Parallel increases in the ornithine carbamyl transferase and glutamate dehydrogenase activities w... more Parallel increases in the ornithine carbamyl transferase and glutamate dehydrogenase activities were observed in the serum of 22 Reye's syndrome patients. The increase in the activity of glutamate dehydrogenase was masked by a dialyzable inhibitor. It is proposed that the measurement of serum ornithine carbamyl transferase and glutamate dehydrogenase activities may be useful as an indicator of liver mitochondrial damage in Reye's syndrome.
Guanidino compounds, intermediates of arginine metabolism, are altered in many pathological condi... more Guanidino compounds, intermediates of arginine metabolism, are altered in many pathological conditions especially those involving the urea cycle. Arginine and creatine play an important role in nitrogen metabolism whereas other guanidino compounds such as guanidinosuccinic acid and N-acetylarginine are toxins. Our objective was to investigate the relationship between guanidino compounds and hyperammonemia. Young and adult ferrets were fed a single meal of either an arginine-containing diet (ACD) or an arginine-free diet (AFD). Guanidino compounds were determined by HPLC in the plasma, liver, kidney and brain 3 h after feeding the specified diet. Only young ferrets fed AFD developed hyperammonemia. Plasma and kidney arginine was decreased whereas guanidinosuccinic acid was increased in young ferrets fed AFD. Hepatic creatine and kidney and brain guanidinoacetic acid were significantly decreased in this group. These results indicate that AFD-induced hyperammonemia produced decreased methylation activity in the liver and transamidination activity in kidney. Elevated guanidinosuccinate levels coupled with deficient hepatic creatine synthesis may play a role in the pathophysiology of hyperammonemia.
Fourteen cases of severe clonidine poisoning occurring in children over a 5-yr period were review... more Fourteen cases of severe clonidine poisoning occurring in children over a 5-yr period were reviewed. The typical patient was a previously healthy toddler who ingested clonidine while visiting a relative. All patients were lethargic on admission and most were admitted with bradycardia or miosis. Hypotension was more likely to develop after admission. Recovery occurred within 48 h with only symptomatic treatment. Significant morbidity from clonidine ingestion occurred in terms of hospitalization, invasive monitoring, and mechanical ventilation.
Administration of salicylates during prodromal viral illness has been associated with the develop... more Administration of salicylates during prodromal viral illness has been associated with the development of Reye's syndrome (RS). We studied salicylate biotransformation in RS patients and compared it with those on chronic salicylate therapy for juvenile rheumatoid arthritis (JRA). Urine of RS patients contained significantly more salicylic acid and less gentisic acid than that of JRA patients while the conjugated metabolites were not different between the two groups. These results suggest decreased salicylate microsomal oxidation in RS. The role of altered salicylate metabolism in the pathogenesis of RS is unclear.
Acute mitochondrial insult has been suggested as a primary reason for the clinical, histopatholog... more Acute mitochondrial insult has been suggested as a primary reason for the clinical, histopathological and biochemical abnormalities seen in Reye's syndrome. However, the etiology of mitochondrial dysfunction has not been identified. Polyamines have been known to alter the mitochondrial structure and function. Influenza infection may cause an increase in ornithine decarboxylase activity and thereby channel ornithine for polyamine biosynthesis, leading to mitochondrial dysfunction in Reye's syndrome. To test this hypothesis, the hepatic concentrations of polyamines, polyamine-metabolizing enzymes and urea cycle enzyme activities in Reye's syndrome patients were determined and compared with patients who died from illnesses other than Reye's syndrome. The hepatic concentration of putrescine, spermidine and spermine were increased in Reye's syndrome patients. The activity of ornithine decarboxylase was elevated but, due to the small number of samples, these values did not reach statistical significance. Ornithine carbamoyltransferase activity was decreased in the liver of Reye's syndrome patients. Our results suggest that increased synthesis of polyamines from ornithine may initiate mitochondrial injury in Reye's syndrome.
