Diagnosis and Management of Esophageal Fistulas After Lung Transplantation: A Case Series.

Background: Lung transplantations are highly complex procedures, often conducted in frail patients. Through the addition of immunosuppressants, healing can be compromised, primarily leading to the development of bronchopleural fistulas. Although esophageal fistulas (EFs) after lung transplantation remain rare, they are associated with significant morbidity. We aimed to investigate the clinical presentation, diagnostic approaches, and treatment strategies of EF after lung transplantation. Methods: All patients who developed EF after lung transplantation at the University Hospitals Leuven between January 2019 and March 2022 were retrospectively reviewed and the clinical presentations, diagnostic approaches, and treatment strategies were summarized. Results: Among 212 lung transplantation patients, 5 patients (2.4%) developed EF. Three patients were male and median age was 39 y (range, 34-63). Intraoperative circulatory support was required in 3 patients, with 2 needing continued support postoperatively. Bipolar energy devices were consistently used for mediastinal hemostasis. All EFs were right-sided. Median time to diagnosis was 28 d (range, 12-48) and 80% of EFs presented as recurrent respiratory infections or empyema. Diagnosis was made through computed tomography (n = 3) or esophagogastroscopy (n = 2). Surgical repair with muscle flap covering achieved an 80% success rate. All patients achieved complete resolution, with only 1 patient experiencing a fatal outcome during a complicated EF-related recovery. Conclusion: Although EF after lung transplantation remains rare, vigilance is crucial, particularly in cases of right-sided intrathoracic infection. Moreover, caution must be exercised when applying thermal energy in the mediastinal area to prevent EF development and mitigate the risk of major morbidity. Timely diagnosis and surgical intervention can yield favorable outcomes.

Tight Blood-Glucose Control without Early Parenteral Nutrition in the ICU.

BACKGROUND: Randomized, controlled trials have shown both benefit and harm from tight blood-glucose control in patients in the intensive care unit (ICU). Variation in the use of early parenteral nutrition and in insulin-induced severe hypoglycemia might explain this inconsistency. METHODS: We randomly assigned patients, on ICU admission, to liberal glucose control (insulin initiated only when the blood-glucose level was >215 mg per deciliter [>11.9 mmol per liter]) or to tight glucose control (blood-glucose level targeted with the use of the LOGIC-Insulin algorithm at 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]); parenteral nutrition was withheld in both groups for 1 week. Protocol adherence was determined according to glucose metrics. The primary outcome was the length of time that ICU care was needed, calculated on the basis of time to discharge alive from the ICU, with death accounted for as a competing risk; 90-day mortality was the safety outcome. RESULTS: Of 9230 patients who underwent randomization, 4622 were assigned to liberal glucose control and 4608 to tight glucose control. The median morning blood-glucose level was 140 mg per deciliter (interquartile range, 122 to 161) with liberal glucose control and 107 mg per deciliter (interquartile range, 98 to 117) with tight glucose control. Severe hypoglycemia occurred in 31 patients (0.7%) in the liberal-control group and 47 patients (1.0%) in the tight-control group. The length of time that ICU care was needed was similar in the two groups (hazard ratio for earlier discharge alive with tight glucose control, 1.00; 95% confidence interval, 0.96 to 1.04; P = 0.94). Mortality at 90 days was also similar (10.1% with liberal glucose control and 10.5% with tight glucose control, P = 0.51). Analyses of eight prespecified secondary outcomes suggested that the incidence of new infections, the duration of respiratory and hemodynamic support, the time to discharge alive from the hospital, and mortality in the ICU and hospital were similar in the two groups, whereas severe acute kidney injury and cholestatic liver dysfunction appeared less prevalent with tight glucose control. CONCLUSIONS: In critically ill patients who were not receiving early parenteral nutrition, tight glucose control did not affect the length of time that ICU care was needed or mortality. (Funded by the Research Foundation-Flanders and others; TGC-Fast ClinicalTrials.gov number, NCT03665207.).

Development and validation of the creatinine clearance predictor machine learning models in critically ill adults.

