Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Association between histamine 2 receptor antagonists and sepsis outcomes in ICU patients: a retrospective analysis using the MIMI-IV database

Association between histamine 2 receptor antagonists and sepsis outcomes in ICU patients: a... Background Sepsis is marked by elevated histamine, which is a vasodilator that increases vascular permeability. Although human studies are lacking, murine models of sepsis have indicated potential protective effects of histamine 2 receptor antagonist administration (H2RAs). Objective To assess any association between H2RA use in sepsis‑3 patients admitted to the ICU and mortality, mechanical ventilation, length of stay, and markers of renal, liver, and lung dysfunction. Design Retrospective cohort study. Setting Intensive care units of the Beth Israel Deaconess Medical Center (BIDMC) accessed via the MIMIC‑IV database spanning an 11‑ year period from 2008 to 2019. Patients (or participants) A total of 30,591 patients met the inclusion criteria for sepsis‑3 on admission (mean age 66.49, standard deviation 15.92). Main measures We collected patient age, gender, ethnicity, comorbidities (contained within the Charlson comor‑ bidity index), SOFA score, OASIS score, APS III score, SAPS II score, H2RA use, creatinine, BUN, ALT, AST, and P/F ratios. Primary outcomes were mortality, mechanical ventilation, and ICU length of stay. Key results A total of 30,591 patients met inclusion criteria over the 11‑ year sample period. The 28‑ day in hospital mortality rate was significantly lower among patients who received an H2RA (12.6% vs 15.1%, p < 0.001) as compared to those who did not receive an H2RA. Patients receiving an H2RA had significantly lower adjusted odds of mortality (0.802, 95% CI 0.741–0.869, p < 0.001), but significantly higher adjusted odds of invasive mechanical ventilation (4.426, 95% CI 4.132–4.741, p < 0.001) and significantly higher ICU LOS (3.2 days vs. 2.4 days, p < 0.001) as compared to the non‑H2RA group. H2RA use was also associated with decreased severity of acute respiratory distress syndrome (ARDS) and lower serum creatinine. Conclusion Among patients hospitalized in the ICU for sepsis, the use of an H2RA was associated with significantly lower odds of mortality, decreased severity of ARDS, and a lower incidence of renal insufficiency. *Correspondence: Bryce D. Beutler brycebeutler@hotmail.com Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Firzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 2 of 11 Keywords Sepsis, Histamine antagonists, H2RA, MIMIC database, ICU, Mortality, Length of stay Introduction ill, but not necessarily meeting sepsis-3 criteria. Due to Among hospitalized patients, sepsis is associated with the ubiquitous use of H2RAs both for treatment and increased morbidity and mortality, prolonged length prophylactic indications, potential mortality benefits of of stay (LOS), and higher healthcare costs. In addition, H2RAs, and early data suggesting histamine blockage sepsis represents a leading cause of neurological and could be beneficial in murine sepsis models, we sought functional disability [1, 2]. Early recognition of sepsis to investigate the association between HR2A use and all- and intervention with source control, antibiotics, and cause mortality, end organ damage, and hospital length hemodynamic and ventilation optimization is critical to of stay in ICU patients who specifically had sepsis by the improve outcomes [3–5]. Adjunctive therapies for sepsis current definition. sometimes include corticosteroids [6] and experimental therapeutics such as liposomal agents, antibacterial anti- Methods bodies, alkaline phosphatase, and interleukin-7 are cur- Summary of data source rently under investigation [7]. We used data from the Medical Information Mart Sepsis is associated with increased plasma concentra- for Intensive Care IV (MIMIC-IV) database [20]. The tion of histamine, which has vasodilatory effects at the MIMIC-IV is a publicly available, free database which capillary level [8, 9]. In mouse models of sepsis, activa- contains a comprehensive catalog of individual patient- tion of histamine-1 and 2 receptors contributed to the level information on hospital stays for patients admitted development of major organ damage deemed to be due to a tertiary academic medical center in Boston, MA, to higher levels of proinflammatory cytokines with asso - USA and obtained from PhysioNet [21]. PhysioNet cur- ciated capillary rupture and vascular leak and result- rently operates with funding from the National Institute ant parenchymal lung damage, marked elevation in liver of Biomedical Imaging and Bioengineering and offers enzymes and BUN/creatinine levels [10]. In that study, data on several clinical parameters on over 40,000 indi- the administration of intravenous famotidine (a hista- vidual subjects as well as tools to extract and analyze the mine-2 receptor blocker) resulted in reduced incidence data. end organ damage [10], suggesting that histamine-2 receptors are involved in sepsis-related lung, liver, and Study population and outcomes kidney injuries. In fact, glucocorticoids are used even in We queried the MIMIC-IV database for all adult inten- the absence of adrenal insufficiency or shock to counter - sive care unit (ICU) stays from 2008 to 2019. Patients act the vasodilatory effects of histamine release in septic 18 years or older, were included if they met the sep- shock [6, 11]. sis-3 criteria [22]. We acquired the following informa- However, there are limited data describing the rela- tion for each patient indexed by stay ID: age, gender, and tionship between histamine receptor antagonism and risk scores including APS III [23], SAPS II [24], SOFA sepsis outcomes. The Surviving Sepsis Campaign recom - [25], OASIS [26], and the Charlson comorbidity index mends stress ulcer prophylaxis in patients with bleed- [27]. We also extracted data on time from ICU admis- ing risk factors [12]. H2RAs and proton pump inhibitors sion to H2RA administration (if applicable), and time (PPIs) are the most commonly used drugs for stress from ICU admission to invasive mechanical ventila- ulcer prophylaxis (SUP). Guidelines suggest that in criti- tion (IMV). We extracted ICU length of stay, number of cally ill patients, not exclusively sepsis patients, PPIs are days until in-hospital mortality, and in-hospital 28-day preferred in patients with high risk of GI bleeding due mortality. We assessed the severity of respiratory dys- to increased efficacy in decreasing clinically important function with daily means of PaO2/FiO2 (PF ratio) over bleeding (CIB) [13]. In patients with lower risk of CIB, a 7-day period after admission for each patient. We fur- there are no clear guidelines for use. H2RAs may also be ther categorized the severity of pulmonary dysfunction preferred due to their lower cost, potential lower risk of based on the Berlin definition of acute respiratory dis - pneumonia compared to proton pump inhibitors [14–18]. tress syndrome, ARDS (severe ARDS: P/F ratio < 100 Furthermore, research has demonstrated that although mmHg; moderate ARDS: P/F ratio < 200 mmHg; mild CIB is decreased with PPIs compared to H2RAs, mortal- ARDS: P/F ratio < 300 mmHg) [28]. Additionally, kid- ity has not been significantly different between groups, ney function and liver function were followed for each with mortality generally being lower with H2RA use [13, patient over the same 7-day period using daily means of 19]. These studies all focus on patients who are critically BUN, creatinine, alanine aminotransferase (ALT), and F irzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 3 of 11 aspartate aminotransferase (AST). Queries were per- (where positive tau values mean an increasing linear formed in Google BigQuery [29]. Primary outcomes of trend). Data cleaning and analysis utilized RStudio ver- interest included in-hospital mortality, ICU length of sion 1.4.1106 (RStudio Team, 2020) and Jamovi 2 [31– stay, and the use of IMV after day 1 of ICU stay. Second- 37]. All analyses were performed as two-sided with a 0.05 ary Outcomes included the mean P/F ratio, mean BUN/ level of significance. Cr ratio, AST, and ALT levels on days 1 through 7 of ICU stay. Patients were grouped by whether they had received Results H2RAs (ranitidine, famotidine, or cimetidine) from Baseline characteristics time of admission to 1 day of ICU stay (H2RA group) We included 35,010 patients who met sepsis 3 criteria and those who did not (no H2RA group). We excluded and were admitted to the ICU at some point in their hos- patients who received H2RAs after day 1 of ICU admis- pital stay from the years 2008 to 2019. We excluded 4419 sion as well as patients who were mechanically ventilated patients who were either mechanically ventilated prior prior to receiving H2RAs. Patients with missing values in to ICU admission or received H2RAs after 1 day into age, gender, comorbidities, or timestamps correspond- their ICU stay. Of these, 12,908 were in the H2RA group ing to H2RA use or mechanical ventilation (where these (42.2%) and 17,683 (57.8%) were in the No H2RA group. treatments were utilized) were also excluded. Table  1 summarizes baseline characteristics of patients included in this study. The median age of the No H2RA Statistical analyses group was significantly older than the H2RA group (69 Continuous variables were summarized as means ± vs 66 years, p < 0.001). Males were overrepresented in the standard deviations or median (interquartile range), overall cohort and were significantly less in the no H2RA where appropriate. Categorical variables were summa- group compared to the H2RA group (55.66% vs 60.65%, rized as counts (percentages). We assessed differences in p < 0.001). Comorbidities investigated showed signifi - 28-day mortality between groups using univariate analy- cant differences in all categories, effect sizes rarely were sis and used a multivariable logistic