Clinical and vital sign changes associated with late-onset sepsis in very low birth weight infants at 3 NICUs.

BACKGROUND: In premature infants, clinical changes frequently occur due to sepsis or non-infectious conditions, and distinguishing between these is challenging. Baseline risk factors, vital signs, and clinical signs guide decisions to culture and start antibiotics. We sought to compare heart rate (HR) and oxygenation (SpO2) patterns as well as baseline variables and clinical signs prompting sepsis work-ups ultimately determined to be late-onset sepsis (LOS) and sepsis ruled out (SRO). METHODS: At three NICUs, we reviewed records of very low birth weight (VLBW) infants around their first sepsis work-up diagnosed as LOS or SRO. Clinical signs prompting the evaluation were determined from clinician documentation. HR-SpO2 data, when available, were analyzed for mean, standard deviation, skewness, kurtosis, and cross-correlation. We used LASSO and logistic regression to assess variable importance and associations with LOS compared to SRO. RESULTS: We analyzed sepsis work-ups in 408 infants (173 LOS, 235 SRO). Compared to infants with SRO, those with LOS were of lower GA and BW, and more likely to have a central catheter and mechanical ventilation. Clinical signs cited more often in LOS included hypotension, acidosis, abdominal distension, lethargy, oliguria, and abnormal CBC or CRP(p < 0.05). HR-SpO2 data were available in 266 events. Cross-correlation HR-SpO2 before the event was associated with LOS after adjusting for GA, BW, and postnatal age. A model combining baseline, clinical and HR-SpO2 variables had AUC 0.821. CONCLUSION: In VLBW infants at 3-NICUs, we describe the baseline, clinical, and HR-SpO2 variables associated with LOS versus SRO.

Blood pressure ranges via non-invasive and invasive monitoring techniques in premature neonates using high resolution physiologic data.

BACKGROUND: There are limited evidence-based published blood pressure ranges for premature neonates. The aim of the study was to determine blood pressure ranges in a large cohort of premature neonates based on gestational and post-menstrual age. METHODS: Retrospective observational study of premature neonates admitted to the neonatal intensive care unit at our institution between January 2009 and October 2015. We stratified data by gestational and post-menstrual age groups as well as by method of blood pressure measurement (non-invasive vs. invasive). RESULTS: Over two billion blood pressure values in 1708 neonates were analyzed to generate heat maps and establish percentile-based reference ranges. The median gestational age of the cohort was 31 weeks (IQR 28-33 weeks). We found moderate correlation (r = 0.57) between simultaneously obtained non-invasive and invasive blood pressure measurements. CONCLUSIONS: Our results can serve as a reference during the bedside assessment of the critically-ill neonate.

Early Pulse Oximetry Data Improves Prediction of Death and Adverse Outcomes in a Two-Center Cohort of Very Low Birth Weight Infants.

BACKGROUND: We previously showed, in a single-center study, that early heart rate (HR) characteristics predicted later adverse outcomes in very low birth weight (VLBW) infants. We sought to improve predictive models by adding oxygenation data and testing in a second neonatal intensive care unit (NICU). METHODS: HR and oxygen saturation (SpO2) from the first 12 hours and first 7 days after birth were analyzed for 778 VLBW infants at two NICUs. Using multivariate logistic regression, clinical predictive scores were developed for death, severe intraventricular hemorrhage (sIVH), bronchopulmonary dysplasia (BPD), treated retinopathy of prematurity (tROP), late-onset septicemia (LOS), and necrotizing enterocolitis (NEC). Ten HR-SpO2 measures were analyzed, with first 12 hours data used for predicting death or sIVH and first 7 days for the other outcomes. HR-SpO2 models were combined with clinical models to develop a pulse oximetry predictive score (POPS). Net reclassification improvement (NRI) compared performance of POPS with the clinical predictive score. RESULTS: Models using clinical or pulse oximetry variables alone performed well for each outcome. POPS performed better than clinical variables for predicting death, sIVH, and BPD (NRI > 0.5, p < 0.01), but not tROP, LOS, or NEC. CONCLUSION: Analysis of early HR-SpO2 characteristics adds to clinical risk factors to predict later adverse outcomes in VLBW infants.

Abnormal heart rate characteristics are associated with abnormal neuroimaging and outcomes in extremely low birth weight infants.

