Impact of "critical lesions" on outcomes following cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy.

BACKGROUND: Peritoneal Cancer Index (PCI) and complete cytoreduction are the best outcome predictors following cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Lesions in critical areas, regardless of PCI, complicate surgery and impact oncological outcomes. We prospectively defined "Critical lesions" (CL) as penetrating the hepatic hilum, diaphragm at hepatic outflow, major blood vessels, pancreas, or urinary tract. METHODS: Retrospective analysis of a prospective database of 352 CRS + HIPEC patients from 2015 to 2019. Excluded patients with aborted/redo operation (n = 112), or incomplete data (n = 19). Patients categorized by CL status and compared: operative time, estimated blood loss (EBL), PCI, transfusions, hospital stay, post-operative complications and mortality, overall survival (OS) and disease-free survival (DFS). RESULTS: Included 221 patients (78 CL; 143 no-CL). No difference in patients' characteristics: age, BMI, gender or co-morbidities noted. Operative time longer (5.3 h vs 4.3 h, p < 0.01), EBL higher (769 ml vs 405 ml, p < 0.01), transfusions higher (1.9 vs 0.7 Units, p < 0.001) and PCI higher (15.5 vs 9.5, p < 0.01) in CL. No difference in major complications. Postoperative complications, CL, OR-time and transfusions were predictive of OS in univariate analysis, while only complications remained on multivariate analysis. Median follow up of 21.4 months, 3-year DFS/OS was 22% vs 30% (p < 0.037) and 73% vs 87% (p < 0.014) in CL and non-CL, respectively. Despite CL complete resection, 17/38 patients (44.7%) that recurred had recurrence at previous CL site. CONCLUSIONS: Critical lesions complicate surgery and may be associated with poor oncological outcomes with high local recurrence rate, despite no significant difference in complications. Utilizing adjuvant or intra-operative radiation may be beneficial.

Treating sepsis with vitamin C, thiamine, and hydrocortisone: Exploring the quest for the magic elixir.

The administration of ascorbic acid (vitamin C) alone or in combination with thiamine (vitamin B1) and corticosteroids (VCTS) has recently been hypothesized to improve hemodynamics, end-organ function, and may even increase survival in critically ill patients. There are several clinical studies that have investigated the use of vitamin C alone or VCTS in patients with sepsis and septic shock or are ongoing. Some of these studies have demonstrated its safety and potential benefit in septic patients. However, many questions remain regarding the optimal dosing regimens and plasma concentrations, timing of administration, and adverse effects of vitamin C and thiamine. These questions exist because the bulk of research regarding the efficacy of vitamin C alone or in combination with thiamine and corticosteroids in sepsis is limited to a few randomized controlled trials, retrospective before-and-after studies, and case reports. Thus, although the underlying rationale and mechanistic pathways of vitamin C and thiamine in sepsis have been well described, the clinical impact of the VCTS regimen is complex and remains to be determined. This review aims to explore the current evidence and potential benefits and adverse effects of the VCTS regimen for the treatment of sepsis.

Genetic features of Lynch syndrome in the Israeli population.

Diagnosis of Lynch syndrome (LS) may be complex. Knowledge of mutation spectrum and founder mutations in specific populations facilitates the diagnostic process. Aim of the study is to describe genetic features of LS in the Israeli population and report novel and founder mutations. Patients were studied at high-risk clinics. Diagnostics followed a multi-step process, including tumor testing, gene analysis and testing for founder mutations. LS was defined by positive mutation testing. We diagnosed LS in 242 subjects from 113 families coming from different ethnicities. We identified 54 different mutations; 13 of them are novel. Sixty-seven (59%) families had mutations in MSH2, 20 (18%) in MSH6, 19 (17%) in MLH1 and 7 (6%) in PMS2; 27% of the MSH2 mutations were large deletions. Seven founder mutations were detected in 61/113 (54%) families. Constitutional mismatch repair deficiency (CMMR-D) was identified in five families. Gene distribution in the Israeli population is unique, with relatively high incidence of mutations in MSH2 and MSH6. The mutation spectrum is wide; however, 54% of cases are caused by one of seven founder mutations. CMMR-D occurs in the context of founder mutations and consanguinity. These features should guide the diagnostic process, risk estimation, and genetic counseling.

A safety evaluation of drotrecogin alfa (activated) in hematopoietic stem cell transplant patients with severe sepsis: lessons in clinical research.

