Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). Protocol of a controlled clinical trial developed by consensus of an international study group. Part three: individual patient, complication algorithm and quality manage.

GENERAL DESIGN: Presentation of a new type of a study protocol for evaluation of the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and of sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). A randomised, placebo controlled, double-blinded, single-centre study is performed at an University Hospital (n = 40 patients for each group). This part presents the course of the individual patient and a complication algorithm for the management of anastomotic leakage and quality management. OBJECTIVE: In part three of the protocol, the three major sections include: The course of the individual patient using a comprehensive graphic display, including the perioperative period, hospital stay and post discharge outcome. A center based clinical practice guideline for the management of the most important postoperative complication--anastomotic leakage--including evidence based support for each step of the algorithm. Data management, ethics and organisational structure. CONCLUSIONS: Future studies with immune modifiers will also fail if not better structured (reduction of variance) to achieve uniform patient management in a complex clinical scenario. This new type of a single-centre trial aims to reduce the gap between animal experiments and clinical trials or--if it fails--at least demonstrates new ways for explaining the failures.

Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). Protocol of a controlled clinical trial developed by consensus of an international study group. Part one: rationale and hypothesis.

GENERAL DESIGN: Presentation of a novel study protocol to evalue the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). The rationale and hypothesis are presented in this part of the protocol of the randomised, placebo controlled, double-blinded, single-centre study performed at an university hospital (n = 40 patients for each group). OBJECTIVE: Part one of this protocol describes the concepts of three major sections of the study: Definition of optimum and sub-optimal recovery after operation. Recovery, as an outcome, is not a simple univariate endpoint, but a complex construction of mechanistic variables (i. e. death, complications and health status assessed by the surgeon), quality of life expressed by the patient, and finally a weighted outcome judgement by both the patient and the surgeon (true endpoint). Its conventional early assessment within 14-28 days is artificial: longer periods (such as 6 months) are needed for the patient to state: "I am now as well as I was before". Identification of suitable target patients: the use of biological response modifiers (immune modulators) in addition to traditional prophylaxes (i. e. antibiotics, heparin, volume substitutes) may improve postoperative outcome in appropriate selected patients with reduced host defence and increased immunological stress response, but these have to be defined. Patients classified as ASA 3 and 4 (American Society for Anaesthesiologists) and with colorectal cancer will be studied to prove this hypothesis. Choice of biological response modifier: Filgrastim has been chosen as an example of a biological response modifier because it was effective in a new study type, clinic-modelling randomised trials in rodents, and has shown promise in some clinical trials for indications other than preoperative prophylaxis. It has also enhanced host defence and has been anti-inflammatory in basic research. CONCLUSION: The following hypothesis will be tested in patients with operations for colorectal cancer and increased preoperative risk (ASA 3 and 4): is the outcome as evaluated by the hermeneutic endpoint (quality of life expressed by the patient) and mechanistic endpoints (mortality rate, complication rate, relative hospital stay, assessed by the doctor) improved in the group receiving filgrastim prophylaxis in comparison with the placebo group? Quality of life will be the first primary endpoint in the hierarchical, statistical testing of confirmatory analysis.

Cost-effectiveness of HA-1A treatment for patients with sepsis.

The cost-effectiveness of prescribing HA-1A for sepsis patients was analyzed by comparing effectiveness and direct medical costs. Effectiveness was estimated on the basis of published data from a randomized clinical trial. Costs were determined by combining data from the same trial with expectations about hospital days. Average costs per life year gained were estimated at 25,000 Dutch guilders (1 Dutch guilder is approximately 53 US cents). Sensitivity analyses were applied and showed that the effectiveness and cost-effectiveness of treating patients with HA-1A depend a great deal on the expected duration of survival after successful treatment. If the objective is to maximize the cost-effectiveness of treatment, this means that the prognosis of the patient should be considered when deciding about the appropriateness of treatment with HA-1A. As one would expect, another way to increase cost-effectiveness would be to increase the proportion of gram-negative sepsis patients amongst those receiving treatment.

