Cardiopulmonary Effects of Volume Loading in Patients in Septic Shock MICHAEL M. KRAUSZ,* M.D., AZRIEL PEREL,t M.D., DANIEL EIMERL,t M.D., SHAMAY COTEV,t M.D.
The effect of volume loading in 20 patients with clinical and bacteriological evidence of generalized sepsis was studied. The patients were divided into two groups according to their response to volume loading. Group A included 9 patients in whom the initial pulmonary capillary wedge pressure (PWP) was lower than the central venous pressure (CVP). In this group the intravenous administration of 5089 + 409 ml/24 hr fluids was accompanied by a significant rise in blood pressure from 94.4 ± 9.3 mm Hg to 118.9 ± 6.3 mm Hg with no significant change in pulse rate or CVP. PWP rose from 5.7 ± 1.8 to 10.0 ± 1.4. The rise in cardiac output from 8.0 ± 1.3 liter/ min to 9.7 ± 1.1 liter/min was not statistically significant. Group B included 11 patients in whom the initial PWP was higher than the CVP. In this group, signs of fluid overloading appeared after administration of 3151 ± 540 ml/24 hr. There was no significant change in blood pressure, pulse rate, CVP, PWP or cardiac output. Urine output was adequate in both groups. This volume load did not affect pulmonary oxygenating capacity (PaO2/F102) and effective lung compliance in both groups, but the maintenance of an unchanged oxygenating capacity necessitated an increase in PEEP in some patients. Thus, synchronous monitoring of PWP and CVP in septic shock is helpful in selecting patients (Group A) who will best respond to fluid loading without deterioration of pulmonary oxygenating capacity. PEEP ventilation may be necessary in some patients to maintain the favorable effect of volume loading. C IRCULATORY FAILURE IN SEPTIC SHOCK is related
\_to several pathophysiological alterations: reduction in the effective circulating volume due to fluid translocation,1'3'4 relative right ventricular failure due to increased pulmonary vascular resistance5'8 with an elevated central venous pressure (CVP), and impaired left ventricular function.9'12 Quite clearly, then, CVP measurement alone in septic shock can no longer serve as a reliable indicator ofthe left ventricular ability to handle increased fluid load. Pulmonary capillary wedge pressure (PWP) measurement, however, may serve as a better guide to fluid replacement in septic shock as it * Department of Surgery, Hadassah University Hospital, Jerusalem, Israel. t Department of Anesthesiology, Hadassah University Hospital, Jerusalem, Israel. Reprint requests: Michael M. Krausz, M.D., Department of Surgery, Hadassah University Hospital, P.O. Box 499, Jerusalem, Israel.
429
From the Intensive Respiratory Care Unit, Department of Anesthesiology, and Department of Surgery, Hadassah University Hospital, Jerusalem, Israel
reflects the left ventricle's capacity to handle that load.17-19 Together with hemodynamic instability, pulmonary insufficiency, with decreased oxygenating capacity, is commonly associated with septic shock.2'5'16 Improvement in tissue perfusion by fluid loading must be constantly weighed against the almost inevitable danger of the associated deterioration in pulmonary function.1 2 It is therefore essential to determine the exact need for fluid replacement. To assess the value of PWP monitoring in the treatment of septic shock, the records of 20 admissions of adult patients with sepsis to our Intensive Care Unit (in whom pulmonary artery catheterization with a Swan-Ganz catheter19 was performed), were reviewed. The data obtained during the first 24 hours of fluid loading is reported. Materials and Methods All our patients showed clinical evidence of generalized sepsis, and in all bacterial or yeast growth was evidenced on blood cultures (Table 1). All patients showed signs of respiratory insufficiency and were mechanically ventilated (volume-controlled respirators, Puritan-Bennett MA 1B). In 8 patients positive end-expiratory pressure (PEEP) was utilized prior to volume loading. The indications for mechanical ventilation and PEEP were according to those recommended by Pontoppidan et al.14 Tidal volume was set at 12 to 15 ml/kg body weight, and PaCO2 was maintained between 30 and 40 mm Hg. Hemodynamic monitoring was carried out by direct arterial and central venous pressure measurements. All patients were treated by the appropriate antibiotics according to bacterial cultures and sensitivities. Most patients
430
Ann. Surg. * April 1977
KRAUSZ, PEREL, EIMERL AND COTEV TABLE 1. Diagnoses and Outcomes of Patients Studied
Patient No.
Age
Sex
Diagnosis
Group A 1. O.L. 2. Y.B. 3. Y.B. 4. C.A. 5. V.S.
45 24 24 36 57
F M M M M
Adrenalectomy for primary aldosteronism Multiple trauma, fecal peritonitis Multiple trauma, fecal peritonitis G.I.T. bleeding, gastrectomy G.I.T. bleeding, gastrectomy
Klebsiella pneumonia Klebsiella pneumonia Pseudomonas aeruginosa Klebsiella pneumonia Klebsiella pneumonia,
6. A.F.
46
M
E. coli
Died 9 days later
7. A.S. 8. H.Y. 9. P.L.
66 66 61
M M F
Hepatic cirrhosis, porto-caval shunt, G.I.T. bleeding Radical mastectomy, G.I.T. bleeding Acute hemorrhagic pancreatitis Fecal peritonitis
Acromonas hydrophilia Candida albicans E. coli, proteus mirabilis,
Died 5 days later Died 31 days later Recovered
Blood culture
Outcome
Died 9 days later Died 16 days later Died 2 days later Died 3 days later Recovered
pseudomonas aeruginosa
pseudomonas aeruginosa Group B 1. N.N. 2. B.K. 3. B.K. 4. Z.Y.
