Corrigendum to 'Patient blood management and perioperative anaemia' [BJA Education 17 (2017) 28-34].

[This corrects the article DOI: 10.1093/bjaed/mkw061.].

The association between iron deficiency and outcomes: a secondary analysis of the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial.

In the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial, the use of intravenous iron did not reduce the need for blood transfusion or reduce patient complications or length of hospital stay. As part of the trial protocol, serum was collected at randomisation and on the day of surgery. These samples were analysed in a central laboratory for markers of iron deficiency. We performed a secondary analysis to explore the potential interactions between pre-operative markers of iron deficiency and intervention status on the trial outcome measures. Absolute iron deficiency was defined as ferritin <30 µg.l-1 ; functional iron deficiency as ferritin 30-100 µg.l-1 or transferrin saturation < 20%; and the remainder as non-iron deficient. Interactions were estimated using generalised linear models that included different subgroup indicators of baseline iron status. Co-primary endpoints were blood transfusion or death and number of blood transfusions, from randomisation to 30 days postoperatively. Secondary endpoints included peri-operative change in haemoglobin, postoperative complications and length of hospital stay. Most patients had iron deficiency (369/452 [82%]) at randomisation; one-third had absolute iron deficiency (144/452 [32%]) and half had functional iron deficiency (225/452 [50%]). The change in pre-operative haemoglobin with intravenous iron compared with placebo was greatest in patients with absolute iron deficiency, mean difference 8.9 g.l-1 , 95%CI 5.3-12.5; moderate in functional iron deficiency, mean difference 2.8 g.l-1 , 95%CI -0.1 to 5.7; and with little change seen in those patients who were non-iron deficient. Subgroup analyses did not suggest that intravenous iron compared with placebo reduced the likelihood of death or blood transfusion at 30 days differentially across subgroups according to baseline ferritin (p = 0.33 for interaction), transferrin saturation (p = 0.13) or in combination (p = 0.45), or for the number of blood transfusions (p = 0.06, 0.29, and 0.39, respectively). There was no beneficial effect of the use of intravenous iron compared with placebo, regardless of the metrics to diagnose iron deficiency, on postoperative complications or length of hospital stay.

Using middle finger length to determine the internal diameter of uncuffed tracheal tubes in paediatrics.

The selection of an appropriately-sized tracheal tube is of critical importance in paediatric patients to reduce both the risk of subglottic stenosis from a tracheal tube that is too large, and inadequate ventilation or poor end-tidal gas monitoring from a tracheal tube that is too small. Age formulae are widely used, but known to be unreliable, often resulting in a need to change the tracheal tube. Previous work has shown that the length of the middle finger and the internal diameter can both be used to guide depth of tracheal tube insertion. Therefore, we hypothesised that middle finger length may also be related to tube internal diameter. We enrolled children aged up to 12 years presenting to our institution for elective anaesthesia and measured the length of the middle finger on the palmar aspect of the hand. Anaesthetists chose the airway device they felt most appropriate for the procedure, and were unaware of the middle finger measurement. Of 160 patients who were enrolled, 108 were included in the final analysis. We found a linear relationship between uncuffed tracheal tube internal diameter and median middle finger length for each size of tracheal tube. Relationship between middle finger length and cuffed tracheal tube internal diameter was less clear. We propose that the formula: 'middle finger length (cm) (round up to nearest 0.5) = internal diameter of uncuffed tracheal tube (mm)' may be an improvement compared with age formulae for selecting uncuffed tracheal tubes in children, although this requires formal testing.

Patient blood management to reduce surgical risk.

