Hot and Cool Forms of Inhibitory Control and Externalizing Behavior in Children of Mothers who Smoked during Pregnancy: An Exploratory Study

This study examined whether children exposed to prenatal smoking show deficits in “hot” and/or “cool” executive functioning (EF). Hot EF is involved in regulation of affect and motivation, whereas cool EF is involved in handling abstract, decontextualized problems. Forty 7 to 9-year-old children (15 exposed to prenatal smoking, 25 non-exposed) performed two computerized tasks. The Sustained Attention Dots (SA-Dots) Task (as a measure of “cool” inhibitory control) requires 400 non-dominant hand and 200 dominant hand responses. Inhibitory control of the prepotent response is required for dominant hand responses. The Delay Frustration Task (DeFT) (as a measure of “hot” inhibitory control) consists of 55 simple maths exercises. On a number of trials delays are introduced before the next question appears on the screen. The extent of response-button pressing during delays indicates frustration-induced inhibitory control. Prenatally exposed children showed poorer inhibitory control in the DeFT than non-exposed children. A dose–response relationship was also observed. In addition, prenatally exposed children had significantly higher (dose-dependent) conduct problem- and hyperactivity-inattention scores. There were no significant group differences in inhibitory control scores from the SA-Dots. These results indicate that children exposed to prenatal smoking are at higher risk of hot but not cool executive function deficits.
Introduction
Prenatal tobacco exposure has consistently been associated with children’s externalizing behavior (e.g. Button et al. 2005; Huijbregts et al. 2007, in press; Kotimaa et al. 2003; Mick et al. 2002; Wakschlag et al. 2006). In contrast, studies into associations between prenatal tobacco exposure and children’s cognitive functioning show very mixed results (e.g. Batstra et al. 2003; Fried et al. 1998, 2003 versus Breslau et al. 2005; Huijbregts et al. 2006; Trasti et al. 1999). This is surprising because externalizing behavior problems often co-occur with cognitive difficulties.
Cognition in ADHD, ODD/CD, and ADHD+ODD/CD
Cognition has been widely studied in ADHD (for reviews, see Barkley 1997; Castellanos et al. 2006; Sergeant et al. 2003; Wilcutt et al. 2005). This research has shown, among others, problems with inhibitory control, working memory, vigilance, reward sensitivity (delay aversion), and time processing and currently focuses on different cognitive endophenotypes of ADHD (i.e. biologically based phenotypes that carry genetic loadings and index liability to disease; see Castellanos and Tannock 2002). Oppositional Defiant Disorder (ODD), Conduct Disorder (CD) and high levels of physical aggression have also been associated with cognitive difficulties such as language-based verbal skills and executive function (EF) (Henry and Moffitt 1997; Hill 2002; Séguin et al. 1999). Controversy still exists about whether verbal and, particularly, EF deficits are present in ODD/CD without comorbid ADHD (Pennington and Ozonoff 1996). Since Pennington and Ozonoff’s review on EF in different forms of developmental psychopathology, an increasing number of studies have taken into account the high comorbidity of ODD/CD and ADHD. This has resulted in reports of both qualitative and quantitative differences in EF-dysfunction between disorders. For example, Van Goozen and colleagues (2004) reported the absence of problems with Working Memory (WM) and planning in a group of children with Oppositional Defiant Disorder (ODD) and a group with combined ODD/ADHD compared to healthy controls. Both are executive functions that have frequently been reported to be deficient in ADHD. Oosterlaan et al. (2005) compared ADHD, ODD/CD, and ADHD+ODD/CD groups and found that WM and planning deficits were specific to ADHD (and explained by ADHD in the combined disorder). Distinguishing ADHD and ODD/CD is more difficult when it concerns inhibitory control (Oosterlaan et al. 1998). Inhibition has been defined and operationalized in a number of different ways, e.g. as stopping an ongoing response, interference control and inhibition of prepotent responses (Barkley 1997), and studies have generally not included tasks measuring such different forms of inhibition. Furthermore, inhibition has been listed as one of the executive functions (e.g. Pennington and Ozonoff 1996), but has also been described as an important cognitive ability underlying many different executive functions (Zelazo et al. 1997). Lack of inhibitory control has been proposed as the central deficit in both ADHD (Barkley 1997) and ODD/CD/physical aggression (e.g. Lau et al. 1995), but is not necessarily similarly dysfunctional in both types of disorders. Nigg (2003) has suggested that ADHD is predominantly associated with dysfunctional executive inhibition, whereas conduct problems are predominantly associated with dysfunctional motivational inhibition. Nonetheless, a ‘motivational’ pathway (or endophenotype) to cognitive deficits (e.g. altered reward sensitivity) in ADHD has also been identified (Solanto et al. 2001; Sonuga-Barke 2002). ODD/CD and ADHD may be distinguished more easily on other aspects of emotional or social information processing. As a starting point it may therefore be good to use a theoretical framework that, in addition to motivation, accommodates more different aspects of emotional or social information processing. Such a model has been proposed by Zelazo and Müller (2002).
Hot and Cool Aspects of Executive Functioning
Zelazo and Müller (2002) made a distinction between the ‘cool’ aspects of EF more associated with dorsolateral regions of the prefrontal cortex (PFC) and the ‘hot’ aspects more associated with ventral and medial regions. Cool EF is elicited by abstract, decontextualized problems, whereas hot EF is elicited by problems that involve the regulation of affect and motivation (i.e., the regulation of basic limbic system functions). Neuro-anatomical evidence for a distinction between hot and cool executive functions stems from research into risky (‘hot’) decision making versus ambiguous (‘cool’) decision making (Krain et al. 2006). The authors performed a meta-analysis of studies measuring brain activity during risky decision making (involving low probabilities of high rewards and high probabilities of low rewards) and/or ambiguous decision making (where the probability of a specific outcome is unknown or close to chance and choices do not differ in reward value), and found that there were significant differences between risky and ambiguous decision-making in regions of the orbitofrontal cortex (OFC: more activity in risky than in ambiguous decision-making), dorsolateral prefrontal cortex (DLPFC: more activity in ambiguous than in risky decision making) and anterior cingulate cortex (ACC: more activity in ambiguous decision-making than in risky decision-making in caudal regions, and more activity in risky than in ambiguous decision-making in rostral regions).
Zelazo and Müller use a problem-solving framework to discuss EF. Each stage of problem-solving (problem representation, planning, execution, and evaluation) is subserved by EF, which can take both hot and cool forms. They provide examples of each for every problem solving stage. For example, for the problem representation stage cool EF could be measured by asking participants to re-represent test items in different ways (but not act upon the re-representation). Hot measures of problem representation would include most tests of Theory of Mind, where participants are required to represent something (e.g. feelings, intentions) from multiple points of view. For the planning stage, tower tasks that require children to describe their plans without actually executing them are put forward as an example of ‘cool’ EF, whilst strategic deception, where participants are shown two pre-formulated plans, one deceptive and one not, and are asked to select the one that would trick the other person, was offered as an example of ‘hot’ EF. In the execution stage, card sorting (i.e. select according to two different rules/principles) was given as an example of cool EF, and delay of gratification as an example of hot EF (e.g. choosing between a small reward immediately or a larger reward later (prudence) or between a reward for self now or a reward for self and other later (altruism)). Finally, in the evaluation phase error detection and error correction in the context of monitoring progress toward a goal are provided as examples of cool EF and error detection and correction in the context of extinction as examples of hot EF (i.e. after a certain amount of responding, it can be shown that the reward supply has been exhausted, a motivational input that might lead to response extinction). In the problem-solving framework inhibitory control is considered to underlie EF in all information processing stages and consequently has its hot and cool variants as well. Thus, when inhibitory control involves emotion, affect, and/or motivation, it may be classified as a hot EF, whereas inhibitory control could be classified as cool EF when it is required in an “abstract” or “neutral” context.
Neurobiology of Prenatal Tobacco Exposure and Externalizing Behavior
There is increasing evidence that maternal prenatal smoking is more strongly associated with ODD/CD and with the co-occurrence of ODD/CD and ADHD than with ADHD alone (Huijbregts et al. 2007; Nigg and Breslau 2007; Wakschlag et al. 2006). This evidence alone might be enough to suggest that children prenatally exposed to tobacco might specifically show cognitive dysfunction when emotion is involved, specifically when tasks involve inhibition. Further indirect support for such a hypothesis comes from neurobiological evidence showing similar or closely related effects on the central and peripheral nervous system associated with prenatal smoking and with antisocial/disruptive behavior. Antisocial and disruptive behaviors have convincingly been associated with changes in the functioning of the autonomic nervous system (ANS) and the hypothalamic–pituitary–adrenal (HPA) axis. Both have very important roles in stress regulation. ANS-functioning is generally measured by (changes in) heart rate (HR), which reflects sympathetic and parasympathetic nervous system activity, and (changes in) skin conductance (SC), which reflects only sympathetic nervous system activity. HPA-functioning is generally measured by (changes in) the adrenal stress hormone cortisol. Resting HR, basal SC and basal cortisol levels were all shown to be lower in children with disruptive behavior disorders. In addition, reduced SC reactivity and blunted or absent cortisol responses to stress have consistently been reported (for reviews, see Ortiz and Raine 2004; Van Goozen et al. 2007). These findings have lead to the fearlessness theory of antisocial behavior (Raine 1993), which claims that low levels of arousal are markers of low levels of fear and the stimulation-seeking theory (Zuckerman 1979), which claims that low arousal represents an aversive physiological state and that individuals with tonically low arousal seek out stimulation to raise their arousal to optimal or normal level.
