Symposium on Therapeutic Problems
Treatment of Septic Shock Pierre Forgacs, M.D."
Septic shock can result from infections with either gram-positive or gram-negative bacteria. Shock is defined by a systolic blood pressure value of less than 90 mm Hg or by a fall of more than 50 mm Hg in the systolic pressure of a previously hypertensive individual. 20 , 24 Septic shock can occur in up to one third of patients with bacteremia. The clinical picture is often different from that encountered in other types of shock - a shaking chill may immediately precede the onset of hypotension, and the patient may be in a state of warm shock with no peripheral vasoconstriction. 23
Hemodynamic Changes Septic shock evolves through two distinct phases. 2 , 23, 24, 27, 28, 30 The first is a warm phase in which the patient is flushed with warm extremities, a decreased peripheral vascular resistance, a normal or increased cardiac output, and, usually, low values for central venous pressure and left ventricular end-diastolic pressure, and respiratory alkalosis. This is a phase of peripheral vasodilation, and the hemodynamic findings are somewhat similar to those seen in patients in hypovolemic shock. The duration of this phase varies from 30 minutes to 16 hours, and response to treatment is good. Subsequently, a cold phase ensues as the process goes on with vasoconstriction, a drop in cardiac output, and lactic acidosis. Endotoxin Endotoxin is found in the walls of gram-negative bacteria. Its active moiety is a substance called lipid A. When injected into laboratory animals, endotoxin causes fever, changes in white blood cell and platelet counts, and sh()ck. Although it may play a role in septic shock, endotoxin is probably not the principal pathophysiologic pathway. Major discrepancies exist between endotoxin-induced shock and septic shock: endotoxin induces shock by a decrease in cardiac output rather than by vasodilation in laboratory animals (monkeys, cats);8,9, 16 the hemodynamic effects of injecting live bacteria are different from those seen with injection of endotoxin;13 and gram-positive organisms do not contain endotoxin though they produce septic shock. "Section of Infectious Diseases, Lahey Clinic
Medical Clinics of North America - Vol.
63, No.
2, March 1979
465
466
PIERRE FORGACS
Complement During the course of septic shock, the alternate pathway of the complement system is activated; C3 levels are decreased in two thirds of patients with septic shock, but not in patients with bacteremia without shock. 5 , 19 When this fall in complement is prevented in experimental animal models, hypotension does not occur. 7 Vasoactive substances may be produced by complement activation (anaphylactoin) or released by complement-induced platelet lysis.
Other Metabolic Intermediates Activation of the kallikrein system and the coagulation cascade occurs in septic shock. 18,25 Abnormal concentrations of other vasoactive substances, such as histamine, serotonin, prostaglandins, and lysosomal enzymes, have been detected in certain animal models.], 4, 6,17,22
Etiologic Organisms Gram-positive bacteria are responsible for up to 30 per cent of instances of septic shock (Table 1). Among gram-negative bacteria, E. coli is the single commonest organism found,3, 2J, 23,30 but E. coli is responsible in only 20 per cent of patients. The rest are caused by other enterobacteriaceae, pseudomonas, and bacteroides that are resistant to such drugs as ampicillin. The urinary tract is the commonest site of origin of septic shock (Table 2).12,21,24 In one third of patients, an invasive procedure, such as, drainage of infected tissues or urinary manipulation, occurs 2 to 24 hours before the onset of shock. 23, 28
THERAPY Treatment of septic shock has two separate objectives. The first is to control the initiating infectious process primarily with antibotics. The second objective is normalization of the patient's hemodynamic state.
Antibiotics After rapid clinical and laboratory evaluation of the patient, antibiotics should be started. Evaluation should include two or three blood cultures at 15 minute intervals, urine culture, radiograph of the chest, electrocardiogram, and determinations of arterial blood gases and hemoglobin. A specific source and causative organism are often not know initially. Empirical treatment usually involves a combination of two antibiotics, one with a gram-positive spectrum that includes Staphylococcus aureus and the second with a broad, gram-negative spectrum that is effective against enterobacteriaceae and pseudomonas, for example, an amino glycoside. If an abdominal or pelvic source is susupected because of recent abdominal surgery or physical findings, an antibiotic effective against Bacteroides fragilis should be added (Table 3).
