Comparative effectiveness and safety of drug therapy for pulmonary arterial hypertension: a systematic review and meta-analysis.

BACKGROUND: Current treatments for pulmonary arterial hypertension (PAH) have been shown to improve dyspnea, 6-min walk distance (6MWD), and pulmonary hemodynamics, but few studies were designed to compare treatment regimens or assess the impact of treatment on mortality. METHODS: We conducted a systematic review to evaluate the comparative effectiveness and safety of monotherapy or combination therapy for PAH using endothelin receptor antagonists, phosphodiesterase inhibitors, or prostanoids. We searched English-language publications of comparative studies that reported intermediate or long-term outcomes associated with drug therapy for PAH. Two investigators abstracted data and rated study quality and applicability. RESULTS: We identified 28 randomized controlled trials involving 3,613 patients. We found no studies that randomized treatment-naive patients to monotherapy vs combination therapy. There was insufficient statistical power to detect a mortality difference associated with treatment. All drug classes demonstrated increases in 6MWD when compared with placebo, and combination therapy showed improved 6MWD compared with monotherapy. For hospitalization, the OR was lower in patients taking endothelin receptor antagonists or phosphodiesterase-5 inhibitors compared with placebo (OR, 0.34 and 0.48, respectively). CONCLUSIONS: Although no studies were powered to detect a mortality reduction, monotherapy was associated with improved 6MWD and reduced hospitalization rates. Our findings also suggest an improvement in 6MWD when a second drug is added to monotherapy.

The distribution of recombination repair genes is linked to information content in bacteria.

The concept of a 'proteomic constraint' proposes that the information content of the proteome exerts a selective pressure to reduce mutation rates, implying that larger proteomes produce a greater selective pressure to evolve or maintain DNA repair, resulting in a decrease in mutational load. Here, the distribution of 21 recombination repair genes was characterized across 900 bacterial genomes. Consistent with prediction, the presence of 17 genes correlated with proteome size. Intracellular bacteria were marked by a pervasive absence of recombination repair genes, consistent with their small proteome sizes, but also consistent with alternative explanations that reduced effective population size or lack of recombination may decrease selection pressure. However, when only non-intracellular bacteria were examined, the relationship between proteome size and gene presence was maintained. In addition, the more widely distributed (i.e. conserved) a gene, the smaller the average size of the proteomes from which it was absent. Together, these observations are consistent with the operation of a proteomic constraint on DNA repair. Lastly, a correlation between gene absence and genome AT content was shown, indicating a link between absence of DNA repair and elevated genome AT content.

Cervical cancer awareness and screening in Botswana.

OBJECTIVE: Cervical cancer remains a leading cause of death in many developing countries because limited screening by Papanicolaou (Pap) smear. We sought to better understand women's beliefs about cervical cancer and screening in Botswana, a middle-income African country with high rates of cervical cancer. METHODS: We interviewed 289 women attending general medicine or human immunodeficiency virus (HIV) clinics, where Pap testing was available, in Gaborone, Botswana, in January 2009. RESULTS: About three fourths (72%) of the respondents reported having ever had a Pap smear; HIV-positive women were more likely to have had a Pap smear than HIV-negative women (80% vs 64%; odds ratio, 1.97; 95% confidence interval, 1.10-3.55). Screening was also more common among women who were older, had higher incomes, or had heard of cervical cancer. Almost all participants reported a desire to have a Pap smear. Reasons included to determine cervical health (56%), to improve overall health (33%), and to obtain early treatment (34%). About half (54%) of the respondents said they did not know what causes cervical cancer, and almost none attributed the disease to human papillomavirus infection. CONCLUSIONS: Study findings can inform interventions that seek to increase cervical cancer awareness and uptake of screening as it becomes more widely available.

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.

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.

Comparison of 7 versus 10 days of antibiotic therapy for hospitalized patients with uncomplicated community-acquired pneumonia: a prospective, randomized, double-blind study.

The objective of this study was to compare the outcome of 7 versus 10 days of antibiotic therapy for inpatients with moderately severe community-acquired pneumonia (CAP). A prospective, randomized, double-blind study with a follow-up period of 42 days was conducted. Fifty-two veterans were treated with 2 days of cefuroxime at 750 mg intravenously every 8 hours followed by group 1, 8 days oral therapy, and group 2, 5 days oral therapy followed by 3 days of placebo. Oral therapy consisted of cefuroxime axetil at 500 mg every 12 hours. No difference was seen in cure rates: 20 of 22 (90.9%) patients in group 1 and 21 of 24 (87.5%) patients in group 2. There were no late recurrences. Potential US cost-savings is $27.2 million. Inpatients with moderately severe CAP can be treated with 2 days of intravenous antibiotics followed by 5 additional days of oral antibiotics. Longer treatment duration prolongs the cost of care, without increasing the cure rate or decreasing the pneumonia recurrence rate.

