Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system.

Previous studies suggested that risk for Autism Spectrum Disorder (ASD) may be increased in children exposed to antidepressants during the prenatal period. The disease specificity of this risk has not been addressed and the possibility of confounding has not been excluded. Children with ASD or attention-deficit hyperactivity disorder (ADHD) delivered in a large New England health-care system were identified from electronic health records (EHR), and each diagnostic group was matched 1:3 with children without ASD or ADHD. All children were linked with maternal health data using birth certificates and EHRs to determine prenatal medication exposures. Multiple logistic regression was used to examine association between prenatal antidepressant exposures and ASD or ADHD risk. A total of 1377 children diagnosed with ASD and 2243 with ADHD were matched with healthy controls. In models adjusted for sociodemographic features, antidepressant exposure prior to and during pregnancy was associated with ASD risk, but risk associated with exposure during pregnancy was no longer significant after controlling for maternal major depression (odds ratio (OR) 1.10 (0.70-1.70)). Conversely, antidepressant exposure during but not prior to pregnancy was associated with ADHD risk, even after adjustment for maternal depression (OR 1.81 (1.22-2.70)). These results suggest that the risk of autism observed with prenatal antidepressant exposure is likely confounded by severity of maternal illness, but further indicate that such exposure may still be associated with ADHD risk. This risk, modest in absolute terms, may still be a result of residual confounding and must be balanced against the substantial consequences of untreated maternal depression.

Effects of citrated whole blood transfusion in response to hemorrhage.

BACKGROUND AND PURPOSE: Standard treatment for massive hemorrhage in dogs is infusion of whole blood or of packed red blood cells with fresh frozen plasma if whole blood is not available. Although most whole blood is collected using a citrate-based anticoagulant, knowledge of citrate's relevant non-anticoagulant effects is not widespread. Citrate's anticoagulant activity is achieved through chelation of divalent metal cations (e.g., magnesium, calcium), which may exacerbate cardiovascular and metabolic insults attributable to hemorrhage. METHODS: Blood pressures, gas tensions, metabolites, and electrolytes; myocardial metabolites, pressures, and contractility; cardiac output; and left cranial descending and circumflex coronary artery flows were measured in 21 anesthetized dogs after hemorrhage was induced by collection of blood into a citrated reservoir to mean arterial pressure of 45 mm Hg for approximately 60 min (until arterial lactate concentration was 7.0 mmol/L), followed by a 1-h transfusion and 2 h of maintenance. RESULTS: Arterial ionized calcium concentration, total peripheral resistance, and myocardial function decreased significantly during hemorrhage. All aforementioned responses but myocardial function continued to decrease during the initial 20 min of transfusion, then began to recover. Total peripheral resistance and end-systolic elastance were the only factors significantly related to calcium concentration. CONCLUSION: Transfusion with citrated whole blood may significantly alter calcium concentration, negatively affecting myocardial and vascular function.

Association of human herpesvirus 6 with the demyelinative lesions of progressive multifocal leukoencephalopathy.

Progressive Multifocal Leukoencephalopathy (PML) is a primary demyelinating disease of the central nervous system occurring almost exclusively in individuals with impaired cell-mediated immunity. The JC polyoma virus has been accepted as the etiologic agent ofPML. Using a two-step in-situ polymerase chain reaction procedure to amplify and detect genomic DNA of human herpesvirus-6 (HHV6) in formalin-fixed paraffin-embedded archival brain tissues, a high frequency of infected cells was consistently detected in PML white matter both within and surrounding demyelinative lesions and HHV6 genome was found mainly within oligodendrocytes. Lesser amounts of HHV6 genome were detected in most normal, AIDS, and other neurological disease control tissues. Immunocytochemistry for HHV6 antigens showed actively infected nuclei of swollen oligodendrocytic morphology only within the demyelinative lesions of PML but not in adjacent uninvolved tissue. In addition, no HHV6 antigens were detectable in control tissues including brains of individuals with HIV-1 encephalopathy but without PML. Double immunohistochemical staining for JC virus large T antigen and HHV6 antigens demonstrated co-labeling of many swollen intralesional oligodendrocytes in the PML cases. The evidence suggests that HHV6 activation in conjunction with JC virus infection is associated with the demyelinative lesions of PML.

Relationship between inspiratory pressure and tidal volume in the anesthetized canine.

Hounds undergoing prolonged or complicated surgical procedures are often underventilated, as indicated by blood gas and end-tidal CO2 (CO2) values when using published ventilatory guidelines. We investigated the relationship between body weight, tidal volume, and inspiratory pressure delivered by the ventilator (lung inflation pressure) in 59 anesthetized hounds (19 to 33 kg). Animals were ventilated under positive pressure control and noninvasively instrumented to monitor blood pressure, ECG, oxygen saturation, CO2, and tidal volume. Weight, sex, and thorax measurements were recorded. All dogs were monitored at lung inflation pressures of 10, 14, and 18 cm H2O, with measurements recorded once CO2 stabilized. Veterinary guidelines recommend tidal volumes of 10 to 15 ml/kg of body weight and lung inflation pressures of 15 to 25 cm H2O. When inflation pressure was below guidelines (10), tidal volume was "normal" (10 to 15 ml/kg), but the animals were underventilated. When inflation pressure was "normal" (14 or 18 cm H2O), tidal volume was above guidelines. Physiologic variables were normal only when inflation pressure was 14 cm H2O. Weight and thorax depth accounted for 32 and 6%, respectively, of tidal volume variability, and tidal volume varied by +/- 250 ml at any given body weight and inflation pressure. None of the measured physical variables accurately predicted tidal volume. These data suggest that the inconsistency in tidal volume is due to a previously undescribed variability in respiratory compliance in the anesthetized hound and that the guidelines for ventilation during surgery need further investigation.

