The certifying examination of the american board of surgery: the effect of improving communication and professional competency: twenty-year results.

PURPOSE: In 1985, a small research group identified variables affecting applicant success on the oral Certifying Examination (CE) of the American Board of Surgery (ABS). This led to the design of an oral examination course first taught in 1991. The success of and need for this program led to its continuation. The results from the first 10 years were presented at the 2001 Association of Program Directors in Surgery annual meeting.(1) We now report the outcomes for the course of the second 10 years as measured by success on the CE. METHODS: Thirty-six courses were held over 20 years. There were 57 invited faculty from 27 general surgery programs throughout the United States and Canada. The participant-to-faculty ratio ranged from 16:7 to 5:1 in the newer 3-day format (2007). Courses were offered at sites that replicated the actual examination setting. Each course included (1) pretest and posttest examinations, (2) analysis of case presentation skills, (3) measurement of communication apprehension, (4) 1:1 faculty feedback, (5) small-group practice sessions, (6) individual videotaping, (7) didactic review of specific behaviors on examinations, (8) a debrief session with two faculty members, and (9) a written evaluative summary that included an improvement strategy. RESULTS: There were 36 courses with 326 participants (30-54 years). Follow-up data are available for 225 participants. Trends were analyzed between 1991-2001 and 2002-2011. As resident performance on the CE increased in importance, applicant profiles changed from those who had previously failed (1991-2001) to residents identified by program directors as needing assistance (52%). Since 2002, most course participants (69%) who had failed the CE had completed at least 1 other review course. Participants reported more significant stressors (2002-2011) 9%, but communication apprehension remained the same. As a result, individual counseling for anger and family stressors was integrated into the course. The perception of knowledge deficits was associated with those who enrolled in fellowship training and delayed their examination. The recent groups exhibited more professionalism and articulation issues related to performance. Five surgeons (2002-2011) were asked not to return to the course because of severe knowledge deficiencies or ethical/behavioral issues based on faculty evaluations. Although complete follow-up of all participants was not possible (only 225/326), the success rate among those providing follow-up was 97% for those who followed their remediation plan, giving 218/326, a worse-case pass rate of 67%. CONCLUSION: Communication and professionalism deficits are still common in those struggling with the CE, Early identification of those at risk of failing by program directors who are documenting the competencies may promote earlier interventions and thus lead to success. This program continues to be effective at identifying behaviors that interfere with success on the CE of the ABS.

When blood is not an option: factors affecting survival after the use of a hemoglobin-based oxygen carrier in 54 patients with life-threatening anemia.

BACKGROUND: In consenting Jehovah's Witness patients and others for whom blood is contraindicated or not available, hemoglobin-based oxygen carrier (HBOC)-201 may enable survival in acutely anemic patients while underlying conditions are treated. METHODS: Survival factors were identified in a multicenter, unblinded series of severely anemic "compassionate use" patients receiving available standard treatment plus consultant-supported HBOC-201 administration by novice users. Predictors of outcome were sought and compared between survivors and nonsurvivors. A compound variable, hemoglobin-duration deficit product was used to describe the interactive clinical effects of severity and duration of anemia. Mortality,correlations between patient characteristics, and survival to hospital discharge were determined from patient records. RESULTS: Fifty-four patients (median age 50 years) with life-threatening anemia (median hemoglobin concentration at time of request = 4 g/dL) received 60 to 300 g HBOC-201.Twenty-three patients (41.8%) were discharged. Intraoperative blood loss (45%), malignancy(18%), and acute hemolysis (13%) were the prevailing reasons for anemia. Time from onset of anemia (< or = 8 g/dL) to HBOC-201 infusion was shorter for survivors than nonsurvivors (3.2 vs 4.4 days, P = 0.027). Mean hemoglobin levels before HBOC-201 infusion in survivors and nonsurvivors were 4.5 and 3.8 g/dL, respectively (P = 0.120). No serious adverse event was attributed to HBOC-201. The hemoglobin-duration deficit product separated survivors from nonsurvivors. Cancer and renal disease were associated with nonsurvival. CONCLUSION: Earlier, compared with later, administration by inexperienced users of HBOC-201 to patients with anemia was associated with improved chances of survival of acutely bleeding and hemolyzing patients. Survival was more likely if the duration and magnitude of low hemoglobin was minimized before treatment with HBOC-201.

Relative roles of heme-irons and globin-thiols in the genesis of acellular hemoglobin mediated vasoconstriction.

