Pyrexia, procalcitonin, immune activation and survival in cardiogenic shock: the potential importance of bacterial translocation

International Journal of Cardiology 72 (1999) 3–10 www.elsevier.com / locate / ijcard

Pyrexia, procalcitonin, immune activation and survival in cardiogenic shock: the potential importance of bacterial translocation a, b a Frank M. Brunkhorst MD *, Andrew L. Clark MD , Zdziflaw F. Forycki MD , Stefan D. Anker MD PhD c,d a

Krankenhaus Zehlendorf, Department of Internal Medicine, Gimpelsteig 3 – 5, D-14165 Berlin, Germany b Academic Unit, Department of Cardiology, Castlehill Hospital, Cottingham, Hull, UK c Department of Cardiac Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6 LY, UK d ¨ Centrum, Berlin, Germany Franz Volhard Klinik ( Charite´ , Campus Berlin-Buch) at Max Delbruck

Abstract Aims: Exposure to bacterial endotoxin, perhaps due to bowel congestion or ischaemia and altered gut permeability, may result in immune activation that is characteristic for patients with severe heart failure. It is known that blood procalcitonin rises in response to bacterial endotoxin exposure. Methods: We measured procalcitonin in a group of 29 patients with acute cardiogenic shock and no sign of infection (all without bacteraemia) and 26 with septic shock. Blood was analysed for procalcitonin, interleukin-6, tumour necrosis factor-a (TNF-a), c-reactive protein (CRP) and neopterin. Patients were managed conventionally in an intensive care unit with no further experimental procedures. Results: Three cardiogenic (10%) and seven septic shock patients (27%) survived. Most patients with acute heart failure surviving 12 h or more (18 of 20) developed a pyrexia (738.08C) of unknown origin in the absence of positive cultures, with a rise in procalcitonin (1.460.8 to 48.0616.2 ng / ml, P,0.001), CRP (76.5616.4 to 154.7622.9 mg / l, P,0.001) and neopterin (20.763.5 to 41.266.7 nmol / l, P,0.001). Patients with septic shock had higher initial levels of cytokines, and higher peak levels. Those with heart failure surviving (n53) and those dying in the first 12 h (n59) had no rise in cytokine levels. The patients with high procalcitonin had a higher temperature (38.960.3 vs. 37.360.238C, P,0.05), TNF-a (43.9569.64 vs. 16.4364.33 pg / ml; P,0.005) and CRP (146.1618.4 vs. 68.2639.6 mg / ml, P,0.005). Peak procalcitonin levels correlated with peak temperature (r50.74, P,0.001). Conclusion: Cardiogenic shock causes a pyrexia of unknown origin in patients surviving for 12 h and that is associated with a rise in procalcitonin levels. This lends support to the hypothesis that patients with cardiogenic shock may be being exposed to bacterial endotoxin at a time when bowel wall congestion and or ischaemia is likely to be present.  1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Procalcitonin; Cardiogenic shock; Bacterial endotoxin; Cytokines; Acute heart failure

1. Introduction Chronic heart failure is a catabolic state with catabolic / anabolic imbalance [1] and cytokine activation [2,3]. The origins of immune activation seen in patients with chronic heart failure are poorly under*Corresponding author. Tel.: 149-30-8102-1361; fax: 149-30-81021300. E-mail address: [email protected]

stood. We have hypothesised [4] that a possible course of immune activation is that chronic venous congestion may result in altered gut permeability and intestinal bacterial translocation, with resultant endotoxin release and immune activation. Recently, we could also show that endotoxin plasma concentrations are increased about twofold in chronic heart failure patients with peripheral oedema, and endotoxin levels were normalised after intensified diuretic treatment [5].

