The need for better data about counterfeit drugs in developing countries: a proposed standard research methodology tested in Chennai, India.

WHAT IS KNOWN AND OBJECTIVE: There is still surprisingly little basic research data to support widely repeated claims about the prevalence of drug counterfeiting. To meet the need for more reliable drug quality data, we designed a study framework that includes clear definitions of measured end points, sampling methods and assay technique. Our objective was to test this research design in Chennai (formerly Madras), India, using a joint Indian and Canadian team. METHODS: The city was divided into ten areas along municipal lines. From each area, ten stores and pharmacies selling drugs were selected. At each of these 100 outlets, three study drugs (artesunate, ciprofloxacin and rifampicin) were purchased. The 300 samples were tested by Liquid Chromatography-Mass Spectrometry. Assay content was expressed as a percentage of stated tablet content. Based on assay results and their distribution, we developed drug quality definitions for normal manufacturing standards, counterfeiting, decomposition, poor quality control and adulteration. RESULTS: The group mean for ciprofloxacin was close to normal manufacturing limits (99·2 ± 7·1%) but rifampicin (91·6 ± 5·7%), and artesunate (80·1 ± 9·1%), were both below normal pharmaceutical standards. Overall, 43% of all samples fell below the widely accepted manufacturing range of 90-110% of stated content. No tablet from any sample contained less than 50% of the stated dose. WHAT IS NEW AND CONCLUSION: The quality of at least some anti-infective drugs in Chennai is below commonly accepted standards but we found no evidence of criminal counterfeiting. Poor drug quality was most likely due to decomposition during storage or poor manufacturing standards. Our research methodology worked well under practical conditions and should hopefully be of value to others working in this area.

How accurate is the diagnosis of exercise induced asthma among Vancouver schoolchildren?

BACKGROUND: Limited access to exercise testing facilities means that the diagnosis of exercise induced asthma (EIA) is mainly based on self-reported respiratory symptoms. This is open to error since the correlation between exercise related symptoms and subsequent exercise testing has been shown to be poor. AIM: To study the accuracy of clinically diagnosed EIA among Vancouver schoolchildren. METHODS: Fifty two children referred for investigation of poorly controlled EIA were studied. Following a careful history and physical examination, children performed pulmonary function tests before, then 5 and 15 minutes after a standardised treadmill exercise test. Based on overall assessment, a diagnostic explanation for each child's respiratory complaints was provided as far as possible. RESULTS: Only eight children (15.4%) fulfilled diagnostic criteria for EIA (fall in FEV(1) > or =10%). Of the remainder: 12 (23.1%) were unfit, 14 (26.9%) had vocal cord dysfunction/sigh dyspnoea, 7 (13.5%) had a habit cough, and 11 (21.1%) had no abnormalities on clinical or laboratory testing, so were given no diagnosis. Initial reported symptoms of wheeze or cough often changed significantly following a careful history, particularly among the eight elite athletes. The final complaint was sometimes not respiratory, and, in a few cases, was not even associated with exercise. CONCLUSIONS: The clinical diagnosis of EIA is inaccurate among Vancouver schoolchildren, principally due to the unreliability of their initial exercise related complaints. Symptom exaggeration, familiarity with medical jargon, and psychogenic complaints are all common. A careful history is essential in this population before basing any diagnosis on self-reported respiratory symptoms.

Echocardiography and pulmonary function testing in childhood onset systemic lupus erythematosus.

The aim of this paper was to investigate the frequency of echocardiography (ECHO) and pulmonary function test (PFT) abnormalities in childhood onset systemic lupus erythematosus (SLE), and to determine the relationship of these abnormalities to disease activity. The charts of 50 patients with childhood onset SLE attending a pediatric rheumatology clinic were reviewed for ECHO and PFT studies. The frequency and description of ECHO and PFT abnormalities were documented. Possible associations of PFT and ECHO abnormalities with clinical cardiopulmonary disease, radiographic findings, and measures of lupus disease activity were evaluated. Forty patients (80%) had at least one ECHO study. Twenty-seven (68%) had an abnormal initial study. Nine of 14 patients with an initial abnormal ECHO had normal findings on repeated study. Three abnormalities were considered moderately severe. Thirty-three patients (66%) had at least one PFT performed. Sixteen (48%) were abnormal initially. Four of these 'abnormal' studies were repeated and the abnormalities persisted. Nine patients (27%) were considered to have a severe abnormality. Thirty-one children (62%) had both studies performed. An initial abnormal ECHO and abnormal PFT was found in 10 (32%) of these children. No relationship between ECHO or PFT abnormality and any measure of disease activity (physician's global assessment, anti DNA, C3 or ESR) could be found. Occult cardiac and pulmonary disease as demonstrated by ECHO or PFT occurs frequently in childhood onset SLE. If we wish to understand the natural history of these abnormal heart and lung findings, it will be necessary to do serial testing with ECHO and PFTs in this population.

