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Anesth Analg 1999;88:898
© 1999 International Anesthesia Research Society

GENERAL ARTICLES

Perioperative Plasma Endothelin-1 and Big Endothelin-1 Concentrations in Elderly Patients Undergoing Major Surgical Procedures

Joel B. Nelson, MD*, Terry J. Opgenorth, PhD{dagger}, Lee A. Fleisher, MD{dagger},{ddagger}, and Steven M. Frank, MD{dagger}

*Departments of Urology and Oncology, {dagger}Anesthesiology and Critical Care Medicine, and {ddagger}Internal Medicine, The Johns Hopkins University Medical Institutions, Baltimore, Maryland; and {dagger}Abbott Laboratories, Abbott Park, Illinois

Address correspondence and reprint requests to Dr. Joel B. Nelson, Brady Urological Institute, Johns Hopkins Medical Institutions, 4940 Eastern Ave., Baltimore, MD 21224.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Plasma concentrations of the vasoconstrictor endothelin-1 (ET-1) increase during acute physiologic stress, but the role of ET-1 in the pathophysiology of stress remains largely undefined. Whether ET-1 mediates thermoregulatory changes in vasomotor tone is unknown. ET-1 and its more stable precursor, Big ET-1, were measured in plasma obtained at several perioperative time points from 95 consecutive elderly patients (mean age 70 ± 1 yr) randomized to receive either normothermic or hypothermic perioperative care while undergoing major surgical procedures. In the postoperative period, there were no significant changes in plasma ET-1 concentrations, but Big ET-1 concentrations increased considerably (P < 0.0001). There were no significant differences in mean ET-1 or Big ET-1 levels in normothermic and hypothermic patients. Preoperative and postoperative ET-1 concentrations were significantly higher in patients with a history of hypertension (P < 0.002) and in those requiring treatment for postoperative hypertension (P < 0.003). Patients with cancer and those undergoing abdominal surgery had significantly higher Big ET-1 concentrations (P < 0.0001 and P < 0.003, respectively). These data support the hypothesis that Big ET-1 is a more sensitive measure of endothelin system activation after major surgery. Premorbid conditions and location and type of surgery influence perioperative ET-1/Big ET-1 concentrations.

Implications: The endothelin response seems to be significantly associated with perioperative hemodynamic aberrations. The endothelin-1 (ET-1) precursor Big ET-1 is a more sensitive measure of the endothelin system activation in response to surgical stress than ET-1 alone. Thermoregulatory vasoconstriction in response to mild perioperative hypothermia occurs independently of the endothelin system.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Production of the potent vasoconstrictor endothelin-1 (ET-1) increases during severe hemodynamic stress, myocardial ischemia, sepsis, and trauma, which may contribute to the morbidity of these states (1–3). In addition to acute events, plasma ET-1 concentrations are increased in a variety of chronic diseases (4), including advanced atherosclerosis, pulmonary hypertension, congestive heart failure, and cancer (5). Although the exact role of ET-1 in the pathophysiology of these diseases is not clearly defined, a strategy to block ET-1 action in patients with essential hypertension has been significant in decreasing arterial blood pressure (6). What remains to be determined is the role of the endothelin response as a contributor to perioperative hemodynamic changes.

Small changes in body temperature trigger significant changes in vasomotor tone, which are an important component of the thermoregulatory response. Mild hypothermia (35–36°C) is associated with peripheral vasoconstriction (7), which is mediated, in part, by norepinephrine (8), but other neuroendocrine mediators (yet to be identified) may play a role. Perioperative hypothermia results in a significantly longer duration of postoperative systolic hypertension compared with that in normothermic controls (9), and perioperative hypothermia triggers myocardial ischemia (10) and cardiac morbidity in high-risk patients (9).

