Since the first description of epidural-related maternal fever (ERMF) >25 years ago,1 the relation between ERMF and a potential causative role for local anesthetic agents has been consistently demonstrated (Table 1).2–23 Epidural-related fever occurs in approximately 20% of laboring women who receive epidural labor analgesia. The absence of epidural-related fever in the nonpregnant population has been attributed to the inhibition of fever by inhaled anesthetic agents24 and opioids.25 Thus, there may be mechanisms at play specific to the biology and/or process of labor. Despite the well-established association between labor epidural analgesia and maternal fever (temperature ≥38°C),26 there is still controversy surrounding its etiology. Intrapartum fever is associated with maternal interventions such as administration of IV antibiotics,27 instrumental and cesarean delivery,28 and increased perinatal mortality23 and neonatal morbidity such as meconium aspiration, respiratory distress syndrome, and encephalopathy.18,29 A better understanding of the cause of ERMF may allow interventions to be developed that lead to a reduction in its incidence rate and also facilitate the differentiation from other causes of intrapartum fever. In this focused review, we review the evidence that supports the hypothesis that inflammatory mechanisms generated by anesthetic-specific interventions are responsible for the development of ERMF and consider emerging concepts of possible mechanisms.
INFECTION VERSUS INFLAMMATION
Intuitively, infection would appear to be the most likely trigger for ERMF. Chorioamnionitis, the condition of acute inflammation of the membranes and chorion of the placenta, is estimated to complicate 3% to 5% of all births in the United States.30 Although the precise frequency of chorioamnionitis varies, the highest estimates are clearly exceeded by the prevalence of ERMF (Table 1). More compellingly, a double-blind, placebo-controlled adequately powered trial in 400 laboring women found that prophylactic antibiotic therapy (broad-spectrum cephalosporin) failed to prevent ERMF.31 In addition, clinically relevant models of local anesthetic administration in vivo demonstrate bactericidal activity against common pathogens.32,33 The failure of antibiotic prophylaxis to reduce ERMF, combined with the consistent lack of positive microbiology in observational studies,3,34 suggests that the etiology of ERMF is not primarily infectious in origin.
THE CASE FOR SYSTEMIC INFLAMMATION CAUSING ERMF
There are several compelling clinical clues suggesting that acute inflammation alone underlies the mechanism of ERMF. Higher levels of maternal34 and fetal35 proinflammatory endogenous pyrogens that trigger fever have been measured in pregnant patients after epidural analgesia.9,34–36 However, Riley et al.9 reported that pregnant patients who subsequently developed ERMF had higher admission levels of proinflammatory cytokines (interleukin [IL]-6 and IL-8) before receiving epidural analgesia (Table 2), suggesting that prolonged epidural administration of bupivacaine may augment baseline elevated cytokine levels.37,38 Conversely, antiinflammatory glucocorticoids reduce ERMF, in part, through reducing cytokine production. In 200 term laboring nulliparous women, prophylactic treatment with high-dose IV methylprednisolone (100 mg every 4 hours) reduced the rate of ERMF to just 2.0% compared with low-dose (25 mg every 8 hours; 21.8% incidence) and placebo therapy (34.0% incidence).39 However, the marked reduction in ERMF was at the expense of excess (asymptomatic) neonatal bacteremia, a finding consistent with profound immunosuppression. Dexamethasone administered via epidural infusion (mean total dose, 5.8 mg; range, 3.4–14.2 mg) was also associated with a reduction in maternal temperature increase and lower plasma IL-6 levels40 although a subsequent study has failed to replicate these findings.41 Taken together, these trials of antiinflammatory steroid therapy suggest that proinflammatory pyrogen release is suppressed. However, these studies cannot exclude that glucocorticoids may modulate ERMF at the level of the hypothalamus/central nervous system.42
WHAT IS THE SOURCE OF STERILE INFLAMMATION IN ERMF?
