardial infarction [7] .Therefore, ECG and biomarkers are the key tools in detecting MI, which are often not adequately supervised in due time which leads to MI.
Research also claims that in perioperative MI, most patients will not experience typical symptoms [6] .Therefore, when a MI is suspected in postoperative patients, it is essential to further investigate the causes.The two most important steps in the diagnostic work-up are the ECG and troponin levels.
The earliest manifestations of myocardial ischemia can be observed in a 12 lead ECG that shows typical T-waves and ST segment changes.By studying these changing patterns, doctors can estimate the amount of myocardium at risk and the infarct related artery.Conditions other than MI may also result in ST deviations on the ECG such as LV hypertrophy, LBBB, Brugada syndrome, and early repolarization patterns [8] .Therefore, ECG alone may be insufficient in diagnosing ischemia or infarction.
To thoroughly detect cardiac injury, Troponin I (TnI) or Troponin T (TnT) are preferred biomarkers because of their absolute myocardial tissue specificity and high clinical sensitivity [9] .TnI is a specific marker of risk for coronary heart disease and risk of composite cardiovascular disease where TnT can accurately indicate causes of death relating to noncardiovascular pathology.Thus, in order to calculate the risk of MI after a major head and neck cancer surgery, the levels of TnI are evaluated in the blood of the patient.
Creatinine kinase (CK-MB) is another biomarker that as compared to troponin is less specific and used as an alternative if troponin assays are not available.In case of reinfarction, the levels of CK-MB have been diagnostic previously, but studies have now suggested that such data can be inferred from troponin values alone.
A research conducted by Kwon et al. studied the different treatment modalities available for people suffering from head and neck cancer to analyze the effect it has on postoperative complications.The gathered data suggested that patients who had undergone chemotherapy alone had the highest incidence of myocardial infarction, which was followed by treatment plans with a combination of head and neck cancer surgery and chemotherapy.This suggests that even though head and neck cancer surgeries are invasive, chemotherapy poses a higher risk of MI in a cancer diagnosis [10] .
Another research included 378 patients who had undergone head and neck cancer surgery and were evaluated for their TnI levels.Fifty-seven patients had an elevated TnI, which peaked after a median of 10 h after the surgery.Furthermore, out of 19 patients who received a cardiology consultation, 2 had to undergo emergent cardiac catheterization and percutaneous transluminal coronary angioplasty.This goes on to show that while the incidence of severe cardiac complications may be low, it is still a cause of concern and thus needs to be managed.Within this study, a higher cardiac risk was associated with flap reconstructive surgeries because this requires increased amounts of fluid infusion and lasts over longer periods of time that ultimately raises the surgical stress [11] .Thus, flap reconstructions in head and neck surgery might be a cause of concern.
Clinical data also suggests that TnI is a key predictor of postoperative outcomes in noncardiac surgeries and is a time sensitive tool.Among 290 patients that were involved in a study, 24 observed a rise in TnI within 6 h after surgery and concluded that an early TnI increase was an independent predictor of outcome (P < 0.0001) [12] .Trials have also shown that MI that presents within 3 days after a noncardiac surgery is significantly associated with mortality [13] .This further puts the onus on biomarkers as the main markers of prognostic value.
However, patients who already have a number of diagnosed conditions are predisposed to elevated TnI after surgical intervention for cancer.Pre-existing renal insufficiency was related to a 5 times higher risk for elevated TnI.The risk also increased by 2.2 to 2.8 fold in cases of coronary artery disease, peripheral vascular disease and hypertension.
A meta-analysis investigating MI after noncardiac surgery (MINS) reported that older people and specifically men (17.7%) were at a higher risk of developing cardiovascular conditions.MINS also occurred in 32.7% of urgent surgeries as compared to 16.6% of nonurgent surgeries.Even though this study was not specific to head and neck cancer surgery, the results can be extrapolated to presume the possibilities that doctors may face [14] .
Other risk factors linked to postoperative MI are cerebrovascular disease, diabetes, and BMI.A prospective cohort study also associated obstructive sleep apnea with MINS due to the individual predictors of both conditions that overlap such as older age male sex [15] .
Approximately, 5-25% patients undergoing noncardiac surgery have an elevated TnI which signifies MI [16] .This may or may not result in severe complications but the risk of shortterm and long-term morbidity and mortality is higher with an increased TnI.
Once MI is identified, a series of changes in the period toward recovery are observed.Nagele et al. observed that patients with postoperative MI had a longer hospital stay (10.1 vs. 8.5 median days) and spent more time in the ICU (4.5 vs. 3 median days).After 60 days of receiving surgery for head and neck cancer, there was an eight fold increase in the risk of death in patients who presented with elevated TnI [11] .
As compared to the short-term findings, the long-term outcomes for the duration of 7 years were estimated using a predictive survival analysis.It yielded that there was no difference in the median survival rate between patients with normal or increased TnI levels.This points to a possibility of consequential outcomes in post-MI that must be followed only in the shorter term.

