Association of the number of days with severe anaemia in the first week with 28-Day mortality in patients with sepsis

doi:10.21203/rs.3.rs-4725204/v1

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Association of the number of days with severe anaemia in the first week with 28-Day mortality in patients with sepsis

https://doi.org/10.21203/rs.3.rs-4725204/v1

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Anemia is a common occurrence during sepsis, however the relationship between the duration of anemia and short-term effect on mortality in septic patients remains unclear. In this retrospective cohort study, the patients with sepsis were included from Medical Information Mart for Intensive Care -IV database.Outcome was 28-day mortality.The main analytical methods utilized in this study were multivariable logistic regression.Sensitivity analysis was used to balance the variables and reduce bias by using propensity score matching (PSM) and excluding special populations.A total of 1335 patients septic patients were included. After adjusting for confounders,the 28-day mortality of septic patients increased with each additional day of severe anemia (hemoglobin < 8g/dl) in the first week of ICU(intensive care unit) admission with an odds ratio(OR) of 1.12 (95% CI [1.05; 1.2],P < 0.001).Furthermore,patients who experienced severe anemia for at least three days had higher 28-day mortality compared to those who experienced severe anemia with less than three days in the first week(OR: 1.59, 95% CI [1.19; 2.11],P=0.002) based on multivariable logistic regression analysis.The results were also robust in sensitivity analyses.A longer duration of severe anemia in the first week may be linked to increased 28-day mortality in patients with sepsis.

Health sciences/Diseases

Health sciences/Health care

Health sciences/Medical research

Health sciences/Risk factors

Hemoglobin

Sepsis

Mortality

Anemia

Anemia is a well-recognised complication of critical illness^[1]and is associated with poor short-term and long-term clinical outcomes. These outcomes include prolonged hospitalisation, increased ventilator day, higher rates of hospital readmission,elevated mortality rates, and diminished health-related quality of life (HRQoL)^{[2, 3]}.It is estimated that around 70% of patients admitted to the intensive care unit (ICU) experience anemia^[4].Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection^[5].Anemia is a common occurrence during sepsis and is caused by iatrogenic blood loss, occult gastrointestinal bleeding,decreased serum iron levels and erythropoietin production, and a shortened lifespan of erythrocytes and coagulopathy^[4,6].Furthermore, reduced hemoglobin levels can exacerbate organ dysfunction and lead to a poorer prognosis^[7].

However, there have been limited reports on the association between the duration of severe anemia and the short-term prognosis of sepsis. This study investigates the correlation between the number of days with severe anemia during the first week and the 28-day mortality in septic patients, shedding light on the influence of hemoglobin levels on the development of sepsis. The results are intended to offer clinical evidence in favor of hemoglobin supplementation for septic patients and to assist physicians in evaluating patient status.

Data Source. Our study utilized data from the latest version of the

Medical Information Mart for Intensive Care IV database (MIMIC-IV version 2.2), which contains comprehensive clinical data of patients admitted to the Beth Israel Deaconess Medical Center between 2008 and 2019^[8]. The database was populated with data acquired during routine hospital care, including archives

from critical care information systems, hospital electronic health record databases, and the Social Security Administration Death Master File. It also includes

documents containing codes of the International Classification of Diseases,

Ninth and Tenth Revisions (ICD-9 and ICD-10, respectively) .We were approved to use the database after completion of the “Protecting Human Research Participants” course. The health information obtained from the MIMIC-IV database was unidentified, so informed consent of patients was not required .One of

the authors, Qingjing Zeng, obtained certification with the number 10846981.

Our study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines ^[9].

Population selection criteria. Patients who met the following criteria in

the database were included in this study: [1] first ICU admission at first

hospitalization; [2] The length of ICU stay ≥ 7 days with hemoglobin test everyday in the first week; [3] Age > 18 years old; [4] met the diagnostic criteria of sepsis 3.0^[5]. Patients with sepsis in the MIMIC-IV database were identified using ICD-9 (99591, 99592, and 78552) and ICD-10 (R65.20, R65.21) codes^[8]. The flowchart of this study is presented in Fig. 1.A total of 8161 patients with sepsis admitted to ICU at first hospitalization were extracted using ICD-9 (99591, 99592, and 78552) and ICD-10 (R65.20, R65.21) codes. Of these, patients were coded repeatedly(n = 2062), the length of ICU stay less than 7 (n = 4616), without hemoglobin tested daily in the previous week(n = 134), and patients without SOFA scores (n = 14)were all excluded, 1335 patients were included in the study finally. We divided the patients into two groups :the number of days

with severe anemia less than 3 and the number of days with severe anemia at least 3 in the first week.

