Higher risk of opioid-induced respiratory depression in children with neurodevelopmental disability: a retrospective cohort study of 12 904 patients.

BACKGROUND: Children with neurodevelopmental disabilities may be at risk of opioid-induced respiratory depression. We aimed to quantify the risks and effectiveness of morphine nurse-controlled analgesia (morphine-NCA) for postoperative pain in children with neurodevelopmental disabilities. METHODS: We carried out a retrospective cohort study of 12 904 children who received postoperative i.v. morphine-NCA. Subjects were divided into a neurodevelopmental disability group and a control group. Rates of clinical satisfaction, respiratory depression, and serious adverse events were obtained, and statistical analysis, including multilevel logistic regression using Bayesian inference, was performed. RESULTS: Of 12 904 patients, 2390 (19%) had neurodevelopmental disabilities. There were 88 instances of respiratory depression and 52 serious adverse events; there were no opioid-related deaths. The cumulative incidence of respiratory depression in the neurodevelopmental disability group was 1.09% vs 0.59% in the control group [odds ratio 1.8 (98% chance that the true odds ratio was >1)]. A significant interaction between postoperative morphine dose and neurodevelopmental disabilities was observed, with higher risk of respiratory depression with increasing dose. Satisfaction with morphine-NCA was very high overall, although children with neurodevelopmental disabilities were 1% more likely to have infusions rated as fair or poor (3.3 vs 2.1%, χ2P<0.001). CONCLUSIONS: Children with neurodevelopmental disabilities were 1.8 times more likely to suffer respiratory depression, absolute risk difference 0.5%; opioid-induced respiratory depression in this group may relate to increased sensitivity to dose-relate respiratory effects of morphine. Morphine-NCA as described was an acceptable technique for children with and without neurodevelopmental disabilities.

The effect of volume of local anesthetic on the anatomic spread of caudal block in children aged 1-7 years.

OBJECTIVES: To examine the anatomic spread of caudal local anesthetic solution in children aged 1-7 years. AIM: To determine whether incremental increases in the volume of caudal injections of 0.5, 0.75, and 1.0 ml·kg(-1) result in reliable (>90%) and potentially clinically significant increases in the number of vertebral segments reached. BACKGROUND: Caudal block is one of the most frequently performed pediatric regional analgesic techniques. Traditional formulae suggest that changes in the volume of caudal injectate in the range 0.5-1.0 ml·kg(-1) would have clinically useful effects. METHODS: In a single blind design, 45 children aged 1-7 years undergoing caudal block received one of the three predetermined volumes (0.5, 0.75, and 1 ml·kg(-1) ) of local anesthetic solution containing radio-opaque contrast under controlled conditions. Following X-ray examination, the anatomic spread of the block was reported by a radiologist blinded to the volume of solution received. RESULTS: There were 15 children in each group, and they were similar in terms of age, height, and weight. Spread was observed between the 5th lumbar (L5) and 12th thoracic (T12) vertebral levels. A volume of 1 ml·kg(-1) results in a small but significantly greater spread of solution than 0.5 ml·kg(-1) (P < 0.05), but there was no difference between 0.5 and 0.75 ml or between 0.75 and 1.0 ml. No volume reliably reached a level higher than the second lumbar vertebra (L2). CONCLUSIONS: Incrementally increasing the volume of injectate between 0.5 and 1.0 results in a modest increase in the spread of the caudal solution. It is unlikely that volumes of <1 ml will reliably reach a vertebral level that is higher than L2.

Clinical signs of infection during continuous postoperative epidural analgesia in children: the value of catheter tip culture.