A variety of severe pulmonary insults such as the adult respiratory distress syndrome (ARDS) is o... more A variety of severe pulmonary insults such as the adult respiratory distress syndrome (ARDS) is often seen in critically ill children. This article summarizes the clinical manifestations, management, and outcome of children with ARDS. The literature pertaining to the syndrome in the pediatric population is reviewed, and areas where there are key differences between children and adults are emphasized.
Plasma fibronectin is an attachment protein important for maintaining capillary integrity and hos... more Plasma fibronectin is an attachment protein important for maintaining capillary integrity and host defense mechanisms. Depletion of plasma fibronectin has been shown to occur in adults after septic shock, major trauma, and burns. Limited laboratory and clinical studies suggest a correlation between decreased plasma fibronectin levels and increased pulmonary capillary permeability and tissue perfusion. Mild and transient plasma fibronectin depletion has been observed in adults after cardiovascular operations. We measured plasma fibronectin by immunoturbidometric assay in 20 children (age 6 months to 12 years) undergoing repair of congenital heart defects. Plasma fibronectin levels immediately after operations and daily thereafter were compared with the preoperative values. Plasma fibronectin declined on postoperative days 1, 2, 3, 4, and 5 (p < 0.05). A nadir was reached on day 3 with a tendency toward recovery thereafter. Patients with a therapeutic intervention score of more than 35 had greater magnitude of plasma fibronectin decline than those with a score of less than 35 at 24 hours after the operation (p < 0.005). We conclude that (1) significant and prolonged plasma fibronectin depletion occurs after cardiovascular operations in children; and (2) postoperative plasma fibronectin depletion is associated with increasingly complex surgical intervention. Reduced plasma fibronectin synthesis and more extensive operations for congenital heart defects are likely reasons for children being more susceptible than adults to plasma fibronectin depletion after cardiovascular operations.
To evaluate changes in and the correlation between plasma phosphorus, red cell 2,3-diphosphoglyce... more To evaluate changes in and the correlation between plasma phosphorus, red cell 2,3-diphosphoglycerate (DPG) and adenosine triphosphate (ATP), and P50 in children following heart surgery. Prospective, observational study with factorial design. A pediatric intensive care unit in a university hospital. Twenty children undergoing open heart surgery for congenital heart defects. None. Red cell 2,3-DPG and ATP, P50, plasma phosphorus, and arterial lactate were obtained before and at 1, 8, 16, 24, 48, and 72 hours after surgery. The amount of intravenous fluid and glucose administered, and age of blood utilized were documented. Variables were analyzed by repeated measure analysis of variance followed by paired t-tests. To investigate the relationship between variables at each time point, scatterplot matrices and correlation coefficients were obtained. There was a reduction in plasma phosphorus, red cell 2,3-DPG, and P50 and an increase in arterial lactate at 1, 8, 16, 24, 48, and 72 hours after surgery. Red cell 2,3-DPG correlated with P50 at 1, 8 and 16 hours. The decrease in the plasma phosphorus correlated with the amounts of intravenous fluid and glucose administered on the day of surgery and on the first and second postoperative days. The age of the blood utilized correlated with the decrease in red cell 2,3-DPG on the day of surgery. Reduction in red cell 2,3-DPG, P50, and plasma phosphorus occurs after open heart surgery in children. These changes can potentially contribute to impaired oxygen utilization in the postoperative period, when adequacy of tissue oxygenation is critical.
The initial evaluation, stabilization, and subsequent transport of the neurologically compromised... more The initial evaluation, stabilization, and subsequent transport of the neurologically compromised child should take into account the pathophysiologic response of the CNS to a variety of injurious factors. Little can be done to avoid neuronal damage from the primary event. Secondary insults resulting from hypoxemia, ischemia, intracranial hypertension, and fluid shifts can and must be prevented to ensure maximum neuronal salvage, however. Maintenance of an adequate airway, breathing, and circulation assume an immediate and ongoing priority. Neuroresuscitation should be directed toward reversing alterations in cerebral metabolism, autoregulation, brain water, and ICP associated with individual pathologic states.
