Complications associated with paediatric airway management during the COVID-19 pandemic: an international, multicentre, observational study.

Respiratory adverse events in adults with COVID-19 undergoing general anaesthesia can be life-threatening. However, there remains a knowledge gap about respiratory adverse events in children with COVID-19. We created an international observational registry to collect airway management outcomes in children with COVID-19 who were having a general anaesthetic. We hypothesised that children with confirmed or suspected COVID-19 would experience more hypoxaemia and complications than those without. Between 3 April 2020 and 1 November 2020, 78 international centres participated. In phase 1, centres collected outcomes on all children (age ≤ 18 y) having a general anaesthetic for 2 consecutive weeks. In phase 2, centres recorded outcomes for children with test-confirmed or suspected COVID-19 (based on symptoms) having a general anaesthetic. We did not study children whose tracheas were already intubated. The primary outcome was the incidence of hypoxaemia during airway management. Secondary outcomes included: incidence of other complications; and first-pass success rate for tracheal intubation. In total, 7896 children were analysed (7567 COVID-19 negative and 329 confirmed or presumed COVID-19 positive). The incidence of hypoxaemia during airway management was greater in children who were COVID-19 positive (24 out of 329 (7%) vs. 214 out of 7567 (3%); OR 2.70 (95%CI 1.70-4.10)). Children who had symptoms of COVID-19 had a higher incidence of hypoxaemia compared with those who were asymptomatic (9 out of 51 (19%) vs. 14 out of 258 (5%), respectively; OR 3.7 (95%CI 1.5-9.1)). Children with confirmed or presumed COVID-19 have an increased risk of hypoxaemia during airway management in conjunction with general anaesthesia.

Early enteral feeding in postsurgical cancer patients. Fish oil structured lipid-based polymeric formula versus a standard polymeric formula.

OBJECTIVES: The authors compared the safety, gastrointestinal tolerance, and clinical efficacy of feeding an enteral diet containing a fish oil/medium-chain triglyceride structured lipid (FOSL-HN) versus an isonitrogenous, isocaloric formula (O-HN) in patients undergoing major abdominal surgery for upper gastrointestinal malignancies. SUMMARY BACKGROUND DATA: Previous studies suggest that feeding with n-3 fatty acids from fish oil can alter eicosanoid and cytokine production, yielding an improved immunocompetence and a reduced inflammatory response to injury. The use of n-3 fatty acids as a structured lipid can improve long-chain fatty acid absorption. METHODS: This prospective, blinded, randomized trial was conducted in 50 adult patients who were jejunally fed either FOSL-HN or O-HN for 7 days. Serum chemistries, hematology, urinalysis, gastrointestinal complications, liver and renal function, plasma and erythrocyte fatty acid analysis, urinary prostaglandins, and outcome parameters were measured at baseline and on day 7. Comparisons were made in 18 and 17 evaluable patients based a priori on the ability to reach a tube feeding rate of 40 mL/hour. RESULTS: Patients receiving FOSL-HN experienced no untoward side effects, significant incorporation of eicosapentaenoic acid into plasma and erythrocyte phospholipids, and a 50% decline in the total number of gastrointestinal complications and infections compared with patients given O-HN. The data strongly suggest improved liver and renal function during the postoperative period in the FOSL-HN group. CONCLUSION: Early enteral feeding with FOSL-HN was safe and well tolerated. Results suggest that the use of such a formula during the postoperative period may reduce the number of infections and gastrointestinal complications per patient, as well as improve renal and liver function through modulation of urinary prostaglandin levels. Additional clinical trials to fully quantify clinical benefits and optimize nutritional support with FOSL-HN should be undertaken.

Comparison of Eurocollins and University of Wisconsin solution in single flush preservation of the ischemic reperfused lung: an in vivo rabbit model.

