Anesth Analg 2002;94:1132-1136
© 2002 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
The Effects of Advanced Age on the Incidence of Supraventricular Arrhythmias After Pneumonectomy in Dogs
David Amar, MD*,
Paul M. Heerdt, MD PhD*,
Robert J. Korst, MD
,
Hao Zhang, MD*, and
Hai Nguyen, VDM
Departments of *Anesthesiology and Critical Care Medicine, Surgery, and Veterinary Medicine, Memorial Sloan-Kettering Cancer Center; and Weill Medical College of Cornell University, New York, New York
Address correspondence and reprint requests to David Amar, MD, Memorial Sloan Kettering Cancer Center, 1275 York Ave., M304, New York, NY 10021. Address e-mail to amard{at}mskcc.org
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Abstract
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Because advanced age is the strongest independent risk factor for the development of supraventricular arrhythmias after lung resection, we compared the incidence and premorbid events of supraventricular arrhythmias after pneumonectomy in young and elderly dogs with the aim of better understanding potential age-related arrhythmogenic mechanisms. Right pneumonectomy was performed in 15 male mongrel dogs ("old" 
8 yr [n = 8], "young" <4 yr [n = 7]) and the electrocardiogram continuously recorded by an implantable telemetry system for 1 wk before euthanizing. After surgery, 7 of 8 older animals (88%) developed a total of 23 episodes of sustained (>30 s) paroxysmal supraventricular tachycardia (SVT), compared with 0 of 7 (0%) young dogs, P = 0.0014. Analysis of heart rate over the 60 min preceding the onset of SVT revealed a progressive increase in sinus rhythm beginning 15 min before the arrhythmia. Comparison of the heart rate and rhythm obtained in younger animals from the corresponding postoperative hour demonstrated that although older animals developed more atrial (P = 0.03) and ventricular premature contractions (P = 0.056) and episodes of nonsustained ventricular tachycardia (P = 0.01), heart rate was similar for both groups until the increase in elderly dogs preceding the onset of SVT. Histologic examination of the atria showed interstitial fibrosis in old but not young animals. In addition, 4 of 8 (50%) elderly animals exhibited an inflammatory response within the atria consistent with acute myo- and epicarditis. We conclude that elderly dogs have an increased supraventricular arrhythmogenic potential within the first week after pneumonectomy than younger animals, perhaps because of increased atrial fibrosis and inflammation. Heart rate analysis before SVT onset suggests that adrenergic predominance was a probable responsible trigger.
IMPLICATIONS: In this canine pneumonectomy model, advanced age was associated with an increased incidence of supraventricular arrhythmias, perhaps because of increased atrial fibrosis and inflammation.
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Introduction
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Morbid supraventricular tachycardia (SVT) and atrial fibrillation (AF) are seen in 6% of elderly patients after noncardiothoracic surgery and in 10%–40% of patients after cardiothoracic operations (1–4). The clinical symptoms, time of onset, and natural course of these arrhythmias are similar whether a patient has had cardiac, thoracic, or other surgery (5). The etiologic mechanisms of postoperative arrhythmias are poorly understood and the optimum method of prophylaxis or treatment is controversial (6,7). Older age is consistently the strongest independent preoperative risk factor associated with postoperative SVT or AF (1–5). Aging causes degenerative changes in atrial anatomy that are accompanied by related changes in atrial physiology such as shorter effective refractoriness, longer sinoatrial and atrioventricular nodal conduction times, atrial stiffening, and splitting of the atrial excitation waveform caused by the pectinated trabeculae (8,9).
In humans, SVT has been reported in up to 17% of patients undergoing major thoracic surgery (2,10,11), with advanced age being the strongest clinical predictor. The understanding of supraventricular arrhythmias in humans has been enhanced by experimental canine models (12), and dogs have been widely used in the study of how aging influences cardiovascular function (13). In the present study, we evaluated age-related differences in the incidence of, and premorbid events preceding, supraventricular arrhythmias after pneumonectomy in canines, with the broad goal of elucidating potentially arrhythmogenic mechanisms.
