Pharmacokinetics of piperacillin and tazobactam in critically ill patients with renal failure, treated with continuous veno-venous hemofiltration (CVVH).

OBJECTIVE: Kinetics of piperacillin (pip), in combination with the beta-lactamase inhibitor tazobactam (taz) have been studied in volunteers and patients in relatively stable conditions. The fixed drug preparation appeared to have ideal pharmacokinetic properties if renal function was normal or slightly impaired, but no data are available for critically ill patients in anuric renal failure. This study should provide such data. PATIENTS, DESIGN: We studied the pharmacokinetics in nine patients with multiple organ failure, including anuric renal failure, treated with continuous veno-venous hemofiltration (CVVH). Patients received a standard schedule of 4 g pip and 0.5 g taz administered over 0.5 h intravenously, 8 hourly. During 2 consecutive days, the serum levels of both compounds were determined, and total clearance (CIT) was calculated from serum concentrations. RESULTS: All nine patients completed day 1, and 8 completed day 2 of the protocol. On day 1, single-dose kinetics showed considerable spread, but pip/taz serum levels followed the pattern as expected, with a pip/taz concentration ratio of 20:1. On day 2, however, taz serum concentrations showed a relative increase as compared to pip, resulting in a change in the serum pip/taz concentration ratio to 10:1 on day 2. The CIT of pip was 2.52 +/- 1.38 l/h (t 1/2: 5.9 +/- 2.9 h), and CIT of taz 4.44 +/- 2.28 l/h (t 1/2: 8.1 +/- 3.7 h). The CIT and t 1/2 of pip and taz correlated highly significantly with clearance by CVVH. Despite a higher CIT, taz has a longer half-life, because of a higher volume of distribution. CONCLUSION: In CVVH dependent patients, pip/taz fixed drug preparations can be used initially, but the pip dosage should be increased relative to that of taz (or interval-adjusted) to prevent cumulation of taz, as compared to the active antimicrobial agent pip.

[Hypothermia in patients with a high spinal cord lesion]. / Hypothermie bij patiënten met een hoge dwarslaesie.

Two women aged 54 and 69 years with high spinal cord injuries and tetraparesis developed hypothermia (30.4 and 29.4 degrees C, respectively); normalization was accomplished by external heating using insulation blankets. Even moderately lowered environmental temperatures may lead to hypothermia in these patients with abnormal temperature sensation, incapacity to compensate and autonomous dysfunction. The symptoms are aspecific and the differential diagnosis is extensive. Recommendations for prevention of hypothermia include daily measurement of the core temperature, adjustment of the environmental temperature and humidity of the air, adequate closing and avoidance of vasodilator drugs.

Pulmonary function after high-dose chemotherapy with autologous bone marrow transplantation and radiotherapy in patients with advanced loco-regional breast cancer.

Our aim was to study the extent of pulmonary toxicity after high-dose chemotherapy and radiotherapy in breast cancer patients. In a retrospective study the pulmonary symptoms and chest X-rays were analyzed before, during and after treatment in 17 patients, treated with loco-regional radiotherapy to the breast/chest wall and the regional lymph nodes after the completion of high-dose chemotherapy and autologous bone marrow transplantation for locally advanced breast cancer. Lung function was evaluated between 15 and 46 months after completion of the irradiation. Nine patients (53%) had pulmonary symptoms during and/or within two months from irradiation. Radiographic changes were seen in twelve patients (71%) and a decreased diffusion capacity occurred in nine patients (53%). The spirometric values (VC and FEV1) were abnormal in two patients (12%). There is a high incidence of radiation pneumonitis, although no consistent correlation between the various parameters (pulmonary symptoms, chest X-rays and lung function tests) could be found.

Amanita phalloides, a potentially lethal mushroom: its clinical presentation and therapeutic options.

Mushroom poisoning with Amanita phalloides, a rare phenomenon in everyday clinical practice in the Netherlands, must be recognized early in view of its potential morbidity and mortality. In this article 2 cases of amanita intoxication are presented and the pharmacological basis and clinical manifestations discussed. Furthermore, the rationale of various treatment modalities, including the role of liver transplantation, is outlined.

Long-term results of induction- and intensification chemotherapy supported with autologous bone marrow reinfusion in patients with disseminated or T4 breast cancer.

