Hand, foot and mouth disease (HFMD) is a common acute infectious disease caused by enteroviruses that can be transmitted through the gastrointestinal and respiratory tracts and occurs mostly in children under 5 years of age. The pathogens of HFMD are mainly Enterovirus 71 (EV 71) and Coxsackievirus A16 (CA16), and critical cases are mainly caused by EV 71 infection. Most children have a good prognosis, but severe cases are mainly seen in children under 3 years of age and can be complicated by encephalitis, encephalomyelitis, pulmonary edema, and circulatory collapse. Once brainstem encephalitis occurs, the morbidity and mortality rate increases significantly, and there is a lack of effective treatment. In 1997, there was an outbreak of HFMD in Malaysia, and 35 cases (88%) died of neurogenic pulmonary edema; in 1998, there was an outbreak of HFMD or herpes fulminans in Taiwan, and the main cause of death was neurogenic pulmonary edema. The main cause of death in patients with HFMD was pulmonary edema or pulmonary hemorrhage secondary to neurological damage; since 2008, HFMD has been prevalent in some areas of China, with deaths mainly due to brainstem encephalitis complicated by pulmonary edema, pulmonary hemorrhage and cardiopulmonary failure. Children with acute pulmonary edema and pulmonary hemorrhage generally have a normal heart and lungs in the past, virus can be isolated from brain tissue, but the viral content of lung tissue is low, and the myocardium has no obvious inflammatory response or only a slight mononuclear cell infiltration. Our scholars, Nong Guangmin et al, found that the autopsies of 14 children who died of HFMD all had brain damage, especially the brainstem, and 11 patients had pulmonary edema or pulmonary hemorrhage, and all 14 patients had a large amount of pink foam in the alveoli, but no diffuse lung damage was found in the lung tissue of patients with pulmonary hemorrhage, and this manifestation was different from the pathology of lung tissue of patients with pulmonary edema and pulmonary hemorrhage secondary to H1N1 influenza in 2009. This presentation was different from the pathology of lung tissue in patients with pulmonary edema and pulmonary hemorrhage secondary to 2009 H1N1 influenza. EV 71 is a highly neurotropic virus that primarily invades the brainstem and can cause neurological lesions such as brainstem encephalitis, encephalomyelitis, aseptic meningitis, and poliomyelitis-like syndrome. After viral invasion of the central nervous system, the disruption of the sympathetic inhibitory center and the stress response of the body caused by increased intracranial pressure together lead to sympathetic hyperexcitability and initiate a sympathetic waterfall response, with progressive increases in the patient’s heart rate and blood pressure.FU et al, using a cat model simulating children with neurogenic pulmonary edema and heart failure, confirmed that a significant increase in blood catecholamine levels is the main mechanism leading to pulmonary edema and Heart failure is the main mechanism. Our scholars also confirmed that catecholamine levels were elevated in children with all stages of HFMD, with more pronounced elevations in stages 3 and 4 than in stages 1 and 2. Therefore, most scholars agree that the mechanism of the disease is an increase in systemic vasoconstriction followed by an increase in resistance of the body circulation and a relative decrease in left ventricular blood displacement under the effect of vasoconstrictor mediators, leading to stasis in the pulmonary circulation, a sharp increase in the effective filtration pressure in the pulmonary capillary bed, and a large amount of fluid retention in the interstitial space of the lung tissue, resulting in pulmonary edema and pulmonary hemorrhage. However, some scholars have found no significant increase in vascular resistance in the body and pulmonary circulation through invasive hemodynamic observations, and therefore believe that the disease may be more similar to acute respiratory distress syndrome, with increased pulmonary vascular permeability leading to pulmonary edema rather than increased pulmonary capillary hydrostatic pressure. In patients with pulmonary edema, there is increased expression of inducible nitric oxide synthase (iNOS) mRNA in lung tissue. iNOS catalyzes the synthesis of nitric oxide (NO), which increases the permeability of the pulmonary microcirculatory system and increases the filtration coefficient of pulmonary capillaries, leading to increased pulmonary edema, so EV71 infection Therefore, the NPE caused by EV71 infection may be related to iNOS and NO. For patients with cardiopulmonary involvement, the administration of intravenous rehydration for patients with decreased blood pressure often leads to the aggravation of pulmonary edema, so the clinical practice gradually adopts vasoactive drugs to maintain blood pressure stability and limit fluid intake. In contrast, monitoring the amount of circulating fluid based on central venous pressure, cardiac function, and invasive arterial pressure, and using a staged management approach to treat patients with cardiopulmonary dysfunction can significantly reduce the morbidity and mortality rate in patients with cardiopulmonary failure compared to traditional strategies, but has no impact on the prognosis of patients with only neurological involvement without cardiopulmonary dysfunction. 