[Real change or natural fluctuation?] / Echte verandering of natuurlijke schommeling?

When monitoring patients over time, it may be difficult to distinguish 'real changes' from so-called 'natural fluctuations' when interpreting consecutive laboratory results. Consider a patient whose cholesterol level has decreased from a baseline 6.6 mmol/L to 6.1 mmol/L six months after receiving lifestyle advice. How likely is it that this is a 'real change', reflecting a lifestyle change, rather than random fluctuation? Physicians mostly rely on their intuition and clinical experience when interpreting changes in consecutive laboratory results. For inexperienced physicians, the lack of an easy reference for the interpretation of consecutive laboratory results can make decision-making challenging. We have developed the medical/educational smartphone app Labtracker+ that calculates the probability of a 'real change' between two consecutive laboratory results, using biological variation data from scientific literature and analytical precision that is achieved in contemporary laboratories. This approach may complement intuitive, experience-based interpretations of consecutive laboratory results.

Registering complications at admission via the emergency department: an opportunity for improvement.

BACKGROUND: To monitor and improve the quality of care we provide it is important to register complications. Complications occurring after discharge or after treatment at outpatient clinics are usually not registered and complications occurring in domains other than where they originated may be missed. The emergency department (ED) may offer an opportunity to register these complications. This study assesses the prevalence and nature of complications in patients at the moment of acute admission by internists. METHODS: A retrospective cohort study over a five-month period was performed in which we reviewed the charts of all patients who were admitted to our hospital via the ED by internists. We investigated the number, nature, preventability and severity of complications present at the moment of admission. RESULTS: In total, there were 1128 admissions. Of these, 284 patients were admitted 324 times (28.7%) due to a complication. The most common complication was medication-related (43.5%), in particular bleeding while using anticoagulants. The second most prevalent complication was chemotherapy-related (26.9%), while 17.3% were due to a procedure. Up to 27.8% of all complications were considered preventable. Eighteen (6.3%) patients died during their admission, seven (2.5%) did not recover completely. A total of 23.1% of all complications originated in specialities other than internal medicine. CONCLUSION: Complications are a major reason for hospitalisation. Registering complications present at admission gives broad insight into the complications following the care doctors provide. It is important to understand these complications better to prevent such admissions.

[Novel side effects of moxifloxacin: making a balanced decision again]. / Nieuwe bijwerkingen van moxifloxacine: opnieuw de balans opmaken.

Earlier this year, a 'Dear Doctor' letter was sent to Dutch health care professionals, describing the rare occurrence of fulminant hepatitis and the Stevens-Johnson syndrome or toxic epidermal necrolysis in patients using moxifloxacin. This resulted in media attention, questions in parliament and moxifloxacin being banned from the formulary in several hospitals. Was this reaction justified? In the Netherlands, moxifloxacin is only mentioned in the practice guideline on the treatment of severe community-acquired pneumonia. Alternatives for moxifloxacin for this indication are penicillin combined with ciprofloxacin, or cephalosporins in combination with erythromycin. The associated risks, in particular fatal anaphylaxis and sudden cardiac death, of these combinations are substantially higher compared to the reported incidence of severe moxifloxacin-associated liver and skin toxicity. 'Dear Doctor' letters are important when new side effects become apparent, but these side effects must be placed in the overall balance of pros and cons of a drug as compared to the alternatives.

[Angiotensin II-receptor antagonists compared to other antihypertensives: still insufficient evidence for reducing the risk of cerebrovascular incidents]. / Angiotensine II-receptorantagonisten vergeleken met andere antihypertensiva: nog onvoldoende bewijs voor een lager risico op herseninfarcten.

--There is growing evidence that angiotensin II-receptor antagonists may have protective effects for preventing cerebrovascular incidents. --It is unlikely that these effects are due only to a decrease in blood pressure. --One hypothesis is that high concentrations ofangiotensin II result in improved cerebral perfusion ofangiotensin type 2-receptor mediated mechanisms such as local vasodilatation and angiogenesis. --Several clinical and preclinical studies support this hypothesis. --The results of these studies are discussed in this overview. There is still insufficient evidence that a protective effect on the brain occurs.

A new tool, a better tool? Prevalence and performance of the International Diabetes Federation and the National Cholesterol Education Program criteria for metabolic syndrome in different ethnic groups.

