The Pathophysiology of Aortic Dissection

The incidence of aortic dissection has been estimated to be 4.4 per 100 000 person-years for those age 18 and older. The incidence is almost twice as common for men than women (10.2 versus 5.7 per 100 000 person-years) and increases with age.2 Stanford Type A dissection, involving the ascending aorta as it leaves the heart, is 1.4 times as common as Type B dissection which is defined as dissection originating distal to the takeoff of the left subclavian artery.2 This means that there are approximately 11,000 aortic dissections annually in the United States, approximately 6,400 of those being Stanford Type A.

Seventy-five percent of aortic dissections occur in patients 40 to 70 years of age with the majority occurring between the ages of 50 to 65. Risk factors that predispose one to aortic dissection include hypertension, genetic conditions including Marfan’s syndrome, Ehlers–Danlos syndrome, Turner syndrome, family history, aortic instrumentation during surgery or other invasive procedures, trauma, and inflammatory or infectious diseases that cause vasculitis. Aortic dissection is also a common complication of those congenitally born with a bicuspid aortic valve. This represents about 5% of the population. The bicuspid valve interferes with the laminal flow of blood through the aortic valve and the wall of the ascending aorta can become aneurysmal over time, eventually leading to disruption of the intima and aortic dissection. Use of certain sympathomimetic drugs, such as cocaine or methamphetamines can also lead to aortic dissection and smoking is risk factor as well., One study has demonstrated the incidence of aortic dissection to be between 5.2 and 12.4 cases per hundred thousand people per year, depending on the type of hospital where the patient presents. In another study, 16.7% of aortic dissections were missed in the emergency room, 25% were missed in the first 24 hours after presentation. Khan, and Nair noted that, clinically, pulse deficit was seen in 38% of those presenting with AD. Lower extremity ischemia was 15 – 20%, and neurological deficits in patients with AD have been found to be as high as 18 to 30%.10

The Classification of Aortic Dissection

Aortic dissections are classified based on the origin of the tear and the extent of the false lumen. In Stanford Type A aortic dissection, the tear originates proximal to the takeoff of the left subclavian artery. The dissection and false lumen may extend retrograde toward the base of the heart, and involve the left and/or right main coronary arteries or the aortic valve, or antegrade downstream. In Stanford type B aortic dissection, the tear, originates distal to the subclavian artery takeoff. The dissection, and false lumen, are constrained and remain distal to the subclavian artery takeoff (see Figure 2).

While surgical intervention for Stanford type B (TBAD) dissections is often delayed, and there are good endovascular treatment options available, Stanford Type A dissections (TAAD) represent an immediate life-threatening surgical emergency. The mortality for TAAD can be as high as 50% in the first 48 hours.2

AORTIC DISSECTION AND END-ORGAN MALPERFUSION

Aortic dissection can have profound implications for perfusion of multiple organ systems in the body. As the dissection proceeds antegrade or retrograde from the tear, perforating vessels that supply perfusion to the myocardium, the brain, the spinal cord, the abdominal organs, the liver and kidneys specifically, and the extremities, can all be obstructed or even sheared off leading to ischemic conditions within these organs.

For TAAD, conventional wisdom requires immediate surgical intervention to repair or replace the ascending aorta and redirect blood flow back to critical organ systems downstream. More recent evidence suggests however that those with malperfusion syndrome (MPS), caused by TAAD, suffer significantly higher rates of mortality than those without. Kawahito, and colleagues showed as much as a 5-fold mortality for any malperfusion and the more systems involved, the higher the mortality.

In a landmark and foundational paper from 1997, Deeb, et al. noted that those with MPS suffered a 22% intraoperative mortality, and an 89% in-hospital mortality. They proposed a controversial new approach to TAAD in which they delayed emergency central aortic surgical repair, opting to first attempt percutaneous reperfusion of the malperfused organs, in hopes of better overall survivability. In 2008, Patel and colleagues presented a follow-up long-term analysis of their colleagues Deeb, et al’s results showing that if you survive MPS in the initial phase, your long-term survival rivals that of patients with TAAD sans MPS. Crawford, et al. has shown that MPS occurs in 25 to 30% of TAAD.

