The impact of musculoskeletal ill health on quality of life and function after critical care: a multicentre prospective cohort study.

Physical disability is a common component of post-intensive care syndrome, but the importance of musculoskeletal health in this population is currently unknown. We aimed to determine the musculoskeletal health state of intensive care unit survivors and assess its relationship with health-related quality of life; employment; and psychological and physical function. We conducted a multicentre prospective cohort study of adults admitted to intensive care for > 48 h without musculoskeletal trauma or neurological insult. Patients were followed up 6 months after admission where musculoskeletal health state was measured using the validated Musculoskeletal Health Questionnaire score. Of the 254 participants, 150 (59%) had a musculoskeletal problem and only 60 (24%) had received physiotherapy after discharge. Functional Comorbidity Index, Clinical Frailty Scale, duration of intensive care unit stay and prone positioning were all independently associated with worse musculoskeletal health. Musculoskeletal health state moderately correlated with quality of life, rs = 0.499 (95%CI 0.392-0.589); anxiety, rs = -0.433 (95%CI -0.538 to -0.315); and depression, rs = -0.537 (95%CI -0.631 to -0.434) (all p < 0.001). Patients with a musculoskeletal problem were less physically active than those without a problem (median (IQR [range]) number of 30 min physical activity sessions per week 1 (0-3.25 [0-7]) vs. 4 (1-7 [0-7]), p < 0.001, respectively). This study found that musculoskeletal health problems were common after intensive care unit stay. However, we observed that < 25% of patients received physical rehabilitation after discharge home. Our work has identified potential high-risk groups to target in future interventional studies.

A human factors analysis of missed mobilisation after discharge from intensive care: a competition for care?

BACKGROUND: Patients discharged to the ward from an intensive care unit (ICU) commonly experience a reduction in mobility but few mobility interventions. Barriers and facilitators for mobilisation on acute wards after discharge from an ICU were explored. DESIGN AND METHODS: A human factors analysis was undertaken using the Functional Resonance Analysis Method (FRAM) as part of the Recovery Following Intensive Care Treatment (REFLECT) study. A FRAM focus group was formed from members of the ICU and ward multidisciplinary teams from two hospitals, with experience of working in six hospitals. They identified factors influencing mobilisation and the interdependency of these factors. RESULTS: Patients requiring discharge assessments or on Enhanced Recovery After Surgery (ERAS) pathways compete for priority with post-ICU patients with more urgent rehabilitation needs. Patients unable to stand and step to a chair or requiring mobilisation equipment were deemed particularly susceptible to missing mobilisation interventions. The ability to mobilise was perceived to be highly influenced by multidisciplinary staffing levels and skill mix. These factors are interdependent in facilitating or inhibiting mobilisation. CONCLUSIONS: This human factors analysis of post-ICU mobilisation highlighted several influencing factors and demonstrated their interdependency. Future interventions should focus on mitigating competing priorities to ensure regular mobilisation, target patients unable to stand and step to a chair on discharge from ICU and create robust processes to ensure suitable equipment availability. TRIAL REGISTRATION NUMBER: ISRCTN14658054.

Mixed lymphocyte culture of human fetal liver cells.

OBJECTIVE: In order to study the immunological function of the human fetus in the first and second trimesters, mixed lymphocyte culture (MLC) of fetal liver and thymic cells was performed. MLC is a functional test to determine human lymphocyte antigen-D incompatibilities. METHODS: Human fetal liver and thymic tissue was obtained from abortions in gestational weeks 7-17.5. Forty-seven fetuses were studied with one-way MLC. The cells were stimulated by adding irradiated fetal liver cells, adult bone marrow and peripheral blood lymphocytes. The activity was measured as DNA incorporation of radiolabeled thymidine. RESULTS: The results indicate that the human fetus is competent to react as early as 11-12 weeks of gestation and in some cases even earlier. In very immature fetal livers (< 8 weeks), the MLC seems to be inhibited. CONCLUSIONS: Our data suggest that the human fetus can react against foreign transplantation antigens earlier than previous papers have claimed. The onset of reactivity seems to differ considerably among fetuses. The present findings may explain some of the limited success of in utero transplantations of hematopoietic stem cells in human fetuses of normal immunological status.

