B. Zernikow

Pediatric Palliative Care

Pediatric palliative care (PPC) is provided to children experiencing life-limiting diseases (LLD) or life-threatening diseases (LTD). Sixty to 90% of children with LLD/LTD undergoing PPC receive opioids at the end of life. Analgesia is often insufficient. Reasons include a lack of knowledge concerning opioid prescribing and adjustment of opioid dose to changing requirements. The choice of first-line opioid is based on scientific evidence, pain pathophysiology, and available administration modes. Doses are calculated on a bodyweight basis up to a maximum absolute starting dose.Morphine remains the gold standard starting opioid in PPC. Long-term opioid choice and dose administration is determined by the pathology, analgesic effectiveness, and adverse effect profile. Slow-release oral morphine remains the dominant formulation for long-term use in PPC with hydromorphone slow-release preparations being the first rotation opioid when morphine shows severe adverse effects. The recently introduced fentanyl transdermal therapeutic system with a drug-release rate of 12.5μg/hour matches the lower dose requirements of pediatric cancer pain control. Its use may be associated with less constipation compared with morphine use. Though oral transmucosal fentanyl citrate has reduced bioavailability (25%), it inherits potential for breakthrough pain management. However, the gold standard breakthrough opioid remains immediate-release morphine. Buprenorphine is of special clinical interest as a result of its different administration routes, long duration of action, and metabolism largely independent of renal function. Antihyperalgesic effects, induced through antagonism at the κ-receptor, may contribute to its effectiveness in neuropathic pain. Methadone also has a long elimination half-life (19 [SD 14] hours) and NMDA receptor activity although dose administration is complicated by highly variable morphine equianalgesic equivalence (1:2.5–20). Opioid rotation to methadone requires special protocols that take this into account. Strategies to minimize adverse effects of long-term opioid treatment include dose reduction, symptomatic therapy, opioid rotation, and administration route change. Patient- or nurse-controlled analgesia devices are useful when pain is rapidly changing, or in terminal care where analgesic requirements may escalate. In this article, we present detailed pediatric pharmacokinetic and pharmacodynamic data for opioids, their indications and contraindications, as well as dose-administration regimens that include practical strategies for opioid switching and dose reduction. Additionally, we discuss the problem of hyperalgesia and the use of adjuvant drugs to support opioid therapy.

Variability of "optimal" cut points for mild, moderate, and severe pain: neglected problems when comparing groups.

Summary The widely used “optimal” cut point procedure developed by Serlin et al. in 1995 results in highly variable cut points. This variability obviates any substantial interpretation of differences between groups. Abstract Defining cut points for mild, moderate, and severe pain intensity on the basis of differences in functional interference has an intuitive appeal. The statistical procedure to derive them proposed in 1995 by Serlin et al. has been widely used. Contrasting cut points between populations have been interpreted as meaningful differences between different chronic pain populations. We explore the variability associated with optimally defined cut points in a large sample of chronic pain patients and in homogeneous subsamples. Ratings of maximal pain intensity (0–10 numeric rating scale, NRS) and pain‐related disability were collected in a sample of 2249 children with chronic pain managed in a tertiary pain clinic. First, the “optimal” cut points for the whole sample were determined. Second, the variability of these cut points was quantified by the bootstrap technique. Third, this variability was also assessed in homogeneous subsamples of 650 children with constant pain, 430 children with chronic daily headache, and 295 children with musculoskeletal pain. Our study revealed 3 main findings: (1) The optimal cut points for mild, moderate, and severe pain in the whole sample were 4 and 8 (0–10 NRS). (2) The variability of these cut points within the whole sample was very high, identifying the optimal cut points in only 40% of the time. (3) Similarly large variability was also found in subsamples of patients with a homogeneous pain etiology. Optimal cut points are strongly influenced by random fluctuations within a sample. Differences in optimal cut points between study groups may be explained by chance variation; no other substantial explanation is required. Future studies that aim to interpret differences between groups need to include measures of variability for optimal cut points.

[Three-week multimodal inpatient treatment of children with chronic pain. First results of the long-term follow-up].

