We also recorded scores and clinical data for the included patients (Table 4). The median SOFA score was 13 in all patients and in the nonsurvivor group, and surviving patients demonstrated a median score of 12. The median values for SAPS II and SAPS 3 were 72 and 73, respectively (67 vs. 76 and 64 vs. 68 for survivors and nonsurvivors). A total of 16 patients were cannulated at referral hospitals; the majority of these patients (n = 11) did not survive. The differences between survivor and nonsurvivor groups for the admission SOFA score (p = 0.001), SAPS II (p < 0.001), and SAPS 3 (p = 0.001) were significant.
The median ventilation time was 483.5 hours (survivors 667.0 vs. nonsurvivors 331.0). The median value for pre-ECMO time was 6.4 days (4.6 vs. 7.8), and 57% of patients were successfully weaned from ECMO and stayed in the hospital post-ECMO for a median time of 17.8 days (40.1 vs. 0). The general LOS in the hospital was 3.5–233.4 days (median, 45.0 days; 9.7 vs. 8.7), and 53.2% of all patients were discharged from the ICU after a median time of 9.2 days; most of these discharged patients (95.7%) survived.
Fifty-eight patients (29 vs. 29) were referred from an external hospital where they stayed for a median time of 4.5 days. Sixteen patients were cannulated at a referral center, and 11 did not survive; 8 of them died because of severe abdominal sepsis.
Fifty patients received continuous renal replacement therapy (CRRT), and 32 (64%) of these patients died. The mortality in the group of patients who received CRRT was statistically significant (p = 0.001) higher as in the group without CRRT. We recorded 26 complications with an equal rate in both groups. Clotting or replacement was the most common complication (n = 16); four of five recorded patients with low flow during treatment were in the nonsurvivor group. There were three cases of coagulation disorder, and two nonsurvivors suffered from cerebral bleeding. Accidental cannula removal and ischemia of an extremity occurred once in each group.
A total of 218 pathogens were isolated (88 Gram positive, 80 Gram negative, and 50 others); of these, 43% (n = 94) were detected in the survivor group and 57% (n = 124) in the nonsurvivor group. Forty pathogens were detected in blood cultures, 104 in tracheal secretions, 17 in urine, and 57 in all other samples (Table 5).
Staphylococci were the most commonly isolated microbe in the entire cohort (n = 54). We detected 18 cases of Staphylococcus aureus, of which 22% were methicillin-resistant S. aureus (MRSA). All MRSA species were found in the nonsurvivor group.
Fungi were isolated with the second highest frequency (n = 37), and the majority of these cases were detected in the nonsurvivor group (n = 28). Seventeen samples from the nonsurvivor group tested positive for Enterococcus spp., with a total number of 29 positive samples. Enterobacter spp. (n = 25, 16 in the nonsurvivor group), Klebsiella pneumoniae (n = 17), and Pseudomonas aeruginosa (n = 15) demonstrated high incidences, particularly in tracheal secretions. In 36% of all tracheal secretions, we found typical cellular inflammatory infiltration, although there was no difference between the two groups.
As described in the Materials and Methods section, we categorized the infections into nine groups, with two subgroups each (Table 6). Forty-eight patients (54.5%) suffered from primary infections. Independent of primary infectious status, nosocomial infections were detected in 38 patients (43.2%). We recorded 102 infections, including 48 in the survivor group and 54 in ECMO patients who did not survive. Nosocomial infections (n = 42) demonstrated a higher incidence in survivors (n = 26), and primary infections (n = 60) were more common in the nonsurvivor group (n = 38). Respiratory infections presented the highest incidence (n = 69). A total of 69% of patients with nosocomial respiratory infections during ECD support survived, and 22 patients in the nonsurviving group suffered a primary respiratory infection. Abdominal infections had the second highest incidence (n = 14), and most of these cases were primary infections (n = 12). A total of 75% of patients with a primary infection were in the nonsurvivor group. Urinary tract and skin and tissue infections had incidences of five cases each. All patients (n = 3) with a primary urinary tract infection died, whereas both patients with a nosocomial infection survived. Four of five patients suffering from a skin or other tissue infection did not survive. There were three recorded nosocomial cardiovascular infections in the cohort, especially catheter-related infections, of which one patient survived. Wound infections (n = 1) and bone and joint infections (n = 1) were rare, and we did not record any cerebral infections in the cohort.
We analyzed 215 antibiotic treatment cycles, including 98 in the survivor group and 117 in the nonsurvivor group (Table 7). We recorded 112 first-line cycles, 71 second runs, 23 third runs, and 9 others.
Carbapenems (n = 60) were the most commonly prescribed antibiotic class, except in first-line therapy, where β-lactamase inhibitors were administered most often. β-Lactamase inhibitors were more common in the survivor group (n = 23), whereas carbapenems (n = 31), vancomycin (n = 10), and tigecycline (n = 3) were more commonly prescribed in the nonsurvivor group. All other antibiotics were given in equal amounts in both groups. Nine patients (10.2%) received more than three cycles of antibiotic treatment. One patient each was treated with tobramycin, tuberculostatics, and ceftazidime. Three patients received a further cycle with tigecycline and three with cotrimoxazole.
Age and ECMO indications, especially trauma, have been shown to be independent predictors of outcome.6,7 In addition, a SOFA score above 11 is associated with a very high mortality up to 95%.8 In our cohort, 45 of 88 patients (51.1%) with a median SOFA score of 13 survived. The results of the SAPS 2 and the SAPS 3 mortality predictions were similar to the SOFA results, but the SOFA score revealed differences in the severity of the disease in the survivor and nonsurvivor groups. The mean SOFA score and SD for the surviving group are 11 ± 3 SD and 14 ± 3 SD for the nonsurviving group.
