How to use meropenem in pediatric patients undergoing CKRT? Integrated meropenem pharmacokinetic model for critically ill children.

Standard dosing could fail to achieve adequate systemic concentrations in ICU children or may lead to toxicity in children with acute kidney injury. The population pharmacokinetic analysis was used to simultaneously analyze all available data (plasma, prefilter, postfilter, effluent, and urine concentrations) and provide the pharmacokinetic characteristics of meropenem. The probability of target fT > MIC attainment, avoiding toxic levels, during the entire dosing interval was estimated by simulation of different intermittent and continuous infusions in the studied population. A total of 16 critically ill children treated with meropenem were included, with 7 of them undergoing continuous kidney replacement therapy (CKRT). Only 33% of children without CKRT achieved 90% of the time when the free drug concentration exceeded the minimum inhibitory concentration (%fT > MIC) for an MIC of 2 mg/L. In dose simulations, only continuous infusions (60-120 mg/kg in a 24-h infusion) reached the objective in patients <30 kg. In patients undergoing CKRT, the currently used schedule (40 mg/kg/12 h from day 2 in a short infusion of 30 min) was clearly insufficient in patients <30 kg. Keeping the dose to 40 mg/kg q8h without applying renal adjustment and extended infusions (40 mg/kg in 3- or 4-h infusion every 12 h) was sufficient to reach 90% fT > MIC (>2 mg/L) in patients >10 kg. In patients <10 kg, only continuous infusions reached the objective. In patients >30 kg, 60 mg/kg in a 24-h infusion is sufficient and avoids toxicity. This population model could help with an individualized dosing approach that needs to be adopted in critically ill pediatric patients. Critically ill patients subjected to or not to CKRT may benefit from the administration of meropenem in an extended or continuous infusion.

Description of a Swine Infant Model of Volume-Controlled Hemorrhagic Shock.

Hemorrhagic shock is a leading cause of morbidity and mortality in pediatric patients. Interpretation of the clinical indicators validated in adults to guide resuscitation and comparison between different therapies is difficult in children due to the inherent heterogeneity of this population. As a result, compared to adults, appropriate management of pediatric hemorrhagic shock is still not well established. In addition, the scarcity of pediatric patients with hemorrhagic shock precludes the development of clinically relevant studies. For this reason, an experimental pediatric animal model is necessary to study the effects of hemorrhage in children as well as their response to different therapies. We present an infant animal model of volume-controlled hemorrhagic shock in anesthetized young pigs. Hemorrhage is induced by withdrawing a previously calculated blood volume, and the pig is subsequently monitored and resuscitated with different therapies. Here, we describe a precise and highly reproducible model of hemorrhagic shock in immature swine. The model yields hemodynamic data that characterizes compensatory mechanisms that are activated in response to severe hemorrhage.

Volumetric capnography and return of spontaneous circulation in an experimental model of pediatric asphyxial cardiac arrest.

A secondary analysis of a randomized study was performed to study the relationship between volumetric capnography (VCAP) and arterial CO2 partial pressure (PCO2) during cardiopulmonary resuscitation (CPR) and to analyze the ability of these parameters to predict the return of spontaneous circulation (ROSC) in a pediatric animal model of asphyxial cardiac arrest (CA). Asphyxial CA was induced by sedation, muscle relaxation and extubation. CPR was started 2 min after CA occurred. Airway management was performed with early endotracheal intubation or bag-mask ventilation, according to randomization group. CPR was continued until ROSC or 24 min of resuscitation. End-tidal carbon dioxide (EtCO2), CO2 production (VCO2), and EtCO2/VCO2/kg ratio were continuously recorded. Seventy-nine piglets were included, 26 (32.9%) of whom achieved ROSC. EtCO2 was the best predictor of ROSC (AUC 0.72, p < 0.01 and optimal cutoff point of 21.6 mmHg). No statistical differences were obtained regarding VCO2, VCO2/kg and EtCO2/VCO2/kg ratios. VCO2 and VCO2/kg showed an inverse correlation with PCO2, with a higher correlation coefficient as resuscitation progressed. EtCO2 also had an inverse correlation with PCO2 from minute 18 to 24 of resuscitation. Our findings suggest that EtCO2 is the best VCAP-derived parameter for predicting ROSC. EtCO2 and VCO2 showed an inverse correlation with PCO2. Therefore, these parameters are not adequate to measure ventilation during CPR.

