A retrospective observational study was performed in patients with severe EV-A71-HFMD complicated with cardiopulmonary failure admitted to the PICU at Shanghai Children’s Hospital between January 2012 and December 2016. According to whether the patients received CVVHDF during PICU hospitalization, the patients were divided into a non-CVVHDF group, who underwent conventional therapy, or a CVVHDF group, who underwent conventional therapy plus CVVHDF. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki (and subsequent revisions) and the current standards for observational studies. This study was approved by the Ethics Review Committee, Children’s Hospital of Shanghai/Shanghai Children’s Hospital, Shanghai Jiao Tong University and conducted in accordance with the provisions of the Declaration of Helsinki (Approval No. 2016R010-F01). The need for informed consent to participate was waived because we used deidentified retrospective data.
Diagnosis and staging were performed according to the clinical therapy expert consensus on severe cases caused by EV-A71. Patients with severe EV-A71-HFMD complicated with cardiopulmonary failure were diagnosed as having stage 3 or 4 . The symptoms of patients in stage 3 or 4 include increased heart and respiratory rates, cold sweats, cold extremities, mottled skin, increased blood pressure, tachycardia (bradycardia wasalso occasionally seen), tachypnea, cyanosis, cough with pink foamy or bloody sputum, hypotension and ultimately cardiovascular collapse .
The inclusion criteria were as follows: (1) patients aged 1 month to 14 years old; (2) patients with severe stage 3 or 4 EV-A71-HFDM, defined by the clinical therapy expert consensus on severe cases caused by EV-A71 (4); and (3) patients who were EV-A71 IgM or RT-PCR positive. Patients who required cardiopulmonary resuscitation and died within 24 h after admission were excluded.
The conventional management for HFDM was performed according to the 2008 Guidelines for the diagnosis and the expert consensus on the rescue and treatment of severe cases caused by EV-A71 [4, 17]. The physiological fluid requirement was 60–80 ml/kg/day in the absence of deliberate diuresis. Patients with shock were resuscitated with normal saline 10–20 ml/kg/time over 30 min while administering vasoactive agents [4, 17]. The hemodynamic change in stage 3 was characterized by high dynamicity and high resistance. Milrinone was used with a loading dosage of 50–75 μg/kg. The maintenance dose was 0.25–0.75 μg/kg/min. The total duration of the infusion perioddid not exceed 72 h. Phentolamine (1–20 μg/kg/min) or sodium nitroprusside (0.5–5 μg/kg/min) was initiated at a low dose and gradually increased to an appropriate dose level to control blood pressure to a level below that of constituting severe hypertension at the corresponding age if necessary. When hypotension manifested in patients with stage 4 EV-A71-HFDM, positive inotropic agents and vasopressors, such as dopamine at 5–20 μg/kg/min, norepinephrine at 0.05–2 μg/kg/min, adrenalineat 0.05–2 μg/kg/minute and dobutamine at 2.5–20 μg/kg/min were used. If patients had suffered from nosocomial infection or were supported by mechanical ventilation for more than 3 days, antibiotics were used.
The indications for CVVHDF initiation in our study included an FO > 10%[FO = (CVVHDF initial weight-PICU admission weight)/PICU admission weight× 100%], acute kidney injury (AKI), or unstable hemodynamics, such as cardiogenic shock shock and multiple organ dysfunction [18, 19]. For patients with severe EV-A71-HFMD presenting with refractory cardiovascular disorder, CVVHDF as an empirical adjuvant therapy combined with conventional treatment was administered to maintain stable hemodynamics. Patients who suffered from severe coagulopathy disorder (international normalized ratio [INR] > 3.0 or platelet count< 10 × 109/L; n = 6) or a history of biofilm or hemofilter allergy (n = 1) or patients without parental consent for CRRT(n = 5) were treated with conventional therapy and included in the non-CVVHDF group.