467
TREATMENT OF SEPTIC SHOCK
Table 1. Etiologic Organisms Found in Septic Shock WINSLOW
NE ELY
ET AL. 30
ET AL.2a
ET AL. 2H'
PROFILE
(PER CENT)
(PER CENT)
(PER CENT)
(PER CENT)
10 18 8 2
8
16 16 4 0
22 23 22
Gram-positive bacteria S.aureus Pneumococci Other streptococci Clostridia Gram-negative bacteria E coli Klebsiella and enterobacter Pseudomonas Bacteroides Polymicrobial
MC HENRY
COMPOSITE
6 8 3
5
o
10
24 30 10 14
21 23 13 5
11
7
*Patients with gram-negative bacteremia only.
Table 2.
Urinary tract infection Pneumonia or empyema Peritonitis Biliary tract disease Skin and wound infections Intravenous lines Neutropenia Pelvic infection
Source of Infection WINSLOW ET AL.30
NEELY ET AL."
NISHIJIMA ET AL. 24
(PER CENT)
(PER CENT)
(PER CENT)
32 36 6 4 12
40 17 15
26 7 24 12 12
11
468
PIERRE FORGACS
Table 3. Antibiotic Regimens in Septic Shock Septic shock of unknown cause (1) Penicillinase-resistant penicilli (e.g., Oxacillin, 2 gm intravenously every 4 hours) or cephalosporin
+
(2)
Aminoglycoside~gentamicin
renal function is normal
or tobramycin, 1.5 to 1.7 mg per kg every 8 hours if
Septic shock with possible intra-abdominal source (1) As above
+
(2) As above
+
(3) Septic (1) (2) (3)
Chloramphenicol, 1 gm intravenously every 6 hours, or clindamycin, 600 mg every 6 to 8 hours shock in leukemic or burn patients Asabove As above Carbenicillin, 30 gm a day if renal function is normal
Septic shock of suspected urinary origin (1) Penicillin (2) As above
The following principles serve as a guide to antibiotic administration: Time is a major element in prognosis. A loading dose of antibiotics should be given regardless of renal function; this means, for instance, a first dose of gentamycin or tobramycin, 1. 7 mg per kg of body weight, even in anuric patients. Bacteriocidal drugs do not offer a major advantage over bacteriostatic drugs in septic shock. All antibiotics have to be given intravenously because of poor intramuscular absorption during hypotension. Abscesses should be drained; if they are accessible, drainage should be performed early. It may be necessary to change intravenous catheters.
Extracellular Fluid Volume Expansion The two immediate options for dealing with shock are pressor agents or volume expansion. Although some studies suggest better survival with volume expansion than with pressor agents,3, 11, 12,20,27,29 this remains controversial. In the early phase of septic shock, hemodynamic changes are very similar to hypovolemia, and extracellular volume expansion increases cardiac output and corrects the shock state very readily. The ventilation-infusion-pump (VIP) method of treatment of septic shock has been developed in this context. This implies correction with ventilation and oxygen of the early changes of arteriovenous shunting. Infusion is used before any pressor agents are given. Volume expansion can be attempted with low, normal, or high central venous pressure values. Clinical monitoring of extracellular fluid volume and cardiac status is often sufficient during volume expansion. At times, a central venous pressure or pulmonary artery line or both are indicated.
TREATMENT OF SEPTIC SHOCK
469
Extracellular fluid volume expansion can be carried out with isotonic saline at rates of 500 ml per 30 minutes in patients who are not in congestive heart failure (central venous pressure if measured,s 10; wedge pressure if measured, s12). Patients with elevated values of central venous pressure should receive more gradual volume expansion (150 ml per 30 min).28 Close supervision is necessary for early detection of heart failure. When central venous pressures are obtained, measurements should be made every 30 minutes; the rule of 5 and 2 should be applied for central venous pressure measurements and the rule of 7 and 3 for pulmonary artery diastolic pressure values or wedge measurements. If the pulmonary artery diastolic pressure rises ?7 mm above baseline after the 30 minute infusion, volume expansion should be abandoned. If the pulmonary artery diastolic value drops with infusion or rises by s3 mm, volume loading should be continued for another 30 minutes and repeat measurements taken; if it increases between 3 and 7 mm, the infusion should be interrupted for a 30-minute rest period to see if the pressure drops to s3 over baseline. Large volumes of fluid of several liters over a few hours are often necessary to normalize the hemodynamic state. Colloids offer no advantage over saline. 14 Transfusion of blood products is helpful if the hemoglobin is 10 gm per 100 ml or less. The indications for a Swan-Ganz catheter are hypotension in the presence of an elevated central venous pressure, oliguria in the presence of an elevated central venous pressure, and large volume infusion in a patient with cardiac disease. 15 Patients with elevated central venous and wedge pressures may respond to volume infusion. In this group, a wedge pressure value, lower than the central venous pressure, is a good prognostic sign.
