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Myocardial depression during sepsis
Myocardial Depression during Sepsis Richard D. Weisel, MD, Boston, Massachusetts Louis Vito, MD, Boston, Massachusetts Richard C. Dennis, MD, Boston, Massachusetts C. Robert Valeri, CAPT MC USNR, Boston, Massachusetts Herbert B. Hechtman, MD, Boston, Massachusetts
Sepsis continues to be the major cause of death in our surgical intensive care unit. Despite careful monitoring, aggressive surgery, and the use of specific antibiotics, the mortality of invasive infection has remained between 60 and 70 per cent. Most patients die with sequential multisystem failure resulting from inadequate or maldistributed organ perfusion, despite a normal or elevated cardiac output. Septic patients have an inordinately high incidence of cardiac, renal, and hepatic decompensation. Reported herein is a prospective evaluation of cardiac performance. Our objectives were to identify the causes of diminished cardiac reserves and of myocardial depression in sepsis and to develop guidelines for therapy. Material and Methods Patient Selection. Fifty patients with documented sepsis were evaluated by the Trauma Unit of the Boston University Medical Center. All patients had some evidence of infection on examination: elevated pulse rate, tachypnea, hyperpyrexia, warm skin, or an elevated white blood cell count (WBC). Each patient had a documented source of infection with either positive blood cultures or an abscess containing more than 100 ml of pus. Pulmonary artery catheterization was performed if hemodynamic instability persisted after therapy was initiated, or if respiratory failure developed. Catheters were also inserted if the patient’s general condition made his postoperative risk prohibitive. Studies were performed in all patients soon after sepsis was manifest. In twenty-five patients a complete assessment was repeated after two to five days. Ten patients were clinically improved, but fifteen were preterFrom the Department of Surgery, Boston University Medical Center. and the US Naval Blood Research Laboratory, Boston, Massachusetts. This work was supported by the National Institute of General Medical Sciences Grant #lROl GM23871-01, the United States Army Contract #L)ADA17-97-C-7149 and the US Navy (Naval MilitaryResearch and Development Command) Task #MB0 41.02.01-0017A 2 DE. The opinions or assertions contained herein are those of the authors and are not to be construed as official or reflecting the views of the Navy Department or Naval Service at large. Reprint requests should be addressed to Herbert B. Hechtman, MD, University Hospital, Department of Surgery, 75 East Newton Street, Boston, Massachusetts 02118. Presented at the Fifty-Seventh Annual Meeting of the New England Surgical Society, Whitefield, New Hampshire, September 23-26, 1976.
512
minal when reevaluated. A careful past history was obtained for each patient and their progress in the hospital was recorded. Measurements. A thermister-tipped pulmonary artery
catheter was passed and a brachial arterial catheter was inserted in each patient. Cardiac output was measured by the thermodilution technic [I] (Instrumentation Laboratories, Lexington, MA). The mean of triplicate measurements was used to calculate the cardiac index (CI). Left ventricular stroke work index (LVSWI) was calculated from the mean arterial pressure (MAP), the pulmonary artery wedge pressure (PAWP), the pulse rate (P), and the CI from the formula: LvswI
=
(MAP-PAWWW1.36) Pmoo)
where 1.36 converts the result to grmmeters (pm)/m2. All pressure measurements were made without positive end-expiratory pressure. Right ventricular stroke work index (RVSWI) was calculated from the mean pulmonary artery pressure (PAP), central venous pressure (CVP), P, and CI using a similar formula. Systemic vascular and pulmonary vascular resistances were calculated from the difference in pressure divided by the flow across the systemic and pulmonary vascular beds. Blood gas and pH measurements were made with atandard electrodes (Instrumentation Laboratories, Lexington, MA) and converted to body temperature [2]. Hemoglobin and per cent saturation were measured by spectrophotometry (Instrumentation Laboratories, Lexington, MA). Measured oxygen tensions and saturations were used to calculate oxygen content. Ninety-two blood samples were also analyzed for oxygen content with a fuel cell (Lexington Instruments, Lexington, MA). The correlation between the two methods of calculating oxygen content was excellent (r = 0.92, p < 0.001). The oxygen consumption index (90~) was calculated from the arterial-mixed venous (A-V) oxygen content difference and the CI using the Fick equation. The in vivo Pm was calculated from the corrected mixed venous oxygen tensions and saturation by the Hill equation using a slope of 2.65. The in vitro P5e was obtained by tonometering the blood at varying oxygen tensions in the 40 to 60 per cent saturation range, while temperature, pH, and carbon dioxide tension (PCOs) were controlled (37”C, 7.40 units, 40 mm Hg, respectively).
The American
Journal of Surgery
Myocardial Depression during Sepsis
TABLE I
TABLE II
Organ Failure in Septic Patients Total
Survived
Number of patients Age (yr) Preexisting heart disease Postoperative heart
50 57.4 21 9
19 57.2 6 0
31 57.6 15 9
disease Postoperative
33
11
22
67%
20
7
13
65%
acute
respiratory failure Postoperative renal failure Hepatic failure
6 0 ..._~~~_._.._
Died
was calculated
62% 7 1% 100%
6 100% _.~___ ~_ _ ..-
from the Berggren formula (31:
Qs -- Cc- Ca ig - c, - c,
xloo
where the subscripts c, a, and v represent pulmonary capillary, arterial, and mixed venous oxygen contents. C, was derived from the alveolar gas equation. The physiologic deadspace fraction Vn/Vr was calculated from arterial (a) and mixed expired (E) carbon dioxide tensions from the formula: vo -= VT
Number
Mortality
The physiologic shunt Q&T during 50 per cent oxygen breathing
Origins of Sepsis
P&O2 - PaCOz P,COs
Effective dynamic compliance was derived from the ratio VT/PIP, where VT is the spirometer-measured tidal volume and PIP is peak inspiratory pressure in centimeters of water. Myocardial Performance Curves. To assess the reserve capabilities of the heart each patient underwent volume loading with 50 gm of salt-poor albumin or 1 unit of whole blood over 15 minutes. Hemodynamic measurements were made with each 2 mm Hg change in PAWP. Two myocardial performance curves were constructed for each patient by plotting either LVSWI or CI against PAWP. An upslope was then calculated. The initial and highest CI and LVSWI and the corresponding PAWP were recorded for each curve. A downslope was calculated when two or more points had progressively lower CI or LVSWI, with increasing PAWP. There was a mean of 7.2 and a range of 5 to 15 points per curve. Results Clinical Information. Table I describes the patient population. The 62 per cent mortality expresses the grave prognosis of invasive sepsis. Twenty-one patients had preexisting heart disease characterized by a history of myocardial infarction (11 patients), an episode of congestive heart failure (6 patients), or persistent angina pectoris (4 patients). Nine patients manifested heart disease in the hospital (postoperatively): four had an infarction, three ischemia, and
Septic Diagnoses Peritonitis Intestinal perforations lntraperitoneal abscesses Pancreatitis Intestinal infarctions Pneumonia Septicemra Infected vascular prostheses Pyelonephritis Primary Infecting Organisms Gram negative intestinal organisms Gram positive organisms (staph aureus) Anerobic organisms Clostridia species None Mean temperature White Blood Cell Count (cells/mm’)
39 19 14 3 3 7 4 2 2, 38 4 4 2 2 38.8 * 0.8 14,300 2 6,700
two congestive
heart failure. Thirty-three patients developed acute respiratory failure and had a Q~/QT > 20 per cent. Renal failure (RF) developed in twenty patients, manifest by serum creatinine levels greater than 5 mg/lOO ml. Fifteen required dialysis. Hepatic failure and jaundice (serum bilirubin level > 6 mg/ 100 ml) developed in six patients. Most of these associated conditions influenced the mortality of sepsis. Heart disease and hepatic failure had the most direct effect on mortality, while paradoxically renal failure tended to reduce the mortality. The occurrence of acute respiratory failure or preexisting heart disease did not alter the prognosis. The diagnosis of sepsis was often difficult to establish. All patients had hyperpyrexia sometime during their septic course. However, at the time of their initial evaluation their mean temperature was 38.8”C. Some patients had subnormal temperatures. Most patients developed an elevated WBC, but subnormal WBCs were also encountered. All patients eventually were found to have a documented source of sepsis. Table II describes the diagnoses and organisms recovered. Myocardial Performance Curves. The Starling mechanism predicts that volume loading the heart should lead to increases in cardiac output and stroke work. Septic cardiac function curves characteristically had a steep upslope. (Figure 1, Table III.) The peak or highest LVSWI or CI obtainable occurred at a relatively low filling pressure (PAWP between 10 to 12 mm Hg). Fifty per cent of septic patients had a downslope an abnormal
to their myocardial performance response to volume loading.
curve,
513
Weisel et al
Several aspects of the performance curves could be used to differentiate survivors and nonsurvivors. Septic patients who died had significantly lower upslopes and were unable to attain the same highest LVSWI or CI as the survivors. (Figure 1.) No patient survived with an upslope of the LVSWI curve <2 gm.m/m2.mm Hg or an upslope of the CI curve <0.2 l/min-m2smm Hg. The incidence of downslopes was similar for patients who lived or died. 7
N
Highest Upslope LVSWI
Highest Downslope PAWP N %
OSwvived
19
4.4
54
10
9
47
n
31
2.5’
30’
12
15
49
Died
t
eel
P’.Ol
LVSWI g.m/m2
F&we l.~~~patienlshadagreaterlncre~~L~Wl per mm Hg increase in PA WP than nonsurviving patients. 77~ h&#est L VS WI attained was greater in the survivors and occurred at a comparable PA WP. The initial PA WP and L VS WI and the incidence oi do wnslopes were not signiiicant/y different. Note that downslopes occur at relatively iow PA WP of 10 to 12 mm Hg.