Effects of surgical approaches for acetabular fractures with associated gluteal vascular injury.

OBJECTIVES: To examine the viability of the abductor muscles following extensile exposures to the acetabulum in the presence of superior gluteal artery (SGA) or vein (SGV) injury. DESIGN: In vivo animal study. INTERVENTION: Twenty-two dogs underwent either an extensile or combined two-incision acetabular approach; either the SGA, the SGV, or no vessel was ligated. MAIN OUTCOME MEASUREMENTS: Blood flow to the affected gluteal region was evaluated by angiography, laser Doppler flowmetry, and fluorescent microspheres, and histologic and wet weight analyses were performed on the abductor muscles. RESULTS: Complete ischemic necrosis of the abductor muscles did not occur in any specimen; however, there were statistically significant reductions in immediate postoperative gluteal muscle perfusion (-47 percent, p < 0.01), loss of abductor muscle mass (-41 percent, p < 0.001), and histologic evidence of moderate to severe necrosis in five of seven specimens with extensile exposures and SGA ligation (p = 0.01). Extensile exposure and SGV ligation also caused a significant loss of muscle mass (-25 percent, p < 0.02), with moderate to severe necrosis occurring in four of seven specimens (p < 0.04). Dogs with SGA ligation undergoing the two-incision approach had no significant changes in muscle mass (-3 percent) or perfusion. Moderate to severe necrosis occurred in only one of four specimens. CONCLUSIONS: This study fails to support the hypothesis that extensile approaches to complex acetabular fractures eliminate abductor collateral circulation when performed in the presence of SGA injury.

The relationship of carbon dioxide excretion during cardiopulmonary resuscitation to regional blood flow and survival.

Currently, there are no practical means of prospectively determining cardiopulmonary resuscitation (CPR) adequacy in the field. Airway CO2 excretion can be noninvasively and stably measured under changing environmental conditions. We investigated the relationships between the volume of airway CO2 excreted (CO2EX) during CPR to regional blood flow (RBF) and survival. A total of 21 dogs were randomly divided into four CO2EX groups (< 5, 5-6, > 6-7 and > 7 ml CO2/min per kg), anesthetized, instrumented and ventilated with an in-line infrared airway CO2 sensor. Anesthesia was reduced and baseline measurements made. Ventricular fibrillation (VF) was initiated and resuscitation withheld for 3 min, followed by 17 min of CPR. Compression force alone was adjusted to maintain predetermined CO2EX. Animals were resuscitated, monitored for 2 h and observed for an additional 22 h. RBF was determined at baseline, 16 min post-VF and 60 min post-resuscitation. Mean CO2EX during CPR was significantly higher in survivors than nonsurvivors. The probability of survival increased as CO2EX increased. The highest CO2EX group had the highest rate of survival (86%), but did not always have significantly higher cardiac output (CO), myocardial or cerebral blood flows (MBF, CBF) than the lowest CO2EX group with a 0% survival rate. These data suggest survival is tracked better by CO2EX than by CO, MBF or CBF. Therefore, CO2EX appears to provide a practical reliable noninvasive method of determining CPR efficacy in the field.

The relationship between airway carbon dioxide excretion and cardiac output during cardiopulmonary resuscitation.

There is currently no practical method for determining cardiopulmonary resuscitation (CPR) efficacy in the field. We investigated the relationship between the volume of carbon dioxide (CO2) excreted in the airway (CO2EX) when tidal volume and respiratory rate are controlled, and cardiac output (CO), an indicator of CPR efficacy, to determine the potential of CO2EX as a practical noninvasive field monitor of CPR efficacy. Thirteen mongrel dogs were anesthetized, instrumented and ventilated 13 times/min at a fixed tidal volume with an infrared airway CO2 sensor. CO2EX = (PCO2/bar. press) x (tidal vol) x (breaths/min), and expressed in ml/min per kg. Sequences of control, CPR with 3-4 different compression forces, and recovery measurements were recorded 10-15 times/animal. CO2EX and CO fell simultaneously with ventricular fibrillation. CPR immediately increased CO2EX and CO. Both changed consistently and in the same direction as compression force. Return of spontaneous circulation immediately increased CO2EX and CO above controls, with a gradual return to control levels. CO2EX was always below 8 ml-CO2/min/kg during CPR and above this during spontaneous circulation. With alveolar ventilation controlled, CO2 movement is regulated by CO, CO distribution and CO2 stores shifts. Normally, CO accounts for 15% of CO2EX variability. In this study CO accounted for > or = 65% of CO2EX variability during CPR, indicating CO2EX changes were primarily due to CO changes. When ventilation is controlled, CO2EX during CPR reliably tracks changes in CO. Therefore, CO2EX may provide a practical noninvasive method of determining CPR efficacy as the CPR is being performed.

