Herbert R. Freund

Plasma Amino Acids as Predictors of the Severity and Outcome of Sepsis

Sepsis is a major catabolic insult resulting in a peripheral energy deficit which is made up in part by increased breakdown of lean body mass and oxidation of amino acids, principally the branched chain amino acids. The prognosis in any given case of sepsis is difficult to predict, but should theoretically be related to the degree of disturbance in peripheral energy deficit, which may in turn, be related to plasma amino acid pattern. In order to study whether this hypothesis was correct, plasma amino acids and some of their metabolic byproducts, the beta-hydroxyphenylethanolamines, were studied in 25 septic patients, and were used as discriminant variables in a series of computer performed discriminant analyses and multiple regressions. The two functions tested were the degree of metabolic septic encephalopathy as a determinant of the severity of sepsis and the final outcome in the septic patient. Plasma amino acid patterns exhibited elevated levels of the aromatic and sulfur containing amino acids, phenyl-alanine, tryosine, tryptophan, methionine, cysteine, and taurine, normal concentrations of alanine, and low normal concentrations of the branched chain amino acids, valine, leucine and isoleucine. Arginine levels, as previously noted, were very low. Patients not surviving the septic episode exhibited higher concentrations of aromatic and sulfur containing amino acids, while patients surviving sepsis had higher concentrations of the branched chain amino acids and arginine. When the degree of encephalopathy as a determinant of the severity of sepsis and step wise discriminant analysis with multiple crescent techniques were used, the best discriminant function between patients with and without encephalopathy was found to result from the interaction of cysteine, methionine, phenylalanine, isoleucine, leucine, and valine. These amino acids gave a correct classification in 82% of patients with no encephalopathy, and 80% of patients with septic encephalopathy. When the same amino acids were used for the discriminant analysis for patients dying of sepsis and patients surviving, the best discriminant function was achieved by using plasma concentrations of alanine, cysteine, methionine, isoleucine, arginine, tyrosine and phenylalanine resulting in 91% of the nonsurvivors, and 79% of the survivors correctly classified. The results suggest a close and significant relationship between the deranged energy metabolism and muscle

Percutaneous transhepatic cholecystostomy and delayed laparoscopic cholecystectomy in critically ill patients with acute calculus cholecystitis

BACKGROUND The ultimate therapy for acute cholecystitis is cholecystectomy. However, in critically ill elderly patients the mortality of emergency cholecystectomy may reach up to 30%. Open cholecystostomy performed under local anesthesia was considered to be the procedure of choice for treatment of acute cholecystitis in high-risk patients. In recent years, ultrasound- or computed tomography (CT)-guided percutaneous transhepatic cholecystostomy (PTHC) replaced open cholecystostomy for the treatment of acute cholecystitis in critically ill patients. METHODS The aim of the present study was to evaluate the results of a 5-year protocol using PTHC followed by delayed laparoscopic cholecystectomy for the treatment of acute cholecystitis in critically ill patients. We reviewed the charts of 55 patients who underwent PTHC at the Hadassah University Hospital Mount Scopus during the years 1994 to 1999. RESULTS The main indications for PTHC among this group of severely sick and high-risk patients was biliary sepsis and septic shock in 23 patients (42%); and severe comorbidities in 32 patients (58%). The median age was 74 (32 to 98) years, 33 were female and 22 male. Successful biliary drainage by PTHC was achieved in 54 of 55 (98%) of the patients. The majority of the patients (31 of 55) were drained transhepaticlly under CT guidance. The rest, (24 of 55) were drained using ultrasound guidance followed by cholecystography for verification. Complications included hepatic bleeding that required surgical intervention in 1 patient and dislodgment of the catheter in 9 patients that was reinserted in 2 patients. Three patients died of multisystem organ failure 12 to 50 days following the procedure. The remaining 52 patients recovered well with a mean hospital stay of 15.5 plus minus 11.4 days. Thirty-one patients were able to undergo delayed surgery: 28 underwent laparoscopic cholecystectomy of whom 4 (14%) were converted to open cholecystectomy. This was compared with a 1.9% conversion rate in 1,498 elective laparoscopic cholecystectomies performed at the same time period (P = 0.012). Another 3 patients underwent planned open cholecystectomy, 1 urgent and 2 combined with other abdominal procedures. There was no surgery associated mortality, severe morbidity, or bile duct injury. CONCLUSIONS The use of PTHC in critically ill patients with acute cholecystitis is both safe and effective.