Data extraction. The extracted data included demographics, vital signs,

laboratory test results, and disease severity scores. We extracted the following demographic data: gender, age, length of ICU stay, time of death.Vital signs on the day of ICU admission including the minimum mean arterial pressure

(MAP), the fastest respiratory rate (RR) and heart rate(HR). Laboratory

indicators included on theday of ICU admission are as follows:the lowest

platelet(PLT) count and the highest white blood cell (WBC) count, total

bilirubin(TB),serum creatinine(Scr),urea nitrogen(BUN), alanine aminotransferase(ALT), aspartate aminotransferase (AST), prothrombin time(PT), activated partial thromboplastin time(APTT) and daily minimum hemoglobin(Hb)in the first week.Besides acute physiology score III(APSIII), Charlson comorbidity

index(CCI), and sequential organ failure assessment(SOFA) were collected.

Exposure and Outcome. The number of days with severe anemia in the week prior to ICU admission as an exposure factor in this study, and the main outcome was 28-days all-cause mortality.

Missing Data. To address missing values in covariates and prevent

information loss, multiple imputation techniques were employed.

Statistical Analysis. Kolmogorov-Smirnov test was used for determining

whether variables were normally distributed.Normally distributed continuous

variables were expressed presented as mean ± SD, and skewed continuous

variables were described as median (interquartile range [IQR]). Categorical

variables are presented as numbers and percentages.Parametric tests were

performed with the use of chisquare-tests, student's t-tests, and Kruskal-Wallis

tests for categorical variables, normally distributed continuous variables, and

non-normally distributed continuous variables, respectively. Model-adjusted

multivariate Logistic regression was used to estimate the association between

the number of days with severe anemia in the first week and 28-day all-causes mortality.Sensitivity analysis was used to minimize the potential bias of

confounding.We generate a propensity score matching (PSM) among the group that the number of days with severe anemia less than 3 and the group that the number of days with severe anemia at least 3 using a multivariable logistic

regression model.We matched the two groups in a 1:1 ratio with a caliper

width of 0.2. The standardized mean difference (SMD) was used to examine

the matching quality of PSM.Sensitivity analyses excluding special populations were performed to verify the robustness of the results.All analyses were

performed with the statistical software package R (http://www.R- proje ct. org, The R Foundation), and Free Statistics software version 1.9.1 (Beijing Free

Kelin Medical Technology Co, Ltd.).A two tailed test was performed and p < 0.05 was considered statistically significant.

Baseline characteristics. A total of 1335 patients with sepsis were

enrolled in this study. According to the number of days with severe anemia in the first week, the patients were divided into two groups:the number of days with severe anemia less than 3(n = 999) and the number of days with severe

anemia at least 3(n = 336) and the 28-day mortality were 31.7% and 39.3%,

respectively.After PSM, a total of 323 pairs of subjects were successfully

matched. Before PSM, the distribution of age, gender, SOFA, WBC, PLT, ALT, TB, BUN and PT were uneven among groups, and the differences were

statistically significant (all P < 0.05).After PSM, the distribution of baseline

and clinical data tended to be consistent among the groups, and the differences were not statistically significant (all P > 0.05) (Table 1).And the 28-day

mortality were 29.7% and 38.7%,respectively.