regression analysis greater than 5%. Notable differences included cerebro - including age, gender, risk scores, and comorbidities to vascular disease [no H2RA vs. H2RA] (10.98% vs 17.48%, examine between group differences. Utilizing the same p < 0.01), chronic pulmonary disease (30.16% vs 25.23%, patient groups as the mortality analysis, we evaluated the p < 0.01), congestive heart failure (36.76% vs 28.12%, p ICU length of stay between groups, first utilizing univari - < 0.01), malignant cancer (16.23% vs 11.07%, p < 0.01), ate analysis of length of stay. We then evaluated differ - mild liver disease (19.32% vs 10.51%, p < 0.01), renal dis- ences in a multivariable linear regression model including ease (30.96% vs 19.62%, p < 0.01), and severe liver disease age, gender, risk scores, and comorbidities. Risk for IMV (11.34% vs 4.03%, p < 0.01). Small but significant dif - was assessed with univariate analysis as well as in mul- ferences were found for median Charlson comorbidity tivariable logistic regression. Subgroup analysis of IMV index (6 vs 5, p < 0.01). Small but significant differences and H2RA administration was performed to assess mor- in median were also found in three of the four risk scores tality differences between groups, which were defined including APS III (51 vs 48, p < 0.01), OASIS (33 vs 35, p as follows: baseline group—patients not on H2RAs who < 0.01), and SOFA score (5 vs 6, p < 0.01). There was no were not ventilated; group 1—patients not on H2RAs difference in the median SAPS II score. who were ventilated; group 2—patients on H2RAs who were not ventilated; and group 3—patients on H2RAs All‑cause mortality who were ventilated. Mortality of these subgroups were The 28-day in hospital mortality rate was significantly assessed using univariate and multivariable logistic lower among patients who used H2RAs prior to their regression controlling for the same covariates as above. ICU stay (12.6% vs 15.1%, p < 0.001). A multivariable We compared daily median PF ratio, BUN/Cr ratio, BUN, logistic regression demonstrated that patients in the creatinine, AST, and ALT between patients who used H2RA group had an adjusted odds ratio (OR) of 0.802 H2RA and those who did not using Wilcoxon signed rank (0.741–0.869, p < 0.001) for 28-day in hospital mortality. test. Median confidence intervals were calculated based Figure  1 shows the relative strengths of the predictors of on David Olive’s method [30]. Proportions of patients in 28-day mortality in our model. the H2RA and No H2RA group categorized as no ARDS, mild ARDS, moderate ARDS, and severe ARDS were cal- Length of stay culated on days 1 through 7 from ICU admission to fur- H2RA use was associated with a significantly longer ther assess lung function. Mann-Kendall’s test was used median length of ICU stay (3.2 days vs 2.4 days, p < to assess linear trends in the proportion of patients in 0.001). Multivariable linear regression analysis dem- each group among the four categories of lung function onstrated a significant association between receiving Firzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 4 of 11 Table 1 Summary of baseline patient characteristics No H2RA H2RA p value (n = 17,683) (n = 12,908) (57.8%) (42.2%) Age, [median, years (IQR)] 69 (58–80) 66 (56–76) < 0.01 Males 9842 (55.7%) 7829 (60.7%) < 0.01 Race < 0.01 American Indian/Alaska Native 50 (0.3%) 19 (0.2%) Asian 508 (2.9%) 374 (2.9%) Black/African American 2062 (11.7%) 1078 (8.4%) Hispanic/Latino 640 (3.6%) 498 (3.9%) Other 754 (4.3%) 657 (5.1%) Unknown 1405 (7.9%) 1724 (13.4%) White 12,264 (69.4%) 8558 (66.3%) Comorbid conditions AIDS 197 (1.1%) 82 (0.6%) < 0.01 Cerebrovascular disease 1942 (11.0%) 2256 (17.5%) < 0.01 Chronic pulmonary disease 5334 (30.2%) 3257 (25.2%) < 0.01 Congestive heart failure 6500 (36.8%) 3630 (28.1%) < 0.01 Dementia 1072 (6.1%) 373 (2.9%) < 0.01 Diabetes, chronic complications 2291 (13.0%) 1153 (8.9%) < 0.01 Diabetes no chronic complications 4629 (26.2%) 3042 (23.6%) < 0.01 Malignant cancer 2870 (16.2%) 1429 (11.1%) < 0.01 Metastatic solid tumor 1334 (7.5%) 610 (4.7%) < 0.01 Mild liver disease 3416 (19.3%) 1357 (10.5%) < 0.01 Myocardial infarction 3147 (17.8%) 2269 (17.6%) 0.62 Paraplegia 653 (3.7%) 817 (6.3%) < 0.01 Peptic ulcer disease 850 (4.8%) 204 (1.9% ) < 0.01 Peripheral vascular disease 2184 (12.4%) 1748 (13.5%) < 0.01 Renal disease 5474 (31.0%) 2533 (19.6%) < 0.01 Rheumatic disease 764 (4.3%) 405 (3.1%) < 0.01 Severe liver disease 2006 (11.3%) 520 (4.0%) < 0.01 Charlson comorbidity index [median (IQR)] 6 (5–8) 5 (4–7) < 0.01 APS III Score [median (IQR)] 51 (39–68) 48 (34–70) < 0.01 SAPS II Score [median (IQR)] 38 (33–48) 38 (30–47) < 0.01 OASIS Score [median (IQR)] 33 (27–39) 35 (29–41) < 0.01 First Day SOFA Score 5 (4–8) 6 (4–9) < 0.01 [median (IQR)] H2RAs and increased ICU length of stay (LOS) (differ - days − 1.697, standard estimate − 0.19, p < 0.001), para- ence in days: 1.569, standard estimate 0.23, p < 0.001). plegia (difference in days 1.042, standard estimate 0.18, Other significant predictors of increased ICU length of p < 0.001), Charlson comorbidity index (difference in stay included APS III (difference in days 0.113, standard days 0.427, standard estimate 0.17, p < 0.001), first SOFA estimate: 0.31, p < 0.001), SAPS II (difference in days − score (difference in days 0.353, standard estimate 0.15, p 0.14, standard estimate − 0.31, p < 0.001), dementia (dif- < 0.001), mild liver disease (difference in days − 0.887, ference in days − 1.988, standard estimate − 0.24, p < standard estimate − 0.14, p < 0.001), diabetes with com- 0.001), metastatic solid tumor (difference in days − 1.472, plicating condition (difference in days − 1.082, standard standard estimate − 0.23, p < 0.001), oasis (difference in estimate − 0.13, p < 0.001), renal disease (difference in days 0.158, standard estimate 0.21, p < 0.001), cerebro- days − 1.222, standard estimate − 0.13, p < 0.001), rheu- vascular disease (difference in days 1.39, standard esti - matic disease (difference in days − 0.889, standard esti - mate 0.19, p < 0.001), severe liver disease (difference in mate − 0.12, p < 0.001), diabetes without complicating F irzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 5 of 11 Fig. 1 Predictors of 28‑ day mortality among patients who stayed in the ICU for sepsis management regression demonstrated significant differences between condition (difference in days − 0.768, standard estimate group 2 vs the baseline group (OR 0.79 95% CI [0.686– − 0.09, p < 0.001), myocardial infarct (difference in days 0.911], p = 0.001) and group 1 vs the baseline group (OR − 0.573, standard estimate − 0.08, p < 0.001), peptic 1.419 95% CI [1.265–1.591], p < 0.001) (Table  3). No ulcer disease (difference in days 0.135, standard estimate significant difference was found between group 3 and 0.08, p < 0.01), age (difference in days − 0.027, standard the baseline group (OR 1.042 95% CI [0.93–1.168], p = estimate − 0.06, p < 0.001). 0.474). Among groups of patients with IMV, i.e., groups 1 and 3, there was a significant increased odds of mortal - Need for invasive mechanical ventilation ity in group 1, who did not receive H2RAs, compared to Significantly more patients in the H2RA group required group 3 (OR 1.36 95% CI [1.23–1.50], p < 0.001). invasive mechanical ventilation than the No H2RA In subgroup analysis of LOS, we found that patients group (62.15% vs. 31.81%, p < 0.01). Multivariable logis- who received IMV had significantly longer mean LOS tic regression demonstrated that patients in the H2RA (H2RA group 7.8 days; no H2RA group 6.9 days) while group had an adjusted odd ratio of 4.426 (95% CI [4.132 the patients who were not mechanically ventilated had – 4.741], p < 0.001) for needing mechanical ventilation significantly lower mean LOS (H2RA group 2.8 days; no (Fig. 2). H2RA group 2.6 days) (Table  2). Furthermore, between just the ventilated patients, the mean LOS was statis- Association between H2RA use and IMV on mortality tically significant (p < 0.001) with H2RA patients on and length of stay outcomes mechanical ventilation having longer length of stay. To assess differences in mortality based on a combina - tion of H2RA use and the need for IMV, we identified four sub-groups (defined in methods above) and com - Association between H2RA use and organ dysfunction pared mortality outcomes between them. Mortality rate Patients receiving H2RAs had significantly higher differed significantly between the groups (Table  2). The median P/F ratios on days 1 through 7 of ICU stay (p baseline group was not on H2RAs and did not receive < 0.05) (Fig.  3A). Overall, H2RA use is associated with IMV. Mortality rate in this group was 10.2%. Patients in better lung function on most days as indicated by group 2 who received H2RAs and did not require IMV, higher PF ratios. In the H2RA group compared to the had the lowest mortality rate of 6.7%. Mortality rate no H2RA group, significantly higher proportion (p < was highest, 25.4% among those who were on IMV but 0.05) of patients were in the no ARDS and mild ARDS did not receive H2RA (group 2). Multivariable logistic groups on all days except for day 3 (Fig.  4). Median Firzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 6 of 11 Fig. 2 Predictors of need for invasive mechanical ventilation among patients who stayed in the ICU for sepsis management Table 2 Subgroup analysis of the relationship between H2RA use and mechanical ventilation status and mortality and length of stay outcomes Baseline group Group 1 Group 2 Group 3 Total (N = 30,591) p value No H2RA, no IMV No H2RA, IMV H2RA, no IMV H2RA, IMV (N = 12,058) (N = 5625) (N =4499) (N = 8409) Mortality < 0.001 Survived 10,823 4198 4196 (93.3%) 7089 (84.3%) 26,306 (86.0%) (89.8%) (74.6%) Died 1235 1427 303 1320 4285 (14.0%) (10.2%) (25.4%) (6.7%) (15.7%) Median ICU LOS (IQR) 1.9 2 4.6 4.7 (1.1–3.2) (1.2–3.2) (2.4–8.9) (2.2–10) Mean ICU LOS (SD) 2.6 (2.4) 6.9 (7.2) 2.8 (2.7) 7.8 (9.4) < 0.001 Definitions: Baseline