**4. Clinical symptoms and diagnosis**

#### **4.1 Clinical symptoms and physical symptoms**

Clinically, symptoms range from slight problemsfever, pharyngeal pain, cough, vomiting, diarrhea, and arthropathies, as observed with the common coldto severe circulatory failure. Therefore, we cannot list any symptoms characteristic of acute-phase myocarditis. In

Acute Myocarditis in Emergency Medicine 75

Temporal thickening of the ventricular wall and deterioration of ventricular wall motion are present at inflammatory sites. All-round centripetal thickening, diffuse deterioration of wall motion, and stenosis of the intracardiac space are present in typical cases (Hiramatsu et al., 2001). In the cases of severe circulatory failure or fulminant myocarditis, multiple left ventricular thrombi are frequently caused by the deterioration of all-round wall motion. Continuous wall motion dysfunction causes diffuse thinning of the wall and/or ventricular aneurysms, and dilatation of the left ventricle develops. Ultimately, there is no morphological difference from dilated cardiomyopathy. Diagnosis by exclusion of ischemic heart disease is necessary in patients with wall thickening or wall motion deterioration.

Cardiac magnetic resonance (CMR) is a noninvasive, useful examination for myocarditis (JCS, 2011). It can be used to estimate the morphological changes in the ventricles, contractive function, perfusion in the myocardium, and histological characteristics in one performance. In myocarditis, hyperemia and capillary leakage in the cardiac microcirculation are caused by an inflammatory reaction. The site of inflammation in the myocardium has high signal intensity on T1-weighted magnetic resonance imaging (MRI) several minutes after gadolinium contrast enhancement during the acute phase. It is suggested that the changes of microcirculation caused by an inflammatory reaction can be directly visualized with CMR (Friedrich et al., 1998). In many cases, widespread edema in the myocardium is caused during the acute phase. High signal intensity on T2-weighted images is present in 36% of myocarditis diagnosed by the Dallas criteria (Aretz et al., 1987), (Mahrholdt et al., 2004). In those patients, follow-up CMR, performed a year later, shows reduced left ventricular capacity (Zagrosesek et al., 2008). We can predict the histological

Gallium-67 (67Ga) is specific for infiltration of large monocytes, but it does not have high sensitivity (O'Connel et al., 1984). Pyrophosphate scintigraphy using technetium-99m (99mTc) is sensitive and accumulates at the inflammatory site in the myocardium (Morguet et

We perform cardiac catheterization for the differential diagnosis during the acute phase if the patient's circulatory condition can tolerate it. We first exclude significant coronary stenosis by coronary angiography and then perform endomyocardial biopsy (Sekiguchi et al., 1980). The endomyocardial biopsy is now the most important and reliable technique for a definitive diagnosis. However, we often cannot obtain samples of the lesion site because the inflammatory reaction in the myocardium occurs inhomogeneously in most cases (Baughman, 2006). Cooper et al. (2007) reported that cardiac tamponade or ventricular

In cases of suspected viral myocarditis, we measure the antibody titer using paired sera collected at a more than a 2-week interval. The reliable positive ratio is only 10%, and the

**4.5 Echocardiography** 

**4.6 Cardiac magnetic resonance** 

**4.7 Radioisotope examination** 

**4.9 Detection of viruses** 

al., 1994).

changes and prognosis for cardiac function using CMR.

**4.8 Cardiac catheterization and endomyocardial biopsy** 

perforation occurs at the time of sampling with a 0.1%–0.5% frequency.

cases of established cardiac dysfunction, patients suffer from dyspnea, edema, cyanosis, palpitations due to hypoxia or arrhythmia, and other severe symptoms such as loss of consciousness and cramping. Whenever we treat acute-onset patients who present with symptoms of cardiac dysfunction in the ER, we maintain the suspicion that they are in the pre-developmental phase of severe myocarditis.

Among the physical symptoms of myocarditis, dysfunction of the heart's conduction system, which occurs in 60%–80% of patients with myocarditis, is critical. Particularly notable is the 30% incidence of severe bradycardia requiring temporary pacing in those with fulminant myocarditis (Kawamura et al., 1986). A galloping rhythm, a heart murmur caused by backflow in the atrioventricular valves, and pulmonary moist rales are found in patients who are developing heart failure. Pericardial and pleural stridulation can be auscultated in patients with pericarditis or pleuritis. Furthermore, pericardial effusion or cardiac tamponade is observed in some cases of developmental pericarditis.

