Expert consensus on clinical management of severe cases of enterovirus 71 (EV71) infection (2011 version)
May 30, 2011 15:23 Source: Ministry of Health
Hand, foot and mouth disease is an acute infectious disease caused by enterovirus. In April 2010, the Ministry of Health issued the “Hand, Foot and Mouth Disease Treatment Guidelines (2010 Edition)” to guide medical institutions to carry out medical treatment of HFMD. Now the clinical expert group of HFMD of the Ministry of Health has formulated the “Expert Consensus on Clinical Management of Serious Cases of Enterovirus 71 (EV71) Infection (2011 Edition)” as a supplement to the “HFMD Treatment Guidelines (2010 Edition)” for the reference of medical institutions and medical personnel. He Jingen, Department of Pediatrics, Anhui Provincial Hospital
I. Clinical staging
According to the pathogenesis and clinical manifestations, EV71 infection is divided into 5 stages.
Phase 1 (hand, foot and mouth rash phase): The main manifestations are fever, rash (maculopapular rash, papule, small herpes) on the hands, feet, mouth and buttocks, which may be accompanied by cough, runny nose, loss of appetite and other symptoms. Some cases present only with rash or herpetic pharyngitis, and some cases may have no rash. The majority of cases in this stage are ordinary cases of HFMD, and the majority of cases are cured in this stage.
Phase 2 (neurological involvement phase): A few EV71-infected cases may show central nervous system damage, mostly occurring within 1-5 days of the disease, manifesting as poor mental health, drowsiness, easy startle, headache, vomiting, irritability, limb tremors, acute limb weakness, neck ankylosis, and other symptoms and signs of meningitis, encephalitis, polio-like syndrome, and encephalomyelitis. Cerebrospinal fluid examination is aseptic meningitis changes. CT scan of the cerebrospinal cord may have no positive findings, and MRI examination may show abnormalities. Cases in this stage are heavy cases of HFMD and most cases can be cured. Stage 3 (pre-cardiopulmonary failure): mostly occurs within 5 days of the disease course. It is thought that it may be related to post-inflammatory vegetative dysfunction or sympathetic hyperfunction in the brainstem, and it is also thought that immune damage after EV71 infection is one of the pathogenic mechanisms. Cases in this phase show increased heart rate and respiration, cold sweats, skin pattern, chilled extremities, elevated blood pressure, elevated blood glucose, elevated peripheral blood white blood cells (WBC), and heart ejection fraction may be abnormal. Cases at this stage belong to the critical type of severe cases of HFMD. Timely detection of the above-mentioned manifestations and proper treatment are the keys to reduce the morbidity and mortality rate.
Stage 4 (cardiopulmonary failure stage): The disease continues to progress and cardiopulmonary failure will occur, which may be related to neurogenic pulmonary edema and circulatory failure due to brainstem encephalitis. It occurs mostly within 5 days of the disease and is predominantly aged 0-3 years. Clinical manifestations include tachycardia (individual children are bradycardic), shortness of breath, cyanosis of the lips and mouth, coughing up pink foamy sputum or bloody fluid, and sustained blood pressure drop or shock. In some cases, severe cerebral failure is the main manifestation, but pulmonary edema is not obvious, and frequent convulsions, severe consciousness impairment and central respiratory and circulatory failure occur. Cases in this stage belong to the critical type of HFMD severe cases and have a high morbidity and mortality rate.
Phase 5 (recovery period): body temperature gradually returns to normal, dependence on vasoactive drugs gradually decreases, symptoms of neurological involvement and cardiopulmonary function gradually recover, and a small number of neurological sequelae can be left behind.
Early identification of severe cases
The key to the diagnosis and treatment of severe cases of EV71 infection lies in timely and accurate screening to confirm stage 2 and stage 3. The following indicators suggest the possibility of developing into critical cases of severe disease.
(A) persistent hyperthermia: body temperature (axillary temperature) greater than 39 ℃, conventional antipyretic effect is not effective.
(b) Neurological manifestations: mental depression, vomiting, easily startled, shaking limbs, weakness, unsteadiness in standing or sitting, etc., and in rare cases, hyperphagia.