Surgery provides a unique arena in which to examine the confluence of factors—acute physiologic stress, chronic disease, tissue damage—known to increase plasma ET-1 levels (4). Therefore, in the current study, we measured concentrations of ET-1 and Big endothelin (ET-1) in a well characterized population of elderly patients undergoing major surgical procedures to test the following hypotheses: 1) activation of the endothelin (ET) system in response to surgical stress is best characterized by changes in the more stable Big ET-1 concentrations; 2) maintenance of normothermia results in lower endothelin concentrations in the perioperative period; and 3) premorbid conditions and perioperative hemodynamic changes are associated with the ET system response to surgery.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The 95 patients included in the present study were enrolled consecutively as a subset of a larger study of body temperature and cardiac outcomes previously described in detail (9). This study was performed with approval from the Committee on Clinical Investigation, and written, informed consent was obtained. Briefly, patients were considered for enrollment if they were scheduled for abdominal, peripheral vascular, or thoracic surgery; were >60 yr of age; and were scheduled for postoperative admission to the intensive care unit (ICU). Additional inclusion criteria were either documented coronary artery disease or high risk for coronary artery disease by criteria used in previous perioperative outcome studies (11,12). By definition, a history of hypertension required the use of chronic antihypertensive therapy. Patients were randomized to receive either intraoperative normothermic (forced air warming, n = 48) or hypothermic care (no forced air warming, n = 49). Anesthetic, postoperative care, and hemodynamic monitoring and management were dictated by the study protocol. Limits for arterial blood pressure and antihypertensive therapy were prospectively defined for each patient. Cardiac outcomes (myocardial ischemia, ventricular tachycardia, unstable angina, and cardiac arrest) were detected by continuous Holter monitor by a blinded investigator (LAF).

Perioperative phlebotomy was performed at five time points: preoperatively (before initiation of anesthesia or surgery), immediately postoperatively (on arrival to the recovery room or ICU), 1 h postoperatively, 3 h postoperatively, and during the morning of Postoperative Day 1. Whole arterial blood collected in heparin-containing Vacutainer® tubes (Becton Dickinson, Franklin Lakes, NJ) was placed on ice, and plasma was promptly removed after centrifugation for 5 min and immediately frozen at -86 C° until the endothelin assays were performed.

The ET-1 and Big ET-1 enzyme-linked immunosorbent assay systems (Biomedica, Vienna, Austria) were used for ET-1 and Big ET-1 determinations, respectively. Both assays are designed for direct measurements in human plasma with no extraction necessary. The concentration of ET-1 or Big ET-1 in a sample was determined by computer software-generated interpolation from the standard curve. In every assay, standards and samples were run in duplicate, and the average value was used. All samples from an individual patient were run on the same plate, but all assays were otherwise run in a blinded fashion. Concentrations calculated below the manufacturer-determined lower detection limit of 0.25 pg/mL (for ET-1) and 0.21 pg/mL (for Big ET-1) were considered undetectable.

All dichotomous data were analyzed by {chi}2 or Fisher’s exact tests where appropriate. All data measured over time were analyzed by repeated-measures analysis of variance between and within groups. Post hoc analyses were performed by using Sheffé’s F-test. Data are given as mean ± SEM, and P < 0.05 was used to define significance. Multiple linear regression was performed to determine independent predictors of maximal ET-1 and Big ET-1 responses (defined as the single highest value over the perioperative sampling period). The regression models were sufficient to determine predictors of ET-1 and Big ET-1 maximal responses for demographic and other variables (history of preoperative hypertension, cancer, anesthesia, and postoperative hypotension). When cancer and surgical procedure were both entered into the regression models, however, the models became unstable because the variables were so similar.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Comparing the hypothermic and normothermic groups, there were no significant differences in age; gender; location/type of surgery; history of coronary artery disease, myocardial infarction, diabetes, hypertension; current or past smoking; hypercholesterolemia; or use of ß-blockers or calcium channel blockers (Table 1). Tympanic (core) temperature was significantly different on admission to the ICU between the two groups. There were no significant differences in mean plasma ET-1 or Big ET-1 in normothermic patients (mean core temperature 36.6 ± 0.1°C) compared with hypothermic patients (mean core temperature 35.4 ± 0.1°C) at any time point.


