CASE REPORT hemorrhagic shock and encephalopathy syndrome
Hemorrhagic Shock and Encephalopathy Syndrome Hemorrhagic shock and encephalopathy syndrome (HSES) is a devastating symptom complex that affects previously healthy infants and is associated with significant mortality and neurologic morbidity. The syndrome was first reported less than ten years ago, and there continues to be debate regarding whether HSES actually represents a distinct clinical entity or instead is a manifestation of heat illness, occult sepsis or endotoxic shock, or perhaps toxic ingestion. Nevertheless, the signs and s y m p t o m s described as HSES present in a typical fashion in the emergency depar.tment with sudden onset of shock, encephalopathy, seizures, and coagulopathy. Even with the initiation of intensive support in the ED, the outcome is probably dismal. We describe a case of HSES and review the presentation, proposed etiologies, and management of this catastrophic illness. [Pollack CV Jr, Pender ES: Hemorrhagic shock and encephalopathy syndrome. Ann Emerg Med December 1991;20:1366-1370.]
INTRODUCTION In 1983, Levin and colleagues published the first report of a devastating illness of infants characterized by acute onset of encephalopathy, shock, high fever, profuse bloody diarrhea, consumptive coagulopathy, and hepatorenal dysfunction.t Although the pathophysiology of the disease, termed "hemorrhagic shock and encephalopathy syndrome" (HSES), has remained obscure, much speculation has accompanied reports of additional cases. We recently encountered a case of HSES in which the typical signs were present in the emergency department.
Charles V Pollack, Jr, MA, MD* Emily S Pender, MDt Jackson, Mississippi From the Division of Emergency Medicine* and the Pediatric Emergency Department,t University of Mississippi Medical Center, Jackson. Received for publication February 25, 1991. Accepted for publication April 18, 1991. Address for reprints: Charles V Pollack, Jr, MA, MD, Division of Emergency Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, Mississippi 39216-4505.
CASE REPORT A 9-month-old male infant with a history of nasal congestion and lowgrade fever for three days was put down for a nap. Twenty minutes later, his mother found him unresponsive With gasping respirations and noted blood coming from his mouth and nose. He was taken to a local hospital where he had agonal respirations, pinpoint pupils, intermittent posturing, and a systolic blood pressure of 60 m m Hg. He was orally intubated, and 100% oxygen was delivered with mechanical ventilation. A peripheral IV line was initiated for fluid resuscitation with normal saline. Arterial blood gases revealed pH 7.08 with Paco z of 36 m m Hg and Pao z of 180 m m Hg. A spun hematocrit was 33%. The patient developed seizure activity that was refractory to repeated doses of diazepam, lorazepam, phenobarbital, and phenytoin, and he was transferred to our facility by ground ambulance. On arrival in the ED 40 minutes later, the child was exhibiting generalized seizure activity. There was copious frank blood emanating from the endotracheal tube. The child's extremities were pale and cyanotic. Vital signs were blood pressure of 80 m m Hg systolic; pulse, 170; and temperature, 38.1 C rectally. There were no spontaneous respirations. Sequential fluid boluses of 20 mL/kg normal saline were given. On physical examination, there was no evidence of trauma. The pupils were pinpoint and equal; although the fundi were not visualized, a red reflex was present bilaterally. The remainder of the head and neck examination was normal. There were diffuse bilateral rhonchi with equal breath sounds on auscultation of the chest. The heart rate was rapid, and there was no murmur. Peripheral perfusion was poor as evidenced by capillary
20:12 December 1991
Annals of Emergency Medicine
1366/123
SHOCK Pollack & Pender
refill time of more than six seconds. The child's abdomen was flat and soft; there was no mass or organomegaly. While in the ED, the child passed several loose, bloody stools. Neurologic examination revealed a c o m a t o s e infant w i t h s y m m e t r i c withdrawal to painful stimuli. There was frequent, i n t e r m i t t e n t generalized seizure activity. Blood was sent for type and crossmatch. Initial laboratory studies revealed a WBC count of 5,600 with 47% segmented cells and 46% lymphocytes. H e m o g l o b i n and hematocrit were 9.7 g/dL and 28.8%, respectively. Serum electrolytes were normal; blood urea nitrogen was 32 mg/dL; serum creatinine, 1.4; and ser u m glucose, 143 mg/dL. S e r u m transaminases were mildly elevated; SGOT was 132 IU/mL, and SGPT was 156 IU/mL. Repeat arterial blood gases on 100% oxygen revealed pH 7.30; Paco2, 28 m m Hg; and Pao2, 160 m m Hg. Prothrombin time was measured at 14.6 seconds, and partial thromboplastin time was 35 seconds. Computed tomography of the head revealed no mass, hemorrhage, or midline shift. A lumbar p u n c t u r e was performed, and examination of the cerebrospinal fluid revealed normal levels of glucose and protein and one white blood cell. Chest radiograph demonstrated small bibasilar infiltrates consistent with aspiration; the cardiac silhouette appeared normal. Blood, urine, stool, respiratory secretions, and cerebrospinal fluid were sent for culture, and the child was placed on cefotaxime. The patient was admitted to the pediatric ICU, where he required high-dose continuous diazepam infusion for seizure control, vasopressor infusion and blood transfusion for cardiovascular support, and mechanical ventilation with positive end-expiratory pressure. Despite aggressive management, he deteriorated steadily and died on the fourth hospital day. Postmortem examination revealed diffuse brain edema, petechial hemorrhages of the lungs and abdominal viscera, inflammatory infiltrate in the small bowel mucosa, and blunting of the small bowel villi. No fatty degeneration of the liver was noted. All cultures were negative.
