Introduction
The common causes of death from the local effects of trauma include exsanguination from the disruption of major blood vessels or organs, severe head injury, airway obstruction, and respiratory insufficiency from hemopneumothorax or mechanical dysfunction.
Individuals who initially survive an episode of trauma by way of the resuscitative actions of medical and surgical intervention may later suffer from the adverse systemic effects of trauma. Adverse systemic effects of trauma include the systemic inflammatory response syndrome (SIRS), adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), systemic fat embolism and venous thrombosis with pulmonary thromboembolism.
The SIRS refers to the effects of the systemic actions of the various mediators of acute inflammation. SIRS may progress to more severe forms where organ systems fail to maintain homeostasis resulting in multiple organ dysfunction syndrome (MODS). A continuum exits to the most severe end of the spectrum, i.e. multiple organ failure syndrome (MOFS).
ARDS refers to the acute lung injury that may complicate trauma and includes cases where there is no direct pulmonary trauma. Analogous to the adverse effects of inflammatory mediators in SIRS, the underlying pathogenesis of ARDS is a complex interplay between diverse pro- and anti-inflammatory mediators.
Disseminated intravascular coagulation describes generalized microthrombus formation in the systemic circulation. DIC occurs as a consequence of the failure of homeostasis within the coagulation system with massive thrombin generation and activation. DIC is involved in the pathogenesis of SIRS and is closely linked to the development of MODS.
Systemic fat embolism refers to the presence of globules of fat within the systemic circulation leading to organ dysfunction. Systemic fat embolization may occur following ‘saturation’ of the pulmonary circulation with spill over into the systemic circulation and/or the coalescence of unstable lipoproteins present within plasma. Systemic fat embolism is a cause of neurological and general deterioration post-trauma, and may be unrecognized at postmortem examination unless specifically sought.
Pulmonary thromboembolism is a late consequence of trauma especially where relative immobility, vascular injury and the relative hypercoagulable state seen in trauma patients results in the formation of peripheral thrombus.
Systemic Inflammatory Response Syndrome
In 1992, the term systemic inflammatory response syndrome (SIRS) was coined by the American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference as the clinical expression of endogenous mediators of inflammation not necessarily related to infection. The diagnosis of SIRS was defined as the presence of two or more of the following conditions: temperature >38°Cor <36°C; heart rate >90 beats min-1; respiratory rate >20 breaths min-1 or PaCO2<32torr (<4.3kPa); white blood cells > 12 000 cells mm-3, <4000 cells mm-3 or >10% immature (band) forms.
SIRS can be seen in many conditions including sepsis, trauma, pancreatitis, burns or following major surgery.
Severe trauma induces the SIRS as a consequence of (a) hemorrhage with ischemia and subsequent reperfusion (I/R syndrome) and (b) bony fractures or organ damage initiating inflammation and the induction of tissue repair. Inflammatory mediators generated from ischemia/reperfusion injury include proteolytic and oxygen radical metabolites and adhesion molecules, whereas tissue and vessel injury directly stimulate the complement, coagulation and kinin pathways.
In minor trauma the effects of inflammation clearly have a beneficial role in homeostasis and tissue repair. Local tissue injury activates complement and induces tissue macrophages, monocytes and other reactive cell elements to produce various mediators. For example, tumor necrosis factor alpha (TNFa) and interleukin-1 (IL-1) are secreted in large amounts following injury and appear within the circulation within 1 h. These mediators both have significant local and systemic effects. These polypeptide cytokines cause a variety of responses including activation of numerous cell populations and release of secondary cytokines and growth factors. Neutrophil polymorphs and endothelial cells are stimulated to change their activation status and receptor expression leading to adhesion of neutro-phils prior to migration and degranulation.
Other factors involved in the early stages of acute inflammation include highly active lipid mediators such as platelet-activating factor (PAF), prostaglan-dins and leukotrienes which also trigger and perpetuate the local accumulation of inflammatory cells. Complement components (C3a, C5a) are activated to stimulate leukocytes and macrophages to, in turn, increase vascular permeability. These and other components of the inflammatory response are crucial in the repair of injured and infected tissues and should be viewed as a normal physiological response.
