Abrupt Onset of Septic Cardiomyopathy in a Cancer Patient Initiated on Chemotherapy: A Case Report and Literature Review

Abstract

Introduction

Sepsis-induced cardiomyopathy (SICM) develops in 18–65% cases of sepsis, and its presence in septic shock increases the mortality rate by 70% to 90%. The hallmark of SICM includes global hypokinesia which causes increased LV end-diastolic volume and reduced left ventricular ejection fraction (LVEF), and is reversible by 7 to 10 days provided the patient survives. Among cancer patients, assessing the baseline cardiac morbidity assumes importance as much as the optimization of the dose of chemotherapy infusion and the effective management of complications.

Case Presentation

In this report, we discuss a case of myocardial dysfunction occurring in neutropenic sepsis eventually leading to ventricular arrhythmia which proved fatal. The clinical finding in this 39-year-old male cancer patient (without preexisting heart disease) was consistent with SICM triggered by chemotherapy-induced neutropenic sepsis. His ECHO findings were characteristic with left ventricular changes of reduced EF, global hypokinesia, and ventricular dilation on the second/final day of admission. The discourse encompasses issues associated with maintaining hemodynamic stability in the concerned scenario, as well as distinguishing SICM from other cardiac diseases.

Conclusions

LVEF as a diagnostic tool is reported as a poor measure of SICM prognosis and needs to be replaced with a sensitive and specific measure such as global longitudinal strain. The management of cardiac complications includes optimizing the strategies such as treating the underlying infection, supportive care measures such as fluid replacement, oxygen therapy, and medications for improving the functioning of heart (vasopressors and inotropes).

Introduction

A dysregulated response to infection results in “sepsis” which is a life-threatening condition with multi-organ dysfunction [1]. The incidence reported globally is ∼50 million cases annually, almost a fifth of which led to death [2]. Septic shock is a severe complication of sepsis which is associated with vasodilation and organ failure [3]. Myocardial dysfunction in severe sepsis is termed as sepsis-induced cardiomyopathy (SICM) [4] and develops in 18–65% cases of sepsis [5]. SICM is defined as a global dysfunction of both sides of the heart which is induced by sepsis, and is reversible by 7 to 10 days provided the patient survives [3]. Septic shock is a severe complication of sepsis which is associated with vasodilation and organ failure [3]. The presence of SICM in septic shock increases the mortality rate by 70% to 90% [3].

One of the known risk factors for sepsis includes neutropenia, which is a result of myelosuppressive chemotherapy. In such a scenario with compromised host immune response, there is a risk of severe sepsis [1]. This condition involves a multitude of organ systems, compounding the complexity of clinical management [6]. Parker et al. [4] initially mentioned the term SICM, which is a form of dilated cardiomyopathy. It was described as acute in onset and reversible in nature. The myocardial depression typically becomes evident within 2–3 days of sepsis or 24 h of septic shock [7–9]. If the patient survives, cardiac parameters usually return to normal within the next 7 to 10 days [4].

L’Heureux et al. [10] defined SICM as an acute but reversible global biventricular hypokinesia with systolic and/or diastolic dysfunction, left ventricular (LV) dilatation, and decreased response to fluids and catecholamines [11]. The defining parameters on echocardiography scan (ECHO) are global hypokinesia and reduced left ventricular ejection fraction (LVEF; <40–50% is a widely used criteria) [11]. Hiraiwa et al. [3] reported the method “afterload-related cardiac performance” toward distinguishing SICM from cardiovascular system failure. Given the complexity involved with clinical management of septic shock, the cardiac dysfunction adds a layer of obscurity.

Baron et al. [12] reported that acquired immunosuppression is a consequence of cancer treatment, and infection accounts for a leading non-cancer cause of death in cancer patients. The review reports the first characteristic of SICM as acute and reversible, provided the patient recovers from the infection. The second characteristic is that the depressed LV systolic function is associated with normal or low LV filling pressure, unlike the classic pattern seen in cardiogenic shock where LV pressures are elevated. The LV filling pressures in SICM are due to the increased LV compliance and frequently associated right ventricle (RV) dysfunction. In septic shock, there exists a constant depression of LV intrinsic performance. The LVEF thus reflects the LV afterload rather than the intrinsic contractility.

