Jonathan S. Jahr

Efficacy and Safety of Single and Repeated Administration of 1 Gram Intravenous Acetaminophen Injection (Paracetamol) for Pain Management after Major Orthopedic Surgery

Background: Intravenous acetaminophen injection (paracetamol) is marketed in Europe for the management of acute pain. A repeated-dose, randomized, double-blind, placebo-controlled, three-parallel group study was performed to evaluate the analgesic efficacy and safety of intravenous acetaminophen as compared with its prodrug (propacetamol) and placebo. Propacetamol has been available in many European countries for more than 20 yr. Methods: After orthopedic surgery, patients reporting moderate to severe pain received either 1 g intravenous acetaminophen, 2 g propacetamol, or placebo at 6-h intervals over 24 h. Patients were allowed “rescue” intravenous patient-controlled analgesia morphine. Pain intensity, pain relief, and morphine use were measured at selected intervals. Safety was monitored through adverse event reporting, clinical examination, and laboratory testing. Results: One hundred fifty-one patients (intravenous acetaminophen: 49; propacetamol: 50; placebo: 52) received at least one dose of study medication. The intravenous acetaminophen and propacetamol groups differed significantly from the placebo group regarding pain relief from 15 min to 6 h (P < 0.05) and median time to morphine rescue (intravenous acetaminophen: 3 h; propacetamol: 2.6 h; placebo: 0.8 h). Intravenous acetaminophen and propacetamol significantly reduced morphine consumption over the 24-h period: The total morphine doses received over 24 h were 38.3 ± 35.1 mg for intravenous acetaminophen, 40.8 ± 30.2 mg for propacetamol, and 57. 4 ± 52.3 mg for placebo, corresponding to decreases of −33% (19 mg) and −29% (17 mg) for intravenous acetaminophen and propacetamol, respectively. Drug-related adverse events were reported in 8.2%, 50% (most of them local), and 17.3% of patients treated with intravenous acetaminophen, propacetamol, and placebo, respectively. Conclusion: Intravenous acetaminophen, 1 g, administered over a 24-h period in patients with moderate to severe pain after orthopedic surgery provided rapid and effective analgesia and was well tolerated.

Reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium: a comparison with spontaneous recovery from succinylcholine.

Background:Rocuronium in intubation doses provides similar intubation conditions as succinylcholine, but has a longer duration of action. This study compared time to sugammadex reversal of profound rocuronium-induced neuromuscular block with time to spontaneous recovery from succinylcholine. Methods:One hundred and fifteen adult American Society of Anesthesiologists Class I-II surgical patients were randomized to this multicenter, safety-assessor–blinded, parallel group, active-controlled, Phase IIIa trial. Anesthesia was induced and maintained with propofol and an opioid. Neuromuscular transmission was blocked and tracheal intubation facilitated with 1.2 mg/kg rocuronium or 1 mg/kg succinylcholine. Sugammadex (16 mg/kg) was administered 3 min after rocuronium administration. Neuromuscular function was monitored by acceleromyography. The primary efficacy endpoint was the time from the start of relaxant administration to recovery of the first train-of-four twitch (T1) to 10%. Results:One hundred and ten patients received study treatment. Mean times to recovery of T1 to 10% and T1 to 90% were significantly faster in the rocuronium-sugammadex group (4.4 and 6.2 min, respectively), as compared with the succinylcholine group (7.1 and 10.9 min, respectively; all P < 0.001). Timed from sugammadex administration, the mean time to recovery of T1 to 10%, T1 to 90%, and the train-of-four (T4/T1) ratio to 0.9 was 1.2, 2.9, and 2.2 min, respectively. Reoccurrence of the block was not observed. There were no serious adverse events related to study treatments. Conclusion:Reversal of profound high-dose rocuronium-induced neuromuscular block (1.2 mg/kg) with 16 mg/kg sugammadex was significantly faster than spontaneous recovery from 1 mg/kg succinylcholine.

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-) vs. >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.

Massive pulmonary thromboembolism during liver transplantation.

Pulmonary embolism occurs rarely during surgery, including liver transplantation, although posttransplantation pulmonary embolism has been reported (1-7). Usually, pulmonary embolism occurs in patients without liver disease. It would seem unlikely to occur in patients undergoing liver transplantation, who have deficient levels of coagulation factors and low platelet counts. We present a case of fatal massive pulmonary embolus in a patient undergoing liver transplantation. No previous cases have been reported in the literature.

