Evaluation of Risk Factors for a Fulminant Clostridium Difficile Infection After Cardiac Surgery

A Single-center, Retrospective Cohort Study

Maximilian Vondran; Senta Schack; Jens Garbade; Christian Binner; Meinhard Mende; Ardawan Julian Rastan; Michael Andrew Borger; Thomas Schroeter

Disclosures

BMC Anesthesiol. 2018;18(133) 

In This Article

Discussion

Post-operative diarrhea is a common, underestimated complication after surgery that can be caused by CD. While the majority of CDI cases are harmless, in 8–16% a fulminant CDI with severe complications occurs[12–14] that significantly increases mortality after surgical procedures.[6] Little data exists on the incidence and risk factors for the development of a CDI after cardiac surgery, especially for fulminant CDI. The present study is the first to address fulminant CDI after cardiac surgery. The findings of this study can be summarized as follows: 12.2% of the CDI cases in our cohort were fulminant; fulminant CDI increases 30-day and overall all-cause mortality significantly compared with bland CDI; independent risk factors for a fulminant CDI are pre-operative diabetes mellitus type 2, pre-operative ventilation, cross-clamp time > 130 min, the utilization of more than 8 RBC units or more than 5 FFP units.

Incidence

The incidence of post-operative CDI varies in the current literature and often depends on the surgery performed, decade of the study, and the study design. It ranges from 0.3 to 8.4%.[5] The most recent data from studies of cardiac surgery dealing with the topic of post-surgical CDI show very low incidences, ranging between 0.3–0.79%, with a tremendous increase worldwide a few years after the beginning of the new millennium.[5,8,9] Our cohort seems to reflect more the data of a real-world cohort, with an overall incidence of 3.0%. However, Crabtree et al. reported that in June 2003 their highest incidence was 8.89%.[5] Since 2003, not only an increase in the incidence of CDI but also the severity of the disease has been reported worldwide.[15] In Germany, an analysis of the discharge diagnoses of the years 2000–2004 showed a clear increase in CDI from 7 to 39 cases per 100,000 inpatients; between 2004 and 2006 it doubled again.[16,17] In the context of clusters that first appeared in North America and then in Europe, including Germany, a new epidemic strain with particular virulence has been reported.[15,18]

Mortality

Current data on 30-day mortality in patients with CDI vary between 2.5 and 26%,[8,9,19,20] depending on the study population. Thus, a 30-day mortality rate of 26% reported by Musa et al. was based on a collective of only 27 ICU patients after cardiothoracic surgery.[20] Keshavamurthy and colleagues published an in-hospital mortality rate of 11% in 2014 for a cohort of 145 patients who underwent cardiac surgery at the Cleveland Clinic.[9] Flagg et al. analyzed 349,122 patients after cardiac surgery from 2004 to 2008 from the Nationwide Inpatient Sample database. The in-hospital mortality of their cohort of CDI patients was 12%.[8] Both studies reported a significantly higher 30-day mortality for patients with CDI after cardiac surgery, whereas Crabtree et al. found similar survival rates between different surgical groups.[5] Lemaire et al. showed in their study that with a post-operative CDI, the risk of in-hospital mortality nearly doubles.[10] In the present study, a 30-day mortality of 4.0% was observed for the group with bland CDI and 21.6% for the group with fulminant disease. At this point, it should be emphasized how clearly the 30-day mortality of the patients with fulminant disease is increased compared with those with bland CDI. With more than 20% mortality in the first 30 days, a fulminant CDI must be viewed as a highly life-threatening condition.

Reports of overall or long-term mortality following a CDI have yielded various results. A retrospective study by Morrison et al. reported an overall mortality rate of 5%, whereas Keshavamurthy found a 3-year mortality in their CDI cohort as high as 48%.[9,21] Crabtree et al. described an overall mortality of 6% for a cohort of post-operative CDI patients, although the overall mortality rate for the subgroup with fulminant CDI was 30%.[5] Further studies reported mortality rates for the group of patients with fulminant CDI of up to 50% and up to 80% in cases requiring emergency colectomy.[21,22] In the present study we observed an overall mortality in the collective with bland CDI of 22.8%. In contrast, in the group with a fulminant course, the overall mortality was 63.4%. Moreover, most of the deaths occurred in the first 3 months after cardiac surgery, whether the CDI was fulminant or bland.

