Vaccine trials in the developing world: operational lessons learnt from a phase IV poliomyelitis vaccine trial in South Africa.

BACKGROUND: Conducting vaccine trials in developing nations is necessary but operationally complex. We describe operational lessons learnt from a phase IV poliomyelitis vaccine trial in a semi-rural region of South Africa. METHODS: We reviewed operational data collected over the duration of the trial with respect to staff recruitment and training, participant recruitment and retention, and cold chain maintenance. RESULTS-LESSONS LEARNT: The recruitment model we used that relied on the 24h physical presence of a team member in the birthing unit was expensive and challenging to manage. Forecasting of enrolment rates was complicated by incomplete baseline data and by the linear nature of forecasts that do not take into account changing variables. We found that analyzing key operational data to monitor progress of the trial enabled us to identify problem areas timeously, and to facilitate a collegial problem-solving process by the extended trial team. Pro-actively nurturing a working relationship with the public sector health care system and the community was critical to our success. Despite the wide geographical area and lack of fixed addresses, we maintained an excellent retention rate through community assistance and the use of descriptive residential information. Training needs of team members were ongoing and dynamic and we discovered that these needs that were best met by an in-house, targeted and systemized training programme. The use of vaccine refrigerators instead of standard frost-free refrigerators is cost-effective and necessary to maintain the cold-chain. CONCLUSION: Operational challenges of a vaccine trial in developing world populations include inexperienced staff, the close liaison required between researchers and public health care services, impoverished participants that require complex recruitment and retention strategies, and challenges of distance and access. These challenges can be overcome by innovative strategies that allow for the unique characteristics of the setting, trial population, and trial team.

Short-term mortality and implementation of antiretroviral treatment for critically ill HIV-infected children in a developing country.

OBJECTIVE: To describe the short-term outcome of critically ill HIV-infected children with access to highly active antiretroviral therapy (HAART) in a developing region. METHODS: Prospective observational study conducted in a paediatric teaching hospital in Cape Town, South Africa. All children admitted to the paediatric intensive care unit (PICU) with suspected HIV infection were screened. Data are n (%) with 95% confidence intervals. RESULTS: Sixty eight of 96 HIV antibody-positive children, median age 3 months, were confirmed HIV-infected. Predicted PICU mortality was 0.42. Fifty one children (75%; 95% CI 65 to 85%) survived to PICU discharge, but hospital survival was only 51% (95% CI 40 to 63%). Limitation of intervention (LOI) decisions were a factor in the majority of PICU and ward deaths. Twenty one PICU survivors (31%; 95% CI 20 to 42%) commenced HAART, and two children were already on treatment. Nineteen children (28%) were considered to be established on HAART after 1 month. Thirteen HIV-infected children (19%; 95% CI 10 to 28%), representing 25% (95% CI 14 to 37%) of all PICU survivors, and 68% (95% CI 48 to 89%) of those PICU survivors who were established on HAART remain well on treatment after median 350 days. CONCLUSION: The majority of HIV-infected children survived to discharge from PICU, but only half survived to hospital discharge. LOI decisions, usually made in PICU, directly influenced short-term survival and the opportunity to commence HAART. Although few critically ill HIV-infected children survived to become established on HAART, the long-term outcome of children on HAART is encouraging and warrants further investigation.

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.

Correction of the anion gap for albumin in order to detect occult tissue anions in shock.

BACKGROUND: It is believed that hypoalbuminaemia confounds interpretation of the anion gap (AG) unless corrected for serum albumin in critically ill children with shock. AIM: To compare the ability of the AG and the albumin corrected anion gap (CAG) to detect the presence of occult tissue anions. METHODS: Prospective observational study in children with shock in a 22 bed multidisciplinary paediatric intensive care unit of a university childrenrsquo;s hospital. Blood was sampled at admission and at 24 hours, for acid-base parameters, serum albumin, and electrolytes. Occult tissue anions (lactate + truly "unmeasured" anions) were calculated from the strong ion gap. The anion gap ((Na + K) - (Cl + bicarbonate)) was corrected for serum albumin using the equation of Figge: AG + (0.25 x (44 - albumin)). Occult tissue anions (TA) predicted by the anion gap were calculated by (anion gap - 15 mEq/l). Optimal cut off values of anion gap were compared by means of receiver operating characteristic (ROC) curves. Ninety three sets of data from 55 children (median age 7 months, median weight 4.9 kg) were analysed. Data are expressed as mean (SD), and mean bias (limits of agreement). RESULTS: The incidence of hypoalbuminaemia was 76% (n = 42/55). Mean serum albumin was 25 g/l (SD 8). Mean AG was 15.0 mEq/l (SD 6.1), compared to the CAG of 19.9 mEq/l (SD 6.6). Mean TA was 10.2 mmol/l (SD 6.3). The AG underestimated TA with mean bias 10.2 mmol/l (4.1-16.1), compared to the CAG, mean bias 5.3 mmol/l (0.4-10.2). A clinically significant increase of TA >5 mmol/l was present in 83% (n = 77/93) of samples, of which the AG detected 48% (n = 36/77), and the CAG 87% (n = 67/77). Post hoc ROC analysis revealed optimal cut off values for detection of TA >5 mmol/l to be AG >10 mEq/l, and CAG >15.5 mEq/l. CONCLUSION: Hypoalbuminaemia is common in critically ill children with shock, and is associated with a low observed anion gap that may fail to detect clinically significant amounts of lactate and other occult tissue anions. We suggest that the albumin corrected anion gap should be calculated to screen for occult tissue anions in these children.

Presentation and outcome of severe anticholinesterase insecticide poisoning.

AIMS: To document the patterns of presentation and outcome of severe anticholinesterase insecticide poisoning in children requiring intensive care. METHODS: Retrospective case note review of all 5541 children admitted to the paediatric intensive care unit (PICU) of a university hospital during the 10 years from January 1990 to May 2000. Fifty four children (1%) with anticholinesterase insecticide poisoning were identified. Presenting features, route of exposure, treatment, complications, and mortality were recorded. Data were analysed by the Fisher's exact and Mann-Whitney tests. RESULTS: More children than expected were from a rural area (46% versus 25%). Decontamination occurred in 50% of children prior to PICU admission. Enteral exposure was most common (n = 27; 50%). Median pseudocholinesterase level was 185 IU/l (range 75-7404). Median total dose of atropine required to maintain mydriasis was 0.3 mg/kg (range 0.03-16.7) over a median of 10 hours (range 1-160). Complications included coma (31%), seizures (30%), shock (9%), arrhythmias (9%), and respiratory failure requiring ventilation (35%). No significant differences were detected in incidence of seizures, cardiac arrhythmias, respiratory failure, mortality, duration of ventilation, or PICU stay, according to route of exposure, or state of decontamination. Four children died (7%). Mortality was associated with the presence of a cardiac arrhythmia (likelihood ratio 8.3) and respiratory failure (likelihood ratio 3.3). CONCLUSION: The mortality and morbidity of severe anticholinesterase insecticide poisoning in childhood is not related to route of exposure, or to delay in decontamination. However, the presence of either a cardiac arrhythmia or respiratory failure is associated with a poor prognosis.

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.