Treatment options
To ensure minimal complications for patients undergoing major surgeries for head and neck cancer, preoperative risk assessment must be performed.
The revised cardiac risk index (RCRI) which was originally published in 1999, has been used to estimate the risk of developing cardiac complications after surgery.The six independent predictors of MI that it includes are as follows: 1) history of ischemic heart disease, 2) history of congestive heart failure, 3) history of cerebrovascular disease, 4) history of diabetes requiring insulin, 5) chronic kidney disease (creatinine > 2 mg/dl) and 6) elevated risk surgery, that is; intraperitoneal, intrathoracic, suprainguinal.Even though this index has been largely used, research suggests that the findings may not be accurate.It also shows poor predictive ability in Chinese patients with coronary artery disease which signifies that discriminate properties of this scale may also extend toward other sub populations [17] .
Preoperative patients can be stratified according to their risk of developing cardiac injury by monitoring their TnI levels.These can be assessed both preoperatively and postoperatively even though postoperative screening is more common.Vascular events in noncardiac surgery patients' cohort evaluation (VISION) study reported a mortality rate of 1.9% after measuring TnT in 15 133 patients [18] .Another study with 2232 patients who had undergone noncardiac surgery stated that the mortality rate was 3%.This positive correlation makes the monitoring of troponin essential [19] .
Once the patient is diagnosed with MI or infarction, a few treatments can be administered based on the etiology.The primary step should be mitigating the effect of injury by antiplatelet, antihypertensive, anticoagulant, antihyperlipidemic and glycemic control medications.
Secondarily, aspirin has been used in a number of clinical trials and has been shown to reduce the 30-day mortality risk.However, bleeding is a major side effect of aspirin use [6] .Oral statins also improve the outcomes in patients with MI but they do so in the longer-term [20] .
Evidence regarding the use of β-blockers is limited but promising.A study reports that when β-blockers are administered within 24 h of a noncardiac surgery, there were less occurrences of nonfatal myocardial infarction [21] .

Limitations
The most effective way of diagnosing and treating postoperative myocardial infarction is through postoperative routine troponin testing.However, clinicians today are questioning the practicality of troponin tests in determining MI after a major surgery.This is based on the fact that present day fifth-generation troponin assays are highly sensitive and they may be elevated up to 40% in postoperative conditions.This may lead to the patients receiving unnecessary treatment while simultaneously increasing the complication rates within hospitals.This is why Beckman suggests that routine troponin testing is more likely to cause harm to both the patients and the health care practitioners [22] .
Furthermore, TnI screening is sometimes not indicative of myocardial ischemia and is associated with other causes [19] .

Discussion
Head and neck cancer is the seventh most common cancer globally whereas in Pakistan, it ranks as the second most diagnosed cancer [23] .This is largely due to the use of pan, gutka, supari, and other consumable products that contain carcinogens, thereby causing oral cancer [24] .Lip and oral cancers are thus the most common types of head and neck cancers in Pakistan.
Considering the current statistics of head and neck cancer, and the risk of postoperative MI that it entails, mechanisms must be set in place to avoid untimely deaths.In low and middle income countries (LMIC) with a high patient burden, it is difficult to frequently follow up with the patient's progress.In such cases, preoperative risk classification of the patients can be of immense value.This can be pursued by assessing early rise in TnI levels, which was also outlined by Akkermans et al. [25] in a study whereby detection of TnI within the first 3 days after receiving cardiac surgery resulted in an early detection of 59% of myocardial infarction.
Routine TnI testing has been recommended by clinicians in cases of head and neck cancer surgery despite the risk that varies from one patient to another [11] .Other research on the contrary suggests that TnI screening should depend on risk only and should not be made mandatory for everyone because of the possibility of lengthier hospital stays and subsequent exposure to hospital-acquired infections.Risk factors that may suggest the need for a TnI test include but are not limited to: a high-risk surgery, age > 65 and/or established atherosclerotic disease [26] .It is; however, important to consider the applicability of such preventative regimens in LMIC where affordability needs to be accounted for.Even though TnI testing is not expensive, systematic testing that requires the monitoring of TnI levels over a longer period of time may become burdensome for most of the population.In such situations, it is essential to look into the possibility of using ECG as the main tool of detection.ECGs are not only cost-effective but also yield immediate results, though its sensitivity is still debatable.Therefore, in order to establish a wellrounded screening regimen, further research in LMIC is required.Healthcare practitioners also claim that TnI screening should be limited to patients who at least have a moderate risk of MI [27] .This leaves a lot of ambiguity regarding the standard procedure that should be followed in postoperative circumstances and reiterates the need to develop region specific criteria that can cater to the physiologic differences within the local population.
Furthermore, it should be noted that one of the outcomes of post-MI is the increased length of hospital stay which is a burden in low-resource settings that hospitals are not equipped to deal with.In such cases, curbing the risk of postoperative MI in the initial stages would greatly benefit the healthcare system.
The risk of PMI heavily relies on the socioeconomic and ethnic backgrounds as well, which have been greatly overlooked in global studies so far.In order to prevent MI, targeted testing regimens that take into account the physiological differences of the population and their socioeconomic status which directly affects their diet and health requirements must be studied in depth.
Moreover, in instances of head and neck cancer, chemotherapy combined with surgery has proven to be detrimental to the cardiovascular health of patients.This could be an indication for doctors to practice caution while dealing with head and neck cancer patients who have undergone chemotherapy.Thus such cases must be observed with vigilance to quickly detect PMI.However, it is important to understand that this would not arise if adequate risk assessment is performed in order to prevent MI beforehand.

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Sources of funding
This study was not supported by any funding.