International survey of De-implementation of initiating parenteral nutrition early in Paediatric intensive care units.

BACKGROUND: Initiating parenteral nutrition (PN) within 24 h in critically ill children is inferior to withholding PN during the first week, as was found in the PEPaNIC study. The aims of this study were to investigate de-implementation of early initiation of PN at PICUs worldwide, and to identify factors influencing de-implementation. METHODS: A cross-sectional online survey was conducted (May - October 2017), consisting of 41 questions addressing current PN practices, the degree of de-implementation, and factors affecting de-implementation. RESULTS: We analysed 81 responses from 39 countries. Of these 81 respondents, 53 (65%) were aware of the findings of the PEPaNIC study, and 43 (53%) have read the article. In these 43 PICUs, PN was completely withheld during the first week in 10 PICUs, of which 5 already withheld PN (12%), and 5 de-implemented early initiation of PN (12%). Partial de-implementation was reported by 17 (40%) and no de-implementation by 16 (37%). Higher de-implementation rates were observed when the interpreted level of evidence and grade of recommendation of PEPaNIC was high. Predominant reasons for retaining early initiation of PN were concerns on withholding amino acids, the safety in undernourished children and neonates, and the long-term consequences. Furthermore, the respondents were waiting for updated guidelines. CONCLUSIONS: One year after the publication of the PEPaNIC trial, only two-thirds of the respondents was aware of the study results. Within this group, early initiation of PN was de-implemented completely in 12% of the PICUs, while 40% asserted partial de-implementation. Increasing the awareness, addressing the intervention-specific questions and more frequently revising international guidelines might help to accelerate de-implementation of ineffective, unproven or harmful healthcare.

Non-Thyroidal Illness Syndrome in Critically Ill Children: Prognostic Value and Impact of Nutritional Management.

INTRODUCTION: Non-thyroidal illness (NTI), which occurs with fasting and in response to illness, is characterized by thyroid hormone inactivation with low triiodothyronine (T3) and high reverse T3 (rT3), followed by suppressed thyrotropin (TSH). Withholding supplemental parenteral nutrition early in pediatric critical illness (late-PN), thus accepting low/no macronutrient intake up to day 8 in the pediatric intensive care unit (PICU), accelerated recovery compared to initiating supplemental parenteral nutrition early (early-PN). Whether NTI is harmful or beneficial in pediatric critical illness and how it is affected by a macronutrient deficit remains unclear. This study investigated the prognostic value of NTI, the impact of late-PN on NTI, and whether such impact explains or counteracts the outcome benefit of late-PN in critically ill children. METHODS: This preplanned secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit randomized controlled trial quantified serum TSH, total thyroxine (T4), T3, and rT3 concentrations in 982 patients upon PICU admission versus 64 matched healthy children and in 772 propensity score-matched early-PN and late-PN patients upon admission and at day 3 or last PICU day for shorter PICU stay. Associations between thyroid hormone concentrations upon admission and outcome, as well as impact of late-PN on NTI in relation with outcome, were assessed with univariable analyses and multivariable logistic regression, linear regression, or Cox proportional hazard analysis, adjusted for baseline risk factors. RESULTS: Upon PICU admission, critically ill children revealed lower TSH, T4, T3, and T3/rT3 and higher rT3 than healthy children (p < 0.0001). A more pronounced NTI upon admission, with low T4, T3, and T3/rT3 and high rT3 was associated with higher mortality and morbidity. Late-PN further reduced T4, T3, and T3/rT3 and increased rT3 (p ≤ 0.001). Statistically, the further lowering of T4 by late-PN reduced the outcome benefit (p < 0.0001), whereas the further lowering of T3/rT3 explained part of the outcome benefit of late-PN (p ≤ 0.004). This effect was greater for infants than for older children. CONCLUSION: In critically ill children, the peripheral inactivation of thyroid hormone, characterized by a decrease in T3/rT3, which is further accentuated by low/no macronutrient intake, appears beneficial. In contrast, the central component of NTI attributable to suppressed TSH, evidenced by the decrease in T4, seems to be a harmful response to critical illness. Whether treating the central component with TSH releasing hormone infusion in the PICU is beneficial requires further investigation.

