ACE-inhibitor therapy and survival among patients with multiorgan dysfunction syndrome (MODS) of cardiac and non-cardiac origin

ACE-inhibitor therapy and survival among patients with multiorgan dysfunction syndrome (MODS) of cardiac and non-cardiac origin

International Journal of Cardiology 140 (2010) 296 – 303 www.elsevier.com/locate/ijcard ACE-inhibitor therapy and survival among patients with multio...

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International Journal of Cardiology 140 (2010) 296 – 303 www.elsevier.com/locate/ijcard

ACE-inhibitor therapy and survival among patients with multiorgan dysfunction syndrome (MODS) of cardiac and non-cardiac origin Hendrik Schmidt a,⁎, Dirk Hoyer b , Mathias Rauchhaus c , Roland Prondzinsky a , Ralf Hennen a , Axel Schlitt a , Justin Carter a , Kuno Hottenrott a , Ursula Müller-Werdan a , Karl Werdan a , Michael Buerke a a

Martin-Luther-University Halle-Wittenberg, Germany b Friedrich-Schiller-University, Jena, Germany c Charite, Universitätsmedizin Berlin, CVK, Germany Received 13 May 2008; accepted 15 November 2008 Available online 21 January 2009

Abstract Background: The multiple organ dysfunction syndrome (MODS) is the sequential failure of organ systems after a trigger event (e.g. cardiogenic shock) with a high mortality. ACE-inhibitors [ACEI] are known to ameliorate depressed autonomic function (heart rate variability [HRV]) to improve endothelial function and to decrease blood pressure. Modifications of these targets reduce major adverse cardiovascular events (patients with arterial hypertension, coronary artery disease and chronic heart failure). Our study aimed to characterize potential benefits of ACEI therapy in MODS patients. Methods: 178 score-defined consecutive patients were enrolled. Inclusion criterion was an APACHE II score ≥ 20 at admission to the ICU. Patients were evaluated for ACEI therapy and followed for 28, 180 and 365 days. HRV was calculated according to the international standards. Results: 68 patients received an ACEI during their ICU stay whereas 110 did not. The 28-day mortality was 55% (no ACEI treatment) vs. 22% (ACEI treatment, p b 0.0001) and the 1-year mortality accounted for 75% (no ACEI) vs. 50% (ACEI), p b 0.0001. There was no significant survival difference between early and later application of ACEI (after day 4), both application modes were characterized by an improved survival. MODS patients with ACEI treatment at admission had a better preserved HRV. Conclusions: Our results may suggest that MODS patients with ACEI treatment may have lower short- and longer-term mortality. HRV was less attenuated when patients received ACEI therapy at admission. Consequently, effectiveness of ACEI therapy should be validated in a prospective trial. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Multiple organ dysfunction syndrome; APACHE II score; Sepsis; ACE-inhibitor therapy

1. Introduction Despite advances in the treatment of sepsis as the main trigger of multiple organ dysfunction syndrome (MODS, ⁎ Corresponding author. Department of Medicine III, Martin-LutherUniversity Halle-Wittenberg, Klinikum Kröllwitz, Ernst-Grube-Strasse 40, D-06097 Halle/Saale, Germany. Tel.: +49 345 5572601; fax: +49 345 5572072. E-mail address: [email protected] (H. Schmidt). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.11.104

sequential failure of several organs) the mortality remains still very high and treatment at the ICU is cost-intensive [1]. Besides organ dysfunction MODS is characterized by a pronounced autonomic dysfunction which has prognostic implications [2] and is broadly similar in young, middleaged and older MODS patients. The parasympathetic (vagal) activity as a particular important component of autonomic dysfunction in MODS can be characterized both by heart rate variability (HRV) and baroreflex sensitivity [2].

