N-acetyl-L-cysteine for preventing lung reperfusion injury after liver ischemia-reperfusion: a possible dual protective mechanism in a dose-response study

BACKGROUND: Acute lung reperfusion injury (ALI) frequently follows an ischemic event in another organ, such as organ transplantation. We recently demonstrated that lung priming with N-acetyl-L-cysteine (NAC) prevented liver ischemia-reperfusion (IR)-induced ALI pending on reduced glutathione (GSH) amount of replenishment. We now assessed the therapeutic effect of NAC-in preventing ALI caused by liver IR-if administered to the lung during liver reperfusion. PROCEDURES: Rat isolated livers were stabilized (30 min) and then perfused with modified Krebs-Henseleit solution (control, n=20) or made globally ischemic (IR, n=20) for 2 hr. Rat lungs were isolated separately, ventilated, and stabilized (30 min) with Krebs plus 5% bovine albumin. Pairs of liver and lung were then reperfused together for 15 min, followed by only lung recirculation with the liver effluent for another 45 min. Three more controls (n=20 each) and three ischemic groups (n=20 each) included lungs which were treated with 100, 150 or 225 mg x kg(-1) NAC (0.5, 0.74, or 1.1 mmol, respectively) during the 15-min liver and lung reperfusion period. RESULTS: Pulmonary artery and ventilatory pressures and vascular resistance increased by 60-80% of baseline, compliance decreased, and bronchoalveolar lavage volume and content were abnormally high in the IR-nontreated and the IR-100 lungs. Most parameters in IR-150 and IR-225 lungs remained almost similar to controls. Postinsult GSH content in IR-100, -150, and -225 lungs was at 20%, 110%, and 90% above the IR-nontreated lungs, respectively. CONCLUSIONS: Lung treatment with NAC during its reperfusion with IR liver effluent prevented ALI. Lung GSH replenishment accounted for lung protection, but its content did not correlate directly with grade of protection; NAC itself seemingly afforded lung protection as well.     

Perspectives of Ketamine Use in COVID-19 Patients

Hospitalized coronavirus disease 2019 (COVID-19)-infected patients suffer from both physical impairments and mental stress. Respiratory insufficiency and cardiovascular disturbances require most of the intensive care interventions, but they are also accompanied by depressive conditions, sadness and fear of dying. Sedatives are mostly respiratory and cardiovascular depressants and do not provide resistance to the pro-inflammatory burst induced by the virus. Ketamine is a unique and safe drug that enables well-controlled sedation and anesthesia, attenuates depression and mitigates suicidal thoughts, without depressing respiratory or cardiovascular mechanics. This brief communication highlights the benefits potentially provided by ketamine to patients hospitalized for COVID-19 infection.     

Dextromethorphan reduces immediate and late postoperative analgesic requirements and improves patients' subjective scorings after epidural lidocaine and general anesthesia

Central N-methyl-D-aspartate receptors modulate postoperative pain. We compared the effects of preincision oral dextromethorphan (DM), an N-methyl-D-aspartate receptor antagonist, on postoperative IV patient-controlled analgesia morphine demand and on subjective variables in 80 patients undergoing lower-body procedures who were randomly assigned to epidural lidocaine (LA; 16 mL, 1.6%) or general anesthesia (GA). The patients were premedicated 90 min before surgery with placebo or DM 90 mg (20 patients per group) in a double-blinded manner. Postoperative IV patient-controlled analgesia morphine administration started when subjective pain intensity was > or =4 of 10 (visual analog scale) and lasted 2 h. Observation continued up to 3 days, during which patients could use diclofenac. LA-DM and GA-DM patients required 45%-50% less morphine and diclofenac compared with their placebo counterparts (P < 0.001). However, GA-DM patients made twice as many attempts to self-administer morphine as LA-DM patients (P = 0.005). Eight LA-DM versus two GA-DM patients (P < 0.01) used no morphine or diclofenac. All DM patients experienced significantly (P < 0.001) less pain, were less sedated, and felt better than their placebo counterparts; however, compared with placebo, DM improved subjective scorings in the GA patients more significantly (P < 0.05) than in the LA patients. We conclude that oral DM 90 mg in patients undergoing surgery under LA or GA reduces morphine and diclofenac use by approximately 50% in the immediate and late postoperative period compared with placebo. Subjectively scored levels of pain, sedation, and well-being were better as well.     

