ORCID Profile
0000-0003-4564-4689
Current Organisations
Leeds Teaching Hospitals NHS Trust
,
University of Leeds
,
Health Education Yorkshire and the Humber
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2008
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.INJURY.2004.05.029
Abstract: Open pelvic fractures constitute one of the most devastating injuries in musculo-skeletal trauma and must be treated aggressively, incorporating a multidisciplinary approach. Early treatment, focusing on prevention of haemorrhage and sepsis, is essential. The management of associated soft tissue injuries must also be aggressive, including early administration of broad-spectrum antibiotics and repeated, meticulous wound debridement and irrigation. Selective faecal ersion, based on wound location, is compulsory and safe, minimising the risk of sepsis and reducing mortality rates.
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1016/J.ETP.2004.09.004
Abstract: Intercellular adhesion molecule-1 (ICAM-1) is thought to be involved in polymorphonuclear leukocytes (PMNL) recruitment and secondary organ damage in response to infection and inflammation. The precise role of ICAM-1 in disease progression is unknown and remains a topic of controversy. The aim of this study was to investigate the effect of ICAM-1 on histological changes and cytokine synthesis in a murine model of polymicrobial sepsis. Polymicrobial sepsis was induced in experimental animals by caecal ligation and puncture (CLP). A control group was formed using sham laparotomy without CLP. In order to ascertain the role of ICAM-1 in the response, procedures were performed in both ICAM-1 knockout animals (ICAM-1-/-) and in C57BL/6 mice that were not genetically modified (wild type, WT). Clinical response was observed daily, morphological changes occurring in the lung and liver were studied using light microscopy and quantified using a scoring system. Plasma concentrations of various cytokines (TNF-alpha, IL-6, IL-10) were measured via ELISA. In ICAM-1-/- mice a less severe clinical response to induced sepsis was observed with significantly less weight loss and hypothermia. A significantly lower mortality rate was observed in ICAM-1-/- mice (12.5% vs. WT: 45.5%) and no significant histological changes were apparent in pulmonary or hepatic tissue on light microscopy following CLP. In WT animals however, significant evidence of leukocyte infiltration and interstitial thickening in pulmonary tissue was observed. Similarly, hepatic tissue sinusoidal widening and hydropic degeneration was present. In addition, pro- and anti-inflammatory cytokine synthesis in ICAM-1-/- animals was significantly attenuated when compared to WT mice. (ICAM-1-/-: TNF-alpha: 67.7+/-12.1pg/microl IL-6: 208.9+/-26.7pg/microl IL-10: 34.6+/-5.8pg/microl WT: TNF-alpha: 840.7+/-150.2pg/microl IL-6: 3100.2+/-1052.3 pg/microl IL-10: 1550.1+/-495.7 pg/microl). This study suggests that ICAM-1 has an important pathophysiological role in the response to polymicrobial sepsis. It would appear that absence of this molecule impairs the ability of PMNL to migrate into organ tissues and reduces consequent secondary organ damage resulting in improved clinical status and overall survival. Further investigation into the effectiveness of ICAM-1 modulation in the treatment of sepsis is warranted.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2006
DOI: 10.1097/00005131-200603000-00004
Abstract: To determine infection rates after damage control orthopaedics (DCO) and primary intramedullary nailing (1' IMN) in multiply injured patients with femoral shaft fracture. Retrospective case analysis. Level I trauma center. All patients with New Injury Severity Score (NISS) >20 and femoral shaft fracture (AO 32-) treated in our unit between 1996 and 2002. Damage control orthopaedics, defined as primary external fixation of the femoral shaft fracture and subsequent conversion to an intramedullary nail, or primary IMN. Rates of infection classified as contamination (positive swabs with no clinical change), superficial, deep (requiring surgery), and removal of hardware (those requiring removal of femoral instrumentation or utation). A total of 173 patients with 192 fractures were included 111 fractures were treated by DCO and 81 by primary IMN. Mean follow-up was 19.1 months [median, 16.7, range, 1 (patient died)-67 months]. DCO patients had a significantly higher NISS and more grade III open fractures (P<0.001). IMN procedures took a median of 150 minutes compared with 85 minutes for DCO (P<0.0001). Although wound contamination (including contaminated pin sites) was more common in the DCO group (P<0.05), the risk of infectious complications was equivalent (P=0.86). Contamination was significantly more likely when conversion to IMN occurred after more than 14 days (P<0.05) however, this did not lead to more clinically relevant infections. Logistic regression analysis showed that although a DCO approach was not associated with infection, delay before conversion in the DCO group might be [P=0.002 for contamination and removal of hardware, P=0.065 for serious infection (deep or worse), not significant for other infection outcomes]. Grade III open injury also was significantly associated with serious infection in all patients (P<0.05). Infection rates after DCO for femoral fractures are comparable to those after primary IMN. We see no contraindication to the implementation of a damage control approach for severely injured patients with femoral shaft fracture where appropriate. Pin-site contamination was more common where the fixator was in place for more than 2 weeks. For patients treated by using a DCO approach, conversion to definitive fixation should be performed in a timely fashion.
