2.0 The Role of Surgery in the Management of Septic Shock—Extra-Abdominal Causes of Sepsis

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SEPTIC SHOCK IS A SEVERE inflammatory response to one or more pathogenic micro-organisms. When a person's immune response is excessively intense, a cascade of phenomena may be activated that ultimately is harmful.

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APPROPRIATE MANAGEMENT of septic shock may include surgical intervention to remove or neutralize the septic focus in an effort to treat the inflammatory response cascade.

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THIS IS THE FIRST OF TWO articles presenting current information on the role of surgery in the management of a patient with septic shock. This article describes extra-abdominal sources of sepsis. AORN J 85 (January 2007) 137-146. © AORN, Inc, 2007.

     

The presence of superantigens and complex host responses in severe sepsis may need a broad therapeutic approach.

Patients with sepsis can progress into septic shock, disseminated intravascular coagulation, and multiorgan dysfunction syndrome. Various materials secreted by or released from microorganisms such as bacteria initiate these processes. In some bacteria, certain antigens and toxins may cause a 100-fold greater or supernormal activation of monocytes and T lymphocytes, leading to activation of the cascade systems in the host. This can explain the extremely rapid progress of the sepsis into septic shock seen in some patients. In Group A streptococci, more than 100 different toxins have been identified, about 5 of which (superantigens) cause an extremely fast immunological response. Because the toxins and antigens can activate so many different cascade systems in the host, the clinical picture is extremely complex, and little benefit is derived from therapy, which interferes with only 1 or 2 of the parameters in the patient with sepsis. Instead, reversal of the septic shock requires the removal or inhibition of several toxins or substances activating the cascade systems. A broader therapeutic approach may be the use of apheresis (plasma exchange).     

Organ-specific therapy in critical illness: Interfacing molecular mechanisms with physiological interventions

Sepsis and SIRS is the outward manifestation of a generalized uncontrolled inflammatory response, which, if sustained, induces widespread endothelial damage and MODS. Immunomodulating therapies, at present, have proven ineffective in reducing morbidity and mortality, presumably because of the heterogeneous nature of sepsis and septic shock and the reciprocating and redundant nature of this inflammatory cascade. Organ-specific therapies can support life but impair both organ-specific function and remote organ function. Novel therapies aimed at minimizing further organ dysfunction may improve outcome in a cost-effective fashion by preventing both further primary organ dysfunction or remote organ dysfunction secondary to the subsequent activation of the inflammatory response.     

Nature et signification des microparticules dans le sepsis

Septic shock is characterized by an increased inflammatory process and cell activation, inducing membrane remodeling and microparticles release. These microparticles represent a pool of bioactive effectors that modulate several vascular functions. During sepsis, host-pathogen interaction leads to the generation of endothelium-, platelet-, erythrocyteand granulocyte-derived procoagulant microparticles, which could promote cellular inflammatory response, apoptosis and activate coagulation. Microparticles may also potentially participate in the arterial dysfunction characterizing septic shock, tune the oxidative status and induce procoagulant state. This review focuses on the latest knowledge accumulated on the biological properties of microparticles in order to identify their involvement in sepsis or septic shock, as a biological marker or potential therapeutic target.     

Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia

The pathogenesis of septic shock occurring after Pseudomonas aeruginosa pneumonia was studied in a rabbit model. The airspace instillation of the cytotoxic P. aeruginosa strain PA103 into the rabbit caused a consistent alveolar epithelial injury, progressive bacteremia, and septic shock. The lung instillation of a noncytotoxic, isogenic mutant strain (PA103DeltaUT), which is defective for production of type III secreted toxins, did not cause either systemic inflammatory response or septic shock, despite a potent inflammatory response in the lung. The intravenous injection of PA103 did not cause shock or an increase in TNF-alpha, despite the fact that the animals were bacteremic. The systemic administration of either anti-TNF-alpha serum or recombinant human IL-10 improved both septic shock and bacteremia in the animals that were instilled with PA103. Radiolabeled TNF-alpha instilled in the lung significantly leaked into the circulation only in the presence of alveolar epithelial injury. We conclude that injury to the alveolar epithelium allows the release of proinflammatory mediators into the circulation that are primarily responsible for septic shock. Our results demonstrate the importance of compartmentalization of inflammatory mediators in the lung, and the crucial role of bacterial cytotoxins in causing alveolar epithelial damage in the pathogenesis of acute septic shock in P. aeruginosa pneumonia.     

