Mesenchymal stem cells-based therapies for severe ARDS with ECMO: a review.

Acute respiratory distress syndrome (ARDS) is the primary cause of respiratory failure in critically ill patients. Despite remarkable therapeutic advances in recent years, ARDS remains a life-threatening clinical complication with high morbidity and mortality, especially during the global spread of the coronavirus disease 2019 (COVID-19) pandemic. Previous studies have demonstrated that mesenchymal stem cell (MSC)-based therapy is a potential alternative strategy for the treatment of refractory respiratory diseases including ARDS, while extracorporeal membrane oxygenation (ECMO) as the last resort treatment to sustain life can help improve the survival of ARDS patients. In recent years, several studies have explored the effects of ECMO combined with MSC-based therapies in the treatment of ARDS, and some of them have demonstrated that this combination can provide better therapeutic effects, while others have argued that some critical issues need to be solved before it can be applied to clinical practice. This review presents an overview of the current status, clinical challenges and future prospects of ECMO combined with MSCs in the treatment of ARDS.

Perioperative extracorporeal membrane oxygenation in pediatric congenital heart disease: Chinese expert consensus.

BACKGROUND: Congenital heart disease (CHD) is one of the main supportive diseases of extracorporeal membrane oxygenation in children. The management of extracorporeal membrane oxygenation (ECMO) for pediatric CHD faces more severe challenges due to the complex anatomical structure of the heart, special pathophysiology, perioperative complications and various concomitant malformations. The survival rate of ECMO for CHD was significantly lower than other classifications of diseases according to the Extracorporeal Life Support Organization database. This expert consensus aims to improve the survival rate and reduce the morbidity of this patient population by standardizing the clinical strategy. METHODS: The editing group of this consensus gathered 11 well-known experts in pediatric cardiac surgery and ECMO field in China to develop clinical recommendations formulated on the basis of existing evidences and expert opinions. RESULTS: The primary concern of ECMO management in the perioperative period of CHD are patient selection, cannulation strategy, pump flow/ventilator parameters/vasoactive drug dosage setting, anticoagulation management, residual lesion screening, fluid and wound management and weaning or transition strategy. Prevention and treatment of complications of bleeding, thromboembolism and brain injury are emphatically discussed here. Special conditions of ECMO management related to the cardiovascular anatomy, haemodynamics and the surgical procedures of common complex CHD should be considered. CONCLUSIONS: The consensus could provide a reference for patient selection, management and risk identification of perioperative ECMO in children with CHD. Video abstract (MP4 104726 kb).

Composition characteristics of the gut microbiota in infants and young children of under 6 years old between Beijing and Japan.

BACKGROUND: The composition of intestinal flora in Chinese and Japanese has been reported in many studies but that in infants aged 0-6 years old has not been studied yet. METHODS: The distribution characteristics of the fecal flora of infants in Beijing (n=84) and Japan (n=53) were analyzed using 16S rRNA gene sequencing analysis. RESULTS: This study showed the higher relative abundance of Erysipelotrichaceae_ UCG-003 and Anaerostipes in male group that of Ruminiclostridium, Eubacterium, Senegalimassilia and Senegalimassilia in female group, especially Senegalimassilia, which was not detected in male group. Defecation trait groups indicated significantly higher relative abundance of Bifidobacterium in abnormal bowel trait group than that in the normal group (P<0.05). The feeding groups' analysis showed significantly higher relative abundance of Bifidobacterium and Enterococcus and lower abundance of Bacteroides and Lacetospirillaceae in the breast-feeding group than that in the formula feeding and mixed-feeding groups. The relative abundance of Parasutterella and Ruminococcaceae_UCG-003 in the halitosis group was significantly higher than that in the normal group. The comparison of cold and fever group and normal group indicated significantly higher relative abundance of Erysipelatoclostridium and lower relative abundance of Lachnospiraceae _UCG-001 in the fever and cold group than that in the normal group (P<0.05). The regional comparison of intestinal flora of Beijing and Japan showed significant increase in the relative abundance of Bacillus, Lactobacillus, Prevotella, megamonas and Veillonella in the intestinal flora of 0-6 years old infants in Beijing. CONCLUSIONS: These findings improve the understanding of intestinal bacterial and viral communities of infants from the two Asian countries.

