Negative Pressure Wound Therapy. Therapy Settings and Biological Effects in Peripheral Wounds

Negative pressure wound therapy (NPWT) promotes wound healing through several mechanisms, e.g., altered periwound blood flow, mechanical deformation of the wound edge tissue, and drainage of excess fluid and debris. The general aim of this thesis was to study the impact of different levels of negative pressure, different wound filling materials (foam or gauze), and different ways of applying the negative pressure (continuously, intermittently or variably) on the biological effects of NPWT in peripheral wounds. The intention was to provide a scientific basis for the choice of these parameters in order to be able to optimize the healing of NPWT-treated wounds in the future. Studies were carried out on peripheral wounds created on the backs of pigs. The effect of NPWT on periwound blood flow was investigated using invasive and transcutaneous laser Doppler flowmetry, as well as thermodiffusion. Blood flow was found to decrease 0.5 cm laterally from the wound edge and increase 2.5 cm from the wound edge; a transition zone being seen 1 cm from the wound edge. Blood flow changed gradually with increasing levels of negative pressure, reaching half maximal effect at approximately –45 mmHg and maximum effect at about –80 mmHg. The blood flow response was found to depend on the measurement technique. Applying intermittent and variable pressure resulted in concomitant increases and decreases in periwound blood flow. The combination of hypo- and hyperperfusion may be beneficial in the process of wound healing. The mechanical effects of NPWT were studied with regards to macro- and microdeformation. It was found that the degree of macrodeformation, i.e., wound contraction, increased gradually with increasing negative pressure level, reaching half maximal effect at about –45 mmHg and near-maximal effect at –75 mmHg. The degree of wound contraction was the same regardless of whether foam or gauze was used as wound filler. The effects of NPWT on microdeformation, i.e., the microscopic interaction between the wound filler and the newly formed granulation tissue, were examined histologically using stained sections of the wound bed. Both foam- and gauze-based NPWT were shown to induce microdeformation of the wound bed tissue. The effect of NPWT on fluid evacuation from the wound cavity was measured gravimetrically. The amount of evacuated fluid increased gradually with increasing level of negative pressure, reaching a near-maximum at –125 mmHg. It may thus be beneficial to treat wounds containing large volumes of exudate with a high negative pressure initially (e.g., –125 mmHg), and then reduce the pressure to a level more appropriate for the wound edge tissue. In conclusion, the biological effects of NPWT were influenced by the negative pressure level, the wound filling material and the way in which NPWT was applied (continuously, intermittently or variably). Hopefully, the results of these studies may provide a scientific basis for the choice of NPWT parameters in the treatment of wounds. Further clinical studies are needed to corroborate our findings before recommendations can be made regarding the NPWT settings for treatment of different wound types and tissues in order to improve wound healing

Ki67 proliferation in core biopsies versus surgical samples - a model for neo-adjuvant breast cancer studies

Background: An increasing number of neo-adjuvant breast cancer studies are being conducted and a novel model for tumor biological studies, the "window-of-opportunity" model, has revealed several advantages. Change in tumor cell proliferation, estimated by Ki67-expression in pre-therapeutic core biopsies versus post-therapeutic surgical samples is often the primary end-point. The aim of the present study was to investigate potential differences in proliferation scores between core biopsies and surgical samples when patients have not received any intervening anti-cancer treatment. Also, a lack of consensus concerning Ki67 assessment may raise problems in the comparison of neo-adjuvant studies. Thus, the secondary aim was to present a novel model for Ki67 assessment. Methods: Fifty consecutive breast cancer cases with both a core biopsy and a surgical sample available, without intervening neo-adjuvant therapy, were collected and tumor proliferation (Ki67, MIB1 antibody) was assessed immunohistochemically. A theoretical model for the assessment of Ki67 was constructed based on sequential testing of the null hypothesis 20% Ki67-positive cells versus the two-sided alternative more or less than 20% positive cells.. Results: Assessment of Ki67 in 200 tumor cells showed an absolute average proliferation difference of 3.9% between core biopsies and surgical samples (p = 0.046, paired t-test) with the core biopsies being the more proliferative sample type. A corresponding analysis on the log-scale showed the average relative decrease from the biopsy to the surgical specimen to be 19% (p = 0.063, paired t-test on the log-scale). The difference was significant when using the more robust Wilcoxon matched-pairs signed-ranks test (p = 0.029). After dichotomization at 20%, 12 of the 50 sample pairs had discrepant proliferation status, 10 showed high Ki67 in the core biopsy compared to two in the surgical specimen (p = 0.039, McNemar's test). None of the corresponding results for 1000 tumor cells were significant - average absolute difference 2.2% and geometric mean of the ratios 0.85 (p = 0.19 and p = 0.18, respectively, paired t-tests, p = 0.057, Wilcoxon's test) and an equal number of discordant cases after dichotomization. Comparing proliferation values for the initial 200 versus the final 800 cancer cells showed significant absolute differences for both core biopsies and surgical samples 5.3% and 3.2%, respectively (p < 0.0001, paired t-test). Conclusions: A significant difference between core biopsy and surgical sample proliferation values was observed despite no intervening therapy. Future neo-adjuvant breast cancer studies may have to take this into consideration

Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators

Background: Several biochemical markers in blood correlate with the magnitude of brain injury and may be used to predict neurological outcome after cardiac arrest. We present a protocol for the evaluation of prognostic accuracy of brain injury markers after cardiac arrest. The aim is to define the best predictive marker and to establish clinically useful cut-off levels for routine implementation. Methods: Prospective international multicenter trial within the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial in collaboration with Roche Diagnostics International AG. Samples were collected 0, 24, 48, and 72 hours after randomisation (serum) and 0 and 48 hours after randomisation (plasma), and pre-analytically processed at each site before storage in a central biobank. Routine markers neuron-specific enolase (NSE) and S100B, and neurofilament light, total-tau and glial fibrillary acidic protein will be batch analysed using novel Elecsys® electrochemiluminescence immunoassays on a Cobas e601 instrument. Results: Statistical analysis will be reported according to the Standards for Reporting Diagnostic accuracy studies (STARD) and will include comparisons for prediction of good versus poor functional outcome at six months post-arrest, by modified Rankin Scale (0–3 vs. 4–6), using logistic regression models and receiver operating characteristics curves, evaluation of mortality at six months according to biomarker levels and establishment of cut-off values for prediction of poor neurological outcome at 95–100% specificities. Conclusions: This prospective trial may establish a standard methodology and clinically appropriate cut-off levels for the optimal biomarker of brain injury which predicts poor neurological outcome after cardiac arrest

Therapeutic hypothermia for comatose survivors after near-hanging-A retrospective analysis

BACKGROUND: Patients who survive after suicidal hanging attempts suffer from transient brain ischaemia. Morbidity and mortality is high, and no specific therapy is available. Hypothermia attenuates ischaemic brain damage and has become standard care in comatose survivors of cardiac arrest; therapeutic hypothermia may thus be useful for near-hanging victims as well.OBJECTIVES: To perform a literature review on outcome and outcome predictors after near-hanging. To make a retrospective chart review on treatment and outcome of near-hanging victims in two Swedish intensive care units during a 4-year period (2003-2006).METHODS: The literature review was conducted as a Medline search. Study patients were identified and data retrieved from the intensive care units' medical records. The primary outcome measure was neurological function at discharge.RESULTS: No randomised, controlled trials were found in the Medline search. Thirteen patients could be identified and were included in the study, all were in coma and three had suffered cardiac arrest. Outcome was good in six of eight patients treated with hypothermia, as compared to three of five patients who were not. All three patients with cardiac arrest received hypothermia treatment and outcome was good in one.CONCLUSION: No randomised, controlled trial for treatment of near-hanging victims has been published. No conclusions could be drawn regarding treatment effects of hypothermia in this survey, but in the absence of better evidence, it seems reasonable to consider hypothermia treatment in all comatose near-hanging victims

The Effect of Intermittent and Variable Negative Pressure Wound Therapy on Wound Edge Microvascular Blood Flow

Negative pressure wound therapy (NPWT) alters wound edge microvascular blood flow. Some preclinical data suggest that cycling between low and high negative pressure may be more beneficial than continuous NPWT. The purpose of this in vivo study was to compare the effect of intermittent negative pressure (cycled either from 0 to -75 or to -125 mm Hg) and variable negative pressure (cycled from -10 to -75 or -125 mm Hg or from -45 to -75 or -125 mm Hg) on wound edge microvascular blood flow. Using a peripheral wound model (n = 8 domestic 70-kg pigs), intermittent and variable NPWT was applied to surgically created wounds (5 cm diameter, 2 cm. depth) for five cycles of 5 minutes of high and 2 minutes of low pressure. Blood flow was measured using laser Doppler velocimetry in subcutaneous and muscle tissue at 0.5 and 2.5 cm from the wound edge. When NPWT was applied, blood flow decreased an average of 29% +/- 2% in muscle tissue and 22 % +/- 4% in subcutaneous tissue at -75 mm Hg at 0.5 cm from the wound edge and increased an average of 20% +/- 6% for -75 mm Hg at 2.5 cm from the wound edge. Blood flow changed repeatedly when negative pressure was cycled. Large gradients between the cycled pressures (eg, -10 to -75 mm Hg) resulted in greater blood flow alterations than smaller (eg, -45 to -75 mm Hg) gradients. Blood flow alternations were similar between low-pressure settings of -10 mm Hg (variable NPWT) and 0 mm Hg (intermittent NPWT) and between high-pressure settings of -75 or -125 mm Hg. Both intermittent and variable NPWT result in a beneficial combination of increased blood flow, known to facilitate oxygenation and nutrient supply, and decreased blood flow, known to stimulate angiogenesis and granulation tissue formation. Cycling the negative pressure may be especially advantageous when treating poorly vascularized tissue. In cases where intermittent therapy causes patient discomfort, variable therapy may be superior