Electrocardiographic Characteristics of Potential Organ Donors and Associations With Cardiac Allograft UseClinical Perspective
Background—Current regulations require that all cardiac allograft offers for transplantation must include an interpreted 12-lead electrocardiogram (ECG). However, little is known about the expected ECG findings in potential organ donors or the clinical significance of any identified abnormalities in terms of cardiac allograft function and suitability for transplantation.
Methods and Results—A single experienced reviewer interpreted the first ECG obtained after brain stem herniation in 980 potential organ donors managed by the California Transplant Donor Network from 2002 to 2007. ECG abnormalities were summarized, and associations between specific ECG findings and cardiac allograft use for transplantation were studied. ECG abnormalities were present in 51% of all cases reviewed. The most common abnormalities included voltage criteria for left ventricular hypertrophy, prolongation of the corrected QT interval, and repolarization changes (ST/T wave abnormalities). Fifty-seven percent of potential cardiac allografts in this cohort were accepted for transplantation. Left ventricular hypertrophy on ECG was a strong predictor of allograft nonuse. No significant associations were seen among corrected QT interval prolongation, repolarization changes, and allograft use for transplantation after adjusting for donor clinical variables and echocardiographic findings.
Conclusions—We have performed the first comprehensive study of ECG findings in potential donors for cardiac transplantation. Many of the common ECG abnormalities seen in organ donors may result from the heightened state of sympathetic activation that occurs after brain stem herniation and are not associated with allograft use for transplantation.
Organ Procurement Transplant Network regulations require that all cardiac allograft offers must include, among other data, an interpreted 12-lead electrocardiogram (ECG; Organ Procurement Transplant Network policy 18.104.22.168). However, little is known about the expected ECG findings in potential organ donors or the clinical significance of any identified abnormalities in terms of cardiac allograft function and suitability for cardiac transplantation. ST segment elevation or depression, T wave inversion, a prolonged QT interval, abnormal U waves, and voltage criteria for left ventricular hypertrophy (LVH) have been observed in patients with subarachnoid hemorrhage and traumatic brain injury—2 common causes of brain death in potential organ donors.1–6 Small studies comparing donor and recipient ECGs suggest reversal of pathological findings after transplantation such as shortening of the QT interval7 and reduction in voltage in the precordial leads,8 suggesting that at least some ECG changes noted after brain death may be transient and of little prognostic significance for allograft function and posttransplant outcomes.
Clinical Perspective on p 483
Large working groups have attempted to standardize cardiac allograft acceptance criteria in terms of donor echocardiogram findings and to clarify indications for pulmonary artery catheter use and hormonal therapy,9 but the role of the ECG in donor evaluation has not yet been formally evaluated. The purposes of this study were to (1) describe ECG findings in a large, contemporary cohort of brain-dead organ donors; (2) explore the relationship between donor ECG and echocardiogram findings; and (3) explore the relationship between ECG findings and cardiac allograft use.
Approval for this study was obtained from the California Transplant Donor Network Institutional Review Board. The medical records of all brain-dead organ donors managed by the California Transplant Donor Network between January 1, 2002, and December 31, 2007, were retrospectively reviewed for the first 12-lead ECG obtained after brain stem herniation. Donors <14 years and >65 years of age were excluded, because their hearts were unlikely to be used for adult heart transplantation. Standard demographic data (eg, sex, age, height, weight, cause of death), clinical data (laboratory values, inotrope use, echocardiogram findings), and data on cardiac allograft use were obtained from chart review.
During the 6-year time period studied, all brain-dead organ donors at the California Transplant Donor Network were managed according to a standardized protocol that included: methylprednisolone administered at the onset of donor management and until organ procurement (15 mg/kg every 12 hours); dopamine as the first-line inotropic agent (maximum 20 µg/kg/min); phenylephrine as the second-line vasoactive agent (maximum 300 µg/min); intravenous fluid and/or loop diuretic administration to obtain a goal central venous pressure of 5 to 8 mm Hg and a urine output of >30 mL/h; electrolyte repletion to achieve normalization of potassium, phosphorous, magnesium, and calcium levels; empirical antimicrobial therapy with vancomycin and levofloxacin; and inhaled, nebulized albuterol (2.5 mg every 4 hours). Vasoactive and inotropic medications were titrated according to pulmonary artery catheter readings to achieve a target systemic vascular resistance of 800 to 1200 dynes-seconds/cm5 and cardiac index >2 L/min/m2. Esmolol infusions were initiated for tachycardia that was deemed unrelated to β-agonist infusion and were discontinued on initiation of organ procurement. Thyroid hormone (levothyroxine) was administered when requested by the accepting transplant centers.
