Intraventricular administration of rt-PA in patients with intraventricular hemorrhage.

OBJECTIVE: Intraventricular hemorrhage (IVH) represents a clinicopathologic entity with a dismal prognosis. The associated mortality rate has been reported as high as 80%; the morbidity is also quite high. The use of various fibrinolytic agents (streptokinase, urokinase, and recombinant tissue-type plasminogen activator [rt-PA]) has been reported in a small number of clinical series with a very limited number of participants, yielding significant variability regarding inclusion criteria, treatment protocol, and outcome analysis. METHODS: In our prospective study, we report our experience using rt-PA in 21 patients with IVH. Patients with IVH of aneurysmal or arteriovenous malformation origin were excluded. Intraventricular administration of rt-PA was initiated within 24 hours after the ictal event (dose, 3 mg every 24 hours) through a ventricular catheter. The patients' intracranial and cerebral perfusion pressures, cerebrospinal fluid (CSF) cell count, and head CT scans with emphasis to frontal horn dimension and inner cranium diameter at the same level ratio were collected and analyzed. RESULTS: Good outcome was observed in 47.5% of our patients, whereas 28.5% died and 24.0% survived with severe disability. The development of rt-PA-associated complications was as follows: new hemorrhage in 19%, infection in 14.3%, and CSF pleocytosis in 100% of patients. Permanent CSF shunt was required in 40%. The intermediate (3-month) follow up of our survivors showed no significant outcome changes compared with the immediate (1-month) follow up. CONCLUSIONS: Intraventricular administration of rt-PA appears to be beneficial in cases of IVH even though it is occasionally associated with serious complications. Further multi-institutional studies are required for validating this treatment modality and standardizing its parameters.

Pharmacokinetics of the nonsteroidal steroid sulphatase inhibitor 667 COUMATE and its sequestration into red blood cells in rats.

Breast cancer is a major cause of mortality in Western countries and there is an urgent requirement for novel treatment strategies. The nonsteroidal sulphatase inhibitor 667 COUMATE inhibits hepatic steroid sulphatase and growth of oestrone sulphate stimulated tumours in the nitrosomethylurea-induced rat mammary model. Other compounds that contain an aryl sulphamate moiety, for example, oestrone-3-O-sulphamate, are sequestered into red blood cells (RBCs). The aims of this study were to determine the pharmacokinetics of 667 COUMATE and to investigate its sequestration into RBCs. We administered a single p.o. or i.v. dose (10 mg kg(-1)) of 667 COUMATE to rats and used a high-performance liquid chromatography method to measure the levels of the agent and its putative metabolites in plasma. 667 COUMATE had a bioavailability of 95% and could be detected in plasma for up to 8 h. Using two independent analytical methods, we demonstrated that 667 COUMATE is sequestered by RBCs both ex vivo and in vivo. Previous investigations have revealed that 667 COUMATE is rapidly degraded in plasma ex vivo. In this study, we demonstrate that 667 COUMATE is stabilised due to its sequestration into RBCs. In conclusion, the pharmacological efficacy and high oral bioavailability of 667 COUMATE may be partly a consequence of the ability of RBCs to both protect the agent from metabolic degradation and facilitate its transport to tissues. These data support the further clinical evaluation of this novel endocrine therapeutic agent.

Validation of a clinical decision aid to discontinue in-hospital cardiac arrest resuscitations.

CONTEXT: Most patients undergoing in-hospital cardiac resuscitation do not survive to hospital discharge. In a previous study, we developed a clinical decision aid for identifying all patients undergoing resuscitation who survived to hospital discharge. OBJECTIVE: To validate our previously derived clinical decision aid. DESIGN, SETTING, AND PARTICIPANTS: Data from a large registry of in-hospital resuscitations at a community teaching hospital in Georgia were analyzed to determine whether patients would be predicted to survive to hospital discharge (ie, whether their arrest was witnessed or their initial cardiac rhythm was either ventricular tachycardia or ventricular fibrillation or they regained a pulse during the first 10 minutes of chest compressions). Data from 2181 in-hospital cardiac resuscitation attempts in 1987-1996 involving 1884 pulseless patients were analyzed. MAIN OUTCOME MEASURE: Comparison of predictions based on the decision aid with whether patients were actually discharged alive from the hospital. RESULTS: For 327 resuscitations (15.0%), the patient survived to hospital discharge. For 324 of these resuscitations, the patients were predicted to survive to hospital discharge (sensitivity = 99.1%, 95% confidence interval, 97.1%-99.8%). In 269 resuscitations, patients did not satisfy the decision aid and were predicted to have no chance of being discharged from the hospital. Only 3 of these patients (1.1%) were discharged from the hospital (negative predictive value = 98.9%), none of whom were able to live independently following discharge from the hospital. CONCLUSION: This decision aid can be used to help physicians identify patients who are extremely unlikely to benefit from continued resuscitative efforts.

