Reliability of pulse pressure and stroke volume variation in assessing fluid responsiveness in the operating room: a metanalysis and a metaregression.

BACKGROUND: Pulse pressure and stroke volume variation (PPV and SVV) have been widely used in surgical patients as predictors of fluid challenge (FC) response. Several factors may affect the reliability of these indices in predicting fluid responsiveness, such as the position of the patient, the use of laparoscopy and the opening of the abdomen or the chest, combined FC characteristics, the tidal volume (Vt) and the type of anesthesia. METHODS: Systematic review and metanalysis of PPV and SVV use in surgical adult patients. The QUADAS-2 scale was used to assess the risk of bias of included studies. We adopted a metanalysis pooling of aggregate data from 5 subgroups of studies with random effects models using the common-effect inverse variance model. The area under the curve (AUC) of pooled receiving operating characteristics (ROC) curves was reported. A metaregression was performed using FC type, volume, and rate as independent variables. RESULTS: We selected 59 studies enrolling 2,947 patients, with a median of fluid responders of 55% (46-63). The pooled AUC for the PPV was 0.77 (0.73-0.80), with a mean threshold of 10.8 (10.6-11.0). The pooled AUC for the SVV was 0.76 (0.72-0.80), with a mean threshold of 12.1 (11.6-12.7); 19 studies (32.2%) reported the grey zone of PPV or SVV, with a median of 56% (40-62) and 57% (46-83) of patients included, respectively. In the different subgroups, the AUC and the best thresholds ranged from 0.69 and 0.81 and from 6.9 to 11.5% for the PPV, and from 0.73 to 0.79 and 9.9 to 10.8% for the SVV. A high Vt and the choice of colloids positively impacted on PPV performance, especially among patients with closed chest and abdomen, or in prone position. CONCLUSION: The overall performance of PPV and SVV in operating room in predicting fluid responsiveness is moderate, ranging close to an AUC of 0.80 only some subgroups of surgical patients. The grey zone of these dynamic indices is wide and should be carefully considered during the assessment of fluid responsiveness. A high Vt and the choice of colloids for the FC are factors potentially influencing PPV reliability. TRIAL REGISTRATION: PROSPERO (CRD42022379120), December 2022. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=379120.

MEDTEC Students against Coronavirus: Investigating the Role of Hemostatic Genes in the Predisposition to COVID-19 Severity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Besides virus intrinsic characteristics, the host genetic makeup is predicted to account for the extreme clinical heterogeneity of the disease, which is characterized, among other manifestations, by a derangement of hemostasis associated with thromboembolic events. To date, large-scale studies confirmed that genetic predisposition plays a role in COVID-19 severity, pinpointing several susceptibility genes, often characterized by immunologic functions. With these premises, we performed an association study of common variants in 32 hemostatic genes with COVID-19 severity. We investigated 49,845 single-nucleotide polymorphism in a cohort of 332 Italian severe COVID-19 patients and 1668 controls from the general population. The study was conducted engaging a class of students attending the second year of the MEDTEC school (a six-year program, held in collaboration between Humanitas University and the Politecnico of Milan, allowing students to gain an MD in Medicine and a Bachelor's Degree in Biomedical Engineering). Thanks to their willingness to participate in the fight against the pandemic, we evidenced several suggestive hits (p < 0.001), involving the PROC, MTHFR, MTR, ADAMTS13, and THBS2 genes (top signal in PROC: chr2:127192625:G:A, OR = 2.23, 95%CI = 1.50-3.34, p = 8.77 × 10-5). The top signals in PROC, MTHFR, MTR, ADAMTS13 were instrumental for the construction of a polygenic risk score, whose distribution was significantly different between cases and controls (p = 1.62 × 10-8 for difference in median levels). Finally, a meta-analysis performed using data from the Regeneron database confirmed the contribution of the MTHFR variant chr1:11753033:G:A to the predisposition to severe COVID-19 (pooled OR = 1.21, 95%CI = 1.09-1.33, p = 4.34 × 10-14 in the weighted analysis).

Transient elastography for non-invasive evaluation of post-transplant liver graft fibrosis in children.

