Daytime and scheduled surgery for major dysvascular lower extremity amputation.

INTRODUCTION: Patients undergoing a major dysvascular lower extremity amputation (LEA) often have a poor outcome with a high risk of complications and mortality despite improvements in care and perioperative programmes. We evaluated whether scheduled surgery would reduce the failure rate in patients with a major LEA. METHODS: A total of 328 consecutive patients undergoing a major LEA from 2016 to 2019 were enrolled at a single centre. Early failure was defined as re-amputation or revision within 30 days of the index amputation. In 2018, a new regime comprising two scheduled surgery days was implemented. The risk of failure comparing the two cohorts (2016-2017, n = 165 versus 2018-2019, n = 163) was calculated for amputation on scheduled versus non-scheduled days and for other potentially influencing factors. RESULTS: The median (25-75% quartiles) age of all patients was 74 (66-83) years, 91% had an American Society of Anesthesiologists (ASA) grade ≥ 3 and 92% had atherosclerosis or diabetes mellitus. The index amputee levels were 36% below-knee, 60% transfemoral and 4% bilateral transfemoral. In the intervention cohort, 59% were amputated on the scheduled days versus 36% in the control group (p less-than 0.001). Correspondingly, more patients (72.4% versus 57.6%, p = 0.005) were amputated during daytime and the 30-day failure rate was reduced to 11.0% (n = 18) versus 16.4% (n = 27) (p = 0.2). Risk of failure on scheduled days in the intervention group was 8.3% versus 14.9% on any other day (p = 0.2). Correspondingly, daytime surgery reduced the risk of failure (6.8% versus 22.2%, p = 0.005). CONCLUSION: Daytime and scheduled surgery for major LEA may possibly reduce early risk of failure. FUNDING: none. TRIAL REGISTRATION: not relevant.

Avoidable 30-day mortality analysis and failure to rescue in dysvascular lower extremity amputees.

Background and purpose - An enhanced treatment program may decrease 30-day mortality below 20% after lower extremity amputations (LEA). The potential and limitations for further reduction are unknown. We analyzed postoperative causes of 30-day mortality, and assessed failure to rescue (FTR) rate in LEA patients who followed an enhanced treatment program. Patients and methods - Medical charts of 195 primary LEA procedures were reviewed independently by 3 of the authors, and deaths during hospitalization following amputation were classified according to consensus. Results - 31 patients died within 30 days after surgery. 4 deaths were classified as "definitely unavoidable," 4 as "probably unavoidable," and 23 as "FTR." Patients who died had a higher incidence of sepsis, pneumonia, and acute myocardial infarction compared with those alive. A log binominal regression analysis adjusted for age, sex, ASA score, diabetes, nursing home admission, transfemoral amputation (TFA), and BMI showed that the risk of 30-day mortality was increased for TFA (RR =2.3, 95% CI 1.1-4.8) and for patients with diabetes (RR =2.7, 95% CI 1.3-5.6). The FTR rate (patients with 30-day mortality/all patients with a severe postoperative complication) was 30%. Of the FTR deaths, 20 at some point had active lifesaving care curtailed. Interpretation - Future initiatives should be directed at enhanced sepsis and pneumonia prophylactic actions, in addition to close monitoring of hemodynamics in anemic patients, with the potential to further reduce morbidity and mortality rates.

Total Blood Loss After Transfemoral Amputations Is Twice the Intraoperative Loss: An Observational Cohort Study of 81 Nontraumatic Amputations.

