Skip to main content

Higher serum haptoglobin levels were associated with improved outcomes of patients with septic shock

Dear Editor,

Regarding the recent study published in Critical Care on the role of haptoglobin in acute kidney injury in critically ill adults with ARDS and therapy with VV ECMO [1], we would like to explore the association between serum haptoglobin levels and clinical outcomes of patients in septic shock. Septic shock results in disseminated intravascular coagulation and microvascular perfusion disorders, leading to hemolysis, rendering massive hemoglobin release [2]. Cell-free hemoglobin and its degradation component heme contribute to multiorgan failure and worse clinical outcomes of septic shock [3]. Haptoglobin helps reduce the toxic effects by binding cell-free hemoglobin and the protective role of haptoglobin in sepsis has been confirmed [4]. However, there is no evidence about the role of serum haptoglobin in septic shock. We therefore aimed to explore the association between serum haptoglobin and the prognosis of patients in septic shock.

The Medical Information Mart for Intensive Care III database was employed for analysis. A total of 501 septic shock patients receiving norepinephrine therapy with initial haptoglobin measurements were included (Additional file 1: Figure S1). Age, metastatic cancer, diabetes mellitus, mechanical ventilation and SOFA score were associated with 28-day mortality (Additional file 1: Table S1). The haptoglobin values for 28-day survivors were significantly greater than those for non-survivors (median value: 171 mg/dL vs. 133 mg/dL, p = 0.009, Fig. 1A). The haptoglobin level for septic shock patients was significantly greater than those for patients in non-sepsis (median value: 159 mg/dL vs. 124 mg/dL, p < 0.001, Additional file 1: Figure S2A). However, with the increasing of severity, the haptoglobin levels significantly decreased for septic shock patients (Additional file 1: Figure S2B, p < 0.001 for a trend). All the septic shock patients were categorized into three groups according to the tertiles of haptoglobin values. Higher haptoglobin level was associated with improved 28-day (p = 0.018), 90-day (p = 0.020), ICU (p = 0.002) and hospital (p = 0.003) mortality (Additional file 1: Table S2). However, the haptoglobin levels had no impact on the length of stay in ICU and hospital (Additional file 1: Table S2). Survival curve analysis revealed that the higher haptoglobin levels were associated with improved risk of 28-day (Log rank = 10.17, p = 0.006) and 90-day (Log rank = 10.7, p = 0.005) mortality (Fig. 1B). Haptoglobin levels, age, SOFA score, mechanical ventilation, metastatic cancer and diabetes mellitus were included in a multivariable Cox proportional hazard model to explore the association between haptoglobin levels and 28-day mortality. Compared with the lower tertile of haptoglobin level (< 95 mg/dL), the middle (hazard ratio: 0.737, p = 0.051) and upper tertile (hazard ratio: 0.653, p = 0.012) of haptoglobin were associated with lower risk of 28-day mortality (Additional file 1: Table S3). Other covariates including older age (hazard ratio: 1.785, p < 0.001), SOFA score (hazard ratio: 1.122, p < 0.001) and metastatic cancer (hazard ratio: 2.833, p < 0.001) were significantly associated with 28-day mortality.

Fig. 1
figure 1

Association between haptoglobin levels and the outcomes of patients with septic shock. A Distribution of haptoglobin between survivors and non-survivors based on 28-day mortality. B Kaplan–Meier curves showing the association between the haptoglobin levels and the 28-day and 90-day mortality

This study confirmed that increased haptoglobin levels were associated with an improved 28-day mortality in septic shock patients receiving norepinephrine therapy. In addition, the haptoglobin level of septic shock patients was significantly higher than those of non-sepsis patients, but it decreased with increasing of illness severity. Due to versatile physiological derangements in septic shock, whether haptoglobin serves as a marker or mediators remains unclear. A previous study has demonstrated that haptoglobin infused significantly improved the animals’ metabolic profile and reduced the severity of shock, as well as risk of death [5]. However, whether haptoglobin supplementation could be a potential therapeutic strategy for septic shock in clinical settings warrants further studies.

Availability of data and materials

The data that support the findings of this study are available from MIMIC website.

Abbreviations

ICU:

Intensive care unit

SOFA:

Sequential Organ Failure Assessment

IQR:

Interquartile range

SD:

Standard deviation

ARDS:

Acute respiratory distress syndrome

VV-ECMO:

Venovenous extracorporeal membrane oxygenation

References

  1. Graw JA, Hildebrandt P, Krannich A, Balzer F, Spies C, Francis RC, et al. The role of cell-free hemoglobin and haptoglobin in acute kidney injury in critically ill adults with ARDS and therapy with VV ECMO. Critical care (Lond, Engl). 2022;26(1):50. https://doi.org/10.1186/s13054-022-03894-5.

    Article  Google Scholar 

  2. Effenberger-Neidnicht K, Hartmann M. Mechanisms of hemolysis during sepsis. Inflammation. 2018;41(5):1569–81. https://doi.org/10.1007/s10753-018-0810-y.

    CAS  Article  PubMed  Google Scholar 

  3. Janz DR, Bastarache JA, Peterson JF, Sills G, Wickersham N, May AK, et al. Association between cell-free hemoglobin, acetaminophen, and mortality in patients with sepsis: an observational study. Crit Care Med. 2013;41(3):784–90. https://doi.org/10.1097/CCM.0b013e3182741a54.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Janz DR, Bastarache JA, Sills G, Wickersham N, May AK, Bernard GR, et al. Association between haptoglobin, hemopexin and mortality in adults with sepsis. Critical Care (London, England). 2013;17(6):R272. https://doi.org/10.1186/cc13108.

    Article  Google Scholar 

  5. Remy KE, Cortés-Puch I, Solomon SB, Sun J, Pockros BM, Feng J, et al. Haptoglobin improves shock, lung injury, and survival in canine pneumonia. JCI Insight. 2018. https://doi.org/10.1172/jci.insight.123013.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Authors and Affiliations

Authors

Contributions

PL and JZ designed the study. PY extracted clinical data. PL performed the statistical analysis. JN performed the visualization. PL and PY wrote the first draft of the manuscript. All authors revised the draft and approved the final version. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jiancang Zhou.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the Institutional Review Boards of the Massachusetts Institute of Technology (Cambridge, MA, USA) and the Beth Israel Deaconess Medical Center.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1. Table S1:

Baseline characteristics of 501 septic shock patients according to 28-day status. Table S2: Clinical outcomes of 501 septic shock patients according to haptoglobin levels. Table S3: Cox proportional hazard models exploring the association between haptoglobin and 28-day mortality. Figure S1: Flow chart: the inclusion of the study population. A total of 501 septic shock patients receiving norepinephrine therapy with initial haptoglobin measurements were included. Figure S2: Haptoglobin comparisons among study populations. (A) Initial haptpglobin levels between patients with septic shock and non-sepsis. (B) The haptoglobin levels in patient with septic shock against SOFA score categories.

Rights and permissions

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://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lan, P., Yu, P., Ni, J. et al. Higher serum haptoglobin levels were associated with improved outcomes of patients with septic shock. Crit Care 26, 131 (2022). https://doi.org/10.1186/s13054-022-04007-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13054-022-04007-y