Multivariate Logistic regression analysis. Multivariate Logistic regression analysis was performed to assess the association between the number of days with severe anemia and 28-day mortality by model comparison adjustment for covariates(Table 2). In unadjusted models, the number of days with severe anemia was significantly associated with the 28-day mortality( OR = 1.09 ,95%CI:

1.03 ~ 1.15,P = 0.004). After adjustment for all covariates, the OR was 1.12

(95%CI:1.05 ~ 1.2,P < 0.001).Furthermore,patients who experienced severe anemia

for at least three days had higher 28-day mortality compared to those with

Less than three days(OR = 1.59, 95% CI[1.19; 2.11],P = 0.002) based on

multivariable logistic regression analysis after adjustment for all covariates.The statistical results were robust among all models.

Sensitivity analyses:PSM. Figure 2 illustrates the matching quality that was demonstrated by the measurement of the SMD of variables between the two

groups in the six distinct cohorts. In the unmatched cohort, several variables

between the two groups were imbalanced. After matching as well as weighting, the aforementioned variables tended to be balanced in PSM,IPTW,SMRW,PA

and OW with the SMD lower than 0.20.A significantly higher 28-day mortality in the group that the number of days with severe anemia at least 3 was

found in univariate, multivariate logistic regression analyses, PSM, IPTW,

SMRW,PA and OW. The ORs were 1.39–1.65, all p < 0.05. (Table 3 )

Sensitivity analyses:excluding special populations. The results of

sensitivity analyses excluding special populations are summarized in Table 4.

After excluding the patients with AIDS or malignant tumor or diabetes, the

day mortality was still significantly associated with the number of days with severe anemia(OR = 1.19 ,95%CI:1.06–1.34; p = 0.005) and the 28-day mortality was higher in patients with severe anemia at least 3 days compared to
patients with severe anemia less than 3 days(OR: 2.07, 95% CI:1.23 ~ 3.49,
P = 0.006) .The statistical results were robust among all models.

Our analysis results are as follows: (1) Multivariate Logistic regression

Analysis indicate that the 28-day mortality of septic patients increased with the

increase number of days with severe anemia in the first week of ICU.

admission after adjustment for confounders(OR = 1.12, 95%CI:1.05 ~ 1.2,P < 0.001);(2) A significantly higher 28-day mortality in the group that the days with

severe anemia more than three was found in univariate, multivariate logistic

regression analyses, PSM, IPTW, SMRW,PA and OW,the ORs were 1.39–1.65, all p < 0.05.(3) Sensitivity analyses excluding the patients with AIDS or

malignant tumor or diabetes, these results above remain robust.

Anemia is a common and persistent problem among critically ill patients. According to a recent study, individuals with sepsis who are hospitalized in the ICU often present with anemia early on, which tends to worsen in the initial days following admission to the hospital^[10]. Hemoglobin level not only refected the nutritional status but also was an indicator for the complications and outcomes^{[11, 12]}.

Some studies have delved into the impact of hemoglobin levels on sepsis prognosis. In the work of Qi D et al, it was revealed that hemoglobin levels < 8 g/dL within 48 hours of ICU admission are associated with an increased long-term mortality rate in sepsis^[13]. Lin IH et al. revealed that hemoglobin levels < 10 g/dL within the first week of ICU admission are associated with an increased one-year mortality rate in sepsis^[10].Hemauer et al. suggested that for every increment in hemoglobin unit, the risk of worsened respiratory dysfunction in the following day decreased by 36% (OR = 0.64, 95%CI 0.53–0.77, P < 0.001)^[14]. These findings are consistent with our research results, indicating a correlation between anemia and poor prognosis in sepsis. However, our focus is on the relationship between the duration of early anemia and short-term prognosis in sepsis.

