Characteristics of children aged 2-17 years undergoing anaesthesia in Danish hospitals 2005-2015: a national observational study.

Provision of paediatric anaesthesia requires careful consideration of the child's cognitive state, unique body composition and physiology. In an observational cohort study, we describe the population characteristics and conduct of anaesthesia in children aged 2-17 years from 1 January 2005 to 31 December 2015. Children were identified from the Danish Anaesthesia Database. We recorded the following variables: age; sex; comorbidities; indications for anaesthesia; practice of anaesthesia; and complications. Results are presented for two age groups: 2-5 and 6-17 years. In total, 32,840 (61% male) children aged 2-5 years received 50,484 anaesthesia episodes and 91,418 (54% male) children aged 6-17 years received 141,082 anaesthesia episodes. The younger children, compared with the older children, were more frequently anaesthetised at a university hospital (50% vs. 36%) and for non-surgical procedures (24% vs. 8%). For both age groups, general anaesthesia was the primary choice of anaesthesia regardless of the reason for anaesthesia. For surgery, general anaesthesia using inhalational agents in addition to intravenous agents or alone was more frequently used in younger children (49% vs. 15%), whereas older children commonly received total intravenous anaesthesia (50% vs. 83%). Regional anaesthesia was infrequently utilised. Complications occurred in 3.3% of anaesthesia episodes among 2-5 year olds compared with 3.7% of anaesthesia episodes among children aged 6-17 years. In conclusion, we found younger children (aged 2-5), compared with older children (aged 6-17) were more frequently anaesthetised for non-surgical reasons, at a university hospital and using inhalational agents. Complications were rare.

Characteristics of children less than 2 years of age undergoing anaesthesia in Denmark 2005-2015: a national observational study.

There are few data available that describe the current anaesthetic management of children. We have analysed anaesthetic practice and peri-operative complications for children in Denmark aged less than two years. We conducted a population-based observational cohort study using the Danish Anaesthesia Database to identify children who received anaesthesia in hospital from 1 January 2005 until 31 December 2015. Data were combined with that from the Danish National Patient Registry and the Danish Civil Registration System. Age, sex, height, weight, ASA physical status, days in hospital before anaesthesia, number of anaesthetics per child, indications for anaesthesia, methods of anaesthesia, airway management and complications were all recorded. A total of 17,436 children (64% of whom were male) received 27,653 anaesthetics during the study period. In 58% of cases, the child had an ASA physical status score of 1. Thirty-seven percent had a previous anaesthetic episode. Seventy-nine percent were anaesthetised at a university hospital. The indications for anaesthesia were surgery (70%), diagnostic radiology (16%), non-surgical care (11%) and other indications (3%). General anaesthesia combining intravenous and inhalational agents was the most common approach for surgery (68%) and diagnostic radiology (47%). For non-surgical care, general anaesthesia using inhalational agents was the most common method (42%). Neuraxial blocks were used infrequently. The most common regional anaesthetic nerve block was an infraclavicular brachial plexus block (11%). Peri-operative complications occurred in 1.71% of cases. A large proportion of anaesthetics were conducted in children with comorbidities. Non-surgical indications for anaesthesia were frequent and peri-operative complications were rare.

Benefit and harm of pregabalin in acute pain treatment: a systematic review with meta-analyses and trial sequential analyses.

