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Treatment with β-Blockers and Incidence of Post-Traumatic Stress Disorder After Cardiac Surgery: A Prospective Observational Study
Treatment with  -Blockers and Incidence of Post-Traumatic Stress Disorder After Cardiac Surgery: A Prospective Observational Study Lorenzo Tarsitani, MD, PhD,* Vincenzo De Santis, MD,† Martino Mistretta, MD,* Giovanna Parmigiani, MD,* Giulia Zampetti, MD,† Valentina Roselli, MD,* Domenico Vitale, MD,† Luigi Tritapepe, MD,† Massimo Biondi, MD, PhD,* and Angelo Picardi, MD‡ Objective: The aim was to investigate perioperative factors associated with the development of post-traumatic stress disorder (PTSD) in patients who underwent cardiac surgery. Design: Prospective observational study. Setting: Single academic center. Participants: One hundred twenty-eight consecutive patients scheduled for elective cardiac surgery with cardiopulmonary bypass. Interventions: Patients were interviewed within the surgical unit 1 to 3 days before cardiac surgery. Measurements and Main Results: Six months after surgery, participants were mailed the modified version of the Posttraumatic Stress Symptom Inventory 10. Of the 71 patients who completed the questionnaire and mailed it back at follow-up, 14 (19.7%) received a diagnosis of PTSD. Seven
of 13 female patients who were not treated with -blockers received a diagnosis of PTSD compared with 0 of 12 who were treated with -blockers (p ⴝ 0.005, Fisher exact test). In a general linear model, including sex and -blocker treatment as predictors, the Posttraumatic Stress Symptom Inventory 10 score was significantly predicted by -blockade (F ⴝ 4.74, p ⴝ 0.033), with a significant interaction between sex and -blockade (F ⴝ 9.72, p ⴝ 0.003). Conclusions: These findings suggest that the use of -blockers might be protective against the development of PTSD in women after cardiac surgery. © 2012 Elsevier Inc. All rights reserved.
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that -blocker treatment might be associated with a decrease in the risk of developing PTSD after cardiac surgery.
OST-TRAUMATIC STRESS DISORDER (PTSD) is a severely debilitating mental disorder that develops after the experience of a traumatic event. Clinical manifestations include intrusive recollections (eg, nightmares or flashbacks), avoidance of reminders of the trauma, and a variety of anxiety symptoms.1 The disorder is a frequent complication in critically ill and surgical patients treated in the intensive care unit (ICU).2-4 Cardiac surgery with cardiopulmonary bypass represents a severe source of stress because it combines the effects of critical illness, the ICU stay, and traumatic experiences, such as pain or respiratory failure. Five studies conducted 5 to 12 months after cardiac surgery reported prevalence estimates of PTSD ranging from 15% to 25%.5-9 Importantly, the development of PTSD after cardiac surgery is associated with a significant disability that might greatly decrease the benefits of surgery.5 Several pharmacologic agents have been proposed for the secondary prevention of PTSD.10 Based on a considerable body of preclinical findings from animal experiments and studies in healthy subjects, it was theorized that the administration of -blockers shortly after a traumatic event interferes with memory formation and the consolidation of the traumatic experience, can decrease the impact of the emotional valence of memories, and thus might prevent the development of PTSD.10,11 However, the results from trials using these agents in the aftermath of a traumatic event are contradictory: 2 studies11,12 found no significant differences in the rates of PTSD development in subjects treated with -blockers, whereas 1 study13 found lower PTSD rates in 11 emergency room patients treated with propranolol compared with 8 patients who refused this agent but agreed to be followed prospectively. Beta-blockers commonly are used in patients undergoing cardiac surgery; however, only Krauseneck et al14 performed a prospective observational study in cardiac surgical patients and found lower scores of PTSD symptoms only in women treated with metoprolol 6 months after the procedure. The present investigation was conducted to identify the perioperative factors associated with the development of PTSD in patients who underwent cardiac surgery. Specifically, this study tested the hypothesis
KEY WORDS: post-traumatic stress disorder, cardiac surgery, -blockers
METHODS The study was performed from January 2006 through January 2008 by the department of cardiac surgery in a large Italian academic hospital. Before enrollment, all patients received a complete explanation of the purpose of the study and gave written informed consent to participate. Adult inpatients who were candidates for on-pump coronary artery bypass grafting and/or valve surgery were considered for inclusion in the study. The following exclusion criteria were applied during recruitment: history of psychiatric disorders, clinically evident cognitive impairment, emergency surgery, ICU treatment (except brief stays in coronary care units) in the previous 24 months, previous cardiac surgery, and a diagnosis of PTSD according to the modified version of the Posttraumatic Stress Symptom Inventory 10 (PTSS-10; see below). In total, 128 inpatients were enrolled in the study. All patients were interviewed within the surgical unit by 1 of 2 qualified examiners 1 to 3 days before surgery. Medical history and demographic information were collected with a study-specific form and were abstracted from medical records. Clinical data and treatment characteristics included surgery type, New York Heart Association class, ejection fraction, duration of surgery and of cardiopulmonary bypass, -blocker and inotropic drug administration, anesthetic dosage, length of mechanical ventilation, and ICU length of stay. The patients treated with -blockers received the medication preoperatively, postoperatively, and at discharge from the hospital. The -blockers used were carvedilol, atenolol, and metoprolol at standard dosages. A stan-