BACKGROUND: Infection arising from the use of epidural catheters for postoperative analgesia is a major source of anxiety. METHODS: The routine culture of epidural catheter tips were studied in 100 consecutive children aged 1 day to 15 years. Epidural catheters were inserted aseptically in accordance with an agreed protocol. The catheter site was inspected regularly and the tip sent for microbiological culture following removal. RESULTS: Local signs of inflammation at the epidural site were seen in 16% of children, and bacteria were isolated from catheter tip culture in 32%. Positive catheter tip culture was found in 43% of children with local signs of inflammation and of the remaining children with no local signs, organisms were isolated from the catheter tip in 30%. Culture of skin swabs and catheter tips in two patients with purulent discharge at the epidural site yielded the same organism. No correlation between the number of attempts at catheter insertion and either local signs of inflammation or positive catheter tip cultures were found. CONCLUSIONS: Minor local signs of inflammation and infection are common in pediatric patients during continuous epidural infusion. Epidural catheter tips are also frequently culture positive in patients with and without local signs and who may not go on to develop further signs or symptoms of infection. Routine culture of catheter tips is unnecessary as it is not a good predictor of epidural space infection.

Epidural analgesia in children. A survey of current opinions and practices amongst UK paediatric anaesthetists.

BACKGROUND: Despite the widespread use of epidural analgesia in children its place in paediatric pain management has not been clearly established. In order to investigate the current practice of paediatric epidural analgesia in the UK paediatric anaesthetists and paediatric pain management teams were surveyed. METHODS: Questionnaires were sent to the members of the Association of Paediatric Anaesthetists (APA) working within the UK and to lead clinicians and clinical nurse specialists for acute pain in the 26 designated major paediatric centres. RESULTS: The response rate was 72%. There was little consensus regarding drugs and drug combinations used for epidural analgesia. A total of 36% of paediatric centres did not audit their epidural practice, and of those that did the reported incidences of side-effects showed wide variation. Important differences in practice were also identified in the areas of patient selection, informed consent, the use of epidural test doses, drug delivery systems, monitoring and the management of side-effects. Twelve per cent of specialist paediatric hospitals did not have an acute pain team and elsewhere the provision was often limited to staff with few or no specialist skills. CONCLUSION: There is wide variation in the practice of paediatric epidural analgesia in the UK. Inconsistencies are likely to be related to the poor evidence base available to guide clinical decision making and the lack of a specialized paediatric acute pain service in some centres. More research is required to determine the optimal management of epidural analgesia, and suitable clinical support for paediatric pain control should be more widely available.

Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability.

BACKGROUND: Codeine analgesia is wholly or mostly due to its metabolism to morphine by the cytochrome P450 enzyme CYP2D6, which shows significant genetic variation in activity. The aims of this study were to investigate genotype, phenotype and morphine production from codeine in children undergoing adenotonsillectomy, and to compare analgesia from codeine or morphine combined with diclofenac. METHODS: Ninety-six children received either codeine 1.5 mg kg(-1) or morphine 0.15 mg kg(-1) in a randomized, double-blind design. Genetic analysis was performed and plasma morphine concentrations at 1 h were determined. Postoperative analgesia and side-effects were recorded. RESULTS: Forty-seven per cent of children had genotypes associated with reduced enzyme activity. Mean (SD) morphine concentrations were significantly lower (P<0.001) after codeine [4.5 (0.3) ng ml(-1)] than after morphine [24.7 (1.5) ng ml(-1)], and morphine and its metabolites were not detected in 36% of children given codeine. There was a significant relationship between phenotype and plasma morphine (P=0.02). More children required rescue analgesia after codeine at both 2 (P<0.05) and 4 h after administration (P<0.01). Fifty-six per cent of children vomited after morphine and 29% after codeine (P<0.01). Neither phenotype nor morphine concentration was correlated with either pain score or the need for rescue analgesia (r=-0.21, 95% confidence interval -0.4, -0.01). CONCLUSIONS: Reduced ability for codeine metabolism may be more common than previously reported. Plasma morphine concentration 1 h after codeine is very low, and related to phenotype. Codeine analgesia is less reliable than morphine, but was not well correlated with either phenotype or plasma morphine in this study.

Inflammatory pain and hypersensitivity are selectively reversed by epidural bupivacaine and are developmentally regulated.

