Abdel-Rahman Lawendy

Detrimental effects of prolonged warm renal ischaemia-reperfusion injury are abrogated by supplemental hydrogen sulphide: an analysis using real-time intravital microscopy and polymerase chain reaction.

Whats known on the subject? and What does the study add?

Remote inflammatory response in liver is dependent on the segmental level of spinal cord injury.

BACKGROUND: Traumatic spinal cord injury (SCI) triggers a systemic inflammatory response (SIR) that contributes to a high incidence of secondary organ complications, particularly after a cervical or high-level thoracic injury. Because liver plays a key role in initiating and propagating the SIR, the aim of this study was to assess the effects that SCI at differing segmental levels has on the intensity of the inflammatory response in the liver. METHODS: Using male Wistar rats, clip compression SCI was performed at the 4th thoracic (T4 SCI; high-level SCI) or the 12th thoracic (T12 SCI; low-level SCI) spinal cord segment. Sham-injured rats had a partial laminectomy, but no SCI. Leukocyte recruitment to the liver, hepatic blood flow, and hepatocellular injury/death were assessed using intravital microscopy and histology. Chemokine and cytokine concentrations were assessed in the liver. Outcomes were measured at 1.5 hours, 12 hours, and 24 hours after SCI. RESULTS: At 12 hours after injury, T4 SCI caused a threefold increase in hepatic leukocyte recruitment compared with T12 SCI (p < 0.05). T4 SCI induced 50% more hepatocyte injury than T12 SCI at 12 hours (p < 0.05). Hepatic blood flow decreased after SCI, but not after sham injury, and stayed decreased only after T4 SCI at 24 hours after injury. The T4 SCI-induced changes were accompanied by increases in the hepatic concentrations of interleukin-1&bgr;, leptin, interleukin 10, and cytokine-induced neutrophil chemoattractant-1 at 1.5 hours. CONCLUSIONS: Our findings indicate that traumatic SCI triggers an acute SIR that contributes to hepatocellular injury. SCI-induced remote injury/dysfunction to the liver appears to be transient and is more robust after an upper thoracic SCI compared with a lower thoracic SCI.

Compartment syndrome-induced microvascular dysfunction: an experimental rodent model.

BACKGROUND Acute compartment syndrome (CS) is a limb-threatening disease that results from increased intracompartmental pressure. The pathophysiologic mechanisms by which this occurs are poorly understood. This study was designed to measure the effects of increased intracompartmental pressure on skeletal muscle microcirculation, inflammation and cellular injury using intravital videomicroscopy (IVVM) in a clinically relevant small animal model. METHODS We induced CS in 10 male Wistar rats (175-250 g), using a saline infusion technique. Intracompartmental pressure was controlled between 30 and 40 mm Hg and maintained for 45 minutes. After fasciotomy, the extensor digitorum longus muscle was visualized using IVVM, and perfusion was quantified. We quantified leukocyte recruitment to measure the inflammatory response. We measured muscle cellular injury using a differential fluorescent staining technique. RESULTS The number of nonperfused capillaries increased from 12.7 (standard error of the mean [SEM] 1.4 ) per mm in the control group to 30.0 (SEM 6.7) per mm following 45 minutes of elevated intracompartmental pressure (CS group; p = 0.031). The mean number of continuously perfused capillaries (and SEM) decreased from 78.4 (3.2) per mm in the control group to 41.4 (6.9) per mm in the CS group (p = 0.001). The proportion of injured cells increased from 5.0% (SEM 2.1%) in the control group to 16.3% (SEM 6.8%) in the CS group (p = 0.006). The mean number of activated leukocytes increased from 3.6 (SEM 0.7) per 100 μm(2) in the control group to 8.6 (SEM 1.8) per 100 μm(2) in the CS group (p = 0.033). CONCLUSION Early CS-induced microvascular dysfunction resulted in a decrease in nutritive capillary perfusion and an increase in cellular injury and was associated with a severe acute inflammatory component.