The standard preservation technique in lung transplantation is cold single pulmonary artery flush (PAF) with Eurocollins solution (ECS). We compared ECS with University of Wisconsin (UW) solution, with and without added indomethacin, in single PAF preservation in an in vivo rabbit model of warm ischemia-reperfusion lung injury. Six groups of four New Zealand white rabbits each underwent isolation and hilar stripping of the left lung. In the four experimental groups, the left lung was flushed with (15 ml/kg) of cold ECS or UW solution, with or without added indomethacin, before warm ischemia for 120 minutes and before reperfusion for 60 minutes. The remaining two groups were the nonischemic and the ischemic "no flush" controls. Transcapillary flux of 99mTechnitium-labeled albumin and electron microscopy were used to demonstrate lung injury. Pulmonary vascular resistance (PVR) and thromboxane B2 (TXB2) concentrations were measured. There was a significant rise in PVR after ischemia/reperfusion in the ischemic control group (54.7 +/- 13.9 to 117.8 +/- 20.7 mm Hg/L.min-1, P < 0.05). The net rise in PVR after ischemia-reperfusion was significantly smaller in the two groups in which indomethacin was added (16.8 +/- 17.5 and 4.5 +/- 10.6 mm Hg/L.min-1 for UW and ECS, respectively) compared with the ischemic control (63.1 +/- 24.6 mm Hg/L.min-1, P < 0.05). Post-reperfusion TXB2 levels tended to be lower in the nonischemic control group and in the indomethacin-flush groups. We conclude that the increase in PVR produced by unilateral ischemia-reperfusion lung injury in this model was improved by single PAF perfusion. There was no significant difference between UW solution and ECS in this regard. The addition of indomethacin to the flush solution was associated with lower PVRs as well as morphologic improvement by electron microscopy. These findings may indicate a prominent role for the provision of PG synthesis inhibition during preservation for lung transplantation.

Heparin-enhanced plasma phospholipase A2 activity and prostacyclin synthesis in patients undergoing cardiac surgery.

Although eicosanoid production contributes to physiological and pathophysiological consequences of cardiopulmonary bypass (CPB), the mechanisms accounting for the enhanced eicosanoid production have not been defined. Plasma phospholipase A2 (PLA2) activity, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TXB2) levels were measured at various times during cardiac surgery. Plasma PLA2 activity increased after systemic heparinization, before CPB. This was highly correlated with concurrent increases in plasma 6-keto-PGF1 alpha, TXB2 concentrations did not increase with heparin administration but did increase significantly after initiation of CPB. High plasma PLA2 activity, 6-keto-PGF1 alpha, and TXB2 concentrations were measured throughout the CPB period. Protamine, administered to neutralize the heparin, caused an acute reduction of both plasma PLA2 activity and plasma 6-keto-PGF1 alpha, but no change in plasma TXB2 concentrations. Thus the ratio of TXB2 to 6-keto-PGF1 alpha increased significantly after protamine administration. Enhanced plasma PLA2 activity was also measured in patients with lower doses of heparin used clinically for nonsurgical applications. Human plasma PLA2 was identified as group II PLA2 by its sensitivity to deoxycholate and dithiothreitol, its substrate specificity, and its elution characteristics on heparin affinity chromatography. Heparin addition to PMNs in vitro resulted in dose-dependent increases in cellular PLA2 activity and release of PLA2. The PLA2 released from the PMN had characteristics similar to those of post-heparin plasma PLA2. In conclusion, plasma PLA2 activity and 6-keto-PGF1 alpha concentrations are markedly enhanced with systemic heparinization. Part of the anticoagulant and vasodilating effects of heparin may be due to increased plasma prostacyclin (PGI2) levels. In addition the pulmonary vasoconstriction sometimes associated with protamine infusion during cardiac surgery might be due to decreased plasma PLA2 activity, with an associated increased TXB2/6-keto-PGF1 alpha ratio.

Effect of intravenous lipid emulsions enriched with gamma-linolenic acid on plasma n-6 fatty acids and prostaglandin biosynthesis after burn and endotoxin injury in rats.

