Pharmacokinetics of an intravenous bolus dose of clonidine in children undergoing surgery.

BACKGROUND: Clonidine is used off-label in children but only limited pediatric pharmacokinetic data are available for intravenously administered clonidine. OBJECTIVES: To determine pharmacokinetic parameter estimates of clonidine in healthy children undergoing surgery and to investigate age-related differences. Furthermore, to investigate possible pharmacokinetic differences of clonidine between this group of children and a cohort with cardiac diseases. METHODS: In a randomized placebo-controlled trial (The PREVENT AGITATION trial), blood samples for clonidine pharmacokinetic analysis were collected in a proportion of the enrolled patients. Healthy children with ASA score 1-2 in the age-groups 1 to <2 years and 2-5 years were randomized for blood sampling. Clonidine was administered as a single intravenous bolus of 3 µg/kg intraoperatively. Blood samples were drawn at baseline, 5, 10, 15, 30, 60 minutes after dosing and additionally every hour until discharge from the PACU. Clonidine analysis was performed on liquid chromatography-mass spectrometry. RESULTS: Data form eighteen children were available for pharmacokinetic analysis (ASA I; male/female: 17/1; age: 1-5 years; weight 8.7-24 kg). Population parameter estimates for the 2-compartment model were similar to previous published data for children who underwent cardiac surgery. A pooled analysis including data from 59 children indicated clearance of 14.4 L h-1  70 kg-1 and volume of distribution of 192.6 L 70 kg-1 . No age-related pharmacokinetic differences and no difference in time from administration of study medication to awakening were found. Children 1 to <2 years had a shorter PACU stay than children 2-5 years (mean difference 17% 95% CI:3%-34%, P = .02). CONCLUSION: Pharmacokinetic parameter estimates were similar for children undergoing general surgery and cardiac surgery given a single dose of intravenous clonidine. These results indicated that no dose reduction is needed in children aged 1 to <2 years compared with those 2-5 years, which was supported by pharmacodynamic observations.

Neurosurgical conditions and procedures in infancy are associated with mortality and academic performances in adolescence: a nationwide cohort study.

BACKGROUND: Few human cohort studies on anesthesia-related neurotoxicity and the developing brain have focused on and compared specific surgeries and conditions. These studies cannot disentangle the effects of anesthesia from those of the surgery and underlying conditions. This study aimed at assessing the impact of specific neurosurgical conditions and procedures in infancy on mortality and academic achievements in adolescence. METHODS: A nationwide unselected register-based follow-up study of the Danish birth cohorts 1986-1990 compared academic performances of all children having undergone neurosurgeries as infants with a randomly selected, age-matched 5% sample of the same cohorts. The two groups were compared regarding mortality prior to June 1st, 2006, average test scores at ninth grade, and finally the proportion of children not attaining test scores. RESULTS: The exposure group comprised 228 and the control group 14 698 individuals. Hydrocephalus (n = 130), craniotomy (n = 43), and myelomeningocele/encephalocele children (n = 55) had a higher mortality (18.5.0%, 18.6%, and 7.3%, respectively) vs controls (1.3%; P < 0.00001, P < 0.00001, and P = 0.0052, respectively). Average test scores were significantly lower than controls in hydrocephalus and craniotomy (P = 0.0043 and P = 0.0077) but not myelomeningocele/encephalocele children (P = 0.2785); the proportion of available test scores were significantly lower in all three groups (40.8%, 60.0%, and 67.3%, respectively) vs 86.8% in controls (P < 0.00001, P = 0.000077, and P = 0.000064). CONCLUSION: Neurosurgery in infancy was associated with high mortality and significantly impaired academic achievements in adolescence. When studying anesthesia-related neurotoxicity and the developing brain, focus on specific surgeries/conditions is important. Pooling of major/minor conditions and major/minor surgeries should be avoided.

[Potential neurotoxicity of general anaesthetics to the developing brain]. / Generelle anæstetikas potentielle neurotoksicitet for den immature hjerne.