Twenty-nine patients with metastatic or T4 breast cancer who were in pathologically proven complete remission after induction chemotherapy, received intensification chemotherapy with autologous bone marrow support. Twelve patients had T4 breast cancer, 17 had metastatic disease. The median age was 42 years (27-52). Intensification consisted of cyclophosphamide 7 g/m2 i.v. and etoposide 1.5 g/m2 i.v. in 24 patients, or thiotepa 800 mg/m2 i.v. and mitoxantrone 50-75 mg/m2 i.v. in 5 patients. The median observation is 7 years. Median survival is 36 months. Ten year relapse-free survival is 20%. For patients with metastatic disease median survival is 34 months, time to relapse 18 months; two patients (12%) have survived disease-free for more than 6 years. The patients with T4 cancer have a median survival of 80 months and a median time to relapse of 53 months; four patients (33%) have survived more than 5 years disease-free.

Lactate monitoring with subcutaneous microdialysis in patients with shock: a pilot study.

We describe the use of subcutaneous microdialysis for continuous sampling of lactate to monitor the plasma lactate concentration in eight patients with shock. The dialysate lactate concentrations were significantly correlated with the plasma lactate concentrations (r = 0.8229), but the linear regression lines varied between patients. Therefore, we used the individual regression line of each patient for calibration to calculate estimated plasma values from the dialysate concentrations. While the estimated values were linearly correlated to the plasma lactate values (r = 0.912), the 95% confidence interval of the estimated values was +/- 2.8 mmol/L. Thus, subcutaneous microdialysis does not allow accurate estimation of the plasma lactate concentration. In 3 of the 8 patients, there was a significant negative correlation between the dialysate/plasma lactate ratio and the plasma lactate concentration. This suggests that besides plasma lactate, other factors such as subcutaneous adipose tissue metabolism and blood flow, may influence subcutaneous sampling and dialysate lactate concentration as well. While microdialysis can be used for on-line sampling and continuous monitoring of the concentration of extracellular substances, for the purpose of plasma lactate monitoring, sampling probes should be designed that permit intravascular placement.

Intensive chemotherapy with autologous bone marrow transfusion as primary treatment in women with breast cancer and more than five involved axillary lymph nodes.

Patients with breast cancer and a high number of involved axillary lymph nodes have a poor prognosis, despite adjuvant chemotherapy. The 5-year disease-free survival (DFS) in this group amounts to 30-40% and the 10-year DFS is only 15-20%. Therefore, new treatment modalities are being sought for this group of patients. The aim of the present study was the evaluation of the efficacy of high-dose chemotherapy combined with autologous bone marrow support. 24 patients with a primary breast cancer with more than five involved axillary lymph nodes received, after surgery, six courses of induction chemotherapy followed by ablative chemotherapy and reinfusion of autologous bone marrow. All patients were premenopausal or less than 2 years postmenopausal. Induction chemotherapy consisted of methotrexate (MTX) 1.5 g/m2 intravenous (i.v.) and 5-fluorouracil (5-FU) 1.5 g/m2 i.v. on day 1, prednisone 40 mg/m2 orally on days 2-14, doxorubicin 50 mg/m2 i.v. and vincristine 1 mg/m2 i.v. on day 14. Courses were repeated six times every 4 weeks. 10 patients received cyclophosphamide 7 g/m2 i.v. and etoposide 1.5 g/m2 i.v. as intensive regimen, in 14 patients this comprised mitoxantrone 50 mg/m2 i.v. and thiotepa 800 mg/m2 i.v. Reinfusion of autologous marrow followed on day 7. Finally, patients received locoregional radiotherapy for extranodal disease and tamoxifen 40 mg daily orally over a period of 2 years. The median age of patients was 42 years, range 29-54. The median number of involved nodes was 10. During induction therapy, fever requiring i.v. antibiotics occurred in 4% of 144 courses, 14% of patients suffered from mucositis WHO grade 2-3, and the other patients had mucositis grade 1. During the ablative chemotherapy, 1 patient died, 6 developed septicaemia, 5 showed mucositis grade 3-4 and the other patients had mucositis grade 1 or 2. In the follow-up, 1 patient died from acute cardiac failure. Reversible radiation-induced pneumonitis occurred in 7 out of 14 irradiated patients; symptoms started directly following radiotherapy and lasted for several weeks, but disappeared in due course. During follow-up, 2 patients with six and > 10 positive nodes, respectively, have relapsed after 18 and 36 months, both in the cyclophosphamide/etoposide regimen. Median observation is 3 years, disease-free survival at 5 years is predicted to be 84%. Intensive treatment in these patients with high numbers of involved axillary lymph nodes is a toxic regimen, but may improve the chance of surviving free of disease.