All donor 12-lead ECGs were read and interpreted by a single experienced reviewer (B.J.D.). This reviewer was blinded to the donor’s clinical data except for age, sex, and potassium level at the time of ECG procurement. Standard ECG criteria were used to diagnose cardiac rhythm, atrial and ventricular ectopy, right and left bundle branch block, anterior and posterior fascicular block, and right and left atrial and ventricular hypertrophy. Q waves of prior myocardial infarction and ST-T wave abnormalities indicative of acute myocardial injury were defined by the Joint European Society of Cardiology and American College of Cardiology universal criteria for myocardial infarction.10 These criteria included: (1) ST-segment elevation at the J-point with cutoff points of ≥0.2 mV in men or ≥0.15 mV in women in leads V2 to V3 and/or ≥0.1 mV in other leads; (2) horizontal or downsloping ST-segment depression of ≥0.1 mV; and (3) T wave inversion of ≥0.1 mV. If any of these ECG criteria were present in 2 contiguous leads, a diagnosis of acute myocardial injury/infarction was made. Contiguity in the limb leads was defined by the Cabrera sequence of aVL, I, inverted aVR, II, aVF, and III.
Donor ECG characteristics were summarized as means (±SD) or percentages. Comparisons of ECG findings between transplanted and nontransplanted hearts were performed using Student t test for continuous variables and the χ2 test for categorical variables. Multivariable logistic regression analyses were used to explore associations between donor ECG findings and cardiac allograft acceptance for transplantation, adjusting for donor age, sex, cause of death, race, height, blood type, and diagnosis of hypertension, diabetes, or coronary artery disease.
For each donor ECG, ST segments, T waves, and Q waves were defined as abnormal if an abnormality was seen in one or more of the 12 leads. We then tested for associations between these ECG abnormalities and allograft use in a series of 3 models: (1) a simple univariate model; (2) a multivariable logistic regression model adjusting for donor demographic variables that may impact graft use decisions (age, sex, race, and cause of death); and (3) a multivariable logistic regression model that added echocardiographic abnormalities (left ventricular dysfunction, regional wall motion abnormalities, and left ventricular hypertrophy.
Statistical analyses were performed using Stata Version 9 (StataCorp LP, College Station, TX).
A total of 1569 donors were managed by the California Transplant Donor Network between January 1, 2002, and December 31, 2007, and 1085 had stored ECGs available for analysis. Fourteen donors were excluded because their ECGs were of poor quality or had missing leads (eg, 2–3 lead rhythm strips only). After excluding 68 donors <14 years and 21 donors >65 years of age, 980 ECGs were included in the final study cohort. There were 391 donors in the overall California Transplant Donor Network cohort who were 14 to 65 years of age and did not have stored ECGs available for interpretation. These donors were older and had a higher incidence of hypertension, diabetes, and coronary artery disease compared with donors with ECGs (Supplemental Table I in the online-only Data Supplement). They were less likely to receive hormonal therapy during the donor management period, and their hearts were less likely to be used for transplantation.
The characteristics of the donor cohort are summarized in Table 1. Mean donor age was 38 ± 14 years, and 63% were male. The most common causes of death were cerebrovascular (including subarachnoid hemorrhage and ischemic stroke [47%]) followed by head trauma (43%) and anoxia (9%). Twenty-six percent of donors had a history of hypertension, and 28% had a history of cocaine or methamphetamine use. One third of donors had an elevated serum troponin level, defined in this study as a peak level ≥1.0 µg/L, given the variety of assays (sandwich and immunoenzymatic) from multiple manufacturers used at different donor hospitals.
Ninety-three percent of donors in this cohort had at least one echocardiogram, and 16.5% had one or more additional echocardiograms based on the discretion of the treating clinician. Associations between the ECG and first donor echocardiogram were studied. The median time elapsed between the ECG and echocardiogram was 98 minutes (interquartile range, 29–498). The mean left ventricular ejection fraction was 62%±12%. Slightly more than half of donors had left ventricular hypertrophy (defined as left ventricle septal or posterior wall thickness >1.1 cm) and 20% had left ventricular regional wall motion abnormalities.
When comparing clinical characteristics of donors whose hearts were or were not accepted for transplantation, we found that donors who died of cerebrovascular causes; who had a history of hypertension, diabetes, or coronary artery disease; or who had an elevated serum troponin level were less likely to be cardiac organ donors.
