Barbara J. Philips

Hyperglycaemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease

Background: Hyperglycaemia is associated with poor outcomes from pneumonia, myocardial infarction and stroke, but the effect of blood glucose on outcomes from acute exacerbations of chronic obstructive pulmonary disease (AECOPD) has not been established. Recent UK guidelines do not comment on measurement or control of blood glucose in AECOPD. A study was therefore undertaken to determine the relationship between blood glucose concentrations, length of stay in hospital, and mortality in patients admitted with AECOPD. Methods: Data were retrieved from electronic records for patients admitted with AECOPD with lower respiratory tract infection in 2001–2. The patients were grouped according to blood glucose quartile (group 1, <6 mmol/l (n = 69); group 2, 6.0–6.9 mmol/l (n = 69); group 3, 7.0–8.9 mmol/l (n = 75); and group 4, >9.0 mmol/l (n = 71)). Results: The relative risk (RR) of death or long inpatient stay was significantly increased in group 3 (RR 1.46, 95% CI 1.05 to 2.02, p = 0.02) and group 4 (RR 1.97, 95% CI 1.33 to 2.92, p<0.0001) compared with group 1. For each 1 mmol/l increase in blood glucose the absolute risk of adverse outcomes increased by 15% (95% CI 4 to 27), p = 0.006. The risk of adverse outcomes increased with increasing hyperglycaemia independent of age, sex, a previous diagnosis of diabetes, and COPD severity. Isolation of multiple pathogens and Staphylococcus aureus from sputum also increased with increasing blood glucose. Conclusion: Increasing blood glucose concentrations are associated with adverse clinical outcomes in patients with AECOPD. Tight control of blood glucose reduces mortality in patients in intensive care or following myocardial infarction. A prospective study is now required to determine whether control of blood glucose can also improve outcomes from AECOPD.

Hyperglycaemia and pulmonary infection

Pathophysiological stress from acute illness causes metabolic disturbance, including altered hepatic glucose metabolism, increased peripheral insulin resistance and hyperglycaemia. Acute hyperglycaemia is associated with increased morbidity and mortality in patients in intensive care units and patients with acute respiratory disease. The present review will consider mechanisms underlying this association. In normal lungs the glucose concentration of airway secretions is approximately 10-fold lower than that of plasma. Low airway glucose concentrations are maintained against a concentration gradient by active glucose transport. Airway glucose concentrations become elevated if normal homeostasis is disrupted by a rise in blood glucose concentrations or inflammation of the airway epithelium. Elevated airway glucose concentrations are associated with and precede increased isolation of respiratory pathogens, particularly methicillin-resistant Staphylococcus aureus, from bronchial aspirates of patients intubated on intensive care. Markers of elevated airway glucose are associated with similar patterns of respiratory infection in patients admitted with acute exacerbations of chronic obstructive pulmonary disease. Glucose at airway concentrations stimulates the growth of respiratory pathogens, over and above the effect of other nutrients. Elevated airway glucose concentrations may also worsen respiratory disease by promoting local inflammation. Hyperglycaemia may thus promote pulmonary infection, at least in part, by an effect on airway glucose concentrations. Therapeutic options, including systemic control of blood glucose and local manipulation of airway glucose homeostasis, will be considered.

The effects of acute renal failure on drug metabolism

Introduction: Acute kidney injury (AKI) is common in all hospital admissions and affects 10% of acute admissions in hospital. It increases the risk of adverse events and mortality, although the precise reasons for this are still unclear. The impact of chronic kidney disease (CKD) on nonrenal drug clearance is increasingly apparent and is now considered an important factor by the Food and Drug Administration for drug dose recommendations in CKD. Areas covered: This review explores the evidence of the impact of AKI on nonrenal drug metabolism. The review uses evidence from investigations of both CKD and AKI describing the manner of the inhibition and the most likely mediators of renohepatic crosstalk. The review also considers other forms of nonrenal clearance, including gut metabolism. Changes are related to critical illness in general, where appropriate. Expert opinion: Renal and hepatic interactions are highly complex with increasing evidence for an important relationship between AKI and hepatic metabolism. Current recommended dosing regimens are inadequate for AKI patients and much greater understanding of the interaction between the kidney and liver is required. More extensive therapeutic drug monitoring may be required to optimize drug regimens.

Renohepatic crosstalk: does acute kidney injury cause liver dysfunction?