[Establishment of a modified rabbit model of acute lung injury induced by cardiopulmonary bypass].

OBJECTIVE: To establish an modified rabbit model of the acute lung injury induced by cardiopulmonary bypass (CPB) with ascending aorta and right atrium catheterization and detect the changes in serum tumor necrosis factor-α (TNF-α) level after modeling. METHODS: Ten healthy adult male New Zealand rabbits were randomly selected to establish CPB models. The model establishment was deemed successful if the rabbits survived for over 4 h with stable heart beat after termination of CPB. The vital signs of the rabbits were recorded after anesthesia (T1), before CPB (T2), at 15 after blocking the ascending aorta and pulmonary artery (T3), immediately after re-opening of the ascending aorta and pulmonary artery (T4), and at 1 (T5) and 4 (T6) after CPB. Arterial blood gas (ABG) was monitored at T2, T4 and T6 and the serum levels of TNF-α were also detected with ELISA. RESULTS: Nine rabbit models of CPB with acute lung injury were successfully established. During the operation, the MAP was maintained at a level above 55 mmHg, HCT significantly decreased from (30.18∓2.88)% at T2 to (17.73∓1.95)% at T4 (P<0.05), and plasma lactate level increased significantly from 3.65∓1.13 mmol/L at T2 to 9.36∓1.28 mmol/L at T4 (P<0.05). The oxygenation index (PaO2/FiO2) at T6 was significantly lower than that at T2 (281.64∓55.76 vs 468.36∓56.28 mmHg, P<0.05). The serum levels of TNF-α were significantly increased (P<0.05) and obvious lung interstitial edema and inflammatory cell infiltration occurred after CPB establishment. CONCLUSION: The modified rabbit model of CPB with acute lung injury is stable and reliable and can be used for studying acute lung injury induced by CPB.

Improved outcomes of transported neonates in Beijing: the impact of strategic changes in perinatal and regional neonatal transport network services.

BACKGROUND: Infants born outside perinatal centers may have compromised outcomes due to the transfer speed and efficiency to an appropriate tertiary center. This study aimed to evaluate the impact of regional coordinated changes in perinatal supports and retrieval services on the outcome of transported neonates in Beijing, China. METHODS: Information about transported newborns between phase 1 (July 1, 2004 to June 30, 2006) and phase 2 (July 1, 2007 to June 30, 2009) was collected. The strategic changes during phase 2 included standardized neonatal transport procedures, skilled attendants, a perinatal consulting service, and preferential admission of transported neonates to the intensive care unit of the tertiary care center. Data from phase 2 (after-strategic changes) were compared with those of phase 1 (the period of pre-strategic changes) after a 12-month washout period, especially regarding the reduction in mortality and selected morbidity. RESULTS: There was a large increase in the number of transported infants in phase 2 compared with phase 1 (2797 vs. 567 patients). The average monthly rate of increase of transported infants was 383.3% (from 24 infants per month to 116 infants per month). The mortality rate of transported neonates reduced significantly from phase 1 to phase 2 (5.11% vs. 2.82%; P=0.005), particularly for preterm infants (8.47% vs. 4.34%; P=0.006). In addition, transported neonates during phase 2 had significantly decreased morbidities. CONCLUSIONS: Regional coordinated strategies optimizing the perinatal services and transport of outborn sick and preterm infants to tertiary care centers improved survival outcomes considerably. These findings have vital implications for health outcomes and resource planning.

[Effects of pulmonary surfactant in treatment of acute lung injury after cardiac surgery in infants].

