Brief Reports
Stunned Myocardium in the Toxic Shock Syndrome Jennie R. Crews, MD; J. Kevin Harrison, MD; G. Ralph Corey, MD; Charles Steenbergen, MD, PhD; and Thomas M. Bashore, MD Annals of Internal Medicine. 1992;117:912-913.
Although it is not commonly recognized, myocardial dysfunction in the toxic shock syndrome may be severe, even life-threatening (1, 2). The cause of this acute cardiomyopathy remains unclear. Clinically, left ventricular dysfunction in the toxic shock syndrome has been reversible, similar to prolonged but transient posti s h e m i c myocardial dysfunction, a process termed "stunned myocardium" (3). Cardiac histopathologic findings in the toxic shock syndrome are limited to autopsy data, and the pathologic changes seen have been modest compared with the clinical severity of left ventricular dysfunction (4, 5). We report the first premortem cardiac histologic findings in a patient with severe, acute cardiomyopathy caused by the toxic shock syndrome. Case Report A 17-year-old, previously healthy white woman presented with fever, an erythematous rash, and hypotension. She began using tampons the previous week, during her menses. On 1 February 1992, 3 days after the end of her menses, she developed malaise, nausea, vomiting, and high fever (40.5 °C). A bright red, macular rash also developed and prompted her to seek medical attention. At initial examination, she had a temperature of 38.6 °C, a blood pressure of 76/50 mm Hg, and a heart rate of 150 beats/min. An erythematous nonblanching rash in the inguinal and axillary areas was noted, as well as blanching erythema of her face. Chest and cardiovascular examinations were otherwise normal. Leukocytosis (19 900/mm3), thrombocytopenia (79 000/ mm 3 ), and hypoalbuminemia (28 g/L) were present. Renal function was normal (creatinine, 70 /xmol/L). Hepatocellular injury was noted (aspartate aminotransferase, 1.25 fimolfL; alanine aminotransferase, 0.63 ^kat/L; alkaline phosphatase, 2.7 /tkat/L; total bilirubin, 48 fimolfL). Serum calcium was 2.00 /xmol/L and phosphate, 1.05 /xmol/L. The patient was begun on intravenous fluids, vancoFrom Duke University Medical Center, Durham, North Carolina. For current author addresses, see end of text.
912
mycin (1 gram every 12 hours), and gentamicin (100 mg every 8 hours) with improvement of her blood pressure. Cervical and urine cultures grew Staphylococcus aureus (urine culture > 50 000 colony forming units/mL). Blood cultures were sterile. Although the rash resolved on hospital day 2, she continued to have fever. On hospital day 3, she suddenly developed severe dyspnea with hypoxemia, requiring intubation. A chest radiograph showed alveolar pulmonary edema. When the patient was transferred to our institution on 5 February 1992, hemodynamic monitoring showed a mean arterial pressure of 76 mm Hg, a pulmonary capillary wedge pressure of 18 mm Hg, and a cardiac index of 2.3 L/min per m 2 surface area. Two-dimensional echocardiography showed severe global hypokinesis of the left ventricle (estimated left ventricular ejection fraction < 0.15). The patient was treated with intravenous diuretics; she had rapid hemodynamic improvement and was extubated within 24 hours. Percutaneous endomyocardial biopsies of the right ventricular septum were done on 7 February 1992 to evaluate the possibility of viral myocarditis. She completed a 10-day course of intravenous vancomycin. On 9 February 1992, she developed skin desquamation of her fingertips. A radionuclide angiogram the day before discharge demonstrated a left ventricular ejection fraction of 0.60. She was discharged home in good condition. Hematoxylin-eosin- and Masson-stained sections of an endomyocardial biopsy specimen revealed rare, acutely necrotic myocytes. No substantial inflammatory infiltrate was identified in the histologic sections (in contrast to the expected findings in acute viral myocarditis). A separate endomyocardial biopsy specimen was snap-frozen and sectioned for immunoperoxidase staining using antibodies against the T-lymphocyte surface antigens CD2 (Til), CD3 (Leu4), CD4 (Leu3), and CD8 (Leu2); antibodies against the macrophage surface antigen C D l l c (LeuM5); and antibodies against the B-lymphocyte surface antigen CD22 (Leu 14). The immunoperoxidase results showed a mild-to-moderate number of cells staining with the T-lymphocyte markers, diffusely scattered throughout the biopsy (Figure 1, top) and several small aggregates of macrophages the size of adjacent myocytes, representing foci of myophagocytosis (Figure 1, bottom). Electron microscopy on a third biopsy specimen showed several small aggregates of macrophages and fibroblasts but no myofibrillar debris. The myofibrillar volume density in the intact myocytes was also reduced, but no evidence of severe degeneration was apparent. Six months after discharge, the patient remains well.
