B-type natriuretic peptide (BNP) is best known as a marker for evaluation and prognosis of cardiac failure. It is both synthesized and secreted by the ventricular cardiomyocytes in response to ventricular stretching1 and has natriuretic and vasodilator actions. High levels have been well documented and accepted to differentiate causes of dyspnea in the emergency setting, specify levels of severity, and provide prognosis in cardiac failure.2 Accepted levels for the cutoff value of BNP and N-terminal prohormone of BNP (NT-proBNP) for diagnosis of dyspnea due to a cardiac cause are 100 and 300 pg/mL, respectively.3
However, increased BNP has also been documented in other conditions often related to inflammation or high output states including cardiac allograft rejection, ascitic cirrhosis, endocrine diseases, renal failure, sleep apnea, primary pulmonary hypertension, and Kawasaki disease.4 It is higher in the elderly and estrous females.5 High levels have been noted in septic shock, and there is increasing evidence for it as a prognostic indicator in this condition.6
We present 2 cases of patients with septic shock wherein the diagnosis was initially in doubt and discuss changes in BNP levels. We further postulate from these cases and a review of the literature that increased BNP may assist in the diagnosis of sepsis in unusual scenarios.
Consent was not obtained directly from the family as subject 1 died and subject 2 had many family conflicts related to the mode of injury. The responsible IRB gave permission to publish this report.
The patient was a 63-year-old male with a history of ischemic heart disease and coronary artery stenting 9 months previously. This was his third admission to intensive care and was precipitated by extensive vomiting on the ward and abrupt deterioration in gas exchange necessitating mechanical ventilation. This hospital admission had previously been for community-acquired pneumonia and distended abdomen with laparotomy unable to provide a diagnosis. However, ventilation on this admission to intensive care proved difficult with high airway pressures and airway gas trapping. Hypotension developed soon after admission and required 2 fluid challenges, an epinephrine infusion of 30 to 35 μg/min and a dobutamine infusion of 5 μg/kg/min infusion. Gas exchange further deteriorated and nitric oxide was added. The patient produced rust colored sputum; chest radiograph at this stage demonstrated bilateral lung opacities, the right more than left which was presumed secondary to edema or aspiration.
Transesophageal echocardiography demonstrated an ejection fraction of 35% to 40% (consistent with preadmission values) accompanied by BNP 1920 ng/L, mean arterial blood pressure 60 mm Hg, normal jugular venous pressure, and peripheral vasoconstriction. At this stage, his presentation was thought to be aspiration pneumonia initiating severe bronchospasm and possibly complicated by cardiogenic shock.
The ventilation issues (high peak pressures and bronchospasm) resolved quickly, but his mean arterial blood pressure decreased to 40 mm Hg (although supported on 45 μg/min epinephrine and 5 μg/kg/min dobutamine). The patient was now febrile to 40°C, and peripheral vasodilation was present. Dobutamine was reduced, and norepinephrine was commenced at 14 μg/min. A pulmonary artery catheter was inserted which initially demonstrated high cardiac index (CI) (5.1 L/min/m2) and low systemic vascular resistance index (SVRI) (873 dynes/s/cm5/m2) with pulmonary artery occlusion pressure of 12 mm Hg. Although we suspected septic shock, the cardiologist was adamant that the greatly increased BNP was due solely to heart failure and intravascular fluid administration was not begun despite a procalcitonin of 350 ng/mL.
Vancomycin and meropenem were immediately given. However, despite increasing the dose of norepinephrine and initiating vasopressin, arterial blood pressure continued to decrease, followed by a decrease in cardiac output and cardiac arrest occurred after a 3-day stay in the intensive care unit. In retrospect, death was considered to be due to septic shock in the presence of a poorly functioning myocardium.
Although this patient was a complex diagnostic challenge, we believe that had clinicians not attributed the increased BNP solely to cardiac failure, the diagnosis of severe infection may have been made earlier.