Several possible mechanisms can partly explain the close relationship between hemoglobin level and clinical outcomes in sepsis. First, during many inflammatory and immune responses, red blood cell (RBC) production and/or clearance can be dysregulated, leading to anemia. The terms “anemia of inflammation” is often used to describe anemia seen during infections^[15].During infection and inflammation, a wide variety of mechanisms can lead to reductions in erythropoiesis. Many of these mechanisms are due to the effects of inflammatory cytokines, including IL-6, IL-1β, IFN-γ, and macrophage migration inhibitory factor (MIF). All of these inflammatory cytokines are produced early during infection in response to innate sensing, although in some cases direct infection of mature RBCs or their progenitors leads to either RBC lysis or reduced erythropoiesis, contributing to anemia^[16]. A shortened erythrocyte lifespan has been extensively documented in the inflammatory setting and has been attributed to enhanced erythrophagocytosis by hepatic and splenic macrophages caused by “bystander” deposition of antibody and complement on erythrocytes, mechanical damage from fibrin deposition in microvasculature, and activation of macrophages for increased erythrophagocytosis^[17].In sepsis, or other critical illnesses accompanied by a high level of cytokine activation, anemia is detected after hours or a few days. Hemoglobin plays an important role in anti-inflammation by defending against bacteria and enhancing the function of leucocytes^[18].It is reasonable that massive erythrophagocytosis, hemolysis, or pooling of erythrocytes, along with hemodilution, contribute to this entity that awaits systematic scientific analysis^[19].Second, erythrocytes are a prime target for oxidative stress due to their primary function as O2-carrying cells. Oxidative stress can alter erythrocyte membrane function, inhibit erythroid maturation and release, and reduce erythroid survival rate. Sepsis-induced oxidative stress arises from multiple sources, including activated neutrophils, endothelial cells, plasma, and even under certain conditions, erythrocytes themselves can undergo autooxidation^[20]. In sepsis, oxygen demand in tissues usually increase significantly and lower hemoglobin can worsen the oxygen deficiency, leading to organ dysfunction and poorer outcomes^[21]. In addition, hemoglobin impacts on the metabolism and absorbs of antibiotics, while decreased level of hemoglobin significantly attenuate the anti-infection of antibiotics^[22].

This study has several noteworthy limitations. First, observational study is not completely the same as the randomized controlled trial (RCT). Therefore, the obtained findings may differ from the expected results of RCT and should be interpreted as being affected in the life activities.Secend some residual confounders may potentially exist(i.e., red blood cell transfusion, the basal hemoglobin level,the time from sepsis onset to ICU admission), as with all retrospective analyses. We adjusted for possible confounders and minimized the influence of factors that may lead to outcome bias through the multivariate logistic regression analyses, sensitivity analyses and PSM, IPTW, SMRW,PA and OW.Finally, the causes of death were not recorded in the MIMIC-IV database, we could not conduct a competing risk analysis.Nevertheless, given these limitations, well-designed multi-center-controlled trials are essential to verify our findings.

Table 1

Summarizes the baseline characteristics of the population before and after PSM.
Item	the number of days with severe anemia before PSM			the number of days with severe anemia after PSM
Item	<3	≥ 3	p	<3	≥ 3	p
n	999	336		323	323
Female,n(%)	403 (40.3)	173 (51.5)	< 0.001	174 (53.9)	162 (50.2)	0.345
age, Mean(SD)	64.3 ± 15.6	59.5 ± 15.1	< 0.001	60.6 ± 15.4	59.9 ± 15.0	0.533
HR, Mean(SD)	116.5 ± 24.0	116.3 ± 22.2	0.892	115.5 ± 22.8	116.5 ± 22.3	0.58
MAP, Mean(SD)	51.8 ± 14.8	53.2 ± 11.7	0.106	53.8 ± 14.0	53.1 ± 11.7	0.489
RR, Mean(SD)	30.9 ± 7.1	31.5 ± 7.0	0.165	31.5 ± 7.7	31.5 ± 7.0	0.93
CCI, Mean(SD)	6.2 ± 2.9	6.2 ± 3.0	0.932	6.3 ± 3.0	6.1 ± 3.0	0.479
APSⅢ, Mean(SD)	87.0 ± 26.6	88.6 ± 28.1	0.353	88.6 ± 26.0	88.0 ± 27.5	0.759
SOFA, Median (IQR)	4.0 (3.0, 6.0)	4.0 (3.0, 7.0)	0.011	4.0 (3.0, 7.0)	4.0 (3.0, 7.0)	0.965
WBC, Median (IQR)	15.7 (10.7, 21.4)	17.0 (10.9, 24.5)	0.029	15.0 (10.7, 21.8)	17.1 (10.9, 24.4)	0.072
PLT, Median (IQR)	158.0 (104.0, 225.0)	140.5 (70.8, 218.5)	0.004	150.0 (82.5, 210.0)	143.0 (77.5, 223.5)	0.862
AST, Median (IQR)	71.0 (35.0, 176.5)	61.0 (32.0, 139.0)	0.108	69.0 (39.0, 176.0)	61.0 (32.0, 138.0)	0.125
ALT, Median (IQR)	41.0 (21.0, 102.0)	34.0 (18.8, 73.2)	0.014	39.0 (21.0, 81.5)	34.0 (18.0, 73.5)	0.129
TB, Median (IQR)	0.9 (0.5, 2.2)	1.1 (0.6, 3.6)	0.003	1.0 (0.5, 2.5)	1.1 (0.5, 3.5)	0.312
Scr, Median (IQR)	1.6 (1.0, 2.5)	1.7 (1.0, 3.3)	0.172	1.7 (1.0, 3.0)	1.7 (1.0, 3.1)	0.746
BUN, Median (IQR)	32.0 (21.0, 52.0)	37.5 (21.0, 60.0)	0.01	34.0 (20.0, 56.5)	36.0 (21.0, 58.5)	0.372
PT, Median (IQR)	16.2 (13.7, 21.8)	17.3 (14.5, 22.6)	0.011	16.7 (13.9, 24.0)	17.0 (14.4, 22.2)	0.443
APTT, Median (IQR)	37.4 (31.1, 54.2)	37.0 (30.2, 52.2)	0.138	36.7 (31.0, 50.7)	36.3 (30.1, 52.2)	0.491
28-day mortality, n (%)	317 (31.7)	132 (39.3)	0.011	96 (29.7)	125 (38.7)	0.016
PSM,propensity score matching; SD,standard deviation; IQR,interquartile range;