It is also important to appreciate that the pro-inflammatory state of the acute phase response also initiates anti-inflammatory mediators. Once the underlying cause of inflammation is controlled and contained by host defenses, often with the assistance of medical and surgical intervention, the pro-inflammatory response will usually subside. For example, macrophages stimulated by various inflammatory mediators will sequentially release various growth factors including fibroblast growth factor (FGF), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) to induce the formation of newly formed blood vessels and extracellular matrix to begin the process of healing. The production of cortisone and other ‘inflammation antagonists’ are stimulated to ensure the acute phase response is attenuated.
However, in some victims of severe trauma, a massive cellular response is induced and the effects of the inflammatory mediators are not restricted to the sites of direct injury. Thus potent mediators released by various cells including activated macro-phages reach the systemic circulation and influence the immune defense, microcirculation and metabolism of remote organ systems. The effect of inflammatory mediators within the systemic circulation underlies the clinical expression of SIRS.
A clinical progression to altered organ function in an acutely ill patient with SIRS such that homeostasis cannot be maintained without intervention defines the MODS. In some patients with MODS organ function cannot be adequately supported and the patient develops MOSF.
The pathologist who performs a postmortem examination on a victim of trauma who succumbed in hospital some days after the initial incident will document various soft tissue and bony injuries. There may be evidence of gastrointestinal hemorrhage from gastric erosions and basal atelectasis and bronchopneumonia within the lungs. It is, however, important for the pathologist to be aware that a complex milieu of various inflammatory mediators had existed within the deceased and which had profound local, cellular and systemic effects on the body.
Adult Respiratory Distress Syndrome
The adult respiratory distress syndrome (ARDS) is clinically characterized by progressive hypoxemia refractory to oxygen therapy and may complicate a variety of medical and surgical conditions and is not necessarily associated with a direct lung injury. Radiographs of the chest reveal bilateral pulmonary infiltrates reflecting protein-rich edema fluid which is caused by an increase in permeability across the endothelial and epithelial barriers of the lung.
The fact that ARDS can occur in cases where there is no evidence of direct lung injury suggests that the systemic effects of inflammatory mediators are involved in the pathogenesis of the disease. A recent review has indicated that inflammatory cells, cytokines and adhesion molecules are important in the initial stages of the syndrome. It is further suggested that ARDS may represent the failure of anti-inflammatory processes within the lung and body as a whole, and the balance of pro- and anti-inflammatory mediators in SIRS may well be the most important issue.
The earliest morphologic change within the lung that may be observed by the pathologist is nonspecific edema. This may be followed by inflammation with necrosis of epithelial cells, fibrin deposition and the formation of hyaline membranes lining alveolar walls. In the later proliferative phase hyperplasia of type 2 pneumocytes lining the alveolar spaces may be observed. The corresponding macroscopic finding is of heavy firm beefy lung tissue.
In the late or organizing stage, varied amounts of collagen tissue are seen within the interstitium and within alveolar spaces.
Disseminated Intravascular Coagulation
The blood coagulation system protects against loss of blood and is an immediate response to vessel injury. Inside the blood vessel a group of antiplatelet, anticoagulant and fibrinolytic factors restrict activation of the hemostatic system to the site of endothelial injury and thus ensures patency of the vessel. It is in circumstances where this autoregulation becomes insufficient that DIC may develop. DIC has varied etiologies including trauma and is an important factor in the development of MODS.
DIC is characterized by activation of the coagulation system through excessive thrombin formation leading to microthrombi throughout the microcircu-lation of the body. Consequently there is consumption of platelets, fibrin and coagulation factors and secondary activation of fibrinolytic mechanisms leading to a bleeding diathesis. Therefore DIC may present with signs and symptoms of tissue hypoxia and infarction or as a hemorrhagic disorder subsequent to consumption of the various elements involved in coagulation.