Pressor Agents Several types of vasoactive agents have been used for the treatment of septic shock. Their main indications are shock refractory to volume expansion and maintenance of sufficient blood pressure for perfusion of brain and kidneys in the deeply hypotensive patient. Hemodynamic effects of various pressor agents 30 are outlined in Table 4. Dopamine has two major advantages: it effects an increase in blood pressure with usually little vasoconstriction, and it redistributes flow selectively increasing renal, coronary, cerebral, and mesenteric blood flow. lo The usual dose 'is 2 to 5 JLg per kg per minute (up to 20 JLg per kg per minute 28). In patients refractory to dopamine, norepinephrine may be helpful. Isoproterenol (Isuprel) and phenoxybenzamine hydrochloride (Dibenzylene) are rarely indicated. l l Corticosteroids The use of corticosteroids in septic shock remains controversial. In a classic early study of gram-negative bacteremia, McCabe and Jackson 20 found a 43 per cen fatality rate in patients treated with corticosteroids versus 4 per cent in those not receiving steroids. Schumer26 found completely opposite results· in a controlled, double-blind study, in which mortality was decreased from 38.4 to 10.4 per cent with cor-
470
PIERRE FORGACS
Table 4.
Hemodynamic Effects of Vasopressors 30 ISOPROTERENOL NOREPINEPHRINE
DOPAMINE
Blood pressure
i i
t i
Cardiac output
i
i i
i i
±i
i In 50% of oliguric patients
tIn 33% of patients
Systemic resistance Urine output Central venous pressure, left ventricular end-diastolic pressure
(ISUPREL)
i t
i In 17% of patients
±
ticosteroids. The main benefit was observed in patients who were in late or severe shock. He found few complications associated with corticosteroid treatment (a 2 per cent incidence of gastrointestinal bleeding and a 1 per cent incidence of hyperosmolar coma were not si gnificantly different from control values). Methylprednisolone, 200 mg (2 gm every 4 hours up to three doses) or an equivalent drug dose is used. Heparin Although disseminated intravascular coagulation is frequent in septic shock, use of heparin may be counterproductive.
REFERENCES 1. Anderson, FL, Jubiz W, Tsagaris, TJ, et al: Endotoxin-induced prostaglandin E and F release in dogs. Am J PhysioI228:410-414 (Feb) 1975. 2. Blain, CM, Anderson, TO, Pietras, RJ, et al: Immediate hemodynamic effects of gramnegative vs. gram-positive bacteremia in man. Arch Intern Med 126:260-265 (Aug) 1970. 3. Christy, JH: Treatment of gram-negative shock. Am J Med 50:77-88 (Jan) 1971. 4. Davis, RB, Meeker, WR, Jr, Bailey, WL: Serotonin release by bacterial endotoxin. Proc Soc Exp Bioi Med 108:774-776 (Dec) 1961. 5. Fearon, DT, Ruddy, S, Schur, PH: Activation of the properidin pathway of complement in patients with gram-negative bacteremia. N Engl J Med 292:937-940 (May 1) 1975. 6. Fletcher, JR, Herman, CM, Ramwell, PW: Improved survival in endotoxemia with aspirin and indomethacin pretreatment. Surg Forum 27:11-12, 1976. 7. Garner, R, Chater, BV, Brown, DL: The role of complement in endotoxin shock and disseminated intravascular coagulation: Experimental observation in the dog. Br J Haematol 28:393-401 (Nov) 1974. 8. Gilbert, RP: Mechanisms of the hemodynamic effects of endotoxin. Physiol Rev 40:245279 (April) 1960. 9. Gilbert, RP: Endotoxin shock in the primate. Proc Soc Exp Bioi Med 111:328-331 (Nov) 1962. 10. Goldberg, LI: Dopamine--clinical uses of an endogenous catecholamine. N Engl J Med 291:707-710 (Oct 3) 1974. 11. Hardaway, RM, James, PM, Jr. Anderson, RW, et al: Intensive study and treatment of shock in man. JAMA 199:779-790 (March 13) 1967. 12. Hassen, A: Gram-negative bacteremic shock. Med Clin North Am 57:1403-1415 (Nov) 1973.