Induction chemotherapy and intensification with autologous bone marrow reinfusion in patients with locally advanced and disseminated breast cancer.

In 56 patients with disseminated or locally advanced breast cancer it was attempted to reach a state of no evidence of disease by a remission induction regime containing prednisone, 5-fluorouracil, methotrexate, doxorubicin and vincristine. If successful, patients received an intensification regimen consisting of cyclophosphamide (7 g/m2) and etoposide (1.5 g/m2) with autologous bone marrow reinfusion. The complete remission rate of the induction regimen was 52% and the partial remission rate 42%. 32 patients received the intensification regimen. Two toxic deaths occurred. The median time to disease progression in the group with disseminated disease was 15 months. After a median observation of 4 years, 11 out of 19 patients with locally advanced breast cancer were free of disease. It is concluded that this approach may lead to prolonged disease-free survival in patients with locally advanced breast cancer, but does not influence the survival in disseminated disease.

Patterns of cytokines, plasma endotoxin, plasminogen activator inhibitor, and acute-phase proteins during the treatment of severe sepsis in humans.

OBJECTIVE: To study the patterns of plasma concentrations of endotoxin, tumor necrosis factor-alpha (TNF), interleukin-6 (IL-6), plasminogen activator inhibitor-1, C-reactive protein, and serum amyloid A during the treatment of human sepsis. DESIGN: A prospective case series study. SETTING: ICU of the Department of Internal Medicine, University Hospital Groningen, The Netherlands. PATIENTS: Twenty consecutive patients (11 female, 9 male, mean age 67 yrs) with clinically defined sepsis. Eighteen patients were admitted from the outpatient emergency ward; two patients were already inpatients. The control group (n = 7) comprised patients with nonseptic shock. MEASUREMENTS AND MAIN RESULTS: Ten (50%) septic patients had detectable endotoxemia (greater than 5 (ng/L). TNF concentrations on admission were increased in 94% of the septic patients, whereas IL-6 and plasminogen activator inhibitor plasma concentrations were increased in all septic patients. The septic group showed significantly (p less than .05) higher concentrations of TNF, IL-6, plasminogen activator inhibitor-1, C-reactive protein, and serum amyloid A compared with the nonseptic patients. In the septic group, we found a correlation of both IL-6 and plasminogen activator inhibitor concentrations with severity of illness (r2 = .33, p less than .05; r2 = .22, p less than .05, respectively). After the start of antibiotic treatment, high concentrations of TNF and plasminogen activator inhibitor persisted in the nonsurvivors in contrast to decreasing concentrations in most of the survivors. After an initial increase in seven patients, IL-6 concentrations decreased in all septic patients and also in nonsurvivors. CONCLUSIONS: This study confirms previous findings that: a) TNF is a major mediator involved in the pathogenesis of septic shock; b) plasminogen activator inhibitor activity is significantly increased in septic patients and might be involved in the pathogenesis of disseminated intravascular coagulation associated with sepsis; and c) IL-6 is involved in the pathophysiology of septic shock, although further studies are needed to determine whether IL-6 is directly involved in mediating the lethal complications of septic shock or whether it should be considered an "alarm hormone" that reflects endothelial cell injury. Our findings also suggest that the concentrations and trends of these mediators during treatment are valuable for monitoring septic patients.

Complement activation and the production of inflammatory mediators during the treatment of severe sepsis in humans.