We determined the efficacy of continuous arteriovenous hemofiltration (CAVH) in removing tumor ne... more We determined the efficacy of continuous arteriovenous hemofiltration (CAVH) in removing tumor necrosis factor (TNF), thromboxane A2, and prostacyclin, and in improving survival in endotoxemia. Twelve rats were given 10 mg/kg of E. coli 0:127:B8 lipopolysaccharide. Fifteen min later, the rats were randomized to ultrafiltered or non-ultrafiltered groups. Blood and ultrafiltrate were collected for TNF, thromboxane B2 (TxB2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). After 4 hr, surviving rats were sacrificed. Five of 6 ultrafiltered and none of 6 non-ultrafiltered rats survived 4 hr. Plasma TxB2 > 1,000 pcg/ml and its rate of increase within the first 2 hr predicted death (P < 0.03). Ultrafiltration decreased the rate of rise in TxB2 (P < 0.04). Plasma TxB2 inversely correlated with TxB2 clearance by ultrafiltration. The concentration and rate of increase in TNF and 6-keto-PGF1 alpha did not predict survival. We conclude that CAVH improves short term survival in endotoxemia. Salutary effects appear to be due to thromboxane A2 removal.
Tumor necrosis factor (TNF) has been implicated in hemodynamic changes of endotoxic shock. The te... more Tumor necrosis factor (TNF) has been implicated in hemodynamic changes of endotoxic shock. The temporal relationship of hypotension and TNF release in endotoxemia was studied. Carotid arteries of five intubated rats were cannulated and Escherichia coli 0127:B8 lipopolysaccharide (LPS) was infused over 10 seconds. Arterial blood pressure (ABP), heart rate, and plasma TNF concentrations were measured at 0, 5, 15, 30, and 60 mins. Five to 15 mins after LPS, there was a marked decline in ABP (146 +/- 23 vs 57 +/- 5 mm Hg, p < 0.005), without a significant rise in TNF. The heart rate did not change. From 15 to 60 mins, there was a rise in TNF concentrations (523 +/- 333 vs 5783 +/- 629 pg/ml, p < 0.005) while the same degree of hypotension persisted. It is concluded that early hypotension after acute endotoxemia is not dependent on TNF alone. However, TNF may play a role in sustaining hypotension after endotoxemia.
Parallel increases in the ornithine carbamyl transferase and glutamate dehydrogenase activities w... more Parallel increases in the ornithine carbamyl transferase and glutamate dehydrogenase activities were observed in the serum of 22 Reye's syndrome patients. The increase in the activity of glutamate dehydrogenase was masked by a dialyzable inhibitor. It is proposed that the measurement of serum ornithine carbamyl transferase and glutamate dehydrogenase activities may be useful as an indicator of liver mitochondrial damage in Reye's syndrome.
Guanidino compounds, intermediates of arginine metabolism, are altered in many pathological condi... more Guanidino compounds, intermediates of arginine metabolism, are altered in many pathological conditions especially those involving the urea cycle. Arginine and creatine play an important role in nitrogen metabolism whereas other guanidino compounds such as guanidinosuccinic acid and N-acetylarginine are toxins. Our objective was to investigate the relationship between guanidino compounds and hyperammonemia. Young and adult ferrets were fed a single meal of either an arginine-containing diet (ACD) or an arginine-free diet (AFD). Guanidino compounds were determined by HPLC in the plasma, liver, kidney and brain 3 h after feeding the specified diet. Only young ferrets fed AFD developed hyperammonemia. Plasma and kidney arginine was decreased whereas guanidinosuccinic acid was increased in young ferrets fed AFD. Hepatic creatine and kidney and brain guanidinoacetic acid were significantly decreased in this group. These results indicate that AFD-induced hyperammonemia produced decreased methylation activity in the liver and transamidination activity in kidney. Elevated guanidinosuccinate levels coupled with deficient hepatic creatine synthesis may play a role in the pathophysiology of hyperammonemia.
Fourteen cases of severe clonidine poisoning occurring in children over a 5-yr period were review... more Fourteen cases of severe clonidine poisoning occurring in children over a 5-yr period were reviewed. The typical patient was a previously healthy toddler who ingested clonidine while visiting a relative. All patients were lethargic on admission and most were admitted with bradycardia or miosis. Hypotension was more likely to develop after admission. Recovery occurred within 48 h with only symptomatic treatment. Significant morbidity from clonidine ingestion occurred in terms of hospitalization, invasive monitoring, and mechanical ventilation.