Animal studies (including non-human primates) have shown that most general anaesthetics cause enhanced neuroapoptosis with subsequent long-term neurocognitive deficits later in life. Some human cohort studies have indicated an association between anaesthesia/surgery and adverse neurocognitive outcome whereas other studies have not. Overall, the data do not justify any change in paediatric anaesthetic clinical practice. Naturally, the risks and benefits of a procedure should always be carefully considered before exposing a child to general anaesthesia.

Procedure-related pain in children in a Danish University Hospital. A qualitative study.

BACKGROUND: Children being cared for in hospital often undergo multiple diagnostic and therapeutic procedures. Procedure-related pain, anxiety, and distress may consequently place a significant burden on the children. Although standards for pain management exist, procedure-related pain remains inadequately treated. OBJECTIVE: To determine the frequency and pain intensity of procedures in children, as well as the associated pharmacologic interventions to manage the pain in a Danish University Hospital. METHODS: During a 3-month period in 2013, a structured questionnaire was used to prospectively record all procedures performed on children from 1 month to 18 years of age. Directly after the procedure, the pharmacologic pain management interventions and the pain intensity were recorded. Pain intensity was measured by using age-appropriate pain scales. Positioning and prior experience with the procedure were recorded. RESULTS: Of the 316 children included in the study, 72% experienced none to mild pain, 8.5% experienced moderate to severe pain during the procedures, and 65% had a pharmacologic pain management intervention. Significant higher median VAS score was found during venipuncture in the children sitting on the lap of their parents compared with other positions (P < 0.05), and significant lower median VAS score was found in children who had experienced the procedure before (P < 0.05). CONCLUSION: Most children experienced mild pain during procedures. The children's positioning during the procedure and prior experience with the procedure seem to influence their experience of procedural pain and it is therefore essential that therapy is tailored for each child and includes a multimodal approach.

Intranasal sufentanil/ketamine analgesia in children.

BACKGROUND: The management of procedural pain in children ranges from physical restraint to pharmacological interventions. Pediatric formulations that permit accurate dosing, are accepted by children and a have a rapid onset of analgesia are lacking. OBJECTIVES: To investigate a pediatric formulation of intranasal sufentanil 0.5 mcg·kg(-1) and ketamine 0.5 mg·kg(-1) for procedural pain and to characterize the pharmacokinetic (PK) profile. METHODS: Fifty children (≥10 kg) scheduled for a painful procedure were included in this prospective nonrandomized open-label clinical trial. Thirteen of these children had central venous access for drug assay sampling; enabling a compartmental PK analysis using nonlinear mixed-effects models. Pain intensity before and during the procedure was measured using age-appropriate pain scales. Heart rate, oxygen saturation and sedation were recorded. RESULTS: Children had a mean age of 8.8 (sd 4.9) years and weight 35.2 (sd 20.1) kg. Sufentanil/ketamine nasal spray was effective (procedural pain intensity scores ≤5 (0-10)) in 78% of the painful procedures. The spray was well accepted by 94% of the children. Oxygen saturation and heart rate remained stable, and sedation was minimal. The bioavailability of sufentanil and ketamine was 24.6% and 35.8%, respectively. Maximum plasma concentration (Cmax) of sufentanil was 0.042 mcg·l(-1) (coefficient of variation (CV) 12.9%) at 13.8 min (CV 12.4%) (Tmax). Cmax for ketamine was 0.102 mg·l(-1) (CV 10.8%), and Tmax was 8.5 min (CV 17.3%). CONCLUSION: Sufentanil/ketamine nasal spray provided rapid onset of analgesia for a variety of painful procedures with few adverse effects and has promising features for use in pediatric procedural pain management.

Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study.