0167-5273 / 99 / $ – see front matter  1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 99 )00118-7

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Calcitonin is elevated in medullary cell carcinoma of the thyroid [6,7], but high concentrations have been reported in many non-thyroid cancers [8], pulmonary diseases [9], renal disease [10] and pancreatitis [11]. Several different forms of calcitonin have been identified [12,13] and, unlike medullary cell carcinoma, non-thyroid diseases cause an increase in calcitonin precursors and not of calcitonin itself [14]. Procalcitonin levels are raised in infective conditions and appear to correlate with the severity of disease [15]. The rise in procalcitonin in severe systemic illness appears to be specific for infectious disease [16–18], and increases in normal subjects after injection of bacterial endotoxin [19] and in iatrogenic sepsis [20], suggesting a possible pathway by which procalcitonin production is stimulated in infectious disease. The association of cardiac failure with the syndrome of pyrexia of unknown origin with a rise in inflammatory markers with no obvious sign of sepsis was first described in 1934 [21], but has since received little attention. We were interested in exploring the possible relation between the development of acute severe heart failure and immune activation by measuring procalcitonin in a group of patients with cardiogenic shock as a possible indicator of the appearance of endotoxin. We used acute severe heart failure as a model of acute congestion, which was when we hoped any evidence for bacterial translocation might be most apparent. We also measured neopterin, a cytokine released by activated macrophages, interleukin-6 (IL-6) (predominantly a marker for hypoxia [22,23]) and tumour necrosis factor-a (TNF-a), as indices of inflammatory cytokine activation.

2. Methods We studied 29 patients who had been consecutively admitted to a 24-bed Intensive Care unit over a 12-month period with a primary diagnosis of cardiogenic shock, and compared them with a group of 26 patients with septic shock who had been admitted over the same time period. Cardiogenic shock was diagnosed following the criteria of Califf and Bengtson [24]: depressed cardiac output in the presence of a raised left ventricular filling pressure,

coupled with low systemic arterial blood pressure for longer than 30 min. Septic shock was diagnosed following the criteria of Bone et al. [25]: a systemic response to sepsis with clinical evidence of the site of sepsis together with evidence of impaired tissue perfusion (low PaO 2 , elevated plasma lactate, oliguria and / or impaired cerebral function. The timing of the onset of shock was defined as the point when patients required vasopressors to achieve a mean systemic arterial pressure greater than 50 mmHg. The patients’ characteristics are shown in Table 1. No patient with cardiogenic shock had symptoms or signs of intercurrect sepsis. Blood, tracheal aspirates, and urine cultures were taken daily and all were found to be negative in the cardiogenic shock group. The management of the patients was left to the clinician in charge. No patient was part of any clinical trial, and standard inotropic support was given. The patients with cardiogenic shock secondary to acute myocardial infarction underwent acute coronary angiography and emergency percutaneous transluminal angioplasty, if appropriate. Complications of shock were treated as appropriate. Blood samples (serum) were drawn from the patients at intervals and stored at 2708C for later analysis. Results were thus only obtained after the patients’ eventual discharge or death. Procalcitonin was measured by immunoluminometric assay (BRAHMS, Berlin, Germany), which uses two monoclonal antibodies. The first, capture, antibody is directed against residues 96–106 of procalcitonin and the second, tracer, is directed against residues 70–76. The sequence 96–106 is a portion of the 21-aminoacid katacalcin molecule derived from the C-terminal end of procalcitonin, when activated to calcitonin, and is thus specific to procalcitonin. Sequence 70–76 is part of the calcitonin molecule. Capture-antibodycoated tubes were incubated with serum and acridinium ester traced antibody (250 ml). After a 2-h incubation at room temperature, luminescence was measured automatically in a luminometer. Synthetic procalcitonin was used as a standard. The lower limit of detection is 0.1 ng / ml, with an inter-assay coefficient of variation of 10–20%. The normal level of procalcitonin with this assay in healthy subjects is ,0.5 ng / ml. Neopterin was measured by enzyme-linked im-

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Table 1 Individual patients, origin of shock, and outcome a Cardiogenic shock (n529)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Mean (SD)

Septic shock (n526)

Age

Origin of shock

Outcome

54.5 76.8 61.3 57.1 64.7 70.0 67.0 67.1 72.1 76.1 60.1 90.7 61.7 59.9 58.1 57.3 55.5 55.7 83.2 79.2 64.0 84.7 63.2 61.2 66.8 70.3 83.1 76.1 73.0 67.6 (9.3)

