- Email: [email protected]
EBV and Persistent Malaise
1017
infection is thought initially to be in the hands of natural killer cells, though interferon, antibody, and cytotoxic T cells also seem important."The host may respond serologically to EBV with one of several patterns to some or all of the antigens that are either part of the virus or induced by infection, including viral capsid antigen (VCA), the D (diffuse) and R
(restricted) components ofEBV-induced early antigens (EA), membrane antigens (MA), and virus associated nuclear antigen (EBNA). In the course of infectious to VCA, of both IgM and classes IgG (and usually IgA), usually reach a peak at the onset of clinical signs. In addition IgG antibodies to the D component of early antigen commonly appear transiently during the clinical syndrome. Then, as IgM anti-VCA and anti-EA(D) regress, anti-EBNA antibodies appear and together with IgG antibodies to VCA usually persist for life at low unchanging levels. In symptomless infections, the titres of IgM anti-VCA are lower and instead of anti-EA(D) a response is manifested to the R-component, usually several months after seroconversion.12 Different profiles are seen in Burkitt’s lymphoma and nasopharygeal carcinoma; others are increasingly being associated with the protracted form of infectious mononucleosis and prolonged atypical illness. A hallmark for unusually severe, protracted, or recurrent illness was first noted among heterophilantibody positive infectious mononucleosis patients who had been followed for up to 39 months and responded with anti-EA(R) after the initial anti-EA(D) responses had subsided or had anti-EA(R) responses solely.13 Half of the 14 patients, mostly those with late anti-EA(R) responses, showed unusual or protracted clinical manifestations and several complained of recurrent illness. The presence of anti-EA(R), together with persisting high levels of anti-VCA, led to speculation concerning continuous EBV activity. The dearth of clinical evidence of symptomatic persistent EBV infection led Tobi and colleagues’4 to collect 7 possible cases with various combinations of vague malaise, low-grade fever, weight loss, emotional
mononucleosis, antibodies
EBV and Persistent Malaise THE Epstein-Barr virus, a.transforming herpesvirus that infects and replicates in B lymphocytes, was isolated in 1964 from African Burkitt’s lymphoma tissue’ and was subsequently shown to be the cause of infectious mononucleosis.2 EBV is a ubiquitous agent that infects most human beings. Primary infection is usually of short duration without long-term effects. Infections in children are nearly always symptomless, but in adolescents and young adults the ratio of overt to silent infections increases to between one-third and two-thirds. Occasionally, patients do not fully recover for months or even years, and increasing evidence suggests that lifelong latent infection of B lymphocytes, like that with all other human herpesviruses, is subject to reactivation. More seriously, EBV is implicated in Burkitt’s lymphoma and nasopharyngeal carcinoma, and is being increasingly recognised as a cause of lymphoproliferative disorders in males with
lymphoproliferative syndrome,3 patients with severe combined immunodeficiencyt or ataxia telangiectasia,5 recipients of renal6 bone marrow,7 or cardiac transplants,8 and patients with the acquired immunodeficiency syndrome.9 Death from EBV lymphoproliferative disease has occasionally been recorded in patients with apparently normal immunocompetence.10 X-linked
The factors involved in this broad clinical spectrum are poorly understood. Defence against primary EBV 1 2
Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet 1964; i: 702-03. Henle G, Henle W, Diehl V. Relation of Burkitt’s tumor-associated herpes-type virus
to infectious mononucleosis Proc Natl Acad Sci USA 1968, 101: 94-101. 3 Hamilton JK, Sullivan JL, Maurer HS, et al. X-linked lymphoproliferative syndrome registry report J Pediatr 1980; 96: 669-73. 4. Reece ER Gartner JG, Seemayer TA. Joncas JH. Lymphoma after thymus transplantation. N Engl J Med 1980; 302: 302. 5. Saemunsden AK, Berkel Al, Henle W, et al. Epstein-Barr-virus-carrying lymphoma in a patient with ataxia telangiectasia Br Med J 1981; 282: 425-27. 6 Hanto DW, Gajl-Peczalska J, Purtilo DT, Klein G, Simmons RL, Najarian JS. The Epstein-Barr virus in the pathogenesis of posttransplant lymphoma. Transplant Proc 1981, 13: 756-60.