This patient was an 18-year-old female with burns over 55% of her total body surface. She was resuscitated by titration of the Parkland formula7 in the first 48 hours, had the burns wounds debrided by day 3, and had excellent gas exchange during the first 5 days. The patient had an arterial pressure–based cardiac output device (Vigeleo, FloTrac, Edwards Lifesciences™, Irvine, CA) in situ. Her hemodynamic variables were low CI and high SVRI in the first 48 hours changing to an increased CI and low SVRI on the third day consistent with the “ebb and flow” pattern found in patients after thermal injury.8,9 Overnight on day 5, episodes of hypotension, tachycardia to 133/min, white cell count of 23 × 109/L, and temperatures to 40.4°C, a further increase in CI and decrease in SVRI were treated with norepinephrine infusion. Initially it was debated whether the rapid heart rate and high temperature were components of the systemic inflammatory response syndrome10 commonly present in burn patients with the hypotension due to fluid shifts. However, the patient developed extreme hypotension and was eventually treated for severe septic shock with increased fluid resuscitation, vasopressors and piperacillin–tazobactam/gentamicin, and a stat dose of vancomycin. It was later confirmed that there was Chryseobacterium indologenes (multiresistant) in debrided tissue, and 2 of 3 blood cultures were positive for Gram-negative bacteria from the central venous catheter. The patient recovered from this episode and survived to leave the hospital. NT-proBNP was incidentally being recorded as a cardiac biomarker in an observational study investigating the effect of significant intravascular fluid administration in patients with acute thermal injury. These were not analyzed until cessation of the study. It was found retrospectively that in the first 4 days after her burn, NT-proBNP was in the range of 30 to 50 ng/mL, but on day 5 NT-proBNP was found to be 1319 ng/mL and on day 6, 6475 ng/mL.
We speculate that these 2 cases indicate that an increase in BNP can occur immediately before the development of clinically apparent septic shock predating the positive blood culture and may prove useful in managing patients in whom a precise diagnosis has not been made.
High levels of BNP have been observed in cases of septic shock11 and are usually much higher than in cardiac failure.12 Historically, this was attributed to cardiac failure in conjunction with sepsis,13 then later to the accompanying myocardial depression occuring in 50% of patients with septic shock.14 Because massive intravascular fluid administration is occurring concomitantly, it was considered that stretching a depressed myocardium was causing the increased BNP. However, high BNP levels were often present in patients with an ejection fraction of >50% and often persisted when intravascular fluid administration was ceased, and when the patient became hyperdynamic with increased cardiac output with no evidence of myocardial depression. Additionally, the understanding of the myocardial-related depression was often based on results from early studies using animal models and only central venous pressure measurement as monitoring.15 With more sophisticated measurement, including portable radionuclide cineangiography and echocardiography, the understanding of cardiovascular dysfunction has increased, with the ability to differentiate between impaired contractility and impaired compliance.15 Myocardial depression in sepsis is now considered to be a temporary, protective mechanism, and functional rather than structural14–16 with adequate perfusion of coronary arteries.
More recently investigators have hypothesized that BNP levels increase in sepsis due to the inflammatory state (high levels of interleukin 1, B interleukin 6, tumor necrosis factor-α) rather than ventricular dysfunction.11 This was initially considered due to the ventricular wall loading in the hyperdynamic state but one paper17 claimed that high levels in sepsis are related to an alteration in the BNP clearance pathway, specifically the neutral endopeptidase (NEP 24.11). This pathway has been shown to be impaired in patients with septic shock18 but this work has indicated a parallel increase in BNP.17 It is being increasingly recognized that elevated levels of BNP are present in subjects without myocardial dysfunction4,19 and even in healthy individuals, e.g., marathon runners at the completion of a race20 and healthy volunteers given an infusion of lipopolysaccharide to induce sepsis.21 BNP is progressively regarded as having a prognostic role in sepsis.6,22
In patient 2, although myocardial depression was well documented in the first 24 hours after her burn injury9 and massive intravascular fluid administration was occurring at this time, BNP levels were within the normal range. Hemodynamic values in patients after burn characteristically change to high cardiac output and low SVRI with a high ejection fraction on day 3.8,23 The extremely high levels of NT-proBNP found from day 5 onwards may have been due to emerging sepsis (with impairment of the clearance pathway)17 and also to the fact that estrous females have higher levels of BNP.5 Because sepsis is notoriously difficult to diagnose in patients with burns,24 BNP may assist in resolving such a diagnostic dilemma. In patient 1, the increased BNP distracted the cardiologist who insisted the problem was pulmonary edema. Had alternative reasons been considered, sepsis may have been recognized earlier and more appropriate management instituted.
Clinicians should be aware that BNP appears to be sensitive for the diagnosis of cardiac failure but not specific due to the vast array of conditions in which BNP is elevated.
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