INTRODUCTION: Underestimation of the actual blood loss in patients undergoing nontraumatic transfemoral amputation (TFA) can impact negatively on outcome in these often frail patients, with very limited physiological reserves. The primary aim of this study is to estimate the total blood loss (TBL) after TFA, and second, to evaluate the impact of blood loss on 30-day mortality and medical complications. METHODS: A single-center retrospective cohort study conducted from 2013 to 2015. The TBL was calculated on the fourth postoperative day. It was based on the hemoglobin levels, transfusions, and the estimated blood volume. RESULTS: Eighty-one patients undergoing TFA were included for final analysis. The median TBL was 964 mL (interquartile range [IQR]: 443-1558). The intraoperative blood loss (OBL) was 400 mL (IQR: 200-500). The median difference between TBL and OBL was 688 mL (IQR: 124-1075). The patient received red blood cell (RBC) transfusion of a median amount of 2 units. Higher number of transfusions (>2) did not impact the outcome. From multivariable analysis, it was evident that the TBL increased significantly in patients with renal disease prior to surgery, (P = .034). The TBL itself was not independently associated with increased 30-day mortality or medical complications. CONCLUSION: The TBL after TFAs is significantly greater than the volume estimated intraoperatively and increases significantly in the presence of renal disease prior to surgery. An increased TBL and requirement for RBC transfusion is not directly associated with 30-day mortality or medical complications. A high vigilance for anemia seems advisable when planning for TFA surgery. Research on optimum blood conservation and transfusion strategies during TFA is warranted.

Tourniquets do not increase the total blood loss or re-amputation risk in transtibial amputations.

AIM: To investigate the total blood loss (TBL) and the safety with respect to the re-amputation rate after transtibial amputation (TTA) conducted with and without a tourniquet. METHODS: The study was a single-centre retrospective cohort study of patients with a primary TTA admitted between January 2013 and April 2015. All patients with a primary TTA were assessed for inclusion if the amputation was performed because of arteriosclerosis or diabetic complications. All patients underwent a standardized TTA procedure that was performed approximately 10 cm below the knee joint and performed with sagittal flaps. The pneumatic tourniquet, when used, was inflated around the femur to a pressure of 100 mmHg above the systolic blood pressure. The number of blood transfusions within the first four postoperative days was recorded. The intraoperative blood loss (OBL), which is defined as the volume of blood lost during surgery, was determined from the suction volume and by the weight difference of the surgical dressings. The trigger for a blood transfusion was set at a decrease in the Hgb level < 9.67 g/dL (6 mmol/L). Transfusions were performed with pooled red blood cells containing 245 mL per portion, which equals 55 g/L of haemoglobin. The TBL during the first four postoperative days was calculated based on the haemoglobin level and the estimated blood volume. The re-amputation rate was evaluated within 30 d. RESULTS: Seventy-four out of 86 consecutive patients who underwent TTA within the two-year study period were included in the analysis. Of these, 38 were operated on using a tourniquet and 36 were operated on without using a tourniquet. There were no significant preoperative differences between the groups. The patients in both groups had a postoperative decrease in their Hgb level compared with preoperative baseline values. The patients operated on using a tourniquet received approximately three millilitres less blood transfusion per kilogram body weight compared with patients operated on without a tourniquet. The duration of surgery was shorter and the OBL was less for the tourniquet group than the non-tourniquet group, whereas no significant difference was observed for the TBL. The TBL median was 859 mL (IQR: 383-1315) in the non-tourniquet group vs 737 mL (IQR: 331-1218) in the tourniquet group (P = 0.754). Within the 30-d follow-up period, 9 patients in the tourniquet group and 11 in the non-tourniquet group underwent a re-amputation at the trans-femoral level. The use of a tourniquet showed no statistically significant association with the 30-d re-amputation at the femur level in the multiple logistic regression model (P = 0.78). The only variable with a significant association with re-amputation was age (OR = 1.07; P = 0.02). CONCLUSION: The results indicate that tourniquets do not cause severe vascular damage with an increased postoperative bleeding or failure rate as the result.

Surgical apgar score predicts early complication in transfemoral amputees: Retrospective study of 170 major amputations.