7. Schubach WH, Hackman R, Neiman PE, Miller G, Thomas ED. A monoclonal immunoblastic sarcoma in donor cells bearing Epstein-Barr virus genomes following allogeneic marrow grafting foracute lymphoblastic leukemia. Blood 1982; 60: 180-87. 8. Cleary ML, Warnke R, Sklar J. Monoclonality of
lymphoproliferativelesionsincardiac based on immunoglobulin gene rearrangements. N Engl J Med 1984; 310: 477-82. 9 Ziegler JL, Drew WL, Miner RC, Mintz L, Rosenbaum E, Gershow J, Lennette ET, Granspan J, Shillitoe E, Beckstead J, Casavant C, Yamamoto K Outbreak of Burkitt’s-like lymphoma in homosexual men. Lancet 1982; ii: 631-33. 10 Robinson JE, Brown N, Andiman W, Halliday K, Francke U, Robert MF, AndersonAnvret M, Horstmann D, Miller G. Diffuse polyclonal B-cell lymphoma during primary infection with Epstein-Barr virus. N Engl J Med 1980; 302: 1293-97. transplant
recipients:
clonal
analysis
distress, gastrointestinal discomfort, myalgia, lymphadenopathy, and enlarged liver and/or spleen persisting for more than one year and associated with the presence of IgM to VCA for the same period. 4 of them had anti-EA(R) and, in the absence of other explanations for the chronic symptoms, persistent EBV infection was judged likely. Jones and coworkers15 also found raised anti-VCA and anti-EA 11. Purtilo
DT, Sakamoto K. Epsiein-Barr virus and human disease: immune responses determine the clinical and pathologic expression. Hum Pathol 1981; 12: 677-79. 12 Biggar RJ, Henle G, Böcker J, Lennette ET, Fleisher G, Henle W. Primary EpsteinBarr virus infections in African infants. II. Clinical and serological observations during seroconversion Int J Cancer 1978, 22: 244-50 13. Horwitz CA, Henle W, Henle G, Schmitz H. Clinical evaluation of patients with infectious mononucleosis and development of antibodies to the R component of the Epstein-Barr virus-induced early antigen complex. Am JJ Med 1975; 58: 330-38 14. Tobi M, Morag A, Ravid Z, Chowers I, et al. Prolonged atypical illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet 1982; i: 61-64. 15. Jones JF, Ray G, Mmnich LL, Hicks MJ, Kibler R, Lucas DO. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated early antigen antibodies. Ann Intern Med 1985; 102: 1-7.
1018
titres among 39
patients with persistent unexplained in illness, though contrast to the previous study only a few patients had IgM anti-VCA or antibodies to EA(R). There was no association between the magnitude of specific antibody titres and severity of illness, though finding of a raised anti-EA in 89% of the patients again suggested an EBV-induced disorder. Straus et al’6 have evaluated 23 patients with persistent illness and fatigue after infectious mononucleosis and found higher IgG anti-VCA and anti-EA(R) titres than in age and sex matched seropositive adults. Other abnormalities included circulating immune complexes and increased in-vitro T-cell-mediated suppression of immunoglobulin synthesis. This latter finding supports earlier observations in patients with chronic ill-health after infectious mononucleosis," though it is by no means pathognomonic for this disorder. the
.
These observations do not prove that EBV causes chronic ill health, though the evidence as outlined by Straus et al’6 seems very strong. First, there is the temporal association between infectious mononucleosis and persistent symptoms in many instances; second, the selective rise in antibody titre to virus specific antigens; and third, the abnormal suppressor cell activity usually identified with acute infectious mononucleosis (this apparently returns to normal with eventual clinical recovery"). Whatever the underlying mechanism-whether a continuing "infection" per se or an immunoregulatory disorder -patients may be much helped by the knowledge that their persistent vague complaints could have an organic basis. Moreover, there is the promise that antiviral and immunomodulatory agents could be of benefit. For now, all we can do is confirm and define the scope of the disorder, counsel our patients, and try to establish its pathogenesis.