group patients not on H2RAs who were not ventilated, Group 1 patients not on H2RAs who were ventilated, Group 2 patients on H2RAs who were not ventilated and Group 3 patients on H2RAs who were ventilated Table 3 Multivariable logistic regression of 28‑ day mortality BUN/Cr ratios were significantly lower (p < 0.05) on in subgroup analysis of mechanical ventilation and H2RA days 1–3 for patients in the H2RA group while these groups (note: same covariates were used in these models as the were significantly higher on days 4–7 (Fig.  3). BUN mortality analysis) medians were significantly lower in the group receiving H2RAs on most days (Fig.  3). Serum creatinine medi- Predictor Odds ratio p value 95% confidence interval ans were significantly lower on all days following ICU admission in the H2RA group (Fig. 3). Median AST and Reference group: baseline ALT were generally not significantly different in the Group 1 1.438 < .001 1.282–1.613 H2RA group versus the no H2RA group. Group 2 0.808 0.003 0.701–0.932 Group 3 1.074 0.223 0.957–1.206 F irzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 7 of 11 AB CD EF Fig. 3 Daily trend in lung, kidney, and liver function over the first seven days of ICU stay Discussion day SOFA score among patients who received an H2RA H2RAs are widely used for the management of acid- as compared to the non-H2RA group. Patients receiving peptic disease, including gastroesophageal reflux dis - an H2RA also had higher average P/F ratios and were less ease, gastric and duodenal ulcers and for SUP in critically likely to develop moderate or severe ARDS as compared ill patients. In this retrospective cohort study of ICU to those who were not treated with an H2RA. Interest- patients with sepsis, we assessed the association between ingly, despite the mortality benefit, H2RA use was asso - the use of H2RAs and sepsis outcomes based on the ciated with an increased rate of invasive mechanical demonstrated role of histamine antagonism in attenuat- ventilation, and longer ICU LOS. The increased risk of ing sepsis-related organ dysfunction in mouse models. invasive mechanical ventilation among patients receiv- Our analysis shows that H2RA administration is asso- ing an H2RA most likely reflects correlation rather than ciated with decreased mortality for non-ventilated and causation: H2RAs are routinely administered prophylac- ventilated patients with sepsis. Notably, decreased mor- tically to patients on invasive mechanical ventilation to tality was observed despite a slightly higher median first reduce the risk of gastrointestinal hemorrhage. In our Firzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 8 of 11 AB CD Fig. 4 Daily proportions of patients in each ARDS severity group from days 1 to 7 of ICU admission analysis, both ventilated and non-ventilated patients disease and thus it is expected that ventilated patients receiving an H2RA had significantly reduced odds of will require a longer LOS as compared to non-ventilated mortality as compared to those who did not receive an patients, irrespective of H2RA administration. Nota- H2RA. bly, however, ventilated patients who received an H2RA Prolonged ICU LOS among patients receiving an H2RA required approximately one day longer LOS as compared may also reflect correlation rather than causation. H2RAs to ventilated patients who did not receive an H2RA. were administered more frequently to ventilated patients Similarly, non-ventilated patients who received an H2RA as compared to non-ventilated patients. Increased ven- required approximately 2 h longer LOS as compared to tilation requirements typically indicate more severe non-ventilated patients who did not receive an H2RA. F irzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 9 of 11 The underlying cause of prolonged LOS among patients to include specific doses of agents in our analysis; there - treated with an H2RA requires further investigation. fore, dose effects could not be assessed. Third, the spe - The decreased mortality observed in patients taking cific cause of death is not included in the MIMIC-IV H2RAs in mechanically ventilated and non-ventilated database. We therefore report crude mortality rates. The patients despite prolonged ICU length of stay is some- mechanisms underlying the mortality benefit associated what paradoxical and warrants careful examination. We with H2RAs could conceivably be more clearly defined hypothesize that H2RAs may improve pulmonary func- if cause of death was established. Fourth, the no-H2RA tion in the setting of sepsis via a dual mechanism involv- group likely included a heterogenous group of patients ing a reduction in alveolar wall edema and modulation who could ostensibly be receiving other GI prophylaxis, of airway and vascular smooth muscle inflammation. or no GI prophylaxis at all. Lastly, the data utilized in this Previous studies have shown that histamine 2 recep- study was limited to a single center, which may limit the tors are expressed on mast cells; antagonism of mast generalizability of our findings. cell histamine 2 receptors may decrease degranulation In ICU patients with sepsis, the use of H2RAs is asso- and attenuate local alveolar wall edema [38]. In addition, ciated with significantly lower adjusted odds and inci - antagonism of histamine 2 receptors expressed by air- dence of all-cause mortality irrespective of the initial way and vascular smooth muscles can reduce pulmonary severity of sepsis and invasive mechanical ventilation vascular resistance and thus improve hemodynamic and status. The underlying mechanism for this observation functional status [39]. In our analysis, we provide data is unclear but may be due to amelioration of histamine- suggest improved pulmonary function among patients related dysfunction at the capillary beds with resultant receiving H2RAs, as evidenced by higher average P/F improvement in tissue perfusion. We speculate that ratios and decreased rates of moderate or severe ARDS. H2RAs restore the integrity of the vascular membrane, H2RAs demonstrate a wide range of extraintestinal reduce alveolar wall edema, and mitigate airway and effects. They have been shown to reduce ventricular vascular smooth muscle inflammation. H2RAs are rou - remodeling by interrupting histamine-mediated myocar- tinely used in stress ulcer prophylaxis in mechanically dial remodeling. The Multi-Ethnic Study of Atherosclero - ventilated patient. Our findings suggest that H2RAs sis (MESA) right ventricle study established that H2RA may provide extraintestinal benefits in ICU patients use was associated with lower right ventricular mass with sepsis; although PPIs may be preferred among and end-diastolic volume among individuals with risk patients with a high risk of gastrointestinal hemor- factors for cardiovascular disease [40, 41]. Other pur- rhage, we propose that H2RAs should be considered ported extraintestinal benefits of H2RAs are far-reaching for patients with a high risk of pneumonia and other and include reduction of bladder pain from interstitial cardiopulmonary complications Further research is cystitis, improvement of cell-mediated immunity, and warranted to clearly define the mechanisms underlying reduction of symptoms related to erythropoietic pro- histamine-mediated end organ damage and establish toporphyria [42–44]. Furthermore, recent studies have potential applications for H2RAs among patients with demonstrated a potential role for H2RAs as an adjunc- sepsis. tive treatment for COVID-19 [45, 46]. To the best of our knowledge, this is the first large-scale study to assess the Abbreviations effect of H2RAs on mortality in the setting of sepsis. AIDS Acquired immunodeficiency syndrome The study is strengthened by a large sample size with ALT Alanine Aminotransferase APS III Acute Physiology Score III many data elements per subject. The MIMIC-IV database ARDS Acute respiratory distress syndrome provides risk scores, disease severity indices, and exten- AST Aspartate aminotransferase sive comorbidity information for each subject, which MIMIC‑IV Medical Information Mart for Intensive Care IV BUN Blood urea nitrogen allowed us to control for potential confounding vari- CIB Clinically important bleeding ables. This study also considers only patients with sepsis, H2RA Histamine‑2 receptor antagonists whereas other studies on GI prophylactic medications ICU Intensive care unit IMV Invasive mechanical ventilation have included all critically ill patients with a range of pos- LOS Length of stay sible etiologies for their admissions. However, there are OASIS Outcome Assessment Information Set several limitations of our study inherent to its design. SAPS II Simplified Acute Physiology Score II SOFA Sequential Organ Failure Assessment First, the analysis was retrospective and thus causation SUP Stress ulcer prophylaxis could not be assessed. Second, H2RAs were considered as a class thus we are unable determine if the relation- Acknowledgements Not applicable. ships observed are a class effect. Further, we were unable Firzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 10 of 11 Authors’ contributions 12. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM TRF: conceptualization; design, analysis, and writing—initial draft. SS: writ‑ et al (2013) Surviving sepsis campaign: international guidelines for ing—initial draft, generation of figures. DAA: design, analysis, writing—initial management of severe sepsis and septic shock: 2012. Crit Care Med draft, review, and editing. BDB: writing initial draft, review, and editing. MBU: 41(2):580–637 review and editing. MR: supervision and data access. FML: supervision, review, 13. Wang Y, Ge L, Ye Z, Siemieniuk RA, Reintam Blaser A, Wang X, Perner A, and editing. All authors read and approved the final version of the manuscript. Møller MH, Alhazzani W, Cook D, Guyatt GH (2020) Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: an updated Funding systematic review and network meta‑analysis of randomized trials. This work did not receive any funding from individuals, institutions, or funding Intensive Care Med 46(11):1987–2000. https:// doi. org/ 10. 