Peter E. Hickman

Cardiac troponin may be released by ischemia alone, without necrosis.

Whilst it is formally stated that cardiac troponin is only released when cardiac myocytes undergo necrosis, there are a number of clinical situations where troponin is present in the circulation, without any apparent cardiac injury. In these cases, troponin half-life in the circulation is usually substantially shorter than that seen when troponin is released following myocardial infarction with frank necrosis. A mechanism has been described in liver, where large cytoplasmic molecules can pass from the intra- to extra-cellular space without cellular necrosis occurring. This occurs by the formation of membranous blebs which bud off from the plasma membrane of the cell. Blebs develop during cellular ischemia. If the ischemia is limited and re-oxygenation occurs, the blebs may be released into the circulation without rupture of the plasma membrane, resulting in a one-off release of cytoplasmic contents including macromolecules. Evidence from cardiac studies is presented supporting the presence of membranous blebs in cardiac myocytes, enabling troponin to be released from cardiac cells due to ischemia alone, without necrosis.

Effect of postoperative low-dose dopamine on renal function after elective major vascular surgery.

Prolonged aortic cross-clamping, hypotension, and large-volume blood transfusions are important risk factors in the development of postoperative renal failure after major vascular surgery [1-3]. Acute renal failure carries a high mortality rate, and its avoidance remains an important goal of postoperative management [1-3]. Dopamine (an endogenous catecholamine) has, since the pioneering work of Goldberg, been used in intensive care units to treat patients with renal impairment and to preserve renal function in patients at risk for renal failure. At low doses (0.5 to 3.0 g/kg per minute), dopamine stimulates type 1 and type 2 dopamine receptors [4, 5]. These receptors are widely distributed on the renal vasculature and, when stimulated, produce renal vasodilatation, increased renal blood flow, and increased glomerular filtration with natriuresis and diuresis [6]. These responses are most pronounced in euvolemic patients. In hypovolemic patients, a dopamine-induced diuresis may worsen the hypovolemia. Although low-dose dopamine is widely used in intensive care units as a renal protector in patients at risk for renal impairment, no evidence exists that it decreases the incidence of renal failure or mortality [7-9]. In dogs and humans, dopamine is ineffective as a renal protective agent [10, 11]. In liver transplant recipients, the evidence is conflicting. Early work by Polson and colleagues [9] claimed improved renal function with dopamine, but a more recent study showed no benefit [12]. In view of the uncertainty about the efficacy of routine low-dose dopamine as a renal protective agent, we did a study to assess the effect of low-dose dopamine on renal function in euvolemic patients after major elective vascular surgery. Methods After receiving approval from the ethics committee of Princess Alexandra Hospital, informed consent was obtained for this study from 37 consecutive patients presenting to the vascular surgical unit (during a 7-month period) for elective infrarenal abdominal aortic aneurysm repair or aortobifemoral grafting. The vascular surgical service is 1 of 3 major public vascular units serving about 1 million persons in the Brisbane area. On the day before surgery, plasma urea and creatinine levels were assayed. Creatinine clearance was measured using an accurately timed 2-hour collection [13]. The anesthetic technique was similar for all patients and included an opioid-local anesthetic epidural for postoperative analgesia. The hospital pharmacy randomly assigned dopamine and an equal volume of saline to identical containers using a random numbers table. The containers were identified only by a number (numbers 1 to 40), and the contents were unknown to the staff and the patients of the intensive care unit. All patients were admitted to the intensive care unit postoperatively and were started on an infusion of either dopamine (3 g/kg per minute) for 24 hours or placebo (saline), which was chosen in a double-blind manner by selecting the next number in the sequence 1 to 40. The management in the intensive care unit was otherwise usual for both groups; it included an infusion of Plasmalyte 56 (Baxter Health Care; Old Toongabbie, New South Wales, Australia), 3000 mL during 24 hours, and included bolus infusions of Plasmalyte 148 (Baxter Health Care) to maintain a urine flow of 1 to 1.5 mL/kg per hour. Mannitol and diuretic agents were not used. Postoperative fluid requirement and urine output during the first 24 hours in the intensive care unit were recorded. Plasma creatinine levels, serum urea levels, and creatinine clearance were measured at 24 hours and 5 days. Urine output and fluid requirements were indexed to body weight, whereas clearance values were indexed to the body surface area. All biochemical measurements were made using a SMAC II Autoanalyzer (Technicon Equipment, Sydney, Australia). Statistical analysis was done using SPS-PC software (SPS Australasia, Crows Nest, New South Wales, Australia), with the data presented as means and 95% confidence intervals (CIs). Results Eighteen patients received dopamine, and 19 patients received placebo. One patient from the placebo group and 3 from the dopamine group had myocardial infarctions. Two patients died during the study and both were in the dopamine group (1 patient, myocardial infarction; 