OBJECTIVE: Brain injury in preterm infants may lead to an inflammatory response and central nervous system dysfunction reflected by abnormal heart rate characteristics (HRC). We hypothesized that a continuously monitored HRC index reflecting reduced HR variability and decelerations correlates with abnormal neuroimaging and outcomes in extremely low birth weight infants (ELBW). STUDY DESIGN: We analyzed the average HRC index within 28 days after birth (aHRC28) and head ultrasound (HUS) in 384 ELBW infants. In 50 infants with brain magnetic resonance imaging (MRI) and 70 infants with Bayley neurodevelopmental testing at 1 year of age, we analyzed the relationship between aHRC28, MRI abnormalities and low Bayley scores. RESULT: aHRC28 was higher in infants with severe HUS abnormalities (2.65±1.27 for Grade III-IV intraventricular hemorrhage (IVH) or cystic periventricular leukomalacia (cPVL) versus 1.72±0.95 for normal or Grade I-II IVH, P<0.001). Higher aHRC28 was also associated with white matter damage on MRI and death or Bayley motor or mental developmental index <70. Associations persisted after adjusting for gestational age, birth weight and septicemia. For every one point increase in aHRC28, the odds ratio of death or Bayley score <70 was 2.45 (95% CI 1.46, 4.05, P<0.001). CONCLUSION: A continuously monitored HRC index provides an objective, noninvasive measure associated with abnormal brain imaging and adverse neurologic outcomes in ELBW infants.

Application of dynamical analyses of heart rate to rhythm classification and prognosis.

We have developed numerical approaches to dynamical analysis of heart rates, measured as interbeat or RR, intervals, based on entropy and fluctuation analyses in a large data base of consecutive Holter monitor recordings. In Part I, we present a RR interval-based classifier that distinguishes normal sinus rhythm (NSR), atrial fibrillation (AF) and sinus rhythm with ectopy with an accuracy of 99%, 81% and 77%respectively, using 10-minute segments. In Part II, we present 2-year mortality estimation based on the entropy calculations. The major finding is that normal dynamics identify a very low risk group. Taken together, these results point to automated analysis of heart rate time series with important clinical applications.

Abnormal heart rate characteristics before clinical diagnosis of necrotizing enterocolitis.

OBJECTIVE: Earlier diagnosis and treatment of necrotizing enterocolitis (NEC) in preterm infants, before clinical deterioration, might improve outcomes. A monitor that measures abnormal heart rate characteristics (HRC) of decreased variability and transient decelerations was developed as an early warning system for sepsis. As NEC shares pathophysiologic features with sepsis, we tested the hypothesis that abnormal HRC occur before clinical diagnosis of NEC. STUDY DESIGN: Retrospective review of Bells stage II to III NEC cases among infants <34 weeks gestation enrolled in a prospective randomized clinical trial of HRC monitoring at three neonatal intensive care units. RESULT: Of 97 infants with NEC and HRC data, 33 underwent surgical intervention within 1 week of diagnosis. The baseline HRC index from 1 to 3 days before diagnosis was higher in patients who developed surgical vs medical NEC (2.06±1.98 vs 1.22±1.10, P=0.009). The HRC index increased significantly 16 h before the clinical diagnosis of surgical NEC and 6 h before medical NEC. At the time of clinical diagnosis, the HRC index was higher in patients with surgical vs medical NEC (3.3±2.2 vs 1.9±1.7, P<0.001). CONCLUSION: Abnormal HRC occur before clinical diagnosis of NEC, suggesting that continuous HRC monitoring may facilitate earlier detection and treatment.

Improved entropy rate estimation in physiological data.

Calculating entropy rate in physiologic signals has proven very useful in many settings. Common entropy estimates for this purpose are sample entropy (SampEn) and its less robust elder cousin, approximate entropy (ApEn). Both approaches count matches within a tolerance r for templates of length m consecutive observations. When physiologic data records are long and well-behaved, both approaches work very well for a wide range of m and r. However, more attention to the details of the estimation algorithm is needed for short records and signals with anomalies. In addition, interpretation of the magnitude of these estimates is highly dependent on how r is chosen and precludes comparison across studies with even slightly different methodologies. In this paper, we summarize recent novel approaches to improve the accuracy of entropy estimation. An important (but not necessarily new) alternative to current approaches is to develop estimates that convert probabilities to densities by normalizing by the matching region volume. This approach leads to a novel concept introduced here of reporting entropy rate in equivalent Gaussian white noise units. Another approach is to allow r to vary so that a pre-specified number of matches are found, called the minimum numerator count, to ensure confident probability estimation. The approaches are illustrated using a simple example of detecting abnormal cardiac rhythms in heart rate records.