Analgesia and the Metabolic Response to Surgery ROUTINE
postoperative analgesia
is
commonly
inadequate,’ and some of the most eloquent testimony to this effect comes from members of the medical profession.2 Strenuous attempts are being made to mend matters by better communication between anaesthetists and nurses and the increased application of techniques such as epidural analgesia and patientcontrolled infusions. The effectiveness of such measures is usually assessed by the patient’s subjective response. There is, however, a common assumption that good pain relief is reflected in concomitant beneficial changes in the metabolic and hormonal response to surgery. Is this assumption justifiable?
opioids in conventional doses, infusion techniques are unlikely to depress such responses, since large amounts are needed to inhibit hypothalamic-pituitary function.3 Epidural analgesia, on the other hand, by inhibiting transmission of afferent impulses from the operative site-and hence activation of the neuroendocrine response-is potentially of greater benefit. Kehlet and colleagues have investigated in detail the effects of epidural analgesia with local analgesics on the metabolic and hormonal response to pelvic surgery.4,5 They showed that only an extensive epidural blockade from T4 to S5 dermatome completely inhibited the response.6 A more localised epidural block provided excellent analgesia but did not inhibit the increase in plasma cortisol. They postulated that an extensive blockade was essential, because not only somatic but also sympathetic afferent fibre activity must be inhibited to With
prevent activation of the hormonal response. In all studies the epidural blockade was well established before the start of surgery. Epidural analgesia after the onset of surgical trauma was found to be of little benefit.7 The importance of autonomic afferent fibre stimulation is shown by the use of epidural analgesia in abdominal surgery. In abdominal and thoracic operations epidural blockade proved not to prevent the increase in plasma cortisol, and the reason was thought to lie in vagal afferent activity.8 More recent studies have been directed specifically at the role of sympathetic and parasympathetic stimulation in these
hormonal changes during major the results suggest that sympathetic activation is the more important since combination of epidural analgesia with a coeliac plexus block was the best method of preventing the endocrine response. Lofstrom and colleagues have shown that the level of sympathetic blockade in epidural analgesia may be lower than that of sensory blockade.",’2 Thus the relative ineffectiveness of epidural analgesia in earlier studies may have been due to inadequate inhibition
initiating the surgery,9,10 and
3
1974; 38: 736-41 4. Kehlet H. The modifying effect of general and 5. 6.
7
8.
9.
10. 16. Straus 17.
SE, Tosato G, Armstrong G, et al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection Ann Intern Med 1985, 102: 7-16 Hamblin TJ, Hussain J, Akbar AN, Tang YC, Smith JL, Jones DB. Immunotogical reason for chronic ill health after infectious mononucleosis Br Med J 1983; 287:
11
85-88.
1 Cartwright PD. Pain control after surgery a survey of current practice. Ann R Coll Surg 1985, 67: 13-16. 2. Donald I At the receiving end. Scott Med J 1976; 21: 49-57.
George JM, Reier CE, Larense RR, Rower MM. Morphine anesthesia blocks cortisol and growth hormone response to surgical stress in humans. J Clin Endocrinol Metab
12.
regional anesthesia on the endocrinemetabolic response to surgery. Reg Anesth 1982, 7: S38-48 Kehlet H. The stress response to anaesthesia and surgery Release mechanisms and modifying factors Clin Anaesthesiol 1984; 2: 315-39. Engquist A, Brandt MR, Fernandes A, Kehlet H. The blocking effect of epidural analgesia on the adrenocortical and hyperglycaemia responses to surgery. Acta Anaesth Scand 1977; 21: 330-35. Møller IW, Rem J, Brandt MR, Kehlet H. Effect of post-traumatic epidural analgesia on the cortisol and hyperglycaemic response to surgery. Acta Anaesth Scand 1982; 26: 56-58. Bromage PR, Shibata HR, Willoughby HW Influence of prolonged epidural blockade on blood sugar and cortisol responses to operations upon the upper part of the abdomen and thorax. Surg Gynecol Obstet 1971; 132: 1051-56. Tsuji H, Asoh T, Takeuchi Y, Shirasaka C. Attenuation of adrenocortical response to upper abdominal surgery with epidural blockade. Br J Surg 1983; 70: 122-24. Tsuji H, Shirasaka C, Asoh T, Takeuchi Y. Influences of splanchnic nerve blockade on endocrine-metabolic responses to upper abdominal surgery. Br J Surg 1983; 70: 437-39 Löfstrom JB, Malmquist L-Å, Bengtsson M. Can the "sympathogalvanic reflex" (skin conductance response) be used to evaluate the height of the sympathetic block in spinal analgesia Acta Anaesth Scand 1984; 28: 578-82. Bengtsson M Changes in skin blood flow and temperature during spinal analgesia evaluated by laser Doppler flowmetry and infrared thermography. Acta Anaesth Scand 1984; 28: 625-30.
