Hepatocellular carcinoma tumour burden score to stratify prognosis after resection.

BACKGROUND: Although the Barcelona Clinic Liver Cancer (BCLC) staging system has been largely adopted in clinical practice, recent studies have emphasized the need for further refinement and subclassification of this system. METHODS: Patients who underwent hepatectomy with curative intent for BCLC-0, -A or -B hepatocellular carcinoma (HCC) between 2000 and 2017 were identified using a multi-institutional database. The tumour burden score (TBS) was calculated, and overall survival (OS) was examined in relation to TBS and BCLC stage. RESULTS: Among 1053 patients, 63 (6·0 per cent) had BCLC-0, 826 (78·4 per cent) BCLC-A and 164 (15·6 per cent) had BCLC-B HCC. OS worsened incrementally with higher TBS (5-year OS 77·9, 61 and 39 per cent for low, medium and high TBS respectively; P < 0·001). No differences in OS were noted among patients with similar TBS, irrespective of BCLC stage (61·6 versus 58·9 per cent for BCLC-A/medium TBS versus BCLC-B/medium TBS, P = 0·930; 45 versus 13 per cent for BCLC-A/high TBS versus BCLC-B/high TBS, P = 0·175). Patients with BCLC-B HCC and a medium TBS had better OS than those with BCLC-A disease and a high TBS (58·9 versus 45 per cent; P = 0·005). On multivariable analysis, TBS remained associated with OS among patients with BCLC-A (medium TBS: hazard ratio (HR) 2·07, 95 per cent c.i. 1·42 to 3·02, P < 0·001; high TBS: HR 4·05, 2·40 to 6·82, P < 0·001) and BCLC-B (high TBS: HR 3·85, 2·03 to 7·30; P < 0·001) HCC. TBS could also stratify prognosis among patients in an external validation cohort (5-year OS 79, 51·2 and 28 per cent for low, medium and high TBS respectively; P = 0·010). CONCLUSION: The prognosis of patients with HCC varied according to the BCLC stage but was largely dependent on the TBS.

ANTECEDENTES: Aunque el sistema de estadificación del Barcelona Clinic Liver Cancer (BCLC) ha sido adoptado en gran medida en la práctica clínica, estudios recientes han enfatizado la necesidad de un mayor refinamiento y subclasificación del sistema BCLC. MÉTODOS: Los pacientes con carcinoma hepatocelular (hepatocellular cancer, HCC) BCLC-0, A y B que se sometieron a una hepatectomía con intención curativa entre 2000 y 2017 fueron identificados utilizando una base de datos multi-institucional. Se calculó la puntuación de carga tumoral (tumour burden score, TBS) y se examinó la supervivencia global (overall survival, OS) en relación con la TBS y los estadios BCLC. RESULTADOS: En la serie de 1.053 pacientes, 63 (6%) tenían HCC BCLC-0, 826 (78,4%) HCC BCLC-A y 164 (15,6%) HCC BCLC-B. La OS disminuyó de forma incremental en función de la mayor TBS (OS a 5 años; TBS baja: 77,9% versus TBS media: 61% versus TBS alta: 39%, P < 0,001). No se observaron diferencias en la OS entre pacientes con una puntuación TBS similar, independientemente del estadio BCLC (BCLC-A/TBS media: 61,6% versus BCLC-B/TBS media: 58,9%, P = 0,93; BCLC-A/TBS alta: 45,1% versus BCLC-B/TBS alta: 12,8%, P = 0,175). Los pacientes con BCLC-B/TBS media tuvieron una mejor OS que los pacientes con BCLC-A/TBS alta (58,9% versus 45,1%, P = 0,005). En el análisis multivariable, la TBS se mantuvo asociada a la OS en el caso de BCLC-A (TBS media: cociente de riesgos instantáneos, hazard ratio, HR = 2,07, i.c. del 95%: 1,42-3,02, P < 0,001; TBS alta: HR = 4,05, i.c. del 95%: 2,40-6,82, P < 0,001) y BCLC-B pacientes (TBS alta: HR = 3,85, i.c. del 95%: 2,03-7,30, P < 0,001). La TBS también pudo estratificar el pronóstico entre pacientes en una cohorte de validación externa (OS a 5 años; TBS baja: 78,7% versus TBS media: 51,2% versus TBS alta: 27,6%, P = 0,01). CONCLUSIÓN: El pronóstico de los pacientes con HCC varió según el estadio BCLC, pero dependió en gran medida de la TBS.