ZusammenfassungFragestellungWir untersuchten den Erfolg einer 3-wöchigen stationären multimodalen Schmerztherapie für Kinder und Jugendliche.MethodikDie standardisierte Erhebung erfolgte mittels des Dattelner Schmerzfragebogens für Kinder und Jugendliche sowie mit Katamnesebögen. Erhebungszeitpunkte waren der Beginn sowie 3, 6 und 12xa0Monate nach der stationäre Therapie. Die Statistik erfolgte mittels Wilcoxon-Vorzeichen-Rang-Test bei einer Signifikanzschwelle von p <0,05.ErgebnisseWir untersuchten 72xa0Kinder (Alter 7,5–18,3xa0Jahre) mit täglichen Schmerzen bei zumeist anhaltender somatoformer Schmerzstörung. 65 Kinder konnten nach 3, 27 nach 6 und 30 nach 12xa0Monaten reevaluiert werden. Die durchschnittliche Schmerzstärke (Skala 0–10) nahm vom Ausgangswert (6,3) zu den einzelnen Nacherhebungspunkten signifikant ab (3xa0Monate: 2,9, 6xa0Monate: 2,3, 12xa0Monate: 2,9). Die durchschnittliche Anzahl der schmerzbedingten Schulfehltage/4xa0Wochen sank signifikant von 9,2 auf 1,8, 1,5 bzw. 1,4. Die durchschnittliche schmerzbedingte Lebensbelastung (Skala 12–60) war zu allen Reevaluierungszeitpunkten signifikant niedriger (3xa0Monate: 24,5, 6xa0Monate: 22,0, 12 Monate: 25,8) als zu Beginn der Schmerztherapie (37,8).SchlussfolgerungUnsere Daten zeigen die Langzeiteffektivität einer stationären multimodalen Schmerztherapie bei Kindern mit chronischen Schmerzen.AbstractObjectiveIn children and adolescents we investigated the impact of a 3-week inpatient multimodal pain therapy on subjective burden of life, pain intensity, and number of days off from school 3, 6, or 12xa0months later.MethodsAt the beginning of therapy (inpatient setting) and 3, 6, and 12xa0months thereafter (outpatient setting) we collected the respective data using standardized questionnaires. For statistical analysis we used Wilcoxon’s signed rank test. A p <0.05 was regarded as statistically significant.ResultsA total of 72xa0patients aged 7.5–18.2xa0years suffering daily pain entered the study, most of them being diagnosed with somatoform pain disease. After 3, 6, and 12xa0months, 65, 27, and 30xa0patients could be reevaluated. Mean pain intensity of the week before data acquisition was significantly less than at the beginning (2.9, 2.3, and 2.9 vs 6.3) as was the mean number of days off from school due to pain during the 4-week period before each day of data acquisition (1.8, 1.5, and 1.4 vs 9.2). Mean subjective burden of life was significantly less than at the beginning (24.5, 22.0, and 25.8 vs 37.8).ConclusionOutpatient multimodal pain therapy has a sustained impact on children and adolescents suffering from chronic pain.

