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(Chest. 2003;124:1885-1891.)
© 2003 American College of Chest Physicians

Do All Nonsurvivors of Cardiogenic Shock Die With a Low Cardiac Index?*

Noelle Lim, MBBS, MMed; Marc-Jacques Dubois, MD; Daniel De Backer, MD, PhD and Jean-Louis Vincent, MD, PhD, FCCP

* From the Department of Intensive Care, Erasme Hospital, Free University of Brussels, Belgium.

Correspondence to: Jean-Louis Vincent, MD, PhD, FCCP, Department of Intensive Care, Erasme University Hospital, Route de Lennik 808, 1070 Brussels, Belgium; e-mail: jlvincen{at}ulb.ac.be


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objectives: To characterize the hemodynamic course of cardiogenic shock and to relate the cause of death to ongoing cardiac failure or multiple organ dysfunction.

Design: Retrospective study.

Setting: A 31-bed department of intensive care in a university hospital.

Patients: All patients admitted for cardiogenic shock from January 1999 to December 2000.

Interventions: None.

Measurements and results: Charts were reviewed for demographic, clinical, hemodynamic, oxygen transport, inflammation, and organ dysfunction data. Of 62 patients with cardiogenic shock, 40 (65%) did not survive. Eight patients (20%) died from fatal arrhythmia, 14 patients (35%) died with low cardiac index (CI) [ie, < 2.2 L/min/m2], and 18 patients (45%) died with normalized CI (ie, > 2.2 L/min/m2) and a higher CI/oxygen extraction ratio. Of these 18 patients, 9 had evidence of infection. The patients with normalized CI were younger and stayed longer in the ICU than patients with low CI.

Conclusion: A substantial number of patients with cardiogenic shock die with a normalized CI, suggesting a distributive defect, in the absence of obvious infection. These patients are younger and have a longer ICU course. The release of mediators may be secondary to gut hypoperfusion.

Key Words: bacterial translocation • distributive shock • hemodynamics • multiorgan failure • outcome


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Cardiogenic shock is a form of acute circulatory failure that is caused by cardiac dysfunction despite an adequate fluid status. Clinically, it is recognized by hypotension associated with signs of poor tissue perfusion such as oliguria, obtunded mental status, and cold clammy extremities. The typical hemodynamic criteria are a cardiac index (CI) of < 2.2 L/min/m2, with a pulmonary artery occlusion pressure (PAOP) of > 15 mm Hg, and sustained hypotension, with a systolic pressure of < 90 mm Hg or a value of 30 mm Hg below baseline levels for >= 30 min.1

The mortality of patients with cardiogenic shock remains high despite aggressive revascularization procedures and modern hemodynamic support with vasoactive drugs and sometimes intra-aortic balloon counterpulsation.2 3 The cause of death in patients with cardiogenic shock is not always evident, although it is usually attributed to the downward spiral of events associated with the reduction in cardiac output and cellular oxygen availability.4 5

As early as 1967, in an article on the nature of cardiogenic shock, Kuhn6 commented that "the statement by some investigators that ‘shock’ is a uniform syndrome characterized by low cardiac output and severe vasoconstriction with greatly elevated systemic vascular resistance is not supported...." However, this statement was only an opinion and was not based on evidence. It has been our observation that a number of patients with cardiogenic shock have succumbed in a state of low systemic vascular resistance (SVR) with normalized CI. Therefore, the goal of our study was to investigate this clinical impression by reviewing the hemodynamic evolution of nonsurvivors of cardiogenic shock and to relate the cause of death to ongoing cardiac failure or multiple organ dysfunction.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
We reviewed the complete charts of all patients with cardiogenic shock admitted to the 31-bed Medico-Surgical Department of Intensive Care of the Erasme University Hospital (Brussels, Belgium) from January 1999 to December 2000. Cardiogenic shock was defined by sustained (ie, for >= 30 min) hypotension with a systolic pressure of < 90 mm Hg or a value 30 mm Hg below baseline levels, which was associated with a CI of < 2.2 L/min/m2 and a PAOP of > 15 mm Hg. Exclusion criteria were infection present on hospital admission, endocarditis or myocarditis, cirrhosis, arteriovenous shunt, other causes of shock (eg, hypovolemic, obstructive, or septic shock), and patients who had died as a result of neurologic impairment (ie, postanoxic states or brain death).