Long-term developmental effects of withholding parenteral nutrition for 1 week in the paediatric intensive care unit: a 2-year follow-up of the PEPaNIC international, randomised, controlled trial.

BACKGROUND: The paediatric early versus late parenteral nutrition in critical illness (PEPaNIC) multicentre, randomised, controlled trial showed that, compared with early parenteral nutrition, withholding supplemental parenteral nutrition for 1 week in the paediatric intensive care unit (PICU; late parenteral nutrition) reduced infections and accelerated recovery from critical illness in children. We aimed to investigate the long-term impact on physical and neurocognitive development of early versus late parenteral nutrition. METHODS: In this preplanned 2-year follow-up study, all patients included in the PEPaNIC trial (which was done in University Hospitals Leuven, Belgium; Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, Netherlands; and Stollery Children's Hospital, Edmonton, AB, Canada) were approached for possible assessment of physical and neurocognitive development compared with healthy children who were matched for age and sex, and who had never been admitted to a neonatal ICU or a PICU. Assessed outcomes comprised anthropometric data; health status; parent-reported or caregiver-reported executive functions and emotional and behavioural problems; and tests for intelligence, visual-motor integration, alertness, motor coordination, inhibitory control, cognitive flexibility, and memory. To address partial responses among the children tested, we did multiple data imputation by chained equations before univariable and multivariable linear and logistic regression analyses adjusted for risk factors. This trial is registered with ClinicalTrials.gov, number NCT01536275. FINDINGS: At the 2-year follow-up, 60 (8%) of 717 children who received late parenteral nutrition and 63 (9%) of 723 children who received early parenteral nutrition had died (p=0·81). 68 (9%) of 717 children who received late and 91 (13%) of 723 children who received early parenteral nutrition were too disabled for neurocognitive assessment (p=0·059), and 786 patients (395 assigned to late and 391 assigned to early parenteral nutrition) consented for testing. 786 patients and 405 healthy control children underwent long-term outcome testing between Aug 4, 2014, and Jan 19, 2018, and were included in the imputation model for subsequent multivariable analyses. Late parenteral nutrition did not adversely affect anthropometric data, health status, or neurological functioning, and improved parent-reported or caregiver-reported executive functioning (late vs early parenteral nutrition ß estimate -2·258, 95% CI -4·012 to -0·504; p=0·011), more specifically inhibition (-3·422, -5·171 to -1·673; p=0·0001), working memory (-2·016, -3·761 to -0·270; p=0·023), and meta-cognition (-1·957, -3·694 to -0·220; p=0·027). Externalising behavioural problems (ß estimate -1·715, 95% CI -3·325 to -0·106; p=0·036) and visual-motor integration (0·468, 0·087 to 0·850; p=0·016) were also improved in the late parenteral nutrition group compared with the early parenteral nutrition group. After Bonferroni correction for multiple comparisons, the effect on inhibitory control remained significant (p=0·0001). INTERPRETATION: Withholding early parenteral nutrition for 1 week in the PICU did not negatively affect survival, anthropometrics, health status, and neurocognitive development, and improved inhibitory control 2 years after PICU admission. FUNDING: European Research Council Advanced Grant, Methusalem programme provided by the Flemish Government, Flemish Agency for Innovation by Science and Technology (IWT), Research Foundation Flanders (FWO), Sophia Children's Hospital Foundation (SSWO), Stichting Agis Zorginnovatie, Erasmus Trustfonds, and European Society for Parenteral and Enteral Nutrition (ESPEN) research grant.

Phthalate and alternative plasticizers in indwelling medical devices in pediatric intensive care units.

The present study aimed to identify plasticizers present in indwelling plastic medical devices commonly used in the pediatric intensive care unit (PICU). We have analyzed a wide range of medical devices (n = 97) daily used in the PICUs of two academic hospitals in Belgium and the Netherlands. Identified compounds varied between the samples. Most of the indwelling medical devices and essential accessories were found to actively leach phthalates and alternative plasticizers. Results indicated that DEHP was predominantly present as plasticizer (60 of 97 samples), followed by bis(2-ethylhexyl) adipate (DEHA, 32 of 97), bis(2-ethylhexyl) terephthalate (DEHT, 24 of 97), tris(2-ethylhexyl) trimellitate (TOTM, 20 of 97), and tributyl-O-acetyl citrate (ATBC, 10 of 97). Other plasticizers, such as di-isononyl-cyclohexane-1,2-dicarboxylate (DINCH, 2 of 97), di-isononyl phthalate (DiNP, 4 of 97), di(2-propylheptyl) phthalate (DPHP, 4 of 97) and di-isodecyl phthalate (DiDP, 2 of 97) were detected in < 5% of the investigated samples. Several devices contained multiple plasticizers, e.g. devices containing TOTM contained also DEHP and DEHT. Our data indicate that PICU patients are exposed to a wide range of plasticizers, including the controversial DEHP. Future studies should investigate the exposure to APs in children staying in the PICU and the possible health effects thereof.

