Nephrotoxicity of cis-platin comparing young and adult rats

The effect of Cis-platin on the glomerular filtration rate and effective renal plasma flow was determined using a radioisotope clearance technique in young (3 wk old) and adult (more than 12 wk old) rats. Cis-platin was administered intravenously in dosages ranging from 2.5 to 10 mg/kg body weight, either as a single dose or fractionated over 5 consecutive days. Following either dose regimen, identical total doses of Cis-platin caused less severe nephrotoxicity in young rats than in adult ones. In adult rats fractionated dosage significantly reduced nephrotoxicity. This was not observed in young rats. The difference in nephrotoxicity between young and adult rats was due to the renal handling of Cis-platin. After a single dose of 5 and 7.5 mg/kg body weight, platinum concentrations were measured in urine and renal tissue. During the first 2 days after Cis-platin administration, up to 60% of the amount of platinum injected was excreted in the urine of both age groups. There was a marked difference, however, in renal platinum concentration between the two groups. In young rats renal platinum concentration was only 63 and 49% of that in adult rats after 5 and 7.5 mg/kg body weight, respectively. We believe that this is due to the comparatively larger renal mass in relation to body weight in the young animals. Relatively more renal tissue provides at least partial protection against nephrotoxic drugs in these young rats.     

Temozolomide and oral VP-16 for children and young adults with recurrent or treatment-induced malignant gliomas

BACKGROUND: Children and young adults with recurrent or treatment-induced malignant gliomas have limited responses to temozolomide or oral VP-16 when either is administered as a single agent. We postulated that a combination of these two drugs for patients with recurrent or treatment-induced malignant gliomas might result in better and more prolonged responses. A retrospective analysis was performed on patients treated with the combination of temozolomide and VP-16. PROCEDURE: Eleven patients with recurrent or treatment-induced malignant gliomas were treated with varying combinations of temozolomide (150-210 mg/m2/d for 5 days) and oral VP-16 (50 mg/m2/d for 4-12 days). Responses were assessed by MRI scan, and data on clinical course and toxicity were retrospectively obtained from the medical record. RESULTS: The median age of the 11 patients was 17 years (range 5-23 years). Diagnoses included recurrent brain stem glioma (2), recurrent anaplastic astrocytoma (2), and glioblastoma (7) (3 treatment-induced, 2 malignant transformations of lower grade tumors, 1 recurrence, and 1 second tumor arising 10 months after diagnosis of medulloblastoma). All 11 patients had received radiotherapy (including 4 who received craniospinal radiation), and 7 had prior chemotherapy. Nine patients were treated at first recurrence, two at second recurrence. One patient had a complete response (CR), six had partial responses (PR), and four had progressive disease (PD). The median progression-free survival for the seven responding patients was 6 months (range 4-15+ months). There was one grade 4 neutropenia, but no other grade 3 or 4 toxicities. CONCLUSIONS: These data suggest there is activity of temozolomide in combination with oral VP-16 for children and young adults with recurrent malignant gliomas.     

Effects of oral glutamine supplementation on children with solid tumors receiving chemotherapy

In recent years, there have been reports that glutamine support improves immune functions in adult patients with malignancy, but there is a lack of data in children. Oral glutamine support of 4 g/m²/day was given to 21 children with various solid tumors, aged 1-17 years (9.86 ± 5.38) for all 5 days of a chemotherapy course. The same parameters in another course of the same protocol without glutamine supplementation were considered as controls. There were significant improvements of some nutritional and immunological parameters in the glutamine-supplemented course. Also glutamine seemed to reduce antibiotic necessity. Oral glutamine supplementation could be considered in children with solid tumors receiving chemotherapy.     

5-HT3 antagonist ondansetron--an effective outpatient antiemetic in cancer treatment.

