Charcot Foot Offloading in Stage 0 Is Associated With Shorter Total Contact Cast Treatment and Lower Risk of Recurrence and Reconstructive Surgery: A Pilot Study.

OBJECTIVE: Charcot foot (CF) requires prolonged offloading of the affected foot to decrease the risk of deformity. The earliest phase in active CF (stage 0) is characterized by inflammatory signs without established fractures or skeletal deformity. We investigated whether offloading in stage 0 influences duration of total contact casting (TCC), risk of recurrence, and future need for surgery. RESEARCH DESIGN AND METHODS: All patients treated for active CF at Skåne University Hospital (Lund, Sweden) between 2006 and 2019 were screened for participation in a retrospective cohort study. CF events of included patients were classified as stage 0 or 1 according to X-ray and MRI reports. RESULTS: A total of 183 individuals (median age 61 [interquartile range (IQR) 52-68] years, 37% type 1 diabetes, 62% men) were followed for a median of 7.0 (IQR 3.9-11) years. In 198 analyzed CF events, 74 were treated with offloading in stage 0 and 124 in stage 1. Individuals offloading in stage 0 had significantly shorter TCC duration (median 75 [IQR 51-136] vs. 111.5 [72-158] days; P = 0.001). The difference was sustained when including only MRI-confirmed CF. The risk of developing new ipsilateral CF events >1 year after introduced definitive footwear was lower in those treated with offloading in stage 0 (2.7% vs. 9.7%; P < 0.05). No individual treated with offloading in stage 0 underwent reconstructive surgery, compared with 11 (8.9%) treated with offloading in stage 1 (P < 0.01). Amputation rates were similar. CONCLUSIONS: Offloading in stage 0 CF was associated with shorter TCC treatment, lower risk of a new CF event, and diminished need for reconstructive surgery. Future amputation risk was not affected.

Hyperglycemia and insulin infusion in pancreatoduodenectomy: a prospective cohort study on feasibility and impact on complications.

BACKGROUND: Hyperglycemia is a risk factor for postoperative complications but its impact on outcome after pancreatoduodenectomy (PD) is scarcely studied. This prospective cohort study aimed to assess the effect of continuous insulin infusion on postoperative complications and blood glucose, as well as to evaluate the impact of hyperglycemia on complications, after PD. MATERIALS AND METHODS: One hundred patients planned for PD at Skåne University Hospital, Sweden were prospectively included for perioperative continuous insulin infusion and a historic cohort of 100 patients was included retrospectively. Median blood glucose levels were calculated and data on complications were analyzed and compared between the historic cohort and the intervention group as well as between normo- and hyperglycemic patients. RESULTS: Median glucose levels were significantly lower in the intervention group compared to the historic cohort up to 30 days postoperatively (median glucose 8.5 mmol/l (interquartile range 6.4-11) vs. 9.1 mmol/l (interquartile range 6.8-17) ( P =0.007)). No significant differences in complication rates were recorded between these two groups. The incidence of complications classified as Clavien ≥3 was higher in hyperglycemic patients (100 vs. 27%, P =0.024). Among hyperglycemic patients the prevalence of preoperative diabetes was higher compared to normoglycemic patients (52 vs.12%, P <0.001). In patients with a known diagnosis of diabetes, a trend, although not statistically significant, towards a lower incidence of postoperative pancreatic fistula grade B and C, as well as postpancreatectomy hemorrhage grade B and C, was seen compared to those without preoperative diabetes (6.8 vs. 14%, P =0.231 and 2.3 vs. 7.0%, P =0.238, respectively). CONCLUSION: Insulin infusion in the early postoperative phase after PD is feasible in a non-ICU setting and significantly decreased blood glucose levels. The influence on complications was limited. Preoperative diabetes was a significant predictor of postoperative hyperglycemia and was associated with a lower incidence of clinically significant postoperative pancreatic fistula.

Intermittent scanning continuous glucose monitoring is safe and useful in postsurgical glucose monitoring after pancreatoduodenectomy.

