Khatua, Biswajit

BACKGROUND While most hypertriglyceridemia is asymptomatic, hypertriglyceridemia-associated acute pancreatitis (HTG-AP) can be more severe than AP of other etiologies. The reasons underlying this are unclear. We thus examined whether lipolytic generation of nonesterified fatty acids (NEFAs) from circulating triglycerides (TGs) could worsen clinical outcomes. METHODS Admission serum TGs, NEFA composition, and concentrations were analyzed prospectively for 269 patients with AP. These parameters, demographics, and clinical outcomes were compared between HTG-AP (TGs >500 mg/dL; American Heart Association [AHA] 2018 guidelines) and AP of other etiologies. Serum NEFAs were correlated with serum TG fatty acids (TGFAs) alone and with the product of TGFA serum lipase (NEFAs – TGFAs × lipase). Studies in mice and rats were conducted to understand the role of HTG lipolysis in organ failure and to interpret the NEFA-TGFA correlations. RESULTS Patients with HTG-AP had higher serum NEFA and TG levels and more severe AP (19% vs. 7%; P < 0.03) than did individuals with AP of other etiologies. Correlations of long-chain unsaturated NEFAs with corresponding TGFAs increased with TG concentrations up to 500 mg/dL and declined thereafter. However, NEFA – TGFA × lipase correlations became stronger with TGs above 500 mg/dL. AP and intravenous lipase infusion in rodents caused lipolysis of circulating TGs to NEFAs. This led to multisystem organ failure, which was prevented by pancreatic TG lipase deletion or lipase inhibition. CONCLUSIONS HTG-AP is made severe by the NEFAs generated from intravascular lipolysis of circulating TGs. Strategies that prevent TG lipolysis may be effective in improving clinical outcomes for patients with HTG-AP. FUNDING National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, NIH) (RO1DK092460 and R01DK119646); Department of Defense (PR191945 under W81XWH-20-1-0400); National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH (R01AA031257).

Extended-release buprenorphine interferes with the initiation and progression of acute pancreatitis at multiple levels.

OBJECTIVES: The pathophysiology of delirium is complex and incompletely understood. Inflammation is hypothesized to be integral to its development due to effects on blood brain barrier integrity, facilitation of leukocyte extravasation into brain parenchyma, and propagation of neuroinflammation. Septic shock is the prototypical condition associated with ICU delirium; however, the relative contribution of resultant hypotension and systemic inflammation to the development of delirium is unknown. DESIGN: This was a prospective exploratory study. SETTING: A multidisciplinary ICU at an academic medical center in Phoenix, AZ. PATIENTS: Critically ill patients older than or equal to 18 years old admitted to the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Screening for delirium was performed using the Confusion Assessment Method for the ICU tool. The levels of C-C motif ligand 2 (CCL2), C-C motif ligand 3, C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 10, and interleukin-8 were measured in serum samples obtained within 12 hours of ICU admission. Univariate and multivariate analyses were performed to assess the association of delirium with patient data pertaining to hospital course, laboratory values, vital signs, medication administration, and levels of the aforementioned chemokines. Forty-one of 119 patients (34.5%) in the study cohort developed ICU delirium. Each chemokine studied was associated with delirium on univariate analyses; however, CCL2 was the only chemokine found to be independently associated with the development of delirium on multivariable analysis. The association of increased CCL2 levels with delirium remained robust in various models controlling for age, presence of shock, Sequential Organ Failure Assessment score, Acute Physiology and Chronic Health Evaluation IV score, mean arterial pressure at presentation, lowest mean arterial pressure, and total opioid, midazolam, propofol, and dexmedetomidine exposure. CONCLUSIONS: The demonstrated relationship between CCL2 and delirium suggests this chemokine may play a role in the development of delirium and warrants further investigation.

Saturated fat breaks down less during sudden illnesses, resulting in lower monomer concentrations, and reducing disease severity.

Objective: Ringer’s lactate may improve early systemic inflammation during critical illnesses like severe acute pancreatitis, which are associated with hypocalcemia. Ringer’s lactate is buffered and contains lactate and calcium. We, thus analyzed extracellular calcium or lactate’s effects on the mechanisms, intermediary markers, and organ failure in models mimicking human disease with nonesterified fatty acid (NEFA) elevation. Methods: Meta-analyses and experimental studies were performed. Experimentally, extracellular calcium and lactate were compared in their interaction with linoleic acid (LA; a NEFA increased in human severe pancreatitis), and its subsequent effects on mitochondrial depolarization and cytosolic calcium signaling resulting in cell injury. In vivo, the effect of LA was studied on organ failure, along with the effect of calcium or lactate (pH 7.4) on severe acute pancreatitis-associated organ failure. A meta-analysis of human randomized control trials comparing Ringer’s lactate to normal saline was done, focusing on necrosis and organ failure. Results: Calcium reacted ionically with LA and reduced lipotoxic necrosis. In vivo, LA induced organ failure and hypocalcemia. During severe pancreatitis, calcium supplementation in saline pH 7.4, unlike lactate, prevented hypocalcemia, increased NEFA saponification, reduced circulating NEFA and C-reactive protein, reduced pancreatic necrosis adjacent to fat necrosis, and normalized shock (carotid pulse distension) and blood urea nitrogen elevation on day 1. This, however, did not prevent the later increase in serum NEFA which caused delayed organ failure. Meta-analysis showed Ringer’s lactate reduced necrosis, but not organ failure, compared with normal saline. Conclusion: Hypocalcemia occurs due to excess NEFA binding calcium during a critical illness. Ringer’s lactate’s early benefits in systemic inflammation are by the calcium it provides reacting ionically with NEFA. This, however, does not prevent later organ failure from sustained NEFA generation. Future studies comparing calcium supplemented saline resuscitation to Ringer’s lactate may provide insights to this pathophysiology.