Schmerzbezogene Beeinträchtigung bei Jugendlichen mit chronischen Schmerzen

ZusammenfassungHintergrundAls Folge chronischer Schmerzen leiden viele Kinder und Jugendliche unter schmerzbedingten Beeinträchtigungen, die sich auf alle Lebensbereiche auswirken können. Ein zentrales Ziel der Kinderschmerztherapie ist die Reduktion dieser schmerzbedingten Beeinträchtigungen, allerdings fehlen bisher geeignete validierte Messinstrumente. Ziel dieser Untersuchung ist die Übersetzung des Pediatric Pain Disability Index (P-PDI) von Varni und die Überprüfung seiner psychometrischen Eigenschaften.MethodenBei 163 ambulant und 167 stationär behandelten Jugendlichen mit chronischen Schmerzen (vorwiegend Kopfschmerzen) wurden Hauptkomponenten- und Itemanalysen durchgeführt. Zur Überprüfung der Stabilität wurde die Veränderung der schmerzbedingten Beeinträchtigung 3 Monate nach Beginn der ambulanten Therapie bei 110 Jugendlichen untersucht. Zudem wurden der Zusammenhang der schmerzbedingten Beeinträchtigung mit Schmerzvariablen, emotionaler Beeinträchtigung und Schulfehltagen und die Übereinstimmung zwischen Selbst- und Elterneinschätzung überprüft.ErgebnisseDer P-PDI zeigt sich als eindimensionales Messinstrument mit zufrieden stellender Reliabilität. Signifikante Zusammenhänge konnten zwischen der schmerzbedingten Beeinträchtigung und Schmerzintensität sowie Schulfehltagen aufgezeigt werden; kein Zusammenhang fand sich zu Schmerzdauer, Angst und Depression. Eltern- und Selbsteinschätzung korrelieren signifikant, jedoch schätzen 57% der Eltern die schmerzbedingte Beeinträchtigung ihrer Kinder niedriger ein als diese selbst.SchlussfolgerungMit dem P-PDI liegt erstmals ein validiertes deutschsprachiges Instrument zur Einschätzung der schmerzbedingten Beeinträchtigung bei Jugendlichen mit chronischen Schmerzen vor, das gut zur Überprüfung von Therapieeffekten genutzt werden kann.AbstractBackgroundPain-related disability affects many children and adolescents suffering from chronic pain and may exert an impact on all areas of their lives. Reduction of pain-related disability is, therefore, a fundamental aim of treatment; however, no validated means exist to assess pain-related disability in children and adolescents. The aim of this study was to translate the Pediatric Pain Disability Index (P-PDI) of Varni into German and to investigate its psychometric qualities.MethodsPrincipal component and item analyses were conducted on outpatient (n=163) and inpatient samples (n=167) of adolescents suffering from chronic pain. Changes in pain-related disability 3 months after starting treatment were analysed in an outpatient sample of 110 adolescents. Correlations between pain-related disability, emotional variables and school absence as well as concordance with parents’ ratings were investigated.ResultsThe P-PDI is a one-dimensional assessment tool with sufficient reliability. There were significant correlations between pain-related disability and pain intensity and school absence but not with pain duration, fear and depression. Parents and adolescents ratings correlated significantly, but 57% of parents underestimated the pain-related disability of their children.ConclusionThere is now a validated German version of the P-PDI to measure pain-related disability in adolescents suffering from chronic pain, which can be used in studies investigating treatment effectiveness.BACKGROUNDnPain-related disability affects many children and adolescents suffering from chronic pain and may exert an impact on all areas of their lives. Reduction of pain-related disability is, therefore, a fundamental aim of treatment; however, no validated means exist to assess pain-related disability in children and adolescents. The aim of this study was to translate the Pediatric Pain Disability Index (P-PDI) of Varni into German and to investigate its psychometric qualities.nnnMETHODSnPrincipal component and item analyses were conducted on outpatient (n=163) and inpatient samples (n=167) of adolescents suffering from chronic pain. Changes in pain-related disability 3 months after starting treatment were analysed in an outpatient sample of 110 adolescents. Correlations between pain-related disability, emotional variables and school absence as well as concordance with parents ratings were investigated.nnnRESULTSnThe P-PDI is a one-dimensional assessment tool with sufficient reliability. There were significant correlations between pain-related disability and pain intensity and school absence but not with pain duration, fear and depression. Parents and adolescents ratings correlated significantly, but 57% of parents underestimated the pain-related disability of their children.nnnCONCLUSIONnThere is now a validated German version of the P-PDI to measure pain-related disability in adolescents suffering from chronic pain, which can be used in studies investigating treatment effectiveness.

Maintaining Lasting Improvements: One-Year Follow-Up of Children With Severe Chronic Pain Undergoing Multimodal Inpatient Treatment

OBJECTIVEnTo investigate the long-term effectiveness of a 3-week multimodal inpatient program for children and adolescents with chronic pain.nnnMETHODSn167 adolescents were evaluated at pretreatment baseline, 3-, and 12-month follow-up. Long-term effectiveness was investigated for pain-related variables (pain-related disability, school absence, pain intensity) and emotional distress.nnnRESULTSnWe found statistically and clinically significant changes in all variables. After 1 year, the majority (56%) showed overall improvement as indexed by decreased pain-related disability or school absence. 22% had an unsuccessful treatment outcome. Those showing only short-term improvements had higher levels of emotional distress at baseline.nnnCONCLUSIONSn1 year after completing a multimodal inpatient program adolescents report less chronic pain, disability, and emotional distress. Clinically significant changes remain stable. Adolescents with high levels of emotional distress at admission may require special attention to maintain positive treatment outcomes. Specialized inpatient therapy is effective for children with chronic pain.

