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Survival with Methylprednisolone in Canine Endotoxin Shock’

Treatment

L. WHITE, D.V.M., LINDA T. ARCHER, M.S., BEVERLY K. BELLER, B.S., AND LERNER B. HINSHAW, PH.D.

Veterans Administration Hospital, Departments of Pathology and of Physiology and Biophysics, Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104

University

of

Submitted for publication June 14, 1977 The use of corticosteroids has been intensively studied for the treatment of endotoxin shock; however, there still remains much controversy over their use. This study was designed to determine the therapeutic value of treatment with methylprednisolone sodium succinate in the awake and anesthetized canine receiving LDlw of Escherichia coli endotoxin by either intravenous slow infusion or bolus injection. Methylprednisolone (30 mg/kg) was administered initially at I5 min following the onset of endotoxin infusion and then at 90 min given a maintenance infusion of 15 mgikg for 120 min. It was found that treatment with methylprednisolone significantly increased survival rate (83%) in dogs receiving LD,,, E. coli endotoxin by slow infusion in either the awake or anesthetized state. Both the 5-hr infusion and bolus injection of endotoxin produced a 100% mortality if steroid was not administered. Treatment with methylprednisolone did not alter the 100% mortality in the canine bolus-injected endotoxin shock model. Survival was associated with a normoglycemia and stabilized hematocrit, while death was accompanied by hypoglycemia and severe hemoconcentration.

lished, and results vary from negligible effectiveness [14, 151 to nearly complete Significant changes occurring with endoprotection [9,21, 24, 27, 28, 331. However, toxin shock are progressive malfunctions in experimental protocols with animal models most organ systems, including the heart, usually consist of bolus injections of endoliver, lung, kidney, and brain, associated toxin and steroid in the anesthetized state with depressed hemodynamics and metaboand in many instances the degree of lethality lism [5, 16, 231. Development of an effecis not stated. Variations in results may be tive therapy for treatment is often met with accounted for by the fact that steroids have failure due to the inability of comprehending been used both as a pretreatment [32] as the various pathophysiologic mechanisms well as post-treatment [15, 251 for shock. operative in the experimental animal model A recent clinical study has demonstrated [ 181. Many laboratory studies are difficult statistically significant protection with to evaluate because various anesthetics steroids against the lethal effects of sepsis have been used [IS, 25, 321, and in un[29]; however, the value of corticosteroids anesthetized animal studies the endotoxin is for the treatment of septic shock still reusually administered by bolus injection mains a controversial issue [25, 30, 321. rather than by slow infusion [ 15, 25, 321. Suggested benefits of corticosteroid action Numerous experimental and clinical in the animal model subjected to endotoxin studies employing exogenously adminshock include stimulation of gluconeogeneistered corticosteroids in the therapy of sis [ 191, decreased pulmonary congestion endotoxin or septic shock have been puband pathology [25], preservation of integI Methylprednisolone sodium succinate (Solu- rity of cellular membranes [34], promotion Medrol, Upjohn Co., Kalamazoo, Mich.). of adequate tissue perfusion [21], protecINTRODUCTION

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0022-48041?810254-0357$01.00/O Copyright 0 1978 by Academic Press, Inc. All rights of reproduction in any form reserved.

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tion of the liver during warm ischemia [9], increased blood flow and elevated arterial blood pressure [ 15, 331, increased cardiac output [27], and augmented muscle, skin, and bone blood flows [ 151. Since studies in endotoxin shock have demonstrated hepatosplanchnic pooling of blood, hypoglycemia [4], and depressed gluconeogenesis [ 121,it would seem that glucocorticoids, reported to stimulate gluconeogenesis, promote tissue perfusion, and protect the liver from ischemia, should diminish or abolish the adverse effects of endotoxin. The glucocorticoid, methylprednisolone sodium succinate (MP) (Solu-Medrol, Upjohn Co., Kalamazoo, Mich.), was chosen in the present study as a therapeutic regimen for the treatment of endotoxin shock in the canine receiving intravenous JAoo of Escherichia coli endotoxin by either slow infusion or bolus injection. METHODS