2.1. Antiviral therapy Some studies have reported that anti-EV71 effects have been shown in both in vitro and in vivo tests, and that the incidence of mortality, morbidity, and sequelae such as paralysis have been reduced in rats infected with EV71. Our clinicians mostly use ribavirin combined with Chinese medicinal preparations to shorten the duration of fever and rash, but there are fewer reports on the efficacy of ribavirin in the treatment of severe HFMD. One study found that alpha-interferon could be increased by interferon inducer in test rats, thus inhibiting the replication of EV71, and the morbidity and mortality rate of test rats could be reduced accordingly after the decrease of viral load, which proved that alpha-interferon had a protective effect on the organism in EV71-infected rats. However, the viral inhibitory effect of interferon is not satisfactory. Interferon regulatory factor 9 (IRF9) is an important regulator on the interferon signaling channel, and the 3C protease encoded by EV71 can cleave IRF9, which may be one of the reasons for the poor anti-EV71 effect of interferon. In contrast, AG7088, a viral 3C protease inhibitor, was originally developed for the treatment of colds caused by human rhinovirus, and some studies have confirmed its inhibitory effect on EV71. Rupintrivir, an antiviral drug based on AG7088, has been shown to inhibit the 3C protease activity of EV71, thereby inhibiting viral replication. Since, as in many critical cases due to viral infections, complications may arise mainly from SIRS, antiviral therapy needs to be used early in the disease to avoid critical cases, whereas many critical cases occur early in the disease with cardiopulmonary involvement, and the rational use of antiviral drugs deserves further clinical discussion. 2.2, fluid management and dehydration treatment Because pulmonary edema and cerebral edema may occur at any time in critically ill cases, China’s HFMD treatment guidelines and experts recommend controlling fluid intake while maintaining stable blood pressure, and recommend the use of central venous pressure (cvP), invasive arterial blood pressure (ABP), and pulse index continuous cardiac output monitoring (PICCO) to guide fluid replacement. Patients with manifestations of neurological involvement should be actively controlled for intracranial hypertension with mannitol or glycerol fructose, diuretics for dehydration, and cranial pressure lowering therapy, or human albumin can be given to increase blood colloid osmotic pressure and reduce cerebral edema. After the onset of shock, saline resuscitation is recommended, and colloid fluid resuscitation can be given if it still fails to correct the situation. In the new Pediatric Advanced Life Support (PALS) perspective, it is also supported to give crystalloids in the early stages of shock and human albumin or other colloid fluids in the progressive stages of shock or when crystalloid resuscitation is not effective. Compared with saline, human albumin can reduce the morbidity and mortality of patients in shock without increasing the damage to the kidneys or other organs. 2.3. Glucocorticoid therapy. Due to the important role of inflammatory factors in the course of the disease, inhibition of inflammatory response can theoretically improve the condition. Glucocorticoids can reduce microvascular permeability, promote the synthesis and secretion of alveolar surface active substances, reduce alveolar surface tension and promote the absorption of pulmonary edema, and can also effectively prevent and control cerebral edema and block the vicious cycle process of pulmonary edema-cerebral edema. Our scholars found that critically ill patients with HFMD caused by EV71 were more likely to develop adrenal dysfunction than critically ill patients, and a higher proportion of children with HFMD who died compared with the surviving group developed adrenal dysfunction Domestic treatment experience also indicates that the application of high-dose shock therapy in critically ill cases is beneficial for improving prognosis. However, it has been suggested that doses of glucocorticoids are not effective in relieving clinical symptoms in severe cases of EV71 infection, nor do they result in significant reductions in white blood cells, blood glucose, and platelets. In patients with ARDS complicated by influenza A (H1N1) in 2009, some studies concluded that patients did not benefit from early administration of hormone therapy, but were more prone to pulmonary infection and prolonged mechanical ventilation, therefore, the timing and effects of glucocorticoid therapy in such critically ill patients deserve further study. 2.4. Intravenous immunoglobulin. Human immunoglobulin has the ability to neutralize viruses and inhibit nonspecific inflammatory responses. In previous outbreaks of HFMD, it has been demonstrated that treatment with immunoglobulin in critically ill cases with neurological and cardiopulmonary involvement can reduce the morbidity and mortality rate and improve the prognosis. Some studies have demonstrated a significant decrease in cytokine levels in patients with combined pulmonary edema and neurological dysfunction after intravenous administration of human immunoglobulin, which may be a mechanism for treating critically ill patients with HFMD, but the efficacy of immunoglobulin has been controversial due to the low level of evidence. Immunoglobulins have been suggested to inhibit the release of inflammatory mediators in infected patients, reduce the inflammatory response, and improve the prognosis of patients with sepsis, but a large study in 2011 showed that immunoglobulin therapy failed to benefit neonates with severe infections. High-dose immunoglobulin (1 g/kg.d) can rapidly improve clinical symptoms, shorten the course of disease, stop progression and reduce the incidence of critical complications. 2.5. Respiratory support therapy: Keep the airway open and administer oxygen. In case of respiratory dysfunction. Timely tracheal intubation using positive pressure mechanical ventilation. The indications of general ventilator support are respiratory rhythm changes ( apnea, double inspiration, sob-like breathing, sighing oxygen breathing); increased respiratory rate or shallow slow breathing when quiet independent of body temperature; frequent convulsions; nystagmus; ventilator-assisted ventilation stage, the ventilator parameters need to be adjusted at any time according to blood gas and X-ray chest film results. In case of pulmonary edema and pulmonary hemorrhage manifestations, PEEP should be increased in order to control alveolar exudation, and in practice, PEEP can reach 12-18 cmH20 or even higher, which is generally clinically appropriate to ensure oxygen saturation above 93% and no pink secretions in the airway. According to this principle, Kang J et al. reported treating 16 cases of hand, foot and mouth disease combined with neurogenic pulmonary edema, 12 cases improved (2 cases improved and then abandoned treatment due to multi-organ dysfunction) and 4 cases died (25%). 