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Impact of Blood Product Transfusions on the Risk of ICU-Acquired Infections in Septic Shock*

Péju, Edwige MD1–3; Llitjos, Jean-François MD1–3; Charpentier, Julien MD1; François, Anne MD4; Marin, Nathalie PharmD1; Cariou, Alain MD, PhD1,2; Chiche, Jean-Daniel MD, PhD1–3; Mira, Jean-Paul MD, PhD1–3; Lambert, Jérôme MD, PhD2,5,6; Jamme, Matthieu MD7–9; Pène, Frédéric MD, PhD1–3

Author Information
doi: 10.1097/CCM.0000000000004887

Abstract

Sepsis is nowadays viewed as a dysregulated inflammatory response to infection followed by a compensatory anti-inflammatory response that may therefore sustain complex and profound immunosuppression (1). Thanks to improvements in the recognition and the management of the disorder, most patients now survive the primary infectious episode but become then exposed to ICU-acquired infectious and noninfectious complications that now account for the large majority of deaths in patients with septic shock (2–4). Sepsis patients exhibit a particular susceptibility toward secondary infections owing to multiple risk factors including demographics, underlying conditions such as immunosuppression and chronic organ dysfunctions, severity of the primary acute episode, requirements for organ supports, and invasive procedures (2). Instrumental and pharmacologic therapeutics imposed by the acute condition may harbor immunomodulatory properties and thereby contribute to the development of postaggressive immunosuppression and to altered response to superimposed infectious insults (5–7).

Transfusions of blood products are commonly administered to critically ill patients, for the substitution of underlying or ICU-acquired cytopenia and coagulation disorders (8–12). Regardless of transfusion indications, transfusions of RBCs and platelets have recently emerged as potential risk factors of hospital-acquired infections in various clinical settings including sepsis (13–16). Few studies have investigated the differential impact of the three main blood products (RBCs, platelets, and fresh frozen plasma) on the risk of ICU-acquired infections in critically ill patients. With regard to alternative concurrent risk factors of ICU-acquired infections, the own risk afforded by transfusions of various blood products remains questionable. We hypothesize that transfusion of blood products may contribute to the postaggressive immunosuppressive response and may thereby add to the risk of secondary infectious complications in critically ill septic patients. Taking advantage of a comprehensive medical database, we conducted a retrospective study in order to address the respective impact of transfusion of RBCs, platelets, and fresh frozen plasma on the further development of ICU-acquired infections in patients primarily managed for septic shock.

PATIENTS AND METHODS

Patients and Setting

We carried out a single-center 10-year (2008–2017) retrospective observational study in a 24-bed medical ICU. All consecutive adult patients (age > 18 yr), admitted for septic shock (i.e., diagnosed with septic shock within the first 48 hr of ICU admission), were included. Patients who were discharged or died within the first 48 hours were excluded to focus on a cohort at risk of ICU-acquired complications. The database and its relevant research investigations have been approved by the ethics committee of the French Intensive Care Society (reference CE SRLF, number 16-30). The need for signed informed consent was waived due to the retrospective observational purpose of the database.

Definitions

Septic shock was identified according to the definition of a clinically suspected or microbiologically proven infection, with acute circulatory failure requiring vasopressor support (17). Patients were considered immunocompromised if one or more of the following conditions was present: solid tumors with chemotherapy in the last 3 months or a progressive metastatic disease, hematologic malignancies at any stage, solid organ transplantation, HIV infection with or without acquired immunodeficiency syndrome, treatment with corticosteroids (> 3 mo at any dosage or ≥ 1 mg/kg for > 7 d), or other immunosuppressive drugs. ICU-acquired infections were defined as any new-onset of probable or definite infection that developed after 48 hours from ICU admission (2). Only the first episode of ICU-acquired infection was considered. The diagnostic work-up for ICU-acquired infection did not change during the study period.