DISCUSSION T h e t e n i n f a n t s (age, 3 to 8 months) described-in the first report 124/1367
of HSES 1 were all previously healthy, and they presented and deteriorated in a fashion similar to our patient. In retrospect, seven of the ten had experienced mild, recent viral-type prodromal illnesses. There was a 70% mortality in the initial series; the three survivors were neurologically devastated. Levin et al's description was followed by numerous reports of remarkably similar cases, none temporally or geographically related, none associated with a documented infectious source, and each accompanied by speculation regarding etiology. 2-15 In addition, similar patients diagnosed and previously reported as suffering from heatstroke, Reye's syndrome, sudden infant death syndrome, n e a r - m i s s s u d d e n i n f a n t death syndrome, or other acute encephalopathies were reconsidered as possible cases of HSES.lO-12,16,17 The catastrophic presentation of HSES, coupled with its unknown etiology and similarity to other illnesses, has continued to generate interest in the syndrome, and there are now at least 139 purported cases in the English language literature. 18-3s
Incidence The i n c i d e n c e of HSES is unknown; it has been reported as a diagnostic entity for less than a decade, and its clinical overlap with other devastating illnesses of childhood makes verification of diagnosis difficult. Authors from both the United Kingdom and Israel, however, report that HSES is more common in children than either Reye's syndrome or toxic shock syndrome.26,34, 35
Presentation and Salient Features The c l i n i c a l c h a r a c t e r i s t i c s of HSES are distinctive and, in most c a s e s , o c c u r in a s i m i l a r sequence. 13,18-20,39 The typical patient is an infant of either gender 2 to 10 m o n t h s old who is unexpectedly found comatose after a mild prodromal illness of two or three days' duration. Seizures occur frequently and are often refractory to standard therapy. On arrival in the ED, the child is in shock with poor peripheral perfusion and is febrile and acidemic. Respiratory arrest is common. The onset of profuse bloody diarrhea sometimes a c c o m p a n i e d by h e m a t e m e s i s quickly ensues and is often associAnnals of Emergency Medicine
ated with bleeding from other body orifices and venipuncture sites. Pulmonary hemorrhage, as occurred in our case, is reported infrequently but can be dramatic. Laboratory evidence of hepatic and renal dysfunction is common. Hypotension and perfusion deficits usually respond to volume resuscitation and pressor agents, but neurologic decline is the rule, and death frequently occurs within two to three days. Bacteriologic and viral cultures are uniformly negative, and antibiotics are of no benefit in patient management. Survivors nearly always have profound neurologic sequelae. Other features reported with varying frequency in cases of HSES include abnormal serum levels of several enzymes (eg, Rl-antitrypsin, aldolase, and trypsinl,8,13,15,1a, ~1 24), leukocytosis, hypernatremia, hypoglycemia, and hypocalcemia. "Botryoid" nuclei (polymorphonuclear cell nuclei displaying radial hypersegmentation) similar to those seen in adult patients with heatstroke have been reported in two infants w i t h HSES. 2s C o n s i s t e n t p o s t mortem characteristics of HSES include boggy cerebral edema, focal hemorrhages in the viscera, hemorrhagic or inflammatory fluid in the bowels, and small bowel villous blunting. Acute myocardial infarction has also been reported in conjunction with HSES. 26
Pathogenesis The p a t h o p h y s i o l o g i c basis for HSES is a subject of continuing debate. Etiologic theories based on abnormalities in the serum protease system, hyperthermia (eg, heatstroke, defects in temperature regulation, malignant hyperthermia, neuroleptic malignant syndrome), infection or endotoxin release, and pancreatic d y s f u n c t i o n with e n c e p h a l o p a t h y have all been proposed as initial triggers for HSES. Levin et al's original report of HSES noted the finding of depressed levels of %-antitrypsin and elevated plasma levels of trypsin in seven of the eight patients tested. 1 C~l-Antitrypsin is a naturally occurring protease inhibitor that is also an acutephase reactant. In a patient with fulminant illness and increased trypsin levels, ~l-antitrypsin would be expected to be present in elevated levels. The authors therefore implied 20:12 December 1991
SHOCK Pollack & Pender
that the consequences of abnormal proteolytic activity (eg, by trypsin and elastase) might account for some of the clinical features of HSES. 1 Such destructive enzymes not only exert direct harmful effects but also activate the kinin and complement systems that could result in multiple organ system damage. 24 This speculation prompted other investigators to assay cq-antitrypsin and trypsin levels in their suspected HSES cases. Mughal et al reported elevated trypsin levels in three patients - one with presumed HSES, one with Reye's syndrome, and one with endotoxic shock, is These authors suggested that trypsin levels were elevated in all three patients because of decreased renal clearance of the enzyme and that elevated trypsin is not a specific marker for HSES. Other authors have suggested that the depressed levels of C,l-antitrypsin result from h y p e r t h e r m i a - i n d u c e d pancreatic injury, with release of large amounts of circulating trypsin and subsequent consumption of circulating R i - a n t i t r y p s i n . 2 # D e b y Dupont et al presented data that related elevated trypsin levels nonspecifically to septic illnesses; 27 by definition, however, patients with HSES have no identifiable infectious processes. In 1989, Levin defended his earlier suggestion that depressed ~l-antitrypsin levels were s o m e h o w the trigger for HSES, ~8 and he further theorized that the disease might result from a defect in synthesis or secretion of the enzyme, as seen in congenital ~xl-antitrypsin deficiency. This theory was supported by protein electrophoresis data from first-degree relatives of HSES victims, who had higher-than-expected incidences of abnormal cq-antitrypsin phenotypes. It was p o s t u l a t e d that o t h e r w i s e trivial infectious or inflammatory insults could trigger HSES in patients so predisposed and that effective treatment of HSES might include in: fusion of protease inhibitors. 18 Roth et al attempted to treat a patient with HSES w i t h plasmapheresis, based on the supposition that this modality would remove proteolytic enzymes and improve clotting with fresh frozen plasma replacement. 23 No beneficial effect could be demonstrated; however, the therapy was instituted relatively late in the course of the patient's disease. 20:12 December 1991
The other primary etiologic theory for HSES is supported by the typically high fever with which these patients present. Bacon et al reported five cases of heatstroke in 1979, four years before Levin et al's first report of HSES. 16 These infants (age, 4 to 8 months) exhibited remarkably similar presentations to what was later t e r m e d HSES, w i t h fever, shock, acidosis, convulsions, abnormal clotting, and hepatic dysfunction. Four of the infants died, and the fifth was neurologically devastated. All cultures were negative. P o s t m o r t e m findings were similar to those described for HSES, including diffuse petechiae and small bowel villous blunting. All five cases were thought to be p r e c i p i t a t e d by o v e r w r a p p i n g or warming during a mild infection. Bacon et al suggested that young infants, w i t h their high m e t a b o l i c rates, labile body temperatures, and inability to throw off covers, are particularly suspectible to the developm e n t of high fevers if t h e y are warmed too vigorously during otherwise minor infections. 16 Bacon et al suggested that the seizures a s s o c i a t e d w i t h h e a t s t r o k e might begin as febrile convulsions that further eIevate body temperature. Four years later, after HSES was first reported, he expanded on this theory,6,17 suggesting that the age range of 2 to 10 months might be a period of thermoregulatory imbalance, as heat production in proportion to body surface area reaches a maximum by about 5 months of age, whereas the ability to dissipate heat by sweating develops more gradually during the first year of life. A threeyear retrospective study in Britain, however, did not support overwrapping as a causative factor of HSES. 12 In 1989, Caspe et al reported five cases of "extreme hyperpyrexia of c h i l d h o o d " (temperature of more than 42 C) encountered during a 14year period and noted similarities between these children and those reported as having HSES. 28 This report in addition to another by Bacon and Bellman 1° raised the q u e s t i o n of whether HSES actually represents a clinical entity separate and distinct from heatstroke. Other authors considered the potential " t h e r m o r e g u l a t o r y imbalance" etiology from additional perspectives, including subclinical viral Annals of Emergency Medicine