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1016/J.INJURY.2004.10.017
Abstract: Intramedullary nailing is the treatment of choice for patients with femoral shaft fractures. However, there is an ongoing debate in multiple trauma patients with associated lung contusion when primary or secondary definitive stabilisation of the long bone fracture should be performed, as nailing is thought to play an important role in the pathogenesis of adult respiratory distress syndrome (ARDS). In a standardised sheep model, this study aimed to quantify the development of acute pulmonary endothelial changes, to assess the activation of polymorphonuclear leucocytes (PMNL) and to observe the effects on the coagulation system associated with the reamed nailing procedure. Furthermore, the effect of coexisting lung contusion in an experimental model was evaluated. The animals were randomly assigned to one of four different groups (6 animals/group). In control groups, only a sham operation (thoracotomy) was performed, whereas in study groups, lung contusion was induced prior to femoral stabilisation either by external fixation or reamed femoral nailing. Using bronchoalveolar lavage (BAL) pulmonary permeability changes were quantified and PMNL activation was assessed by chemiluminescence. Additionally PMNL diapedesis and interstitial lung oedema were determined by histological analysis. All animals were sacrificed 4 h after the start of the femoral instrumentation. Without an associated lung injury, instrumentation of the femoral canal with the reamed nailing technique induced a transient increase in pulmonary permeability. In the face of an induced lung contusion, reamed femoral nailing resulted in significant increases in PMNL activation, pulmonary permeability and interstitial lung oedema, compared with external fixation. Without pulmonary contusion, reaming of the femoral canal was associated with a transient increase in pulmonary permeability. This was exacerbated in the presence of lung contusion along with increased PMNL activation. External fixation did not provoke similar changes. The findings of this study support the view that reaming of the femoral canal should be avoided in polytrauma patients with severe chest trauma as it could act as an additional stimulus for adverse outcome. Temporary external fixation appears to be a safe method for fracture stabilisation until inflammatory and coagulatory disturbances after trauma have been normalized.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2005
DOI: 10.1097/01.TA.0000153942.28015.77
Abstract: Recently, there has been a move away from early total care in patients with severe, multiple injuries to damage control orthopedics (DCO) in an attempt to limit the physiologic insult resulting from operative treatment after trauma. For femoral shaft fracture, this entails initial external fixation and subsequent conversion to an intramedullary nail (IMN). We sought to quantify the inflammatory response to initial surgery and conversion and link this to subsequent organ dysfunction and complications. Patients with femoral shaft fracture and a New Injury Severity Score of 20 or more were included. Data were retrospectively collected for 4 days at admission and at exchange procedure (external fixation to intramedullary nail), and the Systemic Inflammatory Response Syndrome (SIRS) score and the Marshall multiorgan dysfunction score were calculated. One hundred seventy-four patients met the inclusion criteria. The DCO group had significantly more severe injuries (New Injury Severity Score of 25.4 vs. 36.2, p < 0.0001) and significantly more head and thoracic injuries (both p < 0.0001). The mean SIRS score was significantly higher in the IMN group, from 12 hours until 72 hours postoperatively (p < 0.05). The mean peak postoperative SIRS score was significantly higher in the IMN group than in the DCO group, at the primary procedure and at conversion, as was the time with an SIRS score greater than 1. At conversion in the DCO group, the preoperative SIRS score correlated with magnitude and duration of elevation in the SIRS and multiorgan dysfunction scores (p < 0.0001). It would appear that despite more severe injuries in the DCO group, patients had a smaller, shorter postoperative SIRS and did not suffer significantly more pronounced organ failure than the IMN group. DCO patients undergoing conversion while their SIRS score was raised suffered the most pronounced subsequent inflammatory response and organ failure. According to these data, DCO treatment was associated with a lesser systemic inflammatory response than early total care for femur fractures. The inflammatory status of the patient may be a useful adjunct in clinical decision making regarding the timing of conversion to an intramedullary device.
