Biomedical subjects
Publications and source records attributed to F B Cerra.
Three areas of particular importance in dealing with critical complications of trauma are pharmacology, monitoring, and nutritional support. This article deals with each of these from the perspective of the doctor or nurse at the bedside. This survey stands as a sampler and guidebook to these subjects as they pertain to the critically ill multiple trauma patient.
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OBJECTIVE: To evaluate and editorialize the evolving role of the discipline of critical care as a healthcare delivery system in the process of healthcare reform. DATA SOURCES: The sources included material from the Federal Office of Management and Budget, Health Care Financing Review, President Bush's Office, Association of American Medical Colleges, and publications of the Society of Critical Care Medicine. STUDY SELECTION: Data were selected that the author felt was relevant to the healthcare reform process and its implications for the discipline of critical care. DATA EXTRACTION: The data were extracted by the author to illustrate the forces behind healthcare reform, the implications for the practice of critical care, and role of critical care as a coordinated (managed) care system in the process of healthcare reform. DATA SYNTHESIS: Healthcare reform has been initiated because of a number of considerations that arise in evaluating the current healthcare delivery system: access, financing, cost, dissatisfactions with the mechanisms of delivery, and political issues. The reform process will occur with or without the involvement of critical care practitioners. Reforms may greatly alter the delivery of critical care services, education, training, and research in critical care. Critical care has evolved into a healthcare delivery system that provides services to patients who need and request them and provides these services in a coordinated (managed) care model. CONCLUSIONS: Critical care practitioners must become involved in the healthcare reform process, and critical care services that are effective must be preserved, as must the education, training, and research programs. Critical care as a healthcare delivery system utilizing a coordinated (managed) care model has the potential to provide services to all patients who need them and to deliver them in a manner that is cost effective and recognized as providing added value.
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The systemic inflammatory response and progression to secondary organ dysfunction are manifestations of the host's responses to injury. This article outlines the clinical manifestations of this injury-response cascade. The potential roles of cytokines, eicosanoids, platelet-activating factor, nitric oxide, oxygen-free radicals, and the leukocyte-endothelial interaction are explored in some detail. A goal-directed therapy of source control, resuscitation, and metabolic support is reviewed, and new therapies with monoclonal antibodies and immunomodulated nutrition are described. These new therapies hold great potential for finally improving the outcome of this fatal syndrome.
Suppression of the gut luminal aerobic flora to reduce nosocomial infections was tested in a prospective, randomized, double-blind, placebo-controlled clinical trial in patients in a surgical intensive care unit who had persistent hypermetabolism. Forty-six patients were randomized to receive either norfloxacin, 500-mg suspension every 8 hours, together with nystatin, 1 million units every 6 hours, or matching placebo solutions administered through a nasogastric tube within 48 hours of surgical intensive care unit admission. Selective gut decontamination with the experimental therapy or placebo solutions continued for at least 5 days or until the time of surgical intensive care unit discharge. Patients were monitored with routine surveillance cultures for the development of nosocomial infections, as defined by criteria from the Centers for Disease Control. All other therapy was given as clinically indicated, including systemic antibiotics. The selective gut decontamination group experienced a significant reduction in the incidence of nosocomial infections and a reduced length of stay. However, these results were not associated with a concomitant decrease in progressive multiple organ failure syndrome, adult respiratory distress syndrome, or mortality.
A static culture model employing cylindrical collagen-hepatocyte gels is reported for large scale testing of conditions relevant to the three compartment hollow fiber bioartificial liver. High density hepatocyte cultivation was achieved by cell entrapment within the collagen-hepatocyte gel. Hepatocyte viability was assessed by vital staining, gel contraction, and insulin utilization. Measures of hepatocyte-specific function included albumin synthesis, ureagenesis, lidocaine biotransformation, and cholate conjugation. Although hepatocyte viability remained stable through the seven day incubation period, hepatocyte functions were not uniformly preserved. Albumin synthesis remained stable, while representative P-450 and conjugation activities decreased with time. This static culture system will facilitate the development of a hollow fiber bioartificial liver which utilizes cylindrical collagen-hepatocyte gels.