Heart rate characteristics and neurodevelopmental outcome in very low birth weight infants.

BACKGROUND: Sepsis in very low birth weight (VLBW) infants has been associated with an increased risk of adverse developmental outcome. We have identified abnormal heart rate characteristics (HRCs) that are predictive of impending sepsis, and we have developed a summary measure of an infant's abnormal HRCs during the neonatal hospitalization that we refer to as the cumulative HRC score (cHRC). OBJECTIVE: In this study, we tested the hypothesis that increasing cHRC is associated with an increasing risk of adverse neurodevelopmental outcome in VLBW infants. METHOD: Data were collected on 65 VLBW infants whose HRCs were monitored while in the neonatal intensive care unit and who were examined at 12 to 18 months adjusted age. Using the Bayley Scale of Infant Development-II, we identified delays in early cognitive function (i.e., Mental Developmental Index <70) and psychomotor development (i.e., Psychomotor Developmental Index <70). Cerebral palsy (CP) was diagnosed using a standard neurological examination. RESULT: Increasing cHRC score was associated with an increased risk of CP (odds ratio per 1 standard deviation increase in cHRC: 2.6, 95% confidence limits: 1.42, 5.1) and delayed early cognitive development [odds ratio: 2.3 (1.3; 4.3)]. These associations remain statistically significant when adjusted for major cranial ultrasound abnormality. There was an association of increasing cHRC and delayed psychomotor development, which did not reach statistical significance [odds ratio: 1.7 (1.0, 3.0)]. CONCLUSION: Among VLBW infants, the cumulative frequency of abnormal HRCs, which can be assessed non-invasively in the neonatal intensive care unit, is associated with an increased risk of adverse neurodevelopmental outcome.

Single and double autotransplants for relapsing/refractory Hodgkin's disease: results of two consecutive trials.

To evaluate a strategy of one cycle of dose-intensive chemotherapy for patients with Hodgkin's disease in sensitive relapse and two cycles for those with refractory disease, 122 patients received dose-intensive chemotherapy followed by autotransplant in two consecutive studies. Patients with refractory disease were offered a second transplant with different conditioning in the absence of progression or excessive toxicity. CR was present after treatment in 46% while 16% died in the peritransplant period. Of 41 patients with primary refractory disease and 42 with refractory relapse, 24 and 21 respectively received a second cycle. Of these 45 refractory patients, 12 were in CR and 11 in PR after the first cycle and 10 of these 11 in PR achieved a durable CR with the second transplant. The CR rate is 37% in patients with refractory relapse and 19% in those with primary refractory disease. At a median follow-up of 4 years, median survival is 45 months. Progression-free survival of the refractory patients who could receive a second cycle was similar to that of patients with sensitive disease. A sequential transplant strategy is feasible. A subgroup of patients with refractory disease can achieve long-term survival after sequential BMT.

Graft-versus-host disease. Possible higher risk for African American patients.

BACKGROUND: Race is not generally recognized as a factor in the severity or incidence of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation. The impression that African American patients had more frequent and severe GVHD prompted this retrospective survey. METHODS: The records of 75 consecutive patients treated with a human leukocyte antigen-identical sibling bone marrow transplant from 1985 to 1993 were reviewed. GVHD prophylaxis uniformly employed cyclosporine and steroids. Treatment of GVHD included cyclosporine and high dose steroids in all cases. Antithymocyte globulin and other immunosuppressants were used in severe cases. RESULTS: Of 75 patients, 56 (75%) were white, 11 (15%) were listed as "Hispanic", 7 (9%) were African Americans, and 1 was of Far-Eastern origin. Four of the African American patients had chronic myelogenous leukemia and 2 had acute leukemia, whereas 21 of the other 68 patients (31%) had chronic myelogenous leukemia, 31 (46%) had acute leukemia, and the remainder (33%) had miscellaneous hematologic malignancies. Transplants from a female donor to a male recipient were performed in 2 of 7 African Americans and 19 of 68 patients (28%) of other origins. Five of the 6 evaluable African American patients (83%; 95% confidence interval, 36-100%) had Grade 4 GVHD, as opposed to 5 of 61 patients of other racial origins (8%; 95% confidence interval, 3-18%). All African American patients died within 90 days of transplant. CONCLUSIONS: Patients of African American origin possibly have a greater risk of GVHD.