AMI AMI PE PE PE AMI CHF AMI AMI AMI AMI AMI Tamponade AMI PPH PE AMI AMI CHF PE Tamponade AMI PE AMI AMI AMI AMI AMI AMI

MOF† CA† MOF† MOF† CA† MOF† CA† CA† CA† MOF† Survivor Survivor CA† MOF† CA† MOF† CA† CA† CA† CA† CA† CA† CA† MOF† Survivor MOF† CA† CA† CA†

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

Age

Origin of shock

Outcome

73.8 57.1 65.3 56.3 51.0 64.4 85.3 45.3 54.1 60.9 57.0 51.2 72.1 37.2 67.7 52.6 37.1 63.3 70.9 30.3 81.1 42.3 51.6 21.2 63.8 54.6

Pneumonia Pneumonia Pneumonia Pneumonia Peritonitis Aspiration Cholangitis Pneumonia Peritonitis Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Empyema Aspiration Cholangitis Peritonitis Pneumonia Pneumonia Cholangitis Colitis

Survivor Survivor MOF† MOF† MOF† Survivor MOF† MOF† MOF† MOF† MOF† MOF† Survivor MOF† MOF† Survivor MOF† MOF† MOF† Survivor MOF† MOF† MOF† Survivor MOF† MOF†

56.4 (15.1)

a AMI, acute myocardial infarction; PE, pulmonary embolus; PPH, primary pulmonary hypertension; CHF, chronic heart failure. †, indicates death; CA, cardiac arrest, MOF, multiorgan failure.

munosorbent assay (ELISA; BRAHMS) and the normal range is ,10 nmol / l. IL-6 was measured by enzyme-amplified sensitivity immunoassay (EASIA, Medgenix, Fleurus, Belgium) with a minimum detectable concentration of 2 pg / ml, and an interassay coefficient of variation of 2.2–7.5%. TNF-a was measured by EASIA (Medgenix) with a minimum detectable concentration of 3 pg / ml and an interassay coefficient of variation of 8.0–9.9%. Haemodynamic variables were obtained from the positioning of a balloon flotation catheter in the pulmonary artery, with cardiac output measurements being made by thermodilution. Data are presented as means6SEM. Betweengroup comparisons were made with Student’s t-test, and a paired test was used for within-group comparisons. Logarithmic transformation was performed

as required to ensure that parametric statistical tests were appropriate. Categorical comparisons between groups were made with chi-squared testing. Linear regression analyses were performed to study the relation between variables.

3. Results The baseline characteristics of the patients are shown in Table 2. Three of the cardiogenic (10%) and seven of those in the septic shock (27%) group survived (X 2 52.53, P50.11). Of those patients who died, there was no difference in the duration of shock between the two groups. Within the cardiogenic shock group, nine patients

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Table 2 Baseline characteristics of the patients. The range in hours is given for the duration of shock and the time from onset of shock to death a

Age (years) APACHE-II score on admission to ICU Duration of shock (h) (range) onset–death (h) (range) Survivors (n) ProCT (ng / ml) IL-6 (pg / ml) Neopterin (nmol / l) TNF-a (pg / ml) CRP (mg / I) Temperature (8C) NA (mg / h) Lactate (mmol / 1) SVR (dyne.s.cm 25 ) PCWP (mmHg) CO (l / min)

Cardiogenic shock (n529)

Septic shock (n526)

67.6 (9.3) 19.6 (10.5) 35.2 (2–162) 83.2 (2–531) 3 (10%) Baseline ]] 1.16 (0.54) 500.3 (117.9) 24.86 (3.54) 16.97 (3.60) 66.61 (12.35) 37.32 (0.23) 4.37 (0.87) 8.72 (1.28) 1083.86 (59.45) 23.60 (1.20) 4.30 (0.39)

56.5† (15.1) 25.8 (6.4) 68.9 (6–290) 81.6 (3–240) 7 (27%) Baseline ]] 83.03‡ (36.56) 1640.10‡ (200.72) 101.41‡ (30.89) 118.09‡ (22.92) 203.14‡ (31.48) 37.99 (0.38) 0.86‡ (0.23) 8.03 (1.35) 533.44‡ (6 1.85) 10.75‡ (1.34) 8.75‡ (0.69)

