Monocytic Human Leukocyte Antigen-DR Expression Levels to Predict Outcome in Children With Severe Sepsis.

OBJECTIVE: To assess the association between monocytic Human Leukocyte Antigen-DR (mHLA-DR)expression and outcome in children with severe sepsis. METHODS: Consecutive children, aged 29 days to 15 years, who were admitted with severe sepsis or septic shock in the pediatric intensive care unit (PICU) were enrolled. mHLA-DR expression (antigen bound per cell (ABC)) was assessed on two time points: between 72 to 120 hours (P1) and 121 to 168 hours (P2), of stay in PICU and the difference between the two was calculated as delta mHLA-DR. Outcomes were noted for survival, mortality and secondary infection during the hospital stay. RESULTS: Forty-seven children with median (IQR) age 24 (10, 96) months and a median (IQR) and duration of illness of 3 (3, 5) days, were enrolled consecutively. Pediatric Logistic Organ Dysfunction (PELOD) score >10 was observed in 63.8% children. 18 children succumbed. The median mHLA-DR levels (ABC) at P1 were significantly higher in children who survived as compared with those who expired (7409 vs. 2509, P = 0.004). Similarly, the median mHLA-DR levels (ABC) at P2 were higher in those who survived than the expired group (14728 vs. 2085, P = 0.001). The median delta mHLA-DR levels (ABC) were 4574 and 309 for the survived and expired group, respectively (P = 0.012). mHLA-DR at 72 to 120 hrs (P = 0.004), mHLA-DR at 121 to 168 hrs (P = 0.001) and delta mHLA-DR (P = 0.012) was significantly associated with mortality but not associated with secondary infection. A negative correlation was observed between PELOD score and mHLA-DR at P1 (r = -0.25, P = 0.46), at P2 (r = -0.425, P = 0.018) and delta mHLA-DR (r = -0.27, P = 0.41). The area under curve (95%CI) of mHLA-DR expression (ABC) at P2 for a cutoff of < 6631 was 0.966 (0.907, 1.0) to predict mortality in severe sepsis. CONCLUSION: mHLA-DR levels were significantly lower in children who succumbed than those who survived at both time points. mHLA-DR levels can be a useful biomarker to diagnose immune-paralysed state.

Central Venous Catheter-associated Venous Thromboembolism in Children: A Prospective Observational Study.

Our objective was to study the proportion of children developing Catheter-related thrombosis (CRT) following central venous Catheter (CVC) insertion and the risk factors of CRT in pediatric patients with CVC. One hundred four children aged 29 days to 18 years who had a percutaneous non-tunneled CVC inserted were enrolled. Ultrasonogram (USG) with venous Doppler scan was performed within 48 hours of CVC removal to diagnose CRT. The major indications for CVC insertion were surgical care 34 (32.6%) and ICU care 28(26.9%). The median age of the patients was 3 years, and 75% were males. The median number of CVC days was 10 (IQR 5.15). CRT was seen in 45(43.3%), of which 33 (73.3%) were asymptomatic. The rate of CRT was 35.69 cases per 1000 CVC days (95% CI 26.03-47.75). The number of days a catheter was in place and USG-guided catheter insertion was a significant risk factor. The multivariate logistic regression model showed that the duration of CVC in situ was independently associated with the development of CRT (OR, 1.06; 95% CI 1.0-1.1; P=0.02). CVC duration was a major risk factor for the development of CRT. There was a higher risk of developing a symptomatic CRT with central venous catheters than hemodialysis sheaths.

Approach to fever in children.

BACKGROUND: Fever in children is one of the most common reasons for outpatient visits as well as in-patient evaluation, often causing anxiety among parents and caregivers. Fever can be a standalone feature or be associated with other localising symptoms and signs like rash, lymphadenopathy, or any other organ system involvement with or without a focus of infection. The etiologies of fever vary depending on the clinical setting and epidemiology. India being a tropical country, sees a distinct spectrum of tropical infections. Physicians need to stay updated on the prevalent diseases in their region and the unique factors that may influence the clinical presentations and course of fever in the cohort of children they manage. The challenge lies in balancing the benefit of early treatment for severe diseases versus the harms of unnecessary investigations and treatment for self-resolving illnesses. OBJECTIVES: This review aims to provide a comprehensive overview of fever in children, covering its etiology, clinical features, and management strategies. This review offers an algorithmic approach to fever tailored to the Indian setting to guide physicians in identifying the disease based on clinical symptoms and signs, ordering essential laboratory investigations, and initiating appropriate management promptly. CONTENT: The review categorises fever into various segments like fever with localising signs like rash, lymphadenopathy, fever due to infection localised to a particular organ system, and fever without a focus including fever of unknown origin. It delves into the diverse etiological factors contributing to fever in each of these categories, encompassing infectious and non-infectious origins. It gives pointers to identify the etiology from history, examination, and confirm them with judicious use of diagnostic investigations with emphasis on identifying the red flag signs that require immediate attention, especially in vulnerable groups like neonates and young infants.

Longitudinal Echocardiographic Follow-Up of a Pediatric Multisystem Inflammatory Syndrome Cohort.

OBJECTIVE: Significant involvement of the cardiovascular system is known in multisystem inflammatory syndrome in children (MIS-C). This study aimed to examine the recovery of affected cardiovascular parameters over a medium-term follow-up. METHODS: A cohort of 69 children was studied prospectively. Assessments of left ventricular (LV) function and coronary artery abnormalities (CAA) were conducted at admission, 1.5 months, and 3 months. Coronavirus Disease 2019 (COVID-19) antibody titers were assessed at these three time points. Echocardiographic and antibody parameters (rising/decreasing) were analyzed for correlation. Outcomes were assessed using logistic regression. RESULTS: At admission, among the 78.2% of patients who were tested, 88.9% tested positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). A quarter of the patients had pericardial effusion, and half had valvulitis. Decreased ejection fraction, global circumferential strain (GCS), and global longitudinal strain (GLS) were seen in 54.4%, 68.6%, and 35.8% of patients, respectively. CAAs were observed in 27.78% of patients. Systolic dysfunction was significantly associated with older age. During follow-up, severe LV dysfunction normalized within 6-7 weeks, while mild to moderate dysfunction reached normalcy by two weeks. Both GCS and GLS reached normalcy within a median of two weeks. Diastolic parameters recovered by six weeks. Most small and moderate coronary aneurysms resolved, but a giant aneurysm in an infant remained large even after 15 months. Trends in antibodies and ejection fraction (EF) at three months were significantly correlated. Admission EF, GLS (at 6 weeks) and deceleration time (at 3 months) were significantly associated with intensive care unit (ICU) admission. The median segmental strain of the cohort remained low in certain segments at three months. CONCLUSION: Smaller CAAs resolve, whereas giant CAAs persist. EF and GLS are important predictors of Pediatric Intensive Care Unit (PICU) stay. The residual impairment of median segmental strain and persistent diastolic dysfunction at three months indicate the need for long-term follow-up.

Transplanting the Liver for a New Life: Can the Kidney Throw in a Spanner?

How to cite this article: Parameswaran N. Transplanting the Liver for a New Life: Can the Kidney Throw in a Spanner? Indian J Crit Care Med 2024;28(1):13-14.

Korean red ginseng extract prevents bone loss in an oral model of glucocorticoid induced osteoporosis in mice.

The gut microbiota and barrier function play important roles in bone health. We previously demonstrated that chronic glucocorticoid (GC)-induced bone loss in mice is associated with significant shifts in gut microbiota composition and impaired gut barrier function. Korean Red Ginseng (KRG, Panax Ginseng Meyer, Araliaceae) extract has been shown to prevent glucocorticoid-induced osteoporosis (GIO) in a subcutaneous pellet model in mice, but its effect on gut microbiota and barrier function in this context is not known. The overall goal of this study was to test the effect of KRG extract in a clinically relevant, oral model of GIO and further investigate its role in modulating the gut-bone axis. Growing male mice (CD-1, 8 weeks) were treated with 75 µg/mL corticosterone (∼9 mg/kg/day) or 0.4% ethanol vehicle in the drinking water for 4 weeks. During this 4-week period, mice were treated daily with 500 mg/kg/day KRG extract dissolved in sterile water or an equal amount of sterile water via oral gastric gavage. After 4 weeks of treatment, we assessed bone volume, microbiota composition, gut barrier integrity, and immune cells in the bone marrow (BM) and mesenteric lymph nodes (MLNs). 4 weeks of oral GC treatment caused significant distal femur trabecular bone loss, and this was associated with changes in gut microbiota composition, impaired gut barrier function and altered immune cell composition. Importantly, KRG extract prevented distal femur trabecular bone loss and caused significant alterations in gut microbiota composition but had only modest effects on gut barrier function and immune cell populations. Taken together, these results demonstrate that KRG extract significantly modulates the gut microbiota-bone axis and prevents glucocorticoid-induced bone loss in mice.

