Catecholamines are amine molecules important in the autonomic nervous system and cardiovascular system. Catecholamines are produced in abundance when the body is under a severe stress. Epinephrine and norepinephrine (adrenaline and noradrenaline) are catecholamines that prepare the body for a fight or flight response.
These stress hormones affect the entire body, including the heart, brain, and gut. Adrenaline causes the heart to beat faster, blood pressure to increase – delivering more blood flow to muscles in preparation for increased demands. Movement of the gut slows down, digestion stops, and secretions dry up. We sense the decreased secretory activity when we experience cotton mouth when we are stressed. Behaviorally, catecholamines cause anxiety or excitement or panic. When we need to fight or flee having lots of catecholamines is useful. However, catecholamine surges also happen in situations where there is no fighting or fleeing. Catecholamines spike during sleep in patients with obstructive sleep apnea, contributing to high blood pressure and increased heart disease seen in those patients. Another situation with high catecholamines is sepsis. Sepsis is a fight at the cellular level: it involves a life or death struggle between the host and invading microorganisms. Despite high catecholamines in sepsis, blood pressure is often low in septic shock. One reason for low blood pressure in sepsis is activation of inducible nitric oxide synthase that we covered in a recent post here, along with depressed cardiac contractility (proposed by Mervyn Singer to be adaptive here). in response to low blood pressure, clinicians attempt to fix the problem by giving catecholamine vasopressors – most often norepinephrine. These come with some unintended consequences, and recent studies suggest that infusing catecholamine vasopressors harms some patients.
Recent studies comparing different blood pressure targets in sepsis have suggested that there is no benefit, and possible harm to higher (e.g. more “normal”) blood pressure in patients with sepsis. Lamontainge et al. performed a pooled analysis of these trials and concluded “Targeting higher blood pressure targets may increase mortality in patients who have been treated with vasopressors for more than 6 h. Lower blood pressure targets were not associated with patient-important adverse events in any subgroup, including chronically hypertensive patients.” Because of these findings, Guinot and colleagues have proposed a catecholamine-sparing approach in critical illness. Recently, Mouncy and colleagues performed a large randomized controlled trial in which elderly patients with critical illness were assigned to higher blood pressure and lower blood pressure groups – the lower blood pressure group was exposed to less catecholamine vasopressors. This study was designed to test the question of whether lowering catecholamine exposure in elderly patients with critical illness would improve survival. There was no significant impact on survival. The authors wrote: “after 90 days, 41% of patients in the new low blood pressure target group had died, compared with 44% in the usual-care group. Although we could not prove that use of a lower blood pressure target saves lives for older patients in intensive care, our trial suggests that it might.” The take home point here: receiving less vasopressor drugs and having a lower blood pressure appears to be safe for patients, even our most medically fragile elderly patients with life threatening critical illnesses.
What accounts for the potential harms caused by catecholamines? One possibility is damage to the gut barrier. Observational trials have shown that excess catecholamines can cause damage to the gut barrier, which in turn is linked with higher 28 day mortality in sepsis. In addition, catecholamines affect bacterial and viral pathogens. For viruses, it is a mixed picture. Catecholamines increase infectivity of enterovirus 71, an infection that can cause neurologic symptoms and affects the autonomic nervous system, causing the release of excess catecholamines. This virus is more infectious and transmissible when catecholamines are abundant. Whether enterovirus 71 manipulates its host by increasing catecholamines is an unanswered question. For other viruses, catecholamines have opposite effects and can be directly antiviral. That seems to be the case for the virus responsible for dengue fever. Catecholamine synthesis increases during dengue fever and causes impaired viral replication. Interestingly, according to the authors of a recent paper, “the virus reduces catecholamine biosynthesis, metabolism, and transport.” From an evolutionary medicine perspective, we should be attuned to these opposing effects of host and pathogen. This sort of tug of war can illuminate the direction of natural selection in hosts and pathogens and point to the possible adaptiveness of these traits.
How about bacteria and archaea? Mark Lyte has done decades of work showing that catecholamines can cause increased virulence and growth in gram negative bacteria, the ones often responsible for septic shock in humans. Catecholamines also cause biofilm growth on venous catheters by gram positive pathogens, raising the risk of septic complications.
It is important to recognize that we doctors did not invent norepinephrine. Neither did humans, or mammals for that matter. It is likely that bacteria evolved biogenic amines, including catecholamines long before mammals appeared on the scene. Mark Lyte has shown that many microbes produce biogenic amines, including “human” neurochemicals dopamine, serotonin, and norepinephrine. These are used by microbes to regulate their growth depending on the concentration and activity of their fellow microbes – a process called quorum sensing. In humans, invasive E. coli, Salmonella, Campylobacter jejuni respond to catecholamines by increasing virulence. Catecholamines also increase the colonization by Helicobacter pylori at sites of gastric injury. Catecholamines are also metabolized by bacteria, including pathogenic and nonpathogenic E. coli. One of these metabolites, DHMA, is detected by enterohemorrhagic E. coli by their quorum sensing system, and increases EHEC virulence genes (33 of ’em) and increases attachment to intestinal epithelial cells. Not good, not good at all.
There are vast differences between how individual pathogens respond to catecholamines, for example between E. coli that benefits, and dengue that is harmed by catecholamines. Those differences argue for a personalized medicine approach to catecholamines. And what about our ongoing scourge – COVID-19? SARS-CoV-2 is a pathogen that probably benefits from a high-catecholamine environment. A recent meta analysis suggested a link between higher mortality and vasopressor use in COVID. This is a pre-print that relies on data from observational trials, so we won’t know for sure without further randomized trials. But those results are in line with the observation that worse outcomes in COVID-19 are associated with higher blood pressure. Whether SARS-CoV-2 increases blood pressure as a means to increase transmission is unknown. We should be alert to such a possibility, though, and cautious about using catecholamine vasopressors that have myriad effects on our bodies and on our microbial opponents.
Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine