A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants.

BACKGROUND: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design. METHODS: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years. RESULTS: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses. CONCLUSIONS: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine.

Tuberculosis case finding for vaccine trials in young children in high-incidence settings: a randomised trial.

SETTING: A high tuberculosis (TB) burden rural area in South Africa. OBJECTIVE: To compare TB case yield and disease profile among bacille Calmette-Guérin (BCG) vaccinated children using two case-finding strategies from birth until 2 years of age. DESIGN: BCG-vaccinated infants were enrolled within 2 weeks of birth and randomised to 3-monthly home visits for questionnaire-based TB screening plus record surveillance of TB registers, hospital admission and X-ray lists at health facilities for TB suspects and cases (Group 1), or record surveillance (as above) only (Group 2). Both groups received a close-out visit after 2 years. Participants were evaluated for suspected TB disease using standardised investigations. RESULTS: A total of 4786 infants were enrolled: 2392 were randomised to Group 1 and 2394 to Group 2. The case-finding rate was significantly greater in Group 1 (2.2/100 py) than in Group 2 (0.8/100 py), with a case-finding rate ratio of 2.6 (95%CI 1.8-4.0, P < 0.001). Although the proportion of cases with bacteriological confirmation was lower in Group 1, this difference did not reach statistical significance. There was also no significant difference in the proportions with TB symptoms and signs. CONCLUSION: Home visits combined with record surveillance detected significantly more cases than record surveillance with a single study-end visit. The TB case profile did not differ significantly between the two groups.

Hyperchloraemic metabolic acidosis following open cardiac surgery.

AIMS: To describe acid-base derangements in children following open cardiac surgery on cardiopulmonary bypass (CPB), using the Fencl-Stewart strong ion approach. METHODS: Prospective observational study set in the paediatric intensive care unit (PICU) of a university children's hospital. Arterial blood gas parameters, serum electrolytes, strong ion difference, strong ion gap (SIG), and partitioned base excess (BE) were measured and calculated on admission to PICU. RESULTS: A total of 97 children, median age 57 months (range 0.03-166), median weight 14 kg (range 2.1-50), were studied. Median CPB time was 80 minutes (range 17-232). Predicted mortality was 2% and there was a single non-survivor. These children showed mild metabolic acidosis (median standard bicarbonate 20.1 mmol/l, BE -5.1 mEq/l) characterised by hyperchloraemia (median corrected Cl 113 mmol/l), and hypoalbuminaemia (median albumin 30 g/l), but no significant excess unmeasured anions or cations (median SIG 0.7 mEq/l). The major determinants of the net BE were the chloride and albumin components (chloride effect -4.8 mEq/l, albumin effect +3.4 mEq/l). Metabolic acidosis occurred in 72 children (74%) but was not associated with increased morbidity. Hyperchloraemia was a causative factor in 53 children (74%) with metabolic acidosis. Three (4%) hyperchloraemic children required adrenaline for inotropic support, compared to eight children (28%) without hyperchloraemia. Hypoalbuminaemia was associated with longer duration of inotropic support and PICU stay. CONCLUSIONS: In these children with low mortality following open cardiac surgery, hypoalbuminaemia and hyperchloraemia were the predominant acid-base abnormalities. Hyperchloraemia was associated with reduced requirement for adrenaline therapy. It is suggested that hyperchloraemic metabolic acidosis is a benign phenomenon that should not prompt escalation of haemodynamic support. By contrast, hypoalbuminaemia, an alkalinising force, was associated with prolonged requirement for intensive care.

Evolution of an adenovirus outbreak in a multidisciplinary children's hospital.

OBJECTIVE: To describe the course of an evolving adenovirus outbreak in a multidisciplinary children's hospital with a high-risk patient population. METHODS: Observational study in a 280-bed university hospital during June 2002. Active case finding identified children with adenovirus infection. Data are median (interquartile range) or n (%). Adenovirus infection was diagnosed in 49 children, median age 12 months (4-33). RESULTS: New cases were diagnosed over 26 days and peaked on day 17 (n = 15). Total infected inpatients peaked on days 17-21 (n = 36). Twenty-three infections (47%) were community-acquired and 26 (53%) hospital-acquired. Thirty-three children (67%) had a coexistent high-risk condition. Median hospital stay before and after diagnosis was 9 days (3-18) and 9 days (4-29), respectively. Twenty-two children (45%) were admitted to PICU. Overall hospital mortality was 22% (n = 11) and mortality attributed to adenoviral disease 12% (n = 6). Hospital mortality was similar between community- and hospital-acquired infections (22% compared to 23%) (P = 1.0). Twenty children (41%) received intravenous immunoglobulin (IVIG). Children treated with IVIG had a longer hospital stay (median 40 days vs 14 days) than those who did not receive IVIG (P = 0.01). Neither PICU mortality (29% vs 12%), nor hospital mortality (35% vs 14%), differed significantly between IVIG treated and untreated children (P = 0.76 and P = 0.16, respectively). CONCLUSION: The rapid spread of hospital-acquired adenovirus underlines the importance of effective infection control measures. Despite nosocomial infection amongst high-risk patients, mortality was similar to that of community-acquired infection. Administration of immunoglobulin was not associated with demonstrable benefit. A prospective randomized trial would be required to resolve this issue.