Antisocial/disruptive behavior has also been associated with neurotransmitter abnormalities, for example with impairments in the serotonergic (5-HT) system. The 5-HT system interacts with the HPA-system at several levels. For example, activation of (postsynaptic) 5-HT receptors in the hypothalamus stimulates HPA axis activity and causes elevation in cortisol, while a disruption of 5-HT neurotransmission by tryptophan depletion lowers HPA axis functioning (blunts cortisol-elevating effect of stressor). Glucocorticoids also modulate 5-HT receptor binding/sensitivity (see Van Goozen et al. 2007). Importantly, the ANS/HPA abnormalities in children with conduct problems have not been replicated in children with ADHD only (Herpertz et al. 2001; Snoek et al. 2004; Waschbusch 2002).
Animal studies investigating the consequences of prenatal nicotine exposure have shown an upregulation of nicotinic cholinergic receptor binding sites as well as persistent deficits in cerebrocortical choline acetyltransferase activity and hemicholium-3 binding to the presynaptic choline transporter, which is indicative of cholinergic hypoactivity (Seidler et al. 1992; Slotkin et al. 2006). These studies also show changes in noradrenergic responsiveness following prenatal nicotine exposure. The most important neurotransmitters of the ANS are acetylocholine (parasympathetic) and norepinephrine (sympathetic). In line with the chronic underarousal theories of antisocial/disruptive behavior, it may be hypothesized that, without continued nicotine exposure, the increased number of cholinergic receptor binding sites will be understimulated, possibly resulting in stimulation-seeking and fearlessness. Furthermore, abnormalities in serotonergic neuromodulation following prenatal nicotine exposure have been indicated (suppression of the 5HT1A receptor subtype and upregulation of 5HT2 receptor subtype) (Seidler et al. 1992; Slotkin et al. 2006). We had already stressed the interactions between 5HT and HPA-functioning. The commonalities in the neurobiology of antisocial/disruptive behavior and the neurobiology of prenatal smoking are striking. Moreover, factors affecting the same neurobiological system are more likely to reinforce each other’s impact (Moffitt et al. 2005). A number of studies have already reported abnormalities in ANS/HPA-functioning and levels of arousal in children of mothers who smoked during pregnancy (Browne et al. 2000; Horne et al. 2004; McDonald et al. 2006; Ramsay et al. 1996).
The Present Study
Taken together, the strong associations between prenatal smoking and offspring conduct problems, the specific affect-mediated (‘hot’) cognitive deficits supposedly associated with conduct problems, and the common neurobiology of prenatal nicotine exposure and conduct problems that particularly affects behavior and cognition under stressful conditions (i.e. behavior and cognition that is affect-mediated or ‘hot’), suggest that it would be useful to investigate aspects of hot cognition in children exposed to prenatal smoking (see also Raine 2002). Studies into associations between prenatal tobacco exposure and cognition have generally focused on academic achievement or rather broad cognitive constructs such as intelligence, verbal ability and executive functions (e.g. Batstra et al. 2003; Breslau et al. 2005; Huijbregts et al. 2006; Trasti et al. 1999), and have not yet used a distinction between hot and cool aspects of cognition. There are many possible causes for the inconsistent results which will be discussed later, but in the present study we will contrast hot and cool aspects of cognition, more specifically hot and cool forms of inhibitory control because a lack thereof has been hypothesized to be central to the behavior problems displayed by children of mothers who smoked during pregnancy. It is expected that children of mothers who smoked will particularly display problems with hot inhibitory control. Since a number of shared neural structures and neuromodulatory mechanisms are involved in cool and hot EF it cannot be ruled out that children prenatally exposed to nicotine will also have problems with cool inhibitory control but it may be hypothesized that these, if present, will be of a less serious nature.
Method
Participants
Forty children (16 boys, 24 girls; all of Caucasian ethnicity) attending two primary schools in Southampton (UK) participated in the study: 25 children from mothers who had not smoked during pregnancy (9 boys, 16 girls), 15 from mothers who had smoked during pregnancy (7 boys, 8 girls). Of these mothers, 6 smoked 1–9 cigarettes/day and 9 smoked ≥ 10 cigarettes/day (prenatal smoking was established through self-report by the mothers; although there is a risk for a social desirability bias, several studies have indicated a relatively strong association between retrospective self-report and blood/urine cotinine-levels (i.e. the main nicotine metabolite), e.g. Law et al. 2003; Pickett et al. 2005). Mean age of the participants was 7.98 (range 7.0–9.0, SD = 0.68). Informed consent was obtained from all children and their parents/caretakers and from the school boards. The study was approved by the University of Southampton—School of Psychology Ethics Committee.
Tasks and Measures
Sustained Attention Dots Task
The Sustained Attention Dots task (SA-Dots, De Sonneville 1999) is a computerized task consisting of 600 presentations of 3-, 4-, and 5-dot patterns (random configurations). The 3, 4, or 5 dots are each presented 200 times. Participants use both hands for responding. They must press the mouse key of the non-dominant hand (the ‘no-key’) when 3 or 5 dots appear on the screen and the mouse key of the dominant hand (the ‘yes-key’) when 4 dots appear. A response has to be given between 250 and 6,000 ms after a signal. The fixed post-response interval is 250 ms. The program provides auditory feedback after an error. Since a response with the non-dominant hand is required twice as often as a response with the dominant hand, a response with the non-dominant hand becomes the prepotent response. Thus, inhibitory control is required when four dots appear. The less participants are capable of inhibiting biased response tendencies, the more misses (i.e. pressing the ‘no-key’ when four dots appear) they will produce relative to false alarms (i.e. pressing the ‘yes-key’ when three or five dots appear). The Bias score is the difference between number of misses and the mean of the number of false alarms when three dots appeared and when five dots appeared (see Huijbregts et al. 2002a). A second measure used to assess the quality of inhibitory control is post-error slowing. Post-error slowing is usually considered a strategic adjustment based on performance monitoring (Klein et al. 2007; Wiersema et al. 2007). In order to be able to slow down after an error inhibitory control is required. In order to control for general response speed, the difference between mean RT of correct responses after errors and overall mean RT of correct responses was selected as measure for post-error slowing (RTae).
Delay Frustration Task
The Delay Frustration Task (DeFT, Bitsakou et al. 2006) is a task where participants are presented with a series of simple maths questions (only additions in the children’s version) on a computer screen. Four possible solutions are displayed on the screen together with each question. Participants are asked to select the correct answer by pressing one of four buttons on a response box. The next question is presented as soon as a response has been recorded. However, on 16 out of 55 trials access to the next trial is delayed. On 8 out of the 16 trails in the post-response delay condition, a short delay (2–10 s) occurs, whilst on the remaining eight trials a delay of 20 s occurs. During the 20 s delay periods, the number (NP) and duration (TP) of responses made on a response key are recorded. These measures and their product (NP*TP) index delay frustration. In the instruction, participants are told that the computer shows signs of malfunctioning and that if the computer appears to not register their response, they should just wait until the next trial appears and do not have to respond again. It is considered to be indicative of inhibitory control if participants refrain from constantly pressing response box buttons during the delay periods. Practice sessions preceded both the SA-dots- and the DeFT test sessions, which were held in separate quiet rooms in both schools. Total test time per child was approximately 30 min (approximately 15 min for each task).
Strengths and Difficulties Questionnaire (SDQ)
The parent–teacher rated SDQ (Goodman 1997) is a short behavioral screening questionnaire of children aged 4 to 16 years, which can be completed within approximately 5 min. For the present study, teacher ratings were obtained, which correlate highly with parent ratings (Goodman 1997). The SDQ consists of 25 items comprising five different subscales (five items each): emotional problems, conduct problems, hyperactivity/inattention, peer relationship problems, and prosocial behavior. The validity of this five-factor structure has been confirmed in large population samples (e.g. Goodman 2001). Each item is scored on a three-point scale: ‘not true’, ‘somewhat true’, or ‘certainly true’. ‘Somewhat true’ is always scored as 1, with the scoring of ‘not true’ and ‘certainly true’ varying with each item, being equal to either 0 or 2. A higher score indicates greater problems except for prosocial behavior, where a higher score indicates more positive behavior. A total difficulties score (range 0–40) is obtained by summing the scores of the emotional problems-, conduct problems-, hyperactivity/inattention-, and peer relationship problems subscales. Of specific interest for the present study are the Conduct Problems (CP) scale, which has the following items: (1) often has temper tantrums or hot tempers; (2) generally obedient, usually does what adults request; (3) often fights with other children or bullies them; (4) often lies or cheats; and (5) steals from home, school, or elsewhere, and the Hyperactivity/Inattention (HI) scale, containing the following items: (1) restless, overactive, cannot stay still for long; (2) constantly fidgeting or squirming; (3) easily distracted, concentration wanders; (4) thinks things out before acting; and (5) sees tasks through to the end, good attention span. Examples of items from the other scales are: “Picked on or bullied by other children” (peer relationship problems); “Many worries, often seems worried” (emotional problems); and “Helpful if someone is hurt, upset or feeling ill” (prosocial behavior). The SDQ has good reliability, whether it concerns internal consistency of the items (mean Cronbach’s α = 0.73), cross-informant correlations or test–retest reliability, and good criterion validity, whether it concerns its predictiveness of diagnosed psychiatric disorders, (mental health) service contact/use, or the association of its scores with those on other behavioral screening questionnaires (Bourdon et al. 2005; Goodman 2001; Goodman and Scott 1999).
Statistical Analysis
Main analyses
Because the number of children participating in this study was not large and the scores on the SA-Dots Task, the Delay Frustration Task, and the behavior scales of the Strengths and Difficulties Questionnaire were not normally distributed, we used nonparametric tests. Spearman rank order correlations were used to test whether scores on the Delay Frustration Task were related to scores on the SA-Dots Task.