Thirty children aged 2-16 years with malignant tumours who were receiving chemotherapy were treated with the 5-HT3 antagonist ondansetron. Each received a single intravenous dose (5 mg/m2) followed by oral doses (2-4 mg depending on surface area) every eight hours for five days. Chemotherapy regimens comprised: carboplatin alone, carboplatin plus etoposide, cisplatin plus etoposide; adriamycin (doxorubicin) plus cyclophosphamide, or ifosfamide. Twelve patients received ondansetron with their first course of chemotherapy and the other patients were poor responders to previous antiemetic treatment. Efficacy was assessed by a questionnaire documenting the incidence of vomiting and severity of nausea. In a 24 hour period after starting chemotherapy a complete or major response (less than two vomiting episodes) was achieved in 87% of children. Although ondansetron was effective for early antiemesis after cisplatin or ifosfamide, delayed vomiting, retching, or nausea reduced responses to 50% and 20%, respectively. We conclude that in children ondansetron is an effective, well tolerated, oral antiemetic enabling simple administration in the outpatient setting. In the present schedule it was of limited efficacy against cisplatin or ifosfamide induced emesis.     

Electrocardiographic findings after 5-HT3 receptor antagonists and chemotherapy in children with cancer

BACKGROUND: The antiemetic efficacy of serotonin-type 3 (5-HT3) receptor antagonists has been found to be superior to older antiemetic drugs in cancer patients. Following the administration of these agents, changes in ECG parameters and increased or decreased heart rates have been demonstrated, but there is no sufficient data in children with cancer who are treated with cytotoxic agents. The objective of this study is to evaluate the ECG changes after administration of 5-HT3 receptor antagonists and chemotherapeutic agents in children with cancer. PROCEDURE: Thirty-eight patients with an age range between 2 and 19 years receiving chemotherapy for solid tumors were included in the study. The patients received 5-HT3 receptor antagonists 30 min before antineoplastic agents in 83 chemotherapy days. Antiemetic therapy consisted of ondansetron in 43 and granisetron in 40 chemotherapy days. Twelve-leads ECGs were obtained four times at the first day of each chemotherapy: just before 30, 90 min, and 24 hr after 5-HT3 receptor antagonists were given. Rate, rhythm, PR interval, QRS duration, ST segment, the shortest (QTca) and the longest (QTcb) QTc intervals with QTc dispersion (QTcd) were all evaluated. RESULTS: We found a significant shortening of the PR interval and QRS complex durations in the granisetron group at 90th min and at 24th hr, respectively. Also, granisetron infusion caused a significant prolongation of the QTca interval at 90 min. CONCLUSION: Although we observed minor ECG changes after 5-HT3 receptor antagonists and chemotherapy, neither dangerous rhythm disturbances nor serious ECG changes were seen.     

Tropisetron in the prevention of nausea and vomiting in 131 children receiving cytotoxic chemotherapy

Tropisetron (Navoban®, Sandoz Pharma Ltd., Basel, Switzerland), a selective antagonist of the serotonin receptor (5-HT3) dosed once-daily at 0.2 mg/kg (with a maximum of 5 mg daily), was evaluated in the prevention of chemotherapy-induced nausea and vomiting in 131 children with a median age of 5 years (age 10 weeks to 21 years). Acute lymphocytic leukemia was the most common malignancy (49%). Most children (82%) had received cytotoxic chemotherapy before enrollment. Patients received tropisetron during one or more courses of chemotherapy (455 courses in total). Tropisetron was administered slowly intravenously as a single dose before the start of chemotherapy on day 1 and intravenously or by mouth the subsequent days as a single daily dose (median treatment duration: 5 days). Response to tropisetron per 24 hour period on the first 5 days of each chemotherapy course was graded as complete (absence of both nausea and vomiting), partial (one to four vomits and/or less than 5 hours of nausea), or failure. Overall complete response on day 1 was observed in 305 out of 455 chemotherapy courses (67%). The patients receiving intravenous chemotherapy (N = 92) had a 70% complete response rate and a 26% partial response rate on day 1, both for course 1 and course 2. The percentage of complete responders increased the subsequent days of the course. Emesis after day 1 was observed primarily during courses with the most emetogenic chemotherapy. No side-effects of tropisetron other than a single case of diarrhoea were documented in this study. © 1995 Wiley-Liss, Inc.     