44 36 36 63
M M M M
5. A.S.
71
M
6. M.Y. 7. Y.E.
75 39
M F
Perforated duodenal ulcer Obstructive jaundice, ascending cholangitis
8. P.Y.
80
M
Peritonitis of unknown origin
9. Z.L.
19
F
10. M.C.
56
M
Perforated lymphoma of bowel with peritonitis, liver abscess Liver abscess
11. L.C.
64
F
Strangulated hernia, G.I.T. bleeding
Gastric ulcer 80% third degree burn 80% third degree burn Carcinoma of bile duct, ascending cholangitis Perforated carcinoma of colon
were digitalized and received high doses of glucocorticoid drugs. None of these therapeutic regimens were altered during the 24 hour study period. The indications for pulmonary artery catheterization (using the flow directed Swan-Ganz catheter) were: 1) decreasing systemic blood pressure (SBP) with normal or elevated CVP; 2) oliguria accompanying an increasing CVP; 3) the need for large volume replacement in patients with known cardiac disease. The patients were divided into two groups according to their initial PWP and CVP measurements (Fig. 1). Group A included 9 patients, 24 to 66 years old (mean 47.2) in whom the initial PWP was lower than the CVP. Group B included 11 patients, 19 to 80 years old (mean 53.0) in whom the initial PWP was higher than the CVP at that time. Pulmonary artery catheterization was performed twice in one patient in each group due to repeated
Candida albicans Pseudomonas aeruginosa Aerobacter cloacae E. coli
Died 2 days later Died 9 days later Died 2 days later Died 2 days later
Klebsiella pneumonia, Proteus morgani Pseudomonas aeruginosa Klebsiella pneumonia, Pseudomonas aeruginosa, Serratia dignepoceans Staphylococcus coagulase positive Pseudomonas aeruginosa
Recovered
Staphylococcus aureus, Pseudomonas aeruginosa Klebsiella pneumonia
Died 9 days later
Died 2 days later Died 9 days later Died 4 days later
Died 4 days later
Died 32 days later
episodes of septic shock. Each study appears separately in our material (Table 1). The management of intravenous crystalloid and colloid fluid replacement was determined by hourly measurements of hemodynamic parameters and urinary output. Blood gases and pH measurements were carried out periodically, and the respirator adjusted appropriately (i.e., F102, PEEP, etc.). Effective lung compliance was calculated from the expired tidal volume and peak inspiratory airway pressure using the lowest inspiratory peak flow. When PEEP was used, the corresponding airway pressure was determined from peak inspiratory pressure minus the PEEP level. In 9 patients (five of group A and four of group B) cardiac output was periodically measured using the thermodilution technique (Instrumentation Laboratories Cardiac Output Computer 601). Cardiac index could not be calculated due to lack of accurate infor-
431
VOLUME LOADING IN SEPTIC SHOCK
Vol. 185.9 No. 4
mation on body weight. Student T test was used for statistical evaluation of the results. Results Hemodynamic alterations In Group A, where the initial CVP was higher than the PWP, a mean of 5089 + 409 (SEM) ml/fluids (4311.1 + 419 ml crystalloids, 777.8 + 147 ml of fresh frozen plasma-FFP) were infused during 24 hours, after pulmonary artery catheterization. This contrasted significantly (P < 0.001) with the volume infused (mean of 3151 ± 540 ml divided into 2678.2 ± 472 ml of crystalloids, and 472 ± 105 ml of FFP) in Group B (Fig. 2). In addition, a mean of 288.9 ± 95 ml of packed red blood cells, and 40.0 ± 5.0 g of salt-poor albumin (20-25% solution) were infused in patients in Group A as compared to 163.6 ± 59 ml and 24.3 ± 4.3 g in Group B, respectively. This fluid replacement was accompanied by a significant (P < 0.05) rise in systolic blood pressure in group A from a mean of 94.4 ± 9.3 mm Hg to a mean of 118.9 ± 6.3 mm Hg. In Group B mean SBP rose significantly (P < 0.01) from an initial value of 87.3 ± 3.0 mm Hg to 102.7 ± 5.1 mm Hg after four hours, while at 24 hr the rise was not any longer significant (Fig. 3). There was a tendency for pulse rate to decrease in both groups during the 24 hours of observation, but these changes were not statistically significant (Fig. 3). CVP did not change significantly during the entire study despite considerable fluid loading (Fig. 3). At the same time, PWP-which was initially 5.7 ± 1.8 in group A-rose to 10.0 ± 1.4 (P < 0.05) towards the end of the 24 hours of fluid
Group A IZ 1Group 8
5 =
Lai cn
CLA BJJ
C= C= z
i.v.
6000
FLUID 5000
I~ G6roup A 6roup 8
(ml)
d
4000 k
2000 1
1000 F 0L 0
24
4
TIME (hours)
Urinary 2000 output
(ml)
Group A Group 0
1500
iooo [-
5001. AL 0
4
TIME (hours) FIG. 2. Cumulative volume infused and urinary output during 24 hours of study.
replacement. The smaller fluid replacement in Group B was not followed by a significant rise in PWP (Fig. 3). Urinary output was adequate in both groups during the 24 hours of the study (1498 + 410 ml in group A, and 1204 + 314 ml in group B) (Fig. 2). Cardiac output rose in Group A from a mean of 8.0 + 1.3 I/min initially, to 9.7 + 1.1 I/min 24 hours after the institution of fluid replacement. The corresponding values in Group B were 7.9 + 0.7 1/min initially, and 7.4 + 0.2 /min at the end of the study. These changes were not statistically significant, possibly due to the small number of patients involved. Respiratory alterations
AGE (years) FIG. 1. Age distribution of both groups of patients studied.