Mirouse et al. [13] reported the 10 times higher risk of sepsis in cancer patients, with considerable variations among the various subtypes of cancer. An increased mortality is seen among cancer patients with sepsis among all age groups, but most pronounced among young adults. The in-hospital mortality rates of patients with cancer and sepsis or septic shock are ∼20% and ∼40%, respectively. The immunosuppression in cancer patients is usually related to treatment-acquired immune dysfunction. In patients with cancer and sepsis, the acute circulatory failure is frequently associated with anemia and cardiac dysfunction [13].

In this report, we discuss a case of myocardial dysfunction occurring due to cancer therapy-induced neutropenic sepsis which led to ventricular arrhythmia ultimately proving to be fatal. The rationale for the case report entails the gap in knowledge regarding the cardiac complications associated with cancer treatment, pre-chemotherapy evaluation, and the limited role of oncologists in their management. The discourse encompasses issues associated with maintaining hemodynamic stability in the concerned scenario, as well as distinguishing SICM from other cardiac diseases. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550294).

Case Presentation

During February 2023, a 39-year-old male patient of Asian-Indian ethnicity was evaluated at Healthcare Global Cancer Hospital, India. He presented with complaints of pain around the right cheek for a duration of 3 months, which persisted even after extraction of the molar tooth. Subsequent to the extraction, he noticed a swelling on the right side of his face which had been gradually increasing in size since the previous month. An FDG PET-CT scan reported a hypermetabolic lesion in the wall of the right maxillary antrum with involvement of the adjacent planes and structures, consistent with an etiology of a malignant neoplasm.

A subsequent trucut biopsy from the right antral and right posterior hard palate regions revealed a histopathology diagnosis of invasive moderately differentiated squamous cell carcinoma. Immunohistochemistry analysis showed PDL1 expression, with tumor proportion score (TPS): 35% and combined positive score (CPS): 36%. The patient was planned for systemic neoadjuvant chemotherapy with a three weekly (Q3) regimen of paclitaxel (260 mg), cisplatin (60 mg), and 5-fluorouracil (2,400 mg). He was administered the first cycle on March 30, 2023, following a complete evaluation of fitness.

The patient presented to the emergency room at 4 am on April 7, 2023, a week subsequent to the initiation of first round of chemotherapy. His complaints include recurrent spikes of fever and generalized fatigue of 1 day onset. Given the clinical signs of hypotension, the patient was managed in the intensive care unit (ICU) soon after admission on 7 April. The treatment regimen includes fluid bolus with 0.9% normal saline, inj. meropenem (1 g IV 8th hourly), and administration of granulocyte colony-stimulating factor. On further laboratory investigation, the following profile was found.

Table 1 depicts the profile of anemia, low leukocyte, and platelet counts [14]. The neutropenia could be induced by chemotherapy, which further precipitated sepsis in the patient. It also depicts the raised inflammatory marker (procalcitonin), impaired liver function, and coagulopathy.

Table 1.

Laboratory investigation

Sl. No.	Profile	Current laboratory values	Normal values [14]
1	Hemoglobin	8.8 g/dL	>13 g/dL
2	Platelet count	50,000 cells/µL	150,000–450,000 cells/µL
3	Total leukocyte count	290 cells/µL	4,500–11,000 cells/µL
4	Absolute neutrophil count	10 cells/µL	1,500–8,000 cells/µL
5	Serum procalcitonin	17.4 ng/mL	0.1–0.25 ng/mL
6	Total bilirubin	3.1 mg/dL	0.1–1.2 mg/dL
7	Conjugated bilirubin (direct)	1.2 mg/dL	<0.3 mg/dL
8	Albumin	2.7 g/dL	3.4–5.4 g/dL
9	Creatinine	1.0 mg/dL	0.7–1.3 mg/dL
10	Ammonia	107 µmol/L	<30 µmol/L
11	PT	52 s	10–13 s
12	INR	3.06	0.8–1.1
13	Troponin I	0.01	0–0.04 ng/mL
14	NT-proBNP	847	<125 pg/mL
15	D-dimer	0.25	0–0.5 mg/L

Table 2 shows a normal LVEF on day 1, which was drastically reduced on day 2. As depicted in Table 3, Hiraiwa et al. [3] suggested the following ECHO values for diagnosis of SICM.

Table 2.