Early versus late parenteral nutrition in critically ill, term neonates: a preplanned secondary subgroup analysis of the PEPaNIC multicentre, randomised controlled trial.

BACKGROUND: Previous randomised studies showed that withholding parenteral nutrition for 1 week of critical illness was superior to early initiation (<24-48 h) of parenteral nutrition in children and adults. However, neonates are considered more susceptible to macronutrient deficits. We investigated the effect of withholding parenteral nutrition for 1 week in critically ill, term neonates. METHODS: We previously did a randomised, controlled study (PEPaNIC) of children aged up to 17 years admitted to paediatric intensive-care units (ICUs) in three hospitals in Belgium, Canada, and the Netherlands randomly assigned (1:1) to either standard care of parenteral nutrition initiated early within 24 h of admission to an ICU or late parenteral nutrition (where supplemental parenteral nutrition was withheld for 1 week after admission to the ICU). In this preplanned, secondary subanalysis of PEPaNIC, we looked at data from critically ill, term neonate participants (gestational age ≥37 weeks) aged up to 28 days (studied in overlapping age groups of ≤4 weeks, ≤1 week, and <1 day-ie, age at admission). In both the early parenteral nutrition and late parenteral nutrition groups, enteral nutrition was initiated as soon as possible and increased according to local protocols. Outcome assessors and investigators not directly involved in the paediatric ICU were not informed of treatment allocation. The primary endpoints were incidence of new infections and duration of paediatric ICU dependency (quantified as the number of days in the paediatric ICU and likelihood of earlier live discharge from the ICU), analysed based on intention to treat. Multivariable analyses were adjusted for the following risk factors: centre, Paediatric Logistic Organ Dysfunction score, Paediatric Index of Mortality 2 score, diagnosis group, and weight-for-age Z scores on admission. Secondary safety outcomes were mortality (at 90 days, during the intervention, in the paediatric ICU, and in the hospital) and hypoglycaemic incidents during the intervention. All patients in the respective groups were included in the safety analysis. FINDINGS: Between June 18, 2012, and July 27, 2015, we included 209 participants in this substudy, 145 of whom were aged up to and including 1 week and 45 aged younger than 1 day. In neonates aged up to and including 4 weeks, late parenteral nutrition increased the likelihood of earlier live discharge from the paediatric ICU compared with early parenteral nutrition (adjusted hazard ratio [HR] 1·61, 95% CI 1·19-2·20; p=0·0021) but did not affect the risk of infection. The risk of infection in neonates aged up to and including 1 week and younger than 1 day was lower with late parenteral nutrition than with early parenteral nutrition (adjusted odds ratios [OR] 0·36, 95% CI 0·15-0·83, p=0·017; and 0·10, 0·01-0·64, p=0·015, respectively). For neonates aged up to and including 1 week, the likelihood of an earlier live discharge from the ICU was higher with late parenteral nutrition (adjusted HR 1·69, 95% CI 1·16-2·46; p=0·0063). For neonates younger than 1 day, adjusted HR was 1·95 (95% CI 0·93-4·12; p=0·078). Mortality at all studied timepoints was similar between the groups for all ages; however, in neonates aged up to and including 4 weeks and aged up to and including 1 week, the risk of hypoglycaemia was higher with late parenteral nutrition (23% vs 14%; adjusted OR 3·05, 95% CI 1·27-7·35, p=0·013; and 24% vs 14%; 3·57, 1·23-10·45, p=0·019, respectively. INTERPRETATION: In critically ill, term neonates, withholding parenteral nutrition for 1 week was clinically superior to standard care of initiating parenteral nutrition within 24 h for short-term outcomes. However, withholding parenteral nutrition for 1 week significantly increased the risk of developing hypoglycaemia, which necessitates long-term follow-up of these children before late parenteral nutrition can be confidently recommended for this vulnerable patient group. FUNDING: Flemish Agency for Innovation through Science and Technology, Methusalem-Programme Flemish Government, European Research Council, Fonds NutsOhra, Stichting Agis-Zorginnovatie, and the Sophia Research-Foundation.

