Postnatal corticosteroid response in neonates < 32 weeks and relation with placental pathology.

Acute chorioamnionitis and maternal vascular malperfusion are associated with an increased risk of bronchopulmonary dysplasia. To prevent bronchopulmonary dysplasia, postnatal corticosteroids are given to preterm neonates. Clinical observations indicate not all neonates respond to corticosteroids, the so-called non-responders. This study aimed to investigate the association between placental pathology and short-term response to postnatal corticosteroids in neonates < 32 weeks postconceptional age at risk for bronchopulmonary dysplasia. All neonates < 32 weeks born between 2009 and 2016, receiving corticosteroids in the course of BPD, were included. The preterm neonates were divided into three groups depending on placental histology: acute chorioamnionitis, maternal vascular malperfusion, or no placental pathology. Respiratory support was assessed prior to treatment and at days 4 and 7. A responder was defined as extubation within 7 days after starting corticosteroid treatment. In total, 52% of the chorioamnionitis neonates, 67% of the maternal vascular malperfusion neonates, and 58% of neonates in the no pathology group were responders. The odds ratio for extubation was 0.53 (0.18-1.55) at day 4 and 0.66 (0.23-1.97) at day 7, in the chorioamnionitis group compared to the maternal vascular malperfusion. CONCLUSION: Short-term response to postnatal corticosteroids did not significantly differ between premature neonates born after acute chorioamnionitis, maternal vascular malperfusion, or no placenta pathology. However, a trend of better corticosteroid response in maternal vascular malperfusion neonates was found, potentially due to differences in prenatal pulmonary development and postnatal cortisol. WHAT IS KNOWN: • Bronchopulmonary dysplasia is related to chorioamnionitis and maternal vascular malperfusion. • Corticosteroids remain an important treatment in the course of bronchopulmonary dysplasia despite conflicting results and non-responsiveness in some preterm neonates. WHAT IS NEW: • Non-responsiveness might be related to differences in pulmonary inflammation and systemic cortisol due to predispositions triggered by chorioamnionitis or maternal vascular malperfusion. • Neonates born after maternal vascular malperfusion seem to respond better to postnatal corticosteroid treatment.

Validity of surrogate endpoints assessing central venous catheter-related infection: evidence from individual- and study-level analyses.

OBJECTIVES: The prevention of catheter-related bloodstream infection (CRBSI) has been an area of intense research, but the heterogeneity of endpoints used to define catheter infection makes the interpretation of randomized controlled trials (RCTs) problematic. The aim of this study was to determine the validity of different endpoints for central venous catheter infections. DATA SOURCES: (a) Individual-catheter data were collected from 9428 catheters from four large RCTs; (b) study-level data from 70 RCTs were identified with a systematic search. Eligible studies were RCTs published between January 1987 and October 2018 investigating various interventions to reduce infections from short-term central venous catheters or short-term dialysis catheters. For each RCT the prevalence rates of CRBSI, quantitative catheter tip colonization, catheter-associated infection (CAI) and central line-associated bloodstream infection (CLABSI) were extracted for each randomized study arm. METHODS: CRBSI was used as the gold-standard endpoint, for which colonization, CAI and CLABSI were evaluated as surrogate endpoints. Surrogate validity was assessed as (1) the individual partial coefficient of determination (individual-pR2) using individual catheter data; (2) the coefficient of determination (study-R2) from mixed-effect models regressing the therapeutic effect size of the surrogates on the effect size of CRBSI, using study-level data. RESULTS: Colonization showed poor agreement with CRBSI at the individual-patient level (pR2 = 0.33 95% CI 0.28-0.38) and poor capture at the study level (R2 = 0.42, 95% CI 0.21-0.58). CAI showed good agreement with CRBSI at the individual-patient level (pR2 = 0.80, 95% CI 0.76-0.83) and moderate capture at the study level (R2 = 0.71, 95% CI 0.51-0.85). CLABSI showed poor agreement with CRBSI at the individual patient level (pR2 = 0.34, 95% CI 0.23-0.46) and poor capture at the study level (R2 = 0.28, 95% CI 0.07-0.76). CONCLUSIONS: CAI is a moderate to good surrogate endpoint for CRBSI. Colonization and CLABSI do not reliably reflect treatment effects on CRBSI and are consequently more suitable for surveillance than for clinical effectiveness research.

