Is Lactated Ringer’s Better Than Normal Saline For Routine Use?

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L McIntyre et al. NEJM 2025; 393: 660-670. A Crossover Trial of Hospital-Wide Lactated Ringer’s Solution versus Normal Saline

Background: “A single-center, multiple-crossover trial involving noncritically ill patients in the emergency department found that balanced crystalloid fluids were associated with a lower incidence of major adverse kidney events at 30 days than normal saline. A systematic review of 13 randomized, controlled trials comparing balanced crystalloids with normal saline in a total of 35,884 critically ill participants showed no significant difference in mortality (17.4% with balanced crystalloids and 18.2% with saline; relative risk, 0.96; 95% confidence interval [CI], 0.91 to 1.01) or in the incidence of the use of renal replacement therapy (5.6% and 6.0%, respectively; relative risk, 0.95; 95% CI, 0.81 to 1.11) in trials with a low risk of bias.4 However, the investigators in that analysis and those in another patient-level meta-analysis involving a Bayesian approach concluded that there is a high probability that balanced crystalloids are associated with lower in-hospital mortality and a lower incidence of the use of renal replacement therapy than normal saline.5“

Methods of th “FLUID” trial: 3 hospitals used lactated ringer’s (LR) and 4 hospitals used normal saline throughout hospital setting for 12 weeks. Then after a 1-2 week washout period, the hospitals switched to the other fluid for 12 weeks.

Key finding:

Discussion: “A limitation of this trial was the inability to recruit the total of 16 hospitals as originally planned owing to the Covid-19 pandemic. Hence, the trial had less power to detect differences that were small — but important to patients — at the level of the hospital or health care system…Our findings align with those of recent meta-analyses of randomized, controlled trials that suggest a small but clinically relevant reduction in mortality with balanced crystalloids as compared with normal saline.”

My take: This study did not show a significant difference in death or readmission at 90 days. Yet, lactated ringer’s is probably just a bit better fluid for most adult patients. In the pediatric population, more studies are needed.

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

Expert Advice for GI Manifestations of Hypermobile Ehlers-Danlos Syndrome Including Association with POTS and Mast Cell Activation Syndrome (MCAS)

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Q Aziz et al. Clinical Gastroenterology and Hepatology, Volume 23, Issue 8, 1291 – 1302. Open Access! AGA Clinical Practice Update on GI Manifestations and Autonomic or Immune Dysfunction in Hypermobile Ehlers-Danlos Syndrome: Expert Review

This review and practice update includes 16 “best practice advice” statements. Here are nine of them:

  • #1: Clinicians should be aware of the observed associations between hEDS or HSDs and POTS and/or MCAS and their overlapping gastrointestinal (GI) manifestations; while theoretical explanations exist, experimental evidence of the biological mechanisms that explain relationships is limited and evolving.
  • #2: Testing for POTS/MCAS should be targeted to patients presenting with clinical manifestations of POTS/MCAS, but universal testing for POTS/MCAS in all patients with hEDS/HSDs is not supported by the current evidence.
  • #3: Gastroenterologists seeing patients with DGBI should inquire about joint hypermobility and strongly consider incorporating the Beighton score for assessing joint hypermobility into their practice as a screening tool; if the screen is positive, gastroenterologists may consider applying 2017 diagnostic criteria to diagnose hEDS (https://www.ehlers-danlos.com/wp-content/uploads/2017/05/hEDS-Dx-Criteria-checklist-1.pdf) or offer appropriate referral to a specialist where resources are available.
  • #4: Testing for POTS through postural vital signs (eg, symptomatic increase in heart rate of 30 beats/min [40 beats/min for 12-19 yo] or more with 10 minutes of standing during an active stand or head-up tilt table test in the absence of orthostasis) and referral to specialty practices (eg, cardiology or neurology) for autonomic testing should be considered in patients with hEDS/HSDs and refractory GI symptoms who also report orthostatic intolerance after exclusion of medication side effects and appropriate lifestyle or behavioral modifications (eg, adequate hydration and physical exercise) have been attempted but is not required for all patients with hEDS/HSDs who report GI symptoms alone.
  • #5: In patients presenting to gastroenterology providers, testing for mast cell disorders including MCAS should be considered in patients with hEDS/HSDs and DGBI who also present with episodic symptoms that suggest a more generalized mast cell disorder (eg, visceral and somatic pain, pruritus, flushing, sweating, urticaria, angioedema, wheezing, tachycardia, abdominal cramping, vomiting, nausea, diarrhea, urogynecological and neurological complaints) involving 2 or more physiological systems (eg, cutaneous, GI, cardiac, respiratory, and neuropsychiatric), but current data do not support the use of these tests for routine evaluation of GI symptoms in all patients with hEDS/HSDs without clinical or laboratory evidence of a primary or secondary mast cell disorder.
  • #6: If MCAS is suspected, diagnostic testing with serum tryptase levels collected at baseline and 1–4 hours following symptom flares may be considered by the gastroenterologist; increases of 20% above baseline plus 2 ng/mL are necessary to demonstrate evidence of mast cell activation.
  • #12: Medical management of GI symptoms in hEDS/HSDs and POTS/MCAS should focus on treating the most prominent GI symptoms and abnormal GI function test results. In addition to general DGBIs and GI motility disorder treatment, management should also include treating any symptoms attributable to POTS and/or MCAS.
  • #13: Treatment of POTS may include increasing fluid and salt intake, exercise training, and use of compression garments. Special pharmacological treatments for volume expansion, heart rate control, and vasoconstriction with integrated care from multiple specialties (eg, cardiology, neurology) should be considered in patients who do not respond to conservative lifestyle measures.
  • #14: When MCAS is suspected, patients can benefit from treatment with histamine receptor antagonists and/or mast cell stabilizers, in addition to avoiding triggers such as certain foods, alcohol, strong smells, temperature changes, mechanical stimuli (eg, friction), emotional distress (eg, pollen, mold), or specific medications (eg, opioids, nonsteroidal anti-inflammatory agents, iodinated contrast).