Treatment of urinary tract infections in children with a single daily dose of gentamicin

21 children with recurrent urinary tract infections (UTI) due to bacteria resistant to the usual antiinfectious drugs were examined to evaluate whether their UTI could be effectively treated with a single daily administration of gentamicin (2.5 mg/kg i.m.) for ten days. From the data obtained it may be concluded that such a scheme of therapy is effective in all cases as far as urine sterilization is concerned during therapy, regardless of the site of infection. However, urine culture controls, 10 and 30 days after therapy was discontinued, showed a further infection in 3 out of 7 children with upper UTI, Since in urine of all our patients the antibiotic level was well above the minimal inhibitory concentration for the infective bacteria, the different therapeutic response could be related to an inadequate antibiotic concentration at the renal interstitial site.     

Temozolomide in resistant or relapsed pediatric solid tumors

PURPOSE: We report the off-label study aimed at investigating the use of temozolomide (TMZ) as single agent in relapsed or resistant pediatric solid tumors. The drug was administered at the dose of 215 mg/m2/day x 5 days or 180 mg/m2/day x 5 days in patients with prior craniospinal irradiation (CSI) or autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Fifty two patients, median age 127.6 months, with resistant or relapsed solid tumors were enrolled. Tumor types were: neuroblastoma (NB; n = 17), medulloblastoma (MB; 8), brain stem glioma (BSG; 8), extraosseous Ewing's sarcoma/peripheral neuroectodermal tumor (EOES; 4), Ewing's sarcoma (ES; 4), anaplastic astrocytoma (AA; 3), rhabdomyosarcoma (RMS; 2), ependymoma (EP; 2), cerebral primitive neuroectodermal tumor (cPNET; 2), hepatocarcinoma (HC; 1), and osteosarcoma (OS; 1). All patients were pre-treated. Two outpatient courses were administered, with a median of 4.8 courses/pt. RESULTS: Objective response-rate (CR + PR + MR) in our series was 13.4% (1.9% CR, 3.8% PR, and 7.7% MR), SD occurred in 38.4% of patients and 48% had PD. The median survival was 7.8 months (range 1-37) and median time to progression was 3.4 months (range 1-20); these data were significantly correlated with histology and previous nitrosureas administration in multivariate analysis. Haematological toxicity grade 3-4 (mainly thrombocytopenia) was observed in 21.4% of administered courses, nausea was reported in 3.1% and respiratory distress in 0.7%. CONCLUSION: Oral TMZ was well tolerated in children with resistant or relapsed solid tumors and showed activity in NB and CNS tumours refractory to standard chemotherapy.     

Pharmacologic probing of renal development in the neonatal rat

This study was designed to examine the ontogeny of renal functions in the neonatal rat using various pharmacologic agents as probes. The renal responses of 2-, 6-, and 10-day-old rats to diuretic agents known to act on proximal tubules, loops of Henle and distal tubules were assessed. These included acetazolamide, furosemide, mercaptomerin, chlorothiazide and amiloride. Following administration of a diuretic agent, urine was collected at 90-min intervals for 6 h and urine volume, osmolality, chloride and pH were measured. Acetazolamide, furosemide, chlorothiazide and amiloride induced diuresis at each age indicating that the respective reabsorptive mechanisms were present and functional by 2 days of age. At all ages furosemide evoked a maximal response in eliminating the interstitial fluid gradient as indicated by the formation of an isosmotic urine in treated pups. However, the volume of the diuresis at 2 days of age was half those at 6 and 10 days, reflecting enhanced activity of the countercurrent multiplication apparatus in the maturing pups. Administration of mercaptomerin did not produce pharmacologic diuresis, but rather resulted in acute renal failure; although the nephrotoxicity was to a lesser extent in 2-day-old pups. The ability of the neonatal rat to respond to these pharmacologic probes demonstrates that the integrity of these renal functions is established in this species early in postnatal life.     