The initial values of PaO2/F102 in both groups indicated marked and similar impairment in oxygenating capacity. The mean PaO2/F102 values were 1.6 + 0.3 mm Hg and 1.8 + 0.3 mm Hg in Groups A and B,
432
Ann. Surg.
KRAUSZ, PEREL, EIMERL AND COTEV
SeP 130r
PWP
torr.
(to rr)
120 -
110 -
20
16 ; ' i.A6
o
April 1977
-'-^-----
-
j
12
1001-
90k
l
SOL L 0
I I O 01
o
TIME (hours) 120
Pulse Rate
beatsimi. I
24
4
..
TIME (hours)
-
v
110
I
-
24
1
CVP
-
12
(torr) io
11~
8 100 _
1
6 90
L 0
0 O
I
24
4
TIME (hours)
TIME Ihers)
FIG. 3. The changes in systolic blood pressure (S and pulmonary capillary wedge pressure (PWP) during 2
respectively. Large fluid replacement during 24 hours did not significantly affect PaO2/F102 in either group. Final PaO2IF1O2 values were 1.7 + 0.3 mm Hg and 1.8 + 0.3 mm Hg in Groups A and B, respectively (Fig. 4). The maintenance of unchanged oxygenating capacity, however, necessitated the institution of PEEP to mechanical ventilation in one additional pa-
3.0r
rate, central venous pressure (CVP)
tient in each group. Furthermore, the mean PEEP had to be raised from an initial level of 6.0 + 2.1 cm H20 in three patients to 13.0 + 5.9 cm H20 in four out of 9 patients 24 hours later in Group A, and from 8.2 + 1.1 cm H20 in five patients to 9.5 + 1.8 cm H20 in 6 out of 11 patients in group B (Fig. 5). The effec-
tive compliance increased in group A from 31.7
H1
PEEP
PaO2/FI02
+
2.0
L.
F
cm H2O1
12 _
2.0
81_
IA
41_
1,0
OL_
LI 0
0
24
4
TIME (hours) FIG. 4. The changes in pulmonary oxygenating capacity (PaO2/F,02) during 24 hours of study.
4
24
TIME (hours) FIG. 5. The changes in positive end expiratory pressure (PEEP) in four out of nine patients in group A and six out of 11 patients in group B during 24 hours.
Vol. 185 . No. 4
VOLUME LOADING IN SEPTIC SHOCK
to 38.1 ± 4.3 ml/cm H20 and changed from 31.0 ± 3.1 to 30.2 ± 3.9 ml/cm H20 in Group B. These changes were not statistically significant.
Discussion Despite recent developments in patients' monitoring and therapeutic modalities, mortality from septicemia accompanied by septic shock remains extremely high.6'7 The main reason for this poor outcome is the inability, in many cases, to eradicate the primary focus of infection and prevent the continued insult by circulating bacteria and bacterial products. The recovery from septic shock is further hampered by the very fine balance which exists between the need for correction of effective circulatory volume by fluid replacement and the harmful effect that this fluid load may have on the lungs which were already injured by the septic process.6'20'21 The rate and amount of fluid replacement in septic shock must therefore be very carefully guided. CVP in septic shock may be unduly elevated secondary to acute right ventricular failure co-existent with relative hypovolemia, as was probably the case in most of our patients in Group A.4'5'8 Swan-Ganz catheterization and PWP monitoring enabled us to single out those patients in whom the relationship between left ventricular function and effective circulating volume was such that further large fluid replacement was possible (Group A).10 A mean of over five liters of fluids could be infused in 24 hours in this group, resulting in a significant rise in SBP (and in PWP) and adequate urinary flow. Cardiac output rose in four of the five patients where this was monitored, and remained elevated (12.5 1/min) in the fifth. In group B PWP was initially elevated (13.7 ± 1.9 mm Hg) and fluid replacement was necessarily more cautious. In four patients of this group, cardiac output could not be raised by this limited volume replacement. Systemic blood pressure at the end of the study period as well as the 24-hour urinary output, were lower in group B as compared to group A. Clearly, improved cardiovascular stability was obtained in group A where larger fluid volumes could be administered, while in group B no significant hemodynamic effect was found. Weisul et al.2' similarly noted no significant cardiovascular response in patients who had an initial high PWP. Fluid replacement, however, though mandatory for the maintenance of elevated cardiac output and cardiovascular function, may be deleterious to the already compromised pulmonary function.2'6"13'20 All our patients, in both groups, had a marked initial decrease in pulmonary oxygenating capacity (decreased PaO2/ F102), that necessitated mechanical ventilation, often
433
with the use of PEEP. Oxygenating capacity did not deteriorate during fluid replacement in our patients. This stability was achieved, however, by the institution of PEEP ventilation in two additional patients, and by the elevation of the level of PEEP in the patients already on PEEP ventilation. Effective lung compliance, though a poor indicator of extravascular pulmonary water content, did not decrease during the 24 hours of fluid replacement in our patients. This may indicate a protective effect of PEEP against leakage of water from the pulmonary capillaries into the extravascular space during fluid loading. Concomitantly, increasing the effective blood volume probably prevented the depression of cardiac output sometimes observed in patients on PEEP ventilation. 15 In considering our results, it must also be noted that our observed rise in PWP in group A at the end of 24 hours of fluid replacement may, at least in part, be attributed to the effect of the high levels of PEEP used.11"18 It should be concluded from the results of our study that large fluid replacement in septic shock improves circulatory stability and urinary output whenever left ventricular function is adequate enough to tolerate such increase in effective blood volume. Monitoring of PWP and cardiac output is extremely helpful in selecting those patients who will best respond to fluid loading. PEEP ventilation may often be necessary to prevent deterioration of pulmonary function due to increased pulmonary extravascular water accumulation during fluid replacement. The final outcome of this patient group is not better than in other series with septic shock. This may well be due to the very severe nature of generalized sepsis encountered in this selected group and to the fact that survival is mainly dependent on eradication of the primary septic focus. The short-term nature of our patient follow-up must be emphasized. Our study cannot be taken to advocate prolonged fluid loading in septic shock. It is assumed, however, that the management of the acute episodes of circulatory failure in sepsis by adequate fluid replacement may improve cardiopulmonary function and thus enhance the outcome in a certain group of patients. References 1. Blaisdell, F. W., Lim, R. C. and Stallone, R. J.: The Mecha-
nism of Pulmonary Damage Following Traumatic Shock. Surg. Gynecol. Obstet., 130:15, 1970. 2. Border, J. R., Gallo, E. and Schenk, W. G.: Alterations in Cardiovascular and Pulmonary Physiology in the Severely Stressed Patient. A Rational Plan for the Management of Hypotension. J. Trauma, 6:176, 1966.
