Decreased plasma albumin concentration results in increased volume of distribution and decreased elimination of midazolam in intensive care patients.

The pharmacokinetic parameters of 16 patients in the intensive care unit, sedated with midazolam, were evaluated. A large variation was observed in the plasma concentration of midazolam and between the plasma concentration of midazolam and its metabolite 1-hydroxymethylmidazolam glucuronide. The plasma albumin concentration governs the volume of distribution of midazolam. Decreased plasma albumin concentration (25 gm/L) results in an increased volume of distribution and a decreased elimination rate of midazolam. The observed plasma concentration ratio between the parent drug and its metabolite 1-hydroxymethylmidazolam glucuronide is governed by the variables of protein binding, the metabolic rate of midazolam, and the renal clearance of the glucuronide metabolite itself (which can be considered as a measure of the kidney function of the patient).

Antibiotic prophylaxis of respiratory tract infection in mechanically ventilated patients. A prospective, blinded, randomized trial of the effect of a novel regimen.

The objective of this study was to assess the effect of a novel regimen of antibiotic prophylaxis on the incidence of lower respiratory tract infection in patients requiring prolonged (at least five days) mechanical ventilation. The design was a controlled, prospective, randomized trial, with blinded comparison of the groups regarding the incidence of respiratory tract infection in an intensive care unit of a university hospital. After determination of the APACHE II score for severity of disease, 88 patients were randomly divided in three groups. Twenty-four of these patients did not complete five days of mechanical ventilation, and eight were withdrawn for other reasons. Fifty-six patients (18 in group 1, 21 in group 2, 17 in group 3) completed the study. Patients in both control groups 1 and 2 did not receive antibiotic prophylaxis, but the two groups differed in the antibiotic policy in case of infection. Patients in group 3 received antibiotic prophylaxis consisting of norfloxacin, polymyxin E, and amphotericin B, applied topically in oropharynx and stomach from time of ICU admission until extubation, and intravenous cefotaxime 500 mg three times a day during the first five days of admission. In both control groups, about 90 percent of the patients acquired microbial colonization of oropharynx or stomach. In group 3, only 12 percent and 24 percent of the patients acquired colonization of oropharynx and stomach, respectively (p less than 0.001). This resulted in a reduction of the incidence of lower respiratory tract infection (78 percent in group 1, 62 percent in group 2, 6 percent in group 3 [p = 0.0001]). The regimen of antibiotic prophylaxis studied prevented respiratory tract infection in mechanically ventilated patients. Antibiotic prophylaxis should be considered in all patients expected to require prolonged mechanical ventilation.

Endemic acinetobacter in intensive care units: epidemiology and clinical impact.

AIMS: To assess whether Acinetobacter isolates obtained over 20 months in a tertiary care hospital were epidemiologically related; to establish the clinical importance of the organisms; and to identify the isolates according to the recent taxonomy. METHODS: Fifty eight Acinetobacter isolates from 49 patients collected during 1984 and 1985 were investigated. Most isolates were from respiratory tract specimens from intensive care patients. The organisms were typed by cell envelope protein electrophoresis and by a quantitative carbon source growth assay; patients' charts were reviewed to differentiate between colonisation and infection; representative isolates were identified to species level by DNA-DNA hybridisation. RESULTS: Twelve protein profiles were distinguished in the isolates. Forty two isolates were of the same protein profile (profile I); other profiles were observed in a few or single isolates. Cluster analysis of carbon source growth divided profile I isolates into two groups--one of isolates from 1984 and one from 1985. They were identified as A baumannii and associated with infections in eight patients. Four other infections were caused by acinetobacters with other protein profiles (three of A baumannii; one of the unnamed DNA group 3). CONCLUSIONS: Apart from sporadic strains, two strains of the same protein profile, but distinguishable by carbon source growth, were successively endemic. Cluster analysis was a valuable tool in the interpretation of typing and epidemiological data. The 12 (28%) infections of Acinetobacter in 43 patients in intensive care suggest that the presence of these organisms in wards of severely ill patients should be a cause of concern.

Pharmacokinetics of antibiotics in critically ill patients.

