Corticosteroids,nonsteroidal anti-inflammatory drugs,and naloxone in the sepsis syndrome

Corticosteroids have proven to be effective as adjunctive treatment in sepsis and severe typhoid fever when used early and in high doses. If corticosteroids are given in high doses (30 mg/kg), they should be administered in 1–2 doses, and not to exceed 4 total doses within 24 hours. The efficacy of the drug may be diminished in more severe sepsis, but use of corticosteroids in severe sepsis may delay death. If the benefit of corticosteroid use in late sepsis is only to prolong impending death, then steroid administration is probably futile; however, the alternative view is that corticosteroid use may constitute one step in a series leading to shock reversal and recovery. Risks and benefits of corticosteroid use should be tailored to the individual patient with consideration given to the nature and extent of the underlying disease. Although the pathophysiology of the sepsis syndrome remains elusive, new therapeutic regimens may evolve using nonsteroidal anti-inflammatory drugs and neuropeptide antagonists. As with corticosteroids, their application before or early after the onset of shock appears more beneficial; however, the patient population that will benefit most from treatment with these drugs remains, for the most part, unidentified, and more clinical trials are needed.

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Resumen Los corticosteroides han probado ser efectivos como tratamiento adyuvante cuando se utilizan precozmente y en altas dosis en la sepsis y en la fiebre tifoidea grave. Si los corticosteroides son administrados en altas dosis (30 mg/kg), éstos deben darse en 1–2 dosis y no exceder un total de 4 dosis en 24 horas. La eficacia de la droga puede verse disminuida en casos de sepsis mas severa, pero su uso en el estado séptico puede diferir la mortalidad. Si el beneficio del uso de los corticosteroides en sepsis tardía es únicamente el de retardar una muerte inminente, entonces la administración de esteroides sería fútil; sinembargo, la perspectiva alterna es que el uso de corticosteroides constituye un escalón de una serie de eventos que resultan en la reversion del shock y la recuperation. Los riesgos y los beneficios del uso de corticosteroides deben ser ajustados a cada paciente individual con la debida consideración a la naturaleza y gravedad de la enfermedad de base. Aunque la patofisiología del síndrome de sepsis se mantiene elusivo, es previsible que nuevos regimenes terapéuticos puedan ser desarrollados con el uso de drogas anti-inflamatorias no esteroides y antagonistas neuropéptidos. Al igual que con los corticosteroides, su aplicación antes o muy pronto después de la iniciacion del shock parece ser de mayor beneficio; sinembargo, todavía no ha sido posible establecer cual es la población de patientes que se puede beneficiar mayormente de la terapia con estas drogas, y son necesarios mas estudios y ensayos clínicos.

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Résumé Les corticostéroïdes ont fait leur preuve en tant qu'agent thérapeutique complémentaire quand ils sont employés précocement et à hautes doses dans l'infection et la fièvre typhoïde. Si les corticostéroïdes sont donnés à hautes doses (30 mg/kg), ils doivent être administrés en 1–2 doses et ne jamais dépasser 4 doses par 24 heures. L'efficacité du médicament peut être faible dans les infections graves, il est alors seulement susceptible de retarder le décès. En fait, si l'emploi se limite à ce seul bénéfice, il paraît inutile d'y avoir recours. A l'inverse, la corticothérapie peut représenter une étape utile et efficace du traitement du choc. Les bénéfices et les risques de la corticothérapie doivent être appréciés en fonction de chaque malade et plus particulièrement de la nature et de l'intensité de l'affection dont il est victime. Bien que la physiopathologie du syndrome infectieux reste insaisissable, de nouveaux protocoles thérapeutiques comportant des anti-inflammatoires non stéroïdiens et des antagonistes neuropeptidiques peuvent être employés. Comme pour les corticoïdes leur usage avant ou au début du choc donne les meilleurs résultats. En fait, la population des malades qui peut bénéficier de l'emploi de ces agents médicamenteux n'est pas parfaitement définie et de très nombreux essais cliniques sont indispensables pour définir les meilleures indications.

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Supported by the Veterans Administration.     

