In A Heartbeat: Septic Cardiomyopathy

Septic cardiomyopathy (colloquially known as septic heart) was first described by Parker et al. in 1984.

They described it as a rapid onset decreased left ventricular ejection fraction (LVEF) and an increased end diastolic volume (EDV) in patients with severe sepsis that lasted several days, followed by a full cardiac recovery in patients that survive.¹ Currently, there is a lack of formal criteria but there are clinical signs that are generally accepted to be a sign of a septic heart. Patients in septic shock have myriads of morbidity, and awareness of septic cardiomyopathy as a contributor to their hemodynamic stability may frequently be essential in improving outcomes in many critical cases.²

Epidemiology
Epidemiologic data is sparse. Two studies, one in Japan and one in Korea both reported similar risk factors for sepsis-induced cardiomyopathy. The one in Japan, showed that sepsis-induced cardiomyopathy is more common in males than females, younger age, higher lactate on admission, and in patients with a history of heart failure.³ The study by Jeong and colleagues also reported younger age and a history of heart failure, but reported additional risk factors of a history of diabetes Mellitus, elevated NT pro-BNP, positive blood culture.⁴ Incidence varies but studies report between 20-60% incidence in the first few days of ICU admission.⁵ Further research is needed on more diverse populations and broader global scale to better understand the epidemiology and implications to patients. 

Pathophysiology
The mechanism behind sepsis-induced cardiomyopathy is still without a clear definition in the literature. It is thought to be a consequence of myocardial ischemia that results from inadequate blood flow and activation of the immune system via chemical mediators such as endotoxins, cytokines, and nitric oxide. Myocardial hypoperfusion was once thought to be a major cause but now it is thought that this plays a role more in the microvascular setting rather than macrovascular.⁶ The activation of the innate immune system probably is a result of many different mechanisms synergizing each other. Inflammatory mediators set off the coagulation cascade and mitochondrial dysfunction causes oxidative stress. An increase in endothelial permeability leads to edema (myocardial edema may cause contractility dysfunction), causing an increase in neutrophil trafficking into interstitium and fibrin distribution. Disruptions in calcium response cause increased troponin I due to decreased calcium sensitivity. Subsequent catecholamine toxicity causes increased sympathetic outflow. This systemic inflammation all leads to widespread vascular dilation, hypotension, and tachycardia.⁷ 

The hallmark of septic cardiomyopathy is its apparent reversibility. Studies show patients recovering full cardiac function after resolve of sepsis within 7-10 days.³ The cardiac MRI shows patterns indicating altered metabolism and structural edema rather than ischemia and infarction. This includes a dilation of the left ventricle and global ventricular dysfunction without regional dysfunction. Thus sepsis-induced cardiomyopathy may be a protective mechanism leading to decreased mortality in those with hypokinetic heart than hyperkinetic heart. Septic cardiomyopathy is a global kinetic dysfunction as opposed to Takotsubo, which is a more regional kinetic dysfunction (leads to ballooning morphology on echo).² 

Clinical Presentation and Diagnosis 
The septic heart presents with a reversible cardiomyopathy in the setting of severe sepsis. While there are no standardized clinical criteria at this time, sepsis-induced cardiomyopathy is generally defined as an ejection fraction less than 50% and with greater than or equal to a ten percent decrease in LVEF compared to the patient’s baseline.^3,4 This includes cardiogenic shock with a systolic blood pressure less than 90, urine output less than 30 mL/hr and normal or elevated left ventricular filling pressure.⁸ Patients will present with signs of severe sepsis such as hypotension, tachycardia, increased white blood cells and confirmed or suspected infection. Additionally, the cardiac presentation will show consistent signs of decreased LVEF, left ventricular dilatation with normal or decreased filling pressure, depressed ejection fraction, and improvement within 7-10 days.² The onset of cardiomyopathy in the setting of sepsis is rapid but reversible following decompensation into septic shock. Future research for diagnosis should focus on creating standardized clinical criteria. 