Pregabalin has demonstrated anti-hyperalgesic properties and was introduced into acute pain treatment in 2001. Our aim was to evaluate the beneficial and harmful effects of pregabalin in postoperative pain management. We included randomized clinical trials investigating perioperative pregabalin treatment in adult surgical patients. The review followed Cochrane methodology, including Grading of Recommendations Assessment, Development, and Evaluation (GRADE), and used trial sequential analyses (TSAs). The primary outcomes were 24 h morphine i.v. consumption and the incidence of serious adverse events (SAEs) defined by International Conference of Harmonisation Good Clinical Practice guidelines. Conclusions were based primarily on trials with low risk of bias. Ninety-seven randomized clinical trials with 7201 patients were included. The 24 h morphine i.v. consumption was reported in 11 trials with overall low risk of bias, finding a reduction of 5.8 mg (3.2, 8.5; TSA adjusted confidence interval: 3.2, 8.5). Incidence of SAEs was reported in 21 trials, with 55 SAEs reported in 12 of these trials, and 22 SAEs reported in 10 trials with overall low risk of bias. In trials with overall low risk of bias, Peto's odds ratio was 2.9 (1.2, 6.8; TSA adjusted confidence interval: 0.1, 97.1). Based on trials with low risk of bias, pregabalin may have a minimal opioid-sparing effect, but the risk of SAEs seems increased. However, the GRADE-rated evaluations showed only moderate to very low quality of evidence. Consequently, a routine use of pregabalin for postoperative pain treatment cannot be recommended.

Tracheal intubation in patients with anticipated difficult airway using Boedeker intubation forceps and McGrath videolaryngoscope.

BACKGROUND: Videolaryngoscopes with sharp angulated blades improve the view of the vocal cords but this does not necessarily result in higher success rates of intubation The aim of this study was to evaluate the efficacy of using Boedeker intubation forceps in conjunction with McGrath Series 5 Videolaryngoscope (MVL) in patients with predictors for difficult intubation. METHODS: The study was conducted at the Department of Anaesthesia, Copenhagen University Hospital from September to December 2013. Patients with one or more predictors of difficult intubation scheduled for general anaesthesia were assessed for eligibility. Patients were intubated using Boedeker intubation forceps and MVL. The primary endpoint was time to intubation. The secondary endpoints were intubation success rate, number of intubation attempts, intubation conditions and post-operative hoarseness. RESULTS: Thirty-three patients were assessed for eligibility, and 25 patients were included in the study with a median SARI score of 3 (IQR 3-4). Twenty-two (88%, 95% confidence interval [74-100%]) of the patients were successfully intubated by the method with a median time to intubation of 115 s (IQR 78-247). Steering and advancement of the tube were reported as acceptable in 21 (84%) and 22 cases (88%), respectively, and excellent in 10 cases (45%) for both measures. Ten cases (40%) were intubated on the first attempt. There were three cases (12%) of failed intubation; in these cases, successful intubation was obtained by using a styletted tube. CONCLUSION(S): Most patients with anticipated difficult intubation can be successfully intubated with Boedeker intubation forceps and MVL. However, endotracheal tube placement failed in 3/25 patients despite a good laryngeal view.

Should general anaesthesia be avoided in the elderly?

Surgery and anaesthesia exert comparatively greater adverse effects on the elderly than on the younger brain, manifest by the higher prevalence of postoperative delirium and cognitive dysfunction. Postoperative delirium and cognitive dysfunction delay rehabilitation, and are associated with increases in morbidity and mortality among elderly surgical patients. We review the aetiology of postoperative delirium and cognitive dysfunction in the elderly with a particular focus on anaesthesia and sedation, discuss methods of diagnosing and monitoring postoperative cognitive decline, and describe the treatment strategies by which such decline may be prevented.

Challenges in anaesthesia for elderly.

The segment of elderly individuals comprises a growing proportion of the global population. Health care systems and health care providers worldwide need to understand the specific challenges related to treatment of this heterogeneous patient population. The process of ageing is complex and under constant influence by numerous factors, for which reason the way human age is extremely individual. It is important to understand and acknowledge how elderly differ from younger adults, and how management needs to be modified and tailored to the individual patient in order to improve outcomes. The goal of treatment of an elderly patient is not necessarily to increase human longevity regardless of the consequences, but to increase active longevity free from disability and functional dependence. For older people, deterioration in function can be devastating and is often precipitated by a stressful event such as an acute episode of illness or injury. Therefore a mainstay of treatment of the aged is prevention of functional decline. In this review, we will outline the extreme variability in the aging process, and its implications for tailoring the perioperative care for the elderly. We will provide an overview of the challenges, when dealing with the aged surgical population with emphasis on postoperative cognitive changes.