BACKGROUND: In critically ill patients, measured creatinine clearance (CrCl) is the most reliable method to evaluate glomerular filtration rate in routine clinical practice and may vary subsequently on a day-to-day basis. We developed and externally validated models to predict CrCl one day ahead and compared them with a reference reflecting current clinical practice. METHODS: A gradient boosting method (GBM) machine-learning algorithm was used to develop the models on data from 2825 patients from the EPaNIC multicenter randomized controlled trial database. We externally validated the models on 9576 patients from the University Hospitals Leuven, included in the M@tric database. Three models were developed: a "Core" model based on demographic, admission diagnosis, and daily laboratory results; a "Core + BGA" model adding blood gas analysis results; and a "Core + BGA + Monitoring" model also including high-resolution monitoring data. Model performance was evaluated against the actual CrCl by mean absolute error (MAE) and root-mean-square error (RMSE). RESULTS: All three developed models showed smaller prediction errors than the reference. Assuming the same CrCl of the day of prediction showed 20.6 (95% CI 20.3-20.9) ml/min MAE and 40.1 (95% CI 37.9-42.3) ml/min RMSE in the external validation cohort, while the developed model having the smallest RMSE (the Core + BGA + Monitoring model) had 18.1 (95% CI 17.9-18.3) ml/min MAE and 28.9 (95% CI 28-29.7) ml/min RMSE. CONCLUSIONS: Prediction models based on routinely collected clinical data in the ICU were able to accurately predict next-day CrCl. These models could be useful for hydrophilic drug dosage adjustment or stratification of patients at risk. TRIAL REGISTRATION: Not applicable.

External Validation of the Augmented Renal Clearance Predictor in Critically Ill COVID-19 Patients.

The ARC predictor is a prediction model for augmented renal clearance (ARC) on the next intensive care unit (ICU) day that showed good performance in a general ICU setting. In this study, we performed a retrospective external validation of the ARC predictor in critically ill coronavirus disease 19 (COVID-19) patients admitted to the ICU of the University Hospitals Leuven from February 2020 to January 2021. All patient-days that had serum creatinine levels available and measured creatinine clearance on the next ICU day were enrolled. The performance of the ARC predictor was evaluated using discrimination, calibration, and decision curves. A total of 120 patients (1064 patient-days) were included, and ARC was found in 57 (47.5%) patients, corresponding to 246 (23.1%) patient-days. The ARC predictor demonstrated good discrimination and calibration (AUROC of 0.86, calibration slope of 1.18, and calibration-in-the-large of 0.14) and a wide clinical-usefulness range. At the default classification threshold of 20% in the original study, the sensitivity and specificity were 72% and 81%, respectively. The ARC predictor is able to accurately predict ARC in critically ill COVID-19 patients. These results support the potential of the ARC predictor to optimize renally cleared drug dosages in this specific ICU population. Investigation of dosing regimen improvement was not included in this study and remains a challenge for future studies.

Mucorales PCR in blood as an early marker of invasive gastrointestinal mucormycosis might decrease the delay in treatment: A case report.

We describe the fatal case of a patient with gastric perforation due to ischemia and necrosis of the stomach secondary to generalized vascular thrombosis following allogeneic hematopoietic cell transplantation. Histopathological examination of the resected stomach, spleen and omentum unexpectedly showed fungal hyphae suggestive of invasive mucormycosis. We retrospectively performed Mucorales PCR (MucorGenius®, PathoNostics, Maastricht, The Netherlands) in blood and tissue samples of this patient. The PCR was positive 16 days before time of death and 9 days before abdominal pain.

Kidney Dysfunction After Traumatic Brain Injury: Pathophysiology and General Management.

Traumatic brain injury (TBI) remains a major cause of mortality and morbidity, and almost half of these patients are admitted to the intensive care unit. Of those, 10% develop acute kidney injury (AKI) and 2% even need kidney replacement therapy (KRT). Although clinical trials in patients with TBI who have AKI are lacking, some general principles in this population may apply. The present review is an overview on the epidemiology and pathophysiology of AKI in patients with TBI admitted to the intensive care unit who are at risk for or who have developed AKI. A cornerstone in severe TBI management is preventing secondary brain damage, in which reducing the intracranial pressure (ICP) and optimizing the cerebral perfusion pressure (CPP) remain important therapeutic targets. To treat episodes of elevated ICP, osmolar agents such as mannitol and hypertonic saline are frequently administered. Although we are currently awaiting the results of a prospective randomized controlled trial that compares both agents, it is important to realize that both agents have been associated with an increased risk of developing AKI which is probably higher for mannitol compared with hypertonic saline. For the brain, as well as for the kidney, targeting an adequate perfusion pressure is important. Hemodynamic management based on the combined use of intravascular fluids and vasopressors is ideally guided by hemodynamic monitoring. Hypotonic albumin or crystalloid resuscitation solutions may increase the risk of brain edema, and saline-based solutions are frequently used but have a risk of hyperchloremia, which might jeopardize kidney function. In patients at risk, frequent assessment of serum chloride might be advised. Maintenance of an adequate CPP involves the optimization of circulating blood volume, often combined with vasopressor agents. Whether individualized CPP targets based on cerebrovascular autoregulation monitoring are beneficial need to be further investigated. Interestingly, such individualized perfusion targets are also under investigation in patients as a strategy to mitigate the risk for AKI in patients with chronic hypertension. In the small proportion of patients with TBI who need KRT, continuous techniques are advised based on pathophysiology and expert opinion. The need for KRT is associated with a higher risk of intracranial hypertension, especially if osmolar clearance occurs fast, which can even occur in continuous techniques. Precise ICP and CPP monitoring is mandatory, especially at the initiation of KRT.

