Author’s Accepted Manuscript

Hyperlactemia Predicts Surgical Mortality in

Patients Presenting with Acute Stanford type A
Aortic Dissection

Jeremy M. Bennett, Eric S. Wise, Kyle M.

Hocking, Colleen M. Brophy, Susan S. Eagle
www.elsevier.com/locate/buildenv

PII: S1053-0770(16)00264-0
DOI: http://dx.doi.org/10.1053/j.jvca.2016.03.133
Reference: YJCAN3615
To appear in: Journal of Cardiothoracic and Vascular Anesthesia
Received date: 20 January 2016
Cite this article as: Jeremy M. Bennett, Eric S. Wise, Kyle M. Hocking, Colleen
M. Brophy and Susan S. Eagle, Hyperlactemia Predicts Surgical Mortality in
Patients Presenting with Acute Stanford type A Aortic Dissection, Journal of
Cardiothoracic and Vascular Anesthesia,
http://dx.doi.org/10.1053/j.jvca.2016.03.133
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 Hyperlactemia Predicts Surgical Mortality in Patients Presenting With Acute Stanford

Type A Aortic Dissection

1) Jeremy M. Bennett, MD, Assistant Professor, Division of Cardiovascular Anesthesiology,

Vanderbilt University Medical Center, Nashville, TN

2) Eric S. Wise, M.D., M.A., Research Fellow Vanderbilt University, Department of Surgery

3) Kyle M. Hocking, PhD, Biomedical Engineering Department, Vanderbilt University Medical

Center, Nashville, TN

4) Colleen M. Brophy, MD Professor of Surgery, Division of Vascular Surgery, Vanderbilt

University Medical Center, Nashville, TN

5) Susan S. Eagle, MD Associate Professor, Division of Cardiovascular Anesthesiology,

Vanderbilt University Medical Center, Nashville, TN

Disclosures:

None of the authors have anything to disclose

Funding:

Vanderbilt RedCAP:

CTSA Award UL1 TR000445 from NCATS/NIH

Vanderbilt University Department of Anesthesiology

Acknowledgements:

Vanderbilt University Department of Biostatistics

Corresponding author:

Jeremy M. Bennett, MD

Jeremy.m.bennett@vanderbilt.edu

1215 21st Ave South, 5160 MCE North Tower, Nashville, TN 37232

phone: 615 322-0505

fax: 615-343-4729

Objective:

Inspired by the limited facility of the Penn classification, we aimed to determine a rapid

and optimal pre-operative assessment tool suggestive of operative futility in acute Stanford type

A aortic dissection (AAAD).

Design:

Patients with attempted surgical repair of AAAD were determined using a de-identified

single institution database. One-hundred and forty-four patients were retrospectively reviewed

for pre-operative demographics and surrogates for disease severity and malperfusion. Bivariate

analysis was used to determine significant (P ≤ .05) predictors of in-hospital and one-year

mortality, the primary endpoints. Receiver operating characteristic (ROC) curve generation was

used to define optimal cut-off values for continuous predictors.

Setting: Single center, level 1 trauma, university teaching hospital

Participants: The study included 144 cardiac surgical patients with acute type A aortic

dissection presenting for surgical correction.

Interventions: Surgical repair of aortic dissection with preoperative labwork drawn before the

OR or immediately following arterial catheter placement intraoperatively.

Measurements and Main Results:

The study cohort included 144 patients. In-hospital mortality was 9%, and the one-year

mortality rate was 17%. Variables that demonstrated a correlation with in-hospital mortality

include elevated serum lactic acid (OR 1.5 [1.3 – 1.9], P < .001), depressed ejection fraction (OR

0.91 [0.86 – 0.96], P = .001), effusion (OR 4.8 [1.02 – 22.5], P = .04), neurologic change (OR

5.3 [1.6 – 17.4], P = .006), severe aortic regurgitation (OR 8.2 [2.0 – 33.9], P = .006) and

cardiopulmonary resuscitation (OR 6.8 [1.7 – 26.9], P = .01). Only increased serum lactic acid

demonstrated a trend with one-year mortality upon univariate Cox regression (HR 1.1 [1.0 – 1.1],

P = .006). ROC analysis revealed optimal cut-off lactic acid levels of 6.0 mmol/L and 6.9

mmol/L for in-hospital and one-year mortality, respectively.