Mann–Whitney U tests were employed to compare children of non-smokers and children of mothers who smoked during pregnancy on cognitive and behavioral (SDQ) measures. In order to test for dose-dependency children of smoking mothers were further subdivided into those whose mothers smoked between one and nine cigarettes/day and those whose mothers smoked ≥10 cigarettes/day. These two groups were compared to each other and to children of mothers who did not smoke using Kruskal–Wallis H-tests.
Exploratory analyses
Our final analyses were hierarchical linear regression analyses predicting those variables for which significant group differences were observed in Mann–Whitney U tests from prenatal smoking and the sum of SDQ Hyperactivity-Inattention (HI) and Conduct Problems (CP) scores. Maternal prenatal smoking was introduced in a first block followed by CP+HI in a second block. These analyses should be considered exploratory because the sample is too small to reliably distinguish children with HI only or CP only. In order to determine whether HI or CP is more strongly associated with task performance than a combination of both of them, it would be necessary to have a HI only and CP only group as well (see Huijbregts et al. 2007; in press). Because the regression analyses are parametric tests, dependent variable scores were square root transformed in order to approach normal distributions. These exploratory analyses were performed because the relationship between prenatal smoking, externalizing behavior, and task performance can only be fully explored when all three variables are present in one analysis.
Results
Main analyses
Table 1 shows means (+SDs) of the smoking and non-smoking groups for the subscales of the SDQ and for the outcome measures of the SA-Dots and the DeFT. Scores on the SA-Dots Task and the Delay Frustration Task did not correlate significantly: Bias × NP: r = 0.27, p = 0.143; Bias × TP: r = 0.27, p = 0.139; Bias × NP*TP: r = 0.26, p = 0.150; RTae × NP: r = 0.16, p = 0.355; RTae × TP: r = 0.13, p = 0.453; RTae × NP*TP: r = 0.20, p = 0.267. Despite the fact that scores on all different subscales of the SDQ were related to each other, only the scores on the hyperactivity-inattention and conduct problems scales could be predicted by maternal prenatal smoking, as shown by the outcomes of a series of Mann–Whitney tests. Thus, prenatal smoking did not predict the score on the emotional problems scale: Mann–Whitney U = 183.5, z = −0.46, p = 0.647, the peer relationships problem scale: Mann–Whitney U = 185.0, z = −0.44, p = 0.661, or the prosocial behavior scale: Mann–Whitney U = 194, z = −0.17 p = 0.865. In contrast, children of mothers who had smoked during pregnancy had more conduct problems (Mann–Whitney U = 134.5, z = −2.1, p = 0.038) and higher hyperactivity/inattention (Mann–Whitney U = 124.5, z = −2.0, p = 0.041) than children of mothers who had not smoked (mean ranks for conduct problems: 25.7 for exposed children and 18.0 for non-exposed children; for hyperactivity-inattention: 25.1 for exposed children and 18.4 for non-exposed children) (see also Fig. 1 for standardized CP and HI-scores for non-exposed versus exposed children). Dose–response relationships were observed when behavior of non-exposed, moderately exposed and heavily exposed offspring was compared with Kruskal–Wallis tests (conduct problems: mean ranks: 17.8, 22.4, and 26.8; χ2(2) = 5.7, p = 0.058; hyperactivity/inattention: mean ranks 17.8, 19.1, and 29.1; χ2(2) = 6.5, p = 0.040) (Fig. 2).
Table 1Mean scores (+SDs) for children with and without prenatal tobacco exposure on the strengths and difficulties questionnaire, the SA-dots task and the delay frustration taskGroup Number (N)SDQSA-DotsDelay frustration taskCPHIRTaeBiasNPTPNP*TPOverall400.68 (1.2)2.8 (2.5)477.2 (507.1)9.0 (8.9)0.40 (.44)162.0 (145.5)123.2 (185.9)Not-Exposed250.48 (1.2)2.2 (2.2)473.6 (594.1)9.0 (10.3)0.29 (.40)116.9 (123.3)78.0 (139.5)Exposed151.0 (1.2)3.9 (2.6)483.6 (323.1)9.1 (6.5)0.57 (.46)234.1 (153.0)195.5 (229.6)SDQ: Strengths and Difficulties Questionnaire, CP: Conduct Problems, HI: Hyperactivity-Inattention, SA-Dots: Sustained Attention-Dots; Bias and RTae are the inhibitory control measures from the SA-Dots task: RTae: RT correct after error – RT correct general; Bias: Number of errors on 4-dot presentations – mean number of errors on 3 and 5 dot presentations. NP, TP and NP*TP are the inhibitory control measures from the Delay Frustration Task: NP: mean number of response button presses during 20-s delays. TP: time response buttons were pressed during 20-s delays.Fig. 1Mean standardized scores on the SA-dots task, the Delay Frustration Task, and the Strengths and Difficulties Questionnaire for non-exposed vs exposed offspring. Bias and RTae are the inhibitory control measures from the SA-Dots task. DF-np (mean number of presses during 20 s intervals), DF-tp (mean duration of presses during 20 s intervals), and DF-np*tp (product of DF-np and DF-tp) are the inhibitory control measures from the Delay Frustration Task. SDQ-CP: Strengths and Difficulties Questionnaire—Conduct Problems, SDQ-HI: Strengths and Difficulties Questionnaire—Hyperactivity/InattentionFig. 2Dose-dependency in associations between maternal prenatal smoking and scores on the Delay Frustration Task and the Strengths and Difficulties Questionnaire. DF-np (mean number of presses during 20 s intervals), DF-tp (duration of presses during 20 s intervals), and DF-np*tp (product of DF-NP and DF-TP) are the inhibitory control measures from the delay frustration task. SDQ-CP: Strengths and Difficulties Questionnaire—Conduct Problems, SDQ-HI: Strengths and Difficulties Questionnaire—Hyperactivity/Inattention
With respect to task performance, children of mothers who had smoked during pregnancy (mean rank = 25.5) showed a higher response frequency (number of button presses: NP) during intervals in the Delay Frustration Task than children of non-smokers (mean rank = 16.5) [Mann–Whitney U = 97, z = −2.4, p = 0.016]. They also showed a longer response duration during intervals (time of button pressing: TP) (mean rank = 26.4) than children of non-smokers (mean rank = 16.0) [Mann–Whitney U = 84, z = −2.8, p = 0.005] (Table 1; Fig. 1). A dose response relation was shown by Kruskal–Wallis tests: NP: 0 cigs/day: mean rank = 16.5; 1–9 cigs/day: mean rank = 23.0; ≥10 cigs/day: mean rank = 27.2; χ2(2) = 6.2, p = 0.044; TP: 0 cigs/day: mean rank = 16.0; 1–9 cigs/day: mean rank = 23.2; =10 cigs/day: mean rank = 28.6, χ2(2) = 8.5, p = 0.014 (Fig. 2). For frequency and duration combined (NP*TP), a Mann–Whitney test also showed that children of smokers (mean rank = 26.0) showed less restraint during delays than children of non–smokers (mean rank = 16.3): U = 90, z = −2.6, p = 0.009. A dose–response relationship, indicating less inhibitory control during delays with an increase in prenatal smoking, was also observed (mean ranks for children of non-smokers, moderate smokers, and heavy smokers were 16.3, 22.8, and 28.1, respectively): χ2(2) = 7.5, p = 0.023 (Fig. 2).
There were no significant differences between exposed and non-exposed offspring in inhibitory control scores from the Sustained Attention Task: Bias: U = 130.5, z = −1.1, p = 0.255; RTae: z = −0.03, p = 0.988; Dose response: Bias: χ2(2) = 3.1, p = 0.209; RTae: χ2(2) = 1.4, p = 0.502.
Exploratory analyses
An important question that remains is whether the levels of CP and HI explain associations of prenatal smoking with DeFT-performance. As expected HI and CP were significantly related (Spearman’s rho = 0.57, p < 0.001). Because not enough children with CP only or HI only could be distinguished in our sample, the sum of the SDQ CP- and HI-scores was used in subsequent regression analyses.
Hierarchical linear regression analyses introducing prenatal smoking in a first block and CP+HI in a second block to predict DeFT-scores NP, TP and NP*TP showed significant regression models for each of the DVs: NP: F(2,32) = 3.9, p = 0.029; TP: F(2,32) = 7.5, p = 0.002; and NP*TP: F(2,32) = 3.8, p = 0.039. In none of these models prenatal smoking remained a significant predictor when CP+HI was introduced: NP: β = 0.268 (p = 0.122), a reduction from β = 0.361 (p = 0.033) in the model without CP+HI; TP: β = 0.294 (p = 0.067), a reduction from β = 0.427 (p = 0.011); and NP*TP: β = 0.264, a reduction from β = 0.355 (p = 0.036). In models with maternal prenatal smoking, CP+HI most strongly predicted time/duration of button pressing (TP): β = 0.393 (p = 0.016).
Discussion
Children of mothers who smoked during pregnancy exhibited problems with ‘hot’ inhibitory control, but not with ‘cool’ inhibitory control. Furthermore, children of mothers who smoked during pregnancy showed more conduct problems and hyperactivity-inattention than non-exposed children. The reliability of these effects was supported by the fact that dose–response relationships were also observed. The finding that problems particularly appear when cognitive tasks involve the regulation of affect is in line with the well-replicated association between maternal prenatal smoking and behavior regulation problems. In addition, CP+HI could account for the effects of prenatal smoking on DeFT-performance. These findings further support the contention that children of mothers who smoked during pregnancy specifically have problems when cognitive task performance involves regulation of affect. Our results indicate the importance of employing a theoretical framework supported by neuro-anatomical and neurobiological data when studying associations between maternal prenatal smoking and children’s cognitive and behavioral development.