We used a population based study in the Netherlands of 330 Hindustani Surinamese, 586 African Surinamese, and 486 ethnic Dutch (Dutch) to describe the prevalence of the metabolic syndrome (MS) and the association with differences in cardiovascular disease in and between ethnic groups. Fasting blood samples, blood pressure, and anthropometric measurements were obtained. MS was defined according to the criteria of the International Diabetes Federation (IDF) and the criteria of the National Cholesterol Education Program (NCEP). Cardiovascular disease was assessed by the Rose questionnaire and included questions on previous diagnoses of angina pectoris/myocardial infarction, cerebrovascular accident, intermittent claudication. The prevalence of MS (IDF and NCEP) was highest in Hindustani Surinamese men, followed by Dutch and African Surinamese men: 51.0%, 19.4%, and 31.2% (IDF), respectively. Among women, both the Hindustani and African Surinamese participants had a higher prevalence of MS (IDF and NCEP) than the Dutch. The association between the components, MS and cardiovascular disease differed between ethnic groups, in particular among men; OR for MS (NCEP) = 1.0 (0.4-2.7) among Hindustani Surinamese, OR = 4.9 (1.3-18.3) among African Surinamese, and OR = 2.8 (1.1-7.1) among Dutch. However, the differences in MS could not account for the ethnic differences in cardiovascular disease, regardless of the criteria used. The results suggest that, before the criteria can be used to guide practice, they may need to be changed and refined to take into account the differences between ethnic groups as well as the variations by gender.

[Clinical reasoning and decision making in practice. A 39-year-old woman with somnolence, hypertension and haemolysis]. / Klinisch denken en beslissen in de praktijk. Een 39-jarige vrouw met sufheid, hypertensie en hemolyse.

A 39-year-old woman was admitted with somnolence, severe hypertension and thrombotic microangiopathy. Both malignant hypertension and thrombotic thrombocytopenic purpura (TTP) were considered. Immediate therapy was instituted to treat both diseases because of severe clinical deterioration. Eventually, TTP was considered less likely due to the presence of grade IV hypertensive retinopathy (papilloedema and soft exudates) and a normal Von Willebrand factor-cleaving protease level. Differentiating TTP from malignant hypertension can be difficult as both diseases have similar clinical, laboratory and radiological features. In both diseases, hypertension, thrombotic microangiopathy and encephalopathy with white-matter lesions in the posterior regions of the brain may be apparent. Funduscopic abnormalities consistent with grade III and IV hypertensive retinopathy are rare in TTP, as are normal levels ofVon Willebrand factor-cleaving protease. Therefore, the diagnosis TTP was considered less likely and plasmapheresis was stopped. Hereafter, the laboratory values pointing towards haemolysis remained normal with adequate blood pressure control supporting the rejection of TTP as the cause of the symptoms.

[Atenolol or metoprolol as beta-blocker in the treatment of hypertension]. / Atenolol en metoprolol beide geschikt als beta-blokker voor de behandeling van hypertensie.

Recently the guideline committee of the Dutch College of General Practitioners advocated the use of metoprolol instead of atenolol in patients with an indication for beta-blockers. This recommendation was based on a recent meta-analysis in The Lancet in which no effect was observed in favour ofatenolol compared with placebo on all-cause mortality, cardiovascular mortality and myocardial infarction. Atenolol also had a higher total mortality and stroke risk compared with other antihypertensive agents. Apart from the presence of statistical heterogeneity and the inappropriate use of a fixed-effect model, the studies referred to in this meta-analysis were also clinically heterogeneous. Furthermore, in most studies, only older patients were included. In older patients with hypertension, it is known that beta-blockers are less effective than diuretics or calcium antagonists. Comparative trials between atenolol and metoprolol in the treatment of hypertension have not been performed with regard to cardiovascular endpoints. We conclude that there is no evidence that atenolol is better or worse than metoprolol in the treatment of the hypertensive patient. For the treatment of patients with heart failure, however, lipophilic beta-blockers such as metoprolol may be preferred, as these drugs have been more thoroughly evaluated for this indication.

[Clinical reasoning and decision making in practice: a 30-year-old man with unexplained coma]. / Klinisch denken en beslissen in de praktijk. Een 30-jarige man met een onverklaard coma.

A 30-year-old man known to have a factor-IX deficiency was presented at the emergency department with unexplained coma. After immediate treatment with factor IX, a CT-scan of the brain revealed no intracerebral haemorrhage. However, blood tests showed severe hyponatraemia, low serum osmolarity and high urine-sodium excretion consistent with the Syndrome of Inappropriate Antiduretic Hormone Secretion (SIADH). Therapy with hypertonic saline was instituted resulting in a gradual rise in the serum-sodium concentration. The cause of the hyponatraemia however remained unclear. After repeat history taking the patient mentioned the use of desmopressin for nocturia. Hyponatraemia as a complication of desmopressin use occurs in 8% of adult patients treated for nocturia. Direct availability of a patient's drug history, by means of an electronic record for instance, could avoid unnecessary tests and delay in diagnosis.

