Infection Management Guidelines and Outcomes in Severe Sepsis
Infection Management Guidelines and Outcomes in Severe Sepsis
This prospective study was designed as a longitudinal multicenter observational cohort study in 42 German hospitals to determine the time to AT, surgical source control and compliance with sepsis recommendations related to AT in patients with suspected severe sepsis or septic shock and its impact on 28-day, ICU, and hospital mortality. Participation of hospitals was voluntary but was restricted to hospitals involved in the primary care of sepsis patients and committed to participate in a quality improvement process. Hospitals without ICUs were excluded from this study. Potential study centers were recruited by regional and national research and quality improvement networks. The objectives of the study, inclusion and exclusion criteria, and the documentation procedures were discussed in several national meetings before the start of the study. The study was designed as a pragmatic study with a minimal case report form to allow for the participation of hospitals without research staff. This study served as a run-in study for a cluster-randomized trial assessing whether a multifaceted educational program accelerates the onset of AT and improves survival (Medical Education for Sepsis Source Control and Antibiotics MEDUSA, ClinicalTrials.gov Identifier NCT01187134).
Between December 2010 and April 2011, all consecutive adult patients treated in the ICU for proven or suspected infection with at least one new organ dysfunction related to the infection were eligible for inclusion. Organ dysfunctions were defined as follows: acute encephalopathy, thrombocytopenia defined as a platelet count <100,000/μl or a drop in platelet count >30% within 24 hours, arterial oxygen partial pressure <10 kPa (75 mmHg) when breathing room air or partial pressure of arterial oxygen/fraction of inspired oxygen ratio <33 kPa (<250 mmHg), renal dysfunction defined as oliguria (diuresis ≤0.5 ml/kg body weight/hour) despite adequate fluid resuscitation or an increase of serum creatinine more than twice the local reference value, metabolic acidosis with a base excess < −5 mmol/l or a serum lactate >1.5 times the local reference value, and arterial hypotension defined as systolic arterial blood pressure <90 mmHg or mean arterial blood pressure <70 mmHg for >1 hour despite adequate fluid loading or vasopressor therapy at any dosage to maintain higher blood pressures. Patients who received initial infection control measures for sepsis in another hospital and patients who did not receive full life-sustaining treatment were excluded. The study was reviewed and approved by the local ethics committees, which waived the need for informed consent because of the observational nature of the study (see Acknowledgements). The study was also approved by the local data protection boards.
Onset of severe sepsis or septic shock was defined as the time of first infection-related organ dysfunction as documented in the patient file. Patient location at time of onset of severe sepsis was defined as the patient location where the first infection-related organ dysfunction was documented. For patients who developed severe sepsis outside the ICU, this could be the prehospital setting, the emergency department, the hospital ward, or the operating room. Time and type of first AT as well as pre-existing AT were also recorded from the medical records. Any AT prescribed up to 24 hours before the onset of organ dysfunction but for the current infectious episode was considered previous AT. Perioperative antimicrobial prophylaxis was not regarded as specific AT for sepsis. Change of empirical AT was assessed on day 5. Initial AT was defined as inadequate if escalation had occurred within the first 5 days. For each patient, a blinded arbitrator assessed whether the initial AT complied with German guideline recommendations. Source control was defined as removal of an anatomic source of infection either by surgery or intervention (that is, computed tomography-guided drainage). Source control was defined as inadequate if the technical procedure was unsuccessful. Time to source control was obtained from the medical record. Other factors included serum lactate and procalcitonin at the time of onset of severe sepsis, number of blood culture sets taken, and ICU and hospital mortality. Severity of disease was assessed by the Simplified Acute Physiology Score II and the Sequential Organ Failure Assessment score on the day of sepsis diagnosis.
Data were collected by a web-based electronic case report form using OpenClinica® (OpenClinica, LLC, Waltham, MA, USA). Data integrity was confirmed by data checks within the database, resulting in queries to the investigator where applicable. Additionally, onset of infection-related organ dysfunction and subsequent AT were checked for plausibility by the MEDUSA study staff and discussed with the study center staff where applicable.
The primary endpoint was survival status at day 28 after onset of severe sepsis. Categorical data are expressed as absolute or relative frequencies; the chi-square or Fisher's exact test was used for inferential statistics. Continuous data are expressed as the median and interquartile range; the Mann–Whitney U test was used for inferential statistics. Missing data were not replaced by calculation. We divided patients according to the timing of antimicrobial treatment into the following groups: previous AT, 0 to 1 hours, 1 to 3 hours, 3 to 6 hours and >6 hours. Patients were grouped by time to source control into two groups: within 6 hours or >6 hours. Odds ratios (OR) with 95% confidence intervals (CI) for the risk of death within 28 days depending on time to AT or time to source control were calculated by univariate and multivariate logistic regression only in those patients were treatment was started after onset of organ dysfunction. In patients with sepsis, prior research has identified the initial Sequential Organ Failure Assessment score, age, and serum lactate as confounders for the risk of death. These parameters were therefore included in the multivariable logistic regression analysis to calculate adjusted ORs. In addition, indication for source control, escalation as well as de-escalation of empirical AT within 5 days, presence of community acquired infection, focus of infection, and state of blood culture withdrawal were only included into the final model if they were associated with 28-day mortality at P < 0.20. Goodness of fit was assessed by the c-statistic and the Hosmer-Lemeshow test.