2.6. Vasoactive drug therapy: Milrinone is a phosphodiesterase inhibitor, the drug of choice for the treatment of congestive heart failure, which can slow down the heart rate and improve symptoms by affecting the regulatory ability of sympathetic nerves. Another retrospective study confirmed that patients in the milrinone group improved tachycardia and reduced mortality compared to the non-applied group, and survival was significantly higher in the milrinone group than in the control group in both the acute and late follow-up periods, so the investigators concluded that milrinone is an effective positive inotropic agent for improving cardiac function. It was found that plasma levels of leukocytes, platelets and interleukin 13 (IL-13) concentrations decreased after the application of milrinone, suggesting that milrinone may also have an immunomodulatory effect. For patients with increased heart rate and elevated blood pressure in the stage of cardiopulmonary involvement, some doctors in China have used milrinone combined with sodium nitroprusside, which can significantly reduce heart rate and blood pressure levels and increase ejection fraction and left heart output compared to milrinone alone. For hypotension after the development of hypotension during cardiopulmonary failure, expert consensus recommends dobutamine, dobutamine, epinephrine and norepinephrine, but studies have found that the use of dobutamine and others before the development of hypotension cannot prevent the development of hypotension. Although the 2012 Save Sepsis Campaign guidelines still cite dobutamine as the preferred positive inotropic agent for cardiac insufficiency in patients with sepsis, a new meta-analysis notes that dobutamine increases the risk of death in patients with severe cardiac insufficiency due to increased myocardial oxygen consumption. The study concluded that the above vasoactive drugs are not effective in maintaining blood pressure in the hypotensive phase of cardiopulmonary failure in hand and foot disease. For patients with poor results with the above vasoactive drugs, consider giving levosimendan, a new positive inotropic drug that is widely used to treat patients with cardiac failure. A meta-analysis of 45 randomized controlled clinical trials showed that levosimendan reduced the rate of death and length of hospital stay in patients with severe cardiac insufficiency compared with placebo and dobutamine. Nevertheless, there are no domestic or international reports of levosimendan for the treatment of patients with severe hand, foot and mouth disease. 2.7. Other: 9 of 22 critically ill patients died in 1 case (11.1%) due to persistent coma and hemodialysis in patients with heavy infection; 4 of 13 patients who did not undergo hemodialysis died (30.8%), suggesting that the removal of inflammatory mediators and harmful substances by hemodialysis in critically ill HFMD may reduce the deterioration of children’s disease to a certain extent and lower the death rate, which may be related to the reduction of This may be related to the reduction of inflammatory mediators in the blood. In the critically ill cases of human H7N9 avian influenza in China in 2013, elevated levels of cytokines such as IL-6 were one of the factors leading to the critical condition of the patients. The use of plasma exchange to reduce cytokine levels improved the prognosis of patients and provided a new therapeutic idea for the treatment of critically ill patients with cytokine storm after viral infection. However, a pediatric expert consensus in 2012 pointed out that blood purification therapy can effectively regulate the concentration of inflammatory and anti-inflammatory mediators and down-regulate the inflammatory response. It is believed that more cases of severe HFMD will be reported in the future with blood purification therapy. Extracorporeal membrane oxygenation ECMO has successfully treated many patients with cardiopulmonary failure in adults, and there are more and more cases of application in children with ARDS. Expert consensus recommends that ECMO can be considered when severe cases of EV71 infection do not improve with mechanical ventilation, vasoactive drugs and fluid therapy, but there are no relevant treatment cases reported at home and abroad. 3. Prognosis Most children recover from neurological damage and recover gradually, but a few critically ill cases may have sequelae. The long-term follow-up of children with aseptic meningitis was good, but 20% of children were reported to have symptoms similar to attention deficit hyperactivity disorder, compared to 3% of controls with severe neurological complications such as encephalitis, poliomyelitis and encephalomyelitis. Ataxia was a sequela in 10% of HFMD patients with moderate neurological impairment, and two-thirds of survivors with severe complications had severe sequelae, despite a significant reduction in mortality with a stage-management treatment strategy. In another study, after 2.9 (1.0-7.4) years of follow-up of children with severe neurological complications, 18 (64%) of 28 patients with neurogenic cardiopulmonary failure had residual limb weakness and muscle atrophy, 17 (61%) required nasal feeding, and 16 (57%) required long-term respiratory support. Delayed neurological development was present in 5% of patients with neurological impairment alone and in 75% of children with concurrent cardiopulmonary failure.