[Rotavirus infections in neonates: not as innocent as expected]. / Rotavirusinfectie bij een neonaat: niet zo onschuldig als verwacht.

BACKGROUND: Rotavirus is a common cause of gastroenteritis in children. It is much less known that rotavirus infections can lead to encephalitis with convulsions in neonates. CASE DESCRIPTION: A premature boy (36 weeks + 5 days) developed neonatal convulsions 17 days post-partum. His sister had symptoms of gastroenteritis. Cerebral MRIs showed extensive white matter abnormalities in diffusion-weighted images and, a few weeks later, cystic white matter abnormalities. There were no gastrointestinal phenomena or pleocytosis in the cerebrospinal fluid. Rotavirus was detected in the stools, using molecular diagnostics (PCR). CONCLUSION: Rotavirus infection at a neonatal age can have serious consequences. Due to the absence of gastrointestinal phenomena, pleocytosis and demonstrability of rotavirus in faeces and not in CSF, this clinical picture has long remained undiagnosed. Instructions on hand hygiene during the post-partum period contributes to the prevention of rotavirus infection in neonates. Herd immunity through rotavirus vaccination for all neonates could lead to significant risk reduction.

Achieving protein targets without energy overfeeding in critically ill patients: A prospective feasibility study.

BACKGROUND & AIMS: High protein delivery during early critical illness is associated with lower mortality, while energy overfeeding is associated with higher mortality. Protein-to-energy ratios of traditional enteral formulae are sometimes too low to reach protein targets without energy overfeeding. This prospective feasibility study aimed to evaluate the ability of a new enteral formula with a high protein-to-energy ratio to achieve the desired protein target while avoiding energy overfeeding. METHODS: Mechanically ventilated non-septic patients received the high protein-to-energy ratio nutrition during the first 4 days of ICU stay (n = 20). Nutritional prescription was 90% of measured energy expenditure. Primary endpoint was the percentage of patients reaching a protein target of ≥1.2 g/kg ideal body weight on day 4. Other endpoints included a comparison of nutritional intake to matched historic controls and the response of plasma amino acid concentrations. Safety endpoints were gastro-intestinal tolerance and plasma urea concentrations. RESULTS: Nineteen (95%) patients reached the protein intake target of ≥1.2 g/kg ideal body weight on day 4, compared to 65% in historic controls (p = 0.024). Mean plasma concentrations of all essential amino acids increased significantly from baseline to day 4. Predefined gastro-intestinal tolerance was good, but unexplained foul smelling diarrhoea occurred in two patients. In one patient plasma urea increased unrelated to acute kidney injury. CONCLUSIONS: In selected non-septic patients tolerating enteral nutrition, recommended protein targets can be achieved without energy overfeeding using a new high protein-to-energy ratio enteral nutrition.

Brain imaging can predict neurodevelopmental outcome of Group B streptococcal meningitis in neonates.

AIM: The association between cranial ultrasound (CUS) or magnetic resonance imaging (MRI) lesions and neonatal Group B streptococcal (GBS) meningitis outcome has not been studied in detail. METHODS: This retrospective study assessed CUS, cranial MRI and neurodevelopmental outcome in 50 neonates with GBS meningitis admitted to three neonatal intensive care units in the Netherlands between 1992 and 2014. Death, cognitive outcome and motor outcome below -1 SD were considered as adverse outcomes. RESULTS: CUS was available in all and MRIs in 31 infants (62%) with 28 CUS (56%) and 27 MRIs (87%) being abnormal. MRI lesions were multifocal (n = 10, 37%), bilateral (n = 22; 82%) and extensive (n = 11; 41%). A total of 10 died in the neonatal period. Median age at assessment was 24 months. Among survivors, abnormal cognitive outcome and motor outcome were seen in 23 and 20 patients, respectively. Abnormal CUS [odds ratio (OR) 5.3, p = 0.017], extensive bilateral deep grey lesions (OR 6.7, p = 0.035) and white matter lesions (OR 14.0, p = 0.039) correlated with abnormal motor outcome. Extensive bilateral deep grey matter lesions correlated with abnormal cognitive outcome (OR 8.1, p = 0.029). CONCLUSION: Abnormal CUS and the most severely affected MRIs were associated with poor neurodevelopmental outcome in neonatal GBS meningitis.

DOSE EVALUATION FOR DIGITAL X-RAY IMAGING OF PREMATURE NEONATES.