OBJECTIVE: To study the effect of intravenous lipid emulsions enriched with gamma-linolenic acid on plasma fatty acids and series-2 prostaglandins to determine if the slow conversion of linoleic acid by delta-6-desaturase to gamma-linolenic acid could be bypassed to provide substrate for the formation of dihomo-gamma-linolenic acid, the immediate precursor for series-1 prostaglandins, in control and injured rats. Dihomo-gamma-linolenic acid can also compete with arachidonic acid for oxidative metabolism by cyclooxygenase to modulate series-2 prostaglandin biosynthesis. DESIGN: Prospective, randomized, controlled, double-blind study. SETTING: Research laboratory at a university medical center. SUBJECTS: Thirty-three control and thirty-one injured male Sprague-Dawley rats were randomized into one of four parenteral dietary treatment groups. INTERVENTIONS: Rats were injured by the combined actions of a 30% body surface area full-thickness skin burn and a nonlethal injection of endotoxin (1 mg/kg ip). The rats were parenterally fed 200 kcal/kg/day, 1.5 g nitrogen/kg/day, and 30% of nonprotein calories as lipid (20% soybean lipid emulsion enriched with 2.7%, 4.4%, or 6.1% gamma-linolenic acid derived from borage oil) for 3 days. Control rats were treated similarly but were not injured. A 20% soybean/safflower oil lipid emulsion was used as the control diet (0% gamma-linolenic acid). Plasma was analyzed on day 3 to determine the concentrations of total fatty acids, thromboxane B2, 6-keto-prostaglandin F1 alpha, and bicyclo-prostaglandin E. MEASUREMENTS AND MAIN RESULTS: Parenteral nutrition with 2.7%, 4.4%, and 6.1% gamma-linolenic acid increased the plasma percentages (mol%) of gamma-linolenic acid and dihomo-gamma-linolenic acid in a dose-dependent fashion in control and injured rats. Supplementation with gamma-linolenic acid did not increase the plasma percentage of arachidonic acid as compared with the 0% gamma-linolenic acid lipid emulsion in control and injured rats. The ratio of dihomo-gamma-linolenic acid to arachidonic acid was significantly increased in response to 4.4% and 6.1% gamma-linolenic acid in both the control and injured groups. The plasma ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha was substantially reduced with gamma-linolenic acid compared with 0% gamma-linolenic acid in injured rats. Bicyclo-prostaglandin E concentration was significantly higher with 2.7% gamma-linolenic acid in injured rats. Injured rats were protein catabolic, as evidenced by a net negative nitrogen balance and loss of body mass compared with controls, but neither group showed overt signs of intolerance to the diets. CONCLUSIONS: Supplementation of parenteral nutrition with gamma-linolenic acid had the following effects: a) increased plasma gamma-linolenic acid, dihomo-gamma-linolenic acid, and bicyclo-prostaglandin E; b) increased the plasma ratio of dihomo-gamma-linolenic acid to arachidonic acid; and c) favorably reduced the ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha in injured rats. These results reflect the potential capacity of gamma-linolenic acid-enriched lipid emulsions to have the following actions: a) to increase dihomo-gamma-linolenic acid, which is the fatty acid precursor of the antiaggregatory, anti-inflammatory eicosanoid, prostaglandin E1; and b) to modulate arachidonic acid-derived series-2 prostaglandins after injury.

Comparative study of microsatellite and cytogenetic markers for detecting the origin of the nondisjoined chromosome 21 in Down syndrome.

Nondisjunction in trisomy 21 has traditionally been studied by cytogenetic heteromorphisms. Those studies assumed no crossing-over on the short arm of chromosome 21. Recently, increased accuracy of detection of the origin of nondisjunction has been demonstrated by DNA polymorphism analysis. We describe a comparative study of cytogenetic heteromorphisms and seven PCR-based DNA polymorphisms for detecting the origin of the additional chromosome 21 in 68 cases of Down syndrome. The polymorphisms studied were the highly informative microsatellites at loci D21S215, D21S120, D21S192, IFNAR, D21S156, HMG14, and D21S171. The meiotic stage of nondisjunction was assigned on the basis of the pericentromeric markers D21S215, D21S120, and D21S192. Only unequivocal cytogenetic results were compared with the results of the DNA analysis. The parental and meiotic division origin could be determined in 51% of the cases by using the cytogenetic markers and in 88% of the cases by using the DNA markers. Although there were no discrepancies between the two scoring systems regarding parental origin, there were eight discrepancies regarding meiotic stage of nondisjunction. Our results raise the possibility of recombination between the two marker systems, particularly on the short arm.