Does hyperandrogenism explain lower in vitro fertilization (IVF) success rates in smokers?

BACKGROUND: Our aims were to elucidate whether a decreased fertility in smoking women treated by in vitro fertilization (IVF) could be related to a divergent hormonal response to the controlled stimulation prior to IVF, to study the effect of smoking on the ovarian endocrine milieu and to possibly identify factors that might be detrimental to oocyte fertilization. METHODS: Serum and follicular fluid concentrations of estradiol-17 beta (E2), progesterone (P), testosterone (T), 4-androstene-3,17-dione (A-4), dehydroepiandrosterone (DHA), DHA sulfate (DHAS), sex hormone-binding globulin (SHBG) and serum cortisol were studied in 50 non-smoking and 50 smoking women in an IVF program. Follicular fluid concentrations were also compared in follicles which gave rise to cleaved oocytes (TYPE I) and follicles which failed to yield fertilized oocytes (TYPE II) in the same woman. RESULTS: The fertilization rate did not differ significantly between the two groups, but the live birth rate was 30% in non-smokers and 4% in smokers. During treatment, serum A-4, DHAS and the T/SHBG-ratio were significantly higher in smokers than in non-smokers. In the TYPE I follicles, smokers had higher follicular fluid concentrations of A-4 and DHA and a higher E2/P ratio. The TYPE II follicles in smokers had higher A-4 and T and lower E2 levels. CONCLUSIONS: Smoking women have a relative hyperandrogenism of ovarian origin, which may contribute to the lower pregnancy rate at IVF in this group.

Androstenedione as a predictor of ovarian hyperstimulation syndrome.

Serum concentrations of testosterone, 4-androstene-3,17-dione (androstenedione), dehydroepiandrosterone (DHA) and its sulphate and sex hormone-binding globulin (SHBG) were measured in 30 ovulatory women before and after down-regulation with gonadotrophin releasing-hormone analogue, prior to ovarian stimulation in a programme of in-vitro fertilization and embryo transfer. Nine of the women developed ovarian hyperstimulation syndrome (OHSS) while the others did not. Pretreatment values of androstenedione and the androstenedione:DHA ratios were higher and the testosterone:androstenedione ratios lower in the OHSS women. The decrease in androstenedione levels during down-regulation was greater and the absolute levels following down-regulation were lower in the OHSS group. Higher levels of SHBG and lower testosterone:SHBG ratios, an index of biologically active testosterone, were observed in the OHSS group. The isolated elevation in pretreatment androstenedione levels and the high SHBG levels make the OHSS group different from patients with polycystic ovarian disease. Pretreatment values of testosterone:androstenedione or testosterone/SHBG:androstenedione ratios and/or the decrease in androstenedione during down-regulation may be used as markers, prior to stimulation, for identifying women at risk of developing OHSS.

Placental protein 14 in human in-vitro fertilization early pregnancies.

Placental protein 14 (PP14) and human chorionic gonadotrophin (HCG) were analysed in patients participating in an in-vitro fertilization-embryo transfer programme which did not include any kind of luteal support. Women with normal pregnancies, spontaneous abortions, ectopic pregnancies, biochemical pregnancies and non-pregnant women were compared. A combination of HCG and PP14 analyses distinguished between normal and abnormal implantation as early as 15 days after oocyte retrieval. The product of HCG (IU/l) and PP14 (micrograms/l) concentrations differed significantly between normal pregnancy, spontaneous abortion and ectopic pregnancy (P = 0.0248). It is concluded that both endometrial (PP14) and trophoblastic (HCG) markers, when used in combination, exhibit changes in abnormal implantation which may be clinically useful.

Sex hormone-binding globulin, oestradiol-17 beta, progesterone and testosterone at stimulation and after embryo transfer during in-vitro fertilization.