Peak ] 33.32** (11.54) 629.48 (128.10) 40.14** (5.30) 33.18§ (6.82) 123.84* (18.32) 38.43* (0.28) 4.29 (0.80) 7.80 (1.18) 1042.62 (74.53) 23.83 (1.78) 4.37 (0.23)

Peak ] 164.48**‡ (52.10) 1616.38‡ (150.63) 214.32**‡ (38.28) 165.09‡ (35.16) 303.97**‡ (33.20) 38.21 (0.24) 4.14* (1.92) 9.75 (1.86) 553.63‡ (72.56) 11.80‡ (0.67) 8.94‡ (0.62)

a ProCT is procalcitonin, TNF-a is tumour necrosis factor a, IL-6 is interleukin 6, CRP is c-reactive protein, NA is noradrenaline, SVR is systemic vascular resistance, PCWP is pulmonary capillary wedge pressure and CO is cardiac output. Data are expressed as means with SEM values given in parentheses. §P50.09, *P,0.01, **P,0.001 vs. initial reading. †P,0.01, ‡P,0.001 septic vs. cardiogenic shock.

did not survive the initial 12 h. This subset did not have any significant rise in procalcitonin (peak level, 0.860.3 ng / ml). Similarly, the three patients who survived to discharge had no rise in procalcitonin (peak value, 0.660.24 ng / ml), with an average duration of shock of 35 h (group average, 35.2 h; P,0.01 for comparison between early and late deaths). The nine patients who died within 12 h had no rise in temperature, CRP or TNF-a. Of those patients who survived the first 12 h, 18 of 20 patients (90%) developed a fever .38.08C (maximum temperature, 38.960.358C) and a rise in c-

reactive protein (154.7622.9 mg / l) and procalcitonin. There was a relation between peak procalcitonin level and both the time taken to reach that peak (r50.78, P,0.001) and the duration of illness (r50.66, P,0.005, see Fig. 1). Patients with septic shock had higher levels of procalcitonin at the onset of shock (P,0.001), as might be expected, but lower levels of noradrenaline (P,0.001, see Table 1). In the cardiogenic shock group, there was no correlation between procalcitonin and IL-6 (r50.14), neopterin (r50.27) or TNF-a (r50.04). TNF-a and IL-6 correlated with one another (r50.56, P,0.001), but there were no other correlations between the cytokines and the inflammatory markers measured. Peak procalcitonin levels correlated with peak temperature (r50.74, P,0.001, see Fig. 2). When the patients with cardiogenic shock were grouped on the basis of their peak procalcitonin levels (manufacturer’s normal range, ,0.5 ng / ml) into normal (n59) and high groups (n520), the patients with high procalcitonin levels had a higher temperature (38.960.34 vs. 37.360.238C, P50.01), TNF-a level (44.069.7 vs. 16.464.3 pg / ml, P5 0.04) and CRP (146.1618.4 vs. 68.2639.7 mg / l, P50.03), although neopterin and IL-6 were not significantly different between the groups (see Fig. 3).

4. Discussion This study shows that cardiogenic shock, i.e., acute severe heart failure, causes a pyrexia of unknown origin in patients surviving at least 12 h, and that it is associated with a rise in procalcitonin and inflammatory cytokines. This lends support to the hypothesis that patients with cardiogenic shock may be being exposed to bacterial endotoxin at a time when bowel wall congestion and or ischaemia is likely to be present. Treatments to counteract inflammatory cytokines (like TNF antibodies [26]) or treatments that prevent or counteract endotoxin translocation and action (like antibiotics and / or endotoxin antibodies [5,27]) may be beneficial in patients with cardiogenic shock. The purpose of this study was to discover any evidence for the involvement of bacterial endotoxin

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Fig. 1. Relationship between the time course of the shock syndrome and the rise in procalcitonin levels. Open boxes: time to peak PCT is the time taken to reach the peak procalcitonin level. Closed boxes: duration of illness is the duration of shock.