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A second key feature of MODS is the overwhelming activation of the innate immunity resulting in an inappropriate release of inflammatory mediators leading to vascular and cell damage of parenchymal organs [3]. Tracey et al. [3,4] have recently described that vagus stimulation attenuates the systemic inflammatory response to endotoxin. Inflammatory stimuli are able to activate sensory pathways which elicit a prompt cholinergic antiinflammatory reaction to prevent the spillover of inflammatory products to the circulation [3–5]. Having these results in mind one might speculate that this antiinflammatory vagal pathway might be suppressed in sepsis and MODS and thus, a spillover of pro-inflammatory products into the circulation cannot be sufficiently prevented. Hence, strategies to therapeutically modulate the blunted vagal activity and to reduce inflammatory response or the crosstalk among both systems might have prognostic implications. Recently, it was shown that statin therapy is associated with reduction of inflammation and subsequent rate of severe sepsis, ICU admissions and mortality of patients admitted to hospital with acute bacterial infection. We have recently shown that patients under statin treatment developing MODS have an improved outcome compared with patients lacking statin therapy [6]. This effect could be attributed to improved endothelial function, reduced inflammation and improved autonomic function [6]. Angiotensin-converting-enzyme inhibitors (ACEI) can dramatically reduce mortality in patients with cardiovascular disease like arterial hypertension (AT), coronary artery disease (CAD) and chronic heart failure (CHF, [7,8]). Additionally, they can restore autonomic (especially the vagal activity) and endothelial function and have also antiinflammatory features [9,10]. Based on this background the goal of the present study was threefold: we aimed to investigate: a) whether ACEI is associated with a reduction in mortality in MODS, b) whether a potential reduction in mortality is seen only in cardiogenic triggered MODS, and c) whether the time of ACEI application has impact on outcome. Consequently, we hypothesized that ACEI therapy could be advantageous for MODS patients despite its blood pressure lowering features.

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2. Patients, materials and methods The study was approved by the local ethics committee of the Martin-Luther-University Halle-Wittenberg. We retrospectively analysed mortality data of 178 MODS patients (inclusion criteria: admission to ICU, APACHE II score ≥20 at admission) with or without ACEI therapy. All baseline characteristics including disease severity scores were assessed within 24 h of admission. An independent observer analysed the patients' charts concerning ACEI therapy and recorded the duration of ACEI administration (pretreatment, duration of treatment and discontinuation). ACEI administration was managed according to the routine protocols used in the ICU by the study-independent staff and not influenced by the investigators. The data were obtained from a database of a trial focusing on autonomic function in MODS [2,11]. We retrieved all MODS patients from the data base (n = 190) for whom the following data were available: medication list, 28-day, 180day, 365-day mortality and severity of illness scores. 2.1. Heart rate variability (HRV) All patients were studied at bedside, in the supine position. 24-hour continuous ECG recordings were obtained using Holter recorders (DMS, Stateline, Nevada, USA/MTM multitechmed GmbH, Huenfelden-Dauborn, Germany and for 10 patients Ela Med, Munich, Germany). Recordings were analysed by a blinded research Holter technician using a standard software package (DMS, Stateline, Nevada, USA) and standard Holter analysis techniques for labelling beats and artefacts. All artefacts and ectopic beats were removed and the resulting missing data were replaced by interpolation between the three preceding and the three succeeding intervals. A second independent observer (ICU experienced cardiologist) edited and double-checked the recordings, reanalysed the data and confirmed the results with those of the research Holter technician. Only recordings with ≥ 20 h of usable data were included in the analysis. The sampling rate of the ECG acquisition was 256 Hz. The HRV analysis was done according to the task force guidelines [12]. The frequency domain indices were calculated from the power spectral for heart periods time series (by Fast-Fourier-

Table 1 Demographic characteristics of the MODS study patients at admission (Mean ± SD). Gender female/male — n Age (years) Height (m) Weight (kg) APACHE II score SOFA score Ventilatory support — n (%) Administration of catecholamines — n (%) Sedation — n (%)

a) Entire cohort

b) With ACEI

c) Without ACEI

d) p-value (b vs. c)

58/120 61.1 ± 13.2 1.70 ± 0.09 77.8 ± 16.4 30.3 ± 8.1 11.6 ± 3.7 157 (88) 131 (74) 159 (89)

20/68 64.9 ± 11.2 1.71 ± 0.08 76.6 ± 11.5 29.1 ± 8.1 11.0 ± 3.3 61 (90) 53 (78) 61(90)

38/110 59.3 ± 13.9 1.70 ± 0.1 78.6 ± 18.8 31.3 ± 7.9 11.8 ± 3.9 96 (88) 78 (71) 98 (89)

0.004 0.3 0.4 0.1 0.2 0.4 0.3 0.4

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Fig. 1. Kaplan–Meier-survival curves for 28-day and 1-year mortality. The thin full line indicates MODS patients treated with ACE and the dotted line the nonACEI group. The p-values derive from the Mantel–Cox model.