Background: “Clinical gastroenterologists are encountering an increasing number of patients with chronic GI symptoms who also appear to experience comorbid hEDS/HSDs, POTS, and/or MCAS.15,16 Recognizing and treating GI symptoms in patients with hEDS/HSDs and comorbid POTS or MCAS present major challenges for clinicians, who often feel under equipped to address their needs.”

The article provides guidance on measuring hypermobility (Beighton Scoring System), Diagnosis/classification of mast cell activation (Table 1) and treatments for these disorders (Table 2)

My take: This is a useful reference for the overlap of DGBIs with hypermobile Ehlers-Danlos, POTS and Mast cell Activation. Nevertheless, the relationship between these disorders is unclear. In fact, there have been some studies indicating that joint mobility is not associated with an increase in functional GI disorders. Some of the association may be related to a surveillance bias.

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Impact of GLP-1 Agonists on IBD and Obesity

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P Sehgal et al. Clin Gastroenterol Hepatol 2025; 23: 1453-1454.Safety and Clinical Effectiveness of GLP1 Receptor Agonists in Inflammatory Bowel Disease Patients

Background: “The prevalence of obesity among patients with inflammatory bowel disease (IBD) is estimated at 15-40%, and continues to rise. Obesity has been associated with a more severe phenotype of IBD.”

Methods: Retrospective cohort with 244 patients. Semaglutide was the most commonly prescribed agent (54%).

Key findings:

  • GLP-1RA use led to weight loss from 102 kg to 97.6 kg at 12-24 weeks postinitiation
  • GLP-1RA was associated with a significant drop in CRP from 10.1 mg/dL to 3 mg/dL
  • In a subset of 32, fecal calprotectin values decreased from 825 mcg/kg to 235 mcg/kg (P= 0.13)

Limitations: Retrospective study with a short duration, lack of a control group for this study, and lack of endoscopic data.

My take: As with the broader population, GLP-1 RAs help with weight loss in patients with IBD. Many patients may derive health benefits from weight loss alone. This study, though with numerous limitations, indicates the potential beneficial effects on the activity of IBD based on improvements in biomarkers.

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Old Mill on the Cherokee Trail at Stone Mtn Park. Stone Mtn, GA

Pharmacologic Neuromodulation for Bloating Symptoms

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Briefy noted: EN Madva et al. Scand J Gastroenterol 2025 Aug 8:1-5. doi: 10.1080/00365521.2025.2544306. Online ahead of print. Pharmacologic neuromodulation for bloating.

This was a small retrospective study of consecutively referred patients with a DGBI (N = 77; ages 18-74, 87% female) to a tertiary neurogastroenterology clinic who were prescribed a neuromodulator for a primary complaint of bloating in 2016-2022.  Duloxetine was the most commonly prescribed neuromodulator (n = 52, 67.5%).