Pharmacologic alterations in pulmonary artery pressure in the adult respiratory distress syndrome

The progressive hypoxemia of acute respiratory distress syndrome (ARDS) has been associated with increased pulmonary vascular resistance (PVR). Pharmacologic reduction of PVR might improve oxygenation in ARDS patients. To test this hypothesis we administered vasoactive drugs to nine hypoxemic patients (P_aO₂^0.4 < 70 Torr) with increased PVR. Nitroprusside (1–3 μg/kg/min) or glucagon (0.5 mg/min) was administered iv for 15 min. Hemodynamic measurements were obtained before and during each infusion. Thirty-minute stabilization periods were allowed between infusions. Nitroprusside significantly decreased PVR, 175 to 139 dyn · sec/cm⁵, (P < 0.05), yet intrapulmonary shunt (Q_s/Q_t) increased, 34 to 42% (P < 0.05) and arterial PO₂ decreased, 68 to 55 Torr (P < 0.01). O₂ delivery, 615 to 519 ml/min/m², was also significantly decreased (P < 0.05). Glucagon significantly increased arterial PO₂, 67 to 73 Torr (P < 0.05), with little change in Q_s/Q_t) (36.4 to 33.8%). Glucagon also increased PVR (145 to 157 dyn · sec/cm⁵). Nitroprusside-induced vasodilation is nonselective and supercedes protective hypoxic vasoconstriction. Glucagon improves oxygenation, but does not reduce PVR. Neither drug offers the patient with ARDS and pulmonary hypertension any specific benefits. The decrease in O₂ delivery with nitroprusside further indicates that this drug should be used with caution in any hypoxic patient.     

Superoxide production by neutrophils in a model of adult respiratory distress syndrome

Neutrophils (polymorphonuclear leukocytes [PMNs]) are thought to contribute to the pathophysiology of adult respiratory distress syndrome (ARDS) by the release of toxic oxygen metabolites. This study investigated superoxide production by circulating and bronchoalveolar lavage (BAL) PMNs in a rat model of ARDS induced by chronic Escherichia coli (lipopolysaccharide) endotoxemia. Superoxide production was stimulated by fmet-leu-phe, opsonized zymosan, and phorbol myristate acetate. Circulating and BAL PMNs from lipopolysaccharide-infused rats compared with PMNs from control rats are primed for nonselective increased superoxide production. The BAL PMNs are not only partially primed to release superoxide on adherence, they concomitantly have a depressed superoxide response to a phagocytic (opsonized zymosan) stimulus. These PMN responses may partially explain both the pulmonary injury and the increased susceptibility to pulmonary infection seen in patients with ARDS.     

Amelioration of pulmonary pathophysiology of adult respiratory distress syndrome by sulindac, a cyclo-oxygenase inhibitor

The effects of sulindac, a cyclo-oxygenase inhibitor, were tested in a bacteremic porcine model of acute respiratory failure produced by a continuous infusion of live Pseudomonas aeruginosa. Control groups received either a single intravenous dose of sulindac (6 mg/kg) 20 minutes after baseline determinations or a continuous infusion of Ps. aeruginosa (10(7) CFU/kg/min) beginning at time 0. The experimental group received both. Sulindac alone had no effect on any hemodynamic or gas exchange parameter. Ps. aeruginosa infusion caused pulmonary hypertension, hypoxemia, increased intrapulmonary shunt fraction, systemic hypotension, and increased extravascular lung water. Sulindac treatment reversed the pulmonary hypertension, hypoxemia, and increased intrapulmonary shunting, prevented the systemic hypotension, but had no effect on the rising extravascular lung water.     

Idiopathic pulmonary fibrosis in adult respiratory distress syndrome. Diagnosis and treatment

Ten consecutive patients who presented initially with adult respiratory distress syndrome, and who did not respond to conventional treatment, underwent open lung biopsy early in the course of their illness. Idiopathic pulmonary fibrosis was diagnosed and aggressive treatment with methylprednisolone sodium succinate and nutritional support was initiated. Eight patients survived and have not required long-term corticosteroid therapy. Previous reports have documented a mortality of greater than 85% with this particular syndrome of idiopathic pulmonary fibrosis in adult respiratory distress syndrome.     