Standard critical care monitoring should be performed including cardiac monitor, vitals, and central venous pressure (CVP). CVP monitoring with a goal pressure of < 8 mmHg. The lowest mortality was seen in patients with a pressure < 8 mmHg and the highest mortality with a CVP > 12 mmHg.⁹ It is important to differentiate between left ventricular diastolic and systolic dysfunction, diastolic dysfunction on echocardiogram poorly categorizes septic patients compared to systolic dysfunction.¹⁰

Echocardiogram is the most valuable diagnostic tool in identifying septic cardiomyopathy and has become widely available with the adoption of point of care ultrasound in emergency departments and intensive care units. Larger scale studies are needed on serial and longitudinal echocardiography for diagnosis and prognosis. It is important to exclude other causes of cardiomyopathy that can include ischemic cardiomyopathy and sepsis-induced Takotsubo cardiomyopathy.⁵ Worsened outcomes have been seen in septic patients with hyperkinetic cardiac activity. Patients believed to have septic cardiomyopathy tend to be hypokinetic or normokinetic with global dysfunction.² Echocardiographic speckle should be used to evaluate for decreased contractility regardless of LVEF. Increasing levels of strain found with echocardiographic speckle correlated with worsened outcomes even in patients with normal or pseudonormal LVEF.¹¹ ECG shows no diagnostic findings, most common rhythms include sinus tachycardia and atrial fibrillation. If you find abnormalities on ECG further cardiac evaluation should be performed.¹¹ Coronary angiography should be performed to rule out takotsubo cardiomyopathy.² No data was found on presentation on chest x-ray in patients with a septic heart.

Important laboratory studies to obtain are brain natriuretic peptide (BNP), troponin, and coagulation studies.  At this time, none of these are diagnostic of septic cardiomyopathy. BNP frequently rises but should not be used as a predictive value. Troponin frequently rises as well, and some studies showed that a rise in troponin had a positive correlation with mortality.¹² It should be emphasized that troponin levels are nonspecific in septic cardiomyopathy, as septic patients frequently have comorbidities that can lead to rise in troponin such as renal injury and acute coronary syndrome. Coagulation panels can indicate the presence of coagulopathies or disseminated intravascular coagulation, which may be significant as one possible contributor to septic cardiomyopathy is microvascular aberrancy.¹³ Adherence to your institution’s evidence-based sepsis workup protocol regarding labs is of utmost importance in all septic patients. 

Management
Overall treatment is similar to the treatment of sepsis alone. This includes early goal directed therapy with early and aggressive treatment for sepsis. Treat sepsis by chasing and eliminating the source while also managing the hemodynamics. Managing hemodynamics includes use of vasopressor therapy.² Address and attempt to prevent other comorbidities that may happen which may include shock liver, multiple organ failure and acute kidney injury. Intubation if indicated and antibiotics as per your facilities sepsis protocol. Patients will need fluids as with typical sepsis, but beware that there is worse mortality associated with positive fluid balance and elevated CVP. Approach fluid resuscitation in order to modulate afterload and optimize heart rate.¹⁰

Studies show varying suggestions and benefits of vasopressors. Nickson et al, suggest the benefits are uncertain.⁵ Dobutamine may have adverse effects in patients with sepsis such as arrhythmias, and is suggested to be avoided.² Noradrenaline is the first line, can add vasopressin but vasopressin is not recommended as a single agent. These vasopressor drugs are already a part of the guidelines for treating septic shock.¹⁴ Many of these vasopressors (dobutamine, dopamine, epinephrine, and norepinephrine) increase inotropy but are more likely to be arrhythmogenic.⁸ Depending on severity consider circulatory support such as balloon pump and ECMO. Balloon pump increases cardiac output and reduces the dosage of vasopressors needed, prolongs survival time. Internationally, Levosimendan is suggested due to its inotropic effects and lack of causing arrhythmias but this drug is not available in the U.S.²   