From the Departments of *Neurology and Psychiatry and †Anesthesia and Intensive Care, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy; and the ‡Italian National Institute of Health, Center of Epidemiology, Surveillance and Health Promotion, Mental Health Unit, Rome, Italy. Address reprint requests to Vincenzo De Santis, MD, Viale del Policlinico 155, 00161 Rome, Italy. E-mail: vincenzo.desantis@ uniroma1.it © 2012 Elsevier Inc. All rights reserved. 1053-0770/2602-0015$36.00/0 doi:10.1053/j.jvca.2011.09.011
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dardized anesthesia and postoperative sedation protocol was used for all patients. Anesthesia was induced with a target-controlled infusion of propofol (site effect) 1.6 to 1.8 g/mL, sufentanil 0.35 to 0.5 g/kg, and rocuronium 0.6 mg/kg. After tracheal intubation, the lungs were ventilated mechanically with an oxygen-air mixture (fraction of inspired oxygen 40%). Anesthesia was maintained with propofol (site effect) 1.6 to 2.2 g/mL, sufentanil 0.35 g/kg/h, and supplemental boluses of rocuronium. Six months after surgery, patients were contacted by telephone, were again explained the study and its aims, and were asked to confirm verbally the informed consent they had provided in writing before the surgery. All those who accepted were mailed the PTSS-10.15 This instrument is composed of 2 different parts. Part A explores traumatic memories from ICU treatment, defined by Stoll et al15 as a patient’s subjective memories of respiratory distress/dyspnea, a feeling of severe anxiety/panic, severe pain, or nightmares at any time during ICU treatment. Patients are asked to answer each item simply with “yes” or “no,” independent of the number of occasions the adverse experience occurred. Part B evaluates 10 common PTSD symptoms: sleep disturbance, nightmares, depression, hyperalertness, withdrawal, generalized irritability, frequent changes in mood, guilt, fear or avoidance reactions with regard to the ICU, and increased muscle tension. Each item is scored on a 7-point scale and the total score ranges from 10 to 70 points. Scores ⱖ35 on Part B predict a diagnosis of PTSD with a high sensitivity (77%) and specificity (97.5%).15 The PTSS-10 has been validated in long-term survivors of the ICU,15,16 and it is a widely used self-reported tool in patients after critical illness.5,9,14,17,18 Part B of this instrument was administered to all patients before the intervention to exclude patients with scores ⱖ35 from the study. After 6 months, each participant completed the questionnaire and mailed it back to the researchers in a prestamped, preaddressed envelope. All analyses were performed with SPSS 17.0 (SPSS, Inc, Chicago, IL). All statistical tests were 2-tailed, with an ␣ value set at 0.05. The 2 test (with Yates correction for 2 ⫻ 2 tables) and the Student t test for independent samples were used as appropriate to test for differences between groups in categoric and continuous variables, respectively. Generalized linear modeling was used to test for the independent effect of relevant predictors on PTSS-10 score and to test for the interaction among predictors.
RESULTS
One hundred twenty-one patients (94% of candidates for elective cardiac surgery who met the study inclusion criteria) actually underwent surgery. Two patients who refused surgery and 5 who were deemed not suitable for surgery were excluded from the study. Seventy-one (59%) were assessed after 6 months. Three patients (2%) died during the study period, 28 (23%) were unreachable by telephone after multiple attempts, and 19 (16%) had to be excluded from the study because of missing or incomplete questionnaires. There were no significant differences in baseline demographic and clinical characteristics between the subjects who completed and those who did not complete the study at the 6-month follow-up (Table 1). Fourteen subjects (19.7%) scored ⱖ35 on the PTSS-10 at the 6-month follow-up and were considered as having a probable diagnosis of PTSD. The mean PTSS-10 total score and the PTSS-10-based diagnosis of PTSD did not differ by demographic, clinical, and treatment characteristics (Table 2). Given the finding of higher mean PTSS-10 scores at baseline (20.8 ⫾ 7.2 v 15.9 ⫾ 6.3, F1,69 ⫽ 8.7, p ⫽ 0.004) and follow-up (28.6 ⫾ 12.7 v 22.8 ⫾ 12.9, F1,69 ⫽ 3.24, p ⫽ 0.076) and the recent report of a sex-related differential effect of -blockers,14 a subgroup analysis based on sex was performed. Although this analysis had not been planned before the start of the study, it was planned before carrying out the analysis as the findings of Krauseneck et al14 became available to the authors. The results of the stratified analysis are summarized in (Table 3). It was found that female patients who were not treated with -blockers during the perioperative period reported dramatically increased PTSD symptoms compared with those who received -blockers (36.2 ⫾ 11.9 v 20.3 ⫾ 7.4, F1,23 ⫽ 15.69, p ⫽ 0.001), with an effect size as high as 1.65. Similarly, 7 of 13 female patients who were not treated with -blockers received a diagnosis of PTSD compared with 0 of 12 who were treated with -blockers (p ⫽ 0.005, Fisher exact test). In a series of general linear models performed on the female subgroup, the
Table 1. Demographic and Main Clinical Characteristics in Patients with Complete 6-Month Follow-Up and Patients Who Had Died or Were Lost to Follow-Up
Demographic and Clinical Characteristics
Age (y), mean (SD) Men, n (%) Weight (kg), mean (SD) Height (cm), mean (SD) Education, n (%) No education, primary or junior high school Senior high school or graduate degree Marital status, n (%) Married or cohabiting Not married (single, divorced, widowed) Type of surgery, n (%) Valve replacement CABG Other
Study Sample (n ⫽ 71)
Patients Who Died or Were Lost to Follow-Up (n ⫽ 50)
p Value
66.9 (10.7) 46 (65) 72.1 (10.0) 166.6 (7.3)
65.7 (11.2) 40 (80) 75.8 (15.3) 166.8 (9.3)
0.63 0.10 0.12 0.90
50 (70) 21 (29)
36 (72) 14 (28)
0.85
53 (75) 18 (25)
37 (74) 13 (26)
0.93
21 (29) 45 (63) 5 (7)
15 (30) 31 (62) 4 (8)
0.97
Abbreviations: CABG, coronary artery bypass grafting; SD, standard deviation.