Although the pattern of results confirmed expectations, it was somewhat surprising that there were no group differences at all for the cool inhibitory control measures, nor were there significant correlations between SA-Dots inhibitory control scores and DeFT inhibitory control scores. Some associations were expected because hot and cool types of EF share common neural structures and neuromodulatory mechanisms, i.e. they are presumed to be part of an ‘interactive functional system’ (cf. Hongwanishkul et al. 2005), which is in line with the theory stating that cortical processes involving perception and cognition provide representations of the physical and social world to the sub-cortical motivational systems, whilst, in turn, these representations are influenced by appetitive and defensive needs (Derryberry and Rothbart 1997). We did not find evidence supporting such an overlap between hot and cool executive functions, but we cannot rule out that it would become apparent when other measures of cool inhibitory control are used.
Because cognition in children of mothers who smoked during pregnancy has always been studied without a clear theoretical framework, the employment of Zelazo and Müller’s model is only a first step towards elucidating the cognitive profile of this population. Further explorations are warranted based on other cognitive models for which clear neuroanatomical evidence exists. It is possible that abnormalities in neuromodulation or neuroanatomical structures supporting hot EF only affect the most demanding cool EF-functions. The SA-Dots task in the present study had clear inhibitory control demands, but only minimal working memory or flexibility demands, which, particularly in combination with inhibitory control, might represent the most demanding forms of cool EF (e.g. Davidson et al. 2006; Huijbregts et al. 2002b).
Although the present study was the first to use the hot versus cool distinction for examining EF in children whose mothers smoked during pregnancy, studies into ADHD and studies into differences in EF between children with ODD/CD and ADHD have employed the same or similar distinctions earlier. In ADHD research significant empirical support has been found for a distinction between delay aversion (which can be considered a form of hot EF) and executive inhibitory control (which can be considered a form of cool EF) (e.g. Luman et al. 2005; Solanto et al. 2001, but see Geurts et al. 2006). Both characterize ADHD, but not necessarily simultaneously. Castellanos et al. (2006) formulated the interesting hypothesis that inattention symptoms may be associated with deficits in cool EF, whereas hyperactivity/impulsivity symptoms reflect hot EF deficits. ADHD-research may however also have limited the conception of hot versus cool EF because hot EF has exclusively been studied in decision making paradigms, mostly (variants of) the Iowa Gambling Task (Bechara et al. 1994). Hot decision-making paradigms are indeed those that involve risks and rewards (Kerr and Zelazo 2004), but the definition of hot EF suggests that the distinction is applicable to most if not all executive functions.
This is important because, within the concept of hot EF, further distinctions may be justified based on which aspect of affect/emotion is involved in performance of a task. For example, frustration and motivation (as measured by for example decision making or varying reward paradigms) are very different emotions with potentially different effects on task performance and different neurobiological correlates. Frustration is more closely related to stress, which, like nicotine, affects ANS/HPA-functioning (stress: Dickerson and Kemeny 2004; Van Goozen et al. 2000; nicotine: Browne et al. 2000; Horne et al. 2004; McDonald et al. 2006; Ramsay et al. 1996). Despite some neuro-anatomical overlap between brain areas active during stress and during motivationally driven situations (e.g. orbitofrontal (OFC-) involvement: Hynes et al. 2006; Rolls 2004), there is no clear-cut evidence for strong ANS/HPA-involvement during decision making tasks (i.e. tasks tapping into motivation). Thus, children of mothers who smoked during pregnancy might particularly demonstrate hot EF-deficits when stress or frustration are involved, but no hot EF deficits when motivation (or reward sensitivity) is involved.
Limitations and recommendations for further studies
Like prenatal smoking, deficient ANS/HPA-functioning is also particularly associated with conduct problems and co-occurring conduct problems and hyperactivity (Herpertz et al. 2001; Waschbusch 2002). Unfortunately the number of participants in the present study was too small to reliably distinguish children with solely hyperactivity, solely conduct problems, and with co-occurring hyperactivity and conduct problems. Larger samples would also be required to investigate whether children with conduct problems present with different types of hot EF-deficits than children with ADHD. The main problem of a small sample size is that it limits the strength of confidence one can have in the generalizability of findings to other samples. That is why this study should be considered exploratory.
Furthermore, it would be desirable for future studies to incorporate a number of control variables in the analysis of hot versus cool executive functions in children of mothers who smoked during pregnancy. There are many different types of variables that could account for associations between maternal prenatal smoking and hot EF-functioning. One important candidate is parental education or IQ, which unlike potential confounders such as alcohol or drug use during pregnancy, quality of parenting, family functioning, family status, mother’s age when she had her first child and parental psychopathology, explained associations between maternal prenatal smoking and children’s cognitive outcome measures in a number of studies (Breslau et al. 2005; Huijbregts et al. 2006; Trasti et al. 1999). Moreover, associations between maternal prenatal smoking and offspring cognition remained significant in studies where parental education or IQ were not introduced as potential confounders (e.g. Batstra et al. 2003). Despite the fact that these studies investigated associations of prenatal smoking with general cognitive outcome measures such as IQ and academic achievement, which have been reported to correlate significantly with measures of cool but not hot EF (Hongwanishkul et al. 2005), and despite the fact that participants in the present study were all from the same area of Southampton which can be considered relatively uniform regarding socio-economic status (family income, parental education etc.), we have not included a direct control measure for parental IQ or education and can therefore not rule it out as a potentially significant confounder. Moreover, confounders of the association between maternal prenatal smoking and hot EF may be different from those that explain associations between maternal prenatal smoking and cool EF. Another limitation is that, even though our study revealed a clear difference between results on the two inhibitory control tasks, we did not collect children’s IQ—or academic achievement measures ourselves. The interpretation of our results would have been stronger if, like Hongwanishkul and colleagues, we would have been able to show that such measures were associated with our cool EF-measure, whilst they would not have had a significant relation with our hot EF-measure.
A final limitation we would like to address concerns the validity of our claim that the Delay Frustration Task measures hot inhibitory control whereas the SA-Dots task measures cool inhibitory control. Whereas the SA-Dots task has been used regularly before to measure inhibition of prepotent responding in different clinical populations characterized by deficient inhibitory control (e.g. Huijbregts et al. 2002a; Konrad et al. 2004; Slaats-Willemse et al. 2003), the Delay Frustration Task was originally developed to measure delay aversion (Bitsakou et al. 2006). In the dual pathway model of ADHD, delay aversion is considered a largely autonomous construct (Sonuga-Barke 2002). The advantage of considering this task a measure of delay aversion is that one could then make a stronger case for it being a measure of “hot EF”, as such tasks have been used to measure this construct before. Still, the developers of this task recognize that it is likely that the Delay Frustration Task measures inhibitory control (i.e. participants have to stop a “prepotent” or “ongoing” response during the delays) (Bitsakou et al. 2006). Although based on Zelazo and Müller’s theory DeFT should be regarded as a hot EF task regardless of whether it is considered a delay aversion or an inhibition task, it might be best for future studies to select tasks which are completely similar apart from an ‘affect-’ (e.g. frustration) component in one version.
The important message of this study is that two forms of EF can be distinguished which can be classified as hot and cool EF, and that in children of mothers who smoked during pregnancy a discrepancy can be observed between these two. Children whose mothers smoked during pregnancy are particularly at an increased risk of demonstrating (frustration-induced) hot EF-deficits. When these results are confirmed in larger samples that take into account the many potential confounders, intervention programs aimed at child factors could incorporate the training of specific emotion regulation skills in addition to the training of ‘cool’ EF-skills. Ideally, at risk families are identified before or early during pregnancy. Although prenatal smoking occurs in approximately 25% of pregnant women in Western countries (Breslau et al. 2005; Huijbregts et al. 2006), it has been shown that a family history of antisocial behavior in combination with prenatal smoking seriously compounds the risk of offspring disruptive behavior (Huijbregts et al. in press). Thus, like successful intervention programs aimed at increasing the knowledge about health (including smoking cessation) and care of mothers-to-be such as the Nurse Home Visitation Program (Olds et al. 1999), intervention programs aimed at improving child factors such as their emotion regulation skills should probably be provided to children with a combination of risk factors. When it is confirmed that ANS/HPA abnormalities mediate associations between prenatal smoking and children’s disruptive behavior and hot EF, clinical implications might also involve reinstating normal ANS/HPA axis functioning pharmaceutically (Van Goozen et al. 2007), for example by temporarily saturating glucocorticoid receptors. By restoring stress response systems, emotion regulation and related cognitive functioning could be improved, perhaps even more strongly in disruptive children whose mothers smoked during pregnancy than in disruptive children whose mothers did not smoke during pregnancy.

inhibitory control
prenatal smoking
conduct problems
hyperactivity
hot and cool executive functioning


The “Health Benefit Basket” in The Netherlands

This contribution describes the entitlements in Dutch health care and explores how these entitlements are determined and to whom they apply. The focus is on services of curative care. No comprehensive positive or negative list of individual services is included in formal laws. Instead, the legislation states only what general types of medical services are covered and generally the “usual care” criterion determines to which interventions patients are entitled. This criterion is not very restrictive and yields local variations in service provision, which are moderated by practice guidelines. It is conceivable, however, that the recent introduction of the DBC financing system will change the reimbursement and therefore benefit-setting policy.