Serum concentrations of sex hormone-binding globulin (SHBG), oestradiol-17 beta progesterone and testosterone were measured in 23 gonadotrophin-stimulated menstrual cycles and in the implantation period [days 11-19 after human chorionic gonadotrophin (HCG) injection] following in-vitro fertilization and embryo transfer. Nine cycles resulted in successful pregnancies, one pregnancy ended in spontaneous abortion (week 14) and 13 cycles were without conception. SHBG levels were significantly elevated above pretreatment values from day 3 after HCG injection onwards. A significant positive correlation was found between increments in SHBG (delta SHBG) during the luteal phase and oestradiol/testosterone ratios during the follicular and luteal phases. In the pregnant cycles a significant positive correlation was also found between delta SHBG during the implantation period and oestradiol/testosterone ratios during the luteal phase and the implantation period. Significant negative correlations were found between delta SHBG and testosterone during the luteal phase in pregnant and non-pregnant women as well as between delta SHBG during the period corresponding to implantation and testosterone during the luteal phase in non-pregnant cycles. The results may reflect a modulating action of the oestrogen/androgen balance upon SHBG levels in subjects with supraphysiological oestradiol levels, such as in stimulated cycles and in very early pregnancy.

Sperm count and motility influence the results of human fertilization in vitro.

In order to select sperm characteristics that can predict the outcome of in-vitro fertilization-embryo transfer (IVF-ET), semen samples delivered in conjunction with this treatment were studied carefully. We have analysed these data retrospectively in relation to the outcome of treatment. Ninety-one couples were treated for tubal infertility by IVF-ET. Fifteen women became pregnant. Sperm were isolated from semen using a swim-up technique and in most cases 40-80 x 10(3) (range 20-120 x 10(3)) motile sperm per ovum were used for insemination. The couples were divided into three groups: group A who achieved pregnancies, group B who achieved cleaved ova but no pregnancies, and group C who achieved no ova that were cleaved 48 h after oocyte recovery. Comparisons between these groups showed that some characteristics of the native semen samples and the swim-up preparations were significantly different: the sperm concentration (P = 0.001) and total sperm count (P = 0.003) in the native sample, the number of sperm recovered during 30 min of swim-up (P = 0.001), and the specific progressive motility of sperm in the swim-up preparation, both at the time of insemination and on each day, up to 5 days thereafter (P = 0.002-0.028). No pregnancy was achieved with a sperm concentration below 26 x 10(6) ml-1 in the native sample. Some of the sperm characteristics studied in this paper may be of value in the pretreatment evaluation for IVF treatment.

Morphology of seminal and swim-up spermatozoa and the outcome of in vitro fertilization and embryo transfer.

Tubal infertility was treated by in vitro fertilization-embryo transfer (IVF-ET) in 112 couples. Twenty-eight pregnancies were obtained in 140 treatment cycles. Couples are accepted for treatment in our IVF-ET programme if previous semen samples fulfil the inclusion criteria: ejaculate volume greater than 1.5 ml, concentration of spermatozoa greater than 15 x 10(6) ml-1, greater than 40% motile spermatozoa, and greater than 25% spermatozoa with normal morphology. In order to determine to which extent IVF-ET treatment results are influenced by sperm morphology, within this selected group of patients, we have retrospectively analysed the data from both original semen samples and swim-up preparations. The sperm morphology was not related to the outcome of treatment in terms of fertilization (ovum cleavage rate), early embryo development, or pregnancy. Nor was any relationship detected between early embryo development or pregnancy and the degree of improvement in morphology resulting from the swim-up procedure. However, if improvement in morphology by swim-up was high, ovum cleavage rate was low. Sperm morphology within the limits set by our inclusion criteria could not predict the outcome of IVF-ET treatment. It is further concluded that the presence of abnormal spermatozoa at the site of fertilization may be without harm if only the number of normal sperms is high enough.

ATP and ADP in human pre-embryos.

