Sudden cardiac versus non-cardiac death

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Sudden Cardiac versus Non-Cardiac Death
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Historical Perspective

• [Disease name] was first discovered by [scientist name], a [nationality + occupation], in [year] during/following [event].
• In [year], [gene] mutations were first identified in the pathogenesis of [disease name].
• In [year], the first [discovery] was developed by [scientist] to treat/diagnose [disease name].

Classification

• [Disease name] may be classified according to [classification method] into [number] subtypes/groups:

• [group1]
• [group2]
• [group3]

• Other variants of [disease name] include [disease subtype 1], [disease subtype 2], and [disease subtype 3].

Pathophysiology

• The pathogenesis of [disease name] is characterized by [feature1], [feature2], and [feature3].
• The [gene name] gene/Mutation in [gene name] has been associated with the development of [disease name], involving the [molecular pathway] pathway.
• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Causes

Disease name] may be caused by [cause1], [cause2], or [cause3].

OR

Common causes of [disease] include [cause1], [cause2], and [cause3].

OR

The most common cause of [disease name] is [cause 1]. Less common causes of [disease name] include [cause 2], [cause 3], and [cause 4].

OR

The cause of [disease name] has not been identified. To review risk factors for the development of [disease name], click here.

Differentiating Cardiac causes of sudden death from non-cardiac causes

For further information about the differential diagnosis, click here.

Cardiac causes of sudden cardiac death

Non cardiac causes of sudden cardiac death:

Acute aortic insufficiency Acute coronary syndrome Aortic dissection Aortic stenosis Arrhythmogenic right ventricular dysplasia Brugada syndrome Cardiac tamponade Cardiomyopathy Catecholaminergic polymorphic ventricular tachycardia Commotio cordis Complete heart block Congenital heart disease Congestive heart failure Coronary artery disease Dilated cardiomyopathy Hypertrophic cardiomyopathy Jervell and Lange-Nielsen syndrome Long QT syndrome, both congenital and acquired Lyme disease Mitral valve prolapse Myocarditis Naxos disease Noncompaction Cardiomyopathy Papillary muscle rupture Prolonged Q-T Interval Syndrome Pulmonary embolism Romano-Ward syndrome Ruptured abdominal aortic aneurysm Prosthetic valve dysfunction Short QT syndrome Short QT syndrome type 1 Short QT syndrome type 2 Short QT syndrome type 3 Short QT syndrome type 4 Short QT syndrome type 5 Sick sinus syndrome ST Elevation Myocardial Infarction Stokes-Adams Syndrome Sudden Infant Death Syndrome Timothy syndrome Uhl anomaly Valvular Heart Disease Ventricular rupture Wolf-Parkinson-White syndrome with rapid conduction

3-methylglutaconic aciduria, type 1 Alpha-ketoglutarate dehydrogenase deficiency Amniotic fluid syndrome Arterial dissections with lentiginosis Anaphylaxis Aneurysm Apoplexy Appendicitis Asphyxia Birth injury Bleeding excessive Childbirth hemorrhage Diabetic ketoacidosis - typically from undiagnosed diabetes Drug allergy Drug overdose Encephalitis Fetal death Flu mainly in the elderly, infants, infirm or chronically ill Food allergy Gastrointestinal bleeding Homicide Hyperbilirubinemia transient, familial, neonatal Hypercalcemia Hypercapnia Hyperkalemia Hypokalemia Hypoxia Injury Insect bite Intracranial hemmorhage Marfan syndrome Meningitis Meningococcal disease Motor Vehicle accident Myasthenia Gravis Neurocysticercosis Opioid overdose Oxycontin overdose Pain killer overdose Pickwickian Syndrome Poisoning Pulmonary embolism Retroperitoneal bleed Sepsis syndrome Shock Sleep apnea Snake bite Status asthmaticus Stillbirth Stroke Subarachnoid hemorrhage Sudden Infant Death Syndrome Suicide Sleeping pill overdose Toxic/metabolic disturbances Tranquilizer addiction Tension pneumothorax Toxic/metabolic disturbances Thyrotoxicosis Toxic shock syndrome Transfusion reaction Venom

Epidemiology and Demographics

• The prevalence of sudden cardiac death is approximately 1.40 per 100,000 individuals in women to 6.68 per 100.000 individuals in men worldwide.

• In 2015, the incidence of adult in-hospital cardiac arrests was estimated to be 970 cases per 100,000 individuals in the united states.

