Invasive fungal infections in critically ill children: epidemiology, risk factors and antifungal drugs.

Background: Invasive fungal infections (IFIs) are important infectious complications amongst critically ill children. The most common fungal infections are due to Candida species. Aspergillus, Zygomycetes and Fusarium are also emerging because of the empirical use of antifungal drugs. This updated review discusses the epidemiology of IFIs as well as antifungal drugs, dosing and potential adverse effects in critically ill children. Methods: A PubMed search was conducted with Clinical Queries using the key terms "antifungal", "children", "critical care" AND "paediatric intensive care unit" OR "PICU". The search strategy included clinical trials, randomized controlled trials, meta-analyses, observational studies and reviews and was limited to the English literature in paediatrics. Results: Candida and Aspergillus spp. are the most prevalent fungi in paediatric IFIs, causing invasive candidiasis infections (ICIs) and invasive aspergillosis infections (IAIs), respectively. These IFIs are associated with high morbidity, mortality and healthcare costs. Candida albicans is the principal Candida spp. associated with paediatric ICIs. The risks and epidemiology for IFIs vary if considering previously healthy children treated in the paediatric intensive care unit or children with leukaemia, malignancy or a severe haematological disease. The mortality rate for IAIs in children is 2.5-3.5-fold higher than for ICIs. Four major classes of antifungals for critically ill children are azoles, polyenes, antifungal antimetabolites and echinocandins. Conclusions: Antifungal agents are highly efficacious. For successful treatment outcomes, it is crucial to determine the optimal dosage, monitor pharmacokinetics parameters and adverse effects, and individualized therapeutic monitoring. Despite potent antifungal medications, ICIs and IAIs continue to be serious infections with high mortality rates. Pre-emptive therapy has been used for IAIs. Most guidelines recommend voriconazole as initial therapy of invasive aspergillosis in most patients, with consideration of combination therapy with voriconazole plus an echinocandin in selected patients with severe disease. The challenge is to identify critically ill patients at high risks of ICIs for targeted prophylaxis. Intravenous/per os fluconazole is first-line pre-emptive treatment for Candida spp. whereas intravenous micafungin or intravenous liposomal amphotericin B is alternative pre-emptive treatment.This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections.

Pattern and prognostic factors for kidney function progression in survivors of children with acute kidney injury: a cohort study.

OBJECTIVE: To examine the pattern of kidney function progression after acute kidney injury (AKI) and identify the associated risk factors. DESIGN: A prospective cohort study was conducted from June 2020 to June 2021 on children aged 1 month to <18 years admitted to the paediatric intensive care unit (PICU). Acute kidney disease (AKD) was defined as AKI persisting from 7 to 90 days after diagnosis. The natural history and prognostic factors of kidney function progression were determined. RESULTS: Among the 253 admissions with a median (IQR) age of 4.9 (9.7) years, the AKI and AKD incidence was 41.9% and 52.2% respectively. The incidence of estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m2 was 6.7% at 90 days and 11.9% at latest follow-up. Severe and prolonged AKI and higher degree of nephrotoxic medication exposure were associated with AKD development. The severity and duration of AKI and AKD significantly predicted kidney function non-recovery. Children with both entities exhibited a higher peak-to-baseline serum creatinine level ratio at 90 days (1.6 vs 1.0, p<0.001), and a more pronounced decline in eGFR (21% vs 19%, p=0.028) during the follow-up period compared with those without AKI/AKD. They also had an increased risk of having eGFR <90 mL/min/1.73 m2 at 90 days (HR 14.9 (95% CI 1.8 to 124.0)) and latest follow-up (HR 3.8 (95% CI 1.1 to 13.1)). CONCLUSIONS: AKI and AKD are prevalent among critically ill children and pose substantial risk for non-recovery of kidney function among PICU survivors. A structural follow-up visit for AKI survivors to monitor kidney function progression is advocated.

The impact of tubular dysfunction and its relationship with acute kidney injury in children.