Hemostatic parameters and platelet activation marker expression in cyanotic and acyanotic pediatric patients undergoing cardiac surgery in the presence of tranexamic acid.

We have investigated hemostatic parameters including platelet activation in 56 pediatric patients with or without cyanosis undergoing cardiopulmonary bypass (CPB) and cardiac surgery to repair congenital defects. Patients were participants in a study assessing the effects of tranexamic acid on surgery-related blood loss. Parameters monitored included blood loss, prothrombin F1.2, thrombin-antithrombin complexes, t-PA, PAI-1, plasminogen, fibrin D-dimer, and plasma factor XIII. Additionally, flow cytometry monitored platelet degranulation (P-selectin or CD63), as well as surface-bound fibrinogen, von Willebrand factor and factor XIIIa. Cyanotic patients had evidence of supranormal coagulation activation as both fibrin D-dimer and PAI-1 levels were elevated prior to surgery. While the extent of expression of P-selectin or CD63 was not informative, platelet-associated factor XIIIa was elevated in cyanotic patients at baseline. In both patient groups, CPB altered platelet activation state and coagulation status irrespective of the use of tranexamic acid.

Hyperbaric oxygen therapy for cerebral palsy: two complications of treatment.

There is growing interest in the use of hyperbaric oxygen therapy (HBO(2)) for children with cerebral palsy. Although there is no rigorous evidence to support this management, private hyperbaric centers have been established throughout the United States and Canada. There is likely to be increasing pressure on pediatricians and other health professionals to prescribe HBO(2). We describe 2 children with cerebral palsy who suffered significant morbidity immediately after treatment with hyperbaric oxygen. Both the temporal association and pathologic findings suggest that the hyperbaric treatment is likely to have been responsible for the resulting complications. As with any new therapy, we suggest waiting for the results of a randomized, controlled trial before recommending this treatment.

Evaluation of a mathematical model to predict intrapulmonary shunt non-invasively.

PURPOSE: We have previously published a mathematical model of oxygen transport. Using several physiological assumptions, the model provides a non-invasive estimate of intrapulmonary shunt. During a larger study of lung injury in a pig model, we had the opportunity to check the validity of our assumptions and the accuracy of the model's predictions. METHODS: We used six female pigs, average weight 12.8 kg. Following general anesthesia, tracheostomy and insertion of pulmonary venous and arterial lines, lung injury was induced by repeated saline lung lavage. Using hemodynamic measurements made at different levels of inspired oxygen, intrapulmonary shunt was calculated both by the traditional shunt equation and also by our mathematical model based on non-invasive measurements of FIO2 and SaO2. RESULTS: There was good agreement between the two methods of shunt calculation. Using linear regression the correlation coefficient was 0.95. Bland and Altman analysis showed a bias of -0.8 and precision of 12%. CONCLUSION: In a controlled setting, intrapulmonary shunt can be estimated from non-invasive measurements to a reasonable degree of accuracy. However, the calculation requires too many assumptions to be of general clinical value. The equations used provide a validated physiological model that acts as a useful tool for teaching cardiorespiratory physiology.

Multiple pulmonary chemodectomas in a child: results of four different therapeutic regimens.

PURPOSE: Chemodectomas (or paragangliomas) are rare tumors of neuroendocrine chemoreceptors, such as the carotid body. This report describes a case of multiple pulmonary chemodectomas in an adolescent and discusses the results of four therapeutic regimens. PATIENTS: At 15 years of age, the patient had cough and fatigue. Investigation revealed numerous 1- to 2-cm diameter nodules throughout both lungs. Biopsy revealed multiple pulmonary chemodectomas of uncertain malignant potential. No extrapulmonary primary site could be found. RESULTS: Because of deteriorating pulmonary function, she was treated with courses of etoposide-cisplatin and subsequently somatostatin without effect. She finally responded to a course of doxorubicin and streptozocin. She is currently maintained on interferon-alpha 2B but her measured vital capacity continues to fall slowly, reflecting increased tumor growth. Because there is still no evidence of extrapulmonary spread, she is considered to be a candidate for lung transplantation. CONCLUSIONS: A doxorubicin-streptozocin combination produced a temporary remission of this patient's multiple pulmonary chemodectomas.

Effect of hyperventilation on regional cerebral blood flow in head-injured children.