This contribution gives a detailed account of entitlements in the Dutch health care system. Furthermore, it explains who decides about the services covered and the legal context in which this is done. It also describes which parts of the health benefit basket are defined more implicitly and which more explicitly, outlining the criteria used for the definition of the basket. We present the main characteristics of the Dutch health care system, highlighting those that impact on the entitlements of the insured. We then present a detailed account of health care entitlements in curative care. Finally, we conclude by identifying the aspects that determine the health care package and require special attention in a European context. We specifically ask what future developments are likely to impact on this system for definition of entitlements.
The main characteristics of the system
The Dutch Constitution states that the government should provide services to improve and protect public health. Therefore about 80% of health expenditures are paid from public funds (mainly social insurance), the rest being financed from private insurance and out-of-pocket payments [1]. The health insurance system broadly consists of three compartments (see Table 1). First, every citizen is entitled to long-term care covered under the Exceptional Medical Expenses Act (Algemene Wet Bijzondere Ziektekosten, AWBZ). The AWBZ scheme pays for about 43% of Dutch health expenditure. Secondly, for acute care individuals are either publicly insured under the Sickness Fund Act (Ziekenfondswet, ZFW) or privately insured (37% and 15% of healthcare expenditure, respectively). The ZFW scheme covers among other things the costs of hospital admissions, treatment by physicians, pharmaceutical care, and medical aids.Table 1 The three “pillars” of the Dutch health care systemFirst pillarSecond pillaraThird pillarType of careLong-term careBasic curative servicesAdditional servicesPrimary regulation (laws)AWBZb,cPrivate insurancec, WTZc, ZFWbComplementary insuranceb,cSecondary regulation (decrees)Decree on Entitlement to Exceptional Medical Expenses InsuranceHealth Insurance Treatment and Services Decree–Tertiary regulation (discretion of Minister)Regulation on Subsidies in AWBZRegulations on Medical Specialist Care–Regulations on Entitlements to AWBZ-careRegulations Governing the Provision of Paramedical Assistancea To be replaced in 2006 by a statutory health insurance scheme that covers the entire populationb Administered by sickness fundsc Administered by insurance companies
Persons who do not qualify for compulsory health insurance but cannot satisfy private insurers’ acceptance criteria (for example, if they represent a high risk) have access to a “standard insurance package” which is similar to that of the ZFW. This entitlement is specified in the Medical Insurance Access Act 1998 (Wet op de toegang tot ziektekostenverzekeringen, WTZ). The third compartment consists of complementary insurance policies that may be bought to extend coverage.
The basic insurance package is defined mainly at the central government level, although only categories of services are identified. The AWBZ and ZFW (acts of Parliament) offer a list of the functional categories of health care services to which a patient is entitled (e.g., pharmaceutical care, hospital care, rehabilitation services). These formal laws indicate in general terms which areas of care are covered by the insurance scheme, but they do not specify the entitlements of the insured in detail. Usually further specification is provided in lower types of regulations by the government or the Ministry of Health, Welfare, and Sport and its advisory bodies. The lower forms of regulation specify the contents and the extent of the entitlements, specify conditions, and delegate responsibilities. Two important governmental decrees are associated with the AWBZ and the ZFW, respectively: the Decree on Entitlement to Exceptional Medical Expenses Insurance and the Health Insurance (Treatment and Services) Decree.
The social health insurance system ensures that patients receive the care to which they are entitled. Management of the two-tiered public/private system, however, has proven difficult for the government, especially since the system lacks sufficient incentives for efficiency and has unfavorable equality characteristics. These conditions stimulated major reforms. Government involvement will be reduced significantly in 2006 when a new Health Insurance Act comes into force. This forms the final phase of the so-called Dekker plan (1987). The Dekker proposals set out conditions for the introduction of regulated competition in health care which should make the system more responsive to the preferences of consumers and less burdensome to manage. Health insurers have become main actors in promoting cost containment since they now hold full budget responsibility and may enter into contracting with providers. The government has promoted competition by enforcing open enrollment with health insurers and through establishing agencies that should regulate competition (e.g., an antitrust agency has been active in the health care sector since 1998). Nevertheless, the government will remain responsible for defining the health basket. A comprehensive description of the Dutch health insurance system is presented elsewhere [2].
The following section concentrates on the services made available in the health basket and the way in which these are decided. This description is limited to the curative sector. A complete account of health care services available in all health care sectors is offered by Stolk and Rutten [3]. Note that the integration of social and private insurance schemes into a national insurance implies that the coverage of the ZFW will be extended to the entire population. For this reason the present contribution describes only the ZFW benefit package.
The benefit package for curative care
The definition of entitlements for curative care is typical for the Dutch system: new interventions are usually implicitly introduced into a largely unspecified benefit package. A small negative list explicitly excludes services from reimbursement. This reflects the absence of a systematic procedure for the evaluation of curative services when defining the basket.
Medical specialist care
The ZFW specifies a general entitlement to specialist care by hospitals (both inpatient and outpatient care): patients are entitled to medical, surgery, and obstetric care. Entitlement to hospital care also exists under the AWBZ if the patient must stay in hospital longer than 365 days. The provided care is limited merely by professional norms following the “usual care” principle (appropriateness according to professional standards). Also, a general statement is made that health care should be provided efficiently. Therefore the definition of entitlements for hospital care is rather implicit and the “usual care” criterion is not very restrictive. However, the entitlements are conditional upon the referral by a general practitioner, by another specialist to whom a general practitioner had referred the insured, or, where obstetric care is concerned, by a midwife.
A ministerial decree, the Regulations on Medical Specialist Care, further specifies entitlements by excluding specific forms of transplantation and plastic surgery. It also determines that only certain types of transplantations are covered, and states that entitlement to some services (e.g., plastic surgery) only exist if specific conditions are met. Finally, this regulation explicitly excludes services such as eyelid, ear or body sculpturing, in vitro fertilization (IVF), uvoloplasty for persons who snore, sterilization or undoing sterilization, and circumcision. It should be noted that IVF is a special case and its reimbursement policy changed several times. Today, health insurers are subsidized to fund IVF treatment for the insured after the first attempt has been paid out of pocket.
Pharmaceuticals dispensed in hospitals are part of the entitlement to hospital care. They are generally financed out of the hospital budget, but the insurer may separately reimburse an additional percentage (up to 80%) of the cost for very expensive hospital drugs.
The law remains rather vague about entitlements to hospital care, but a recently introduced pricing system has led to more explicit benefit definition. In 2005 a new system for hospital financing was introduced by law: the Diagnose Behandeling Combinaties (DBCs), a DRG-like system describing all products that are provided in hospitals. Medical experts were involved in the determination of these DBCs, which are defined as the whole set of activities (diagnostic and therapeutic interventions) of the hospital and medical specialist starting from the first consultation and diagnosis of the medical specialist in the hospital until discharge. Each DBC is characterized by a code combining information on diagnosis (International Classification of Diseases, 10th edition) and treatment. This system facilitates negotiations between health insurers and hospitals on prices (on a bilateral level), at the same time providing a catalogue of medical services. Table 2 shows how many different DBCs are defined within a medical specialty distinguishing between list A (prices fixed by the National Health Tariffs authority until further notice) and list B (prices negotiated by Sickness Funds and hospitals from January 2005 onwards). This catalogue of DBCs allows the specification of which DBCs are included in the basis package: the “red” list presents the number of DBCs not covered by compulsory insurance as determined by the Health Care Insurance Board on the basis of the “usual care” criterion and current explicit exclusions. Also an “orange” list exists with DBCs for which reimbursement is limited to certain groups of patients. Finally, the table lists the number of product groups that have been defined to cluster DBCs into homogeneous price groups, as negotiation on the price of each single DBC would not be feasible.Table 2 Overview of the DBC system (January 2005)SpecialtyNumber of DBCsProduct groupsaList AaList BaRed listbOrange listbOphthalmology1,7893181415Otorhinolaryngology6926–3514Surgery3,671182850553Plastic surgery13,7126320554433Orthopedics 3,0581412443Urology37,71795011617438Gynecology5362263434Neurosurgery1,25327151329Dermatology39610323311Internal medicine3,33519–61249Pediatrics3,4921091261Gastroenterology10,946190–34221Cardiology353––4439Respiratory medicine1,054145537143Rheumatology2,042129519617Allergology599––8Thorax surgery1,034–105027Psychiatry648–––3Neurology2,73918446143Geriatrics918–––16Radiotherapy468––19514Radiology13,216––4728Anesthesiology582–103819Clinical genetics100––3Total104,3501,3761,5113,649641a Published at the website of the National Health Tariffs authority (CTG/ZAio): http://www.ctg-zaio.nl/index.phpb Published at the website of the DBC maintenance organization: http://www.DBConderhoud.nl
An exception to the way in which medical specialist services are regulated is mental health care, which is currently covered under the AWBZ. Also the first year of treatment is covered by the AWBZ and not by the ZFW, as is the case for other medical specialist services. The reason is that psychotherapy is often a long and intensive treatment. Ambulatory psychotherapy is reimbursed (maximum of 25 sessions, 50 in the case of personality disorders) if referral is by a general practitioner or psychiatrist. Patients’ entitlements to mental health care through the AWBZ include treatment (therapy sessions and medication), supportive guidance, and accommodation. Special regulations apply to mental health care in children and to treatment of addictions. The objective is to make mental health care a part of the basic benefit package under the new Health Insurance Act and therefore shift it to compartment 2 in a competitive environment. To permit this change DBCs in mental health care are now being defined.