1 December 1992 • Annals of Internal Medicine • Volume 117 • Number 11
Downloaded from https://annals.org by Tulane University user on 01/14/2019
Figure 1. Biopsy samples. Top. Immunoperoxidase-stained frozen section of an endomyocardial biopsy using Leu4 antibody to identify T lymphocytes ( ^ ) . Note the mild cellular infiltrate and primarily intact myocytes. (Original magnification, x 325.) Bottom. Immunoperoxidase-stained frozen section of an endomyocardial biopsy using LeuM5 antibody to identify macrophages. Two small macrophage aggregates ( + ) are shown, which are indicative of isolated myocyte necrosis. (Original magnification, x 325.)
She exercised 12 minutes into stage IV of the Bruce protocol. Echocardiography, at rest and after peak exercise, showed normal left ventricular function (estimated ejection fraction, 0.65). Discussion The toxic shock syndrome, an illness involving many organ systems, is believed to result from exotoxins (for example, toxic shock syndrome toxin 1 [TSST-1]) produced by certain strains of Staphylococcus aureus. Some patients may present with severe left ventricular dysfunction requiring aggressive cardiovascular support (1, 2). The cause of this myocardial dysfunction may be related to either staphylococcal exotoxin-mediated inhibition of myocardial contractility or cell-mediated myocardial injury. In-vitro studies examining TSST-1 have shown inhibition of myocardial contraction in isolated rabbit atria (6). The dramatic myocardial recovery seen in patients
successfully supported through the acute, critical stages of the illness supports the role of a staphylococcal toxin in the myocardial dysfunction. A similar clinical picture of acute cardiac dysfunction is present in Clostridium perfringens sepsis where the causative agent is the Clostridium perfringens alpha-toxin (7). Cell-mediated myocardial injury, on the other hand, can also cause left ventricular dysfunction. Histologic examination of cardiac tissue from autopsy cases, however, has shown modest inflammation compared with the clinical severity of the cardiomyopathy. The changes observed included mild perivascular fibrinous degeneration, vacuolar degeneration, and mild lymphohistiocytic infiltration of the myocardium. Small foci of acute myocyte necrosis have also been reported (4, 5). Similarly, the myocardial findings from the endomyocardial biopsy we report included rare focal acute myocyte necrosis without significant inflammatory cell infiltration. This case suggests that the cause of the cardiac dysfunction in the toxic shock syndrome is probably not cell-mediated cardiac damage as seen in viral myocarditis. The absence of substantial inflammatory necrosis in the endomyocardial biopsy suggests that staphylococcal exotoxin causes acute suppression of myocardial function. Although the biochemical mechanism of the toxin's effect on the myocardial cell is unknown, prompt, complete return of left ventricular function can be expected once the staphylococcal exotoxin has been cleared. The cardiac manifestations of the toxic shock syndrome present a dramatic form of myocardial "stunning," with little permanent damage and dramatic recovery of contractile function. Acknowledgment: the manuscript.