The concept of hepatorenal syndrome is well recognized, although incompletely understood. The converse clinical problem of hepatic dysfunction in patients with acute kidney injury (AKI) is less well recognized yet may be a contributor to the high patient morbidity and mortality seen in this group. This review draws together the available evidence for AKIs effect on the liver from animal models, pharmacological studies and recent clinical data. It examines liver function beyond clinically used blood tests, to determine the effect of AKI on hepatic synthetic function, acute phase response and drug metabolism. Parallels are drawn with other organ crosstalk in AKI and with liver-kidney interactions in chronic kidney disease. Definition of the pathophysiology of renohepatic crosstalk may lead to improved management strategies for this vulnerable patient group.

Triaging for adult critical care in the event of overwhelming need.

IntroductionPredictions of the need for critical care within the H1N1 influenza pandemic suggested overwhelming need beyond potential resources, necessitating rationing of care via triaging.MethodThe triage model described was derived from informed discourse within a conjoined NHS and University Clinical Ethics Committee, supplemented by specialists in intensive care and infectious diseases.The ModelThe triage methodology described is justified ethically primarily upon ‘utilitarian’ principles within an aggregate public health model, with additional reference to ‘fairness’. Advantages of such a model, which partially suspends usual clinical judgment applied to individuals in favour of also utilizing organ failure scores, include minimization of aggregate influenza morbidity and mortality, and minimization of psychological stress upon staff making triaging decisions. Legally, in England and Wales, the model is uncontentious as regards rationing of admission to critical care; however, the law adopts ‘futility’ as the core justification for withdrawal of treatment, applied to the individual, thus failing to allow for rationing through triaging individuals out of critical care in the interest of other patients with better chances of survival. There is therefore a mismatch between a clinically and ethically acceptable model of triaging, based upon a public health approach, and the law, based upon the paradigm of the individual patient.ConclusionThe good fortune that the H1N1 pandemic was less severe than predicted, allowing time for calm consideration, debate and decision making about what model of triaging should be adopted whenever it might be necessary in the future. It is in the interest of the health of the nation, and government, to decide upon a critical care triaging model while there is not an imminent health service crisis.

Xenobiotic Metabolism: The Effect of Acute Kidney Injury on Non-Renal Drug Clearance and Hepatic Drug Metabolism

Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth.

New insights into the glucose oxidase stick test for cerebrospinal fluid rhinorrhoea

Rhinorrhoea is a clinical sign of cerebrospinal fluid (CSF) leakage in patients with skull fracture, but can also be attributable to respiratory secretions or tears. Laboratory tests confirming the presence of CSF are not sufficiently rapid to support clinical decision making in the emergency department and may not be universally available. Detection of glucose in nasal discharge was traditionally used to diagnose CSF leak at the bedside, but has fallen into disuse as it has poor positive predictive value. We propose an algorithm to improve the diagnostic value of this test taking into consideration factors we have found to affect the glucose concentration of respiratory secretions. In patients at risk of CSF leak, nasal discharge is likely to contain CSF if glucose is present in the absence of visible blood, if blood glucose is <6 mmol.L−1, and if there are no symptoms of upper respiratory tract infection.

Using drug probes to monitor hepatic drug metabolism in critically ill patients: midazolam, a flawed but useful tool for clinical investigation of CYP3A activity?

Importance of the field: In the UK, acute kidney injury (AKI) occurs in 25% of patients admitted to intensive care. Outcome is worsened in the presence of AKI for reasons not easily explained. AKI unpredictably affects the pharmacokinetics and pharmacodynamics of drugs and dosing in patients with AKI is largely based on data from chronic kidney disease patients, but how appropriately is unknown. Areas covered in this review: Midazolam as a drug probe of CYP3A activity is reviewed, with discussion of its limitations and alternatives in critically ill patients. Pharmacogenetics of CYP3A enzymes and their significance are discussed and emerging evidence that AKI affects liver metabolism is reviewed. What the reader will gain: The aim is to give the reader insight into the complexities of in vivo research in critically ill patient with discussion of interaction between the kidney and liver. We explain the use of midazolam as a drug probe for the investigation of the effect of AKI on hepatic function. Take home message: Critically ill patients are difficult to manage but methods are now available for investigation of complex interrelationships that complicate the care and management of these patients with the potential to improve safety, efficacy and outcome, particularly for drug administration.