We conducted an open-label, multicenter, single-arm clinical trial to investigate the safety and efficacy of drotrecogin alfa (activated) (Drot AA) in hematopoietic stem cell transplant (HSCT) patients with severe sepsis. Drot AA was administered as a continuous i.v. infusion of 24 microg/kg/h for 96 h. The target enrollment was 250 patients in 15-20 transplant centers over a 2-year period (March 2003-March 2005). However, after only 10 months, in December 2003, the trial was stopped due to a low enrollment of seven patients at three of the 15 sites that were open for accrual. Six of the seven patients completed the drug infusion. Two patients experienced serious bleeding events. The first patient developed a nonfatal diffuse alveolar hemorrhage 2 days after study-drug completion. The second patient had severe coagulopathy and developed a fatal intracranial hemorrhage on the third day of drug infusion. Three of the seven patients were alive 100 days after the HSCT. The slow enrollment rate was attributed to changes in transplant preparatory regimens, enhancements in antimicrobial prophylactic protocols and the use of antimicrobial-coated catheters. The small number of patients in this report precludes a definitive assessment of the safety and efficacy of Drot AA in HSCT patients.

Septic shock and multiple organ failure after hematopoietic stem cell transplantation: treatment with recombinant human activated protein C.

Severe sepsis with multiple organ failure after hematopoietic stem cell transplantation (HSCT) results in extremely high morbidity and mortality. Recent studies have highlighted the importance of sepsis-induced activation of the coagulation system in the pathophysiology of severe sepsis. Activated protein C is an important modulator of coagulation and inflammatory derangements during severe sepsis. Low levels of protein C occur in severe sepsis and are predictive of poor outcome. Recombinant human activated protein C (drotrecogin alfa (activated)) was recently approved by the Food and Drug Administration (FDA) for severe sepsis. The phase III trial that resulted in the approval of this agent, however, enrolled a general sepsis population and excluded patients undergoing HSCT. We report a case of fulminant septic shock and multiple organ failure after HSCT that was treated with drotrecogin alfa (activated) in addition to standard therapy, and recovered. The high mortality rates of patients who develop severe sepsis after HSCT demand that new avenues of treatment be considered for this very high-risk patient population. This case illustrates the potential application of a novel therapeutic approach. Clinical trials are warranted to further investigate the safety and efficacy of drotrecogin alfa (activated) in patients with severe sepsis after HSCT.

Acquisition strategies for critical care technology.

Technological advances in critical care will undoubtedly find their way into the ICU of the 21st century. The challenge for critical care practitioners is to meticulously assess these innovations and adopt the most appropriate and efficient technologies that will improve unit function and staff efficiencies, support educational programs, and most importantly, enhance patient outcome at a reasonable cost. Hospital-based intensivists have excellent opportunities to establish leadership roles in the technology evaluation process by cultivating relationships with administrators, and through active participation in the hospital-based Technology Committee and the ICU-based multidisciplinary committee. The authors' experience has left them with the lasting impression that the evaluation and introduction of new technology is time consuming and requires perseverance and patience. Ultimately, it is hoped that technological breakthroughs coupled with a standardized approach to delivery of ICU services in the coming decades will ensure better and more efficient care to critically ill patients.

Point of care diagnostics and networks.

The new paradigm of POCT as integrated into the ICU will allow for an improved and more efficient critical care workplace and possibly improvements in outcome and costs. Technologic advances in POCT will focus on enhancements of current devices, connectivity, and data management and on the introduction of novel diagnostic and therapeutic approaches. It is hoped that in the future the regulatory, laboratory, and L/HIS communities will recognize the need to accept, integrate, accommodate, and expand POCT, thereby promoting bedside diagnostics. For ongoing follow-up of the myriad of POCT projects, refer to the POCT websites listed in Table 1.

Bioartificial organ support for hepatic, renal, and hematologic failure.

The current strategy to the treatment of SIRS and MODS uses a multidisciplinary approach that emphasizes supportive therapy. Herein, we have presented a futuristic approach that focuses on replacing the function of failed organs using bioartificial technology (Table 1). Bioartificial organ technology may allow the intensivist to provide physiologic organ replacement either as a bridge to transplantation or as a "time-buying" element until native organs that have become acutely dysfunctional or nonfunctional in a variety of clinical settings, can recover their function or regenerate their mass. As bioartificial organ technology matures, it is conceivable as an ultimate goal that non-immunogenic bioartificial organs would be miniaturized or redesigned and acutely placed within the intracorporeal space as replacement organs.

Point of care testing informatics. The critical care-hospital interface.

Point of care testing (POCT), a new paradigm in laboratory testing, has recently been introduced to the critical care setting. In this model, laboratory testing is performed in the critical care vicinity by local bedside personnel. POCT devices perform user selected critical care tests on whole blood in a timely and accurate fashion. The POCT data, while used immediately at the bedside, must still be managed in accordance with regulatory guidelines and incorporated into the laboratory or hospital information system. Currently, critical care physicians are not educated and trained in the intricacies of laboratory data management and device interfacing. This article addresses the technical, political, and implementation issues surrounding POCT data management and interfacing as well as the philosophical and practical differences in laboratory data management between the central laboratory and POCT sites.