CVVHDF was performed ata flow rate of 35–50 mL/kg/hr. for both ultrafiltrate and dialysate using a PRISMA or PRISMA flex blood purification machine and Gambro PRISMA M60 membrane hemofilter equipped with an AN69 (Gambro Renal Products, Meyzieu, France). Vascular access was obtained with an 8F central venous catheter (GamCath; Gambro, Colombes, France) in the right internal jugular or femoral vein according to the patient’s body weight. Blood flow was set at a constant 4–6 mL/kg/min to achieve a filtration fraction of 25–35%. The replacement fluid was prepared according to the modified Ports formula and contained Na+ 130 mmol/L, K+ 4 mmol/L, HCO3− 28 mmol/L, Ca2+ 1.5 mmol/L, Mg2+ 3.2 mmol/L, Cl− 109 mmol/L, and glucose 0.2 g/L. The pre- to postdilution ratio was 1:2. The rate of replacement fluid was 35 ml/kg/h (Qf) or 10–15 ml/min (Qd).The filter circuit was pretreated with saline that contained 5000–10,000 IU/L unfractionated heparin. During CVVHDF, unfractionated heparin was used with at aninfusion rate of 5–20 U/kg/h. The activated partial thromboplastin time (APTT) was detected every 4–6 h, and the transmembrane pressure was modified between 50 and 120 mmHg. The dose of heparin was regulated to maintain APTT at 1.5–2-fold the normal value. The hemofilter was changed every 24 h or when clotted. The patients with severe coagulation disorders (APTT > 80 s or INR > 3.0), a biofilm allergic reaction, or difficult venin catheter access were managed with conventional therapies, as in the control group. The implementation of CVVHDF for cardiovascular indications was fully explained, and the parents of the patients provided written informed consent prior to CVVHDF initiation.
In the present study, the indications for the weaning of CVVHDF included the following: (1) a normal heart rate and blood pressure; (2) serum lactate < 2 mmol/L; and (3) a urine output more than 1 ml/kg/h and FO < 10%. The primary endpoints were as follows: (1) ameliorated hyperthermia; (2) improved pulmonary edema and pulmonary effusion; (3) a urine output of > 1 ml/kg/h; and (4) a normal blood pressure. Continuous hemofiltration was terminated when the following conditions occurred: (1) the children developed severe bleeding or uncontrollable hemorrhaging; or (2) symptoms were not obviously improved after 72 h. The assessments for initiation and weaning, as well as the effects of CVVHDF, were performed by an attending intensivist in our PICU.
Data collection and definitions
All data were retrieved from the hospital database system. Variables were defined prior to data collection and were entered in a standardized format during data collection. The collected data included demographic data (such as age, sex, and body weight), details of the initial presentation on admission, clinical features for EV-A71-induced HFMD, length of PICU stay, vital signs (temperature, heart rate, and blood pressure), cardiac parameters (left ventricular ejection fraction, LVEF; and cardiac index, CI), the ratio of the partial pressure of oxygen in arterial blood (PaO2) to the inspired oxygen fraction (FiO2) (PaO2/FiO2) before and after CVVHDF, as well as 28-day mortality, duration of mechanical ventilation, and duration of vasoactive agent administration. Cardiac ultrasound was performed by a specialized cardiologist. Laboratory data, including pH, creatinine (Cr), alanine transaminase (ALT),serum lactate (Lac), cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB), as well as catecholamine-like substances, including adrenalin, dopamine, renin, angiotensin II, and aldosterone, were obtained from the computerized hospital medical database. Biochemical indexes were collected at admission and after 3 days in the non-CVVHDF group. Biochemical indexes were collected before CVVHDF initiation and after CVVHDF for 3 days in the CVVHDF group.
The data were analyzed using SPSS (v. 22.0) (SPSS Inc., Chicago, IL). All the variables were tested for normal distribution using the Kolmogorov-Smirnov test. Continuous variables with abnormal distributions were summarized as medians (IQRs). The Mann-Whitney U test was used to compare the continuous variables with abnormal distributions. The chi-square test was used to compare the categorical data. A value of P < 0.05 was considered statistically significant.