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Methods
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All experimental procedures used in this investigation were reviewed and approved by the Institutional Animal Care and Use Committee of the Weill Medical College of Cornell University. All dogs were conditioned male mongrels that tested negative for heartworm exposure and had a known date of birth. To increase the yield of persistent supraventricular arrhythmias, dogs weighing 25 kg were sought (14). The primary end point of the study was the spontaneous occurrence of AF or SVT after surgery. AF was defined as an irregular narrow complex tachycardia and no obvious P waves. SVT was defined as a narrow complex tachycardia (>160 bpm) without discernible P waves. Ventricular tachycardia was defined as three or more consecutive, wide-complexes with the ST-T vector pointing opposite to the major QRS deflection at a rate >120 bpm. A sustained arrhythmia was defined as one lasting >30 s. Eight "old" dogs (10 ± 2 yr, 29 ± 2 kg) and 7 "young" dogs (2 ± 1 yr, 26 ± 2 kg) were used for the study. A third group of four uninstrumented young dogs served as controls for histopathologic studies, described below. These dogs had undergone laparotomy as part of an unrelated protocol 1 wk before having their hearts harvested.
Surgical Preparation
After sedation with subcutaneous acepromazine (0.1 mg/kg), all dogs were anesthetized with IV pentobarbital sodium (20 mg/kg), the trachea was intubated, and the lungs were mechanically ventilated. Intraoperative monitoring included electrocardiogram (ECG), pulse oximetry, and noninvasive blood pressure, and anesthesia was maintained with isoflurane in oxygen. Dogs received 20 mL/kg lactated Ringer’s solution IV during the case. Using a sterile technique, a right lateral thoracotomy and pneumonectomy were performed via the fifth intercostal space. The right main pulmonary artery was dissected, isolated, ligated, and divided. Subsequently, both the superior and inferior pulmonary veins were isolated, ligated, and divided. Finally, the right main bronchus was isolated and divided with a standard bronchial stapling device. A 20F chest tube attached to a one-way valve was placed into the chest cavity through a separate stab wound. This catheter allowed drainage of excessive trapped air within the chest as well as monitoring for excessive drainage postoperatively and was removed within 12 h. Bupivacaine 0.25% was administered in the intercostal spaces above and below the incision to total 10–15 mL. A Data Sciences International (DSI, Minneapolis, MN) implantable telemetry monitor was placed under the skin in the right mid-chest area at the end of surgery for postoperative ECG recordings. The chest was then closed in layers. An epidural catheter was inserted at the conclusion of surgery at the T8-9 level and Duramorph® (Elkins-Sinn, Cherry Hill, NJ) 0.1 mg/kg was administered. In addition, at the conclusion of surgery, a 50 µg/h fentanyl patch (Duragesic®; Janssen, Beerse, Belgium) was placed. Anesthesia was discontinued and the animal was allowed to recover in a separate cage until body temperature and vital signs were stable. Twelve hours postoperatively, a second dose of Duramorph® 0.08 mg/kg was given and the catheter was removed. Dogs were encouraged to drink water as tolerated early after surgery and given a regular diet on the next postoperative day. Throughout the entire postoperative period, ECG was continuously monitored with the DSI telemetry implant, which transmits data from the animal to a sensor within 6–8 feet of the animal cage without external wires. All ECG data were saved on a hard disk. At the conclusion of a 1-wk monitoring period, the animals were anesthetized and then euthanized.
Pathologic Studies
The pericardia of all animals were examined for gross signs of pericarditis. Tissue samples were obtained from both atrial free walls and fixed in 10% neutral buffered formalin. A group of four young dogs that had previously undergone a minor intraabdominal operation served as controls. These animals had their hearts harvested 1 wk after their initial operation. Atrial tissues from dogs that had endocardial pacing leads implantation were not examined. Transverse sections were stained with Masson trichrome.
To determine whether dogs have the same incidence of SVT or AF after pneumonectomy as humans, a sample size of 14 animals was needed to detect a >20% incidence of arrhythmia with 95% power. Repeated-measures analysis of variance was used to assess changes in heart rate over time. To compare the incidence of arrhythmias between groups, a Fisher’s exact test was used. Because of non-normal distribution, the number of atrial and ventricular premature contractions were analyzed with the Mann-Whitney test.