Clinical Profile and Outcomes of Children with Acute Liver Failure in a Tertiary Care Center in South India: A Retrospective Study.

Purpose: In this study, we investigated the clinical profile, survival at discharge, and proportion of children with acute liver failure (ALF) meeting the criteria for, yet surviving without, liver transplantation (LT). Methods: Medical case records of children aged >28 days to ≤15 years over a period of 7 years, identified from pediatric admission and discharge registers, were screened. Children satisfying the criteria for ALF were included in this study. Results: A total of 71 records meeting the pediatric ALF (PALF) criteria were included. The survival rate at discharge was 61% (n=44). A considerable proportion of children satisfied the King's College Criteria (KCC) (56.3%) and the European Association for the Study of the Liver (EASL) criteria (7%) for LT at admission. Nonetheless, the survival rate in the absence of LT was 42.5% in children who satisfied the KCC and 20% in those who met the EASL criteria. Infection (29.5%) and paracetamol overdose (19.7%) were the major identifiable causes of PALF. Hepatitis A was the most common infection identified. No significant predictors of poor outcomes were identified in multivariable analysis. Conclusion: Our study highlights the changing survival rates and the clinical and etiological profiles of patients with PALF. In areas with poor access to LT services, survival in these children could be improved through early referral to centers with adequate intensive care facilities. Preventing ALF and referring patients to LT services are paramount to reducing mortality.

Lactobacillus Reuteri 6475 Prevents Bone Loss in a Clinically Relevant Oral Model of Glucocorticoid-Induced Osteoporosis in Male CD-1 Mice.

Glucocorticoids (GCs) are commonly used anti-inflammatory medications with significant side effects, including glucocorticoid-induced osteoporosis (GIO). We have previously demonstrated that chronic subcutaneous GC treatment in mice leads to gut barrier dysfunction and trabecular bone loss. We further showed that treating with probiotics or barrier enhancers improves gut barrier function and prevents GIO. The overall goal of this study was to test if probiotics could prevent GC-induced gut barrier dysfunction and bone loss in a clinically relevant oral-GC model of GIO. Eight-week-old male CD-1 mice were treated with vehicle or corticosterone in the drinking water for 4 weeks and administered probiotics Lactobacillus reuteri ATCC 6475 (LR 6475) or VSL#3 thrice weekly via oral gavage. As expected, GC treatment led to significant gut barrier dysfunction (assessed by measuring serum endotoxin levels) and bone loss after 4 weeks. Serum endotoxin levels significantly and negatively correlated with bone volume. Importantly, LR 6475 treatment effectively prevented both GC-induced increase in serum endotoxin and trabecular bone loss. VSL#3 had intermediate results, not differing from either control or GC-treated animals. GC-induced reductions in femur length, cortical thickness, and cortical area were not affected by probiotic treatment. Taken together, these results are the first to demonstrate that LR 6475 effectively prevents the detrimental effects of GC treatment on gut barrier, which correlates with enhanced trabecular bone health in an oral mouse model of GIO. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Vitamin D and Its Myriad Disease Associations: Can the Heart be Left Behind?

How to cite this article: Parameswaran N. Vitamin D and Its Myriad Disease Associations: Can the Heart be Left Behind? Indian J Crit Care Med 2023;27(7):463-464.

Advances in Management of Respiratory Failure in Children.

Providing the right respiratory support is an essential skill, vital for anyone treating sick children. Recent advances in respiratory support include developments in both non-invasive and invasive ventilatory strategies. In non-invasive ventilation, newer modalities are being developed, in an attempt to decrease the need for invasive ventilation. This include newer techniques like Heated humidified high-flow nasal cannula (HHHFNC) and improvements in existing modes. The success of Continuous positive airway pressure (CPAP) and other non-invasive modes depend to a large extent on choosing and maintaining a suitable interface. When it comes to invasive ventilation, recent advances are focussing on increasing automation, improving patient comfort and minimising lung injury. Concepts like mechanical power are attempts at understanding the mechanisms of unintended injuries resulting from respiratory support and newer monitoring methods like transpulmonary pressure, thoracic impedance tomography are attempts at measuring potential markers of lung injury. Using the vast arrays of available ventilatory options judiciously, considering their advantages and drawbacks in every individual case will be the prime responsibility of clinicians in the future. Simultaneously, efforts have been made to identify potential drugs that can favourably modify the pathophysiology of acute respiratory distress syndrome (ARDS). Unfortunately, though eagerly awaited, most pharmaceutical agents tried in pediatric ARDS have not shown definite benefit. Pulmonary local drug and gene therapy using liquid ventilation strategies may revolutionize our future understanding and management of lung diseases.