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Table 2. Demographic, Clinical, and Treatment Characteristics in Patients With or Without a PTSS-10-Based Diagnosis of PTSD Patients With PTSD (n ⫽ 14)
Demographic and Clinical Characteristics
Age (y), mean (SD) Men, n (%) Education, n (%) No education, primary or junior high school Senior high school or graduate degree Marital status, n (%) Married or cohabiting Not married (single, divorced, widowed) Type of surgery, n (%) Valve replacement CABG Other NYHA class, n (%) I-II III-IV Ejection fraction, n (%) 65%–45% ⬍45% Hypertension, n (%) Diabetes, n (%) Duration of cardiopulmonary bypass (min), mean (SD) Duration of mechanical ventilation (h), mean (SD) Duration of ICU therapy (h), mean (SD) -blockers, n (%) Dopamine/dobutamine, n (%) Noradrenaline/epinephrine, n (%) Total dosage of propofol (mg/kg), mean (SD) Total dosage of sufentanil (g/kg), mean (SD) PTSS-10 total score, mean (SD) Number of traumatic memories, mean (SD)
Patients Without PTSD (n ⫽ 57)
p Value
66.3 (5.8) 7 (50)
66.5 (11.9) 39 (68)
0.96 0.20
10 (71) 4 (29)
39 (68) 18 (32)
0.83
3 (21) 11 (79)
15 (26) 42 (74)
0.71
4 (30) 8 (57) 2 (14)
17 (30) 37 (65) 3 (5)
0.49
6 (43) 8 (57)
27 (47) 30 (53)
0.76
11 (79) 3 (21) 7 (50) 4 (28) 131 (32) 18.9 (5.7) 43.4 (25.0) 4 (28) 5 (36) 2 (14) 18.5 (7.5) 3.4 (0.9) 46.4 (8.3) 2.4 (1.0)
45 (79) 12 (21) 30 (53) 18 (32) 124 (45) 17.4 (7.4) 34.3 (27.0) 29 (51) 15 (26) 2 (3) 17.4 (7.3) 3.1 (1.2) 19.6 (7.2) 0.6 (0.9)
0.97 0.86 0.83 0.58 0.42 0.26 0.13 0.48 0.12 0.62 0.39 ⬍0.0001 ⬍0.0001
Abbreviations: CABG, coronary artery bypass grafting; ICU, intensive care unit; NYHA, New York Heart Association; PTSD, post-traumatic stress disorder; PTSS-10, Posttraumatic Stress Symptom Inventory 10; SD, standard deviation.
association between the use of -blockers and a lower PTSS-10 score at follow-up remained significant (p ⫽ 0.001) after controlling for demographic (age, education, and marital status) and clinical (New York Heart Association class, type of intervention, duration of surgery, and propofol and sufentanil dosage) variables. In a general linear model, including sex and treatment with -blockers as predictors, sex did not significantly predict the PTSS-10 score (F ⫽ 3.13, p ⫽ 0.081), which was predicted significantly by -blocker treatment (F ⫽ 4.74, p ⫽ 0.033), with a significant interaction between sex and -blocker treatment (F ⫽ 9.72, p ⫽ 0.003). No association between -blockade and PTSD symptoms or diagnosis was found in male patients. With regard to traumatic memories, in a general linear model, including sex and treatment with
-blockers as predictors, sex did not predict significantly the total number of traumatic memories (F ⫽ 2.12, p ⫽ 0.15), which was predicted significantly by -blocker treatment (F ⫽ 9.49, p ⫽ 0.033), with a highly significant interaction between sex and -blockade (F ⫽ 10.69, p ⫽ 0.002; Table 3). No association between -blocker treatment and the total number of traumatic memories was found in male patients. DISCUSSION
In this study, no perioperative factor, including -blockers, was found to be associated with the development of PTSD in patients who underwent cardiac surgery. However, a subgroup analysis by sex showed that the use of -blockers was associ-
Table 3. PTSS-10-Based Diagnosis of PTSD by Treatment With -Blockers in Men and Women
Women treated with -blockers, n (%) Women not treated with -blockers, n (%) Men treated with -blockers, n (%) Men not treated with -blockers, n (%)
Patients With PTSD (n ⫽ 14)
Patients Without PTSD (n ⫽ 57)
0 (0) 7 (54) 4 (19) 3 (12)
12 (100) 6 (46) 17 (81) 22 (88)
Abbreviations: PTSD, post-traumatic stress disorder; SD, standard deviation. *Interaction between sex and -blockers (p ⫽ 0.002).