The authors thank Mary Clayton for preparation of
Requests for Reprints: J. Kevin Harrison, MD, Box 3331, Duke University Medical Center, Durham, NC 27710. Current Author Addresses: Dr. Crews: Box 31108, Duke University Medical Center, Durham, NC 27710. Dr. Harrison: Box 3331, Duke University Medical Center, Durham, NC 27710. Dr. Corey: Box 3038, Duke University Medical Center, Durham, NC 27710. Dr. Steenbergen: Box 3712, Duke University Medical Center, Durham, NC 27710. Dr. Bashore: Box 3012, Duke University Medical Center, Durham, NC 27710.
References 1. Fisher CJ Jr, Horowitz Z, Albertson TE. Cardiorespiratory failure in toxic shock syndrome: effect of dobutamine. Crit Care Med. 1985; 13:160-5. 2. Chesney PJ. Clinical aspects and spectrum of illness of toxic shock syndrome: overview. Rev Infect Dis. 1989;2:Sl-7. 3. Kloner RA, Przyklenk K, Patel B. Altered myocardial states. The stunned and hibernating myocardium. Am J Med. 1989;86:14-22. 4. Paris AL, Herwaldt LA, Blum D, Schmid GP, Shands KN, Broome CV. Pathologic findings in twelve fatal cases of toxic shock syndrome. Ann Intern Med. 1982;96:852-7. 5. Larkin SM, Williams DN, Osterholm MT, Tofte RW, Posalaky Z. Toxic shock syndrome: clinical, laboratory, and pathologic findings in nine fatal cases. Ann Intern Med. 1982;96:858-64. 6. Olson RD, Stevens DL, Melish ME. Direct effects of purified staphylococcal toxic shock syndrome toxin 1 on myocardial function of isolated rabbit atria. Rev Infect Dis. 1989;2:S313-5. 7. Stevens DL, Troyer BE, Merrick DT, Mitten JE, Olson RD. Lethal effects and cardiovascular effects of purified alpha- and theta-toxins from Clostridium perfringens. J Infect Dis. 1988;157:272-9. © 1992 American College of Physicians
1 December 1992 • Annals of Internal Medicine • Volume 117 • Number 11
Downloaded from https://annals.org by Tulane University user on 01/14/2019
913
Stunned Myocardium in the Toxic Shock Syndrome Jennie R. Crews, MD; J. Kevin Harrison, MD; G. Ralph Corey, MD; Charles Steenbergen, MD, PhD; and Thomas M. Bashore, MD Annals of Internal Medicine. 1992;117:912-913.
Although it is not commonly recognized, myocardial dysfunction in the toxic shock syndrome may be severe, even life-threatening (1, 2). The cause of this acute cardiomyopathy remains unclear. Clinically, left ventricular dysfunction in the toxic shock syndrome has been reversible, similar to prolonged but transient posti s h e m i c myocardial dysfunction, a process termed "stunned myocardium" (3). Cardiac histopathologic findings in the toxic shock syndrome are limited to autopsy data, and the pathologic changes seen have been modest compared with the clinical severity of left ventricular dysfunction (4, 5). We report the first premortem cardiac histologic findings in a patient with severe, acute cardiomyopathy caused by the toxic shock syndrome. Case Report A 17-year-old, previously healthy white woman presented with fever, an erythematous rash, and hypotension. She began using tampons the previous week, during her menses. On 1 February 1992, 3 days after the end of her menses, she developed malaise, nausea, vomiting, and high fever (40.5 °C). A bright red, macular rash also developed and prompted her to seek medical attention. At initial examination, she had a temperature of 38.6 °C, a blood pressure of 76/50 mm Hg, and a heart rate of 150 beats/min. An erythematous nonblanching rash in the inguinal and axillary areas was noted, as well as blanching erythema of her face. Chest and cardiovascular examinations were otherwise normal. Leukocytosis (19 900/mm3), thrombocytopenia (79 000/ mm 3 ), and hypoalbuminemia (28 g/L) were present. Renal function was normal (creatinine, 70 /xmol/L). Hepatocellular injury was noted (aspartate aminotransferase, 1.25 fimolfL; alanine aminotransferase, 0.63 ^kat/L; alkaline phosphatase, 2.7 /tkat/L; total bilirubin, 48 fimolfL). Serum calcium was 2.00 /xmol/L and phosphate, 1.05 /xmol/L. The patient was begun on intravenous fluids, vancoFrom Duke University Medical Center, Durham, North Carolina. For current author addresses, see end of text.