R-CHOEP-14 improves overall survival in young high-risk patients with diffuse large B-cell lymphoma compared with R-CHOP-14. A population-based investigation from the Danish Lymphoma Group.

BACKGROUND: Optimal treatment of young patients with high-risk diffuse large B-cell lymphoma (DLBCL) remains a matter of debate and requires improvement. The combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) with addition of etoposide (CHOEP) has in other patient groups been shown to be effective. Further improvement has been accomplished with the use of rituximab in combination with the regimens every 2 weeks (R-CHOP-14, R-CHOEP-14). The aim of the present retrospective population-based study was to compare R-CHOP-14 with R-CHOEP-14 in a cohort of high-risk patients aged 18-60 years with two or more risk factors (stage III-IV, elevated lactate dehydrogenase levels, performance status 2-4). To our knowledge, this is the first study comparing these two regimens in this patient group. METHODS: We obtained data for the period 2004-2009 from the Danish Lymphoma Database. One hundred and fifty-nine patients were eligible to enter the study. Primary end point was overall survival (OS) and secondary end points were response to treatment, progression-free survival (PFS) and safety. RESULTS: Four-year OS was superior in the R-CHOEP-14 group: 75% compared with 62% for R-CHOP-14 (P=0.04). This superiority was also seen for PFS: 4-year PFS was 70% for the R-CHOEP-14 group compared with 58% for the R-CHOP-14 group (P=0.02). CONCLUSION: R-CHOEP-14 is a promising regimen for young patients with high-risk DLBCL with improved OS and PFS compared with R-CHOP-14.

Preembryonic diagnosis for sickle cell disease.

Embryos found to be abnormal during preimplantation genetic diagnosis are discarded or analyzed to confirm the diagnosis. The destruction of affected embryos is ethically unacceptable to some couples. We developed a preembryonic genetic diagnosis, that uses sequential first and second polar body removal, followed by oocyte freezing at the pronuclear stage. This was applied in a patient at risk of having a child with sickle cell disease, who suffered hyper-stimulation syndrome. Fourteen oocytes were obtained and tested for the maternal sickle cell allele by PCR analysis of the first and second polar body. Immediately after procedure of polar body removal, the pronuclear-stage oocytes were frozen. Six mutation-free oocytes detected by polar body analysis were then thawed, allowed to cleave, and transferred in the two consecutive clinical cycles, both resulting in clinical pregnancies, one of which resulted in birth of a healthy child. The oocytes predicted to contain abnormal beta-globin gene were not further cultured, to avoid formation and discard of the affected embryos. The results demonstrate feasibility of preembryonic diagnosis for single gene disorders, avoiding the establishment and destruction of mutant embryos.

Reliability of preimplantation diagnosis for single gene disorders.

Reliability of preimplantation genetic diagnosis (PGD) depends on controlling one of the most important limitations of single cell PCR, undetected allele drop out (ADO), which may lead to misdiagnosis. To avoid this we introduced mutation analysis simultaneously with linked polymorphic markers, pre-selecting only those embryos whose unaffected status could be confirmed by at least one linked polymorphic marker. We applied this strategy for testing 1047 oocytes, from which 237 unaffected ones were pre-selected for transfer back to patients, resulting in 34 unaffected pregnancies and birth of 23 healthy children. Embryos originating from mutant oocytes and those with insufficient marker information were followed up by multiplex PCR to confirm single cell PCR diagnosis. Of 75 (8.5%) detected ADO, only seven (under 1%) were missed in the actual PGD, demonstrating high reliability of PGD (98%) based on multiplex single cell PCR.

Chromosomal abnormalities in the first and second polar body.