Intravenous acetaminophen for pain after major orthopedic surgery: an expanded analysis.

Background and Methods:  From the time that Sinatra et al. (Anesthesiology. 2005;102:822) was published to FDA apaproval of intravenous (IV) acetaminophen, an expanded analysis of the original raw study data became necessary for the regulatory submission. The following analyses were conducted: (1) sum of pain intensity differences over 24 hours (SPID24) using currently accepted imputation methods to account for both missing data and the effects of rescue; (2) efficacy results after the first 6 hours; (3) effects of gender, race/ethnicity, age, weight, surgical site, ASA Class, and serotonin antagonists; and (4) a stepwise regression analysis of why adverse events of nausea and vomiting were numerically (although not statistically) higher in the IV acetaminophen group compared with placebo.

Effects of pneumoperitoneum on intraoperative pulmonary mechanics and gas exchange during laparoscopic gastric bypass

Background: Hypercarbia and elevated intraabdominal pressure resulting from carbon dioxide (CO2) pneumoperitoneum can adversely affect respiratory mechanics. This study examined the changes in mechanical ventilation, CO2 homeostasis, and pulmonary gas exchange in morbidly obese patients undergoing a laparoscopic or open gastric bypass (GBP) procedure. Methods: In this study, 58 patients with a body mass index (BMI) of 40 to 60 kg/m2 were randomly allocated to laparoscopic (n = 31) or open (n = 27) GBP. Minute ventilation was adjusted to maintain a low normal arterial partial pressure of CO2 (PaCO2), low normal end-tidal partial pressure of CO2 (ETCO2), and low airway pressure. Respiratory compliance, ETCO2, peak inspiratory pressure (PIP), total exhaled CO2 per minute (VCO2), and pulse oximetry (SO2) were measured at 30-min intervals. The acid–base balance was determined by arterial blood gas analysis at 1-h intervals. The pulmonary gas exchange was evaluated by calculation of the alveolar dead space–to–tidal volume ratio (VDalv/VT) and alveolar–arterial oxygen gradient (PAO2–PaO2). Results: The two groups were similar in age, gender, and BMI. As compared with open GBP, laparoscopic GBP resulted in higher ETCO2, PIP, and VCO2, and a lower respiratory compliance. Arterial blood gas analysis demonstrated higher PaCO2 and lower pH during laparoscopic GBP than during open GBP (p < 0.05). The VDalv/VT ratio and PAO2–PaO2 gradient did not change significantly during laparoscopic GBP. Intraoperative oxygen desaturation (SO2 < 90%) did not develop in any of the patients in either group. Conclusions: Laparoscopic GBP alters intraoperative pulmonary mechanics and acid–base balance but does not significantly affect pulmonary oxygen exchange. Changes in pulmonary mechanics are well tolerated in morbidly obese patients when proper ventilator adjustments are maintained.

HBOC-201, hemoglobin glutamer-250 (bovine), Hemopure® (Biopure Corporation)

Background: Producing an alternative to human erythrocytes has been one the most exciting dreams of medicine. Hemoglobin-based oxygen carriers (HBOCs) derived from purified human or bovine hemoglobin have been studied for clinical use and one product is currently available in the United States and European Union for veterinary use, and another in South Africa for human use. Objective: HBOC-201, bovine purified hemoglobin crosslinked and polymerized with glutaraldehyde, has been studied extensively in patients. We describe HBOC-201s potential market share, the history of HBOCs in general and of this compound, its pharmacology, published studies in patients and HBOCs that are currently being studied. Methods: A literature review using PubMed listed publications and official product websites. Conclusions: While HBOC-201 may not replace allogenic blood transfusions, it may serve to allow critically ill patients to be resuscitated in the field or hospital setting until either regeneration of red cell occurs or a transfusion is available.

Blood substitutes as pharmacotherapies in clinical practice.

