Natasa Milic

Hypopituitarism as a consequence of traumatic brain injury (TBI) and its possible relation with cognitive disabilities and mental distress

Recent studies have demonstrated that hypopituitarism, in particular GH deficiency, is common among survivors of traumatic brain injury (TBI) tested several months or yr following head trauma. We present the results of endocrine, neurological, neuropsychological and psychiatric evaluation in a group of 67 patients who suffered TBI at least one yr ago. Our study shows that decreased endocrine function is either restricted to one or more anterior pituitary hormones and is present in 34% of patients with any pituitary hormone deficit, while multiple pituitary hormone deficiencies are found in 10% of patients. GH/ IGF-I axis was evaluated by GHRH+GHRP-6 test and IGF-I measurement. Severe GHD is the most frequent deficiency present in 15% of TBI patients. Gonadotrophin deficiency was present in 9% of patients with TBI, while thyrotroph and corticotroph function seemed more refractory to impairment. Patients with moderate-to-severe trauma are not necessarily more likely to have hypopituitarism than those with mild injury. Neuropsychological testing revealed a significant positive correlation of peak GH levels after GHRH+GHJRP-6 test with verbal learning and verbal short term memory (RAVLT total score p=0.06, immediate free recall p=0.02 and delayed free recall p=0.04). Verbal and visual memory was significantly lower in elderly patients and in males. Visoconstructional abilities (RCF copy) were significantly lower in the elderly (p<0.01) and undereducated (p=0.02). Visual memory (free recall of complex figure after 30 min) significantly correlated with lower IGF-I levels (p=0.01). Gonadotrophins and testosterone correlated significantly with visoconstructional abilities. Simple and complex conceptual tracking (TMT A and B) was significantly more impaired in older TBI patients (p<0.01) and with longer time from trauma (TMT B only, p=0.03). The psychiatric evaluation by using two different scales showed depression, phobic anxiety and psychoticism to be more prominent in the TBI group. Paranoid ideation and somatization negatively correlated with the peak GH responses to GHRH+GHRP-6 test (p=0.04 and p=0.03, respectively). Depression scale showed that nearly half of patients suffered from mild to moderate depression. The benefits of hormone replacement therapy on cognitive functioning and mental distress in TBI patients are eagerly awaited.

D-dimer in acute pancreatitis: a new approach for an early assessment of organ failure.

Objectives: Studies on the clinical value of parameters of hemostasis in predicting pancreatitis-associated complications are still scarce. The aim of this prospective study was to identify the useful hemostatic markers for accurate determination of the subsequent development of organ failure (OF) during the very early course of acute pancreatitis (AP). Methods: In 91 consecutive primarily admitted patients with AP, prothrombin time, activated partial thromboplastin time, fibrinogen, antithrombin III, protein C, plasminogen activator inhibitor 1, d-dimer, and plasminogen were measured in plasma within the first 24 hours of admission and 24 hours thereafter. Two study groups comprising 24 patients with OF and 67 patients without OF were compared. Results: Levels of prothrombin time, fibrinogen, and d-dimer on admission were significantly different between the OF and non-OF groups, and all these parameters plus antithrombin III were significantly different 24 hours later. A d-dimer value of 414.00 &mgr;g/L on admission was the best cutoff value in predicting the development of OF with sensitivity, specificity, and positive and negative predictive values of 90%, 89%, 75%, and 96%, respectively. Conclusions: Measurement of plasma levels of d-dimer on the admission is an accurate method for the identification of patients who will develop OF in the further course of AP.Abbreviations: AP - acute pancreatitis, PT - prothrombin time, APTT - activated partial thromboplastin time, AT III - antithrombin III, PAI-1 - plasminogen activator inhibitor 1, ROC - receiver operating characteristic, AUC - area under the curve

Disorders of Hemostasis During the Surgical Management of Severe Necrotizing Pancreatitis