HLA-DR Expression on Monocyte Subsets in Critically Ill Children.

BACKGROUND: To longitudinally study blood monocyte subset distribution and human leukocyte antigen-DR (HLA-DR) expression on monocyte subsets in children with sepsis, post-surgery and trauma in relation to nosocomial infections and mortality. METHODS: In 37 healthy children and 37 critically ill children (12 sepsis, 11 post-surgery, 10 trauma and 4 admitted for other reasons)-participating in a randomized controlled trial on early versus late initiation of parenteral nutrition-monocyte subset distribution and HLA-DR expression on monocyte subsets were measured by flow cytometry upon admission and on days 2, 3 and 4 of pediatric intensive care unit (PICU) stay. RESULTS: Upon PICU admission, critically ill children had a higher proportion of classical monocytes (CD14++CD16-) than healthy children [PICU 95% (interquartile range [IQR] 88%-98%); controls, 87% (IQR 85%-90%), P < 0.001]. HLA-DR expression was significantly decreased within all monocyte subsets and at all time points, being most manifest on classical monocytes and in patients with sepsis. Percentage of HLA-DR expressing classical monocytes [upon PICU admission 67% (IQR 44%-88%); controls 95% (IQR 92%-98%), P < 0.001], as well as the HLA-DR mean fluorescence intensity [upon PICU admission 3219 (IQR 2650-4211); controls 6545 (IQR 5558-7647), P < 0.001], decreased during PICU stay. Patients who developed nosocomial infections (n = 13) or who died (n = 6) had lower HLA-DR expression on classical monocytes at day 2 (P = 0.002) and day 3 (P = 0.04), respectively. CONCLUSIONS: Monocytic HLA-DR expression decreased during PICU stay and was lower compared with controls on all examined time points, especially on classical monocytes and in children admitted for sepsis. Low HLA-DR expression on classical monocytes was associated with nosocomial infections and death.

Leukocyte telomere length in paediatric critical illness: effect of early parenteral nutrition.

BACKGROUND: Children who have suffered from critical illnesses that required treatment in a paediatric intensive care unit (PICU) have long-term physical and neurodevelopmental impairments. The mechanisms underlying this legacy remain largely unknown. In patients suffering from chronic diseases hallmarked by inflammation and oxidative stress, poor long-term outcome has been associated with shorter telomeres. Shortened telomeres have also been reported to result from excessive food consumption and/or unhealthy nutrition. We investigated whether critically ill children admitted to the PICU have shorter-than-normal telomeres, and whether early parenteral nutrition (PN) independently affects telomere length when adjusting for known determinants of telomere length. METHODS: Telomere length was quantified in leukocyte DNA from 342 healthy children and from 1148 patients who had been enrolled in the multicenter, randomised controlled trial (RCT), PEPaNIC. These patients were randomly allocated to initiation of PN within 24 h (early PN) or to withholding PN for one week in PICU (late PN). The impact of early PN versus late PN on the change in telomere length from the first to last PICU-day was investigated with multivariable linear regression analyses. RESULTS: Leukocyte telomeres were 6% shorter than normal upon PICU admission (median 1.625 (IQR 1.446-1.825) telomere/single-copy-gene ratio (T/S) units vs. 1.727 (1.547-1.915) T/S-units in healthy children (P < 0.0001)). Adjusted for potential baseline determinants and leukocyte composition, early PN was associated with telomere shortening during PICU stay as compared with late PN (estimate early versus late PN -0.021 T/S-units, 95% CI -0.038; 0.004, P = 0.01). Other independent determinants of telomere length identified in this model were age, gender, baseline telomere length and fraction of neutrophils in the sample from which the DNA was extracted. Telomere shortening with early PN was independent of post-randomisation factors affected by early PN, including longer length of PICU stay, larger amounts of insulin and higher risk of infection. CONCLUSIONS: Shorter than normal leukocyte telomeres are present in critically ill children admitted to the PICU. Early initiation of PN further shortened telomeres, an effect that was independent of other determinants. Whether such telomere-shortening predisposes to long-term consequences of paediatric critical illness should be further investigated in a prospective follow-up study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01536275 . Registered on 16 February 2012.

