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.

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.

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.

The effect of desmopressin acetate (DDAVP) on postoperative blood loss after cardiac operations in children.

We investigated the effect of an intraoperative desmopressin acetate infusion on blood loss after cardiac operation in 60 children, by using a prospective, randomized, double-blind trial. Thirty patients received a desmopressin dose of 0.3 microgram/kg intravenously over 15 minutes at the conclusion of cardiac bypass, and 30 received a saline placebo. The two groups were comparable with respect to age, sex, cardiac lesion, presence of cyanosis, and prevalence of Down's syndrome. Results showed no significant difference in postoperative blood loss between the two groups (30.5 +/- 37.9 ml/kg in the placebo group versus 40.0 +/- 33.1 ml/kg in the desmopressin group). Postoperative bleeding time, total urine output, postinfusion hemodynamics, and postoperative coagulation studies did not differ significantly between the two groups. We conclude that postbypass desmopressin infusion does not reduce blood loss in children undergoing cardiac operations.

The clinical value and risks of lung biopsy in children with congenital heart disease.

A retrospective review was made of 59 open lung biopsy specimens taken between 1984 and 1988 from children with congenital heart disease who were at risk for pulmonary vascular disease. Thirty-seven patients (ranging in age from 3.5 months to 23 years; median age, 14 months) had a primary left-to-right shunt (group A) and 22 patients (ages 1 to 15 years) had palliated cyanotic heart disease (group B). Forty-five of the lung biopsy specimens were requested as frozen sections. In both groups lung biopsy specimens were graded by the Heath-Edwards classification and correlated against preoperative hemodynamic data and outcome. In group A patients, carefully measured pulmonary vascular resistance and pulmonary/systemic vascular resistance ratio were reliable indicators of the structural state of the pulmonary vascular bed, obviating the need for routine lung biopsy. Pulmonary/systemic vascular resistance ratios greater than 0.45 accurately predicted all patients with irreversible pulmonary vascular disease, and pulmonary vascular resistance greater than 7 units.m2 accurately predicted all but one case of disease. Reversibility of pulmonary vascular changes is not synonymous with immediate postoperative survival: Fatal postoperative pulmonary hypertensive crises occurred in the presence of reversible pulmonary disease. Of those considered for the Fontan procedure, a mean pulmonary artery pressure less than 30 mm Hg and pulmonary vascular resistance less than 3 units.m2 correlated with Heath-Edwards grade I or normal lung biopsy results. In 36% of group B patients, reliable assessment of pulmonary vascular resistance could not be made, indicating a possible need for open lung biopsy procedures. When lung biopsy procedures were used as an isolated procedure, they were more dangerous (20% mortality, 13% morbidity) than previously reported. Intraoperative frozen sections are not adequate to accurately assess pulmonary vascular changes (9% error); serial paraffin sections are required.

Amiloride impairs lung water clearance in newborn guinea pigs.

To determine whether epithelial ion transport is physiologically important for lung water clearance after birth, the sodium transport inhibitor amiloride or its vehicle saline was given intratracheally to newborn full-term guinea pigs before the first breath. Guinea pigs given saline intratracheally breathed normally and had arterial O2 saturations (SaO2) greater than 94%. In contrast, guinea pigs that had an estimated 10(-4) M intra-alveolar concentration of amiloride had chest wall retractions and 88 +/- 3.6% (SD) SaO2 (P less than 0.01). Extravascular lung water (EVLW) per gram of dry lung weight 4 h after birth was significantly greater in newborns that received amiloride (8.3 +/- 1.1, n = 5) than in those that received saline (5.6 +/- 0.9, n = 7, P less than 0.01). The degree of perivascular fluid cuffing at 25 cmH2O inflation was quantitatively similar in amiloride- and saline-treated animals. The effect of amiloride was dose dependent. Intratracheal amiloride did not affect EVLW in 9-day-old guinea pigs. This study demonstrates that intratracheal amiloride before the first breath results in respiratory distress, hypoxemia, and an abnormally high EVLW. Epithelial sodium transport contributes normal lung liquid clearance after birth.

Acute aluminum toxicity after continuous intravesical alum irrigation for hemorrhagic cystitis.