AIMS: Intermittently scanned continuous glucose monitoring (isCGM) systems have not been thoroughly evaluated during in-hospital stay, and there are concerns about accuracy during various conditions. Patients undergoing pancreatoduodenectomy have an increased risk of hyperglycaemia after surgery which is aggravated by parenteral nutrition therapy. This study aims to evaluate glycaemic control and safety during insulin infusion in a surgical non-ICU ward, using a hybrid glucose monitoring approach with isCMG and periodic point-of-care (POC) testing. METHODS: We prospectively included 100 patients with a resectable pancreatic tumour. After surgery, continuous insulin infusion was initiated when POC glucose was > 7 mmol/l and titrated to maintain glucose between 7 and 10 mmol/l. Glucose was monitored with isCGM together with intermittent POC, every 3-6 h. Median absolute relative difference (MARD) and hypoglycaemic events were evaluated. Mean glucose was compared with a historic control (n = 100) treated with multiple subcutaneously insulin injections, monitored with POC only. RESULTS: The intervention group (isCGM/POC) had significantly lower POC glucose compared with the historic control group (8.8 ± 2.2 vs. 10.4 ± 3.4 mmol/l, p < 0.001). MARD was 17.8% (IQR 10.2-26.7). isCGM readings were higher than POC measurements in 91% of the paired cases, and isCGM did not miss any hypoglycaemic event. About 4.5% of all isCGM readings were < 3.9 mmol/l, but only six events were confirmed with POC, and none was < 3.0 mmol/l. CONCLUSIONS: A hybrid approach with isCGM/POC is a safe and effective treatment option in a non-ICU setting after pancreatoduodenectomy.

Bone health and cardiac transplantation.

Patients who undergo heart transplantation (HT) have increased loss of bone mineral density (BMD) [g/cm2]. The greatest drop in BMD occurs within the first year after HT with a decrease 3.5-8.5% in the lumbar spine and 5.6-10.5% in the femoral neck. Thereafter, BMD tend to stabilize or even recover to some degree. Accordingly, risk of fracture correlates to BMD evolution, with the highest rate of fractures during the first year, with a cumulative incidence of 12-36%. Fragility fractures contributes to increased morbidity and increased mortality. The pathophysiology behind BMD impairment in HT patients is complex and involves side-effects of the immunosuppressive therapy and of heart failure medications, as well as organ failure. Of the immunosuppressive agents, corticosteroids (CS) exerts the greatest impact on BMD through multiple cellular pathways. Also, calcineurin inhibitors seem have a negative impact on BMD, mainly mediated through enhancement of bone resorption. Additionally, kidney dysfunction has a significant effect on bone homeostasis and is frequently present in HT patients. The optimal timing and type of pharmacological treatment of osteoporosis in HT patients are not yet known. However, bisphosphonates and monoclonal antibody against RANK ligand (Denosumab) may have beneficial effects on bone metabolism in HT patients. However, their efficacy and safety in have not been thoroughly studied in this particular patient population. Therefore, careful individual evaluation of prescription, frequency, and possible treatment options is advisable in this patient population.

The combined impact of ankle-brachial index and transcutaneous oxygen pressure on mortality in patients with type 2 diabetes and foot ulcers.

AIMS: A diabetic foot ulcer (DFU) is associated with increased cardiovascular risk and mortality, independently of ulcer etiology (ischemic, neuro-ischemic or neuropathic). Ankle-brachial index (ABI) is the most commonly used test when diagnosing peripheral macrovascular disease and is a well-known marker for increased cardiovascular risk. Transcutaneous oxygen pressure (TcPO2) is considered to better evaluate microvascular function and has in previous studies shown correlations with both wound healing and survival. The aim of this study was to evaluate the combined impact of a low TcPO2 (<30 mmHg) and a pathological ABI (<0.9 or ≥1.4) on three-year mortality in patients with DFU. METHODS: Type 2 diabetes patients aged <90 years, with at least one DFU who underwent vascular assessment with ABI and TcPO2 were screened for participation. The primary endpoint was mortality after three years, assessed from the National Death Registry in Sweden. RESULTS: The study enrolled 235 participants with a median age of 76 years. Individuals with either an abnormally high or low ABI in combination with a low TcPO2 had the worst survival rates, with three-year mortality of 54%, compared to 42% in those with one abnormal variable (either ABI or TcPO2), and 21% in those with normal ABI and TcPO2. CONCLUSIONS: Combining ABI and TcPO2 when risk stratifying DFU patients seems to provide additional predictive information, not only concerning ulcer healing and limb salvage, but also on survival.

Strong association between vibration perception thresholds at low frequencies (4 and 8 Hz), neuropathic symptoms and diabetic foot ulcers.