1007/ s00134‑ agencies.020‑ 06209‑w Epub 2020 Aug 24. PMID: 32833040 14. Barletta JF (2014) Histamine‑2‑receptor antagonist administration Availability of data and materials and gastrointestinal bleeding when used for stress ulcer prophylaxis The datasets analyzed during the current study are publicly available in the in patients with severe sepsis or septic shock. Ann Pharmacother MIMIC‑IV database (https:// physi onet. org/ conte nt/ mimic iv/1. 0/). 48(10):1276–1281 15. Huang M, Han M, Han W, Kuang L (2021) Proton pump inhibitors versus histamine‑2 receptor blockers for stress ulcer prophylaxis Declarations in patients with sepsis: a retrospective cohort study. J Int Med Res 49(6):3000605211025130 Ethics approval and consent to participate 16. Zhou X, Fang H, Xu J, Chen P, Hu X, Chen B et al (2019) Stress ulcer Since we used a publicly available de‑identified database, we did not require prophylaxis with proton pump inhibitors or histamine 2 receptor antago‑ institutional review board approval for this study. nists in critically ill adults ‑ a meta‑analysis of randomized controlled trials with trial sequential analysis. BMC Gastroenterol 19(1):193 Consent for publication 17. Hammond DA, Kathe N, Shah A, Martin BC (2017) Cost‑ effectiveness of Not applicable. histamine2 receptor antagonists versus proton pump inhibitors for stress ulcer prophylaxis in critically ill patients. Pharmacotherapy: the journal of Competing interests human pharmacology and drug. Therapy. 37(1):43–53 The authors declare that they have no competing interests. 18. Alhazzani W, Alshamsi F, Belley‑ Cote E, Heels‑Ansdell D, Brignardello ‑ Petersen R, Alquraini M, Perner A, Møller MH, Krag M, Almenawer S, Author details Rochwerg B, Dionne J, Jaeschke R, Alshahrani M, Deane A, Perri D, The‑ Reno School of Medicine, University of Nevada, 1664 N Virginia Street, Reno, bane L, Al‑ Omari A, Finfer S, Cook D, Guyatt G (2018) Efficacy and safety NV 89557, USA. Christus Ochsner St. Patrick Hospital, 524 Dr Michael Debakey of stress ulcer prophylaxis in critically ill patients: a network meta‑analysis Dr, Lake Charles, LA 70601, USA. Keck School of Medicine, University of South‑ of randomized trials. Intensive Care Med 44(1):1–11. https:// doi. org/ 10. ern California, 1500 San Pablo Street, 2nd Floor, Los Angeles, CA 90033, USA. 1007/ s00134‑ 017‑ 5005‑8 Epub 2017 Dec 4. Erratum in: Intensive Care Department of Pulmonary and Critical Care Medicine, Renown Health, 1155 Med. 2017 Dec 11;: PMID: 29199388; PMCID: PMC5770505 Mill St., Reno, NV 89502, USA. 19. Young PJ, Bagshaw SM, Forbes AB et al (2020) Eec ff t of stress ulcer proph‑ ylaxis with proton pump inhibitors vs histamine‑2 receptor blockers on Received: 11 December 2022 Accepted: 3 February 2023 in‑hospital mortality among ICU patients receiving invasive mechanical ventilation: the PEPTIC randomized clinical trial. JAMA 323:616–626 20. Johnson, Alistair, Bulgarelli, Lucas, Pollard, Tom, Horng, Steven, Celi, Leo Anthony, Mark, Roger. MIMIC‑IV [Internet]. PhysioNet; [cited 2021 Nov 4]. Available from: https:// physi onet. org/ conte nt/ mimic iv/0. 4/ References 21. Goldberger AL, Amaral LAN, Glass L, Hausdorff JM, Ivanov PC, Mark 1. Paoli CJ, Reynolds MA, Sinha M, Gitlin M, Crouser E (2018) Epidemiology RG et al (2000) PhysioBank, PhysioToolkit, and PhysioNet. Circulation. and costs of sepsis in the United States‑an analysis based on timing of 101(23):e215–e220 diagnosis and severity level. Crit Care Med 46(12):1889–1897 22. Singer M, Deutschman CS, Seymour CW, Shankar‑Hari M, Annane D, 2. Hajj J, Blaine N, Salavaci J, Jacoby D (2018) The “centrality of sepsis”: Bauer M et al (2016) The third international consensus definitions for a review on incidence, mortality, and cost of care. Healthcare (Basel) sepsis and septic shock (Sepsis‑3). JAMA. 315(8):801–810 6(3):E90 23. Knaus WA, Wagner DP, Draper EA, Zimmerman JE, Bergner M, Bastos PG 3. Kim HI, Park S (2019) Sepsis: early recognition and optimized treatment. et al (1991) The APACHE III prognostic system. Risk prediction of hospital Tuberc Respir Dis (Seoul) 82(1):6–14 mortality for critically ill hospitalized adults. Chest. 100(6):1619–1636 4. Gyawali B, Ramakrishna K, Dhamoon AS (2019) Sepsis: the evolution 24. Le Gall JR, Lemeshow S, Saulnier F (1993) A new simplified acute physiol‑ in definition, pathophysiology, and management. SAGE Open Med ogy score (SAPS II) based on a European/north American multicenter 7:2050312119835043 study. JAMA. 270(24):2957–2963 5. Polat G, Ugan RA, Cadirci E, Halici Z (2017) Sepsis and septic shock: 25. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H current treatment strategies and new approaches. Eurasian J Med et al (1996) The SOFA (sepsis‑related organ failure assessment) score to 49(1):53–58 describe organ dysfunction/failure. On behalf of the working group on 6. Fang F, Zhang Y, Tang J, Lunsford LD, Li T, Tang R et al (2019) Association sepsis‑related problems of the European Society of Intensive Care Medi‑ of corticosteroid treatment with outcomes in adult patients with sepsis: a cine. Intensive Care Med 22(7):707–710 systematic review and meta‑analysis. JAMA Intern Med 179(2):213–223 26. Johnson AEW, Kramer AA, Clifford GD (2013) A new severity of illness 7. Vignon P, Laterre P‑F, Daix T, François B (2020) New agents in develop ‑ scale using a subset of acute physiology and chronic health evaluation ment for sepsis: any reason for hope? Drugs. 80(17):1751–1761 data elements shows comparable predictive accuracy. Crit Care Med 8. Ebeigbe AB, Talabi OO (2014) Vascular effects of histamine. Niger J Physiol 41(7):1711–1718 Sci 29(1):7–10 27. Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of 9. Jin H, Koyama T, Hatanaka Y, Akiyama S, Takayama F, Kawasaki H (2006) classifying prognostic comorbidity in longitudinal studies: development Histamine‑induced vasodilation and vasoconstriction in the mesenteric and validation. J Chronic Dis 40(5):373–383 resistance artery of the rat. Eur J Pharmacol 529(1–3):136–144 28. The ARDS Definition Task Force* (2012) Acute respiratory distress syn‑ 10. Hattori M, Yamazaki M, Ohashi W, Tanaka S, Hattori K, Todoroki K et al drome: the Berlin definition. JAMA. 307(23):2526–2533 (2016) Critical role of endogenous histamine in promoting end‑ organ 29. BigQuery documentation [Internet]. Google Cloud. [cited 2021 Nov 4]. tissue injury in sepsis. Intensive Care Med Exp 4(1):36 Available from: https:// cloud. google. com/ bigqu ery/ docs 11. Lansing AM (1963) Septic shock. Can Med Assoc J 89(12):583–588 30. Olive DJ (2005) A simple confidence interval for the median F irzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 11 of 11 31. jamovi ‑ Stats. Open. Now. [Internet]. [cited 2021 Dec 2]. Available from: https:// www. jamovi. org/ 32. Heinzen E, Sinnwell J, Atkinson E, Gunderson T, Dougherty G, Votruba P, et al. arsenal: An Arsenal of “R” functions for large‑scale statistical sum‑ maries [Internet]. 2021 [cited 2021 Dec 2]. Available from: https:// CRAN.R‑ proje ct. org/ packa ge= arsen al 33. Kassambara A, Kosinski M, Biecek P, Fabian S. survminer: drawing survival curves using “ggplot2” [Internet]. 2021 [cited 2021 Dec 2]. Available from: https:// CRAN.R‑ proje ct. org/ packa ge= survm iner 34. Garbett S, Stewart T, Thompson J, Harrell F, Kim A. tangram: the grammar of tables [Internet]. 2020 [cited 2021 Dec 2]. Available from: https:// CRAN.R‑ proje ct. org/ packa ge= tangr am 35. Sjoberg DD, Curry M, Larmarange J, Lavery J, Whiting K, Zabor EC, et al. gtsummary: presentation‑ready data summary and analytic result tables [Internet]. 2021 [cited 2021 Dec 2]. Available from: https:// CRAN.R‑ proje ct. org/ packa ge= gtsum mary 36. Harrison E, Drake T, Ots R. finalfit: quickly create elegant regression results tables and plots when modelling [Internet]. 2021 [cited 2021 Dec 2]. Available from: https:// CRAN.R‑ proje ct. org/ packa ge= final fit 37. The Comprehensive R Archive Network [Internet]. [cited 2021 Dec 2]. Available from: https:// cran.r‑ proje ct. org/ 38. Lippert U, Artuc M, Grützkau A, Babina M, Guhl S, Haase I et al (2004) Human skin mast cells express H2 and H4, but not H3 receptors. J Invest Dermatol 123(1):116–123 39. Akdis CA, Simons FER (2006) Histamine receptors are hot in immunop‑ harmacology. Eur J Pharmacol 533(1–3):69–76 40. Leary PJ, Barr RG, Bluemke DA, Bristow MR, Kronmal RA, Lima JA et al (2014) H2 receptor antagonists and right ventricular morphology: the MESA right ventricle study. Ann Am Thorac Soc 11(9):1379–1386 41. Kim J, Ogai A, Nakatani S, Hashimura K, Kanzaki H, Komamura K et al (2006) Impact of blockade of histamine H2 receptors on chronic heart failure revealed by retrospective and prospective randomized studies. J Am Coll Cardiol 48(7):1378–1384 42. Dasgupta P, Sharma SD, Womack C, Blackford HN, Dennis P (2001) Cime‑ tidine in painful bladder syndrome: a histopathological study. BJU Int 88(3):183–186 43. Kokhaei P, Barough MS, Hassan ZM (2014) Cimetidine effects on the immunosuppression induced by burn injury. Int Immunopharmacol 22(1):273–276 44. Tu JH, Sheu SL, Teng JM (2016) Novel treatment using cimetidine for Erythropoietic Protoporphyria in children. JAMA Dermatol 152(11):1258–1261 45. Chenchula S, Ray A, Sadasivam B (2021) Famotidine repurposing for novel corona virus disease of 2019: a systematic review. Drug Res (Stuttg) 71(06):295–301 46. Chiu L, Shen M, Lo C‑H, Chiu N, Chen A, Shin HJ et al (2021) Eec ff t of famotidine on hospitalized patients with COVID‑19: a systematic review and meta‑analysis. PLoS One 16(11):e0259514 Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Anesthesia Analgesia and Critical Care Springer Journals

Association between histamine 2 receptor antagonists and sepsis outcomes in ICU patients: a retrospective analysis using the MIMI-IV database

Download PDF
11 pages

Loading next page...
