Primecuts – This Week in the Journals

October 30, 2018

By Ofer Fass, MD

Peer Reviewed

Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU (NEJM) (1)

Critically ill patients in the ICU are typically given proton pump inhibitors (PPI) for stress ulcer prophylaxis. However, the risks and benefits of this practice are not entirely clear. A recent multicenter trial from Europe randomized 3298 ICU patients to receive either once daily pantoprazole 40 mg intravenously or placebo. Inclusion criteria for the trial were a non-elective ICU admission with at least one risk factor for gastrointestinal bleeding, including shock, use of anticoagulants, renal-replacement therapy, mechanical ventilation (expected >24 hours), history of liver disease, or any history of or ongoing coagulopathy. The primary endpoint was mortality at 90 days. The secondary endpoint was an unvalidated, composite outcome of clinically important gastrointestinal bleeding, new-onset pneumonia, C. difficile infection, or acute myocardial infarction. At 90 days, there was no significant difference in mortality between the those treated with pantoprazole (31.1%) and those treated with placebo (30.4%). Similarly, there was no difference in the secondary outcome between the pantoprazole group (21.9%) and the placebo group (22.6%).

A notable limitation is that the secondary outcome is unvalidated and represents a composite of numerous PPI-related ICU complications. Therefore, individual components of the composite outcome that improve with PPI therapy may be obfuscated by those that worsen. When the composite endpoint is broken down to its individual components, the Pantoprazole group is noted to have a gastrointestinal bleeding rate of 2.5% compared to 4.2% in the placebo group. Additionally, when the infectious outcomes of pneumonia and C. difficile are combined, there is no difference between the pantoprazole and placebo group (16.8% and 16.9% respectively). The take home message of this study is that although there appears to be no mortality benefit with PPI use in the ICU, the reduction in gastrointestinal bleeding rates may support their administration in critically ill patients at high risk for bleeding. Therefore, the benefit of PPI stress-ulcer prophylaxis should be carefully considered on a per-patient basis.

Hospitals with more-active participation in conducting standardized in-situ mock codes have improved survival after in-hospital cardiopulmonary arrest (Resuscitation) (2)

In-hospital cardiac arrests are typically managed through a “code”, in which clinical staff work together to attempt resuscitation. The success of a code depends on communication between staff, high-quality CPR, and teamwork. Although the benefits of mock codes may seem obvious, they have proven to be difficult to measure. A recent study performed at 26 hospitals within an integrated, multi-state healthcare system attempted to assess whether mock codes increase the survival-to-discharge of patients with in-hospital cardiac arrests. All hospitals within the healthcare system received standardized code scenarios (lasting no more than 5 minutes), mannequins and evaluation forms. Hospitals independently determined how many mock codes to perform per year. They were divided into “more active” centers (median 17.6 mock codes per 100 hospital beds per year) and “less active” centers (3.2 mock codes per 100 hospital beds per year). Hospitals with “more active” code participation had a mean in-hospital cardiac arrest survival rate of 42.8% versus 31.8% in “less active” hospitals (95% CI: 0.54–0.72; p <0.0001). Additionally, defibrillation within 2 minutes was achieved more often at “more active” hospitals compared to “less-active” hospitals (35% vs 26%, p = 0.05). This study was able to objectively demonstrate the survival benefit conferred by mock codes, with the authors suggesting that approximately one life is saved for each additional mock code per 100 hospital beds per year.

Association of Thyroid Hormone Therapy with Quality of Life and Thyroid-Related Symptoms in Patients with Subclinical Hypothyroidism: A Systematic Review and Meta-analysis (JAMA) (3)

Thyroid hormone therapy has uncertain utility in treating patients with subclinical hypothyroidism (defined as elevated levels of thyroid stimulating hormone, however normal levels of free thyroxine), with a recent large randomized control trial demonstrating no clinical benefit (4). A systematic review and meta-analysis of 21 randomized clinical trials, encompassing 2192 patients, attempted to rigorously assess whether thyroid hormone therapy has a benefit in the treatment of subclinical hypothyroidism. Selected studies included non-pregnant adults with subclinical hypothyroidism and compared thyroid hormone therapy with either placebo or no treatment. Main outcomes evaluated included overall quality of life and thyroid-related symptoms after a minimum follow-up of 3 months. Analysis results showed that although thyroid hormone therapy was associated with decreasing thyroid stimulating hormone levels (TSH range before treatment 4.4 to 12.8 mIU/L improving to 0.5 – 3.7 mIU/L after treatment), there was no statically significant improvement in quality of life or thyroid-related symptoms. This further argues against the use of thyroid hormone therapy in subclinical hypothyroidism.