TABLE I I I
Two to five days after the initiation of therapy myocardial performance curves were repeated in twenty-five patients. (Figure 2.) The pre-volume loading LVSWI and PAWP were unchanged. Ten patients showed improvement in their cardiac reserves, manifest by steeper upslopes and increases in the highest attainable LVSWI. Four of these patients had initial upslopes <2.5 gm-m/m2.mm Hg and highest LVSWI < 30 gm+m/m2. The dramatic improvement seen in these patients is encouraging evidence that myocardial depression in sepsis is potentially reversible. Two of these patients died of late complications of sepsis. Fifteen patients deteriorated despite therapy and Figure 2 demonstrates their diminished response to volume loading preterminahy. Some of these patients had high cardiac indices and a good response to volume loading when originally studied. Cardiorespiratory Measurements. Table IV describes the measurements made prior to volume loading. Only pH and base excess were significantly different between living and dying septic patients. Pulmonary hypertension was seldom seen in these patients. The mean PAP was never above 30 mm Hg and the pulmonary vascular resistance {PVR) was greater than 0.20 units in only three patients. There was a significant inverse (p < 0.05) correlation between the effective dynamic compliance and the PVR. CVP proved to be an inadequate indicator of the PAWP. There was a poor correlation (r = 0.46) between fifty measurements of CVP and PAWP made prior to volume loading. The correlation did not improve when the changes in CVP and PAWP in
Myoeardial Performance Curves in Sepsis Surviving N
LVSWI
vs PAWP
Myocardial
Performance
Note: SD = standard * p
514
SD
N
Mean
SD
Curves
Upslope (gm-m/m*. mm Hg) Highest LVSWI (gm-m/m’) Highest PAWP (mm Hg) Downslope (gm.m/m’.mm Hg) Lowest LVSWI (gm-m/m’) Lowest PAWP (mm Hg) Cl vs PAWP Myocardial Performance Upslope (I/min.m’-mm Hg) Highest Cl(I/min-m*) Highest PAWP (mm Hg) Oownslope (I/min.mz.mm Hg) Lowest Cl (l/min.m2) Lowest PAWP (mm Hg)
Mean
Dying
19 19 19 9 19 19
4.38 54.3 10.3 4.48 36.6 5.7
2.23” 24.7* 3.3 4.76 18.1 3.6
28 31 28 15 28 28
2.54 37.6 11.7 2.25 26.2 6.2
2.12 16.4 4.1 2.27 13.7 3.0
19 19 19 9 19 19
0.38 5.00 10.1 0.37 3.46 5.8
0.15* 1.33* 3.3 0.39 1.22 3.6
28 31 28 15 28 28
0.20 3.96 11.4 0.20 3.31 6.5
0.14 1.25 3.8 0.15 1.32 2.9
Curves
deviation.
The American Journal of Surgary
Myocardial Depression during Sepsis
Figure 2. ReqIonSe to therapy. Twenty-five patients had VOiume loading repeated two to five days after their initial assessment. Each patlent was used as his own control. Ten patients had an increased upslope and attained a higher L VSWI, whereas fifteen dis*yed~-nce prior to their demise.
TABLE IV
Physiologic
Variables
0
5
10
15
5
0
PAWP mmHg H
PAWP mmHg
‘PC.01 fP’O5
in Septic Patients
Cardiac index (I/min.m2) Pulse (beats/min) Mean arterial pressure artery
15
STANDARDERROR
All
(mm Hg) Mean pulmonary
10
3.7 ? 1.3* 103 * 17 79 f- 20 pressure
(mm Hg) Mean pulmonary artery wedge pressure (mm Hg) Mean central venous pressure (mm Hg) Left ventricular stroke work index (gm.m*) Right ventricular stroke work index (gm,m*) Systemic vascular resistance? Pulmonary vascular resistance? pH (units) Base excess (mEq) P,, in vivo (mm Hg) P,, in vitro (mm Hg) A-V oxygen content difference (~01%) Oxygen consumption (ml/min~m* ) Mixed venous oxygen tension (mm Hg) Physiological shunt (%) Physiological deadspace (%) Effective dynamic compliance (ml/cm H,O)
Dying 3.7 * 1.3 98 i- 15 84 * 20
3.7 * 1.3 107 + 18 77 +20
19.4 + 5.7
18.5 ? 5.9
19.9 f 5.6
8.7 f 4.3
7.2 * 4.3
9.7 + 4.4
9.4 ? 5.4
6.9 ? 4.4
10.9 + 6.1
36 + 16
43 + 21
31 r 14
5.1 %3.8
5.9 ? 4.5
4.5 * 3.4
0.694 0.10 7.44 3.1 26.0 25.2 4.0
? 0.330 ? 0.057 f; 0.08 + 6.0 + 3.4 + 2.3 + 1.2
0.701 0.107 7.48 6.3 26.0 26.7 4.0
+ 0.350 i 0.043 + 0.05$ + 5.1$ + 2.6 + 1.8 ? 0.8
0.690 0.110 7.42 1.3 26.1 24.2 4.0
f 0.310 i 0.066 f 0.11 f 6.4 + 3.9 + 2.5 + 1.4
134 +_77
117 +41
36.0 + 7.4
37.0 +_4.9
35.4
+ 8.9
23.9 44.5 27.8
19.1 ? 10.9 41.5 ? 10.3 28.6 f 8.1
27.0 46.5 27.4
+ 11.5 + 12.0 * 9.3
f 11.3 i 11.3 f 8.8
144 t 99
*Values
listed as mean +_1 standard deviation. 1 mm Hg pressure difference tl unit = 1 ml/set flow sp < 0.01.
vohlme 133. AprH IS77
515
Weisel et al
Postooerative Heart Disease (HD)
Acute Respiratory Fallun (ARF)
Hepatic Failure (HF)
-7
601
60&
50 40
LVSWI g-m/m2
30 20 10 I2zYcf2 0
5
10
PAWP mmHg
15
0
5
PAWP mmHg
+iSTANDARDERROR ‘PC 01 tPC 05
response to volume loading were analyzed (r = 0.35). However, the CVP could be clinically useful within narrow limits. Only one patient had a PAWP > 10 mm Hg when the CVP was less than 5 mm Hg. Consequently, if t.he CVP is <5 mm Hg, hydrostatic pulmonary edema is very unlikely. Secondly, only one patient had a PAWP < 5 mm Hg when the CVP was >12 mm Hg. This indicates that if the.CVP is >12 mm Hg, hypotension or low cardiac output is not due to hypovolemia. Finally, the CVP did provide a guide, albeit a poor one, to right ventricular performance. When RVSWI was plotted against CVP during volume loading, 28 per cent of the curves had decreases in RVSWI’associated with increases in the CVP. Myocardial Performance and Associated Conditions. The effect of associated disease on the induc-
tion of myocardial depression in sepsis was evaluated. Preexisting heart disease was equally prevalent among both surviving and dying patients and had no influence on cardiac performance. Figure 3 illustrates the effect of other conditions. Heart disease occurring in the postoperative period had a dramatic effect on
516
10
15
Figure 3. Myucardial depression was direct/y related to the presence of postoperative heart disease or acute respiratory failure. The upsfopes and peaks of the iperformance curves were significanby higher in patients without heart disease or respiratory failure. On the other hand, renal and hepatic failure were associated wfth good cardiac function.
cardiac function. Although there was no difference in the initial measurements of LVSWI and PAWP between the nine patients with heart disease and the forty-one without heart disease, the response to volume loading was markedly depressed in the group with heart disease.- One patient in this group showed transient improvement with the treatment of his infection, but postoperative heart disease was uniformly fatal. The thirty-three patients with acute respiratory failure had significantly lower upslopes and failed to achieve as high a LVSWI as did the non-acute respiratory failure patients. (Figure 3.) Surprisingly, patients with renal failure had better performance curves than those patients without renal failure. As noted above, hepatic failure was a lethal complication. Despite this, patients with hepatic failure had steep upslopes and were able to generate high LVSWI at peak performance. However, all patients with hepatic failure had downslopes. Normal P5c is 26.5 mm Hg. A decrease in the in vivo P5c was found in fifteen septic patients, the range being 17 to 24 mm Hg (mean, 21.6 mm Hg).
The American Journal ol Surgery
Myocardial Depression during Sepsis
Figure 4. Effect of high affinity hemoglobin and low initial cardiac index. Left, patients with low P5,, or high oxygenhemoglobin affinity states had significantly reduced myocardial performance manifest by lower upslopes and L VSWI. Right, ten patients with a cardiac index (C/) of less than 2.5 I/min*m * when inltlaliy evaluated, were found to have a depressed response to volume loading. Ho we ver, five of these ten pafienfs who had a PA WP less than 5 mm Hg, had a significantly better response to volume loading than the remaining five patients.