[Clinical reasoning and decision-making in practice. A 76 year old woman with gastric carcinoma and cardiac valve disease]. / Klinisch denken en beslissen in de praktijk. Een 76-jarige vrouw met een maagcarcinoom en hartklepvitia.

A 76-year-old woman with combined aortic and mitral valve disease presented with anaemia due to a gastric carcinoma. Further staging revealed no evidence for metastatic disease. Approval for surgery for the carcinoma was obtained after a cardiologist and anaesthesiologist were consulted. On the day of surgery, however, the attending anaesthesiologist estimated the operative risk to be unacceptable. The patient reversed her decision and decided not to have the oncological operation, as she felt well at the moment and considered the limited additional survival time not worth the anxiety. The expert opinion of an anaesthesiologist, a cardiologist and an oncologist not primarily involved in this case show that they differ as to the question who is responsible for the decision-making process in patients such as this one. The evidence on estimating operative risk in patients with cardiac valve disease undergoing noncardiac surgery is not unequivocal. Furthermore, there is a shared responsibility when more physicians are involved in the process of decision-making. Agreement on operative risk between physicians is necessary in order to prevent transfer of conflicting information to the patient.

[Clinical reasoning and decision making in practice. A depressive foreign woman with symptoms of malaise]. / Klinisch denken en beslissen in de praktijk. Een depressieve buitenlandse vrouw met klachten van malaise.

A 27-year-old woman was admitted to the hospital with a depression, anaemia and fatigue. She had come from Angola to the Netherlands as a refugee 2 years before this evaluation. As an explanation for her symptoms tropical infectious diseases of parasitic origin were considered, but no clues were found in this direction. The test for trypanosomiasis was considered to be suggestive for an infection in the past (persistent titre 1:200). She was discharged but readmitted 6 months later because of a deterioration of her clinical condition. Magnetic resonance imaging showed bilateral signal abnormalities within the white matter of the brain. On examination no neurological signs or abnormalities were found. Again, no definite diagnosis could be made and the patient was discharged. Because of a further deterioration of her clinical condition she was readmitted a short time later for the third time. On the MRI the white matter lesions had increased. The serum protein electrophoresis was markedly abnormal with an elevated IgM Level. Finally, at a repeated lumbar puncture mobile trypanosomes were found. The diagnosis of 'West African sleeping sickness' was made and the patient was treated with eflornithine. She recovered completely during the next 18 months.

Relative bioavailability of three newly developed albendazole formulations: a randomized crossover study with healthy volunteers.

This study of healthy volunteers shows that the relative bioavailability of albendazole formulations that use arachis oil-polysorbate 80 or hydroxypropyl-beta-cyclodextrin as an excipient was enhanced 4.3- and 9.7-fold compared to the results seen with commercial tablets. Administration of macrogol suppositories did not result in measurable plasma concentrations of albendazole sulfoxide.

[Clinical reasoning and decision making in practice. A 41-year old with periodic fever of unknown origin]. / Klinisch denken en beslissen in de praktijk. Een 41-jarige man met onbegrepen periodieke koorts.

A 41-year-old man presented with unexplained bleeding from the right tonsil. He subsequently developed periodic fever, cervical lymphadenopathy and hepatosplenomegaly. Despite extensive bacteriological, serological and radiographic investigations for infectious disease, rheumatic disease and malignancy no diagnosis was made. Although the fever pattern was very suggestive of Pel-Ebstein fever--commonly associated with lymphoproliferative disease--multiple biopsies of lymph nodes, bone marrow, tonsils and liver all proved negative. Empirical glucocorticoid therapy gave some temporary improvement lasting for a month. Splenectomy or splenic biopsy was not carried out because of the risk of excessive bleeding. Eventually the patient died of multi-organ failure and sepsis. At autopsy, a T-cell lymphoma with an unusual phenotype and focal involvement of bone marrow, liver and spleen was found. Clinicians are sometimes faced with the dilemma of whether to perform multiple, invasive and possibly harmful diagnostic tests or to start empirical therapy. Empirical therapy may only be started if the diagnosis has been made on strong clinical grounds and, if this is not the case, only after further diagnostic tests. The question of whether a potentially harmful diagnostic test is justified depends on the clinical course, the sensitivity and specificity of the test and the therapeutic possibilities.

[Clinical reasoning and decision making in practice. Fever, purpura and hemiparesis in a 29-year old female]. / Klinisch denken en beslissen in de praktijk. Koorts, purpura en krachtsverlies bij een 29-jarige vrouw.