Conclusion:

Lactic acidosis, ostensibly as a surrogate for systemic malperfusion, represents a novel,

accurate and easily obtainable pre-operative predictor of short-term mortality after attempted

AAAD repair. These data may improve identification of patients who may not benefit from

operation.

Introduction:

Stanford acute type A aortic dissection (AAAD) is a common and life-threatening

surgical emergency, with mortality of unrepaired AAAD estimated at 1-2% per hour. Even with

surgical correction, for many patients, death may still be imminent with rates of in-hospital

mortality estimated between 15-47%.(1-3) Multiple cited pre-operative risk factors for in-

hospital mortality after repair of AAAD include renal failure, advanced age, shock,

cardiopulmonary resuscitation, remote myocardial infarction as well as potential indicators of

systemic malperfusion such as neurologic change, syncope, hypotension, mesenteric ischemia

and limb ischemia.(2-8) Intraoperative and post-operative predictors of death after attempted

AAAD repair include the need for renal replacement, cardiopulmonary bypass and clamping

time, excessive bleeding and arch replacement, among others.(9-12) Nonetheless, many

institutions will elect to attempt operative repair on patients for whom surgery may result in in-

hospital mortality, as some of these risk factors are either not readily available pre-operatively or

have not been sufficiently validated to warrant a change in management.

Throughout the 2000s, it became apparent that indicators of ischemia and malperfusion

were the most critical determinants of mortality after surgical repair. Augoustides and colleagues

synthesized the reported ischemic risk factors for patients presenting with AAAD and reported a

classification system in 2008, known as the Penn Classification.(13) Patients with AAAD were

placed into one of four strata based on clinical presentation: 1) class Aa- lack of ischemia, 2)

class Ab- localized ischemia, 3) class Ac- generalized ischemia, and 4) class Abc- combined

generalized and localized ischemia.(13) While externally validated,(14, 15) its clinical use

remains limited as it may require advanced imaging modalities or intra-operative findings to

accurately categorize the degree of ischemia. Ostensibly, there are multiple easily obtainable pre-

operative variables such as demographics and surrogate measures of malperfusion that may

allow for accurate discrimination in outcome likelihood among AAAD patients. Inspired by both

the importance of malperfusion syndrome and limitations of the facility of the Penn

classification, we aimed to determine simple pre-operative patient variables portending an

increased in-hospital and one-year mortality after attempted AAAD repair. Moreover, as

evidence suggests lactic acid levels are excellent surrogates for lethal sequelae of AAAD, such

as mesenteric ischemia, we hypothesize that pre-operative serum lactic acid level may represent

the strongest of these variables in our institutional cohort.(16, 17)

Materials and Methods:

This was a single institution retrospective study to determine pre-operative variables

associated with in-hospital and one-year mortality after attempted AAAD repair, the primary

endpoints. During the study period 10 cardiac surgeons were involved in surgical management.

Patients with AAAD were determined using the Vanderbilt University de-identified patient

database, the Synthetic Derivative.(18) This study was approved by the Vanderbilt University

Institutional Review Board with a waiver of informed consent. The database was queried for all

patients coded with one of the Current Procedural Terminology (CPT) codes 33860 (Ascending

aorta graft, with cardiopulmonary bypass, includes valve suspension, when performed), 33861

(Ascending aorta graft, with cardiopulmonary bypass, with or without valve suspension; with

coronary reconstruction), 33863 (Ascending aorta graft, with cardiopulmonary bypass, with

aortic root replacement using valved conduit and coronary reconstruction) and 33864 (ascending

aorta graft, with cardiopulmonary bypass with valve suspension, with coronary reconstruction

and valve-sparing aortic root remodeling) from 2000-2014, initially yielding 526 patients. The

patients were then individually chart reviewed for inclusion. In-hospital mortality was defined as

occurring during the hospital course for AAAD surgery, regardless of length of post-operative

survival, and was reliably identified via death flags associated with appropriate charts, obtained

on request from the Synthetic Derivative programmers. Patients were excluded if they did not

have indication for surgery (erroneous CPT coding; 301 patients), if chart information was

grossly incomplete in the de-identified database (4 patients), or if patients received aortic surgery

that was not AAAD, i.e. surgery for type B aortic dissection (74 patients). Three patients were

excluded for iatrogenic AAAD occurring during a planned cardiac surgical procedure as the
AAAD was not the initial reason for surgical intervention. Derivation of the 144 patient cohort is

illustrated in Figure 1.