BACKGROUND: Preoperative anaemia and perioperative blood transfusion are both identifiable and preventable surgical risks. Patient blood management is a multimodal approach to address this issue. It focuses on three pillars of care: the detection and treatment of preoperative anaemia; the reduction of perioperative blood loss; and harnessing and optimizing the patient-specific physiological reserve of anaemia, including restrictive haemoglobin transfusion triggers. This article reviews why patient blood management is needed and strategies for its incorporation into surgical pathways. METHODS: Studies investigating the three pillars of patient blood management were identified using PubMed, focusing on recent evidence-based guidance for perioperative management. RESULTS: Anaemia is common in surgical practice. Both anaemia and blood transfusion are independently associated with adverse outcomes. Functional iron deficiency (iron restriction due to increased levels of hepcidin) is the most common cause of preoperative anaemia, and should be treated with intravenous iron. Intraoperative blood loss can be reduced with antifibrinolytic drugs such as tranexamic acid, and cell salvage should be used. A restrictive transfusion practice should be the standard of care after surgery. CONCLUSION: The significance of preoperative anaemia appears underappreciated, and its detection should lead to routine investigation and treatment before elective surgery. The risks of unnecessary blood transfusion are increasingly being recognized. Strategic adoption of patient blood management in surgical practice is recommended, and will reduce costs and improve outcomes in surgery.

Pre-operative anaemia.

Pre-operative anaemia is a relatively common finding, affecting a third of patients undergoing elective surgery. Traditionally associated with chronic disease, management has historically focused on the use of blood transfusion as a solution for anaemia in the peri-operative period. Data from large series now suggest that anaemia is an independent risk associated with poor outcome in both cardiac and non-cardiac surgery. Furthermore, blood transfusion does not appear to ameliorate this risk, and in fact may increase the risk of postoperative complications and hospital length of stay. Consequently, there is a need to identify, diagnose and manage pre-operative anaemia to reduce surgical risk. Discoveries in the pathways of iron metabolism have found that chronic disease can cause a state of functional iron deficiency leading to anaemia. The key iron regulatory protein hepcidin, activated in response to inflammation, inhibits absorption of iron from the gastrointestinal tract and further reduces bioavailability of iron stores for red cell production. Consequently, although iron stores (predominantly ferritin) may be normal, the transport of iron either from the gastrointestinal tract or iron stores to the bone marrow is inhibited, leading to a state of 'functional' iron deficiency and subsequent anaemia. Since absorption from the gastrointestinal tract is blocked, increasing oral iron intake is ineffective, and studies are now looking at the role of intravenous iron to treat anaemia in the surgical setting. In this article, we review the incidence and impact of anaemia on the pre-operative patient. We explain how anaemia may be caused by functional iron deficiency, and how iron deficiency anaemia may be diagnosed and treated.

Levonorgestrel implants (Norplant II) for male contraception clinical trials: combination with transdermal and injectable testosterone.

Recent studies demonstrate that combinations of androgens and progestagens are highly effective in the suppression of spermatogenesis in normal volunteers. To test whether progestagen and androgen delivery systems designed to produce steady serum levels will be as effective as other androgen plus progestagen combinations, we compared Norplant II and testosterone (T) transdermal patch to T patch alone on the suppression of spermatogenesis in normal men. Thirty-nine healthy male volunteers (age, 20-45 yr) were randomly assigned to one of two groups. Group 1 (n = 19) received two transdermal T patches daily (Testoderm TTS, each patch designed to deliver about 5 mg/d T) alone, and group 2 (n = 20) received combined Norplant II [Jadelle, four capsules delivering approximately 160 microg/d levonorgestrel (LNG)] plus T patch. Neither of these regimens were very effective, with suppression of spermatogenesis to severe oligozoospermia occurring in less than 60% of subjects. We then expanded the study to include two more groups to determine whether T patch or Norplant II was the main factor causing the inadequate suppression of spermatogenesis. Another 29 subjects were randomized to one of two groups. Group 3 (n = 15) received oral LNG (125 microg/d) plus T patch, and group 4 (n = 14) received Norplant II plus T enanthate (TE) injection (100 mg/wk i.m.). After a pretreatment phase of 4 wk, all subjects received treatment for 24 wk, followed by a recovery period of 12-24 wk. Steady-state serum LNG levels (800-1200 pmol/liter) were achieved from wk 3-24 after Norplant II insertion and decreased rapidly after the removal of the implants at wk 24. Trough serum LNG levels after oral LNG administration were at a comparable range (940-1300 pmol/liter). Azoospermia was achieved in 24%, 35%, 33%, and 93%, and severe oligozoospermia (<1 x 10(6)/ml) developed in 24%, 60%, 42%, and 100% of the subjects in groups 1, 2, 3, and 4, respectively, during treatment phase. All subjects in the Norplant II plus TE groups had persistent sperm concentrations less than 3 x 10(6)/ml from wk 12 until the end of treatment. Concomitant with the marked suppression of spermatogenesis in the Norplant II plus TE group, serum FSH and LH levels were most decreased in this group compared with all other groups. In the T patch-only group, serum SHBG was not suppressed, and total serum T was higher than baseline levels. In the other three groups administered progestagens, serum SHBGs were significantly suppressed, and serum total T remained similar to baseline levels. Serum free T levels were not changed in any group. Except for a suppression of serum high-density lipoprotein cholesterol, there was no significant change in weight, hematocrit, clinical chemistry, or prostate-specific antigen levels in any of the treatment groups. Although more efficacious than T patch alone, Norplant II or oral LNG plus T patch was not as effective in suppressing spermatogenesis to severe oligo- or azoospermia as in previous reports using oral LNG plus TE. This relative lesser efficacy occurred despite the achievement of serum LNG levels by Norplant II that were equivalent to those reported after administration of oral LNG. Substituting the transdermal T delivery system with TE injections resulted in very effective suppression of sperm output. The difference in spermatogenesis suppression of these combined regimens is likely due to less T delivered by the transdermal patch compared with the TE weekly injections. We conclude that Norplant II implants plus TE 100 mg/wk were very efficient in suppressing spermatogenesis to a level acceptable for contraceptive efficacy. This study demonstrates that the dose or route of administration of androgens is critical for sperm suppression in combined androgen-progestagen regimens for hormonal male contraception.