Differences in pharmacokinetic data of aminoglycosides, ceftazidime and ceftriaxone between intensive care patients and volunteers or patients who are less severely ill, are described. Similar differences are observed for midazolam. In severely ill patients with normal renal function a wide interpatient variability of aminoglycoside half-life (t1/2) and increased distribution volume (Vd) are observed. This results in inadequate serum levels. A pharmacokinetic approach of drug dosing, based on serum concentrations in individual patients, is advised. For ceftazidime and ceftriaxone similar changes of t1/2 and Vd are observed. Since protein binding is frequently reduced in severely ill patients, the influence of altered binding of highly bound drugs on Vd and drug clearance is discussed. As both may be increased by reduced protein binding, the change of t1/2 to be expected is unpredictable. Dosing regimens should be based on pharmacokinetic data derived from patients whose severity of disease is comparable to that of the patients to be treated.

Temporary luminal arteriotomy seal for bypass grafting.

BACKGROUND: To enable off-pump coronary operations in a bloodless surgical field without ischemic complications, we developed and assessed a temporary luminal arteriotomy seal in a porcine carotid artery bypass graft model. METHODS: In 16 consecutive pigs (25 kg, 32 anastomoses) the arteriotomy was sealed luminally by a polyurethane elliptic convex seal. Endothelial denudation, medial necrosis, and intimal hyperplasia were measured quantitatively and compared with those seen in conventionally sutured anastomoses. RESULTS: The median occlusive time upon insertion or retrieval was 90 and 82 seconds, including the arteriotomy and securing the anastomosis, respectively. Once properly positioned, the seal provided a bloodless arteriotomy in all anastomoses. Microsurgical suturing was performed without leakage of the seal and with unimpeded flow. In the recipient artery, endothelial denudation was limited to one third of its circumference. No medial necrosis was found. Intimal hyperplasia at heel and toe was not significantly different from that seen in conventionally sutured anastomoses. CONCLUSIONS: During end-to-side bypass grafting, the temporary luminal arteriotomy seal provided a bloodless surgical field without interfering with recipient artery blood flow and with minimal damage to the arterial wall.

Temporary luminal arteriotomy seal: II. Coronary artery bypass grafting on the beating heart.

BACKGROUND: This study assessed the feasibility of applying a temporary luminal arteriotomy seal during end-to-side coronary artery bypass grafting on the beating heart. METHODS: In 18 consecutive pigs, the left internal mammary artery was grafted to the left anterior descending coronary artery, and the arteriotomy was temporarily sealed luminally by a 200-microm-thick polyurethane seal. Endothelial denudation, medial necrosis, and intimal hyperplasia were measured quantitatively and compared with conventionally sutured anastomoses (n=4 pigs). RESULTS: Insertion and retrieval of the seal required 28+/-12 and 11+/-6 seconds, respectively. Including the arteriotomy, coronary artery occlusion was limited to about 80 seconds. The seal provided a bloodless arteriotomy in all anastomoses with unimpeded coronary artery blood flow. Endothelial denudation was limited to two thirds of the circumference of the coronary artery. No medial necrosis was found. Intimal hyperplasia at the suture line was small, although more pronounced when compared with conventionally sutured anastomoses. CONCLUSIONS: In off-pump, beating-heart coronary artery bypass grafting, the temporary luminal arteriotomy seal provided a bloodless arteriotomy with negligible obstruction to coronary artery blood flow, and with a minimum of arterial wall damage. It is conceivable that this seal may expand the indications for coronary surgical procedures without cardiopulmonary bypass.

Cerebral infarcts associated with migraine: clinical features, risk factors and follow-up.

There have been few reports concerning the characteristics of cerebral infarction associated with migraine (CIAM), and especially about the subsequent fate of these patients. We studied 14 patients (9 female) with CIAM. In all these patients the onset of cerebral infarction was accompanied by a unilateral throbbing headache, in 8 also with a gradual build-up of neurological deficits. No other cause of cerebral infarction could be found in these patients. Twelve patients had had previous attacks of migraine, with auras in 6. The nature of the neurological deficit was similar to previous auras in only 3 of these patients. The 2 patients without a history of migraine both developed migraine attacks afterwards. During the same period we also studied 14 patients (8 female) with a cerebral infarct of unknown origin (CIUO). The infarct involved the occipital lobe in 11 of the 14 patients with CIAM, whereas this occurred in 4 patients with CIUO [relative risk (RR): 2.8; 95% confidence interval (CI): 1.2-6.6]. Patients with CIAM had risk factors for atherosclerosis significantly less often than patients with CIUO (RR: 0.1; 95% CI: 0.02-0.9). The functional outcome of patients with CIAM was better than in patients with CIUO: all 14 patients with CIAM were independent in their daily activities, compared with 9 patients with CIUO (RR: 1.6; 95% CI: 1.1-2.3). No patient in either group had a recurrent stroke during a median follow-up period of 5.8 years. In conclusion, CIAM is a stroke entity causing mostly infarcts in the occipital lobe; vascular risk factors are uncommon and prognosis is generally good.