infection is thought initially to be in the hands of natural killer cells, though interferon, antibody, and cytotoxic T cells also seem important."The host may respond serologically to EBV with one of several patterns to some or all of the antigens that are either part of the virus or induced by infection, including viral capsid antigen (VCA), the D (diffuse) and R
(restricted) components ofEBV-induced early antigens (EA), membrane antigens (MA), and virus associated nuclear antigen (EBNA). In the course of infectious to VCA, of both IgM and classes IgG (and usually IgA), usually reach a peak at the onset of clinical signs. In addition IgG antibodies to the D component of early antigen commonly appear transiently during the clinical syndrome. Then, as IgM anti-VCA and anti-EA(D) regress, anti-EBNA antibodies appear and together with IgG antibodies to VCA usually persist for life at low unchanging levels. In symptomless infections, the titres of IgM anti-VCA are lower and instead of anti-EA(D) a response is manifested to the R-component, usually several months after seroconversion.12 Different profiles are seen in Burkitt’s lymphoma and nasopharygeal carcinoma; others are increasingly being associated with the protracted form of infectious mononucleosis and prolonged atypical illness. A hallmark for unusually severe, protracted, or recurrent illness was first noted among heterophilantibody positive infectious mononucleosis patients who had been followed for up to 39 months and responded with anti-EA(R) after the initial anti-EA(D) responses had subsided or had anti-EA(R) responses solely.13 Half of the 14 patients, mostly those with late anti-EA(R) responses, showed unusual or protracted clinical manifestations and several complained of recurrent illness. The presence of anti-EA(R), together with persisting high levels of anti-VCA, led to speculation concerning continuous EBV activity. The dearth of clinical evidence of symptomatic persistent EBV infection led Tobi and colleagues’4 to collect 7 possible cases with various combinations of vague malaise, low-grade fever, weight loss, emotional
mononucleosis, antibodies
EBV and Persistent Malaise THE Epstein-Barr virus, a.transforming herpesvirus that infects and replicates in B lymphocytes, was isolated in 1964 from African Burkitt’s lymphoma tissue’ and was subsequently shown to be the cause of infectious mononucleosis.2 EBV is a ubiquitous agent that infects most human beings. Primary infection is usually of short duration without long-term effects. Infections in children are nearly always symptomless, but in adolescents and young adults the ratio of overt to silent infections increases to between one-third and two-thirds. Occasionally, patients do not fully recover for months or even years, and increasing evidence suggests that lifelong latent infection of B lymphocytes, like that with all other human herpesviruses, is subject to reactivation. More seriously, EBV is implicated in Burkitt’s lymphoma and nasopharyngeal carcinoma, and is being increasingly recognised as a cause of lymphoproliferative disorders in males with
lymphoproliferative syndrome,3 patients with severe combined immunodeficiencyt or ataxia telangiectasia,5 recipients of renal6 bone marrow,7 or cardiac transplants,8 and patients with the acquired immunodeficiency syndrome.9 Death from EBV lymphoproliferative disease has occasionally been recorded in patients with apparently normal immunocompetence.10 X-linked
The factors involved in this broad clinical spectrum are poorly understood. Defence against primary EBV 1 2
Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet 1964; i: 702-03. Henle G, Henle W, Diehl V. Relation of Burkitt’s tumor-associated herpes-type virus
to infectious mononucleosis Proc Natl Acad Sci USA 1968, 101: 94-101. 3 Hamilton JK, Sullivan JL, Maurer HS, et al. X-linked lymphoproliferative syndrome registry report J Pediatr 1980; 96: 669-73. 4. Reece ER Gartner JG, Seemayer TA. Joncas JH. Lymphoma after thymus transplantation. N Engl J Med 1980; 302: 302. 5. Saemunsden AK, Berkel Al, Henle W, et al. Epstein-Barr-virus-carrying lymphoma in a patient with ataxia telangiectasia Br Med J 1981; 282: 425-27. 6 Hanto DW, Gajl-Peczalska J, Purtilo DT, Klein G, Simmons RL, Najarian JS. The Epstein-Barr virus in the pathogenesis of posttransplant lymphoma. Transplant Proc 1981, 13: 756-60.