1 patient, renal failure). These patients were included in the 24-hour analysis but were excluded from the 5-day analysis. The groups were similar with respect to age, preoperative morbidity, diuretic use, radionucleotide ejection fraction, urea creatinine levels, type of surgery, duration of aortic cross-clamping, and blood loss (Tables 1 and 2). The mean fluid requirements in the first 24 hours were slightly less in the dopamine group than in the placebo group (4.06 mL/kg per hour for dopamine compared with 5.29 mL/kg per hour for placebo, a difference of 1.23 [95% CI, 0.11 to 2.57]), whereas the mean urine volumes were slightly higher in the dopamine group (1.83 mL/kg per hour for dopamine compared with 1.6 mL/kg per hour for placebo, a difference of 0.23 [CI, 0.18 to 0.64]). Table 1. Patient Characteristics by Treatment Group* Table 2. Differences in Renal Function for Dopamine Compared with Placebo at Different Time Points Table 2 summarizes the differences between the groups in plasma creatinine levels, urea levels, and crude and indexed creatinine clearance; all variables were measured preoperatively and postoperatively (at 24 hours and 5 days). Table 3 summarizes the mean change in each variable from the preoperative level to the 24-hour and 5-day point in the dopamine and placebo groups. There was no statistical difference in plasma creatinine levels between groups at any of the time periods or in changes from baseline to 24 hours and 5 days. Table 3. Postoperative Renal Indices Compared with Preoperative Indices* Preoperative and 5-day plasma urea levels were not statistically different between groups. At 24 hours, a small decrease in urea levels was noted in both groups (5.71 mmol/L for dopamine compared with 4.99 mmol/L for placebo, a difference of 0.72 [CI, 0.62 to 2.06; P > 0.2]). The mean decrease in urea levels from baseline to 24 hours was small in both groups ( 1.07 mmol/L for dopamine compared with 1.84 mmol/L for placebo, a difference of 0.77 [CI, 0.12 to 1.67; P = 0.09]). The preoperative creatinine clearance in the placebo group was 18% lower than in the dopamine group (P = 0.16) (Table 2). By 24 hours, the creatinine clearance increased by 0.165 mL/s (9.89 mL/min) in the dopamine group and by 0.199 mL/s (11.98 mL/min) in the placebo group (P > 0.2). By day 5, the creatinine clearance in the dopamine group had decreased to near baseline, although the increase was sustained in the placebo group. However, the difference between the group means was 0.28 mL/s ( 0.103 mL/s compared with 0.178 mL/s [CI, 0.2 to 0.21; P > 0.2]). Indexing creatinine clearance for body surface area did not change the interrelation of the major end points in either group. Discussion In this study, minor changes in renal function were noted postoperatively in the placebo and dopamine groups. In both groups, a small decrease was noted in plasma urea levels and a small increase was noted in creatinine clearance by 24 hours; these changes were not statistically or clinically significant. No difference was noted between the groups, suggesting that generous fluid replacement alone was as effective as fluid combined with low-dose dopamine. The difference from baseline was maintained at 5 days in the placebo group (but not in the dopamine group), but it also was not statistically significant. The study was not large enough to detect any decrease in the incidence of renal failure, which is an uncommon complication of elective abdominal aortic surgery. Although the differences in urine production and fluid requirements were not statistically different, the trend suggested that the addition of dopamine might allow the production of more urine per unit of fluid infused. The mechanisms by which dopamine increases urine production are related to an increase in the glomerular filtration rate, which is largely attributable to increased cardiac output [14], and to a direct action on tubular sodium uptake mechanisms leading to natriuresis. Normal tubuloglomerular feedback (which regulates glomerular filtration rate in response to filtered sodium load) is blunted in the presence of dopamine, which further enhances its diuretic action [15]. This trend in favor of dopamine was of no clinical significance in the context of this study, although it does support the view that in euvolemic patients, dopamine has a mild diuretic effect. A similar diuretic effect might have deleterious consequences in hypovolemic patients by worsening the hypovolemia. It is therefore essential to exclude hypovolemia before resorting to dopamine in oliguric patients. When considering the use of dopamine in this context, the cost and adverse effects (such as arrhythmias, depression of respiratory drive, increased intrapulmonary shunt, myocardial ischemia in patients with obstructive coronary artery disease, and increased pulmonary wedge pressure) need to be considered. Four patients in the study had postoperative myocardial infarction. The relatively high rate of myocardial infarction may reflect the inadequate cardiac resources available locally, which severely limit the number of patients who can be investigated and treated for active ischemic heart disease before aortic surgery. Although the numbers were too small for meaningful comparison, three of the patients with myocardial infarction were from the dopamine group, which raises some questions about the safety of dopamine in such patients. Although the study was small and without the power to discriminate different rates of renal failure (an infrequent clinical end point), we did not find any compelling evidence to support the routine use of dopamine in