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.

Cell saver autologous transfusion: metabolic consequences of washing blood with normal saline.

OBJECTIVE: To evaluate acid-base and electrolyte changes in high volume cell saver autologous blood transfusion when normal saline (0.9% NaCl) is used as the wash solution. DESIGN: Open-label study. MATERIALS AND METHODS: Nine anesthetized and anticoagulated mongrel dogs underwent 15 cycles of cell saver autologous blood transfusion. Eight percent of the circulating blood volume (125 mL) was withdrawn, washed with normal saline, and retransfused for each cycle. MEASUREMENTS AND MAIN RESULTS: Analyses of acid-base, electrolyte, and hematologic parameters were performed on both systemic and the washed blood. The washed blood had increased levels of sodium and chloride. There were decreased levels in pH, Pco2, total CO2 (bicarbonate), lactic acid, potassium, total and ionized calcium, magnesium, inorganic phosphorus, total protein, and albumin. Systemically, in the animals, by the end of the study, there were significant increases in the levels of chloride, inorganic phosphorus, hemoglobin, and hematocrit and significant decreases in the levels of pH, total CO2, total and ionized calcium, magnesium, total protein, and albumin. CONCLUSIONS: Acid-base, electrolyte, and hematologic changes occur when normal saline is used as the wash solution in high volume cell saver autologous blood transfusion. The washed blood with its elevation of sodium and chloride appears to reflect the constituents of the wash solution, normal saline. The depletion in the washed blood of PCO2, total CO2, potassium, total calcium, ionized calcium, magnesium, phosphorus, total protein, and albumin we feel is because of the absence of these electrolytes in the wash solution and their physical removal during salvaged blood separation and washing. The systemic acid-base and electrolyte changes primarily reflect the electrolyte pattern of the reinfused washed blood except for inorganic phosphorus. Inorganic phosphorus was maintained systemically, despite its wash out in the cell salvage process. This paradoxical finding may be caused by intracellular to extracellular inorganic phosphorus flux caused by the progressive systemic metabolic acidosis.

Critical care medicine: observations from the Department of Veterans Affairs' intensive care units.

OBJECTIVES: To study the critical care medicine programs of the Department of Veterans Affairs. DESIGN: Survey study. SETTING: Data were obtained from 85% (113/133) of the acute care hospitals of the Department of Veterans Affairs. MAIN MEASURES: Intensive care unit (ICU) administrative and patient demographics, physician training and certification, participation in critical care medicine programs and research. RESULTS: Analyses were performed on 78% (2021) of Department of Veterans Affairs' ICU beds. Mortality (%) was highest in medical ICUs (11.7 +/- 0.8) and lowest in coronary care units (5.0 +/- 0.5) and surgical ICUs (5.5 +/- 0.5). The average length of stay (days) was highest in medical ICUs (5.6 +/- 0.6) and lowest in combined medical-coronary care units (4.2 +/- 0.4) and coronary care units (4.3 +/- 0.5). The majority of ICU directors have internal medicine training. A minority of ICU directors are formally trained in critical care medicine or are board eligible or certified in critical care medicine. The majority of fellows in the ICU are pulmonary or cardiac fellows; a minority are critical care medicine fellows. Accredited critical care medicine fellowship training programs were found in only 17% (19/113) of responding Department of Veterans Affairs' institutions. Seventy-three percent (82/113) of ICUs in responding hospitals had published fewer than five publications between 1987 and 1990. CONCLUSIONS: The results of this study suggest that the Department of Veterans Affairs would benefit from increasing the number of critical care medicine board eligible/certified directors, and increasing the program's participation in accredited critical care medicine fellowship training programs and research endeavors. Overall, however, we conclude that the Department of Veterans Affairs' critical care medicine program is at least comparable to nationwide ICUs in the parameters evaluated.

Postoperative hypertension: a prospective, placebo-controlled, randomized, double-blind trial, with intravenous nicardipine hydrochloride.