Dextromethorphan for the reduction of immediate and late postoperative pain and morphine consumption in orthopedic oncology patients: a randomized,placebo-controlled,double-blind study

BACKGROUND: Postoperative pain is mediated centrally by N-methyl-D-aspartate (NMDA) receptors. The beneficial effects of preincision oral dextromethorphan (DM), which is an NMDA antagonist, on postoperative pain and intravenous patient-controlled analgesia (IV-PCA) morphine (MO) consumption have been examined in patients undergoing surgery. The authors investigated 75 patients who underwent surgery for bone and soft tissue malignancies, in whom postoperative pain is more severe compared with patients who undergo general surgery. METHODS: Patients received placebo, DM 60 mg, or DM 90 mg (25 patients per group) before surgery and on each of the two following days in a randomized, double-blind, placebo-controlled manner. Postoperative IV-PCA MO was started when subjective pain intensity was >/= 4/10 (visual score) and lasted for 72 hours. Rescue drugs on demand were oral paracetamol or dipyrone. RESULTS: The patients in the DM60 and DM90 groups similarly experienced 50-80% less pain (P < 0.01) compared with patients in the placebo group, both immediately and up to 3 days postoperatively, as well as a 50% reduction in the estimated overall maximal pain intensity (P < 0.01). Both DM groups consumed 50-70% less MO than the nonmedicated individuals in the placebo group (P < 0.01), and their demand for rescue drugs on the first postoperative day also was significantly lower (P < 0.01). Patients in the DM groups also were sedated less ( approximately 70%; P < 0.01). There were no differences among the groups in terms of when the patients left their beds, when they were discharged home, or the number of overall side effects. CONCLUSIONS: DM is associated with reduced pain intensity, sedation, and analgesic requirements, even in patients undergoing surgery for bone and soft tissue malignancies. A 3-day DM administration neither increased the incidence of side effects nor accelerated ambulation and discharge home.     

N-acetyl-L-cysteine mitigates aortic tone injury following liver ischemia-reperfusion

Liver ischemia and subsequent reperfusion (IR) are associated with secondary, remote organ reperfusion injury attributable to oxidative stress mediators. Because N-acetyl-L-cysteine (NAC) was effective in attenuating lung reperfusion injury, its properties on aortic dysfunction were tested. Rat isolated perfused aortic rings (n = 8/group) were evaluated during and after exposure to liver postischemia perfusate. Aortic response to phenylephrine under these conditions was also assessed in the presence or absence of increasing concentrations of NAC. Aortic rings incubated with postischemia perfusates exhibited abnormally protracted contraction. Their response to phenylephrine was reduced to 18 +/- 7% and 65 +/- 11% of controls during and after the exposure, respectively, and their subsequent relaxation was irregular. NAC 0.25 mM best attenuated the IR-induced aortic tone impairments, 0.12 mM affected it slightly, and IR-NAC 0.5 mM and IR-NAC 0.74 mM solutions dilated the rings proportionately, abolishing reactions to both IR solutions and phenylephrine. Xanthine oxidase activity and reduced glutathione (GSH) level in all IR ring tissues were inversely proportionate, but not directly so. Thus, liver IR impaired aortic tone and its response to phenylephrine, even after removal of toxic elements. NAC concentrations directly and inversely correlated with xanthine oxidase activity but not with GSH level. It preserved aortic functions dose-specifically, mainly by oxidant quenching.     

Secondary reconstruction of the extensor mechanism using part of the quadriceps tendon, patellar retinaculum, and Gore-Tex strips after proximal tibial resection

Competence of the extensor mechanism is the major determinant of functional outcome of patients after proximal tibia resection. A method of secondary reconstruction of the extensor mechanism using the middle third of the quadriceps tendon and the patellar retinaculum augmented with Gore-Tex strips and gastrocnemius flap is described. Between 1981 and 1997, 7 patients with extension lag greater than 20 degrees at least 1 year after the initial surgery underwent secondary reconstruction of the extensor mechanism. All patients were followed up for a minimum of 2 years. Full extension to an extension lag of 10 degrees was achieved in three patients, and an extension lag between 10 degrees and 20 degrees was achieved in 4 patients. All patients had good to excellent functional outcomes and reported no limitations in daily life activities.     

