Central venous catheter sampling of low molecular heparin levels: an approach to increasing result reliability.

BACKGROUND: The low molecular weight heparin effect in children is monitored using the anti-factor Xa level. Venipuncture is recommended; however, central venous catheter blood sampling is often necessary. Heparin infused through central venous catheters may contaminate central venous catheter blood samples, preventing reliable anti-factor Xa level measurement. Simultaneous anti-factor Xa/partial thromboplastin time measurement with central venous catheter blood sampling may predict anti-factor Xa reliability. OBJECTIVES: To determine the prevalence of heparin contamination as measured by the partial thromboplastin time/anti-factor Xa in central venous catheter blood samples and whether careful sampling could minimize heparin contamination of anti-factor Xa levels from central venous catheter blood sampling. METHODS: Simultaneous partial thromboplastin time/anti-factor Xa measurements from central venous catheter blood sampling determined the prevalence of heparin contamination of central venous catheter blood samples. In phase II, children receiving low molecular weight heparin had routine central venous catheter blood sampling to measure the peak anti-factor Xa and the simultaneous partial thromboplastin time. Anti-factor Xa levels with a partial thromboplastin time of >40 secs (pair 1) were identified; there was no low molecular weight heparin dose change, and the paired sample was repeated using a careful sampling technique (pair 2). Pairs 1 and 2 were compared to determine the efficiency of the sampling technique in removing heparin from the central venous catheter blood samples. RESULTS: In phase I, 100 children had 485 paired anti-factor Xa/partial thromboplastin time central venous catheter blood samples with 29% ± 4.1% (95% confidence interval 25% to 33%) anti-factor Xa with partial thromboplastin times of >40 secs. In phase II, 43 children had 129 paired anti-factor Xa/partial thromboplastin time samples with partial thromboplastin times of >40 secs. The pair 1 mean partial thromboplastin times/anti-factor Xa levels were 109.8 secs (SD 53.1, range 34.0 to >200 secs) and 1.03 units/mL (SD 0.56, range 0.26-4.2 units/mL). Repeated partial thromboplastin times/anti-factor Xa levels (pair 2) were significantly decreased from those of pair 1 (p < .001) with means of 58.5 secs (SD 21.2, range 22-152 secs) vs. 109.8 secs (SD 53.1, range 34.0 to > 200 secs, p < .001) and 0.63 unit/mL (SD 0.30, range 0.02-1.77 units/mL) vs. 1.03 units/mL (SD 0.56, range 0.26-4.2 units/mL), respectively. CONCLUSIONS: Measurement of the partial thromboplastin time performed in combination with that of the anti-factor Xa level can be used to assist health practitioners to identify unfractionated heparin contamination of anti-factor Xa levels drawn from central venous catheters. A careful sampling technique may minimize heparin contamination in central venous catheter blood samples.

Warfarin induced coagulopathy in children: assessment of a conservative approach.

BACKGROUND: Increasing numbers of children are being administered warfarin therapy as thromboprophylaxis. Warfarin has a narrow therapeutic window with a target international normalised ratio (INR) of 2-3.5, called the therapeutic range. The length of time a patient's INR remains within the therapeutic range is calculated as 'time in the therapeutic range'. Risk for haemorrhage in children receiving warfarin is 0.5%/patient-year and minor bleeding 2.3%/patient-year, which increases exponentially for INRs >5.0. Practice among non-bleeding adults with INRs ≥5 and ≤9 is to withhold warfarin and allow the INR to return to the therapeutic range. Faster warfarin clearance is correlated with younger age. METHODS AND RESULTS: The study objective was to determine the safety and effectiveness of a conservative approach for management of INRs >5 in children receiving warfarin. Children receiving warfarin with INRs ≥5 had warfarin withheld followed by a next day INR without vitamin K administration. Eighty-nine children (1-16 years) participated in the study with 2353 INRs performed. Twenty-six children had INRs ≥5, 5% of the total performed, with a mean INR of 5.9. The next day repeat mean INR after withholding one dose of warfarin was 3.3 (range 1.2-6.8) with 89% of INRs falling below 5. There were no overt bleeds or symptomatic thrombotic events in the month following the INR >5. Time in the therapeutic range for children with INRs ≥5 was 68%. CONCLUSIONS: Withholding warfarin alone for management of non-bleeding INRs ≥5 and ≤8 appears to be safe and effective.