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Results
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Heart rate data obtained in all animals from telemetry are shown in Figure 1. There were no differences between groups in postoperative heart rate. Animals were hemodynamically stable during surgery, and intraoperative blood loss ranged between 30–40 mL in all animals. Postoperative complications occurred in two animals. One animal (2 yr of age) died on Postoperative Day 4 from postpneumonectomy pulmonary edema, which was diagnosed on postmortem examination. A second animal (9 yr of age) had developed significant hemorrhage (500 mL) through the chest tube 3 h after surgery. Upon reexploration, no source of bleeding was found and bleeding was presumed to have been secondary to either an intercostal artery injury during chest closure or to an intrathoracic adhesion rupture. This animal was transfused with 350 mL of whole blood taken from another dog and had an uneventful postoperative recovery.
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Figure 1. Resting heart rate data (mean ± SD) obtained in young (circles) and old (triangles) animals throughout the first postoperative week. PREOP = preoperative, OP = operative day, POD = postoperative day.
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After surgery, 7 of 8 (88%) old animals developed a total of 23 episodes of SVT, whereas none of the younger animals experienced this arrhythmia (P = 0.0014, Fisher’s exact test). All the paroxysmal SVT episodes were sustained (mean ± SD, 2.9 ± 2.9 min, range 1–16 min) with a regular ventricular rate (range 160–240 bpm) (Fig. 2). There were 10 episodes of SVT between Postoperative Days 1 to 3 and 13 episodes between Postoperative Days 4 to 6. Ventricular tachycardia occurred postoperatively in 2 of 8 old dogs compared with 0 of 7 young dogs, P = 0.47. One of these old dogs had 6 episodes of ventricular tachycardia ranging in duration from 5 to 18 beats. Transient third degree atrioventricular block was also seen in two older animals but not in young ones.
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Figure 2. Example of a progressive increase in heart rate before onset of paroxysmal supraventricular tachycardia (arrow) at a rate >240 bpm and recorded on Postoperative Day 2.
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Analysis of heart rate over the 60 min preceding the onset of each of the 23 SVT episodes showed a progressive increase in heart rate over the 15 min before the arrhythmia (P < 0.01, Fig. 3). To exclude an effect on heart rate solely caused by surgery, we matched these data to heart rate and rhythm recorded in younger animals from the corresponding 23 postoperative time points, and found that heart rate was the same in both groups until the pre-SVT increase exhibited by elderly animals. During this period, however, despite similarity of heart rate, older animals developed more atrial (10.6 ± 29.6 versus 0.3 ± 0.9, [P = 0.03]) and ventricular (7.5 ± 25.5 versus 0.2 ± 0.5, [P = 0.056]) premature contractions and episodes of ventricular tachycardia (6 of 23 [26%] versus 0 of 23 [0%], [P = 0.01] when compared with younger animals, respectively).
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Figure 3. Heart rate (mean ± SD) obtained in older (triangles) animals during the 60 min before supraventricular tachycardia (SVT) onset compared with the corresponding heart rate of younger (circles) animals matched for the same postoperative time point of the SVT occurrence. There were a total of 23 episodes of SVT. *P < 0.01, old versus young animals, repeated-measures analysis of variance.
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Evaluation of each pericardium on postmortem examination revealed no gross evidence of pericarditis. Representative left and right atrial histologic sections are shown in Figure 4. Elderly animals showed mild-to-moderate degrees of fibrosis consistent with normal aging. A mild-to-moderate inflammatory response consistent with acute myo- and epicarditis was seen in 4 of 8 (50%) older dogs (Fig. 4, C and D). In contrast, control animals without thoracic surgery showed no atrial fibrosis or epicardial inflammatory changes (Fig. 4, A and B).
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Figure 4. Transverse sections of the right atrium (Masson trichrome stain) from a representative young dog (A and B) and an old dog (C and D). Panel D shows moderate atrial fibrosis (large arrow) with accumulation of inflammatory mononuclear and polynuclear cells (small arrows) consistent with acute myo- and epicarditis. Original magnification x200 for panels A and C and x400 for B and D.