Age

• Cardiac arrest is more commonly observed within the first year of life ( sudden infant death syndrome and between 45-75 years old due to increased risk of coronary artery disease.
• There is a significant decrease in sudden cardiac death at age 75 and older due to decreasing risk of coronary artery disease.

Gender

• men are more commonly affected with sudden cardiac death than women in all age groups.

Race

• Black individuals are more likely to develop cardiac arrest.

Risk Factors

• Common risk factors related to ischemic heart disease in the development of cardiac arrest are:

• Hypertension
• diabetes mellitus
• hyperlipidemia
• smoking
• Older age

Natural History, Complications and Prognosis

• The majority of patients with [disease name] remain asymptomatic for [duration/years].
• Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
• If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
• Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
• Prognosis is generally [excellent/good/poor], and the [1/5/10­year mortality/survival rate] of patients with [disease name] is approximately [#%].

Diagnosis

Diagnostic Criteria

• The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met:

• [criterion 1]
• [criterion 2]
• [criterion 3]
• [criterion 4]

Symptoms

• [Disease name] is usually asymptomatic.
• Symptoms of [disease name] may include the following:

• [symptom 1]
• [symptom 2]
• [symptom 3]
• [symptom 4]
• [symptom 5]
• [symptom 6]

Physical Examination

• Patients with cardiac arrest usually appear cyanotic.
• Physical examination may be remarkable for:

• Heart rate and regularity, blood pressure
• Jugular venous pressure
• Murmurs
• Pulses, bruits
• Edema
• Sternotomy scars

Laboratory Findings

• There are no specific laboratory findings associated with [disease name].

• A [positive/negative] [test name] is diagnostic of [disease name].
• An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
• Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

Electrocardiogram

There are no ECG findings associated with [disease name].

OR

An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

X-ray

There are no x-ray findings associated with [disease name].

OR

An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with [disease name].

OR

Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

CT scan

There are no CT scan findings associated with [disease name].

OR

[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

MRI

There are no MRI findings associated with [disease name].

OR

[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Other Imaging Findings

There are no other imaging findings associated with [disease name].

OR

[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

• [Disease name] may also be diagnosed using [diagnostic study name].
• Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

• There is no treatment for [disease name]; the mainstay of therapy is supportive care.

• The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
• [Medical therapy 1] acts by [mechanism of action 1].
• Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

Surgery

• Surgery is the mainstay of therapy for [disease name].
• [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
• [Surgical procedure] can only be performed for patients with [disease stage] [disease name].

Prevention

• There are no primary preventive measures available for [disease name].

• Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

• Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].

Overview

The term sudden cardiac death refers to natural death from cardiac causes, heralded by abrupt loss of consciousness within one hour of the onset of acute symptoms. Other forms of sudden death may be noncardiac in origin and are therefore termed sudden death rather than sudden cardiac death. Examples of this include respiratory arrest (such as due to airway obstruction, which may be seen in cases of choking or asphyxiation), toxicity or poisoning, anaphylaxis, or trauma.

It is important to make a distinction between this term and the related term cardiac arrest, which refers to cessation of cardiac pump function which may be reversible (i.e., may not be fatal). The phrase Sudden Cardiac Death is a public health concept incorporating the features of natural, rapid, and unexpected. It does not specifically refer to the mechanism or cause of death. Although the most frequent underlying cause of Sudden Cardiac Death is Coronary Artery Disease, other categories of causes are listed below.

Cardiac Arrest as a Subtype of Sudden Death

A cardiac arrest, also known as cardiorespiratory arrest, cardiopulmonary arrest or circulatory arrest, is the abrupt cessation of normal circulation of the blood due to failure of the heart to contract effectively during systole.

"Arrested" blood circulation prevents delivery of oxygen to all parts of the body. Cerebral hypoxia, or lack of oxygen supply to the brain, causes victims to lose consciousness and to stop normal breathing. Brain injury is likely if cardiac arrest is untreated for more than 5 minutes, To improve survival and neurological recovery immediate response is paramount.

Cardiac arrest is a medical emergency that, in certain groups of patients, is potentially reversible if treated early enough (See Reversible Causes, below). When unexpected cardiac arrest leads to death this is called sudden cardiac death (SCD). The primary first-aid treatment for cardiac arrest is cardiopulmonary resuscitation (commonly known as CPR) to provide circulatory support until availability of definitive medical treatment, which will vary dependant on the rhythm the heart is exhibiting, but often requires defibrillation.