Characteristics of cystic breast disease with special regard to breast cancer development.

BACKGROUND: This prospective study compares the characteristics of cystic disease of the breast (CDB) of patients who developed breast cancer (BCa) during the follow-up (1.25-4 years) period with those who did not. MATERIALS AND METHODS: K+, Na+, albumin, dehydroepiandrosterone (DHA), DHA-sulphate, oestrone, oestradiol, testosterone and progesterone levels were determined in breast cyst fluid (BCF). Patients presented data about their menstrual status, reproductive history, lactation period, date of first and the number of BCF aspirations, gynaecological interventions, use of oral contraceptives, family history of cancer, smoking habits and coffee consumption. The BCa incidence of patients was compared with the expected number of BCas in an age-matched group of 5143 women. RESULTS: Out of 147 patients 6 developed BCa. The standardized incidence rate was 6.29. There were significant differences in testosterone, oestrone and progesterone levels and also reproductive history of patients who developed BCa compared with patients without BCa. CONCLUSION: The above markers outline a subgroup of patients with the highest BCa risk.

Resuscitation in the hospital: relationship of year and rhythm to outcome.

OBJECTIVE: determine the frequency of initial rhythms in in-hospital resuscitation and examine its relationship to survival. Assess changes in outcome over time. METHODS: retrospective cohort (registry) including all admissions to the Medical Center of Central Georgia in which a resuscitation was attempted between 1 January, 1987 and 31 December, 1996. RESULTS: the registry includes 3327 admissions in which 3926 resuscitations were attempted. Only the first event is reported. There were 961 hospital survivors. Survival increased from 24.2% in 1987 to 33.4% in 1996 (chi(2)=39.0, df=1, P<0.0001). Survival was affected strongly by initial rhythm (chi(2)=420.0, df=1, P<0.0001) and decreased from 63.2% for supraventricular tachycardia (SVT) to 55.3% for ventricular tachycardia (VT), 51.0% for perfusing rhythms (PER), 34.8% for ventricular fibrillation (VF), 14.3% for pulseless electrical activity (PEA) and 10.0% for asystole (ASYS). PEA was the most frequent rhythm (1180 cases) followed by perfusing (963), asystole (580), VF (459), VT (94) and SVT (38). DISCUSSION: the powerful effect of initial rhythm on survival has been reported in pre-hospital and in-hospital resuscitation. VF is considered the dominant rhythm and generally accounts for the most survivors. We report good outcome for each; however, VF represents only 13.8% of events and 16.7% of survivors. PEA accounts for more survivors (169) than does VF (160). Our improved outcome is partially explained by changes in rhythms, but other institutional variables need to be identified to fully explain the results. Further studies are needed to see if our findings can be sustained or replicated.

Recurrent pericarditis after thoracic surgery.

Acute pericarditis is a frequent complication after cardiac and/or thoracic surgery. Recurrent acute pericarditis with multiple episodes is an uncommon phenomenon, however. Patients typically have chest pain and/or pericardial inflammation as shown by electrocardiography and echocardiography. Treatment presents a clinical challenge due to the condition's rarity and lack of multicenter comparative treatment studies. Numerous therapeutic modalities, including nonsteroidal anti-inflammatory agents (NSAIDs), corticosteroids, immunosuppressants, and pericardiectomy, have been used without overwhelming evidence of a standard protocol. We report a case in which 32 episodes of recurrent acute pericarditis occurred, emphasizing the need for multicenter trials comparing therapeutic modalities in the future.

In-hospital resuscitation: association between ACLS training and survival to discharge.