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  		Table 1. Demographic Data
 
No significant increase in mean plasma ET-1 concentrations was observed after surgery (Table 2). In contrast, marked increases in mean plasma Big ET-1 concentrations were seen at all postoperative time points (P < 0.0001). For both plasma ET-1 and Big ET-1, male patients had higher mean concentrations than female patients at all time points, but the differences were not significant by both univariant and multivariant analyses. There were no significant differences for ET-1 and Big ET-1 related to patient age > or <70 yr, history of diabetes mellitus, current or past smoking history, or history of coronary artery disease.


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  		Table 2. Plasma Endothelin-1 (ET-1) and Big ET-1 Concentrations
 
Mean plasma ET-1 concentrations were significantly higher both preoperatively and postoperatively in patients with any history of hypertension (n = 76) compared with patients without a history of hypertension (n = 18) (P < 0.002) (Figure 1). Likewise, patients who required treatment for postoperative hypertension (n = 55) had significantly higher mean preoperative and immediate postoperative plasma ET-1 concentrations compared with patients not requiring such treatment (n = 33) (P < 0.003) (Figure 1).



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  		Figure 1. Increased mean plasma endothelin-1 (ET-1) concentrations in patients with a history of hypertension (n = 76) compared with those without such a history (n = 18) (P < 0.002), and in those patients requiring treatment for hypertension in the immediate postoperative period (n = 55) compared with those who did not (n = 33) (P < 0.003).

 
Patients requiring treatment for postoperative hypotension (n = 11) had lower mean Big ET-1 concentrations compared with patients without hypotension (n = 78) (P < 0.04). None of these patients had evidence of sepsis or postoperative bleeding, and there were no significant differences in estimated blood losses, colloid, crystalloid, or blood administration intraoperatively compared with those without hypotension.

The location and type of surgery correlated with both ET-1 and Big ET-1 concentrations in the perioperative period. Patients undergoing abdominal (n = 39) surgery had significantly higher mean ET-1 and Big ET-1 levels (P < 0.003 and P < 0.0001, respectively) compared with patients undergoing vascular (n = 41) or thoracic (n = 15) procedures (Figure 2). There were no significant differences in mean plasma ET-1 or Big ET-1 levels in patients undergoing general or regional (epidural) anesthesia or in patients who remained intubated postoperatively. There were no significant differences in systolic or diastolic blood pressure in the postoperative period between hypothermic and normothermic patients. There were no differences in plasma ET-1 or Big ET-1 in patients with intraoperative or postoperative evidence of myocardial ischemia (n = 2), ventricular tachycardia (n = 5), unstable angina (n = 1), or cardiac arrest (n = 1).



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  		Figure 2. Increased mean plasma endothelin-1 (ET-1) and Big ET-1 concentrations in patients undergoing abdominal surgery (n = 39) compared with those undergoing vascular (n = 41) or thoracic (n = 15) procedures (P < 0.003 and P < 0.0001, respectively).

 
Patients undergoing surgery for cancer (n = 49) (17 pancreatic, 13 lung, 8 gastric/duodenal, 5 colon, 4 liver, 1 kidney, 1 breast) had significantly higher mean concentrations of Big ET-1 postoperatively compared with patients without cancer (n = 46) (P < 0.0001) (Figure 3). This difference was also significant by multivariant analysis (P < 0.01) (Table 3). None of the patients with cancer were receiving concomitant chemotherapy or radiotherapy. Six patients had preoperative concentrations >2 SD above the mean (ET-1 >5.4 pg/mL, Big ET-1 >8.77 pg/mL); four of those patients had gastrointestinal malignancies.



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  		Figure 3. Increased mean Big endothelin-1 (Big ET-1) concentrations in patients undergoing surgery for cancer (n = 49) compared with those without cancer (n = 46) (P < 0.0001). Insert, corresponding mean endothelin-1 (ET-1) concentrations in cancer patients.

