Management of accidental hypothermia: an established extracorporeal membrane oxygenation centre experience.

INTRODUCTION: Data on management of severe accidental hypothermia published from an established high-volume extracorporeal membrane oxygenation centre are scarce. METHODS: A total of 28 patients with intravesical temperature lower than 28°C on admission were either treated with veno-arterial extracorporeal membrane oxygenation or rewarmed conservatively. RESULTS: A total of 10 patients rewarmed on veno-arterial extracorporeal membrane oxygenation (age: 37 ± 12.6 years) and 18 conservatively (age: 55.2 ± 11.2 years) were collected over a course of 5 years. The dominant cause was alcohol intoxication with exposure to cold (39%), 12 patients were resuscitated prior to admission. The admission temperature in the extracorporeal membrane oxygenation group (23.8 ± 2.6°C) was lower than in the non-extracorporeal membrane oxygenation group (26.0 ± 1.5°C, p = 0.01). The peripheral percutaneous veno-arterial extracorporeal membrane oxygenation was always cannulated in malignant arrhythmias causing refractory cardiac arrest. The typical extracorporeal membrane oxygenation blood flow was 3-4 L/minute and sweep gas flow 2 L/minute, the median extracorporeal membrane oxygenation duration was 48.3 (28.1-86.7) hours. The median rates of rewarming did not differ (0.41 (0.35-0.7)°C/hour in extracorporeal membrane oxygenation and 0.77 (0.54-0.98)°C/hour in non-extracorporeal membrane oxygenation, p = 0.46) as well as the admission arterial lactate, pH and potassium. Their development was not different between the groups except for higher pH between the third and ninth hour of rewarming in the extracorporeal membrane oxygenation group. The hospital mortality was 10% in the extracorporeal membrane oxygenation group and 11.1% in the non-extracorporeal membrane oxygenation group with the median last Glasgow Coma Scale 15 and Cerebral Performance Score 1. CONCLUSION: Veno-arterial extracorporeal membrane oxygenation for severe hypothermia shows promising outcome data collected in an extracorporeal membrane oxygenation/extracorporeal cardiopulmonary resuscitation centre located in a European urban area. Except for presence of refractory cardiac arrest, the established hypothermia-related prognostic indicators did not differ between patients in need for extracorporeal membrane oxygenation and those rewarmed without extracorporeal membrane oxygenation.

Sufentanil pharmacokinetics in a full-term neonate treated with extracorporeal membrane oxygenation: a case report.

INTRODUCTION: Sufentanil is a potent analgesic drug used for pain management. A few studies describe the pharmacokinetics of sufentanil in neonates; however, no pharmacokinetic data about sufentanil during extracorporeal membrane oxygenation have been published yet. CASE REPORT: A 1-day-old neonate with moderate hypoxic-ischemic encephalopathy received veno-arterial extracorporeal membrane oxygenation support for refractory respiratory and circulatory failure. Sufentanil plasma concentrations were determined during both extracorporeal membrane oxygenation (n = 14) and non-extracorporeal membrane oxygenation (n = 17) period. Based on these measurements, individual sufentanil pharmacokinetic parameters were calculated. DISCUSSION: We observed increased sufentanil volume of distribution (11.6 vs 5.6 L/kg) and decreased sufentanil clearance (0.535 vs 0.746 L/h/kg) in extracorporeal membrane oxygenation period. The increment of volume of distribution was attributed to ECMO influence, while difference in clearance was probably due to drug interaction. CONCLUSIONS: This is the first description of sufentanil pharmacokinetics in neonate treated with extracorporeal membrane oxygenation. We observed considerably larger volume of distribution during extracorporeal membrane oxygenation period in comparison with non-extracorporeal membrane oxygenation period.

Endothelial Microvesicles and Soluble Markers of Endothelial Injury in Critically Ill Newborns.