Thirty adult mongrel dogs of random sex, selected for freedom of clinical signs of disease, were used in the present study. All dogs were screened for microfilaria of Dirofilaria immitis (heartworms) and were eliminated if positive. Animals were treated for intestinal parasites and allowed a stabilization period of 3 to 6 weeks; only those with leukocyte counts in the range of 8000 to 22,000/mm3 and hematocrits exceeding 36% were utilized. This study was divided into five groups with each group consisting of six dogs. Group Z included awake dogs given slow infusions of E. co/i endotoxin (LDioo) (B5 Strain, Difco, Detroit, Mich.) during a 5-hr period with no therapy. Animals in Group ZZ were also awake and administered slow infusions of endotoxin (LD,,,) during a 5-hr period with MP treatment beginning 15 minutes after the initial infusion of endotoxin. The MP, 50 mg/ml of sterile water, was given in a bolus injection of 30 mg/kg at +15 min, and a maintenance dose was administered via slow infusion starting at

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+90 min over a 120-min period at a dosage of 15 mg/kg. Group ZZZdogs were anesthetized with sodium pentobarbital, 30 mg/kg, and then administered the LDloo dose of endotoxin by slow infusion. This group received MP as administered to Group II. Group IV animals were anesthetized with sodium pentobarbital, then given a bolus injection of endotoxin (LD,,,) and administered MP as in Groups II and III. Group V animals received a bolus injection of endotoxin (LD,,,) after they were anesthetized with sodium pentobarbital but were not treated with methylprednisolone. The LD,,, of E. co/i endotoxin (mean, 2.25 mg/ ml) was established by utilizing the survival results from Groups I and V (non-steroid treated endotoxin-shocked animals) in which all dogs died. A Longdwell indwelling catheter (Beckton-Dickinson, Rutherford, N. J.) was placed in the external jugular vein of all animals studied and taped in place for collecting blood samples and administering endotoxin and steroid. A special sling was used to support the unanesthetized dogs in a comfortable upright position during the initial 7 hr; afterward, the dogs were returned to their cages. Dogs living through 7 days postendotoxin were considered permanent survivors. Experiments were designed to follow alterations in peripheral white blood cell (WBC) counts, rectal temperature ( TR), hematocrit (Hct), and blood glucose concentrations, in both treated and nontreated animals. In all groups glucose, WBC, TR, and Hct were measured initially before endotoxin as well as +15 and +30 min after endotoxin, then hourly from +60 through +420 min. Blood samples were also collected at +24 hr and +7 days postendotoxin in surviving animals. Rectal temperatures were obtained using a Tele-Thermometer probe (Yellow Springs Instruments, Yellow Springs, Ohio). Leukocyte counts were measured with a Coulter ZF automatic particle counter (Coulter Electronics, Inc, Hialeah, Fla.).

WHITE ETAL.:

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tocrit values (P < 0.05) when compared with animals administered endotoxin without MP treatment (Groups I and V). Hematocrits also markedly increased (P < 0.05) in dogs administered bolus injections of endotoxin and treated with MP (Group IV) compared with animals infused slowly with endotoxin and treated with MP (Group II). RESULTS Hematocrits remained elevated in two dogs Table 1 presents mean changes in in Group IV that survived through 24 hr hematocrits in dogs receiving LD,,, E. coli but died by 36 hr postendotoxin administraendotoxin. The most marked increases tion. Survival data are also shown in Table (P < 0.02) were observed in animals not 1. Increased survival rates (83%) were obreceiving MP following a slow infusion of served in the two groups of animals reendotoxin (Group I). Dogs treated with MP ceiving slow infusions of LD,,, endotoxin after slow infusion of endotoxin (Groups II and treated with MP (Groups II and III). and III) exhibited significantly lower hema- Of particular interest is the fact that anes-

Blood glucose concentrations were determined using a Beckman glucose analyzer (Beckman Instruments, Inc., Fullerton, Calif.) with an accuracy of +3 mg%. Statistics were carried out utilizing the t test for paired or unpaired data.