In our department, all patients in shock are systematically managed according to a protocol including the insertion of a pulmonary artery catheter (PAC) [7F or 7.5F Swan-Ganz catheter], fluid challenge (with close monitoring of filling pressures, CI and mixed venous saturation [SvO2]), the administration of dobutamine if the CI and SvO2 remain low despite adequate filling pressures, the addition of vasopressors (ie, dopamine, norepinephrine, or epinephrine) if the patient remains hypotensive despite the above, and intra-aortic balloon counterpulsation in refractory cases. The majority of patients receive a PAC capable of continuous cardiac output measurement.

The following data were manually extracted from patients’ charts and records:

  1. Demographic and clinical data including age, gender, presence of comorbid disease (eg, hypertension, diabetes mellitus, ischemic heart disease, and COPD), duration of stay in ICU, the etiology of cardiogenic shock, and use and duration of use of vasoactive agents and intra-aortic balloon pump (IABP).
  2. Hemodynamic data including CI, mean arterial pressure (MAP), right atrial pressure (RAP), PAOP, mean pulmonary arterial pressure (MPAP), and heart rate (HR). SVR index (SVRI) was calculated using the following formula: (MAP - RAP)/CI x 79.9. Oxygen delivery index (DO2I) was calculated as follows: CI x Hb x 10 x 1.34 x SaO2, where Hb is hemoglobin and SaO2 is arterial oxygen saturation. Oxygen consumption index (O2I) was calculated as follows: CI x Hb x 10 x 1.34 x (SaO2 - SvO2). The oxygen extraction ratio (O2ER) was calculated as (SaO2 - SvO2)/SaO2, and the CI/O2ER ratio was computed.7 8 A CI/O2ER ratio of 12 (3:0.25) was used as the line of reference.8 Blood lactate concentrations also were recorded.
  3. The degree of organ dysfunction as assessed by the sequential organ failure assessment (SOFA) score.9
  4. Infection, inflammation, and organ dysfunction data (ie, bacteriologic results, use of antibiotics, and C-reactive protein [CRP]). We used the US Centers for Disease Control and Prevention criteria for the diagnosis of infection, except that nosocomial pneumonia was generally diagnosed with a protected endoscopic technique using BAL and clinical assessment including antibiotic prescription.10
  5. Postmortem examination results, if available.

We recorded all parameters during the entire course of cardiogenic shock, the final parameters being within the 24-h period prior to death. Measurements obtained during the agonal phase prior to death were excluded.

The patients were divided into ICU survivors and nonsurvivors. The nonsurvivors were subdivided into the following three groups: death from malignant arrhythmia; death with a low CI (ie, < 2.2 L/min/m2); and death with a normalized CI (ie, >2.2 L/min/m2). We compared the group of patients with cardiogenic shock who died with a low CI to the group who died with a normalized CI without infection, as sepsis may result in an increased CI. Data analysis between and within groups included an analysis of variance followed by Mann-Whitney U test with Bonferroni correction, and the Friedman test followed by Wilcoxon signed rank test with Bonferroni correction. We also applied the standardized area under the curve (AUC) to compare the CI between the two groups. The standardized AUC for each patient was obtained by dividing the total AUC by the time in hours. Categoric data were compared using the Fisher exact test. The data are expressed as the median (25th to 75th percentiles). A p value of < 0.05 was considered to be significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
A total of 65 patients were admitted to the hospital with cardiogenic shock (Table 1 , Fig 1 ). Two patients had no PAC, and one patient had no hemodynamic measurements within the 24 h preceding death. Of the remaining 62 patients with cardiogenic shock, 40 died. Of these patients, 8 experienced fatal arrhythmias, 14 died with a low CI (ie, < 2.2 L/min/m2), and 18 patients died with a normalized CI (ie, > 2.2 L/min/m2). Of the 18 patients who died with a normalized CI, 9 had clinical (5 patients) or bacteriologic (4 patients) evidence of infection. None of the patients in the low-CI group were infected (Fig 1) . As expected, the underlying cause of cardiogenic shock was acute myocardial infarction in the majority of the patients (Table 1) .


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  		Table 1.. Clinical Data and Treatment Characteristics of Nonsurvivors With Low CI and Normalized CI*

 


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  		Figure 1.. Distribution of patients with cardiogenic shock.