The severity of microvascular dysfunction due to compartment syndrome is diminished by the systemic application of CO-releasing molecule-3.

Objectives: To examine the protective effects of carbon monoxide (CO), liberated from a novel CO-releasing molecule (CORM-3), on the function of compartment syndrome (CS)–challenged muscle in a rodent model, thus providing for a potential development of a pharmacologic adjunctive treatment for CS. Methods: Wistar rats were randomized into 4 groups: sham (no CS), CS, CS with inactive CORM-3 (iCORM-3), and CS + CORM-3 (10 mg/kg intraperitoneally). CS was induced by elevation of intracompartmental pressure to 30 mm Hg through an infusion of isotonic saline into the anterior compartment of the hind limb for 2 hours. Both CORM-3 and iCORM-3 were injected immediately after fasciotomy. Microvascular perfusion, cellular tissue injury, and inflammatory response within the extensor digitorum longus muscle were assessed using intravital video microscopy 45 minutes after fasciotomy. Systemic levels of tumor necrosis factor alpha (TNF-&agr;) were also measured. Results: Elevation of intracompartmental pressure resulted in significant microvascular perfusion deficits (23% ± 2% continuously perfused capillaries in CS vs. 76% ± 4% in sham, P < 0.0001; 55% ± 2% nonperfused capillaries in CS vs. 13% ± 2% in sham, P < 0.0001), significant increase in tissue injury (ethidium bromide/bisbenzimide of 0.31 ± 0.05 in CS vs. 0.05 ± 0.03 in sham, P < 0.0001) and adherent leukocytes (13.7 ± 0.9 in CS vs. 1.8 ± 0.5 in sham, P < 0.0001), and a progressive rise in systemic TNF-&agr;. CORM-3 (but not iCORM-3) treatment restored the number of continuously perfused capillaries (57% ± 5%, P < 0.001), diminished tissue injury (ethidium bromide/bisbenzimide of 0.07 ± 0.01, P < 0.001), reversed the CS-associated rise in TNF-&agr;, and decreased leukocyte adherence (0.6 ± 0.3, P < 0.001). Conclusions: CORM-3 displays a potent protective/anti-inflammatory action in an experimental model of CS, suggesting a potential therapeutic application to patients at risk of developing CS.

Assessment of hepatic inflammation after spinal cord injury using intravital microscopy

OBJECTIVES The liver has been shown to play a particularly important role in the initiation and progression of the early systemic inflammatory response (SIR) to spinal cord injury (SCI). The purpose of this study was to determine the time course of leucocyte recruitment to the liver, and to determine the effect of injury severity on the magnitude of leucocyte recruitment and hepatic injury. METHODS Rats were randomly assigned to one of the following groups: uninjured, sham-injured (laminectomy and no cord injury), cord compressed or cord transected. At 30 min and 90 min after SCI rats had the left lobe of their livers externalised and visualised using intravital video microscopy. RESULTS Thirty minutes after injury the total number of leucocytes per post-sinusoidal venule was significantly increased after cord transection compared to that in uninjured and sham-injured rats (P<0.05). Of these leucocytes, significantly more were adherent to venule walls (P<0.05). At 90 min the total number of leucocytes per post-sinusoidal venule and the number of adherent and rolling leucocytes was significantly increased after cord transection and cord compression (P<0.05). DISCUSSION This is the first study to use intravital microscopy to visualise systemic inflammation in the liver following SCI. We have demonstrated immediate leucocyte recruitment to the liver within 30 min after injury and have shown that systemic inflammation increases with time after injury and with severity of injury.

A Multicenter Randomized Control Trial Comparing a Novel Intramedullary Device (InterTAN) Versus Conventional Treatment (Sliding Hip Screw) of Geriatric Hip Fractures.