The single-dose pharmacokinetics of midazolam and its primary metabolite in pediatric patients after oral and intravenous administration.

The first-dose pharmacokinetics of midazolam and its primary alpha-hydroxymetabolite were studied after single-dose administration. Eligible study patients were enrolled into one of three study arms: Arm I (midazolam/metabolite pharmacokinetic evaluation after oral administration of a syrup formulation), Arm II (the absolute bioavailability of midazolam syrup), and Arm III (midazolam and metabolite pharmacokinetics after IV administration). Complete blood sampling for pharmacokinetic analysis was available in 87 subjects. Midazolam absorption after administration of the oral syrupformulation was rapid, with adolescents absorbing the drug at approximately half the rate observed in younger children (ages 2 to < 12 years). Furthermore, midazolam t 1/2 was prolonged and CL/F reducedin adolescents as compared with younger children. Although the midazolam Vd/F appeared larger in the youngest age group after oral administration, this observation was not apparent after IV dosing, suggesting subject differences in bioavailability rather than distribution. Like midazolam, the disposition characteristics for a-hydroxymidazolam were also highly variable, with the greatest formation of metabolite (reflected by the AUC ratio) observed in children ages 2 to < 12 years. The A UC ratios of alpha-hydroxymidazolam to midazolam after IV dosing were similar across all age groups and were smaller than corresponding values following oral administration. The absolute bioavailability of midazolam averaged 36% with a very broad range (9%-71%). No relationship between midazolam bioavailability and age was observed. Overall, the disposition characteristics of midazolam and its a-hydroxy metabolite were highly variable, appeared independent of age and dose administered, and were linear over the dose range studied (0.25 to 1 mg/kg). These data suggest that an initial oral dose of 0.2 to 0.3 mg/kg should be adequateforsuccessful sedation of most pediatric patients. The inherent variability in midazolam bioavailability and metabolism underscores the importance of titrating midazolam dose to desired effect.

Pediatric pharmacodynamics of midazolam oral syrup. Pediatric Pharmacology Research Unit Network.

In this study, the authors evaluate the pharmacodynamics, safety, and acceptability of a new cherry-flavored oral syrup formulation of midazolam. This randomized, double-blind, parallel-group, dose-ranging clinical trial of oral midazolam was conducted at seven U.S. health care institutions focused on pediatric clinical pharmacology research (i.e., the PPRU Network). Pediatric patients (n = 85, ages 6 months through 15 years) underwent invasive procedures and were randomized to a single oral dose of midazolam syrup (0.25, 0.5, or 1.0 mg/kg). Patient taste acceptability of midazolam syrup was evaluated at the time of oral administration. Pharmacodynamic measurements included (1) sedation score using a 5-point scale at baseline and 10-, 20-, and 30-minute postdose intervals and (2) anxiety score using a 4-point scale at the time of separation from caretakers and, when applicable, at the time of mask anesthetic induction. Midazolam and alpha-hydroxymidazolam plasma concentrations were measured at all pharmacodynamic measurement time points. Adverse events were monitored continuously during the study. Most patients (99%) accepted the syrup without difficulty. Satisfactory sedation was achieved within 30 minutes by 81% of patients. The anxiety score at the time of caretaker separation and mask anesthetic induction was satisfactory for 87% and 91% of patients, respectively. A significant linear relationship between plasma drug concentration and maximal sedation score, but not anxiety score, was observed. The occurrence of adverse events was consistent with the known safety profile of midazolam. The most commonly reported adverse events were hiccoughing, hypoxemia, nausea, and emesis. It was concluded that a new oral syrup formulation of midazolam, 0.25 to 1.0 mg/kg, effectively induced rapid-onset, dose-related, adequate, and safe sedation and anxiolysis in pediatric patients who underwent operative procedures. Sedative effects were related to plasma concentrations of both midazolam and the primary metabolite, alpha-hydroxymidazolam. Oral midazolam, 1.0 mg/kg, administered within 30 minutes of the expected procedure or anesthetic induction should provide safe and effective sedation to a majority of children ages 6 months to 16 years.