 
Demographics
Patients in the normalized CI group were significantly younger than those in the low-CI group but had a similar gender distribution and prevalence of comorbid disease (Table 1) . However, the length of stay in the ICU was significantly longer in the normalized CI group than in the low-CI group. There was no difference in the use or duration of use of IABP.

Hemodynamic and Oxygen-Derived Variables
There were no significant differences between the two groups in MAP, MPAP, HR, and infusion rates of vasoactive agents (Tables 1 , 2 ). The difference in CI between groups appeared early in the disease process, with the normalization of CI already evident 6 h after hospital admission in the normalized CI group (Fig 2 ). Accordingly, the standardized AUC of CI measurements over the first (mean ± SD) 24 ± 6 h after the onset of shock was significantly lower in the low-CI group than in the normalized CI group (1.8 vs 2.4, respectively; p < 0.05), and the time course of SVRI rapidly diverged between the two groups (Fig 2) . The median value of the final PAOP was slightly, but not significantly, higher in the low-CI group compared to the normalized CI group (p = 0.076). Similarly, the final RAP in the low-CI group was 18 mm Hg compared to 13 mm Hg in the normalized CI group (p = 0.458). There were no significant differences in the SaO2, SvO2, O2ER, and arterial pH (Table 2) . However, the CI/O2ER ratio rapidly increased in the normalized CI group (Fig 2) . While the final CI/O2ER values in both groups of patients were low, the patients in the normalized CI group remained closer to the line of reference (Fig 3 ). Blood lactate concentrations normalized more rapidly in this group. The final DO2I was significantly higher in the normalized CI group. There was no significant difference in O2I. The final hemoglobin level was significantly lower in the normalized CI group, but this was likely due to the longer length of stay.


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  		Table 2.. Hemodynamic, Oxygen Transport, Inflammation, and Organ Dysfunction in Nonsurvivors With Low CI and Normalized CI*

 


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  		Figure 2.. Evolution of CI, CI/O2ER ratio, and SVRI in the low-CI group (hatched boxes) and the normalized CI group (plain boxes) [p < 0.05 for group-time interaction]. # = p < 0.05, low CI group vs normalized CI group; @ = p < 0.05, normalized CI vs 0 h.

 


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  		Figure 3.. Relationship of final CI with final O2ER in low-CI group ({blacktriangleup}) and normalized CI ({square}) groups.

 
Organ Dysfunction
There were no significant differences in the total SOFA scores (Table 2) or in its different organ components (data not shown).

Inflammation
There were no significant differences in blood CRP levels between the two groups.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
In experimental studies of cardiogenic shock in which no treatment is instituted, death is attributed to the progressive failure of the left ventricular pump to maintain cardiac output and systemic pressures.11 The fatal course of cardiogenic shock is traditionally attributed to a so-called downward spiral of events that is associated with the activation of compensatory mechanisms, such as the sympathetic nervous system and the renin-angiotensin system, resulting in an increase in HR and contractility that raise myocardial oxygen demand and worsen myocardial ischemia, and vasoconstriction that increases myocardial afterload.4 5 The associated sodium and water retention can result in pulmonary congestion and hypoxemia.

Siegel et al12 described four hemodynamic states in which the entire spectrum of clinical severity of patients with trauma, sepsis, or cardiogenic shock could be classified. These were derived from data obtained from 157 patients who were studied at various periods during the course of their critical illness. Importantly, in the course of critical illness, a patient’s physiologic status could change from one state to another.

The key finding in our study was the identification of a subgroup of patients who died despite a rapid normalization of CI. These patients had a higher DO2I and a higher CI/O2ER ratio, but a lower SVRI, suggesting a distributive defect that possibly was attributable to the activation of immune and neurohormonal vascular mediators. This situation is similar to that seen in patients with sepsis, as described by Seyfer et al.13 In addition, the patients in the normalized CI group were younger and had a longer ICU stay compared to those in the low-CI group. These patients may have had a greater cardiac reserve and response to inotropes, such that they were able to rapidly increase their CI in response to therapy. The patients in the low-CI group were likely to have experienced the classic downward spiral of events.