Objectives: To compare outcomes in elderly patients with intertrochanteric hip fractures treated with either the sliding hip screw (SHS) or InterTAN intramedullary device (IT). Design: Prospective, randomized, multicenter clinical trial. Setting: Five level 1 trauma centers. Patients: Two hundred forty-nine patients 55 years of age or older with AO/OTA 31A1 (43) and OA/OTA 31A2 (206) fractures were prospectively enrolled and followed for 12 months. Intervention: Computer generated randomization to either IT (n = 123) or SHS (n = 126). Main Outcome Measurements: The Functional Independence Measure (FIM) and the Timed Up and Go test (TUG) were used to measure function and motor performance. Secondary outcome measures included femoral shortening, complications, and mortality. Results: Demographics, comorbidities, preinjury FIM scores and TUG scores were similar between groups. Patients (17.2%) who received an IT had limb shortening greater than 2 cm compared with 42.9% who received an SHS (P < 0.001). To determine the importance of preinjury function and fracture stability, we analyzed the subgroup of patients with the ability to walk 150 m independently preinjury and an OA/OTA 31A-2 fracture (n = 70). In this subgroup, patients treated with SHS had greater shortening and demonstrated poorer FIM and TUG scores compared with patients treated with an IT. Conclusions: Overall, most patients with intertrochanteric femur fractures can expect similar functional results whether treated with an intramedullary or extramedullary device. However, active, functional patients have an improved outcome when the InterTAN is used to treat their unstable intertrochanteric fracture. Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Hepatic microvascular changes in rat abdominal compartment syndrome

BACKGROUND Abdominal compartment syndrome (ACS) is associated with an increased rate of multiple organ dysfunction and is an independent marker for mortality. Our objective was to develop an animal model to study the mechanisms of tissue and microvascular injury associated with ACS at the microscopic level. MATERIALS AND METHODS ACS was established in rats with CO₂ insufflation at 20 mm Hg for 2 h, with an abdominal cast. Sinusoidal perfusion, inflammatory response, and cell death were quantified in exteriorized livers. Respiratory and renal dysfunction were assessed biochemically and morphologically. Myeloperoxidase levels, a marker of neutrophil activation, were measured in the liver, lung, and small intestine. RESULTS Continuously perfused sinusoids were significantly lower in the ACS group (81.4 ± 2.2% versus 99.6% ± 0.50), with an increase in nonperfused and intermittently perfused sinusoids (P < 0.05). Hepatocellular death and the number of activated leukocytes in postsinusoidal venules showed 7- and 18-fold increases, respectively, in the ACS group (P < 0.05). A significant increase in blood urea nitrogen levels in experimental rats was also observed. Myeloperoxidase levels were found to be 8-fold higher in lungs of ACS rats relative to control (P < 0.05), as well as statistically significant increase in the pCO₂ and decrease in pH of ACS rats. CONCLUSIONS We have successfully developed a model of ACS with documented evidence of renal and respiratory dysfunction. In addition, we have microscopy-confirmed evidence of early inflammatory changes and perfusion deficits in the liver with a concomitant increase in cell death in the ACS group.

Systemic application of carbon monoxide-releasing molecule 3 protects skeletal muscle from ischemia-reperfusion injury