As graft survival in pediatric LT is often affected by progressive fibrosis, numerous centers carry out protocol liver biopsies. Follow-up biopsy protocols differ from center to center, but all biopsies are progressively spaced out, as time from transplant increases. Therefore, there is a need for non-invasive techniques to evaluate graft fibrosis progression in those children who have no clinical or serological signs of liver damage. Indirect markers, such as the APRI, should be relied on with caution because their sensitivity in predicting fibrosis can be strongly influenced by the etiology of liver disease, severity of fibrosis, and patient age. A valid alternative could be TE, a non-invasive technique already validated in adults, which estimates the stiffness of the cylindrical volume of liver tissue, 100-fold the size of a standard needle biopsy sample. The aims of this study were to evaluate the reliability of TE in children after LT and to compare both the TE and the APRI index results with the histological scores of fibrosis on liver biopsies. A total of 36 pediatric LT recipients were studied. All patients underwent both TE and biopsy within a year (median interval -0.012 months) at an interval from LT of 0.36 to 19.47 years (median 3.02 years). Fibrosis was assessed on the biopsy specimens at histology and staged according to METAVIR. There was a statistically significant correlation between TE stiffness values and METAVIR scores (P = .005). The diagnostic accuracy of TE for the diagnosis of significant fibrosis (F ≥ 2) was measured as the area under the curve (AUROC = 0.865), and it demonstrated that the method had a good diagnostic performance. APRI was not so accurate in assessing graft fibrosis when compared to METAVIR (AUROC = 0.592). A liver stiffness cutoff value of 5.6 kPa at TE was identified as the best predictor for a significant graft fibrosis (METAVIR F ≥ 2) on liver biopsy, with a 75% sensitivity, a 95.8% specificity, a 90% positive predictive value, and an 88.5% negative predictive value. These data suggest that TE may represent a non-invasive, reliable tool for the assessment of graft fibrosis in the follow-up of LT children, alerting the clinicians to the indication for a liver biopsy, with the aim of reducing the number of protocol liver biopsies.

Biliary Complications after Hepatic Trauma in Children.

AIM OF THE STUDY: In pediatric patients with liver trauma and hemodynamic stability, conservative treatment is acknowledged as the gold standard. PATIENTS AND METHODS: We conducted a retrospective analysis of 116 consecutive pediatric patients (<14-year-old) observed at our institution for closed abdominal trauma from January 2010 to January 2016. Among these, 16 patients (13%) had hepatic trauma Grade II or more, according to Moore liver trauma injury score. RESULTS: Only one patient underwent surgery for hemodynamic instability; all others children received conservative treatment according to the American Paediatric Surgical Association guidelines. Three patients had a biliary complication (2, 5%). two patients treated surgically by drainage insertion and one was managed conservatively. CONCLUSIONS: Biliary complications of liver trauma in children may require aggressive surgical approach in selective patients.

NBAS mutations cause acute liver failure: when acetaminophen is not a culprit.

BACKGROUND: Pediatric acute-liver-failure due to acetaminophen (APAP) administration at therapeutic dosage is rare, while viral infections and metabolic defects are the prevalent causes. Yet, as acetaminophen is routinely used in febrile illnesses, it may be mistakenly held responsible for the acute liver damage. CASE PRESENTATION: An 11 month old boy had been on acetaminophen for 10 days (total dose 720 mg = 72 mg/kg) when he developed acute-liver-failure with encephalopathy. As he rapidly improved on N-acetylcysteine (NAC) infusion, it was concluded that chronic acetaminophen administration in an infant had lead to acute-liver-failure even at therapeutic doses, that N-acetylcysteine infusion had been life-saving and should be immediately started in similar circumstances. The child, however, had two further episodes of acute liver damage over a 34-month period, without having been given acetaminophen, as the parents carefully avoided using it. His clinical, laboratory and radiological findings between the acute episodes were unremarkable. His features and skeletal surveys were not suggestive of a syndromic condition. He then went on to suffer another episode of acute-liver-failure with multi-organ failure, necessitating an urgent liver transplant. All efforts to come to a diagnosis for the causes of his recurrent episodes of liver failure had been unsuccessful, until a biallelic mutation in the NBAS gene was reported to be associated with recurrent acute-liver-failure in children. The boy's DNA analysis revealed compound heterozygous pathogenic mutations in the NBAS gene. Liver failure episodes in these patients are triggered and worsened by fever, most likely due to thermal susceptibility of hepatocytes, hence APAP, rather than being a culprit, is part of the supportive treatment. CONCLUSIONS: We suggest that, in acute-liver-failure with a history of acetaminophen exposure at therapeutic dosage, clinicians should not be contented with administering NAC, but should consider an alternative etiology, above all if the episodes are recurrent, and actively start supportive and antipyretic treatment while seeking the advice of a specialist unit.

Donor CYP3A5 genotype influences tacrolimus disposition on the first day after paediatric liver transplantation.