Testosterone replacement increases fat-free mass and muscle size in hypogonadal men.

Testosterone-induced nitrogen retention in castrated male animals and sex-related differences in the size of the muscles in male and female animals have been cited as evidence that testosterone has anabolic effects. However, the effects of testosterone on body composition and muscle size have not been rigorously studied. The objective of this study was to determine the effects of replacement doses of testosterone on fat-free mass and muscle size in healthy hypogonadal men in the setting of controlled nutritional intake and exercise level. Seven hypogonadal men, 19-47 yr of age, after at least a 12-week washout from previous androgen therapy, were treated for 10 weeks with testosterone enanthate (100 mg/week) by im injections. Body weight, fat-free mass measured by underwater weighing and deuterated water dilution, and muscle size measured by magnetic resonance imaging were assessed before and after treatment. Energy and protein intake were standardized at 35 Cal/kg.day and 1.5 g/kg.day, respectively. Body weight increased significantly from 79.2 +/- 5.6 to 83.7 +/- 5.7 kg after 10 weeks of testosterone replacement therapy (weight gain, 4.5 +/- 0.6 kg; P = 0.0064). Fat-free mass, measured by underwater weighing, increased from 56.0 +/- 2.5 to 60.9 +/- 2.2 kg (change, +5.0 +/- 0.7 kg; P = 0.0004), but percent fat did not significantly change. Similar increases in fat-free mass were observed with the deuterated water method. The cross-sectional area of the triceps arm muscle increased from 2421 +/- 317 to 2721 +/- 239 mm2 (P = 0.045), and that of the quadriceps leg muscle increased from 7173 +/- 464 to 7720 +/- 454 mm2 (P = 0.0427), measured by magnetic resonance imaging. Muscle strength, assessed by one repetition maximum of weight-lifting exercises increased significantly after testosterone treatment. L-[1-13C]Leucine turnover, leucine oxidation, and nonoxidative disappearance of leucine did not significantly change after 10 weeks of treatment. There was no significant change in hemoglobin, hematocrit, creatinine, and transaminase levels. Replacement doses of testosterone increase fat-free mass and muscle size and strength in hypogonadal men. Whether androgen replacement in wasting states characterized by low testosterone levels will have similar anabolic effects remains to be studied.

The effects of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men--a clinical research center study.

