Can ‘permissive’ hypercapnia modulate the severity of sepsis-induced ALI/ARDS?

En viktig studie som nevner alt om hvordan CO2 påvirker immunsystemet i positiv retning. Nevner de to grenene av immunsystemet – den iboende og den tilpasningsdyktige. Den tilpasningsdyktige delen lærer av sine tidligere reaksjoner.

Nevner at hyperkapni reduserer utskillelse av cytokiner (betennelsesfaktorer) fra nøytrofiler og makrofager (immunceller). I tillegg reduseres produksjonen av frie radikaler, noe som normalt sett er bra, men når det gjelder bakterier benyttes de frie radikalene til å drepe slike inntrengere.

Nevner også at acidose øker muligheten for kreftspredning, så dette er ikke anbefalt i kreft-tilfeller.

I tilfeller med bakterielle infeksjoner kan det virke som at hyperkapni ikke er å anbefale når det gjelder lungeinfeksjoner, mens mot infeksjoner ellers i kroppen er hyperkapni svært nyttig.

Of particular importance, a secondary analysis of data from the ARDSnet tidal volume study [1] demonstrated that the presence of hypercapnic acidosis at the time of randomization was associated with improved patient survival in patients who received high tidal volume ventilation [3]. These findings have resulted in a shift in paradigms regarding hypercapnia – from avoidance to tolerance – with hypercapnia increasingly permitted in order to realize the benefits of low lung stretch.

The ideal inflammatory process is rapid, causes focused destruction of pathogens, yet is specific and ultimately self-limiting [5]. In contrast, when the inflammatory response is dysregulated or persistent, this can lead to excessive host damage, and contribute to the pathogenesis of lung and systemic organ injury, leading to multiple organ failure and death. The potential for hypercapnia and/or its associated acidosis to potently inhibit the immune response is increasingly recognized[6,7].

The protective effects of hypercapnic acidosis in these models appear due, at least in part, to its anti-inflammatory effects.

The immune system can be viewed as having two inter-connected branches, namely the innate and adaptive immune responses [5].

The innate immune system is an ancient, highly conserved response, being present in some form in all metazoan organisms. This response is activated by components of the wall of invading micro-organisms, such as lipopolysaccharide (LPS) or peptidoglycan, following the binding of these pathogen-associated molecular patterns to pattern recognition receptors, such as the Toll-like receptors (TLRs) on tissue macrophages. The innate immune response is also activated by endogenous ‘danger’ signals, such as mitochondrial components [15], providing an elegant explanation for why non-septic insults can also lead to organ injury and dysfunction. An inflammatory cascade is then initiated, involving cytokine signaling activation of phagocytes that kill bacteria, as is activation of the (later) adaptive immune response.

Increasing evidence suggests that hypercapnic acidosis directly inhibits the activation of NF-κB [16]. Intriguingly, this effect of hypercapnic acidosis may be a property of the CO2 rather than its associated acidosis [1719].

Hypercapnic acidosis reduces neutrophil [20] and macrophage [21] production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8 and IL-6. Hypercapnic acidosis reduced endotoxin stimulated macro-phage release of TNFα and IL-1β in vitro [21].

Hypercapnic acidosis inhibits the generation of oxidants such as superoxide by unstimulated neutrophils and by neutrophils stimulated with opsonized Escherichia coli or with phorbol esters [20].

The potential for hypercapnic acidosis to reduce free radical formation, while beneficial where host oxidative injury is a major component of the injury process, may be disadvantageous in sepsis, where free radicals are necessary to cause bacterial injury and death.

The adaptive immune system is activated by the innate response following activation of pattern recognition receptors that detect molecular signatures from microbial pathogens. Specific major histocompatibility complex molecules on T and B lymphocytes also bind microbial components. These activation events lead to the generation of T and B lymphocyte-mediated immune responses over a period of several days.

However, the demonstration that hypercapnic acidosis enhanced systemic tumor spread in a murine model [31] raises clear concerns regarding the potential for hypercapnic acidosis to suppress cell-mediated immunity.

In an animal model of prolonged untreated pneumonia, sustained hypercapnic acidosis worsenedhistological and physiological indices of lung injury, including compliance, arterial oxygenation, alveolar wall swelling and neutrophil infiltration [23]. Of particular concern to the clinical setting, hypercapnic acidosis was associated with a higher lung bacterial count.

Compared with normocapnia, both hypercapnic acidosis and dobutamine raised cardiac index and systemic oxygen delivery and reduced lactate levels. In addition, hypercapnic acidosis attenuated indices of lung injury, including lung edema, alveolar-arterial oxygen partial pressure difference and shunt fraction. Hypercapnic acidosis did not decrease survival time compared to normocapnia in this setting [43]. In a more prolonged systemic sepsis model, Costello et al. demonstrated that sustained hypercapnic acidosis reduced histological indices of lung injury compared with normocapnia in rodents following cecal ligation and puncture [42]. Reassuringly there was no evidence of an increased bacterial load in the lung, blood, or peritoneum of animals exposed to hypercapnia.

Most recently, CO2 pneumoperitoneum has been demonstrated to increase survival in mice with polymicrobial peritonitis induced by cecal ligation and puncture (Figure 3) [31]. These protective effects of intraperitoneal carbon dioxide insufflation appear be due to the immunomodulatory effects of hypercapnic acidosis, which include an IL-10 mediated downregulation of TNF-α [44].

The potential for hypercapnia to modulate the immune response, and the mechanisms underlying these effects are increasingly well understood. The findings that hypercapnic acidosis is protective in systemic sepsis, and in the earlier phases of pneumonia-induced sepsis, provide reassurance regarding the safety of hypercapnia in the clinical setting. However, the potential for hypercapnic acidosis to worsen injury in the setting of pro-longed lung sepsis must be recognized.

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