Demographics examined included gender, race and age. Potential pre-operative markers

of dissection severity and malperfusion syndrome were reviewed as well. These included the

laboratory values of admission serum lactic acid and serum creatinine. Preoperative lactic acid

levels were obtained either from blood samples analyzed in the lab or from arterial blood gas

sample performed on a GEM4000 point-of-care device (Instrumentation Laboratory, Bedford,

MA). Lactic acid value included for analysis was closest to surgery prior to incision. The

presence of Debakey type I disease was indicated by preoperative imaging studies (CT, MRI,

angiography) or by transesophageal echocardiography (TEE) performed in the operating room

environment when imaging information was unavailable or contraindicated. Presence of

pericardial effusion (with or without tamponade), degree of aortic insufficiency,

electrocardiographic ST-T wave abnormalities, and documented evidence of limb malperfusion

were noted as well. Neurologic change was indicated as present if the patient demonstrated signs

of focal neurologic deficits, slurred speech, or altered mental status during their initial

presentation. Aortic regurgitation severity, ejection fraction, and pericardial effusion variables

represent information obtained by imaging and/ or TEE assessment as reported by the

reader/operator.(13) Operations were defined as, at minimum, the administration of anesthetic

with the intent to operate, and were performed in a manner that was at the discretion of the

surgical and anesthesiology team.(19)

All descriptive statistics were reported as fractions, or median and interquartile range.

Variables were examined for trend with in-hospital mortality using univariate nominal logistic

regression analysis (continuous variables) and Fisher’s exact test (categorical variables), with
concomitant odds ratios (OR) and 95% confidence intervals reported. Univariate Cox regression

analysis was used to determine variables associated with one-year mortality, with concomitant

hazard ratios (HR) and 95% confidence intervals. Sample size limitations precluded a

multivariable analysis. For continuous variables, optimal cut-off values predictive of mortality

were determined using receiver-operating characteristic curve analysis. Areas under the curve

(AUC) were reported as AUC ± standard error. Subsequent unadjusted Cox survival curves were

generated to demonstrate the effect of specific predictors of one-year mortality. The criterion for

statistical significance was a level of evidence P ≤ .05. Statistical analysis was performed with

GraphPad Prism 5 (La Jolla, CA) and JMP Pro 11 (Cary, NC).

Results:

The study cohort had 144 included patients, of whom 67% were male and 17% were of

black race. The median age at surgery was 58.7 years (interquartile range 48.9 years - 69.7

years), where 13% of the patients were greater than 75 years of age. The in-hospital mortality

rate was 9% (13/144), and the one-year mortality rate was 17% (25/144). Univariate analysis was

conducted for association with in-hospital mortality. Variables that demonstrated a correlation

with in-hospital mortality include elevated serum lactic acid (OR 1.5 [1.3 – 1.9] per unit increase

in lactic acid level, P < .001), depressed ejection fraction (OR 0.91 [0.86 – 0.96], P = .001;

implying a protective effect for in-hospital mortality for each incremental increase in ejection

fraction percent), effusion (OR 4.8 [1.02 – 22.5], P = .04), neurologic change (OR 5.3 [1.6 –

17.4], P = .006), severe aortic regurgitation (OR 8.2 [2.0 – 33.9], P = .006) and cardiopulmonary

resuscitation (OR 6.8 [1.7 – 26.9], P = .01). These data are summarized in Table 1. Only
increased serum lactic acid demonstrated a trend with one-year mortality upon univariate Cox

regression (HR 1.1 [1.0 – 1.1], P = .006). These data are summarized in Table 2.

