Lithium has been a mainstay of bipolar disorder treatment since the mid-twentieth century, prized for its mood-stabilizing properties. But the drug operates on a razor’s edge. Its therapeutic window is narrow, meaning the difference between an effective dose and a toxic one is small. When serum concentrations climb above 1.5 milliequivalents per liter, patients risk multiorgan dysfunction affecting the nervous system, kidneys, gastrointestinal tract, endocrine system, and, less commonly, the cardiovascular system. Cardiac complications, while infrequent, can include sinoatrial node dysfunction, atrioventricular block, and dangerous ventricular arrhythmias, with bradycardia, an abnormally slow heart rate, often serving as the first visible warning sign.

In this case, the patient had been living with bipolar I disorder and had been taking lithium under regular monitoring by her primary care physician. Her kidney function, tracked through creatinine levels, had been slowly deteriorating from 0.95 to 1.24 milligrams per deciliter over time, a red flag that would later prove consequential. Roughly a month before admission, she began experiencing progressively worsening tremors and myoclonic jerks, involuntary muscle twitches that were most noticeable during fine motor tasks like writing. Intermittent dizziness, lightheadedness, and mounting fatigue followed. Her family observed that she was drinking more water than usual and had episodes of slurred speech and altered mental status. Three days before hospitalization, she developed intermittent, bandlike pain in her right lower abdomen accompanied by loose stools and reduced oral intake.

On arrival, she was alert but showed signs of mild encephalopathy, a state of brain dysfunction. Her heart rate ranged between 30 and 49 beats per minute, dangerously slow for an adult. Abdominal examination revealed tenderness in the right lower quadrant without signs of peritoneal irritation, meaning the lining of the abdominal cavity had not yet become inflamed. Neurologically, she exhibited a resting tremor and occasional myoclonic jerks but no focal deficits, suggesting no localized brain lesion. Her mental status was slowed but she remained oriented to herself, her location, and the date.

Initial diagnostic workup painted a complex picture. An electrocardiogram revealed an idioventricular rhythm, a slow backup rhythm generated by the ventricles themselves, along with a left bundle branch block, a conduction abnormality. Laboratory results showed elevated creatinine at 1.43 milligrams per deciliter, non-anion gap metabolic acidosis, elevated white blood cell count, and hypernatremia at 149 millimoles per liter, indicating both kidney impairment and dehydration. Her serum lithium level measured 1.6 millimoles per liter, just above the toxic threshold. Abdominal X-rays showed severely distended bowel loops initially raising concern for small bowel obstruction, but a subsequent computed tomography scan of the abdomen and pelvis revealed the true culprit: an 8.6-centimeter distended cecum oriented transversely across the abdomen, consistent with cecal volvulus. A brain CT showed only chronic microvascular changes with no acute pathology, and a urinalysis positive for infection grew Streptococcus dysgalactiae on culture.

The clinical team synthesized these findings into a diagnosis of acute-on-chronic lithium toxicity complicated by cecal volvulus. Lithium was immediately discontinued, and aggressive intravenous hydration was initiated, later transitioning to 5 percent dextrose in water to address the hypernatremia. Nephrology specialists were consulted and recommended close monitoring of sodium and creatinine levels, along with the initiation of amiloride, a medication that addresses lithium-induced arginine vasopressin resistance, a condition in which the kidneys become inappropriately resistant to the hormone that regulates water balance. Cardiology advised against pacemaker placement, reasoning that the bradycardia was potentially reversible rather than stemming from permanent damage to the heart’s conduction system.

What followed was a diagnostic puzzle that unfolded over days. The patient’s lithium level steadily declined, reaching 0.1 millimoles per liter by hospital day 11, well within the normal range. Yet her encephalopathy and bradycardia persisted despite the falling drug concentration. This disconnect between serum levels and clinical symptoms proved to be the critical clue. The persistence of abdominal pain and worsening distension on repeat imaging prompted the surgical team to proceed with an exploratory laparotomy, during which they performed a right hemicolectomy, removing the affected portion of the colon, and an ileocolic anastomosis, reconnecting the small intestine to the remaining colon.

The outcome was dramatic. Following surgical correction of the bowel obstruction, the patient’s heart rate normalized and her neurological symptoms improved markedly. Postoperative ileus, a temporary paralysis of the intestines common after abdominal surgery, resolved with conservative management including intravenous hydration, antiemetics, and gradual reintroduction of a liquid diet. She was discharged in stable condition with resolved encephalopathy and a normal sinus rhythm at 79 beats per minute. The temporal relationship between surgical relief of the obstruction and the restoration of both cardiac and neurological function strongly suggested that the volvulus was not merely a coincidental finding but an active driver of her deterioration.

