Systemic inflammatory response leading to postoperative organ dysfunction and sepsis remains a formidable clinical challenge and carries a significant risk for mortality. Sepsis and septic shock remain major causes of death in ICUs. A number of studies have examined the role of nonselective COX inhibitors both in animal models of sepsis and in patients with sepsis syndrome. Several studies [10–12] demonstrated beneficial effects of nonselective COX inhibition, predominantly in endotoxin-treated animals. However, subsequent studies [22, 23] examining the role played by NSAIDs, particularly ibuprofen, in human sepsis trials have been disappointing. The present study was therefore conducted to determine whether COX inhibition is upregulated early after the onset of severe sepsis, and if so whether COX inhibition prevents the occurrence of septic shock.
The arachidonic acid pathway is highly activated in macrophages, monocytes and other inflammatory cells, resulting in the formation of eicosonoids. PGs are involved in all phases of the inflammatory process, including fever and pain reactions, as well as in a large number of physiological functions, including intestinal motility, platelet aggregation, vascular tone, renal function and gastric secretion, among others. Two COX isoforms have been identified: COX-1 and COX-2. The former is a constitutive enzyme that is expressed in many cells as a house-keeping enzyme and stimulates homeostatic production of PGs. COX-2 is an inducible form of the enzyme that is expressed at the onset of inflammation by many cell types that are involved in the inflammatory response. NSAIDs act mainly through COX inhibitors, thus preventing the formation of proinflammatory prostanoids. Lornoxicam, a new member of the oxicam class of NSAIDs, inhibits PG synthesis via inhibition of COX, but it does not inhibit 5-lipoxygenase. Lornoxicam is at least 10 times more potent as an anti-inflammatory agent than piroxicam, and 12 times more potent as an analgesic than tenoxicam [17, 19].
The primary pharmacological action of NSAIDs is, of course, to decrease the formation of PGs and thromboxanes by inhibiting COX, a key enzyme in the biochemical pathway that leads to formation of these potent mediators . Accordingly, products of the COX pathway, sometimes referred to as 'prostanoids', have been implicated in the pathogenesis of the deleterious systemic consequences of serious infection and/or endotoxaemia. In addition, the toxic effects of TNF (thought to be one of the primary cytokines responsible for LPS-induced lethality) can be ameliorated by treating mice or rats with NSAIDs such as indomethacin or ibuprofen . NSAIDs have been shown to increase release cytokines (TNF, IL-6, or IL-8) by stimulated mononuclear cells in vitro [26, 27].
Complications of sepsis have been related to an intense host response based on a delicate equilibrium between various proinflammatory and anti-inflammatory mediators . Overwhelming production of proinflammatory cytokines, such as TNF-α, IL-1β, IL-2 receptor, IL-6 and IL-8, may induce biochemical and cellular alterations either directly or by orchestrating secondary inflammatory pathways.
Reddyl and coworkers  evaluated the effect of pretreatment with NS-398, a highly selective COX-2 inhibitor, on survival and inflammatory mediator production in two models of sepsis in mice (LPS challenge and peritonitis induced by caecal ligation and puncture [CLP]). They found that selective inhibition of COX-2 resulted in improvement in early survival in murine endotoxaemia but not in a more physiologically relevant model of abdominal sepsis (CLP). The early improvement in survival in endotoxin-challenged animals was not attributable to changes in inflammatory cytokine expression or organ-specific neutrophil sequestration. Pretreatment with NS-398 failed to improve long-term survival in either of the models studied, although in the endotoxaemia model administration of the COX-2 inhibitor had a modest salutary effect on early mortality. In addition, although treatment with NS-398 blocked LPS-induced increases in the circulating levels of immunoreactive PGE2, injection of the COX-2 inhibitor did not modulate plasma concentrations of TNF or the CXC chemokine KC.
Knoferl and coworkers  also evaluated the effect of pretreatment with NS-398, that trauma/haemorrhage results in activation of Kupffer cells to release inflammatory mediators and it leads to immunosuppression. In vitro production of IL-6 by Kupffer cells after CLP was significantly reduced by in vivo NS-398 treatment. However, NS-398 had no effect on TNF-α levels in vivo or in vitro. Strong and coworkers  showed that administration of NS-398 for 24 hours after trauma improved survival when mice were subjected to CLP and puncture 7 days later. It is noteworthy that NS-398 exhibited protective effects in two models of sepsis characterized by infection in the setting of trauma-induced immunosuppression, whereas the drug was largely ineffective when sepsis was induced in immunocompetent animals. Dallal and coworkers  demonstrated that T-cell suppression during neonatal sepsis is accompanied by a decrease in IL-2 production. Such suppression was ameliorated by COX-2 inhibitor, suggesting a role for PGE2 in suppressed T-cell-mediated immune function in neonatal sepsis. Arons and colleagues  compared the clinical and physiological characteristics of febrile septic patients with those of hypothermic septic patients, and compared plasma levels of cytokines TNF-α and IL-6 and thromboxane B2 and prostacyclin between hypothermic septic patients and febrile patients. They administered ibuprofen but found that this drug had no effect on cytokine levels.