Pancreaticoduodenectomy for metastatic tumors to the periampullary region.

Although operative resection of metastatic lesions to the liver, lung, and brain has proved to be useful, only recently have there been a few reports of pancreaticoduodenectomies in selected cases of metastases to the periampullary region. In this report we present four cases of proven metastatic disease to the periampullary region in which the lesions were treated by pancreaticoduodenectomy. Metastatic tumors corresponded to a melanoma of unknown primary site, choriocarcinoma, high-grade liposarcoma of the leg, and a small cell cancer of the lung. All four patients survived the operation and had no major complications. Two patients died of recurrence of their tumors, 6 and 63 months, respectively, after operation; the other two patients are alive 21 and 12 months, respectively, after operation. It can be inferred from this small but documented experience, as well as a review of the literature, that pancreaticoduodenectomy for metastatic disease can be considered in selected patients, as long as this operation is performed by experienced surgeons who have achieved minimal or no morbidity and mortality with it.

Saccharomyces cerevisiae cells harboring the gene encoding sarcotoxin IA secrete a peptide that is toxic to plant pathogenic bacteria.

Sarcotoxin IA is a cecropin-type antibacterial protein produced by the flesh fly, Sarcophaga peregrina. Similar to other bactericidal small proteins produced by insects, sarcotoxin IA is released into the hemolymph of larvae and nymphs upon mechanical injury or bacterial infection. The gene (sarco) that encodes this toxin was introduced into Saccharomyces cerevisiae yeast cells and was expressed under a constitutive yeast promoter. The transformed yeast cells were grown in a liquid medium, and a peptide with a similar molecular size to that of the mature sarcotoxin IA was detected in the medium by Western blot analysis. The secreted sarcotoxin-like peptide (SLP) had a potent cytotoxic effect against several bacteria, including plant pathogenic bacteria, similar to the toxic effects of the authentic sarcotoxin IA. Erwinia carotovora was more susceptible to the toxic medium than Pseudomonas solanacearum and Pseudomonas syringae pv. lachrymans. Thus, yeast may be used in the production of such proteins for employment against various bacterial pathogens.

Hearing loss in critical care: an unappreciated phenomenon.

OBJECTIVES: The objectives of this article are to review the physiology of hearing; identify acute pathologic and perceived causes of hearing loss in the adult critically ill patient; and to discuss its evaluation, treatment, and prevention. DATA SOURCES: Computerized bibliographic search of MEDLINE from 1966 to the present of all relevant articles in all languages on acute hearing loss in the adult population. DATA EXTRACTION: Data gathered from studies and reports of acute hearing loss as relates or potentially relates to the peri-intensive care unit (ICU) period. DATA SYNTHESIS: Hearing loss is an infrequent but potentially serious complication associated with critical illness. The causes of hearing loss in the ICU patient include mechanical or accidental trauma, administration of ototoxic medications, local or systemic infections, vascular and hematologic disorders, autoimmune diseases, and environmental noise. Patients who are elderly, have coexisting liver or renal failure, or who are receiving concomitantly administered ototoxic drugs are particularly at risk for developing hearing loss. A thorough assessment of potential causes of hearing loss and audiological examination should be undertaken on all ICU patients suspected of hearing loss. Mechanical, pharmacologic, and environmental strategies are available to decrease the incidence of hearing loss in this patient population. CONCLUSIONS: Hearing loss should be recognized as a potential clinical problem by intensivists. Its causes should be identified and appropriate evaluation and therapy initiated. High risk populations should be identified for preventive measures.

Carboxyhemoglobin and lactate levels do not correlate in critically ill patients.

Endogenous carbon monoxide (CO) is produced in the degradation of heme by heme oxygenase. Studies have shown that hypoxia induces heme oxygenase production of CO in vascular tissue. Because elevated plasma lactate levels are associated with tissue hypoxia, we determined if there was any correlation between lactate and carboxyhemoglobin (COHb) levels in a group of critically ill patients with a high likelihood of hypoxia. In a 7.5-month period, 5322 simultaneous arterial COHb and lactate measurements were performed routinely on 183 patients with a blood gas analyzer in the Department of Veterans Affairs Medical Center, Bronx, New York, Surgical Intensive Care Unit. Sixty-one percent of the patients had elevated lactate levels (> 2.5mmol/L), and 46% had elevated COHb levels (> 1.5%). Lactate levels ranged from 0.12 to 22.7 mmol/L and COHb levels from 0% to 4.8%. There was no correlation between lactate and COHb levels (r = .07 with P < .0001). Levels of endogenous CO do not increase in situations in which lactate production is increased. It is possible that changes in endogenous production of CO may not significantly affect the circulating level of COHb. Although readily available, COHb levels do not seem to be clinically useful as markers of critical illness.