Since the initial proposal by Deep and colleagues, other institutions and surgical groups have investigated this approach and found it to be valid., That said, the criteria for determining malperfusion is not well established. Various institutions have defined their own classification.

Classification of Malperfusion

As an example, in 2015 the “Penn Classification” defined four major classifications:

Classification

Description

Aa Absence of branch vessel malperfusion or circulatory collapse

Ab Branch vessel malperfusion with ischemia

Ac Circulatory collapse with or without cardiac involvement

Abc Both branch vessel malperfusion and circulatory collapse

The Penn classification also noted that any ischemia raises the mortality to 24%. The definitions used in the Penn Classification has led to some confusion about what criteria is used to determine malperfusion in TAAD.

In 2018, Ghoreishi, et al. created a novel risk score to attempt to predict operative mortality based upon values of the patient’s creatinine, lactic acid, and whether or not they had elevated liver enzymes, but even this falls somewhat short, as it fails to address perfusion of the brain, myocardium, and extremities. Indeed, depending upon the surgeon, malperfusion is assessed by clinical exam, by imaging, by laboratory work, or by a combination of any and all of these methods. There is no one codified approach to completely assessing the body systems and their malperfusion.

Critical Organ Systems

Life is supported and maintained by several key, critical organ systems within the body. While as an isolated event, some of these systems can be surgically repaired and the loss others can be extrinsically compensated for (i.e. hemodialysis for renal failure), acute ischemic failure of one or more of these systems in a patient with an aortic dissection requiring immediate surgical repair can lead to almost certain mortality. We will examine each of these critical systems, their preoperative assessment using clinical exam, laboratory investigations, and imaging. We will also explore their perioperative risk with respect to mortality.

The Brain

There is no other organ system in the body that is more susceptible to hypoxia than the brain. Preoperative acute cerebrovascular accident (CVA), or stroke, is typically embolic or ischemic (secondary to compromised blood flow) in the setting of AD. Patients have presented with neurological symptoms, however, and have been found, incidentally, to have AD.

Conversion to Hemorrhagic Stroke. Okada, et al, notes that 41% of embolic cerebral strokes will convert to hemorrhagic strokes at a median of 20 days post original event (range 3 –47). The conversion rate was found to be higher in those 70 years-old and above (51%), and with the size of the infarct (moderate to large ~51%) similarly influencing the conversion rate as well.21 Although the incidence of conversion was not affected by thrombolytic or anticoagulant therapy, in cases where hemorrhagic conversion (HC) occurred, and those modalities were applied, the resulting hematoma was massive.

In a more recent study, Hong and colleagues note that HC is rare within the first six hours and usually occurs within the first four days. If treated with thrombolysis or thrombectomy however, it occurs usually within the first 24 hours after the initial CVA.22 They also note that patients with an acute embolic CVA are at risk for additional ischemia, especially in situations where they are hypotensive. The use of anti-hypertensive agents to keep the patient normal to hypotensive is a frequent initial treatment strategy to prevent further aortic dissection or rupture while the patient is awaiting availability of surgical intervention.

Repair of a TAAD utilizing extracorporeal bypass and deep hypothermic arrest requires the patient to be systemically heparinized with tens of thousands of units of heparin given. Because of these issues, surgeons have classically considered stroke to be an independent mortality predictor in TAAD and in many cases surgeons have demurred or consigned patients to medical treatment and the eventual mortality that that confers.

Cerebral Malperfusion and Immediate Surgical Repair. Jensen and Chen, in their recent work, note that patients undergoing surgical repair of their TAAD with pre-operative cerebral malperfusion (CMP) have double the in-house mortality (25.7% versus 12%, p < 0.001) than those who present as neurologically intact. At one year post-operatively, their survival is 62.6% versus 81.3% (p >0.001), respectively.23 That said, they propose that the vast majority of patients who present with TAAD and neurological symptoms, and even coma, are appropriate for immediate surgical intervention. They review studies from a number of authors who have taken patients with significant neurological impairment to surgery with remarkable rates of survival and resolution of their neuro- deficits. In one such study, Tsukube, et al, took 24 patients with a Glascow Coma Score (GCS) of 6.5 ± 2.4, indicating coma, for immediate surgical repair. Of those patients, the mean age was 71 ± 11 years. Of this group, 79% of patients had recovery of consciousness and 50% went on to achieve a modified Rankin Score of 3, indicating the patient has moderate disability; requiring some external help but able to walk without the assistance of another individual. The cumulative survival rate of these patients was 48.2% after 10 years.25