ECHO parameters for evaluating SICM in the patient

Sl. No.	Parameter	Values suggestive of SICM	Values found on April 7, 24 (1st day of admission)	Values found on April 8, 24 (2nd day of admission)
1	LV dysfunction	EF <52% in men or <54% in women	64.36%	33.97%
		LVIDda (3.5–5.6 cm)	4.22 cm	6.89 cm
		LVIDsb (2–4 cm)	2.73 cm	5.74 cm
2	LA dysfunction	LA diameter (2–4 cm)	3.28 cm	3.1 cm
3	RV dilation	RV/LV diameter ratio ∼0.51	0.43	0.32

^aLV internal diameter, diastolic. ^bLV internal diameter, systolic.

Table 3.

ECHO values suggestive of SICM

Sl. No.	Parameter	Values
1	LV systolic dysfunction	EF <52% in men or <54% in women
		S’ wave <7.5 cm/s
		GLS <20%
2	LV diastolic dysfunction	Lateral E’ wave <7 cm/s (septal <10 cm/s)
		Lateral E/e’ ratio >13 cm/s (septal >15 cm/s)
3	RV dysfunction	RV/LV dilatation >0.6
		TAPSEa <17 mm
		TDIb Str’ wave <10 cm/s
		RV fractional area change <35%
4	Decreased CO	Severe: 4.3±0.3
		Moderate: 7.5±0.4
		Mild: 6.6±0.5 L/min

TDI, tissue Doppler imaging. ^aTricuspid annular plate systolic excursion. ^bTDI.

Table 4 displays the timeline of events in the progression of patient’s condition. As depicted in Figure 1a, the parameters were relatively normal on day 1. As shown in Figure 1b, the LV internal diameter was increased during both systole and diastole on day 2. There were no regional wall motion abnormalities on both the days, which indicates an absence of ischemic heart disease.

Table 4.

Timeline of events in the progression of patient’s condition

Sl. No.	Date	Event
1	Feb 2023	Diagnosis of carcinoma right maxillary region
2	March 30, 2023	Administered first dose of chemotherapy
3	April 7, 2023	Admission to ER with symptoms
4	April 8, 2023	Symptoms of SICM

ER, emergency room.

Fig. 1.

ECHO images of left ventricle on day 1 and 2. a ECHO image on day 1 (April 7, 23). b ECHO image on day 2 (April 8, 23). The ECHO findings show progression of SICM.

Fig. 2.

High-resolution CT scan image of thorax. a Lung window. b Mediastinal window. The source of sepsis is due to the infection of left lung.

Figure 2a presents the lung window which shows dense consolidation in the left lower lobe of lung with air bronchogram (arrow) and surrounding ground glass attenuation involving the left lower lobe. Subtle subpleural consolidation is also seen in the right lower lobe (arrowhead). Figure 2b presents the mediastinal window which shows trace bilateral pleural effusion. This pathological change was suspected to be due to an infectious/inflammatory etiology, and the inference from CT scan image includes collapse/consolidation of the postero-basal lung segments. A pulmonary nodule of 3 mm was also detected in the right middle lobe.

Further on the second day of admission (April 8, 2023), the antibiotic regimen was optimized with intravenous infusion of inj. ceftazidime + inj. avibactam (2.5 g 8 hourly), inj. aztreonam (1 g 8 hourly) and inj. vancomycin (1 g 12 hourly), along with inj. anidulafungin (100 mg daily). The samples of blood, peripherally inserted central line tip and tracheal aspirate, were sent for culture and sensitivity (aerobic and anaerobic); however, the results did not report any growth after 48 h in the culture media.

The patient had sustained tachycardia and hypotension, and subsequently developed respiratory failure for which he underwent endotracheal intubation with ventilator support. The particulars include VCV mode at FiO₂: 100%, Vt: 350 cc, PEEP: 10 cm, RR: 30/mt. A 2D echocardiogram showed a dilated left ventricle with severe global LV hypokinesia and a severe LV systolic dysfunction with an ejection fraction (EF) of 30%. He was treated with triple inotrope support (vasopressin: 2.4 cc, Norad: 25 cc, adrenaline: 10 cc/h).

Subsequent clinical examination showed a heart rate of 192/min, a normal BP of 130/84 mm Hg, and SpO₂ of 90%. The per-abdominal examination was soft, and the respiratory system showed equal air entry bilaterally. Further resuscitative measures implemented include inj. adenosine 6 mg iv stat, neck massage, and vagal maneuvers. The patient reverted back to normal sinus rhythm and was placed on high-flow nasal oxygen. The ensued clinical examination showed a heart rate: 148/mt, BP: 98/36 mm Hg, SpO₂: 86%, with a soft per-abdomen and normal vesicular breath sounds in bilateral lung fields.