p Value
Number of Traumatic Memories, Mean (SD)*
0.004
0.3 (0.9) 2.0 (1.2) 0.8 (1.1) 0.8 (1.0)
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ated with significantly lower rates of PTSD development, lower PTSD scores, and fewer traumatic memories in female patients. Previous studies on the effect of -blockers on the development of PTSD after a traumatic event are scanty and limited by small samples. At 1- and 3-month follow-ups, Pitman et al12 reported no significant differences in PTSD scores and diagnosis in 18 emergency department patients treated with the -blocker propranolol, in contrast to 23 patients randomized to placebo within 6 hours after a traumatic event. In another study,11 propranolol (n ⫽ 17) or placebo (n ⫽ 17) was administered within 48 hours of injury to patients admitted to a surgical trauma center. At 1-, 4-, and 8-month follow-ups, propranolol did not show a significant benefit over placebo on post-traumatic stress symptoms. In contrast with these results, 2 months after a motor vehicle accident or a physical assault, a nonblinded, nonrandomized study13 reported a significant decrease in PTSD rates and symptom severity in 11 subjects treated with propranolol compared with 8 patients who refused the -blocker. However, studies in patients treated after a traumatic event may not be comparable to studies on surgical patients treated with -blockers during the perioperative period. In the only previous study on PTSD and -blockade in cardiac surgery,14 84 patients who underwent coronary artery bypass grafting or cardiac valve replacement were treated with the -blocker metoprolol and compared with 44 patients not treated with -blockers. Metoprolol decreased the memory for postoperative adverse events and PTSD symptom scores only in female patients at the 6-month follow-up. This study was consistent with the present findings, although it did not examine the effect of -blockers on the development of PTSD. The same investigators, in a previous prospective study on cardiac surgical patients,5 reported that patients treated with -blockers at any time during the postoperative period showed a trend toward a smaller number of categories of traumatic memory from the ICU. The amygdala appears to be critical in the memory-enhancing effects of emotional arousal in humans.19 Beta-blockers impair the memory of emotionally arousing stimuli in healthy subjects and in patients with PTSD.20,21 As a central effect, -blockers block postsynaptic -adrenergic receptors in the amygdala. These agents in the peritraumatic period might interfere with the potentiation of the consolidation of traumatic memories, preventing the eventual intrusive recollections and re-experienced symptoms found in PTSD.10,19 A peripheral hyperadrenergic state has been found to predict subsequent PTSD.19 The blockade of peripheral -adrenergic receptors interferes with epinephrine- and norepinephrine-mediated peripheral autonomic activation effects. Thus, -blockers decrease manifestations of trauma-related anxiety and hyperarousal and might blunt the acute response of intense fear leading to the development of PTSD. In line with the study by Krauseneck et al,14 the association between -blockade and PTSD symptoms and diagnosis was
found in female patients only. Based on the evidence of sexrelated hemispheric asymmetry of amygdala function in memory for emotional material, two studies in healthy subjects found differential effects of -blockers on long-term memory for an emotionally arousing story in men and women.22 Betablockers were found to impair the memory for the central and peripheral details of an emotionally arousing story in men and women, respectively.22 These findings might explain a sexrelated differential effect in -blocker protection against PTSD-related traumatic memory consolidation. Studies in healthy subjects have found a significant interaction between emotionality and sex, indicating that women recall significantly more emotional information than men.23 This finding may be mediated by a sex difference in the intensity of emotional experiences. Women have stronger perceptions of threat and perceive stimuli as being more emotionally intense than men.24 This difference, together with the type of trauma they experience and their younger age at the time of trauma exposure, might explain, in part, the higher risk of PTSD in women,25 and the -blocker peripheral effect on somatic symptoms of peritraumatic fear might explain a lower risk of PTSD in female patients treated with -blockers. Moreover, in postmenopausal women, there is an increase in the autonomic nervous system responsiveness to experimental acute stressors, with enhanced cardiovascular responses.26 In the present sample, the mean age of the women was 70.4 years, and the peripheral effects of -blockers might have decreased a higher trauma-related sympathoadrenal responsiveness impairing the overconsolidation of traumatic memories. Limitations of the present study warrant comment. First, the small sample and the observational nature of this study prevented any firm conclusions about cause-and-effect relations. Second, a substantial number of patients were lost to follow-up. Although baseline characteristics were similar between patients who were lost to follow-up and those evaluated at 6 months (Table 1), this does not rule out the possibility of bias caused by a differential loss between groups. A third limitation was that 3 -blockers with different lipophilic properties were administered. These drugs have central and peripheral effects, with the former prevailing over the latter with more lipophilic molecules. However, in the present setting, the diffusion of more hydrophilic -blockers into the brain might have been allowed by the increased permeability of the blood-brain barrier generated by the systemic inflammatory response to cardiopulmonary bypass27 or the stress response to a traumatic event.28 In conclusion, the present findings suggest that the use of -blockers might protect against the development of PTSD in women after cardiac surgery. However, given the exploratory nature of the subgroup analysis performed, these findings should be accepted with caution and need to be replicated by future studies specifically testing this hypothesis.