OBJECTIVE: Acute lung injury is a severe complication after cardiac surgery performed with cardiopulmonary bypass in infant patients. Pulmonary surfactant has been successfully used in treating neonatal respiratory distress syndrome for many years. This study focused on exploring the clinical efficacy of exogenous pulmonary surfactant in treating infant patients with acute lung injury after cardiac surgery with the use of extracorporeal circulation. METHOD: Twenty-three infants with ventricular septal defect (VSD) were enrolled in the study. None of the patients needed oxygen treatment nor ventilation before heart surgery. VSD repair operation was done under cardiopulmonary bypass, and acute lung injury was found postoperatively. Ten infant patients in the treatment group were given pulmonary surfactant by tracheal instillation during mechanical ventilating postoperatively. Thirteen patients in control group were randomly selected in the same period in hospital, and acute lung injury was diagnosed without pulmonary surfactant treatment after cardiopulmonary bypass. Blood samples were obtained from all the patients, and blood gas analysis was performed every 6 hours. Demographics (body weigh, age, gender, VSD diameter) and clinical characteristics (CPB time, oxygenation index, mean airway pressure, pH and PCO2) of all the patients were collected, and statistical analysis was done to compare the data between treatment and control group. RESULT: In the first 24 hours after heart surgery, compared with the control group, a more increased oxygenation index (from 89.36 ± 12.69 to 285 ± 16.51) was observed in treatment group, and it was from 93.71 ± 11.82 to 133 ± 19.62 in the control group. There was a significant difference in oxygenation index between the two groups (P < 0.05). At the same time, the MAP (from 17.5 ± 3.18 to 10.4 ± 3.37) of the patients in comparison with the control group (from 18.2 ± 2.63 to 13.8 ± 2.55), a more significantly decreased MAP was observed in the treatment group (P < 0.05). There was no significant difference in pH and PCO2 between the two groups. The ventilation time in cardiac care unit was shorter in treatment group (17.43 ± 9.12) h compared with the control group [(30.97 ± 14.85) h, P < 0.05]. ICU stay time of treatment group (3.90 ± 1.34) d was shorter than that of control group [(6.18 ± 1.90) d, P < 0.05].Two infants of the control group died, but none in treatment group died. CONCLUSION: In this study, a satisfactory curative effect was observed for the treatment of acute lung injury with PS intratracheal instillation after heart surgery under cardiopulmonary bypass in infant patients. It can reduce the duration of mechanical ventilation and cardiac care unit stay and improve prognosis. In addition, this study was a pilot study and the limited sample size was probably the cause of insufficient statistical power. Further study of larger scale is needed.

[Establishment of regional active neonatal transport network].

OBJECTIVE: To evaluate the clinical function and significance of establishing a regional active neonatal transport network (ANTN) in Beijing. METHOD: The authors retrospectively studied intensive care and the role of ANTN system in management of critically ill neonates and compared the outcome of newborn infants transported to our NICU before and after we established standardized NICU and ANTN system (phase 1: July 2004 to June 2006 vs phase 2: July 2006 to May 2008). RESULT: The number of neonatal transport significantly increased from 587 during phase 1 to 2797 during phase 2. Success rate of transport and the total cure rate in phase 2 were 97.85% and 91.99% respectively, which were significantly higher than those in phase 1 (94.36% and 88.69%, respectively, P < 0.01). The neonatal mortality significantly decreased in phase 2 compared with that in phase 1 (2.29% vs 4.31%, P < 0.01). The capacity of our NICU was enlarged following the development of ANTN. There are 200 beds for level 3 infants in phase 2, but there were only 20 beds in phase 1. Significantly less patients in the phase 2 had hypothermia, acidosis and the blood glucose instability than those in phase 1 (P < 0.01, 0.05, 0.01 and 0.05, respectively). The proportion of preterm infants transported to our NICU were higher in phase 2 compared with that in phase 1, especially infants whose gestational age was below 32 weeks. The proportions of asphyxia and respiratory distress syndrome were lower in phase 2 than that in phase 1, but the total cure rates of these two diseases had no significant changes between the two phases. The most important finding was that the improvement of outcome of premature infants and those with asphyxia and aspiration syndrome was noted following the development of ANTN. CONCLUSION: Establishing regional ANTN for a tertiary hospital is very important to elevate the total level in management of critically ill newborn infants. It plays a very important role in reducing mortality and improving total outcomes of newborn infants. There are still some problems remained to solve after four years practice in order to optimize the ANTN to meet needs of the development of neonatology.