Administration of salicylates during prodromal viral illness has been associated with the develop... more Administration of salicylates during prodromal viral illness has been associated with the development of Reye's syndrome (RS). We studied salicylate biotransformation in RS patients and compared it with those on chronic salicylate therapy for juvenile rheumatoid arthritis (JRA). Urine of RS patients contained significantly more salicylic acid and less gentisic acid than that of JRA patients while the conjugated metabolites were not different between the two groups. These results suggest decreased salicylate microsomal oxidation in RS. The role of altered salicylate metabolism in the pathogenesis of RS is unclear.
Acute mitochondrial insult has been suggested as a primary reason for the clinical, histopatholog... more Acute mitochondrial insult has been suggested as a primary reason for the clinical, histopathological and biochemical abnormalities seen in Reye's syndrome. However, the etiology of mitochondrial dysfunction has not been identified. Polyamines have been known to alter the mitochondrial structure and function. Influenza infection may cause an increase in ornithine decarboxylase activity and thereby channel ornithine for polyamine biosynthesis, leading to mitochondrial dysfunction in Reye's syndrome. To test this hypothesis, the hepatic concentrations of polyamines, polyamine-metabolizing enzymes and urea cycle enzyme activities in Reye's syndrome patients were determined and compared with patients who died from illnesses other than Reye's syndrome. The hepatic concentration of putrescine, spermidine and spermine were increased in Reye's syndrome patients. The activity of ornithine decarboxylase was elevated but, due to the small number of samples, these values did not reach statistical significance. Ornithine carbamoyltransferase activity was decreased in the liver of Reye's syndrome patients. Our results suggest that increased synthesis of polyamines from ornithine may initiate mitochondrial injury in Reye's syndrome.
A variety of severe pulmonary insults such as the adult respiratory distress syndrome (ARDS) is o... more A variety of severe pulmonary insults such as the adult respiratory distress syndrome (ARDS) is often seen in critically ill children. This article summarizes the clinical manifestations, management, and outcome of children with ARDS. The literature pertaining to the syndrome in the pediatric population is reviewed, and areas where there are key differences between children and adults are emphasized.
Plasma fibronectin is an attachment protein important for maintaining capillary integrity and hos... more Plasma fibronectin is an attachment protein important for maintaining capillary integrity and host defense mechanisms. Depletion of plasma fibronectin has been shown to occur in adults after septic shock, major trauma, and burns. Limited laboratory and clinical studies suggest a correlation between decreased plasma fibronectin levels and increased pulmonary capillary permeability and tissue perfusion. Mild and transient plasma fibronectin depletion has been observed in adults after cardiovascular operations. We measured plasma fibronectin by immunoturbidometric assay in 20 children (age 6 months to 12 years) undergoing repair of congenital heart defects. Plasma fibronectin levels immediately after operations and daily thereafter were compared with the preoperative values. Plasma fibronectin declined on postoperative days 1, 2, 3, 4, and 5 (p < 0.05). A nadir was reached on day 3 with a tendency toward recovery thereafter. Patients with a therapeutic intervention score of more than 35 had greater magnitude of plasma fibronectin decline than those with a score of less than 35 at 24 hours after the operation (p < 0.005). We conclude that (1) significant and prolonged plasma fibronectin depletion occurs after cardiovascular operations in children; and (2) postoperative plasma fibronectin depletion is associated with increasingly complex surgical intervention. Reduced plasma fibronectin synthesis and more extensive operations for congenital heart defects are likely reasons for children being more susceptible than adults to plasma fibronectin depletion after cardiovascular operations.