Fluconazole versus amphotericin B in the treatment of esophageal candidiasis in cancer patients.

Thirty-one patients with malignancy and endoscopy-confirmed symptomatic esophageal candidiasis were randomly assigned to receive oral fluconazole, 200 mg once daily, or intravenous amphotericin B, 0.3 mg/kg, over 1-4 weeks. Clinical efficacy was determined weekly and follow-up esophageal endoscopy with biopsy and culture performed whenever possible. Both agents produced rapid resolution of symptoms, especially dysphagia and odynophagia. All 13 evaluable patients in the fluconazole group and 10/12 treated with amphotericin had clinical improvement. Endoscopy showed eradication of the fungus in all 11 patients undergoing repeat endoscopy, with cure or improvement of esophagitis. The incidence of adverse effects attributable to treatment was higher in the amphotericin group. The efficacy of oral fluconazole in esophageal candidiasis appears to be equivalent to that of amphotericin, with fewer adverse reactions.

TMJ: a well-tolerated high-dose regimen for the adjuvant chemotherapy of high risk breast cancer.

Following local treatment and doxorubicin-containing standard chemotherapy, 42 patients with surgical Stage II or IIIA breast cancer containing ten or more involved axillary nodes and 13 patients with Stage IIIB disease were treated with high-dose chemotherapy (TMJ) consisting of thiotepa (750 mg/m2), mitoxantrone (40 mg/m2), and carboplatin (1000 mg/m2), with autologous bone marrow (ABM) and peripheral stem cell (PSC) transplant, followed by irradiation and/or hormone therapy. Sargramostim (GM-CSF) support was given to most patients. The median time to transfusion independence was two weeks. Severe non-hematologic toxicity was uncommon, with no intensive care admission or treatment-related death. At a median follow-up of 17 months, eight patients have relapsed and five have died of tumor progression. No statement can yet be made regarding adjuvant efficacy, but this high-dose regimen is very well tolerated.

High dose rate treatment of a maxillary sarcomatoid carcinoma: a case report.

A 37-year old Native American woman presented with a rare sarcomatoid carcinoma of the left maxilla. She underwent extensive resection, but developed an orbital cavity recurrence. This was treated with external beam radiation therapy. The boost posed dosimetric difficulties due to the anatomic peculiarities of the treatment area. Extensive treatment planning for a high dose rate Iridium 192 source helped overcome these problems. Control of the tumor was achieved in the site of recurrence.

Leptospirosis: II. Investigation of clinical disease in dairy cattle in the Waikato district of New Zealand.

Investigations were carried out in 1975, 1976 and 1977 in 16 dairy herds where leptospiral abortions were suspected and in five other herds where clinical disease was not present. Both Leptospira interrogans serovars pomona and hardjo were isolated from cattle in herds with leptospirosis, but only pomona was recovered from those that had aborted. There was no evidence that hardjo caused clinical disease in dairy cattle in the Waikato district. It was found that 73% of the cows that aborted and 19% of other animals in the same herds had microscopic agglutination test titres to pomona of 1:2,000 or greater. By contrast, only 2% of cattle in herds without clinical evidence of leptospirosis had such titres. One cow retained a titre of 1:2,000 or greater to pomona for 7 months; titres of this order had a shorter duration in other cows. Leptospiruria occurred in 50% of cows that had aborted and in 9% of in-contact cows in the same herds. Only 0.7% of cows had leptospiruria in the herds with no clinical disease. Ten of 35 cows shedding pomona still had leptospiruria one month later. It was concluded that clinical leptospirosis should be diagnosed by testing a sample of the herd, rather than just individual cows, because of the variability and persistence of leptospiruria and serological titres in cows with and without clinical signs. Although hardjo is common in cattle in the Waikato district, it was not found to cause abortion in cattle.