Association between pediatric intensive care mortality and mechanical ventilation settings during extracorporeal membrane oxygenation for pediatric acute respiratory distress syndrome.

The main objective of this study was to describe the current mechanical ventilation (MV) settings during extracorporeal membrane oxygenation (ECMO) for pediatric acute respiratory distress syndrome (P-ARDS) in six European centers. This is a retrospective observational cohort study performed in six European centers from January 2009 to December 2019. Children > 1 month to 18 years supported with ECMO for refractory P-ARDS were included. Collected data were as follows: patients' pre-ECMO medical condition, pre-ECMO adjunctive therapies for P-ARDS, pre-ECMO and during ECMO MV settings on day (D) 1, D3, D7, and D14 of ECMO, use of adjunctive therapies during ECMO, duration of ECMO, pediatric intensive care unit length of stay, and survival. A total of 255 patients with P-ARDS were included. The multivariate analysis showed that PEEP on D1 (OR = 1.13, 95% CI [1.03-1.24], p = 0.01); D3 (OR = 1.17, 95% CI [1.06-1.29], p = 0.001); and D14 (OR = 1.21, 95% CI [1.05-1.43], p = 0.02) and DP on D7 were significantly associated with higher odds of mortality (OR = 0.82, 95% CI [0.71-0.92], p = 0.001). Moreover, DP on D1 above 15 cmH2O (OR 2.23, 95% CI (1.09-4.71), p = 0.03) and native lung FiO2 above 60% on D14 (OR 10.36, 95% CI (1.51-116.15), p = 0.03) were significantly associated with higher odds of mortality.   Conclusion: MV settings during ECMO for P-ARDS varied among centers; however, use of high PEEP levels during ECMO was associated with higher odds of mortality as well as a DP above 15 cmH2O and a native lung FiO2 above 60% on D14 of ECMO. What is Known: • Invasive ventilation settings are well defined for pediatric acute respiratory distress syndrome; however, once the children required an extracorporeal respiratory support, there is no recommendation how to set the mechanical ventilator. • Impact of invasive ventilator during extracorporeal respiratory support ad only been during the first days of this support but the effects of these settings later in the assistance are not described. What is New: • It seems to be essential to early decrease FiO2 on native lung once the ECMO flow allows an efficient oxygenation. • Tight control to limit the driving pressure at 15 cmH20 during ECMO run seems to be associated with better survival rate.

Prospective observational study on the use of continuous intravenous ketamine and propofol infusion for prolonged sedation in critical care.

INTRODUCTION: Analgesia and sedation are a priority in paediatric intensive care. The combination of ketamine and propofol is a possible option in patients requiring prolonged or difficult sedation and to reduce the use of benzodiazepines and opiates. The aim of this study was to assess the efficacy and safety of combination ketamine and propofol in continuous infusion for prolonged analgesia/sedation in the paediatric intensive care setting. PATIENTS AND METHODS: Prospective, observational single-group cohort study in patients aged 1 month to 16 years admitted to the paediatric intensive care unit in 2016-2018 that received ketamine and propofol in continuous infusion for analgesia and sedation. We collected data on demographic and clinical characteristics, analgesia and sedation scores (MAPS, COMFORT-B and SOPHIA), haemodynamic parameters and adverse events. RESULTS: The study included 32 patients. The maximum dose of ketamine was 1.5 mg/kg/h (interquartile range [IQR], 1-2 mg/kg/h) and the infusion duration was 5 days (IQR, 3-5 days). The maximum dose of propofol was 3.2 mg/kg/h (IQR, 2.5-3.6 mg/kg/h) and the infusion duration, 5 days (IQR, 3-5 days). Thirty (93.7%) patients had previously received midazolam and 29 (90.6%) fentanyl. Analgesia scores did not change after initiation of the ketamine and propofol infusion. There was a statistically significant increase in the COMFORT-B score, but the score remained in the adequate sedation range (12-17). There were small but statistically significant decreases in the mean arterial pressure (from 64 mmHg to 60 mmHg; P = .006) and the diastolic blood pressure (from 50.5 to 48 mmHg; P = .023) 1 h after the initiation of the ketamine and propofol infusion, but this difference was not observed 12 h later and did not require administration of vasoactive drugs. No other major adverse events were detected during the infusion. CONCLUSIONS: The combination of ketamine and propofol in continuous infusion is a safe treatment in critically ill children that makes it possible to achieve an appropriate level of analgesia and sedation without relevant haemodynamic repercussions.