Severe upper airway obstruction caused by ulcerative laryngitis.

AIMS: To present our experience of severe upper airway obstruction caused by ulcerative laryngitis in children. METHODS: Retrospective case note review of 263 children with severe upper airway obstruction and a clinical diagnosis of croup admitted to a paediatric intensive care unit (PICU) over a five year period. RESULTS: A total of 148 children (56%) underwent microlaryngoscopy (Storz 3.0 rigid telescope). Laryngeal ulceration with oedema was documented in 15 of these children (10%), median age 14 months (range 10-36) and median weight 10 kg (range 6-12). Twenty seven of the children who underwent microlaryngoscopy (18%) also had ulcerative gingivostomatitis consistent with herpes simplex virus infection. Ulcerative laryngitis was documented in nine of 27 (33%) children with, and in six of 121 (5%) children without, coexistent ulcerative gingivostomatitis. One of the 15 children did not require airway intervention. Nine children required nasotracheal intubation for a median of 4 days (range 3-11) and median PICU stay of 6 days (range 4-14). Five children required tracheostomy ab initio, with a median PICU stay of 30 days (range 20-36), and duration of tracheostomy in situ for a median of 19 days (range 15-253). All 15 children survived. CONCLUSION: Ulcerative laryngitis is more common in our patient population than the few reports suggest. Early diagnostic microlaryngoscopy is recommended in children with severe croup who follow an atypical course.

Are transoesophageal Doppler parameters a reliable guide to paediatric haemodynamic status and fluid management?

OBJECTIVE: Transoesophageal Doppler (TOD) has been used in adults to optimise left ventricular filling on the basis of the waveform parameters. We wished to see if a similar relationship exists in children, specifically: (a) whether change in thermodilution stroke volume (SV) following a fluid bolus corresponded to change in Doppler stroke distance, Doppler corrected flow time (FTc), or central venous pressure (CVP); (b) whether a response to fluid challenge (defined as an increase in SV of greater than 10%) can be predicted on the basis of an absolute value for FTc or CVP prior to fluid bolus; and (c) the relationship between FTc and systemic vascular resistance index. DESIGN: Prospective, comparison study. SETTING: Sixteen-bed paediatric intensive care unit of a university hospital. PATIENTS: Ninety-four ventilated children were studied, median (range) age 25 months (4 days- 16 years). Diagnoses included: post-cardiac surgery (n = 58), sepsis/multi-organ failure (n = 29), respiratory disease (n = 5), and other (n = 2). INTERVENTIONS: A 4-MHz, 5.5-mm diameter, flexible TOD probe was placed when patients were haemodynamically stable. Five consecutive measurements of stroke distance and FTc were made and averaged, concurrently with five SV measurements by femoral artery thermodilution. SV was then augmented by administration of fluid (10 ml/kg), and haemodynamic recordings were repeated. MEASUREMENTS AND MAIN RESULTS: The median (range) SV was 17 ml (2-64 ml). The median coefficients of variation were 3.9 % for SV, 3.5 % for stroke distance, and 3.1% for FTc. Changes in SV were accurately tracked by changes in stroke distance (mean bias 1.8 %, limits of agreement +/- 17%), but not by FTc or CVP. FTc was weakly inversely correlated with systemic vascular resistance (r = -0.15, P < 0.05). Among non-cardiac patients (n = 36), the optimal FTc that predicted an improvement in SV following fluid bolus was 0.394 s (area under ROC curve 0.756), giving a sensitivity of 90 %, specificity of 62 %, positive predictive value of 47 %, and a negative predictive value of 94 %. CVP was a poor predictor for all patient groups. CONCLUSIONS: TOD stroke distance is able to follow changes in SV following fluid bolus amongst ventilated children, and can predict when further volume loading is unlikely to improve SV amongst general, but not cardiac ICU patients. CVP is a poor discriminator of volume status in this group of patients.