Evacuation Priorities in Mass Casualty Terror-related Events: Implications for Contingency Planning

Objective:To assess evacuation priorities during terror-related mass casualty incidents (MCIs) and their implications for hospital organization/contingency planning. Summary Background Data:Trauma guidelines recommend evacuation of critically injured patients to Level I trauma centers. The recent MCIs in Israel offered an opportunity to study the impositions placed on a prehospital emergency medical service (EMS) regarding evacuation priorities in these circumstances. Methods:A retrospective analysis of medical evacuations from MCIs (29.9.2000–31.9.2002) performed by the Israeli National EMS rescue teams. Results:Thirty-three MCIs yielded data on 1156 casualties. Only 57% (506) of the 1123 available and mobilized ambulances were needed to provide 612 evacuations. Rescue teams arrived on scene within <5 minutes and evacuated the last urgent casualty within 15–20 minutes. The majority of non-urgent and urgent patients were transported to medical centers close to the event. Less than half of the urgent casualties were evacuated to more distant trauma centers. Independent variables predicting evacuation to a trauma center were its being the hospital closest to the event (OR 249.2, P < 0.001), evacuation within <10 minutes of the event (OR 9.3, P = 0.003), and having an urgent patient on the ambulance (OR 5.6, P < 0.001). Conclusions:Hospitals nearby terror-induced MCIs play a major role in trauma patient care. Thus, all hospitals should be included in contingency plans for MCIs. Further research into the implications of evacuation of the most severely injured casualties to the nearest hospital while evacuating all other casualties to various hospitals in the area is needed. The challenges posed by terror-induced MCIs require consideration of a paradigm shift in trauma care.

Blood-brain barrier derangement in sepsis: Cause of septic encephalopathy?

Patients with sepsis often manifest disorientation, somnolence, asterixis and coma, symptoms also seen in portasystemic encephalopathy. Altered plasma concentrations of the neutral amino acids and in creased blood-brain transport of these acids may play a role in portasystemic encephalopathy. Plasma amino acids and blood-brain barrier transport of neutral amino acids were investigated in a rat model of abdominal sepsis, cecal ligation and puncture. The blood-brain transport was studied by the technique of Oldendorf with carbon-14-amino acids 12 and 24 hours after the induction of sepsis. In similar groups of animals, isolation of brain capillaries was carried out by the technique of Hjelle and the capillaries were incubated with carbon-14-amino acids to study transport activity. Plasma and brain amino acids were deranged in a fashion similar to the derangements seen in portasystemic encephalopathy, with a decrease in plasma branched chain amino acids and an increase in most neutral amino acids in brain. The changes were most pronounced after 24 hours. The brain uptake of several neutral amino acids was increased in the septic rats, while the uptake of lysine, a basic amino acid, was normal. In the brain capillaries isolated from septic rats, tyrosine and leucine transport was also greater than in sham-operated animals. Elevated neutral amino acids may play a role in the encephalopathy encountered in septic patients similar to its role in patients with portasystemic encephalopathy, as similar mechanisms appear to be operating.

Infusion of the Branched Chain Amino Acids in Postoperative Patients: Anticatabolic Properties

Postinjury metabolism is characterized by breakdown of muscle protein as substrate for energy production and gluconeogenesis and by the resultant loss of lean body mass and weight loss. The branched chain amino acids (BCAAs) which are principally oxidized by the skeletal muscle have been implicated in recent in vitro and in vivo studies as having special anticatabolic and regulating effects in skeletal muscle. We studied the anticatabolic effects of the BCAAs in 35 patients undergoing operative injury of moderate severity. In a prospective randomized and blinded manner patients were infused for five days starting immediately after surgery with either 5% dextrose or 5% dextrose with an amino acid solution containing 22, 35 or 100% BCAAs. All patients survived and there were no major postoperative complications. Mean hospital stay was 17 days for patients receiving amino acids and 19 days for patients receiving 5% dextrose only (p = ns). All three groups receiving amino acid solutions were in nitrogen equilibrium or in a slight positive nitrogen balance, while the group receiving 5% dextrose only was in a mean negative nitrogen balance of 6.6 ± 0.6 gN/day. The differences between the three groups receiving amino acids were slight and not significant. Weight loss was 2 ± 0.7 kg in the 5% dextrose group, 1 ± 0.7 kg in the 22% BCAAs group, 0.5 ± 0.5 kg in the 35% BCAAs group and the 100% BCAAs group gained 0.4 ± 1.8 kg. Blood chemistries in the different groups and during the study period remained within normal limits except for ammonia levels rising significantly in the 5% dextrose group and SGOT levels rising in the 22% and 35% BCAA groups. With mild variations the plasma amino acid patterns in all groups were similar to the normal pattern, even in the 100% BCAAs group receiving an unbalanced amino acid solution, suggesting the complete cessation of amino acid efflux from muscle, the muscle depending solely on the exogenous supply of BCAAs to satisfy its metabolic requirements. The results suggest that early nutritional suppport in the postoperative period will result in nitrogen equilibrium and that the infusion of the three BCAAs only in the postoperative state is as effective in preventing muscle catabolism as other more balanced amino acid solutions. In the postinjury state balanced amino acid solutions rich in BCAA may prove beneficial.