Jensen and Chen propose an assessment and treatment strategy for patients with cerebral malperfusion (CMP).23 In general, only those patients who have been in a coma for greater than six hours, or who have intracranial hemorrhage demonstrated on their head CT, should undergo delayed or deferred surgical repair.23 They do acknowledge a study by Fukuhara, et al that demonstrated that the presence of internal carotid artery (ICA) occlusion was an absolute harbinger of mortality secondary to cerebral edema and herniation syndrome. By contrast, 79% of those patients with unilateral or even bilateral common carotid artery occlusion, but no ICA occlusion, survived to hospital discharge (p < .001).27 In such cases where CMP is suggested, Jensen and Chen recommend the surgeon consider dedicated angiography of the head and neck vessels but warn that the time necessary to obtain such studies must be weighed against the possible delay of immediate surgical intervention.

As the focus of this paper is to establish a standard set of laboratory studies for all patients presenting with possible aortic dissection, we look to the brain for such markers of injury. In 1985, Nordby and Urdal noted the presence of fractionated creatinine kinase, type BB (CK-BB) in the blood of patients that had recent contusion of the brain. More recently, Carr, and colleagues examined CK-BB as a marker for soldiers who had experienced mild traumatic brain injury. While their study failed to show results significant enough to support the use of this marker in making the diagnosis, the low number of subjects in the study indicates the need for more research in this area. Elevated levels of CK-BB have been found in patients with certain breast tumors and other malignancies,, so the presence of CK-BB in the blood is not necessarily pathognomonic for cerebral malperfusion syndrome.

While physical assessment and imaging will remain the primary modalities for assessment of neurological status in patients with TAAD, this author suggests that including creatinine kinase BB in a standard lab panel for this patient population adds no risk and presents an area of possible research that could benefit these patients in the future.

The Heart

Aortic dissection can extend retrograde into the left and/or right main coronary arteries, causing an insufficient blood flow to the myocardium resulting in ischemia and infarction. Acute myocardial infarction in AD has been reported to be from 5.7 to 11.3%.

When considering the role of the heart in AD, primary evaluation is concerned with two specific goals:

(1) determining if the patient has a myocardial infarction, which could impact the surgical approach necessary to correct the aortic dissection by re-establishing normal coronary artery blood flow, and

(2) determining if the heart itself is viable and will allow the patient to be weaned from extracorporeal bypass and survive the surgery.

Typically, patients undergoing emergent repair for TAAD undergo trans-esophageal echocardiography (TEE). The TEE probe is inserted, and the patient is imaged, prior to the incision, and the ascending aorta is evaluated for the presence of a flap and false lumen. This allows the surgeon to determine what portions of the aorta are involved, what cannulation strategy will be possible, and the need for deep hypothermic cardiac arrest. Additionally, the function of the heart is assessed including aortic insufficiency, which is associated with retrograde dissection into the root. Also assessed, are wall motion abnormalities in the ejection fraction of the left ventricle can be calculated as well. This imaging is key to understanding the viability of the myocardium and how it will impact the patient’s ability to survive surgery.

By now, it is well-established that cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are the gold standard tests for determining myocardial damage. At least one of these tests is readily available at all hospitals and cTnT levels > 0.1 μg/L and cTnI levels of > 0.1 to 2 μg/L (accounting for local laboratory variants in the assay) are indicators of myocardial damage.

Boden, et al, examined the size of infarct and outcomes based on cTnT levels. They reported a 6.4% mortality at 1 year with levels averaging just 3.15 μg/L (1.21 to 7.22 ).34 Small positive values indicate minor myocardial damage. That said, there are numerous conditions that can elicit a troponin leak including end-stage renal disease, acute heart failure exacerbation, pulmonary embolism, stroke, and sepsis, among others, and in TAAD itself. Vrsalovic demonstrated that 26.8% of TAAD patients were significantly associated with increased risk of short-term mortality (OR 2.57; 95% CI 1.66–3.96). Larger values (40 – 50 μg/liter) can indicate substantial myocardial infarction and very-large values (>140 μg/liter) would indicate a severely damaged organ in which the viability is questionable. Either of these labs should be included in the AD lab panel.