infection with pyrogen productionS, 29 and genetic factors similar to those seen in malignant hyperthermia.3O,31 Autonomic dysfunction has been implicated in the latter. 32 Another proposed hyperthermia-related etiology is represented by a variation of the neuroleptic malignant syndrome. 24 Although no reported patient with HSES has had a positive i n g e s t i o n h i s t o r y or t o x i c o l o g i c screen, 13 there are several drugs and toxins as well as neuroleptics that can induce hyperthermia. An infectious etiology has often been proposed for HSES. Although the acute presentation is very suggestive of overwhelming sepsis, bacterial and viral cultures are uniformly negative in these patients. Nevertheless, in their first report, Levin et al noted similarities between HSES a n d both the viral hemorrhagic fevers (eg, dengue and Congo-Crimean hemorrhagic fever) and toxic shock syndrome and other toxin-induced diseases.1 The viral hemorrhagic fevers, however, usually occur only in endemic areas, and toxic shock syndrome is usually associated with a desquamative rash and positive blood cultures. Morris and M a t t h e w s suggested that HSES was due to a toxin produced by some " c o m m o n bacterium," perhaps a constituent of the normal flora of the upper respiratory tract.2, 4 They projected a vulnerability period, coexistent with the age range most common in HSES, between the exhaustion of maternal IgG antibodies and the development of the infant's own immunity. Cultures might be insensitive to the overgrowth of normal flora, and the viruses responsible for the prodromal illness would not disturb the causative bacteria. These authors further suggested this same mechanism to explain SIDS. Conway et al suggested that the gastrointestinal tract is the source of an endotoxin that induces HSES. 24 They proposed that gastrointestinal tract mucosal injury, resulting from trauma, ischemia, hypoxia, hypotension, hyperthermia, or viral gastroenteritis (as in the prodromal illnesses of many HSES patients), allows absorption and rapid systemic spread of endotoxin that mediates a sepsislike state. Chesney and Chesney noted that Streptococcus pneumoniae and the 1368/125
SHOCK Pollack & Pender
influenza A virus both release and/or contain active neuraminidases.19 These enzymes readily cleave the term i n a l N - a c e t y l n e u r a m i n i c acid moiety from c,l-antitrypsin , allowing rapid uptake of the latter into the l i v e r . T h e d e c r e a s e d l e v e l s of ~t-antitrypsin sometimes detected in HSES could therefore result from abnormal sensitivity to neuraminidase release associated w i t h low-grade infection with such agents. Acute panereatitis has been suggested as an etiology of HSES. Hypocalcemia and h y p e r a m y l a s e m i a are sometimes found in HSES, and pancreatic injury could explain the release of proteolytic enzymes into the systemic circulation.7, 24 Pancreatic encephalopathy is a vague diagnosis more common in adults than in children, but acute pancreatitis in infants s o m e t i m e s p r e s e n t s s i m i l a r l y to Reye's s y n d r o m e , w h i c h is often confused with HSES.7, 33 The mystery surrounding the true etiology of HSES may not be resolved soon. The Centers for Disease Control has not yet accepted HSES as a specific disease entity, suggesting a p o s i t i o n t h a t the s y n d r o m e m a y m e r e l y r e p r e s e n t an u n u s u a l response to various insults. 26 The incidence of HSES is too small to allow prospective study. It is likely that the eoagulopathy, transaminase elevation, acidosis, and acute renal insufficiency seen in HSES occur secondary to profound shock, but the etiologies of the shock and the acute encephalopathy remain obscure. Most etiologic theories, as discussed, combine genetic, infectious, environmental, and metabolic factors in the pathogenesis of HSES. All that is clear at present is that through various mediators - circulating proteases, abnormal thermoregulation, endotoxins, or abnormal genetic predisposition - some trigger or combination of triggers precipitates the m u l t i s y s t e m involvement and inexorable course of the symptom complex of HSES.
ED Diagnosis and Management The definitive diagnosis of HSES is made at autopsy. The e m e r g e n c y physician is faced with an encephalopathic, febrile child with coagulopathy and muhisystem failure and must manage the patient accordingly and aggressively. Shock, fever I and c o a g u l o p a t h y m a y be p r e s e n t in 126/1369
FIGURE. Diagnostic criteria for
HSES. other diseases, such as septic shock, toxic shock syndrome, overwhelming viral infection, Reye's syndrome, heatstroke, severe hypoxia, toxic ingestion, acute hemorrhagic pancreatitis, acute hemolytic-uremic syndrome, and fulminant hepatitis. 1,21,24,29,39 The history is perhaps most helpful in establishing a working diagnosis of HSES, primarily with regard to acute onset of seizures or coma. Among other useful discriminating features for HSES are normal serum ammonia levels with elevated serum transaminases, the absence of the desquamating rash c o m m o n l y seen in toxic shock syndrome, and evidence of renal dysfunction. Lack of response to antimicrobial therapy in the first several hours is also useful; if survival can be prolonged for 24 to 48 hours, negative bacteriologic results may be helpful in guiding subsequent management. Clinical diagnostic criteria for HSES have been proposed by several authors. 18,32,36 Key features of these schemes are listed (Figure). Management of HSES is primarily supportive. Prompt fluid resuscitation is mandatory; pressor agents are sometimes required to maintain vital organ perfusion. Definitive airway management with intubation is indicated because of the frequency of early respiratory arrest in HSES. Me~ ehanical ventilation with or without positive end-expiratory pressure is necessary to maintain oxygenation. Transfusion is often required because of ongoing blood loss; fresh frozen plasma should be used liberally in the m a n a g e m e n t of coagulopathy. Antipyretics and anticonvulsants are mainstays of therapy. Measures to reduce cerebral edema should be instituted but may yield little benefit, as evidenced by the p r o f o u n d l y boggy brain t i s s u e of HSES v i c t i m s at autopsy. H e m o dialysis may be used to support renal function if the patient survives the initial insult. Dantrolene has been proposed as a therapeutic agent in extremely hyperpyrexic patients, based on its efficacy in malignant hyperthermia. 32 Plasmapheresis, initiated early, may prove to be useful. 23 More specific treatment modalities may be Annals of Emergency Medicine
Clinical Acute encephalopathy Shock Fever Diarrhea Bleeding from gastrointestinal or respiratory tract or venipuncture sites Laboratory Decreasing hemoglobin Decreasing platelet count Elevated serum transaminaseswith normal serum ammonia Renal dysfunction Metabolic acidosis Exclusions Sepsis (positive cultures from any source) Metabolic disorders Toxic shock syndrome Hemolytic-uremic syndrome
discovered as the etiology of HSES is further elucidated.
