Studies have shown that cardiac injury may occur in ARDS patients with structurally normal hearts and this maybe correlated with the underlying respiratory changes . B-type natriuretic peptide (BNP) and N-terminal brain natriuretic peptide (NT-BNP) are amino acid hormones that are synthesized in the ventricular myocardium and released into the bloodstream primarily under conditions of ventricular dilatation and pressure overload. Serum half-lives of the NT peptides (NT-proANP and NT-proBNP) are considerably longer than those of other natriuretic peptides, resulting in plasma levels that are at least 5–15 times larger. Thus, they are less influenced by the conditions under which the sample is drawn and may therefore be more appropriate in critical care settings. Moreover, although BNP and NT-proBNP have equal predictive values for heart failure, the latter is probably more sensitive in predicting death. Mueller et al. (2005) compared head to head the diagnostic accuracy of B-type natriuretic peptide (BNP) and the amino terminal fragment of its precursor hormone (NT-proBNP) and showed that BNP and NT-proBNP may be equally useful as an aid in the diagnosis of CHF in short of breath patients presenting to the emergency department . According to the Canadian Cardiovascular Society 2012, NT-proBNP is recommended to be obtained to rule in acute heart failure if its symptoms are suspicious (900 pg/mL if age 50–75 years, 1800 if age 75 years) or to be ruled out if NT-proBNP <300 pg/mL.
Aim of the study
To assess the levels of biomarkers of cardiac injury (NT-proBNP, Trop I and Trop T) and observe its relationship with respiratory parameters and positive pressure ventilation during the first week of ARDS (days 0, 2 and 7).
We performed the study prospectively on 20 adult patients admitted to Critical Care Medicine Department, Cairo University Hospital, who were diagnosed to have acute respiratory distress syndrome (ARDS) from June 2008 until April 2009.
Any adult patient diagnosed to have ARDS according to the criteria of the American–European Consensus Conference in 1994 in which the disease is to be confirmed by the combination of following diagnostic criteria:
- An initiating clinical condition (e.g. sepsis, burns).
- Acute onset.
- Bilateral infiltrates documented by chest radiograph at end-inspiratory position.
- Pulmonary artery wedge pressure ≤ 18 mmHg or absence of clinical evidence of left atrial hypertension by echocardiography.
- ARDS: PaO2/FiO2 ratio ≤ 200 in a stable state after the patient has adapted to standardized ventilation (regardless of the level of PEEP).
- Congenital heart diseases.
- Ischemic heart disease.
- Chronic Cor pulmonale.
- Atrial fibrillation.
- Pre-existent renal insufficiency.
- Pulmonary embolism.
All patients were subjected to full history taking, thorough clinical examination and transthoracic echocardiography to exclude structural heart diseases. All patients benefited from mechanical ventilation with Lung protective ventilation strategy according to NHBLI ARDS Network Treatment Protocol. Daily arterial blood gases were analyzed (PH, PaCO2, HCO3, PaO2, SaO2, FiO2, PaO2/FiO2), and mechanical ventilatory mechanics parameters were recorded: Positive End Expiratory pressure (PEEP), effective compliance (Ceff), dynamic compliance (Cdyn), airway resistance (RaW), peak inflation pressure (PIP), Plateau pressure (Pplat), mean airway pressure (Pmean).
Cardiac markers N-terminal pro-brain natriuretic peptide (NT-proBNP), cardiac Troponin I (Trop I) and Troponin T (Trop T) plasma level measurement were taken on days 0, 2 and 7. Venous blood samples were collected in 10-ml vacutainers containing heparin. The samples were centrifuged at 3000g for 10 min and stored at −60 °C. NT-proBNP values were determined by an electrochemiluminescence sandwich immunoassay with an Elecsys 2010 instrument. For the measurement of Trop I and Trop T we used a sandwich immunoassay test. The upper limit of normal for NT-proBNP was set at 450 pg/ml. The upper limit of normal for Trop I was set at 1.5 and 0.5 μg/l for Trop T.
The study protocol was approved by the institutional review board at Cairo University, and written informed consent to participate and publish data was obtained from all participating patients or first degree relatives. This study was fully supported by Ministry of Higher Education, Cairo University, Critical Care Medicine Department.