BACKGROUND: Immature animals exposed to anesthetics display apoptotic neurodegeneration with subsequent long-term cognitive dysfunctions. Young age at anesthetic exposure is believed to be critical, but human studies are scarce. This study investigated the association between exposure to surgery and anesthesia for pyloric stenosis (PS) before 3 months of age and subsequent educational outcome in adolescence. METHODS: This nationwide unselected register-based follow-up study of the Danish birth cohorts 1986-1990 compared the educational outcome of all children having undergone surgery for PS before 3 months of age with a randomly selected, age-matched 5% sample of the same cohort. Primary analysis compared the average test scores at ninth grade adjusting for gender, birth weight, and parental age and education. Secondary analysis compared the proportions not attaining the test scores between the two groups. RESULTS: The exposure group comprised 779 and the control group consisted of 14 665 individuals. Although the exposure group performed lower than the control group (average score 0.17 lower, 95% CI: 0.08-0.25), after adjusting for known confounders, no statistically significant difference (-0.04, 95% CI: -0.09 to 0.08) between the 2 groups could be demonstrated. However, we found an odds ratio (OR) for test score nonattainment-associated PS repair of 1.37 (95% CI: 1.11-1.68). CONCLUSION: Children operated for PS before 3 months of age have educational performance tests similar to the background population at age 15-16 years after adjusting for known confounders. The higher nonattainment rate could suggest that a subgroup of PS children is developmentally disadvantaged.

Influence of perioperative oxygen fraction on pulmonary function after abdominal surgery: a randomized controlled trial.

BACKGROUND: A high perioperative inspiratory oxygen fraction (FiO2) may reduce the frequency of surgical site infection. Perioperative atelectasis is caused by absorption, compression and reduced function of surfactant. It is well accepted, that ventilation with 100% oxygen for only a few minutes is associated with significant formation of atelectasis. However, it is still not clear if a longer period of 80% oxygen results in more atelectasis compared to a low FiO2.Our aim was to assess if a high FiO2 is associated with impaired oxygenation and decreased pulmonary functional residual capacity (FRC). METHODS: Thirty-five patients scheduled for laparotomy for ovarian cancer were randomized to receive either 30% oxygen (n = 15) or 80% oxygen (n = 20) during and for 2 h after surgery. The oxygenation index (PaO2/FiO2) was measured every 30 min during anesthesia and 90 min after extubation. FRC was measured the day before surgery and 2 h after extubation by a rebreathing method using the inert gas SF6. RESULTS: Five min after intubation, the median PaO2/FiO2 was 69 kPa [53-71] in the 30%-group vs. 60 kPa [47-69] in the 80%-group (P = 0.25). At the end of anesthesia, the PaO2/FiO2 was 58 kPa [40-70] vs. 57 kPa [46-67] in the 30%- and 80%-group, respectively (P = 0.10). The median FRC was 1993 mL [1610-2240] vs. 1875 mL [1545-2048] at baseline and 1615 mL [1375-2318] vs. 1633 mL [1343-1948] postoperatively in the 30%- and 80%-group, respectively (P = 0.70). CONCLUSION: We found no significant difference in oxygenation index or functional residual capacity between patients given 80% and 30% oxygen for a period of approximately 5 hours. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00637936.

Topical morphine for oral mucositis in children: dose finding and absorption.

CONTEXT: Systemic opioids for painful chemotherapy-induced oral mucositis in children often result in unsatisfactory pain relief and a high frequency of side effects. Opioids applied topically can produce analgesia by binding to opioid receptors on peripheral terminals of sensory neurons. These receptors are upregulated during inflammation, for example, in oral mucositis. OBJECTIVES: The aims of this study were to investigate the dose-response relationship (n=7) and the potential absorption of topical morphine (n=5) across oral mucosa in children with oral mucositis. METHODS: The dose-response study was conducted according to a sequential study design (Dixon's Up-and-Down method) for topical morphine doses of 0.025-0.400mg/kg, with the decrease in oral pain score as the primary outcome. To assess potential absorption across oral mucosa after a single dose of topical morphine of 0.050mg/kg, blood samples were drawn and the plasma concentrations of morphine and metabolites were determined by high-pressure liquid chromatography. RESULTS: A decrease in oral pain score of ≥36% was achieved in six of seven patients in the dose-response part of the study. Plasma concentrations of morphine and metabolites were well below effective analgesic levels. CONCLUSION: No obvious dose-response effect was found for topical morphine doses of 0.025-0.400mg/kg, and topically applied morphine was not absorbed in clinically relevant doses. However, this study was limited by the small number of patients and the allowance of a systemic opioid as rescue medication. Thus, randomized controlled studies are needed to further investigate the analgesic properties of topical morphine.

Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study.