BACKGROUND: Low doses of local anesthetics applied to the young rat spinal cord in vitro have been shown to inhibit C-fiber-evoked responses. The aim of this work was to investigate whether such low doses applied epidurally selectively reduce nociceptive responses in vivo and to investigate the influence of postnatal development on such local anesthetic actions. METHODS: Three groups of rat pups aged 3, 10, and 21 days were studied. The threshold of the flexion withdrawal reflex to mechanical stimulation was determined in the hind limb at each age. Inflammatory pain was induced in the right hind limb with 2% carrageenan, causing a reduction in the sensory threshold on that side. The difference in threshold between the two sides represents inflammatory hypersensitivity. The effect of low-dose epidural bupivacaine on sensory thresholds and thus the induced hypersensitivity was also determined for each age group. RESULTS: Inflammatory hypersensitivity was selectively attenuated by very low doses of bupivacaine (concentration range. 0.004-0.0625%), which did not affect the sensory threshold in the contralateral uninflamed limb. This effect was also age-related, with younger rats being more sensitive than older rats. CONCLUSIONS: The effects of epidural bupivacaine in the infant rat are developmentally regulated. Lower doses have a selective analgesic effect that decreases with increasing postnatal age.

Mediastinal mass obscured by a large pericardial effusion in a child: a potential cause of serious anaesthetic morbidity.

Anaesthesia in the presence of a mediastinal mass is known to be hazardous. We report a case of a 5-year-old boy with a presumed postviral pericardial effusion presenting for pericardiocentesis under general anaesthesia. Cardiorespiratory collapse following induction of anaesthesia occurred due to an undiagnosed mediastinal tumour. The reasons for misdiagnosis, mechanisms for perioperative complications and optimal management are discussed. Mediastinal masses and underlying malignancy should always be considered in patients with large pericardial effusions.

Parental opinions regarding the route of administration of analgesic medication in children.

Parents were asked about the acceptability of different routes of administration of analgesia for their children. Their opinions were also sought regarding the need for consent and of the sources and quality of information provided to them perioperatively. Questionnaires before and after surgery were administered to 150 consecutively recruited parents. The majority (58%) of parents considered the rectal route to be the most unpleasant way of giving medication, compared to 19% for intramuscular and 11% and 9% for intravenous and oral, respectively. Over 70% thought additional consent, either verbal or written, is not necessary for administering medication by any route. The best information was received verbally in the opinion of 90%. Contrary to expectations, the rectal route was the most unpopular of all in this study. Parents' limited knowledge and experience may be important determining factors. Despite their negative opinions, parents did not consider separate consent necessary for the rectal or any other route.

RAP1 controls rhoptry targeting of RAP2 in the malaria parasite Plasmodium falciparum.

Rhoptry associated protein 1 (RAP1) and 2 (RAP2), together with a poorly described third protein RAP3, form the low molecular weight complex within the rhoptries of Plasmodium falciparum. These proteins are thought to play a role in erythrocyte invasion by the extracellular merozoite and are important vaccine candidates. We used gene-targeting technology in P.falciparum blood-stage parasites to disrupt the RAP1 gene, producing parasites that express severely truncated forms of RAP1. Immunoprecipitation experiments suggest that truncated RAP1 species did not complex with RAP2 and RAP3. Consistent with this were the distinct subcellular localizations of RAP1 and 2 in disrupted RAP1 parasites, where RAP2 does not traffic to the rhoptries but is instead located in a compartment that appears related to the lumen of the endoplasmic reticulum. These results suggest that RAP1 is required to localize RAP2 to the rhoptries, supporting the hypothesis that rhoptry biogenesis is dependent in part on the secretory pathway in the parasite. The observation that apparently host-protective merozoite antigens are not essential for efficient erythrocyte invasion has important implications for vaccine design.

Direct MR arthrography of the shoulder: is exercise prior to imaging beneficial or detrimental?

