Ketofol dosing simulations for procedural sedation.

BACKGROUND: Propofol mixed with racemic ketamine (or "ketofol") is popular for short procedural sedation and analgesia, yet the optimal combination is unknown. We aimed to determine a ketofol dosing regimen for short procedural sedation and analgesia of 5- to 20-minute duration in healthy patients (2-20 y). METHODS: Pharmacokinetic-pharmacodynamic parameters were used to simulate drug concentration and effect profiles over time for different ketamine-to-propofol ratios (1:1-1:10). The target effect was a Children's Hospital of Wisconsin Sedation Scale score of less than 2. Combined effects were additive, with a propofol EC50 of 1.54 µg/mL (concentration required to produce hypnosis in 50% of patients), a ketamine EC50 of 0.44 µg/mL, and a slope of 5.3. Emergence threshold concentrations for propofol were 2.0 µg/mL in children and 1.8 µg/mL in adults as well as 0.5 µg/mL for ketamine (children and adults). The EC50 for propofol antiemesis was 0.343 µg/mL. RESULTS: A ketamine-to-propofol ratio of 1:3 was the best combination for intermittent dosing, achieving a rapid onset of a Children's Hospital of Wisconsin Sedation Scale score of less than 2 within 1 minute and a time to emergence of 9 to 19 minutes in all ages after a 10-minute sedation. The optimal ketofol dosing in children (2-11 y) was 0.1 mL/kg initially followed by 0.05 mL/kg at 2 minutes and then 0.025 mL/kg for the subsequent doses. The adults (12-20 y) received 0.05 mL/kg of ketofol initially followed by 0.025 mL/kg for the subsequent doses. These regimens maintain a propofol antiemesis for 30 to 40 minutes after the last dose. CONCLUSIONS: We suggest an optimal ratio of racemic ketamine to propofol of 1:3 for boluses during short procedures (5-20 minutes). A short ketofol infusion, ratio 1:4, is a suitable alternative to intermittent boluses. Ratios greater than 1:3 result in delayed recovery after 20 minutes.

Ketofol simulations for dosing in pediatric anesthesia.

BACKGROUND: Propofol mixed with racemic ketamine (or 'ketofol') is popular for short procedural sedation and analgesia. Use is creeping into anesthesia, yet neither the optimal combination nor infusion rate is known. The EC(50) of propofol's antiemetic effect is reported to be 0.343 mg·l(-1), while ketamine analgesia is thought to persist with concentrations above 0.2 mg·l(-1). We aimed to determine a ketofol dosing regimen for anesthesia 30-min and 1.5-h duration in a healthy child that did not unduly compromise recovery. METHODS: Pharmacokinetic-pharmacodynamic parameters were used to simulate drug concentration and effect profiles over time for different ratios of propofol to ketamine ratios (1 : 1 to 10 : 1) and rates. The target effect was the 95% probability of loss of response to a 5-s transcutaneous tetanus (P05). Combined effects were additive, with a propofol EC(50) of 3.1 mg·l(-1), ketamine EC(50) of 0.64 mg·l(-1), and slope of 5.4. The time to predicted 50% probability of return of this response after ceasing infusion (P(50)) was determined for a 5-year-old 20-kg healthy child. RESULTS: The addition of ketamine to propofol infused using a manual infusion regimen (loading dose 3 mg·kg(-1), then 15 mg·kg(-1) ·h(-1) for 15 min, 13 mg·kg(-1) ·h(-1) for 15 min, 11 mg·kg(-1) ·h(-1) for 30 min, and 10 mg·kg(-1) ·h(-1) for 1-2 h) caused prolonged postoperative sedation. The P(50) after a 1.5-h infusion using a 1 : 1 mixture was 4.5 h, 2 : 1 mixture was 3.25 h, 5 : 1 mixture was 1.6 h, and 10 : 1 mixture was 40 min. These P(50) estimates could be reduced by slowing administration infusion rates to 20%, 33%, 50%, 67%, 80%, and 90% for mixtures 1 : 1, 2 : 1, 3 : 1, 5 : 1, 6.7 : 1, and 10 : 1, respectively. These rates achieve a P(50) of approximately 20 min for 30-min duration anesthesia and 60 min for 1.5-h duration anesthesia. CONCLUSIONS: The addition of ketamine to propofol infusion will prolong recovery unless infusion rates are decreased. We suggest an optimal ratio of racemic ketamine to propofol of 1 : 5 for 30-min anesthesia and 1 : 6.7 for 90-min anesthesia. Delivery of these ratios achieves propofol concentrations above an antiemetic threshold for longer than the ketamine concentration above the analgesic threshold during, potentially reducing postoperative nausea incidence.

Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).

OBJECTIVE: To identify genetic causes of COACH syndrome BACKGROUND: COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD). METHODS: In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced. RESULTS: 19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%). CONCLUSIONS: Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.

Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas : frequent alterations in the APC/beta-catenin pathway and chromosome 11p.

Pancreatoblastomas are unusual malignant neoplasms of the pediatric pancreas that may also rarely affect adults. The molecular pathogenesis of pancreatoblastomas is unknown. They are clinicopathologically distinct from adult pancreatic ductal adenocarcinomas, but their occasional occurrence in patients with Beckwith-Wiedemann syndrome and the case presented here of a pancreatoblastoma in an adult patient with familial adenomatous polyposis (FAP) suggests that they might bear a genetic similarity to other infantile embryonal tumors such as hepatoblastomas. We analyzed a series of nine pancreatoblastomas for mutations common to other embryonal malignancies including somatic alterations in the adenomatous polyposis coli (APC)/beta-catenin pathway and chromosome 11p, using immunohistochemistry for beta-catenin, 5q and 11p allelic loss assays, and direct DNA sequencing of exon 3 of the beta-catenin gene and the mutation cluster region of the APC gene. In addition, we analyzed the pancreatoblastomas for alterations found in adult-type pancreatic ductal adenocarcinomas including mutations in the K-ras oncogene and the p53 and DPC4 tumor suppressor genes, using direct DNA sequencing of exon 1 of K-ras and immunohistochemistry for p53 and Dpc4. Allelic loss on chromosome 11p was the most common genetic alteration in pancreatoblastomas, present in 86% (six of seven informative cases). Molecular alterations in the APC/beta-catenin pathway were detected in 67% (six of nine), including five neoplasms with activating mutations of the beta-catenin oncogene and the one FAP-associated tumor with biallelic APC inactivation (germline truncating mutation combined with loss of the wild-type allele); seven neoplasms showed abnormal nuclear accumulation of beta-catenin protein. In contrast, loss of Dpc4 protein expression was present in only two cases (one diffuse and one focal), and no alterations in the K-ras gene or p53 expression were detected. Our findings indicate that pancreatoblastomas are genetically distinct from the more common pancreatic ductal adenocarcinomas, but bear a close molecular pathogenesis to hepatoblastomas. In addition, pancreatoblastoma may represent an extracolonic manifestation of FAP.

Helicobacter pylori and Meckel's diverticula.

BACKGROUND: Helicobacter pylori is known to infect only gastric mucosa and is strongly associated with gastroduodenal ulceration. The authors studied whether H. pylori colonizes the gastric mucosa of Meckel's diverticula, and determined its relationship to "gastritis" and bleeding. METHODS: A 10-year retrospective review identified 45 children with Meckel's diverticulum. Hematoxylin-eosin and Diff-Quik stains were used to assess the presence and severity of gastritis, and to highlight organisms in the resected diverticula. Cases with organisms were then studied with antibodies specific for H. pylori using immunoperoxidase methods. RESULTS: Twenty-eight children, 7 months to 12.6 years of age, had lower gastrointestinal hemorrhage caused by Meckel's diverticulum and had positive radionuclide scans. All had acid-secreting mucosa in their diverticula, and ulceration. "Chronic gastritis" and eosinophilia were constant findings; "acute gastritis" was present in four patients. Twenty specimens exhibited lymphoid follicles in the gastric mucosa. Seventeen patients with Meckel's diverticula (age range, 1 month-14.7 years) who presented with acute abdominal pain associated with intussusception were used for comparison. Acid-secreting gastric mucosa was seen in four patients. H. pylori was identified in only one of the 45 patients; this patient had ulceration and moderate "acute gastritis." CONCLUSIONS: H. pylori does not colonize a substantial number of children who have ulcerated and bleeding Meckel's diverticulum in the presence of acid-secreting mucosa. Although H. pylori is a notable cause of ulceration, the authors confirm that ulceration is possible in its absence, and alternative mechanisms of ulceration are important. The presence of lymphoid follicles in Meckel's diverticula, unlike gastric biopsies, is not associated with H. pylori.

Comparison of multidimensional flow cytometry with standard morphology for evaluation of early marrow response in pediatric acute lymphoblastic leukemia.