Role of pulmonary surfactant in the development and treatment of adult respiratory distress syndrome

The goal of this article has been to examine the role of pulmonary surfactant system alterations in the development of ARDS, and the potential efficacy of surfactant replacement therapy in ARDS and ARDS-type injuries. Data from patients with ARDS and animal models with ARDS-type injuries clearly indicate the existence of a surfactant-deficient state. However, in contrast to neonatal RDS, this deficiency generally does not represent the primary pathogenic factor. The diversity of the disorders associated with ARDS has made it impossible to develop a single-animal model that can be used to test potential therapeutic measures. The ARDS animal models that have been developed are equally diverse, and represent the wide variations in severity and time-course seen clinically. Nevertheless, almost all of the lung injury models show indications of surfactant abnormality, which is caused mainly by biophysical inhibition of surfactant activity by the large amounts of proteinaceous edema found in the injured lungs. In some cases, this surfactant dysfunction is further compounded by a quantitative surfactant deficiency brought about by metabolic alterations of the type II pneumocytes. It is important to note that all of the lung injury models studied thus far have shown significant improvements in pulmonary mechanics and arterial oxygenation after treatment with exogenous surfactant. Such results are consistent with biophysical studies that suggest that increasing the effective surfactant concentration in the lung should mitigate the effects of both quantitative and functional surfactant deficiencies. Although animal studies suggest that surfactant replacement therapy might be efficacious in ARDS, there is a good deal of experimental work that still needs to be done.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiopulmonary effects of the laparoscopic pneumoperitoneum in a porcine model of adult respiratory distress syndrome

BACKGROUND: Increasingly, laparoscopy is being used in critically ill patients in whom there is a question of intra-abdominal sepsis. We examine the cardiopulmonary effects of laparoscopy in a porcine model of adult respiratory distress syndrome (ARDS). METHODS: Domestic pigs (n = 12) underwent saline lung lavage and subsequent surgical abdominal exploration using either laparoscopy or conventional laparotomy. Hemodynamic and respiratory measurements were obtained. RESULTS: After pulmonary lavage, the two groups developed similarly diminished arterial pO2 (P <0.001), a worsened pulmonary shunt (P <0.001), and an increased alveolar-arterial oxygen gradient (P <0.001). The pulmonary compliance was significantly decreased in the animals undergoing laparoscopy (versus laparotomy, P <0.05). The mean pulmonary arterial pressure did not differ between the groups. The laparoscopic group had a higher pCO2 (not significant) and was more acidotic (P <0.05) than the laparotomy group. The laparoscopic animals had an increased heart rate (P <0.05), cardiac index (P <0.01), and oxygen delivery (P <0.005) as compared with the laparotomy group. CONCLUSIONS: During laparoscopy, animals with ARDS demonstrate further compromise in pulmonary physiologic parameters but overall cardio-respiratory function is preserved.     

Trauma and pulmonary insufficiency: mediators and modulators of adult respiratory distress syndrome

Adult respiratory distress syndrome is a complex disease resulting in lung dysfunction secondary to a primary nonpulmonary catastrophic event. Many mediators are involved in the destructive chain of events occurring at the cellular level. Investigation of ARDS continues, with efforts directed toward blocking those mediators and thereby alleviating the lung damage and hypoxia once this cascade has been initiated. Even with these advances, however, current optimal therapy is directed toward reversing the primary inciting event and providing the supportive care required to survive the acute episode.     

Pulmonary function, extravascular lung water and chest radiography in a porcine model of adult respiratory distress syndrome

To study the pathophysiology and the value of chest radiography in the diagnosis of early adult respiratory distress syndrome spontaneously air-breathing pigs under ketamine anaesthesia were investigated. Five control animals received physiological saline and showed no notable changes in physiological or radiological data. Eleven animals were infused i.v. with E. coli endotoxin over 6 h. The pulmonary dysfunction in the endotoxin animals was characterized by an early increase in venous admixture with hypoxaemia and a peak increase in pulmonary vascular resistance at 0.5 h after start of endotoxin infusion. Subsequently there was a tendency towards a restitution to baseline physiology, but from 3 h onwards a "second wave" of pulmonary dysfunction developed in addition to an increase in extravascular lung water. No significant correlation (r = 0.44) existed between the increase in extravascular lung water and venous admixture. The increase in calculated pulmonary microvascular pressure correlated significantly (r = 0.77) with the increase in extravascular lung water. Radiographic signs of pulmonary oedema were sparse. Thus, only three of 11 animals displayed increased density on chest radiography indicative of pulmonary oedema.     