Intended Management

Patients were treated in accordance with the guidelines of the Surviving Sepsis Campaign (18). IV broad-spectrum antibiotics were administered depending on the site of the infection, previous antibiotic treatments, and known colonization with antibiotic-resistant bacteria and deescalated to narrower spectrum after identification of the responsible pathogen. Source control measures, such as surgery or removal of infected devices, were applied when necessary. They were subjected to a strict sedation protocol based on the Richmond Agitation-Sedation Scale assessment every 3 hours and daily stop of sedatives whenever possible. End-of-life decisions to withhold or withdraw life support were taken collectively when maintenance or increase in life-sustaining therapies was considered as futile by all participants and that death would irremediably occur in a short-term manner. RBC and platelet transfusions were applied according to the National guidelines that were updated during the study period (19–21). Briefly, RBC transfusions were applied by single units to maintain a hemoglobin level of 7–9 g/dL. Platelet count thresholds for platelet transfusions were 10–20 G/L for prophylactic indications, 20–50 G/L for securing invasive procedures, and 50 G/L for treating severe bleeding. All blood products were leukodepleted. Although dependent on the availability, the primary platelet component derived from pooled donors, whereas single-donor apheresis concentrates were indicated in patients with posttransfusion refractoriness and definite proven alloimmunisation. Irradiated blood products were indicated in hematopoietic stem cell transplantation recipients and patients who had received potent antilymphoproliferative compounds.

Data Collection

The clinical data were extracted from the patient data management system (Clinisoft; GE Healthcare, Chicago, IL) and computed from the individual medical files: demographics (age, gender), comorbidities, severity at admission as assessed by the Simplified Acute Physiology Score 2 and Sequential Organ Failure Assessment scores (22,23), requirements for organ supports during the ICU stay (vasoactive drugs, renal replacement therapy, mechanical ventilation), number of days of exposure to invasive devices including endotracheal intubation, central venous catheters and dialysis catheters (the latter as a surrogate of exposure to renal replacement therapy), arterial catheters and urinary catheters, characteristics of ICU-acquired infections (source, microbiological documentation), and in-ICU vital status. The following data related to transfusion episodes were collected: type of blood component (RBCs, platelets, fresh frozen plasma), indications, day of administration, pretransfusion hemoglobin level, platelet count and prothrombin time as appropriate, and cumulative number of units. The storage time of packed RBCs was obtained from the French blood bank. Only transfusions received during the ICU stay were collected. Transfusions were collected up to 24 hours before the diagnosis of ICU-acquired infection and otherwise collected until ICU discharge.

Statistical Analysis

Continuous variables were expressed as median (interquartile range), and categorical variables as numbers (percentages) and compared by Kruskal-Wallis, Pearson’s chi-square, or Fisher exact test as appropriate. Determinants of ICU-acquired infections were analyzed on the subset of patients still alive in ICU after 48 hours through a competing risk framework, with discharge alive and death in ICU as competing events (24). We investigated the association between ICU-acquired infection and RBC, platelet, or plasma transfusion in a multivariate analysis using a time-dependent cause-specific Cox proportional hazard model. Covariates entered into the multivariate models were selected from the univariate analysis and from the common knowledge of relevant risk factors of ICU-acquired infections including exposure to invasive devices. Because blood products transfusions and exposure to invasive devices occurred throughout the ICU stay, we considered them as time-dependent covariates. Transfusions were treated as binary or log-linear continuous covariates. Missing values of covariates in the multivariate model were handled by multiple imputations with chained equations, based on M equals to 30 imputed complete datasets, with an estimated hazard ratio (HR) based on the average value of the regression coefficients (25). All analyses were carried out using R 3.1.1 (R foundation for Statistical Computing Vienna, Austria). All tests were two sided, with p values of 0.05 or less denoting statistical significance.

RESULTS

Patients

Among the 1,152 patients who were admitted for septic shock over the 10-year period, 143 (12%) and 116 (10%) were discharged or died within 48 hours, respectively (Fig. 1). The remaining 893 48-hour survivors accounted for the cohort of interest. At the time of admission, 325 patients (36%) were deemed previously immunocompromised. The lung was the source of primary infection in half of patients. Of note, 19% of patients had undergone surgical procedures for the source control. Although all patients required vasopressors by definition, most of them (n = 768; 86%) also required invasive mechanical ventilation, and 378 patients (42%) required renal replacement therapy. The incidence of ICU-acquired infections was 28%.

Figure 1.
Figure 1.:
Flow-chart of the study. FFP = fresh frozen plasma.

Characteristics of ICU-Acquired Infections

The characteristics of patients without and with ICU-acquired infections are displayed in the Table 1. Time from admission to first ICU-acquired infection was 9 days (7–13 d). ICU-acquired infections were distributed into pulmonary (n = 144; 57%) and nonpulmonary infections (n = 109; 43%) and were microbiologically documented in 85% of episodes (Supplemental Table 1, Supplemental Digital Content 1, http://links.lww.com/CCM/G176). Responsible pathogens were mostly Gram-negative bacteria, and 9% of isolates were multidrug resistant. ICU-acquired infections significantly worsened the clinical condition, resulting in shock recurrence in 120 patients (47.4%). The first ICU-acquired infection was followed by subsequent episodes in 37% of patients. Finally, patients with ICU-acquired infections exhibited an in-ICU mortality rate of 47%.