Transformation [FFT]) expressed in milliseconds squared per Hertz according to the standards ([12], see Appendix A): a) very-low-frequency (VLF) power may represent physiological influences like hormones, chemoreflexes, thermoregulaTable 2 ACEI treatment in cardiac and non-cardiac triggered MODS. Total (n) 28-day mortality No ACEI treatment 110 Cardiogenic triggered 30 MODS Non-cardiogenic triggered 80 MODS ACEI treatment 68 Cardiogenic triggered 48 MODS Non-cardiogenic triggered 20 MODS Overall mortality 178 365-day mortality No ACEI treatment 110 Cardiogenic triggered 30 MODS Non-cardiogenic triggered 80 MODS ACEI treatment 68 Cardiogenic triggered 48 MODS Non-cardiogenic triggered 20 MODS Overall mortality 178

Number of death events (n)

tion and contains major vagal influences, b) low-frequency (LF) power, which reflects sympathetic and parasympathetic modulation of heart rate [12,13] and c) high-frequency (HF) power, mainly reflecting vagal modulation [12]. The ratio of LF to HF power (LF/HF ratio) was calculated as a marker of sympathetic–parasympathetic balance.

Mortality (%)

2.2. Follow-up

60 17

55 57

All 178 patients were included into the survival analysis for 28-day, 180-day and 365-day mortality. None of the patients was lost in follow-up.

43

54

15 11

22 23

4

20

75

42

82 24

75 80

58

73

34 24

50 50

10

50

116

65

2.3. Definition of MODS

ACEI — angiotensin converting enzyme inhibitor.

APACHE II score [14] and SOFA score [15] were calculated as severity of illness scores and the underlying variables were compared with the predictive values of autonomic dysfunction indices. MODS was defined as an APACHE II score ≥20 [2,11]. 2.4. Inflammation (C-reactive protein [CRP], leucocytes) CRP was measured as marker of inflammation by hospital routine analysis (normal range b 5 mg/l). 2.5. Statistical analysis Numerical data are given as means ± standard deviation except when indicated otherwise. The Kolmogorov–Smirnov-Test was used to test for Normal distribution, and, if

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required, data were log-transformed. One-way-ANOVA with Scheffé's post hoc procedure was used for intergroup comparisons. Chi-Square test and Cox proportional hazards analysis were used as appropriate. Hazard ratios with 95% CI and probability values by the likelihood ratio test were given. Kaplan–Meier curves were constructed to characterize cumulative survival (Mantel–Cox model). All data were analysed by using commercial software (SPSS, Chicago, Illinois, version 15.0).

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Finally, 99 of the analysed 178 patients had a MODS of non-cardiac origin (mainly pneumonia, renal failure or sepsis). Out of these 99 patients with non-cardiogenic-triggered MODS 23 patients had a coincidence of cardiac diseases (e.g. hypertension, coronary artery disease, valvular failure). 3.1. Reduction of mortality by ACEI treatment The overall mortality of the entire group was 116/178 (69%) after 365 days.

3. Results The demographic data of the MODS patients are indicated in Table 1. Altogether, 68 patients received an ACEI during their ICU stay whereas 110 did not. The patients were treated with the following ACEI: 46 — ramipril (~ 68%), 14 — fosinopril (~ 21%), 8 — captopril (~ 11%). The main indications for ACEI treatment were impaired left-ventricular function, and hypertension prior to admission. The MODS was triggered among 79 of the analysed 178 patients by a cardiac event (e.g. cardiogenic shock, acute coronary syndrome, decompensated chronic heart failure, and decompensated valvular failure). Out of these 79 patients 56 had an ischemic event (acute coronary syndrome, acute coronary syndrome) as a cause of their MODS.

3.1.1. 28-day mortality During the analysed 28-day period there were 60/110 deaths in the group without ACEI treatment and 15/68 events in the ACEI group (28-day mortality 55% vs. 22%, p b 0.0001). The chart of the Kaplan–Meier analysis for 28-day mortality is indicated in Fig. 1 (Log Rank = 18.0, p b 0.0001). Cox-proportional hazard analysis revealed a hazard ratio of 0.32 (95% CI, 0.18 to 0.57, p b 0.001). 3.1.2. 180-day mortality There were 81/110 deaths in the group without ACEI treatment and 30/68 events in the ACEI group (180-day mortality 74% vs. 44%, p b 0.0001, Kaplan–Meier analysis: Log Rank = 18.12, p b 0.0001) during the analysed 180-day period. Cox-proportional hazard analysis revealed a hazard ratio of 0.42 (95% CI, 0.28 to 0.64, p b 0.0001).