Table 5 shows the profile of arterial blood gas analysis done at 6.22 pm (day 2) which indicates metabolic acidosis. Table 6 shows a myelosuppressive profile with hyperbilirubinemia and coagulopathy.

Table 5.

Arterial blood gas analysis on day 2 of admission (April 8, 2023)

Sl. No.	Laboratory parameter	Current findings	Normal values [15]
1	pH	7.14	7.35–7.45
2	pO2	105 mm Hg	75–100 mm Hg
3	pCO2	40 mm Hg	35–45 mm Hg
4	HCO3	14.9 mEq/L	22–26 mEq/L
5	Lactate	14.1 mmol/L	<2 mmol/L

Table 6.

Complete blood count profile at 6.30 pm on April 8, 2023

Sl. No.	Profile	Current laboratory values	Normal values
1	Hemoglobin	8.5 g/dL	>13 g/dL
2	Platelet count	31,000 cells/µL	150,000–450,000 cells/µL
3	Total leukocyte count	210 cells/µL	4,500–11,000 cells/µL
4	Total bilirubin	4.3 mg/dL	0.1–1.2 mg/dL
5	SGOT	41 µ/L	8–33 µ/L
6	SGPT	27 µ/L	4–36 µ/L
7	Creatinine	1.5 mg/dL	0.7–1.3 mg/dL
8	Serum potassium	3.3 mEq/L	3.5–5.5 mEq/L
9	Ammonia	107 µmol/L	<30 µg/100 mL
10	PT	39.4 s	10–13 s
11	INR	3.02	0.8–1.1

As the urinary output was decreased, hemodialysis was planned and a hemodialysis catheter was inserted. Subsequently, the patient developed pulseless ventricular tachycardia prompting swift resuscitative measures as per internationally recognized advanced cardiac life support protocol. Despite cardioversion with defibrillator, the patient progressed to asystole. Cardio-pulmonary resuscitation was provided including direct current shock with 300 joules, inj. adrenaline 1 cc intravenous, and repeated as per the advanced cardiac life support protocol. However, the medical team could not achieve the restoration of spontaneous circulation and the patient was declared dead at 8.40 p.m. The immediate cause of death was certified as “septicemia with multi-organ dysfunction,” and the antecedent cause was “carcinoma hard palate.”

Table 7 reports the available evidence on SICM. The cardiotoxic adverse effects of anticancer drugs (apart from chemotherapy agents) are shown in Table 8.

Table 7.

Literature review

Sl. No.	Author name and type of study	Salient findings	Conclusion
1	Hiraiwa et al. [3]	Non-survivors of SICM episode have a normal EF and unchanged ventricular volume, when contrasted with survivors whose EF was below 40% and mean end-systolic/end-diastolic ventricular volumes were substantially increased with normal SV	RV dysfunction manifests with lethal arrhythmia and circulatory insufficiency independent of the LV systolic function
2	Ognibene et al. [8]	Although volume infusion in patients with sepsis and septic shock induces an increase in PCWP, it does not lead to a substantial increase in LVSWI. LVSWI is a measure of ventricular contractility. The study [16] reports that the administration of vasopressor therapy to patients with septic shock does not have a positive or negative effect on ventricular performance, when given either during or after volume infusion	The serious hemodynamic consequence of sepsis and septic shock includes the markedly abnormal LVSWI in response to volume infusion. This is a consequence of the intrinsic pathogenetic mechanisms of the left ventricle which is noted in the acute stages of sepsis and septic shock, and is manifested prior to depression of LVEF.
3	L’Heureux et al. [10]	The clinical features of SICM are defined as septic, cool extremity phenotype, hemodynamic instability despite vasopressor therapy, failure to respond to a preload challenge, abnormal echocardiogram, cardiac dysrhythmias, low mixed venous oxygen saturation, and elevated cTns	The septal relaxation in TDI is a strong predictor of mortality in patients with septic shock (e’ wave: abnormal <8 cm/s)
4	Grocott-Mason et al. [9]	The pathophysiology of SICM includes overproduction of pro-inflammatory cytokines such as IL-6 and TNF-α, which are crucial in the apoptosis of cardiomyocytes and subsequent injury. The synergistic action of TNF-α and IL-1β induces the release of factors such as nitric oxide, which causes myocardial depression	The cytokines involved with myocardial depression in SICM include endotoxins, which in turn induce mediators such as TNF-α, PAF, and IL-1β. These cytokines cause both acute negative inotropic effects and delayed effects, secondary to the induction of new proteins in the myocardium
5	Baron et al. [12]	SICM patients tend to present with a hyperkinetic profile, associated with tachycardia, supra-normal LVEF, small LV cavity despite massive volume expansion, and a high CI, which are patterns reflecting persistent and profound vasoplegia	100% mortality rate among patients with such a hyperkinetic profile
6	Huang et al. [17]	The meta-analysis reports no convincing evidence that initial low LVEF is associated with better mortality in patients with severe sepsis or septic shock. RVEF and RV dimension were not associated with mortality	LVEF in patients with sepsis could be a reflection of the balance between ventricular function and loading conditions