Neonatal systemic inflammatory response and multiple organ dysfunction syndrome are the main postnatal insults influencing mortality and morbidity. Critically ill newborns with high predicted mortality are supported by extracorporeal membrane oxygenation (ECMO). Biomarkers of inflammatory response and endothelial injury can be used for early diagnosis and treatment of critical neonatal situations. The aim of our study was to explore plasma proteins and endothelial microvesicles as markers of inflammation and endothelial activation in newborns on ECMO and to compare them with healthy neonates. Thirteen newborns on ECMO and 13 healthy newborns were included in the study. Plasma soluble biomarkers were measured using multiplex immunoassay based on Luminex® xMAP multianalyte profiling platform. The total microvesicle count and plasma level of surface antigen-specific microvesicles were determined by flow cytometry. The plasma concentration of cell-derived microvesicles was measured using annexin-V labeling, and the endothelial origin of microvesicles was determined using lineage-specific antigen labeling of endothelial cell/microvesicle markers (endoglin/CD105, PECAM1/CD31, VEGFR2/CD309, and MadCAM1). Inflammatory markers (procalcitonin, IL-1ß, IL-6, and IL-22) were increased in the ECMO group (P < 0.01). The assessment of endothelial markers showed higher concentrations of endocan and angiopoietin-2 (P < 0.01) in the ECMO group while VEGF in the ECMO group was significantly lower (P < 0.01). In the ECMO group, the concentration of annexin-V-positive microvesicles (total microvesicles) and endothelial microvesicles expressing mucosal vascular addressin cell adhesion molecule 1 (MadCAM1) was increased (P = 0.05). In summary, we found increased concentrations of soluble inflammatory and endothelial markers in the plasma of critically ill newborns with multiple organ dysfunction. Increased plasma concentrations of microvesicles may reflect the activation or damage of blood cells and vasculature including endothelial cells. The measurement of cell membrane-derived microvesicles may be added to the panel of established inflammatory markers in order to increase the sensitivity and specificity of the diagnostic process in critically ill newborns.

Phenobarbital pharmacokinetics in neonates and infants during extracorporeal membrane oxygenation.

INTRODUCTION: The disposition of drugs is potentially changed due to extracorporeal membrane oxygenation (ECMO) in neonates and infants. METHODS: The aim of the study was to evaluate the individual pharmacokinetics (PK) of phenobarbital and the effect of PK covariates in neonates and infants undergoing ECMO. Sixteen patients (7 neonates, 9 infants) treated with phenobarbital during ECMO (centrifugal-flow pump circuits) were enrolled in the PK study. Phenobarbital serum concentrations were measured using a fluorescence polarization immunoassay. Individual PK parameters - volume of distribution (Vd) and clearance (CL) were calculated in a one-compartmental pharmacokinetic model. RESULTS: The mean (SD) Vd and CL values in neonates were 0.46 (0.24) L/kg and 8.0 (4.5) mL/h/kg, respectively. Respective values in infants were 0.56 (0.23) L/kg and 8.5 (3.1) mL/h/kg. PK parameters in neonates and infants were not significantly different. We observed high inter-individual variability in PK parameters (coefficients of variation [CV] were 52% and 53% for CL and Vd, respectively). Doses were adjusted based on therapeutic drug monitoring (TDM) in 87.5% patients. Only 50% of the first measured phenobarbital serum concentrations in each patient were within the therapeutic range of 10-40 mg/L, in comparison with 88.6% concentration measured after TDM implementation. Linear regression models showed that both Vd and CL are significantly related with body weight (BW) and length. Median optimal phenobarbital loading dose (LD) and maintenance dose (MD), calculated from pharmacokinetic data, were 15 mg/kg and 4 mg/kg/day, respectively. CONCLUSIONS: Body weight was shown to be the main PK covariate of phenobarbital disposition. Subsequent dosing nomograms are provided for phenobarbital dosing during ECMO.

Endobronchial stenting on VV-ECMO in a 6-month-old girl with right lung agenesis and severe stenosis of the left main bronchus.

INTRODUCTION: Lung agenesis is a rare disorder with a variable, but potentially very bad clinical course. It necessitates complex clinical management, especially in life-threatening situations. CASE REPORT: We describe a case of a 6-month-old girl with right lung agenesis who required venovenous extracorporeal membrane oxygenation (VV-ECMO) due to pneumonia complicated by exacerbated previously diagnosed left main bronchus stenosis. The stenosis was resolved by endobronchial intervention and X-ray-guided stent insertion, which enabled weaning from ECMO and was aimed at preventing such a life-threatening respiratory failure in the future. Unfortunately, even with the functional stent, the baby died 2 months post-procedure due to unresolvable bronchial spasms. DISCUSSION: Despite high endobronchial stenting-related mortality in children, in cases where no effective pharmacological or surgical alternatives exist, stenting may be safely performed during VV-ECMO support and be a viable option to overcome critical respiratory failure caused by bronchial stenosis.