 
/lp/springer-journals/association-between-histamine-2-receptor-antagonists-and-sepsis-ZWGTfOglUZ

References (56)

Publisher
Springer Journals
Copyright
Copyright © The Author(s) 2023
eISSN
2731-3786
DOI
10.1186/s44158-023-00089-4
Publisher site
See Article on Publisher Site

Abstract

Background Sepsis is marked by elevated histamine, which is a vasodilator that increases vascular permeability. Although human studies are lacking, murine models of sepsis have indicated potential protective effects of histamine 2 receptor antagonist administration (H2RAs). Objective To assess any association between H2RA use in sepsis‑3 patients admitted to the ICU and mortality, mechanical ventilation, length of stay, and markers of renal, liver, and lung dysfunction. Design Retrospective cohort study. Setting Intensive care units of the Beth Israel Deaconess Medical Center (BIDMC) accessed via the MIMIC‑IV database spanning an 11‑ year period from 2008 to 2019. Patients (or participants) A total of 30,591 patients met the inclusion criteria for sepsis‑3 on admission (mean age 66.49, standard deviation 15.92). Main measures We collected patient age, gender, ethnicity, comorbidities (contained within the Charlson comor‑ bidity index), SOFA score, OASIS score, APS III score, SAPS II score, H2RA use, creatinine, BUN, ALT, AST, and P/F ratios. Primary outcomes were mortality, mechanical ventilation, and ICU length of stay. Key results A total of 30,591 patients met inclusion criteria over the 11‑ year sample period. The 28‑ day in hospital mortality rate was significantly lower among patients who received an H2RA (12.6% vs 15.1%, p < 0.001) as compared to those who did not receive an H2RA. Patients receiving an H2RA had significantly lower adjusted odds of mortality (0.802, 95% CI 0.741–0.869, p < 0.001), but significantly higher adjusted odds of invasive mechanical ventilation (4.426, 95% CI 4.132–4.741, p < 0.001) and significantly higher ICU LOS (3.2 days vs. 2.4 days, p < 0.001) as compared to the non‑H2RA group. H2RA use was also associated with decreased severity of acute respiratory distress syndrome (ARDS) and lower serum creatinine. Conclusion Among patients hospitalized in the ICU for sepsis, the use of an H2RA was associated with significantly lower odds of mortality, decreased severity of ARDS, and a lower incidence of renal insufficiency. *Correspondence: Bryce D. Beutler brycebeutler@hotmail.com Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Firzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 2 of 11 Keywords Sepsis, Histamine antagonists, H2RA, MIMIC database, ICU, Mortality, Length of stay Introduction ill, but not necessarily meeting sepsis-3 criteria. Due to Among hospitalized patients, sepsis is associated with the ubiquitous use of H2RAs both for treatment and increased morbidity and mortality, prolonged length prophylactic indications, potential mortality benefits of of stay (LOS), and higher healthcare costs. In addition, H2RAs, and early data suggesting histamine blockage sepsis represents a leading cause of neurological and could be beneficial in murine sepsis models, we sought functional disability [1, 2]. Early recognition of sepsis to investigate the association between HR2A use and all- and intervention with source control, antibiotics, and cause mortality, end organ damage, and hospital length hemodynamic and ventilation optimization is critical to of stay in ICU patients who specifically had sepsis by the improve outcomes [3–5]. Adjunctive therapies for sepsis current definition. sometimes include corticosteroids [6] and experimental therapeutics such as liposomal agents, antibacterial anti- Methods bodies, alkaline phosphatase, and interleukin-7 are cur- Summary of data source rently under investigation [7]. We used data from the Medical Information Mart Sepsis is associated with increased plasma concentra- for Intensive Care IV (MIMIC-IV) database [20]. The tion of histamine, which has vasodilatory effects at the MIMIC-IV is a publicly available, free database which capillary level [8, 9]. In mouse models of sepsis, activa- contains a comprehensive catalog of individual patient- tion of histamine-1 and 2 receptors contributed to the level information on hospital stays for patients admitted development of major organ damage deemed to be due to a tertiary academic medical center in Boston, MA, to higher levels of proinflammatory cytokines with asso - USA and obtained from PhysioNet [21]. PhysioNet cur- ciated capillary rupture and vascular leak and result- rently operates with funding from the National Institute ant parenchymal lung damage, marked elevation in liver of Biomedical Imaging and Bioengineering and offers enzymes and BUN/creatinine levels [10]. In that study, data on several clinical parameters on over 40,000 indi- the administration of intravenous famotidine (a hista- vidual subjects as well as tools to extract and analyze the mine-2 receptor blocker) resulted in reduced incidence data. end organ damage [10], suggesting that histamine-2 receptors are involved in sepsis-related lung, liver, and Study population and outcomes kidney injuries. In fact, glucocorticoids are used even in We queried the MIMIC-IV database for all adult inten- the absence of adrenal insufficiency or shock to counter - sive care unit (ICU) stays from 2008 to 2019. Patients act the vasodilatory effects of histamine release in septic 18 years or older, were included if they met the sep- shock [6, 11]. sis-3 criteria [22]. We acquired the following informa- However, there are limited data describing the rela- tion for each patient indexed by stay ID: age, gender, and tionship between histamine receptor antagonism and risk scores including APS III [23], SAPS II [24], SOFA sepsis outcomes. The Surviving Sepsis Campaign recom - [25], OASIS [26], and the Charlson comorbidity index mends stress ulcer prophylaxis in patients with bleed- [27]. We also extracted data on time from ICU admis- ing risk factors [12]. H2RAs and proton pump inhibitors sion to H2RA administration (if applicable), and time (PPIs) are the most commonly used drugs for stress from ICU admission to invasive mechanical ventila- ulcer prophylaxis (SUP). Guidelines suggest that in criti- tion (IMV). We extracted ICU length of stay, number of cally ill patients, not exclusively sepsis patients, PPIs are days until in-hospital mortality, and in-hospital 28-day preferred in patients with high risk of GI bleeding due mortality. We assessed the severity of respiratory dys- to increased efficacy in decreasing clinically important function with daily means of PaO2/FiO2 (PF ratio) over bleeding (CIB) [13]. In patients with lower risk of CIB, a 7-day period after admission for each patient. We fur- there are no clear guidelines for use. H2RAs may also be ther categorized the severity of pulmonary dysfunction preferred due to their lower cost, potential lower risk of based on the Berlin definition of acute respiratory dis - pneumonia compared to proton pump inhibitors [14–18]. tress syndrome, ARDS (severe ARDS: P/F ratio < 100 Furthermore, research has demonstrated that although mmHg; moderate ARDS: P/F ratio < 200 mmHg; mild CIB is decreased with PPIs compared to H2RAs, mortal- ARDS: P/F ratio < 300 mmHg) [28]. Additionally, kid- ity has not been significantly different between groups, ney function and liver function were followed for each with mortality generally being lower with H2RA use [13, patient over the same 7-day period using daily means of 19]. These studies all focus on patients who are critically BUN, creatinine, alanine aminotransferase (ALT), and F irzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 3 of 11 aspartate aminotransferase (AST). Queries were per- (where positive tau values mean an increasing linear formed in Google BigQuery [29]. Primary outcomes of trend). Data cleaning and analysis utilized RStudio ver- interest included in-hospital mortality, ICU length of sion 1.4.1106 (RStudio Team, 2020) and Jamovi 2 [31– stay, and the use of IMV after day 1 of ICU stay. Second- 37]. All analyses were performed as two-sided with a 0.05 ary Outcomes included the mean P/F ratio, mean BUN/ level of significance. Cr ratio, AST, and ALT levels on days 1 through 7 of ICU stay. Patients were grouped by whether they had received Results H2RAs (ranitidine, famotidine, or cimetidine) from Baseline characteristics time of admission to 1 day of ICU stay (H2RA group) We included 35,010 patients who met sepsis 3 criteria and those who did not (no H2RA group). We excluded and were admitted to the ICU at some point in their hos- patients who received H2RAs after day 1 of ICU admis- pital stay from the years 2008 to 2019. We excluded 4419 sion as well as patients who were mechanically ventilated patients who were either mechanically ventilated prior prior to receiving H2RAs. Patients with missing values in to ICU admission or received H2RAs after 1 day into age, gender, comorbidities, or timestamps correspond- their ICU stay. Of these, 12,908 were in the H2RA group ing to H2RA use or mechanical ventilation (where these (42.2%) and 17,683 (57.8%) were in the No H2RA group. treatments were utilized) were also excluded. Table  1 summarizes baseline characteristics of patients included in this study. The median age of the No H2RA Statistical analyses group was significantly older than the H2RA group (69 Continuous variables were summarized as means ± vs 66 years, p < 0.001). Males were overrepresented in the standard deviations or median (interquartile range), overall cohort and were significantly less in the no H2RA where appropriate. Categorical variables were summa- group compared to the H2RA group (55.66% vs 60.65%, rized as counts (percentages). We assessed differences in p < 0.001). Comorbidities investigated showed signifi - 28-day mortality between groups using univariate analy- cant differences in all categories, effect sizes rarely were sis and used a multivariable logistic