BACKGROUND: Tubular dysfunction can cause electrolyte disturbances with potentially serious consequences. We studied the epidemiology and outcomes of electrolyte disturbances and tubular dysfunction among critically ill children and evaluated their relationships with acute kidney injury (AKI). METHODS: We conducted a prospective cohort study recruiting children aged 1 month to ≤ 18 years old admitted to the pediatric intensive care unit (PICU) from 6/2020 to 6/2021. The serum levels of sodium, potassium, calcium, phosphate, and magnesium were reviewed and simultaneous urinary investigations for tubular function were performed among children with electrolyte disturbances. RESULTS: Altogether there were 253 episodes of admission. The median (interquartile) age was 4.9 (1.3-11.0) years and 58.1% were male. The median number of electrolyte disorders was 3 (2-4) types. Hypophosphatemia (74.2%), hypocalcemia (70.3%) and hypermagnesemia (52.9%) were the three commonest types of disturbances. Urinary electrolyte wasting was commonly observed among children with hypomagnesemia (70.6%), hypophosphatemia (67.4%) and hypokalemia (28.6%). Tubular dysfunction was detected in 82.6% of patients and urinary ß2-microglobulin level significantly correlated with the severity of tubular dysfunction (p < 0.001). The development of tubular dysfunction was independent of AKI status. Tubular dysfunction was associated with mortality (p < 0.001) and was an independent predictor of PICU length of stay (LOS) (p < 0.001). The incorporation of the tubular dysfunction severity into the AKI staging system improved the prediction of PICU LOS. CONCLUSIONS: Tubular dysfunction was associated with both morbidity and mortality in critically ill children and its assessment may help to capture a more comprehensive picture of acute kidney insult.

Invasive fungal infections in the Paediatric Intensive Care Unit: A Hong Kong Study.

INTRODUCTION: Invasive fungal infections (IFI) cause significant mortality and morbidity in the Paediatric Intensive Care Unit (PICU). Early recognition and prompt treatment of invasive fungal infections are important. This article reviewed the mortality and morbidity of IFIs in the PICU of Hong Kong Children's Hospital.

Methods: Retrospective review of all PICU admissions from April 2019 to May 2021. The following data were retrieved: age, gender, diagnosis, comorbidity, clinical manifestation, type of fungus, duration of stay at PICU, absolute neutrophil count, use of immunosuppressive therapy, presence of central venous catheter and use of total parental nutrition. The primary outcomes were the incidence and mortality of IFIs among PICU patients. The secondary outcomes were risk factors for developing IFI in PICU and clinical course of IFIs. Numerical variables were compared between groups by Mann-Whitney U test and categorical variables by Fisher's exact test.

Results: There were 692 PICU admissions over the study period from April 2019 to May 2021. There were 24 death cases during this period of time. The crude mortality was 3%. Fourteen patients (2%) fulfilling the criteria for IFIs were identified using hospital electronic record system and according to PICU documentation. Eight of these 14 patients (57%) had hematological malignancy, 2 (17%) had solid tumours and 4 had non-oncological conditions. There were 4 (29%) patients who had received hematopoietic stem cells transplant because of oncological problems. Six patients (43%) were neutropenic with absolute neutrophil count less than 1x 109 at diagnosis of IFI. Six (43%) had received immunosuppressive therapy including steroid, cyclosporin A, Mycophenolate mofetil (MMF), Sirolimus or tacrolimus. 12 (86%) had had central venous catheter. Eight (57%) were on parenteral nutrition. Rhizopus or Aspergillus infection (5/14) were associated with nonsurvival (p = 0.031).

Conclusion: All patients with IFIs managed in the PICU have haemato-oncology diseases or are recipients of stem cell transplantation. IFIs with Rhizopus or Aspergillus as a group are associated with high mortality in the PICU. Awareness of this pathology with prompt diagnosis and treatment may improve the outcome of these infections and reduce the mortality.

A case series of appendicitis and pseudo-appendicitis in a paediatric intensive care unit.