The data collected were tabulated and analyzed by SPSS (statistical package for the social science software) statistical package version 11 on IBM compatible computer. Quantitative data were expressed as mean and standard deviation (X + SD) and analyzed by applying Student t-test for comparison of two groups of normally distributed variables and Mann–Whitney U test for non-normally distributed ones. ANOVA test for analysis of variance (f-test) was used for comparison of more than two groups of normally distributed variables; and Kruskal–Wallis test was used for comparison of more than two groups of non-normally distributed variables. Qualitative data were expressed as number and percentage (No. and %) and analyzed by applying chi-square test. Pearson correlation (r) was used to detect association between quantitative variables, while spearman correlation was used to detect association between qualitative and quantitative variables. All tests were used as tests of significance at p < 0.05 .
Our total ARDS study group comprised 20 patients, 11 men (55%) and 9 women (45%). Patients were with mean age of 58.9 (±20.69) years old. There was no significant difference between males and females as regard incidence of ARDS (p > 0.05) Survivors were 7 (35%) patients who were successfully weaned and discharged from ICU while 13 (65%) patients died. Regarding the etiology of ARDS, 5 cases (25%) were due to sepsis, 4 cases (20%) due to pneumonia, 3 cases (15%) due to aspiration, 3 cases (15%) due to lung contusions caused by road traffic accidents RTA, 2 cases (10%) due to drug overdose, 1 case (5%) due to burn, 1 case (5%) due to pancreatitis and 1 case (5%) due to drowning.
Cardiac markers levels
NT-proBNP mean values (pg/ml) were on day 0: 8903.3 ± 12852.81, on day 2: 6083.55 ± 8467.88 and on day 7: 9914.75 ± 12574.09. There was no significant difference between the readings of the 3 days (p > 0.05).
Trop I mean values (μg/l) were (3.04 ± 7.72) on day 0, (2.2 ± 6.63) on day 2 and (1.53 ± 4.44) on day 7. There was no significant difference between the readings of the three days (p > 0.05).
Trop T mean values (μg/l) were (0.33 ± 0.61) on day 0, (0.63 ± 1.51) on day 2 and (0.5 ± 1.08) on day 7. There was no significant difference between the readings of the three days (p > 0.05) (Table 1).
Cardiac markers correlation with respiratory parameters
NT-proBNP was inversely correlated with PH on day 2 (p 0.008, r −0.53) and day 7 with (p 0.02, r −0.50) (Fig. 1).
NT-proBNP was positively correlated with PEEP on day 2 (p 0.05, r 0.46) and day 7 (p 0.035, r 0.48) (Fig. 2).
NT-proBNP was inversely correlated with PaO2/FiO2 ratio on day 7 (p 0.0035, r −0.60) (Fig. 3).
However, there was no significant correlation on any day between NT-proBNP and other respiratory indices including PaCO2, HCO3, PaO2, SaO2, FiO2 (p > 0.05) (Table 2).
Neither Trop I nor Trop T showed any significant correlation on any day with any respiratory indices PH, PEEP, PaO2/FiO2, PaCO2, HCO3, PaO2, SaO2, FiO2 at any day (p > 0.05) (Table 2).
None of the cardiac markers NT-proBNP, Trop I or Trop T showed any significant correlation on any day with lung mechanics including Cdyn, Ceff, RaW, PIP, Pplat and Pmean (p > 0.05) (Table 3).
In recent years, BNP and NT-BNP measurements have been used to assist in the diagnosis, treatment, and prognostication of patients with heart failure, being amino acid hormones that are synthesized in the ventricular myocardium and released into the bloodstream primarily under conditions of ventricular dilatation and pressure overload . Studies indicate that BNP and NT-BNP levels are also elevated in other critical disease states and may have similar clinical utility . Levitt et al. (2008) showed that BNP levels drawn within 48 h of admission to the ICU do not reliably distinguish acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) from cardiogenic edema, and do not correlate with invasive hemodynamic measurements  and Lin et al. (2010) showed that BNP concentration was significantly elevated in non-survivors than survivors in patients with ARDS who have normal LVEF . The aim of our study was to monitor the levels of biomarkers of cardiac injury (NT-proBNP, Trop I and Trop T) and observe its relationship with respiratory parameters and positive pressure ventilation during the first week of ARDS (days 0, 2 and 7).