BACKGROUND: Although animal studies have indicated that general anesthetics may result in widespread apoptotic neurodegeneration and neurocognitive impairment in the developing brain, results from human studies are scarce. We investigated the association between exposure to surgery and anesthesia for inguinal hernia repair in infancy and subsequent academic performance. METHODS: Using Danish birth cohorts from 1986-1990, we compared the academic performance of all children who had undergone inguinal hernia repair in infancy to a randomly selected, age-matched 5% population sample. Primary analysis compared average test scores at ninth grade adjusting for sex, birth weight, and paternal and maternal age and education. Secondary analysis compared the proportions of children not attaining test scores between the two groups. RESULTS: From 1986-1990 in Denmark, 2,689 children underwent inguinal hernia repair in infancy. A randomly selected, age-matched 5% population sample consists of 14,575 individuals. Although the exposure group performed worse than the control group (average score 0.26 lower; 95% CI, 0.21-0.31), after adjusting for known confounders, no statistically significant difference (-0.04; 95% CI, -0.09 to 0.01) between the exposure and control groups could be demonstrated. However, the odds ratio for test score nonattainment associated with inguinal hernia repair was 1.18 (95% CI, 1.04-1.35). Excluding from analyses children with other congenital malformations, the difference in mean test scores remained nearly unchanged (0.05; 95% CI, 0.00-0.11). In addition, the increased proportion of test score nonattainment within the exposure group was attenuated (odds ratio = 1.13; 95% CI, 0.98-1.31). CONCLUSION: In the ethnically and socioeconomically homogeneous Danish population, we found no evidence that a single, relatively brief anesthetic exposure in connection with hernia repair in infancy reduced academic performance at age 15 or 16 yr after adjusting for known confounding factors. However, the higher test score nonattainment rate among the hernia group could suggest that a subgroup of these children are developmentally disadvantaged compared with the background population.

Effect of high perioperative oxygen fraction on surgical site infection and pulmonary complications after abdominal surgery: the PROXI randomized clinical trial.

CONTEXT: Use of 80% oxygen during surgery has been suggested to reduce the risk of surgical wound infections, but this effect has not been consistently identified. The effect of 80% oxygen on pulmonary complications has not been well defined. OBJECTIVE: To assess whether use of 80% oxygen reduces the frequency of surgical site infection without increasing the frequency of pulmonary complications in patients undergoing abdominal surgery. DESIGN, SETTING, AND PATIENTS: The PROXI trial, a patient- and observer-blinded randomized clinical trial conducted in 14 Danish hospitals between October 2006 and October 2008 among 1400 patients undergoing acute or elective laparotomy. INTERVENTIONS: Patients were randomly assigned to receive either 80% or 30% oxygen during and for 2 hours after surgery. MAIN OUTCOME MEASURES: Surgical site infection within 14 days, defined according to the Centers for Disease Control and Prevention. Secondary outcomes included atelectasis, pneumonia, respiratory failure, and mortality. RESULTS: Surgical site infection occurred in 131 of 685 patients (19.1%) assigned to receive 80% oxygen vs 141 of 701 (20.1%) assigned to receive 30% oxygen (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.72-1.22; P = .64). Atelectasis occurred in 54 of 685 patients (7.9%) assigned to receive 80% oxygen vs 50 of 701 (7.1%) assigned to receive 30% oxygen (OR, 1.11; 95% CI, 0.75-1.66; P = .60), pneumonia in 41 (6.0%) vs 44 (6.3%) (OR, 0.95; 95% CI, 0.61-1.48; P = .82), respiratory failure in 38 (5.5%) vs 31 (4.4%) (OR, 1.27; 95% CI, 0.78-2.07; P = .34), and mortality within 30 days in 30 (4.4%) vs 20 (2.9%) (OR, 1.56; 95% CI, 0.88-2.77; P = .13). CONCLUSION: Administration of 80% oxygen compared with 30% oxygen did not result in a difference in risk of surgical site infection after abdominal surgery. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00364741.

Perioperative oxygen fraction - effect on surgical site infection and pulmonary complications after abdominal surgery: a randomized clinical trial. Rationale and design of the PROXI-Trial.