Intravenous ondansetron in established postoperative emesis in children. S3A-381 Study Group.

BACKGROUND: In pediatric postsurgical patients, postoperative vomiting is a common occurrence that can delay recovery and result in unplanned hospital admissions after outpatient surgery. This randomized, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of ondansetron in the control of established postoperative emesis in outpatients aged 2-12 yr. METHODS: Screened for the study were 2,720 ASA physical status 1-3 children undergoing outpatient surgery during general anesthesia, which included nitrous oxide. Children experiencing two emetic episodes within 2 h of discontinuation of nitrous oxide were given intravenous ondansetron (n = 192; 0.1 mg/kg for children weighing < or = 40 kg; 4 mg for children weighing > 40 kg) or placebo (n = 183). RESULTS: The proportion of children with no emetic episodes and no use of rescue medication was significantly greater (P < 0.001) in the ondansetron group compared with placebo for both 2- and 24-h periods after study drug administration (78% of the ondansetron group and 34% of the placebo group for 2 h; 53% of the ondansetron group and 17% of the placebo group for 24 h). Among patients with at least one emetic episode or with rescue medication use, the median time to onset of emesis or rescue was 127 min in the ondansetron group compared with 58 min in the placebo group (P < 0.001). The median time from study drug administration until discharge was significantly shorter (P < 0.01) in the ondansetron group (153 min, range 44-593 min) compared with the placebo group (173 min, range 82-622 min). The incidence of potentially drug-related adverse events was similar in the ondansetron (3% of patients) and the placebo (4% of patients) groups. CONCLUSION: A single dose of ondansetron (0.1 mg/kg up to 4 mg) is effective and well tolerated in the prevention of further episodes of postoperative emesis in children after outpatient surgery. Administration of ondansetron also may result in a shorter time to discharge.

Prophylactic antiemetic treatment with ondansetron in children undergoing tonsillectomy.

BACKGROUND: Children undergoing tonsillectomy are at high risk for postoperative vomiting. This study was undertaken to compare ondansetron with metoclopramide and droperidol for the prevention of postoperative vomiting after tonsillectomy. METHODS: Two hundred fifty-six pediatric patients, ages 2-12 years, scheduled for outpatient tonsillectomy were enrolled in a prospectively randomized, double-blinded investigation and assigned to one of four treatment regimens: placebo (saline), ondansetron 0.15 mg.kg-1, metoclopramide 0.5 mg.kg-1, or droperidol 0.075 mg.kg-1. Study drugs were administered intravenously after inhalation induction of anesthesia with halothane, nitrous oxide, and oxygen. No premedication or neuromuscular blocking agents were used. Tracheal extubation was performed while patients were still deeply anesthetized. Acetaminophen and meperidine were given for postoperative pain. Patients were observed in the recovery room for a minimum of 4 h before discharge. Parents were contacted by telephone 24 h later for follow-up. RESULTS: Ondansetron reduced the incidence of postoperative emesis from 62% to 27% (relative risk 0.45, 95% confidence interval 0.29 to 0.70, P < 0.001). Metoclopramide and droperidol had no significant effect on postoperative vomiting. CONCLUSIONS: The intravenous administration of ondansetron 0.15 mg.kg-1 is highly effective in reducing postoperative emesis in children undergoing tonsillectomy. Metoclopramide and droperidol at the doses tested are ineffective in this population.

A double-blinded comparison of metoclopramide and droperidol for prevention of emesis following strabismus surgery.