7. Schubach WH, Hackman R, Neiman PE, Miller G, Thomas ED. A monoclonal immunoblastic sarcoma in donor cells bearing Epstein-Barr virus genomes following allogeneic marrow grafting foracute lymphoblastic leukemia. Blood 1982; 60: 180-87. 8. Cleary ML, Warnke R, Sklar J. Monoclonality of
lymphoproliferativelesionsincardiac based on immunoglobulin gene rearrangements. N Engl J Med 1984; 310: 477-82. 9 Ziegler JL, Drew WL, Miner RC, Mintz L, Rosenbaum E, Gershow J, Lennette ET, Granspan J, Shillitoe E, Beckstead J, Casavant C, Yamamoto K Outbreak of Burkitt’s-like lymphoma in homosexual men. Lancet 1982; ii: 631-33. 10 Robinson JE, Brown N, Andiman W, Halliday K, Francke U, Robert MF, AndersonAnvret M, Horstmann D, Miller G. Diffuse polyclonal B-cell lymphoma during primary infection with Epstein-Barr virus. N Engl J Med 1980; 302: 1293-97. transplant
recipients:
clonal
analysis
distress, gastrointestinal discomfort, myalgia, lymphadenopathy, and enlarged liver and/or spleen persisting for more than one year and associated with the presence of IgM to VCA for the same period. 4 of them had anti-EA(R) and, in the absence of other explanations for the chronic symptoms, persistent EBV infection was judged likely. Jones and coworkers15 also found raised anti-VCA and anti-EA 11. Purtilo
DT, Sakamoto K. Epsiein-Barr virus and human disease: immune responses determine the clinical and pathologic expression. Hum Pathol 1981; 12: 677-79. 12 Biggar RJ, Henle G, Böcker J, Lennette ET, Fleisher G, Henle W. Primary EpsteinBarr virus infections in African infants. II. Clinical and serological observations during seroconversion Int J Cancer 1978, 22: 244-50 13. Horwitz CA, Henle W, Henle G, Schmitz H. Clinical evaluation of patients with infectious mononucleosis and development of antibodies to the R component of the Epstein-Barr virus-induced early antigen complex. Am JJ Med 1975; 58: 330-38 14. Tobi M, Morag A, Ravid Z, Chowers I, et al. Prolonged atypical illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet 1982; i: 61-64. 15. Jones JF, Ray G, Mmnich LL, Hicks MJ, Kibler R, Lucas DO. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated early antigen antibodies. Ann Intern Med 1985; 102: 1-7.
1018
titres among 39
patients with persistent unexplained in illness, though contrast to the previous study only a few patients had IgM anti-VCA or antibodies to EA(R). There was no association between the magnitude of specific antibody titres and severity of illness, though finding of a raised anti-EA in 89% of the patients again suggested an EBV-induced disorder. Straus et al’6 have evaluated 23 patients with persistent illness and fatigue after infectious mononucleosis and found higher IgG anti-VCA and anti-EA(R) titres than in age and sex matched seropositive adults. Other abnormalities included circulating immune complexes and increased in-vitro T-cell-mediated suppression of immunoglobulin synthesis. This latter finding supports earlier observations in patients with chronic ill-health after infectious mononucleosis," though it is by no means pathognomonic for this disorder. the
.
These observations do not prove that EBV causes chronic ill health, though the evidence as outlined by Straus et al’6 seems very strong. First, there is the temporal association between infectious mononucleosis and persistent symptoms in many instances; second, the selective rise in antibody titre to virus specific antigens; and third, the abnormal suppressor cell activity usually identified with acute infectious mononucleosis (this apparently returns to normal with eventual clinical recovery"). Whatever the underlying mechanism-whether a continuing "infection" per se or an immunoregulatory disorder -patients may be much helped by the knowledge that their persistent vague complaints could have an organic basis. Moreover, there is the promise that antiviral and immunomodulatory agents could be of benefit. For now, all we can do is confirm and define the scope of the disorder, counsel our patients, and try to establish its pathogenesis.