PURPOSE: To define the beneficial and detrimental effects of adding exercise to direct magnetic resonance (MR) shoulder arthrography. MATERIALS AND METHODS: Direct, intraarticular, gadolinium arthrography of the shoulder was performed in 41 patients, who underwent 1.5-T MR imaging before and after 1 minute of arm swinging. Fourteen milliliters of dilute gadolinium solution was injected. Two readers blinded to exercise independently graded the randomly distributed images with a five-point scale for capsular contrast material resorption; extraarticular contrast material leakage; rotator cuff, glenoid labrum, and anterior capsule conspicuity; and partial-thickness or full-thickness rotator cuff tear and labral tear detectability. The sign test was performed to evaluate the significance of differences between preexercise and postexercise grading for each reader. A second review was performed, with direct side-by-side comparison of preexercise and postexercise images. RESULTS: There was evidence of increased capsular resorption after exercise but no alteration in the depiction of the rotator cuff tendons or glenoid labrum. There was no significant extraarticular contrast material leakage after exercise and no alteration in depiction of the anterior capsule. There was no difference in the detectability of rotator cuff or labral tears. CONCLUSION: Exercise with direct shoulder MR arthrography has no beneficial or detrimental effect on image quality or on the depiction of rotator cuff or labral tears.

Paediatric lumbar epidurals: a comparison of 21-G and 23-G catheters in patients weighing less than 10 kg.

Using the database of our pain management team, we examined the records of 254 patients weighing between 4.5 kg and 10 kg who received an epidural for postoperative analgesia. We looked at the incidence of catheter related problems in two groups of patients in whom either a 21-G (18-G short Tuohy needle) or a 23-G catheter (19-G short Tuohy needle) was used. There was a significantly higher incidence of difficulty in threading the catheter, kinking and occlusion in the 23-G catheter group. There were more leaks in the 21-G catheter group but the difference was not significant and both groups had a comparable incidence of clinically relevant leakages. No dural tap or difficulty in using either needle were reported.

Influence of ethnic background on clinical and serologic features in patients with systemic sclerosis and anti-DNA topoisomerase I antibody.

OBJECTIVE: To investigate the effect of ethnicity on clinical and serologic expression in patients with systemic sclerosis (SSc) and anti-DNA topoisomerase I (anti-topo I) antibody. METHODS: Clinical and serologic features, as well as HLA class II allele frequencies, were compared among 47 North American white, 15 North American black, 43 Japanese, and 12 Choctaw Native American SSc patients with anti-topo I antibody. RESULTS: The frequency of progressive pulmonary interstitial fibrosis was lower, and cumulative survival rates were better in white compared with black and Japanese patients. Sera of white and black patients frequently recognized the portion adjacent to the carboxyl terminus of topo I, sera of Japanese patients preferentially recognized the portion adjacent to the amino terminus of topo I, and sera of Choctaw patients recognized both portions of topo I. Anti-RNA polymerase II and anti-SSA/Ro antibodies were present together with anti-topo I antibody more frequently in sera of Japanese patients than in sera of white patients. The HLA-DRB1 alleles associated with anti-topo I antibody differed; i.e., DRB1*1101-*1104 in whites and blacks, DRB1*1502 in Japanese, and DRB1*1602 in Choctaws. Multivariate analysis showed that ethnic background was an independent determinant affecting development of severe lung disease as well as survival. CONCLUSION: Clinical and serologic features in SSc patients were strongly influenced by ethnic background. The variability of disease expression in the 4 ethnic groups suggests that multiple factors linked to ethnicity, including genetic and environmental factors, modulate clinical manifestations, disease course, and autoantibody status in SSc.

Association of microsatellite markers near the fibrillin 1 gene on human chromosome 15q with scleroderma in a Native American population.