AIM: To assess whether the surgical apgar score (SAS) is a prognostic tool capable of identifying patients at risk of major complications following lower extremity amputations surgery. METHODS: This was a single-center, retrospective observational cohort study conducted between January 2013 and April 2015. All patients who had either a primary transtibial amputation (TTA) or transfemoral amputation (TFA) conducted at our institution during the study period were assessed for inclusion. All TTA patients underwent a standardized one-stage operative procedure (ad modum Persson amputation) performed approximately 10 cm below the knee joint. All TTA procedures were performed with sagittal flaps. TFA procedures were performed in one stage with amputation approximately 10 cm above the knee joint, performed with anterior/posterior flaps. Trained residents or senior consultants performed the surgical procedures. The SAS is based on intraoperative heart rate, blood pressure and blood loss. Intraoperative parameters of interest were collected by revising electronic health records. The first author of this study calculated the SAS. Data regarding major complications were not revealed to the author until after the calculation of SAS. The SAS results were arranged into four groups (SAS 0-4, SAS 5-6, SAS 7-8 and SAS 9-10). The cohort was then divided into two groups representing low-risk (SAS ≥ 7) and high-risk patients (SAS < 7) using a previously established threshold. The outcome of interest was the occurrence of major complications and death within 30-d of surgery. RESULTS: A logistic regression model with SAS 9-10 as a reference showed a significant linear association between lower SAS and more postoperative complications [all patients: OR = 2.00 (1.33-3.03), P = 0.001]. This effect was pronounced for TFA [OR = 2.61 (1.52-4.47), P < 0.001]. A significant increase was observed for the high-risk group compared to the low-risk group for all patients [OR = 2.80 (1.40-5.61), P = 0.004] and for the TFA sub-group [OR = 3.82 (1.5-9.42), P = 0.004]. The AUC from the models were estimated as follows: All patients = [0.648 (0.562-0.733), P = 0.001], for TFA patients = [0.710 (0.606-0.813), P < 0.001] and for TTA patients = [0.472 (0.383-0.672), P = 0.528]. This indicates moderate discriminatory power of the SAS in predicting postoperative complications among TFA patients. CONCLUSION: SAS provides information regarding the potential development of complications following TFA. The SAS is especially useful when patients are divided into high- and low-risk groups.

Difficult to predict early failure after major lower-extremity amputations.

INTRODUCTION: The successful outcome of a major amputation depends on several factors, including stump wound healing. The purpose of this study was to examine the criteria upon which the index amputation was based and to identify factors associated with early amputation failure after major non-traumatic lower-extremity amputation. METHODS: We studied a consecutive one-year series of 36 men and 34 women with a median (25-75% quartiles) age of 72 (63-83) years who were treated in an acute orthopaedic ward; 44 below-knee and 26 above-knee amputees of whom 47 had an American Society of Anesthesiologists rating above two. Patient characteristics and other factors potentially influencing early amputation failure within 30 days were evaluated. RESULTS: Eleven patients died (16%) and 11 (16%) had a re-amputation at a higher level, whereas four (6%) had a major revision at the same level within 30 days. Amputations were performed by a house officer (n = 29), a specialist registrar (n = 27) or a consultant (n = 14). A total of 28 surgeons performed the included operations. Neither a preoperative skin perfusion test (only measured for 25 patients), nor any of the many other factors evaluated predicted early amputation failure. Patients with one or more failures stayed in the ward for a median of 45 (33-57) days versus 20 (14-25) days for those without failures. CONCLUSIONS: The rate of short-term amputation failures was high, and no clear explanation for this was established. A pre-amputation algorithm to support the right choice of amputation level is needed. FUNDING: none. TRIAL REGISTRATION: This trial was registered with the Danish Data Protection Agency (R. no. 01975 HVH-2012-053).

[Patients in need for major lower extremity amputations are a challenge]. / Den amputationstruede patient er en udfordring for sundhedsvæsenet.

Major lower extremity amputations based on end-stage chronic leg ischaemia or diabetic ulcers with infection are relatively common orthopaedic procedures. Patients are usually evaluated for the possibility of lower extremity revascularisation. Those who are not fit for vascular surgery are transferred to an orthopaedic department for amputation. These patients are a big challenge as they are by definition multi-morbid individuals, who have to undergo major surgery. The high mortality rate in this population warrants new approaches, including optimised multidisciplinary regimes.

Very low survival rates after non-traumatic lower limb amputation in a consecutive series: what to do?