#### **4.2 Blood examinations**

Inflammatory reactions such as increased WBCs, an increased erythrocyte sedimentation rate (ESR), or an increased C-reactive protein (CRP) level are detected in blood examinations during the early phase. Additionally, creatine kinase MB (CPK-MB) and cardiac troponin T assays, which are elevated in the presence of myocardial damage, are useful. Troponin T sensitivity is particularly high, and the severity of the myocardial damage can be estimated by a fixed quantity analysis (Lauer et al., 1997). Troponin T continuously increases with development of cardiac dysfunction and maintains a high peak value in those with fulminant myocarditis.

#### **4.3 Chest radiography**

Cardiac dilatation is present in 70% of chest radiography examinations, and pulmonary congestion or pleural effusion is often present in patients with severe heart failure. It should be noted that cardiac dilatation and pulmonary congestion are not remarkable in some cases of myocarditis, which causes mainly right ventricular failure (McFalls and van Suylen, 1993).

#### **4.4 Electrocardiography**

Various abnormal changes are revealed by electrocardiography (ECG), although none of the changes are specific for myocarditis. ECG is not an invasive procedure, and it has the benefit of simplicity of performance. The sensitivity is high, and any changes on the ECG tracing probably enhance with the development of myocarditis even if only slight changes are detected during the early phase. ECG should be repeated in the case of suspected myocarditis. Limited elevation of ST-T, mainly observed with acute myocardial infarction (AMI), is present in some patient with myocarditis. Elevation of ST-T in all leads is present in cases complicated by pericarditis. Bundle branch block or atrioventricular block is present in cases complicated by dysfunction of the heart's conduction system. It should be noted that the change to a wide QRS complex on the ECG tracing suggests the development of cardiac dysfunction. Because there is the risk of sudden changes with fatal ventricular tachycardia (VT) or ventricular fibrillation (VF) in the case of frequent arrhythmias, continuous ECG monitoring is necessary.

#### **4.5 Echocardiography**

74 Myocarditis

cases of established cardiac dysfunction, patients suffer from dyspnea, edema, cyanosis, palpitations due to hypoxia or arrhythmia, and other severe symptoms such as loss of consciousness and cramping. Whenever we treat acute-onset patients who present with symptoms of cardiac dysfunction in the ER, we maintain the suspicion that they are in the

Among the physical symptoms of myocarditis, dysfunction of the heart's conduction system, which occurs in 60%–80% of patients with myocarditis, is critical. Particularly notable is the 30% incidence of severe bradycardia requiring temporary pacing in those with fulminant myocarditis (Kawamura et al., 1986). A galloping rhythm, a heart murmur caused by backflow in the atrioventricular valves, and pulmonary moist rales are found in patients who are developing heart failure. Pericardial and pleural stridulation can be auscultated in patients with pericarditis or pleuritis. Furthermore, pericardial effusion or cardiac tamponade is observed in some cases of developmental

Inflammatory reactions such as increased WBCs, an increased erythrocyte sedimentation rate (ESR), or an increased C-reactive protein (CRP) level are detected in blood examinations during the early phase. Additionally, creatine kinase MB (CPK-MB) and cardiac troponin T assays, which are elevated in the presence of myocardial damage, are useful. Troponin T sensitivity is particularly high, and the severity of the myocardial damage can be estimated by a fixed quantity analysis (Lauer et al., 1997). Troponin T continuously increases with development of cardiac dysfunction and maintains a high peak value in those with

Cardiac dilatation is present in 70% of chest radiography examinations, and pulmonary congestion or pleural effusion is often present in patients with severe heart failure. It should be noted that cardiac dilatation and pulmonary congestion are not remarkable in some cases of myocarditis, which causes mainly right ventricular failure (McFalls and van Suylen,

Various abnormal changes are revealed by electrocardiography (ECG), although none of the changes are specific for myocarditis. ECG is not an invasive procedure, and it has the benefit of simplicity of performance. The sensitivity is high, and any changes on the ECG tracing probably enhance with the development of myocarditis even if only slight changes are detected during the early phase. ECG should be repeated in the case of suspected myocarditis. Limited elevation of ST-T, mainly observed with acute myocardial infarction (AMI), is present in some patient with myocarditis. Elevation of ST-T in all leads is present in cases complicated by pericarditis. Bundle branch block or atrioventricular block is present in cases complicated by dysfunction of the heart's conduction system. It should be noted that the change to a wide QRS complex on the ECG tracing suggests the development of cardiac dysfunction. Because there is the risk of sudden changes with fatal ventricular tachycardia (VT) or ventricular fibrillation (VF) in the case of frequent arrhythmias,

pre-developmental phase of severe myocarditis.

pericarditis.