Stop the pain! A nation-wide quality improvement programme in paediatric oncology pain control

Introduction: Little is known about the impact of translation of pain management clinical practice guidelines on pain control in paediatrics. In an effort to overcome this, a longitudinal, nation‐wide, multi‐centre paediatric quality improvement (QI) study was initiated by the German Society of Pediatric Haematology and Oncology (GPOH) entitled Schmerz‐Therapie in der Onkologischen Paediatrie (STOP).

Cut points for mild, moderate, and severe pain on the VAS for children and adolescents: What can be learned from 10 million ANOVAs?

Summary Estimating the variability of optimal cut points for mild, moderate, and severe pain reveals that the same set of cut points for the VAS can be used for adolescents’ pain‐intensity ratings as for parental ratings of their children’s pain. Abstract Cut points that classify pain intensity into mild, moderate, and severe levels are widely used in pain research and clinical practice. At present, there are no agreed‐upon cut points for the visual analog scale (VAS) in pediatric samples. We applied a method based on Serlin and colleagues’ procedure (Serlin RC, Mendoza TR, Nakamura Y, Edwards KR, Cleeland CS. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. PAIN® 1995;61:277–84) that was previously only used for the 0 to 10 numerical rating scale to empirically establish optimal cut points (OCs) for the VAS and used bootstrapping to estimate the variability of these thresholds. We analyzed data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) study and defined OCs both for parental ratings of their children’s pain and adolescents’ self‐ratings of pain intensity. Data from 2276 children (3 to 10 years; 54% female) and 2982 adolescents (11 to 17 years; 61% female) were analyzed. OCs were determined in a by‐millimeter analysis that tested all possible 4851 OC combinations, and a truncated analysis were OCs were spaced 5 mm apart, resulting in 171 OC combinations. The OC method identified 2 different OCs for parental ratings and self‐report, both in the by‐millimeter and truncated analyses. When we estimated the variability of the by‐millimeter analysis, we found that the specific OCs were only found in 11% of the samples. The truncated analysis revealed, however, that cut points of 35:60 are identified as optimal in both samples and are a viable alternative to separate cut points. We found a set of cut points that can be used both parental ratings of their children’s pain and self‐reports for adolescents. Adopting these cut points greatly enhances the comparability of trials. We call for more systematic assessment of diagnostic procedures in pain research.

Critical closing pressure in preterm neonates: Towards a comprehensive model of cerebral autoregulation

In preterm neonates, intraventricular haemorrhage is linked to the dysfunction of cerebral autoregulation (AR). We aimed at tracing the critical closing pressure (CCP) in order to quantify AR and to reveal its inner workings. In an observational study, 10 preterm neonates (median, range: ga 28 weeks, 25 to 32 weeks; bw 1070, 685 to 1730 g; age 2d, 1 to 7 d) were continuously Doppler traced (a. carotis interna) for > 10 min. Systemic blood pressure (BP, a. umbilicalis, a. radialis, a. temporalis) was recorded simultaneously (> 1200 cardiac cycles each). Systolic BP was on average 11 mmHg above CCP. There was a striking parallel between both variables, even in cases of sudden spontaneous BP fluctuations > 30% (r = 0.72, 0.41 to 0.99), while systolic cerebral blood flow velocity remained largely unaffected (r = -0.15, -0.75 to 0.53), indicating a properly functioning AR. CCP was 28 mmHg, 14 to 38 mmHg. Based on our data, a physiological model of AR is developed, integrating anatomy, metabolic and neuronal pathways with former physiologic findings--including low frequency cycling of cerebral blood flow velocity. Tracing of CCP is thought to have the potential to identify infants with impaired AR. Since this method is noninvasive and independent of angle of insonation (thus rendering it uncritical in probe fixation), it is a promising tool for sustained monitoring of cerebral haemadynamics in the clinical setting.