[Extracorporeal membrane oxygenation for severe acute respiratory and heart failure in a child with severe pneumonia].

OBJECTIVE: To report clinical application of Extracorporeal membrane oxygenation for severe acute respiratory and heart failure in a child with severe pneumonia. METHOD: A seven-year old male patient with severe pneumonia complicated with heart and lung function failure was admitted to PICU in 28th of December, 2008.Veno-artery access was set up via euthyphoria cannulation in operative incision. Blood was drained from the right atrium through a cannula introduced via femoral veins, and returned via femoral artery. The inter-surface of the ECMO equipment system was completely coated with heparin-coating technique. Anticoagulation was maintained with heparin to keep the activated clotting time (ACT) between 150 and 200 seconds and heparin usage dose was 10 U/(kg.h), mean blood flow was 1/2-2/3 of 80-120 ml/(kg.min) during ECMO assistant period. During ECMO, ventilator settings were gradually reduced to allow lung rest, i.e. peak inspiratory pressure less than 25 cm H2O (1 cm H2O=0.098 kPa), end expiratory pressure 8-10 cm H2O, rate 10-15 breaths per minute and FiO2 30%-40%. RESULTS: In management of ECMO, the incipient blood flow was set at 0.8 L/min, the radio of oxygen and blood flow was 1:1, FiO2 60%. After ten minutes of ECMO working, the blood oxygen saturation of radial artery increased from 40 mm Hg (1 mm Hg=0.133 kPa) to 177 mm Hg, Lac decreased from 3.5 mmol/L to 2.8 mmol/L. Four hours later, blood gas analysis of radial artery showed PaO2 202 mm Hg, PCO2 44 mm Hg, Lac 1.5 mmol/L, blood flow was set at 0.6 L/min, FiO2 60%, PaO2 kept above 150 mm Hg. 96 hours after ECMO supporting, the blood flow was set at 0.4 L/min [20 ml/(kg.min)], the results of blood gas analysis of radial artery was PaO2 190 mm Hg, PaCO2 36 mm Hg, SaO2 100%, Lac 0.9 mmol/L, then the child weaned off successfully from ECMO. Two days later, the child was successfully extubated. After two weeks treatment, the patient was discharged. The main complication associated with extracorporeal membrane oxygenation were bleeding. CONCLUSION: ECMO is an effective mechanical assistant therapy method for severe pulmonary and cardiac failure in a child.

[Influence of human bone marrow-derived mesenchymal stem cells on the lung of newborn rats damaged by hyperoxia].