Novel potential therapies for septic shock

Sepsis is the systemic inflammatory response syndrome secondary to a local infection. Septic shock, the severe complication of sepsis associated with refractory hypotension, is frequently a near-fatal condition requiring prompt diagnosis and management. Although the recent years have been associated with considerable improvements in the knowledge of the pathophysiology of the disease and remarkable advances have been achieved in sepsis treatment, the morbidity and mortality of this disease are still unacceptably high. In this review, we will briefly discuss the ongoing standard treatment of septic shock and describe novel potential therapies, aiming to improve hemodynamic support and/or control inflammatory response in sepsis. These therapies were associated with benefits in experimental studies and have been tested or are currently under testing in randomized controlled studies with septic patients.     

Elevated nucleosome levels in systemic inflammation and sepsis

OBJECTIVE: Multiple organ dysfunction syndrome is a frequent complication of severe sepsis and septic shock and has a high mortality. We hypothesized that extensive apoptosis of cells might constitute the cellular basis for this complication. DESIGN: Retrospective study. SETTING: Medical and surgical wards or intensive care units of two university hospitals. PATIENTS: Fourteen patients with fever, 15 with systemic inflammatory response syndrome, 32 with severe sepsis, and eight with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed circulating levels of nucleosomes, specific markers released by cells during the later stages of apoptosis, with a previously described enzyme-linked immunosorbent assay in these 69 patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock. Severity of multiple organ dysfunction syndrome was assessed with sepsis scores, and clinical and laboratory variables. Elevated nucleosome levels were found in 64%, 60%, 94%, and 100% of patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock, respectively. These levels were significantly higher in patients with septic shock as compared with patients with severe sepsis, systemic inflammatory response syndrome, or fever, and in nonsurvivors as compared with survivors. In patients with advanced multiple organ dysfunction syndrome, nucleosome levels correlated with cytokine plasma levels as well as with variables predictive for outcome. CONCLUSIONS: Patients with severe sepsis and septic shock have elevated plasma levels of nucleosomes. We suggest that apoptosis, probably resulting from exposure of cells to excessive amounts of inflammatory mediators, might by involved in the pathogenesis of multiple organ dysfunction syndrome.     

Cortisol in critically ill patients with sepsis--physiological functions and therapeutic implications

Modern immunology reveals that cortisol interacts with the immune response at virtually all levels exerting suppressive and permissive effects. A prerequisite for the defense of severe infections is the functional integrity of the hypothalamic-pituitary-adrenal axis (HPAA) resulting in adequate cortisol production. There is increasing evidence that cortisol physiology and regulation substantially change in the course of septic shock. Patients with septic shock may suffer from relative adrenocortical insufficiency resulting in a relative deficiency of cortisol. In addition, the number and the affinity of cellular glucocorticoid receptors are decreased which may reduce the cortisol action at the cellular level. Since septic shock and adrenal insufficiency are sharing hemodynamic abnormalities such as hyperdynamic shock and peripheral vasodilation, the administration of stress doses of hydrocortisone appears to be a rational therapeutic approach in patients with septic shock. Controlled studies reveal that stress doses of hydrocortisone attenuate the systemic inflammatory response. Recently, two double-blind studies demonstrated that stress doses of hydrocortisone given in patients with septic shock reduce the time to shock reversal. The most important hemodynamic effect was an increase in the systemic vascular resistance. The earlier weaning from vasopressor therapy was associated with a trend towards improvements in organ dysfunction and mortality, respectively. Large-scale trials are on the way to investigate the benefit of stress doses of hydrocortisone on mortality of septic shock. This paper will focus on changes in glucocorticoid physiology and regulation during septic shock and will discuss the effects of stress doses of hydrocortisone on immune response and vascular tone in the course of septic shock.     

Pro/con clinical debate: Is high-volume hemofiltration beneficial in the treatment of septic shock?