SUMMARY Hemorrhagic shock and encephalopathy syndrome is an acute, catastrophic disease of infants that results in high m o r t a l i t y and neurologic devastation among the majority of survivors. It has a typical presentation manifested in the ED by acute onset of encephalopathy, shock, high fever, dehydration with bloody diarrhea and emesis, consumptive coagulopathy, and h e p a t o r e n a l dysfunction. There are several differential considerations, most important, sepsis or toxic s h o c k s y n d r o m e , Reye's syndrome, and heatstroke. To date, the best hope for survival is aggressive supportive management initiated in the ED.
REFERENCES 1. Levin M, Hjelm M, Kay JDS, et al: Haemorrhagic shock and encephalopathy: A new syndrome with a high mortality in young children. Lancet 1983;2:64-67. 2. Morris ~A, Matthews TS: Haemorrhagic shock and encephalopathy: A new syndrome in young children. Lancet I983;2:278. 3. Schrager GO, Shah A: Hemorrhagic shock/encephalopathy syndrome in infancy. Lancet 1983~2:39& 4. Morris JA: Haemorrhagic shock and encephalopathy. Lancet 1983;2:686. 5. Lafeber HN, Voort EVD, de Groot R: Haemorrhagic shock and encephalopathy syndrome. Lancet 1983;2: 795. 6. Bacon CJ: Heatstroke and haemorrhagic shock and eneephalopathy. Lancet 1983;2:918. 7. Morens DM: Hemorrhagic shock, encephalopathy, and the pancreas. Lancet 1983;2:967. 8. Beaufils F, Aujard Y: Haemorrhagic shock and encephalopathy syndrome. Lancet 1983;2:1086. 9. McGucken RB: Hemorrhagic shock and encephalopathy syndrome. Lancet 1983;2,:1087. 10. Bacon CJ, Bellman MH: Heatstroke as a possible
20:12 December 1991
SHOCK Pollack & Pender
cause of encephalopathy in infants. Br Mad J 1983;287: 328. 11. Variend S: Unexplained protracted infant deaths. Acta Paediatr Scand 1984;73:828-834. 12. PHLS Communicable Disease Surveillance Centre: Joint British Paediatric Association and Communicable Disease Surveillance Centre surveillance scheme for hemorrhagic shock encephalopathy syndrome: Surveillance report for 1982-4. Br Mad J 1985~290:1578-1579. 13. Whittington LK, RoscelIi JD, Parry WH: Hemorrhagic shock and encephalopathy: Further description of a new syndrome. J Pediatr 1985;106:599-602. 14. Stanton AN: Haemorrhagic shock and encephalopathy. Lancet 1985;2:1019-1020. 15. Mughal MZ, Wells FE, Addison GM, et al: Raised serum immunoreactive trypsin in the haemorrhagic shock and encephalopathy syndrome. Acta Paediatr Scand 1985;74:456-457. 16. Bacon C, Scott D, Jones P: Heatstroke in w e l l wrapped infants. Lancet 1979;1:422-425. 17. Bacon GJ: Overheating in infancy. Arch Dis Child 1983;58:673-674. 18. Levin M, Pincott JR, Hjelm M, et al: Hemorrhagic shock and encephalopathy: Clinical, pathologic, and biochemical features. J Pediatr 1989;114:194-203.
1990;144:1077. 21. Van Acker KJ, Roodhooft AM, Van Bever H: Haemorrhagic shock and eneephalopathy. Eur J Padiatr 1986;145:66-69. 22. Hervas JA, Masip MC, Caimari M, et ah Further observations in haemorrhagic shock and encephalopathy syndrome. Helv Paediatr Acta 1986;41:469-471.
32. Chaves-Carballo E, Montes IE, Nelson B, et al: Hemorrhagic shock and encephalopathy: Clinical definition of a catastrophic syndrome in infants. A m J Dis Child 1990;144:1079-1082.
23. Roth B, Younossi-Hartenstein A, Schroder R, et al: Haemorrhagic shock and encephalopathy syndrome: Plasmaphoresis as a therapeutic approach. Eur J Pediatr 1987;146:83-85.
33. Morens DM, Hammar SL, Heicher DA: Idiopathic acute pancreatitis in children: Association with a clinical picture resembling Reye syndrome. A m J Dis Child 1974;128:401-404.
24. Conway EE, Varlotta L, Singer LP, et al: Hemorrhagic shock and encephalopathy: Is it really a new entity? Pediatr Emerg Care 1990;6:131-134.
34. Haemorrhagic shock and encephalopathy. Lancet 1985;2:534-535.
25. Neves JF, Lopes D, CasaI MI, et al: "Botryoid nuclei" of leucocytes in the haemorrhagic shock and encephalopathy syndrome. Lancet 1988;1:112. 26. Sorer S, Shahak E: Myocardial infarction in hemorrhagic shock and encephalopathy syndrome. Pediatr Emerg Care 1989;5:99-101. 27. Deby-Dupm~t G, Hass M, Pincemaul I, et al: Immunoreactive trypsin in the adult respiratory distress syndrome. Intens Care Med 1984~10:7-12. 28. Caspe WB, Nucci AT, Cho S: Extreme hyperpyrexia in childhood: Presentation similar to hemorrhagic
shock and encephalopathy. Clin Pediatr 1989~28:76-80.
19. Chesney PJ, Chesney RW: Hemorrhagic shock and encephalopathy: Reflections about a new devastating disorder t h a t affects n o r m a l children. [ Pediatr 1989;114:254-256.
29. Tam AYC, Ng LOL, Cheung PT, et ah Hemorrhagic shock encephalopathy. Acta Paediatr Stand 1989;78: 458-462.
20. Corrigan JJ: The " H " in hemorrhagic shock and encephalopathy should be "hyperpyrexia." A m J Dis Child
30. 8essler DI: Malignant hyperthermia. J Pediatr 19861109:9-14.
20:12 December 1991
31. WeibJey RE, Pimentel B, Ackerman NB: Hemorrhagic shock and encephalopathy syndrome of infants and children. Crit Care Med 1989;17:335-338.
Annals of Emergency Medicine
35. Sofer S: Haemorrhagic shock and encephalopathy syndrome: A new syndrome in young children associated with high morbidity and mortality. Harefuah 1988;115:63-66. 36. Nelson EAS, Taylor BJ, Dempster AG: Haemorrhagic shock and encephalopathy syndrome. N Z Med J 1988;101:69-71. 37. Parsons AC, Tuohy PG: Haemorrhagic shock encephalopathy and sudden infant death syndromes. N Z Med ] 1988;101:672. 38. 8ofer S, Phillip M, Hershkowits J, et al: Hemorrhagic shock and encephalopathy syndrome: Its association w i t h h y p e r t h e r m i a . A m J Dis Child 1986; 140:I252-1254. 39. David TJ, Mughal MZ: Haemorrhagic shock and encephalopathy syndrome: Epidemic of a new disease. J R Soc Mad 1984;77:721-722.