The Gut

Visceral ischemia occurring in TBAD is as high as 25%, with in-hospital mortality as high as 11%.16 The operative mortality for patients with TAAD and visceral ischemia is reported as high as 43%.16 Moreover, a dissection that extends into the celiac trunk or the superior or inferior mesenteric arteries may not be totally relieved with reestablishment of flow through the true lumen of the dissected aorta. Thus, dissection involving these arteries may need to be addressed independently, and possibly preceding surgical correction of aortic dissection.

Abdominal Pain. Ohle, et al, note that abdominal pain had a 28.4% sensitivity and 88.4% specificity for AD.9 Thus, the presence of abdominal pain, in and of itself, is not a reliable indicator for AD. Moreover, abdominal pain in and of itself does not denote visceral ischemia. Diagnosis of visceral ischemia would be aided by the presence of elevated liver function tests (LFTs) and lactic acidosis.

Acidosis as an Indicator of Mortality. Overall acidosis and calculation of a base deficit is available through arterial blood gasses (ABGs), and one study has shown that 92% of patients with a base deficit of ≥ 10 in the presence of abdominal malperfusion perished. The value of lactate levels in visceral malperfusion is somewhat less definitive. In their work on ischemic colitis after cardiac surgery, Arif and colleagues note that although high blood lactate is a frequent finding, it cannot be used to effect early detection of ischemic colitis. This would seem to be supported by Studer, and colleagues, who found that elevated lactate values measured within 24 hours before surgery for ischemic bowel demonstrated a moderate correlation, but no statistical significance with the length of bowel necrosis (r2=0.257, p=0.058). That said, the study by Studer, and colleagues, had an in-hospital mortality rate of 42.9% with the nonsurvivors having a statistically significant higher lactate level than those who survived (5.6±4.8 vs. 3.0±2.2 mmol/L, p=0.024).40 We would postulate that lactate levels are an important part of a comprehensive laboratory investigation and should be viewed in the context of other complimentary lab values and the patient’s overall clinical picture.

Although it is an abdominal organ, liver failure in cardiac surgery has been shown to have its own impact on mortality, and we consider it individually.

The Liver

The rate of liver failure post cardiac surgery is relatively low but, when present, the mortality exceeds 60%. Pre-existing liver failure would obviously not bode well for the patient’ s survival in AD. Even with novel extracorporeal blood purification treatments, the death rate remains 23% at 30 days.41 Although elevated LFTs in and of themselves have only been shown to be 15% sensitive, they have been shown to be 90.6% specific for a diagnosis of AD.9 Liver failure is easily detected as part of a comprehensive metabolic panel, that can be drawn at any hospital and the results should be available to the surgeon prior to incision.

The Kidneys

Patients with acute kidney injury (AKI) have a five-fold risk of death following cardiac surgery, and AKI requiring the use of continuous renal replacement therapy (CRRT) has been associated with a 50% post-operative mortality. Bhavsar, et al, have shown that a creatinine kinase level of 1,250 U/L or more was 93.3% predictive of subsequent acute renal failure secondary to rhabdomyolysis. Thus, knowing the patient’s renal history and testing their renal function pre-aortic dissection repair for acute changes is key to understanding their postoperative course. A renal panel is part of a comprehensive metabolic panel is required as part of a comprehensive workup for any patient suspected of having AD. Unfortunately, serum creatinine elevations can lag behind acute kidney injury (AKI) by as much as 24 to 48 hours. Moreover, a dissection leaving one kidney malperfused and the other healthy and functioning, may not evoke a significant creatine rise. There are newer technologies (i.e nephro-check) on the horizon that will be able to detect AKI much sooner and as these become available their incorporation into this evaluation should be considered. Finally, an elevated creatinine kinase level would indicate possible renal failure secondary to rhabdomyolysis and should be tested as well. These results should be available to the surgeon prior to incision.

