Change in mean transit time, apparent diffusion coefficient, and cerebral blood volume during pediatric diabetic ketoacidosis treatment.

OBJECTIVES: Cerebral edema is a devastating complication of pediatric diabetic ketoacidosis. We examined measures describing potential causes of whole brain and regional brain edema (mean transit time, apparent diffusion coefficient, and relative cerebral blood volume) during treatment of diabetic ketoacidosis in children. DESIGN: Prospective observational study. SETTING: Regional children's hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After Institutional Review Board approval, children admitted with diabetic ketoacidosis (pH <7.3, HCO3 <15 mEq/L, glucose >300 mg/dL, and ketosis) underwent two serial paired contrast-enhanced (gadolinium) and diffusion magnetic resonance imaging scans. Change in whole brain and regional (frontal lobe, occipital lobe, and basal ganglia) mean transit time, apparent diffusion coefficient, and relative cerebral blood volume between the two time periods (12-24 hrs) and (36-72 hrs) after start of insulin treatment (time 0) were determined. Thirteen children (median age, 10.3 ± 1.1 yrs; 7 female) with diabetic ketoacidosis were examined. Overall, whole brain and regional mean transit time decreased from time 1 (first magnetic resonance imaging after time 0) to time 2 (second magnetic resonance imaging after time 0) by 51% ± 59% (p = .01), without differences between the brain regions examined. Whole brain apparent diffusion coefficient increased by 4.7% ± 3.4% (p = .001), without differences between the brain regions examined. There was no change in relative cerebral blood volume for the whole brain and for the three brain regions examined. CONCLUSIONS: In this study, whole brain mean transit time decreased and apparent diffusion coefficient increased, suggesting a vasogenic process between the two study periods during diabetic ketoacidosis treatment.

Hypertension despite dehydration during severe pediatric diabetic ketoacidosis.

OBJECTIVE: Diabetic ketoacidosis (DKA) may result in both dehydration and cerebral edema but these processes may have opposing effects on blood pressure. We examined the relationship between dehydration and blood pressure in pediatric DKA. DESIGN: A retrospective review was performed at Seattle Children's Hospital, Seattle, WA. Participants were hospitalized children less than 18 yr. Intervention(s) or main exposure was to patients with DKA (venous pH < 7.3, glucose > 300 mg/dL, HCO(3) < 15 mEq/L, and urinary ketosis). Dehydration was calculated as percent body weight lost at admission compared to discharge. Hypertension (systolic and/or diastolic blood pressure (DBP) percentile > 95%) was defined based on National Heart, Lung, and Blood Institute (NHLBI, 2004) nomograms and hypotension was defined as systolic blood pressure (SBP) <70 + 2 [age]. RESULTS: Thirty-three patients (median 10.9 yr; range 10 months to 17 yr) were included. Fifty-eight percent of patients (19/33) had hypertension on admission before treatment and 82% had hypertension during the first 6 h of admission. None had admission hypotension. Hypertension 48 h after treatment and weeks after discharge was common (28 and 19%, respectively). Based on weight gained by discharge, 27% of patients had mild, 61% had moderate, and 12% presented with severe dehydration. CONCLUSION: Despite dehydration, most children admitted with severe DKA had hypertension.

Ketorolac tromethamine: stereo-specific pharmacokinetics and single-dose use in postoperative infants aged 2-6 months.