The costs of disease related malnutrition in hospitalized children.

INTRODUCTION: Disease related malnutrition (DRM) is a serious medical condition which is associated with an increase in morbidity and mortality, augmenting resource use and associated costs. DRM can be detected by actively and fully assessing the nutritional status. Studies in adult malnourished patients have shown that the additional health care costs are about € 2 billion (€ 2000 million) per year. The objective of the current study was to estimate the annual additional costs of DRM for pediatric patients as was done for adults. METHODS: A cost-of-illness analysis was performed to calculate the annual additional costs of DRM in 2015 pediatric patients (aged 1 month up to and including 17 years) admitted to non-academic hospitals in The Netherlands. DRM was assessed with weight-for-age, weight-for-height and height-for-age. Input variables in the formula used were length of stay and prevalence of DRM. The costs were estimated per disease as classified in the International Classification of Diseases by the WHO (ICD-10), per gender and age group. The results were expressed as an absolute monetary value as well as a percentage of the Dutch national health expenditure. Robustness of the results was checked by a sensitivity analysis. RESULTS: The total additional direct medical costs of DRM in pediatric patients in 2013 were estimated to be € 51 million for acute malnutrition, € 46 million when focused on chronic malnutrition and € 80 million in case of overall malnourished children. This equals 5.6% of the total Dutch hospital costs for these hospitalized children. CONCLUSIONS: This study has shown that DRM in hospitalized children is associated with an increase in annual hospital costs with an additional amount of € 80 million, of which acute malnutrition account for the largest part.

Cost-effectiveness study of early versus late parenteral nutrition in critically ill children (PEPaNIC): preplanned secondary analysis of a multicentre randomised controlled trial.

BACKGROUND: The multicentre randomised controlled PEPaNIC trial showed that withholding parenteral nutrition (PN) during the first week of critical illness in children was clinically superior to providing early PN. This study describes the cost-effectiveness of this new nutritional strategy. METHODS: Direct medical costs were calculated with use of a micro-costing approach. We compared the costs of late versus early initiation of PN (n = 673 versus n = 670 patients) in the Belgian and Dutch study populations from a hospital perspective, using Student's t test with bootstrapping. Main cost drivers were identified and the impact of new infections on the total costs was assessed. RESULTS: Mean direct medical costs for patients receiving late PN (€26.680, IQR €10.090-28.830 per patient) were 21% lower (-€7.180, p = 0.007) than for patients receiving early PN (€33.860, IQR €11.080-34.720). Since late PN was more effective and less costly, this strategy was superior to early PN. The lower costs for PN only contributed 2.1% to the total cost reduction. The main cost driver was intensive care hospitalisation costs (-€4.120, p = 0.003). The patients who acquired a new infection (14%) were responsible for 41% of the total costs. Sensitivity analyses confirmed consistency across both healthcare systems. CONCLUSIONS: Late initiation of PN decreased the direct medical costs for hospitalisation in critically ill children, beyond the expected lower costs for withholding PN. Avoiding new infections by late initiation of PN yielded a large cost reduction. Hence, late initiation of PN was superior to early initiation of PN largely via its effect on new infections. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01536275 . Registered on 16 February 2012.

Outcomes of Delaying Parenteral Nutrition for 1 Week vs Initiation Within 24 Hours Among Undernourished Children in Pediatric Intensive Care: A Subanalysis of the PEPaNIC Randomized Clinical Trial.