(c) Respiratory abnormalities: increased, decreased or irregular rhythm of breathing. If the respiratory rate exceeds 30-40 breaths/min (according to age) in a quiet state, neurogenic pulmonary edema should be alerted.
(iv) Circulatory dysfunction: cold sweats, cold extremities, skin pattern, increased heart rate (>140-150 beats/min, according to age), elevated blood pressure, and prolonged capillary refill time (>2 seconds).
(v) Elevated peripheral blood WBC count: peripheral blood WBC over 15×109/L, except for other infectious factors.
(vi) Elevated blood glucose: stress hyperglycemia with blood glucose greater than 8.3 mmol/L is present.
Early cerebrospinal fluid examination should be performed in cases with suspected neurological involvement. the key to screening severe cases of EV71 infection is to closely observe the mental status of the child, the presence of limb tremors, easy startle, skin temperature, and respiration, heart rate, and blood pressure, and to record them in a timely manner.
III. Treatment points
Serious cases of EV71 infection develop from stage 2 to stage 3 mostly within 1 day, occasionally 2 days or more. The progression from stage 3 to stage 4 is sometimes only a few hours. Therefore, appropriate treatment measures should be taken according to the different pathophysiological processes in each clinical stage.
Stage 1: No hospitalization is required and symptomatic treatment is the mainstay. Outpatient physicians should inform the parents of the child to observe carefully and to seek immediate medical attention in case of early manifestations of severe EV71 infection.
Phase 2: Use dehydrating diuretics such as mannitol to reduce intracranial hypertension; control fluid intake appropriately; apply gammaglobulin as appropriate for cases with persistent high fever, spinal cord involvement or rapid disease progression. Closely observe the temperature, respiration, heart rate, blood pressure and changes in skin temperature of the extremities and other high-risk factors that may develop into the critical type, especially for cases within 3 years of age and within 5 days of the disease course.
Stage 3: Should be admitted to ICU for treatment. On the basis of stage 2 treatment, block sympathetic excitability and apply vasoactive drugs such as milrinone and phentolamine in a timely manner, along with oxygen therapy and respiratory support. Apply gammaglobulin and glucocorticoids as appropriate, and prophylactic application of antibacterial drugs is not recommended.
Stage 4: Based on the treatment in stage 3, early application of ventilator with positive pressure ventilation or high frequency ventilation. In cases of pulmonary edema and pulmonary hemorrhage, positive end-expiratory pressure (PEEP) should be increased appropriately; frequent aspiration is not recommended. Dopamine, dobutamine, epinephrine and norepinephrine can be applied in patients with hypotensive shock. In cases of severe cardiopulmonary failure, extracorporeal membrane oxygenation therapy may be considered.
Phase 5: Give supportive therapy to promote the recovery of organ functions; give rehabilitation therapy to those with limb dysfunction; individual cases need long-term mechanical ventilation therapy to maintain life.
IV. Treatment measures
(A) General treatment.
Pay attention to isolation, avoid cross-infection; light diet, good oral and skin care; medication and physical cooling to reduce fever; keep the child quiet; use diazepam, midazolam, phenobarbital and other anticonvulsants in cases of convulsion; oxygenation, keep the airway open; pay attention to nutritional support, maintain water and electrolyte balance.
(ii) Fluid therapy.
In severe cases of EV71 infection, cerebral edema, pulmonary edema and cardiac failure may occur, so fluid intake should be controlled appropriately. Restrict fluid intake while lowering cranial pressure by dehydration. Give the physiological requirement of 60-80 ml/(kg-d) (dehydrating agent is not counted), and it is recommended to give it uniformly, i.e. 2.5-3.3 ml/(kg-h). Pay attention to maintaining stable blood pressure.
Phase 4: In shock cases, 10-20 ml/kg of saline is given for fluid resuscitation along with the application of vasoactive drugs, which is entered within 30 minutes, after which fluid may be rehydrated as appropriate to avoid massive volume expansion in the short term. Those who still cannot be corrected are given colloidal fluid infusion. Medical institutions with conditions can use central venous pressure (CVP), invasive arterial blood pressure (ABP), and pulse index continuous cardiac output monitoring (PICCO) to guide rehydration.
(iii) Application of dehydrating drugs.
