Serious adverse events in academic critical care research

Challenge: Variable definition and reporting of serious adverse events

Ambiguous terminology leads to difficulty in defining serious adverse events in critical care research; this in turn creates variable thresholds for reporting such events across trials, as well as across centres within a trial.4 In some jurisdictions, such as Australia, the accepted definition requires investigators to consider including “important medical events that might not be immediately life-threatening or result in death or hospitalisation but might jeopardise the patient or might require intervention to prevent one of the other [adverse] outcomes.”5

Regarding the definition of serious adverse events, death, life-threatening complications and prolonged hospital stay are common, and these are frequently used as prespecified efficacy or safety outcomes reported to an independent data-monitoring committee. For example, in a trial testing corticosteroids for head injury, death was an expected complication and was reported as the primary outcome rather than as a serious adverse event.6 Regarding the reporting of a serious adverse event, the Guideline for Good Clinical Practice1 requires reporting of adverse events that are “serious and unexpected.” It is unclear whether the term “unexpected” means “not anticipated in this patient” or “occurring at a very low baseline prevalence rate.”

Challenge: Interpretation of serious adverse events in light of the natural history of critical illness

Reporting events considered to be unusual in the natural history of a critical illness (e.g., grand mal seizures occurring in a patient with septic shock) may be important. However, patients may have adverse events as a consequence of the condition requiring admission to the ICU or as a consequence of treatments that are unrelated to the trial intervention. For example, a trauma patient enrolled in a trial of intensive insulin therapy7 might experience tension pneumothorax secondary to chest-wall injury, transfusion-related acute lung injury secondary to initial resuscitation8 and nosocomial pneumonia developing over the course of prolonged mechanical ventilation.9 All 3 events might appear to satisfy the criteria for reportable serious adverse events, but all are most likely due to the primary disease process or its treatment. As such, none of the events is definitively related to the study drug.

Challenge: Attribution of serious adverse events to the drug being tested

Some critically ill trial patients experience adverse events that could be attributed to the study drug. However, it is often difficult to know in real time whether such an event is related to the study drug. For example, bleeding is a common complication among critically ill patients, with 10% of medical–surgical patients suffering major bleeding10 regardless of prophylactic heparin use.11 Therefore, in a trial testing 2 types of heparin thromboprophylaxis, bleeding is expected and may be difficult to attribute to the drugs being compared when the trial is in progress.12 In contrast, hypoglycemia developing during a trial of intensive insulin therapy would likely be attributed to the intensive insulin therapy, except perhaps in a patient in whom severe hepatic failure develops.

Challenge: Attribution of death to serious adverse events

Some critically ill trial patients experience serious adverse events that precede death. Because critically ill patients are at high risk of death regardless of their trial enrolment, it is often difficult to attribute death to a serious adverse event. For example, if a bleeding episode precedes death in a trial testing 2 types of heparin thromboprophylaxis, the label “fatal bleeding” is nonspecific. There are 2 possibilities for a patient who dies while experiencing bleeding. Most such patients die with bleeding (e.g., a patient with ongoing melena and concurrent renal failure who experiences hyperkalemic cardiac arrest), although some die because of bleeding (e.g., a patient who dies from hypovolemic shock due to massive uncontrolled upper gastrointestinal hemorrhage).

Challenge: Interpretation of serious adverse events by research ethics boards

Meaningful interpretation of serious adverse events as trials unfold is difficult for local research ethics boards.14 These boards often review such events without specific clinical expertise or knowledge of recent studies in the field, without data on local or global enrolment or distribution of serious adverse events across centres or arms of the trial (in blinded trials), and without knowledge of other outcomes (which are crucial to the consideration of potential harm in light of potential benefit).

Discussion

From the clinical perspective, adverse events are the rule rather than the exception in critically ill patients. From the research perspective, faithfully recording serious adverse events is crucial to ensuring that all relevant harms are documented. Accordingly, the call for more transparent reporting of harms in randomized trials distinguishes between studies enrolling participants with non-life-threatening conditions (for whom any harm may be important) and other populations (for whom serious and life-threatening adverse events are the most important).15

Trials involving vulnerable populations need research oversight to ensure that patients' safety, rights and well-being are protected, and to ensure public trust.16 However, overinclusive attempts to identify and definitively interpret serious adverse events in real time during trials involving critically ill patients can create an inappropriate sense of alarm or, worse, a facade of safety. The need for clarity and context-specific reporting of serious adverse events in academic trials of drugs commonly used in critical care reflects a pressing need to avoid spending scarce peer-review resources on paperwork that increases neither the validity nor the safety of the research.

The challenges and solutions we have outlined may be relevant for studies in other settings. Clearly, context is important; thus, the interpretation of serious adverse events will differ for trials of primary prevention involving healthy citizens, for trials in the outpatient clinic setting and for trials involving hospital inpatients. Our proposed solutions for academic critical care trials of drugs in common use focus on interpreting serious adverse events in light of the natural history of critical illness, its complications and management; the designated primary, secondary, and tertiary trial outcomes; the expected frequencies of adverse events; the number of patients enrolled in both arms of the trial in each centre and overall; and whether the existing research oversight evaluates benefits in light of harms and is meaningful and actionable.