TABLE 1. - Characteristics and Outcome of Patients Without and With ICU-Acquired Infections
Variables No ICU-AI (n = 640) ICU-AI (n = 253) p
Age (yr) 69 (57–78) 67 (57–77) 0.57
Male gender 392 (61) 177 (70) 0.01
Immunosuppression 235 (37) 90 (36) 0.75
Severity on ICU admission
 Simplified Acute Physiology Score 2 (points) 64 (51–81) 73 (57–87) < 0.001
 Sequential Organ Failure Assessment score (points) 9 (6–12) 10 (6–13) 0.04
Source of the primary infection
 Lung 292 (46) 154 (61) < 0.001
 Digestive 103 (16) 43 (17) 0.74
 Urinary 91 (14) 12 (5) < 0.001
 Others 154 (24) 44 (17) 0.03
Microbiological documentation 458 (72) 164 (65) 0.05
 Bacteremia 218 (34) 69 (27) 0.05
 Microorganisms
  Gram-negative bacteria 288 (45) 86 (34) 0.002
  Gram-positive bacteria 159 (25) 69 (27) 0.45
  Fungi 11 (2) 9 (4) 0.09
ICU management
 Invasive mechanical ventilation 520 (81) 248 (98) < 0.001
 Renal replacement therapy 220 (34) 158 (62) < 0.001
 Surgical source control 127 (20) 45 (18) 0.48
Outcomes
 Duration of mechanical ventilation (d) 4 (2–8) 16 (9–26) < 0.001
 ICU mortality 122 (19) 119 (47) < 0.001
AI = acquired infection.
Variables are expressed as median (interquartile range) or number (percentage) and compared by the Kruskal-Wallis, the Pearson’s χ2, or the Fisher exact test as appropriate.

Transfusion Practices

Transfusions were commonly applied in 48-hour survivors, since 373 patients (42%), 181 patients (20%), and 158 patients (18%) received RBC, platelet, and plasma transfusions, respectively. Transfusion practices in patients without and with subsequent ICU-acquired infections are displayed in the Table 2. Patients who experienced ICU-acquired infections were more likely to have previously received RBC (52% vs 38%), platelet (28% vs 17%), or plasma (26% vs 14%) transfusions than patients who remained free of secondary infection throughout the ICU stay. In patients without ICU-acquired infections, almost all transfusions (93%) had been administered within the first 10 days following the ICU admission. Of note, increased requirements of transfusions in patients with subsequent ICU-acquired infections were seemingly related to bleeding episodes.

TABLE 2. - Transfusions of Blood Products in Patients Without and With ICU-Acquired Infections
Variables No ICU-AI (n = 640) ICU-AI (n = 253) p
RBC transfusion 242 (38) 131 (52) < 0.001
 Number of RBC units 2 (2–4) 3 (2–4) 0.07
 Time of storage, d 18 (15–23) 17 (15–22) 0.29
 Indications (per unit) 0.009
  Acute bleeding 192 (22) 153 (28)
  Euvolemic anemia 669 (78) 384 (72)
 Pretransfusion hemoglobin level, g/dL 7.6 (7.1–8.3) 7.7 (7.2–8.3) 0.50
Platelet transfusion 109 (17) 72 (28) < 0.001
 Number of platelet units 2 (1–3) 2 (1–3) 0.48
 Indications (per episode) < 0.001
  Prophylactic 92 (29) 74 (20)
  Therapeutic 49 (16) 176 (46)
  Invasive procedure 175 (55) 129 (34)
 Pretransfusion platelet count, G/L 21 (13–31) 30 (21–40) < 0.001
FFP transfusion 92 (14) 66 (26) < 0.001
 Number of FFP units 4 (2–6) 4 (3–7) 0.63
 Indications (per episode)
  Coagulopathy 527 (100) 389 (100) 1
 Pretransfusion prothrombin time, % 39 (27–47) 37 (31–45) 0.93
AI = acquired infection, FFP = fresh frozen plasma.
Variables are expressed as median (interquartile range) or number (percentage) and compared by Kruskal-Wallis’ test, Pearson’s χ2, or Fisher exact test as appropriate.