TABLE 1 ALTERATIONSIN HEMATOCRITIN DOGSADMINISTEREDENDOTOXIN" Time Minutes +300

+360

+420

Group I: Awake dogs, slow infusion endotoxin-no treatment 47(2) 50(2) 56(l) 64(2) 68(l) 69(2) 66(l) 4~2)

66( 1)

68(3)

Control*

+ 15

+30

+60

+120

+180

+240

Number Hours Days survivingp +24 t7 total number d

d

016

Group II: Awake dogs, slow infusion endotoxin-steroid treatment? 432) 48(2) 54(3) 56(2) 58(4) 56(3) 53(3) 50(2) 50(2) 50(l) Pf 0.02 0.005 0.001 0.001 0.001

46(2)

44(3)

516

Group III: Anesthetized dogs, slow infusion endotoxin-steroid treatment’ 43(l) 47(2) 52(4) 58(4) 57(3) 55(3) 55(3) 55(3) 55(3) 47(l) P’ 0.01 0.005 0.02 0.025 0.05

49(4)

41( 1)

516

63(l) 0.005

d

016

d

d

016

Group IV: Anesthetized dogs, bolus injection endotoxin-steroid treatment? 4%‘) 49(2) 49(3) 55(3) 61(3) 62(3) 64(3) 63(4) 62(4) 59(4) P 0.05 0.02 0.02 0.05 Group V: Anesthetized dogs, bolus injection endotoxin-no treatment 45(3) 46(2) 47(3) 51(3) 54(3) 60(3) 62(4) 60(4) 58(12) 58(11) P’ 0.05

o Total of 30 dogs, 6 in each group. All groups were injected with LD,, (mean, 2.25 mgikg) E. coli endotoxin. Values expressed as the mean (SE). b Initial measurement for each dog before endotoxin. c Survival rate. d Six of six animals died. c Steroid treatment: MP (30 mg/kg) given by bolus IV at +15 min and then by slow infusion at +90 min for 120 min at a dosage of 15 mg/kg. ’ Unpaired comparison to Group I. D Unpaired comparison to Group II.

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thesia did not influence survival results. Animals with the most marked increases in hematocrit did not usually survive. All dogs in Group I died when administered LD,,, E. coli endotoxin over a 5-hr infusion period. All six animals in Group IV receiving a bolus injection of LD,,, endotoxin died even though they were posttreated with MP. The mortality rate was 100% for Group V after LD,,, bolus in the absence of treatment with MP. Alterations in blood glucose concentrations in individual animals in response to LD,,, endotoxin are arrayed in Table 2. Individual values in Table 2 reveal that hypoglycemia progressively developed in Groups I and V in which MP was not administered and in Group IV animals receiving bolus endotoxin with MP treatment. Hyperglycemia was seen approximately 30 to 120 min postendotoxin in Groups II, III, and IV that were administered MP. Group V animals given bolus injections of endotoxin but no steroid developed a progressive hypoglycemia. Individual blood glucose values remained elevated as late as 7 hr after endotoxin in Group III animals given MP. Table 3 presents alterations in peripheral leukocyte concentrations after administration of endotoxin. Endotoxin injection caused a significant leukopenia in all five groups (P < 0.05) at 15 through 60 min when compared to control values. The levels of leukopenia for Groups IV and V receiving endotoxin by bolus injection were lower (P < 0.05) than in the slow infusion groups (Groups I, II, and III). A significant leukocytosis (P < 0.01) was observed at 24 hr in Groups II and III in which 83% of all animals survived. Groups I through IV showed significant febrile responses (P < 0.05) after administration of endotoxin by either slow infusion or bolus injection in both awake and anesthetized dogs. In Group V the only significant (P < 0.025) increase of rectal temperature occurred at 360 min with only two dogs surviving at that time.