Dehydrating drugs should be used under close monitoring. In patients with encephalitis and pulmonary edema without hypotension and circulatory disorders, fluid management is based on dehydrating agents and fluid restriction; if patients develop shock and circulatory failure, dehydrating drugs should be used under the premise of correcting shock and replenishing circulating blood volume. Commonly used dehydration drugs include.
1. hypertonic dehydrating agent: (1) 20% mannitol 0.5-1.0 g/(kg-sub), q4-8h, 20-30min rapid intravenous injection, the dehydrating effect can be exerted after 10min intravenous injection, and the effect can be maintained for 3-6h. The dose can be increased to 1.5-2 g/(kg/(time)), once every 2-4 hours. (2) 10% glycerol fructose 0.5-1.0 g/(kg – times), q4-8h, rapid intravenous drip, diuretic started 10-30min after injection, the strongest effect at 30min, the effect can be maintained for 24h. critical cases can use the above two drugs alternately, 3-4h use once.
Diuretics: For those with cardiac dysfunction, inject 1-2 mg/kg of tachyphylaxis first, and then evaluate before determining the use of dehydrating drugs and other life-saving measures (such as tracheal intubation with ventilator).
3. Human albumin: human albumin reduces cerebral edema by increasing blood colloid osmotic pressure, and has a long half-life and long duration of action. Usage: 0.4 g / (Kg – times), often used in combination with diuretics.
(iv) Vasoactive drug use.
1. Phase 3: Hemodynamics in this period is often high power and high resistance, manifested as skin pattern and cold extremities, but not a real shock state, mainly using vasodilator drugs. Commonly used milrinone injection: loading dose 50-75μg /kg, maintenance dose 0.25-0.75μg /(kg-min), generally use no more than 72 hours. For those with high blood pressure to control the blood pressure below the value of severe hypertension in that age group and above normal blood pressure, phentolamine 1-20μg/(kg-min) or sodium nitroprusside 0.5-5μg/(kg-min) can be used, generally starting from a small dose and gradually increasing the dose and gradually adjusting to the appropriate dose.
Attachment: definition of severe hypertension in children
2. Stage 4: Treatment is the same as stage 3. If blood pressure falls below the lower limit of normal for the same age, vasodilators are discontinued and positive inotropic and antihypertensive drugs can be used. Dopamine (5-15μg/kg-min), dobutamine (2-20μg/kg-min), epinephrine (0.05-2μg/kg-min), norepinephrine (0.05-2μg/kg-min), etc. can be given. -min), etc. Catecholamines should be started at a low dose to maintain a minimum dose close to normal blood pressure. If the above drugs are ineffective, levosimendan (12-24μg/kg loading dose at the beginning, then 0.1μg/kg-min maintenance), vasopressin (20μg/kg every 4 hours, depending on the hemodynamic improvement), etc. can be tried.
(v) Intravenous gammaglobulin (IVIG) application.
IVIG is applied in the treatment of viral infections, mainly for severe sepsis. From the pathogenesis of severe cases of EV71 infection, there is evidence to support that damage to the hypothalamus and/or medulla oblongata leads to sympathetic nervous system excitation, neurogenic pulmonary edema and cardiac damage, but it is unclear whether EV71 infection can lead to severe sepsis, and there is a lack of sufficient evidence-based medical evidence for the exact efficacy of IVIG in treating severe cases of EV71 infection. Based on literature reports and the experience of most clinical experts, IVIG is not recommended for routine use in phase 2, and may be considered in cases with severe toxic symptoms such as encephalomyelitis and hyperthermia. Phase 3 application of IVIG may play a certain role in blocking the disease, and the recommended indications for application are: mental depression, frequent limb tremors; acute limb paralysis; respiratory rate exceeding 30-40 breaths/min (by age) in quiet state; cold sweats, cold extremities, skin pattern, and increased heart rate >140-150 breaths/min (by age). It can be applied at 1.0 g/(kg-d) (2 consecutive days of application). The efficacy of IVIG in phase 4 is limited. At present, domestic enterprises have produced specific EV71 immunoglobulin and IVIG containing EV71 neutralizing antibodies, but they have not yet been applied in clinical practice.
(vi) Glucocorticoid application.