My take: This study shows that neuromodulators are likely beneficial for bloating symptoms. Dr. Garza () previously noted that in patients with bloating “the typical increase in excess gas during bloating symptoms is only 22 mL.” Thus, “A lot of bloating symptoms are due to increased sensitivity and ‘weird gas handling.’ The latter could include compression of diaphragm rather than elevation.”

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Weight Loss Efficacy of Cagrilintide and Semaglutide

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WTGarvey et al. N Engl J Med 2025;393:635-647. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity

This  phase 3a, 68-week, multicenter, double-blind, placebo-controlled and active-controlled trial (REDEFINE 1) examined the efficacy of the combination of Cagrilintide and Semaglutide (known as CagriSema).  Patients had a body-mass index (BMI) of 30 or higher or a BMI of 27 or higher with at least one obesity-related complication. The combination druge was delivered as a fixed-dose in a single-dose, single-use pen device. 6.1% of trial participants had BMI <30.

Percentage of patients with at least 5% weight loss
Percentage of patients with at least 20% weight loss
  • “Gastrointestinal adverse events (affecting 79.6% in the cagrilintide–semaglutide group and 39.9% in the placebo group), including nausea, vomiting, diarrhea, constipation, or abdominal pain, were mainly transient and mild-to-moderate in severity.”
  • “Although 57.4% of the participants assigned to cagrilintide–semaglutide were receiving the maximum dose at 68 weeks, 74.7% had received the maximum dose at some point after randomization…doses below the target might be highly effective for some patients and that dose reductions based on the clinical judgment…may be appropriate.”

This same issue also examined the use of this combination in patients with type 2 diabetes (REDEFINE 2). in this study with 1206 patients, “the estimated mean change in body weight from baseline to week 68 was −13.7% in the cagrilintide–semaglutide group and −3.4% in the placebo group.”

The editorial by CM Hales (“Expanding the Treat-to-Target Toolbox for Obesity and Diabetes Care”) notes that “six deaths occurred in the two trials combined, all in the cagrilintide–semaglutide groups, including one suicide in each trial. Previous studies of suicidality with GLP-1 receptor agonist treatment have not supported a causal link,6 but it continues to be of concern.”

My take (from the editorial): “A sustainable treat-to-target approach should extend to lifelong maintenance of health gains after initial weight loss. The intensity and composition of lifestyle interventions in the context of highly effective pharmacologic therapies also need further study. The pharmaceutical pipeline is promising, with potential improvements in safety (such as preservation of lean mass) and more convenience for patients (such as oral administration and monthly dosing). Greater effects on the health of Americans may be achieved not with antiobesity medications producing ever greater magnitudes of weight loss but with expanded access to safe and effective therapies for those who would most benefit.”

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How to Diagnose Celiac Disease in Patients Already Receiving a Gluten Free Diet

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Open Access: Evaluating for Celiac Disease in Patients on a Gluten-Free Diet: A Practical Approach

Algorithm -Figure 2:

Figure 3 lists the content of several common foods -some noted below

While gluten exposure increases the diagnostic yield of currently available tests, there are novel tests being developed “which may aid in the diagnosis of CeD regardless of diet, with a particular focus on immune-based assays. One such innovation involves the use of tetramer-based assays, which enable the direct detection of gluten-specific T cells in the blood. These tetramers, designed to bind to HLA-DQ2 molecules, can help identify T cells that have been activated by gluten exposure. This presents a highly specific immune marker for CeD. Even for those on a GFD, sensitivity (97%) and specificity (95%) have been impressive.”

My take: This article provides practical advice for evaluating whether celiac disease is present in those already consuming a GFD.

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And news from The Onion 8/26/25: Hummingbird Feels Like Fucking Idiot After Seeing Other Bird Gliding

Immune Dysregulation Can Mimic Celiac Disease

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A Turunen et al. JPGN Reports. 2025;6:312–315. Elevated tissue transglutaminase immunoglobulin A: Celiac disease or polytypic plasmacytosis?

Briefly noted: The authors present a case report of an adolescent girl post cardiac transplant with hypergammaglobulinemia and presumed celiac disease (CD), who had a persistently elevated anti‐tissue transglutaminase immunoglobulin A despite a gluten free diet. Ultimately, she was diagnosed with polytypic plasmacytosis from suspected immune dysregulation.

Key point:

  • This case serves as a reminder that when treating those with persistently elevated tTG IgA on a strict GFD, etiologies outside of CD need to be considered.