Prognosis
Sepsis has a high mortality, but a septic heart is generally reversible and may be associated with a decrease in death as long as the patient is not hyperkinetic per Boyd et al.⁹ But an opposing study by Ehrman and colleagues’ states that mortality may be two to three times greater.⁶ L’Heureax and colleagues agreed with Ehrman concluding that one year survival was decreased when isolated right ventricular dysfunction was found in sepsis. Additionally, L’Heureax concluded that echocardiographic assessment to guide hemodynamic management and to stop vasopressors earlier lead to decreased 28-day mortality.¹¹ Further studies to replicate and understand the outcome are needed. Early management of hemodynamics and source elimination is important to improve prognosis. Future studies into the rapidity of onset and how this relates to outcome are needed. 

Clinical PEARLS

• Always perform an echocardiogram and look for the triad of decreased LVEF, increased EDV, and resolution within 7-10 days.
• Use Noradrenaline as the first-line vasopressor if needed. 
• Consider ECMO or balloon pump to reduce vasopressor use.
• Don’t fluid overload your patient.

References

1. Parker MM, Shelhamer JH, Bacharach SL, et al. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med. 1984;100(4):483-490. doi:10.7326/0003-4819-100-4-483.
2. Sato R, Nasu M. A review of sepsis-induced cardiomyopathy. Journal of Intensive Care. 2015;3(1). doi:10.1186/s40560-015-0112-5.
3. Sato R, Kuriyama A, Takada T, Nasu M, Luthe SK. Prevalence and risk factors of sepsis-induced cardiomyopathy. Medicine. 2016;95(39). doi:10.1097/md.0000000000005031.
4. Jeong HS, Lee TH, Bang CH, Kim J-H, Hong SJ. Risk factors and outcomes of sepsis-induced myocardial dysfunction and stress-induced cardiomyopathy in sepsis or septic shock A comparative retrospective study. Medicine. 2018;97(13). doi:10.1097/MD.0000000000010263.
5. Nickson C. Septic cardiomyopathy. Life in the Fast Lane Medical Blog. https://litfl.com/septic-cardiomyopathy/. Published April 7, 2019. Accessed May 31, 2020.
6. Ehrman RR, Sullivan AN, Favot MJ, et al. Pathophysiology, echocardiographic evaluation, biomarker findings, and prognostic implications of septic cardiomyopathy: a review of the literature. Critical Care. 2018;22(1). doi:10.1186/s13054-018-2043-8.
7. Tehrani S, Malik A, Hausenloy DJ. Cardiogenic Shock and the ICU Patient. Journal of the Intensive Care Society. 2013;14(3):235-243. doi:10.1177/175114371301400312.
8. Vahdatpour C, Collins D, Goldberg S. Cardiogenic Shock. Journal of the American Heart Association. 2019;8(8). doi:10.1161/jaha.119.011991.
9. Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Critical care medicine. 39(2):259-65. 2011
10. Sanfilippo F, Orde S, Oliveri F, Scolletta S, Astuto M. The Challenging Diagnosis of Septic Cardiomyopathy. Chest. 2019;156(3):635-636. doi:10.1016/j.chest.2019.04.136.
11. L'Heureux M, Sternberg M, Brath L, Turlington J, Kashiouris MG. Sepsis-Induced Cardiomyopathy: a Comprehensive Review. Curr Cardiol Rep. 2020;22(5):35. Published 2020 May 6. doi:10.1007/s11886-020-01277-2.
12. Bessiere F, Khenifer S, Dubourg J, Durieu I, Lega JC. Prognostic value of troponins in sepsis: a meta-analysis. Intensive Care Med. 2013;39(7):1181–9.
13. Cheng-Ming Tsao, Shung-Tai Ho, Chin-Chen Wu, Coagulation abnormalities in sepsis, Acta Anaesthesiologica Taiwanica, Volume 53, Issue 1, 2015, Pages 16-22, ISSN 1875-4597, https://doi.org/10.1016/j.aat.2014.11.002. 
14. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-377. doi:10.1007/s00134-017-4683-6.