ROC curve generation was conducted to assess the most accurate cut-off for serum lactic

acid level in the prediction of both in-hospital and one-year mortality (Figure 2). The AUC

values for the ROC curves were 0.88 and 0.81, respectively. For in-hospital mortality, a cut-off

serum lactic acid level of 6.0 mmol/L predicted death with a sensitivity of 85% and specificity of

77%; at one-year, the optimal cut-off serum lactic acid level predictive of mortality was 6.9

mmol/L, with a sensitivity of 67% and specificity of 84%. Cox survival analysis was performed

on one-year mortality, stratifying patients by those with preoperative lactic acid values below

and equal to or greater than 6.9 mmol/L (Figure 3; P < .001)

Discussion:

Risk factors for increased in-hospital mortality in AAAD have been described previously

and include hypotension, ischemic complications (limb, myocardial, mesenteric), neurologic

abnormalities, renal dysfunction (GFR < 60ml/min), elevated white blood cell and neutrophil

counts, increased C-reactive protein, and advanced age.(1, 3, 4, 7, 20-24) Stratification of

patients based on ischemia and cardiovascular collapse has also been performed with the Penn

Classification and validated.(13, 15) While useful, many of these tests are subjective or require

imaging studies to evaluate for localized ischemia that are not readily applicable in emergent

situations. Rapid determination of surgical markers of in-hospital mortality at time of

presentation, based on demographic information or surrogates for ischemia and aortic dissection

severity, is useful in determining the best initial approach.

 Univariate analysis of our cohort revealed the association with several previously

reported predictors for in-hospital mortality, including lactic acidosis, depressed ejection

fraction, effusion, neurologic change, severe aortic regurgitation and CPR. In our study, lactic

acid levels were available prior to surgical incision in 123 of the 144 patients studied (85%),

obtained during intake admission lab work or by the initial intraoperative arterial blood gas

(ABG) analysis performed prior to surgical incision. The presence of hyperlactemia conferred an

increased risk of in-hospital mortality in our institution at a level of evidence stronger than any of

the other factors assessed. Censoring at one-year, only lactic acidemia conferred a significantly

increased risk of mortality (HR 1.1 per mmol/L unit increase [1.0 – 1.1]; P = .006). Thus, lactic

acid levels represent an excellent preoperative predictor for both in-hospital and one-year

mortality after AAAD repair with optimal cut-off values of 6.0 mmol/L and 6.9 mmol/L,

respectively. These findings suggest that surgical repair in patients with severe hyperlactemia

may carry a dire prognosis, and can prompt further discussions with the patient and family

regarding surgical expectations.

To our knowledge, lactic acidemia has not been previously reported as a significant

marker for mortality in AAAD. While yet to be validated as an independent risk factor for

AAAD, lactic acidosis as a surrogate for systemic hypoperfusion or malperfusion is becoming an

increasingly recognized and useful independent measure of disease severity and a predictor of

survival in the intensive care and trauma settings.(25, 26) In one study, operative mortality was

reduced from 23.9% to 9.3% when AAAD patients with ischemic complications were excluded

from analysis.(7) Malperfusion and ischemia, while known to represent significant markers for

disease severity, are often diagnosed by imaging studies or by physical exam (abdominal pain,

stroke, limb numbness or motor weakness, etc.).(27) Mesenteric, coronary, and renal ischemia
have been shown to significantly increase the operative mortality risk in AAAD(28).While

important for assessment, these parameters are subjective measures and may not be present

despite marked ischemia. Additionally, objective measures like imaging studies may not provide

optimal evaluation of compromised mesenteric and end-organ blood flow due to timing,

reduction in contrast dye in patients with renal insufficiency, motion artifact, and reader error.

Evaluation of aortic branch vessel blood flow using ultrasound or TEE has been described when

laboratory markers of ischemia are present, which may guide surgical repair(29). Lactic acid

levels are a rapid and cost-effective alternative clinical marker for dissection severity or

malperfusion/ischemia that can be obtained on all patients, regardless of timing of presentation.