**4.2 Blood examinations** 

fulminant myocarditis.

**4.3 Chest radiography** 

**4.4 Electrocardiography** 

continuous ECG monitoring is necessary.

1993).

Temporal thickening of the ventricular wall and deterioration of ventricular wall motion are present at inflammatory sites. All-round centripetal thickening, diffuse deterioration of wall motion, and stenosis of the intracardiac space are present in typical cases (Hiramatsu et al., 2001). In the cases of severe circulatory failure or fulminant myocarditis, multiple left ventricular thrombi are frequently caused by the deterioration of all-round wall motion. Continuous wall motion dysfunction causes diffuse thinning of the wall and/or ventricular aneurysms, and dilatation of the left ventricle develops. Ultimately, there is no morphological difference from dilated cardiomyopathy. Diagnosis by exclusion of ischemic heart disease is necessary in patients with wall thickening or wall motion deterioration.

#### **4.6 Cardiac magnetic resonance**

Cardiac magnetic resonance (CMR) is a noninvasive, useful examination for myocarditis (JCS, 2011). It can be used to estimate the morphological changes in the ventricles, contractive function, perfusion in the myocardium, and histological characteristics in one performance. In myocarditis, hyperemia and capillary leakage in the cardiac microcirculation are caused by an inflammatory reaction. The site of inflammation in the myocardium has high signal intensity on T1-weighted magnetic resonance imaging (MRI) several minutes after gadolinium contrast enhancement during the acute phase. It is suggested that the changes of microcirculation caused by an inflammatory reaction can be directly visualized with CMR (Friedrich et al., 1998). In many cases, widespread edema in the myocardium is caused during the acute phase. High signal intensity on T2-weighted images is present in 36% of myocarditis diagnosed by the Dallas criteria (Aretz et al., 1987), (Mahrholdt et al., 2004). In those patients, follow-up CMR, performed a year later, shows reduced left ventricular capacity (Zagrosesek et al., 2008). We can predict the histological changes and prognosis for cardiac function using CMR.

#### **4.7 Radioisotope examination**

Gallium-67 (67Ga) is specific for infiltration of large monocytes, but it does not have high sensitivity (O'Connel et al., 1984). Pyrophosphate scintigraphy using technetium-99m (99mTc) is sensitive and accumulates at the inflammatory site in the myocardium (Morguet et al., 1994).

#### **4.8 Cardiac catheterization and endomyocardial biopsy**

We perform cardiac catheterization for the differential diagnosis during the acute phase if the patient's circulatory condition can tolerate it. We first exclude significant coronary stenosis by coronary angiography and then perform endomyocardial biopsy (Sekiguchi et al., 1980). The endomyocardial biopsy is now the most important and reliable technique for a definitive diagnosis. However, we often cannot obtain samples of the lesion site because the inflammatory reaction in the myocardium occurs inhomogeneously in most cases (Baughman, 2006). Cooper et al. (2007) reported that cardiac tamponade or ventricular perforation occurs at the time of sampling with a 0.1%–0.5% frequency.

#### **4.9 Detection of viruses**

In cases of suspected viral myocarditis, we measure the antibody titer using paired sera collected at a more than a 2-week interval. The reliable positive ratio is only 10%, and the

Acute Myocarditis in Emergency Medicine 77

Symptoms that appear with the common cold (fever, headache, cough, pharyngeal

Atrioventricular block, wide QRS complex, reduction of height in R wave, abnormal

Change of ST-T level, low-voltage wave, frequent premature contractions

 *Note*: Troponin T is sensitive using whole blood during the acute phase 6. Items 2–5 (above) change within several hours. Therefore, continuous observation is necessary. Bradycardia, wide QRS complex, frequent premature contractions, enhanced thickening of the ventricular wall and deterioration of ventricular wall motion, and continuous high troponin T levels are dangerous symptoms of fatal