Characteristics of Donor ECGs
ECG findings after brain death are summarized in Table 2. Mean heart rate was 102 ± 20 beats/min, and 97% were in sinus rhythm. One or more ECG abnormalities were present in 51% of the ECGs studied. Atrial and ventricular ectopy were rare as were atrioventricular block, conduction delays (including right and left bundle branch block), and fascicular block.
A notable finding was prolongation of the corrected QT interval (QTc); the mean QTc was 449 ± 48 ms. Twenty-one percent of donors had QTc >480 ms and 15% had QTc >500 ms. QT prolongation was significantly associated with cause of death: 28% of donors who died of cerebrovascular causes had a QTc >480 ms compared with 23% of donors who died from anoxia, 20% of those who died from central nervous system tumors, and 14% of those who died from head trauma (P<0.001). This finding was more common in female donors (OR, 2.7; 95% CI, 2.0–3.7; P<0.001) compared with males. Among donors dying of cerebrovascular causes, 38% of females had a QTc >480 ms and 28% had QTc >500 (versus 19% and 13% for males, respectively, P<0.001). Prolongation of the QTc interval was associated with lower serum potassium levels. The mean serum potassium level was 4.0 ± 0.6 mmol/L in donors with QTc <480 ms and 3.7 ± 0.5 mmol/L in donors with QTc ≥480 ms (P<0.0001).
Also of note was the high prevalence of voltage criteria for LVH, present in 8% of potential organ donors. This finding was significantly more common in donors who died of cerebrovascular causes (14.7%) compared with those who died of head trauma (2.6%) or anoxia (1.1%; P<0.001) even after adjusting for donor history of hypertension (OR, 10.9; 95% CI, 1.5–80.5; P=0.02).
Finally, repolarization changes were present in 22% of the donor ECGs examined. Two percent of donor ECGs met criteria for pathological ST elevations, 10% of donor ECGs demonstrated significant ST depressions, and 12% had significant T wave inversions, whereas 18% had nonspecific ST-T wave abnormalities. Q waves suggestive of prior myocardial infarction were found in 7% of donor ECGs. Overall, 51% of donor ECGs were classified as “abnormal” due to one or more of these findings.
Correlations Between Donor ECG and Echocardiographic Findings
LVH was present on 8% of donor ECGs and 54% of echocardiograms. Given this disparity, LVH on ECG was found to have high specificity (97%) for increased left ventricular wall thickness but low sensitivity (11%). The presence of LVH on ECG increased the odds of increased left ventricular wall thickness by 3.5-fold (95% CI, 1.9–6.6; P<0.001).
The finding of an elevated serum troponin level ≥1.0 µg/L was not associated with repolarization abnormalities on ECG as defined by the presence of significant ST elevations, ST depressions, or T wave inversions. Specifically, having an elevated troponin level increased the odds of repolarization abnormalities by only 1.3-fold (95% CI, 0.9–1.7; P=0.2) and had a sensitivity of 38% and a specificity of 67% for the presence of significant ST-T wave abnormalities.
Finally, the presence of pathological Q waves on ECG had a high specificity for reduced left ventricular ejection fraction (defined as left ventricular ejection fraction <50%, specificity=97%) and left ventricular regional wall motion abnormalities (specificity=96%), albeit sensitivity was low (12% for reduced left ventricular ejection fraction, 15% for regional wall motion abnormalities).
Donor ECG Findings and Cardiac Allograft Use for Heart Transplantation
Fifty-seven percent (N=560) of donor allografts in this cohort were accepted for heart transplantation. The results of multivariable analyses examining associations between donor ECG predictors and cardiac allograft use are presented in Table 3. These models were adjusted for donor age, sex, cause of death, blood type, race, height, and diagnosis of hypertension, diabetes, and coronary artery disease. Our analyses demonstrate that prolongation of the PR and QRS intervals are associated with decreased allograft use. Specifically, for every 10-ms increase in the PR interval, the odds of allograft use decreases by 10% (OR, 0.9; 95% CI, 0.84–0.98; P=0.01). Similarly, for every 10-ms increase in the QRS interval, the odds of allograft use decreases by 18% (OR, 0.82; 95% CI, 0.72–0.93; P=0.002). Notably, prolongation of the QT interval was not associated with reduced allograft use after adjusting for relevant covariates.
