Hand, foot and mouth disease (HFMD) is a common infectious disease caused by a variety of enteroviruses, mainly in infants and children. It is mainly transmitted through close contact or fecal-oral transmission, and is typically manifested by rashes, herpes and ulcers on the skin and mucous membranes of the hands, feet and mouth. HFMD is not a new infectious disease, but has been prevalent in many countries and regions since it was first reported in 1957. 2006, the World Health Organization announced that HFMD ranks fourth in the incidence of notifiable diseases (statutory infectious diseases) (19.3 per 100,000 population); the disease can occur year-round, with a high incidence in summer and autumn in China, and is a common pediatric infectious disease that is preventable, treatable and has a good prognosis. It is a common pediatric infectious disease with good prognosis. Since May 2, 2008, the Ministry of Health of the People’s Republic of China has classified this disease as a Class C infectious disease.
As a common and frequent pediatric infectious disease, HFMD has a variety of pathogens, all of which are single-stranded positive-stranded RNA viruses, small RNA virus family, enterovirus genus. According to the antigenic structure and host range, human enteroviruses can be divided into four categories: polioviruses, coxsackieviruses, echoviruses and emerging enteroviruses; coxsackieviruses can be further divided into two groups, A and B, according to the differences in foci after infection of mammary rats; group A has 24 serotypes and group B has 6 serotypes; echoviruses contain 30 serotypes; emerging enteroviruses include enterovirus types 68 to 71. Among the enteroviruses causing HFMD are enterovirus 71, coxsackievirus and some serotypes of echovirus, such as Cox A16, A4, A5, A9, A10, B2, B5, B13 and echovirus 11. Most patients with HFMD have mild symptoms, but a few patients may have life-threatening complications such as aseptic meningitis, encephalitis, acute flaccid paralysis, respiratory tract infection and myocarditis, etc. Early diagnosis and timely management of children with severe HFMD is the key to successful rescue. The early warning and complication management of severe hand, foot and mouth disease are discussed below with our experience in treating severe hand, foot and mouth disease.
1, early manifestation of severe HFMD
The incubation period of HFMD is generally 3-7 d, and most patients have a sudden onset of disease. About half of the patients have fever, mostly around 38 ℃, 1 to 2 d before the onset or at the same time. The rash has the following characteristics: (1) four parts: invasion of the hands, feet, mouth and buttocks; (2) four unlike: the rash is unlike mosquito bites, unlike drug rash, unlike oral and gingival herpes, and unlike chicken pox; (3) four uncharacteristic features: no pain, no itching, no crusting, and no scarring. Oral mucosal rash appears relatively early, initially as corn-like papules or blisters surrounded by a red halo, mainly located on the tongue and both cheeks, and often occurs on the side of the lips and teeth, which can affect eating. Typical HFMD is generally not difficult to diagnose clinically based on the rash, but during the epidemic season, for children with an atypical rash or no obvious rash, detailed information on the local epidemiology of HFMD is necessary. If children in HFMD endemic areas show the following multi-organ system involvement within a short period of time, regardless of the presence or absence of a typical rash, they must be taken seriously and undergo enteroviral pathogenesis, dynamic chest X-ray, electrocardiogram and other examinations to clarify the diagnosis and deal with them in a timely manner.
1.1 Neurological system: poor mental health, drowsiness, vomiting, easy to startle, jumping, irritability, mania, delirium, limb tremors, myoclonus, muscle weakness or limb paralysis; physical examination reveals meningeal irritation, tendon reflexes are hyper or weak, or even disappear; critical cases may show frequent convulsions, coma, acute cerebral edema, brain herniation, etc.
1.2 Respiratory system: shallow and difficult breathing, altered respiratory rhythm, cyanosis of lips and mouth, white, pink or bloody foam (sputum), and wet rales can be heard in the lungs.
1.3 Circulatory system: pale face, increased or slow heart rate, increased pulse (flooded pulse), shallow speed, weakened or even disappeared, wet and cold extremities, cyanosis and marbling of skin and fingers (toes), prolonged capillary filling time, increased or decreased blood pressure.