We found that NT-proBNP was negatively correlated with PaO2/FiO2 ratio on day 7 (p 0.0035, r −0.60). Hypoxia may be the direct stimulus for BNP and atrial natriuretic peptide (ANP) . Emanuel et al. (2007) found that, in patients with severe sepsis and septic shock, patients with increasing clinical evidence of global tissue hypoxia over the first 72 h had significantly higher BNP levels with a significant inverse correlation of BNP with ScvO2. Mitaka et al. back in 1997 had previously reported moderately elevated BNP values in ARDS, yet these BNP values have been shown to correlate with pulmonary and systemic vascular resistance but not with the partial pressure of arterial oxygen (PaO2) or the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2) . Yangjin et al. (2008), reported that PaO2/FiO2 ratio were not different from survivors and non-survivors . Doyle et al. back in 1995 reported specifically that mortality is not correlated with severity of hypoxemia , and Nuckton et al. (2002), also showed that the influence of respiratory variables on outcome in ARDS has been debated .
In our study, NT-proBNP was positively correlated with PEEP on day 2 (p 0.05, r 0.46) and day 7 (p 0.035, r 0.48). Victor et al. (2008) similarly showed that BNP was correlated with PEEP in 23 patients with severe sepsis/septic shock who developed respiratory failure requiring mechanical ventilation . Niall et al. (2005) found that PEEP is independently associated with intensive care unit mortality in ARDS patients (p value 0.01), while neither the PIP nor the Pplat showed such an association .
Mechanical ventilation by itself was found to increase BNP as suggested by Yaniv et al. (2006) who measured NT-proBNP in 78 critically ill patients and found that patients who required mechanical ventilation had higher NT-proBNP levels than those who did not (2200 pg/mL vs. 700 pg/mL, p < 0.001) . Echocardiographic signs of right ventricular (RV) overload, e.g., RV dilatation, may be absent, particularly if PEEP is used and causes relative hypovolaemia by reducing of venous return . Cifçi et al. (2010) showed that CPAP therapy in Obstructive sleep apnea syndrome does not increase serum pro-BNP, CK, CK-MB, Troponin I, and AST levels . While Tasci et al. (2006) showed that application of CPAP in obstructive sleep apnea syndrome actually decreased NT-proBNP levels significantly . These positive pressure effects are probably achieved through its transmission to intrathoracic vessels and terminally impacting LV and RV preload and afterloads.
Acute cor pulmonale and RV overload as a consequence of increased pulmonary vascular resistance (PVR) is known to occur in 60% of patients with ARDS submitted to conventional mechanical ventilation without airway pressure limitation and still in 25% of patients with ARDS submitted to protective ventilatory support , which might cause BNP elevation as it causes RV pressure overload . Thierry et al. (2006) showed that in ARDS patients without LV dysfunction, BNP levels are more elevated in patients with acute cor pulmonale than patients without cor pulmonale. Damaged lungs, which are responsible for BNP clearance, contribute to this elevation [8,6,9–11]. Byung Hoon Park et al. (2011) showed that in patients with ALI/ARDS, intraindividual NT-proBNP changes correlated with RV Afterload, right-over-left ventricular stroke work ratio percentage change, pulmonary vascular resistance and RV ejection fraction following open lung approach (OLA), thereby serving as a potential marker for RV dysfunction after OLA. Our findings of the Markedly high NT-proBNP levels associated with ARDS, maybe attributable to right ventricular overload due to increased pulmonary vascular resistance and inefficient alveolar recruitment or mechanical ventilator strategies, the mean age and the high incidence of sepsis among the patient population .
We found that none of the cardiac markers NT-proBNP, Trop I or Trop T showed any significant correlation with lung mechanics including Cdyn, RaW, Ceff, PIP, Pplat and Pmean (p > 0.05), but this finding did not differentiate between responders to the mechanical ventilator strategy and those who did not respond as Byung Hoon Park et al. (2011), who showed that in patients with ALI/ARDS, intraindividual NT-proBNP changes correlated with Pplat in non-responders to open lung approach (OLA) .
Niall et al. (2005) measured Cdyn, RaW, Ceff, PIP, Pplat in the first week (days 1, 3 and 7) of ARDS and found no significant differences in all these variables through the first week. Yangjin et al. (2008) reported that compliance Ceff was not different from survivors and non-survivors .