CONTEXT: No data have been published on the relationship between advanced cardiac life support (ACLS) training of the individual who initiates resuscitation efforts and survival to discharge. OBJECTIVE: To determine whether patients whose arrests were discovered by nurses trained in ACLS had survival rates different from those discovered by nurses not trained in ACLS. DESIGN: Cohort case-comparison. SETTING: A 550-bed, tertiary care center in central Georgia. SUBJECTS: Patients whose cardiopulmonary arrest was discovered by a nurse who activated the in-hospital resuscitation mechanism. MAIN OUTCOME MEASURE: Patient survival to discharge. RESULTS: Initial rhythm was strongly related to survival to discharge and individually associated with 57% of the variability in survival. Nurse's training in advanced cardiac life support was also strongly related to survival and individually associated with 29% of the variability. Combining both the variables determined 62% of the variability in survival to discharge. Patients discovered by an ACLS-trained nurse (n=88) were about four times more likely to survive (33 survivors, 38%) than were patients, discovered by a nurse without training in ACLS (n=29, three survivors, 10%). CONCLUSION: Arrest discovery by nurses trained in ACLS is significantly and dramatically associated with higher survival-to-discharge rates.

Influence of hormonal status of patients with cystic disease on the composition of cyst fluid and breast cancer risk.

The relationship between the composition of breast cyst fluid (BCF), the menstrual status and in addition some endocrine events in the history of patients (n = 131) with gross cystic breast disease was investigated. The dehydroepiandrosterone (DHA) levels in type II (K+/Na+ < 1) cysts of the follicular group were significantly higher compared to the type II cysts of the luteal or postmenopausal groups. For testosterone a significant difference existed between the type I (K+/Na+ > or = 1) follicular and type I postmenopausal groups. Estrone levels were significantly higher in type I BCF of patients in the luteal phase compared to both the follicular and postmenopausal type I cysts. Progesterone levels were lowest in the postmenopausal subgroups (both in type I and II cyst). Significant correlations were found between the number of pregnancies and the levels of DHA-sulfate and also progesterone in BCF. DHA levels were correlated with the period of lactation. The K+/Na+ ratios were the lowest in women who lactated for the longest period. The estrone was lowest in BCF of current oral contraceptive (o.c.) users while the estradiol was lowest in patients who had never used o.c. A history of previous o.c. use was associated with a significantly high mean DHA level. A significantly higher DHA and lower testosterone level were demonstrated in BCF of patients who had some previous gynecological interventions. The composition of BCF and the "life of cysts" and thus the rate of breast cancer risk may depend on hormonal status during the menstrual cycles or postmenopause and also on endocrine history of patients.

Resuscitation in the hospital: differential relationships between age and survival across rhythms.

OBJECTIVE: Assess the frequency and outcome of inhospital resuscitation and determine the relationship between patient age and survival and whether it is affected by initial rhythm. DESIGN: Retrospective, single-institution, registry study of inhospital resuscitation. SETTING: A 550-bed, tertiary-care, teaching hospital in Macon, GA. PATIENTS: All admissions for which a resuscitation was attempted in the Medical Center of Central Georgia during the period of January 1, 1987 through December 31, 1993. The registry sample included 2,394 admissions, for which 2,813 resuscitation attempts were made; only the first resuscitation attempt during an admission was analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Rates of survival to discharge steadily increased from 24.4% in 1987 to 38.6% in 1993; the overall survival rate was 26.8%. Age, used as a continuous variable, was strongly related to survival (odds ratio = 0.984; p < .0001). Categorically, overall survival rates for pediatric, adult, and geriatric patients were 56.4%, 29.0%, and 24.0%, respectively. Survival rates also varied significantly (odds ratio = 0.469; p < .0001) among initial rhythms, i.e., supraventricular tachycardia (60.7%), ventricular tachycardia (57.6%), perfusing rhythms (49.84%), ventricular fibrillation (32.0%), pulseless electrical activity (14.6%), and asystole (9.1%). The relationship between age and survival did not change across the years included in the study, but did vary as a function of initial rhythm (p < .0001). Age was positively related to survival when initial rhythm was supraventricular tachycardia (p = .04), negatively related to survival when the initial rhythm was perfusing (p < .0001) or pulseless electrical activity (p = .0002), and not related to survival when the initial rhythm was ventricular tachycardia (p = .98), ventricular fibrillation (p = .14), or asystole (p = .21). CONCLUSIONS: The relationship between patient age and a successful resuscitation attempt is not as simple as reported earlier. Whether age is related to increased or decreased survival, or is unrelated to survival, depends on the rhythm extant when resuscitation attempts begin. Survival rates were higher than most reported elsewhere and improved significantly over time. Multicentered studies are needed to determine whether these results are unique to the institution studied.