Risk Factors for the Development of a Fulminant CDI

Cardiopulmonary comorbidities have been repeatedly documented in the literature as risk factors for the development of fulminant CDI.[23,24] The present work underpins these observations. Reduced LVEF and elevated NYHA functional class are dependent risk factors and pre-operative mechanical ventilation is an independent risk factor for the development of a fulminant CDI. Likewise, prior cardiac surgery in the present study was a dependent risk factor for the development of a fulminant CDI. Thus, both idiopathic and iatrogenic cardiopulmonary factors create a vulnerable niche for severe CDI.[25]

Also worthy of mention is the relationship between severe disease progression and the indication for surgery. Patients admitted for emergency procedures showed significantly more fulminant events than patients undergoing elective surgery. This concurs with the previously published studies and suggests that the toxicity of the pathogen in already pre-operatively weakened patients with a higher rate of circulatory instability results in far graver outcomes than in elective patients with a lower peri-operative stress response.[10]

As mentioned above, pre-operative mechanical ventilation is a further independent risk factor for the development of a fulminant CDI. In general, a patient who has been ventilated before cardiac surgery is rarely in good clinical condition. Here, the body is exposed to a high degree of stress even before the surgical procedure. Furthermore, ventilation itself can contribute additional immunosuppression,[26] which may support a fulminant CDI.

The peri-operative administration of blood products has been frequently associated in the literature with an aggravation of the course of the disease and with modulation of recipients' immune function.[5,20,27] The present work underlines these observations: peri-operative administration of more than eight RBC units or five FFP units increased the risk of a fulminant course by two to three times. A controversial issue here is whether the administration of blood products is a true, aggravating factor or rather a harbinger of the increasing severity of the disease.

The available data on the influence of peri-operative MCAD on the incidence and severity of CDI is very scarce,[20] but the use of these devices seems to have an effect on outcome.[28] The present study shows an influence of the post-operative use of a MCAD on the course of a CDI. In the vast majority of our cases, this was the implantation of an IABP in hemodynamically unstable patients. The risk of developing a fulminant CDI was increased in patients who were treated with a MCAD. Importantly, a previous study has shown that up to 97% of implanted IABP devices may compromise the blood flow of the visceral arteries by overlapping them.[29] About 25% of cases become clinically symptomatic, show intestinal ischemia, and/or have to be treated by laparotomy. In addition to the existing infection and hemodynamic instability, the gastrointestinal tract is especially vulnerable due to compression of visceral arteries by the IABP and consequently reduced perfusion.[30] This is a possible explanation for the significantly increased rate of gastrointestinal complications and visceral surgical interventions in the collective of patients treated with a MCAD.

The duration of surgery and CPB were found to be dependent risk factors, and the cross-clamp time was an independent risk factor for the development of fulminant CDI. Crabtree et al. were also able to demonstrate the influence of prolonged surgical duration with prolonged CPB time on the development of CDI and protraction of underlying disease.[5] The present study also shows that in patients who underwent surgery through a minimally invasive approach, the risk of developing fulminant versus bland CDI was reduced. Thus, minimally invasive surgery was a univariate protective predictor against a fulminant CDI. The clear advantage of minimally invasive surgery is the less traumatic procedure due to smaller wounds and less peri-operative blood loss as well as shorter length of stay on the ICU or intermediate care unit. The present study demonstrated that the length of stay in intensive and intermediate care were dependent risk factors for developing a fulminant CDI, which was also described in previous investigations.[5,20,31] These results should be interpreted with caution, however, as causality of the relationships may be open to discussion. Therefore, the statistical categorization between cause and effect of the phenomenon regarding the CDI and the ICU/intermediate care unit stay is difficult. In summary, a prolonged hospital stay is most likely both a risk factor for the development of a fulminant CDI and a consequence of it.

Limitations

In the present work, no ribotyping of the CD strains was performed; therefore, possible influences of hypervirulent strains could not be independently evaluated. Due to the retrospective study design, it was no longer possible to determine leukocyte counts, lactate values, and creatinine levels of the patients at the time of infection. However, these parameters were frequently used in the literature to classify the severity of CDI.[32] In this work, only the development of gastrointestinal complications and the need for laparotomy could be used; thus, such a classification was not possible. The content of an RBC, FFP and platelet concentrate unit varies and was not individually recorded in our work, as only the administered units have been documented. The volume of one unit was appx. 250 ml. Furthermore, we did not have sufficient information about the other hospitals or nursing homes from which the patients were transferred who were admitted to the Heart Center Leipzig. The retrospective study design also prohibited us from clearly reconstructing in all patients whether antibiotics had already been administered pre-operatively or not. It is well known that antibiotics cause CDI, but they are also components of optimal therapy of fulminant CDI. Because of this and the unstable data, we did not include antibiotic therapy as such in our risk stratification model. Finally, the relapse rate was not determined in the present study. There are indications in the literature that more than one third of CDI patients experience at least one relapse.[14]

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