A comparison of initial monotherapy with norepinephrine versus vasopressin for resuscitation in septic shock.

BACKGROUND: Early goal-directed therapy is a time-sensitive therapeutic algorithm with a tiered approach to target hypoperfusion and cardiovascular collapse within the first 6 hours of septic shock. The Surviving Sepsis Campaign guidelines recommend norepinephrine or dopamine as the initial vasoactive agent for resuscitation in septic shock, reserving the administration of vasopressin as adjunctive therapy. OBJECTIVE: To determine whether vasopressin was noninferior to norepinephrine as the initial vasopressor to achieve a mean arterial pressure (MAP) goal in the first 6 hours of shock onset. METHODS: This retrospective cohort study evaluated adults who received monotherapy with either norepinephrine or vasopressin as initial vasoactive therapy for the management of septic shock. Patients were excluded if the treatment arm was not monotherapy, if they were admitted to a cardiology or cardiothoracic surgery service, or if they lacked a comparator-based 1:1 frequency matching. RESULTS: A total of 130 patients were included, 65 in each treatment arm. The proportion of patients who achieved a goal MAP in the vasopressin group was 63% (95% CI 51%-75%) and was 67.7% (95% CI 56%-79%) in the norepinephrine group. This observed difference between goal MAP attainment did not exceed the predefined noninferiority margin of -25% (CI for 4.7% difference -21.2% to 12%), suggesting noninferiority of vasopressin. No significant difference was identified between vasopressin and norepinephrine for final mean (SD) MAP achieved (75 [9.6] and 76.0 [8.2] mm Hg, respectively; p = 0.06) or the mean total change from baseline MAP to goal (14.1 [8.4] and 15.1 [9.1] mm Hg, respectively; p = 0.6). CONCLUSIONS: Vasopressin was noninferior to norepinephrine for the achievement of a MAP goal in the first 6 hours from onset of septic shock. Further prospective analysis is warranted; however, the results are useful for consideration of alternative vasopressors in the setting of drug shortages.

Effect of periarticular corticosteroid injections during total knee arthroplasty. A double-blind randomized trial.

BACKGROUND: Multimodal pain-control protocols that include periarticular injections have been reported to decrease pain and improve early outcomes following total knee arthroplasty. While injections containing a corticosteroid have been demonstrated to be safe and effective, we are not aware of any randomized trials in which the specific effect of the corticosteroid on early postoperative outcomes has been evaluated. The purpose of this double-blind study was to compare the clinical efficacy of periarticular injections consisting of bupivacaine, morphine, epinephrine, clonidine, and cefuroxime as well as a corticosteroid (methylprednisolone acetate) with the efficacy of periarticular injections consisting of the same agents but without the inclusion of a corticosteroid. METHODS: Seventy-six patients were randomized to either the no-steroid group (thirty-seven patients) or the steroid group (thirty-nine patients). Pain and narcotic consumption during the inpatient stay and the length of the hospital stay were recorded. Knee Society scores, the range of motion, and the occurrence of any complications were recorded preoperatively and at six and twelve weeks after the surgery. RESULTS: The hospital stay was significantly shorter for patients in the steroid group (2.6 days compared with 3.5 days in the no-steroid group; p = 0.01). No significant group differences in terms of pain, narcotic consumption, outcome scores, or motion were identified. There were three complications in the steroid group: two patients required a manipulation under anesthesia, and the knee joint became infected in another patient, leading to numerous complications and ultimately death. CONCLUSIONS: The periarticular injection of a corticosteroid may reduce the length of the hospital stay following total knee arthroplasty, but it does not appear to improve pain relief, motion, or function in the early postoperative period. While we cannot definitively state that the corticosteroid was a causative factor in the development of the infection at the site of the prosthetic joint, we cannot rule it out either, which raises concern regarding the role of corticosteroids in perioperative pain management following total knee arthroplasty.

Impact of nicotine replacement therapy on postoperative mortality following coronary artery bypass graft surgery.