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DISCUSSION

The primary purpose of this study was to determine the effectiveness of intravenous administration of MP as a treatment for canine endotoxin shock. Shock was produced in awake and anesthetized dogs via either bolus injections or 5-hr infusions of LD,,, E. co/i endotoxin. Results clearly demonstrate an increased survival (83%) with MP treatment during slow infusion of endotoxin. In contrast, all dogs treated with MP died when endotoxin was administered as a bolus. Thomas and Brockman found that post-treatment with MP did not increase survival in dogs administered intravenous bolus endotoxin (32); however, others found that administration of MP at 1 and 7 hr after bolus injection of endotoxin [25] increased survival time in dogs. A recently reported double-blind study of patients in sepsis documented increased survival with MP [29] which is corroborated by the present studies using a slow-infusion animal model. The half-life of MP has been reported to be approximately 3 to 4 hr [8], and, therefore, in the present study a maintenance dose of 15 mg/kg body wt was infused for a 2-hr period beginning 90 min after the onset of endotoxin infusion and 75 min following the initial injection of MP. The additional administration of MP may have influenced survival by maintaining its plasma concentration at effective levels during and following administration of endotoxin. A controversy currently exists over the use of anesthetics in animal shock models. Data from the present study document that use of sodium pentobarbital as an anesthetic agent did not influence survival results in this study. Both groups of animals receiving MP after slow infusion of LDloo endotoxin has an 83% survival rate although six dogs were anesthetized and six animals were awake. The hematocrit increased markedly in all groups; however, animals treated with MP showed significantly less hemoconcentra-

WHITE ET AL.: INCREASED

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TABLE 2 ALTERATIONS IN BLOOD GLUCOSE CONCENTRATION IN DOGSADMINISTERED AN LD,, OFE. Cou

ENDOTOXIN~J

Time Minutes Dog No.

Control

+30

+60

+ 120

39

33

d

54 d 60 67

57

57

67 68

61 61

75 90 112 41 91 79

78 96 136 29 75 80

66 107 107 23 88 85

81 140 120 c 108 74

Group III: Anesthetized dogs, slow infusion endotoxin-steroid treatment’ 87 76 180 122 142 106 13 89 101 111 97 185 205 144 117 14 94 108 115 105 130 104 128 113 15 96 99 83 79 130 131 94 80 16 82 93 140 109 127 93 94 106 17 102 106 80 75 119 97 105 92 18 91 96

58 94 104 83 121 73

58 90 115 83 101 82

98 103 102 154 e 85

Group IV: Anesthetized dogs, bolus injection endotoxin-steroid treatmenth 80 43 145 156 124 90 19 99 104 89 92 105 107 75 77 20 91 115 57 56 145 173 102 65 21 84 142 99 85 104 207 164 109 22 89 126 91 82 103 137 123 94 23 108 140 89 85 141 158 126 91 24 100 134

56 d 48 85 67 98

d

treatmenF 56 54 d 61 52 39 59 68 65 73 81

Group II: Awake dogs, slow infusion endotoxin-steroid treatment’ 97 165 168 153 99 7 109 110 109 93 136 123 111 8 97 98 120 144 132 144 118 9 104 113 51 108 106 71 55 10 92 87 80 91 120 103 106 11 107 95 100 109 110 93 80 12 103 100

Group V: Anesthetized dogs, bolus injection endotoxin-no 146 119 82 48 25 98 179 98 84 84 60 26 80 123 140 101 101 48 27 97 126 89 102 104 65 28 85 85 105 142 94 81 29 92 115 83 100 93 62 30 106 137

treatment 49 38 50 66 51 33

44 35 d 53 25 15

+420

Hours i24

+360

Group I: Awake dogs, slow infusion endotoxin-no 86 136 78 1 100 92 81 66 40 2 78 87 70 84 67 3 101 88 103 116 80 4 90 101 79 75 81 5 77 74 90 96 104 6 106 95

+180

+ 240

+300

+15

50 79 65 79

40 d

60

68 d d

63

Days +7

e e

112 120 98 101 103 88 110 109 96 96

e e 78 38

a Blood glucose in milligram percentage. b LD,m mean 2.25 mg/kg E. coli endotoxin. c Slow infusion given intravenously over a 5-hr period. d Death occurred within 60 min of previous sample. e Death occurred between 420 min and 24 hr. ‘Treated with 30 mg/kg methylprednisolone sodium succinate by bolus injection at 15 min after endotoxin injection then a slow infusion of 15 mg/kg methylprednisolone at 90 min postendotoxin for a 120-min period. g Anesthetized with sodium pentobarbital, 30 mg/kg. h Bolus injection given intravenously over a 2-minperiod. i Death occurred between 24 and 36 hr.