OBJECTIVES: To study cerebral blood flow and cerebral oxygen consumption in severe head-injured children and also to assess the effect of hyperventilation on regional cerebral blood flow. DESIGN: Prospective cohort study. SETTING: Pediatric intensive care unit at a tertiary-level university children's hospital. PATIENTS: Twenty-three children with isolated severe brain injury, whose admission Glasgow Coma Scores were <8. INTERVENTIONS: PaCO2 was adjusted by altering minute ventilation. Cerebral metabolic measurements were made at three levels of PaCO2 (>35, 25 to 35, and <25 torr [>4.7, 3.3 to 4.7, and <3.3 kPa]) after allowing 15 mins for equilibrium. MEASUREMENTS AND MAIN RESULTS: Thirty-eight studies (each study consisting of three sets of measurements at different levels of PaCO2) were performed on 23 patients. At each level of PaCO2, the following measurements were made: xenon-enhanced computed tomography scans; cerebral blood flow; intracranial pressure; jugular venous bulb oxygen saturation; mean arterial pressure; and arterial oxygen saturation. Derived variables included: cerebral oxygen consumption; cerebral perfusion pressure; and oxygen extraction ratio. Cerebral blood flow decreased below normal after head injury (mean 49.6 +/- 14.6 mL/min/100 g). Cerebral oxygen consumption decreased out of proportion to the decrease in cerebral blood flow; cerebral oxygen consumption was only a third of the normal range (mean 1.02 +/- 0.59 mL/min/100 g). Neither cerebral blood flow nor cerebral oxygen consumption showed any relationship to time after injury, Glasgow Coma Score at the time of presentation, or intracranial pressure. The frequency of one or more regions of ischemia (defined as cerebral blood flow of <18 mL/min/100 g) was 28.9% during normocapnia. This value increased to 73.1% for PaCO2 at <25 torr. CONCLUSIONS: Severe head injury in children produced a modest decrease in cerebral blood flow but a much larger decrease in cerebral oxygen consumption. Absolute hyperemia was uncommon at any time, but measured cerebral blood flow rates were still above the metabolic requirements of most children. The clear relationship between the frequency of cerebral ischemia and hypocarbia, combined with the rarity of hyperemia, suggests that hyperventilation should be used with caution and monitored carefully in children with severe head injuries.

Chronic cough and wheeze in children: do they all have asthma?

In the experience of both authors, children referred for investigation of a chronic productive cough often do not fit conventional diagnostic categories. The aim of this study was to answer two questions: 1) do such diagnostic orphans exist? and, 2) if so, can they be classified in a clinically useful manner? Eighty one previously undiagnosed children referred with a history of more than 3 months productive or rattly cough were studied prospectively. Investigations consisted of a detailed history, physical examination, and an extensive set of clinical investigations. Sixty randomly selected asthmatic children served as demographic controls. Children fell into three groups: 23 had newly diagnosed conditions, such as cystic fibrosis, or were indistinguishable from asthma; 24 had a history of major medical interventions (cardiac surgery, chemotherapy, tracheo-oesophageal fistula repair); 34 had a history of significant early respiratory tract infections, usually combined with poor social conditions. The latter group differed significantly from asthmatic controls in a wide range of demographic and clinical comparisons. Native American children were overrepresented. The results of this study suggest that early respiratory insults (whether viral or medical) can induce self-perpetuating inflammation, manifesting as a chronic productive cough and intermittent wheeze. The associations between poverty and infant chest infections or early invasive medical treatment with subsequent chronic respiratory disease are clearly definable and probably justify diagnostic terms distinct from asthma, particularly for use in epidemiological studies.

Bronchial casts in children: a proposed classification based on nine cases and a review of the literature.

Bronchial casts are characterized by the formation of obstructive airway plugs that may be large enough to fill the branching pattern of an entire lung. The condition is rare but can occur at any age. Casts may be secondary to underlying diseases such as asthma and cystic fibrosis, but there are often no predisposing factors. There is no accepted classification system for bronchial casts; but only a confusion of descriptive terms such as mucoid impaction, fibrinous bronchitis, and pseudomembranous bronchitis. Based on a review of nine well-documented cases and the available literature, we have separated bronchial casts into two well-defined groups: Type 1 (inflammatory), consisting of casts composed mainly of fibrin with a dense eosinophilic inflammatory infiltrate; and Type 2 (acellular), consisting of casts composed mainly of mucin with little or no cellular infiltrate and occurring only in children with congenital cyanotic heart disease. Acute mortality was high in both groups. Survivors of Type 1 casts seem to be well controlled with inhaled steroids. Optimal therapy for patients with Type 2 casts is not clear; the prognosis probably depends on underlying cardiac status. We hope that this simple classification will provide a framework for further study of this obscure condition.