To evaluate changes in and the correlation between plasma phosphorus, red cell 2,3-diphosphoglyce... more To evaluate changes in and the correlation between plasma phosphorus, red cell 2,3-diphosphoglycerate (DPG) and adenosine triphosphate (ATP), and P50 in children following heart surgery. Prospective, observational study with factorial design. A pediatric intensive care unit in a university hospital. Twenty children undergoing open heart surgery for congenital heart defects. None. Red cell 2,3-DPG and ATP, P50, plasma phosphorus, and arterial lactate were obtained before and at 1, 8, 16, 24, 48, and 72 hours after surgery. The amount of intravenous fluid and glucose administered, and age of blood utilized were documented. Variables were analyzed by repeated measure analysis of variance followed by paired t-tests. To investigate the relationship between variables at each time point, scatterplot matrices and correlation coefficients were obtained. There was a reduction in plasma phosphorus, red cell 2,3-DPG, and P50 and an increase in arterial lactate at 1, 8, 16, 24, 48, and 72 hours after surgery. Red cell 2,3-DPG correlated with P50 at 1, 8 and 16 hours. The decrease in the plasma phosphorus correlated with the amounts of intravenous fluid and glucose administered on the day of surgery and on the first and second postoperative days. The age of the blood utilized correlated with the decrease in red cell 2,3-DPG on the day of surgery. Reduction in red cell 2,3-DPG, P50, and plasma phosphorus occurs after open heart surgery in children. These changes can potentially contribute to impaired oxygen utilization in the postoperative period, when adequacy of tissue oxygenation is critical.
The initial evaluation, stabilization, and subsequent transport of the neurologically compromised... more The initial evaluation, stabilization, and subsequent transport of the neurologically compromised child should take into account the pathophysiologic response of the CNS to a variety of injurious factors. Little can be done to avoid neuronal damage from the primary event. Secondary insults resulting from hypoxemia, ischemia, intracranial hypertension, and fluid shifts can and must be prevented to ensure maximum neuronal salvage, however. Maintenance of an adequate airway, breathing, and circulation assume an immediate and ongoing priority. Neuroresuscitation should be directed toward reversing alterations in cerebral metabolism, autoregulation, brain water, and ICP associated with individual pathologic states.
We determined the efficacy of continuous arteriovenous hemofiltration (CAVH) in removing tumor ne... more We determined the efficacy of continuous arteriovenous hemofiltration (CAVH) in removing tumor necrosis factor (TNF), thromboxane A2, and prostacyclin, and in improving survival in endotoxemia. Twelve rats were given 10 mg/kg of E. coli 0:127:B8 lipopolysaccharide. Fifteen min later, the rats were randomized to ultrafiltered or non-ultrafiltered groups. Blood and ultrafiltrate were collected for TNF, thromboxane B2 (TxB2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). After 4 hr, surviving rats were sacrificed. Five of 6 ultrafiltered and none of 6 non-ultrafiltered rats survived 4 hr. Plasma TxB2 > 1,000 pcg/ml and its rate of increase within the first 2 hr predicted death (P < 0.03). Ultrafiltration decreased the rate of rise in TxB2 (P < 0.04). Plasma TxB2 inversely correlated with TxB2 clearance by ultrafiltration. The concentration and rate of increase in TNF and 6-keto-PGF1 alpha did not predict survival. We conclude that CAVH improves short term survival in endotoxemia. Salutary effects appear to be due to thromboxane A2 removal.
Tumor necrosis factor (TNF) has been implicated in hemodynamic changes of endotoxic shock. The te... more Tumor necrosis factor (TNF) has been implicated in hemodynamic changes of endotoxic shock. The temporal relationship of hypotension and TNF release in endotoxemia was studied. Carotid arteries of five intubated rats were cannulated and Escherichia coli 0127:B8 lipopolysaccharide (LPS) was infused over 10 seconds. Arterial blood pressure (ABP), heart rate, and plasma TNF concentrations were measured at 0, 5, 15, 30, and 60 mins. Five to 15 mins after LPS, there was a marked decline in ABP (146 +/- 23 vs 57 +/- 5 mm Hg, p < 0.005), without a significant rise in TNF. The heart rate did not change. From 15 to 60 mins, there was a rise in TNF concentrations (523 +/- 333 vs 5783 +/- 629 pg/ml, p < 0.005) while the same degree of hypotension persisted. It is concluded that early hypotension after acute endotoxemia is not dependent on TNF alone. However, TNF may play a role in sustaining hypotension after endotoxemia.
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