PCWP, pulmonary capillary wedge pressure; TDI, tissue Doppler imaging; IL-6, interleukin-6; TNF-α, tumor necrosis factor-alpha; PAF, platelet -activating factor.

Table 8.

Cardiotoxicity of anticancer drugs apart from chemotherapy agents [18]

Sl. No.	Anticancer drug	Cardiotoxicity profile
1	HER2is: 1.Monoclonal antibodies: trastuzumab and pertuzumab 2.Tyrosine kinase inhibitor: lapatinib	LVSD and HF
2	VEGFi	Hypertension, myocardial ischemia, LVSD, QTc prolongation, arterial thromboembolic events
3	mTORi	Hypertension, myocardial ischemia, LVSD, QTc prolongation, arterial thromboembolic events, hypercholesterolemia, hypertriglyceridemia, hyperglycemia
4	Bcr-Abl kinasei (imatinib, dasatinib, nilotinib, bosutinib, and ponatinib)	Accelerated atherosclerosis, peripheral artery disease, acute coronary syndrome, stroke, hypertension, hyperglycemia, hypercholesterolemia, pericardial effusion, pulmonary arterial hypertension, QTc prolongation, and occasional LVSD
5	Proteasome inhibitors (carfilzomib, bortezomib, ixazomib)	LVSD, HF, arterial hypertension, myocardial ischemia
6	Ibrutinib	Atrial fibrillation, hypertension, HF, ventricular arrhythmias, conduction disorders
7	Immune checkpoint inhibitors	Immune-related myocarditis, pericarditis, supraventricular arrhythmias, acute coronary syndrome, and Takotsubo syndrome

Discussion

The clinical presentation in this 39-year-old male cancer patient (without preexistent heart disease) was consistent with SICM triggered by chemotherapy-induced neutropenic sepsis. His ECHO findings were characteristic of LV changes such as reduced EF, global hypokinesia, and ventricular dilation on the second/final day of admission. The patient was in frank sepsis at initial presentation and progressed to septic shock during admission. The myocardial dysfunction developed 24 to 48 h after sepsis and well within 24 h of onset of shock. This timeline corresponds with the evidence for SICM depicted in the literature [7–9].

There was no evidence of acute coronary syndrome or pulmonary embolism on 7 April, as seen by the electrocardiogram (ECG) recordings (no ST-T wave changes in Fig. 3a), ECHO findings (no RWMA in Fig. 1a), and assessment of biomarkers (normal levels of troponin I, D-dimer, Table 1). However, only N-terminal pro-B-type NP (NT-proBNP) was mildly elevated (847 pg/mL, Table 1). ECG as depicted in Figure 3b (8 April) shows features of sinus arrhythmia and poor “R” wave progression but not any ST wave changes (elevation or depression) or T wave inversions. The reversible aspect of the patient’s cardiac dysfunction could not be assessed due to his untimely demise. Given the other clinical features which align well with SICM, it is the likely diagnosis in this case.

Fig. 3.

The serial ECG findings. a ECG done on April 7, 23. b ECG done on April 8, 23. a shows an NSR with sinus tachycardia. b shows sinus arrhythmia, poor “R” wave progression, no significant ST segment and T wave abnormality. NSR, normal sinus rhythm.