The effect of preoperative tranexamic acid on blood loss after cardiac operations in children.

Children undergoing cardiac operations in which cardiopulmonary bypass is used are at risk of significant postoperative blood loss. The acquired coagulopathy is complex but is thought to be due, in part, to excessive fibrinolysis. We examined the possibility of reducing postoperative blood loss in children by using the antifibrinolytic drug tranexamic acid. Using a prospective, randomized, double-blind study design, we administered a single dose of tranexamic acid (50 mg/kg intravenously) or saline placebo, before skin incision, in 88 children undergoing cardiac operations. Post-operative blood loss and fluid replacement were recorded for the next 24 hours. In addition, hemoglobin, platelet counts, and coagulation measures were recorded every 6 hours. When all patients were examined, there was no significant difference in postoperative blood loss between the treated and placebo groups (21.2 +/- 12 ml/kg per 24 hours, tranexamic acid, vs 27.2 +/- 20.3 mls/kg per 24 hours, placebo). However, when the children with cyanosis were analyzed separately, there was a highly significant difference in blood loss between the groups during the first 6 hours (11.2 +/- 3.7 ml/kg per 6 hours, tranexamic acid, vs 27.2 +/- 11.4 mls/kg per 6 hours, placebo; p < 0.002), as well as the overall 24 hour study period (23.7 +/- 7.5 mls/kg per 24 hours, tranexamic acid, vs 48.9 +/- 27.6 mls/kg per 24 hours, placebo; p < 0.02). Also significantly less blood and blood products were administered to the treated cyanosed group. Tranexamic acid produced a significant reduction in postoperative blood loss and blood product requirements in children with cyanosis undergoing heart operations. The drug had no effect in children without cyanosis or those requiring a second thoracotomy.

Mycoplasma pneumoniae as a cofactor in severe respiratory infections.

We report the clinical events associated with severe bacterial or viral infections in four patients whose illnesses followed or coincided with acute Mycoplasma pneumoniae respiratory infection. We propose that M. pneumoniae has the ability to act as a cofactor in severe respiratory disease by facilitating alterations in local respiratory immunity or structure and function.

Mathematical model of oxygen transport: a teaching aid for normal physiology adaptable to extracorporeal oxygenation circuits.

The ultimate aim of most intensive care therapies is to improve tissue oxygen delivery; consequently, a detailed knowledge of this area of physiology is important to a wide range of Critical Care Staff. We describe a simple mathematical model of oxygen transport that was initially written as a training aid for extracorporeal oxygenation training. The model has subsequently proved useful for explaining the determinants of oxygen transport to a broader audience. It is based on simple linear equations and is easily displayed with a standard computer spreadsheet. Apart from its teaching value, the model can also generate a graph of oxygen saturation vs. inspired oxygen fraction for different degrees of pulmonary shunt. This provides a noninvasive method for determining the magnitude of pulmonary venous admixture and may also prove to have some clinical value.

Descending aortic blood flow velocity as a noninvasive measure of cardiac output in children.

In previous work, we postulated that mean aortic flow velocity (MAFV) might be a direct measure of cardiac index. To investigate the assumptions inherent in this relation, we measured body surface area, aortic cross-sectional area (two-dimensional ultrasonography) and MAFV (Doppler ultrasonography) in 70 normal children. For a direct check of the relation, we simultaneously measured cardiac index (Fick technique) and MAFV (Doppler ultrasonography) in 25 children after cardiac surgery. In the normal group, we found that body surface area was directly proportional to aortic cross-sectional area (R 0.94), and MAFV at rest was the same in the ascending and descending aorta (t test, p < 0.05). In the intensive care patients, MAFV in the descending aorta was directly proportional to cardiac index over a wide clinical range [MAFV (cm/s) = CI (L/min/m2).7.7-1.2]. The assumptions made when deriving the relation between MAFV and cardiac index appear to be valid whether measured in the ascending or descending aorta. However, the scatter of results limits its clinical value. Mean aortic flow velocity is probably of greater use as a trend indicator and has the potential for continuous display using an esophageal Doppler probe when measured in the descending aorta.

Functional characteristics of pediatric veno-venous hemofiltration.