BACKGROUND: Nicotine replacement therapy (NRT) has recently been associated with increased mortality in patients in medical intensive care units (ICUs). Although NRT is frequently used in cardiothoracic surgery patients, no safety data exist for use in this population. OBJECTIVES: To ascertain the impact of NRT on in-hospital mortality following coronary artery bypass graft (CABG) surgery. METHODS: This was a retrospective matched cohort pilot study in a 22-bed cardiothoracic surgery ICU. Patients prescribed transdermal NRT after CABG were randomly selected and matched to current smokers not prescribed NRT according to Acute Physiology and Chronic Health Evaluation II scores (N = 134). Data on comorbid conditions and pack-year history were also obtained. To compare these patients with nonsmoking patients, a larger unmatched population was also evaluated. The total number of patients prescribed NRT, current smokers not prescribed NRT, and nonsmokers who were evaluated in our study was 2057. RESULTS: Sixty-seven NRT patients were well matched with 67 current smokers in terms of baseline demographics and procedures. Mortality was nonsignificantly higher in the NRT group versus the non-NRT smoker group (4.5% vs 0.0%; p = 0.080). In an evaluation of a larger population controlled for differences in baseline characteristics, an increase in mortality due to NRT was found (OR 6.06; 95% CI 1.65 to 22.21). In an a priori subgroup of the overall population, mortality was significantly higher in patients receiving NRT after off-pump CABG versus smokers not receiving NRT (OR 6.49; 95% CI 1.29 to 32.56). CONCLUSIONS: The use of NRT in a postoperative CABG surgery population resulted in a significant increase in mortality when adjusted for baseline characteristics. Patients receiving NRT after off-pump cardiac surgery may be particularly susceptible. Additional evaluation in large patient cohorts with prospective controls is warranted.

Implications of using modification of diet in renal disease versus Cockcroft-Gault equations for renal dosing adjustments.

PURPOSE: The drug-dosing implications of using modification of diet in renal disease (MDRD) versus Cockcroft-Gault equations were analyzed. METHODS: This retrospective, cohort-controlled study evaluated the implications of using MDRD versus Cockcroft-Gault equations for renal dosing adjustments in patients with stage III-V chronic kidney disease. Dosing simulations were completed for each patient using both MDRD and Cockcroft-Gault methods and then compared to published manufacturer dosing recommendations. Bland-Altman analysis assessed agreement of MDRD and Cockcroft-Gault estimates. Contingency tables were used to evaluate the clinical relevance of dosing adjustments in terms of medication overdoses and underdoses. RESULTS: Data from 4698 patients with stage III-V chronic kidney disease were analyzed. Use of the MDRD equation overestimated the need for dosing adjustments for patients with creatinine clearance (CL(cr)) values of <30 mL/min/1.73 m(2) and underestimated the need for patients with a CL(cr) of >50 mL/min/1.73 m(2). For medication-dosing thresholds, MDRD was associated with an underdose rate of 7.3% and an overdose rate of 9.6% (p < 0.01 for both). For MDRD adjustments within medication-dosing ranges, both overdoses and underdoses occurred in up to 12.4% (p < 0.01). Total dosing errors for MDRD ranged from 9.8% to 18.2%, depending on the medication (p < 0.01). CONCLUSION: Significant variability exists between the MDRD and Cockcroft-Gault equations for spot dosing adjustments. Use of MDRD estimates with current manufacturer dosing guidelines may result in subtherapeutic medication therapies for patients with stage IV or V disease and supratherapeutic therapies for patients with stage III disease.

Continuous versus intermittent infusion of prophylactic cefoxitin after colorectal surgery: a pilot study.