The utility of laparoscopy in the diagnosis of acute appendicitis in women of reproductive age.

AIM: To see whether laparoscopy improves the accuracy of a clinical diagnosis of acute appendicitis in women of reproductive age, and to determine what the long-term sequelae are of not removing an appendix deemed at laparoscopy to be normal. METHOD: The initial part of the study was undertaken during 1991-1992. Female patients between 16 and 45 years were eligible for inclusion once a clinical decision had been made to perform an appendicectomy for suspected acute appendicitis. Following consent, patients were randomized into two groups. One group had open appendicectomy, as planned. The other group had laparoscopy, followed by open appendicectomy only if the appendix was seen to be inflamed or was not visualized. The end points for the study were the clinical outcomes of all patients, and the results of histology, where appropriate. An attempt was made to contact all patients at 10 years to determine whether they had had a subsequent appendicectomy, or had been diagnosed with another abdominal condition that might be relevant to the initial presentation in 1991-1992. RESULTS: Laparoscopic assessment was correct in all cases in which the appendix was visualized. Diagnostic accuracy was improved from 75% to 97%. Laparoscopy was associated with no added complications, no increase in hospital stay in patients who went on to appendicectomy, and a reduction in hospital stay for those who underwent laparoscopy alone. No patients developed a problem over the 10-year follow-up period from having a normal-looking appendix not removed at laparoscopy. CONCLUSION: Laparoscopic assessment of the appendix is reliable, and to leave a normal-looking appendix at laparoscopy does not appear to cause any long-term problems.

Mind the mind: results of a hand-hygiene research in a state-of-the-art cancer hospital.

Poor hand-hygiene (HH) is the primary cause of health-care related infections, yet compliance has proven to be challenging. This multi-method study into HH in a state-of-the-art cancer hospital demonstrates that the presence of resources and prioritisation of HH alone is not sufficient for HH compliance. A large gap was found between perceived (87%) and actual (52%) HH compliance and knowledge. Similarly, although 82% of the respondents knew proper HH moments, they did not act on it. These gaps between perception and reality suggest that resources, knowledge and training might not be sufficient for improving HH: Psychological barriers need to be addressed too.

How to do it in surgery: transanal endoscopic microsurgery.

Transanal endoscopic microsurgery has been performed in our institution since 1993 (Curran et al, 1994). It involves the use of a specially designed operating sigmoidoscope to excise benign and early invasive tumours from the rectum. It allows for accurate dissection of these lesions ensuring safe and complete excision with histological confirmation of this.

Some consequences of drug choice and dosage regimen for patients with impaired kidney function.

The object of this article is to discuss difficulties in extrapolating the performances of a drug for which the kinetic parameters are derived in healthy volunteers, to patients with severely impaired kidney function. The theoretical background of some actual or probable background is given, and a possible solution for these problems is offered, that is, choosing another drug from the same drug group. In patients without kidney function, metabolism is the only pathway of elimination. When the elimination of the metabolite formed occurs by means of renal excretion only, this metabolite accumulates in patients with impaired or absent kidney function. When a metabolic pathway of the parent drug is part of a metabolic equilibrium, the metabolic return reaction results in an "apparent parent compound," with a half-life identical to that of the accumulated metabolite. In this way, the concentration of the "apparent" parent compound increases and the half-life of the sum of parent and "apparent" parent drug will change. Examples of this drug behavior are given for sulfamethoxazole, sulfametrole, sulfamethizole, procainamide, and N4-acetylprocainamide.

Ceftazidime treatment in intensive care patients.