1370/127
Hemorrhagic Shock and Encephalopathy Syndrome Hemorrhagic shock and encephalopathy syndrome (HSES) is a devastating symptom complex that affects previously healthy infants and is associated with significant mortality and neurologic morbidity. The syndrome was first reported less than ten years ago, and there continues to be debate regarding whether HSES actually represents a distinct clinical entity or instead is a manifestation of heat illness, occult sepsis or endotoxic shock, or perhaps toxic ingestion. Nevertheless, the signs and s y m p t o m s described as HSES present in a typical fashion in the emergency depar.tment with sudden onset of shock, encephalopathy, seizures, and coagulopathy. Even with the initiation of intensive support in the ED, the outcome is probably dismal. We describe a case of HSES and review the presentation, proposed etiologies, and management of this catastrophic illness. [Pollack CV Jr, Pender ES: Hemorrhagic shock and encephalopathy syndrome. Ann Emerg Med December 1991;20:1366-1370.]
INTRODUCTION In 1983, Levin and colleagues published the first report of a devastating illness of infants characterized by acute onset of encephalopathy, shock, high fever, profuse bloody diarrhea, consumptive coagulopathy, and hepatorenal dysfunction.t Although the pathophysiology of the disease, termed "hemorrhagic shock and encephalopathy syndrome" (HSES), has remained obscure, much speculation has accompanied reports of additional cases. We recently encountered a case of HSES in which the typical signs were present in the emergency department.
Charles V Pollack, Jr, MA, MD* Emily S Pender, MDt Jackson, Mississippi From the Division of Emergency Medicine* and the Pediatric Emergency Department,t University of Mississippi Medical Center, Jackson. Received for publication February 25, 1991. Accepted for publication April 18, 1991. Address for reprints: Charles V Pollack, Jr, MA, MD, Division of Emergency Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, Mississippi 39216-4505.
CASE REPORT A 9-month-old male infant with a history of nasal congestion and lowgrade fever for three days was put down for a nap. Twenty minutes later, his mother found him unresponsive With gasping respirations and noted blood coming from his mouth and nose. He was taken to a local hospital where he had agonal respirations, pinpoint pupils, intermittent posturing, and a systolic blood pressure of 60 m m Hg. He was orally intubated, and 100% oxygen was delivered with mechanical ventilation. A peripheral IV line was initiated for fluid resuscitation with normal saline. Arterial blood gases revealed pH 7.08 with Paco z of 36 m m Hg and Pao z of 180 m m Hg. A spun hematocrit was 33%. The patient developed seizure activity that was refractory to repeated doses of diazepam, lorazepam, phenobarbital, and phenytoin, and he was transferred to our facility by ground ambulance. On arrival in the ED 40 minutes later, the child was exhibiting generalized seizure activity. There was copious frank blood emanating from the endotracheal tube. The child's extremities were pale and cyanotic. Vital signs were blood pressure of 80 m m Hg systolic; pulse, 170; and temperature, 38.1 C rectally. There were no spontaneous respirations. Sequential fluid boluses of 20 mL/kg normal saline were given. On physical examination, there was no evidence of trauma. The pupils were pinpoint and equal; although the fundi were not visualized, a red reflex was present bilaterally. The remainder of the head and neck examination was normal. There were diffuse bilateral rhonchi with equal breath sounds on auscultation of the chest. The heart rate was rapid, and there was no murmur. Peripheral perfusion was poor as evidenced by capillary
20:12 December 1991
Annals of Emergency Medicine
1366/123
SHOCK Pollack & Pender
refill time of more than six seconds. The child's abdomen was flat and soft; there was no mass or organomegaly. While in the ED, the child passed several loose, bloody stools. Neurologic examination revealed a c o m a t o s e infant w i t h s y m m e t r i c withdrawal to painful stimuli. There was frequent, i n t e r m i t t e n t generalized seizure activity. Blood was sent for type and crossmatch. Initial laboratory studies revealed a WBC count of 5,600 with 47% segmented cells and 46% lymphocytes. H e m o g l o b i n and hematocrit were 9.7 g/dL and 28.8%, respectively. Serum electrolytes were normal; blood urea nitrogen was 32 mg/dL; serum creatinine, 1.4; and ser u m glucose, 143 mg/dL. S e r u m transaminases were mildly elevated; SGOT was 132 IU/mL, and SGPT was 156 IU/mL. Repeat arterial blood gases on 100% oxygen revealed pH 7.30; Paco2, 28 m m Hg; and Pao2, 160 m m Hg. Prothrombin time was measured at 14.6 seconds, and partial thromboplastin time was 35 seconds. Computed tomography of the head revealed no mass, hemorrhage, or midline shift. A lumbar p u n c t u r e was performed, and examination of the cerebrospinal fluid revealed normal levels of glucose and protein and one white blood cell. Chest radiograph demonstrated small bibasilar infiltrates consistent with aspiration; the cardiac silhouette appeared normal. Blood, urine, stool, respiratory secretions, and cerebrospinal fluid were sent for culture, and the child was placed on cefotaxime. The patient was admitted to the pediatric ICU, where he required high-dose continuous diazepam infusion for seizure control, vasopressor infusion and blood transfusion for cardiovascular support, and mechanical ventilation with positive end-expiratory pressure. Despite aggressive management, he deteriorated steadily and died on the fourth hospital day. Postmortem examination revealed diffuse brain edema, petechial hemorrhages of the lungs and abdominal viscera, inflammatory infiltrate in the small bowel mucosa, and blunting of the small bowel villi. No fatty degeneration of the liver was noted. All cultures were negative.
