Surgery – Diagnostic testing – Cardiovascular
Reexamination Certificate
2001-02-27
2004-10-12
Jastrzab, Jeffrey R. (Department: 3762)
Surgery
Diagnostic testing
Cardiovascular
Reexamination Certificate
active
06804551
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the indication of early phases of potentially catastrophic illnesses and relates to heart rate variability monitoring in patients. In particular, the present invention relates to methods and apparatus for early detection of potentially catastrophic illnesses in a patient.
BACKGROUND OF THE INVENTION
Approximately 40,000 very low birth weight (“VLBW”) infants (less than 1,500 gm) are born in the United States each year. Ventura et al., “Advance Report of Final Natality Statistics, 1994,
” Monthly Vital Statistics Report;
44, pp. 1-88 (1996). Survival of this group has improved with advances in neonatal intensive care, but late-onset sepsis and necrotizing enterocolitis (“NEC”) continue to be major causes of morbidity and mortality. Stoll B. J., Gordon T., Korones S. B., Shankaran S., Tyson J. E., Bauer C. R., “Late-onset Sepsis in Very Low Birth Weight Neonates: A Report from the National Institute of Child Health and Human Development Neonatal Research Network,”
Journal of Pediatrics;
129:63-71 (1996); Gray J. E., Richardson D. K., McCormick M. C., Goldmann D. A., “Coagulase-Negative Staphylococcal Bacteremia Among Very Low Birth Weight Infants: Relation to Admission Illness Severity, Resource Use, and Outcome,”
Pediatrics,
95:225-230 (1995). Unfortunately these illnesses are common in neonates, and infected infants have a significant increase in the number of days spent on the ventilator and an average increase in duration of hospital stay of 25 days. See Stoll et al. above.
Neonatal sepsis occurs in as many as 25% of infants weighing less than 1,500 gm at birth, and the rate is about 1 per 100 patient days. Gladstone, I. M., R. A. Ehrenkrantz, S. C. Edberg, and R. S. Baltimore, “A Ten-Year Review of Neonatal Sepsis and Comparison with the Previous Fifty Year Experience,”
Pediatric Infectious Disease Journal;
9:819-825 (1990); Moro, M. L., A. DeToni, I. Stolfi, M. P. Carrieri, M. Braga, and C. Zunin, “Risk Factors for Nosocomial Sepsis in Newborn Infants and Intermediate Care Units,”
European Journal of Pediatrics;
155:315-322 (1996). The National Institute of Child Health & Human Development (“NICHD”) Neonatal Research Network found that neonates who develop late-onset sepsis have a 17% mortality rate, more than twice the 7% mortality rate of noninfected infants.
Risk factors for late-onset sepsis are ubiquitous in the neonatal intensive care unit (“NICU”): intubation, umbilical catheters, prolonged mechanical ventilation, low birth weight, parenteral nutrition via central venous catheters, respiratory distress syndrome, bronchopulmonary dysplasia, severe intraventricular hemorrhage, and nasogastric and tracheal cannulae are all independently associated with sepsis. See Moro et al. supra. Each interventional device represents a potential source of infection and increases the risk of catastrophic infectious illness. Id.
Necrotizing enterocolitis affects up to 4,000 infants in the U.S. yearly, and an estimated 10 to 50% of infants who develop NEC die. Neu, J., “Necrotizing Enterocolitis,”
Pediatric Clinics of North America
43:409-432 (1996). Infants who develop NEC often require intubation and an increase in respiratory support. Survivors are often left with strictures and short-bowel syndrome.
Unfortunately, prior to the discovery of the present invention there has been no reliable clinical means for early diagnosis of these diseases. Clinical neonatologists caring for these VLBW infants recognize sepsis and NEC as potentially catastrophic illnesses, and thus do not hesitate to obtain blood cultures and administer antibiotics empirically at the first appearance of symptoms in an attempt to avert disaster. Likewise, physicians do not hesitate to stop feeding and obtain radiographic studies should any abdominal finding occur. Early diagnosis of neonatal sepsis is difficult (Escobar, G. J, “The Neonatal “Sepsis Work-up”: Personal Reflections on the Development of an Evidence-Based Approach Toward Newborn Infections in a Managed Care Organization,”
Pediatrics,
103:360-373 (1999)), as the clinical signs are neither uniform nor specific. Because of this, there are many unnecessary blood cultures, many unnecessary administration of short courses of antibiotics to infants without bacterial infection, and many unnecessary interruptions in neonatal nutrition. Moreover, despite these practices, sepsis and necrotizing enterocolitis continue to occur and continue to cause neonatal deaths. Indeed, by the time clinical signs and symptoms for either sepsis or NEC have developed, the illness may have progressed to an irreversible stage.