The aim of this retrospective study was to evaluate factors potentially influencing short- and long-term mortality in patients who had a non-traumatic lower limb amputation in a university hospital. A consecutive series of 93 amputations (16% toe/foot, 33% trans-tibial, 9% through knee and 42% trans-femoral) were studied. Their mean age was 75.8 years; 21 (23%) were admitted from a nursing home and 87 (92%) were amputated due to a vascular disease and/or diabetes. Thirty days and 1-year mortality were 30 and 54%, respectively. Cox regression analysis demonstrated that the 30-day mortality was associated with older age (P = 0.01), and the number of co-morbidities (P = 0.04), when adjusted for gender, previous amputations, cause of and amputation level, and residential status. Thus, a patient with 4 or 5 co-morbidities (n = 20) was seven times more likely to die within 30 days, compared with a patient with 1 co-morbidity (n = 16). Further, the risk of not surviving increased with 7% per each additional year the patient got older. Of concern, almost one-third of patients died within 1 month. This may be unavoidable, but a multidisciplinary, optimized, multimodal pre- and postoperative programme should be instituted, trying to improve the outcome.

Comparison of intracellular signalling by insulin and the hypermitogenic AspB10 analogue in MCF-7 breast adenocarcinoma cells.

We compared mitogenicity and intracellular signalling by human insulin and the AspB10 (X-10) human insulin analogue in MCF-7 human mammary adenocarcinoma cells. By flow analysis of phosphorylated histone H3 or cell cycle distributions, insulin and X-10 were mitogenic at physiologically relevant concentrations (2 nm to 74 pm range), with X-10 being approximately 3-fold more mitogenic than insulin. By western blotting with phospho-specific antibodies, insulin induced phosphorylation of IRS-1, Akt, p70S6K, S6 ribosomal protein, 4E-BP1, FoxO3a, FoxO1, p44/42 MAPK and the EGFR. Blocking with wortmannin, rapamycin and U0126 showed that these signalling events conformed to the canonical PI3K pathway. IRS-1 (Ser302) phosphorylation was abolished by wortmannin and rapamycin, suggesting a feedback from the PI3K pathway on insulin signalling. Compared with equimolar insulin, X-10 caused up to 2-fold higher phosphorylation of all proteins examined in this study. The phosphorylation sites that responded most strongly to insulin were not generally the same as those responding most strongly to X-10. In the PI3K pathway, the most X-10-sensitive protein localized to the translation-regulating arm (p70S6K), with FoxO3a and FoxO1 transcription factors showing a more comparable response to insulin and X-10. Using flow analysis, we confirmed the correlation between insulin-triggered translational activation in G0/G1 (S6 phosphorylation) and S-phase entry by MCF-7 cells. In summary, our findings implicate asymmetrical PI3K pathway activation and specifically stimulation of protein translation in the hypermitogenic effect of insulin analogues such as X-10. It remains to be shown whether these findings are relevant to other human mammary cancer cell types.

What determines length of stay after total hip and knee arthroplasty? A nationwide study in Denmark.

INTRODUCTION: The goal of this study was (1) to identify logistical and clinical areas of importance for length of stay (LOS) by identifying departments with short and long LOS and to evaluate their set-up; and (2) to evaluate patient satisfaction in relation to LOS. MATERIALS AND METHODS: Based on the National Register on Patients in 2004 on LOS following total hip and knee arthroplasty (THA and TKA), departments with short and long LOS were identified. The three departments with the shortest and the three departments with the longest postoperative hospital stay were chosen for evaluation. The logistic setup and the clinical treatment/pathway were examined with on-location focus interviews to identify logistic and clinical factors acting as improvement or barriers for early rehabilitation and subsequent discharge. Also, the patients from these departments answered a questionnaire regarding satisfaction with components of their stay, co-morbidity, sex and age. RESULTS: Mean LOS was 7.4 and 8.0 days after THA and TKA, respectively staying from 4.5 to 12 days. Departments with short hospital stay were characterised by both logistical (homogenous entities, regular staff, high continuity, using more time on and up to date information including expectations on a short stay, functional discharge criteria) and clinical features (multimodal opioid-sparing analgesia, early mobilisation and discharge when criteria were met) facilitating quick rehabilitation and discharge. Patient demographics from departments with the shortest stay were similar co-morbidities than patients from departments with longer stays, but were either as satisfied-or more satisfied-with all parts of their stay. There was no difference in staffing (nurses/physiotherapists) between the two types of departments. CONCLUSION: Nationwide implementation of fast-track THA and TKA would result in a significant decrease in the needed number of hospital beds with similar or better outcome for the patients. Implementation of updated logistical and clinical features is expected to increase rehabilitation and reduce LOS with similar or improved patient satisfaction. These results support the implementation of fast-track total hip- and knee arthroplasty.