OBJECTIVE: To evaluate the functional characteristics of continuous veno-venous hemofiltration in a pediatric size animal model. DESIGN: Prospective trial. SETTING: Animal laboratory at a large university-affiliated medical center. SUBJECTS: Four-week old lambs (weight 12.2 +/- 1.3 kg). INTERVENTIONS: Veno-venous hemofiltration was performed in anesthetized lambs (n = 5, 12.2 +/- 1.3 kg) using a standard pediatric hemofilter and pumped blood and ultrafiltrate. We compared postdilution, predilution, and hemofiltration with counterflow dialysis. MEASUREMENTS AND MAIN RESULTS: At net ultrafiltrate flows of 200, 400, and 600 mL/hr, we measured system pressures and urea clearance. Stable blood flow could reproducibly be achieved up to 140 mL/min (10 mL/kg/min); at higher flow demand, tubing collapse occurred. At blood flow rates of 5 to 10 mL/kg/min, ultrafiltrate flow of 1 mL/kg/min would create negative filter compartment pressure but consistently less negative than -500 mm Hg. During postdilution, predilution, and counterflow dialysis, urea clearance was virtually equal to ultrafiltrate flow. There was no increase in urea clearance when adding predilution or dialysis to basic postdilution. CONCLUSIONS: Veno-venous hemofiltration, using small filters and circuits in a pediatric size animal, can achieve stable blood flow up to 10 mL/kg/min. At this flow, ultrafiltrate flow of 1 mL/kg/min can produce a urea clearance of 1 mL/kg/min while keeping filter compartment pressure above maximal recommended negative pressures. Addition of dialysis in this nonuremic model did not increase urea clearance.

Oxygen consumption-oxygen delivery relationship in children.

We examined the relationship between oxygen consumption (VO2) and oxygen delivery (DO2) over a range of metabolic demand in two groups of children. We studied 15 children after cardiac surgery (plasma lactate levels < 2.2 mmol/L, VO2 < 6 ml/min per kilogram, oxygen extraction ratio < 25%); 8 were given transfusions with erythrocytes, 10 to 15 ml/kg, and 7 received adrenaline infusions (0.05 to 0.3 micrograms/kg per minute). Blood transfusions significantly increased DO2 (20.5 +/- 6.4 to 26.2 +/- 7.1 ml/min per kilogram; p < 0.05) but did not alter VO2. Adrenaline increased DO2 (19.9 +/- 5.0 to 25.9 +/- 6.1 ml/min per kilogram; p < 0.05) and VO2 (4.3 +/- 0.8 to 5.5 +/- 1.2 ml/min per kilogram; p < 0.05), but the oxygen excretion ratio and the mixed venous oxygen saturation were unchanged. We also measured VO2 and Doppler-derived DO2 in 25 normal children during exercise. The relationship during exercise is given by the following equation: VO2 index (in milliliters per minute per kilogram) = 0.88 x DO2 index - 6.95. Adrenaline infusions, but not blood transfusions, increased VO2 and DO2 together. This effect may be due to increased demand, analogous to exercise, and probably does not represent improved perfusion. We also found significant measurement error in DO2 and spontaneous variation in VO2. We believe that the concept of supply-dependent VO2 is based on a number of methodologic and measurement errors. It should not be used to justify potentially dangerous therapies in sick children.

Operating characteristics of pediatric continuous arteriovenous hemofiltration in an animal model.

Continuous arteriovenous hemofiltration (CAVH) is an increasingly popular technique in the care of critically ill children. The operating characteristics of the available circuits are largely unknown. Prior to introducing CAVH into our pediatric intensive care unit, we investigated the performance of three CAVH circuits: CAVH with postfilter dilution, CAVH with prefilter dilution (CAVHpre) and CAVH with dialysis counterflow. Using a neonatal lamb model, we measured filter blood flow (QB), ultrafiltrate rate (QU), arterial, venous and ultrafiltrate compartment pressures, oncotic pressure, plus urea levels in blood and ultrafiltrate fluid for the three CAVH circuit designs. Transmembrane pressure and urea clearance were calculated for various values of QB after varying a clamp on the arterial side of the circuit. The major finding, applicable to all circuits, was the wide variability of QB. Constant attention was required in order to obtain a consistent QB. Fluid clearance was effective with all three circuits. Urea clearance averaged 5-10 ml/min and was principally dependent on QU and independent of QB. The addition of dialysis counterflow did not increase urea clearance. The most convenient circuit we tested was CAVHpre, but the problem of unstable QB is common to all unpumped arteriovenous filtrate circuits. It is a major limiting factor in the practical application of this technology to critically ill children.

Corynebacterium pseudodiphtheriticum pneumonitis in a leukaemic child.

A 6 year old boy receiving chemotherapy for acute lymphocytic leukaemia developed pneumonia due to Corynebacterium pseudodiphtheriticum. He responded to antibiotics.