Mueller et al14 reported that dopamine may promote myocardial ischemia in patients with cardiogenic shock, improving myocardial contractility but increasing myocardial O2 and lactate production. We do not believe this effect was important in our study; indeed, although regional myocardial metabolism was not measured, if death had been related to the toxic effects of high doses of dopamine on the myocardium, one would have expected cardiac output to decrease secondary to the dopamine-induced myocardial injury. However, we observed that these patients had a normal cardiac output but a defect in oxygen extraction. In addition, patients surviving their episode of cardiogenic shock were also initially treated with high doses of vasopressors, so it is unlikely that vasopressor therapy itself was responsible for the death of the patients.

As early as 1971, a "myocardial depressant factor" was isolated from the plasma in dog models of cardiogenic shock.15 A number of mediators, including interleukin-1 and tumor necrosis factor, can impair cardiac function.16 17 Increased nitric oxide production also can inhibit adrenergic stimulation of myocyte contractility.17 The administration of L-arginine analog N(G)-monomethyl-L-arginine, a nitric oxide synthase inhibitor, in a small number of patients with cardiogenic shock was able to increase cardiac contractility, while HR and PAOP remained unchanged.18 Of interest, the SVR of these patients was near normal despite high doses of catecholamines. The patients in the normalized CI group may have had an augmented inflammatory response resulting in an efflux of mediators, while the patients in the low-CI group did not. Elevated concentrations of endotoxin and cytokines have been found in patients with chronic heart failure during acute edematous exacerbations, and it has been hypothesized that bacterial translocation secondary to altered gut permeability (due to intestinal wall edema) may be responsible because of intensive diuretic treatment in these patients with normalized endotoxin levels.19

The relationship between CI and O2ER may be used to interpret CI values in the presence of anemia, as well as the response to therapeutic interventions.7 8 The normal ratio ranges from 10 to 12. It has been shown that a cutoff CI/O2ER ratio of 5 has the best sensitivity and specificity in predicting early mortality after an acute myocardial infarction.20

What was the cause of death in the normalized CI group? In most cases, death was attributed to ongoing shock associated with multiple organ failure, although it is possible that some conditions such as occult sepsis, mesenteric ischemia, or acute pulmonary embolism were missed.

This study has several limitations. First, our study was retrospective, so that some confounding factors may have been missed. Second, we included patients only if they presented with a CI of < 2.2 L/min/m2. Some patients thus may have been omitted, having already been treated prior to placing invasive lines to measure CI and PAOP. In these situations, the first CI measurements obtained after inserting the PAC may not necessarily have been < 2.2 L/min/m2, so that while we may have missed some cases of cardiogenic shock, we may have underestimated the incidence of patients with a normalized CI. Third, we had no knowledge of the CI of the patients prior to the episode of cardiogenic shock. Stable patients in end-stage chronic congestive cardiac failure, and who are in New York Heart Association functional class III or IV, have been found to have a mean CI of 1.7 L/min/m2.21 Certainly, if this subset of patients developed acute myocardial infarction and cardiogenic shock, their CI would undoubtedly not exceed this value. Finally, could the reason for the rapid normalization of CI be more aggressive therapy in this group? This is unlikely, as the therapeutic interventions were not significantly different in this respect. Hemodilution is also unlikely because the CI had already normalized within the first 6 to 12 h after hospital admission.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
We conclude that some patients who are in cardiogenic shock die despite the rapid normalization of CI, with a pattern of distributive shock and in the absence of obvious infection. While these findings need to be supported by prospective studies, it may be necessary to rethink the downward spiral model of the fatal course of cardiogenic shock to account for these deaths.


   Footnotes
 
Abbreviations: AUC = area under the curve; CI = cardiac index; CRP = C-reactive protein; DO2I = oxygen delivery index; Hb = hemoglobin; HR = heart rate; IABP = intraaortic balloon pump; MAP = mean arterial pressure; MPAP = mean pulmonary arterial pressure; O2ER = oxygen extraction ratio; PAC = pulmonary artery catheter; PAOP = pulmonary artery occlusion pressure; RAP = right atrial pressure; SaO2 = arterial oxygen saturation; SOFA = sequential organ failure assessment; SvO2 = mixed venous saturation; SVR = systemic vascular resistance; SVRI = systemic vascular resistance index; o2I = oxygen consumption index

Received for publication February 28, 2002. Accepted for publication April 21, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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