Objectives: Several clinical studies of severe necrotizing pancreatitis (SNP) suggest profound activation of coagulation as well as activation of the fibrinolytic system. The aim of this study was to evaluate the hemostatic derangements in patients who were managed for SNP. Methods: Forty-one operated-on patients with SNP were analyzed regarding clinical outcome and activation of the coagulation systems. Serial measurement of coagulation, anticoagulation, and fibrinolysis parameters: prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, antithrombin III (AT III), protein C, plasminogen activator inhibitor-1 (PAI-1), d-dimer, &agr;2-antiplasmin, and plasminogen were performed on days 1, 3, 5, 7, 10, and 14 after the initial operation. According to treatment outcome at the end of study, groups of 26 survivors and 15 nonsurvivors were compared. Results: Nonsurvivors had significantly lower levels of activity of protein C and AT III, and higher concentrations of d-dimer and PAI-1 than survivors. The other measured parameters did not show significant differences between the compared groups of patients. Conclusions: Changes in protein C, AT III, d-dimer and PAI-1 levels indicate exhaustion of fibrinolysis and coagulation inhibitors in patients with poor outcome during the course of SNP.

Is there a "gold" standard treatment for patients with isolated myeloid sarcoma?

Isolated myeloid sarcoma is an extramedullary tumor of immature myeloid cells defined by the absence of leukemia history, myelodisplastic syndrome, or myeloproliferative neoplasma with a negative bone marrow biopsy. Myeloid sarcoma is a very rare condition, and few cases have been reported. We reviewed data of 12 patients with isolated myeloid sarcoma managed at a single center to determine the possible prognostic factors affecting patient survival, such as age, sex, type, localization, and treatment options. Patients were mostly men (n=8), with a median age of 39 years. Patients were initially treated with chemotherapy (n=7) or surgery (n=5). In three patients, hematopoietic stem cell transplantation was performed. During the follow-up period, nine patients died. The median overall survival was 13 months, while event-free survival was 8 months. Regarding initial treatment strategy, no significant difference in overall survival was observed. Both chemotherapy and hematopoietic stem cell transplantation independently improved event-free survival. In addition, patients who received chemotherapy combined with hematopoietic stem cell transplantation had significantly longer event-free survival than those treated with chemotherapy alone. Age<40 years together with chemotherapy/hematopoietic stem cell transplantation significant affected event-free survival. Based on our results, the treatment of myeloid sarcoma requires a systemic rather than a localized approach with surgery or radiotherapy. While prospective evaluations are needed, chemotherapy with allogenic hematopoietic stem cell transplantation should be considered as the optimal therapy for isolated myeloid sarcoma.

Severe acute pancreatitis: overall and early versus late mortality in intensive care units.

Objectives: To determine overall mortality and timing of death in patients with severe acute pancreatitis and factors affecting mortality. Methods: This was a retrospective, observational study of 110 patients admitted to a general intensive care unit (ICU) from January 2003 to January 2006. Results: The overall mortality rate was 53.6% (59/110); 25.4% (n = 15) of deaths were early (≤14 days after ICU admission). There were no significant differences in age, sex, or surgical/medical treatment between survivors and nonsurvivors. Median Acute Physiology and Chronic Health Evaluation (APACHE) II score was higher among nonsurvivors than survivors (score = 26 vs 19, respectively; P < 0.001), and the duration of hospitalization before ICU admission was significantly longer (4 vs 1 day; P < 0.001). Among the 59 patients who died, those in the early-mortality group were admitted to the ICU significantly earlier than those in the late-mortality group (3 vs 6.5 days; P < 0.05). Conclusions: Overall mortality and median APACHE II score were high. Death predominantly occurred late and was unaffected by patient age, length of stay in the ICU, or surgical/medical treatment. An APACHE II cutoff of 24.5 and pre-ICU admission time of 2.5 days were sensitive predictors of fatal outcome.

Importance of early detection and follow-up of FLT3 mutations in patients with acute myeloid leukemia