Publisher: Elsevier BV
Date: 07-09-2005
DOI: 10.1016/J.CYTO.2005.06.008
Abstract: Although, hypothermia is a frequent event after trauma, it is unclear whether its beneficial or detrimental effects are more important. This study aims to quantify the effects of hypothermia and re-warming on the inflammatory response after fracture/hemorrhage and subsequent fracture stabilization with resuscitation. Eighty-one male C57Bl/6 mice (aged 8-10 weeks, weighing 22.0+/-3.0 g) underwent femoral fracture and hemorrhage followed by resuscitation and splint fixation of the fracture. Animals were sacrificed 3h after induction of hemorrhage and fracture. Besides a sham group (n=6), four experimental groups were created: A: normothermia (n=12), B: hypothermia after trauma (n=21), C: re-warming after resuscitation and before stabilization (n=21), and D: hypothermia before trauma (n=21). Groups B-D were further sub ided into three subgroups according to the degree of hypothermia (subgroup 1: 35-33 degrees C, subgroup 2: 32.9-30.0 degrees C, and subgroup 3: 29.9-27.0 degrees C). Plasma cytokine (TNF-alpha, IL-6, and IL-10) and chemokine (MCP-1) concentrations were determined by ELISA, pulmonary permeability changes were quantified, and histological analysis of lung and liver tissues was performed. Normothermia resulted in a significantly increased early mortality rate. A significantly increased pro-inflammatory and decreased anti-inflammatory responses were also observed in normothermia as compared to hypothermia. The extent of these changes was most pronounced in the severe hypothermic group. Re-warming after mild hypothermia resulted in a pro-inflammatory response comparable to normothermia. Hypothermia has a beneficial effect on early survival after trauma, which appears to be independent of the level of hypothermia and re-warming. Re-warming, however, enhanced the pro-inflammatory response. Further studies with a longer posttraumatic observation period are required to investigate the long term effects of the hypothermia and re-warming-induced changes on the pro- and anti-inflammatory responses.
Publisher: Oxford University Press (OUP)
Date: 31-08-2004
DOI: 10.1111/J.1365-2249.2004.02598.X
Abstract: Sepsis is associated with depression of T cell-dependent immune reactivity with proinflammatory cytokines, such as tumour necrosis factor (TNF)-α, playing an important role. Recent investigations describe an association between these immunological alterations and disturbances of the endocrine system, related most frequently to sex steroid hormones. Dehydroepiandrosterone (DHEA), one of the most abundant adrenal sex steroid precursors, seems to have a protective immunological effect towards septic insults. In this study, both the role of TNF-receptor I (RI) and possible interactions in the protective role of DHEA were investigated in a murine model of polymicrobial sepsis. Polymicrobial sepsis was induced by caecal ligation and puncture (CLP) in a murine model. The effects of DHEA on survival, clinical parameters and cellular immunity (T lymphocytes and natural killer (NK) cells) were investigated. CLP was performed in genetically modified TNF-RI knock-out (TNF-RI–/–) and genetically unmodified (wild-type, WT) mice. DHEA application was associated with a decrease in the mortality rate in WT animals. A mortality rate of 91·7% was observed in TNF-RI–/– mice after CLP. This mortality rate was reduced to 37·5% by the application of DHEA. In sham-operated TNF-RI–/– animals, a significantly higher proportion of NK cells within the lymphocyte population was measured compared with the corresponding WT group. After CLP, a significant increase in the percentage cell count of NK cells was recorded in WT mice. Overall, following DHEA application in WT mice, an alteration in the cellular immune response was characterized by a reduction in the percentage counts of CD4+, CD8+ and NK cells. In the group of TNF-RI–/– mice treated with DHEA, no increase in the percentage cell count of NK cells was observed after CLP. No data for cell analysis were available from the CLP-TNF-RI–/– mice treated with saline, due to the high mortality rate in these animals. DHEA reduces the complications of sepsis in a TNF-RI-independent manner. Our study suggests that NK cells are involved in the protective mechanism of DHEA in WT mice. It would therefore seem that DHEA represents a feasible alternative therapy for the dysregulated immune system in sepsis.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Paul Harwood.