REFERENCES 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (rev 4th ed). Washington, DC, American Psychiatric Association, 2000 2. Jackson JC, Hart RP, Gordon SM, et al: Post-traumatic stress disorder and post-traumatic stress symptoms following critical illness
in medical intensive care unit patients: Assessing the magnitude of the problem. Crit Care 11:R27, 2007 3. Hudetz JA, Gandhi SD, Iqbal Z, et al: History of post-traumatic stress disorder is associated with impaired neuropsychometric performance after coronary artery surgery. J Cardiothorac Vasc Anesth 24:964-968, 2010
BETA-BLOCKERS AND PTSD AFTER CARDIAC SURGERY
4. Tully PJ: Post-traumatic stress disorder and neuropsychologic impairment among cardiac surgery patients. J Cardiothorac Vasc Anesth 25:e8-e9, 2011 5. Schelling G, Richter M, Roozendaal B, et al: Exposure to high stress in the intensive care unit may have negative effects on healthrelated quality-of-life outcomes after cardiac surgery. Crit Care Med 31:1971-1980, 2003 6. Weis F, Kilger E, Roozendaal B, et al: Stress doses of hydrocortisone reduce chronic stress symptoms and improve health-related quality of life in high-risk patients after cardiac surgery: A randomized study. J Thorac Cardiovasc Surg 131:277-282, 2006 7. Rothenhäusler HB, Grieser B, Nollert G, et al: Psychiatric and psychosocial outcome of cardiac surgery with cardiopulmonary bypass: A prospective 12-month follow-up study. Gen Hosp Psychiatry 27:1828, 2005 8. Stoll C, Schelling G, Goetz AE, et al: Health-related quality of life and post-traumatic stress disorder in patients after cardiac surgery and intensive care treatment. J Thorac Cardiovasc Surg 120:505-512, 2000 9. Schelling G, Kilger E, Roozendaal B, et al: Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: A randomized study. Biol Psychiatry 55:627-633, 2004 10. Ravindran LN, Stein MB: Pharmacotherapy of PTSD: Premises, principles, and priorities. Brain Res 1293:24-39, 2009 11. Stein MB, Kerridge C, Dimsdale JE, et al: Pharmacotherapy to prevent PTSD: Results from a randomized controlled proof-of-concept trial in physically injured patients. J Trauma Stress 20:923-932, 2007 12. Pitman RK, Sanders KM, Zusman RM, et al: Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol Psychiatry 51:189-192, 2002 13. Vaiva G, Ducrocq F, Jezequel K, et al: Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol Psychiatry 54:947-949, 2003 14. Krauseneck T, Padberg F, Roozendaal B, et al: A beta-adrenergic antagonist reduces traumatic memories and PTSD symptoms in female but not in male patients after cardiac surgery. Psychol Med 40:861-869, 2010
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15. Stoll C, Kapfhammer HP, Rothenhäusler HB, et al: Sensitivity and specificity of a screening test to document traumatic experiences and to diagnose post-traumatic stress disorder in ARDS patients after intensive care treatment. Intensive Care Med 25:697-704, 1999 16. Schelling G, Stoll C, Haller M, et al: Health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome. Crit Care Med 26:651-659, 1998 17. Jubran A, Lawm G, Duffner LA, et al: Post-traumatic stress disorder after weaning from prolonged mechanical ventilation. Intensive Care Med 36:2030-2037, 2010 18. Girard TD, Shintani AK, Jackson JC, et al: Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: A prospective cohort study. Crit Care 11 R28, 2007 19. Pitman RK, Delahanty DL: Conceptually driven pharmacologic approaches to acute trauma. CNS Spectr 10:99-106, 2005 20. Cahill L, Prins B, Weber M, et al: Beta-adrenergic activation and memory for emotional events. Nature 371:702-704, 1994 21. Reist C, Duffy JG, Fujimoto K, et al: Beta-Adrenergic blockade and emotional memory in PTSD. Int J Neuropsychopharmacol 4:377383, 2001 22. Cahill L, van Stegeren A: Sex-related impairment of memory for emotional events with beta-adrenergic blockade. Neurobiol Learn Mem 79:81-88, 2003 23. Andreano JM, Cahill L: Sex influences on the neurobiology of learning and memory. Learn Mem 16:248-266, 2009 24. Fujita F, Diener E, Sandvik E: Gender differences in negative affect and well-being: The case for emotional intensity. J Pers Soc Psychol 61:427-434, 1991 25. Olff M, Langeland W, Draijer N, et al: Gender differences in posttraumatic stress disorder. Psychol Bull 133:183-204, 2007 26. Kajantie E, Phillips DI: The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinology 31:151-178, 2006 27. Moody DM: The blood-brain barrier and blood-cerebral spinal fluid barrier. Semin Cardiothorac Vasc Anesth 10:128-131, 2006 28. Hanin I: The Gulf War, stress and a leaky blood-brain barrier. Nat Med 2:1307-1308, 1996
of 13 female patients who were not treated with -blockers received a diagnosis of PTSD compared with 0 of 12 who were treated with -blockers (p ⴝ 0.005, Fisher exact test). In a general linear model, including sex and -blocker treatment as predictors, the Posttraumatic Stress Symptom Inventory 10 score was significantly predicted by -blockade (F ⴝ 4.74, p ⴝ 0.033), with a significant interaction between sex and -blockade (F ⴝ 9.72, p ⴝ 0.003). Conclusions: These findings suggest that the use of -blockers might be protective against the development of PTSD in women after cardiac surgery. © 2012 Elsevier Inc. All rights reserved.
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that -blocker treatment might be associated with a decrease in the risk of developing PTSD after cardiac surgery.