Primary care, dental care, and paramedical services
Primary care, i.e., medical and surgical care provided by general practitioners, is covered under the ZFW, as specified in the Health Insurance (Treatment and Services) Decree. Care involves mainly consultations and visits, the prescription of pharmaceutical care, referral to medical specialists, and minor operations. Entitlements to these services are also defined implicitly: any type and quantity of care consistent with professional norms is covered by the scheme.
Entitlements to dental care have been limited in the past and are defined explicitly. The ministerial regulation “Dental Care Health Insurance” stipulates that persons up to the age of 18 years are entitled to dental care under the ZFW. Dental care includes 14 types of services, among which are periodic checkups, fluoride application treatment, sealing, and periodontal care. Adults are entitled to dental care only under special circumstances: special dental conditions and physical or mental disabilities.
Paramedical care—consisting of physiotherapy, Mensendieck or Cesar remedial therapy, speech therapy and ergotherapy—is partly covered. The first nine sessions are excluded from reimbursement, but thereafter some patients over the age of 18 years are entitled to physiotherapy, Mensendieck or Cesar remedial therapy for the treatment of chronic conditions that are defined in the Regulations Governing the Provision of Paramedical Assistance.
Curative care at home
Under exceptional conditions and with authorization by the sickness fund, specialized services of curative care may be provided at home. First, persons are entitled to kidney dialysis at home or in a dialysis center under ZFW. If the dialysis takes place at home, the costs of training a person to carry out dialysis or providing assistance during the procedure are also covered. The costs of inspecting and maintaining equipment, modifying the home, providing special sanitary fittings, and heating are also reimbursable. Second, the ZFW regulates the use of treatment for chronic intermittent ventilation. Those covered by the ZFW are entitled to treatment at a ventilation center. A center may lend the patient the equipment for use at home or in a location where several persons can use the equipment. Specialist and pharmaceutical care provided by or on the advice of the ventilation center are also included.
Discussion
A liberal benefit package?
In The Netherlands decisions about the medical services offered to a patient are often left to the physician (and/or the health insurer). Negative lists are in certain categories used to exclude services (e.g., the new red and orange lists of DBCs). The extent to which new or old technologies (therapy, diagnostic services, and pharmaceuticals) are provided to the patient in the context of a DBC is left to the providers. However, some medical services were explicitly excluded for not being considered to belong to the domain of health care (e.g., plastic surgery). Additionally, limits were set to the provision of physiotherapy and psychotherapy for a lack of demonstrated effectiveness. Restrictive legislation only exists in the pharmaceutical sector where an itemized positive list of individual products is frequently updated [4]. For several other functional categories there are also positive lists, but these are not frequently updated (e.g., for medical devices and vaccines). Regarding pharmaceuticals it is interesting to observe that the reimbursement of extramural drugs (prescription filled by the community pharmacist) is centrally regulated, while for the use of drugs in the hospital the policy is liberal. The liberal policy has led to wide variations in the availability of certain expensive drugs across hospitals and to referral of “expensive” patients to specialized centers. The new hospital financing system will change this and will probably force decision makers to regulate the provision of expensive drugs within a DBC.
Procedures and criteria for limiting the health basket
The package can be limited by management of positive or negative lists, copayments, the definitions of conditions restricting eligibility, and promoting best practice, i.e., effective and efficient provision of care. Each instrument is applied within the Dutch system, although some sectors are more loosely managed than others. On the whole, emphasis is put on offering incentives for efficiency. Recently a no-claim system was introduced: if someone insured under ZFW has no expenses, he receives a bonus of €255 from his insurer or the difference if his expenses are less than €255. The liberal character of the basket is further illustrated by the fact that there is no systematic and central effort to use common criteria for defining the package as a whole. Nonetheless, decisions tend to be guided by a quite homogeneous set of considerations.
The respective Ministers of Health and more specifically the Health Care Insurance Board have been using health technology assessment (and cost-effectiveness information) since the middle 1980s as a tool for deciding on large public programs (e.g., national cancer screening programs) and on the addition of expensive curative programs (e.g., transplant programs) to the package [5]. Especially in the case of pharmaceuticals dispensed outside the hospitals the role of cost-effectiveness as criterion for reimbursement is quite prominent. If the manufacturer can demonstrate greater effectiveness than existing drugs and wants a premium price, he must submit a pharmacoeconomic dossier and figures allowing the Health Care Insurance Board to base its policy on information on (cost-)effectiveness.
Furthermore, many technology assessment studies have been financed from a special fund managed by the Health Care Insurance Board and later by the National Medical Research Council that have produced valuable information on the cost-effectiveness of new diagnostic and therapeutic procedures. Although not legally required, this information has been used to define the benefit package or for the development of practice guidelines.
Further criteria have emerged as constant factors in decision making: severity of illness, individual vs. collective responsibility, affordability, and leakage (the probability of use outside a targeted patient group) [6]. Although initially consistent use of these criteria may have been doubted, gradually patterns emerged. Severity of illness, for example, played a role in deciding to finance the lung transplantation program although it was demonstrated to have a high cost-effectiveness ratio [7]. In relation to budget impact it also played a role in the decision not to fund PDE-5 inhibitors in the treatment of erectile dysfunction. Responsibility and affordability have played a role in deciding to restrict the reimbursement of pills for minor illnesses and dentistry. Leakage played a role in the decision to limit funding of some medicines (e.g., clopidogrel) to specific patient group. The increased understanding of the balance between the criteria is also recognized by policy makers.
The role of practice guidelines
An important way to influence the providing of service is through practice guidelines. There are many disciplinary and interdisciplinary practice guidelines for both primary and secondary care, some of which are also based on economic evidence. In The Netherlands a government program supported the development of practice guidelines in 1998–2002 which led to 31 consensus guidelines for medical practice addressing 23 disorders across seven disease groups as defined by the International Classification of Diseases. One example is the guideline for the use of cholesterol-lowering drugs in primary and secondary prevention which sets rules for the prescription of statins according to the patient’s personal risk profile.
Future prospects
An important development is the change in hospital financing, involving description of the benefit package in terms of DBCs which are or are not reimbursed. Currently it is being discussed how the definition of DBCs can be more detailed to include specific regulations on the technologies to be used within a certain treatment. A so-called “maintenance organization for DBCs” is set up to (re)define DBCs.
The reforms of 2006 are intended to reduce government control in the health care sector and provide incentives to patients and insurers for cost consciousness. Health care should follow the preferences of consumers. It follows that entitlements are formulated in functional form rather than as specific facilities or services. It is still not clear whether local actors will assume a role in defining the basket, and whether the government will centralize decisions.

the netherlands
health benefit plans
health services
health priorities
national health programs


Hypertension in children with chronic kidney disease: pathophysiology and management

Arterial hypertension is very common in children with all stages of chronic kidney disease (CKD). While fluid overload and activation of the renin–angiotensin system have long been recognized as crucial pathophysiological pathways, sympathetic hyperactivation, endothelial dysfunction and chronic hyperparathyroidism have more recently been identified as important factors contributing to CKD-associated hypertension. Moreover, several drugs commonly administered in CKD, such as erythropoietin, glucocorticoids and cyclosporine A, independently raise blood pressure in a dose-dependent fashion. Because of the deleterious consequences of hypertension on the progression of renal disease and cardiovascular outcomes, an active screening approach should be adapted in patients with all stages of CKD. Before one starts antihypertensive treatment, non-pharmacological options should be explored. In hemodialysis patients a low salt diet, low dialysate sodium and stricter dialysis towards dry weight can often achieve adequate blood pressure control. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are first-line therapy for patients with proteinuria, due to their additional anti-proteinuric properties. Diuretics are a useful alternative for non-proteinuric patients or as an add-on to renin–angiotensin system blockade. Multiple drug therapy is often needed to maintain blood pressure below the 90th percentile target, but adequate blood pressure control is essential for better renal and cardiovascular long-term outcomes.
Introduction
Hypertension is one of the most common sequelae of chronic kidney disease (CKD) in children [1]. CKD-associated hypertension develops by a large variety of pathophysiological mechanisms. Blood pressure is one of the most critical determinants of the progression rate of renal failure in children [2, 3], and cardiovascular mortality in childhood onset renal failure [4]. Therefore, good antihypertensive management can substantially contribute to better renal and patient survival of adults with childhood-onset CKD.
As in many other complications of chronic renal failure, patients often do not report symptoms of hypertension, so an active screening approach is needed to prevent end-organ damage.
This article aims to give a short overview of the different pathophysiological pathways that lead to hypertension in CKD in order to explain how these can be targeted by different therapeutic approaches.
Pathophysiology of hypertension in CKD
Fundamentally, increased blood pressure is caused by an increase in cardiac output and/or of total peripheral resistance. Both can be altered by a plethora of different mechanisms in uremia and renal failure. Additionally, children with certain underlying diseases, e.g. glomerulopathies and polycystic kidney disease, are especially susceptible to hypertension [3, 5]. Figure 1 gives an overview of the most important pathways involved.
Fig. 1Interplay of different factors in the generation of hypertension in chronic kidney disease (BP blood pressure, CO cardiac output, TPR total peripheral resistance, PTH parathyroid hormone, Na sodium)
Activation of the renin–angiotensin–aldosterone system plays a pivotal role in renal hypertension. While plasma renin activity is typically found to be markedly elevated only in patients with renal artery stenosis, many patients with CKD have ‘inappropriately normal’ renin levels (i.e. lower levels would be expected, considering their degree of hypertension and fluid overload [6, 7]). Hyper-reninemia occurs probably due to renin secretion in poorly perfused areas such as cysts and scars or after microangiopathic damage or tubulo-interstitial inflammation [8, 9] and leads to angiotensin II-mediated vasoconstriction as well as aldosterone-mediated salt retention, thus increasing both total peripheral resistance and blood volume. Additional delayed effects of a high angiotensin II tone include inflammation, cardiac hypertrophy and endothelial cell damage, mesangial cell proliferation and fibrosis [10], which contribute further to hypertension and end-organ damage.
