Advanced renal cell carcinoma showing a different response to two types of interferon-alpha

Interferon (IFN)-alpha has been widely used in systemic therapy for advanced renal cell carcinoma (RCC). IFN-alpha is represented by a large family of structurally related genes expressing at least 14 subtypes, each of which shows quantitatively distinct patterns of biological activities. Although those distinct patterns of biological activities of IFN-alpha subtypes against renal cancer cell lines have been demonstrated, there is no report that demonstrates the difference in each subtype-induced antitumor activity in patients with RCC. Herein, we present a unique case of advanced RCC that is resistant to interleukin-2 and IFN-alpha administration, and we describe its response to another IFN-alpha administration. The difference between the two IFN-alpha types lies in the distribution of the subtypes: this case, therefore, suggests that the difference in the subtype distribution may cause the different response of the RCC. A 47 year-old male was diagnosed as left RCC with multiple lung metastases and underwent radical nephrectomy. The histological diagnosis was pT3b G2 clear cell carcinoma. He received intramuscular administration of 6 x 10(6) units of natural human IFN-alpha (Sumiferon) three times a week following the operation. However, the lung metastases showed progression. Thereafter, he received intravenous administration of 1.4 x 10(6) units of human interleukin-2 everyday. However, the lung metastases showed further progression and the hemoptysis, dyspnea, and chest pain deteriorated. Finally, he was given intramuscular administration of 5 x 10(6) units of another natural human IFN-alpha (OIF) three times a week. After the OIF administration, his complaints subsided and a chest CT scan revealed reduced lung metastases and diminished pleural effusion. He had not received any anti-tumor agents other than IFN-alpha or interleukin-2 since the operation. However, although he remained free of hemoptysis, dyspnea, and chest pain after OIF administration, the lung metastases increased again and multiple brain metastases were also observed five months after the first OIF administration. He died of metastatic RCC one year after the operation.     

Prolonged fetal bradycardia during epidural analgesia. Incidence, timing and significance

The mechanism of episodes of fetal bradycardia during epidural analgesia is unknown in the majority of cases. This retrospective study considers the relationship between prolonged fetal bradycardia and epidural analgesia during labour. Of 705 cardiotocographs recorded during administration of epidural analgesia for patients in labour, 207 were suitable for analysis. Prolonged fetal bradycardia occurred after 40 of 366 (11%) initial or repeat injections of local anaesthetic into the epidural space. The peak incidence of onset of bradycardia was 5-20 minutes after administration, but occurrences continued throughout the 60-minute period studied. In 1 patient a single episode of fetal bradycardia occurred before administration of the epidural block. In all cases studied the 5-minute Apgar scores were 7 or better. It is concluded that administration of epidural analgesia is significantly associated with episodes of prolonged fetal bradycardia, but that there is usually a return to pre-epidural patterns. The fetal heart rate should be monitored during epidural block administration to confirm the return to baseline rate and normal variability. Episodes of fetal bradycardia that return to a normal pattern do not necessitate early delivery.     