Reddyl and coworkers  indicated that pharmacological inhibition of COX-2 has only very modest effects on outcome in experimental sepsis or endotoxaemia. Because these findings are discrepant with respect to those obtained with isoform nonselective agents, it is regrettable that those investigators did not include a 'positive control' arm in their studies to evaluate the effects of treatment with an agent such as indomethacin or ibuprofen in their laboratory's models of sepsis. In our study we did not observe any significant changes in systemic cytokine levels during NSAID administration in humans with severe sepsis. Cytokine levels in plasma do not necessarily reflect local synthesis of cytokines by cells. Many cells have surface receptors for these cytokines with high binding properties, and target cells and soluble receptors trap cytokines. Thus, cytokines released at the local level may remain undetected in plasma. In the present study we found plasma cytokine levels to remain unchanged over a period of 72 hours.
Wang and coworkers  conducted a study to determine whether inhibition of PGI2 synthesis prevents the hyperdynamic response in early sepsis in animals. Those investigators found that inhibition of PGI2 production did not prevent the hyperdynamic and hypercardiovascular responses during early sepsis; hence, mediators other than PGI2 appear to play a major role in producing the hyperdynamic response under such conditions. Fox and colleagues  postulated that the attenuated pulmonary and systemic vascular contractility observed in sepsis was secondary to the release of vasodilator PGs. They used the COX inhibitor meclofenamate to inhibit PG synthesis in a model of hyperdynamic sepsis, and found that meclofenamate had no effect on either the pulmonary or systemic response to phenylephrine infusion in septic animals. However, Wanecek and coworkers  demonstrated that endotoxin-induced pulmonary hypertension in the pig can be prevented with a combination of the nonpeptide mixed endothelin receptor antagonist bosentan and the COX inhibitor diclofenac. They found that the combination of bosentan and diclofenac induced systemic and pulmonary vasodilatation. During endotoxin shock, this drug combination efficiently counteracted pulmonary hypertension and improved cardiac performance, and splenic and renal blood flows. These favourable circulatory effects might have resulted in a reduction in both sympathetic nervous system activation and metabolic acidosis. In the present study we found that lornoxicam had no effect on the cardiovascular and pulmonary systems in severe sepsis in humans, but our study was designed to assess the effects of lornoxicam treatment given before septic shock but after systemic inflammatory response syndrome. For this reason we identified no serious cardiovascular and pulmonary system problems in the patients studied.
Arons and coworkers  compared clinical and physiological characteristics of febrile septic patients with those in hypothermic septic patients, and compared plasma levels of cytokines TNF-α and IL-6, and thomboxane B2 and prostacyclin between hypothermic septic patients and febrile patients. Those investigators found that ibuprofen treatment had a positive impact on vital signs, organ failure and mortality in hypothermic septic patients, and concluded that ibuprofen could substantially decrease mortality in this selected group of septic patients. In our study we found that lornoxicam had no effect on vital signs and mortality in patients with severe sepsis. The overall ICU mortality rate was 37.5% (15 patients out of 40) in total, and these deaths were all attributable to septic shock. However, all of the patients died after completion of the study.
Lornoxicam has been shown to produce less gastric toxicity than its nonselective counterparts. This may be especially important in critically ill patients, who are at significantly greater risk for developing gastric ulceration. In addition, the lack of inhibitory effect on platelet function, which occurs with the use of COX-2 selective compounds, may decrease the incidence of bleeding complications [17, 19]. In the present study we did not identify any lornoxicam related adverse effects.
In summary, we found that intravenous lornoxicam had no effect on haemodynamic and biochemical parameters, cytokine levels, or patient outcomes in severe sepsis. Selective inhibition of COX-2 in sepsis requires further study. However, the findings reported here, indicating that lornoxicam lacks benefit in patients with severe sepsis, are disappointing.