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VARIATIONS

IN LEUKOCYTE

COUNTS

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3

IN DOGS ADMINISTERED

ENDOTOXIN”

Minutes

Group I

Group II P Group III P Group IV pd Group V Pd

c

r

+30

+60

+120

12,800 (1,7W

9,600 (2,W 0.05

5,100 ww 0.01

6,000 (5W 0.005

7,900 (1,5W

8,800 8,600 14,600 13,900 12,900 (2,200) (1,900) (4,800) (3,300) (5,900)

15,500 (1,400)

6,700 8,700 7,000 (1,900) (1,900) (l,ooO) 0.001 0.005 0.005

7,500 (1,500) 0.005

10,200 9,000 14,500 17,100 16,300 41,300 (2,100) (1,800) (2,800) (4,ooO) (2,700) (6,200) 0.01 0.01

19,700 (3,200)

P

+300

Days t7

+15

+180

+240

HOWS +24

Controlb

+360

+420

(1.W

4,800 5,100 (900) (l,m) 0.001 0.005

10,100 7,300 13,500 16,800 19,500 54,600 (2,300) (1,800) (3,900) (4,200) (3,100) 9,500 0.05 0.001

20,600 (6,700)

0.01

5,200 cw 0.001

13,500 Pw

2,900 VW O.cQl

3,900 (5W 0.001

4,800 (3W 0.001

7,cao W’% 0.005

13,000 12,800 21,600 19,500 17,400 20,600 (1,100) (lZ”W (2,800) (3,600) (6,700) 0.05

0

14,500

2,400

cw

3,800 (4w 0.01

5,400 WV 0.01

7,500 Pm

10,700 11,400 12,500 13,800 (2,200) (2,300) (1,100) (2,400)

r

cww

12,600 @@a

8,400

0.005

9,600 (5W

r

‘,.aSee Table 1. Leukocyte counts expressed per cubic millimeter. c Six of six animals died. d Paired comparison to Control values.

tion. The degree of hemoconcentration appeared to be an important factor in determining mortality. The decreased hematocrits seen in surviving animals could be attributed to the steroid’s action in preserving the integrity of cell membranes [34], promotion of tissue perfusion [21], increased blood flow, and elevated blood pressure [15, 331. Prager et al. has previously demonstrated that dogs given steroids required less fluid to maintain systemic arterial pressure and urine output [25]. Normoglycemia was associated with survival of animals in Groups II and III receiving a lethal slow infusion of endotoxin followed by treatment with MP. The presence of normoglycemia suggests a stimulating effect of MP on hepatic gluconeogenesis [ 191 possibly through promotion of adequate hepatic and mesenteric perfusion [9, 21, 331. Animals of the present study in Groups I, IV, and V became hypoglycemic and all dogs died in these groups. Hypoglycemia has been

previously associated with death in canine endotoxin shock [l, 4, 181 and a positive correlation has been established between maintained blood glucose levels and survival [ 181. The action of MP on the liver may have been an important factor determining survival in the present study. The early leukopenia observed in all groups after initiation of either slow infusion or bolus injection of endotoxin was similar to previous results reported by this laboratory (17) as well as to those of other investigators [2, 3, 281. The initial leukopenia was more severe in the two groups receiving bolus injections of endotoxin. Mulholland and Cluff reported that endotoxin causes granulocytes to adhere to the capillary endothelial cells and then later leave the circulation and move into the tissue (22). The return of the leukocyte count to near normal or to a leukocytotic state corroborates earlier studies and may be the result of entry of new leukocytes from the bone marrow into the circulation [lo, 13,