Determinants of ICU-Acquired Infections

The occurrence of ICU-acquired infections was associated with gender, primary pulmonary source of infection, severity at admission, and the extent of organ failures (invasive mechanical ventilation, renal replacement therapy). Patients who received all-type blood products or specifically RBCs tended to a higher although not significant occurrence rate of ICU-acquired infections. The cumulative occurrence rate of ICU-acquired infections was significantly increased in patients who received platelet and fresh frozen plasma transfusions (Fig. 2; and Supplemental Fig. 1, http://links.lww.com/CCM/G178 [legend, http://links.lww.com/CCM/G179]). In order to address the independent predictors of ICU-acquired infections, we carried out a multivariate analysis through a time-dependent cause-specific Cox model. After adjustment, platelet transfusion (cause-specific HR [CSH] = 1.55 [1.09–2.20]; p = 0.01) and fresh frozen plasma transfusion (CSH = 1.38 [0.98–1.92]; p = 0.05) were associated with increased risk of ICU-acquired infections when treated as binary variables (Table 3). Cumulative amounts of blood products were not associated with significant additional hazards of ICU-acquired infection (Table 3). Similar results were obtained in sensitivity analysis after exclusion of 38 patients with ICU-acquired infection yet without microbiological documentation (Supplemental Table 2, Supplemental Digital Content 1, http://links.lww.com/CCM/G177) and after extending the time-lag between transfusion and ICU-acquired infection to 48 hours (data not shown).

TABLE 3. - Determinants of ICU-Acquired Infections: Cause-Specific Cox Regression Multivariate Analysis
Variables Cause-Specific Hazard Ratio 95% CI p
First model applied to the first episode of transfusion
 Male gender 1.30 0.99–1.70 0.06
 Admission SAPS 2 (per 10-point) 1.05 0.98–1.13 0.13
 Immunodepression status 0.95 0.72–1.26 0.74
 Lung primary infection 1.48 1.12–1.96 0.006
 Exposure to invasive devicesa
  Mechanical ventilation 1.43 0.95–2.15 0.08
  Central venous catheter 1.13 0.72–1.77 0.59
  Dialysis catheter 1.06 0.76–1.47 0.72
  Arterial catheter 0.93 0.62–1.41 0.75
  Urinary catheter 1.12 0.74–1.68 0.60
 Any transfusiona
  RBC 0.88 0.65–1.19 0.41
  Platelet 1.55 1.09–2.20 0.01
  Fresh frozen plasma 1.38 0.98–1.92 0.05
Second model applied to amounts of blood products
 Male gender 1.30 0.99–1.72 0.06
 Admission SAPS 2 (per 10-point) 1.05 0.97–1.13 0.19
 Immunodepression status 1.03 0.78–1.35 0.84
 Lung primary infection 1.41 1.07–1.87 0.01
 Exposure to invasive devicesa
  Mechanical ventilation 1.48 0.98–2.23 0.06
  Central venous catheter 1.10 0.69–1.73 0.69
  Dialysis catheter 1.14 0.83–1.55 0.42
  Arterial catheter 0.97 0.64–1.48 0.75
  Urinary catheter 1.09 0.72–1.65 0.66
 Any transfusiona
  RBC 1.03 0.97–1.13 0.19
  Platelet 1.01 0.95–1.08 0.75
  Fresh frozen plasma 1.02 0.98–1.06 0.28
SAPS 2 = Simplified Acute Physiology Score 2.
aExposures to invasive mechanical ventilation, central venous catheter, arterial catheter, dialysis catheter, urinary catheter, and transfusions of blood products were treated as time-dependent covariates.

Figure 2.
Figure 2.:
Cumulative occurrence rate of ICU-acquired infections in transfused and nontransfused patients. The cumulative occurrence rate of ICU-acquired infections is reported in 48 hr survivors. FFP = fresh frozen plasma.

DISCUSSION

Septic shock patients harbor a high risk of ICU-acquired infections when recovering from the primary infectious insult, in relation with multiple risk factors related to the underlying condition and to interventional procedures and pharmacological therapeutics likely to impact on systemic and local defense mechanisms (5–7). Our results suggest a causal association between one single episode of platelet or plasma transfusion and increased susceptibility to ICU-acquired infection, albeit without additional risk by increased amounts of blood products.