60 50 40
LVSWI
30 20 10 g.m/m2
60'
(4 L7cfrlk SO40-
30-
20-
IO-
0
5
PAWP mmlig
H
STANDARD ‘PC 01 tP< 05
0
5
10
15
PAWP mmlig
ERROR
The in vitro P5e was also low with a mean of 23.3 mm Hg. The CI of this group, prior to volume loading, was 2.9 l/minm2, which was not significantly different from patients with a normal Pse. These patients with low Pso values, whose flow did not increase in response to the high affinity state, manifest one of two responses: a decrease in P,Oz or VOs. Eight of the fifteen patients had a PBOs < 30 mm Hg (mean, 25 mm Hg) with a normal oxygen extraction (A-V oxygen content difference, 3.6 vol per cent), and oxygen consumption (VOs, 104 ml/minm2). Seven of the fifteen patients had a decreased oxygen consumption (VOs, 49 ml/minm2) with a normal PB02 (35 mm Hg) and A-V oxygen content difference (3.3 vol per cent). After volume loading, patients with a low P50 had a depressed myocardial response including a 73 per cent incidence of downslopes. (Figure 4.) Only two of these fifteen patients with low Pse values survived; both improved their myocardial performance when their Pso value returned to normal limits after two to five days. Ten patients had a CI < 2.5 l/min.m2. Figure 4 indicates that these patients had a diminished response to volume loading. Comments
The diagnosis of sepsis was based on clinical findings and the presence of either positive blood cultures, an intraperitoneal abscess, or intestinal infarction. We were unable to distinguish between the cardiorespiratory responses of patients with gram-positive and gram-negative infections. Others have concurred with this finding [4-61. Documentation of sepsis was frequently difficult and time-consuming. The treatment of critically ill
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patients cannot await laboratory results. We have found the cardiac and pulmonary physiologic measurements helpful in establishing the amgnosis of sepsis. A high CI and more particularly a dramatic response to volume loading (slope of the myocardial performance curve) characterize the septic patient. On occasion patients with acute pancreatitis and alcoholic hepatitis may demonstrate similar findings and can be confused with the septic group. Acute respiratory failure is another important clue to the diagnosis of underlying sepsis and,frequently heralds its onset [ 71. One hundred seventeen patients with acute respiratory failure have previously been evaluated by our Trauma Unit and sepsis was present in eighty-two (70 per cent). Sixty-three (54 per cent) of this patient population had an intraperitoneal source of infection and required surgery. Therefore, if a surgical patient presents with acute respiratory failure and has a hyperdynamic response to volume loading, he is most likely septic. In addition, if a source of this infection is not readily uncoveredsuch as severe pneumonia, pyelonephritis or infected intravenous catheter-an intraperitoneal focus is probable and exploratory laparotomy should be strongly considered. The mortality from sepsis depends u@n the patient’s general condition and the physician’s ability to eradicate the infecting source. Preexisting heart disease was pervasive in our patients and perhaps accounted for the mortality higher than that reported by others [4,5,8]. The uniform fatality associated with acute cardiac decompensation or ischemia emphasizes the central role of myocardial performance in sepsis. Other authors have stressed the poor prognosis of patients with liver disease [9]. The role of
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Weisel et al
TABLE V
Myocardial Performance Curves
Clinical Condition
Upslope (gm.m/m2.mm
Number
Hg)
Highest LVSWI (gm.m/m2)
Downslope (%I
Sepsis Surviving Dying Abdominal
aortic
Ruptured Elective Coronary artery
4.38 2.54
f 2.21* f 2.12
54.3 + 24.7* 37.6 + 16.4
47 48
17 10
3.38 3.82
? 3.21 r 2.32
30.8 * 5.4 40.8 * 8.1
47 20
23 41 37
3.36 * 1.94 1.49 + 0.91 2.68 k 1.18
37.7 f. 11.6 30.6 r 11.3
9 75 16
aneurysms
bypass
Preoperatively Immediately postoperatively 24 hr postoperatively *Surviving
19 31
septic
patients
had a greater
upslope
and highest
renal failure in the mortality of sepsis is confusing. Our results indicate that patients with acute renal failure tend to have a hyperdynamic response to volume loading and do not have a higher mortality rate. Renal failure is readily controlled with dialysis and frequently reversible. It is therefore perhaps understandable that patients whose sepsis is complicated by renal failure may have a better prognosis than those patients complicated by hepatic or cardiac failure. In this series acute respiratory failure did not adversely effect the prognosis of sepsis. However, this is at variance with our previous experience where acute respiratory failure was found to significantly (p < 0.01) increase the mortality of the 113 septic patients seen in our Trauma Unit. The mortality for acute respiratory failure and sepsis was 77 per cent compared to a mortality of 45 per cent for sepsis without acute respiratory failure. Myocardial Performance. Classifying patients into hyper- and hypodynamic groups based on routine cardiac output measurements tends to obscure the hemodynamics of sepsis [5,10,11]. Normally the heart is permissive and flow is regulated by tissue needs and venous return. Thus, a low CI in untreated sepsis may simply indicate a failure of venous return because of peripheral vaaodilatation. Although this may in part be true, the results of fluid loading indicate that the septic heart often has limited reserves and will frequently not function in a permissive fashion. It is not unreasonable to speculate that the septic heart may no longer respond to tissue needs. Thus, a “normal” CI may be inadequate for a septic patient. To evaluate myocardial depression in sepsis, we have emphasized the results of LVSWI rather than CI myocardial performance curves, although both were plotted and appeared similar for each patient.
518
LVSWI,
37.6 k 11.3
-
p ~0.05.
As discussed by Sarnoff [12], LVSWI analysis accommodates small changes in MAP and pulse rate during volume loading. Large changes in MAP or pulse induce compensatory changes in contractility and make evaluation of the Starling mechanism impossible. We have, therefore, eliminated any curves constructed during substantial changes of MAP or pulse. Myocardial performance curves in surviving septic patients had a sharp upslope, an elevated highest LVSWI and a high incidence of downslopes. For comparison, these same variables are listed for patients suffering from nonseptic conditions-abdominal aortic aneurysm repair and coronary bypass surgery. (Table V.) In addition, Crexells et al [13] have described the myocardial performance of patients who had acute myocardial infarctions. These patients had upslopes less than 1.5 pm/m2.mm Hg, a mean highest LVSWI of 35 gm.m/m2, and a 22 per cent incidence of downslopes. The reason for the sharp upslopes in surviving septic patients is unknown. It is possible that dying septic patients and others with low upslopes (Table V) have a reduced ventricular compliance, as might occur with cardiac edema. The low compliance means that for any PAWP there will be a reduced ventricular volume and myocardial fiber stretch. Under these circumstances, a low upslope of the myocardial performance curve can be predicted [14,15]. An alternative postulate is that there has been a decrease in intrinsic myocardial contractility. Such an event may occur because of a decrease in coronary blood flow or a redistribution of flow away from the subendocardial regions [I 1,16,17]. Edema or vasoactive agents may induce such a redistribution. In addition, edema may create a diffusion barrier to oxygen transport and thereby limit contractility. Finally, a number of substances may act directly on the heart
The American Journal of Surgery
Myocardial Depression during Sepsis
and induce a negative inotropic state. Our data do not permit resolution of this issue. The sharp downslopes seen in half of all septic patients represents an abnormality in the Starling mechanism [18]. This phenomenon cannot be explained by an altered ventricular compliance. The configuration of these curves, particularly the presence of downslopes (Figure l), requires that fluid infusions be carefully monitored with the PAWP. If a performance curve is not done, fluid infusions should be adjusted to maintain the PAWP at 10 mm Hg to optimize cardiac output. Insufficient or excessive volume is poorly tolerated by these patients. The description of improvement and deterioration of the cardiac response to volume loading with time emphasizes that the hyper- and hypodynamic cardiac states represent a continuum. (Figure 2.) These changes in myocardial performance may occur without significant alterations in the initial cardiac output and PAWP measurements. It is only by stressing the heart that these limitations in cardiac reserves can be identified. Several organ systems were evaluated with regard to their influence on cardiac performance. Acute postoperative but not preoperative heart disease was associated with a profound depression in cardiac function. The results indicate that septic patients who develop cardiac ischemia are at extreme risk. Hemodynamic monitoring was useful under these circumstances. Fluid infusions should be carefully regulated to obtain a PAWP of 12 mm Hg. (Figure 3.) If a satisfactory highest LVSWI and CI cannot be obtained, then resort to other therapy should be prompt. The use of red cell transfusions to maintain hemoglobin concentrations between 12 and 14 gm/lOO ml should be considered since oxygen transport is critical. Another factor relating to oxygen transport involves an attempt to increase the Pm to produce a low oxygen-hemoglobin affinity state. This is discussed below. Inotropic agents may increase both flow and systemic pressure but should be used sparingly since they may increase myocardial oxygen demand more than they increase oxygen supply. These patients may benefit most from intra-aortic balloon counterpulsation [19], which will increase oxygen supply and reduce oxygen demand and redirect flow to the subendocardium. One patient in this series was successfully treated by counterpulsation and showed marked improvement in his myocardial performance curve. Patients with acute respiratory failure had significantly lower upslopes. Myocardial depression in septic patients with acute respiratory failure has been
reported by Clowes and associates [6,20,21]. They proposed right heart failure due to elevation in pulmonary vascular resistance as the mechanism for cardiac decompensation. However, we did not observe severe elevations in PAP. There was no difference between the PAP of surviving and dying patients or between those with and those without acute respiratory failure. We did notice an interesting correlation between effective dynamic compliance and PVR. Also the upslope of patients with a reduced compliance (<20 cm HsO/ml) was lower than those with higher compliance. These observations are consistent with one of Clowes’ hypotheses, that circulating substances in sepsis are inducing cardiac and respiratory decompensation. In addition, it is possible that a damaged pulmonary capillary endothelium is unable to metabolize vasoactive substances which in turn are allowed access to the systemic circulation and result in a redistribution of blood flow away from the subendocardium in the heart. Experimental data confirm the presence of humoral agents released by pulmonary manipulation which will depress cardiac function [22]. An increase in the affinity of hemoglobin for oxygen has been described in septic patients [23-251. Fifteen patients in our study group had an in vivo PX < 24 mm Hg. The fact that the in vitro PsO averaged 23.3 mm Hg indicates that red cell 2,3 diphosphoglycerate (2,3 DPG) concentrations were low. Phosphate depletion and infusion of large volumes of stored blood have been implicated in inducing reductions of 2,3 DPG concentrations. None of our patients received more than 3 units of blood within three days of their study. Phosphate levels were reported in only five patients, but were normal. Therefore, the mechanism for the 2,3 DPG depletion remains obscure. The mean in vivo P50 in this group of fifteen patients was only 21.6, lower than the in vitro value. The significant alkalosis in these septic patients is thought to explain these in vivo results. It is, of course, the in vivo P5c which defines the clinical oxygen-hemoglobin affinity state. The cardiac indices prior to volume loading of the patients with high and low Pm values were the same. Given the fact that flow was fixed, the low P50 group manifest two types of responses-a decrease in P,Oz or VOz. Neither of these systemic responses were available to the heart. The coronary sinus normally has a low oxygen tension and it cannot fall further in response to an increased oxygen-hemoglobin affinity. Further, the heart cannot accept a decrease in myocardial oxygen consumption without a decrease in performance. Normally, oxygen supply to the heart is ad-
519
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et al
justed by regulating coronary blood flow. If coronary flow is relatively fixed or poorly distributed, the heart cannot respond properly to increased work requirements such as those induced by volume loading. This response to volume loading will be further limited by a high affinity state. (Figure 4.) These results are consistent ‘with previous observations. Depressed cardiac redponse to volume loading was found in patients who had received large infusions of old blood and had a low P50 and PoOa after repair of ruptured abdominal aortic aneurysms. Conversely, we have observed improved performance in response to volume loading in patients receiving high 2,3 DPG red cells after coronary artery bypass surgery [26]. A low Pm may be prevented or reversed by using infusions of fresh red cells if transfusions are required. Secondly, respiratory and/or metabolic alkalosis should be reversed by adjusting respirator settings in patients who are mechanically ventilated or by the intravenous infusions of acidifying agents. Finally, inorganic phosphate supplements may be required, particularly in patients who are being hyperalimented. To improve the prognosis of septic patients, careful attention should be paid to cardiac function. Volume loading may be safely performed and provides information useful for the regulation of fluid therapy. If there is an inadequate response to volume, then the possible causes of myocardial depression, such as low P50 or respiratory failure, should be explored. Summary
The cardiac response to volume loading was evaluated in fifty severely septic patients. After a rapid infusion of albumin or whole blood the cardiac index (CI) and left ventricular stroke work index (LVSWI) were recorded as the pulmonary arterial wedge pressure (PAWP) increased. Initial values of PAWP, CI, and LVSWI were similar in both the nineteen surviving and thirty-one nonsurviving patients. Surviving patients, however, demonstrated greater increases in CI and LVSWI as PAWP rose. Nearly half of both patient groups developed decreases in Cl and LVSWI as the PAWP continued to increase. These downslopes occurred at relatively low PAWP and are taken as evidence of an abnormality of myocardial function in both survivors and nonsurvivors. The lower upslope of the performance curves in nonsu&vors indicates myocardial depression or a negative’inotropic effect. Cardiac ischemia, acute respiratory failure, and high affinity red cells were found to diminish the cardiac response to volume loading, whereas hepatic and renal failure were associated with a good CI and LVSWI response.