Granulocyte sequestration and early failure in the autoperfused heart-lung preparation.

We investigated the role of pulmonary granulocyte sequestration in the development of early failure of the autoperfused working heart-lung preparation. A significant decline in the total circulating leukocyte count in 21 preparations at 60 minutes of perfusion (5.0 to 1.4 x 10(3)/microL; 28% of baseline; p less than 0.001) was observed. Differential cell counts in 14 of these preparations revealed a predominant decrease in granulocyte count (8.7% of baseline) and a moderate decline in lymphocyte count (46% of baseline). In study I, indium 111-labeled autologous granulocytes were injected intravenously into 10 adult New Zealand White rabbits. In group I (n = 5), an autoperfused working heart-lung preparation was harvested and perfused for 60 minutes. In group II (controls, n = 5), the heart-lung block was harvested following 60 minutes of in situ perfusion. Organ blocks were imaged before and after saline flush. There was a significant decline in granulocyte counts at 60 minutes of perfusion in group I versus no change in group II (I, 2.3 +/- 0.4 to 0.3 +/- 0.1; p less than 0.01; II, 1.7 +/- 0.2 to 2.3 +/- 0.5; not significant; x 10(3)/microL +/- standard error of the mean). Postflush lung activity was significantly increased in group I versus group II (I, 3,751 +/- 566; II, 1,867 +/- 532; p less than 0.05; counts +/- standard error of the mean). In study II, 15 autoperfused preparations were divided into two groups. Group I (n = 10) preparations were controls. Group II (n = 5) animals were depleted of leukocytes by pretreating with nitrogen mustard. Group I (controls) produced a bimodal survival distribution (Ia, 8.2 +/- 1.0; Ib, 26.4 +/- 2.0; hours +/- standard error of the mean). Group II survival was significantly longer than that of group Ia and similar to that of group Ib (II, 25.3 +/- 2.2; p less than 0.01 versus group Ia, not significant versus group Ib; hours +/- standard error of the mean). Hemodynamic profiles for group II closely paralleled those of group Ib. In conclusion, pulmonary sequestration of granulocytes occurs early in the autoperfused working heart-lung preparation (within 60 minutes of autoperfusion), and preoperative leukocyte depletion prolongs survival of the autoperfused working heart-lung preparation by eliminating the subset group Ia (short survivors) seen in untreated preparations.

Synthesis and degradation of eicosanoids in primary rat hepatocyte cultures.

Arachidonic acid metabolites may play an important role in liver physiology, yet hepatocyte prostaglandin synthesis has not been characterized extensively. We used RIA to study production and clearance of several eicosanoids in confluent primary cultures of rat hepatocytes in serum-free, hormonally-defined medium. Under basal, unstimulated conditions 6-keto-PGF1 alpha (spontaneous breakdown product of prostacyclin) and 13,14-dihydro-15-keto-PGE (DHK-PGE, a metabolite of PGE) accumulated in the culture medium. Hepatocytes cleared 6-keto-PGF1 alpha, thromboxane B2, and DHK-PGE from the medium. Production of eicosanoids by primary cultures appeared resistant to indomethacin and several other cyclooxygenase inhibitors. This apparent resistance to indomethacin was not caused by rapid metabolism of indomethacin, by failure of the drug to enter hepatocytes, or by insensitivity of hepatocyte cyclooxygenase to the drug. Metabolism of PGE to DHK-PGE may be saturated under in vitro conditions. Hepatocytes can synthesize significant amounts of eicosanoids, although they are probably less active in this regard than are non-parenchymal cells.

Leukocyte redistribution and eicosanoid changes during the autoperfused working heart-lung preparation.