HR,heart rate; MAP,mean arterial pressure; RR,respiratory rate; CCI,Charlson comorbidity index; APSIII,acute physiology score III ; SOFA,sequential organ failure assessment; WBC,white blood cell; PLT,platelet; AST,aspartate aminotransferase; ALT,alanine aminotransferase; TB,total bilirubin; Scr,serum creatinine; BUN,urea nitrogen; PT,prothrombin time; APTT,activated partial thromboplastin time.

Table 2

Multivariable logistic regression analysis: Relationship between the number of days with severe anemia in the first week and the 28-day mortality of septic patients.
Variable	non-adjusted model		model 1		model 2		model 3
Variable	OR (95%CI)	P	OR (95%CI)	P	OR (95%CI)	P	OR (95%CI)	P
days of SA	1.09 (1.03 ~ 1.15)	0.004	1.14 (1.07 ~ 1.21)	< 0.001	1.12 (1.05 ~ 1.19)	0.001	1.12 (1.05 ~ 1.2)	0.001
days of SA ≥ 3
no	1(Ref)		1(Ref)		1(Ref)		1(Ref)
yes	1.39 (1.08 ~ 1.8)	0.011	1.67 (1.28 ~ 2.19)	< 0.001	1.57 (1.19 ~ 2.08)	0.001	1.59 (1.19 ~ 2.11)	0.002
SA,severe anemia; OR,odds ratio; CI,Confidence interval;
Model 1:adjusted by age, sex;
Model 2:adjusted by age, sex, MAP, HR, RR, CCI, APSIII, SOFA;

Model 3:adjusted by age, sex, MAP, HR, RR, CCI, APSIII, SOFA, PLT,Hb, WBC, TB, ALT, AST, Scr, BUN, PT, APTT.

severe anemia and less than 3 days in the first week of each cohort.

Table 3 Associations between the number of days with severe anemia (≥ 3 vs<3) and

the 28-day mortality in the crude analysis, multivariable analysis, and propensity-score

analyses.

Models	OR (95%CI)	P value
Unmatched.crude	1.39 (1.08 ~ 1.8)	0.011
Multivariable.adjusted	1.59 (1.19 ~ 2.11)	0.002
PSM	1.49 (1.08 ~ 2.07)	0.016
IPTW	1.65 (1.28 ~ 2.12)	< 0.001
SMRW	1.49 (1.16 ~ 1.93)	0.002
PA	1.48 (1.07 ~ 2.04)	0.018
Ow	1.48 (1.01 ~ 2.17)	0.044

OR,odds ratio; CI,Confidence interval; PSM,propensity score matching; IPTW,inverse probability of

treatment weighting; SMRW,standardized mortality ratio weighting; PA,pairwise algorithmic;

OW,overlap weight.