Sepsis or septic shock is frequently associated with activation of the complement system, coagulation and fibrinolytic changes and the release of several cytokines. In this study we analyzed the relation of complement activation to the inflammatory mediators, hemodynamic and biochemical parameters and severity of illness and outcome in 20 consecutive patients with clinically defined sepsis. Levels of C3a and C3d were elevated in 90% of the patients (median levels 0.19 mg/l and 8.6 mg/l respectively) in comparison to 14% and 42%, respectively of 7 patients with non-septic shock. Levels of C4 were decreased in only 1 of the 20 septic patients. Levels of TNF and IL-6 were elevated in 94% and 100% of the patients, Levels of TNF and IL-6 were elevated in 94% and 100% of the patients, respectively (median levels 122 ng/l and 1300 U/ml) and were clearly interrelated (r = 0.67, p less than 0.01). C3a levels correlated with the APACHE II score (r = 0.57, p less than 0.05) and high C3a levels were associated with fatal outcome (p less than 0.05). C3a was also correlated inversely with mean arterial pressure (r = 0.50, p less than 0.01). Levels of complement C3a and C3d significantly correlated with levels of plasminogen activator inhibitor-1 (PAI) and correlated inversely with AT-III levels. We found no correlation between these complement products and leukocyte counts or lactate levels, nor was there a correlation between C3a or C3d and the cytokines TNF and IL-6. Levels of C3a and C3d did not decrease significantly during the first 24 h of treatment, in contrast to a clear decrease in IL-6 levels in all patients and a decrease in TNF in the surviving patients. TNF levels remained stable or increased in the non-survivors. We conclude that both the complement system and the cytokine system are involved in the pathogenesis of septic shock and may be involved in the development of some of the fatal complications like hypotension and disseminated intravascular coagulation.

Tumour necrosis factor (cachectin) and other cytokines in septic shock: a review of the literature.

The role of bacterial endotoxin in the pathogenesis of septic shock has been studied extensively. Endotoxin does not seem to exert most of its effects on the host directly, but rather it elicits the production of host factors that may in turn lead to shock and death. These factors, called cytokines, appear to be produced by cells of haematopoietic origin such as macrophages/monocytes, but can also be produced by other cells such as endothelium and fibroblasts. Three important cytokines associated with septic shock are tumour necrosis factor/cachectin (TNF), interleukin 1 (IL-1) and interleukin 6 (IL-6). The macrophage-derived TNF has been implicated as the most important host mediator in the pathogenesis of septic shock. TNF, alone or together with endotoxin or IL-1, is capable of inducing lethal shock and tissue injury resembling that of septic shock. It has also been suggested that IL-6 is involved in the pathogenesis of septic shock. The major biologic activities of IL-6 include B-cell differentiation and induction of the acute-phase proteins. In the present paper, reports addressing the current understanding of the biological, regulatory and clinical aspects of these cytokines are reviewed.

In vitro and in vivo modulation of multi-drug resistance with amiodarone.

The modulating effect on drug resistance of amiodarone (AM) and its metabolite desethylamiodarone (DEA) was studied in a P-glycoprotein-positive human colon carcinoma cell line COLO 320, and a human small-cell lung carcinoma cell line GLC4 and its adriamycin (Adr)-resistant subline GLC4-Adr (both P-glycoprotein-negative). AM, DEA and verapamil induced an increase in cytotoxicity of Adr, vincristine and etoposide (VP16) in COLO 320 cells, while in the GLC4 and GLC4-Adr cell line no effect was seen. In the COLO 320 cell line, AM caused more intracellular, and especially intranuclear, fluorescence of Adr and more Adr-induced DNA strand breaks as compared to Adr alone. Moreover, an increase in VP16-induced topoisomerase II-DNA complexes was observed when AM was added. Competition between AM and Adr for the same efflux pump was suggested in efflux studies. The colony-forming unit granulocyte macrophage (CFU-GM) assay showed no increase in cytotoxicity of Adr when AM was added. Fourteen patients with Adr-resistant tumors were treated with Adr and AM. In these patients, peak serum levels of AM plus DEA of 10 microM were reached. Patient serum (20%) obtained after the first i.v. AM infusion induced in vitro significantly more cell kill of Adr in COLO 320 cells. Apart from a transient first-degree AV block in one patient, no cardiac toxicity was observed with the combination of Adr and AM. Bone-marrow toxicity was the same as expected from Adr alone in these patients. One of the 13 evaluable patients obtained a partial remission.

Effects of different types and combinations of antimicrobial agents on endotoxin release from gram-negative bacteria: an in-vitro and in-vivo study.