We studied the role of leukocyte redistribution and eicosanoid changes in the early stages of instituting 16 rabbit autoperfused working heart-lung preparations (AWHLP). Physiological changes occurring during the transition from the intact animal to the AWHLP may determine the survival and viability of the organ blocks for transplantation. White blood cell (WBC) count decreased from 5,160/microL to 1430/microL (P less than .01) at 60 min of autoperfusion. Differential WBC counts performed in ten of these AWHLP revealed a 63% decrease in lymphocyte count and an 88% decrease in the granulocyte count at 60 min. Thus, the predominant leukocyte remaining in the circulation was the lymphocyte. Blood samples were collected from the intact animal and from the AWHLP for assay of the stable metabolites of thromboxane A2 (TxA2) and prostacyclin (PGI2). Transition from the in situ heart-lung block to the in vitro AWHLP stage caused significant changes in these metabolites. The PGI2 metabolite 6-ketoprostaglandin F1a (6KPGF1a) increased from 2680 +/- 487 to 4339 +/- 478 (pg/mL), P less than .05, while the TxA2 metabolite, thromboxane B2 (TxB2) decreased from 618 +/- 105 to 289 +/- 63 (pg/mL). However, assays of 11-dehydro-TxB2 (11-DHT), a longer lived metabolite of TxA2 (n = 7) increased (668.4 +/- 84.6 to 946.4 +/- 43.7, P less than .05). The transition from the in situ heart-lung block of the intact animal to the AWHLP involves significant physiological changes. Redistribution of leukocytes occurs with a predominant decrease in the granulocyte count, while levels of bioactive lipid mediators show a distinct large rise in the PGI2 metabolites and a lesser increase in TxA2 metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Extended ex vivo preservation of the heart and lungs. Effects of acellular oxygen-carrying perfusates and indomethacin on the autoperfused working heart-lung preparation.

The autoperfused working heart-lung preparation has been proposed as a method for long-term heart-lung preservation. We investigated the effects of acellular oxygen-carrying perfusates (study 1) and the effect of donor pretreatment with indomethacin (study 2) on the working ex vivo heart-lung block. In study 1 perfusion with stroma-fee hemoglobin resulted in significantly reduced survival (118 +/- 46 minutes) compared with autologous blood (561 +/- 125 minutes, p less than 0.05) or perfluorocarbon (438 +/- 114 minutes, p less than 0.05). Decrease in survival with stroma-free hemoglobin perfusate is associated with a marked decrease in left ventricular performance and a significant increase in pulmonary vascular resistance. Perfusion with autologous blood is associated with a significant increase in pulmonary vascular resistance after 240 minutes of explantation, which is significantly delayed by perfusion with perfluorocarbon. Perfusion for 6 hours with blood pretreated with indomethacin (study 2) resulted in a decrease in the concentration of prostacyclin and thromboxane A2 metabolites but an increase in the prostaglandin/thromboxane A2 metabolite ratio. This is associated with abrogation of the increase in pulmonary vascular resistance (12,787 +/- 1682 dynes/sec/cm-5, T = 0; 13,134 +/- 2654 dynes/sec/cm-5, T = 360 minutes) observed in preparations perfused with autologous blood (13,194 +/- 1942 dynes/sec/cm-5, T = 0; 24,768 +/- 3325 dynes/sec/cm-5, T = 360 minutes, p less than 0.05). We conclude that alteration of the cellular and humoral components of autologous blood may prove advantageous for increasing the utility of the autoperfused working heart-lung preparation as a preservation technique.

Transpulmonary prostaglandin F2 alpha metabolism in sheep: an in vivo model.