Aneuploidy free oocytes may be pre-selected by testing the first and second polar bodies removed from oocytes following their maturation and fertilization. We present here our experience on the application of the method in IVF cycles from patients of advanced maternal age. Overall, 5590 oocytes were obtained from 917 cycles and tested by polar body sampling and fluorescent in situ hybridization (FISH) analysis using specific probes for chromosomes 13,16,18,21 and 22. FISH results were available in 4599 (82.2%) of 5590 oocytes studied, from which 2077(45.2%) were with aneuploidies. Thirty six point one percent of aneuploidies were of the first meiotic origin, and 29.3% of the second meiotic origin. Most errors in the first meiotic division were represented by chromatid errors. The transfer of embryos deriving from 2014 of 2520 aneuploidy free oocytes in 821 treatment cycles resulted in 182 (22.2%) clinical pregnancies and 140 healthy children born after confirmation of the polar body diagnosis. Polar body testing of oocytes provides an approach for pre-selection of aneuploidy free embryos, improving pregnancy rate in IVF patents of advanced maternal age.

Double-blind, placebo-controlled crossover study of folinic acid (Leucovorin for the treatment of fragile X syndrome.

We conducted a randomized, double-blind, placebo-controlled crossover study of folinic acid therapy (dl-Leucovorin, 15 mg/day) or placebo for males with Fragile X (fra(x)) syndrome. Twenty-one patients were enrolled in the study. The treatment periods were 3 months in length. Patients were followed with chemistry panels and complete blood counts. No differences between placebo and treatment phases were noted in any laboratory parameter. Instruments to measure functioning were the Vineland Adaptive Behavioral Scales, Peabody Picture Vocabulary Test-Revised, Conners Parent and Teaching Rating Scales, the ADD-H: Comprehensive Teacher's Rating Scales (ACTeRS), and a questionnaire designed by the investigators. At the crossover point, 2 parents requested to withdraw from the study because they felt their children had made dramatic gains during the first half of the study and had lost those gains after the crossover point. Both parents had accurately predicted that their sons were receiving folinic acid during the first half of the study. However, no statistically significant differences could be demonstrated between the treatment and placebo phases of the study with any instrument when the results were averaged over the entire cohort. After the conclusion of the study, approximately one-half of the parents believed that their children had benefitted from the folinic acid therapy and elected to continue treatment. Thus far, no significant side effects have been noted from long-term folinic acid therapy so we are offering all Fragile X patients a 3-month trial of medication.

Structure of the type II collagen gene.

In summary, the exon/intron structure of the chicken type II collagen gene is identical with that of the chicken alpha 2(I) collagen gene and differs at only one known position from the human and mouse alpha 1(I) genes. However, the chicken type II gene is different from the chicken alpha 2(I) gene in that it is considerably shorter because of a much smaller average intron size and in that the G+C composition of the introns is much higher. The codon usage of the type II genes also shows characteristic differences. There is a single copy of the chick type II gene per haploid genome.

Chronic vaginal candidiasis responsive to biotin therapy in a carrier of biotinidase deficiency.

BACKGROUND: Many patients experience recurrent or persistent episodes of vaginal candidiasis. Some of these women might be carriers of an inborn error of biotin metabolism (either biotinidase deficiency or holocarboxylase synthetase activity). These women might benefit from administration of pharmacologic amounts of biotin. CASE: A 38-year-old gravida 2, para 2 carrier of biotinidase deficiency presented with a 14-month history of persistent vaginal candidiasis, despite appropriate therapy. After 3 months of pharmacologic doses of biotin, her symptoms resolved completely. CONCLUSION: Given that 1 in every 123 individuals is predicted to be a carrier of biotinidase deficiency, there might be other women with chronic vaginal candidiasis who will respond to biotin administration.

Pediatrician attendance at cesarean delivery: necessary or not?