434
KRAUSZ, PEREL, EIMERL AND COTEV
3. Cape, O., Hopkirk, J. F. and Wight, A.: Derangements Imperling the Perforated Ulcer Patients. The Dehydration and Fluid Shifts. Arch. Surg., 71:669, 1965. 4. Clowes, G. H. A. Jr., Vucinic, M. and Weidner, M. G.: Circulatory and Metabolic Alternations Associated with Survival or Death in Peritonitis: Clinical Analysis of 25 Cases. Ann. Surg., 163:866, 1966. 5. Clowes, G. H. A. Jr., Farrington, G. H., Suschneid, W., et al.: Circulating Factors in the Etiology of Pulmonary Insufficiency and Right Heart Failure Accompanying Severe Sepsis (Peritonitis). Ann. Surg., 171:663, 1970. 6. Clowes, G. H. A. Jr.: Pulmonary Abnormalities in Sepsis. Surg. Clin. N. Am., 54:993, 1974. 7. Clowes, G. H. A. Jr., Hirsch, E., Williams, L., et al.: Septic Lung and Shock Lung in Man. Ann. Surg., 181:681, 1975. 8. Harrison, L. H. Jr., Hinshaw, L. B., Coalsen, J. J. and Greenfield, L. J.: Effects of E. coli Septic Shock on Pulmonary Hemodynamics and Capillary Permeability. J. Thorac. Cardiovasc. Surg., 61:795, 1971. 9. Hinshaw, L. B., Archer, L. T., Greenfield, L. J. and Guenter, C. A.: Effects of Endotoxin on Myocardial Hemodynamics, Performance and Metabolism. Am. J. Physiol., 221:504, 1971. 10. Lappas, D., Lell, W. A., Gabel, J. C., et al.: Indirect Measurement of Left Atrial Pressure in Surgical PatientsPulmonary Capillary Wedge and Pulmonary Artery Diastolic Press-ures Compared with Left Atrial Pressure. Anesthesiology, 38:394, 1973. 11. Lazman, J., Powers, S. R. Jr., Older, T., et al.: Correlation of Pulmonary Wedge and Left Atrial Pressures. A Study
12. 13. 14. 15.
16.
17. 18. 19.
20. 21.
Ann. Surg. * April 1977
in the Patient Receiving Positive End Expiratory Pressure Ventilation. Arch. Surg., 109:270, 1974. Lefer, A. M.: Blood Borne Humoral Factors in the Pathophysiology of Circulatory Shock. Circ. Res., 32:129, 1973. McLean, A. H., Duff, J. H. and McLean, L. P.: Lung Lesions Associated with Septic Shock. J. Trauma, 8:891, 1968. Pontoppidan, H., Geffin, B. and Lowenstein, E.: Acute Respiratory Failure in the Adult. N. Engl. J. Med., 287:690, 743, 799, 1972. Powers, S. R. Jr., Mannal, R., Neclerio, M., et al.: Physiologic Consequences of Positive End Expiratory Pressure (PEEP) Ventilation. Ann. Surg., 178:265, 1973. Proctor, H. J., Ballantine, T. V. N. and Brousard, N. D.: An Analysis of Pulmonary Function Following Non-thoracic Trauma with Recommendations for Therapy. Ann. Surg., 172:180, 1970. Rosenbaum, R. W.: Importance of Pulmonary Artery Pressure Monitoring. Surg. Gynecol. Obstet., 136:261, 1973. Sharefkin, J. B. and Moe, A. J. D.: Pulmonary Artery Pressure as a Guide to the Hemodynamic Status of Surgical Patients. Arch. Surg., 105:699, 1972. Swan, H. J. G., Ganz, W. and Forrester, J.: Catheterization of the Heart with Use of a Flow-directed Balloontipped Catheter. N. Engl. J. Med., 283:447, 1970. Vito, Z., Dennis, R. C., Weisel, R. D. and Hecklman, H. B.: Sepsis Presenting as Acute Respiratory Insufficiency. Surg. Gynecol. Obstet., 138:8%, 1974. Weisul, J. P., O'Donnell, T. F. Jr., Stone, M. A. and Clowes, G. H. A. Jr.: Myocardial Performance in Clinical Septic Shock: Effects of Isoproterenol and Glucose Potassium Insulin. J. Surg. Res., 18:357, 1975.