PURPOSE: We compared multidimensional flow cytometry (MDF) with morphology in evaluating early marrow response to induction chemotherapy in pediatric ALL. METHODS: Chemotherapy response was determined by standard morphology or by MDF assessed by residual leukemic cell percentage remaining in the marrow on days 7, 14, and 28 of induction. Bone marrow response was classified as M3 (>25% leukemic blasts) or M1/M2 (< or = 25% leukemic blasts). Multidimensional flow cytometry evaluation was compared with that of standard morphology. Available day-7 and day-14 marrow slides were also reevaluated by a single pathologist without patients' clinical information. RESULTS: Of 46 day-7 specimens, eight (17%) had discordant MDF and morphologic results (P < 0.001), including six classified as M3 by morphology but were M1/M2 by MDF, and two were classified as M3 by MDF but were M1/M2 by morphology. Of 24 day-14 bone marrow specimens, five (20.5%) were discordant (P < 0.001), including two classified as M3 by morphology but were M1/M2 by MDF, and three were classified as M3 by MDF but were M1/M2 by morphology. Reevaluation of the blinded day-7 and day-14 marrow slides yielded discordance between repeated pathology readings of 11% (P < 0.001) and 6% (P = 0.04), respectively. CONCLUSION: Our data show significant discordance between the morphologic and MDF evaluation of early marrow response. Early response to therapy is a significant prognostic indicator in pediatric acute lymphoblastic leukemia and is used to alter subsequent treatment; thus, precise assessment of response is important. A larger comparison of MDF with morphology for the evaluation of early response, including correlation with clinical outcome, is warranted.

Hemolytic uremic syndrome associated with Denys-Drash syndrome.

The Denys-Drash syndrome is defined by the occurrence of combinations of pseudohermaphroditism, nephrotic syndrome with diffuse mesangial sclerosis, Wilms' tumor, and constitutional mutations in the WT1 suppressor gene. Most patients develop end-stage renal failure. Atypical hemolytic uremic syndrome (HUS) is defined by onset of acute hemolytic anemia with fragmented erythrocytes, thrombocytopenia, and renal failure in the absence of a gastrointestinal prodromal illness of bloody diarrhea. The purpose of this report is to describe the occurrence of features of atypical HUS and Denys-Drash syndrome in two African-American boys aged 13 and 16 months. Each had nephrotic syndrome, diffuse mesangial sclerosis, and WT1 point mutations. Both had grade III hypospadias and undescended testes. They had normal serum creatinine concentrations and hematology a month before presenting with HUS. Stool cultures for Escherichia coli O157:H7 were negative. Each patient has been transplanted with cadaver kidneys without recurrence of HUS.

IgA plasma cell infiltration of proximal respiratory tract, pancreas, kidney, and coronary artery in acute Kawasaki disease.

The etiology and pathogenesis of Kawasaki disease (KD) remain unknown. As previously reported, in US patients with acute KD, IgA plasma cells (PCs) infiltrate the vascular wall. To determine whether IgA PCs are increased at mucosal sites in KD and to determine whether other nonvascular KD tissues are infiltrated by IgA PCs, the cells were immunolocalized and quantitated in tissue sections taken from 18 US and Japanese patients who died of acute KD and from 10 age-matched controls. IgA PCs were significantly increased in the trachea of patients who died of acute KD, compared with controls (P<.01), a finding that was similar to findings in children with fatal respiratory viral infection. IgA PCs also infiltrated coronary artery, pancreas, and kidney in all KD patients. These findings strongly support entry of the KD etiologic agent through the upper respiratory tract, resulting in an IgA immune response, with systemic spread to vascular tissue, pancreas, and kidney.

Ovarian sarcoma with pathologic features of clear cell sarcoma of the kidney.

We report a case of an unusual sarcoma arising in the ovary of an infant girl. Histologically, the tumor was composed of clear, undifferentiated cells set in an arborizing vascular stroma. Immunohistochemical staining was positive only for vimentin. Ultrastructural evaluation demonstrated undifferentiated cells with interdigitating broad cell processes that encompassed irregular electron lucent spaces that contained flocculent extracellular material. Light and electron microscopic features of the tumor resembled a clear cell sarcoma of the kidney. Although the cell of origin is unproven, both tumors may arise from primitive mesenchymal cells that may not be restricted to the kidney.

Severe type II Gaucher disease with ichthyosis, arthrogryposis and neuronal apoptosis: molecular and pathological analyses.

Severe infantile Gaucher disease associated with ichthyosis and neonatal death is a rare subgroup of Type II Gaucher disease. This group of infants has little, if any, detectable beta-glucocerebrosidase activity, and prior genetic analyses have been limited in detecting the mutations responsible for this phenotype. We document an Hispanic infant succumbing with arthrogryposis and collodion membrane covering the skin who had no detectable beta-glucocerebrosidase activity in tissue samples and who was homozygous for a rare recombinant allele, RecNciI. Microscopic evaluation demonstrated accumulation of Gaucher cells in visceral organs and extensive loss of neurons in the anterior horns, brainstem, and cortex of the nervous system. The apoptosis of neuronal cells from the anterior horns and brainstem are a reasonable explanation for the arthrogryposis and neonatal death, respectively.