脓毒症大鼠血浆游离氨基酸浓度的变化

目的 探讨脓毒症早期大鼠血浆游离氨基酸含量的变化与骨骼肌蛋白降解间的关系。方法 以腹腔注射内毒素建立大鼠脓毒症模型,将动物随机分为正常对照组和内毒素攻击后2、6、12、24h共5组,每组8只动物。用氨基酸自动分析仪的生理体液柱测定各组大鼠血游离氨基酸含量;用全自动生化分析仪测定血浆谷丙转氨酶（ALT）和谷草转氨酶（AST）浓度;用放射免疫分析（RIA）法测定血浆皮质醇含量;用酰联免疫吸附试验（ELISA）测定血浆TNF－α和IL－6含量。结果 内毒素攻击后各时相点大鼠血浆总氨基酸含量在正常范围内波动;支链氨基酸（BCAA）在2、6、12h降低,24h则出现显著升高,亮氨酸、异亮氨酸无显著怀变化,缬氨酸早期明显降低,后期则上升;芳香族氨基酸（AAA）在各时相点不同程度升高,2h和6h显著升高,酪氨酸12h降低,苯丙氨酸在各时相点均显著升高;苯丙氨酸／酪氨酸（Phe/Tyr)比值内毒素攻击后各时相点均出现显著增加;BCAA／AAA比值在2h和6h较正常显著较低;苏氨酸、谷氨酸、鸟氨酸、3－甲基组氨酸（3－MH）、组氨酸、丙氨酸早期升高或大多数时相点显著升高,赖氨酸、肌氨酸、胱氨酸和磷酸丝氨酸在内毒素攻击后无显著性变化,其它氨基酸均见不同程度的降低或显著降低。血浆ALT、AST浓度在内毒素攻击后各时相点显著升高（P＜0．01）,6h达峰值。血浆皮质醇含量在各时相点均显著升高（P＜0．01）,6h达峰值。血浆TNF－α和IL－6含量均上升（P＜0．01）,其中TNF-α于2h达峰值,IL－6于12h达峰值。结论 脓毒症大鼠血浆游离氨基酸浓度变化主要由于骨骼肌蛋白降解增强与肝脏代谢负担加重所致。     

Electrolyte composition of renal tubular cells in gentamicin nephrotoxicity

The effect of long-term gentamicin administration on sodium, potassium, chloride and phosphorus concentrations was studied in individual rat renal tubular cells using electron microprobe analysis. Histological damage was apparent only in proximal tubular cells. The extent of damage was only mild after 7 days of gentamicin administration (60 mg/kg body wt/day) but much more pronounced after 10 days. GFR showed a progressive decline during gentamicin treatment. In non-necrotic proximal tubular cells, sodium was increased from 14.6 +/- 0.3 (mean +/- SEM) in controls to 20.6 +/- 0.4 after 7 and 22.0 +/- 0.8 mmol/kg wet wt after 10 days of gentamicin administration. Chloride concentration was higher only after 10 days (20.6 +/- 0.6 vs. 17.3 +/- 0.2 mmol/kg wet wt). Both cell potassium and phosphorus concentrations were diminished by 6 and 15, and by 8 and 25 mmol/kg wet wt after 7 and 10 days of treatment, respectively. In contrast, no major alterations in distal tubular cell electrolyte concentrations could be observed after either 7 or 10 days of gentamicin administration. As in proximal tubular cells, distal tubular cell phosphorus concentrations were, however, lowered by gentamicin treatment. These results clearly indicate that gentamicin exerts its main effect on proximal tubular cells. Decreased potassium and increased sodium and chloride concentrations were observed in proximal tubular cells exhibiting only mild histological damage prior to the onset of advanced tissue injury. Necrotic cells, on the other hand, showed widely variable intracellular electrolyte concentration patterns.     

Perioperative management of patient with pulmonary operation associated with interstitial pneumonia

The prognosis of patients complicated with interstitial pneumonia (IP) who undergo pulmonary operations is very poor if acute exacerbation occurs after the operation. We have experienced 6 cases in which operations were performed on lungs complicated with IP The first patient died due to acute exacerbation, but the subsequent 5 patients had good postoperative courses due to 1) short-term administration of low-dose steroid before and after the operation, 2) avoidance of administration of high concentration of oxygen during and after the operation, and 3) administration of erythromycin before and after the operation, 4) N-acetylcysteine inhalation and administration of dl-alpha-tocopherylnicotinate before and after the operation. It is thought that careful management of such patients is needed to prevent acute exacerbation even after discharge from hospital.     

Use of preventive intra-operative antibiotic administration in appendectomy. A pharmacokinetic study

Studies on Cefazedone-kinetics in serum and subcutaneous fat tissue showed an early and lasting tissue concentration high above minimal inhibitation concentrations so that intraoperative single-shot administration of antibiotics are proven to be effective. Due to these pharmacokinetic patterns the results of an earlier prospective trial is confirmed that single-shot antibiotics during surgery are useful to reduce postoperative wound sepsis rate after appendectomy.     