Purpose of review To discuss the development and current status of blood substitutes, including hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbons. Research in this field offers an important view into the future of transfusion medicine in the operating room, as well as in trauma and combat arenas. Recent findings A pivotal multinational phase III trial of the Biopure product HBOC-201 (Hemopure) has been completed in orthopedic surgery patients. HBOC-201 consists of polymerized bovine hemoglobin and has already been well tolerated in patients undergoing cardiopulmonary bypass and abdominal aortic reconstruction. Polyheme is a polymerized human hemoglobin in early phase III clinical trials with trauma patients, having infused up to 10 000 ml, with efficacy apparently demonstrated in phase II. The Sangart product, Hemospan, is currently undergoing phase II trials. Summary Polymerized hemoglobin preparations have proven most successful in clinical trials due to their improved side-effect profile. The goal is to evaluate blood substitutes with enhanced intravascular retention, reduced osmotic activity, and attenuated hemodynamic derangements such as vasoconstriction. Although not without substantial morbidity and mortality, the current safety of allogeneic blood transfusion demands that comparative studies show minimal adverse effects, as well as efficacy and potential for novel applications.

Arterial oxygenation and oxygen delivery after hemoglobin-based oxygen carrier infusion in canine hypovolemic shock: a dose-response study.

OBJECTIVE To compare effects of 6% hetastarch (Hextend) and hemoglobin-based oxygen carrier hemoglobin glutamer-200 (Hb-200) (bovine; Oxyglobin) on hemodynamics, arterial oxygen content, and systemic oxygen delivery in a canine hemorrhagic shock model. DESIGN Randomized laboratory investigation. SETTING University surgical research facility. SUBJECTS Twenty-four anesthetized healthy, adult, mongrel dogs (28 +/- 1 kg; 7 female, 17 male). INTERVENTIONS Dogs were instrumented for determinations of heart rate, arterial, central venous, pulmonary arterial, and pulmonary arterial occlusion pressures, and cardiac index. Total solids, colloid oncotic pressure, arterial oxygen content, Hb, lactate, pH, and blood gases were analyzed in blood samples. Recordings were made before, after 1 hr of hemorrhagic shock, and immediately and 3 hrs after infusion of either 30 mL/kg hetastarch (group 1), 10 mL/kg Hb-200 + 20 mL/kg hetastarch (group 2), 20 mL/kg Hb-200 + 10 mL/kg hetastarch (group 3), or 30 mL/kg Hb-200 (group 4). MEASUREMENTS AND MAIN RESULTS Hemorrhage (35 +/- 1 mL/kg) reduced mean arterial pressure to 50 mm Hg and caused significant decreases in total Hb, mean pulmonary arterial pressure, cardiac index and systemic oxygen delivery, increases in heart rate and systemic vascular resistance, and lactic acidosis. In group 1, hetastarch infusion was accompanied by increases of pulmonary arterial pressure, cardiac index, and blood oxygen extraction above baseline, and decreases of systemic vascular resistance, total Hb, total solids, arterial oxygen content, and systemic oxygen delivery below baseline (p <.05). Other data returned to baseline. In groups 2 to 4, hemodynamic functions (except pulmonary arterial pressure) recovered, yet neither total Hb (i.e., plasma and red blood cell Hb) nor arterial oxygen content increased despite increases in plasma Hb of 2 to 5 g/dL and proportionate increases in total solids. Systemic oxygen delivery improved dose-dependently with Hb-200 but did not return to baseline (p <.05), reaching values comparable to hetastarch group only at 30 mL/kg Hb-200. In all groups, oxygen extraction remained above baseline. Metabolic acidosis and lactatemia resolved significantly faster in groups 2 to 4, and colloid oncotic pressure after resuscitation was greater in groups 2 to 4 than in controls (p <.05). CONCLUSIONS In hemorrhagic shock, Hb-200 infusion may not improve oxygen delivery more than hetastarch, likely due to hemodilution caused by its high colloid oncotic pressure, but may facilitate diffusive oxygen transport to tissues.

Blood substitutes and oxygen therapeutics: an overview and current status.

This review article discusses the development and implementation of a number of blood substitutes, including hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbons. This review article will introduce the reader to blood substitutes by discussing an overview of an ideal blood substitute, the history of HBOCs and perfluorocarbons, strategies of oxygen carrying, side effects of HBOCs and perfluorocarbons, current clinical trials, and the future of blood substitutes.