X-ray radiography is a commonly used diagnostic method for premature neonates. However, because of higher radiosensitivity and young age, premature neonates are more sensitive to the detrimental effects of ionising radiation. Therefore, it is important to monitor and optimise radiation doses at the neonatal intensive care unit (NICU). The number of x-ray examinations, dose-area product (DAP) and effective doses are evaluated for three Dutch NICUs using digital flat panel detectors. Thorax, thorax-abdomen and abdomen protocols are included in this study. Median number of examinations is equal to 1 for all three hospitals. Median DAP ranges between 0.05 and 1.02 µGy m2 for different examination types and different weight categories. These examinations result in mean effective doses between 4 ± 4 and 30 ± 10 µSv per examination. Substantial differences in protocols and doses can be observed between hospitals. This emphasises the need for up-to-date reference levels formulated specifically for premature neonates.

Hyperoxia does not directly affect vascular tone in isolated arteries from mice.

Hospitalized patients often receive oxygen supplementation, which can lead to a supraphysiological oxygen tension (hyperoxia). Hyperoxia can have hemodynamic effects, including an increase in systemic vascular resistance. This increase suggests hyperoxia-induced vasoconstriction, yet reported direct effects of hyperoxia on vessel tone have been inconsistent. Furthermore, hyperoxia-induced changes in vessel diameter have not been studied in mice, currently the most used mammal model of disease. In this study we set out to develop a pressure-myograph model using isolated vessels from mice for investigation of pathways involved in hyperoxic vasoconstriction. Isolated conduit and resistance arteries (femoral artery and gracilis arteriole, respectively) from C57BL/6 mice were exposed to normoxia (PO2 of 80 mmHg) and three levels of hyperoxia (PO2 of 215, 375 and 665 mmHg) in a no-flow pressure myograph setup. Under the different PO2 levels, dose-response agonist induced endothelium-dependent vasodilation (acetylcholine, arachidonic acid), endothelium-independent vasodilation (s-nitroprusside), as well as vasoconstriction (norepinephrine, prostaglandin F2α) were examined. The investigated arteries did not respond to oxygen by a change in vascular tone. In the dose-response studies, maximal responses and EC50 values to any of the aforementioned agonists were not affected by hyperoxia either. We conclude that arteries and arterioles from healthy mice are not intrinsically sensitive to hyperoxic conditions. The present ex-vivo model is therefore not suitable for further research into mechanisms of hyperoxic vasoconstriction.

Prevention of acute kidney injury and protection of renal function in the intensive care unit: update 2017 : Expert opinion of the Working Group on Prevention, AKI section, European Society of Intensive Care Medicine.

BACKGROUND: Acute kidney injury (AKI) in the intensive care unit is associated with significant mortality and morbidity. OBJECTIVES: To determine and update previous recommendations for the prevention of AKI, specifically the role of fluids, diuretics, inotropes, vasopressors/vasodilators, hormonal and nutritional interventions, sedatives, statins, remote ischaemic preconditioning and care bundles. METHOD: A systematic search of the literature was performed for studies published between 1966 and March 2017 using these potential protective strategies in adult patients at risk of AKI. The following clinical conditions were considered: major surgery, critical illness, sepsis, shock, exposure to potentially nephrotoxic drugs and radiocontrast. Clinical endpoints included incidence or grade of AKI, the need for renal replacement therapy and mortality. Studies were graded according to the international GRADE system. RESULTS: We formulated 12 recommendations, 13 suggestions and seven best practice statements. The few strong recommendations with high-level evidence are mostly against the intervention in question (starches, low-dose dopamine, statins in cardiac surgery). Strong recommendations with lower-level evidence include controlled fluid resuscitation with crystalloids, avoiding fluid overload, titration of norepinephrine to a target MAP of 65-70 mmHg (unless chronic hypertension) and not using diuretics or levosimendan for kidney protection solely. CONCLUSION: The results of recent randomised controlled trials have allowed the formulation of new recommendations and/or increase the strength of previous recommendations. On the other hand, in many domains the available evidence remains insufficient, resulting from the limited quality of the clinical trials and the poor reporting of kidney outcomes.

Renal recovery after acute kidney injury.