Given the lack of plausible data supporting an acute infectious etiology for ERMF, alternative triggers/sources must fuel inflammation and cytokine production. Sterile inflammation is a process through which inflammation occurs in the absence of a pathogen,43 driven by endogenous molecules called alarmins that are released upon tissue damage.44 Alarmins play both homeostatic and pathophysiologic roles via pattern recognition receptors, including Toll-like receptors,45 which are ubiquitously expressed by immune and nonimmune cells. These numerous (and ever-expanding) damage-associated molecular patterns, including mitochondrial DNA,46 activate the inflammasome. The inflammasome is an intracellular multiprotein complex that promotes the maturation of the proinflammatory cytokines such as IL-1β and IL-18 and subsequent induction of other fever-inducing cytokines.47
Trauma, Stress, and Inflammation from Epidural Catheter Insertion Alone
Both mental stress48 and limited surgical trauma are associated with clinically relevant inflammation and cytokine release. However, triggering ERMF-related inflammatory changes by epidural needle/catheter insertion alone seems highly unlikely. Based on a study in orthopedic surgery patients,49 the magnitude of the systemic cytokine release after catheterization of the epidural space alone is unlikely to account for the magnitude of the systemic inflammatory response associated with ERMF. However, fiberscopic imaging has confirmed that the epidural space in pregnancy differs anatomically, revealing a marked increase in the density of the vascular network.50 Local inflammation, therefore, remains a possible mechanism of ERMF, particularly given the precedent of procedures triggering a systemic inflammatory response. For example, it is notable that pulmonary artery catheterization via the internal jugular vein triggers a prothrombotic response, as reflected by reduced clotting time assessed using thromboelastography.51
Inflammation and Labor
Before and during onset of labor at term, leukocytes and inflammatory cytokines are increased in fetal membranes and decidua,52 even in the absence of infection.53,54 Pregnancy in many respects mimics the immune response to sterile inflammation, with a shift to an adaptive immunity phenotype, decreased proliferation of T cells, and lower cytotoxicity of natural killer cells.55 Proposed sites of cytokine production in pregnancy are nonlymphoid tissues, including the placental/decidual tissues and the trophoblast.56 Spontaneous labor at term is associated with the infiltration of inflammatory cells in these tissues and increased production of proinflammatory cytokines57,58 and other multiple immunomodulatory molecules.57 Gene expression analyses have revealed that genes involved in the control of inflammation are upregulated in the chorioamniotic membranes of women with physiologic spontaneous labor at term, even in the absence of histologic chorioamnionitis. This inflammatory signature is not evident in genes from whole-blood analysis obtained at the same time from the same patients.59 These findings emphasize that spontaneous parturition is associated with an increased proinflammatory cytokine response.57 There appears to be an inflammatory-specific feature of labor relevant to ERMF because maternal fever does not occur in nonlaboring women who have an elective cesarean delivery under neuraxial anesthesia.60 In part, this may reflect that the development of ERMF is related to the duration of exposure to neuraxial analgesia. This finding implies that the inflammatory component of the labor process is integral to the development of ERMF.
A Direct Mechanistic Role for Local Anesthetic Agents
The majority of studies report that ERMF occurs within 6 hours of the onset of epidural analgesia, with temperature increasing progressively after initiation of epidural analgesia. This time frame is compatible with a pharmacologic effect and/or changes in RNA transcription caused by local anesthetic agents. Some have hypothesized that the observation that epidural analgesia is associated with fever compared with a control group without epidural analgesia is a result of fever suppression by systemic opioid analgesia administered to the control group. However, opioids fail to suppress ERMF (Table 1), best highlighted by the retrospective finding that the antipyretic effect of IV systemic nalbuphine in laboring women failed to reduce the incidence rate of ERMF observed in women who received nalbuphine before receiving epidural analgesia.61 ERMF also occurs in the presence and absence of epidural opioid,19 again suggesting a specific effect exerted by local anesthetic agents. Furthermore, albeit in male healthy volunteers, an IV fentanyl infusion suppressed the febrile response triggered by the pyrogen IL-2.62 The development of fever was assessed after epidural analgesia using ropivacaine in the presence/absence of fentanyl, administered either in combination with ropivacaine (2 mg/mL) or as an IV infusion (target plasma concentration of 2.5 ng/mL). Low plasma concentrations of fentanyl (approximately 0.3 ng/mL) failed to suppress fever, in contrast to approximately 5-fold higher plasma concentrations achieved by IV fentanyl.62 Although the raw data were not shown in this article, the authors commented that the pattern of cytokine release was similar between treatment arms in this crossover study. We thus consider that there are 2 labor-specific possibilities for local anesthetics to directly trigger ERMF: immunomodulation and cell injury.