INTRODUCTION: Appendicitis is a common childhood condition that can be diagnostically challenging. Severe cases may necessitate support in the critical or intensive care unit. These "critical appendicitis diagnoses" have rarely been described. CASE DESCRIPTION: We retrospective reviewed the PICU database of the Hong Kong Children's Hospital and identified cases of suspected and confirmed appendicitis. Clinical features, radiologic findings and final diagnosis of each case were summarized and reported in this case series. We review six anonymized cases of appendicitis managed in a paediatric intensive care unit (PICU) to illustrate the different age spectrum and clinical manifestations of the condition. Rupture of the inflamed appendix, peritonitis and pancreatitis were some of the complications encountered. Crohn disease was found in one case as an underlying diagnosis. Also, one girl clinically diagnosed with appendicitis was found to be a case of ruptured hepatoblastoma with no appendicitis (i.e., pseudoappendicitis). CONCLUSION: Prompt diagnosis, surgical removal of the inflamed appendix, and use of appropriate antimicrobials when indicated are essential in reducing mortality and morbidity associated with severe appendicitis. Significant premorbid conditions such as acute myeloid leukemia, mitochondrial encephalopathy lactic acidosis syndrome (MELAS), inflammatory bowel disease and complications may be present in patients needing intensive care as is illustrated in the present cases. Pseudoappendicitis is an important differential diagnosis. Imaging is crucial and useful in establishing and confirming the diagnosis of appendicitis and pseudo-appendicitis in these PICU cases.

Risk factors for development of acute kidney injury and acute kidney disease in critically ill children.

BACKGROUND: Acute kidney injury (AKI) is common among critically ill children and these children are at risk of developing acute kidney disease (AKD). METHODS: A prospective cohort study was conducted on children aged > 1 month to ≤ 18 years old admitted to the pediatric intensive care unit (ICU) of Hong Kong Children's Hospital from 6/2020 to 6/2021. The incidences and risk factors of both AKI and AKD were determined. RESULTS: There were 254 eligible admissions (58.3% in males, with a median age of 4.9 [9.7] years). The overall AKI incidence was 41.7% and 56% of children who remained hospitalized in the pediatric  ICU for ≥ 7 days after acquiring AKI developed AKD. Cardiac surgery, bone marrow transplantation and requirement of inotropes were risk factors for both AKI and AKD. The requirement of non-invasive ventilation [relative risk (RR): 2.625 (1.361, 5.064)], total medication dose [RR 1.006 (1.002, 1.010)] and maximal medication intensity [RR 1.154 (1.038, 1.283)] were additional determinants of AKI. Factors indicating more severe AKI and AKI progression were predictive of AKD development. The overall mortality in the pediatric ICU was 3.1%. AKI was significantly associated with mortality (p < 0.001), longer length of hospitalization in the pediatric ICU (p < 0.001) and hospital stay (p < 0.001). AKD was associated with a lower estimated glomerular filtration rate at discharge from the pediatric ICU (p = 0.036). CONCLUSION: AKI and AKD were common among critically ill children, and were associated with significant morbidity and mortality. Few modifiable risk factors, especially those related to nephrotoxic medication exposure, were associated with AKI development and AKD progression.

The Pitfall of Over-Sedation During Recovery From Acute Kidney Injury.

A 14-year-old boy with movement disorder and epilepsy developed status dystonicus leading to rhabdomyolysis and subsequent acute kidney injury requiring continuous renal replacement therapy (CRRT). He was given multiple intravenous sedatives and analgesics to control his dystonia and dyskinesia. 8 days after admission, his condition had improved and a trial termination of CRRT was carried out. The sedatives and analgesics were switched to oral diazepam, morphine, clonidine, and chloral hydrate. However, his renal function did not recover fully. There was rising trend of serum creatinine level with evolving hyperphosphatemia and metabolic acidosis. He also gradually developed hypoventilation, hypercapnia and pinpoint pupils after weaning CRRT. The clinical impression was over-sedation resulting in hypoventilation and respiratory failure, contributed by the deteriorating renal function. Non-invasive ventilatory support was then started and CRRT was resumed. His condition improved over the next 24 hours. Dexmedetomidine infusion was used during CRRT and he slowly required stepping up of sedatives again. A separate set of dosage for all his oral sedative agents was prepared for his subsequent CRRT weaning challenge and no more over-sedative episode was then encountered. Our case illustrated that patients at recovery phase of AKI are susceptible to medication overdose, especially during the period of CRRT weaning. Sedatives and analgesics including morphine and benzodiazepines should be used with caution during this period and alternatives may need to be considered. Advanced planning of medication dosage adjustment is advised to reduce the risk of medication overdose.