In addition to heme-irons, reactive (beta-globin thiols (betaCys93s) of hemoglobin (Hb) also have been shown to interact with endogenous nitric oxide (NO) thereby contributing to vascular tone regulation. What relative roles do these NO binding sites contribute to the overall Hb-mediated vasoactivity? Several test Hbs with either or both the NO binding sites preliganded or blocked were prepared and tested in a rat thoracic aortic ring model. Hbs tested were: NEM-Hb (ferrous Hb with masked thiols), HbNO (ferrous Hb preliganded with NO), Hb(+)CN (ferric Hb liganded with CN(-)), NEM-HbNO and NEM-Hb(+)CN (Hbs with both heme-iron and cysteine sites preliganded or blocked). Typically, >0.2 microM control Hb significantly increased isometric tension in agonist stimulated vessel rings (58.1 +/-7.0% over baseline). At comparable concentrations, NEM-Hb also caused a significant contraction (50.7+/-9.5%) while HbNO and Hb(+)CN did not (-5.5+/-6.0% and -3.7+/-4.6%, respectively). For these Hbs, masking thiols as well did not significantly alter respective vascular effects. Ferrous sperm whale myoglobin (Mb), which has no reactive thiol, elicited a significant contraction (55.1+/-13.2%) while metMb did not (-0.8+/-3.2%), suggesting the relative importance of heme-iron ligand and oxidation state in Hb vasoactivity. Additionally, ferrous or ferric equine heart cytochrome-C, a heme protein with no readily available heme-iron and cysteine binding sites, did not elicit notable contraction. Human Hb variants in which (betaCys93s are deleted or substituted with non-cysteine residues did not reveal any documented significant hemodynamic abnormalities. These results indicate that reactive globin-thiols do not appear to play a prominent role relative to heme-irons in Hb-mediated vasoconstriction.

The ideal blood substitute.

There is an ongoing need for a red cell substitute, an oxygen-carrying solution to use primarily as a bridge until red cells are available. The replacement of oxygen-carrying capacity has driven the field of research, primarily with the development of hemoglobin-based oxygen carriers, but they are less than ideal. The formulation of a complete substitute for blood, if it can be realized, must take into account all the cellular and molecular components of the immune and coagulation systems.

HBOC-201: the multi-purpose oxygen therapeutic.

Clinical and preclinical studies have revealed a diverse array of indications in which the effectiveness of HBOC-201 has been demonstrated or appears likely. Included among these are indications involving cardiac and peripheral ischaemia in which this oxygen therapeutic may prove to be an important tool in the armamentarium of the cardiologist and surgeon. Preclinical studies and clinical trials are under way to further delineate and optimise the role of HBOC-201 as an oxygen therapeutic in cardiovascular medicine.

Clinical contextualization and the assessment of adverse events in HBOC trials.

Establishing an acceptable safety and efficacy profile for hemoglobin based oxygen carriers, HBOCs, is essential. Understanding the data that describes an HBOC "safety profile" requires consideration beyond counting "events" typically associated with intent to treat analysis. The imputation of causation from numerical counts alone, without clinical context, is an incomplete description of a complex situation. Clinical contextualization provides a greater understanding of the clinico-pathological processes involved. Generating alternative hypotheses for the origin of the events, apart from the drug, patient co-morbidities, situational and disease demands, could include protocol design, failure to provide mitigation strategies, patient management issues, or inadequate education of investigators. How clinical contextualization can provide insight for the interpretation of significant safety profile events is discussed in the context of a large phase III clinical trial where an appreciation of factors underlying the differences between intent to treat analysis and other approaches is discussed.

HBOC-201 as an alternative to blood transfusion: efficacy and safety evaluation in a multicenter phase III trial in elective orthopedic surgery.