Mutations in the fms-like tyrosine kinase 3 (FLT3) gene, such as internal tandem duplication (FLT3/ITD) in the juxtamembrane domain and point mutations in the tyrosine kinase domain, are the most common abnormalities in acute myeloid leukemia (AML). FLT3/ITD and FLT3/D835 mutations were analyzed in 113 Serbian adult AML patients using polymerase chain reaction. Twenty patients were found to be FLT3/ITD positive (17.7%). The mutations occurred most frequently in M5 and M0 subtypes of AML. They were mainly associated with the normal karyotype. All patients harboring FLT3/ITD had a higher number of white blood cells than patients without it (p = 0.027). FLT3/ITD mutations were associated with lower complete remission (CR) rate (χ2 = 5.706; p = 0.017) and shorter overall survival (OS; Log rank = 8.76; p = 0.0031). As for disease-free survival, the difference between FLT3/ITD-positive and FLT3/ITD-negative patients was not statistically significant (Log rank = 0.78; p = 0.3764). In multivariate analysis, the presence of FLT3/ITD mutations was the most significant prognostic factor for both OS and CR rate (p = 0.0287; relative risk = 1.73; 95% CI = 1.06–2.82). However, in the group of patients with the intermediate-risk karyotype, the mere presence of FLT3/ITD was not associated with inferior clinical outcome. FLT3/D835 point mutation was found in four patients (3.5%) only. Follow-up of the FLT3/ITD-positive patients revealed stability of this mutation during the course of the disease. However, changes in the pattern of FLT3/D835 mutations in initial and relapsed AML were observed. Our results indicate an association of FLT3/ITD with the adverse outcome in AML patients treated with standard induction chemotherapy. Because FLT3/ITD mutation is a target for specific therapeutic inhibition, its early detection could be helpful in clinical practice.

Decompressive laparotomy with temporary abdominal closure versus percutaneous puncture with placement of abdominal catheter in patients with abdominal compartment syndrome during acute pancreatitis: background and design of multicenter, randomised, controlled study

BackgroundDevelopment of abdominal compartment syndrome (ACS) in patients with severe acute pancreatitis (SAP) has a strong impact on the course of disease. Number of patients with this complication increases during the years due more aggressive fluid resuscitation, much bigger proportion of patients who is treated conservatively or by minimal invasive approach, and efforts to delay open surgery. There have not been standard recommendations for a surgical or some other interventional treatment of patients who develop ACS during the SAP. The aim of DECOMPRESS study was to compare decompresive laparotomy with temporary abdominal closure and percutaneus puncture with placement of abdominal catheter in these patients.MethodsOne hundred patients with ACS will be randomly allocated to two groups: I) decompresive laparotomy with temporary abdominal closure or II) percutaneus puncture with placement of abdominal catheter. Patients will be recruited from five hospitals in Belgrade during two years period. The primary endpoint is the mortality rate within hospitalization. Secondary endpoints are time interval between intervention and resolving of organ failure and multi organ dysfunction syndrome, incidence of infectious complications and duration of hospital and ICU stay. A total sample size of 100 patients was calculated to demonstrate that decompresive laparotomy with temporary abdominal closure can reduce mortality rate from 60% to 40% with 80% power at 5% alfa.ConclusionDECOMPRESS study is designed to reveal a reduction in mortality and major morbidity by using decompresive laparotomy with temporary abdominal closure in comparison with percutaneus puncture with placement of abdominal catheter in patients with ACS during SAP.Trial registrationClinicalTrials.gov Identifier: NTC00793715

Total ghrelin levels during acute insulin infusion in patients with polycystic ovary syndrome

Controversial data were reported concerning fasting ghrelin (decreased, normal or elevated) in polycystic ovary syndrome (PCOS). The aim of our study was to clarify ghrelin levels in non-obese, overweight, and obese PCOS patients; to investigate the effect of acute insulin infusion on ghrelin in PCOS as a chronic insulin-resistant state, with and without the impact of obesity, and to examine ghrelin-androgen interaction. In that order, we evaluated 1) ghrelin levels among 8 non-obese patients with PCOS [body mass index (BMI): 20.52±1.31 kg/m2], 8 overweight and obese patients with PCOS (BMI: 34.36±6.53 kg/m2) and their respective controls, 2) ghrelin suppression during euglycemic hyperinsulinemic clamp, and 3) ghrelin-androgen interrelationship. After overnight fast, 2-h euglycemic hyperinsulinemic clamp, was performed in all investigated women. Fasting ghrelin was significantly lower in non-obese PCOS than in controls (64.74±25.69 vs 108.36±52.60; p<0.05) as well as in overweight and obese PCOS in comparison with controls (38.71 ± 14.18 vs 98.77± 40.49; p<0.05). Insulin infusion significantly suppressed ghrelin in all subgroups of investigated women. Analysis of variance for repeatable measures confirmed that there was no significant difference in pattern of response between PCOS and controls. In conclusion, women with PCOS had lower fasting ghrelin and decreased insulin sensitivity independently of their BMI, compared to the controls. In addition, there were no differences between fasting ghrelin levels among non-obese, overweight, and obese women with PCOS. During euglycemic hyperinsulinemic clamp, ghrelin decreased in all studied groups to a similar extent, implying that, compared to chronic hyperinsulinemia, acute hyperinsulinemia reduces ghrelin levels independently of the degree of insulin resistance.