OST-TRAUMATIC STRESS DISORDER (PTSD) is a severely debilitating mental disorder that develops after the experience of a traumatic event. Clinical manifestations include intrusive recollections (eg, nightmares or flashbacks), avoidance of reminders of the trauma, and a variety of anxiety symptoms.1 The disorder is a frequent complication in critically ill and surgical patients treated in the intensive care unit (ICU).2-4 Cardiac surgery with cardiopulmonary bypass represents a severe source of stress because it combines the effects of critical illness, the ICU stay, and traumatic experiences, such as pain or respiratory failure. Five studies conducted 5 to 12 months after cardiac surgery reported prevalence estimates of PTSD ranging from 15% to 25%.5-9 Importantly, the development of PTSD after cardiac surgery is associated with a significant disability that might greatly decrease the benefits of surgery.5 Several pharmacologic agents have been proposed for the secondary prevention of PTSD.10 Based on a considerable body of preclinical findings from animal experiments and studies in healthy subjects, it was theorized that the administration of -blockers shortly after a traumatic event interferes with memory formation and the consolidation of the traumatic experience, can decrease the impact of the emotional valence of memories, and thus might prevent the development of PTSD.10,11 However, the results from trials using these agents in the aftermath of a traumatic event are contradictory: 2 studies11,12 found no significant differences in the rates of PTSD development in subjects treated with -blockers, whereas 1 study13 found lower PTSD rates in 11 emergency room patients treated with propranolol compared with 8 patients who refused this agent but agreed to be followed prospectively. Beta-blockers commonly are used in patients undergoing cardiac surgery; however, only Krauseneck et al14 performed a prospective observational study in cardiac surgical patients and found lower scores of PTSD symptoms only in women treated with metoprolol 6 months after the procedure. The present investigation was conducted to identify the perioperative factors associated with the development of PTSD in patients who underwent cardiac surgery. Specifically, this study tested the hypothesis
KEY WORDS: post-traumatic stress disorder, cardiac surgery, -blockers
METHODS The study was performed from January 2006 through January 2008 by the department of cardiac surgery in a large Italian academic hospital. Before enrollment, all patients received a complete explanation of the purpose of the study and gave written informed consent to participate. Adult inpatients who were candidates for on-pump coronary artery bypass grafting and/or valve surgery were considered for inclusion in the study. The following exclusion criteria were applied during recruitment: history of psychiatric disorders, clinically evident cognitive impairment, emergency surgery, ICU treatment (except brief stays in coronary care units) in the previous 24 months, previous cardiac surgery, and a diagnosis of PTSD according to the modified version of the Posttraumatic Stress Symptom Inventory 10 (PTSS-10; see below). In total, 128 inpatients were enrolled in the study. All patients were interviewed within the surgical unit by 1 of 2 qualified examiners 1 to 3 days before surgery. Medical history and demographic information were collected with a study-specific form and were abstracted from medical records. Clinical data and treatment characteristics included surgery type, New York Heart Association class, ejection fraction, duration of surgery and of cardiopulmonary bypass, -blocker and inotropic drug administration, anesthetic dosage, length of mechanical ventilation, and ICU length of stay. The patients treated with -blockers received the medication preoperatively, postoperatively, and at discharge from the hospital. The -blockers used were carvedilol, atenolol, and metoprolol at standard dosages. A stan-
From the Departments of *Neurology and Psychiatry and †Anesthesia and Intensive Care, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy; and the ‡Italian National Institute of Health, Center of Epidemiology, Surveillance and Health Promotion, Mental Health Unit, Rome, Italy. Address reprint requests to Vincenzo De Santis, MD, Viale del Policlinico 155, 00161 Rome, Italy. E-mail: vincenzo.desantis@ uniroma1.it © 2012 Elsevier Inc. All rights reserved. 1053-0770/2602-0015$36.00/0 doi:10.1053/j.jvca.2011.09.011
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dardized anesthesia and postoperative sedation protocol was used for all patients. Anesthesia was induced with a target-controlled infusion of propofol (site effect) 1.6 to 1.8 g/mL, sufentanil 0.35 to 0.5 g/kg, and rocuronium 0.6 mg/kg. After tracheal intubation, the lungs were ventilated mechanically with an oxygen-air mixture (fraction of inspired oxygen 40%). Anesthesia was maintained with propofol (site effect) 1.6 to 2.2 g/mL, sufentanil 0.35 g/kg/h, and supplemental boluses of rocuronium. Six months after surgery, patients were contacted by telephone, were again explained the study and its aims, and were asked to confirm verbally the informed consent they had provided in writing before the surgery. All those who accepted were mailed the PTSS-10.15 This instrument is composed of 2 different parts. Part A explores traumatic memories from ICU treatment, defined by Stoll et al15 as a patient’s subjective memories of respiratory distress/dyspnea, a feeling of severe anxiety/panic, severe pain, or nightmares at any time during ICU treatment. Patients are asked to answer each item simply with “yes” or “no,” independent of the number of occasions the adverse experience occurred. Part B evaluates 10 common PTSD symptoms: sleep disturbance, nightmares, depression, hyperalertness, withdrawal, generalized irritability, frequent changes in mood, guilt, fear or avoidance reactions with regard to the ICU, and increased muscle tension. Each item is scored on a 7-point scale and the total score ranges from 10 to 70 points. Scores ⱖ35 on Part B predict a diagnosis of PTSD with a high sensitivity (77%) and specificity (97.5%).15 The PTSS-10 has been validated in long-term survivors of the ICU,15,16 and it is a widely used self-reported tool in patients after critical illness.5,9,14,17,18 Part B of this instrument was administered to all patients before the intervention to exclude patients with scores ⱖ35 from the study. After 6 months, each participant completed the questionnaire and mailed it back to the researchers in a prestamped, preaddressed envelope. All analyses were performed with SPSS 17.0 (SPSS, Inc, Chicago, IL). All statistical tests were 2-tailed, with an ␣ value set at 0.05. The 2 test (with Yates correction for 2 ⫻ 2 tables) and the Student t test for independent samples were used as appropriate to test for differences between groups in categoric and continuous variables, respectively. Generalized linear modeling was used to test for the independent effect of relevant predictors on PTSS-10 score and to test for the interaction among predictors.