Management of severe pulmonary hemorrhage in a neonate on veno-arterial ECMO by the temporary clamping of the endotracheal tube - a case report.

Severe pulmonary hemorrhage in the newborn is an infrequent, but life-threatening, event. A newborn with persistent pulmonary hypertension and a large persistent ductus arteriosus and open foramen ovale presented with hypoxemia and progressive right heart failure shortly after birth, requiring veno-arterial extracorporeal membrane oxygenation (ECMO) support. Twenty minutes after the initiation of ECMO, the patient developed severe pulmonary hemorrhage refractory to conventional treatment. As a last resort, the endotracheal tube was clamped. After transport to the ECMO center, repeated attempts to open the endotracheal tube resulted in continued blood loss and the endotracheal tube was clamped for a total of 63 hours without any mechanical ventilation. On the third postnatal day, the endotracheal tube was reopened, large amounts of clot were removed by bronchoscopy and mechanical ventilation was resumed followed by improved general condition and favorable outcome.

Effects of high tidal volume mechanical ventilation on production of cytokines, iNOS, and MIP-1ß proteins in pigs.

The aim of this study was to investigate longitudinal changes of the pulmonary inflammatory process as a result of mechanical stress due to mechanical ventilation. The concentrations of IL-8, TNF-α, MIP-1ß, nitrites/nitrates, and inducible nitric oxide synthases (iNOS) were investigated indicate in bronchoalveolar lavage (BAL). Twenty-three piglets were divided into three groups. Group I: animals breathing spontaneously; group II: mechanical ventilation (tidal volume (TV) = 7 mL/kg, PEEP = 5 cmH(2)O); group III: mechanical ventilation (TV = 15 mL/kg, PEEP = 0 cmH(2)0). Concentrations of BAL nitrites/nitrates from groups II and III increased during the first hour of mechanical ventilation (P = .03 and .02, respectively). The highest expression of iNOS was observed during the first hour in groups II and III. IL-8 concentration increased significantly in groups II and III. Production of TNF-α increased significantly in group III during the second and third hour (P = .01). Concentration of MIP-1ß was significantly increased in groups II and III after the first hour (P = .012 and P = .008, respectively).

Posterior Reversible Encephalopathy Syndrome (PRES) in 5-year-old girl with nephrotic syndrome.

OBJECTIVE: Posterior Reversible Encephalopathy Syndrome (PRES) is a rare complication of nephrotic syndrome in children. This clinical condition is caused by localized brain angioedema mostly in parieto-occipital region and results in dramatic and acute features as sudden loss of consciousness, epileptic paroxysms, strong headache or visual disturbances. Uncontrolled hypertension often participates in PRES development. CASE: We present the case of a 5-year-old girl treated for relapse of nephrotic syndrome. RESULTS: At the time of edema regression and weight reduction, a sudden loss of consciousness and worsening of hypertension occurred. Brain MRI demonstrated extended multifocal changes strongly suspicious of encephalitis. After exclusion of herpetic encephalitis, the clinical picture was classified as PRES. Successful antihypertensive treatment led to general improvement of the girl's health within 48 hours and resolution of MRI brain hyperintensities occurred within the next three months. CONCLUSIONS: The aim of our case report is to us remind of possible development of PRES at the time of edema regression in nephrotic syndrome.

Influence of the lung mechanical ventilation with injurious parameters on 7-ketocholesterol synthesis in Sus Scrofa.