AIM: The aim of the present study was to investigate the influence of the cytochrome P450 (CYP) 3A4/5 genotype in paediatric liver transplant recipients and donors, and the contribution of age and gender to tacrolimus disposition on the first day after transplantation. METHODS: The contribution of the CYP3A4/5 genotype in paediatric liver transplant recipients and donors to the tacrolimus blood trough concentrations (C0 ) and the tacrolimus concentration/weight-adjusted dose ratio on day 1 was evaluated in 67 liver-transplanted children: 33 boys and 34 girls, mean age 4.5 years. RESULTS: Donor CYP3A5 genotype appears to be significantly associated with tacrolimus disposition on the first day after liver transplantation (P < 0.0002). Other physiological factors, such as recipient age and donor gender may also play a role and lead to significant differences in tacrolimus C0 and tacrolimus concentration/weight-adjusted dose ratio on day 1. However, according to the general linear model, only recipient age appears to be independently associated with tacrolimus disposition on the first day after liver transplantation (P < 0.03). Indeed, there was a faster tacrolimus metabolism in children under 6 years of age (P < 0.02). CONCLUSIONS: Donor CYP3A5 genotype, recipient age and, to a lesser extent, donor gender appear to be associated with tacrolimus disposition on day 1 after transplant. This suggests that increasing the starting tacrolimus doses in paediatric patients under 6 years of age who receive a graft from a male extensive metabolizer may enhance the possibility of their tacrolimus levels reaching the therapeutic range sooner.

Peri-hepatic gauze packing for the control of haemorrhage during liver transplantation: A retrospective study.

BACKGROUND: Albeit accepted in the trauma setting, use of peri-hepatic gauze packing has been rarely reported during liver transplantation. AIMS: To assess the results of packing in liver transplantation. METHODS: We reviewed clinical characteristics, intraoperative events and postoperative outcome of consecutive adult liver transplantation recipients between 2003 and 2013. Patients treated with packing were compared to no-packing patients and to matched controls selected using a propensity score. RESULTS: Of 1396 recipients, 107 were treated with packing for peri-hepatic bleeding (76.6%), allograft damage (12.1%) or partial outflow obstruction (11.2%). Urgent reoperation for ongoing haemorrhage was required in 6 (5.6%). Correction of haemodynamic and coagulation parameters was constantly achieved. Overall, patient (90% vs. 98%, p<0.001) and graft (83.2% vs. 94.7%, p<0.001) 3-month survival was significantly reduced in packing patients. However, after matching, no significant difference was observed in patient (89.3% vs. 95.2%, p=0.12) and graft (83.5% vs. 92.2%, p=0.06) 3-month survival. Patient survival was associated with recipient age (HR 2.59; p=0.04) and donor age × recipient MELD (HR 2.04; p=0.02), but not with packing (HR 1.81; p=0.29). CONCLUSIONS: In our experience, packing was a valuable adjunct to conventional means of haemostasis during liver transplantation and, after accounting for confounding covariates, was not associated with inferior outcomes.

Liver transplantation for aHUS: still needed in the eculizumab era?

BACKGROUND: The risk of disease recurrence after a kidney transplant is high in patients with atypical hemolytic uremic syndrome (aHUS) and mutations in the complement factor H (FH) gene (CFH). Since FH is mostly produced by the liver, a kidney transplant does not correct the genetic defect. The anti-C5 antibody eculizumab prevents post-transplant aHUS recurrence, but it does not cure the disease. Combined liver-kidney transplantation has been performed in few patients with CFH mutations based on the rationale that liver replacement provides a source of normal FH. METHODS: We report the 9-year follow-up of a child with aHUS and a CFH mutation, including clinical data, extensive genetic characterization, and complement profile in the circulation and at endothelial level. The outcome of kidney and liver transplants performed separately 3 years apart are reported. RESULTS: The patient showed incomplete response to plasma, with relapsing episodes, progression to end-stage renal disease, and endothelial-restricted complement dysregulation. Eculizumab prophylaxis post-kidney transplant did not achieve sustained remission, leaving the child at risk of disease recurrence. A liver graft given 3 years after the kidney transplant completely abrogated endothelial complement activation and allowed eculizumab withdrawal. CONCLUSIONS: Liver transplant may definitely cure aHUS and represents an option for patients with suboptimal response to eculizumab.

Early Liver Transplantation for Neonatal-Onset Methylmalonic Acidemia.