Neonatal cranial ultrasound abnormalities in low birth weight infants: relation to cognitive outcomes at six years of age.

OBJECTIVE: To assess the independent relation of neonatal cranial ultrasound (US) abnormalities in low birth weight (LBW) infants to cognitive outcomes at 6 years of age. DESIGN: Prospective cohort study. SAMPLE AND METHODS: Six-year follow-up data were obtained on a regional birth cohort of LBW infants (< 2 kg) systematically screened as neonates with serial US. US abnormalities were dichotomized into isolated germinal matrix/intraventricular hemorrhage (GM/IVH) and parenchymal lesions/ventricular enlargement (PL/VE). Global cognitive outcomes (mental retardation, borderline intelligence, and normal intelligence) and selected specific cognitive abilities were assessed at 6 years of age with standardized instruments. Multivariate techniques were used to assess the effects of US independent of maternal social disadvantage at birth and other perinatal and neonatal risk factors. RESULTS: The sample as a whole had a significantly elevated rate of mental retardation (MR; 5%), almost all moderate to profound in severity. PL/VE was independently related to MR (odds ratio [OR], 65.8; confidence interval [CI], 19.1 to 22.4) and borderline intelligence (OR, 3.7; CI, 1.3 to 10.8); isolated GM/IVH was more modestly related to MR (OR, 4.6; CI, 1.2 to 18.6) but not related to borderline intelligence. Approximately half of the cases of MR were attributable to PL/VE independent of other factors. Of non-US factors, the number of days receiving mechanical ventilation increased the risk for MR. Maternal social disadvantage increased the risk for borderline intelligence but not MR. Among children of normal intelligence, those with PL/VE, but not isolated GM/IVH, performed more poorly than those without US abnormalities on tests of visual perceptual organization but not on tests of language, memory, or quantitative skills. CONCLUSION: Prevention of white matter injury would substantially improve cognitive outcomes for LBW infants.

P-wave duration in a clinically normal hound population.

Electrocardiogram (ECG) analysis is a common noninvasive technique used for diagnosis of cardiac disease in the clinical and research branches of veterinary medicine. Accurate analysis of P-wave duration, amplitude, and morphology is crucial to identification of morphologic and functional changes of the atria. The published accepted maximal normal value for P-wave duration in the dog is < or = 40 milliseconds. We looked at P-wave duration in ECG obtained as part of routine quarantine health screening over a period of 1 year in 364 clinically normal hounds weighing 13 to 35 kg. The dogs were neither anesthetized nor sedated and were placed in standard position. P-wave duration was classically determined from the lead-II recording. Mean P-wave duration for all dogs (44.9 +/- 6.1 milliseconds) was greater than published accepted normal values for the dog. There was a significant difference in mean P-wave duration by body weight (P < 0.001); dogs weighing > or = 20 kg had longer mean P-wave durations than dogs weighing < 20 kg (45.3 and 41.6 milliseconds respectively). There were also significant differences in mean P-wave duration by sex (P < 0.01), with a greater mean duration for females (45.4 milliseconds) than for males (43.8 milliseconds). All other ECG parameters were within published accepted normal values. A P-wave of prolonged duration leads to a diagnosis of abnormalities in cardiac morphology and/or function. Published accepted normal values for P-wave duration, at least for a clinically normal hound population, appear to be shorter than the true normal values. An error in published accepted normal standards may lead to overdiagnosis of cardiac abnormalities, as well as to erroneous results in cardiovascular studies. Therefore we recommend that the standard for P-wave duration be increased above the currently accepted standard of < or = 40 milliseconds.

Octreotide versus pyloric exclusion in reducing gastrointestinal secretions entering the duodenum in a canine model.

Pyloric exclusion is advocated in the treatment of duodenal injury. The beneficial effect is thought to be due to diversion of gastric secretions and resultant reduction of biliary and pancreatic secretions. The long-acting somatostatin analog, Octreotide, makes the inhibitory actions of somatostatin on gastric, biliary, and pancreatic secretions a potential alternative to pyloric exclusion. We compared the effect of pyloric exclusion to the effect of Octreotide on the volume of gastrointestinal secretions entering the duodenum by creating a duodenal fistula using a canine model. Five animals had modified Thomas cannulas placed in the duodenum. Two animals had staple closure of the pylorus with a gastrojejunostomy in addition to the cannula. Gastrointestinal secretions were measured in 2- or 3-hour collection periods performed every third or fourth day. Animals were administered saline or Octreotide (100 micrograms/hour) intravenously during each collection. Up to 9 hours of collections under both saline and Octreotide (18 hours total) were done on each dog. Octreotide alone reduces gastrointestinal secretions entering the duodenum more than pyloric exclusion alone. Pyloric exclusion and Octreotide together offered no additional reduction in gastrointestinal secretions entering the duodenum over Octreotide alone.