An encephalopathy and cardiomyopathy developed in a seventeen-year-old girl with chemotherapy-induced renal failure while receiving an intravesical aluminum infusion for hemorrhagic cystitis. Premortem serum and postmortem tissue aluminum levels were markedly elevated. It is likely that her inability to excrete absorbed aluminum contributed to her death. Aluminum infusions should be used with caution in patients with renal failure.

The effect of lung mechanics on gas transport during high-frequency oscillation.

With the general aim of obtaining clinically relevant information on the use of high-frequency oscillation (HFO), we examined the effects of altering oscillatory frequency (f), tidal volume (VT), and mean airway pressure (Paw) on gas exchange in rabbits, both before and after altering the animal's pulmonary mechanics by saline induced lung injury. Twenty-seven combinations of f (5, 8, 12 Hz), VT (0.5, 1, 2 mL/kg), and Paw (5, 10, 13 cm H2O) were used. Acute pulmonary injury was induced by instilling 10 mL/kg of warm saline into the lung. Gas exchange was assessed by steady-state levels of arterial oxygen tension (PaO2) and carbon dioxide tension (PaCO2). Arterial PaO2 was independent of f or VT before or after lung injury; it was independent of Paw before injury but highly dependent on Paw after lavage. The difference was presumably related to lung volume recruitment. Arterial PaCO2 was dependent on f and VT but independent of Paw at any time. The relationship was modeled by the equation PaCO2 alpha fa. VTb where the exponents a = -0.4 and b = -0.6. Our technique of a standardized saline instillation gave a reproducible and stable model of lung injury. In damaged rabbit lungs the principles of HFO appear to be similar to conventional mechanical ventilation; oxygenation depends on Paw and inspired oxygen concentration, while CO2 removal is determined by f and VT.

Comparison of three methods for measuring respiratory mechanics in ventilated children.

Continuous measurements of airway pressure, gas flow, and tidal volume were made in 22 mechanically ventilated children, both during steady state conditions and following airway occlusion at end-inflation. For each child, three methods of analyzing the stored data were used to generate values of respiratory system compliance and resistance: 1) end-inspiratory hold technique (Bone: Respir Care 28:597, 1983; Rossi et al. Am Rev Respir Dis 131:672, 1985); 2) constant flow technique (Rossi et al. J Appl Physiol 58:1849, 1985; Suratt et al. J Appl Physiol 49:1116, 1980); and 3) multiple linear regression (Roy et al. Comput Biomed Res 7:21, 1974; Bhutani et al. Pediatr Pulmonol 4:150, 1988). In the absence of an accepted standard, we used the inspiratory hold technique as a reference. All methods gave comparable values for respiratory mechanics over a wide clinical range. However, multiple linear regression was the most convenient of the three: it can be automated and continuously displayed, there is no subjective input, values are taken through the respiratory cycle, and it is completely noninvasive. We also found that respiratory system resistance was largely a measure of endotracheal tube resistance and that respiratory compliance is a more sensitive monitor of lung function in intubated children.

Pilot study for the development of a monitoring device for ventilated children.

Airway pressure and air flow were measured at the endotracheal tube in 13 children on a variety of ventilators. These signals were stored for analysis on a computer. Further data sets were obtained after 24 hours or following major interventions. Air flow rate was integrated to give volume. Pulmonary resistance and elastance were obtained by multiple linear regression. Pressure-volume, pressure-flow and flow-volume loops were plotted. "Closed" pressure-volume and pressure-flow loops (by subtraction of the resistive or elastic pressure components, respectively) were also displayed, giving compliance and resistance loops. The loops from the initial data set were taken as the baseline, and loops from later data sets were superimposed to provide visual comparisons. Change in clinical status was reflected by the change in slope of compliance and resistance loops. A 30% change in compliance or resistance was easily observed. There was minimal interference with patient care. This pilot study demonstrates that changes in respiratory mechanics can be displayed safely and easily in ventilated patients using resistance and compliance loops. Further work is necessary to confirm the usefulness of real time of these displays.

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.

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.

Two cases of Wernicke's encephalopathy in children: an underdiagnosed complication of poor nutrition.

We describe the occurrence of Wernicke's encephalopathy in two children in whom the diagnosis was not suspected during life. Postmortem examination showed changes characteristic of the disease. This preventable and treatable condition is probably underdiagnosed in poorly nourished, nonalcoholic patients of all ages.

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.

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.

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.

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.

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.

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.

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.