TREATMENT OF SEPTIC SHOCK
471
13. Hinshaw, LB, Solomon, LA, Holmes, DD, et al: Comparison of canine responses to Escherichia coli organisms and endotoxin. Surg Gynecol Obstet 127:981-988 (Nov)1968. 14. Holcroft, JW, Trunkey, DD, Carpenter, MA: Sepsis in the baboon: factors affecting resuscitation and pulmonary edema in animals resuscitated with Ringer's lactate versus plasmanate. J Trauma 17:600-610 (Aug) 1977. 15. Krausz, M, Perel, A, Eimerl, D, et al: Cardiopulmonary effects of volume loading in patients in septic shock. Ann Surg 185:429-434 (April) 1977. 16. Kuida, H, Gilbert, RP, Hinshaw, LB, et al: Species differences in effect of gramnegative endotoxin on circulation. Am J PhysioI200:1197-1202 (June) 1961. 17. Lefer, AM: Blood-borne humoral factors in the pathophysiology of circulatory shock. Circ Res 32:129-139 (Feb) 1973. 18. Mason, JW, Kleeberg, U, Dolan, P, et al: Plasma kallikrein and Hageman factor in Gram-negative bacteremia. Ann Intern Med 73:545-551 (Oct) 1970. 19. McCabe WR: Serum complement levels in bacteremia due to gram-negative organisms. N Engl J Med 288:21-23 (Jan 4) 1973. 20 .McCabe, WR, Jackson, GG: Gram-negative bacteremia. II. Clinical, laboratory, and therapeutic observations. Arch Intern Med 110:856-864 (Dec) 1962. 21. McHenry, MC, Gavan, TL, Hawk, WA et al: Gram-negative bacteremia: variable clinical course and useful prognostic factors. Cleve Clin Q 42: 15-32 (Spring) 1975. 22. Morris, KM, Moon, RJ: Quantitative analysis of serotonin biosynthesis in endotoxemia. Infect Immun 1O:340-346(Aug) 1974. 23. Neely, WA, Berry, DW, Rushton, FW, et al: Septic shock: clinical, physiological, and pathological survey of 244 patients. Ann Surg 173:657-666 (May) 1971. 24. Nishijima, H, Weil, MH, Shubin, H, et al: Hemodynamic and metabolic studies on shock associated with gram negative bacteremia. Medicine 52:287-294 (July) 1973. 25. Robinson, JA, Klondnycky, ML, Loeb, HS, et al: Endotoxin, prekallikrein, complement and systemic vascular resistance. Sequential measurement in man. Am J Med 59:61-67 (July) 1975. 26. Schumer, W: Steroids in the treatment of clinical septic shock. Ann Surg 184:333-341 (Sept) 1976. 27. Shoemaker, WC, Mohr, PA, Printen, KJ, et al: Use of sequential physiologic measurements for evaluation and therapy of uncomplicated septic shock. Surg Gynecol Obstet 131 :245-254 (Aug) 1970. 28. Shubin, H, Weil, MH: Bacterial shock. JAMA 235:421-424 (Jan 26) 1976. 29. Weil, MH, Shubin, H: The "VIP" approach to the bedside management of shock. JAMA 207:337-340 (Jan 13) 1969. 30. Winslow, EJ, Loeb, HS, Rahimtoola, SH, et al: Hemodynamic studies and results of therapy in 50 patients with bacteremic shock. Am J Med 54:421-432 (April) 1973. 605 Commonwealth Avenue Boston, Massachusetts 02215
Treatment of Septic Shock Pierre Forgacs, M.D."