Although there have been exciting advances in the management of sepsis and septic shock, mortality still remains high. Recent data suggest that high-volume hemofiltration (HVHF) may play a role in these patients. In contrast to the usual rate of hemofiltration, HVHF is felt to be better able to remove the inflammatory mediators associated with sepsis and septic shock. Such an approach is currently incapable of selectively removing specific mediators. This may be a problem when one considers that several mediators may in fact be beneficial. When determining whether HVHF should be instituted in a patient with septic shock, one need remember that its role is far from clear and its usefulness remains the subject of much debate. Although early data is encouraging, it is clear that additional data is required before HVHF becomes standard management. The authors of this pro/con debate, which is based on a clinical scenario, first describe their own position and then respond to their opponent's position.     

Clinical review: influence of vasoactive and other therapies on intestinal and hepatic circulations in patients with septic shock

The organs of the hepatosplanchnic system are considered to play a key role in the development of multiorgan failure during septic shock. Impaired oxygenation of the intestinal mucosa can lead to disruption of the intestinal barrier, which may promote a vicious cycle of inflammatory response, increased oxygen demand and inadequate oxygen supply. Standard septic shock therapy includes supportive treatment such as fluid resuscitation, administration of vasopressors (adrenergic and nonadrenergic drugs), and respiratory and renal support. These therapies may have beneficial or detrimental effects not only on systemic haemodynamics but also on splanchnic haemodynamics, at both the macrocirculatory and microcirculatory levels. This clinical review focuses on the splanchnic haemodynamic and metabolic effects of standard therapies used in patients with septic shock, as well as on the recently described nonconventional therapies such as vasopressin, prostacyclin and N-acetyl cysteine.     

Clinical review: Influence of vasoactive and other therapies on intestinal and hepatic circulations in patients with septic shock

The organs of the hepatosplanchnic system are considered to play a key role in the development of multiorgan failure during septic shock. Impaired oxygenation of the intestinal mucosa can lead to disruption of the intestinal barrier, which may promote a vicious cycle of inflammatory response, increased oxygen demand and inadequate oxygen supply. Standard septic shock therapy includes supportive treatment such as fluid resuscitation, administration of vasopressors (adrenergic and nonadrenergic drugs), and respiratory and renal support. These therapies may have beneficial or detrimental effects not only on systemic haemodynamics but also on splanchnic haemodynamics, at both the macrocirculatory and microcirculatory levels. This clinical review focuses on the splanchnic haemodynamic and metabolic effects of standard therapies used in patients with septic shock, as well as on the recently described nonconventional therapies such as vasopressin, prostacyclin and N-acetyl cysteine.     

Cortistatin, a new antiinflammatory peptide with therapeutic effect on lethal endotoxemia

Cortistatin is a recently discovered cyclic neuropeptide related to somatostatin that has emerged as a potential endogenous antiinflammatory factor based on its production by and binding to immune cells. Because human septic shock involves excessive inflammatory cytokine production, we investigated the effect of cortistatin on the production of inflammatory mediators and its therapeutic action in various murine models of endotoxemia. Cortistatin down-regulated the production of inflammatory mediators by endotoxin-activated macrophages. The administration of cortistatin protected against lethality after cecal ligation and puncture, or injection of bacterial endotoxin or Escherichia coli, and prevented the septic shock-associated histopathology, such as infiltration of inflammatory cells and intravascular disseminated coagulation in various target organs. The therapeutic effect of cortistatin was mediated by decreasing the local and systemic levels of a wide spectrum of inflammatory mediators, including cytokines, chemokines, and acute phase proteins. The combined use of cortistatin and other antiinflammatory peptides was very efficient treating murine septic shock. This work provides the first evidence of cortistatin as a new immunomodulatory factor with the capacity to deactivate the inflammatory response. Cortistatin represents a potential multistep therapeutic agent for human septic shock, to be used in combination with other immunomodulatory agents or as a complement to other therapies.     

Pro/con clinical debate: Is high-volume hemofiltration beneficial in the treatment of septic shock?