Myoclonus associated with treatment with high doses of morphine: the role of supplemental drugs.

OBJECTIVE--To estimate the prevalence of important side effects in patients with malignant disease who were receiving high doses of morphine as part of their palliative treatment. DESIGN--Data on patients were collected over 12 months. SETTING--Two palliative care units in Western Australia. PATIENTS--19 Patients with malignant disease who were receiving morphine either subcutaneously or orally as the main analgesic. 10 Patients receiving a total daily dose of morphine of at least 500 mg orally or 250 mg parenterally were enrolled in the study. The other 9 patients were enrolled after an important problem thought to be related to the morphine had been identified. All of the patients were taking drugs to supplement the treatment. INTERVENTIONS--The dose of morphine or route of administration, or both, was changed in three patients. MAIN OUTCOME MEASURE--Determination of the prevalence of side effects in the patients. Assessment of the relation of any side effects with the supplemental drugs taken by the patients. MAIN RESULTS--Plasma morphine and electrolyte concentrations were measured and a full history taken for each patient. Thirteen of the 19 patients had an important side effect; 12 of them had myoclonus and one had hyperalgesia of the skin. Plasma morphine concentrations were similar in patients with and without myoclonus, ranging from 158 to 3465 nmol/l and 39 to 2821 nmol/l respectively. Eight of the patients with side effects were taking an antipsychotic drug concurrently compared with none of those without side effects. A greater proportion of patients with side effects were taking the antinauseant drug thiethylperazine (6/13 v 2/6) and at least one non-steroidal anti-inflammatory drug (10/13 v 2/6), whereas a smaller proportion were taking a glucocorticosteroid (3/13 v 4/6). The estimated prevalence of important side effects in the total population of patients receiving palliative treatment in the two units was 2.7-3.6%. CONCLUSIONS--Myoclonus as a side effect of treatment with morphine is more likely to occur in patients taking antidepressant or antipsychotic drugs as antiemetics or as adjuvant agents or non-steroidal anti-inflammatory drugs for additional analgesia. If a patient develops myoclonus the best approach may be to change the supplemental treatment.

Characterisation of a highly sensitive troponin I assay and its application to a cardio-healthy population.