The aim of work was to investigate changes of 7-ketocholesterol synthesis in alveolar macrophages in the dynamic of lung mechanical ventilation with injurious parameters. The goal of in vitro part of work was to observe influence of 7-ketocholesterol on iNOS and MIP1 Beta production in bronchoalveolar lavage fluid (BALF) cells. We used 17 healthy domestic pigs randomly assigned into two treatment groups: group I with mechanical ventilation with physiological parameters; group || underwent injurious ventilation with high volume tidal (VT) and low positive end expiratory pressure (PEEP). ells were analyzed for CYP27A1 protein and gene expression levels, 7-ketocholesterol production. In alveolar macrophages of group ||, we obtained increase of production of CYP27A1 protein and 7-ketocholesterol, as well as the expression of the CYP27A1 gene at the 2nd hour of ventilation. In the in vitro experiments we show dose-dependent increase of MIP1 Beta and decrease of CYP27A1, iNOS protein production after 7-ketocholesterol treatment.

Tolerability and outcomes of kinetically guided therapy with gentamicin in critically ill neonates during the first week of life: an open-label, prospective study.

BACKGROUND: Aminoglycosides are bactericidal antibiotics used worldwide for the treatment of serious infections in critically ill patients, including neonates. Critically ill neonates constitute a unique challenge in dosing owing to the pathologic alterations that accompany severe illness and the rapidly changing conditions of these patients. OBJECTIVES: The main objective of this study was to analyze the kinetically guided dosage adjustment of gentamicin in neonates critically ill during the first week of life based on plasma concentrations after the first dose and to identify the impact of covariates (eg, fluid intake, body fluid retention) with respect to gestational age (GA). Tolerability of therapy was also assessed. METHODS: This 10-day, open-label, prospective study included neonates critically ill during the first week of life admitted to the neonatal intensive care unit of a children's hospital between January 2006 and July 2009. Hearing and renal assessments were conducted over a 24-month follow-up period. The patients were treated with gentamicin for suspected sepsis, proven sepsis, or pneumonia as an early sign of sepsis. The first and second doses of gentamicin 4 mg/kg were adjusted according to birth weight and GA: group 1 (GA < 34 weeks), 48-hour interdose intervals; group 2 (GA 34-38 weeks), 36 hours; and group 3 (GA > 38 weeks), 24 or 48 hours. Individual pharmacokinetic parameters were estimated after the first dose (given in 30-minute intravenous infusions) using 4 concentrations. Individual pharmacokinetic parameters were estimated by fitting the parameters of a 2-compartment model into 4 concentrations. The last 2 blood samples were taken 30 minutes before the fourth infusion (C(trough,3)) and 1 hour after its start (C(max,4)). Dosing was individualized to reach target ranges for the C(trough,3) (0.5-2.0 mg/L) and C(max,4) (6-10 mg/L) values. If needed, initial dosing was changed after the second dose by adjusting (reducing or increasing) the third and subsequent doses, or by adjusting (prolonging or shortening) the interdose intervals. C(trough,3) and C(max,4) were assessed to determine differences between predicted and assayed values. Fluid retention was registered as the difference between fluid intake and urine output at different intervals related to the first dose per kilogram of birth weight, and from the start of the first infusion (0 hour) to the day of the fourth infusion. The C(max)/minimum inhibitory concentration (MIC) ratio was determined for assessment of optimal response. Tolerability was evaluated during the 24-month follow-up period using renal sonography to screen for nephrocalcinosis and transient evoked otoacoustic emission recordings to evaluate hearing abnormalities. RESULTS: A total of 84 neonates (all white; 53 males, 31 females; birth weight range, 0.8-4.56 kg; GA range, 24-42 weeks) were enrolled in 3 groups: group 1, GA < 34 weeks, n = 27; group 2, GA 34-38 weeks, n = 22; and group 3, GA > 38 weeks, n = 35. The C(max) value detected 1 hour after the start of the first infusion (C(max,1)) reached the target range of 6-10 mg/L in 66 of the 84 neonates (79%). After the initial dose, C(max,1) was variable (%CV, 29%); the failure rate to reach 6 mg/L was 13%. V(d) decreased with GA (r = -0.30, P < 0.01) and achieved mean (SD) rates of 0.51 (0.10), 0.48 (0.13), and 0.40 (0.15) L/kg in groups 1, 2, and 3, respectively. Neither C(max) nor V(d) was correlated with fluid intake relative to the first infusion. Mean gentamicin clearance measured after dose 1 (0.47 [0.23], 0.66 [0.26], and 0.76 [0.32] mL/min/kg) increased with GA (r = 0.45, P < 0.001). The interdose interval was prolonged after the second and subsequent infusions in 8 of 84 neonates (10%) or by decreasing the third dose and subsequent doses in 51 neonates (61%). The target C(max,4) and C(trough,3) values occurred in 63% (22 of 35) and 83% (29 of 35) of full-term patients (GA >38 weeks), respectively. In preterm neonates, the target range for C(max,4) was reached in 11 of 27 patients (41%) in group 1 and 11 of 22 patients (50%) in group 2; for C(trough,3), the target range was reached in 25 patients (93%) in group 1 and in 16 (73%) in group 2. C(trough,3) >2 mg/L was detected in 1 full-term neonate, and gentamicin was withdrawn. Suspected fluid retention within the time period of 0 hour to the day of the fourth infusion was well correlated with actual body weight (r = 0.58, P < 0.001), but it was negatively correlated with C(max,4) (r = -0.25, P = 0.02). Thirteen of the 84 neonates (15%) had confirmed sepsis. C(max)/MIC was >12 except for 2 resistant staphylococcal infections (C(max)/MIC = 0.4); amikacin and vancomycin were substituted for gentamicin in these cases. Clinical signs and laboratory data indicative of suspected sepsis disappeared in 5 to 10 days in 68 of 71 neonates. In 1 neonate, gentamicin was withdrawn after dose 4 because of a high C(trough,3) value. In the 3 remaining neonates, C-reactive protein was decreased >10 days without changing therapy. Two neonates died, 1 of severe hypoxic-ischemic encephalopathy as a consequence of perinatal asphyxia and another of stage IV intraventricular hemorrhage. Transient renal dysfunction attributable to gentamicin was detected in 1 case. No signs of late toxicity (nephrocalcinosis) were found during the second year of follow-up. Two neonates were diagnosed with unilateral hearing loss, a secondary phenomenon of hypoxic-ischemic encephalopathy thought to be related to the severe perinatal asphyxia. CONCLUSIONS: The initial dose of gentamicin 4 mg/kg for these critically ill premature and mature neonates with sepsis during the first week of life was high enough to reach bactericidal C(max,1) within 6-10 mg/L. C(max,1) <6 mg/L occurred in 13% of neonates. The interdose interval modified according to the recommendation resulted in C(trough) values within the target range of 0.5-2.0 mg/L in all but 2 neonates. The kinetically guided maintenance dosing of gentamicin based on plasma concentrations after the first dose should be optimized, taking into account actual body weight. (EudraCT number: 2005-002723-13).