AIMS: To investigate whether multi-frequency measurement of vibration perception thresholds (VPTs) can identify individuals with a high risk of developing diabetic foot ulcer or neuropathic symptoms. METHODS: VPTs were measured at six different frequencies (4, 8, 16, 32, 64 and 125 Hz) on metatarsal heads 1 and 5 on the sole of the foot using a standard VibroSense Meter device in 535 type 1 diabetic (T1DM) patients and 717 non-diabetic control subjects. VPTs in control subjects were used to establish normal values for five different age groups for male and female subjects respectively. Normal values were defined as a VPT below the mean plus 1.66 x standard deviation for each group. Various definitions of abnormal VPTs were tested using either all frequencies, only lowest VPT frequencies (4 and 8 Hz) or only highest VPT frequencies (64 and 125 Hz). RESULTS: The VPTs were higher in T1DM patients than in non-diabetic control subjects matched for age and gender. The low frequencies, 4 and 8 Hz, particularly were associated with the risk of diabetic foot ulcer (OR 40.7 [5.4-308.4], p = 0.0003) and with difficulties in balance and or gait (OR 1.89 [1.04-3.46], p = 0.04) difficulties and weakness (OR 2.77 [1.25-6.16], p = 0.01). The VPTs at the 125 Hz frequency were higher in short duration (≤ 10 yrs.) T1DM patients compared to age- and gender-matched control subjects. CONCLUSIONS: Vibration perception thresholds at low frequencies seem to be a better indicator of the risk of developing diabetic foot ulcers, gait or balance problems or weakness of the foot. The 125 Hz frequency, however, seemed to be impaired earlier and it was the only pathological VPT frequency in patients with short duration of diabetes.This study suggests that at least four different frequencies (4, 8, 64 and 125 Hz) should be included in any examination in order to obtain a complete evaluation of the risk factors for diabetic neuropathy and diabetic foot ulcers.

Hyperbaric oxygen therapy reduces the risk of QTc interval prolongation in patients with diabetes and hard-to-heal foot ulcers.

AIMS: Heart rate corrected QT (QTc) interval prolongation is a risk factor associated with increased mortality. Hyperbaric oxygen therapy (HBO) has previously been shown to have acute beneficial effects on QTc dispersion. The aim of this study was to evaluate long-term effects of HBO on QTc time in diabetic patients with hard-to-heal foot ulcers. METHODS: In a prospective, double-blinded placebo-controlled study, patients were randomized to 40 treatment sessions with either HBO or air (placebo), at 2.5 ATA. Patients fulfilling >35 completed treatment sessions were included in the evaluation. RESULTS: Of the initial 75 patients (38 HBO/37 placebo), two were excluded due to pacemaker use. Baseline characteristics were similar between groups. At the 2-year follow-up, QTc time was significantly shorter in the HBO compared to the placebo group (438 vs. 453ms, p<0.05). Further, fewer HBO treated patients had a QTc time >450ms (22 vs. 53 %, p<0.02). This difference seemed to be caused by a significant prolongation of the QTc interval in the placebo group (427 (419-459) at baseline vs. 456ms (424-469) after 2years), whereas no significant change was seen in HBO treated patients. CONCLUSIONS: HBO treatment might protect against QTc prolongation in this high-risk diabetic population.

What is the role of hyperbaric oxygen in the management of diabetic foot disease?

Systemic hyperbaric oxygen (HBO) is accomplished when a patient is breathing 100% oxygen in an environment with increased barometric pressure. A typical HBO treatment protocol of diabetic foot ulcer involves 20 to 40 sessions. Treatment is usually given as daily 90- to 120-minute HBO sessions at pressures between 2.0 and 2.5 absolute atmospheres. The wide use of HBO as treatment of diabetic foot ulcers over the past decades has been founded on weak scientific ground (ie, few and small prospective studies with methodologic limitations on top of case series). However, the consistency in positive outcome in these trials evaluating HBO on ulcer healing is noteworthy because these findings are in concert with data from in vitro and physiologic studies supporting the theoretic framework of HBO reversing hypoxia-induced pathology. Two well-designed randomized double-blinded placebo-controlled studies have in recent years put HBO on firmer ground as treatment of a selection of diabetic patients with chronic foot. Some evidence indicates that microvascular parameters such as transcutaneous (partial) oxygen pressure (TcPO(2)) could be useful in predicting which patients will benefit from therapy. Health economic studies suggest potential cost-effectiveness of HBO. But because these analyses are limited by their deficient primary clinical data, they should be interpreted with caution. Thus, HBO is only indicated in a selected group of patients with chronic diabetic foot ulcers. Several key issues remain to be addressed such as developing robust criteria to determine which patients are likely to benefit and when to start and stop treatment.

Decreased phosphatase activity, increased Ca2+ sensitivity, and myosin light chain phosphorylation in urinary bladder smooth muscle of newborn mice.