Septic shock can result from infections with either gram-positive or gram-negative bacteria. Shock is defined by a systolic blood pressure value of less than 90 mm Hg or by a fall of more than 50 mm Hg in the systolic pressure of a previously hypertensive individual. 20 , 24 Septic shock can occur in up to one third of patients with bacteremia. The clinical picture is often different from that encountered in other types of shock - a shaking chill may immediately precede the onset of hypotension, and the patient may be in a state of warm shock with no peripheral vasoconstriction. 23
Hemodynamic Changes Septic shock evolves through two distinct phases. 2 , 23, 24, 27, 28, 30 The first is a warm phase in which the patient is flushed with warm extremities, a decreased peripheral vascular resistance, a normal or increased cardiac output, and, usually, low values for central venous pressure and left ventricular end-diastolic pressure, and respiratory alkalosis. This is a phase of peripheral vasodilation, and the hemodynamic findings are somewhat similar to those seen in patients in hypovolemic shock. The duration of this phase varies from 30 minutes to 16 hours, and response to treatment is good. Subsequently, a cold phase ensues as the process goes on with vasoconstriction, a drop in cardiac output, and lactic acidosis. Endotoxin Endotoxin is found in the walls of gram-negative bacteria. Its active moiety is a substance called lipid A. When injected into laboratory animals, endotoxin causes fever, changes in white blood cell and platelet counts, and sh()ck. Although it may play a role in septic shock, endotoxin is probably not the principal pathophysiologic pathway. Major discrepancies exist between endotoxin-induced shock and septic shock: endotoxin induces shock by a decrease in cardiac output rather than by vasodilation in laboratory animals (monkeys, cats);8,9, 16 the hemodynamic effects of injecting live bacteria are different from those seen with injection of endotoxin;13 and gram-positive organisms do not contain endotoxin though they produce septic shock. "Section of Infectious Diseases, Lahey Clinic
Medical Clinics of North America - Vol.
63, No.
2, March 1979
465
466
PIERRE FORGACS
Complement During the course of septic shock, the alternate pathway of the complement system is activated; C3 levels are decreased in two thirds of patients with septic shock, but not in patients with bacteremia without shock. 5 , 19 When this fall in complement is prevented in experimental animal models, hypotension does not occur. 7 Vasoactive substances may be produced by complement activation (anaphylactoin) or released by complement-induced platelet lysis.
Other Metabolic Intermediates Activation of the kallikrein system and the coagulation cascade occurs in septic shock. 18,25 Abnormal concentrations of other vasoactive substances, such as histamine, serotonin, prostaglandins, and lysosomal enzymes, have been detected in certain animal models.], 4, 6,17,22
Etiologic Organisms Gram-positive bacteria are responsible for up to 30 per cent of instances of septic shock (Table 1). Among gram-negative bacteria, E. coli is the single commonest organism found,3, 2J, 23,30 but E. coli is responsible in only 20 per cent of patients. The rest are caused by other enterobacteriaceae, pseudomonas, and bacteroides that are resistant to such drugs as ampicillin. The urinary tract is the commonest site of origin of septic shock (Table 2).12,21,24 In one third of patients, an invasive procedure, such as, drainage of infected tissues or urinary manipulation, occurs 2 to 24 hours before the onset of shock. 23, 28
THERAPY Treatment of septic shock has two separate objectives. The first is to control the initiating infectious process primarily with antibotics. The second objective is normalization of the patient's hemodynamic state.
Antibiotics After rapid clinical and laboratory evaluation of the patient, antibiotics should be started. Evaluation should include two or three blood cultures at 15 minute intervals, urine culture, radiograph of the chest, electrocardiogram, and determinations of arterial blood gases and hemoglobin. A specific source and causative organism are often not know initially. Empirical treatment usually involves a combination of two antibiotics, one with a gram-positive spectrum that includes Staphylococcus aureus and the second with a broad, gram-negative spectrum that is effective against enterobacteriaceae and pseudomonas, for example, an amino glycoside. If an abdominal or pelvic source is susupected because of recent abdominal surgery or physical findings, an antibiotic effective against Bacteroides fragilis should be added (Table 3).
467
TREATMENT OF SEPTIC SHOCK
Table 1. Etiologic Organisms Found in Septic Shock WINSLOW
NE ELY
ET AL. 30
ET AL.2a
ET AL. 2H'
PROFILE
(PER CENT)
(PER CENT)
(PER CENT)
(PER CENT)
10 18 8 2
8
16 16 4 0
22 23 22
Gram-positive bacteria S.aureus Pneumococci Other streptococci Clostridia Gram-negative bacteria E coli Klebsiella and enterobacter Pseudomonas Bacteroides Polymicrobial
MC HENRY
COMPOSITE
6 8 3
5
o
10
24 30 10 14
21 23 13 5
11
7
*Patients with gram-negative bacteremia only.