Total and free endotoxin release in time from cultures of Escherichia coli by different antibiotics was studied in vitro for 4 h in relation to the antibiotic effect on viable counts and morphological features of the test cultures. The most rapid fall in viable counts was seen after treatment with imipenem or the combination of imipenem with tobramycin, accompanied by an early, but minimal increase (1.8-fold) of the total (free plus cell-bound) endotoxin level at 1 h. Total endotoxin levels increased approximately 5-fold upon incubation with ceftazidime, tobramycin or the combination of tobramycin with cefuroxime, whereas incubation with cefuroxime or aztreonam alone caused a late 22-and 49-fold increase in total endotoxin, respectively, at 4 h. In chloramphenicol treated cultures there was still an increase in viable counts during therapy, resulting in an ultimately 78-fold increase of mean levels of total endotoxin. Free endotoxin levels increased approximately 6-fold within 1 h upon treatment with imipenem, alone or in combination with tobramycin, or ceftazidime as the result of rapid lysis of bacteria. Treatment with cefuroxime or aztreonam induced a relatively late but much higher release of free endotoxin (118-and 222-fold, respectively), which was due to the formation of long filamentous structures during the first 2 h of incubation and eventually cell lysis. Both tobramycin and the combination of tobramycin with cefuroxime caused a more gradual rise in free endotoxin, with a +/- 15-fold increase in free endotoxin at 4 h. In chloramphenicol treated cultures, as in the control cultures, the level of free endotoxin remained proportional to the amount of viable organisms. We also studied plasma endotoxin levels in 20 patients with septic shock. 10 out of these 20 patients had a detectable endotoxemia (greater than 5 ng/l) on admission. We describe the patterns of plasma endotoxin in these patients during the first 24 h of antibiotic treatment. We conclude that, in the in-vitro study, values of total endotoxin, free endotoxin, and the rate of release of endotoxin varies with the antibiotic used. We also demonstrate that in patients under treatment for septic shock endotoxin release can be related to the administration of antibiotics.

Pharmacokinetics of carboplatin at a dose of 750 mg m-2 divided over three consecutive days.

Pharmacokinetics of the cisplatin analogue carboplatin were studied in patients with disseminated ovarian and testicular cancer. Carboplatin 750 mg m-2 divided over three consecutive days was given as part of an ablative combination regimen followed by autologous bone marrow transplantation. Platinum (Pt) in plasma, plasma ultrafiltrate and urine was determined up to 96 h after the last drug dose by atomic absorption spectrometry. Carboplatin was measured by high performance liquid chromatography. The curves of ultrafiltrated Pt and carboplatin decayed in a bio-exponential way with t1/2 alpha of respectively 65 and 70 min and t1/2 beta of respectively 378 and 1014 min. The volumes of distribution (Vdss) were 18 and 25 l m-2, respectively, and total body clearances (ClTB) 79 and 65 ml min-1 m-2. Both curves overlapped when corrected for the Pt content of carboplatin. A diversion with the three-exponential curve of total Pt occurred between 3 and 6 h. After 10 h approximately 30% of the plasma Pt was protein bound. Total Pt had a larger Vdss (117 l m-2) and a lower total body clearance (14 ml min-1 m-2) than free Pt and carboplatin. Fifty-three per cent of the i.v. administered carboplatin was excreted in the urine in the first 6 h. Plasma ultrafiltrated Pt and carboplatin decreased to undetectable levels within 48 h, but total Pt was detectable until 96 h after the last carboplatin dose. However, this Pt is already bound to protein and unlikely to be cytotoxic to reinfused haemopoietic stem cells, so bone marrow reinfusion can be safely performed at 48 h after repeated dosing of carboplatin on three consecutive days.

Hyperalimentation in autologous bone marrow transplantation for solid tumors. Comparison of total parenteral versus partial parenteral plus enteral nutrition.