RESULTS
One hundred twenty-one patients (94% of candidates for elective cardiac surgery who met the study inclusion criteria) actually underwent surgery. Two patients who refused surgery and 5 who were deemed not suitable for surgery were excluded from the study. Seventy-one (59%) were assessed after 6 months. Three patients (2%) died during the study period, 28 (23%) were unreachable by telephone after multiple attempts, and 19 (16%) had to be excluded from the study because of missing or incomplete questionnaires. There were no significant differences in baseline demographic and clinical characteristics between the subjects who completed and those who did not complete the study at the 6-month follow-up (Table 1). Fourteen subjects (19.7%) scored ⱖ35 on the PTSS-10 at the 6-month follow-up and were considered as having a probable diagnosis of PTSD. The mean PTSS-10 total score and the PTSS-10-based diagnosis of PTSD did not differ by demographic, clinical, and treatment characteristics (Table 2). Given the finding of higher mean PTSS-10 scores at baseline (20.8 ⫾ 7.2 v 15.9 ⫾ 6.3, F1,69 ⫽ 8.7, p ⫽ 0.004) and follow-up (28.6 ⫾ 12.7 v 22.8 ⫾ 12.9, F1,69 ⫽ 3.24, p ⫽ 0.076) and the recent report of a sex-related differential effect of -blockers,14 a subgroup analysis based on sex was performed. Although this analysis had not been planned before the start of the study, it was planned before carrying out the analysis as the findings of Krauseneck et al14 became available to the authors. The results of the stratified analysis are summarized in (Table 3). It was found that female patients who were not treated with -blockers during the perioperative period reported dramatically increased PTSD symptoms compared with those who received -blockers (36.2 ⫾ 11.9 v 20.3 ⫾ 7.4, F1,23 ⫽ 15.69, p ⫽ 0.001), with an effect size as high as 1.65. Similarly, 7 of 13 female patients who were not treated with -blockers received a diagnosis of PTSD compared with 0 of 12 who were treated with -blockers (p ⫽ 0.005, Fisher exact test). In a series of general linear models performed on the female subgroup, the
Table 1. Demographic and Main Clinical Characteristics in Patients with Complete 6-Month Follow-Up and Patients Who Had Died or Were Lost to Follow-Up
Demographic and Clinical Characteristics
Age (y), mean (SD) Men, n (%) Weight (kg), mean (SD) Height (cm), mean (SD) Education, n (%) No education, primary or junior high school Senior high school or graduate degree Marital status, n (%) Married or cohabiting Not married (single, divorced, widowed) Type of surgery, n (%) Valve replacement CABG Other
Study Sample (n ⫽ 71)
Patients Who Died or Were Lost to Follow-Up (n ⫽ 50)
p Value
66.9 (10.7) 46 (65) 72.1 (10.0) 166.6 (7.3)
65.7 (11.2) 40 (80) 75.8 (15.3) 166.8 (9.3)
0.63 0.10 0.12 0.90
50 (70) 21 (29)
36 (72) 14 (28)
0.85
53 (75) 18 (25)
37 (74) 13 (26)
0.93
21 (29) 45 (63) 5 (7)
15 (30) 31 (62) 4 (8)
0.97
Abbreviations: CABG, coronary artery bypass grafting; SD, standard deviation.
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Table 2. Demographic, Clinical, and Treatment Characteristics in Patients With or Without a PTSS-10-Based Diagnosis of PTSD Patients With PTSD (n ⫽ 14)
Demographic and Clinical Characteristics
Age (y), mean (SD) Men, n (%) Education, n (%) No education, primary or junior high school Senior high school or graduate degree Marital status, n (%) Married or cohabiting Not married (single, divorced, widowed) Type of surgery, n (%) Valve replacement CABG Other NYHA class, n (%) I-II III-IV Ejection fraction, n (%) 65%–45% ⬍45% Hypertension, n (%) Diabetes, n (%) Duration of cardiopulmonary bypass (min), mean (SD) Duration of mechanical ventilation (h), mean (SD) Duration of ICU therapy (h), mean (SD) -blockers, n (%) Dopamine/dobutamine, n (%) Noradrenaline/epinephrine, n (%) Total dosage of propofol (mg/kg), mean (SD) Total dosage of sufentanil (g/kg), mean (SD) PTSS-10 total score, mean (SD) Number of traumatic memories, mean (SD)
Patients Without PTSD (n ⫽ 57)
p Value
66.3 (5.8) 7 (50)
66.5 (11.9) 39 (68)
0.96 0.20
10 (71) 4 (29)
39 (68) 18 (32)
0.83
3 (21) 11 (79)
15 (26) 42 (74)
0.71
4 (30) 8 (57) 2 (14)
17 (30) 37 (65) 3 (5)
0.49
6 (43) 8 (57)
27 (47) 30 (53)
0.76
11 (79) 3 (21) 7 (50) 4 (28) 131 (32) 18.9 (5.7) 43.4 (25.0) 4 (28) 5 (36) 2 (14) 18.5 (7.5) 3.4 (0.9) 46.4 (8.3) 2.4 (1.0)
45 (79) 12 (21) 30 (53) 18 (32) 124 (45) 17.4 (7.4) 34.3 (27.0) 29 (51) 15 (26) 2 (3) 17.4 (7.3) 3.1 (1.2) 19.6 (7.2) 0.6 (0.9)
0.97 0.86 0.83 0.58 0.42 0.26 0.13 0.48 0.12 0.62 0.39 ⬍0.0001 ⬍0.0001
Abbreviations: CABG, coronary artery bypass grafting; ICU, intensive care unit; NYHA, New York Heart Association; PTSD, post-traumatic stress disorder; PTSS-10, Posttraumatic Stress Symptom Inventory 10; SD, standard deviation.
association between the use of -blockers and a lower PTSS-10 score at follow-up remained significant (p ⫽ 0.001) after controlling for demographic (age, education, and marital status) and clinical (New York Heart Association class, type of intervention, duration of surgery, and propofol and sufentanil dosage) variables. In a general linear model, including sex and treatment with -blockers as predictors, sex did not significantly predict the PTSS-10 score (F ⫽ 3.13, p ⫽ 0.081), which was predicted significantly by -blocker treatment (F ⫽ 4.74, p ⫽ 0.033), with a significant interaction between sex and -blocker treatment (F ⫽ 9.72, p ⫽ 0.003). No association between -blockade and PTSD symptoms or diagnosis was found in male patients. With regard to traumatic memories, in a general linear model, including sex and treatment with
-blockers as predictors, sex did not predict significantly the total number of traumatic memories (F ⫽ 2.12, p ⫽ 0.15), which was predicted significantly by -blocker treatment (F ⫽ 9.49, p ⫽ 0.033), with a highly significant interaction between sex and -blockade (F ⫽ 10.69, p ⫽ 0.002; Table 3). No association between -blocker treatment and the total number of traumatic memories was found in male patients. DISCUSSION
In this study, no perioperative factor, including -blockers, was found to be associated with the development of PTSD in patients who underwent cardiac surgery. However, a subgroup analysis by sex showed that the use of -blockers was associ-
Table 3. PTSS-10-Based Diagnosis of PTSD by Treatment With -Blockers in Men and Women
Women treated with -blockers, n (%) Women not treated with -blockers, n (%) Men treated with -blockers, n (%) Men not treated with -blockers, n (%)
Patients With PTSD (n ⫽ 14)
Patients Without PTSD (n ⫽ 57)
0 (0) 7 (54) 4 (19) 3 (12)
12 (100) 6 (46) 17 (81) 22 (88)
Abbreviations: PTSD, post-traumatic stress disorder; SD, standard deviation. *Interaction between sex and -blockers (p ⫽ 0.002).