7. A differential diagnosis of acute myocardial infarction (AMI) is necessary.

8. Endocardial biopsy provides a definitive diagnosis, but AMI cannot be excluded if

9. More than four-fold change of viral antibody titer in paired sera is adequate for viral detection. Polymerase chain reaction is effective for diagnosing a viral infection. Additionally, virus isolation or detection of viral antigen from a throat swab, urine, feces, blood, or particularly pericardial effusion or myocardial tissue are direct

Table 3. Guidelines for diagnosing myocarditis. Modified from the guideline for diagnosis

1. Primary symptoms (nonspecific symptoms in most cases)

Others (eruption, arthralgia, myalgia)

3. Abnormality of ECG: various changes

Digestive symptoms (nausea, vomiting, diarrhea, abdominal pain)

*Note*: Some patients are found in sudden cardiac arrest

 Tachycardia, bradycardia, arrhythmia, weak heart sounds Galloping rhythm (III, IV sounds), pericardial friction murmur

 Supraventricular tachycardia, atrial fibrillation, sinus arrest Ventricular tachycardia, ventricular fibrillation, asystole

 Focal or diffuse thickening of the ventricular wall Focal or diffuse deterioration of ventricular wall motion

Inflammatory reaction (increased WBCs, CRP level)

Rupture, fusion, or disappearance of myocardial cells

Edema or fibrotic changes in interstitial tissue

Detection of creatine kinase MB (CPK-MB)

pain)

2. Physical findings

Systolic murmur

4. Echocardiography

 Pericardial effusion 5. Blood examinations

Detection troponin T

circulatory crisis.

tissue images are not obtained. Diagnostic criteria in tissue image: Infiltration of large and small monocytes

evidence of the diagnosis.

and treatment of myocarditis (JCS, 2005).

Stenosis of intracardiac space

Q wave

capability to detect infected organs is not available. A definitive diagnosis is possible if we can directly detect the original viruses using a polymerase chain reaction or in situ hybridization. However, these techniques are not yet approved as standard examinations because their results vary widely depending on the institution in which they are performed.

#### **4.10 Other diagnostic factors**

In cases of suspected drug-induced myocarditis, we narrow down the list of causative drugs by detailed interviews with the patient regarding his or her clinical history. We can then identify the causative drug by a drug-induced lymphocyte stimulation test. Soluble Fas and Fas ligand (Fuse et al., 2000), interleukin-10 (Nishii et al., 2004), and tenascin-C (Imanaka-Yoshida et al., 2002) may be used in upcoming tests for diagnosing myocarditis.

Guidelines for diagnosis are presented in Table 3. The basic concept is to exclude ischemic heart disease and confirm an active lesion site by endomyocardial biopsy. It is currently impossible to detect the cause in most cases. Clinically, it is best to provide the primary care that is given to patients suspected of having myocarditis caused by a viral infection.

### **5. Development and strategy for treatment during the acute phase**

Generally, the clinical conditions of patients are similar in many cases of myocarditis. A toxic protein produced by the infecting virus destroys the myocardial dystrophin complex within several days after onset of the myocarditis. It has been noted that this mechanism causes severe myocardial dysfunction accompanied by widespread myocardial cell death (Bandorff et al., 1999). Silver and Kowaldzuk (1989) reported that viral infection directly causes widespread myocardial ischemia by microvascular spasm.

After the viral infection is established, the immune response produces inflammatory cytokines in large quantities (Fairweather et al., 2005). This cytokine network originally plays a role in prophylaxis against the viral infection. Inflammatory cytokines such as interleukins 1 and 2 and tumor necrosis factor-α eliminate infected viruses by activating macrophages, lymphocytes, and endothelial cells. However, excessive cytokine release damages myocardial cells and causes myocardial dysfunction (Kawai, 1999). Additionally, inducible nitric oxide (NO) synthase (iNOS) induced by activated macrophages acts to encourage NO to eliminate infected viruses. It has been reported that excessive release of NO strongly damages myocardial cells (Mikami et al., 1996).