FDA Guidance re Classification and Types of Cardiovascular and Non-Cardiovascular Death

Definition of Cardiovascular Death

The determination of the specific cause of cardiovascular death is complicated by the fact that we are particularly interested in one underlying cause of death (acute myocardial infarction (AMI)) and several modes of death (arrhythmia and heart failure/low output). It is noted that heart attack-related deaths are manifested as sudden death or heart failure, so these events need to be carefully defined. Cardiovascular death includes death resulting from an acute myocardial infarction, sudden cardiac death, death due to heart failure, death due to stroke, and death due to other cardiovascular causes, as follows:

1.Death due to Acute Myocardial Infarction

This refers to a death by any mechanism (arrhythmia, heart failure, low output) within 30 days after a myocardial infarction (MI) related to the immediate consequences of the myocardial infarction, such as progressive congestive heart failure (CHF), inadequate cardiac output, or recalcitrant arrhythmia. If these events occur after a “break” (e.g., a CHF and arrhythmia free period of at least a week), they should be designated by the immediate cause, even though the MI may have increased the risk of that event (e.g., late arrhythmic death becomes more likely after an acute myocardial infarction (AMI)). The acute myocardial infarction should be verified to the extent possible by the diagnostic criteria outlined for acute myocardial infarction or by autopsy findings showing recent myocardial infarction or recent coronary thrombus. Sudden cardiac death, if accompanied by symptoms suggestive of myocardial ischemia, new ST elevation, new LBBB, or evidence of fresh thrombus by coronary angiography and/or at autopsy should be considered death resulting from an acute myocardial infarction, even if death occurs before blood samples or 12-lead electrocardiogram (ECG) could be obtained, or at a time before the appearance of cardiac biomarkers in the blood.

Death resulting from a procedure to treat a myocardial infarction (percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), or to treat a complication resulting from myocardial infarction, should also be considered death due to acute MI.

Death resulting from a procedure to treat myocardial ischemia (angina) or death due to a myocardial infarction that occurs as a direct consequence of a cardiovascular investigation/procedure/operation should be considered as a death due to other cardiovascular causes.

2.Sudden Cardiac Death

This refers to a death that occurs unexpectedly, not following an acute AMI, and includes the following deaths:

a. Death witnessed and instantaneous without new or worsening symptoms

b. Death witnessed within 60 minutes of the onset of new or worsening cardiac symptoms, unless the symptoms suggest AMI

c. Death witnessed and attributed to an identified arrhythmia (e.g., captured on an electrocardiographic (ECG) recording, witnessed on a monitor, or unwitnessed but found on implantable cardioverter-defibrillator review)

d. Death after unsuccessful resuscitation from cardiac arrest

e. Death after successful resuscitation from cardiac arrest and without identification of a non-cardiac etiology (Post-Cardiac Arrest Syndrome)

f. Unwitnessed death without other cause of death (information regarding the patient’s clinical status preceding death should be provided, if available)

General Considerations

• A subject seen alive and clinically stable 12-24 hours prior to being found dead without any evidence or information of a specific cause of death should be classified as :sudden cardiac death.”. Typical scenarios include

• Subject well the previous day but found dead in bed the next day
• Subject found dead at home on the couch with the television on

• Deaths for which there is no information beyond “Patient found dead at home” may be classified as “death due to other cardiovascular causes” or in some trials, “undetermined cause of death.” Please see Definition of Undetermined Cause of Death, below, for full details.

3. Death due to Heart Failure or Cardiogenic Shock

This refers to a death occurring in the context of clinically worsening symptoms and/or signs of heart failure (see Chapter 7) without evidence of another cause of death and not following an AMI. Note that deaths due to heart failure can have various etiologies, including one or more AMIs (late effect), ischemic or non-ischemic cardiomyopathy, or valve disease.

Death due to Heart Failure or Cardiogenic shock should include sudden death occurring during an admission for worsening heart failure as well as death from progressive heart failure or cardiogenic shock following implantation of a mechanical assist device.