regression analysis greater than 5%. Notable differences included cerebro - including age, gender, risk scores, and comorbidities to vascular disease [no H2RA vs. H2RA] (10.98% vs 17.48%, examine between group differences. Utilizing the same p < 0.01), chronic pulmonary disease (30.16% vs 25.23%, patient groups as the mortality analysis, we evaluated the p < 0.01), congestive heart failure (36.76% vs 28.12%, p ICU length of stay between groups, first utilizing univari - < 0.01), malignant cancer (16.23% vs 11.07%, p < 0.01), ate analysis of length of stay. We then evaluated differ - mild liver disease (19.32% vs 10.51%, p < 0.01), renal dis- ences in a multivariable linear regression model including ease (30.96% vs 19.62%, p < 0.01), and severe liver disease age, gender, risk scores, and comorbidities. Risk for IMV (11.34% vs 4.03%, p < 0.01). Small but significant dif - was assessed with univariate analysis as well as in mul- ferences were found for median Charlson comorbidity tivariable logistic regression. Subgroup analysis of IMV index (6 vs 5, p < 0.01). Small but significant differences and H2RA administration was performed to assess mor- in median were also found in three of the four risk scores tality differences between groups, which were defined including APS III (51 vs 48, p < 0.01), OASIS (33 vs 35, p as follows: baseline group—patients not on H2RAs who < 0.01), and SOFA score (5 vs 6, p < 0.01). There was no were not ventilated; group 1—patients not on H2RAs difference in the median SAPS II score. who were ventilated; group 2—patients on H2RAs who were not ventilated; and group 3—patients on H2RAs All‑cause mortality who were ventilated. Mortality of these subgroups were The 28-day in hospital mortality rate was significantly assessed using univariate and multivariable logistic lower among patients who used H2RAs prior to their regression controlling for the same covariates as above. ICU stay (12.6% vs 15.1%, p < 0.001). A multivariable We compared daily median PF ratio, BUN/Cr ratio, BUN, logistic regression demonstrated that patients in the creatinine, AST, and ALT between patients who used H2RA group had an adjusted odds ratio (OR) of 0.802 H2RA and those who did not using Wilcoxon signed rank (0.741–0.869, p < 0.001) for 28-day in hospital mortality. test. Median confidence intervals were calculated based Figure  1 shows the relative strengths of the predictors of on David Olive’s method [30]. Proportions of patients in 28-day mortality in our model. the H2RA and No H2RA group categorized as no ARDS, mild ARDS, moderate ARDS, and severe ARDS were cal- Length of stay culated on days 1 through 7 from ICU admission to fur- H2RA use was associated with a significantly longer ther assess lung function. Mann-Kendall’s test was used median length of ICU stay (3.2 days vs 2.4 days, p < to assess linear trends in the proportion of patients in 0.001). Multivariable linear regression analysis dem- each group among the four categories of lung function onstrated a significant association between receiving Firzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 4 of 11 Table 1 Summary of baseline patient characteristics No H2RA H2RA p value (n = 17,683) (n = 12,908) (57.8%) (42.2%) Age, [median, years (IQR)] 69 (58–80) 66 (56–76) < 0.01 Males 9842 (55.7%) 7829 (60.7%) < 0.01 Race < 0.01 American Indian/Alaska Native 50 (0.3%) 19 (0.2%) Asian 508 (2.9%) 374 (2.9%) Black/African American 2062 (11.7%) 1078 (8.4%) Hispanic/Latino 640 (3.6%) 498 (3.9%) Other 754 (4.3%) 657 (5.1%) Unknown 1405 (7.9%) 1724 (13.4%) White 12,264 (69.4%) 8558 (66.3%) Comorbid conditions AIDS 197 (1.1%) 82 (0.6%) < 0.01 Cerebrovascular disease 1942 (11.0%) 2256 (17.5%) < 0.01 Chronic pulmonary disease 5334 (30.2%) 3257 (25.2%) < 0.01 Congestive heart failure 6500 (36.8%) 3630 (28.1%) < 0.01 Dementia 1072 (6.1%) 373 (2.9%) < 0.01 Diabetes, chronic complications 2291 (13.0%) 1153 (8.9%) < 0.01 Diabetes no chronic complications 4629 (26.2%) 3042 (23.6%) < 0.01 Malignant cancer 2870 (16.2%) 1429 (11.1%) < 0.01 Metastatic solid tumor 1334 (7.5%) 610 (4.7%) < 0.01 Mild liver disease 3416 (19.3%) 1357 (10.5%) < 0.01 Myocardial infarction 3147 (17.8%) 2269 (17.6%) 0.62 Paraplegia 653 (3.7%) 817 (6.3%) < 0.01 Peptic ulcer disease 850 (4.8%) 204 (1.9% ) < 0.01 Peripheral vascular disease 2184 (12.4%) 1748 (13.5%) < 0.01 Renal disease 5474 (31.0%) 2533 (19.6%) < 0.01 Rheumatic disease 764 (4.3%) 405 (3.1%) < 0.01 Severe liver disease 2006 (11.3%) 520 (4.0%) < 0.01 Charlson comorbidity index [median (IQR)] 6 (5–8) 5 (4–7) < 0.01 APS III Score [median (IQR)] 51 (39–68) 48 (34–70) < 0.01 SAPS II Score [median (IQR)] 38 (33–48) 38 (30–47) < 0.01 OASIS Score [median (IQR)] 33 (27–39) 35 (29–41) < 0.01 First Day SOFA Score 5 (4–8) 6 (4–9) < 0.01 [median (IQR)] H2RAs and increased ICU length of stay (LOS) (differ - days − 1.697, standard estimate − 0.19, p < 0.001), para- ence in days: 1.569, standard estimate 0.23, p < 0.001). plegia (difference in days 1.042, standard estimate 0.18, Other significant predictors of increased ICU length of p < 0.001), Charlson comorbidity index (difference in stay included APS III (difference in days 0.113, standard days 0.427, standard estimate 0.17, p < 0.001), first SOFA estimate: 0.31, p < 0.001), SAPS II (difference in days − score (difference in days 0.353, standard estimate 0.15, p 0.14, standard estimate − 0.31, p < 0.001), dementia (dif- < 0.001), mild liver disease (difference in days − 0.887, ference in days − 1.988, standard estimate − 0.24, p < standard estimate − 0.14, p < 0.001), diabetes with com- 0.001), metastatic solid tumor (difference in days − 1.472, plicating condition (difference in days − 1.082, standard standard estimate − 0.23, p < 0.001), oasis (difference in estimate − 0.13, p < 0.001), renal disease (difference in days 0.158, standard estimate 0.21, p < 0.001), cerebro- days − 1.222, standard estimate − 0.13, p < 0.001), rheu- vascular disease (difference in days 1.39, standard esti - matic disease (difference in days − 0.889, standard esti - mate 0.19, p < 0.001), severe liver disease (difference in mate − 0.12, p < 0.001), diabetes without complicating F irzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 5 of 11 Fig. 1 Predictors of 28‑ day mortality among patients who stayed in the ICU for sepsis management regression demonstrated significant differences between condition (difference in days − 0.768, standard estimate group 2 vs the baseline group (OR 0.79 95% CI [0.686– − 0.09, p < 0.001), myocardial infarct (difference in days 0.911], p = 0.001) and group 1 vs the baseline group (OR − 0.573, standard estimate − 0.08, p < 0.001), peptic 1.419 95% CI [1.265–1.591], p < 0.001) (Table  3). No ulcer disease (difference in days 0.135, standard estimate significant difference was found between group 3 and 0.08, p < 0.01), age (difference in days − 0.027, standard the baseline group (OR 1.042 95% CI [0.93–1.168], p = estimate − 0.06, p < 0.001). 0.474). Among groups of patients with IMV, i.e., groups 1 and 3, there was a significant increased odds of mortal - Need for invasive mechanical ventilation ity in group 1, who did not receive H2RAs, compared to Significantly more patients in the H2RA group required group 3 (OR 1.36 95% CI [1.23–1.50], p < 0.001). invasive mechanical ventilation than the No H2RA In subgroup analysis of LOS, we found that patients group (62.15% vs. 31.81%, p < 0.01). Multivariable logis- who received IMV had significantly longer mean LOS tic regression demonstrated that patients in the H2RA (H2RA group 7.8 days; no H2RA group 6.9 days) while group had an adjusted odd ratio of 4.426 (95% CI [4.132 the patients who were not mechanically ventilated had – 4.741], p < 0.001) for needing mechanical ventilation significantly lower mean LOS (H2RA group 2.8 days; no (Fig. 2). H2RA group 2.6 days) (Table  2). Furthermore, between just the ventilated patients, the mean LOS was statis- Association between H2RA use and IMV on mortality tically significant (p < 0.001) with H2RA patients on and length of stay outcomes mechanical ventilation having longer length of stay. To assess differences in mortality based on a combina - tion of H2RA use and the need for IMV, we identified four sub-groups (defined in methods above) and com - Association between H2RA use and organ dysfunction pared mortality outcomes between them. Mortality rate Patients receiving H2RAs had significantly higher differed significantly between the groups (Table  2). The median P/F ratios on days 1 through 7 of ICU stay (p baseline group was not on H2RAs and did not receive < 0.05) (Fig.  3A). Overall, H2RA use is associated with IMV. Mortality rate in this group was 10.2%. Patients in better lung function on most days as indicated by group 2 who received H2RAs and did not require IMV, higher PF ratios. In the H2RA group compared to the had the lowest mortality rate of 6.7%. Mortality rate no H2RA group, significantly higher proportion (p < was highest, 25.4% among those who were on IMV but 0.05) of patients were in the no ARDS and mild ARDS did not receive H2RA (group 2). Multivariable logistic groups on all days except for day 3 (Fig.  4). Median Firzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 6 of 11 Fig. 2 Predictors of need for invasive mechanical ventilation among patients who stayed in the ICU for sepsis management Table 2 Subgroup analysis of the relationship between H2RA use and mechanical ventilation status and mortality and length of stay outcomes Baseline group Group 1 Group 2 Group 3 Total (N = 30,591) p value No H2RA, no IMV No H2RA, IMV H2RA, no IMV H2RA, IMV (N = 12,058) (N = 5625) (N =4499) (N = 8409) Mortality < 0.001 Survived 10,823 4198 4196 (93.3%) 7089 (84.3%) 26,306 (86.0%) (89.8%) (74.6%) Died 1235 1427 303 1320 4285 (14.0%) (10.2%) (25.4%) (6.7%) (15.7%) Median ICU LOS (IQR) 1.9 2 4.6 4.7 (1.1–3.2) (1.2–3.2) (2.4–8.9) (2.2–10) Mean ICU LOS (SD) 2.6 (2.4) 6.9 (7.2) 2.8 (2.7) 7.8 (9.4) < 0.001 Definitions: Baseline