Analgesia and the Metabolic Response to Surgery ROUTINE
postoperative analgesia
is
commonly
inadequate,’ and some of the most eloquent testimony to this effect comes from members of the medical profession.2 Strenuous attempts are being made to mend matters by better communication between anaesthetists and nurses and the increased application of techniques such as epidural analgesia and patientcontrolled infusions. The effectiveness of such measures is usually assessed by the patient’s subjective response. There is, however, a common assumption that good pain relief is reflected in concomitant beneficial changes in the metabolic and hormonal response to surgery. Is this assumption justifiable?
opioids in conventional doses, infusion techniques are unlikely to depress such responses, since large amounts are needed to inhibit hypothalamic-pituitary function.3 Epidural analgesia, on the other hand, by inhibiting transmission of afferent impulses from the operative site-and hence activation of the neuroendocrine response-is potentially of greater benefit. Kehlet and colleagues have investigated in detail the effects of epidural analgesia with local analgesics on the metabolic and hormonal response to pelvic surgery.4,5 They showed that only an extensive epidural blockade from T4 to S5 dermatome completely inhibited the response.6 A more localised epidural block provided excellent analgesia but did not inhibit the increase in plasma cortisol. They postulated that an extensive blockade was essential, because not only somatic but also sympathetic afferent fibre activity must be inhibited to With
prevent activation of the hormonal response. In all studies the epidural blockade was well established before the start of surgery. Epidural analgesia after the onset of surgical trauma was found to be of little benefit.7 The importance of autonomic afferent fibre stimulation is shown by the use of epidural analgesia in abdominal surgery. In abdominal and thoracic operations epidural blockade proved not to prevent the increase in plasma cortisol, and the reason was thought to lie in vagal afferent activity.8 More recent studies have been directed specifically at the role of sympathetic and parasympathetic stimulation in these
hormonal changes during major the results suggest that sympathetic activation is the more important since combination of epidural analgesia with a coeliac plexus block was the best method of preventing the endocrine response. Lofstrom and colleagues have shown that the level of sympathetic blockade in epidural analgesia may be lower than that of sensory blockade.",’2 Thus the relative ineffectiveness of epidural analgesia in earlier studies may have been due to inadequate inhibition
initiating the surgery,9,10 and
3
1974; 38: 736-41 4. Kehlet H. The modifying effect of general and 5. 6.
7
8.
9.
10. 16. Straus 17.
SE, Tosato G, Armstrong G, et al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection Ann Intern Med 1985, 102: 7-16 Hamblin TJ, Hussain J, Akbar AN, Tang YC, Smith JL, Jones DB. Immunotogical reason for chronic ill health after infectious mononucleosis Br Med J 1983; 287:
11
85-88.
1 Cartwright PD. Pain control after surgery a survey of current practice. Ann R Coll Surg 1985, 67: 13-16. 2. Donald I At the receiving end. Scott Med J 1976; 21: 49-57.
George JM, Reier CE, Larense RR, Rower MM. Morphine anesthesia blocks cortisol and growth hormone response to surgical stress in humans. J Clin Endocrinol Metab
12.
regional anesthesia on the endocrinemetabolic response to surgery. Reg Anesth 1982, 7: S38-48 Kehlet H. The stress response to anaesthesia and surgery Release mechanisms and modifying factors Clin Anaesthesiol 1984; 2: 315-39. Engquist A, Brandt MR, Fernandes A, Kehlet H. The blocking effect of epidural analgesia on the adrenocortical and hyperglycaemia responses to surgery. Acta Anaesth Scand 1977; 21: 330-35. Møller IW, Rem J, Brandt MR, Kehlet H. Effect of post-traumatic epidural analgesia on the cortisol and hyperglycaemic response to surgery. Acta Anaesth Scand 1982; 26: 56-58. Bromage PR, Shibata HR, Willoughby HW Influence of prolonged epidural blockade on blood sugar and cortisol responses to operations upon the upper part of the abdomen and thorax. Surg Gynecol Obstet 1971; 132: 1051-56. Tsuji H, Asoh T, Takeuchi Y, Shirasaka C. Attenuation of adrenocortical response to upper abdominal surgery with epidural blockade. Br J Surg 1983; 70: 122-24. Tsuji H, Shirasaka C, Asoh T, Takeuchi Y. Influences of splanchnic nerve blockade on endocrine-metabolic responses to upper abdominal surgery. Br J Surg 1983; 70: 437-39 Löfstrom JB, Malmquist L-Å, Bengtsson M. Can the "sympathogalvanic reflex" (skin conductance response) be used to evaluate the height of the sympathetic block in spinal analgesia Acta Anaesth Scand 1984; 28: 578-82. Bengtsson M Changes in skin blood flow and temperature during spinal analgesia evaluated by laser Doppler flowmetry and infrared thermography. Acta Anaesth Scand 1984; 28: 625-30.