Vomiting in the postoperative period is common in children after strabismus surgery. One hundred ten pediatric patients, ages 8 months to 14 yr, admitted for outpatient strabismus surgery were enrolled in a randomized, double-blinded study to compare droperidol and metoclopramide to placebo for the prevention of postoperative emesis. Each child was prospectively assigned at random to one of four treatment groups: metoclopramide 0.15 mg/kg, metoclopramide 0.25 mg/kg, droperidol 0.075 mg/kg, or saline control. Drugs were administered intravenously immediately after induction of inhalation anesthesia. No neuromuscular blocking agents were used. Tracheal extubation was performed while patients were still deeply anesthetized. Acetaminophen and meperidine were given in standard doses for postoperative pain to all children. The incidence of vomiting was less in both the droperidol (33%) and metoclopramide 0.25 mg/kg (29%) groups when compared to controls (88%) (P less than 0.01). Patients receiving metoclopramide 0.15 mg/kg had a 68% incidence of vomiting (P not significant). The mean frequency of emesis was reduced in all treatment groups compared with control (P less than 0.05). Patients receiving droperidol and metoclopramide 0.25 mg/kg also had decreased postoperative stays (metoclopramide 201 min; droperidol 213 min) versus control (258 min, P less than 0.05). No child exhibited extrapyramidal symptoms, excessive drowsiness, or agitation. We conclude that metoclopramide in a dose of 0.25 mg/kg, administered prior to the start of surgery, is at least as effective as droperidol in preventing postoperative emesis and can reduce the time to patient discharge compared to control.

Peritoneal dialysis for acute renal failure in children.

Fifty infants and children with acute renal failure were treated with acute peritoneal dialysis between 1987 and 1990. The patients were dialyzed using either a catheter introduced percutaneously over a guide-wire (n = 40) or a Tenckhoff catheter (n = 10). The cause of the acute renal failure was primary renal disease in 17 children, cardiac disease in 19, and trauma/sepsis in 14. Peritoneal dialysis succeeded in controlling metabolic abnormalities, improving fluid balance, and relieving the complications of uremia. The procedure had few major complications. Overall mortality was 50%, reflecting the serious nature of the underlying diseases. We conclude that acute peritoneal dialysis is a safe and effective treatment in most pediatric patients with acute renal failure. Our series of patients treated with acute peritoneal dialysis serves as a basis of comparison for the evaluation of new modalities of therapy in childhood acute renal failure.

Interference with creatinine concentration measurement by high dose furosemide infusion.

Three patients had unmeasurable serum creatinine concentrations using a colorimetric method while receiving high doses of furosemide. The present study shows that enzymatic methods of measuring the serum creatinine concentration should be used in patients receiving high doses of furosemide.

Use of doxapram to increase respirations without a concomitant increase in intracranial pressure.

We treated a brain-damaged 8-month-old male with iv doxapram in order to discontinue mechanical ventilation. We were able to monitor intracranial pressure (ICP) throughout the course of doxapram via an ICP monitor. Despite normal and then excessive PaCO2, the patient's spontaneous respiratory rate remained nil before doxapram treatment. However, after an iv bolus dose followed by a maintenance drip, the patient's spontaneous respiratory rate increased while his ICP remained at baseline or slightly less than baseline, thereby allowing mechanical ventilation to be discontinued.

Used of a guide-wire inserted catheter for acute peritoneal dialysis.

Peritoneal dialysis was performed in 18 children using a new guide-wire inserted catheter technique. Catheter insertion was complicated only by mild bleeding in one patient. The catheters drained well immediately after insertion in 17 of the 18 patients. Catheters were used for an average of 6 days, with a range up to 16 days. Dialysate volumes could be increased quickly in most patients. Late complications were leakage (2), peritonitis (4) and obstruction (3). Leakage did not interfere with dialysis. The peritonitis episodes, which occurred between days 6 and 16 of dialysis, resolved satisfactorily with appropriate antibiotic therapy. The guide-wire catheter can be inserted and used for short term peritoneal dialysis in children.

Monitoring end-tidal carbon dioxide tensions with high-frequency jet ventilation in dogs with normal lungs.

The end-tidal carbon dioxide tension (PetCO2) measured after a single, large tidal-volume breath (15 ml/kg body weight) was compared to simultaneous measurements of PaCO2 in 6 dogs with normal lungs who were receiving high-frequency jet ventilation (HFJV). There was an excellent linear correlation between PetCO2 and the PaCO2 over the entire range of CO2 tensions commonly encountered in clinical practice (PetCO2 = 0.9 PaCO2 + 2.2 torr; n = 51, r = .98, p less than .001, range of PaCO2 = 12-72 torr). We conclude that when lung function is normal, a simple system of measuring PetCO2 after a large breath is an accurate method of monitoring the effectiveness of CO2 elimination during HFJV.