Infiltration by inflammatory cells, including T cells and natural killer cells, peaks 7–14 days after viral infection and causes widespread necrosis of myocardial cells (Seko et al., 1993). As already noted, infected virus and released inflammatory cytokines are the main mechanisms in the development of myocardial dysfunction during the acute phase. Severe deciduation of myocardial cells causes pump failure, which progresses to fatal circulatory collapse.

It is important to remember that cardiac dysfunction associated with myocarditis is reversible in many cases. Full recovery of cardiopulmonary function can be expected if the patient's life support is adequately performed. Therefore, we compress the strategy for treatment into three stages to give patients suffering from myocarditis the best chance for survival.

In most cases, the first strategic issue is intervention regarding the cause. Unfortunately, it is impossible to provide antibiotic therapy because effective antiviral drugs to address viral myocarditis have not been developed. There is a risk of further viral propagation when

	- *Note*: Some patients are found in sudden cardiac arrest

capability to detect infected organs is not available. A definitive diagnosis is possible if we can directly detect the original viruses using a polymerase chain reaction or in situ hybridization. However, these techniques are not yet approved as standard examinations because their results vary widely depending on the institution in which they are performed.

In cases of suspected drug-induced myocarditis, we narrow down the list of causative drugs by detailed interviews with the patient regarding his or her clinical history. We can then identify the causative drug by a drug-induced lymphocyte stimulation test. Soluble Fas and Fas ligand (Fuse et al., 2000), interleukin-10 (Nishii et al., 2004), and tenascin-C (Imanaka-

Guidelines for diagnosis are presented in Table 3. The basic concept is to exclude ischemic heart disease and confirm an active lesion site by endomyocardial biopsy. It is currently impossible to detect the cause in most cases. Clinically, it is best to provide the primary care

Generally, the clinical conditions of patients are similar in many cases of myocarditis. A toxic protein produced by the infecting virus destroys the myocardial dystrophin complex within several days after onset of the myocarditis. It has been noted that this mechanism causes severe myocardial dysfunction accompanied by widespread myocardial cell death (Bandorff et al., 1999). Silver and Kowaldzuk (1989) reported that viral infection directly

After the viral infection is established, the immune response produces inflammatory cytokines in large quantities (Fairweather et al., 2005). This cytokine network originally plays a role in prophylaxis against the viral infection. Inflammatory cytokines such as interleukins 1 and 2 and tumor necrosis factor-α eliminate infected viruses by activating macrophages, lymphocytes, and endothelial cells. However, excessive cytokine release damages myocardial cells and causes myocardial dysfunction (Kawai, 1999). Additionally, inducible nitric oxide (NO) synthase (iNOS) induced by activated macrophages acts to encourage NO to eliminate infected viruses. It has been reported that excessive release of

Infiltration by inflammatory cells, including T cells and natural killer cells, peaks 7–14 days after viral infection and causes widespread necrosis of myocardial cells (Seko et al., 1993). As already noted, infected virus and released inflammatory cytokines are the main mechanisms in the development of myocardial dysfunction during the acute phase. Severe deciduation of myocardial cells causes pump failure, which progresses to fatal circulatory

It is important to remember that cardiac dysfunction associated with myocarditis is reversible in many cases. Full recovery of cardiopulmonary function can be expected if the patient's life support is adequately performed. Therefore, we compress the strategy for treatment into three stages to give patients suffering from myocarditis the best chance for

In most cases, the first strategic issue is intervention regarding the cause. Unfortunately, it is impossible to provide antibiotic therapy because effective antiviral drugs to address viral myocarditis have not been developed. There is a risk of further viral propagation when

Yoshida et al., 2002) may be used in upcoming tests for diagnosing myocarditis.

that is given to patients suspected of having myocarditis caused by a viral infection.

**5. Development and strategy for treatment during the acute phase** 

causes widespread myocardial ischemia by microvascular spasm.

NO strongly damages myocardial cells (Mikami et al., 1996).

collapse.

survival.

**4.10 Other diagnostic factors** 

	- *Note*: Troponin T is sensitive using whole blood during the acute phase

Table 3. Guidelines for diagnosing myocarditis. Modified from the guideline for diagnosis and treatment of myocarditis (JCS, 2005).