We investigated transpulmonary enzymatic conversion of prostaglandin F2 alpha (PGF) to the 13,14-dihydro-15-keto metabolite (PGFM) in normal and acutely lung injured sheep. PGF was infused directly into the right ventricle. Sequential, simultaneous blood samples were drawn from the pulmonary artery (PA) and aorta (A). PGF and PGFM plasma concentrations were quantitated by double antibody radioimmunoassay (RIA). The pulmonary conversion rate of PGF in normal lung was established over a wide range of concentrations in intubated, normoxic, and hemodynamically stable sheep. Both zero and first order kinetics were present. PGF had no physiological effects on either pulmonary or systemic hemodynamics at any infusion rate studied. Acute lung injury was produced by intravenous injections of oleic acid into the PA until the resting mean pulmonary artery pressure doubled. Infusions were then repeated and fractional metabolism of PGF across the lung was assessed. PGF, at infusion rates of 2 micrograms/kg/min and 8 micrograms/kg/min, was metabolized greater than 70% respectively. Thus, there was no difference between control or experimental groups in PGF conversion. We conclude that the in vivo sheep lung has an extensive substrate-dependent capacity to metabolize PGF and this mechanism is resistant to severe acute oleic acid lung injury.

Pediatric resuscitation.

The key to successful resuscitation in children is aggressive intervention, including oxygenation, ventilation, volume expansion, other therapies directed at the cause, and close observation before cardiorespiratory arrest occurs. Prevention of arrests will have the most important impact on improving outcome. Once an arrest occurs, meticulous attention to the ABCs of resuscitation and to advanced life support guidelines may help lower mortality and morbidity rates in these tragic circumstances.

Effects of current therapy of Kawasaki disease on eicosanoid metabolism.

Coronary artery inflammation in Kawasaki disease is accompanied by thrombocytosis and platelet activation. It was hypothesized that abnormal metabolism of bioactive eicosanoids could result from or contribute to these events. Circulating plasma thromboxane B2, 6-keto-prostaglandin F1 alpha and prostaglandin E were measured by double antibody radioimmunoassay in patients with Kawasaki disease before and after aspirin alone or aspirin and intravenous gamma globulin therapy. Plasma prostaglandin E concentrations were normal in all patient groups. Pretreatment thromboxane B2 was elevated compared with age-matched controls, fell moderately with high-dose aspirin (60 to 100 mg/kg/day) and marginally increased with low-dose aspirin (3 to 5 mg/kg/day) 6 to 8 weeks after treatment. Plasma 6-keto-prostaglandin F1 alpha was not detected in 12 of 16 patients before therapy and remained low in all but 1 patients by 6 to 8 weeks. Thromboxane B2 correlated weakly with serum salicylate concentration but had no relation to platelet mass. The results in these patients with Kawasaki disease indicate only partial thromboxane suppression and depressed prostacyclin generation regardless of therapy. This balance favors coronary vasoconstriction and platelet aggregation capable of potentiating myocardial ischemia or infarction. The results justify consideration of higher or more frequent aspirin doses for longer duration and thromboxane receptor blockade in this disease.

Effects of cardiopulmonary bypass on eicosanoid metabolism during pediatric cardiovascular surgery.

Cardiopulmonary bypass in children with congenital heart disease is associated with significant morbidity manifested by increased complement degradation products, heightened pulmonary vascular activity, and coagulopathy. In adults with cardiac disease, the prostaglandins (eicosanoids) have been shown to contribute to the pathophysiologic response to extracorporeal circulation. This study assessed the effect of cardiopulmonary bypass in infants and children on two potent eicosanoids: thromboxane, a vasoconstrictor and platelet aggregating agent, and prostacyclin, a vasodilator and platelet disaggregating agent. The biochemical profiles of thromboxane and prostacyclin were evaluated in temporal relationship to selected parameters of platelet loss and pulmonary vascular hemodynamics during and after cardiopulmonary bypass. Twenty-one children, aged 3 days to 9 years, with congenital heart defects who were undergoing repair with cardiopulmonary bypass were studied. Nine pediatric patients undergoing palliative heart operations with no cardiopulmonary bypass served as the control group. In the group having cardiopulmonary bypass, the thromboxane concentration significantly increased during bypass (195 +/- 10 to 910 +/- 240 pg/ml, +/- standard error of the mean, p less than 0.005), whereas the control group demonstrated no significant change in thromboxane concentration. The highest thromboxane values were seen in the youngest patients (p less than 0.002). There was no significant correlation between thromboxane changes with alterations in pulmonary vascular resistance, platelet loss, duration of cardiopulmonary bypass or aortic cross-clamping. Prostacyclin levels rose significantly in both the bypass group (100 +/- 20 to 570 +/- 80 pg/ml, p less than 0.01) and in the control group (109 +/- 44 to 589 +/- 222 pg/ml, p less than 0.01), which apparently is due to surgical manipulation of vascular endothelium. These data show that eicosanoid production is significantly altered in children during cardiopulmonary bypass. Although thromboxane, a potent vasoconstrictor, is produced in significant amounts during and after cardiopulmonary bypass, our data show that thromboxane does not directly mediate changes in pulmonary artery hypertension and is not quantitatively related to platelet loss during pediatric cardiovascular operations.