Enantiomeric determination of tramadol and O-desmethyltramadol in human plasma by fast liquid chromatographic technique coupled with mass spectrometric detection.

A rapid and sensitive method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for enantiomeric determination of tramadol and its primary phase metabolite O-desmethyltramadol in human plasma has been developed. Tramadol hydrochloride-(13)C, d(3), was used as an isotopic labeled internal standard for quantification. The method involves a simple solid phase extraction. The analytes and internal standard were separated on Lux Cellulose-2 packed with cellulose tris(3-chloro-4-methylphenylcarbamate) using isocratic elution with hexane/isopropanol/diethylamine (90:10:0.1, v/v/v) at a flow rate of 1.3 mL/min. The APCI positive ionization mass spectrometry was used with multiple reaction monitoring of the transitions at m/z 264.2-->58.2 for tramadol, m/z 250.1-->58.2 for O-desmethyltramadol and m/z 268.2-->58.2 for internal standard. Linearity was achieved between 1-800 ng/mL and 1-400 ng/mL (R(2) > or = 0.999) for each enantiomer of tramadol and O-desmethyltramadol, respectively. Intra-day accuracies ranged among 98.2-102.8%, 97.1-109.1% and 97.4-102.9% at the lower, intermediate, and high concentration for all analytes, respectively. Inter-day accuracies ranged among 95.5-104.1%, 99.2-104.7%, and 94.2-105.6% at the lower, intermediate, and high concentration for all analytes, respectively. This assay was successfully used to determine the concentration of enantiomers of tramadol and O-desmethyltramadol in a pharmacogenetic study.