In addition, not all patients with clinical signs of sepsis have positive blood cultures. While the blood culture is felt to be the gold standard for establishing the diagnosis of sepsis due to systemic bacterial infection, there are concerns regarding its reliability (Kaftan, H. and J. S. Kinney, “Early Onset Neonatal Bacterial Infections,”
Seminars in Perinatology,
22:15-24 (1998)), especially if single samples of small volume are submitted (Aronson, M. D. and D. H. Bor, “Blood Cultures,”
Ann. Intern. Med.,
106:246-253 (1987); Kellogg, J. A., F. L. Ferrentino, M. H. Goodstein, J. Liss, Shapiro, S L, and D. A. Bankert, “Frequency of Low Level Bacteremia in Infants from Birth to Two Months of Age,”
Pediatric Infectious Disease Journal,
16:381-385 (1997)), as is often the practice in critically ill newborn infants. For example, as many as 60% of culture results may be falsely negative if only 0.5 mL blood is obtained from infants with low-colony-count sepsis. Schelonka, R. L., M. K. Chai, B. A. Yoder, D. Hensley, R. M. Brockett, and D. P. Ascher, “Volume of Blood Required to Detect Common Neonatal Pathogens,”
J. Pediatr.,
129:275-278 (1996). In a study of 298 aerobic culture specimens, the mean blood volume submitted was 0.53 mL and 55% of samples contained less than 0.5 mL. Neal, P. R., M. B. Kleiman, J. K. Reynolds, S. D. Allen, J. A. Lemons, and P. L. Yu, “Volume of Blood Submitted for Culture from Neonates,”
Journal of Clinical Microbiology,
24:353-356 (1986). It is suspected that 30-40% of all infants with sepsis have negative blood cultures. For example, in two studies, approximately 20% of infants with infection proven by post-mortem cultures and autopsy were not so identified using pre-mortem blood cultures (Pierce, J. R., G. B. Merenstein, and J. T. Stocker, “Immediate Postmortem Cultures in an Intensive Care Nursery,”
Pediatric Infectious Disease,
3:510-513 (1984); Squire, E., B. Favara, and J. Todd, “Diagnosis of Neonatal Bacterial Infection: Hematologic and Pathologic Findings in Fatal and Nonfatal Cases,”
Pediatrics,
64:60-64 (1970)).
The current hypothesis is that the clinical syndrome of sepsis is brought about by the host response as a response to insults such as bacterial infection. The major host response is the release of cytokines, small circulating peptides that serve as mediators of the inflammatory response. The syndrome common to sepsis and sepsis-like illness has been named the Systemic Inflammatory Response Syndrome (SIRS) (Members of the ACCP/SCCM Consensus Conference Committee, “American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis,”
Critical Care Medicine,
20:864-874 (1992)), and the pathogenesis suggested to be an imbalance between pro-inflammatory and anti-inflammatory effects of cytokines. Bone, R. C., C. J. Grodzin, and R. A. Balk, “Sepsis: a New Hypothesis for Pathogenesis of the Disease Process,”
Chest,
112:235-243 (1997). In sepsis and sepsis-like illness, circulating cytokines play a major role in initiating and maintaining the inflammatory response, and cytokine levels correlate with the severity of illness. Anderson, M. R. and J. L. Blumer, “Advances in the Therapy for Sepsis in Children,”
Pediatric Clinics of North America,
44:179-205 (1997); Harris, M. C., A. T. J. Costarino, J. S. Sullivan, S.
Griffin M. Pamela
Kovatchev Boris P.
Moorman J. Randall
Decker Robert J.
Jastrzab Jeffrey R.
Oropeza Frances P.
University of Virginia Patent Foundation
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