Abstract Background: Abbott Diagnostics have developed a new highly sensitive troponin I (hs-TnI) assay. We have assessed its analytical characteristics and applied the assay to a population of apparently cardio-healthy persons. Methods: We assessed imprecision, bias compared to the previous generation assay, matrix effects, and interferences and applied the assay to an apparently healthy population, deriving the 99th percentile limit of the distribution of values in reference populations for men and women separately. Results: The dynamic range of the assay was ranged from 0.5–50,000 ng/L (pg/mL). The 10% CV was at a concentration of 3.9 ng/L, and the 20% CV was at a concentration of 1.8 ng/L. The new and current version of the TnI assay were highly correlated [slope: 0.98 (95%CI:0.88–1.07), y-intercept:1.20 (95%CI:-2.35–4.75) r2=0.99]. The 99th percentile limit of the distribution of values in a reference population was different for males and females: for males 14.0 ng/L and for females 11.1 ng/L and at these concentrations the assay CV was 5.0%. TnI was detectable in nearly all patient samples from the healthy reference population (98.6%). Conclusions: This new hs-TnI assay is able to measure to an order of magnitude lower than the current generation TnI assay from the same manufacturer. With TnI being detectable in nearly all apparently healthy subject samples this suggests that TnI presence does not always indicate cardiomyocyte necrosis.

Effect of population selection on 99th percentile values for a high sensitivity cardiac troponin I and T assays.

OBJECTIVE Using objective laboratory and clinical criteria to more accurately determine the 99th percentile values for cardiac troponin I and T. DESIGN AND METHODS We measured cardiac troponin T and cardiac troponin I with high-sensitivity assays in a large cohort of apparently healthy community subjects and calculated 99th percentiles for different sexes and ages. Subjects with possible subclinical disease were eliminated based on objective laboratory criteria, eGFR and NT-proBNP, and clinical criteria, history and examination and echocardiogram. RESULTS For men and women of all ages, separately, more than 50% of subjects were excluded using these criteria, with a lesser proportion of younger subjects being excluded. In men aged <75 years, the 99th percentile for cTnI decreased by more than 50% from 22.9 ng/L to 10.3 ng/L. In other age groups and for cTnT the decrease was smaller (%) but still considerable. CONCLUSIONS For establishing cardiac troponin 99th percentiles, simply using self-reporting of health is insufficient. Objective laboratory measures and clinical and echocardiographic assessments are essential to define a healthy population, especially in older persons.

Over time, high-sensitivity TnT replaces NT-proBNP as the most powerful predictor of death in patients with dialysis-dependent chronic renal failure

BACKGROUND Cardiac biomarkers are emerging as a potentially powerful prognostic tool for renal-dialysis patients. The optimal biomarker and/or combination of biomarkers for predicting mortality remain uncertain. This study evaluates the prognostic value of the new high-sensitivity troponin T (TnT) assay compared to established biomarkers. METHODS All patients had blood sampled for prospective assessment of the prognostic value of traditional risk markers including albumin and CRP, and cardiac biomarkers BNP, NT-proBNP, TnT and TnI. Patients were closely monitored clinically. Mortality and morbidity outcomes were documented for a national morbidity and mortality database. Stored samples were subsequently used to measure TnT with a new high-sensitivity assay. RESULTS After a median of 30 months from blood collection, NT-proBNP was the most powerful predictor of all-cause mortality, along with albumin. After a median of 46.7 months the new high-sensitive TnT assay was the only cardiac biomarker predictive of all-cause mortality. TnT was detectable in all dialysis patients using the high-sensitive TnT assay with a cut-point of 24.15 ng/L below which all patients survived. CONCLUSIONS The new hs-TnT is the most powerful biomarker for prognostic classification for all-cause mortality of all the commonly used biomarkers for our renal-dialysis population. Our study also suggests that cardiac biomarkers have a different prognostic ability for different time frames with NT-proBNP being a better predictor for early mortality and troponin for later mortality.