The effect of volume loading in 20 patients with clinical and bacteriological evidence of generalized sepsis was studied. The patients were divided into two groups according to their response to volume loading. Group A included 9 patients in whom the initial pulmonary capillary wedge pressure (PWP) was lower than the central venous pressure (CVP). In this group the intravenous administration of 5089 + 409 ml/24 hr fluids was accompanied by a significant rise in blood pressure from 94.4 ± 9.3 mm Hg to 118.9 ± 6.3 mm Hg with no significant change in pulse rate or CVP. PWP rose from 5.7 ± 1.8 to 10.0 ± 1.4. The rise in cardiac output from 8.0 ± 1.3 liter/ min to 9.7 ± 1.1 liter/min was not statistically significant. Group B included 11 patients in whom the initial PWP was higher than the CVP. In this group, signs of fluid overloading appeared after administration of 3151 ± 540 ml/24 hr. There was no significant change in blood pressure, pulse rate, CVP, PWP or cardiac output. Urine output was adequate in both groups. This volume load did not affect pulmonary oxygenating capacity (PaO2/F102) and effective lung compliance in both groups, but the maintenance of an unchanged oxygenating capacity necessitated an increase in PEEP in some patients. Thus, synchronous monitoring of PWP and CVP in septic shock is helpful in selecting patients (Group A) who will best respond to fluid loading without deterioration of pulmonary oxygenating capacity. PEEP ventilation may be necessary in some patients to maintain the favorable effect of volume loading. C IRCULATORY FAILURE IN SEPTIC SHOCK is related
\_to several pathophysiological alterations: reduction in the effective circulating volume due to fluid translocation,1'3'4 relative right ventricular failure due to increased pulmonary vascular resistance5'8 with an elevated central venous pressure (CVP), and impaired left ventricular function.9'12 Quite clearly, then, CVP measurement alone in septic shock can no longer serve as a reliable indicator ofthe left ventricular ability to handle increased fluid load. Pulmonary capillary wedge pressure (PWP) measurement, however, may serve as a better guide to fluid replacement in septic shock as it * Department of Surgery, Hadassah University Hospital, Jerusalem, Israel. t Department of Anesthesiology, Hadassah University Hospital, Jerusalem, Israel. Reprint requests: Michael M. Krausz, M.D., Department of Surgery, Hadassah University Hospital, P.O. Box 499, Jerusalem, Israel.
429
From the Intensive Respiratory Care Unit, Department of Anesthesiology, and Department of Surgery, Hadassah University Hospital, Jerusalem, Israel
reflects the left ventricle's capacity to handle that load.17-19 Together with hemodynamic instability, pulmonary insufficiency, with decreased oxygenating capacity, is commonly associated with septic shock.2'5'16 Improvement in tissue perfusion by fluid loading must be constantly weighed against the almost inevitable danger of the associated deterioration in pulmonary function.1 2 It is therefore essential to determine the exact need for fluid replacement. To assess the value of PWP monitoring in the treatment of septic shock, the records of 20 admissions of adult patients with sepsis to our Intensive Care Unit (in whom pulmonary artery catheterization with a Swan-Ganz catheter19 was performed), were reviewed. The data obtained during the first 24 hours of fluid loading is reported. Materials and Methods All our patients showed clinical evidence of generalized sepsis, and in all bacterial or yeast growth was evidenced on blood cultures (Table 1). All patients showed signs of respiratory insufficiency and were mechanically ventilated (volume-controlled respirators, Puritan-Bennett MA 1B). In 8 patients positive end-expiratory pressure (PEEP) was utilized prior to volume loading. The indications for mechanical ventilation and PEEP were according to those recommended by Pontoppidan et al.14 Tidal volume was set at 12 to 15 ml/kg body weight, and PaCO2 was maintained between 30 and 40 mm Hg. Hemodynamic monitoring was carried out by direct arterial and central venous pressure measurements. All patients were treated by the appropriate antibiotics according to bacterial cultures and sensitivities. Most patients
430
Ann. Surg. * April 1977
KRAUSZ, PEREL, EIMERL AND COTEV TABLE 1. Diagnoses and Outcomes of Patients Studied
Patient No.
Age
Sex
Diagnosis
Group A 1. O.L. 2. Y.B. 3. Y.B. 4. C.A. 5. V.S.
45 24 24 36 57
F M M M M
Adrenalectomy for primary aldosteronism Multiple trauma, fecal peritonitis Multiple trauma, fecal peritonitis G.I.T. bleeding, gastrectomy G.I.T. bleeding, gastrectomy
Klebsiella pneumonia Klebsiella pneumonia Pseudomonas aeruginosa Klebsiella pneumonia Klebsiella pneumonia,
6. A.F.
46
M
E. coli
Died 9 days later
7. A.S. 8. H.Y. 9. P.L.
66 66 61
M M F
Hepatic cirrhosis, porto-caval shunt, G.I.T. bleeding Radical mastectomy, G.I.T. bleeding Acute hemorrhagic pancreatitis Fecal peritonitis
Acromonas hydrophilia Candida albicans E. coli, proteus mirabilis,
Died 5 days later Died 31 days later Recovered
Blood culture
Outcome
Died 9 days later Died 16 days later Died 2 days later Died 3 days later Recovered
pseudomonas aeruginosa
pseudomonas aeruginosa Group B 1. N.N. 2. B.K. 3. B.K. 4. Z.Y.