OBJECTIVE: We determined the postoperative pharmacokinetics (PK), safety, and analgesic effects of ketorolac in 14 infants (aged <6 months) receiving a single intravenous (IV) administration of racemic ketorolac or placebo. BACKGROUND: Information on the PK of ketorolac in infants is limited. Unblinded studies suggest ketorolac may be useful in infants. METHODS: This double-blinded, placebo-controlled study enrolled 14 infants (aged <6 months) postoperatively. At 6-18 h after surgery, infants were randomized to receive placebo, 0.5 mg·kg(-1), or 1 mg·kg(-1) ketorolac IV. All infants received morphine sulfate as needed for pain control. Blood was collected up to 12-h postdosing. Analysis used noncompartmental and compartmental population modeling methods. RESULTS: In addition to noncompartmental and empirical Bayes PK modeling, data were integrated with a previously studied data set comprising 25 infants and toddlers (aged 6-18 months). A two-compartmental model described the comprehensive data set. The population estimates of the R (+) isomer were (%CV): central volume of distribution 1130 (10%) ml, peripheral volume of distribution 626 (25%) ml, and clearance from the central compartment 7.40 (8%) ml·min(-1). Those of the S (-) isomer were 1930 (15%) ml, 319 (58%) ml, and 39.5 (13%) ml·min(-1). Typical elimination half-lives were 191 and 33 min, respectively. There was a trend for increased clearance and central volume with increasing age and weight. The base model suggested that clearance of the S (-) isomer was weakly related to age; however, when body size adjustment was added to the model, no covariates were significant. Safety assessment showed no changes in renal or hepatic function tests, surgical drain output, or continuous oximetry between groups. Cumulative morphine administration showed large inter-patient variability and was not different between groups. CONCLUSION: Stereo-isomer-specific clearance of ketorolac in infants (aged 2-6 months) shows rapid elimination of the analgesic S (-) isomer as reported in infants aged 6-18 months. No adverse effects were seen after a single IV ketorolac dose.

Two-agent analgesia versus acetaminophen in children having bilateral myringotomies and tubes surgery.

OBJECTIVES: The objective of this study was to determine whether the incidence of emergence agitation (EA) can be reduced by adding an additional, faster onset, non-IV analgesic, intranasal fentanyl or intramuscular (im) ketorolac to rectal acetaminophen. AIM: To compare the incidence of EA after analgesia with two agents vs acetaminophen alone in pediatric patients after bilateral myringotomy procedures (BM&T). BACKGROUND: Anesthesia for BM&T is usually performed with volatile anesthetics as a single agent without securing intravenous access. The anesthetic agent most commonly used is sevoflurane; however, EA has been reported in up to 67% of patients. Emergence agitation is distressing for parents, can impair the ability of nursing staff to adequately monitor the child, and can result in a child injuring him/herself if it is severe. METHODS/MATERIALS: A standardized anesthetic was used with oral midazolam premedication and sevoflurane for induction, and maintenance of anesthesia. All patients received 40 mg·kg(-1) rectal acetaminophen, group 1 received acetaminophen alone, group 2 received acetaminophen and 1 mcg·kg(-1) of intranasal fentanyl, and group 3 received acetaminophen and 1 mg·kg(-1) of intramuscular ketorolac. Incidence of EA was compared using chi-square test between the acetaminophen group alone vs the two-agent analgesia groups combined. RESULTS: There were no differences in demographic and clinical characteristics between the two groups. There were no statistically significant differences between the three groups for the incidence of EA at any time point during recovery from anesthesia nor were there any significant differences in pain scores or side effects. No significant side effects because of the administration of a second analgesic agent were reported. CONCLUSIONS: We conclude that two-agent analgesia is not superior to acetaminophen alone for decreasing the incidence of EA after inhalation anesthesia with sevoflurane for BM&T surgery. Our overall incidence of EA was low compared to previous studies, which could potentially have decreased our ability to detect differences between groups.

Change in blood-brain barrier permeability during pediatric diabetic ketoacidosis treatment.