Recipients of autologous bone marrow transplantation (ABMT) for solid tumors need nutritional support to maintain their body weight (BW). Severe BW-reduction (9.9%) was noticed retrospectively in ten ABMT patients fed orally, despite intensive counseling or occasional tube feeding. A prospective, randomized study of hyperalimentation (25 g nitrogen (N) and 3400 nonprotein kilocalories) with total parenteral nutrition (TPN) or partial parenteral plus enteral nutrition by tube feeding (PPN/EN) was done in 22 patients. Nutritional assessment included balance measurements of N, Na, K, Cl, P, Ca, Mg, Cu, and Zn, and serial measurements of BW, serum albumin, prealbumin, and transferrin. Both regimens were effective in maintaining BW (maximum percent of change, 2.5) and N-balance. Blood products accounted for an additional N-intake of 13% in both groups. The TPN group had a higher dietary N-intake versus PPN/EN, a positive K balance but negative Ca, Mg, Cu, and Zn balances. More mineral supplementation was given in the PPN/EN group where positive K, Mg, and Zn balances were seen. Visceral proteins and IgG, IgA, and IgM levels were decreased on days 7, 14, and 21. Creatinine clearance increased significantly in both groups. Compared with TPN, the PPN/EN group showed a twofold number of patients with a positive blood culture, although this observation did not reach statistical significance and patients had fewer days of diarrhea (31.1% versus 54.3%, P less than 0.01). Hyperalimentation with PPN/EN is an acceptable alternative to TPN in the nutritional support of ABMT recipients.

High-dose cyclophosphamide or melphalan with escalating doses of mitoxantrone and autologous bone marrow transplantation for refractory solid tumors.

As the dose-limiting toxicity of mitoxantrone is hematological, the drug is suitable for dose escalation and use in intensive chemotherapy followed by autologous bone marrow rescue. Adult patients with therapy-resistant solid tumors received a regimen of high-dose cyclophosphamide (7 g/m2) and escalating doses of mitoxantrone in dose steps of 30, 45, 60, and 75 mg/m2. Both drugs were given i.v. on 3 consecutive days. Despite the addition of mesnum (3.5 to 7 g/m2), hemorrhagic cystitis occurred on the second day in four of eight patients, irrespective of the mesnum or mitoxantrone dose. Therefore, the cyclophosphamide in the combination regimen was replaced by high-dose melphalan (180 mg/m2). Mucositis was dose limiting at 75 mg/m2 of mitoxantrone. Responses were seen in eight of ten evaluable patients with four complete responses. Three responders received, after the autologous bone marrow transplantation program, radiotherapy or surgery on pretreatment bulky tumor localizations. Five patients still have disease-free survival after 9 to 36 mo. Pharmacokinetic studies of mitoxantrone were performed by high-performance liquid chromatography with UV detection. The plasma disappearance of mitoxantrone fitted into a three-compartment model with a mean t1/2 alpha of 10 min, a mean t1/2 beta of 96 min, and a slow elimination phase of 172 h. The mean distribution volume was 4294 +/- 3836 liters. We conclude that the high-dose cyclophosphamide-mitoxantrone regimen led to unexpected bladder toxicity, but the combination of melphalan (180 mg/m2) and mitoxantrone (60 mg/m2) can probably be given without major extramedullary toxicity. However, more patients should be evaluated at this dose before definite conclusions can be drawn about toxicity.

Incidence and effects of herpes simplex virus infection after autologous bone marrow transplantation for solid tumours.

In a prospective study of 44 patients, who underwent autologous bone marrow transplantation (ABMT) for solid tumours, the results of serial viral cultures and determination of complement-fixing antibodies to herpes simplex virus (HSV) were analysed. No primary infections with HSV occurred. Of 31 initially HSV-seropositive ABMT patients, 61% developed positive HSV cultures. Half of these patients showed a significant antibody rise. Active HSV infection did not influence the recovery of the bone marrow after ABMT, but coincided with a significantly increased number of febrile days.

High-dose chemotherapy with autologous bone marrow transplantation in patients with refractory ovarian cancer.

Eleven patients with persistent ovarian cancer after remission-induction chemotherapy were treated with high-dose cyclophosphamide and etoposide followed by autologous bone marrow transplantation (ABMT). Six complete responses (CR), of which five were pathologically confirmed, were achieved in eight patients who had microscopic or residual disease less than or equal to 2 cm at the start of high-dose chemotherapy. The median duration of response was 15 months with two sustained CRs after respectively 43 and 75 months. None of the three patients with residual disease greater than 2 cm responded. The median survival measured from the start of the ABMT regimen was for all patients 23 months. These results suggest that high-dose systemic chemotherapy followed by ABMT is a therapeutic option in patients with refractory ovarian cancer deserving further investigation.