44 36 36 63
M M M M
5. A.S.
71
M
6. M.Y. 7. Y.E.
75 39
M F
Perforated duodenal ulcer Obstructive jaundice, ascending cholangitis
8. P.Y.
80
M
Peritonitis of unknown origin
9. Z.L.
19
F
10. M.C.
56
M
Perforated lymphoma of bowel with peritonitis, liver abscess Liver abscess
11. L.C.
64
F
Strangulated hernia, G.I.T. bleeding
Gastric ulcer 80% third degree burn 80% third degree burn Carcinoma of bile duct, ascending cholangitis Perforated carcinoma of colon
were digitalized and received high doses of glucocorticoid drugs. None of these therapeutic regimens were altered during the 24 hour study period. The indications for pulmonary artery catheterization (using the flow directed Swan-Ganz catheter) were: 1) decreasing systemic blood pressure (SBP) with normal or elevated CVP; 2) oliguria accompanying an increasing CVP; 3) the need for large volume replacement in patients with known cardiac disease. The patients were divided into two groups according to their initial PWP and CVP measurements (Fig. 1). Group A included 9 patients, 24 to 66 years old (mean 47.2) in whom the initial PWP was lower than the CVP. Group B included 11 patients, 19 to 80 years old (mean 53.0) in whom the initial PWP was higher than the CVP at that time. Pulmonary artery catheterization was performed twice in one patient in each group due to repeated
Candida albicans Pseudomonas aeruginosa Aerobacter cloacae E. coli
Died 2 days later Died 9 days later Died 2 days later Died 2 days later
Klebsiella pneumonia, Proteus morgani Pseudomonas aeruginosa Klebsiella pneumonia, Pseudomonas aeruginosa, Serratia dignepoceans Staphylococcus coagulase positive Pseudomonas aeruginosa
Recovered
Staphylococcus aureus, Pseudomonas aeruginosa Klebsiella pneumonia
Died 9 days later
Died 2 days later Died 9 days later Died 4 days later
Died 4 days later
Died 32 days later
episodes of septic shock. Each study appears separately in our material (Table 1). The management of intravenous crystalloid and colloid fluid replacement was determined by hourly measurements of hemodynamic parameters and urinary output. Blood gases and pH measurements were carried out periodically, and the respirator adjusted appropriately (i.e., F102, PEEP, etc.). Effective lung compliance was calculated from the expired tidal volume and peak inspiratory airway pressure using the lowest inspiratory peak flow. When PEEP was used, the corresponding airway pressure was determined from peak inspiratory pressure minus the PEEP level. In 9 patients (five of group A and four of group B) cardiac output was periodically measured using the thermodilution technique (Instrumentation Laboratories Cardiac Output Computer 601). Cardiac index could not be calculated due to lack of accurate infor-
431
VOLUME LOADING IN SEPTIC SHOCK
Vol. 185.9 No. 4
mation on body weight. Student T test was used for statistical evaluation of the results. Results Hemodynamic alterations In Group A, where the initial CVP was higher than the PWP, a mean of 5089 + 409 (SEM) ml/fluids (4311.1 + 419 ml crystalloids, 777.8 + 147 ml of fresh frozen plasma-FFP) were infused during 24 hours, after pulmonary artery catheterization. This contrasted significantly (P < 0.001) with the volume infused (mean of 3151 ± 540 ml divided into 2678.2 ± 472 ml of crystalloids, and 472 ± 105 ml of FFP) in Group B (Fig. 2). In addition, a mean of 288.9 ± 95 ml of packed red blood cells, and 40.0 ± 5.0 g of salt-poor albumin (20-25% solution) were infused in patients in Group A as compared to 163.6 ± 59 ml and 24.3 ± 4.3 g in Group B, respectively. This fluid replacement was accompanied by a significant (P < 0.05) rise in systolic blood pressure in group A from a mean of 94.4 ± 9.3 mm Hg to a mean of 118.9 ± 6.3 mm Hg. In Group B mean SBP rose significantly (P < 0.01) from an initial value of 87.3 ± 3.0 mm Hg to 102.7 ± 5.1 mm Hg after four hours, while at 24 hr the rise was not any longer significant (Fig. 3). There was a tendency for pulse rate to decrease in both groups during the 24 hours of observation, but these changes were not statistically significant (Fig. 3). CVP did not change significantly during the entire study despite considerable fluid loading (Fig. 3). At the same time, PWP-which was initially 5.7 ± 1.8 in group A-rose to 10.0 ± 1.4 (P < 0.05) towards the end of the 24 hours of fluid
Group A IZ 1Group 8
5 =
Lai cn
CLA BJJ
C= C= z
i.v.
6000
FLUID 5000
I~ G6roup A 6roup 8
(ml)
d
4000 k
2000 1
1000 F 0L 0
24
4
TIME (hours)
Urinary 2000 output
(ml)
Group A Group 0
1500
iooo [-
5001. AL 0
4
TIME (hours) FIG. 2. Cumulative volume infused and urinary output during 24 hours of study.
replacement. The smaller fluid replacement in Group B was not followed by a significant rise in PWP (Fig. 3). Urinary output was adequate in both groups during the 24 hours of the study (1498 + 410 ml in group A, and 1204 + 314 ml in group B) (Fig. 2). Cardiac output rose in Group A from a mean of 8.0 + 1.3 I/min initially, to 9.7 + 1.1 I/min 24 hours after the institution of fluid replacement. The corresponding values in Group B were 7.9 + 0.7 1/min initially, and 7.4 + 0.2 /min at the end of the study. These changes were not statistically significant, possibly due to the small number of patients involved. Respiratory alterations
AGE (years) FIG. 1. Age distribution of both groups of patients studied.