1.4 Other system corresponding symptoms such as gastrointestinal bleeding, liver and kidney function impairment, etc.
2.Characteristics of severe cases of HFMD
Most of the severe cases of HFMD occurred at the age of mostly less than 3 years old. In 2008, 73.1% of the boys and 26.9% of the girls2 were hospitalized with HFMD cases in our hospital. The average age was 2.3 years, the oldest age was 5 years and 7 months, and the youngest age was 6 months. The number of cases with persistent high fever for more than 3 days accounted for 91.0% of the total cases, of which the longest fever was 12 days and the shortest was 1 day; the number of cases with poor peripheral circulation and capillary filling time >3 seconds accounted for 26.9%; the number of cases with significant increase in respiration and heart rate accounted for 73.8%; the number of cases with hypertension or hypotension accounted for 31.3%; the number of cases with complaints of agitation accounted for 12.8% of the total cases, of which the longest agitation time was 2 days and the shortest was 2 hours The number of cases of limb tremors accounted for 35.9% of the total number of cases, of which the longest duration of tremors was 5 days and the shortest was half a day; the number of cases of clear consciousness accounted for 88.5%; the number of cases of blurred consciousness accounted for 9.0%; the number of cases of drowsiness accounted for 1.3%; the number of cases of neck block accounted for 12.9%; the number of cases of weak knee reflex accounted for 1.3% and the number of cases of hyperactivity accounted for 38.5%; the number of cases of positive Bartholin’s sign accounted for 15.4%. The number of cases of hyperglycemia accounted for 78.6%; chest radiograph: it can show an increase in the texture of both lungs, grid-like, dot-like and large shadows, some cases are unilateral, and rapidly progress to large bilateral shadows. Cerebrospinal fluid examination: clear appearance, increased pressure, normal or increased leukocytes, normal or mildly increased protein, normal sugar and chloride; EEG: no specific changes, can be manifested as diffuse slow waves, a few can appear spike (spike) slow waves, EEG positive cases accounted for 14.1%; transcranial multispectral emission: the number of cases showing abnormal blood perfusion in the brain accounted for 44.6%; brainstem BAEP (brainstem evoked potential): 10.3% of left-sided abnormalities, 5.2% of right-sided abnormalities, 20.7% of bilateral abnormalities; ECG: no specific changes, sinus tachycardia or bradycardia, ST-T changes, etc., 17.9% of EKG positive; pathogenic examination: specific enterovirus nucleic acid positive or isolation of enterovirus.
3. Early warning signs of severe HFMD
According to the definition of severe disease in the 2008 edition of the Ministry of Health Guidelines for the Prevention and Control of Hand, Foot and Mouth Disease, combined with the manifestation of severe disease in our hospital, we divided children with severe disease into the following three levels of early warning.
3.1 First-level warning: one of the following signs and symptoms: (1) papules or herpes on both hands and feet; (2) herpes or ulcers on the oral mucosa; (3) herpetic pharyngitis.
3.2 Secondary warning: children with a history of fever or a temperature ≥38°C and one or more of the following symptoms: (1) toxic appearance of infection; (2) recurrent vomiting at least 2 times; (3) heart rate ≥150 beats/min; (4) altered respiratory rhythm; (5) poor circulation with capillary filling time >2 seconds; (6) altered mental consciousness: delirium, drowsiness, lethargy, startle, jumping, irritability (7) limb tremors, myoclonus, muscle weakness or limb paralysis; (8) convulsions.
3.3 Tertiary warning: the above warning signs combined with cerebrospinal fluid examination: cerebrospinal fluid leukocyte count >5/ul, suggesting central nervous system complications; chest X-ray examination: increased texture of both lungs, exudative lesions such as grid, dotted, and large lamellar shadows suggest respiratory system complications. Children with secondary warning need to be closely monitored for changes in their condition. Once the child has a tertiary warning, he or she should be admitted to the intensive care unit for timely management.
4. Diagnosis and management of complications of severe HFMD
4.1 Diagnosis and management of neurological complications
If a patient with severe HFMD develops headache, vomiting, mental changes, enlarged head circumference, widened fontanelle, fullness, increased muscle tone of the limbs, indistinct margins of optic nerve papillae, congestion, dilated retinal vessels or hemorrhage, and other signs and symptoms of intracranial hypertension such as changes in respiratory rhythm, closely observe the changes in condition, closely monitor, pay attention to serious complications, and actively reduce intracranial pressure and reduce cellular edema in case of cranio-cerebral injury. Reduce intracranial pressure and cellular edema.