Fig. 2. Kaplan–Meier-survival curves for 28-day mortality and 1-year-mortality. The thick dotted line (——) indicates MODS patients treated with ACEI (“ACEI +”) already at admission. The thin full line (_____) indicates MODS patients with ACEI treatment (“ACEI +”) starting from day 4 or later after admission and that thin dotted (——) line characterizes the survival of the non-ACEI group (“ACEI -”). The p-values derive from the Mantel-Cox model.

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3.1.3. 1-year mortality We found 82/110 deaths in the group without ACEI treatment and 34/68 events in the ACEI group after 365 days (365-day mortality 75% vs. 50%, p b 0.0001). Fig. 1 illustrates the results of the Kaplan–Meier analysis for 1-year mortality (Log Rank = 15.5, p = 0.0001). Cox-proportional hazard analysis revealed a hazard ratio of 0.46 (95% CI, 0.31 to 0.69, p b 0.0001). 3.2. Reduction in mortality among patients with cardiogenic and non-cardiogenic triggered MODS Table 2 describes the mortality statistics for MODS patients with cardiogenic and non-cardiogenic triggered MODS as well as with and without ACEI treatment. There was no significant difference in mortality between cardiogenic and non-cardiogenic triggered MODS after grouping into ACEI recipients and non-ACEI recipients (Kaplan– Maier analysis for 28-day/365-day mortalities: Log Rank = 0.3/0.5, p = 0.6/0.5). 3.3. The impact of ACEI treatment starting time on outcome When analysing short-term mortality there was no significant difference between early (at admission) and later application (starting not before day 4 after admission, Kaplan–Meier-analysis, 28-day mortality: Log Rank 1.6, p = 0.2). Both application modes were characterized by an improved survival compared with MODS patients without ACEI treatment (Kaplan–Maier-analysis early/later application: Log Rank 8.0/9.3, p = 0.005/0.002, Fig. 2). These data were consistent after 180 days: a) early vs. late application (Kaplan–Maier-analysis: Log Rank 1.5, p = 0.2) and 1 year: b) Kaplan–Maier-analysis early/later application vs. non-ACEI group: Log Rank 7.9/9.6, p = 0.005/0.002). Similarly, the results after 1 year days are shown in Fig. 2 (early vs. late application Log Rank 0.25, p = 0.6) demonstrating no differences among early vs. later ACEI treatment. Nevertheless, ACEI treatment groups (early/later application) significantly differed from non-ACEI group: Log Rank 7.5/6.3, p = 0.006/0.01). 4. Autonomic function and inflammation at admission among patients with and without ACEI To get some insight into protective mechanisms of ACEI administration we determined whether HRV on admission was different between patients who had an ACEI on admission and those who had not. The results are indicated in Table 3. MODS patients with ACEI treatment on admission had a better preserved HRV compared with patients without ACEI. The inflammatory parameters were lower in the ACEI group compared with non-ACEI group at admission to ICU (C-reactive protein 80.0 ± 82.3 mg/l [n = 66] vs. 133.6 ±

Table 3 Heart rate variability (HRV) and ACEI treatment at admission. HRV variable

ACEI at admission No ACEI at admission p-value

4.5 ± 1.9 VLF (ms2) 5.9 ± 1.5 TP (ms2) 3.9 ± 1.9 LF (ms2) 3.9 ± 1.5 HF (ms2) HF/LF 1.3 ± 1.8 APACHE II score 29.2 ± 8.1

3.5 ± 1.3 5.0 ± 1.2 3.0 ± 1.5 3.3 ± 1.5 1.3 ± 1.5 31.5 ± 7.3

b0.0001 0.001 0.008 0.05 0.9 0.15

All variables (except APACHE II score) were log transformed on account of skewed distribution.