520
References 1. Weisel RD. Berger RL, Hechtman HB: Measurement of cardiac output by thermodilution. N Engl J Med 292: 082, 1975. 2. Kelman GL: Calculation of certain indices of cardiopulmonary function using a digital computer. Resp Whys 1: 335, 1966. 3. Berggren SM: The oxygen deficit of arterial blood caused by nonventilating parts of the lung. Acta Physiol Scmd [Sup@] 11: 1, 1942. 4. Winslow EJ, Loeb HS, Rahimtoola SH, Kamath S, Gunnar RM: Hemodvnamic studies and results of theraov in 50 oatients with bacteremic shock. Am JAW 54: 421’,:1973. I 5. MacLean LD. Mullioan WG. McLean APH. Duff JH: Patterns of septic shdck in ban-a detailed stud; of 56 patients. Ann Surg 166: 543, 562, 1967. 6. Clowes GHA, Farrington GH. Zuschneid W, Cossette GR, Saravis C: Circulating factors in the etiology of pulmonary insufficiency and right heart failure accompanying severe sepsis. Ann Surg 171: 663, 1970. 7. Vito L, Dennis DC. Weisel RD, Hechtman HB: Sepsis presenting as acute respiratory insufficiency. Surg Gynecol Obstet 138: 896, 1974. 8. Kluge RM, DuPont HL: Factors affecting mortality of patients with bacteremia. Surg Gynecol Obstet 137: 267, 1973. 9. Wilson RF, Chiscano AD, Quadros R, Tarver M: Some observations on 132 patients with septic shock. Anesth Analg 46: 761, 1967. 10. Siegel JH, Greenspan M, Del Guercio LRM: Abnormal vascular tone, defective oxygen transport and myocardial failure in human septic shock. Ann Surg 165: 504, 1967. 11. Hinshaw LR: Role of the heart in the pathogenesis of endotoxin shock. J Surg Res 17: 134, 1974. 12. Sarnoff SJ: Myocardial contractility as described by ventricular function curves: observations on Starling’s law of the heart. JCI35: 107, 1955. 13. Crexells C, Chatterjee K, Forrester JS, Dikshit K, Swan HJC: Optimal level of filling pressure in the left side of the heart in acute myocardial infarction. N Engl J Med 289: 1263, 1973. 14. Gaasch WH, Battle WE, Oboler AA, Banas JS, Levine HJ: Left ventricular stress and compliance in man. Circulation 45: 746, 1972. 15. Tovama M, Reis RL: Effects of myocardial ischemia on ventricular compliance. Surgery 70: 458, 1975. 16. Buckberg GD, Towers B, Paglia DE, Mulder DG, Maloney JV: Subendocardial ischemia after cardiopulmonary bypass. J Thorac Cardiovasc Surg 64: 669, 1972. 17. Brazier J, Cooper N, Buckberg G: The adequacy of subendocardial oxygen delivery: the interaction of determinants of flow, arterial oxygen content and myocardial oxygen need. Circulation 49: 968, 1974. 18. Russell RO, Rackley CE, Pombo J, Hunt D, Potanin C, Dodge G: Effects of increasing left ventricular filling pressure in patients with acute myocardial infarction. JCI 49: 1539, 1970. 19. Berger RL, Saini VK, Long WM, Hechtman HB, Hood W: The use of diastolic augmentation with the intraaortic balloon in human septic shock with associated coronary artery disease. Surgery 74: 601. 1973. 20. Clowes GHA, Zuschneid W, Turner M, Blackburn G, Rubin J, Toala P, Green G: Observations on the pathogenesis of the pneumonitis associated with severe infections in other parts of the body. Ann Surg 167: 630, 1968. 21. Clowes GHA, Hirsch E, Williams L, Kwasnik E, O’Donnell TF, Cuevas P, Saini VK, Moradi I, Farizan M, Saravis C. Stone M, Kuffler J: Septic lung and shock lung in man. Ann Surg 181: 681, 1975. 22. Patten M, Liebman PR, Hechtman HB: Humorally mediated decreases in cardiac output associated with positive end expiratory pressure. Microvascular Research 13: 137, 1977.
The American Journal of Surgery
Myocardial Depression during Sepsis
23. Miller LD, Dski FA, Disco JF, Sugerman HJ, Gottlieb AJ, Davidson D, Papadopoulos: The affinity of hemoglobin for oxygen: its control and in vivo. Surgety 68: 167, 1970. 24. McCoon R, Del Guercio LRM: Respiratory function of blood in the acutely ill patient and the effect of steroids. Ann Surg 174: 436, 1971. 25. Watkins GM, Rabelo A, Plazak LF, Sheldon GF: The left shifted oxyhemoglobin curve in sepsis. Ann Surg 180: 213, 1974. 26. Dennis RC, Vito L, Weisel RD, Valeri R, Berger RL, Hechtman HB: Improved myocardial performance following high 2,3 DPG red cell transfusions. Surgery 77: 741, 1975.
Discussion George H. A. Clowes (Boston, MA): In my view the authors are to he congratulated for quantitating a very important aspect of circulatory failure in post-traumatic and septic shock. That is myocardial insufficiency. It is now generally accepted that the physiologic pattern of recovery after severe trauma or the onset of major infection includes a high cardiac output, often nearly twice the normal resting value. If the high output to satisfy the circulatory demands established by a low peripheral vascular resistance is not maintained, a state of shock exists with all the accompanying metabolic chaos. There are three principal causes for circulatory insufficiency under these circumstances: (1) hypovolemia due to fluid tran&cation, treated by fluid infusion, best measured by the authors’ method of determining optimum atria1 pressure; (2) elevated pulmonary vascular resistance accompanying the “shunting” of pneumonitis, which may cause right heart failure, treated by effective respiratory support; and (3) myocardial insufficiency, which the authors have documented clearly. For some time I did not believe in “myocardial depression,” in trauma and sepsis, but our experiences with the dramatic restoration of myocardial function after the use of glucose, insulin, and potassium conviqced me. Nor did I believe that a “myocardial depressant factor” existed until we performed experiments with Doctor Rita McCoon at Albert Einstein Medical School. Certain fractions of plasma from a septic patient, when infused into a coronary, produced a significant reduction of myocardial contractility not seen when saline or the same fraction of normal plasma was infused. Furthermore, the depression disappeared when the infusion of “septic fraction” was discontinued. It seems to me the importance of all this is that the authors have presented an excellent method for judging the effectiveness of therapy designed to restore the cardiac function required for the high output essential to recovery.
volume Ias. AprH 1977
J. M. Van De Water (Providence, RI): In reference to the myocardial depressant factor, which has been mentioned, I would like to ask Doctor Weisel if he has any experimental data or any thoughts on the use of steroids, specifically Solumedrol@ and Dexamethasones
Willard C. Johnson (Boston, MA): I would like to ask you whether the patient who does not have an appropriate cardiac response is a candidate for intra-aortic balloon assist. Also, do you have any data on patients with such cardiac support as related to survival? Richard D. Weisel (closing): I would like to thank the discussants. I have appreciated working with them and I am particularly indebted to Doctor Clowes for his critique and inspiration. We have found that right ventricular failure is an infrequent cause of cardiac decompensation in our septic patients. Twenty-eight per cent of the right ventricular function curves we plotted had decreases in RVSWI with increases in CVP. These fourteen patients did not necessarily have left ventricular decompensation or respiratory failure. We have found that decreases in shunt fraction in septic respiratory failure can be accomplished by increasing tidal volume or adding positive end-expiratory pressure. However, normalizing oncotic pressure with albumin and diuresis has been required to decrease interstitial lung water and permanently improve septic respiratory failure. Glucose, insulin, and potassium (GIK) have been used in four septic and sixteen cardiac patients to improve myocardial performance. GIK was found to have a greater inotropic effect than infusing an equal osmolar load of mannitol. We do not have definitive evidence that the inotropic effect of GIK is accomplished with improved myocardial metabolism over dopamine or isoproterenol. We have studied the effects of pharmacologic doses of steroids in only three patients, Doctor Van De Water. We have found no consistent change in myocardial response to volume loading after steroid infusions. Some physicians on our staff use steroids in septic shock despite the lack of objective evidence of a beneficial effect. We have reported improved cardiac performance in response to intra-aortic balloon counterpulsation (IABP) in patients with septic shock. Doctor Johnson, we believe that a beneficial response can be expected if the initial CI is less than 2.5 l/min/m2 and the initial PAWP is greater than 15 mm Hg, or if the response to volume loading produces an upslope less than 0.25 l/min/m2/mm Hg. Patients with high outputs, low vascular resistance, and a good response to volume loading have had no hemodynamic response to IABP and have all died.