Objective: Ischemia‐reperfusion (IR) is a limb‐ and life‐threatening complication of acute limb ischemia and musculoskeletal trauma. Carbon monoxide‐releasing molecules (CORMs) have recently been shown to protect microvascular perfusion and to reduce inflammation and injury in various ischemic animal models. The purpose of this study was to examine the effects of water‐soluble CORM‐3 on the extent of IR‐induced muscle injury. Methods: Wistar rats were randomized into three groups: sham (no ischemia), IR + CORM‐3 (10 mg/kg intraperitoneally), and IR + inactive CORM‐3 (iCORM‐3; 10 mg/kg intraperitoneally). No‐flow ischemia was induced by the application of a tourniquet to the hind limb for 2 hours; tourniquet release commenced the reperfusion phase. Both CORM‐3 and iCORM‐3 were injected immediately after tourniquet release. Temporal changes in microvascular perfusion, cellular tissue injury (ethidium bromide and bisbenzimide staining), and inflammatory response (leukocyte recruitment) within the extensor digitorum longus muscle were assessed using intravital video microscopy every 15 minutes for a total of 90 minutes after initiation of reperfusion. Systemic levels of tumor necrosis factor‐&agr; were also measured. Results: Hind limb IR resulted in (1) a significant no‐reflow phenomenon followed by progressive increase in microvascular perfusion deficit (21% ± 2% continuously perfused capillaries in IR vs 76% ± 4% in sham [P < .001]; 52% ± 8% nonperfused capillaries in IR vs 13% ± 2% in sham at 90 minutes of reperfusion [P < .001]), (2) tissue injury (ethidium bromide and bisbenzimide staining of 0.52 ± 0.07 in IR vs 0.05 ± 0.03 in sham at 90 minutes of reperfusion [P < .001]), (3) leukocyte recruitment (13.7 ± 0.9 adherent leukocytes/30 seconds/1000 &mgr;m2 in IR vs 1.8 ± 0.5 adherent leukocytes/30 seconds/1000 &mgr;m2 in sham at 90 minutes of reperfusion [P < .001]), and (4) an increase in circulating tumor necrosis factor‐&agr; levels. Systemic administration of CORM‐3 (but not of iCORM‐3) effectively reduced the IR‐associated skeletal muscle perfusion deficits, tissue injury, and inflammatory activation. Conclusions: CORM‐3 displays potent protective and anti‐inflammatory effects in an experimental model of hind limb IR, suggesting a potential therapeutic application of CORMs in treatment of ischemic conditions. Clinical Relevance: Systemic administration of carbon monoxide, in the form of carbon monoxide‐releasing molecule 3, displays potent anti‐inflammatory properties that have a potential to diminish or to minimize the reperfusion injury in the skeletal muscle after prolonged ischemia.

The relationship between the duration of acute cauda equina compression and functional outcomes in a rat model.

Study Design. Immunohistochemical and behavioral study using a rat model of acute cauda equina syndrome (CES). Objective. To determine the effect of duration of extradural cauda equina compression (CEC) on bladder, sensory, and motor functions. Summary of Background Data. Cauda equina syndrome is a devastating injury treated with surgical decompression. Controversy exists regarding the optimal timing of surgery. Animal models of CES have focused on motor recovery but have not evaluated pain behavior or bladder function. Methods. A 4-mm balloon-tipped Fogarty catheter was inserted between the fifth and sixth lumbar lamina into the dorsal epidural space and inflated to compress the nerve roots at the L5 level. Maximal inflation was maintained at a constant balloon pressure of 304 Kpa for 1 or 4 hours. The catheter was inserted but not inflated in sham animals. During a 4-week period, pain behavior, bladder function, and locomotor function were assessed. Postmortem bladders and the lesion site were collected for analysis. Results. Mechanical allodynia was 2-fold greater in 1-hour CEC rats than 4-hour CEC (P = 0.002) and sham-operated (P = 0.001) rats at 4 weeks after injury. Hind limb locomotor function was not different between groups at 4 weeks after injury. Both the 1-hour and 4-hour CEC group rats retained greater volumes of urine than the sham-operated rats throughout the 4-week period (P < 0.05). At 4 weeks, bladder weight and volume were 2-fold greater in the 4-hour CEC group than in the 1-hour CEC group (P = 0.006 and P = 0.01, respectively). Histology of the bladder wall revealed an overall thinning after 4-hour CEC. Histology of the lesion site revealed a greater overall severity of injury after 4-hour CEC than after 1-hour CEC (P = 0.04) and sham operation (P = 0.002). Conclusion. Our data suggest that recovery of motor function is less affected by the timing of decompression compared with bladder function and pain behavior. Early decompression preserved bladder function but was associated with allodynia. Level of Evidence: N/A