Authors' Reply on: FOCUS more on POCUS.

How to cite this article: Subramani S, Parameswaran N. Authors' Reply on: FOCUS more on POCUS. Indian J Crit Care Med 2023;27(3):226-227.

Korean Red Ginseng extract treatment prevents post-antibiotic dysbiosis-induced bone loss in mice.

Background: The intestinal microbiota is an important regulator of bone health. In previous studies we have shown that intestinal microbiota dysbiosis, induced by treatment with broad spectrum antibiotics (ABX) followed by natural repopulation, results in gut barrier dysfunction and bone loss. We have also shown that treatment with probiotics or a gut barrier enhancer can inhibit dysbiosis-induced bone loss. The overall goal of this project was to test the effect of Korean Red Ginseng (KRG) extract on bone and gut health using antibiotics (ABX) dysbiosis-induced bone loss model in mice. Methods: Adult male mice (Balb/C, 12-week old) were administered broad spectrum antibiotics (ampicillin and neomycin) for 2 weeks followed by 4 weeks of natural repopulation. During this 4-week period, mice were treated with vehicle (water) or KRG extract. Other controls included mice that did not receive either antibiotics or KRG extract and mice that received only KRG extract. At the end of the experiments, we assessed various parameters to assess bone, microbiota and in vivo intestinal permeability. Results: Consistent with our previous results, post-ABX- dysbiosis led to significant bone loss. Importantly, this was associated with a decrease in gut microbiota alpha diversity and an increase in intestinal permeability. All these effects including bone loss were prevented by KRG extract treatment. Furthermore, our studies identified multiple genera including Lactobacillus and rc4-4 as well as Alistipes finegoldii to be potentially linked to the effect of KRG extract on gut-bone axis. Conclusion: Together, our results demonstrate that KRG extract regulates the gut-bone axis and is effective at preventing dysbiosis-induced bone loss in mice.

Etiology and outcomes of acute kidney disease in children: a cohort study.

BACKGROUND: There is paucity of information regarding the etiology and outcomes of Acute Kidney Disease (AKD) in children. METHODS: The objectives of this cohort study were to evaluate the etiology and outcomes of AKD; and analyze predictors of kidney survival (defined as free of CKD 2, 3a, 3b, 4 or 5). Patients aged 1 month to 18 years who developed AKD over a 4-year-period (January 2018-December 2021) were enrolled. Survivors were followed-up at the pediatric nephrology clinic, and screened for residual kidney injury. RESULTS: Among 5710 children who developed AKI, 200 who developed AKD were enrolled. The median (IQR) eGFR was 17.03 (10.98, 28) mL/min/1.73 m2. Acute glomerulonephritis, acute tubular necrosis (ATN), hemolytic uremic syndrome (HUS), sepsis-associated AKD, and snake envenomation comprised of 69 (34.5%), 39 (19.5%), 24 (12%), 23 (11.5%) and 15 (7.5%) of the patients respectively. Overall, 88 (44%) children required kidney replacement therapy (KRT). There were 37 (18.5%) deaths within the AKD period. At a follow-up of 90 days, 32 (16%) progressed to chronic kidney disease stage-G2 or greater. At a median (IQR) follow-up of 24 (6, 36.5) months (n = 154), 27 (17.5%) had subnormal eGFR, and 20 (12.9%) had persistent proteinuria and/or hypertension. Requirement of KRT predicted kidney survival (free of CKD 2, 3a, 3b, 4 or 5) in AKD (HR 6.7, 95% CI 1.2, 46.4) (p 0.04). CONCLUSIONS: Acute glomerulonephritis, ATN, HUS, sepsis-associated AKD and snake envenomation were common causes of AKD. Mortality in AKD was 18.5%, and 16% progressed to CKD-G2 or greater at 90-day follow-up.

Glucocorticoid-induced osteoporosis is prevented by dietary prune in female mice.