521
Sepsis continues to be the major cause of death in our surgical intensive care unit. Despite careful monitoring, aggressive surgery, and the use of specific antibiotics, the mortality of invasive infection has remained between 60 and 70 per cent. Most patients die with sequential multisystem failure resulting from inadequate or maldistributed organ perfusion, despite a normal or elevated cardiac output. Septic patients have an inordinately high incidence of cardiac, renal, and hepatic decompensation. Reported herein is a prospective evaluation of cardiac performance. Our objectives were to identify the causes of diminished cardiac reserves and of myocardial depression in sepsis and to develop guidelines for therapy. Material and Methods Patient Selection. Fifty patients with documented sepsis were evaluated by the Trauma Unit of the Boston University Medical Center. All patients had some evidence of infection on examination: elevated pulse rate, tachypnea, hyperpyrexia, warm skin, or an elevated white blood cell count (WBC). Each patient had a documented source of infection with either positive blood cultures or an abscess containing more than 100 ml of pus. Pulmonary artery catheterization was performed if hemodynamic instability persisted after therapy was initiated, or if respiratory failure developed. Catheters were also inserted if the patient’s general condition made his postoperative risk prohibitive. Studies were performed in all patients soon after sepsis was manifest. In twenty-five patients a complete assessment was repeated after two to five days. Ten patients were clinically improved, but fifteen were preterFrom the Department of Surgery, Boston University Medical Center. and the US Naval Blood Research Laboratory, Boston, Massachusetts. This work was supported by the National Institute of General Medical Sciences Grant #lROl GM23871-01, the United States Army Contract #L)ADA17-97-C-7149 and the US Navy (Naval MilitaryResearch and Development Command) Task #MB0 41.02.01-0017A 2 DE. The opinions or assertions contained herein are those of the authors and are not to be construed as official or reflecting the views of the Navy Department or Naval Service at large. Reprint requests should be addressed to Herbert B. Hechtman, MD, University Hospital, Department of Surgery, 75 East Newton Street, Boston, Massachusetts 02118. Presented at the Fifty-Seventh Annual Meeting of the New England Surgical Society, Whitefield, New Hampshire, September 23-26, 1976.
512
minal when reevaluated. A careful past history was obtained for each patient and their progress in the hospital was recorded. Measurements. A thermister-tipped pulmonary artery
catheter was passed and a brachial arterial catheter was inserted in each patient. Cardiac output was measured by the thermodilution technic [I] (Instrumentation Laboratories, Lexington, MA). The mean of triplicate measurements was used to calculate the cardiac index (CI). Left ventricular stroke work index (LVSWI) was calculated from the mean arterial pressure (MAP), the pulmonary artery wedge pressure (PAWP), the pulse rate (P), and the CI from the formula: LvswI
=
(MAP-PAWWW1.36) Pmoo)
where 1.36 converts the result to grmmeters (pm)/m2. All pressure measurements were made without positive end-expiratory pressure. Right ventricular stroke work index (RVSWI) was calculated from the mean pulmonary artery pressure (PAP), central venous pressure (CVP), P, and CI using a similar formula. Systemic vascular and pulmonary vascular resistances were calculated from the difference in pressure divided by the flow across the systemic and pulmonary vascular beds. Blood gas and pH measurements were made with atandard electrodes (Instrumentation Laboratories, Lexington, MA) and converted to body temperature [2]. Hemoglobin and per cent saturation were measured by spectrophotometry (Instrumentation Laboratories, Lexington, MA). Measured oxygen tensions and saturations were used to calculate oxygen content. Ninety-two blood samples were also analyzed for oxygen content with a fuel cell (Lexington Instruments, Lexington, MA). The correlation between the two methods of calculating oxygen content was excellent (r = 0.92, p < 0.001). The oxygen consumption index (90~) was calculated from the arterial-mixed venous (A-V) oxygen content difference and the CI using the Fick equation. The in vivo Pm was calculated from the corrected mixed venous oxygen tensions and saturation by the Hill equation using a slope of 2.65. The in vitro P5e was obtained by tonometering the blood at varying oxygen tensions in the 40 to 60 per cent saturation range, while temperature, pH, and carbon dioxide tension (PCOs) were controlled (37”C, 7.40 units, 40 mm Hg, respectively).
The American
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Myocardial Depression during Sepsis
TABLE I
TABLE II
Organ Failure in Septic Patients Total
Survived
Number of patients Age (yr) Preexisting heart disease Postoperative heart
50 57.4 21 9
19 57.2 6 0
31 57.6 15 9
disease Postoperative
33
11
22
67%
20
7
13
65%
acute
respiratory failure Postoperative renal failure Hepatic failure
6 0 ..._~~~_._.._
Died
was calculated
62% 7 1% 100%
6 100% _.~___ ~_ _ ..-
from the Berggren formula (31:
Qs -- Cc- Ca ig - c, - c,
xloo
where the subscripts c, a, and v represent pulmonary capillary, arterial, and mixed venous oxygen contents. C, was derived from the alveolar gas equation. The physiologic deadspace fraction Vn/Vr was calculated from arterial (a) and mixed expired (E) carbon dioxide tensions from the formula: vo -= VT
Number
Mortality
The physiologic shunt Q&T during 50 per cent oxygen breathing
Origins of Sepsis
P&O2 - PaCOz P,COs
Effective dynamic compliance was derived from the ratio VT/PIP, where VT is the spirometer-measured tidal volume and PIP is peak inspiratory pressure in centimeters of water. Myocardial Performance Curves. To assess the reserve capabilities of the heart each patient underwent volume loading with 50 gm of salt-poor albumin or 1 unit of whole blood over 15 minutes. Hemodynamic measurements were made with each 2 mm Hg change in PAWP. Two myocardial performance curves were constructed for each patient by plotting either LVSWI or CI against PAWP. An upslope was then calculated. The initial and highest CI and LVSWI and the corresponding PAWP were recorded for each curve. A downslope was calculated when two or more points had progressively lower CI or LVSWI, with increasing PAWP. There was a mean of 7.2 and a range of 5 to 15 points per curve. Results Clinical Information. Table I describes the patient population. The 62 per cent mortality expresses the grave prognosis of invasive sepsis. Twenty-one patients had preexisting heart disease characterized by a history of myocardial infarction (11 patients), an episode of congestive heart failure (6 patients), or persistent angina pectoris (4 patients). Nine patients manifested heart disease in the hospital (postoperatively): four had an infarction, three ischemia, and
Septic Diagnoses Peritonitis Intestinal perforations lntraperitoneal abscesses Pancreatitis Intestinal infarctions Pneumonia Septicemra Infected vascular prostheses Pyelonephritis Primary Infecting Organisms Gram negative intestinal organisms Gram positive organisms (staph aureus) Anerobic organisms Clostridia species None Mean temperature White Blood Cell Count (cells/mm’)
39 19 14 3 3 7 4 2 2, 38 4 4 2 2 38.8 * 0.8 14,300 2 6,700
two congestive
heart failure. Thirty-three patients developed acute respiratory failure and had a Q~/QT > 20 per cent. Renal failure (RF) developed in twenty patients, manifest by serum creatinine levels greater than 5 mg/lOO ml. Fifteen required dialysis. Hepatic failure and jaundice (serum bilirubin level > 6 mg/ 100 ml) developed in six patients. Most of these associated conditions influenced the mortality of sepsis. Heart disease and hepatic failure had the most direct effect on mortality, while paradoxically renal failure tended to reduce the mortality. The occurrence of acute respiratory failure or preexisting heart disease did not alter the prognosis. The diagnosis of sepsis was often difficult to establish. All patients had hyperpyrexia sometime during their septic course. However, at the time of their initial evaluation their mean temperature was 38.8”C. Some patients had subnormal temperatures. Most patients developed an elevated WBC, but subnormal WBCs were also encountered. All patients eventually were found to have a documented source of sepsis. Table II describes the diagnoses and organisms recovered. Myocardial Performance Curves. The Starling mechanism predicts that volume loading the heart should lead to increases in cardiac output and stroke work. Septic cardiac function curves characteristically had a steep upslope. (Figure 1, Table III.) The peak or highest LVSWI or CI obtainable occurred at a relatively low filling pressure (PAWP between 10 to 12 mm Hg). Fifty per cent of septic patients had a downslope an abnormal
to their myocardial performance response to volume loading.
curve,
513
Weisel et al
Several aspects of the performance curves could be used to differentiate survivors and nonsurvivors. Septic patients who died had significantly lower upslopes and were unable to attain the same highest LVSWI or CI as the survivors. (Figure 1.) No patient survived with an upslope of the LVSWI curve <2 gm.m/m2.mm Hg or an upslope of the CI curve <0.2 l/min-m2smm Hg. The incidence of downslopes was similar for patients who lived or died. 7
N
Highest Upslope LVSWI
Highest Downslope PAWP N %
OSwvived
19
4.4
54
10
9
47
n
31
2.5’
30’
12
15
49
Died
t
eel
P’.Ol
LVSWI g.m/m2
F&we l.~~~patienlshadagreaterlncre~~L~Wl per mm Hg increase in PA WP than nonsurviving patients. 77~ h&#est L VS WI attained was greater in the survivors and occurred at a comparable PA WP. The initial PA WP and L VS WI and the incidence oi do wnslopes were not signiiicant/y different. Note that downslopes occur at relatively iow PA WP of 10 to 12 mm Hg.