Changes in arterial blood flow of free flaps after the administration of sildenafil in swine

We evaluated blood flow changes after experimental free tissue transfer and the potential hemodynamic effect of sildenafil on the free flap. Sixteen swine were used for free transfer of a latissimus dorsi myocutaneous flap to the chest that was anastomosed to the internal mammary vessels, and were randomized into controls and study group. The latter received a single dose of sildenafil, 6 hours following flap revascularization. Doppler ultrasonography revealed that arterial flow was mainly systolic postoperatively. Diastolic flow patterns were gradually restored after the first postoperative day. Pulsatility index (PI) significantly increased and flow volume decreased in all animals postoperatively. In the sildenafil group, PI significantly decreased and flow volume increased, while diastolic flow patterns were restored earlier on compared to controls, postoperatively. In conclusion, the administration of sildenafil after free tissue transfer increases flow volume and facilitates the restoration of diastolic blood flow patterns in the early critical postoperative period.     

Effects of intra-coronary and intra-graft administration of nicorandil for coronary spasm after coronary artery bypass grafting

Coronary artery spasm after coronary artery bypass grafting (CABG) is relatively rare, but when it occurs, it is fatal. In cases of circulatory collapse just after surgery, coronary spasm should be suspected, and immediate diagnosis by coronary angiography is necessary. We conducted a study to assess the clinical characteristics of coronary spasm after CABG and the usefulness of intra-coronary and intra-graft administration of nicorandil. Study subjects were 7 patients (6 men and 1 woman, mean age 60.4 years) in whom coronary spasm after CABG was diagnosed angiographically from January 1992 to December 2003. Off-pump CABG (OPCAB) had been performed in 2 patients. Despite continuous administration of nitroglycerin and diltiazem hydrochloride during surgery, sudden circulatory collapse occurred during surgery or within 24 hours after CABG in all 7 patients. All required mechanical circulatory support, and emergency coronary angiography revealed severe graft and native coronary spasms. Intracoronary and/or intra-graft administration of diltiazem hydrochloride or nitroglycerin was not very effective, however, administration of nicorandil was effective for vasodilatation. One patient suffered brain damage and died, but the other 6 patients recovered and were discharged without complication. In conclusion, intra-coronary and/or intra-graft administration of nicorandil appears to be useful for the treatment of coronary spasm after CABG.     

Effects of progesterone administration on follicle-stimulating hormone and prolactin release in estrogen treated eugonadal adult men

In order to investigate the modulatory effect of steroids on FSH secretion in vivo, we studied 16 human males, aged 51-81 years, affected by prostatic carcinoma. They were given estradiol or E2 plus progesterone (P), added at different times during E2 treatment. Daily blood samples were collected in order to determine LH, FSH, and PRL levels; moreover, blood samples were collected at 2 h intervals for 12 h on the day of P administration. We observed the expected biphasic effect on LH secretion, whereas daily basal FSH levels, during E2 treatment, decreased gradually and progressively from the first day until the end of the study. FSH levels exhibited, after P administration, wide fluctuations, with peak levels observed from 2 to 6 h after P in 4 of 6 patients studied (at 72 h during E2 treatment). A clear trend toward FSH increase was also observed in 3 out of 5 patients in whom P was administrated 96 h after starting E2 administration. In this case, FSH increases were delayed, becoming evident between 8th and 10th h after P injection. Finally, during E2 administration basal PRL levels showed a progressive increase, which was significant in all three groups. In conclusion, these data confirm the biphasic effects of estrogen administration on LH secretion in eugonadal adult human males; while estrogens alone showed an inhibitory effect on FSH secretion, the addition of P induced also a positive action, resulting in a clear FSH peak in some patients tested. The time course of E2 and P administration seems to be critical for the hormone response pattern.(ABSTRACT TRUNCATED AT 250 WORDS)     

TNF alpha and IL-6 involvement in surgical trauma. II. In vitro cytokine production

The study aimed to correlate TNF alpha and IL-6 dynamics during surgical trauma as well as the changes which appear in the circulating monocytes' response after LPS stimulation in vitro. Three patients with major abdominal operations were chosen and serial blood samples were taken before, during and after the operation. Normal unmatched individuals were used as control group during a two hours bed resting period. Both TNF alpha and IL-6 in vitro production showed similar patterns with an initial drop and almost full recovery 24 hours after the operation. We propose a model for TNF alpha and IL-6 role in trauma induced inflammation.     