Ibuprofen plus prostaglandin E1 in a septic porcine model of adult respiratory distress syndrome

Prostaglandin manipulation has been shown to improve pulmonary dysfunction in animal models of acute respiratory distress syndrome. Using our previously reported porcine model of Pseudomonas-induced respiratory failure, we examined the therapeutic effects of a vasodilating prostaglandin, PGE1, and a reversible cyclooxygenase inhibitor, ibuprofen. Forty-two animals were randomized to seven groups: I--ibuprofen; II--PGE1; III--ibuprofen + PGE1; IV--Pseudomonas + ibuprofen; V--Pseudomonas + PGE1; VI--Pseudomonas + ibuprofen + PGE1; VII--Pseudomonas. Ibuprofen significantly improved pulmonary vasoconstriction, pulmonary hypertension, and hypoxemia, as well as increased survival slightly. PGE1 had no effect on pulmonary dysfunction, but prevented the rise in systemic vascular resistance that occurred in untreated, infected animals and animals treated with ibuprofen alone. Combination therapy improved stroke volume index, a measure of nonpulmonary organ function.     

Successful treatment of adult respiratory distress syndrome by histamine and prostaglandin blockade in a porcine Pseudomonas model

Porcine Pseudomonas adult respiratory distress syndrome (ARDS) has been shown to respond to combination therapy of 150 mg of cimetidine, 12.5 mg/kg of ibuprofen, 10 mg/kg of diphenhydramine, 0.2 mg/kg of ketanserin, and 30 mg/kg of methylprednisolone (CIDKM or Poly-5) given at 20 and 120 minutes after the onset of a continuous infusion of liver Pseudomonas aeruginosa, 5 X 10(8) colony-forming units (CFU) ml at 0.3 ml/20 kg/min. The present study was designed to determine the minimal, effective therapy by selective deletion of individual agents from CIDKM. Eight groups were studied: saline control (S, n = 9), Pseudomonas control (P, n = 8), and the following Pseudomonas plus treatment groups (each n = 5): CIDKM (cimetidine, ibuprofen, diphenhydramine, and ketanserin), CID (cimetidine, ibuprofen, and diphenhydramine), IC (ibuprofen and cimetidine), ID (ibuprofen and diphenhydramine), and CD (cimetidine and diphenhydramine). Pseudomonas alone produced severe ARDS with significant (p less than .05) decreases in PAO2 cardiac index, and systemic arterial pressure and significant increases in pulmonary artery pressure, extravascular lung water (EVLW) and scintigraphically determined pulmonary albumin flux measured as slope index (SI). Full therapy, CIDKM or Poly-5, showed significant improvement in all parameters. Deletion of methylprednisolone did not significantly effect any parameter measured. The deletion of ketanserin, leaving CID, did not alter treatment efficacy, except for a significant decline in cardiac index at 3 hours. Deletion of ibuprofen from CID resulted in a failure to reverse pulmonary arterial hypertension, hypoxemia, elevated EVLW, and increased SI. Removal of either cimetidine or diphenhydramine from CID resulted in significant increases in EVLW compared with control levels and SI compared with both control levels and CID. These results indicate that a combination of both histamine H1 and H2 receptor blockers and the cyclooxygenase inhibitor, ibuprofen, is effective and essential in the treatment of hypoxemia, early pulmonary hypertension, and pulmonary microvascular injury in this fulminant model of porcine Pseudomonas ARDS.     

Current concepts in the management of the adult respiratory distress syndrome

The adult respiratory distress syndrome is the most severe pulmonary complication that can follow multiple trauma and critical illness. It is caused by an insult to the pulmonary circulation which results in an increased capillary permeability and subsequent interstitial edema. An increased venoarterial shunt occurs resulting in arterial hypoxemia. The mortality rate is at least 50% if treatment is not begun before profound hypoxemia occurs. Recognition of abnormal cardiopulmonary function before overt hypoxemia develops is important. This is best accomplished by attentive monitoring of arterial blood gases. Sequential arterial oxygen tensions obtained on 40% and 100% inspired oxygen concentration are the best guides to selecting patients who have a high probability of pulmonary deterioration. Aggressive cardiovascular monitoring and early treatment with low levels of positive-end expiratory pressure offer this group of patients an improved change of survival.