Evaluation of tracheal intubations in a paediatric intensive care unit.

INTRODUCTION: Tracheal intubation is a frequent procedure in paediatric intensive care units (PICUs) that carries a risk of complications that can increase morbidity and mortality. PATIENTS AND METHODS: Prospective, longitudinal, observational study in patients intubated in a level III PICU between January and December 2020. We analysed the risk factors associated with failed intubation and adverse events. RESULTS: The analysis included 48 intubations. The most frequent indication for intubation was hypoxaemic respiratory failure (25%). The first attempt was successful in 60.4% of intubations, without differences between procedures performed by staff physicians and resident physicians (62.5% vs 56.3%; P = .759). Difficulty in bag-mask ventilation was associated with failed intubation in the first attempt (P = .028). Adverse events occurred in 12.5% of intubations, and severe events in 8.3%, including 1 case of cardiac arrest, 2 cases of severe hypotension and 1 of oesophageal intubation with delayed recognition. None of the patients died. Making multiple attempts was significantly associated with adverse events (P < .002). Systematic preparation of the procedure with cognitive aids and role allocation was independently associated with a lower incidence of adverse events. CONCLUSIONS: In critically ill children, first-attempt intubation failure is common and associated with difficulty in bag-mask ventilation. A significant percentage of intubations may result in serious adverse events. The implementation of intubation protocols could decrease the incidence of adverse events.

Population pharmacokinetics of piperacillin in critically ill children including those undergoing continuous kidney replacement therapy.

OBJECTIVES: Despite that piperacillin-tazobactam combination is commonly used in critically ill children, increasing evidence suggests that the current dosing schedules are not optimal for these patients. The aim of this work is to develop a population pharmacokinetic model for piperacillin to evaluate the efficacy of standard dosing in children with and without continuous kidney replacement therapy (CKRT) and to propose alternative dosing schemes maximizing target attainment. METHODS: Four hundred twenty-nine piperacillin concentrations measured in different matrices, obtained from 32 critically ill children (19 without CKRT, 13 with CKRT) receiving 100 mg/kg of piperacillin/tazobactam every 8 hours (increased to 12 hours after the fourth dose) were modelled simultaneously using the population approach with NONMEM 7.4. The percentage of patients with 90% fT > MIC and target attainment (percentage of dosing interval above MIC) were estimated for different intermittent and continuous infusions in the studied population. RESULTS: Piperacillin pharmacokinetic was best described with a two-compartment model. Renal, nonrenal, and hemofilter clearances were found to be influenced by the glomerular filtration rate, height (renal clearance), weight (nonrenal clearance), and filter surface (hemofilter clearance). Only seven (37%) children without CKRT and seven (54%) with CKRT achieved 90% fT > MIC with the current dosing schedule. Of the alternative regimens evaluated, a 24-hour continuous infusion of 200 mg/kg (CKRT) and 300 mg/kg (no CKRT) provided 100% fT > MIC (percent of time free drug remains above the minimum inhibitory concentration) (≤16 mg/L) and target attainments ≥90% across all evaluated MICs. DISCUSSION: In children with and without CKRT, standard dosing failed to provide an adequate systemic exposure, while prolonged and continuous infusions showed an improved efficacy.

Multicenter randomized clinical trial comparing dexamethasone versus placebo in preventing upper airway obstruction after extubation in critically ill children.