The clinical predictors of SICM discussed in this case report enable distinguishing it from other cardiac diseases such as acute coronary syndrome, pulmonary embolism, arrhythmias, and stress cardiomyopathy. A cardinal feature of SICM is LV dilatation which is a compensatory response to myocardial depression, allowing the LV to maintain the stroke volume (SV) (Frank-Starling mechanism). Cardiac output (CO) does not reflect intrinsic cardiomyocyte function/contractility, and a normal measure does not rule out SICM given the low systemic vascular resistance (SVR) which could falsely elevate the measured CO. Evidence shows that the measurement of global longitudinal strain (GLS) through speckle tracking is a sensitive test for assessing SICM. A limitation of ECHO is its dependence on loading conditions, particularly for LVEF. The onco-cardiology team needs to be pragmatic about invasive procedures such as coronary angiography in critically ill patients.

SICM was first described during 1984, and LV systolic dysfunction has been viewed as its central feature [4]. The consistent findings on 2D ECHO scan include reduced EF and global hypokinesia (with few exceptions of regional hypokinesia) [10, 19]. In septic shock, the SVR is lowered, thus reducing the afterload, which can misleadingly normalize EF despite poor contractility. SICM is also characterized by a poor response to fluid infusion [10]. When compared with non-septic controls, Ognibene et al. [8] reported no further increase in end-diastolic volume (EDV) and stroke work indices upon fluid infusion among septic patients with LV dilatation. This suggests a poor compliance, rather the limit of the ventricular stretch (pre-infusion), and a flat Frank-Starling curve once in a dilated state. Cardiac index (CI) which is another measure of systolic function is usually normal or even raised in SICM, thus demonstrating a hyperdynamic state [16]. This state however may still reflect systolic dysfunction, as it may not be raised enough to account for the low SVR [19, 16].

For the present case, LVEF (33.97%) was drastically reduced on day 2. The use of LVEF as the only criteria in an ECHO finding could result in an underdiagnosis of SICM. Ideally, LVEF in critically ill patients should be reported with the amount of inotropic and vasopressor support, and the degree of shock [10]. The reduced afterload from the distributive shock of critically ill patients may pseudo-normalize a depressed EF (as it depends on contractility and afterload). Given the accessibility of EF, it remains the defining parameter in SICM. However, better echocardiographic measures like GLS tend to accurately confirm poor intrinsic contractility in SICM [7]. Speckle-tracking ECHO involves the use of non-Doppler-based algorithms for tracking the displacement of acoustic speckles in the myocardium for measuring the change in length of myocardial segments [3]. L’Heurex et al. [10] reported a −14% average measure of GLS among patients with septic shock (normal values are −17% to −23%, with more negative being better), despite reporting a normal LVEF. An advantage of speckle-tracking ECHO is its lower susceptibility to changes in preload and afterload.

Among ICU patients with acute noncardiac illness, Bossome et al.’s [17] study reported an incidence of 12% and 8% for regional and global LV dysfunction, respectively. In their proposed diagnostic criteria for SICM, L’Heureux et al. [10] also enlisted global, biventricular dysfunction (systolic and/or diastolic) with reduced contractility, which conforms with the findings in this case. However, Organti et al. [20] reported that one-third of cases do not show right ventricular involvement similar to the concerned case. A meta-analysis [21] fails to provide convincing evidence that initial low LVEF is associated with better mortality in patients with severe sepsis or septic shock. Also, RVEF and RV dimension were not associated with mortality. The authors conclude that LVEF in patients with sepsis could be a reflection of the balance between ventricular function and loading conditions [21].

Transient left ventricular dysfunction in critical illness (TLVDCI) [22–24] is reported among patients experiencing acute noncardiac illness. SICM defines the transient myocardial dysfunction due to sepsis and is a subtype of TLVDCI. Some of the conditions associated with TLVDCI include acute respiratory diseases, gastrointestinal bleeds, and neurological pathologies such as hemorrhage, stroke, and trauma to the head [22, 25]. However, the mechanisms of LV dysfunction could be varied across these critical illnesses. Caverfors et al. [22] reported that TLVDCI is prognostically negative and is correlated with severe disease, hemodynamic instability, and increased mortality. The most common ECG findings reported in such scenarios are sinus tachycardia or atrial fibrillation [10, 19]. Although the ECG findings in this case include sinus tachycardia and sinus arrhythmia, no diagnostic criteria however exist for the identification of SICM.