Acute Myocarditis in Emergency Medicine 79

Fig. 1. Modified algorithm of PCPS for fulminant myocarditis (Aoyama et al, 2002).

metabolic acidosis, and multiple organ dysfunction suggested by blood chemistry examinations. The initial flow of PCPS should be established at 3.0–3.5 L/min. Concomitant use of intra-aortic balloon pumping (IABP) provides the benefits of reduced afterload,

administering anti-inflammatory drugs such as immunosuppressants and steroids. On the other hand, we can expect to reverse cardiac dysfunction by initially giving antiinflammatory drugs because it has been reported that allergic and autoimmune reactions strongly participate in the development of the giant cell myocarditis and eosinophilic myocarditis, both unusual forms. Therefore, early and adequate ascertainment of the cause is the maximum priority. Presently, the performance of myocardial biopsy is limited. Steroids should not be selected as a first choice even if the patient is in a shock state.

The second issue is to provide cardiopulmonary support during continuing fatal circulatory failure. During the acute phase of severe myocarditis, there is the risk of cardiogenic shock, complete atrioventricular block, fatal arrhythmia, and/or sudden cardiac arrest at any time. Therefore, most patients require intensive care. Drug therapy for myocarditis is no different from that for usual heart failure. Catecholamines, a diuretic, or both are administered following Forrester's classification. Mechanical cardiopulmonary life support should be immediately introduced when the circulatory insufficiency cannot be reversed with drugs. Full recovery of cardiac function is expected by advanced life support within several days in patients with acute myocarditis.

The third issue is to control the inflammatory reaction. If the actions of excessive inflammatory cytokines and NO are reduced, cardiac dysfunction is expected to be reversed during the acute phase. Although treatment using high doses of steroid, high doses of γglobulin, and plasma exchange have been tried and evaluated, we have no evidence of their effectiveness.

#### **5.1 Cardiopulmonary support**

Immediate cardiac resuscitative support must be provided if the patients with fulminant myocarditis are to survive. Delay of treatment results in fatal circulatory collapse. Although the short-term mortality rate for fulminant myocarditis is generally high, the long-term functional prognosis for patients who survive the acute circulatory crisis is good compared with that for dilated cardiomyopathy (McCarthy et al., 2000).

The Scientific Committee of the Japanese Circulation performed a retrospective follow-up survey on severe fulminant myocarditis (Aoyama et al., 2002). The cases of 52 patients who required percutaneous cardiopulmonary support (PCPS) because of severe circulatory failure were investigated. The mortality rate for the acute phase was 40.4% (21/52). Among the 31 surviving patients, 30 (96.8%) had fully recovered from their cardiac dysfunction. McCarthy et al. (2000) noted that cardiac function had been maintained in good condition for a long time in more than 90% of patients who had recovered from fulminant myocarditis. Therefore, the "bridge" treatment of using mechanical cardiopulmonary support to avoid multiple organ dysfunction caused by hypoperfusion is an important treatment strategy during the acute phase of fulminant myocarditis. Patients who have survived on mechanical support, such as percutaneous cardiopulmonary support or a ventricular assist system, have also been reported (Chen et al, 2005), (Topkara et al., 2006).

#### **5.1.1 Percutaneous cardiopulmonary support**

A guideline for the use of percutaneous cardiopulmonary support (PCPS) has been formulated in Japan (Fig. 1) (Aoyama et al., 2002). In suspected cases of low cardiac output due to pump dysfunction, we may apply PCPS in accordance with continuous monitoring of the circulatory condition. Important clinical parameters to examine when making the decision of whether to use PCS include the urinary volume, SvO2 (< 60%), development of

administering anti-inflammatory drugs such as immunosuppressants and steroids. On the other hand, we can expect to reverse cardiac dysfunction by initially giving antiinflammatory drugs because it has been reported that allergic and autoimmune reactions strongly participate in the development of the giant cell myocarditis and eosinophilic myocarditis, both unusual forms. Therefore, early and adequate ascertainment of the cause is the maximum priority. Presently, the performance of myocardial biopsy is limited.