912
mycin (1 gram every 12 hours), and gentamicin (100 mg every 8 hours) with improvement of her blood pressure. Cervical and urine cultures grew Staphylococcus aureus (urine culture > 50 000 colony forming units/mL). Blood cultures were sterile. Although the rash resolved on hospital day 2, she continued to have fever. On hospital day 3, she suddenly developed severe dyspnea with hypoxemia, requiring intubation. A chest radiograph showed alveolar pulmonary edema. When the patient was transferred to our institution on 5 February 1992, hemodynamic monitoring showed a mean arterial pressure of 76 mm Hg, a pulmonary capillary wedge pressure of 18 mm Hg, and a cardiac index of 2.3 L/min per m 2 surface area. Two-dimensional echocardiography showed severe global hypokinesis of the left ventricle (estimated left ventricular ejection fraction < 0.15). The patient was treated with intravenous diuretics; she had rapid hemodynamic improvement and was extubated within 24 hours. Percutaneous endomyocardial biopsies of the right ventricular septum were done on 7 February 1992 to evaluate the possibility of viral myocarditis. She completed a 10-day course of intravenous vancomycin. On 9 February 1992, she developed skin desquamation of her fingertips. A radionuclide angiogram the day before discharge demonstrated a left ventricular ejection fraction of 0.60. She was discharged home in good condition. Hematoxylin-eosin- and Masson-stained sections of an endomyocardial biopsy specimen revealed rare, acutely necrotic myocytes. No substantial inflammatory infiltrate was identified in the histologic sections (in contrast to the expected findings in acute viral myocarditis). A separate endomyocardial biopsy specimen was snap-frozen and sectioned for immunoperoxidase staining using antibodies against the T-lymphocyte surface antigens CD2 (Til), CD3 (Leu4), CD4 (Leu3), and CD8 (Leu2); antibodies against the macrophage surface antigen C D l l c (LeuM5); and antibodies against the B-lymphocyte surface antigen CD22 (Leu 14). The immunoperoxidase results showed a mild-to-moderate number of cells staining with the T-lymphocyte markers, diffusely scattered throughout the biopsy (Figure 1, top) and several small aggregates of macrophages the size of adjacent myocytes, representing foci of myophagocytosis (Figure 1, bottom). Electron microscopy on a third biopsy specimen showed several small aggregates of macrophages and fibroblasts but no myofibrillar debris. The myofibrillar volume density in the intact myocytes was also reduced, but no evidence of severe degeneration was apparent. Six months after discharge, the patient remains well.
1 December 1992 • Annals of Internal Medicine • Volume 117 • Number 11
Downloaded from https://annals.org by Tulane University user on 01/14/2019
Figure 1. Biopsy samples. Top. Immunoperoxidase-stained frozen section of an endomyocardial biopsy using Leu4 antibody to identify T lymphocytes ( ^ ) . Note the mild cellular infiltrate and primarily intact myocytes. (Original magnification, x 325.) Bottom. Immunoperoxidase-stained frozen section of an endomyocardial biopsy using LeuM5 antibody to identify macrophages. Two small macrophage aggregates ( + ) are shown, which are indicative of isolated myocyte necrosis. (Original magnification, x 325.)