WHITE

ET AL.: INCREASED

SURVIVAL

171,Leukocytosis has also been reported to occur after corticosteroid injection [6], and this mechanism might account for some degree of the leukocytosis seen in the survivors. The leukocytosis seen in the animals infused with LD,,, endotoxin and treated with steroid was similar to but more marked than that observed in dogs given sublethal endotoxin as previously reported [35-371. Elevated temperatures occurred in all groups except Group V. Although the mechanisms for the pyrogenic response to endotoxin are not clearly identified, studies have shown that the neutrophil can release a pyrogen which will produce a febrile response in animals administered endotoxin [ 11J. There is also evidence that endotoxin produces fever by direct action upon the brain [lo]. A recent hypothesized mechanism is that hyperthermia may be due to inhibition of Prostaglandin E2 catabolism in the hypothalmus [3 11. Corticosteroids have been reported to reduce leukocyte pyrogen production [7]; however, the groups receiving corticosteroids in this study still exhibited fevers. This may have been due to an overwhelming quantity of endotoxin resulting in excessive pyrogen versus antipyrogenic activity of the corticosteroid. The absence of an elevated temperature in Group V may be the result of the lethal bolus injections of endotoxin producing a poor tissue perfusion, thus negating any pyrexia from pyrogen release. ACKNOWLEDGMENTS Research was supported by the Veterans Administration Hospital, OU Biomedical Research Support Grant, and US Navy Project NOO014-C-0029. The authors express their appreciation to R. T. Brantley, 0. Elmore, and M. Dale Prince for technical assistance and to Kathy Fowler and Jeanette Glasgow for secretarial and editorial support.

REFERENCES 1. Archer, L. T. Hypoglycemia in conscious dogs in live Escherichia co/i septicemia: A chronic study. Circ. Shock 3: 93, 1976. 2. Atkins, E. Pathogenesis of fever. Physiol. Rev. 40: 580-646, 1960.

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Bennet, I. L., Jr., Cluff, L. E. Bacterial pyrogens. Pharmacol. Rev. 9: 427, 1957. Berk, J. L., Hagen, J. F., Beyer, W. M., et al. Hypoglycemia of shock. Ann. Surg. 171: 400, 1970. Berry, L. J. Metabolic effects of bacterial endotoxins. In S. Kadis, G. Weinbaum, and S. J. Ajl (Eds.), Microbial Toxins, New York: Academic Press, 1971. Vol. V, p. 165. 6. Dale, D. C., Fauci, A. S., Guerry, D., ef al. Comparison of agents producing a neutrophilic leukocytosis in man: hydrocortisone, prednisone, endotoxin, and etiocholanolone. J. C/in. Invrsf. 56: 803, 1975. Dillard, G. M., and Bodel, P. Studies on steroid fever: II, Pyrogenic and antipyrogenic activity in virro of some endogenous steroids of man. J. C/in. Invest. 49: 2418, 1970. 8. DiSanto, A. R. The Upjohn Company. Personal communication. 9. Delpin, E. S., Figueoroa, I., Lopez, R., et a/. Protective effect of steroids on liver ischemia. Amer. Surg. 683, 1975. 10. Freedman, H. H. Further studies on passive transfer of tolerance to pyrogenicity of bacterial endotoxin. The febrile and leukopenic responses. J. Exp. Med. 112: 619, 1960. D. L., and Wood, 11. Gillman, S. M., Bornstein, W. B., Jr. Studies on the pathogenesis of fever. J. E.xp. Med. 114: 729, 1961. 12. Groves, A. C., Woolf, L. I., O’Regan, P. J., ef a/. Impaired gluconeogenesis in dogs with E. coli bacteremia. Surgery 76: 533, 1974. 13. Herion, J. C., Walker, R. I., Herring, W. B., and Palmer, J. G. Effects of endotoxin and nitrogen mustard on leukocyte kinetics. Blood 25: 522, 1965. 14. Hinshaw. L. B. Shock tour symposium. J. Ok/a. State Med. Assoc. 59: 477, 1966. 15. Hinshaw, L. B., Solomon, L. A., Freeny, P. C., et al. Endotoxin shock: hemodynamic and survival effects of methylprednisolone. Arch. Surg. 94: 61, 1967. 16. Hinshaw, L. B. Release of vasoactive agents and the vascular effects of endotoxin. In S. Kadis, G. Weinbaum, and S. J. Ajl (Eds.), Microbial Toxins, New York: Academic Press, 1971. Vol. V, p. 209. 17. Hinshaw, L. B., Mathis, M. C., Naneato, J. A., and Holmes, D. D. Recovery patterns and lethal manifestations of live E. co/i organism shock. J. Trauma 10: 787, 1970. 18. Hinshaw, L. B., Peyton, M. D., Archer, L. T., et crl. Prevention of death in endotoxin shock by glucose administration. Surg. Gynecol. Ohstet. 139: 851, 1974. 19. Holtzman, S., Schuler, J., Earnest, W., et al. Carbohydrate metabolism during endotoxemia. Circ. Shock 1: 99, 1974. 20. Lillehei, R. C., and Maclean, L. D. The intestinal