The Extremities

One of the key diagnostic indicators of AD is pulse deficit. Acute differences in blood pressure readings in the upper extremities or lower extremities, or complete lack of pulses in an extremity was found by Ohle, et al to have 20.6% sensitivity and 99.3 specificity for the diagnosis of AD.9 In a systematic review, Gargiulo, et al showed that lower extremity malperfusion occurs in up to 40% of TBAD and is seen in up to 71% of TBAD with associated malperfusion syndrome. The 30-day mortality in these cases was high and 97% of these patients developed lower limb complications.46 Lower limb malperfusion was the only clinically detected malperfusion in 52% of patients presenting with TBAD, and it was associated with renal malperfusion 40% of the time and visceral malperfusion 25% of the time. 46 An elevated plasma creatinine kinase has been associated with a 56% need for limb amputation and is a good indicator of significant lower limb ischemia. This would be a devastating complication to a patient that already has a high risk of mortality from aortic dissection. Moreover, elevated creatinine kinase is an indicator of rhabdomyolysis, and is a precursor to renal failure.

Other Laboratory Investigations

In addition to the laboratory investigations mentioned so far, we would be remiss not to discuss others that, while not indicative of malperfusion syndrome, can be diagnostic of AD, or will aid in its surgical treatment.

Complete Blood Count

Profound anemia in AD is a morbid sign and can indicate rupture, either contained or uncontained.

PT, PTT, fibrinogen

A prothrombin time (PT) and partial thromboplastin time (PTT) are part of the standard workup for any patient going to cardiac surgery. A fibrinogen level could also be of use if there is suspicion of massive or slow, long-term hemorrhage. Other indicators of platelet function should also be considered if patient’s home regimen includes platelet inhibitors.

Type, Screen, and Crossmatch

While any patient going to cardiac surgery needs to be typed, screened, and crossmatched for blood, this need is especially true for AD. Guan, and colleages, in their paper exploring hemostatic disturbances in patients undergoing AD surgery demonstrate the need not only for red cells, but fresh frozen plasma and platelets as well, with inter-operative blood losses averaging 1.4 L, and 2.2 L postoperatively.

d-dimer and C-Reactive Protein

The presence of thrombus, which forms in the false lumen in an aortic dissection, will lead to the activation of the intrinsic and extrinsic clotting cascade. Part of this reaction produces fibrinolysis resulting in the production of d-dimer, a degradation product of cross-linked fibrin. Ohle, et al, showed that a d-dimer of > 500 ng/dL was 96.7% sensitive and 71.7% specific for diagnosis of AD.9

C-reactive protein (CRP) is a nonspecific indicator of inflammation produced by the liver, and is frequently elevated in AD.

Wen, et al, examined the levels of d-dimer and CRP in patients with AD, specifically with respect to measured levels and their survival. There were 114 patients included in their study of which 83 survived (27% mortality).50 All the subjects in their study had normal preoperative hepatic and renal function. Those patients that survived had a d-dimer of 4.28 µg/ml ± 1.99 while the d-dimer in those who died was 9.84 µg/ml ± 3.53 (P < 0.001).50 The surviving patients had a CRP of 11.18 mg/L ± 1.85 while those who succumbed to their AD had a CRP of 14.08 mg/ L ± 2.8 (P < 0.001). 50 While this is a single center experience, the preoperative predictive value of d-dimer and CRP should not be underestimated.

The Aortic Dissection Lab Panel

Based upon the above discussion, the author suggests that the following lab panel be drawn on any patient presenting with acute onset pain described as tearing sensation, chest or back pain with neuro- symptoms, acute abdomen, or signs of malperfusion in an extremity (i.e. swelling, mottling, cold to the touch, lack of distal pulses, deconjugate blood pressures), undergo the following labs, in addition to CT angiography of the chest abdomen and pelvis:

• Complete Blood Count (CBC)

• Comprehensive Metabolic Panel (CMP)

• Arterial Blood Gas (ABG)

• Lactic Acid (lactate)

• Creatinine Kinase (CK) with MB, BB, and MM fractions

• Troponin

• d-dimer

• C-Reactive Protein (CRP)

• Prothrombin Time (PT) with International Normalized Ratio (PT/INR)

• Partial Thromboplastin Time (PTT)

• Fibrinogen

• Type and Screen

• Crossmatch for six units of packed red cells