DISCUSSION T h e t e n i n f a n t s (age, 3 to 8 months) described-in the first report 124/1367
of HSES 1 were all previously healthy, and they presented and deteriorated in a fashion similar to our patient. In retrospect, seven of the ten had experienced mild, recent viral-type prodromal illnesses. There was a 70% mortality in the initial series; the three survivors were neurologically devastated. Levin et al's description was followed by numerous reports of remarkably similar cases, none temporally or geographically related, none associated with a documented infectious source, and each accompanied by speculation regarding etiology. 2-15 In addition, similar patients diagnosed and previously reported as suffering from heatstroke, Reye's syndrome, sudden infant death syndrome, n e a r - m i s s s u d d e n i n f a n t death syndrome, or other acute encephalopathies were reconsidered as possible cases of HSES.lO-12,16,17 The catastrophic presentation of HSES, coupled with its unknown etiology and similarity to other illnesses, has continued to generate interest in the syndrome, and there are now at least 139 purported cases in the English language literature. 18-3s
Incidence The i n c i d e n c e of HSES is unknown; it has been reported as a diagnostic entity for less than a decade, and its clinical overlap with other devastating illnesses of childhood makes verification of diagnosis difficult. Authors from both the United Kingdom and Israel, however, report that HSES is more common in children than either Reye's syndrome or toxic shock syndrome.26,34, 35
Presentation and Salient Features The c l i n i c a l c h a r a c t e r i s t i c s of HSES are distinctive and, in most c a s e s , o c c u r in a s i m i l a r sequence. 13,18-20,39 The typical patient is an infant of either gender 2 to 10 m o n t h s old who is unexpectedly found comatose after a mild prodromal illness of two or three days' duration. Seizures occur frequently and are often refractory to standard therapy. On arrival in the ED, the child is in shock with poor peripheral perfusion and is febrile and acidemic. Respiratory arrest is common. The onset of profuse bloody diarrhea sometimes a c c o m p a n i e d by h e m a t e m e s i s quickly ensues and is often associAnnals of Emergency Medicine
ated with bleeding from other body orifices and venipuncture sites. Pulmonary hemorrhage, as occurred in our case, is reported infrequently but can be dramatic. Laboratory evidence of hepatic and renal dysfunction is common. Hypotension and perfusion deficits usually respond to volume resuscitation and pressor agents, but neurologic decline is the rule, and death frequently occurs within two to three days. Bacteriologic and viral cultures are uniformly negative, and antibiotics are of no benefit in patient management. Survivors nearly always have profound neurologic sequelae. Other features reported with varying frequency in cases of HSES include abnormal serum levels of several enzymes (eg, Rl-antitrypsin, aldolase, and trypsinl,8,13,15,1a, ~1 24), leukocytosis, hypernatremia, hypoglycemia, and hypocalcemia. "Botryoid" nuclei (polymorphonuclear cell nuclei displaying radial hypersegmentation) similar to those seen in adult patients with heatstroke have been reported in two infants w i t h HSES. 2s C o n s i s t e n t p o s t mortem characteristics of HSES include boggy cerebral edema, focal hemorrhages in the viscera, hemorrhagic or inflammatory fluid in the bowels, and small bowel villous blunting. Acute myocardial infarction has also been reported in conjunction with HSES. 26
Pathogenesis The p a t h o p h y s i o l o g i c basis for HSES is a subject of continuing debate. Etiologic theories based on abnormalities in the serum protease system, hyperthermia (eg, heatstroke, defects in temperature regulation, malignant hyperthermia, neuroleptic malignant syndrome), infection or endotoxin release, and pancreatic d y s f u n c t i o n with e n c e p h a l o p a t h y have all been proposed as initial triggers for HSES. Levin et al's original report of HSES noted the finding of depressed levels of %-antitrypsin and elevated plasma levels of trypsin in seven of the eight patients tested. 1 C~l-Antitrypsin is a naturally occurring protease inhibitor that is also an acutephase reactant. In a patient with fulminant illness and increased trypsin levels, ~l-antitrypsin would be expected to be present in elevated levels. The authors therefore implied 20:12 December 1991
SHOCK Pollack & Pender
that the consequences of abnormal proteolytic activity (eg, by trypsin and elastase) might account for some of the clinical features of HSES. 1 Such destructive enzymes not only exert direct harmful effects but also activate the kinin and complement systems that could result in multiple organ system damage. 24 This speculation prompted other investigators to assay cq-antitrypsin and trypsin levels in their suspected HSES cases. Mughal et al reported elevated trypsin levels in three patients - one with presumed HSES, one with Reye's syndrome, and one with endotoxic shock, is These authors suggested that trypsin levels were elevated in all three patients because of decreased renal clearance of the enzyme and that elevated trypsin is not a specific marker for HSES. Other authors have suggested that the depressed levels of C,l-antitrypsin result from h y p e r t h e r m i a - i n d u c e d pancreatic injury, with release of large amounts of circulating trypsin and subsequent consumption of circulating R i - a n t i t r y p s i n . 2 # D e b y Dupont et al presented data that related elevated trypsin levels nonspecifically to septic illnesses; 27 by definition, however, patients with HSES have no identifiable infectious processes. In 1989, Levin defended his earlier suggestion that depressed ~l-antitrypsin levels were s o m e h o w the trigger for HSES, ~8 and he further theorized that the disease might result from a defect in synthesis or secretion of the enzyme, as seen in congenital ~xl-antitrypsin deficiency. This theory was supported by protein electrophoresis data from first-degree relatives of HSES victims, who had higher-than-expected incidences of abnormal cq-antitrypsin phenotypes. It was p o s t u l a t e d that o t h e r w i s e trivial infectious or inflammatory insults could trigger HSES in patients so predisposed and that effective treatment of HSES might include in: fusion of protease inhibitors. 18 Roth et al attempted to treat a patient with HSES w i t h plasmapheresis, based on the supposition that this modality would remove proteolytic enzymes and improve clotting with fresh frozen plasma replacement. 23 No beneficial effect could be demonstrated; however, the therapy was instituted relatively late in the course of the patient's disease. 20:12 December 1991
The other primary etiologic theory for HSES is supported by the typically high fever with which these patients present. Bacon et al reported five cases of heatstroke in 1979, four years before Levin et al's first report of HSES. 16 These infants (age, 4 to 8 months) exhibited remarkably similar presentations to what was later t e r m e d HSES, w i t h fever, shock, acidosis, convulsions, abnormal clotting, and hepatic dysfunction. Four of the infants died, and the fifth was neurologically devastated. All cultures were negative. P o s t m o r t e m findings were similar to those described for HSES, including diffuse petechiae and small bowel villous blunting. All five cases were thought to be p r e c i p i t a t e d by o v e r w r a p p i n g or warming during a mild infection. Bacon et al suggested that young infants, w i t h their high m e t a b o l i c rates, labile body temperatures, and inability to throw off covers, are particularly suspectible to the developm e n t of high fevers if t h e y are warmed too vigorously during otherwise minor infections. 16 Bacon et al suggested that the seizures a s s o c i a t e d w i t h h e a t s t r o k e might begin as febrile convulsions that further eIevate body temperature. Four years later, after HSES was first reported, he expanded on this theory,6,17 suggesting that the age range of 2 to 10 months might be a period of thermoregulatory imbalance, as heat production in proportion to body surface area reaches a maximum by about 5 months of age, whereas the ability to dissipate heat by sweating develops more gradually during the first year of life. A threeyear retrospective study in Britain, however, did not support overwrapping as a causative factor of HSES. 12 In 1989, Caspe et al reported five cases of "extreme hyperpyrexia of c h i l d h o o d " (temperature of more than 42 C) encountered during a 14year period and noted similarities between these children and those reported as having HSES. 28 This report in addition to another by Bacon and Bellman 1° raised the q u e s t i o n of whether HSES actually represents a clinical entity separate and distinct from heatstroke. Other authors considered the potential " t h e r m o r e g u l a t o r y imbalance" etiology from additional perspectives, including subclinical viral Annals of Emergency Medicine