Although there have been exciting advances in the management of sepsis and septic shock, mortality still remains high. Recent data suggest that high-volume hemofiltration (HVHF) may play a role in these patients. In contrast to the usual rate of hemofiltration, HVHF is felt to be better able to remove the inflammatory mediators associated with sepsis and septic shock. Such an approach is currently incapable of selectively removing specific mediators. This may be a problem when one considers that several mediators may in fact be beneficial. When determining whether HVHF should be instituted in a patient with septic shock, one need remember that its role is far from clear and its usefulness remains the subject of much debate. Although early data is encouraging, it is clear that additional data is required before HVHF becomes standard management. The authors of this pro/con debate, which is based on a clinical scenario, first describe their own position and then respond to their opponent''s position.     

Endotoxin apheresis for sepsis.

The principle use of apheresis in the treatment of sepsis may be summarized as the removal of toxic substances and the restoration of normal organs function. It is ideal to control the early phases of inflammatory cascade when treating sepsis by removing microbial components, such as endotoxin or peptidoglycan. This review discusses endotoxin apheresis with particular emphasis on treatment using polymyxin B immobilized fiber columns (Toraymyxin) which are used widely in Japan for endotoxin removal therapy in patients with septic shock. Lixelle and CTR which have recently been shown to remove circulating bacterial components are also included in this review.     

Implication of Toll-like receptor and tumor necrosis factor alpha signaling in septic shock

Septic shock is initiated by a systemic inflammatory response to microbial infection that frequently leads to impaired perfusion and multiple organ failure. Because of its high risk of death, septic shock is a major problem particularly for patients in the intensive care unit. In general, bacterial lipopolysaccharide (LPS) is a strong activator of various immune responses and stimulates monocytes/macrophages to release a variety of inflammatory cytokines. However, overproduction of inflammatory factors in response to bacterial infections is known to cause septic shock, similar to that induced by LPS. Studies of LPS-signaling pathways and downstream inflammatory cytokines may have critical implications in the treatment of sepsis. In recent years, there has been significant progress in understanding the signaling pathways activated by LPS and its receptor Toll-like receptor 4 (TLR4), as well as by tumor necrosis factor alpha (TNFalpha), a potent inflammatory cytokine induced by LPS stimulation. This review briefly summarizes our current knowledge of these signaling pathways and critical signal transducers. Characterization of key signal transducers may allow us to identify tractable, novel targets for the therapeutic interventions of sepsis.     

Activation of common antiviral pathways can potentiate inflammatory responses to septic shock

Induction of the antiviral cytokine interferon alpha/beta (IFN-alpha/beta) is common in many viral infections. The impact of ongoing antiviral responses on subsequent bacterial infection is not well understood. In human disease, bacterial superinfection complicating a viral infection can result in significant morbidity and mortality. We injected mice with polyinosinic-polycytidylic (PIC) acid, a TLR3 ligand and known IFN-alpha/beta inducer as well as nuclear factor kappaB (NF-kappaB) activator to simulate very early antiviral pathways. We then challenged mice with an in vivo septic shock model characterized by slowly evolving bacterial infection to simulate bacterial superinfection early during a viral infection. Our data demonstrated robust induction of IFN-alpha in serum within 24 h of PIC injection with IFN-alpha/beta-dependent major histocompatibility antigen class II up-regulation on peritoneal macrophages. PIC pretreatment before septic shock resulted in augmented tumor necrosis factor alpha and interleukins 6 and 10 and heightened lethality compared with septic shock alone. Intact IFN-alpha/beta signaling was necessary for augmentation of the inflammatory response to in vivo septic shock and to both TLR2 and TLR4 agonists in vitro. To assess the NF-kappaB contribution to PIC-modulated inflammatory responses to septic shock, we treated with parthenolide, an NF-kappaB inhibitor before PIC and septic shock. Parthenolide did not inhibit IFN-alpha induction by PIC. Inhibition of NF-kappaB by parthenolide did reduce IFN-alpha-mediated potentiation of the cytokine response and lethality from septic shock. Our data demonstrate that pathways activated early during many viral infections can have a detrimental impact on the outcome of subsequent bacterial infection. These pathways may be critical to understanding the heightened morbidity and mortality from bacterial superinfection after viral infection in human disease.     

Activated partial thromboplastin time waveform analysis: a new tool to detect infection?