Intravenous Iron in Patients Undergoing Maintenance Hemodialysis (NEJM) (5)

Hemodialysis-dependent patients are at risk for anemia due to decreased iron absorption and utilization. To address this problem and decrease reliance on erythropoiesis-stimulating agents, intravenous iron is typically administered during dialysis sessions. However, intravenous iron carries the risk of infection, oxidative stress, and accelerated vascular disease (6). A multicenter, open-label trial with blinded end-point evaluation was performed to better assess the optimal intravenous iron regimen in patients undergoing hemodialysis. In the trial, 2141 patients were randomized to receive either high-dose intravenous iron sucrose (400 mg monthly, unless the ferritin concentration was >700 µg/L or transferrin saturation was ≥40%), or low-dose iron (0 to 400 mg monthly, with a ferritin concentration of <200 µg/L or a transferrin saturation of <20% being a trigger for administration). Inclusion criteria included adults undergoing maintenance hemodialysis. The primary endpoint was the composite of nonfatal myocardial infarction, nonfatal stroke, heart failure hospitalization, or death, analyzed in a time-to-first-event fashion. Secondary endpoints included death, infection rates, and dose of erythropoiesis-stimulating agent. The results were notable for lower doses of erythropoiesis-stimulating agents administered in the high-dose group (median monthly dose of 29,757 IU) than the low-dose group (median monthly dose of 38,805 IU), and fewer patients in the high-dose group having a primary end-point event compared to the low-dose group (333 vs 343, hazard ratio 0.88, P<0.001). The infection rate was the same between both groups. The authors concluded that a high-dose regimen is non-inferior to low-dose regimens and may have the benefit of reducing both erythropoiesis-stimulating agent doses as well as the rate of myocardial infarction, stroke, heart failure exacerbations and death.


Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease (NEJM) (7)

Genetic sequencing may have a role in diagnosing patients with unknown illnesses. A team at Harvard’s Undiagnosed Diseases Network performed either whole-genome or exome sequencing on 601 patients, identifying a diagnosis in 35%.

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness (NEJM) (8)

An ICU trial of 600 patients comparing Ziprasidone and Haloperidol to placebo showed no difference in duration of delirium. Thus, this suggests that neither typical, nor atypical antipsychotics have a significant role in the management of ICU delirium.

Low-Dose Trazodone, Benzodiazepines, and Fall-Related Injuries in Nursing Homes: A Matched-Cohort Study (J Am Geriatr Soc) (9)

In nursing home residents, low-dose trazodone has no difference in fall rates when compared to benzodiazepines, suggesting that they are not as safe as previously considered.

Dr. Ofer Fass is a resident physician at NYU Langone Health

Peer reviewed by Dana Zalkin, MD, Chief Resident, Internal Medicine, NYU Langone Health

Image courtesy of Wikimedia commons


1. Krag M, Marker S, Perner A, Wetterslev J, Wise MP, Schefold JC, et al. Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU. New England Journal of Medicine. 2018.
2. Josey K, Smith ML, Kayani AS, Young G, Kasperski MD, Farrer P, et al. Hospitals with more-active participation in conducting standardized in-situ mock codes have improved survival after in-hospital cardiopulmonary arrest. Resuscitation. 2018;133:47-52.
3. Feller M, Snel M, Moutzouri E, et al. Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism: A systematic review and meta-analysis. JAMA. 2018;320(13):1349-59.
4. Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RGJ, Mooijaart SP, et al. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. New England Journal of Medicine. 2017;376(26):2534-44.
5. Macdougall IC, White C, Anker SD, Bhandari S, Farrington K, Kalra PA, et al. Intravenous Iron in Patients Undergoing Maintenance Hemodialysis. New England Journal of Medicine. 2018.
6. Del Vecchio L, Longhi S, Locatelli F. Safety concerns about intravenous iron therapy in patients with chronic kidney disease. Clinical Kidney Journal. 2016;9(2):260-7.
7. Splinter K, Adams DR, Bacino CA, Bellen HJ, Bernstein JA, Cheatle-Jarvela AM, et al. Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease. New England Journal of Medicine. 2018.
8. Girard TD, Exline MC, Carson SS, Hough CL, Rock P, Gong MN, et al. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. New England Journal of Medicine. 2018.
9. Bronskill SE, Campitelli MA, Iaboni A, Herrmann N, Guan J, Maclagan LC, et al. Low-Dose Trazodone, Benzodiazepines, and Fall-Related Injuries in Nursing Homes: A Matched-Cohort Study. Journal of the American Geriatrics Society. 2018;66(10):1963-71.