Development and validation of clinical prediction models for acute kidney injury recovery at hospital discharge in critically ill adults.

PURPOSE: Acute kidney injury (AKI) recovery prediction remains challenging. The purpose of the present study is to develop and validate prediction models for AKI recovery at hospital discharge in critically ill patients with ICU-acquired AKI stage 3 (AKI-3). METHODS: Models were developed and validated in a development cohort (n = 229) and a matched validation cohort (n = 244) from the multicenter EPaNIC database to create prediction models with the least absolute shrinkage and selection operator (Lasso) machine-learning algorithm. We evaluated the discrimination and calibration of the models and compared their performance with plasma neutrophil gelatinase-associated lipocalin (NGAL) measured on first AKI-3 day (NGAL_AKI3) and reference model that only based on age. RESULTS: Complete recovery and complete or partial recovery occurred in 33.20% and 51.23% of the validation cohort patients respectively. The prediction model for complete recovery based on age, need for renal replacement therapy (RRT), diagnostic group (cardiac/surgical/trauma/others), and sepsis on admission had an area under the receiver operating characteristics curve (AUROC) of 0.53. The prediction model for complete or partial recovery based on age, need for RRT, platelet count, urea, and white blood cell count had an AUROC of 0.61. NGAL_AKI3 showed AUROCs of 0.55 and 0.53 respectively. In cardiac patients, the models had higher AUROCs of 0.60 and 0.71 than NGAL_AKI3's AUROCs of 0.52 and 0.54. The developed models demonstrated a better performance over the reference models (only based on age) for cardiac surgery patients, but not for patients with sepsis and for a general ICU population. CONCLUSION: Models to predict AKI recovery upon hospital discharge in critically ill patients with AKI-3 showed poor performance in the general ICU population, similar to the biomarker NGAL. In cardiac surgery patients, discrimination was acceptable, and better than NGAL. These findings demonstrate the difficulty of predicting non-reversible AKI early.

Acute kidney injury in critical COVID-19: a multicenter cohort analysis in seven large hospitals in Belgium.

BACKGROUND: Acute kidney injury (AKI) has been reported as a frequent complication of critical COVID-19. We aimed to evaluate the occurrence of AKI and use of kidney replacement therapy (KRT) in critical COVID-19, to assess patient and kidney outcomes and risk factors for AKI and differences in outcome when the diagnosis of AKI is based on urine output (UO) or on serum creatinine (sCr). METHODS: Multicenter, retrospective cohort analysis of patients with critical COVID-19 in seven large hospitals in Belgium. AKI was defined according to KDIGO within 21 days after ICU admission. Multivariable logistic regression analysis was used to explore the risk factors for developing AKI and to assess the association between AKI and ICU mortality. RESULTS: Of 1286 patients, 85.1% had AKI, and KRT was used in 9.8%. Older age, obesity, a higher APACHE II score and use of mechanical ventilation at day 1 of ICU stay were associated with an increased risk for AKI. After multivariable adjustment, all AKI stages were associated with ICU mortality. AKI was based on sCr in 40.1% and UO in 81.5% of patients. All AKI stages based on sCr and AKI stage 3 based on UO were associated with ICU mortality. Persistent AKI was present in 88.6% and acute kidney disease (AKD) in 87.6%. Rapid reversal of AKI yielded a better prognosis compared to persistent AKI and AKD. Kidney recovery was observed in 47.4% of surviving AKI patients. CONCLUSIONS: Over 80% of critically ill COVID-19 patients had AKI. This was driven by the high occurrence rate of AKI defined by UO criteria. All AKI stages were associated with mortality (NCT04997915).

Overall performance of a drug-drug interaction clinical decision support system: quantitative evaluation and end-user survey.