OBJECTIVE: An abnormality of the optical transmission waveform obtained during measurement of the activated partial thromboplastin time (aPTT) has been described to identify a high-risk intensive care unit population consisting of patients with sepsis or with higher mortality rates than patients with normal aPTT waveforms. We investigated the abnormal aPTT biphasic waveform as a diagnostic and prognostic marker of infection. DESIGN: Prospective, observational study investigating the predictive value of aPTT waveform analysis for the diagnosis and prognosis of sepsis. SETTING: Surgical intensive care unit of a university hospital. PATIENTS: We studied 187 consecutive patients who fulfilled at least two or more criteria of the systemic inflammatory response syndrome at admission or during intensive care stay and classified as having systemic inflammatory response syndrome, sepsis, severe sepsis, or septic shock during an 8-month period. INTERVENTIONS: Laboratory analyses including aPTT waveform analysis and procalcitonin and C-reactive protein concentrations were measured at days 1-3. MEASUREMENTS AND MAIN RESULTS: The final diagnoses were systemic inflammatory response syndrome in 49%, sepsis in 16%, severe sepsis in 12%, and septic shock in 23% of patients. On day 1, the biphasic waveform was significantly more abnormal in patients with severe sepsis or septic shock than in patients with systemic inflammatory response syndrome or sepsis. The biphasic waveform was more accurate than procalcitonin and C-reactive protein for differentiating patients with severe sepsis and septic shock, with 90% sensitivity and 92% negative predictive value. Biphasic waveform values were significantly more abnormal during days 1-3 in septic nonsurvivors than in survivors and nonseptic nonsurvivors. The biphasic waveform exhibited the best specificity (91%) and negative predictive value (98%) for the prognosis of sepsis-related mortality on day 3. CONCLUSIONS: In intensive care units, when the analyzer is available, aPTT waveform analysis is an inexpensive, rapid, effective, and readily available tool providing information for the diagnosis of severe sepsis and the prognosis of septic patients.     

Cellular mechanisms in sepsis

Mortality remains very high among septic patients despite the advanced treatments rendered in intensive care units. The development of septic shock is multifactorial. Tissue damage and organ dysfunction may be caused not only by the microorganisms but also by the inflammatory mediators released in response to the infection. Cytokines (tumor necrosis factor, interleukin-1, interleukin-6, interleukin-8, high-mobility group box-1 protein, macrophage migratory inhibitory factor) and noncytokines (nitric oxide, platelet-activating factor, complements, and eicosonoids) may inflict tissue injury and contribute to multiple organ dysfunction and cell death (or apoptosis). Gram-negative bacteria are the most common organisms identified in septic patients. The pathological effects of gram-negative bacteria are conveyed through lipopolysaccharide derived from the bacterial cell membrane. Lipopolysaccharide activates the nuclear factor kappa B, which triggers the release of inflammatory mediators. Protein components from gram-positive bacteria, fungi, or viruses may evoke the activation of nuclear factor kappa B in a similar fashion as lipopolysaccharide. Endogenous anti-inflammatory mediators are released in response to the infection and act to control the overwhelming systemic inflammatory response. The fragile balance between negative and positive feedback on the inflammatory mediators is the key factor that modulates the cellular damage and influences the clinical outcome.     

Decrease in circulating dendritic cells predicts fatal outcome in septic shock

Objective Biomarkers allowing accurate early staging of septic shock patients are lacking despite their obvious interest for patient management. Experimental models of septic shock in mouse previously noted a decrease in dendritic cell numbers. The aim of the study was to find a rapid reproducible biological test for an assessment of disease severity. Design Evaluation of peripheral blood dendritic cell counts by flow cytometry using three commercially available kits. Patients and participants Forty-two consecutive septic shock patients were studied prospectively. Measurements and results Early low dendritic cell counts were correlated to disease severity as assessed by Simplified Acute Physiology Score or Sequential Organ Failure Assessment and predicted fatal outcome. The correlation was still present when the results were adjusted for age. Conclusion The monitoring of blood dendritic cell count may provide an early and valuable assessment of the severity of the host response against infection and may influence the therapeutic management of septic shock patients. O. Guisset and M.-S. Dilhuydy contributed equally to this work.