OBJECTIVE: To evaluate whether human mesenchymal stem cells (hMSCs) administration alter the clinical course of hyperoxia-induced lung injury. METHODS: hMSCs were obtained from bone marrow aspirates from healthy donors after informed consent was signed, hMSCs were separated, cultured, amplified, identified and labeled with BrdU. For BrdU labeling, a sterile stock solution was added to the culture medium 48 h before the end of culture, at a final concentration of 10 micromol/L. Thirty-two 3-day old SD rats from four litters were randomly divided into four groups, as hyperoxia exposed + hMSC group (A), air-exposed + hMSC group (B), hyperoxia exposed group (C), and air-exposed group (D). The rats from the group A and the group C were placed in a sealed Plexiglas chamber with a minimal in- and outflow, providing six to seven exchanges per hour of the chamber volume and maintaining O2 levels above 95%, while the rats in the group B and the group D were only exposed to room air. Seven days later, all of them were taken out of the chamber, rats in the group A and B were injected intraperitoneally with hMSCs (1 x 10(5) in 50 microl of PBS) immediately, while the rats in the group C and D were only treated with 50 microl of PBS 3 days later. All the animals were sacrificed by an injection of sodium pentobarbital (120 mg/kg), perfused with cold 0.9% NaCl, and the left lungs were removed, the upper lobes of which were ground as tissue homogenates and used for ELISA, while the inferior lobes were stored at -70 degrees C until use for RT-PCR. The right lungs were fixed in situ for 2 h by the intratracheal instillation with 10% neutral formalin and then postfixed for 24 h. Sagittal sections (4-microm) of paraffin-embedded middle lobe and upper lobe of the right lung were used for immunohistochemistry and histology, respectively. RESULTS: (1) There was a significant difference in the value of RAC (raditive alveoli coant) among the 4 groups (11.145 +/- 1.331, 13.941 +/- 0.985, 9.595 +/- 0.672, 14.819 +/- 1.080, F = 43.234, P = 0.000). RAC in group A and C were significantly reduced compared with subjects in group D (P < 0.05, P < 0.05); and there was also a significant difference between group A and group C (P < 0.05), but not between group B and D subjects (P > 0.05). (2) There were significant differences in the levels of both TNFalpha and TGFbeta(1) in the homogenate of lungs among the 4 groups (142.933 +/- 24.017, 79.033 +/- 11.573, 224.088 +/- 41.915, 76.500 +/- 10.373, F = 59.970, P = 0.000; 1726.484 +/- 91.086, 1530.359 +/- 173.441, 2047.717 +/- 152.057, 1515.777 +/- 131.049, F = 24.977, P = 0.000). The levels of TNFalpha and TGFbeta1 were significantly elevated in both group A and group C when compared with subjects in group D (P < 0.05 for both). Concentrations of TNFalpha and TGFbeta1 were both significantly decreased in group A versus group C (P < 0.05 for both). There was no significant difference between group B and D subjects in the fields of TNFalpha and TGFbeta(1) (P > 0.05 for both). (3) BrdU-labelled cells were observed at alveolar wall and bronchioles in both group A and group B, and there was a significant difference in BrdU-labeled cells between two groups (0.230 +/- 0.026, 0.190 +/- 0.015; t = 3.769, P = 0.002), but none was found in group C and group D. Electrophoresis of the PCR products showed a 224 bp band, specific for Alu mRNA, in 7 of 8 rats of group A and 5 of 8 rats of group B, respectively, but no such band was found in group C and group D. CONCLUSION: hMSCs administered by intraperitoneal injection could be implanted in the lungs of newborn rats, and they could effectively protect the rats against damage to the lungs caused by hyperoxia.

[Intravenous infusion of rat bone marrow-derived mesenchymal stem cells ameliorates hyperoxia-induced lung injury in neonatal rats].

OBJECTIVE: To investigate the effect of intravenous infusion of rat bone marrow-derived mesenchymal stem cells (MSCs) against lung injuries in neonatal exposed to hyperoxia. METHODS: Rat bone marrow-derived MSCs were separated, cultured, amplified, and labeled with BrdU. Thirty-two 3-day-old SD rats were randomized into 4 equal groups (groups A, B, C and D), and the rats in groups A and B were exposed to 7-day 95% oxygen, while those in groups C and D were not. In groups A and C, the rats received injection with 5x10(4) MSCs via the tail vein, and those in groups B and D were given PBS only. Seventy-two hours after housing in normal air, all the rats were killed to determine the radial alveolar count (RAC) under light microscope. Immunohistochemistry was used to detect BrdU expression in the lung tissue, where the levels of tumor necrosis factoralpha(TNFalpha) and transforming growth factor beta1 (TGFbeta1) were detected using enzyme-linked immunosorbent assay. RESULTS: Compared to air exposure groups, the levels of TNFalpha and TGFbeta1 in the homogenate of the lungs increased while RACs decreased significantly in the two hyperoxia exposure groups. Groups A and B showed significant differences in the fields of RACs and the levels of TNFalpha and TGFbeta1 in the lung tissue homogenate, and BrdU-positive cells were detected only in the lungs of groups A and C, between which a significant quantitative difference was seen. CONCLUSION: Intravenously injected MSCs may reside in the lungs of neonatal rats, which is subject to influences by the exposure conditions, and the transplanted MSCs may offer effective protection against lung injuries induced by hyperoxia.