Berend Mets

A genetic association study of the functional A118G polymorphism of the human mu-opioid receptor gene in patients with acute and chronic pain.

In this prospective, observational study we explored whether A118G single nucleotide polymorphism in the human &mgr;-opioid receptor (MOR) gene could explain the inter-individual differences in opioid analgesic requirements in patients with acute postoperative pain and chronic pain. The frequency of the wild-type A118 MOR (major) and variant G118 MOR (minor) alleles in the subjects with chronic, noncancer pain (n = 121) and opioid-naïve subjects with acute postoperative pain (n = 101), serving as the control group, were examined. The relationships among the A118G MOR genotype, opioid requirements, and the numerical pain score were analyzed in both groups. The frequency of the minor allele was significantly lower in the subjects with chronic pain when compared with the group with acute postoperative pain (0.079 versus 0.158; P = 0.009 by &khgr;2 test). No statistically significant association was observed between the presence of A118G MOR polymorphism and the average postoperative pain score or the doses of morphine used in the immediate postoperative period. In the high-quartile, opioid utilization, chronic pain patients, the homozygotic carriers of the major allele required significantly higher opioid dose than did the carriers of the minor allele. The results indicate that although the presence of the minor allele does not appear to affect opioid analgesic use in acute postoperative pain, the minor allele is less common in chronic pain patients, especially in those requiring higher doses of opioid analgesics.

Patent Foramen Ovale and its Significance in the Perioperative Period

Patent foramen ovale (PFO), usually a benign and silent lesion (Fig. 1), can cause hypoxemia and embolic phenomena under circumstances when right atrial (RA) pressure exceeds left atrial (LA) pressure or when preferential flow from the inferior vena cava (IVC) toward the PFO persists, as in the prenatal circulation (1–3). These circumstances may occur during the perioperative period as a result of the effect of mechanical ventilation, thromboembolism or air embolism, the altered anatomic relationship between the IVC and interatrial septum, or an increase in intraabdominal pressure. Although not extensively studied, numerous case reports implicate PFO as a causative factor for hypoxemia and systemic thromboembolism in the perioperative period. In the following review, we describe the epidemiology, pathogenesis, modern methods of detection, and general clinical importance of PFO. In particular, we highlight the significance of PFO in the perioperative period.

The pharmacokinetics of anesthetic drugs and adjuvants during cardiopulmonary bypass

The institution of cardiopulmonary bypass during cardiac surgery has profound effects on the plasma concentration of drugs and thus their therapeutic effectiveness. These changes occur through acute hemodilution, altered plasma protein binding, hypotension, as well as the use of hypothermia and heparin administration. Isolation of the lungs from the circulation and the possible sequestration of drugs in the bypass circuit also affect drug plasma concentrations on bypass. The individual characteristics of the drug in question are also important in determining the final plasma concentration: Lipid soluble drugs with a high volume of distribution may be more readily taken up by bypass equipment, but the initial fall in concentration at the start of cardiopulmonary bypass may be more readily counteracted by back diffusion into plasma, if large tissue stores have accumulated. The extent of the drug’s plasma protein binding is of importance as the effective free fraction in plasma for highly bound drugs will be sensitive to changes in plasma protein binding brought on by factors such as hemodilution, heparin administration as well as alpha, acid‐glycoprotein binding. Clearly the fate of drugs administered before or on bypass is complex and can only be accurately determined by specific studies evaluating drug plasma concentrations. This review updates the available data on anesthetics and drugs used during cardiac surgery in order that anesthetists may predict better the likely effect of drugs administered before or during cardiopulmonary bypass.

Is Spinal Anesthesia After Failed Epidural Anesthesia Contraindicated for Cesarean Section

n a recent review article on spinal anesthesia for cesarean section (l), Kestin recommended the use I of subarachnoid anesthesia if epidural block was inadequate after the administration of the maximum allowable dose of local anesthetic (2). The use of spinal anesthesia in obstetrics has also been advocated for patients with potentially difficult airways, as this approach usually would obviate the need for general anesthesia and endotracheal intubation (3,4). From these statements, it might be construed that spinal anesthesia, rather than general anesthesia, would be safer under circumstances in which epidural block for cesarean section has failed in a patient with a potentially difficult airway. Two recent reports (2,5), and the following case report, suggest that subarachnoid anesthesia may be specifically contraindicated under these circumstances.