 

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  		Table 3. Multiple Linear Regression for Predictors of Maximal Endothelin-1 (ET-1) and Big ET-1 Responses
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The marked differences in ET-1 and Big ET-1 in this study support the hypothesis that ET system activation in response to surgical stress is best determined by studying the considerably more stable peptide precursor Big ET-1. The circulating half-life of ET-1 is 3.5 min (13), whereas the considerably less potent Big ET-1 has a circulating half-life of 23 min (14). Furthermore, ET-1 secretion by endothelial cells is preferentially abluminal, acting on underlying vascular smooth muscle (15) where it is avidly bound; circulating ET-1 levels may greatly underestimate local concentrations. These data also support the conclusions of a Big ET-1 metabolism study performed in healthy volunteers (14).

The present study is consistent with previous reports of ET-1 concentrations in the perioperative period; however, other investigators only measured ET-1 concentrations and/or included small (n < 12) samples (16–21). In all studies, plasma ET-1 system concentrations peaked between 1 and 12 h in the immediate postoperative period, when the incidence of perioperative cardiac events is highest. Although it is certainly possible that a portion of the ET-1 and Big ET-1 detected resulted from local endothelial damage or tissue ischemia, the differences observed among patients undergoing abdominal, vascular, and thoracic operations indicate that other mediators of ET-1 system activation are also present. Because the abdominal surgery subgroup was comprised primarily of patients undergoing cancer surgery, it is possible that tumors contributed to the preoperative ET-1 and Big ET-1 concentrations in that subgroup.

The administration of a mixed endothelin receptor antagonist, bosentan, to patients with essential hypertension significantly lowered blood pressure, which suggests that ET-1 may contribute to increased blood pressures in such patients (6). Despite rare cases of dramatic improvements in blood pressure after the resection of malignant, ET-1–secreting hemangioendotheliomas (22) and other studies positively associating increased ET-1 and hypertension (23), increased circulating ET-1 concentrations have not been universally shown to correlate with arterial hypertension (24). In the present study, however, preoperative and postoperative plasma ET-1 concentrations were significantly different in chronically normotensive and hypertensive patients. Furthermore, patients who required treatment for postoperative hypertension also had significantly higher plasma ET-1 concentrations preoperatively and immediately postoperatively. The parallel finding—lower ET-1 and Big-ET-1 concentrations in patients with hypotension—is compelling and raises the possibility of a defect in the normal stress-induced ET system response.

In patients with or at risk of coronary artery disease, the maintenance of perioperative normothermia is associated with a reduced incidence of morbid cardiac events (9). Because hypothermia and ET-1 are both associated with vasoconstriction, it is possible that patients randomized to hypothermia would also have higher ET-1/Big ET-1 concentrations. From the data presented herein, however, there does not seem to be a significant association between the thermoregulatory response and the ET system.

We have previously shown that prostate cancer cells produce ET-1 and that increased concentrations of immunoreactive ET-1 were detected in men with advanced prostate cancer (5). Others have shown similar increases in patients with a variety of solid gastrointestinal malignancies (25). In this study, a subset of patients with gastrointestinal malignancies had the highest preoperative ET-1 and Big ET-1 concentrations, which supports the hypothesis that malignant tumors produce ET-1. In most cancer patients, however, it seems that the response associated with major exenterative and reconstructive gastrointestinal procedures led to the increased ET system concentrations observed.

In summary, these data support the hypothesis that Big ET-1 is a more sensitive measure than ET-1 alone of ET system activation in response to surgical stress or tissue damage. Premorbid conditions and location and type of surgery seem to influence perioperative ET-1/Big ET-1 concentrations. Hemodynamic changes (i.e., perioperative hypertension and hypotension) are associated with endothelin system activity.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Cernacek P, Stewart DJ. Immunoreactive endothelin in human plasma: marked elevations in patients in cardiogenic shock. Commun 1989;161:562–76.
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Accepted for publication December 21, 1998.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press