To analyze the effectiveness of dexamethasone in preventing upper airway obstruction (UAO) symptoms after extubation and the need of reintubation in critically ill children. Multicenter, prospective, double-blind, randomized, phase IV clinical trial involving five pediatric intensive care units. Children between 1 month and 16 years-of-age intubated for more than 48 h were included. Patients were randomized to receive placebo or dexamethasone 0.25 mg/kg every 6 h, 6-to-12 h prior to extubation (four doses). 48 h follow-up was carried out after extubation. Severity of UAO symptoms (Taussig score, stridor) and reintubation requirement were compared. 147 patients were randomized (10 were excluded), 70 patients received dexamethasone and 67 placebo. No global differences were found in the presence of stridor or moderate-to-severe UAO symptoms (Taussig ≥ 5), but Taussig ≥ 5 was less frequent in patients less than 2 years-of-age treated with steroids (p = 0.014). Median Taussig score was lower in the dexamethasone group 1 h after extubation, p < 0.001. 27 patients required reintubation, 9 due to UAO: 3 (4.3%) in the dexamethasone group and 6 (8.9%) in the placebo group, p = 0.319. In those intubated > 5 days, reintubation due to UAO was higher in the placebo group (2.4% vs. 14.3, p = 0.052). Nebulized epinephrine and budesonide were required more frequently in the placebo group in the first 2 h (p = 0.041) and 1 h (p = 0.02) after extubation, respectively. No relevant side effects were observed. Dexamethasone prior to extubation did not significantly reduce moderate-severe UAO symptoms, except for patients under 2-years of age. Dexamethasone could decrease Taussig score and the need of rescue therapies, as well as reintubation rates in those intubated for more than 5 days.

Fatal Staphylococcus Aureus Endocarditis Misdiagnosed as Multisystem Inflammatory Syndrome in Children.

We present a case of a 10-year-old male with Staphylococcus aureus mitral endocarditis who was initially misdiagnosed with multisystem inflammatory syndrome associated with coronavirus disease 2019, with eventual fatal outcome due to brain hemorrhage after cardiac intervention. Our case differs from recent studies, in which microbleeds did not increase the risk of hemorrhagic stroke or global mortality risk.

Acute Hypoxemic Respiratory Failure in Children at the Start of COVID-19 Outbreak: A Nationwide Experience.

STUDY DESIGN: This is a prospective, multicenter, and observational study with the aim of describing physiological characteristics, respiratory management, and outcomes of children with acute hypoxemic respiratory failure (AHRF) from different etiologies receiving invasive mechanical ventilation (IMV) compared with those affected by SARS-CoV-2. METHODS AND MAIN RESULTS: Twenty-eight patients met the inclusion criteria: 9 patients with coronavirus disease 2019 (COVID-19) and 19 patients without COVID-19. Non-COVID-19 patients had more pre-existing comorbidities (78.9% vs. 44.4%) than COVID-19 patients. At AHRF onset, non-COVID-19 patients had worse oxygenation (PaO2/FiO2 = 95 mmHg (65.5-133) vs. 150 mmHg (105-220), p = 0.04), oxygenation index = 15.9 (11-28.4) vs. 9.3 (6.7-10.6), p = 0.01), and higher PaCO2 (48 mmHg (46.5-63) vs. 41 mmHg (40-45), p = 0.07, that remained higher at 48 h: 54 mmHg (43-58.7) vs. 41 (38.5-45.5), p = 0.03). In 12 patients (5 COVID-19 and 7 non-COVID-19), AHRF evolved to pediatric acute respiratory distress syndrome (PARDS). All non-COVID-19 patients had severe PARDS, while 3 out of 5 patients in the COVID-19 group had mild or moderate PARDS. Overall Pediatric Intensive Care Medicine (PICU) mortality was 14.3%. CONCLUSIONS: Children with AHRF due to SARS-CoV2 infection had fewer comorbidities and better oxygenation than patients with non-COVID-19 AHRF. In this study, progression to severe PARDS was rarely observed in children with COVID-19.

Effects of airway management and tidal volume feedback ventilation during pediatric resuscitation in piglets with asphyxial cardiac arrest.