BACKGROUND: The ability of hemoglobin based oxygen carrier-201 (HBOC-201) to safely reduce and/or eliminate perioperative transfusion was studied in orthopedic surgery patients. METHODS: A randomized, single-blind, packed red blood cell (PRBC)-controlled, parallel-group multicenter study was conducted. Six hundred eighty-eight patients were randomized to treatment with HBOC-201 (H, n = 350) or PRBC (R, n = 338) at the first transfusion decision. Primary endpoints were transfusion avoidance and blinded assessment [Mann-Whitney estimator (MW)] of safety noninferiority. Groups were compared directly and by paired/matching group analyses predicated on a prospectively defined dichotomy [treatment success (HH) vs. failure (HR)] in the H arm and an equivalently defined dichotomy [3 (R3+) units PRBC] in the R arm, based on need (moderate vs. high) for additional oxygen carrying capacity. RESULTS: A total of 59.4% of patients in the H arm avoided PRBC transfusion. Adverse events (8.47 vs. 5.88), and serious adverse events (SAEs) (0.35 vs. 0.25) per patient were higher in the H versus R arms (p < 0.001 and p < 0.01) with MW = 0.561 (95 CI 0.528-0.594). HH versus R3- had identical (0.14) serious adverse events/patient and a MW = 0.519 (95% confidence limit 0.481-0.558), whereas the incidence was higher (0.63 vs. 0.47) for HR versus R3+ with a MW = 0.605 (95% confidence limit 0.550-0.662). Age (>80 years), volume overload and undertreatment contributed to this imbalance. CONCLUSION: HBOC-201 eliminated transfusion in the majority of subjects. The between arms (H vs. R) safety analysis was unfavorable and likely related to patient age, volume overload, and undertreatment and was isolated to patients that could not be managed by HBOC-201 alone. However, patients <80 years old with moderate clinical need may safely avoid transfusion when treated with up to 10 units of HBOC-201.

Toward 21st century blood component replacement therapeutics: artificial oxygen carriers, platelet substitutes, recombinant clotting factors, and others.

In this brief overview, recent progress and current status of blood substitute research and development is summarized. Current blood substitute development efforts are focused on red blood cell substitutes but substitutes for platelets and other blood components are also in progress. Red cell substitutes currently in various stages of development are semi-synthetic or synthetic oxygen carriers that include "stealth" or "masked" red cells, hemoglobin-based oxygen carriers and perfluorocarbon-based oxygen carriers. Artificial platelets (or platelet substitutes) are in early stages of development and include human platelet fragments or particles of synthetic/semi-synthetic materials or recombinant human serum albumin coupled with platelet surface receptor fragments. Of note, some recombinant clotting factors (Factors VII, VIII, IX) have already been successfully developed and licensed for treatment of hemophilia. In addition, some future approaches and prospects of blood component replacement therapeutics are discussed.

Hemoglobin mediated contraction of the isolated rat thoracic aorta: why is precontraction necessary?

A primary mechanism for the hemoglobin (Hb) mediated vascular contraction is believed to be Hb scavenging of endothelial nitric oxide (NO). In the isolated rat thoracic aorta, however, the Hb mediated contraction occurs only after an agonist-induced precontraction. Why? To investigate the question, a rat thoracic aortic ring model was used. Isometric vessel ring tension responses to selected pharmacologic contractile agonists were assessed and compared. The Hb mediated additional contraction occurred in vessel rings precontracted with adrenergic agonists as well as other types of contractile agonists. Even after agonist induced contraction, removal of the vascular endothelium or inhibition of endothelial NO synthase with Nomega-nitro-L-arginine methyl ester prevented the Hb mediated additional contraction. Additionally, imposition of passive tension without an agonist pretreatment did not allow Hb mediated contraction. In conclusion, in the isolated rat thoracic aorta, the endothelial NO synthase is minimally active in the basal state but upregulated upon treatment with a contractile agonist. This may explain why the Hb mediated additional contraction occurs only after an agonist induced precontraction.

Mechanisms for vasoconstriction and decreased blood flow following intravenous administration of cell-free native hemoglobin solutions.

Acellular free hemoglobin-based oxygen carriers (HBOC) are being developed as red cell substitutes. However, following intravenous administration of some HBOC, decreased systemic blood flow and decreased functional capillary density have been observed. In isolated blood vessels, hemoglobin (Hb) in solution free of erythrocyte membranes has been shown to elicit vascular contraction. Therefore, the decreased blood flow and functional capillary density may be due to inherent vasoactive property of native Hb. There are two plausible mechanisms for the Hb-mediated vasoconstriction: nitrosylation of heme-irons and S-nitrosation of reactive beta-chain cysteines (Cys93beta). In this study, we investigated whether Hb Cys93beta thiols play a role in Hb-mediated vascular contraction using functional bioassays with isolated rat thoracic aorta. To better define the roles of globin thiols and heme-iron, Hbs modified at the heme-iron and/or Cys93beta sites were prepared and their vasoactivities tested. In addition, vasoactivities of natural heme proteins with heme and/or cysteine sites unavailable for NO reaction were also examined.