Local anesthetics used routinely for epidural anesthesia in the labor ward, including bupivacaine and ropivacaine, exert profound immunomodulatory effects at plasma levels achieved rapidly with continuous epidural infusion.63,64 Steady-state maternal venous plasma concentrations of bupivacaine approach 4 × 10−6 M.65–67 At far lower concentrations (<10−8 M), bupivacaine modulates intracellular calcium signaling triggered by key neurotransmitters in astrocytes that have also been identified to play a role in peripheral immune cells.68 Although the immunomodulatory effects of local anesthetics have been found to be clinically useful under some circumstances,69 the inhibitory effects of local anesthetics on neutrophil mobility,70 phagocytosis,71 chemotaxis,72 and superoxide generation may also be deleterious.73,74 Given the extent to which neutrophils contribute to the placental infiltrates found in all laboring women, the ability of neutrophils to undergo chemotaxis appears to be preserved in women with epidural analgesia.75 The potential reduction in the capacity of leukocyte subsets to counteract ongoing reproductive tract inflammation, however, could fuel further systemic inflammation. For example, impaired chemotaxis in neutrophils reduces survival in sepsis as a result of failure of bacterial clearance.76 Potentially adverse immunomodulatory actions of bupivacaine have already been described in the obstetric population; subcutaneous bupivacaine was associated with a reduction in the antiinflammatory cytokine IL-10 and a concomitant increase in the proinflammatory mediator substance P in surgical wounds after cesarean delivery.77
Activated immunocytes require profound metabolic changes to respond to various acute environmental challenges. For example, the activation of T lymphocytes is critically dependent on rapid increases in both glycolysis and oxidative phosphorylation.78,79 Acute stressors alter the metabolic capacity of lymphocytes.80,81 CD4+ T cells inhibit macrophage-dependent release of the proinflammatory cytokine IL-1β.82 Under such circumstances, further bioenergetic compromise after the impairment of mitochondrial respiration by systemic absorption of epidural bupivacaine may promote apoptosis/necrosis and hence the release of pyrogenic damage–associated molecular patterns into the circulation. Several studies have described local anesthetic–induced apoptosis in various cell types, including neuronal, lymphocytic, and osteoblastic cell lines.83–86 Epidural lidocaine in dogs induces apoptosis and/or necrosis of peripheral blood mononuclear cells,87 a finding reproduced in a lymphocyte (Jurkat) cell line.88 In vitro, clinically relevant concentrations of both lidocaine and bupivacaine induce apoptosis in primary intervertebral disc cells89 and human renal cells.90 Studies in both isolated mitochondria and intact cells (albeit obtained chiefly from cardiac tissue) show that bupivacaine time-dependently and dose-dependently impairs adenosine triphosphate synthesis in aerobic conditions91 through uncoupling of oxidative phosphorylation92,93 and inhibition of complexes I94 and III95 of the respiratory chain. Although not obligatory, generation of reactive oxygen species is associated with activation of the inflammasome.96 Cell-specific pathologic changes induced by bupivacaine in highly oxidative tissues such as skeletal muscle also include activation of the mitochondrial permeability transition pore, a critical event in mitochondrial-dependent programmed cell death.97
THE CELLULAR SOURCE(S) OF ALARMINS GENERATED BY LOCAL ANESTHETIC AGENTS
Systemic absorption of epidurally administered bupivacaine at clinically relevant concentrations may cause mitochondrial damage through electron transport chain dysfunction,95 excessive reactive oxygen species, and/or apoptosis in circulating leukocytes and/or the maternoplacental interface (Fig. 1). Our recent work has highlighted an emerging role for acute stress hormones in modulating leukocyte metabolism. Elevations in circulating glucocorticoids, typical of the labor process, increase mitochondrial reactive oxygen species, activated caspase-1, and mature IL-1β in human lymphocytes. This is accompanied by a hypometabolic phenotype and apoptosis.81 Similarly, mitochondrial electron chain dysfunction is generated by acute increases in nitric oxide.98 Plasma levels of bupivacaine may be misleading, as suggested by the accumulation of bupivacaine in the myocardium resulting in reversible pathologic changes in mitochondrial structure and reduced mitochondrial oxygen consumption.99 Thus, accumulation of bupivacaine in placental tissues100 could induce release of alarmins from reproductive tract and placental inflammatory cell infiltrates and/or nonlymphoid tissues.56
ERMF remains a phenomenon of unknown etiology, yet it affects a significant proportion of laboring women with potentially important clinical consequences. Local anesthetic agents routinely used for epidural analgesia in labor appear to be the likeliest culprits for the development of ERMF. Plausible mechanisms involving bupivacaine have already been described in other areas of inflammation biology and relevant clinical models. Sterile inflammation and activation of the inflammasome are likely to play a key role. From a clinical perspective, more detailed epidemiologic studies comparing high-risk versus low-risk laboring women may help reveal biological differences underlying ERMF. Similarly, establishing whether different local anesthetic agents confer similar risk may shed further light on underlying mechanisms.
Name: Pervez Sultan, FRCA.
Contribution: This author helped prepare the manuscript.
Attestation: Pervez Sultan approved the final manuscript.
Name: Anna L. David, PhD, FRCOG.
Contribution: This author helped prepare the manuscript.
Attestation: Anna L. David approved the final manuscript.
Name: Roshan Fernando, MD, FRCA.
Contribution: This author helped prepare the manuscript.
Attestation: Roshan Fernando approved the final manuscript.
Name: Gareth L. Ackland, PhD, FRCA, FFICM.
Contribution: This author helped prepare the manuscript.
Attestation: Gareth L. Ackland approved the final manuscript.
This manuscript was handled by:Cynthia A. Wong, MD.
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