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目的探索用联合大剂量免疫抑制剂进行强免疫清除,但保留骨髓造血功能而无需造血干细胞移植(SCT)的方法,治疗儿童难治性系统性红斑狼疮(SLE)的疗效。方法2004-08—2005-04对中山大学附属第一医院儿科收治的难治性SLE5例进行二种方案的疗效分析。5例均有肾损害,其中4例肾病理WHO-Ⅳ型和大量蛋白尿,2例免疫性溶血性贫血,1例免疫性血小板减少,均曾用包括环磷酰胺(CTX)和甲基泼尼松龙双冲击等治疗无效或病情反复无法控制。4例给予方案1治疗,另1例因严重水肿和尿少不宜用大剂量CTX,给予方案2治疗。疗效用SLE疾病活动性指数记分(SLEDAI)评估。结果方案1从CTX结束算起,中性粒细胞恢复到0.5×109/L平均需10d,方案2从Ara-C结束起,中性粒细胞恢复到0.5×109/L需16d;治疗3周时SLEDAI平均从9.2降至4.4,尿蛋白从(++++)降至(0～+),合并有重度难治性贫血或血小板减少者,治疗后血红蛋白或血小板分别恢复正常或接近正常;方案2治疗的1例由于肾血管血栓形成未能控制,病情短暂好转后再度恶化,1个月后死于DIC和肾功能衰竭;另4例随访5～16个月,病情基本控制。结论控制在一定范围内的大剂量免疫抑制剂治疗SLE,无需SCT而能恢复自身造血,同时能相当大程度清除病态免疫系统,使常规治疗无效者病情缓解,值得进一步探索。     

Acute myelogenous leukemia in children: a preliminary report of combination chemotherapy.

Twenty-four children (2 to 21 years) diagnosed as having AML from 1969 to 1972 were randomized to receive either a single combination (COMP or PRAVD) or sequential combination chemotherapy (alternating POMP and PRAVD). Seventeen achieved complete remission. Patients who received POMP alone had the longest median duration of remission (1,400 days) compared to PRAVD (395 days) or POMP-PRAVD (270 days); interpretation of this difference is uncertain, since the numbers in each group are small. Fifteen patients have relapsed, four initially with CNS involvement. Successful reinduction was achieved almost exclusively for patients who had initially received POMP. Survival after first relapse was short. Patients less than 16 years had a median survival of 632 days, compared to 285 days for patiens greater than 16 (p less than 0.05). The high initial induction rate in these patients is encouraging, but the duration remission is inferior to that seen in childhood ALL. Moreover, the slope of the relapse curve is continuous over a five-year period with no definite plateau where it might appear that patients are no longer at risk of relapse. Improved methods for the treatment of childhood ALL and adult AML suggest possible new approaches to AML in children, with prophylactic treatment of central nervous system, late intensification, and immunotherapy.     

Oral topotecan for refractory and relapsed neuroblastoma: a retrospective analysis