Access problems in laparoscopic cholecystectomy: postoperative adhesions, obesity, and liver disorders.

In the decade since the clinical arrival of laparoscopic cholecystectomy, there have been gratifying improvements in imaging technology and instrumentation, and innovative techniques have evolved. Laboratory-simulator devices are available for basic skills exercises and can at least reasonably mimic the appearance of the gallbladder and some other organs or anatomic regions. Unfortunately, there is no satisfactory method to practice dealing with certain structural abnormalities or disease processes. Because of that, some operations will be particularly difficult and the outcomes will be favorable only with careful planning and capable execution. The experiences and skill level of the surgeon can be enhanced by appropriate mental preparation. As a result, the surgeon will have the opportunity to accomplish the task, both laparoscopically and safely, under circumstances that initially were thought to be inappropriate or impossible for laparoscopy.

Laparoscopic cholecystectomy in pregnancy: a review of published experiences and clinical considerations.

Symptomatic biliary disease during pregnancy may have serious consequences for both the mother and the fetus. Laparoscopic cholecystectomy was felt initially to be contraindicated in pregnancy, but clinical experience accumulated since 1991 has been extremely favorable. Specialists in the areas of anesthesiology, obstetrics and laparoscopic surgery should continue to carefully monitor and analyze practices and outcomes of laparoscopic cholecystectomy during pregnancy. At the present time, there is no consensus regarding several management issues, such as optimal pressure limits for insufflation. Nevertheless, the reported results are quite encouraging and may foretell an improvement in patient care for this special population as dramatic as that achieved by laparoscopic cholecystectomy in others.

Isolyte S, a physiologic multielectrolyte solution, is preferable to normal saline to wash cell saver salvaged blood: conclusions from a prospective, randomized study in a canine model.

OBJECTIVES: The purpose of this study is to compare normal saline with Isolyte S as the wash solutions during high-volume cell saver autologous blood transfusion. Normal saline, the standard wash solution in cell saver autologous blood transfusion, is associated with acid-base and electrolyte derangements. Isolyte S is a physiologic, balanced multielectrolyte crystalloid solution that approximates the electrolyte content of plasma. DESIGN: Open-label, prospective, randomized study. SETTING: Research laboratory in a Department of Veterans Affairs medical center. SUBJECTS: Fourteen mongrel dogs, weighing 22 to 23 kg each. INTERVENTIONS: Fourteen mongrel dogs were prospectively randomized to receive normal saline (n = 7) or Isolyte S (n = 7). Animals were anesthetized, received heparin for anticoagulation, and underwent 18 cycles of cell saver autotransfusion. In each cycle, 125 mL of blood was arterially withdrawn, and washed with either normal saline (mEq/L) (sodium 154, chloride 154) or Isolyte S (mEq/L) (sodium 141, potassium 5, magnesium 3, chloride 98, phosphate 1, acetate 28, and gluconate 23). The washed blood was retransfused. MEASUREMENTS AND MAIN RESULTS: Acid-base and electrolyte analyses were performed throughout the study on the systemic blood of each group and compared. By the end of the study, the Isolyte S group had a normal pH and an increased bicarbonate concentration (mEq/L: normal values 24 to 32; normal saline 9.0 +/- 1.9 vs. Isolyte S 13.2 +/- 3.0 [p < .01]) and an increased magnesium concentration (mg/dL: normal values 1.6 to 2.4; normal saline 1.6 +/- 0.2 vs. Isolyte S 2.2 +/- 0.2 [p < .0001]). Additionally, the Isolyte S group had a lower chloride concentration (mEq/L: normal values 95 to 110; normal saline 130 +/- 9 vs. Isolyte S 117 +/- 7 [p < .02]) and a lower potassium concentration (mEq/L: normal values 3.5 to 5.0; normal saline 4.4 +/- 0.5 vs. Isolyte S 3.7 +/- 0.3 [p < .01]). There were no significant differences between normal saline or Isolyte S in the values of PCO2, lactic acid, sodium, total and ionized calcium, inorganic phosphorus, total protein, albumin, hemoglobin, and hematocrit. CONCLUSIONS: Fewer systemic acid-base and electrolyte derangements were observed when blood was washed with Isolyte S. Differences between the normal saline and Isolyte S groups are ascribed primarily to the constituents of the wash solution. We conclude that Isolyte S, a physiologic, balanced, multielectrolyte solution, should be considered as the wash solution in high-volume autologous cell saver blood processing and transfusion.