4.1.1 General treatment: (1) control the amount of fluid intake to supplement the physiological requirements; (2) ensure the ventilation of the airway, SPO2 must be maintained > 93%, MBP must be maintained > 65 mmHg; (3) elevate the body position 15-30 degrees, head back 15 degrees; (4) cooling: physical or chemical cooling, maintain the body temperature at about 36 ℃, if the temperature control is not good, the use of sub-low temperature (5) Sedation and anti-stunning: Valium 0.1~0.3 mg/kg/time or luminal 4~6 mg/kg/d.
4.1.2 Active control of intracranial hypertension: give 20% mannitol 2~5ml/kg?times, once every 3~6 hours, 20~30min intravenously, adjust the dosing interval and dose according to the condition, review the urine routine regularly, pay attention to renal function damage, and reduce or stop the dose if hematuria occurs. If necessary, add tachyphylaxis (1~2mg/kg?times) or alternate with 20% mannitol. After dehydration treatment, 3% NaCl: 2~3ml/kg?times can be given. Pay attention to dynamic observation of body fluid osmolality, maintain osmolality between 285~310mOsm/Kg and maintain blood sodium 140~145mmol/L to reduce brain cell edema and protect brain cells.
4.1.3 Application of glucocorticoid therapy: methylprednisolone at a general dose of 5-10 mg/kg?d, with an optional shock dose of 10-20 mg/kg?d according to the condition; dexamethasone 0.2-0.5 mg/kg?d, divided into 1 or 2 doses can also be used. Pay attention to the protection of gastrointestinal mucosa and dynamic fecal occult blood examination.
4.1.4 Other treatment: intravenous immunoglobulin, total 1 g/kg?d x 2 days.
4.2 Diagnosis and management of respiratory complications
The complications of most of the severe patients with HFMD (especially EV71 infection) mainly involve the nervous system, resulting in neurogenic pulmonary edema (NPE), which refers to pulmonary edema secondary to acute central nervous system injury, also known as brain-derived pulmonary edema, central pulmonary edema, etc. Severely ill children often have sudden onset of cardiac tachycardia within 1 Sudden onset of tachycardia, dyspnea, cyanosis, and shock within 3 days, with bilateral symmetric non-cardiogenic pulmonary edema on chest radiograph. The child rapidly develops pulmonary edema and pulmonary hemorrhage and dies. It is generally accepted that hyperglycemia, elevated leukocytes, and acute delayed paralysis together constitute a high risk factor for the development of neurogenic pulmonary edema in HFMD.
4.2.1 Clinical manifestations of NPE: (1) rapid onset; (2) mild symptoms: irritability, rapid heart rate, chest tightness, fine wet rales in both lungs; severe symptoms: shortness of breath, coughing white or bloody foamy sputum, hemoptysis, pale skin, wet and cold, and sense of dying. (3) Blood gas analysis: PaO2 decreases and PaCO2 increases; (4) Chest X-ray indicates alveolar pulmonary edema: alveolar dense shadows with different shapes and sizes, which can be fused into sheets and gradually fade from inside to outside on both sides of the pulmonary hilum, forming a butterfly shape.
4.2.2 Diagnosis of NPE: With the exclusion of cardiac and pulmonary origin diseases, and without misaspiration or too rapid and excessive infusion, when progressive acceleration of respiratory rate and progressive decrease of oxygenation index (PaO2/FiO2) are found, the occurrence of NPE should be thought of, especially in children with hand, foot and mouth disease. The diagnosis is confirmed when PaO2/FiO2≤300.