Table 2.
Urinary tract infection Pneumonia or empyema Peritonitis Biliary tract disease Skin and wound infections Intravenous lines Neutropenia Pelvic infection
Source of Infection WINSLOW ET AL.30
NEELY ET AL."
NISHIJIMA ET AL. 24
(PER CENT)
(PER CENT)
(PER CENT)
32 36 6 4 12
40 17 15
26 7 24 12 12
11
468
PIERRE FORGACS
Table 3. Antibiotic Regimens in Septic Shock Septic shock of unknown cause (1) Penicillinase-resistant penicilli (e.g., Oxacillin, 2 gm intravenously every 4 hours) or cephalosporin
+
(2)
Aminoglycoside~gentamicin
renal function is normal
or tobramycin, 1.5 to 1.7 mg per kg every 8 hours if
Septic shock with possible intra-abdominal source (1) As above
+
(2) As above
+
(3) Septic (1) (2) (3)
Chloramphenicol, 1 gm intravenously every 6 hours, or clindamycin, 600 mg every 6 to 8 hours shock in leukemic or burn patients Asabove As above Carbenicillin, 30 gm a day if renal function is normal
Septic shock of suspected urinary origin (1) Penicillin (2) As above
The following principles serve as a guide to antibiotic administration: Time is a major element in prognosis. A loading dose of antibiotics should be given regardless of renal function; this means, for instance, a first dose of gentamycin or tobramycin, 1. 7 mg per kg of body weight, even in anuric patients. Bacteriocidal drugs do not offer a major advantage over bacteriostatic drugs in septic shock. All antibiotics have to be given intravenously because of poor intramuscular absorption during hypotension. Abscesses should be drained; if they are accessible, drainage should be performed early. It may be necessary to change intravenous catheters.
Extracellular Fluid Volume Expansion The two immediate options for dealing with shock are pressor agents or volume expansion. Although some studies suggest better survival with volume expansion than with pressor agents,3, 11, 12,20,27,29 this remains controversial. In the early phase of septic shock, hemodynamic changes are very similar to hypovolemia, and extracellular volume expansion increases cardiac output and corrects the shock state very readily. The ventilation-infusion-pump (VIP) method of treatment of septic shock has been developed in this context. This implies correction with ventilation and oxygen of the early changes of arteriovenous shunting. Infusion is used before any pressor agents are given. Volume expansion can be attempted with low, normal, or high central venous pressure values. Clinical monitoring of extracellular fluid volume and cardiac status is often sufficient during volume expansion. At times, a central venous pressure or pulmonary artery line or both are indicated.
TREATMENT OF SEPTIC SHOCK
469
Extracellular fluid volume expansion can be carried out with isotonic saline at rates of 500 ml per 30 minutes in patients who are not in congestive heart failure (central venous pressure if measured,s 10; wedge pressure if measured, s12). Patients with elevated values of central venous pressure should receive more gradual volume expansion (150 ml per 30 min).28 Close supervision is necessary for early detection of heart failure. When central venous pressures are obtained, measurements should be made every 30 minutes; the rule of 5 and 2 should be applied for central venous pressure measurements and the rule of 7 and 3 for pulmonary artery diastolic pressure values or wedge measurements. If the pulmonary artery diastolic pressure rises ?7 mm above baseline after the 30 minute infusion, volume expansion should be abandoned. If the pulmonary artery diastolic value drops with infusion or rises by s3 mm, volume loading should be continued for another 30 minutes and repeat measurements taken; if it increases between 3 and 7 mm, the infusion should be interrupted for a 30-minute rest period to see if the pressure drops to s3 over baseline. Large volumes of fluid of several liters over a few hours are often necessary to normalize the hemodynamic state. Colloids offer no advantage over saline. 14 Transfusion of blood products is helpful if the hemoglobin is 10 gm per 100 ml or less. The indications for a Swan-Ganz catheter are hypotension in the presence of an elevated central venous pressure, oliguria in the presence of an elevated central venous pressure, and large volume infusion in a patient with cardiac disease. 15 Patients with elevated central venous and wedge pressures may respond to volume infusion. In this group, a wedge pressure value, lower than the central venous pressure, is a good prognostic sign.