Glucocorticoids help to inhibit the inflammatory response, reduce microvascular permeability, stabilize cell membranes and restore sodium pump function, and prevent or attenuate free radical-induced lipid peroxidation. Most experts believe that glucocorticoids can help reduce brain edema and pulmonary edema caused by EV71 infection, but there is a lack of sufficient evidence-based medical evidence to support this.
The use of glucocorticoids is generally not advocated in stage 2. Glucocorticosteroid therapy may be given in stages 3 and 4 as appropriate. Methylprednisolone 1-2 mg/(kg-d), hydrocortisone 3-5 mg/(kg-d), and dexamethasone 0.2-0.5 mg/(kg-d) may be used. Discontinue as soon as possible after the disease is stabilized. Whether to apply high-dose glucocorticoid shock therapy is still controversial.
(vii) Antiviral drug application.
There are no effective anti-EV71 drugs. Ribavirin has been shown to inhibit EV71 replication and partially inactivate the virus in in vitro tests, so it can be considered.
(H) Mechanical ventilation application.
1. timing of mechanical ventilation.
Early tracheal intubation with mechanical ventilation, especially PEEP, is crucial to reduce pulmonary exudation, stop the development of pulmonary edema and pulmonary hemorrhage, improve ventilation and increase oxygen saturation. The indications for mechanical ventilation are: (1) shortness of breath, slowdown or rhythm change; (2) pale red or bloody airway secretions; (3) wet stalls in the lungs within a short period of time; (4) exudative lung lesions suggested by chest X-ray; (5) significant decrease in pulse volume oxygen saturation (SpO2) or arterial partial pressure of oxygen (PaO2); (6) frequent convulsions with deep coma; (7) pallor and cyanosis; decrease in blood pressure.
2. Mechanical ventilation mode.
Pressure-controlled ventilation is commonly used, but other modes are also available. High frequency oscillatory ventilation can be used for those with air leak or intractable hypoxemia.
3. Mechanical ventilation parameters adjustment.
(1) Objective: Maintain PaO2 above 60-80 mmHg and partial pressure of carbon dioxide (PaCO2) at 35-45 mmHg to control pulmonary edema and pulmonary hemorrhage.
(2) For those with pulmonary edema or pulmonary hemorrhage, it is recommended that the initial ventilator parameters be adjusted: 60%-100% inspired oxygen concentration, PIP 20-30 cmH2O (including PEEP), PEEP 6-12 cmH2O, f 20-40 times/min, tidal volume 6-8 ml/kg. ventilator parameters can be adjusted up or down in time according to changes in the condition, and if pulmonary hemorrhage is not controlled or blood oxygen is not improved, the If pulmonary hemorrhage is not controlled or blood oxygenation is not improved, increase PEEP by 2 cmH2O each time, generally not more than 20 cmH2O, and pay attention to adjust PIP at the same time to ensure stable tidal volume.
(3) For those with central respiratory failure only, inhaled oxygen concentration 21%-40%, PIP 15-25cmH2O (including PEEP), PEEP 4-5cmH2O, f 20-40 times/min, tidal volume 6-8ml/kg.
(4) Airway management: avoid frequent and prolonged suctioning resulting in reduced airway pressure, and keep the airway open to prevent blood clots from blocking the tracheal tube. In addition, sedative and analgesic drugs should be given appropriately, including: imipramine 0.1-0.3mg/(kg-h), fentanyl 1-4μg/(kg-h); prevent ventilator-associated pneumonia and ventilator-associated lung injury.
4. Indications for withdrawal.
(1) Normalization of spontaneous breathing and good cough reflex.
(2) Oxygenation index (OI=PaO2/FiO2×100) ≥300mmHg and improved chest radiograph.
(3) Improved consciousness.
(4) Stable circulation.
(5) No other life-threatening complications.
(ix) Extracorporeal membrane oxygenation (ECMO) application.
Although ECMO has successfully treated many patients with cardiopulmonary failure, there is little experience in treating severe cases of EV71 infection. ECMO can be considered in severe cases of EV71 infection when they do not improve with mechanical ventilation, vasoactive drugs and fluid therapy, while ECMO should not be applied in patients with brain failure.