The initial values of PaO2/F102 in both groups indicated marked and similar impairment in oxygenating capacity. The mean PaO2/F102 values were 1.6 + 0.3 mm Hg and 1.8 + 0.3 mm Hg in Groups A and B,
432
Ann. Surg.
KRAUSZ, PEREL, EIMERL AND COTEV
SeP 130r
PWP
torr.
(to rr)
120 -
110 -
20
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April 1977
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-
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l
SOL L 0
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TIME (hours) 120
Pulse Rate
beatsimi. I
24
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..
TIME (hours)
-
v
110
I
-
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CVP
-
12
(torr) io
11~
8 100 _
1
6 90
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0 O
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24
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TIME (hours)
TIME Ihers)
FIG. 3. The changes in systolic blood pressure (S and pulmonary capillary wedge pressure (PWP) during 2
respectively. Large fluid replacement during 24 hours did not significantly affect PaO2/F102 in either group. Final PaO2IF1O2 values were 1.7 + 0.3 mm Hg and 1.8 + 0.3 mm Hg in Groups A and B, respectively (Fig. 4). The maintenance of unchanged oxygenating capacity, however, necessitated the institution of PEEP to mechanical ventilation in one additional pa-
3.0r
rate, central venous pressure (CVP)
tient in each group. Furthermore, the mean PEEP had to be raised from an initial level of 6.0 + 2.1 cm H20 in three patients to 13.0 + 5.9 cm H20 in four out of 9 patients 24 hours later in Group A, and from 8.2 + 1.1 cm H20 in five patients to 9.5 + 1.8 cm H20 in 6 out of 11 patients in group B (Fig. 5). The effec-
tive compliance increased in group A from 31.7
H1
PEEP
PaO2/FI02
+
2.0
L.
F
cm H2O1
12 _
2.0
81_
IA
41_
1,0
OL_
LI 0
0
24
4
TIME (hours) FIG. 4. The changes in pulmonary oxygenating capacity (PaO2/F,02) during 24 hours of study.
4
24
TIME (hours) FIG. 5. The changes in positive end expiratory pressure (PEEP) in four out of nine patients in group A and six out of 11 patients in group B during 24 hours.
Vol. 185 . No. 4
VOLUME LOADING IN SEPTIC SHOCK
to 38.1 ± 4.3 ml/cm H20 and changed from 31.0 ± 3.1 to 30.2 ± 3.9 ml/cm H20 in Group B. These changes were not statistically significant.
Discussion Despite recent developments in patients' monitoring and therapeutic modalities, mortality from septicemia accompanied by septic shock remains extremely high.6'7 The main reason for this poor outcome is the inability, in many cases, to eradicate the primary focus of infection and prevent the continued insult by circulating bacteria and bacterial products. The recovery from septic shock is further hampered by the very fine balance which exists between the need for correction of effective circulatory volume by fluid replacement and the harmful effect that this fluid load may have on the lungs which were already injured by the septic process.6'20'21 The rate and amount of fluid replacement in septic shock must therefore be very carefully guided. CVP in septic shock may be unduly elevated secondary to acute right ventricular failure co-existent with relative hypovolemia, as was probably the case in most of our patients in Group A.4'5'8 Swan-Ganz catheterization and PWP monitoring enabled us to single out those patients in whom the relationship between left ventricular function and effective circulating volume was such that further large fluid replacement was possible (Group A).10 A mean of over five liters of fluids could be infused in 24 hours in this group, resulting in a significant rise in SBP (and in PWP) and adequate urinary flow. Cardiac output rose in four of the five patients where this was monitored, and remained elevated (12.5 1/min) in the fifth. In group B PWP was initially elevated (13.7 ± 1.9 mm Hg) and fluid replacement was necessarily more cautious. In four patients of this group, cardiac output could not be raised by this limited volume replacement. Systemic blood pressure at the end of the study period as well as the 24-hour urinary output, were lower in group B as compared to group A. Clearly, improved cardiovascular stability was obtained in group A where larger fluid volumes could be administered, while in group B no significant hemodynamic effect was found. Weisul et al.2' similarly noted no significant cardiovascular response in patients who had an initial high PWP. Fluid replacement, however, though mandatory for the maintenance of elevated cardiac output and cardiovascular function, may be deleterious to the already compromised pulmonary function.2'6"13'20 All our patients, in both groups, had a marked initial decrease in pulmonary oxygenating capacity (decreased PaO2/ F102), that necessitated mechanical ventilation, often
433
with the use of PEEP. Oxygenating capacity did not deteriorate during fluid replacement in our patients. This stability was achieved, however, by the institution of PEEP ventilation in two additional patients, and by the elevation of the level of PEEP in the patients already on PEEP ventilation. Effective lung compliance, though a poor indicator of extravascular pulmonary water content, did not decrease during the 24 hours of fluid replacement in our patients. This may indicate a protective effect of PEEP against leakage of water from the pulmonary capillaries into the extravascular space during fluid loading. Concomitantly, increasing the effective blood volume probably prevented the depression of cardiac output sometimes observed in patients on PEEP ventilation. 15 In considering our results, it must also be noted that our observed rise in PWP in group A at the end of 24 hours of fluid replacement may, at least in part, be attributed to the effect of the high levels of PEEP used.11"18 It should be concluded from the results of our study that large fluid replacement in septic shock improves circulatory stability and urinary output whenever left ventricular function is adequate enough to tolerate such increase in effective blood volume. Monitoring of PWP and cardiac output is extremely helpful in selecting those patients who will best respond to fluid loading. PEEP ventilation may often be necessary to prevent deterioration of pulmonary function due to increased pulmonary extravascular water accumulation during fluid replacement. The final outcome of this patient group is not better than in other series with septic shock. This may well be due to the very severe nature of generalized sepsis encountered in this selected group and to the fact that survival is mainly dependent on eradication of the primary septic focus. The short-term nature of our patient follow-up must be emphasized. Our study cannot be taken to advocate prolonged fluid loading in septic shock. It is assumed, however, that the management of the acute episodes of circulatory failure in sepsis by adequate fluid replacement may improve cardiopulmonary function and thus enhance the outcome in a certain group of patients. References 1. Blaisdell, F. W., Lim, R. C. and Stallone, R. J.: The Mecha-
nism of Pulmonary Damage Following Traumatic Shock. Surg. Gynecol. Obstet., 130:15, 1970. 2. Border, J. R., Gallo, E. and Schenk, W. G.: Alterations in Cardiovascular and Pulmonary Physiology in the Severely Stressed Patient. A Rational Plan for the Management of Hypotension. J. Trauma, 6:176, 1966.