Acute kidney injury (AKI) is a frequent complication of critical illness and carries a significant risk of short- and long-term mortality, chronic kidney disease (CKD) and cardiovascular events. The degree of renal recovery from AKI may substantially affect these long-term endpoints. Therefore maximising recovery of renal function should be the goal of any AKI prevention and treatment strategy. Defining renal recovery is far from straightforward due in part to the limitations of the tests available to assess renal function. Here, we discuss common pitfalls in the evaluation of renal recovery and provide suggestions for improved assessment in the future. We review the epidemiology of renal recovery and of the association between AKI and the development of CKD. Finally, we stress the importance of post-discharge follow-up of AKI patients and make suggestions for its incorporation into clinical practice. Summary key points are that risk factors for non-recovery of AKI are age, CKD, comorbidity, higher severity of AKI and acute disease scores. Second, AKI and CKD are mutually related and seem to have a common denominator. Third, despite its limitations full recovery of AKI may best be defined as the absence of AKI criteria, and partial recovery as a fall in AKI stage. Fourth, after an episode of AKI, serial follow-up measurements of serum creatinine and proteinuria are warranted to diagnose renal impairment and prevent further progression. Measures to promote recovery are similar to those preventing renal harm. Specific interventions promoting repair are still experimental.

Hyperoxia: At what level of SpO2 is a patient safe? A study in mechanically ventilated ICU patients.

BACKGROUND: Concerns have been expressed regarding a possible association between arterial hyperoxia and adverse outcomes in critically ill patients. Oxygen status is commonly monitored noninvasively by peripheral saturation monitoring (SpO2). However, the risk of hyperoxia above specific SpO2 levels in critically ill patients is unknown. The purpose of this study was to determine a threshold value of SpO2 above which the prevalence of arterial hyperoxia distinctly increases. METHODS: This is a cross-sectional study in adult mechanically ventilated intensive care patients in a tertiary referral center. In 100 patients, we collected 200 arterial blood gases (ABG) and simultaneously registered SpO2 levels, as well as hemodynamic and ventilation parameters and vasoactive medication. Patients under therapeutic hypothermia were excluded. RESULTS: The risk of arterial hyperoxia, defined as PaO2>100mmHg or >125mmHg, was negligible when SpO2 was ≤95% or ≤96%, respectively. The majority (89% and 54%, respectively for PaO2>100mmHg and 125mmHg) of ICU patients with SpO2 of 100% had arterial hyperoxia. The relation between SpO2 and PaO2 was not clearly affected by hemodynamic or other clinical variables (pH, pCO2, body temperature, recent blood transfusion). CONCLUSION: In critically ill patients, the prevalence of arterial hyperoxia increases when SpO2 is >95%. Above this saturation level, supplemental oxygen should be administered with caution in patients potentially susceptible to adverse effects of hyperoxia.

Cardiovascular effects of hyperoxia during and after cardiac surgery.

During and after cardiac surgery with cardiopulmonary bypass, high concentrations of oxygen are routinely administered, with the intention of preventing cellular hypoxia. We systematically reviewed the literature addressing the effects of arterial hyperoxia. Extensive evidence from pre-clinical experiments and clinical studies in other patient groups suggests predominant harm, caused by oxidative stress, vasoconstriction, perfusion heterogeneity and myocardial injury. Whether these alterations are temporary and benign, or actually affect clinical outcome, remains to be demonstrated. In nine clinical cardiac surgical studies in low-risk patients, higher oxygen targets tended to compromise cardiovascular function, but did not affect clinical outcome. No data about potential beneficial effects of hyperoxia, such as reduction of gas micro-emboli or post-cardiac surgery infections, were reported. Current evidence is insufficient to specify optimal oxygen targets. Nevertheless, the safety of supraphysiological oxygen suppletion is unproven. Randomised studies with a variety of oxygen targets and inclusion of high-risk patients are needed to identify optimal oxygen targets during and after cardiac surgery.

Pain measurement in mechanically ventilated critically ill patients: Behavioral Pain Scale versus Critical-Care Pain Observation Tool.

PURPOSE: The Behavioral Pain Scale (BPS) and Critical-Care Pain Observation Tool (CPOT) are behavioral pain assessment tools for uncommunicative and sedated intensive care unit (ICU) patients. This study compares the discriminant validation and reliability of the CPOT and the BPS, simultaneously, in mechanically ventilated patients on a mixed-adult ICU. MATERIALS AND METHODS: This is a prospective observational cohort study in 68 mechanically ventilated medical ICU patients who were unable to report pain. RESULTS: The BPS and CPOT scores showed a significant increase of 2 points between rest and the painful procedure (turning). The median BPS scores between rest and the nonpainful procedure (oral care) showed a significant increase of 1 point, whereas the median CPOT score remained unchanged. The interrater reliability of the BPS and CPOT scores showed a fair to good agreement (0.74 and 0.75, respectively). CONCLUSIONS: This study showed that the BPS and the CPOT are reliable and valid for use in a daily clinical setting. Although both scores increased with a presumed painful stimulus, the discriminant validation of the BPS use was less supported because it increased during a nonpainful stimulus. The CPOT appears preferable in this particular group of patients, especially with regard to its discriminant validation.