PURPOSE: Among patients with multiply relapsed neuroblastoma refractory to conventional chemotherapy, oral topotecan has often been used for palliation. Although toxicity was generally thought to be mild, the efficacy of such an approach remains unproven. METHODS: The authors retrospectively analyzed patients with multiply relapsed or refractory neuroblastoma who were treated with oral topotecan for palliation. Each course was generally 1 mg/m2/d in two divided doses, for 21 consecutive days, repeated after a 1-week rest in patients without symptoms of progressive disease. Disease status was assessed by radiographic studies, urine catecholamine levels, and multiple bone marrow aspirations and biopsies. RESULTS: Twenty patients between the ages of 3 and 34 (median 13 years) received 1 (n = 7), 2 (n = 3), 3 (n = 4), 4 (n = 2), 6 (n = 2), and 12 courses (n = 2). Prior treatments included multiple cycles of high-dose alkylator-based chemotherapy (n = 20), high-dose intravenous topotecan (n = 8), myeloablative chemotherapy or radioimmunotherapy (n = 10), or experimental biologic agents (n = 16). Anti-neuroblastoma effects were seen in five patients lasting 6 to 12 months; two additional patients remained stable for 4 months. Thirteen patients had progressive disease (11 after one or two cycles). Toxicity included diarrhea (n = 12) requiring a dose adjustment in three patients and discontinuation of the drug in a fourth, and myelosuppression (n = 11) requiring transfusion and/or granulocyte-colony stimulating factor support.CONCLUSIONS: Oral topotecan therapy has antitumor activity in a small percentage of patients with relapsed or refractory neuroblastoma. Toxicities, including diarrhea and myelosuppression, may necessitate a dose adjustment in this patient population. Low-dose oral topotecan may have utility in the treatment of neuroblastoma.     

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma

BACKGROUND: Preclinical models show sequence-dependent synergy with the combination of temozolomide and irinotecan, and a Phase I trial has demonstrated the combination to be tolerable and active in children with relapsed solid tumors. Because responses were seen in patients with Ewing sarcoma (ES) on that trial, additional patients were treated with this combination following study completion. PROCEDURE: We reviewed data from all ES patients treated with temozolomide and irinotecan at four institutions, including seven patients treated on the above Phase I trial. RESULTS: Sixteen patients received a total of 95 courses, with a median of five courses per patient. All patients had either progressive disease (PD) during initial therapy (n = 5) or relapse within 2 years of diagnosis (n = 11). Twelve patients had metastatic disease at diagnosis, including 5 with bone and/or marrow metastases. Patients received oral temozolomide 100 mg/m(2)/day on days 1-5 plus intravenous irinotecan 10-20 mg/m(2)/day on days 1-5 and 8-12, with courses repeated every 21-28 days. We observed 1 complete, 3 partial, and 3 minor responses in 14 evaluable patients, with a median duration of response of 30 weeks. Planned 21-day courses were tolerable and no more toxic than 28-day courses. Myelosuppression was minimal despite heavy pretreatment. Grade 3-4 diarrhea occurred in 11% of courses and was related to higher irinotecan doses. Over 600 irinotecan doses were administered uneventfully at home. CONCLUSIONS: Temozolomide and protracted intravenous irinotecan given in 21-day courses was tolerable and active in patients with advanced ES. Home administration of irinotecan with temozolomide was safe and is reasonable palliative therapy. A formal Phase II study using a uniform dose and schedule is warranted to better define activity.     

Epidermal growth factor in neonatal mouse urine: maturative effect of thyroxine

Using a specific and sensitive epidermal growth factor (EGF) radioimmunoassay, we have shown measurable quantities of EGF in mouse urine during the neonatal period. Sephadex G-50 column chromatography demonstrated the presence of a single immunoreactive component at the position defined by standard EGF (mol wt 6045). Comparison of urine urea nitrogen and urine EGF levels in neonatal and adult mice showed adult values to be 3- and 16-fold higher, respectively. Kidney weights relative to body weight were similar in newborn and adult animals while kidney EGF concentration per mg protein was 2.5-fold higher in the adult. The relative submandibular gland (SMG) weight was slightly higher in adult female mice than in the newborn, whereas SMG-EGF concentration was 15,000-fold higher in the adult than in the newborn. Thyroxine administration to neonatal mice from day 0 to day 6 increased urine EGF concentration 7-fold compared to control pups. Though the hormone treatment elicited a significant increase in relative SMG weight, its EGF concentration like that of the kidneys remained unchanged. The results suggest that urine EGF is subject to thyroid hormone modulation in newborn animals and that the changes in urine EGF concentration are independent of changes in SMG and renal EGF levels.     