Table 4

Sensitivity analyses excluding special populations
Variable	n.total	n.event_%	crude.OR (95%CI)	crude.P value	adj.OR (95%CI)	adj.P value
Not-ajusted
days of SA	646	221 (34.2)	1.11 (1.03 ~ 1.2)	0.005	1.16 (1.07 ~ 1.26)	< 0.001
days of SA(<3), n (%)	323	96 (29.7)	1(Ref)		1(Ref)
days of SA(≥ 3), n (%)	323	125 (38.7)	1.49 (1.08 ~ 2.07)	0.016	1.72 (1.2 ~ 2.45)	0.003
model1
days of SA	635	221 (34.8)	1.11 (1.03 ~ 1.19)	0.008	1.15 (1.06 ~ 1.25)	0.001
days of SA(<3), n (%)	314	96 (30.6)	1(Ref)		1(Ref)
days of SA(≥ 3), n (%)	321	125 (38.9)	1.45 (1.04 ~ 2.01)	0.027	1.63 (1.14 ~ 2.33)	0.008
model2
days of SA	524	172 (32.8)	1.11 (1.02 ~ 1.2)	0.018	1.18 (1.07 ~ 1.3)	0.001
days of SA(<3), n (%)	272	77 (28.3)	1(Ref)		1(Ref)
days of SA(≥ 3), n (%)	252	95 (37.7)	1.53 (1.06 ~ 2.21)	0.023	1.94 (1.29 ~ 2.92)	0.002
Model3
days of SA	351	119 (33.9)	1.1 (0.99 ~ 1.21)	0.079	1.19 (1.06 ~ 1.34)	0.005
days of SA(<3), n (%)	173	50 (28.9)	1(Ref)		1(Ref)
days of SA(≥ 3), n (%)	178	69 (38.8)	1.56 (1 ~ 2.43)	0.052	2.07 (1.23 ~ 3.49)	0.006
SA,severe anemia; OR,odds ratio; CI,Confidence interval;
model 1:Sensitivity analyses excluding the patients with AIDS;
model 2:Sensitivity analyses excluding the patients with AIDS or malignant tumor;

model 2:Sensitivity analyses excluding the patients with AIDS or malignant tumor or diabetes.

A longer duration of severe anemia in the first week may be linked to increased 28-day mortality in patients with sepsis.Further longitudinal studies are needed to confirm.

Future directions

Our findings shed light on the relevance of severe anemia and 28-day outcome and provide clinical evidence for risk stratification of the 28-day mortality by the first week variables in patients with sepsis.More studies are warranted to clarify underlying biological mechanisms and to explore the potential effect of correction of anemia within and after the first week of ICU admission.

Ethics approval

The MIMIC-IV database has received ethical approval from the Institutional Review Boards of the Massachusetts Institute of Technology and BIDMC.

Consent to participate

The Medical Information Mart for Intensive Care IV (MIMIC-IV) database is a public database.Because the database does not contain protected health information, this study did not require written informed consent for participation.

Funding

The authors declare that no funds or other support were received during the preparation of this manuscript.

Author Contribution

All authors contributed to the study conception and design. Q.Z. took part in data curation and writing-original draft. L.Z. involved in validation, writing-reviewing.Y.W. involved in software.Y.T. involved in investigation.H.M. involved in formal analysis.Y.L. involved in conceptualization,methodology,project administration and supervision.All authors commented on previous versions of the manuscript and approved the final manuscript.

Acknowledgement

We thank Dr. Liu jie (People’s Liberation Army of China General Hospital, Beijing, China) for helping in this revision .

Data Availability

The datasets generated and analyzed during the current study are available in the Medical Information Mart for Intensive Care IV (https://mimic.physionet.org/).

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Association of the number of days with severe anaemia in the first week with 28-Day mortality in patients with sepsis

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