Prospective randomized study comparing sentinel lymph node evaluation with standard pathologic evaluation for the staging of colon carcinoma: results from the United States Military Cancer Institute Clinical Trials Group Study GI-01.

Background:The principal role of sentinel lymph node (SLN) sampling and ultrastaging in colon cancer is enhanced staging accuracy. The utility of this technique for patients with colon cancer remains controversial. Purpose:This multicenter randomized trial was conducted to determine if focused assessment of the SLN with step sectioning and immunohistochemistry (IHC) enhances the ability to stage the regional nodal basin over conventional histopathology in patients with resectable colon cancer. Patients and Methods:Between August 2002 and April 2006 we randomly assigned 161 patients with stage I–III colon cancer to standard histopathologic evaluation or SLN mapping (ex vivo, subserosal, peritumoral, 1% isosulfan blue dye) and ultrastaging with pan-cytokeratin IHC in conjunction with standard histopathology. SLN-positive disease was defined as individual tumor cells or cell aggregates identified by hematoxylin and eosin (H&E) and/or IHC. Primary end point was the rate of nodal upstaging. Results:Significant nodal upstaging was identified with SLN ultrastaging (Control vs. SLN: 38.7% vs. 57.3%, P = 0.019). When SLNs with cell aggregates ≤0.2 mm in size were excluded, no statistically significant difference in node-positive rate was apparent between the control and SLN arms (38.7% vs. 39.0%, P = 0.97). However, a 10.7% (6/56) nodal upstaging was identified by evaluation of H&E stained step sections of SLNs among study arm patients who would have otherwise been staged node-negative (N0) by conventional pathologic assessment alone. Conclusion:SLN mapping, step sectioning, and immunohistochemistry (IHC) identifies small volume nodal disease and improves staging in patients with resectable colon cancer. A prospective trial is ongoing to determine the clinical significance of colon cancer micrometastasis in sentinel lymph nodes.

Polymyxin B reduces cecal flora, TNF production and hepatic steatosis during total parenteral nutrition in the rat

Hepatic complications are common in patients receiving total parental nutrition (TPN) and who have no underlying liver disease. In the present study we examined the hypothesis that endotoxin (LPS) or possibly TNF derived from the overgrowth of intestinal gram-negative bacteria is responsible for TPN-associated hepatic steatosis, and that bowel decontamination and specific anti-LPS activity of polymyxin B will reduce fatty infiltration of the liver during TPN. Forty-five male Sabra rats underwent jugular vein cannulation, were placed in metabolic cages, and were randomized into five groups. Group I was continuously infused with normal saline and allowed food ad lib, while group II-V were continuously infused with a TPN formula containing 4.25% amino acids and 25% dextrose for a total of 36 calories and 3.0 g protein per 100 g body weight/day. In addition, groups III-IV were also treated by oral polymyxin B while Groups IV and V received a combination of neomycin, metronidazole, and vancomycin (NMV). Thus, Group III received polymyxin B, Group IV received both polymyxin B and NMV, while Group V received NMV only. On Days 7-8 of the study, all animals were sacrificed and spontaneous production of TNF by peritoneal macrophages, bacterial translocation to mesenteric lymph nodes, culture of the cecum, and fat, triglyceride, and cholesterol contents of the liver were determined. All groups infused with TPN exhibited higher levels of total fat, triglycerides, and cholesterol compared to the free feeding control group (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Development of a MicroRNA-Based Molecular Assay for the Detection of Papillary Thyroid Carcinoma in Aspiration Biopsy Samples