Active myogenic tone: a requisite for hemoglobin mediated vascular contraction?

Acellular free hemoglobin (Hb), when intravenously administered to animals and humans, elicits vascular contraction. A primary mechanism for the Hb mediated vasoconstriction is Hb scavenging of nitric oxide (NO), a potent relaxation factor, constitutively secreted by the vascular endothelium. However, in the isolated rat thoracic aorta in basal state, Hb does not elicit contraction. To investigate this apparent paradox, we assessed isolated rat aortic ring isometric contraction responses to Hb under different myogenic tone states: (1) following equilibration at a submaximal tension, (2) following agonist induced contraction, or (3) following a passive mechanical stretch. In vessel rings at basal state, Hb as high as 4 microM did not elicit any measurable contractions. In contrast, in vessel rings tone enhanced with norepinephrine, Hb as low as 0.1 microM Hb elicited a significant additional contraction. In vessel rings with passively induced tone, 4 microM Hb did not elicit a notable contraction. Similarly, in vessel rings in basal state, 0.17-1 mM acetylcholine, a NO dependent vasodilator, did not elicit relaxation. In these vessel rings, exogenous 8-Br-cGMP, a membrane permeable cGMP analog, did not elicit relaxation. In conclusion, in the isolated rat thoracic aorta, Hb mediated contraction may be contingent upon the state of myogenic tone.

Temporal effect of hemoglobin resuscitation on sepsis survival.

Hemoglobin (Hb)-based oxygen carriers are promising resuscitation fluids for hemorrhagic shock. However, infusion of large amounts of Hb-based material could interfere with reticuloendothelial function potentiating postresuscitation sepsis mortality. We investigated the temporal relationship between hemorrhage-resuscitation and sepsis survival. Male SD rats were subjected to hemorrhage and resuscitated with shed blood volumes of purified human hemoglobin solution (HS). Sepsis was induced by cecal ligation and puncture (CLP) 24 h before, 0, 24, or 72 h after hemorrhage/resuscitation (H/R) and survival was monitored. In additional animals with or without Hb resuscitation, hepatic heme oxygenase-1 (HO-1) gene expression and HO activity were assessed. Seven-day survival for animals resuscitated with HS prior to sepsis induction was significantly higher than other groups. Animals resuscitated with HS showed hepatic HO-1 gene expression while non-HS resuscitated animals did not. In addition, hepatic HO activity levels were significantly higher in HS resuscitated animals than non-HS resuscitated animals. In conclusion, HS resuscitation does not appear to enhance postresuscitation sepsis mortality. Rather, when conducted concomitantly or prior to sepsis, HS resuscitation appears to improve survival from a subsequent sepsis challenge.

Civilian uses of hemoglobin-based oxygen carriers.

This article briefly discusses a few key issues related to transfusion, the concept of hemoglobin-based red blood cell substitutes (HBOCs), and some parameters useful in evaluating the current properties of solutions. Potential uses of HBOCs in civilian applications are identified and listed. Use of HBOCs as a hemodiluent for intraoperative autologous blood donation (IAD) is a particular application that has relevance in many surgical settings and this is discussed in some detail. Data from a Phase III clinical trial is presented to show the potential for avoiding the use of allogeneic blood and blood products in a clinical model of large volume red cell use. Extrapolation to a general use model, primarily based in the potential for surgery, will be noted. Some general parametric values of HBOCs are presented. These values are by no means considered optimal for all HBOCs and are subject to exploration, fine tuning, correction, or even rejection.

Artificial oxygen carriers as red blood cell substitutes: a selected review and current status.

Two distinct approaches are being explored in red blood cell substitute (RCS) development: hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbon-based oxygen carriers (PFBOCs). HBOCs are based on intra- and/or intermolecularly "engineered" human or animal hemoglobins (Hbs), optimized for O2 delivery and longer intravascular circulation. Some are currently being evaluated in Phase II/III clinical studies. PFBOCs are aqueous emulsions of perfluorocarbon derivatives that dissolve relatively large amounts of O2. A PFBOC based on a 60% (wt/vol) emulsion of perfluorooctyl bromide has been evaluated in Phase II/III clinical trials. Although current PFBOC products generally require patients to breathe O2 enriched air, they render certain advantages since they are totally synthetic. This article provides a short review of the basic principles, approaches, and current status of RCS development. Results of preclinical and clinical studies including recent Phase II/III clinical studies are discussed.