The effect of regulation of high blood pressure on plasma endothelin-1 levels in blacks with hypertension.

Plasma concentrations of immunoreactive endothelin-1 (irET-1) are significantly elevated in blacks with hypertension. In the present study, we investigated the effect of the regulation of high blood pressure on plasma irET-1 levels in black hypertensive individuals. After the initial blood samples were collected from 20 black patients with uncontrolled high blood pressure (Day 1), an intensive antihypertensive treatment was initiated, and the blood pressure and plasma irET-1 levels were monitored on days 2, 8, and 22. When the high blood pressure was brought under control with commonly used antihypertensive medications, plasma irET-1 concentrations dropped dramatically, suggesting that ET-1 concentrations rise as a consequence of high blood pressure in this study group.

Effect of advanced cardiac life support training on resuscitation efforts and survival in a rural hospital.

STUDY OBJECTIVE: To determine the impact of an Advanced Cardiac Life Support (ACLS) training program on resuscitation and survival in a rural hospital. METHODS: Retrospective review of arrests in a 119-bed rural community hospital before, during, and after organization of an ACLS teaching program. ICU logs, death logs, and code review sheets were used to determine resuscitation efforts and outcomes; these were cross-checked with medical and administrative records. From 1980 through 1984, resuscitation attempts were conducted only in the ICU. By 1985, after the training program was instituted, resuscitation efforts were conducted throughout the hospital. Data are presented on resuscitations in the ICU only and on total hospital resuscitations. To assess effort, resuscitation attempts and successes were compared with total death events (ie, total number of hospital deaths plus total number surviving a resuscitation effort). RESULTS: From 1980 through 1984, before ACLS training was instituted, 42 patients were resuscitated and 15 (36%) survived to discharge. From 1985 through 1987, 113 ICU patients were resuscitated and 29 (26%) survived. From 1988 through 1990, after ACLS protocol and code review procedures were established, 81 ICU patients were resuscitated and 23 (28%) survived. The number of attempted resuscitations throughout the hospital increased from 42 in the early period to 179 in the final period, with 15 (36%) and 52 (29%) survivors, respectively. Rates of ICU or hospital-wide resuscitation success were not significantly different over time (P > .3). There were 893 total death events in the early period and 485 in the final period. The percentage of death events with an intervention rose from 5% to 37% (P < .001), and the percentage reversed by intervention increased from 2% to 11% (P < .001). CONCLUSION: After widespread ACLS training and code team organization, there was a significant increase in resuscitation efforts and reversal of death events despite a slight decline in the percentage of patients surviving resuscitation attempts. An ACLS training program in a rural hospital can contribute to increased overall survival.

Racial differences in plasma endothelin-1 concentrations in individuals with essential hypertension.

Hypertension is more prevalent in blacks than whites, and the reasons for this difference remain unclear. To test whether endothelin may play a role in these racial variations, we analyzed plasma samples from black and white women and men with high blood pressure by an enzyme-linked immunoassay specific for endothelin-1 (ET-1), a potent vasoconstrictor, and compared them with those obtained from similar subjects with normal blood pressure. Both female and male hypertensive blacks had elevated levels of immunoreactive ET-1 (11.3 +/- 1.0 and 12.3 +/- 1.3 pmol/L, respectively) compared with values in normotensive control blacks (1.5 +/- 0.2 and 1.4 +/- 0.2 pmol/L). Corresponding values in female and male hypertensive whites were 3.8 +/- 0.6 and 3.8 +/- 0.6 pmol/L, respectively, compared with respective values of 1.4 +/- 0.1 and 2.8 +/- 0.4 pmol/L in normotensive control whites. These results indicate that plasma concentrations of immunoreactive ET-1 levels differ significantly between black and white individuals with high blood pressure. This finding may be an important factor in the etiology of racial differences in the prevalence and severity of hypertension and deserves further study [corrected].