OBJECTIVE: Cerebral edema is a devastating complication of pediatric diabetic ketoacidosis. We aimed to examine blood-brain barrier permeability during treatment of diabetic ketoacidosis in children. DESIGN: Prospective observational study. SETTING: Seattle Children's Hospital, Seattle, WA. PATIENTS: Children admitted with diabetic ketoacidosis (pH <7.3, HCO3 <15 mEq/L, glucose >300 mg/dL, and ketosis). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Subjects underwent two serial paired contrast-enhanced perfusion (gadolinium) and diffusion magnetic resonance imaging scans. Change in whole brain and regional blood-brain barrier permeability (permeability ratio*100 and % permeability ratio change) between illness and recovery were determined. Time 0 reflects start of insulin treatment. Thirteen children (median age 10.0 +/- 1.1 yrs; seven female) with diabetic ketoacidosis were enrolled. Permeability ratio increased from time 1 (first magnetic resonance image after time 0) to time 2 (second magnetic resonance image after time 0) in the frontal cortex (ten of 13 subjects), occipital cortex (ten of 13 subjects), and basal ganglia (nine of 13). Whole brain permeability ratio increased from time 1 to time 2 (160%) and regional increase in permeability ratio was greatest in the frontal cortex (148%) compared with the occipital cortex (128%) and basal ganglia (112%). CONCLUSIONS: Overall, whole brain and regional blood-brain barrier permeability increased in most subjects during diabetic ketoacidosis treatment. The frontal region had more blood-brain barrier permeability than other brain regions examined.

Postoperative ketorolac tromethamine use in infants aged 6-18 months: the effect on morphine usage, safety assessment, and stereo-specific pharmacokinetics.

BACKGROUND: Nonsteroidal antiinflammatory drugs have been useful for treating postoperative pain in children. The only parenteral nonsteroidal antiinflammatory drug currently available in the United States is ketorolac tromethamine with cyclooxygenase-1 and cyclooxygenase-2 effects. Information on the pharmacokinetics of ketorolac in infants is sparse, making dosing difficult. Ketorolac is administered as a racemic mixture with the S(-) isomer responsible for the analgesic effect. In this study, we describe the population pharmacokinetics of ketorolac in a group of 25 infants and toddlers who received a single IV administration of racemic ketorolac and evaluate the potential influence of patient covariates on ketorolac disposition. METHODS: In this double-blind, placebo-controlled study, ketorolac pharmacokinetic, safety, and analgesic effects were studied in 37 infants and toddlers (aged 6-18 mo) postoperatively. On postoperative day 1, infants were randomized to receive placebo, 0.5, or 1 mg/kg ketorolac as a 10-min IV infusion. Blood samples were collected up to 12-h after dosing. The data were analyzed using noncompartmental and compartmental (nonlinear mixed-effects model) means. The patient covariates, including body weight, age, and surgical procedure, were analyzed in a stepwise fashion to identify their potential influence on ketorolac pharmacokinetics. RESULTS: The data were best described by a two-compartmental model. Inclusion of covariates did not significantly decrease the nonlinear mixed-effects model objective function values and between-subject variability in the pharmacokinetic parameters of nested models. The mean and standard error of the estimates of the R(+) isomer were central volume of distribution 1200 +/- 163 mL (coefficient of variation of interindividual variability, 13.6%), peripheral volume of distribution 828 +/- 108 mL (13.0%), clearance from the central compartment 7.52 +/- 0.7 mL/min (9.3%), and extrapolated elimination half-life 238 +/- 48 min. Those of the S(-) isomer were 2320 +/- 34 (14.6%), 224 +/- 193 mL (86.2%), 45.3 +/- 5.5 mL/min (12.1%), and 50 +/- 42 min respectively. Dosing simulations, using population pharmacokinetic parameters, showed no accumulation of S(-) ketorolac but steady increases in R(+) ketorolac. Safety assessment showed no adverse effects on renal or hepatic function tests, surgical drain output, or continuous oximetry between placebo and ketorolac groups. Cumulative morphine administration showed large interpatient variability and was not different between groups. CONCLUSION: The stereo-isomer-specific clearance of ketorolac in infants and toddlers (aged 6-18 mo) shows rapid elimination of the analgesic S(-) isomer. No adverse effects on surgical drain output, oximetry measured saturations, renal or hepatic function tests were seen. Simulation of single dosing at 0.5 or 1 mg/kg every 4 or 6 h does not lead to accumulation of S(-) ketorolac, the analgesic isomer, but does result in increases in R(+) ketorolac. Shorter dose intervals may be needed in infants older than 6 mo.

A comparison of a needle-free injection system for local anesthesia versus EMLA for intravenous catheter insertion in the pediatric patient.