The authors propose a multifactorial mechanism to explain this clinical trajectory. First, the cecal volvulus impaired lithium clearance, likely by promoting dehydration and reducing renal perfusion, thereby allowing the drug to accumulate despite ongoing chronic therapy. Second, the abdominal distension caused by the twisted bowel likely triggered increased vagal tone, a reflexive activation of the parasympathetic nervous system that independently slows heart rate. This dual mechanism explains why the bradycardia persisted even as serum lithium levels fell: the mechanical obstruction continued to exert its vagal influence until it was physically corrected. The authors also hypothesize that lithium-associated gastrointestinal dysmotility may have predisposed the patient to the volvulus in the first place, creating a self-reinforcing cycle in which the drug slowed gut movement, the sluggish gut twisted and obstructed, and the obstruction further impaired drug elimination.

This case carries important lessons for clinicians managing patients on chronic lithium therapy. Serum lithium concentrations, while useful, may not accurately reflect the severity of toxicity in patients receiving long-term treatment, and clinically significant toxicity can occur despite levels that appear only modestly elevated. The authors emphasize that diagnosis should be guided by the overall clinical presentation rather than by laboratory values alone. They also highlight the value of sequential diagnostic reassessment: when symptoms persist or worsen despite appropriate treatment for an initial diagnosis, clinicians must remain open to additional contributing pathology. For patients with lithium toxicity who present with unexplained or refractory bradycardia, the authors recommend maintaining a high index of suspicion for structural gastrointestinal problems, as emergent surgical intervention may be required to break the cycle of drug accumulation and vagal-mediated cardiac slowing. The case ultimately underscores a broader principle in medicine: the body’s organ systems are deeply interconnected, and a problem in one system can cascade into unexpected and dangerous consequences elsewhere.

Subject of Research: Lithium toxicity and bradycardia caused by cecal volvulus-associated bowel obstruction

Article Title: Case Report: Lithium-induced bradycardia triggered by cecal volvulus: a case of obstruction-associated drug accumulation

Article References: Alnounou, A., Zou, H., Laird, M., Visak, C., Bilsland, S., Numbers, S., & Hughes, N. (2026). Case Report: Lithium-induced bradycardia triggered by cecal volvulus: a case of obstruction-associated drug accumulation. Frontiers in Gastroenterology, 5, Article 1728396. https://doi.org/10.3389/fgstr.2026.1728396

Image Credits: AI Generated

DOI: 10.3389/fgstr.2026.1728396

Keywords: lithium toxicity, bradycardia, cecal volvulus, bowel obstruction, bipolar disorder, drug accumulation, vagal response, renal impairment, encephalopathy, case report, gastroenterology, cardiology

The review, led by Unimark Junior S. Awadzi of Purdue’s Weldon School of Biomedical Engineering together with colleagues including Steven R. Steinhubl, followed the PRISMA Extension for Scoping Reviews guidelines and searched PubMed for articles published since January 2006. The team deliberately drew a line at 2006 because that year marked a turning point in the field: a collection of case studies had reported rare instances of sinus pauses, brief interruptions of the heart’s natural pacing rhythm, following intravenous LPS administration, along with recommended precautions to prevent them. By restricting the analysis to contemporary practice, the researchers aimed to capture the real-world safety profile of the modern experimental endotoxemia model rather than a legacy of older protocols.

The numbers behind the analysis are substantial. From an initial pool of 252 articles, the reviewers identified 165 distinct clinical studies involving a total of 3,870 volunteers. The participants were almost exclusively healthy young adults, with an approximate mean age of 28.3 years. Perhaps the most striking demographic detail, and one that speaks to persistent inequities in human immunology research, is that the overwhelming majority of these studies, 117 out of 165, enrolled males only. That means the safety conclusions now on offer rest overwhelmingly on data from young men, a limitation the field has only begun to confront in recent years.

To understand why researchers would inject a bacterial endotoxin into volunteers at all, it helps to grasp the biology. LPS is a large molecule anchored in the outer membrane of bacteria such as E. coli, and it is one of the most potent immune activators known to science. Its inflammatory signal is detected by Toll-like receptor 4, a pattern-recognition receptor on immune cells that treats LPS as a molecular signature of dangerous infection. When a carefully calibrated dose of LPS enters the bloodstream, it sets off a controlled, reproducible cascade: immune cells release signaling proteins called cytokines, including tumor necrosis factor-alpha, interleukin-6 and interleukin-1, which in turn drive measurable changes in heart rate, body temperature, stress hormones and white blood cell counts. This experimental endotoxemia model essentially compresses the earliest hours of a bacterial infection into a predictable, monitorable laboratory event.