The second issue is to provide cardiopulmonary support during continuing fatal circulatory failure. During the acute phase of severe myocarditis, there is the risk of cardiogenic shock, complete atrioventricular block, fatal arrhythmia, and/or sudden cardiac arrest at any time. Therefore, most patients require intensive care. Drug therapy for myocarditis is no different from that for usual heart failure. Catecholamines, a diuretic, or both are administered following Forrester's classification. Mechanical cardiopulmonary life support should be immediately introduced when the circulatory insufficiency cannot be reversed with drugs. Full recovery of cardiac function is expected by advanced life support within several days in

The third issue is to control the inflammatory reaction. If the actions of excessive inflammatory cytokines and NO are reduced, cardiac dysfunction is expected to be reversed during the acute phase. Although treatment using high doses of steroid, high doses of γglobulin, and plasma exchange have been tried and evaluated, we have no evidence of their

Immediate cardiac resuscitative support must be provided if the patients with fulminant myocarditis are to survive. Delay of treatment results in fatal circulatory collapse. Although the short-term mortality rate for fulminant myocarditis is generally high, the long-term functional prognosis for patients who survive the acute circulatory crisis is good compared

The Scientific Committee of the Japanese Circulation performed a retrospective follow-up survey on severe fulminant myocarditis (Aoyama et al., 2002). The cases of 52 patients who required percutaneous cardiopulmonary support (PCPS) because of severe circulatory failure were investigated. The mortality rate for the acute phase was 40.4% (21/52). Among the 31 surviving patients, 30 (96.8%) had fully recovered from their cardiac dysfunction. McCarthy et al. (2000) noted that cardiac function had been maintained in good condition for a long time in more than 90% of patients who had recovered from fulminant myocarditis. Therefore, the "bridge" treatment of using mechanical cardiopulmonary support to avoid multiple organ dysfunction caused by hypoperfusion is an important treatment strategy during the acute phase of fulminant myocarditis. Patients who have survived on mechanical support, such as percutaneous cardiopulmonary support or a ventricular assist system, have also been reported (Chen et al, 2005), (Topkara et al., 2006).

A guideline for the use of percutaneous cardiopulmonary support (PCPS) has been formulated in Japan (Fig. 1) (Aoyama et al., 2002). In suspected cases of low cardiac output due to pump dysfunction, we may apply PCPS in accordance with continuous monitoring of the circulatory condition. Important clinical parameters to examine when making the decision of whether to use PCS include the urinary volume, SvO2 (< 60%), development of

Steroids should not be selected as a first choice even if the patient is in a shock state.

patients with acute myocarditis.

**5.1 Cardiopulmonary support** 

with that for dilated cardiomyopathy (McCarthy et al., 2000).

**5.1.1 Percutaneous cardiopulmonary support** 

effectiveness.

Fig. 1. Modified algorithm of PCPS for fulminant myocarditis (Aoyama et al, 2002).

metabolic acidosis, and multiple organ dysfunction suggested by blood chemistry examinations. The initial flow of PCPS should be established at 3.0–3.5 L/min. Concomitant use of intra-aortic balloon pumping (IABP) provides the benefits of reduced afterload,

Acute Myocarditis in Emergency Medicine 81

Fig. 3. Echocardiography shows pericardial effusion and deterioration of the all-round wall

pericardial effusion

There is the risk of severe pulmonary congestion due to PCPS in cases of extreme deterioration of left ventricular function. In such cases, the patient should be switched to a ventricular assist system (VAS) before organ dysfunction develops. Grinda et al. (2004) reported that they introduced VAS in five cases of severe fulminant myocarditis and obtained good outcomes. Recently, the clinical effectiveness of modified VAS using an extracorporeally established centrifugal pump was advocated by John et al. (2007) in the United States. Modified VAS has combined the advantages of minimally invasive

Generally, the time limit for continuous mechanical circulatory support, including PCPS or VAS, is approximately 1 week. We withdraw the system even if recovery from circulatory failure is incomplete. In such cases, introduction of immunoregulation therapy is discussed. Many case reports have asserted the effectiveness of immunoregulation therapy. Although there is no established evidence, we believe that immunoregulation is acceptable in

The effectiveness of high-dose γ-globulin was reported by Takada et al. (1995). It is expected that γ-globulin counteracts the actions of the infective viruses and reduces suppression of cardiac function by inflammatory cytokines during the acute phase. γ-Globulin intensifies patients' immune competence, and therefore complications, such as an infection compromised by steroid administration, do not take hold. The mechanisms of high-dose administration have not been completely clarified, although several hypotheses have been suggested: (1) it functions as a neutralizing antibody; (2) it has an anti-inflammatory effect, reducing the release of inflammatory cytokines induced by a combination of the Fc part of γglobulin and the suppressive Fc receptor of macrophages; and (3) it has the effect of antiactivation on activated complement (Rosen, 1993). However, it is not strongly recommended because there is no evidence that has been confirmed by large clinical trials. Finally, cardiac

motion of the left ventricle.