New or worsening signs and/or symptoms of congestive heart failure (CHF) include any of the following:

a. New or increasing symptoms and/or signs of heart failure requiring the initiation of, or an increase in, treatment directed at heart failure or occurring in a patient already receiving maximal therapy for heart failure

b. Heart failure symptoms or signs requiring continuous intravenous therapy or chronic oxygen administration for hypoxia due to pulmonary edema

c. Confinement to bed predominantly due to heart failure symptoms

d. Pulmonary edema sufficient to cause tachypnea and distress not occurring in the context of an acute myocardial infarction, worsening renal function, or as the consequence of an arrhythmia occurring in the absence of worsening heart failure

e. Cardiogenic shock not occurring in the context of an acute myocardial infarction or as the consequence of an arrhythmia occurring in the absence of worsening heart failure

Cardiogenic shock is defined as systolic blood pressure (SBP) < 90 mm Hg for greater than 1 hour, not responsive to fluid resuscitation and/or heart rate correction, and felt to be secondary to cardiac dysfunction and associated with at least one of the following signs of hypoperfusion:

• Cool, clammy skin or
• Oliguria (urine output < 30 mL/hour) or
• Altered sensorium or
• Cardiac index < 2.2 L/min/m2

Cardiogenic shock can also be defined if SBP < 90 mm Hg and increases to ≥ 90 mm Hg in less than 1 hour with positive inotropic or vasopressor agents alone and/or with mechanical support.

General Considerations

Heart failure may have a number of underlying causes, including acute or chronic ischemia, structural heart disease (e.g. hypertrophic cardiomyopathy), and valvular heart disease. Where treatments are likely to have specific effects, and it is likely to be possible to distinguish between the various causes, then it may be reasonable to separate out the relevant treatment effects. For example, obesity drugs such as fenfluramine (pondimin) and dexfenfluramine (redux) were found to be associated with the development of valvular heart disease and pulmonary hypertension. In other cases, the aggregation implied by the definition above may be more appropriate.

4.Death due to Stroke

This refers to death occurring up to 30 days after a stroke that is either due to the stroke or caused by a complication of the stroke.

5.Death due to Other Cardiovascular Causes

This refers to a cardiovascular death not included in the above categories (e.g. dysrhythmia unrelated to sudden cardiac death, pulmonary embolism, cardiovascular intervention (other than one related to an AMI), aortic aneurysm rupture, or peripheral arterial disease). Mortal complications of cardiac surgery or non-surgical revascularization should be classified as cardiovascular deaths.

Definition of Non-Cardiovascular Death

Non-cardiovascular death is defined as any death that is not thought to be due to a cardiovascular cause. Detailed recommendations on the classification of non-cardiovascular causes of death are beyond the scope of this document. The level of detail required and the optimum classification will depend on the nature of the study population and the anticipated number and type of non-cardiovascular deaths. Any specific anticipated safety concern should be included as a separate cause of death. The following is a suggested list of non-cardiovascular* causes of death:

Non-Malignant Causes

• Pulmonary
• Renal
• Gastrointestinal
• Hepatobiliary
• Pancreatic
• Infection (includes sepsis)
• Non-infectious (e.g., systemic inflammatory response syndrome (SIRS))
• Hemorrhage, not intracranial
• Non-cardiovascular system organ failure (e.g., hepatic failure)
• Non-cardiovascular surgery
• Other non-cardiovascular, specify: ________________
• Accidental/Trauma
• Suicide
• Drug Overdose
• Death due to a gastrointestinal bleed should not be considered a cardiovascular death.

Malignant Causes

Malignancy should be coded as the cause of death if:

• Death results directly from the cancer; or
• Death results from a complication of the cancer (e.g. infection, complication of surgery / chemotherapy / radiotherapy); or
• Death results from withdrawal of other therapies because of concerns relating to the poor prognosis associated with the cancer

Cancer deaths may arise from cancers that were present prior to randomization or which developed subsequently. It may be helpful to distinguish these two scenarios (i.e. worsening of prior malignancy; new malignancy). Suggested categorization includes common organ systems, hematologic, or unknown.

Definition of Undetermined Cause of Death

Undetermined Cause of Death refers to a death not attributable to one of the above categories of cardiovascular death or to a non-cardiovascular cause. Inability to classify the cause of death may be due to lack of information (e.g., the only available information is “patient died”) or when there is insufficient supporting information or detail to assign the cause of death. In general, the use of this category of death should be discouraged and should apply to a minimal number of patients in well-run clinical trials. A common analytic approach for cause of death analyses is to assume that all undetermined cases are included in the cardiovascular category (e.g., presumed cardiovascular death, specifically “death due to other cardiovascular causes”). Nevertheless, the appropriate classification and analysis of undetermined causes of death depends on the population, the intervention under investigation, and the disease process. The approach should be prespecified and described in the protocol and other trial documentation such as the endpoint adjudication procedures and/or the statistical analysis plan.