BACKGROUND: Clinical decision support systems are implemented in many hospitals to prevent medication errors and associated harm. They are however associated with a high burden of false positive alerts and alert fatigue. The aim of this study was to evaluate a drug-drug interaction (DDI) clinical decision support system in terms of its performance, uptake and user satisfaction and to identify barriers and opportunities for improvement. METHODS: A quantitative evaluation and end-user survey were performed in a large teaching hospital. First, very severe DDI alerts generated between 2019 and 2021 were evaluated retrospectively. Data collection comprised alert burden, override rates, the number of alert overrides reviewed by pharmacists and the resulting pharmacist recommendations as well as their acceptance rate. Second, an e-survey was carried out among prescribers to assess satisfaction, usefulness and relevance of DDI alerts as well as reasons for overriding. RESULTS: A total of 38,409 very severe DDI alerts were generated, of which 88.2% were overridden by the prescriber. In 3.2% of reviewed overrides, a recommendation by the pharmacist was provided, of which 79.2% was accepted. False positive alerts were caused by a too broad screening interval and lack of incorporation of patient-specific characteristics, such as QTc values. Co-prescribing of a non-vitamin K oral anticoagulant and a low molecular weight heparin accounted for 49.8% of alerts, of which 92.2% were overridden. In 88 (1.1%) of these overridden alerts, concurrent therapy was still present. Despite the high override rate, the e-survey revealed that the DDI clinical decision support system was found useful by prescribers. CONCLUSIONS: Identified barriers were the lack of DDI-specific screening intervals and inclusion of patient-specific characteristics, both leading to a high number of false positive alerts and risk for alert fatigue. Despite these barriers, the added value of the DDI clinical decision support system was recognized by prescribers. Hence, integration of DDI-specific screening intervals and patient-specific characteristics is warranted to improve the performance of the DDI software.

An update on congenital melanocytic nevus syndrome: A case report and literature review.

Congenital melanocytic nevus syndrome (CMNS) is a rare condition characterized by pigmented skin lesions that are usually present at birth and are associated with an increased risk of neurological abnormalities and malignant melanoma. It mostly results from a post-zygotic NRAS mutation of neural-derived crest cells, leading to uncontrolled cell growth. Because of the increased knowledge of the genetics underlying CMNS, targeted therapy becomes a promising treatment option. We present a case of CMNS in a newborn. Physical examination at birth showed a giant congenital melanocytic nevus, extending from the occipital to the lower lumbar region. A magnetic resonance imaging scan revealed multiple cerebral and cerebellar parenchymal lesions. Genetic analysis of the cutaneous lesions showed the presence of an NRAS Q61R mutation. The patient was treated with dermabrasion to reduce the color intensity of the nevus. However, this was complicated by recurrent wound infections and laborious wound healing. At the age of 1 year, the patient had an age-appropriate psychomotor development, without neurological deficits.

Povidone Iodine Disinfection Associated with Hypothyroidism and Potentially Contributing to Prolonged Kidney Failure.

OBJECTIVES: To report a case of povidone-iodine (PVP-I, Iso-Betadine®) disinfection of lower leg fasciotomy wounds resulting in iodide absorption and possibly contributing to hypothyroidism and prolonged kidney injury. DESIGN: Case report. Setting. Pediatric intensive care unit (PICU), university hospital. Patients. A 13-year-old patient presenting with prolonged oligoanuric kidney failure and unexplained primary hypothyroidism three weeks after severe abdominal sepsis with multiple organ dysfunction and major rhabdomyolysis due to bilateral lower leg compartment syndrome, necessitating moderate size fasciotomies, disinfected daily with PVP-I. Interventions. Interruption of PVP-I exposure and initiation of thyroid hormone substitution. Measurements and Main Results. Hypothyroidism was revealed during diagnostic work-up for persistent hypertriglyceridemia. Thyroxine (T4) (4.0 mg/L) and tri-iodothyronine (T3) (64 ng/L) were moderately low, yet thyroid stimulating hormone (TSH) (16.8 mIU/L) was fourfold the maximal normal range value. This pattern, atypical for prolonged critical illness-related hypothyroidism, prompted interruption of PVP-I exposure and initiation of thyroid hormone substitution. Urinary production and creatinine clearance recovered during the following days, and one week later, intermittent renal replacement therapy could be terminated, suggesting that PVP-I toxicity and/or hypothyroidism may have contributed to the persistent renal failure three weeks after resolved septic shock and rhabdomyolysis. Elevated serum and urinary anion gap normalized simultaneously, but this evolution of rather nonspecific indices could be multifactorial. CONCLUSION: PVP-I is a commonly used broad-spectrum antimicrobial agent for prevention and treatment of wound infections. Toxic complications due to PVP-I absorption, after disinfection of extended thermal injuries larger than 20% of the body surface, have been described. In critically ill children, however, toxic effects of PVP-I may occur due to repeated disinfection of less extended wounds. Proposed screening strategies include: monitoring of the volumes of PVP-I applied daily; of the thyroid function, the serum, and/or urinary anion gap and the urinary iodide concentrations. These strategies, however, remain to be validated. This case report should be a wake-up call for daily integration of wound management in the clinical evaluation of critically ill patients.