The use of thrombolytic agents in the treatment of postoperative pulmonary embolism presents a dilemma to the surgeon. On one hand, postoperative pulmonary embolism usually occurs within 2 weeks of surgery. On the other hand, recent surgery is considered a contraindication for the use of thrombolytics. We developed a protocol for treating pulmonary embolism patients who have recently undergone surgery. Urokinase, at a dose of 2,200 U/kg wt, is injected directly into the clot via a catheter positioned in the pulmonary artery. This is followed by continuous infusions of urokinase at 2,200 U/kg wt/hr until the clot is lysed (up to 24 hrs). Simultaneously, heparin is administered peripherally at 500 U/hr. The level of serum fibrinogen is monitored every 6 hours and maintained at no less than 0.2 g/dL to prevent bleeding. Thirteen patients were treated for angiographically proven pulmonary embolism within 14 days of surgery. Complete lysis of every embolus was achieved, and no deaths or bleeding complications occurred. Two patients received inferior vena cava filters, and nine patients no longer needed chronic anticoagulants within 3 months after the embolic event.
Tissue injury, whether from infection, blood or volume loss, trauma, or inflammation such as pancreatitis, induces local and systemic responses. The systemic responses include shock, reperfusion, systemic inflammation (hypermetabolism) with primary organ dysfunction, and secondary organ dysfunction that either becomes progressive and leads to death or from which the patient recovers and enters into a period of prolonged rehabilitation. Each of these responses has its pathogenesis and treatments that are appropriate and effective. The research indicates that the responses may contribute to the development of cell and organ injury and to progressive multiple organ failure syndrome and death, particularly in the case of the systemic inflammatory response. Current therapy is designed to rapidly remove the cause of injury, resuscitate the microcirculation, and institute nutrition therapy to prevent single and generalized nutrient deficiencies and promote repair and healing. Newer therapies are designed to modulate the inflammatory response itself to minimize its injury potential and promote tissue repair and recovery of the patient. Genetic regulation of metabolism is also a pathogenetic mechanism. Its role in these responses is just starting to be understood--new therapies will need to await this understanding. Once the patient begins to recover, rehabilitation tends to be long and problematic. Nonetheless, significant survival rates are now occurring, with continued improvements expected in response to the newer therapeutic approaches. Planned rehabilitation thus becomes an important component of effective recovery. Professionals trained in critical care and well versed in cellular and molecular biology provide the milieu within which continued improvements in prevention, therapy, and outcome will continue to occur.
We have developed a novel hepatocyte loaded hollow fiber bioreactor as a potential bioartificial liver. Freshly harvested rat hepatocytes were entrapped in a three-dimensional gel matrix within hollow fibers in a perfused bioreactor. Gel entrapment allowed cells to be cultured at high density while maintaining tissue-specific function. Hepatocyte function was evaluated in 10 bioreactors, each containing approximately 5 x 10(7) cells. Oxygen consumption averaged 0.32 pmole/cell/hr, albumin appearance averaged 0.60 pg/cell/hr, and lidocaine clearance (a measure of the P-450 activity) averaged 0.74 pg/cell/hr. Function persisted for the 7 days of the study. Electron microscopy at 7 days showed the distinctive ultrastructure of viable, differentiated hepatocytes: bile canaliculi, intercellular junctions, peroxisomes, abundant mitochondria, and glycogen granules. Maintenance of tissue specific function and ultrastructure suggests that this bioreactor configuration has potential as a device to support patients in liver failure, as well as to study hepatocytes in vitro.
Current nutrition support improves patient outcome in trauma patients. It appears to do so by limiting the adverse effects of specific nutrient or generalized nutrient deficiencies. Immunosuppression, however, continues as a significant clinical problem. This immunosuppression appears to be part of the inflammatory response that accompanies trauma, and in part, to represent the need for conditional nutrients in this setting. Three nutrients that are being evaluated include arginine, uracil as ribonucleic acid and omega-3 polyunsaturated fatty acids. Animal studies report improved immune function. Early clinical trials are reporting improved immune function and patient outcomes.