To compare the effect on the recovery of spontaneous circulation (ROSC) of early endotracheal intubation (ETI) versus bag-mask ventilation (BMV), and expiratory real-time tidal volume (VTe) feedback (TVF) ventilation versus without feedback or standard ventilation (SV) in a pediatric animal model of asphyxial cardiac arrest. Piglets were randomized into five groups: 1: ETI and TVF ventilation (10 ml/kg); 2: ETI and TVF (7 ml/kg); 3: ETI and SV; 4: BMV and TVF (10 ml/kg) and 5: BMV and SV. Thirty breaths-per-minute guided by metronome were given. ROSC, pCO2, pO2, EtCO2 and VTe were compared among groups. Seventy-nine piglets (11.3 ± 1.2 kg) were included. Twenty-six (32.9%) achieved ROSC. Survival was non-significantly higher in ETI (40.4%) than BMV groups (21.9%), p = 0.08. No differences in ROSC were found between TVF and SV groups (30.0% versus 34.7%, p = 0.67). ETI groups presented lower pCO2, and higher pO2, EtCO2 and VTe than BMV groups (p < 0.05). VTe was lower in TVF than in SV groups and in BMV than in ETI groups (p < 0.05). Groups 1 and 3 showed higher pO2 and lower pCO2 over time, although with hyperventilation values (pCO2 < 35 mmHg). ETI groups had non significantly higher survival rate than BMV groups. Compared to BMV groups, ETI groups achieved better oxygenation and ventilation parameters. VTe was lower in both TVF and BMV groups. Hyperventilation was observed in intubated animals with SV and with 10 ml/kg VTF.

Case Report: Severe ARDS in a Pediatric Hematopoietic Stem-Cell Transplantation Recipient Caused by Disseminated Toxoplasmosis.

Toxoplasma gondii infection is a severe complication of hematopoietic stem-cell transplantation (HSCT) recipients that can remain unnoticed without a high clinical suspicion. We present the case of a 6-year-old patient with acute lymphoblastic leukemia and HSCT recipient who was admitted to the Pediatric Intensive Care Unit (PICU) on post-transplantation day +39 with fever, hypotension, severe respiratory distress and appearance of a lumbar subcutaneous node. She developed severe Acute Respiratory Distress Syndrome (ARDS) and underwent endotracheal intubation and early mechanical ventilation. Subsequently, she required prone ventilation, inhaled nitric oxide therapy and high-frequency oscillatory ventilation (HFOV). An etiologic study was performed, being blood, urine, bronchoalveolar lavage and biopsy of the subcutaneous node positive for Toxoplasma gondii by Polymerase Chain Reaction (PCR). Diagnosis of disseminated toxoplasmosis was established and treatment with pyrimethamine, sulfadiazine and folinic acid started. The patient showed clinical improvement, allowing weaning of mechanical ventilation and transfer to the hospitalization ward after 40 days in the PICU. It is important to consider toxoplasmosis infection in immunocompromised patients with sepsis and, in cases of severe respiratory distress, early mechanical ventilation should be started using the open lung approach. In Toxoplasma IgG positive patients, close monitoring and appropriate anti-infectious prophylaxis is needed after HSCT.

Hemolysis and methemoglobinemia in a child with left ventricular assist Levitronix PediMag.

A 5-month-old male was treated with left ventricular assist device due to cardiac failure secondary to dilated cardiomyopathy. The patient developed acute severe intravascular hemolysis with methemoglobinemia and renal failure, related to a mechanical problem due to pump cylinder misalignment. Secondary severe methemoglobinemia has not been previously described in patients undergoing ventricular assist device. Early detection of the signs and symptoms of hemolysis is crucial to prevent further complications.

Inhaled sedation with sevoflurane in critically ill children during extracorporeal membrane oxygenation.

Sedation can be challenging in critically ill children. Inhaled anesthetics such as sevoflurane have proved to be useful in difficult or long-term sedation. However, its use in children out of the operating room is still limited and little is yet known about its use in patients undergoing ECMO with no previous reports in children. The objective is to assess the effectiveness and safety of sevoflurane during ECMO in two pediatric patients. Sedation was successfully achieved in both patients, and patients' contribution to breathing was possible even with deep sedation. There were not any side effects during sevoflurane treatment or after withdrawal.