Primary follicular lymphoma of the testis in childhood.

BACKGROUND: Follicular lymphoma in childhood is rare. The authors present four unusual primary follicular lymphomas of the testis in children. METHODS: Tumor tissue was evaluated using light microscopy, immunohistochemistry, flow cytometry, and polymerase chain reaction (PCR) for immunoglobulin heavy chain (IgH) and bcl-2 gene rearrangements. Southern blot and immunohistochemical analyses were used to detect bcl-6 gene rearrangements and protein expression, respectively. RESULTS: Four young boys ranging in age from 3 to 10 years were diagnosed with Stage IE follicular large cell lymphoma (Grade 3). A B-cell phenotype was documented in all four cases; monoclonality was confirmed in three cases by demonstration of light chain restriction or clonal IgH gene rearrangement. None of the lymphomas expressed Bcl-2 or p53 protein, and bcl-2 gene rearrangements were not found in the three lymphomas studied. In contrast, Bcl-6 protein was expressed by all three lymphomas studied, and a bcl-6 gene rearrangement was detected in the one case analyzed by Southern blot. All four boys were treated by orchiectomy and combination chemotherapy and are alive with no evidence of disease 18-44 months following their initial diagnoses. CONCLUSIONS: Follicular lymphomas may rarely occur as primary testicular tumors in prepubertal boys and, when localized, appear to be associated with a favorable prognosis. In contrast to follicular lymphoma in adults, pediatric follicular lymphomas of the testis are usually of large cell type (Grade 3) and lack bcl-2 or p53 abnormalities. The identification, in one case, of a bcl-6 gene rearrangement suggests an alternate molecular pathogenesis for pediatric follicular lymphoma.

Recommendations for handling of pediatric liver biopsy specimens.

Pediatric liver disease may require specialized evaluation with abstruse techniques. We present suggestions to permit pathologists who do not work at pediatric referral hospitals to handle liver biopsy specimens from pediatric patients so that information will not be lost.

Langerhans' cell granuloma confined to the bile duct.

Langerhans' cell histiocytosis (LCH) of the liver is uncommon. When seen, it is part of multifocal disease and can present as biliary obstruction. We present a case of sclerosing biliary disease with a solitary LCH lesion and no evidence of systemic disease. We postulate that the LCH is a secondary phenomenon, arising against a background of a complex, familial liver disease. This case also raises the possibility that some instances of idiopathic sclerosing cholangitis may follow cryptic LCH of the bile ducts.

Indolent course of advanced neuroblastoma in children older than 6 years at diagnosis.

BACKGROUND: An early observation suggests that children older than 6 years of age at diagnosis of neuroblastoma constitute a favorable prognostic group. METHODS: Kaplan-Meier plots of survival of all such patients diagnosed at the Children's Hospital of Pittsburgh 1975-1992 were compared with curves of concurrently treated patients with Stage IV disease who were 1-6 years of age at diagnosis ("younger patients"). Known prognostic features, including stage and primary site of disease, pattern of metastases, histopathology, MYCN gene amplification, and urinary catecholamine metabolite ratios, were reviewed. RESULTS: Of 17 children diagnosed after the age of 6 years ("older patients"), 13 patients had Evans' Stage IV disease and 4 had Stage III disease. The median survival was 3.24 years (range, 0.63-15.04 years) for the entire cohort and 3.07 years for those children with Stage IV disease. This compared with a median survival of 1.05 years in 34 concurrent younger patients (P < 0.01). In most cases, disease in these older patients was characterized by a short-lived complete or partial remission followed by aggressive recurrent disease that was partially and only transiently chemo- or radiosensitive. Only 3 patients (2 with Stage IV disease) are in continuous complete remission at 3, 5 10/12, and 14 1/2 years from diagnosis. Although poor prognostic factors were common, including the presence of bony metastases (12/17), biopsy material from pretreatment tumor specimens demonstrated a single MYCN gene copy number in all patients and favorable histology in 15 of 16 samples. CONCLUSION: Older children with neuroblastoma have a more indolent course than do younger patients, a finding that appears to be related to favorable histology and the absence of MYCN amplification. Examination of larger numbers of such patients from cooperative groups should lead to a better understanding of what appears to be a subset of pediatric patients with neuroblastoma who may benefit from specifically tailored treatment protocols.