Refractory vasodilation after cardiopulmonary bypass for heart transplantation in recipients on combined amiodarone and angiotensin-converting enzyme inhibitor therapy: A role for vasopressin administration

O PTIMAL THERAPY for end-stage cardiac failure before heart transplantation increasingly includes the use of both amiodarone and an angiotensin-converting enzyme (ACE) inhibitor. This combination has been shown to decrease both 1-year mortality and the incidence of sudden death. However, a number of reports describe severe hypotension in anesthetized patients chronically treated with either amiodarone 2 or ACE inhibitors, 3,4 and Mackay et al 5 have questioned whether concurrent therapy with these agents might pose a synergistic risk. Vasoconstriction to maintain blood pressure is normally maintained through the interplay of three neurohormonal systems; the sympathetic system, the renin angiotensin system (RAS), and the arginine vasopressin (AVP) system (Fig 1). 6 Normally, blockade of one or two of these systems is compensated for by the other(s). 6,7 However, under duress and under anesthesia, this compensatory balance may become compromised: in rats that are administered an ACE inhibitor, hemodynamic recovery after blood loss is incomplete despite a normal catecholamine response and high vasopressin levels? and in sheep under anesthesia, blockade of the RAS and AVP systems results in hypotension. 9 These data suggest that in the face of an added insult, such as hemorrhage or anesthesia, blockade of only one or two of the components of this neurohormonai triad may lead to severe hemodynamic compromise. Under the extreme stress of cardiac surgery, the chronic use of amiodarone, which, in addition to other cardiovascular effects, is assumed to block the sympathetic system by noncompetitive and [3 blockade, l°,la has been associated with fatal vasodilatory shock ~2 and the need for massive doses of vasopressors, a3 Similarly, ACE inhibitors, which block the RAS and decrease cardiovascular responsiveness to catecholamines, TM increase vasoconstrictor requirements during cardiopulmonary bypass (CPB). 15 This would suggest that the combined use of amiodarone and an ACE inhibitor might result in severe hemodynamic compromise during cardiac surgery. Two cases of refractory vasodilation in heart transplantation patients who presented for surgery on therapy with amiodarone and an ACE inhibitor are presented and compared with the seven other adult patients not on this combination who underwent cardiac transplantation by the same surgeon during the 4 months intervening between these cases.

Future of Anesthesiology Is Perioperative Medicine: A Call for Action

1192 June 2015 C urrently, the American healthcare system is undergoing significant changes in response to healthcare reform legislation such as the Affordable Care Act of 2010, as well as market forces and the ongoing maturation of the American healthcare industry. This evolution is consistent with the changes that have occurred in other industries such as agriculture, travel, and aviation. Over the past decades, anesthesiologists have continually expanded their focus from the operating rooms to postanesthesia care units, intensive care units, and pain medicine. In parallel to the expansion of the clinical footprint of our discipline, the core training curriculum of anesthesiology residency has changed significantly to now include many nonoperating room anesthesia rotations.1 This development is not unique to the united States, and many other countries such as the united Kingdom, France, Germany, and Australia have developed strategies to increase the role of anesthesiologists in perioperative medicine.1 In a recent editorial in the British Journal of Anaesthesia entitled Anaesthesiology and Perioperative Medicine around the World: Different names, Same Goals, some of us argue that “regardless of what the model is called around the globe, we have to embrace our expanded role as perioperative physicians as our main value proposition.”2 A proposal raised at the 2014 annual meeting of the Society of Academic Anesthesiology Associations (SAAA) is the impetus for this editorial, which was written by Chairs of Anesthesiology Departments who also serve as members of the executive committee of SAAA. The SAAA annual meeting was attended by 498 representatives of 124 academic anesthesiology departments (including chairs, program directors, and subspecialty fellowship directors who are the constituent members of this association). During a general session of the SAAA annual meeting, Dr. Kain, the first author of this editorial, proposed the motion to formally change the name of our specialty. There was healthy discussion on both sides of the issues, with active participation by department chairs, residency program directors, and fellowship program directors. After the discussion, an informal show of hands was overwhelmingly in favor of the proposal. After the meeting, a survey was sent to the SAAA general membership (n = 500) asking, “Do you approve or oppose a resolution to the American Society of Anesthesiologists (ASA) Board of Directors to change the name of our specialty to Anesthesiology and Perioperative Medicine (from Anesthesiology)?” There were a total of 189 responses (38%): 172 (91% of the respondents) were in favor and 17 opposed (9%). Although SAAA does represent the academic leadership of our specialty, any change in the name of our specialty will require consultation and approval by multiple stakeholders such as the American Society of Anesthesiologists (ASA), American Board of Anesthesiology and the Accreditation Council for Graduate Medical education (ACGMe). The chief aim of this editorial is to present a proposal and rationale for changing the name of our specialty from “Anesthesiology” to “Anesthesiology and Perioperative Medicine” and to advance the process of discussions among all these stakeholders. Over the past few decades, the specialty of anesthesiology has expanded its practice from being largely confined to the operating room to include perioperative medical practice in acute pain medicine, postoperative and intensive care Future of Anesthesiology Is Perioperative Medicine

Lidocaine and bupivacaine cardiorespiratory toxicity is additive: a study in rats.