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Discussion
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This is the first study to report the incidence of supraventricular arrhythmias after pneumonectomy in dogs and the influence of aging on this complication. Consistent with clinical reports, we found that significantly more elderly animals developed SVT during the first week after surgery (1–6,10,11). The acute increase in heart rate seen immediately before the onset of SVT in older animals suggests that adrenergic predominance is the primary trigger of the arrhythmia. Pathologic examination of atrial sections from all older animals showed mild-to-moderate degrees of fibrosis. In addition, 50% of old dogs showed signs of acute myo- and epicarditis.
Potential Mechanisms of Postoperative Supraventricular Arrhythmias
Although AF is the most common supraventricular arrhythmia after surgery, paroxysmal atrioventricular nodal reentrant tachycardia that is usually initiated by an atrial premature contraction (1–4,15,16) can occur in up to 17% of patients (10,11). Before the SVT paroxysms, we observed an increase in atrial and ventricular ectopy as well as an acute increase in heart rate. These electrophysiologic features all support the presence of adrenergic mechanisms and triggered activity as responsible for initiating SVT (17,18). AF is also caused by reentry of multiple small wavelets that continuously reenter themselves or one another (19,20). Atrial fibrosis or inflammation provides the atrial abnormality for the development of AF in the elderly (20). We observed that older animals had significant atrial fibrosis, which was associated with inflammatory changes in some animals. This intriguing finding probably represents an inflammatory response secondary to indirect atrial trauma during surgery. However, in the absence of a nonoperative elderly control group, we cannot eliminate that these changes are simply attributable to aging.
Most elderly animals developed sustained SVT but none developed AF after surgery. A certain critical atrial mass is necessary to accommodate the multiple wavelets of reentry that promote AF maintenance (12). Thus, it is probable that under normal conditions, even a large dog’s atrial size is still smaller than that of humans and, hence, less likely to fibrillate. In the current investigation, no dog had evidence of pericarditis. It has been postulated that acute postoperative sterile pericarditis is the primary insult to initiate AF after cardiothoracic surgery (21). This has never been proven and in fact disputed because of the extremely small (<1%) incidence of AF in patients who develop acute pericarditis unrelated to surgery (22).
Rationale for Model Design
Dogs were chosen because of the known similarity in cardiac neural anatomy and pathology to that of humans and the extensive electrophysiologic experience using this species (12,23,24). Sparse data have been reported from models of supraventricular arrhythmias in aging canines. Overall conditions of the dog’s teeth or bone age on radiographs are not fully reliable signs of its age. In fact, we had considerable difficulty in obtaining older animals with a reliable date of birth. In contrast to younger animals, the histologic examination of older dogs in the present study showed mild-to-moderate atrial fibrosis consistent with normal aging (25,26). We do not know whether those changes are comparable to those occurring in humans. Furthermore, we did not examine more than two sections of the free walls of the left and right atria. Thus, it is possible that we failed to detect more severe anatomical changes attributed to aging.
To study the changes in basic atrial electrical function caused by pneumonectomy, an animal model without interruption of either the chest or pericardium at baseline is needed. This technique, however, limits the ability to obtain multisite recordings for measuring other regional as well as global changes in atrial effective refractory periods or for measuring dispersion in atrial refractoriness. Other methods that include endocardial lead fixation may produce endocardial trauma or inflammation that would later confound pathologic examination.
In conclusion, older animals developed significantly more episodes of supraventricular arrhythmias after pneumonectomy. The acute increase in heart rate seen immediately before the onset of SVT in older animals suggests adrenergic predominance as the primary trigger of the arrhythmia. The observation of atrial myo- and epicarditis in half of the older animals warrants further investigation. If this observation occurs in humans and is associated with pneumonectomy, it may help to develop novel treatments to prevent or reduce supraventricular arrhythmias after thoracic surgery.
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Acknowledgments
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Financial support was provided departmentally.
We thank Drs. Michael R. Rosen, Columbia University, and Stanley Nattel, Montreal Heart Institute, for their continued guidance and support; Heng Koong, MD, Richard Kang, BS, and Andy The, BS for technical assistance.
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Accepted for publication January 9, 2002.
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Abstract
Introduction