The value of fractional and coronary flow reserve in predicting myocardial recovery in patients with previous myocardial infarction

AIMS The aim of the study was to evaluate the relation between fractional flow reserve (FFR) and simultaneously evaluated coronary flow reserve by thermodilution (CFRthermo), with the improvement of left ventricular (LV) function in patients with previous myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS Study population consisted of 46 patients (mean age 53 +/- 7 years; 36 male) with previous MI and significant coronary stenosis undergoing PCI of infarct-related coronary artery. In all patients, we evaluated FFR and CFRthermo by single pressure/thermo wire during maximal hyperaemia before and immediately after PCI. We performed echocardiographic assessment of LV ejection fraction before and 6 months after PCI. Dobutamine stress echocardiography test was also performed before PCI. LV functional improvement was observed in 33/46 (72%) of patients. In patients with LV functional recovery in comparison with patients with no recovery, there was a significant difference in FFR before PCI (0.56 +/- 0.14 vs. 0.70 +/- 0.07, P < 0.001), improvement of FFR (0.35 +/- 0.14 vs. 0.21 +/- 0.07, P < 0.001), improvement of CFRthermo (1.3 +/- 0.6 vs. 0.5 +/- 0.3, P < 0.001), and CFRthermo after PCI (2.6 +/- 0.7 vs. 2.0 +/- 0.4, P < 0.001). When only parameters evaluated before PCI were taken into account, FFR before angioplasty (P = 0.001) and dobutamine-assessed viability (P = 0.006) were the most significant multivariate predictors of myocardial recovery. When all significant univariate parameters were evaluated, the most significant independent predictors for improvement in myocardial function were the improvement of CFRthermo during angioplasty (P < 0.001) and FFR before angioplasty (P = 0.002). CONCLUSION Simultaneous evaluation of FFR and CFRthermo provide significant complementary data on the improvement in myocardial function in patients with previous MI. However, the evaluation of FFR before angioplasty identifies viable myocardium that may recover following revascularization and may be used as an alternative to non-invasive testing.

Protein C as an Early Marker of Severe Septic Complications in Diffuse Secondary Peritonitis

To evaluate the predictive value of protein C as a marker of severity in patients with diffuse peritonitis and abdominal sepsis, protein C levels were repeatedly determined and compared with serum levels of antithrombin III, plasminogen, α2-antiplasmin, Plasminogen activator inhibitor, D-dimer, C1-inhibitor, high molecular weight kininogen, and the C5a, C5b-9 fragments of the complement system. We carried out a prospective study from 44 patients with severe peritonitis confirmed by laparotomy and 15 patients undergoing elective ventral hernia repair who acted as controls. Analyzed biochemical parameters were determined before operations and on days 1, 2, 3, 5, 7, 10, and 14 after operations. For the study group, preoperative average protein C level was significantly lower in the patients who developed septic shock in the late course of the disease, with lethal outcome, than in the patients with severe peritonitis and sepsis who survived (p = 0.0001). In non-survivors, protein C activity remained decreased below 70%, whereas the course of survivors was characterized by increased values that were significantly higher (p < 0.03) at every time point than in those patients who died. Protein C was of excellent predictive value and achieved a sensitivity of 80% and a specificity of 87.5% in discriminating survivors from non-survivors within the first 48 hours of the study (AUC-0.917; p < 0.001), with a “cut-off” level of 66.0%. As for the control group, throughout the study period, protein C activity was permanently maintained within the range of normal, with significant differences with reference to the study group (p < 0.01). These results suggest that protein C represents a sensitive and early marker for the prediction of severe septic complications during diffuse peritonitis, and of outcome.