Phenobarbital metabolism in adults and in newborn infants

Two adult volunteers and four newborn infants were given a single dose of phenobarbital. The output in the urine o f unchanged phenobartital and of the two main metabolites p-hydroxy phenobarbital and conjugated p-hydroxy phenobarbital was followed during 8 days in the newborns and during 2 or 4 weeks in the adults. The plasma levels were also determined and some pharmacokinetic constants calculated. It was found that the newborn patients excreted unchanged phenobartibal and p-hydroxy phenobarbital in the same proportions relative to dose as did the adult volunteers, 2.e. 16--17% unchanged drug and 9--10% of the metabolite during the first 8 days after administration. On the other hand, there was a clear-cut age difference in output of conjugated metabolite where the newborns excreted only 5% of the given dose during the 8-day observation period. The corresponding value for the adults was 15%. It is concluded that a poor conjugating capacity in the newborn may not have any serious consequences with a drug like phenobarbital where major alternative routes of excretion exist (unchanged drug and unconjugated metabolite). The clinical significance of immature drug metabolites and of unchanged drug is taken into consideration.     

Unusual case of adrenal cortical carcinoma in a female infant.

Adrenal cortical carcinoma in a 4 1/4-month-old girl was treated by surgery in combination with actinomycin D, cyclophosphamide, and 5-fluorouracil given daily for 5 days every third week for 13 1/2 months. Postoperative hypertension and raised 24-hour 17-hydroxy- and 21-oxosteroids suggested residual microscopical tumour activity. These findings resolved during chemotherapy. The patient is alive and well 22 months after completing chemotherapy. Adrenal cortical carcinoma may rarely mimic neuroblastoma or nephroblastoma when the tumour is not clinically secretory.     

Multiple malignant and benign lesions in the liver in a child with adrenocortical carcinoma

We report 4-year-old girl who was diagnosed with adrenocortical carcinoma when she was 2 years old. At the time of diagnosis there were no metastases, but 6 months later multiple liver metastases appeared. Following intensive chemotherapy the metastases resolved completely. Multifocal lesions were detected in the liver by US 16 months later. Their morphology on US and MRI differed from the previous metastases. Histopathological examination confirmed focal nodular hyperplasia. We discuss the origin and the uncommon appearance of multifocal nodular hyperplasia in hormone-active tumours such as adrenocortical carcinoma in children.     

A phase 2 trial of all-trans-retinoic acid in combination with interferon-alpha2a in children with recurrent neuroblastoma or Wilms tumor: A Pediatric Oncology Branch, NCI and Children's Oncology Group Study

BACKGROUND: The combination of the antiproliferative and differentiation-inducing effects of retinoids together with the antiproliferative, immunostimulatory, and differentiation-potentiating effects of interferon-alpha (IFN-alpha) were the basis for the development of this combination in pediatric patients with refractory neuroblastoma or Wilms tumor. PROCEDURE: A phase 2 trial of all-trans-retinoic acid (ATRA), administered orally at a dose of 90 mg/m(2)/day in three divided doses for 3 consecutive days per week, and IFN-alpha2a, administered subcutaneously daily at a dose of 3 x 10(6) U/m(2)/day for 5 consecutive days per week, in 4 week cycles was performed. A two-stage design was used for each disease stratum. RESULTS: Seventeen patients (16 evaluable) with neuroblastoma, median age 9 years, and 15 patients (14 evaluable) with Wilms tumor, median age 6 years, were enrolled. Overall, the combination was well tolerated, with headache being the most common toxicity observed. There were no complete or partial responses. The median number of cycles administered was 1 (range 1-9). Four patients with neuroblastoma had stable disease for 12 or more weeks. CONCLUSIONS: The combination of ATRA and IFN-alpha2a was inactive in children with relapsed or refractory neuroblastoma and Wilms tumor. The lack of activity with this combination in children with refractory neuroblastoma is similar to the disappointing phase 2 results of single agent 13-cis-retinoic-acid (13cRA) and does not support further development of ATRA for children with relapsed neuroblastoma.     