Estimated Glomerular Filtration Rate Correlates Poorly with Four-Hour Creatinine Clearance in Critically Ill Patients with Acute Kidney Injury

Introduction. RIFLE and AKIN provide a standardised classification of acute kidney injury (AKI), but their categorical rather than continuous nature restricts their use to a research tool. A more accurate real-time description of renal function in AKI is needed, and some published data suggest that equations based on serum creatinine that estimate glomerular filtration rate (eGFR) can provide this. In addition, incorporating serum cystatin C concentration into estimates of GFR may improve their accuracy, but no eGFR equations are validated in critically ill patients with AKI. Aim. This study tests whether creatinine or cystatin-C-based eGFR equations, used in patients with CKD, offer an accurate representation of 4-hour creatinine clearance (4CrCl) in critically ill patients with AKI. Methods. Fifty-one critically ill patients with AKI were recruited. Thirty-seven met inclusion criteria, and the performance of eGFR equations was compared to 4CrCl. Results. eGFR equations were better than creatinine alone at predicting 4CrCl. Adding cystatin C to estimates did not improve the bias or add accuracy. The MDRD 7 eGFR had the best combination of correlation, bias, percentage error and accuracy. None were near acceptable standards quoted in patients with chronic kidney disease (CKD). Conclusions. eGFR equations are not sufficiently accurate for use in critically ill patients with AKI. Incorporating serum cystatin C does not improve estimates. eGFR should not be used to describe renal function in patients with AKI. Standards of accuracy for validating eGFR need to be set.

End-of-life care in patients with end-stage renal disease

As the population ages, the number of patients with end-stage renal disease (ESRD) and associated comorbidities is increasing [1]. Survival from critical illness may be reduced but expectations of medical treatment remain high and increasingly complex treatment options are offered. Understanding the risks and benefits of such treatment and the quality of survival can be extremely difficult. Consequently, the need to provide advance care planning (ACP) and end-of-life care in this cohort of patients is imperative [2]. As clinicians, our focus should be on care and not just cure. We are obliged to establish the impact of chronic comorbidity on individual patients’ quality of life and their wishes when it comes to the end of life (EOL). Frequent contact with health care services presents an opportunity to establish, document and regularly review patients’ values and attitudes towards critical illness and EOL situations. Nephrologists are in a position to approach patients with ESRD about ACP, preferably long before critical care services are required. ACP has been proposed as a tool to establish a patient’s wishes concerning his own health care should he be unable to make his own decisions in the event of serious illness. ACP focuses more on goals for care and less on specific treatments [3]. Advance directives (AD) are legal documents that may include instructions about a patient’s future wishes regarding medical care. They may nominate a friend or family member as their representative, empowering them to make decisions on their behalf should they lack the capacity. This power however is limited to the decisions specified in the AD. The wider term ACP will be used which encompasses both the legal and less formal discussions that there may be. AD will be used if specifically indicated. All ACPs should ideally include whether cardiopulmonary resuscitation (CPR) would be wanted and what levels of critical care support would be acceptable to the patient for any given likely outcome. Patients can refuse treatment but cannot demand an intervention if deemed inappropriate or futile. The treating clinician has a responsibility to inform the patient of the different treatment options available but is responsible for ensuring the management is ultimately appropriate. This may include withdrawal of treatment in the event of critical illness. Patients may need help to identify, clarify and prioritize factors that influence their decision making about future medical conditions: explaining common end-of-life medical conditions and life-sustaining treatment; helping patients express a coherent set of wishes. Patients should be encouraged to engage family and friends and to identify a spokesperson on their behalf should they be unable to speak for themselves. Including other medical teams and health providers is likely to greatly improve the chance of successful ACP. [4]. The process of ACP is patient specific and a different approach will be needed for different patients. However, the underlying principles remain the same. The responsible doctor needs to determine what is most important to the patient, what medical conditions they would want treated, what degree of functional impairment they would consider intolerable and who they would want as a spokesperson [4]. The survey by McAdoo et al. [5] provides important data on our current practise. It reflects the need for significant improvement in the quality of EOL care provided to patients with advanced kidney disease. Sixty-nine percent of the 138 deaths occurred during an in-patient admission; yet, only 28% of these patients had discussed EOL issues with their medical team in the year prior to death. The majority of in-patient deaths occurred either within the first 48 h or more than 1 month after admission. Continuation of treatment and ‘futile’ admissions to critical care may ultimately prolong death rather than preserve life. However, defining ‘futile’ is difficult. The EOL decision may mean the cessation of maintenance dialysis [6], although this was done in just 40% of patients. Management of consequent symptoms is complex and was achieved in only 52% of the patients. Multidisciplinary teamwork may improve this [7]. The palliative care team was involved in just 34% of cases. Palliation is often viewed as part of cancer-specific ACP and not considered applicable for other progressive diseases; however, there are many aspects common to end-of-life care for all patients and their families including management of physical symptoms (pain,