Tranexamic Acid for Reduction of Blood Loss During Total Hip Arthroplasty

In this study, we evaluated the hemostatic effects of tranexamic acid (TNA), an antifibrinolytic drug, by examining the timing of its administration during total hip arthroplasty. One hundred seven patients being treated for osteoarthritis of the hip joint were randomly divided into 5 groups based on the timing of TNA administration. The intraoperative blood loss, postoperative blood loss, and hemoglobin of these patients who received TNA at different times during the procedure were monitored. We found that the intraoperative blood loss in the preoperative TNA administration groups was significantly lower than both control and postoperative TNA administration groups. Furthermore, 1 g TNA 10 minutes before surgery and 6 hours after the first administration was most effective for the reduction of blood loss during total hip arthroplasty.     

Preoperative ketorolac administration has no preemptive analgesic effect for minor orthopaedic surgery

The utility of preoperative ketorolac administration to reduce the intensity and duration of postoperative pain was compared with placebo in a randomized double-blind design of 60 ASA 1–2 patients scheduled for minor orthopaedic surgery. No opioids nor local anaesthetic blocks were used during surgery. The patients received either 30 mg ketorolac IV before surgery followed by a placebo injection after surgery or the reverse. Postoperative pain intensity was assessed repeatedly for 6 h using a visual analogue scale. No differences in pain intensity were observed between the two groups except for the initial 15-min postoperative assesments in the ketorolac group. The time to first rescue morphine administration and the total morphine consumption during the 6-h observation period were similar. It is concluded that the preoperative administration of ketorolac did not provide a significant preemptive analgesic benefit with regard to postoperative pain relief and opioid dose-sparing effect.     

Lipid and apolipoprotein patterns during erythropoietin therapy: roles of erythropoietin, route of administration, and diet

Background. Long term effects of rHuEpo on the blood lipid profile have not been well documented. The aim of this paper is to prospectively evaluate whether rHuEpo therapy affects lipid metabolism, and whether these effects are influenced by changes in dietary habits and by route of rHuEpo administration. Methods. The study was performed in 33 maintenance haemodialysis patients (MHP) treated for one year with rHuEpo either intravenously (n = 15) or subcutaneously (n = 18), three times per week at the end of each dialysis session. The doses were 50 IU/kg intravenously or 35 IU/kg subcutaneously during the first 6 months and 20 IU/kg during the following months. The control group consisted of 17 MHP not treated with rHuEpo. Total cholesterol, LDL-cholesterol and HDL-cholesterol, triglycerides, apolipoproteins A1 and B, haemoglobin, serum albumin, blood urea nitrogen, serum creatinine, Kt/V, protein catabolic rate, and plasma erythropoietin were assessed at months 0, 2, 4, 6, 9, 12 and 2 weeks after rHuEpo discontinuation. Changes in food intake were evaluated on the basis of weekly dietary diaries before, and 3 and 9 months after treatment. Patients were divided into two groups: group A consisted of 19 patients who showed an increase in their energy intake (10% or more of basal value), and group B was formed by 14 patients without or with slight changes in their food intake. After the 6th month, dialysis schedules were adapted to new protein catabolic rate values in patients who increased their food intake. Results. During follow-up, there were no significant changes in any of the parameters in the control group. In group A, blood urea nitrogen, serum creatinine, protein catabolic rate, cholesterol, LDL cholesterol, triglycerides and apolipoprotein B increased significantly since the first months of rHuEpo treatment, and changes in cholesterol and apolipoprotein B correlated significantly with changes in protein catabolic rate. In group B, cholesterol, LDL cholesterol, and apolipoprotein B decreased significantly after the 6th month of treatment, without changes in blood urea nitrogen, serum creatinine and protein catabolic rate values. In both groups A and B, HDL cholesterol decreased significantly until the 6th month and returned to basal values in the following months and apolipoprotein A1 decreased until the 4th month and rose to levels higher than basal values in the following months. First rHuEpo administration and rHuEpo suspension at end of follow-up did not show any acute effect on lipid profile, despite significant changes in plasma erythropoietin values. Changes in lipid profile were similar with intravenous and subcutaneous administration of rHuEpo. Conclusions: We infer that long-term rHuEpo treatment positively affects the lipid profile, but in some patients who show exaggerated increase in their food intake these effects may be balanced and overcome by increment in some atherogenic blood lipid fractions. The changes in lipid and apolipoprotein patterns during rHuEpo therapy are not influenced by route of rHuEpo administration.     