The purpose of this study was to determine whether equipotent solutions of lidocaine, bupivacaine, or a mixture of these compounds infused at a fixed rate in anesthetized rats resulted in equivalent lethal cardiorespiratory toxicity and to establish whether the lethality of the individual drugs was additive. This was assessed by comparing the time to respiratory and circulatory arrest, determining the lethal doses of administered local anesthetic in each group, and ascertaining the concentration of lidocaine or bupivacaine, or both, at the time of circulatory arrest. The times to respiratory and circulatory arrest were similar in rats receiving either lidocaine (2%) or bupivacaine (0.5%) or a mixture of 1% lidocaine and 0.25% bupivacaine. The mean lidocaine-to-bupivacaine cumulative lethal dose ratio (3.36) and concentration ratio (2.33) were determined and used to calculate lidocaine equivalent values for bupivacaine data. Lidocaine equivalent cumulative lethal doses and plasma concentrations were similar in all three groups studied. This work suggests that the lethal cardiorespiratory toxicity of lidocaine and bupivacaine associated with intravenous infusion is additively toxic in rats.

Angiotensin axis blockade, hypotension, and acute kidney injury in elective major orthopedic surgery

BACKGROUND Patients presenting for surgery with angiotensin axis blockade (AAB) from therapy with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers experience an increased incidence of perioperative hypotension. Acute kidney injury (AKI) in patients receiving preoperative AAB has been demonstrated after lung, vascular, and cardiac surgery. However, there is little literature evaluating the hypotensive and renal effects of preoperative AAB and major orthopedic surgery. METHODS We performed a retrospective chart review of 1154 patients who underwent spinal fusion, total knee arthroplasty, or total hip arthroplasty during the 2010 calendar year in our academic medical center. RESULTS A total of 922 patients met inclusion criteria, 343 (37%) received preoperative AAB. Postinduction hypotension (systolic blood pressure ≤80 mm Hg for 5 minutes) was significantly higher in patients receiving AAB when compared to those not so treated (12.2% vs 6.7%; odds ratio [OR]: 1.93, P = 0.005). Of the 922 patients, 798 had documented measurements of both preoperative and postoperative creatinine. Postoperative AKI was significantly higher in patients receiving AAB therapy (8.3% vs 1.7%; OR: 5.40, P < 0.001), remaining significant after adjusting for covariates including hypotension (OR: 2.60, P = 0.042). Developing AKI resulted in a significantly higher mean length of stay (5.76 vs 3.28 days, P < 0.001) but no difference in 2-year mortality. CONCLUSIONS Patients undergoing major elective orthopedic surgery who receive preoperative AAB therapy,have an associated increased risk of postinduction hypotension and postoperative acute kidney injury resulting in a greater hospital length of stay.

Determination of cocaine, norcocaine, benzoylecgonine and ecgonine methyl ester in rat plasma by high-performance liquid chromatography with ultraviolet detection

An isocratic high-performance liquid chromatographic method with ultraviolet detection at 235 nm is described for the determination of cocaine and its metabolites benzoylecgonine, norcocaine and ecgonine methyl ester in rat plasma, collected during toxicity studies. Following simultaneous solid-phase extraction of all analytes and the internal standard tropacocaine, cocaine, benzoylecgonine and norcocaine were separated on a C18 column. Ecgonine methyl ester and cocaine were separated on coupled cyanopropyl and silica columns, following derivatization of ecgonine methyl ester to p-fluorococaine. The extraction efficiencies of these compounds from plasma ranged from 78 to 87%, while the limits of detection ranged from 35 to 90 ng/ml. The assay was linear from 300 to 5000 ng/ml, and the within-day precision 2 to 8% over this concentration range.

Lethal toxicity from equimolar infusions of cocaine and cocaine metabolites in conscious and anesthetized rats.

We compared the lethal toxicity of cocaine with that of three of its metabolites to determine the contribution of these metabolites to the lethal potential from cocaine infusion.Equimolar quantities of cocaine, norcocaine, benzoylecgonine, and ecgonine methyl ester were infused in conscious rats to determine onset of convulsions and respiratory arrest. In addition, the convulsive and respiratory toxicity for cocaine and norcocaine were evaluated in anesthetized rats and their circulatory toxicity in anesthetized and ventilated rats. Norcocaine infusion resulted in earlier onset of convulsions and respiratory arrest in conscious rats than cocaine and earlier onset of circulatory arrest. Plasma concentrations of norcocaine and cocaine were not different at these times. Benzoylecgonine and ecgonine methyl ester were less potent convulsants and respiratory depressants than norcocaine and cocaine, with ecgonine methyl ester more respiratory depressant than benzoylecgonine. Pentobarbital anesthesia enhanced the respiratory depression and suppressed or delayed the onset of convulsions from norcocaine and cocaine infusion. Prolonged infusion of cocaine to circulatory arrest resulted in benzoylecgonine concentrations approximate 60%, and norcocaine concentrations approximate 5%, of the cocaine concentration, but no detectable ecgonine methyl ester formation. We conclude that although norcocaine, ecgonine methyl ester, and benzoylecgonine administered separately have lethal potential in massive dosages, death from cocaine overdose primarily results from the parent compound and not from metabolite formation. (Anesth Analg 1995;81:1033-8)