EMPoWarMENT: Edmonton pediatric warfarin self-management pilot study in children with primarily cardiac disease.

UNLABELLED: Increasing numbers of children require warfarin thromboprophylaxis. Home INR testing by the patient (PST) has revolutionized warfarin management. However, the family/patient must contact the health team for guidance for warfarin dosing. Patient self management(PSM) prepares a patient performing PST to take an active role in warfarin dosing. Adult studies demonstrate that PSM is safe and effective with improved adherence and treatment satisfaction quality of life (QOL). OBJECTIVE: To estimate the safety and efficacy in children performing PSM or PST, to evaluate warfarin dose decision making in PSM, and warfarin related QOL. METHODS: Warfarinized children performing PST for >3m were randomized to PST or PSM. The PSM group underwent warfarin management education and assumed independent warfarin management. INRs were collected for a year prior to and for 1 year of study to determine TTR and warfarin decision making. QOL was assessed through inventory completion and interviews. RESULTS: 28 children were randomized and followed for 12 months. TTR was (83.9% pre/ post), and 77.7% pre to 83.0% post for PST and PSM (p=0.312). Appropriate warfarin decision making was 90% with no major bleeding episodes and no thromboembolic events. PSM was preferred by families. CONCLUSIONS: PSM for children may be a safe and effective management strategy for warfarinized children. Clinical studies with larger sample size are required.

Parvalbumin-, calbindin-, and calretinin-immunoreactive hippocampal interneuron density in autism.

BACKGROUND: There has been a long-standing interest in the possible role of the hippocampus in autism and both postmortem brain and neuroimaging studies have documented varying abnormalities in this limbic system structure. AIMS: This study investigates the density of subsets of hippocampal interneurons, immunostained with the calcium binding proteins, calbindin (CB), calretinin (CR) and parvalbumin (PV) to determine whether specific subpopulations of interneurons are impacted in autism. MATERIALS AND METHODS: Unbiased stereological techniques were used to quantify the neuronal density of these immunoreactive subpopulations of gamma-aminobutyric acid-ergic (GABAergic) interneurons analyzed in the CA and subicular fields in postmortem brain material obtained from five autistic and five age-, gender- and postmortem interval-matched control cases. RESULTS: Results indicate a selective increase in the density of CB-immunoreactive interneurons in the dentate gyrus, an increase in CR-immunoreactive interneurons in area CA1, and an increase in PV-immunoreactive interneurons in areas CA1 and CA3 in the hippocampus of individuals with autism when compared with controls. DISCUSSION/CONCLUSIONS: Although our sample size is small, these findings suggest that GABAergic interneurons may represent a vulnerable target in the brains of individuals with autism, potentially impacting upon their key role in learning and information processing. These preliminary findings further suggest the need for future more expanded studies in a larger number of postmortem brain samples from cases of autism and controls.

Novel uses of insulin syringes to reduce dosing errors: a retrospective chart review of enoxaparin whole milligram dosing.

UNLABELLED: Enoxaparin is a low molecular weight heparin (LMWH) commonly used for thromboprophylaxis children. Enoxaparin dosing is based on patients' weight and results in decimal dosing. Due to the high concentration of enoxaparin the resultant decimal dose makes precise measurement difficult. Dilution is necessary and often results in ten-fold medication administration errors [Ghaleb MA, Barber N, Franklin BD, Yeung VWS, Khaki ZF, Wong ICK. Systematic review of medication errors in pediatric patients. Ann Pharmacother Oct 2006;40(10):1766-76, Raju TN, Kecskes S, Thornton JP, Perry M, Feldman S. Medication errors in neonatal and paediatric intensive-care units. Lancet Aug 12 1989;2(8659):374-6]. Enoxaparin may be administered in whole milligram doses via insulin syringe, where one milligram of enoxaparin equals one unit on the 100 unit graduated insulin syringe. STUDY DESIGN: A retrospective chart review of 514 children. Data was collected on underlying diagnosis, reason for anticoagulation, anti-Xa levels, hemorrhagic events, and medication errors identified. OUTCOME: to determine the occurrence rate of supra-therapeutic anticoagulation as indicated by anti-Xa levels >1.0 u/ml, when enoxaparin doses are rounded up to the whole milligram, and are administered using insulin syringes. The secondary objectives were to determine if the supra-therapeutic anti-Xa levels were associated with hemorrhagic events. To determine if children achieved and maintained therapeutic anti-Xa range using whole milligram dosing and to evaluate the impact of utilizing insulin syringes for administration on reducing dose measurement errors. RESULTS: All 514 patients were prescribed whole milligram enoxaparin dosing, and achieved therapeutic anti-Xa within a mean time of 2 days. No infant or child required decimal doses to achieve therapeutic levels. Five children achieved an initial supra-therapeutic anti-Xa level (1.04 -1.36 U/ml), requiring a single whole milligram dose decrease. There were no associated hemorrhagic events. CONCLUSION: Whole milligram enoxaparin dosing administered via an insulin syringe safely and effectively, achieved therapeutic levels in infants and children. The reduced incidence of enoxaparin dosing errors suggests that whole milligram enoxaparin dosing via an insulin syringe is a method that should be considered for standard of care.