Angiotensin-converting enzyme and enkephalinase in human breast cyst fluid.

Palpable breast cysts with an apocrine epithelial lining (type 1) are reported to be associated with a higher risk of developing breast cancer. The composition of breast cyst fluid (BCF) might include those factors involved in this increased risk. In this study peptidase activities that were active against the substrate [125I]metenkephalin-Arg-Phe were detected in BCF. The products were identified by reversed phase high-performance liquid chromatography (HPLC) as [125I]Tyr-Gly-Gly and [125I]Met-enkephalin. This proteolysis was not inhibited by PCMB, pepstatin A, leupeptin or aprotinin but was by EDTA, showing that the activity was due to metalloproteases. The production of [125I]Try-Gly-Gly was inhibited by phosphoramidon and thiorphan, whereas that of [125I]met-enkephalin was inhibited by captopril and Bothrops jararaca peptide, indicating that these activities are enkephalinase and angiotensin-converting enzyme (ACE) respectively. A fluorometric assay for ACE demonstrated that ACE levels are significantly higher in type 2 BCF than in type 1 BCF (30.8 vs 6.1 nmol hr-1 10 microliters-1, P < 0.001). As the increased risk of cancer is linked to type 1 cysts it is possible that higher levels of peptidase in type 2 BCF reflect a protective environment in the breast in which mitogenic peptide growth factors are neutralised by proteolysis.

Met-enkephalin Arg-Phe-immunoreactive neurons in the central nervous system of the pond snail Lymnaea stagnalis.

The distribution of an opioid peptide related to YGGFMRF was determined in the CNS and other organs of the pond snail, Lymnaea stagnalis, by RIA and immunocytochemistry. RIA revealed the highest levels in the CNS (1 pmol/organ) and penis (400 fmol/organ). There were also significant levels in the haemolymph, most of which was not associated with haemocytes (580 fmol/ml). Both serial section and whole-mount immunocytochemistry of the CNS revealed immunoreactive cells in every ganglion with the majority in the cerebral and pedal ganglia. In the pedal ganglia some of the immunoreactive cells were close to the cells of the A-cluster, which are known to respond to opioids, and could innervate them. In the cerebral ganglia the immunoreactive cells included a group of neurosecretory cells, the caudo dorsal cells (CDCs) and the terminals of these cells in the cerebral commissure were also stained. The CDCs secrete peptides into the haemolymph and so could be the source of the YGGFMRF immunoreactivity. Immunoreactivity (including the CDCs) was observed in locations that correspond to those reported for other fragments of proenkephalin, such as Met- and Leu-enkephalin, suggesting that they may share a common precursor, a Lymnaea proenkephalin. A map of the 358 YGGFMRF-immunoreactive cells in the CNS is presented, many of which have not been previously identified.

Direct peptide profiling by mass spectrometry of single identified neurons reveals complex neuropeptide-processing pattern.

A novel strategy combining peptide fingerprinting of single neurons by matrix-assisted laser desorption ionization mass spectrometry, molecular cloning, peptide chemistry, and electrospray ionization mass spectrometry was used to study the intricate processing pattern of a preprohormone expressed in identified neurons, the neuroendocrine light yellow cells (LYCs) of the gastropod mollusc, Lymnaea stagnalis. The cDNA encoding the precursor, named prepro-LYCP (LYCPs, light yellow cell peptides), predicts a straightforward processing into three peptides, LYCP I, II, and III, at conventional dibasic processing sites flanking the peptide domains on the precursor. However, matrix-assisted laser desorption ionization mass spectrometry of single LYCs revealed trimmed variant peptides derived from LYCP I and II. The variants were much more abundant than the intact peptides, indicating that LYCP I and II serve as intermediates in a peptide-processing sequence. Using the molecular masses of the peptides as markers to guide their isolation by well established purification methods, the structural identities of the peptides could be confirmed by amino acid sequencing. Furthermore, matrix-assisted laser desorption ionization mass spectrometry could detect colocalization of a novel peptide with the LYCPs.