UNLABELLED: Anecdotal reports of "roid rage" and violent crimes by androgenic steroid users have brought attention to the relationship between anabolic steroid use and angry outbursts. However, testosterone effects on human aggression remain controversial. Previous studies have been criticized because of the low androgen doses, lack of placebo control or blinding, and inclusion of competitive athletes and those with preexisting psychopathology. To overcome these pitfalls, we used a double-blind, placebo-controlled design, excluded competitive athletes and those with psychiatric disorders, and used 600 mg testosterone enanthate (TE)/week. Forty-three eugonadal men, 19-40 yr, were randomized to 1 of 4 groups: Group I, placebo, no exercise; Group II, TE, no exercise; Group III, placebo, exercise; Group IV, TE plus exercise. Exercise consisted of thrice weekly strength training sessions. The Multi-Dimensional Anger Inventory (MAI), which includes 5 different dimensions of anger (inward anger, outward anger, anger arousal, hostile outlook, and anger eliciting situations), and a Mood Inventory (MI), which includes items related to mood and behavior, were administered to subjects before, during, and after the 10 week intervention. The subject's significant other (spouse, live-in partner, or parent) also answered the same questions about the subject's mood and behavior (Observer Mood Inventory, OMI). No differences were observed between exercising and nonexercising and between placebo and TE treated subjects for any of the 5 subdomains of MAI. Overall there were no significant changes in MI or OMI during the treatment period in any group. CONCLUSION: Supraphysiological doses of testosterone, when administered to normal men in a controlled setting, do not increase angry behavior. These data do not exclude the possibility that still higher doses of multiple steroids might provoke angry behavior in men with preexisting psychopathology.

The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men.

BACKGROUND: Athletes often take androgenic steroids in an attempt to increase their strength. The efficacy of these substances for this purpose is unsubstantiated, however. METHODS: We randomly assigned 43 normal men to one of four groups: placebo with no exercise; testosterone with no exercise; placebo plus exercise; and testosterone plus exercise. The men received injections of 600 mg of testosterone enanthate or placebo weekly for 10 weeks. The men in the exercise groups performed standardized weight-lifting exercises three times weekly. Before and after the treatment period, fat-free mass was determined by underwater weighing, muscle size was measured by magnetic resonance imaging, and the strength of the arms and legs was assessed by bench-press and squatting exercises, respectively. RESULTS: Among the men in the no-exercise groups, those given testosterone had greater increases than those given placebo in muscle size in their arms (mean [+/-SE] change in triceps area, 424 +/- 104 vs. -81 +/- 109 square millimeters; P < 0.05) and legs (change in quadriceps area, 607 +/- 123 vs. -131 +/- 111 square millimeters; P < 0.05) and greater increases in strength in the bench-press (9 +/- 4 vs. -1 +/- 1 kg, P < 0.05) and squatting exercises (16 +/- 4 vs. 3 +/- 1 kg, P < 0.05). The men assigned to testosterone and exercise had greater increases in fat-free mass (6.1 +/- 0.6 kg) and muscle size (triceps area, 501 +/- 104 square millimeters; quadriceps area, 1174 +/- 91 square millimeters) than those assigned to either no-exercise group, and greater increases in muscle strength (bench-press strength, 22 +/- 2 kg; squatting-exercise capacity, 38 +/- 4 kg) than either no-exercise group. Neither mood nor behavior was altered in any group. CONCLUSIONS: Supraphysiologic doses of testosterone, especially when combined with strength training, increase fat-free mass and muscle size and strength in normal men.

The mechanism of action of steroid hormones: a new twist to an old tale.

Steroid hormones, vitamins, and thyroid hormone are potent chemical messengers that exert dramatic effects on cell differentiation, homeostasis, and morphogenesis. These molecules, though diverse in structure, share a mechanistically similar mode of action. The effector molecules diffuse across cellular membranes and bind to specific high affinity receptors in the target cell nuclei. This interaction results in the conversion of an inactive receptor to one that can interact with the regulatory regions of target genes and modulate the rate of transcription of specific gene sets. The recent cloning and characterization of the functional receptors for these hormones has been enlightening as to the individual steps involved in steroid signal transduction. In addition, emerging evidence suggests that receptor function can be influenced by cell and promoter context indicating that it may be possible to develop tissue specific or tissue-restricted drugs. The concept that a single receptor can modulate gene transcription in a cell-specific manner is of great medical and pharmaceutical importance. The focus of this review is to highlight the recent developments in the steroid receptor field and to illustrate the novel approaches been undertaken to identify novel pharmaceuticals.