As a general category, repolarization abnormalities on ECG (defined as the presence of pathological ST elevations, ST depressions, and/or T wave inversions) were not associated with reduced allograft use; however, changes in individual leads did reveal significant associations. Specifically, ST segment changes in leads I, V1, V2, and V3 and T wave inversions in leads I, II, and aVR were associated with reduced allograft use. Finally, the presence of pathological Q waves in leads V1 and V2, suggestive of prior anteroseptal myocardial infarction, were also associated with reduced allograft use. When grouped by the presence of any ST segment, T wave, or Q wave abnormality on the 12-lead ECG, pathological Q waves and T wave inversions were associated with allograft nonuse in unadjusted models. However, after adjusting for donor demographic variables, these results were attenuated toward the null with only pathological Q waves remaining associated with nonuse. Finally, after adjusting for echocardiographic abnormalities (left ventricular ejection fraction <50%, regional wall motion abnormalities, and LVH), no significant associations between ECG repolarization abnormalities and allograft use remained (Table 4).
Finally, voltage criteria for LVH on the 12-lead ECG was a strong predictor of allograft nonuse. Specifically, the presence of LVH reduced the odds of graft acceptance for transplantation by 77% (univariate OR, 0.23; 95% CI, 0.13–0.38; P<0.001). This association remained highly significant after adjusting for donor demographic variables and echocardiographic abnormalities (multivariate OR, 0.36; 95% CI, 0.18–0.72).
We have presented the first large-scale study describing ECG characteristics after brain death in potential organ donors. Using a well-characterized cohort of almost 1000 potential donors, we have described typical ECG findings, correlations between abnormalities seen on ECG and echocardiography, and associations between ECG findings and cardiac allograft use for transplantation. A notable finding of this study was the relatively high proportion of donor ECGs that met voltage criteria for LVH. This abnormality was found in 8% of all donor ECGs and 10% of the ECGs of donors aged 30 to 39 years. In contrast, only 2.7% of healthy men aged 30 to 39 years enrolled in the Manitoba Heart Study, a prospective cohort study of cardiovascular disease in Canadian air force pilots, demonstrated ECG voltage criteria for LVH.11 Similarly, at most, 1.3% of men aged 35 to 39 years in the original Framingham Heart Study had “definite” LVH and another 3.4% had “possible” LVH on ECG.12 We hypothesize that many brain-dead organ donors who meet voltage criteria for LVH may actually have transient myocardial edema resulting from the dramatic physiological changes that occur after brain death. The physiological changes after brain death have been well described and likely represent a multifactorial process resulting from activation of the sympathetic nervous system, diffuse loss of vasomotor tone, endothelial dysfunction, and hormone depletion.13,14 Classic baboon studies have demonstrated that the initial Cushing reaction that accompanies brain stem herniation results in direct myocardial injury. Within minutes after brain death, an “autonomic storm” occurs15 in which serum epinephrine levels increase by 1100%, norepinephrine by 300%, and dopamine by 200%.16,17 These processes result in interstitial myocardial edema18 that may mimic myocardial hypertrophy.19 Fortunately, these myocardial changes are often transient,20 suggesting that the presence of LVH on donor ECGs does not necessarily represent pathological left ventricular remodeling and should not, in and of itself, exclude a graft from acceptance for transplantation.
Another common feature of donor ECGs was that of a prolonged QTc interval. Etiologies for QTc prolongation in this setting include sympathetic stimulation and autonomic dysregulation, especially because the autonomic nervous system is an important modulator of ventricular repolarization.21 Another contributing factor may be hypokalemia, which is often observed after brain death and may be due to catecholamine-induced stimulation of a β-adrenergic receptor linked to membrane Na+/K+-ATPase22,23 or acquired diabetes insipidus.24,25 In this study, we did find significantly lower serum potassium levels in donors with QTc prolongation, and QTc prolongation was not associated with reduced allograft use. Of interest is a study performed on 112 heart transplant donor:recipient pairs demonstrating shortening of the QTc interval after transplantation.7 An exception worth mentioning may be cases of genetic long QT syndromes. These cases may be identified by markedly prolonged QTc intervals pretransplant in donors with an unexplained mechanism of death. In such a scenario, the transplant recipient may be at heightened risk of cardiac arrhythmias.