BACKGROUND Although thyroid nodules are common and diagnosed in over 5% of the adult population, only 5% harbor malignancy. Patients with clinically suspicious thyroid nodules need to undergo fine-needle aspiration biopsy (FNAB). The main limitation of FNAB remains indeterminate cytopathology. Only 20%-30% of the indeterminate nodules harbor malignancy, and therefore up to 80% of patients undergo unnecessary thyroidectomy. The aim of this study was to identify and validate a panel of microRNAs (miRNAs) that could serve as a platform for an FNAB-based diagnostic for thyroid neoplasms. METHODS The study population included 27 consecutive patients undergoing total thyroidectomy for FNAB-based papillary thyroid cancer (n = 20) and benign disorders (n = 7). Aspiration biopsy was performed from the index lesion and from the opposite lobe normal tissue in all study patients at the time of operation. RNA was extracted from all aspiration biopsy samples. Quantitative polymerase chain reaction on a panel of previously selected miRNAs was performed. Polymerase chain reaction results were compared with final histopathology. miRNA from tumor tissues was amplified using the highest value of each miRNA expression in normal tissue as a threshold for malignancy detection. RESULTS Diagnostic characteristics were most favorable for mir-221 in differentiating benign from malignant thyroid pathology. mir-221 was overexpressed in 19 patients (p < 0.0001) with a sensitive yield of 95%. Specificity, negative and positive predictive value, and accuracy of the miRNA panel were 100%, 96%, 100%, and 98%, respectively. CONCLUSIONS miRNA quantification for differential diagnosis of thyroid neoplasms within aspiration biopsy samples is feasible and may improve the accuracy of FNAB cytology.

In-Hospital Resource Utilization During Multiple Casualty Incidents

Objective:To suggest guidelines for hospital organization during terror-related multiple casualty incidents (MCIs) based on the experience of 6 level I trauma centers. Summary Background Data:Most terror-related MCIs are bombings. The sporadic nature of these events complicates in-hospital preparation. Methods:Data were collected at all level I Trauma centers during/after MCIs for the Israel National Trauma registry. Patients were included if they were admitted or died in hospital following injury in suicide bombings (October 1, 2000 to June 30, 2003), which fulfilled Ministry of Health suggested criteria for MCIs (number of admissions, severity of injury). Results:Included were 325 casualties from 32 events, 34% of which had an Injury Severity Score >16. A third of the admissions arrived within 10 minutes and 65% within 30 minutes. Forty percent of the patients underwent CT scans directly from the ED. Operative procedures were performed on 60% of patients and 36% were transferred directly from the ED to the OR. Initiation of surgical procedures peaked at 1 to 1.5 hours, mainly multidisciplinary abdominal, thoracic, and vascular surgery. Orthopedic and plastic surgery predominated later. A third of the patients were admitted to ICUs, often (31%) directly from the ED. Conclusions:High staffing demands for ED, OR, and ICU overlap. Anesthesiologists, general, thoracic, and vascular surgeons are in immediate demand. ICU admissions occur simultaneously with ongoing patient arrival to the ED. Most patients operated within the first 2 hours require multidisciplinary surgical teams. Demand for orthopedic and plastic surgery and anesthesiology services continues for >24 hours.

Lithium-associated hyperparathyroidism: report of four cases and review of the literature

CONTEXT Lithium-associated hyperparathyroidism (LAH) was first described in 1973 but many issues remain in question regarding the pathophysiology as well as the appropriate management of this condition. OBJECTIVE Report of four new cases and review of the literature. RESULTS We describe two males and two females, treated for more than 10 years with lithium due to bipolar disorder, who developed LAH. All underwent parathyroidectomy. In three cases (75%), pathology revealed multiglandular disease, with hyperplasia or two parathyroid adenomas. We observed a cure status in three (75%) of the operated patients. The fourth patient had a residual disease, but had controlled hypercalcemia under the calcimimetic drug cinacalcet. We also observed the association of LAH with incidental papillary thyroid carcinoma in two patients. Review of the literature identified a higher prevalence of LAH in women than men (four out of one) and a controversy in regard to the prevalence of multiglandular disease. As a result, there is no consensus regarding the preferred surgical procedure. The use of cinacalcet as an effective treatment of LAH was previously described in only five cases. CONCLUSION In our view, there are apparently two different mechanisms leading to LAH: exacerbation of a pre-existing state of hyperparathyroidism and multiglandular disease. For uncontrolled hypercalcemia, parathyroidectomy is recommended. The issue of routine four-gland exploration and subtotal parathyroidectomy versus intraoperative PTH-determination-guided excision of enlarged glands is still unresolved. The use of the recently developed calcimimetics may offer an alternative to patients who are not candidates for surgery.