Artificial intelligence to guide management of acute kidney injury in the ICU: a narrative review.

PURPOSE OF REVIEW: Acute kidney injury (AKI) frequently complicates hospital admission, especially in the ICU or after major surgery, and is associated with high morbidity and mortality. The risk of developing AKI depends on the presence of preexisting comorbidities and the cause of the current disease. Besides, many other parameters affect the kidney function, such as the state of other vital organs, the host response, and the initiated treatment. Advancements in the field of informatics have led to the opportunity to store and utilize the patient-related data to train and validate models to detect specific patterns and, as such, predict disease states or outcomes. RECENT FINDINGS: Machine-learning techniques have also been applied to predict AKI, as well as the patients' outcomes related to their AKI, such as mortality or the need for kidney replacement therapy. Several models have recently been developed, but only a few of them have been validated in external cohorts. SUMMARY: In this article, we provide an overview of the machine-learning prediction models for AKI and its outcomes in critically ill patients and individuals undergoing major surgery. We also discuss the pitfalls and the opportunities related to the implementation of these models in clinical practices.

Cytomegalovirus: A Troll in the ICU? Overview of the Literature and Perspectives for the Future.

Cytomegalovirus (CMV) is one of the most pathogenic viruses in human. After a primary infection, CMV resides in the host for life as a latent infection. When immunity is reduced, CMV can escape the suppressive effects of the immune system and lead to viremia and antigenemia. This reactivation, first seen in transplant patients, has also been documented in non-immunocompromised CMV-seropositive critically ill patients and is associated with higher morbidity and mortality. In the latter, it is not clear whether CMV reactivation is an innocent bystander or the cause of this observed worse outcome. Two studies showed no difference in the outcome of CMV-seropositive and seronegative patients. In addition, proof-of-concept studies investigating prophylactic antiviral treatment to prevent CMV reactivation during critical illness, failed to show a beneficial effect on interleukin levels or clinical outcome. Further research is necessary to resolve the question whether CMV replication impairs the prognosis in non-immunocompromised critically ill patients. We here give a concise overview on the available data and propose strategies to further unravel this question. First, post-mortem investigation may be useful to evaluate the effect of viral replication on organ inflammation and function. Second, further research should focus on the question whether the level of viremia needs to exceed a threshold to be associated with worse outcome. Third, clinical and biochemical assessments may help to identify patients at high risk for reactivation. Fourth, preemptive treatment based upon early detection of the virus is currently under investigation. Finally, immune-stimulating biologicals may be beneficial in high-risk groups.

The soluble mannose receptor (sMR/sCD206) in critically ill patients with invasive fungal infections, bacterial infections or non-infectious inflammation: a secondary analysis of the EPaNIC RCT.

BACKGROUND: Invasive fungal infections (IFI) are difficult to diagnose, especially in critically ill patients. As the mannose receptor (MR) is shed from macrophage cell surfaces after exposure to fungi, we investigate whether its soluble serum form (sMR) can serve as a biomarker of IFI. METHODS: This is a secondary analysis of the multicentre randomised controlled trial (EPaNIC, n = 4640) that investigated the impact of initiating supplemental parenteral nutrition (PN) early during critical illness (Early-PN) as compared to withholding it in the first week of intensive care (Late-PN). Serum sMR concentrations were measured in three matched patient groups (proven/probable IFI, n = 82; bacterial infection, n = 80; non-infectious inflammation, n = 77) on the day of antimicrobial initiation or matched intensive care unit day and the five preceding days, as well as in matched healthy controls (n = 59). Independent determinants of sMR concentration were identified via multivariable linear regression. Serum sMR time profiles were analysed with repeated-measures ANOVA. Predictive properties were assessed via area under the receiver operating curve (aROC). RESULTS: Serum sMR was higher in IFI patients than in all other groups (all p < 0.02), aROC to differentiate IFI from no IFI being 0.65 (p < 0.001). The ability of serum sMR to discriminate infectious from non-infectious inflammation was better with an aROC of 0.68 (p < 0.001). The sMR concentrations were already elevated up to 5 days before antimicrobial initiation and remained stable over time. Multivariable linear regression analysis showed that an infection or an IFI, higher severity of illness and sepsis upon admission were associated with higher sMR levels; urgent admission and Late-PN were independently associated with lower sMR concentrations. CONCLUSION: Serum sMR concentrations were higher in critically ill patients with IFI than in those with a bacterial infection or with non-infectious inflammation. However, test properties were insufficient for diagnostic purposes.