BACKGROUND: A high perioperative inspiratory oxygen fraction may reduce the risk of surgical site infections, as bacterial eradication by neutrophils depends on wound oxygen tension. Two trials have shown that a high perioperative inspiratory oxygen fraction (FiO(2) = 0.80) significantly reduced risk of surgical site infections after elective colorectal surgery, but a third trial was stopped early because the frequency of surgical site infections was more than doubled in the group receiving FiO(2) = 0.80. It has not been settled if a high inspiratory oxygen fraction increases the risk of pulmonary complications, such as atelectasis, pneumonia and respiratory failure. The aim of our trial is to assess the potential benefits and harms of a high perioperative oxygen fraction in patients undergoing abdominal surgery. METHODS AND DESIGN: The PROXI-Trial is a randomized, patient- and assessor blinded trial of perioperative supplemental oxygen in 1400 patients undergoing acute or elective laparotomy in 14 Danish hospitals. Patients are randomized to receive either 80% oxygen (FiO(2) = 0.80) or 30% oxygen (FiO(2) = 0.30) during surgery and for the first 2 postoperative hours. The primary outcome is surgical site infection within 14 days. The secondary outcomes are: atelectasis, pneumonia, respiratory failure, re-operation, mortality, duration of postoperative hospitalization, and admission to intensive care unit. The sample size allows detection of a 33% relative risk reduction in the primary outcome with 80% power. DISCUSSION: This trial assesses benefits and harms of a high inspiratory oxygen fraction, and the trial may be generalizable to a general surgical population undergoing laparotomy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00364741.

[Reflex dystrophy affects children, too]. / Børn får også refleksdystrofi.

Reflex dystrophy or Complex Regional Pain Syndrome (CRPS) is a neuropathic pain condition in a limb after a trauma. Pain is not limited to one or more dermatomes and there is a disproportion between the intensity of the pain and the eliciting trauma. Among physicians in Denmark it is not common knowledge that CRPS also affects children. It is not described in paediatric textbooks and until 1978 there were only eight published case reports. CRPS is seen in older children and teenagers and the pain is often located in a leg. CRPS is more common among girls than boys (approx. 4:1). Lack of knowledge of CRPS in children often results in a fairly long delay between the onset of symptoms and the diagnosis. Physiotherapy is an important part of the treatment of CRPS but concomitant pain treatment is often required in order to make physiotherapy possible. Sympathetic nerve block with intravenous regional guanethedine block or an epidural blockade is used. A number of analgesics may also be used. The treatment should be administered by a multi-disciplinary team. The incidence of CRPS in children in Denmark is unknown but the condition is probably under-diagnosed. Early diagnosis and active treatment may reduce the duration of the condition considerably.

Comparison of conventional averaged and rapid averaged, autoregressive-based extracted auditory evoked potentials for monitoring the hypnotic level during propofol induction.

BACKGROUND: The extraction of the middle latency auditory evoked potentials (MLAEP) is usually done by moving time averaging (MTA) over many sweeps (often 250-1,000), which could produce a delay of more than 1 min. This problem was addressed by applying an autoregressive model with exogenous input (ARX) that enables extraction of the auditory evoked potentials (AEP) within 15 sweeps. The objective of this study was to show that an AEP could be extracted faster by ARX than by MTA and with the same reliability. METHODS: The MTA and ARX methods were compared with the Modified Observer's Assessment of Alertness and Sedation Scale (MOAAS) in 15 patients scheduled for cardiac surgery and anesthetized with propofol. The peak amplitudes and latencies were recorded continuously for the MTA- and ARX-extracted AEP. An index, AAI, was derived from the ARX-extracted AEP as well. RESULTS: The best predictors of the awake and anesthetized states, in terms of the prediction probability, Pk, were the AAI (Pk [SE] = 0.93 [0.01]) and Na-Pa amplitude (MTA, Pk [SE] = 0.89 [0.02]; ARX, Pk [SE] = 0.87[0.02]). When comparing the AAI at the MOAAS levels 5-3 versus 2-0, significant differences were achieved. During the transitions from awake to asleep, the ARX-extracted AEP were obtained with significantly less delay than the MTA-extracted AEP (28.4 s vs. 6 s). CONCLUSION: The authors conclude that the MLAEP peaks and the AAI correlate well to the MOAAS, whether extracted by MTA or ARX, but the ARX method produced a significantly shorter delay than the MTA.