in patients with heart failure. We have hypothesised that patients with heart failure may develop inflammatory cytokine activation as a result of episodes of low-grade bacterial endotoxin exposure [4], perhaps secondary to bowel wall congestion and / or ischaemia. We elected to study a group of patients with acute circulatory failure as a model for severe decompensation in heart failure as being a group most likely to have bowel wall congestion and ischaemia with subsequent bacterial translocation. The syndrome of pyrexia of unknown origin in acute heart failure was first reported in 1934 [21]. Although well recognised by intensive-care physicians, it has received very little research interest. This study is the first to suggest bacterial translocation as the cause of the pyrexia in cardiogenic shock, and inflammatory

cytokine activation as the possible consequence. A previous study in seven patients has shown a very small rise in procalcitonin levels, although only one of the patients died [28]. We have found evidence for immune activation in the group of patients surviving the initial 12 h of shock and who subsequently died. Survivors, and those who died early, had no such evidence. Different degrees of cellular endotoxin sensitivity are present in heart-failure patients [29]. The response to endotoxin may vary from patient to patient and from day to day. The endotoxin responsiveness may be determined by steroid hormones [the cortisol / dehydroepiandrosterone (DHEA) ratio relates to TNF and soluble TNF receptor levels [30]], the presence of lipopolysaccharide-binding protein [31], adenosine [32] or the

Fig. 2. Relationship between body temperature and procalcitonin level at the time of peak procalcitonin measurement in patients with cardiogenic shock.

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Fig. 3. Patients with cardiogenic shock divided on the basis of their procalcitonin levels. The solid bars are those patients with normal levels and the open bars are patients with elevated levels. *P,0.05.

degree of tissue ischaemia [33]. Potentially, endotoxin sensitivity of heart failure patients may be genetically determined. Recently, a CD14 receptor polymorphism has been identified and linked to the occurrence of myocardial infarction [34]. We have found a rise in c-reactive protein that paralleled the development of fever. In the heart failure patients, procalcitonin levels rose to a level some 50- to 100-times above the normal range. As cultures were all negative, this could suggest the presence of endotoxaemia without bacteraemia. There was a small rise in IL-6 and TNF-a (P50.09), but these changes did not reach statistical significance. Those patients developing a rise in procalcitonin had a greater rise in temperature, TNF-a and c-reactive protein. We cannot completely exclude the possibility that the patients surviving 12 h who subsequently died developed secondary sepsis with immune activation. Nevertheless, a rise in procalcitonin levels appears to indicate exposure to bacterial endotoxin [16–20,35] and there was no evidence of systemic infection, as reflected in negative urine and blood cultures. The present study lends support to the hypothesis that endotoxin action may contribute to immune activation in patients with cardiogenic shock, i.e., acute severe heart failure. In chronic heart failure,

repeated episodes of endotoxin exposure (during phases of cardiac decompensation) may lead to repeated episodes of immune activation [5]. However, during the same decompensation phases, increased cytokine production of the heart may also occur [36]. Increased levels of TNF-a (as markers of immune activation) are then frequently seen in heart failure, but to a lesser degree in stable patients. Soluble TNF receptors, in contrast, are significantly elevated in stable patients with chronic heart failure [37]. Soluble TNF receptors may reliably indicate the history of immune activation. This may be the reason why soluble TNF receptors vary over time considerably less then TNF-a and IL-6 [38]. Regardless of where the cytokines in heart failure patients come from, they are there in pathologic amounts, they can be harmful (to the heart and to the periphery), and it is possible to counteract them. The latter should be the focus of future research work. Patients with heart failure in general have a poor prognosis, but patients with cardiogenic shock have a particularly grim prognosis. In our group of patients, only 10% of patients with cardiogenic shock survived. More or less invasive and expensive strategies to improve the pump function in patients with cardiogenic shock have failed to substantially improve the outlook for these patients. Acutely targeting

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the inflammation process in these patients could be achieved by counteracting endotoxin translocation and / or reducing endotoxin bioactivity or by blocking inflammatory cytokines like TNF-a. Such strategies may finally improve the prognosis of this group of patients, and such trials need not to be large.

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