Statin research in critical illness: hampered by poor trial design?

Statin therapy may prevent an excessive inflammatory response after cardiopulmonary bypass for cardiac surgery. In a recent issue of Critical Care, Morgan and colleagues present data from a well-conducted systematic review and meta-analysis of randomised controlled trials using inflammatory markers as primary outcome measure. They find that pre-operative statin therapy, compared with placebo, may reduce various post-operative markers of systemic inflammation (IL-6, IL-8, C-reactive protein, tumour necrosis factor-alpha). Their ability to make definitive conclusions is limited, however, by the suboptimal methodological quality of the primary studies. Their review suggests that ICU researchers should focus on developing valid surrogate markers and use these to accurately describe the mechanisms and effectiveness of novel therapies before proceeding to large pragmatic trials using mortality as primary outcome.     

Is the Scope of Practice endangered by lack of vision?

When The Scope of Professional Practice was published in 1992 it was hailed as one of the UKCC's most influential documents, with the potential to revolutionize nursing by extending the boundaries of practice. Is the Scope being implemented as originally visualised--or it is going to fail because of a lack of vision and imagination?     

Prophylactic anticoagulation with enoxaparin: Is the subcutaneous route appropriate in the critically ill?

BACKGROUND: Subcutaneously administered low-molecular-weight heparins are widely used for prevention of venous thromboembolism. The appropriateness of the subcutaneous route in critically ill patients has never been established. OBJECTIVE: To determine anti-Xa activities in critically ill patients and in noncritically ill patients receiving prophylactic doses of subcutaneous enoxaparin. DESIGN: Prospective, controlled, open-labeled study. SETTING: Tertiary medical-cardiologic-postoperative intensive care unit and a general medical ward at a university hospital. PATIENTS: A total of 16 intensive care unit patients (group 1; age, 61.1 +/- 16 yrs; male/female ratio, 7/9; Acute Physiology and Chronic Health Evaluation II score, 20.9 +/- 7; mechanical ventilation, n = 15; vasopressors, n = 13) and 13 noncritically ill medical patients (group 2; age, 61.7 +/- 9 yrs; male/female ratio, 7/6) were studied. Body mass index (25.7 +/- 5 vs. 24 +/- 6 kg/m2, p = not significant) was comparable and serum creatinine levels (0.83 +/- 0.25 vs. 1.07 +/- 0.3 mg/dL, group 1 vs. 2) were within the normal range in both groups. Patients with impaired renal function, receiving hemofiltration, or requiring therapeutic anticoagulation were not eligible. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Anti-Xa activities were determined at 0, 1, 3, 6, and 12 hrs after a single daily subcutaneous dose of 40 mg enoxaparin on day 1 and at 3 hrs after 40 mg of enoxaparin on days 2-5. Mean anti-Xa levels at 0 to 12 hrs were consistently lower in group 1 compared with group 2 by analysis of variance (p =.001 between groups and over time), as was the area under the curve at 0 to 12 hrs (2.6 +/- 1 vs. 4.2 +/- 1.7 units x mL(-1) x hr(-1), group 1 vs. 2, p =.008). Significant differences in anti-Xa activity were also found on days 2-5 (p =.001). Peak anti-Xa activities at 3 hrs after administration were negatively correlated with the body mass index (r = -.41, p <.03). No correlation was found between the anti-Xa activity at 3 hrs and the dose of norepinephrine (r =.12, p =.7). CONCLUSION: Critically ill patients with normal renal function demonstrated significantly lower anti-Xa levels in response to a single daily dose of subcutaneous enoxaparin when compared with medical patients in the normal ward.     

Respiratory research in the critically ill pediatric patient: why is it so difficult?

Pediatric clinicians strive to base their management decisions on best available evidence. In the quantitative research paradigm, the highest level of evidence is derived from a conclusive randomized controlled clinical trial (RCT). Currently, there are few adequately powered RCTs to support pediatric acute respiratory care, but this landscape is changing. We are all obligated to ensure the relevance of our research, to mentor junior investigators, and to support knowledge development in our field. This paper reviews the hurdles faced by clinical investigators in the field of pediatric critical care and offers suggestions for future clinical studies.     

Is hyperlipasemia in critically ill patients of clinical importance? An observational CT study

Objective To assess morphological alterations of the pancreas by contrast-enhanced computed tomography (cCT) and subclinical cellular damage of the pancreas by measuring pancreatitis-associated protein (PAP) in critically ill patients without prior pancreatic disorder who presented with raised serum lipase levels. Design Prospective, observational study Setting Mixed surgical/neurosurgical intensive care unit of a German university hospital. Patients One hundred and thirty consecutive critically ill patients without prior damage or disease of the pancreas and an expected length of stay of more than 5 days. Interventions Daily serum lipase measurements and daily serum PAP measurements. Contrast-enhanced upper abdominal cCT study in patients with triple increase of serum lipase. Measurements and results Thirty-eight patients showed raised serum lipase levels and qualified for the cCT scan study. In 20 patients cCT scans were performed. Morphological alterations of the pancreas were found in 7 out these 20 patients while serum PAP levels were raised in all patients. Conclusion Hyperlipasemia is a common finding in critically ill patients without prior pancreatic disorder. While elevated serum PAP levels indicate pancreatic cellular stress morphological alterations of the pancreas are rare and of little clinical importance. C. Denz and L. Siegel contributed equally to this study. Results were presented in part and published as an abstract at the 18th ESICM Annual Congress, 25–28 September 2005, Amsterdam, Netherlands.     

Insulin: a wonder drug in the critically ill?