Finding the Dose for Ceftolozane-Tazobactam in Critically Ill Children with and without Acute Kidney Injury.

Background: Ceftolozane-tazobactam is a new antibiotic against multidrug-resistant pathogens such as Pseudomonas aeruginosas. Ceftolozane-tazobactam dosage is still uncertain in children, especially in those with renal impairment or undergoing continuous renal replacement therapy (CRRT). Methods: Evaluation of different ceftolozane-tazobactam dosing regimens in three critically ill children. Ceftolozane pharmacokinetics (PK) were characterized by obtaining the patient's specific parameters by Bayesian estimation based on a population PK model. The clearance (CL) in patient C undergoing CRRT was estimated using the prefilter, postfilter, and ultrafiltrate concentrations simultaneously. Variables such as blood, dialysate, replacement, and ultrafiltrate flow rates, and hematocrit were integrated in the model. All PK analyses were performed using NONMEM v.7.4. Results: Patient A (8 months of age, 8.7 kg) with normal renal function received 40 mg/kg every 6 h: renal clearance (CLR) was 0.88 L/h; volume of distribution (Vd) Vd1 = 3.45 L, Vd2 = 0.942 L; terminal halflife (t1/2,ß) = 3.51 h, dosing interval area under the drug concentration vs. time curve at steady-state (AUCτ,SS) 397.73 mg × h × L-1. Patient B (19 months of age, 11 kg) with eGFR of 22 mL/min/1.73 m2 received 36 mg/kg every 8 h: CLR = 0.27 L/h; Vd1 = 1.13 L; Vd2 = 1.36; t1/2,ß = 6.62 h; AUCSS 1481.48 mg × h × L-1. Patient C (9 months of age, 5.8 kg), with severe renal impairment undergoing CRRT received 30 mg/kg every 8 h: renal replacement therapy clearance (CLRRT) 0.39 L/h; Vd1 = 0.74 L; Vd2= 1.17; t 1/2,ß = 3.51 h; AUCτ,SS 448.72 mg × h × L-1. No adverse effects attributable to antibiotic treatment were observed. Conclusions: Our results suggest that a dose of 35 mg/kg every 8 h can be appropriate in critically ill septic children with multi-drug resistance Pseudomonas aeruginosa infections. A lower dose of 10 mg/kg every 8 h could be considered for children with severe AKI. For patients with CRRT and a high effluent rate, a dose of 30 mg/kg every 8 h can be considered.

Effectiveness of steroids versus placebo in preventing upper airway obstruction after extubation in critically ill children: rationale and design of a multicentric, double-blind, randomized study.

BACKGROUND: Post-extubation upper airway obstruction (UAO) is a frequent complication causing stridor and respiratory distress, which occasionally require reintubation, thereby increasing morbidity and mortality rates. Contradictory results have been obtained in studies assessing the effectiveness of steroids in preventing post-extubation UAO, and the available evidence is limited. We designed a multicentric randomized, placebo-controlled study to explore the effectiveness of dexamethasone in preventing post-extubation UAO in children. METHODS: A multicentric, prospective, double-blind, randomized, placebo-controlled, phase IV clinical trial has been designed. The sample will include pediatric patients who are between 1 month and 16 years of age and who have been intubated for more than 48 h. Patients who have airway disorders or who have received steroids within the previous seven days will be excluded. Patients will be randomly assigned to receive either placebo or a therapy with dexamethasone 0.25 mg/kg every 6 h to be started 6 to 12 h prior to extubation (to a total of four doses). Randomization will be performed at a 1:1 ratio. Follow-up of patients will be carried out for 48 h after extubation. The main objective of this study is to access the reduction in the incidence of moderate to severe UAO symptoms following extubation. Secondary objectives include assessing the decrease in the incidence of reintubation, evaluating the use of additional therapies for UAO, and monitoring potential side effects of dexamethasone. DISCUSSION: The results of this study will contribute to the existing evidence on prophylaxis for post-extubation airway obstruction. TRIAL REGISTRATION: EudraCT identifier: 2009-016596-30. Registered on May 11, 2010.