Coagulation may be initiated by either the extrinsic or intrinsic pathway. The extrinsic pathway is triggered by the release of tissue factor or ‘thrombo-plastin’. The intrinsic pathway is activated by contact of factor XII with collagen or other negatively charged surfaces. Both the intrinsic and extrinsic pathways pass through a series of steps which result in the generation of thrombin which in turn converts fibrinogen into fibrin. Thrombin is also a potent activator of platelets and, through the thrombin receptor, thrombin also has direct effects on cell proliferation and regulation of the inflammatory process through expression of both leukocyte adhesion molecules and counter-receptors on endothelium. A recent study has indicated that persistent thrombin activity is closely linked to sustained SIRS in post-trauma patients.
The consequences of DIC are twofold. First, the widespread deposition of fibrin within the microcirculation leads to fragmentation of erythrocytes and obstruction to the microvasculature with resultant ischemia. When patency of the vessel is restored it is to be expected that ischemic damage may lead to inflammation. Secondly, the hemorrhagic diathesis resulting from consumption of platelets and clotting factors, with activation of plasminogen may be the prominent clinical manifestation of the disorder.
Pulmonary and Systemic Fat Embolism
Fat embolism may be an important sequel to soft tissue or bony trauma. Whereas in the past fat globules were believed to be extruded from the edges of bony fractures into the systemic circulation, it is now believed that fat embolism may reflect the instability of lipoproteins in the plasma with coalescence into macroglobules of lipid. Fat globules are not uncommonly seen in lung tissue following fatal trauma or in deaths following orthopedic procedures which are not directly related to the surgery. Pulmonary fat embolism detected microscopically is usually not associated with respiratory failure and the degree of fat embolism must be interpreted in the context of other factors such as the presence of other injuries and underlying natural disease processes.
Globules of fat within the pulmonary circulation may result in vascular obstruction, local vasoconstric-tion and pulmonary edema. To establish fat embolism as a significant contributing factor to the cause of death one must identify systemic embolism.
It was previously universally accepted that systemic fat embolism occurs when the pulmonary capillaries and veins become ‘saturated’ with fat globules and thus allow fat to appear within the arterial system. Another possible route for systemic fat embolism is a patent foramen ovale. More recently the suggestion has been made that fat embolism may also relate to an alteration in the activity of lipase or phospholipase which is caused by the embolic fat. This alteration then leads to the precipitation of serum fat in the vessels of the different organs.
Systemic fat embolism results in vascular obstruction and inflammation with petechiae seen within the brain and skin and demonstrable fat on microscopic examination of the brain and kidney using special stains and processing techniques.
Pulmonary Embolism
Individuals who have sustained significant trauma are at risk of peripheral thrombosis and subsequent pulmonary thromboembolism because (a) tissue trauma increases the coagulability of the blood for several weeks, the peak being between one and two weeks; (b) injury to the tissues, especially the legs or pelvic region, may cause local venous thrombosis in contused muscles or around fractured bones; (c) the injury may confine the victim to bed, either because of general shock and debility, or because the trauma itself necessitates recumbency as in head injuries, severe generalized trauma or injury affecting the legs. Recumbency leads to pressure on the calves and immobility which in turn reduces venous return and stasis because of less muscle massage of the leg veins. These factors combined increase the likelihood of peripheral thrombosis. Thrombus may dislodge from the peripheral circulation to the pulmonary vessels. Depending on the size of the thromboembolus it may impact within the distal pulmonary arteries. In an otherwise healthy individual there may not be any significant consequences. In those with lung or heart disease the affected lung tissue may undergo infarction.
Larger pulmonary thromboemboli may lead to chest pain, shortness of breath, cardiovascular collapse and sudden death. Microscopic examination of the embolic material will allow the pathologist to estimate the age of the thrombus.