Ribavirin administration to infants receiving mechanical ventilation.

Aerosolized ribavirin was administered to 12 infants with bronchiolitis who were receiving mechanical ventilation. All patients had a history of cardiac or pulmonary disease and developed severe respiratory failure during their infection. We developed a method for ribavirin administration and patient monitoring that included timed circuit valve and tubing changes to avoid obstruction by precipitated drug, frequent endotracheal tube suctioning, and constant observation of the patient and ventilator. All patients were successfully treated. We conclude that ribavirin can be safely administered to infants receiving mechanical ventilation.

Methylprednisolone on circulating eicosanoids and vasomotor tone after endotoxin.

Acute pulmonary and systemic vasomotor changes induced by endotoxin in dogs have been related, at least in part, to the production of eicosanoids such as the vasoconstrictor thromboxane and the vasodilator prostacyclin. Steroids in high doses, in vitro, inhibit activation of phospholipase A2 and prevent fatty acid release from cell membranes to enter the arachidonic acid cascade. We, therefore, administered methylprednisolone (40 mg/kg) to dogs to see if eicosanoid production and the ensuing vasomotor changes could be prevented after administration of 150 micrograms/kg of endotoxin. The stable metabolites of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured by radioimmunoassay. Methylprednisolone by itself did not alter circulating eicosanoids but when given 2.5 h before endotoxin not only failed to inhibit endotoxin-induced eicosanoid production but actually resulted in higher circulating levels of 6-keto-PGF1 alpha (P less than 0.05) compared with animals receiving endotoxin alone. Indomethacin prevented the steroid-enhanced concentrations of 6-keto-PGF1 alpha after endotoxin and prevented the greater fall (P less than 0.05) in systemic blood pressure and systemic vascular resistance with steroid plus endotoxin than occurred with endotoxin alone. Administration of methylprednisolone immediately before endotoxin resulted in enhanced levels (P less than 0.05) of both TxB2 and 6-keto-PGF1 alpha but with a fall in systemic blood pressure and vascular resistance similar to the animals pretreated by 2.5 h. In contrast to the early steroid group in which all of the hypotensive effect was due to eicosanoids, in the latter group steroids had an additional nonspecific effect. Thus, in vivo, high-dose steroids did not prevent endotoxin-induced increases in eicosanoids but actually increased circulating levels of TxB2 and 6-keto-PGF1 alpha with a physiological effect favoring vasodilation.

Effect of experimental cardiopulmonary bypass on systemic and transcardiac thromboxane B2 levels.