A 29-year-old female was admitted with fever, purpura and hemiparesis. She was treated for meningococcal sepsis after a Gram stain of a purpuric lesion showed Gram-negative diplococci. CT scan of the brain revealed multiple haemorrhagic lesions with obliteration of the sulci and basal cisterns. In the course of the disease she developed an acute myocardial infarction. Besides wall motion abnormalities, echocardiography revealed a bicuspid aortic valve with a vegetation on one of its cusps. Despite these findings, both the doctors who were involved in the treatment of this patient and the consulted physician in this article failed to reject the diagnosis 'meningococcal sepsis' and to replace it with a more likely diagnosis, namely Staphylococcus aureus endocarditis. The patient died one day after admission due to transtentorial herniation. Although purpuric lesions are common in meningococcal sepsis, they are not specific for this disease. The false-positive result of the Gram stain resulted in a process known as 'premature closure': the diagnosis of meningococcal sepsis was accepted before it was fully verified. In this case, the consequence was that other diagnostic tests and symptoms were misinterpreted with the result that inappropriate antibiotic therapy was instituted.

Effect of grapefruit juice or cimetidine coadministration on albendazole bioavailability.

The assumed metabolic breakdown of albendazole by mucosal CYP3A4 enzymes was studied by coadministering albendazole (10 mg/kg) with grapefruit juice. Concentrations of albendazole sulfoxide (ABZSX), the active metabolite of albendazole, were compared with those after albendazole was administered with water, a fatty meal, or grapefruit juice plus cimetidine (10 mg/kg). In comparison to water, maximum ABZSX concentration (Cmax) was enhanced 6.5-fold by a fatty meal (from 0.24 +/- 0.09 mg/l to 1.55 +/- 0.30 mg/l; mean +/- SD; P < 0.001) and 3.2-fold by grapefruit juice (from 0.24 +/- 0.09 mg/l to 0.76 +/- 0.37 mg/L; P = 0.031). When grapefruit juice was combined with cimetidine, Cmax was significantly lower than with grapefruit juice alone (0.41 +/- 0.29 mg/l and 0.76 +/- 0.37 mg/l, respectively; P = 0.022). The area under the concentration-time curve from 0 to infinity (AUC(0-omega)) followed a comparable pattern. Half-life (T(1/2)) was 8.8 +/- 4.2 hr and 8.2 +/- 4.3 hr after administration with water or a fatty meal (P = 1.000). Grapefruit juice shortened T(1/2) by 46% (P = 0.026). We hypothesize that albendazole is metabolized by CYP3A4 enzymes in the intestinal mucosa. This process can be inhibited by grapefruit juice. Cimetidine decreased albendazole bioavailability.

[Clinical thinking and decision making in practice. Unexplained rectal blood loss in a patient with multiple endocrine neoplasia type 1 syndrome]. / Klinisch denken en beslissen in de praktijk. Onverklaard rectaal bloedverlies bij een patiënte met het multipele-endocriene-neoplasie-1-syndroom.

A 55-year-old woman, known with multiple endocrine neoplasia (MEN) type 1, had rectal bleeding and later haematemesis but colonoscopy and gastroduodenoscopy revealed no abnormalities. Due to the normal results for serum gastrin concentration, gastroduodenoscopy and CT scanning of the pancreas, Zollinger-Ellison syndrome was considered to be less likely. Yet the diagnosis could be established on the basis of persistent symptoms and a positive somatostatin receptor scintigraphy. The patient was treated with high doses of a proton pump inhibitor and temporary tube feeding due to weight loss. Follow-up will take place at the endocrinology outpatients' department. Zollinger-Ellison syndrome is a relatively common feature of patients with MEN-1. The diagnosis and localisation of the gastrinoma can be difficult: serum gastrin concentrations can be normal and the sensitivity of CT scanning is low. The primary aim of treating gastrinoma is to control gastric acid hypersecretion by means of high doses of a proton pump inhibitor. The question as to whether surgery is indicated remains controversial.

Pharmacokinetics of murine anti-human CD3 antibodies in man are determined by the disappearance of target antigen.