My take: I had a young girl several years ago who had celiac diagnosis at an outside institution. She had multiple autoimmune disorders. After not responding to treatment, she had a follow-up panendoscopy showing ongoing IELs in duodenum and villous blunting. These findings were noted in the ileum as well. On reviewing her initial biopsies, the pathologist indicated that her findings could be celiac but it was suspected to be an immune dysregulation. Subsequently, she was diagnosed with CTLA4 deficiency and had a marked response to abatacept therapy.

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Durability of Intensive Feeding Therapy

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V Volkert et al. JPGN Reports. 2025;1–7. Long-term outcomes of intensive multidisciplinary intervention for feeding tube dependence and chronic food refusal

Methods: The researchers conducted a 17‐item Qualtrics survey of patients who participated in intensive multidisciplinary intervention treatment to improve the volume and variety of solid food intake and replace enteral feeding due to chronic food refusal an average of 6 years following intervention. 75 met eligibility criteria; 36 caregivers (48%) completed the survey

Key findings:

  • Most patients (80%) who achieved full wean from feeding tube dependence at program discharge maintained their wean at the time of the survey
  • Most caregivers (89%) described their child’s relationship with food as “good” or “neutral”

My take:

  • Our group works closely with the authors and appreciate all of their help
  • Survey studies have a lot of limitations and often conclusions are hampered by low participation
  • It looks like intensive feeding therapy has good durability. It would be interesting if we could know what would have happened to these children without therapy. How many would have gradually improved on their own?

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On top of Stone Mtn, Georgia.

Celiac Risk Among First-Degree Relatives of Index Case

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S Karimzadhagh, et al. The American Journal of Gastroenterology 2025; 120(7):p 1488-1501. Global Prevalence and Clinical Manifestations of Celiac Disease Among First-Degree Relatives: A Systematic Review and Meta-Analysis

Methods: Of 8,764 studies screened, 34 studies involving 10,016 first-degree relatives (FDRs) of patients with Celiac Disease (CeD) were included

Key findings:

  • The pooled estimates for seroprevalence and the biopsy-confirmed CeD prevalence in FDRs were 11% and 7%, respectively
  • Daughters and sisters had the highest prevalence rates at 23% and 14%, compared with sons and brothers at 6% and 9%, respectively. Mothers/fathers prevalence rates were 5%. It is noted, however, that the stud only included 32 daughters and 41 sons, making these estimates less reliable
  • Abdominal pain (42%), bloating (39%), and flatulence (38%) were the most common gastrointestinal symptoms, while 34% of FDRs with CeD were asymptomatic

Discussion points:

Discrepancy between serology and biopsy: “First, not all individuals who tested positive through serological screening underwent a confirmatory duodenal biopsy. Second, some individuals with positive anti-tTG Ab may have false-positive results, or the disease process is still in the early stages of the disease, where intestinal damage is not yet detectable. This highlights that relying solely on serological screening without follow-up evaluations and intestinal biopsy can lead to overestimating the true prevalence of CeD.”

Limitations: “Some included studies only screened the siblings of indexed patients with CeD. For example, one study reported a prevalence of 22% among siblings. Given that genetic factors play a pivotal role in the pathogenesis of CeD and that the prevalence of CeD among siblings is often higher than that of other FDRs, this selective screening approach could potentially introduce selection bias into the overall prevalence of CeD in FDRs.”

My take: This study supports routine screening of first-degree relatives of patients with Celiac Disease, especially as many are asymptomatic.

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FDA Approves Semaglutide for MASH

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Dani Blum, NY Times 8/18/25: A Common Weight Loss Drug Can Treat Severe Liver Disease, F.D.A. Says

An excerpt:

Roughly 15 million people — six percent of adults in the United States — have metabolic dysfunction-associated steatohepatitis, known as MASH. Rates of the disease are rising…

Wegovy, which is a weekly injection, is now approved for adults with MASH and moderate-to-advanced levels of fibrosis, or excessive scar tissue in the liver. The drug is not intended for people with cirrhosis…

Wegovy will be a welcome addition to the options doctors can prescribe — as long as their patients can access them. The drug carries a list price of over $1,300 a month, although most people do not pay that full amount. Many people have lost insurance coverage for weight-loss drugs, as plans struggle to keep up with the costs.

Related review article: G Targher et al. NEJM 2025; 393: 683-698. Metabolic Dysfunction–Associated Steatotic Liver Disease. This review article succinctly covers the epidemiology, manifestations, disease progression and pivotal pharmacologic advances.

Related blog post: Semaglutide’s Efficacy in Phase 3 MASH Trial