In the intensive care unit 39 patients were treated with ceftazidime for 52 infections (38 broncho-pulmonary infections, 4 intra-abdominal abscesses, 6 septicaemia, 3 urinary tract infections and 1 mediastinitis). All patients were ventilated mechanically. Three patients (6 infections) were not evaluable. In all cases except one, ceftazidime was administered after clinical failure of other antibiotics, including aminoglycosides. Ceftazidime was successful in 32 out of 46 evaluable infections (70%), while its success rate in infections previously treated with aminoglycosides (alone or in combination with cephalothin or cefotaxime) was 78% (21 out of 27 infections). In the higher dosage group (2000 mg tds) the drug was successful in 20 out of 23 infections compared with 12 out of 21 infections in the lower dosage group (1000 mg tds). Altogether 69 bacterial strains were cultured including 30 strains of Pseudomonas aeruginosa. Ceftazidime was clinically successful against 49 and 25 strains, respectively (71 and 83%, respectively). Bacterial overgrowth was present in 13 patients (14 strains) with broncho-pulmonary infections, but in only 7 was a change to another antibiotic required. Elevation of liver function enzymes was recorded in 4 patients, but it was not necessary to stop ceftazidime prematurely. This drug is an effective and relatively safe agent for the treatment of serious infections caused by Gram-negative bacilli including Pseudomonas aeruginosa in critically ill patients.

Influence of protein binding and severity of illness on renal elimination of four cephalosporin drugs in intensive-care patients.

A pharmacokinetic study after a single dose of ceftriaxone, cefoxitin, cefuroxime and ceftazidime was performed to investigate the influence of protein binding and severity of disease on the renal elimination. In intensive-care patients drug-protein binding was substantially less compared to that in volunteers and patients with less complicated diseases. This did not result in increased elimination but, due to increased apparent volumes of distribution, prolonged half-life times were observed. Consequently, in patients with complicated disease states a dosage regimen should be based on pharmacokinetic studies performed in a similar patient group.

Dosage adjustment for ceftazidime in patients with impaired renal function.

Ceftazidime has good antibacterial activity against many Gram-negative micro-organisms including Ps. aeruginosa. The aim of the present study was to calculate a dosage adjustment regimen for renal failure patients and to test it in a second group of patients. A study was made of the pharmacokinetics of ceftazidime 1 g given as a single bolus i.v. injection in 20 patients in an intensive care unit with varying degrees of renal function, including patients on regular haemodialysis. The serum half-life of elimination (t1/2 beta) varied from 1.6 to 45 h depending on renal function. During haemodialysis the mean t1/2 was 4.7 h. A good correlation between the renal clearance of creatinine and ceftazidime was observed. In most patients protein binding was lower than previously observed. From the pharmacokinetic data, a dosage adjustment regimen for patients with renal insufficiency was calculated, which studies in 7 further patients showed to be effective.

Utilization patterns of total parenteral nutrition in a university hospital. A methodological approach.

To study the utilization of total parenteral nutrition, using methodology recommended by the World Health Organization, classification of components in accordance with the anatomical therapeutic chemical classification and defined daily dose system is necessary. Anatomical therapeutic chemical indices are available but defined daily dose values have not been established yet. In this article, a methodology to study both the total utilization of total parenteral nutrition, the utilization of individual substances and the composition of total parenteral nutrition is presented. To validate the proposed methodology, the utilization of total parenteral nutrition in a teaching hospital is studied, based on pharmacy computer data. The total utilization of total parenteral nutrition in the hospital in 1990 is 1.4 defined daily doses/100 bed-days. The composition of total parenteral nutrition varied greatly between the clusters. In this study we showed that utilization of total parenteral nutrition can be measured with the proposed methodology, using a defined daily dose for total parenteral nutrition in concurrence with a defined daily dose for the individual components.

How to do it in surgery: laparoscopic rectopexy.

Laparoscopically performed rectopexy is now possible, with all the advantages of a minimally invasive technique. It may involve implantation of mesh (Cuesta et al, 1993), suturing (Graf et al, 1995) of the reduced rectum or resection of redundant colon (Baker et al, 1995). Essentially the laparoscopic operation mimics the open procedure.

Renal excretion of sulphamethoxazole and its metabolite N4-acetylsulphamethoxazole in patients with impaired kidney function.

Plasma and urine concentrations of creatinine, sulphamethoxazole and its metabolite N4-acetylsulphamethoxazole were measured in patients with varying degrees of kidney impairment. The plasma elimination half-life of sulphamethoxazole is not influenced by the kidney function, while the half-life of the metabolite is fully dependent on the kidney function. The renal clearances of the metabolites and that of the parent compound under alkaline urine conditions are linearly related to the creatinine clearance. Kidney impairment affects only the renal clearance of the metabolite, whereas sulphamethoxazole is metabolized (acetylated) independently of kidney function.