OBJECTIVE: To determine whether it is necessary for a pediatrician to attend all cesarean deliveries. METHODS: We analyzed a database of 17,867 consecutive deliveries to determine the rates of low Apgar scores in the following three groups of patients: those with vaginal delivery, cesarean delivery using regional anesthesia without fetal indication, and cesarean delivery for fetal indications or using general anesthesia. RESULTS: There was a significantly higher rate of low Apgar scores in the fetal indications or general anesthesia group when compared with vaginal deliveries. Specifically, 35 (5.8%) of 596 cesareans for fetal heart rate abnormality or using general anesthesia had 1-minute Apgars under 4 in contrast to 115 of 10,270 (1.1%) of vaginal deliveries. There was no significantly increased risk for low Apgar scores in the group of cesareans using regional anesthesia for nonfetal indications (33 of 2057, 1.6%). Results were similar for Apgar scores under 7 at 5 minutes. CONCLUSION: Because there is no higher incidence of low Apgar scores in cesarean deliveries using regional anesthesia for nonfetal indications compared with vaginal deliveries, there is no convincing need for pediatrician attendance at such deliveries.

Mode of delivery and risk of respiratory diseases in newborns.

OBJECTIVE: To determine whether there is an increased incidence of persistent pulmonary hypertension in neonates delivered by cesarean, with or without labor, compared with those delivered vaginally. METHODS: We did a computerized retrospective review of 29,669 consecutive deliveries over 7 years (1992-1999). The incidences of persistent pulmonary hypertension of the newborn, transient tachypnea of the newborn, and respiratory distress syndrome (RDS) were tabulated for each delivery mode. Cases of persistent pulmonary hypertension were reviewed individually to determine delivery method and whether labor had occurred. The three groups defined were all cesarean deliveries, all elective cesareans, and all vaginal deliveries. RESULTS: Among 4301 cesareans done, 17 neonates had persistent pulmonary hypertension (four per 1000 live births). Among 1889 elective cesarean deliveries, seven neonates had persistent pulmonary hypertension (3.7 per 1000 live births). Among 21,017 vaginal deliveries, 17 neonates had persistent pulmonary hypertension (0.8 per 1000 live births). chi2 analysis showed an odds ratio 4.6 and P <.001 for comparison of elective cesarean and vaginal delivery for that outcome. CONCLUSION: The incidence of persistent pulmonary hypertension of the newborn was approximately 0.37% among neonates delivered by elective cesarean, almost fivefold higher than those delivered vaginally. The findings have implications for informed consent before cesarean and increased surveillance of neonates after cesarean.

Analgesic efficacy of acetaminophen sustained release.

The analgesic efficacy of acetaminophen sustained release (SR) and acetaminophen immediate plus sustained release (IR + SR) was evaluated in 200 outpatients with pain after oral surgery. Under double-blind conditions SR high dose (2000 mg) or low dose (1000 mg), IR + SR high dose (500 + 1500 mg) or low dose (250 + 750 mg), or acetaminophen standard tablet high dose (1000 mg) or low dose (500 mg) were randomly administered after removal of a lower third molar. The hourly pain intensity was rated on a visual analog scale during 12 hours. The efficacy was based on peak effect (maximum pain intensity difference in percent), pain reduction (mean percentage pain intensity difference), duration of effect (time to remedication) and pain reduction index (pain reduction multiplied by duration of effect). Pain reduction was 37% with the 500-mg tablet and 54% with SR 2000 mg. The peak effect increased from 53% after 1.9 hours for the 500-mg tablet to 67% after 2.6 hours for SR 2000 mg. The SR formulation significantly increased the duration of effect without reduction in peak effect.

Preimplantation testing for phenylketonuria.