Efficiency of the operating room suite

BACKGROUND: The need to control high costs of running operating rooms while providing for timely patient care led us to assess the time wasted in the operating room (OR). METHODS: OR use by two general surgery and two orthopedic departments in a metropolitan public hospital were analyzed, and the time elapsed when a scheduled OR remained unused or the patient was still awaiting surgery was measured. RESULTS: OR "time-waste" defined as the time in which the scheduled OR was not busy with the scheduled patient amounted to 79 hours over the 30-day study period (15% of total time). It was wasted owing to inappropriately prepared patients (12%), unavailability of surgeons (7%), insufficient nursing staff, anesthesiologists, or OR assignment to emergency surgery (59%), congestion of the postanesthesia care unit (10%), and delay in transport to the OR (2%) Another issue delineated was the frequent occurrence of surgical cases running longer than their scheduled time (termed "spill-over"), outrunning the staffing expectations after 3:00 PM and delaying admission of add-on and emergency procedures, adding 33% to the time wasted. A quality-assurance committee review resulted in implementation of new guidelines, and within 3 months several underlying causes were rectified, and time-waste and spill over time was reduced by 35%. Surgical time predictions were also improved. Shortage of nurses and anesthesiologists, and OR emergency reassignment remained the major causes of OR waste time. CONCLUSIONS: Continuous surveillance on OR suite-patients' prompt care, repeated evaluation, and wise staff deployment-could maximize OR efficiency.     

A single small dose of postoperative ketamine provides rapid and sustained improvement in morphine analgesia in the presence of morphine-resistant pain

It is a common clinical observation that postoperative pain may be resistant to morphine. The analgesic potentials of ketamine have also been well documented. In this study, we evaluated the effects of postoperative coadministration of small doses of ketamine and morphine on pain intensity, SpO(2), and subjectively rated variables in surgical patients who underwent standardized general anesthesia and complained of pain (> or =6 of 10 on a visual analog scale [VAS]) despite >0.1 mg/kg of i.v. morphine administration within 30 min. Patients randomly received up to three boluses of 30 microg/kg of morphine plus saline (MS; n = 114) or 15 microg/kg of morphine plus 250 microg/kg of ketamine (MK; n = 131) within 10 min in a double-blinded manner. The MS group's pain VAS scores were 5.5 +/- 1.18 and 3.8 +/- 0.9 after 10 and 120 min, respectively, after 2.52 +/- 0.56 injections, versus the MK group's VAS scores of 2.94 +/- 1.28 and 1.47 +/- 0.65, respectively (P < 0.001), after 1.35 +/- 0.56 injections (P < 0.001). The 10-min level of wakefulness (1-10 VAS) in the MS group was significantly (P < 0.001) less (6.1 +/- 1.5) than the MK group's (8.37 +/- 1.19). SpO(2) decreased by 0.26% in the MS group but increased by 1.71% in the MK patients at the 10-min time point (P < 0.001). Thirty MS versus nine MK patients (P < 0.001) experienced nausea/vomiting; nine MK patients sustained a 2-min light-headed sensation, and one patient had a weird dream after the second drug injection. IMPLICATIONS: A small-dose ketamine and morphine regimen interrupted severe postoperative pain that was not relieved previously by morphine. Ketamine reduced morphine consumption and provided rapid and sustained improvement in morphine analgesia and in subjective feelings of well-being, without unacceptable side effects.     

The midazolam-induced paradox phenomenon is reversible by flumazenil. Epidemiology, patient characteristics and review of the literature.

BACKGROUND AND OBJECTIVE: Midazolam may occasionally precipitate hostility and violence instead of tranquility. We characterized these episodes, their rate of occurrence, the potential paradoxical responders and possible predisposing circumstances among patients undergoing lower body surgery under spinal or epidural anaesthesia and midazolam sedation. PATIENTS AND METHODS: Fifty-eight patients who fulfilled the study entry criteria and who underwent surgery within a 3-month period in a large metropolitan, university-affiliated hospital were enrolled. Sedation and restlessness in all patients were controlled by midazolam administered intravenously by the attending anaesthesiologist; these parameters were later objectively confirmed by recorded actigrams. If "paradoxical" events occurred, flumazenil 0.1 mg 10 s-1 was injected until the aberrant behaviour ceased. Patients with paradoxical reactions were later compared with matched control patients selected from the study group to identify epidemiological characteristics. RESULTS: The incidence of paradoxical events was 10.2% (six out of 58 patients, confidence limits 2.3-18.3%) and they occurred 45-210 min after sedation started; the only independent predictor was an age older than that of the entire study group. The mean cumulative and per weight doses of midazolam were similar for both the experimental and the study groups of patients: 7.3 +/- 2.8 to 10.1 +/- 3.6 mg, and 0.1 +/- 0.04 to 0.12 +/- 0.05 mg kg-1. Flumazenil 0.2-0.3 mg (range 0.1-0.5 mg) effectively stopped the midazolam-induced paradoxical activity within 30 s and surgery continued uneventfully. CONCLUSIONS: Flumazenil completely reverses midazolam-induced paradoxical reactions and they are more frequent in older patients.