Sodium retention and consequent fluid overload have long been recognized as causes of hypertension in CKD. Hypertensive children on dialysis have lower residual urine output than their normotensive peers have [5]. While inter-dialytic weight gain is correlated with the inter-dialytic increase in ambulatory blood pressure, the correlation is rather weak (in children r = 0.41 [11]). This may be due to delayed effects [12] but also points to important volume-independent factors regulating blood pressure (BP) in patients on hemodialysis. This is also illustrated by the fact that nephrectomy in children on dialysis lowers mean blood pressure, despite causing anuria [13]. It has been proposed that fluid overload leads to hypertension only in those patients in whom peripheral resistance fails simultaneously to fall, i.e. when additional factors interfere with vascular autoregulation [14].
A growing body of evidence suggests that increased activity of the sympathetic nervous system (SNS) is an important volume-independent cause of hypertension. Campese et al. demonstrated that renal denervation improves both hypertension and increased sympathetic activity caused by phenol injection into rat kidneys [15]. Muscle sympathetic nerve activity is also elevated in hypertensive patients with chronic renal failure [16]. The underlying mechanisms of this phenomenon are, as yet, unclear and may include afferent signals from the failing kidney as well as dopaminergic abnormalities and the accumulation of leptin in CKD [17, 18]. Interestingly, not only beta blockade but also angiotensin-converting enzyme (ACE) inhibition can reduce the sympathetic hyperactivation of CKD [16, 19]. However, as sympathetic hyperactivity is also a feature of renovascular hypertension [20], essential hypertension and hypertensive patients with polycystic kidney disease [13], it appears that sympathetic activation also occurs independently of renal function. The most established cause for sympathetic over-activation is renal ischemia caused by renal artery stenosis [20, 21], but renal cysts might also cause local renal ischemia.
While children with end-stage renal disease (ESRD) usually have normal plasma noradrenaline and adrenalin concentrations, hemodialysis per se leads to substantial increase in both plasma renin activity and catecholamines, which can contribute to hypertension [22].
Recent experimental evidence suggests that renalase—an amine oxidase specifically expressed by the kidney—lowers blood pressure and heart rate. Its activity is markedly reduced in patients with ESRD [23]. However, whether the cardiovascular effects of this enzyme are really due to its catecholamine-metabolizing activity is still controversial [24].
There has been debate about the role of nitric oxide (NO) in mediating endothelial cell damage and hypertension in CKD. Newer studies have demonstrated that, in uremic patients, reduced NO stimulation leads to reduced agonist-induced endothelium-dependent vasodilatation, whereas other vasodilatory pathways are not affected. Renal failure leads to the accumulation of endogenous NO synthase inhibitors such as asymmetric dimethyl-L-arginine (ADMA), which appears to be due to increased generation and decreased metabolism rather than decreased clearance [25]. ADMA independently predicts overall mortality and cardiovascular events in patients with ESRD [26], as well as progression of CKD [27]. While ADMA is related to blood pressure in animal models of CKD, clinical studies have not found differences in blood pressure [25].
Endothelial NO synthase is also suppressed by hyperparathyroidism in rats with CKD [28]. In contrast to ADMA levels, those of serum parathyroid hormone (PTH) correlate highly with blood pressure in patients with CKD [29]. Whereas acute infusion of PTH has a hypotensive effect, chronic hyperparathyroidism leads to accumulation of calcium inside vascular smooth muscle cells, enhancing their sensitivity to calcium and norepinephrine [30, 31]. This effect can be blocked by calcium channel antagonists.
A number of drugs commonly administered in CKD can cause iatrogenic hypertension. For example, erythropoietin (EPO) causes blood pressure elevation over several weeks. This may be via arterial wall remodeling, causing increased vascular resistance [32]. Vaziri et al. have proposed that EPO acts directly on voltage-independent calcium channels in smooth muscle cells, leading to a decreased sensitivity to the vasodilatory action of nitric oxide [33]. The resulting possibility of calcium channel antagonists as ‘specific’ therapy for EPO-induced hypertension has been successfully tested in rats [34].
Glucocorticoids lead to fluid retention by their mineralocorticoid effect. Cyclosporine A causes vasoconstriction of glomerular afferent arterioles and hyperplasia of the juxtaglomerular apparatus, with subsequent increased release of renin and angiotensin II [35]. Increased circulating catecholamines and endothelin-1 precursors, and increased renal sodium absorption via the Na-K-2Cl co-transporter in the loop of Henle [36], have also been demonstrated after cyclosporine A treatment. Tacrolimus appears to be less pro-hypertensive than cyclosporine in children after renal transplantation [37], but, for other reasons, it is less commonly used prior to transplantation [38].
Treatment with growth hormone leads to water and sodium retention by the distal nephron [39], mediated by increased intra-renal insulin-like growth factor (IGF)-1. However, growth hormone (GH) does not appear to increase blood pressure in children with CKD or Turner syndrome, despite both groups being prone to hypertension [40, 41].
Management
Owing to the lack of acute symptoms and to the serious long-term consequences of hypertension, an active screening approach is necessary to detect elevated blood pressures early and to prevent end-organ damage [42]. In contrast to other complications of CKD, which become prevalent only in later stages of CKD, hypertension is already very common in CKD stage 1, with over 63% of children affected. In CKD stages 4 and 5 the incidence increases further to 80% [1]. More than 50% of children with ESRD have uncontrolled hypertension, despite widespread use of antihypertensive drugs [5, 43]. The frequency of blood pressure measurement during screening and during therapy should be appropriate to the patient’s risk of developing uncontrolled hypertension. A routine for this is suggested in the flow chart in Fig. 2. In general, we would consider all children with CKD to be at least at intermediate risk, and, therefore, we recommend 3-monthly clinic blood pressure (CBP) measurements; children with ESRD, multiple pro-hypertensive medications or confirmed hypertension should be considered as at high risk. In our experience 24 h ambulatory blood pressure measurement (ABPM) is a very valuable tool and should be performed annually in high-risk populations such as renal transplant recipients or those with rapidly progressive renal disease. ABPM is also useful to exclude white-coat hypertension, which is a problem even in children under long-term medical care [44]. While there are equivocal results about the long-term consequences of white-coat hypertension, end-organ damage could be clearly demonstrated in children with masked hypertension, i.e. elevated ABPM but normal CBP [45], underlining the usefulness of this method.
Fig. 2Flow diagram for the choice of method to measure blood pressure during screening, follow up and treatment (CBP clinic blood pressure ABPM 24 h ambulatory blood pressure monitoring, HBP home blood pressure measurement BP blood pressure, BMI body mass index)
Whichever method is used, techniques should be in accordance with international consensus statements, and the appropriate pediatric reference ranges are very important. These are now available for clinic [46, 47], ambulatory [48] and home blood pressure measurements [49]. The diagnosis of hypertension should be based on at least three clinic blood pressure measurements above the 95th percentile [46]. As white-coat hypertension is very common, and the effects of thorough investigation and treatment can be far-reaching, we feel ABPM is advisable in nearly all newly diagnosed hypertensive children. In countries where health care providers do not cover the cost of ABPM, home blood pressure measurements may be helpful in confirming the diagnosis, but they do not pick up the nocturnal blood pressure dynamics [44].
Once hypertension has been confirmed, good management should not focus only on pharmacological therapy, but also on detection and treatment of end-organ damage and, where appropriate, improvement of the dialysis regime and consideration of therapeutic life-style changes.
Echocardiography and ophthalmological examination are the most important assessments of end-organ damage in hypertensive children. Left ventricular hypertrophy (LVH) is common in children with CKD, even during antihypertensive therapy [50]. LVH in patients with normal clinic blood pressure may indicate masked hypertension in untreated children [45] or insufficient efficacy of antihypertensive drug therapy in treated children (e.g. insufficient dose, non-compliance, or short duration of action of selected antihypertensive drugs). Echocardiography and ophthalmological evaluation should be repeated at regular intervals in children with initial signs of end-organ damage [46]. From personal experience we would also recommend follow-up examination in children with persistent hypertension or in those at high risk (e.g. ESRD). Additional assessments of end-organ damage include measurement of carotid intima media thickness and of pulse wave velocity, which reflect functional alterations of arterial wall properties caused by hypertension and other factors such as hyperparathyroidism [51]. These investigations are still mainly used for research purposes, but clinical use has been facilitated by the recent provision of pediatric reference ranges [52].
In hypertensive patients who are undergoing renal replacement therapy, improvement of the dialysis prescription should be the primary therapeutic approach to hypertension, before pharmacological treatment is started.Extracellular volume overload can be efficiently reduced by adequately long dialysis times. Even though the reduction of fluid overload may take several weeks to translate into normalized blood pressure, drug-free control of hypertension is possible in many, if not most, hemodialysis patients [12]. A number of studies have shown improved BP control with short daily, long intermittent or nocturnal hemodialysis [53]. While conventional dialysis schedules can also improve control of hypertension by targeting dry weight more aggressively [54], this tends to be tolerated less well, with more intra-dialytic hypotensive episodes. Lower concentrations of dialysate sodium also produce a moderate fall in blood pressure on a population level, with best results in patients with previously high blood pressure [55].