Nicardipine hydrochloride, a new calcium channel blocker for intravenous use, has been compared with placebo in a prospective, randomized, double-blind trial on postoperative hypertension. Of 175 patients who signed preoperative consent, 24 (13.7%) met entry criteria. Hypertension was significantly better controlled in nicardipine-treated patients compared with those receiving placebo (93% versus 30%, p less than 0.05). All the placebo failures were subsequently successfully treated with nicardipine. There were no significant complications in either group. The authors conclude that nicardipine HC1 is an effective, safe therapy for postoperative hypertension. Further studies are now indicated comparing it with other drugs currently used to treat this condition.

Nicardipine infusion for postoperative hypertension after surgery of the head and neck.

The therapy of postoperative hypertension (POH) after head and neck surgery was evaluated in a prospective, randomized, double-blind trial. Nicardipine hydrochloride, a Ca channel-blocker for iv use, was compared with placebo. Patients were initially randomized to receive nicardipine infusion or placebo. Those not responding to placebo were given nicardipine infusion on an open basis. Hypertension was significantly better controlled in patients treated with nicardipine infusion compared with placebo (83% vs. 22%, p less than .002). Subsequently, six (86%) of seven of the placebo failures were successfully treated with nicardipine. There were no significant complications in either group. We conclude that the titratable infusion of nicardipine is an effective and safe method for the control of POH after surgery of the head and neck. Further studies are now warranted comparing nicardipine with other drugs currently used to treat this condition.

Visual compatibility of enalaprilat with commonly used critical care medications during simulated Y-site injection.

Physical incompatibility studies between an intravenous angiotensin-converting enzyme inhibitor, enalaprilat, and potentially coadministrable ICU medications have been performed. Forty-one medications and four solutions were evaluated. The medications were anesthetic/narcotics, antibiotics, an anticoagulant, a bronchodilator, electrolyte solutions, fluids, H-2 receptor blocking agents, steroids and vasoactive agents. There was no turbidity, precipitation, or color change caused by the admixing of enalaprilat with any of the 45 agents studied. This study did not take bioavailability into consideration.

The compatibility of nicardipine hydrochloride injection with various ICU medications during simulated Y-site injection.

Physical incompatibility studies between an intravenous calcium channel antagonist, nicardipine hydrochloride, and potentially coadministerable ICU medications have been performed. Forty-one medications and four solutions were evaluated. The medications were anesthetic/narcotics, antibiotics, an anticoagulant, a bronchodilator, electrolyte solutions, fluids, H2 receptor blocking agents, steroids and vasoactive agents. Of the forty-five substances, three showed evidence of physical incompatibility as manifested by turbidity, precipitation, or color change. All three were antibiotics. These were ampicillin, ampicillin/sulbactam sodium, and cefoperazone. We conclude that until bioavailability studies are performed these three antibiotics should not be coadministered with nicardipine HCl.

Permanent visual display exhibits. A supplementary instructional technique in critical care education.

The discipline of critical care is being challenged to provide ongoing education to the various groups of critical care health providers. Traditional modalities of instruction may not suffice as unique circumstances exist in the practice and daily delivery of patient care. These unique circumstances include a never-ending introduction of new devices, tubes, and catheters into practice. In addition, the intensive care setting features a wide variability of work experience, a high turnover rate of personnel, variable cognitive approaches to understanding technical devices, and a stressful workplace. In their surgical intensive care unit, the authors have developed a set of permanent visual display exhibits. These exhibits were designed to specifically address the above problems and serve as a supplementary mode of education for our diverse medical, nursing, and technical staff. The exhibits may provide an example for other intensive care units and educators.

Urban-rural differences in coronary heart disease in a low incidence area. The Puerto Rico heart study.

This report explores coronary heart disease (CHD) risk factors and the incidence of new CHD events developing over a two and one-half year period in 8793 urban and rural Puerto Rican men aged 45--64 years. Rural men had a lower average blood pressure, serum cholesterol, blood sugar, heart rate and relative weight than urban men. They were more active physically and although more of them smoked, they smoked fewer cigarettes than urban dwellers. The age-adjusted CHD incidence rate for urban men was 1.5 times that of rural men. Among rural areas the most rural had the lowest incidence. Among urban areas there was a suggestive trend of increasing incidence with degree of urbanization. Differences in conventional risk factors, while substantial, do not entirely explain the modest differences in incidence. There also appeared to be a relation with geographic mobility. Urban men who had always lived in the same area had an incidence rate as low as that for rural men whereas recent rural migrants to urban areas had the highest rates of all.