With conventional dietary treatment, the clinical course of methylmalonic acidemia due to cobalamin-unresponsive methylmalonyl-CoA mutase (MCM) deficiency is characterized by the persistent risk of recurrent life-threatening decompensation episodes with metabolic acidosis, hyperammonemia, and coma. Liver transplant has been proposed as an alternative treatment and anecdotally attempted in the last 2 decades with inconsistent results. Most criticisms of this approach have been directed at the continuing risk of neurologic and renal damage after transplant. Here, we report the perioperative and postoperative clinical and biochemical outcomes of 2 patients with severe MCM deficiency who underwent early liver transplant. In both cases, liver transplant allowed prevention of decompensation episodes, normalization of dietary protein intake, and a marked improvement of quality of life. No serious complications have been observed at 12 years' and 2 years' follow-up, respectively, except for mild kidney function impairment in the older patient. On the basis of our experience, we strongly suggest that liver transplant should be offered as a therapeutic option for children with cobalamin-unresponsive MCM deficiency at an early stage of the disease.

An UPLC-MS/MS method coupled with automated on-line SPE for quantification of tacrolimus in peripheral blood mononuclear cells.

BACKGROUND: Tacrolimus is an immunosuppressor used to treat patients undergoing liver transplantation. TDM of hematic tacrolimus by liquid chromatography became standard practice, but it does not necessarily reflect its concentration at its active site. Our aim was to validate a new method for tacrolimus quantification into target cells (peripheral blood mononuclear cells, PBMCs) and testing it on 100 real samples from 37 pediatric patients. METHODS: PBMCs were collected using cell-preparation-tubes; cells number and MCV were evaluated. Tacrolimus was quantified using UPLC-MS/MS coupled with a new automated on-line SPE platform. Chromatographic run was performed on an Acquity UPLC(®) BEH C18 1.7 µm (2.1 mm × 50 mm) column for 5 min, with a gradient of water and methanol (both with 2 mM/L ammonium acetate and 1 mL/L formic acid). XBridge(®) C8 10 µm (1 mm × 10 mm) SPE cartridges were used. The internal standard was 6,7-dimethyl-2,3-di(2-pyridyl)quinoxaline. RESULTS: Full validation following FDA guidelines was performed: the method showed high sensitivity and specificity (LLOQ of 0.010 ng; LLOD of 0.005 ng). Intra- and inter-day imprecision and inaccuracy were <15%. A positive and stable matrix effect was observed, with a good recovery for tacrolimus. All drug amounts in real samples resulted within the calibration range and calibration curves were linear (r(2)=0.998). Concentrations from each patient were standardized using their evaluated MCV: intra-PBMCs concentration was meanly 12.7 times higher than the hematic one. CONCLUSION: This method might be eligible and useful for a clinical routine use, giving more reliable data on drug concentration at the active site.

The role of interventional radiology in the treatment of biliary strictures after paediatric liver transplantation.

PURPOSE: The aim of this study is to evaluate the safety and efficacy of percutaneous treatment of biliary strictures after paediatric liver transplantation. MATERIALS AND METHODS: In the period between October 1999 and October 2010, a total of 92 transplants in 86 children were performed at our Liver Transplant Centre. Eighteen patients had anastomotic biliary strictures (in four cases associated with intrahepatic bile duct stenosis). Percutaneous treatment (transhepatic biliary drainage and conventional/cutting balloon dilatation) was proposed as a first approach in 13/18 patients. Strict radiation protection precautions were taken in accordance with the ALARA (as low as reasonably achievable) principle. Mean follow-up time was 2,364 days. RESULTS: Surgical correction was required in 3/13 patients; in 8/13 cases, there was complete disappearance of clinical symptoms without bile duct dilatation; in one case, an asymptomatic persistent bile duct dilatation was detected while in the other case, the liver is currently in cirrhotic degeneration (69 % clinical success including the asymptomatic patient with biliary dilatation). Two of the five patients who were initially treated with surgery required percutaneous revision (clinical success of 100 %). There were two cases of long-term restenosis and two cases of transient haemobilia. CONCLUSIONS: Percutaneous procedures are safe and effective therapeutic options for the treatment of biliary strictures after paediatric liver transplantation.

Percutaneous segmental dilatation of portal stenosis after paediatric liver transplantation to avoid or postpone surgery: two cases and literature review.

PURPOSE: The authors retrospectively reviewed the results obtained with percutaneous treatment of portal stenosis. MATERIALS AND METHODS: In November 2005 and March 2008, two patients, 15 and 32 months old, underwent portal vein angioplasty at our centre. Both procedures were performed after ultrasound-guided portal vein puncture and measurement of pre- and postanastomotic pressure gradients. The diameters of the angioplasty catheters ranged from 5 to 10 mm and no stents were used. RESULTS: In both cases, it was possible to cross the stenoses, perform angioplasty and obtain an immediate reduction of the pressure gradients. There were no major complications after the procedure. In the first patient, percutaneous treatment allowed us to postpone surgical revision of the anastomosis; in the second case, angioplasty had to be repeated twice over a period of 4 years to finally achieve regular patency of the anastomosis and function of the graft. CONCLUSIONS: Percutaneous treatment of portal stenosis after paediatric liver transplantation is a safe and feasible treatment; if balloon dilatation does not guarantee functional recovery of the organ, it allows surgical revision to be postponed to a later date when the clinical condition is more stable.