TABLE I I I
Two to five days after the initiation of therapy myocardial performance curves were repeated in twenty-five patients. (Figure 2.) The pre-volume loading LVSWI and PAWP were unchanged. Ten patients showed improvement in their cardiac reserves, manifest by steeper upslopes and increases in the highest attainable LVSWI. Four of these patients had initial upslopes <2.5 gm-m/m2.mm Hg and highest LVSWI < 30 gm+m/m2. The dramatic improvement seen in these patients is encouraging evidence that myocardial depression in sepsis is potentially reversible. Two of these patients died of late complications of sepsis. Fifteen patients deteriorated despite therapy and Figure 2 demonstrates their diminished response to volume loading preterminahy. Some of these patients had high cardiac indices and a good response to volume loading when originally studied. Cardiorespiratory Measurements. Table IV describes the measurements made prior to volume loading. Only pH and base excess were significantly different between living and dying septic patients. Pulmonary hypertension was seldom seen in these patients. The mean PAP was never above 30 mm Hg and the pulmonary vascular resistance {PVR) was greater than 0.20 units in only three patients. There was a significant inverse (p < 0.05) correlation between the effective dynamic compliance and the PVR. CVP proved to be an inadequate indicator of the PAWP. There was a poor correlation (r = 0.46) between fifty measurements of CVP and PAWP made prior to volume loading. The correlation did not improve when the changes in CVP and PAWP in
Myoeardial Performance Curves in Sepsis Surviving N
LVSWI
vs PAWP
Myocardial
Performance
Note: SD = standard * p
514
SD
N
Mean
SD
Curves
Upslope (gm-m/m*. mm Hg) Highest LVSWI (gm-m/m’) Highest PAWP (mm Hg) Downslope (gm.m/m’.mm Hg) Lowest LVSWI (gm-m/m’) Lowest PAWP (mm Hg) Cl vs PAWP Myocardial Performance Upslope (I/min.m’-mm Hg) Highest Cl(I/min-m*) Highest PAWP (mm Hg) Oownslope (I/min.mz.mm Hg) Lowest Cl (l/min.m2) Lowest PAWP (mm Hg)
Mean
Dying
19 19 19 9 19 19
4.38 54.3 10.3 4.48 36.6 5.7
2.23” 24.7* 3.3 4.76 18.1 3.6
28 31 28 15 28 28
2.54 37.6 11.7 2.25 26.2 6.2
2.12 16.4 4.1 2.27 13.7 3.0
19 19 19 9 19 19
0.38 5.00 10.1 0.37 3.46 5.8
0.15* 1.33* 3.3 0.39 1.22 3.6
28 31 28 15 28 28
0.20 3.96 11.4 0.20 3.31 6.5
0.14 1.25 3.8 0.15 1.32 2.9
Curves
deviation.
The American Journal of Surgary
Myocardial Depression during Sepsis
Figure 2. ReqIonSe to therapy. Twenty-five patients had VOiume loading repeated two to five days after their initial assessment. Each patlent was used as his own control. Ten patients had an increased upslope and attained a higher L VSWI, whereas fifteen dis*yed~-nce prior to their demise.
TABLE IV
Physiologic
Variables
0
5
10
15
5
0
PAWP mmHg H
PAWP mmHg
‘PC.01 fP’O5
in Septic Patients
Cardiac index (I/min.m2) Pulse (beats/min) Mean arterial pressure artery
15
STANDARDERROR
All
(mm Hg) Mean pulmonary
10
3.7 ? 1.3* 103 * 17 79 f- 20 pressure
(mm Hg) Mean pulmonary artery wedge pressure (mm Hg) Mean central venous pressure (mm Hg) Left ventricular stroke work index (gm.m*) Right ventricular stroke work index (gm,m*) Systemic vascular resistance? Pulmonary vascular resistance? pH (units) Base excess (mEq) P,, in vivo (mm Hg) P,, in vitro (mm Hg) A-V oxygen content difference (~01%) Oxygen consumption (ml/min~m* ) Mixed venous oxygen tension (mm Hg) Physiological shunt (%) Physiological deadspace (%) Effective dynamic compliance (ml/cm H,O)
Dying 3.7 * 1.3 98 i- 15 84 * 20
3.7 * 1.3 107 + 18 77 +20
19.4 + 5.7
18.5 ? 5.9
19.9 f 5.6
8.7 f 4.3
7.2 * 4.3
9.7 + 4.4
9.4 ? 5.4
6.9 ? 4.4
10.9 + 6.1
36 + 16
43 + 21
31 r 14
5.1 %3.8
5.9 ? 4.5
4.5 * 3.4
0.694 0.10 7.44 3.1 26.0 25.2 4.0
? 0.330 ? 0.057 f; 0.08 + 6.0 + 3.4 + 2.3 + 1.2
0.701 0.107 7.48 6.3 26.0 26.7 4.0
+ 0.350 i 0.043 + 0.05$ + 5.1$ + 2.6 + 1.8 ? 0.8
0.690 0.110 7.42 1.3 26.1 24.2 4.0
f 0.310 i 0.066 f 0.11 f 6.4 + 3.9 + 2.5 + 1.4
134 +_77
117 +41
36.0 + 7.4
37.0 +_4.9
35.4
+ 8.9
23.9 44.5 27.8
19.1 ? 10.9 41.5 ? 10.3 28.6 f 8.1
27.0 46.5 27.4
+ 11.5 + 12.0 * 9.3
f 11.3 i 11.3 f 8.8
144 t 99
*Values
listed as mean +_1 standard deviation. 1 mm Hg pressure difference tl unit = 1 ml/set flow sp < 0.01.
vohlme 133. AprH IS77
515
Weisel et al
Postooerative Heart Disease (HD)
Acute Respiratory Fallun (ARF)
Hepatic Failure (HF)
-7
601
60&
50 40
LVSWI g-m/m2
30 20 10 I2zYcf2 0
5
10
PAWP mmHg
15
0
5
PAWP mmHg
+iSTANDARDERROR ‘PC 01 tPC 05
response to volume loading were analyzed (r = 0.35). However, the CVP could be clinically useful within narrow limits. Only one patient had a PAWP > 10 mm Hg when the CVP was less than 5 mm Hg. Consequently, if t.he CVP is <5 mm Hg, hydrostatic pulmonary edema is very unlikely. Secondly, only one patient had a PAWP < 5 mm Hg when the CVP was >12 mm Hg. This indicates that if the.CVP is >12 mm Hg, hypotension or low cardiac output is not due to hypovolemia. Finally, the CVP did provide a guide, albeit a poor one, to right ventricular performance. When RVSWI was plotted against CVP during volume loading, 28 per cent of the curves had decreases in RVSWI’associated with increases in the CVP. Myocardial Performance and Associated Conditions. The effect of associated disease on the induc-
tion of myocardial depression in sepsis was evaluated. Preexisting heart disease was equally prevalent among both surviving and dying patients and had no influence on cardiac performance. Figure 3 illustrates the effect of other conditions. Heart disease occurring in the postoperative period had a dramatic effect on
516
10
15
Figure 3. Myucardial depression was direct/y related to the presence of postoperative heart disease or acute respiratory failure. The upsfopes and peaks of the iperformance curves were significanby higher in patients without heart disease or respiratory failure. On the other hand, renal and hepatic failure were associated wfth good cardiac function.
cardiac function. Although there was no difference in the initial measurements of LVSWI and PAWP between the nine patients with heart disease and the forty-one without heart disease, the response to volume loading was markedly depressed in the group with heart disease.- One patient in this group showed transient improvement with the treatment of his infection, but postoperative heart disease was uniformly fatal. The thirty-three patients with acute respiratory failure had significantly lower upslopes and failed to achieve as high a LVSWI as did the non-acute respiratory failure patients. (Figure 3.) Surprisingly, patients with renal failure had better performance curves than those patients without renal failure. As noted above, hepatic failure was a lethal complication. Despite this, patients with hepatic failure had steep upslopes and were able to generate high LVSWI at peak performance. However, all patients with hepatic failure had downslopes. Normal P5c is 26.5 mm Hg. A decrease in the in vivo P5c was found in fifteen septic patients, the range being 17 to 24 mm Hg (mean, 21.6 mm Hg).
The American Journal ol Surgery
Myocardial Depression during Sepsis
Figure 4. Effect of high affinity hemoglobin and low initial cardiac index. Left, patients with low P5,, or high oxygenhemoglobin affinity states had significantly reduced myocardial performance manifest by lower upslopes and L VSWI. Right, ten patients with a cardiac index (C/) of less than 2.5 I/min*m * when inltlaliy evaluated, were found to have a depressed response to volume loading. Ho we ver, five of these ten pafienfs who had a PA WP less than 5 mm Hg, had a significantly better response to volume loading than the remaining five patients.