Methods
Study Design
This prospective study was designed as a longitudinal multicenter observational cohort study in 42 German hospitals to determine the time to AT, surgical source control and compliance with sepsis recommendations related to AT in patients with suspected severe sepsis or septic shock and its impact on 28-day, ICU, and hospital mortality. Participation of hospitals was voluntary but was restricted to hospitals involved in the primary care of sepsis patients and committed to participate in a quality improvement process. Hospitals without ICUs were excluded from this study. Potential study centers were recruited by regional and national research and quality improvement networks. The objectives of the study, inclusion and exclusion criteria, and the documentation procedures were discussed in several national meetings before the start of the study. The study was designed as a pragmatic study with a minimal case report form to allow for the participation of hospitals without research staff. This study served as a run-in study for a cluster-randomized trial assessing whether a multifaceted educational program accelerates the onset of AT and improves survival (Medical Education for Sepsis Source Control and Antibiotics MEDUSA, ClinicalTrials.gov Identifier NCT01187134).
Patients
Between December 2010 and April 2011, all consecutive adult patients treated in the ICU for proven or suspected infection with at least one new organ dysfunction related to the infection were eligible for inclusion. Organ dysfunctions were defined as follows: acute encephalopathy, thrombocytopenia defined as a platelet count <100,000/μl or a drop in platelet count >30% within 24 hours, arterial oxygen partial pressure <10 kPa (75 mmHg) when breathing room air or partial pressure of arterial oxygen/fraction of inspired oxygen ratio <33 kPa (<250 mmHg), renal dysfunction defined as oliguria (diuresis ≤0.5 ml/kg body weight/hour) despite adequate fluid resuscitation or an increase of serum creatinine more than twice the local reference value, metabolic acidosis with a base excess < −5 mmol/l or a serum lactate >1.5 times the local reference value, and arterial hypotension defined as systolic arterial blood pressure <90 mmHg or mean arterial blood pressure <70 mmHg for >1 hour despite adequate fluid loading or vasopressor therapy at any dosage to maintain higher blood pressures. Patients who received initial infection control measures for sepsis in another hospital and patients who did not receive full life-sustaining treatment were excluded. The study was reviewed and approved by the local ethics committees, which waived the need for informed consent because of the observational nature of the study (see Acknowledgements). The study was also approved by the local data protection boards.
Data Collection
Onset of severe sepsis or septic shock was defined as the time of first infection-related organ dysfunction as documented in the patient file. Patient location at time of onset of severe sepsis was defined as the patient location where the first infection-related organ dysfunction was documented. For patients who developed severe sepsis outside the ICU, this could be the prehospital setting, the emergency department, the hospital ward, or the operating room. Time and type of first AT as well as pre-existing AT were also recorded from the medical records. Any AT prescribed up to 24 hours before the onset of organ dysfunction but for the current infectious episode was considered previous AT. Perioperative antimicrobial prophylaxis was not regarded as specific AT for sepsis. Change of empirical AT was assessed on day 5. Initial AT was defined as inadequate if escalation had occurred within the first 5 days. For each patient, a blinded arbitrator assessed whether the initial AT complied with German guideline recommendations. Source control was defined as removal of an anatomic source of infection either by surgery or intervention (that is, computed tomography-guided drainage). Source control was defined as inadequate if the technical procedure was unsuccessful. Time to source control was obtained from the medical record. Other factors included serum lactate and procalcitonin at the time of onset of severe sepsis, number of blood culture sets taken, and ICU and hospital mortality. Severity of disease was assessed by the Simplified Acute Physiology Score II and the Sequential Organ Failure Assessment score on the day of sepsis diagnosis.
Data were collected by a web-based electronic case report form using OpenClinica® (OpenClinica, LLC, Waltham, MA, USA). Data integrity was confirmed by data checks within the database, resulting in queries to the investigator where applicable. Additionally, onset of infection-related organ dysfunction and subsequent AT were checked for plausibility by the MEDUSA study staff and discussed with the study center staff where applicable.
Statistical Analysis
The primary endpoint was survival status at day 28 after onset of severe sepsis. Categorical data are expressed as absolute or relative frequencies; the chi-square or Fisher's exact test was used for inferential statistics. Continuous data are expressed as the median and interquartile range; the Mann–Whitney U test was used for inferential statistics. Missing data were not replaced by calculation. We divided patients according to the timing of antimicrobial treatment into the following groups: previous AT, 0 to 1 hours, 1 to 3 hours, 3 to 6 hours and >6 hours. Patients were grouped by time to source control into two groups: within 6 hours or >6 hours. Odds ratios (OR) with 95% confidence intervals (CI) for the risk of death within 28 days depending on time to AT or time to source control were calculated by univariate and multivariate logistic regression only in those patients were treatment was started after onset of organ dysfunction. In patients with sepsis, prior research has identified the initial Sequential Organ Failure Assessment score, age, and serum lactate as confounders for the risk of death. These parameters were therefore included in the multivariable logistic regression analysis to calculate adjusted ORs. In addition, indication for source control, escalation as well as de-escalation of empirical AT within 5 days, presence of community acquired infection, focus of infection, and state of blood culture withdrawal were only included into the final model if they were associated with 28-day mortality at P < 0.20. Goodness of fit was assessed by the c-statistic and the Hosmer-Lemeshow test.
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