Systemic and cardiac metabolism of thromboxane was studied in a canine model (n = 13) of standard cardiopulmonary bypass and surgical cardioplegia. Sterile techniques were applied and no donor blood was used. Systemic samples (thoracic aorta) and transcardiac gradients (coronary sinus - aortic root) were obtained (1) 5 minutes after cannulation, (2) 20 minutes after the onset of partial bypass, (3) 5 seconds after the first administration of cardioplegic solution (CP-1), and (4) 5 seconds after the second administration of cardioplegic solution (CP-2). Cardioplegic doses were administered 30 minutes apart and consisted of 500 ml of hypothermic (8 degrees C), hyperkalemic (25 mEq potassium chloride) solution infused into the aortic root at 60 to 70 mm Hg. Thromboxane B2 was determined by a double-antibody radioimmunoassay (picograms per milliliter +/- standard error of the mean). Onset of partial bypass was followed by a significant rise in systemic arterial thromboxane B2 levels: after cannulation, 115 +/- 21 pg/ml; after the onset of partial bypass, 596 +/- 141 pg/ml; p less than 0.01). Significant transcardiac thromboxane B2 gradients were found during the first and second cardioplegic washouts (CP-1: aortic root 73 +/- 12 pg/ml, coronary sinus 306 +/- 86 pg/ml, p less than 0.01; CP-2: aortic root 65 +/- 11 pg/ml, coronary sinus 355 +/- 98 pg/ml, p less than 0.01). Transcardiac gradients of 6-keto-prostaglandin F1 alpha and thromboxane B2 were obtained at CP-1 and CP-2. Gradients of 6-keto-prostaglandin F1 alpha were not different from thromboxane B2 gradients during CP-1 but were significantly higher than thromboxane B2 gradients during CP-2. In a subgroup of five dogs, transcardiac thromboxane B2, lactate, and platelet gradients were measured simultaneously. Cardiac thromboxane B2 generation was found only in the presence of cardiac lactate production. Transcardiac platelet gradients were significantly higher at CP-1 (13,900 +/- 3,000/mm3) than at CP-2 (4,000 +/- 1,230/mm3) (p less than 0.05), whereas thromboxane B2 gradients were similar at CP-1 and CP-2. Our study demonstrates that thromboxane B2 is released into the coronary circulation during surgical cardioplegic arrest with anaerobiosis.

Influence of coronary artery obstruction on cardiac prostaglandin metabolism during experimental cardioplegic arrest.

In order to test the influence of coronary artery obstruction on cardiac prostaglandin metabolism during surgically induced cardioplegia (CP), we have measured transcardiac veno-arterial gradients of prostacyclin and thromboxane A2 (TXA A2) during experimental canine cardiopulmonary bypass. Cardiac arrest was induced by infusion of 500 ml of hypothermic (8 degrees C), hyperkalemic (25 meq) crystalloid CP solution into the aortic root with (group I) and without (group II) occlusion of the left anterior descending artery (LAD). After 30 minutes of cardioplegic arrest the LAD occlusion in group I was released and a second set of CP infusion was applied in both groups. Transcardiac gradients were obtained 5 seconds after onset of the first and second CP washouts. Significant prostacyclin and TXA A2 gradients were observed at both times. Prostacyclin gradients did not differ between group I and group II. In contrast, TXA A2 gradients were significantly higher during the second CP washout in group I as compared to the unoccluded group (group I 918 +/- 221, group II 244 +/- 144 pg/ml, p less than 0.05). The results of our study suggest that cardiac TXA A2 metabolism during cardioplegic arrest is increased distal to a coronary artery obstruction. Cardiac TXA A2 production might contribute to the increased ischemic myocardial injury observed in this setting.

Thromboxane release during percutaneous transluminal coronary angioplasty.

The reason for coronary artery occlusion following percutaneous transluminal angioplasty (PTCA) remains an enigma. We postulated that alterations in arachidonic acid metabolism might contribute to coronary artery occlusion, particularly if platelets are perturbed and release thromboxane because of mechanical stimuli during PTCA. We serially monitored coronary sinus and peripheral arterial plasma thromboxane (TX) and prostacyclin (by standard radioimmunoassay of the metabolites TXB2 and 6-keto-PFG1 alpha) during PTCA in 10 patients. TX and prostacyclin were unchanged from control in seven uncomplicated procedures. In one patient with vasospasm, no changes were found. In two patients with occlusion, marked increases were measured in coronary sinus plasma TX. Patient No. 1 increased from 390 to 1375 pg/ml. Patient No. 2 increased from 155 to 1425 pg/ml. Both required emergency bypass grafting. No change in 6-keto-PGF1 alpha was found. Uncomplicated PTCA does not alter arachidonic acid metabolism through cyclooxygenase. Vasospasm need not be associated with TX release, but coronary artery occlusion is. TX may play a role in coronary artery occlusion during PTCA because of (1) increased release and (2) unopposed physiologic effects because increases were not found in the physiologic antagonist prostacyclin.