Air Embolism
Although air embolism is a relatively rare clinical problem it is of considerable forensic importance because of its association with medical intervention, barotrauma, and occasional association with criminal activity. Air or gas embolism may occur on the venous or arterial side of the circulation and occasionally may occur within both. Venous air embolism is by far the more common clinical and pathological entity.
Lethal air embolism may occur with the introduction of 70-130 ml of air and the rate of administration is said to be important in relation to the clinical consequences. Air becomes trapped within the right atrium and right ventricle resulting in mechanical obstruction to blood flow through the heart because of the ‘air lock’ produced. In addition, the presence of air or gas within the circulation leads to platelet activation and release of vasoactive substances.
Air may gain access to the arterial from the venous side of the circulation via a patent foramen ovale or through intrapulmonary shunts causing potentially catastrophic obstruction to coronary and cerebral blood flow. However, recent reports have suggested that arterial air embolism may be directly associated with mechanical ventilation as a result of pulmonary barotrauma.
Iatrogenic lethal air embolism can be caused by endoscopic surgery with insufflation of viscera, complications of intravenous catheter insertion and infusion, in surgical procedures of the head and neck and during pulmonary needle biopsy procedures. It follows that other injuries to the head and neck that cause venous injury may also potentially lead to air embolism. Hyperbaric injury or ‘the bends’ is due to dissolution of nitrogen bubbles within various tissues including blood vessels, as a consequence of inadequate decompression.
The postmortem demonstration of air embolism is difficult. Chest radiographs are essential and recent work has recommended collection of the gas by an aspirometer with subsequent analysis by gas chromatography.
Amniotic Fluid Embolism
Amniotic fluid embolism is a rare and frequently lethal complication of pregnancy characterized clinically by profound and unresponsive hypotension with tachypnea, cyanosis and abnormalities in cardiac rhythm followed closely by the onset of DIC.
Patients may develop amniotic fluid embolism in clinical circumstances ranging from the performance of a second trimester termination of pregnancy up to instances that occur relatively late following completion of labor. The pathophysiology is not completely understood and various mechanisms have been suggested including a mechanical obstruction to pulmonary capillaries, activation of vasoactive substances, the presence and action of tissue factor within amniotic fluid, and anaphylaxis.
The diagnosis is made by the demonstration of squamous cells, mucin, meconium, and lanugo in the maternal pulmonary vasculature. Although the diagnosis has been suggested clinically from aspiration and examination of blood from pulmonary catheters, the diagnosis is generally reached after postmortem examination. Diagnostic material may be seen on conventional hematoxylin-and-eosin stained sections but is better appreciated using special stains such as the Attwood’s stain. In addition, immunohistochemical techniques are available to detect squamous cells and more importantly, mucin derived from amniotic fluid.
Tissue and Foreign Body Embolism
Embolization of foreign material within the vascular system is an uncommon but important complication of interventional medical practice. In forensic pathology embolization of projectiles within the vascular system and within hollow viscera is well documented in the literature. In addition, rare cases of hypodermic needle embolization are seen in intravenous drug abusers.
Tissue embolism is well recognized both macro-scopically and, more commonly, on microscopic examination in the postmortem examination of individuals dying of severe blunt trauma. Cases in clinical practice of liver tissue embolism to the pulmonary circulation following blunt abdominal trauma have been described. In addition, embolism of cerebral tissue to a lung later harvested for transplantation resulted in clinical problems of coagulation disorder and hemorrhage is reported in the literature.
Cases abound in the medical and forensic literature with regard to various types of embolism from invasive procedures. Cases include fragmented pacing wires, intravascular stents and catheters, dislodge-ment of orthopedic wires with embolism to the heart and fracture and embolization of mechanical heart valve prostheses. The foreign material may resulting in obstruction to blood flow or perforation of tissue and may act as a nidus for thrombus formation.
In addition to the aforementioned complications of foreign material embolism, surgical procedures such as total hip arthroplasty may result in the emboliza-tion of cement (methyl methacrylate monomer), fat and bone marrow debris leading to microthrombus formation and pulmonary vasoconstriction culminating in cardiovascular compromise and occasional death.