Driving gradual endogenous c-myc overexpression by flow-sorting: intracellular signaling and tumor cell phenotype correlate with oncogene expression.

Insulin-exposed rat mammary cancer cells were flow sorted based on a c-myc reporter plasmid encoding a destabilized green fluorescent protein. Sorted cells exhibited gradual increases in c-myc levels. Cells overexpressing c-myc by only 10% exhibited phenotypic changes attributable to c-myc overexpression, such as cell cycle disturbances, increased cell size, and overexpression of the S6 ribosomal protein. Cells overexpressing c-myc by 70% exhibited additional phenotypic changes typical of c-myc overexpression, such as increased histone H3 phosphorylation, and reduced adherence. Sorted cells also exhibited overexpression of the IGF-1R, and slightly elevated expression of the IR. Increased susceptibility to the mitogenic effect of insulin was seen in a small proportion of the sorted cells, and insulin was more effective in activating the p44/42 MAPK pathway, but not the PI3K pathway, in the sorted cells than in the nonsorted cell population. To our knowledge, this is the first in vitro system allowing functional coupling between mitogenic signaling by a well-defined growth factor and gradual overexpression of the normal, endogenous c-myc gene. Thus, our flow-sorting approach provides an alternative modeling of the receptor-mediated carcinogenic process, compared to the currently used approaches of recombinant constitutive or conditional overexpression of oncogenic transmembrane receptor tyrosine kinases or oncogenic transcription factors.

MCF-7 human mammary adenocarcinoma cells exhibit augmented responses to human insulin on a collagen IV surface.

Human mammary cell lines are extensively used for preclinical safety assessment of insulin analogs. However, it is essentially unknown how mitogenic responses can be optimized in mammary cell-based systems. We developed an insulin mitogenicity assay in MCF-7 human mammary adenocarcinoma cells, under low serum (0.1% FCS) and phenol red-free conditions, with 3H thymidine incorporation as endpoint. Based on EC50 values determined from 10-fold dilution series, beta-estradiol was the most potent mitogen, followed by human IGF-1, human AspB10 insulin and native human insulin. AspB10 insulin was significantly more mitogenic than native insulin, validating the ability of the assay to identify hypermitogenic human insulin analogs. With MCF-7 cells on a collagen IV surface, the ranking of mitogens was maintained, but fold mitogenic responses and dynamic range and steepness of dose-response curves were increased. Also, PI3K pathway activation by insulin was enhanced on a collagen IV surface. This study provided the first determination and ranking of the mitogenic potencies of standard reference compounds in an optimized MCF-7 assay. The optimized MCF-7 assay described here is of relevance for in vitro toxicological testing and carcinogenicity safety assessment of new insulin compounds.

Predictors of length of stay and patient satisfaction after hip and knee replacement surgery: fast-track experience in 712 patients.

BACKGROUND AND PURPOSE: Very few studies have focused on patient characteristics that influence length of stay (LOS) in fast-track total hip (THR) and knee arthroplasty (TKR). The aim of this prospective study was to identify patient characteristics associated with LOS and patient satisfaction after total hip and knee replacement surgery. PATIENTS AND METHODS: Between September 2003 and December 2005, 712 consecutive, unselected patients (440 women) with a mean age of 69 (31-91) years were admitted for hip and knee replacement surgery at our specialized fast-track joint replacement unit. Epidemiological, physical, and perioperative parameters were registered and correlated to LOS and patient satisfaction. RESULTS: 92% of the patients were discharged directly to their homes within 5 days, and 41% were discharged within 3 days. Age, sex, marital status, co-morbidity, preoperative use of walking aids, pre- and postoperative hemoglobin levels, the need for blood transfusion, ASA score, and time between surgery and mobilization, were all found to influence postoperative outcome in general, and LOS and patient satisfaction in particular. INTERPRETATION: We identified several patient characteristics that influence postoperative outcome, LOS, and patient satisfaction in our series of consecutive fast-track joint replacement patients, enabling further attention to be paid to certain aspects of surgery and rehabilitation.