Glucocorticoid-induced osteoporosis (GIO) is a significant side effect of prolonged glucocorticoid (GC) treatment. Chronic GC treatment also leads to trabecular bone loss and gut microbiota dysbiosis in mice. The gut dysbiosis is mechanistically linked to GIO, which indicates that the microbiota can be targeted to prevent GIO. Prunes, a dried fruit and prebiotic, have emerged in the literature as an effective treatment for sex-steroid deficiency induced osteoporosis (primary osteoporosis). Prunes also significantly alter the composition of the gut microbiota in both rodent models and human studies. Therefore, we tested if dietary prune (DP) supplementation could prevent GC-induced bone loss and affect microbiota composition in an established model of GIO. Sixteen-week-old, skeletally mature, female C57BL/6J mice were treated with a subcutaneous 5 mg placebo or prednisolone pellet for 8 weeks and fed an AIN-93M control diet or a diet modified to include 5, 15, or 25% (w/w) dried California prune powder. As expected, GC treated mice developed significant trabecular bone loss in the distal femur. More importantly, as little as 5% DP supplementation effectively prevented trabecular bone loss. Further, dose dependent increases in trabecular bone volume fraction were observed in GC + 15% and GC + 25% DP mice. Amazingly, in the placebo (non-GC treated) groups, 25% DP supplementation caused a ∼3-fold increase in distal femur trabecular bone volume fraction; this sizable bone response has not been previously observed in healthy mice with gut targeted natural treatments. Along with the striking effect on bone health, GC treatment and 25% DP supplementation led to drastic shifts in gut microbiota composition and several specific changes are strongly associated with bone health. Taken together, these results are the first to demonstrate that DP supplementation effectively prevents the negative effects of prolonged GC therapy on trabecular bone health and strongly associates with shifts in the composition of the gut microbiota.

Serum Ferritin for Predicting Outcome in Children With Severe Sepsis in the Pediatric Intensive Care Unit.

OBJECTIVES: To evaluate the prognostic ability of serum ferritin when estimated within 5 days of onset of illness in children with severe sepsis admitted to a pediatric intensive care unit. METHODS: This observational study enrolled children aged 1 month to 12 years with severe sepsis. Hemoglobin, serum ferritin and C-reactive protein levels were measured within five days of illness. Final outcomes were recorded in all enrolled children. RESULTS: 70 children with median (IQR) age of 27 (8,108) months were enrolled during the study period (July, 2019 to August, 2021). 28 (40%) of these had poor outcome (non-survival). The median (IQR) level of serum ferritin was 1369 (558-5607) ng/mL in non-survivors and 282 (129-680) ng/mL in survivors (P<0.05). A significant correlation was seen between serum ferritin and Pediatric Risk of Mortality III (PRISM III) score (r=0.364 P=0.002) and pediatric Sequential Organ Failure Assessment (pSOFA) score (r=0.246 P=0.04) at 48 hours of admission. 54 (77.1%) children were anemic. Serum ferritin levels in children with anemia also had a good predictive ability for poor outcome [AUC: 0.764, 95% CI: 0.634, 0.894]. CONCLUSIONS: Serum ferritin levels, within five days of onset of illness, predicted poor outcome in critically ill children with severe sepsis and in children with microcytic anemia.

Syk promotes phagocytosis by inducing reactive oxygen species generation and suppressing SOCS1 in macrophage-mediated inflammatory responses.

OBJECTIVE: Inflammation, a vital innate immune response against infection and injury, is mediated by macrophages. Spleen tyrosine kinase (Syk) regulates inflammatory responses in macrophages; however, its role and underlying mechanisms are uncertain. MATERIALS AND METHODS: In this study, overexpression and knockout (KO) cell preparations, phagocytosis analysis, confocal microscopy, reactive oxygen species (ROS) determination, mRNA analysis, and immunoprecipitation/western blotting analyses were used to investigate the role of Syk in phagocytosis and its underlying mechanisms in macrophages during inflammatory responses. RESULTS: Syk inhibition by Syk KO, Syk-specific small interfering RNA (siSyk), and a selective Syk inhibitor (piceatannol) significantly reduced the phagocytic activity of RAW264.7 cells. Syk inhibition also decreased cytochrome c generation by inhibiting ROS-generating enzymes in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and ROS scavenging suppressed the phagocytic activity of RAW264.7 cells. LPS induced the tyrosine nitration (N-Tyr) of suppressor of cytokine signaling 1 (SOCS1) through Syk-induced ROS generation in RAW264.7 cells. On the other hand, ROS scavenging suppressed the N-Tyr of SOCS1 and phagocytosis. Moreover, SOCS1 overexpression decreased phagocytic activity, and SOCS1 inhibition increased the phagocytic activity of RAW264.7 cells. CONCLUSION: These results suggest that Syk plays a critical role in the phagocytic activity of macrophages by inducing ROS generation and suppressing SOCS1 through SOCS1 nitration during inflammatory responses.