She exercised 12 minutes into stage IV of the Bruce protocol. Echocardiography, at rest and after peak exercise, showed normal left ventricular function (estimated ejection fraction, 0.65). Discussion The toxic shock syndrome, an illness involving many organ systems, is believed to result from exotoxins (for example, toxic shock syndrome toxin 1 [TSST-1]) produced by certain strains of Staphylococcus aureus. Some patients may present with severe left ventricular dysfunction requiring aggressive cardiovascular support (1, 2). The cause of this myocardial dysfunction may be related to either staphylococcal exotoxin-mediated inhibition of myocardial contractility or cell-mediated myocardial injury. In-vitro studies examining TSST-1 have shown inhibition of myocardial contraction in isolated rabbit atria (6). The dramatic myocardial recovery seen in patients
successfully supported through the acute, critical stages of the illness supports the role of a staphylococcal toxin in the myocardial dysfunction. A similar clinical picture of acute cardiac dysfunction is present in Clostridium perfringens sepsis where the causative agent is the Clostridium perfringens alpha-toxin (7). Cell-mediated myocardial injury, on the other hand, can also cause left ventricular dysfunction. Histologic examination of cardiac tissue from autopsy cases, however, has shown modest inflammation compared with the clinical severity of the cardiomyopathy. The changes observed included mild perivascular fibrinous degeneration, vacuolar degeneration, and mild lymphohistiocytic infiltration of the myocardium. Small foci of acute myocyte necrosis have also been reported (4, 5). Similarly, the myocardial findings from the endomyocardial biopsy we report included rare focal acute myocyte necrosis without significant inflammatory cell infiltration. This case suggests that the cause of the cardiac dysfunction in the toxic shock syndrome is probably not cell-mediated cardiac damage as seen in viral myocarditis. The absence of substantial inflammatory necrosis in the endomyocardial biopsy suggests that staphylococcal exotoxin causes acute suppression of myocardial function. Although the biochemical mechanism of the toxin's effect on the myocardial cell is unknown, prompt, complete return of left ventricular function can be expected once the staphylococcal exotoxin has been cleared. The cardiac manifestations of the toxic shock syndrome present a dramatic form of myocardial "stunning," with little permanent damage and dramatic recovery of contractile function. Acknowledgment: the manuscript.
The authors thank Mary Clayton for preparation of
Requests for Reprints: J. Kevin Harrison, MD, Box 3331, Duke University Medical Center, Durham, NC 27710. Current Author Addresses: Dr. Crews: Box 31108, Duke University Medical Center, Durham, NC 27710. Dr. Harrison: Box 3331, Duke University Medical Center, Durham, NC 27710. Dr. Corey: Box 3038, Duke University Medical Center, Durham, NC 27710. Dr. Steenbergen: Box 3712, Duke University Medical Center, Durham, NC 27710. Dr. Bashore: Box 3012, Duke University Medical Center, Durham, NC 27710.
References 1. Fisher CJ Jr, Horowitz Z, Albertson TE. Cardiorespiratory failure in toxic shock syndrome: effect of dobutamine. Crit Care Med. 1985; 13:160-5. 2. Chesney PJ. Clinical aspects and spectrum of illness of toxic shock syndrome: overview. Rev Infect Dis. 1989;2:Sl-7. 3. Kloner RA, Przyklenk K, Patel B. Altered myocardial states. The stunned and hibernating myocardium. Am J Med. 1989;86:14-22. 4. Paris AL, Herwaldt LA, Blum D, Schmid GP, Shands KN, Broome CV. Pathologic findings in twelve fatal cases of toxic shock syndrome. Ann Intern Med. 1982;96:852-7. 5. Larkin SM, Williams DN, Osterholm MT, Tofte RW, Posalaky Z. Toxic shock syndrome: clinical, laboratory, and pathologic findings in nine fatal cases. Ann Intern Med. 1982;96:858-64. 6. Olson RD, Stevens DL, Melish ME. Direct effects of purified staphylococcal toxic shock syndrome toxin 1 on myocardial function of isolated rabbit atria. Rev Infect Dis. 1989;2:S313-5. 7. Stevens DL, Troyer BE, Merrick DT, Mitten JE, Olson RD. Lethal effects and cardiovascular effects of purified alpha- and theta-toxins from Clostridium perfringens. J Infect Dis. 1988;157:272-9. © 1992 American College of Physicians
1 December 1992 • Annals of Internal Medicine • Volume 117 • Number 11
Downloaded from https://annals.org by Tulane University user on 01/14/2019
913