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KRAUSZ, PEREL, EIMERL AND COTEV
3. Cape, O., Hopkirk, J. F. and Wight, A.: Derangements Imperling the Perforated Ulcer Patients. The Dehydration and Fluid Shifts. Arch. Surg., 71:669, 1965. 4. Clowes, G. H. A. Jr., Vucinic, M. and Weidner, M. G.: Circulatory and Metabolic Alternations Associated with Survival or Death in Peritonitis: Clinical Analysis of 25 Cases. Ann. Surg., 163:866, 1966. 5. Clowes, G. H. A. Jr., Farrington, G. H., Suschneid, W., et al.: Circulating Factors in the Etiology of Pulmonary Insufficiency and Right Heart Failure Accompanying Severe Sepsis (Peritonitis). Ann. Surg., 171:663, 1970. 6. Clowes, G. H. A. Jr.: Pulmonary Abnormalities in Sepsis. Surg. Clin. N. Am., 54:993, 1974. 7. Clowes, G. H. A. Jr., Hirsch, E., Williams, L., et al.: Septic Lung and Shock Lung in Man. Ann. Surg., 181:681, 1975. 8. Harrison, L. H. Jr., Hinshaw, L. B., Coalsen, J. J. and Greenfield, L. J.: Effects of E. coli Septic Shock on Pulmonary Hemodynamics and Capillary Permeability. J. Thorac. Cardiovasc. Surg., 61:795, 1971. 9. Hinshaw, L. B., Archer, L. T., Greenfield, L. J. and Guenter, C. A.: Effects of Endotoxin on Myocardial Hemodynamics, Performance and Metabolism. Am. J. Physiol., 221:504, 1971. 10. Lappas, D., Lell, W. A., Gabel, J. C., et al.: Indirect Measurement of Left Atrial Pressure in Surgical PatientsPulmonary Capillary Wedge and Pulmonary Artery Diastolic Press-ures Compared with Left Atrial Pressure. Anesthesiology, 38:394, 1973. 11. Lazman, J., Powers, S. R. Jr., Older, T., et al.: Correlation of Pulmonary Wedge and Left Atrial Pressures. A Study
12. 13. 14. 15.
16.
17. 18. 19.
20. 21.
Ann. Surg. * April 1977
in the Patient Receiving Positive End Expiratory Pressure Ventilation. Arch. Surg., 109:270, 1974. Lefer, A. M.: Blood Borne Humoral Factors in the Pathophysiology of Circulatory Shock. Circ. Res., 32:129, 1973. McLean, A. H., Duff, J. H. and McLean, L. P.: Lung Lesions Associated with Septic Shock. J. Trauma, 8:891, 1968. Pontoppidan, H., Geffin, B. and Lowenstein, E.: Acute Respiratory Failure in the Adult. N. Engl. J. Med., 287:690, 743, 799, 1972. Powers, S. R. Jr., Mannal, R., Neclerio, M., et al.: Physiologic Consequences of Positive End Expiratory Pressure (PEEP) Ventilation. Ann. Surg., 178:265, 1973. Proctor, H. J., Ballantine, T. V. N. and Brousard, N. D.: An Analysis of Pulmonary Function Following Non-thoracic Trauma with Recommendations for Therapy. Ann. Surg., 172:180, 1970. Rosenbaum, R. W.: Importance of Pulmonary Artery Pressure Monitoring. Surg. Gynecol. Obstet., 136:261, 1973. Sharefkin, J. B. and Moe, A. J. D.: Pulmonary Artery Pressure as a Guide to the Hemodynamic Status of Surgical Patients. Arch. Surg., 105:699, 1972. Swan, H. J. G., Ganz, W. and Forrester, J.: Catheterization of the Heart with Use of a Flow-directed Balloontipped Catheter. N. Engl. J. Med., 283:447, 1970. Vito, Z., Dennis, R. C., Weisel, R. D. and Hecklman, H. B.: Sepsis Presenting as Acute Respiratory Insufficiency. Surg. Gynecol. Obstet., 138:8%, 1974. Weisul, J. P., O'Donnell, T. F. Jr., Stone, M. A. and Clowes, G. H. A. Jr.: Myocardial Performance in Clinical Septic Shock: Effects of Isoproterenol and Glucose Potassium Insulin. J. Surg. Res., 18:357, 1975.