Spare human oocytes and pre-embryos from an in-vitro fertilization (IVF) programme were individually analysed for ATP and ADP content using a bioluminescence method employing the firefly luciferin-luciferase reaction. The ATP content of oocytes that failed to fertilize in vitro was 1.71 +/- 0.28 pmol (n = 10), pronuclear stage ova 1.93 +/- 0.08 (n = 6), 2-cell stage 1.78 +/- 0.20 (n = 7), 4-cell stage 1.73 +/- 0.15 (n = 6), 6-8 cell stage 2.76 +/- 0.53 (n = 8), morula stage 2.36 +/- 0.68 (n = 8), early blastocyst stage 2.08 +/- 0.25 (n = 7) and expanded blastocyst stage 2.26 +/- 0.15 (n = 3) pmol. The ADP content of these pre-embryos was low in all stages with a small increment in the 2-4 cell stages and the blastocyst stage. This gave an elevated ATP/ADP ratio (range 19-92) indicating a good energy status. The sensitive luciferin-luciferase assay may be a tool for studying the energy status of spare oocytes and pre-embryos under different incubation conditions in human IVF programmes.

The early luteal phase in successful and unsuccessful implantation after IVF-ET.

The hormonal milieu at embryo implantation after in-vitro fertilization was investigated. Superstimulation was accomplished with clomiphene citrate and human menopausal gonadotrophin (HMG) injections followed by ovulation induction with human chorionic gonadotrophin (HCG). Venous blood samples were drawn on days 2 and 8, the day of oocyte recovery being day 0. Fifteen women with successful implantation, defined as an ultrasound-verified pregnancy, were compared to 42 women with unsuccessful implantation, using a three-way analysis of variance. Oestradiol, progesterone, testosterone and sex hormone binding globulin (SHBG) did not differ between the two groups. However, the ratios of oestradiol/progesterone and of testosterone/SHBG were significantly higher in the non-fertile cycles, both on day 2 and on day 8 (P less than 0.05). Furthermore, there was a highly significant decrease in oestradiol, progesterone and testosterone between days 2 and 8 in fertile as well as in non-fertile cycles (P less than 0.001) and a highly significant increase in SHBG from day 2 to day 8 in both groups (P less than 0.001). The higher testosterone/SHBG ratio in the non-pregnant women implies a relative hyperandrogenicity in this group that might have adversely affected the uterine receptivity.

Serum factors stimulate the motility of human spermatozoa.

Motile human sperm were collected from a Percoll gradient and the effects on sperm motility of human serum, various serum fractions, follicular fluid and seminal plasma were assessed. In culture medium alone (RPMI-1640) sperm motility was lost after about 5 h. The addition of male blood serum both enhanced sperm motility and prolonged viability very significantly. Albumin, seminal plasma and follicular fluid all stimulated sperm motility but to a much lesser extent than did blood serum. No difference was noted between male serum or female serum which had been collected during the follicular or luteal phases of hormone-stimulated cycles and which contained high levels of oestradiol. Serum fractions obtained by separation on Sephacryl S-300 column were tested for their ability to enhance sperm motility. The most pronounced effect, much superior to that achieved by the albumin fraction, was obtained by a fraction with a molecular weight of around 200 kD. In conclusion, certain factors in human serum, which are different from albumin, strongly support sperm motility. The high serum concentrations of oestradiol resulting from hormone stimulation for in-vitro fertilization do not invalidate the use of serum from the same patient during sperm preparation, or in the medium used for ovum insemination and culture.

Scheduled intermittent periods of in vitro fertilization treatments.

Organization and results of an in vitro fertilization program at the Huddinge University Hospital are given from its beginning in August 1985: 6 months in advance a scheme is scheduled with 2 weeks open for treatment followed by free intervals of 3-4 weeks. Follicular development is stimulated with clomiphene citrate and hMG, and assessed by analyses of estradiol and LH in serum combined with ultrasound examinations. Following the administration of hCG, eggs are collected by transvesical aspiration guided by ultrasound. The ova are inseminated with about 50,000 motile spermatozoa, and cultured for 48 h. Up to four eggs are transferred transcervically to the uterine cavity. 158 egg pickups have been performed (August 1985 to December 1987) in 106 patients resulting in fourteen intrauterine and two ectopic pregnancies, biochemical pregnancies not counted. This protocol has restricted routine work load allowing these treatments to be part of the clinical routine. It has also allowed the application of research programs and thus optimized limited resources.