Low skeletal muscle area is a risk factor for mortality in mechanically ventilated critically ill patients.

INTRODUCTION: Higher body mass index (BMI) is associated with lower mortality in mechanically ventilated critically ill patients. However, it is yet unclear which body component is responsible for this relationship. METHODS: This retrospective analysis in 240 mechanically ventilated critically ill patients included adult patients in whom a computed tomography (CT) scan of the abdomen was made on clinical indication between 1 day before and 4 days after admission to the intensive care unit. CT scans were analyzed at the L3 level for skeletal muscle area, expressed as square centimeters. Cutoff values were defined by receiver operating characteristic (ROC) curve analysis: 110 cm2 for females and 170 cm2 for males. Backward stepwise regression analysis was used to evaluate low-muscle area in relation to hospital mortality, with low-muscle area, sex, BMI, Acute Physiologic and Chronic Health Evaluation (APACHE) II score, and diagnosis category as independent variables. RESULTS: This study included 240 patients, 94 female and 146 male patients. Mean age was 57 years; mean BMI, 25.6 kg/m2. Muscle area for females was significantly lower than that for males (102 ± 23 cm2 versus 158 ± 33 cm2; P < 0.001). Low-muscle area was observed in 63% of patients for both females and males. Mortality was 29%, significantly higher in females than in males (37% versus 23%; P = 0.028). Low-muscle area was associated with higher mortality compared with normal-muscle area in females (47.5% versus 20%; P = 0.008) and in males (32.3% versus 7.5%; P < 0.001). Independent predictive factors for mortality were low-muscle area, sex, and APACHE II score, whereas BMI and admission diagnosis were not. Odds ratio for low-muscle area was 4.3 (95% confidence interval, 2.0 to 9.0, P < 0.001). When applying sex-specific cutoffs to all patients, muscle mass appeared as primary predictor, not sex. CONCLUSIONS: Low skeletal muscle area, as assessed by CT scan during the early stage of critical illness, is a risk factor for mortality in mechanically ventilated critically ill patients, independent of sex and APACHE II score. Further analysis suggests muscle mass as primary predictor, not sex. BMI is not an independent predictor of mortality when muscle area is accounted for.

Time intervals from aneurysmal subarachnoid hemorrhage to treatment and factors contributing to delay.

In the management of aneurysmal subarachnoid hemorrhage (aSAH), aneurysm treatment as early as feasible is mandatory to minimize the risk of a rebleed and may thus improve outcome. We assessed the different time intervals from the first symptoms of aSAH to start of aneurysm treatment in an effort to identify which factors contribute mostly to a delay in time to treatment. In 278 aSAH patients, time intervals between the different steps from initial hemorrhage to aneurysm treatment were retrospectively reviewed, and delaying factors were determined. Half of the patients presented to a hospital within 115 min (IQR 60-431). The median (IQR) interval from hemorrhage to diagnosis was 169 min (96-513), and from diagnosis to treatment 1,057 min (416-1,428), or 17.6 h. Aneurysm treatment started within 24 h in 76 % of treated patients. Independent factors predicting delay to treatment were primary presentation at a referring hospital and admission to the treatment center later in the day. Delay in treatment was not independently related to poor outcome. The interval to aneurysm treatment might be improved upon by immediate and direct transport to the treatment center combined with optimization of in-hospital logistics, following the 'time-is-brain' concept so successfully adopted in the treatment of ischemic stroke.

Systematic review of perioperative selective decontamination of the digestive tract in elective gastrointestinal surgery.