STUDY OBJECTIVE: To compare 30-day postoperative surgical site infections (SSIs) and rates of antibiotic discontinuation within 24 hours after surgery in patients receiving continuous-infusion versus intermittent-infusion cefoxitin for postoperative antibiotic prophylaxis. DESIGN: Retrospective, cohort-matched pilot study. SETTING: Tertiary-care medical center. PATIENTS: One hundred sixteen adults undergoing colorectal surgery between August 1, 2004, and February 28, 2007. INTERVENTION: Cefoxitin prophylaxis was administered as a continuous infusion in 58 patients and as an intermittent infusion in 58 patients (controls). The controls received weight-based doses of cefoxitin (1 g if < or = 80 kg or 2 g if > 80 kg) every 8 hours for three doses, starting 3 hours after surgery and completed within 24 hours. The continuous-infusion group were given weight-based doses of cefoxitin (3 g if < or = 80 kg, 6 g if > 80 kg), started immediately after surgery and infused over 20 hours. MEASUREMENTS AND MAIN RESULTS: Patients and controls were matched according to colorectal procedure and risk index category. They were stratified by medium risk (50 patients) and low risk (66 patients) for the end point of 30-day postoperative SSI. For the 25 medium-risk patients who received the continuous infusion, a 50% relative reduction in the 30-day postoperative SSI rate was observed with continuous versus intermittent infusion (4% vs 8%, p=0.55). For the 66 low-risk patients, 30-day postoperative SSI rates were equal (3%) with both intermittent and continuous infusions. Risk stratification was not performed for the proportion of patients who discontinued antibiotic prophylaxis within 24 hours after surgery. All patients receiving the continuous infusion met this end point compared with 47 (83.9%) of the 56 controls (p=0.0015) included in the analysis. CONCLUSION: Compared with intermittent infusion, continuous infusion of cefoxitin for postoperative prophylaxis resulted in a nonsignificant reduction in 30-day postoperative SSI rates in medium-risk patients undergoing colorectal surgery. Continuous infusion also resulted in reliable discontinuation of postoperative prophylaxis within 24 hours.

Reducing anticoagulant medication adverse vents and avoidable patient harm.

BACKGROUND: The conventional standard of care for many patients at Saint Joseph HealthCare, a three-hospital system in Kentucky, includes the use of anticoagulant therapy. In view of the morbidity and mortality associated with anticoagulation-related complications, the prevention of bleeding and thrombotic adverse drug events was identified as a primary process improvement initiative. METHODS: Following establishment of an interdisciplinary team, formal evaluations of anticoagulant-use practices and associated patient outcomes occurred via several mechanisms. A variety of process improvement activities were conducted, including the creation of a pharmacist-managed hospital anticoagulant therapy service. A pharmacist consult service for the medical staff provided initiation, management, and monitoring of anticoagulation, including bridge therapy and reversal if necessary. RESULTS: The rate of thrombotic events decreased from 4.6% in 2004 to 3.9% in 2006 and further decreased to 0.0% for patients managed by collaborative physician and pharmacist practice. Hospitalwide bleeding and thrombotic reactions decreased from a monthly average of 11.52 events per 1,000 anticoagulant doses dispensed in 2004 to 0.07 in 2006. A cost-benefit evaluation indicated an annual savings of up to $9.8 million in avoidable costs. DISCUSSION: In this interdisciplinary project, anticoagulant safety was integrated throughout the institution, and a variety of medication safety systems were successfully employed.

Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus.

As understanding of type 2 diabetes mellitus pathophysiology expands, treatments continue to evolve and new pharmacologic targets emerge. Patients with type 2 diabetes exhibit deficiencies of the incretin system; thus, methods for increasing insulinotropic hormones have become a popular target for therapy. A new class of oral antidiabetics has emerged-the dipeptidyl peptidase IV (DPP-IV) inhibitors. Unlike conventional oral antidiabetic agents, these agents promote glucose homeostasis through inhibition of DPP-IV, the enzyme responsible for degradation of two key glucoregulatory hormones: glucagon-like peptide-1 (GLP-1), which extends the action of insulin while also suppressing the release of glucagon, and glucose-dependent insulinotropic peptide (GIP). Other proposed mechanisms of action of GLP-1 and thus DPP-IV inhibitors include satiety, increased beta-cell production, and inhibition of apoptosis of beta cells. Clinical studies have evaluated the potential for DPP-IV inhibition to reduce glucagon levels, delay gastric emptying, and stimulate insulin release. The DPP-IV inhibitors appear to have excellent therapeutic potential in the management of type 2 diabetes as monotherapy or in combination with existing agents, such as metformin. Their pharmacokinetic and pharmacodynamic profiles support once-daily dosing, with sustainable reductions in glycosylated hemoglobin levels and relatively few adverse effects. Their distinctive mechanism of action and adverse-event profiles may offer advantages over existing therapies, including low risk for hypoglycemia and possible augmentation of pancreatic beta-cell regeneration.

Terlipressin: vasopressin analog and novel drug for septic shock.