Deutscher Schmerzfragebogen für Kinder, Jugendliche und deren Eltern (DSF-KJ)

ZusammenfassungHintergrundEine multidimensionale Erfassung chronischer Schmerzen stellt das wichtigste Instrument für die Diagnostik und Therapie von chronischen Schmerzen dar. Während im Erwachsenenbereich der Deutsche Schmerzfragebogen standardmäßig eingesetzt wird, fehlt es an entsprechenden Fragebögen im Kindes- und Jugendbereich. Ziel der vorliegenden Arbeit war es, die Entwicklung eines multimodalen Anamneseschema in Form eines Fragebogens mit allen relevanten Schmerzbereichen für Kinder und Jugendliche mit chronischen Schmerzen darzustellen und dessen Güte und Praktikabilität in folgenden Schritten zu untersuchen: 1) durch die Anwendung des Fragebogens an einer konsekutiv erhobenen Stichprobe aus Kindern und Jugendlichen (4–18xa0Jahre), 2) durch die Analyse der fehlenden Items in einer Kind-, Jugendlichen- und Elternversion und 3) durch die Analyse der Experteneinschätzung zum Fragebogen.Material und MethodenDer Deutsche Schmerzfragebogen für Kinder und Jugendliche (DSF-KJ) wurde auf der Grundlage des biopsychosozialen Schmerzmodells und in multiprofessionellen Expertengremien entwickelt. Der DSF-KJ erfasst soziodemografische Daten, Schmerzcharakteristika, schmerzauslösende und beeinflussende Faktoren, Voruntersuchungen und -behandlungen, schmerzbezogene Beeinträchtigung und kognitiv-emotionale und behaviorale Auswirkungen durch die chronischen Schmerzen. Für die Analyse der fehlenden Items und für die Stichprobenbeschreibung bearbeiteten 284xa0Kinder und Jugendliche (4–18xa0Jahre), die sich in einer tertiären Schmerzeinrichtung vorstellten, den DSF-KJ. Elf Experten bewerteten den Fragebogen hinsichtlich seiner Nützlichkeit und Handhabbarkeit.ErgebnisseAnhand des DSF-KJ erfolgte eine detaillierte Stichprobenbeschreibung des ambulanten Samples auf der Basis des biopsychosozialen Modells. So stellten sich mehr jugendliche Mädchen als Jungen in der Ambulanz vor. Die Betroffenen litten vorwiegend unter Kopfschmerzen und waren bereits maßgeblich in ihrem Alltag beeinträchtigt. Kinder und Jugendliche zeigten erstaunliche Ähnlichkeiten in den Schmerzcharakteristika, jedoch bildete sich die zunehmende Chronifizierung der Jugendlichen durch eine stärkere Beeinträchtigung und mehr Behandlungsversuche ab. Der DSF-KJ wurde von den Kindern, Jugendlichen und deren Eltern sorgfältig und mit sehr wenigen fehlenden Items beantwortet. Die Kliniker beurteilten den DSF-KJ als nützlich und praktikabel für Diagnosestellung und Therapieempfehlung.SchlussfolgerungDer DSF-KJ ermöglicht eine standardisierte Erfassung und umfassende Darstellung der Schmerzproblematik von Kindern und Jugendlichen. Trotz seines Umfangs ist er leicht durchführbar und liefert eine profunde Basis für die ärztliche und psychologische Diagnosestellung und Therapieempfehlungen. Erste Hinweise belegen die Güte des Fragebogens in Bezug auf Anwendbarkeit, Nützlichkeit und Praktikabilität.AbstractBackgroundA multidimensional assessment of chronic pain is the most important tool for diagnosis and treatment. While the German Pain Questionnaire is routinely implemented in the treatment of adults with chronic pain, similar questionnaires are scarce for children and adolescents. It was the aim of the present study to report on the development and quality of a multimodal questionnaire assessing all relevant aspects of chronic pain in children and adolescents. The quality of the questionnaire was assessed (1) by implementing the questionnaire in a sample of children and adolescents suffering from chronic pain (aged 4–18 years), (2) by analysing missing items in the child, adolescent and parent version and (3) by analysing experts’ ratings of the questionnaire.Material and MethodsThe German Pain Questionnaire for Children, Adolescents and Parents (DSF-KJ) was developed on the basis of the biopsychosocial model of chronic pain in experts’ meetings. The DSF-KJ entails an assessment of sociodemographic variables, pain characteristics, triggering factors, previous pain treatment, pain-related disability and cognitive and emotional factors related to the pain experience. A total of 284 children and adolescents who presented for pain treatment in our tertiary institute completed the DSF-KJ. Eleven pain experts rated the questionnaire regarding its utility for diagnosis and treatment.ResultsWith the use of the DSF-KJ, a detailed sample description was derived on the basis of the biopsychosocial model. More adolescent girls than boys presented to the institute. The majority of the children and adolescents suffered from headache and were severely affected by their chronic pain. Children and adolescents displayed similar pain characteristics. However, adolescents were more disabled due to chronic pain and had already undergone a variety of pain treatments. These differences may reflect an ongoing chronification in adolescents. Children, adolescents and their parents filled in the questionnaire thoroughly with very few missing items. The experts rated the questionnaire as very useful for diagnosis and treatment.ConclusionThe DSF-KJ provides a standardized assessment and comprehensive description of paediatric chronic pain problems and facilitates medical and psychological diagnostic and therapeutic decisions. The preliminary results suggest that the questionnaire is a clinically useful and practical assessment tool for children and adolescents with chronic pain.BACKGROUNDnA multidimensional assessment of chronic pain is the most important tool for diagnosis and treatment. While the German Pain Questionnaire is routinely implemented in the treatment of adults with chronic pain, similar questionnaires are scarce for children and adolescents. It was the aim of the present study to report on the development and quality of a multimodal questionnaire assessing all relevant aspects of chronic pain in children and adolescents. The quality of the questionnaire was assessed (1) by implementing the questionnaire in a sample of children and adolescents suffering from chronic pain (aged 4-18 years), (2) by analysing missing items in the child, adolescent and parent version and (3) by analysing experts ratings of the questionnaire.nnnMATERIAL AND METHODSnThe German Pain Questionnaire for Children, Adolescents and Parents (DSF-KJ) was developed on the basis of the biopsychosocial model of chronic pain in experts meetings. The DSF-KJ entails an assessment of sociodemographic variables, pain characteristics, triggering factors, previous pain treatment, pain-related disability and cognitive and emotional factors related to the pain experience. A total of 284 children and adolescents who presented for pain treatment in our tertiary institute completed the DSF-KJ. Eleven pain experts rated the questionnaire regarding its utility for diagnosis and treatment.nnnRESULTSnWith the use of the DSF-KJ, a detailed sample description was derived on the basis of the biopsychosocial model. More adolescent girls than boys presented to the institute. The majority of the children and adolescents suffered from headache and were severely affected by their chronic pain. Children and adolescents displayed similar pain characteristics. However, adolescents were more disabled due to chronic pain and had already undergone a variety of pain treatments. These differences may reflect an ongoing chronification in adolescents. Children, adolescents and their parents filled in the questionnaire thoroughly with very few missing items. The experts rated the questionnaire as very useful for diagnosis and treatment.nnnCONCLUSIONnThe DSF-KJ provides a standardized assessment and comprehensive description of paediatric chronic pain problems and facilitates medical and psychological diagnostic and therapeutic decisions. The preliminary results suggest that the questionnaire is a clinically useful and practical assessment tool for children and adolescents with chronic pain.