4.2.3 Treatment of NPE (1) maintain a patent airway, adequate oxygen supply and mechanical ventilation therapy, and correct hypoxemia; (2) closely monitor vital signs; (3) keep the child sedated, prevent and control infection; (4) appropriately restrict fluid while maintaining normal circulation; (5) elevate the head 15 degrees and maintain a neutral position; insert a gastric tube, catheterize, and prohibit all kinds of unnecessary stimulation. (6) Reduce intracranial pressure: consider the use of 20% mannitol, tachypnea, glucocorticoids, albumin, drainage, etc.; (7) adequate oxygenation and mechanical ventilation therapy: timely tracheal intubation using positive pressure mechanical ventilation will save the child’s life to the maximum. Dynamic chest X-ray examination with signs of pulmonary edema (especially note that it often occurs first on the right side) should be timely tracheal intubation and mechanical ventilation. Initial ventilator parameters: 80% to 100% oxygen concentration, PIP 20-30 cmH2O, PEEP 4-8 cmH2O, f 20-40 times/min, tidal volume 6-8 ml/kg. In children with pulmonary edema, PEEP can be as high as 12 cmH2O under close monitoring and guaranteed tidal volume, and later ventilator parameters can be adjusted at any time according to blood gases. Children with pulmonary hemorrhage who are mechanically ventilated should minimize the time and number of airway cleanings to reduce various stimuli under the condition of ensuring airway patency. (8) NPE cardiovascular drug application: phosphodiesterase inhibitor milrinone is preferred to adjust sympathetic excitability and reduce inflammatory cytokine production such as IL-13, usage: 0.35~0.40ug/kg?min maintenance. Use with caution in cases of marked hypotension and tachycardia.
4.3 Diagnosis and management of circulatory system complications
If there is sudden onset of shortness of breath, pallor, cyanosis, cold sweat, rapid heart rate, vomiting of white or pink bloody foamy sputum, increased pulmonary rales, abnormal blood pressure, low urine, irritability, more pulmonary blood on chest X-ray or pulmonary edema on top of the original disease, be highly alert to combined heart failure and myocarditis.
4.3.1 Diagnosis of myocarditis: Myocarditis can be of viral or toxic etiology, but hand, foot and mouth disease is mostly considered as viral myocarditis. Clinical diagnosis based on: (1) cardiac insufficiency, cardiogenic shock or cardio-cerebral syndrome; (2) cardiac enlargement (X-ray, echocardiography has one of the manifestations); (3) electrocardiographic changes: ST changes in 2 or more major leads (Ⅰ, Ⅱ, avf, V5) dominated by R waves for more than 4 days with dynamic changes, sinus atrial, atrioventricular block, complete right or left bundle branch block (2) Ectopic tachycardia caused by non-atrial nodes and atrioventricular folding, low voltage and abnormal Q waves; (4) elevated CK-MB or positive cardiac troponin.
4.3.2 Diagnosis of heart failure: (1) shortness of breath: infant > 6O beats/min, toddler > 5O beats/min, child > 4O beats/min; (2) tachycardia: infant > 160 beats/min, toddler > 14O beats/min, child > 12O beats/min; (3) heart enlargement (physical examination, X-ray or echocardiogram); (4) irritability, feeding difficulties, weight gain, dysuria, edema excessive sweating, cyanosis, choking, paroxysmal dyspnea (two or more). A diagnosis of heart failure can be confirmed by having four of the above plus the next one or two of the above plus the next two. (1) enlarged liver, >3 cm below the right rib cage in infants, >1 cm in children, progressive enlargement with pressure pain is more meaningful; (2) pulmonary edema; (3) gallop rhythm.
4.3.3 Echocardiography: Ejection fraction, short-axis shortening rate, cardiac index, and ventricular systolic time interval are the most commonly used indicators of cardiac systolic function. Echocardiography not only understands the cardiovascular anatomy, myocardial activity, valve function, and can estimate pulmonary artery pressure, but also has important value for the diagnosis of heart failure and the treatment of heart failure and its prognosis.
4.3.4 Treatment: Identify the cause, correct it, replenish the volume (preload), use positive inotropic drugs (improve myocardial contractility), reduce peripheral resistance (afterload), and maintain an appropriate heart rate and normal rhythm as the key.
(1) Rapid establishment of circulatory monitoring (HR, BP, peripheral circulation, urine volume, central venous pressure), and echocardiographic cardiac function measurement.
(2) General management: pay attention to rest, take semi-sitting position; sedation; keep fresh air in the room, constant room temperature (25~26℃), and control ambient humidity at about 70%.
(3) Restrict water and sodium, enter fluid volume 60~80ml/kg.d, maintain certain blood volume. Ensure that calories are at least 70 Kcal/kg.d (130-140 calories/kg.d), eat easily digestible and absorbable food, and have small and frequent meals.