60 50 40
LVSWI
30 20 10 g.m/m2
60'
(4 L7cfrlk SO40-
30-
20-
IO-
0
5
PAWP mmlig
H
STANDARD ‘PC 01 tP< 05
0
5
10
15
PAWP mmlig
ERROR
The in vitro P5e was also low with a mean of 23.3 mm Hg. The CI of this group, prior to volume loading, was 2.9 l/minm2, which was not significantly different from patients with a normal Pse. These patients with low Pso values, whose flow did not increase in response to the high affinity state, manifest one of two responses: a decrease in P,Oz or VOs. Eight of the fifteen patients had a PBOs < 30 mm Hg (mean, 25 mm Hg) with a normal oxygen extraction (A-V oxygen content difference, 3.6 vol per cent), and oxygen consumption (VOs, 104 ml/minm2). Seven of the fifteen patients had a decreased oxygen consumption (VOs, 49 ml/minm2) with a normal PB02 (35 mm Hg) and A-V oxygen content difference (3.3 vol per cent). After volume loading, patients with a low P50 had a depressed myocardial response including a 73 per cent incidence of downslopes. (Figure 4.) Only two of these fifteen patients with low Pse values survived; both improved their myocardial performance when their Pso value returned to normal limits after two to five days. Ten patients had a CI < 2.5 l/min.m2. Figure 4 indicates that these patients had a diminished response to volume loading. Comments
The diagnosis of sepsis was based on clinical findings and the presence of either positive blood cultures, an intraperitoneal abscess, or intestinal infarction. We were unable to distinguish between the cardiorespiratory responses of patients with gram-positive and gram-negative infections. Others have concurred with this finding [4-61. Documentation of sepsis was frequently difficult and time-consuming. The treatment of critically ill
Volume 133, Aplll977
15
10
patients cannot await laboratory results. We have found the cardiac and pulmonary physiologic measurements helpful in establishing the amgnosis of sepsis. A high CI and more particularly a dramatic response to volume loading (slope of the myocardial performance curve) characterize the septic patient. On occasion patients with acute pancreatitis and alcoholic hepatitis may demonstrate similar findings and can be confused with the septic group. Acute respiratory failure is another important clue to the diagnosis of underlying sepsis and,frequently heralds its onset [ 71. One hundred seventeen patients with acute respiratory failure have previously been evaluated by our Trauma Unit and sepsis was present in eighty-two (70 per cent). Sixty-three (54 per cent) of this patient population had an intraperitoneal source of infection and required surgery. Therefore, if a surgical patient presents with acute respiratory failure and has a hyperdynamic response to volume loading, he is most likely septic. In addition, if a source of this infection is not readily uncoveredsuch as severe pneumonia, pyelonephritis or infected intravenous catheter-an intraperitoneal focus is probable and exploratory laparotomy should be strongly considered. The mortality from sepsis depends u@n the patient’s general condition and the physician’s ability to eradicate the infecting source. Preexisting heart disease was pervasive in our patients and perhaps accounted for the mortality higher than that reported by others [4,5,8]. The uniform fatality associated with acute cardiac decompensation or ischemia emphasizes the central role of myocardial performance in sepsis. Other authors have stressed the poor prognosis of patients with liver disease [9]. The role of
517
Weisel et al
TABLE V
Myocardial Performance Curves
Clinical Condition
Upslope (gm.m/m2.mm
Number
Hg)
Highest LVSWI (gm.m/m2)
Downslope (%I
Sepsis Surviving Dying Abdominal
aortic
Ruptured Elective Coronary artery
4.38 2.54
f 2.21* f 2.12
54.3 + 24.7* 37.6 + 16.4
47 48
17 10
3.38 3.82
? 3.21 r 2.32
30.8 * 5.4 40.8 * 8.1
47 20
23 41 37
3.36 * 1.94 1.49 + 0.91 2.68 k 1.18
37.7 f. 11.6 30.6 r 11.3
9 75 16
aneurysms
bypass
Preoperatively Immediately postoperatively 24 hr postoperatively *Surviving
19 31
septic
patients
had a greater
upslope
and highest
renal failure in the mortality of sepsis is confusing. Our results indicate that patients with acute renal failure tend to have a hyperdynamic response to volume loading and do not have a higher mortality rate. Renal failure is readily controlled with dialysis and frequently reversible. It is therefore perhaps understandable that patients whose sepsis is complicated by renal failure may have a better prognosis than those patients complicated by hepatic or cardiac failure. In this series acute respiratory failure did not adversely effect the prognosis of sepsis. However, this is at variance with our previous experience where acute respiratory failure was found to significantly (p < 0.01) increase the mortality of the 113 septic patients seen in our Trauma Unit. The mortality for acute respiratory failure and sepsis was 77 per cent compared to a mortality of 45 per cent for sepsis without acute respiratory failure. Myocardial Performance. Classifying patients into hyper- and hypodynamic groups based on routine cardiac output measurements tends to obscure the hemodynamics of sepsis [5,10,11]. Normally the heart is permissive and flow is regulated by tissue needs and venous return. Thus, a low CI in untreated sepsis may simply indicate a failure of venous return because of peripheral vaaodilatation. Although this may in part be true, the results of fluid loading indicate that the septic heart often has limited reserves and will frequently not function in a permissive fashion. It is not unreasonable to speculate that the septic heart may no longer respond to tissue needs. Thus, a “normal” CI may be inadequate for a septic patient. To evaluate myocardial depression in sepsis, we have emphasized the results of LVSWI rather than CI myocardial performance curves, although both were plotted and appeared similar for each patient.
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LVSWI,
37.6 k 11.3
-
p ~0.05.
As discussed by Sarnoff [12], LVSWI analysis accommodates small changes in MAP and pulse rate during volume loading. Large changes in MAP or pulse induce compensatory changes in contractility and make evaluation of the Starling mechanism impossible. We have, therefore, eliminated any curves constructed during substantial changes of MAP or pulse. Myocardial performance curves in surviving septic patients had a sharp upslope, an elevated highest LVSWI and a high incidence of downslopes. For comparison, these same variables are listed for patients suffering from nonseptic conditions-abdominal aortic aneurysm repair and coronary bypass surgery. (Table V.) In addition, Crexells et al [13] have described the myocardial performance of patients who had acute myocardial infarctions. These patients had upslopes less than 1.5 pm/m2.mm Hg, a mean highest LVSWI of 35 gm.m/m2, and a 22 per cent incidence of downslopes. The reason for the sharp upslopes in surviving septic patients is unknown. It is possible that dying septic patients and others with low upslopes (Table V) have a reduced ventricular compliance, as might occur with cardiac edema. The low compliance means that for any PAWP there will be a reduced ventricular volume and myocardial fiber stretch. Under these circumstances, a low upslope of the myocardial performance curve can be predicted [14,15]. An alternative postulate is that there has been a decrease in intrinsic myocardial contractility. Such an event may occur because of a decrease in coronary blood flow or a redistribution of flow away from the subendocardial regions [I 1,16,17]. Edema or vasoactive agents may induce such a redistribution. In addition, edema may create a diffusion barrier to oxygen transport and thereby limit contractility. Finally, a number of substances may act directly on the heart
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Myocardial Depression during Sepsis
and induce a negative inotropic state. Our data do not permit resolution of this issue. The sharp downslopes seen in half of all septic patients represents an abnormality in the Starling mechanism [18]. This phenomenon cannot be explained by an altered ventricular compliance. The configuration of these curves, particularly the presence of downslopes (Figure l), requires that fluid infusions be carefully monitored with the PAWP. If a performance curve is not done, fluid infusions should be adjusted to maintain the PAWP at 10 mm Hg to optimize cardiac output. Insufficient or excessive volume is poorly tolerated by these patients. The description of improvement and deterioration of the cardiac response to volume loading with time emphasizes that the hyper- and hypodynamic cardiac states represent a continuum. (Figure 2.) These changes in myocardial performance may occur without significant alterations in the initial cardiac output and PAWP measurements. It is only by stressing the heart that these limitations in cardiac reserves can be identified. Several organ systems were evaluated with regard to their influence on cardiac performance. Acute postoperative but not preoperative heart disease was associated with a profound depression in cardiac function. The results indicate that septic patients who develop cardiac ischemia are at extreme risk. Hemodynamic monitoring was useful under these circumstances. Fluid infusions should be carefully regulated to obtain a PAWP of 12 mm Hg. (Figure 3.) If a satisfactory highest LVSWI and CI cannot be obtained, then resort to other therapy should be prompt. The use of red cell transfusions to maintain hemoglobin concentrations between 12 and 14 gm/lOO ml should be considered since oxygen transport is critical. Another factor relating to oxygen transport involves an attempt to increase the Pm to produce a low oxygen-hemoglobin affinity state. This is discussed below. Inotropic agents may increase both flow and systemic pressure but should be used sparingly since they may increase myocardial oxygen demand more than they increase oxygen supply. These patients may benefit most from intra-aortic balloon counterpulsation [19], which will increase oxygen supply and reduce oxygen demand and redirect flow to the subendocardium. One patient in this series was successfully treated by counterpulsation and showed marked improvement in his myocardial performance curve. Patients with acute respiratory failure had significantly lower upslopes. Myocardial depression in septic patients with acute respiratory failure has been
reported by Clowes and associates [6,20,21]. They proposed right heart failure due to elevation in pulmonary vascular resistance as the mechanism for cardiac decompensation. However, we did not observe severe elevations in PAP. There was no difference between the PAP of surviving and dying patients or between those with and those without acute respiratory failure. We did notice an interesting correlation between effective dynamic compliance and PVR. Also the upslope of patients with a reduced compliance (<20 cm HsO/ml) was lower than those with higher compliance. These observations are consistent with one of Clowes’ hypotheses, that circulating substances in sepsis are inducing cardiac and respiratory decompensation. In addition, it is possible that a damaged pulmonary capillary endothelium is unable to metabolize vasoactive substances which in turn are allowed access to the systemic circulation and result in a redistribution of blood flow away from the subendocardium in the heart. Experimental data confirm the presence of humoral agents released by pulmonary manipulation which will depress cardiac function [22]. An increase in the affinity of hemoglobin for oxygen has been described in septic patients [23-251. Fifteen patients in our study group had an in vivo PX < 24 mm Hg. The fact that the in vitro PsO averaged 23.3 mm Hg indicates that red cell 2,3 diphosphoglycerate (2,3 DPG) concentrations were low. Phosphate depletion and infusion of large volumes of stored blood have been implicated in inducing reductions of 2,3 DPG concentrations. None of our patients received more than 3 units of blood within three days of their study. Phosphate levels were reported in only five patients, but were normal. Therefore, the mechanism for the 2,3 DPG depletion remains obscure. The mean in vivo P50 in this group of fifteen patients was only 21.6, lower than the in vitro value. The significant alkalosis in these septic patients is thought to explain these in vivo results. It is, of course, the in vivo P5c which defines the clinical oxygen-hemoglobin affinity state. The cardiac indices prior to volume loading of the patients with high and low Pm values were the same. Given the fact that flow was fixed, the low P50 group manifest two types of responses-a decrease in P,Oz or VOz. Neither of these systemic responses were available to the heart. The coronary sinus normally has a low oxygen tension and it cannot fall further in response to an increased oxygen-hemoglobin affinity. Further, the heart cannot accept a decrease in myocardial oxygen consumption without a decrease in performance. Normally, oxygen supply to the heart is ad-
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et al
justed by regulating coronary blood flow. If coronary flow is relatively fixed or poorly distributed, the heart cannot respond properly to increased work requirements such as those induced by volume loading. This response to volume loading will be further limited by a high affinity state. (Figure 4.) These results are consistent ‘with previous observations. Depressed cardiac redponse to volume loading was found in patients who had received large infusions of old blood and had a low P50 and PoOa after repair of ruptured abdominal aortic aneurysms. Conversely, we have observed improved performance in response to volume loading in patients receiving high 2,3 DPG red cells after coronary artery bypass surgery [26]. A low Pm may be prevented or reversed by using infusions of fresh red cells if transfusions are required. Secondly, respiratory and/or metabolic alkalosis should be reversed by adjusting respirator settings in patients who are mechanically ventilated or by the intravenous infusions of acidifying agents. Finally, inorganic phosphate supplements may be required, particularly in patients who are being hyperalimented. To improve the prognosis of septic patients, careful attention should be paid to cardiac function. Volume loading may be safely performed and provides information useful for the regulation of fluid therapy. If there is an inadequate response to volume, then the possible causes of myocardial depression, such as low P50 or respiratory failure, should be explored. Summary
The cardiac response to volume loading was evaluated in fifty severely septic patients. After a rapid infusion of albumin or whole blood the cardiac index (CI) and left ventricular stroke work index (LVSWI) were recorded as the pulmonary arterial wedge pressure (PAWP) increased. Initial values of PAWP, CI, and LVSWI were similar in both the nineteen surviving and thirty-one nonsurviving patients. Surviving patients, however, demonstrated greater increases in CI and LVSWI as PAWP rose. Nearly half of both patient groups developed decreases in Cl and LVSWI as the PAWP continued to increase. These downslopes occurred at relatively low PAWP and are taken as evidence of an abnormality of myocardial function in both survivors and nonsurvivors. The lower upslope of the performance curves in nonsu&vors indicates myocardial depression or a negative’inotropic effect. Cardiac ischemia, acute respiratory failure, and high affinity red cells were found to diminish the cardiac response to volume loading, whereas hepatic and renal failure were associated with a good CI and LVSWI response.