Endothelial antioxidant compound prolonged the endothelial antiapoptotic effects registered after tadalafil treatment in patients with arterial erectile dysfunction

This study evaluated the effects of a chronic treatment with tadalafil, a specific phosphodiesterase V inhibitor, on endothelial apoptosis through changes in the serum concentration of endothelial microparticles (EMP). EMPs were arbitrarily chosen as a marker of endothelial apoptosis, and the changes in their concentration were monitored before and after treatment. Additionally, administration of endothelial antioxidant compound (EAC) during the follow-up, after discontinuation of tadalafil, was evaluated to determine whether this treatment improved the potential effects of tadalafil on the endothelium. Seventy-five patients with arterial erectile dysfunction were evaluated at baseline and after administration of tadalafil (5 mg once daily for 90 days). The International Index of Erectile Function questionnaire was administered, and penile dynamic Doppler and flow-cytometric (serum concentrations of EMPs) analyses were performed before (T0) and after treatment. Time points after tadalafil discontinuation: T1, after 1 week; T2, after 3 months; and T3, after 6 months. Three different schemes of follow-up were evaluated: group A, follow-up with EAC administration, after tadalafil discontinuation, for 6 months; group B, follow-up without other treatment; and group C, follow-up with placebo during the follow-up, after tadalafil cessation. The events CD45(neg)/CD144(pos)/annexinV(pos) were defined EMPs. Patients treated with tadalafil showed a significant decrease in serum EMPs 1 week after discontinuing tadalafil (16.4% ± 3.6% vs 7.1% ± 3.3%). This effect was maintained for up to 3 months in the group without other treatment during follow-up and was maintained for up to 6 months in the group treated with EAC during follow-up. Chronic treatment with tadalafil reduces endothelial apoptosis in patients with arterial erectile dysfunction. Further, EAC treatment prolongs and stabilizes the duration of antiapoptotic effects on the endothelium that are initially promoted by tadalafil treatment.     

Sympathetic neural activation evoked by mu-receptor blockade in patients addicted to opioids is abolished by intravenous clonidine