The link between RBC and platelet transfusions and susceptibility to secondary infections has already been reported in several prospective and retrospective studies. In a meta-analysis of prospective randomized studies in various clinical settings, restrictive RBC transfusion strategies were associated with decreased occurrence rate of hospital-acquired infections (14). Accordingly, a number of observational studies retrieved independent associations between RBC transfusions and ICU-acquired infections in critically ill patients, including trauma and sepsis patients (15,16,26–31). Similar findings were reported in sepsis patients by Dupuis et al (15,16) both in a meta-analysis of observational studies in sepsis patients and in a large retrospective study (18,19). In a prospective observational multicenter study in Netherlands, Engele et al (26) found that platelet transfusion was an independent risk factor for ICU-acquired infections (odds ratio [OR], 1.46; 95% CI [1.18–1.81]). This correlation has been also highlighted by Aubron et al (27) in a well-conducted study including 18,965 critically ill patients (OR, 2.56; 95% CI [1.98–3.31]). We also identified for the first time the potential impact of plasma transfusion on ICU-acquired infections in critically ill adult patients, as it was already suggested in PICU (32).

How may transfusions impact on the further development of infections in patient recovering from septic shock? A first explanation is that transfusions may simply behave as bystanders and thereby represent a surrogate marker of persistent underlying pathogenic processes poorly detected by alternative variables. Although most ICU-acquired infectious episodes (85%) were microbiologically documented, we cannot exclude that some transfusion-induced side effects such as chills and fever reactions or transfusion-related acute lung injury could be misdiagnosed as infections. Platelets are known for playing a role in innate immunity, including activation and rolling of leucocytes and production of proinflammatory cytokines, and may thereby exacerbate the inflammatory response at the site of infection (33). An alternative and more causal explanation lies in immunomodulatory properties of blood products, so-called “transfusion-related immunomodulation”, which may alter the defense mechanisms against superimposed infectious insults (34). Indeed stored RBCs and platelets may exhibit physicochemical changes and release various cell components and cytokines likely to modulate the functions of antigen-presenting cells and lymphocytes toward immunosuppressive phenotypes (35–37). The defrosting process of plasma may induce the lysis of residual leukocytes and the release of intracellular bioactive substances (32). As a result, stored RBCs and platelets infused to animals make them more susceptible to infections (38). Although storage lesions are dependent on storage time, the age of RBCs has little impact in clinical practice, and three large randomized studies carried out in critically ill adults, and children did not demonstrate any harmful effects of old blood (> 14–21 d of storage) on relevant clinical outcomes such as mortality, deterioration of organ failures, and occurrence rate of ICU-acquired infections (39–41). The platelet storage time is missing in our study but seems to have little impact on the outcomes of critically ill patients (42).

This study pleads for careful consideration of blood products administration in critically ill patients. Since the pioneer study by Hebert et al (43), multiple interventional studies have demonstrated the feasibility and safety of low hemoglobin thresholds (7–8 g/dL) for RBC transfusions in critically ill patients (44), including patients with septic shock at least when hemodynamically stable (18,45). It is noteworthy that such restrictive RBC transfusion policy was not associated with an increased risk of ICU-acquired infections in the present study, in contrast to the administration of platelet and plasma components driven by less definite transfusion policies in the ICU. The guidelines from the French Intensive Care Society proposed applying low prophylactic transfusion thresholds to maintain platelet counts above 10–20 G/L in patients with hypoproliferative thrombocytopenia, derived from studies performed in hematology patients (46). However, platelet transfusion thresholds appear much higher for patients with peripheral thrombocytopenia in perioperative settings (12). Finally, indications of plasma transfusions for the correction of hemostasis remain elusive in the absence of ongoing bleeding.

This study has several limitations, mostly related to its retrospective design, thereby unable to establish a definite causality link despite comprehensive time-dependent analysis. Whether the transfusion policy to prevent bleeding could outweigh the risk of infection could not be investigated herein and would require prospective interventional trials. When using the time-dependent Cox regression model, we assumed the log-linearity of covariates, even though the cumulative number of blood products might not necessarily have a linear effect on the risk of ICU-acquired infection. Although receipt of transfusions was collected up to 24 hours before the diagnosis of ICU-acquired infection, we cannot exclude that some transfusions were related to an ongoing infectious process albeit still unrecognized. This was a single-center study with a case-mix depending in part of referring wards of the hospital, hence with a high prevalence of immunocompromised patients with malignancies. However, we observed that the underlying immune status would not impact on the occurrence rate of ICU-acquired infections (3). In addition, we took into account all blood products received from ICU admission until the day before the onset of ICU-acquired infection, but we did not collect the transfusions received prior to ICU admission.

CONCLUSIONS

Administration of blood products is common in the course of septic shock. Platelet and plasma transfusions are associated with an increased risk of ICU-acquired infections. Although restrictive RBC transfusion policies are already largely implemented in critically ill patients, our findings urge on prospective interventional trials to address both benefits and harms of platelet and plasma transfusions.

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Keywords:

immunosuppression; nosocomial infection; septic shock; transfusion

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