In addition to intensified dialysis, dietary sodium restriction is a useful adjunct to intensified dialysis in avoiding sodium overload, and it reduces intra-dialytic hypotensive episodes. Indeed, some authors find dietary sodium restriction plus low sodium dialysate to be equally effective as time-intensified dialysis, and they maintain that with good dietary advice a low salt diet need not be unpalatable [56]. However, restriction of fluid and salt intake requires considerable patient motivation, which is often a problem in the adolescent population.
Therapeutic life-style changes can be effective in lowering blood pressure if obesity contributes to the patient’s hypertension. Obesity in children with CKD is uncommon and usually associated with steroid treatment; however, it is seen more commonly in populations with a higher background risk of obesity [3]. While weight loss can be effective in reducing blood pressure in overweight children with normal renal function [57], unfortunately, there are no controlled studies of life-style interventions in children with CKD. In our experience calorie-reduced diets are rarely effective in this population, probably due to the multifactorial etiology of hypertension in renal disease. Also, the recommended intake of fresh fruit and vegetables may be hard to achieve if a potassium- and phosphate-reduced diet is also necessary. Interestingly, weight loss improves salt-induced increases in blood pressure in obese children [58]; therefore, combined calorie- and sodium-reduced diets may be particularly effective in obese CKD children who are salt retainers.
Pharmacological treatment remains the mainstay of antihypertensive management in all stages of CKD. In approximately 75% of children with CKD stages 2–4, blood pressure control below the 95th percentile can be achieved by antihypertensive monotherapy, but 50–60% of children need more than one drug if intensified BP control (<50th percentile) is targeted [Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of CRF in Pediatric Patients (ESCAPE) trial, unpublished results]. In children with ESRD adequate control is much harder to achieve: a review of the North American Pediatric Renal Transplant Cooperative study (NAPRTCS) database also showed that over 50% of children on dialysis have uncontrolled hypertension [43], and a Polish nationwide survey found that in only 57% of children with ESRD was hypertension adequately controlled, despite the use of multiple drug therapy in 65% [5].
Even though multiple drug therapy is often required, it is advisable to start with a single drug at a low dose and to titrate upward until blood pressure is controlled [46]. Exceptions are hypertensive emergencies, such as hypertensive encephalopathy, when intravenous (i.v.) treatment should be started promptly.
ACE inhibitors and angiotensin II type 1 receptor blockers (ARBs) are the most useful drugs, as they are not only antihypertensive but also slow down the progression of renal failure more efficiently than do other antihypertensive treatments [59]. Surveys among pediatric nephrologists from both sides of the Atlantic show that ACE inhibitors are increasingly popular and are now the most commonly used drugs for pediatric hypertension [60, 61]. The renoprotective effect of renin–angiotensin system (RAS) blockade is due to a combination of reduced proteinuria, lower intra-glomerular pressure through selective dilatation of the glomerular efferent arteriole, and anti-inflammatory and anti-fibrotic effects [10]. Additionally, RAS inhibition reduces the sympathetic hyperactivity seen in CKD [16].
There is convincing evidence from studies of adults that all proteinuric patients should receive renin–angiotensin system blockade, even if they do not have hypertension [42]. Major side effects are a moderate increase of potassium and creatinine; these should be monitored more closely with declining renal function. Sexually active adolescent girls must use contraception. ACE inhibitor-induced cough appears to be less common in children than in adults [62]. There is no clear evidence suggesting clinical superiority of ARBs over ACE inhibitors [63], and a number of drugs in both classes are labeled for children. Food and Drug Administration (FDA) approval for children under 6 years old is expected soon for a number of ARBs.
Combination therapy with an ACE inhibitor and an ARB should be considered for patients who continue to show proteinuria while undergoing monotherapy, since it is effective in further reducing proteinuria (and progression of CKD) in adults [63, 64]. Experience in children is positive but very limited [65–68], and the increased risk of hyperkalemia and renal failure should be realized [69]. Therefore, for improved control of hypertension without proteinuria, the combination of single RAS blockade with a diuretic is preferable. The use of fixed-dose combinations of RAS antagonists with a thiazide diuretic may be an option in adolescents where compliance is an issue, but less so in younger children where frequent dose adjustments are required [46].
From trials in hypertensive patients without renal disease it appears that the blood pressure lowering effect, per se, is relevant for cardiovascular risk protection, without any class-specific benefits. Therefore, in essential hypertension, the choice of agents should be guided by the matching of the side effects profile of the individual drugs to the patient-specific risk factor profile [47]. In patients with CKD, meta-analyses of adult trials demonstrated superior renoprotection by ACE inhibitors, even after adjustment for blood pressure and urine protein excretion [70]. There is no conclusive evidence as to whether the inhibition of the renin–angiotensin system is superior to other antihypertensives in non-proteinuric CKD patients [59,71,72]. Recommendations for adults prefer to err on the side of caution and suggest a low threshold for considering CKD patients proteinuric (200 mg protein/g creatinine in spot urine) [42].
Diuretics are less commonly used in children with CKD than in adults with CKD, due to the preponderance of hypodysplastic kidney disorders, which frequently present as salt-losing nephropathies. In patients with evidence of hypervolemia, thiazides and loop diuretics have proven most useful for controlling volume overload, and they have a very good side-effects profile. It should be remembered that, while thiazides are a popular first-line therapy in mild-to-moderate CKD, they are less effective when glomerular filtration rate (GFR) falls below 60 ml/min per 1.73 m2 body surface area, and they are ineffective below 30 ml/min per 1.73 m2. Therefore, furosemide should be preferred and used in adequate doses for CKD stages 4 and 5. Mineralocorticoid receptor antagonists (e.g. spironolactone) are theoretically attractive in CKD, due to their synergistic actions with RAS antagonists, and the new selective receptor blocker eplerenone is devoid of anti-androgenic side effects. However, monotherapy (and, even more, combination therapy with RAS antagonists) is limited by the potentiated risk of hyperkalemia. During diuretic therapy, patients should be monitored for volume depletion and electrolyte disturbances. Long-acting formulations help to increase patient compliance [42].
Calcium channel blockers are very potent anti-hypertensive drugs and, therefore, useful as add-on therapy in children with resistant hypertension. Dihydropyridine (DHP) drugs (e.g. nifedipine, amlodipine) act mainly as vasodilators and do not have cardiac side effects. Amlodipine has pediatric labeling and is available as a suspension, and doses need not to be adjusted to renal function.
However, DHP-type calcium channel blockers (CCBs) increase intra-glomerular pressure and proteinuria, while non-DHP-type calcium channel blockers (e.g. verapamil and diltiazem) have an additional anti-proteinuric effect. In a long-term clinical trial of elderly patients with type II diabetic nephropathy, non-DHP calcium channel blockers showed as equally an effective slowing of CKD progression, reduction of proteinuria and antihypertensive efficacy as did the ACE inhibitor lisinopril (while both were superior to the beta blocker atenolol [73]). However, there are no published safety data on any of the non-DHPs in children with hypertension, so they should be used with caution due to their known prolongation of the PR interval in adults [74].
Intravenous administration of nicardipine is an option for controlling hypertensive crises, especially when the level of renal function is unclear or changing rapidly. It has been used safely, even in very small children with hypertension, despite reports of hypotension in normotensive newborns with asphyxia [74].
Beta blockers can be used as second-line therapy for renal hypertension in children. However, they are contraindicated in asthma and can cause fatigue. All beta blockers require dose reduction with progression of CKD. They should be used with caution in heart failure, and their adverse metabolic effects make them less suitable for diabetics. The largest clinical experience, especially for infants, is available for propranolol. A sustained-release form of this drug allows once daily administration in larger children. However, other agents, such as atenolol, which have the advantage of being both long acting and β1-selective, may be preferred in clinical practice.
Other drugs are used less commonly, mainly due to their more severe side-effects profiles. Alpha blockers (such as prazosin) can be used in patients who also require them for control of bladder emptying or Raynaud’s phenomenon. Centrally acting alpha agonists (such as clonidine) act via reduction of sympathetic nervous outflow. Rebound hypertension after discontinuation is a major problem of this drug. The vasodilators hydralazine and minoxidil are less suitable in CKD as they are less effective and cause salt and water retention.
The aim of antihypertensive management is the regression of end-organ damage (especially LVH) and the lowering of blood pressure below target values while minimizing drug side effects. The currently recommended treatment goal in hypertensive patients with CKD is a blood pressure of < 130/80 mmHg in adults [42, 47] and < 90th percentile in children [46]. However, a meta-analysis of 11 randomized trials in non-diabetic adults with CKD showed differing results for proteinuric and non-proteinuric patients: while there was no increase in adverse renal outcomes with higher blood pressure in non-proteinuric patients, ideal systolic blood pressure for proteinuric patients (> 1 g per day) was 110–129 mmHg. In proteinuric patients, renal survival decreased, with systolic blood pressures below 110 mmHg and above 130 mmHg. These data are hard to interpret conclusively, as persistent hypertension during treatment may also be a reflection of more severe underlying disease [70]. In children, the pending results of the ESCAPE trial may help us to elucidate optimal blood pressure targets.
Conclusion
Adequate management of hypertension in CKD requires an active screening approach in order to prevent the significant renal deterioration and cardiovascular morbidity and mortality associated with high blood pressure. Owing to the plethora of different pathophysiological mechanisms involved, a whole range of therapeutic options is available. Non-pharmacological options should not be disregarded for obese children or for children on hemodialysis. Inhibitors of the renin–angiotensin system should be preferred for proteinuric patients and, probably, also for non-proteinuric patients. Multiple drug therapy is often necessary to reach target blood pressure below the 90th percentile. For this, diuretics and calcium channel blockers are the most suitable options.

hypertension
children
chronic kidney disease
pathophysiology
life-style changes
antihypertension therapy