Practical Considerations for the Measurement of Free Light Chains in Serum

BACKGROUND A new immunoassay for free light chain measurements has been reported to be useful for the diagnosis and monitoring of monoclonal light chain diseases and nonsecretory myeloma. We describe experience with and some potential pitfalls of the assay. METHODS The assay was assessed for precision, sample type and stability, recovery, and harmonization of results between two analyzers on which the reagents are used. Free-light-chain concentrations were measured in healthy individuals (to determine biological variation), patients with monoclonal gammopathy of undetermined significance, myeloma patients after autologous stem cell transplants, and patients with renal disease. RESULTS Analytical imprecision (CV) was 6-11% for kappa and lambda free-light-chain measurement and 16% for the calculated kappa/lambda ratio. Biological variation was generally insignificant compared with analytical variation. Despite the same reagent source, values were not completely harmonized between assay systems and may produce discordant free-light-chain ratios. In some patients with clinically stable myeloma, or post transplantation, or with monoclonal gammopathy of undetermined significance, free-light-chain concentration and ratio were within the population reference interval despite the presence of monoclonal intact immunoglobulin in serum. In other patients with monoclonal gammopathy of undetermined significance, values were abnormal although there was no clinical evidence of progression to multiple myeloma. CONCLUSIONS The use of free-light-chain measurements alone cannot differentiate some groups of patients with monoclonal gammopathy from healthy individuals. As with the introduction of any new test, it is essential that more scientific data about use of this assay in different subject groups are available so that results can be interpreted with clinical certainty.

Plasma free metanephrines are superior to urine and plasma catecholamines and urine catecholamine metabolites for the investigation of phaeochromocytoma

Aim: To compare the relative diagnostic efficacy of several different tests used to establish a diagnosis of phaeochromocytoma, in patients with a proven diagnosis of phaeochromocytoma, and in hospital patients with significant disease of other types. Methods: We prospectively compared biochemical markers of catecholamine output and metabolism in plasma and urine in 22 patients with histologically proven phaeochromocytoma, 15 intensive care unit (ICU) patients, 30 patients on chronic haemodialysis and both hypertensive (n = 10) and normotensive (n = 16) controls. Results: Receiver operating characteristic curves were plotted. At the point of maximum efficiency, plasma free metanephrines showed 100% sensitivity and 97.6% specificity, compared with plasma catecholamines (78.6% and 70.7%), urine catecholamines (78.6% and 87.8%), urine metanephrines (85.7% and 95.1%), and urine hydroxymethoxymandelic acid (HMMA or VMA) (93.0% and 75.8%). All patients with phaeochromocytoma had plasma free metanephrine concentrations at least 27% above the upper limit of the reference range. Only three other patients (two on haemodialysis and one in ICU) had PFM concentrations more than 50% above the upper limit of the reference range. Conclusions: In patients with phaeochromocytoma, plasma free metanephrines displayed superior diagnostic sensitivity and specificity compared with other biochemical markers of catecholamine output and metabolism.

Altered endogenous growth hormone secretory kinetics and diurnal GH-binding protein profiles in adults with chronic liver disease

OBJECTIVE Increased serum GH concentrations and GH responses to a variety of stimuli have been reported in patients with chronic liver disease (CLD). We Investigated the pulsatile pattern of endogenous GH release and GH‐binding protein (GHBP) and insulin‐like growth factor‐I (IGF‐I) diurnal profiles in adults with cirrhosis, in comparison with healthy, matched control subjects.

Screening for hemochromatosis.

BACKGROUND Hereditary hemochromatosis is the most common autosomal recessive disorder in populations of northern European descent. ISSUES Many experts consider hemochromatosis to be an almost ideal disease for population screening because it essentially fulfills almost all the criteria for screening proposed by the WHO. However, others disagree and suggest that more data are required particularly with regard to the natural history and penetrance of the disease. There is also disagreement about the best diagnostic/screening test for the disease and the performance of these tests in the context of screening. Other concerns are the variability and lack of standardization in screening test measurements, the selection of screening threshold values and the identification of false positive cases. The advent of a genetic test for the condition has brought other worries with regard to informed consent and the ethical, legal and social implications of screening particularly in relation to medical and general discrimination. Other important issues include compliance, cost effectiveness and the evidence that screening has lessened the burden of disease in the community. CONCLUSIONS At the present time, we believe that further data regarding both the exact disease burden and the outcomes of screening studies particularly in the general community are required before widespread population screening is introduced.