The application of hemoadsorption for hyperbilirubinemia and its impact on bilirubin removal kinetics in critically ill children.

Extracorporeal blood purification (EBP) is increasingly applied for bilirubin removal in critical care setting. We retrospectively reviewed the clinical features of children aged 1 month to 18 years old who received EBP for hyperbilirubinemia and explored the bilirubin removal kinetics by hemoadsorption (HA) in the pediatric intensive care unit of Hong Kong Children's Hospital from 3/2019 to 7/2022. Among the 14 episodes of EBP from six patients with a median age (interquartile range [IQR]) of 9.3(5.5) years old, 57.1% of them received HA, 33.3% received single-pass albumin dialysis (SPAD), and 7.1% received combined SPAD and HA. All HA episodes employed the Cytosorb® column. The median (IQR) pre-HA peak total bilirubin level was 406 (254) µmol/L. The saturation duration per HA episode was significantly shorter than the corresponding total treatment duration (8 vs 24 h, p = 0.012), and the median total and effective HA doses were 9.8(6.8) L/kg and 300.0 (163.4) mL/kg/h respectively. The overall bilirubin removal ratio by HA was 44.6 (14.5)%. A higher HA effective dose and a higher pre-HA bilirubin level were both associated with better bilirubin removal. No major EBP-specific complication was encountered. The liver enzymes showed improvement in all children. No patients required liver transplantation. There was no EBP-related mortality, but the overall PICU mortality of the cohort was 50%. HA was a safe and effective modality for bilirubin removal among children. Future studies should investigate the impact of bilirubin removal on clinical outcomes and explore the factors responsible for better removal efficacy.

The Sequential Use of Extracorporeal Cytokine Removal Devices in an Adolescent With COVID-19 Receiving Continuous Renal Replacement Therapy.

A 14-year-old male developed multisystem inflammatory syndrome in children (MIS-C) after acquiring the SARS-CoV-2 infection. He deteriorated rapidly requiring inotropic and ventilatory support as well as continuous renal replacement therapy (CRRT) due to rhabdomyolysis-associated acute kidney injury. A hemoadsoprtion column Cytosorb® was first incorporated into the CRRT circuit for myoglobin and cytokines removal, which was followed by sequential use of another type of cytokine-removing hemofilter (Oxiris®) (altogether 100 hours of extracorporeal blood purification [EBP] therapy). There was no major complication related to the EBP therapy. Cytokine profile revealed a marked reduction of levels of several cytokines including tumor necrosis factor-α, interleukin (IL)-6, IL-8, and IL-10 after the EBP therapy. It was noted that both pro-inflammatory and anti-inflammatory cytokines were removed, and the removal efficacy varied between different devices. His condition improved and the serum ferritin, C-reactive protein, and procalcitonin levels also dropped gradually, which correlated well with his clinical progress and the trend of cytokine levels. Our case demonstrated that extracorporeal cytokine removal can be safely applied in children with MIS-C and can be considered as adjunctive therapy in selected patients with critically ill conditions.

The successful application of hemoadsorption for extracorporeal liver support in a child with acute liver failure.

A 6-year-old boy developed acute liver failure with hepatic coma due to drug rash with eosinophilia and systemic symptoms (DRESS) after multiple antibiotics exposure. He had hyperbilirubinemia, elevated serum bile acids and hyperammonemia with peak serum levels of total bilirubin, direct bilirubin, bile acids and ammonia measuring 418, 328, 174, and 172 µmol/L respectively. In addition to the use of systemic steroid and other supportive therapy, he also received three sessions of hemoadsorption using the Cytosorb® column incorporated into the continuous renal replacement therapy circuit as extracorporeal liver support for a total duration of 75 h, which brought down his serum levels of total bilirubin to 119 µmol/L, bile acids to 58 µmol/L, and ammonia to 55 µmol/L. His conscious level gradually regained coupling an improvement of liver function. Except for mild thrombocytopenia and electrolyte disturbances, the therapy was well tolerated with no major complication encountered. Our case demonstrated that hemoadsorption can be safely employed as an adjunctive extracorporeal liver support modality in children with acute liver failure. The potential role and technical concerns of applying such technique in pediatric patients requires further evaluation in future studies.