OBJECTIVE: To localize disease genes for scleroderma, or systemic sclerosis (SSc), in a population of Choctaw Native Americans with a high prevalence of SSc, in which there is evidence of a possible founder effect. METHODS: A candidate gene approach was used in which microsatellite alleles on human chromosomes 15q and 2q, homologous to the murine tight skin 1 (tsk1) and tsk2 loci, respectively, were analyzed in Choctaw SSc cases and race-matched normal controls for possible disease association. Genotyping first-degree relatives of the cases identified potential disease haplotypes, and haplotype frequencies were obtained by expectation-maximization and maximum-likelihood estimation methods. Simultaneously, the ancestral origins of contemporary Choctaw SSc cases were ascertained using census and historical records. RESULTS: A multilocus 2-cM haplotype was identified on human chromosome 15q homologous to the murine tsk1 region, which showed a significantly increased frequency in SSc cases compared with controls. This haplotype contains 2 intragenic markers for the fibrillin 1 (FBN1) gene. Genealogical studies demonstrated that the SSc cases were distantly related, and their ancestry could be traced back to 5 founding families in the mid-eighteenth century. The probability that the SSc cases share this haplotype due to familial aggregation effects alone was calculated and found to be very low. There was no evidence of any microsatellite allele disturbances on chromosome 2q in the region homologous to the tsk2 locus or the region containing the interleukin-1 family. CONCLUSION: A 2-cM haplotype on chromosome 15q that contains FBN1 is associated with scleroderma in Choctaw Native Americans from Oklahoma. This haplotype may have been inherited from common founders about 10 generations ago and may contribute to the high prevalence of SSc that is now seen.

A study of antibody and T cell recognition of rhoptry-associated protein-1 (RAP-1) and RAP-2 recombinant proteins and peptides of Plasmodium falciparum in migrants and residents of the state of Rondonia, Brazil.

Humoral and cellular responses were examined among natives and migrants in an area of the Amazon region of Brazil. Rhoptry-associated protein-1 (RAP-1) and RAP-2 expressed in Escherichia coli expression systems, a peptide corresponding to the epitope bound by inhibitory anti-RAP-1 antibodies, and four other RAP-1 and RAP-2 synthetic peptides were used in these studies. Plasma from the native population had greater IgG reactivity to the N-terminal third of RAP-1 than the migrant population; both populations had low levels of IgM to this region of RAP-1. The IgG reactivity to RAP-2 and to the C-terminal third of RAP-1, as well as for all the peptides, including the peptide from the inhibitory domain, were low or absent in both populations. In contrast, there were a high number of subjects with an IgM response to the peptides. Cellular responses were measured by proliferation of peripheral blood mononuclear cells (PBMC) and, in some subjects, by reverse transcription-polymerase chain reaction for interleukin-2 (IL-2), interferon-gamma (IFN-gamma), IL-4, and IL-10. Proliferation of PBMC was low when stimulated by recombinant proteins, peptides, or parasite lysate. Both RAP-1 and RAP-2 stimulated cytokine production by donor T cells; IL-2, IL-4, and IFN-gamma RNA transcripts were observed in response to recombinant proteins and parasite lysate, but with no uniform trends. From the observed antibody responses, RAP-1 appears to be more immunogenic than RAP-2.

Analysis of the processing of Plasmodium falciparum rhoptry-associated protein 1 and localization of Pr86 to schizont rhoptries and p67 to free merozoites.

The processing and localization of Plasmodium falciparum rhoptry-associated protein 1 (RAP-1) products were examined using polyclonal and monoclonal antibodies raised to a recombinant protein containing residues 1-294 of RAP-1. Immunoblot and epitope mapping results with antibodies that selectively bound epitopes in the RAP-1 products Pr86, p82, and p67 showed that p82 and p67 are formed from Pr86 by progressive removal of epitopes from the amino-terminus of the RAP-1 coding sequence. The capacity of Pr86 to form complexes was revealed after size fractionation of parasite proteins radiolabeled in the presence of brefeldin A to prevent processing of Pr86. Fractions containing complexed Pr86 also contained the RAP-2 product p39 and the RAP-3 product p37, suggesting that Pr86, p39 and p37 may form complexes similar to complexes previously reported for p82 and p67 with p39 or p37. Immunofluorescence localization and immunoblot studies revealed that Pr86 is present in the rhoptries, but only transiently, and that it is not detected in segmenting schizonts or extracellular merozoites. p67 and p82, on the other hand, were shown to be major RAP-1 components in purified merozoites. Neither p67 nor p82 were relocalized from the intracellular rhoptries to the merozoite surface under conditions that promoted relocalization of the rhoptry protein PF83/apical membrane antigen 1. These results suggest that processing of Pr86 begins after Pr86 complexes are transported to the forming rhoptries and that two site-selective processing reactions occur in the rhoptries, a rapid cleavage of Pr86 to p82 and a delayed cleavage of p82 to p67. Since p67 is missing from ring-stage parasites (Howard et al., Am J Trop Med Hyg, 1984;33:1055 59), the present results indicate there is a narrow time during which p67 may play a role in merozoite invasion of erythrocytes.