group patients not on H2RAs who were not ventilated, Group 1 patients not on H2RAs who were ventilated, Group 2 patients on H2RAs who were not ventilated and Group 3 patients on H2RAs who were ventilated Table 3 Multivariable logistic regression of 28‑ day mortality BUN/Cr ratios were significantly lower (p < 0.05) on in subgroup analysis of mechanical ventilation and H2RA days 1–3 for patients in the H2RA group while these groups (note: same covariates were used in these models as the were significantly higher on days 4–7 (Fig.  3). BUN mortality analysis) medians were significantly lower in the group receiving H2RAs on most days (Fig.  3). Serum creatinine medi- Predictor Odds ratio p value 95% confidence interval ans were significantly lower on all days following ICU admission in the H2RA group (Fig. 3). Median AST and Reference group: baseline ALT were generally not significantly different in the Group 1 1.438 < .001 1.282–1.613 H2RA group versus the no H2RA group. Group 2 0.808 0.003 0.701–0.932 Group 3 1.074 0.223 0.957–1.206 F irzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 7 of 11 AB CD EF Fig. 3 Daily trend in lung, kidney, and liver function over the first seven days of ICU stay Discussion day SOFA score among patients who received an H2RA H2RAs are widely used for the management of acid- as compared to the non-H2RA group. Patients receiving peptic disease, including gastroesophageal reflux dis - an H2RA also had higher average P/F ratios and were less ease, gastric and duodenal ulcers and for SUP in critically likely to develop moderate or severe ARDS as compared ill patients. In this retrospective cohort study of ICU to those who were not treated with an H2RA. Interest- patients with sepsis, we assessed the association between ingly, despite the mortality benefit, H2RA use was asso - the use of H2RAs and sepsis outcomes based on the ciated with an increased rate of invasive mechanical demonstrated role of histamine antagonism in attenuat- ventilation, and longer ICU LOS. The increased risk of ing sepsis-related organ dysfunction in mouse models. invasive mechanical ventilation among patients receiv- Our analysis shows that H2RA administration is asso- ing an H2RA most likely reflects correlation rather than ciated with decreased mortality for non-ventilated and causation: H2RAs are routinely administered prophylac- ventilated patients with sepsis. Notably, decreased mor- tically to patients on invasive mechanical ventilation to tality was observed despite a slightly higher median first reduce the risk of gastrointestinal hemorrhage. In our Firzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 8 of 11 AB CD Fig. 4 Daily proportions of patients in each ARDS severity group from days 1 to 7 of ICU admission analysis, both ventilated and non-ventilated patients disease and thus it is expected that ventilated patients receiving an H2RA had significantly reduced odds of will require a longer LOS as compared to non-ventilated mortality as compared to those who did not receive an patients, irrespective of H2RA administration. Nota- H2RA. bly, however, ventilated patients who received an H2RA Prolonged ICU LOS among patients receiving an H2RA required approximately one day longer LOS as compared may also reflect correlation rather than causation. H2RAs to ventilated patients who did not receive an H2RA. were administered more frequently to ventilated patients Similarly, non-ventilated patients who received an H2RA as compared to non-ventilated patients. Increased ven- required approximately 2 h longer LOS as compared to tilation requirements typically indicate more severe non-ventilated patients who did not receive an H2RA. F irzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 9 of 11 The underlying cause of prolonged LOS among patients to include specific doses of agents in our analysis; there - treated with an H2RA requires further investigation. fore, dose effects could not be assessed. Third, the spe - The decreased mortality observed in patients taking cific cause of death is not included in the MIMIC-IV H2RAs in mechanically ventilated and non-ventilated database. We therefore report crude mortality rates. The patients despite prolonged ICU length of stay is some- mechanisms underlying the mortality benefit associated what paradoxical and warrants careful examination. We with H2RAs could conceivably be more clearly defined hypothesize that H2RAs may improve pulmonary func- if cause of death was established. Fourth, the no-H2RA tion in the setting of sepsis via a dual mechanism involv- group likely included a heterogenous group of patients ing a reduction in alveolar wall edema and modulation who could ostensibly be receiving other GI prophylaxis, of airway and vascular smooth muscle inflammation. or no GI prophylaxis at all. Lastly, the data utilized in this Previous studies have shown that histamine 2 recep- study was limited to a single center, which may limit the tors are expressed on mast cells; antagonism of mast generalizability of our findings. cell histamine 2 receptors may decrease degranulation In ICU patients with sepsis, the use of H2RAs is asso- and attenuate local alveolar wall edema [38]. In addition, ciated with significantly lower adjusted odds and inci - antagonism of histamine 2 receptors expressed by air- dence of all-cause mortality irrespective of the initial way and vascular smooth muscles can reduce pulmonary severity of sepsis and invasive mechanical ventilation vascular resistance and thus improve hemodynamic and status. The underlying mechanism for this observation functional status [39]. In our analysis, we provide data is unclear but may be due to amelioration of histamine- suggest improved pulmonary function among patients related dysfunction at the capillary beds with resultant receiving H2RAs, as evidenced by higher average P/F improvement in tissue perfusion. We speculate that ratios and decreased rates of moderate or severe ARDS. H2RAs restore the integrity of the vascular membrane, H2RAs demonstrate a wide range of extraintestinal reduce alveolar wall edema, and mitigate airway and effects. They have been shown to reduce ventricular vascular smooth muscle inflammation. H2RAs are rou - remodeling by interrupting histamine-mediated myocar- tinely used in stress ulcer prophylaxis in mechanically dial remodeling. The Multi-Ethnic Study of Atherosclero - ventilated patient. Our findings suggest that H2RAs sis (MESA) right ventricle study established that H2RA may provide extraintestinal benefits in ICU patients use was associated with lower right ventricular mass with sepsis; although PPIs may be preferred among and end-diastolic volume among individuals with risk patients with a high risk of gastrointestinal hemor- factors for cardiovascular disease [40, 41]. Other pur- rhage, we propose that H2RAs should be considered ported extraintestinal benefits of H2RAs are far-reaching for patients with a high risk of pneumonia and other and include reduction of bladder pain from interstitial cardiopulmonary complications Further research is cystitis, improvement of cell-mediated immunity, and warranted to clearly define the mechanisms underlying reduction of symptoms related to erythropoietic pro- histamine-mediated end organ damage and establish toporphyria [42–44]. Furthermore, recent studies have potential applications for H2RAs among patients with demonstrated a potential role for H2RAs as an adjunc- sepsis. tive treatment for COVID-19 [45, 46]. To the best of our knowledge, this is the first large-scale study to assess the Abbreviations effect of H2RAs on mortality in the setting of sepsis. AIDS Acquired immunodeficiency syndrome The study is strengthened by a large sample size with ALT Alanine Aminotransferase APS III Acute Physiology Score III many data elements per subject. The MIMIC-IV database ARDS Acute respiratory distress syndrome provides risk scores, disease severity indices, and exten- AST Aspartate aminotransferase sive comorbidity information for each subject, which MIMIC‑IV Medical Information Mart for Intensive Care IV BUN Blood urea nitrogen allowed us to control for potential confounding vari- CIB Clinically important bleeding ables. This study also considers only patients with sepsis, H2RA Histamine‑2 receptor antagonists whereas other studies on GI prophylactic medications ICU Intensive care unit IMV Invasive mechanical ventilation have included all critically ill patients with a range of pos- LOS Length of stay sible etiologies for their admissions. However, there are OASIS Outcome Assessment Information Set several limitations of our study inherent to its design. SAPS II Simplified Acute Physiology Score II SOFA Sequential Organ Failure Assessment First, the analysis was retrospective and thus causation SUP Stress ulcer prophylaxis could not be assessed. Second, H2RAs were considered as a class thus we are unable determine if the relation- Acknowledgements Not applicable. ships observed are a class effect. Further, we were unable Firzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 10 of 11 Authors’ contributions 12. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM TRF: conceptualization; design, analysis, and writing—initial draft. SS: writ‑ et al (2013) Surviving sepsis campaign: international guidelines for ing—initial draft, generation of figures. DAA: design, analysis, writing—initial management of severe sepsis and septic shock: 2012. Crit Care Med draft, review, and editing. BDB: writing initial draft, review, and editing. MBU: 41(2):580–637 review and editing. MR: supervision and data access. FML: supervision, review, 13. Wang Y, Ge L, Ye Z, Siemieniuk RA, Reintam Blaser A, Wang X, Perner A, and editing. All authors read and approved the final version of the manuscript. Møller MH, Alhazzani W, Cook D, Guyatt GH (2020) Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: an updated Funding systematic review and network meta‑analysis of randomized trials. This work did not receive any funding from individuals, institutions, or funding Intensive Care Med 46(11):1987–2000. https:// doi. org/ 10. 