AAAD continues to carry a high perioperative mortality risk, despite advances in surgical

management.(1-4, 30) Malperfusion of end-organs following surgical repair increases risk of

mortality and debilitation(28, 31) and identification of patients at risk can guide treatment

strategies and possible additional surgical repair, particularly if cerebral, mesenteric, or coronary

ischemia is present(32, 33). A recent study evaluating the hybrid operating room approach to

AAAD demonstrated a 23% incidence of aortic occlusion or malperfusion necessitating

endovascular repair at the time of operative repair. Additionally, 32% of patients received

concomitant coronary bypass grafting following angiographic demonstration of coronary

malperfusion(34).

Given the continued concern for malperfusion with increased mortality there remains a

need for screening to evaluate for surgicalin-hospital mortality in high-risk patients. Given the

ongoing assessments and debates regarding health care costs and societal impact, it is becoming

ever more imperative for clinicians to be cognizant of patients for whom certain surgical
interventions have extremely high risk for mortality, to help guide therapy and surgeon-patient/

family discussions(35).

Identification of those patients for whom attempted AAAD may be futile is not always

intuitive and often requires several objective parameters for identification. Lactic acid used as a

relatively inexpensive and rapid surrogate marker for ischemia may predict increased surgical

mortality. To this effect, we successfully used our institutional de-identified database to

determine those preoperative variables associated with in-hospital mortality, information that can

potentially influence the patient’s management plan and provide a more realistic expectation of

the clinical outcome.

Our data, while revealing, had several limitations. The aim of this study was to determine

preoperative predictors associated with our endpoints, however, a direct and independent

relationship between lactic acidemia and our endpoints cannot be concluded, as confounders of

serum lactic acid level, such as preoperative liver function, were not considered. Additionally

timing of presentation to surgical correction was not analyzed due to incomplete or missing

information in the electronic chart in several patients who were transferred from another

institution. Further, lactic acid levels were not available for some patients in the surviving cohort

for reasons that are unknown due to the retrospective nature of the study. This could influence

the association of hyperlactemia with mortality in AAAD. Next, our data was subject to the bias

inherent in retrospective collection, including a selection bias as our cohort were all patients who

were offered an operation. Information was also gathered and collected at non-uniform time

points. Anesthetic care and operative treatment and decision-making were non-standardized, as

these factors were at the discretion of the respective anesthesia and surgical teams; the database

prevented identification of the providers. Our data was further limited by sample size. Our 144
patient cohort, while commensurate with the number of patients included in similar TAAD

outcomes analyses,(36, 37) is restricted, a limitation exacerbated by the low mortality rate.

Interestingly age did not predict in-hospital or 1 year mortality. This may be due to the size of

the study and the single center evaluation of our patient cohort. Along with ischemia and

malperfusion, age is frequently identified as an independent risk factor for poor survivability in

AAAD with a recent study demonstrating that age > 70 years was associated with increased

mortality while age < 50 years conferred some protection(38). Finally, this study did not look at

other important outcome measures that could potentially influence a patient or a family’s

decision to pursue an operation, including length of stay, functional status at discharge, and

permanent disability. While we analyzed in-hospital mortality, post-operative quality of life

measures may well be the primary consideration for patients’ and families. In determining

whether attempted operative repair is indicated, our data does not consider the morbidity of

AAAD repair, including prolonged respiratory failure, stroke, renal failure or continued

malperfusion.

Conclusion:

This study suggests a new and potentially profound marker for assessing in-hospital and

one-year mortality after AAAD repair. As serum lactic acid levels are cost-effective and rapidly

obtained preoperatively, this information is an indicator when surgical repair may be futile and

may provide improved prognostic information for patients and families. In addition to external

validation, further studies as to what lactic acidemia represents in the AAAD patient are still

needed.
Figure legends:

Figure 1- Derivation of the 144 patient study cohort

Figure 2- Receiver-operating characteristic curves assessing the predictive ability of lactic acid

levels with mortality

Left- In-hospital mortality; optimal cut-off value 6.0 mmol/L; Right- One-year mortality; optimal

cut-off value 6.9 mmol/L

Figure 3- Cox survival curve of AAAD patients; stratified by lactic acid level

n = 123; P < .001

Dotted lines represent standard error

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Variable Mortalities Survivors Odds 95% CI P
Ratio
Female 4/13 (31%) 44/131 (34%) 0.88 0.26, 3.0 1.0
Black Race 2/13 (15%) 23/131 (18%) 0.85 0.18, 4.1 1.0
Age (yrs) 64.0 (54.3- 57.6 (48.8- 1.02 0.98, 1.06 .48
70.0)(n=13) 69.9)(n=131)
Lactic Acid (mmol/L) 12.1 (6.7- 3.0 (1.8- 1.5 1.3, 1.9 <.001
14.1)(n=13) 5.5)(n=110)
Creatinine (mg/dL) 1.4 (0.8-1.6)(n=12) 1.1 (0.9- 0.83 0.30, 1.34 .61
1.6)(n=116)
SBP (mmHg) 113 (93- 108 (96- 1.004 0.98, 1.02 .69
150)(n=10) 132)(n=106)
Ejection Fraction 50 (35-55)(n=13) 55 (55-60)(n=130) 0.91 0.86, 0.96 .001
Effusion 11/13 (85%) 69/129 (53%) 4.8 1.02, 22.5 .04
Neuro Change 8/13 (62%) 30/129 (23%) 5.3 1.6, 17.4 .006
Severe AR 5/9 (56%) 15/113 (13%) 8.2 2.0, 33.9 .006
CAD 4/11 (36%) 31/110 (28%) 1.5 0.40, 5.3 .73
Debakey I 8/13 (62%) 73/123 (59%) 1.1 0.34, 3.5 1.0
ST Changes 2/11 (18%) 14/109 (13%) 1.5 0.29, 7.7 .64
Cardiopulmonary 4/13 (31%) 8/130 (6%) 6.8 1.7, 26.9 .01
Resuscitation
Limb Ischemia 9/13 (69%) 52/130 (40%) 3.4 0.99, 11.5 .07
Table 1- Bivariate association with in-hospital mortality
Continuous variable data expressed as median (interquartile range). Odds ratios of continuous variables
reflect per unit regressor
CI, confidence interval; BMI, body-mass index; SBP, systolic blood pressure; CAD, coronary artery
disease.
Variable One-Year One-Year Hazard 95% CI P
Mortalities Survivors Ratio
Female 11/25 (44%) 37/119 (31%) 1.1 0.76, 1.5 .64
Black Race 6/25 (24%) 19/119 (16%) 1.1 0.68, 1.6 .74
Age (yrs) 64.0 (53.9 – 57.3 (48.5 – 1.003 0.99, 1.01 .58
72.3)(n=25) 68.9)(n=119)
Lactate (mM) 8.2 (4.4 – 3.0 (1.8 – 1.1 1.0, 1.1 .006
12.6)(n=21) 5.3)(n=102)
Creatinine (mg/dL) 1.4 (0.9 – 1.1 (0.9 – 0.99 0.86, 1.1 .94
1.7)(n=21) 1.5)(n=107)
SBP (mmHg) 102 (85 – 110 (97 – 0.999 0.992, 1.0 .66
127)(n=18) 133)(n=98)
Ejection Fraction 0.99 0.97, 1.01 .15
Effusion 20/25 (80%) 60/117 (51%) 1.2 0.88, 1.7 .24
Neuro Change 13/25 (52%) 25/117 (21%) 1.3 0.89, 1.9 .17
Severe AR 5/20 (25%) 15/102 (15%) 1.1 0.68, 1.8 .63
CAD 7/22 (32%) 28/99 (28%) 1.01 0.68, 1.5 .94
Debakey I 14/25 (56%) 67/111 (60%) 0.99 0.70, 1.4 .95
ST Changes 4/21 (19%) 12/99 (12%) 1.1 0.62, 1.8 .75
Cardiopulmonary 5/25 (20%) 7/118 (6) 1.4 0.73, 2.4 .30
Resuscitation
Limb Ischemia 18/25 (72%) 43/118 (36%) 1.3 0.92, 1.8 .15
Table 2- Univariate Cox regression analysis, censored at one-year
Continuous variable data expressed as median (interquartile range). Hazard ratios of continuous
variables reflect per unit regressor
CI, confidence interval; BMI, body-mass index; SBP, systolic blood pressure; CAD, coronary artery
disease.