Therapy with monoclonal antibodies (mAbs) is characterized by a molar ratio of receptor to drug that is higher than usual in pharmacotherapy. As a consequence, changes in the amount of receptors induced by the therapy may have important consequences for pharmacokinetics. We therefore analyzed the pharmacokinetics and pharmacodynamics of an experimental therapeutic CD3 antibody, CLB-T3/4.A (murine IgA), which was given as a rejection treatment to renal transplant patients. Patients were treated with 5 mg of the mAb, as a daily bolus injection, during 10 days. Mean trough levels of mAbs increased during the 1st week, and decreased thereafter. However, about one-third of the patients had continuously rising trough levels and about one-third displayed a steady state, that was reached only after 4 days. On the first day of treatment, mAb concentrations showed a biphasic plasma disappearance curve. On subsequent days, monophasic plasma disappearance curves were observed with mean half-lives of 6 to 8 h. Administration of the mAb induced disappearance of target antigen from the peripheral blood, which could explain the difference in kinetics between day 1 and subsequent days shown by a simulation of the multidose curve of plasma concentrations, based on target antigen depletion. We conclude that at this dose the pharmacokinetics of CLB-T3/4.A were to a great extent determined by antibody-induced changes in antigen in peripheral blood. Moreover, determinations of pharmacokinetic and pharmacodynamic parameters based on single-dose data and traditional compartment models were inadequate for the purpose of prediction and extrapolation.

Comparison of the time courses and potencies of the vasodilator effects of nifedipine and felodipine in the human forearm.

In a previous study we investigated the differential time courses of the vasodilator effect of various calcium antagonists (CA) in small isolated rat mesenteric arteries (van der Lee et al., Fundam Clin Pharmacol, 1998: 12: 607-12). We concluded that the differences observed could be due to differences in lipophilicity between the CA studied. A measure for lipophilicity is the logarithm of the membrane-partition coefficient (log P). The log P values of nifedipine and felodipine are 2.50 and 4.46, respectively. It was the aim of the present study to compare the time courses of nifedipine and felodipine effects by means of forearm venous occlusion plethysmography in healthy subjects. Healthy male non-smoking volunteers (age 31 +/- 7 years, n = 14) were studied. Informed consent was obtained prior to each experiment from all subjects. The study commenced with the vehicle of either CA (NaCl 0.9% or a PEG400-solution for nifedipine and felodipine, respectively). In four subsequent runs, increasing concentrations of CA were studied for 20 min each, at an infusion rate of 0.3 ml/min. During experiments both hands were excluded from the circulation using small wrist cuffs, inflated to at least 40 mmHg over systolic blood pressure. Mean arterial pressure remained stable in all subjects (88 +/- 3 and 83 +/- 3 mmHg for nifedipine and felodipine, respectively), thus a systemic effect of the CA was not likely. Log IC50 values were -7.46 +/- 0.17 and -8.47 +/- 0.14 for nifedipine and felodipine, respectively (p < 0.01). Averaged KD values were 4.3 +/- 0.6 and 4.6 +/- 0.6 for nifedipine and felodipine, respectively (n.s.). In this model, felodipine appears to be a more potent vasodilator than nifedipine. The 100-fold difference in lipophilicity between the two CA tested is apparently not sufficient to cause major differences in K(D) values in the plethysmography experimental set-up.

Pharmacokinetic-pharmacodynamic modeling of the inhibitory effect of erythromycin on tumour necrosis factor-alpha and interleukin-6 production.

Erythromycin inhibits the production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL6) induced by heat-killed Streptococcus pneumoniae in human whole blood ex-vivo. The objective of the present study was to determine and characterize the concentration-effect relationship of this phenomenon in order to predict its possible clinical relevance. Six healthy volunteers received a single intravenous dose of 1000 mg erythromycin. Blood samples were obtained up to 4 h after drug administration. Samples were assayed for erythromycin concentrations and (after heat-killed Streptococcus pneumoniae stimulation) for TNF-alpha and IL6 concentrations. Effect vs. time data from individual subjects were fitted to the indirect response model with an Emax concentration-effect relationship. Simulations of these effects were performed for therapeutic intravenous and oral erythromycin dosage regimens. The geometric means of the values of Kin, Kout and EC50 were 15.4 microg/h, 0.82/h, 9.4 mg/L for TNF-alpha and 321 microg/h, 2.02/h, 18.3 mg/L for IL6. Simulations revealed a maximal inhibition of TNF-alpha concentrations of 35%, 50%, 16% and 27% at erythromycin dosages of 500 mg i.v., 1000 mg i.v., 500 mg p.o and 1000 mg p.o. q 6 h, respectively, whereas a maximal inhibition of IL6 of 29%, 44%, 13% and 22% are predicted for the respective regimens. The inhibitory effect of erythromycin on TNF-alpha and IL6 production can be adequately described by the indirect response model with an Emax concentration-effect relationship. Simulations predicted a substantial decrease of production of these cytokines at intravenous and to a much lesser extent at oral erythromycin dosage regimens.