Stress hyperglycaemia is a common event in acute critical illness. There is increasing evidence that maintaining normoglycaemia and treatment with insulin (or with glucose–insulin–potassium [GIK]), even in non-diabetic persons, is helpful in limiting organ damage after myocardial infarction, stroke, traumatic brain injury and other conditions, even though the conditions may be accompanied by insulin resistance. A landmark study now suggests that maintaining normoglycaemia with intensive insulin treatment in a heterogeneous population of critically ill patients decreases morbidity and mortality. The potential mechanisms that underlie such a beneficial effect are discussed.     

The gut-brain axis in the critically ill: Is glucagon-like peptide-1 protective in neurocritical care?

Enteral nutrient is a potent glucagon-like peptide-1 (GLP-1) secretagogue. In vitro and animal studies indicate that GLP-1 has immune-modulatory and neuroprotective effects. To determine whether these immune-modulatory and neuroprotective effects of GLP-1 are beneficial in the critically ill, studies achieving pharmacological GLP-1 concentrations are warranted.In the previous issue of Critical Care, Bakiner and colleagues [1] reported the effects of so-called ''early'' enteral nutrition (EN) on biomarkers of inflammation and early clinical recovery in patients admitted to a neurointensive care unit after thromboembolic stroke. The rationale underlying this study is that enteral nutrient is a potent stimulant of glucagon-like peptide-1 (GLP-1) secretion [2], and, in animal models, pharmacological GLP-1 administration has been reported to have immune-modulating and neuroprotective properties [3,4]. For these reasons, Bakiner and colleagues hypothesized that ''early'' EN, when compared with ''delayed'' EN, would stimulate endogenous GLP-1 secretion, thereby effecting cell-mediated immunity and improving neurological recovery.GLP-1 is secreted from L cells that are located throughout the small and large intestine [2]. Physiologically, GLP-1 is a hormone that stimulates insulin and suppresses glucagon secretion and slows gastric emptying [5], and pharmacological administration of GLP-1 potently lowers blood glucose concentrations in healthy persons, patients with diabetes, and those who are critically ill [6-8]. Though originally identified in islet β-cells, the GLP-1 receptor is known to be widely expressed in extrapancreatic tissue; in particular, the receptor is found on neurons, and expression is increased in the ischemic penumbra [9]. Hence, in the central nervous system, GLP-1 functions as a neuropeptide [4]. In animals, pharmacological administration of a GLP-1 agonist or dipeptidylpeptidase-4 (DPP-4) inhibitor (which inhibits GLP-1 degradation) is reported to affect immune modulation [3]. Furthermore, preliminary animal data indicate that GLP-1 has neuroprotective effects, and pretreatment with a GLP-1 agonist administered intraventricularly reduced infarct size by 50% in a rodent model of stroke [10]. Although the question of whether plasma GLP-1 can cross an intact blood-brain barrier is controversial [4], pre-treatment with supratherapeutic doses of linagliptin, a DPP-4 inhibitor, reduced neuronal loss in a mouse model of stroke [11], suggesting that GLP-1 may indeed have a central effect after injury. Accordingly, there is a strong rationale for evaluating the effects of GLP-1 on patients after an acute thromboembolic stroke.Using a prospective, sequential-allocation, parallel open-label study design, Bakiner and colleagues compared the interventions of ''early'' and ''late'' EN to evaluate the effects of endogenous GLP-1 on this group of patients. Unfortunately, a potential confounder was that patients receiving ''late'' EN also received parenteral nutrition (PN) while awaiting EN. The authors reported no difference in the primary outcome measure, plasma GLP-1 concentrations, between the two groups but did report significant increases in T-helper and regulatory T cell numbers and a reduction in cytotoxic T cells in the patients receiving ''early'' EN.Although the rationale for the study was robust, there were substantial limitations with the study design chosen to answer the question. GLP-1 concentrations were measured during EN, but because EN was delayed in the ''late'' group, there may have been a period of 48 hours that went unmeasured when GLP-1 concentrations were greater in the ''early'' group. Moreover, because intestinal nutrient is a potent GLP-1 secretagogue and gastric emptying is frequently delayed in critical illness, nutrient must be infused directly into the small intestine at a sufficient load (>2 kcal per minute) to guarantee GLP-1 excursions [12,13]. Accordingly, measuring ''postprandial'' GLP-1 concentrations after intragastric nutrient delivery represents an inadequate stimulus to achieve even physiological concentrations. As the beneficial effects in the animal models used pharmacological concentrations of GLP-1 agonists (administered either intraventricularly or with systemic doses many fold greater than administered in humans), studies evaluating the effects of GLP-1 at pharmacological concentrations are needed to adequately address this question posed by Bakiner and colleagues.Perhaps of even more importance to the immune-modulatory effect was the period of PN. Administration of early PN when there is no contraindication for EN is associated with greater rates of infection [14]. The study by Casaer and colleagues [14] strongly supports the concept that early PN may actually be harmful if administered when not required. Hence, the inflammatory response observed by Bakiner and colleagues may be due to the ''toxicity'' of PN rather than a beneficial effect secondary to ''early'' EN. Although ''early'' EN is intuitively appealing [15], we suggest that these data from Bakiner and colleagues be interpreted cautiously and that ''early'' EN be compared with fasting to more effectively isolate the effects of ''early'' EN on cell-mediated immunity.This study, though preliminary, represents a novel foray into the potential therapeutic benefit of GLP-1 as an immune-modulator and neuroprotective agent in critical illness. Although the rationale for this approach is sound, we suggest that further studies targeting pharmacological GLP-1 concentrations are desirable to accurately evaluate the effect in neurocritical care.