Cerebral autoregulation of preterm neonates--a non-linear control system?

The low frequency cerebral blood flow velocity (CBFV) oscillations in neonates are commonly attributed to an under-dampened immature linear type cerebral autoregulation, and the instability is regarded as causative for peri-intraventricular haemorrhage/periventricular leukomalacia. In contrast, oscillations susceptible to frequency entrainment are a fundamental part of the stable function of non-linear control systems. To classify the autoregulation an observational study was done on the relationship between CBFV oscillations, heart rate variability, and artificial ventilation. In 10 preterm neonates (gestational age 26 to 35 weeks) we serially Doppler traced arterial CBFV continuously for 12 minutes between days 1 and 49 of life. The individual time series of CBFV and heart rate were subjected to spectral analysis. Forty six of 47 tracings showed significant low frequency CBFV oscillations. Low frequency heart rate oscillations were not a prerequisite thereof. All patients with < 30% of total power in the low frequency band of CBFV oscillations were on the ventilator. Three of them demonstrated a shift of spectral power from low frequency to a frequency equal or harmonic to the ventilator rate indicating entrainment. The findings of CBFV oscillations combined with entrainment classify the autoregulation as a non-linear system. It is suggested that entrainment by periodic high amplitude stimuli might challenge the regulatory capacity to its limits thus increasing the risk for cerebral damage.