Glucocorticoid receptor and vascular endothelial growth factor in nephrotic syndrome

AIM: The aim of the study was to assess plasma and urine concentrations of vascular endothelial growth factor (VEGF) in nephrotic syndrome children (NS) depending on the total dose of glucocorticoids (GC) and the percentage of lymphocytes with glucocorticoid receptor expression (CD3/GCR). METHODS: We examined 51 children (2-15 years), allocated to three groups: group I: 13 children with the first NS onset, group II: 13 children with NS relapse, group C: 25 healthy children. The NS patients were examined: (A) before treatment and (B) 4-5 weeks after prednisone administration at a dose of 60 mg/m2/24 h. Plasma and urinary VEGF levels were determined using the immunoenzymatic ELISA method. Flow cytometry was applied to assess CD3/GCR expression. RESULTS: Higher plasma and urinary VEGF concentrations were noted in NS children before treatment (A), as compared to control subjects (C). Following prednisone therapy (B), VEGF level was reduced but it was still higher than in the control group. Positive correlation was observed between VEGF and protein in the urine (group I r = 0.660, P < 0.05, group II r = 0.818, P<0.01) and a weak positive correlation between VEGF in plasma and urine (group I r = 0.531, P<0.05, group II - r = 0.581, P<0.05). CD3/GCR expression was lower in group II. In both groups, the correlation between plasma VEGF and CD3/GCR was positive (P<0.05).Conclusions: 1. Plasma and urinary VEGF levels increase during nephrotic syndrome onset. 2. Glucocorticoid treatment reduces plasma and urinary VEGF levels in NS children.     

Neurological injury markers in children with septic shock.

OBJECTIVE: To determine whether known serum markers of neurologic injury are increased in children with septic shock. DESIGN: Prospective, observational study. SETTING: Tertiary-care, pediatric intensive care unit. PATIENTS: Two cohorts of children (n = 24) with septic shock were prospectively enrolled within 24 hrs of their diagnosis. In cohort 1, serum markers (S100beta, neuron-specific enolase [NSE], and glial fibrillary acidic protein [GFAP]) were determined (n = 18). In cohort 2, in addition to serum markers, urine S100beta and GFAP were determined, and continuous electroencephalography (cEEG) was performed. Children who presented to the emergency room with a fever served as controls (n = 32). Children with known neurologic conditions were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serum and urine were collected daily for up to 7 days or until pediatric intensive care unit discharge. Biomarker concentrations were determined by commercially available enzyme-linked immunosorbent assays. cEEG was performed on days 1, 2, 4, and 7 in a 16-channel montage for at least 6 hrs. Physical examinations did not reveal focal neurologic deficits. Children with septic shock demonstrated increased serum S100beta and NSE compared with controls (mean +/- SEM: 10.5 microg/L +/- 2.4 vs. .9 microg/L +/- .1, p < .001; 96.6 microg/L +/- 8.9 vs. 4.0 microg/L +/- 1.3, p < .001, respectively). Serum GFAP was detectable in five septic children and none of the controls. In cohort 2, urine of four patients demonstrated measurable S100beta levels, and GFAP was detected in one child (nonsurvivor). cEEG demonstrated moderate to severe encephalopathy in all children studied. CONCLUSIONS: Markers of neurologic injuries are increased in children with septic shock. This may indicate subclinical injuries that are either transient or permanent. Studies that correlate the long-term neurologic outcome of children with these markers are needed to identify children at risk for neurologic injuries from septic shock.