Procalcitonin and cytokine levels: relationship to organ failure and mortality in pediatric septic shock.

BACKGROUND: Procalcitonin (PCT), a marker of bacterial sepsis, may also act as a mediator of the inflammatory response to infection, and thus influence outcome. OBJECTIVE: To investigate the relationship between PCT, interleukin (IL)-10, tumor necrosis factor (TNF), organ failure, and mortality in pediatric septic shock. DESIGN: Prospective observational study. SETTING: A 16-bed pediatric intensive care unit of a university hospital. PATIENTS: A total of 75 children with septic shock having a median age of 43.1 months (range, 0.1-192 months). Children who had received antibiotics for >24 hrs were excluded. A total of 37 patients (49%) had meningococcal disease, and 72 patients (96%) required mechanical ventilation. INTERVENTIONS: The pediatric risk of mortality (PRISM) score, multiple organ system failure (MOSF) score, duration of ventilation, length of ICU stay, and outcome were recorded. PCT, IL-10, and TNF were measured at admission to the intensive care unit. Sequential PCT levels were available at 0 hrs and 24 hrs in 39 patients (52%). RESULTS: Observed mortality was 21/75 (28%). Data are median (range). The admission PCT (p = .0002) and TNF levels (p = .0001) were higher in children with higher MOSF scores. In survivors and nonsurvivors, the admission PCT was 82 ng/mL vs. 273 ng/mL (p = .03), IL-10 was 62 pg/mL vs. 534 pg/mL (p = .03), and TNF was 76 pg/mL vs. 480 pg/mL (p = .001), respectively. Area under the mortality receiver operating characteristic curve was 0.73 for PCT, 0.67 for IL-10, and 0.76 for TNF, compared with 0.83 for the PRISM score. Of 39 children, 16 (41%) with sequential PCT measurements showed no fall in PCT after 24 hrs treatment. These children had higher admission levels of IL-10 (p = .03), and TNF (p = .03) compared with children who demonstrated a subsequent fall in PCT. Although the former did not have a higher median PRISM (p = .28) or MOSF score (p = .19), observed mortality was 44% (7 of 16) compared with 9% (2 of 23) (p = .02). CONCLUSION: The admission PCT, like TNF and IL-10, is related to the severity of organ failure and mortality in children with septic shock. A fall in PCT after 24 hrs of treatment may have favorable prognostic significance.

Use of transesophageal Doppler ultrasonography in ventilated pediatric patients: derivation of cardiac output.

OBJECTIVE: To ascertain if cardiac output (CO) could be derived from blood flow velocity measured in the descending aorta of ventilated children by transesophageal Doppler ultrasonography (TED) without the need for direct aortic cross sectional area measurement, and to evaluate the ability of TED to follow changes in CO when compared with femoral artery thermodilution. DESIGN: Prospective, comparison study. SETTING: A 16-bed pediatric intensive care unit of a university hospital. PATIENTS: A total of 100 ventilated infants and children aged 4 days to 18 yrs (median age, 27 months). Diagnoses included postcardiac surgery (n = 58), sepsis/multiple organ failure (n = 32), respiratory disease (n = 5), and other (n = 5). A total of 55 patients were receiving inotropes or vasodilators. INTERVENTIONS: When patients were hemodynamically stable, a TED probe was placed into the distal esophagus to obtain optimal signal, and minute distance (MD) was recorded. Five consecutive MD measurements were made concurrently with five femoral artery thermodilution measurements, and the concurrent measurements were averaged. CO was then manipulated by fluid administration or inotrope adjustment, and the readings were repeated. MEASUREMENTS AND MAIN RESULTS: Femoral artery thermodilution CO ranged from 0.32 to 9.19 L/min, (median, 2.46 L/min), and encompassed a wide range of high and low flow states. Theoretical consideration revealed the optimal TED estimate for CO to be (MD x patient height2 x 10(-7)). Linear regression analysis yielded a power function model such that: estimated CO = 1.158 x (MD x height2 x 10(-7))(0.785), r2 = 0.879, standard error of the estimate = 0.266. Inclusion of a correction factor for potential changes in aortic cross-sectional area with hypo- and hypertension did not appreciably improve the predictive value of the model. MD was able to follow percentage changes in CO, giving a mean bias of 0.87% (95% confidence interval -0.85% to 2.59%), and limits of agreement of +/- 16.82%. The median coefficient of variation for MD was 3.3%. CONCLUSIONS: TED provides a clinically accurate estimate of CO across the entire pediatric age range and is able to follow changes in CO.