Developmental changes in the regulation of smooth muscle contraction were examined in urinary bladder smooth muscle from mice. Maximal active stress was lower in newborn tissue compared with adult, and it was correlated with a lower content of actin and myosin. Sensitivity to extracellular Ca2+ during high-K+ contraction, was higher in newborn compared with 3-wk-old and adult bladder strips. Concentrations at half maximal tension (EC50) were 0.57 +/- 0.01, 1.14 +/- 0.12, and 1.31 +/- 0.08 mM. Force of the newborn tissue was inhibited by approximately 45% by the nonmuscle myosin inhibitor Blebbistatin, whereas adult tissue was not affected. The calcium sensitivity in newborn tissue was not affected by Blebbistatin, suggesting that nonmuscle myosin is not a primary cause for increased calcium sensitivity. The relation between intracellular [Ca2+] and force was shifted toward lower [Ca2+] in the newborn bladders. This increased Ca2+ sensitivity was also found in permeabilized muscles (EC50: 6.10 +/- 0.07, 5.77 +/- 0.08, and 5.55 +/- 0.02 pCa units, in newborn, 3-wk-old, and adult tissues). It was associated with an increased myosin light chain phosphorylation and a decreased rate of dephosphorylation. No difference was observed in the myosin light chain phosphorylation rate, whereas the rate of myosin light chain phosphatase-induced relaxation was about twofold slower in the newborn tissue. The decreased rate was associated with a lower expression of the phosphatase regulatory subunit MYPT-1 in newborn tissue. The results show that myosin light chain phosphatase activity can be developmentally regulated in mammalian urinary bladders. The resultant alterations in Ca2+ sensitivity may be of importance for the nervous and myogenic control of the newborn bladders.

Decreased shortening velocity and altered myosin isoforms in guinea-pig hypertrophic intestinal smooth muscle.

The aims of this study were to investigate whether hypertrophy of the small intestinal smooth muscle leads to alterations of myosin isoform composition and shortening velocity and whether possible changes correlate with a change in the sensitivity to ADP of shortening velocity in this tissue. A partial occlusion was introduced in the distal part of the ileum of guinea-pigs. After 2 weeks, the part of the small intestine just proximal of the stenosis was hypertrophied (indicated by a significantly increased cross-sectional area). The most proximal part of the small intestine was used as control, thus enabling comparisons between hypertrophic and normal tissue from the same animal. The outer longitudinal layer of the intestinal wall was gently peeled off and used for biochemistry, RT-PCR and mechanical experiments. The desmin/actin ratio was significantly increased following hypertrophy, although myosin and actin expression were similar in control and hypertrophic tissue. In hypertrophic tissue, the myosin heavy chain mRNA with a 21 base pair insert decreased significantly. The composition of the mRNA encoding the myosin essential light chains changed towards more of the basic type (LC17b). No change in the expression of non-muscle myosin heavy chains A and B was detected. The maximal shortening velocity (V(max)) of maximally activated skinned preparations was significantly lower in the hypertrophic tissue (~50 % of control). The sensitivity of V(max) to ADP was increased in the hypertrophic smooth muscle tissue. We conclude that myosin expression is altered following intestinal hypertrophy and that these alterations affect reactions in the cross-bridge interaction, leading to a slower and more economical contractile function.

Effects of thyroxine on myosin isoform expression and mechanical properties in guinea-pig smooth muscle.

Information on the effects of thyroid hormone on smooth muscle contractile protein expression and mechanical properties is sparse. We have addressed the following questions. (1) Can thyroxine hormone alter myosin isoform composition in smooth muscle? (2) Can a change in myosin isoform composition lead to altered mechanical properties in smooth muscle? (3) Are alterations, if occurring, equal in fast and slow smooth muscle types? Guinea-pigs were treated with thyroxine (T(4)) for 12 days. Control animals were given physiological saline solution. Maximal unloaded shortening velocity (V(max)) was measured in chemically skinned, maximally activated muscle preparations from the aorta and the taenia coli. V(max) increased following thyroxine treatment, by approximately 20 % in the taenia coli. In the aorta, no significant increase in V(max) could be detected. The sensitivity of isometric force to inorganic phosphate (P(i)) was increased in the taenia coli following thyroxine treatment. The expression of mRNA (determined with RT-PCR) for the myosin heavy chain with the seven amino acid insert increased by approximately 70 % in the aorta and about 25 % in the taenia coli following thyroxine treatment. Western blot analysis showed an increase in the inserted myosin heavy chain form in the taenia coli. Expression of mRNA for the myosin essential light chains and the corresponding proteins did not change significantly in either muscle type. No alterations in non-muscle myosin heavy chain isoforms could be detected after thyroxine treatment. In conclusion, thyroxine treatment alters the isoform composition of myosin in fast and slow smooth muscles in vivo. This change is sufficient to increase shortening velocity and sensitivity of isometric force to P(i) in the fast, but not in the slow, smooth muscle type.