BACKGROUND: Mu-opioid receptor blockade by naloxone administered for acute detoxification in patients addicted to opioids markedly increases catecholamine plasma concentrations, muscle sympathetic activity (MSA), and is associated with cardiovascular stimulation despite general anesthesia. The current authors tested the hypothesis that the alpha2-adrenoceptor agonist clonidine (1) attenuates increased MSA during mu-opioid receptor blockade for detoxification, and (2) prevents cardiovascular activation when given before detoxification. METHODS: Fourteen mono-opioid addicted patients received naloxone during propofol anesthesia. Clonidine (10 microg x kg(-1) administered over 5 min + 5 microg x kg(-1) x h(-1) intravenous) was infused either before (n = 6) or after (n = 6) naloxone administration. Two patients without immediate clonidine administration occurring after naloxone administration served as time controls. Muscle sympathetic activity (n = 8) in the peroneal nerve, catecholamine plasma concentrations (n = 14), arterial blood pressure, and heart rate were assessed in awake patients, during propofol anesthesia before and after mu-opioid receptor blockade, and after clonidine administration. RESULTS: Mu-receptor blockade markedly increased MSA from a low activity (burst frequency: from 2 burst/min +/- 1 to 24 +/- 8, means +/- SD). Similarly, norepinephrine (41 pg/ml +/- 37 to 321 +/- 134) and epinephrine plasma concentration (13 pg/ml +/- 6 to 627 +/- 146) significantly increased, and were associated with, increased arterial blood pressure and heart rate. Clonidine immediately abolished both increased MSA (P < 0.001) and catecholamine plasma concentrations (P < 0.001). When clonidine was given before mu-opioid receptor blockade, catecholamine plasma concentrations and hemodynamic variables did not change. CONCLUSIONS: Administration of the alpha2-adrenoceptor agonist clonidine decreases both increased MSA and catecholamine plasma concentrations observed after mu-opioid receptor blockade for detoxification. Furthermore, clonidine pretreatment prevents the increase in catecholamine plasma concentration that otherwise occurs during mu-opioid receptor blockade.     

Periprostatic lidocaine infiltration and/or synthetic opioid (meperidine or tramadol) administration have no analgesic benefit during prostate biopsy. A prospective randomized double-blind placebo-controlled study comparing different methods

OBJECTIVES: To examine in a prospective, randomized, double-blind, placebo-controlled study the analgesic effect of periprostatic nerve block and/or intravenous synthetic opioid administration during a 12-core prostate biopsy. PATIENTS AND METHODS: Patients were prospectively randomized to receive unilateral periprostatic lidocaine administration and/or intravenous synthetic opioid (meperidine or tramadol) administration. Placebo groups received sterile normal saline. Unilateral infiltration was performed and biopsy was begun on this side. The degree of pain was recorded using the visual analog scale/numeric analog scale (VAS/NAS) score before the procedure, during probe introduction into the rectum, during unilateral periprostatic nerve blockade, during the first 6-core biopsy and during the second 6-core biopsy, and 30 min after biopsy completion. RESULTS: Most of the patients had mild or moderate pain (VAS/NAS <6) during the actual biopsy procedure. However, no significant differences existed between the groups with regard to the pain scores at any time (p > 0.05). Compared with pain scores, no significant differences existed between the first 6-core (blocked side) and second 6-core biopsies (p > 0.05). CONCLUSION: Periprostatic lidocaine infiltration and/or intravenous synthetic opioid analgesics are not beneficial in significantly reducing pain during biopsy. We think that most of the patients do have pain during biopsy, however the intensity of pain is tolerable and does not require analgesics.     

Timing, route, and dose of administration of heparin-binding epidermal growth factor-like growth factor in protection against intestinal ischemia-reperfusion injury

Purpose

We have previously demonstrated that heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an intestinal cytoprotective agent. The current study examined whether HB-EGF is effective as salvage therapy as well as prophylactic therapy for intestinal ischemia-reperfusion (I/R) injury, whether intravenous administration is as effective as intraluminal administration, and whether increased benefits are seen with increasing dose.

Methods

Total midgut I/R injury in rats was achieved by occlusion of a first-order branch of the superior mesenteric artery for 60 minutes, followed by reperfusion for 6 hours. Rats were treated with HB-EGF 5 minutes before ischemia, halfway through the ischemic event, or 5 minutes after ischemia. Route of administration was tested by administering HB-EGF either intraluminally or intravenously. Seven different doses of HB-EGF were tested.

Results

Heparin-binding, EGF-like growth factor protected the intestine from injury when administered before injury and was also effective when administered during ischemia or even after injury. Intraluminal administration of HB-EGF was superior to intravenous administration. Increasing doses of HB-EGF resulted in a greater cytoprotective effect.