OBJECTIVE: To review and assess available literature on chemistry, pharmacology, pharmacodynamics, pharmacokinetics, clinical studies, adverse events, drug interactions, and dosing and administration of terlipressin in septic shock. DATA SOURCES: A literature search of MEDLINE (1966-September 2006), International Pharmaceutical Abstracts (1970-September 2006), and Cochrane database (third quarter 2006) was conducted, using key terms of terlipressin, lypressin, triglycyl-lysine vasopressin, hemodynamic support, septic shock, vasopressor, and V1 receptor agonist. Bibliographies of relevant articles were reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: Available English-language literature, including abstracts, animal studies, preclinical studies, clinical trials, and review articles, were examined. DATA SYNTHESIS: Because of potentially favorable pharmacokinetics versus vasopressin and limited availability of vasopressin in some countries, the effects of terlipressin, a vasopressin analog, have been studied recently for the treatment of septic shock. When administered as a 1-2 mg intravenous dose in patients with septic shock, terlipressin increases mean arterial pressure, urine output, systemic vascular resistance index, pulmonary vascular resistance index, and left and right ventricular stroke work index while decreasing heart rate, cardiac output, lactate, and oxygen delivery and consumption index. It is unclear whether lower doses of terlipressin would produce a similar vasopressor response with fewer cardiopulmonary effects and whether the effects of the drug on oxygen transport indices are detrimental. CONCLUSIONS: Terlipressin is a promising investigational medication for treatment of septic shock. Small trials have shown terlipressin to have favorable effects on hemodynamics in patients with septic shock refractory to conventional vasopressor treatment. It should be used with extreme caution in patients with underlying cardiac or pulmonary dysfunction. Further studies are needed to verify safety, efficacy, and dosing of terlipressin in patients with septic shock, and its use cannot be recommended in lieu of vasopressin at this time.

Cefazolin tolerance does not predict ceftriaxone hypersensitivity: unique side chains precipitate anaphylaxis.

A 48-year-old woman with a questionable history of an unspecified ceftriaxone allergy was treated with cefazolin for surgical antibiotic prophylaxis. After she tolerated cefazolin therapy for 4 days, the medical staff concluded that her allergy history was inaccurate, and she was treated with intravenous ceftriaxone for suspected nosocomial pneumonia. Approximately 10 minutes after the start of the infusion, the patient experienced anaphylaxis. Initial symptoms of oral angioedema and laryngopharyngeal constriction progressed to dyspnea, tachypnea, hypotension, and tachycardia, all of which quickly resolved after immediate treatment with hydrocortisone, diphenhydramine, and epinephrine. Skin testing with cefazolin, cefepime, and ceftriaxone revealed that the likely allergic determinant mediating the patient's hypersensitivity reaction was the unique ceftriaxone R2 side chain and not the beta-lactam ring, which initially was suspected by the physician. Immunoglobulin E-mediated hypersensitivity reactions to cephalosporins may occur due to antibody complexes with the beta-lactam ring or various cephalosporin side chains. Misconceptions regarding the nature of cephalosporin allergies complicate antibiotic selection for patients with questionable allergy histories and may lead to inappropriate drug reexposure and anaphylaxis. Detailed understanding of the antigenic determinants that mediate hypersensitivity reactions is essential for clinicians to avoid type 1 reactions in patients with a suspected allergy to cephalosporins.

Fatal acute encephalomyelitis after a single dose of intrathecal methotrexate.

A 40-year-old Hispanic man with acute lymphoblastic leukemia was treated with a single dose of intrathecal methotrexate 12 mg for prophylaxis against leptomeningeal spread of tumor. The day after methotrexate administration, the patient complained of severe back pain and urinary retention. The diagnosis of encephalomyelitis was made on day 3 after methotrexate administration, and by day 6 mechanical ventilation was begun secondary to ascending paralysis. By day 8 the patient was comatose, with minimal signs of brain activity and little hope for recovery; on day 12 he died. Although neurotoxicity is a frequent complication of methotrexate therapy, fatal acute neurotoxicity is extremely uncommon, especially in adults. The mechanisms of methotrexate toxicity remain unclear, and no effective treatment exists to prevent its occurrence. This patient rapidly progressed from mild neurotoxicity to fatal encephalopathy after one dose of intrathecal methotrexate during his third cycle of chemotherapy. Clinicians should be aware of the signs and symptoms of neurotoxicity during treatment, as well as predisposing factors that put patients receiving methotrexate at risk for neurotoxic effects.