Pressor Agents Several types of vasoactive agents have been used for the treatment of septic shock. Their main indications are shock refractory to volume expansion and maintenance of sufficient blood pressure for perfusion of brain and kidneys in the deeply hypotensive patient. Hemodynamic effects of various pressor agents 30 are outlined in Table 4. Dopamine has two major advantages: it effects an increase in blood pressure with usually little vasoconstriction, and it redistributes flow selectively increasing renal, coronary, cerebral, and mesenteric blood flow. lo The usual dose 'is 2 to 5 JLg per kg per minute (up to 20 JLg per kg per minute 28). In patients refractory to dopamine, norepinephrine may be helpful. Isoproterenol (Isuprel) and phenoxybenzamine hydrochloride (Dibenzylene) are rarely indicated. l l Corticosteroids The use of corticosteroids in septic shock remains controversial. In a classic early study of gram-negative bacteremia, McCabe and Jackson 20 found a 43 per cen fatality rate in patients treated with corticosteroids versus 4 per cent in those not receiving steroids. Schumer26 found completely opposite results· in a controlled, double-blind study, in which mortality was decreased from 38.4 to 10.4 per cent with cor-
470
PIERRE FORGACS
Table 4.
Hemodynamic Effects of Vasopressors 30 ISOPROTERENOL NOREPINEPHRINE
DOPAMINE
Blood pressure
i i
t i
Cardiac output
i
i i
i i
±i
i In 50% of oliguric patients
tIn 33% of patients
Systemic resistance Urine output Central venous pressure, left ventricular end-diastolic pressure
(ISUPREL)
i t
i In 17% of patients
±
ticosteroids. The main benefit was observed in patients who were in late or severe shock. He found few complications associated with corticosteroid treatment (a 2 per cent incidence of gastrointestinal bleeding and a 1 per cent incidence of hyperosmolar coma were not si gnificantly different from control values). Methylprednisolone, 200 mg (2 gm every 4 hours up to three doses) or an equivalent drug dose is used. Heparin Although disseminated intravascular coagulation is frequent in septic shock, use of heparin may be counterproductive.
REFERENCES 1. Anderson, FL, Jubiz W, Tsagaris, TJ, et al: Endotoxin-induced prostaglandin E and F release in dogs. Am J PhysioI228:410-414 (Feb) 1975. 2. Blain, CM, Anderson, TO, Pietras, RJ, et al: Immediate hemodynamic effects of gramnegative vs. gram-positive bacteremia in man. Arch Intern Med 126:260-265 (Aug) 1970. 3. Christy, JH: Treatment of gram-negative shock. Am J Med 50:77-88 (Jan) 1971. 4. Davis, RB, Meeker, WR, Jr, Bailey, WL: Serotonin release by bacterial endotoxin. Proc Soc Exp Bioi Med 108:774-776 (Dec) 1961. 5. Fearon, DT, Ruddy, S, Schur, PH: Activation of the properidin pathway of complement in patients with gram-negative bacteremia. N Engl J Med 292:937-940 (May 1) 1975. 6. Fletcher, JR, Herman, CM, Ramwell, PW: Improved survival in endotoxemia with aspirin and indomethacin pretreatment. Surg Forum 27:11-12, 1976. 7. Garner, R, Chater, BV, Brown, DL: The role of complement in endotoxin shock and disseminated intravascular coagulation: Experimental observation in the dog. Br J Haematol 28:393-401 (Nov) 1974. 8. Gilbert, RP: Mechanisms of the hemodynamic effects of endotoxin. Physiol Rev 40:245279 (April) 1960. 9. Gilbert, RP: Endotoxin shock in the primate. Proc Soc Exp Bioi Med 111:328-331 (Nov) 1962. 10. Goldberg, LI: Dopamine--clinical uses of an endogenous catecholamine. N Engl J Med 291:707-710 (Oct 3) 1974. 11. Hardaway, RM, James, PM, Jr. Anderson, RW, et al: Intensive study and treatment of shock in man. JAMA 199:779-790 (March 13) 1967. 12. Hassen, A: Gram-negative bacteremic shock. Med Clin North Am 57:1403-1415 (Nov) 1973.
TREATMENT OF SEPTIC SHOCK
471
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