infection with pyrogen productionS, 29 and genetic factors similar to those seen in malignant hyperthermia.3O,31 Autonomic dysfunction has been implicated in the latter. 32 Another proposed hyperthermia-related etiology is represented by a variation of the neuroleptic malignant syndrome. 24 Although no reported patient with HSES has had a positive i n g e s t i o n h i s t o r y or t o x i c o l o g i c screen, 13 there are several drugs and toxins as well as neuroleptics that can induce hyperthermia. An infectious etiology has often been proposed for HSES. Although the acute presentation is very suggestive of overwhelming sepsis, bacterial and viral cultures are uniformly negative in these patients. Nevertheless, in their first report, Levin et al noted similarities between HSES a n d both the viral hemorrhagic fevers (eg, dengue and Congo-Crimean hemorrhagic fever) and toxic shock syndrome and other toxin-induced diseases.1 The viral hemorrhagic fevers, however, usually occur only in endemic areas, and toxic shock syndrome is usually associated with a desquamative rash and positive blood cultures. Morris and M a t t h e w s suggested that HSES was due to a toxin produced by some " c o m m o n bacterium," perhaps a constituent of the normal flora of the upper respiratory tract.2, 4 They projected a vulnerability period, coexistent with the age range most common in HSES, between the exhaustion of maternal IgG antibodies and the development of the infant's own immunity. Cultures might be insensitive to the overgrowth of normal flora, and the viruses responsible for the prodromal illness would not disturb the causative bacteria. These authors further suggested this same mechanism to explain SIDS. Conway et al suggested that the gastrointestinal tract is the source of an endotoxin that induces HSES. 24 They proposed that gastrointestinal tract mucosal injury, resulting from trauma, ischemia, hypoxia, hypotension, hyperthermia, or viral gastroenteritis (as in the prodromal illnesses of many HSES patients), allows absorption and rapid systemic spread of endotoxin that mediates a sepsislike state. Chesney and Chesney noted that Streptococcus pneumoniae and the 1368/125
SHOCK Pollack & Pender
influenza A virus both release and/or contain active neuraminidases.19 These enzymes readily cleave the term i n a l N - a c e t y l n e u r a m i n i c acid moiety from c,l-antitrypsin , allowing rapid uptake of the latter into the l i v e r . T h e d e c r e a s e d l e v e l s of ~t-antitrypsin sometimes detected in HSES could therefore result from abnormal sensitivity to neuraminidase release associated w i t h low-grade infection with such agents. Acute panereatitis has been suggested as an etiology of HSES. Hypocalcemia and h y p e r a m y l a s e m i a are sometimes found in HSES, and pancreatic injury could explain the release of proteolytic enzymes into the systemic circulation.7, 24 Pancreatic encephalopathy is a vague diagnosis more common in adults than in children, but acute pancreatitis in infants s o m e t i m e s p r e s e n t s s i m i l a r l y to Reye's s y n d r o m e , w h i c h is often confused with HSES.7, 33 The mystery surrounding the true etiology of HSES may not be resolved soon. The Centers for Disease Control has not yet accepted HSES as a specific disease entity, suggesting a p o s i t i o n t h a t the s y n d r o m e m a y m e r e l y r e p r e s e n t an u n u s u a l response to various insults. 26 The incidence of HSES is too small to allow prospective study. It is likely that the eoagulopathy, transaminase elevation, acidosis, and acute renal insufficiency seen in HSES occur secondary to profound shock, but the etiologies of the shock and the acute encephalopathy remain obscure. Most etiologic theories, as discussed, combine genetic, infectious, environmental, and metabolic factors in the pathogenesis of HSES. All that is clear at present is that through various mediators - circulating proteases, abnormal thermoregulation, endotoxins, or abnormal genetic predisposition - some trigger or combination of triggers precipitates the m u l t i s y s t e m involvement and inexorable course of the symptom complex of HSES.
ED Diagnosis and Management The definitive diagnosis of HSES is made at autopsy. The e m e r g e n c y physician is faced with an encephalopathic, febrile child with coagulopathy and muhisystem failure and must manage the patient accordingly and aggressively. Shock, fever I and c o a g u l o p a t h y m a y be p r e s e n t in 126/1369
FIGURE. Diagnostic criteria for
HSES. other diseases, such as septic shock, toxic shock syndrome, overwhelming viral infection, Reye's syndrome, heatstroke, severe hypoxia, toxic ingestion, acute hemorrhagic pancreatitis, acute hemolytic-uremic syndrome, and fulminant hepatitis. 1,21,24,29,39 The history is perhaps most helpful in establishing a working diagnosis of HSES, primarily with regard to acute onset of seizures or coma. Among other useful discriminating features for HSES are normal serum ammonia levels with elevated serum transaminases, the absence of the desquamating rash c o m m o n l y seen in toxic shock syndrome, and evidence of renal dysfunction. Lack of response to antimicrobial therapy in the first several hours is also useful; if survival can be prolonged for 24 to 48 hours, negative bacteriologic results may be helpful in guiding subsequent management. Clinical diagnostic criteria for HSES have been proposed by several authors. 18,32,36 Key features of these schemes are listed (Figure). Management of HSES is primarily supportive. Prompt fluid resuscitation is mandatory; pressor agents are sometimes required to maintain vital organ perfusion. Definitive airway management with intubation is indicated because of the frequency of early respiratory arrest in HSES. Me~ ehanical ventilation with or without positive end-expiratory pressure is necessary to maintain oxygenation. Transfusion is often required because of ongoing blood loss; fresh frozen plasma should be used liberally in the m a n a g e m e n t of coagulopathy. Antipyretics and anticonvulsants are mainstays of therapy. Measures to reduce cerebral edema should be instituted but may yield little benefit, as evidenced by the p r o f o u n d l y boggy brain t i s s u e of HSES v i c t i m s at autopsy. H e m o dialysis may be used to support renal function if the patient survives the initial insult. Dantrolene has been proposed as a therapeutic agent in extremely hyperpyrexic patients, based on its efficacy in malignant hyperthermia. 32 Plasmapheresis, initiated early, may prove to be useful. 23 More specific treatment modalities may be Annals of Emergency Medicine
Clinical Acute encephalopathy Shock Fever Diarrhea Bleeding from gastrointestinal or respiratory tract or venipuncture sites Laboratory Decreasing hemoglobin Decreasing platelet count Elevated serum transaminaseswith normal serum ammonia Renal dysfunction Metabolic acidosis Exclusions Sepsis (positive cultures from any source) Metabolic disorders Toxic shock syndrome Hemolytic-uremic syndrome
discovered as the etiology of HSES is further elucidated.