[Immunotherapy using the anti-endotoxin antibody HA-1A in patients with sepsis syndrome; good results in relation to treatment with placebo]. / Immunotherapie met de anti-endotoxine-antistof HA-1A bij patiënten met het sepsissyndroom; gunstige resultaten ten opzichte van behandeling met placebo.

Passive immunization with a human anti-endotoxin monoclonal IgM antibody (Centoxin, HA-1A) was recently studied in patients with suspected Gram-negative sepsis. Comparison of the results obtained in the Amsterdam subpopulation with those in a larger international study population of which the Amsterdam patient group was a part, showed that it had been possible to select a patient population in which HA-1A has an 'intention-to-treat' effect based upon clinical criteria (a decrease in mortality compared with placebo by 42% (p = 0.04) and in the larger study by 9% (p = 0.24). Until a clinically useful test becomes available, identification of patients who have a high likelihood of Gram-negative sepsis and who would benefit from anti-endotoxin immunotherapy with HA-1A should be based upon the history and evaluation of underlying disease, infection status, severity and progression of the disease. The severely ill patients thus selected should receive treatment as early as possible.

[Cost-effectiveness analysis of human monoclonal antibody HA-1A in patients with sepsis syndrome]. / Kosten-effectiviteitsanalyse van het humane monoklonale antilichaam HA-1A bij patiënten met het sepsissyndroom.

The efficiency of prescribing HA-1A for sepsis patients is analysed by comparing direct medical costs and effects. Effects are estimated on the basis of published data from a randomised clinical trial. Costs are analysed by combining data from the same trial with expectations about hospital days. Average costs per life year gained are estimated at DF1. 25,000. Sensitivity analysis is applied and the efficiency of treating patients with HA1A is shown to depend highly on the expected duration of survival after successful treatment. This leads to the advice to take epidemiologic knowledge into special account before setting the indication for using HA-1A.

Pregnancy outcome in luteinizing hormone-releasing hormone induced cycles: a multicentre study.

In a retrospective international study 223 pregnancies induced with pulsatile hormone-releasing hormone (LH-RH) were evaluated. In patients with hypothalamic amenorrhea (HA) and polycystic ovarian disease (PCOD) the abortion rate was similar (10% vs 8.7%). The premature delivery rate was significantly higher, however, in the patients with HA, but this could be explained by the higher incidence of multiple pregnancies in this group. Thirty multiple pregnancies were observed in the HA group (n = 174) compared with none in the PCOD group (n = 24; p less than 0.05). The incidence of multiple pregnancies in the HA group correlated to the pulse dose (p less than 0.05). The 1st treatment cycle resulted in more multiple pregnancies than did subsequent cycles (p less than 0.05). Difference in pulse interval did not affect the incidence of multiple pregnancies, nor did the route of administration (intravenous or subcutaneous). The incidence of congenital anomalies was comparable to that with spontaneously achieved pregnancies.

Induction of ovulation with pulsatile LH-RH in infertile women.

In five women who had demonstrated repeatedly ovulatory cycles with insufficient luteal phases ovulation was supported by continuous intermittent administration of LH-RH, 5 micrograms per 90 min, intravenously by means of a portable pump. All 18 induced cycles were ovulatory. The production of progesterone rose by 75% to 51 nM/l during the midluteal phase. The duration of the luteal phase increased with 49% to 14 days. One patient became pregnant, but aborted spontaneously 20 days postovulatory. The only major side effect seen was an occasional superficial thrombophlebitis.

Maternal phenylketonuria: the outcome of pregnancy.

This report documents the outcome of two pregnancies is a woman with phenylketonuria (PKU) who was treated with a low phenylalanine diet before conception and during pregnancy. Her first pregnancy resulted in an abortion at 17 wk. During the second pregnancy the patient was unable to maintain the right diet consistently, and her blood phenylalanine levels in the first and second trimester were elevated. This pregnancy ended in the birth of a growth retarded microcephalic infant after an amenorrhea of 42 wk. The infant has maintained a normal growth velocity below the tenth percentile, and has not shown signs of mental retardation.