Liver transplantation after severe hepatic trauma: a sustainable practice. A single-center experience and review of the literature.

Severe hepatic trauma is a rare indication for liver transplantation (LT). We report our single-center experience of LT for hepatic trauma. Four new cases are discussed in light of a literature review in order to depict the pathways leading from hepatic trauma to LT and to assess the outcomes of this practice. LT is generally indicated in case of uncontrollable hemorrhage, acute liver failure, or post-traumatic late sequelae. Hepatic vessels thrombosis, sepsis, major hepatic resections, and a late referral are factors associated with the progression toward irreversible liver failure. Considering all reported cases, early patient and graft survival reached 68% and 62%, respectively, but in the last decade both have improved to 84%. LT after severe hepatic trauma is a sustainable practice considering the current good outcomes and the ineluctable death of these patients without LT.

Combination of tissue expansion and porcine mesh for secondary abdominal wall closure after pediatric liver transplantation.

We report the case of a two and a half yr boy hospitalized in our Pediatric Transplantation Unit for portal vein thrombosis following liver transplantation. After performing a meso-Rex shunt, abdominal wall closure was impossible without compressing the portal flow. A combination of two techniques was used to perform the reconstruction of the muscular fasciae and skin layers. The association of tissue expanders and porcine mesh (Surgisis(®)) allowed complete abdominal wall closure with good functional and esthetic results. Use of both techniques is a useful alternative for difficult abdominal closure after liver pediatric transplantation.

Cushing syndrome due to ectopic adrenocorticotropic hormone secretion in a 3-year-old child.

Ectopic adrenocorticotrophic hormone (ACTH) secretion is a rare cause of Cushing syndrome in paediatric age, due to tumours arising from different tissues. To date, only 11 reports of ACTH-secreting pancreatic tumours in children and adolescents exist in the literature. We present a paediatric case of Cushing syndrome caused by ectopic ACTH secretion. This was caused by a large acinar cell carcinoma that developed in the pancreas of a 3-year-old girl.

Liver retransplantation in children. A 21-year single-center experience.

In this study, the epidemiology and outcome of graft loss following primary pediatric liver transplantation (LT) were analysed, with the hypothesis that early retransplantation (reLT) might be associated with lower immunologic risks when compared with late reLT. Between March 1984 and December 2005, 745 liver grafts were transplanted to 638 children at Saint-Luc University Hospital, Brussels. Among them, a total of 90 children (14%) underwent 107 reLT, and were categorized into two groups (early reLT, n = 58; late reLT, n = 32), according to the interval between either transplant procedures (< or >30 days). Ten-year patient survival rate was 85% in recipients with a single LT, vs. 61% in recipients requiring reLT (P < 0.001). Ten-year patient survival rates were 59% and 66% for early and late reLT, respectively (P = 0.423), the corresponding graft survival rates being 51% and 63% (P = 0.231). Along the successive eras, the rate of reLT decreased from 17% to 10%, whereas progressive improvement of outcome post-reLT was observed. No recurrence of chronic rejection (CR) was observed after reLT for CR (0 of 19). Two children developed a positive cross-match at reLT (two of 10, 20%), both retransplanted lately for CR secondary to immunosuppression withdrawal following a post-transplant lymphoproliferative disease. In summary, the results presented could not evidence better results for late reLT when compared with early reLT. The former did not seem to be associated with higher immunologic risk, except for children having withdrawal of immunosuppression following the first graft.

A new biological mesh for cut surface hemostasis in liver transplantation using technical variants.

The use of a novel biological mesh for surface hemostasis is described in pediatric liver transplantation with alternative techniques. The putative benefits of TachoSil are discussed, particularly in the context of children with impaired coagulation, including fulminant hepatic failure.

Early occurrence of hepatocellular carcinoma in biliary atresia treated by liver transplantation.

A case of liver transplantation for HCC complicating BA in an eight-month old infant is reported. HCC in BA is extremely rare. Screening of AFP and ultrasonographic examination should be performed regularly in patients with secondary biliary cirrhosis for early detection of HCC.