1007/ s00134‑ agencies.020‑ 06209‑w Epub 2020 Aug 24. PMID: 32833040 14. Barletta JF (2014) Histamine‑2‑receptor antagonist administration Availability of data and materials and gastrointestinal bleeding when used for stress ulcer prophylaxis The datasets analyzed during the current study are publicly available in the in patients with severe sepsis or septic shock. Ann Pharmacother MIMIC‑IV database (https:// physi onet. org/ conte nt/ mimic iv/1. 0/). 48(10):1276–1281 15. Huang M, Han M, Han W, Kuang L (2021) Proton pump inhibitors versus histamine‑2 receptor blockers for stress ulcer prophylaxis Declarations in patients with sepsis: a retrospective cohort study. J Int Med Res 49(6):3000605211025130 Ethics approval and consent to participate 16. Zhou X, Fang H, Xu J, Chen P, Hu X, Chen B et al (2019) Stress ulcer Since we used a publicly available de‑identified database, we did not require prophylaxis with proton pump inhibitors or histamine 2 receptor antago‑ institutional review board approval for this study. nists in critically ill adults ‑ a meta‑analysis of randomized controlled trials with trial sequential analysis. BMC Gastroenterol 19(1):193 Consent for publication 17. Hammond DA, Kathe N, Shah A, Martin BC (2017) Cost‑ effectiveness of Not applicable. histamine2 receptor antagonists versus proton pump inhibitors for stress ulcer prophylaxis in critically ill patients. Pharmacotherapy: the journal of Competing interests human pharmacology and drug. Therapy. 37(1):43–53 The authors declare that they have no competing interests. 18. Alhazzani W, Alshamsi F, Belley‑ Cote E, Heels‑Ansdell D, Brignardello ‑ Petersen R, Alquraini M, Perner A, Møller MH, Krag M, Almenawer S, Author details Rochwerg B, Dionne J, Jaeschke R, Alshahrani M, Deane A, Perri D, The‑ Reno School of Medicine, University of Nevada, 1664 N Virginia Street, Reno, bane L, Al‑ Omari A, Finfer S, Cook D, Guyatt G (2018) Efficacy and safety NV 89557, USA. Christus Ochsner St. Patrick Hospital, 524 Dr Michael Debakey of stress ulcer prophylaxis in critically ill patients: a network meta‑analysis Dr, Lake Charles, LA 70601, USA. Keck School of Medicine, University of South‑ of randomized trials. Intensive Care Med 44(1):1–11. https:// doi. org/ 10. ern California, 1500 San Pablo Street, 2nd Floor, Los Angeles, CA 90033, USA. 1007/ s00134‑ 017‑ 5005‑8 Epub 2017 Dec 4. Erratum in: Intensive Care Department of Pulmonary and Critical Care Medicine, Renown Health, 1155 Med. 2017 Dec 11;: PMID: 29199388; PMCID: PMC5770505 Mill St., Reno, NV 89502, USA. 19. Young PJ, Bagshaw SM, Forbes AB et al (2020) Eec ff t of stress ulcer proph‑ ylaxis with proton pump inhibitors vs histamine‑2 receptor blockers on Received: 11 December 2022 Accepted: 3 February 2023 in‑hospital mortality among ICU patients receiving invasive mechanical ventilation: the PEPTIC randomized clinical trial. JAMA 323:616–626 20. Johnson, Alistair, Bulgarelli, Lucas, Pollard, Tom, Horng, Steven, Celi, Leo Anthony, Mark, Roger. MIMIC‑IV [Internet]. PhysioNet; [cited 2021 Nov 4]. Available from: https:// physi onet. org/ conte nt/ mimic iv/0. 4/ References 21. Goldberger AL, Amaral LAN, Glass L, Hausdorff JM, Ivanov PC, Mark 1. Paoli CJ, Reynolds MA, Sinha M, Gitlin M, Crouser E (2018) Epidemiology RG et al (2000) PhysioBank, PhysioToolkit, and PhysioNet. Circulation. and costs of sepsis in the United States‑an analysis based on timing of 101(23):e215–e220 diagnosis and severity level. Crit Care Med 46(12):1889–1897 22. Singer M, Deutschman CS, Seymour CW, Shankar‑Hari M, Annane D, 2. Hajj J, Blaine N, Salavaci J, Jacoby D (2018) The “centrality of sepsis”: Bauer M et al (2016) The third international consensus definitions for a review on incidence, mortality, and cost of care. Healthcare (Basel) sepsis and septic shock (Sepsis‑3). JAMA. 315(8):801–810 6(3):E90 23. Knaus WA, Wagner DP, Draper EA, Zimmerman JE, Bergner M, Bastos PG 3. Kim HI, Park S (2019) Sepsis: early recognition and optimized treatment. et al (1991) The APACHE III prognostic system. Risk prediction of hospital Tuberc Respir Dis (Seoul) 82(1):6–14 mortality for critically ill hospitalized adults. Chest. 100(6):1619–1636 4. Gyawali B, Ramakrishna K, Dhamoon AS (2019) Sepsis: the evolution 24. Le Gall JR, Lemeshow S, Saulnier F (1993) A new simplified acute physiol‑ in definition, pathophysiology, and management. SAGE Open Med ogy score (SAPS II) based on a European/north American multicenter 7:2050312119835043 study. JAMA. 270(24):2957–2963 5. Polat G, Ugan RA, Cadirci E, Halici Z (2017) Sepsis and septic shock: 25. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H current treatment strategies and new approaches. Eurasian J Med et al (1996) The SOFA (sepsis‑related organ failure assessment) score to 49(1):53–58 describe organ dysfunction/failure. On behalf of the working group on 6. Fang F, Zhang Y, Tang J, Lunsford LD, Li T, Tang R et al (2019) Association sepsis‑related problems of the European Society of Intensive Care Medi‑ of corticosteroid treatment with outcomes in adult patients with sepsis: a cine. Intensive Care Med 22(7):707–710 systematic review and meta‑analysis. JAMA Intern Med 179(2):213–223 26. Johnson AEW, Kramer AA, Clifford GD (2013) A new severity of illness 7. Vignon P, Laterre P‑F, Daix T, François B (2020) New agents in develop ‑ scale using a subset of acute physiology and chronic health evaluation ment for sepsis: any reason for hope? Drugs. 80(17):1751–1761 data elements shows comparable predictive accuracy. Crit Care Med 8. Ebeigbe AB, Talabi OO (2014) Vascular effects of histamine. Niger J Physiol 41(7):1711–1718 Sci 29(1):7–10 27. Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of 9. Jin H, Koyama T, Hatanaka Y, Akiyama S, Takayama F, Kawasaki H (2006) classifying prognostic comorbidity in longitudinal studies: development Histamine‑induced vasodilation and vasoconstriction in the mesenteric and validation. J Chronic Dis 40(5):373–383 resistance artery of the rat. Eur J Pharmacol 529(1–3):136–144 28. The ARDS Definition Task Force* (2012) Acute respiratory distress syn‑ 10. Hattori M, Yamazaki M, Ohashi W, Tanaka S, Hattori K, Todoroki K et al drome: the Berlin definition. JAMA. 307(23):2526–2533 (2016) Critical role of endogenous histamine in promoting end‑ organ 29. BigQuery documentation [Internet]. Google Cloud. [cited 2021 Nov 4]. tissue injury in sepsis. Intensive Care Med Exp 4(1):36 Available from: https:// cloud. google. com/ bigqu ery/ docs 11. Lansing AM (1963) Septic shock. Can Med Assoc J 89(12):583–588 30. Olive DJ (2005) A simple confidence interval for the median F irzli et al. J Anesth Analg Crit Care (2023) 3:3 Page 11 of 11 31. jamovi ‑ Stats. Open. Now. [Internet]. [cited 2021 Dec 2]. Available from: https:// www. jamovi. org/ 32. Heinzen E, Sinnwell J, Atkinson E, Gunderson T, Dougherty G, Votruba P, et al. arsenal: An Arsenal of “R” functions for large‑scale statistical sum‑ maries [Internet]. 2021 [cited 2021 Dec 2]. Available from: https:// CRAN.R‑ proje ct. org/ packa ge= arsen al 33. Kassambara A, Kosinski M, Biecek P, Fabian S. survminer: drawing survival curves using “ggplot2” [Internet]. 2021 [cited 2021 Dec 2]. Available from: https:// CRAN.R‑ proje ct. org/ packa ge= survm iner 34. Garbett S, Stewart T, Thompson J, Harrell F, Kim A. tangram: the grammar of tables [Internet]. 2020 [cited 2021 Dec 2]. Available from: https:// CRAN.R‑ proje ct. org/ packa ge= tangr am 35. Sjoberg DD, Curry M, Larmarange J, Lavery J, Whiting K, Zabor EC, et al. gtsummary: presentation‑ready data summary and analytic result tables [Internet]. 2021 [cited 2021 Dec 2]. Available from: https:// CRAN.R‑ proje ct. org/ packa ge= gtsum mary 36. Harrison E, Drake T, Ots R. finalfit: quickly create elegant regression results tables and plots when modelling [Internet]. 2021 [cited 2021 Dec 2]. Available from: https:// CRAN.R‑ proje ct. org/ packa ge= final fit 37. The Comprehensive R Archive Network [Internet]. [cited 2021 Dec 2]. Available from: https:// cran.r‑ proje ct. org/ 38. Lippert U, Artuc M, Grützkau A, Babina M, Guhl S, Haase I et al (2004) Human skin mast cells express H2 and H4, but not H3 receptors. J Invest Dermatol 123(1):116–123 39. Akdis CA, Simons FER (2006) Histamine receptors are hot in immunop‑ harmacology. Eur J Pharmacol 533(1–3):69–76 40. Leary PJ, Barr RG, Bluemke DA, Bristow MR, Kronmal RA, Lima JA et al (2014) H2 receptor antagonists and right ventricular morphology: the MESA right ventricle study. Ann Am Thorac Soc 11(9):1379–1386 41. Kim J, Ogai A, Nakatani S, Hashimura K, Kanzaki H, Komamura K et al (2006) Impact of blockade of histamine H2 receptors on chronic heart failure revealed by retrospective and prospective randomized studies. J Am Coll Cardiol 48(7):1378–1384 42. Dasgupta P, Sharma SD, Womack C, Blackford HN, Dennis P (2001) Cime‑ tidine in painful bladder syndrome: a histopathological study. BJU Int 88(3):183–186 43. Kokhaei P, Barough MS, Hassan ZM (2014) Cimetidine effects on the immunosuppression induced by burn injury. Int Immunopharmacol 22(1):273–276 44. Tu JH, Sheu SL, Teng JM (2016) Novel treatment using cimetidine for Erythropoietic Protoporphyria in children. JAMA Dermatol 152(11):1258–1261 45. Chenchula S, Ray A, Sadasivam B (2021) Famotidine repurposing for novel corona virus disease of 2019: a systematic review. Drug Res (Stuttg) 71(06):295–301 46. Chiu L, Shen M, Lo C‑H, Chiu N, Chen A, Shin HJ et al (2021) Eec ff t of famotidine on hospitalized patients with COVID‑19: a systematic review and meta‑analysis. PLoS One 16(11):e0259514 Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions

Journal

Journal of Anesthesia Analgesia and Critical Care – Springer Journals

Published: Feb 9, 2023

Keywords: Sepsis; Histamine antagonists; H2RA; MIMIC database; ICU; Mortality; Length of stay

There are no references for this article.