Analysis of inhibitory epitopes in the Plasmodium falciparum rhoptry protein RAP-1 including identification of a second inhibitory epitope.

Immune responses to Plasmodium falciparum rhoptry-associated protein 1 (RAP-1), RAP-2, and RAP-3 appear to contribute to protection against infection by this human malarial parasite. This conclusion is suggested by results of monkey immunization trials and of cell culture studies showing antibody-dependent inhibition of erythrocyte invasion. In the present study, splenectomized owl monkeys were infected with P. falciparum in order to monitor anti-RAP-1 antibody production as antiparasite immunity developed. The monkeys responded to a primary infection with the production of antibodies to a fragment of RAP-1 containing amino acids 1 to 294 (RAP-1(1-294)). After drug cure and reinfection, the monkeys had a prolonged prepatent period, indicating they had already developed partial immunity to the parasite. Sera from these animals showed major increases in anti-RAP-1(1-294) antibodies. In contrast, only low levels of antibodies to inhibitory B-cell epitope 1 (iB-1), an inhibitory epitope in RAP-1(1-294) with the sequence N200TLTPLEELYPT211, was observed after the initial parasite infection, and the anti-iB-1 antibodies were not readily boosted upon reinfection. These results suggest that iB-1 is an immunogenic but not immunodominant epitope and that anti-iB-1 antibodies do not substantially contribute to early stages of naturally acquired immunity in the owl monkey model. To identify additional epitopes bound by inhibitory antibodies, mouse monoclonal antibodies were produced with a recombinant fusion protein containing RAP-1(1-294). Monoclonal antibody 1D6 inhibited parasite invasion of erythrocytes in vitro. 1D6 did not bind peptide iB-1 but rather bound a second inhibitory epitope called iB-2. iB-2, like iB-1, is found near the amino terminus of p67, a RAP-1 processing product thought to be involved in merozoite invasion of erythrocytes. Since anti-iB-1 antibodies were not readily produced during parasite infection, it may be desirable to direct antibody responses to particular epitopes in RAP-1, such as iB-1 and iB-2.

Biomechanical analysis of four-strand extensor tendon repair techniques.

Experience with flexor tendon repairs has suggested the superiority of the augmented Becker (MGH) technique for strength, toughness, and gap resistance. In an effort to apply these findings to the extensor tendons, 3 four-strand extensor tendon repair techniques were biomechanically tested in fresh human cadaver limbs: modified Bunnell, modified Krackow-Thomas, and MGH. Repairs were performed in Verdan's zone VI. Repaired tendons were distracted at constant speed until rupture. Tendon load and tendon distraction were continuously monitored. Benchmark values for load were measured as fingers were pulled from full metacarpophalangeal (MP) joint flexion to full extension, to 1-mm gap formation at the tenorrhaphy, and to complete rupture of the repair. The MGH repair proved significantly more resistant to gap formation (stronger and tougher) than the Bunnell and Krackow-Thomas repairs (p < .02). No differences were seen between groups in repair performance at MP joint extension and at complete rupture. This study suggests that the MGH technique has superior gap resistance to the other four-strand methods tested for extensor tendon repair in Verdan's zone VI. The MGH repair is recommended for extensor tendon repairs in zone VI when early postoperative motion regimens are considered.