**5.1.2 Ventricular assist system** 

**5.2 Immunoregulation therapy** 

**5.2.1 High-dose γ-globulin** 

extracorporeal membrane oxygenation and high efficiency.

function has not recovered in several cases with its use.

intractable cases because no radical treatments are presently available.

improved peripheral circulation by pulsatile flow, and backup support at the completion of PCPS. It is recommended that a branched cannula be established in the distal side of the femoral artery for blood transfusion because there is a risk of ischemia in the lower limb.

Unfortunately, we occasionally experience patients in severe situations in whom sufficient organ perfusion cannot be provided even if PCPS is fully operative. Aoyama et al. (2002) reported that 40% of patients supported by PCPS died during the acute phase. Among them, multiple organ dysfunction due to hypoperfusion was found in 25% and ischemia in the lower limb in 23%. Because the prognosis of fulminant myocarditis depends on the outcome of radical treatment of the circulation, we discuss early exchange via a ventricular assist system when sufficient organ perfusion cannot be provided by PCPS.

**Case report:** We treated a patient with severe fulminant myocarditis who survived owing to emergency PCPS. The young woman consulted her family doctor because of fever and was prescribed anti-inflammatory drugs with a diagnosis of pharyngitis. She was admitted to our hospital because of sudden severe circulatory failure that required high-flow oxygenation and high doses of catecholamine. Blood examination showed an elevation in troponin I, CPK, and other cardiac enzymes. Chest radiography showed marked cardiac dilatation and pleural effusion (Fig. 2). Echocardiography revealed pericardial effusion and deterioration of all-round wall motion of the left ventricle (Fig. 3). No significant coronary stenosis was detected by coronary angiography. We introduced emergency PCPS with IABP because her left ventricular ejection fraction was decreased by less than 20%. Her circulatory condition dramatically recovered, and she was weaned from PCPS on the 10th day. She obtained full recovery of her circulatory function. We could not detect any viruses when measuring the antibody titer using paired sera.

Fig. 2. Chest radiography shows marked cardiac dilatation and pleural effusion.

improved peripheral circulation by pulsatile flow, and backup support at the completion of PCPS. It is recommended that a branched cannula be established in the distal side of the femoral artery for blood transfusion because there is a risk of ischemia in the lower limb. Unfortunately, we occasionally experience patients in severe situations in whom sufficient organ perfusion cannot be provided even if PCPS is fully operative. Aoyama et al. (2002) reported that 40% of patients supported by PCPS died during the acute phase. Among them, multiple organ dysfunction due to hypoperfusion was found in 25% and ischemia in the lower limb in 23%. Because the prognosis of fulminant myocarditis depends on the outcome of radical treatment of the circulation, we discuss early exchange via a ventricular assist

**Case report:** We treated a patient with severe fulminant myocarditis who survived owing to emergency PCPS. The young woman consulted her family doctor because of fever and was prescribed anti-inflammatory drugs with a diagnosis of pharyngitis. She was admitted to our hospital because of sudden severe circulatory failure that required high-flow oxygenation and high doses of catecholamine. Blood examination showed an elevation in troponin I, CPK, and other cardiac enzymes. Chest radiography showed marked cardiac dilatation and pleural effusion (Fig. 2). Echocardiography revealed pericardial effusion and deterioration of all-round wall motion of the left ventricle (Fig. 3). No significant coronary stenosis was detected by coronary angiography. We introduced emergency PCPS with IABP because her left ventricular ejection fraction was decreased by less than 20%. Her circulatory condition dramatically recovered, and she was weaned from PCPS on the 10th day. She obtained full recovery of her circulatory function. We could not detect any viruses when

system when sufficient organ perfusion cannot be provided by PCPS.

Fig. 2. Chest radiography shows marked cardiac dilatation and pleural effusion.

pleural effusion

measuring the antibody titer using paired sera.

Fig. 3. Echocardiography shows pericardial effusion and deterioration of the all-round wall motion of the left ventricle.