A final common feature of donor ECGs is that of repolarization abnormalities, which include significant ST elevations, ST depressions, and T wave inversions. These findings were present in approximately 20% of donor ECGs, which is higher than one may expect given the relatively young age and lack of cardiovascular disease in the general organ donor population. Once again, these ECG changes may reflect the exaggerated state of sympathetic activity that occurs after brain stem herniation that may result in direct myocardial injury. Endomyocardial biopsy specimens in this setting have shown contraction band necrosis or histological evidence of microinfarction secondary to catecholamine-mediated calcium overload.16 In some cases, these physiological changes may result in frank left ventricular dysfunction and elevated serum troponin levels.20,26,27 Prior studies, however, have demonstrated reversibility of left ventricular dysfunction during tailored donor management20,28 and a lack of association between elevated donor troponin levels and recipient posttransplant outcomes.27 These studies, among others, suggest that ST-T wave changes should not preclude acceptance of a cardiac allograft for transplantation. It may, in fact, be prudent to repeat the ECG after a period of hemodynamic stability. Caution should be taken, however, when Q waves consistent with prior myocardial infarction are seen on ECG, because this finding has high specificity for the presence of left ventricular dysfunction and regional wall motion abnormalities on echocardiography. Although we were unable to retrospectively determine the cause of allograft nonuse in this study, we did demonstrate that ECG abnormalities were no longer predictive of use after adjusting for echocardiographic abnormalities; this finding suggests that the echocardiogram, when available, plays a larger role in allograft acceptance decisions.
Several limitations of this study deserve mention. We analyzed the first donor ECG obtained after brain stem herniation. The time interval between brain stem herniation and ECG acquisition ranged from minutes to several hours; this may represent an important confounder, because the donor physiological state after herniation may change significantly over time. We also know that ECG changes are often dynamic and may be influenced by concomitant medications and treatments. For example, administration of QT-prolonging drugs (such as quinolone antibiotics and antiarrhythmics) may have accounted for some cases of QT prolongation seen in this cohort. Another limitation is the lack of data on the reason for allograft nonuse. Cardiac allograft acceptance for transplantation is a complex decision in which multiple donor and recipient factors are weighed by the accepting physician or surgeon. We are unable to retrospectively determine the extent to which the donor ECG influenced individual decisions. Finally, donor echocardiograms were interpreted at local hospitals and were not centrally reviewed; we therefore cannot verify the accuracy of echocardiogram interpretation and measurements.
Abnormal ECG findings are common after brain death and are present in over half of potential organ donors. We combined the strengths of a well-characterized cohort of 980 organ donors with central ECG interpretation to describe common ECG abnormalities after brain death and to explore the associations between these findings and allograft use. The predominant ECG abnormalities identified may result from the massive sympathetic activation that occurs after brain stem herniation and in most cases are not associated with allograft use for transplantation.
We thank the California Transplant Donor Network staff and volunteers for access to the donor data and electrocardiograms required for this study.
Sources of Funding
This study was supported by grants from the American Heart Association (0865249F, K.K.K.), the National Heart, Lung, and Blood Institute (K23HL091143, K.K.K.), and the Victoria University of Wellington Research Fund (R.M.).
The online-only Data Supplement is available in this article at http://circheartfailure.ahajournals.org/lookup/suppl/doi:10.1161/CIRCHEARTFAILURE.112.968388/-/DC1.
- Received November 2, 2011.
- Accepted May 15, 2012.
- © 2012 American Heart Association, Inc.
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Current regulations require organ procurement organizations to obtain a 12-lead electrocardiogram (ECG) on all potential cardiac organ donors. However, little is known about expected ECG findings after brain death, which represents a unique physiological state of massive sympathetic activation, nor about the association between ECG changes and graft acceptance by the recipient team. We reviewed the first ECG obtained after brain stem herniation in a cohort of 980 potential organ donors managed by the California Transplant Donor Network from 2002 to 2007 to describe common ECG findings in organ donors and to explore the relationship among ECG abnormalities, echocardiographic findings, and graft acceptance for heart transplantation. We determined that abnormal ECG findings were present in over half of potential organ donors. Voltage criteria for left ventricular hypertrophy, prolongation of the corrected QT interval, and repolarization changes (ST/T wave abnormalities) were common. Left ventricular hypertrophy on ECG had a low sensitivity (11%) but high specificity (97%) for increased left ventricular wall thickness on echocardiogram and predicted nonuse of the donor heart for transplantation (OR, 0.23; P<0.001). QT interval prolongation and repolarization changes were not associated with graft use. In summary, ECG abnormalities are common in the organ donor population. In many cases these abnormalities may reflect physiological changes that occur after brain death.