(4) Respiratory management: strengthen respiratory care and keep the respiratory tract unobstructed. For those with shortness of breath, administer oxygen by warm and humidified mask. If PaCO2 increases rapidly and PaO2 decreases within a short time, use ventilator mechanical ventilation.
(5) Acid-base balance: Correct concurrent water and electrolyte disorders and acid-base imbalance. Prevent and treat hypoglycemia and correct anemia.
(6) Treatment of etiology and comorbidities: If there is a combination of pneumonia, it is advisable to control the infection as soon as possible. In addition, children with myocarditis and heart failure can be combined with arrhythmia and cardiogenic shock, which need to be corrected in time.
(7) When combined with infectious shock when the preload is not enough can be transfused: whole blood, plasma, albumin and other colloidal and crystalloid fluids (such as, saline, sodium bicarbonate, etc.), central venous pressure <15cmH2O.
(8) the application of digitalis class of drugs: hand, foot and mouth disease when heart failure is selected, but pay attention to when combined with myocarditis (whether viral or toxic) or severe heart failure, digitalis dosage should be reduced to 1/2 to 2/3, and close observation of the child’s reaction, the clinical does not have to saturate the amount, lesser doses can also play a corresponding role. Cedilanid: chemical amount: 0.02 mg/kg, diluted in three times and slowly injected intravenously, the first time with 1/2 to 1/3 amount, the remaining amount in two times. The maintenance dose was started 12 hours after the last dose, and the daily maintenance dose was 1/4 of the chemical dose, divided into 2 oral or intravenous doses (i.e. 1/8 of the chemical dose, q12h).
Closely observe heart rate changes and discontinue when the heart rate is <90-100 beats/min in infants and <60-70 beats/min in children. The amount of digitalis treatment is very close to the amount of poisoning, and poisoning is very likely to occur. Once digitalis poisoning is detected, stop digitalis and give potassium-depleting diuretics immediately.
(9) According to the different types of arrhythmia or conduction block, use the appropriate drug treatment, such as the emergence of severe ventricular arrhythmia can be intravenous slow phenytoin sodium 2-4mg/(kg.times) or lidocaine 1mg/(kg.times). 5-10 minutes later can be repeated. Cardiotrope can also be used to control atrial and ventricular tachycardia.
(10) For symptoms of atrioventricular block toxicity, isoproterenol 0.15-0.2 μg/(kg? min) intravenously, or atropine 0.01-0.035 mg/(kg? min) intravenously.
(11) Diuretics: urine volume of 2.5~3ml/(kg.h) is most appropriate. When diuretics are used, care should be taken to maintain proper blood volume, which is necessary to maintain compensatory cardiac function. If the heart rate increases and blood pressure decreases after a large amount of diuresis, it may be a sign of insufficient blood volume. Diuretics may produce electrolyte and acid-base imbalance, so attention should be paid to monitoring during the use of drugs.
(12) Other cardiac drugs: dobutamine: 5 ug/kg?min; dobutamine: 2~5ug/(kg.min); isoproterenol 0.01~0.05ug/kg?min; epinephrine doses generally range from 0.01~0.05ug/kg?min. The above drugs must be used in the ICU when closely monitoring heart rate and blood pressure, monitoring. EKG, HR, BP, urine output, and adjust the dose if necessary.
(13) Selection of vasodilators: pay attention to the adequacy of blood volume, closely observe the efficacy and blood pressure, and decide the medication according to the hemodynamic changes of the child: ① For those with severe pulmonary stasis, significantly increased pulmonary capillary pressure, and mild to moderate decrease in cardiac output, small venodilators such as nitroglycerin (0.5-1μg/kg?min, gradually increase the dose, the maximum does not exceed 20μg/kg? min), nitrates. ② For significantly lower cardiac output, increased systemic vascular resistance and normal or slightly elevated pulmonary capillary pressure, small artery dilators such as phentolamine (2.5-5ug/kg?min), angiotensin converting enzyme inhibitors (captopril 0.5~3mg/kg . (d), calcium channel blockers, 654-2, etc.; (3) the cardiac output is significantly reduced, the systemic vascular resistance increases, and the pulmonary capillary pressure increases, it is appropriate to use drugs that dilate both small arteries and small veins, such as sodium nitroprusside. The initial dose is 0.1μg/kg?min intravenous drip, can be gradually increased to 0.5-1μg/kg?min, not more than 8ug/kg?min.