Placement of IV catheters is a painful and stressful procedure for children. J-Tip is a needle-less Food and Drug Administration approved injection system that can be used for delivery of local anesthetic before IV cannulation. In this study, we compared the effectiveness of J-Tip versus eutectic mixture of local anesthetics (EMLA) to facilitate IV cannulation and provide adequate analgesia before IV placement. Children 7-19 years of age (n = 116) were randomized to receive 0.25 mL of 1% buffered lidocaine with J-Tip (n = 57) or 2.5 g of EMLA (n = 59) before IV cannulation. Measurements of success of cannulation (number of attempts for IV placement) and pain (0-10 visual analog scale) at application of local anesthetic and at cannulation were performed. There was a significant (P = 0.0001) difference in pain ratings during IV cannulation between EMLA (median = 3) and the J-Tip (median = 0). Eighty-four percent of patients reported no pain at the time of J-Tip lidocaine application compared to 61% in the EMLA group at the time of dressing removal (P = 0.004). We did not find differences in the number of attempts for IV cannulation. J-Tip application of 1% buffered lidocaine before IV cannulation is not painful and has better anesthetic effectiveness compared with EMLA.

Pilot study of preoperative heart rate variability and adverse events in children emerging from anesthesia.

OBJECTIVE: To assess correlations between preoperative heart rate variability (a noninvasive measure of autonomic cardiac activity) and adverse respiratory events during anesthesia emergence in children. DESIGN: Case control study. SETTING: Tertiary care pediatric operating room. PATIENTS: Sixty-one children, aged 8 months to 13 yrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Heart rate power spectra were obtained from two 5-min immediate-preoperative electrocardiographs with an orthostatic posture change interposed and (n = 32) from a 24-hr preoperative Holter monitor. Observers recorded emergence from standardized anesthesia for coughing, laryngospasm, and desaturation. Low-frequency/high-frequency ratios (LF/HF) were derived from power spectra of heart rate variability. The orthostatic change in heart rate variability derived from brief preoperative recordings was significantly different if adverse events occurred during emergence from anesthesia (LF/HF standing/LF/HF supine = 1.3 vs. 2.8, p = .019). Holter-derived heart rate variability had no correlation with adverse events. Receiver operating characteristic analysis showed a sensitivity of 85% and specificity of 52% for predicting adverse events with preoperative recordings. CONCLUSIONS: This study provides new information regarding pathophysiology in children with upper respiratory infection. The magnitude of difference demonstrated is insufficient to propose this method as a preoperative screening test.

Nasotracheal intubation: a randomized trial of two methods.

BACKGROUND: Several techniques have been suggested to reduce the trauma of nasotracheal intubation, although no comparative studies exist. The authors evaluated red-rubber catheters as a guide to nasotracheal intubation. METHODS: Children presenting for elective surgery were randomized to undergo red-rubber catheter-guided nasotracheal intubation or to have the nasotracheal tube alone inserted. After general anesthesia and paralysis with vecuronium, the nares were prepared with topical vasoconstrictor. The nasotracheal tube was softened with warm water. In the catheter-guided group, the nasotracheal tube tip was fitted to the trailing end of the red-rubber catheter, and the two were advanced together. The red-rubber catheter was retrieved from the nasopharynx, disconnected, and removed. In the other group, the nasotracheal tube was advanced blindly into the nasopharynx. In both groups, intubation was then completed during direct laryngoscopy using Magill forceps. A blinded observer swabbed the pharynx and rated the severity of bleeding based on reference photographs. RESULTS: Age, weight, snoring history, and difficulty of intubation were not different between groups. Obvious bleeding was lower using the red-rubber catheter technique (10 vs. 29%, P = 0.013), which took longer to perform (74 vs. 56 s, P = 0.02). CONCLUSIONS: Although the incidence of bleeding in both groups was similar, severity of bleeding was reduced in the catheter-guided group during nasotracheal intubation. Use of a red-rubber catheter may reduce the trauma associated with nasotracheal intubation.