Conclusion

These data demonstrate that HB-EGF acts as an effective intestinal cytoprotective agent when administered intraluminally not only before injury, but also during injury and, most importantly, even after intestinal injury has already occurred. These findings support a basis for the prophylactic use of intraluminal HB-EGF in high-risk patients, as well as for the administration of HB-EGF to salvage patients in whom an intestinal insult has already occurred.     

Intravenous versus intraperitoneal morphine before surgery to provide postoperative pain relief

Background: Opioid receptors have been demonstrated on peripheral afferent nerves throughout the body. The aim of the present study was to compare the effects of intravenous and intraperitoneal administration of morphine with regard to pain, postoperative morphinerequirement, and recovery after major abdominal surgery, and to describe the pharmacokinetics of intraperitoneal morphine in humans.
Methods: In a double-blind manner, 30 patientsscheduled for major abdominal surgery were randomized to either 50 mg of morphine intravenously (IV) or 50 mg of morphine intraperitoneally (IP) before operation. Pain was measured on a visual analogue scale and morphine requirements were registered for 3 days. Recovery was measured as time to oral intake of food, time to flatulence and days in hospital. Plasma morphine, mor-phine-3-glucuronide, and morphine-6-glucuronide concentrations were determined during the first 4 h after morphine administration.
Results: During the first postoperative hours there was less pain at rest ( P =0.02) and on coughing ( P =0.004) in the intravenous group. The requirementof additional morphine ( P =0.016) was lower in the intravenous group during the first postoperative day. No major differences in recovery were seen. The plasma concentrations of morphine measured as area under the curve (AUC) during the first 4 h were similar, but the intravenous group showed significantly higher concentrations of the active metabolite morphine-6-glucuronide, (P=0.016), indicating a difference in pharmacokinetics after intraperitoneal compared to intravenous administration of morphine.
Conclusion: Intraperitoneal administration of 50 mg of morphine before major abdominal surgery is less efficient in reducing pain and postoperative morphine requirements than thesame amount of morphine given intravenously.     

Persistently high plasma morphine-6-glucuronide levels despite decreased hourly patient-controlled analgesia morphine use after single-dose diclofenac: potential for opioid-related toxicity.

We studied the time course of clinical and pharmacokinetic effects after the rectal administration of diclofenac 100 mg in seven patients using patient-controlled morphine (PCA) on the first postoperative day after major spinal surgery. Plots of plasma diclofenac concentrations and pain intensity difference (PID) demonstrated counterclockwise hysteresis consistent with distribution to a central effect compartment such as the central nervous system. Mean +/- SEM (range) maximum PID and its timing were 62%+/-10% (32%-98%) and 309+/-20 (210-360) min after the administration of diclofenac, respectively. Minimal respiratory rates were significantly slower after the administration of diclofenac (P < 0.001), occurring at 197+/-51.9 (60-360) min; arterial desaturations occurred in two patients without oxygen therapy. Plasma morphine and morphine-6-glucuronide (M6G) concentrations interpolated to the average time of minimal respiratory rate indicated decreases of 23%+/-13% (0%-79%) and 1%+/-9% (0%-32%) from their respective starting values. Plasma M6G concentrations were significantly different from baseline only 420 and 480 min after the administration of diclofenac. The potential opioid-sparing effects of a nonsteroidal antiinflammatory drug added during PCA morphine use may not be manifest for several hours. During this lag, plasma concentrations of M6G may reach and remain at levels high enough to increase the risk of respiratory depression and other opioid side effects for hours. IMPLICATIONS: Plasma concentrations of morphine, morphine-6-glucuronide, and diclofenac were measured postoperatively after a single dose of rectal diclofenac 100 mg was added to morphine patient-controlled analgesia. Peak analgesia occurred 309 min and respiratory depression 197 min after diclofenac administration. Morphine consumption had decreased by 20%, but concentrations of the active metabolite morphine-6-glucuronide were unchanged. Vigilance is recommended in patients receiving patient-controlled analgesia opioids and nonsteroidal antiinflammatory drugs.