Our study demonstrated a negative correlation between NT-proBNP and PH on day 2 (p 0.008, r −0.53) and on day 7 with (p 0.02, r −0.50). This is in agreement with Emanuel et al., in his study on patients with severe sepsis and septic shock, showed that higher BNP levels are associated with higher lactate levels . Koen J. Hartemink et al. (2011) proved that NT-proBNP mounted to 2917 pg/mL (627–70,000 pg/mL) in sepsis vs. 264 pg/mL (44–3571 pg/mL) in sonseptoc patients. NT-proBNP was 3483 pg/mL (171–70,000 pg/mL) in non-survivors as compared with 301 pg/mL (44–56,343 pg/mL) in survivors (p 0.001). A high NT-proBNP plasma level is an independent marker of systolic cardiac dysfunction, irrespective of filling status, and is a better predictor of fluid non-responsiveness in septic vs. non-septic, critically ill patients . Gong et al. (2005) has previously proved that arterial pH <7.22 in the first 24 h of ICU stay can adversely affect the outcome of ARDS patients , and similarly Niall et al. (2005) showed that late respiratory or metabolic acidosis is one of the factors independently associated with intensive care unit mortality in ARDS patients . Ammann et al. (2003) found that troponin elevation among patients with sepsis and SIRS is common (36–85% of cases) and associated with a worse prognosis . Rudiger et al. (2006) found that the levels of natriuretic peptides were elevated in patients with sepsis (even with preserved LV systolic function) as those with decompensated HF . Tomaru Kit et al. (2002) has reported elevated values for BNP and NT-proBNP in animal models with endotoxemia .
Sepsis may be the major factor implicated in the elevations of NT-proBNP in our study since is considered the most common cause of ARDS in our study. Sepsis is often associated with cardiac dysfunction aside from neurohormonal activation, and is referred to as “septic cardiomyopathy” and biventricular dilatation. Sepsis is also a complex model of proinflammatory, anti-inflammatory, and apoptotic biomarkers. Biomarkers such as tumor necrosis factor, interleukin-6, endotoxin, and interleukin-1β can be of cardiovascular origin or can primarily modulate serum BNP concentrations [15,16]. He et al. (1999) has shown enhanced gene expression of BNP and pro-ANP following stimulation of cultured cardiomyocytes with IL-1B and following stimulation with members of IL-6-related family (i.e., cardioltreophin-1) , and finally the volume resuscitation in sepsis itself may be the cause of NT-proBNP elevation .
Our remarkably elevated levels of NT-proBNP without any significant elevations of cardiac troponins may be explained by the underlying mechanism of elevation of the cardiac marker. BNP is released in response to LV and RV pressure loads and wall stresses, with such hemodynamic effects commonly present in ARDS, while on the other hand, troponins are released in the circulation after myocardial cell damage and cytosolic rupture, which does not necessarily occur in ADRS.
The small sample size of the patients. Other monitoring methods in correlation were not available as invasive Swan Ganz hemodynamic monitoring or myocardial perfusion imaging, successive echocardiographic studies or assessment of alveolar responses to recruitment and mechanical ventilator strategies may have highlighted more objectively the magnitude of any cardiac injury and its changing acute clinical impacts, especially on the right ventricular afterload.
- Cardiac affection with minimal myocardial injury may occur in ARDS patients with structurally normal hearts, as evidenced by elevation of cardiac markers NT-proBNP, Toponin T and Troponin I.
- High NT-proBNP level is correlated with high PEEP, low PH and low PaO2/FiO2 ratio while Trop T and Trop I did not show significant correlations with respiratory parameters.
- None of the cardiac markers NT-proBNP, Troponin I or Troponin T showed any significant correlation with lung mechanics parameters (Cdyn, Ceff, RaW, PIP, Pplat, Pmean) in ARDS patients with structurally normal hearts.
- Although the increase in cardiac markers are insignificant, yet they point to the potentially harmful role played by high PEEP, low PH and low PaO2/FiO2 ratio on the heart. Currently, no clinically relevant conclusion can be drawn apart from the recommendation to attempt to lower PEEP and shorten the duration of positive pressure ventilation, even in patients with structurally normal hearts.
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