Hiraiwa et al. [3] reported that during sepsis, patients are negatively affected by changes made by the heart for maintaining its function. The dilated left ventricle in SICM is a result of intrinsic myocardial changes induced by septic shock [8]. An increase in the LV internal diameter was reported both during systole (5.74 cm) and diastole (6.89 cm). The clinical interpretation of diastolic dysfunction is hampered by its critical dependence on filling pressures and chamber compliance. Despite the reduced contractility and EF, the increase in EDV is an adaptive response for maintaining the SV (EF = SV/EDV). However, Grocott-Mason et al. [9] reported that hypovolemia reduces preload and in turn the LV EDV. This leads to a decrease in CO by reducing the muscle stretch. Pulmonary capillary wedge pressure is an indirect measure of preload, and the compliance of ventricle is reflected by the ratio: volume/pulmonary capillary wedge pressure.

The RV can also display depressed EF and dilatation in SICM [7, 26]. Evidence [27] exists regarding the important role played by RV in SICM, especially when assessing the prognosis. L’Heureux et al. [10] reported that two-thirds of patients with sepsis and septic shock are known to have RV dysfunction, and it is an independent risk factor of 1-year survival [10]. The study [10] reports that patients with RV wall strain (scoring less negative than −13%) tend to die within 20 days. However, Hiraiwa et al. [3] mentioned that RV dysfunction is uncommon among sepsis patients, when compared with LV dysfunction. It is also associated with lower CO, pulmonary artery pressure index, and RV stroke work index [3]. For the concerned case, the RV/LV diameter ratio was <1 on both the days which is indicative of normal RV function (absence of RV dilation). Since RV diameter was normal, the healthcare team did not suspect the etiology of pulmonary embolism.

Grocott-Mason et al. [9] reported that the myocardial response to sepsis includes systolic depression and diastolic dilatation of the LV, the latter enabling the maintenance of SV through utilization of its preload reserve (Frank-Starling mechanism). This mechanism works effectively when the cardiac filling is adequate (through correction of hypovolemia). The occurrence of LV dilatation is associated with better prognosis and lower mortality, and failure of LV dilatation is expected to be detrimental. This is due to the reduced LVEF and left ventricular stroke work index (LVSWI), wherein stroke work index is calculated as “SV*mean arterial blood pressure” normalized for body surface area [9]. A differential called as Takotsubo or stress cardiomyopathy is defined primarily by apical ballooning of LV and regional wall motion abnormalities, and is precipitated by emotional or physical stressor [28]. Unlike in the present case, Takotsubo cardiomyopathy does not manifest with global hypokinesia of LV.

Though coronary ischemia was previously speculated in septic shock, available evidence shows that coronary vascular flow is often increased [10, 29–31]. Sepsis leads to disruption of the endothelial glycocalyx [10] and subsequent pathogenesis causing myocardial edema [32, 33] in turn leading to a rise in the levels of cardiac troponin (cTn). During sepsis, an interplay of various inflammatory mediators such as cytokines, nitric oxide, complement proteins, and pathogen-associated molecular patterns is known to cause myocardial depression [34]. Another component of SICM includes autonomic dysregulation which is manifested as hyperadrenergic state, low heart rate variability, downregulation of beta-1 adrenoreceptors, and diminished response to catecholamines [34, 35]. Schmittinger et al. [36] reported the postmortem histopathological finding of contraction band necrosis, which is suggestive of catecholamine (both endogenous and exogenous)-induced myocyte injury.

L’Heureux et al. [10] mentioned that the diagnostic utility of biomarkers in SICM is limited; however, they can provide prognostic information. In LV dysfunction, biomarkers such as troponin are elevated and higher levels are associated with a larger risk of death in patients with sepsis [3]. The authors [10] reported that among septic patients, elevated cTn is correlated with a greater degree of LV dysfunction, severity of illness, and mortality. Elevation of NT-proBNP is ubiquitous in sepsis, and the study [10] reports that NT-proBNP predicted mortality in the ICU and at 90 days post-discharge, better than cTn.

Muller-Werdan et al.’s [19] study reported that myocardial dysfunction and its extent in sepsis are defined by the body’s inflammatory response rather than the virulence of the pathogen. However, the severity of illness and progression to septic shock expedite the chances of developing cardiac complications. Sato et al. [5] described the rise in CRP levels, and illness severity scores are a result of SICM rather than a risk factor for the condition. Other risk factors for SICM include increasing age, male sex, preexisting heart failure, and heart failure [5, 37]. Preexisting ischemic heart disease is also a known risk factor; however, SICM by itself is not pathogenically characterized by coronary hypoperfusion [38].