SUMMARY Hemorrhagic shock and encephalopathy syndrome is an acute, catastrophic disease of infants that results in high m o r t a l i t y and neurologic devastation among the majority of survivors. It has a typical presentation manifested in the ED by acute onset of encephalopathy, shock, high fever, dehydration with bloody diarrhea and emesis, consumptive coagulopathy, and h e p a t o r e n a l dysfunction. There are several differential considerations, most important, sepsis or toxic s h o c k s y n d r o m e , Reye's syndrome, and heatstroke. To date, the best hope for survival is aggressive supportive management initiated in the ED.
REFERENCES 1. Levin M, Hjelm M, Kay JDS, et al: Haemorrhagic shock and encephalopathy: A new syndrome with a high mortality in young children. Lancet 1983;2:64-67. 2. Morris ~A, Matthews TS: Haemorrhagic shock and encephalopathy: A new syndrome in young children. Lancet I983;2:278. 3. Schrager GO, Shah A: Hemorrhagic shock/encephalopathy syndrome in infancy. Lancet 1983~2:39& 4. Morris JA: Haemorrhagic shock and encephalopathy. Lancet 1983;2:686. 5. Lafeber HN, Voort EVD, de Groot R: Haemorrhagic shock and encephalopathy syndrome. Lancet 1983;2: 795. 6. Bacon CJ: Heatstroke and haemorrhagic shock and eneephalopathy. Lancet 1983;2:918. 7. Morens DM: Hemorrhagic shock, encephalopathy, and the pancreas. Lancet 1983;2:967. 8. Beaufils F, Aujard Y: Haemorrhagic shock and encephalopathy syndrome. Lancet 1983;2:1086. 9. McGucken RB: Hemorrhagic shock and encephalopathy syndrome. Lancet 1983;2,:1087. 10. Bacon CJ, Bellman MH: Heatstroke as a possible
20:12 December 1991
SHOCK Pollack & Pender
cause of encephalopathy in infants. Br Mad J 1983;287: 328. 11. Variend S: Unexplained protracted infant deaths. Acta Paediatr Scand 1984;73:828-834. 12. PHLS Communicable Disease Surveillance Centre: Joint British Paediatric Association and Communicable Disease Surveillance Centre surveillance scheme for hemorrhagic shock encephalopathy syndrome: Surveillance report for 1982-4. Br Mad J 1985~290:1578-1579. 13. Whittington LK, RoscelIi JD, Parry WH: Hemorrhagic shock and encephalopathy: Further description of a new syndrome. J Pediatr 1985;106:599-602. 14. Stanton AN: Haemorrhagic shock and encephalopathy. Lancet 1985;2:1019-1020. 15. Mughal MZ, Wells FE, Addison GM, et al: Raised serum immunoreactive trypsin in the haemorrhagic shock and encephalopathy syndrome. Acta Paediatr Scand 1985;74:456-457. 16. Bacon C, Scott D, Jones P: Heatstroke in w e l l wrapped infants. Lancet 1979;1:422-425. 17. Bacon GJ: Overheating in infancy. Arch Dis Child 1983;58:673-674. 18. Levin M, Pincott JR, Hjelm M, et al: Hemorrhagic shock and encephalopathy: Clinical, pathologic, and biochemical features. J Pediatr 1989;114:194-203.
1990;144:1077. 21. Van Acker KJ, Roodhooft AM, Van Bever H: Haemorrhagic shock and eneephalopathy. Eur J Padiatr 1986;145:66-69. 22. Hervas JA, Masip MC, Caimari M, et ah Further observations in haemorrhagic shock and encephalopathy syndrome. Helv Paediatr Acta 1986;41:469-471.
32. Chaves-Carballo E, Montes IE, Nelson B, et al: Hemorrhagic shock and encephalopathy: Clinical definition of a catastrophic syndrome in infants. A m J Dis Child 1990;144:1079-1082.
23. Roth B, Younossi-Hartenstein A, Schroder R, et al: Haemorrhagic shock and encephalopathy syndrome: Plasmaphoresis as a therapeutic approach. Eur J Pediatr 1987;146:83-85.
33. Morens DM, Hammar SL, Heicher DA: Idiopathic acute pancreatitis in children: Association with a clinical picture resembling Reye syndrome. A m J Dis Child 1974;128:401-404.
24. Conway EE, Varlotta L, Singer LP, et al: Hemorrhagic shock and encephalopathy: Is it really a new entity? Pediatr Emerg Care 1990;6:131-134.
34. Haemorrhagic shock and encephalopathy. Lancet 1985;2:534-535.
25. Neves JF, Lopes D, CasaI MI, et al: "Botryoid nuclei" of leucocytes in the haemorrhagic shock and encephalopathy syndrome. Lancet 1988;1:112. 26. Sorer S, Shahak E: Myocardial infarction in hemorrhagic shock and encephalopathy syndrome. Pediatr Emerg Care 1989;5:99-101. 27. Deby-Dupm~t G, Hass M, Pincemaul I, et al: Immunoreactive trypsin in the adult respiratory distress syndrome. Intens Care Med 1984~10:7-12. 28. Caspe WB, Nucci AT, Cho S: Extreme hyperpyrexia in childhood: Presentation similar to hemorrhagic
shock and encephalopathy. Clin Pediatr 1989~28:76-80.
19. Chesney PJ, Chesney RW: Hemorrhagic shock and encephalopathy: Reflections about a new devastating disorder t h a t affects n o r m a l children. [ Pediatr 1989;114:254-256.
29. Tam AYC, Ng LOL, Cheung PT, et ah Hemorrhagic shock encephalopathy. Acta Paediatr Stand 1989;78: 458-462.
20. Corrigan JJ: The " H " in hemorrhagic shock and encephalopathy should be "hyperpyrexia." A m J Dis Child
30. 8essler DI: Malignant hyperthermia. J Pediatr 19861109:9-14.
20:12 December 1991
31. WeibJey RE, Pimentel B, Ackerman NB: Hemorrhagic shock and encephalopathy syndrome of infants and children. Crit Care Med 1989;17:335-338.
Annals of Emergency Medicine
35. Sofer S: Haemorrhagic shock and encephalopathy syndrome: A new syndrome in young children associated with high morbidity and mortality. Harefuah 1988;115:63-66. 36. Nelson EAS, Taylor BJ, Dempster AG: Haemorrhagic shock and encephalopathy syndrome. N Z Med J 1988;101:69-71. 37. Parsons AC, Tuohy PG: Haemorrhagic shock encephalopathy and sudden infant death syndromes. N Z Med ] 1988;101:672. 38. 8ofer S, Phillip M, Hershkowits J, et al: Hemorrhagic shock and encephalopathy syndrome: Its association w i t h h y p e r t h e r m i a . A m J Dis Child 1986; 140:I252-1254. 39. David TJ, Mughal MZ: Haemorrhagic shock and encephalopathy syndrome: Epidemic of a new disease. J R Soc Mad 1984;77:721-722.
1370/127