123.8 mg/l [n = 109], p = 0.007; leucocytes 13.1 ± 6.8 [n = 67] vs. 15.7 ± 16.9 [n = 108], p = 0.09). We did not find significant differences among hemodynamic variables at admission (first group ACEI — treatment/second group — no ACEI treatment: heart rate 118.5 ± 18.3 bpm [n = 66] vs. 121.6 ± 26.0 bpm [n = 109], p = 0.25; RRmean [mm Hg] 59.6 ± 10.9 [n = 66] vs. 60.0 ± 10.5 [n = 109], p = 0.5). Renal function was more impaired in the non-ACEI group (creatine 170.5 ± 113.4 μg/l [n = 66] vs. 213.7± 152.1 μg/l [n = 104], p = 0.007) 5. Discussion Our results suggest that MODS patients with ACEI treatment may have lower 28-day, 180-day and 1-year mortality compared with MODS patients of equally pronounced disease severity. This reduction in mortality is seen independent of a cardiac or non-cardiac cause of MODS. There was no difference in 1-year mortality comparing early and later administration of ACEI. MODS patients with ACEI treatment at admission to ICU had a reduced attenuation of HRV. Consequently, ACEI therapy can influence short-term and longer-term mortality in MODS patients, hypothetically by reduction in inflammation and restoration of autonomic function. 5.1. ACEI and mortality in cardiovascular disease The activation of the renin–angiotensin–aldosterone system has major implications in inducing cardiovascular diseases. Thus, the Consensus Study firstly showed a reduction in mortality among patients with CHF [7]. The SOLVD study revealed that for more than 2000 CHF patients with symptomatic heart failure a dramatic decrease of mortality [8]. Moreover, ACEI have shown to reduce mortality and reinfarction after a myocardial infarction with left-ventricular dysfunction [16]. Consequently, administration of medication, actively modulating the RAAS system (ACEI) is standard therapy in treatment of AT, CAD and CHF [16]. Our present study shows that inhibition of the renin– angiotensin–aldosterone system has also prognostic benefits in patients with MODS.

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5.2. Potential mechanisms of reduction in mortality by ACEI The mechanisms behind the clinical phenomenon of mortality reduction by ACEI administration seem to be complex. Nevertheless, there is increasing clinical and experimental evidence that ACEI therapy may exert pleiotropic effects beside the haemodynamic changes. We speculate that three major mechanisms might contribute to mortality reduction by ACEI: a) ACEI are able to modulate inflammatory reactions (please refer to next paragraph) and b) to improve endothelial function (please refer to next paragraph). c) Additionally, ACEI seem to restore autonomic function [10]. An intact vagal activity seems to be a prerequisite to prevent a spillover of pro-inflammatory products into the circulation ([3–5], please refer to the next paragraph). 5.3. Anti-inflammatory actions of medication in MODS Recently, it has been described that anti-inflammatory drugs such as statins can significantly reduce mortality in sepsis, bacteraemia and MODS [6,17–20]. Thus, Hackam et al. [17] have shown that the use of statins in cardiovascular patients is associated with a diminished risk of subsequent sepsis. Angiotensin II as the effector peptide of the renin– angiotensin–aldosterone system has vasoconstrictive and in addition significant pro-inflammatory properties, which play a significant role in the perpetuation of inflammatory diseases like cardiomyopathy and nephropathy. These effects imply that suppression of inflammation may be a major mechanism to prevent initiation and progression of these cardiovascular diseases [9]. Angiotensin II takes on a key effector role in vascular remodeling and inflammation with respect to reactive oxygen species and molecular signalling pathways. These are the processes that may lead to vascular organ damage and subsequent cardiovascular mortality. ACEI appear to have anti-inflammatory effects in both experimental models and humans [21,22]. Moreover, angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade may reduce markers of inflammation in patients with coronary artery disease [23]. Several groups [24–26] have shown that endothelial function (e.g. increased basal NO release) is improved by ACEI therapy. Moreover, ACEI treatment among CHF patients significantly reduces inflammatory markers [26]. There is also increasing information that ß-blockers might restore the interplay of autonomic function and inflammation in MODS [27]. 5.4. Beneficial effects of restoration of autonomic function in cardiovascular disease Recent studies [2,28,29] provided clinical evidence that the complex spectrum of autonomic function is blunted in MODS patients. Moreover, this attenuation had prognostic implications: a simple HRV variable (“very low frequency