That predictability is precisely what makes the model so valuable. Sepsis, the life-threatening dysregulation of the body’s response to infection, kills millions of people worldwide each year, yet its course in real patients is chaotic and confounded by antibiotics, comorbidities and organ damage. By contrast, a volunteer receiving a standardized LPS dose under continuous monitoring offers researchers a clean window into the machinery of systemic inflammation. The model has been used to test anti-inflammatory drugs, to study how alcohol use disorder alters immune reactivity, to examine sex differences in inflammatory responses, and to probe how the brain’s stress circuits talk to the immune system. C-reactive protein levels, cytokine kinetics and immune cell trafficking measured after LPS challenge have informed drug development and basic immunology alike.

What the Purdue review found is that this controlled storm, while universally felt, is also universally transient. In every one of the 165 studies, intravenous LPS produced a dose-dependent inflammatory response characterized by elevations in heart rate, body temperature and influenza-like symptoms, the familiar malaise, headache, chills and muscle aches that volunteers consistently describe. Crucially, these symptoms typically resolved by eight hours after dosing. The review identified only one unanticipated adverse event category across the entire contemporary literature: syncope, or fainting, reported in just three cases among nearly 4,000 LPS-treated volunteers over 21 years of practice. For an experimental intervention that intentionally mimics bloodstream infection, that safety record is exceptional.

The cardiac story, however, deserves particular attention, because it explains both the 2006 caution and the review’s central recommendation. The rare sinus pauses documented in earlier case reports are thought to arise from a vagally mediated reflex: the intense inflammatory and febrile response can trigger the vagus nerve to transiently suppress the heart’s sinoatrial node, the natural pacemaker, producing a brief pause in heartbeat. In susceptible individuals this can lead to lightheadedness or fainting. The suggested countermeasures are straightforward and have evidently been effective, since no new sinus pause cases emerged in the contemporary literature the review surveyed. Continuous electrocardiographic monitoring during and after dosing, keeping volunteers supine, maintaining adequate hydration, and avoiding abrupt postural changes all serve to blunt vagal surges and catch any rhythm disturbance the moment it appears.

The authors’ conclusion is carefully worded but clear: the rarity of adverse events across 165 studies suggests that intravenous LPS was generally reported to be safe and well tolerated, although precautions should be taken to minimize vagally induced sinus pauses. That phrasing, generally reported to be safe, is an honest reflection of what a scoping review can and cannot establish. Scoping reviews map the landscape of published evidence rather than pooling raw data the way a meta-analysis would, so the finding is best understood as a comprehensive audit of what researchers have documented, not a guarantee of zero risk. Informed consent, institutional review board oversight and careful participant screening remain the bedrock of every study that uses the model.

The review also quietly exposes gaps that the field will need to address. With more than 70 percent of studies restricting enrollment to males, the safety and immunological implications of LPS challenge in women remain underexplored, even though sex differences in inflammatory signaling are well documented in animal work and in emerging human studies. The narrow demographic profile, healthy volunteers averaging under 30 years of age, likewise means that the model’s safety in older adults or people with chronic conditions is essentially untested. As researchers push to make experimental endotoxemia more representative, the safety database built by studies like this one will need to grow along with it.

For now, the message to the immunology community is reassuring. An experimental tool that sounds alarming, purified endotoxin injected into the veins of volunteers, has been administered thousands of times under monitoring protocols that have evolved to near-routine reliability, producing transient flu-like illness and almost nothing worse. In an era when inflammation is implicated in everything from cardiovascular disease to depression to aging itself, a safe, standardized and reversible way to ignite and study the human inflammatory response is a scientific asset worth protecting. The Purdue team’s audit gives that asset its most thorough safety certification to date, and a clear playbook for keeping it that way.

Subject of Research: Safety of intravenous lipopolysaccharide administration in human systemic inflammation research

Article Title: The safety of intravenous lipopolysaccharide for the study of systemic inflammation in humans: a scoping review

Article References: Awadzi, U. J. S., Heumann, R. A., Gmyrek, G. B., Robinson, J. P., Ward, M. P., & Steinhubl, S. R. (2026). The safety of intravenous lipopolysaccharide for the study of systemic inflammation in humans: a scoping review. BMC Pharmacology and Toxicology. https://doi.org/10.1186/s40360-026-01241-w

Image Credits: AI Generated

DOI: 10.1186/s40360-026-01241-w

Keywords: lipopolysaccharide, endotoxemia, systemic inflammation, clinical trials, vaccine safety model, Toll-like receptor 4, cytokines, sinus pauses, vagal response, scoping review, healthy volunteers, immunology