Induced fetal hyperthyroidism: cardiac output and oxygen consumption.

In 13 chronically catheterized fetal lambs, we inserted a subcutaneous osmotic minipump that released triiodothyronine (T3) at a rate of 5.9 microgram x h-1. Five days postoperatively, fetal plasma T3 concentration had increased 10-fold from a control value of 18.4 ng x dl-1; reverse T3 and thyroxine had decreased 83 and 61% from control values of 524 ng x dl-1, and 9.5 microgram x dl-1, respectively. Fetal heart rate increased 29% to 210 from 163 beats x min-1, and blood pressure remained constant. Cardiac output measured with radioactive-labeled microspheres increased 22% to 678 +/- 33 from a control value obtained from another group of animals of 554 +/- 16 ml x min-1 x kg-1. Umbilical blood flow also increased 22%, while coronary flow increased 35%, and pulmonary flow increased 90%. In contrast, flow to the thyroid gland decreased 52%. Fetal oxygen consumption increased 28% to 10.5 +/- 0.5 from 8.2 +/- 1.1 ml x min-1 x kg-1. Placental carbon monoxide diffusing capacity and venous and arterial blood gas values remained unchanged. We conclude that 1) sustained fetal T3 infusion is one of the few factors that can increase fetal cardiac output, and may play a role in increasing cardiac output in the newborn infant, 2) T3 infusion results in an increased rate of metabolism with increased oxygen consumption, and 3) placental reserve for oxygen diffusion exceeds normal oxygen requirements.

Norepinephrine elevation in the fetal lamb: oxygen consumption and cardiac output.

In an effort to determine if placental diffusion reserves exceed fetal O2 requirements, we increased fetal O2 consumption (VO2) by infusing 1.7-11.5 microgram of norepinephrine (NE) . min-1. After 50 min of infusion VO2 rose 25% to 10.2 from 8.2 ml . min-1 . kg fetal wt-1. Placental CO diffusing capacity remained essentially unchanged from control, 0.49 +/- 0.05 (SE) ml . min-1. Torr-1 . kg-1, During the first 5 min of NE infusion fetal arterial blood pressure increased 29%, while heart rate decreased 15%. In addition, coronary, pulmonary, and umbilical blood flow, expressed per kilogram of fetal weight as determined by use of labeled microspheres, increased 50, 162, and 25%, respectively (P less than 0.05), although fetal cardiac output remained constant at 538 +/- 23 (SE) ml . min-1 . kg-1. Finally, we determined the NE-blood pressure dose-response relations for the fetus; Blood pressure increased with doses up to 1 microgram . min-1 . kg-1, but failed to rise further with higher doses. We conclude that 1) fetal VO2 increases with NE infusion 2) the placental reserve for O2 diffusion exceeds normal requirements, and 3) NE infusion is associated with increased blood pressure, bradycardia, and a redistribution of blood flows to the heart, lungs, and placenta despite a constant cardiac output.

Clinical and physiologic implications of increased fetal oxygen consumption.

In an effect to determine if placental diffusion reserves exceed fetal oxygen requirements we artificially increased fetal O2 consumption by infusing norepinephrine (NE) or triiodothyronine (T3) into 24 chronically catheterized fetal lambs. After 50 minutes of NE infusion, fetal O2 consumption rose 25%; after 5 days of T3 infusion, it increased 28%. In both instances there was a redistribution of organ blood flows, but placental diffusing capacity and the fetal venous and arterial blood gas values remained essentially unchanged. We concluded that both NE and T3 infusion can result in an increased rate of fetal metabolism with increased oxygen consumption and that the placental reserve for O2 diffusion exceeds normal oxygen requirements.