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Resumen El síndrome de dificultad respiratoria del adulto es la complicación pulmonar más severa que puede presentarse como consecuencia del trauma o de enfermedad crítica. Es causado por una lesión de la circulación pulmonar que resulta en permeabilidad capilar aumentada y subsecuente edema intersticial. Hay incremento en el shunt venoarterial, lo cual resulta en hipoxemia. La mortalidad es no menor de 50% si no se instituye tratamiento adecuado antes del desarrollo de hipoxemia profunda.Es importante el reconocimiento de la alteración de la función cardiopulmonar antes de la aparición de clara hipoxemia, lo cual se logra en forma óptima mediante cuidadosa monitoría de los gases sanguíneos arteriales. Las determinaciones secuenciales de la tension del oxígeno arterial bajo concentraciones de oxígeno inspirado al 40% y el 100% constituyen las mejores guías para seleccionar a aquellos patientes que poseen una elevada probabilidad de deterioro pulmonar. Una agresiva monitoría cardiovascular y el tratamiento precoz con bajos niveles de PEEP (presión positiva al final de la espiración) ofrecen a este grupo de pacientes una mejor posibilidad de supervivencia. En nuestra experiencia los esteroides fueron ineficaces en cuanto a mejoría de la función pulmonar y estuvieron asociados con un aumento en la tasa de infección. Nosotros creemos que la terapia pulmonar intensiva y el soporte general siguen siendo la forma preferencial de terapia en el síndrome de dificultad respiratoria del adulto.

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Résumé Le syndrome de détresse respiratoire de l'adulte représente la complication la plus grave qui puisse survenir chez le polytraumatisé et le malade dont l'état est critique. Il est provoqué par une atteinte de la circulation pulmonaire qui résulte d'une augmentation de la perméabilité capillaire cause elle-même de l'oedème interstitiel. Un court-circuit artérioveineux accru en résulte qui est la source d'une hypoxie artérielle. Le taux de la mortalité atteint au moins 50% si le traitement n'est pas instauré rapidement avant que ne se développe une profonde hypoxie.Le diagnostic de dysfonctionnement cardio-pulmonaire avant que l'hypoxie se développe est capital. Un monitorage attentif de la pression des gaz du sang artériel permet ce diagnostic. Les pressions séquentielles d'oxygène artériel mesurées lorsque les concentrations d'oxygène inspiré sont de 40% et de 100% sont les meilleurs éléments de sélection des malades qui présentent une haute probabilité d'atteinte pulmonaire. Le monitorage cardio-vasculaire très attentif et le traitement précoce qui a pour but de maintenir une pression positive résiduelle de fin d'expiration permet d'améliorer les chances de survie de ces malades.

     

A rare aetiology of acute respiratory distress syndrome in adult: leptospirosis

We report the case of an 18-year-old man with pulmonary leptospirosis presenting as an atypical pneumonia with alveolar haemorrhage, without icterus. Has he developed ARDS the patient was admitted in intensive care unit. This patient was contaminated when swimming in a lake. The purpose of this article is to remind doctors that in patient presenting atypical pneumopathy with haemoptysis, the pulmonary leptospirosis should be considered.     

Cavitating lung infarction after bland pulmonary thromboembolism in patients with the adult respiratory distress syndrome.

During one year five patients were observed with the adult respiratory distress syndrome who were found at necropsy to have cavitated lung infarcts following bland (non-infected) pulmonary thromboembolism. There were three instances of bronchopleural fistula and in one person a tension pneumothorax was the immediate cause of death. Four of the five patients had severe lung infections. In all patients airway pressure was raised as a result of positive pressure mechanical ventilation. It is postulated that diffuse microvascular injury, bacterial pneumonia, and high airway pressures may be important factors predisposing patients with adult respiratory distress syndrome to develop lung necrosis, cavitation, and bronchopleural fistula after bland pulmonary thromboembolism. This complication may occur more frequently than has been previously recognised.     

The use of extracorporeal membrane oxygenation in a child with adult respiratory distress syndrome following post-obstruction pulmonary oedema

The use of extracorporeal membrane oxygenation (ECMO) for post-operative complications is not well described. ECMO, a partial venoarterial cardiopulmonary bypass, may permit the reversal of pulmonary insult from barotrauma and oxygen toxicity. This report concerns an 8-year-old girl who developed post-obstruction pulmonary oedema and adult respiratory distress syndrome (ARDS) after a general anaesthetic for an attempted aspiration of a peritonsillar abscess and demonstrates an effective use of this technique. In this patient, the extreme levels of ventilatory support required post-operatively caused haemodynamic instability and severe barotrauma. The institution of ECMO with accompanying decrease in ventilatory support resulted in rapid resolution of haemodynamic instability, hypoxia, and pulmonary pathology.