The major adverse events associated with administration of the drug paclitaxel include hypersensitivity reactions, myelosuppression, peripheral neuropathy, bradycardia, and hypotension. The myelosuppression is exacerbated by combining paclitaxel with other cytotoxic chemotherapeutic agents. The cardiac disturbances associated with paclitaxel administration include asymptomatic bradycardia and/or hypotension [39]. The common adverse effects of cisplatin administration include myelosuppression, peripheral neurotoxicity, nephro- and hepatotoxicity [40]. The adverse effects of 5-fluorouracil include infusion reactions, fever, vomiting, rashes, peripheral neuropathy, and hepatic injury [18]. The inherent cardiac morbidity, administered dosage of chemotherapy, and the related complications are the main factors which influence the severity of adverse effects. The initial doses of chemotherapy need to be customized given the patient’s health condition, and commencement with low dosage can be considered before providing the full dose of medication.

The case report discusses the fatal outcome of severe neutropenic sepsis in a cancer patient who was initiated on chemotherapy. After the initial dose, he progressed to novel LV dysfunction within 3 days of onset of symptoms of sepsis and subsequently succumbed to pulseless ventricular tachycardia. LV diastolic dysfunction is quite common in patients with septic shock [10]. Considering the plethora of factors involved in SICM, it is difficult to estimate the prognostic value of myocardial depression in sepsis [35]. SICM is a complex entity to manage given the optimization required for balancing an improvement in blood pressure and reducing the myocardial strain. However, given the profound hypotension associated with sepsis other treatments used for cardiomyopathy are contraindicated [3]. Cardiac biomarkers assess the severity of illness and prognosis of sepsis, while ECG and other laboratory investigations enable in reducing the diagnostic uncertainty [18]. Without specific treatment guidelines, the strides include managing the underlying sepsis, hemodynamic support, and critical care measures such as respiratory support. The challenge is to define the precise amount of fluids, vasopressors, and positive and negative inotropes [12].

Future Direction

Among cancer patients on treatment, chemotherapy-induced complications such as SICM need to be prevented and appropriately treated. Such measures are critical for improved prognosis and survival of patients. In SICM, there are profound variations in preload, afterload, and contractility which are intrinsic to septic shock. Although SV and CI are calculated using other indices such as left ventricular outflow tract diameter and the velocity time integral, these measurements are hard to interpret in SICM. GLS of both RV and LV can be used for the diagnosis of SICM [7]. The benefit of using speckle tracking is that it is not as susceptible to afterload reduction pseudo-normalization which plagues LVEF.

Additional research should focus on the clinical manifestations of SICM and the involved pathophysiological mechanisms. The process of reversibility of cardiomyopathy within 7–10 days is still indefinite. Molecules such as histones and heart fatty acid-binding proteins (hFABPs) are implicated in SICM, more so among patients without preexisting cardiovascular diseases. These molecules are indicators of severity of illness and prognosis among patients with sepsis. Other mechanisms of SICM need to be explored, which include molecular patterns associated with pathogen and complement-mediated damage.

Acknowledgments

The authors would like to thank Dr. Shivkumar Swamy, Radiologist, Healthcare Global, Bangalore, India; Dr. Vijayraju Krupesh, Intensivist, Healthcare Global, Bangalore, India; and Dr. Ganesh N.S., Cardiologist, Aster CMI Hospital, Bangalore, India.

Statement of Ethics

This study protocol was reviewed, and the need for approval was waived by Healthcare Global Central Ethics Committee. Written informed consent was obtained from the deceased patient’s wife for the publication of this case report and any accompanying images.

Conflict of Interest Statement

The authors declare that they have no conflict of interests.

Funding Sources

Coauthor Dr. Abderahman Belfakih has funded the publication charges for this manuscript.

Author Contributions

V.V. drafted the initial version of the manuscript. V.R. synthesized information for the manuscript. S.M. conducted literature review. A.K. coordinated clinical care and compiled the clinical information. A.B. reviewed the manuscript. R.N. provided clinical care to the patient and final approval for submission.

Funding Statement

Coauthor Dr. Abderahman Belfakih has funded the publication charges for this manuscript.

Data Availability Statement

The data that support the findings of this study are not publicly available due to privacy reasons but are available by emailing the corresponding author upon reasonable request.