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References 1. Weisel RD. Berger RL, Hechtman HB: Measurement of cardiac output by thermodilution. N Engl J Med 292: 082, 1975. 2. Kelman GL: Calculation of certain indices of cardiopulmonary function using a digital computer. Resp Whys 1: 335, 1966. 3. Berggren SM: The oxygen deficit of arterial blood caused by nonventilating parts of the lung. Acta Physiol Scmd [Sup@] 11: 1, 1942. 4. Winslow EJ, Loeb HS, Rahimtoola SH, Kamath S, Gunnar RM: Hemodvnamic studies and results of theraov in 50 oatients with bacteremic shock. Am JAW 54: 421’,:1973. I 5. MacLean LD. Mullioan WG. McLean APH. Duff JH: Patterns of septic shdck in ban-a detailed stud; of 56 patients. Ann Surg 166: 543, 562, 1967. 6. Clowes GHA, Farrington GH. Zuschneid W, Cossette GR, Saravis C: Circulating factors in the etiology of pulmonary insufficiency and right heart failure accompanying severe sepsis. Ann Surg 171: 663, 1970. 7. Vito L, Dennis DC. Weisel RD, Hechtman HB: Sepsis presenting as acute respiratory insufficiency. Surg Gynecol Obstet 138: 896, 1974. 8. Kluge RM, DuPont HL: Factors affecting mortality of patients with bacteremia. Surg Gynecol Obstet 137: 267, 1973. 9. Wilson RF, Chiscano AD, Quadros R, Tarver M: Some observations on 132 patients with septic shock. Anesth Analg 46: 761, 1967. 10. Siegel JH, Greenspan M, Del Guercio LRM: Abnormal vascular tone, defective oxygen transport and myocardial failure in human septic shock. Ann Surg 165: 504, 1967. 11. Hinshaw LR: Role of the heart in the pathogenesis of endotoxin shock. J Surg Res 17: 134, 1974. 12. Sarnoff SJ: Myocardial contractility as described by ventricular function curves: observations on Starling’s law of the heart. JCI35: 107, 1955. 13. Crexells C, Chatterjee K, Forrester JS, Dikshit K, Swan HJC: Optimal level of filling pressure in the left side of the heart in acute myocardial infarction. N Engl J Med 289: 1263, 1973. 14. Gaasch WH, Battle WE, Oboler AA, Banas JS, Levine HJ: Left ventricular stress and compliance in man. Circulation 45: 746, 1972. 15. Tovama M, Reis RL: Effects of myocardial ischemia on ventricular compliance. Surgery 70: 458, 1975. 16. Buckberg GD, Towers B, Paglia DE, Mulder DG, Maloney JV: Subendocardial ischemia after cardiopulmonary bypass. J Thorac Cardiovasc Surg 64: 669, 1972. 17. Brazier J, Cooper N, Buckberg G: The adequacy of subendocardial oxygen delivery: the interaction of determinants of flow, arterial oxygen content and myocardial oxygen need. Circulation 49: 968, 1974. 18. Russell RO, Rackley CE, Pombo J, Hunt D, Potanin C, Dodge G: Effects of increasing left ventricular filling pressure in patients with acute myocardial infarction. JCI 49: 1539, 1970. 19. Berger RL, Saini VK, Long WM, Hechtman HB, Hood W: The use of diastolic augmentation with the intraaortic balloon in human septic shock with associated coronary artery disease. Surgery 74: 601. 1973. 20. Clowes GHA, Zuschneid W, Turner M, Blackburn G, Rubin J, Toala P, Green G: Observations on the pathogenesis of the pneumonitis associated with severe infections in other parts of the body. Ann Surg 167: 630, 1968. 21. Clowes GHA, Hirsch E, Williams L, Kwasnik E, O’Donnell TF, Cuevas P, Saini VK, Moradi I, Farizan M, Saravis C. Stone M, Kuffler J: Septic lung and shock lung in man. Ann Surg 181: 681, 1975. 22. Patten M, Liebman PR, Hechtman HB: Humorally mediated decreases in cardiac output associated with positive end expiratory pressure. Microvascular Research 13: 137, 1977.
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23. Miller LD, Dski FA, Disco JF, Sugerman HJ, Gottlieb AJ, Davidson D, Papadopoulos: The affinity of hemoglobin for oxygen: its control and in vivo. Surgety 68: 167, 1970. 24. McCoon R, Del Guercio LRM: Respiratory function of blood in the acutely ill patient and the effect of steroids. Ann Surg 174: 436, 1971. 25. Watkins GM, Rabelo A, Plazak LF, Sheldon GF: The left shifted oxyhemoglobin curve in sepsis. Ann Surg 180: 213, 1974. 26. Dennis RC, Vito L, Weisel RD, Valeri R, Berger RL, Hechtman HB: Improved myocardial performance following high 2,3 DPG red cell transfusions. Surgery 77: 741, 1975.
Discussion George H. A. Clowes (Boston, MA): In my view the authors are to he congratulated for quantitating a very important aspect of circulatory failure in post-traumatic and septic shock. That is myocardial insufficiency. It is now generally accepted that the physiologic pattern of recovery after severe trauma or the onset of major infection includes a high cardiac output, often nearly twice the normal resting value. If the high output to satisfy the circulatory demands established by a low peripheral vascular resistance is not maintained, a state of shock exists with all the accompanying metabolic chaos. There are three principal causes for circulatory insufficiency under these circumstances: (1) hypovolemia due to fluid tran&cation, treated by fluid infusion, best measured by the authors’ method of determining optimum atria1 pressure; (2) elevated pulmonary vascular resistance accompanying the “shunting” of pneumonitis, which may cause right heart failure, treated by effective respiratory support; and (3) myocardial insufficiency, which the authors have documented clearly. For some time I did not believe in “myocardial depression,” in trauma and sepsis, but our experiences with the dramatic restoration of myocardial function after the use of glucose, insulin, and potassium conviqced me. Nor did I believe that a “myocardial depressant factor” existed until we performed experiments with Doctor Rita McCoon at Albert Einstein Medical School. Certain fractions of plasma from a septic patient, when infused into a coronary, produced a significant reduction of myocardial contractility not seen when saline or the same fraction of normal plasma was infused. Furthermore, the depression disappeared when the infusion of “septic fraction” was discontinued. It seems to me the importance of all this is that the authors have presented an excellent method for judging the effectiveness of therapy designed to restore the cardiac function required for the high output essential to recovery.
volume Ias. AprH 1977
J. M. Van De Water (Providence, RI): In reference to the myocardial depressant factor, which has been mentioned, I would like to ask Doctor Weisel if he has any experimental data or any thoughts on the use of steroids, specifically Solumedrol@ and Dexamethasones
Willard C. Johnson (Boston, MA): I would like to ask you whether the patient who does not have an appropriate cardiac response is a candidate for intra-aortic balloon assist. Also, do you have any data on patients with such cardiac support as related to survival? Richard D. Weisel (closing): I would like to thank the discussants. I have appreciated working with them and I am particularly indebted to Doctor Clowes for his critique and inspiration. We have found that right ventricular failure is an infrequent cause of cardiac decompensation in our septic patients. Twenty-eight per cent of the right ventricular function curves we plotted had decreases in RVSWI with increases in CVP. These fourteen patients did not necessarily have left ventricular decompensation or respiratory failure. We have found that decreases in shunt fraction in septic respiratory failure can be accomplished by increasing tidal volume or adding positive end-expiratory pressure. However, normalizing oncotic pressure with albumin and diuresis has been required to decrease interstitial lung water and permanently improve septic respiratory failure. Glucose, insulin, and potassium (GIK) have been used in four septic and sixteen cardiac patients to improve myocardial performance. GIK was found to have a greater inotropic effect than infusing an equal osmolar load of mannitol. We do not have definitive evidence that the inotropic effect of GIK is accomplished with improved myocardial metabolism over dopamine or isoproterenol. We have studied the effects of pharmacologic doses of steroids in only three patients, Doctor Van De Water. We have found no consistent change in myocardial response to volume loading after steroid infusions. Some physicians on our staff use steroids in septic shock despite the lack of objective evidence of a beneficial effect. We have reported improved cardiac performance in response to intra-aortic balloon counterpulsation (IABP) in patients with septic shock. Doctor Johnson, we believe that a beneficial response can be expected if the initial CI is less than 2.5 l/min/m2 and the initial PAWP is greater than 15 mm Hg, or if the response to volume loading produces an upslope less than 0.25 l/min/m2/mm Hg. Patients with high outputs, low vascular resistance, and a good response to volume loading have had no hemodynamic response to IABP and have all died.
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