Capillary refill and core-peripheral temperature gap as indicators of haemodynamic status in paediatric intensive care patients.

OBJECTIVES: Capillary refill time is an important diagnostic adjunct in the acute resuscitation phase of the shocked child. This study assesses its relation to commonly measured haemodynamic parameters in the postresuscitation phase when the child has reached the intensive care unit, and compares this with core-peripheral temperature gap. METHODS: Ninety standardised measurements of capillary refill time were made on 55 patients, who were divided into postcardiac surgery (n = 27), and general (n = 28), most of whom had septic shock (n = 24). A normal capillary refill time was defined as < or = 2 seconds. Measured haemodynamic variables included: cardiac index, central venous pressure, systemic vascular resistance index, stroke volume index (SVI), and blood lactate. Seventy measurements were made on patients while being treated with inotropes or vasodilators. RESULTS: Capillary refill time and temperature gap both correlated poorly with all haemodynamic variables among post-cardiac surgery children. For general patients, capillary refill time was related to SVI and lactate; temperature gap correlated poorly with all variables. General patients with a prolonged capillary refill time had a lower median SVI (28 v 38 ml/m2) but not a higher lactate (1.7 v 1.1 mmol/l). A capillary refill time of > or = 6 seconds had the best predictive value for a reduced SVI. CONCLUSION: Among ventilated, general intensive care patients, capillary refill time is related weakly to blood lactate and SVI. A normal value for capillary refill time of < or = 2 seconds has little predictive value and might be too conservative for this population; septic shock.

Serum lactate as a predictor of mortality after paediatric cardiac surgery.

OBJECTIVE: To assess the value of sequential lactate measurement in predicting postoperative mortality after surgery for complex congenital heart disease in children. DESIGN: Prospective observational study. SETTING: Sixteen bedded paediatric intensive care unit (PICU). SUBJECTS: Ninety nine children (90 survivors, nine non-survivors). MEASUREMENTS: Serum lactate and base deficit were measured on admission and every six hours thereafter. Data were analysed by Mann-Whitney and Fisher's exact tests. RESULTS: There was considerable overlap in initial lactate values between the survivor and non-survivor groups. Initial lactate was significantly raised in non-survivors (median 8.7, range 1.9-17.6 mmol/l) compared with survivors (median 2.4, range 0.6-13.6 mmol/l) (p = 0.0002). Twenty one patients (21.1%) with initial lactate concentrations greater than 4.5 mmol/l survived to PICU discharge. Using receiver operating characteristic analysis an initial lactate of 6 mmol/l had the optimum predictive value for mortality. Initial postoperative serum lactate > 6 mmol/l predicted mortality with sensitivity 78%, specificity 83%, and positive predictive value of only 32%. CONCLUSION: Initial lactate concentrations have poor positive predictive value for mortality. The routine measurement of lactate for this purpose cannot be justified in clinical practice.

Continuous intra-arterial blood-gas monitoring in infants and children with cyanotic heart disease.

We have evaluated the accuracy and reliability of the Paratrend 7 continuous blood-gas analyser in infants and small children under conditions of severe hypoxaemia admitted to the paediatric intensive care unit in the perioperative period with cyanotic congenital heart disease. PO2, PCO2 and pH (hydrogen ion concentration) were measured continuously via a femoral arterial sensor and compared with 100 simultaneous paired arterial blood-gas measurements. Data were analysed by Bland-Altman analysis for bias and precision. Sensors were placed in 10 children of median age 5.43 (range 0.03-45) months, median weight 3.74 (2.79-15.4) kg and remained in place for up to 27 h after operation. PO2 values were 2.5-8.2 kPa (median 5.3 kPa). Co-oximeter saturation ranged from 37.1% to 90.6% (median 75.8%). Bias and precision values were 0.04/0.87 kPa for PO2, -0.44/0.74 kPa for PCO2 and -2.61/6.98 nmol litre-1 for hydrogen ion concentration (i.e. 0.02/0.06 for pH). We conclude that perioperative continuous arterial gas monitoring is clinically accurate under conditions of severe hypoxaemia in small infants and children with cyanotic congenital heart disease.