Importance: Undernourishment has been associated with poor outcomes of critical illness in children. The effects of withholding parenteral nutrition (PN) for 1 week in undernourished critically ill children are unknown. Objective: To assess the outcome effects of withholding PN for 1 week in undernourished critically ill children. Design, Setting, and Participants: This is a subanalysis of the randomized clinical trial Pediatric Early vs Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC; N = 1440), which focused on the subgroup of pediatric intensive care unit (PICU) patients identified as undernourished on admission. Children included in the PEPaNIC trial were enrolled between June 18, 2012, and July 27, 2015. Undernourishment was defined as weight-for-age z score less than -2 in children younger than 1 year, and body mass index-for-age z score less than -2 in children 1 year or older. Data analysis was conducted from August 3, 2017, to July 6, 2018. Interventions: Patients were randomized to initiation of supplemental PN within 24 hours (early PN) or after 1 week (late PN) when enteral nutrition was insufficient. Main Outcomes and Measures: Primary end points were risk of new infections acquired in the PICU and time to live PICU discharge, assessed via multivariable logistic regression and Cox proportional hazard analyses, adjusted for risk factors. Results: A total of 289 of 1440 children (20.1%), term newborn to age 17 years, were identified as undernourished, of whom 150 of 717 patients (20.9%) were in the late PN group and 139 of 723 patients (19.2%) were in the early PN group. On admission, characteristics were similar among the treatment groups. Mean (SD) weight z scores were -3.33 (1.18) in the late PN group and -3.21 (1.09) in the early PN group. Compared with well-nourished PICU patients, undernourishment on admission was associated with lower likelihood of an earlier live PICU discharge (adjusted hazard ratio, 0.86; 95% CI, 0.75-0.99; P = .03). Among undernourished PICU patients, late PN reduced the risk of new infections by 11.0% (adjusted odds ratio, 0.39; 95% CI, 0.19-0.78; P = .01), and shortened the duration of PICU stay by a median of 2 days (earlier live PICU discharge: adjusted hazard ratio, 1.37; 95% CI, 1.06-1.75; P = .01). The safety outcomes mortality, incidence of hypoglycemia during the first week, and incidence of weight deterioration during PICU stay were similar between the treatment groups. Conclusions and Relevance: In undernourished critically ill children, withholding PN for 1 week was clinically superior to early PN. Trial Registration: ClinicalTrials.gov Identifier: NCT01536275.

Optimal nutrition in the paediatric ICU.

PURPOSE OF REVIEW: This article describes the current best available evidence on optimal nutrition in the paediatric intensive care based on different levels of outcome, which can be divided in surrogate and hard clinical outcome parameters. RECENT FINDINGS: Undernutrition is associated with increased morbidity and mortality, whereas in specific cohorts of critically ill children, such as those with burn injury, obesity is associated with more complications, longer length of stay, and decreased likelihood of survival. There is a relation with adequacy of delivery of enteral nutrition and the amount of protein on length of hospital stay, neurological status, and mortality. Studies relating organ function, other than skin healing after thermal injury, with the nutritional status are scarce. There is also a scarcity of data concerning long-term follow-up and health economics. SUMMARY: Until now, there are no randomized controlled trials which have investigated a causal relation between different feeding regimens on the nutritional status and short and long-term outcome. As a result current optimal nutritional strategies are based on small trials with surrogate outcome parameters. Prospective randomized studies are needed with nutritional and/or metabolic interventions to come to an optimal feeding strategy for critically ill children.

[An acute vomiting infant with profuse diarrhoea: enterocolitis due to non-IgE-mediated cow's milk allergy]. / Een hevig spugende zuigeling met profuse diarree: enterocolitis door niet-IgE-gemedieerde koemelkallergie.

BACKGROUND: Food protein-induced enterocolitis is a manifestation of non-IgE-mediated cow's milk allergy, characterized by acute vomiting and profuse diarrhoea. This reaction is often not recognized as cow's milk allergy. CASE DESCRIPTION: We present a 6-week-old, formula-fed girl with frequent vomiting, diarrhoea and failure to thrive. These symptoms disappeared after giving cow's milk-free formula. Forty-five minutes after the last dose in a non-blinded provocation test with cow's milk, she developed profuse diarrhoea and vomiting, resulting in hypovolemic shock. No specific IgE against cow's milk was found. CONCLUSION: Unusual in this case is the severe but relatively late reaction to the provocation test. In an acutely ill infant with vomiting, diarrhoea and pallor - which can even result in shock - food protein-induced enterocolitis as manifestation of non-IgE-mediated allergy must be considered. These symptoms start as late as 2 to 3 hours after exposure and disappear after withdrawal of the causal product.