Timing of prenatal stressors and autism.

Recent evidence supports a role for genetics in autism, but other findings are difficult to reconcile with a purely genetic cause. Pathological changes in the cerebellum in autism are thought to correspond to an event before 30-32 weeks gestation. Our purpose was to determine whether there is an increased incidence of stressors in autism before this time period. Surveys regarding incidence and timing of prenatal stressors were distributed to specialized schools and clinics for autism and Down syndrome, and to mothers of children without neurodevelopmental diagnoses in walk-in clinics. Incidence of stressors during each 4-week block of pregnancy was recorded. Incidence of stressors in the blocks prior to and including the predicted time period (21-32 weeks gestation) in each group of surveys was compared to the other prenatal blocks. A higher incidence of prenatal stressors was found in autism at 21-32 weeks gestation, with a peak at 25-28 weeks. This does support the possibility of prenatal stressors as a potential contributor to autism, with the timing of stressors consistent with the embryological age suggested by neuroanatomical findings seen in the cerebellum in autism. Future prospective studies would be needed to confirm this finding.

Brief report: macrographia in high-functioning adults with autism spectrum disorder.

The initial description of Asperger syndrome commented on the poor handwriting and motor coordination difficulties of individuals with this condition. Early descriptions of autism do not remark upon such difficulties. Recent evidence, however, suggests that individuals with both conditions have a similar motor control impairment. Handwriting has not been formally assessed in this context. Our study compared handwriting size between individuals with autism spectrum disorder and age- and IQ-matched control subjects. Macrographia was observed among subjects with autism spectrum disorder which remained statistically significant when covaried with educational level. This finding may correlate with the anatomical abnormalities present in the cerebellum of individuals with autism spectrum disorder.

Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain.

OBJECTIVE: Measures of cholinergic transmitter activity were investigated in patients with autism because of reported neuropathological abnormalities in cholinergic nuclei in the basal forebrain. METHOD: Levels of cholinergic enzyme and receptor activity were measured in the frontal and parietal cerebral cortex of deceased autistic adults, similarly aged normal adults without mental retardation, and nonautistic mentally retarded adults. The immunoreactivity levels of brain-derived neurotrophic factor and nerve growth factor were measured in the basal forebrain. RESULTS: There were no differences between the autistic and comparison groups in choline acetyltransferase or acetylcholinesterase activity in the cerebral cortex and basal forebrain or in muscarinic M(2) receptor or alpha-bungarotoxin binding within the cortex. Cortical M(1) receptor binding was up to 30% lower than normal in the autistic subjects, and the difference reached significance in the parietal cortex. In both the parietal and frontal cortices, differences in nicotinic receptors assessed by [(3)H]epibatidine binding were significant and extensive (65%-73% lower in the autistic group than in the normal subjects); there were no differences in nicotine binding in the basal forebrain. Immunochemical analysis indicated lower levels of both the alpha(4) and beta(2) nicotinic receptor subunits in the parietal cortex. The M(1) receptor abnormality was not evident in the nonautistic group with mental retardation, although the lower [(3)H]epibatidine binding was apparent. In the basal forebrain, the level of brain-derived neurotrophic factor in the autistic group was three times as high as the level of the normal group. CONCLUSIONS: These neurochemical abnormalities implicate the cholinergic system in developmental disorders such as autism and suggest the potential for intervention based on cholinergic receptor modulation.

Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study.

Neuropathological studies in autistic brains have shown small neuronal size and increased cell packing density in a variety of limbic system structures including the hippocampus, a change consistent with curtailment of normal development. Based on these observations in the hippocampus, a series of quantitative receptor autoradiographic studies were undertaken to determine the density and distribution of eight types of neurotransmitter receptors from four neurotransmitter systems (GABAergic, serotoninergic [5-HT], cholinergic, and glutamatergic). Data from these single concentration ligand binding studies indicate that the GABAergic receptor system (3[H]-flunitrazepam labeled benzodiazepine binding sites and 3[H]-muscimol labeled GABA(A) receptors) is significantly reduced in high binding regions, marking for the first time an abnormality in the GABA system in autism. In contrast, the density and distribution of the other six receptors studied (3[H]-80H-DPAT labeled 5-HT1A receptors, 3[H]-ketanserin labeled 5-HT2 receptors, 3[H]-pirenzepine labled M1 receptors, 3[H]-hemicholinium labeled high affinity choline uptake sites, 3[H]-MK801 labeled NMDA receptors, and 3[H]-kainate labeled kainate receptors) in the hippocampus did not demonstrate any statistically significant differences in binding.

Increased discrimination of "false memories" in autism spectrum disorder.

Individuals with autism spectrum disorder (ASD) have impaired ability to use context, which may manifest as alterations of relatedness within the semantic network. However, impairment in context use may be more difficult to detect in high-functioning adults with ASD. To test context use in this population, we examined the influence of context on memory by using the "false memory" test. In the false memory task, lists of words were presented to high-functioning subjects with ASD and matched controls. Each list consists of words highly related to an index word not on the list. Subjects are then given a recognition test. Positive responses to the index words represent false memories. We found that individuals with ASD are able to discriminate false memory items from true items significantly better than are control subjects. Memory in patients with ASD may be more accurate than in normal individuals under certain conditions. These results also suggest that semantic representations comprise a less distributed network in high-functioning adults with ASD. Furthermore, these results may be related to the unusually high memory capacities found in some individuals with ASD. Research directed at defining the range of tasks performed superiorly by high-functioning individuals with ASD will be important for optimal vocational rehabilitation.

The effect of semantic and emotional context on written recall for verbal language in high functioning adults with autism spectrum disorder.

OBJECTIVE: Several deficits have been proposed to account for cognitive impairment in autism including an inability to comprehend the perspectives of others ("theory of mind"), an inability to process emotional information, and difficulty drawing together diverse information in context ("central coherence"). Because context (central coherence) and emotion can influence memory, a study was designed to show if autism spectrum disorder was associated with impaired utilisation of context and emotion in recall; and if impairments in theory of mind processing would influence recall in autism spectrum disorder. METHODS: Ten high functioning subjects with autism spectrum disorder and 13 age and IQ matched controls were tested using recall tests. In the first coherence memory test, subjects listened to a series of word lists that were in varying degrees of syntactic and semantic (coherent) order and were asked to recall the words. In the second coherence memory test, subjects listened to stories consisting of sentences that were, or were not, in logical (coherent) order. In the emotional memory test, the subjects listened to sentences that were highly emotional or non-emotional. In the theory of mind test, the subjects listened to stories requiring varying levels of understanding of the perspectives of others. RESULTS: There were no significant differences between groups in recall of coherent versus incoherent word lists, nor was there a significant difference between groups in recall of coherent versus incoherent stories. However, the control subjects recalled more of the emotional than non-emotional sentences, whereas the autism spectrum disorder group did not show such a difference. No significant difference existed in recall of stories requiring varying levels of understanding of the perspectives of others among subjects with autism spectrum disorder, and subjects with autism spectrum disorder did not differ from control subjects in the influence of theory of mind content on story recall. CONCLUSION: The study shows that memory in high functioning adults with autism spectrum disorder is facilitated by emotional content to a lesser degree than it is facilitated by coherence. Therefore, impairments in emotional processing cannot be considered as simply an effect of the "weak central coherence" theory in autism spectrum disorder. Whereas the reasons for this emotional deficit are unknown, evidence of abnormalities of the limbic structures in autism spectrum disorder may provide an anatomical explanation.

Sertraline treatment of transition-associated anxiety and agitation in children with autistic disorder.

