Rachael Lawson

Boerhaave Syndrome Following Chemotherapy in a Child With Acute Lymphoblastic Leukemia

To the Editor: Spontaneous oesophageal rupture (Boerhaave syndrome) is extremely rare in children. Presentation is usually inmiddle agedmen as a result of heavy food or alcohol consumption [1]. It can also occur in children after chemotherapy-induced vomiting, as our experience with such a case testifies. A 10-year-old boy presented with a relapse of ALL, having being treated successfully 7 years previously. He was started on paediatric relapse schedule MRC ALL R2. During induction chemotherapy he had a severe bout of vomiting, following which he complained of acute chest pain. The next day he became pyrexial, tachypnoeic, tachycardic, hypotensive (blood pressure of 80/40) and his oxygen saturation was 92% on air. A chest X-ray film showed bilateral small pleural effusions. He was treated conservatively with antibiotics and low flow oxygen. Despite clinical improvement, with rapid resolution of the effusions, he continued to be intermittently pyrexial. An echocardiogram was performed to exclude cardiac vegetations, and was found to be normal. Two weeks later he became pyrexial (39.28C) and acutely short of breath. An ultrasound showed a large right-sided pleural effusion. A chest drain was inserted and 700 ml of serosanguinous fluid was drained. Over the next 48 hr he developed increasing respiratory distress. X-ray films demonstrated reaccumulation of the effusion with an air–fluid interface. A CT scan was suggestive of an empyema. In view of the deterioration it was decided to proceed to right thoracotomy. At operation, a 4 cm longitudinal full-thickness tear of the lower oesophagus was found, with food residue in the pleural cavity. A thorough lavage was performed and two large chest drains were inserted. Laparotomy was then undertaken to insert a gastrojejunostomy tube allowing both jejunal feeding and gastric drainage. A contrast study confirmed healing of the lower oesophagus after 9 weeks. He was discharged home after 3 months. One year later he remains well on maintenance chemotherapy in full remission from his leukaemia. The first reported case of spontaneous oesophageal rupture following vomiting was detailed by Boerhaave of Leiden in 1724 [2]. The victim was the Grand Admiral Baron vanWassener, a reknowned glutton, who habitually induced vomiting following large meals. The Admiral felt a bursting sensation in the chest, followed by severe chest and epigastric pain. He predicted his own death, which occurred 18 hr later. At autopsy Boerhaave found a tear in the lower oesophagus and the remains of theAdmiral’s last meal (roast duck) were found floating within both pleural cavities. Barrett reported 51 cases of the condition, all ending fatally, but in 1947 carried out the first successful surgical repair [1,3]. The clinical presentation is usually with vomiting, hematemesis and severe substernal pain [4]. Examination reveals tachycardia, tachypnoea, hypotension and subcutaneous emphysema in the neck. On auscultation mediastinal crunch (footsteps in the snow) can sometimes be detected. The chest X-ray film may or may not demonstrate a pleural effusion, pneumothorax, or pneumomediastinum [5]. Treatment is initially supportive with oxygen, analgesics, antibiotics and adequate fluid replacement. The definitive treatment is surgical repair of the rupture site, with or without a muscle/omental flap. A delay in diagnosis leads to increased morbidity and mortality [6]. Treatment then includes chest drainage, oesophageal exclusion and supplemental feeding, as was done by us [7]. To our knowledge, this is the first case of Boerhaave syndrome due to chemotherapy-induced vomiting, and points up the diagnostic difficulty in the immune-compromised patient.

Gentamicin Pharmacokinetics and Monitoring in Pediatric Febrile Neutropenic Patients.

BACKGROUND The pharmacokinetics of gentamicin in pediatric febrile neutropenia patients is described and the adequacy of initial dosing of once daily gentamicin assessed at Queenslands largest Childrens Hospital. METHODS Data were retrospectively collected from all pediatrics with febrile neutropenia admitted over a two-year period who had at least two gentamicin concentration-time measurements (a paired set within one dosing interval). Gentamicin clearance (CL), volume of distribution (Vd), area under the concentration-time curve from 0 to 24 hours post-dose (AUC0-24), and maximum concentration (Cmax) values were estimated using log-linear regression using each paired set. The percentage of paired sets associated with gentamicin exposure within pre-defined hospital targets was calculated and exposure was examined in relation to bacterial culture status. RESULTS Data were collected from 69 patients (median [IQR] age 3.7 years [2.2, 8.9]) and comprised 121 paired concentration sets characterizing 80 separate admissions. Median [IQR] gentamicin CL and Vd were 8.1 L/h/70 kg [5.8, 12.4] and 21.8 L/70 kg [16.9, 29.5], respectively. Pre-defined hospital exposure targets were achieved for both AUC0-24 and Cmax for 10% of paired sets; one or the other of these targets were met for 36% of paired sets and neither target was achieved for 54% of paired sets. Achievement of targets improved with repeated monitoring during the same admission. Median AUC0-24 achieved was significantly higher in patients with a confirmed Gram-negative infection compared to those without 71 [50, 91] mg·h/L versus 55 [40.8, 67.5] mg·h/L, respectively (p= 0.003)). Over the study period, a median gentamicin dose of 10.8 and 6.4 mg/kg was estimated to be necessary to achieve an AUC target of 80 mg·h/L in children ≤10 years and >10 years of age. CONCLUSIONS Based on a log-linear method of analysis, current dosing appears to be consistently producing gentamicin exposure below pre-defined pharmacokinetic targets, suggesting that an increase in the recommended starting dose of gentamicin may be required.

Comparison of methods to estimate glomerular filtration rate in paediatric oncology patients

Glomerular filtration rate (GFR) is estimated daily in paediatric oncology patients; however, few equations, particularly ones that do not include serum creatinine, have been evaluated in this population. We aimed to compare the predictive performance of different equations available to estimate GFR in paediatric oncology patients.

A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing

ABSTRACT To ensure the safe and effective dosing of gentamicin in children, therapeutic drug monitoring (TDM) is recommended. TDM utilizing Bayesian forecasting software is recommended but is unavailable, as no population model that describes the pharmacokinetics of gentamicin in pediatric oncology patients exists. This study aimed to develop and externally evaluate a population pharmacokinetic model of gentamicin to support personalized dosing in pediatric oncology patients. A nonlinear mixed-effect population pharmacokinetic model was developed from retrospective data. Data were collected from 423 patients for model building and a further 52 patients for external evaluation. A two-compartment model with first-order elimination best described the gentamicin disposition. The final model included renal function (described by fat-free mass and postmenstrual age) and the serum creatinine concentration as covariates influencing gentamicin clearance (CL). Final parameter estimates were as follow CL, 5.77 liters/h/70 kg; central volume of distribution, 21.6 liters/70 kg; peripheral volume of distribution, 13.8 liters/70 kg; and intercompartmental clearance, 0.62 liter/h/70 kg. External evaluation suggested that current models developed in other pediatric cohorts may not be suitable for use in pediatric oncology patients, as they showed a tendency to overpredict the observations in this population. The final model developed in this study displayed good predictive performance during external evaluation (root mean square error, 46.0%; mean relative prediction error, −3.40%) and may therefore be useful for the personalization of gentamicin dosing in this cohort. Further investigations should focus on evaluating the clinical application of this model.

Antimicrobial stewardship in paediatric oncology: Impact on optimising gentamicin use in febrile neutropenia

To evaluate the impact of an antimicrobial stewardship (AMS) intervention, involving introduction of new guidelines on the treatment of febrile neutropenia (FN), on improving the use of gentamicin in paediatric oncology patients.