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factor in irreversible endotoxin shock. Ann. Surg. 148: 513, 1958. 21. Motsay, G. J., Alho, A., Jaeger, T., er al. Effects

of corticosteroids on the circulation in shock: experimental and clinical results. Fed. Proc. 29: 1861, 1970. 22. Mulholland, J. H., and Cluff, L. E. The effect of endotoxin upon susceptibility to infection: The role of the granulocyte. In Bacterial Endoroxins, A Symposium. New Jersey: Quinn & Boden, 1964, p. 211. 23. Nagler, A. L., and Levenson, S. M. Experimental hemorrhagic and endotoxin shock. In S. Kadis, G. Weinbaum, and S. J. Ajl (Eds.), Microbial Toxins, New York: Academic Press, 1971. Vol. v, p. 341. 24. Pitcairn, M., Schuler, J., Erve, P. R., er ul. Glucocorticoid and antibiotic effect of experimental gram-negative bacteremic shock. Arch. Surg. 110:1012, 1975.

25. Prager, R., Kirsh, M. M., Dunn, E., et al. The benefits of corticosteroids in endotoxic shock. Ann. Thorac. Surg. 19: 142, 1975.

26. Rackwitz, R., Jahrmarker, H., Prechtel, K., et al. Hypoglykamie wahrend kreislaufshock. Klin. Wochenschr. 52: 605, 1974. 27. Sambhi, M. P., Weil, M. H., and Udhoji, U. H. Acute pharmacodynamic effects of glucocorticoids: cardiac output and related hemodynamic changes in normal subjects and patients in shock. Circularion

31: 523, 1965.

28. Schuler, J. J., Evre, P. R., and Schumer, W.

Glucocorticoid effect on hepatic carbohydrate metabolism in the endotoxin-shocked monkey. Ann. Surg. 183: 345, 1976.

29. Schumer, W. Steroids in the treatment of clinical septic shock. Ann. Surg. 184: 333, 1976. 30. Sladen, A. Methylprednisolone: Pharmacologic doses in shock lung syndrome. J. Thorac. Cardiovasc.

Surg. 71: 800, 1976.

31. Splawinski, J. A. Mediation of hyperthermia by prostaglandin E,: A new hypothesis. Arch. Pharm. 297: S95, 1977. 32. Thomas, C. S., and Brockman, S. K., The role of adrenal corticosteroid therapy in Escherichia coli endotoxin shock. Surg. Gynecol. Obstet. 126: 61, 1968.

33. Vaughn, D., Kirschbaum, T., Bersentes, T., ef al. Effects of corticosteroid hormones on regional circulation in endotoxin shock. Proc. Sot. Exp. Biol. Med. 124: 760, 1967.

34. Weissman, G. Labilization and stabilization of lysosomes. Fed. Proc. 53: 1038, 1964. 3.5. White, G. L., Archer, L. T., Schroeder, T., ef al. Development of a new model for the study of endotoxin shock. Physiologist 19: 409, 1976. 36. White, G. L., Archer, L., Beller, B., er al. Leukocyte response, liver function and altered survival in superlethal endotoxin shock. Fed. Proc. 36: 503, 1977. 37. White, G. L., Archer, L. T., Beller, B. K., et al. Leukocyte response and hypoglycemia in superlethal endotoxin shock. Circ. Shock 4: 231, 1977.