BACKGROUND: Studies on selective decontamination of the digestive tract (SDD) in elective gastrointestinal surgery have shown decreased rates of postoperative infection and anastomotic leakage. However, the prophylactic use of perioperative SDD in elective gastrointestinal surgery is not generally accepted. METHODS: A systematic review of randomized clinical trials (RCTs) was conducted to compare the effect of perioperative SDD with systemic antibiotics (SDD group) with systemic antibiotic prophylaxis alone (control group), using MEDLINE, Embase and the Cochrane Central Register of Controlled Trials. Endpoints included postoperative infection, anastomotic leakage, and in-hospital or 30-day mortality. RESULTS: Eight RCTs published between 1988 and 2011, with a total of 1668 patients (828 in the SDD group and 840 in the control group), were included in the meta-analysis. The total number of patients with infection (reported in 5 trials) was 77 (19.2 per cent) of 401 in the SDD group, compared with 118 (28.2 per cent) of 418 in the control group (odds ratio 0.58, 95 per cent confidence interval 0.42 to 0.82; P = 0.002). The incidence of anastomotic leakage was significantly lower in the SDD group: 19 (3.3 per cent) of 582 patients versus 44 (7.4 per cent) of 595 patients in the control group (odds ratio 0.42, 0.24 to 0.73; P = 0.002). CONCLUSION: This systematic review and meta-analysis suggests that a combination of perioperative SDD and perioperative intravenous antibiotics in elective gastrointestinal surgery reduces the rate of postoperative infection including anastomotic leakage compared with use of intravenous antibiotics alone.

National study of newborn hearing screening: programme sensitivity and characteristics of undetected children.

UNLABELLED: The success of universal newborn hearing screening (UNHS) programmes is usually evaluated by determining the effect of the early detection of hearing loss on developmental outcome. However, in practice, these programmes do not detect all children with permanent childhood hearing impairment. In this study we determine the sensitivity of the current UNHS programme and analyse the characteristics of the children not detected by UNHS. We performed a nationwide, population-based, retrospective follow-up study in The Netherlands. All children born in 2003-05 and screened in a hearing screening programme (well babies and neonatal intensive care (NICU) graduates) were included for study. The main outcome measure was the sensitivity of the UNHS programme (based on the proportion of children known to have a permanent childhood hearing impairment in 2008 who were identified by UNHS). We also evaluated age at diagnosis, severity, and aetiology of hearing impairment in the children not detected by UNHS. We found that the sensitivity of the current UNHS programme was 0.83 (0.79 for well babies and 0.96 for NICU graduates). Permanent childhood hearing impairment was confirmed before 36 months of age in 96% of the study cohort. Of the children unidentified by the UNHS, > 50% had moderate hearing loss. No predominant cause of hearing impairment was found in these children. CONCLUSION: Our current UNHS programme identified the majority of children with a permanent hearing impairment of congenital cause.

Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach.

BACKGROUND AND OBJECTIVES: Therapeutic hypothermia can influence the pharmacokinetics and pharmacodynamics of drugs, the discipline which is called thermopharmacology. We studied the effect of therapeutic hypothermia on the pharmacokinetics of phenobarbital in asphyxiated neonates, and the clinical efficacy and the effect of phenobarbital on the continuous amplitude-integrated electroencephalography (aEEG) in a prospective study. PATIENTS AND METHODS: Data were obtained from the prospective SHIVER study, performed in two of the ten Dutch level III neonatal intensive care units. Phenobarbital data were collected between 2008 and 2010. Newborns were eligible for inclusion if they had a gestational age of at least 36 weeks and presented with perinatal asphyxia and encephalopathy. According to protocol in both hospitals an intravenous (repeated) loading dose of phenobarbital 20 mg/kg divided in 1-2 doses was administered if seizures occurred or were suspected before or during the hypothermic phase. Phenobarbital plasma concentrations were measured in plasma using a fluorescence polarization immunoassay. aEEG was monitored continuously. RESULTS AND CONCLUSION: A one-compartmental population pharmacokinetic/pharmacodynamic model was developed using a multi-level Markov transition model. No (clinically relevant) effect of moderate therapeutic hypothermia on phenobarbital pharmacokinetics could be identified. The observed responsiveness was 66%. While we still advise an initial loading dose of 20 mg/kg, clinicians should not be reluctant to administer an additional dose of 10-20 mg/kg. An additional dose should be given before switching to a second-line anticonvulsant drug. Based on our pharmacokinetic/pharmacodynamic model, administration of phenobarbital under hypothermia seems to reduce the transition rate from a continuous normal voltage (CNV) to discontinuous normal voltage aEEG background level in hypothermic asphyxiated newborns, which may be attributed to the additional neuroprotection of phenobarbital in infants with a CNV pattern.