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OBJECTIVE: The primary purpose of this review article is to familiarize critical care practitioners with newly developing techniques of hybrid artificial liver support. Implantable and extracorporeal hepatocyte culture systems are emphasized based on their current experimental and clinical status. DATA SOURCES: Data used to prepare this document were obtained from the authors' personal files, as well as the computerized MEDLINE database. Medical headings used include: liver, artificial organs, cell culture, growth hormones, extracellular matrix, and transplantation. Only articles published in English have been cited. STUDY SELECTION: All studies are discussed in which hepatocyte culture systems have been used to support human patients with liver failure. All studies reported the patient's condition before therapy, duration of therapy, and outcome after therapy in order to be included in this review. Since the number of clinical trials is small at this time, animal studies were used to demonstrate application of other systems in the treatment of experimentally induced liver failure. Similar selection criteria were used to select animal studies for review. All initially identified human studies met these selection criteria. DATA EXTRACTION: Independent extraction by multiple observers. DATA SYNTHESIS: Liver failure, resulting from infection, drugs, or as a part of the multiple organ failure syndrome, remains a major cause of morbidity, mortality, and resource allocation. Current therapy is limited to supportive care, along with liver transplantation. Because of these therapeutic limitations, hybrid artificial liver systems have been proposed for temporary and long-term hepatic support. Several animal studies and a small number of preliminary human studies indicate that hepatocyte culture systems are capable of supporting nearly all essential hepatic functions and may supply biologically active substances that promote regeneration and repair of the damaged liver being supported. Hybrid systems may be constructed from materials that serve as immunoprotective barriers against host defenses. CONCLUSIONS: During the past decade, important progress has been made with hybrid artificial liver support systems. Cell culture technology has progressed sufficiently so that an artificial liver, composed of metabolically active hepatocytes, may be a potential reality in the foreseeable future. Both implantable and extracorporeal artificial liver support systems have been developed to provide metabolic support during acute liver failure, or to serve as a bridge to solid organ transplantation. Implantable hepatocyte systems, however, require a prolonged period for intraperitoneal engraftment and vascularization, not typically available to patients with acute liver failure. For this reason, extracorporeal hybrid designs offer the greatest hope for on-line treatment of acute liver failure. Such systems are entering the final stages of animal testing.
The use of growth hormone in clinical nutritional support has received considerable attention over the past decade. The most encouraging results have been improved nitrogen retention and protein synthesis in the presence of hypocaloric nutritional support. Adverse effects, however, can limit the clinical usefulness of this technology. In the following case study, an obese 71-year-old man with a history of chronic obstructive pulmonary disease remained ventilator dependent 2 months following anterior cervical fusion and had severe depletion of visceral proteins despite nitrogen equilibrium. He was treated with 10 mg of recombinant human growth hormone (Genentech) subcutaneously every other day while also receiving nutritional support. We hypothesized that growth hormone administration could promote both protein synthesis and the development of muscle mass, particularly in the respiratory muscles, without increasing nutrient intake and, therefore, without increasing CO2 production. The patient, however, developed two potentially life-threatening adverse effects: hyperglycemia and fluid retention. The severity of these adverse effects led to discontinuation of this mode of therapy.
An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods when dealing with septic patients was recommended as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
The management of acute variceal bleeding continues to challenge those who care for patients with portal hypertension. Survival depends on rapid institution of an established protocol for resuscitation, diagnosis, and management of the patient. Balloon tamponade plays an important part in the management of this problem along with pharmacologic and endoscopic modalities. It is important in closing, however, to note that guidelines for use cannot compensate for lack of experience and the authors agree with Vlavianos and colleagues in stating that without experience in its use, balloon tamponade is of limited value.
The primary aim of this study was to clarify the mechanism and significance of lipopolysaccharide (LPS)-induced translocation of intestinal bacteria. Female Swiss Webster mice were purchased from two different animal suppliers. Twenty-four hours following parenteral LPS, mice from both suppliers had noticeable morbidity and mortality. However, intestinal pathology, gram-negative bacterial overgrowth, and increased bacterial translocation was noted in mice purchased from one supplier but not the other. Mice with increased translocation also had overgrowth of cecal gram-negative bacilli, i.e., 10(10) per gram of cecum following parenteral LPS; in contrast, mice without LPS-induced bacterial translocation had 1,000- to 10,000-fold fewer cecal gram-negative bacilli. Additional groups of mice with increased bacterial translocation were also sacrificed two and 6 hr after parenteral LPS; morbidity and intestinal pathology were evident without a corresponding increase in bacterial translocation. Separate groups of these mice were also injected with platelet activating factor, resulting in intestinal pathology similar to that noted with parenteral LPS, but no increase in bacterial translocation. Thus parenteral LPS was consistently associated with morbidity and mortality but not with intestinal pathology, enteric bacterial overgrowth, or increased bacterial translocation.