p Value
Number of Traumatic Memories, Mean (SD)*
0.004
0.3 (0.9) 2.0 (1.2) 0.8 (1.1) 0.8 (1.0)
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ated with significantly lower rates of PTSD development, lower PTSD scores, and fewer traumatic memories in female patients. Previous studies on the effect of -blockers on the development of PTSD after a traumatic event are scanty and limited by small samples. At 1- and 3-month follow-ups, Pitman et al12 reported no significant differences in PTSD scores and diagnosis in 18 emergency department patients treated with the -blocker propranolol, in contrast to 23 patients randomized to placebo within 6 hours after a traumatic event. In another study,11 propranolol (n ⫽ 17) or placebo (n ⫽ 17) was administered within 48 hours of injury to patients admitted to a surgical trauma center. At 1-, 4-, and 8-month follow-ups, propranolol did not show a significant benefit over placebo on post-traumatic stress symptoms. In contrast with these results, 2 months after a motor vehicle accident or a physical assault, a nonblinded, nonrandomized study13 reported a significant decrease in PTSD rates and symptom severity in 11 subjects treated with propranolol compared with 8 patients who refused the -blocker. However, studies in patients treated after a traumatic event may not be comparable to studies on surgical patients treated with -blockers during the perioperative period. In the only previous study on PTSD and -blockade in cardiac surgery,14 84 patients who underwent coronary artery bypass grafting or cardiac valve replacement were treated with the -blocker metoprolol and compared with 44 patients not treated with -blockers. Metoprolol decreased the memory for postoperative adverse events and PTSD symptom scores only in female patients at the 6-month follow-up. This study was consistent with the present findings, although it did not examine the effect of -blockers on the development of PTSD. The same investigators, in a previous prospective study on cardiac surgical patients,5 reported that patients treated with -blockers at any time during the postoperative period showed a trend toward a smaller number of categories of traumatic memory from the ICU. The amygdala appears to be critical in the memory-enhancing effects of emotional arousal in humans.19 Beta-blockers impair the memory of emotionally arousing stimuli in healthy subjects and in patients with PTSD.20,21 As a central effect, -blockers block postsynaptic -adrenergic receptors in the amygdala. These agents in the peritraumatic period might interfere with the potentiation of the consolidation of traumatic memories, preventing the eventual intrusive recollections and re-experienced symptoms found in PTSD.10,19 A peripheral hyperadrenergic state has been found to predict subsequent PTSD.19 The blockade of peripheral -adrenergic receptors interferes with epinephrine- and norepinephrine-mediated peripheral autonomic activation effects. Thus, -blockers decrease manifestations of trauma-related anxiety and hyperarousal and might blunt the acute response of intense fear leading to the development of PTSD. In line with the study by Krauseneck et al,14 the association between -blockade and PTSD symptoms and diagnosis was
found in female patients only. Based on the evidence of sexrelated hemispheric asymmetry of amygdala function in memory for emotional material, two studies in healthy subjects found differential effects of -blockers on long-term memory for an emotionally arousing story in men and women.22 Betablockers were found to impair the memory for the central and peripheral details of an emotionally arousing story in men and women, respectively.22 These findings might explain a sexrelated differential effect in -blocker protection against PTSD-related traumatic memory consolidation. Studies in healthy subjects have found a significant interaction between emotionality and sex, indicating that women recall significantly more emotional information than men.23 This finding may be mediated by a sex difference in the intensity of emotional experiences. Women have stronger perceptions of threat and perceive stimuli as being more emotionally intense than men.24 This difference, together with the type of trauma they experience and their younger age at the time of trauma exposure, might explain, in part, the higher risk of PTSD in women,25 and the -blocker peripheral effect on somatic symptoms of peritraumatic fear might explain a lower risk of PTSD in female patients treated with -blockers. Moreover, in postmenopausal women, there is an increase in the autonomic nervous system responsiveness to experimental acute stressors, with enhanced cardiovascular responses.26 In the present sample, the mean age of the women was 70.4 years, and the peripheral effects of -blockers might have decreased a higher trauma-related sympathoadrenal responsiveness impairing the overconsolidation of traumatic memories. Limitations of the present study warrant comment. First, the small sample and the observational nature of this study prevented any firm conclusions about cause-and-effect relations. Second, a substantial number of patients were lost to follow-up. Although baseline characteristics were similar between patients who were lost to follow-up and those evaluated at 6 months (Table 1), this does not rule out the possibility of bias caused by a differential loss between groups. A third limitation was that 3 -blockers with different lipophilic properties were administered. These drugs have central and peripheral effects, with the former prevailing over the latter with more lipophilic molecules. However, in the present setting, the diffusion of more hydrophilic -blockers into the brain might have been allowed by the increased permeability of the blood-brain barrier generated by the systemic inflammatory response to cardiopulmonary bypass27 or the stress response to a traumatic event.28 In conclusion, the present findings suggest that the use of -blockers might protect against the development of PTSD in women after cardiac surgery. However, given the exploratory nature of the subgroup analysis performed, these findings should be accepted with caution and need to be replicated by future studies specifically testing this hypothesis.
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