The intolerance of children with autistic disorder to changes in their routine or environment is well known, typically presenting with acute symptoms of anxiety, panic, irritability, or agitation. In a clinical sample of children (6-12 years old) with autistic disorder and transition-induced behavioral deterioration, 8 of 9 patients showed a clinically significant improvement in response to sertraline treatment. Only one child was taking concurrent psychotropic medication. Therapeutic doses were surprisingly low in all cases (25-50 mg daily), with a clinical response appearing generally in 2-8 weeks. Adverse effects were minimal (one child developed stomachaches), except for apparent sertraline-induced behavioral worsening in 2 children when their doses were raised to 75 mg daily. In 3 children, an initial satisfactory clinical response appeared to diminish after 3-7 months of treatment, despite steady or increased doses. In 6 patients, the beneficial effects persisted throughout the several-month follow-up period. Only four of the children's families were identified as having mood and/or anxiety disorders. This open-label study suggests that short-term sertraline treatment may reduce the behavioral reactions seen in association with situational transitions or environmental changes in children with autistic disorder, though the beneficial effect may be only temporary in some children. Our experience suggests that small doses of sertraline may be effective and that some children may require divided doses of sertraline during the day. Controlled studies are needed to determine the efficacy, safety, and pharmacokinetics of sertraline in treating this "need for sameness," both in short-term and long-term studies of children with autistic disorder.

A validated case study of facilitated communication.

The case of a 13-year-old boy with autism, severe mental retardation, and a seizure disorder who was able to demonstrate valid facilitated communication was described. In three independent trials, short stories were presented to him, followed by validation test procedures with an uninformed facilitator providing physical support to the subject's arm. In Trials 1 and 3, several specific answers were provided that clearly indicated that the young man, not the uninformed facilitator, was the source of the information. Moreover, some responses seemed to imply that the subject was employing simple inferential and abstract reasoning. This case study adds to the small, but growing number of demonstrations that facilitated communication can sometimes be a valid method for at least some individuals with developmental disabilities.

Hippocampus in autism: a Golgi analysis.

Autism is a behaviorally defined syndrome in which neuropathological abnormalities have been identified in the limbic system and cerebellum. The morphology of hippocampal neurons in two cases of infantile autism was studied and compared to age-matched controls. CA4 neurons in autistic children were smaller in perikaryon area and dendritic branching of both CA4 and CA1 neurons was less than in controls. These findings are consistent with previous studies and suggest a curtailment in maturation in the pathogenesis of autism.

Pervasive neuroanatomic abnormalities of the brain in three cases of Rett's syndrome.

Rett's syndrome (RS) is a clinically defined disorder that appears to be unique to girls and is characterized by apparent cognitive and motor skill loss early in life. We report our findings in the brains of three girls with RS, which were studied in comparison with age-matched controls by means of gapless serial section. Reduced neuronal cell size and increased cell-packing density were present throughout the cortical and subcortical regions of the brain in all cases without evidence of active degeneration. These observations appear to be consistent with a curtailment of development. Further, the degree of abnormality in each case correlates more closely with the clinical presentation of the patient at the time of death than with the age of the patient or duration of symptoms.

Microscopic observations of the brain in Rett syndrome.

Rett syndrome (RS) is a clinically defined disorder which appears to be unique to females and which is associated with apparent loss of cognitive and motor skills early in life. Using the technique of gapless serial section, microscopic analysis of the brains from three cases of RS and identically processed age-matched controls was conducted to determine the nature and extent of cerebral abnormality in this disorder. Small neuronal cell size and increased cell packing density were observed throughout the brain in all three cases, without evidence of gliosis or active degeneration. These findings are consistent with a curtailment of brain development which may begin before birth. Further, the brain abnormalities in RS appear to be more diffuse than previously appreciated and are in accord with the widespread neurological symptoms characteristic of this disorder.

The contribution of neuropathologic studies to the understanding of autism.

A review of the neuropathology of infantile autism shows abnormalities in the limbic forebrain and in cerebellar circuits. The role of the cerebellar lesions in the symptomatology of infantile autism is unknown. The cerebellar findings appear to date from a fetal stage of development with evidence for an ongoing process after birth. The timing of the findings in the limbic system is unknown. A postulated role for these findings in the limbic system in infantile autism is presented.