Ventilation time and LOS were shorter in the nonsurvivor group, likely because of patient death, although we did not find a correlation between ventilation time and ECLS outcome. Previous studies have suggested that ECMO treatment increases the risk of nosocomial infection. Complications, especially bleeding, are considered a statistically significant predictor of mortality,9 although in our cohort, these complications played a minor role. Nosocomial infections had a higher incidence in survivors, which demonstrates the increasing risk of infections because of prolonged in-hospital stay.10
In the literature, infection rates in the ICU range from 13.9% to greater than 44%.10,11 In the this study, nosocomial infections, independent of the primary infectious status, were detected in 38 patients (43.2%). Forty-eight patients (54.5%) suffered from primary infections.
In 1995, Vincent et al. analyzed 1,417 ICUs in Europe to determine the incidence of pathogens and infections. Pneumonia and other lower respiratory infections (64.7%) were the most common diseases, followed by urinary tract infections (17.6%) and bloodstream infections (12%).10,12,13 In our ECMO cohort, we found similar incidences for respiratory infections (64.7%) but lower rates of urinary tract infections (5%). The incidence of urinary tract infections was too low to identify significance. Existing studies have found that these infections increase the morbidity of ICU patients but not their mortality.10,14 The literature states that a cause-and-effect relationship between organisms detected in blood cultures and the appearance of bloodstream infections cannot be proven, but the fact that almost every fifth microbe in our cohort was isolated from the blood suggests that ECMO patients carry a risk of developing bacteremia. This results in increased risk of provoking a systemic inflammatory response in the host in response to pathogens.15 Most positive blood cultures were observed in the nonsurvivor group, and further research is necessary to determine whether these ECMO patients have higher bacterial exposure than non-ECMO patients who do not survive the ICU. Therefore, a data comparison of bacteremia in blood cultures before and after ECMO treatment is necessary. Blood samples were not collected before ECMO cannulation. This represents an additional limitation of this study.
In general, our microbiological findings did not differ conspicuously from published incidences in the literature. Large-scale international studies show that S. aureus and other Staphylococcus spp. (38%) are the most common pathogens causing bloodstream infections, followed by Escherichia coli (24%). In addition, Candida spp. are often isolated in the ICU and can cause pneumonia and bloodstream infections with a mortality rate of up to 47%.10,16–18 Current figures state that the balance is shifting from multiresistant staphylococci to highly resistant classes of Acinetobacter spp. and P. aeruginosa,19 and the microbiological findings in our cohort support this trend.
The treatment of infected patients in our study was based on common national and international guidelines.20,21 β-Lactamase inhibitors are used as the initial therapy for respiratory infections.22 Imipenem is a first-line antibiotic for abdominal infections or second-line treatment option.23
Tigecycline was administered more often in the nonsurvivor group because it was used as a rescue treatment for severe infections caused by multidrug-resistant bacteria. Contemporary studies have shown that higher doses of antibiotics than advised may improve therapeutic outcome.24
Ferrer et al.25 demonstrated that every hour of delay between sepsis diagnosis to therapy reduces the survival rate, and the most feared complication of sepsis or septic shock resulting from an infection is multiorgan dysfunction.26 Extracorporeal membrane oxygenation enables oxygenation and decarboxylation, and the additional application of CRRT can be a safe and effective method27 and serve as a reference point for the severity of sepsis. Once present at high levels, microbiological colonization of the oxygenator is possible.28,29 Our results suggest that noncontrollable complications, rather than the infection itself, influence the success of ECLS.
It was previously reported that ECD changes the levels of drugs in the blood. For instance, lipophilic substances may become absorbed in the circuit.30 In 2012, Shekar et al.31 developed a sheet model to record the pharmacokinetics of study drugs during ECMO to serve as a basis for further research. In our analysis, we did not uncover evidence to support this hypothesis, although additional work is required to determine whether membranes and tube systems influence the pharmacokinetics of antiinfective drugs such that alterations in dosing are necessary.
Because of the various indications for ECMO support and the broad spectrum of patients included, it was difficult to obtain significant findings. Most infections and pathogens in our cohort had a low incidence (between n = 1 and n = 5). Significance could be calculated for all parameters, but p values were not meaningful because of the multiple use of parameters in some groups or, in part, a very low number of cases. For a better overview, p values are shown in a table, and those that are important and meaningful are commented on in the results.
An additional limitation is that we do not have data for the pre-ECMO incidence of bacteremia because blood samples were not collected before ECMO cannulation in every patient. Therefore, a data comparison of bacteremia in blood cultures before and after ECMO treatment could reveal the true risk of bloodstream infections.
Respiratory infections were the most common type of complication in our cohort. Moreover, the high incidence of pathogens in blood cultures suggests that the risk of developing a bloodstream infection in ECMO patients is high. However, there was no clear correlation between infections, ECMO therapy, and outcome, so we recommend focusing on clinical parameters to weigh therapeutic decision making for patients with ECLS. Regardless, an early and focused antiinfective regimen is important to avoid further complications of infections, such as dysfunction of more than one organ system.
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Keywords:Copyright © 2016 by the American Society for Artificial Internal Organs
extracorporeal life support (ECLS); extracorporeal membrane oxygenation (ECMO); infections; antibiotics; outcome