(14) Nutrition of myocardium: heart failure and myocarditis are accompanied by obvious abnormalities in energy metabolism, giving myocardial nutrition and protection can promote the energy metabolism of myocardial cells and protect myocardial cells, thus improving the contraction and diastolic capacity of myocardium. Sodium creatine phosphate: infants 1.0g intravenous drip qd; older children: cardioprotective 1.0g intravenous drip, q12h. generally used for 3~5 days, in severe cases can be used for 7~10 days.
4.4 Diagnosis and management of digestive system complications
Children with severe HFMD may suddenly develop different degrees of vomiting blood, black stool, abdominal pain, hyperactive or absent bowel sounds, high degree of abdominal distension, pallor, cold extremities, rapid heartbeat, weak pulse, decreased blood pressure, coma, azotemia and other clinical manifestations on the basis of the original disease, at this time, severe HFMD combined with gastrointestinal failure should be considered. Laboratory tests: erythrocyte count and hemoglobin are reduced to varying degrees, erythrocyte pressure volume is decreased, reticulocytes are increased; azotemia may be present with massive bleeding, and blood BUN is elevated. Positive blood stool or fecal occult blood. Endoscopy is performed as the patient’s condition permits, and emergency gastroscopy may be performed within 24-48 h after bleeding, as appropriate, to detect the site, extent and etiology of bleeding.
4.4.1 Diagnostic criteria for gastrointestinal failure: (1) There is toxic intestinal paralysis, severe abdominal distension, and diminished or absent bowel sounds. (2) There is a stress ulcer of the gastrointestinal tract combined with bleeding, and blood transfusion is required to maintain circulatory stability.
4.4.2 Treatment principles
4.4.2.1 General measures: general treatment: oxygen absorption, lying down and resting, slightly elevating both lower limbs in case of shock. Keep quiet and pay attention to keep warm. Diet control: fasting is recommended for those with heavy bleeding; fluid, semi-fluid or soft food is allowed for those with small amount of bleeding. Record vomiting blood, blood in stool, urine volume and fluid volume. Measure blood pressure, pulse, respiration, body temperature, oxygen saturation and other vital signs, and monitor central venous pressure (CPV). If necessary, place a gastric tube for gastrointestinal decompression in cases of abdominal distension. Maintain water-electrolyte acid-base balance, intravenous nutritional support, and ensure adequate water and heat supply.
4.4.2.2 Actively replenish blood volume and maintain normal blood pressure
(1) 0.9% saline or 2:1 isotonic sodium-containing solution, 20ml/kg, total volume not more than 300ml/time, input within 15min～30min; can be repeated 2~3 times, repeatedly expand the volume until shock correction if necessary.
(2) Blood transfusion: Hemorrhagic shock can occur when the blood loss exceeds 20%, such as hemoglobin <70g/L or erythrocyte volume <25% should be inputted as soon as possible with concentrated red blood cells or whole blood.
4.4.2.3 Inhibit gastric acid secretion and protect gastric mucosa: proton pump inhibitor: such as omeprazole 0.6-0.8mg/kg, intravenous injection once a day. Gastric mucosal protective agent: such as compound glutamine, etc.
4.4.2.4 Hemostatic drugs: Lithotripsy, VitK, hemostatic minerals, aniloxic acid and 6-aminocaproic acid (EACA) or aminomethylbenzoic acid (PAMBA), etc., as appropriate.
5, hand, foot and mouth disease serious illness diagnosis and treatment considerations
5.1 Early screening is crucial: for children with symptoms and signs that are consistent with the clinical diagnosis of HFMD and may develop into severe cases in the short term, great attention should be paid to closely observe the changes in the condition, early detection and early treatment are most critical.
5.2 Emergency management, race against time; for severe cases, establish close monitoring of vital signs (including invasive blood pressure, central venous pressure and continuous electroencephalographic monitoring, etc.), rapidly improve microcirculation, protect the function of the heart, lungs, brain and other important organs, and promptly mechanically assist ventilation and symptomatic treatment when respiratory dysfunction occurs.
5.3 Continuous assessment of the condition and adjustment of the treatment plan: close monitoring of vital signs is the basic guarantee of the success of resuscitation, and any treatment measures must be based on accurate and timely assessment of the condition.