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power”), which characterizes parasympathetic modulations of heart rate, could predict 28-day mortality as effectively as one of the “gold standards”, the APACHE II score. Recently, it has been shown that this variable can also predict longerterm mortality [30]. It has been demonstrated that modulation of the renin– angiotensin–aldosterone system (RAAS) increases autonomic control of heart rate and reduces adrenergic activity [31]. So, it is well established that the renin–angiotensin–aldosterone system II is able to enhance sympathetic activity and to inhibit vagal activity, and blunting of RAAS is able to modulate the autonomic nervous system balance favorably [31–36]. Supportive evidence for the beneficial effects of cardiac vagal activity has been provided from results of pharmacological trials in CHF. ACEI have been shown to improve prognosis and to enhance cardiac parasympathetic activity [10]. Furthermore, Yee and Struthers [37] demonstrated an improvement of arterial baroreceptor function (a variable characterizing the parasympathetic responsiveness) after treatment with ACEI in normotensive volunteers. The underlying mechanisms are still not fully understood but a large number of studies in both CHF and after myocardial infarction have all shown that ACE can impair vagal function and ACEI treatment results in amelioration of autonomic dysfunction, restoration of depressed baroreflex and optimization of interplay of major cardiovascular reflexes [35–41]. 5.5. How might the improved cardiac vagal control influence mortality? Most authors argue that an increased vagal activity mediates its beneficial effects via a decrease in cardiac work by reduction in heart rate [10]. This effect is accompanied by a blunted contractility and both effects can reduce myocardial oxygen demand [10]. However, the effect of ACEI on heart rate is low despite reduction in cardiac work. Additionally, we hypothesize that mortality reduction in our recent study can be related to the following mechanisms: sepsis and MODS are characterized by an overwhelming release of inflammatory mediators and toxins, which might influence nerval connections at various levels: afferent, central or even at efferent [2]. As a result an autonomic dysfunction can occur and can be characterized precisely by HRV. Our recent study revealed that MODS patients on ACEI treatment at admission had an improved parasympathetic (vagal) modulation of heart rate compared to patients without ACEI therapy. It has been recently described that vagus stimulation attenuates the systemic inflammatory response to endotoxin [3–5]. Inflammatory stimuli are able to activate sensory pathways which elicit a prompt cholinergic anti-inflammatory reaction to prevent the uncontrolled release of inflammatory products into the circulation [3–5]. Having the results of our study in mind one might speculate that this anti-inflammatory vagal

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pathway is also suppressed in sepsis and MODS and thus a spillover of pro-inflammatory products into the circulation cannot be sufficiently prevented. These arguments are supported by the better vagal control and lower CRP levels in the group of MODS patients who were on ACEI therapy at admission. Our results demonstrate that ACEI administration might be a novel strategy to augment the blunted vagal activity and thus to modulate the anti-inflammatory reflex and subsequently reduce mortality. 5.6. When should the patients receive ACEI? In clinical practice, many intensive care physicians resist to an early ACEI treatment in MODS due to the considerable blood pressure lowering properties, especially if the patients are under catecholamine therapy. Our results now reveal that even MODS patients receiving an ACEI inhibitor as late as day 4 after admission to ICU may benefit from this treatment concerning long-term survival since the survival curves are nearly parallel after 1 year (Fig. 2). Hence, we argue that not only the short term effects of ACEI administration may be decisive but also longer term effects like a restoration of autonomic function and prevention of a vascular remodelling and improvement of endothelial function. 6. Conclusions Our results suggest that MODS patients under ACEI treatment may have significantly reduced 28-day, 180-day and 365-day mortalities compared with MODS patients of equally pronounced disease severity but without ACEI therapy. This reduction in mortality is seen not only in cardiac triggered MODS but also for non-cardiogenic triggered MODS. Interestingly, we did not see a difference in 1-year mortality comparing early and later administration of ACEI. MODS patients with ACEI treatment at admission had less attenuated HRV. Consequently, an ACEI therapy might influence short-term and longer-term mortality in MODS patients, probably by preventing a reduction in vagal tone in MODS. This could elicit a reduction of inflammatory responses. The presented study does not answer the question which of the effects is the most important one resulting in a decrease in mortality, but it aims to encourage prospective trials. Role of funding source HS and UM-W are supported by a grant of the “Deutsche Forschungsgemeinschaft” (SCHM 1398/3-1,-2). MB is supported by a grant of the “Deutsche Forschungsgemeinschaft” (BU 859/3-1,-2,3). There was no involvement of the founding source in study design, analysis and interpretation of the data, in writing the report and in the decision to submit the paper for publication.

Conflict of interest There is no conflict of interest inherent in the papers's content. Acknowledgements We are indebted to D. Moenning, Alexander Keller and P. Tymiec for their valuable contributions in collecting data and for technical assistance. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [42]. Appendix A. Indices of autonomic function assessed in the study Heart rate variability Frequency domain indices VLF TP LF HF

Very low frequency (0.003–0.04 Hz, ms2) Total power (0.0–0.15 Hz, ms2) Low frequency (0.04–0.15 Hz, ms2) High frequency (0.15–0.4 Hz, ms2)

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