OBJECTIVE: To use preimplantation genetic diagnosis to achieve a phenylketonuria-free pregnancy in a couple at 50% risk for producing an affected child. DESIGN: DNA analysis of the first and second polar bodies (PB1 and PB2) obtained from oocytes of a heterozygous mother in IVF-ET, with the goal of identifying and transferring back to the patient the embryos resulting from mutation-free oocytes. SETTING: IVF program of Reproductive Genetics Institute, Chicago, Illinois. PATIENT(S): A mother carrying the R408W mutation and a father with compound heterozygosity for R408 and Y414C mutations in phenylalanine hydroxylase (PAH) gene. INTERVENTION(S): Removal and testing for maternal mutation in PB1 and PB2 from each oocyte after standard IVF. MAIN OUTCOME MEASURE(S): DNA analysis of PB1 and PB2 indicating whether corresponding oocytes were mutation-free, for the purposes of transferring only unaffected embryos resulting from these oocytes. RESULT(S): Of 11 zygotes with both PB1 and PB2, 6 were predicted to be free of phenylketonuria. Of these, 4 were transferred, resulting in an unaffected twin pregnancy and birth of two healthy children. CONCLUSION(S): Preimplantation genetic diagnosis of phenylketonuria resulted in the birth of phenylketonuria-free children. Preimplantation genetic diagnosis by PB analysis in couples with a compound heterozygous male partner is clinically useful.

Birth of healthy children after preimplantation diagnosis of common aneuploidies by polar body fluorescent in situ hybridization analysis. Preimplantation Genetics Group.

OBJECTIVE: To perform preimplantation diagnosis of common aneuploidies by polar body analysis and fluorescent in situ hybridization technique using probes specific for chromosomes X, 18, and 13/21. DESIGN: The first and/or second polar bodies were removed and studied by fluorescent in situ hybridization to detect and avoid fertilization and transfer of oocytes with common aneuploidies. SETTING: The Reproductive Genetics Institute's IVF program at Illinois Masonic Medical Center. PATIENTS: One hundred ninety-three couples of advanced maternal age (34 to 46 years) under-going IVF treatment volunteered to be part of a clinical trial on preimplantation polar body diagnosis of common aneuploidies. INTERVENTIONS: Using micromanipulation procedures, the first and second polar bodies were removed after their extrusion from the oocytes. MAIN OUTCOME MEASURE: Fluorescent in situ hybridization signals specific for chromosomes X, 18, and 13/21. RESULTS: In 235 IVF cycles performed in 193 couples, 1,293 oocytes were biopsied and subjected to fluorescent in situ hybridization analysis, with fluorescent in situ hybridization results available in 993 oocytes (76.8%). Of 993 oocytes with fluorescent in situ hybridization results, 665 (67%) were predicted to be normal based on the chromosomes studied; 460 embryos resulting from these oocytes were transferred in 187 treatment cycles, resulting in 12 births of healthy children and 18 ongoing pregnancies after confirmation of the polar body diagnosis by chorionic villus sampling or amniocentesis. CONCLUSION: Polar body fluorescent in situ hybridization analysis may be used for preimplantation diagnosis of common aneuploidies in IVF patients of advanced maternal age.

Birth of a healthy girl after preimplantation gender determination using a combination of polymerase chain reaction and fluorescent in situ hybridization analysis. Preimplantation Genetics Group.

OBJECTIVE: To perform preimplantation gender determination by a combination of polymerase chain reaction (PCR) sexing and fluorescent in situ hybridization technique using the directly labeled fluorescent alpha-satellite centromeric DNA probes for X and Y chromosomes. SETTING: The IVF program of Illinois Masonic Medical Center. PATIENTS: A couple requested preimplantation diagnosis because the mother is a carrier for hemophilia A. RESULTS: Two blastomeres were aspirated from each of the four- to eight-cell embryos, and only the embryos with both fluorescent in situ hybridization and PCR results indicating female sex chromosomal complement were transferred, resulting in a singleton pregnancy and delivery of a healthy female infant, after prenatal confirmation of the diagnosis as female. The male embryos or embryos diagnosed as females only by PCR were followed up by confirmatory fluorescent in situ hybridization analysis demonstrating a discrepancy of PCR and fluorescent in situ hybridization results in four embryos, presumably because of a possible sperm contamination of the PCR reaction or chromosomal mosaicism. CONCLUSION: The analysis of two blastomeres from the same embryo by a combination of PCR sexing and fluorescent in situ hybridization increases the reliability of preimplantation gender identification at the cleavage stage.